Cross-linked poly(allylamine) polymer pharmaceutical composition

Abstract

A pharmaceutical composition and method for treating animals, including humans, and a method for preparing the composition. The pharmaceutical composition contains a cross-linked amine polymer and may be used to treat diseases or other metabolic conditions in which the removal of a target species from the gastrointestinal tract may provide physiological benefits.

Description

Technology Field

[0001] The present disclosure relates to a cross-linked poly(allylamine) polymer, preferably a beberimer, comprising residues of 2-propene-1-ylamine or its salt, 1,3-bis(allylamino)propane or its salt, and 1,2-dichloroethane, which can be used as a non-absorbable pharmaceutical for therapeutic purposes, e.g., to treat metabolic acidosis. More specifically, the present invention relates to a pharmaceutical composition comprising such a polymer, a pharmaceutical product comprising such a polymer or a pharmaceutical composition thereof, and a method for preparing such a polymer. Background Technology

[0002] In U.S. Patent No. 9,205,107, Klaerner et al. disclose a cross-linked poly(allylamine) polymer that can be used to treat a metabolic condition in which the removal of protons and / or chloride ions from the gastrointestinal tract can provide physiological benefits, such as an increase in serum bicarbonate concentrations. Various cross-linked amine polymers are disclosed in the aforementioned literature, including cross-linked poly(allylamine) polymers prepared by the co-polymerization of allylamine and the cross-linking of the polymer with diallylamine.

[0003] Beberimer is a cross-linked poly(allylamine) polymer that can be used to treat metabolic conditions. The literature incorporated herein by reference [Wesson et al. "Long-term safety and efficacy of veverimer in patients with metabolic acidosis in chronic kidney disease: a multicentre, randomised, blinded, placebo-controlled, 40-week extension", The Lancet, Volume 394, Issue 10196, P396-406, 2019 and Bushinsky et al. "Randomized, Controlled Trial of TRC101 to Increase Serum Bicarbonate in Patients with CKD", Clin. J. Am. Soc. Nephrol. 13: 26-35, 2018] describes the treatment of metabolic acidosis using Beberimer.

[0004] One method for manufacturing the polymeric drug Beberimer is described in Exemplary Synthesis A of WO2019 / 236636 A1 and WO2016 / 094685 A1. The Beberimer polymer manufactured in this manner is unique ID 019070-A3 FA in Table S-1 of Exemplary Synthesis A of WO2019 / 236636 A1. For example, an improved Beberimer polymer due to improved stability in the presence of oxygen, as well as a method for manufacturing it, and a packaged Beberimer designed to alleviate oxygen stability concerns are disclosed.

[0005] The preparation of poly(allylamine) polymers from allylamine and diallylamine as described by Bianchi et al., Inoue et al., and Klaerner et al. offers certain advantages over the crosslinking of linear poly(allylamine) and epichlorohydrin, but the resulting crosslinked amine polymer may have undesirable process-related impurities or degradation products, such as allylamine or its derivatives. In some cases, incomplete incorporation of diallylamine or multiallylamine, such as 1,3-bis(allylamino)propane or its salt, may induce covalently attached unsaturated substituents on the polymer backbone, which may lead to limitations in stability due to the formation of allylamine and related impurities during post-processing, including drying of the poly(allylamine), or during storage. The mechanism for generating these allylamine impurities includes, but is not limited to, the generation of allylamine or related impurities due to the oxygen, temperature, water, acid, and base-mediated removal of unsaturated substituents.

[0006] One approach to improving the purity and stability profiles of polymers comprising residues of 2-propene-1-ylamine or its salt, and 1,3-bis(allylamino)propane or its salt, such as Beberimers, is to improve polymerization efficiency (i.e., improve the conversion of allyl groups). Generally, methods to improve polymerization efficiency favor chain propagation over propagation-limiting processes, such as chain transfer, chain termination, and radical coupling. During the radical polymerization step, these methods include, but are not limited to, the following:

[0007] a) Increasing the concentration of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in a monomer droplet solution,

[0008] b) Increasing the relative concentration of 1,3-bis(allylamino)propane or its salt by adding 2-propene-1-ylamine or its salt throughout the reaction process in a semi-batch or continuous process,

[0009] c) reducing the reaction temperature in a way that is favorable for propagation, or

[0010] d) Increasing the concentration or amount of the initiator.

[0011] Any one of these or other methods or a combination thereof 13 Crosslinking efficiency can be improved as measured by residual polymer backbone-attached (i.e., pendant) allyl groups in C NMR and reduced allylamine formation in the final polymer, preferably Bebeler. Specifically, by minimizing the number of unreacted allyl groups from 1,3-bis(allylamino)propane or its salt, the purity profile and stability profile of the resulting polymer, preferably Bebeler, can be improved.

[0012] Accordingly, among the various aspects of the present disclosure, a method for preparing a composition having a therapeutic use may be noted. The method comprises the following:

[0013] (a) As a first step, a poly(allylamine) polymer in the form of beads is formed in a polymerization and crosslinking co-reaction mixture comprising 2-propene-1-ylamine or its salt, 1,3-bis(allylamino)propane or its salt, a radical polymerization initiator, a surfactant, an acid, water, and an organic solvent system, wherein less than 1.1% of the total number of carbon atoms contained in the crosslinked poly(allylamine) polymer is sp 2 allyl carbon phase,

[0014] (b) As a second step, further crosslinking the poly(allylamine) polymer in a reaction mixture comprising 1,2-dichloroethane, a swelling agent for the poly(allylamine) polymer, and a dispersion solvent system to form a crosslinked poly(allylamine) polymer having a swelling ratio of less than 2.

[0015] A further aspect of the present disclosure is a cross-linked poly(allylamine) polymer in bead form comprising residues of 2-propene-1-ylamine or its salt, 1,3-bis(allylamino)propane or its salt, and 1,2-dichloroethane, wherein sp is pendantd to the cross-linked poly(allylamine) polymer backbone. 2 Allyl carbons constitute less than 1.0% of the total number of carbon atoms contained in the cross-linked poly(allylamine) polymer, and the cross-linked poly(allylamine) polymer has a swelling ratio of less than 2.

[0016] A further aspect of the present disclosure is a pharmaceutical composition comprising the cross-linked poly(allylamine) polymer described herein, in particular Beberimer.

[0017] The compositions, non-absorbent compositions, pharmaceutical compositions, or cross-linked poly(allylamine) polymers of the present invention may comprise, consist essentially of, or be the polymer itself as defined anywhere in this invention. For example, the compositions, non-absorbent compositions, pharmaceutical compositions, or cross-linked poly(allylamine) polymers may comprise, consist essentially of, or be the drug substance Beberimer itself.

[0018] Beberimers are polymeric drugs that can have the following structural characteristics:

[0019] Beberimer can be poly(allylamine-co-N,N'-diallyl-1,3-diaminopropane-co-1,2-diaminoethane).

[0020] More specifically, Beberimers are poly[(N 1 ,N 3 -di(prop-2-en-1-yl)propane-1,3-diamine)-co-prop-2-en-1-amine] (molar ratio is approximately 2:5:2 (i.e., N 1 ,N 3It may be a polymer with a crosslinking ratio of about 2: about 5: about 2)) di(prop-2-en-1-yl)propane-1,3-diamine : prop-2-en-1-amine : N,N'-ethane-1,2-diyl crosslinking ratio of about 2: about 5: about 2.

[0021] The structural representation of Beberimer can be the following chemical formula 5:

[0022]

[0023] Here

[0024] a = a residue of N,N'-diallyl-1,3-diaminopropane dihydrochloride, and

[0025] b = a residue of allylamine, and

[0026] c = a residue of 1,2-dichloroethane (ethylene crosslinking between two amines); and an ethylene linkage between two allylamine groups is presented as one example of a number of possible links between amines, and

[0027] m = a large number representing an extended polymer network.

[0028] Beberimer may contain the following amounts of monomer residues:

[0029] a) 20-25 mol% of residue of N,N'-diallyl-1,3-diaminopropane or its salt (also called 1,3-bis(allylamino)propane or its salt),

[0030] b) 50-60 mol% of residues of 2-propene-1-ylamine or its salt, and

[0031] c) 20-25 mol% of residue of 1,2-dichloroethane,

[0032] Here, the total mol% of the residue is 100 mol% or less.

[0033] Beberimers may each have a carbon-to-nitrogen weight ratio in the range of about 3.7:1 to about 3.8:1. The carbon-to-nitrogen weight ratio can be determined by elemental analysis. For example, the carbon-to-nitrogen weight ratio can be determined by elemental analysis using a Perkin-Elmer 2400 elemental analyzer as described more fully elsewhere in this invention.

[0034] Beberimer may be a non-absorbent composition that is insoluble under physiological conditions, for example.

[0035] Beberimers can have a median particle size greater than 1 micrometer and less than 1 millimeter. The particle size of Beberimers can be measured by wet laser diffraction using Mie theory.

[0036] Beberimer can be manufactured as follows:

[0037] Beberimer can be obtained by first copolymerizing 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to form a poly(allylamine) polymer, and then crosslinking the poly(allylamine) polymer with 1,2-dichloroethane.

[0038] For example, Beberimer can be obtained by first copolymerizing 2-propene-1-ylamine hydrochloride and 1,3-bis(allylamino)propane dihydrochloride to form a poly(allylamine) polymer, and then crosslinking the poly(allylamine) polymer with 1,2-dichloroethane.

[0039] One aspect of the present disclosure comprises the cross-linked poly(allylamine) polymers described herein, particularly Beberimers, wherein less than 1.0% of the total number of carbon atoms present in the cross-linked poly(allylamine) polymers is sp 2 It is a composition of allyl carbon.

[0040] An additional aspect of the present disclosure is a composition comprising the cross-linked poly(allylamine) polymer described herein, particularly Beberimer, wherein the allylamine (H2C=CHCH2NH2) content of the cross-linked poly(allylamine) polymer increases to less than 2.6 ppm / day allylamine when tested by a heat stability test (stability test 2).

[0041] A further aspect of the present disclosure is a unit dosage form having an outer and an inner portion comprising the cross-linked poly(allylamine) polymer described herein, in particular Beberimer, wherein the oxygen transfer rate between the outer and inner portions of the unit dosage form is about 0.050 CC / m² 2 It is a unit administration form of less than / day.

[0042] Further aspects of the present disclosure comprise a sealed enclosure containing the cross-linked poly(allylamine) polymer described herein, in particular Beberimer, wherein the sealed enclosure comprises a multilayer laminate comprising an inner contact layer, an outer layer; and a barrier layer disposed between the contact layer and the outer layer, wherein the oxygen transfer rate between the multilayer laminates is about 0.050 CC / m 2 It is a unit administration form of less than / day.

[0043] A further aspect of the present disclosure is a composition comprising the cross-linked poly(allylamine) polymer described herein, in particular Beberimer, for therapeutic use.

[0044] A further aspect of the present disclosure is a composition comprising the cross-linked poly(allylamine) polymer described herein, in particular Beberimer, for treating acid-base disorders.

[0045] A further aspect of the present disclosure is a composition comprising the cross-linked poly(allylamine) polymer described herein, in particular Beberimer, for use in treating metabolic acidosis.

[0046] A further aspect of the present disclosure is a composition comprising the cross-linked poly(allylamine) polymer described herein, in particular Beberimer, for use in slowing the progression of kidney disease.

[0047] A further aspect of the present disclosure is a composition comprising the cross-linked poly(allylamine) polymer described herein, in particular Beberimer, for use in slowing the progression of chronic kidney disease.

[0048] A further aspect of the present disclosure is a composition comprising the cross-linked poly(allylamine) polymer described herein, particularly Beberimer, for use in slowing the progression of renal disease in patients with metabolic acidosis associated with chronic renal disease.

[0049] A further aspect of the present disclosure is a composition comprising the cross-linked poly(allylamine) polymer described herein, in particular Beberimer, for use in improving a patient's physical function.

[0050] A further aspect of the present disclosure is a composition comprising the cross-linked poly(allylamine) polymer described herein, in particular Beberimer, for use in improving physical function in a patient with metabolic acidosis.

[0051] A further aspect of the present disclosure is a composition comprising the cross-linked poly(allylamine) polymer described herein, in particular Beberimer, for use in improving the quality of life of a patient.

[0052] A further aspect of the present disclosure is a composition comprising the cross-linked poly(allylamine) polymer described herein, in particular Beberimer, for use in improving the quality of life of a patient with metabolic acidosis.

[0053] A further aspect of the present disclosure is a cross-linked poly(allylamine) polymer as described herein, in particular Beberimer, in a sealed container.

[0054] A further aspect of the present disclosure is a pharmaceutical product comprising a cross-linked poly(allylamine) polymer as described herein, in particular Beberimer, in a sealed container comprising a moisture barrier.

[0055] A further aspect of the present disclosure is a pharmaceutical product comprising a cross-linked poly(allylamine) polymer, particularly Beberimer, as described herein, in a sealed container containing an oxygen barrier.

[0056] A further aspect of the present disclosure is a pharmaceutical product comprising a cross-linked poly(allylamine) polymer, particularly Beberimer, as described herein, in a sealed container comprising a moisture barrier and an oxygen barrier.

[0057] A further aspect of the present disclosure is a pharmaceutical product comprising a cross-linked poly(allylamine) polymer as described herein, in particular Beberimer, in a sealed sachet.

[0058] A further aspect of the present disclosure is a pharmaceutical product comprising a cross-linked poly(allylamine) polymer, particularly Beberimer, as described herein, in a sealed container comprising a polymer, metal, glass or ceramic material.

[0059] A further aspect of the present disclosure is a pharmaceutical product comprising a cross-linked poly(allylamine) polymer as described herein, particularly Beberimer, and a sealed container containing an inert atmosphere.

[0060] Further aspects of the present disclosure are pharmaceutical products comprising a sealed container and a cross-linked poly(allylamine) polymer as described herein, particularly Beberimer, within the sealed container, wherein the sealed container comprises a multilayer laminate of an inner contact layer, an outer layer; and a barrier layer disposed between the contact layer and the outer layer.

[0061] Further aspects of the present disclosure are pharmaceutical products comprising a sealed container and a cross-linked poly(allylamine) polymer as described herein, particularly Beberimer, within the sealed container, wherein the sealed container comprises a multilayer laminate of an inner contact layer, an outer layer; and an oxygen-barrier layer disposed between the contact layer and the outer layer.

[0062] Further aspects of the present disclosure are pharmaceutical products comprising a sealed container and a cross-linked poly(allylamine) polymer as described herein, particularly a Beberimer, within the sealed container, wherein the sealed container comprises a multilayer laminate of an inner contact layer, an outer layer; and a moisture-barrier layer disposed between the contact layer and the outer layer.

[0063] Further aspects of the present disclosure are pharmaceutical products comprising a sealed container and a cross-linked poly(allylamine) polymer as described herein, particularly a Beberimer, within the sealed container, wherein the sealed container comprises an inner contact layer, an outer layer; and a multilayer laminate of an oxygen-barrier layer and a moisture-barrier layer disposed between the contact layer and the outer layer.

[0064] A further aspect of the present disclosure is a pharmaceutical product comprising a sealed container and a cross-linked poly(allylamine) polymer, particularly Beberimer, as described herein, within the sealed container, wherein the sealed container comprises a multilayer laminate of an inner contact layer, an outer layer; and an oxygen-scavenging layer disposed between the contact layer and the outer layer.

[0065] A further aspect of the present disclosure is a method for treating acid / base disorders in animals by oral administration of a pharmaceutical composition comprising a cross-linked poly(allylamine), particularly Beberimer, as described herein.

[0066] A further aspect of the present disclosure is a method for treating an individual suffering from an acid-base disorder characterized by a baseline serum bicarbonate value of less than 22 mEq / l, comprising orally administering a daily dose of a pharmaceutical composition comprising a cross-linked poly(allylamine), particularly Beberimer, as described herein, to increase the patient's serum bicarbonate value from baseline by at least 1 mEq / l within a treatment period of 1 month or less.

[0067] Other aspects and features are partially obvious and will be presented below.

[0068] Abbreviations and Definitions

[0069] The following definitions and methods are provided to better define the invention and to guide those skilled in the art in practicing the invention. Unless otherwise indicated, terms should be understood by those skilled in the art in their ordinary usage. As used herein in relation to polymers and swelling agents (or, in the case of a mixture of swelling agents, a mixture of swelling agents), the term “absorption capacity” is the amount of swelling agent (or such mixture) absorbed by a given amount of dry polymer (e.g., in the form of dry beads) immersed in an excess amount of swelling agent (or such mixture) for at least 16 hours at room temperature.

[0070] The abbreviations shown in the table below will have the meanings indicated below:

[0071]

[0072] The term "cycloaliphatic" means a saturated monocyclic group of 3 to 8 carbon atoms, including cyclopentyl, cyclohexyl, cycloheptyl, etc.

[0073] The term "alkyl group," used alone or within other terms, encompasses a saturated linear or branched carbon radical having, for example, 1 to about 20 carbon atoms, or 1 to about 12 carbon atoms in specific embodiments. In other embodiments, the alkyl group is a "lower alkyl" group having 1 to about 6 carbon atoms. Examples of such groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, etc. In more specific embodiments, the lower alkyl group has 1 to 4 carbon atoms.

[0074] As used herein, the term "allyl" refers to a moiety having the structural formula H2C=CH-CH2-*, where * indicates the attachment point of the moiety to the remainder of the molecule. In some embodiments, the attachment point * is to a heteroatom within the remainder of the molecule, e.g., nitrogen.

[0075] The term “allyl equivalent” as used herein means the total number of moles of allyl groups consisting of a combination of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt present in the reaction mixture.

[0076] The terms "allylamine" and AAH represent a moiety having the structural formula H2C=CH-CH2NH2.

[0077] The term "aqueous solid content" refers to the concentration of solids in the aqueous phase at the start of polymerization = (mass AAH + mass DAPDA + mass initiator (e.g., V-50)) / (mass AAH + mass DAPDA + mass initiator (e.g., V-50) + mass water); "mass initiator" is the mass composed solely of the addition of the first initiator (e.g., V-50). To express the aqueous solid content in wt%, the value is multiplied by 100.

[0078] The terms “aromatic group” or “aryl group” refer to an aromatic group having one or more rings that can be attached together in a pendant manner or fused. In certain embodiments, the aromatic group has one, two, or three rings. A monocyclic aromatic group may contain 5 to 10 carbon atoms, typically 5 to 7 carbon atoms, and more typically 5 to 6 carbon atoms within the ring. A typical polycyclic aromatic group has two or three rings. A polycyclic aromatic group having two rings typically has 8 to 12 carbon atoms, preferably 8 to 10 carbon atoms, within the ring. Examples of aromatic groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl, or acenaphthyl.

[0079] The phrase "at the time of shipment" likely refers to the state exactly as it was manufactured at the time of completion of production.

[0080] As used herein, the term "batch process" refers to a process in which reactants are supplied to a reactor, a reaction is carried out, and reaction products are removed from the reactor at the end of the reaction.

[0081] The term "bead" is used to describe a cross-linked polymer that is substantially spherical in shape.

[0082] The term "bicarbonate equivalent" is used to describe organic acids or anions that produce bicarbonates when metabolized. Citrate and succinate are exemplary bicarbonate equivalents.

[0083] The term “to bond” as used herein in relation to polymers and one or more ions, namely cations (e.g., “proton-bonded” polymers) and anions, is used in relation to “ion-bonded” polymers and / or in relation to cases where the polymer associates with ions in a non-covalent manner, generally but not necessarily, and has an association strength sufficient to ensure that at least some of the ions remain bound under in vitro or in vivo conditions in which the polymer is used for a sufficient amount of time for the removal of ions from the solution or body to occur.

[0084] In certain embodiments, the term “clinically significant increase” as used herein in relation to treatment refers to a treatment that improves from a state of dysfunction back to a state of relatively normal function, provides a valuable change in the individual, shifts a measure of that state toward normal function, or provides at least a significant improvement compared to non-treatment. Clinical significance may be calculated using a number of methods. A non-comprehensive list of methods for calculating clinical significance includes: Jacobson-Truax, Guliksen-Lord-Novick, Edwards-Nunnally, Hageman-Arrindell, and Hierarchical Linear Modeling (HLM).

[0085] As used herein, "continuous process" refers to a process in which one or more reactants are continuously supplied to a reactor and reaction products are produced as a continuous stream of products.

[0086] The term “crosslinking agent,” used alone or within other terms, encompasses ethylene crosslinking agents, such as dihaloethanes selected from the group consisting of 1,2-dichloroethane, 1,2-dibromoethane, 1,2-diiodoethane, 1,2-difluoroethane, 1-chloro-2-iodoethane, 1-chloro-2-bromoethane, 1-chloro-2-fluoroethane, 1-bromo-2-iodoethane, 1-fluoro-2-iodoethane, and 1-fluoro-2-bromoethane. Any reference to 1,2-dichloroethane herein may be replaced with any ethylene crosslinking agent, including those disclosed in this paragraph.

[0087] The term "diallylamine" refers to an amino moiety having two allyl groups.

[0088] The terms "dry beads" and "dry polymer" refer to beads or polymers containing 5 weight percent or less of a non-polymer swelling agent or solvent. Often, the swelling agent / solvent is water remaining at the end of purification. This is generally removed by freeze-drying or oven-drying before storage or further crosslinking of the pre-formed poly(allylamine) polymer. The amount of swelling agent / solvent can be measured by heating (e.g., heating to 100-200°C) and measuring the resulting weight change. This is referred to as "loss on drying" or "LOD".

[0089] The term "gel" is used to describe cross-linked polymers having an irregular shape.

[0090] The term “heteroaryl” means a monocyclic or noncyclic aromatic radical of 5 to 10 ring atoms, unless otherwise noted, wherein one or more (in one embodiment, 1, 2, or 3) ring atoms are heteroatoms selected from N, O, or S, and the remaining ring atoms are carbons. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, etc. The terms “heteroaryl” and “aryl” as defined herein are mutually exclusive. “Heteroarylene” means a divalent heteroaryl radical.

[0091] The term "heteroatom" means an atom other than carbon and hydrogen. Typically, but non-exclusively, heteroatoms are selected from the group consisting of halogens, sulfur, phosphorus, nitrogen, boron, and oxygen atoms. A group containing more than one heteroatom may contain different heteroatoms.

[0092] The term “heterocyclo,” “heterocyclic,” or “heterocyclil” refers to a saturated or unsaturated group of 4 to 8 ring atoms, wherein 1 or 2 ring atoms are heteroatoms, e.g., N, O, B, P, and S(O)n, where n is an integer from 0 to 2, and the remaining ring atoms are carbons. Additionally, 1 or 2 ring carbon atoms within the heterocyclil ring may be optionally replaced by -C(O)- groups. More specifically, the term heterocyclil includes, but is not limited to, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydropyranyl, thiomomorpholino, etc. When the heterocyclyl ring is unsaturated, it may contain one or two ring double bonds, and the ring is not aromatic. When the heterocyclyl group contains at least one nitrogen atom, it is also referred to herein as heterocycloamino and is a subset of the heterocyclyl group.

[0093] "Initiator" is a term used to describe a reagent that initiates polymerization.

[0094] The molar percentage or "mol%" of a specific component of a cross-linked poly(allylamine) polymer can be calculated as follows:

[0095]

[0096] The cross-linked poly(allylamine) polymer component here is the residue specified in the given embodiment. For example, residues of 2-propene-1-ylamine or its salt, 1,3-bis(allylamino)propane or its salt, and 1,2-dichloroethane.

[0097] A cross-linked poly(allylamine) polymer can be defined by the mol% of the components of the cross-linked poly(allylamine) polymer (e.g., residues of monomers and crosslinking agents). In these embodiments, the total mol% will not exceed 100 mol%. For example, mol% of 1,3-bis(allylamino)propane or its salt + mol% of 2-propene-1-ylamine or its salt + mol% of 1,2-dichloroethane is ≤ 100 mol%.

[0098] Working examples of a method for calculating molar ratios and mol% are provided below. These examples calculate the mol% of each component in the final cross-linked poly(allylamine) polymer using known input molar ratios of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt used to prepare the intermediate poly(allylamine) polymer, and the amount of HCl produced by the 1,2-dichloroethane (DCE) crosslinking of the second-stage poly(allylamine) polymer.

[0099] This example is based on the principle that DCE can produce 2 equivalents of HCl when it reacts with two amine groups to introduce ethylene residues into a cross-linked poly(allylamine) polymer. Therefore, the amount of HCl produced indicates how many ethylene residues have been incorporated into the cross-linked poly(allylamine) polymer.

[0100] This example is performed on a sample of a crudely cross-linked poly(allylamine) polymer (i.e., immediately after DCE cross-linking). HCl is extracted from the sample of the crudely cross-linked poly(allylamine) polymer using a sodium hydroxide solution, and Cl is analyzed by anion chromatography.

[0101] More specifically, approximately 2 grams of crudely cross-linked poly(allylamine) polymer were sampled immediately after the DCE cross-linking reaction. The sample was washed with 20 mL of methanol by mixing on an orbital shaker for 2 hours, followed by vacuum filtration over a frit. The methanol washing was repeated for a total of two washes. The drying loss of the methanol-washed polymer was determined by using a standard moisture balance. Approximately 100 mg of the methanol-washed crudely cross-linked poly(allylamine) polymer was accurately weighed into a vial, and 10 mL of an aqueous 50 mM sodium hydroxide solution was added. The supernatant was filtered through a 0.45 µm nylon syringe filter, and Cl was extracted from the polymer at 37°C for 16 hours. The concentration of Cl in the supernatant was determined using anion chromatography. The IC method (e.g., Dionex ICS-5000, Thermo Scientific) consists of an AG19 guard column and an AS19 analytical column, a potassium hydroxide (KOH) eluent generator, an injection volume of 25 microliters, a run time of approximately 17 minutes, and a flow rate of 1.0 mL / min. The KOH concentration is 20 mM for 8 minutes, followed by maintenance at 70 mM KOH for 4 minutes, and re-equilibration at 20 mM KOH for 5 minutes. Chloride standards were used for the following quantifications.

[0102] The chloride concentration (mM) in the sample solution was calculated as follows:

[0103]

[0104] Here:

[0105] C = concentration of chloride in sample solution, mM;

[0106] C s = Concentration of chloride in chloride standards, mM;

[0107] P = peak area of ​​the sample;

[0108] P s= Average peak of 6 injections of chloride standard.

[0109] These calculations can be performed by a chromatography data system.

[0110] Determination of the mass of the extracted poly(allylamine) polymer:

[0111]

[0112] Here:

[0113] W P = Mass of sample converted into poly(allylamine) polymer in dry free amine form, mg;

[0114] W s = Mass of sample, mg;

[0115] LOD = Loss on drying of sample (wt%);

[0116] 100 = Conversion to a fraction of the percentage for LOD;

[0117] C = concentration of chloride in the extract filtrate, mM;

[0118] 0.01 = Volume of 50 mM sodium hydroxide solution, L;

[0119] 98.96 = molecular mass of 1,2-dichloroethane, g / mol;

[0120] 2 = molar ratio of chloride to 1,2-dichloroethane.

[0121] Determination of the reacted DCE:

[0122]

[0123] Here:

[0124] C = concentration of chloride in the extract filtrate, mM;

[0125] W P = Mass of the above-calculated poly(allylamine) polymer, mg;

[0126] 0.01 = Volume of 50 mM sodium hydroxide solution, L.

[0127] Calculation of weight percentage of ethylene crosslinking per gram of poly(allylamine) polymer

[0128] For example, the amount of ethylene below can be calculated using the method described above: 3.97 mmol ethylene / g poly(allylamine) polymer.

[0129] 3.97 mmol ethylene / g poly(allylamine) polymer = 111.1 mg ethylene / g poly(allylamine) polymer;

[0130] wt% ethylene / g poly(allylamine) polymer = 111.1 mg ethylene / (1000 mg poly(allylamine) polymer + 111.1 mg ethylene) = 10 wt% ethylene or DCE residue in cross-linked poly(allylamine) polymer.

[0131] Calculation of weight % of residues of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in cross-linked poly(allylamine) polymer:

[0132] The wt% of residues of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in the cross-linked poly(allylamine) polymer can be calculated using the weight fraction of the poly(allylamine) polymer in the cross-linked poly(allylamine) polymer and the known input molar ratio of 2-propene-1-ylamine and 1,3-bis(allylamino)propane used to prepare the intermediate poly(allylamine) polymer.

[0133] For example, 35.7 wt% of 2-propene-1-ylamine residues and 64.3 wt% of 1,3-bis(allylamino)propane residues calculated using the poly(allylamine) polymer weight fraction of 0.90 (i.e., 10% of the cross-linked poly(allylamine) polymer is ethylene and 90% is poly(allylamine) polymer) of the cross-linked poly(allylamine) polymer, and the input molar ratio of 2-propene-1-ylamine and 1,3-bis(allylamino)propane used to prepare the poly(allylamine) polymer (60 mol% 2-propene-1-ylamine : 40 mol% 1,3-bis(allylamino)propane):

[0134] 60 mol% of 2-propene-1-ylamine can be converted into wt% of a poly(allylamine) polymer as follows:

[0135] (57.1 x 60) / 100 = 34.26;

[0136] (34.26 / 34.26 + 61.68) x 100 = 35.7 wt% residue of 2-propene-1-ylamine;

[0137] 40 mol% of 1,3-bis(allylamino)propane can be converted into wt% of a poly(allylamine) polymer as follows:

[0138] (154.2 x 40) / 100 = 61.68;

[0139] (61.68 / 34.26 + 61.68) x 100 = 64.3 wt% residue of 1,3-bis(allylamino)propane;

[0140] wt% of the residues of 2-propene-1-ylamine and 1,3-bis(allylamino)propane in the poly(allylamine) polymer can be converted to wt% of the cross-linked poly(allylamine) polymer as follows:

[0141] wt% of residues of 2-propene-1-ylamine = 0.90 x 35.7 wt% = 32.1 wt% of cross-linked poly(allylamine) polymer;

[0142] wt% of residues of 1,3-bis(allylamino)propane = 0.90 x 64.3 wt% = 57.9 wt% of cross-linked poly(allylamine) polymer;

[0143] Calculation of mmol / g of residues of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in a cross-linked poly(allylamine) polymer from the weight % of residues of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in a cross-linked poly(allylamine) polymer:

[0144] From the above wt% calculation, 0.32g of residues of 2-propene-1-ylamine, 0.58g of residues of 1,3-bis(allylamino)propane, and 0.1g of ethylene are present in 1g of cross-linked poly(allylamine) polymer;

[0145] 0.32 g residue of 2-propene-1-ylamine / 57.1 g / mol = 5.6 mmol residue of 2-propene-1-ylamine;

[0146] 0.58g residue of 1,3-bis(allylamino)propane / 154.15 g / mol = 3.8 mmol residue of 1,3-bis(allylamino)propane;

[0147] 0.10 g ethylene / 28 g / mol = 3.6 mmol ethylene.

[0148] Calculation of mol% of residues of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in a cross-linked poly(allylamine) polymer from weight% of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in a cross-linked poly(allylamine) polymer:

[0149] Residue of mol% 2-propene-1-ylamine = (5.6 / (5.6+3.8+3.6) = 43%;

[0150] Residue of mol% 1,3-bis(allylamino)propane = (3.8 / (5.6+3.8+3.6) = 29%;

[0151] Residue of mol% 1,2-dichloroethane = (3.6 / (5.6+3.8+3.6) = 28%.

[0152] Another example of a method for calculating molar ratios and mol% is provided below. This example determines the weight percentage of ethylene crosslinking using elemental analysis. Then, using the weight percentage of ethylene crosslinking, the molar ratios and mol% can be calculated using the above equation.

[0153] Calculation of mmol-incorporated ethylene / g poly(allylamine) polymer using elemental analysis

[0154]

[0155] Here:

[0156] C wt%-pp is the weight percent of carbon in the poly(allylamine) polymer from elemental analysis;

[0157] C wt%-cpp is the weight percent of carbon in the cross-linked poly(allylamine) polymer from elemental analysis;

[0158] N wt%-pp is the weight percent of nitrogen in the poly(allylamine) polymer from elemental analysis;

[0159] N wt%-cpp is the weight percent of nitrogen in the cross-linked poly(allylamine) polymer from elemental analysis;

[0160] 1000 is the conversion from moles to millimoles;

[0161] 2 x 12.02 is the carbon ethylene mass (weight of 2 moles of carbon);

[0162] 100 is the conversion from wt% to weight.

[0163] The C wt% and N wt% of the poly(allylamine) polymer and the cross-linked poly(allylamine) polymer can be determined using elemental analysis, for example, the elemental analysis procedure described to determine the carbon-to-nitrogen weight ratio.

[0164] The term "monoallylamine" refers to an amino moiety having one allyl group.

[0165] The term "multiallylamine" refers to an amino moiety having two or more allyl groups, and includes, for example, diallylamine, trialylamine, etc.

[0166] The term "non-absorbable" as used herein has its ordinary meaning in the relevant art. Thus, if something is non-absorbable, it is not absorbed during its passage through the human GI tract. This can be measured by any appropriate means. One option known to a person skilled in the art would be to examine the feces to determine whether the non-absorbable substance is recovered after passing through the GI tract. As a matter of practice, the amount of non-absorbable substance recovered in this scenario would not be 100% of the administered substance. For example, about 90-99% of the substance may be recovered from the feces. Another option known to a person skilled in the art might be to detect the presence of the substance in lymph, blood, interstitial fluid, secretions from various organs (e.g., pancreas, liver, intestines, etc.), or in the organs themselves (e.g., liver, kidneys, lungs, etc.), because oral administration of the non-absorbable substance would not cause an increase in the amount of the substance in these matrices and tissues.

[0167] The non-absorbable composition may be a particulate composition that is essentially insoluble in the human GI tract and has a particle size large enough to avoid passive or active absorption through the human GI tract. For example, the non-absorbable composition is intended to mean that the substance does not enter lymph, blood, interstitial fluid, or organs through the major entry points of the human GI tract via active or passive transport processes, namely by pericellular entry between intestinal epithelial cells, by endocellular absorption through intestinal epithelial cells, or by entry through M cells including the intestinal epithelial antigen sampling and immune surveillance system (Jung, 2000). Size limits for particulates to be absorbed into the human GI duct are known (Jung et al., European Journal of Pharmaceutics and Biopharmaceutics 50 (2000) 147-160; Jani et al., International Journal of Pharmaceutics, 84 (1992) 245-252; and Jani et al., J. Pharm. Pharmacol. 1989, 41:809-812), and therefore, a person skilled in the art will know that a material having a size of at least 1 micrometer will be non-absorbable in the GI duct.

[0168] "Optional" or "optional" means that subsequently described events or situations may occur but do not necessarily have to occur, and that the description includes cases where the events or situations occur and cases where they do not occur. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that an alkyl group may be present but does not necessarily have to be present, and the description includes embodiments in which the heterocyclyl group is substituted with an alkyl group and embodiments in which the heterocyclyl group is not substituted with an alkyl group.

[0169] As used herein, the term “partially incorporated multiallylamine residue” refers to a residue of multiallylamine that (i) is incorporated into a poly(allylamine) polymer and (ii) possesses at least one pendant allyl group (i.e., at least one allyl group that is merely “hanging” from the backbone chain of the poly(allylamine) polymer without participating in a reaction to become a chain atom). For example, a partially incorporated diallylamine residue is a residue of diallylamine in which one of the two allyl groups of the incorporated diallylamine is a pendant allyl group of the polymer chain.

[0170] "Particle size" is measured by wet laser diffraction using micro-theory. Particles are dispersed in a suitable solvent, such as water or methanol, and added to a sample chamber to achieve 10-20% red channel shielding. Ultrasonic treatment may be performed, and a dispersant, such as a surfactant (e.g., Tween-80), may be added to break weak particle-particle interactions. The refractive index setting of the particles used in the size distribution calculation is selected to minimize artifacts in the result, and the R parameter value is determined by laser diffraction software. The D(0.1), D(0.5), and D(0.9) values ​​characterizing the particle size distribution on a volume-by-volume basis are recorded.

[0171] For example, particle size is measured by wet laser diffraction using the Mi theory as follows. Particles were dispersed in methanol and added to a sample chamber to achieve 10-20% red channel shielding. Ultrasonic treatment was performed. The refractive index setting of the particles used in the size distribution calculation was selected to minimize artifacts in the result, and the R parameter value was determined by the laser diffraction software. The D(0.1), D(0.5), and D(0.9) values ​​characterizing the particle size distribution on a volume-by-volume basis are recorded.

[0172] The term "pharmaceutical acceptable" as used in relation to carriers, diluents, or excipients means each of the carriers, diluents, or excipients useful for preparing a pharmaceutical composition that is generally safe, non-toxic, and not biologically or otherwise undesirable for veterinary and / or human pharmaceutical uses.

[0173] The term "post-polymerization crosslinking" describes a reaction to an already formed bead or gel, wherein more crosslinking is introduced to the already formed bead or gel to produce a bead or gel having an increased amount of crosslinking.

[0174] The term “post-polymerization modification” describes modification of already formed beads or gels, wherein a reaction or treatment introduces additional functional groups. These functional groups may be attached to the already formed beads covalently or non-covalently.

[0175] As used herein, the term "semi-batch process" refers to a variation of a batch process in which one or more reactants are added to a reactor intermittently or continuously.

[0176] The “artificial gastric juice” or “SGF” assay describes a test to determine the total chloride binding capacity for a test polymer using a prescribed buffer that mimics the contents of gastric juice as follows: Artificial gastric juice (SGF) consists of 35 mM NaCl and 63 mM HOI (pH 1.2). To perform the assay, the free-amine polymer to be tested is prepared at a concentration of 2.5 mg / ml (25 mg dry mass) in 10 mL of SGF buffer. The mixture is incubated overnight at 37°C for ~12–16 hours with stirring on a rotary mixer. Unless otherwise noted, the SGF binding data or binding capacity mentioned herein is determined within the duration of the above period. After incubation and mixing, the tubes containing the polymer are centrifuged at 500–1000Xg for 2 minutes to pellet the test sample. Remove approximately 750 microliters of supernatant and filter using a suitable filter, e.g., a 0.45 micrometer pore-size syringe filter or an 800 microliter, 1 micrometer pore-size, 96-well glass filter plate mounted on a 96-well 2 mL collection plate. Using the latter arrangement, multiple samples to be tested in SGF buffer for analysis can be prepared, including control tubes containing blank buffer processed through all assay steps. Filter the samples by centrifuging the unit at 1000xg for 1 minute using the samples arranged on the filter plate and the collection plate mounted on the bottom. For small sample sets, a syringe filter may be used instead of a filter plate to recover ~2-4 mL of filtrate into a 15 mL container. After filtration, each filtrate is diluted 4X with water, and the chloride content of the filtrate is measured via ion chromatography (IC).The IC method (e.g., Dionex ICS-2100, Thermo Scientific) consists of an AS11 column and a 15 mM KOH mobile phase, an injection volume of 5 microliters, a run time of 3 minutes, a wash / rinse volume of 1000 microliters, and a flow rate of 1.25 mL / min. To measure the chloride bound to the polymer, complete the following calculations:

[0177]

[0178] Binding capacity expressed as mmol chloride / g polymer (where Cl starting corresponds to the starting concentration of chloride in the SGF buffer, Cl eq corresponds to the equilibrium value of chloride in the filtrate measured by dilution after exposure to the test polymer, 4 is the dilution factor, and 2.5 is the polymer concentration in mg / ml).

[0179] "Artificial small intestine inorganic buffer" or "SIB" is a test to determine the chloride and phosphate binding capacity of free amine test polymers in the Selective Specific Interference Buffering Assay (SIB). The chloride and phosphate binding capacity of free amine test polymers was determined using the Selective Specific Interference Buffering Assay (SIB) as follows: The buffer used in the SIB assay contains 2-(N-morpholino)ethanesulfonic acid (MES) buffered with 36 mM NaCl, 20 mM NaH2PO4, and 50 mM pH 5.5. SIB buffer contains the concentrations and pH of chloride and phosphate present in the human duodenum and upper gastrointestinal tract (Stevens T, Conwell DL, Zuccaro G, Van Lente F, Khandwala F, Purich E, et al. Electrolyte composition of endoscopically collected duodenal drainage fluid after synthetic porcine secretin stimulation in healthy subjects. Gastrointestinal endoscopy. 2004;60(3):351-5, Fordtran J, Locklear T. Ionic constituents and osmolality of gastric and small-intestinal fluids after eating. Digest Dis Sci. 1966;11 (7):503-21), and is an effective measure of the selectivity of chloride binding relative to phosphate binding by polymers. To perform the assay, the free amine polymer to be tested is prepared at a concentration of 2.5 mg / ml (25 mg dry mass) in 10 mL of SIB buffer. The mixture is incubated at 37°C for 1 hour while stirring on an orbital shaker at 200 to 300 revolutions per minute.Unless otherwise noted, the SIB binding data or binding capacity mentioned herein is determined during this duration. After incubation and mixing, the tubes containing the polymer are centrifuged at 1000Xg for 2 minutes to pellet the test samples. 750 microliters of supernatant are removed and filtered using an 800 microliter, 1 micrometer pore-size, 96-well glass filter plate mounted on a 96-well 2 mL collection plate; using this arrangement, multiple samples to be tested in SIB buffer for analysis can be prepared, including standard controls of free amine sevelamer and free amine bixalomer, and control tubes containing blank buffer processed through all assay steps. Using the samples arranged on the filter plate and the collection plate mounted on the bottom, the unit is centrifuged at 1000Xg for 1 minute to filter the samples. For small sample sets, a syringe filter (0.45 micrometer) may be used instead of a filter plate to collect ~2–4 mL of filtrate into a 15 mL vial. After filtration to the collection plate, each filtrate is diluted, and the chloride or phosphate content is measured. For the measurement of chloride and phosphate, the filtrate under analysis is diluted 4X with water. The chloride and phosphate content of the filtrate is measured via ion chromatography (IC). The IC method (e.g., Dionex ICS-2100, Thermo Scientific) consists of an AS24A column, a 45 mM KOH mobile phase, an injection volume of 5 microliters, a run time of approximately 10 minutes, a wash / rinse volume of 1000 microliters, and a flow rate of 0.3 mL / min. To measure the chloride bound to the polymer, complete the following calculations:

[0180] Binding capacity expressed as mmol chloride / g polymer =

[0181] Here, Cl출발 corresponds to the starting concentration of chloride in the SIB buffer, and Cl 최종 ≡ corresponds to the final value of chloride in the diluted filtrate measured after exposure to the test polymer, 4 is the dilution factor, and 2.5 is the polymer concentration in mg / ml. To measure the phosphate bound to the polymer, complete the following calculation:

[0182] Binding capacity expressed as mmol phosphate / g polymer =

[0183] Here, P 출발 corresponds to the starting concentration of phosphate in the SIB buffer, and P 최종 0 corresponds to the final value of phosphate in the diluted filtrate measured after exposure to the test polymer, 4 is the dilution factor, and 2.5 is the polymer concentration in mg / ml units.

[0184] The term "sp" used in this document 2 The "allyl carbon" consists of two sp ions contained by the allyl moiety. 2 Each hybridized carbon atom is represented.

[0185] As used herein, the terms “substituted hydrocarbyl,” “substituted alkyl,” “substituted alkenyl,” “substituted aryl,” “substituted heterocyclo,” or “substituted heteroaryl” refer to hydrocarbyl, alkyl, alkenyl, aryl, heterocyclo, or heteroaryl moiety substituted with at least one atom other than carbon and hydrogen, comprising a moiety in which a carbon chain atom is substituted with a heteroatom, such as nitrogen, oxygen, silicon, phosphorus, boron, sulfur, or halogen atom. These substituents include halogen, heterocyclo, alkoxy, alkenoxy, alkyneoxy, aryloxy, hydroxy, keto, acyl, acyloxy, nitro, amino, amido, nitro, cyano, thiol, ketal, acetal, ester, and ether.

[0186] "Swelling ratio," or simply "swelling," describes the amount of water absorbed by a given amount of polymer divided by the weight of the polymer fraction. The swelling ratio is expressed as Swelling = (g swollen polymer - g dry polymer) / g dry polymer. Methods used to determine the swelling ratio for any given polymer include the following:

[0187] a. 50-100 mg of dry polymer (water content less than 5 wt%) is placed in an 11 mL sealable test tube (having a screw cap) of known weight (weight of tube = weight A).

[0188] b. Add deionized water (10 mL) to the tube containing the polymer. Seal the tube and tumble at room temperature for 16 hours (overnight). After incubation, centrifuge the tube at 3000 xg for 3 minutes and carefully remove the supernatant by vacuum aspiration. For polymers that form a very loose precipitate, an additional centrifugation step is performed.

[0189] c. After step (b), record the weight of the swollen polymer + tube (weight B).

[0190] d. Freeze at -40℃ for 30 minutes. Freeze-dry for 48 hours. Weigh the dried polymer and test tube (record as weight C).

[0191] e. Calculate the g of water absorbed per g of polymer, defined as [(weight B - weight A) - (weight C - weight A)] / (weight C - weight A).

[0192] "Target ion" refers to an ion to which the polymer binds, typically the major ion bound by the polymer, or an ion whose binding to the polymer is believed to produce the polymer's therapeutic effect (e.g., proton and chloride bonds inducing the net removal of HCl).

[0193] The term "theoretical capacity" refers to the calculated expected binding of hydrochloric acid in the "SGF" assay and is expressed in mmol / g. The theoretical capacity is based on the assumption that 100% of the amines from the monomer(s) and crosslinker(s) are incorporated into the crosslinked polymer according to their respective feed ratios. Therefore, the theoretical capacity is equal to the concentration of amine functional groups (mmol / g) in the polymer. The theoretical capacity is assumed to be available for binding to each anion and cation, and is not adjusted for the type of amine formed (e.g., this does not subtract the capacity of quaternary amines that are not available for binding to protons).

[0194] "Therapeutic effective dose" refers to an amount of proton-linked cross-linked amine polymer sufficient to perform such treatment for the disease when administered to a patient to treat the disease. The amount constituting the "therapeutic effective dose" will vary depending on the polymer, the severity of the disease, and the age, body weight, etc. of the mammal to be treated.

[0195] "Treating" or "treating" a disease includes (i) suppressing the disease, i.e., stopping or reducing the occurrence of the disease or its clinical symptoms; or (ii) alleviating the disease, i.e., causing the regression of the disease or its clinical symptoms. Suppression of the disease may include, for example, prevention.

[0196] The term "triallylamine" refers to an amino moiety having three allyl groups.

[0197] The term "vinyl" has the structural chemical formula R x H yA moiety having C=CH-* is represented, where * represents the attachment point of the moiety to the remainder of the molecule, X and Y are independently 0, 1, or 2 such that X+Y=2, and R is hydrocarbyl or substituted hydrocarbyl. In some embodiments, the attachment point * is to a heteroatom within the remainder of the molecule, e.g., nitrogen.

[0198] The term "water equivalent" refers to the number of moles of water.

[0199] The term "weight% crosslinker" refers to the calculated mass percentage of the polymer sample derived from the crosslinker. Weight% crosslinker is calculated using the feed ratio of the polymerization and assumes the complete conversion of the monomer and crosslinker(s). The mass attributed to the crosslinker is equal to the expected molecular weight increase of the infinite polymer network after the reaction (e.g., 1,3-dichloropropane is 113 amu, but only 42 amu is added to the polymer network after crosslinking with DCP because the chlorine atom as a leaving group is not incorporated into the polymer network).

[0200] Protocols for other tests and decisions mentioned herein

[0201] Cation IC Extraction ProcedureIn a tightly closed vial with a capacity of 15 to 50 mL, add a poly(allylamine) polymer (~1.0 g) to 10 mL of 1.2 M HCl. Shake the vial at room temperature for at least 24 hours. Filter the supernatant through a 0.45 micrometer syringe filter followed by a neutralization column, and then analyze it by ion chromatography (IC). The IC method (e.g., Dionex ICS-5000, Thermo Scientific) consists of a CG19 guard column and a CS19 analytical column, a methanesulfonic acid (MSA) eluent generator, an injection volume of 25 microliters, a run time of about 40 minutes, and a flow rate of 0.3 mL / min. The MSA concentration is 2 mM for 10 minutes, then increased to 70 mM MSA from 10 to 28 minutes, maintained at 70 mM MSA for 3 minutes, and re-equilibrated at 2 mM MSA for 9 minutes. This procedure is used to measure allylamine content greater than 0.25 ppm. If the sample contains less than 0.25 ppm, the extract supernatant is analyzed by LCMS as described in the procedure below.

[0202] Add polyallylamine polymer (~1.0 g) to 10 mL of 1.2 M HCl in a tightly closed vial with a capacity of 15 to 50 mL. Shake the vial at 200 RPM at room temperature for at least 24 hours. Filter the supernatant through a 0.45 micrometer syringe filter. Dilute the sample twofold with an internal standard (IS) consisting of 10 micrograms / mL diethylamine in 0.1% heptafluorobutyric acid (HFBA) in water. The HPLC method (e.g., Agilent 1260 HPLC) consists of an Acclaim 120 C 182.1 x 50 mm column, a particle size of 5 micrometers, an injection volume of 5 microliters, and a mobile phase consisting of: A) 0.1% HFBA in water and B) 0.1% HFBA in acetonitrile, a gradient of 0% B for 3 minutes, rising to 100% B from 3-3.5 minutes, maintaining at 100% B from 3.5-6 minutes, and equilibrium at 0% B up to 10 minutes, with a flow rate of 0.4 mL / min. Mass spectrometry (MS) methods (e.g., API 4000 triple quadrupole tandem MS) are electrospray ionized into cations at a source temperature of approximately 500°C and a voltage of approximately 5000 V, and multiple reaction monitoring modes are performed with allylamine Q1 and Q3 masses of approximately 58.7 and 58.1 amu, respectively, and Q1 and Q3 masses of approximately 74.7 and 73.1 amu, respectively. The gas source pressure, collision energy, declustering potential, inlet potential, and outlet potential are optimized for the instrument used.

[0203] Quantitative 13 % sp by solid-state Magic Angle Spinning (MAS) NMR 2 Crystallization of allyl carbon: Quantitative 13 C Solid State Magic Angle Spinning (MAS) NMR Measurement 1 H and 13For C, the experiment was performed at a spin frequency of 16 kHz using a 4 mm zirconia rotor system on a Bruker AVANCE III 800 MHz (18.8T) standard aperture spectrometer operating at 800.25 MHz and 201.24 MHz, respectively. Single-pulse experiments were performed with a 30-degree excitation pulse of 1.2 ps using an 8 s relaxation delay, an 8.6 ms acquisition time, and an accumulation of approximately 20,000 scans, which were optimized for quantitative analysis. 13 100 kHz proton decoupling was applied during C data acquisition. Chemical shifts are based on TMS standards. Using the integration of the allyl carbon peak between 110 and 150 ppm and the alkyl carbon peak between 0 and 80 ppm, the % sp of the poly(allylamine) polymer was calculated using the following equation. 2 Quantify the allyl carbon:

[0204]

[0205] When introducing elements of the present invention or preferred embodiment(s) thereof, the singular expression and "the above" are intended to mean that one or more elements exist. The terms "comprising," "including," and "having" are intended to be inclusive and non-exclusive (i.e., other elements may exist in addition to the mentioned elements).

[0206] Quantitative 13 % sp by C solid-state cross-polarized magic angle spinning (CPMAS) NMR 2 Crystallization of allyl carbon:

[0207] Quantitative 13 C Solid State Cross-Polarized Magic Angle Spinning (CPMAS) NMR measurements for poly(allylamine) polymer samples 1 H and 13 For C, it is performed using a 7 mm zirconium probe with a spin frequency of 7 kHz using a Redstone 360 ​​MHz spectrometer operating at 363.331 MHz and 91.369 MHz, respectively.

[0208] The cross-biased experiment is 90 degrees 1 The procedure was performed using an H excitation pulse with a contact time of 5 ps, 2.5 ms, and a recirculation delay of 3 s, and was calibrated for the analysis of poly(allylamine) polymers based on quantitative single-pulse spectra. Proton decoupling at 12 V and 18 V and linewidth broadening at 35 Hz were used, and approximately 3500 spectra were acquired and accumulated. Using the integration of the allyl carbon peak between 110–150 ppm and the alkyl carbon peak between 0–80 ppm, the % sp of the poly(allylamine) polymer was calculated using the following equation. 2 Quantify the allyl carbon:

[0209]

[0210] Determination of the Carbon-to-Nitrogen Weight Ratio of Cross-linked Poly(Allylamine) Polymers by Elemental Analysis:

[0211] Elemental analysis is a standard method for measuring the carbon, hydrogen, and nitrogen content of organic materials, which falls within the ordinary general knowledge of a person skilled in the art. A person skilled in the art will recognize that all elemental analysis measurement methodologies yield the same results within appropriate limits of measurement accuracy. Elemental analysis can be performed by any elemental analyzer suitable for measuring organic carbon, hydrogen, and nitrogen. The following elemental analysis method is provided as an example of how elemental analysis can be performed.

[0212] Carbon, hydrogen, and nitrogen are determined using a Perkin-Elmer 2400 elemental analyzer. This analyzer uses combustion to convert sample elements into simple gases, namely CO2, H2O, and N2. Upon entering the analyzer, the sample is combusted in a pure oxygen environment. The product gases are separated under steady-state conditions and measured as a function of thermal conductivity. The instrument is calibrated with National Institute of Standards and Technology (NIST) traceable organic standards prior to sample analysis. For example, the standard may have a nitrogen content ranging from approximately 11 to 45 wt%. System suitability is verified by analyzing the NIST traceable organic standards. The standards must be checked to be within ±0.1% of their theoretical values ​​for all three elemental carbon, hydrogen, and nitrogen. Cross-linked poly(allylamine) polymer samples for analysis are typically dried in a vacuum oven at 60°C prior to analysis to remove moisture.

[0213] The carbon-to-nitrogen weight ratio of the poly(allylamine) polymer used to prepare the cross-linked poly(allylamine) polymer can also be determined by elemental analysis. The procedure used to determine the carbon-to-nitrogen weight ratio of the poly(allylamine) polymer may be as described above.

[0214] GC-FID Extraction ProcedureAdd 5 mL of acetonitrile to a tightly closed vial with a volume of 10 to 20 mL containing a poly(allylamine) polymer (~0.1 g). Add 5 mL of methanol to a second tightly closed vial with a volume of 10 to 20 mL containing a polyallylamine polymer (~1.5 g). Close the vials and shake at 200 RPM for 24 hours at room temperature. Filter the supernatant through a 0.45 micrometer syringe filter and analyze it by gas chromatography with flame ionization detection (GC-FID). The GC (e.g., Agilent 6890) method consists of an approximately 4 meter DB-1 column (0.32 mm inner diameter) coupled in series with a 30 meter DB-wax column (0.32 mm inner diameter) at a constant helium flow rate of 2.5 mL / min. 2 microliters are injected into the inlet at 200°C with a 1:10 split ratio. The oven gradient program consists of holding at 40°C for 5 minutes, followed by an increase to 180°C at 10°C / min, followed by a gradient to 240°C at 20°C / min and holding for 3 minutes. FID acquisition is performed at a temperature of 300°C.

[0215] Heating stability test (Stability Test 2): Poly(allylamine) polymer (1.0 g each) is placed into two separate, tightly closed vials with a capacity of 15 to 50 mL. A sample is directly extracted from one vial to determine the starting allylamine content according to the cationic IC extraction procedure. The remaining sample is tightly sealed and placed in a convection oven set to 60°C. After 72 hours, the sample is removed from the oven, cooled to 4°C, and then extracted in the same manner as described in the cationic IC extraction procedure.

[0216] Impurity analysis and testing at shipment:The dried poly(allylamine) polymer (1.0 g in the first vial, 1.5 g in the second vial, and 0.1 g in the third vial) is placed into three separate tightly closed vials having a capacity of 15 to 50 mL. A sample is extracted from one vial containing 1.0 g of the poly(allylamine) polymer to determine the starting allylamine content according to the cationic IC extraction procedure. The remaining two samples are extracted to determine the starting allyl methyl ether and allyl alcohol content according to the GC-FID extraction procedure.

[0217] Air stability test (Stability Test 1): 4.5 g of poly(allylamine) polymer is added to a 35 mL HOPE bottle. After closing the bottle, it is stored in a 60% humidity controlled chamber maintained at 25°C for 7 days. The bottle is removed from the chamber, and the polymer sample is extracted to determine the allylamine content according to the cation IC extraction procedure.

[0218] Stability evaluation test when packaging in MylarFoil sachets (Stability Test 3): Approximately 3 g of poly(allylamine) polymer is added to a 3-sided seal of an approximately 2.5" x 3" sachet composed of a laminate containing a metal foil layer, and then the sachet is heat-sealed. Multiple sachets of the poly(allylamine) polymer are prepared and then placed in individual test chambers controlled at 25°C and 60% relative humidity, and 40°C and 75% relative humidity, for up to 6 months. At a preferred time, the sachet is removed from each test chamber, and a polymer sample is extracted to determine the allylamine content according to the cation IC extraction procedure. Brief explanation of the drawing

[0219] Fig. 1a: Allylamine (AA) concentrations (ppm) present when Beberimer is packaged in packet materials A, B, and C at 25°C / 60% RH over 6 weeks. Unit dosage forms A, B, and C were stored at 25°C / 60% RH for 6 weeks, and allylamine concentrations were measured at TO (initial) and at weeks 1, 2, 4, and 6. In Fig. 1a, unit dosage form A is shown as a square (e.g., top line at week 6), unit dosage form B as a circle (e.g., bottom line at week 6), and unit dosage form C as a cross (e.g., middle line at week 6). Unit dosage form A shows an increasing concentration of allylamine over the 6-week period, while no increase in concentration is observed in unit dosage forms B and C. Fig. 1b: Allylamine (AA) concentrations (ppm) present when Beberimer is packaged in unit dosage forms A, B, and C at 40°C / 75% RH over 6 weeks. Unit dosage forms A, B, and C were stored at 40°C / 75% RH for 6 weeks, and allylamine concentrations were measured at TO (initial) and at weeks 1, 2, 4, and 6. In Fig. 1b, unit dosage form A is shown as a square (e.g., top line at week 6), B as a circle (e.g., middle line at week 6), and C as a cross (e.g., bottom line at week 6). Unit dosage form A shows increasing concentrations of allylamine over the 6-week period under conditions that are not present in unit dosage forms B and C. Fig. 2: Allylamine (AA) concentrations (ppm) of 1.5, 3.0, and 4.5 g unit dosage forms over 3 months at 25°C / 60% RH. The 1.5, 3.0, and 4.5 g unit dosage forms were stored at 25°C / 60% RH for 3 months, and allylamine concentrations were measured at TO (initial) and then monthly thereafter. In Fig. 2, 1.5 g is represented by a circle (e.g., top line at 3 months), 3.0 g by a square (e.g., middle line at 3 months), and 4.5 g by a triangle (e.g., bottom line at 3 months). The 1.5, 3.0, and 4.5 g unit dosage forms show that the concentration of AA increases over time. Fig. 3: Allylamine (AA) concentrations (ppm) of 1.5, 3.0, and 4.5 g unit dosage forms over 3 months at 40°C / 75% RH. The 1.5, 3.0, and 4.5 g unit dosage forms were stored at 40°C / 75% RH for 3 months, and allylamine concentrations were measured at TO (initial) and then monthly thereafter. In Fig. 3, 1.5 g is represented by a circle (e.g., the top line at the 3rd month time point), 3.0 g by a square (e.g., the middle line at the 3rd month time point), and 4.5 g by a triangle (e.g., the bottom line at the 3rd month time point). The 1.5, 3.0, and 4.5 g unit dosage forms show that the concentration of AA increases over time. Fig. 4: Allylamine (AA) concentrations (ppm) in 1.5 g unit dose forms with oxygen scavengers over 6 months at 25°C / 60% RH and 40°C / 75% RH. Allylamine concentrations in the unit dose forms were measured at TO and at various intervals thereafter. In Fig. 4, the 1.5 g unit dose form at 25°C / 60% RH is illustrated as a cross (X) (e.g., the top line at the 2-month mark), and the 1.5 g unit dose form at 40°C / 75% RH is illustrated as a triangle (e.g., the bottom line at the 2-month mark). The unit dose forms show that the concentration of AA is approximately constant over 6 months. Fig. 5: Allylamine (AA) concentrations (ppm) of the 1.5 g unit dosage form over 6 months in environments of air, 8% oxygen, % nitrogen, and 99+% nitrogen at 25°C / 60% RH. Allylamine concentrations in the unit dosage form were measured at TO and at various intervals thereafter. In Fig. 5, the 1.5 g unit dosage form in air is illustrated as a cross (X) (e.g., top line at 6 months), the 1.5 g unit dosage form in 8% oxygen and 92% nitrogen is illustrated as a triangle (e.g., middle line at 6 months), and the 1.5 g unit dosage form in 99+% nitrogen is illustrated as a circle (e.g., bottom line at 6 months). The unit dosage forms show that the concentration of AA is approximately constant over 6 months. Fig. 6: Allylamine (AA) concentrations (ppm) of the 1.5 g unit dosage form over 6 months in environments of air, 8% oxygen and 92% nitrogen, and 99+% nitrogen at 40°C / 75% RH. Allylamine concentrations in the unit dosage forms were measured at TO and at various intervals thereafter. In Fig. 6, the 1.5 g unit dosage form in air is depicted as a cross (X) (e.g., top line at 6 months), the 1.5 g unit dosage form in 8% oxygen and 92% nitrogen is depicted as a triangle (e.g., middle line at 6 months), and the 1.5 g unit dosage form in 99+% nitrogen is depicted as a circle (e.g., bottom line at 6 months). The unit dosage forms show that the concentration of AA is approximately constant over 6 months. Specific details for implementing the invention

[0220] Mode of implementation

[0221] The present disclosure includes the observation that during the synthesis of cross-linked poly(allylamine) polymers, such as Beberimers, unincorporated 2-propene-1-ylamine monomer and / or partially incorporated 1,3-bis(allylamino)propane monomer residues may be sources of allylamine impurities (i.e., allylamine and its derivatives, such as allylalkyl ethers and allyl alcohols) in the poly(allylamine) product. These monomers may exist as salts. Without wishing to be bound by theory, it is believed that residual unincorporated 2-propene-1-ylamine monomer and / or partially incorporated 1,3-bis(allylamino)propane monomer residues present in cross-linked poly(allylamine) polymers, such as Beberimers, may react with oxygen after the polymer is prepared to produce allylamine impurities (e.g., H2C=CHCH2NH2). For example, the Beberimer polymer designated as unique ID 019070-A3 FA in Table S-1 of the exemplary synthesis A of WO2019 / 236636 A1 was found to produce H2C=CHCH2NH2 upon exposure to oxygen. High levels of impurities, such as H2C=CHCH2NH2, are undesirable in the final product to be administered to patients, for example, due to potential safety concerns.

[0222] Several methods for reducing the level of allylamine impurities, such as H2C=CHCH2NH2, in cross-linked poly(allylamine) polymers (e.g., Beberimer) are disclosed herein.

[0223] One approach disclosed herein is to prepare a cross-linked poly(allylamine) polymer, such as a Beberimer, containing a smaller amount of an unincorporated 2-propene-1-ylamine monomer or its salt, and / or a partially incorporated 1,3-bis(allylamino)propane monomer residue or its salt. A reduction in the amount of such unincorporated and / or partially incorporated monomers can reduce the amount of allylamine impurities present in the final product. Thus, for example, sp present in the product 2A method for preparing a cross-linked poly(allylamine) polymer (e.g., Beberimer) having reduced levels of such non-incorporated and / or partially incorporated monomers when measured with reference to carbon levels is disclosed herein. Additionally, sp₂ present in the product, for example 2 Cross-linked poly(allylamine) polymers (e.g., Beberimers) having reduced levels of such non-incorporated and / or partially incorporated monomers when measured with reference to carbon levels are disclosed herein. These products are shown to have desirable properties, for example, reduced levels of allylamine impurities (e.g., H2C=CHCH2NH2) in these products.

[0224] Another approach disclosed herein is to package a cross-linked poly(allylamine) polymer, e.g., Beberimer, in a manner that reduces its exposure to oxygen. The approach of using packaging to mitigate concerns regarding the level of impurities, e.g., allylamine impurities (e.g., H2C=CHCH2NH2), may be used in combination with any cross-linked poly(allylamine) polymer, e.g., Beberimer, disclosed herein or known from the prior art.

[0225] According to one aspect of the present disclosure, the cross-linked poly(allylamine) polymers disclosed herein, particularly Beberimers, may be used therapeutically. In one embodiment, the cross-linked poly(allylamine) polymer may be used to achieve a therapeutic or preventive benefit by binding to HCl from the gastrointestinal tract of animals, for example, including humans, upon administration of a therapeutically effective amount (i.e., an effective dose) of the cross-linked poly(allylamine) polymer.

[0226] The therapeutic methods and medical uses of the cross-linked poly(allylamine) polymers, particularly Beberimers, disclosed herein are described in WO201 4 / 197725 A1, WO2016 / 094685 A1, WO2017 / 193050 A1, WO2017 / 193064 A1, WO2017 / 193024 A1, WO2019 / 090176 A1, WO2019 / 090177 A1, WO2019 / 236639 A1, WO2019 / 236636 A1 and WO2019 / 236124 A1, which are incorporated herein by reference.

[0227] According to one aspect of the present disclosure, the cross-linked poly(allylamine) polymers disclosed herein, particularly Beberimers, are intended for use in any therapeutic method or medical use described in any of WO201 4 / 197725 A1, WO2016 / 094685 A1, WO2017 / 193050 A1, WO2017 / 193064 A1, WO201 7 / 193024 A1, WO2019 / 090176 A1, WO2019 / 090177 A1, WO2019 / 236639 A1, WO2019 / 236636 A1 and WO2019 / 236124 A1.

[0228] According to one aspect of the present disclosure, a cross-linked poly(allylamine) polymer may be formed in the steps of (a first) polymerization and cross-linking co-step (sometimes referred to as the “first cross-linking step” or, more simply, the “first step”) and, optionally, (a second) post-polymerization cross-linking step (sometimes referred to as the “second cross-linking step” or, more simply, the “second step”). In the first step, the cross-linking is preferably dose-conserving, i.e., free amine-conserving, and is a cross-linking from carbon to carbon. In the second step, the cross-linking is amine-consuming and is intended to adjust selectivity for a target species. Based on the desired high dose, the CN weight ratio is preferably optimized to maximize amine functional groups for target species binding while still maintaining spherical polymer particles of controlled particle size to ensure stable non-absorption and acceptable oral tactile sensation under GI conditions. It should be noted that the terms "first" and "second" are used merely to specify the relative order between these two steps, and that other steps may be considered as part of the method before, after, or between "first step" and "second step".

[0229] In the first step, 2-propene-1-ylamine or its salt, 1,3-bis(allylamino)propane or its salt, are simultaneously polymerized and crosslinked in a heterogeneous reaction mixture comprising 2-propene-1-ylamine or its salt, 1,3-bis(allylamino)propane or its salt, a radical initiator, water, and an organic solvent to form a polymer network crosslinked through a carbon backbone. Advantageously, each crosslinking reaction at this step forms a carbon-carbon bond (in contrast to a substitution reaction in which a carbon-heteroatom bond is formed during crosslinking), and the amine functional groups of 2-propene-1-ylamine or its salt, and 1,3-bis(allylamino)propane or its salt, are preserved in the final polymer without undergoing a crosslinking reaction (i.e., the primary amines of 2-propene-1-ylamine or its salt, and 1,3-bis(allylamino)propane or its salt, retain their primary amines, the secondary amines retain their secondary amines, and the tertiary amines retain their tertiary amines). The resulting poly(allylamine) polymer can then be further crosslinked with 1,2-dichloroethane in a second step.

[0230] As mentioned above, unincorporated 2-propene-1-ylamine or its salt (i.e., 2-propene-1-ylamine or its salt not covalently incorporated into the polymer) and partially incorporated 1,3-bis(allylamino)propane or its salt, residues may be sources of allylamine impurities (i.e., allylamine and its derivatives, e.g., allylalkyl ethers and allyl alcohols) in the poly(allylamine) product. According to one embodiment of the present disclosure, process parameters may be controlled to limit the amount of allyl impurities released by (i) the cross-linked poly(allylamine) polymer in its as-manufactured state (i.e., at the completion of the second step, also sometimes referred to herein as “shipping time”), and / or (ii) the amount of allyl impurities released by the cross-linked poly(allylamine) polymer as a function of storage and time.

[0231] Generally, it is desirable for the cross-linked poly(allylamine) polymer to contain less than 20 ppm of allylamine in its as-manufactured state. For example, in one embodiment, the cross-linked poly(allylamine) polymer contains less than 15 ppm of allylamine in its as-manufactured state. Additionally, for example, in this one embodiment, the cross-linked poly(allylamine) polymer contains less than 12.5 ppm of allylamine in its as-manufactured state. Additionally, for example, in this one embodiment, the cross-linked poly(allylamine) polymer contains less than 10 ppm of allylamine in its as-manufactured state. Additionally, for example, in this one embodiment, the cross-linked poly(allylamine) polymer contains less than 7.5 ppm of allylamine in its as-manufactured state. Additionally, for example, in this one embodiment, the cross-linked poly(allylamine) polymer contains less than 5 ppm of allylamine in its as-manufactured state. Additionally, for example, in this one embodiment, the cross-linked poly(allylamine) polymer contains less than 4 ppm of allylamine in its as-manufactured state. Additionally, for example, in this one embodiment, the cross-linked poly(allylamine) polymer contains less than 3 ppm of allylamine in its as-manufactured state. Additionally, for example, in this one embodiment, the cross-linked poly(allylamine) polymer contains less than 2 ppm of allylamine in its as-manufactured state. Additionally, for example, in this one embodiment, the cross-linked poly(allylamine) polymer contains less than 1 ppm of allylamine in its as-manufactured state. Additionally, for example, in this one embodiment, the cross-linked poly(allylamine) polymer contains less than 500 ppb of allylamine in its as-manufactured state. Additionally, for example, in this one embodiment, the cross-linked poly(allylamine) polymer contains less than 100 ppb of allylamine in its as-manufactured state.Additionally, for example, in one embodiment, the cross-linked poly(allylamine) polymer contains less than 50 ppb of allylamine in its as-manufactured state. Additionally, for example, in one embodiment, the cross-linked poly(allylamine) polymer contains less than 1 ppb of allylamine in its as-manufactured state. Additionally, for example, in one embodiment, the amount of allylamine (if present) in the cross-linked poly(allylamine) polymer is below the detection limit for allylamine in its as-manufactured state. In each of these exemplary embodiments mentioned in this paragraph, the allylamine content may be determined by a cationic IC extraction procedure following impurity analysis testing at shipment.

[0232] In one embodiment, the cross-linked poly(allylamine) polymer contains less than 20 ppm of allylamine when stored in a sealed enclosure at 25°C for 3 months after manufacturing. In one embodiment, the cross-linked poly(allylamine) polymer contains less than 20 ppm of allylamine when stored in a sealed enclosure at 25°C for 6 months after manufacturing. In one embodiment, the cross-linked poly(allylamine) polymer contains less than 20 ppm of allylamine when stored in a sealed enclosure at 25°C for 9 months after manufacturing. In one embodiment, the cross-linked poly(allylamine) polymer contains less than 20 ppm of allylamine when stored in a sealed enclosure at 25°C for 12 months after manufacturing. In one embodiment, the allylamine content of the cross-linked poly(allylamine) polymer increases to less than 20 ppm of allylamine when stored in a sealed enclosure at 25°C for 3 months. In one embodiment, the allylamine content of the cross-linked poly(allylamine) polymer increases to less than 20 ppm allylamine when stored in a sealed enclosure at 25°C for 6 months. In one embodiment, the allylamine content of the cross-linked poly(allylamine) polymer increases to less than 20 ppm allylamine when stored in a sealed enclosure at 25°C for 9 months. In one embodiment, the allylamine content of the cross-linked poly(allylamine) polymer increases to less than 20 ppm allylamine when stored in a sealed enclosure at 25°C for 12 months. In each of these exemplary embodiments mentioned in this paragraph, the allylamine content may be determined by a cation IC extraction procedure.

[0233] To facilitate polymerization and crosslinking co-reactions, 2-propene-1-ylamine or its salt, and 1,3-bis(allylamino)propane or its salt are preferably protonated in the reaction mixture. Thus, in one embodiment, 2-propene-1-ylamine or its salt and / or 1,3-bis(allylamino)propane or its salt are introduced into the reaction mixture as their respective acid salts (e.g., in the form of hydrochloric acid, phosphoric acid, sulfuric acid, or hydrobromide salts). Alternatively, 2-propene-1-ylamine or its salt and / or 1,3-bis(allylamino)propane or its salt may be introduced into the reaction mixture as their free amine form(s), and the acid may be added individually to the reaction mixture. For example, the acid may be sulfuric acid, phosphoric acid, or hydrochloric acid (HCl). As an additional example, the acid is HCl. In any embodiment, the reaction mixture contains an acid sufficient to retain 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in the aqueous phase. Typically, the reaction mixture will contain at least 0.5 equivalents of acid per equivalent of allylamine in the reaction mixture (regardless of whether the acid is introduced as an acid salt of 2-propene-1-ylamine or its salt and / or 1,3-bis(allylamino)propane or its salt, or whether it is added individually to the reaction mixture). In certain embodiments, the reaction mixture will contain at least 0.75 equivalents of acid per equivalent of allylamine in the reaction mixture. In certain embodiments, the reaction mixture will contain at least 1 equivalent of acid per equivalent of allylamine in the reaction mixture.

[0234] 2-propene-1-ylamine and 1,3-bis(allylamino)propane are listed in Table C. As exemplified, 2-propene-1-ylamine and 1,3-bis(allylamino)propane are in the form of HCl salts. As mentioned above, each of 2-propene-1-ylamine and 1,3-bis(allylamino)propane may be introduced into the reaction mixture in the form of a salt (e.g., as a hydrochloric acid salt, sulfate salt, phosphate salt, hydrobromide salt, or a combination thereof), in the form of a free base, or in a combination thereof.

[0235] Table C

[0236]

[0237] The polymerization and crosslinking co-step reaction mixture comprises a radical polymerization initiator in addition to 2-propene-1-ylamine or its salt, and 1,3-bis(allylamino)propane or its salt. The initiator may be selected from any broad range of initiators, including cationic and radical polymerization initiators. Exemplary polymerization initiators for polymerization and crosslinking co-step reactions are peroxy and azo free-radical initiators, such as azodiisobutyronitrile, azodiisovaleronitrile, dimethylazodiisobutyrate, 2,2'-azobis(isobutyronitrile), 2,2'-azobis(N,N'-dimethyl-enisobutyramidine) dihydrochloride, 2,2'-azobis(2-methylpropionamidine) dihydrochloride, 2,2'-azobis(2-amidinopropane) dihydrochloride, 2,2'-azobis(N,N'-dimethyleneisobutyramidine), 1,1'-azobis(l-cyclohexanecarbonitrile), 4,4'-azobis(4-cyanopentanic acid), It includes 2,2'-azobis(isobutyramide) dihydrate, 2,2'-azobis(2-methylpropane), 2,2'-azobis(2-methylbutyronitrile), VAZO 67, cyanopentanic acid, peroxypivalate, dodecylbenzene peroxide, benzoyl peroxide, di-t-butyl hydroperoxide, t-butyl peracetate, acetyl peroxide, dicumyl peroxide, cumyl hydroperoxide, and dimethyl bis(butylperoxy)hexane. For example, the radical polymerization initiator is V-50 (2,2'-azobis(2-methylpropionamidine) dihydrochloride).

[0238] Experience to date has shown that the amount of initiator relative to the amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in the reaction mixture affects the characteristics of the resulting polymer. For example, the amount of partially incorporated 1,3-bis(allylamino)propane or its salt tends to increase as the ratio of allyl equivalents to initiator equivalents in the reaction mixture increases. Therefore, typically, the ratio of the combined allyl equivalents of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the initiator equivalents introduced into the reaction mixture will be in the range of about 6:1 to about 70:1, respectively. For example, in one such embodiment, the ratio of the combined retained allyl equivalents of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the initiator equivalents introduced into the reaction mixture will each be about 7:1 to about 60:1. Additionally, for example, in one such embodiment, the ratio of the combined retained allyl equivalents of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the initiator equivalents introduced into the reaction mixture will each be about 8:1 to about 50:1. Additionally, for example, in one such embodiment, the ratio of the combined retained allyl equivalents of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the initiator equivalents introduced into the reaction mixture will each be about 10:1 to about 45:1. Additionally, for example, in one such embodiment, the ratio of the combined retained allyl equivalents of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the initiator equivalents introduced into the reaction mixture will each be about 15:1 to about 40:1.Additionally, for example, in one embodiment, the ratio of the combined retained allyl equivalents of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the initiator equivalents introduced into the reaction mixture will each be about 17.5:1 to about 35:1. Additionally, for example, in one embodiment, the ratio of the combined retained allyl equivalents of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the initiator equivalents introduced into the reaction mixture will each be about 20:1 to about 30:1. Additionally, for example, in one embodiment, the ratio of the combined retained allyl equivalents of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the initiator equivalents introduced into the reaction mixture will each be about 22.5:1 to about 30:1. Additionally, for example, in one such embodiment, the ratio of the combined retained allyl equivalents of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the initiator equivalents introduced into the reaction mixture will be about 25:1 to about 27.5:1, respectively.

[0239] Experience to date has also shown that the combined amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt relative to the amount of water in the reaction mixture affects the characteristics of the resulting polymer. Accordingly, typically, the weight ratio of the combined amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the amount of water in the reaction mixture will be in the range of about 0.01 to about 3, respectively. For example, in one embodiment, the weight ratio of the combined amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the amount of water in the reaction mixture will be in the range of about 0.05 to about 2.75, respectively. Additionally, for example, in one embodiment, the weight ratio of the combined amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the amount of water in the reaction mixture will each be in the range of about 0.07 to about 2.5. Additionally, for example, in one embodiment, the weight ratio of the combined amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the amount of water in the reaction mixture will each be in the range of about 0.1 to about 2.25. Additionally, for example, in one embodiment, the weight ratio of the combined amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the amount of water in the reaction mixture will each be in the range of about 0.15 to about 2. Additionally, for example, in one embodiment, the weight ratio of the combined amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the amount of water in the reaction mixture will each be in the range of about 0.2 to about 1.75. Additionally, for example, in one embodiment, the weight ratio of the combined amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the amount of water in the reaction mixture will each be in the range of about 0.25 to about 1.5.Additionally, for example, in one embodiment, the weight ratio of the combined amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the amount of water in the reaction mixture will each be in the range of about 0.25 to about 1.25. Additionally, for example, in one embodiment, the weight ratio of the combined amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the amount of water in the reaction mixture will each be in the range of about 0.3 to about 1. Additionally, for example, in one embodiment, the weight ratio of the combined amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the amount of water in the reaction mixture will each be in the range of about 0.35 to about 0.75. Additionally, for example, in one of these embodiments, the weight ratio of the combined amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in the reaction mixture to the amount of water will each be in the range of about 0.4 to about 0.5. In each of these exemplary embodiments of this paragraph, the 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt species are assumed to exist in their respective free amine forms for the purpose of calculating the weight ratio.

[0240] Experience to date has also shown that the ratio of allyl equivalents to water equivalents in a reaction mixture affects the properties of the polymer produced. Accordingly, typically, the ratio of the combined retained allyl equivalents of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the water equivalents introduced into the reaction mixture will be in the range of about 0.01:1 to about 1:1, respectively. For example, in one such embodiment, the ratio of the combined retained allyl equivalents of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the water equivalents introduced into the reaction mixture will be about 0.015:1 to about 0.75:1, respectively. Additionally, for example, in one embodiment, the ratio of the combined retained allyl equivalents of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the water equivalents introduced into the reaction mixture will each be about 0.02:1 to about 0.5:1. Additionally, for example, in one embodiment, the ratio of the combined retained allyl equivalents of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the water equivalents introduced into the reaction mixture will each be about 0.03:1 to about 0.4:1. Additionally, for example, in one embodiment, the ratio of the combined retained allyl equivalents of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the water equivalents introduced into the reaction mixture will each be about 0.04:1 to about 0.3:1. Additionally, for example, in one such embodiment, the ratio of the combined retained allyl equivalents of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the water equivalents introduced into the reaction mixture will each be about 0.05:1 to about 0.25:1.Additionally, for example, in one embodiment, the ratio of the combined retained allyl equivalents of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the water equivalents introduced into the reaction mixture will each be about 0.06:1 to about 0.2:1. Additionally, for example, in one embodiment, the ratio of the combined retained allyl equivalents of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the water equivalents introduced into the reaction mixture will each be about 0.07:1 to about 0.175:1. Additionally, for example, in one embodiment, the ratio of the combined retained allyl equivalents of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the water equivalents introduced into the reaction mixture will each be about 0.08:1 to about 0.15:1.

[0241] To produce polymer beads rather than gels, the reaction mixture for the polymerization and crosslinking co-steps is preferably a heterogeneous reaction mixture comprising a surfactant, water, and an organic solvent system (in addition to 2-propene-1-ylamine or its salt, 1,3-bis(allylamino)propane or its salt, acid, and initiator). Advantageously, the heterogeneous polymerization method produces polymer particles in the form of substantially spherical beads, the diameter of which can be controlled to a range of 3 to 1000 micrometers, preferably 10 to 500 micrometers, and in some embodiments, 40 to 180 micrometers.

[0242] Generally, surfactants included in the reaction mixture for the polymerization and crosslinking co-steps may be ionic or non-ionic. Exemplary surfactants include sorbitan monolaurate, sorbitan monooleate, sorbitan monostearate, sorbitan monopalmitate, ethylene glycol monostearate, glyceryl monostearate, polyethylene glycol monostearate, polyethylene glycol hydrogenated castor oil, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polyethylene glycol and diisooctyl sulfosuccinate, branched dodecylbenzenesulfonic acid, linear dodecylbenzenesulfonic acid, sodium branched alkylbenzenesulfonate, sodium branched dodecylbenzenesulfonate, sodium alpha-olefin sulfonate, sodium linear alkylbenzenesulfonate, isopropylamine branched alkylbenzenesulfonate, and sodium lauryl sulfate. For example, the surfactant is branched dodecylbenzenesulfonic acid.

[0243] The organic solvent system included in the polymerization and crosslinking co-step reaction mixture may be any broad range of water-immiscible organic solvents that can be used to disperse the aqueous phase. Exemplary organic solvent systems may include hexane, cyclohexane, heptane, octane, decane, petroleum ether, liquid paraffin, chlorobenzene, toluene, xylene, ethyl acetate, propyl acetate, and isopropyl acetate, or combinations of two or more thereof. For example, the organic solvent system may include heptane.

[0244] The polymerization and crosslinking co-step reaction mixture contains any wide range of acids. For example, in one embodiment, the polymerization and crosslinking co-step reaction mixture contains an inorganic acid or an organic acid. Exemplary inorganic acids include hydrochloric acid, sulfuric acid, and phosphoric acid. Exemplary organic acids include formic acid, acetic acid, and citric acid. In one embodiment, the polymerization and crosslinking co-step reaction mixture contains an acid selected from the group consisting of hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, methyl phosphoric acid, formic acid, citric acid, and combinations thereof. In one embodiment, the polymerization and crosslinking co-step reaction mixture contains an acid selected from the group consisting of hydrochloric acid, phosphoric acid, sulfuric acid, and combinations thereof. In one embodiment, the polymerization and crosslinking co-step reaction mixture contains hydrochloric acid. Generally, the polymerization and crosslinking co-step reaction mixture contains at least 0.4 equivalents of acid per allylamine equivalent. For example, in one embodiment, the polymerization and crosslinking co-step reaction mixture contains at least 0.6 equivalents of acid per allylamine equivalent. Additionally, for example, in this one embodiment, the reaction mixture for the polymerization and crosslinking co-reaction step comprises at least 0.8 equivalents of acid per allylamine equivalent. Additionally, for example, in this one embodiment, the reaction mixture for the polymerization and crosslinking co-reaction step comprises at least 0.9 equivalents of acid per allylamine equivalent. Additionally, for example, in this one embodiment, the reaction mixture for the polymerization and crosslinking co-reaction step comprises at least 0.95 equivalents of acid per allylamine equivalent. Additionally, for example, in this one embodiment, the reaction mixture for the polymerization and crosslinking co-reaction step comprises at least 1.0 equivalents of acid per allylamine equivalent. Additionally, for example, in this one embodiment, the reaction mixture for the polymerization and crosslinking co-reaction step comprises at least 1 equivalent of acid per allylamine equivalent.

[0245] In each of the above embodiments, the acid may be introduced into the polymerization and crosslinking co-reaction step reaction mixture independently of the addition of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the first step reaction mixture. Alternatively, in each of the above embodiments, the acid may be introduced into the polymerization and crosslinking co-reaction step reaction mixture as a component of the acid salt of 2-propene-1-ylamine or its salt, 1,3-bis(allylamino)propane or its salt, or both of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt.

[0246] The polymerization and crosslinking co-reaction step may be carried out at a temperature in the range of about 25°C to about 85°C. Typically, the polymerization and crosslinking co-reaction step will be carried out at a temperature in the range of about 30°C to about 85°C. In some embodiments, the polymerization and crosslinking co-reaction step will be carried out at a temperature in the range of about 35°C to about 85°C. In some embodiments, the polymerization and crosslinking co-reaction step will be carried out at a temperature in the range of about 40°C to about 85°C. In some embodiments, the polymerization and crosslinking co-reaction step will be carried out at a temperature in the range of about 45°C to about 85°C. In some embodiments, the polymerization and crosslinking co-reaction step will be carried out at a temperature of about 60-80°C. Generally, the temperature may be maintained relatively constant throughout the reaction process or may be increased or decreased in a continuous or stepwise manner.

[0247] The polymerization and crosslinking co-reaction step may be carried out for a reaction time of at least about 2 hours. Typically, the polymerization and crosslinking co-reaction step will be carried out for a reaction time of at least about 5 hours. In some embodiments, the polymerization and crosslinking co-reaction step will be carried out for a reaction time of at least about 10 hours. In some embodiments, the polymerization and crosslinking co-reaction step will be carried out for a reaction time of at least about 15 hours. In some embodiments, the polymerization and crosslinking co-reaction step will be carried out for a reaction time of at least about 20 hours. In some embodiments, the polymerization and crosslinking co-reaction step will be carried out for a reaction time of at least about 25 hours. In some embodiments, the polymerization and crosslinking co-reaction step will be carried out for a reaction time of at least about 30 hours. In some embodiments, the polymerization and crosslinking co-reaction step will be carried out for a reaction time of at least about 35 hours. In some embodiments, the polymerization and crosslinking co-reaction step will be carried out for a reaction time of at least about 40 hours. However, typically, the polymerization and crosslinking co-reaction step will be carried out for a reaction time of about 50 hours or less.

[0248] The aqueous solid content (ASC) of the polymerization and crosslinking co-reaction step may be about 20 to about 60 wt%. In some embodiments, the aqueous solid content is about 30 to about 50 wt%. In some embodiments, the aqueous solid content is about 30 to about 45 wt%. In some embodiments, the aqueous solid content is about 43 wt%.

[0249] Generally, the polymerization and crosslinking co-reaction steps may include homopolymerization reactions, stepwise addition of individual starting materials through a series of reactions, stepwise addition of monomer blocks, or a combination thereof. The reaction may be carried out as a batch, semi-batch, or continuous process.

[0250] In one embodiment, the polymerization and crosslinking co-steps produce pre-formed poly(allylamine) polymer beads having a target species binding capacity and a target swelling ratio. For example, in this embodiment, the beads have a chloride binding capacity of at least 10 mmol / g in artificial gastric fluid ("SGF") and a swelling ratio in the range of 1 to 10. In one embodiment, the pre-formed poly(allylamine) polymer beads are characterized by a swelling ratio of about 2 to 10, more typically about 2 to about 8, and in some embodiments about 2 to 3, about 3 to 4, or about 4 to about 6. Additionally, if the pre-formed poly(allylamine) polymer beads produced from the first polymerization step are protonated, this may reduce the amount of nitrogen-nitrogen crosslinking in the second crosslinking step. Accordingly, in certain embodiments, the pre-formed poly(allylamine) polymer is at least partially deprotonated by treatment with a base, preferably a strong base, such as a hydroxyl base. For example, in one embodiment, the base may be NaOH, KOH, NH4OH, NaHCO3, Na2CO3, K2CO3, LiOH, Li2CO3, CsOH, or other metal hydroxides. Additionally, for example, the base is NaOH. When charge is removed from the cross-linked amine polymer beads pre-formed by deprotonation, the beads will tend to disintegrate, and the 1,2-dichloroethane crosslinking agent used in the second crosslinking step may not be able to access the bonding sites on the polymer unless the disintegration of the beads is prevented. One means of preventing the disintegration of the cross-linked polymer beads is to swell the beads using a swelling agent, such as water, so that the 1,2-dichloroethane second-step crosslinking agent can access the bonding sites.

[0251] As mentioned above, the 1,3-bis(allylamino)propane or its salt monomer, which is only partially incorporated into the poly(allylamine) polymer in the first step, will introduce a pendant allyl group (i.e., at least one allyl group that is merely "hanging" on the poly(allylamine) polymer backbone chain without participating in the reaction to become a chain atom) into the poly(allylamine) polymer. Thus, at the completion of the polymerization and crosslinking co-step (i.e., the first step), sp dangling on the crosslinked poly(allylamine) polymer backbone remaining in the poly(allylamine) polymer 2 Determination of the number of allyl carbons can be used to determine the amount of partially incorporated 1,3-bis(allylamino)propane, or its salt. Generally, sp 2 It is desirable that the number of allyl carbons constitutes a low percentage of the total carbon atoms in the poly(allylamine) polymer. For example, in one embodiment, sp attached to the poly(allylamine) polymer backbone 2 The allyl carbon constitutes less than 1.1% of the total number of carbon atoms in the polymer. Additionally, for example, in one embodiment, sp attached to the poly(allylamine) polymer backbone 2 The allyl carbon constitutes less than 1.0% of the total number of carbon atoms in the polymer. Additionally, for example, in one embodiment, sp attached to the poly(allylamine) polymer backbone 2 The allyl carbon constitutes less than 0.9% of the total number of carbon atoms in the polymer. Additionally, for example, in one embodiment, sp attached to the poly(allylamine) polymer backbone 2 The allyl carbon constitutes less than 0.8% of the total number of carbon atoms in the polymer. Additionally, for example, in one embodiment, sp attached to the poly(allylamine) polymer backbone 2 The allyl carbon constitutes less than 0.75% of the total number of carbon atoms in the polymer. Additionally, for example, in one embodiment, sp attached to the poly(allylamine) polymer backbone 2The allyl carbon constitutes less than 0.7% of the total number of carbon atoms in the polymer. Additionally, for example, in one embodiment, sp attached to the poly(allylamine) polymer backbone 2 The allyl carbon constitutes less than 0.6% of the total number of carbon atoms in the polymer. Additionally, for example, in one embodiment, sp attached to the poly(allylamine) polymer backbone 2 The allyl carbon constitutes less than 0.5% of the total number of carbon atoms in the polymer. Additionally, for example, in one embodiment, sp attached to the poly(allylamine) polymer backbone 2 The allyl carbon constitutes less than 0.4% of the total number of carbon atoms in the polymer. Additionally, for example, in one embodiment, sp attached to the poly(allylamine) polymer backbone 2 The allyl carbon constitutes less than 0.3% of the total number of carbon atoms in the polymer. Additionally, for example, in one embodiment, sp attached to the poly(allylamine) polymer backbone 2 The allyl carbon constitutes less than 0.25% of the total number of carbon atoms in the polymer. Additionally, for example, in one embodiment, sp attached to the poly(allylamine) polymer backbone 2 The allyl carbon constitutes less than 0.2% of the total number of carbon atoms in the polymer. Additionally, for example, in one embodiment, sp attached to the poly(allylamine) polymer backbone 2 The allyl carbon constitutes less than 0.1% of the total number of carbon atoms in the polymer. Additionally, for example, in one embodiment, sp attached to the poly(allylamine) polymer backbone 2 The allyl carbon constitutes less than 0.05% of the total number of carbon atoms in the polymer. Additionally, for example, in one embodiment, sp attached to the poly(allylamine) polymer backbone 2 Allyl carbon is not detectable in polymer beads. Additionally, for example, in one embodiment sp suspended from a poly(allylamine) polymer backbone 2Allyl carbons may constitute more than 0.3% of the total number of carbon atoms in the polymer, but less than the upper limit indicated above, e.g., 1.0%. In each of the exemplary embodiments above, sp suspended from the poly(allylamine) polymer backbone in the beads 2 The percentage of allyl carbon is quantitative as more fully described elsewhere in this application 13 By C solid-state magic angle spinning (MAS) NMR measurement 1 H and 13 For C, measurements can be performed at a spin frequency of 16 kHz using a 4 mm zirconia rotor system on a Bruker Avance III 800 MHz (18.8T) standard aperture spectrometer operating at 800.25 MHz and 201.24 MHz, respectively. In each of the above exemplary embodiments, sp suspended on a poly(allylamine) polymer backbone within the bead 2 The percentage of allyl carbon can be determined by any method disclosed herein.

[0252] In the second crosslinking step, the pre-formed poly(allylamine) polymer is crosslinked using 1,2-dichloroethane.

[0253] Generally, sp 2 It is desirable that the number of allyl carbons constitutes a low percentage of the total carbon atoms in the crosslinked polymer after polymerization. For example, in one embodiment, sp attached to the crosslinked polymer backbone after polymerization of the crosslinked poly(allylamine) polymer 2 Allyl carbons constitute less than 1.0% of the total number of carbon atoms in the polymer. Additionally, for example, in one embodiment, sp suspended from the cross-linked polymer backbone after polymerization 2 Allyl carbons constitute less than 0.9% of the total number of carbon atoms in the polymer. Additionally, for example, in one embodiment, sp suspended from the cross-linked polymer backbone after polymerization 2Allyl carbons constitute less than 0.8% of the total number of carbon atoms in the polymer. Additionally, for example, in one embodiment, sp suspended from the cross-linked polymer backbone after polymerization 2 Allyl carbons constitute less than 0.75% of the total number of carbon atoms in the polymer. Additionally, for example, in one embodiment, sp suspended from the cross-linked polymer backbone after polymerization 2 Allyl carbons constitute less than 0.7% of the total number of carbon atoms in the polymer. Additionally, for example, in one embodiment, sp suspended from the cross-linked polymer backbone after polymerization 2 Allyl carbons constitute less than 0.6% of the total number of carbon atoms in the polymer. Additionally, for example, in one embodiment, sp suspended from the cross-linked polymer backbone after polymerization 2 Allyl carbons constitute less than 0.5% of the total number of carbon atoms in the polymer. Additionally, for example, in one embodiment, sp suspended from the cross-linked polymer backbone after polymerization 2 Allyl carbons constitute less than 0.4% of the total number of carbon atoms in the polymer. Additionally, for example, in one embodiment, sp suspended from the cross-linked polymer backbone after polymerization 2 Allyl carbons constitute less than 0.3% of the total number of carbon atoms in the polymer. Additionally, for example, in one embodiment, sp suspended from the cross-linked polymer backbone after polymerization 2 Allyl carbons constitute less than 0.25% of the total number of carbon atoms in the polymer. Additionally, for example, in one embodiment, sp suspended from the cross-linked polymer backbone after polymerization 2 Allyl carbons constitute less than 0.2% of the total number of carbon atoms in the polymer. Additionally, for example, in one embodiment, sp suspended from the cross-linked polymer backbone after polymerization 2 Allyl carbons constitute less than 0.1% of the total number of carbon atoms in the polymer. Additionally, for example, in one embodiment, sp suspended from the cross-linked polymer backbone after polymerization 2Allyl carbons constitute less than 0.05% of the total number of carbon atoms in the polymer. Additionally, for example, in one embodiment, sp suspended from the cross-linked polymer backbone after polymerization 2 Allyl carbon is not detectable in the polymer beads. In each of the above exemplary embodiments, sp is suspended from the post-polymerization cross-linked polymer backbone within the beads. 2 The percentage of allyl carbon is quantitative as more fully described elsewhere in this application 13 By C solid-state magic angle spinning (MAS) NMR measurement 1 H and 13 For C, measurements can be performed at a spin frequency of 16 kHz using a 4 mm zirconia rotor system on a Bruker Avance III 800 MHz (18.8T) standard aperture spectrometer operating at 800.25 MHz and 201.24 MHz, respectively. In each of the above exemplary embodiments, sp suspended from the post-polymerization cross-linked polymer backbone within the bead 2 The percentage of allyl carbon can be determined by any method disclosed herein.

[0254] The resulting post-polymerization cross-linked polymer is sp in the pre-formed poly(allylamine) polymer 2 sp for carbon 3 sp greater than the ratio of carbon 2 sp for carbon 3 It will have a carbon ratio. Therefore, the second crosslinking reaction with 1,2-dichloroethane will have sp compared to the pre-formed poly(allylamine) polymer. 2 sp in the cross-linked polymer after polymerization while the amount of carbon remains unchanged 3 The amount of carbon will be increased. For example, in a specific embodiment in which a pre-formed poly(allylamine) polymer is significantly crosslinked in the second crosslinking step, sp 3 The incremental increase in carbon is sp 2It may be sufficient to reduce measurement sensitivity by lowering the signal-to-noise ratio for carbon. Therefore, in certain embodiments, sp in the cross-linked polymer after polymerization produced 2 Carbon and sp 3 Rather than directly measuring the amount of carbon by NMR, sp² in the pre-formed poly(allylamine) polymer 2 Measure the amount of carbon and the sp added to the polymer during the second crosslinking step. 3 Carbon (and sp if present) 2 Determine the amount of carbon, and then in the resulting post-polymerization crosslinked polymer, sp 2 and sp 3 It may be advantageous to calculate the relative proportion of carbon. For both the pre-formed poly(allylamine) polymer and the corresponding cross-linked poly(allylamine) polymer, sp 2 Examples of experimentally determined carbon % are presented in Tables 10 and 11. In pre-formed cross-linked poly(allylamine) polymers, sp 2 In the case of examples where carbon can be quantified, sp of the cross-linked poly(allylamine) polymer for the corresponding pre-formed poly(allylamine) polymer 2 The average ratio of the percentage of carbon was approximately 0.9. The above factor is sp, including specific examples of cross-linked poly(allylamine) polymers in Table 11. 2 To calculate the % of carbon, Table 11 was applied where applicable throughout Part 2.

[0255] In the example, the crosslinking agent for the step 2 crosslinking reaction is 1,2-dichloroethane (see Table B).

[0256] Table B

[0257]

[0258] In one embodiment, the pre-formed poly(allylamine) polymer formed in the polymerization and crosslinking co-reaction is further crosslinked in a reaction mixture comprising 1,2-dichloroethane, a swelling agent for the pre-formed poly(allylamine) polymer, and a dispersion solvent system in a second crosslinking step. The dispersion solvent system contains an amount of solvent sufficient to disperse the pre-formed poly(allylamine) polymer in the reaction mixture to avoid crosslinking reactions between polymer particles (i.e., between beads) and the formation of aggregation. In this embodiment, for example, the ratio of the solvent contained in the dispersion solvent system in the reaction mixture to the pre-formed poly(allylamine) polymer is at least 2:1 (milliliters of solvent : grams of pre-formed poly(allylamine) polymer). Additionally, for example, in this embodiment, the ratio of the solvent contained in the dispersion solvent system in the reaction mixture to the pre-formed poly(allylamine) polymer is at least 3:1 (milliliters of solvent : grams of pre-formed poly(allylamine) polymer). Additionally, for example, in one embodiment, the ratio of the solvent to the pre-formed poly(allylamine) polymer contained in the dispersion solvent system of the reaction mixture is at least 4:1 (milliliters of solvent : grams of pre-formed poly(allylamine) polymer). Additionally, for example, in one embodiment, the ratio of the solvent to the pre-formed poly(allylamine) polymer contained in the dispersion solvent system of the reaction mixture is at least 5:1 (milliliters of solvent : grams of pre-formed poly(allylamine) polymer). Additionally, for example, in one embodiment, the ratio of the solvent to the pre-formed poly(allylamine) polymer contained in the dispersion solvent system of the reaction mixture is at least 7.5:1 (milliliters of solvent : grams of pre-formed poly(allylamine) polymer). Additionally, for example, in one embodiment, the ratio of the solvent to the pre-formed poly(allylamine) polymer contained in the dispersion solvent system of the reaction mixture is at least 10:1 (milliliters of solvent : grams of pre-formed poly(allylamine) polymer).Additionally, for example, in one embodiment, the ratio of the solvent contained in the dispersion solvent system in the reaction mixture to the pre-formed poly(allylamine) polymer is at least 20:1 (milliliters of solvent : grams of pre-formed poly(allylamine) polymer). In each of the above embodiments, the dispersion solvent system may comprise a combination of (i) an inert solvent (for the pre-formed poly(allylamine) polymer), such as one of the non-polar solvents previously identified in relation to organic solvent systems in the first crosslinking step in which the pre-formed poly(allylamine) polymer is formed, and (ii) 1,2-dichloroethane (DCE) as a crosslinking solvent. Alternatively, in each of the above embodiments, the dispersion solvent system may comprise 1,2-dichloroethane (DCE) exclusively without including an inert solvent as a solvent, thus serving a dual-purpose role as both a solvent (dispersant) and a crosslinking agent. In additional alternatives, in each of the above embodiments, the dispersion solvent system may exclusively contain pure 1,2-dichloroethane (DCE) without including an inert solvent as a solvent, and thus perform a dual-purpose role as both a solvent (dispersant) and a crosslinking agent.

[0259] As mentioned above, in certain embodiments, a swelling agent for the pre-formed poly(allylamine) polymer is included in the second crosslinking step reaction mixture, i.e., together with 1,2-dichloroethane. Generally, the swelling agent and 1,2-dichloroethane may be miscible or inmiscible, and the swelling agent may be any composition or combination of compositions having the ability to swell the pre-formed poly(allylamine) polymer. Exemplary swelling agents include polar solvents, such as water, methanol, ethanol, n-propanol, isopropanol, n-butanol, formic acid, acetic acid, acetonitrile, dimethylformamide, dimethyl sulfoxide, nitromethane, propylene carbonate, or combinations thereof. For example, the swelling agent is water. Additionally, the amount of swelling agent included in the second crosslinking step reaction mixture will typically be less than the absorption capacity of the pre-formed poly(allylamine) polymer for the swelling agent. For example, it is generally preferable that the weight ratio of the swelling agent to the pre-formed polymer in the second crosslinking step reaction mixture is less than 4:1. Additionally, for example, in some embodiments, the weight ratio of the swelling agent to the pre-formed polymer in the second crosslinking step reaction mixture will be less than 3:1. Additionally, for example, in some embodiments, the weight ratio of the swelling agent to the pre-formed polymer in the second crosslinking step reaction mixture will be less than 2:1. Additionally, for example, in some embodiments, the weight ratio of the swelling agent to the pre-formed polymer in the second crosslinking step reaction mixture will be less than 1:1. Additionally, for example, in some embodiments, the weight ratio of the swelling agent to the pre-formed polymer in the second crosslinking step reaction mixture will be less than 0.5:1. Additionally, for example, in some embodiments, the weight ratio of the swelling agent to the pre-formed polymer in the second crosslinking step reaction mixture will be less than 0.4:1. Additionally, for example, in some embodiments, the weight ratio of the swelling agent to the pre-formed polymer in the reaction mixture will be less than 0.3:1.However, generally, the weight ratio of the swelling agent to the pre-formed polymer in the second crosslinking step reaction mixture will typically be at least 0.05:1 each.

[0260] The second crosslinking step may be performed at a temperature in the range of about 25°C to about 85°C. Typically, the second crosslinking step will be performed at a temperature in the range of about 35°C to about 80°C. In some embodiments, the second crosslinking step will be performed at a temperature in the range of about 45°C to about 80°C. In some embodiments, the second crosslinking step will be performed at a temperature in the range of about 55°C to about 75°C. In some embodiments, the second crosslinking step will be performed at a temperature in the range of about 60°C to about 75°C. In some embodiments, the second crosslinking step will be performed at a temperature in the range of about 65°C to about 75°C. Generally, the temperature may be maintained relatively constant throughout the process of the second crosslinking step, or it may be increased or decreased in a continuous or stepwise manner.

[0261] The second crosslinking step may be performed for about 2 to 20 hours. Typically, the second crosslinking step will be performed for about 4 to 20 hours. In some embodiments, the second crosslinking step will be performed for about 5 to 20 hours. In some embodiments, the second crosslinking step will be performed for about 6 to 20 hours. In some embodiments, the second crosslinking step will be performed for about 8 to 20 hours. In some embodiments, the second crosslinking step will be performed for about 10 to 20 hours. In some embodiments, the second crosslinking step will be performed for about 12 to 18 hours. In some embodiments, the second crosslinking step will be performed for about 14 to 18 hours. In some embodiments, the second crosslinking step will be performed for about 15 to 17 hours.

[0262] In one embodiment, the resulting pre-formed poly(allylamine) polymer is at least partially deprotonated with a base and combined with a non-protonating swelling agent to swell the free amine polymer without protonating the amine functional groups prior to the second crosslinking step. Thus, for example, the amount of the non-protonating swelling agent can be selected to effectively form a template by adjusting the subsequent degree of crosslinking, and then fix it in place through an amine-consuming crosslinking step.

[0263] The advantage of the pre-formed polymer beads deprotonated in the second crosslinking step highlights the advantage of achieving the final product using two steps. In the first crosslinking step, to form amine polymer beads, all monomers (i.e., 2-propene-1-ylamine, or its salt, and 1,3-bis(allylamino)propane, or its salt) are protonated and left in the aqueous phase, avoiding radical transfer reactions of non-protonated allylamines (and derivatives) that severely limit polymerization. Once beads are formed through carbon-carbon crosslinking, the beads can then be deprotonated and further crosslinked with 1,2-dichloroethane in the second crosslinking step.

[0264] In one embodiment, selectivity for chloride relative to other competing ions is achieved with a highly cross-linked amine polymer. For example, a relatively high chloride binding ability can be achieved by reacting pre-formed poly(allylamine) polymer beads with pure 1,2-dichloroethane in the presence of a swelling agent (water). While this "non-dispersed" reaction provides access to high selectivity for chloride relative to competing ions in SIB assays, it also produces aggregated polymer beads visible to the naked eye (and under a microscope). Therefore, it is advantageous to include a solvent (e.g., heptane) in the second cross-linking step to disperse the pre-formed cross-linked polymer beads, thereby avoiding inter-bead reactions and the formation of aggregation. However, the use of too much solvent (dispersant) can dilute the reaction solution to a point where the resulting beads are not sufficiently cross-linked to achieve the desired selectivity for chloride relative to other competing anions. However, by using a crosslinking agent (i.e., 1,2-dichloroethane) that also functions as a solvent (dispersant), sufficient solvent (dispersant) can be included in the reaction mixture to avoid inter-bead reactions and aggregation without diluting the mixture to the point where the degree of amine-consumption crosslinking is insufficient. For example, in an effort to utilize the dispersion properties of the solvent (to avoid aggregation during the reaction) while maintaining reactivity, 1,2-dichloroethane (DCE) was used in its pure form to serve a dual purpose as both a solvent (dispersant) and a crosslinking agent. Interestingly, compared to similar reactions with DCP and / or heptane, DCE was found to possess excellent dispersion properties as a solvent. Additionally, less aggregation was observed when the beads were first dispersed in DCE and then water was added as a second step to swell the beads. Aggregation may occur when water is added to the pre-formed poly(allylamine) polymer before the beads are dispersed in DCE.

[0265] In each of the above embodiments, the reaction mixture for the second crosslinking step may contain a wide amount of 1,2-dichloroethane. For example, in one embodiment, 1,2-dichloroethane may be used in a very excess amount relative to the amount of the pre-formed poly(allylamine) polymer in the reaction mixture. In other words, in this embodiment, 1,2-dichloroethane is a crosslinking solvent, that is, it is both a solvent for the reaction mixture and a crosslinking agent for the pre-formed poly(allylamine) polymer. In this embodiment, other solvents may optionally be included in the dispersion solvent system of the second crosslinking step reaction mixture, but are not necessarily required. Alternatively, the pre-formed poly(allylamine) polymer, the swelling agent, and 1,2-dichloroethane may be dispersed in a dispersion solvent system that is miscible with 1,2-dichloroethane and immiscible with the swelling agent. For example, in some embodiments, the swelling agent may be a polar solvent; In some of these embodiments, for example, the swelling agent may comprise water, methanol, ethanol, n-propanol, isopropanol, formic acid, acetic acid, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, nitromethane, or a combination thereof. As a further example, if the swelling agent comprises a polar solvent, the dispersion solvent system for the second crosslinking step will typically comprise a non-polar solvent, such as pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, chloroform, diethyl ether, dichloromethane, dichloroethane, dichloropropane, dichlorobutane, or a combination thereof. In certain embodiments, 1,2-dichloroethane and the solvent included in the dispersion solvent system may be the same.

[0266] It is noteworthy that in crosslinking solvents (e.g., DCE-dispersed reactions), a very excess amount of crosslinking agent is present regardless of the amount of crosslinking solvent (e.g., 1,2-dichloroethane (DCE)) used to disperse the beads (e.g., in both 1 g:3 mL::beads:DCE and 1 g:10 mL::beads:DCE, the crosslinking agent is very excess, most of which is not consumed during the reaction). Nevertheless, the relative degree of crosslinking, and the chloride capacity and performance in SIB assays, are relatively unaffected by changes in the ratio of reactive crosslinking agent to polymer beads. This is possible because the reaction is limited by the acid-neutralizing ability of the polymer beads rather than the amount of crosslinking agent (e.g., DCE).

[0267] To react more efficiently with 1,2-dichloroethane (DCE), the amines in the pre-formed polymer beads preferably have free electron pairs (neutral, deprotonated). As the free amines in the pre-formed polymer beads react with 1,2-dichloroethane (DCE), HCl is produced and the amines are protonated, which limits the reaction. For this reason, the pre-formed poly(allylamine) polymer beads preferably start as free amines in the second crosslinking step. If the pre-formed poly(allylamine) polymer beads are protonated after the first step of carbon-carbon crosslinking, the amine-consumed crosslinking in the second crosslinking step will be limited, and thus the desired selectivity for chloride will be reduced compared to other competing ions. This has been demonstrated by adding a known amount of HCl to the pre-formed poly(allylamine) polymer beads immediately before crosslinking with DCE in the second crosslinking step. When less than 3 mol% of HCl is added (with respect to the amine in the pre-formed polymer amine beads) before crosslinking in the second crosslinking step, the total chloride capacity (SGF) and chloride selectivity in the SIB are similar to the beads not treated with HCl in the second crosslinking step. When more than 5 mol% of HCl is added (with respect to the amine in the pre-formed polymer amine beads) before crosslinking in the second crosslinking step, the total chloride capacity (SGF) increases and the chloride selectivity in the SIB decreases, which indicates a lower incorporation of 1,2-dichloroethane.

[0268] The use of 1,2-dichloroethane ("DCE") as a crosslinking solvent also generates HCl molecules during the second crosslinking step. These HCl molecules protonate some of the free amine sites, which blocks reaction sites for the crosslinking reaction and limits the number of binding sites available for crosslinking. Consequently, the use of DCE creates a self-limiting effect on secondary crosslinking.

[0269] When considering an excess of 1,2-dichloroethane as a dual crosslinking agent / solvent, the single incorporation of 1,2-dichloroethane can induce alkyl chloride functional groups on crosslinked polymer beads that are effectively hydrophobic and can increase non-specific interactions with undesirable solutes other than HCl, which is effectively more hydrophobic. Washing with an ammonium hydroxide solution minimizes non-specific interactions with undesirable solutes and converts the alkyl chlorides into hydrophilic alkyl amine functional groups. Other modifications that produce groups more hydrophilic than alkyl chlorides, such as crosslinking agents / solvents with single -OH incorporation, are suitable for quenching.

[0270] As mentioned above, in certain embodiments, a swelling agent for a pre-formed poly(allylamine) polymer may be included in the second crosslinking step reaction mixture for a second crosslinking step together with 1,2-dichloroethane. Generally, the swelling agent and 1,2-dichloroethane may be miscible or inmiscible, and the swelling agent may be any composition or combination of compositions having the ability to swell the pre-formed poly(allylamine) polymer. Exemplary swelling agents include polar solvents, such as water, methanol, ethanol, n-propanol, isopropanol, n-butanol, formic acid, acetic acid, acetonitrile, dimethylformamide, dimethyl sulfoxide, nitromethane, propylene carbonate, or combinations thereof. For example, the swelling agent is water. Additionally, the amount of swelling agent included in the second crosslinking step reaction mixture will typically be less than the absorption capacity of the pre-formed poly(allylamine) polymer relative to the swelling agent. For example, it is generally preferable that the weight ratio of the swelling agent to the pre-formed polymer in the second crosslinking step reaction mixture is less than 4:1. Additionally, for example, in some embodiments, the weight ratio of the swelling agent to the pre-formed polymer in the second crosslinking step reaction mixture will be less than 3:1. Additionally, for example, in some embodiments, the weight ratio of the swelling agent to the pre-formed polymer in the second crosslinking step reaction mixture will be less than 2:1. Additionally, for example, in some embodiments, the weight ratio of the swelling agent to the pre-formed polymer in the second crosslinking step reaction mixture will be less than 1:1. Additionally, for example, in some embodiments, the weight ratio of the swelling agent to the pre-formed polymer in the second crosslinking step reaction mixture will be less than 0.5:1. Additionally, for example, in some embodiments, the weight ratio of the swelling agent to the pre-formed polymer in the second crosslinking step reaction mixture will be less than 0.4:1. Additionally, for example, in some embodiments, the weight ratio of the swelling agent to the pre-formed polymer in the second crosslinking step reaction mixture will be less than 0.3:1.However, generally, the weight ratio of the swelling agent to the pre-formed polymer in the second crosslinking step reaction mixture will typically be at least 0.05:1 each.

[0271] If the swelling agent contains water, the weight ratio of water to the pre-formed poly(allylamine) polymer in the second crosslinking step reaction mixture will typically be less than about 4:1 (water to polymer). For example, in one embodiment, the second crosslinking step reaction mixture contains water as a swelling agent, and the weight ratio of water to the pre-formed poly(allylamine) polymer in the second crosslinking step reaction mixture will typically be less than about 3.5:1. Additionally, for example, in one embodiment, the second crosslinking step reaction mixture contains water as a swelling agent, and the weight ratio of water to the pre-formed poly(allylamine) polymer in the second crosslinking step reaction mixture will typically be less than about 3:1. Additionally, for example, in one embodiment, the second crosslinking step reaction mixture contains water as a swelling agent, and the weight ratio of water to the pre-formed poly(allylamine) polymer in the second crosslinking step reaction mixture will typically be less than about 2.5:1. Additionally, for example, in one embodiment, the second crosslinking step reaction mixture comprises water as a swelling agent, and the weight ratio of water to the pre-formed poly(allylamine) polymer in the second crosslinking step reaction mixture will typically be less than about 2:1. Additionally, for example, in one embodiment, the second crosslinking step reaction mixture comprises water as a swelling agent, and the weight ratio of water to the pre-formed poly(allylamine) polymer in the second crosslinking step reaction mixture will typically be less than about 1.5:1. Additionally, for example, in one embodiment, the second crosslinking step reaction mixture comprises water as a swelling agent, and the weight ratio of water to the pre-formed poly(allylamine) polymer in the second crosslinking step reaction mixture will typically be less than about 1:1. Additionally, for example, in one embodiment, the second crosslinking step reaction mixture comprises water as a swelling agent, and the weight ratio of water to the pre-formed poly(allylamine) polymer in the second crosslinking step reaction mixture will typically be less than about 0.75:1.Additionally, for example, in one embodiment, the second crosslinking step reaction mixture comprises water as a swelling agent, and the weight ratio of water to the pre-formed poly(allylamine) polymer in the second crosslinking step reaction mixture will typically be less than about 0.5:1. Additionally, for example, in one embodiment, the second crosslinking step reaction mixture comprises water as a swelling agent, and the weight ratio of water to the pre-formed poly(allylamine) polymer in the second crosslinking step reaction mixture will typically be less than about 0.25:1. However, generally, when water is used as a swelling agent, the weight ratio of water to the pre-formed poly(allylamine) polymer in the second crosslinking step reaction mixture will typically be at least about 0.15:1 (water to polymer), but will be less than the water absorption capacity of the pre-formed poly(allylamine) polymer. Additionally, for example, in one embodiment, the weight ratio of water to the pre-formed poly(allylamine) polymer in the second crosslinking step reaction mixture is typically at least about 0.2:1, but will be less than the water absorption capacity of the pre-formed poly(allylamine) polymer. Additionally, for example, in one embodiment, the weight ratio of water to the pre-formed poly(allylamine) polymer in the second crosslinking step reaction mixture is typically at least about 0.25:1, but will be less than the water absorption capacity of the pre-formed poly(allylamine) polymer. Additionally, for example, in one embodiment, the weight ratio of water to the pre-formed poly(allylamine) polymer in the second crosslinking step reaction mixture is typically at least about 0.5:1, but will be less than the water absorption capacity of the pre-formed poly(allylamine) polymer. Additionally, for example, in one embodiment, the weight ratio of water to the pre-formed poly(allylamine) polymer in the second crosslinking step reaction mixture is typically at least about 0.75:1, but will be less than the water absorption capacity of the pre-formed poly(allylamine) polymer.Additionally, for example, in one embodiment, the weight ratio of water to the pre-formed poly(allylamine) polymer in the second crosslinking step reaction mixture is typically at least about 1:1, but will be less than the water absorption capacity of the pre-formed poly(allylamine) polymer. Additionally, for example, in one embodiment, the weight ratio of water to the pre-formed poly(allylamine) polymer in the second crosslinking step reaction mixture is typically at least about 1.5:1, but will be less than the water absorption capacity of the pre-formed poly(allylamine) polymer. Additionally, for example, in one embodiment, the weight ratio of water to the pre-formed poly(allylamine) polymer in the second crosslinking step reaction mixture is typically at least about 2:1, but will be less than the water absorption capacity of the pre-formed poly(allylamine) polymer. Additionally, for example, in one embodiment, the weight ratio of water to the pre-formed poly(allylamine) polymer in the second crosslinking step reaction mixture is typically at least about 2.5:1, but will be less than the water absorption capacity of the pre-formed poly(allylamine) polymer. Additionally, for example, in one embodiment, the weight ratio of water to the pre-formed poly(allylamine) polymer in the second crosslinking step reaction mixture is typically at least about 3:1, but will be less than the water absorption capacity of the pre-formed poly(allylamine) polymer. Additionally, for example, in one embodiment, the weight ratio of water to the pre-formed poly(allylamine) polymer in the second crosslinking step reaction mixture is typically at least about 3.5:1, but will be less than the water absorption capacity of the pre-formed poly(allylamine) polymer. Accordingly, in certain embodiments, the weight ratio of water to the pre-formed poly(allylamine) polymer will be in the range of about 0.15:1 to about 4:1. Additionally, for example, in certain embodiments, the weight ratio of water to the pre-formed poly(allylamine) polymer will be in the range of about 0.2:1 to about 3.5:1. Additionally, for example, in certain embodiments, the weight ratio of water to the pre-formed poly(allylamine) polymer will be in the range of about 0.2:1 to about 3:1.

[0272] The second crosslinking step reaction mixture may contain a wide range of amounts of 1,2-dichloroethane. For example, in one embodiment, 1,2-dichloroethane may be used in a very excess amount relative to the amount of the pre-formed poly(allylamine) polymer in the second crosslinking step reaction mixture. In other words, in this embodiment, 1,2-dichloroethane is a crosslinking solvent, that is, it is both a solvent for the second crosslinking step reaction mixture and a crosslinking agent for the pre-formed poly(allylamine) polymer. In this embodiment, other solvents may optionally be included in the second crosslinking step reaction mixture, but are not necessarily required. Alternatively, the pre-formed poly(allylamine) polymer, the swelling agent, and 1,2-dichloroethane may be dispersed in a solvent that is miscible with 1,2-dichloroethane but immiscible with the swelling agent. For example, in some embodiments, the swelling agent may be a polar solvent; In some of these embodiments, for example, the swelling agent may comprise water, methanol, ethanol, n-propanol, isopropanol, formic acid, acetic acid, acetonitrile, dimethylformamide, dimethyl sulfoxide, nitromethane, or a combination thereof. As a further example, if the swelling agent comprises a polar solvent, the solvent system for the second crosslinking step reaction mixture will typically comprise a non-polar solvent, such as pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, chloroform, diethyl ether, dichloromethane, dichloroethane, dichloropropane, dichlorobutane, or a combination thereof. In certain embodiments, the crosslinking agent and the solvent may be the same; that is, the solvent is 1,2-dichloroethane.

[0273] In embodiments where the second crosslinking step reaction mixture comprises a swelling agent, it is sometimes preferable to combine the pre-formed poly(allylamine) polymer with a solvent (sometimes alternatively referred to as a dispersant) before the pre-formed poly(allylamine) polymer is combined with the swelling agent in the second crosslinking step reaction mixture. In certain embodiments, the resulting crosslinked polymer tends to aggregate less when the pre-formed poly(allylamine) polymer is combined with a solvent (dispersant) that is immiscible with the swelling agent before the pre-formed poly(allylamine) polymer is combined with the swelling agent. Accordingly, in certain embodiments, less than 25% of the particles in a representative sample of a population of crosslinked amine particles after polymerization aggregate into aggregates. For example, in some embodiments, less than 20% of the particles in a representative sample of a population of crosslinked amine particles after polymerization aggregate into aggregates. Additionally, for example, in some embodiments, less than 15% of the particles in a representative sample of a population of crosslinked amine particles after polymerization aggregate into aggregates. Additionally, for example, in some embodiments, less than 10% of the particles in a representative sample of a group of cross-linked amine particles after polymerization aggregate into aggregates. Additionally, for example, in some embodiments, less than 5% of the particles in a representative sample of a group of cross-linked amine particles after polymerization aggregate into aggregates. Additionally, for example, in some embodiments, less than 1% of the particles in a representative sample of a group of cross-linked amine particles after polymerization aggregate into aggregates. Aggregation can be evaluated using a microscope or other means of measuring particle size distribution. The absence of aggregation may be defined as generally separated free-flowing beads lacking macroscopic and / or microscopic clumps. The particle size distribution (as defined elsewhere) may indicate that aggregation has occurred, for example, if the average size (d(50)) and / or d(90) of the cross-linked poly(allylamine) polymer after the cross-linking step increases compared to the pre-formed poly(allylamine) polymer beads as previously described.

[0274] In one embodiment, a pre-formed poly(allylamine) polymer is formed in a first step, and the pre-formed poly(allylamine) polymer is further crosslinked in a second crosslinking step without isolating the pre-formed poly(allylamine) polymer between the first and second crosslinking steps (sometimes referred to as "one-pot synthesis"). For example, in this embodiment, the pre-formed poly(allylamine) polymer is formed in a first-step reaction mixture (as previously described herein), and without isolating the pre-formed poly(allylamine) polymer formed in the first-step reaction mixture, the pre-formed poly(allylamine) polymer is subsequently crosslinked using 1,2-dichloroethane. Additionally, for example, in this embodiment, the pre-formed polymer may be dispersed in any non-polar solvent disclosed herein (e.g., including 1,2-dichloroethane as a crosslinking solvent) to form a second crosslinking step reaction mixture, and a swelling agent is added to this reaction mixture. In one exemplary embodiment, the crosslinking agent and solvent are 1,2-dichloroethane, and the swelling agent comprises water. In each of the above embodiments, the pre-formed polymer is an amine-containing polymer containing residues of 2-propene-1-ilamine or its salt, and 1,3-bis(allylamino)propane or its salt.

[0275] In one exemplary embodiment, a pre-formed polyamine polymer is crosslinked, for example, under suspension conditions to produce particles of targeted particle size and morphology. When a water-immiscible crosslinking agent (e.g., 1,2-dichloroethane (DCE)) is used as a dispersant, high chloride binding selectivity is achieved, for example, as demonstrated in SIB.

[0276] In one embodiment, the amine polymer is formed and then further crosslinked in the same reaction flask and in a single reaction series. The crosslinked amine polymer can be prepared, for example, under suspension conditions to produce particles of a targeted particle size and morphology. In the same reaction flask, without isolation, the water content within the beads can be reduced by the Dean Stark method or other similar evaporation techniques. The water is adjusted to a target amount so that a second crosslinking reaction can be performed to produce a final polymer having the desired properties and characteristics.

[0277] In one embodiment, the cross-linked poly(allylamine) amine polymer formed in the second cross-linking step (as previously described) is treated with 1,2-dichloroethane to reduce the concentration of any residual amine-reactive groups (i.e., alkyl chloride functional groups) introduced into the cross-linked polymer. For example, in this embodiment, the cross-linked poly(allylamine) polymer is treated with a quenching agent, such as a base, washed, heated, or otherwise treated to remove or quench the amine-reactive groups. Additionally, for example, in this embodiment, the cross-linked poly(allylamine) polymer is treated with ammonium hydroxide. The ammonium hydroxide treatment may occur immediately after the reaction, during the washing step, or after the polymer has been washed and dried, in which case the polymer may be processed through another series of washing steps. In another such embodiment, the cross-linked poly(allylamine) polymer is heated in a conventional oven or vacuum oven at a temperature above room temperature for a certain period, for example, at 60°C for more than 36 hours. Oven incubation may be performed under an inert atmosphere (e.g., nitrogen or argon) to reduce the possibility of oxidation.

[0278] Cross-linked poly(allylamine) polymer

[0279] As mentioned above, the cross-linked poly(allylamine) polymer having medical uses described herein has the ability to remove HCl.

[0280] In some embodiments, the cross-linked poly(allylamine) polymer of the present invention is in the form of beads and essentially comprises (i) 20-25 mol% of residues of 1,3-bis(allylamino)propane or its salt, (ii) 50-60 mol% of residues of 2-propene-1-ylamine or its salt, and (iii) 20-25 mol% of residues of 1,2-dichloroethane, wherein (i) the cross-linked poly(allylamine) polymer is sp 2 It contains an allyl carbon atom and has a swelling ratio of less than 2.

[0281] In some embodiments, the cross-linked poly(allylamine) polymer of the present invention comprises residues of 2-propene-1-ylamine or its salt, 1,3-bis(allylamino)propane or its salt, and 1,2-dichloroethane.

[0282] In some embodiments, the cross-linked poly(allylamine) polymer of the present invention essentially consists of residues of 2-propene-1-ylamine or its salt, 1,3-bis(allylamino)propane or its salt, and 1,2-dichloroethane.

[0283] In some embodiments, the cross-linked poly(allylamine) polymer of the present invention consists of residues of 2-propene-1-ylamine or its salt, 1,3-bis(allylamino)propane or its salt, and 1,2-dichloroethane.

[0284] In some embodiments, the cross-linked poly(allylamine) polymer of the present invention comprises 1,3-propanediamine having 1,2-dichloroethane and 2-propene-1-amine, N 1 ,N 3 -di-2-propene-1-yl-, is a polymer.

[0285] In some embodiments, the cross-linked poly(allylamine) polymer of the present invention is N with 1,2-dichloroethane and prop-2-en-1-amine 1,N 3 It is a bis(prop-2-en-1-yl)propane-1,3-diamine copolymer.

[0286] In some embodiments, the cross-linked poly(allylamine) polymer of the present invention is It includes the remainders of, where x, y, and z are positive integers.

[0287] In some embodiments, the cross-linked poly(allylamine) polymer of the present invention is It includes the remainders of, where x, y, and z are positive integers.

[0288] In some embodiments, the cross-linked poly(allylamine) polymer of the present invention comprises a structure corresponding to Formula 5a:

[0289]

[0290] Here

[0291] a = N,N'-diallyl-1,3-diaminopropane, or a residue of its salt, and

[0292] b = a residue of 2-propene-1-ylamine, or a residue of its salt, and

[0293] c = two residues of 2-propene-1-ylamine cross-linked with 1,2-dichloroethane, and

[0294] m = repeating unit of the polymer.

[0295] In some embodiments, the cross-linked poly(allylamine) polymer of the present invention comprises a structure corresponding to Formula 5b:

[0296]

[0297] Here

[0298] a = a residue of N,N'-diallyl-1,3-diaminopropane or its salt, and

[0299] b = a residue of 2-propene-1-ylamine or its salt, and

[0300] c = two residues of 2-propene-1-ylamine crosslinked with an ethylene crosslinking agent, e.g., 1,2-dichloroethane (which is presented as one of a number of possible crosslinks that can be formed in the polymer).

[0301] In some embodiments, the cross-linked poly(allylamine) polymer of the present invention is poly(allylamine-co-N,N'-diallyl-1,3-diaminopropane-co-1,2-diaminoethane).

[0302] In some embodiments, the cross-linked poly(allylamine) polymer of the present invention comprises a structure corresponding to Formula 4:

[0303]

[0304] Here, each R is independently hydrogen or ethylene crosslinking between two nitrogen atoms of the crosslinked amine polymer. and a, b, c, and m are integers.

[0305] In some embodiments, the cross-linked poly(allylamine) polymer of the present invention is [(C3H7N) ~5 (C9H 18 N2) ~2 (C8H 16 N2) ~2 ] n Includes the remainder of (n = ∞).

[0306] In some embodiments, the cross-linked poly(allylamine) polymer of the present invention comprises the following residues: .

[0307] In some embodiments, the cross-linked poly(allylamine) polymer of the present invention is a non-absorbing free-flowing powder composed of low-swelling spherical beads with a diameter of approximately 100 micrometers; each bead is a cross-linked single high molecular weight molecule.

[0308] In some embodiments, the cross-linked poly(allylamine) polymer is Beberimer.

[0309] Generally, the cross-linked poly(allylamine) polymer has a desirable particle size range that is (i) large enough to avoid passive or active absorption through the GI duct, and (ii) small enough not to cause grit or unpleasant oral sensation when ingested in the form of a powder, sachet, and / or chewable tablet / dosage having an average particle size of at least 3 micrometers. For example, in one embodiment, the cross-linked poly(allylamine) polymer comprises a particle population having an average particle size (volume distribution) greater than 1 micrometer and less than 1 millimeter. For example, in one embodiment, the cross-linked poly(allylamine) polymer comprises a particle population having an average particle size (volume distribution) in the range of 5 to 1,000 micrometers. Additionally, for example, in one embodiment, the cross-linked poly(allylamine) polymer comprises a particle population having an average particle size (volume distribution) in the range of 5 to 500 micrometers. Additionally, for example, in one embodiment, the cross-linked poly(allylamine) polymer comprises a population of particles having an average particle size (volume distribution) in the range of 10 to 400 micrometers. Additionally, for example, in one embodiment, the cross-linked poly(allylamine) polymer comprises a population of particles having an average particle size (volume distribution) in the range of 10 to 300 micrometers. Additionally, for example, in one embodiment, the cross-linked poly(allylamine) polymer comprises a population of particles having an average particle size (volume distribution) in the range of 20 to 250 micrometers. Additionally, for example, in one embodiment, the cross-linked poly(allylamine) polymer has a particle size range of 30 to 250 micrometers. Additionally, for example, in one embodiment, the cross-linked poly(allylamine) polymer has a particle size range of 40 to 180 micrometers. In a specific embodiment, less than 7% (on a number basis) of the particles in the population have a diameter of less than 10 micrometers.For example, in these embodiments, less than 5% (by number) of the particles in the population have a diameter of less than 10 micrometers. Additionally, for example, in these embodiments, less than 2.5% (by number) of the particles in the population have a diameter of less than 10 micrometers. Additionally, for example, in these embodiments, less than 1% (by number) of the particles in the population have a diameter of less than 10 micrometers. In each exemplary embodiment mentioned in this paragraph, the particles are preferably in the form of beads.

[0310] To minimize GI side effects often associated with large volume polymer gels moving through the GI tract in patients, a low swelling ratio of the cross-linked poly(allylamine) polymer is desirable (0.5 to 10 times its own weight in water). For example, in one embodiment, the cross-linked poly(allylamine) polymer has a swelling ratio of less than 2. Additionally, for example, in one embodiment, the cross-linked poly(allylamine) polymer has a swelling ratio of less than 1.9. Additionally, for example, in one embodiment, the cross-linked poly(allylamine) polymer has a swelling ratio of less than 1.8. Additionally, for example, in one embodiment, the cross-linked poly(allylamine) polymer has a swelling ratio of less than 1.7. Additionally, for example, in one embodiment, the cross-linked poly(allylamine) polymer has a swelling ratio of less than 1.6. Additionally, for example, in one embodiment, the cross-linked poly(allylamine) polymer has a swelling ratio of less than 1.5. Additionally, for example, in this one embodiment, the cross-linked poly(allylamine) polymer has a swelling ratio of less than 1.4. Additionally, for example, in this one embodiment, the cross-linked poly(allylamine) polymer has a swelling ratio of less than 1.3. Additionally, for example, in this one embodiment, the cross-linked poly(allylamine) polymer has a swelling ratio of less than 1.2. Additionally, for example, in this one embodiment, the cross-linked poly(allylamine) polymer has a swelling ratio of less than 1. Additionally, for example, in this one embodiment, the cross-linked poly(allylamine) polymer has a swelling ratio of less than 0.9. Additionally, for example, in this one embodiment, the cross-linked poly(allylamine) polymer has a swelling ratio of less than 0.8. Additionally, for example, in this one embodiment, the cross-linked poly(allylamine) polymer has a swelling ratio of less than 0.7. Additionally, for example, in this one embodiment, the cross-linked poly(allylamine) polymer has a swelling ratio of less than 0.6. Additionally, for example, in one embodiment, the cross-linked poly(allylamine) polymer is at least 0.It has a swelling ratio of 5 and less than 2. Additionally, for example, in one embodiment, the cross-linked poly(allylamine) polymer has a swelling ratio of about 0.7 to about 1.7.

[0311] Generally, the cross-linked poly(allylamine) polymer will have a theoretical binding capacity for at least about 7.5 mEq / g of protons (as determined by the SGF assay). For example, in some embodiments, the cross-linked poly(allylamine) polymer will have a theoretical binding capacity for at least about 8 mEq / g of protons. Additionally, for example, in some embodiments, the cross-linked poly(allylamine) polymer will have a theoretical binding capacity for at least about 8.5 mEq / g of protons. Additionally, for example, in some embodiments, the cross-linked poly(allylamine) polymer will have a theoretical binding capacity for at least about 9 mEq / g of protons. Additionally, for example, in some embodiments, the cross-linked poly(allylamine) polymer will have a theoretical binding capacity for at least about 9.5 mEq / g of protons. Additionally, for example, in some embodiments, the cross-linked poly(allylamine) polymer will have a theoretical binding capacity for at least about 10 mEq / g of protons. Additionally, for example, in some embodiments, the cross-linked poly(allylamine) polymer will have a theoretical binding capacity for protons of at least about 10.5 mEq / g. Additionally, for example, in some embodiments, the cross-linked poly(allylamine) polymer will have a theoretical binding capacity for protons of at least about 11 mEq / g. Generally, the cross-linked poly(allylamine) polymer will typically have a theoretical binding capacity for protons not exceeding about 35 mEq / g. For example, in some embodiments, the theoretical binding capacity of the cross-linked poly(allylamine) polymer for protons does not exceed 30 mEq / g. The binding capacities mentioned in this paragraph are the theoretical binding capacity for protons and the theoretical binding capacity for chloride ions independently and individually, and are not the sum thereof.

[0312] Phosphate, bicarbonate, bicarbonate equivalents, bile, and fatty acid conjugate bases are potential interfering anions for chloride or other strong acid conjugate bases in the stomach and small intestine. Therefore, rapid and preferential binding of chloride to phosphate, bicarbonate equivalents, and bile and fatty acid conjugate bases in the small intestine is desirable, and the SIB assay can be used to determine kinetics and preferential binding. Because the transit time in the colon is slower than in the small intestine (2–3 days), and because orally administered cross-linked poly(allylamine) polymers will not face conditions in the colon until after they have faced gastric and small intestine conditions, the kinetics of chloride binding by cross-linked poly(allylamine) polymers do not need to be as rapid in the colon, or under in vitro conditions designed to mimic the late small intestine / colon. However, it is desirable for chloride binding and selectivity to be high compared to other interfering anions, for example, at 24 and / or 48 hours or longer.

[0313] In one embodiment, the cross-linked poly(allylamine) polymer is characterized by a chloride ion binding capacity of at least 2.5 mEq / g in an artificial small intestine inorganic ("SIB") assay. For example, in this one embodiment, the cross-linked poly(allylamine) polymer is characterized by a chloride ion binding capacity of at least 3 mEq / g in the SIB assay. Additionally, for example, in this one embodiment, the cross-linked poly(allylamine) polymer is characterized by a chloride ion binding capacity of at least 3.5 mEq / g in the SIB assay. Additionally, for example, in this one embodiment, the cross-linked poly(allylamine) polymer is characterized by a chloride ion binding capacity of at least 4 mEq / g in the SIB assay. Additionally, for example, in this one embodiment, the cross-linked poly(allylamine) polymer is characterized by a chloride ion binding capacity of at least 4.5 mEq / g in the SIB assay. Additionally, for example, in one embodiment, the cross-linked poly(allylamine) polymer is characterized by a chloride ion binding capacity of at least 5 mEq / g in the SIB test. Additionally, for example, in one embodiment, the cross-linked poly(allylamine) polymer is characterized by a chloride ion binding capacity of at least 5.5 mEq / g in the SIB test. Additionally, for example, in one embodiment, the cross-linked poly(allylamine) polymer is characterized by a chloride ion binding capacity of at least 6 mEq / g in the SIB test. Additionally, for example, in one embodiment, the cross-linked poly(allylamine) polymer is characterized by a chloride ion binding capacity of about 4.1 mEq / g to about 5.4 mEq / g in the SIB test.

[0314] In one embodiment, the cross-linked poly(allylamine) polymer is bound to a significant amount of chloride relative to phosphate, for example, as shown in the SIB assay. For example, in one embodiment, the ratio of the amount of bound chloride to the amount of bound phosphate in the SIB assay is at least 1:1. Additionally, for example, in this embodiment, the ratio of the amount of bound chloride to the amount of bound phosphate in the SIB assay is at least 2:1. Additionally, for example, in this embodiment, the ratio of the amount of bound chloride to the amount of bound phosphate in the SIB assay is at least 2.25:1. Additionally, for example, in this embodiment, the ratio of the amount of bound chloride to the amount of bound phosphate in the SIB assay is at least 2.5:1. Additionally, for example, in this embodiment, the ratio of the amount of bound chloride to the amount of bound phosphate in the SIB assay is at least 2.75:1. Additionally, for example, in this embodiment, the ratio of the amount of bound chloride to the amount of bound phosphate in the SIB assay is at least 3:1. Additionally, for example, in one embodiment, the ratio of the amount of combined chloride to the amount of combined phosphate in the SIB test is at least 4:1. Additionally, for example, in one embodiment, the ratio of the amount of combined chloride to the amount of combined phosphate in the SIB test is at least 5:1. Additionally, for example, in one embodiment, the ratio of the amount of combined chloride to the amount of combined phosphate in the SIB test is about 2.1:1 to about 10.8:1.

[0315] In one embodiment, the cross-linked poly(allylamine) polymer is characterized by having a proton-binding capacity and a chloride-binding capacity in artificial gastric fluid in an SGF assay of at least 7.5 mEq / g. For example, in this one embodiment, the cross-linked poly(allylamine) polymer is characterized by having a proton-binding capacity and a chloride-binding capacity of at least 8 mEq / g in an SGF assay. Additionally, for example, in this one embodiment, the cross-linked poly(allylamine) polymer is characterized by having a proton-binding capacity and a chloride-binding capacity of at least 8.5 mEq / g in an SGF assay. Additionally, for example, in this one embodiment, the cross-linked poly(allylamine) polymer is characterized by having a proton-binding capacity and a chloride-binding capacity of at least 9 mEq / g in an SGF assay. Additionally, for example, in this one embodiment, the cross-linked poly(allylamine) polymer is characterized by having a proton-binding capacity and a chloride-binding capacity of at least 9.5 mEq / g in an SGF assay. Additionally, for example, in one embodiment, the cross-linked poly(allylamine) polymer is characterized by having a proton-binding capacity and a chloride-binding capacity of at least 10 mEq / g in an SGF assay. Additionally, for example, in one embodiment, the cross-linked poly(allylamine) polymer is characterized by having a proton-binding capacity and a chloride-binding capacity of at least 10.5 mEq / g in an SGF assay. Additionally, for example, in one embodiment, the cross-linked poly(allylamine) polymer is characterized by having a proton-binding capacity and a chloride-binding capacity of at least 11 mEq / g in an SGF assay. Additionally, for example, in one embodiment, the cross-linked poly(allylamine) polymer is characterized by having a proton-binding capacity and a chloride-binding capacity of at least 11.5 mEq / g in an SGF assay.Additionally, for example, in one embodiment, the cross-linked poly(allylamine) polymer is characterized by having a proton-binding capacity and a chloride-binding capacity of at least 12 mEq / g in an SGF assay. Additionally, for example, in one embodiment, the cross-linked poly(allylamine) polymer is characterized by having a proton-binding capacity and a chloride-binding capacity of at least 12.5 mEq / g in an SGF assay. Additionally, for example, in one embodiment, the cross-linked poly(allylamine) polymer is characterized by having a proton-binding capacity and a chloride-binding capacity of about 9.0 mEq / g to about 12.6 mEq / g in an SGF assay.

[0316] Additionally, for example, in one embodiment, the cross-linked poly(allylamine) polymer is characterized in that the proton-binding capacity and chloride-binding capacity after 1 hour in SGF are each at least 50% of the proton-binding capacity and chloride-binding capacity of the cross-linked poly(allylamine) polymer after 24 hours in SGF. Additionally, for example, in one embodiment, the cross-linked poly(allylamine) polymer is characterized in that the proton-binding capacity and chloride-binding capacity after 1 hour in SGF are each at least 60% of the proton-binding capacity and chloride-binding capacity of the cross-linked poly(allylamine) polymer after 24 hours in SGF. Additionally, for example, in one embodiment, the cross-linked poly(allylamine) polymer is characterized in that the proton-binding capacity and chloride-binding capacity after 1 hour in SGF are each at least 70% of the proton-binding capacity and chloride-binding capacity of the cross-linked poly(allylamine) polymer after 24 hours in SGF. Additionally, for example, in one embodiment, the cross-linked poly(allylamine) polymer is characterized in that the proton-binding capacity and chloride-binding capacity after 1 hour in SGF are each at least 80% of the proton-binding capacity and chloride-binding capacity of the cross-linked poly(allylamine) polymer after 24 hours in SGF. Additionally, for example, in one embodiment, the cross-linked poly(allylamine) polymer is characterized in that the proton-binding capacity and chloride-binding capacity after 1 hour in SGF are each at least 90% of the proton-binding capacity and chloride-binding capacity of the cross-linked poly(allylamine) polymer after 24 hours in SGF.

[0317] In embodiments where the cross-linked poly(allylamine) polymer binds to chloride ions, it is generally preferred that the cross-linked poly(allylamine) polymer binds selectively to chloride ions compared to other counterions, such as bicarbonate equivalent anions, phosphate anions, and conjugate bases of bile acids and fatty acids. In other words, in these embodiments, it is generally preferred that the cross-linked poly(allylamine) polymer removes (i) more chloride ions than bicarbonate equivalent anions, (ii) more chloride ions than phosphate anions, and (iii) more chloride ions than conjugate bases of bile acids and fatty acids. Thus, advantageously, treatment with the cross-linked poly(allylamine) polymer does not induce or worsen hypophosphatemia (i.e., serum phosphorus concentrations of less than about 2.4 mg / dL), does not significantly increase low-density lipoprotein ("LDL"), or otherwise has a negative effect on serum or colon levels of metabolically relevant anions.

[0318] In some embodiments, the carbon-to-nitrogen weight ratio of the cross-linked poly(allylamine) polymer of the present invention may each range from about 2:1 to about 6:1. For example, in one such embodiment, the carbon-to-nitrogen weight ratio of the cross-linked poly(allylamine) polymer of the present invention may each range from about 2.5:1 to about 5:1. Additionally, for example, in one such embodiment, the carbon-to-nitrogen weight ratio of the cross-linked poly(allylamine) polymer of the present invention may each range from about 3:1 to about 4.5:1. Additionally, for example, in one such embodiment, the carbon-to-nitrogen weight ratio of the cross-linked poly(allylamine) polymer of the present invention may each range from about 3.25:1 to about 4.25:1. Additionally, for example, in one such embodiment, the carbon-to-nitrogen weight ratio of the cross-linked poly(allylamine) polymer of the present invention may each range from about 3.4:1 to about 4:1. Additionally, for example, in one embodiment, the carbon-to-nitrogen weight ratio of the cross-linked poly(allylamine) polymer of the present invention may each be in the range of about 3.5:1 to about 4:1. Additionally, for example, in one embodiment, the carbon-to-nitrogen weight ratio of the cross-linked poly(allylamine) polymer of the present invention may each be in the range of about 3.6:1 to about 3.9:1. Additionally, for example, in one embodiment, the carbon-to-nitrogen weight ratio of the cross-linked poly(allylamine) polymer of the present invention may each be in the range of about 3.7:1 to about 3.8:1. In each of the above embodiments, the carbon-to-nitrogen weight ratio may be determined by elemental analysis. For example, the carbon-to-nitrogen weight ratio may be determined by elemental analysis using a Perkin-Elmer 2400 elemental analyzer as more fully described elsewhere in this invention.

[0319] In one embodiment, the cross-linked poly(allylamine) polymer is a cross-linked poly(allylamine) polymer comprising a structure corresponding to Formula 4:

[0320]

[0321] Here, each R is independently hydrogen or ethylene crosslinking between two nitrogen atoms of the crosslinked amine polymer. And, a, b, c, and m are integers. Typically, m is a large integer representing an extended polymer network where each polymer bead is considered a single molecule. In other words, if the molecular weight is calculated using the volume of the polymer beads and the bulk density of the polymer, m is 3.2 x 10⁻⁶ 8It is sufficiently large to exhibit a molecular weight exceeding g / mol. In one such embodiment, the ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 1:1 to 9:1. For example, in one such embodiment, the ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 1:1 to 8:1. Additionally, for example, in one such embodiment, the sum of a and b to c (i.e., a+b:c) is in the range of about 1:1 to 7:1. Additionally, for example, in one such embodiment, the sum of a and b to c (i.e., a+b:c) is in the range of about 1:1 to 6:1. Additionally, for example, in one such embodiment, the ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 1:1 to 5:1. Additionally, for example, in one such embodiment, the sum of a and b to c (i.e., a+b:c) is in the range of about 1:1 to 4:1. Additionally, for example, in this one embodiment, the sum of a and b to c (i.e., a+b:c) is in the range of about 1:1 to 3:1. Additionally, for example, in this one embodiment, the sum of a and b to c (i.e., a+b:c) is in the range of about 1:1 to 2:1. Additionally, for example, in this one embodiment, the sum of a and b to c (i.e., a+b:c) is about 1:1. Additionally, for example, in this one embodiment, the ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 1.5:1 to 4:1. Additionally, for example, in this one embodiment, the ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 1.75:1 to 3:1. For example, in this one embodiment, the ratio of the sum of a and b is 57, c is 24, and m is a large integer representing an extended polymer network. In each of the above embodiments, the ratio of the sum of a and b to c (i.e., a+b:c) may be in the range of about 2:1 to 2.5:1. For example, in these embodiments, the ratio of the sum of a and b to c (i.e., a+b:c) is about 2.1:1 to 2.It may be in the range of 2:1. Additionally, for example, in these embodiments, the ratio of the sum of a and b to c (i.e., a+b:c) may be in the range of about 2.2:1 to 2.3:1. Additionally, for example, in these embodiments, the ratio of the sum of a and b to c (i.e., a+b:c) may be in the range of about 2.3:1 to 2.4:1. Additionally, for example, in these embodiments, the ratio of the sum of a and b to c (i.e., a+b:c) may be in the range of about 2.4:1 to 2.5:1. In each of the above embodiments, each R may independently be hydrogen or an ethylene crosslink between two nitrogen atoms. However, typically, 35-95% of the R substituents will be hydrogen, and 5-65% will be ethylene crosslinks. It will be. For example, in one such embodiment, 50-95% of the R substituents will be hydrogen, and 5-50% will be ethylene crosslinked. It will be. For example, in one such embodiment, 55-90% of the R substituents are hydrogen, and 10-45% are ethylene crosslinked. is. As an additional example, in this one embodiment, 60-90% of the R substituents are hydrogen and 10-40% are ethylene crosslinks. Additionally, as an example, in this one embodiment, 65-90% of the R substituents are hydrogen and 10-35% are ethylene crosslinks. is. As an additional example, in one embodiment, 70-90% of the R substituents are hydrogen and 10-30% are ethylene crosslinks. Additionally, for example, in one embodiment, 75-85% of the R substituents are hydrogen and 15-25% are ethylene crosslinks. Additionally, for example, in one embodiment, 65-75% of the R substituents are hydrogen and 25-35% are ethylene crosslinks. Additionally, for example, in one embodiment, 55-65% of the R substituents are hydrogen and 35-45% are ethylene crosslinks. It will be apparent to a person skilled in the art that in each of these embodiments, the sum of the percentage of the R substituents that are hydrogen and the percentage of the R substituents that are ethylene crosslinks between the two nitrogen atoms of the crosslinked amine polymer is 100%. In some embodiments, a, b, c, and R allow the carbon-to-nitrogen weight ratio of the polymer of Formula 4 to be in the range of about 2:1 to about 6:1, respectively. For example, in one embodiment, the carbon-to-nitrogen weight ratio of the polymer of Formula 4 may each range from about 2.5:1 to about 5:1. Additionally, for example, in one embodiment, the carbon-to-nitrogen weight ratio of the polymer of Formula 4 may each range from about 3:1 to about 4.5:1. Additionally, for example, in one embodiment, the carbon-to-nitrogen weight ratio of the polymer of Formula 4 may each range from about 3.25:1 to about 4.25:1. Additionally, for example, in one embodiment, the carbon-to-nitrogen weight ratio of the polymer of Formula 4 may each range from about 3.4:1 to about 4:1. Additionally, for example, in one embodiment, the carbon-to-nitrogen weight ratio of the polymer of Formula 4 may each range from about 3.5:1 to about 3.9:1. Additionally, for example, in one embodiment, the carbon-to-nitrogen weight ratio of the polymer of Formula 4 may each range from about 3.55:1 to about 3.85:1.In each of the above embodiments mentioned in this paragraph, the polymer of Formula 4 is derived from a monomer and a crosslinking agent containing less than 5 wt% oxygen.

[0322] In an exemplary embodiment, the cross-linked poly(allylamine) polymer is a cross-linked poly(allylamine) polymer comprising (i) 2-propene-1-ylamine or its salt, (ii) a residue of 1,3-bis(allylamino)propane or its salt, and (iii) a residue of 1,2-dichloroethane, wherein the molar ratio of 2-propene-1-ylamine (or its salt(s)) to 1,3-bis(allylamino)propane (or its salt(s)) is in the range of 60:40 to 95:5, respectively. In another exemplary embodiment, the cross-linked poly(allylamine) polymer is a cross-linked poly(allylamine) polymer comprising (i) 2-propene-1-ylamine or its salt, (ii) residues of 1,3-bis(allylamino)propane or its salt, and (iii) residues of 1,2-dichloroethane, wherein the molar ratio of 2-propene-1-ylamine (or its salt(s)) to 1,3-bis(allylamino)propane (or its salt(s)) is in the range of 65:35 to 90:10, respectively. In another exemplary embodiment, the cross-linked poly(allylamine) polymer is a cross-linked poly(allylamine) polymer comprising (i) 2-propene-1-ylamine or its salt, (ii) a residue of 1,3-bis(allylamino)propane or its salt, and (iii) a residue of 1,2-dichloroethane, wherein the molar ratio of 2-propene-1-ylamine (or its salt(s)) to 1,3-bis(allylamino)propane (or its salt(s)) is in the range of 65:35 to 75:25, respectively. For example, in each of the exemplary embodiments mentioned in this paragraph, the residue of 2-propene-1-ylamine or its salt, and / or the residue of 1,3-bis(allylamino)propane or its salt, may be a residue of a hydrochloric acid salt, a sulfate salt, a phosphate salt, a hydrobromide salt, or a combination thereof. Additionally, for example, in each of the exemplary embodiments mentioned in this paragraph, the residue of 2-propene-1-ylamine or its salt, and / or the residue of 1,3-bis(allylamino)propane or its salt is a residue of hydrochloric acid salt.

[0323] In an exemplary embodiment, the crosslinked poly(allylamine) polymer comprises (i) 10-35 mol% of residues of 1,3-bis(allylamino)propane or its salt, (ii) 30-80 mol% of residues of 2-propene-1-ylamine or its salt, and (iii) 10-35 mol% of residues of 1,2-dichloroethane, wherein the sum of (i) mol% of residues of 1,3-bis(allylamino)propane or its salt, (ii) mol% of residues of 2-propene-1-ylamine or its salt, and (iii) mol% of residues of 1,2-dichloroethane is less than 100 mol%. In another exemplary embodiment, the crosslinked poly(allylamine) polymer comprises (i) 10-35 mol% of residues of 1,3-bis(allylamino)propane or its salt, (ii) 40-70 mol% of residues of 2-propene-1-ylamine or its salt, and (iii) 10-35 mol% of residues of 1,2-dichloroethane, wherein the sum of (i) mol% of residues of 1,3-bis(allylamino)propane or its salt, (ii) mol% of residues of 2-propene-1-ylamine or its salt, and (iii) mol% of residues of 1,2-dichloroethane is less than 100 mol%. In another exemplary embodiment, the crosslinked poly(allylamine) polymer comprises (i) 15-30 mol% of residues of 1,3-bis(allylamino)propane or its salt, (ii) 40-70 mol% of residues of 2-propene-1-ylamine or its salt, and (iii) 15-30 mol% of residues of 1,2-dichloroethane, wherein the sum of (i) mol% of residues of 1,3-bis(allylamino)propane or its salt, (ii) mol% of residues of 2-propene-1-ylamine or its salt, and (iii) mol% of residues of 1,2-dichloroethane is less than 100 mol%.In another exemplary embodiment, the crosslinked poly(allylamine) polymer comprises (i) 15-30 mol% of residues of 1,3-bis(allylamino)propane or its salt, (ii) 45-65 mol% of residues of 2-propene-1-ylamine or its salt, and (iii) 15-30 mol% of residues of 1,2-dichloroethane, wherein the sum of (i) mol% of residues of 1,3-bis(allylamino)propane or its salt, (ii) mol% of residues of 2-propene-1-ylamine or its salt, and (iii) mol% of residues of 1,2-dichloroethane is less than 100 mol%. In another exemplary embodiment, the crosslinked poly(allylamine) polymer comprises (i) 20-25 mol% of residues of 1,3-bis(allylamino)propane or its salt, (ii) 50-60 mol% of residues of 2-propene-1-ylamine or its salt, and (iii) 20-25 mol% of residues of 1,2-dichloroethane, wherein the sum of (i) mol% of residues of 1,3-bis(allylamino)propane or its salt, (ii) mol% of residues of 2-propene-1-ylamine or its salt, and (iii) mol% of residues of 1,2-dichloroethane is less than 100 mol%.

[0324] In an exemplary embodiment, the crosslinked poly(allylamine) polymer is essentially composed of (i) 10-35 mol% of residues of 1,3-bis(allylamino)propane or its salt, (ii) 30-80 mol% of residues of 2-propene-1-ylamine or its salt, and (iii) 10-35 mol% of residues of 1,2-dichloroethane, wherein the sum of (i) mol% of residues of 1,3-bis(allylamino)propane or its salt, (ii) mol% of residues of 2-propene-1-ylamine or its salt, and (iii) mol% of residues of 1,2-dichloroethane is less than 100 mol%. In another exemplary embodiment, the crosslinked poly(allylamine) polymer is essentially composed of (i) 10-35 mol% of residues of 1,3-bis(allylamino)propane or its salt, (ii) 40-70 mol% of residues of 2-propene-1-ylamine or its salt, and (iii) 10-35 mol% of residues of 1,2-dichloroethane, wherein the sum of (i) mol% of residues of 1,3-bis(allylamino)propane or its salt, (ii) mol% of residues of 2-propene-1-ylamine or its salt, and (iii) mol% of residues of 1,2-dichloroethane is less than 100 mol%. In another exemplary embodiment, the crosslinked poly(allylamine) polymer is essentially composed of (i) 15-30 mol% of residues of 1,3-bis(allylamino)propane or its salt, (ii) 40-70 mol% of residues of 2-propene-1-ylamine or its salt, and (iii) 15-30 mol% of residues of 1,2-dichloroethane, wherein the sum of (i) mol% of residues of 1,3-bis(allylamino)propane or its salt, (ii) mol% of residues of 2-propene-1-ylamine or its salt, and (iii) mol% of residues of 1,2-dichloroethane is less than 100 mol%.In another exemplary embodiment, the crosslinked poly(allylamine) polymer is essentially composed of (i) 15-30 mol% of residues of 1,3-bis(allylamino)propane or its salt, (ii) 45-65 mol% of residues of 2-propene-1-ylamine or its salt, and (iii) 15-30 mol% of residues of 1,2-dichloroethane, wherein the sum of (i) mol% of residues of 1,3-bis(allylamino)propane or its salt, (ii) mol% of residues of 2-propene-1-ylamine or its salt, and (iii) mol% of residues of 1,2-dichloroethane is less than 100 mol%. In another exemplary embodiment, the crosslinked poly(allylamine) polymer is essentially composed of (i) 20-25 mol% of residues of 1,3-bis(allylamino)propane or its salt, (ii) 50-60 mol% of residues of 2-propene-1-ylamine or its salt, and (iii) 20-25 mol% of residues of 1,2-dichloroethane, wherein the sum of (i) mol% of residues of 1,3-bis(allylamino)propane or its salt, (ii) mol% of residues of 2-propene-1-ylamine or its salt, and (iii) mol% of residues of 1,2-dichloroethane is less than 100 mol%.

[0325] In an exemplary embodiment, the crosslinked poly(allylamine) polymer is composed of (i) 10-35 mol% of residues of 1,3-bis(allylamino)propane or its salt, (ii) 30-80 mol% of residues of 2-propene-1-ylamine or its salt, and (iii) 10-35 mol% of residues of 1,2-dichloroethane, wherein the sum of (i) mol% of residues of 1,3-bis(allylamino)propane or its salt, (ii) mol% of residues of 2-propene-1-ylamine or its salt, and (iii) mol% of residues of 1,2-dichloroethane is 100 mol%. In another exemplary embodiment, the cross-linked poly(allylamine) polymer is composed of (i) 10-35 mol% of residues of 1,3-bis(allylamino)propane or its salt, (ii) 40-70 mol% of residues of 2-propene-1-ylamine or its salt, and (iii) 10-35 mol% of residues of 1,2-dichloroethane, wherein the sum of (i) mol% of residues of 1,3-bis(allylamino)propane or its salt, (ii) mol% of residues of 2-propene-1-ylamine or its salt, and (iii) mol% of residues of 1,2-dichloroethane is 100 mol%. In another exemplary embodiment, the cross-linked poly(allylamine) polymer is composed of (i) 15-30 mol% of residues of 1,3-bis(allylamino)propane or its salt, (ii) 40-70 mol% of residues of 2-propene-1-ylamine or its salt, and (iii) 15-30 mol% of residues of 1,2-dichloroethane, wherein the sum of (i) mol% of residues of 1,3-bis(allylamino)propane or its salt, (ii) mol% of residues of 2-propene-1-ylamine or its salt, and (iii) mol% of residues of 1,2-dichloroethane is 100 mol%.In another exemplary embodiment, the crosslinked poly(allylamine) polymer is composed of (i) 15-30 mol% of residues of 1,3-bis(allylamino)propane or its salt, (ii) 45-65 mol% of residues of 2-propene-1-ylamine or its salt, and (iii) 15-30 mol% of residues of 1,2-dichloroethane, wherein the sum of (i) mol% of residues of 1,3-bis(allylamino)propane or its salt, (ii) mol% of residues of 2-propene-1-ylamine or its salt, and (iii) mol% of residues of 1,2-dichloroethane is 100 mol%. In another exemplary embodiment, the cross-linked poly(allylamine) polymer is composed of (i) 20-25 mol% of residues of 1,3-bis(allylamino)propane or its salt, (ii) 50-60 mol% of residues of 2-propene-1-ylamine or its salt, and (iii) 20-25 mol% of residues of 1,2-dichloroethane, wherein the sum of (i) mol% of residues of 1,3-bis(allylamino)propane or its salt, (ii) mol% of residues of 2-propene-1-ylamine or its salt, and (iii) mol% of residues of 1,2-dichloroethane is 100 mol%.

[0326] For example, in each of the exemplary embodiments mentioned in the paragraph above, a residue of 2-propene-1-ylamine or its salt, and / or a residue of 1,3-bis(allylamino)propane or its salt, may be a residue of hydrochloric acid, sulfate, phosphate, hydrobromide, or a combination thereof. Additionally, for example, in each of the exemplary embodiments mentioned in the paragraph above, a residue of 2-propene-1-ylamine or its salt, and / or a residue of 1,3-bis(allylamino)propane or its salt, is a residue of hydrochloric acid.

[0327] Pharmaceutical composition & administration

[0328] Generally, the dosage level of cross-linked poly(allylamine) polymers, particularly Beberimers, for therapeutic and / or prophylactic use may be in the range of about 3 g / day to about 9 g / day.

[0329] Optionally, the daily dose may be administered as a single dose (i.e., once a day) or divided into multiple doses over a day (e.g., two, three, or more doses). Preferably, the daily dose is administered once a day.

[0330] Generally, cross-linked poly(allylamine) polymers may be administered at a fixed daily dose or titrated based on the serum bicarbonate values ​​or other indicators of acidosis in patients requiring treatment. Titration may be performed at the start of treatment or throughout treatment as needed, and starting and maintenance dose levels may vary from patient to patient based on the severity of the underlying disease.

[0331] For example, in one embodiment, the recommended starting dose of a cross-linked poly(allylamine) polymer, particularly Beberimer, for therapeutic and / or prophylactic use is about 6 g / day. In one embodiment, the starting dose is adjusted in increments of about 3 g, up to about 9 g / day or at least about 3 g / day. In one embodiment, dose adjustment is performed to achieve the desired serum bicarbonate level. In one embodiment, dose adjustment is performed at intervals of about 2 weeks.

[0332] In one embodiment, a cross-linked poly(allylamine) polymer, particularly Beberimer, is administered with food. In one embodiment, a cross-linked poly(allylamine) polymer, particularly Beberimer, is administered orally as a suspension in water.

[0333] The efficacy of cross-linked poly(allylamine) polymers can be established in animal models, or in human volunteers and patients. Furthermore, in vitro, in vitro, and in vivo approaches are useful for establishing binding to HCl or other target species. In vitro binding solutions can be used to measure binding capacities for protons, chlorides, and other ions at different pH values. In vitro extracts, such as gastrointestinal lumen contents from human volunteers or model animals, can be used for similar purposes. Selectivity to preferentially bind to and / or retain specific ions relative to others can also be demonstrated in these in vitro and in vitro solutions. The efficacy of cross-linked poly(allylamine) polymers in normalizing acid-base balance can be tested using in vivo models of metabolic acidosis—for example, 5 / 6 renal resection rats fed a casein-containing diet (as described in [Phisitkul S, Hacker C, Simoni J, Tran RM, Wesson DE. Dietary protein causes a decline in the glomerular filtration rate of the remnant kidney mediated by metabolic acidosis and endothelin receptors. Kidney international.2008;73(2):192-9]), or adenine-fed rats ([Terai K, K Mizukami and M Okada. 2008. Comparison of chronic renal failure rats and modification of the preparation protocol as a hyperphosphatemia model. Nephrol.13: 139-146]).

[0334] Metabolic acidosis, regardless of etiology, lowers extracellular fluid bicarbonate and consequently reduces extracellular pH. The relationship between serum pH and serum bicarbonate is described by the Henderson-Hasselbach equation:

[0335]

[0336] Here, 0.03 is the physical solubility coefficient for CO2, and [HCO3 - ] and PaCO2 are the concentration of bicarbonate and the partial pressure of carbon dioxide, respectively.

[0337] There are several laboratory tests that can be used to diagnose metabolic acidosis. The tests essentially measure bicarbonate (HCO3) in various biological samples, including venous or arterial blood. - ) or proton (H + ) The concentration is measured. These tests measure bicarbonate (HCO3) by enzymatic methodology, by ion-selective electrodes, or by blood gas analysis. - ) or proton (H + ) concentration can be measured. In both enzymatic and ion-selective electrode methods, bicarbonate is "measured." Using blood gas analysis, bicarbonate levels can be calculated using the Henderson-Hasselbach equation.

[0338] In one embodiment, a cross-linked poly(allylamine) polymer is provided to animals, including humans (by oral administration) in a regimen of doses administered once, twice, or even multiple times (i.e., at least three times) per day to treat acid-base disorders (e.g., metabolic acidosis) and to achieve a sustained increase in serum bicarbonate or other target species as previously described.

[0339] The cross-linked poly(allylamine) polymer disclosed herein may be provided in any form suitable for oral administration. Such forms include powders, tablets, pills, lozenges, sachets, cases, elixirs, suspensions, syrups, gels, soft or hard gelatin capsules, etc. In one embodiment, the pharmaceutical composition comprises only the cross-linked poly(allylamine) polymer. Alternatively, the pharmaceutical composition may comprise a carrier, a diluent, or an excipient in addition to the cross-linked poly(allylamine) polymer. Examples of carriers, excipients, and diluents that may be used in these formulations as well as other formulations include food, beverages, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, propylhydroxybenzoate, and talc. Pharmaceutical excipients useful in pharmaceutical compositions include binders, e.g., microcrystalline cellulose, colloidal silica and combinations thereof (Prosolv 90), carbopol, providon, and xanthan gum; flavoring agents, e.g., sucrose, mannitol, xylitol, maltodextrin, fructose, or sorbitol; Lubricants, such as magnesium stearate, stearic acid, sodium stearyl fumurate, and plant-based fatty acids; and optionally further comprising disintegrants, such as sodium croscarmellose, gellan gum, low-substituted hydroxypropyl ether of cellulose, and sodium starch glycolate. Other additives may include plasticizers, pigments, talc, etc. Such additives and other suitable ingredients are widely known in the relevant art; for example, see the literature [Gennaro AR (ed), Remington's Pharmaceutical Sciences, 20th Edition].

[0340] In one embodiment, a cross-linked poly(allylamine) polymer may be co-administered with other active pharmaceutical agents depending on the condition to be treated. Such co-administration may include simultaneous administration of two agents of the same dosage form, simultaneous administration of individual dosage forms, and individual administration. For example, for the treatment of metabolic acidosis, the cross-linked poly(allylamine) polymer may be co-administered with conventional treatment required to treat underlying comorbidities, including but not limited to hypertension, diabetes, obesity, heart failure, and complications of chronic kidney disease. These drugs and the cross-linked poly(allylamine) polymer may be formulated together in the same dosage form and co-administered unless they exhibit any clinically significant drug-drug interactions. Alternatively, these therapeutic agents and the cross-linked poly(allylamine) polymer may be administered individually and sequentially, with the other administered after the other.

[0341] In one embodiment, the daily dose for the treatment of chronic metabolic acidosis improves compliance (3 g / day, 6 g / day, or 9 g / day of a cross-linked poly(allylamine) polymer, particularly Beberimer), and achieves an increase of approximately 3 mEq / L of serum bicarbonate at these daily doses. The non-absorbable nature of the polymer and the lack of sodium loading and / or introduction of other harmful ions for these oral drugs enable, for the first time, the safe and chronic treatment of metabolic acidosis without exacerbation of blood pressure / hypertension and / or induction of increased fluid retention and fluid overload. Another benefit is that it also delays the progression of renal disease and the time to the initiation of lifelong renal replacement therapy (end-stage renal disease "ESRD," including three dialysis sessions per week) or the need for a kidney transplant. All of these are associated with significant mortality, low quality of life, and a significant burden on healthcare systems worldwide. In the United States alone, approximately 20% of the 400,000 ESRD patients die each year, and 100,000 new patients begin dialysis.

[0342] Further aspects of the present disclosure are a pharmaceutical product comprising a sealed package and a cross-linked poly(allylamine) polymer of the present disclosure, e.g., Beberimer, within the sealed package. The unit dosage forms disclosed herein may take any form that conforms to one or more of the disclosed requirements. For example, the unit dosage form may include a vial, bottle, tube, jar, box, container, blister pack, sachet (including stick pack), or other sealed container. In one exemplary embodiment, the unit dosage form is a sachet.

[0343] As disclosed herein, the cross-linked poly(allylamine) polymer of the present disclosure, e.g., Beberimer, may produce certain impurities, e.g., H2C=CHCH2NH2, upon exposure to oxygen. A unit dosage form may include features to treat or reduce these potential impurities, e.g., features to reduce the amount of oxygen that comes into contact with the polymer during storage.

[0344] Packaging approaches for treating or reducing such potential impurities include: a unit dosage form having low permeability to oxygen; a unit dosage form having a small amount of gas within the unit dosage form; a unit dosage form containing a gas other than air within the unit dosage form and / or a unit dosage form containing an oxygen-absorbing component, e.g., a scavenger. Each packaging approach may be used alone or in combination with any other packaging approach disclosed herein. Each packaging approach may be used alone or in combination with any cross-linked poly(allylamine) polymer of the present disclosure, e.g., Beberimer, and / or any polymer from the publications mentioned herein, and all such combinations are disclosed. For example, using one or more of the packaging approaches disclosed herein for treating or reducing potential impurities, e.g., the approach summarized in this paragraph, to achieve a low level of sp as disclosed herein.2 Less than 1.0% of the total number of carbon atoms present in a cross-linked poly(allylamine) polymer is sp 2 A pharmaceutical product comprising a cross-linked poly(allylamine) polymer of the present disclosure (which is an allyl carbon), e.g., Beberimer, may be provided. Such pharmaceutical products may provide an acceptable or improved shelf life as defined somewhere in this invention. In another example, by using one or more of the approaches disclosed herein for treating or reducing such potential impurities, e.g., the approach summarized in this paragraph, a higher level of sp as disclosed herein and / or disclosed in the references provided herein may be used. 2 Having carbon (e.g., more than 1.0% of the total number of carbon atoms present in a cross-linked poly(allylamine) polymer is sp 2 A pharmaceutical product comprising the cross-linked poly(allylamine) polymer of the present disclosure (which is an allyl carbon), e.g., Beberimer, may be provided. Such pharmaceutical products may have a higher level of sp 2 Acceptable or improved shelf life can be provided despite the presence of carbon, because, for example, the approach used or the combination of packaging approaches limits the amount of oxygen in contact with the polymer and thus limits the level of purity present (e.g., after storage).

[0345] In some embodiments, the unit dosage form comprises a sealed package preferably substantially impermeable to moisture and oxygen to increase the stability of the pharmaceutical composition (e.g., the stability of Beberimer). For example, the dosage unit form may comprise a sealed container (e.g., a sealed sachet) that prevents or reduces the ingress of moisture and oxygen when packaging a poly(allylamine) polymer within the container.

[0346] The container size used to form the unit dosage form, and / or the amount of the pharmaceutical composition within the container, may be selected to reduce the headspace within the container after packing. Headspace is the volume contained within the unit dosage form, not the pharmaceutical composition. Headspace contains one or more gases, for example, an inert gas, such as nitrogen, or a mixture of gases, such as air. By minimizing the volume of headspace, the stability of the cross-linked poly(allylamine) polymer of the present disclosure, for example, Beberimer, may be increased during storage, particularly when the headspace contains oxygen.

[0347] In some embodiments, the unit dosage form comprises a pharmaceutical composition and a headspace, wherein the headspace volume is 0 cm² 3 to 120 cm 3 is. In some embodiments, the unit dosage form comprises a pharmaceutical composition and a headspace, wherein the headspace volume is 10 cm³ 3 to 110 cm 3 is. In some embodiments, the unit dosage form comprises a pharmaceutical composition and a headspace, wherein the headspace volume is 20 cm³ 3 to 100 cm 3 is. In some embodiments, the unit dosage form comprises a pharmaceutical composition and a headspace, wherein the headspace volume is 20 cm³ 3 up to 40 cm 3 is. In some embodiments, the unit dosage form comprises a pharmaceutical composition and a headspace, wherein the headspace volume is 0 cm² 3 up to 20 cm 3 is. In some embodiments, the unit dosage form comprises a pharmaceutical composition and a headspace, wherein the headspace volume is 50 cm³ 3 to 70 cm 3 am.

[0348] In some embodiments, the unit dosage form comprises a pharmaceutical composition and a headspace, wherein the headspace volume is less than 70% of the total volume of the unit dosage form. In some embodiments, the unit dosage form comprises a pharmaceutical composition and a headspace, wherein the headspace volume is less than 65% of the total volume of the unit dosage form. In some embodiments, the unit dosage form comprises a pharmaceutical composition and a headspace, wherein the headspace volume is less than 60% of the total volume of the unit dosage form. In some embodiments, the unit dosage form comprises a pharmaceutical composition and a headspace, wherein the headspace volume is less than 55% of the total volume of the unit dosage form. In some embodiments, the unit dosage form comprises a pharmaceutical composition and a headspace, wherein the headspace volume is less than 45% of the total volume of the unit dosage form. In some embodiments, the unit dosage form comprises a pharmaceutical composition and a headspace, wherein the headspace volume is less than 35% of the total volume of the unit dosage form. In some embodiments, the unit dosage form comprises a pharmaceutical composition and a headspace, wherein the headspace volume is less than 25% of the total volume of the unit dosage form. In some embodiments, the unit dosage form comprises a pharmaceutical composition and a headspace, wherein the headspace volume is less than 15% of the total volume of the unit dosage form. In some embodiments, the unit dosage form comprises a pharmaceutical composition and a headspace, wherein the headspace volume is less than 5% of the total volume of the unit dosage form.

[0349] In some embodiments, headspace is minimized by compressing the unit dosage form before sealing the pharmaceutical composition inside the unit dosage form.

[0350] A unit dosage form having a relatively low headspace will have a relatively high gram weight of the pharmaceutical composition relative to its headspace volume. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is [amount] cm of the headspace volume of the unit dosage form. 3 It is present in an amount of at least 0.01 g per. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is cm of the headspace volume of the unit dosage form. 3 It is present in an amount of at least 0.02 g per serving. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is a cm² of the headspace volume of the unit dosage form. 3 It is present in an amount of at least 0.03 g per serving. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is a cm² of the headspace volume of the unit dosage form. 3 It is present in an amount of at least 0.04 g per serving. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is a cm² of the headspace volume of the unit dosage form. 3 It is present in an amount of at least 0.05 g per serving. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is the headspace volume cm of the unit dosage form. 3 It is present in an amount of 0.01 g to 0.5 g per serving. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is the headspace volume cm of the unit dosage form. 3 It is present in an amount of 0.01 g to 0.2 g per serving. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is the headspace volume cm of the unit dosage form. 3It is present in an amount of 0.05 g to 0.2 g per serving. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is the headspace volume cm of the unit dosage form. 3 It exists in an amount of 0.05 g to 0.15 g per day.

[0351] In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 3 g, and wherein the headspace volume of the unit dosage form is 90 cm² 3 It is less. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 3 g, and wherein the headspace volume of the unit dosage form is 75 cm² 3 It is less. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 3 g, and wherein the headspace volume of the unit dosage form is 60 cm² 3 It is less. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 3 g, and wherein the headspace volume of the unit dosage form is 45 cm² 3 It is less than.

[0352] In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 6 g, and wherein the headspace volume of the unit dosage form is 120 cm² 3 It is less. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 6 g, and wherein the headspace volume of the unit dosage form is 105 cm² 3 It is less. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 6 g, and wherein the headspace volume of the unit dosage form is 90 cm² 3It is less. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 6 g, and wherein the headspace volume of the unit dosage form is 75 cm² 3 It is less than.

[0353] In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 9 g, and wherein the headspace volume of the unit dosage form is 140 cm² 3 It is less. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 9 g, and wherein the headspace volume of the unit dosage form is 125 cm² 3 It is less. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 9 g, and wherein the headspace volume of the unit dosage form is 110 cm² 3 It is less. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 9 g, and wherein the headspace volume of the unit dosage form is 95 cm² 3 It is less than.

[0354] A sealed unit dosage form having a relatively low headspace will have a relatively high gram weight of the pharmaceutical composition relative to its total volume. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is a cm³ of the total volume of the sealed unit dosage form. 3 It is present in an amount of at least 0.02 g per gram. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is 1 cm³ of the total volume of the sealed unit dosage form. 3 It is present in an amount of at least 0.03 g per gram. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is 1 cm³ of the total volume of the sealed unit dosage form. 3It is present in an amount of at least 0.04 g per gram. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is 1 cm³ of the total volume of the sealed unit dosage form. 3 It is present in an amount of 0.01 g to 0.5 g per serving. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is 1 cm³ of the total volume of the sealed unit dosage form. 3 It is present in an amount of 0.01 g to 0.25 g per serving. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is 1 cm³ of the total volume of the sealed unit dosage form. 3 It is present in an amount of 0.01 g to 0.15 g per gram. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is 1 cm³ of the total volume of the sealed unit dosage form. 3 It is present in an amount of 0.02 g to 0.1 g per serving. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is 1 cm³ of the total volume of the sealed unit dosage form. 3 It is present in an amount of 0.03 g to 0.08 g per serving. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is 1 cm³ of the total volume of the sealed unit dosage form. 3 It is present in an amount of 0.04 g to 0.07 g per serving. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is 1 cm³ of the total volume of the sealed unit dosage form. 3 It is present in an amount of 0.02 g to 0.2 g per serving. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is 1 cm³ of the total volume of the sealed unit dosage form. 3 It is present in an amount of 0.04 g to 0.18 g per serving. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is 1 cm³ of the total volume of the sealed unit dosage form. 3It exists in an amount of 0.06 g to 0.16 g per day.

[0355] In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 3 g, and wherein the total sealed volume of the unit dosage form is 100 cm³ 3 It is less. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 3 g, and wherein the total sealed volume of the unit dosage form is 90 cm³ 3 It is less. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 3 g, and wherein the total sealed volume of the unit dosage form is 80 cm³ 3 It is less. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 3 g, and wherein the total sealed volume of the unit dosage form is 70 cm³ 3 It is less than.

[0356] In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 6 g, and wherein the total volume of the sealed unit dosage form is 160 cm³ 3 It is less. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 6 g, and wherein the total volume of the sealed unit dosage form is 150 cm³ 3 It is less. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 6 g, and wherein the total volume of the sealed unit dosage form is 140 cm³ 3 It is less. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 6 g, and wherein the total volume of the sealed unit dosage form is 130 cm³ 3 It is less than.

[0357] In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 9 g, and wherein the total volume of the sealed unit dosage form is 200 cm³ 3 It is less. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 9 g, and wherein the total volume of the sealed unit dosage form is 190 cm³ 3 It is less. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 9 g, and wherein the total volume of the sealed unit dosage form is 180 cm³ 3 It is less. In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 9 g, and wherein the total sealed volume of the unit dosage form is 170 cm³ 3 It is less than.

[0358] In some embodiments, the unit dosage form is a sachet. In these embodiments, the sachet has a height (h) and a width (w), the walls of the sachet can be bent but not stretched, and the total volume of the sealed sachet can be estimated according to the following formula X:

[0359] .

[0360] If the dosage form is a sachet, Equation X can be used to define the total volume of the sealed unit dosage form. For example, if the unit dosage form is a sachet, cm of the total volume 3 Any specification of the amount of drug expressed in grams per unit is cm³ of the total sealed volume as estimated by Equation X. 3 It refers to the amount of drug expressed in grams.

[0361] In some embodiments, the unit dosage form is a sachet containing a pharmaceutical composition in an amount of 3 g, 6 g, or 9 g, wherein the width of the sachet is less than 25 cm and the height of the sachet is less than 25 cm. In some embodiments, the unit dosage form is a sachet containing a pharmaceutical composition in an amount of 3 g, 6 g, or 9 g, wherein the width of the sachet is less than 20 cm and the height of the sachet is less than 25 cm. In some embodiments, the unit dosage form is a sachet containing a pharmaceutical composition in an amount of 3 g, 6 g, or 9 g, wherein the width of the sachet is less than 15 cm and the height of the sachet is less than 20 cm. In some embodiments, the unit dosage form is a sachet containing a pharmaceutical composition in an amount of 3 g, 6 g, or 9 g, wherein the width of the sachet is less than 10 cm and the height of the sachet is less than 15 cm.

[0362] In some embodiments, the unit dosage form is a sachet containing 9 g of the pharmaceutical composition, wherein the width of the sachet is less than 25 cm and the height of the sachet is less than 25 cm. In some embodiments, the unit dosage form is a sachet containing 9 g of the pharmaceutical composition, wherein the width of the sachet is less than 20 cm and the height of the sachet is less than 25 cm. In some embodiments, the unit dosage form is a sachet containing 9 g of the pharmaceutical composition, wherein the width of the sachet is less than 15 cm and the height of the sachet is less than 20 cm. In some embodiments, the unit dosage form is a sachet containing 9 g of the pharmaceutical composition, wherein the width of the sachet is less than 10 cm and the height of the sachet is less than 15 cm. In some embodiments, the unit dosage form is a sachet containing 9 g of the pharmaceutical composition, wherein the width of the sachet is less than 9 cm and the height of the sachet is less than 12 cm.

[0363] In some embodiments, the unit dosage form is a sachet containing 6 g of the pharmaceutical composition, wherein the width of the sachet is less than 25 cm and the height of the sachet is less than 25 cm. In some embodiments, the unit dosage form is a sachet containing 6 g of the pharmaceutical composition, wherein the width of the sachet is less than 20 cm and the height of the sachet is less than 25 cm. In some embodiments, the unit dosage form is a sachet containing 6 g of the pharmaceutical composition, wherein the width of the sachet is less than 15 cm and the height of the sachet is less than 20 cm. In some embodiments, the unit dosage form is a sachet containing 6 g of the pharmaceutical composition, wherein the width of the sachet is less than 10 cm and the height of the sachet is less than 15 cm. In some embodiments, the unit dosage form is a sachet containing 6 g of the pharmaceutical composition, wherein the width of the sachet is less than 8 cm and the height of the sachet is less than 11 cm.

[0364] In some embodiments, the unit dosage form is a sachet containing 3 g of the pharmaceutical composition, wherein the width of the sachet is less than 25 cm and the height of the sachet is less than 25 cm. In some embodiments, the unit dosage form is a sachet containing 3 g of the pharmaceutical composition, wherein the width of the sachet is less than 20 cm and the height of the sachet is less than 25 cm. In some embodiments, the unit dosage form is a sachet containing 3 g of the pharmaceutical composition, wherein the width of the sachet is less than 15 cm and the height of the sachet is less than 20 cm. In some embodiments, the unit dosage form is a sachet containing 3 g of the pharmaceutical composition, wherein the width of the sachet is less than 10 cm and the height of the sachet is less than 15 cm. In some embodiments, the unit dosage form is a sachet containing 3 g of the pharmaceutical composition, wherein the width of the sachet is less than 9 cm and the height of the sachet is less than 10 cm. In some embodiments, the unit dosage form is a sachet containing 3 g of the pharmaceutical composition, wherein the width of the sachet is less than 8 cm and the height of the sachet is less than 9 cm.

[0365] Any headspace present in any unit dosage form disclosed herein may be filled with an inert gas, such as nitrogen, or may otherwise contain a reduced level of oxygen gas. Any headspace present in a unit dosage form may contain any gas, and the gas present in the headspace is referred to herein as the headspace gas. In some embodiments, the headspace gas is nitrogen. In some embodiments, the headspace gas is argon. In some embodiments, the headspace gas is helium. In some embodiments, the headspace gas is neon. In some embodiments, the headspace gas is carbon dioxide. In some embodiments, the headspace gas is nitrogen. In some embodiments, the headspace gas is a mixture of the gases mentioned herein. For example, in some embodiments, the headspace gas is a mixture of inert gases, such as a mixture of nitrogen and carbon dioxide. In some embodiments, the mention that the headspace gas is a specific gas means that the headspace gas is essentially made of or consists of the gas mentioned.

[0366] In some embodiments, the headspace gas contains other gases that are not inert, such as oxygen. In some embodiments, the percentage of oxygen present in the headspace gas is less than 21%. In some embodiments, the percentage of oxygen present in the headspace gas is less than 20%. In some embodiments, the percentage of oxygen present in the headspace gas is less than 18%. In some embodiments, the percentage of oxygen present in the headspace gas is less than 16%. In some embodiments, the percentage of oxygen present in the headspace gas is less than 14%. In some embodiments, the percentage of oxygen present in the headspace gas is less than 12%. In some embodiments, the percentage of oxygen present in the headspace gas is less than 10%. In some embodiments, the percentage of oxygen present in the headspace gas is less than 8%. In some embodiments, the percentage of oxygen present in the headspace gas is less than 6%. In some embodiments, the percentage of oxygen present in the headspace gas is less than 4%. In some embodiments, the percentage of oxygen present in the headspace gas is less than 2%. In some embodiments, the percentage of oxygen present in the headspace gas is less than 1%. In some embodiments, the percentage of oxygen present in the headspace gas is less than 0.5%.

[0367] In some embodiments, the headspace gas is a mixture of oxygen and a second gas. In some embodiments, the headspace gas is ≤20% oxygen (O2) and ≥80% nitrogen (N2). In some embodiments, the headspace gas is ≤18% O2 and ≥82% N2. In some embodiments, the headspace gas is ≤16% O2 and ≥84% N2. In some embodiments, the headspace gas is ≤14% O2 and ≥86% N2. In some embodiments, the headspace gas is ≤12% O2 and ≥88% N2. In some embodiments, the headspace gas is ≤10% O2 and ≥90% N2. In some embodiments, the headspace gas is ≤8% O2 and ≥92% N2. In some embodiments, the headspace gas is ≤6% O2 and ≥94% N2. In some embodiments, the headspace gas is ≤4% O2 and ≥96% N2. In some embodiments, the headspace gas is ≤2% O2 and ≥98% N2. In some embodiments, the headspace gas is ≤1% O2 and ≥99% N2. In some embodiments, the headspace gas is ≤0.5% O2 and ≥99.5% N2. In these embodiments, the headspace gas is essentially made of the mentioned gas or may be made of it.

[0368] In other embodiments, the unit dosage form disclosed herein is packaged in air, and / or the headspace of the unit dosage form is air. The headspace gas can be achieved by packaging in the presence of the gas. The headspace gas can also be varied after the packaging step, for example after production, by adding or changing the gas inside the pharmaceutical dosage form, for example through a valve inside the packaging.

[0369] The container material of the composition used for the unit dosage forms disclosed herein may be selected to minimize the ingress of moisture and oxygen into the container after packaging. For example, a poly(allylamine) polymer, e.g., Beberimer, may be packaged in a multilayer sachet containing at least one layer that acts as a barrier layer against the ingress of moisture and oxygen. In another example, the poly(allylamine) polymer may be packaged in a single-layer or multilayer plastic, metal, or glass container having at least one barrier layer included in a structure that restricts the ingress of oxygen and / or moisture after packaging. For example, in one such embodiment, the sachet (or other container or package) may comprise a multilayer laminate comprising an inner contact layer, an outer layer; and a barrier layer disposed between the contact layer and the outer layer. In this embodiment, the multilayer laminate may also comprise one or more adhesive layers and / or printing layers. For example, the laminate may comprise the following layers in the following order: an inner contact layer, an adhesive, a barrier layer, an adhesive, a printing layer, and an outer layer. In some embodiments, one or more of the layers of any multi-laminate disclosed herein may be attached to each other through an adhesive and / or lamination (e.g., lamination by extrusion). In some embodiments, the layers of any multi-laminate disclosed herein are attached to each other through an adhesive and / or lamination (e.g., lamination by extrusion). In some embodiments, the layers of any multi-laminate disclosed herein are attached to each other through an adhesive. In some embodiments, the layers of any multi-laminate disclosed herein are attached to each other through lamination (e.g., lamination by extrusion).

[0370] In one embodiment, the unit dosage form is made of or comprises plastic. For example, the plastic may be polyethylene (e.g., linear low-density polyethylene or low-density polyethylene), polypropylene, poly(ethylene terephthalate), polyester, nylon, or polyvinyl chloride. In this embodiment, the plastic may be in the form of a film or a sheet. For example, if the unit dosage form is a sachet, the sachet may be made of any one of polyethylene, polypropylene, poly(ethylene terephthalate), polyester, nylon, or polyvinyl chloride, optionally as part of a multilayer laminate. In one embodiment, the sachet (or other container or package) comprises a multilayer laminate comprising an inner contact layer, an outer layer; and a barrier layer disposed between the contact layer and the outer layer. In this embodiment, any layer may be made of any of the mentioned plastics. More specifically, the inner contact layer may comprise any one of polyethylene, polypropylene, poly(ethylene terephthalate), polyester, nylon, or polyvinyl chloride. In one embodiment, the inner contact layer comprises polyethylene. In one embodiment, the inner contact layer is linear low-density polyethylene. In one embodiment, the inner contact layer is low-density polyethylene. More specifically, the outer layer may comprise any one of polyethylene, polypropylene, poly(ethylene terephthalate), polyester, nylon, polyvinyl chloride, or paper. In one embodiment, the outer layer is poly(ethylene terephthalate). In one embodiment, the barrier layer may be any aluminum layer disclosed herein. In one embodiment, the barrier layer may comprise any plastic layer disclosed herein and any aluminum layer disclosed herein. For example, the barrier layer may comprise low-density polyethylene and an aluminum film.In one exemplary embodiment, the unit dosage form disclosed herein is a sachet made from a laminate of the following components in the following order: an inner contact layer made of low-density polyethylene, followed by an aluminum film, a barrier layer made of low-density polyethylene, a printing layer made of ink, and an outer layer made of poly(ethylene terephthalate), optionally having an adhesive between any of these layers, optionally wherein the aluminum film is about 18 µm thick. In one exemplary embodiment, the unit dosage form disclosed herein is a sachet made from a laminate of the following components in the following order: an inner contact layer made of low-density polyethylene, followed by an aluminum film, a barrier layer made of low-density polyethylene, a printing layer made of ink, and an outer layer made of poly(ethylene terephthalate), optionally wherein these layers are laminated together by extrusion, optionally wherein the aluminum film is about 18 µm thick.

[0371] In one aspect, the unit dosage form has an outer and an inner layer, the inner layer comprising a cross-linked poly(allylamine) polymer, e.g., Beberimer, wherein the oxygen transfer rate between the outer and inner layers of the unit dosage form is approximately 0.050 cubic centimeters / square meter / day (CC / m²). 2 Less than / day.

[0372] In one aspect, the unit dosage form comprises a sealed enclosure containing a cross-linked poly(allylamine) polymer, e.g., Beberimer, wherein the sealed enclosure comprises a multilayer laminate comprising an inner contact layer, an outer layer; and a barrier layer disposed between the contact layer and the outer layer, wherein the oxygen transfer rate between the multilayer laminates is approximately 0.050 cubic centimeters / cubic meter / day (CC / m²). 2 Less than / day.

[0373] In any aspect, the specified oxygen delivery rate is, in some embodiments, about 0.030 CC / m 2It is less than / day. In any aspect, the specified oxygen delivery rate is, in some embodiments, about 0.010 CC / m² 2 It is less than / day. In any aspect, the specified oxygen delivery rate is, in some embodiments, about 0.009 CC / m² 2 It is less than / day. In any aspect, the specified oxygen delivery rate is, in some embodiments, about 0.007 CC / m² 2 It is less than / day. In any aspect, the specified oxygen delivery rate is, in some embodiments, about 0.005 CC / m² 2 It is less than / day. In any aspect, the specified oxygen delivery rate is, in some embodiments, about 0.003 CC / m² 2 Less than / day.

[0374] Where oxygen delivery rates are specified for the unit dosage forms disclosed herein, said delivery rates may be controlled by selecting appropriate materials and appropriate thicknesses of such materials when constituting the unit dosage forms. Materials that may be used to control the oxygen delivery rates of the unit dosage forms include aluminum, ethylene vinyl alcohol, glass, polyester (e.g., polyethylene terephthalate), and polyamide (e.g., nylon). One or more of these materials may be used to achieve the specified oxygen delivery rates.

[0375] For example, one or more layers of aluminum can be used to control the oxygen delivery rate. Accordingly, in one embodiment, the unit dosage form disclosed herein comprises at least one aluminum layer. For example, the layer containing aluminum may be part of a barrier layer as described herein. More specifically, the layer containing aluminum may be a barrier layer. For example, the barrier layer may comprise any aluminum layer disclosed herein. For example, the barrier layer may essentially consist of any aluminum layer disclosed herein. For example, the barrier layer may consist of any aluminum layer disclosed herein. In some embodiments, the barrier layer and / or the aluminum layer have any one of the oxygen delivery rates disclosed herein when measured alone.

[0376] In one embodiment, the thickness of the aluminum layer disclosed herein is greater than 5 μm. In one embodiment, the thickness of the aluminum layer disclosed herein is greater than 8 μm. In one embodiment, the thickness of the aluminum layer disclosed herein is greater than 10 μm. In one embodiment, the thickness of the aluminum layer disclosed herein is greater than 12 μm. In one embodiment, the thickness of the aluminum layer disclosed herein is greater than 15 μm. In one embodiment, the thickness of the aluminum layer disclosed herein is greater than 18 μm. In one embodiment, the thickness of the aluminum layer disclosed herein is greater than 20 μm. In one embodiment, the thickness of the aluminum layer disclosed herein is greater than 25 μm. In one embodiment, the thickness of the aluminum layer disclosed herein is 9 to 20 μm. In one embodiment, the thickness of the aluminum layer is 15 to 20 μm. In one embodiment, the thickness of the aluminum layer is about 18 μm.

[0377] In any aspect, the unit dosage form is manufactured from a sachet made from a single consistent material, for example, a single type of sheet or multiple laminates. In some embodiments, the unit dosage form may contain different materials in different parts of the unit dosage form (e.g., the ends). In such scenarios, the requirements specified herein for the unit dosage form may apply to one or more of these parts. Or, in such scenarios, the requirements specified herein for the unit dosage form may apply substantially to all of these parts. Or, in such scenarios, the requirements specified herein for the unit dosage form may apply to all of these parts. Thus, for example, the unit dosage form disclosed herein comprises a sealed vial (e.g., made of plastic or glass) sealed by a lid, wherein both parts (lid and vial) have an oxygen delivery rate as specified herein, e.g., 0.005 CC / m² 2 It has less than / day. In this example, the closed vial has an oxygen transfer rate between the outside and inside of a unit dose form as specified herein, e.g., 0.005 CC / m² 2 It may be less than / day.

[0378] In any aspect, the unit dosing form may include layers forming the dosing form, e.g., an inner contact layer, an outer layer and a barrier layer, and potentially additional layers. Any of these layers may achieve the specified oxygen delivery rate alone or together. The layers may be bonded together using an adhesive, heat seal, extrusion lamination, or any other fastening method.

[0379] In one embodiment, the unit dosage form comprises an oxygen scavenger. In one exemplary embodiment, the unit dosage form comprises one or more oxygen-scavenging layers comprising an oxygen scavenger. In one embodiment, the unit dosage form comprises an oxygen scavenger in contact with a cross-linked poly(allylamine) polymer, for example, as an excipient. In one embodiment, the oxygen scavenger is present inside the unit dosage form, for example, in an individual insert. In one embodiment, the oxygen scavenger communicates with the interior of the unit dosage form and is formed, for example, as a lid of the unit dosage form.

[0380] The oxygen scavenger disclosed herein may be any material that absorbs oxygen. In one embodiment, the oxygen scavenger is any material that can be oxidized under ambient conditions. In one embodiment, the oxygen scavenger is one or more of iron (e.g., iron powder or activated iron), ferrous oxide, iron oxide powder, ferrous salt, e.g., ferrous sulfate or ferrous chloride, sulfite, non-sulfite, reduced sulfur compounds, e.g., dithionite, ascorbic acid and / or its salts, Pd, Cu, Zn, Mg, Mn, Co(II), Zn, ascorbic acid, ascorbic acid salts, isoascorbic acid, tocopherol, hydroquinone, catechol, longalite, sorbose, lignin, gallic acid, gallic acid and potassium carbonate, erythorbic acid, quinone, catechol, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), polyunsaturated fatty acids, glucose oxidase, laccase and ethanol oxidase. Additional oxygen scavengers are available, for example, in U.S. Patent Publications Nos. 20060076536, 20070084144, and 20060260967. Oxygen scavengers are commercially available, for example, as StabilOx® (MultisorbTechnologies), cyclohexene methyl acrylate (EMCM) polymer (Chevron-Phillips Chemical Company), or SHELFPLUS™ of Ciba's Specialty Chemical. In one exemplary embodiment, the scavenger is iron.

[0381] In one embodiment, the oxygen scavenger unit dosing form comprises one or more oxygen-scavenging layers containing an oxygen scavenger. Such layers are known in the art, for example, see the document [Gaikwad et al., Environmental Chemistry Letters volume 16, pages 523-538 (2018)]. In one embodiment, the unit dosing form disclosed herein comprises a layer (film) as disclosed by Gaikwad et al., specifically any one of those disclosed in Table 2 of Gaikwad et al., or a combination thereof. In one embodiment, the unit dosing form disclosed herein comprises a layer (film) as disclosed in Table 3 of Gaikwad et al., or a combination thereof. In one embodiment, the unit dosing form disclosed herein comprises a layer (film) as disclosed in the document [Gaikwad et al.], specifically any one of those disclosed in the "Multilayer Active Film" section, or a combination thereof. In fact, such layers are already commercially available, and, for example, the unit dosage forms disclosed herein may include Oxy Vanish-Dry Film (Mitsubishi), Ageless Omac (Mitsubishi), Activ-Films™ (Sorbead India), Oxbar (Crown, Cork and Seal), Amosorb 3000 (AMOCO), Self Plus (Ciba Specialty Chemicals), ZERO2 (Visy Industries), and OS1000 (Cryovac Sealed Air). In one exemplary embodiment, the unit dosage form disclosed herein comprises an oxyvarnish-dry film (Mitsubishi).

[0382] An additional aspect of the present disclosure is a product comprising a plurality of unit dosage forms disclosed herein. The product may further comprise one or more oxygen scavengers as defined herein. For example, the product may comprise individual containers containing oxygen scavengers in addition to the plurality of unit dosage forms.

[0383] In one embodiment, the product and / or unit dosage form includes a statement that the product has a shelf life of at least one year. In one embodiment, the product and / or unit dosage form includes a statement that the product has a shelf life of one year. In one embodiment, the product and / or unit dosage form includes a statement that the product has a shelf life of at least two years. In one embodiment, the product and / or unit dosage form includes a statement that the product has a shelf life of two years. In one embodiment, the product and / or unit dosage form includes a statement that the product has a shelf life of at least three years. In one embodiment, the product and / or unit dosage form includes a statement that the product has a shelf life of three years. In one embodiment, the product and / or unit dosage form includes a statement that the product has a shelf life of at least four years. In one embodiment, the product and / or unit dosage form includes a statement that the product has a shelf life of four years. In one embodiment, the product and / or unit dosage form includes a statement that the product has a shelf life of at least five years. In one embodiment, the product and / or unit dosage form includes a statement that the product has a shelf life of five years.

[0384] In any of these embodiments, the description regarding the shelf life may specify that the shelf life begins from the date of manufacture (e.g., the description may specify that the product must be used within two years of manufacture). and / or in any of these embodiments, the description regarding the shelf life may be expressed by an expiration date (or a similar description), in which case the shelf life is the difference between the expiration date and the date on which the expiration date is read (e.g., the expiration date may be more than two years after the date on which it is read, in which case the shelf life will be more than two years).

[0385] The unit dosage forms disclosed herein may exhibit a high degree of stability. For example, a cross-linked poly(allylamine) polymer, e.g., Beberimer, will not contain significant amounts of impurities even after storage for an extended period, e.g., at least 1, 2, 3, 4, or 5 years.

[0386] In one embodiment, the unit dosage form disclosed herein protects a cross-linked poly(allylamine) polymer, e.g., Beberimer, so that the polymer will have less than 20 ppm of CH2CHCH2NH2 after at least 5 years after being placed in the unit dosage form. In one embodiment, the unit dosage form disclosed herein protects a cross-linked poly(allylamine) polymer, e.g., Beberimer, so that the polymer will have less than 15 ppm of CH2CHCH2NH2 after at least 5 years after being placed in the unit dosage form. In one embodiment, the unit dosage form disclosed herein protects a cross-linked poly(allylamine) polymer, e.g., Beberimer, so that the polymer will have less than 20 ppm of CH2CHCH2NH2 after at least 4 years after being placed in the unit dosage form. In one embodiment, the unit dosage form disclosed herein protects a cross-linked poly(allylamine) polymer, e.g., Beberimer, so that the polymer will have less than 15 ppm of CH2CHCH2NH2 after at least 4 years after being placed in the unit dosage form. In one embodiment, the unit dosage form disclosed herein protects a cross-linked poly(allylamine) polymer, e.g., Bebermer, so that the polymer will have less than 20 ppm of CH2CHCH2NH2 after at least 3 years after being placed in the unit dosage form. In one embodiment, the unit dosage form disclosed herein protects a cross-linked poly(allylamine) polymer, e.g., Bebermer, so that the polymer will have less than 15 ppm of CH2CHCH2NH2 after at least 3 years after being placed in the unit dosage form. In one embodiment, the unit dosage form disclosed herein protects a cross-linked poly(allylamine) polymer, e.g., Bebermer, so that the polymer will have less than 20 ppm of CH2CHCH2NH2 after at least 2 years after being placed in the unit dosage form. In one embodiment, the unit dosage form disclosed herein protects a cross-linked poly(allylamine) polymer, e.g., Bebermer, so that the polymer will have less than 15 ppm of CH2CHCH2NH2 after at least 2 years after being placed in the unit dosage form.In one embodiment, the unit dosage form disclosed herein protects a cross-linked poly(allylamine) polymer, e.g., Beberimer, so that the polymer will have less than 20 ppm CH2CHCH2NH2 at least one year after being placed in the unit dosage form. In one embodiment, the unit dosage form disclosed herein protects a cross-linked poly(allylamine) polymer, e.g., Beberimer, so that the polymer will have less than 15 ppm CH2CHCH2NH2 at least one year after being placed in the unit dosage form. In all these embodiments, the purity requirement referred to using the term "at least X years after being placed in the unit dosage form" discloses an option that the purity requirement is also met in X years.

[0387] Therapeutic methods and medical uses of cross-linked poly(allylamine) polymers

[0388] The therapeutic methods and medical uses of the cross-linked poly(allylamine) polymers, particularly Beberimers, disclosed herein are described in WO2014 / 197725 A1, WO2016 / 094685 A1, WO2017 / 193050 A1, WO2017 / 193064 A1, WO2017 / 193024 A1, WO2019 / 090176 A1, WO2019 / 090177 A1, WO2019 / 236639 A1, WO2019 / 236636 A1 and WO2019 / 236124 A1, which are incorporated herein by reference.

[0389] According to one aspect of the present disclosure, the cross-linked poly(allylamine) polymers disclosed herein, particularly Beberimers, are intended for use in any therapeutic method or medical use as described in any of WO2014 / 197725 A1, WO2016 / 094685 A1, WO2017 / 193050 A1, WO2017 / 193064 A1, WO2017 / 193024 A1, WO2019 / 090176 A1, WO2019 / 090177 A1, WO2019 / 236639 A1, WO2019 / 236636 A1 and WO2019 / 236124 A1.

[0390] For example, the cross-linked poly(allylamine) polymers disclosed herein, particularly Beberimers, are intended for use in any method for treating acid-base disorders, such as metabolic acidosis, as described in any of WO2014 / 197725 A1, WO2016 / 094685 A1, WO2017 / 193050 A1, WO2017 / 193064 A1, WO2017 / 193024 A1, WO2019 / 090176 A1, WO2019 / 090177 A1, WO2019 / 236639 A1, WO2019 / 236636 A1 and WO2019 / 236124 A1.

[0391] The baseline serum bicarbonate value may be a serum bicarbonate concentration determined at a single time point, or the average or median of two or more serum bicarbonate concentrations determined at two or more time points. For example, in one embodiment, the baseline serum bicarbonate value may be a value of serum bicarbonate concentration determined at a single time point, and the baseline serum bicarbonate value is used as a basis for determining an acute acidic condition requiring immediate treatment. In another embodiment, the baseline serum bicarbonate therapeutic value is the average value of serum bicarbonate concentrations for serum samples taken at different time points (e.g., different days). Additionally, for example, in this one embodiment, the baseline serum bicarbonate therapeutic value is the average value of serum bicarbonate concentrations for serum samples taken at different days (e.g., at least 2, 3, 4, 5 days or more, which may be consecutive or separated by more than 1 day or even more than 1 week). Additionally, for example, in one embodiment, the baseline serum bicarbonate treatment value is the average value of serum bicarbonate concentrations for serum samples taken on two consecutive days prior to the start of treatment.

[0392] In one embodiment, the baseline serum bicarbonate value is the value of the serum bicarbonate concentration determined at a single time point. In another embodiment, the baseline serum bicarbonate value is the average value of at least two serum bicarbonate concentrations determined at different time points. For example, in this one embodiment, the baseline serum bicarbonate value is the average value of at least two serum bicarbonate concentrations for serum samples taken on different days. As an additional example, the baseline serum bicarbonate value is the average or median of at least two serum bicarbonate concentrations for serum samples taken on non-consecutive days. Additionally, for example, in this one method, the non-consecutive days are separated by at least two days. Additionally, for example, in this one method, the non-consecutive days are separated by at least one week. Additionally, for example, in this one method, the non-consecutive days are separated by at least two weeks. Additionally, for example, in this one method, the non-consecutive days are separated by at least three weeks.

[0393] In a specific embodiment, the subject is treated with a daily dose for a period of at least one day. For example, in one such embodiment, the subject is treated with a daily dose for a period of at least one week. Additionally, for example, in one such embodiment, the subject is treated with a daily dose for a period of at least one month. Additionally, for example, in one such embodiment, the subject is treated with a daily dose for a period of at least two months. Additionally, for example, in one such embodiment, the subject is treated with a daily dose for a period of at least three months. Additionally, for example, in one such embodiment, the subject is treated with a daily dose for a period of at least several months. Additionally, for example, in one such embodiment, the subject is treated with a daily dose for a period of at least six months. Additionally, for example, in one such embodiment, the subject is treated with a daily dose for a period of at least one year.

[0394] Treatment of individuals suffering from cancer and diabetes

[0395] The literature [Gillies et al. (BBA - Reviews on Cancer 1871 (2019) 273-280)] describes the effects of acidosis on cancer progression and diabetes. Acidification of the tumor microenvironment causes significant sequelae of cancer progression, including increased invasion and metastasis. Acidification also affects diabetes by preventing insulin from binding to its receptors, thereby causing peripheral resistance and worsening of symptoms.

[0396] Gillies et al. propose acidosis as a relevant therapeutic target for the treatment of cancer and describe three approaches for targeting: buffers, nanomedicines, and proton pump inhibitors. Gillies et al. concluded that directly targeting extracellular acidity has been shown to provide preclinical or clinical benefits in cancer and diabetes. A number of therapeutic agents are proposed, including a commercially available mix of bicarbonate and carbonate salts for controlling melanoma growth.

[0397] Beberimer (TRC101) is mentioned by Gillis et al. as an alternative agent that can be used to directly raise pH. A further aspect of the present disclosure is a composition comprising the cross-linked poly(allylamine) polymer described herein, in particular Beberimer, for use in treating individuals suffering from cancer.

[0398] In this respect, cancer is associated with acidosis. In this respect, acidosis is metabolic acidosis. In this respect, acidosis is lactic acidosis.

[0399] A further aspect of the present disclosure is a composition comprising the cross-linked poly(allylamine) polymer described herein, in particular Beberimer, for use in treating diabetes mellitus.

[0400] In this respect, diabetes is Type 1 diabetes. In this respect, diabetes is Type 2 diabetes.

[0401] The present disclosure further includes the embodiments listed below.

[0402] Embodiment 1. A method for preparing a cross-linked poly(allylamine) polymer comprising the following steps:

[0403] (a) As a first step, a poly(allylamine) polymer in the form of beads is formed in a polymerization and crosslinking co-reaction mixture comprising 2-propene-1-ylamine or its salt, 1,3-bis(allylamino)propane or its salt, a radical polymerization initiator, a surfactant, an acid, water, and an organic solvent system, wherein less than 1.1% of the total number of carbon atoms contained in the poly(allylamine) polymer is sp 2 allyl carbon phase,

[0404] (b) As a second step, further crosslinking the poly(allylamine) polymer in a reaction mixture comprising 1,2-dichloroethane, a swelling agent for the poly(allylamine) polymer, and a dispersion solvent system to form a crosslinked poly(allylamine) polymer having a swelling ratio of less than 2.

[0405] Embodiment 2. In any of the embodiments listed above, sp included in the poly(allylamine) polymer 2 A method in which the allyl carbon constitutes less than 1.0% of the total number of carbon atoms included in the poly(allylamine) polymer formed in the first step.

[0406] Embodiment 3. In any of the embodiments listed above, sp included in the poly(allylamine) polymer 2 A method in which the allyl carbon constitutes less than 0.9% of the total number of carbon atoms included in the poly(allylamine) polymer formed in the first step.

[0407] Embodiment 4. In any of the embodiments listed above, sp included in the poly(allylamine) polymer 2 A method in which the allyl carbon constitutes less than 0.8% of the total number of carbon atoms included in the poly(allylamine) polymer formed in the first step.

[0408] Embodiment 5. In any of the embodiments listed above, sp included in the poly(allylamine) polymer 2 A method in which the allyl carbon constitutes less than 0.75% of the total number of carbon atoms included in the poly(allylamine) polymer formed in the first step.

[0409] Embodiment 6. In any of the embodiments listed above, sp included in the poly(allylamine) polymer 2 A method in which the allyl carbon constitutes less than 0.7% of the total number of carbon atoms included in the poly(allylamine) polymer formed in the first step.

[0410] Embodiment 7. In any of the embodiments listed above, sp included in the poly(allylamine) polymer 2 A method in which the allyl carbon constitutes less than 0.6% of the total number of carbon atoms included in the poly(allylamine) polymer formed in the first step.

[0411] Embodiment 8. In any of the embodiments listed above, sp included in the poly(allylamine) polymer 2 A method in which the allyl carbon constitutes less than 0.5% of the total number of carbon atoms included in the poly(allylamine) polymer formed in the first step.

[0412] Embodiment 9. In any of the embodiments listed above, sp included in the poly(allylamine) polymer 2 A method in which the allyl carbon constitutes less than 0.4% of the total number of carbon atoms included in the poly(allylamine) polymer formed in the first step.

[0413] Embodiment 10. In any one of the listed embodiments 1-10, sp included in the poly(allylamine) polymer 2 A method in which the allyl carbon constitutes more than 0.3% of the total number of carbon atoms contained in the poly(allylamine) polymer formed in the first step.

[0414] Embodiment 11. In any of the embodiments listed above, sp included in the poly(allylamine) polymer2 A method in which the allyl carbon constitutes less than 0.3% of the total number of carbon atoms included in the poly(allylamine) polymer formed in the first step.

[0415] Embodiment 12. In any of the embodiments listed above, sp included in the poly(allylamine) polymer 2 A method in which the allyl carbon constitutes less than 0.25% of the total number of carbon atoms included in the poly(allylamine) polymer formed in the first step.

[0416] Embodiment 13. In any of the embodiments listed above, sp included in the poly(allylamine) polymer 2 A method in which the allyl carbon constitutes less than 0.2% of the total number of carbon atoms included in the poly(allylamine) polymer formed in the first step.

[0417] Embodiment 14. In any of the embodiments listed above, sp included in the poly(allylamine) polymer 2 A method in which the allyl carbon constitutes less than 0.1% of the total number of carbon atoms included in the poly(allylamine) polymer formed in the first step.

[0418] Embodiment 15. In any of the embodiments listed above, sp included in the poly(allylamine) polymer 2 A method in which the allyl carbon constitutes less than 0.05% of the total number of carbon atoms included in the poly(allylamine) polymer formed in the first step.

[0419] Embodiment 16. In any of the embodiments listed above, sp included in the poly(allylamine) polymer 2 A method or poly(allylamine) polymer in which the number of allyl carbons (if present) is below the detection limit when determined by NMR.

[0420] Embodiment 17. In any of the embodiments listed above, sp included in the poly(allylamine) polymer 2The percentage of allyl carbon is determined by NMR; arbitrarily here between 110 and 150 ppm sp⁻¹ 2 % sp of the poly(allylamine) polymer using the following formula, by integrating the allyl carbon peak and the alkyl carbon peak between 0 and 80 ppm. 2 A method for quantifying allyl carbon:

[0421] .

[0422] Embodiment 18. In any of the embodiments listed above, sp included in the poly(allylamine) polymer formed in the first step 2 When the percentage of allylic carbon (if present) is determined by NMR, sp 2 Below the detection limit for allyl carbon; optionally here between 110 and 150 ppm sp 2 % sp of the poly(allylamine) polymer using the following formula, by integrating the allyl carbon peak and the alkyl carbon peak between 0 and 80 ppm. 2 A method for quantifying allyl carbon:

[0423] .

[0424] Embodiment 19. A method in which, in any of the embodiments listed above, the poly(allylamine) polymer formed in the first step has a swelling ratio of less than 10.

[0425] Embodiment 20. A method in which, in any of the embodiments listed above, the poly(allylamine) polymer formed in the first step has a swelling ratio of less than 9.

[0426] Embodiment 21. A method in which, in any of the embodiments listed above, the poly(allylamine) polymer formed in the first step has a swelling ratio of less than 8.

[0427] Embodiment 22. A method in which, in any of the embodiments listed above, the poly(allylamine) polymer formed in the first step has a swelling ratio of less than 7.

[0428] Embodiment 23. A method in which, in any of the embodiments listed above, the poly(allylamine) polymer formed in the first step has a swelling ratio of less than 6.

[0429] Embodiment 24. A method in which, in any of the embodiments listed above, the poly(allylamine) polymer formed in the first step has a swelling ratio of less than 5.

[0430] Embodiment 25. A method in which, in any of the embodiments listed above, the poly(allylamine) polymer formed in the first step has a swelling ratio of at least 4.

[0431] Embodiment 26. A method in which, in any of the embodiments listed above, the poly(allylamine) polymer formed in the first step has a swelling ratio of at least 3.

[0432] Embodiment 27. A method in which, in any of the embodiments listed above, the cross-linked poly(allylamine) polymer contains less than 20 ppm of allylamine.

[0433] Embodiment 28. A method in which, in any of the embodiments listed above, the polymerization and crosslinking co-reaction mixture comprises a radical polymerization selected from the group consisting of cationic and free-radical polymerization initiators.

[0434] Embodiment 29. A method in which, in any of the embodiments listed above, the polymerization and crosslinking co-reaction mixture comprises a free-radical polymerization initiator selected from free-radical peroxypolymerization initiators and azopolymerization initiators.

[0435] Embodiment 30. In any of the embodiments listed above, the polymerization and crosslinking co-reaction mixture comprises azodiisobutyronitrile, azodiisovaleronitrile, dimethylazodiisobutyrate, 2,2'-azobis(isobutyronitrile), 2,2'-azobis(N,N'-dimethyl-enisobutyramidine) dihydrochloride, 2,2'-azobis(2-methylpropionamidine) dihydrochloride, 2,2'-azobis(2-amidinopropane) dihydrochloride, 2,2'-azobis(N,N'-dimethyleneisobutyramidine), 1,1-azobis(l-cyclohexanecarbonitrile), 4,4'-azobis(4-cyanopentanic acid), A method comprising a free-radical polymerization initiator selected from the group consisting of 2,2'-azobis(isobutyramide) dihydrate, 2,2'-azobis(2-methylpropane), 2,2'-azobis(2-methylbutyronitrile), VAZO 67, cyanopentanic acid, peroxypivalate, dodecylbenzene peroxide, benzoyl peroxide, di-t-butyl hydroperoxide, t-butyl peracetate, acetyl peroxide, dicumyl peroxide, cumyl hydroperoxide, and dimethyl bis(butylperoxy)hexane.

[0436] Embodiment 31. A method in which, in any of the embodiments listed above, the ratio of the combined allyl equivalents of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in the polymerization and crosslinking co-reaction mixture to the initiator equivalents is each in the range of about 6:1 to about 70:1.

[0437] Embodiment 32. A method in which, in any of the embodiments listed above, the combined allyl equivalent to initiator equivalent of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in the polymerization and crosslinking co-reaction mixture is in the range of about 7:1 to about 60:1.

[0438] Embodiment 33. A method in which, in any of the embodiments listed above, the combined allyl equivalent to initiator equivalent of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in the polymerization and crosslinking co-reaction mixture is in the range of about 8:1 to about 50:1.

[0439] Embodiment 34. A method in which, in any of the embodiments listed above, the combined allyl equivalent to initiator equivalent of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in the polymerization and crosslinking co-reaction mixture is in the range of about 10:1 to about 45:1.

[0440] Embodiment 35. A method in which, in any of the embodiments listed above, the combined allyl equivalent to initiator equivalent of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in the polymerization and crosslinking co-reaction mixture is each in the range of about 15:1 to about 40:1.

[0441] Embodiment 36. A method in which, in any of the embodiments listed above, the combined allyl equivalent to initiator equivalent of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in the polymerization and crosslinking co-reaction mixture is each in the range of about 17.5:1 to about 35:1.

[0442] Embodiment 37. A method in which, in any of the embodiments listed above, the combined allyl equivalent to initiator equivalent of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in the polymerization and crosslinking co-reaction mixture is each in the range of about 20:1 to about 30:1.

[0443] Embodiment 38. A method in which, in any of the embodiments listed above, the combined allyl equivalent to initiator equivalent of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in the polymerization and crosslinking co-reaction mixture is each in the range of about 22.5:1 to about 30:1.

[0444] Embodiment 39. A method in which, in any of the embodiments listed above, the combined allyl equivalent to initiator equivalent of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in the polymerization and crosslinking co-reaction mixture is in the range of about 25:1 to about 27.5:1.

[0445] Embodiment 40. A method in which, in any of the embodiments listed above, the weight ratio of the combined amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the amount of water in the polymerization and crosslinking co-reaction mixture is each in the range of about 0.01 to about 3, wherein the weight ratio is calculated using the weight of 2-propene-1-ylamine and 1,3-bis(allylamino)propane in their respective free amine forms.

[0446] Embodiment 41. A method in which, in any of the embodiments listed above, the weight ratio of the combined amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the amount of water in the polymerization and crosslinking co-reaction mixture is each in the range of about 0.05 to about 2.75, wherein the weight ratio is calculated using the weight of 2-propene-1-ylamine and 1,3-bis(allylamino)propane in their respective free amine forms.

[0447] Embodiment 42. A method in which, in any of the embodiments listed above, the weight ratio of the combined amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the amount of water in the polymerization and crosslinking co-reaction mixture is each in the range of about 0.07 to about 2.5, wherein the weight ratio is calculated using the weight of 2-propene-1-ylamine and 1,3-bis(allylamino)propane in their respective free amine forms.

[0448] Embodiment 43. A method in which, in any of the embodiments listed above, the weight ratio of the combined amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the amount of water in the polymerization and crosslinking co-reaction mixture is each in the range of about 0.1 to about 2.25, wherein the weight ratio is calculated using the weight of 2-propene-1-ylamine and 1,3-bis(allylamino)propane in their respective free amine forms.

[0449] Embodiment 44. A method in which, in any of the embodiments listed above, the weight ratio of the combined amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the amount of water in the polymerization and crosslinking co-reaction mixture is each in the range of about 0.15 to about 2, wherein the weight ratio is calculated using the weight of 2-propene-1-ylamine and 1,3-bis(allylamino)propane in their respective free amine forms.

[0450] Embodiment 45. A method in which, in any of the embodiments listed above, the weight ratio of the combined amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the amount of water in the polymerization and crosslinking co-reaction mixture is each in the range of about 0.2 to about 1.75, wherein the weight ratio is calculated using the weight of 2-propene-1-ylamine and 1,3-bis(allylamino)propane in their respective free amine forms.

[0451] Embodiment 46. A method in which, in any of the embodiments listed above, the weight ratio of the combined amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the amount of water in the polymerization and crosslinking co-reaction mixture is each in the range of about 0.25 to about 1.5, wherein the weight ratio is calculated using the weight of 2-propene-1-ylamine and 1,3-bis(allylamino)propane in their respective free amine forms.

[0452] Embodiment 47. A method in which, in any of the embodiments listed above, the weight ratio of the combined amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the amount of water in the polymerization and crosslinking co-reaction mixture is each in the range of about 0.25 to about 1.25, wherein the weight ratio is calculated using the weight of 2-propene-1-ylamine and 1,3-bis(allylamino)propane in their respective free amine forms.

[0453] Embodiment 48. A method in which, in any of the embodiments listed above, the weight ratio of the combined amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the amount of water in the polymerization and crosslinking co-reaction mixture is each in the range of about 0.3 to about 1, wherein the weight ratio is calculated using the weight of 2-propene-1-ylamine and 1,3-bis(allylamino)propane in their respective free amine forms.

[0454] Embodiment 49. A method in which, in any of the embodiments listed above, the weight ratio of the combined amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the amount of water in the polymerization and crosslinking co-reaction mixture is in the range of about 0.35 to about 0.75, wherein the weight ratio is calculated using the weight of 2-propene-1-ylamine and 1,3-bis(allylamino)propane in their respective free amine forms.

[0455] Embodiment 50. A method in which, in any of the embodiments listed above, the weight ratio of the combined amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the amount of water in the polymerization and crosslinking co-reaction mixture is each in the range of about 0.4 to about 0.5, wherein the weight ratio is calculated using the weight of 2-propene-1-ylamine and 1,3-bis(allylamino)propane in their respective free amine forms.

[0456] Embodiment 51. A method in which, in any of the embodiments listed above, the ratio of allyl equivalents to water equivalents in the polymerization and crosslinking co-reaction mixture is each in the range of about 0.01:1 to about 1:1.

[0457] Embodiment 52. A method in which, in any of the embodiments listed above, the ratio of allyl equivalents to water equivalents in the polymerization and crosslinking co-reaction mixture is each in the range of about 0.015:1 to about 0.75:1.

[0458] Embodiment 53. A method in which, in any of the embodiments listed above, the ratio of allyl equivalents to water equivalents in the polymerization and crosslinking co-reaction mixture is each in the range of about 0.02:1 to about 0.5:1.

[0459] Embodiment 54. A method in which, in any of the embodiments listed above, the ratio of allyl equivalents to water equivalents in the polymerization and crosslinking co-reaction mixture is each in the range of about 0.03:1 to about 0.4:1.

[0460] Embodiment 55. A method in which, in any of the embodiments listed above, the ratio of allyl equivalents to water equivalents in the polymerization and crosslinking co-reaction mixture is in the range of about 0.04:1 to about 0.3:1, respectively.

[0461] Embodiment 56. A method in which, in any of the embodiments listed above, the ratio of allyl equivalents to water equivalents in the polymerization and crosslinking co-reaction mixture is each in the range of about 0.05:1 to about 0.25:1.

[0462] Embodiment 57. A method in which, in any of the embodiments listed above, the ratio of allyl equivalents to water equivalents in the polymerization and crosslinking co-reaction mixture is in the range of about 0.06:1 to about 0.2:1, respectively.

[0463] Embodiment 58. A method in which, in any of the embodiments listed above, the ratio of allyl equivalents to water equivalents in the polymerization and crosslinking co-reaction mixture is each in the range of about 0.07:1 to about 0.175:1.

[0464] Embodiment 59. A method in which, in any of the embodiments listed above, the ratio of allyl equivalents to water equivalents in the polymerization and crosslinking co-reaction mixture is each in the range of about 0.08:1 to about 0.15:1.

[0465] Embodiment 60. A method in which, in any of the embodiments listed above, the surfactant included in the polymerization and crosslinking co-reaction mixture comprises an ionic or non-ionic surfactant.

[0466] Embodiment 61. A method in which, in any of the embodiments listed above, the surfactant included in the polymerization and crosslinking co-reaction mixture comprises an ionic surfactant.

[0467] Embodiment 62. A method in which, in any of the embodiments listed above, the surfactant included in the polymerization and crosslinking co-reaction mixture comprises a non-ionic surfactant.

[0468] Embodiment 63. In any of the embodiments listed above, the surfactant included in the polymerization and crosslinking co-reaction mixture is an ionic or selected from the group consisting of sorbitan monolaurate, sorbitan monooleate, sorbitan monostearate, sorbitan monopalmitate, ethylene glycol monostearate, glyceryl monostearate, polyethylene glycol monostearate, polyethylene glycol hydrogenated castor oil, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polyethylene glycol and diisooctyl sulfosuccinate, branched dodecylbenzenesulfonic acid, linear dodecylbenzenesulfonic acid, sodium branched alkylbenzenesulfonate, sodium branched dodecylbenzenesulfonate, sodium alpha-olefin sulfonate, sodium linear alkylbenzenesulfonate, isopropylamine branched alkylbenzenesulfonate and sodium lauryl sulfate. A method using a non-ionic surfactant.

[0469] Embodiment 64. A method in which, in any of the embodiments listed above, the surfactant included in the polymerization and crosslinking co-reaction mixture is branched dodecylbenzenesulfonic acid.

[0470] Embodiment 65. A method in which, in any of the embodiments listed above, the organic solvent system included in the polymerization and crosslinking co-reaction mixture comprises a water-immiscible organic solvent.

[0471] Embodiment 66. A method in which, in any of the embodiments listed above, the organic solvent system included in the polymerization and crosslinking co-reaction mixture comprises hexane, cyclohexane, heptane, octane, decane, petroleum ether, liquid paraffin, chlorobenzene, toluene, xylene, ethyl acetate, propyl acetate and isopropyl acetate, or a combination of two or more of these.

[0472] Embodiment 67. A method in which, in any of the embodiments listed above, the organic solvent system included in the polymerization and crosslinking co-reaction mixture comprises heptane.

[0473] Embodiment 68. A method in which, in any of the embodiments listed above, the organic solvent system included in the polymerization and crosslinking co-reaction mixture is composed of heptane.

[0474] Embodiment 69. A method in which, in any of the embodiments listed above, the polymerization and crosslinking co-reaction mixture is heated to a temperature in the range of about 25°C to about 85°C.

[0475] Embodiment 70. A method in which, in any of the embodiments listed above, the polymerization and crosslinking co-reaction mixture is heated to a temperature in the range of about 30°C to about 85°C.

[0476] Embodiment 71. A method in which, in any of the embodiments listed above, the polymerization and crosslinking co-reaction mixture is heated to a temperature in the range of about 35°C to about 85°C.

[0477] Embodiment 72. A method in which, in any of the embodiments listed above, the polymerization and crosslinking co-reaction mixture is heated to a temperature in the range of about 40°C to about 85°C.

[0478] Embodiment 73. A method in which, in any of the embodiments listed above, the polymerization and crosslinking co-reaction mixture is heated to about 45°C to about 85°C.

[0479] Embodiment 74. A method in which, in any of the embodiments listed above, the polymerization and crosslinking co-reaction mixture is heated to about 60°C to about 80°C.

[0480] Embodiment 75. A method in which, in any of the embodiments listed above, the temperature of the polymerization and crosslinking co-reaction mixture is maintained relatively constant throughout the reaction process.

[0481] Embodiment 76. A method in which, in any of the embodiments listed above, the temperature of the polymerization and crosslinking co-reaction mixture is increased or decreased in a continuous or stepwise manner over the reaction process.

[0482] Embodiment 77. A method in which, in any of the embodiments listed above, the polymerization and crosslinking co-reaction steps are carried out for a reaction time of at least about 2 hours.

[0483] Embodiment 78. A method in which, in any of the embodiments listed above, the polymerization and crosslinking co-reaction steps are carried out for a reaction time of at least about 5 hours.

[0484] Embodiment 79. A method in which, in any of the embodiments listed above, the polymerization and crosslinking co-reaction steps are carried out for a reaction time of at least about 10 hours.

[0485] Embodiment 80. A method in which, in any of the embodiments listed above, the polymerization and crosslinking co-reaction steps are carried out for a reaction time of at least about 15 hours.

[0486] Embodiment 81. A method in which, in any of the embodiments listed above, the polymerization and crosslinking co-reaction steps are carried out for a reaction time of at least about 20 hours.

[0487] Embodiment 82. A method in which, in any of the embodiments listed above, the polymerization and crosslinking co-reaction steps are carried out for a reaction time of at least about 25 hours.

[0488] Embodiment 83. A method in which, in any of the embodiments listed above, the polymerization and crosslinking co-reaction steps are carried out for a reaction time of at least about 30 hours.

[0489] Embodiment 84. A method in which, in any of the embodiments listed above, the polymerization and crosslinking co-reaction steps are carried out for a reaction time of at least about 35 hours.

[0490] Embodiment 85. A method in which, in any of the embodiments listed above, the polymerization and crosslinking co-reaction steps are carried out for a reaction time of at least about 40 hours.

[0491] Embodiment 86. A method in which, in any of the embodiments listed above, the polymerization and crosslinking co-reaction steps are carried out for a reaction time of at least about 50 hours.

[0492] Embodiment 87. A method in which, in any of the embodiments 77-80 listed above, the polymerization and crosslinking co-reaction steps are performed for a reaction time of less than 16 hours.

[0493] Embodiment 88. A method in which, in any of the embodiments listed above, the polymerization and crosslinking co-reaction steps are performed as a batch process.

[0494] Embodiment 89. A method in which, in any of the embodiments listed above, the polymerization and crosslinking co-reaction steps are performed as a semi-batch process.

[0495] Embodiment 90. A method in which, in any of the embodiments listed above, the polymerization and crosslinking co-reaction steps are performed as a continuous process.

[0496] Embodiment 91. A method in which, in any of the embodiments listed above, the reaction mixture of the polymerization and crosslinking co-reaction step comprises at least 0.4 equivalents of acid per allylamine equivalent.

[0497] Embodiment 92. A method in which, in any of the embodiments listed above, the reaction mixture of the polymerization and crosslinking co-reaction step comprises at least 0.6 equivalents of acid per allylamine equivalent.

[0498] Embodiment 93. A method in which, in any of the embodiments listed above, the reaction mixture of the polymerization and crosslinking co-reaction step comprises at least 0.8 equivalents of acid per allylamine equivalent.

[0499] Embodiment 94. A method in which, in any of the embodiments listed above, the reaction mixture of the polymerization and crosslinking co-reaction step comprises at least 0.9 equivalents of acid per allylamine equivalent.

[0500] Embodiment 95. A method in which, in any of the embodiments listed above, the reaction mixture of the polymerization and crosslinking co-reaction step comprises at least 0.95 equivalents of acid per equivalent of allylamine.

[0501] Embodiment 96. A method in which, in any of the embodiments listed above, the reaction mixture of the polymerization and crosslinking co-reaction step comprises at least 1.0 equivalent of acid per allylamine equivalent.

[0502] Embodiment 97. A method in which, in any of the embodiments listed above, the reaction mixture of the polymerization and crosslinking co-reaction step comprises at least 1 equivalent of acid per equivalent of allylamine.

[0503] Embodiment 98. A method in which, in any of the embodiments listed above, the polymerization and crosslinking co-reaction step reaction mixture comprises an acid selected from the group consisting of hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, methyl phosphoric acid, formic acid, citric acid, and combinations thereof.

[0504] Embodiment 99. A method in which, in any of the embodiments listed above, the acid is an inorganic acid.

[0505] Embodiment 100. A method in which, in any of the embodiments listed above, the acid comprises hydrochloric acid, sulfuric acid, or phosphoric acid.

[0506] Embodiment 101. A method in which, in any of the embodiments listed above, the acid comprises hydrochloric acid.

[0507] Embodiment 102. A method in which, in any of the embodiments listed above, the acid is hydrochloric acid.

[0508] Embodiment 103. A method in which, in any of the embodiments listed above, an acid is introduced into the first-stage reaction mixture independently of the addition of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the first-stage reaction mixture.

[0509] Embodiment 104. A method in which, in any of the embodiments listed above, an acid is introduced into a first-step reaction mixture as a component of 2-propene-1-ylamine or its salt, 1,3-bis(allylamino)propane or its salt, or an acid salt of both 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt.

[0510] Embodiment 105. A method in which, in any of the embodiments listed above, the aqueous solid content is about 20 to about 60 wt%.

[0511] Embodiment 106. A method in which, in any of the embodiments listed above, the aqueous solid content is about 30 to about 50 wt%.

[0512] Embodiment 107. A method in which, in any of the embodiments listed above, the aqueous solid content is about 30 to about 45 wt%.

[0513] Embodiment 108. A method in which, in any of the embodiments listed above, the aqueous solid content is about 43 wt%.

[0514] Embodiment 109. A method in any of the embodiments listed above, wherein the poly(allylamine) polymer has an absorption capacity for a swelling agent, and the amount of swelling agent in the second-stage reaction mixture is less than the absorption capacity for a swelling agent of the poly(allylamine) polymer formed in the first stage.

[0515] Embodiment 110. A method in which, in any of the embodiments listed above, the poly(allylamine) polymer has an absorption capacity for a swelling agent, the poly(allylamine) polymer is swollen with a swelling agent, and the poly(allylamine) polymer is deprotonated with a base before being swollen with a swelling agent.

[0516] Embodiment 111. A method in which, in any of the embodiments listed above, the dispersion solvent system comprises a non-polar solvent.

[0517] Embodiment 112. A method in which, in any of the embodiments listed above, the dispersion solvent system comprises a solvent that is chemically inert to the pre-formed poly(allylamine) polymer.

[0518] Embodiment 113. A method in which, in any of the embodiments listed above, the dispersion solvent system comprises 1,2-dichloroethane.

[0519] Embodiment 114. A method in which, in any of the embodiments listed above, the dispersion solvent system is pure 1,2-dichloroethane.

[0520] Embodiment 115. A method in which, in any of the embodiments listed above, the swelling agent is immiscible with the dispersion solvent system.

[0521] Embodiment 116. A method in which, in any of the embodiments listed above, the weight ratio of the swelling agent to the poly(allylamine) polymer in the second-stage reaction mixture is less than 4:1.

[0522] Embodiment 117. A method in which, in any of the embodiments listed above, the weight ratio of the swelling agent to the poly(allylamine) polymer in the second-stage reaction mixture is less than 3:1.

[0523] Embodiment 118. A method in which, in any of the embodiments listed above, the weight ratio of the swelling agent to the poly(allylamine) polymer in the second-stage reaction mixture is less than 2:1.

[0524] Embodiment 119. A method in which, in any of the embodiments listed above, the weight ratio of the swelling agent to the poly(allylamine) polymer in the second-stage reaction mixture is less than 1:1.

[0525] Embodiment 120. A method in which, in any of the embodiments listed above, the swelling agent is a polar solvent.

[0526] Embodiment 121. A method in any of the embodiments listed above, wherein the swelling agent is water, methanol, ethanol, n-propanol, isopropanol, n-butanol, formic acid, acetic acid, acetonitrile, dimethylformamide, dimethyl sulfoxide, nitromethane, propylene carbonate, or a combination thereof.

[0527] Embodiment 122. A method in which, in any of the embodiments listed above, the swelling agent is water.

[0528] Embodiment 123. A method in which, in any of the embodiments listed above, the weight ratio of the swelling agent to the poly(allylamine) polymer in the second-stage reaction mixture is less than 0.5:1.

[0529] Embodiment 124. A method in which, in any of the embodiments listed above, the weight ratio of the swelling agent to the poly(allylamine) polymer in the second-stage reaction mixture is less than 0.4:1.

[0530] Embodiment 125. A method in which, in any of the embodiments listed above, the weight ratio of the swelling agent to the poly(allylamine) polymer in the second-stage reaction mixture is less than 0.3:1.

[0531] Embodiment 126. A method in which, in any of the embodiments listed above, the weight ratio of the swelling agent to the poly(allylamine) polymer in the second-stage reaction mixture is at least 0.15:1.

[0532] Embodiment 127. A method in which, in any of the embodiments listed above, the swelling agent and 1,2-dichloroethane are immiscible.

[0533] Embodiment 128. A method in which, in any of the embodiments listed above, a cross-linked poly(allylamine) polymer is combined with 1,2-dichloroethane and a dispersion solvent system, and then the polymer is swollen with a swelling agent.

[0534] Embodiment 129. A method in which, in any of the embodiments listed above, the second-stage reaction mixture is at a temperature in the range of about 25°C to about 85°C.

[0535] Embodiment 130. A method in which, in any of the embodiments listed above, the second step reaction is carried out at a temperature in the range of about 35°C to about 80°C.

[0536] Embodiment 131. A method in which, in any of the embodiments listed above, the second step reaction mixture is carried out at a temperature in the range of about 45°C to about 80°C.

[0537] Embodiment 132. A method in which, in any of the embodiments listed above, the second step reaction is carried out at a temperature in the range of about 55°C to about 75°C.

[0538] Embodiment 133. A method in which, in any of the embodiments listed above, the second step reaction is carried out at a temperature in the range of about 60°C to about 75°C.

[0539] Embodiment 134. A method in which, in any of the embodiments listed above, the second step reaction is carried out at a temperature in the range of about 65°C to about 75°C.

[0540] Embodiment 135. A method in which, in any of the embodiments listed above, the temperature of the second-stage reaction mixture is maintained within 10% of the target temperature throughout the second-stage process.

[0541] Embodiment 136. A method in which, in any of the embodiments listed above, the temperature of the second-stage reaction mixture is maintained relatively constant throughout the second-stage process.

[0542] Embodiment 137. A method in which, in any of the embodiments listed above, the temperature of the second-stage reaction mixture is increased in a continuous or stepwise manner over the course of the second stage.

[0543] Embodiment 138. A method in which, in any of the embodiments listed above, the second step reaction is carried out for about 2 to 20 hours.

[0544] Embodiment 139. A method in which, in any of the embodiments listed above, the second step reaction is carried out for about 4 to 20 hours.

[0545] Embodiment 140. A method in which, in any of the embodiments listed above, the second step reaction is carried out for about 5 to 20 hours.

[0546] Embodiment 141. A method in which, in any of the embodiments listed above, the second step reaction is carried out for about 6 to 20 hours.

[0547] Embodiment 142. A method in which, in any of the embodiments listed above, the second step reaction is carried out for about 8 to 20 hours.

[0548] Embodiment 143. A method in which, in any of the embodiments listed above, the second step reaction is carried out for about 10 to 20 hours.

[0549] Embodiment 144. A method in which, in any of the embodiments listed above, the second step reaction is carried out for about 12 to 18 hours.

[0550] Embodiment 145. A method in which, in any of the embodiments listed above, the second step reaction is carried out for about 14 to 18 hours.

[0551] Embodiment 146. A method in which, in any of the embodiments listed above, the second step reaction is carried out for about 15 to 17 hours.

[0552] Embodiment 147. A product obtainable by the method of any of the embodiments listed above.

[0553] Embodiment 148. A cross-linked poly(allylamine) polymer in bead form prepared according to any one of the above method embodiments.

[0554] Embodiment 149. A cross-linked poly(allylamine) polymer essentially comprising (i) 20-25 mol% of residues of N,N'-diallyl-1,3-diaminopropane or its salt, (ii) 50-60 mol% of residues of 2-propene-1-ylamine or its salt, and (iii) 20-25 mol% of residues of 1,2-dichloroethane, wherein (i) the cross-linked poly(allylamine) polymer is sp 2 (ii) containing an allyl carbon atom and having a swelling ratio of less than 2, and sp included in the poly(allylamine) polymer 2 A cross-linked poly(allylamine) polymer in the form of beads, wherein the allyl carbon constitutes less than 1.0% of the total number of carbon atoms contained in the cross-linked poly(allylamine) polymer.

[0555] Embodiment 150. A cross-linked poly(allylamine) polymer comprising residues of 2-propene-1-ylamine or its salt, 1,3-bis(allylamino)propane or its salt, and 1,2-dichloroethane, wherein (i) the cross-linked poly(allylamine) polymer has a swelling ratio of less than 2, and (ii) sp included in the cross-linked poly(allylamine) polymer 2 A cross-linked poly(allylamine) polymer in the form of beads, wherein the allyl carbon constitutes less than 1.0% of the total number of carbon atoms contained in the cross-linked poly(allylamine) polymer.

[0556] Embodiment 151. A cross-linked poly(allylamine) polymer comprising residues of 2-propene-1-ylamine or its salt, 1,3-bis(allylamino)propane or its salt, and 1,2-dichloroethane, wherein (i) the cross-linked poly(allylamine) polymer contains less than 20 ppm of allylamine, and (ii) sp contained in the cross-linked poly(allylamine) polymer 2 A cross-linked poly(allylamine) polymer in the form of beads, wherein the allyl carbon constitutes less than 1.0% of the total number of carbon atoms contained in the cross-linked poly(allylamine) polymer.

[0557] Embodiment 152. In any of the embodiments listed above, sp included in the cross-linked poly(allylamine) polymer 2 A method in which the allyl carbon constitutes less than 0.9% of the total number of carbon atoms included in the cross-linked poly(allylamine).

[0558] Embodiment 153. In any of the embodiments listed above, sp contained in the cross-linked poly(allylamine) polymer 2 A method in which the allyl carbon constitutes less than 0.8% of the total number of carbon atoms included in the cross-linked poly(allylamine).

[0559] Embodiment 154. In any of the embodiments listed above, sp included in the cross-linked poly(allylamine) polymer 2 A method in which the allyl carbon constitutes less than 0.75% of the total number of carbon atoms included in the cross-linked poly(allylamine).

[0560] Embodiment 155. In any of the embodiments listed above, sp contained in the cross-linked poly(allylamine) polymer 2 A method in which the allyl carbon constitutes less than 0.7% of the total number of carbon atoms included in the cross-linked poly(allylamine).

[0561] Embodiment 156. In any of the embodiments listed above, sp contained in the cross-linked poly(allylamine) polymer 2 A method in which the allyl carbon constitutes less than 0.6% of the total number of carbon atoms included in the cross-linked poly(allylamine).

[0562] Embodiment 157. In any of the embodiments listed above, sp included in the cross-linked poly(allylamine) polymer 2 A method in which the allyl carbon constitutes less than 0.5% of the total number of carbon atoms included in the cross-linked poly(allylamine).

[0563] Embodiment 158. In any of the embodiments listed above, sp included in the cross-linked poly(allylamine) polymer 2A method in which the allyl carbon constitutes less than 0.4% of the total number of carbon atoms included in the cross-linked poly(allylamine).

[0564] Embodiment 158A. In any of the embodiments listed above, sp contained in the cross-linked poly(allylamine) polymer 2 A method in which the allyl carbon constitutes more than 0.3% of the total number of carbon atoms contained in the cross-linked poly(allylamine).

[0565] Embodiment 159. In any of the embodiments listed above, sp included in the cross-linked poly(allylamine) polymer 2 A method in which the allyl carbon constitutes less than 0.3% of the total number of carbon atoms included in the cross-linked poly(allylamine).

[0566] Embodiment 160. In any of the embodiments listed above, sp included in the cross-linked poly(allylamine) polymer 2 A method in which the allyl carbon constitutes less than 0.25% of the total number of carbon atoms included in the cross-linked poly(allylamine).

[0567] Embodiment 161. In any of the embodiments listed above, sp contained in the cross-linked poly(allylamine) polymer 2 A method in which the allyl carbon constitutes less than 0.2% of the total number of carbon atoms included in the cross-linked poly(allylamine) polymer, or a cross-linked poly(allylamine) polymer.

[0568] Embodiment 162. In any of the embodiments listed above, sp contained in the cross-linked poly(allylamine) polymer 2 A method in which the allyl carbon constitutes less than 0.1% of the total number of carbon atoms included in the cross-linked poly(allylamine) polymer, or a cross-linked poly(allylamine) polymer.

[0569] Embodiment 163. In any of the embodiments listed above, sp included in the poly(allylamine) polymer 2The percentage of allyl carbon is determined by NMR; arbitrarily here between 110 and 150 ppm sp⁻¹ 2 % sp of the poly(allylamine) polymer using the following formula, by integrating the allyl carbon peak and the alkyl carbon peak between 0 and 80 ppm. 2 A method for quantifying allyl carbon:

[0570] .

[0571] Embodiment 164. In any of the embodiments listed above, sp contained in the cross-linked poly(allylamine) polymer 2 A method or cross-linked poly(allylamine) polymer in which the number of allyl carbons (if present) is below the detection limit when determined by NMR.

[0572] Embodiment 165. Any of the embodiments listed above, wherein the cross-linked poly(allylamine) polymer contains less than 15 ppm of allylamine, or the cross-linked poly(allylamine) polymer.

[0573] Embodiment 166. Any of the embodiments listed above, wherein the cross-linked poly(allylamine) polymer contains less than 12.5 ppm of allylamine or the cross-linked poly(allylamine) polymer.

[0574] Embodiment 167. Any of the embodiments listed above, wherein the cross-linked poly(allylamine) polymer contains less than 10 ppm of allylamine, or the cross-linked poly(allylamine) polymer.

[0575] Embodiment 168. Any of the embodiments listed above, wherein the cross-linked poly(allylamine) polymer contains less than 7.5 ppm of allylamine, or the cross-linked poly(allylamine) polymer.

[0576] Embodiment 169. Any of the embodiments listed above, wherein the cross-linked poly(allylamine) polymer contains less than 5 ppm of allylamine, or the cross-linked poly(allylamine) polymer.

[0577] Embodiment 170. Any of the embodiments listed above, wherein the cross-linked poly(allylamine) polymer contains less than 4 ppm of allylamine, or the cross-linked poly(allylamine) polymer.

[0578] Embodiment 171. Any of the embodiments listed above, wherein the cross-linked poly(allylamine) polymer contains less than 3 ppm of allylamine, or the cross-linked poly(allylamine) polymer.

[0579] Embodiment 172. Any of the embodiments listed above, wherein the cross-linked poly(allylamine) polymer contains less than 2 ppm of allylamine, or the cross-linked poly(allylamine) polymer.

[0580] Embodiment 173. Any of the embodiments listed above, wherein the cross-linked poly(allylamine) polymer contains less than 1 ppm of allylamine, or the cross-linked poly(allylamine) polymer.

[0581] Embodiment 174. Any of the embodiments listed above, wherein the cross-linked poly(allylamine) polymer contains less than 500 ppb of allylamine, or the cross-linked poly(allylamine) polymer.

[0582] Embodiment 175. Any of the embodiments listed above, wherein the cross-linked poly(allylamine) polymer contains less than 100 ppb of allylamine, or the cross-linked poly(allylamine) polymer.

[0583] Embodiment 176. Any of the embodiments listed above, wherein the cross-linked poly(allylamine) polymer contains less than 50 ppb of allylamine, or the cross-linked poly(allylamine) polymer.

[0584] Embodiment 177. Any of the embodiments listed above, wherein the cross-linked poly(allylamine) polymer contains less than 1 ppb of allylamine, or the cross-linked poly(allylamine) polymer.

[0585] Embodiment 178. Any of the embodiments listed above, wherein the cross-linked poly(allylamine) polymer has a swelling ratio of less than 1.9 or the cross-linked poly(allylamine) polymer.

[0586] Embodiment 179. Any of the embodiments listed above, wherein the cross-linked poly(allylamine) polymer has a swelling ratio of less than 1.8 or the cross-linked poly(allylamine) polymer.

[0587] Embodiment 180. In any of the embodiments listed above, a method in which the cross-linked poly(allylamine) polymer has a swelling ratio of less than 1.7 or a cross-linked poly(allylamine) polymer.

[0588] Embodiment 181. Any of the embodiments listed above, wherein the cross-linked poly(allylamine) polymer has a swelling ratio of less than 1.6 or the cross-linked poly(allylamine) polymer.

[0589] Embodiment 182. Any of the embodiments listed above, wherein the cross-linked poly(allylamine) polymer has a swelling ratio of less than 1.5 or the cross-linked poly(allylamine) polymer.

[0590] Embodiment 183. Any of the embodiments listed above, wherein the cross-linked poly(allylamine) polymer has a swelling ratio of less than 1.4 or the cross-linked poly(allylamine) polymer.

[0591] Embodiment 184. Any of the embodiments listed above, wherein the cross-linked poly(allylamine) polymer has a swelling ratio of less than 1.3 or the cross-linked poly(allylamine) polymer.

[0592] Embodiment 185. Any of the embodiments listed above, wherein the cross-linked poly(allylamine) polymer has a swelling ratio of less than 1.2 or the cross-linked poly(allylamine) polymer.

[0593] Embodiment 186. Any of the embodiments listed above, wherein the cross-linked poly(allylamine) polymer has a swelling ratio of less than 1.1 or the cross-linked poly(allylamine) polymer.

[0594] Embodiment 187. Any of the embodiments listed above, wherein the cross-linked poly(allylamine) polymer has a swelling ratio of less than 1 or the cross-linked poly(allylamine) polymer.

[0595] Embodiment 188. In any of the embodiments listed above, a method in which the cross-linked poly(allylamine) polymer has a swelling ratio of less than 0.9 or a cross-linked poly(allylamine) polymer.

[0596] Embodiment 189. Any of the embodiments listed above, wherein the cross-linked poly(allylamine) polymer has a swelling ratio of less than 0.8 or the cross-linked poly(allylamine) polymer.

[0597] Embodiment 190. Any of the embodiments listed above, wherein the cross-linked poly(allylamine) polymer has a swelling ratio of less than 0.7 or the cross-linked poly(allylamine) polymer.

[0598] Embodiment 191. In any of the embodiments listed above, a method or cross-linked poly(allylamine) polymer having a stability profile such that the poly(allylamine) polymer contains less than 20 ppm of allylamine when stored in a sealed enclosure at 25°C for 3 months after preparation.

[0599] Embodiment 192. Any of the embodiments listed above, wherein the poly(allylamine) polymer contains less than 15 ppm of allylamine when stored in a sealed enclosure at 25°C for 3 months after preparation, or the cross-linked poly(allylamine) polymer.

[0600] Embodiment 193. Any of the embodiments listed above, wherein the poly(allylamine) polymer contains less than 12.5 ppm of allylamine when stored in a sealed enclosure at 25°C for 3 months after preparation, or the cross-linked poly(allylamine) polymer.

[0601] Embodiment 194. Any of the embodiments listed above, wherein the poly(allylamine) polymer contains less than 10 ppm of allylamine when stored in a sealed enclosure at 25°C for 3 months after preparation, or the cross-linked poly(allylamine) polymer.

[0602] Embodiment 195. Any of the embodiments listed above, wherein the poly(allylamine) polymer contains less than 7.5 ppm of allylamine when stored in a sealed enclosure at 25°C for 3 months after preparation, or the cross-linked poly(allylamine) polymer.

[0603] Embodiment 196. Any of the embodiments listed above, wherein the poly(allylamine) polymer contains less than 5 ppm of allylamine when stored in a sealed enclosure at 25°C for 3 months after preparation, or the cross-linked poly(allylamine) polymer.

[0604] Embodiment 197. Any of the embodiments listed above, wherein the poly(allylamine) polymer contains less than 4 ppm of allylamine when stored in a sealed enclosure at 25°C for 3 months after preparation, or the cross-linked poly(allylamine) polymer.

[0605] Embodiment 198. Any of the embodiments listed above, wherein the poly(allylamine) polymer contains less than 3 ppm of allylamine when stored in a sealed enclosure at 25°C for 3 months after preparation, or the cross-linked poly(allylamine) polymer.

[0606] Embodiment 199. Any of the embodiments listed above, wherein the poly(allylamine) polymer contains less than 2 ppm of allylamine when stored in a sealed enclosure at 25°C for 3 months after preparation, or the cross-linked poly(allylamine) polymer.

[0607] Embodiment 200. Any of the embodiments listed above, wherein the poly(allylamine) polymer contains less than 1 ppm of allylamine when stored in a sealed enclosure at 25°C for 3 months after preparation, or a cross-linked poly(allylamine) polymer.

[0608] Embodiment 201. Any of the embodiments listed above, wherein the poly(allylamine) polymer contains less than 500 ppb of allylamine when stored in a sealed enclosure at 25°C for 3 months after preparation, or the cross-linked poly(allylamine) polymer.

[0609] Embodiment 202. Any of the embodiments listed above, wherein the poly(allylamine) polymer contains less than 100 ppb of allylamine when stored in a sealed enclosure at 25°C for 3 months after preparation, or the cross-linked poly(allylamine) polymer.

[0610] Embodiment 203. Any of the embodiments listed above, wherein the poly(allylamine) polymer contains less than 50 ppb of allylamine when stored in a sealed enclosure at 25°C for 3 months after preparation, or the cross-linked poly(allylamine) polymer.

[0611] Embodiment 204. Any of the embodiments listed above, wherein the poly(allylamine) polymer contains less than 1 ppb of allylamine when stored in a sealed enclosure at 25°C for 3 months after preparation, or the cross-linked poly(allylamine) polymer.

[0612] Embodiment 205. In any of the embodiments listed above, a method or cross-linked poly(allylamine) polymer in which the amount of allylamine (if present) in the poly(allylamine) polymer is below the detection limit for allylamine when stored in a sealed enclosure at 25°C for 3 months after preparation.

[0613] Embodiment 206. In any of the embodiments listed above, a method or cross-linked poly(allylamine) polymer having a stability profile such that the poly(allylamine) polymer contains less than 20 ppm of allylamine when stored in a sealed enclosure at 25°C for 6 months after preparation.

[0614] Embodiment 207. Any of the embodiments listed above, wherein the poly(allylamine) polymer contains less than 15 ppm of allylamine when stored in a sealed enclosure at 25°C for 6 months after preparation, or the cross-linked poly(allylamine) polymer.

[0615] Embodiment 208. Any of the embodiments listed above, wherein the poly(allylamine) polymer contains less than 12.5 ppm of allylamine when stored in a sealed enclosure at 25°C for 6 months after preparation, or the cross-linked poly(allylamine) polymer.

[0616] Embodiment 209. Any of the embodiments listed above, wherein the poly(allylamine) polymer contains less than 10 ppm of allylamine when stored in a sealed enclosure at 25°C for 6 months after preparation, or the cross-linked poly(allylamine) polym...

Claims

Claim 1 Cross-linked poly(allylamine) polymer having the structure of the following chemical formula 5a: <Chemical Formula 5a> Here, a = a residue of N,N'-diallyl-1,3-diaminopropane or its salt, b = a residue of 2-propene-1-ylamine or its salt, c = two residues of 2-propene-1-ylamine cross-linked with 1,2-dichloroethane, and m = a repeating unit of the polymer. Claim 2 In claim 1, less than 0.9% of the total number of carbon atoms present in the cross-linked poly(allylamine) polymer is sp 2 A cross-linked poly(allylamine) polymer containing allyl carbon. Claim 3 In claim 1 or 2, less than 0.8% of the total number of carbon atoms present in the cross-linked poly(allylamine) polymer is sp 2 A cross-linked poly(allylamine) polymer containing allyl carbon. Claim 4 In claim 1 or 2, less than 0.7% of the total number of carbon atoms present in the cross-linked poly(allylamine) polymer is sp 2 A cross-linked poly(allylamine) polymer containing allyl carbon. Claim 5 In claim 1 or 2, less than 0.6% of the total number of carbon atoms present in the cross-linked poly(allylamine) polymer is sp 2 A cross-linked poly(allylamine) polymer containing allyl carbon. Claim 6 In paragraph 2, more than 0.3% of the total number of carbon atoms present in the cross-linked poly(allylamine) polymer is sp 2 A cross-linked poly(allylamine) polymer containing allyl carbon. Claim 7 In paragraph 2, sp 2 sp in cross-linked poly(allylamine) polymers with a percentage of allyl carbon 2 A cross-linked poly(allylamine) polymer that can be determined by measuring the percentage of allyl carbon. Claim 8 In paragraph 2, sp 2 sp⁻¹, the percentage of allyl carbon measured in the pre-formed poly(allylamine) polymer before crosslinking with 1,2-dichloroethane to prepare the crosslinked poly(allylamine) polymer 2 sp in cross-linked poly(allylamine) polymers from the percentage of allyl carbon 2 A cross-linked poly(allylamine) polymer that can be determined by calculating the percentage of allyl carbon. Claim 9 In paragraph 8, sp in the cross-linked poly(allylamine) polymer 2 The percentage of allyl carbon, sp in the pre-formed poly(allylamine) polymer 2 A cross-linked poly(allylamine) polymer that can be determined by multiplying the percentage of allyl carbon by the ratio of the carbon to nitrogen weight ratio of the pre-formed poly(allylamine) polymer to the carbon to nitrogen weight ratio of the cross-linked poly(allylamine) polymer. Claim 10 A cross-linked poly(allylamine) polymer according to claim 9, wherein the ratio of the carbon to nitrogen weight ratio of the pre-formed poly(allylamine) polymer to the carbon to nitrogen weight ratio of the cross-linked poly(allylamine) polymer is 0.

9. Claim 11 A cross-linked poly(allylamine) polymer according to claim 9, wherein the carbon-to-nitrogen weight ratio of the pre-formed poly(allylamine) polymer and the carbon-to-nitrogen weight ratio of the cross-linked poly(allylamine) polymer can be determined by elemental analysis. Claim 12 In paragraph 2, sp in the cross-linked poly(allylamine) polymer 2 The percentage of allyl carbon 13 A cross-linked poly(allylamine) polymer that can be determined by C NMR. Claim 13 In paragraph 8, sp in the pre-formed poly(allylamine) polymer 2 The percentage of allyl carbon 13 A cross-linked poly(allylamine) polymer that can be determined by C NMR. Claim 14 In paragraph 12, sp between 110 and 150 ppm 2 Using the integration of the allyl carbon peak and the alkyl carbon peak between 0 and 80 ppm, sp using the following formula 2 Cross-linked poly(allylamine) polymer for quantifying the percentage of allyl carbon: . Claim 15 In Paragraph 12, 13 C NMR is quantitative 13 C cross-linked poly(allylamine) polymer with solid-state magic angle spinning (MAS) NMR. Claim 16 In Paragraph 12, 13 C NMR is quantitative 13 C-type solid-state cross-polarized magic angle spinning (CPMAS) NMR cross-linked poly(allylamine) polymer. Claim 17 A cross-linked poly(allylamine) polymer according to claim 1 or 2, containing less than 20 ppm of allylamine (H2C=CHCH2NH2) as an impurity. Claim 18 A cross-linked poly(allylamine) polymer in which the allylamine content of claim 17 can be determined by a cationic IC extraction procedure. Claim 19 A cross-linked poly(allylamine) polymer according to claim 1 or 2, wherein the allylamine content of the cross-linked poly(allylamine) polymer increases by less than 2.5 ppm / day allylamine when tested by a heat stability test (stability test 2). Claim 20 A cross-linked poly(allylamine) polymer according to claim 1 or 2, wherein the allylamine content of the cross-linked poly(allylamine) polymer increases by less than 2.0 ppm / day allylamine when tested by heat stability test (stability test 2). Claim 21 A cross-linked poly(allylamine) polymer according to claim 1 or 2, wherein the allylamine content of the cross-linked poly(allylamine) polymer increases by less than 1.5 ppm / day allylamine when tested by a heat stability test (stability test 2). Claim 22 A pharmaceutical composition for use in a method for treating metabolic acidosis, comprising a cross-linked poly(allylamine) polymer of claim 1 or 2.

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