Cross-linked poly(allylamine) polymer pharmaceutical composition

Abstract

The present invention provides a unit dosage form having an outer and inner layer, the inner layer containing a cross-linked poly(allylamine) polymer. [Solution] The unit dosage form includes a sealed enclosure containing a crosslinked poly(allylamine) polymer containing formula 5a. The sealed enclosure includes a multilayer laminate of an internal contact layer, an outer layer, and a barrier layer, and the oxygen transfer rate between the multilayer laminates is approximately 0.050 CC / m 2 It is less than one day. JPEG2026102594000091.jpg6458

Description

[Technical Field]

[0001] The present invention relates to a crosslinked poly(allylamine) polymer, preferably a bevelimer, comprising residues of 2-propene-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 pharmaceutical 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 pharmaceutical 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 a crosslinked poly(allylamine) polymer that can be used for metabolic conditions in which the removal of protons and / or chloride ions from the gastrointestinal tract provides physiological benefits such as increased serum bicarbonate concentration. A wide range of crosslinked amine polymers are disclosed therein, including crosslinked poly(allylamine) polymers produced by simultaneous allylamine polymerization and crosslinking 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 multicentre, randomised, 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, incorporated herein by reference, describe the treatment of metabolic acidosis with veverimer.

[0004] One method for producing polymer drug bevelimmers is disclosed in WO2019 / 236636A1 Synthesis Example A and WO2016 / 094685A1. The bevelimmer polymer produced by this method is uniquely identified as 019070-A3 FA in Table S-1 of Synthesis Example A of WO2019 / 236636A1. Disclosed herein is a method for producing and packaging bevelimmer polymers that have been improved, for example, by improving stability in the presence of oxygen, as well as bevelimmers designed to mitigate oxygen stability concerns.

[0005] The production of poly(allylamine) polymers from allylamines and diallylamines, as described by Bianchi et al., Inoue et al., and Klaerner et al., offers certain advantages over crosslinking linear poly(allylamine) with epichlorohydrin; however, 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 diallylamine or polyfunctional allylamines such as 1,3-bis(allylamino)propane or salts thereof can lead to covalently bonded unsaturated substituents on the polymer backbone, which can cause production that limits the stability of allylamine and related impurities during post-treatment, including drying of the poly(allylamine), or during storage. Such mechanisms of allylamine impurity production include, but are not limited to, the removal of unsaturated substituents to allylamine or related impurities via oxygen, temperature, water, acid, and base.

[0006] One approach to improving the purity and stability profiles of polymers such as bevelomers containing residues of 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof is to improve polymerization efficiency (i.e., improve the conversion of allyl groups). Generally, methods to improve polymerization efficiency are those that favor chain growth over growth-limiting processes such as chain transfer, chain termination, and radical coupling. During radical polymerization steps, these methods a) Increasing the concentration of 2-propen-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in monomer droplet solution, b) Increase in the relative concentration of 1,3-bis(allylamino)propane or a salt thereof by adding 2-propen-1-ylamine or a salt thereof in a semi-batch or continuous process during the reaction. c) Lowering the reaction temperature to facilitate growth or d) Increase in initiator concentration or quantity This includes, but is not limited to, the following:

[0007] Any of these or other methods, or any combination thereof, 13 Crosslinking efficiency is improved by measuring the reduction in allylamine formation in the remaining polymer backbone (i.e., pendant) allyl groups and the final polymer, preferably the bevelimmer, in 13C NMR. In particular, the purity profile and stability profile of the resulting polymer, preferably the bevelimmer, can be improved by minimizing the number of unreacted allyl groups from 1,3-bis(allylamino)propane or its salts. [Overview of the project]

[0008] Among the various aspects of the present invention, a method for producing a composition having therapeutic applications can therefore be specifically mentioned. (a) Formation of poly(allylamine) polymer in the form of beads in a co-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 the first step, wherein less than 1.1% of the total number of carbon atoms in the crosslinked poly(allylamine) polymer is sp 2 Formation of allyl carbons, and (b) In the second step, the poly(allylamine) polymer is further crosslinked in a reaction mixture containing 1,2-dichloroethane, a swelling agent for the poly(allylamine) polymer and a dispersion solvent system to form a crosslinked poly(allylamine) polymer with 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-propene-1-ylamine or a salt thereof, 1,3-bis(allylamino)propane or a salt thereof, and 1,2-dichloroethane, wherein sp protruding from the crosslinked poly(allylamine) polymer backbone 2 Allyl carbons constitute less than 1.0% of the total number of carbon atoms contained in the cross-linked poly(allylamine) polymer, and the cross-linked poly(allylamine) polymer has a swelling ratio of less than 2.

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

[0011] The compositions, non-absorbable compositions, pharmaceutical compositions, or crosslinked poly(allylamine) polymers of the present invention may contain, essentially consist of, or be polymers as defined elsewhere herein. For example, the compositions, non-absorbable compositions, pharmaceutical compositions, or crosslinked poly(allylamine) polymers may contain, essentially consist of, or be drug substance bevelomers.

[0012] Bevelimers are polymer drugs that may have the following structural properties: The bevelomer may be poly(allylamine-co-N,N'-diallyl-1,3-diaminopropane-co-1,2-diaminoethane).

[0013] More specifically, Beberimer is a poly[(N 1 ,N 3 -di(prop-2-en-1-yl)propan-1,3-diamine)-coprop-2-en-1-amine](the molar ratio is approximately 2:5:2 (i.e., N 1 ,N 3 -Di(prop-2-en-1-yl)propane-1,3-diamine:prop-2-en-1-amine:N,N'-ethane-1,2-diyl bridge may be approximately 2:5:2)) polymer.

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

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

[0016] Each bevelimer may have a carbon-to-nitrogen weight ratio in the range of approximately 3.7:1 to approximately 3.8:1. The carbon-to-nitrogen weight ratio can be determined by elemental analysis. For example, the carbon-to-nitrogen weight ratio can be determined by elemental analysis using a Perkin-Elmer 2400 Elemental Analyzer, which is described in more detail elsewhere in this specification.

[0017] Bevelimers can be, for example, non-absorbable compositions that are insoluble under physiological conditions.

[0018] Bevelimers may have a median particle diameter greater than 1 micrometer and less than 1 millimeter. The particle diameter of bevelimers can be measured by wet laser diffraction using Mie theory.

[0019] Beberimer can be manufactured as follows: Bevelomers can be obtained by first copolymerizing 2-propene-1-ylamine or a salt thereof with 1,3-bis(allylamino)propane or a salt thereof to form a poly(allylamine) polymer, and then crosslinking the poly(allylamine) polymer with 1,2-dichloroethane.

[0020] For example, bevelimer 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 a crosslinked poly(allylamine) polymer described herein, particularly bevelimer, wherein less than 1.0% of the total number of carbon atoms present in the crosslinked poly(allylamine) polymer is sp 2 allyl carbon, the composition.

[0022] A further aspect of the present invention is a composition comprising a crosslinked poly(allylamine) polymer described herein, particularly bevelimer, wherein when tested in a heat stability assay (Stability Assay 2), the allylamine (H2C=CHCH2NH2) content of the crosslinked poly(allylamine) polymer increases at less than 2.6 ppm / day of allylamine, the composition.

[0023] A further aspect of the present invention is a unit dosage form having an outer and an inner side, the inner side comprising a crosslinked poly(allylamine) polymer described herein, particularly bevelimer, wherein the oxygen transfer rate between the outer and inner sides of the unit dosage form is less than about 0.050 CC / m 2 / day, the unit dosage form.

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

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

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

[0027] A further aspect of the present invention is a composition comprising the cross-linked poly(allylamine) polymers described herein, particularly bevelimers, for use in the treatment of metabolic acidosis.

[0028] A further aspect of the present invention is a composition comprising the cross-linked poly(allylamine) polymer, particularly bevelimer, described herein, for use in delaying the progression of renal disease.

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

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

[0031] A further aspect of the present invention is a composition comprising the cross-linked poly(allylamine) polymer, particularly bevelimer, described herein, for use in improving the physical function of patients.

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

[0033] A further aspect of the present invention is a composition comprising the cross-linked poly(allylamine) polymers, particularly bevelimers, described herein, for use in improving the quality of life of patients.

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

[0035] Further aspects of the present invention are cross-linked poly(allylamine) polymers, particularly bevelomers, described herein in sealed containers.

[0036] A further aspect of the present invention is a pharmaceutical product comprising the cross-linked poly(allylamine) polymer, particularly bevelimer, described herein in a sealed container including a moisture barrier.

[0037] A further aspect of the present invention is a pharmaceutical product comprising the cross-linked poly(allylamine) polymer, particularly bevelimer, described herein in a sealed container containing an oxygen barrier.

[0038] A further aspect of the present invention is a pharmaceutical product comprising the cross-linked poly(allylamine) polymer, particularly bevelimer, described herein in a sealed container including a moisture barrier and an oxygen barrier.

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

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

[0041] Further aspects of the present invention include pharmaceuticals comprising the crosslinked poly(allylamine) polymer described herein, particularly bevelomers, and sealed containers containing an inert atmosphere.

[0042] Further aspects of the present invention are a sealed container and a pharmaceutical product comprising a crosslinked poly(allylamine) polymer, particularly bevelimer, within the sealed container, wherein the sealed container comprises a multilayer lamination of an internal contact layer, an outer layer, and a barrier layer disposed between the contact layer and the outer layer.

[0043] Further aspects of the present invention are a sealed container and a pharmaceutical product comprising a crosslinked poly(allylamine) polymer, particularly bevelimer, within the sealed container, wherein the sealed container comprises a multilayer lamination of an internal contact layer, an outer layer, and an oxygen barrier layer positioned between the contact layer and the outer layer.

[0044] Further aspects of the present invention include a sealed container and a pharmaceutical product comprising a crosslinked poly(allylamine) polymer, particularly bevelimer, within the sealed container, wherein the sealed container comprises a multilayer lamination of an internal contact layer, an outer layer, and a moisture barrier layer positioned between the contact layer and the outer layer.

[0045] Further aspects of the present invention are a sealed container and a pharmaceutical product comprising a crosslinked poly(allylamine) polymer, particularly bevelimer, within the sealed container, wherein the sealed container comprises a multilayer lamination of an internal contact layer, an outer layer, and an oxygen barrier layer and a moisture barrier layer positioned between the contact layer and the outer layer.

[0046] Further aspects of the present invention are a sealed container and a pharmaceutical product comprising a crosslinked poly(allylamine) polymer, particularly bevelimer, within the sealed container, wherein the sealed container comprises a multilayer lamination of an internal contact layer, an outer layer, and an oxygen removal layer positioned between the contact layer and the outer layer.

[0047] A further aspect of the present invention is a method for treating acid / base injuries in animals by oral administration of a pharmaceutical composition comprising the cross-linked poly(allylamine), particularly bevelimer, described herein.

[0048] A further aspect of the present invention is a method for 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 daily dose of a pharmaceutical composition comprising the cross-linked poly(allylamine), particularly bevelimer, described herein, to increase the patient's serum bicarbonate level by at least 1 mEq / l from baseline within a treatment period not exceeding one month.

[0049] Other aspects and characteristics are partially self-evident and are partially shown below.

[0050] Abbreviations and definitions The following definitions and methods are provided to more precisely define the present invention and to guide those skilled in the art in carrying it out. Unless otherwise noted, terms should be understood to follow the customary usage of those skilled in the art. The term “absorbent capacity” as used herein in relation to polymers and swelling agents (or, in the case of swelling agent mixtures, swelling agent mixtures) is the amount of swelling agent (or such mixture) absorbed at room temperature over a period of at least 16 hours by a certain amount 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 shown in the following table have the meanings indicated: [Table 1]

[0052] The term "alicyclic" refers to a saturated monocyclic group consisting of 3 to 8 carbon atoms, including cyclopentyl, cyclohexyl, and cycloheptyl.

[0053] As used alone or in other contexts, the term “alkyl group” includes, for example, saturated linear or branched carbon radicals having 1 to about 20 carbon atoms or, in specific embodiments, 1 to about 12 carbon atoms. In other embodiments, an alkyl group is a “lower alkyl” group having 1 to about 6 carbon atoms. Examples of such groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, and hexyl. In even more specific embodiments, a lower alkyl group has 1 to 4 carbon atoms.

[0054] The term "allyle" used here refers to the structural formula H2C=CH-CH2- * (In the formula, * This refers to a portion that has a bond point to the rest of the molecule. In one embodiment, the bond point * These are heteroatoms in the remainder of molecules such as nitrogen.

[0055] The term "allyl equivalent" used here refers to the total number of moles of allyl groups present in the reaction mixture in combination of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt.

[0056] The term "allylamine" and AAH refer to the part of the structure that has the formula H2C=CH-CH2NH2.

[0057] The term "aqueous solid content" refers to the concentration of solids in the aqueous phase at the start of polymerization (mass AAH). + (Mass DAPDA + Mass Initiator (e.g., V-50)) / (Mass AAH + Mass DAPDA + Mass Initiator (e.g., V-50) + Mass Water); "Mass Initiator" represents the mass derived solely from the addition of the first initiator (e.g., V-50). Multiply the value by 100 to express the aqueous solid content as weight %.

[0058] The terms “aromatic group” or “aryl group” mean an aromatic group having one or more rings, where such rings may be bonded to each other in a pendant-like manner or fused together. In particular embodiments, aromatic groups are monocyclic, dicyclic, or tricyclic. Monocyclic aromatic groups may have 5 to 10 carbon atoms in the ring, typically 5 to 7 carbon atoms and more typically 5 to 6 carbon atoms. Typical polycyclic aromatic groups are dicyclic or tricyclic. Bicyclic polycyclic aromatic groups typically have 8 to 12 carbon atoms in the ring, preferably 8 to 10 carbon atoms. Examples of aromatic groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl, or ace-naphthyl.

[0059] The term "release time" refers to the state of the product at the time of manufacturing completion.

[0060] The term "batch process" used here 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 in shape.

[0062] The term "bicarbonate equivalent" is used to refer to organic acids or anions that produce bicarbonates when metabolized. Citric acid and succinic acid are exemplary bicarbonate equivalents.

[0063] The term "bonding" as used herein in relation to polymers and one or more ions, i.e., cations (e.g., "proton-bonded" polymers) and anions, i.e., "ionic-bonded" polymers, and / or in relation to ions, is a bond strength sufficient to ensure that at least some of the ions remain bonded under in vitro or in vivo conditions, where the polymer is used for a sufficient amount of time to remove the ions from the solution or body, without generally requiring the bond to be in a non-covalent manner.

[0064] In some embodiments, the term “clinically significant increase” as used herein in relation to treatment means a treatment that restores an individual from a dysfunctional state to a relatively normal functioning state, or moves an indicator of that state toward normal functioning, or at least provides a significant improvement or change compared to the untreated state. Several methods can be used to calculate clinical significance. A non-extensive list of methods for calculating clinical significance includes Jacobson-Truax, Gulliksen-Lord-Novick, Edwards-Nunnally, Hageman-Arrindell, and Hierarchical Linear Modeling (HLM).

[0065] The term "continuous process" used here refers to a process in which one or more reactants are continuously supplied to a reactor, and the reaction product is formed as a continuous flow of products.

[0066] The term “crosslinking agent,” used alone or in other contexts, encompasses ethylene crosslinking agents, specifically 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 to 1,2-dichloroethane here are replaceable with any ethylene crosslinking agent, including those listed in this paragraph.

[0067] The term "diallylamine" refers to the amino portion that has two allyl groups.

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

[0069] The term "gel" is used to refer to cross-linked polymers with irregular shapes.

[0070] The term "heteroaryl" refers to a monocyclic or bicyclic aromatic radical having 5 to 10 ring atoms, where, unless otherwise specified, 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, pyridadinyl, triazolyl, and tetrazolyl. The terms "heteroaryl" and "aryl" as defined herein are mutually exclusive. "Heteroarylene" means a divalent heteroaryl group.

[0071] The term "heteroatom" refers to an atom other than carbon and hydrogen. Typically, but not exclusively, heteroatoms are selected from the group consisting of halogens, 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 a ring with one or two ring atoms containing N, O, B, P, and S(O). nA heterocyclyl group is a saturated or unsaturated group of 4 to 8 ring atoms, where n is an integer between 0 and 2, and the remaining ring atoms are carbon atoms. Furthermore, one or two ring carbon atoms of the heterocyclyl ring may be replaced by -C(O)- groups as an option. More specifically, the term heterocyclyl includes, but is not limited to, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydropyranyl, thiomorpholino, etc. When the heterocyclyl ring is unsaturated, it may contain one or two ring double bonds, provided the ring is not aromatic. When the heterocyclyl group contains at least one nitrogen atom, it is also referred to here as heterocycloamino and is a subgroup of the heterocyclyl group.

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

[0074] The molar percentage or "mol%" of a specific component of a cross-linked poly(allylamine) polymer can be calculated as follows:

number

[0075] A crosslinked poly(allylamine) polymer can be defined by the mol% of its components (e.g., monomer and crosslinking agent residues). In these embodiments, the total mol% cannot exceed 100 mol%. For example, the mol% of 1,3-bis(allylamino)propane or a salt thereof + the mol% of 2-propene-1-ylamine or a salt thereof + the mol% of 1,2-dichloroethane is ≤100 mol%.

[0076] An example of how to calculate molar ratios and mol% is shown below. In this example, the known molar ratios of 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof, used in the production of 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 and, when ethylene residues are introduced into a cross-linked poly(allylamine) polymer, it produces two equivalents of HCl. Therefore, the amount of HCl produced indicates how many ethylene residues have been incorporated into the cross-linked poly(allylamine) polymer.

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

[0079] More specifically, approximately 2 grams of crude crosslinked poly(allylamine) polymer was sampled immediately after the DCE crosslinking reaction. The sample was washed with 20 mL of methanol by mixing in an orbital shaker for 2 hours, and then vacuum filtered from the frit. Methanol washing was repeated up to a total of two washes. The drying loss of the methanol-washed polymer was determined using a standard moisture balance. Approximately 100 mg of methanol-washed crude crosslinked poly(allylamine) polymer was accurately weighed into a vial, and 10 mL of 50 mM sodium hydroxide aqueous solution was added. Cl was extracted from the polymer for 16 hours at 37°C, and the supernatant was then 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 consists of an AG19 guard column and an AS19 analytical column, a potassium hydroxide (KOH) eluent generator, an injection volume of 25 microliters, a runtime of approximately 17 minutes, and a flow rate of 1.0 mL / min. KOH concentration is maintained at 20 mM for 8 minutes, followed by a 4-minute retention at 70 mM KOH and a 5-minute re-equilibrium at 20 mM KOH. Chloride standards were used for quantification 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 the mass of extracted poly(allylamine) polymer:

number

[0083] Determination of reaction DCE:

number

[0084] Calculation of the weight percentage of crosslinked ethylene per gram of poly(allylamine) polymer For example, the following amount of ethylene can be calculated using the method described above: 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 residue in cross-linked poly(allylamine) polymer.

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

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

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

[0088] Below is another working example of how molar ratios and mol% can be calculated. This example uses elemental analysis to determine the weight percentage of ethylene crosslinks. The weight percentage of ethylene crosslinks can then be used to calculate the molar ratio and mol% using the formulas above.

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

number

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

[0091] The term "monoallylamine" refers to the amino portion that has one allyl group.

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

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

[0094] Non-absorbable compositions may be particle compositions that are intrinsically insoluble in the human GI tubule and have a particle size large enough to avoid passive or active absorption through the human GI tubule. For example, a non-absorbable composition implies that the substance does not enter the lymph, blood, interstitial fluid, or organs via the main entry points of the human GI tubule, i.e., via paracellular entry between intestinal epithelial cells, endocytotic uptake via intestinal epithelial cells, or entry via M cells including intestinal epithelial antigen sampling and immune surveillance systems (Jung, 2000), either through active or passive transport processes. The size limit of particles absorbed by human GI tubes is known from 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). Therefore, it is known to those skilled in the art that substances at least 1 micrometer in size are unabsorbable when in a GI tube.

[0095] The phrases "optionally" or "in cases" mean that the events or circumstances described thereafter may occur but are not mandatory, and this description includes cases where such events or circumstances occur and cases where they do not. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that an alkyl group may be present but is not necessarily present, and this 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] The term "partially incorporated polyfunctional allylamine residue" as used herein refers to a polyfunctional allylamine residue 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 the reaction to become a chain atom of the poly(allylamine) polymer backbone, but simply "suspends" from it). For example, a partially incorporated diallylamine residue is a diallylamine residue in which one of the two incorporated allyl groups is a pendant allyl group of the polymer chain.

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

[0098] For example, particle size is measured by wet laser diffraction a using Mie theory as follows: Particles are dispersed in methanol and added to a sample chamber to achieve 10-20% red channel obfuscation. Acoustic processing is performed. The refractive index setting of the particles used for size distribution calculations is selected to minimize artifacts and R parameter values ​​determined by the laser diffraction software. D(0.1), D(0.5), and D(0.9) values ​​characterizing the particle size distribution on a volume basis are recorded.

[0099] As used herein in relation to carriers, diluents, or additives, “pharmaceutically acceptable” means a carrier, diluent, or additive, respectively, that is generally safe, non-toxic, and not biologically or otherwise undesirable for veterinary and / or human pharmaceutical use, and that is useful in the manufacture of a pharmaceutical composition.

[0100] The term "post-polymerization crosslinking" refers to a reaction of already formed beads or gels, where further crosslinking is introduced to the already formed beads or gels to obtain beads or gels with an increased amount 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. These functional groups can be bonded to the already formed beads covalently or non-covalently.

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

[0103] The "Simulated Gastric Juice" or "SGF" assay is a test to determine the total chloride binding capacity of a test polymer using a specified buffer that mimics the composition of gastric juice, as follows: Simulated gastric juice (SGF) consists of 35 mM NaCl, 63 mM HCl, and 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 for approximately 12–16 hours with stirring using a Rotisserie mixer. Unless otherwise specified, the SGF binding data or binding capacity described herein is determined during this period. After incubation and mixing, the tubes containing the polymer are centrifuged at 500–1000 × g for 2 minutes to pelletize the test sample. Approximately 750 microliters of supernatant are taken and filtered using a suitable 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 2 mL 96-well collection plate. In the latter configuration, multiple samples can be prepared for analysis, including a control tube containing a blank buffer that will be processed throughout the entire assay process, in SGF buffer. The samples, placed on the filter plate and the collection plate mounted below, are centrifuged at 1000 × g for 1 minute to filter the samples. For small sample settings, a syringe filter can be used instead of a filter plate to collect approximately 2–4 mL of filtrate in a 15 mL container. After filtration, each filtrate is diluted four-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 runtime of 3 minutes, a wash / rinse volume of 1000 microliters, and a flow rate of 1.25 mL / min. To determine the chlorides that bind to the polymer, complete the following calculations:

number

[0104] The "Simulated Small Intestine Inorganic Buffer" or "SIB" is a test for determining 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 in the SIB assay contained 36 mM NaCl, 20 mM NaH2PO4, and 50 mM 2-(N-morpholino)ethanesulfonic acid (MES) buffered to pH 5.5. SIB buffer contains chloride and phosphate concentrations and pH 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 valid indicator of chloride binding selectivity compared to phosphate binding by polymers. 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. Incubate the mixture at 37°C for 1 hour while stirring in an orbital shaker at 200–300 rpm. Unless otherwise specified, the SIB binding data or binding capacity described herein is determined during this period. After incubation and mixing, pelletize the test sample by centrifuging the polymer-containing tube at 1000 × g for 2 minutes.Take 750 microliters of supernatant and filter it using an 800 microliter, 1 micrometer bore, 96-well glass filter plate mounted on a 2 mL 96-well collection plate; in this configuration, multiple samples to be tested with SIB buffer can be prepared for analysis, including a control tube containing a standard control sevelamer of free amine, a free amine bixalomer, and a blank buffer processed throughout the entire assay process. Centrifuge the samples placed on the filter plate and the collection plate mounted below at 1000 × g for 1 minute and filter the samples. For small sample settings, a syringe filter (0.45 micrometers) can be used instead of the filter plate to collect approximately 2–4 mL of filtrate into a 15 mL vial. After filtering to the collection plate, dilute each filtrate and then measure the chloride or phosphate content. For chloride and phosphate measurements, dilute the filtrate under analysis four-fold with water. Measure the chloride and phosphate content of the filtrate by ion chromatography (IC). The IC method (e.g., Dionex ICS-2100, Thermo Scientific) consists of an AS24A column, 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 chlorides that bind to the polymer, complete the following calculations: The binding capacity expressed as mmol chloride / g polymer =

number

number

[0105] The term "sp 2 allyl carbon" as used herein refers to each of the two sp 2 hybrid carbon atoms contained in the allyl moiety.

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

[0107] "Swelling ratio" or simply "swelling" refers to the amount of water absorbed by a certain amount of polymer divided by the weight of that polymer aliquot. The swelling ratio is expressed as: swelling = (g swollen polymer - g dry polymer) / g dry polymer. The method used to determine the swelling 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 (equipped with a screw cap) of known weight (weight of tube = weight A). b. Add deionized water (10 mL) to the tube containing the polymer. Seal the tube and subject it to a rotary drum at room temperature for 16 hours (overnight). After incubation, centrifuge the tube at 3000 × g for 3 minutes and carefully remove the supernatant by vacuum aspiration. For polymers that form a very loose precipitate, perform an additional centrifugation step. c. After step (b), record the weight of the swollen polymer + tube (weight B). d. Freeze at -40 °C for 30 minutes. Lyophilize for 48 hours. Weigh the dried polymer and test tube (record as weight C). e. Calculate the grams of water absorbed per gram 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, usually the main ion bound by the polymer or an ion whose binding to the polymer is considered to bring about the therapeutic effect of the polymer (e.g., protons and chloride binding leading to net removal of HCl).

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

[0110] "Therapeutically effective amount" means a proton-binding crosslinked amine polymer that is sufficiently effective for such treatment of a disease when administered to a patient for treatment of the disease. The amount constituting a "therapeutically effective amount" varies depending on the polymer, disease severity, and age, weight, etc. of the mammal being treated.

[0111] "To treat" or "to treat" a disease includes (i) preventing the disease, i.e., preventing or reducing the progression of the disease or its clinical symptoms; or (ii) reducing the disease, i.e., inducing the regression of the disease or its clinical symptoms. Prevention of disease includes, for example, prevention.

[0112] The term "triallylamine" refers to the amino portion that has three allyl groups.

[0113] The term "vinyl" is derived from the structural formula RxHyC=CH- * (In the formula, * The part refers to the portion having a bond point to the rest of the molecule, where X and Y are independently 0, 1, or 2 such that X + Y = 2, and R is hydrocarbyl or substituted hydrocarbyl). In one embodiment, the bond point * These are heteroatoms in the remainder of molecules such as nitrogen.

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

[0115] The term "weight percent crosslinking agent" refers to the calculated mass percentage of the polymer sample derived from the crosslinking agent. The weight percent crosslinking agent is calculated using the polymerization supply ratio and is based on the assumption that the monomer and crosslinking agent are completely converted. The mass attributable to the crosslinking agent is equal to the predicted increase in molecular weight of the infinite polymer network after the reaction (for example, 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 here Cationic extraction method: Add approximately 1.0 g of poly(allylamine) polymer to a sealed vial of 15-50 mL volume with 10 mL of 1.2 M HCl. Shake the vial at room temperature for at least 24 hours. Filter the supernatant through a 0.45 micrometer syringe filter, followed by a neutralization column, and then analyze by ion chromatography (IC). The IC method (e.g., Dionex ICS-5000, Thermo Scientific) consists of a CG19 guard column and a CS19 analytical column, a methanesulfonic acid (MSA) eluent generator, an injection volume of 25 microliters, a runtime of approximately 40 minutes, and a flow rate of 0.3 mL / min. The MSA concentration is 2 mM for 10 minutes, then gradient to 70 mM MSA over 10-28 minutes, maintained at 70 mM MSA for 3 minutes, and re-equilibrium at 2 mM MSA for 9 minutes. This method is used to measure allylamine content of 0.25 ppm or higher. If the sample contains less than 0.25 ppm, the extracted supernatant is analyzed by LC-MS as described in the following method.

[0117] Add approximately 1.0 g of polyallylamine polymer to a sealed vial of 15-50 mL volume 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 2-fold with an internal standard (IS) consisting of 10 micrograms / mL of diethylamine in 0.1% heptafluorobutyric acid (HFBA) aqueous solution. The HPLC method (e.g., Agilent 1260 HPLC) uses an Acclaim 120 C18 2.1 × 50 mm column with a particle size of 5 micrometers, an injection volume of 5 microliters, and a mobile phase consisting of A) a 0.1% HFBA aqueous solution and B) a 0.1% HFBA acetonitrile solution, with a gradient of 0%B for 3 minutes, a gradient to 100%B for 3–3.5 minutes, maintenance of 100%B for 3.5–6 minutes, and equilibrium to 0%B up to 10 minutes, and a flow rate of 0.4 mL / min. The mass spectrometer (MS) method (e.g., API 4000 triple quadrupole tandem MS) uses electrospray ionization at a source temperature of approximately 500°C and a voltage of 5000 V, with cation, multiple reaction monitoring mode, yielding allylamine Q1 and Q3 masses of approximately 58.7 and 58.1 amu, respectively, and IS Q1 and Q3 masses of approximately 74.7 and 73.1 amu. The measurement methods using gas source pressure, collision energy, declustering voltage, inlet potential, and outlet potential are optimized.

[0118] quantitative 13 Percentage sp² obtained by 14C solid-state magic angle rotation (MAS) NMR 2 Determination of allyl carbon: quantitative 13 ¹¹¹ Solid State Magic Angle Rotation (MAS) NMR Measurement 1 H and 13 The experiment is performed using a Bruker AVANCE III 800 MHz (18.8T) standard aperture spectrometer with a 4mm zirconia rotor system at a rotational speed of 16kHz, operating at 800.25MHz and 201.24MHz for C, respectively. A single-pulse experiment is performed using a 1.2ps 30-degree excitation pulse with an 8-second relaxation delay optimized for quantitative analysis, an 8.6ms capture time, and the accumulation of approximately 20,000 scans. 100kHz proton separation is performed.13 Applied during C data acquisition. Chemical shifts are compared with TMS standards. sp spectroscopy is performed at 110-150 ppm. 2 Using the integral of the allyl carbon peak and the alkyl carbon peak from 0 to 80 ppm, the following formula is used to determine the percentage sp of poly(allylamine) polymer. 2 Quantify allyl carbon:

number

[0119] When introducing elements of the present invention or its preferred embodiments, singular expressions are intended to mean one or more such elements. The terms “include,” “contain,” and “have” are intended to be inclusive and not exclusive (i.e., other elements may exist in addition to those described).

[0120] quantitative 13 Percent sp² obtained by C solid-state cross-polarization magic angle rotation (CPMAS) NMR 2 Determination of allyl carbon: quantitative 13 ¹¹¹C solid-state cross-polarization magic angle rotation (CPMAS) NMR measurements were performed on poly(allylamine) polymer samples using a Redstone 360 ​​MHz spectrometer with a 7 mm zirconium probe at a rotation speed of 7 kHz. 1 H and 13 The experiment was conducted at 363.331 MHz and 91.369 MHz for C, respectively. The cross-polarization experiment was performed at 90 degrees, calibrated for poly(allylamine) polymer analysis based on a quantitative single-pulse spectrum. 1 The procedure was performed with a 5 ps H excitation pulse, a 2.5 ms contact time, and a 3 s recycle delay. Approximately 3500 spectral captures were accumulated using 12V and 18V proton separation and linewidth expansion at 35 Hz. Sp spectrum captures were performed for 110–150 ppm. 2 Using the integral of the allyl carbon peak and the alkyl carbon peak from 0 to 80 ppm, the following formula is used to determine the percentage sp of poly(allylamine) polymer. 2 Quantify allyl carbon:

Number

[0121] Determination of the carbon-to-nitrogen weight ratio of crosslinked poly(allylamine) polymers by elemental analysis: Elemental analysis is a standard method for measuring the carbon, hydrogen, and nitrogen content of organic substances that belongs to the common technical knowledge of those skilled in the art. Those skilled in the art recognize that all elemental analysis measurement methods will yield the same results within the appropriate measurement accuracy limits. Elemental analysis can be carried out using any elemental analyzer suitable for the measurement of organic carbon, hydrogen, and nitrogen. The following elemental analysis method is provided as an example of how elemental analysis can be carried out.

[0122] Carbon, hydrogen, and nitrogen are determined using a Perkin-Elmer 2400 elemental analyzer. This analyzer uses combustion for the conversion of sample elements to simple gases, namely CO2, H2O, and N2. When entering the analyzer, the sample is burned in a pure oxygen environment. The product gas is separated under steady-state conditions and measured as a function of thermal conductivity. The apparatus is calibrated prior to sample analysis using a National Institute of Standards and Technology (NIST)-traceable organic standard. For example, the standard can have a nitrogen content in the range of about 11 - 45 wt%. System suitability is confirmed by analysis of a NIST-traceable organic standard. The standard must be confirmed to be within ±0.1% of its theoretical value for all three of the elemental carbon, hydrogen, and nitrogen. The crosslinked poly(allylamine) polymer sample for analysis is typically dried in an oven at 60 °C prior to analysis to remove moisture under reduced pressure.

[0123] The carbon-to-nitrogen weight ratio of the poly(allylamine) polymer used in the production of 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: Add 5 mL of acetonitrile to a sealed 10-20 mL vial containing approximately 0.1 g of poly(allylamine) polymer. Add 5 mL of methanol to a second sealed 10-20 mL vial containing approximately 1.5 g of polyallylamine polymer. Seal the vials and permeate at room temperature at 200 RPM for 24 hours. Filter the supernatant through a 0.45 micrometer syringe filter and then detect by flame ionization detection gas chromatography (GC-FID). The GC (e.g., Agilent 6890) method consists of a series of 30 m DB-wax columns, a 0.32 mm inner diameter, and an approximately 4 m DB-1 column, 0.32 mm inner diameter, combined with a constant helium flow of 2.5 mL / min. A 2 microliter injection is performed at a 200°C inlet with a split ratio of 1:10. The oven gradient program consists of maintaining a temperature of 40°C for 5 minutes, followed by a 10°C / min gradient to 180°C, then a 20°C / min gradient to 240°C and a 3-minute maintenance. FID capture is performed at a temperature of 300°C.

[0125] Heat Stability Assay (Stability Assay 2): Weigh 1.0 g of poly(allylamine) polymer into two separate sealed vials of 15-50 mL volume. Determine the starting allylamine content by directly extracting the sample from one vial using cationic extraction. Seal the remaining sample and place it in a convection oven set to 60°C. After 72 hours, remove the sample from the oven, cool it to 4°C, and then extract it using the same method as described for cationic extraction.

[0126] Impurity analysis in release assay: Weigh 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) into three separate sealed vials of 15-50 mL volume. Extract the sample containing 1.0 g of poly(allylamine) polymer from one vial according to cationic extraction to determine the starting allylamine content. Extract the remaining two samples by GC-FID extraction to determine the starting allylmethyl ether and allyl alcohol content.

[0127] Air Stability Assay (Stability Assay 1): Add 4.5 g of poly(allylamine) polymer to a 35 mL HOPE bottle. Seal the bottle and store it in a 60% humidity controlled chamber maintained at 25°C for 7 days. Remove the bottle from the chamber and determine the allylamine content by extracting the polymer sample according to a cationic extraction method.

[0128] Stability evaluation assay when packaged in Mylar foil sachets (Stability Assay 3): Approximately 3 g of poly(allylamine) polymer is added to an approximately 2.5" × 3" sachet, sealed on three sides, consisting of a laminate including a metal foil layer, and the sachet is then heat-sealed. Multiple sachets of poly(allylamine) polymer are prepared and then placed in individual test chambers, where they are controlled for up to 6 months at 25°C and 60% relative humidity and 40°C and 75% relative humidity. At the desired time, the sachets are removed from each test chamber, and the polymer samples are extracted according to a cationic extraction method to determine the allylamine content. [Brief explanation of the drawing]

[0129] [Figure 1A] The concentration of allylamine (AA) present in bevelimer after packaging it in packet materials A, B, and C and storing it at 25°C / 60%RH for 6 weeks was measured (ppm). Unit dosage forms A, B, and C were stored at 25°C / 60%RH for 6 weeks, and the allylamine concentration was measured at T0 (initial) and at weeks 1, 2, 4, and 6. In Figure 1A, unit dosage form A is shown as a square (e.g., the top line at week 6), unit dosage form B as a circle (e.g., the bottom line at week 6), and unit dosage form C as an X (e.g., the middle line at week 6). Unit dosage form A showed an increase in allylamine concentration over 6 weeks, but this was not observed in unit dosage forms B and C.

[0130] [Figure 1B]The allylamine (AA) concentration (ppm) present when bevelimer was packaged in packet materials A, B, and C and stored 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 T0 (initial) and at weeks 1, 2, 4, and 6. In Figure 1B, unit dosage form A is shown as a square (e.g., the top line at week 6), B as a circle (e.g., the middle line at week 6), and C as an X (e.g., the bottom line at week 6). Unit dosage form A showed an increase in allylamine concentration over 6 weeks, but this was not observed in unit dosage forms B and C under the same conditions.

[0131] [Figure 2] Allylamine (AA) concentrations (ppm) in 1.5g, 3.0g, and 4.5g dosage forms over 3 months at 25°C / 60% RH. The 1.5g, 3.0g, and 4.5g dosage forms were stored at 25°C / 60% RH for 3 months, and allylamine concentrations were measured at T0 (initial) and monthly thereafter. Figure 2 shows the 1.5g dose as a circle (e.g., the top line at 3 months), the 3.0g dose as a square (e.g., the middle line at 3 months), and the 4.5g dose as a triangle (e.g., the bottom line at 3 months). The 1.5g, 3.0g, and 4.5g dosage forms show the increase in AA concentration over time.

[0132] [Figure 3] Allylamine (AA) concentrations (ppm) in 1.5g, 3.0g, and 4.5g dosage forms over 3 months at 40°C / 75% RH. The 1.5g, 3.0g, and 4.5g dosage forms were stored at 40°C / 75% RH for 3 months, and allylamine concentrations were measured at T0 (initial) and monthly thereafter. In Figure 3, 1.5g is represented by a circle (e.g., the top line at month 3), 3.0g by a square (e.g., the middle line at month 3), and 4.5g by a triangle (e.g., the bottom line at month 3). The 1.5g, 3.0g, and 4.5g dosage forms show the increase in AA concentration over time.

[0133] [Figure 4]Allylamine (AA) concentrations (ppm) in 1.5g units containing oxygen scavenger over 6 months at 25°C / 60%RH and 40°C / 75%RH. Allylamine concentrations in the unit dosage form were measured at T0 and at various intervals thereafter. In Figure 4, the 1.5g unit dosage form at 25°C / 60%RH is indicated by an "X" (e.g., the top line at 2 months), and the 1.5g unit dosage form at 40°C / 75%RH is indicated by a triangle (e.g., the bottom line at 2 months). The unit dosage form shows that the AA concentration remained nearly constant over 6 months.

[0134] [Figure 5] Allylamine (AA) concentrations (ppm) in 1.5 g units over 6 months in air, 8% oxygen and 92% nitrogen, and 99+% nitrogen at 25°C / 60% RT. Allylamine concentrations in the unit dosage form were measured at T0 and at various intervals thereafter. In Figure 5, the 1.5 g unit dosage form in air is indicated by an "X" (e.g., the top line for 6 months), the 1.5 g unit dosage form in 8% oxygen and 92% nitrogen is indicated by a triangle (e.g., the middle line for 6 months), and the 1.5 g unit dosage form in 99+% nitrogen is indicated by a circle (e.g., the bottom line for 6 months). The unit dosage form indicates that the AA concentration remained approximately constant over 6 months.

[0135] [Figure 6] Allylamine (AA) concentrations (ppm) in 1.5 g units over 6 months in air, 8% oxygen and 92% nitrogen, and 99+% nitrogen at 40°C / 75% RT. Allylamine concentrations in the unit dosage form were measured at T0 and at various intervals thereafter. In Figure 6, the 1.5 g unit dosage form in air is indicated by an "X" (e.g., the top line for 6 months), the 1.5 g unit dosage form in 8% oxygen and 92% nitrogen is indicated by a triangle (e.g., the middle line for 6 months), and the 1.5 g unit dosage form in 99+% nitrogen is indicated by a circle (e.g., the bottom line for 6 months). The unit dosage form indicates that the AA concentration remained approximately constant over 6 months. [Modes for carrying out the invention]

[0136] Embodiment The present invention includes the observation that, during the synthesis of crosslinked poly(allylamine) polymers such as bevelimmers, unincorporated 2-propene-1-ylamine monomers and / or partially incorporated 1,3-bis(allylamino)propane monomer residues can serve as raw materials for allylamine impurities (i.e., allylamine and derivatives such as allyl alkyl ethers and allyl alcohols) in the poly(allylamine) product. These monomers may exist as salts. While not intended to be theoretically bound, it is conceivable that residual unincorporated 2-propene-1-ylamine monomers and / or partially incorporated 1,3-bis(allylamino)propane monomer residues present in crosslinked poly(allylamine) polymers such as bevelimmers may react with oxygen after the polymer has been manufactured, thereby producing allylamine impurities (e.g., H2C=CHCH2NH2). For example, the bevelimer polymer referred to 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 the final product administered to patients, for example, due to potential safety concerns.

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

[0138] One approach disclosed herein is the production of crosslinked poly(allylamine) polymers, such as bevelimmers, that contain little to no unincorporated 2-propene-1-ylamine monomers or salts thereof and / or partially incorporated 1,3-bis(allylamino)propane monomer residues or salts thereof. Such reductions in the amount of unincorporated and / or partially incorporated monomers can reduce the amount of allylamine impurities present in the final product. Therefore, disclosed herein is, for example, sp(sp) present in the product. 2Disclosed herein is a method for producing a crosslinked poly(allylamine) polymer (e.g., beveler) in which the levels of such unincorporated and / or partially incorporated monomers are reduced by measurement with reference to carbon levels. Also disclosed herein is sp present in the product, for example. 2 The cross-linked poly(allylamine) polymer (e.g., bevelimmer) is characterized by reduced levels of such unincorporated and / or partially incorporated monomers, measured by reference to carbon levels. Such products have been shown to possess 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, e.g., bevelimmers, in a manner that reduces exposure to oxygen. Approaches used in packaging to mitigate concerns regarding the levels of impurities, such as allylamine impurities (e.g., H2C=CHCH2NH2), can be used in combination with any crosslinked poly(allylamine) polymers, e.g., bevelimmers disclosed herein or known from prior art.

[0140] In some aspects of the present invention, the cross-linked poly(allylamine) polymers, particularly bevelimers, disclosed herein may be used therapeutically. In some embodiments, the cross-linked poly(allylamine) polymers may be used, for example, to bind HCl from the gastrointestinal tract of animals, including humans, by administration of a therapeutically effective amount (i.e., an effective dose) of the cross-linked poly(allylamine) polymer to achieve a therapeutic or preventive benefit.

[0141] Methods for treating and medical uses of the cross-linked poly(allylamine) polymers, particularly bevelimers, disclosed herein are incorporated herein by reference in WO2014 / 197725A1, WO2016 / 094685A1, WO2017 / 193050A1, WO2017 / 193064A1, WO2017 / 193024A1, WO2019 / 090176A1, WO2019 / 090177A1, WO2019 / 236639A1, WO2019 / 236636A1 and WO2019 / 236124A1.

[0142] In some aspects of the present invention, the crosslinked poly(allylamine) polymers, particularly bevelimers, disclosed herein are intended for use in any of the treatment methods 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] In one aspect of the present invention, a crosslinked poly(allylamine) polymer may be produced in the following steps: (First) a co-polymerization and crosslinking step (sometimes referred to as the "first crosslinking step" or more simply as the "first step") and, optionally, a (Second) post-polymerization crosslinking step (sometimes referred to as the "second crosslinking step" or more simply as the "second step"). In the first step, the crosslinking is preferably a carbon-to-carbon volume-saving, i.e., free amine-saving, crosslinking. In the second step, the crosslinking is amine-consuming and is directed toward adjusting selectivity for the target species. Based on the desired volume, the CN weight ratio is preferably optimized to maximize amine functional groups for target species binding while still maintaining a controlled particle size of spherical polymer particles that ensure non-absorbable and acceptable mouthfeel that is stable under Gl conditions. It should be noted that the terms "first" and "second" are used simply to specify the relative order between these two steps, and other steps may be intended as part of the process before, after, or between the "first step" and the "second step".

[0144] In the first step, 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof are simultaneously polymerized and crosslinked in a heterogeneous reaction mixture containing 2-propene-1-ylamine or a salt thereof, 1,3-bis(allylamino)propane or a salt thereof, a radical initiator, water, and an organic solvent, forming a polymer network that is crosslinked via the carbon backbone. Advantageously, each crosslinking reaction in this step forms a carbon-carbon bond (the opposite of substitution reactions where carbon-heteroatom bonds are formed during crosslinking), and the amine functional groups of 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof are not crosslinked and are preserved in the final polymer (i.e., primary amines of 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof remain primary, secondary amines remain secondary, and tertiary amines remain tertiary). Next, the obtained poly(allylamine) polymer can be further crosslinked with l,2-dichloroethane in a second step.

[0145] As previously shown, unincorporated 2-propene-1-ylamine or salts thereof (i.e., 2-propene-1-ylamine or salts thereof that are not covalently incorporated into the polymer) and partially incorporated 1,3-bis(allylamino)propane or salt residues thereof can be sources of allylamine impurities (i.e., allylamine and its derivatives such as allyl alkyl ethers and allyl alcohols) in the poly(allylamine) product. In one embodiment of the present invention, process parameters can be controlled to limit the amount of allyl impurities released by the crosslinked poly(allylamine) polymer in the production state (i.e., at the completion of the second step, sometimes referred to here as “release time”) and / or (ii) released from the crosslinked poly(allylamine) polymer as a function of storage and time.

[0146] Generally, cross-linked poly(allylamine) polymers preferably contain less than 20 ppm of allylamine in their state of manufacture. For example, in one embodiment, the cross-linked poly(allylamine) polymer contains less than 15 ppm of allylamine in its state of manufacture. As a further example, in one such embodiment, the cross-linked poly(allylamine) polymer contains less than 12.5 ppm of allylamine in its state of manufacture. As a further example, in one such embodiment, the cross-linked poly(allylamine) polymer contains less than 10 ppm of allylamine in its state of manufacture. As a further example, in one such embodiment, the cross-linked poly(allylamine) polymer contains less than 7.5 ppm of allylamine in its state of manufacture. As a further example, in one such embodiment, the cross-linked poly(allylamine) polymer contains less than 5 ppm of allylamine in its state of manufacture. As a further example, in one such embodiment, the cross-linked poly(allylamine) polymer contains less than 4 ppm of allylamine in its state of manufacture. As a further example, in one such embodiment, the cross-linked poly(allylamine) polymer contains less than 3 ppm of allylamine in its state of manufacture. As a further example, in one such embodiment, the crosslinked poly(allylamine) polymer contains less than 2 ppm of allylamine in its state of manufacture. As a further example, in one such embodiment, the crosslinked poly(allylamine) polymer contains less than 1 ppm of allylamine in its state of manufacture. As a further example, in one such embodiment, the crosslinked poly(allylamine) polymer contains less than 500 ppb of allylamine in its state of manufacture. As a further example, in one such embodiment, the crosslinked poly(allylamine) polymer contains less than 100 ppb of allylamine in its state of manufacture. As a further example, in one such embodiment, the crosslinked poly(allylamine) polymer contains less than 50 ppb of allylamine in its state of manufacture. As a further example, in one such embodiment, the crosslinked poly(allylamine) polymer contains less than 1 ppb of allylamine in its state of manufacture.As a further example, in one such embodiment, the amount of allylamine in the crosslinked poly(allylamine) polymer is, if any, below the detection limit of allylamine in the state of manufacture. In each such exemplary embodiment described in this paragraph, the allylamine content may be determined by impurity analysis in a release assay, followed by cationic extraction.

[0147] In one embodiment, the cross-linked poly(allylamine) polymer contains less than 20 ppm of allylamine after being stored in a sealed enclosure at 25°C for 3 months after production. In another embodiment, the cross-linked poly(allylamine) polymer contains less than 20 ppm of allylamine after being stored in a sealed enclosure at 25°C for 6 months after production. In yet another embodiment, the cross-linked poly(allylamine) polymer contains less than 20 ppm of allylamine after being stored in a sealed enclosure at 25°C for 9 months after production. In yet another embodiment, the cross-linked poly(allylamine) polymer contains less than 20 ppm of allylamine after being stored in a sealed enclosure at 25°C for 12 months after production. In yet another embodiment, the allylamine content of the cross-linked poly(allylamine) polymer increases by less than 20 ppm after being stored in a sealed enclosure at 25°C for 3 months. In one embodiment, the allylamine content of a cross-linked poly(allylamine) polymer increases by less than 20 ppm after storage in a sealed enclosure at 25°C for 6 months. In another embodiment, the allylamine content of a cross-linked poly(allylamine) polymer increases by less than 20 ppm after storage in a sealed enclosure at 25°C for 9 months. In yet another embodiment, the allylamine content of a cross-linked poly(allylamine) polymer increases by less than 20 ppm after storage in a sealed enclosure at 25°C for 12 months. In each of these exemplary embodiments described in this paragraph, the allylamine content can be determined by cationic extraction.

[0148] To facilitate simultaneous polymerization and crosslinking reactions, 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof are preferably protonated in the reaction mixture. In one embodiment, therefore, 2-propene-1-ylamine or a salt thereof and / or 1,3-bis(allylamino)propane or a salt thereof are introduced into the reaction mixture as their respective salts (e.g., in the form of hydrochloric acid, phosphoric acid, sulfuric acid, or hydrobromide). Alternatively, 2-propene-1-ylamine or a salt thereof and / or 1,3-bis(allylamino)propane or a salt thereof may be introduced into the reaction mixture in free amine form, and an acid may be added separately to the reaction mixture. For example, the acid may be an acid, phosphoric acid, or hydrochloric acid (HCl). As a further example, the acid is HCl. In either embodiment, the reaction mixture contains enough acid to maintain 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof in the aqueous phase. Typically, the reaction mixture contains at least 0.5 equivalents of acid per allylamine equivalent (regardless of which acid was introduced as an acid salt of 2-propene-1-ylamine or a salt thereof and / or 1,3-bis(allylamino)propane or a salt thereof, or whether the acid was added separately to the reaction mixture). In one embodiment, the reaction mixture contains at least 0.75 equivalents of acid per allylamine equivalent. In another embodiment, the reaction mixture contains at least 1 equivalent of acid per allylamine equivalent.

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

[0150] The simultaneous polymerization and crosslinking reaction mixture comprises a radical polymerization initiator in addition to 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof. The initiator can be selected from any of a broad range of initiators, including cationic and radical polymerization initiators. Examples of polymerization initiators for simultaneous polymerization and crosslinking reactions include peroxy and azo-free radical initiators, such as azodiisobutyronitrile, azodiisovaleronitrile, dimethylazodiisobutyrate, 2,2'-azobis(isobutyronitrile), 2,2'-azobis(N,N'-dimethyl-enisobutylamidine) dihydrochloride, and 2,2'-azobis(2-methylpropionamidine) disalt. This includes salts, 2,2'-azobis(2-amidinopropane) dihydrochloride, 2,2'-azobis(N,N'-dimethylene isobutylamidine), 1,1'-azobis(l-cyclohexanecarbonitrate), 4,4'-azobis(4-cyanopentanoic acid), 2,2'-azobis(isobutylamide) dihydrate, 2,2'-azobis(2-methylpropane), 2,2'-azobis(2-methylbutyronitrile), VAZO 67, cyanopentanoic acid, peroxypivalates, dodecylbenzene peroxide, benzoyl peroxide, di-t-butyl hydroperoxide, t-butyl peracetate, acetyl peroxide, dicumyl peroxide, cumyl hydroperoxide, and 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 amounts of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in the reaction mixture affects the characteristics of the resulting polymer. For example, the amount of partially incorporated 1,3-bis(allylamino)propane or its salt tends to increase with increasing allyl equivalent to initiator equivalent ratio in the reaction mixture. Typically, and therefore, the allyl equivalent to initiator equivalent ratio of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt combined introduced into the reaction mixture ranges from about 6:1 to about 70:1, respectively. For example, in one such embodiment, the allyl equivalent to initiator equivalent ratio of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt combined introduced into the reaction mixture is about 7:1 to about 60:1, respectively. As a further example, in one such embodiment, the ratio of allyl equivalents to initiator equivalents of 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof combined in the reaction mixture is about 8:1 to about 50:1, respectively. As a further example, in one such embodiment, the ratio of allyl equivalents to initiator equivalents of 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof combined in the reaction mixture is about 10:1 to about 45:1, respectively. As a further example, in one such embodiment, the ratio of allyl equivalents to initiator equivalents of 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof combined in the reaction mixture is about 15:1 to about 40:1, respectively. As a further example, in one such embodiment, the ratio of allyl equivalents to initiator equivalents of the combined 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof introduced into the reaction mixture is approximately 17.5:1 to approximately 35:1, respectively.As a further example, in one such embodiment, the ratio of allyl equivalents to initiator equivalents of 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof combined, introduced into the reaction mixture, is about 20:1 to about 30:1, respectively. As a further example, in one such embodiment, the ratio of allyl equivalents to initiator equivalents of 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof combined, introduced into the reaction mixture, is about 22.5:1 to about 30:1, respectively. As a further example, in one such embodiment, the ratio of allyl equivalents to initiator equivalents of 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof combined, introduced into the reaction mixture, is about 25:1 to about 27.5:1, respectively.

[0152] Experience to date has shown that the combined amounts of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt relative to the amount of water in the reaction mixture also affect the characteristics of the resulting polymer. Typically, and therefore, the weight ratio of the combined amounts of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt relative to the amount of water in the reaction mixture is in the range of about 0.01 to about 3, each. For example, in one embodiment, the weight ratio of the combined amounts of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt relative to the amount of water in the reaction mixture is in the range of about 0.05 to about 2.75, each. As a further example, in one such embodiment, the weight ratio of the combined amounts of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt relative to the amount of water in the reaction mixture is in the range of about 0.07 to about 2.5, each. As a further example, in one such embodiment, the weight ratio of the combined amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in the reaction mixture to the amount of water is in the range of about 0.1 to about 2.25, each. As a further example, in one such embodiment, the weight ratio of the combined amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in the reaction mixture to the amount of water is in the range of about 0.15 to about 2, each. As a further example, in one such embodiment, the weight ratio of the combined amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in the reaction mixture to the amount of water is in the range of about 0.2 to about 1.75, each. As a further example, in one such embodiment, the weight ratio of the combined amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in the reaction mixture to the amount of water is in the range of about 0.25 to about 1.5, each.As a further example, in one such embodiment, the weight ratio of the combined amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in the reaction mixture to the amount of water is in the range of about 0.25 to about 1.25, each. As a further example, in one such embodiment, the weight ratio of the combined amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in the reaction mixture to the amount of water is in the range of about 0.3 to about 1, each. As a further example, in one such embodiment, the weight ratio of the combined amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in the reaction mixture to the amount of water is in the range of about 0.35 to about 0.75, each. As a further example, in one such embodiment, the weight ratio of the combined amount of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt in the reaction mixture to the amount of water is in the range of about 0.4 to about 0.5, each. In each of the exemplary embodiments of this paragraph, 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof are assumed to be their respective free amine forms for the purposes of weight ratio calculations.

[0153] Experience to date has further demonstrated that the ratio of allyl equivalents to water equivalents in the reaction mixture influences the characteristics of the resulting polymer. Typically, and therefore, the combined ratio of allyl equivalents to water equivalents of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt introduced into the reaction mixture is in the range of about 0.01:1 to about 1:1, respectively. For example, in one such embodiment, the combined ratio of allyl equivalents to water equivalents of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt introduced into the reaction mixture is about 0.015:1 to about 0.75:1, respectively. As a further example, in one such embodiment, the ratio of allyl equivalents to water equivalents of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt combined into the reaction mixture is about 0.02:1 to about 0.5:1, respectively. As a further example, in one such embodiment, the ratio of allyl equivalents to water equivalents of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt combined into the reaction mixture is about 0.03:1 to about 0.4:1, respectively. As a further example, in one such embodiment, the ratio of allyl equivalents to water equivalents of 2-propene-1-ylamine or its salt and 1,3-bis(allylamino)propane or its salt combined into the reaction mixture is about 0.04:1 to about 0.3:1, respectively. As a further example, in one such embodiment, the ratio of allyl equivalents to water equivalents of 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof introduced into the reaction mixture is about 0.05:1 to about 0.25:1, respectively. As a further example, in one such embodiment, the ratio of allyl equivalents to water equivalents of 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof introduced into the reaction mixture is about 0.06:1 to about 0.2:1, respectively.As a further example, in one such embodiment, the ratio of allyl equivalents to water equivalents of 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof introduced into the reaction mixture is about 0.07:1 to about 0.175:1, respectively. As a further example, in one such embodiment, the ratio of allyl equivalents to water equivalents of 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof introduced into the reaction mixture is about 0.08:1 to about 0.15:1, respectively.

[0154] To produce polymer beads rather than gels, the reaction mixture for the co-polymerization and crosslinking steps is preferably a heterogeneous reaction mixture comprising a surfactant, water, and an organic solvent system (in addition to 2-propene-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, with a diameter that can be controlled to a range of 3 to 1000 micrometers, preferably 10 to 500 micrometers, and in some embodiments, 40 to 180 micrometers.

[0155] Generally, surfactants included in reaction mixtures for simultaneous polymerization and crosslinking steps may 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 sulfosuccinate, branched dodecylbenzenesulfonic acid, linear dodecylbenzenesulfonic acid, sodium branched alkylbenzenesulfonate, sodium branched dodecylbenzenesulfonate, sodium alphaolefin sulfonate, sodium linear alkylbenzenesulfonate, isopropylamine branched alkylbenzenesulfonate, and sodium lauryl sulfate. For example, the surfactant is branched dodecylbenzenesulfonic acid.

[0156] The organic solvent system included in the simultaneous polymerization and crosslinking reaction mixture may be any of the broad range of water-immiscible organic solvents that can be used to disperse the aqueous phase. Examples of organic solvent systems may include hexane, cyclohexane, heptane, octane, decane, petroleum ether, liquid paraffin, chlorobenzene, toluene, xylene, ethyl acetate, propyl acetate, and isopropyl acetate, or combinations of two or more of these. For example, the organic solvent system may include heptane.

[0157] The simultaneous polymerization and crosslinking reaction mixture contains any of the broad range of acids. For example, in one embodiment, the simultaneous polymerization and crosslinking reaction mixture contains 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 one embodiment, the simultaneous polymerization and crosslinking reaction mixture contains an acid selected from the group consisting of hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, methyl phosphoric acid, formic acid, citric acid, and combinations thereof. In one embodiment, the simultaneous polymerization and crosslinking reaction mixture contains an acid selected from the group consisting of hydrochloric acid, phosphoric acid, sulfuric acid, and combinations thereof. In one embodiment, the simultaneous polymerization and crosslinking reaction mixture contains hydrochloric acid. Generally, the simultaneous polymerization and crosslinking reaction mixture contains at least 0.4 equivalents of acid per allylamine equivalent. For example, in one embodiment, the simultaneous polymerization and crosslinking reaction mixture contains at least 0.6 equivalents of acid per allylamine equivalent. As a further example, in one such embodiment, the reaction mixture for the simultaneous polymerization and crosslinking reaction step contains at least 0.8 equivalents of acid per allylamine equivalent. As a further example, in one such embodiment, the reaction mixture for the simultaneous polymerization and crosslinking reaction step contains at least 0.9 equivalents of acid per allylamine equivalent. As a further example, in one such embodiment, the reaction mixture for the simultaneous polymerization and crosslinking reaction step contains at least 0.95 equivalents of acid per allylamine equivalent. As a further example, in one such embodiment, the reaction mixture for the simultaneous polymerization and crosslinking reaction step contains at least 1.0 equivalent of acid per allylamine equivalent. As a further example, in one such embodiment, the reaction mixture for the simultaneous polymerization and crosslinking reaction step contains at least 1 equivalent of acid per allylamine equivalent.

[0158] In each of the embodiments described above, the acid may be introduced into the reaction mixture of the co-polymerization and crosslinking step independently of the addition of 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof to the first step reaction mixture. Alternatively, in each of the embodiments described above, the acid may be introduced into the reaction mixture of the co-polymerization and crosslinking step as a component of 2-propene-1-ylamine or a salt thereof, 1,3-bis(allylamino)propane or a salt thereof, or an acid salt of both 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof.

[0159] The simultaneous polymerization and crosslinking reaction steps can be carried out in a temperature range of approximately 25°C to approximately 85°C. Typically, the simultaneous polymerization and crosslinking reaction steps are carried out in a temperature range of approximately 30°C to approximately 85°C. In one embodiment, the simultaneous polymerization and crosslinking reaction steps are carried out in a temperature range of approximately 35°C to approximately 85°C. In one embodiment, the simultaneous polymerization and crosslinking reaction steps are carried out in a temperature range of approximately 40°C to approximately 85°C. In one embodiment, the simultaneous polymerization and crosslinking reaction steps are carried out in a temperature range of approximately 45°C to approximately 85°C. In one embodiment, the simultaneous polymerization and crosslinking reaction steps are carried out at a temperature of approximately 60 to 80°C. Generally, the temperature may be kept relatively constant during the reaction, or it may be raised or lowered continuously or stepwise.

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

[0161] The aqueous solid content (ASC) in the simultaneous polymerization and crosslinking reaction steps can be about 20 to about 60% by weight. In one embodiment, the aqueous solid content is about 30 to about 50% by weight. In one embodiment, the aqueous solid content is about 30 to about 45% by weight. In one embodiment, the aqueous solid content is about 43% by weight.

[0162] Generally, simultaneous polymerization and crosslinking reaction processes can be lone polymerization, stepwise addition of individual starting materials through a series of reactions, stepwise addition of monomer blocks, or a combination thereof. The reactions can be carried out as batch, semi-batch, or continuous processes.

[0163] In one embodiment, co-polymerization and crosslinking steps produce preformed poly(allylamine) polymer beads having target species binding ability and target swelling ratio. For example, in one such embodiment, the beads have a chloride binding ability of at least 10 mmol / g in pseudo-gastric juice ("SGF") and a swelling ratio in the range of 1 to 10. In one embodiment, the preformed poly(allylamine) polymer beads are characterized by swelling ratios of about 2 and 10, more typically about 2 to about 8, and in one embodiment, about 2 to 3, about 3 to 4, or about 4 to about 6. Furthermore, if the preformed poly(allylamine) polymer beads obtained from the first polymerization step are protonated, the amount of nitrogen-nitrogen crosslinking in the second crosslinking step can be reduced. Thus, in one embodiment, 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 one embodiment, the base may 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 preformed crosslinked amine polymer beads by deprotonation, the beads tend to collapse, and the 1,2-dichloroethane crosslinking agent used in the second crosslinking step cannot access the polymer binding sites unless the collapse of the beads is prevented. One way to prevent the collapse of the crosslinked polymer beads is to use a swelling agent such as water, which swells the beads, thereby allowing the 1,2-dichloroethane second-step crosslinking agent to access the binding sites.

[0164] As previously shown, the monomer 1,3-bis(allylamino)propane or a salt thereof, which is partially incorporated into the poly(allylamine) polymer in the first step, introduces pendant allyl groups (i.e., at least one allyl group that does not participate in the reaction to become a chain atom of the poly(allylamine) polymer main chain, but simply "suspends" from it) into the poly(allylamine) polymer. In other words, the pendant sp is introduced into the cross-linked poly(allylamine) polymer remaining in the poly(allylamine) polymer at the completion of the simultaneous polymerization and cross-linking steps (i.e., the first step).2 By determining the number of allyl carbon atoms, the amount of partially incorporated 1,3-bis(allylamino)propane or its salt can be determined. Generally, sp 2 The number of allyl carbon atoms is preferably low in percentage of the total carbon atoms in the poly(allylamine) polymer. For example, in one embodiment, the poly(allylamine) polymer backbone contains the sp-coated pendants. 2 Allyl carbons account for less than 1.1% of the total number of carbon atoms in the polymer. As a further example, in one embodiment, the poly(allylamine) polymer backbone contains pendant sp 2 Allyl carbons account for less than 1.0% of the total number of carbon atoms in the polymer. As a further example, in one embodiment, the poly(allylamine) polymer backbone contains pendant sp 2 Allyl carbons account for less than 0.9% of the total number of carbon atoms in the polymer. As a further example, in one embodiment, the poly(allylamine) polymer backbone contains pendant sp 2 Allyl carbons account for less than 0.8% of the total number of carbon atoms in the polymer. As a further example, in one embodiment, the poly(allylamine) polymer backbone contains pendant sp 2 Allyl carbons account for less than 0.75% of the total number of carbon atoms in the polymer. As a further example, in one embodiment, the poly(allylamine) polymer backbone contains pendant sp 2 Allyl carbons account for less than 0.7% of the total number of carbon atoms in the polymer. As a further example, in one embodiment, the poly(allylamine) polymer backbone contains pendant sp 2 Allyl carbons account for less than 0.6% of the total number of carbon atoms in the polymer. As a further example, in one embodiment, the poly(allylamine) polymer backbone contains pendant sp 2 Allyl carbons account for less than 0.5% of the total number of carbon atoms in the polymer. As a further example, in one embodiment, the poly(allylamine) polymer backbone contains pendant sp 2 Allyl carbons account for less than 0.4% of the total number of carbon atoms in the polymer. As a further example, in one embodiment, the poly(allylamine) polymer backbone contains pendant sp2 Allyl carbons account for less than 0.3% of the total number of carbon atoms in the polymer. As a further example, in one embodiment, the poly(allylamine) polymer backbone contains pendant sp 2 Allyl carbons account for less than 0.25% of the total number of carbon atoms in the polymer. As a further example, in one embodiment, the poly(allylamine) polymer backbone contains pendant sp 2 Allyl carbons account for less than 0.2% of the total number of carbon atoms in the polymer. As a further example, in one embodiment, the poly(allylamine) polymer backbone contains pendant sp 2 Allyl carbons account for less than 0.1% of the total number of carbon atoms in the polymer. As a further example, in one embodiment, the poly(allylamine) polymer backbone contains pendant sp 2 Allyl carbons account for less than 0.05% of the total number of carbon atoms in the polymer. As a further example, in one embodiment, the poly(allylamine) polymer backbone contains pendant sp 2 Allyl carbon is undetectable in polymer beads. As a further example, in one embodiment, the poly(allylamine) polymer backbone contains the sp of a pendant. 2 Allyl carbon may account for more than 0.3% of the total number of carbon atoms in the polymer, but is less than the above upper limit, for example, 1.0%. In each of the above exemplary embodiments, the poly(allylamine) polymer main chain in the beads contains the sp of the pendant. 2 The percentage of allyl carbon is described in more detail elsewhere in this specification. 1 H and 13 The Bruker AVANCE III 800MHz (18.8T) standard aperture spectrometer was used to quantitatively measure C at 800.25MHz and 201.24MHz respectively, using a 4mm zirconia rotor system with a rotational speed of 16kHz. 13 This can be determined by 14C solid-state magic angle rotation (MAS) NMR measurement. In each of the above exemplary embodiments, the pendant sp is attached to the poly(allylamine) polymer backbone in the beads. 2 The percentage of allyl carbon can 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] Generally, sp 2 Preferably, the number of allyl carbon atoms accounts for a low percentage of the total carbon atoms of the crosslinked polymer after polymerization. For example, in one embodiment, the crosslinked polymer main chain of the crosslinked poly(allylamine) polymer contains pendant sp 2 Allyl carbons account for less than 1.0% of the total number of carbon atoms in the polymer. As a further example, in one embodiment, the post-polymerized crosslinked polymer main chain contains pendant sp 2 Allyl carbons account for less than 0.9% of the total number of carbon atoms in the polymer. As a further example, in one embodiment, the post-polymerized crosslinked polymer main chain contains pendant sp 2 Allyl carbons account for less than 0.8% of the total number of carbon atoms in the polymer. As a further example, in one embodiment, the post-polymerized crosslinked polymer main chain contains pendant sp 2 Allyl carbons account for less than 0.75% of the total number of carbon atoms in the polymer. As a further example, in one embodiment, the post-polymerized crosslinked polymer main chain contains pendant sp 2 Allyl carbons account for less than 0.7% of the total number of carbon atoms in the polymer. As a further example, in one embodiment, pendant sp is added to the main chain of the crosslinked polymer after polymerization. 2 Allyl carbons account for less than 0.6% of the total number of carbon atoms in the polymer. As a further example, in one embodiment, pendant sp is added to the main chain of the crosslinked polymer after polymerization. 2 Allyl carbons account for less than 0.5% of the total number of carbon atoms in the polymer. As a further example, in one embodiment, the post-polymerized crosslinked polymer main chain contains pendant sp 2 Allyl carbons account for less than 0.4% of the total number of carbon atoms in the polymer. As a further example, in one embodiment, pendant sp is added to the main chain of the crosslinked polymer after polymerization. 2 Allyl carbons account for less than 0.3% of the total number of carbon atoms in the polymer. As a further example, in one embodiment, the post-polymerized crosslinked polymer main chain contains pendant sp2 Allyl carbons account for less than 0.25% of the total number of carbon atoms in the polymer. As a further example, in one embodiment, the post-polymerized crosslinked polymer main chain contains pendant sp 2 Allyl carbons account for less than 0.2% of the total number of carbon atoms in the polymer. As a further example, in one embodiment, the post-polymerized crosslinked polymer main chain contains pendant sp 2 Allyl carbons account for less than 0.1% of the total number of carbon atoms in the polymer. As a further example, in one embodiment, the post-polymerized crosslinked polymer main chain contains pendant sp 2 Allyl carbons account for less than 0.05% of the total number of carbon atoms in the polymer. As a further example, in one embodiment, pendant sp is added to the main chain of the crosslinked polymer after polymerization. 2 Allyl carbon is undetectable in polymer beads. In each of the above exemplary embodiments, the post-polymerization crosslinked polymer main chain in the beads contains the sp of the pendant. 2 The percentage of allyl carbon is described in more detail elsewhere in this specification. 1 H and 13 The quantitative analysis of C was performed using a Bruker AVANCE III 800MHz (18.8T) standard aperture spectrometer, scanning at 800.25MHz and 201.24MHz respectively, with a 4mm zirconia rotor system rotating at 16kHz. 13 This can be determined by 14C solid-state magic angle rotation (MAS) NMR measurement. In each of the above exemplary embodiments, the post-polymerization crosslinked polymer main chain in the beads contains the sp of the pendant. 2 The percentage of allyl carbon can be determined by any of the methods disclosed herein.

[0167] The resulting post-polymerization crosslinked polymer is a preformed poly(allylamine) polymer sp 3 carbon vs sp 2 sp (sp) higher than carbon ratio 3 carbon vs sp 2 It has a carbon ratio. Therefore, the second crosslinking reaction with 1,2-dichloroethane results in sp in the post-polymerization crosslinked polymer compared to the pre-formed poly(allylamine) polymer. 3 Increase the amount of carbon, sp2 The amount of carbon remains unchanged. For example, in certain embodiments where the preformed poly(allylamine) polymer is significantly cross-linked in the second cross-linking step, sp 3 The gradual increase in carbon is sp 2 Sufficient to worsen the signal-to-noise ratio of carbon, thereby reducing the measurement sensitivity. In certain embodiments, therefore, in the post-polymerization cross-linked polymer obtained by NMR, sp 2 Carbon and sp 3 Rather than a direct measurement of the amount of carbon, the degree of sp 3 Carbon (and if present, sp 2 Carbon) added to the polymer during the second cross-linking step is determined, and then the total ratio of sp 2 And sp 3 Carbon in the preformed poly(allylamine) polymer is calculated. Examples are shown in Tables 10 and 11 below, and sp 2 The percentage of carbon was determined experimentally for both the preformed poly(allylamine) polymer and the corresponding cross-linked poly(allylamine) polymer. sp 2 For those where carbon is quantitative in the preformed cross-linked poly(allylamine) polymer, the average ratio of the percentage of sp 2 Carbon in the cross-linked poly(allylamine) polymer to the corresponding preformed poly(allylamine) polymer was about 0.9. This coefficient was applied, where applicable, throughout Part 2 of Table 11 to calculate the percentage of sp 2 Carbon included in an example of the cross-linked poly(allylamine) polymer in Table 11. 2 To calculate the percentage of carbon, Table 11, Part 2 was followed and applied when applicable.

[0168] In these embodiments, the cross-linking agent for the step 2 cross-linking reaction is 1,2-dichloroethane (see Table B).

Table 3

[0169] In one embodiment, a preformed poly(allylamine) polymer formed by co-polymerization and crosslinking is further crosslinked in a second crosslinking step in a reaction mixture comprising 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 one such embodiment, for example, the solvent-to-preformed poly(allylamine) polymer ratio 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 one such embodiment, the solvent-to-preformed poly(allylamine) polymer ratio in the dispersion solvent system in the reaction mixture is at least 3:1 (milliliters of solvent: grams of preformed poly(allylamine) polymer). As a further example, in one such embodiment, the solvent-to-preformed poly(allylamine) polymer ratio in the dispersed solvent system of the reaction mixture is at least 4:1 (milliliters of solvent:grams of preformed poly(allylamine) polymer). As a further example, in one such embodiment, the solvent-to-preformed poly(allylamine) polymer ratio in the dispersed solvent system of the reaction mixture is at least 5:1 (milliliters of solvent:grams of preformed poly(allylamine) polymer). As a further example, in one such embodiment, the solvent-to-preformed poly(allylamine) polymer ratio in the dispersed solvent system of the reaction mixture is at least 7.5:1 (milliliters of solvent:grams of preformed poly(allylamine) polymer). As a further example, in one such embodiment, the solvent-to-preformed poly(allylamine) polymer ratio in the dispersed solvent system of the reaction mixture is at least 10:1 (milliliters of solvent:grams of preformed poly(allylamine) polymer). As a further example, in one such embodiment, the solvent-to-preformed poly(allylamine) polymer ratio in the dispersed solvent system of the reaction mixture is at least 20:1 (milliliters of solvent:grams of preformed poly(allylamine) polymer).In each of the embodiments, the dispersion solvent system may comprise a combination of (i) an inert solvent (for the preformed poly(allylamine) polymer), such as one of the nonpolar solvents previously identified in relation to 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 embodiments, the dispersion solvent system may comprise 1,2-dichloroethane (DCE) exclusively as the solvent and not the inert solvent, and thus serve a dual purpose as both a solvent (dispersant) and a crosslinking agent. As a further alternative, in each of the embodiments, the dispersion solvent system may comprise stock 1,2-dichloroethane (DCE) exclusively as the solvent and not the inert solvent, and thus serve a dual purpose as both a solvent (dispersant) and a crosslinking agent.

[0170] As described above, in one embodiment, the 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 having the ability to swell 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 is 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 preferable that the weight ratio of swelling agent to preformed polymer in the second crosslinking step reaction mixture is less than 4:1. As a further example, in one embodiment, the weight ratio of the swelling agent to the preforming polymer in the second crosslinking step reaction mixture is less than 3:1. As a further example, in one embodiment, the weight ratio of the swelling agent to the preforming polymer in the second crosslinking step reaction mixture is less than 2:1. As a further example, in one embodiment, the weight ratio of the swelling agent to the preforming polymer in the second crosslinking step reaction mixture is less than 1:1. As a further example, in one embodiment, the weight ratio of the swelling agent to the preforming polymer in the second crosslinking step reaction mixture is less than 0.5:1. As a further example, in one embodiment, the weight ratio of the swelling agent to the preforming polymer in the second crosslinking step reaction mixture is less than 0.4:1. As a further example, in one embodiment, the weight ratio of the swelling agent to the preforming polymer in the reaction mixture is less than 0.3:1. In general, however, the weight ratio of the swelling agent to the preforming polymer in the second crosslinking step reaction mixture is typically at least 0.05:1 each.

[0171] The second crosslinking process can be carried out in a temperature range of approximately 25°C to approximately 85°C. Typically, the second crosslinking process is carried out in a temperature range of approximately 35°C to approximately 80°C. In one embodiment, the second crosslinking process is carried out in a temperature range of approximately 45°C to approximately 80°C. In one embodiment, the second crosslinking process is carried out in a temperature range of approximately 55°C to approximately 75°C. In one embodiment, the second crosslinking process is carried out in a temperature range of approximately 60°C to approximately 75°C. In one embodiment, the second crosslinking process is carried out in a temperature range of approximately 65°C to approximately 75°C. Generally, the temperature may be kept relatively constant during the second crosslinking process, or it may be raised or lowered continuously or in stages.

[0172] The second crosslinking process can be carried out over a period of approximately 2 to 20 hours. Typically, the second crosslinking process is carried out over a period of approximately 4 to 20 hours. In one embodiment, the second crosslinking process is carried out over a period of approximately 5 to 20 hours. In one embodiment, the second crosslinking process is carried out over a period of approximately 6 to 20 hours. In one embodiment, the second crosslinking process is carried out over a period of approximately 8 to 20 hours. In one embodiment, the second crosslinking process is carried out over a period of approximately 10 to 20 hours. In one embodiment, the second crosslinking process is carried out over a period of approximately 12 to 18 hours. In one embodiment, the second crosslinking process is carried out over a period of approximately 14 to 18 hours. In one embodiment, the second crosslinking process is carried out over a period of approximately 15 to 17 hours.

[0173] In one embodiment, 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 before the second crosslinking step, and is combined with a non-protonating swelling agent. Therefore, for example, the amount of non-protonating swelling agent can be selected to fine-tune the subsequent degree of crosslinking, which efficiently forms a template that is then locked via an 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 amine polymer beads, all monomers (i.e., 2-propene-1-ylamine or its salts and 1,3-bis(allylamino)propane or its salts) are protonated and remain in the aqueous phase, avoiding radical transfer reactions that severely limit the polymerization of unprotonated allylamine (and its derivatives). Once the beads are formed by carbon-carbon crosslinking, the beads can then be deprotonated and further crosslinked with 1,2-dichloroethane in the second crosslinking step.

[0175] In one embodiment, the selectivity of chlorides for other competing ions is achieved with highly crosslinked amine polymers. For example, relatively high chloride binding capacity can be achieved by the reaction of preformed poly(allylamine) polymer beads with stock 1,2-dichloroethane in the presence of a swelling agent (water). This "non-dispersive" reaction provides highly selective access of chlorides for competing ions in the SIB assay, while also resulting in macroscopic (and microscopic) aggregated polymer beads. Therefore, it is advantageous to include a solvent (e.g., heptane) in the second crosslinking step to disperse the preformed crosslinked polymer beads in order to avoid inter-bead reactions and resulting aggregation. However, using too much solvent (dispersant) can dilute the reaction solution to the point where the resulting beads are not sufficiently crosslinked for the desired selectivity of chlorides for other competing anions. However, by using a crosslinking agent that also functions as a solvent (dispersant) (i.e., 1,2-dichloroethane), sufficient solvent (dispersant) can be included in the reaction mixture to avoid inter-bead reactions and aggregation without diluting the mixture to the point where the amine-consuming degree of crosslinking is insufficient. For example, in efforts to utilize the dispersive properties of a solvent while maintaining reactivity (to avoid aggregation during the reaction), 1,2-dichloroethane (DCE) is used without a solvent, thus fulfilling a dual role as both a solvent (dispersant) and a crosslinking agent. Interestingly, DCE was found to have superior dispersive properties as a solvent compared to similar reactions with DCP and / or heptane. Furthermore, when the beads were first dispersed in DCE, and then water was added in the second step to swell the beads, almost no aggregation was observed. Aggregation may occur when water is added to the preformed poly(allylamine) polymer before dispersing the beads in DCE.

[0176] In each of the embodiments described above, the reaction mixture of the second crosslinking step may contain a wide range of amounts of 1,2-dichloroethane. For example, in one embodiment, 1,2-dichloroethane may be used in a large excess relative to the amount of preformed poly(allylamine) polymer in the reaction mixture. In other words, in such an embodiment, 1,2-dichloroethane is the crosslinking solvent, i.e., the solvent of the reaction mixture and the crosslinking agent of the preformed poly(allylamine) polymer. In such an embodiment, other solvents may, if desired, be included in the dispersion solvent system of the second crosslinking step reaction mixture, but are not required. Alternatively, the preformed poly(allylamine) polymer, the swelling agent and 1,2-dichloroethane may be dispersed in a dispersion solvent system that is miscible with 1,2-dichloroethane and immiscible with the swelling agent. For example, in one embodiment, the swelling agent may be a polar solvent; in one such embodiment, for example, 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 contains a polar solvent, the dispersion solvent system of the second crosslinking step typically contains a nonpolar solvent, such as pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, chloroform, diethyl ether, dichloromethane, dichloroethane, dichloropropane, dichlorobutane, or a combination thereof. In one embodiment, 1,2-dichloroethane and the solvent included in the dispersion solvent system may be the same.

[0177] In crosslinking solvents (e.g., DCE dispersion reactions), it is evident that a large excess of crosslinking agent is present regardless of the amount of crosslinking solvent (e.g., 1,2-dichloroethane (DCE)) used to disperse the beads (for example, 1g:3mL::beads:DCE and 1g:10mL::beads:DCE Yanagi-sha contain a large excess of crosslinking agent, most of which is not consumed during the reaction). Regardless of this, the relative degree of crosslinking, chloride activity, and performance in the SIB assay are relatively unaffected by changes in the reactive crosslinking agent to polymer bead ratio. This is likely because the reaction is limited by the acid-neutralizing ability of the polymer beads rather than the amount of crosslinking agent (e.g., DCE).

[0178] To react more efficiently with 1,2-dichloroethane (DCE), the amine in the preformed polymer beads preferably has a free electron pair (neutral, deprotonated). Since the amine in the free preformed polymer beads reacts with 1,2-dichloroethane (DCE), HCl is produced, the amine is protonated, and therefore the reaction is limited. For this reason, the preformed poly(allylamine) polymer beads preferably start as a free amine in the second crosslinking step. If the preformed poly(allylamine) polymer beads are protonated after the first carbon-carbon crosslinking step, the amine-consuming crosslinking in the second crosslinking step is limited, and therefore the selectivity of the chloride for other desired competing ions is reduced. This is demonstrated by the addition of a known amount of HCl to the preformed poly(allylamine) polymer beads immediately before crosslinking with DCE in the second crosslinking step. When less than 3 mol% of HCl (relative to the amine in the preformed polymer amine beads) is added before crosslinking in the second crosslinking step, the total chloride activity (SGF) and chloride selectivity in the SIB are equivalent to those of beads not treated with HCl in the second crosslinking step. When more than 5 mol% of HCl (relative to the amine in the preformed polymer amine beads) is added before crosslinking in the second crosslinking step, the total chloride activity (SGF) in the SIB increases, the chloride selectivity decreases, and less 1,2-dichloroethane is incorporated.

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

[0180] Using a large excess of 1,2-dichloroethane as a double crosslinking agent / solvent allows for the incorporation of 1,2-dichloroethane alone, resulting in alkyl chloride functional groups on the inherently hydrophobic crosslinked polymer beads, which can increase nonspecific interactions with undesirable solutes other than HCl, which is inherently even more hydrophobic. Washing with ammonium hydroxide solution converts the alkyl chlorides to hydrophilic alkylamine functional groups, minimizing nonspecific interactions with undesirable solutes. Other modifications that produce more hydrophilic groups than alkyl chlorides, such as -OH, are suitable for quenching crosslinking agents / solvents incorporated alone.

[0181] As described above, in one embodiment, a swelling agent for the preformed poly(allylamine) polymer may be included in the reaction mixture of the second crosslinking step together with 1,2-dichloroethane in the second crosslinking step. 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 having the ability to swell 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 is water. Furthermore, the amount of swelling agent included in the reaction mixture of the second crosslinking step is typically less than the absorption capacity of the preformed poly(allylamine) polymer for the swelling agent. For example, it is generally preferable that the weight ratio of swelling agent to preformed polymer in the reaction mixture of the second crosslinking step is less than 4:1. As a further example, in one embodiment, the weight ratio of the swelling agent to the preforming polymer in the second crosslinking reaction mixture is less than 3:1. As a further example, in one embodiment, the weight ratio of the swelling agent to the preforming polymer in the second crosslinking reaction mixture is less than 2:1. As a further example, in one embodiment, the weight ratio of the swelling agent to the preforming polymer in the second crosslinking reaction mixture is less than 1:1. As a further example, in one embodiment, the weight ratio of the swelling agent to the preforming polymer in the second crosslinking reaction mixture is less than 0.5:1. As a further example, in one embodiment, the weight ratio of the swelling agent to the preforming polymer in the second crosslinking reaction mixture is less than 0.4:1. As a further example, in one embodiment, the weight ratio of the swelling agent to the preforming polymer in the second crosslinking reaction mixture is less than 0.3:1. In general, however, the weight ratio of the swelling agent to the preforming polymer in the second crosslinking reaction mixture is typically at least 0.05:1 each.

[0182] When the swelling agent is water, the weight ratio of water to preformed poly(allylamine) polymer in the second crosslinking reaction mixture is typically less than about 4:1 (water to polymer). For example, in one such embodiment, the second crosslinking reaction mixture contains water as a swelling agent, and the weight ratio of water to preformed poly(allylamine) polymer in the second crosslinking reaction mixture is typically less than about 3.5:1. As a further example, in one such embodiment, the second crosslinking reaction mixture contains water as a swelling agent, and the weight ratio of water to preformed poly(allylamine) polymer in the second crosslinking reaction mixture is typically less than about 3:1. As a further example, in one such embodiment, the second crosslinking reaction mixture contains water as a swelling agent, and the weight ratio of water to preformed poly(allylamine) polymer in the second crosslinking reaction mixture is typically less than about 2.5:1. As a further example, in one such embodiment, the second crosslinking reaction mixture contains water as a swelling agent, and the weight ratio of water to preformed poly(allylamine) polymer in the second crosslinking reaction mixture is typically less than about 2:1. As a further example, in one such embodiment, the second crosslinking reaction mixture contains water as a swelling agent, and the weight ratio of water to preformed poly(allylamine) polymer in the second crosslinking reaction mixture is typically less than about 1.5:1. As a further example, in one such embodiment, the second crosslinking reaction mixture contains water as a swelling agent, and the weight ratio of water to preformed poly(allylamine) polymer in the second crosslinking reaction mixture is typically less than about 1:1. As a further example, in one such embodiment, the second crosslinking reaction mixture contains water as a swelling agent, and the weight ratio of water to preformed poly(allylamine) polymer in the second crosslinking reaction mixture is typically less than about 0.75:1. As a further example, in one such embodiment, the second crosslinking reaction mixture contains water as a swelling agent, and the weight ratio of water to preformed poly(allylamine) polymer in the second crosslinking reaction mixture is typically less than about 0.5:1. As a further example, in one such embodiment, the second crosslinking reaction mixture contains water as a swelling agent, and the weight ratio of water to preformed poly(allylamine) polymer in the second crosslinking reaction mixture is typically less than about 0.25:1.Generally, however, when water is used as a swelling agent, the weight ratio of water to preformed poly(allylamine) polymer in the second crosslinking reaction mixture is typically at least about 0.15:1 (water to polymer), but is less than the water absorption capacity of the preformed poly(allylamine) polymer. As a further example, in one embodiment, the weight ratio of water to preformed poly(allylamine) polymer in the second crosslinking reaction mixture is typically at least about 0.2:1, but is less than the water absorption capacity of the preformed poly(allylamine) polymer. As a further example, in one embodiment, the weight ratio of water to preformed poly(allylamine) polymer in the second crosslinking reaction mixture is typically at least about 0.25:1, but is less than the water absorption capacity of the preformed poly(allylamine) polymer. As a further example, in one embodiment, the weight ratio of water to preformed poly(allylamine) polymer in the second crosslinking reaction mixture is typically at least about 0.5:1, but is less than the water absorption capacity of the preformed poly(allylamine) polymer. As a further example, in one embodiment, 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 is less than the water absorption capacity of the preformed poly(allylamine) polymer. As a further example, in one embodiment, 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 is less than the water absorption capacity of the preformed poly(allylamine) polymer. As a further example, in one embodiment, 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 is less than the water absorption capacity of the preformed poly(allylamine) polymer. As a further example, in one embodiment, 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 is less than the water absorption capacity of the preformed poly(allylamine) polymer. As a further example, in one embodiment, the weight ratio of water to preformed 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 preformed poly(allylamine) polymer.As a further example, in one embodiment, 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. As a further example, in one embodiment, 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. Therefore, in one embodiment, the weight ratio of water to preformed poly(allylamine) polymer is in the range of about 0.15:1 to about 4:1. As a further example, in one embodiment, the weight ratio of water to preformed poly(allylamine) polymer is in the range of about 0.2:1 to about 3.5:1. As a further example, in one embodiment, the weight ratio of water to preformed poly(allylamine) polymer is in the range of about 0.2:1 to about 3:1.

[0183] The second crosslinking step reaction mixture may contain a wide range of amounts of 1,2-dichloroethane. For example, in one embodiment, 1,2-dichloroethane may be used in a large excess relative to the amount of preformed poly(allylamine) polymer in the second crosslinking step reaction mixture. In other words, in such an embodiment, 1,2-dichloroethane is the crosslinking solvent, i.e., both the solvent of the second crosslinking step reaction mixture and the crosslinking agent for the preformed poly(allylamine) polymer. In such an embodiment, other solvents may 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 may be dispersed in a dispersion solvent system that is miscible with 1,2-dichloroethane and immiscible with the swelling agent. For example, in one embodiment, the swelling agent may be a polar solvent; in one such embodiment, for example, the swelling agent may include 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 contains 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 one embodiment, the crosslinking agent and the solvent may be the same; that is, the solvent is 1,2-dichloroethane.

[0184] In embodiments where the second crosslinking reaction mixture contains a swelling agent, it is sometimes preferable to combine the preformed poly(allylamine) polymer with a solvent (sometimes referred to as a dispersant) before combining the preformed poly(allylamine) polymer with the swelling agent in the second crosslinking reaction mixture. In some embodiments, the resulting crosslinked polymer tends to aggregate less 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. Therefore, in some embodiments, less than 25% of the particles in a representative sample of the post-polymerized crosslinked amine particle population aggregate. For example, in some embodiments, less than 20% of the particles in a representative sample of the post-polymerized crosslinked amine particle population aggregate. As a further example, in some embodiments, less than 15% of the particles in a representative sample of the post-polymerized crosslinked amine particle population aggregate. As a further example, in some embodiments, less than 10% of the particles in a representative sample of the post-polymerized crosslinked amine particle population aggregate. As a further example, in one embodiment, less than 5% of the particles in a representative sample of the post-polymerization crosslinked amine particle population aggregate. As a further example, in one embodiment, less than 1% of the particles in a representative sample of the post-polymerization crosslinked amine particle population aggregate. Aggregation can be evaluated using microscopy or other means of measuring particle size distribution. The absence of aggregation is generally defined as separated, free-flowing beads without macroscopic and / or microscopic clumps. The particle size distribution (defined elsewhere) may indicate that aggregation is occurring if, for example, the average size (d(50)) and / or d(90) of the crosslinked poly(allylamine) polymer increases relative to the crosslinked preformed poly(allylamine) polymer beads, as previously described.

[0185] In one embodiment, 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 (sometimes referred to as "one-pot synthesis"). For example, in one such embodiment, a preformed poly(allylamine) polymer is formed in a first step reaction mixture (as described above), and the preformed poly(allylamine) polymer formed in the first step reaction mixture is then crosslinked using 1,2-dichloroethane without isolating it. As a further example, in one such embodiment, the preformed polymer can be separated into a non-polar 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 this reaction mixture. In one such exemplary embodiment, the crosslinking agent and solvent are 1,2-dichloroethane, and the swelling agent is water. In each of the above 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 one exemplary embodiment, a preformed polyamine polymer is crosslinked, for example, under suspension conditions to produce particles of a target particle size and morphology. When a water-immiscible crosslinking agent (e.g., 1,2-dichloroethane (DCE)) is used as a dispersant, high chloride bond selectivity is achieved, for example, as shown in SIB.

[0187] In one embodiment, an amine polymer may be formed and then crosslinked in the same reaction flask and a series of reactions. The crosslinked amine polymer is produced, for example, under suspension conditions to produce particles of a target particle size and shape. In the same reaction flask and without isolation, the water content of the beads can be reduced by the Dean-Stark method or other similar evaporation techniques. The water is adjusted to a target amount so that a second crosslinking reaction can be carried out to produce a final polymer having the desired properties and characteristics.

[0188] In one embodiment, 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 one such embodiment, 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 one such embodiment, the crosslinked poly(allylamine) polymer is treated with ammonium hydroxide. The ammonium hydroxide treatment can be performed immediately after the reaction, during the washing step, or after washing and drying the polymer, in which case the polymer can be treated through a further series of washing steps. In another such embodiment, the crosslinked poly(allylamine) polymer is heated in a conventional or vacuum oven at a temperature above room temperature for a certain period, for example, longer than 36 hours at 60°C. Oven incubation may be performed under an inert atmosphere (e.g., nitrogen or argon) to reduce the possibility of oxidation.

[0189] Cross-linked poly(allylamine) polymer As previously stated, the cross-linked poly(allylamine) polymers with medical applications described herein have the ability to remove HCl.

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

[0191] In one embodiment, the crosslinked poly(allylamine) polymer of the present invention comprises 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 one embodiment, the crosslinked poly(allylamine) polymer of the present invention essentially consists 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 one embodiment, the crosslinked poly(allylamine) polymer of the present invention comprises 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 one embodiment, the crosslinked poly(allylamine) polymer of the present invention is 1,3-propanediamine with 1,2-dichloroethane and 2-propen-1-amine, N 1 ,N 3 -Di-2-propen-1-yl- polymer.

[0195] In one embodiment, the crosslinked poly(allylamine) polymer of the present invention is N with 1,2-dichloroethane and prop-2-ene-1-amine. 1 ,N 3 - It is a bis(prop-2-en-1-yl)propane-1,3-diamine copolymer.

[0196] In one embodiment, the crosslinked poly(allylamine) polymer of the present invention is a residue [ka] The expression includes x, y, and z, where x, y, and z are positive integers.

[0197] In one embodiment, the crosslinked poly(allylamine) polymer of the present invention is [ka] [In the equation, x, y, and z are positive integers.] It contains the residue of .

[0198] In one embodiment, the crosslinked poly(allylamine) polymer of the present invention is given by formula 5a: [ka] [During the ceremony, a = N,N'-diallyl-1,3-diaminopropane or a residue of its salt, b = residue of 2-propene-1-ylamine or a salt thereof, c=1,2-dichloroethane and two 2-propen-1-ylamine residues crosslinked with it m = repeating unit of polymer. Includes a corresponding structure.

[0199] In one embodiment, the crosslinked poly(allylamine) polymer of the present invention is given by formula 5b: [ka] [During the ceremony, a = N,N'-diallyl-1,3-diaminopropane or a residue of its salt, b = residues of 2-propen-1-ylamine or its salt and c = ethylene crosslinking agent, e.g., two 2-propen-1-ylamine residues crosslinked with 1,2-dichloroethane, which is shown as one of many possible crosslinks formed in the polymer. Includes a corresponding structure.

[0200] In one embodiment, 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 one embodiment, the crosslinked poly(allylamine) polymer of the present invention is given by formula 4: [ka] [In the formula, each R is independently hydrogen or ethylene that crosslinks two nitrogen atoms of the crosslinked amine polymer.] [ka] And a, b, c, and m are integers. Includes a corresponding structure.

[0202] In one embodiment, the crosslinked poly(allylamine) polymer of the present invention is [(C3H7N) ~5 (C9H 18 N2) ~2 (C8H 16 N2) ~2 ] n , containing n=∞ residues.

[0203] In one embodiment, the crosslinked poly(allylamine) polymer of the present invention is [ka] It contains the residue of .

[0204] In one embodiment, the crosslinked poly(allylamine) polymer of the present invention is a non-absorbable, free-flowing powder consisting of low-swelling, spherical beads with a diameter of approximately 100 micrometers; each bead is a single crosslinked, high-molecular-weight molecule.

[0205] In one embodiment, the cross-linked poly(allylamine) polymer is a bevelimmer. Generally, cross-linked poly(allylamine) polymers have a preferred particle size range that is (i) large enough to avoid passive or active absorption through GI tubes and (ii) small enough 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 one such embodiment, the cross-linked 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 one such embodiment, the cross-linked 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 one such embodiment, the cross-linked 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 one such embodiment, the cross-linked poly(allylamine) polymer comprises a population of particles having an average particle size (volume distribution) in the range of 10 to 400 microns. As a further example, in one such embodiment, the crosslinked poly(allylamine) polymer comprises a population of particles having an average particle diameter (volume distribution) in the range of 10 to 300 microns. As a further example, in one such embodiment, the crosslinked poly(allylamine) polymer comprises a population of particles having an average particle diameter (volume distribution) in the range of 20 to 250 microns. As a further example, in one such embodiment, the crosslinked poly(allylamine) polymer has a particle diameter range of 30 to 250 microns. As a further example, in one such embodiment, the crosslinked poly(allylamine) polymer has a particle diameter range of 40 to 180 microns. In one embodiment, less than 7% (based on number) of the particles in the population have a diameter of less than 10 microns. For example, in one such embodiment, less than 5% (based on number) of the particles in the population have a diameter of less than 10 microns. As a further example, in one such embodiment, less than 2.5% (based on number) of the particles in the population have a diameter of less than 10 microns. As a further example, in such an embodiment, less than 1% (based on number) of the particles in the group have a diameter of less than 10 microns.In each of the exemplary embodiments described in this paragraph, the particles are preferably in the form of beads.

[0206] To minimize GI side effects in patients, which are often associated with large amounts of polymer gel moving through the GI tube, a low swelling ratio of cross-linked poly(allylamine) polymer is preferred (0.5 to 10 times its own weight in water). For example, in one such embodiment, the cross-linked poly(allylamine) polymer has a swelling ratio of less than 2. As a further example, in one such embodiment, the cross-linked poly(allylamine) polymer has a swelling ratio of less than 1.9. As a further example, in one such embodiment, the cross-linked poly(allylamine) polymer has a swelling ratio of less than 1.8. As a further example, in one such embodiment, the cross-linked poly(allylamine) polymer has a swelling ratio of less than 1.7. As a further example, in one such embodiment, the cross-linked poly(allylamine) polymer has a swelling ratio of less than 1.6. As a further example, in one such embodiment, the cross-linked poly(allylamine) polymer has a swelling ratio of less than 1.5. As a further example, in one such embodiment, the cross-linked poly(allylamine) polymer has a swelling ratio of less than 1.4. As a further example, in one such embodiment, the crosslinked poly(allylamine) polymer has a swelling ratio of less than 1.3. As a further example, in one such embodiment, the crosslinked poly(allylamine) polymer has a swelling ratio of less than 1.2. As a further example, in one such embodiment, the crosslinked poly(allylamine) polymer has a swelling ratio of less than 1. As a further example, in one such embodiment, the crosslinked poly(allylamine) polymer has a swelling ratio of less than 0.9. As a further example, in one such embodiment, the crosslinked poly(allylamine) polymer has a swelling ratio of less than 0.8. As a further example, in one such embodiment, the crosslinked poly(allylamine) polymer has a swelling ratio of less than 0.7. As a further example, in one such embodiment, the crosslinked poly(allylamine) polymer has a swelling ratio of less than 0.6. As a further example, in one such embodiment, the crosslinked poly(allylamine) polymer has a swelling ratio of at least 0.5 and less than 2.As a further example, in one such embodiment, the crosslinked poly(allylamine) polymer has a swelling ratio of about 0.7 to about 1.7.

[0207] Generally, cross-linked poly(allylamine) polymers have a theoretical proton binding capacity of at least about 7.5 mEq / g (determined by SGF assay). For example, in one embodiment, a cross-linked poly(allylamine) polymer has a theoretical proton binding capacity of at least about 8 mEq / g. As a further example, in one embodiment, a cross-linked poly(allylamine) polymer has a theoretical proton binding capacity of at least about 8.5 mEq / g. As a further example, in one embodiment, a cross-linked poly(allylamine) polymer has a theoretical proton binding capacity of at least about 9 mEq / g. As a further example, in one embodiment, a cross-linked poly(allylamine) polymer has a theoretical proton binding capacity of at least about 9.5 mEq / g. As a further example, in one embodiment, a cross-linked poly(allylamine) polymer has a theoretical proton binding capacity of at least about 10 mEq / g. As a further example, in one embodiment, a crosslinked poly(allylamine) polymer has a theoretical proton-binding capacity of at least about 10.5 mEq / g. As a further example, in one embodiment, a 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 not exceeding about 35 mEq / g. For example, in one embodiment, the theoretical proton-binding capacity of a 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 are independent and individual, not their sum.

[0208] Phosphates, bicarbonates, bicarbonate equivalents, bile acids, and fatty acid conjugate bases are anions that can interfere with other conjugate bases of chlorides or strong acids in the stomach and small intestine. Therefore, rapid binding of chlorides to phosphates, bicarbonate equivalents, and preferred binding of bile acids and fatty acids in the small intestine is desirable, and the kinetics and preferred binding can be determined using an SIB assay. Because the transit time through the colon is slower than that of the small intestine (2-3 days), and orally administered cross-linked poly(allylamine) polymers do not encounter colonic conditions until after encountering gastric and small intestinal conditions, the kinetics of chlorides 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 is desirable, for example, for 24 hours and / or 48 hours or longer.

[0209] In one embodiment, the cross-linked poly(allylamine) polymer is characterized by a chloride ion binding capacity of at least 2.5 mEq / g in a pseudo-intestinal inorganic ("SIB") assay. For example, in one such embodiment, the cross-linked poly(allylamine) polymer is characterized by a chloride ion binding capacity of at least 3 mEq / g in a SIB assay. As a further example, in one such embodiment, the cross-linked poly(allylamine) polymer is characterized by a chloride ion binding capacity of at least 3.5 mEq / g in a SIB assay. As a further example, in one such embodiment, the cross-linked poly(allylamine) polymer is characterized by a chloride ion binding capacity of at least 4 mEq / g in a SIB assay. As a further example, in one such embodiment, the cross-linked poly(allylamine) polymer is characterized by a chloride ion binding capacity of at least 4.5 mEq / g in a SIB assay. As a further example, in one such embodiment, the crosslinked poly(allylamine) polymer is characterized by a chloride ion binding capacity of at least 5 mEq / g in the SIB assay. As a further example, in one such embodiment, the crosslinked poly(allylamine) polymer is characterized by a chloride ion binding capacity of at least 5.5 mEq / g in the SIB assay. As a further example, in one such embodiment, the crosslinked poly(allylamine) polymer is characterized by a chloride ion binding capacity of at least 6 mEq / g in the SIB assay. As a further example, in one such embodiment, 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 the SIB assay.

[0210] In one embodiment, the crosslinked poly(allylamine) polymer binds to a considerable amount of chloride relative to the phosphate, as shown, for example, in the SIB assay. For example, in one embodiment, the ratio of bound chloride to bound phosphate in the SIB assay is at least 1:1. As a further example, in one such embodiment, the ratio of bound chloride to bound phosphate in the SIB assay is at least 2:1. As a further example, in one such embodiment, the ratio of bound chloride to bound phosphate in the SIB assay is at least 2.25:1. As a further example, in one such embodiment, the ratio of bound chloride to bound phosphate in the SIB assay is at least 2.5:1. As a further example, in one such embodiment, the ratio of bound chloride to bound phosphate in the SIB assay is at least 2.75:1. As a further example, in one such embodiment, the ratio of bound chloride to bound phosphate in the SIB assay is at least 3:1. As a further example, in one such embodiment, the ratio of bound chloride to bound phosphate in the SIB assay is at least 4:1. As a further example, in one such embodiment, the ratio of bound chloride to bound phosphate in the SIB assay is at least 5:1. As a further example, in one such embodiment, the ratio of bound chloride to bound phosphate in the SIB assay is about 2.1:1 to about 10.8:1.

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

[0212] As a further example, in one such embodiment, the crosslinked poly(allylamine) polymer is characterized by its proton-binding and chloride-binding capabilities after 1 hour in SGF, which are at least 50% of the proton-binding and chloride-binding capabilities of the crosslinked poly(allylamine) polymer after 24 hours in SGF. As a further example, in one such embodiment, the crosslinked poly(allylamine) polymer is characterized by its proton-binding and chloride-binding capabilities after 1 hour in SGF, which are at least 60% of the proton-binding and chloride-binding capabilities of the crosslinked poly(allylamine) polymer after 24 hours in SGF. As a further example, in one such embodiment, the crosslinked poly(allylamine) polymer is characterized by its proton-binding and chloride-binding capabilities after 1 hour in SGF, which are at least 70% of the proton-binding and chloride-binding capabilities of the crosslinked poly(allylamine) polymer after 24 hours in SGF. As a further example, in one such embodiment, the crosslinked poly(allylamine) polymer is characterized by its proton-binding and chloride-binding capabilities after 1 hour in SGF, which are at least 80% of the proton-binding and chloride-binding capabilities of the crosslinked poly(allylamine) polymer after 24 hours in SGF. As a further example, in one such embodiment, the crosslinked poly(allylamine) polymer is characterized by its proton-binding and chloride-binding capabilities after 1 hour in SGF, which are at least 90% of the proton-binding and chloride-binding capabilities of the crosslinked poly(allylamine) polymer after 24 hours in SGF.

[0213] In embodiments in which a cross-linked poly(allylamine) polymer binds chloride ions, it is generally preferred that the cross-linked poly(allylamine) polymer selectively binds to chloride ions compared to other counterions such as bicarbonate equivalent anions, phosphate anions, and conjugated bases of bile acids and fatty acids. In other words, it is generally preferred in these embodiments that the cross-linked 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, and therefore, treatment with a cross-linked poly(allylamine) polymer does not induce or exacerbate hypophosphatemia (i.e., serum phosphorus concentration less than about 2.4 mg / dL), does not significantly increase low-density lipoprotein ("LDL"), or negatively or otherwise affect serum or colonic levels of metabolism-related anions.

[0214] In one embodiment, the carbon-to-nitrogen weight ratio of the crosslinked poly(allylamine) polymer of the present invention may be in the range of about 2:1 to about 6:1. For example, in one such embodiment, the carbon-to-nitrogen weight ratio of the crosslinked poly(allylamine) polymer of the present invention may be in the range of about 2.5:1 to about 5:1. As a further example, in one such embodiment, the carbon-to-nitrogen weight ratio of the crosslinked poly(allylamine) polymer of the present invention may be in the range of about 3:1 to about 4.5:1. As a further example, in one such embodiment, the carbon-to-nitrogen weight ratio of the crosslinked poly(allylamine) polymer of the present invention may be in the range of about 3.25:1 to about 4.25:1. As a further example, in one such embodiment, the carbon-to-nitrogen weight ratio of the crosslinked poly(allylamine) polymer of the present invention may be in the range of about 3.4:1 to about 4:1. As a further example, in one such embodiment, the carbon-to-nitrogen weight ratio of the crosslinked poly(allylamine) polymer of the present invention may be in the range of about 3.5:1 to about 4:1. As a further example, in one such embodiment, the carbon-to-nitrogen weight ratio of the crosslinked poly(allylamine) polymer of the present invention may be in the range of about 3.6:1 to about 3.9:1, respectively. As a further example, in one such embodiment, the carbon-to-nitrogen weight ratio of the crosslinked poly(allylamine) polymer of the present invention may be in the range of about 3.7:1 to about 3.8:1, respectively. In each of the above embodiments, the carbon-to-nitrogen weight ratio may be determined by elemental analysis. For example, the carbon-to-nitrogen weight ratio may be determined by elemental analysis using a Perkin-Elmer 2400 elemental analyzer, which is described in more detail elsewhere in this specification.

[0215] In one embodiment, the crosslinked poly(allylamine) polymer is given by formula 4: [ka] [In the formula, R is independently hydrogen or ethylene that crosslinks two nitrogen atoms of the crosslinked amine polymer, and a, b, c, and m are integers.] It is a cross-linked poly(allylamine) polymer containing the corresponding structure. Typically, m is a large integer representing an elongated polymer network where each polymer bead is considered a single molecule. In other words, when calculating the molecular weight using the volume of the polymer beads and the bulk density of the polymer, m is 3.2 × 10⁻⁶. 8Large enough to exhibit a molecular weight greater than g / mol. In one such embodiment, the ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 1:1 to 9:1. For example, in one such embodiment, the ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 1:1 to 8:1. As a further example, in one such embodiment, the ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 1:1 to 7:1. As a further example, in one such embodiment, the ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 1:1 to 6:1. As a further example, in one such embodiment, the ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 1:1 to 5:1. As a further example, in one such embodiment, the ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 1:1 to 4:1. As a further example, in one such embodiment, the ratio of the sum of a and b to c (i.e., a+b:c) is in the range of approximately 1:1 to 3:1. As a further example, in one such embodiment, the ratio of the sum of a and b to c (i.e., a+b:c) is in the range of approximately 1:1 to 2:1. As a further example, in one such embodiment, the ratio of the sum of a and b to c (i.e., a+b:c) is in the range of approximately 1.5:1 to 4:1. As a further example, in one such embodiment, the ratio of the sum of a and b to c (i.e., a+b:c) is in the range of approximately 1.75:1 to 3:1. For example, in one such embodiment, the ratio of the sum of a and b is 57, c is 24, and m is a large integer representing an elongated polymer network. In each of the embodiments described above, the ratio of the sum of a and b to c (i.e., a+b:c) may be in the range of approximately 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) may be in the range of approximately 2.1:1 to 2.2:1. As a further example, in such embodiments, the ratio of the sum of a and b to c (i.e., a+b:c) may be in the range of approximately 2.2:1 to 2.3:1.As a further example, in such embodiments, the ratio of the sum of a and b to c (i.e., a+b:c) may be in the range of about 2.3:1 to 2.4:1. As a further example, in such embodiments, the ratio of the sum of a and b to c (i.e., a+b:c) may be in the range of about 2.4:1 to 2.5:1. In each of the embodiments, each R may be independently 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 one such embodiment, 50-95% of the R substituents are hydrogen, and 5-50% are ethylene crosslinks. [ka] For example, in one such embodiment, 55-90% of the R substituents are hydrogen and 10-45% are ethylene crosslinks. [ka] As a further example, in one such embodiment, 60-90% of the R substituents are hydrogen and 10-40% are ethylene bridges. [ka] As a further example, in one such embodiment, 70-90% of the R substituents are hydrogen and 10-30% are ethylene crosslinks. As a further example, in one such embodiment, 75-85% of the R substituents are hydrogen and 15-25% are ethylene crosslinks. As a further example, in one such embodiment, 65-75% of the R substituents are hydrogen and 25-35% are ethylene crosslinks. As a further example, in one such embodiment, 55-65% of the R substituents are hydrogen and 35-45% are ethylene crosslinks. In each of these embodiments, it will be apparent to those skilled in the art that the percentage of R substituents that are hydrogen and the percentage of R substituents that are ethylene crosslinks between two nitrogen atoms in the crosslinked amine polymer total 100 mol%. In one embodiment, a, b, c and R are such that the carbon-to-nitrogen weight ratio of the polymer of formula 4 may range from about 2:1 to about 6:1, respectively. For example, in one such embodiment, the carbon-to-nitrogen weight ratio of the polymer of formula 4 may range from about 2.5:1 to about 5:1, respectively. As a further example, in one such embodiment, the carbon-to-nitrogen weight ratio of the polymer of formula 4 may be in the range of about 3:1 to about 4.5:1, respectively. As a further example, in one such embodiment, the carbon-to-nitrogen weight ratio of the polymer of formula 4 may be in the range of about 3.25:1 to about 4.25:1, respectively. As a further example, in one such embodiment, the carbon-to-nitrogen weight ratio of the polymer of formula 4 may be in the range of about 3.4:1 to about 4:1, respectively. As a further example, in one such embodiment, the carbon-to-nitrogen weight ratio of the polymer of formula 4 may be in the range of about 3.5:1 to about 3.9:1, respectively. As a further example, in one such embodiment, the carbon-to-nitrogen weight ratio of the polymer of formula 4 may be in the range of about 3.55:1 to about 3.85:1, respectively. In each of the embodiments described in this paragraph, the polymer of formula 4 is derived from a monomer and a crosslinking agent, each containing less than 5% by weight of oxygen.

[0216] In exemplary embodiments, the crosslinked poly(allylamine) polymer is a crosslinked poly(allylamine) polymer comprising (i) residues of 2-propene-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, where the molar ratio of 2-propene-1-ylamine (or a salt thereof) to 1,3-bis(allylamino)propane (or a salt thereof) is in the range of 60:40 to 95:5, respectively. In other exemplary embodiments, the crosslinked poly(allylamine) polymer is a crosslinked poly(allylamine) polymer comprising (i) residues of 2-propene-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, where the molar ratio of 2-propene-1-ylamine (or a salt thereof) to 1,3-bis(allylamino)propane (or a salt thereof) is in the range of 65:35 to 90:10, respectively. In other exemplary embodiments, the crosslinked poly(allylamine) polymer is a crosslinked poly(allylamine) polymer comprising (i) residues of 2-propene-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, where the molar ratio of 2-propene-1-ylamine (or a salt thereof) to 1,3-bis(allylamino)propane (or a salt thereof) is in the range of 65:35 to 75:25, respectively. For example, in each of the exemplary embodiments described in this paragraph, the residues of 2-propene-1-ylamine or a salt thereof and / or residues of 1,3-bis(allylamino)propane or a salt thereof may be hydrochloride, sulfate, phosphate, hydrobromide, or combinations thereof. As a further example, in each of the exemplary embodiments described in this paragraph, the residue of 2-propene-1-ylamine or a salt thereof and / or the residue of 1,3-bis(allylamino)propane or a salt thereof is a hydrochloride salt residue.

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

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

[0219] In an exemplary embodiment, the crosslinked poly(allylamine) polymer consists of (i) 10-35 mol% of 1,3-bis(allylamino)propane or a salt thereof, (ii) 30-80 mol% of 2-propen-1-ylamine or a salt thereof, and (iii) 10-35 mol% of 1,2-dichloroethane, where (i) mol% of 1,3-bis(allylamino)propane or a salt thereof, (ii) mol% of 2-propen-1-ylamine or a salt thereof, and (iii) mol% of 1,2-dichloroethane total 100 mol%. In another exemplary embodiment, the crosslinked poly(allylamine) polymer consists of (i) 10-35 mol% of 1,3-bis(allylamino)propane or a salt thereof, (ii) 40-70 mol% of 2-propen-1-ylamine or a salt thereof, and (iii) 10-35 mol% of 1,2-dichloroethane, where (i) mol% of 1,3-bis(allylamino)propane or a salt thereof, (ii) mol% of 2-propen-1-ylamine or a salt thereof, and (iii) mol% of 1,2-dichloroethane total 100 mol%. In another exemplary embodiment, the crosslinked poly(allylamine) polymer consists of (i) 15-30 mol% of 1,3-bis(allylamino)propane or a salt thereof, (ii) 40-70 mol% of 2-propen-1-ylamine or a salt thereof, and (iii) 15-30 mol% of 1,2-dichloroethane, where (i) mol% of 1,3-bis(allylamino)propane or a salt thereof, (ii) mol% of 2-propen-1-ylamine or a salt thereof, and (iii) mol% of 1,2-dichloroethane are totaling 100 mol%.In another exemplary embodiment, the crosslinked poly(allylamine) polymer consists of (i) 15-30 mol% of 1,3-bis(allylamino)propane or a salt thereof, (ii) 45-65 mol% of 2-propen-1-ylamine or a salt thereof, and (iii) 15-30 mol% of 1,2-dichloroethane, where (i) mol% of 1,3-bis(allylamino)propane or a salt thereof, (ii) mol% of 2-propen-1-ylamine or a salt thereof, and (iii) mol% of 1,2-dichloroethane are totaling 100 mol%. In another exemplary embodiment, the crosslinked poly(allylamine) polymer consists of (i) 20-25 mol% of 1,3-bis(allylamino)propane or a salt thereof, (ii) 50-60 mol% of 2-propen-1-ylamine or a salt thereof, and (iii) 20-25 mol% of 1,2-dichloroethane, where (i) mol% of 1,3-bis(allylamino)propane or a salt thereof, (ii) mol% of 2-propen-1-ylamine or a salt thereof, and (iii) mol% 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-propene-1-ylamine or a salt thereof and / or the residue of 1,3-bis(allylamino)propane or a salt thereof may be a hydrochloride salt, sulfate salt, phosphate salt, hydrobromide salt, or a combination thereof. As a further example, in each of the exemplary embodiments described in the paragraph above, the residue of 2-propene-1-ylamine or a salt thereof and / or the residue of 1,3-bis(allylamino)propane or a salt thereof is a hydrochloride salt residue.

[0221] Pharmaceutical composition and administration In general, the dosage levels of cross-linked poly(allylamine) polymers, particularly bevelimer, for therapeutic and / or prophylactic use may range from approximately 3 g / day to approximately 9 g / day.

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

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

[0224] For example, in one embodiment, the recommended starting dose of a cross-linked poly(allylamine) polymer, particularly bevelimer, for therapeutic and / or prophylactic use is approximately 6 g / day. In one embodiment, the starting dose is increased in increments of approximately 3 g up to approximately 9 g / day or decreased up to approximately 3 g / day. In one embodiment, dose adjustments are made to achieve the desired serum bicarbonate level. In one embodiment, dose adjustments are made at intervals of approximately two weeks.

[0225] In one embodiment, a cross-linked poly(allylamine) polymer, particularly bevelimer, is administered with food. In another embodiment, a cross-linked poly(allylamine) polymer, particularly bevelimer, is administered orally as a suspension in water.

[0226] The efficacy of cross-linked poly(allylamine) polymers can be established in animal models or in 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, chlorides, and other ions at various pH levels. Ex vivo extracts, such as digestive tract contents from human volunteers or model animals, can be used for similar purposes. Selectivity in binding and / or retaining certain ions more favorably than others may also be demonstrated in such in vitro and ex vivo solutions. The effectiveness of cross-linked poly(allylamine) polymers in normalizing acid / base balance can be tested using in vivo models of metabolic acidosis—for example, 5 / 6 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 its etiology, lowers extracellular fluid bicarbonate levels and therefore reduces extracellular pH. The correlation between serum pH and serum bicarbonate is given by the Henderson-Hasselbalch equation. pH = pK' + log[HCO3] - ] / [(0.03 × PaCO2)] (In the formula, 0.03 is the physical solubility coefficient of CO2, and [HCO3 - This is expressed by (where PaCO2 is the bicarbonate concentration and PaCO2 is the partial pressure of carbon dioxide, respectively).

[0228] There are several clinical tests that can be used to confirm metabolic acidosis. The tests involve the bicarbonate (HCO3) of various biological samples, including venous or arterial blood. - ) or proton (H + The concentration of bicarbonate (HCO3) is measured by enzymatic methods, ion-selective electrodes, or blood gas analysis. - ) or proton (H + The concentration can be measured. Bicarbonate is "measured" in both enzyme and ion-selective electrode methods. Using blood gas analysis, bicarbonate levels can be calculated using the Henderson-Hasselbalch formula.

[0229] In one embodiment, a cross-linked poly(allylamine) polymer is provided to animals, including humans, in a drug regimen of once, twice, or more times (i.e., at least three times) daily (oral administration) for acid-base disorders (e.g., metabolic acidosis), and a sustained increase in serum bicarbonate or other target species is achieved as previously described.

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

[0231] In some embodiments, cross-linked poly(allylamine) polymers may be co-administered with other active agents, depending on the condition being treated. This co-administration may include simultaneous administration of two agents in the same dosage form, simultaneous administration of separate dosage forms, and separate administrations. For example, for the treatment of metabolic acidosis, cross-linked poly(allylamine) polymers may be co-administered with general treatments necessary for the treatment of underlying comorbidities, including but not limited to complications of hypertension, diabetes, obesity, heart failure, and chronic kidney disease. These pharmaceuticals and cross-linked poly(allylamine) polymers may be formulated together in the same dosage form and administered simultaneously, provided that no clinically significant drug-drug interactions are observed. Alternatively, these treatments and cross-linked poly(allylamine) polymers may be administered separately and sequentially, one followed by the other.

[0232] In one embodiment, the daily dose for treating chronic metabolic acidosis is compliance enhancement (cross-linked poly(allylamine) polymer, particularly bevelimer, 3 g / day, 6 g / day, or 9 g / day), achieving an increase of approximately 3 mEq / l in serum bicarbonate at these daily doses. The non-absorption of polymers and the absence of sodium loading and / or introduction of other harmful ions for such oral drugs enable, for the first time, safe, chronic treatment of metabolic acidosis without worsening of blood pressure / hypertension and / or causing increased fluid retention and fluid overload. Other benefits include further delay in the progression of renal disease and the initiation of lifelong renal replacement therapy (end-stage renal disease "ESRD" includes dialysis three times a week) or kidney transplantation. Both are associated with significant mortality, low quality of life, and a significant burden of healthcare costs worldwide. In the United States alone, approximately 20% of 400,000 ESRD patients die each year, and 100,000 new patients begin dialysis.

[0233] Further aspects of the present invention relate to a sealed package and a pharmaceutical product comprising the crosslinked poly(allylamine) polymer of the present invention, such as bevelimer, within the sealed package. The unit dosage forms disclosed herein are any form that matches one or more of the disclosed requirements. For example, the unit dosage forms include vials, bottles, tubes, jars, boxes, tab-type containers, blister packs, sachets (including stick packs) or other sealed containers. 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 bevelimers, may produce certain impurities, such as H2C=CHCH2NH2, when exposed to oxygen. The unit dosage form may have properties that address or reduce the possibility of such impurities, such as properties that reduce the amount of oxygen that comes into contact with the polymer during storage.

[0235] Packaging means to address or reduce the possibility of such impurities include: oxygen-low permeable unit formulations; unit formulations containing small amounts of gas within the unit formulation; unit formulations containing gases other than air within the unit formulation and / or unit formulations containing oxygen-absorbing components, e.g., scavenging agents. 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 crosslinked poly(allylamine) polymer of the present invention, e.g., bevelomers and / or any polymers of the publications cited herein, and all such combinations are disclosed. For example, using one or more of the packaging means disclosed herein for addressing or reducing the possibility of impurities, e.g., the means summarized in this paragraph, low levels of sp as disclosed herein. 2 The present invention provides pharmaceuticals containing a cross-linked poly(allylamine) polymer having carbon, for example, bevelimer (for example, less than 1.0% of the total number of carbon atoms present in the cross-linked poly(allylamine) polymer is sp 2(It is an allyl carbon). Such pharmaceuticals provide an acceptable or improved shelf life as defined elsewhere. In other examples, one or more of the means disclosed herein for addressing or reducing the possibility of impurities, for example, the means summarized in this paragraph, as disclosed herein and / or in the references provided herein, are used to achieve a high level of sp. 2 A pharmaceutical product comprising a carbon-crosslinked poly(allylamine) polymer, such as a bevelimmer, is provided (for example, less than 1.0% of the total number of carbon atoms present in the crosslinked poly(allylamine) polymer is sp 2 (Not allyl carbon). Such pharmaceuticals, for example, the combination of approach or packaging means 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), thus limiting high levels of sp 2 Despite the presence of carbon, it may offer an acceptable or improved shelf life.

[0236] In one embodiment, the unit dosage form preferably includes a substantially moisture- and oxygen-impermeable sealed package to enhance the stability of the pharmaceutical composition (e.g., the stability of the bevelimer). For example, the dosage unit form may include 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 container size 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. Headspace is the volume contained within the unit dosage form that is not the pharmaceutical composition. Headspace contains one or more gases, such as an inert gas such as nitrogen or a mixture of gases such as air. Minimizing the volume of headspace can increase the stability of the crosslinked poly(allylamine) polymer of the present invention, such as bevelimer, during storage, especially when the headspace contains oxygen.

[0238] In one embodiment, a unit dosage form comprises a pharmaceutical composition and a headspace, where the headspace volume is 0 cm³.3 ~120cm 3 In one embodiment, the unit dosage form comprises a pharmaceutical composition and a headspace, where the headspace volume is 10 cm³. 3 ~110cm 3 In one embodiment, the unit dosage form comprises a pharmaceutical composition and a headspace, where the headspace volume is 20 cm³. 3 ~100cm 3 In one embodiment, the unit dosage form comprises a pharmaceutical composition and a headspace, where the headspace volume is 20 cm³. 3 ~40cm 3 In one embodiment, the unit dosage form comprises a pharmaceutical composition and a headspace, where the headspace volume is 0 cm³. 3 ~20cm 3 In one embodiment, the unit dosage form comprises a pharmaceutical composition and a headspace, where the headspace volume is 50 cm³. 3 ~70cm 3 That is the case.

[0239] In one embodiment, the unit dosage form includes a pharmaceutical composition and headspace, where the headspace volume is less than 70% of the total volume of the unit dosage form. In another embodiment, the unit dosage form includes a pharmaceutical composition and headspace, where the headspace volume is less than 65% of the total volume of the unit dosage form. In yet another embodiment, the unit dosage form includes a pharmaceutical composition and headspace, where the headspace volume is less than 60% of the total volume of the unit dosage form. In yet another embodiment, the unit dosage form includes a pharmaceutical composition and headspace, where the headspace volume is less than 55% of the total volume of the unit dosage form. In yet another embodiment, the unit dosage form includes a pharmaceutical composition and headspace, where the headspace volume is less than 45% of the total volume of the unit dosage form. In yet another embodiment, the unit dosage form includes a pharmaceutical composition and headspace, where the headspace volume is less than 35% of the total volume of the unit dosage form. In yet another embodiment, the unit dosage form includes a pharmaceutical composition and headspace, where the headspace volume is less than 25% of the total volume of the unit dosage form. In one embodiment, the unit dosage form comprises a pharmaceutical composition and a headspace, where the headspace volume is less than 15% of the total volume of the unit dosage form. In another embodiment, the unit dosage form comprises a pharmaceutical composition and a headspace, where the headspace volume is less than 5% of the total volume of the unit dosage form.

[0240] In one embodiment, headspace is minimized by compressing the unit dosage form before sealing the pharmaceutical composition into the unit dosage form.

[0241] A unit dosage form having a relatively low headspace contains a relatively large amount of the pharmaceutical composition in grams relative to its headspace volume. In one embodiment, the unit dosage form contains the pharmaceutical composition in a quantity of cm³ of the headspace volume of the unit dosage form. 3 It is present in an amount of at least 0.01 g per unit. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is present in a volume of cm³ of the headspace volume of the unit dosage form. 3It is present in an amount of at least 0.02 g per unit. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is present in a volume of cm³ of the headspace volume of the unit dosage form. 3 It is present in an amount of at least 0.03 g per unit. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is present in a volume of cm³ of the headspace volume of the unit dosage form. 3 It is present in an amount of at least 0.04 g per unit. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is present in a volume of cm³ of the headspace volume of the unit dosage form. 3 It is present in an amount of at least 0.05 g per unit. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is present in a volume of cm³ of the headspace volume of the unit dosage form. 3 It is present in an amount of 0.01g to 0.5g per unit. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is present in a volume of cm³ of the headspace volume of the unit dosage form. 3 It is present in an amount of 0.01g to 0.2g per unit. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is present in a volume of cm³ of the headspace volume of the unit dosage form. 3 It is present in an amount of 0.05 g to 0.2 g per unit. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is present in a volume of cm³ of the headspace volume of the unit dosage form. 3 It exists in amounts of 0.05g to 0.15g per unit.

[0242] In one embodiment, the unit dosage form comprises a pharmaceutical composition present in an amount of 3 g, and the headspace volume of the unit dosage form is 90 cm³. 3 It is less than. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is present in an amount of 3 g, and the headspace volume of the unit dosage form is 75 cm³. 3 It is less than. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is present in an amount of 3 g, and the headspace volume of the unit dosage form is 60 cm³. 3 It is less than. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is present in an amount of 3 g, and the headspace volume of the unit dosage form is 45 cm³. 3 It is less than.

[0243] In one embodiment, the unit dosage form comprises a pharmaceutical composition present in an amount of 6 g, and the headspace volume of the unit dosage form is 120 cm³. 3 It is less than. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is present in an amount of 6 g, and the headspace volume of the unit dosage form is 105 cm³. 3 It is less than. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is present in an amount of 6 g, and the headspace volume of the unit dosage form is 90 cm³. 3 It is less than. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is present in an amount of 6 g, and the headspace volume of the unit dosage form is 75 cm³. 3 It is less than.

[0244] In one embodiment, the unit dosage form comprises a pharmaceutical composition present in an amount of 9 g, and the headspace volume of the unit dosage form is 140 cm³. 3 It is less than. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is present in an amount of 9 g, and the headspace volume of the unit dosage form is 125 cm³. 3 It is less than. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is present in an amount of 9 g, and the headspace volume of the unit dosage form is 110 cm³. 3 It is less than. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is present in an amount of 9 g, and the headspace volume of the unit dosage form is 95 cm³. 3 It is less than.

[0245] A sealed unit dosage form with a relatively low headspace contains a relatively large amount of the pharmaceutical composition in grams relative to its total volume. In one embodiment, the unit dosage form contains the pharmaceutical composition, where the pharmaceutical composition is contained in the total volume of the sealed unit dosage form in cm³. 3 It is present in an amount of at least 0.02 g per unit. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is in the total volume cm³ of the sealed unit dosage form. 3It is present in an amount of at least 0.03 g per unit. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is in the total volume cm³ of the sealed unit dosage form. 3 It is present in an amount of at least 0.04 g per unit. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is in the total volume cm³ of the sealed unit dosage form. 3 It is present in an amount of 0.01g to 0.5g per unit. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is contained in the total volume cm³ of the sealed unit dosage form. 3 It is present in amounts of 0.01g to 0.25g per unit. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is contained in the total volume cm³ of the sealed unit dosage form. 3 It is present in amounts of 0.01g to 0.15g per unit. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is contained in the total volume cm³ of the sealed unit dosage form. 3 It is present in an amount of 0.02g to 0.1g per unit. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is contained in the total volume cm³ of the sealed unit dosage form. 3 It is present in an amount of 0.03g to 0.08g per unit. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is contained in the total volume cm³ of the sealed unit dosage form. 3 It is present in an amount of 0.04g to 0.07g per unit. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is contained in the total volume cm³ of the sealed unit dosage form. 3 It is present in an amount of 0.02g to 0.2g per unit. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is contained in the total volume cm³ of the sealed unit dosage form. 3 It is present in amounts of 0.04g to 0.18g per unit. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is contained in the total volume cm³ of the sealed unit dosage form. 3 It is present in amounts ranging from 0.06g to 0.16g per unit.

[0246] In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is present in an amount of 3 g, and the total sealed volume of the unit dosage form is 100 cm³. 3It is less than. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is present in an amount of 3 g, and the sealed total volume of the unit dosage form is 90 cm³. 3 It is less than. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is present in an amount of 3 g, and the sealed total volume of the unit dosage form is 80 cm³. 3 It is less than. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is present in an amount of 3 g, and the sealed total volume of the unit dosage form is 70 cm³. 3 It is less than.

[0247] In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is present in an amount of 6 g, and the total volume of the sealed unit dosage form is 160 cm³. 3 It is less than. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is present in an amount of 6 g, and the total volume of the sealed unit dosage form is 150 cm³. 3 It is less than. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is present in an amount of 6 g, and the total volume of the sealed unit dosage form is 140 cm³. 3 It is less than. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is present in an amount of 6 g, and the total volume of the sealed unit dosage form is 130 cm³. 3 It is less than.

[0248] In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is present in an amount of 9 g, and the total volume of the sealed unit dosage form is 200 cm³. 3 It is less than. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is present in an amount of 9 g, and the total volume of the sealed unit dosage form is 190 cm³. 3 It is less than. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is present in an amount of 9 g, and the total volume of the sealed unit dosage form is 180 cm³. 3 It is less than. In one embodiment, the unit dosage form comprises a pharmaceutical composition, where the pharmaceutical composition is present in an amount of 9 g, and the sealed total volume of the unit dosage form is 170 cm³. 3 It is less than.

[0249] In one embodiment, the unit dosage form is a sachet. In such an embodiment, the sachet has a height (h) and a width (w), the walls of the sachet can be bent but not stretched, and the total volume of the sealed sachet can be estimated according to 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 is cm³. 3 Any description of the amount of drug per gram is calculated using formula X, which is the total sealed volume cm³. 3 This refers to the amount of drug per gram.

[0251] In one embodiment, the unit dosage form is a sachet containing 3g, 6g, or 9g of the pharmaceutical composition, with a width of less than 25cm and a height of less than 25cm. In another embodiment, the unit dosage form is a sachet containing 3g, 6g, or 9g of the pharmaceutical composition, with a width of less than 20cm and a height of less than 25cm. In yet another embodiment, the unit dosage form is a sachet containing 3g, 6g, or 9g of the pharmaceutical composition, with a width of less than 15cm and a height of less than 20cm. In yet another embodiment, the unit dosage form is a sachet containing 3g, 6g, or 9g of the pharmaceutical composition, with a width of less than 10cm and a height of less than 15cm.

[0252] In one embodiment, the unit dosage form is a sachet containing 9 g of pharmaceutical composition, with a width of less than 25 cm and a height of less than 25 cm. In another embodiment, the unit dosage form is a sachet containing 9 g of pharmaceutical composition, with a width of less than 20 cm and a height of less than 25 cm. In yet another embodiment, the unit dosage form is a sachet containing 9 g of pharmaceutical composition, with a width of less than 15 cm and a height of less than 20 cm. In yet another embodiment, the unit dosage form is a sachet containing 9 g of pharmaceutical composition, with a width of less than 10 cm and a height of less than 15 cm. In yet another embodiment, the unit dosage form is a sachet containing 9 g of pharmaceutical composition, with a width of less than 9 cm and a height of less than 12 cm.

[0253] In one embodiment, the unit dosage form is a sachet containing 6 g of pharmaceutical composition, with a width of less than 25 cm and a height of less than 25 cm. In another embodiment, the unit dosage form is a sachet containing 6 g of pharmaceutical composition, with a width of less than 20 cm and a height of less than 25 cm. In yet another embodiment, the unit dosage form is a sachet containing 6 g of pharmaceutical composition, with a width of less than 15 cm and a height of less than 20 cm. In yet another embodiment, the unit dosage form is a sachet containing 6 g of pharmaceutical composition, with a width of less than 10 cm and a height of less than 15 cm. In yet another embodiment, the unit dosage form is a sachet containing 6 g of pharmaceutical composition, with a width of less than 8 cm and a height of less than 11 cm.

[0254] In one embodiment, the unit dosage form is a sachet containing 3 g of pharmaceutical composition, with a width of less than 25 cm and a height of less than 25 cm. In another embodiment, the unit dosage form is a sachet containing 3 g of pharmaceutical composition, with a width of less than 20 cm and a height of less than 25 cm. In yet another embodiment, the unit dosage form is a sachet containing 3 g of pharmaceutical composition, with a width of less than 15 cm and a height of less than 20 cm. In yet another embodiment, the unit dosage form is a sachet containing 3 g of pharmaceutical composition, with a width of less than 10 cm and a height of less than 10 cm. In yet another embodiment, the unit dosage form is a sachet containing 3 g of pharmaceutical composition, with a width of less than 8 cm and a height of less than 9 cm.

[0255] Any headspace present in any of the unit formulations disclosed herein may be filled with an inert gas such as nitrogen, or with a low level of oxygen, or other. The headspace present in a unit formulation may contain any gas, which is referred to hereby as the headspace gas. In one embodiment, the headspace gas is nitrogen. In one embodiment, the headspace gas is argon. In one embodiment, the headspace gas is helium. In one embodiment, the headspace gas is neon. In one embodiment, the headspace gas is carbon dioxide. In one embodiment, the headspace gas is nitrogen. In one embodiment, the headspace gas is a mixture of the gases described herein. For example, in one embodiment, the headspace gas is an inert gas mixture, such as a mixture of nitrogen and carbon dioxide. In one embodiment, when a headspace gas refers to a specific gas, it means that the headspace gas is essentially composed of or consists of the gases described.

[0256] In one embodiment, the headspace gas contains other gases, such as non-inert oxygen. In one embodiment, the percentage of oxygen present in the headspace gas is less than 21%. In one embodiment, the percentage of oxygen present in the headspace gas is less than 20%. In one embodiment, the percentage of oxygen present in the headspace gas is less than 18%. In one embodiment, the percentage of oxygen present in the headspace gas is less than 16%. In one embodiment, the percentage of oxygen present in the headspace gas is less than 14%. In one embodiment, the percentage of oxygen present in the headspace gas is less than 12%. In one embodiment, the percentage of oxygen present in the headspace gas is less than 10%. In one embodiment, the percentage of oxygen present in the headspace gas is less than 8%. In one embodiment, the percentage of oxygen present in the headspace gas is less than 6%. In one embodiment, the percentage of oxygen present in the headspace gas is less than 4%. In one embodiment, the percentage of oxygen present in the headspace gas is less than 2%. In one embodiment, the percentage of oxygen present in the headspace gas is less than 1%. In another embodiment, the percentage of oxygen present in the headspace gas is less than 0.5%.

[0257] In one embodiment, the headspace gas is a mixture of oxygen and a secondary gas. In one embodiment, the headspace gas is ≤20% oxygen (O2) and ≥80% nitrogen (N2). In one embodiment, the headspace gas is ≤18% O2 and ≥82% N2. In one embodiment, the headspace gas is ≤16% O2 and ≥84% N2. In one embodiment, the headspace gas is ≤14% O2 and ≥86% N2. In one embodiment, the headspace gas is ≤12% O2 and ≥88% N2. In one embodiment, the headspace gas is ≤10% O2 and ≥90% N2. In one embodiment, the headspace gas is ≤8% O2 and ≥92% N2. In one embodiment, the headspace gas is ≤6% O2 and ≥94% N2. In one embodiment, the headspace gas is ≤4% O2 and ≥96% N2. In one embodiment, the headspace gas is ≤2%O2 and ≥98%N2. In another embodiment, the headspace gas is ≤1%O2 and ≥99%N2. In yet another embodiment, the headspace gas is ≤0.5%O2 and ≥99.5%N2. In such embodiments, the headspace gas is essentially one of or can consist of the gases described.

[0258] In other embodiments, the unit dosage forms disclosed herein are packaged in air and / or the headspace in 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 altered after the packaging process, for example, by adding or replacing the gas in the post-manufacturing pharmaceutical dosage form, for example, through a valve in the package.

[0259] The container material of the construction for use with the unit formulations disclosed herein may be selected to minimize the ingress of moisture and oxygen into the container after packaging. For example, a poly(allylamine) polymer, e.g., beveler, may be packaged in a multilayer sachet having at least one layer that acts as a barrier layer against moisture and oxygen ingress. In other examples, a poly(allylamine) polymer may be packaged in a single-layer or multilayer plastic, metal, or glass container having at least one barrier layer incorporated into a structure that limits oxygen and / or moisture ingress after packaging. For example, in one such embodiment, the sachet (or other container or package) may include a multilayer lamination of an internal contact layer, an outer layer; and a barrier layer positioned between the contact layer and the outer layer. In such embodiments, the multilayer lamination may also include one or more adhesive layers and / or printed layers. For example, the lamination may include the following layers in the order: internal contact layer, adhesive, barrier layer, adhesive, printed layer, and outer layer. In one embodiment, one or more layers of any of the multilayer laminations disclosed herein may be bonded to each other via adhesive and / or lamination (e.g., lamination by extrusion). In one embodiment, the multiple layers disclosed herein are bonded to each other via adhesion and / or lamination (e.g., lamination by extrusion). In one embodiment, the multiple layers disclosed herein are bonded to each other via adhesion. In one embodiment, the multiple layers disclosed herein are bonded to each other via lamination (e.g., lamination by extrusion).

[0260] In some embodiments, the unit dosage form is or includes plastic. For example, the plastic may be polyethylene (e.g., linear low-density polyethylene or low-density polyethylene), polypropylene, poly(ethylene terephthalate), polyester, nylon, or polyvinyl chloride. In such embodiments, the plastic may be in the form of a film or sheet. For example, when the dosage form is a sachet, the sachet may be made of 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) includes a multilayer laminate comprising an inner contact layer, an outer layer, and a barrier layer positioned between the contact layer and the outer layer. In such embodiments, any of the layers may be made of any of the described plastics. More specifically, the inner contact layer may include any of polyethylene, polypropylene, poly(ethylene terephthalate), polyester, nylon, or polyvinyl chloride. In some embodiments, the inner contact layer includes 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 may comprise polyethylene, polypropylene, poly(ethylene terephthalate), polyester, nylon, polyvinyl chloride, or paper. In one embodiment, the outer layer is poly(ethylene terephthalate). In one embodiment, the barrier layer may be any aluminum layer disclosed herein. In one embodiment, the barrier layer may comprise any plastic layer disclosed herein and any aluminum layer disclosed herein. For example, the barrier layer may comprise low-density polyethylene and an aluminum film. In one exemplary embodiment, the unit formulation disclosed herein is a sachet manufactured from a lamination of the following components in the following order: an inner contact layer 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 of poly(ethylene terephthalate), optionally bonded 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 manufactured from a lamination of the following components in the following order: an inner contact layer 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 of poly(ethylene terephthalate), which optionally are laminated together by extrusion, and optionally the aluminum film is about 18 μm thick.

[0261] In one embodiment, the unit dosage form has an outer and inner part, the inner part comprising a cross-linked poly(allylamine) polymer, such as bevelimer, where the oxygen transfer rate between the outer and inner parts of the unit dosage form is approximately 0.050 cubic centimeters / square meter / day (CC / m²). 2 It is less than / day.

[0262] In one embodiment, the unit dosage form comprises a sealed enclosure containing a crosslinked poly(allylamine) polymer, such as bevelimer, the sealed enclosure comprising a multilayer lamination comprising an inner contact layer, an outer layer, and a barrier layer disposed between the contact layer and the outer layer, where the oxygen transfer rate between the multilayer laminations is approximately 0.050 cubic centimeters / square meter / day (CC / m²). 2 It is less than / day.

[0263] In either embodiment, the specified oxygen transfer rate is, in one embodiment, approximately 0.030 CC / m³. 2 It is less than / day. In any embodiment, the specified oxygen transport rate is, in one embodiment, about 0.010 CC / m³. 2 It is less than / day. In any embodiment, the specified oxygen transport rate is, in one embodiment, about 0.009 CC / m³. 2 It is less than / day. In any embodiment, the specified oxygen transport rate is, in one embodiment, about 0.007 CC / m³. 2 It is less than / day. In any embodiment, the specified oxygen transport rate is, in one embodiment, about 0.005 CC / m³. 2 It is less than / day. In any embodiment, the specified oxygen transport rate is, in one embodiment, about 0.003 CC / m³. 2It is less than one day.

[0264] When the oxygen transfer rate is measured for the unit dosage forms disclosed herein, the transfer rate can be controlled by selecting appropriate materials and appropriate thicknesses of those materials during the manufacturing 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). A specific oxygen transfer rate can be achieved using one or more of these materials.

[0265] For example, the oxygen transport rate can be controlled using one or more layers of aluminum. Therefore, in some embodiments, the unit formulation disclosed herein comprises at least one aluminum layer. For example, the aluminum-containing layer may be part of the barrier layer disclosed herein. More specifically, the aluminum-containing layer may be a barrier layer. For example, the barrier layer may comprise any of the aluminum layers disclosed herein. For example, the barrier layer may essentially consist of any of the aluminum layers disclosed herein. For example, the barrier layer may consist of any of the aluminum layers disclosed herein. In some embodiments, the barrier layer and / or the aluminum layer, when measured individually, have one of the oxygen transport rates disclosed herein.

[0266] In one embodiment, the thickness of the aluminum layer disclosed herein is greater than 5 μm. In one embodiment, the thickness of the aluminum layer disclosed herein is greater than 8 μm. In one embodiment, the thickness of the aluminum layer disclosed herein is greater than 10 μm. In one embodiment, the thickness of the aluminum layer disclosed herein is greater than 12 μm. In one embodiment, the thickness of the aluminum layer disclosed herein is greater than 15 μm. In one embodiment, the thickness of the aluminum layer disclosed herein is greater than 18 μm. In one embodiment, the thickness of the aluminum layer disclosed herein is greater than 20 μm. In one embodiment, the thickness of the aluminum layer disclosed herein is greater than 25 μm. In one embodiment, the thickness of the aluminum layer is 9 to 20 μm. In one embodiment, the thickness of the aluminum layer is 15 to 20 μm. In one embodiment, the thickness of the aluminum layer is approximately 18 μm.

[0267] In any embodiment, the unit dosage form is manufactured from a single consistent substance, for example, a sachet is manufactured from one type of sheet or multiple layers. In some embodiments, the unit dosage form may contain different substances in different parts of the unit dosage form (e.g., terminals). In such a scenario, the requirements herein specified for the unit dosage form may be applied to one or more of these parts. Or, in such a scenario, the requirements herein specified for the unit dosage form may be applied to substantially all of these parts. Or, in such a scenario, the requirements herein specified for the unit dosage form may be applied to all of these parts. Therefore, for example, the unit dosage form disclosed herein includes a sealed vial (e.g., made of plastic or glass) sealed with a lid, where both parts (lid and vial) have an oxygen transfer rate specified in the other part, for example, 0.005 CC / m³. 2 It has less than / day. In such an example, the sealed vial has an oxygen transfer rate specified in other parts, e.g., 0.005 CC / m³. 2 The oxygen transfer rate between the outer and inner parts of the unit dosage form is less than 1 / day.

[0268] In any embodiment, the unit dosage form may include layers forming the dosage form, such as an internal contact layer, an outer layer, and a barrier layer, and potentially further layers. Any of these layers, individually or together, may be responsible for a specific oxygen transfer rate. The layers may be joined together using adhesive, heat sealing, extrusion lamination, or any other fastening method.

[0269] In one embodiment, the unit formulation comprises an oxygen scavenger. In one exemplary embodiment, the unit formulation comprises one or more oxygen removal layers comprising an oxygen scavenger. In one embodiment, the unit formulation comprises an oxygen scavenger in contact with a crosslinked poly(allylamine) polymer, for example, as an additive. In one embodiment, the oxygen scavenger is located inside the unit formulation, for example, in a separate insert. In one embodiment, the oxygen scavenger is formed from, for example, a lid of the unit formulation, which is in contact with the inside of the unit formulation.

[0270] The oxygen scavengers disclosed herein are 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, iron oxide powder, ferrous salts, e.g., ferrous sulfate or ferrous chloride, sulfites, bisulfites, dithionites and other reducing sulfur compounds, ascorbic acid and / or salts thereof, Pd, Cu, Zn, Mg, Mn, Co(II), Zn, ascorbic acid, ascorbic acid salts, isoascorbic acid, tocopherol, hydroquinone, catechol, longalit, 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. Further oxygen scavenging agents are available, for example, U.S. Patent Publications 20060076536, 20070084144, and 20060260967. Oxygen scavenging agents are commercially available, for example, StabilOx® (Multisorb Technologies), cyclohexene methyl acrylic (EMCM) polymer (Chevron-Phillips Chemical Company), or Ciba's Specialty Chemical's SHELFPLUS.TM. In one exemplary embodiment, the scavenging agent is iron.

[0271] In one embodiment, the oxygen scavenger unit formulation comprises one or more oxygen removal layers containing an oxygen scavenger. Such layers are known in the art; see, for example, Gaikwad et al., Environmental Chemistry Letters volume 16, pages 523-538 (2018). In one embodiment, the unit formulation disclosed herein comprises any or a combination thereof of the layers (films) disclosed in Gaikwad et al., particularly those disclosed in Table 2 of Gaikwad et al. In one embodiment, the unit formulation disclosed herein comprises any or a combination thereof of the layers (films) disclosed in Table 3 of Gaikwad et al. In one embodiment, the unit formulation disclosed herein comprises any or a combination thereof of the layers (films) disclosed in Gaikwad et al., particularly those disclosed in the “multilayer active films” section. In fact, such layers are already commercially available, and the unit dosage forms disclosed herein may include, for example, 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 in addition to the oxygen scavenger.

[0273] In one embodiment, the product and / or unit dosage form includes a statement that the product has an expiration date of at least one year. In one embodiment, the product and / or unit dosage form includes a statement that the product has an expiration date of one year. In one embodiment, the product and / or unit dosage form includes a statement that the product has an expiration date of at least two years. In one embodiment, the product and / or unit dosage form includes a statement that the product has an expiration date of two years. In one embodiment, the product and / or unit dosage form includes a statement that the product has an expiration date of at least three years. In one embodiment, the product and / or unit dosage form includes a statement that the product has an expiration date of three years. In one embodiment, the product and / or unit dosage form includes a statement that the product has an expiration date of at least four years. In one embodiment, the product and / or unit dosage form includes a statement that the product has an expiration date of four years. In one embodiment, the product and / or unit dosage form includes a statement that the product has an expiration date of at least five years. In one embodiment, the product and / or unit dosage form includes a statement that the product has an expiration date of five years.

[0274] In any of these embodiments, the statement relating to the expiration period may specify that the expiration period begins from the date of manufacture (for example, the statement may specify that the product should be used within two years of manufacture). And / or in any of these embodiments, the statement relating to the expiration period may be expressed as an expiration date (or similar), in which case the expiration period is the difference between the expiration date and the date on which the expiration date is read (for example, the expiration date is more than two years after the date on which it is read, in which case the expiration period is more than two years).

[0275] The unit dosage forms disclosed herein exhibit high stability. For example, cross-linked poly(allylamine) polymers, such as bevelimers, remain free of significant amounts of impurities even after long-term storage, for example, for at least one, two, three, four, or five years.

[0276] In one embodiment, the unit dosage form disclosed herein protects a crosslinked poly(allylamine) polymer, such as a bevelimmer, so that the polymer contains less than 20 ppm of CH2CH2NH2 at least 5 years after being placed in the unit dosage form. In one embodiment, the unit dosage form disclosed herein protects a crosslinked poly(allylamine) polymer, such as a bevelimmer, so that the polymer contains less than 15 ppm of CH2CH2NH2 at least 5 years after being placed in the unit dosage form. In one embodiment, the unit dosage form disclosed herein protects a crosslinked poly(allylamine) polymer, such as a bevelimmer, so that the polymer contains less than 20 ppm of CH2CH2NH2 at least 4 years after being placed in the unit dosage form. In one embodiment, the unit dosage form disclosed herein protects a crosslinked poly(allylamine) polymer, such as a bevelimmer, so that the polymer contains less than 15 ppm of CH2CH2NH2 at least 4 years after being placed in the unit dosage form. In one embodiment, the unit dosage form disclosed herein protects a cross-linked poly(allylamine) polymer, such as a bevelimmer, so that the polymer contains less than 20 ppm of CH2CH2NH2 at least 3 years after being placed in the unit dosage form. In one embodiment, the unit dosage form disclosed herein protects a cross-linked poly(allylamine) polymer, such as a bevelimmer, so that the polymer contains less than 15 ppm of CH2CH2NH2 at least 3 years after being placed in the unit dosage form. In one embodiment, the unit dosage form disclosed herein protects a cross-linked poly(allylamine) polymer, such as a bevelimmer, so that the polymer contains less than 20 ppm of CH2CH2NH2 at least 2 years after being placed in the unit dosage form. In one embodiment, the unit dosage form disclosed herein protects a cross-linked poly(allylamine) polymer, such as a bevelimmer, so that the polymer contains less than 15 ppm of CH2CH2NH2 at least 2 years after being placed in the unit dosage form. In one embodiment, the unit dosage form disclosed herein protects a cross-linked poly(allylamine) polymer, such as a beveler, to contain less than 20 ppm of CH2CHCH2NH2 at least one year after the polymer is placed in the unit dosage form.In one embodiment, the unit dosage form disclosed herein protects a cross-linked poly(allylamine) polymer, such as a bevelimmer, to contain less than 15 ppm of CH2CH2NH2 at least one year after the polymer is placed in the unit dosage form. In all such embodiments, the purity requirement described using the term “at least X years after being placed in the unit dosage form” also describes the option that the purity requirement is met in year X.

[0277] Treatment methods and medical applications of cross-linked poly(allylamine) polymers Methods for treating and medical uses of the cross-linked poly(allylamine) polymers, particularly bevelimers, 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] In some aspects of the present invention, the crosslinked poly(allylamine) polymers, particularly bevelimers, disclosed herein are intended for use in any of the treatment methods 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 cross-linked poly(allylamine) polymers, particularly bevelimers, disclosed herein are intended for use in any of the methods for treating acid-base disorders such as metabolic acidosis as 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 the serum bicarbonate concentration determined at one time point, or the mean or median of two or more serum bicarbonate concentrations determined at two or more time points. For example, in one embodiment, the baseline serum bicarbonate value may be the serum bicarbonate concentration value determined at one time point, and the baseline serum bicarbonate value is used as a basis for determining an acute acidic condition requiring immediate treatment. In another embodiment, the baseline serum bicarbonate treatment value is the mean value of serum bicarbonate concentrations from serum samples taken at different time points (e.g., different days). As a further example, in one such embodiment, the baseline serum bicarbonate treatment value is the mean value of serum bicarbonate concentrations from serum samples taken on different days (e.g., at least two, three, four, five or more days, which may be consecutive, separated by one or more days, or separated by several weeks). As a further example, in one such embodiment, the baseline serum bicarbonate treatment value is the mean value of serum bicarbonate concentrations from serum samples taken over two consecutive days prior to the start of treatment.

[0281] In one embodiment, the baseline serum bicarbonate value is the serum bicarbonate concentration value determined at one point in time. In another embodiment, the baseline serum bicarbonate value is the mean of at least two serum bicarbonate concentrations determined at different point in time. For example, in one such embodiment, the baseline serum bicarbonate value is the mean of at least two serum bicarbonate concentrations from serum samples taken on different days. As a further example, the baseline serum bicarbonate value is the mean or median of at least two serum bicarbonate concentrations from serum samples taken on non-contiguous days. As a further example, in one such method, the non-contiguous days are separated by at least two days. As a further example, in one such method, the non-contiguous days are separated by at least one week. As a further example, in one such method, the non-contiguous days are separated by at least two weeks. As a further example, in one such method, the non-contiguous days are separated by at least three weeks.

[0282] In one embodiment, the patient is treated with a daily dose for a period of at least one day. For example, in one such embodiment, the patient is treated with a daily dose for a period of at least one week. In a further example, in one such embodiment, the patient is treated with a daily dose for a period of at least one month. In a further example, in one such embodiment, the patient is treated with a daily dose for a period of at least two months. In a further example, in one such embodiment, the patient is treated with a daily dose for a period of at least three months. In a further example, in one such embodiment, the patient is treated with a daily dose for a period of at least several months. In a further example, in one such embodiment, the patient is treated with a daily dose for a period of at least six months. In a further example, in one such embodiment, the patient is 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 effects of acidosis on cancer progression and diabetes. Acidification of the peritumoral microenvironment leads to significant complications of cancer progression, including invasion and metastasis. Acidification also affects diabetes by inhibiting insulin binding to its receptors, leading to peripheral resistance and symptom exacerbation.

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

[0285] Bevelimer (TRC101) is described in Gillies et al. as an alternative that can be used to directly raise pH. Further aspects of the present invention are compositions comprising the cross-linked poly(allylamine) polymers described herein, particularly bevelimer, for use in the treatment of patients with cancer.

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

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

[0288] In one aspect, diabetes is type 1 diabetes. In another aspect, diabetes is type 2 diabetes.

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

[0290] Embodiment 1. A method for producing a crosslinked poly(allylamine) polymer, (a) Formation of a poly(allylamine) polymer in the form of beads in a co-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 the first step, wherein less than 1.1% of the total number of carbon atoms in the poly(allylamine) polymer is sp 2 Those that are allyl carbons, and (b) In the second step, the poly(allylamine) polymer is further crosslinked in a reaction mixture containing 1,2-dichloroethane, a swelling agent for the poly(allylamine) polymer and a dispersion solvent system to form a crosslinked poly(allylamine) polymer with a swelling ratio of less than 2. Methods that include...

[0291] Embodiment 2. sp contained in poly(allylamine) polymer 2 Any of the embodiments described above, wherein the allyl carbon accounts for less than 1.0% of the total number of carbon atoms in the poly(allylamine) polymer formed in the first step.

[0292] Embodiment 3. sp contained in poly(allylamine) polymer 2 Any of the embodiments described above, wherein the allyl carbon accounts for less than 0.9% of the total number of carbon atoms in the poly(allylamine) polymer formed in the first step.

[0293] Embodiment 4. sp contained in poly(allylamine) polymer 2 Any of the embodiments described above, wherein the allyl carbon accounts for less than 0.8% of the total number of carbon atoms in the poly(allylamine) polymer formed in the first step.

[0294] Embodiment 5. sp contained in poly(allylamine) polymer 2Any of the embodiments described above, wherein the allyl carbon accounts for less than 0.75% of the total number of carbon atoms in the poly(allylamine) polymer formed in the first step.

[0295] Embodiment 6. sp contained in poly(allylamine) polymer 2 Any of the embodiments described above, wherein the allyl carbon accounts for less than 0.7% of the total number of carbon atoms in the poly(allylamine) polymer formed in the first step.

[0296] Embodiment 7. sp contained in poly(allylamine) polymer 2 Any of the embodiments described above, wherein the allyl carbon accounts for less than 0.6% of the total number of carbon atoms in the poly(allylamine) polymer formed in the first step.

[0297] Embodiment 8. sp contained in poly(allylamine) polymer 2 Any of the embodiments described above, wherein the allyl carbon accounts for less than 0.5% of the total number of carbon atoms in the poly(allylamine) polymer formed in the first step.

[0298] Embodiment 9. sp contained in poly(allylamine) polymer 2 Any of the embodiments described above, wherein the allyl carbon accounts for less than 0.4% of the total number of carbon atoms in the poly(allylamine) polymer formed in the first step.

[0299] Embodiment 10. sp contained in poly(allylamine) polymer 2 Any of the methods described in Embodiments 1 to 10, wherein allyl carbons account for more than 0.3% of the total number of carbon atoms in the poly(allylamine) polymer formed in the first step.

[0300] Embodiment 11. sp contained in poly(allylamine) polymer 2Any of the embodiments described above, wherein the allyl carbon accounts for less than 0.3% of the total number of carbon atoms in the poly(allylamine) polymer formed in the first step.

[0301] Embodiment 12. sp contained in poly(allylamine) polymer 2 Any of the embodiments described above, wherein the allyl carbon accounts for less than 0.25% of the total number of carbon atoms in the poly(allylamine) polymer formed in the first step.

[0302] Embodiment 13. sp contained in poly(allylamine) polymer 2 Any of the embodiments described above, wherein the allyl carbon accounts for less than 0.2% of the total number of carbon atoms in the poly(allylamine) polymer formed in the first step.

[0303] Embodiment 14. sp contained in poly(allylamine) polymer 2 Any of the embodiments described above, wherein the allyl carbon accounts for less than 0.1% of the total number of carbon atoms in the poly(allylamine) polymer formed in the first step.

[0304] Embodiment 15. sp contained in poly(allylamine) polymer 2 Any of the embodiments described above, wherein the allyl carbon accounts for less than 0.05% of the total number of carbon atoms in the poly(allylamine) polymer formed in the first step.

[0305] Embodiment 16. sp contained in poly(allylamine) polymer 2 The number of allyl carbons, if present, is determined by NMR and is below the detection limit, using any of the embodiments described above or a poly(allylamine) polymer.

[0306] Embodiment 17. sp contained in poly(allylamine) polymer 2 The percentage of allyl carbon was determined by NMR; optionally, 110-150 ppm sp 2The integral of the allyl carbon peak and the alkyl carbon peak from 0 to 80 ppm is given by the formula

number

[0307] Embodiment 18. sp contained in the poly(allylamine) polymer formed in the first step 2 If the percentage of allyl carbon is available, it can be determined by NMR and sp 2 The allyl carbon is below the detection limit; 110-150 ppm sp is available upon request. 2 The integral of the allyl carbon peak and the alkyl carbon peak from 0 to 80 ppm is given by the formula

number

[0308] Embodiment 19. Any of the embodiments described above, wherein the poly(allylamine) polymer formed in the first step has a swelling ratio of less than 10.

[0309] Embodiment 20. Any of the embodiments described above, wherein the poly(allylamine) polymer formed in the first step has a swelling ratio of less than 9.

[0310] Embodiment 21. Any of the embodiments described above, wherein the poly(allylamine) polymer formed in the first step has a swelling ratio of less than 8.

[0311] Embodiment 22. Any of the embodiments described above, wherein the poly(allylamine) polymer formed in the first step has a swelling ratio of less than 7.

[0312] Embodiment 23. Any of the embodiments described above, wherein the poly(allylamine) polymer formed in the first step has a swelling ratio of less than 6.

[0313] Embodiment 24. Any of the embodiments described above, wherein the poly(allylamine) polymer formed in the first step has a swelling ratio of less than 5.

[0314] Embodiment 25. Any of the embodiments described above, wherein the poly(allylamine) polymer formed in the first step has a swelling ratio of at least 4.

[0315] Embodiment 26. Any of the embodiments described above, wherein the poly(allylamine) polymer formed in the first step has a swelling ratio of at least 3.

[0316] Embodiment 27. Any of the embodiments described above, wherein the crosslinked poly(allylamine) polymer contains less than 20 ppm of allylamine.

[0317] Embodiment 28. Any method of the embodiments described above, wherein the co-polymerization and crosslinking reaction mixture comprises radical polymerization selected from the group consisting of cationic and free radical polymerization initiators.

[0318] Embodiment 29. Any of the embodiments described above, wherein the co-polymerization and crosslinking reaction mixture includes a free radical polymerization initiator selected from a free radical peroxy polymerization initiator and an azo polymerization initiator.

[0319] Embodiment 30. The mixture of the simultaneous polymerization and crosslinking reaction is azodiisobutyronitrile, azodiisovaleronitrile, dimethylazodiisobutyrate, 2,2'-azobis(isobutyronitrile), 2,2'-azobis(N,N'-dimethyl-eneisobutylamidine) dihydrochloride, 2,2'-azobis(2-methylpropionamidine) dihydrochloride, 2,2'-azobis(2-amidinopropane) dihydrochloride, 2,2'-azobis(N,N'-methyleneisobutylamidine), 1,1-azobis(l-cyclohexanecarbonitride), 4,4'-azobis(4-cyanopentanoic acid), 2,2'-azobis(isobutylamide) dihydrate, 2,2'-azobis(2-methylpropane), 2,2'-azobis(2-methylbutyronitrile), VAZO 67. Any method of the embodiments described above, 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. Any of the embodiments described above, wherein the ratio of allyl equivalents to initiator equivalents contained in the combination of 2-propen-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof in the co-polymerization and crosslinking reaction mixture is in the range of about 6:1 to about 70:1.

[0321] Embodiment 32. Any of the embodiments described above, wherein the allyl equivalent to initiator equivalent ratio 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 is in the range of about 7:1 to about 60:1.

[0322] Embodiment 33. Any of the embodiments described above, wherein the allyl equivalent to initiator equivalent ratio 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 is in the range of about 8:1 to about 50:1.

[0323] Embodiment 34. Any of the embodiments described above, wherein the allyl equivalent to initiator equivalent ratio 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 is in the range of about 10:1 to about 45:1.

[0324] Embodiment 35. Any of the embodiments described above, wherein the allyl equivalent to initiator equivalent ratio 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 is in the range of about 15:1 to about 40:1.

[0325] Embodiment 36. Any of the embodiments described above, wherein the allyl equivalent to initiator equivalent ratio 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 is in the range of about 17.5:1 to about 35:1.

[0326] Embodiment 37. Any of the embodiments described above, wherein the allyl equivalent to initiator equivalent ratio 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 is in the range of about 20:1 to about 30:1.

[0327] Embodiment 38. Any of the embodiments described above, wherein the allyl equivalent to initiator equivalent ratio 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 is in the range of about 22.5:1 to about 30:1.

[0328] Embodiment 39. Any of the embodiments described above, wherein the allyl equivalent to initiator equivalent ratio 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 is in the range of about 25:1 to about 27.5:1.

[0329] Embodiment 40. The weight ratio of the combined amount of 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof to the amount of water in the co-polymerization and crosslinking reaction mixture is in the range of about 0.01 to about 3, where the weight ratio is calculated using the respective free amine forms of 2-propene-1-ylamine and 1,3-bis(allylamino)propane, as in any of the embodiments described above.

[0330] Embodiment 41. The weight ratio of the combined amount of 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof to the amount of water in the co-polymerization and crosslinking reaction mixture is in the range of about 0.05 to about 2.75, where the weight ratio is calculated using the respective free amine forms of 2-propene-1-ylamine and 1,3-bis(allylamino)propane, as in any of the embodiments described above.

[0331] Embodiment 42. The weight ratio of the combined amount of 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof to the amount of water in the co-polymerization and crosslinking reaction mixture is in the range of about 0.07 to about 2.5, where the weight ratio is calculated using the respective free amine forms of 2-propene-1-ylamine and 1,3-bis(allylamino)propane, as in any of the embodiments described above.

[0332] Embodiment 43. The weight ratio of the combined amount of 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof to the amount of water in the co-polymerization and crosslinking reaction mixture is in the range of about 0.1 to about 2.25, where the weight ratio is calculated using the respective free amine forms of 2-propene-1-ylamine and 1,3-bis(allylamino)propane, as in any of the embodiments described above.

[0333] Embodiment 44. The weight ratio of the combined amounts of 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof to the amount of water in the co-polymerization and crosslinking reaction mixture is in the range of about 0.15 to about 2, where the weight ratio is calculated using the respective free amine forms of 2-propene-1-ylamine and 1,3-bis(allylamino)propane, as in any of the embodiments described above.

[0334] Embodiment 45. The weight ratio of the combined amount of 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof to the amount of water in the co-polymerization and crosslinking reaction mixture is in the range of about 0.2 to about 1.75, where the weight ratio is calculated using the respective free amine forms of 2-propene-1-ylamine and 1,3-bis(allylamino)propane, as in any of the embodiments described above.

[0335] Embodiment 46. 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 co-polymerization and crosslinking reaction mixture is in the range of about 0.25 to about 1.5, where the weight ratio is calculated using the respective free amine forms of 2-propen-1-ylamine and 1,3-bis(allylamino)propane, as in any of the embodiments described above.

[0336] Embodiment 47. The weight ratio of the combined amounts of 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof to the amount of water in the co-polymerization and crosslinking reaction mixture is in the range of about 0.25 to about 1.25, where the weight ratio is calculated using the respective free amine forms of 2-propene-1-ylamine and 1,3-bis(allylamino)propane, as in any of the embodiments described above.

[0337] Embodiment 48. In the co-polymerization and crosslinking reaction mixture, the weight ratio of the combined amounts of 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof to the amount of water is in the range of about 0.3 to about 1, where the weight ratio is calculated using the respective free amine forms of 2-propene-1-ylamine and 1,3-bis(allylamino)propane, as in any of the embodiments described above.

[0338] Embodiment 49. In a simultaneous polymerization and crosslinking reaction mixture, the weight ratio of the combined amounts of 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof to the amount of water is in the range of about 0.35 to about 0.75, where the weight ratio is calculated using the respective free amine forms of 2-propene-1-ylamine and 1,3-bis(allylamino)propane, as in any of the embodiments described above.

[0339] Embodiment 50. The weight ratio of the combined amount of 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof to the amount of water in the co-polymerization and crosslinking reaction mixture is in the range of about 0.4 to about 0.5, where the weight ratio is calculated using the respective free amine forms of 2-propene-1-ylamine and 1,3-bis(allylamino)propane, as in any of the embodiments described above.

[0340] Embodiment 51. Any of the embodiments described above, wherein the ratio of allyl equivalents to water equivalents in the co-polymerization and crosslinking reaction mixture is in the range of approximately 0.01:1 to approximately 1:1.

[0341] Embodiment 52. Any of the embodiments described above, wherein the ratio of allyl equivalents to water equivalents in the co-polymerization and crosslinking reaction mixture is in the range of approximately 0.015:1 to approximately 0.75:1.

[0342] Embodiment 53. Any of the embodiments described above, wherein the ratio of allyl equivalents to water equivalents in the co-polymerization and crosslinking reaction mixture is in the range of approximately 0.02:1 to approximately 0.5:1.

[0343] Embodiment 54. Any of the embodiments described above, wherein the ratio of allyl equivalents to water equivalents in the co-polymerization and crosslinking reaction mixture is in the range of approximately 0.03:1 to approximately 0.4:1.

[0344] Embodiment 55. Any of the embodiments described above, wherein the ratio of allyl equivalents to water equivalents in the co-polymerization and crosslinking reaction mixture is in the range of approximately 0.04:1 to approximately 0.3:1.

[0345] Embodiment 56. Any of the embodiments described above, wherein the ratio of allyl equivalents to water equivalents in the co-polymerization and crosslinking reaction mixture is in the range of approximately 0.05:1 to approximately 0.25:1.

[0346] Embodiment 57. Any of the embodiments described above, wherein the ratio of allyl equivalents to water equivalents in the co-polymerization and crosslinking reaction mixture is in the range of approximately 0.06:1 to approximately 0.2:1.

[0347] Embodiment 58. Any of the embodiments described above, wherein the ratio of allyl equivalents to water equivalents in the co-polymerization and crosslinking reaction mixture is in the range of approximately 0.07:1 to approximately 0.175:1.

[0348] Embodiment 59. Any of the embodiments described above, wherein the ratio of allyl equivalents to water equivalents in the co-polymerization and crosslinking reaction mixture is in the range of approximately 0.08:1 to approximately 0.15:1.

[0349] Embodiment 60. Any of the embodiments described above, wherein the surfactant contained in the co-polymerization and crosslinking reaction mixture includes an ionic or nonionic surfactant.

[0350] Embodiment 61. Any of the embodiments described above, wherein the surfactant contained in the simultaneous polymerization and crosslinking reaction mixture includes an ionic surfactant.

[0351] Embodiment 62. Any of the embodiments described above, wherein the surfactant contained in the co-polymerization and crosslinking reaction mixture includes a nonionic surfactant.

[0352] Embodiment 63. Any of the embodiments described above, wherein the surfactant included in the simultaneous polymerization and crosslinking reaction mixture is an ionic or nonionic surfactant selected from the group consisting of sorbitan monolaurate, sorbitan monooleate, sorbitan monostearate, sorbitan monopalmitate, ethylene glycol monostearate, glyceryl monostearate, polyethylene glycol monostearate, polyethylene glycol hydrogenated castor oil, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polyethylene glycol, and diisooctyl sulfosuccinate, branched dodecylbenzenesulfonic acid, linear dodecylbenzenesulfonic acid, sodium branched alkylbenzenesulfonate, sodium branched dodecylbenzenesulfonate, sodium alphaolefin sulfonate, sodium linear alkylbenzenesulfonate, isopropylamine branched alkylbenzenesulfonate, and sodium lauryl sulfate.

[0353] Embodiment 64. Any of the embodiments described above, wherein the surfactant contained in the mixture of simultaneous polymerization and crosslinking reaction is branched dodecylbenzenesulfonic acid.

[0354] Embodiment 65. Any of the embodiments described above, wherein the organic solvent system contained in the co-polymerization and crosslinking reaction mixture contains a water-immiscible organic solvent.

[0355] Embodiment 66. Any method of the embodiments described above, wherein the organic solvent system contained in the co-polymerization and crosslinking reaction mixture includes hexane, cyclohexane, heptane, octane, decane, petroleum ether, liquid paraffin, chlorobenzene, toluene, xylene, ethyl acetate, propyl acetate, and isopropyl acetate, or a combination of two or more of these.

[0356] Embodiment 67. Any of the embodiments described above, wherein the organic solvent system contained in the co-polymerization and crosslinking reaction mixture contains heptane.

[0357] Embodiment 68. Any of the embodiments described above, wherein the organic solvent system contained in the co-polymerization and crosslinking reaction mixture consists of heptane.

[0358] Embodiment 69. Any of the embodiments described above, wherein the simultaneous polymerization and crosslinking reaction mixture is heated to a temperature in the range of approximately 25°C to approximately 85°C.

[0359] Embodiment 70. Any of the embodiments described above, wherein the simultaneous polymerization and crosslinking reaction mixture is heated to a temperature in the range of approximately 30°C to approximately 85°C.

[0360] Embodiment 71. Any of the embodiments described above, wherein the simultaneous polymerization and crosslinking reaction mixture is heated to a temperature in the range of approximately 35°C to approximately 85°C.

[0361] Embodiment 72. Any method of the embodiments described above, wherein the simultaneous polymerization and crosslinking reaction mixture is heated to a temperature in the range of approximately 40°C to approximately 85°C.

[0362] Embodiment 73. Any of the embodiments described above, wherein the simultaneous polymerization and crosslinking reaction mixture is heated to approximately 45°C to approximately 85°C.

[0363] Embodiment 74. Any of the embodiments described above, wherein the simultaneous polymerization and crosslinking reaction mixture is heated to approximately 60°C to approximately 80°C.

[0364] Embodiment 75. Any method of the embodiments described above for maintaining the temperature of the co-polymerization and crosslinking reaction mixture relatively constant during the reaction.

[0365] Embodiment 76. Any method of the embodiments described above, wherein the temperature of the co-polymerization and crosslinking reaction mixture is gradient continuously or stepwise during the reaction.

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

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

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

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

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

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

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

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

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

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

[0376] Embodiment 87. Any of the embodiments 77 to 80 described above, wherein the simultaneous polymerization and crosslinking reaction steps are carried out for a reaction time of less than 16 hours.

[0377] Embodiment 88. Any of the embodiments described above, wherein the simultaneous polymerization and crosslinking reaction steps are carried out in a batch manner.

[0378] Embodiment 89. Any of the embodiments described above, wherein the simultaneous polymerization and crosslinking reaction steps are carried out in a semi-batch manner.

[0379] Embodiment 90. Any of the embodiments described above, wherein the simultaneous polymerization and crosslinking reaction steps are carried out in a continuous manner.

[0380] Embodiment 91. Any of the embodiments described above, wherein the reaction mixture for the simultaneous polymerization and crosslinking reaction step contains at least 0.4 equivalents of acid per allylamine equivalent.

[0381] Embodiment 92. Any of the embodiments described above, wherein the reaction mixture for the simultaneous polymerization and crosslinking reaction step contains at least 0.6 equivalents of acid per allylamine equivalent.

[0382] Embodiment 93. Any of the embodiments described above, wherein the reaction mixture for the simultaneous polymerization and crosslinking reaction step contains at least 0.8 equivalents of acid per allylamine equivalent.

[0383] Embodiment 94. Any of the embodiments described above, wherein the reaction mixture for the simultaneous polymerization and crosslinking reaction step contains at least 0.9 equivalents of acid per allylamine equivalent.

[0384] Embodiment 95. Any of the embodiments described above, wherein the reaction mixture for the simultaneous polymerization and crosslinking reaction step contains at least 0.95 equivalents of acid per allylamine equivalent.

[0385] Embodiment 96. Any of the embodiments described above, wherein the reaction mixture for the simultaneous polymerization and crosslinking reaction step contains at least 1.0 equivalent of acid per allylamine equivalent.

[0386] Embodiment 97. Any of the embodiments described above, wherein the reaction mixture for the simultaneous polymerization and crosslinking reaction step contains at least 1 equivalent of acid per equivalent of allylamine.

[0387] Embodiment 98. Any method of the embodiments described above, wherein the reaction mixture for the simultaneous polymerization and crosslinking reaction step is an acid selected from the group consisting of hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, methyl phosphoric acid, formic acid, citric acid, and combinations thereof.

[0388] Embodiment 99. Any of the embodiments described above, wherein the acid is a mineral acid.

[0389] Embodiment 100. Any of the embodiments described above, wherein the acid comprises hydrochloric acid, sulfuric acid, or phosphoric acid.

[0390] Embodiment 101. Any of the embodiments described above, wherein the acid includes hydrochloric acid.

[0391] Embodiment 102. Any of the embodiments described above, wherein the acid is hydrochloric acid.

[0392] Embodiment 103. Any method of the embodiments described above, wherein the acid is introduced into the first-step reaction mixture independently of the addition of 2-propene-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. Any of the embodiments described above, wherein the acid is introduced into the first step reaction mixture as a component of 2-propene-1-ylamine or a salt thereof, 1,3-bis(allylamino)propane or a salt thereof, or an acid salt of both 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof.

[0394] Embodiment 105. Any of the embodiments described above, wherein the aqueous solid content is approximately 20 to approximately 60% by weight.

[0395] Embodiment 106. Any of the embodiments described above, wherein the aqueous solid content is approximately 30 to approximately 50% by weight.

[0396] Embodiment 107. Any of the embodiments described above, wherein the aqueous solid content is approximately 30 to approximately 45% by weight.

[0397] Embodiment 108. Any of the embodiments described above, wherein the aqueous solid content is approximately 43% by weight.

[0398] Embodiment 109. Any of the embodiments described above, wherein the poly(allylamine) polymer has the ability to absorb a swelling agent, 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. Any of the embodiments described above, wherein the poly(allylamine) polymer has the ability to absorb a swelling agent, the poly(allylamine) polymer is swollen with the swelling agent, and the poly(allylamine) polymer is deprotonated by a base before being swollen with the swelling agent.

[0400] Embodiment 111. Any of the embodiments described above, wherein the dispersion solvent system includes a nonpolar solvent.

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

[0402] Embodiment 113. Any of the embodiments described above, wherein the dispersion solvent system contains 1,2-dichloroethane.

[0403] Embodiment 114. Any of the embodiments described above, wherein the dispersion solvent system is stock solution 1,2-dichloroethane.

[0404] Embodiment 115. Any of the embodiments described above, wherein the swelling agent is immiscible with the dispersion solvent system.

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

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

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

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

[0409] Embodiment 120. Any of the embodiments described above, wherein the swelling agent is a polar solvent.

[0410] Embodiment 121. Any method of the embodiments described above, wherein the swelling agent is water, methanol, ethanol, n-propanol, isopropanol, n-butanol, formic acid, acetic acid, acetonitrile, dimethylformamide, dimethyl sulfoxide, nitromethane, propylene carbonate, or a combination thereof.

[0411] Embodiment 122. Any of the embodiments described above, wherein the swelling agent is water.

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

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

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

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

[0416] Embodiment 127. Any of the embodiments described above, wherein the swelling agent and 1,2-dichloroethane are immiscible.

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

[0418] Embodiment 129. Any of the embodiments described above, wherein the second-step reaction mixture is at a temperature in the range of about 25°C to about 85°C.

[0419] Embodiment 130. Any of the embodiments described above, wherein the second step reaction is carried out at a temperature in the range of approximately 35°C to approximately 80°C.

[0420] Embodiment 131. The second step reaction reaction is carried out at a temperature in the range of approximately 45°C to approximately 80°C, using any of the embodiments described above.

[0421] Embodiment 132. Any of the embodiments described above, wherein the second step reaction is carried out at a temperature in the range of approximately 55°C to approximately 75°C.

[0422] Embodiment 133. Any of the embodiments described above, wherein the second step reaction is carried out at a temperature in the range of approximately 60°C to approximately 75°C.

[0423] Embodiment 134. Any of the embodiments described above, wherein the second step reaction is carried out at a temperature in the range of approximately 65°C to approximately 75°C.

[0424] Embodiment 135. Any method of the embodiments described above, wherein the temperature of the second-step reaction mixture is maintained within 10% of the target temperature during the second step.

[0425] Embodiment 136. Any of the embodiments described above, wherein the temperature of the second-step reaction mixture is maintained relatively constant during the second step.

[0426] Embodiment 137. Any method of the embodiments described above, wherein the temperature of the second step reaction mixture is raised continuously or stepwise during the second step.

[0427] Embodiment 138. Any of the embodiments described above, wherein the reaction in the second step is carried out for a period of approximately 2 to 20 hours.

[0428] Embodiment 139. Any of the embodiments described above, wherein the reaction in the second step is carried out for a period of approximately 4 to 20 hours.

[0429] Embodiment 140. Any of the embodiments described above, wherein the reaction in the second step is carried out for a period of approximately 5 to 20 hours.

[0430] Embodiment 141. Any of the embodiments described above, wherein the reaction in the second step is carried out for a period of approximately 6 to 20 hours.

[0431] Embodiment 142. Any of the embodiments described above, wherein the reaction in the second step is carried out for a period of approximately 8 to 20 hours.

[0432] Embodiment 143. Any of the embodiments described above, wherein the reaction in the second step is carried out for a period of approximately 10 to 20 hours.

[0433] Embodiment 144. Any of the embodiments described above, wherein the reaction in the second step is carried out for a period of approximately 12 to 18 hours.

[0434] Embodiment 145. Any of the embodiments described above, wherein the reaction in the second step is carried out for a period of approximately 14 to 18 hours.

[0435] Embodiment 146. Any of the embodiments described above, wherein the reaction in the second step is carried out for a period of approximately 15 to 17 hours.

[0436] Embodiment 147. A product obtained by any of the embodiments described above.

[0437] Embodiment 148. Bead-shaped cross-linked poly(allylamine) polymer produced by the previous embodiment of the method.

[0438] Embodiment 149. A bead-shaped crosslinked poly(allylamine) polymer essentially comprising (i) 20-25 mol% of N,N'-diallyl-1,3-diaminopropane or a salt thereof residues, (ii) 50-60 mol% of 2-propene-1-ylamine or a salt thereof residues, and (iii) 20-25 mol% of 1,2-dichloroethane residues, wherein (i) the crosslinked poly(allylamine) polymer is sp 2 (ii) containing allyl carbon atoms and having a swelling ratio of less than 2, and sp contained in poly(allylamine) polymers 2 A cross-linked poly(allylamine) polymer in which allyl carbons account for less than 1.0% of the total number of carbon atoms in the cross-linked poly(allylamine) polymer.

[0439] Embodiment 150. A cross-linked poly(allylamine) polymer in bead form comprising residues of 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof and 1,2-dichloroethane, wherein (i) the cross-linked poly(allylamine) polymer has a swelling ratio of less than 2 and (ii) the cross-linked poly(allylamine) polymer contains sp 2 Allyl carbon accounts for less than 1.0% of the total number of carbon atoms in the cross-linked poly(allylamine) polymer.

[0440] Embodiment 151. A cross-linked poly(allylamine) polymer in bead form comprising residues of 2-propene-1-ylamine or a salt thereof and 1,3-bis(allylamino)propane or a salt thereof and 1,2-dichloroethane, wherein (i) the cross-linked poly(allylamine) polymer contains less than 20 ppm of allylamine and (ii) sp contained in the cross-linked poly(allylamine) polymer.2 Allyl carbon accounts for less than 1.0% of the total number of carbon atoms in the cross-linked poly(allylamine) polymer.

[0441] Embodiment 152. sp contained in cross-linked poly(allylamine) polymer 2 Any of the embodiments described above, wherein the allyl carbon accounts for less than 0.9% of the total number of carbon atoms in the cross-linked poly(allylamine).

[0442] Embodiment 153. sp contained in cross-linked poly(allylamine) polymer 2 Any of the embodiments described above, wherein the allyl carbon accounts for less than 0.8% of the total number of carbon atoms in the cross-linked poly(allylamine).

[0443] Embodiment 154. sp contained in cross-linked poly(allylamine) polymer 2 Any of the embodiments described above, wherein the allyl carbon accounts for less than 0.75% of the total number of carbon atoms in the cross-linked poly(allylamine).

[0444] Embodiment 155. sp contained in cross-linked poly(allylamine) polymer 2 Any of the embodiments described above, wherein the allyl carbon accounts for less than 0.7% of the total number of carbon atoms in the cross-linked poly(allylamine).

[0445] Embodiment 156. sp contained in cross-linked poly(allylamine) polymer 2 Any of the embodiments described above, wherein the allyl carbon accounts for less than 0.6% of the total number of carbon atoms in the cross-linked poly(allylamine).

[0446] Embodiment 157. sp contained in cross-linked poly(allylamine) polymer 2 Any of the embodiments described above, wherein the allyl carbon accounts for less than 0.5% of the total number of carbon atoms in the cross-linked poly(allylamine).

[0447] Embodiment 158. sp contained in cross-linked poly(allylamine) polymer 2Any of the embodiments described above, wherein the allyl carbon accounts for less than 0.4% of the total number of carbon atoms in the cross-linked poly(allylamine).

[0448] Embodiment 158A. sp contained in cross-linked poly(allylamine) polymer 2 Any of the embodiments described above, wherein the allyl carbon accounts for more than 0.3% of the total number of carbon atoms in the cross-linked poly(allylamine).

[0449] Embodiment 159. sp contained in cross-linked poly(allylamine) polymer 2 Any of the embodiments described above, wherein the allyl carbon accounts for less than 0.3% of the total number of carbon atoms in the cross-linked poly(allylamine).

[0450] Embodiment 160. sp contained in cross-linked poly(allylamine) polymer 2 Any of the embodiments described above, wherein the allyl carbon accounts for less than 0.25% of the total number of carbon atoms in the cross-linked poly(allylamine).

[0451] Embodiment 161. sp contained in cross-linked poly(allylamine) polymer 2 Any of the embodiments described above, or a cross-linked poly(allylamine) polymer, wherein the allyl carbon accounts for less than 0.2% of the total number of carbon atoms in the cross-linked poly(allylamine) polymer.

[0452] Embodiment 162. sp contained in cross-linked poly(allylamine) polymer 2 Any of the embodiments described above, or a cross-linked poly(allylamine) polymer, wherein the allyl carbon accounts for less than 0.1% of the total number of carbon atoms in the cross-linked poly(allylamine) polymer.

[0453] Embodiment 163. sp contained in poly(allylamine) polymer 2 The percentage of allyl carbon was determined by NMR; optionally, 110-150 ppm sp 2 The integral of the allyl carbon peak and the alkyl carbon peak from 0 to 80 ppm is given by the formula

number

[0454] Embodiment 164. sp contained in cross-linked poly(allylamine) polymer 2 A cross-linked poly(allylamine) polymer, or any of the embodiments described above, wherein the number of allyl carbons, if any, is determined by NMR and is below the detection limit.

[0455] Embodiment 165. Any method of the above embodiments or a cross-linked poly(allylamine) polymer comprising a cross-linked poly(allylamine) polymer containing less than 15 ppm of allylamine.

[0456] Embodiment 166. Any method of the above embodiments or a cross-linked poly(allylamine) polymer comprising a cross-linked poly(allylamine) polymer containing less than 12.5 ppm of allylamine.

[0457] Embodiment 167. Any method of the above embodiments or a cross-linked poly(allylamine) polymer comprising a cross-linked poly(allylamine) polymer containing less than 10 ppm of allylamine.

[0458] Embodiment 168. Any method of the above embodiments or a cross-linked poly(allylamine) polymer comprising less than 7.5 ppm of allylamine.

[0459] Embodiment 169. Any method of the above embodiments or a cross-linked poly(allylamine) polymer comprising less than 5 ppm of allylamine in the cross-linked poly(allylamine) polymer.

[0460] Embodiment 170. Any method of the above embodiments or a cross-linked poly(allylamine) polymer comprising less than 4 ppm of allylamine in the cross-linked poly(allylamine) polymer.

[0461] Embodiment 171. Any method of the above embodiments or a cross-linked poly(allylamine) polymer comprising less than 3 ppm of allylamine in the cross-linked poly(allylamine) polymer.

[0462] Embodiment 172. Any of the above embodiments or a cross-linked poly(allylamine) polymer comprising a cross-linked poly(allylamine) polymer containing less than 2 ppm of allylamine.

[0463] Embodiment 173. Any of the above embodiments or a cross-linked poly(allylamine) polymer comprising a cross-linked poly(allylamine) polymer containing less than 1 ppm of allylamine.

[0464] Embodiment 174. Any of the embodiments described above or a cross-linked poly(allylamine) polymer comprising a cross-linked poly(allylamine) polymer containing less than 500 ppb of allylamine.

[0465] Embodiment 175. Any method of the above embodiments or a cross-linked poly(allylamine) polymer comprising a cross-linked poly(allylamine) polymer containing less than 100 ppb of allylamine.

[0466] Embodiment 176. Any method of the above embodiments or a cross-linked poly(allylamine) polymer comprising a cross-linked poly(allylamine) polymer containing less than 50 ppb of allylamine.

[0467] Embodiment 177. Any method of the above embodiments or a cross-linked poly(allylamine) polymer comprising a cross-linked poly(allylamine) polymer containing less than 1 ppb of allylamine.

[0468] Embodiment 178. Any of the embodiments described above or a cross-linked poly(allylamine) polymer having a swelling ratio of less than 1.9.

[0469] Embodiment 179. Any of the embodiments described above or a cross-linked poly(allylamine) polymer having a swelling ratio of less than 1.8.

[0470] Embodiment 180. Any of the embodiments described above or a cross-linked poly(allylamine) polymer having a swelling ratio of less than 1.7.

[0471] Embodiment 181. Any of the embodiments described above or a cross-linked poly(allylamine) polymer having a swelling ratio of less than 1.6.

[0472] Embodiment 182. Any of the embodiments described above or a cross-linked poly(allylamine) polymer having a swelling ratio of less than 1.5.

[0473] Embodiment 183. Any of the embodiments described above or a cross-linked poly(allylamine) polymer having a swelling ratio of less than 1.4.

[0474] Embodiment 184. Any of the embodiments described above or a cross-linked poly(allylamine) polymer having a swelling ratio of less than 1.3.

[0475] Embodiment 185. Any of the embodiments described above or a cross-linked poly(allylamine) polymer having a swelling ratio of less than 1.2.

[0476] Embodiment 186. Any of the embodiments described above or a cross-linked poly(allylamine) polymer having a swelling ratio of less than 1.1.

[0477] Embodiment 187. Any method of the above embodiments or a cross-linked poly(allylamine) polymer having a swelling ratio of less than 1.

[0478] Embodiment 188. Any of the embodiments described above or a cross-linked poly(allylamine) polymer having a swelling ratio of less than 0.9.

[0479] Embodiment 189. Any of the embodiments described above or a cross-linked poly(allylamine) polymer having a swelling ratio of less than 0.8.

[0480] Embodiment 190. Any of the embodiments described above or a cross-linked poly(allylamine) polymer having a swelling ratio of less than 0.7.

[0481] Embodiment 191. A poly(allylamine) polymer having a stability profile such that, after being stored in a sealed enclosure at 25°C for 3 months after production, the poly(allylamine) polymer contains less than 20 ppm of allylamine, by any of the embodiments described above or by a cross-linked poly(allylamine) polymer.

[0482] Embodiment 192. A cross-linked poly(allylamine) polymer, wherein the poly(allylamine) polymer contains less than 15 ppm of allylamine after being stored at 25°C for 3 months in a sealed enclosure after production, by any of the embodiments described above.

[0483] Embodiment 193. A cross-linked poly(allylamine) polymer, which contains less than 12.5 ppm of allylamine after being stored at 25°C for 3 months in a sealed enclosure after production, by any of the embodiments described above.

[0484] Embodiment 194. A cross-linked poly(allylamine) polymer, wherein the poly(allylamine) polymer contains less than 10 ppm of allylamine after being stored in a sealed enclosure at 25°C for 3 months after production, by any of the embodiments described above.

[0485] Embodiment 195. A cross-linked poly(allylamine) polymer, which contains less than 7.5 ppm of allylamine after being stored at 25°C for 3 months in a sealed enclosure after production, by any of the embodiments described above.

[0486] Embodiment 196. A cross-linked poly(allylamine) polymer, which contains less than 5 ppm of allylamine after being stored at 25°C for 3 months in a sealed enclosure after production, by any of the embodiments described above.

[0487] Embodiment 197. A cross-linked poly(allylamine) polymer, which contains less than 4 ppm of allylamine after being stored at 25°C in a sealed enclosure for 3 months after production, by any of the embodiments described above.

[0488] Embodiment 198. A cross-linked poly(allylamine) polymer, which contains less than 3 ppm of allylamine after being stored at 25°C in a sealed enclosure for 3 months after production, by any of the embodiments described above.

[0489] Embodiment 199. A cross-linked poly(allylamine) polymer, which contains less than 2 ppm of allylamine after being stored at 25°C for 3 months in a sealed enclosure after production, by any of the embodiments described above.

[0490] Embodiment 200. A cross-linked poly(allylamine) polymer, which contains less than 1 ppm of allylamine after being stored at 25°C in a sealed enclosure for 3 months after production, by any of the embodiments described above.

[0491] Embodiment 201. A cross-linked poly(allylamine) polymer, wherein the poly(allylamine) polymer contains less than 500 ppb of allylamine after being stored in a sealed enclosure at 25°C for 3 months after production, using any of the embodiments described above.

[0492] Embodiment 202. A cross-linked poly(allylamine) polymer, wherein the poly(allylamine) polymer contains less than 100 ppb of allylamine after being stored in a sealed enclosure at 25°C for 3 months after production, by any of the embodiments described above.

[0493] Embodiment 203. A cross-linked poly(allylamine) polymer, wherein the poly(allylamine) polymer contains less than 50 ppb of allylamine after being stored in a sealed enclosure at 25°C for 3 months after production, by any of the embodiments described above.

[0494] Embodiment 204. A cross-linked poly(allylamine) polymer, wherein the poly(allylamine) polymer contains less than 1 ppb of allylamine after being stored in a sealed enclosure at 25°C for 3 months after production, by any of the embodiments described above.

[0495] Embodiment 205. A cross-linked poly(allylamine) polymer, any poly(allylamine) polymer, wherein the amount of allylamine in the poly(allylamine) polymer is below the detection limit of allylamine after being stored in a sealed enclosure at 25°C for three months after manufacture.

[0496] Embodiment 206. A poly(allylamine) polymer having a stability profile such that, after being sealed in a sealed enclosure at 25°C for 6 months after production, the poly(allylamine) polymer contains less than 20 ppm of allylamine, by any of the embodiments described above or a cross-linked poly(allylamine) polymer.

[0497] Embodiment 207. A cross-linked poly(allylamine) polymer, wherein the poly(allylamine) polymer contains less than 15 ppm of allylamine after being stored at 25°C for 6 months in a sealed enclosure after production, by any of the embodiments described above.

[0498] Embodiment 208. A cross-linked poly(allylamine) polymer, which contains less than 12.5 ppm of allylamine after being stored at 25°C for 6 months in a sealed enclosure after production, by any of the embodiments described above.

[0499] Embodiment 209. A cross-linked poly(allylamine) polymer, which contains less than 10 ppm of allylamine after being stored at 25°C for 6 months in a sealed enclosure after production, by any of the embodiments described above.

[0500] Embodiment 210. A cross-linked poly(allylamine) polymer, which contains less than 7.5 ppm of allylamine after being stored at 25°C for 6 months in a sealed enclosure after production, by any of the embodiments described above.

[0501] Embodiment 211. A cross-linked poly(allylamine) polymer, which contains less than 5 ppm of allylamine after being stored at 25°C for 6 months in a sealed enclosure after production, by any of the embodiments described above.

[0502] Embodiment 212. A cross-linked poly(allylamine) polymer, wherein the poly(allylamine) polymer contains less than 4 ppm of allylamine after being stored at 25°C for 6 months in a sealed enclosure after production, by any of the embodiments described above.

[0503] Embodiment 213. A cross-linked poly(allylamine) polymer, wherein the poly(allylamine) polymer contains less than 3 ppm of allylamine after being stored at 25°C for 6 months in a sealed enclosure after production, by any of the embodiments described above.

[0504] Embodiment 214. A cross-linked poly(allylamine) polymer, wherein the poly(allylamine) polymer contains less than 2 ppm of allylamine after being stored at 25°C for 6 months in a sealed enclosure after production, by any of the embodiments described above.

[0505] Embodiment 215. A cross-linked poly(allylamine) polymer, which contains less than 1 ppm of allylamine after being stored at 25°C for 6 months in a sealed enclosure after production, by any of the embodiments described above.

[0506] Embodiment 216. A cross-linked poly(allylamine) polymer, wherein the poly(allylamine) polymer contains less than 500 ppb of allylamine after being stored in a sealed enclosure at 25°C for 6 months after production, by any of the embodiments described above.

[0507] Embodiment 217. A cross-linked poly(allylamine) polymer, wherein the poly(allylamine) polymer contains less than 100 ppb of allylamine after being stored at 25°C for 6 months in a sealed enclosure after production, by any of the embodiments described above.

[0508] Embodiment 218. A cross-linked poly(allylamine) polymer, wherein the poly(allylamine) polymer contains less than 50 ppb of allylamine after being stored in a sealed enclosure at 25°C for 6 months after production, by any of the embodiments described above.

[0509] Embodiment 219. A cross-linked poly(allylamine) polymer, wherein the poly(allylamine) polymer contains less than 1 ppb of allylamine after being stored at 25°C for 6 months in a sealed enclosure after production, by any of the embodiments described above.

[0510] Embodiment 220. A cross-linked poly(allylamine) polymer, any amount of allylamine present in the poly(allylamine) polymer is below the detection limit of allylamine after being stored in a sealed enclosure at 25°C for 6 months after manufacture, according to any of the embodiments described above.

[0511] Embodiment 221. A poly(allylamine) polymer having a stability profile such that, after being stored in a sealed enclosure at 25°C for 9 months after production, the poly(allylamine) polymer contains less than 20 ppm of allylamine, by any of the embodiments described above or by a cross-linked poly(allylamine) polymer.

[0512] Embodiment 221A. A poly(allylamine) polymer having a stability profile such that, after being stored in a sealed enclosure at 25°C for 9 months after production, the poly(allylamine) polymer contains less than 15 ppm of allylamine, by any of the embodiments described above or by a cross-linked poly(allylamine) polymer.

[0513] Embodiment 222. A cross-linked poly(allylamine) polymer, wherein the poly(allylamine) polymer contains less than 12.5 ppm of allylamine after being stored in a sealed enclosure at 25°C for 9 months after production, by any of the embodiments described above.

[0514] Embodiment 223. A cross-linked poly(allylamine) polymer, which contains less than 10 ppm of allylamine after being stored at 25°C for 9 months in a sealed enclosure after production, by any of the embodiments described above.

[0515] Embodiment 224. A cross-linked poly(allylamine) polymer, wherein the poly(allylamine) polymer contains less than 7.5 ppm of allylamine after being stored in a sealed enclosure at 25°C for 9 months after production, by any of the embodiments described above.

[0516] Embodiment 225. A cross-linked poly(allylamine) polymer, which contains less than 5 ppm of allylamine after being stored at 25°C for 9 months in a sealed enclosure after production, by any of the embodiments described above.

[0517] Embodiment 226. A cross-linked poly(allylamine) polymer, wherein the poly(allylamine) polymer contains less than 4 ppm of allylamine after being stored in a sealed enclosure at 25°C for 9 months after production, by any of the embodiments described above.

[0518] Embodiment 227. A cross-linked poly(allylamine) polymer, which contains less than 3 ppm of allylamine after being stored at 25°C for 9 months in a sealed enclosure after production, by any of the embodiments described above.

[0519] Embodiment 228. A cross-linked poly(allylamine) polymer, wherein the poly(allylamine) polymer contains less than 2 ppm of allylamine after being stored in a sealed enclosure at 25°C for 9 months after production, by any of the embodiments described above.

[0520] Embodiment 229. A cross-linked poly(allylamine) polymer, which contains less than 1 ppm of allylamine after being stored at 25°C for 9 months in a sealed enclosure after production, by any of the embodiments described above.

[0521] Embodiment 230. A cross-linked poly(allylamine) polymer, wherein the poly(allylamine) polymer contains less than 500 ppb of allylamine after being stored in a sealed enclosure at 25°C for 9 months after production, using any of the embodiments described above.

[0522] Embodiment 231. A cross-linked poly(allylamine) polymer, wherein the poly(allylamine) polymer contains less than 100 ppb of allylamine after being stored in a sealed enclosure at 25°C for 9 months after production, by any of the embodiments described above.

[0523] Embodiment 232. A cross-linked poly(allylamine) polymer, wherein the poly(allylamine) polymer contains less than 50 ppb of allylamine after being stored in a sealed enclosure at 25°C for 9 months after production, using any of the embodiments described above.

[0524] Embodiment 233. A cross-linked poly(allylamine) polymer, wherein the poly(allylamine) polymer contains less than 1 ppb of allylamine after being stored in a sealed enclosure at 25°C for 9 months after production, by any of the embodiments described above.

[0525] Embodiment 234. A cross-linked poly(allylamine) polymer, any poly(allylamine) polymer in which the amount of allylamine, if present, is below the detection limit of allylamine after being stored in a sealed enclosure at 25°C for 9 months after manufacture.

[0526] Embodiment 235. A poly(allylamine) polymer having a stability profile such that, after being stored in a sealed enclosure at 25°C for 12 months after production, the poly(allylamine) polymer contains less than 20 ppm of allylamine, by any of the embodiments described above or by a cross-linked poly(allylamine) polymer.

[0527] Embodiment 236. A cross-linked poly(allylamine) polymer, wherein the poly(allylamine) polymer contains ...

Claims

1. The cross-linked poly(allylamine) polymer is a bevelomer, and less than 1.0% of the total number of carbon atoms present in the cross-linked poly(allylamine) polymer is sp ２ A cross-linked poly(allylamine) polymer containing allyl carbon atoms.

2. Less than 0.9% of the total number of carbon atoms present in the cross-linked poly(allylamine) polymer is sp ２ The crosslinked poly(allylamine) polymer according to claim 1, wherein the carbon atom is allyl.

3. Less than 0.8% of the total number of carbon atoms present in the cross-linked poly(allylamine) polymer is sp ２ A crosslinked poly(allylamine) polymer according to claim 1 or 2, wherein the carbon atom is allyl carbon.

4. Less than 0.7% of the total number of carbon atoms present in the cross-linked poly(allylamine) polymer is sp ２ A crosslinked poly(allylamine) polymer according to any one of claims 1 to 3, wherein the carbon atom is allyl.

5. Less than 0.6% of the total number of carbon atoms present in the cross-linked poly(allylamine) polymer is sp ２ A crosslinked poly(allylamine) polymer according to any one of claims 1 to 4, wherein the allyl carbon is an allyl carbon.

6. More than 0.3% of the total number of carbon atoms present in the cross-linked poly(allylamine) polymer is sp ２ A crosslinked poly(allylamine) polymer according to any one of claims 1 to 5, wherein the carbon atom is allyl.

7. sp ２ The percentage of allyl carbon in cross-linked poly(allylamine) polymers ２ A cross-linked poly(allylamine) polymer according to any one of claims 1 to 6, which can be determined by measuring the percentage of allyl carbons.

8. sp ２ sp measured in the poly(allylamine) polymer crosslinked to produce the crosslinked poly(allylamine) polymer, where the percentage of allyl carbon ２ sp in the crosslinked poly(allylamine) polymer from the percentage of allyl carbon ２ A crosslinked poly(allylamine) polymer according to any one of claims 1 to 7, which can be determined by calculating the percentage of allyl carbon.

9. sp in cross-linked poly(allylamine) polymers ２ The percentage of allyl carbons in poly(allylamine) polymers is sp ２ The crosslinked poly(allylamine) polymer according to claim 8, wherein the percentage of allyl carbons can be determined by multiplying it by 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.

10. The cross-linked poly(allylamine) polymer according to claim 9, wherein the ratio of the carbon-to-nitrogen weight ratio of the poly(allylamine) polymer to the carbon-to-nitrogen weight ratio of the cross-linked poly(allylamine) polymer is approximately 0.

9.

11. A cross-linked poly(allylamine) polymer according to claim 9 or claim 10, wherein the carbon-to-nitrogen weight ratio of the poly(allylamine) polymer and the carbon-to-nitrogen weight ratio of the cross-linked poly(allylamine) polymer can be determined by elemental analysis.

12. sp in cross-linked poly(allylamine) polymers ２ The percentage of allyl carbon is １３ A cross-linked poly(allylamine) polymer according to any one of claims 1 to 7, which can be determined by 13C NMR.

13. sp in poly(allylamine) polymers ２ The percentage of allyl carbon is １３ A cross-linked poly(allylamine) polymer according to any one of claims 8 to 11, which can be determined by 13C NMR.

14. sp 110-150 ppm ２ The integral of the allyl carbon peak and the alkyl carbon peak from 0 to 80 ppm is given by the formula [Math 1] Using sp ２ A cross-linked poly(allylamine) polymer according to claim 12 or claim 13, for use in determining the percentage of allyl carbon.

15. １３ 13C NMR is quantitative １３ A cross-linked poly(allylamine) polymer according to any one of claims 12 to 14, wherein C is a solid-state magic angle rotation (MAS) NMR.

16. １３ 13C NMR is quantitative １３ A cross-linked poly(allylamine) polymer according to any one of claims 12 to 14, wherein the solid-state cross-polarization magic angle rotation (CPMAS) NMR is used.

17. Cross-linked poly(allylamine) polymer contains less than 20 ppm of allylamine (H) as an impurity. ２ C = CHCH ２ NH ２ A crosslinked poly(allylamine) polymer according to any one of claims 1 to 16, comprising ).

18. The crosslinked poly(allylamine) polymer of claim 17, wherein the allylamine content can be determined by a cationic extraction method.

19. A cross-linked poly(allylamine) polymer according to any one of claims 1 to 18, wherein, when tested by a heat stability assay (stability assay 2), the allylamine content of the cross-linked poly(allylamine) polymer increases by less than 2.5 ppm / day of allylamine.

20. A cross-linked poly(allylamine) polymer according to any one of claims 1 to 19, wherein, when tested by a heat stability assay (stability assay 2), the allylamine content of the cross-linked poly(allylamine) polymer increases by less than 2.0 ppm / day of allylamine.

21. A cross-linked poly(allylamine) polymer according to any one of claims 1 to 20, wherein, when tested by a heat stability assay (stability assay 2), the allylamine content of the cross-linked poly(allylamine) polymer increases by less than 1.5 ppm / day of allylamine.

22. A cross-linked poly(allylamine) polymer according to any one of claims 1 to 21, for use in a method for treating metabolic acidosis.

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