Crosslinked poly(allylamine) polymer pharmaceutical compositions

Abstract

The present invention relates to pharmaceutical compositions and methods for treating animals, including humans, and methods of making such compositions. The pharmaceutical compositions include crosslinked amine polymers and may be used, for example, in the treatment of diseases or other metabolic conditions in which removal of target species from the digestive tract provides a physiological benefit.

Description

[Technical Field]

[0001] The present invention relates to a crosslinked poly(allylamine) polymer, preferably beverimer, comprising residues of 2-propen-1-ylamine or a salt thereof, 1,3-bis(allylamino)propane or a salt thereof, and 1,2-dichloroethane, which can be used as a non-absorbable drug for therapeutic applications, for example, for the treatment of metabolic acidosis. More specifically, the present invention relates to a pharmaceutical composition comprising such a polymer, a medicament or pharmaceutical composition comprising such a polymer, and a method for producing such a polymer.

[0002] In U.S. Patent 9,205,107, Klaerner et al. disclose cross-linked poly(allylamine) polymers that can be used in metabolic conditions where removal of protons and / or chloride ions from the gastrointestinal tract provides physiological benefits, such as increased serum bicarbonate concentrations. A wide range of cross-linked amine polymers are disclosed therein, including cross-linked poly(allylamine) polymers prepared by simultaneous polymerization of allylamine and cross-linking of the polymer with diallylamine.

[0003] Veverimer is a cross-linked poly(allylamine) polymer that can be used to treat metabolic conditions. Wesson et al. "Long-term safety and efficacy of veverimer in patients with metabolic acidosis in chronic kidney disease: a multicenter, randomized, blinded, placebo-controlled, 40-week extension," The Lancet, Volume 394, Issue 10196, pp. 396-406, 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, both of which are incorporated herein by reference, describe the treatment of metabolic acidosis with veverimer.

[0004] One method for making the polymer drug Beverimer is disclosed in WO2019 / 236636A1 Synthesis Example A and WO2016 / 094685A1. The Beverimer polymer made by this method has unique ID 019070-A3 FA in Table S-1 of Synthesis Example A of WO2019 / 236636A1. Disclosed herein are improved Beverimer polymers, for example, with improved stability in the presence of oxygen, as well as methods for making and packaging Beverimer designed to mitigate oxygen stability concerns.

[0005] While the preparation of poly(allylamine) polymers from allylamine and diallylamine described by Bianchi et al., Inoue et al., and Klaerner et al. offers certain advantages over the crosslinking of linear poly(allylamine) with epichlorohydrin, the resulting crosslinked amine polymers may contain undesirable process-related impurities or degradation products such as allylamine or its derivatives. In some cases, incomplete incorporation of polyfunctional allylamines or their salts, such as diallylamine or 1,3-bis(allylamino)propane, can lead to unsaturated substituents covalently attached to the polymer backbone, which can cause the production of stability-limiting allylamine and related impurities during post-processing, including drying, or upon storage of the poly(allylamine). Such mechanisms for allylamine impurity production include, but are not limited to, oxygen-, temperature-, water-, acid-, and base-mediated removal of unsaturated substituents, leading to allylamine or related impurities.

[0006] One approach to improving the purity and stability profile of polymers such as beverimers containing residues of 2-propen-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt is to improve the 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 process, these methods a) increasing concentrations of 2-propen-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in the monomer droplet solution; b) increasing the relative concentration of 1,3-bis(allylamino)propane or its salt by adding 2-propen-1-ylamine or its salt in a semi-batch or continuous process during the reaction; c) Decreasing the reaction temperature to favor growth or d) Increase in initiator concentration or amount Including, but not limited to:

[0007] Any or a combination of these or other methods may be used: 13 Improved crosslinking efficiency, as measured by C NMR of remaining polymer backbone-bound (i.e., pendant) allyl groups and reduced allylamine formation in the final polymer, preferably beverimer. In particular, by minimizing the number of unreacted allyl groups from 1,3-bis(allylamino)propane or its salt, the purity and stability profile of the resulting polymer, preferably beverimer, can be improved. Summary of the Invention

[0008] Among the various aspects of the present invention, therefore, there may be mentioned a method for preparing a composition having therapeutic application. (a) forming a poly(allylamine) polymer in the form of beads in a simultaneous polymerization and crosslinking reaction mixture comprising 2-propen-1-ylamine or a salt thereof, 1,3-bis(allylamino)propane or a salt thereof, a radical polymerization initiator, a surfactant, an acid, water, and an organic solvent system, in a first step, wherein less than 1.1% of the total number of carbon atoms in the crosslinked poly(allylamine) polymer are sp 2 Formation of what is an allylic carbon, and (b) in 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; Includes.

[0009] A further aspect of the present invention is a crosslinked poly(allylamine) polymer in the form of beads comprising residues of 2-propen-1-ylamine or a salt thereof, 1,3-bis(allylamino)propane or a salt thereof, and 1,2-dichloroethane, wherein the crosslinked poly(allylamine) polymer has sp 2 The allylic carbons constitute less than 1.0% of the total number of carbon atoms contained by the crosslinked poly(allylamine) polymer, and the crosslinked poly(allylamine) polymer has a swelling ratio of less than 2.

[0010] A further aspect of the present invention is a pharmaceutical composition comprising the crosslinked poly(allylamine) polymers described herein, particularly beverimer.

[0011] The compositions, non-absorbable compositions, pharmaceutical compositions, or cross-linked poly(allylamine) polymers of the present invention can comprise, consist essentially of, or be a polymer as defined elsewhere herein. For example, the compositions, non-absorbable compositions, pharmaceutical compositions, or cross-linked poly(allylamine) polymers can comprise, consist essentially of, or be the drug substance beverimer.

[0012] Beverimer is a polymeric drug that may have the following structural properties: The beverimer can be poly(allylamine-co-N,N'-diallyl-1,3-diaminopropane-co-1,2-diaminoethane).

[0013] More specifically, Beverimer is a poly[(N 1 ,N 3 -di(prop-2-en-1-yl)propane-1,3-diamine)-co-prop-2-en-1-amine] (molar ratio of about 2:5:2 (i.e., N 1 ,N 3 The polymer may have a ratio of about 2:5:2) di(prop-2-en-1-yl)propane-1,3-diamine:prop-2-en-1-amine:N,N'-ethane-1,2-diyl bridges.

[0014] A structural representation of bevelimer can be Formula 5: [ka] [During the ceremony, a=residue of N,N'-diallyl-1,3-diaminopropane dihydrochloride; b = residue of allylamine, c = residue of 1,2-dichloroethane (ethylene bridging two amines); the ethylene bond between two allylamine groups is shown as one example of many possible linkages between amines. m = a large number indicating an extended polymer network.

[0015] The beverimer may contain residues of the following amounts of monomers: a) 20 to 25 mol % of a residue of N,N'-diallyl-1,3-diaminopropane or a salt thereof (also known as 1,3-bis(allylamino)propane or a salt thereof), b) 50 to 60 mol % of a residue of 2-propen-1-ylamine or a salt thereof, and c) 20-25 mol% of residues of 1,2-dichloroethane; Here, the total mol % of the residues does not exceed 100 mol %.

[0016] The beverimers may each have a carbon to nitrogen weight ratio ranging from about 3.7:1 to about 3.8:1. 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, which is described in more detail elsewhere herein.

[0017] The bevelimer can be, for example, a non-absorbable composition that is insoluble under physiological conditions.

[0018] The beverimer may have a median particle size of greater than 1 micrometer and less than 1 millimeter. The particle size of the beverimer may be measured by wet laser diffraction using Mie theory.

[0019] Beverimer may be prepared as follows: Beverimer can be obtained by first copolymerizing 2-propen-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.

[0020] For example, beverimer can be obtained by first copolymerizing 2-propen-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.

[0021] Summary of the Invention One aspect of the present invention is a composition comprising the crosslinked poly(allylamine) polymers described herein, particularly beverimers, wherein less than 1.0% of the total number of carbon atoms present in the crosslinked poly(allylamine) polymer are sp 2 It is a composition that is an allylic carbon.

[0022] A further aspect of the present invention is a composition comprising the crosslinked poly(allylamine) polymer described herein, particularly Bevelimer, wherein when tested in a thermal stability assay (Stability Assay 2), the allylamine (HC=CHCHNH) content of the crosslinked poly(allylamine) polymer increases at less than 2.6 ppm / day allylamine.

[0023] A further aspect of the present invention is a unit dosage form having an exterior and an interior, the interior comprising a crosslinked poly(allylamine) polymer as described herein, particularly Bevelimer, wherein the oxygen transfer rate between the exterior and interior of the unit dosage form is about 0.050 CC / m 2 It is a unit dosage form that is less than 100 mg / day.

[0024] A further aspect of the present invention is a unit dosage form comprising a sealed enclosure comprising a crosslinked poly(allylamine) polymer, particularly a beverimer, as described herein, the sealed enclosure comprising a multi-layer stack of 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 multi-layer stack is about 0.050 CC / m 2 It is a unit dosage form that is less than 100 mg / day.

[0025] A further aspect of the present invention is a composition comprising the crosslinked poly(allylamine) polymers described herein, particularly beverimer, for use in therapy.

[0026] A further aspect of the present invention is a composition comprising the crosslinked poly(allylamine) polymers described herein, particularly beverimer, for treating acid-base disorders.

[0027] A further aspect of the present invention is a composition comprising the crosslinked poly(allylamine) polymers described herein, particularly beverimer, for use in treating metabolic acidosis.

[0028] A further aspect of the invention is a composition comprising a crosslinked poly(allylamine) polymer as described herein, particularly bevelimer, for use in delaying the progression of kidney disease.

[0029] A further aspect of the invention is a composition comprising a crosslinked poly(allylamine) polymer as described herein, particularly bevelimer, for use in delaying the progression of chronic kidney disease.

[0030] A further aspect of the present invention is a composition comprising a crosslinked poly(allylamine) polymer as described herein, particularly Bevelimer, for use in delaying the progression of kidney disease in patients with metabolic acidosis associated with chronic kidney disease.

[0031] A further aspect of the present invention is a composition comprising the crosslinked poly(allylamine) polymers described herein, particularly bevelimer, for use in improving physical function in a patient.

[0032] A further aspect of the present invention is a composition comprising the crosslinked poly(allylamine) polymers described herein, particularly Bevelimer, for use in improving physical function in patients with metabolic acidosis.

[0033] A further aspect of the present invention is a composition comprising the crosslinked poly(allylamine) polymers described herein, particularly beverimer, for use in improving the quality of life of a patient.

[0034] A further aspect of the present invention is a composition comprising the crosslinked poly(allylamine) polymers described herein, particularly beverimer, for use in improving the quality of life of patients with metabolic acidosis.

[0035] A further aspect of the present invention is a crosslinked poly(allylamine) polymer, particularly a beverimer, as described herein in a sealed container.

[0036] A further aspect of the present invention is a pharmaceutical product comprising a crosslinked poly(allylamine) polymer, particularly Bevelimer, as described herein, within a sealed container that includes a moisture barrier.

[0037] A further aspect of the present invention is a pharmaceutical product comprising a crosslinked poly(allylamine) polymer, particularly Beverimer, as described herein, in a sealed container that includes an oxygen barrier.

[0038] A further aspect of the present invention is a pharmaceutical product comprising a crosslinked poly(allylamine) polymer, particularly Beverimer, as described herein, in a sealed container that includes a moisture barrier and an oxygen barrier.

[0039] A further aspect of the present invention is a pharmaceutical product comprising a crosslinked poly(allylamine) polymer as described herein, particularly Beverimer, in a sealed sachet.

[0040] A further aspect of the present invention is a pharmaceutical product comprising a crosslinked poly(allylamine) polymer, particularly a beverimer, as described herein within a sealed container comprising a polymeric, metal, glass, or ceramic material.

[0041] A further aspect of the present invention is a pharmaceutical product comprising a crosslinked poly(allylamine) polymer described herein, particularly a beverimer, and a sealed container containing an inert atmosphere.

[0042] A further aspect of the present invention is a pharmaceutical product comprising a sealed container as described herein and a cross-linked poly(allylamine) polymer, particularly a beverimer, within the sealed container, wherein the sealed container comprises a multilayer stack of an inner contact layer, an outer layer; and a barrier layer disposed between the contact layer and the outer layer.

[0043] A further aspect of the present invention is a sealed container as described herein and a pharmaceutical product comprising a crosslinked poly(allylamine) polymer, particularly Beverimer, within the sealed container, wherein the sealed container comprises a multilayer stack of an inner contact layer, an outer layer; and an oxygen barrier layer disposed between the contact layer and the outer layer.

[0044] A further aspect of the present invention is a sealed container as described herein and a pharmaceutical product comprising a cross-linked poly(allylamine) polymer, particularly Beverimer, within the sealed container, wherein the sealed container comprises a multilayer stack of an inner contact layer, an outer layer; and a moisture barrier layer disposed between the contact layer and the outer layer.

[0045] Further aspects of the present invention are the sealed containers described herein and pharmaceutical products comprising a crosslinked poly(allylamine) polymer, particularly Beverimer, within the sealed container, wherein the sealed container comprises a multilayer stack of an inner contact layer, an outer layer; and an oxygen barrier layer and a moisture barrier layer disposed between the contact layer and the outer layer.

[0046] A further aspect of the present invention is a sealed container as described herein and a pharmaceutical product comprising a crosslinked poly(allylamine) polymer, particularly Beverimer, within the sealed container, wherein the sealed container comprises a multilayer stack of an inner contact layer, an outer layer; and an oxygen scavenging layer disposed between the contact layer and the outer layer.

[0047] A further aspect of the present invention is a method for treating acid / base disorders in an animal by oral administration of a pharmaceutical composition comprising the crosslinked poly(allylamine) described herein, particularly bevelimer.

[0048] A further aspect of the present invention is a method of treating a patient with an acid-base disorder characterized by a baseline serum bicarbonate level of less than 22 mEq / l, comprising oral administration of a pharmaceutical composition comprising a daily dose of a crosslinked poly(allylamine) as described herein, particularly bevelimer, to increase the patient's serum bicarbonate level from baseline by at least 1 mEq / l within a treatment period not exceeding one month.

[0049] Other aspects and features will be in part apparent and in part pointed out hereinafter.

[0050] Abbreviations and Definitions The following definitions and methods are provided to more precisely define the present invention and to guide those of ordinary skill in the art in practicing the present invention. Unless otherwise specified, terms should be understood according to conventional usage by those of ordinary skill in the relevant art. The term "absorbent capacity," as used herein in connection with a polymer and a swelling agent (or swelling agent mixture, in the case of a swelling agent mixture), is the amount of swelling agent (or such mixture) absorbed at room temperature for at least 16 hours by a quantity of dry polymer (e.g., in the form of dry beads) immersed in an excess amount of swelling agent (or such mixture).

[0051] The abbreviations in the following table have the meanings indicated: [Table 1]

[0052] The term "alicyclic" means a saturated monocyclic group of 3 to 8 carbon atoms, and includes cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0053] The term "alkyl group," used alone or within other terms, includes saturated straight- or branched-chain carbon radicals, e.g., having from 1 to about 20 carbon atoms, or in specific embodiments, from 1 to about 12 carbon atoms. In other embodiments, alkyl groups are "lower alkyl" groups having from 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, and the like. In more specific embodiments, lower alkyl groups have from 1 to 4 carbon atoms.

[0054] As used herein, the term "allyl" refers to a group having the structural formula H2C=CH-CH2- * (In the formula, * denotes the point of attachment of the moiety to the rest of the molecule. * is a heteroatom in the rest of the molecule, such as nitrogen.

[0055] The term "allyl equivalent" as used herein means the total number of moles of allyl groups contained in the combination of 2-propen-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof present in the reaction mixture.

[0056] The terms "allylamine" and AAH refer to a moiety having the structural formula H2C=CH-CH2NH2.

[0057] The term "aqueous solids 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" constitutes the mass resulting from the first initiator (e.g., V-50) addition alone. To express the aqueous solids content as a weight percent, multiply values ​​by 100.

[0058] The terms "aromatic group" or "aryl group" refer to an aromatic group having one or more rings, where such rings may be pendantly attached to one another or may be fused. In particular embodiments, aromatic groups are mono-, bi-, or tricyclic. Monocyclic aromatic groups can contain 5 to 10 carbon atoms, typically 5 to 7 carbon atoms, and more typically 5 to 6 carbon atoms, per ring. Typical polycyclic aromatic groups are bi- or tricyclic. Bicyclic polycyclic aromatic groups typically have 8 to 12 carbon atoms, preferably 8 to 10 carbon atoms, per ring. Examples of aromatic groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl, or aceto-naphthyl.

[0059] The term "as released" means the as-manufactured condition upon completion of manufacturing.

[0060] As used herein, "batch process" refers to a process in which reactants are placed in a reactor, the reaction is carried out, and the reaction product is removed from the reactor at the end of the reaction.

[0061] The term "beads" is used to refer to cross-linked polymers that are substantially spherical.

[0062] The term "bicarbonate equivalent" is used to refer to an organic acid or anion that, when metabolized, yields bicarbonate. Citric acid and succinic acid are exemplary bicarbonate equivalents.

[0063] The term "bonded" as used herein in connection with a polymer and one or more ions, i.e., cations (e.g., "proton-bonded" polymers) and anions, i.e., "ion-bonded" polymers, and / or in connection with ions, generally does not necessarily have to be in a non-covalent manner, but is of sufficient strength that at least a portion of the ions remain bound under the in vitro or in vivo conditions in which the polymer is used for a time sufficient for removal of the ions from solution or the body.

[0064] In some embodiments, the term "clinically significant increase" as used herein in connection with a treatment refers to a treatment that returns an individual from a dysfunctional state to a relatively normal functioning state, or a movement of indicators of the state toward normal function, or at least a significant improvement or significant change compared to untreated. Several methods for calculating clinical significance can be used. A non-exhaustive list of methods for calculating clinical significance includes Jacobson-Truax, Gulliksen-Lord-Novick, Edwards-Nunnally, Hageman-Arrindell, and Hierarchical Linear Modeling (HLM).

[0065] As used herein, "continuous process" refers to a process in which one or more reactants are continuously fed to a reactor and the reaction product is formed as a continuous stream of product.

[0066] The term "crosslinker," used alone or within other terms, includes ethylene crosslinkers, 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. References herein to 1,2-dichloroethane are interchangeable with any ethylene crosslinker, including those listed in this paragraph.

[0067] The term "diallylamine" refers to an amino moiety bearing two allyl groups.

[0068] The terms "dry beads" and "dry polymer" refer to beads or polymers containing no more than 5% by weight of a non-polymeric swelling agent or solvent. The swelling agent / solvent is often water remaining at the end of purification. This is generally removed by freeze-drying or oven-drying or further cross-linking of the preformed poly(allylamine) polymer before storage. The amount of swelling agent / solvent can be measured by heating (e.g., to 100-200°C) and measuring the resulting weight change. This is referred to as "loss on drying" or "LOD."

[0069] The term "gel" is used to refer to irregularly shaped cross-linked polymers.

[0070] The term "heteroaryl" refers to a monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms, unless otherwise specified, wherein one or more (in some embodiments, 1, 2, or 3) ring atoms are heteroatoms selected from N, O, or S, and the remaining ring atoms are carbon. 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, and the like. As defined herein, the terms "heteroaryl" and "aryl" are mutually exclusive. "Heteroarylene" refers to a divalent heteroaryl group.

[0071] The term "heteroatom" refers to an atom other than carbon or hydrogen. Typically, but not exclusively, heteroatoms are selected from the group consisting of halogen, sulfur, phosphorus, nitrogen, boron, and oxygen atoms. Groups containing more than one heteroatom may contain different heteroatoms.

[0072] The terms "heterocyclo", "heterocyclic" or "heterocyclyl" refer to heterocyclic rings in which one or two ring atoms are N, O, B, P and S(O). n(where n is an integer from 0 to 2), and the remaining ring atoms are carbon. Furthermore, one or two ring carbon atoms of the heterocyclyl ring may optionally be replaced with a —C(O)— group. More specifically, the term heterocyclyl includes, but is not limited to, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydropyranyl, thiomorpholino, and the like. When the heterocyclyl ring is unsaturated, it may contain one or two ring double bonds, as long as the ring is not aromatic. When a heterocyclyl group contains at least one nitrogen atom, it is also referred to herein as heterocycloamino and is a subset of the heterocyclyl group.

[0073] "Initiator" is a term used to refer to a reagent that starts polymerization.

[0074] The mole percentage or "mol %" of a particular component of a crosslinked poly(allylamine) polymer can be calculated as follows:

number

[0075] Crosslinked poly(allylamine) polymers can be defined by the mol% of the components of the crosslinked poly(allylamine) polymer (e.g., residues of monomers and crosslinkers). In these embodiments, the total mol% cannot exceed 100 mol%. For example, the mol% of 1,3-bis(allylamino)propane or its salt + mol% of 2-propen-1-ylamine or its salt + mol% of 1,2-dichloroethane is ≦100 mol%.

[0076] A working example of how to calculate mole ratios and mol% is provided below, where known input mole ratios of 2-propen-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt used to produce the intermediate poly(allylamine) polymer and the amount of HCl produced by the second step 1,2-dichloroethane (DCE) crosslinking of the poly(allylamine) polymer are used to calculate the mol% of each component in the final crosslinked poly(allylamine) polymer.

[0077] This example is based on the principle that DCE can react with two amine groups to produce two equivalents of HCl when introducing ethylene residues into a crosslinked poly(allylamine) polymer. Therefore, the amount of HCl produced indicates how many ethylene residues have been incorporated into the crosslinked poly(allylamine) polymer.

[0078] This example is performed on a sample of crude cross-linked poly(allylamine) polymer (i.e., immediately after DCE cross-linking). HCl is extracted from the crude cross-linked poly(allylamine) polymer sample using sodium hydroxide solution, and Cl is quantified by anion chromatography.

[0079] More specifically, approximately 2 grams of crude cross-linked poly(allylamine) polymer was 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 and then vacuum filtered through a frit. The methanol wash was repeated for a total of two washes. The loss on drying of the methanol-washed polymer was determined using standard techniques on a moisture balance. Approximately 100 mg of the methanol-washed crude cross-linked poly(allylamine) polymer was accurately weighed into a vial and 10 mL of 50 mM aqueous sodium hydroxide was added. Cl was extracted from the polymer for 16 hours at 37°C, after which the supernatant was filtered through a 0.45 μm nylon syringe filter. The Cl concentration of the supernatant was determined using anion chromatography. The IC (e.g., Dionex ICS-5000, Thermo Scientific) method consisted of an AG19 guard column and an AS19 analytical column, a potassium hydroxide (KOH) eluent generator, an injection volume of 25 microliters, with a runtime of approximately 17 minutes and a flow rate of 1.0 mL / min. The KOH concentration included 20 mM for 8 minutes, followed by a 4 minute hold at 70 mM KOH and a 5 minute re-equilibration at 20 mM KOH. Chloride standards were used for quantitation as follows:

[0080] The chloride concentration (mM) of the sample solution was calculated as follows:

number

[0081] This calculation can be performed using a chromatography data system.

[0082] Determination of extracted poly(allylamine) polymer mass:

number

[0083] Determination of reaction DCE:

number

[0084] Calculation of weight percent of crosslinked ethylene per gram of poly(allylamine) polymer. For example, the following amount of ethylene can be calculated using the above method: 3.97 mmol ethylene / g poly(allylamine) polymer. 3.97 mmol ethylene / g poly(allylamine) polymer = 111.1 mg ethylene / g poly(allylamine) polymer; Wt% ethylene / g poly(allylamine) polymer = 111.1 mg ethylene / (1000 mg poly(allylamine) polymer + 111.1 mg ethylene) = 10 wt% ethylene or DCE residues in the crosslinked poly(allylamine) polymer.

[0085] Calculation of the weight percent of residues of 2-propen-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in the crosslinked poly(allylamine) polymer: The weight percent of residues of 2-propen-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in the crosslinked poly(allylamine) polymer can be calculated using the weight fraction of the crosslinked poly(allylamine) polymer and the known input molar ratios of 2-propen-1-ylamine and 1,3-bis(allylamino)propane used to make the poly(allylamine) polymer and the intermediate poly(allylamine) polymer: For example, using a poly(allylamine) polymer weight fraction of 0.90 for the crosslinked poly(allylamine) polymer (i.e., 10% crosslinked poly(allylamine) polymer is ethylene and 90% poly(allylamine) polymer) and 35.7 wt. % residues of 2-propen-1-ylamine and 64.3 wt. % residues of 1,3-bis(allylamino)propane calculated from the input molar ratios of 2-propen-1-ylamine and 1,3-bis(allylamino)propane used to prepare the poly(allylamine) polymer (60 mol. % 2-propen-1-ylamine:40 mol. % 1,3-bis(allylamino)propane): 60 mol % of 2-propen-1-ylamine can be converted to the weight % of poly(allylamine) polymer as follows: (57.1×60) / 100=34.26; (34.26 / 34.26+61.68)×100=35.7 wt% residues of 2-propen-1-ylamine; 40 mol % of 1,3-bis(allylamino)propane can be converted to the following weight percentages of poly(allylamine) polymer: (154.2×40) / 100=61.68; (61.68 / 34.26+61.68)×100=64.3 wt% residues of 1,3-bis(allylamino)propane; The weight percent of residues of 2-propen-1-ylamine and 1,3-bis(allylamino)propane in the poly(allylamine) polymer can be converted to the weight percent of crosslinked poly(allylamine) polymer as follows: wt% of residues of 2-propen-1-ylamine = 0.90 × 35.7 wt% = 32.1 wt% in the crosslinked poly(allylamine) polymer; wt% of residues of 1,3-bis(allylamino)propane = 0.90 × 64.3 wt% = 57.9 wt% in the crosslinked poly(allylamine) polymer;

[0086] Calculation of moles / g of residues of 2-propen-1-ylamine or salts thereof and 1,3-bis(allylamino)propane or salts thereof in crosslinked poly(allylamine) polymer from the weight percent of residues of 2-propen-1-ylamine or salts thereof and 1,3-bis(allylamino)propane or salts thereof in the crosslinked poly(allylamine) polymer: From the above weight percent calculation, in 1 g of crosslinked poly(allylamine) polymer, 0.32g residues of 2-propen-1-ylamine, 0.58g residues of 1,3-bis(allylamino)propane, 0.1g ethylene; 0.32 g residues of 2-propen-1-ylamine / 57.1 g / mol = 5.6 mmol residues of 2-propen-1-ylamine; 0.58 g residues of 1,3-bis(allylamino)propane / 154.15 g / mol = 3.8 mmol residues of 1,3-bis(allylamino)propane; 0.10g ethylene / 28g / mol=3.6mmol ethylene exists.

[0087] Calculation of mol% of residues of 2-propen-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in crosslinked poly(allylamine) polymer from weight percent of 2-propen-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in crosslinked poly(allylamine) polymer: mol% of 2-propen-1-ylamine residues = (5.6 / (5.6+3.8+3.6)=43%; mol% residues of 1,3-bis(allylamino)propane = (3.8 / (5.6+3.8+3.6) = 29%; mol% residues of 1,2-dichloroethane = (3.6 / (5.6+3.8+3.6) = 28%.

[0088] Another working example of how mole ratios and mol% can be calculated is provided below. This example uses elemental analysis to determine the weight percent of ethylene bridges. The weight percent of ethylene bridges can then be used to calculate mole ratios and mol% using the formulas above.

[0089] Calculation of incorporated ethylene mmol / poly(allylamine) polymer g using elemental analysis

number

[0090] The C weight % and N weight % of poly(allylamine) polymers and crosslinked poly(allylamine) polymers can be determined using elemental analysis, such as the elemental analysis methods described for determining the carbon to nitrogen weight ratio.

[0091] The term "monoallylamine" refers to an amino moiety having one allyl group.

[0092] The term "polyfunctional allylamine" refers to an amino moiety having two or more allyl groups, including, for example, diallylamine, triallylamine, and the like.

[0093] The term "non-absorbable" as used herein has its usual meaning in the art. Therefore, if something is non-absorbable, it is not absorbed during passage through the human GI tract. This can be measured by any suitable means. One option known to those skilled in the art is a fecal test to see if the non-absorbable substance is recovered after passage through the GI tract. In practice, the amount of non-absorbable substance recovered in this scenario is not 100% of the administered substance. For example, approximately 90-99% of the substance is recovered in the feces. Other components known to those skilled in the art are substances in lymph, blood, interstitial fluid, secretions from various organs (e.g., pancreas, liver, intestine, etc.) or organ bodies (e.g., liver, kidney, lung, etc.), because oral administration of a non-absorbable substance does not increase the amount of substance in these matrices and tissues.

[0094] A non-absorbable composition can 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. By way of example, a non-absorbable composition implies that the substance does not enter lymph, blood, interstitial fluid, or organs via the primary entry points of the human GI tract, i.e., via paracellular entry between intestinal epithelial cells, endocytic uptake through intestinal epithelial cells, or entry via M cells, which comprise the intestinal epithelial antigen sampling and immune surveillance system (Jung, 2000). The size limits of particles absorbed in the human GI tract are known in the literature (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). Thus, those skilled in the art know that materials of at least 1 micrometer in size are non-absorbable when present in the GI tract.

[0095] "Optionally" or "optionally" means that the subsequently described event or circumstance may, but is not required to, occur, and the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. For example, a "heterocyclyl group optionally substituted with an alkyl group" means that alkyl may, but is not necessarily, 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.

[0096] As used herein, the term "partially incorporated polyfunctional allylamine residue" refers to a residue of a polyfunctional allylamine that (i) is incorporated into a poly(allylamine) polymer and (ii) has at least one pendant allyl group (i.e., at least one allyl group that does not participate in a reaction to become a chain atom of the poly(allylamine) polymer backbone, but simply "pends" therefrom). For example, a partially incorporated diallylamine residue is a residue of a diallylamine in which one of the two allyl groups of the incorporated diallylamine is a pendant allyl group of the polymer chain.

[0097] "Particle size" is measured by wet laser diffraction using Mie theory. Particles are dispersed in a suitable solvent, such as water or methanol, and added to the sample chamber to achieve 10-20% red channel obscuration. Sonication may be performed, and dispersing agents, such as surfactants (e.g., Tween-80), are added to disrupt weak particle-particle interactions. The refractive index settings of the particles used for size distribution calculations are selected to minimize artifacts in the results and R parameter values ​​determined using laser diffraction software. The D(0.1), D(0.5), and D(0.9) values, which characterize the particle size distribution on a volume basis, are recorded.

[0098] For example, particle size is measured by wet laser diffraction using Mie theory as follows: Disperse particles in methanol and add to the sample chamber to achieve 10-20% red channel obscuration. Sonicate. Select the refractive index settings of the particles used for size distribution calculation to minimize resulting artifacts and the R parameter value determined by the laser diffraction software. Record the D(0.1), D(0.5), and D(0.9) values ​​that characterize the particle size distribution on a volume basis.

[0099] As used herein, "pharmaceutically acceptable" in reference to a carrier, diluent, or excipient means a carrier, diluent, or excipient, respectively, that is generally safe, non-toxic, and not biologically or otherwise undesirable for veterinary and / or human pharmaceutical use and is useful in the preparation of pharmaceutical compositions.

[0100] The term "post-polymerization crosslinking" refers to the reaction of already formed beads or gels where additional crosslinks are introduced into the already formed beads or gels to obtain beads or gels with increasing amounts of crosslinking.

[0101] The term "post-polymerization modification" refers to the modification of already formed beads or gels, where a reaction or treatment introduces additional functional groups that can be covalently or non-covalently attached to the already formed beads.

[0102] As used herein, the term "semi-batch process" refers to a variation of the batch process in which one or more reactants are added intermittently or continuously to a reactor.

[0103] The "Simulated Gastric Fluid" or "SGF" assay refers to a test to determine the total chloride binding capacity of a test polymer using a defined buffer that mimics the contents of gastric fluid as follows: Simulated Gastric Fluid (SGF) consists of 35 mM NaCl, 63 mM HCl, pH 1.2. To perform this assay, the free amine polymer to be tested is prepared at a concentration of 2.5 mg / ml (25 mg dry weight) in 10 mL of SGF buffer. The mixture is incubated overnight at 37°C with agitation on a rotisserie mixer for approximately 12-16 hours. Unless otherwise specified, the SGF binding data or binding capacity reported herein is determined over this time period. After incubation and mixing, the tube containing the polymer is centrifuged at 500-1000 x g for 2 minutes to pellet the test sample. Approximately 750 microliters of supernatant is removed and filtered using an appropriate filter, such as a 0.45 micrometer-diameter syringe filter or an 800 microliter, 1 micrometer-diameter, 96-well, glass filter plate mounted on a 96-well, 2 mL collection plate. In the latter configuration, multiple samples can be prepared for analysis, each run in SGF buffer, including a control tube containing blank buffer that is run through the entire assay process. With samples placed on the filter plate and the collection plate mounted underneath, the unit is centrifuged at 1,000 x g for 1 minute to filter the samples. For small sample setups, a syringe filter can be used instead of the filter plate, collecting approximately 2-4 mL of filtrate in a 15 mL container. After filtration, each filtrate is diluted 4-fold with water, and the chloride content of the filtrate is measured by 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, with 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 determine the chloride bound to the polymer, complete the following calculation:

number

[0104] "Simulated Small Intestinal Inorganic Buffer" or "SIB" is a test to determine the chloride and phosphate binding capacity of free amine test polymers in a selective specific interference buffer assay (SIB). The chloride and phosphate binding capacity of free amine test polymers was performed using a selective specific interference buffer assay (SIB) as follows: The buffer used for the SIB assay contained 36 mM NaCl, 20 mM NaH2PO4, 50 mM 2-(N-morpholino)ethanesulfonic acid (MES) buffered to pH 5.5. SIB buffer contains chloride, phosphate, and pH concentrations 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 a useful indicator of the selectivity of chloride binding relative to phosphate binding by the polymer. To perform this assay, the free amine polymer to be tested is prepared at a concentration of 2.5 mg / ml (25 mg dry weight) in 10 mL of SIB buffer. The mixture is incubated at 37°C for 1 hour with agitation at 200-300 rpm on an orbital shaker. Unless otherwise specified, the SIB binding data or binding capacity reported here was determined over this time period. After incubation and mixing, the tube containing the polymer is centrifuged at 1000 x g for 2 minutes to pellet the test sample.750 microliters of supernatant is removed and filtered using an 800-microliter, 1-micrometer diameter, 96-well, glass filter plate mounted on a 96-well, 2-mL collection plate. In this configuration, multiple samples can be prepared for analysis, including a control tube containing the free amine standard control sevelamer, the free amine bixalomer, and blank buffer, all of which are processed through the entire assay process. With the sample placed on the filter plate and the collection plate mounted underneath, the unit is centrifuged at 1,000 x g for 1 minute to filter the sample. For small sample setups, a syringe filter (0.45 micrometer) can be used in place of the filter plate, allowing approximately 2-4 mL of filtrate to be collected in a 15 mL vial. After filtration into the collection plate, each filtrate is diluted and subsequently measured for chloride or phosphate content. For chloride and phosphate measurements, the filtrate under analysis is diluted 4-fold with water. The chloride and phosphate content of the filtrate is measured by 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 runtime of approximately 10 minutes, a wash / rinse volume of 1000 microliters, and a flow rate of 0.3 mL / min. To determine the chloride bound to the polymer, complete the following calculation: Binding capacity expressed as mmol chloride / g polymer =

number

number

[0105] The term "sp" used here 2 The "allylic carbon" is the two sp carbons contained in the allyl moiety. 2 Each of the hybridized carbon atoms.

[0106] As used herein, the terms "substituted hydrocarbyl," "substituted alkyl," "substituted alkenyl," "substituted aryl," "substituted heterocyclo," or "substituted heteroaryl" refer to a hydrocarbyl, alkyl, alkenyl, aryl, heterocyclo, or heteroaryl moiety substituted with at least one atom other than carbon and hydrogen, including moieties in which a carbon chain atom is replaced with a heteroatom such as nitrogen, oxygen, silicon, phosphorus, boron, sulfur, or a halogen atom. These substituents include halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, keto, acyl, acyloxy, nitro, amino, amido, nitro, cyano, thiol, ketal, acetal, ester, and ether.

[0107] "Swelling ratio" or simply "swelling" refers to the amount of water absorbed by a quantity of polymer divided by the weight of that polymer aliquot. Swelling ratio is expressed as: swell = (g swollen polymer - g dry polymer) / g dry polymer. The method used to determine the swell ratio of any given polymer is as follows: a. Place 50-100 mg of dry (less than 5 wt% water content) polymer into an 11 mL sealable test tube (with a screw cap) of known weight (weight of tube = weight A). b. Deionized water (10 mL) is added to the tube containing the polymer. The tube is sealed and placed on a rotator cavities at room temperature for 16 hours (overnight). After incubation, the tube is centrifuged at 3000 x g for 3 minutes and the supernatant is carefully removed by vacuum aspiration. Polymers that form a very loose precipitate are subjected to an additional centrifugation step. c. After step (b), record the weight of the swollen polymer plus tubing (Weight B). d. Freeze at -40°C for 30 minutes. Freeze dry for 48 hours. Weigh the dried polymer and test tube (record as weight C). e. Calculate g of water absorbed per g of polymer defined as [(Weight B - Weight A) - (Weight C - Weight A)] / (Weight C - Weight A).

[0108] "Target ion" refers to the ion to which the polymer binds, typically the primary ion bound by the polymer or the ion whose binding to the polymer is believed to result in the therapeutic effect of the polymer (e.g., proton and chloride binding leading to the net removal of HCl).

[0109] The term "theoretical capacity" refers to the calculated, predicted binding of hydrochloric acid in the "SGF" assay, expressed in mmol / g. Theoretical capacity is based on the assumption that 100% of the amines from the monomers and crosslinker are incorporated into the crosslinked polymer based on the respective feed ratios. Thus, theoretical capacity is equal to the amine functional group concentration (mmol / g) of the polymer. Theoretical capacity assumes that each amine is available for binding to each anion and cation and is not modified by the type of amine formed (e.g., do not subtract the capacity of quaternary amines that are not available for proton binding).

[0110] A "therapeutically effective amount" means a proton-linked crosslinked amine polymer that, when administered to a patient for treating a disease, is sufficiently effective to treat such disease. What constitutes a "therapeutically effective amount" will vary depending on the polymer, the severity of the disease, and the age, weight, etc., of the mammal being treated.

[0111] "Treating" or "treatment" of a disease includes (i) preventing the disease, i.e., preventing or reducing the progression of the disease or its clinical symptoms; or (ii) ameliorating the disease, i.e., inducing regression of the disease or its clinical symptoms. Preventing a disease includes, for example, prophylaxis.

[0112] The term "triallylamine" refers to an amino moiety bearing three allyl groups.

[0113] The term "vinyl" refers to a group having the structure RxHyC=CH- * (In the formula, * denotes the point of attachment of the moiety to the rest of the molecule, X and Y are independently 0, 1, or 2 such that X+Y=2, and R is hydrocarbyl or substituted hydrocarbyl. * is a heteroatom in the rest of the molecule, such as nitrogen.

[0114] The term "water equivalent" refers to the number of moles of water.

[0115] The term "weight percent crosslinker" refers to the calculated percentage by mass of a polymer sample that is derived from crosslinker. Weight percent crosslinker is calculated using the feed ratio of the polymerization and is based on the assumption of complete conversion of the monomer and crosslinker. The mass attributed to the crosslinker is equal to the predicted increase in molecular weight 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).

[0116] Other assay and determination protocols referenced herein Cationic extraction method: To a sealed vial of 15-50 mL volume, add poly(allylamine) polymer (approximately 1.0 g) with 10 mL of 1.2 M HCl. Shake the vial at room temperature for at least 24 hours. The supernatant is filtered through a 0.45 micrometer syringe filter followed by a neutralization column and then analyzed by ion chromatography (IC). The IC (e.g., Dionex ICS-5000, Thermo Scientific) method consists of a CG19 guard column and a CS19 analytical column, a methanesulfonic acid (MSA) eluent generator, a 25 microliter injection volume, a runtime of approximately 40 minutes, and a flow rate of 0.3 mL / min. The MSA concentration is 2 mM for 10 minutes, followed by a ramp to 70 mM MSA from minutes 10 to 28, a 3-minute hold at 70 mM MSA, and a 9-minute re-equilibration at 2 mM MSA. This method is used to measure allylamine content above 0.25 ppm. If the sample contains less than 0.25 ppm, the extract supernatant is analyzed by LCMS as described in the next method.

[0117] To a sealed vial of 15-50 mL volume, add polyallylamine polymer (approximately 1.0 g) with 10 mL of 1.2 M HCl. Stir 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 2x with an internal standard (IS) consisting of 10 micrograms / mL diethylamine in 0.1% aqueous heptafluorobutyric acid (HFBA). The HPLC method (e.g., Agilent 1260 HPLC) consisted of a 5-micrometer particle size Acclaim 120 C18 2.1 x 50 mm column, a 5-microliter injection volume, and a mobile phase consisting of A) 0.1% HFBA in water and B) 0.1% HFBA in acetonitrile, with a gradient of 0% B for 3 minutes, ramping to 100% B from 3 to 3.5 minutes, maintaining at 100% B for 3.5 to 6 minutes, and equilibrating to 0% B for 10 minutes. The mass spectrometer (MS) method (e.g., API 4000 triple quadrupole tandem MS) was run in positive ion, multiple reaction monitoring mode with a source temperature of approximately 500 °C and an electrospray ionization voltage of 5000 V. The arylamine Q1 and Q3 masses were approximately 58.7 and 58.1 amu, respectively, and the IS Q1 and Q3 masses were approximately 74.7 and 73.1 amu, respectively. The measurement procedure using gas source pressure, collision energy, declustering voltage, entrance potential and exit potential is optimized.

[0118] quantitative 13 Percent sp by C solid-state magic angle spinning (MAS) NMR 2 Allylic carbon determination: quantitative 13 C solid-state magic angle spinning (MAS) NMR measurements 1 H and 13 Spectroscopy is performed on a Bruker AVANCE III 800 MHz (18.8 T) standard aperture spectrometer using a 4 mm zirconia rotor system with a 16 kHz spinning frequency, operating at 800.25 MHz and 201.24 MHz for C, respectively. Single pulse experiments are used with a 1.2 ps 30-degree excitation pulse using an 8 s relaxation delay optimized for quantitative analysis, an 8.6 ms acquisition time, and an accumulation of approximately 20,000 scans. 100 kHz proton decoupling is performed.13 C was applied during data collection. Chemical shifts are relative to a TMS standard. sp 2 Using the integral of the allyl carbon peak and the alkyl carbon peak from 0 to 80 ppm, calculate the percent sp of the poly(allylamine) polymer using the following equation: 2 Quantify allylic carbon:

number

[0119] When introducing elements of the present invention or preferred embodiments thereof, the singular form "a," "an," or "the" is intended to mean one or more of such elements. The terms "comprise," "include," and "have" are intended to be inclusive and not exclusive (i.e., other elements may be present in addition to the listed elements).

[0120] quantitative 13 Percent sp by C solid-state cross-polarization magic-angle spinning (CPMAS) NMR 2 Determination of allylic carbons: quantitative 13 C solid-state cross-polarization magic-angle spinning (CPMAS) NMR measurements were performed on poly(allylamine) polymer samples using a Redstone 360 ​​MHz spectrometer with a 7 mm zirconium probe at a spinning speed of 7 kHz. 1 H and 13 The cross-polarization experiments were performed at 90° C. and 363.331 MHz and 91.369 MHz, respectively, calibrated for poly(allylamine) polymer analysis based on quantitative single-pulse spectra. 1 H excitation pulses of 5 ps, 2.5 ms contact time, and 3 s recycle delay were performed. Proton decoupling of 12 V and 18 V and line broadening of 35 Hz were used, and approximately 3500 spectral acquisitions were accumulated. 2 Using the integral of the allyl carbon peak and the alkyl carbon peak from 0 to 80 ppm, calculate the percent sp of the poly(allylamine) polymer using the following equation: 2 Quantify allylic carbon:

number

[0121] Determination of carbon to nitrogen weight ratio of crosslinked poly(allylamine) polymers by elemental analysis: Elemental analysis is a standard method for determining the carbon, hydrogen, and nitrogen content of organic materials that is within the general knowledge of those skilled in the art. Those skilled in the art will recognize that all elemental analysis measurement methods will yield the same results within appropriate measurement precision limits. Elemental analysis can be performed on any elemental analyzer suitable for measuring organic carbon, hydrogen, and nitrogen. The following elemental analysis methods are provided as examples of how elemental analysis can be performed.

[0122] Carbon, hydrogen, and nitrogen are determined using a Perkin-Elmer 2400 elemental analyzer. This analyzer uses combustion to convert sample elements to simple gases, i.e., CO2, HO, and N2. Upon entering the analyzer, the sample is combusted in a pure oxygen environment. 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 standards may have nitrogen contents ranging from approximately 11 to 45% by weight. System suitability is confirmed by analysis of NIST-traceable organic standards. Standards must be confirmed to be within ±0.1% of their theoretical values ​​for all three elements: carbon, hydrogen, and nitrogen. Crosslinked poly(allylamine) polymer samples for analysis are typically dried in an oven at 60°C under reduced pressure to remove moisture before analysis.

[0123] The carbon to nitrogen weight ratio of the poly(allylamine) polymer used to prepare the crosslinked poly(allylamine) polymer can also be confirmed by elemental analysis. The method used to determine the carbon to nitrogen weight ratio of the poly(allylamine) polymer can be as described above.

[0124] GC-FID extraction method: To a sealed 10-20 mL vial containing approximately 0.1 g of poly(allylamine) polymer, add 5 mL of acetonitrile. To a second sealed 10-20 mL vial containing approximately 1.5 g of polyallylamine polymer, add 5 mL of methanol. The vial is sealed and shaken at 200 RPM for 24 hours at room temperature. The supernatant is filtered through a 0.45 micrometer syringe filter and then detected by gas chromatography with flame ionization detection (GC-FID). The GC (e.g., Agilent 6890) method consists of a series of approximately 4 meter DB-1 column, 0.32 mm internal diameter, coupled with a 30 meter DB-wax column, 0.32 mm internal diameter, and a constant helium flow of 2.5 mL / min. Two microliter injections are performed with a 1:10 split ratio at 200°C inlet. The oven gradient program consists of a 5 minute hold at 40°C, followed by a 10°C / min ramp to 180°C, followed by a 20°C / min ramp to 240°C and a 3 minute hold. FID capture is performed at a temperature of 300°C.

[0125] Heat Stability Assay (Stability Assay 2): Poly(allylamine) polymer (1.0 g each) was weighed into two separate sealed vials of 15-50 mL volume. A sample from one vial was directly extracted by the cationic extraction method to determine the starting allylamine content. The remaining sample was sealed and then placed in a convection oven set at 60°C. After 72 hours, the sample was removed from the oven, cooled to 4°C, and then extracted in the same manner as described for the cationic extraction method.

[0126] Impurity analysis in the release assay: Dry 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 weighed into three separate sealed vials of 15-50 mL volume. A sample containing 1.0 g poly(allylamine) polymer from one vial is extracted according to the cationic extraction method to determine the starting allylamine content. The remaining two samples are extracted by the GC-FID extraction method to determine the starting allyl methyl ether and allyl alcohol contents.

[0127] Air Stability Assay (Stability Assay 1): To a 35 mL HOPE bottle, add 4.5 g of poly(allylamine) polymer. The bottle is sealed and then stored in a 60% humidity controlled chamber maintained at 25° C. for 7 days. The bottle is removed from the chamber and a polymer sample is extracted according to the cationic extraction method to determine the allylamine content.

[0128] Stability Assessment Assay When Packaged in Mylar Foil Sachets (Stability Assay 3): Approximately 3 g of poly(allylamine) polymer is added to a three-sided sealed approximately 2.5" x 3" sachet consisting of a laminate including a metal foil layer, and the sachet is then heat-sealed. Multiple sachets of poly(allylamine) polymer are manufactured and then placed in individual test chambers, which are controlled at 25°C and 60% relative humidity and 40°C and 75% relative humidity for up to 6 months. At the desired time points, sachets are removed from each test chamber and polymer samples are extracted according to the cationic extraction method to determine allylamine content. [Brief explanation of the drawings]

[0129] [Figure 1A] The allylamine (AA) concentration (ppm) present when Bevelimer was packaged in packet materials A, B, and C and placed at 25°C / 60% RH for 6 weeks. Unit dosage forms A, B, and C were stored at 25°C / 60% RH for 6 weeks, and the allylamine concentration was measured at TO (initial) and at weeks 1, 2, 4, and 6. In Figure 1A, unit dosage form A is represented by a square (e.g., the top line at week 6), unit dosage form B is represented by a circle (e.g., the bottom line at week 6), and unit dosage form C is represented by a cross (x) (e.g., the middle line at week 6). Unit dosage form A showed an increase in allylamine concentration over the 6 weeks, but unit dosage forms B and C did not.

[0130] [Figure 1B]The allylamine (AA) concentration (ppm) present when Bevelimer was packaged in packet materials A, B, and C and placed at 40°C / 75% RH for 6 weeks. Unit dosage forms A, B, and C were stored at 40°C / 75% RH for 6 weeks, and the allylamine concentration was measured at TO (initial) and at weeks 1, 2, 4, and 6. In Figure 1B, unit dosage form A is represented by a square (e.g., the top line at week 6), B is represented by a circle (e.g., the middle line at week 6), and C is represented by a cross (x) (e.g., the bottom line at week 6). Unit dosage form A showed an increase in allylamine concentration over the 6 weeks, which was not seen in unit dosage forms B and C under those conditions.

[0131] [Figure 2] Allylamine (AA) concentration (ppm) in 1.5g, 3.0g, and 4.5g unit dosage forms over 3 months at 25°C / 60% RT. 1.5g, 3.0g, and 4.5g unit dosage forms were stored at 25°C / 60% RH for 3 months, and allylamine concentration was measured at TO (initial) and monthly thereafter. In Figure 2, 1.5g is represented by a circle (e.g., the top line at 3 months), 3.0g is represented by a square (e.g., the middle line at 3 months), and 4.5g is represented by a triangle (e.g., the bottom line at 3 months). The 1.5g, 3.0g, and 4.5g unit dosage forms show the increase in AA concentration over time.

[0132] [Figure 3] Allylamine (AA) concentration (ppm) in 1.5g, 3.0g, and 4.5g unit dosage forms over 3 months at 40°C / 75% RT. 1.5g, 3.0g, and 4.5g unit dosage forms were stored at 40°C / 75% RH for 3 months, and allylamine concentration was measured at TO (initial) and monthly thereafter. In Figure 3, 1.5g is represented by a circle (e.g., the top line at 3 months), 3.0g is represented by a square (e.g., the middle line at 3 months), and 4.5g is represented by a triangle (e.g., the bottom line at 3 months). The 1.5g, 3.0g, and 4.5g unit dosage forms show the increase in AA concentration over time.

[0133] [Figure 4]Allylamine (AA) concentration (ppm) of 1.5 g unit dosage forms containing oxygen scavenger at 25°C / 60% RH and 40°C / 75% RT over 6 months. Allylamine concentration in the unit dosage forms was measured at TO and at various intervals thereafter. In Figure 4, the 1.5 g unit dosage forms at 25°C / 60% RH are indicated by a cross (x) (e.g., the top line at 2 months), and the 1.5 g unit dosage forms at 40°C / 75% RH are indicated by a triangle (e.g., the bottom line at 2 months). The unit dosage forms demonstrate a fairly constant AA concentration over the 6 months.

[0134] [Figure 5] Allylamine (AA) concentrations (ppm) in 1.5 g unit dosage forms in air, 8% oxygen and 92% nitrogen, and 99+% nitrogen 25°C / 60% RT over a 6-month period. Allylamine concentrations in the unit dosage forms were measured at TO and at various intervals thereafter. In Figure 5, 1.5 g unit dosage forms in air are indicated by a cross (e.g., the top line at 6 months), 1.5 g unit dosage forms in 8% oxygen and 92% nitrogen are indicated by a triangle (e.g., the middle line at 6 months), and 1.5 g unit dosage forms in 99+% nitrogen are indicated by a circle (e.g., the bottom line at 6 months). The unit dosage forms demonstrate fairly constant AA concentrations over the 6-month period.

[0135] [Figure 6] Allylamine (AA) concentrations (ppm) in 1.5 g unit dosage forms in air, 8% oxygen and 92% nitrogen, and 99+% nitrogen at 40°C / 75% RT over a 6-month period. Allylamine concentrations in the unit dosage forms were measured at TO and at various intervals thereafter. In Figure 6, 1.5 g unit dosage forms in air are indicated by a cross (e.g., the top line at 6 months), 1.5 g unit dosage forms in 8% oxygen and 92% nitrogen are indicated by a triangle (e.g., the middle line at 6 months), and 1.5 g unit dosage forms in 99+% nitrogen are indicated by a circle (e.g., the bottom line at 6 months). The unit dosage forms demonstrate fairly constant AA concentrations over the 6-month period. DETAILED DESCRIPTION OF THE INVENTION

[0136] Implementation The present invention involves the observation that during the synthesis of crosslinked poly(allylamine) polymers such as beverimer, unincorporated 2-propen-1-ylamine monomer and / or partially incorporated 1,3-bis(allylamino)propane monomer residues can be a source of allylamine impurities (i.e., allylamine and derivatives such as allyl alkyl ethers and allyl alcohol) in the poly(allylamine) product. These monomers may be present as salts. While not intending to be bound by theory, it is believed that the remaining unincorporated 2-propen-1-ylamine monomer and / or partially incorporated 1,3-bis(allylamino)propane monomer residues present in crosslinked poly(allylamine) polymers such as beverimer can react with oxygen after the polymer is produced, thereby producing allylamine impurities (e.g., HC=CHCHNH). For example, the beverimer polymer designated as unique ID 019070-A3 FA in Table S-1 of Synthesis Example A of WO2019 / 236636A1 produced H2C=CHCH2NH2 when exposed to oxygen. High levels of impurities such as H2C=CHCH2NH2 are undesirable in final products administered to patients, for example, due to potential safety concerns.

[0137] Disclosed herein are several methods for reducing the level of allylamine impurities, such as H2C=CHCH2NH2, in crosslinked poly(allylamine) polymers (e.g., Beverimer).

[0138] One approach disclosed herein is the preparation of crosslinked poly(allylamine) polymers, such as beverimers, that are substantially free of unincorporated 2-propen-1-ylamine monomer or its salts and / or partially incorporated 1,3-bis(allylamino)propane monomer residues or their salts. This reduction in the amount of unincorporated and / or partially incorporated monomers can reduce the amount of allylamine impurities present in the final product. Thus, disclosed herein is a method for reducing, for example, sp 1,2,3-bis(allylamino)propane monomer residues present in the product. 2Also disclosed herein are methods for producing crosslinked poly(allylamine) polymers (e.g., beverimers) having reduced levels of such unincorporated and / or partially incorporated monomers, as measured by reference to carbon levels. ... 2 Crosslinked poly(allylamine) polymers (e.g., beverimers) having reduced levels of such unincorporated and / or partially incorporated monomers, as measured by reference to carbon levels, have been shown to have desirable properties, such as reduced levels of allylamine impurities (e.g., H2C=CHCH2NH2) in such products.

[0139] Another approach disclosed herein is the packaging of crosslinked poly(allylamine) polymers, such as Beverimer, in a manner that reduces exposure to oxygen. The approach used for packaging to mitigate concerns about the level of impurities, allylamine impurities (e.g., H2C=CHCH2NH2), can be used in combination with any crosslinked poly(allylamine) polymer, such as Beverimer, disclosed herein or known from the prior art.

[0140] According to certain aspects of the present invention, the crosslinked poly(allylamine) polymers disclosed herein, particularly beverimer, may be used in therapy. In certain embodiments, the crosslinked poly(allylamine) polymers may be used to bind HCl from the digestive tract of animals, including humans, by administering a therapeutically effective amount (i.e., an effective dose) of the crosslinked poly(allylamine) polymer to achieve a therapeutic or prophylactic benefit.

[0141] Methods of treatment and medical uses of the crosslinked poly(allylamine) polymers disclosed herein, particularly bevelimer, are described in WO2014 / 197725A1, WO2016 / 094685A1, WO2017 / 193050A1, WO2017 / 193064A1, WO2017 / 193024A1, WO2019 / 090176A1, WO2019 / 090177A1, WO2019 / 236639A1, WO2019 / 236636A1 and WO2019 / 236124A1, which are incorporated herein by reference.

[0142] According to one aspect of the present invention, the crosslinked poly(allylamine) polymers disclosed herein, particularly Bevelimer, are for use in any of the methods of treatment or medical applications described in any of WO2014 / 197725A1, WO2016 / 094685A1, WO2017 / 193050A1, WO2017 / 193064A1, WO2017 / 193024A1, WO2019 / 090176A1, WO2019 / 090177A1, WO2019 / 236639A1, WO2019 / 236636A1 and WO2019 / 236124A1.

[0143] According to certain embodiments of the present invention, crosslinked poly(allylamine) polymers can be prepared in the following steps: a (first) simultaneous polymerization and crosslinking step (sometimes referred to as the "first crosslinking step" or more simply "first step") and, optionally, a (second) post-polymerization crosslinking step (sometimes referred to as the "second crosslinking step" or more simply "second step"). In the first step, crosslinking is preferably carbon-to-carbon volume-saving, i.e., free amine-saving, crosslinking. In the second step, crosslinking is amine-consuming, directed toward tailoring selectivity for the target species. Based on the desired volumetric capacity, the C-N weight ratio is preferably optimized to maximize amine functionality for target species binding while still maintaining a controlled particle size of spherical polymer particles that ensure non-adsorption and acceptable mouthfeel that are stable under GI conditions. It should be noted that the terms "first" and "second" are used merely to designate the relative order between these two steps, and that other steps may be contemplated as part of the process before, after, or between the "first step" and "second step."

[0144] In the first step, 2-propen-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt are simultaneously polymerized and crosslinked in a heterogeneous reaction mixture containing 2-propen-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 the carbon backbone. Advantageously, each crosslinking reaction in this step forms a carbon-carbon bond (as opposed to a substitution reaction, in which a carbon-heteroatom bond is formed during the crosslinking), and the amine functional groups of 2-propen-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt do not undergo crosslinking reactions and are preserved in the final polymer (i.e., the primary amines of 2-propen-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt remain primary, the secondary amines remain secondary, and the tertiary amines remain tertiary). The resulting poly(allylamine) polymer can then be further crosslinked with 1,2-dichloroethane in a second step.

[0145] As indicated above, unincorporated 2-propen-1-ylamine or salt thereof (i.e., 2-propen-1-ylamine or salt thereof that is not covalently incorporated into the polymer) and partially incorporated residues of 1,3-bis(allylamino)propane or salt thereof can be the source of allylamine impurities (i.e., allylamine and its derivatives, such as allyl alkyl ethers and allyl alcohols) in the poly(allylamine) product. According to certain embodiments of the present invention, process parameters can be controlled to limit the amount of allyl impurities (i) liberated by the crosslinked poly(allylamine) polymer in the as-manufactured state (i.e., upon completion of the second step, sometimes referred to herein as "upon release") and / or (ii) released from the crosslinked poly(allylamine) polymer as a function of storage and time.

[0146] Generally, it is preferred that the crosslinked poly(allylamine) polymer contain less than 20 ppm allylamine in its as-manufactured state. For example, in certain embodiments, the crosslinked poly(allylamine) polymer contains less than 15 ppm allylamine in its as-manufactured state. By way of further example, in certain such embodiments, the crosslinked poly(allylamine) polymer contains less than 12.5 ppm allylamine in its as-manufactured state. By way of further example, in certain such embodiments, the crosslinked poly(allylamine) polymer contains less than 10 ppm allylamine in its as-manufactured state. By way of further example, in certain such embodiments, the crosslinked poly(allylamine) polymer contains less than 7.5 ppm allylamine in its as-manufactured state. By way of further example, in certain such embodiments, the crosslinked poly(allylamine) polymer contains less than 5 ppm allylamine in its as-manufactured state. By way of further example, in certain such embodiments, the crosslinked poly(allylamine) polymer contains less than 4 ppm allylamine in its as-manufactured state. By way of further example, in certain such embodiments, the crosslinked poly(allylamine) polymer contains less than 3 ppm allylamine in its as-manufactured state. By way of further example, in some such embodiments, the crosslinked poly(allylamine) polymer contains less than 2 ppm allylamine in its as-manufactured state. By way of further example, in some such embodiments, the crosslinked poly(allylamine) polymer contains less than 1 ppm allylamine in its as-manufactured state. By way of further example, in some such embodiments, the crosslinked poly(allylamine) polymer contains less than 500 ppb allylamine in its as-manufactured state. By way of further example, in some such embodiments, the crosslinked poly(allylamine) polymer contains less than 100 ppb allylamine in its as-manufactured state. By way of further example, in some such embodiments, the crosslinked poly(allylamine) polymer contains less than 50 ppb allylamine in its as-manufactured state. By way of further example, in some such embodiments, the crosslinked poly(allylamine) polymer contains less than 1 ppb allylamine in its as-manufactured state.By way of further example, in certain such embodiments, the amount of allylamine in the crosslinked poly(allylamine) polymer is below the detection limit of allylamine in the as-manufactured state, if any. In each such exemplary embodiment described in this paragraph, the allylamine content can be determined by impurity analysis in a release assay followed by a cationic extraction method.

[0147] In some embodiments, the crosslinked poly(allylamine) polymer contains less than 20 ppm allylamine after storage at 25° C. in a sealed enclosure for 3 months after manufacture. In some embodiments, the crosslinked poly(allylamine) polymer contains less than 20 ppm allylamine after storage at 25° C. in a sealed enclosure for 6 months after manufacture. In some embodiments, the crosslinked poly(allylamine) polymer contains less than 20 ppm allylamine after storage at 25° C. in a sealed enclosure for 9 months after manufacture. In some embodiments, the crosslinked poly(allylamine) polymer contains less than 20 ppm allylamine after storage at 25° C. in a sealed enclosure for 12 months after manufacture. In some embodiments, the allylamine content of the crosslinked poly(allylamine) polymer increases by less than 20 ppm allylamine after storage at 25° C. in a sealed enclosure for 3 months. In certain embodiments, the allylamine content of the crosslinked poly(allylamine) polymer increases by less than 20 ppm allylamine after storage in a sealed enclosure for 6 months at 25° C. In certain embodiments, the allylamine content of the crosslinked poly(allylamine) polymer increases by less than 20 ppm allylamine after storage in a sealed enclosure for 9 months at 25° C. In certain embodiments, the allylamine content of the crosslinked poly(allylamine) polymer increases by less than 20 ppm allylamine after storage in a sealed enclosure for 12 months at 25° C. In each such exemplary embodiment described in this paragraph, the allylamine content can be determined by a cationic extraction method.

[0148] To promote the simultaneous polymerization and crosslinking reactions, 2-propen-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt are preferably protonated in the reaction mixture. Therefore, in some embodiments, 2-propen-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., hydrochloric acid, phosphoric acid, sulfuric acid, or hydrobromide salt forms). Alternatively, 2-propen-1-ylamine or its salt and / or 1,3-bis(allylamino)propane or its salt may be introduced into the reaction mixture in the form of a free amine, and an acid can be added separately to the reaction mixture. For example, the acid can be phosphoric acid, or hydrochloric acid (HCl). As a further example, the acid is HCl. In any embodiment, the reaction mixture contains enough acid to maintain 2-propen-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in the aqueous phase. Typically, the reaction mixture comprises 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-propen-1-ylamine or its salt and / or 1,3-bis(allylamino)propane or its salt, or whether the acid is added separately to the reaction mixture). In some embodiments, the reaction mixture comprises at least 0.75 equivalents of acid per equivalent of allylamine in the reaction mixture. In some embodiments, the reaction mixture comprises at least 1 equivalent of acid per equivalent of allylamine in the reaction mixture.

[0149] 2-propen-1-ylamine and 1,3-bis(allylamino)propane are listed in Table C. As noted, 2-propen-1-ylamine and 1,3-bis(allylamino)propane are in the HCl salt form. As previously indicated, each of 2-propen-1-ylamine and 1,3-bis(allylamino)propane can be introduced into the reaction mixture in salt form (e.g., as a hydrochloride, sulfate, phosphate, hydrobromide, or a combination thereof), free base form, or a combination thereof. [Table 2]

[0150] The simultaneous polymerization and crosslinking step reaction mixture includes a radical polymerization initiator in addition to 2-propen-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt. The initiator can be selected from a wide range of initiators, including cationic and radical polymerization initiators. Examples of polymerization initiators for the simultaneous polymerization and crosslinking step reactions include peroxy and azo free radical initiators, such as azodiisobutyronitrile, azodiisovaleronitrile, dimethyl azodiisobutyrate, 2,2'-azobis(isobutyronitrile), 2,2'-azobis(N,N'-dimethyl-eneisobutylamidine) dihydrochloride, and 2,2'-azobis(2-methylpropionamidine) disalt. Acid salt, 2,2'-azobis(2-amidinopropane) dihydrochloride, 2,2'-azobis(N,N'-dimethyleneisobutylamidine), 1,1'-azobis(l-cyclohexanecarbonitrile), 4,4'-azobis(4-cyanopentanoic acid), 2,2'-azobis(isobutyramide) dihydrate, 2,2'-azobis(2-methylpropane), 2,2'-azobis(2-methylbutyronitrile), VAZO 67, cyanopentanoic acid, peroxypivalate, dodecylbenzene peroxide, benzoyl peroxide, di-t-butyl hydroperoxide, t-butyl peracetate, acetyl peroxide, dicumyl peroxide, cumyl hydroperoxide, dimethylbis(butylperoxy)hexane. For example, the radical polymerization initiator is V-50 (2,2'-azobis(2-methylpropionamidine) dihydrochloride).

[0151] Experience to date has shown that the amount of initiator relative to the amount of 2-propen-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. Typically, therefore, the ratio of the combined allyl equivalents to initiator equivalents of 2-propen-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt introduced into the reaction mixture ranges from about 6:1 to about 70:1, respectively. For example, in some such embodiments, the ratio of the combined allyl equivalents to initiator equivalents of 2-propen-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt introduced into the reaction mixture ranges from about 7:1 to about 60:1, respectively. By way of further example, in some such embodiments, the ratio of the number of allyl equivalents to the number of initiator equivalents of the 2-propen-1-ylamine or salt thereof and the 1,3-bis(allylamino)propane or salt thereof combined introduced into the reaction mixture is from about 8:1 to about 50:1, respectively. By way of further example, in some such embodiments, the ratio of the number of allyl equivalents to the number of initiator equivalents of the 2-propen-1-ylamine or salt thereof and the 1,3-bis(allylamino)propane or salt thereof combined introduced into the reaction mixture is from about 10:1 to about 45:1, respectively. By way of further example, in some such embodiments, the ratio of the number of allyl equivalents to the number of initiator equivalents of the 2-propen-1-ylamine or salt thereof and the 1,3-bis(allylamino)propane or salt thereof combined introduced into the reaction mixture is from about 15:1 to about 40:1, respectively. By way of further example, in certain such embodiments, the ratio of the number of allyl equivalents to the number of initiator equivalents of the combined 2-propen-1-ylamine or salt thereof and 1,3-bis(allylamino)propane or salt thereof introduced into the reaction mixture is from about 17.5:1 to about 35:1, respectively.By way of further example, in some such embodiments, the ratio of the number of allyl equivalents to the number of initiator equivalents of the 2-propen-1-ylamine or salt thereof and the 1,3-bis(allylamino)propane or salt thereof combined introduced into the reaction mixture is from about 20:1 to about 30:1, respectively. By way of further example, in some such embodiments, the ratio of the number of allyl equivalents to the number of initiator equivalents of the 2-propen-1-ylamine or salt thereof and the 1,3-bis(allylamino)propane or salt thereof combined introduced into the reaction mixture is from about 22.5:1 to about 30:1, respectively. By way of further example, in some such embodiments, the ratio of the number of allyl equivalents to the number of initiator equivalents of the 2-propen-1-ylamine or salt thereof and the 1,3-bis(allylamino)propane or salt thereof combined introduced into the reaction mixture is from about 25:1 to about 27.5:1, respectively.

[0152] Experience to date has also shown that the combined amount of 2-propen-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. Typically, therefore, the weight ratio of the combined amount of 2-propen-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the amount of water in the reaction mixture ranges from about 0.01 to about 3, respectively. For example, in certain embodiments, the weight ratio of the combined amount of 2-propen-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the amount of water in the reaction mixture ranges from about 0.05 to about 2.75, respectively. By way of further example, in certain such embodiments, the weight ratio of the combined amount of 2-propen-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt to the amount of water in the reaction mixture ranges from about 0.07 to about 2.5, respectively. By way of further example, in certain such embodiments, the weight ratio of the combined amount of 2-propen-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof to the amount of water in the reaction mixture is each in the range of about 0.1 to about 2.25. By way of further example, in certain such embodiments, the weight ratio of the combined amount of 2-propen-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof to the amount of water in the reaction mixture is each in the range of about 0.15 to about 2. By way of further example, in certain such embodiments, the weight ratio of the combined amount of 2-propen-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof to the amount of water in the reaction mixture is each in the range of about 0.2 to about 1.75. By way of further example, in certain such embodiments, the weight ratio of the combined amount of 2-propen-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof to the amount of water in the reaction mixture is each in the range of about 0.25 to about 1.5.By way of further example, in certain such embodiments, the weight ratio of the combined amount of 2-propen-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof to the amount of water in the reaction mixture is each in the range of about 0.25 to about 1.25. By way of further example, in certain such embodiments, the weight ratio of the combined amount of 2-propen-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof to the amount of water in the reaction mixture is each in the range of about 0.3 to about 1. By way of further example, in certain such embodiments, the weight ratio of the combined amount of 2-propen-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof to the amount of water in the reaction mixture is each in the range of about 0.35 to about 0.75. By way of further example, in certain such embodiments, the weight ratio of the combined amount of 2-propen-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof to the amount of water in the reaction mixture is each in the range of about 0.4 to about 0.5. In each of the exemplary embodiments in this paragraph, the 2-propen-1-ylamine or salt thereof and 1,3-bis(allylamino)propane or salt thereof species are assumed to be in their respective free amine forms for purposes of calculating weight ratios.

[0153] Experience to date has further shown that the ratio of allyl equivalents to water equivalents in the reaction mixture affects the characteristics of the resulting polymer.Typically, therefore, the ratio of the combined allyl equivalents to water equivalents of 2-propen-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof introduced into the reaction mixture ranges from about 0.01:1 to about 1:1, respectively.For example, in some such embodiments, the ratio of the combined allyl equivalents to water equivalents of 2-propen-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof introduced into the reaction mixture ranges from about 0.015:1 to about 0.75:1, respectively. By way of further example, in certain such embodiments, the ratio of the number of allyl equivalents to the number of water equivalents of the 2-propen-1-ylamine or salt thereof and the 1,3-bis(allylamino)propane or salt thereof combined introduced into the reaction mixture is from about 0.02:1 to about 0.5:1, respectively. By way of further example, in certain such embodiments, the ratio of the number of allyl equivalents to the number of water equivalents of the 2-propen-1-ylamine or salt thereof and the 1,3-bis(allylamino)propane or salt thereof combined introduced into the reaction mixture is from about 0.03:1 to about 0.4:1, respectively. By way of further example, in certain such embodiments, the ratio of the number of allyl equivalents to the number of water equivalents of the 2-propen-1-ylamine or salt thereof and the 1,3-bis(allylamino)propane or salt thereof combined introduced into the reaction mixture is from about 0.04:1 to about 0.3:1, respectively. By way of further example, in certain such embodiments, the ratio of the combined number of allyl equivalents to the number of water equivalents of the 2-propen-1-ylamine or salt thereof and the 1,3-bis(allylamino)propane or salt thereof introduced into the reaction mixture is from about 0.05:1 to about 0.25:1, respectively. By way of further example, in certain such embodiments, the ratio of the combined number of allyl equivalents to the number of water equivalents of the 2-propen-1-ylamine or salt thereof and the 1,3-bis(allylamino)propane or salt thereof introduced into the reaction mixture is from about 0.06:1 to about 0.2:1, respectively.By way of further example, in certain such embodiments, the ratio of the combined number of allyl equivalents to the number of water equivalents of the 2-propen-1-ylamine or salt thereof and the 1,3-bis(allylamino)propane or salt thereof introduced into the reaction mixture is from about 0.07:1 to about 0.175:1, respectively. By way of further example, in certain such embodiments, the ratio of the combined number of allyl equivalents to the number of water equivalents of the 2-propen-1-ylamine or salt thereof and the 1,3-bis(allylamino)propane or salt thereof introduced into the reaction mixture is from about 0.08:1 to about 0.15:1, respectively.

[0154] To produce polymer beads rather than a gel, the reaction mixture for the simultaneous polymerization and crosslinking steps is preferably a heterogeneous reaction mixture comprising a surfactant, water, and an organic solvent system (in addition to 2-propen-1-ylamine or a salt thereof, 1,3-bis(allylamino)propane or a salt thereof, an acid, and an initiator). Advantageously, the heterogeneous polymerization process produces polymer particles in the form of substantially spherical beads whose diameters can be controlled in the range of 3 to 1000 micrometers, preferably in the range of 10 to 500 micrometers, and in some embodiments, in the range of 40 to 180 micrometers.

[0155] Generally, the surfactant contained in the reaction mixture for the simultaneous polymerization and crosslinking process can be ionic or nonionic.Examples of 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 sulfosuccinic acid, branched dodecylbenzene sulfonic acid, linear dodecylbenzene sulfonic acid, sodium branched alkylbenzene sulfonate, sodium branched dodecylbenzene sulfonate, sodium alpha olefin sulfonate, sodium linear alkylbenzene sulfonate, isopropylamine branched alkylbenzene sulfonate, and sodium lauryl sulfate.For example, the surfactant is branched dodecylbenzene sulfonic acid.

[0156] The organic solvent system included in the simultaneous polymerization and crosslinking step reaction mixture can be any of a wide variety of water-immiscible organic solvents that can be used to disperse the aqueous phase. Examples of organic solvent systems include 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 thereof. For example, the organic solvent system can include heptane.

[0157] The simultaneous polymerization and crosslinking reaction mixture may contain any of a wide variety of acids. For example, in some embodiments, the simultaneous polymerization and crosslinking reaction mixture may contain a mineral acid or an organic acid. Examples of mineral acids include hydrochloric acid, sulfuric acid, and phosphoric acid. Examples of organic acids include formic acid, acetic acid, and citric acid. In some embodiments, the simultaneous polymerization and crosslinking reaction mixture may contain an acid selected from the group consisting of hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, methyl phosphate, formic acid, citric acid, and combinations thereof. In some embodiments, the simultaneous polymerization and crosslinking reaction mixture may contain an acid selected from the group consisting of hydrochloric acid, phosphoric acid, sulfuric acid, and combinations thereof. In some embodiments, the simultaneous polymerization and crosslinking reaction mixture may contain hydrochloric acid. Generally, the simultaneous polymerization and crosslinking reaction mixture may contain at least 0.4 equivalents of acid per equivalent of allylamine. For example, in some embodiments, the simultaneous polymerization and crosslinking reaction mixture may contain at least 0.6 equivalents of acid per equivalent of allylamine. By way of further example, in some such embodiments, the simultaneous polymerization and crosslinking reaction step reaction mixture comprises at least 0.8 equivalents of acid per equivalent of allylamine. By way of further example, in some such embodiments, the simultaneous polymerization and crosslinking reaction step reaction mixture comprises at least 0.9 equivalents of acid per equivalent of allylamine. By way of further example, in some such embodiments, the simultaneous polymerization and crosslinking reaction step reaction mixture comprises at least 0.95 equivalents of acid per equivalent of allylamine. By way of further example, in some such embodiments, the simultaneous polymerization and crosslinking reaction step reaction mixture comprises at least 1.0 equivalent of acid per equivalent of allylamine. By way of further example, in some such embodiments, the simultaneous polymerization and crosslinking reaction step reaction mixture comprises at least 1 equivalent of acid per equivalent of allylamine.

[0158] In each of the foregoing embodiments, the acid may be introduced into the first step reaction mixture, into the simultaneous polymerization and crosslinking reaction step reaction mixture independently of the addition of 2-propen-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt. Alternatively, in each of the foregoing embodiments, the acid may be introduced into the simultaneous polymerization and crosslinking reaction step reaction mixture as a component of 2-propen-1-ylamine or its salt, 1,3-bis(allylamino)propane or its salt, or acid salts of both 2-propen-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt.

[0159] The simultaneous polymerization and cross-linking reaction steps may be carried out at a temperature ranging from about 25°C to about 85°C. Typically, the simultaneous polymerization and cross-linking reaction steps are carried out at a temperature ranging from about 30°C to about 85°C. In some embodiments, the simultaneous polymerization and cross-linking reaction steps are carried out at a temperature ranging from about 35°C to about 85°C. In some embodiments, the simultaneous polymerization and cross-linking reaction steps are carried out at a temperature ranging from about 40°C to about 85°C. In some embodiments, the simultaneous polymerization and cross-linking reaction steps are carried out at a temperature ranging from about 45°C to about 85°C. In some embodiments, the simultaneous polymerization and cross-linking reaction steps are carried out at a temperature ranging from about 60°C to 80°C. Generally, the temperature may be maintained relatively constant during the reaction or may be increased or decreased continuously or in steps.

[0160] The simultaneous polymerization and crosslinking reaction steps may be carried out for a reaction time of at least about 2 hours. Typically, the simultaneous polymerization and crosslinking reaction steps are carried out for a reaction time of at least about 5 hours. In some embodiments, the simultaneous polymerization and crosslinking reaction steps are carried out for a reaction time of at least about 10 hours. In some embodiments, the simultaneous polymerization and crosslinking reaction steps are carried out for a reaction time of at least about 15 hours. In some embodiments, the simultaneous polymerization and crosslinking reaction steps are carried out for a reaction time of at least about 20 hours. In some embodiments, the simultaneous polymerization and crosslinking reaction steps are carried out for a reaction time of at least about 25 hours. In some embodiments, the simultaneous polymerization and crosslinking reaction steps are carried out for a reaction time of at least about 30 hours. In some embodiments, the simultaneous polymerization and crosslinking reaction steps are carried out for a reaction time of at least about 35 hours. In some embodiments, the simultaneous polymerization and crosslinking reaction steps are carried out for a reaction time of at least about 40 hours. Typically, however, the simultaneous polymerization and crosslinking reaction steps are carried out for a reaction time not exceeding about 50 hours.

[0161] The aqueous solids content (ASC) of the simultaneous polymerization and crosslinking reaction step can be about 20 to about 60 wt %. In some embodiments, the aqueous solids content is about 30 to about 50 wt %. In some embodiments, the aqueous solids content is about 30 to about 45 wt %. In some embodiments, the aqueous solids content is about 43 wt %.

[0162] In general, the simultaneous polymerization and crosslinking reaction steps can be a one-on-one polymerization, a stepwise addition of individual starting materials through a series of reactions, a stepwise addition of blocks of monomers, or a combination thereof. The reaction can be carried out as a batch, semi-batch, or continuous process.

[0163] In certain embodiments, the simultaneous polymerization and crosslinking steps result in preformed poly(allylamine) polymer beads having a target species binding capacity and a target swelling ratio. For example, in certain such embodiments, the beads have a chloride binding capacity of at least 10 mmol / g in simulated gastric fluid ("SGF") and a swelling ratio ranging from 1 to 10. In certain embodiments, the preformed poly(allylamine) polymer beads are characterized by a swelling ratio of about 2 and 10, more typically about 2 to about 8, and in certain embodiments, about 2 to 3, about 3 to 4, or about 4 to about 6. Furthermore, if the preformed poly(allylamine) polymer beads resulting from the first polymerization step are protonated, the amount of nitrogen-nitrogen crosslinking in the second crosslinking step can be reduced. Thus, in certain embodiments, the preformed poly(allylamine) polymer is at least partially deprotonated by treatment with a base, preferably a strong base such as a base hydroxide. For example, in certain embodiments, the base can be NaOH, KOH, NH4OH, NaHCO3, Na2CO3, K2CO3, LiOH, Li2CO3, CsOH, or other metal hydroxides. As a further example, the base is NaOH. If the charge is removed from the pre-formed cross-linked amine polymer beads by deprotonation, the beads tend to collapse, and the 1,2-dichloroethane cross-linking agent used in the second cross-linking step cannot access the binding sites of the polymer unless the bead collapse is prevented. One means of preventing the collapse of cross-linked polymer beads is the use of a swelling agent, such as water, to swell the beads, thereby allowing the 1,2-dichloroethane second-step cross-linking agent access to the binding sites.

[0164] As previously indicated, 1,3-bis(allylamino)propane or a salt thereof, the monomer that is only partially incorporated into the poly(allylamine) polymer in the first step, introduces pendant allyl groups to the poly(allylamine) polymer (i.e., at least one allyl group that does not participate in the reaction to become a chain atom of the poly(allylamine) polymer backbone, but simply "dangles" therefrom). That is, the pendant sp groups are present on the crosslinked poly(allylamine) polymer that remain in the poly(allylamine) polymer upon completion of the simultaneous polymerization and crosslinking steps (i.e., the first step).2 Determination of the number of allyl carbon atoms can be used to determine the amount of partially incorporated 1,3-bis(allylamino)propane or its salt. 2 The allyl carbon atoms preferably make up a low percentage of the total carbon atoms in the poly(allylamine) polymer. For example, in some embodiments, the poly(allylamine) polymer backbone contains pendant sp 2 The allylic carbons account for less than 1.1% of the total number of carbon atoms in the polymer. By way of further example, in some embodiments, the poly(allylamine) polymer backbone contains pendant sp 2 The allylic carbons comprise less than 1.0% of the total number of carbon atoms in the polymer. By way of further example, in some embodiments, the poly(allylamine) polymer backbone contains pendant sp 2 The allylic carbons account for less than 0.9% of the total number of carbon atoms in the polymer. By way of further example, in some embodiments, the poly(allylamine) polymer backbone contains pendant sp 2 The allylic carbons account for less than 0.8% of the total number of carbon atoms in the polymer. By way of further example, in some embodiments, the poly(allylamine) polymer backbone contains pendant sp 2 The allylic carbons comprise less than 0.75% of the total number of carbon atoms in the polymer. By way of further example, in some embodiments, the poly(allylamine) polymer backbone contains pendant sp 2 The allylic carbons account for less than 0.7% of the total number of carbon atoms in the polymer. By way of further example, in some embodiments, the poly(allylamine) polymer backbone contains pendant sp 2 The allylic carbons account for less than 0.6% of the total number of carbon atoms in the polymer. By way of further example, in some embodiments, the poly(allylamine) polymer backbone contains pendant sp 2 The allylic carbons comprise less than 0.5% of the total number of carbon atoms in the polymer. By way of further example, in some embodiments, the poly(allylamine) polymer backbone contains pendant sp 2 The allylic carbons comprise less than 0.4% of the total number of carbon atoms in the polymer. By way of further example, in some embodiments, the poly(allylamine) polymer backbone contains pendant sp2 The allylic carbons account for less than 0.3% of the total number of carbon atoms in the polymer. By way of further example, in some embodiments, the poly(allylamine) polymer backbone contains pendant sp 2 The allylic carbons comprise less than 0.25% of the total number of carbon atoms in the polymer. By way of further example, in some embodiments, the poly(allylamine) polymer backbone contains pendant sp 2 The allylic carbons account for less than 0.2% of the total number of carbon atoms in the polymer. By way of further example, in some embodiments, the poly(allylamine) polymer backbone contains pendant sp 2 The allylic carbons account for less than 0.1% of the total number of carbon atoms in the polymer. By way of further example, in some embodiments, the poly(allylamine) polymer backbone contains pendant sp 2 The allylic carbons comprise less than 0.05% of the total number of carbon atoms in the polymer. By way of further example, in some embodiments, the poly(allylamine) polymer backbone contains pendant sp 2 Allylic carbons are not detectable in the polymer beads. As a further example, in one embodiment, the poly(allylamine) polymer backbone has pendant sp 2 The allylic carbons may account for more than 0.3% of the total number of carbon atoms in the polymer, but are below the upper limit noted above, e.g., 1.0%. In each of the above exemplary embodiments, the poly(allylamine) polymer backbone in the beads has pendant sp 2 The percentage of allylic carbons is determined as follows, as described in more detail elsewhere herein: 1 H and 13 Quantitative measurements were performed on a Bruker AVANCE III 800 MHz (18.8 T) standard aperture spectrometer operating at 800.25 MHz and 201.24 MHz for C, respectively, using a 4 mm zirconia rotor system with a 16 kHz rotation speed. 13 C solid-state magic angle spinning (MAS) NMR measurements. In each of the above exemplary embodiments, the beads have pendant sp 2 The percentage of allylic carbons may be determined by any of the methods disclosed herein.

[0165] In the second crosslinking step, the preformed poly(allylamine) polymer is crosslinked with 1,2-dichloroethane.

[0166] In general, sp 2 Preferably, the number of allyl carbon atoms comprises a small percentage of the total carbon atoms of the crosslinked polymer after polymerization. For example, in one embodiment, the crosslinked poly(allylamine) polymer contains pendant sp 2 The allylic carbons account for less than 1.0% of the total number of carbon atoms in the polymer. By way of further example, in some embodiments, the crosslinked polymer backbone may have pendant sp 2 The allylic carbons account for less than 0.9% of the total number of carbon atoms in the polymer. By way of further example, in some embodiments, the crosslinked polymer backbone may have pendant sp 2 The allylic carbons account for less than 0.8% of the total number of carbon atoms in the polymer. By way of further example, in some embodiments, the crosslinked polymer backbone may have pendant sp 2 The allylic carbons account for less than 0.75% of the total number of carbon atoms in the polymer. By way of further example, in some embodiments, the crosslinked polymer backbone may have pendant sp 2 The allylic carbons account for less than 0.7% of the total number of carbon atoms in the polymer. By way of further example, in some embodiments, the crosslinked polymer backbone may have pendant sp 2 The allylic carbons account for less than 0.6% of the total number of carbon atoms in the polymer. By way of further example, in some embodiments, the crosslinked polymer backbone may have pendant sp 2 The allylic carbons comprise less than 0.5% of the total number of carbon atoms in the polymer. By way of further example, in some embodiments, the crosslinked polymer backbone may have pendant sp 2 The allylic carbons account for less than 0.4% of the total number of carbon atoms in the polymer. By way of further example, in some embodiments, the crosslinked polymer backbone may have pendant sp 2 The allylic carbons account for less than 0.3% of the total number of carbon atoms in the polymer. By way of further example, in some embodiments, the crosslinked polymer backbone may have pendant sp2 The allylic carbons account for less than 0.25% of the total number of carbon atoms in the polymer. By way of further example, in some embodiments, the crosslinked polymer backbone may have pendant sp 2 The allylic carbons account for less than 0.2% of the total number of carbon atoms in the polymer. By way of further example, in some embodiments, the crosslinked polymer backbone may have pendant sp 2 The allylic carbons account for less than 0.1% of the total number of carbon atoms in the polymer. By way of further example, in some embodiments, the crosslinked polymer backbone may have pendant sp 2 The allylic carbons account for less than 0.05% of the total number of carbon atoms in the polymer. By way of further example, in some embodiments, the crosslinked polymer backbone may have pendant sp 2 Allylic carbons are undetectable in the polymer beads. In each of the exemplary embodiments described above, the beads contain pendant sp 2 The percentage of allylic carbons, as described in more detail elsewhere herein, is 1 H and 13 Quantitative measurements were performed on a Bruker AVANCE III 800 MHz (18.8 T) standard aperture spectrometer scanning at 800.25 MHz and 201.24 MHz for C, respectively, using a 4 mm zirconia rotor system with a rotation speed of 16 kHz. 13 C solid-state magic angle spinning (MAS) NMR measurements. In each of the above exemplary embodiments, the beads are polymerized and then crosslinked, with pendant sp 2 The percentage of allylic carbons may be determined by any of the methods disclosed herein.

[0167] The resulting post-polymerization crosslinked polymer was the sp of the preformed poly(allylamine) polymer. 3 Carbon vs. sp 2 Larger sp than carbon ratio 3 Carbon vs. sp 2 Therefore, the second crosslinking reaction with 1,2-dichloroethane results in a higher sp in the post-polymerization crosslinked polymer compared to the preformed poly(allylamine) polymer. 3 Increasing the amount of carbon and sp2 The amount of carbon remains unchanged. For example, in certain embodiments where the preformed poly(allylamine) polymer is significantly crosslinked in the second crosslinking step, sp 3 The gradual increase in carbon 2 This may be sufficient to deteriorate the signal-to-noise ratio of the carbon, thereby reducing the sensitivity of the measurement. In some embodiments, therefore, the sp in the resulting post-polymerization crosslinked polymer by NMR can be measured. 2 carbon and sp 3 It is not a direct measurement of the amount of carbon, but rather how much sp 3 Carbon (and sp, if present) 2 (carbon) was added to the polymer during the second crosslinking step, and then the sp in the resulting post-polymerization crosslinked polymer was determined. 2 and sp 3 Calculate the total carbon to sp ratio in preformed poly(allylamine) polymers. 2 It is advantageous to measure the amount of carbon. Examples are given in Tables 10 and 11 below, where sp 2 The percent carbon was experimentally determined in both the preformed poly(allylamine) polymer and the corresponding cross-linked poly(allylamine) polymer. 2 For those carbons quantitatively determined in preformed crosslinked poly(allylamine) polymers, the sp in crosslinked poly(allylamine) polymers versus the corresponding preformed poly(allylamine) polymers. 2 The average ratio of percent carbon was about 0.9. This factor was compared with the sp 2 To calculate percent carbon, Table 11, Part 2 was applied where applicable.

[0168] In these embodiments, the crosslinker for the Step 2 crosslinking reaction is 1,2-dichloroethane (see Table B). [Table 3]

[0169] In some embodiments, the preformed poly(allylamine) polymer formed by the simultaneous polymerization and crosslinking reaction is further crosslinked in a second crosslinking step using a reaction mixture containing 1,2-dichloroethane, a swelling agent for the preformed poly(allylamine) polymer, and a dispersion solvent system. The dispersion solvent system contains a sufficient amount of solvent to disperse the preformed poly(allylamine) polymer in the reaction mixture to avoid interpolymer particle (i.e., interbead) crosslinking reactions and resulting aggregation. In some such embodiments, for example, the ratio of solvent to preformed poly(allylamine) polymer contained in the dispersion solvent system in the reaction mixture is at least 2:1 (milliliters of solvent:grams of preformed poly(allylamine) polymer). As a further example, in some such embodiments, the ratio of solvent to preformed poly(allylamine) polymer contained in the dispersion solvent system in the reaction mixture is at least 3:1 (milliliters of solvent:grams of preformed poly(allylamine) polymer). By way of further example, in some such embodiments, the ratio of solvent to preformed poly(allylamine) polymer in the dispersing solvent system in the reaction mixture is at least 4:1 (milliliters of solvent:grams of preformed poly(allylamine) polymer). By way of further example, in some such embodiments, the ratio of solvent to preformed poly(allylamine) polymer in the dispersing solvent system in the reaction mixture is at least 5:1 (milliliters of solvent:grams of preformed poly(allylamine) polymer). By way of further example, in some such embodiments, the ratio of solvent to preformed poly(allylamine) polymer in the dispersing solvent system in the reaction mixture is at least 7.5:1 (milliliters of solvent:grams of preformed poly(allylamine) polymer). By way of further example, in some such embodiments, the ratio of solvent to preformed poly(allylamine) polymer in the dispersing solvent system in the reaction mixture is at least 10:1 (milliliters of solvent:grams of preformed poly(allylamine) polymer). By way of further example, in certain such embodiments, the ratio of solvent to preformed poly(allylamine) polymer in the dispersing solvent system in the reaction mixture is at least 20:1 (milliliters of solvent:grams of preformed poly(allylamine) polymer).In each of the foregoing embodiments, the dispersing solvent system can comprise a combination of (i) an inert solvent (relative to the preformed poly(allylamine) polymer), such as one of the nonpolar solvents identified above in connection with the organic solvent system in which the preformed poly(allylamine) polymer is formed in the first crosslinking step, and (ii) 1,2-dichloroethane (DCE) as a crosslinking solvent. Alternatively, in each of the foregoing embodiments, the dispersing solvent system can comprise 1,2-dichloroethane (DCE) exclusively as the solvent, excluding the inert solvent, and thus serving the dual purpose of both solvent (dispersant) and crosslinker. As a further alternative, in each of the foregoing embodiments, the dispersing solvent system can comprise neat 1,2-dichloroethane (DCE) exclusively as the solvent, excluding the inert solvent, and thus serving the dual purpose of both solvent (dispersant) and crosslinker.

[0170] As noted above, in some embodiments, a swelling agent for the preformed 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 immiscible, and the swelling agent may be any composition or combination of compositions capable of swelling the preformed poly(allylamine) polymer. Examples of 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 may be water. Furthermore, the amount of swelling agent included in the second crosslinking step reaction mixture may typically be less than the absorption capacity of the preformed poly(allylamine) polymer for the swelling agent. For example, it is generally preferred that the weight ratio of swelling agent to preformed polymer in the second crosslinking step reaction mixture be less than 4:1. By way of further example, in certain embodiments, the weight ratio of swelling agent to preformed polymer in the second crosslinking step reaction mixture is less than 3:1. By way of further example, in certain embodiments, the weight ratio of swelling agent to preformed polymer in the second crosslinking step reaction mixture is less than 2:1. By way of further example, in certain embodiments, the weight ratio of swelling agent to preformed polymer in the second crosslinking step reaction mixture is less than 1:1. By way of further example, in certain embodiments, the weight ratio of swelling agent to preformed polymer in the second crosslinking step reaction mixture is less than 0.5:1. By way of further example, in certain embodiments, the weight ratio of swelling agent to preformed polymer in the second crosslinking step reaction mixture is less than 0.4:1. By way of further example, in certain embodiments, the weight ratio of swelling agent to preformed polymer in the reaction mixture is less than 0.3:1. Generally, however, the weight ratio of swelling agent to preformed polymer in the second crosslinking step reaction mixture is typically at least 0.05:1, respectively.

[0171] The second crosslinking step may be carried out at a temperature range of about 25°C to about 85°C. Typically, the second crosslinking step is carried out at a temperature range of about 35°C to about 80°C. In some embodiments, the second crosslinking step is carried out at a temperature range of about 45°C to about 80°C. In some embodiments, the second crosslinking step is carried out at a temperature range of about 55°C to about 75°C. In some embodiments, the second crosslinking step is carried out at a temperature range of about 60°C to about 75°C. In some embodiments, the second crosslinking step is carried out at a temperature range of about 65°C to about 75°C. Generally, the temperature may be maintained relatively constant during the course of the second crosslinking step, or may be increased or decreased continuously or stepwise.

[0172] The second crosslinking step may be carried out for a period of about 2 to 20 hours. Typically, the second crosslinking step is carried out for a period of about 4 to 20 hours. In some embodiments, the second crosslinking step is carried out for a period of about 5 to 20 hours. In some embodiments, the second crosslinking step is carried out for a period of about 6 to 20 hours. In some embodiments, the second crosslinking step is carried out for a period of about 8 to 20 hours. In some embodiments, the second crosslinking step is carried out for a period of about 10 to 20 hours. In some embodiments, the second crosslinking step is carried out for a period of about 12 to 18 hours. In some embodiments, the second crosslinking step is carried out for a period of about 14 to 18 hours. In some embodiments, the second crosslinking step is carried out for a period of about 15 to 17 hours.

[0173] In some embodiments, the resulting preformed poly(allylamine) polymer is at least partially deprotonated with a base to swell the free amine polymer without protonating the amine functional groups prior to the second crosslinking step, and combined with a non-protonated swelling agent. Thus, for example, the amount of non-protonated swelling agent can be selected to fine-tune the degree of subsequent crosslinking to effectively form a template that is then locked via the amine-consuming crosslinking step.

[0174] The benefit of deprotonated preformed polymer beads in the second crosslinking step highlights the advantages of using two steps to obtain the final product. In the first crosslinking step, to form the amine polymer beads, all monomers (i.e., 2-propen-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt) are protonated and remain in the aqueous phase, avoiding radical transfer reactions that severely limit the polymerization of unprotonated allylamine (and derivatives). Once the beads are formed by carbon-carbon crosslinking, they can then be deprotonated and further crosslinked with 1,2-dichloroethane in the second crosslinking step.

[0175] In some embodiments, chloride selectivity over other competing ions is achieved with highly crosslinked amine polymers. For example, relatively high chloride binding capacity can be achieved by reacting preformed poly(allylamine) polymer beads with neat 1,2-dichloroethane in the presence of a swelling agent (water). This "non-dispersive" reaction provides highly selective access of chloride over competing ions in SIB assays while also resulting in macroscopic (and microscopic) aggregation of polymer beads. Therefore, to avoid inter-bead reaction and resulting aggregation, it is advantageous to include a solvent (e.g., heptane) to disperse the preformed crosslinked polymer beads in the second crosslinking step. However, using too much solvent (dispersant) can dilute the reaction solution to the point where the resulting beads are not sufficiently crosslinked to have the desired selectivity for chloride over other competing anions. However, by using a crosslinker (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 reaction and aggregation without diluting the mixture to the point where the degree of amine-consuming crosslinking is insufficient. For example, in an effort to utilize the dispersing properties of the solvent (to avoid agglomeration during the reaction) while maintaining reactivity, 1,2-dichloroethane (DCE) was used solvent-free, thus serving the dual purpose of both solvent (dispersant) and crosslinker. Interestingly, DCE was found to have superior dispersing properties as a solvent when compared to similar reactions with DCP and / or heptane. Furthermore, when beads were first dispersed in DCE and then, in a second operation, water was added to swell the beads, little agglomeration was observed. Agglomeration can occur when water is added to a preformed poly(allylamine) polymer before dispersing the beads in DCE.

[0176] In each of the above embodiments, the second crosslinking step reaction mixture can contain a wide range of amounts of 1,2-dichloroethane. For example, in some embodiments, 1,2-dichloroethane can be used in large excess relative to the amount of preformed poly(allylamine) polymer in the reaction mixture. Stated another way, in such embodiments, 1,2-dichloroethane is the crosslinking solvent, i.e., the solvent for the reaction mixture and the crosslinker for the preformed poly(allylamine) polymer. In such embodiments, other solvents can be included in the dispersion solvent system of the second crosslinking step reaction mixture, if desired, but are not required. Alternatively, the preformed poly(allylamine) polymer, swelling agent, and 1,2-dichloroethane can 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 such embodiments, the swelling agent may include 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, when the swelling agent includes a polar solvent, the dispersion solvent system of the second crosslinking step typically includes 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 some embodiments, 1,2-dichloroethane and the solvent included in the dispersion solvent system may be the same.

[0177] It is notable that in crosslinking solvents (e.g., DCE dispersion reactions), there is a large excess of crosslinker regardless of the amount of crosslinking solvent (e.g., 1,2-dichloroethane (DCE)) used to disperse the beads (e.g., 1 g:3 mL::beads:DCE and 1 g:10 mL::beads:DCE Yanagiya are large excesses of crosslinker, most of which is not consumed during the reaction). Regardless of this, the relative degree of crosslinking and chloride capacity and performance in SIB assays are relatively insensitive to changes in the reactive crosslinker to polymer bead ratio. This is likely because the reaction is limited by the acid-neutralizing capacity of the polymer beads, not the amount of crosslinker (e.g., DCE).

[0178] To react more efficiently with 1,2-dichloroethane (DCE), the amines of the preformed polymer beads preferably have a free electron pair (neutral, deprotonated). As the amines of the free preformed polymer beads react with 1,2-dichloroethane (DCE), HCl is produced, protonating the amine and thus limiting the reaction. For this reason, the preformed poly(allylamine) polymer beads preferably begin as free amines in the second crosslinking step. If the preformed poly(allylamine) polymer beads are protonated after the first step of carbon-carbon crosslinking, amine-consumptive crosslinking in the second crosslinking step is limited, thus reducing the selectivity of chloride over other desired competing ions. This is demonstrated by adding a known amount of HCl to the preformed poly(allylamine) polymer beads immediately prior to crosslinking with DCE in the second crosslinking step. When less than 3 mol% HCl (relative to the amines in the preformed polymeric amine beads) was added before crosslinking in the second crosslinking step, the total chloride capacity (SGF) and chloride selectivity in the SIB were comparable to beads not treated with HCl in the second crosslinking step. When more than 5 mol% HCl (relative to the amines in the preformed polymeric amine beads) was added before crosslinking in the second crosslinking step, the total chloride capacity (SGF) in the SIB increased and chloride selectivity decreased, indicating less uptake of 1,2-dichloroethane.

[0179] The use of 1,2-dichloroethane ("DCE") as a cross-linking solvent also produces HCl molecules during the secondary cross-linking step. These HCl molecules protonate some of the free amine sites, thereby blocking the cross-linking reaction at those reactive sites, thereby limiting the number of bonding sites available for cross-linking. Consequently, the use of DCE has a self-limiting effect on the secondary cross-linking.

[0180] A large excess of 1,2-dichloroethane as a dual crosslinker / solvent allows for the incorporation of 1,2-dichloroethane alone, resulting in alkyl chloride functional groups on the inherently hydrophobic crosslinked polymer beads, which may increase nonspecific interactions with undesired solutes other than HCl, which is inherently even more hydrophobic. Washing with ammonium hydroxide solution converts the alkyl chloride to a hydrophilic alkyl-amine functional group, minimizing nonspecific interactions with undesired solutes. Other modifications that result in more hydrophilic groups than alkyl chloride, such as -OH, are suitable for quenching the crosslinker / solvent incorporated alone.

[0181] As described above, in some embodiments, a swelling agent for the preformed poly(allylamine) polymer can be included in the second crosslinking step reaction mixture along with 1,2-dichloroethane in the second crosslinking step. Generally, the swelling agent and 1,2-dichloroethane can be miscible or immiscible, and the swelling agent can be any composition or combination of compositions capable of swelling the preformed poly(allylamine) polymer. Examples of 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 can be water. Furthermore, the amount of swelling agent included in the second crosslinking step reaction mixture is typically less than the absorption capacity of the preformed poly(allylamine) polymer for the swelling agent. For example, it is generally preferred that the weight ratio of swelling agent to preformed polymer in the second crosslinking step reaction mixture be less than 4:1. By way of further example, in certain embodiments, the weight ratio of swelling agent to preformed polymer in the second crosslinking step reaction mixture is less than 3:1. By way of further example, in certain embodiments, the weight ratio of swelling agent to preformed polymer in the second crosslinking step reaction mixture is less than 2:1. By way of further example, in certain embodiments, the weight ratio of swelling agent to preformed polymer in the second crosslinking step reaction mixture is less than 1:1. By way of further example, in certain embodiments, the weight ratio of swelling agent to preformed polymer in the second crosslinking step reaction mixture is less than 0.5:1. By way of further example, in certain embodiments, the weight ratio of swelling agent to preformed polymer in the second crosslinking step reaction mixture is less than 0.4:1. By way of further example, in certain embodiments, the weight ratio of swelling agent to preformed polymer in the second crosslinking step reaction mixture is less than 0.3:1. Generally, however, the weight ratio of swelling agent to preformed polymer in the second crosslinking step reaction mixture is typically at least 0.05:1, respectively.

[0182] When the swelling agent is water, the weight ratio of water to pre-formed poly(allylamine) polymer in the second crosslinking step reaction mixture is typically less than about 4:1 (water to polymer). For example, in some such embodiments, when the second crosslinking step reaction mixture contains water as the swelling agent, the weight ratio of water to pre-formed poly(allylamine) polymer in the second crosslinking step reaction mixture is typically less than about 3.5:1. By way of further example, in some such embodiments, when the second crosslinking step reaction mixture contains water as the swelling agent, the weight ratio of water to pre-formed poly(allylamine) polymer in the second crosslinking step reaction mixture is typically less than about 3:1. By way of further example, in some such embodiments, when the second crosslinking step reaction mixture contains water as the swelling agent, the weight ratio of water to pre-formed poly(allylamine) polymer in the second crosslinking step reaction mixture is typically less than about 2.5:1. By way of further example, in some such embodiments, the second crosslinking-step reaction mixture includes water as a swelling agent, and the weight ratio of water to pre-formed poly(allylamine) polymer in the second crosslinking-step reaction mixture is typically less than about 2:1. By way of further example, in some such embodiments, the second crosslinking-step reaction mixture includes water as a swelling agent, and the weight ratio of water to pre-formed poly(allylamine) polymer in the second crosslinking-step reaction mixture is typically less than about 1.5:1. By way of further example, in some such embodiments, the second crosslinking-step reaction mixture includes water as a swelling agent, and the weight ratio of water to pre-formed poly(allylamine) polymer in the second crosslinking-step reaction mixture is typically less than about 1:1. By way of further example, in some such embodiments, the second crosslinking-step reaction mixture includes water as a swelling agent, and the weight ratio of water to pre-formed poly(allylamine) polymer in the second crosslinking-step reaction mixture is typically less than about 0.75:1. By way of further example, in some such embodiments, the second crosslinking-step reaction mixture includes water as a swelling agent, and the weight ratio of water to pre-formed poly(allylamine) polymer in the second crosslinking-step reaction mixture is typically less than about 0.5: 1. By way of further example, in some such embodiments, the second crosslinking-step reaction mixture includes water as a swelling agent, and the weight ratio of water to pre-formed poly(allylamine) polymer in the second crosslinking-step reaction mixture is typically less than about 0.25: 1.Generally, however, when water is used as the swelling agent, the weight ratio of water to preformed poly(allylamine) polymer in the second crosslinking step reaction mixture is typically at least about 0.15:1 (water to polymer), but less than the water absorption capacity of the preformed poly(allylamine) polymer. As a further example, in certain embodiments, the weight ratio of water to preformed poly(allylamine) polymer in the second crosslinking step reaction mixture is typically at least about 0.2:1, but less than the water absorption capacity of the preformed poly(allylamine) polymer. As a further example, in certain embodiments, the weight ratio of water to preformed poly(allylamine) polymer in the second crosslinking step reaction mixture is typically at least about 0.25:1, but less than the water absorption capacity of the preformed poly(allylamine) polymer. As a further example, in certain embodiments, the weight ratio of water to preformed poly(allylamine) polymer in the second crosslinking step reaction mixture is typically at least about 0.5:1, but less than the water absorption capacity of the preformed poly(allylamine) polymer. By way of further example, in certain embodiments, the weight ratio of water to preformed poly(allylamine) polymer in the second crosslinking step reaction mixture is typically at least about 0.75:1, but less than the water absorption capacity of the preformed poly(allylamine) polymer. By way of further example, in certain embodiments, the weight ratio of water to preformed poly(allylamine) polymer in the second crosslinking step reaction mixture is typically at least about 1:1, but less than the water absorption capacity of the preformed poly(allylamine) polymer. By way of further example, in certain embodiments, the weight ratio of water to preformed poly(allylamine) polymer in the second crosslinking step reaction mixture is typically at least about 1.5:1, but less than the water absorption capacity of the preformed poly(allylamine) polymer. By way of further example, in certain embodiments, the weight ratio of water to preformed poly(allylamine) polymer in the second crosslinking step reaction mixture is typically at least about 2:1, but less than the water absorption capacity of the preformed poly(allylamine) polymer. By way of further example, in certain embodiments, the weight ratio of water to pre-formed poly(allylamine) polymer in the second crosslinking step reaction mixture is typically at least about 2.5:1, but less than the water absorption capacity of the pre-formed poly(allylamine) polymer.By way of further example, in certain embodiments, the weight ratio of water to preformed poly(allylamine) polymer in the second crosslinking step reaction mixture is typically at least about 3:1, but less than the water absorption capacity of the preformed poly(allylamine) polymer. By way of further example, in certain embodiments, the weight ratio of water to preformed poly(allylamine) polymer in the second crosslinking step reaction mixture is typically at least about 3.5:1, but less than the water absorption capacity of the preformed poly(allylamine) polymer. Thus, in certain embodiments, the weight ratio of water to preformed poly(allylamine) polymer ranges from about 0.15:1 to about 4:1. By way of further example, in certain embodiments, the weight ratio of water to preformed poly(allylamine) polymer ranges from about 0.2:1 to about 3.5:1. By way of further example, in certain embodiments, the weight ratio of water to preformed poly(allylamine) polymer ranges from about 0.2:1 to about 3:1.

[0183] The second crosslinking step reaction mixture can contain a wide range of amounts of 1,2-dichloroethane. For example, in some embodiments, 1,2-dichloroethane can be used in large excess relative to the amount of preformed poly(allylamine) polymer in the second crosslinking step reaction mixture. Stated another way, in such embodiments, 1,2-dichloroethane is the crosslinking solvent, i.e., both the solvent for the second crosslinking step reaction mixture and the crosslinker for the preformed poly(allylamine) polymer. In such embodiments, other solvents can be included in the second crosslinking step reaction mixture, if desired, but are not required. Alternatively, the preformed poly(allylamine) polymer, swelling agent, and 1,2-dichloroethane can 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 can be a polar solvent; in some such embodiments, the swelling agent can include, for example, water, methanol, ethanol, n-propanol, isopropanol, formic acid, acetic acid, acetonitrile, dimethylformamide, dimethyl sulfoxide, nitromethane, or a combination thereof. As a further example, when the swelling agent includes a polar solvent, the solvent system of the second crosslinking step reaction mixture typically includes 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 some embodiments, the crosslinker and the solvent can be the same; that is, the solvent is 1,2-dichloroethane.

[0184] In embodiments where the second crosslinking step reaction mixture includes a swelling agent, it may be preferable to combine the preformed poly(allylamine) polymer with a solvent (also sometimes referred to as a dispersant) before combining the preformed poly(allylamine) polymer with the swelling agent in the second crosslinking step reaction mixture. In certain embodiments, the resulting crosslinked polymer is less prone to agglomeration when the preformed poly(allylamine) polymer is combined with a solvent (dispersant) that is immiscible with the swelling agent before combining the preformed poly(allylamine) polymer with the swelling agent. Thus, in certain embodiments, fewer than 25% of the particles in a representative sample of the crosslinked amine particle population after polymerization are aggregated. For example, in certain embodiments, fewer than 20% of the particles in a representative sample of the crosslinked amine particle population after polymerization are aggregated. As a further example, in certain embodiments, fewer than 15% of the particles in a representative sample of the crosslinked amine particle population after polymerization are aggregated. As a further example, in certain embodiments, fewer than 10% of the particles in a representative sample of the crosslinked amine particle population after polymerization are aggregated. By way of further example, in some embodiments, less than 5% of the particles in a representative sample of the crosslinked amine particle population after polymerization are aggregated. By way of further example, in some embodiments, less than 1% of the particles in a representative sample of the crosslinked amine particle population after polymerization are aggregated. Aggregation can be assessed using microscopy or other means of measuring particle size distribution. Absence of agglomeration is generally defined as discrete, free-flowing beads without macroscopic and / or microscopic clumps. The particle size distribution (defined elsewhere) can indicate that aggregation is occurring, for example, if the average size (d(50)) and / or d(90) of the crosslinked poly(allylamine) polymer increases relative to the pre-formed poly(allylamine) polymer beads after the crosslinking process, as described above.

[0185] In some embodiments, a preformed poly(allylamine) polymer is formed in a first step, and the preformed poly(allylamine) polymer is further crosslinked in a second crosslinking step without isolating the preformed poly(allylamine) polymer between the first and second crosslinking steps (referred to as a "one-pot synthesis" childFor example, in certain such embodiments, a preformed poly(allylamine) polymer is formed in a first-step reaction mixture (as described previously herein), and the preformed poly(allylamine) polymer is then crosslinked using 1,2-dichloroethane without isolating the preformed poly(allylamine) polymer formed in the first-step reaction mixture. By way of further example, in certain such embodiments, the preformed polymer can be separated into a nonpolar solvent disclosed herein (e.g., including 1,2-dichloroethane as the crosslinking solvent) to form a second-crosslinking-step reaction mixture, and a swelling agent is added to the reaction mixture. In certain such exemplary embodiments, the crosslinking agent and solvent are 1,2-dichloroethane, and the swelling agent comprises water. In each of the foregoing embodiments, the preformed polymer is an amine-containing polymer comprising residues of 2-propen-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof.

[0186] In certain exemplary embodiments, preformed polyamine polymers are crosslinked, e.g., under suspension conditions, to produce particles of targeted particle size and morphology. When using a water-immiscible crosslinker (e.g., 1,2-dichloroethane (DCE)) as the dispersant, high chloride binding selectivity is achieved, as shown, for example, in SIB.

[0187] In some embodiments, the amine polymer can be formed and then further crosslinked in the same reaction flask and sequence. The crosslinked amine polymer can be produced, for example, under suspension conditions to produce particles of a targeted particle size and morphology. In the same reaction flask, and without isolation, the water content of the beads can be reduced by Dean-Stark or other similar evaporation techniques. The water content is then adjusted to a targeted level to perform a second crosslinking reaction to produce a final polymer with the desired properties and characteristics.

[0188] In some embodiments, the crosslinked poly(allylamine) amine polymer formed in the second crosslinking step (as described above) is treated to reduce the concentration of any remaining amine-reactive groups (i.e., alkyl chloride functional groups) introduced into the crosslinked polymer by 1,2-dichloroethane. For example, in some such embodiments, the crosslinked poly(allylamine) polymer is treated with a quenching agent such as a base, washing, heating, or other treatment to remove or quench the amine-reactive groups. As a further example, in some such embodiments, the crosslinked poly(allylamine) polymer is treated with ammonium hydroxide. The ammonium hydroxide treatment can be performed immediately after the reaction, during a washing step, or after the polymer has been washed and dried; in either case, the polymer can be treated through a series of additional washing steps. In other such embodiments, the crosslinked poly(allylamine) polymer is heated in a conventional or vacuum oven at a temperature above room temperature for a period of time, e.g., at 60°C for greater than 36 hours. Oven incubation can be performed under an inert atmosphere (e.g., nitrogen or argon) to reduce the possibility of oxidation.

[0189] Crosslinked poly(allylamine) polymer As previously indicated, the crosslinked poly(allylamine) polymers having medical uses described herein have the ability to scavenge HCl.

[0190] In certain embodiments, the crosslinked poly(allylamine) polymer of the present invention is in the form of beads and consists essentially of (i) 20-25 mol % residues of 1,3-bis(allylamino)propane or a salt thereof, (ii) 50-60 mol % residues of 2-propen-1-ylamine or a salt thereof, and (iii) 20-25 mol % residues of 1,2-dichloroethane, wherein (i) the crosslinked poly(allylamine) polymer is sp 2 It contains allylic carbon atoms and has a swelling ratio of less than 2.

[0191] In certain embodiments, the crosslinked poly(allylamine) polymers of the present invention comprise residues of 2-propen-1-ylamine or a salt thereof, 1,3-bis(allylamino)propane or a salt thereof, and 1,2-dichloroethane.

[0192] In certain embodiments, the crosslinked poly(allylamine) polymers of the present invention consist essentially of residues of 2-propen-1-ylamine or a salt thereof, 1,3-bis(allylamino)propane or a salt thereof, and 1,2-dichloroethane.

[0193] In certain embodiments, the crosslinked poly(allylamine) polymers of the present invention consist of residues of 2-propen-1-ylamine or a salt thereof, 1,3-bis(allylamino)propane or a salt thereof, and 1,2-dichloroethane.

[0194] In certain embodiments, the crosslinked poly(allylamine) polymers of the present invention are prepared by crosslinking 1,3-propanediamine with 1,2-dichloroethane and 2-propen-1-amine, N 1 ,N 3 -di-2-propen-1-yl-, polymer.

[0195] In certain embodiments, the crosslinked poly(allylamine) polymers of the present invention are N-allylamine polymers of 1,2-dichloroethane and prop-2-en-1-amine. 1 ,N 3 -bis(prop-2-en-1-yl)propane-1,3-diamine copolymer.

[0196] In certain embodiments, the crosslinked poly(allylamine) polymers of the present invention comprise a crosslinked poly(allylamine) polymer having the residue [ka] where x, y, and z are positive integers.

[0197] In some embodiments, the crosslinked poly(allylamine) polymers of the present invention are [ka] (wherein x, y, and z are positive integers.) Contains residues of

[0198] In certain embodiments, the crosslinked poly(allylamine) polymers of the present invention have the formula 5a: [ka] [During the ceremony, a=N,N′-diallyl-1,3-diaminopropane or a salt thereof; b=a residue of 2-propen-1-ylamine or a salt thereof; c = two residues of 2-propen-1-ylamine bridged with 1,2-dichloroethane and m = repeat unit of the polymer. It includes a structure corresponding to:

[0199] In certain embodiments, the crosslinked poly(allylamine) polymers of the present invention have the formula 5b: [ka] [During the ceremony, a=N,N′-diallyl-1,3-diaminopropane or a salt thereof; b=a residue of 2-propen-1-ylamine or a salt thereof; and c = residues of two 2-propen-1-ylamines crosslinked with an ethylene crosslinker, e.g., 1,2-dichloroethane; this is shown as one of many possible crosslinks formed in the polymer. It includes a structure corresponding to:

[0200] In certain embodiments, the crosslinked poly(allylamine) polymer of the present invention is poly(allylamine-co-N,N'-diallyl-1,3-diaminopropane-co-1,2-diaminoethane).

[0201] In certain embodiments, the crosslinked poly(allylamine) polymers of the present invention have Formula 4: [ka] wherein each R independently represents hydrogen or an ethylene bridge between two nitrogen atoms of the crosslinked amine polymer. [ka] where a, b, c, and m are integers. It includes a structure corresponding to:

[0202] In some embodiments, the crosslinked poly(allylamine) polymers of the present invention are [(C3H7N) ~5 (C9H 18 N2) ~2 (C8H 16 N2) ~2 ] n , containing residues with n=∞.

[0203] In one embodiment, the crosslinked poly(allylamine) polymers of the present invention comprise: [ka] Contains residues of

[0204] In one embodiment, the crosslinked poly(allylamine) polymers of the present invention are non-absorbent, free-flowing powders consisting of low-swelling, spherical beads about 100 micrometers in diameter; each bead is a single crosslinked, high molecular weight molecule.

[0205] In some embodiments, the crosslinked poly(allylamine) polymer is a beverimer. In general, crosslinked poly(allylamine) polymers have a preferred particle size range that is (i) large enough to avoid passive or active absorption via the GI tract and (ii) small enough so as not to cause a gritty or unpleasant mouthfeel when ingested as a powder, sachet, and / or chewable tablet / dosage form with an average particle size of at least 3 microns. For example, in some such embodiments, the crosslinked poly(allylamine) polymer comprises a population of particles having an average particle size (volume distribution) greater than 1 micrometer and less than 1 millimeter. For example, in some such embodiments, the crosslinked poly(allylamine) polymer comprises a population of particles having an average particle size (volume distribution) in the range of 5 to 1,000 microns. As a further example, in some such embodiments, the crosslinked poly(allylamine) polymer comprises a population of particles having an average particle size (volume distribution) in the range of 5 to 500 microns. As a further example, in some such embodiments, the crosslinked poly(allylamine) polymer comprises a population of particles having an average particle size (volume distribution) in the range of 10 to 400 microns. By way of further example, in certain such embodiments, the crosslinked poly(allylamine) polymer comprises a population of particles having an average particle size (volume distribution) in the range of 10 to 300 microns. By way of further example, in certain such embodiments, the crosslinked poly(allylamine) polymer comprises a population of particles having an average particle size (volume distribution) in the range of 20 to 250 microns. By way of further example, in certain such embodiments, the crosslinked poly(allylamine) polymer has a particle size range of 30 to 250 microns. By way of further example, in certain such embodiments, the crosslinked poly(allylamine) polymer has a particle size range of 40 to 180 microns. In certain embodiments, fewer than 7% of the particles (by number) in the population have a diameter of less than 10 microns. For example, in such embodiments, fewer than 5% of the particles (by number) in the population have a diameter of less than 10 microns. By way of further example, in certain such embodiments, fewer than 2.5% of the particles (by number) in the population have a diameter of less than 10 microns. By way of further example, in such embodiments, less than 1% (by number) of the particles in the population have a diameter of less than 10 microns.In each of the exemplary embodiments listed in this paragraph, the particles are preferably in the form of beads.

[0206] A low swelling ratio of the crosslinked poly(allylamine) polymer (0.5 to 10 times its own weight in water) is preferred to minimize GI side effects in patients, often associated with large amounts of polymer gel traveling through the GI tract. For example, in some such embodiments, the crosslinked poly(allylamine) polymer has a swelling ratio of less than 2. As a further example, in some such embodiments, the crosslinked poly(allylamine) polymer has a swelling ratio of less than 1.9. As a further example, in some such embodiments, the crosslinked poly(allylamine) polymer has a swelling ratio of less than 1.8. As a further example, in some such embodiments, the crosslinked poly(allylamine) polymer has a swelling ratio of less than 1.7. As a further example, in some such embodiments, the crosslinked poly(allylamine) polymer has a swelling ratio of less than 1.6. As a further example, in some such embodiments, the crosslinked poly(allylamine) polymer has a swelling ratio of less than 1.5. As a further example, in some such embodiments, the crosslinked poly(allylamine) polymer has a swelling ratio of less than 1.4. By way of further example, in some such embodiments, the crosslinked poly(allylamine) polymer has a swelling ratio of less than 1.3. By way of further example, in some such embodiments, the crosslinked poly(allylamine) polymer has a swelling ratio of less than 1.2. By way of further example, in some such embodiments, the crosslinked poly(allylamine) polymer has a swelling ratio of less than 1. By way of further example, in some such embodiments, the crosslinked poly(allylamine) polymer has a swelling ratio of less than 0.9. By way of further example, in some such embodiments, the crosslinked poly(allylamine) polymer has a swelling ratio of less than 0.8. By way of further example, in some such embodiments, the crosslinked poly(allylamine) polymer has a swelling ratio of less than 0.7. By way of further example, in some such embodiments, the crosslinked poly(allylamine) polymer has a swelling ratio of at least 0.5 and less than 2.By way of further example, in certain such embodiments, the crosslinked poly(allylamine) polymer has a swelling ratio of from about 0.7 to about 1.7.

[0207] Generally, crosslinked poly(allylamine) polymers have a theoretical proton binding capacity of at least about 7.5 mEq / g (as determined by SGF assay). For example, in some embodiments, crosslinked poly(allylamine) polymers have a theoretical proton binding capacity of at least about 8 mEq / g. As a further example, in some embodiments, crosslinked poly(allylamine) polymers have a theoretical proton binding capacity of at least about 8.5 mEq / g. As a further example, in some embodiments, crosslinked poly(allylamine) polymers have a theoretical proton binding capacity of at least about 9 mEq / g. As a further example, in some embodiments, crosslinked poly(allylamine) polymers have a theoretical proton binding capacity of at least about 9.5 mEq / g. As a further example, in some embodiments, crosslinked poly(allylamine) polymers have a theoretical proton binding capacity of at least about 10 mEq / g. By way of further example, in some embodiments, the crosslinked poly(allylamine) polymer has a theoretical proton binding capacity of at least about 10.5 mEq / g. By way of further example, in some embodiments, the crosslinked poly(allylamine) polymer has a theoretical proton binding capacity of at least about 11 mEq / g. In general, crosslinked poly(allylamine) polymers typically have a theoretical proton binding capacity of no more than about 35 mEq / g. For example, in some embodiments, the theoretical proton binding capacity of the crosslinked poly(allylamine) polymer does not exceed 30 mEq / g. The binding capacities described in this paragraph are the theoretical proton binding capacities and the theoretical chloride ion binding capacities, which are independent and separate, not the sum of them.

[0208] Phosphate, bicarbonate, bicarbonate equivalents, bile acid, and fatty acid conjugated bases are anions that may interfere with chloride or other conjugated bases of strong acids in the stomach and small intestine. Therefore, rapid and preferential binding of chloride over phosphate, bicarbonate equivalents, and bile acid and fatty acid conjugated bases in the small intestine is desirable, and the SIB assay can be used to determine kinetics and preferential binding. Because colonic transit time is slower (2-3 days) than in the small intestine, orally administered cross-linked poly(allylamine) polymers do not encounter colonic conditions until after encountering gastric and small intestinal conditions, the kinetics of chloride bound to cross-linked poly(allylamine) polymers do not need to be as rapid as under in vitro conditions designed to mimic the colon or late small intestine / colon. However, high selectivity over chloride binding and other interfering anions, for example, for 24 and / or 48 hours or longer, is desirable.

[0209] In certain embodiments, the crosslinked poly(allylamine) polymer is characterized by a chloride ion binding capacity of at least 2.5 mEq / g in a simulated small intestine inorganic ("SIB") assay. For example, in certain such embodiments, the crosslinked poly(allylamine) polymer is characterized by a chloride ion binding capacity of at least 3 mEq / g in a SIB assay. By way of further example, in certain such embodiments, the crosslinked poly(allylamine) polymer is characterized by a chloride ion binding capacity of at least 3.5 mEq / g in a SIB assay. By way of further example, in certain such embodiments, the crosslinked poly(allylamine) polymer is characterized by a chloride ion binding capacity of at least 4 mEq / g in a SIB assay. By way of further example, in certain such embodiments, the crosslinked poly(allylamine) polymer is characterized by a chloride ion binding capacity of at least 4.5 mEq / g in a SIB assay. By way of further example, in some such embodiments, the crosslinked poly(allylamine) polymer is characterized by a chloride ion binding capacity of at least 5 mEq / g in a SIB assay. By way of further example, in some such embodiments, the crosslinked poly(allylamine) polymer is characterized by a chloride ion binding capacity of at least 5.5 mEq / g in a SIB assay. By way of further example, in some such embodiments, the crosslinked poly(allylamine) polymer is characterized by a chloride ion binding capacity of at least 6 mEq / g in a SIB assay. By way of further example, in some such embodiments, the crosslinked poly(allylamine) polymer is characterized by a chloride ion binding capacity of about 4.1 mEq / g to about 5.4 mEq / g in a SIB assay.

[0210] In certain embodiments, the crosslinked poly(allylamine) polymer binds a significant amount of chloride relative to phosphate, e.g., as shown by a SIB assay. For example, in certain embodiments, the ratio of bound chloride to bound phosphate in the SIB assay is at least 1:1, respectively. As a further example, in certain such embodiments, the ratio of bound chloride to bound phosphate in the SIB assay is at least 2:1, respectively. As a further example, in certain such embodiments, the ratio of bound chloride to bound phosphate in the SIB assay is at least 2.25:1, respectively. As a further example, in certain such embodiments, the ratio of bound chloride to bound phosphate in the SIB assay is at least 2.5:1, respectively. As a further example, in certain such embodiments, the ratio of bound chloride to bound phosphate in the SIB assay is at least 2.75:1, respectively. As a further example, in certain such embodiments, the ratio of bound chloride to bound phosphate in the SIB assay is at least 3:1, respectively. By way of further example, in certain such embodiments, the ratio of the amount of bound chloride to bound phosphate in the SIB assay is at least 4:1, respectively. By way of further example, in certain such embodiments, the ratio of the amount of bound chloride to bound phosphate in the SIB assay is at least 5:1, respectively. By way of further example, in certain such embodiments, the ratio of the amount of bound chloride to bound phosphate in the SIB assay is from about 2.1:1, respectively, to about 10.8:1, respectively.

[0211] In some embodiments, the crosslinked poly(allylamine) polymer is characterized by a proton binding capacity and chloride binding capacity of at least 7.5 mEq / g in simulated gastric fluid in an SGF assay. For example, in some such embodiments, the crosslinked poly(allylamine) polymer is characterized by a proton binding capacity and chloride binding capacity of at least 8 mEq / g in an SGF assay. By way of further example, in some such embodiments, the crosslinked poly(allylamine) polymer is characterized by a proton binding capacity and chloride binding capacity of at least 8.5 mEq / g in an SGF assay. By way of further example, in some such embodiments, the crosslinked poly(allylamine) polymer is characterized by a proton binding capacity and chloride binding capacity of at least 9 mEq / g in an SGF assay. By way of further example, in some such embodiments, the crosslinked poly(allylamine) polymer is characterized by a proton binding capacity and chloride binding capacity of at least 9.5 mEq / g in an SGF assay. By way of further example, in some such embodiments, the crosslinked poly(allylamine) polymer is characterized by a proton binding capacity and chloride binding capacity in an SGF assay of at least 10 mEq / g. By way of further example, in some such embodiments, the crosslinked poly(allylamine) polymer is characterized by a proton binding capacity and chloride binding capacity in an SGF assay of at least 10.5 mEq / g. By way of further example, in some such embodiments, the crosslinked poly(allylamine) polymer is characterized by a proton binding capacity and chloride binding capacity in an SGF assay of at least 11 mEq / g. By way of further example, in some such embodiments, the crosslinked poly(allylamine) polymer is characterized by a proton binding capacity and chloride binding capacity in an SGF assay of at least 11.5 mEq / g. By way of further example, in some such embodiments, the crosslinked poly(allylamine) polymer is characterized by a proton binding capacity and chloride binding capacity in an SGF assay of at least 12 mEq / g.By way of further example, in certain such embodiments, the crosslinked poly(allylamine) polymer is characterized by a proton binding capacity and chloride binding capacity in the SGF assay of at least 12.5 mEq / g. By way of further example, in certain such embodiments, the crosslinked poly(allylamine) polymer is characterized by a proton binding capacity and chloride binding capacity in the SGF assay of about 9.0 mEq / g to about 12.6 mEq / g.

[0212] By way of further example, in certain such embodiments, the crosslinked poly(allylamine) polymer is characterized by a proton binding capacity and a chloride binding capacity after 1 hour in SGF that are at least 50% of the proton binding capacity and chloride binding capacity, respectively, of the crosslinked poly(allylamine) polymer after 24 hours in SGF. R By way of further example, in certain such embodiments, the crosslinked poly(allylamine) polymer is characterized by a proton binding capacity and a chloride binding capacity after 1 hour in SGF that are at least 60% of the proton binding capacity and chloride binding capacity, respectively, of the crosslinked poly(allylamine) polymer after 24 hours in SGF. R By way of further example, in certain such embodiments, the crosslinked poly(allylamine) polymer is characterized by a proton binding capacity and a chloride binding capacity after 1 hour in SGF that are at least 70% of the proton binding capacity and chloride binding capacity, respectively, of the crosslinked poly(allylamine) polymer after 24 hours in SGF. R By way of further example, in certain such embodiments, the crosslinked poly(allylamine) polymer is characterized by a proton binding capacity and a chloride binding capacity after 1 hour in SGF that are at least 80% of the proton binding capacity and the chloride binding capacity, respectively, of the crosslinked poly(allylamine) polymer after 24 hours in SGF. By way of further example, in certain such embodiments, the crosslinked poly(allylamine) polymer is characterized by a proton binding capacity and a chloride binding capacity after 1 hour in SGF that are at least 90% of the proton binding capacity and the chloride binding capacity, respectively, of the crosslinked poly(allylamine) polymer after 24 hours in SGF. R can.

[0213] In embodiments in which the crosslinked poly(allylamine) polymer binds chloride ions, it is generally preferred that the crosslinked poly(allylamine) polymer selectively bind chloride ions over other counterions, such as bicarbonate equivalent anions, phosphate anions, and conjugated bases of bile acids and fatty acids. Stated differently, it is generally preferred in these embodiments that the crosslinked poly(allylamine) polymer (i) removes more chloride ions than bicarbonate equivalent anions, (ii) removes more chloride ions than phosphate anions, and (iii) removes more chloride ions than conjugated bases of bile acids and fatty acids. Advantageously, therefore, treatment with the crosslinked poly(allylamine) polymer does not induce or exacerbate hypophosphatemia (i.e., serum phosphorus concentrations less than about 2.4 mg / dL), significantly increase low-density lipoprotein ("LDL"), or otherwise negatively affect serum or colonic levels of metabolically relevant anions.

[0214] In certain embodiments, the carbon-to-nitrogen weight ratio of the crosslinked poly(allylamine) polymers of the present invention may range from about 2:1 to about 6:1, respectively. For example, in certain such embodiments, the carbon-to-nitrogen weight ratio of the crosslinked poly(allylamine) polymers of the present invention may range from about 2.5:1 to about 5:1, respectively. By way of further example, in certain such embodiments, the carbon-to-nitrogen weight ratio of the crosslinked poly(allylamine) polymers of the present invention may range from about 3:1 to about 4.5:1, respectively. By way of further example, in certain such embodiments, the carbon-to-nitrogen weight ratio of the crosslinked poly(allylamine) polymers of the present invention may range from about 3.25:1 to about 4.25:1, respectively. By way of further example, in certain such embodiments, the carbon-to-nitrogen weight ratio of the crosslinked poly(allylamine) polymers of the present invention may range from about 3.4:1 to about 4:1, respectively. By way of further example, in certain such embodiments, the carbon-to-nitrogen weight ratio of the crosslinked poly(allylamine) polymers of the present invention may range from about 3.5:1 to about 4:1, respectively. By way of further example, in certain such embodiments, the carbon-to-nitrogen weight ratio of the crosslinked poly(allylamine) polymers of the invention may range from about 3.6:1 to about 3.9:1, respectively. By way of further example, in certain such embodiments, the carbon-to-nitrogen weight ratio of the crosslinked poly(allylamine) polymers of the invention may range from about 3.7:1 to about 3.8:1, respectively. In each of the foregoing 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 described in more detail elsewhere herein.

[0215] In certain embodiments, the crosslinked poly(allylamine) polymer has Formula 4: [ka] wherein R is independently hydrogen or ethylene bridging two nitrogen atoms of the crosslinked amine polymer, and a, b, c, and m are integers. Typically, m is a large integer that indicates an extended polymer network in which each polymer bead is considered a single molecule. In other words, when the molecular weight is calculated using the volume of the polymer bead and the bulk density of the polymer, m is 3.2×10 8The ratio is large enough to exhibit a molecular weight of greater than 1000 g / mol. In some such embodiments, 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 some such embodiments, 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. As a further example, in some such embodiments, 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 7:1. As a further example, in some such embodiments, 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 6:1. As a further example, in some such embodiments, 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. As a further example, in some such embodiments, 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 4:1. By way of further example, in some such embodiments, 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 3:1. By way of further example, in some such embodiments, 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 2:1. By way of further example, in some such embodiments, 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. By way of further example, in some such embodiments, 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 some such embodiments, the ratio of the sum of a and b is 57, c is 24, and m is a large integer indicating an extended polymer network. In each of the foregoing embodiments, the ratio of the sum of a and b to c (i.e., a+b:c) can be in the range of about 2:1 to 2.5:1. For example, in such embodiments, the ratio of the sum of a and b to c (i.e., a+b:c) can be in the range of about 2.1:1 to 2.2:1. By way of further example, in such embodiments, the ratio of the sum of a and b to c (i.e., a+b:c) can be in the range of about 2.2:1 to 2.3:1.By way of further example, in such embodiments, the ratio of the sum of a and b to c (i.e., a+b:c) can be in the range of about 2.3:1 to 2.4:1. By way of further example, in such embodiments, the ratio of the sum of a and b to c (i.e., a+b:c) can be in the range of about 2.4:1 to 2.5:1. In each of the foregoing embodiments, each R can independently be hydrogen or ethylene bridging two nitrogen atoms. Typically, however, 35-95% of the R substituents are hydrogen and 5-65% are ethylene bridges. [ka] For example, in some such embodiments, 50-95% of the R substituents are hydrogen and 5-50% are ethylene bridges. [ka] For example, in some such embodiments, 55-90% of the R substituents are hydrogen and 10-45% are ethylene bridges. [ka] By way of further example, in some such embodiments, 60-90% of the R substituents are hydrogen and 10-40% are ethylene bridges. By way of further example, in some such embodiments, 65-90% of the R substituents are hydrogen and 10-35% are ethylene bridges. [ka] As a further example, in some such embodiments, 70-90% of the R substituents are hydrogen and 10-30% are ethylene bridges. As a further example, in some such embodiments, 75-85% of the R substituents are hydrogen and 15-25% are ethylene bridges. As a further example, in some such embodiments, 65-75% of the R substituents are hydrogen and 25-35% are ethylene bridges. As a further example, in some such embodiments, 55-65% of the R substituents are hydrogen and 35-45% are ethylene bridges. It will be apparent to one of skill in the art that in each of these embodiments, the % of R substituents that are hydrogen and the % of R substituents that are ethylene bridges between two nitrogens of the crosslinked amine polymer add up to 100 mol %. In some embodiments, a, b, c, and R are such that the carbon-to-nitrogen weight ratio of the polymer of Formula 4 can each range from about 2:1 to about 6:1. For example, in some such embodiments, the carbon-to-nitrogen weight ratio of the polymer of Formula 4 can each range from about 2.5:1 to about 5:1. By way of further example, in some such embodiments, the carbon-to-nitrogen weight ratio of the polymer of Formula 4 may range from about 3:1 to about 4.5:1, respectively. By way of further example, in some such embodiments, the carbon-to-nitrogen weight ratio of the polymer of Formula 4 may range from about 3.25:1 to about 4.25:1, respectively. By way of further example, in some such embodiments, the carbon-to-nitrogen weight ratio of the polymer of Formula 4 may range from about 3.4:1 to about 4:1, respectively. By way of further example, in some such embodiments, the carbon-to-nitrogen weight ratio of the polymer of Formula 4 may range from about 3.5:1 to about 3.9:1, respectively. By way of further example, in some such embodiments, the carbon-to-nitrogen weight ratio of the polymer of Formula 4 may range from about 3.55:1 to about 3.85:1, respectively. In each of the foregoing embodiments described in this paragraph, the polymer of Formula 4 is derived from a monomer and a crosslinker, each of which contains less than 5% oxygen by weight.

[0216] In an exemplary embodiment, the crosslinked poly(allylamine) polymer is a crosslinked poly(allylamine) polymer comprising residues of (i) 2-propen-1-ylamine or a salt thereof, (ii) 1,3-bis(allylamino)propane or a salt thereof, and (iii) 1,2-dichloroethane, wherein the molar ratio of 2-propen-1-ylamine (or a salt thereof) to 1,3-bis(allylamino)propane (or a salt thereof) ranges from 60:40 to 95:5, respectively. In other exemplary embodiments, the crosslinked poly(allylamine) polymer is a crosslinked poly(allylamine) polymer comprising residues of (i) 2-propen-1-ylamine or a salt thereof, (ii) 1,3-bis(allylamino)propane or a salt thereof, and (iii) 1,2-dichloroethane, wherein the molar ratio of 2-propen-1-ylamine (or a salt thereof) to 1,3-bis(allylamino)propane (or a salt thereof) ranges from 65:35 to 90:10, respectively. In other exemplary embodiments, the crosslinked poly(allylamine) polymer comprises (i) 2-propen-1-ylamine or a salt thereof, (ii) residues of 1,3-bis(allylamino)propane or a salt thereof, and (iii) residues of 1,2-dichloroethane, wherein the molar ratio of 2-propen-1-ylamine (or a salt thereof) to 1,3-bis(allylamino)propane (or a salt thereof) ranges from 65:35 to 75:25, respectively. For example, in each of the exemplary embodiments described in this paragraph, the residues of 2-propen-1-ylamine or a salt thereof and / or the residues of 1,3-bis(allylamino)propane or a salt thereof can be residues of hydrochloride, sulfate, phosphate, hydrobromide, or a combination thereof. By way of further example, in each of the exemplary embodiments described in this paragraph, the residue of 2-propen-1-ylamine or a salt thereof and / or the residue of 1,3-bis(allylamino)propane or a salt thereof is a residue of a hydrochloride salt.

[0217] In an exemplary embodiment, the crosslinked poly(allylamine) polymer comprises (i) 10 to 35 mol % residues of 1,3-bis(allylamino)propane or a salt thereof, (ii) 30 to 80 mol % residues of 2-propen-1-ylamine or a salt thereof, and (iii) 10 to 35 mol % residues of 1,2-dichloroethane, where (i) mol % residues of 1,3-bis(allylamino)propane or a salt thereof, (ii) mol % residues of 2-propen-1-ylamine or a salt thereof, and (iii) mol % residues of 1,2-dichloroethane total 100 mol %. In other exemplary embodiments, the crosslinked poly(allylamine) polymer comprises (i) 10 to 35 mol % residues of 1,3-bis(allylamino)propane or a salt thereof, (ii) 40 to 70 mol % residues of 2-propen-1-ylamine or a salt thereof, and (iii) 10 to 35 mol % residues of 1,2-dichloroethane, wherein (i) mol % residues of 1,3-bis(allylamino)propane or a salt thereof, (ii) mol % residues of 2-propen-1-ylamine or a salt thereof, and (iii) mol % residues of 1,2-dichloroethane total 100 mol %. In another exemplary embodiment, the crosslinked poly(allylamine) polymer comprises (i) 15 to 30 mol % residues of 1,3-bis(allylamino)propane or a salt thereof, (ii) 40 to 70 mol % residues of 2-propen-1-ylamine or a salt thereof, and (iii) 15 to 30 mol % residues of 1,2-dichloroethane, wherein (i) mol % residues of 1,3-bis(allylamino)propane or a salt thereof, (ii) mol % residues of 2-propen-1-ylamine or a salt thereof, and (iii) mol % residues of 1,2-dichloroethane total 100 mol %.In another exemplary embodiment, the crosslinked poly(allylamine) polymer comprises (i) 15 to 30 mol % residues of 1,3-bis(allylamino)propane or a salt thereof, (ii) 45 to 65 mol % residues of 2-propen-1-ylamine or a salt thereof, and (iii) 15 to 30 mol % residues of 1,2-dichloroethane, wherein (i) mol % residues of 1,3-bis(allylamino)propane or a salt thereof, (ii) mol % residues of 2-propen-1-ylamine or a salt thereof, and (iii) mol % residues of 1,2-dichloroethane total 100 mol %. In another exemplary embodiment, the crosslinked poly(allylamine) polymer comprises (i) 20-25 mol % residues of 1,3-bis(allylamino)propane or a salt thereof, (ii) 50-60 mol % residues of 2-propen-1-ylamine or a salt thereof, and (iii) 20-25 mol % residues of 1,2-dichloroethane, wherein (i) mol % residues of 1,3-bis(allylamino)propane or a salt thereof, (ii) mol % residues of 2-propen-1-ylamine or a salt thereof, and (iii) mol % residues of 1,2-dichloroethane total 100 mol %.

[0218] In an exemplary embodiment, the crosslinked poly(allylamine) polymer consists essentially of (i) 10 to 35 mol % residues of 1,3-bis(allylamino)propane or a salt thereof, (ii) 30 to 80 mol % residues of 2-propen-1-ylamine or a salt thereof, and (iii) 10 to 35 mol % residues of 1,2-dichloroethane, where (i) mol % residues of 1,3-bis(allylamino)propane or a salt thereof, (ii) mol % residues of 2-propen-1-ylamine or a salt thereof, and (iii) mol % residues of 1,2-dichloroethane total 100 mol %. In other exemplary embodiments, the crosslinked poly(allylamine) polymer consists essentially of (i) 10 to 35 mol % residues of 1,3-bis(allylamino)propane or a salt thereof, (ii) 40 to 70 mol % residues of 2-propen-1-ylamine or a salt thereof, and (iii) 10 to 35 mol % residues of 1,2-dichloroethane, wherein (i) mol % residues of 1,3-bis(allylamino)propane or a salt thereof, (ii) mol % residues of 2-propen-1-ylamine or a salt thereof, and (iii) mol % residues of 1,2-dichloroethane total 100 mol %. In other exemplary embodiments, the crosslinked poly(allylamine) polymer consists essentially of (i) 15 to 30 mol % residues of 1,3-bis(allylamino)propane or a salt thereof, (ii) 40 to 70 mol % residues of 2-propen-1-ylamine or a salt thereof, and (iii) 15 to 30 mol % residues of 1,2-dichloroethane, wherein (i) mol % residues of 1,3-bis(allylamino)propane or a salt thereof, (ii) mol % residues of 2-propen-1-ylamine or a salt thereof, and (iii) mol % residues of 1,2-dichloroethane total 100 mol %.In other exemplary embodiments, the crosslinked poly(allylamine) polymer consists essentially of (i) 15 to 30 mol % residues of 1,3-bis(allylamino)propane or a salt thereof, (ii) 45 to 65 mol % residues of 2-propen-1-ylamine or a salt thereof, and (iii) 15 to 30 mol % residues of 1,2-dichloroethane, wherein (i) mol % residues of 1,3-bis(allylamino)propane or a salt thereof, (ii) mol % residues of 2-propen-1-ylamine or a salt thereof, and (iii) mol % residues of 1,2-dichloroethane total 100 mol %. In other exemplary embodiments, the crosslinked poly(allylamine) polymer consists essentially of (i) 20-25 mol % residues of 1,3-bis(allylamino)propane or a salt thereof, (ii) 50-60 mol % residues of 2-propen-1-ylamine or a salt thereof, and (iii) 20-25 mol % residues of 1,2-dichloroethane, wherein (i) mol % residues of 1,3-bis(allylamino)propane or a salt thereof, (ii) mol % residues of 2-propen-1-ylamine or a salt thereof, and (iii) mol % residues of 1,2-dichloroethane total 100 mol %.

[0219] In an exemplary embodiment, the crosslinked poly(allylamine) polymer consists of (i) 10 to 35 mol % residues of 1,3-bis(allylamino)propane or a salt thereof, (ii) 30 to 80 mol % residues of 2-propen-1-ylamine or a salt thereof, and (iii) 10 to 35 mol % residues of 1,2-dichloroethane, where (i) mol % residues of 1,3-bis(allylamino)propane or a salt thereof, (ii) mol % residues of 2-propen-1-ylamine or a salt thereof, and (iii) mol % residues of 1,2-dichloroethane total 100 mol %. In other exemplary embodiments, the crosslinked poly(allylamine) polymer consists of (i) 10 to 35 mol % residues of 1,3-bis(allylamino)propane or a salt thereof, (ii) 40 to 70 mol % residues of 2-propen-1-ylamine or a salt thereof, and (iii) 10 to 35 mol % residues of 1,2-dichloroethane, wherein (i) mol % residues of 1,3-bis(allylamino)propane or a salt thereof, (ii) mol % residues of 2-propen-1-ylamine or a salt thereof, and (iii) mol % residues of 1,2-dichloroethane total 100 mol %. In another exemplary embodiment, the crosslinked poly(allylamine) polymer consists of (i) 15 to 30 mol % residues of 1,3-bis(allylamino)propane or a salt thereof, (ii) 40 to 70 mol % residues of 2-propen-1-ylamine or a salt thereof, and (iii) 15 to 30 mol % residues of 1,2-dichloroethane, wherein (i) mol % residues of 1,3-bis(allylamino)propane or a salt thereof, (ii) mol % residues of 2-propen-1-ylamine or a salt thereof, and (iii) mol % residues of 1,2-dichloroethane total 100 mol %.In another exemplary embodiment, the crosslinked poly(allylamine) polymer consists of (i) 15 to 30 mol % residues of 1,3-bis(allylamino)propane or a salt thereof, (ii) 45 to 65 mol % residues of 2-propen-1-ylamine or a salt thereof, and (iii) 15 to 30 mol % residues of 1,2-dichloroethane, wherein (i) mol % residues of 1,3-bis(allylamino)propane or a salt thereof, (ii) mol % residues of 2-propen-1-ylamine or a salt thereof, and (iii) mol % residues of 1,2-dichloroethane total 100 mol %. In another exemplary embodiment, the crosslinked poly(allylamine) polymer consists of (i) 20-25 mol % residues of 1,3-bis(allylamino)propane or a salt thereof, (ii) 50-60 mol % residues of 2-propen-1-ylamine or a salt thereof, and (iii) 20-25 mol % residues of 1,2-dichloroethane, wherein (i) mol % residues of 1,3-bis(allylamino)propane or a salt thereof, (ii) mol % residues of 2-propen-1-ylamine or a salt thereof, and (iii) mol % residues of 1,2-dichloroethane total 100 mol %.

[0220] For example, in each of the exemplary embodiments described in the paragraph above, the residue of 2-propen-1-ylamine or a salt thereof and / or the residue of 1,3-bis(allylamino)propane or a salt thereof can be a residue of a hydrochloride salt, a sulfate salt, a phosphate salt, a hydrobromide salt, or a combination thereof. By way of further example, in each of the exemplary embodiments described in the paragraph above, the residue of 2-propen-1-ylamine or a salt thereof and / or the residue of 1,3-bis(allylamino)propane or a salt thereof is a residue of a hydrochloride salt."

[0221] Pharmaceutical Compositions and Administration In general, dosage levels of crosslinked poly(allylamine) polymers, particularly beverimer, for therapeutic and / or prophylactic use can range from about 3 g / day to about 9 g / day.

[0222] If desired, the daily dose can be administered as a single dose (i.e., once daily) or divided into multiple doses (e.g., two, three or more) throughout the day. Preferably, the daily dose is administered once daily.

[0223] Generally, the crosslinked poly(allylamine) polymer may be administered as a fixed daily dose or titrated based on the serum bicarbonate level or other indicators of acidosis in patients requiring treatment. Titration may be performed at the start of treatment or, as needed, throughout treatment, with starting and maintenance dosage levels varying from patient to patient based on the severity of the underlying disease.

[0224] For example, in some embodiments, the recommended starting dose of crosslinked poly(allylamine) polymer, particularly beverimer, for therapeutic and / or prophylactic use is about 6g / day.In some embodiments, the starting dose is increased to about 9g / day by about 3g increments or reduced to about 3g / day.In some embodiments, dose adjustment is carried out to achieve desired serum bicarbonate level.In some embodiments, dose adjustment is carried out at intervals of about 2 weeks.

[0225] In some embodiments, the crosslinked poly(allylamine) polymer, particularly beverimer, is administered with food. In some embodiments, the crosslinked poly(allylamine) polymer, particularly beverimer, is administered orally as a suspension in water.

[0226] The efficacy of cross-linked poly(allylamine) polymers can be established in animal models or human volunteers and patients. Furthermore, in vitro, ex vivo, and in vivo approaches are useful for establishing HCl or other target species binding. In vitro binding solutions can be used to measure the binding capacity of protons, chloride, and other ions at various pH levels. Ex vivo extracts, such as the contents of the digestive tract lumen from human volunteers or model animals, can be used for similar purposes. The selectivity for binding and / or retaining certain ions over others can also be demonstrated in such in vitro and ex vivo solutions. In vivo models of metabolic acidosis can be used to test the efficacy of cross-linked poly(allylamine) polymers in normalizing acid / base balance—for example, 5 / 6 nephrectomized 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 rats fed adenine (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).

[0227] Metabolic acidosis, regardless of etiology, reduces extracellular bicarbonate and therefore extracellular pH. The correlation between serum pH and serum bicarbonate is determined by the Henderson-Hasselbalch equation: pH = pK' + log [HCO3 - ] / [(0.03 × PaCO2)] (where 0.03 is the physical solubility coefficient of CO2 and [HCO3 - ] and PaCO2 are the bicarbonate concentration and partial pressure of carbon dioxide, respectively).

[0228] There are several laboratory tests that can be used to confirm metabolic acidosis. Tests primarily involve measuring bicarbonate (HCO3 - ) or proton (H + ) concentrations. These tests measure bicarbonate (HCO3 - ) or proton (H + ) concentration can be measured. In both the enzymatic and ion-selective electrode methods, bicarbonate is "measured." Using blood gas analysis, bicarbonate levels can be calculated using the Henderson-Hasselbalch equation.

[0229] In certain embodiments, crosslinked poly(allylamine) polymers are provided to animals, including humans, for acid-base disorders (e.g., metabolic acidosis) in a dosing regimen of once, twice, or even more frequently (i.e., at least three times) daily administration (oral administration) to achieve sustained increases in serum bicarbonate or other target species, as described above.

[0230] The cross-linked poly(allylamine) polymers disclosed herein can be provided in any form suitable for oral administration. Such forms include powders, tablets, pills, lozenges, sachets, cachets, elixirs, suspensions, syrups, gels, soft or hard gelatin capsules, and the like. In some embodiments, the pharmaceutical composition contains only the cross-linked poly(allylamine) polymer. Alternatively, the pharmaceutical composition may contain a carrier, diluent, or additive in addition to the cross-linked poly(allylamine) polymer. Examples of carriers, additives, and diluents that can be used in these formulations include food, beverages, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, alginic acid, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, propyl hydroxybenzoate, and talc. Further pharmaceutical additives useful in pharmaceutical compositions include binders such as microcrystalline cellulose, colloidal silica, and combinations thereof (Prosolv 90), carbopol, povidone, and xanthan gum; flavoring agents such as sucrose, mannitol, xylitol, maltodextrin, fructose, or sorbitol; lubricants such as magnesium stearate, stearic acid, sodium stearyl fumarate, and vegetable-based fatty acids; and, optionally, disintegrants such as croscarmellose sodium, gellan gum, low-substituted hydroxypropyl ethers of cellulose, and sodium starch glycolate. Other additives include plasticizers, dyes, talc, and the like. Such additives and other suitable ingredients are well known in the art; see, for example, Gennaro AR (ed.), Remington's Pharmaceutical Sciences, 20th Edition.

[0231] In some embodiments, crosslinked poly(allylamine) polymers can be co-administered with other active agents depending on the condition being treated. This co-administration can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. For example, to treat metabolic acidosis, crosslinked poly(allylamine) polymers can be co-administered with the general treatments required to treat the underlying comorbidities, including but not limited to, hypertension, diabetes, obesity, heart failure, and complications of chronic kidney disease. These drugs and crosslinked poly(allylamine) polymers can be formulated together in the same dosage form and administered simultaneously, as long as they do not show clinically significant drug-drug interactions. Alternatively, these treatments and crosslinked poly(allylamine) polymers can be administered separately and sequentially, one after the other.

[0232] In certain embodiments, daily doses for the treatment of chronic metabolic acidosis are compliance-enhancing (3 g / day, 6 g / day, or 9 g / day of crosslinked poly(allylamine) polymer, particularly Beverimer), achieving an increase in serum bicarbonate of approximately 3 mEq / L at these daily doses. The non-absorbability of the polymer and the lack of sodium and / or other harmful ion introduction for such oral medications allows for the first time safe, chronic treatment of metabolic acidosis without worsening blood pressure / hypertension and / or causing increased fluid retention and fluid overload. Another benefit is the further delay in time to renal disease progression and the onset of lifelong renal replacement therapy (end-stage renal disease, "ESRD," includes dialysis three times per week) or the need for a kidney transplant, both of which are associated with significant mortality, reduced quality of life, and significant healthcare costs worldwide. In the United States alone, approximately 20% of the 400,000 ESRD patients die each year, and 100,000 new patients begin dialysis.

[0233] A further aspect of the present invention is a pharmaceutical product comprising a sealed package and a crosslinked poly(allylamine) polymer of the present invention, e.g., Beverimer, within the sealed package. The unit dosage forms disclosed herein can be in any form that meets one or more of the disclosed requirements. For example, the unit dosage form can be a vial, bottle, tube, jar, box, tub, blister pack, sachet (including stick pack), or other sealed container. In one exemplary embodiment, the unit dosage form is a sachet.

[0234] As disclosed herein, the crosslinked poly(allylamine) polymers of the present invention, such as Beverimer, can produce certain impurities, such as H2C=CHCH2NH2, when exposed to oxygen. The unit dosage forms can have properties that address or reduce the potential for such impurities, such as properties that reduce the amount of oxygen that comes into contact with the polymer during storage.

[0235] Packaging means that address or reduce the possibility of such impurities include: low oxygen permeable unit dosage forms; unit dosage forms with small amounts of gas present within the unit dosage form; unit dosage forms containing gases other than air within the unit dosage form and / or unit dosage forms containing an oxygen-absorbing component, such as a scavenger. Each packaging means may be used alone or in combination with any other packaging means disclosed herein. Each packaging means, alone or in combination, may be used with any of the crosslinked poly(allylamine) polymers of the present invention, such as beverimer, and / or any of the polymers of the publications cited herein, and all such combinations are disclosed. For example, one or more of the packaging means disclosed herein for addressing or reducing the possibility of impurities, such as those summarized in this paragraph, may be used to deliver low levels of sp as disclosed herein. 2 Pharmaceutical products can be provided that include crosslinked poly(allylamine) polymers of the invention, e.g., beverimer, having sp carbon atoms (e.g., less than 1.0% of the total number of carbon atoms present in the crosslinked poly(allylamine) polymer). 2(the carbon atom is an allylic carbon). Such pharmaceuticals provide acceptable or improved shelf life as defined elsewhere. In other examples, high levels of sp are obtained using one or more of the means disclosed herein for addressing or reducing potential impurities, such as those summarized in this paragraph, as disclosed herein and / or in the references provided herein. 2 Pharmaceutical products are provided that include the crosslinked poly(allylamine) polymers of the invention, e.g., beverimer (e.g., crosslinked poly(allylamine) polymers in which less than 1.0% of the total number of carbon atoms present in the crosslinked poly(allylamine) polymer are sp 2 Such pharmaceuticals may contain high levels of sp because, for example, the combination of approaches or packaging measures used limits the amount of oxygen that comes into contact with the polymer, and thus limits the level of impurities present (e.g., after storage). 2 Despite the presence of carbon, acceptable or improved shelf life may be provided.

[0236] In some embodiments, the unit dosage form comprises a sealed package that is preferably substantially impermeable to moisture and oxygen to enhance the stability of the pharmaceutical composition (e.g., the stability of the veverimer). 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 the poly(allylamine) polymer is packaged in the container.

[0237] The size of the container used to form the unit dosage form and / or the amount of pharmaceutical composition in the container can be selected to reduce the headspace of the container after packaging. The headspace is the volume contained within the unit dosage form that is not the pharmaceutical composition. The headspace contains one or more gases, e.g., an inert gas such as nitrogen or a gas mixture such as air. By minimizing the headspace volume, the stability of the crosslinked poly(allylamine) polymers of the present invention, such as Beverimer, can be increased during storage, especially when the headspace contains oxygen.

[0238] In some embodiments, the unit dosage form comprises a pharmaceutical composition and a headspace, wherein the headspace volume is 0 cm3 ~120cm 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition and a headspace, wherein the headspace volume is 10 cm 3 ~110cm 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition and a headspace, wherein the headspace volume is 20 cm 3 ~100cm 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition and a headspace, wherein the headspace volume is 20 cm 3 ~40cm 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition and a headspace, wherein the headspace volume is 0 cm 3 ~20cm 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition and a headspace, wherein the headspace volume is 50 cm 3 ~70cm 3 is.

[0239] 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.

[0240] In some embodiments, the headspace is minimized by compression of the unit dosage form prior to sealing the pharmaceutical composition within the unit dosage form.

[0241] A unit dosage form having a relatively low headspace contains a relatively large number of grams of pharmaceutical composition relative to its headspace volume. In some embodiments, the unit dosage form contains a pharmaceutical composition, wherein the pharmaceutical composition is less than or equal to the cm of the headspace volume of the unit dosage form. 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of at least 0.01 g per cm of the headspace volume of the unit dosage form. 3In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of at least 0.02 g per cm of the headspace volume of the unit dosage form. 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of at least 0.03 g per cm of the headspace volume of the unit dosage form. 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of at least 0.04 g per cm of the headspace volume of the unit dosage form. 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of at least 0.05 g per cm of the headspace volume of the unit dosage form. 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 0.01 g to 0.5 g per cm of the headspace volume of the unit dosage form. 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 0.01 g to 0.2 g per cm of the headspace volume of the unit dosage form. 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 0.05 g to 0.2 g per cm of the headspace volume of the unit dosage form. 3 It is present in amounts of 0.05g to 0.15g per serving.

[0242] In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 3 g and the headspace volume of the unit dosage form is 90 cm 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 3 g and the headspace volume of the unit dosage form is less than 75 cm 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 3 g and the headspace volume of the unit dosage form is less than 60 cm 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 3 g and the headspace volume of the unit dosage form is less than 45 cm 3 is less than.

[0243] In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 6 g and the headspace volume of the unit dosage form is 120 cm 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 6 g and the headspace volume of the unit dosage form is less than 105 cm 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 6 g and the headspace volume of the unit dosage form is less than 90 cm 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 6 g and the headspace volume of the unit dosage form is less than 75 cm 3 is less than.

[0244] In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 9 g and the headspace volume of the unit dosage form is 140 cm 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 9 g and the headspace volume of the unit dosage form is less than 125 cm 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 9 g and the headspace volume of the unit dosage form is less than 110 cm 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 9 g and the headspace volume of the unit dosage form is less than 95 cm 3 is less than.

[0245] A sealed unit dosage form having a relatively low headspace contains a relatively large number of grams of pharmaceutical composition relative to its total volume. In some embodiments, the unit dosage form contains a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount that is less than the total volume cm of the sealed unit dosage form. 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of at least 0.02 g per cm of total volume of the sealed unit dosage form. 3In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of at least 0.03 g per cm of total volume of the sealed unit dosage form. 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of at least 0.04 g per cm of total volume of the sealed unit dosage form. 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 0.01 g to 0.5 g per cm of total volume of the sealed unit dosage form. 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 0.01 g to 0.25 g per cm of total volume of the sealed unit dosage form. 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 0.01 g to 0.15 g per cm of total volume of the sealed unit dosage form. 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 0.02 g to 0.1 g per cm of total volume of the sealed unit dosage form. 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 0.03 g to 0.08 g per cm of total volume of the sealed unit dosage form. 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 0.04 g to 0.07 g per cm of total volume of the sealed unit dosage form. 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 0.02 g to 0.2 g per cm of total volume of the sealed unit dosage form. 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 0.04 g to 0.18 g per cm of total volume of the sealed unit dosage form. 3 It is present in amounts of 0.06g to 0.16g per serving.

[0246] In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 3 g and the total sealed volume of the unit dosage form is 100 cm 3In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 3 g and the total sealed volume of the unit dosage form is less than 90 cm 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 3 g and the total sealed volume of the unit dosage form is less than 80 cm 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 3 g and the total sealed volume of the unit dosage form is less than 70 cm 3 is less than.

[0247] In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 6 g and the total volume of the sealed unit dosage form is 160 cm 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 6 g and the total volume of the sealed unit dosage form is less than 150 cm 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 6 g and the total volume of the sealed unit dosage form is less than 140 cm 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 6 g and the total volume of the sealed unit dosage form is less than 130 cm 3 is less than.

[0248] In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 9 g and the total volume of the sealed unit dosage form is 200 cm 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 9 g and the total volume of the sealed unit dosage form is less than 190 cm 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 9 g and the total volume of the sealed unit dosage form is less than 180 cm 3 In some embodiments, the unit dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition is present in an amount of 9 g and the total sealed volume of the unit dosage form is less than 170 cm 3 is less than.

[0249] In some embodiments, the unit dosage form is a sachet. In such embodiments, the sachet has a height (h) and a width (w), the walls of the sachet are flexible but not stretchable, and the total volume of the sealed sachet can be estimated according to formula X:

number

[0250] Formula X can be used to define the total volume of a sealed unit dosage form when the dosage form is a sachet. For example, when the dosage form is a sachet, the total volume cm 3 Any mention of the amount of drug in grams per cm is based on the sealed total volume estimated by the formula X. 3 The term "drug" refers to the amount of drug in grams per tablet.

[0251] In some embodiments, the unit dosage form is a sachet containing a 3g, 6g or 9g amount of the pharmaceutical composition, wherein the width of the sachet is less than 25cm and the height of the sachet is less than 25cm. In some embodiments, the unit dosage form is a sachet containing a 3g, 6g or 9g amount of the pharmaceutical composition, wherein the width of the sachet is less than 20cm and the height of the sachet is less than 25cm. In some embodiments, the unit dosage form is a sachet containing a 3g, 6g or 9g amount of the pharmaceutical composition, wherein the width of the sachet is less than 15cm and the height of the sachet is less than 20cm. In some embodiments, the unit dosage form is a sachet containing a 3g, 6g or 9g amount of the pharmaceutical composition, wherein the width of the sachet is less than 10cm and the height of the sachet is less than 15cm.

[0252] In some embodiments, the unit dosage form is a sachet containing a 9g amount of the pharmaceutical composition, wherein the width of the sachet is less than 25cm and the height of the sachet is less than 25cm. In some embodiments, the unit dosage form is a sachet containing a 9g amount of the pharmaceutical composition, wherein the width of the sachet is less than 20cm and the height of the sachet is less than 25cm. In some embodiments, the unit dosage form is a sachet containing a 9g amount of the pharmaceutical composition, wherein the width of the sachet is less than 15cm and the height of the sachet is less than 20cm. In some embodiments, the unit dosage form is a sachet containing a 9g amount of the pharmaceutical composition, wherein the width of the sachet is less than 10cm and the height of the sachet is less than 15cm. In some embodiments, the unit dosage form is a sachet containing a 9g amount of the pharmaceutical composition, wherein the width of the sachet is less than 9cm and the height of the sachet is less than 12cm.

[0253] In some embodiments, the unit dosage form is a sachet containing a 6g amount of the pharmaceutical composition, wherein the width of the sachet is less than 25cm and the height of the sachet is less than 25cm. In some embodiments, the unit dosage form is a sachet containing a 6g amount of the pharmaceutical composition, wherein the width of the sachet is less than 20cm and the height of the sachet is less than 25cm. In some embodiments, the unit dosage form is a sachet containing a 6g amount of the pharmaceutical composition, wherein the width of the sachet is less than 15cm and the height of the sachet is less than 20cm. In some embodiments, the unit dosage form is a sachet containing a 6g amount of the pharmaceutical composition, wherein the width of the sachet is less than 10cm and the height of the sachet is less than 15cm. In some embodiments, the unit dosage form is a sachet containing a 6g amount of the pharmaceutical composition, wherein the width of the sachet is less than 8cm and the height of the sachet is less than 11cm.

[0254] In some embodiments, the unit dosage form is a sachet containing a 3g amount of the pharmaceutical composition, wherein the width of the sachet is less than 25cm and the height of the sachet is less than 25cm. In some embodiments, the unit dosage form is a sachet containing a 3g amount of the pharmaceutical composition, wherein the width of the sachet is less than 20cm and the height of the sachet is less than 25cm. In some embodiments, the unit dosage form is a sachet containing a 3g amount of the pharmaceutical composition, wherein the width of the sachet is less than 15cm and the height of the sachet is less than 20cm. In some embodiments, the unit dosage form is a sachet containing a 3g amount of the pharmaceutical composition, wherein the width of the sachet is less than 10cm and the height of the sachet is less than 15cm. In some embodiments, the unit dosage form is a sachet containing a 3g amount of the pharmaceutical composition, wherein the width of the sachet is less than 9cm and the height of the sachet is less than 10cm. In some embodiments, the unit dosage form is a sachet containing a 3g amount of the pharmaceutical composition, wherein the width of the sachet is less than 8cm and the height of the sachet is less than 9cm.

[0255] Any headspace present in any of the unit dosage forms disclosed herein may be filled with an inert gas such as nitrogen or other gas with low levels of oxygen gas. The headspace present in a unit dosage form may comprise 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 gases described herein. For example, in some embodiments, the headspace gas is an inert gas mixture, such as a mixture of nitrogen and carbon dioxide. In some embodiments, a headspace gas referring to a particular gas means that the headspace gas consists essentially of or consists of the described gas.

[0256] In some embodiments, the headspace gas contains other gases, such as oxygen, that are not inert. 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%.

[0257] 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 such embodiments, the headspace gas can consist essentially of or consist of the recited gases.

[0258] In other embodiments, the unit dosage forms disclosed herein are 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 changed after the packaging process, for example, by adding or exchanging gas within the pharmaceutical dosage form after manufacture, for example, via a valve in the package.

[0259] Container materials of construction for use in the unit dosage forms disclosed herein can be selected to minimize moisture and oxygen ingress into the container after packaging. For example, poly(allylamine) polymers, such as beverimer, can be packaged in multi-layer sachets that include at least one layer that acts as a barrier layer against moisture and oxygen ingress. In other examples, poly(allylamine) polymers can be packaged in single- or multi-layer plastic, metal, or glass containers with at least one barrier layer incorporated into their construction to limit oxygen and / or moisture ingress after packaging. For example, in some such embodiments, a sachet (or other container or package) can include a multi-layer stack of an inner contact layer, an outer layer, and a barrier layer disposed between the contact layer and the outer layer. In such embodiments, the multi-layer stack can also include one or more adhesive and / or printed layers. For example, the stack can include the following layers in the following order: inner contact layer, adhesive, barrier layer, adhesive, printed layer, and outer layer. In some embodiments, one or more layers of any of the multi-layer stacks disclosed herein can be bonded to each other via adhesive and / or lamination (e.g., extrusion lamination). In some embodiments, the layers of the multilayer structures disclosed herein are bonded to one another via adhesive and / or lamination (e.g., extrusion lamination). In some embodiments, the layers of the multilayer structures disclosed herein are bonded to one another via adhesive. In some embodiments, the layers of the multilayer structures disclosed herein are bonded to one another via lamination (e.g., extrusion lamination).

[0260] In some embodiments, the unit dosage form is made of or comprises a plastic. For example, the plastic can be polyethylene (e.g., linear low-density polyethylene or low-density polyethylene), polypropylene, poly(ethylene terephthalate), polyester, nylon, or polyvinyl chloride. In such embodiments, the plastic can be in the form of a film or sheet. For example, when the dosage form is a sachet, the sachet can be made from any of polyethylene, polypropylene, poly(ethylene terephthalate), polyester, nylon, or polyvinyl chloride, optionally as part of a multilayer laminate. In some embodiments, 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 such embodiments, any of the layers can be made from any of the described plastics. More specifically, the inner contact layer can comprise any of polyethylene, polypropylene, poly(ethylene terephthalate), polyester, nylon, or polyvinyl chloride. In some embodiments, the inner contact layer comprises polyethylene. In some embodiments, the inner contact layer is linear low-density polyethylene. In some embodiments, the inner contact layer is low-density polyethylene. More specifically, the outer layer can comprise any of polyethylene, polypropylene, poly(ethylene terephthalate), polyester, nylon, polyvinyl chloride, or paper. In some embodiments, the outer layer is poly(ethylene terephthalate). In some embodiments, the barrier layer can be any aluminum layer disclosed herein. In some embodiments, the barrier layer can comprise any plastic layer disclosed herein and any aluminum layer disclosed herein. For example, the barrier layer can comprise low-density polyethylene and an aluminum film. In some exemplary embodiments, 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, an aluminum film, followed by a barrier layer made of low-density polyethylene, an ink print layer, and an outer layer made of poly(ethylene terephthalate), optionally with adhesive between any of these layers, and optionally the aluminum film being 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, an aluminum film, followed by a barrier layer made of low density polyethylene, an ink print layer, and an outer layer made of poly(ethylene terephthalate), optionally laminated together by extrusion, and optionally the aluminum film being about 18 μm thick.

[0261] In some embodiments, the unit dosage form has an outer surface and an inner surface, the inner surface comprising a cross-linked poly(allylamine) polymer, e.g., Bevelimer, wherein the oxygen transfer rate between the outer surface and the inner surface of the unit dosage form is about 0.050 cubic centimeters per square meter per day (CC / m 2 / day).

[0262] In some embodiments, the unit dosage form comprises a sealed enclosure comprising a crosslinked poly(allylamine) polymer, e.g., Bevelimer, the sealed enclosure comprising a multi-layer stack of 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 multi-layer stack is about 0.050 cubic centimeters per square meter per day (CC / m 2 / day).

[0263] In either embodiment, the specified oxygen transfer rate is, in one embodiment, about 0.030 CC / m 2 In either embodiment, the specified oxygen transfer rate is less than about 0.010 CC / m 2 In either embodiment, the specified oxygen transfer rate is less than about 0.009 CC / m 2 In either embodiment, the specified oxygen transfer rate is less than about 0.007 CC / m 2 In either embodiment, the specified oxygen transfer rate is less than about 0.005 CC / m 2 In either embodiment, the specified oxygen transfer rate is less than about 0.003 CC / m 2 / day.

[0264] When oxygen transfer rates are measured for the unit dosage forms disclosed herein, the transfer rate can be controlled by the selection of appropriate materials and appropriate thicknesses of those materials during the manufacture of the unit dosage form. Materials that can be used to control the oxygen transfer rate of a unit dosage form include aluminum, ethylene vinyl alcohol, glass, polyester (e.g., polyethylene terephthalate), and polyamide (e.g., nylon). One or more of these materials can be used to achieve a particular oxygen transfer rate.

[0265] For example, one or more aluminum layers can be used to control the oxygen transfer rate. Thus, in some embodiments, the unit dosage form disclosed herein comprises at least one aluminum layer. For example, the aluminum-containing layer can be part of the barrier layer disclosed herein. More specifically, the aluminum-containing layer can be a barrier layer. For example, the barrier layer can comprise any of the aluminum layers disclosed herein. For example, the barrier layer can consist essentially of any of the aluminum layers disclosed herein. For example, the barrier layer can consist of any of the aluminum layers disclosed herein. In some embodiments, the barrier layer and / or the aluminum layer, measured independently, have any of the oxygen transfer rates disclosed herein.

[0266] In some embodiments, the aluminum layer disclosed herein has a thickness greater than 5 μm. In some embodiments, the aluminum layer disclosed herein has a thickness greater than 8 μm. In some embodiments, the aluminum layer disclosed herein has a thickness greater than 10 μm. In some embodiments, the aluminum layer disclosed herein has a thickness greater than 12 μm. In some embodiments, the aluminum layer disclosed herein has a thickness greater than 15 μm. In some embodiments, the aluminum layer disclosed herein has a thickness greater than 18 μm. In some embodiments, the aluminum layer disclosed herein has a thickness greater than 20 μm. In some embodiments, the aluminum layer disclosed herein has a thickness greater than 25 μm. In some embodiments, the aluminum layer has a thickness between 9 and 20 μm. In some embodiments, the aluminum layer has a thickness between 15 and 20 μm. In some embodiments, the aluminum layer has a thickness of about 18 μm.

[0267] In either embodiment, the unit dosage form is manufactured from one consistent material, e.g., a sachet is manufactured from one type of sheet or multiple layers. In some embodiments, the unit dosage form may comprise different materials in different portions (e.g., ends) of the unit dosage form. In such a scenario, the requirements specified herein for the unit dosage form may apply to one or more of such portions. Alternatively, in such a scenario, the requirements specified herein for the unit dosage form may apply to substantially all of such portions. Alternatively, in such a scenario, the requirements specified herein for the unit dosage form may apply to all of such portions. Thus, for example, a unit dosage form disclosed herein may comprise a sealed vial (e.g., made of plastic or glass) sealed with a cap, wherein both portions (cap and vial) have an oxygen transfer rate specified for the other portion, e.g., 0.005 CC / m 2 In such instances, the sealed vial has an oxygen transfer rate of less than 0.005 CC / m 2 The oxygen transfer rate between the outside and inside of the unit dosage form is less than 1 / day.

[0268] In either embodiment, the unit dosage form may include the layers that form the dosage form, such as an inner contact layer, an outer layer, and a barrier layer, and potentially additional layers. Any of these layers, alone or together, may be responsible for a particular oxygen transfer rate. The layers may be bonded together using adhesive, heat sealing, extrusion lamination, or any other fastening method.

[0269] In some embodiments, the unit dosage form contains an oxygen scavenger. In some exemplary embodiments, the unit dosage form contains one or more oxygen scavenging layers containing an oxygen scavenger. In some embodiments, the unit dosage form contains an oxygen scavenger, for example, as an additive, in contact with the crosslinked poly(allylamine) polymer. In some embodiments, the oxygen scavenger is present inside the unit dosage form, for example, in a separate insert. In some embodiments, the oxygen scavenger is in contact with the inside of the unit dosage form, for example, formed from the lid of the unit dosage form.

[0270] The oxygen scavenger disclosed herein is any substance that absorbs oxygen. In some embodiments, the oxygen scavenger is any substance that can be oxidized under ambient conditions. In some embodiments, the oxygen scavenger is one or more of the following: iron (e.g., iron powder or activated iron), ferrous oxide, ferrous oxide powder, ferrous salts, such as ferrous sulfate or ferrous chloride, reduced sulfur compounds such as sulfite, bisulfite, and dithionite, ascorbic acid and / or its salts, Pd, Cu, ZN, Mg, Mn, Co(II), Zn, ascorbic acid, ascorbate, isoascorbic acid, tocopherol, hydroquinone, catechol, rongalite, 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, e.g., U.S. Patent Publications 20060076536, 20070084144, and 20060260967. Oxygen scavengers are commercially available, e.g., StabilOx® (Multisorb Technologies), cyclohexene methyl acrylate (EMCM) polymer (Chevron-Phillips Chemical Company), or Ciba's Specialty Chemical's SHELFPLUS™. In one exemplary embodiment, the scavenger is iron.

[0271] In some embodiments, the oxygen scavenger unit dosage form comprises one or more oxygen-scavenging layers containing an oxygen scavenger. Such layers are known in the art; see, e.g., Gaikwad et al., Environmental Chemistry Letters, volume 16, pages 523-538 (2018). In some embodiments, the unit dosage form disclosed herein comprises a layer (film) disclosed in Gaikwad et al., particularly any one or combination of layers disclosed in Table 2 of Gaikwad et al. In some embodiments, the unit dosage form disclosed herein comprises a layer (film) disclosed in Table 3 of Gaikwad et al. In some embodiments, the unit dosage form disclosed herein comprises a layer (film) disclosed in Gaikwad et al., particularly any one or combination of layers disclosed in the "multilayer active films" section. Indeed, such layers are already commercially available; 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 includes Oxy Vanish-Dry Film (Mitsubishi).

[0272] A further aspect of the present invention is a product comprising a plurality of the unit dosage forms disclosed herein. The product may further comprise one or more oxygen scavengers, as defined herein. For example, the product may comprise separate containers containing the plurality of unit dosage forms as well as an oxygen scavenger.

[0273] In some embodiments, the product and / or unit dosage form includes a statement that the product has a shelf life of at least one year. In some embodiments, the product and / or unit dosage form includes a statement that the product has a one-year shelf life. In some embodiments, the product and / or unit dosage form includes a statement that the product has a shelf life of at least two years. In some embodiments, the product and / or unit dosage form includes a statement that the product has a two-year shelf life. In some embodiments, the product and / or unit dosage form includes a statement that the product has a shelf life of at least three years. In some embodiments, the product and / or unit dosage form includes a statement that the product has a three-year shelf life. In some embodiments, the product and / or unit dosage form includes a statement that the product has a shelf life of at least four years. In some embodiments, the product and / or unit dosage form includes a statement that the product has a four-year shelf life. In some embodiments, the product and / or unit dosage form includes a statement that the product has a shelf life of at least five years. In some embodiments, the product and / or unit dosage form includes a statement that the product has a five-year shelf life.

[0274] In any such embodiment, the statement regarding the shelf life may specify that the shelf life begins from the date of manufacture (e.g., the statement may specify that the product should be used within two years of manufacture), and / or in any such embodiment, the statement regarding the shelf life may be expressed in terms of an expiration date (or the like), 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 is more than two years in the future relative to the date on which it is read, in which case the shelf life is more than two years).

[0275] The unit dosage forms disclosed herein exhibit a high degree of stability, for example, the crosslinked poly(allylamine) polymers, such as Beverimer, are free of significant amounts of impurities even after extended periods of storage, e.g., at least 1, 2, 3, 4, or 5 years.

[0276] In some embodiments, the unit dosage forms disclosed herein are protected to contain less than 20 ppm of CH2CHCH2NH2 at least 5 years after the polymer is placed in the unit dosage form. In some embodiments, the unit dosage forms disclosed herein are protected to contain less than 15 ppm of CH2CHCH2NH2 at least 5 years after the polymer is placed in the unit dosage form. In some embodiments, the unit dosage forms disclosed herein are protected to contain less than 20 ppm of CH2CHCH2NH2 at least 4 years after the polymer is placed in the unit dosage form. In some embodiments, the unit dosage forms disclosed herein are protected to contain less than 15 ppm of CH2CHCH2NH2 at least 4 years after the polymer is placed in the unit dosage form. In some embodiments, the unit dosage forms disclosed herein are protected to contain less than 20 ppm CH2CHCH2NH2 of the crosslinked poly(allylamine) polymer, e.g., Beverimer, at least three years after the polymer is placed in the unit dosage form. In some embodiments, the unit dosage forms disclosed herein are protected to contain less than 15 ppm CH2CHCH2NH2 of the crosslinked poly(allylamine) polymer, e.g., Beverimer, at least three years after the polymer is placed in the unit dosage form. In some embodiments, the unit dosage forms disclosed herein are protected to contain less than 20 ppm CH2CHCH2NH2 of the crosslinked poly(allylamine) polymer, e.g., Beverimer, at least two years after the polymer is placed in the unit dosage form. In some embodiments, the unit dosage forms disclosed herein are protected to contain less than 15 ppm CH2CHCH2NH2 of the crosslinked poly(allylamine) polymer, e.g., Beverimer, at least two years after the polymer is placed in the unit dosage form. In some embodiments, the unit dosage forms disclosed herein are protected to contain less than 20 ppm of CH2CHCH2NH2, such as Beverimer, at least one year after the polymer is placed in the unit dosage form.In some embodiments, the unit dosage forms disclosed herein protect the crosslinked poly(allylamine) polymer, e.g., Beverimer, so that the polymer contains less than 15 ppm CHCHCHNH at least one year after being placed in the unit dosage form. In all such embodiments, purity requirements stated using the phrase "at least X years after being placed in the unit dosage form" also state the option that the purity requirement is met in X years.

[0277] Treatment methods and medical uses of crosslinked poly(allylamine) polymers Methods of treatment and medical uses of the crosslinked poly(allylamine) polymers, particularly bevelimer, disclosed herein are described in WO2014 / 197725A1, WO2016 / 094685A1, WO2017 / 193050A1, WO2017 / 193064A1, WO2017 / 193024A1, WO2019 / 090176A1, WO2019 / 090177A1, WO2019 / 236639A1, WO2019 / 236636A1 and WO2019 / 236124A1, which are incorporated herein by reference.

[0278] According to one aspect of the present invention, the crosslinked poly(allylamine) polymers disclosed herein, particularly Bevelimer, are for use in any of the methods of treatment or medical applications described in any of WO2014 / 197725A1, WO2016 / 094685A1, WO2017 / 193050A1, WO2017 / 193064A1, WO2017 / 193024A1, WO2019 / 090176A1, WO2019 / 090177A1, WO2019 / 236639A1, WO2019 / 236636A1 and WO2019 / 236124A1.

[0279] For example, the crosslinked poly(allylamine) polymers disclosed herein, particularly Bevelimer, are for use in any of the methods of treating acid-base disorders, such as metabolic acidosis, described in any of WO2014 / 197725A1, WO2016 / 094685A1, WO2017 / 193050A1, WO2017 / 193064A1, WO2017 / 193024A1, WO2019 / 090176A1, WO2019 / 090177A1, WO2019 / 236639A1, WO2019 / 236636A1, and WO2019 / 236124A1.

[0280] The baseline serum bicarbonate value may be a serum bicarbonate concentration determined at one time point, or may be the average or median of two or more serum bicarbonate concentrations determined at two or more time points. For example, in some embodiments, the baseline serum bicarbonate value may be a serum bicarbonate concentration determined at one time point, and the baseline serum bicarbonate value is used as a basis for determining whether an acute acidic condition requires immediate treatment. In other embodiments, the baseline serum bicarbonate treatment value is the average of the serum bicarbonate concentrations of serum samples taken at different time points (e.g., different days). By way of further example, in some such embodiments, the baseline serum bicarbonate treatment value is the average of the serum bicarbonate concentrations of serum samples taken on different days (e.g., at least two, three, four, five, or more days, which may be consecutive or separated by one or more days or several weeks). By way of further example, in some such embodiments, the baseline serum bicarbonate treatment value is the average of the serum bicarbonate concentrations of serum samples taken on two consecutive days before the start of treatment.

[0281] In certain embodiments, the baseline serum bicarbonate value is a serum bicarbonate concentration value determined at a single time point. In other embodiments, the baseline serum bicarbonate value is the average of at least two serum bicarbonate concentrations determined at different time points. For example, in certain such embodiments, the baseline serum bicarbonate value is the average of at least two serum bicarbonate concentrations of serum samples taken on different days. As a further example, the baseline serum bicarbonate value is the average or median of at least two serum bicarbonate concentrations of serum samples taken on non-consecutive days. As a further example, in certain such methods, the non-consecutive days are at least two days apart. As a further example, in certain such methods, the non-consecutive days are at least one week apart. As a further example, in certain such methods, the non-consecutive days are at least two weeks apart. As a further example, in certain such methods, the non-consecutive days are at least three weeks apart.

[0282] In some embodiments, patients are treated with a daily dose for a period of at least one day. For example, in some such embodiments, patients are treated with a daily dose for a period of at least one week. As a further example, in some such embodiments, patients are treated with a daily dose for a period of at least one month. As a further example, in some such embodiments, patients are treated with a daily dose for a period of at least two months. As a further example, in some such embodiments, patients are treated with a daily dose for a period of at least three months. As a further example, in some such embodiments, patients are treated with a daily dose for a period of at least several months. As a further example, in some such embodiments, patients are treated with a daily dose for a period of at least six months. As a further example, in some such embodiments, patients are treated with a daily dose for a period of at least one year.

[0283] Treatment of patients with cancer and diabetes Gillies et al. (BBA - Reviews on Cancer 1871 (2019) 273-280) describe the impact of acidosis on cancer progression and diabetes. Acidification of the peritumoral microenvironment leads to important sequelae of cancer progression, including invasion and metastasis. Acidification also affects diabetes by preventing the binding of insulin to its receptor, leading to peripheral resistance and exacerbation of symptoms.

[0284] Gillies et al. proposed acidosis as a suitable therapeutic target for cancer treatment and described three approaches for targeting: buffers, nanomedicines, and proton pump inhibitors. Gillies et al. showed that direct targeting of extracellular acidity provided preclinical or clinical benefits in cancer and diabetes. Several therapeutic agents, including commercially available bicarbonate and carbonate mixtures, are proposed to control melanoma growth.

[0285] Beverimer (TRC101) is described in Gillies et al. as an alternative agent that can be used to directly raise pH. A further aspect of the present invention is a composition comprising the crosslinked poly(allylamine) polymers described herein, particularly Beverimer, for use in treating patients with cancer.

[0286] In some embodiments, the cancer is associated with acidosis. In some embodiments, the acidosis is metabolic acidosis. In some embodiments, the acidosis is lactic acidosis.

[0287] A further aspect of the present invention is a composition comprising the crosslinked poly(allylamine) polymers described herein, particularly bevelimer, for use in the treatment of diabetes.

[0288] In some embodiments, the diabetes is type 1 diabetes. In some embodiments, the diabetes is type 2 diabetes.

[0289] The present invention further includes the following numbered embodiments:

[0290] Embodiment 1. A method for making a crosslinked poly(allylamine) polymer, comprising: (a) in a first step, the formation of a poly(allylamine) polymer in the form of beads in a simultaneous polymerization and crosslinking reaction mixture comprising 2-propen-1-ylamine or a salt thereof, 1,3-bis(allylamino)propane or a salt thereof, 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 in the poly(allylamine) polymer are sp 2 an allylic carbon, and (b) in 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; A method comprising:

[0291] Embodiment 2. Poly(allylamine) polymer containing sp 2 The process of any of the preceding embodiments, wherein the allylic carbons comprise less than 1.0% of the total number of carbon atoms in the poly(allylamine) polymer formed in the first step.

[0292] Embodiment 3. Poly(allylamine) polymer containing sp 2 The process of any of the preceding embodiments, wherein the allylic carbons comprise less than 0.9% of the total number of carbon atoms in the poly(allylamine) polymer formed in the first step.

[0293] Embodiment 4. Poly(allylamine) polymer containing sp 2 The process of any of the preceding embodiments, wherein the allylic carbons comprise less than 0.8% of the total number of carbon atoms in the poly(allylamine) polymer formed in the first step.

[0294] Embodiment 5. Poly(allylamine) polymer containing sp 2The process of any of the preceding embodiments, wherein the allylic carbons comprise less than 0.75% of the total number of carbon atoms in the poly(allylamine) polymer formed in the first step.

[0295] Embodiment 6. Poly(allylamine) polymer containing sp 2 The process of any of the preceding embodiments, wherein the allylic carbons comprise less than 0.7% of the total number of carbon atoms in the poly(allylamine) polymer formed in the first step.

[0296] Embodiment 7. Poly(allylamine) polymer containing sp 2 The process of any of the preceding embodiments, wherein the allylic carbons comprise less than 0.6% of the total number of carbon atoms in the poly(allylamine) polymer formed in the first step.

[0297] Embodiment 8. Poly(allylamine) polymer containing sp 2 The process of any of the preceding embodiments, wherein the allylic carbons comprise less than 0.5% of the total number of carbon atoms in the poly(allylamine) polymer formed in the first step.

[0298] Embodiment 9. Poly(allylamine) polymer containing sp 2 The process of any of the preceding embodiments, wherein the allylic carbons comprise less than 0.4% of the total number of carbon atoms in the poly(allylamine) polymer formed in the first step.

[0299] Embodiment 10. Poly(allylamine) polymer containing sp 2 The method of any of embodiments 1-10, wherein the allylic carbons comprise more than 0.3% of the total carbon atoms in the poly(allylamine) polymer formed in the first step.

[0300] Embodiment 11. Poly(allylamine) polymer containing sp 2The process of any of the preceding embodiments, wherein the allylic carbons comprise less than 0.3% of the total number of carbon atoms in the poly(allylamine) polymer formed in the first step.

[0301] Embodiment 12. Poly(allylamine) polymer containing sp 2 The process of any of the preceding embodiments, wherein the allylic carbons comprise less than 0.25% of the total number of carbon atoms in the poly(allylamine) polymer formed in the first step.

[0302] Embodiment 13. Poly(allylamine) polymer containing sp 2 The process of any of the preceding embodiments, wherein the allylic carbons comprise less than 0.2% of the total number of carbon atoms in the poly(allylamine) polymer formed in the first step.

[0303] Embodiment 14. Poly(allylamine) polymer containing sp 2 The method of any of the preceding embodiments, wherein the allylic carbons comprise less than 0.1% of the total number of carbon atoms in the poly(allylamine) polymer formed in the first step.

[0304] Embodiment 15. Poly(allylamine) polymer containing sp 2 The process of any of the preceding embodiments, wherein the allylic carbons comprise less than 0.05% of the total number of carbon atoms in the poly(allylamine) polymer formed in the first step.

[0305] Embodiment 16. Poly(allylamine) polymer containing sp 2 The method or poly(allylamine) polymer of any of the preceding embodiments, wherein the number of allyl carbon atoms, if any, is below the detection limit as determined by NMR.

[0306] Embodiment 17. Poly(allylamine) polymer containing sp 2 The percentage of allylic carbons is determined by NMR; optionally, sp 110-150 ppm. 2The integral of the allylic carbon peak and the alkyl carbon peak from 0 to 80 ppm is calculated using the formula

number

[0307] Embodiment 18. The poly(allylamine) polymer formed in the first step contains sp 2 The percentage of allylic carbons, if any, is determined by NMR to be sp 2 below the detection limit of allylic carbon; optionally 110 to 150 ppm sp 2 The integral of the allylic carbon peak and the alkyl carbon peak from 0 to 80 ppm is calculated using the formula

number

[0308] Embodiment 19. The method of any of the preceding embodiments, wherein the poly(allylamine) polymer formed in the first step has a swelling ratio of less than 10.

[0309] Embodiment 20. The method of any of the preceding embodiments, wherein the poly(allylamine) polymer formed in the first step has a swelling ratio of less than 9.

[0310] Embodiment 21. The method of any of the preceding embodiments, wherein the poly(allylamine) polymer formed in the first step has a swelling ratio of less than 8.

[0311] Embodiment 22. The method of any of the preceding embodiments, wherein the poly(allylamine) polymer formed in the first step has a swelling ratio of less than 7.

[0312] Embodiment 23. The method of any of the preceding embodiments, wherein the poly(allylamine) polymer formed in the first step has a swelling ratio of less than 6.

[0313] Embodiment 24. The method of any of the preceding embodiments, wherein the poly(allylamine) polymer formed in the first step has a swelling ratio of less than 5.

[0314] Embodiment 25. The method of any of the preceding embodiments, wherein the poly(allylamine) polymer formed in the first step has a swelling ratio of at least 4.

[0315] Embodiment 26. The method of any of the preceding embodiments, wherein the poly(allylamine) polymer formed in the first step has a swelling ratio of at least 3.

[0316] Embodiment 27. The method of any of the preceding embodiments, wherein the crosslinked poly(allylamine) polymer contains less than 20 ppm allylamine.

[0317] Embodiment 28. The method of any of the preceding embodiments, wherein the simultaneous polymerization and crosslinking reaction mixture comprises a radical polymerization initiator selected from the group consisting of cationic and free radical polymerization initiators.

[0318] Embodiment 29. The method of any of the preceding embodiments, wherein the simultaneous polymerization and crosslinking reaction mixture comprises a free radical polymerization initiator selected from a free radical peroxy polymerization initiator and an azo polymerization initiator.

[0319] Embodiment 30. The simultaneous polymerization and crosslinking reaction mixture is selected from the group consisting of azodiisobutyronitrile, azodiisovaleronitrile, dimethyl azodiisobutyrate, 2,2'-azobis(isobutyronitrile), 2,2'-azobis(N,N'-dimethyl-eneisobutyramidine) 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-cyanopentanoic acid), 2,2'-azobis(isobutyramide) dihydrate, 2,2'-azobis(2-methylpropane), 2,2'-azobis(2-methylbutyronitrile), VAZO. 67, the process of any of the preceding embodiments, comprising a free radical polymerization initiator selected from the group consisting of cyanopentanoic acid, peroxypivalate, dodecylbenzene peroxide, benzoyl peroxide, di-t-butyl hydroperoxide, t-butyl peracetate, acetyl peroxide, dicumyl peroxide, cumyl hydroperoxide, and dimethylbis(butylperoxy)hexane.

[0320] Embodiment 31. The method of any of the preceding embodiments, wherein the combination of 2-propen-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof in the simultaneous polymerization and crosslinking reaction mixture comprises a ratio of allyl equivalents to initiator equivalents ranging from about 6:1 to about 70:1, respectively.

[0321] Embodiment 32. The method of any of the preceding embodiments, wherein the number of allyl equivalents to initiator equivalents of the 2-propen-1-ylamine or salt thereof and the 1,3-bis(allylamino)propane or salt thereof in the simultaneous polymerization and crosslinking reaction mixture is in the range of about 7:1 to about 60:1, respectively.

[0322] Embodiment 33. The method of any of the preceding embodiments, wherein the number of allyl equivalents to initiator equivalents of the 2-propen-1-ylamine or salt thereof and the 1,3-bis(allylamino)propane or salt thereof in the simultaneous polymerization and crosslinking reaction mixture is in the range of about 8:1 to about 50:1, respectively.

[0323] Embodiment 34. The method of any of the preceding embodiments, wherein the number of allyl equivalents to initiator equivalents of the 2-propen-1-ylamine or salt thereof and the 1,3-bis(allylamino)propane or salt thereof in the simultaneous polymerization and crosslinking reaction mixture is in the range of about 10:1 to about 45:1, respectively.

[0324] Embodiment 35. The method of any of the preceding embodiments, wherein the number of allyl equivalents to initiator equivalents of the 2-propen-1-ylamine or salt thereof and the 1,3-bis(allylamino)propane or salt thereof in the simultaneous polymerization and crosslinking reaction mixture is in the range of about 15:1 to about 40:1, respectively.

[0325] Embodiment 36. The method of any of the preceding embodiments, wherein the number of allyl equivalents to initiator equivalents of the 2-propen-1-ylamine or salt thereof and the 1,3-bis(allylamino)propane or salt thereof in the simultaneous polymerization and crosslinking reaction mixture is in the range of about 17.5:1 to about 35:1, respectively.

[0326] Embodiment 37. The method of any of the preceding embodiments, wherein the number of allyl equivalents to initiator equivalents of the 2-propen-1-ylamine or salt thereof and the 1,3-bis(allylamino)propane or salt thereof in the simultaneous polymerization and crosslinking reaction mixture is in the range of about 20:1 to about 30:1, respectively.

[0327] Embodiment 38. The method of any of the preceding embodiments, wherein the number of allyl equivalents to initiator equivalents of the 2-propen-1-ylamine or salt thereof and the 1,3-bis(allylamino)propane or salt thereof in the simultaneous polymerization and crosslinking reaction mixture is in the range of about 22.5:1 to about 30:1, respectively.

[0328] Embodiment 39. The method of any of the preceding embodiments, wherein the number of allyl equivalents to initiator equivalents of the 2-propen-1-ylamine or salt thereof and the 1,3-bis(allylamino)propane or salt thereof in the simultaneous polymerization and crosslinking reaction mixture is in the range of about 25:1 to about 27.5:1, respectively.

[0329] Embodiment 40. The method of any of the preceding embodiments, wherein the weight ratio of the combined amount of 2-propen-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof to the amount of water in the simultaneous polymerization and crosslinking reaction mixture is in the range of about 0.01 to about 3, respectively, wherein the weight ratio is calculated using the free amine forms of 2-propen-1-ylamine and 1,3-bis(allylamino)propane, respectively.

[0330] Embodiment 41. The method of any of the preceding embodiments, wherein the weight ratio of the combined amount of 2-propen-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof to the amount of water in the simultaneous polymerization and crosslinking reaction mixture is in the range of about 0.05 to about 2.75, respectively, wherein the weight ratio is calculated using the free amine forms of 2-propen-1-ylamine and 1,3-bis(allylamino)propane, respectively.

[0331] Embodiment 42. The method of any of the preceding embodiments, wherein the weight ratio of the combined amount of 2-propen-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof to the amount of water in the simultaneous polymerization and crosslinking reaction mixture is in the range of about 0.07 to about 2.5, respectively, wherein the weight ratio is calculated using the free amine forms of 2-propen-1-ylamine and 1,3-bis(allylamino)propane, respectively.

[0332] Embodiment 43. The method of any of the preceding embodiments, wherein the weight ratio of the combined amount of 2-propen-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof to the amount of water in the simultaneous polymerization and crosslinking reaction mixture is in the range of about 0.1 to about 2.25, respectively, wherein the weight ratio is calculated using the free amine forms of 2-propen-1-ylamine and 1,3-bis(allylamino)propane, respectively.

[0333] Embodiment 44. The method of any of the preceding embodiments, wherein the weight ratio of the combined amount of 2-propen-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof to the amount of water in the simultaneous polymerization and crosslinking reaction mixture is in the range of about 0.15 to about 2, respectively, wherein the weight ratio is calculated using the free amine forms of 2-propen-1-ylamine and 1,3-bis(allylamino)propane, respectively.

[0334] Embodiment 45. The method of any of the preceding embodiments, wherein the weight ratio of the combined amount of 2-propen-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof to the amount of water in the simultaneous polymerization and crosslinking reaction mixture is in the range of about 0.2 to about 1.75, respectively, wherein the weight ratio is calculated using the free amine forms of 2-propen-1-ylamine and 1,3-bis(allylamino)propane, respectively.

[0335] Embodiment 46. The method of any of the preceding embodiments, wherein the weight ratio of the combined amount of 2-propen-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof to the amount of water in the simultaneous polymerization and crosslinking reaction mixture is in the range of about 0.25 to about 1.5, respectively, wherein the weight ratio is calculated using the free amine forms of 2-propen-1-ylamine and 1,3-bis(allylamino)propane, respectively.

[0336] Embodiment 47. The method of any of the preceding embodiments, wherein the weight ratio of the combined amount of 2-propen-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof to the amount of water in the simultaneous polymerization and crosslinking reaction mixture is in the range of about 0.25 to about 1.25, respectively, wherein the weight ratio is calculated using the free amine forms of 2-propen-1-ylamine and 1,3-bis(allylamino)propane, respectively.

[0337] Embodiment 48. The method of any of the preceding embodiments, wherein the weight ratio of the combined amount of 2-propen-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof to the amount of water in the simultaneous polymerization and crosslinking reaction mixture is in the range of about 0.3 to about 1, respectively, wherein the weight ratio is calculated using the free amine forms of 2-propen-1-ylamine and 1,3-bis(allylamino)propane, respectively.

[0338] Embodiment 49. The method of any of the preceding embodiments, wherein the weight ratio of the combined amount of 2-propen-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof to the amount of water in the simultaneous polymerization and crosslinking reaction mixture is in the range of about 0.35 to about 0.75, respectively, wherein the weight ratio is calculated using the free amine forms of 2-propen-1-ylamine and 1,3-bis(allylamino)propane, respectively.

[0339] Embodiment 50. The method of any of the preceding embodiments, wherein the weight ratio of the combined amount of 2-propen-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof to the amount of water in the simultaneous polymerization and crosslinking reaction mixture is in the range of about 0.4 to about 0.5, respectively, wherein the weight ratio is calculated using the free amine forms of 2-propen-1-ylamine and 1,3-bis(allylamino)propane, respectively.

[0340] Embodiment 51. The method of any of the preceding embodiments, wherein the ratio of allyl equivalents to water equivalents in the simultaneous polymerization and crosslinking reaction mixture ranges from about 0.01:1 to about 1:1, respectively.

[0341] Embodiment 52. The method of any of the preceding embodiments, wherein the ratio of allyl equivalents to water equivalents in the simultaneous polymerization and crosslinking reaction mixture ranges from about 0.015:1 to about 0.75:1, respectively.

[0342] Embodiment 53. The method of any of the preceding embodiments, wherein the ratio of allyl equivalents to water equivalents in the simultaneous polymerization and crosslinking reaction mixture ranges from about 0.02:1 to about 0.5:1, respectively.

[0343] Embodiment 54. The method of any of the preceding embodiments, wherein the ratio of allyl equivalents to water equivalents in the simultaneous polymerization and crosslinking reaction mixture ranges from about 0.03:1 to about 0.4:1, respectively.

[0344] Embodiment 55. The method of any of the preceding embodiments, wherein the ratio of allyl equivalents to water equivalents in the simultaneous polymerization and crosslinking reaction mixture ranges from about 0.04:1 to about 0.3:1, respectively.

[0345] Embodiment 56. The method of any of the preceding embodiments, wherein the ratio of allyl equivalents to water equivalents in the simultaneous polymerization and crosslinking reaction mixture ranges from about 0.05:1 to about 0.25:1, respectively.

[0346] Embodiment 57. The method of any of the preceding embodiments, wherein the ratio of allyl equivalents to water equivalents in the simultaneous polymerization and crosslinking reaction mixture ranges from about 0.06:1 to about 0.2:1, respectively.

[0347] Embodiment 58. The method of any of the preceding embodiments, wherein the ratio of allyl equivalents to water equivalents in the simultaneous polymerization and crosslinking reaction mixture ranges from about 0.07:1 to about 0.175:1, respectively.

[0348] Embodiment 59. The method of any of the preceding embodiments, wherein the ratio of allyl equivalents to water equivalents in the simultaneous polymerization and crosslinking reaction mixture ranges from about 0.08:1 to about 0.15:1, respectively.

[0349] Embodiment 60. The method of any of the preceding embodiments, wherein the surfactant included in the simultaneous polymerization and crosslinking reaction mixture comprises an ionic or nonionic surfactant.

[0350] Embodiment 61. The method of any of the preceding embodiments, wherein the surfactant included in the simultaneous polymerization and crosslinking reaction mixture comprises an ionic surfactant.

[0351] Embodiment 62. The method of any of the preceding embodiments, wherein the surfactant included in the simultaneous polymerization and crosslinking reaction mixture comprises a nonionic surfactant.

[0352] Embodiment 63. The method of any of the preceding embodiments, wherein the surfactant included in the simultaneous polymerization and crosslinking reaction mixture is 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 an ionic or nonionic surfactant selected from the group consisting of diisooctyl sulfosuccinic acid, branched dodecylbenzene sulfonic acid, linear dodecylbenzene sulfonic acid, sodium branched alkylbenzene sulfonate, sodium branched dodecylbenzene sulfonate, sodium alpha olefin sulfonate, sodium linear alkylbenzene sulfonate, isopropylamine branched alkylbenzene sulfonate, and sodium lauryl sulfate.

[0353] Embodiment 64. The method of any of the preceding embodiments, wherein the surfactant included in the simultaneous polymerization and crosslinking reaction mixture is branched dodecylbenzenesulfonic acid.

[0354] Embodiment 65. The method of any of the preceding embodiments, wherein the organic solvent system included in the simultaneous polymerization and crosslinking reaction mixture comprises a water-immiscible organic solvent.

[0355] Embodiment 66. The method of any of the preceding embodiments, wherein the organic solvent system included in the simultaneous polymerization and crosslinking 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 thereof.

[0356] Embodiment 67. The method of any of the preceding embodiments, wherein the organic solvent system included in the simultaneous polymerization and crosslinking reaction mixture comprises heptane.

[0357] Embodiment 68. The method of any of the preceding embodiments, wherein the organic solvent system included in the simultaneous polymerization and crosslinking reaction mixture consists of heptane.

[0358] Embodiment 69. The method of any of the preceding embodiments, wherein the simultaneous polymerization and crosslinking reaction mixture is heated to a temperature ranging from about 25°C to about 85°C.

[0359] Embodiment 70. The method of any of the preceding embodiments, wherein the simultaneous polymerization and crosslinking reaction mixture is heated to a temperature ranging from about 30°C to about 85°C.

[0360] Embodiment 71. The method of any of the preceding embodiments, wherein the simultaneous polymerization and crosslinking reaction mixture is heated to a temperature ranging from about 35°C to about 85°C.

[0361] Embodiment 72. The method of any of the preceding embodiments, wherein the simultaneous polymerization and crosslinking reaction mixture is heated to a temperature ranging from about 40°C to about 85°C.

[0362] Embodiment 73. The method of any of the preceding embodiments, wherein the simultaneous polymerization and crosslinking reaction mixture is heated to about 45°C to about 85°C.

[0363] Embodiment 74. The method of any of the preceding embodiments, wherein the simultaneous polymerization and crosslinking reaction mixture is heated to about 60°C to about 80°C.

[0364] Embodiment 75. The method of any of the preceding embodiments, wherein the temperature of the simultaneous polymerization and crosslinking reaction mixture is maintained relatively constant during the reaction.

[0365] Embodiment 76. The method of any of the preceding embodiments, wherein the temperature of the simultaneous polymerization and crosslinking reaction mixture is ramped continuously or in a stepwise manner during the reaction.

[0366] Embodiment 77. The method of any of the preceding embodiments, wherein the simultaneous polymerization and crosslinking reaction steps are carried out for a reaction time of at least about 2 hours.

[0367] Embodiment 78. The method of any of the preceding embodiments, wherein the simultaneous polymerization and crosslinking reaction steps are carried out for a reaction time of at least about 5 hours.

[0368] Embodiment 79. The method of any of the preceding embodiments, wherein the simultaneous polymerization and crosslinking reaction steps are carried out for a reaction time of at least about 10 hours.

[0369] Embodiment 80. The method of any of the preceding embodiments, wherein the simultaneous polymerization and crosslinking reaction steps are carried out for a reaction time of at least about 15 hours.

[0370] Embodiment 81. The method of any of the preceding embodiments, wherein the simultaneous polymerization and crosslinking reaction steps are carried out for a reaction time of at least about 20 hours.

[0371] Embodiment 82. The method of any of the preceding embodiments, wherein the simultaneous polymerization and crosslinking reaction steps are carried out for a reaction time of at least about 25 hours.

[0372] Embodiment 83. The method of any of the preceding embodiments, wherein the simultaneous polymerization and crosslinking reaction steps are carried out for a reaction time of at least about 30 hours.

[0373] Embodiment 84. The method of any of the preceding embodiments, wherein the simultaneous polymerization and crosslinking reaction steps are carried out for a reaction time of at least about 35 hours.

[0374] Embodiment 85. The method of any of the preceding embodiments, wherein the simultaneous polymerization and crosslinking reaction steps are carried out for a reaction time of at least about 40 hours.

[0375] Embodiment 86. The method of any of the preceding embodiments, wherein the simultaneous polymerization and crosslinking reaction steps are carried out for a reaction time of at least about 50 hours.

[0376] Embodiment 87. The method of any of the preceding embodiments, Embodiments 77-80, wherein the simultaneous polymerization and crosslinking reaction steps are carried out for a reaction time of less than 16 hours.

[0377] Embodiment 88. The method of any of the preceding embodiments, wherein the simultaneous polymerization and crosslinking reaction steps are carried out in a batch process.

[0378] Embodiment 89. The method of any of the preceding embodiments, wherein the simultaneous polymerization and crosslinking reaction steps are carried out in a semi-batch manner.

[0379] Embodiment 90. The method of any of the preceding embodiments, wherein the simultaneous polymerization and crosslinking reaction steps are carried out in a continuous manner.

[0380] Embodiment 91. The method of any of the preceding embodiments, wherein the simultaneous polymerization and crosslinking reaction step reaction mixture comprises at least 0.4 equivalents of acid per equivalent of allylamine.

[0381] Embodiment 92. The method of any of the preceding embodiments, wherein the simultaneous polymerization and crosslinking reaction step reaction mixture comprises at least 0.6 equivalents of acid per equivalent of allylamine.

[0382] Embodiment 93. The method of any of the preceding embodiments, wherein the simultaneous polymerization and crosslinking reaction step reaction mixture comprises at least 0.8 equivalents of acid per equivalent of allylamine.

[0383] Embodiment 94. The method of any of the preceding embodiments, wherein the simultaneous polymerization and crosslinking reaction step reaction mixture comprises at least 0.9 equivalents of acid per equivalent of allylamine.

[0384] Embodiment 95. The method of any of the preceding embodiments, wherein the simultaneous polymerization and crosslinking reaction step reaction mixture comprises at least 0.95 equivalents of acid per equivalent of allylamine.

[0385] Embodiment 96. The method of any of the preceding embodiments, wherein the simultaneous polymerization and crosslinking reaction step reaction mixture comprises at least 1.0 equivalent of acid per equivalent of allylamine.

[0386] Embodiment 97. The method of any of the preceding embodiments, wherein the simultaneous polymerization and crosslinking reaction step reaction mixture comprises at least 1 equivalent of acid per equivalent of allylamine.

[0387] Embodiment 98. The method of any of the preceding embodiments, wherein the simultaneous polymerization and crosslinking reaction step reaction mixture comprises an acid selected from the group consisting of hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, methyl phosphate, formic acid, citric acid, and combinations thereof.

[0388] Embodiment 99. The method of any of the preceding embodiments, wherein the acid is a mineral acid.

[0389] Embodiment 100. The method of any of the preceding embodiments, wherein the acid comprises hydrochloric acid, sulfuric acid, or phosphoric acid.

[0390] Embodiment 101. The method of any of the preceding embodiments, wherein the acid comprises hydrochloric acid.

[0391] Embodiment 102. The method of any of the preceding embodiments, wherein the acid is hydrochloric acid.

[0392] Embodiment 103. The method of any of the preceding embodiments, wherein the acid is introduced into the first step reaction mixture independently of the addition of 2-propen-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof to the first step reaction mixture.

[0393] Embodiment 104. The process of any of the preceding embodiments, wherein the acid is introduced into the first step reaction mixture as a component of 2-propen-1-ylamine or a salt thereof, 1,3-bis(allylamino)propane or a salt thereof, or an acid salt of both 2-propen-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof.

[0394] Embodiment 105. The method of any of the preceding embodiments, wherein the aqueous solids content is about 20 to about 60 weight percent.

[0395] Embodiment 106. The method of any of the preceding embodiments, wherein the aqueous solids content is about 30 to about 50 weight percent.

[0396] Embodiment 107. The method of any of the preceding embodiments, wherein the aqueous solids content is about 30 to about 45 weight percent.

[0397] Embodiment 108. The method of any of the preceding embodiments, wherein the aqueous solids content is about 43% by weight.

[0398] Embodiment 109. The method of any of the preceding embodiments, wherein the poly(allylamine) polymer has a swelling agent absorption capacity, and the amount of swelling agent in the second-step reaction mixture is less than the swelling agent absorption capacity of the poly(allylamine) polymer formed in the first step.

[0399] Embodiment 110. The method of any of the preceding embodiments, wherein the poly(allylamine) polymer is capable of absorbing a swelling agent, the poly(allylamine) polymer is swollen with the swelling agent, and the poly(allylamine) polymer is deprotonated with a base before being swollen with the swelling agent.

[0400] Embodiment 111. The method of any of the preceding embodiments, wherein the dispersion solvent system comprises a non-polar solvent.

[0401] Embodiment 112. The method of any of the preceding embodiments, wherein the dispersion solvent system comprises a solvent that is chemically inert with the preformed poly(allylamine) polymer.

[0402] Embodiment 113. The method of any of the preceding embodiments, wherein the dispersion solvent system comprises 1,2-dichloroethane.

[0403] Embodiment 114. The method of any preceding embodiment, wherein the dispersion solvent system is neat 1,2-dichloroethane.

[0404] Embodiment 115. The method of any of the preceding embodiments, wherein the swelling agent is immiscible with the dispersion solvent system.

[0405] Embodiment 116. The method of any of the preceding embodiments, wherein the weight ratio of swelling agent to poly(allylamine) polymer in the second step reaction mixture is less than 4:1.

[0406] Embodiment 117. The method of any of the preceding embodiments, wherein the weight ratio of swelling agent to poly(allylamine) polymer in the second step reaction mixture is less than 3:1.

[0407] Embodiment 118. The method of any of the preceding embodiments, wherein the weight ratio of swelling agent to poly(allylamine) polymer in the second step reaction mixture is less than 2:1.

[0408] Embodiment 119. The method of any of the preceding embodiments, wherein the weight ratio of swelling agent to poly(allylamine) polymer in the second step reaction mixture is less than 1:1.

[0409] Embodiment 120. The method of any of the preceding embodiments, wherein the swelling agent is a polar solvent.

[0410] Embodiment 121. The method of any of the preceding embodiments, 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.

[0411] Embodiment 122. The method of any of the preceding embodiments, wherein the swelling agent is water.

[0412] Embodiment 123. The method of any of the preceding embodiments, wherein the weight ratio of swelling agent to poly(allylamine) polymer in the second step reaction mixture is less than 0.5:1.

[0413] Embodiment 124. The method of any of the preceding embodiments, wherein the weight ratio of swelling agent to poly(allylamine) polymer in the second step reaction mixture is less than 0.4:1.

[0414] Embodiment 125. The method of any of the preceding embodiments, wherein the weight ratio of swelling agent to poly(allylamine) polymer in the second step reaction mixture is less than 0.3:1.

[0415] Embodiment 126. The method of any of the preceding embodiments, wherein the weight ratio of swelling agent to poly(allylamine) polymer in the second step reaction mixture is at least 0.15:1.

[0416] Embodiment 127. The method of any of the preceding embodiments, wherein the swelling agent and 1,2-dichloroethane are immiscible.

[0417] Embodiment 128. The method of any of the preceding embodiments, wherein the crosslinked poly(allylamine) polymer is combined with 1,2-dichloroethane and the dispersion solvent system before swelling the polymer with the swelling agent.

[0418] Embodiment 129. The method of any of the preceding embodiments, wherein the second step reaction mixture is at a temperature ranging from about 25°C to about 85°C.

[0419] Embodiment 130. The method of any of the preceding embodiments, wherein the second step reaction is carried out at a temperature ranging from about 35°C to about 80°C.

[0420] Embodiment 131. The method of any of the preceding embodiments, wherein the second step reaction mixture is carried out at a temperature ranging from about 45°C to about 80°C.

[0421] Embodiment 132. The method of any of the preceding embodiments, wherein the second step reaction is carried out at a temperature ranging from about 55°C to about 75°C.

[0422] Embodiment 133. The method of any of the preceding embodiments, wherein the second step reaction is carried out at a temperature ranging from about 60°C to about 75°C.

[0423] Embodiment 134. The method of any of the preceding embodiments, wherein the second step reaction is carried out at a temperature ranging from about 65°C to about 75°C.

[0424] Embodiment 135. The method of any of the preceding embodiments, wherein the temperature of the second step reaction mixture is maintained within 10% of the target temperature during the second step.

[0425] Embodiment 136. The method of any of the preceding embodiments, wherein the temperature of the second-step reaction mixture is maintained relatively constant during the second step.

[0426] Embodiment 137. The method of any of the preceding embodiments, wherein the temperature of the second-step reaction mixture is increased continuously or in a stepwise manner during the second step.

[0427] Embodiment 138. The method of any of the preceding embodiments, wherein in the second step, the reaction is carried out for a period of about 2 to 20 hours.

[0428] Embodiment 139. The method of any of the preceding embodiments, wherein in the second step, the reaction is carried out for a period of about 4 to 20 hours.

[0429] Embodiment 140. The method of any of the preceding embodiments, wherein in the second step, the reaction is carried out for a period of about 5 to 20 hours.

[0430] Embodiment 141. The method of any of the preceding embodiments, wherein in the second step, the reaction is carried out for a period of about 6 to 20 hours.

[0431] Embodiment 142. The method of any of the preceding embodiments, wherein in the second step, the reaction is carried out for a period of about 8 to 20 hours.

[0432] Embodiment 143. The method of any of the preceding embodiments, wherein in the second step, the reaction is carried out for a period of about 10 to 20 hours.

[0433] Embodiment 144. The method of any of the preceding embodiments, wherein in the second step, the reaction is carried out for a period of about 12 to 18 hours.

[0434] Embodiment 145. The method of any of the preceding embodiments, wherein in the second step, the reaction is carried out for a period of about 14 to 18 hours.

[0435] Embodiment 146. The method of any of the preceding embodiments, wherein in the second step, the reaction is carried out for a period of about 15 to 17 hours.

[0436] Embodiment 147. A product obtained by the method of any of the preceding embodiments.

[0437] Embodiment 148. A crosslinked poly(allylamine) polymer in the form of beads, prepared by the previous method embodiment.

[0438] Embodiment 149. A crosslinked poly(allylamine) polymer in the form of beads consisting essentially of (i) 20 to 25 mol % of the residues of N,N'-diallyl-1,3-diaminopropane or a salt thereof, (ii) 50 to 60 mol % of the residues of 2-propen-1-ylamine or a salt thereof, and (iii) 20 to 25 mol % of the residues of 1,2-dichloroethane, wherein (i) the crosslinked poly(allylamine) polymer is sp 2 (ii) a poly(allylamine) polymer containing sp 2 A crosslinked poly(allylamine) polymer, wherein the allylic carbons account for less than 1.0% of the total number of carbon atoms in the crosslinked poly(allylamine) polymer.

[0439] Embodiment 150. A crosslinked poly(allylamine) polymer in the form of beads, comprising residues of 2-propen-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof, and 1,2-dichloroethane, wherein (i) the crosslinked poly(allylamine) polymer has a swelling ratio of less than 2, and (ii) the crosslinked poly(allylamine) polymer contains sp 2 The allylic carbons account for less than 1.0% of the total carbon atoms in the crosslinked poly(allylamine) polymer.

[0440] Embodiment 151. A crosslinked poly(allylamine) polymer in the form of beads, comprising residues of 2-propen-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof, and 1,2-dichloroethane, wherein (i) the crosslinked poly(allylamine) polymer contains less than 20 ppm allylamine, and (ii) the crosslinked poly(allylamine) polymer contains less than 20 ppm sp2 The allylic carbons account for less than 1.0% of the total carbon atoms in the crosslinked poly(allylamine) polymer.

[0441] Embodiment 152. A crosslinked poly(allylamine) polymer containing sp 2 The method of any of the preceding embodiments, wherein the allylic carbons account for less than 0.9% of the total number of carbon atoms in the crosslinked poly(allylamine).

[0442] Embodiment 153. A crosslinked poly(allylamine) polymer containing sp 2 The method of any of the preceding embodiments, wherein the allylic carbons account for less than 0.8% of the total number of carbon atoms in the crosslinked poly(allylamine).

[0443] Embodiment 154. A crosslinked poly(allylamine) polymer comprising sp 2 The method of any of the preceding embodiments, wherein the allylic carbons account for less than 0.75% of the total number of carbon atoms in the crosslinked poly(allylamine).

[0444] Embodiment 155. A crosslinked poly(allylamine) polymer comprising sp 2 The method of any of the preceding embodiments, wherein the allylic carbons account for less than 0.7% of the total number of carbon atoms in the crosslinked poly(allylamine).

[0445] Embodiment 156. A crosslinked poly(allylamine) polymer comprising sp 2 The method of any of the preceding embodiments, wherein the allylic carbons account for less than 0.6% of the total number of carbon atoms in the crosslinked poly(allylamine).

[0446] Embodiment 157. A crosslinked poly(allylamine) polymer comprising sp 2 The method of any of the preceding embodiments, wherein the allylic carbons account for less than 0.5% of the total number of carbon atoms in the crosslinked poly(allylamine).

[0447] Embodiment 158. A crosslinked poly(allylamine) polymer comprising sp 2The method of any of the preceding embodiments, wherein the allylic carbons comprise less than 0.4% of the total number of carbon atoms in the crosslinked poly(allylamine).

[0448] Embodiment 158A. Crosslinked poly(allylamine) polymer containing sp 2 The method of any of the preceding embodiments, wherein the allylic carbons comprise more than 0.3% of the total carbon atoms in the crosslinked poly(allylamine).

[0449] Embodiment 159. A crosslinked poly(allylamine) polymer containing sp 2 The method of any of the preceding embodiments, wherein the allylic carbons account for less than 0.3% of the total number of carbon atoms in the crosslinked poly(allylamine).

[0450] Embodiment 160. A crosslinked poly(allylamine) polymer comprising sp 2 The method of any of the preceding embodiments, wherein the allylic carbons account for less than 0.25% of the total number of carbon atoms in the crosslinked poly(allylamine).

[0451] Embodiment 161. A crosslinked poly(allylamine) polymer containing sp 2 The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the allylic carbons account for less than 0.2% of the total number of carbon atoms in the crosslinked poly(allylamine) polymer.

[0452] Embodiment 162. A crosslinked poly(allylamine) polymer containing sp 2 The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the allylic carbons account for less than 0.1% of the total number of carbon atoms in the crosslinked poly(allylamine) polymer.

[0453] Embodiment 163. Poly(allylamine) polymers containing sp 2 The percentage of allylic carbons is determined by NMR; optionally, sp 110-150 ppm. 2 The integral of the allylic carbon peak and the alkyl carbon peak from 0 to 80 ppm is calculated using the formula

number

[0454] Embodiment 164. A crosslinked poly(allylamine) polymer comprising sp 2 The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the number of allyl carbon atoms, if any, is below the detection limit as determined by NMR.

[0455] Embodiment 165. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the crosslinked poly(allylamine) polymer contains less than 15 ppm allylamine.

[0456] Embodiment 166. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the crosslinked poly(allylamine) polymer contains less than 12.5 ppm allylamine.

[0457] Embodiment 167. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the crosslinked poly(allylamine) polymer contains less than 10 ppm allylamine.

[0458] Embodiment 168. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the crosslinked poly(allylamine) polymer contains less than 7.5 ppm allylamine.

[0459] Embodiment 169. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the crosslinked poly(allylamine) polymer contains less than 5 ppm allylamine.

[0460] Embodiment 170. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the crosslinked poly(allylamine) polymer contains less than 4 ppm allylamine.

[0461] Embodiment 171. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the crosslinked poly(allylamine) polymer contains less than 3 ppm allylamine.

[0462] Embodiment 172. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the crosslinked poly(allylamine) polymer contains less than 2 ppm allylamine.

[0463] Embodiment 173. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the crosslinked poly(allylamine) polymer contains less than 1 ppm allylamine.

[0464] Embodiment 174. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the crosslinked poly(allylamine) polymer contains less than 500 ppb allylamine.

[0465] Embodiment 175. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the crosslinked poly(allylamine) polymer contains less than 100 ppb allylamine.

[0466] Embodiment 176. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the crosslinked poly(allylamine) polymer contains less than 50 ppb allylamine.

[0467] Embodiment 177. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the crosslinked poly(allylamine) polymer contains less than 1 ppb allylamine.

[0468] Embodiment 178. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the crosslinked poly(allylamine) polymer has a swelling ratio of less than 1.9.

[0469] Embodiment 179. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the crosslinked poly(allylamine) polymer has a swelling ratio of less than 1.8.

[0470] Embodiment 180. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the crosslinked poly(allylamine) polymer has a swelling ratio of less than 1.7.

[0471] Embodiment 181. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the crosslinked poly(allylamine) polymer has a swelling ratio of less than 1.6.

[0472] Embodiment 182. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the crosslinked poly(allylamine) polymer has a swelling ratio of less than 1.5.

[0473] Embodiment 183. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the crosslinked poly(allylamine) polymer has a swelling ratio of less than 1.4.

[0474] Embodiment 184. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the crosslinked poly(allylamine) polymer has a swelling ratio of less than 1.3.

[0475] Embodiment 185. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the crosslinked poly(allylamine) polymer has a swelling ratio of less than 1.2.

[0476] Embodiment 186. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the crosslinked poly(allylamine) polymer has a swelling ratio of less than 1.1.

[0477] Embodiment 187. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the crosslinked poly(allylamine) polymer has a swelling ratio of less than 1.

[0478] Embodiment 188. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the crosslinked poly(allylamine) polymer has a swelling ratio of less than 0.9.

[0479] Embodiment 189. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the crosslinked poly(allylamine) polymer has a swelling ratio of less than 0.8.

[0480] Embodiment 190. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the crosslinked poly(allylamine) polymer has a swelling ratio of less than 0.7.

[0481] Embodiment 191. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the poly(allylamine) polymer has a stability profile such that after storage at 25°C in a sealed enclosure for 3 months after manufacture, the poly(allylamine) polymer contains less than 20 ppm allylamine.

[0482] Embodiment 192. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the poly(allylamine) polymer contains less than 15 ppm allylamine after storage at 25° C. for 3 months in a sealed enclosure after manufacture.

[0483] Embodiment 193. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the poly(allylamine) polymer contains less than 12.5 ppm allylamine after storage at 25° C. in a sealed enclosure for 3 months after manufacture.

[0484] Embodiment 194. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the poly(allylamine) polymer contains less than 10 ppm allylamine after storage at 25° C. in a sealed enclosure for 3 months after manufacture.

[0485] Embodiment 195. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the poly(allylamine) polymer contains less than 7.5 ppm allylamine after storage at 25° C. in a sealed enclosure for 3 months after manufacture.

[0486] Embodiment 196. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the poly(allylamine) polymer contains less than 5 ppm allylamine after storage at 25°C for 3 months in a sealed enclosure after manufacture.

[0487] Embodiment 197. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the poly(allylamine) polymer contains less than 4 ppm allylamine after storage at 25°C for 3 months in a sealed enclosure after manufacture.

[0488] Embodiment 198. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the poly(allylamine) polymer contains less than 3 ppm allylamine after storage at 25°C for 3 months in a sealed enclosure after manufacture.

[0489] Embodiment 199. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the poly(allylamine) polymer contains less than 2 ppm allylamine after storage at 25°C for 3 months in a sealed enclosure after manufacture.

[0490] Embodiment 200. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the poly(allylamine) polymer contains less than 1 ppm allylamine after storage at 25° C. for 3 months in a sealed enclosure after manufacture.

[0491] Embodiment 201. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the poly(allylamine) polymer contains less than 500 ppb of allylamine after storage at 25°C for 3 months in a sealed enclosure after manufacture.

[0492] Embodiment 202. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the poly(allylamine) polymer contains less than 100 ppb of allylamine after storage at 25°C for 3 months in a sealed enclosure after manufacture.

[0493] Embodiment 203. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the poly(allylamine) polymer contains less than 50 ppb of allylamine after storage at 25°C for 3 months in a sealed enclosure after manufacture.

[0494] Embodiment 204. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the poly(allylamine) polymer contains less than 1 ppb of allylamine after storage at 25°C for 3 months in a sealed enclosure after manufacture.

[0495] Embodiment 205. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the amount of allylamine in the poly(allylamine) polymer is below the detection limit of allylamine, if any, after storage in a sealed enclosure at 25°C for 3 months after manufacture.

[0496] Embodiment 206. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the poly(allylamine) polymer has a stability profile such that after 6 months from manufacture and in a sealed enclosure at 25°C, the poly(allylamine) polymer contains less than 20 ppm allylamine.

[0497] Embodiment 207. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the poly(allylamine) polymer contains less than 15 ppm allylamine after storage at 25°C for 6 months in a sealed enclosure after manufacture.

[0498] Embodiment 208. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the poly(allylamine) polymer contains less than 12.5 ppm allylamine after storage at 25°C for 6 months in a sealed enclosure after manufacture.

[0499] Embodiment 209. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the poly(allylamine) polymer contains less than 10 ppm allylamine after storage at 25°C for 6 months in a sealed enclosure after manufacture.

[0500] Embodiment 210. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the poly(allylamine) polymer contains less than 7.5 ppm allylamine after storage at 25°C for 6 months in a sealed enclosure after manufacture.

[0501] Embodiment 211. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the poly(allylamine) polymer contains less than 5 ppm allylamine after storage at 25°C for 6 months in a sealed enclosure after manufacture.

[0502] Embodiment 212. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the poly(allylamine) polymer contains less than 4 ppm allylamine after storage at 25°C for 6 months in a sealed enclosure after manufacture.

[0503] Embodiment 213. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the poly(allylamine) polymer contains less than 3 ppm allylamine after storage at 25°C for 6 months in a sealed enclosure after manufacture.

[0504] Embodiment 214. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the poly(allylamine) polymer contains less than 2 ppm allylamine after storage at 25°C for 6 months in a sealed enclosure after manufacture.

[0505] Embodiment 215. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the poly(allylamine) polymer contains less than 1 ppm allylamine after storage at 25°C for 6 months in a sealed enclosure after manufacture.

[0506] Embodiment 216. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the poly(allylamine) polymer contains less than 500 ppb of allylamine after storage at 25°C for 6 months in a sealed enclosure after manufacture.

[0507] Embodiment 217. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the poly(allylamine) polymer contains less than 100 ppb of allylamine after storage at 25°C for 6 months in a sealed enclosure after manufacture.

[0508] Embodiment 218. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the poly(allylamine) polymer contains less than 50 ppb of allylamine after storage at 25°C for 6 months in a sealed enclosure after manufacture.

[0509] Embodiment 219. The method or crosslinked poly(allylamine) polymer of any of the preceding embodiments, wherein the poly(allylamine) polymer contains less than 1 ppb of allyl...

Claims

1. 1. A packaged pharmaceutical comprising a crosslinked poly(allylamine) polymer, the crosslinked poly(allylamine) polymer having formula (I): 【Chemistry 1】 [During the ceremony, a is a residue of N,N'-diallyl-1,3-diaminopropane or a salt thereof contained in the crosslinked poly(allylamine) polymer in an amount of 20 to 25 mol %; b is a residue of allylamine contained in the crosslinked poly(allylamine) polymer in an amount of 50 to 60 mol %; c is the residue of 1,2-dichloroethane present in the crosslinked poly(allylamine) polymer at 20 to 25 mol %; and m represents a repeat unit of a crosslinked poly(allylamine) polymer; Here, the total mol % of the residues does not exceed 100 mol %. wherein less than 1.0% of the total number of carbon atoms present in the crosslinked poly(allylamine) polymer are sp ２ and the packaged drug product has an oxygen transfer rate of 0.050 CC / m ２ A packaged pharmaceutical product containing one or more layers, oxygen scavengers, or an inert environment within the packaged pharmaceutical product, the shelf life of which is less than 1 / day.

2. 10. The packaged pharmaceutical product of claim 1, further comprising an oxygen scavenger.

3. 3. The packaged pharmaceutical product of claim 2, wherein the oxygen scavenger is selected from iron, ferrous oxide, ferrous oxide powder, ferrous salts, sulfite, bisulfite, reduced sulfur compounds, Pd, Cu, ZN, Mg, Mn, Co(II), Zn, ascorbic acid, ascorbate, isoascorbic acid, tocopherol, hydroquinone, catechol, rongalite, sorbose, lignin, gallic acid, potassium carbonate, erythorbic acid, quinone, catechol, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), polyunsaturated fatty acids, glucose oxidase, laccase, or ethanol oxidase.

4. 10. The packaged pharmaceutical of claim 1, comprising an inert environment within the packaged pharmaceutical.

5. 5. The packaged pharmaceutical product of claim 4, wherein the inert environment is 99+% nitrogen.

6. 10. The packaged pharmaceutical of claim 1, further comprising an oxygen scavenger and / or an inert environment within the packaged pharmaceutical.

7. Less than 0.9% of the total number of carbon atoms present in the crosslinked poly(allylamine) polymer are sp ２ 7. The packaged pharmaceutical product of any one of claims 1 to 6, wherein the carbon is an allylic carbon.

8. Less than 0.8% of the total number of carbon atoms present in the crosslinked poly(allylamine) polymer are sp ２ 8. The packaged pharmaceutical product of claim 1, wherein the carbon is an allylic carbon.

9. More than 0.3% of the total number of carbon atoms present in the crosslinked poly(allylamine) polymer are sp ２ 9. The packaged pharmaceutical product of claim 1, wherein the carbon is an allylic carbon.

10. 2. The packaged pharmaceutical product of claim 1, wherein the ratio of the carbon to nitrogen weight ratio of the poly(allylamine) polymer to the carbon to nitrogen weight ratio of the crosslinked poly(allylamine) polymer is 0.

9.

11. 110 to 150 ppm sp ２ The integral of the allyl carbon peak and the alkyl carbon peak from 0 to 80 ppm is calculated using the formula [Equation 1] Using sp ２ 10. The packaged pharmaceutical product of claim 1 for use in quantifying the percentage of allylic carbons.

12. Crosslinked poly(allylamine) polymer sp ２ The percentage of allylic carbons is １３ as determined by C NMR, １３ C NMR is quantitative １３ 12. The packaged pharmaceutical product of claim 11, wherein the C solid-state magic angle spinning (MAS) NMR.

13. Crosslinked poly(allylamine) polymer contains less than 20 ppm of allylamine (H) as an impurity. ２ C=CHCH ２ NH ２ 13. The packaged pharmaceutical product of any one of claims 1 to 12, comprising:

14. 14. The packaged pharmaceutical of any of claims 1-13, wherein the allylamine content of the crosslinked poly(allylamine) polymer increases by less than 1.5 ppm allylamine / day when tested in a heat stability assay (Stability Assay 2).

15. 15. The packaged pharmaceutical product of any one of claims 1 to 14 for use in a method for treating metabolic acidosis.

16. 16. The packaged pharmaceutical of any one of claims 1 to 15, wherein the crosslinked poly(allylamine) polymer is produced by a process comprising polymerizing N,N'-diallyl-1,3-diaminopropane or a salt thereof and allylamine or a salt thereof, wherein the ratio of the number of allyl equivalents to the number of initiator equivalents of the N,N'-diallyl-1,3-diaminopropane or a salt thereof and the allylamine or a salt thereof introduced into the reaction mixture is in the range of 6:1 to 70:1, respectively.

17. 17. The packaged pharmaceutical product of claim 16, wherein the ratio is from 6:1 to 10:1, respectively.

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