Proton binding polymers for oral administration

Abstract

Pharmaceutical compositions and methods for treating animals, including humans, and methods of making such compositions. The pharmaceutical compositions comprise crosslinked amine polymers and are useful, for example, in treating diseases or other metabolic disorders in animals, including humans, in which removal of protons and / or chloride ions from the gastrointestinal tract would provide a physiological benefit, such as normalizing serum bicarbonate concentration and blood pH.

Description

[0001] This application is a divisional application of Chinese Patent Application 201580075741.9, the original application of which was filed on December 10, 2015, and entitled "Proton Binding Polymers for Oral Administration."

[0002] The present invention relates generally to proton binding polymers for oral administration useful in the treatment of metabolic acidosis.

[0003] Metabolic acidosis is a condition that results from metabolic and dietary processes that produce non-volatile acids that accumulate in the body, resulting in a net increase in protons (H+) or loss of bicarbonate (HCO3 - ) ions. Metabolic acidosis occurs when the body accumulates acid produced by metabolic and dietary processes and the excess acid cannot be completely removed from the body by the kidneys. Chronic kidney disease is often associated with metabolic acidosis because of the inability to recover filtered bicarbonate (HCO3 -), synthesis of ammonia (ammonia production), and excretion of an incremental acid, the ability of the kidney to excrete hydrogen ions is reduced. Clinical practice guidelines recommend that alkali therapy be initiated in patients with non-dialysis dependent chronic kidney disease (CKD) when serum bicarbonate levels are <22 mEq / L to prevent or treat complications of metabolic acidosis. (Clinical practice guidelines for nutrition in chronic renal failure, K / DOQI, National Kidney Foundation, Am. J. Kidney Dis. 2000; 35:S1-140; Raphael, KL, Zhang, Y, Wei, G, et al. 2013, Serum bicarbonate and mortality in adults in NHANES III, Nephrol. Dial. Transplant 28:1207-1213). These complications include malnutrition and stunted growth in children, worsening bone disease, increased muscle degradation, decreased albumin synthesis, and increased inflammation.(Leman, J, Litzow, JR, Lennon, EJ. 1966. The effects of chronic acid loads in normal man: further evidence for the participation of bone mineral in the defense against chronic metabolic acidosis, J. Clin. Invest. 45: 1608-1614; Franch HA, Mitch WE, 1998, Catabolism in uremia: the impact of metabolic acidosis, J. Am. Soc. Nephrol. 9:S78-81; Ballmer, PE, McNurlan, MA, Hulter, HN et al., 1995, Chronic metabolic acidosis decreases albumin synthesis and induces negative nitrogen balance in humans, J. Clin. Invest. 95:39-45; Farwell, WR, Taylor, EN, 2010, Serum anion gap, bicarbonate and biomarkers of inflammation in healthy individuals in a national survey, CMAJ 182:137-141). When the estimated glomerular filtration rate is lower than 30 ml / min / 1.73 m. 2At times, there is a significant metabolic acidosis in a large proportion of patients. (KDOQI bone guidelines: American Journal of Kidney Diseases (2003) 42:S1-S201. (Suppl); Widmer B, Gerhardt RE, Harrington JT, Cohen JJ, Serum electrolyte and acid base composition: The influence of graded degrees of chronic renal failure, Arch Intern Med 139: 1099-1102, 1979; Dobre M, Yang, W, Chen J, et al. Association of serum bicarbonate with risk of renal and cardiovascular outcomes in CKD: a report from the chronic renal insufficiency cohort (CRIC) study. Am. J. Kidney Dis. 62:670-678, 2013; Yaqoob, MM. Acidosis and progression of chronic kidney disease. Curr. Opin. Nephrol. Hypertens. 19:489-492, 2010).

[0004] Regardless of the etiology, metabolic acidosis decreases extracellular fluid bicarbonate and thus extracellular pH. The relationship between serum pH and serum bicarbonate is described by the Henderson-Hasselbalch equation:

[0005] pH = pK' + log [HCO3 - ] / [(0.03 X PaCO2)]

[0006] where 0.03 is the physical solubility coefficient of CO2, [HCO3 - ] and PaCO2 are the concentrations of bicarbonate and partial pressure of carbon dioxide, respectively.

[0007] There are several laboratory tests that can be used to define metabolic acidosis. These tests primarily measure the concentration of bicarbonate (HCO3 - ) or protons (H + ) in various biological samples, including venous or arterial blood.

[0008] The most useful measurements for determining acidosis rely on the measurement of venous plasma bicarbonate (or total carbon dioxide [tCO2]), serum electrolytes Cl - , K + , and Na + , and the determination of the anion gap. In the clinical laboratory, the measurement of venous plasma or serum electrolytes includes the assessment of tCO2. This measurement reflects the sum of circulating CO2 [i.e., total CO2 represented by bicarbonate (HCO3 - ), carbonic acid (H2CO3), and dissolved CO2 (0.03 X PCO2)]. tCO2 can also be related to HCO3 - by using a simplified and standardized form of the Henderson-Hasselbalch equation: tCO2 = HCO3 - + 0.03 PCO2, where PCO2 is the measured CO2 partial pressure. Since the HCO3 - concentration is greater than 90% of tCO2, and there is a small amount of H2CO3, venous tCO2 is commonly used as a reasonable approximation of venous HCO3 - concentration in the blood. Abnormal plasma HCO3 - values of <22 mEq / L typically indicate metabolic acidosis, especially during the course of chronic kidney disease.

[0009] Changes in serum Cl - concentration can provide additional insight into possible acid-base imbalances, especially when they are not proportional to changes in serum Na + concentration. When this occurs, changes in serum Cl - concentration are typically associated with reciprocal changes in serum bicarbonate. Thus, in metabolic acidosis with a normal anion gap, serum Cl - increases >105 mEq / L when serum bicarbonate decreases <22 mEq / L.

[0010] Calculation of the anion gap [defined as serum Na + - (Cl - + HCO3 - )] is an important aspect of the diagnosis of metabolic acidosis. Metabolic acidosis can exist with a normal or elevated anion gap. However, an elevated anion gap is usually indicative of the presence of metabolic acidosis, regardless of whether serum HCO3 - is altered. An anion gap greater than 20 mEq / L (the normal anion gap is 8 to 12 mEq / L) is a typical feature of metabolic acidosis.

[0011] Arterial blood gases are used to identify the type of acid-base disturbance and to determine if a mixed disorder is present. In general, the results of arterial blood gas measurements should be interpreted in conjunction with the history, physical examination, and routine laboratory data listed above. Arterial blood gas measurements provide the arterial carbon dioxide tension (P a CO2), the acidity (pH), and the oxygen tension (P a O2) of the blood. The bicarbonate (HCO3 - ) concentration is calculated from the pH and PaCO2. The hallmark of metabolic acidosis is a pH < 7.35, a P a CO2< 35 mm Hg, and a HCO3 - < 22 mEq / L. The P a O2value (normal value 80-95 mm Hg) is not used in the diagnosis of metabolic acidosis but can help determine the cause. Acid-base disorders are first classified as respiratory or metabolic. Respiratory disorders result from abnormal pulmonary elimination of CO2, resulting in an excess (acidosis) or deficiency (alkalosis) of CO2 in the extracellular fluid. In respiratory acid-base disturbances, the change in serum bicarbonate (HCO3 - ) is initially a direct result of the change in Pco2, with further increases in Pco2 leading to increases in HCO3 - . (Adrogue HJ, Madias NE, 2003, Respiratory acidosis, respiratory alkalosis, and mixed disorders, in Johnson RJ, Feehally J (eds): Comprehensive Clinical Nephrology. London, CV Mosby, pp 167-182). Metabolic disorders are those resulting from excess intake or metabolic production or loss of nonvolatile acids or bases in the extracellular fluid. These changes are reflected as alterations in the concentration of the bicarbonate anion (HCO3 - ) in the blood; adaptations in this setting include buffer (immediate), respiratory (hours to days), and renal (days) mechanisms. (DuBose TD, MacDonald GA: renal tubular acidosis, 2002, in DuBose TD, Hamm LL (eds): Acid-base and electrolyte disorders: A companion to Brenner & Rector's the Kidney. Philadelphia, WB Saunders, pp 189-206).

[0012] The total hydrogen ion concentration in the blood is defined as the sum of the HCO3 -The ratio of the two quantities, the content (regulated by the kidney) and the PCO2 content (regulated by the lung), and is expressed as follows:

[0013] [H + ]∝(PCO2 / [HCO3 - ])

[0014] The result of the increase in total hydrogen ion concentration is a decrease in the main extracellular buffer, bicarbonate. Normal blood pH is between 7.38 and 7.42, corresponding to a hydrogen ion (H + ) concentration of 42 to 38 nmol / L (Goldberg M: Approach to Acid-Base Disorders. 2005. In Greenberg A, Cheung AK (eds) Primer on Kidney Diseases, National Kidney Foundation, Philadelphia, Elsevier-Saunders, pp 104-109). Bicarbonate (HCO3 - ) is the anion that buffers against pH disturbances in the body, and normal levels of plasma bicarbonate are in the range of 22-26 mEq / L (Szerlip HM: Metabolic Acidosis, 2005, In Greenberg A, Cheung AK (eds) Primer on Kidney Diseases, National Kidney Foundation, Philadelphia, Elsevier-Saunders, pp 74-89). Acidosis is a process that causes a decrease in blood pH (acidemia) and reflects the accumulation of hydrogen ions (H + ) and their subsequent buffering by bicarbonate ions (HCO3 - ), resulting in a decrease in serum bicarbonate. Metabolic acidosis can be expressed as follows:

[0015]

[0016] (Clinical practice guidelines for nutrition in chronic renal failure. K / DOQI, National Kidney Foundation. Am. J. Kidney Dis. 2000; 35:S1-140). Using this balance equation, the loss of one HCO3 - corresponds to the addition of one H + , and vice versa, the increase of one HCO3 - corresponds to the loss of one H+ Thus, changes in blood pH, particularly increases in H + CO3 - or equivalently by decreasing serum H + CO3

[0017] In order to maintain extracellular pH in the normal range, the daily production of acid must be excreted from the body. Acid production in the body results from the metabolism of dietary carbohydrates, fats, and amino acids. Complete oxidation of these metabolic substrates produces water and CO2. This CO2 produced by oxidation (~20,000 mmol / day) is effectively excreted by the lungs and represents the volatile acid component of acid-base balance.

[0018] In contrast, non-volatile acid (~50-100 mEq / day) is produced by the metabolism of sulfur- and phosphate-containing amino acids and nucleic acids. Additional non-volatile acid (lactic, butyric, acetic, other organic acids) is produced by incomplete oxidation of fats and carbohydrates and by carbohydrate metabolism in the colon, where bacteria residing in the colonic lumen convert substrates into small organic acids, which are then absorbed into the bloodstream. The impact of short-chain fatty acids on acidosis is minimized to some extent by anabolism (e.g., anabolism into longer-chain fatty acids) or catabolism into water and CO2.

[0019] The kidneys maintain pH balance in the blood by two mechanisms: reabsorption of filtered HCO3 - to prevent bicarbonate depletion and elimination of non-volatile acid from the urine. Both mechanisms are necessary to prevent bicarbonate depletion and acidosis.

[0020] In the first mechanism, the kidney reabsorbs HCO3 - filtered by the glomerulus. This reabsorption occurs in the proximal tubule and accounts for ~4500 mEq / day of reabsorbed HCO3 - This mechanism prevents loss of HCO3 - in the urine and thus prevents metabolic acidosis. In the second mechanism, the kidney eliminates sufficient H + CO3 + equal to the non-volatile acid produced daily by metabolism and oxidation of proteins, fats, and carbohydrates. This elimination of acid load is accomplished by two different pathways in the kidney, including active secretion of H - CO3

[0021] Thus, maintenance of acid-base balance requires normal kidney function. In the course of chronic kidney disease, HCO3 -filtration and recovery are impaired by the generation and secretion of ammonia. These defects rapidly lead to chronic metabolic acidosis, which in itself is an effective precursor to end-stage renal disease. As the metabolism continues to produce acid, the reduction in acid elimination will overwhelm the body's buffering capacity and result in a progressive decline in blood pH. + / HCO3 - balance, thus lowering the blood pH below the normal value of pH = 7.38-7.42.

[0022] Alkali therapy to treat metabolic acidosis is generally manifested as elevating and maintaining the plasma pH to greater than 7.20. Sodium bicarbonate (NaHC03) is the most commonly used agent to correct metabolic acidosis. NaHC03 can be administered intravenously in order to sufficiently elevate the serum HC03 - level to increase the pH to greater than 7.20. Additional correction depends on the individual situation, and can not be applicable if the underlying process is treatable or the patient is asymptomatic. This is especially true in certain forms of metabolic acidosis. For example, in high anion gap (AG) acidosis secondary to organic acid lactate and ketone accumulation, the isohydric anion is eventually metabolized to HC03 - When treating the underlying imbalance, the serum pH is corrected; thus, when alkali is provided to elevate the pH well above 7.20, caution should be exercised in these patients to prevent the increase in bicarbonate above the normal range (>26 mEq / L).

[0023] Citrate in the form of potassium or sodium salts is an appropriate alkali therapy for oral or IV administration, as it is metabolized by the liver and results in the formation of three moles of bicarbonate per mole of citrate. IV administered potassium citrate should be used with caution in the presence of renal impairment, and should be closely monitored to avoid hyperkalemia.

[0024] Intravenous sodium bicarbonate (NaHC03) solution can be administered if the metabolic acidosis is severe or if correction is not possible without administration of exogenous alkali. In persons with chronic metabolic acidosis, oral administration of alkali is the preferred approach to therapy. The most commonly used form of alkali for oral therapy includes NaHC03 tablets, where 1 g of NaHC03 is equivalent to 11.9 mEq of HC03 - However, the oral form of NaHC03 is not approved for medical use, and the package insert for intravenous sodium bicarbonate solution includes the following contraindications, warnings, and precautions (Hospira label for NDC 0409-3486-16):

[0025] Contraindications: Sodium bicarbonate injection, USP is contraindicated in patients who have lost chloride ions due to vomiting or continuous gastrointestinal suctioning and in patients receiving diuretics known to produce hypochloremic alkalosis.

[0026] Warnings: In patients with congestive heart failure, severe renal impairment, and in those with conditions where edema with sodium and / or fluid retention could be exacerbated, caution should be exercised when using sodium ion-containing solutions. In patients with reduced renal function, administration of sodium ion-containing solutions can lead to sodium retention. Intravenous administration of these solutions can cause fluid and / or solute overload which can result in serum electrolyte concentrations, dilution of plasma volume, excessive fluid in the body, congestive state, or pulmonary edema.

[0027] Caution: […] The potential for a large sodium load with bicarbonate administration requires careful use of sodium bicarbonate in patients with congestive heart failure or other edematous or sodium retaining states, and in patients with oliguria or anuria.

[0028] Acid-base imbalance is common in patients with chronic kidney disease and heart failure. Chronic kidney disease (CKD) progressively reduces the renal excretion of the approximately 1 mmol / kg body weight of hydrogen ions generated in healthy adults (Yaqoob, MM. 2010, Acidosis and progression of chronic kidney disease, Curr. Opin. Nephrol. Hyperten. 19: 489-492.). Accumulation of acid (H + ) in the body or depletion of base (HCO3 - ) leads to metabolic acidosis, a common complication in patients with CKD, especially when the glomerular filtration rate (GFR, a measure of kidney function) is less than 30 ml / min / 1.73 m 2Metabolic acidosis has profound long-term effects on protein and muscle metabolism, bone turnover, and the development of renal osteodystrophy. In addition, metabolic acidosis affects various paracrine and endocrine functions, also with long-term consequences such as increased inflammatory mediators, decreased leptin, insulin resistance, and increased production of corticosteroids and parathyroid hormone (Mitch WE, 1997, Influence of metabolic acidosis on nutrition, Am. J. Kidney Dis. 29:46-48.). The net effect of persistent metabolic acidosis in CKD patients is loss of bone and muscle mass, negative nitrogen balance, and acceleration of chronic kidney failure due to hormonal and cellular abnormalities (De Brito-Ashurst I, Varagunam M, Raftery MJ, et al., 2009, Bicarbonate supplementation slows progression of CKD and improves nutritional status, J. Am. Soc. Nephrol. 20:2075-2084). Conversely, potential concerns with the use of alkali therapy in CKD patients include expansion of extracellular fluid volume associated with sodium intake, which leads to development or worsening of hypertension, promotion of vascular calcification, and decompensation of existing heart failure. Patients with moderate (GFR 20-25% of normal) CKD first develop hyperchloremic acidosis with a normal anion gap, due to inability to recover filtered bicarbonate and inability to excrete proton and ammonium cations. As they progress to late CKD, the anion gap increases, reflecting continued decrease in the kidney's ability to excrete unexcreted proton- bound anions. Serum bicarbonate is rarely below 15 mmol / L in these patients, with a maximum elevated anion gap of about 20 mmol / L. Accumulated non-metabolizable anions in CKD are buffered by alkali salts from bone (Lemann J Jr, Bushinsky DA, Hamm LL Bone buffering of acid and base in humans. Am. J. Physiol Renal Physiol. 2003 Nov, 285(5):F811-32).

[0029] Most patients with chronic kidney disease have underlying diabetes (diabetic nephropathy) and hypertension, which leads to deterioration of kidney function. In almost all hypertensive patients, a high sodium intake will worsen hypertension. Therefore, kidney, heart failure, diabetes and hypertension guidelines strictly limit sodium intake in these patients to less than 1.5 g or 65 mEq per day (HFSA 2010 guidelines, Lindenfeld 2010, J Cardiac Failure V16 No 6 P475). Long-term antihypertensive therapy usually induces sodium excretion (diuretics) or alters the ability of the kidney to excrete sodium and water (such as, for example, "RAASi" drugs that inhibit the renin angiotensin aldosterone system). However, as kidney function worsens, diuretics become less effective because the tubules are unable to respond. RAASi drugs induce life-threatening hyperkalemia because they inhibit kidney potassium excretion. Given the additional sodium load, it is not reasonable to treat metabolic acidosis patients chronically with sodium-containing bases in amounts that often exceed the total recommended daily sodium intake. As a result, oral sodium bicarbonate is not usually prescribed chronically in these diabetic nephropathy patients. Potassium bicarbonate is also not acceptable because patients with CKD cannot easily excrete potassium, leading to severe hyperkalemia.

[0030] Despite these shortcomings, oral sodium bicarbonate has been studied in small subgroups of non-hypertensive CKD patients. As part of the Kidney Research National Dialogue, base therapy was identified as having the potential to slow CKD progression as well as correct metabolic acidosis. In normal individuals, the age-related decrease in glomerular filtration rate (GFR) is 0.75-1.0 ml / min / 1.73 m 2 . In patients with rapidly progressing CKD, a faster decrease of >4 ml / min / 1.73 m 2 per year can be observed.

[0031] In a outcomes study, De Brito-Ashurst et al. showed that bicarbonate supplementation preserved kidney function in CKD (De Brito-Ashurst I, Varagunam M, Raftery MJ, et al. 2009, Bicarbonate supplementation slows progression of CKD and improves nutritional status. J. Am. Soc. Nephrol. 20:2075-2084). This study included 134 patients with CKD (creatinine clearance [CrCl] 15-30 ml / min / 1.73 m 2) and 16-20 mmol / L serum bicarbonate, adult patients were randomized to receive oral sodium bicarbonate supplementation or standard-of-care for 2 years. In this study, the mean dose of bicarbonate was 1.82 g / day, which provided 22 mEq of bicarbonate daily. The primary endpoints were the rate of decline in CrCl, the proportion of patients with rapid CrCl decline (>3 ml / min / 1.73 m 2 / yr) and end-stage renal disease ("ESRD") (CrCl <10 ml / min). Compared with the control group, bicarbonate supplementation slowed the decline in CrCl (1.88 ml / min / 1.73 m 2 in patients receiving bicarbonate, versus a decline of 5.93 ml / min / 1.73 m 2 in the control group; P<0.0001). Patients receiving bicarbonate supplementation were significantly less likely to experience rapid progression (9% versus 45%; relative risk 0.15; 95% confidence interval 0.06-0.40; P<0.0001). Similarly, patients receiving bicarbonate supplementation were less likely to develop ESRD (6.5% versus 33%; relative risk 0.13; 95% confidence interval 0.04-0.40; P<0.001).

[0032] Hyperphosphatemia is a common complication in patients with CKD, particularly those with advanced or end-stage renal disease. Sevelamer hydrochloride is a commonly used ion-exchange resin to lower serum phosphate concentrations. However, reported drawbacks of this agent include metabolic acidosis, which is apparently due to net absorption of HCl during the binding of phosphate in the small intestine. Several studies in patients with CKD and hyperphosphatemia receiving hemodialysis or peritoneal dialysis found that use of sevelamer hydrochloride lowered serum bicarbonate concentrations (Brezina, 2004 Kidney Int. V66 S90 (2004) S39-S45; Fan, 2009 Nephrol Dial Transplant (2009) 24:3794).

[0033] Thus, in various aspects of the invention, compositions and methods for treating animals, including humans, and methods of making such compositions can be noted. The compositions comprise crosslinked amine polymers and can be used, for example, to treat diseases or other metabolic disorders in which removal of protons and / or chloride ions from the gastrointestinal tract would provide a physiologic benefit. For example, the polymers described herein can be used to modulate acid-base related diseases in animals, including humans. In one such embodiment, the polymers described herein can be used to normalize serum bicarbonate concentration and blood pH in animals, including humans. By way of another example, the polymers described herein can be used to treat acidosis. There are several different physiologic disorders that describe this imbalance, each of which can be treated with a polymer that binds and removes HC1.

[0034] Metabolic acidosis resulting from a net increase in acid includes processes that increase endogenous hydrogen ion production, such as ketoacidosis, L-lactic acidosis, D-lactic acidosis, and salicylate poisoning. Metabolism of ingested toxins such as methanol, ethylene glycol, and triose, can also increase hydrogen ion concentration. Reduced renal excretion of hydrogen ions in uremic acidosis and distal (type I) renal tubular acidosis are another cause of a net increase in acid in the body that leads to metabolic acidosis. Metabolic acidosis resulting from bicarbonate loss is a hallmark of proximal (type II) renal tubular acidosis. In addition, gastrointestinal loss of bicarbonate in acute or chronic diarrhea also leads to metabolic acidosis. Primary or secondary aldosteronism is a common disorder that leads to hyperkalemia and metabolic acidosis and forms the basis of the type IV renal tubular acidosis classification. Hyporeninemic hypoaldosteronism is the most frequently encountered variety of this disorder.

[0035] Another way to describe metabolic acidosis is in terms of anion gap. Causes of high anion gap acidosis include diabetic ketoacidosis, L-lactic acidosis, D-lactic acidosis, alcoholic ketoacidosis, starvation ketoacidosis, uremic acidosis associated with end-stage renal failure (CKD stages 4-5), salicylate poisoning, and exposure to selected toxins including methanol, ethylene, propylene glycol, and triose. Causes of normal anion gap acidosis include early stage renal failure (CKD stages 1-3), gastrointestinal loss of bicarbonate from acute or chronic diarrhea, distal (type I) renal tubular acidosis, proximal (type II) renal tubular acidosis, type IV renal tubular acidosis, dilutional acidosis associated with large volume intravenous fluid administration, and treatment of diabetic ketoacidosis resulting from loss of ketones in the urine.

[0036] With respect to lactic acidosis, hypoxic lactic acidosis is caused by an imbalance between oxygen balance and oxygen supply and is associated with tissue ischemia, seizures, extreme exercise, shock, cardiac arrest, low cardiac output and congestive heart failure, severe anemia, severe hypoxemia and carbon monoxide poisoning, vitamin deficiency, and sepsis. In other types of lactic acidosis, oxygen delivery is normal, but oxidative phosphorylation is impaired, usually as a result of cellular mitochondrial defects. This is common in inborn errors of metabolism or caused by ingestion of drugs or toxins. Alternative sugars used for tube feeding or as irrigants during surgery, such as fructose, sorbitol, can also cause a metabolism that triggers lactic acidosis.

[0037] There are three main types of renal tubular acidosis, each with different etiologies, with several subtypes. Distal (type I) renal tubular acidosis can be caused by genetic and genomic alterations, particularly HCO3 - / Cl - exchange protein (AE1) or H +Mutations in the / ATPase lead to examples of acquired distal (type I) renal tubular acidosis, including hyperparathyroidism, Sjogren’s syndrome, medullary sponge kidney, cryoglobulinemia, systemic lupus erythematosus, renal transplant rejection, chronic tubulointerstitial disease, and exposure to various drugs, including amphotericin B, lithium, ifosfamide, foscarnet, toluene, and vanadium. A special category of distal (type IV) renal tubular acidosis with hyperkalemia is found in lupus nephritis, obstructive nephropathy, sickle cell anemia, and voltage defects. Genetic examples include type I pseudohypoaldosteronism and type II pseudohypoaldosteronism (Gordon’s disease), and exposure to certain drugs (amiloride, triamterene, trimethoprim, and pentamidine) can also lead to distal (type IV) renal tubular acidosis with hyperkalemia. Proximal (type II) renal tubular acidosis can also be caused by genetic or acquired causes. Genetic causes include Wilson’s disease and Lowe’s syndrome. Acquired causes include cystinosis, galactosemia, multiple myeloma, light chain disease, amyloidosis, vitamin D deficiency, lead and mercury ingestion, and exposure to certain drugs, including ifosfamide, cidofovir, aminoglycosides, and acetazolamide. Isolated defects in bicarbonate reabsorption can be a cause of proximal (type II) renal tubular acidosis; examples of such defects include exposure to carbonic anhydrase inhibitors, acetazolamide, topiramate, sulfamylon, and carbonic anhydrase deficiency. Combined proximal and distal renal tubular acidosis (type III) is uncommon, resulting from defects in both proximal bicarbonate reabsorption and distal proton secretion. Mutations in the gene for cytosolic carbonic anhydrase, as well as certain drugs including ifosfamide, can cause the defect. Type IV renal tubular acidosis with hyperkalemia is a cause of metabolic acidosis. The primary etiology behind this type of acidosis is aldosterone deficiency; aldosterone reduction is caused by primary adrenal failure, the low-renin hypoadosteronism syndrome of old age (type IV RTA), Addison’s disease, and type I pseudohypoaldosteronism due to resistance to mineralocorticoids. Chronic interstitial nephritis due to analgesic nephropathy, chronic pyelonephritis, obstructive nephropathy, and sickle cell disease can also produce acidosis with hyperkalemia. Finally, drugs such as amiloride, spironolactone, triamterene, trimethoprim, heparin therapy, NSAIDs, angiotensin receptor blockers, and angiotensin-converting enzyme inhibitors can induce metabolic acidosis with hyperkalemia.

[0038] All of the above causes and etiologies of metabolic acidosis can be treated with polymers designed to bind and remove HC1 in the gastrointestinal tract.

[0039] Methods of treatment generally include administration of a therapeutically effective amount of a crosslinked amine polymer having the ability to remove protons and chloride ions from the gastrointestinal tract of an animal, such as a human. In general, such crosslinked amine polymers can have advantageous characteristics, such as relatively low swelling, relatively high binding of protons and chloride ions, and / or relatively low binding of interfering anions, such as phosphate, bicarbonate, citrate, short chain fatty acids, and bile acids.

[0040] In general, it is preferred that once the polymer becomes protonated, the polymer binds chloride ions as the counterion, rather than other "interfering" anions listed above, for example, as these interfering anions can metabolically equate to bicarbonate in the patient being treated. Removal of chloride ions from the body, as well as protons, by binding with the amine polymers of the present disclosure will have an alkalinizing effect, whereas removal of interfering anions can have less or even no alkalinizing effect.

[0041] In certain embodiments, the polymers preferably bind protons and anions found under physiological conditions along the gastrointestinal (GI) tract and retain their ability to bind the protons and anions. These conditions can vary according to dietary intake (see, e.g., 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 location along the GI tract (Binder, H, et al. Chapters 41-45, in "Medical Physiology", 2nd Edition, Elsevier

[2011] . Boron and Boulpaep [eds]). Rapid binding of protons and chloride ions in the stomach and small intestine is desirable. Subsequent high levels of binding and selectivity of chloride ions in the GI tract (lower small intestine and large intestine) are also desirable. In general, the polymers also preferably have a pK a such that a large fraction of the amines are protonated under the various pH and electrolyte conditions encountered along the GI tract and are thereby able to remove protons from the body, along with the appropriate counter anion, preferably chloride, into the feces.

[0042] Because the stomach is a rich source of HC1 and because the stomach is the first site of potential HC1 binding after the oral cavity, and because of the short residence time in the stomach (gastric residence half-life of approximately 90 minutes) compared to the residence time in the gastrointestinal tract (small intestinal transit time of approximately 4 hours; whole intestinal transit time of 2-3 days; Read, NW, et al., Gastroenterology

[1980] 79: 1276), it is desirable that the polymers of the present disclosure exhibit rapid proton and chloride binding kinetics in the lumen of this organ, and in in vitro conditions designed to mimic the stomach lumen (e.g., SGF). Phosphate is a potential interfering anion for chloride binding in the stomach and small intestine, and phosphate is most absorbed therein (Cross, HS, et al. Miner Electrolyte Metab

[1990] 16: 115-24). Thus, in the small intestine and in vitro conditions designed to mimic the small intestinal lumen (e.g., SIB), it is desirable that chloride be bound rapidly and preferentially over phosphate. Because the transit time in the colon is slower (2-3 days) relative to the small intestine, and because orally administered polymers will not encounter conditions in the colon until after encountering conditions in the stomach and small intestine, the kinetics of chloride binding by the polymers of the present disclosure will not necessarily be as rapid in the colon or in in vitro conditions designed to mimic the subsequent small intestine / colon (e.g., SOB). However, it is important that the importance of chloride binding and selectivity be high compared to interfering anions, e.g., over 24 and / or 48 hours or more.

[0043] In one embodiment, the crosslinked amine polymers are administered in the form of a pharmaceutical composition comprising the crosslinked amine polymers, and optionally a pharmaceutically acceptable carrier, diluent or excipient or combination thereof that does not significantly interfere with the proton and / or chloride binding characteristics of the crosslinked amine polymers in vivo. Optionally, the pharmaceutical composition can further comprise an additional therapeutic agent.

[0044] Another aspect of the present disclosure is a method for preparing a crosslinked amine polymer that can be administered in the form of a pharmaceutical composition. The method comprises crosslinking a preformed amine polymer in a reaction mixture comprising the preformed amine polymer, a solvent, a crosslinking agent, and a swelling agent for the preformed amine polymer. The swelling agent is preferably immiscible with the solvent, and the preformed amine polymer has an absorption capacity for the swelling agent, and the amount of the swelling agent in the reaction mixture is less than the absorption capacity of the preformed amine polymer for the swelling agent.

[0045] Another aspect of the present disclosure is a method for preparing a crosslinked amine polymer that can be administered in the form of a pharmaceutical composition. The method includes crosslinking a preformed amine polymer in a reaction mixture comprising the preformed amine polymer, a solvent, and a crosslinking agent to form a crosslinked amine polymer. Prior to the crosslinking step, the preformed amine polymer binds a first amount of chloride and a competing anion (e.g., phosphate, citrate, and / or taurocholate) in an appropriate assay (e.g., SIB or SOB), and after the crosslinking step, the crosslinked amine polymer binds a second (different) amount of chloride and the competing anion (e.g., phosphate, citrate, and / or taurocholate). For example, in one such embodiment, the second amount of the competing anion (e.g., phosphate, citrate, and / or taurocholate) binds relatively less compared to the first amount of the competing anion.

[0046] Amine monomers typically polymerize in free radical polymerization through their protonated form because free amines cause chain transfer reactions and often limit the degree of polymerization to low molecular weight. To overcome the limitations of electrostatic repulsion to crosslink and achieve crosslinking within the crosslinked particle, two discrete polymerization / crosslinking steps are performed according to one aspect of the present disclosure. In the first step, a preformed amine polymer is prepared. In the second polymerization / crosslinking step, the preformed amine polymer is deprotonated and further crosslinked to form a post-polymerized crosslinked polymer. Advantageously, the primary crosslinking reaction in the first step is between carbon atoms (i.e., carbon-carbon crosslinking), while the crosslinking in the second step occurs primarily between amine moieties comprised by the preformed amine polymer.

[0047] Another aspect of the present disclosure is a method for preparing a crosslinked amine polymer that includes two discrete polymerization / crosslinking steps. In the first step, a preformed amine polymer is formed having a chloride binding capacity of at least 10 mmol / g in simulated gastric fluid (“SGF”) and a swelling ratio in the range of 2 to 10. In the second step, the preformed amine polymer is crosslinked with a crosslinking agent comprising an amine-reactive moiety to form a post-polymerized crosslinked amine polymer. The resulting post-polymerized crosslinked amine polymer has a binding capacity for a competing anion (e.g., phosphate, citrate, and / or taurocholate) in an appropriate assay (e.g., SIB or SOB) that is less than the binding capacity of the preformed polymer for the competing anion (e.g., phosphate, citrate, and / or taurocholate) in the same appropriate assay (e.g., SIB or SOB). In one embodiment, the preformed amine polymer has a swelling ratio in the range of 3 to 8. In one such embodiment, the preformed amine polymer has a swelling ratio in the range of 4 to 6.

[0048] Another aspect of the present disclosure is a method for making a crosslinked amine polymer comprising two discrete crosslinking steps. In a first crosslinking step, a preformed amine polymer is formed, the preformed amine polymer having a chloride binding capacity in simulated gastric fluid ("SGF") of at least 10 mmol / g and a swelling ratio in the range of 2 to 10, and an average particle size of at least 80 microns. The preformed amine polymer is (at least partially) deprotonated with a base, and in a second step, the deprotonated preformed amine polymer is crosslinked with a crosslinking agent comprising an amine reactive moiety to form a post-polymerization crosslinked amine polymer. In one embodiment, the preformed amine polymer has a swelling ratio in the range of 3 to 8. In one such embodiment, the preformed amine polymer has a swelling ratio in the range of 4 to 6.

[0049] Another aspect of the present disclosure is a method for making a crosslinked amine polymer comprising two discrete polymerization / crosslinking steps. In a first step, a preformed amine polymer is formed, having a chloride binding capacity in simulated gastric fluid ("SGF") of at least 10 mmol / g and a swelling ratio in the range of 2 to 10. The preformed amine polymer is (at least partially) deprotonated with a base and contacted with a swelling agent to swell the deprotonated preformed amine polymer. In a second step, the swollen, deprotonated preformed amine polymer is crosslinked with a crosslinking agent comprising an amine reactive moiety to form a post-polymerization crosslinked amine polymer. In one embodiment, the preformed amine polymer has a swelling ratio in the range of 3 to 8. In one such embodiment, the preformed amine polymer has a swelling ratio in the range of 4 to 6.

[0050] Another aspect of the present disclosure is a pharmaceutical composition comprising a crosslinked amine polymer and a pharmaceutically acceptable excipient. The crosslinked amine polymer, for example, can be made as described in paragraphs

[0035] ,

[0036] ,

[0037] ,

[0038] ,

[0039] , or

[0040] .

[0051] Another aspect of the present disclosure is a pharmaceutical composition comprising a crosslinked amine polymer having a chloride binding capacity in simulated small intestinal inorganic buffer ("SIB") of at least 4 mmol / g. In one embodiment, the crosslinked amine polymer has a chloride binding capacity in simulated small intestinal inorganic buffer ("SIB") of at least 4.5, 5, 5.5, or even at least 6 mmol / g.

[0052] Another aspect of the present disclosure is a pharmaceutical composition comprising a crosslinked amine polymer having a ratio of chloride ion binding capacity to phosphate ion binding capacity of at least 2.3: 1, respectively, in Simulated Intestinal Inorganic Buffer ("SIB"). In one embodiment, the crosslinked amine polymer has a ratio of chloride ion binding capacity to phosphate ion binding capacity of at least 2.5: 1, 3: 1, 3.5: 1, or even 4: 1, respectively, in Simulated Intestinal Inorganic Buffer ("SIB").

[0053] Another aspect of the present disclosure is a pharmaceutical composition comprising a crosslinked amine polymer having a chloride ion binding capacity in Simulated Intestinal Inorganic Buffer ("SIB") of at least 1 mmol / g, a phosphate ion binding capacity in SIB of less than 0.4 mmol / g, and a chloride to phosphate ion binding ratio in SIB of at least 2.3: 1, respectively. In one such embodiment, the crosslinked amine polymer has a chloride ion binding capacity in Simulated Intestinal Inorganic Buffer ("SIB") of at least 1.5 mmol / g, a phosphate ion binding capacity in SIB of less than 0.6 mmol / g, and a chloride to phosphate ion binding ratio in SIB of at least 2.3: 1, respectively. In another such embodiment, the crosslinked amine polymer has a chloride ion binding capacity in Simulated Intestinal Inorganic Buffer ("SIB") of at least 2.0 mmol / g, a phosphate ion binding capacity in SIB of less than 0.8 mmol / g, and a chloride to phosphate ion binding ratio in SIB of at least 2.3: 1, respectively. In one such embodiment, the crosslinked amine polymer has a chloride ion binding capacity in Simulated Intestinal Inorganic Buffer ("SIB") of at least 2.5 mmol / g, a phosphate ion binding capacity in SIB of less than 1.0 mmol / g, and a chloride to phosphate ion binding ratio in SIB of at least 2.3: 1, respectively. In one such embodiment, the crosslinked amine polymer has a chloride ion binding capacity in Simulated Intestinal Inorganic Buffer ("SIB") of at least 3.0 mmol / g, a phosphate ion binding capacity in SIB of less than 1.3 mmol / g, and a chloride to phosphate ion binding ratio in SIB of at least 2.3: 1, respectively. In one such embodiment, the crosslinked amine polymer has a chloride ion binding capacity in Simulated Intestinal Inorganic Buffer ("SIB") of at least 3.5 mmol / g, a phosphate ion binding capacity in SIB of less than 1.5 mmol / g, and a chloride to phosphate ion binding ratio in SIB of at least 2.3: 1, respectively. In one such embodiment, the crosslinked amine polymer has a chloride ion binding capacity in Simulated Intestinal Inorganic Buffer ("SIB") of at least 4.0 mmol / g, a phosphate ion binding capacity in SIB of less than 1.7 mmol / g, and a chloride to phosphate ion binding ratio in SIB of at least 2.3: 1, respectively. In one such embodiment, the crosslinked amine polymer has a chloride ion binding capacity in Simulated Intestinal Inorganic Buffer ("SIB") of at least 4.5 mmol / g, a phosphate ion binding capacity in SIB of less than 1.9 mmol / g, and a chloride to phosphate ion binding ratio in SIB of at least 2.3: 1, respectively.In one such embodiment, the crosslinked amine polymer has a chloride ion binding capacity in simulated small intestinal inorganic buffer ("SIB") of at least 5.0 mmol / g, a phosphate ion binding capacity in SIB of less than 2.1 mmol / g, and a chloride to phosphate ion binding ratio in SIB of at least 2.3: 1, respectively. In each of the above embodiments, the crosslinked amine polymer can have a chloride to phosphate ion binding ratio in SIB of at least 2.5, at least 3, at least 3.5, or even at least 4, respectively.

[0054] Another aspect of the present disclosure is a pharmaceutical composition comprising a crosslinked amine polymer having a chloride ion binding capacity to phosphate ion binding capacity ratio in simulated small intestinal inorganic buffer ("SIB") of at least 2.3: 1, respectively, and a swell ratio of less than 5. For example, in one such embodiment, the crosslinked amine polymer can have a chloride to phosphate ion binding ratio in SIB of at least 2.3: 1, at least 2.5, at least 3, at least 3.5, or even at least 4, respectively, and a swell ratio of less than 5, less than 4, less than 3, less than 2, less than 1.5, or even less than 1.

[0055] Another aspect of the present disclosure is a pharmaceutical composition comprising a crosslinked amine polymer having a retained chloride ion content of at least 30% of the chloride ions initially bound in a gastrointestinal chamber transit assay ("GICTA"), i.e., bound in the SGF binding step. In one such embodiment, the crosslinked amine polymer has a retained chloride ion content of at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or even at least 90% of the chloride ions initially bound in the gastrointestinal chamber transit assay.

[0056] Another aspect of the present disclosure is a pharmaceutical composition comprising a crosslinked amine polymer having a retained chloride ion content of at least 30% of the chloride ions initially bound in a gastrointestinal chamber transit assay ("GICTA"), i.e., bound in the SGF binding step. In one such embodiment, the crosslinked amine polymer has a retained chloride ion content of at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or even at least 90% of the chloride ions initially bound in the gastrointestinal chamber transit assay.

[0057] Another aspect of the present disclosure is a pharmaceutical composition comprising a crosslinked amine polymer having a retained chloride content of at least 0.5 mmol chloride / g polymer in a Gastrointestinal Chamber Transit Assay ("GICTA"), and a chloride retention of at least 30% of the chloride initially bound in the GICTA (i.e., bound during the SGF binding step) at the end of the GICTA. In one such embodiment, the crosslinked amine polymer has a retained chloride content of at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or even at least 90% of the chloride initially bound in the Gastrointestinal Chamber Transit Assay, and a retained chloride content of at least 0.5, at least 1, at least 1.5, at least 2, at least 2.5, at least 3, at least 3.5, at least 4, at least 4.5, or even at least 5 mmol chloride / g polymer in a Gastrointestinal Chamber Transit Assay ("GICTA").

[0058] Another aspect of the present disclosure is a pharmaceutical composition comprising a crosslinked amine polymer having a chloride binding capacity of at least 5 mmol / g in a 1 hour Simulated Gastric Fluid ("SGF") assay, and a chloride binding capacity of at least 8 mmol / g in a 24 hour Simulated Gastric Fluid ("SGF") assay. In one such embodiment, the crosslinked amine polymer has a chloride binding capacity of at least 5 mmol / g in a 1 hour Simulated Gastric Fluid ("SGF") assay, and a chloride binding capacity of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, or even at least 14 mmol / g in a 24 hour Simulated Gastric Fluid ("SGF") assay.

[0059] Another aspect of the present disclosure is a pharmaceutical composition comprising a crosslinked amine polymer having a chloride binding capacity in a 1 hour Simulated Gastric Fluid ("SGF") assay that is at least 50% of its chloride binding capacity in a 24 hour Simulated Gastric Fluid ("SGF") assay. In one such embodiment, the crosslinked amine polymer has a chloride binding capacity in a 1 hour Simulated Gastric Fluid ("SGF") assay that is at least 50%, at least 60%, at least 70%, at least 80%, or even at least 90% of its chloride binding capacity in a 24 hour Simulated Gastric Fluid ("SGF") assay.

[0060] Another aspect of the present disclosure is a pharmaceutical composition comprising a crosslinked amine polymer having a chloride binding capacity of at least 5 mmol / g in a 1 hour simulated gastric fluid ("SGF") assay, a chloride binding capacity of at least 8 mmol / g in a 24 hour simulated gastric fluid ("SGF") assay, and a chloride binding capacity in the 1 hour simulated gastric fluid ("SGF") assay that is at least 50% of its chloride binding capacity in the 24 hour simulated gastric fluid ("SGF") assay. In one such embodiment, the crosslinked amine polymer has a chloride binding capacity of at least 5 mmol / g in a 1 hour simulated gastric fluid ("SGF") assay and a chloride binding capacity of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, or even at least 14 mmol / g in a 24 hour simulated gastric fluid ("SGF") assay, and the crosslinked amine polymer has a chloride binding capacity in the 1 hour simulated gastric fluid ("SGF") assay that is at least 50%, at least 60%, at least 70%, at least 80%, or even at least 90% of its chloride binding capacity in the 24 hour simulated gastric fluid ("SGF") assay.

[0061] Another aspect of the present disclosure is a pharmaceutical composition comprising a crosslinked amine polymer having a chloride binding capacity of at least 2.5 mmol chloride / g polymer in a 24 hour simulated small intestinal organic and inorganic buffer ("SOB") assay. In one such embodiment, the crosslinked amine polymer has a chloride binding capacity of at least 2.5, at least 3, at least 3.5, at least 4, at least 4.5, or even at least 5 mmol chloride / g polymer in a 24 hour simulated small intestinal organic and inorganic buffer ("SOB") assay.

[0062] Another aspect of the present disclosure is a pharmaceutical composition comprising a crosslinked amine polymer having a chloride binding capacity of at least 0.5 mmol chloride / g polymer in a 2 hour simulated small intestinal organic and inorganic buffer ("SOB") assay and a chloride binding capacity of at least 2.5 mmol chloride / g polymer in a 24 hour simulated small intestinal organic and inorganic buffer ("SOB") assay. In one such embodiment, the crosslinked amine polymer has a chloride binding capacity of at least 0.5, at least 1, at least 1.5, at least 2, at least 2.5, or even at least 3 mmol chloride / g polymer in a 2 hour simulated small intestinal organic and inorganic buffer ("SOB") assay and a chloride binding capacity of at least 2.5, at least 3, at least 3.5, at least 4, at least 4.5, or even at least 5 mmol chloride / g polymer in a 24 hour simulated small intestinal organic and inorganic buffer ("SOB") assay.

[0063] Another aspect of the present disclosure is a pharmaceutical composition comprising a crosslinked amine polymer having a chloride binding capacity of at least 2 mmol chloride ion / g polymer at 4 hours in Simulated Intestinal Inorganic Buffer ("SIB"). In one such embodiment, the crosslinked amine polymer has a chloride binding capacity of at least 2, at least 2.5, at least 3, at least 3.5, or even at least 4 mmol chloride ion / g polymer at 4 hours in Simulated Intestinal Inorganic Buffer ("SIB").

[0064] Another aspect of the present disclosure is a pharmaceutical composition comprising a crosslinked amine polymer having a chloride binding capacity of at least 2 mmol chloride ion / g polymer at 4 hours in Simulated Intestinal Inorganic Buffer ("SIB") and a chloride binding capacity of at least 2 mmol chloride ion / g polymer at 24 hours in Simulated Intestinal Inorganic Buffer ("SIB"). In one such embodiment, the crosslinked amine polymer has a chloride binding capacity of at least 2, at least 2.5, at least 3, at least 3.5, or even at least 4 mmol chloride ion / g polymer at 4 hours in Simulated Intestinal Inorganic Buffer ("SIB") and a chloride binding capacity of at least 2, at least 2.5, at least 3, at least 3.5, or even at least 4 mmol chloride ion / g polymer at 24 hours in Simulated Intestinal Inorganic Buffer ("SIB").

[0065] Another aspect of the present disclosure is a pharmaceutical composition comprising a crosslinked amine polymer having a chloride binding capacity of at least 5.5 mmol chloride ion / g polymer in a 24 hour Simulated Intestinal Organic and Inorganic Buffer ("SOB") assay. In one such embodiment, the crosslinked amine polymer has a chloride binding capacity of at least 6 mmol chloride ion / g polymer in a 24 hour Simulated Intestinal Organic and Inorganic Buffer ("SOB") assay.

[0066] Another aspect of the present disclosure is a pharmaceutical composition comprising a crosslinked amine polymer as described in any one of paragraphs

[0038] to

[0056] , wherein the crosslinked amine polymer has a pKa (measured at equilibrium in 100 mM NaCl) of at least 6. In one such embodiment, the crosslinked amine polymer has a pKa (measured at equilibrium in 100 mM NaCl) of at least 6.5, at least 7, or even at least 7.5.

[0067] Another aspect of the present disclosure is a pharmaceutical composition comprising a crosslinked amine polymer having (i) a proton binding capacity and a chloride ion binding capacity in simulated gastric fluid of at least 5 mmol / g; and (ii) a chloride ion binding capacity in simulated small intestinal inorganic buffer ("SIB") of at least 4 mmol / g at 1 hour.

[0068] Another aspect of the present disclosure is a pharmaceutical composition comprising a crosslinked amine polymer having (i) a proton binding capacity and a chloride ion binding capacity in simulated gastric fluid of at least 5 mmol / g; and (ii) a chloride ion binding capacity in simulated small intestinal inorganic buffer ("SIB") of at least 4 mmol / g at 1 hour.

[0069] Another aspect of the present disclosure is a pharmaceutical composition comprising a crosslinked amine polymer having (i) a proton binding capacity and a chloride ion binding capacity in simulated gastric fluid of at least 5 mmol / g; and (ii) a chloride ion binding capacity in simulated small intestinal inorganic buffer ("SIB") of at least (i) 2 mmol / g, (ii) 2.5 mmol / g, or (iii) 3 mmol / g at 1 hour.

[0070] Another aspect of the present disclosure is a pharmaceutical composition comprising a crosslinked amine polymer having (i) a proton binding capacity and a chloride ion binding capacity in simulated gastric fluid of at least 5 mmol / g; and (ii) a chloride ion to phosphate ion binding ratio of at least 2.3: 1, respectively, in simulated small intestinal inorganic buffer ("SIB").

[0071] Another aspect of the present disclosure is a pharmaceutical composition comprising a crosslinked amine polymer having (i) a proton binding capacity and a chloride ion binding capacity in simulated gastric fluid of at least 5 mmol / g at 1 hour; and (ii) a proton binding capacity and a chloride ion binding capacity in simulated gastric fluid of at least (a) 8 mmol / g, (b) 10 mmol / g, (c) 12 mmol / g, or (d) 14 mmol / g.

[0072] Another aspect of the present disclosure is a pharmaceutical composition comprising a crosslinked amine polymer having a proton binding capacity and a chloride ion binding capacity in simulated gastric fluid at 1 hour that is at least X% of the corresponding proton binding capacity and chloride ion binding capacity of the crosslinked amine polymer in simulated gastric fluid at 24 hours, wherein X% is at least (i) 50%, (ii) 60%, (iii) 70%, (iv) 80%, or even (v) 90%.

[0073] Another aspect of the present disclosure is a pharmaceutical composition comprising a crosslinked amine polymer having (i) selectivity for chloride over citrate, phosphate, and taurocholate in simulated small intestinal organic and inorganic buffer ("SOB") and (ii) a chloride binding capacity of at least 4 mmol / g at 24 hours in SOB.

[0074] Another aspect of the present disclosure is a pharmaceutical composition comprising a crosslinked amine polymer having selectivity for chloride over citrate, phosphate, and taurocholate in simulated small intestinal organic and inorganic buffer ("SOB") at (i) 1 hour, (ii) 4 hours, (iii) 12 hours, (iv) 18 hours, (v) 24 hours, (vi) 30 hours, (vii) 36 hours, or even (viii) 48 hours.

[0075] Another aspect of the present disclosure is a pharmaceutical composition comprising a crosslinked amine polymer having a chloride binding capacity of at least 4 mmol / g and a phosphate ion binding capacity of less than 2 mmol / g in simulated small intestinal inorganic buffer ("SIB") at (i) 1 hour, (ii) 2 hours, (iii) 3 hours, (iv) 4 hours, and / or (v) greater than 4 hours.

[0076] Other aspects and features will be in part apparent and in part described below. BRIEF DESCRIPTION OF DRAWINGS

[0077] Figures 1A-1C is a flow chart schematically depicting the mechanism of action of the polymer as it passes through the gastrointestinal tract of an individual from oral ingestion / gastric Figure 1A ) to the upper gastrointestinal tract Figure 1B ) to the lower gastrointestinal tract / colon Figure 1C ) to the lower gastrointestinal tract / colon

[0078] Figure 2 is a plot of chloride binding equilibration at different pH levels (Example 019067-A2), as more fully described in the Examples.

[0079] Figure 3 is a series of photographs showing particulate amine polymers exhibiting no aggregation in solvent-dispersed Step 2 reactions, as compared to aggregation in non-dispersed Step 2 reactions, as more fully described in the Examples.

[0080] Figure 4 is a plot of the swelling of preformed amine polymers according to one embodiment of the present disclosure relative to the amount of crosslinking agent used in the first polymerization / crosslinking step.

[0081] ABBREVIATIONS AND DEFINITIONS

[0082] The following definitions and methods are provided to better define the present application and to guide the practice of the application by others in the art. The terms are to be understood by those of ordinary skill in the relevant art in accordance with the conventional usage, unless otherwise indicated.

[0083] The term "absorption capacity" as used herein in connection with a polymer and a swelling agent (or, in the case of a mixture of swelling agents, a mixture of swelling agents) is the amount of swelling agent (or such mixture) absorbed by a given amount of dry mixture (e.g., in the form of dry beads) immersed in an excess of the swelling agent (or such mixture) at room temperature during a period of at least 16 hours.

[0084] The term "acrylamide" denotes a moiety having the structural formula H2C=CH-C(O)NR-* where * denotes the point of attachment of the moiety to the rest of the molecule, and R is hydrogen, a hydrocarbyl group, or a substituted hydrocarbyl group.

[0085] The term "acrylic acid" denotes a moiety having the structural formula H2C=CH-C(O)O-* where * denotes the point of attachment of the moiety to the rest of the molecule.

[0086] The term "alicyclic group," "alicyclic radical," or "alicyclic radical" means a saturated monocyclic group of 3 to 8 carbon atoms, including cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0087] The term "aliphatic group" denotes a saturated and non-aromatic unsaturated hydrocarbyl moiety having, for example, 1 to about 20 carbon atoms, or in specific embodiments, 1 to about 12 carbon atoms, 1 to about 10 carbon atoms, 1 to about 8 carbon atoms, or even 1 to about 4 carbon atoms. Aliphatic groups include, for example, alkyl moieties such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, i-pentyl, hexyl, and the like, as well as comparable chain lengths of alkenyl moieties.

[0088] The term "alkanol" denotes an alkyl moiety that has been substituted with at least one hydroxyl group. In some embodiments, an alkanol group is a "lower alkanol" group that includes 1 to 6 carbon atoms, in which one carbon atom is attached to an oxygen atom. In other embodiments, a lower alkanol group includes 1 to 3 carbon atoms.

[0089] The term "alkenyl" encompasses straight-chain or branched carbon groups having at least one carbon-carbon double bond. The term "alkenyl" can encompass conjugated or unconjugated carbon-carbon double bonds or a combination thereof. Alkenyl can encompass, for example and without limitation, from 2 to about 20 carbon atoms, or in a particular embodiment, from 2 to about 12 carbon atoms. In certain embodiments, alkenyl is a "lower alkenyl" group having from 2 to about 4 carbon atoms. Examples of alkenyl include, but are not limited to, ethenyl, propenyl, allyl, ethynyl, butenyl, and 4-methylbutenyl. The terms "alkenyl" and "lower alkenyl" encompass groups having "cis" or "trans" orientation or "E" or "Z" orientation.

[0090] The term "alkyl," used alone or in other terms such as "haloalkyl," "aminoalkyl," and "alkylamino," encompasses saturated straight-chain or branched carbon groups having, for example, from 1 to about 20 carbon atoms, or in a particular embodiment, from 1 to about 12 carbon atoms. In other embodiments, alkyl is a "lower alkyl" group having from 1 to about 6 carbon atoms. Examples of such groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, i-pentyl, hexyl, and the like. In a more particular embodiment, lower alkyl has from 1 to 4 carbon atoms.

[0091] The term "alkylamino" refers to an amino group directly attached to the remainder of the molecule through a nitrogen atom of the amino group, and wherein the nitrogen atom of the alkylamino group is substituted with 1 or 2 alkyl groups. In some embodiments, alkylamino is a "lower alkylamino" group having 1 or 2 alkyl groups of 1 to 6 carbon atoms attached to the nitrogen atom. In other embodiments, lower alkylamino has from 1 to 3 carbon atoms. Suitable "alkylamino" groups can be monoalkylamino or dialkylamino, such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, pentamethyleneamine, and the like.

[0092] The term "allyl" denotes a moiety having the structural formula H2C=CH-CH 2-* The term "allyl" denotes a moiety having the structural formula H2C=CH-CH

[0093] The term "allylamine" denotes a moiety having the structural formula H2C=CH-CH2N(X8)(X9), wherein X8and X9are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl, or X8and X9together form a substituted or unsubstituted alicyclic, aryl, or heterocyclic moiety, each as defined in connection with this term, typically having from 3 to 8 atoms in the ring.

[0094] The term "amine" or "amino" used alone or as part of another group, represents a radical of the formula -N(X8)(X9), where X8and X9are independently hydrogen, hydrocarbyl or substituted hydrocarbyl, heteroaryl or heterocyclyl, or X8and X9together form a substituted or unsubstituted alicyclic, aryl, or heterocyclyl moiety, each as defined in connection with this term, typically having from 3 to 8 atoms in the ring.

[0095] The term "aminoalkyl" encompasses straight-chain or branched alkyl groups having from 1 to about 10 carbon atoms, wherein any of the carbon atoms can be substituted with one or more amino groups, attached directly to the remainder of the molecule through an atom other than the nitrogen atom of the amine group. In some embodiments, the aminoalkyl is a "lower aminoalkyl" group having from 1 to 6 carbon atoms and one or more amino groups. Examples of such groups include aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminohexyl.

[0096] The term "aromatic group" or "aryl" refers to an aromatic group having one or more rings, wherein such rings can be attached to each other in a pendent manner or can be fused. In particular embodiments, the aromatic group is 1, 2, or 3 rings. A monocyclic aromatic group can contain from 5 to 10 carbon atoms in the ring, typically 5 to 7 carbon atoms, more typically 5 to 6 carbon atoms. Typical polycyclic aromatic groups have 2 or 3 rings. Polycyclic aromatic groups having 2 rings typically have from 8 to 12 carbon atoms in the rings, preferably 8 to 10 carbon atoms. Examples of aromatic groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl, or acenaphthyl.

[0097] The term "bead" is used to describe a crosslinked polymer that is substantially spherical.

[0098] The term "binds" as used herein in connection with a polymer and one or more ions (i.e., cations (e.g., "proton binding" polymers) and anions) is an "ion binding" polymer and / or has sufficient binding strength when it binds to an ion, although generally not necessarily in a non-covalent manner, that at least a portion of the ion remains bound under in vitro or in vivo conditions for a time sufficient for the polymer to be used to effect removal of the ion from solution or from the body.

[0099] The term "crosslinker," alone or in other terms, encompasses a linear or branched molecule that is capable of reacting more than once with either the monomers or infinite polymer network as described in Formula 1. The reactive groups in the crosslinker can include, but are not limited to, alkyl halides, epoxides, phosgene, anhydrides, carbamates, carbonates, isocyanates, isothiocyanates, esters, activated esters, carboxylic acids and derivatives, sulfonate esters and derivatives, acyl halides, aziridines, α,β-unsaturated carbonyls, ketones, aldehydes, pentafluoroaryl groups, vinyl groups, allyl groups, acrylates, methacrylates, acrylamides, methacrylamides, styrenes, acrylonitriles, and combinations thereof. In one exemplary embodiment, the reactive groups of the crosslinker include alkyl halides, epoxides, anhydrides, isocyanates, allyl groups, vinyl groups, acrylamides, and combinations thereof. In one such embodiment, the reactive groups of the crosslinker will be alkyl halides, epoxides, or allyl groups.

[0100] The term "diallylamine" means an amino moiety having 2 allyl groups.

[0101] The terms "dry bead" and "dry polymer" mean a bead or polymer that contains no more than 5 wt% of non-polymer swelling agent or solvent. Typically, the swelling agent / solvent is water remaining at the end of purification. This is typically removed by lyophilization or oven drying prior to storage or further crosslinking of the preformed amine polymer. The amount of swelling agent / solvent can be measured by heating (e.g., to 100-200 °C) and measuring the resulting change in weight. This is referred to as "loss on drying" or "LOD."

[0102] The term "ethereal" means a moiety having an oxygen bound to 2 separate carbon atoms as depicted by the structure x C-O-CH x * depicted moiety having an oxygen bound to 2 separate carbon atoms, where * indicates the point of attachment of the moiety to the rest of the molecule, and x independently equals 0, 1, 2, or 3.

[0103] The term "gel" is used to describe a crosslinked polymer having an irregular shape.

[0104] The term "Gastrointestinal Chamber Transport Assay" or "GICTA" refers to an assay in which free amine test polymers, including free amine sevelamer and bixalomer controls, are sequentially exposed to different buffers that simulate the different conditions to which the polymers will be exposed as they pass through the human gastrointestinal tract. In these different conditions, the incubation times are chosen to represent the approximate transit times of the polymers through specific sections of the gastrointestinal tract. The first step in the "GICTA" is to perform a "Simulated Gastric Fluid (SGF)" assay in which the polymers are incubated in SGF buffer at a polymer concentration of 2.5 mg / ml. The SGF composition reflects the typical ion concentrations in the stomach of a person who is fasting (described elsewhere). The polymers are incubated in solid phase extraction (SPE) tubes fitted with 20 micron pore size frits at 37°C for 1 hour. Blank SPE tubes containing SGF buffer without polymer are included and treated in the same manner throughout the "GICTA" screen. A 400 microliter sample is removed, filtered, diluted if necessary, and the chloride ion content is determined using ion chromatography. For each polymer being tested, the chloride ion binding is calculated using the following formula

[0105]

[0106] The binding capacity is expressed as mmol chloride ion per gram of polymer: where Clstartcorresponds to the initial concentration of chloride ion in the SGF buffer (mM), Cleqcorresponds to the equilibrium value of chloride ion in the diluted measured filtrate after 1 hour of exposure to the test polymer (mM), 4 is the dilution factor, and 2.5 is the polymer concentration (mg / ml). The SPE tubes are further rinsed twice with DI water and excess liquid is removed by applying negative pressure at the bottom. The simulated small intestine organic and inorganic (SOB) buffer is then added to the tubes to achieve a polymer concentration of 2.5 mg / ml (assuming no loss of polymer when sampling the supernatant for ion chromatography analysis in the SGF binding step). The concentrations of potential competing anions in the SOB buffer reflect the typical composition of fluids present in the small intestine (described elsewhere). The polymers are incubated in this buffer at 37°C for 2 hours. A 400 microliter sample is removed, filtered, diluted if necessary, and the ions bound or released in this buffer are determined using ion chromatography. For each polymer being tested, and for each anion present in the SOB buffer, the binding is calculated as mmol of anion bound per gram of polymer.

[0107]

[0108] where [ion] 起始 corresponds to the initial concentration of ion in the SOB buffer (mM), [ion] 最终corresponds to the final value (mM) of the particular ion measured in the filtrate after exposure to the test polymer, and 2.5 is the polymer concentration (mg / ml). Excess SOB buffer is then removed by applying negative pressure to the bottom of the tube, the tube is further rinsed twice with DI water, and excess liquid is removed by applying negative pressure to the bottom. A "retention buffer" is then added to the tube to achieve a polymer concentration of 2.5 mg / ml (assuming no loss of polymer when sampling the supernatant for ion chromatography analysis during the SGF and SOB binding steps). The retention buffer comprises 50 mM N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES), 100 mM sodium acetate, 2 mM sodium phosphate, 3 mM sodium sulfate, 17 mM sodium chloride, and 30 mM sodium bicarbonate, adjusted to pH 7. The anion composition in the retention buffer represents typical late colon lumen concentrations (Wrong, O, et al.

[1965] Clinical Science 28, 357-375). The SPE tube is capped and sealed and incubated at 37°C for approximately 40 hours, which is a typical transit time for the human large intestine (Metcalf, AM, et al. Gastroenterology

[1987] 92:40-47). A 400 microliter sample is removed, filtered, diluted if necessary, and the anion content is determined as described above for SOB. For each polymer tested, the following calculation is used to calculate the ions bound or released from the polymer in the retention matrix:

[0109]

[0110] where [ion] = the final concentration of the ion in the retention buffer (mM), and [ion] = the initial concentration of the ion in the retention buffer (mM). 起始 where [ion] = the final concentration of the ion in the retention buffer (mM), and [ion] = the initial concentration of the ion in the retention buffer (mM). 最终 corresponds to the final value (mM) of the particular ion measured in the filtrate after exposure to the test polymer for 40 hours, and 2.5 is the polymer concentration (mg / ml). Excess retention matrix is removed by applying negative pressure to the bottom of the SPE tube. The tube is further rinsed twice with DI water and excess liquid is removed by applying negative pressure to the bottom. The ions held bound to the polymer are eluted by adding 0.2 M NaOH to the SPE tube to achieve a final polymer concentration of 2.5 mg / ml (assuming no loss of polymer during the previous three binding steps) and incubating at 37°C for 16-20 hours. A 600 microliter sample is removed, filtered, diluted if necessary, and the anion content is determined as described above for SOB. For each polymer tested, the following calculation is used to calculate the ions released from the polymer in the retention matrix:

[0111]

[0112] where [ion] = the final concentration of the ion in the retention buffer (mM), and [ion] = the initial concentration of the ion in the retention buffer (mM). 起始corresponding to the initial concentration (mM) of the ion in the elution solution (0.2 M NaOH), [ion] 最终 corresponding to the final value (mM) of the particular ion measured in the filtrate after 20 hours exposure to the test polymer in 0.2 M NaOH, and 2.5 is the polymer concentration (mg / ml).

[0113] The term "halo" means a halogen, such as a fluorine, chlorine, bromine, or iodine atom.

[0114] The term "haloalkyl" encompasses groups in which any one or more of the alkyl carbon atoms are substituted with a halo group as defined above. Specifically encompassed are mono-haloalkyl, di-haloalkyl, and poly-haloalkyl groups, including per-haloalkyl groups. Mono-haloalkyl groups can have, for example, an iodine, bromine, chlorine, or fluorine atom within the group. Di- and poly-haloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups. "Lower haloalkyl" encompasses groups having 1-6 carbon atoms. In some embodiments, lower haloalkyl groups have 1 to 3 carbon atoms. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl.

[0115] The term "heteroaliphatic" describes a chain of 1 to 25 carbon atoms, typically 1 to 12 carbon atoms, more typically 1 to 10 carbon atoms, most typically 1 to 8 carbon atoms, and in some embodiments 1 to 4 carbon atoms, which can be saturated or unsaturated (but not aromatic), containing one or more heteroatoms, such as halogen, oxygen, nitrogen, sulfur, phosphorus, or boron. The heteroatom can be part of a pendant group (or side chain) attached to the atom chain (e.g., -CH(OH)- -CH(NH2)-, where the carbon atom is a member of the atom chain), or it can be one of the chain atoms (e.g., -ROR- or -RNHR-, where each R is an aliphatic group). Heteroaliphatic groups encompass heteroalkyl and heterocyclyl, but not heteroaryl.

[0116] The term "heteroalkyl" describes a completely saturated heteroaliphatic moiety.

[0117] The term "heteroaryl" means a monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms, unless otherwise specified, wherein one or more (in one embodiment, 1, 2, or 3) ring atoms are a heteroatom selected from N, O, or S, with the remaining ring atoms being carbon. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like. As defined herein, the terms "heteroaryl" and "aryl" are mutually exclusive. "Heteroarylene" means a divalent heteroaryl group.

[0118] The term "heteroatom" means an atom other than carbon and hydrogen. Typically, the heteroatom is selected from a halogen, a sulfur, a phosphorus, a nitrogen, a boron, and an oxygen atom, but is not limited thereto. A group containing more than one heteroatom can contain different heteroatoms.

[0119] The term "heterocycle," "heterocyclic," or "heterocyclyl" means a saturated or unsaturated radical of 4 to 8 ring atoms, wherein one or two ring atoms are heteroatoms, such as N, O, B, P, and S(O) n wherein n is an integer from 0 to 2, with the remaining ring atoms being carbon. Additionally, 1 or 2 ring carbon atoms in the heterocyclyl ring can optionally be replaced by a -C(O)- group. More specifically, the term heterocyclyl includes, but is not limited to, pyrrolidinyl, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydro-pyranyl, thiomorpholino, and the like. When the heterocyclyl ring is unsaturated, it can contain 1 or 2 ring double bonds, provided that the ring is not aromatic. When the heterocyclyl group contains at least one nitrogen atom, it is also referred to herein as a heterocyclic amino group and is a subset of heterocyclyl groups.

[0120] The term "hydrocarbon group" or "hydrocarbyl group" means a chain of 1 to 25 carbon atoms, typically 1 to 12 carbon atoms, more typically 1 to 10 carbon atoms, most typically 1 to 8 carbon atoms. The hydrocarbon group can have a straight- chain or branched-chain structure. Typically, the hydrocarbon group has 1 or 2 branches, typically 1 branch. Typically, the hydrocarbon group is saturated. Unsaturated hydrocarbon groups can have one or more double bonds, one or more triple bonds, or a combination thereof. Typically, the unsaturated hydrocarbon group has 1 or 2 double bonds or 1 triple bond; more typically, the unsaturated hydrocarbon group has 1 double bond.

[0121] An "initiator" is a term used to describe an agent that initiates polymerization.

[0122] The term "molecular weight / nitrogen" or "MW / N" means the calculated molecular weight / nitrogen atoms of a polymer. It represents the average molecular weight of the crosslinking polymer that provides one amine functionality. It is calculated by dividing the mass of the polymer sample by the number of moles of nitrogen present in the sample. "MW / N" is the inverse of the theoretical capacity, calculated based on the feed ratio while assuming complete reaction of the crosslinker and monomer. The lower the molecular weight / nitrogen, the higher the theoretical capacity of the crosslinking polymer.

[0123] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "heterocyclyl optionally substituted with alkyl" means that alkyl can or can not be present, and that the description includes embodiments where the heterocyclyl is substituted with alkyl and embodiments where the heterocyclyl is not substituted with alkyl.

[0124] "Pharmaceutically acceptable" in connection with carriers, diluents or excipients used in combination with the compounds means carriers, diluents or excipients that are useful in preparing pharmaceutical compositions, are generally safe, non-toxic and neither biologically nor otherwise undesirable, and are included in the art of preparing pharmaceutical compositions.

[0125] The "simulated gastric fluid" or "SGF" assay describes the determination of the total chloride binding capacity of a test polymer using the following determination buffer using simulated gastric fluid contents: Simulated Gastric Fluid (SGF) consists of 35 mM NaCl, 63 mM HC1, pH 1.2. To perform the assay, a free amine polymer to be tested is prepared at a concentration of 2.5 mg / ml (25 mg dry mass) in 10 mL of SGF buffer. The mixture is incubated overnight, ~12-16 hours, at 37°C with stirring on an electrically heated mixer. The SGF binding data or binding capacity described herein is determined over the period of this duration, unless another time period is indicated. After incubation and mixing, the tube containing the polymer is centrifuged at 500-1000 X g for 2 minutes to pellet the test sample. Approximately 750 microliters of supernatant is removed and filtered using an appropriate filter, such as a 0.45 micron pore size syringe filter or an 800 microliter 1 micron pore size 96 well glass filter plate that has been assembled on a 96 well 2 mL collection plate. With the latter arrangement, multiple samples to be tested in SGF buffer can be prepared for analysis, including free amine sevelamer, free amine bismuthalaminoacetate standard controls and control tubes containing blank buffer that go through all of the assay steps. With the samples arranged in the filter plate and bottom assembled collection plate, the device is centrifuged at 1000 X g for 1 minute to filter the samples. In the case of small sample groups, a syringe filter can be used in place of the filter plate in order to recover ~2-4 mL of filtrate into a 15 mL container. After filtration, each filtrate is diluted 4X with water and the chloride content of the filtrate is measured by ion chromatography (IC). The IC method (e.g., Dionex ICS-2100, Thermo Scientific) consists of an AS11 column and 15 mM KOH mobile phase, 5 microliter injection volume with 3 minute run time, 1000 microliter wash / rinse volume and a flow rate of 1.25 mL / min. To determine the chloride bound to the polymer, the following calculation is completed:

[0126]

[0127] Binding capacity is expressed as mmol chloride / g polymer: where Clstartcorresponds to the initial concentration of chloride in the SGF buffer, Cleqcorresponds to the equilibrium value of chloride in the diluted measured filtrate after exposure to the test polymer, 4 is the dilution factor and 2.5 is the polymer concentration (mg / ml).

[0128] "Simulated small intestinal inorganic buffer" or "SIB" is a test to determine the chloride and phosphate binding capacity of free amine test polymers in the Selective Specific Interference Buffer Assay (SIB). The chloride and phosphate binding capacity of free amine test polymers and the chloride and phosphate binding capacity of free amine sevelamer and bismuthalamum control polymers are determined using the Selective Specific Interference Buffer Assay (SIB) as follows: The buffer used for the SIB assay contains 36 mM NaCl, 20 mM NaH2PO4, 50 mM 2-(N-morpholino)ethanesulfonic acid (MES) buffered to pH 5.5. The SIB buffer contains the chloride, phosphate concentrations and pH found 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), which is an effective measure of selectivity of chloride binding over phosphate binding for polymers. To perform the assay, the free amine polymer to be tested is prepared at a concentration of 2.5 mg / ml (25 mg dry mass) in 10 mL of SIB buffer. The mixture is incubated at 37°C for 1 hour with stirring on an electrically heated mixer. The SIB binding data or binding capacity described herein is determined over the period of time for this duration, unless another period of time is indicated. After incubation and mixing, the tube containing the polymer is centrifuged at 1000 X g for 2 minutes to pellet the test sample. 750 microliters of supernatant is removed, filtered using 800 microliters of a 96-well glass filter plate with a 1 micron pore size that has been assembled on a 96-well 2 mL collection plate; with this arrangement, multiple samples to be tested in SIB buffer can be prepared for analysis, including free amine sevelamer, free amine bismuthalamum standard controls, and control tubes containing blank buffer that go through all of the assay steps. With the samples arranged in the filter plate and bottom-assembled collection plate, the device is centrifuged at 1000 X g for 1 minute to filter the samples.In the case of small sample sets, an injection filter (0.45 micron) can be used in place of the filter plate to recover ~2-4 mL of filtrate into a 15 mL vial. After filtration into the collection plate, each filtrate is diluted and then the chloride or phosphate content is measured. To measure chloride and phosphate, the filtrate to be analyzed is diluted 4X with water. The chloride and phosphate content of the filtrate is measured by ion chromatography (IC). The IC method (e.g., Dionex ICS-2100, Thermo Scientific) consists of an AS24A column, 45 mM KOH mobile phase, 5 microliter injection volume with about 10 minute run time, 1000 microliter wash / rinse volume, and a flow rate of 0.3 mL / min. To determine the chloride bound to the polymer, the following calculation is done:

[0129]

[0130] where Cl 起始 corresponds to the initial concentration of chloride in the SIB buffer, Cl 最终 corresponds to the final value of chloride in the diluted filtrate measured after exposure to the test polymer, 4 is the dilution factor and 2.5 is the polymer concentration (mg / ml). To determine the phosphate bound to the polymer, the following calculation is done:

[0131]

[0132] where P 起始 corresponds to the initial concentration of phosphate in the SIB buffer, P 最终 corresponds to the final value of phosphate in the diluted filtrate measured after exposure to the test polymer, 4 is the dilution factor and 2.5 is the polymer concentration (mg / ml).

[0133] "Simulated Small Intestinal Organic and Inorganic Buffer" or "SOB" is an assay to determine chloride binding capacity in the presence of specific organic and inorganic interferents commonly found in the gastrointestinal tract. The chloride binding capacity of free amine test polymers as well as free amine sevelamer and bismuthalamum control polymers and the binding capacity of other anions are determined in the presence of specific organic interferents commonly found in the gastrointestinal tract as follows: To simulate the conditions of the gastrointestinal lumen, the SOB screen determines the chloride binding capacity of free amine polymers exposed to chloride in the presence of other potentially competing anions such as bile acids, fatty acids, phosphate, acetate, and citrate. The test buffer for the SOB assay contains 50 mM 2-(N-morpholino)ethanesulfonic acid (MES), 50 mM sodium acetate, 36 mM sodium chloride, 7 mM sodium phosphate, 1.5 mM sodium citrate, 30 mM oleic acid, and 5 mM sodium taurocholate, buffered to pH 6.2. The concentrations of the potentially competing anions reflect typical gastrointestinal lumen concentrations found at different points in the gastrointestinal tract, and the pH is an average of representative pH values encountered in the duodenum and large intestine. The chloride concentration used is the same as used in the SIB screen. To perform the assay, the free amine polymer to be tested is accurately weighed into a 16 x 100 mm glass tube with a liquid-tight screw cap. An appropriate amount of SOB buffer is added to the test tube to achieve a final polymer concentration of 2.5 mg / ml. The mixture is incubated at 37°C for 2 hours with stirring on an electrically heated mixer (unless a different time is stated). The SOB binding data or binding capacity described herein is determined over the course of this time period, unless another time period is indicated. After incubation and mixing, 600 microliters of supernatant is removed and filtered using a 96-well glass filter plate. The apparatus is centrifuged at 1000 X g for 1 minute to filter the samples, with the samples arrayed in the filter plate and a bottom-fitted collection plate. In the case of small sample sets, an injection filter can be used in place of the filter plate, in order to recover ~2-4 mL of filtrate into a 15 mL vial. After filtration into the collection plate, each filtrate is appropriately diluted and then the anion content is measured. The IC method (e.g., Dionex ICS-2100, Thermo Scientific) consists of an AS24A column, a 20 mM to 100 mM KOH gradient, a 5 microliter injection volume, about 30 minute run time, 1000 microliters wash / rinse volume, and a flow rate of 0.3 mL / min. This method is suitable for quantifying chloride, phosphate, and taurocholate. Other suitable methods can be substituted. To determine the ions bound to the polymer, the following calculations are completed:

[0134]

[0135] where [ion] 起始 corresponds to the initial concentration of the ion in the SOB buffer, [ion] 最终Corresponding to the final value of the particular ion measured in the filtrate after exposure to the test polymer, the dilution factor is the dilution factor and 2.5 is the polymer concentration (mg / ml).

[0136] The terms "substituted hydrocarbyl," "substituted alkyl," "substituted alkenyl," "substituted aryl," "substituted heterocyclyl," or "substituted heteroaryl" as used herein mean a hydrocarbyl, alkyl, alkenyl, aryl, heterocyclyl, or heteroaryl moiety that is substituted with at least one atom other than carbon and hydrogen, including moieties in which a carbon chain atom is replaced by a heteroatom such as nitrogen, oxygen, silicon, phosphorus, boron, sulfur, or a halogen atom. These substituents include halogen, heterocyclyl, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxyl, keto, acyl, acyloxy, nitro, amino, amido, nitro, cyano, thiol, ketal, acetal, ester, and ether.

[0137] "Swelling ratio" or simply "swelling" describes the amount of water absorbed by a given amount of polymer divided by the weight of an aliquot of the polymer. Swelling is expressed as: Swelling = (g swollen polymer - g dry polymer) / g dry polymer. The method for determining the swelling ratio of any given polymer includes the following steps:

[0138] a. Place 50-100 mg of dry (less than 5% water by weight) polymer into a sealable test tube (with screw cap) of known weight (tube weight = weight A) 11 mL.

[0139] b. Add deionized water (10 mL) to the tube containing the polymer. Seal the tube and invert at room temperature for 16 hours (overnight). After incubation, centrifuge the tube at 3000 x g for 3 minutes and carefully remove the supernatant by vacuum suction. For polymers that form very loose precipitates, perform another centrifugation step.

[0140] c. After step (b), record the weight of the swollen polymer + tube (weight B).

[0141] d. Freeze for 30 minutes at -40°C. Lyophilize for 48 h. Weigh the dry polymer and test tube (recorded as weight C).

[0142] e. Calculate g water absorbed / g polymer defined as: [(weight B - weight A) - (weight C - weight A)] / (weight C - weight A).

[0143] A "target ion" is an ion to which a polymer binds, typically referring to the primary ion to which a polymer binds, or the ion whose binding to the polymer is believed to produce the therapeutic effect of the polymer (e.g., the proton and chloride ion binding that results in net removal of HC1).

[0144] The term "theoretical capacity" represents the expected hydrochloric acid binding calculated in the "SGF" assay, expressed in mmol / g. The theoretical capacity is based on the assumption that 100% of the amines from the monomer and crosslinker are incorporated into the crosslinked polymer according to their respective feed ratios. Thus, the theoretical capacity is equal to the concentration of amine functional groups in the polymer (mmol / g). The theoretical capacity assumes that each amine is available to bind the respective anion and cation and does not need to be adjusted for the type of amine formed (e.g., it does not subtract the capacity of quaternary amines that are not available to bind protons).

[0145] "Therapeutically effective amount" means the amount of proton binding crosslinked amine polymer that, when administered to a patient for treatment of a disease, is sufficient to effect such treatment for the disease. The amount that constitutes a "therapeutically effective amount" will vary depending on the polymer, the severity of the disease, and the age, weight, etc. of the mammal to be treated.

[0146] "Treatment" of a disease or "treatment" of a disease includes (i) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; or (ii) relieving the disease, i.e., causing the regression of the disease or its clinical symptoms. Inhibiting the disease, for example, will include preventing.

[0147] The term "triallylamine" represents an amino moiety with 3 allyl groups.

[0148] The term "vinyl" represents a moiety with the structural formula R x H y C=CH-* where * represents the point of attachment of the moiety to the rest of the molecule, where the point of attachment is a heteroatom or an aryl group, X and Y are independently 0, 1, or 2, such that X+Y=2, and R is a hydrocarbyl or substituted hydrocarbyl group.

[0149] The term "crosslinker weight percent" represents the calculated percent of the polymer sample by mass that originated from the crosslinker. The crosslinker weight percent is calculated using the feed ratios of the polymerization, assuming complete conversion of the monomer and crosslinker. The mass attributed to the crosslinker is equal to the expected increase in molecular weight in the infinite polymer network after reaction (e.g., 1,3-dichloropropane is 113 amu, but only 42 amu is added to the polymer network after crosslinking with DCP, because the chlorine atom as a leaving group is not incorporated into the polymer network).

[0150] When introducing elements of the application or the preferred embodiments thereof, the articles "a", "an", "the" and "said" are intended to mean that there are one or more of the elements. The terms "comprising", "including" and "having" are intended to be inclusive and not exclusive (i.e., there can be additional elements other than the elements listed).

[0151] Embodiments

[0152] As noted previously, in various aspects of the disclosure, it can be noted that treatment methods using compositions comprising nonabsorptive crosslinked polymers containing free amine moieties are contemplated. In one embodiment, the crosslinked amine polymer has the capacity to remove a clinically significant amount of protons and chloride ions from the gastrointestinal tract of an animal, including, for example, a human, when a therapeutically effective amount (i.e., an effective dose) of the crosslinked amine polymer is administered to achieve a therapeutic or prophylactic benefit.

[0153] The therapeutically effective dose of the crosslinked amine polymer disclosed herein will depend, at least in part, on the disease being treated, the capacity of the crosslinked free amine polymer, and the intended effect. In one embodiment, the daily dose of the crosslinked free amine polymer is sufficient to slow the rate of decrease in serum bicarbonate levels over an extended period of time. In another embodiment, the daily dose of the crosslinked free amine polymer is sufficient to maintain serum bicarbonate levels over an extended period of time. In another embodiment, the daily dose of the crosslinked free amine polymer is sufficient to increase serum bicarbonate levels over an extended period of time. For example, in one embodiment, the daily dose is sufficient to achieve or maintain serum bicarbonate levels of at least about 20 mEq / L over an extended period of time. By way of another example, in one such embodiment, the daily dose is sufficient to achieve or maintain serum bicarbonate levels of at least about 21 mEq / L over an extended period of time. By way of another example, in one such embodiment, the daily dose is sufficient to achieve or maintain serum bicarbonate levels of at least about 22 mEq / L over an extended period of time. In another embodiment, the daily dose is sufficient to achieve or maintain serum bicarbonate levels of at least about 24 mEq / L over an extended period of time. In each of the above embodiments, the extended period of time is at least 1 month, such as at least 2 months, at least 3 months, or even at least a number of months.

[0154] Generally, the dosage level of the crosslinked amine polymer for therapeutic and / or prophylactic use can be in the range of about 0.5 g / day to about 20 g / day. To facilitate patient compliance, it is generally preferred that the dosage be in the range of about 1 g / day to about 10 g / day. For example, in one such embodiment, the dosage will be about 2 g / day to about 7 g / day. By way of another example, in one such embodiment, the dosage will be about 3 g / day to about 6 g / day. By way of another example, in one such embodiment, the dosage will be about 4 g / day to about 5 g / day. Optionally, the daily dose can be administered in a single dose (i.e., once a day) or divided into multiple doses (e.g., 2, 3, or more doses) over the course of a day. Generally, the crosslinked amine polymer for therapeutic and / or prophylactic use can be administered in a fixed daily dose or adjusted according to the serum bicarbonate value or other indicator of acidosis of the patient being treated. The adjustment can occur at the beginning of treatment or throughout as needed, with the initial and maintenance dosage levels varying from patient to patient based on the severity of the underlying disease.

[0155] As Figures 1A-1C schematically depicted in FIG. 1 and according to one embodiment, the non-absorbing free amine polymer of the present disclosure is orally ingested for use in treating metabolic acidosis in a mammal (including by increasing serum bicarbonate and normalizing blood pH) by binding HCl in the gastrointestinal ("GI") tract and by removing HCl through feces. The free amine polymer is orally ingested in a dose that enhances compliance Figure 1A ), with the goal of binding sufficient HCl over time to enable a clinically meaningful increase of 3 mEq / L in serum bicarbonate. In the stomach Figure 1B ), the free amine becomes protonated by binding H + . The positive charge on the polymer can then be utilized to bind Cl - ; other larger organic anions (e.g., acetate, propionate, butyrate, etc., depicted as X - and Y - ) are bound to a lesser extent, if at all, by controlling access to the binding sites through cross-linking and hydrophilic / hydrophobic properties. Thus, the net effect is binding of HCl. In the lower GI / colon Figure 1C ), Cl - is not fully released and HCl is removed from the body through regular intestinal motility and fecal excretion, resulting in net alkalization in the serum. Cl - bound in this way is not available for exchange by the Cl - / HCO3 - antiporter system.

[0156] In one embodiment, the polymer is designed to maximize efficacy (net HCl binding and excretion) and minimize GI side effects (through low-swelling particulate design and particle size distribution) simultaneously. Optimal HCl binding can be achieved by carefully balancing the following: capacity (number of amine binding sites), selectivity (preferential binding of chloride over other anions, especially organic anions in the colon), and retention (not releasing significant amounts of chloride in the lower GI to avoid activation of the Cl - / HCO3 - antiporter in the colon and intestine; if chloride is not tightly bound to the polymer, then the Cl - / HCO3 - antiporter can mediate the exchange of chloride from the lumen and bicarbonate from the serum, thereby effectively reducing serum bicarbonate.

[0157] Displacement of chloride ions by competing anions results in net bicarbonate reduction through the following mechanisms. First, displacement of chloride ions from the polymer in the gastrointestinal lumen, especially the colonic lumen, provides a ready exchange with serum bicarbonate. The colon has anion exchangers (chloride / bicarbonate antiporters) that remove chloride from the luminal side, exchanging secreted bicarbonate. When free chloride ions are released from the polymer in the gastrointestinal tract, they will exchange out bicarbonate, which is then lost in the stool and results in a total extracellular bicarbonate reduction (Davis, 1983; D'Agostino, 1953). Binding of short chain fatty acids (SCFA) that exchange the bound chloride ions on the polymer will result in extracellular HCO 3- Depletion of reserves. Short chain fatty acids are bacterial metabolites of complex carbohydrates that are not catabolized by normal digestive processes (Chemlarova, 2007). Short chain fatty acids that reach the colon are absorbed and distributed to various tissues, the common metabolic fate being generation of H2O and CO2, which is converted to bicarbonate equivalents. Therefore, binding of SCFA to the polymer to neutralize the proton charge will be detrimental to the total bicarbonate reserve and buffering capacity, necessitating the design of chemical and physical features in the polymer that limit SCFA exchange. Finally, binding of phosphate to the polymer should also be limited, as phosphate represents an additional source of buffering capacity in the event that ammonia generation and / or hydrogen ion secretion is impaired in chronic kidney disease.

[0158] For each binding of protons, binding of anions is preferred because the positive charge seeks to exit the human body in the form of a neutral polymer. The "binding" of ions is greater than a minimum binding, i.e., at least about 0.2 mmol of ions / g of polymer, in some embodiments at least about 1 mmol of ions / g of polymer, in some embodiments at least about 1.5 mmol of ions / g of polymer, in some embodiments at least about 3 mmol of ions / g of polymer, in some embodiments at least about 5 mmol of ions / g of polymer, in some embodiments at least about 10 mmol of ions / g of polymer, in some embodiments at least about 12 mmol of ions / g of polymer, in some embodiments at least about 13 mmol of ions / g of polymer, or even in some embodiments at least about 14 mmol of ions / g of polymer. In one embodiment, the polymer is characterized by its high proton binding capacity while at the same time providing selectivity for anions; selectivity for chloride is achieved by reducing the binding of interfering anions including but not limited to phosphate, citrate, acetate, bile acids, and fatty acids. For example, in some embodiments, the polymers of the present disclosure bind phosphate with a binding capacity of less than about 5 mmol / g, less than about 4 mmol / g, less than about 3 mmol / g, less than about 2 mmol / g, or even less than about 1 mmol / g. In some embodiments, the polymers of the present disclosure bind bile acids and fatty acids with a binding capacity of less than about less than about 5 mmol / g, less than about 4 mmol / g, less than about 3 mmol / g, less than about 2 mmol / g, in some embodiments less than about 1 mmol / g, in some embodiments less than about 0.5 mmol / g, in some embodiments less than about 0.3 mmol / g, and in some embodiments less than about 0.1 mmol / g.

[0159] The effectiveness of the polymers can be established in animal models or in human volunteers and patients. In addition, in vitro, ex vivo, and in vivo methods can be used to establish HCl binding. In vitro binding solutions can be used to measure the binding capacity for protons, chloride ions, and other ions at different pH. Ex vivo extracts from human volunteers or from model animals, such as gastrointestinal luminal contents, can be used for similar purposes. The selectivity of the polymers for preferential binding and / or retention of certain ions over other ions can also be demonstrated in such in vitro and ex vivo solutions. In vivo models of metabolic acidosis can be used to test the effectiveness of the polymers in normalizing acid / base balance - for example, 5 / 6 nephrectomized rats fed a chow diet containing casein (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).

[0160] In one embodiment, the polymers of the disclosure are provided to animals, including humans, in a dosing regimen of 1, 2, or 3 times a day (most preferably a daily dose of no more than 5 g or less per day) to treat metabolic acidosis and achieve a clinically significant and sustained increase in serum bicarbonate of about 3 mEq / L at these daily doses. The amount of HCl binding achieved by oral administration of the polymers is determined by the binding capacity of the polymers, which is typically in the range of 5-25 mEq HCl / 1 g of polymer. In addition, the polymers are preferably selective in the anions bound to counterbalance the proton binding, with chloride being the preferred anion. Anions other than chloride bound to neutralize the proton positive charge include phosphate, short chain fatty acids, long chain fatty acids, bile acids, or other organic or inorganic anions. Binding of these anions other than chloride affects the total bicarbonate stores in intracellular and extracellular compartments.

[0161] In one embodiment, the mechanism of action of the HC1 polymer binder includes the following. In the stomach or in other parts of the gastrointestinal tract, the free amine polymer becomes protonated by binding protons (H + ) As a result of this binding, the positive charge formed is available for chloride anion binding. Upon exiting the stomach, the polymer encounters different gastrointestinal environments in sequence, the duodenum, the jejunum, the ileum, and the colon, each with a different complement of organic and inorganic anions. The physical and chemical properties of the polymer are designed to control the proximity of the protonated binding sites to this anion collection. Physical barriers include crosslinking (size exclusion to prevent anion binding) and chemical moieties (exclusion of larger organic ions such as acetate, propionate, butyrate, or other short chain fatty acids commonly found in the colon) and combinations of these two properties to limit phosphate, bile acid, and fatty acid binding. By adjusting the bead crosslinking and chemical properties of the amine binding sites, it is possible to bind chloride tightly, with reduced or eliminated exchange of other anions and release in the lower gastrointestinal tract. Without being bound by theory, by incorporating these properties into the HC1 binding polymer, it is possible to exclude or reduce binding of anions with larger ionic and / or hydrated radii than chloride. For example, the ionic radius of chloride, in hydrated or unhydrated form, is smaller than the corresponding values for phosphate and other anions commonly found in the gastrointestinal lumen (Supramolecular Chemistry, Steed, JW (2009) John Wiley and Sons, p. 226; Kielland, J (1937), J. Am. Chem. Soc. 59: 1675-1678). To selectively bind the smaller ions, the polymer typically exhibits a high crosslinking density so as to create preferential access to the polymer binding sites. However, high crosslinking density materials are typically characterized by low swelling ratios. Swelling ratio can be influenced by the following composition and process variables: 1) molar ratio of amine monomer (or polymer) and crosslinking agent, 2) ratio of monomer + crosslinking agent to solvent in the crosslinking reaction, 3) net charge of the polymer (at the physiological pH and environmental tonicity at which it will be used), 4) hydrophilic / hydrophobic balance of the backbone polymer, and / or 5) post-crosslinking of the existing material.

[0162] In some embodiments, the theoretical chloride ion binding capacity of the polymers of the present disclosure can range from about 1 mmol / g to about 25 mmol / g. In one embodiment, the theoretical chloride ion binding capacity of the polymer is from about 3 mmol / g to about 25 mmol / g. In another embodiment, the theoretical chloride ion binding capacity of the polymer is from about 6 mmol / g to about 20 mmol / g. In another embodiment, the theoretical chloride ion binding capacity of the polymer is from about 9 mmol / g to about 17 mmol / g.

[0163] In one embodiment, the crosslinked polymers of the present disclosure are characterized by a chloride binding capacity of at least 2 mmol / g at 1 hour in simulated small intestinal inorganic buffer ("SIB"). For example, in one such embodiment, the crosslinked polymers of the present disclosure are characterized by a chloride binding capacity of at least 2.5 mmol / g at 1 hour in SIB. By way of another example, in one such embodiment, the crosslinked polymers of the present disclosure are characterized by a chloride binding capacity of at least 3 mmol / g at 1 hour in SIB. By way of another example, in one such embodiment, the crosslinked polymers of the present disclosure are characterized by a chloride binding capacity of at least 3.5 mmol / g at 1 hour in SIB. By way of another example, in one such embodiment, the crosslinked polymers of the present disclosure are characterized by a chloride binding capacity of at least 4 mmol / g at 1 hour in SIB. By way of another example, in one such embodiment, the crosslinked polymers of the present disclosure are characterized by a chloride binding capacity of at least 4.5 mmol / g at 1 hour in SIB. By way of another example, in one such embodiment, the crosslinked polymers of the present disclosure are characterized by a chloride binding capacity of at least 5 mmol / g at 1 hour in SIB. By way of another example, in one such embodiment, the crosslinked polymers of the present disclosure are characterized by a chloride binding capacity of at least 5.5 mmol / g at 1 hour in SIB. By way of another example, in one such embodiment, the crosslinked polymers of the present disclosure are characterized by a chloride binding capacity of at least 6 mmol / g at 1 hour in SIB. In one exemplary embodiment of each of the above embodiments of this paragraph, the crosslinked amine polymer can have a swell ratio of no more than about 1.5.

[0164] In one embodiment, the crosslinked polymers of the present disclosure are characterized by a chloride ion binding capacity of at least 4 mmol / g and a phosphate ion binding capacity of less than 2 mmol / g in a simulated small intestinal inorganic buffer ("SIB"). For example, in one such embodiment, the crosslinked amine polymer has a chloride ion binding capacity of at least 4 mmol / g and a phosphate ion binding capacity of less than 2 mmol / g after 1 hour in SIB. By way of another example, in one such embodiment, the crosslinked amine polymer has a chloride ion binding capacity of at least 4 mmol / g and a phosphate ion binding capacity of less than 2 mmol / g after 2 hours in SIB. By way of another example, in one such embodiment, the crosslinked amine polymer has a chloride ion binding capacity of at least 4 mmol / g and a phosphate ion binding capacity of less than 2 mmol / g after 3 hours in SIB. By way of another example, in one such embodiment, the crosslinked amine polymer has a chloride ion binding capacity of at least 4 mmol / g and a phosphate ion binding capacity of less than 2 mmol / g after 4 hours in SIB. By way of another example, in one such embodiment, the crosslinked amine polymer has a corresponding chloride ion to phosphate ion binding ratio of at least 2.5: 1 in SIB. In one exemplary embodiment of each of the above embodiments of this paragraph, the crosslinked amine polymer can have a swell ratio of no more than about 1.5.

[0165] In one embodiment, the crosslinked polymers of the present disclosure are characterized by a proton binding capacity and a chloride binding capacity in simulated gastric fluid ("SGF") of at least 8 mmol / g. For example, in one such embodiment, the crosslinked polymers of the present disclosure are characterized by a proton binding capacity and a chloride binding capacity in SGF of at least 10 mmol / g. By way of further example, in one such embodiment, the crosslinked polymers of the present disclosure are characterized by a proton binding capacity and a chloride binding capacity in SGF of at least 12 mmol / g. By way of further example, in one such embodiment, the crosslinked polymers of the present disclosure are characterized by a proton binding capacity and a chloride binding capacity in SGF of at least 14 mmol / g. By way of further example, in one such embodiment, the crosslinked polymers of the present disclosure are characterized by a proton binding capacity and a chloride binding capacity after 1 hour in SGF that is at least 50% of the corresponding proton binding capacity and chloride binding capacity of the crosslinked amine polymer after 24 hours in SGF. By way of further example, in one such embodiment, the crosslinked polymers of the present disclosure are characterized by a proton binding capacity and a chloride binding capacity after 1 hour in SGF that is at least 60% of the corresponding proton binding capacity and chloride binding capacity of the crosslinked amine polymer after 24 hours in SGF. By way of further example, in one such embodiment, the crosslinked polymers of the present disclosure are characterized by a proton binding capacity and a chloride binding capacity after 1 hour in SGF that is at least 70% of the corresponding proton binding capacity and chloride binding capacity of the crosslinked amine polymer after 24 hours in SGF. By way of further example, in one such embodiment, the crosslinked polymers of the present disclosure are characterized by a proton binding capacity and a chloride binding capacity after 1 hour in SGF that is at least 80% of the corresponding proton binding capacity and chloride binding capacity of the crosslinked amine polymer after 24 hours in SGF. By way of further example, in one such embodiment, the crosslinked polymers of the present disclosure are characterized by a proton binding capacity and a chloride binding capacity after 1 hour in SGF that is at least 90% of the corresponding proton binding capacity and chloride binding capacity of the crosslinked amine polymer after 24 hours in SGF.

[0166] In one embodiment, the crosslinked polymers of the present disclosure are characterized by a selectivity for chloride over citrate, phosphate, and taurocholate in simulated small intestinal organic and inorganic buffer ("SOB"), or a chloride binding capacity in SOB of at least 4 mmol / g at 24 hours.

[0167] In one embodiment, the crosslinked polymers of the present disclosure are characterized by selectivity for chloride over citrate, phosphate, and taurocholate after 1 hour in simulated small intestinal organic and inorganic buffer ("SOB"). For example, in one such embodiment, the crosslinked polymers are characterized by selectivity for chloride over citrate, phosphate, and taurocholate after 4 hours in SOB. By way of another example, in one such embodiment, the crosslinked polymers are characterized by selectivity for chloride over citrate, phosphate, and taurocholate after 12 hours in SOB. By way of another example, in one such embodiment, the crosslinked polymers are characterized by selectivity for chloride over citrate, phosphate, and taurocholate after 18 hours in SOB. By way of another example, in one such embodiment, the crosslinked polymers are characterized by selectivity for chloride over citrate, phosphate, and taurocholate after 24 hours in SOB. By way of another example, in one such embodiment, the crosslinked polymers are characterized by selectivity for chloride over citrate, phosphate, and taurocholate after 30 hours in SOB. By way of another example, in one such embodiment, the crosslinked polymers are characterized by selectivity for chloride over citrate, phosphate, and taurocholate after 36 hours in SOB. By way of another example, in one such embodiment, the crosslinked polymers are characterized by selectivity for chloride over citrate, phosphate, and taurocholate after 42 hours in SOB. By way of another example, in one such embodiment, the crosslinked polymers are characterized by selectivity for chloride over citrate, phosphate, and taurocholate after 48 hours in SOB.

[0168] Generally, it is preferred that the crosslinked polymers having the features described above and elsewhere herein have a pKa in physiological ionic conditions of at least 6, at least 6.5, at least 7, at least 7.5, or at least 8, which is the upper limit of the pH encountered along the gastrointestinal tract (Fallingborg, J Aliment. Pharmacol. Therap

[1989] 3: 05-613).

[0169] In some embodiments, the molecular weight / nitrogen of the polymers of the present disclosure can range from about 40 to about 1000 Daltons. In one embodiment, the molecular weight / nitrogen of the polymers is from about 40 to about 500 Daltons. In another embodiment, the molecular weight / nitrogen of the polymers is from about 50 to about 170 Daltons. In another embodiment, the molecular weight / nitrogen of the polymers is from about 60 to about 110 Daltons.

[0170] In some embodiments, the crosslinker weight % range will be from about 10 to 90 weight % of the crosslinked amine polymer. For example, in some embodiments, the crosslinker weight % range will be from about 15 to 90 weight % of the crosslinked amine polymer or even from about 25 to 90 weight % of the crosslinked amine polymer.

[0171] As noted previously, crosslinked amine polymers that have a high capacity for and high selectivity for chloride ion binding over other competing anions can be prepared in a two-step process according to one embodiment of the present disclosure. Generally, the selectivity of a polymer is a function of its crosslinking density and the capacity of a polymer is a function of the free amine density of the crosslinked amine polymer. Advantageously, the two-step process disclosed herein provides high capacity for and high selectivity for chloride ion binding over other competing ions by relying primarily on carbon-carbon crosslinking in the first step and nitrogen-nitrogen crosslinking in the second step.

[0172] In the first step, the crosslinking is preferably capacity-retaining, i.e., free amine- preserving, from carbon to carbon. In the second step, the crosslinking is amine-consuming and directed toward tuning for selectivity. Based on the desired high capacity, the C-N ratio is preferably optimized to maximize the amine functionality available for HC1 binding while still maintaining spherical polymer particles with controlled particle size to ensure non-absorption and acceptable mouthfeel under gastrointestinal conditions. The preferred degree of carbon-carbon crosslinking achieved after the first step is sufficient to allow the resulting beads to swell between 4X and 6X in water (i.e., a swelling ratio of 4 to 6).

[0173] Generally, the crosslinked amine polymer can be a crosslinked homopolymer or a crosslinked copolymer that includes free amine moieties. The free amine moieties can be separated, for example, by identical or different length repeating linker (or intervening) units. In some embodiments, the polymer includes repeating units that include an amine moiety and an intervening linker unit. In other embodiments, multiple amine-containing repeating units are separated by one or more linker units. Alternatively, the multifunctional crosslinker can include HC1 binding functionality, e.g., an amine (“active crosslinker”), or can lack HC1 binding functionality such as an amine (“passive crosslinker”).

[0174] In one preferred embodiment, the first polymerization (crosslinking) step produces a preformed amine polymer bead having a target size and chloride binding capacity. For example, in one such embodiment, the bead has a chloride binding capacity of at least 10 mmol / g in simulated gastric fluid ("SGF") and a swelling ratio in the range of 4 to 6. The resulting preformed amine polymer is then preferably deprotonated (at least in part) with a base and combined with an aprotic swelling agent to swell the free amine polymer without protonating the amine functionality. Further, the amount of aprotic swelling agent is selected to tune the degree of subsequent crosslinking, effectively forming a template that is then locked into place by an amine-consuming crosslinking step. In the second crosslinking step, the swollen, deprotonated preformed amine polymer is crosslinked with a crosslinking agent comprising an amine-reactive moiety to form a post-polymerization crosslinked amine polymer.

[0175] In general, the use of highly crosslinked amine polymers enables selectivity for chloride over other competing ions. For example, a relatively high chloride binding capacity can be achieved by reacting preformed amine polymer beads with pure crosslinking agent in the presence of a swelling agent (water). While this "non-dispersive" reaction provides a route to achieve high selectivity for chloride over competing ions in SIB and SOB assays, it also results in macroscopic (and microscopic) aggregated polymer beads. Thus, advantageously, a solvent (e.g., heptane) is included in the second crosslinking step to disperse the preformed crosslinked polymer beads in order to avoid inter-bead reactions and resulting aggregation. However, the use of too much solvent (dispersant) can dilute the reaction solution to a point where the resulting beads are not sufficiently crosslinked to have the desired selectivity for chloride over other competing anions (see Table 12). However, by using a crosslinking agent that also acts as a solvent (dispersant), sufficient solvent (dispersant) can be included in the reaction mixture to avoid inter-bead reactions and aggregation without diluting the mixture to a point where the degree of crosslinking that consumes amine is insufficient. For example, to take advantage of the dispersing properties of a solvent (to avoid aggregation during the reaction) while maintaining reactivity, pure DCE and DCP are used, thereby performing a dual purpose role as a solvent (dispersant) and crosslinking agent. Interestingly, DCE was found to have superior dispersing properties as a solvent when compared to similar reactions utilizing DCP and / or heptane. Additionally, less aggregation was observed when the beads were first dispersed in DCE and then water was added in a second operation to swell the beads. If water was added to the preformed amine polymer prior to dispersing the beads in DCE, aggregation could occur.

[0176] The use of 1,2-dichloroethane ("DCE") as the crosslinking solvent also generates HCl molecules during the second step. These HCl molecules protonate some of the free amine sites, which will close off reaction sites for the crosslinking reaction, thereby limiting the number of binding sites available for crosslinking. Thus, the use of DCE creates a self-limiting effect on secondary crosslinking.

[0177] In each of the above embodiments, the reaction mixture can contain a wide range of amounts of the crosslinking agent. For example, in one embodiment, the crosslinking agent can be used in a substantial excess relative to the preformed amine polymer in the reaction mixture. In other words, in such embodiments, the crosslinking agent is the crosslinking solvent, i.e., it is both the solvent for the reaction mixture and the crosslinking agent for the preformed amine polymer. In such embodiments, other solvents can optionally be included in the reaction mixture, but are not necessary. Alternatively, the preformed amine polymer, the swelling agent, and the crosslinking agent can be dispersed in a solvent that is miscible with the crosslinking agent and immiscible with the swelling agent. For example, in some embodiments, the swelling agent can be a polar solvent; in some such embodiments, for example, the swelling agent can include water, methanol, ethanol, n-propanol, isopropanol, formic acid, acetic acid, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, nitromethane, or combinations thereof. By way of another example, when the swelling agent includes a polar solvent, the solvent system for the reaction mixture will typically include a non-polar solvent, such as pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, trichloromethane, diethyl ether, dichloromethane, dichloroethane, dichloropropane, dichlorobutane, or combinations thereof. In certain embodiments, the crosslinking agent and the solvent can be the same, i.e., the solvent is the crosslinking agent, such as 1,2-dichloroethane, 1,3-dichloropropane, 1,4-dichlorobutane, or combinations thereof.

[0178] In one embodiment, the preformed amine polymer is dispersed in a reaction mixture comprising a crosslinking agent, a swelling agent for the preformed amine polymer, and a (dispersing) solvent. In one such embodiment, for example, the ratio of (dispersing) solvent to preformed amine polymer in the reaction mixture is at least 2: 1 (milliliters of solvent: grams of preformed amine polymer). By way of further example, in one such embodiment, the ratio of (dispersing) solvent to preformed amine polymer in the reaction mixture is at least 3: 1 (milliliters of solvent: grams of preformed amine polymer). By way of further example, in one such embodiment, the ratio of (dispersing) solvent to preformed amine polymer in the reaction mixture is at least 4: 1 (milliliters of solvent: grams of preformed amine polymer). By way of further example, in one such embodiment, the ratio of (dispersing) solvent to preformed amine polymer in the reaction mixture is at least 5: 1 (milliliters of solvent: grams of preformed amine polymer). By way of further example, in one such embodiment, the ratio of (dispersing) solvent to preformed amine polymer in the reaction mixture is at least 7.5: 1 (milliliters of solvent: grams of preformed amine polymer). By way of further example, in one such embodiment, the ratio of (dispersing) solvent to preformed amine polymer in the reaction mixture is at least 10: 1 (milliliters of solvent: grams of preformed amine polymer). In each of the above embodiments, the (dispersing) solvent can comprise a combination of an inert solvent (relative to the preformed amine polymer) such as the previously identified non-polar solvents and a crosslinking solvent, or the (dispersing) solvent can comprise exclusively a crosslinking solvent (e.g., DCE or DCP).

[0179] Notably, in crosslinking solvent (e.g., DCE dispersed reactions), there is a large excess of crosslinking agent (e.g., 1 g: 3 mL : :beads: DCE and 1 g: 10 mL : :beads: DCE are both large excesses of crosslinking agent, much of which is not consumed during the reaction) regardless of the amount of crosslinking solvent (e.g., DCE) used to disperse the beads. Nonetheless, both the relative degree of crosslinking and performance in the SIB and SOB assays are not affected by changes in the ratio of reactive crosslinking agent to polymer beads (see Table 6). This is possible because the reaction is limited by the acid neutralization capacity of the polymer beads, not the amount of crosslinking agent (e.g., DCE).

[0180] To more effectively react with DCE or other crosslinking agents, the amines of the preformed polymer beads are preferably free of an electron pair (neutral, deprotonated). When the free amines of the preformed polymer beads react with a crosslinking agent (e.g., DCE), HCl is produced and the amines become protonated, thereby limiting the reaction. To this end, the preformed amine polymer beads preferably start as free amines in the second crosslinking step. If the preformed amine polymer is protonated after the first step of carbon-carbon crosslinking, then the crosslinking of the spent amines in the second step will be limited, thereby reducing the desired selectivity for chloride ions over other competing ions. This has been demonstrated by adding a known amount of HCl to the preformed amine polymer beads immediately prior to the second step crosslinking with DCE (Table 7). When less than 3 mol% HCl (to the amines in the preformed polymer amine beads) is added prior to the second step crosslinking, the total chloride ion capacity (SGF) and chloride ion selectivity in the SIB and SOB are similar to beads that were not treated with HCl in the second step. When greater than 5 mol% HCl (to the amines in the preformed polymer amine beads) is added prior to the second step crosslinking, the total chloride ion capacity (SGF) in the SIB and SOB increases and the chloride ion selectivity decreases, indicating lower incorporation of the crosslinking agent.

[0181] The benefits of deprotonating the preformed polymer beads in the second step crosslinking highlight the advantages of using two steps to achieve the final product. In the first step, to form the amine polymer beads, all monomers (e.g., allyl amine and DAPDA) are protonated to remain in the aqueous phase and to avoid radical transfer reactions that severely limit the polymerization of non-protonated allyl amine (and derivatives). Once the beads are formed by carbon-carbon crosslinking, the beads can then be deprotonated and further crosslinked with an amine-reactive crosslinking agent in the second step.

[0182] Given a large excess of the dual crosslinking agent / solvent, single incorporation of this reagent can occur, creating alkyl chloride functional groups on the crosslinked polymer beads that are inherently hydrophobic, and can increase non-specific interactions with undesirable solutes that are more hydrophobic than HCl. Washing with ammonium hydroxide solution converts the alkyl chlorides to hydrophobic alkyl amine functional groups and minimizes non-specific interactions with undesirable solutes. Other modifications that create groups that are more hydrophilic than alkyl chlorides, such as -OH, are suitable for quenching single-incorporated crosslinking agents / solvents.

[0183] In the first reaction step, any of a range of polymerization chemistries can be employed, provided that the crosslinking mechanism is primarily carbon-carbon crosslinking. Thus, in one exemplary embodiment, the first reaction step comprises free radical polymerization. In such reactions, the amine monomer will typically be a monofunctional vinyl, allyl, or acrylamide (e.g., an allyl amine) and the crosslinker will have two or more vinyl, allyl, or acrylamide functional groups (e.g., a diallyl amine). Free radical initiated polymerization by a mixture of monofunctional and polyfunctional allyl amines occurs with simultaneous polymerization and crosslinking. The resulting polymer network is thus crosslinked through the carbon backbone. Each crosslinking reaction forms a carbon-carbon bond (as opposed to substitution reactions in which a carbon-heteroatom bond is formed during crosslinking). In the process of simultaneous polymerization and crosslinking, the amine functionality of the monomers does not undergo crosslinking reactions and is preserved in the final polymer (i.e., primary amines remain as primary amines, secondary amines remain as secondary amines, and tertiary amines remain as tertiary amines).

[0184] In those embodiments in which the first reaction step comprises free radical polymerization, a wide range of initiators can be used, including cationic and free radical initiators. Some examples of suitable initiators that can be used include: free radical peroxide and azo type compounds such as azobisisobutyronitrile, azobisisovaleronitrile, dimethyl azodicarboxylate, 2,2'azobis(isobutyronitrile), 2,2'-azobis(N,N'-dimethyleneisobutyramidine) dihydrochloride, 2,2'-azobis(2-amidinopropane) dihydrochloride, 2,2'-azobis(N,N'-dimethyleneisobutyramidine), 1,1'-azobis(1- cyclohexanecarbonitrile), 4,4'-azobis(4-cyanovaleric acid), 2,2'-azobis(isobutyramide) dihydrate, 2,2'-azobis(2-methylpropane), 2,2'-azobis(2-methylbutyronitrile), VAZO 67, cyanovaleric acid, peroxypivalate, dodecylbenzene peroxide, benzoyl peroxide, di-t-butyl hydroperoxide, t-butyl peracetate, acetyl peroxide, dicumyl peroxide, cumyl hydroperoxide, dimethyl bis(butylperoxy) hexane.

[0185] In some embodiments, the preformed amine polymer comprises residues of amines corresponding to Formula 1:

[0186]

[0187] wherein R1, R2, and R3are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, with the proviso that at least one of R1, R2, and R3is not hydrogen. In other words, at least one of R1, R2, and R3is a hydrocarbyl or substituted hydrocarbyl group, and the remainder of R1, R2, and R3are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl. In one embodiment, for example, R1, R2, and R3are independently hydrogen, aryl, aliphatic, heteroaryl, or heteroaliphatic, with the proviso that each of R1, R2, and R3is not hydrogen. By way of another example, in one such embodiment, R1, R2, and R3are independently hydrogen, saturated hydrocarbon, unsaturated aliphatic, unsaturated heteroaliphatic, heteroalkyl, heterocyclyl, aryl, or heteroaryl, with the proviso that each of R1, R2, and R3is not hydrogen. By way of another example, in one such embodiment, R1, R2, and R3are independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ether, heteroaryl, or heterocyclyl, with the proviso that each of R1, R2, and R3is not hydrogen. By way of another example, in one such embodiment, R1, R2, and R3are independently hydrogen, alkyl, aminoalkyl, alkanol, aryl, haloalkyl, hydroxyalkyl, ether, heteroaryl, or heterocyclyl, with the proviso that each of R1, R2, and R3is not hydrogen. By way of another example, in one such embodiment, R1and R2, in combination with the nitrogen atom to which they are attached, together form part of a ring structure, such that the monomer of Formula 1 is a nitrogen-containing heterocycle (e.g., piperidine), and R3is hydrogen or a heteroaliphatic group. By way of another example, in one embodiment, R1, R2, and R3are independently hydrogen, aliphatic, or heteroaliphatic, with the proviso that at least one of R1, R2, and R3is not hydrogen. By way of another example, in one embodiment, R1, R2, and R3are independently hydrogen, allyl, or aminoalkyl.

[0188] In one embodiment, the preformed amine polymer comprises residues of amines corresponding to Formula 1, wherein R1, R2, and R3are independently hydrogen, heteroaryl, aryl, aliphatic, or heteroaliphatic, with the proviso that at least one of R1, R2, and R3is aryl or heteroaryl. For example, in this embodiment, R1and R2, in combination with the nitrogen atom to which they are attached, together can form a saturated or unsaturated nitrogen-containing heterocyclyl ring. By way of another example, R1and R2, in combination with the nitrogen atom to which they are attached, together can form part of a pyrrolidinyl, pyrrole, pyrazolidine, pyrazole, imidazolidine, imidazole, piperidine, pyridine, piperazine, diazine, or triazine ring structure. By way of another example, R1and R2, in combination with the nitrogen atom to which they are attached, together can form part of a piperidine ring structure.

[0189] In one embodiment, the preformed amine polymer comprises residues of amines corresponding to Formula 1, wherein R1, R2, and R3are independently hydrogen, an aliphatic group, or a heteroaliphatic group, with the proviso that at least one of R1, R2, and R3is not hydrogen. For example, in this embodiment, R1, R2, and R3may be independently hydrogen, an alkyl group, an alkenyl group, an allyl group, a vinyl group, an aminoalkyl group, an alkanol, a haloalkyl group, a hydroxyalkyl group, an ether group, or a heterocyclic group, with the proviso that at least one of R1, R2, and R3is not hydrogen. By way of another example, in one such embodiment, R1and R2, taken together with the nitrogen atom to which they are attached, can form a saturated or unsaturated nitrogen-containing heterocyclic group ring. By way of another example, in one such embodiment, R1and R2, taken together with the nitrogen atom to which they are attached, can constitute part of a pyrrolidinyl, pyrrole, pyrazolidinyl, pyrazole, imidazolidinyl, imidazole, piperidinyl, piperazinyl, or diazine ring structure. By way of another example, in one such embodiment, R1and R2, taken together with the nitrogen atom to which they are attached, can constitute part of a piperidinyl ring structure. By way of another example, in one such embodiment, the amine corresponding to Formula 1 is acyclic and at least one of R1, R2, and R3is an aliphatic group or a heteroaliphatic group. By way of another example, in one such embodiment, R1, R2, and R3are independently hydrogen, an alkyl group, an allyl group, a vinyl group, an alicyclic group, an aminoalkyl group, an alkanol, or a heterocyclic group, with the proviso that at least one of R1, R2, and R3is not hydrogen.

[0190] In some embodiments, the amine-containing monomer is polymerized and the polymer is simultaneously crosslinked in a substitution polymerization in the first reaction step. For substitution polymerization, the amine reactant (monomer) in the simultaneously occurring polymerization and crosslinking reactions can react more than once. In one such embodiment, the amine monomer is a linear amine having at least two reactive amine moieties that participate in the substitution polymerization. In another embodiment, the amine monomer is a branched amine having at least two reactive amine moieties that participate in the substitution polymerization. The crosslinking agent for the simultaneously occurring substitution polymerization and crosslinking typically has at least two amine-reactive moieties, such as alkyl chloride and alkyl epoxide. To be incorporated into the polymer, primary amines can react with the crosslinking agent at least once and potentially up to 3 times, secondary amines can react with the crosslinking agent up to 2 times, and tertiary amines can react with the crosslinking agent only 1 time. In general, however, formation of significant amounts of quaternary nitrogen / amine is generally not preferred because quaternary amines cannot bind protons.

[0191] Exemplary amines useful in the substitution polymerization reactions described herein include 1,3-bis[bis(2-aminoethyl)amino]propane, 3-amino-1-{[2-(bis{2-[bis(3- aminopropyl)amino]ethyl}amino)ethyl](3-aminopropyl)amino}propane, 2-[bis(2- aminoethyl)amino]ethanamine, tris(3-aminopropyl)amine, 1,4-bis[bis(3- aminopropyl)amino]butane, 1,2-ethanediamine, 2-amino-1-(2-aminoethylamino)ethane, 1,2-bis(2-aminoethylamino)ethane, 1,3-propanediamine, 3,3'-diaminodipropylamine, 2,2-dimethyl-1,3-propanediamine, 2-methyl-1,3-propanediamine, N,N'-dimethyl-1,3- propanediamine, N-methyl-1,3-diaminopropane, 3,3'-diamino-N-methyldipropylamine, 1,3-diaminopentane, 1,2-diamino-2-methylpropane, 2-methyl-1,5- diaminopentane, 1,2-diaminopropane, 1,10-diaminodecane, 1,8-diaminoctane, 1,9- diaminooctane, 1,7-diaminoheptane, 1,6-diaminohexane, 1,5-diaminopentane, 3- bromopropylamine hydrobromide, N,2-dimethyl-1,3-propanediamine, N-isopropyl-1,3- diaminopropane, N,N'-bis(2-aminoethyl)-1,3-propanediamine, N,N'-bis(3- aminopropyl)ethylenediamine, N,N'-bis(3-aminopropyl)-1,4-butanediamine tetrahydrochloride, 1,3-diamino-2-propanol, N-ethylethylenediamine, 2,2'-diamino-N- methyldiethylamine, N,N'-diethylethylenediamine, N-isopropylethylenediamine, N- methylethylenediamine, N,N'-di-t-butylethylenediamine, N,N'-diisopropylethylenediamine, N,N'-dimethylethylenediamine, N-butylethylenediamine, 2-(2- aminoethylamino)ethanol, 1,4,7,10,13,16-hexaazacyclooctadecane, 1,4,7,10- tetraazacyclododecane, 1,4,7-triazacyclononane, N,N'-bis(2-hydroxyethyl)ethylenediamine, piperazine, bis(hexamethylene)triamine, N-(3-hydroxypropyl)ethylenediamine, N-(2-aminoethyl)piperazine, 2-methylpiperazine, homopiperazine, 1,4,8,11- tetraazacyclotetradecane, 1,4,8,12-tetraazacyclopentadecane, 2-(aminomethyl)piperidine, 3-(methylamino)pyrrolidine

[0192] Exemplary crosslinking agents that can be used in substitution of the polymerization reaction and post-polymerization crosslinking reaction include, but are not limited to, one or more polyfunctional crosslinking agents such as dihaloalkanes, haloalkylethylene oxides, alkylethylene oxide sulfonates, di(haloalkyl)amines, tri(haloalkyl)amines, diepoxides, triepoxides, tetraepoxides, bis(halomethyl)benzenes, tris(halomethyl)benzenes, tetra(halomethyl)benzenes, epihalohydrins such as epichlorohydrin and epibromohydrin, poly(epichlorohydrin), (iodomethyl)ethylene oxide, glycidyl toluene sulfonate, glycidyl 3-nitrobenzenesulfonate, 4-toluenesulfonyloxy-1,2-epoxybutane, bromo-1,2-epoxybutane, 1,2-dibromoethane, 1,3-dichloropropane, 1,2-dichloroethane, 1-bromo-2-chloroethane, 1,3-dibromopropane, bis(2-chloroethyl)amine, tris(2-chloroethyl)amine, and bis(2-chloroethyl)methylamine, 1,3-butadiene diepoxide, 1,5-hexadiene diepoxide, diglycidyl ether, 1,2,7,8-diepoxyoctane, 1,2,9,10-diepoxydecane, ethylene glycol diglycidyl ether, propylene glycol diglycidyl ether, 1,4-butanediol diglycidyl ether, 1,2-ethanediol diglycidyl ether, glycerol diglycidyl ether, 1,3-diglycidyl glyceryl ether, N,N-diglycidyl aniline, neopentyl glycol diglycidyl ether, diethylene glycol diglycidyl ether, 1,4-bis(glycidyloxy)benzene, resorcinol diglycidyl ether, 1,6-hexanediol diglycidyl ether, trimethylolpropane diglycidyl ether, 1,4-cyclohexanedimethanol diglycidyl ether, 1,3-bis-(2,3-epoxypropoxy)-2-(2,3-dihydroxypropoxy)propane, 1,2-cyclohexanedicarboxylic acid diglycidyl ester, 2,2'-bis(glycidyloxy)diphenylmethane, bisphenol F diglycidyl ether, 1,4-bis(2',3'-epoxypropyl)perfluoro-n-butane, 2,6-bis(oxirane-2-ylmethyl)-1,2,3,5,6,7-hexahydro-pyrrolo[3,4-f]isoindol-1,3,5,7-tetraone, bisphenol A diglycidyl ether, 5-hydroxy-6,8-bis(oxirane-2-ylmethyl)-4-oxo-4-H-chromene-2-carboxylic acid ethyl ester, bis[4-(2,3-epoxy-propylthio)phenyl]-sulfide, 1,3-bis(3-glycidyloxypropyl)tetramethyldisiloxane, 9,9-bis[4-(glycidyloxy)phenyl]fluorine, tris-epoxy isocyanurate, glycerol triglycidyl ether, N,N-diglycidyl-4-glycidyloxyaniline, (S,S,S)-triglycidyl isocyanurate, (R,R,R)-triglycidyl isocyanurate, triglycidyl isocyanurate, trimethylolpropane triglycidyl ether, glycerol propoxylated triglycidyl ether, trishydroxyphenylmethane triglycidyl ether, 3,7,14-tris[[3-(glycidyloxy)propyl]dimethylsilylmethyloxy]-1,3,5,7,9,11,14- heptacyclopentyltricyclo[7,3,3,15,11]pentasiloxane, 4,4'-methylenebis(N,N-diglycidylaniline), bis(halomethyl)benzene, bis(halomethyl)biphenyl, and bis(halomethyl)naphthalene, toluene diisocyanate, acryloyl chloride, methyl acrylate, ethylene bisacrylamide, pyromellitic dianhydride, succinyl dichloride, dimethyl succinate, 3-chloro-1-(3-chloropropylamino-2-propanol, 1,2-bis(3-chloropropylamino)ethane, bis(3-chloropropyl)amine, 1,3-dichloro-2-propanol, 1,3-dichloropropane, 1-chloro-2,3-epoxypropane, tris[(2-oxiranylmethyl]amine.

[0193] In some embodiments, the preformed amine polymer is a crosslinked amine polymer comprising residues of amines corresponding to Formula 1a and the crosslinked amine polymer is prepared by free radical polymerization of amines corresponding to Formula 1a:

[0194]

[0195] wherein R4and R5are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl. In one embodiment, for example, R4and R5are independently hydrogen, saturated hydrocarbyl, unsaturated aliphatic, aryl, heteroaryl, unsaturated heteroaliphatic, heterocyclyl, or heteroalkyl. By way of further example, in one such embodiment, R4and R5are independently hydrogen, aliphatic, heteroaliphatic, aryl, or heteroaryl. By way of further example, in one such embodiment, R4and R5are independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ether, heteroaryl, or heterocyclyl. By way of further example, in one such embodiment, R4and R5are independently hydrogen, alkyl, allyl, aminoalkyl, alkanol, aryl, haloalkyl, hydroxyalkyl, ether, or heterocyclyl. By way of further example, in one such embodiment, R4and R5, in combination with the nitrogen atom to which they are attached, together form part of a ring structure, such that the monomer of Formula 1a is a nitrogen-containing heterocycle (e.g., piperidine). By way of further example, in one embodiment, R4and R5are independently hydrogen, aliphatic, or heteroaliphatic. By way of further example, in one embodiment, R4and R5are independently hydrogen, allyl, or aminoalkyl.

[0196] In some embodiments, the preformed amine polymer is a crosslinked amine polymer comprising residues of amines corresponding to Formula 1b and the crosslinked amine polymer is prepared by substitution polymerization of amines corresponding to Formula 1b with a multifunctional crosslinking agent (optionally also comprising amine moieties):

[0197]

[0198] wherein R4and R5are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl, R6is an aliphatic group, and R 61 and R 62 are independently hydrogen, an aliphatic group, or a heteroaliphatic group. In one embodiment, for example, R4and R5are independently hydrogen, saturated hydrocarbon, unsaturated aliphatic group, aryl, heteroaryl, heteroalkyl, or unsaturated heteroaliphatic group. By way of another example, in one such embodiment, R4and R5are independently hydrogen, aliphatic group, heteroaliphatic group, aryl, or heteroaryl. By way of another example, in one such embodiment, R4and R5are independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ether group, heteroaryl, or heterocyclyl. By way of another example, in one such embodiment, R4and R5are independently hydrogen, alkyl, alkenyl, aminoalkyl, alkanol, aryl, haloalkyl, hydroxyalkyl, ether group, heteroaryl, or heterocyclyl. By way of another example, in one such embodiment, R4and R5, in combination with the nitrogen atom to which they are attached, together form part of a ring structure, such that the monomer of Formula la is a nitrogen-containing heterocycle (e.g., piperidine). By way of another example, in one embodiment, R4and R5are independently hydrogen, aliphatic group, or heteroaliphatic group. By way of another example, in one embodiment, R4and R5are independently hydrogen, allyl, or aminoalkyl. By way of another example, in each of the embodiments described in this paragraph, R6may be methylene, ethylene, or propylene, and R 61 and R 62 may independently be hydrogen, allyl, or aminoalkyl.

[0199] In some embodiments, the preformed amine polymer is a crosslinked amine polymer comprising residues of amines corresponding to Formula lc:

[0200]

[0201] wherein R7is hydrogen, an aliphatic group, or a heteroaliphatic group, and R8is an aliphatic group or a heteroaliphatic group. For example, in one such embodiment, R7is hydrogen and R8is an aliphatic group or a heteroaliphatic group. By way of another example, in one such embodiment, R7and R8are independently an aliphatic group or a heteroaliphatic group. By way of another example, in one such embodiment, at least one of R7and R8comprises an allyl moiety. By way of another example, in one such embodiment, at least one of R7and R8comprises an aminoalkyl moiety. By way of another example, in one such embodiment, each of R7and R8comprises an allyl moiety. By way of another example, in one such embodiment, each of R7and R8comprises an aminoalkyl moiety. By way of another example, in one such embodiment, R7comprises an allyl moiety and R8comprises an aminoalkyl moiety.

[0202] In some embodiments, the preformed amine polymer is a crosslinked amine polymer comprising residues of amines corresponding to Formula 2:

[0203]

[0204] wherein

[0205] m and n are independently non-negative integers;

[0206] R 10 , R 20 , R 30 , and R 40 are independently hydrogen, a hydrocarbyl group, or a substituted hydrocarbyl group;

[0207] X1is

[0208] X2is a hydrocarbyl group or a substituted hydrocarbyl group;

[0209] each X 11 is independently hydrogen, a hydrocarbyl group, a substituted hydrocarbyl group, a hydroxyl group, an amino group, a boronic acid, or a halo group; and

[0210] z is a non-negative number.

[0211] In one embodiment, the preformed amine polymer is a crosslinked amine polymer comprising residues of amines corresponding to Formula 2, which is prepared by (i) a substitution polymerization of amines corresponding to Formula 2 with a multifunctional crosslinking agent (optionally also comprising an amine moiety), or (2) a free radical polymerization of amines corresponding to Formula 2, and m and n are independently 0, 1, 2, or 3, and n is 0 or 1.

[0212] In one embodiment, the preformed amine polymer is a crosslinked amine polymer comprising residues of amines corresponding to Formula 2, prepared by (i) substitution polymerization of amines corresponding to Formula 2 with a multifunctional crosslinking agent (optionally also comprising amine moieties), or (2) free radical polymerization of amines corresponding to Formula 2, and R 10 , R 20 , R 30 , and R 40 are independently hydrogen, aliphatic, aryl, heteroaliphatic, or heteroaryl. By way of further example, in one such embodiment, R 10 , R 20 , R 30 , and R 40 are independently hydrogen, aliphatic, or heteroaliphatic. By way of further example, in one such embodiment, R 10 , R 20 , R 30 , and R 40 are independently hydrogen, alkyl, allyl, vinyl, or aminoalkyl. By way of further example, in one such embodiment, R 10 , R 20 , R 30 , and R 40 are independently hydrogen, alkyl, allyl, vinyl, -(CH2) d NH2, -(CH2) d N[(CH2) e NH2)]2, where d and e are independently 2-4. In each of the above exemplary embodiments of this paragraph, m and z can independently be 0, 1, 2, or 3, and n is 0 or 1.

[0213] In one embodiment, the preformed amine polymer is a crosslinked amine polymer comprising residues of amines corresponding to Formula 2, prepared by (i) substitution polymerization of amines corresponding to Formula 2 with a multifunctional crosslinking agent (optionally also comprising amine moieties), or (2) free radical polymerization of amines corresponding to Formula 2, and X2is an aliphatic or heteroaliphatic group. For example, in one such embodiment, X2is an aliphatic or heteroaliphatic group, and R 10 , R 20 , R 30 , and R 40 are independently hydrogen, aliphatic, heteroaliphatic. By way of further example, in one such embodiment, X2is alkyl or aminoalkyl, and R 10 , R 20 , R 30 , and R 40independently hydrogen, alkyl, allyl, vinyl, or aminoalkyl. In each of the above exemplary embodiments of this paragraph, m and z can independently be 0, 1, 2, or 3, and n is 0 or 1. 10 , R 20 , R 30 , and R 40 independently hydrogen, alkyl, allyl, vinyl, or aminoalkyl. In each of the above exemplary embodiments of this paragraph, m and z can independently be 0, 1, 2, or 3, and n is 0 or 1.

[0214] In one embodiment, the preformed amine polymer is a crosslinked amine polymer comprising residues of amines corresponding to Formula 2, prepared by (i) substitution polymerization of amines corresponding to Formula 2 with a multifunctional crosslinking agent (optionally also comprising amine moieties), or (2) free radical polymerization of amines corresponding to Formula 2, and m is a positive integer. For example, in one such embodiment, m is a positive integer, z is 0, and R 20 is hydrogen, an aliphatic group, or a heteroaliphatic group. By way of another example, in one such embodiment, m is a positive integer (e.g., 1 to 3), z is a positive integer (e.g., 1 to 2), X 11 is hydrogen, an aliphatic group, or a heteroaliphatic group, and R 20 is hydrogen, an aliphatic group, or a heteroaliphatic group. By way of another example, in one such embodiment, m is a positive integer, z is 0, 1, or 2, X 11 is hydrogen, an aliphatic group, or a heteroaliphatic group, and R 20 is hydrogen, an aliphatic group, or a heteroaliphatic group. By way of another example, in one such embodiment, m is a positive integer, z is 0, 1, or 2, X

[0215] In one embodiment, the preformed amine polymer is a crosslinked amine polymer comprising residues of amines corresponding to Formula 2, prepared by (i) substitution polymerization of amines corresponding to Formula 2 with a multifunctional crosslinking agent (optionally also comprising amine moieties), or (2) free radical polymerization of amines corresponding to Formula 2, n is a positive integer and R 30 is hydrogen, an aliphatic group, or a heteroaliphatic group. By way of another example, in one such embodiment, n is 0 or 1, and R 30 is hydrogen, an aliphatic group, or a heteroaliphatic group. By way of another example, in one such embodiment, n is 0 or 1, and R

[0216] In one embodiment, the preformed amine polymer is a crosslinked amine polymer comprising residues of amines corresponding to Formula 2, prepared by (i) substitution polymerization of amines corresponding to Formula 2 with a multifunctional crosslinking agent (optionally also comprising amine moieties), or (2) free radical polymerization of amines corresponding to Formula 2, m and n are independently non-negative integers and X2is an aliphatic group or a heteroaliphatic group. For example, in one such embodiment, m is 0 to 2, n is 0 or 1, X2is an aliphatic group or a heteroaliphatic group, and R10 R 20 R 30 and R 40 are independently hydrogen, aliphatic, or heteroaliphatic. By way of further example, in one such embodiment, m is 0 to 2, n is 0 or 1, X2is alkyl or aminoalkyl, and R 10 R 20 R 30 and R 40 are independently hydrogen, aliphatic, or heteroaliphatic. By way of further example, in one such embodiment, m is 0 to 2, n is 0 or 1, X2is alkyl or aminoalkyl, and R 10 R 20 R 30 and R 40 are independently hydrogen, alkyl, alkenyl, or aminoalkyl.

[0217] In some embodiments, the preformed amine polymer is a crosslinked amine polymer comprising residues of amines corresponding to Formula 2a and the crosslinked amine polymer is prepared by substitution polymerization of amines corresponding to Formula 2a with a multifunctional crosslinking agent (optionally also comprising amine moieties):

[0218]

[0219] wherein

[0220] m and n are independently non-negative integers;

[0221] each R 11 is independently hydrogen, hydrocarbyl, heteroaliphatic, or heteroaryl;

[0222] R 21 and R 31 are independently hydrogen or heteroaliphatic;

[0223] R 41 is hydrogen, substituted hydrocarbyl, or hydrocarbyl;

[0224] X1is

[0225] X2is alkyl or substituted hydrocarbyl;

[0226] each X 12 is independently hydrogen, hydroxyl, amino, aminoalkyl, boronic acid, or halo; and

[0227] z is a non-negative number.

[0228] In one embodiment, the preformed amine polymer is a crosslinked amine polymer comprising residues of amines corresponding to Formula 2a, the crosslinked amine polymer prepared by substitution polymerization of amines corresponding to Formula 1 with a multifunctional crosslinking agent (optionally also comprising an amine moiety). For example, in one such embodiment, m and z are independently 0, 1, 2, or 3, and n is 0 or 1.

[0229] In one embodiment, the preformed amine polymer is a crosslinked amine polymer comprising residues of amines corresponding to Formula 2a, the crosslinked amine polymer prepared by substitution polymerization of amines corresponding to Formula 2a with a multifunctional crosslinking agent (optionally also comprising an amine moiety), and each R 11 is independently hydrogen, an aliphatic group, an aminoalkyl group, a haloalkyl group, or a heteroaryl group, R 21 and R 31 are independently hydrogen or a heteroaliphatic group, and R 41 is hydrogen, an aliphatic group, an aryl group, a heteroaliphatic group, or a heteroaryl group. For example, in one such embodiment, each R 11 is hydrogen, an aliphatic group, an aminoalkyl group, or a haloalkyl group, R 21 and R 31 are independently hydrogen or a heteroaliphatic group, and R 41 is hydrogen, an alkylamino group, an aminoalkyl group, an aliphatic group, or a heteroaliphatic group. By way of further example, in one such embodiment, each R 11 is hydrogen, an aliphatic group, an aminoalkyl group, or a haloalkyl group, R 21 and R 31 is hydrogen or an aminoalkyl group, and R 41 is hydrogen, an aliphatic group, or a heteroaliphatic group. By way of further example, in one such embodiment, each R 11 and R 41 are independently hydrogen, an alkyl group, or an aminoalkyl group, and R 21 and R 31 are independently hydrogen or a heteroaliphatic group. By way of further example, in one such embodiment, each R 11 and R 41 are independently hydrogen, an alkyl group, -(CH2) d NH2, -(CH2) d N[(CH2) e NH2)]2, where d and e are independently 2-4, and R 21 and R 31 are independently hydrogen or a heteroaliphatic group. In each of the above exemplary embodiments of this paragraph, m and z can be independently 0, 1, 2, or 3, and n is 0 or 1.

[0230] Exemplary amines for use in the synthesis of polymers comprising repeat units corresponding to Formula 2a include, but are not limited to, the amines given in Table A.

[0231]

[0232]

[0233] Exemplary crosslinking agents for synthesizing polymers comprising residues of amines corresponding to Formula 2a include, but are not limited to, the crosslinking agents given in Table B.

[0234] Table B

[0235]

[0236] In some embodiments, the preformed amine polymer is a crosslinked amine polymer comprising residues of amines corresponding to Formula 2b and the crosslinked amine polymer is prepared by free radical polymerization of amines corresponding to Formula 2b:

[0237]

[0238] wherein

[0239] m and n are independently non-negative integers;

[0240] each R 12 is independently hydrogen, substituted hydrocarbyl, or hydrocarbyl;

[0241] R 22 and R 32 are independently hydrogen, substituted hydrocarbyl, or hydrocarbyl;

[0242] R 42 is hydrogen, hydrocarbyl, or substituted hydrocarbyl;

[0243] X1is

[0244] X2is alkyl, aminoalkyl, or alkanol;

[0245] each X 13 is independently hydrogen, hydroxyl, cycloaliphatic, amino, aminoalkyl, halogen, alkyl, heteroaryl, boronic acid, or aryl;

[0246] z is a non-negative number, and

[0247] The amines corresponding to Formula 2b include at least one allyl group.

[0248] In one embodiment, the preformed amine polymer is a crosslinked amine polymer comprising residues of amines corresponding to Formula 2b, the crosslinked amine polymer is prepared by free radical polymerization of amines corresponding to Formula 2b, and m and z are independently 0, 1, 2, or 3, and n is 0 or 1.

[0249] In one embodiment, the preformed amine polymer is a crosslinked amine polymer comprising residues of amines corresponding to Formula 2b, which is prepared by free radical polymerization of amines corresponding to Formula 1, and (i) R 12 or R 42 independently comprises at least one allyl or vinyl moiety, (ii) m is a positive integer, and R 22 comprises at least one allyl or vinyl moiety, and / or (iii) n is a positive integer, and R 32 comprises at least one allyl moiety. For example, in one such embodiment, m and z are independently 0, 1, 2, or 3, and n is 0 or 1. For example, in one such embodiment, R 12 or R 42 in combination comprise at least two allyl or vinyl moieties. By way of another example, in one such embodiment, m is a positive integer, and R 12 , R 22 , and R 42 in combination comprise at least two allyl or vinyl moieties. By way of another example, in one such embodiment, n is a positive integer, and R 12 , R 32 , and R 42 in combination comprise at least two allyl or vinyl moieties. By way of another example, in one such embodiment, m is a positive integer, n is a positive integer, and R 12 , R 22 , R 32 , and R 42 in combination comprise at least two allyl or vinyl moieties.

[0250] In one embodiment, the preformed amine polymer is a crosslinked amine polymer comprising residues of amines corresponding to Formula 2b, which is prepared by free radical polymerization of amines corresponding to Formula 2b, and each R 12 independently is hydrogen, aminoalkyl, allyl, or vinyl, R 22 , and R 32 independently is hydrogen, alkyl, aminoalkyl, haloalkyl, alkenyl, alkanol, heteroaryl, alicyclic, heterocyclyl, or aryl, and R 42 is hydrogen or substituted hydrocarbyl. For example, in one such embodiment, each R 12 is aminoalkyl, allyl, or vinyl, R 22 , and R 32 independently is hydrogen, alkyl, aminoalkyl, haloalkyl, alkenyl, or alkanol, and R 42 is hydrogen or substituted hydrocarbyl. By way of another example, in one such embodiment, each R 12 , and R 42independently hydrogen, alkyl, allyl, vinyl, -(CH2) d NH2or -(CH2) d N[(CH2) e NH2]2, wherein d and e are independently 2-4, and R 22 and R 32 are independently hydrogen or heteroaliphatic.

[0251] Exemplary amines and crosslinking agents (or salts thereof, such as hydrochloride, phosphate, sulfate, or hydrobromide salts thereof) for use in the synthesis of the polymers described by Formula 2b include, but are not limited to, those in Table C.

[0252] Table C

[0253]

[0254]

[0255] In some embodiments, the preformed amine polymer is a crosslinked amine polymer obtained from the reaction of a linear polymer composed of the resulting preformed polymer of the monomer described by any one of Formulas 1, 1a, 1b, 1c, 2, 2a, and 2b or repeating units described by Formula 3 with an external crosslinking agent or pre-existing polymer functional groups that can serve as crosslinking sites. Formula 3 can be a repeating unit of a preformed copolymer or terpolymer, wherein X 15 is a random copolymer, an alternating copolymer, or a block copolymer. The repeating unit in Formula 3 can also represent a repeating unit of a branched or hyperbranched preformed polymer, where the primary branching points can come from any atom on the backbone of the polymer:

[0256]

[0257] wherein

[0258] R 15 , R 16 and R 17 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxyl, amino, boronic acid, or halide;

[0259] X 15 is

[0260] X5is hydrocarbyl, substituted hydrocarbyl, oxo (-O-), or amino; and

[0261] z is a non-negative number.

[0262] In one embodiment, R 15 , R 16 and R 17independently hydrogen, aryl or heteroaryl, X5is hydrocarbyl, substituted hydrocarbyl, oxo or amino, and m and z are non-negative integers. In another embodiment, R 15 , R 16 and R 17 are independently aliphatic or heteroaliphatic, X5is hydrocarbyl, substituted hydrocarbyl, oxo (-O-), or amino, and m and z are non-negative integers. In another embodiment, R 15 , R 16 and R 17 are independently unsaturated aliphatic or unsaturated heteroaliphatic, X5is hydrocarbyl, substituted hydrocarbyl, oxo or amino, and z is a non-negative integer. In another embodiment, R 15 , R 16 and R 17 are independently alkyl or heteroalkyl, X5is hydrocarbyl, substituted hydrocarbyl, oxo or amino, and z is a non-negative integer. In another embodiment, R 15 , R 16 and R 17 are independently alkylamino, aminoalkyl, hydroxyl, amino, boronic acid, halo, haloalkyl, alkanol or ether, X5is hydrocarbyl, substituted hydrocarbyl, oxo or amino, and z is a non-negative integer. In another embodiment, R 15 , R 16 and R 17 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxyl, amino, boronic acid or halo, X5is oxo, amino, alkylamino, ether, alkanol or haloalkyl, and z is a non-negative integer.

[0263] Exemplary crosslinking agents that can be used in free radical polymerization reactions include, but are not limited to, one or more multifunctional crosslinking agents such as: 1,4-bis(allylamino)butane, 1,2-bis(allylamino)ethane, 2-(allylamino)-l-[2-(allylamino)ethylamino]ethane, 1,3-bis(allylamino)propane, 1,3-bis(allylamino)-2-propanol, triallylamine, diallylamine, divinylbenzene, 1,7-octadiene, 1,6-heptadiene, 1,8-nonadiene, 1,9-decadiene, 1,4-divinyl- oxybutane, 1,6-hexamethylene bisacrylamide, ethylene bisacrylamide, N,N'-bis(vinylsulfonyl acetyl)ethylenediamine, 1,3-bis(vinylsulfonyl) 2-propanol, vinyl sulfone, N,N'-methylene bisacrylamide polyvinyl ether, polyallyl ether, divinylbenzene, 1,4-divinyl-oxybutane, and combinations thereof.

[0264] Crosslinked polymers derived from monomers and polymers of Formula 1-3 can be synthesized in solution or in bulk or in a dispersion medium. Examples of solvents suitable for synthesis of the polymers of the present disclosure include, but are not limited to, water, low boiling alcohols (methanol, ethanol, propanol, butanol), dimethylformamide, dimethylsulfoxide, heptane, chlorobenzene, toluene.

[0265] As indicated previously, the product of the first polymerization step is preferably in the form of beads, the diameter of which is controlled in the range of 5 to 1000 microns, preferably 10 to 500 microns and most preferably 40-180 microns.

[0266] The product of the first polymerization step is preferably in the form of beads, the swelling ratio of which in water is between 2 and 10, more preferably about 3 to about 8, and most preferably about 4 to about 6.

[0267] Additionally, if the crosslinked polymer beads resulting from the first polymerization step are protonated, this can reduce the amount of nitrogen-nitrogen crosslinking in the second crosslinking step. Thus, in certain embodiments, the preformed amine polymer is at least partially deprotonated by treatment with a base, preferably a strong base such as a hydroxide base. For example, in one embodiment, the base can be NaOH, KOH, NH4OH, NaHCO3, Na2CO3, K2CO3, LiOH, Li2CO3, CsOH, or other metal hydroxides. If the charge is removed from the preformed crosslinked amine polymer by deprotonation, the beads will tend to collapse and the crosslinking agent used in the second step can not have access to the binding sites on the polymer unless the beads are prevented from collapsing. One means of preventing the crosslinked polymer beads from collapsing is to use a swelling agent, such as water, to swell the beads, allowing the second step crosslinking agent to access the binding sites.

[0268] Any of a range of crosslinking compounds containing at least two amine reactive functional groups can be used to crosslink the preformed polymer to form the post-polymerization crosslinked polymer. In one such embodiment, the crosslinking agent is a compound containing at least two amine reactive groups selected from the group consisting of halides, epoxides, phosgene, anhydrides, carbamates, carbonates, isocyanates, isothiocyanates, esters, activated esters, carboxylic acids and derivatives thereof, sulfonates and derivatives thereof, acyl halides, aziridines, alpha, beta-unsaturated carbonyls, ketones, aldehydes, and pentafluoroaryl groups. The crosslinking agent can be, for example, any of the crosslinking agents disclosed herein, including a crosslinking agent selected from Table B. By way of further example, in one such embodiment, the crosslinking agent is a dihalide, such as a dichloroalkane.

[0269] As noted above, in certain embodiments, a swelling agent for the preformed amine polymer can be included in the reaction mixture for the second polymerization step along with the crosslinking agent. Generally, the swelling agent and the crosslinking agent can be miscible or immiscible, and the swelling agent can be any composition or combination of compositions that has the ability to swell the preformed amine polymer. Exemplary swelling agents include polar solvents such as water, methanol, ethanol, n-propanol, isopropanol, n-butanol, formic acid, acetic acid, acetonitrile, dimethylformamide, dimethylsulfoxide, nitromethane, propylene carbonate, or combinations thereof. Additionally, the amount of swelling agent included in the reaction mixture will generally be less than the absorption capacity of the preformed amine polymer for the swelling agent. For example, it is generally preferred that the weight ratio of the swelling agent to the preformed polymer in the reaction mixture be less than 4: 1. By way of further example, in some embodiments, the weight ratio of the swelling agent to the preformed polymer in the reaction mixture will be less than 3: 1. By way of further example, in some embodiments, the weight ratio of the swelling agent to the preformed polymer in the reaction mixture will be less than 2: 1. By way of further example, in some embodiments, the weight ratio of the swelling agent to the preformed polymer in the reaction mixture will be less than 1 : 1. By way of further example, in some embodiments, the weight ratio of the swelling agent to the preformed polymer in the reaction mixture will be less than 0.5: 1. By way of further example, in some embodiments, the weight ratio of the swelling agent to the preformed polymer in the reaction mixture will be less than 0.4: 1. By way of further example, in some embodiments, the weight ratio of the swelling agent to the preformed polymer in the reaction mixture will be less than 0.3: 1. Generally, however, the weight ratio of the swelling agent to the preformed polymer in the reaction mixture will typically correspondingly be at least 0.05: 1.

[0270] When the swelling agent comprises water, the weight ratio of water to preformed amine polymer in the reaction mixture will generally be less than about 4:1 (water: polymer). For example, in one such embodiment, the reaction mixture comprises water as the swelling agent and the weight ratio of water to preformed amine polymer in the reaction mixture will generally be less than about 3.5:1. By way of another example, in one such embodiment, the reaction mixture comprises water as the swelling agent and the weight ratio of water to preformed amine polymer in the reaction mixture will generally be less than about 3:1. By way of another example, in one such embodiment, the reaction mixture comprises water as the swelling agent and the weight ratio of water to preformed amine polymer in the reaction mixture will generally be less than about 2.5:1. By way of another example, in one such embodiment, the reaction mixture comprises water as the swelling agent and the weight ratio of water to preformed amine polymer in the reaction mixture will generally be less than about 2:1. By way of another example, in one such embodiment, the reaction mixture comprises water as the swelling agent and the weight ratio of water to preformed amine polymer in the reaction mixture will generally be less than about 1.5:1. By way of another example, in one such embodiment, the reaction mixture comprises water as the swelling agent and the weight ratio of water to preformed amine polymer in the reaction mixture will generally be less than about 1 :1. By way of another example, in one such embodiment, the reaction mixture comprises water as the swelling agent and the weight ratio of water to preformed amine polymer in the reaction mixture will generally be less than about 0.75:1. By way of another example, in one such embodiment, the reaction mixture comprises water as the swelling agent and the weight ratio of water to preformed amine polymer in the reaction mixture will generally be less than about 0.5:1. By way of another example, in one such embodiment, the reaction mixture comprises water as the swelling agent and the weight ratio of water to preformed amine polymer in the reaction mixture will generally be less than about 0.25:1. Generally, however, when water is employed as the swelling agent, the weight ratio of water to preformed amine polymer in the reaction mixture will generally be at least about 0.15:1 (water: polymer), but less than the water absorption capacity of the preformed amine polymer. By way of another example, in one embodiment, the weight ratio of water to preformed amine polymer in the reaction mixture will generally be at least about 0.2:1, but less than the water absorption capacity of the preformed amine polymer. By way of another example, in one embodiment, the weight ratio of water to preformed amine polymer in the reaction mixture will generally be at least about 0.25:1, but less than the water absorption capacity of the preformed amine polymer. By way of another example, in one embodiment, the weight ratio of water to preformed amine polymer in the reaction mixture will generally be at least about 0.5:1, but less than the water absorption capacity of the preformed amine polymer.By way of further example, in one embodiment, the weight ratio of water to preformed amine polymer in the reaction mixture will generally be at least about 0.75:1, but less than the water uptake capacity of the preformed amine polymer. By way of further example, in one embodiment, the weight ratio of water to preformed amine polymer in the reaction mixture will generally be at least about 1 :1, but less than the water uptake capacity of the preformed amine polymer. By way of further example, in one embodiment, the weight ratio of water to preformed amine polymer in the reaction mixture will generally be at least about 1.5:1, but less than the water uptake capacity of the preformed amine polymer. By way of further example, in one embodiment, the weight ratio of water to preformed amine polymer in the reaction mixture will generally be at least about 2:1, but less than the water uptake capacity of the preformed amine polymer. By way of further example, in one embodiment, the weight ratio of water to preformed amine polymer in the reaction mixture will generally be at least about 2.5:1, but less than the water uptake capacity of the preformed amine polymer. By way of further example, in one embodiment, the weight ratio of water to preformed amine polymer in the reaction mixture will generally be at least about 3:1, but less than the water uptake capacity of the preformed amine polymer. By way of further example, in one embodiment, the weight ratio of water to preformed amine polymer in the reaction mixture will generally be at least about 3.5:1, but less than the water uptake capacity of the preformed amine polymer. Thus, in certain embodiments, the weight ratio of water to preformed amine polymer will range from about 0.15:1 to about 4:1. By way of further example, in certain embodiments, the weight ratio of water to preformed amine polymer will range from about 0.2:1 to about 3.5:1. By way of further example, in certain embodiments, the weight ratio of water to preformed amine polymer will range from about 0.2:1 to about 3:1.

[0271] In each of the above embodiments, the reaction mixture can contain a wide range of amounts of the crosslinking agent. For example, in one embodiment, the crosslinking agent can be used in great excess relative to the amount of preformed amine polymer in the reaction mixture. In other words, in such embodiments, the crosslinking agent is a crosslinking solvent, i.e., it is both a solvent for the reaction mixture and a crosslinking agent for the preformed amine polymer. In such embodiments, other solvents can optionally be included in the reaction mixture, but are not necessary. Alternatively, the preformed amine polymer, the swelling agent, and the crosslinking agent can be dispersed in a solvent that is miscible with the crosslinking agent and immiscible with the swelling agent. For example, in some embodiments, the swelling agent can be a polar solvent, and in some such embodiments, for example, the swelling agent can include water, methanol, ethanol, n-propanol, isopropanol, formic acid, acetic acid, acetonitrile, dimethylformamide, dimethyl sulfoxide, nitromethane, or combinations thereof. By way of another example, when the swelling agent includes a polar solvent, the solvent system used in the reaction mixture will typically include a non-polar solvent, such as pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, trichloromethane, diethyl ether, dichloromethane, dichloroethane, dichloropropane, dichlorobutane, or combinations thereof. In certain embodiments, the crosslinking agent and the solvent can be the same, i.e., the solvent is the crosslinking agent, such as 1,2-dichloroethane, 1,3-dichloropropane, 1,4-dichlorobutane, or combinations thereof.

[0272] In those embodiments in which the reaction mixture includes a swelling agent, it is sometimes preferred to combine the preformed amine polymer with a solvent (sometimes referred to alternatively as a dispersant) prior to combining the preformed amine polymer in the reaction mixture with the swelling agent. In certain embodiments, when the preformed amine polymer is combined with a solvent (dispersant) that is immiscible with the swelling agent prior to combining the preformed amine polymer with the swelling agent, the resulting crosslinked polymer tends to be less aggregated. Thus, in certain embodiments, less than 25% of the particles in a representative sample of the population of crosslinked amine particles after polymerization are aggregated into clumps. For example, in some embodiments, less than 20% of the particles in a representative sample of the population of crosslinked amine particles after polymerization are aggregated into clumps. By way of further example, in some embodiments, less than 15% of the particles in a representative sample of the population of crosslinked amine particles after polymerization are aggregated into clumps. By way of further example, in some embodiments, less than 10% of the particles in a representative sample of the population of crosslinked amine particles after polymerization are aggregated into clumps. By way of further example, in some embodiments, less than 5% of the particles in a representative sample of the population of crosslinked amine particles after polymerization are aggregated into clumps. By way of further example, in some embodiments, less than 1% of the particles in a representative sample of the population of crosslinked amine particles after polymerization are aggregated into clumps. Aggregation can be assessed using microscopy or other means of measuring particle size distribution. Lack of aggregation can be defined as a generally separate, free-flowing bead lacking macroscopic and / or microscopic clumps. Particle size distribution (as defined elsewhere) can be indicative of the occurrence of aggregation, for example, if the average size (d(50)) and / or d(90) of the crosslinked amine polymer after polymerization is increased relative to the preformed amine polymer bead as previously described following the crosslinking step.

[0273] In one embodiment, the preformed amine polymer is formed in a first step and the preformed amine polymer is crosslinked in a second step to form a post-polymerization crosslinked polymer without isolating the preformed amine polymer between the first step and the second step (sometimes referred to as "one-pot synthesis"). For example, in one such embodiment, the preformed amine polymer is formed in a first reaction mixture (as described herein previously) and the preformed amine polymer formed in the first reaction mixture is crosslinked without isolating the preformed amine polymer using any of the crosslinking agents disclosed herein (including, for example, a crosslinking agent selected from Table B). By way of another example, in one such embodiment, the preformed polymer can be dispersed in any of the non-polar solvents disclosed herein (including, for example, a crosslinking solvent) to form a reaction mixture and a swelling agent is added to the reaction mixture. In one such exemplary embodiment, the crosslinking agent is selected from Table B, the solvent is a crosslinking water-immiscible solvent such as 1,2-dichloroethane ("DCE") or 1,3-dichloropropane ("DCP") and the swelling agent includes water. In each of the above-described embodiments, the preformed polymer can be an amine-containing polymer comprising residues of monomers described by any of Formulae 1, 1a, 1b, 1c, 2, 2a, and 2b or a linear polymer composed of repeating units described by Formula 3; for example, in each of the above-described embodiments, the preformed polymer can comprise residues of two or more small molecule amines and a crosslinking agent disclosed in Table C.

[0274] In one exemplary embodiment, the preformed polyamine polymer is crosslinked under, for example, suspension conditions to generate particles of target particle size and morphology. The crosslinking agent can be water-miscible or water-immiscible. When a water-immiscible crosslinking agent (e.g., DCE or DCP) is used as a dispersant, high chloride binding selectivity is achieved in, for example, SIB and / or SOB, as demonstrated.

[0275] In one embodiment, an amine polymer can be formed and then further crosslinked in the same reaction flask and in one reaction series. The crosslinked amine polymer can be prepared under, for example, suspension conditions to generate particles of target particle size and morphology. In the same reaction flask and without isolation, the water content of the beads can be reduced by a Dean Stark method or other similar evaporation technique. The water is adjusted to a target amount, thereby enabling a second crosslinking reaction to occur to produce a final polymer having desired properties and characteristics.

[0276] In one embodiment, the crosslinked amine polymer is treated to reduce the concentration of any residual amine-reactive groups (e.g., amine-reactive functional groups) introduced into the crosslinked polymer by the crosslinking agent. For example, in one such embodiment, the crosslinked polymer (e.g., a post-polymerization crosslinked polymer as previously described) is treated with a quencher such as a base, washed, heated, or otherwise treated to remove or quench the amine-reactive groups. For example, in one embodiment, the crosslinked polymer is treated with ammonium hydroxide. The ammonium hydroxide treatment can occur immediately after the reaction, during a washing step, or after the polymer has been washed and dried, in which case the polymer can be treated by another series of washing steps. In another embodiment, the crosslinked polymer is heated in a conventional or vacuum oven at a temperature above room temperature, for example, 60 °C, for greater than 36 hours. The oven incubation can occur under an inert atmosphere (e.g., nitrogen or argon) to reduce the likelihood of oxidation.

[0277] In one embodiment, a preformed amine polymer characterized by a first selectivity for chloride over citrate, phosphate, and / or taurocholate in SGF, SIB, and / or SOB is crosslinked in a post-polymerization crosslinking reaction to provide a crosslinked polymer (i.e., a post-polymerization crosslinked polymer) that is characterized by a second (different) selectivity for chloride over citrate, phosphate, and / or taurocholate in SGF, SIB, and / or SOB. In one such embodiment, the preformed amine polymer is a substituted polymeric reaction product of a multifunctional reagent comprising at least one amine moiety. In another such embodiment, the preformed polymer is a free radical polymerized reaction product of a monomer comprising at least one amine moiety or nitrogen-containing moiety. In the second crosslinking step (which can optionally be performed after isolation of the preformed polymer or as a second step of a one-pot reaction), the preformed amine polymer is crosslinked with a multifunctional crosslinking agent that optionally comprises an amine moiety.

[0278] In one exemplary embodiment, the post-polymerization crosslinked polymer has an increased capacity for binding chloride ions and a decreased capacity for binding phosphate ions in SIB relative to the preformed amine polymer. For example, in one such embodiment, the post-polymerization crosslinked polymer has an increased capacity for binding chloride ions in SIB and a decreased capacity for binding phosphate ions in SIB relative to the preformed polymer. By way of another example, in one such embodiment, the post-polymerization crosslinked polymer has a capacity for chloride ions in SIB that is at least 10% greater than the capacity for chloride ions in SIB of the preformed polymer. By way of another example, in one such embodiment, the post-polymerization crosslinked polymer has a capacity for chloride ions in SIB that is at least 25% greater than the capacity for chloride ions in SIB of the preformed polymer. By way of another example, in one such embodiment, the post-polymerization crosslinked polymer has a capacity for chloride ions in SIB that is at least 50% greater than the capacity for chloride ions in SIB of the preformed polymer. By way of another example, in one such embodiment, the post-polymerization crosslinked polymer has a capacity for chloride ions in SIB that is at least 75% greater than the capacity for chloride ions in SIB of the preformed polymer. By way of another example, in one such embodiment, the post-polymerization crosslinked polymer has a capacity for chloride ions in SIB that is at least 100% greater than the capacity for chloride ions in SIB of the preformed polymer. By way of another example, in one such embodiment, the post-polymerization crosslinked polymer has a capacity for chloride ions in SIB that is at least 125% greater than the capacity for chloride ions in SIB of the preformed polymer. By way of another example, in one such embodiment, the post-polymerization crosslinked polymer has a capacity for chloride ions in SIB that is at least 150% greater than the capacity for chloride ions in SIB of the preformed polymer. By way of another example, in one such embodiment, the post-polymerization crosslinked polymer has a capacity for chloride ions in SIB that is at least 200% greater than the capacity for chloride ions in SIB of the preformed polymer. By way of another example, in one such embodiment, the post-polymerization crosslinked polymer has a capacity for phosphate ions in SIB that is at least 10% less than the capacity for phosphate ions in SIB of the preformed polymer. By way of another example, in one such embodiment, the post-polymerization crosslinked polymer has a capacity for phosphate ions in SIB that is at least 20% less than the capacity for phosphate ions in SIB of the preformed polymer. By way of another example, in one such embodiment, the post-polymerization crosslinked polymer has a capacity for phosphate ions in SIB that is at least 30% less than the capacity for phosphate ions in SIB of the preformed polymer.By way of further example, in one such embodiment, the post-polymerization crosslinked polymer has a capacity for phosphate in the SIB that is at least 40% less than the binding capacity for phosphate in the SIB of the preformed polymer. By way of further example, in one such embodiment, the post-polymerization crosslinked polymer has a capacity for phosphate in the SIB that is at least 50% less than the binding capacity for phosphate in the SIB of the preformed polymer. By way of further example, in one such embodiment, the post-polymerization crosslinked polymer has a capacity for phosphate in the SIB that is at least 60% less than the binding capacity for phosphate in the SIB of the preformed polymer. By way of further example, in one such embodiment, the post-polymerization crosslinked polymer has a capacity for phosphate in the SIB that is at least 70% less than the binding capacity for phosphate in the SIB of the preformed polymer. By way of further example, in one such embodiment, the post-polymerization crosslinked polymer has a capacity for phosphate in the SIB that is at least 80% less than the binding capacity for phosphate in the SIB of the preformed polymer. By way of further example, in one such embodiment, the post-polymerization crosslinked polymer has a capacity for phosphate in the SIB that is at least 90% less than the binding capacity for phosphate in the SIB of the preformed polymer. By way of further example, in one such embodiment, the post-polymerization crosslinked polymer has a capacity for phosphate in the SIB that is at least 95% less than the binding capacity for phosphate in the SIB of the preformed polymer. By way of further example, in one such embodiment, the post-polymerization crosslinked polymer has (i) an increased binding capacity for chloride in the SIB relative to the preformed amine polymer (increased by at least 10%, 25%, 50%, 75%, 100%, 125%, 150%, 175%, or even at least 200%) and a decreased binding capacity for phosphate (decreased by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or even at least 95%) and (ii) a decreased binding capacity for chloride in the SGF relative to the preformed amine polymer.

[0279] In one exemplary embodiment, the post-polymerization crosslinked polymer has an increased binding capacity for chloride ions and a decreased binding capacity for phosphate, citrate, or taurocholate in SOB relative to the preformed amine polymer. For example, in one such embodiment, the post-polymerization crosslinked polymer has an increased binding capacity for chloride ions and a decreased binding capacity for phosphate in SOB relative to the preformed polymer. By way of another example, in one such embodiment, the post-polymerization crosslinked polymer has an increased binding capacity for chloride ions and a decreased binding capacity for citrate in SOB relative to the preformed amine polymer. By way of another example, in one such embodiment, the post-polymerization crosslinked polymer has an increased binding capacity for chloride ions and a decreased binding capacity for taurocholate in SOB relative to the preformed amine polymer. By way of another example, in one such embodiment, the post-polymerization crosslinked polymer has an increased binding capacity for chloride ions and a decreased binding capacity for the combination of phosphate, citrate, and taurocholate in SOB relative to the preformed amine polymer.

[0280] By way of further example, in one such embodiment, the capacity of the post-polymerization crosslinked polymer for chloride ions in SOB is at least 10% greater than the combined capacity of the preformed polymer for chloride ions in SOB. By way of further example, in one such embodiment, the capacity of the post-polymerization crosslinked polymer for chloride ions in SOB is at least 25% greater than the combined capacity of the preformed polymer for chloride ions in SOB. By way of further example, in one such embodiment, the capacity of the post-polymerization crosslinked polymer for chloride ions in SOB is at least 50% greater than the combined capacity of the preformed polymer for chloride ions in SOB. By way of further example, in one such embodiment, the capacity of the post-polymerization crosslinked polymer for chloride ions in SOB is at least 75% greater than the combined capacity of the preformed polymer for chloride ions in SOB. By way of further example, in one such embodiment, the capacity of the post-polymerization crosslinked polymer for chloride ions in SOB is at least 100% greater than the combined capacity of the preformed polymer for chloride ions in SOB. By way of further example, in one such embodiment, the capacity of the post-polymerization crosslinked polymer for chloride ions in SOB is at least 125% greater than the combined capacity of the preformed polymer for chloride ions in SOB. By way of further example, in one such embodiment, the capacity of the post-polymerization crosslinked polymer for chloride ions in SOB is at least 150% greater than the combined capacity of the preformed polymer for chloride ions in SOB. By way of further example, in one such embodiment, the capacity of the post-polymerization crosslinked polymer for chloride ions in SOB is at least 200% greater than the combined capacity of the preformed polymer for chloride ions in SOB. By way of further example, in one such embodiment, the capacity of the post-polymerization crosslinked polymer for phosphate, citrate, and taurocholate ions in SOB is at least 10% less than the combined capacity of the preformed polymer for phosphate, citrate, and taurocholate ions in SOB. By way of further example, in one such embodiment, the capacity of the post-polymerization crosslinked polymer for phosphate, citrate, and taurocholate ions in SOB is at least 20% less than the combined capacity of the preformed polymer for phosphate, citrate, and taurocholate ions in SOB. By way of further example, in one such embodiment, the capacity of the post-polymerization crosslinked polymer for phosphate, citrate, and taurocholate ions in SOB is at least 30% less than the combined capacity of the preformed polymer for phosphate, citrate, and taurocholate ions in SOB. By way of further example, in one such embodiment, the capacity of the post-polymerization crosslinked polymer for phosphate, citrate, and taurocholate ions in SOB is at least 40% less than the combined capacity of the preformed polymer for phosphate, citrate, and taurocholate ions in SOB.By way of further example, in one such embodiment, the post-polymerization crosslinked polymer has a capacity for phosphate, citrate, and taurocholate in SOB that is at least 50% less than the combined capacity of the preformed polymer for phosphate, citrate, and taurocholate in SOB. By way of further example, in one such embodiment, the post-polymerization crosslinked polymer has a capacity for phosphate, citrate, and taurocholate in SOB that is at least 60% less than the combined capacity of the preformed polymer for phosphate, citrate, and taurocholate in SOB. By way of further example, in one such embodiment, the post-polymerization crosslinked polymer has a capacity for phosphate, citrate, and taurocholate in SOB that is at least 70% less than the combined capacity of the preformed polymer for phosphate, citrate, and taurocholate in SOB. By way of further example, in one such embodiment, the post-polymerization crosslinked polymer has a capacity for phosphate, citrate, and taurocholate in SOB that is at least 80% less than the combined capacity of the preformed polymer for phosphate, citrate, and taurocholate in SOB. By way of further example, in one such embodiment, the post-polymerization crosslinked polymer has a capacity for phosphate, citrate, and taurocholate in SOB that is at least 90% less than the combined capacity of the preformed polymer for phosphate, citrate, and taurocholate in SOB. By way of further example, in one such embodiment, the post-polymerization crosslinked polymer has a capacity for phosphate, citrate, and taurocholate in SOB that is at least 95% less than the combined capacity of the preformed polymer for phosphate, citrate, and taurocholate in SOB. By way of further example, in one such embodiment, the post-polymerization crosslinked polymer has (i) an increased binding capacity for chloride ions in SOB relative to the preformed amine polymer (increased by at least 10%, 25%, 50%, 75%, 100%, 125%, 150%, 175%, or even at least 200%) and a decreased binding capacity for phosphate, citrate, and taurocholate (decreased by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or even at least 95%) and (ii) a decreased binding capacity in SGF relative to the preformed amine polymer.

[0281] The starting molecules described in Formulas 1-3 can be copolymerized with one or more other monomers, oligomers, or other polymerizable groups of the present application. Such copolymer structures can include, but are not limited to, block polymers or block-like polymers, graft copolymers, and random copolymers. Incorporation of the monomers described in Formulas 1-3 can range from 1% to 99%. In some embodiments, incorporation of the co-monomer is between 20% and 80%.

[0282] Non-limiting examples of comonomers that can be used individually or in combination include: styrene, allyl amine hydrochloride, substituted allyl amine hydrochloride, substituted styrene, alkyl acrylate, substituted alkyl acrylate, alkyl methacrylate, substituted alkyl methacrylate, acrylonitrile, methacrylonitrile, acrylamide, methacrylamide, N-alkyl acrylamide, N-alkyl methacrylamide, N,N-dialkyl acrylamide, N,N-dialkyl methacrylamide, isoprene, butadiene, ethylene, vinyl acetate, N-vinyl amide, maleic acid derivatives, vinyl ether, allyle, methacryl monomers, and combinations thereof. Functionalized versions of these monomers can also be used. Additional specific monomers or comonomers that can be used in the present application include, but are not limited to, 2-propen-1-ylamine, 1-(allylamino)-2-aminoethane, 1-[N-allyl(2-aminoethyl)amino]-2-aminoethane, methyl methacrylate, ethyl methacrylate, propyl methacrylate (all isomers), butyl methacrylate (all isomers), 2-ethylhexyl methacrylate, isobornyl methacrylate, methacrylic acid, benzyl methacrylate, phenyl methacrylate, methacrylonitrile, a-methylstyrene, methyl acrylate, ethyl acrylate, propyl acrylate (all isomers), butyl acrylate (all isomers), 2-ethylhexyl acrylate, isobornyl acrylate, acrylic acid, benzyl acrylate, phenyl acrylate, acrylonitrile, styrene, glycidyl methacrylate, 2-hydroxyethyl methacrylate, hydroxypropyl methacrylate (all isomers), hydroxybutyl methacrylate (all isomers), N,N-dimethylaminoethyl methacrylate, N,N-diethylaminoethyl methacrylate, triethylene glycol methacrylate, itaconic anhydride, itaconic acid, glycidyl acrylate, 2-hydroxyethyl acrylate, hydroxypropyl acrylate (all isomers), hydroxybutyl acrylate (all isomers), N,N-dimethylaminoethyl acrylate, N,N-diethylaminoethyl acrylate, triethylene glycol acrylate, methacrylamide, N-methyl acrylamide, N,N-dimethyl acrylamide, N,N-diethyl acrylamide, N,N-dimethylaminoethyl acrylamide, N,N-diethylaminoethyl acrylamide, N,N-dimethylaminopropyl acrylamide, N,N-diethylaminopropyl acrylamide, N,N-dimethylaminopropyl methacrylamide, N,N-diethylaminopropyl methacrylamide, N,N-dimethylaminoethyl methacrylamide, N,N-diethylaminoethyl methacrylamide, N,N-dimethylaminopropyl methacrylamide, N,N-diethylaminopropyl methacrylamide, N,N-dimethylaminoethyl methacrylamide, N,N-diethylaminoethyl methacrylamide, N,N-dimethylaminopropyl methacrylamide, N,N-diethylaminopropyl methacrylamide, N,N-dimethylaminoethyl methacrylamide, N,N-diethylaminoethyl methacrylamide, N,N-dimethylaminopropyl methacrylamide, N,N-diethylaminopropyl methacrylamide, N,N-dimethylaminoethyl methacrylamide, N,N-diethylaminoethyl methacrylamide, N,N-dimethylaminopropyl methacrylamide, N,N-diethylaminopropyl methacrylamide, N,N-dimethylaminoethyl methacrylamide, N,N-diethylaminoethyl methacrylamide, N,N-dimethylaminopropyl methacrylamide, N,N-diethylaminopropyl methacrylamide, N,N-dimethylaminoethyl methacrylamide, N,N-diethylaminoethyl methacrylamide, N,N-dimethylaminopropyl methacrylamide, N,N-diethylaminopropyl methacrylamide, N,N-dimethylaminoethyl methacrylamide, N,N-diethylaminoethyl methacrylamide, N,N-dimethylaminopropyl methacrylamide, N,N-diethylaminopropyl methacrylamide, N,N-dimethylaminoethyl methacrylamide, N,N-diethylaminoethyl methacrylamide, N,N-dimethylaminopropyl methacrylamide, N,N-diethylaminopropyl methacrylamide, N,N-dimethylaminoethyl methacrylamide, N,N-diethylaminoethyl methacrylamide, N,N-dimethylaminopropyl methacrylamide, N,N-diethylaminopropyl methacrylamide, N,N-dimethylaminoethyl methacrylamide, N,N-diethylaminoethyl methacrylamide, N,N-dimethylaminopropyl methacrylamide, N,N-diethylaminopropyl methacrylamide, N,N-dimethylaminoethyl methacrylamide, N,N-diethylaminoethyl methacrylamide, N,N-dimethylaminopropyl methacrylamide, N,N-diethylaminopropyl methacrylamide, N,N-dimethylaminoethyl methacrylamide, N,N-diethylaminoethyl methacrylamide, N,N-dimethylaminopropyl methacrylamide, N,N-diethylaminopropyl methacrylamide, N,N-dimethylaminoethyl methacrylamide, N,N-diethylaminoethyl methacrylamide, N,N-dimethylaminopropyl methacrylamide, N,N-diethylaminopropyl methacrylamide, N,N-dimethylaminoethyl methacrylamide, N,N-diethylaminoethyl methacrylamide, N,N-dimethylaminopropyl methacrylamide, N,N-diethylaminopropyl methacrylamide, N,N-dimethylaminoethyl methacrylamide, N,N-diethylaminoethyl methacrylamide, N,N-dimethylaminopropyl methacrylamide, N,N-diethylaminopropyl methacrylamide, N,N-dimethylaminoethyl methacrylamide, N,N-diethylaminoethyl methacrylamide, N,N-dimethylaminopropyl methacrylamide, N,N-diethylaminopropyl methacrylamide, N,N-dimethylaminoethyl methacrylamide, N,N-diethylaminoethyl methacrylamide, N,N-dimethylaminopropyl methacrylamide, N,N-diethylaminopropyl methacrylamide, N,N-dimethylaminoethyl methacrylamide, N,N-diethylaminoethyl methacrylamide, N,N-dimethylaminopropyl methacrylamide, N,N-diethylaminopropyl methacrylamide, N,N-dimethylaminoethyl methacrylamide, N,N-diethylaminoethyl methacrylamide, N,N-dimethylaminopropyl methacrylamide, N,N-diethylaminopropyl methacrylamide, N,N-dimethylaminoethyl methacrylamide, N,N-diethylaminoethyl methacrylamide, N,N-dimethylaminopropyl methacrylamide, N,N-diethylaminopropyl methacrylamide, N,N-dimethylaminoethyl methacrylamide, N,N-diethylaminoethyl methacrylamide, N,N-dimethylaminopropyl methacrylamide, N,N-diethylaminopropyl methacrylamide, N,N-dimethylaminoethyl methacrylamide, N,N-diethylaminoethyl methacrylamide, N,N-dimethylaminopropyl methacrylamide, N,N-diethylaminopropyl methacrylamide, N,N-dimethylaminoethyl methacrylamide, N,N-diethylaminoethyl methacrylamide, N,N-dimethylaminopropyl methacrylamide, N,N-diethylaminopropyl methacrylamide, N,N-dimethylaminoethyl methacrylamide, N,N-diethylaminoethyl methacrylamide, N,N-dimethylaminopropyl methacrylamide, N,N-diethylaminopropyl methacrylamide, N,N-dimethylN-dimethylacrylamide, N-tert-butylmethacrylamide, N-N-butylmethacrylamide, N- hydroxymethylmethacrylamide, N-hydroxyethylmethacrylamide, N-tert-butylacrylamide, N-N butylacrylamide, N-hydroxymethylacrylamide, N-hydroxyethylacrylamide, 4- acryloylmorpholine, vinylbenzoic acid (all isomers), diethylaminostyrene (all isomers), a- methylvinylbenzoic acid (all isomers), diethylaminostyrene (all isomers), p-vinylbenzenesulfonic acid, p-vinylbenzenesulfonic acid sodium salt, trimethoxysilylpropyl methacrylate, triethoxysilylpropyl methacrylate, tributoxysilylpropyl methacrylate, dimethoxymethylsilylpropyl methacrylate, diethoxymethylsilylpropyl methacrylate, dibutoxymethylsilylpropyl methacrylate, diisopropoxymethylsilylpropyl methacrylate, dimethoxysilylpropyl methacrylate, diethoxysilylpropyl methacrylate, dibutoxysilylpropyl methacrylate, diisopropoxysilylpropyl methacrylate, trimethoxysilylpropyl acrylate, triethoxysilylpropyl acrylate, tributoxysilylpropyl acrylate, dimethoxymethylsilylpropyl acrylate, diethoxymethylsilylpropyl acrylate, dibutoxymethylsilylpropyl acrylate, diisopropoxymethylsilylpropyl acrylate, dimethoxysilylpropyl acrylate, diethoxysilylpropyl acrylate, dibutoxysilylpropyl acrylate, diisopropoxysilylpropyl acrylate, maleic anhydride, N-phenylmaleimide, N-butylmaleimide, N-vinylformamide, N-vinylacetamide, allylamine, methallylamine, allyl alcohol, methyl-vinyl ether, ethyl-vinyl ether, butyl-vinyl ether, butadiene, isoprene, chlorobutadiene, ethylene, vinyl acetate, and combinations thereof.

[0283] Additional modifications to the preformed crosslinked polymer can be achieved by the addition of modifying agents including, but not limited to, amine monomers, additional crosslinking agents, and polymers. Modifications can be achieved by covalent or non-covalent methods. These modifications can be uniformly or non-uniformly dispersed throughout the preformed polymeric material, including modifications biased to the surface of the preformed crosslinked polymer. Further, modifications can be made to alter the physical properties of the preformed crosslinked polymer, including, but not limited to, reactions with the remaining reactive groups in the preformed polymer such as haloalkyl and allyl groups. Reactions with and modifications to the preformed crosslinked polymer can include, but are not limited to, acid-base reactions, nucleophilic substitution reactions, Michael reactions, non-covalent electrostatic interactions, hydrophobic interactions, physical interactions (crosslinking), and free radical reactions.

[0284] In one embodiment, the post-polymerization crosslinked amine polymer is a crosslinked amine polymer comprising a structure corresponding to Formula 4:

[0285]

[0286] wherein each R is independently hydrogen or an ethylene crosslink between two nitrogen atoms of the crosslinked amine polymer and a, b, c, and m are integers. Typically, m is a large integer indicating an extended polymer network. 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. 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 1.5: 1 to 4: 1. By way of another 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 1.75: 1 to 3: 1. For example, in one such embodiment, the sum of a and b is 57, c is 24, and m is a large integer indicating an extended polymer network. In each of the above embodiments, R can be in the ratio of about 2: 1 to 2.5: 1 to c (i.e., a+b:c). As indicated in each of the above embodiments, each R can be independently hydrogen or an ethylene crosslink between two nitrogen atoms. Typically, however, 50-95% of the R substituents will be hydrogen and 5-50% will be ethylene crosslinks For example, in one such embodiment, 55-90% of the R substituents are hydrogen and 10-45% are ethylene crosslinks By way of another example, in one such embodiment, 60-90% of the R substituents are hydrogen and 10-40% are ethylene crosslinks. By way of another example, in one such embodiment, 65-90% of the R substituents are hydrogen and 10-35% are ethylene crosslinks By way of another example, in one such embodiment, 70-90% of the R substituents are hydrogen and 10-30% are ethylene crosslinks. By way of another example, in one such embodiment, 75-85% of the R substituents are hydrogen and 15-25% are ethylene crosslinks. By way of another example, in one such embodiment, 80-85% of the R substituents are hydrogen and 15-20% are ethylene crosslinks. By way of another example, in one such embodiment, about 81% of the R substituents are hydrogen and about 19% are ethylene crosslinks.

[0287] As described in more detail in the Examples, polymers in which crosslinking and / or entanglement is increased have lower swelling than those with less crosslinking and / or entanglement, but also have binding capacity for target ions (e.g. chloride) that is as large or larger than that of polymers with less crosslinking and / or entanglement, while binding of interfering ions such as phosphate is significantly reduced. The selective effect is introduced in two different ways: 1) Sacrifice total capacity for chloride specificity. Crosslinking agents that do not include chloride binding sites (e.g. epichlorohydrin) allow crosslinking to increase while total capacity decreases in proportion to the amount of crosslinking agent incorporated into the polymer. 2) Preserve total capacity for chloride specificity: Crosslinking agents that include chloride binding sites (e.g. diallylamine) allow crosslinking to increase while total capacity remains the same or decreases only slightly.

[0288] The polymers described herein exhibit ion binding properties, typically proton binding, to form a positive charge, followed by anion binding. In preferred embodiments, the polymers exhibit chloride ion binding properties. Ion (e.g. chloride ion) binding capacity is a measure of the amount of a particular ion that an ion binding agent can bind in a given solution. For example, the binding capacity of an ion binding polymer can be measured in vitro, for example in water or in a saline solution or in a solution / matrix comprising representative cations and anions of the conditions of the gastrointestinal lumen, or in vivo, for example by urinary excretion of ions (e.g. bicarbonate or citrate), or ex vivo, for example using aspirated fluid, for example chyme / gastrointestinal lumen contents obtained from a laboratory animal, patient or volunteer. The measurement can be made in a solution comprising only the target ion, or at least no other competing solutes that compete with the target ion for binding to the polymer. In these cases, a non-interfering buffer will be used (e.g. a hydrochloric acid solution with or without additional sodium chloride). Alternatively, the measurement can be made in an interfering buffer comprising other competing solutes, for example other ions or metabolites, that compete with the target ion for binding to the resin.

[0289] In some embodiments, the polymers bind hydrochloric acid. For in vivo use, for example in the treatment of metabolic acidosis, it is desirable that the polymers have high proton and chloride binding capacity. In vitro measurements of binding capacity do not necessarily indicate in vivo binding capacity. It is therefore useful to define binding capacity in terms of both in vitro and in vivo quantities.

[0290] The in vitro chloride binding capacity of the polymers of the present application in HC1 can be greater than about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mmol / g. In some embodiments, the in vitro chloride binding capacity of the polymers of the present application for the target ion is greater than about 5.0 mmol / g, preferably greater than about 7.0 mmol / g, even more preferably greater than about 9.0 mmol / g, even more preferably greater than about 10.0 mmol / g. In some embodiments, the chloride binding capacity can range from about 5.0 mmol / g to about 25 mmol / g, preferably from about 7.5 mmol / g to about 20 mmol / g, even more preferably from about 10 mmol / g to about 15 mmol / g. Several techniques for determining chloride binding capacity are known in the art.

[0291] The in vivo maximum binding capacity (i.e., the maximum amount of [proton and] chloride ions bound under conditions likely to be encountered in the human gastrointestinal tract) can be evaluated with 12-16 h chloride binding in a simulated gastric fluid assay ("SGF") and is a measure of how well the monomers and crosslinking agents are incorporated into the structure. The SGF value represents experimental evidence of the theoretical maximum binding capacity of the polymer, falling within the same range as the capacity calculated stoichiometrically based on the starting materials.

[0292] To counteract proton binding, chloride is the ion of choice to be bound because its removal has no negative impact on serum bicarbonate. Anions other than chloride that are bound to neutralize the positive charge of the protons include phosphate, short chain fatty acids, long chain fatty acids, bile acids, or other organic or inorganic anions. Binding of these anions other than chloride affects the total bicarbonate reserve in both the intracellular and extracellular compartments.

[0293] The selectivity of the polymer to bind chloride can be evaluated in vitro using conditions that mimic different conditions, anions encountered in the gastrointestinal lumen, and anion concentrations. Chloride binding can be compared to phosphate alone (e.g., SIB [simulated intestinal buffer]; or to a range of anions present in the gastrointestinal tract (e.g., SOB).

[0294] In some embodiments, the chloride binding of the polymer in the SIB assay after exposure to the test buffer at 37°C for 1 hour is greater than about 2.0 mmol / gram of polymer, preferably greater than about 2.5 mmol / g of polymer, more preferably greater than about 3.0 mmol / g of polymer, even more preferably greater than about 3.5 mmol / g of polymer, and most preferably greater than about 4.0 mmol / g of polymer.

[0295] In some embodiments, the polymer has a chloride binding in the SOB assay of greater than about 1.0 mmol / gram of polymer, preferably greater than about 2.0 mmol / g of polymer, more preferably greater than about 3.0 mmol / g of polymer, even more preferably greater than about 3.5 mmol / g of polymer, and most preferably greater than about 4.0 mmol / g of polymer after exposure to the test buffer at 37°C for 2 hours.

[0296] In some embodiments, the polymer has a chloride binding in the SOB assay of greater than about 0.5 mmol / gram of polymer, preferably greater than about 1 mmol / g of polymer, more preferably greater than about 1.5 mmol / g of polymer, even more preferably greater than about 2.0 mmol / g of polymer, even more preferably greater than about 2.5 mmol / g of polymer, and most preferably greater than about 3.0 mmol / g of polymer after exposure to the test buffer at 37°C for 24 hours. The chloride binding in the SOB after 24 hours of exposure at 37°C is a measure of the polymer's ability to retain chloride ions as they pass through the gastrointestinal tract.

[0297] Another way to measure (proton and) chloride ion retention is to first expose the polymer to SGF to dissociate the polymer, then expose the polymer to SOB to again dissociate the polymer, followed by exposure of the polymer to conditions typical of the colonic lumen, for example using "Gastrointestinal Lumen Transmission Assay" (GICTA) buffer. In some embodiments, the amount of chloride ion that remains bound to the polymer after exposure to SGF for 1 hour at 37°C, then to SOB for 2 hours, and then to GICTA for 48 hours at 37°C is greater than about 0.5 mmol / gram of polymer, preferably greater than about 0.5 mmol / g of polymer, more preferably greater than about 1.0 mmol / g of polymer, even more preferably greater than about 2.0 mmol / g of polymer, and most preferably greater than about 3.0 mmol / g of polymer. In one embodiment, the polymer has a retained chloride ion content of at least 30% of the chloride ions initially bound in a Gastrointestinal Lumen Transmission Assay ("GICTA") (i.e., bound in the SGF binding step). In one such embodiment, the crosslinked amine polymer has a retained chloride ion content of at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or even at least 90% of the chloride ions initially bound in a Gastrointestinal Lumen Transmission Assay. In one embodiment, the polymer has a retained chloride ion content of at least 0.5, at least 1, at least 1.5, at least 2, at least 2.5, at least 3, at least 3.5, at least 4, at least 4.5, or even at least 5 mmol chloride ion / g of polymer in a Gastrointestinal Lumen Transmission Assay ("GICTA"). In one embodiment, the crosslinked amine polymer has a retained chloride ion content of at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or even at least 90% of the chloride ions initially bound in a Gastrointestinal Lumen Transmission Assay, and a retained chloride ion content of at least 0.5, at least 1, at least 1.5, at least 2, at least 2.5, at least 3, at least 3.5, at least 4, at least 4.5, or even at least 5 mmol chloride ion / g of polymer in a Gastrointestinal Lumen Transmission Assay ("GICTA").

[0298] In some embodiments, the in vivo binding performance of the polymers of the present disclosure can be evaluated by measuring changes in uric acid levels after administration to an animal (including a human) with normal kidney function. If there is sufficient time to reach metabolic equilibrium, removal of extra HCl (or HCl equivalent) from the body by the action of the administered polymer is reflected as a change in the excretion of urinary bicarbonate, titratable acid, citrate, or other indicators of uric acid.

[0299] To bind protons, the amine component of the polymer can be a primary, secondary, or tertiary amine, but not a quaternary amine. Quaternary amines remain substantially charged under all physiological conditions, and therefore do not bind protons until before binding anions. The percentage of quaternary amines can be measured in a variety of ways, including titration and back-titration methods. Another simple but accurate method is to compare the binding of anions (e.g., chloride) at low and high pH. While chloride binding at low pH (e.g., SGF buffer conditions; pH 1.2) does not distinguish between quaternary amines and other amines, chloride binding assays at high pH (e.g., QAA buffer conditions; pH 11.5) do. At this high pH, primary, secondary, and tertiary amines are not substantially protonated and do not contribute to chloride binding. Therefore, any binding observed under these conditions can be attributed to the presence of quaternary amines, which are permanently charged. The comparison of chloride binding at low pH (e.g., SGF conditions) to that at high pH (e.g., QAA conditions) is a measure of the degree of quaternization, and by extension, the amount of protons bound with chloride. The polymers of the present disclosure contain no more than 40%, 30%, 20%, 10%, most preferably 5% quaternary amines.

[0300] The swelling ratio of the polymers of the present disclosure is a measure of the degree of crosslinking, and by extension, the relative pore size of the polymer and the accessibility of anions larger (or with a larger hydration ratio) than chloride. In some embodiments, the swelling is measured in deionized water and expressed as g water / g dry polymer. The polymers of the present disclosure have a swelling ratio in deionized water of <5 g / g, <4 g / g, <3 g / g, <2 g / g, or <1 g / g.

[0301] The ability of the polymer to retain chloride ions (and not release them, thereby allowing exchange with other anions) as they pass through the different conditions experienced by the gastrointestinal lumen is an important feature, which can be a predictor of relative in vivo efficacy. A gastric intestinal chamber transport assay (GICTA) can be used to evaluate chloride retention. First, SGF and then SOB (simulated intestinal organic / inorganic buffer) screening is performed to allow chloride and other anions to bind the polymer, the polymer is isolated and exposed to conditions simulating the colon lumen (e.g., GICTA retention assay matrix) for 40 hours. The polymer is again isolated and the anions held bound to the polymer are eluted in sodium hydroxide and measured. The polymers of the present disclosure retain more than 30%, 40%, 50%, 60%, 70%, 80%, or most preferably more than 90% of the chloride bound in SGF after being subjected to the chloride retention assay described.

[0302] Using a heterogeneous polymerization process, polymer particles in the form of spherical beads are obtained, with diameters controlled in the range of 5 to 1000 microns, preferably 10 to 500 microns, and most preferably 40 to 180 microns.

[0303] Generally, the pharmaceutical compositions of the present disclosure comprise a proton binding crosslinked amine polymer described herein. Preferably, the pharmaceutical compositions comprising the crosslinked amine polymer are formulated for oral administration. The pharmaceutical forms in which the polymer is administered include powders, tablets, pills, lozenges, sachets, cachets, elixirs, suspensions, syrups, soft or hard gelatin capsules, and the like. In one embodiment, the pharmaceutical composition comprises only the crosslinked amine polymer. Alternatively, the pharmaceutical composition can comprise a carrier, diluent, or excipient in addition to the crosslinked amine polymer. Examples of carriers, excipients, and diluents that can be used in these formulations, as well as other formulations, include food, beverages, lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia, alginic acid, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, propylhydroxybenzoate, and talc. Pharmaceutical excipients that can be used in the pharmaceutical compositions also include: binders such as microcrystalline cellulose, colloidal silicon dioxide and combinations thereof (Prosolv 90), carbopol, providone, and xanthan gum; flavoring agents such as sucrose, mannitol, xylitol, maltodextrin, fructose, or sorbitol; lubricants such as magnesium stearate, stearic acid, sodium stearyl fumarate, and plant-based fatty acids; and optionally, disintegrants such as croscarmellose sodium, gellan gum, low-substituted hydroxypropyl ethers of cellulose, sodium starch glycolate. Other additives can include plasticizers, pigments, talc, and the like. Such additives and other suitable ingredients are well known in the art; see, e.g., Gennaro A R (ed.), Remington's Pharmaceutical Sciences, 20th Edition.

[0304] In one embodiment, the pharmaceutical composition comprising the crosslinked amine polymer of the present disclosure contains a relatively low amount of sodium. For example, in one such embodiment, the pharmaceutical composition comprises less than 1 g of sodium per dose. By way of another example, in one such embodiment, the pharmaceutical composition comprises less than 0.5 g of sodium per dose. By way of another example, in one such embodiment, the pharmaceutical composition comprises less than 0.1 g of sodium per dose. By way of another example, in one such embodiment, the pharmaceutical composition is free of sodium.

[0305] In one implementation, the new daily dose for chronic metabolic acidosis treatment is designed to enhance adherence (approximately 5g or less daily) and achieves a clinically significant and sustained increase in serum bicarbonate at these daily doses of approximately 3 mEq / L. The non-absorbable nature of the polymer and the absence of sodium loading and / or the introduction of other ions detrimental to this type of oral medication enable, for the first time, safe, long-term treatment of metabolic acidosis without worsening blood pressure / hypertension and / or causing increased fluid retention and fluid overload. Another benefit is a further slowing of kidney disease progression and the time to initiate lifelong renal replacement therapy (end-stage renal disease, “ESRD”, includes dialysis three times a week) or the need for kidney transplantation. Both are associated with significant mortality, low quality of life, and a significant burden on healthcare systems worldwide. In the United States alone, approximately 20% of the 400,000 patients with ESRD die each year, and 100,000 new patients begin dialysis.

[0306] In one embodiment, the pharmaceutical composition comprises a sodium-free, non-absorbable cross-linked amine polymer for treating metabolic acidosis, which increases serum bicarbonate and normalizes blood pH in mammals by binding HCl. A preferred embodiment comprises a polymer that binds H in sufficient amounts in the stomach / upper gastrointestinal tract. + Then combine Cl - This results in a clinically significant increase in serum bicarbonate levels of at least 1.6 mEq / L, more preferably at least 2 mEq / L, and most preferably equal to or greater than 3 mEq / L. The amount of HCl bound is determined by the polymer's capacity (target range of HCl binding capacity of 5-20 mEq HCl / 1 g polymer) and selectivity. In the stomach, free amines bind H+... + It becomes protonated. The positive charge formed in situ on the polymer can then be used to bind Cl. - By controlling the proximity of binding sites via cross-linking (size exclusion, mesh size) and chemical motifs (by adjusting hydrophilicity / hydrophobicity to repel larger organic ions such as acetate, propionate, and butyrate, or other short-chain fatty acids commonly found in the colon), phosphate, bile acids, and fatty acids), anions other than chloride ions are bound to a lesser extent (if any). By adjusting the chemical properties of the bead cross-linking and amine binding sites, chloride ions can be tightly bound to ensure they are not released in the lower gastrointestinal tract. HCl is removed from the body through regular intestinal motility / feces, resulting in net HCl binding. In another embodiment, a polymer with some quaternized / protonated amine groups is pre-formed, and chloride ion binding is achieved through ion exchange with citrate or carbonate ions, wherein up to 90% of the cation binding sites on the polymer are pre-loaded with citrate and / or carbonate ions as counterions.

[0307] In one embodiment, the key feature of the non-absorbed, non-sodium amine polymer for treating metabolic acidosis in a mammal that increases serum bicarbonate and normalizes blood pH is that it does not elevate or worsen hypertension, which is of particular concern in patients with diabetic nephropathy. Another benefit of not introducing sodium is the lack of an associated increase in fluid retention that leads to fluid overload, which is of particular concern in patients with heart failure. The ability of the polymer to safely and effectively treat metabolic acidosis without introducing a harmful counterion slows the progression of kidney disease, which is of particular concern in patients with chronic kidney disease who have not yet progressed to dialysis. The initiation of dialysis can be delayed by at least 3, 6, 9, or 12 months.

[0308] In another embodiment of the non-sodium, non-absorbed amine polymer for treating metabolic acidosis, the polymer is a crosslinked bead having a preferred particle size range that is (i) large enough to avoid passive or active absorption through the gastrointestinal tract and (ii) small enough to not cause grittiness or an unpleasant mouth feel when ingested in a dosage form of a powder, sachet, and / or chewable tablet having a mean particle size of 40-180 microns. Preferably, the desired particle size morphology is achieved by a heterogeneous polymerization reaction such as suspension polymerization or emulsion polymerization. To minimize patient gastrointestinal side effects typically associated with large volume polymer gels moving through the gastrointestinal tract, a polymer of low swelling ratio (0.5-5 times its weight in water) is preferred. In another embodiment, the polymer carries a permanent / covalent and / or transiently attached to the polymer or its own blocking of the Cl - / HCO3 - the molecular entity of the exchanger (antiporter). The net effect of blocking the antiporter is to decrease the uptake of Cl"from the lumen and the associated exchange of bicarbonate from serum, effectively increasing serum bicarbonate.

[0309] In one embodiment, the crosslinked amine polymer can be co-administered with other pharmaceutically active agents depending on the condition being treated. This co-administration can include simultaneous administration of both agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. For example, to treat metabolic acidosis, the crosslinked amine polymer can be co-administered with commonly used therapies needed to treat underlying comorbidities including, but not limited to, hypertension, diabetes, obesity, heart failure, and chronic kidney disease complications. These drugs and the crosslinked amine polymer can be formulated together in the same dosage form and administered simultaneously, as long as they do not exhibit any clinically significant drug-drug interactions. Alternatively, these therapies and the crosslinked polymer can be administered separately and sequentially, one after the other.

[0310] The present disclosure also includes the following enumerated embodiments.

[0311] Embodiment 1. A method for preparing a crosslinked amine polymer comprising crosslinking a preformed amine polymer in a reaction mixture to form a crosslinked amine polymer; the reaction mixture comprising the preformed amine polymer, a solvent, a crosslinking agent, and a swelling agent for the preformed amine polymer; wherein the preformed amine polymer has an absorption capacity for the swelling agent, and the amount of swelling agent in the reaction mixture is less than the absorption capacity of the preformed amine polymer for the swelling agent.

[0312] Embodiment 2. A method for preparing a particulate crosslinked amine polymer, the method comprising (i) polymerizing an amine-containing monomer to form a particulate preformed amine polymer; (ii) deprotonating the preformed amine polymer with a base; (iii) swelling the deprotonated preformed amine polymer with a swelling agent; and (iv) crosslinking the preformed amine polymer with a crosslinking agent comprising an amine-reactive moiety in a reaction mixture; wherein carbon-carbon crosslinks are formed predominantly in the polymerization step and nitrogen-nitrogen crosslinks are formed predominantly in the crosslinking step.

[0313] Embodiment 3. A method for preparing a particulate crosslinked amine polymer, the method comprising forming the particulate crosslinked amine polymer in at least two polymerization / crosslinking steps, the first step comprising polymerizing an amine-containing monomer to form a preformed amine polymer having a chloride binding capacity in simulated gastric fluid (“SGF”) of at least 10 mmol / g and a swelling ratio in the range of 2 to 10, the second step comprising crosslinking the preformed amine polymer with a crosslinking agent in a reaction mixture to produce nitrogen-nitrogen crosslinks within the preformed amine polymer.

[0314] Embodiment 4. A method for preparing a particulate crosslinked amine polymer, the method comprising two discrete polymerization / crosslinking steps, the first step comprising forming a preformed amine polymer having a chloride binding capacity in simulated gastric fluid (“SGF”) of at least 10 mmol / g and a swelling ratio in the range of 2 to 10, the second step comprising crosslinking the preformed amine polymer with a crosslinking agent containing an amine-reactive moiety to form a post-polymerization crosslinked amine polymer in a reaction mixture, the resulting post-polymerization crosslinked amine polymer having a binding capacity for phosphate, citrate, and / or taurocholate in SIB or SOB that is less than the binding capacity of the preformed amine polymer for phosphate, citrate, and / or taurocholate in the same assay.

[0315] Embodiment 5. A method for making a particulate crosslinked amine polymer, the method comprising (i) forming a preformed amine polymer having a chloride binding capacity in simulated gastric fluid ("SGF") of at least 10 mmol / g, a swelling ratio in the range of 2 to 10, and an average particle size of at least 80 microns; (ii) at least partially deprotonating the preformed amine polymer with a base; and (iii) crosslinking the deprotonated preformed amine polymer in a reaction mixture with a crosslinking agent containing amine-reactive moieties to form a post-polymerization crosslinked amine polymer.

[0316] Embodiment 6. A method for making a particulate crosslinked amine polymer, the method comprising (i) forming a preformed amine polymer having a chloride binding capacity in simulated gastric fluid ("SGF") of at least 10 mmol / g and a swelling ratio in the range of 2 to 10; (ii) at least partially deprotonating the preformed amine polymer with a base; (iii) contacting the preformed amine polymer with a swelling agent to swell the deprotonated preformed amine polymer; and (iv) crosslinking the swollen, deprotonated preformed amine polymer in a reaction mixture with a crosslinking agent containing amine-reactive moieties to form a post-polymerization crosslinked amine polymer.

[0317] Embodiment 7. The method according to any one of the preceding embodiments, wherein the swelling agent is a polar solvent.

[0318] Embodiment 8. The method according to any one of the preceding embodiments, wherein the swelling agent is water, methanol, ethanol, n-propanol, isopropanol, n-butanol, formic acid, acetic acid, acetonitrile, dimethylformamide, dimethylsulfoxide, nitromethane, propylene carbonate, or a combination thereof.

[0319] Embodiment 9. The method according to any one of the preceding embodiments, wherein the weight ratio of swelling agent to preformed amine polymer in the reaction mixture is less than 4: 1.

[0320] Embodiment 10. The method according to any one of the preceding embodiments, wherein the weight ratio of swelling agent to preformed amine polymer in the reaction mixture is less than 3: 1.

[0321] Embodiment 11. The method according to any one of the preceding embodiments, wherein the weight ratio of swelling agent to preformed amine polymer in the reaction mixture is less than 2: 1.

[0322] Embodiment 12. The method according to any one of the preceding embodiments, wherein the weight ratio of swelling agent to preformed amine polymer in the reaction mixture is less than 1: 1.

[0323] Embodiment 13. The method according to any one of the preceding embodiments, wherein the weight ratio of swelling agent to preformed amine polymer in the reaction mixture is less than 0.5:1.

[0324] Embodiment 14. The method according to any one of the preceding embodiments, wherein the weight ratio of swelling agent to preformed amine polymer in the reaction mixture is less than 0.4:1.

[0325] Embodiment 15. The method according to any one of the preceding embodiments, wherein the weight ratio of swelling agent to preformed amine polymer in the reaction mixture is less than 0.3:1.

[0326] Embodiment 16. The method according to any one of the preceding embodiments, wherein the weight ratio of swelling agent to preformed amine polymer in the reaction mixture is at least 0.15:1.

[0327] Embodiment 17. The method according to any one of the preceding embodiments, wherein the crosslinking agent comprises at least two amine-reactive functional groups.

[0328] Embodiment 18. The method according to any one of the preceding embodiments, wherein the crosslinking agent is a compound containing at least two amine-reactive groups selected from the group consisting of alkyl halides, epoxides, phosgenes, anhydrides, carbamates, carbonates, isocyanates, isothiocyanates, esters, activated esters, carboxylic acids and derivatives thereof, sulfonic acid esters and derivatives thereof, acyl halides, aziridines, α,β-unsaturated carbonyls, ketones, aldehydes, and pentafluoroaryl groups.

[0329] Embodiment 19. The method according to any one of the preceding embodiments, wherein the crosslinking agent is a crosslinking agent selected from Table B.

[0330] Embodiment 20. The method according to any one of the preceding embodiments, wherein the crosslinking agent is a dichloroalkane.

[0331] Embodiment 21. The method according to any one of the preceding embodiments, wherein the crosslinking agent is dichloroethane or dichloropropane.

[0332] Embodiment 22. The method according to any one of the preceding embodiments, wherein the reaction mixture comprises a non-polar solvent.

[0333] Embodiment 23. The method according to any one of the preceding embodiments, wherein the reaction mixture comprises a crosslinking solvent.

[0334] Embodiment 24. The method according to any one of the preceding embodiments, wherein the swelling agent and the solvent are immiscible.

[0335] Embodiment 25. The method according to any one of the preceding embodiments, wherein the swelling agent and the crosslinking agent are immiscible.

[0336] Embodiment 26. The method according to any one of the preceding embodiments, wherein the preformed polymer is combined with the crosslinking agent and the solvent prior to combining the polymer with the swelling agent.

[0337] Embodiment 27. The method according to any one of the preceding embodiments, wherein the method further comprises forming the preformed amine polymer in a solvent system and forming the crosslinked amine polymer without isolating the preformed amine polymer from the solvent system.

[0338] Embodiment 28. The method according to any one of the preceding embodiments, wherein the preformed amine polymer comprises a residue of an amine selected from Table C.

[0339] Embodiment 29. The method according to any one of the preceding embodiments, wherein the preformed amine polymer comprises a residue of an amine corresponding to Formula 1:

[0340]

[0341] wherein R1, R2, and R3 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, provided however that at least one of R1, R2, and R3 is not hydrogen.

[0342] Embodiment 30. The method according to any one of the preceding embodiments, wherein the preformed amine polymer is characterized by a first selectivity for chloride over citrate, phosphate, and / or taurocholate in SIB and / or SOB, and the crosslinked polymer is characterized by a second selectivity for chloride over citrate, phosphate, and / or taurocholate in SIB and / or SOB, wherein:

[0343] (i) the crosslinked polymer has an increased binding capacity for chloride and a decreased binding capacity for phosphate in SIB relative to the preformed amine polymer,

[0344] (ii) the crosslinked polymer has an increased binding capacity for chloride and a decreased binding capacity for phosphate in SOB relative to the preformed amine polymer,

[0345] (iii) the crosslinked polymer has an increased binding capacity for chloride and a decreased binding capacity for citrate in SOB relative to the preformed amine polymer, or

[0346] (iv) the crosslinked polymer has an increased binding capacity for chloride and a decreased binding capacity for taurocholate in SOB relative to the preformed amine polymer.

[0347] Embodiment 31. The method of embodiment 30, wherein the crosslinked polymer has a decreased binding capacity for chloride in SGF relative to the preformed amine polymer.

[0348] Embodiment 32. The method of embodiment 30, wherein the post-polymerization crosslinked polymer has (i) an increased binding capacity for chloride and a decreased binding capacity for phosphate in SIB and (ii) a decreased binding capacity in SGF relative to the preformed amine polymer.

[0349] Embodiment 33. The method of embodiment 30, wherein the post-polymerization crosslinked polymer has (i) an increased binding capacity for chloride and a decreased binding capacity for a combination of phosphate, citrate, and / or taurocholate in SOB and (ii) a decreased binding capacity in SGF relative to the preformed amine polymer.

[0350] Embodiment 34. A method for making a crosslinked amine polymer, comprising crosslinking a preformed amine polymer in a reaction mixture to form a crosslinked amine polymer, the reaction mixture comprising the preformed amine polymer, a solvent, and a crosslinking agent, wherein the preformed amine polymer is characterized by a first selectivity for chloride over citrate, phosphate, and / or taurocholate in SIB and / or SOB, and the crosslinked polymer is characterized by a second selectivity for chloride over citrate, phosphate, and / or taurocholate in SIB and / or SOB, wherein:

[0351] (i) the crosslinked polymer has an increased binding capacity for chloride and a decreased binding capacity for phosphate in SIB relative to the preformed amine polymer,

[0352] (ii) the crosslinked polymer has an increased binding capacity for chloride and a decreased binding capacity for citrate in SIB relative to the preformed amine polymer,

[0353] (iii) the crosslinked polymer has an increased binding capacity for chloride and a decreased binding capacity for citrate in SOB relative to the preformed amine polymer, or

[0354] (iv) the crosslinked polymer has an increased binding capacity for chloride and a decreased binding capacity for taurate relative to the preformed amine polymer in SOB.

[0355] Embodiment 35. The method of embodiment 34, wherein the crosslinked polymer has a decreased binding capacity for chloride in SGF relative to the preformed amine polymer.

[0356] Embodiment 36. The method of embodiment 34, wherein the post-polymerization crosslinked polymer has (i) an increased binding capacity for chloride and a decreased binding capacity for phosphate in SIB and (ii) a decreased binding capacity in SGF relative to the preformed amine polymer.

[0357] Embodiment 37. The method of embodiment 34, wherein the post-polymerization crosslinked polymer has (i) an increased binding capacity for chloride and a decreased binding capacity for a combination of phosphate, citrate, and / or taurate in SOB and (ii) a decreased binding capacity in SGF relative to the preformed amine polymer.

[0358] Embodiment 38. A pharmaceutical composition comprising a crosslinked amine polymer characterized by a binding capacity for chloride and / or selectivity for chloride over citrate, phosphate, and / or taurate in SGF, SIB, and / or SOB, as described in any one of paragraphs

[0042] -

[0066] .

[0359] Embodiment 39. A method of treating acid / base imbalance in an animal, including a human, by removing HC1 via oral administration of a pharmaceutical composition according to embodiment 38.

[0360] Embodiment 40. A method of treating acid / base imbalance in an animal, including a human, by removing HC1 via oral administration of a pharmaceutical composition comprising a crosslinked amine polymer prepared by the method according to any one of embodiments 1-37.

[0361] Embodiment 41. A method for making a crosslinked amine polymer, the method comprising (i) swelling a preformed amine polymer with a swelling agent; (ii) dispersing the preformed amine polymer in a reaction mixture comprising a dispersion solvent, a crosslinking agent, and the swelling agent; and (iii) crosslinking the preformed amine polymer in the reaction mixture to form the crosslinked amine polymer; wherein the preformed amine polymer is crosslinked and has an absorption capacity for the swelling agent, and the amount of swelling agent in the reaction mixture is less than the absorption capacity of the preformed amine polymer for the swelling agent.

[0362] Embodiment 42. The method of Embodiment 41, wherein the method further comprises deprotonating the preformed amine polymer with a base prior to swelling the preformed amine polymer with the swelling agent.

[0363] Embodiment 43. The method of Embodiment 41 or 42, wherein the crosslinks in the preformed amine polymer are primarily carbon-carbon crosslinks and nitrogen-nitrogen crosslinks are primarily formed in the crosslinking step.

[0364] Embodiment 44. The method of any one of Embodiments 41-43, wherein the preformed amine polymer has a chloride binding capacity in simulated gastric fluid (“SGF”) of at least 10 mmol / g and a swelling ratio in the range of 2 to 10, and the crosslinked amine polymer has a binding capacity for phosphate, citrate, and / or taurocholate in SIB or SOB that is less than the binding capacity of the preformed amine polymer for phosphate, citrate, and / or taurocholate in the same assay.

[0365] Embodiment 45. The method of any one of Embodiments 41-44, wherein the dispersion solvent comprises a nonpolar solvent.

[0366] Embodiment 46. The method of any one of Embodiments 41-45, wherein the dispersion solvent comprises a solvent that is chemically inert to the preformed amine polymer.

[0367] Embodiment 47. The method of any one of Embodiments 41-46, wherein the dispersion solvent comprises a crosslinking solvent.

[0368] Embodiment 48. The method of any one of Embodiments 41-44, wherein the crosslinking agent is the dispersion solvent.

[0369] Embodiment 49. The method of any one of Embodiments 41-48, wherein the swelling agent and the dispersion solvent are immiscible.

[0370] Embodiment 50. The method of any one of embodiments 41-49, wherein the weight ratio of the swelling agent to the pre-formed amine polymer in the reaction mixture is less than 4: 1.

[0371] Embodiment 51. The method of any one of embodiments 41-50, wherein the weight ratio of the swelling agent to the pre-formed amine polymer in the reaction mixture is less than 3: 1.

[0372] Embodiment 52. The method of any one of embodiments 41-51, wherein the weight ratio of the swelling agent to the pre-formed amine polymer in the reaction mixture is less than 2: 1.

[0373] Embodiment 53. The method of any one of embodiments 41-52, wherein the weight ratio of the swelling agent to the pre-formed amine polymer in the reaction mixture is less than 1: 1.

[0374] Embodiment 54. A method for preparing a crosslinked amine polymer, the method comprising (i) swelling a pre-formed amine polymer with a swelling agent; and (ii) crosslinking the pre-formed amine polymer to form the crosslinked amine polymer in a reaction mixture comprising a crosslinking agent and the swelling agent, wherein the pre-formed amine polymer is crosslinked and has an absorption capacity for the swelling agent, the amount of swelling agent in the reaction mixture is less than the absorption capacity of the pre-formed amine polymer for the swelling agent, and the weight ratio of the swelling agent to the pre-formed amine polymer in the reaction mixture is less than 1: 1.

[0375] Embodiment 55. The method of any one of embodiments 41-54, wherein the swelling agent is a polar solvent.

[0376] Embodiment 56. The method of any one of embodiments 41-55, wherein the swelling agent is water, methanol, ethanol, n-propanol, isopropanol, n-butanol, formic acid, acetic acid, acetonitrile, dimethylformamide, dimethylsulfoxide, nitromethane, propylene carbonate, or a combination thereof.

[0377] Embodiment 57. The method of any one of embodiments 41-56, wherein the swelling agent is water.

[0378] Embodiment 58. The method of any one of embodiments 41-57, wherein the weight ratio of the swelling agent to the pre-formed amine polymer in the reaction mixture is less than 0.5: 1.

[0379] Embodiment 59. The method of any one of embodiments 41-58, wherein the weight ratio of the swelling agent to the pre-formed amine polymer in the reaction mixture is less than 0.4: 1.

[0380] Embodiment 60. The method of any one of embodiments 41 to 59, wherein the weight ratio of the swelling agent to the preformed amine polymer in the reaction mixture is less than 0.3:1.

[0381] Embodiment 61. The method of any one of embodiments 41 to 60, wherein the weight ratio of the swelling agent to the preformed amine polymer in the reaction mixture is at least 0.15:1.

[0382] Embodiment 62. The method of any one of embodiments 41 to 61, wherein the crosslinking agent comprises at least two amine-reactive functional groups.

[0383] Embodiment 63. The method of any one of embodiments 41 to 62, wherein the crosslinking agent is a compound containing at least two amine-reactive groups selected from the group consisting of alkyl halides, epoxides, phosgenes, anhydrides, carbamates, carbonates, isocyanates, isothiocyanates, esters, activated esters, carboxylic acids and derivatives thereof, sulfonate esters and derivatives thereof, acyl halides, aziridines, α,β-unsaturated carbonyls, ketones, aldehydes, and pentafluoroaryl groups.

[0384] Embodiment 64. The method of any one of embodiments 41 to 63, wherein the crosslinking agent is a crosslinking agent selected from Table B.

[0385] Embodiment 65. The method of any one of embodiments 41 to 64, wherein the crosslinking agent is a dichloroalkane.

[0386] Embodiment 66. The method of any one of embodiments 41 to 65, wherein the crosslinking agent is dichloroethane or dichloropropane.

[0387] Embodiment 67. The method of any one of embodiments 41 to 66, wherein the swelling agent and the crosslinking agent are immiscible.

[0388] Embodiment 68. The method of any one of embodiments 41 to 67, wherein the preformed polymer is combined with the crosslinking agent and the dispersion solvent prior to swelling the polymer with the swelling agent.

[0389] Embodiment 69. The method of any one of embodiments 41 to 68, wherein the method further comprises forming the preformed amine polymer in a solvent system and forming the crosslinked amine polymer without isolating the preformed amine polymer from the solvent system.

[0390] Embodiment 70. The method according to any one of embodiments 41 to 69, wherein the preformed amine polymer comprises residues of amines corresponding to Formula 1:

[0391]

[0392] Embodiment 71. The method according to any one of embodiments 41 to 69, wherein the preformed amine polymer comprises residues of amines corresponding to Formula la

[0393]

[0394] wherein R4and R5are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl.

[0395] Embodiment 72. The method according to embodiment 71, wherein R4and R5are independently hydrogen, aliphatic, or heteroaliphatic.

[0396] Embodiment 73. The method according to embodiment 71, wherein R4and R5are independently hydrogen, allyl, or aminoalkyl.

[0397] Embodiment 74. The method according to any one of embodiments 41 to 73, wherein the preformed amine polymer comprises residues of amines of Table C.

[0398] Embodiment 75. The method according to any one of embodiments 41 to 74, wherein the preformed amine polymer comprises residues of allylamine.

[0399] Embodiment 76. The method according to any one of embodiments 41 to 75, wherein the preformed amine polymer comprises residues of diallylpropyl diamine.

[0400] Embodiment 77. The method according to any one of embodiments 41 to 76, wherein the preformed amine polymer is a copolymer comprising residues of allylamine and diallylpropyl diamine.

[0401] Embodiment 78. The method according to any one of embodiments 41 to 77, wherein the preformed amine polymer is characterized by a first selectivity for chloride over citrate, phosphate, and / or taurocholate in SIB and / or SOB, and the crosslinked polymer is characterized by a second selectivity for chloride over citrate, phosphate, and / or taurocholate in SIB and / or SOB, wherein:

[0402] (i) the crosslinked polymer has an increased binding capacity for chloride and a decreased binding capacity for phosphate in SIB relative to the preformed amine polymer,

[0403] (ii) the crosslinked polymer has an increased binding capacity for chloride and a decreased binding capacity for phosphate in SOB relative to the preformed amine polymer,

[0404] (iii) the crosslinked polymer has an increased binding capacity for chloride and a decreased binding capacity for citrate in SOB relative to the preformed amine polymer, or

[0405] (iv) the crosslinked polymer has an increased binding capacity for chloride and a decreased binding capacity for taurocholate in SOB relative to the preformed amine polymer.

[0406] Embodiment 79. The method of embodiment 78, wherein the crosslinked polymer has a decreased binding capacity for chloride in SGF relative to the preformed amine polymer

[0407] Embodiment 80. The method of embodiment 78, wherein the post-polymerization crosslinked polymer has (i) an increased binding capacity for chloride and a decreased binding capacity for phosphate in SIB and (ii) a decreased binding capacity in SGF relative to the preformed amine polymer.

[0408] Embodiment 81. The method of embodiment 78, wherein the post-polymerization crosslinked polymer has (i) an increased binding capacity for chloride and a decreased binding capacity for a combination of phosphate, citrate, and / or taurocholate in SOB and (ii) a decreased binding capacity in SGF relative to the preformed amine polymer.

[0409] Embodiment 82. A method for making a crosslinked amine polymer, the method comprising crosslinking a preformed amine polymer in a reaction mixture to form the crosslinked amine polymer, the reaction mixture comprising the preformed amine polymer, a swelling agent to swell the preformed amine polymer, and dichloroethane.

[0410] Embodiment 83. The method of embodiment 82, wherein the reaction mixture comprises a dispersing solvent.

[0411] Embodiment 84. The method of embodiment 82 or 83, wherein the reaction mixture comprises a dispersing solvent that is chemically inert to the preformed amine polymer.

[0412] Embodiment 85. The method of embodiment 82 or 83, wherein the reaction mixture comprises a dispersing solvent and the dispersing solvent is dichloroethane.

[0413] Embodiment 86. The method of any one of embodiments 82-85, wherein the swelling agent and dichloroethane are immiscible.

[0414] Embodiment 87. The method of any one of embodiments 82-86, wherein the weight ratio of the swelling agent to preformed amine polymer in the reaction mixture is less than 4:1.

[0415] Embodiment 88. The method of any one of embodiments 82-86, wherein the weight ratio of the swelling agent to preformed amine polymer in the reaction mixture is less than 3:1.

[0416] Embodiment 89. The method of any one of embodiments 82-86, wherein the weight ratio of the swelling agent to preformed amine polymer in the reaction mixture is less than 2:1.

[0417] Embodiment 90. The method of any one of embodiments 82-86, wherein the weight ratio of the swelling agent to preformed amine polymer in the reaction mixture is less than 1:1.

[0418] Embodiment 91. The method of any one of embodiments 82-86, wherein the weight ratio of the swelling agent to preformed amine polymer in the reaction mixture is less than 0.5:1.

[0419] Embodiment 92. The method of any one of embodiments 82-86, wherein the weight ratio of the swelling agent to preformed amine polymer in the reaction mixture is less than 0.4:1.

[0420] Embodiment 93. The method of any one of embodiments 82-86, wherein the weight ratio of the swelling agent to preformed amine polymer in the reaction mixture is less than 0.3:1.

[0421] Embodiment 94. The method of any one of embodiments 82-86, wherein the weight ratio of the swelling agent to preformed amine polymer in the reaction mixture is at least 0.15:1.

[0422] Embodiment 95. The method of any one of embodiments 82-94, wherein the preformed amine polymer is deprotonated with a base prior to crosslinking the preformed amine polymer in the reaction mixture.

[0423] Embodiment 96. The method of any one of embodiments 82-95, wherein the preformed amine polymer is crosslinked and the crosslinking is primarily carbon-carbon crosslinking.

[0424] Embodiment 97. The method of any one of embodiments 82-96, wherein the swelling agent is a polar solvent.

[0425] Embodiment 98. The method of any one of embodiments 82-96, wherein the swelling agent is water, methanol, ethanol, n-propanol, isopropanol, n-butanol, formic acid, acetic acid, acetonitrile, dimethylformamide, dimethylsulfoxide, nitromethane, propylene carbonate, or a combination thereof.

[0426] Embodiment 99. The method of any one of embodiments 82-96, wherein the swelling agent is water.

[0427] Embodiment 100. The method of any one of embodiments 82-99, wherein the preformed amine polymer comprises residues of an amine corresponding to Formula 1:

[0428]

[0429] Embodiment 101. The method of any one of embodiments 82-99, wherein the preformed amine polymer comprises residues of an amine corresponding to Formula la

[0430]

[0431] wherein R4and R5are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl.

[0432] Embodiment 102. The method of embodiment 101, wherein R4and R5are independently hydrogen, aliphatic, or heteroaliphatic.

[0433] Embodiment 103. The method of embodiment 101, wherein R4and R5are independently hydrogen, allyl, or aminoalkyl.

[0434] Embodiment 104. The method of any one of embodiments 82-99, wherein the preformed amine polymer comprises residues of an amine of Table C.

[0435] Embodiment 105. The method of any one of embodiments 82-99, wherein the preformed amine polymer comprises residues of an allyl amine.

[0436] Embodiment 106. The method of any one of embodiments 82-99, wherein the preformed amine polymer comprises residues of a diallylpropyl diamine.

[0437] Embodiment 107. The method of any one of embodiments 82-99, wherein the preformed amine polymer is a copolymer comprising residues of an allyl amine and a diallylpropyl diamine.

[0438] Embodiment 108. The method of any one of embodiments 82-107, wherein the preformed amine polymer is characterized by a first selectivity for chloride over citrate, phosphate, and / or taurocholate in SIB and / or SOB, and the crosslinked polymer is characterized by a second selectivity for chloride over citrate, phosphate, and / or taurocholate in SIB and / or SOB, wherein:

[0439] (i) the crosslinked polymer has an increased binding capacity for chloride and a decreased binding capacity for phosphate in SIB relative to the preformed amine polymer,

[0440] (ii) the crosslinked polymer has an increased binding capacity for chloride and a decreased binding capacity for phosphate in SOB relative to the preformed amine polymer,

[0441] (iii) the crosslinked polymer has an increased binding capacity for chloride and a decreased binding capacity for citrate in SOB relative to the preformed amine polymer, or

[0442] (iv) the crosslinked polymer has an increased binding capacity for chloride and a decreased binding capacity for taurocholate in SOB relative to the preformed amine polymer.

[0443] Embodiment 109. The method of embodiment 108, wherein the crosslinked polymer has a decreased binding capacity for chloride in SGF relative to the preformed amine polymer.

[0444] Embodiment 110. The method of embodiment 108, wherein the post-polymerization crosslinked polymer has (i) an increased binding capacity for chloride and a decreased binding capacity for phosphate in SIB and (ii) a decreased binding capacity in SGF relative to the preformed amine polymer.

[0445] Embodiment 111. The method of embodiment 108, wherein the post-polymerization crosslinked polymer has (i) an increased binding capacity for chloride and a decreased binding capacity for a combination of phosphate, citrate, and / or taurocholate in SOB and (ii) a decreased binding capacity in SGF relative to the preformed amine polymer.

[0446] Embodiment 112. A pharmaceutical composition comprising a crosslinked amine polymer having a chloride binding capacity of at least 4 mmol / g in simulated small intestinal inorganic buffer (“SIB”).

[0447] Embodiment 113. A pharmaceutical composition comprising a crosslinked amine polymer having a chloride ion binding capacity to phosphate ion binding capacity ratio of at least 2.3: 1, respectively, in Simulated Intestinal Inorganic Buffer ("SIB").

[0448] Embodiment 114. A pharmaceutical composition comprising a crosslinked amine polymer having a chloride ion binding capacity of at least 1 mmol / g in Simulated Intestinal Inorganic Buffer ("SIB"), a phosphate ion binding capacity of less than 0.4 mmol / g in SIB, and a chloride to phosphate ion binding ratio of at least 2.3: 1, respectively, in SIB.

[0449] Embodiment 115. A pharmaceutical composition comprising a crosslinked amine polymer having a chloride ion binding capacity to phosphate ion binding capacity ratio of at least 2.3: 1, respectively, and a swell ratio of less than 5, in Simulated Intestinal Inorganic Buffer ("SIB").

[0450] Embodiment 116. A pharmaceutical composition comprising a crosslinked amine polymer having a retained chloride ion content of at least 30% of the chloride ion bound initially in a Gastrointestinal Chamber Transit Assay ("GICTA").

[0451] Embodiment 117. A pharmaceutical composition comprising a crosslinked amine polymer having a retained chloride ion content of at least 0.5 mmol chloride ion / g polymer in a Gastrointestinal Chamber Transit Assay ("GICTA").

[0452] Embodiment 118. A pharmaceutical composition comprising a crosslinked amine polymer having a retained chloride ion content of at least 0.5 mmol chloride ion / g polymer in a Gastrointestinal Chamber Transit Assay ("GICTA"), and a chloride ion retention of at least 30% of the chloride ion bound initially in the GICTA at the end of the GICTA.

[0453] Embodiment 119. A pharmaceutical composition comprising a crosslinked amine polymer having a chloride ion binding capacity of at least 5 mmol / g in a 1 hour Simulated Gastric Fluid ("SGF") assay, and a chloride ion binding capacity of at least 8 mmol / g in a 24 hour Simulated Gastric Fluid ("SGF") assay.

[0454] Embodiment 120. A pharmaceutical composition comprising a crosslinked amine polymer having a chloride ion binding capacity in a 1 hour Simulated Gastric Fluid ("SGF") assay that is at least 50% of its chloride ion binding capacity in a 24 hour Simulated Gastric Fluid ("SGF") assay.

[0455] Embodiment 121. A pharmaceutical composition comprising a crosslinked amine polymer having a chloride binding capacity of at least 5 mmol / g in a 1 hour simulated gastric fluid ("SGF") assay, a chloride binding capacity of at least 8 mmol / g in a 24 hour simulated gastric fluid ("SGF") assay, and a chloride binding capacity in a 1 hour simulated gastric fluid ("SGF") assay that is at least 50% of its chloride binding capacity in a 24 hour simulated gastric fluid ("SGF") assay.

[0456] Embodiment 122. A pharmaceutical composition comprising a crosslinked amine polymer having a chloride binding capacity of at least 2.5 mmol chloride / g polymer in a 24 hour simulated small intestine organic and inorganic buffer ("SOB") assay.

[0457] Embodiment 123. A pharmaceutical composition comprising a crosslinked amine polymer having a chloride binding capacity of at least 0.5 mmol chloride / g polymer in a 2 hour simulated small intestine organic and inorganic buffer ("SOB") assay and at least 2.5 mmol chloride / g polymer in a 24 hour simulated small intestine organic and inorganic buffer ("SOB") assay.

[0458] Embodiment 124. A pharmaceutical composition comprising a crosslinked amine polymer having a chloride binding capacity of at least 2 mmol chloride / g polymer at 4 hours in simulated small intestine inorganic buffer ("SIB").

[0459] Embodiment 125. A pharmaceutical composition comprising a crosslinked amine polymer having a chloride binding capacity of at least 2 mmol chloride / g polymer at 4 hours in simulated small intestine inorganic buffer ("SIB") and a chloride binding capacity of at least 2 mmol chloride / g polymer at 24 hours in simulated small intestine inorganic buffer ("SIB").

[0460] Embodiment 126. A pharmaceutical composition comprising a crosslinked amine polymer having a chloride binding capacity of at least 5.5 mmol chloride / g polymer in a 24 hour simulated small intestine organic and inorganic buffer ("SOB") assay.

[0461] Embodiment 127. A pharmaceutical composition comprising a crosslinked amine polymer as described in any one of paragraphs

[0038] to

[0056] , wherein the crosslinked amine polymer has a pKa (measured at equilibrium in 100 mM NaCl) of at least 6.

[0462] Embodiment 128. A pharmaceutical composition comprising a crosslinked amine polymer having (i) a proton binding capacity and a chloride ion binding capacity of at least 5 mmol / g in simulated gastric fluid; and (ii) a chloride ion binding capacity of at least 4 mmol / g in simulated small intestinal inorganic buffer ("SIB") at 1 hour.

[0463] Embodiment 129. A pharmaceutical composition comprising a crosslinked amine polymer having (i) a proton binding capacity and a chloride ion binding capacity of at least 5 mmol / g in simulated gastric fluid; and (ii) a chloride ion binding capacity of at least 4 mmol / g and a phosphate ion binding capacity of less than 2 mmol / g in simulated small intestinal inorganic buffer ("SIB").

[0464] Embodiment 130. A pharmaceutical composition comprising a crosslinked amine polymer having (i) a proton binding capacity and a chloride ion binding capacity of at least 5 mmol / g in simulated gastric fluid; and (ii) a chloride ion binding capacity of at least 2 mmol / g in simulated small intestinal inorganic buffer ("SIB") at 1 hour.

[0465] Embodiment 131. A pharmaceutical composition comprising a crosslinked amine polymer having (i) a proton binding capacity and a chloride ion binding capacity of at least 5 mmol / g in simulated gastric fluid; and (ii) a chloride ion to phosphate ion binding ratio of at least 2.3: 1, respectively, in simulated small intestinal inorganic buffer ("SIB").

[0466] Embodiment 132. A pharmaceutical composition comprising a crosslinked amine polymer having (i) a proton binding capacity and a chloride ion binding capacity of at least 5 mmol / g in simulated gastric fluid at 1 hour; and (ii) a proton binding capacity and a chloride ion binding capacity of at least 8 mmol / g in simulated gastric fluid.

[0467] Embodiment 133. A pharmaceutical composition comprising a crosslinked amine polymer having a proton binding capacity and a chloride ion binding capacity in simulated gastric fluid at 1 hour that is at least X% of the corresponding proton binding capacity and chloride ion binding capacity of the crosslinked amine polymer in simulated gastric fluid at 24 hours, wherein X% is at least 50%.

[0468] Embodiment 134. A pharmaceutical composition comprising a crosslinked amine polymer having (i) a selectivity for chloride ion over citrate, phosphate, and taurocholate in simulated small intestinal organic and inorganic buffer ("SOB"), and (ii) a chloride ion binding capacity of at least 4 mmol / g in SOB at 24 hours.

[0469] Embodiment 135. A pharmaceutical composition comprising a crosslinked amine polymer having a selectivity for chloride over citrate, phosphate, and taurocholate at (i) 1 hour, (ii) 4 hours, (iii) 12 hours, (iv) 18 hours, (v) 24 hours, (vi) 30 hours, (vii) 36 hours, or even (viii) 48 hours in simulated small intestinal organic and inorganic buffer ("SOB").

[0470] Embodiment 136. A pharmaceutical composition comprising a crosslinked amine polymer having a chloride binding capacity of at least 4 mmol / g and a phosphate ion binding capacity of less than 2 mmol / g at (i) 1 hour, (ii) 2 hours, (iii) 3 hours, (iv) 4 hours, and / or (v) greater than 4 hours in simulated small intestinal inorganic buffer ("SIB").

[0471] Embodiment 137. A method of treating acid / base imbalance in an animal, including a human, by removing HC1 via oral administration of a pharmaceutical composition according to any one of embodiments 122-136.

[0472] Embodiment 138. A method of treating acid / base imbalance in an animal, including a human, by removing HC1 via oral administration of a pharmaceutical composition comprising a crosslinked amine polymer prepared by a method according to any one of embodiments 41-111.

[0473] Embodiment 139. A polymer comprising a structure corresponding to Formula 4:

[0474]

[0475] wherein each R is independently hydrogen or an ethylene crosslink between two nitrogen atoms of the crosslinked amine polymer and a, b, c, and m are integers.

[0476] Embodiment 140. The polymer according to embodiment 139, wherein m is a large integer indicating an extended polymer network.

[0477] Embodiment 141. The polymer according to embodiments 139 or 140, wherein 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.

[0478] Embodiment 142. The polymer according to embodiments 139 or 140, wherein the ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 1.5:1 to 4:1.

[0479] Embodiment 143. The polymer of Embodiments 139 or 140, wherein the ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 1.75:1 to 3:1.

[0480] Embodiment 144. The polymer of Embodiments 139 or 140, wherein the ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 2:1 to 2.5:1.

[0481] Embodiment 145. The polymer of Embodiments 139 or 140, wherein the sum of a and b is 57 and c is 24.

[0482] Embodiment 146. The polymer of any one of Embodiments 139-145, wherein 50-95% of the R substituents are hydrogen and 5-50% are ethylene crosslinks between two nitrogens of the crosslinked amine polymer.

[0483] Embodiment 147. The polymer of any one of Embodiments 139-145, wherein 55-90% of the R substituents are hydrogen and 10-45% are ethylene crosslinks between two nitrogens of the crosslinked amine polymer.

[0484] Embodiment 148. The polymer of any one of Embodiments 139-145, wherein 60-90% of the R substituents are hydrogen and 10-40% are ethylene crosslinks between two nitrogens of the crosslinked amine polymer.

[0485] Embodiment 149. The polymer of any one of Embodiments 139-145, wherein 65-90% of the R substituents are hydrogen and 10-35% are ethylene crosslinks between two nitrogens of the crosslinked amine polymer.

[0486] Embodiment 150. The polymer of any one of Embodiments 139-145, wherein 70-90% of the R substituents are hydrogen and 10-30% are ethylene crosslinks between two nitrogens of the crosslinked amine polymer.

[0487] Embodiment 151. The polymer of any one of Embodiments 139-145, wherein 75-85% of the R substituents are hydrogen and 15-25% are ethylene crosslinks between two nitrogens of the crosslinked amine polymer.

[0488] Embodiment 152. The polymer of any one of Embodiments 139-145, wherein 80-85% of the R substituents are hydrogen and 15-205% are ethylene crosslinks between two nitrogens of the crosslinked amine polymer.

[0489] Embodiment 153. The polymer of any one of embodiments 139-145, wherein about 81% of the R substituents are hydrogen and about 19% are ethylene crosslinks.

[0490] Embodiment 154. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a crosslinked amine polymer according to any one of embodiments 139-153.

[0491] Embodiment 155. A method of treating acid / base imbalance in an animal, including a human, by removing HC1 via oral administration of a pharmaceutical composition according to embodiment 154.

[0492] In view of the detailed description of the application, it will be readily apparent to those skilled in the art that modifications and changes can be made without departing from the scope of the application as defined by the appended claims. Moreover, it should be understood that all examples in the present disclosure are provided as non-limiting examples. Examples

[0493] The following non-limiting examples are provided to further illustrate the present application. Those skilled in the art will appreciate that the techniques disclosed in the following examples represent the best of the inventors' knowledge of methods presently known to be practiced and therefore can be viewed as examples of embodiments of the application. However, those skilled in the art will further appreciate, in light of the present disclosure, that many changes can be made to the particular embodiments disclosed in the examples without departing from the spirit and scope of the application, and that similar or equivalent results can be achieved by altering the techniques presented in the examples accordingly.

[0494] General procedure for DCE dispersion crosslinking

[0495] A reaction vessel equipped with a stirring paddle and nitrogen inlet was charged with dry preformed amine polymer beads. To the beads was added 1,2-dichloroethane (DCE). The beads were dispersed in the DCE using mechanical stirring. Water was added directly to the dispersion and stirring was continued for 30 minutes. After 30 minutes, the flask was immersed in an oil bath held at the selected temperature. The reaction was held in the oil bath and stirred using mechanical stirring under a nitrogen atmosphere for the selected amount of time. Methanol was added to the reaction and the solvent was removed by decanting. The beads were then filtered and purified by washing (MeOH twice, H2O once, 1 N HC1 twice, H2O once, 1 N NaOH three times, followed by H2O until the pH of the solution after washing was 7). The purified beads were then dried by lyophilization for 48 hours.

[0496] Specific exemplary procedure for DCE dispersion crosslinking

[0497] The following exemplary procedure is the standard protocol for all examples in this section unless otherwise noted. Specifically, this indicates a 1 :6 ratio of beads to DCE (g / mL), a 0.25:1 ratio of water to beads mass, a 70 °C jacket (oil bath) temperature, and a 16 hour reaction time.

[0498] A 250 mL round bottom flask, equipped with a stirring paddle and nitrogen inlet, was charged with dry preformed amine polymer beads (15.00 g). To the beads was added 1,2-dichloroethane (DCE) (90 mL, resulting in a 1 :6 ratio of beads to DCE (g / mL)). The beads were dispersed in the DCE using mechanical stirring (~ 150 rpm stirring). Water (3.75 mL, resulting in a 0.25:1 ratio of water to beads mass) was added directly to the dispersion and stirring was continued for 30 minutes. After 30 minutes, the flask was immersed in an oil bath held at 70 °C. The reaction was held in the oil bath and stirred using mechanical stirring under a nitrogen atmosphere for 16 hours. Methanol (100 mL) was added to the reaction and the solvent was removed by decanting. The beads were then filtered, followed by purification by washing (MeOH twice, H2O once, 1 N HC1 twice, H2O once, 1 N NaOH three times, followed by H2O until the pH of the solution after washing was 7). The purified beads were then dried by lyophilization for 48 hours.

[0499] - Effect of water on crosslinking reaction of DCE dispersions

[0500] The effect of the amount of water added to the exemplary reaction mixture was explored (Table 1). Under these conditions, chloride binding in the SIB and SOB increased relative to the preformed amine polymer (Sample 019069-A1), while phosphate, citrate, and taurocholate binding decreased. Particle size decreased after the second step crosslinking. The water content that resulted in the highest selectivity and highest total chloride binding was found to be in the range of 0.25-0.35 water to bead ratio in the SIB.

[0501] Preformed amine polymer beads as a source of dry beads for crosslinking reaction for DCE dispersion were prepared as follows. Two monomer stock aqueous solutions (50% w / w) were prepared by dissolving 43.83 g of allyl amine hydrochloride and 45.60 g of DAPDA in water independently. A 3 necked 2 L round bottom flask with 4 side baffles, equipped with an overhead stirrer (stirring at 180 rpm), a Dean-Stark apparatus and a condenser, and a nitrogen inlet was charged with 12 g of surfactant (Stean Sulfonic 100 dissolved in 1,200 g of heptane / chlorobenzene solution (26 / 74 v / v), followed by the aqueous stock solutions and another portion of water (59.14 g). In a separate vessel, an aqueous solution of 15 wt% of initiator V-50 (9.08 g) was prepared. Both mixtures were sparged with nitrogen independently while the reaction vessel was brought to 67 °C in an oil bath (approximately 30 min). Under inert atmosphere, the initiator solution was added to the reaction mixture, followed by heating at 67 °C for 16 h. A second aliquot of the initiator solution (equal to the first aliquot) and the reaction mixture were sparged with nitrogen for 30 min and combined, after which the temperature was increased to 115 °C for the final dehydration step (Dean-Stark). The reaction was kept at 115 °C until water stopped being collected in the Dean-Stark trap (6 h, 235 mL removed, >90% total water, T 内部 >99 °C). The reaction was allowed to cool to room temperature and stirring was stopped to allow the beads to settle. The organic phase was removed from the bead cake by decantation. The beads were purified by washing (MeOH twice, H2O once, 1 N HCI twice, H2O once, 1 N NaOH three times, followed by H2O until the pH of the solution after washing was 7) and dried by lyophilization.

[0502]

[0503] - Effect of time and temperature

[0504] The effect of temperature on the reaction was investigated by following the reaction progress as a function of time. In these experiments, it was found that the desired properties were obtained at all temperatures studied between 55 °C and 70 °C, but the reaction progress was slower at lower temperatures (Tables 2, 3, 4 and 5).

[0505]

[0506]

[0507]

[0508]

[0509] Effect of DCE to pre-formed amine polymer ratio on second step crosslinking

[0510] The effect of the amount of DCE added to the reaction mixture to disperse the beads was explored (Table 6). Under these conditions, it was found that the ratio of DCE to beads (pre-formed amine polymer) did not significantly change the chloride binding or selectivity in either the SIB or SOB. It should be noted that a ratio of 3: 1 is approximately the minimum with sufficient DCE to disperse the beads.

[0511]

[0512] Effect of HCL in pre-formed amine polymer on second step crosslinking

[0513] The effect of residual hydrochloric acid in the pre-formed amine polymer (e.g. due to insufficient washing) on second step crosslinking was investigated (Table 7). In these experiments, it was found that if less than 3% of the amines in the pre-formed amine polymer were protonated, then the chloride selectivity and binding capacity were not affected.

[0514]

[0515] -2) General procedure for solvent dispersed crosslinking - DCE

[0516] Into a reaction vessel fitted with a stirring paddle and nitrogen inlet, dry pre-formed amine polymer beads were added. To the beads, an inert (i.e. non-crosslinking agent) dispersion solvent was added. The beads were dispersed in the solvent using mechanical stirring. Water was added directly to the dispersion and stirring was continued for 30 minutes. To the flask, pure dichloroethane was added, which was then immersed in an oil bath heated to the selected temperature. The reaction was heated under a nitrogen atmosphere for 16 hours using mechanical stirring. Methanol was added to the reaction and the solvent was removed by decanting. The beads were then filtered, followed by purification by washing (MeOH twice, H2O once, 1 N HCI twice, H2O once, 1 N NaOH three times, followed by H2O until the pH of the solution after washing was 7). The purified beads were then dried by lyophilization for 48 hours.

[0517] - Specific exemplary procedure for solvent dispersed crosslinking - DCE crosslinking agent

[0518] Unless otherwise stated, the following exemplary procedure is the standard protocol used for all examples in this section. Specifically, this represents a bead to dispersion solvent (g / mL) ratio of 1 :6, a water to bead mass ratio of 1 : 1, a 70 °C jacket temperature, and a reaction time of 16 hours.

[0519] A 250 mL round bottom flask, fitted with a stirring paddle and nitrogen inlet, was charged with dry beads (3.00 g). To the beads was added heptane (18 mL, resulting in a 1 :6 bead to DCE g / mL ratio). The beads were dispersed in the heptane using mechanical stirring (~ 100 rpm stirring). To the dispersion was added water directly (3 mL, resulting in a 1 : 1 water to bead ratio) and stirring was continued for 20 minutes. To the flask was added neat dichloroethane (3.57 g, 35.9 mmol) and then heated to 70 °C. The reaction was heated under a nitrogen atmosphere using mechanical stirring for 16 hours. To the reaction was added methanol (100 mL) and the solvent was removed by decanting. The beads were then filtered and then purified by washing (MeOH twice, H2O once, 1 N HC1 twice, H2O once, 1 N NaOH three times, followed by H2O until the pH of the solution after washing was 7). The purified beads were then dried by lyophilization for 48 hours.

[0520] Effect of amount of DCE crosslinker on heptane dispersed reactions

[0521] The effect of the amount of DCE added for the second step crosslinking of the inert solvent dispersed step was explored (Table 8). In these experiments, 2 equivalents of DCE (relative to the nitrogen in the preformed amine polymer) resulted in a material that had the best combination of high selectivity and high chloride binding as measured in the SIB and SOB.

[0522]

[0523] Effect of dispersion solvent - DCE crosslinker

[0524] The effect of using different inert dispersion solvents was explored (Table 9). Dimethylformamide (DMF, miscible with water) was found to provide a material with high chloride binding in the SOB, but relatively low chloride selectivity and chloride binding in the SIB. The addition of water to the DMF reaction mixture did not affect the SIB performance, but significantly decreased the chloride selectivity and binding in the SOB.

[0525]

[0526] 3) General procedure for solvent dispersed crosslinking: DCE / DCP mixed crosslinking system

[0527] A reaction vessel equipped with a stirring paddle and nitrogen inlet was charged with dry preformed amine polymer beads. To the beads was added 1,3-dichloropropane (DCP) and 1,2-dichloroethane (DCE) sequentially. The beads were dispersed in the DCE / DCP solution using mechanical stirring. Water was added directly to the dispersion and stirring was continued for 30 minutes. After 30 minutes, the flask was immersed in an oil bath held at the selected temperature. The reaction was held in the oil bath and stirred using mechanical stirring under a nitrogen atmosphere for the selected amount of time. Methanol was added to the reaction and the solvent was removed by decantation. The beads were then filtered and purified by washing (MeOH twice, H2O once, 1 N HC1 twice, H2O once, 1 N NaOH three times, followed by H2O until the pH of the solution after washing was 7). The purified beads were then dried by lyophilization for 48 hours.

[0528] Specific exemplary procedure for solvent-dispersed crosslinking: DCE / DCP mixed crosslinker system

[0529] Unless otherwise noted, the following exemplary procedure is the standard protocol for all examples in this section. Specifically, this indicates a 1:6 bead to crosslinker (g / mL) ratio, a 1:1 water to bead mass ratio, a 70 °C jacket (oil bath) temperature, and a 16 hour reaction time.

[0530] A 100 mL round bottom flask equipped with a stirring paddle and nitrogen inlet was charged with dry preformed amine polymer beads (3.00 g). To the beads was added DCP (4.30 mL) and DCE (13.70 mL), resulting in a 1:6 mass / volume ratio of beads to DCE). The beads were dispersed in the DCE using mechanical stirring (~ 150 rpm stirring). Water was added directly to the dispersion (3.00 mL, resulting in a 1:1 water to bead mass ratio) and stirring was continued for 30 minutes. After 30 minutes, the flask was immersed in an oil bath held at 70 °C. The reaction was held in the oil bath and stirred using mechanical stirring under a nitrogen atmosphere for 16 hours. Methanol was added to the reaction (60 mL) and the solvent was removed by decantation. The beads were then filtered and purified by washing (MeOH twice, H2O once, 1 N HC1 twice, H2O once, 1 N NaOH three times, followed by H2O until the pH of the solution after washing was 7). The purified beads were then dried by lyophilization for 48.

[0531] Effect of amount of DCE in DCE / DCP dispersed crosslinking

[0532] The effect of using different ratios in a mixed crosslinker system where the crosslinker is also the dispersion solvent was explored (Table 10). It was found that increasing the amount of DCP resulted in a decrease in selectivity for phosphate over chloride in the SIB.

[0533]

[0534] Effect of crosslinking water content on DCE / DCP dispersions

[0535] The effect of water content in the second-step crosslinking process with the addition of a mixed crosslinking agent was investigated (Table 11). Using these conditions, the ideal water content was found to be 0.5–1.0 g water / g of the pre-formed amine polymer.

[0536]

[0537] Effect of heptane amount on the DCE / DCP mixed crosslinking agent system

[0538] The effect of diluting the mixed DCE / DCP crosslinking agent system with heptane was investigated (Table 12). As the amount of heptane increased (e.g., 80% heptane), the reaction mixture became more closely similar to a crosslinking reaction in which the dispersing solvent was an inert solvent (i.e., not a crosslinking agent). Under these conditions, selective chloride ion binding and total chloride ion binding in SIB were achieved with the addition of more heptane. Alternatively, neither the selectivity nor the total chloride ion binding, as measured by SOB, was significantly affected up to 40% by volume of heptane.

[0539]

[0540] -4) General procedure for crosslinking in "non-dispersed" reactions - DCP crosslinking agent

[0541] Add dried, pre-formed amine polymer beads to the reaction vessel. Add water to the beads. Then gently stir the beads with a spatula to ensure the water evenly wets the beads. Allow the beads to equilibrate for 20 minutes. Add pure dichloropropane to the vial and stir the beads again with a spatula. Heat the vial to 70°C and maintain this temperature for 16 hours. Add methanol to the reaction solution. Filter the beads and then purify them by washing (MeOH twice, H₂O once, 1N HCl twice, H₂O once, 1N NaOH three times, followed by H₂O, until the pH of the solution after washing is 7). Then dry the purified beads by lyophilization for 48 hours.

[0542] -Specific exemplary procedures for "non-dispersive" reactive crosslinking-DCP crosslinking agent

[0543] Unless otherwise stated, the following exemplary procedures are standard practices for all embodiments in this section. Specifically, this represents a 0.68 mol eq DCP ratio (molar ratio of DCP to total nitrogen in the pre-formed amine polymer), a 0.25:1 water to bead molar ratio, a jacket (heating hood) temperature of 70°C, and a reaction time of 16 hours.

[0544] To a 20 mL scintillation vial was added dry preformed amine polymer beads (0.40 g). To the beads was added water (0.10 g, resulting in a 0.25: 1 water to bead mass ratio). The beads were then gently stirred with a spatula to ensure the water evenly wetted the beads. The beads were allowed to equilibrate for 20 minutes. To the vial was added neat 1,3-dichloropropane (0.46 g, 4.1 mmol, 0.68 mol eq DCP per 1 mol nitrogen in the preformed amine polymer) and the beads were again stirred with a spatula. The vial was heated to 70 °C for 16 hours. To the reaction was added methanol (10 mL). The beads were filtered and then purified by washing (MeOH twice, H2O once, 1 N HCl twice, H2O once, 1 N NaOH three times, followed by H2O until the pH of the solution after washing was 7). The purified beads were then dried by lyophilization for 48 hours.

[0545] Effect of water amount in non-dispersive crosslinking reactions

[0546] The effect of water added to non-dispersive crosslinking reactions was investigated (Table 13). In these experiments, it was found that the water content that produced the highest selectivity and highest chloride binding as measured in the SIB was less than 0.5: 1 water to bead ratio.

[0547]

[0548] Effect of molar equivalents of DCP crosslinker on "non-dispersive" reaction crosslinking

[0549] The effect of the amount of DCP added to non-dispersive crosslinking reactions was investigated (Table 14). Under these conditions, it was found that the molar equivalents of DCP that produced the highest selectivity and highest total chloride binding as measured in the SIB was less than 0.5: 1 water to bead weight ratio.

[0550]

[0551] 5) General procedure for solvent-dispersive crosslinking - DCP crosslinker

[0552] A reaction vessel equipped with a stirring paddle and nitrogen inlet was charged with dry preformed amine polymer beads. To the beads was added an inert (i.e. non-crosslinker) dispersion solvent. The beads were dispersed in the solvent using mechanical stirring. Water was added directly to the dispersion and stirring was continued for 30 minutes. To the flask was added neat 1,3-dichloropropane (DCP) and then immersed in an oil bath heated to 70 °C. The reaction was heated under a nitrogen atmosphere using mechanical stirring for 16 hours. Methanol was added to the reaction and the solvent was removed by decantation. The beads were then filtered and then purified by washing (MeOH twice, H2O once, 1 N HCl twice, H2O once, 1 N NaOH three times followed by H2O until the pH of the solution after washing was 7). The purified beads were then dried by lyophilization for 48 hours.

[0553] - Specific exemplary procedure for solvent-dispersed crosslinking - DCP crosslinker

[0554] Unless otherwise noted, the following exemplary procedure is the standard protocol for all examples in this section. Specifically, this indicates a 1 :6 bead to dispersion solvent (g / mL) ratio, a 1 : 1 water to bead mass ratio, 1 molar equivalent of DCP (relative to nitrogen in the preformed amine polymer), a 70 °C jacket (bath) temperature, and a 16 hour reaction time.

[0555] A 100 mL round bottom flask with a stirring paddle and nitrogen inlet was charged with dry preformed amine polymer beads (3.00 g). To the beads was added an inert (i.e. non-crosslinker) dispersion solvent (18 mL, resulting in a 1 :6 bead to solvent (g / mL) ratio). The beads were dispersed in the solvent using mechanical stirring. Water was added directly to the dispersion (3 mL, resulting in a 1 : 1 water to bead mass ratio) and stirring was continued for 30 minutes. To the flask was added neat 1,3-dichloropropane (DCP) (5.22 g, 46.2 mmol) and then immersed in an oil bath heated to 70 °C. The reaction was heated under a nitrogen atmosphere using mechanical stirring for 16 hours. Methanol was added to the reaction (100 mL) and the solvent was removed by decantation. The beads were then filtered and then purified by washing (MeOH twice, H2O once, 1 N HCl twice, H2O once, 1 N NaOH three times followed by H2O until the pH of the solution after washing was 7). The purified beads were then dried by lyophilization for 48 hours.

[0556] - Effect of molar equivalent crosslinker to heptane-dispersed reaction - DCP crosslinker

[0557] The effect of the equivalent of DCP added in the second step of crosslinking dispersed in an inert solvent was explored (Table 15). In these experiments, 1.0-1.2 molar equivalents of DCP (relative to the nitrogen in the preformed amine polymer) produced materials with the best combination of high selectivity and high total chloride binding as measured in SIB and SOB (Table 15). Effect of water content in the DCP-heptane reaction on chloride selectivity. (100 mL vessel, 1 g beads, 1 :3 bead to heptane (g / mL) ratio, 1 : 1 water to bead mass ratio, 70 °C, 16 hours, no Dean-Stark). The above exemplary procedure was used, but with a 1 :3 : :bead to heptane (g / mL) ratio.

[0558]

[0559] Effect of water on heptane dispersed reactions - DCP crosslinker

[0560] The effect of the amount of water added in the second step of crosslinking dispersed in an inert solvent was explored (Table 16). Under these conditions, water contents of less than 0.5: 1 water to bead ratio produced materials with the best combination of high selectivity and high total chloride binding as measured in SIB and SOB.

[0561]

[0562] Effect of dispersing solvent - DCP crosslinker

[0563] Examples of second step crosslinking of preformed amine polymers using different non-polar dispersing solvents are summarized in Table 17. Reactions with 1-octanol and 2-MeTHF were performed on 0.4 g of preformed amine polymer in 20 mL scintillating vials with a 1 : 10 bead to solvent (g / mL) ratio and 0.68 molar equivalents of DCP (relative to 1 mol of nitrogen in the preformed amine polymer). Cyclohexane was used at a 1 g scale using the exemplary procedure with a 1 :3 bead to solvent (g / mL) ratio. Chlorobenzene reactions used the exemplary procedure.

[0564]

[0565] Dispersing solvent - DCP crosslinker

[0566] Examples of second step crosslinking of preformed amine polymers using different water miscible dispersing solvents summarized in the exemplary procedure above were used, but with 0.5 g of preformed amine polymer in scintillating vials and no water added to any of the reaction solutions.

[0567]

[0568] Alternative swelling agent

[0569] In most of the examples in Table 17 (except DMF), water was added to swell the beads and was immiscible with the dispersing solvent used. The effect of using an alternative immiscible non-aqueous swelling agent is summarized in Table 19. Reactions using methanol were performed on 0.5 g of preformed amine polymer in a 20 mL scintillation vial. Reactions using DMF followed the example procedure above. All conditions tested produced material with lower selectivity and total chloride binding compared to similar reactions where water was the swelling agent of choice.

[0570]

[0571] 6) General procedure for ammonium hydroxide treatment after post-crosslinking

[0572] The general procedure can be performed using beads that have been purified by washing and dried by lyophilization or using beads that have been partially purified by washing. In the latter case, the treatment with ammonium hydroxide is typically performed after three methanol washes and the normal purification by washing is resumed by washing with 1 N HC1.

[0573] An aqueous solution of NH4OH preheated to the desired reaction temperature is added to the post-crosslinked beads (either dry or in the process of being washed). The beads are dispersed in the solution using mechanical stirring and heated in the ammonium hydroxide solution for a selected amount of time. After the treatment is complete, the beads are filtered and then purified by washing (2x 1 N HC1, 1x H2O, 3x 1 N NaOH followed by H2O until the pH of the post-wash solution is 7). The purified beads are then dried by lyophilization for 48 hours.

[0574] Specific example procedure for ammonium hydroxide treatment after post-crosslinking

[0575] Secondary crosslinking was performed by reacting the preformed amine polymer (100 g of dry beads) with DCE in the presence of water as the swelling agent. After the reaction, the beads were filtered and washed with methanol three times. The wet beads were transferred to a 2000 mL round bottom flask fitted with a nitrogen inlet and an overhead stirrer. To the beads was added 1000 mL of 1 N NH4OH solution preheated to 70 °C (10:1 :1 N NH4OH:dry beads (ml / g)). The round bottom flask was immersed in an oil bath heated to 75 °C and the beads were stirred under a nitrogen atmosphere for four hours. The beads were filtered and then purified by washing (2x 1 N HC1, 1x H2O, 3x 1 N NaOH followed by H2O until the pH of the post-wash solution was 7). The purified beads were then dried by lyophilization for 48 hours.

[0576] Ammonia treatment as part of a washing protocol

[0577] Ammonia treatment of post-crosslinked polymers was performed according to the above exemplary procedure, but with 10 g of beads, where 0.5 g of sample was taken, and a jacket temperature of 75 °C. Ammonia treatment was performed as part of the wash after the methanol wash and before the 1 N HC1 wash. Treatment times were varied between 0 and 24 hours and data are summarized in Table 20.

[0578]

[0579] Ammonia treatment of post-crosslinked purified and dried beads

[0580] Ammonia treatment of post-crosslinked polymers was performed according to the above exemplary procedure, except that the treatment was performed after the post-crosslinked polymers were purified and dried (Table 21).

[0581]

[0582] 7) Effect of heating post-crosslinked polymers during drying step on chloride ion selectivity in SOB Example

[0583] Preformed amine polymer beads were prepared as follows. Two monomer stock aqueous solutions (50% w / w) were prepared by separately dissolving allyl amine hydrochloride (93.9 g) and DAPDA (97.7) in water. A 3 L Ace Glass jacketed reactor, equipped with an overhead stirrer (stirred at 180 rpm), an additional funnel, a temperature probe, and a nitrogen inlet, was charged with Stepan Sulf-100 (25.7 g) dissolved in a heptane / chlorobenzene solution (26 / 74 v / v, 2571.4 g), followed by the aqueous stock solutions and additional water (126.7 g). In a separate vessel, a 15 wt% aqueous solution of V-50 (19.4 g) was prepared and added to the additional funnel. The two mixtures were separately sparged with nitrogen while the reaction vessel was brought to 67 °C (~1 h, T 内部 Under an inert atmosphere, the initiator solution was added to the reaction mixture, which was subsequently heated at 67 °C for 16 h. A second aliquot of the initiator solution (equal to the first aliquot) and the reaction mixture were sparged with nitrogen for 30 min and combined, after which the temperature was increased to 115 °C for a final dehydration step (Dean-Stark). The reaction was held at 115 °C until water collection in the Dean-Stark trap ceased (6 h, >90% of total water removed, T 内部> 99 °C). The reaction was allowed to cool to room temperature and stirring was stopped to allow the beads to settle. The organic phase was siphoned from the bead cake and methanol (1 L) was added to resuspend the beads (under stirring, 150 rpm). The organic solvent removal step was repeated twice. The beads were drained into a 2 L media bottle and the reactor was rinsed with methanol (500 mL). The beads were purified by washing (MeOH twice, H2O once, 1 N HC1 twice, H2O once, 1 N NaOH three times, followed by H2O until the pH of the solution after washing was 7) and dried by lyophilization.

[0584] Preformed amine polymer beads were subjected to a second crosslinking step according to the general procedure for solvent-dispersed crosslinking. DCE was scaled to 10 g of preformed amine polymer beads using the specific exemplary procedure described above. At the end of the washing step, the resulting polymer was again dried in a lyophilizer or in a conventional oven at 60 °C for 40 hours. The oven-dried polymer had similar binding in SIB compared to the lyophilized polymer, but improved chloride binding in SOB (Table 22).

[0585]

[0586] 8) Binding kinetics examples

[0587] Selected polymers were evaluated in SGF, SIB, and SOB assays (described elsewhere), where samples were taken at multiple time points (1, 2, 4, and 24 hours of incubation) to evaluate anion binding kinetics under these assay conditions. Results are shown in Tables 23, 24, and 25 below, which represent three sets of experiments. These polymers were synthesized by subjecting preformed amine polymers prepared using the general method for preparing preformed amine polymers described above to a second crosslinking step according to the general procedure for solvent-dispersed crosslinking described above: DCE.

[0588]

[0589]

[0590]

[0591]

[0592] Equilibrium chloride binding measurements of amine polymers

[0593] The pH dependent equilibrium chloride binding of selected polymers was measured using an automatic titrator. The polymer at a starting concentration of 4 mg / ml was incubated in a solution containing 100 mM sodium chloride at room temperature for 16 hours. The sample was continued to be stirred and maintained at a set pH throughout the length of the incubation by slow addition of a 0.1 N HC1 solution using an automatic titrator. Following incubation, 400 microliters of sample was removed, filtered, diluted if necessary and then the chloride content was determined using ion chromatography. For each polymer tested, the chloride binding was calculated using the following equation:

[0594]

[0595] where [C1] 起始 is the starting chloride concentration in the incubation solution (mM), [C1] HCl is the chloride added by the automatic titration using 0.1 N HC1 (mM), and concentration (mg / ml) is the final concentration of polymer in the solution (after accounting for the volume of 0.1 N HC1 added).

[0596] Equilibrium chloride binding was measured using the above method at pH ranging from 1.5 to 12. The plot of chloride binding versus pH allows the construction of a titration curve and the determination of the average pKa Figure 3 ) of a given polymer. The following example shows the equilibrium chloride binding (Table 26) and plot of chloride binding versus pH for 019067-A2 in the free amine form, measured using the above procedure (see Figure 2 ).

[0597] The average pKa of this example was determined to be 6.15. The data was fit using a 4th order polynomial fit. The equilibrium chloride binding at various pH values was calculated from the equation obtained by curve fitting, and the pH value at half of the maximum binding was taken as the average pKa of the polymer.

[0598] Table 26: Equilibrium chloride binding measured at different pH

[0599]

[0600]

[0601] 9) GICTA Data Example

[0602] The polymers described in the following table were synthesized by subjecting preformed amine polymers prepared using the general method for preparing preformed amine polymers described above to a second crosslinking step according to the general procedure for solvent dispersed crosslinking - DCE or the general procedure for solvent dispersed crosslinking - DCE / DCT mixed crosslinking reagent system described above. For 019067-A2, water removal was performed by applying an additional dean-stark step after the reaction. The resulting polymers were evaluated using GICTA assay. The results are described in Table 27.

[0603]

[0604] 10) Examples of preparing polymers from polyallyl amines

[0605] Specific examples for preparing polyallyl amine / DCE preformed amine polymers

[0606] To a 500 mL round bottom flask was added polyallyl amine (14 g, 15 kDa) and water (28 mL). The solution was purged with nitrogen and stirred overhead at 220 rpm for 1 hour to fully dissolve the polymer. Next, 30 wt% NaOH aqueous solution (7 mL, 0.21 g) was added and stirred for 5 minutes. To the aqueous solution was added a pre-prepared solution of DCE (175 mL), n-heptane (105 mL), and Span 80 (2.8 g). The solution was heated to 70 °C and stirred for 16 hours. A Dean-Stark step was initiated by adding cyclohexane (100 mL) and heating the reaction to...

Claims

1. A pharmaceutical composition for treating acid-base imbalance in an animal, including a human, comprising a polymer having a structure corresponding to Formula 4: ###0001### wherein the ratio of chloride ion binding capacity to phosphate ion binding capacity of the crosslinked amine polymer in simulated small intestinal inorganic buffer ("SIB") is at least 2.3: 1, respectively, wherein the buffer for the SIB assay comprises 36 mM NaCl, 20 mM NaH2PO4, and 50 mM 2-(N-morpholino)ethanesulfonic acid (MES) buffered to pH 5.5, and the ratio of chloride ion binding capacity to phosphate ion binding capacity in SIB is determined using a method comprising the following steps: incubating 2.5 mg / ml, or 25 mg dry weight, of the crosslinked amine polymer in 10 mL of the SIB buffer at 37°C for 1 hour with stirring. wherein each R is independently hydrogen or an ethylene crosslink between two nitrogen atoms of a crosslinked amine polymer and a, b, c, and m are integers, 2. The pharmaceutical composition of claim 1, wherein the ratio of the sum of a and b to c, a+b:c, is in the range of 1:1 to 5:

1.

3. The pharmaceutical composition of claim 1, wherein the ratio of the sum of a and b to c, a+b:c, is in the range of 1.5:1 to 4:

1.

4. The pharmaceutical composition of any one of claims 1-3, wherein the ratio of the sum of a and b to c, a+b:c, is in the range of 1.75:1 to 3:

1.

5. The pharmaceutical composition of any one of claims 1-3, wherein the ratio of the sum of a and b to c, a+b:c, is in the range of 2:1 to 2.5:

1.

6. The pharmaceutical composition of any one of claims 1-3, wherein the sum of a and b is 57 and c is 24.

7. The pharmaceutical composition of any one of claims 1-3, wherein 50-95% of the R substituents are hydrogen and 5-50% are ethylene crosslinks between two nitrogens of the crosslinked amine polymer.

8. The pharmaceutical composition of any one of claims 1-3, wherein 55-90% of the R substituents are hydrogen and 10-45% are ethylene crosslinks between two nitrogens of the crosslinked amine polymer.

9. The pharmaceutical composition of any one of claims 1-3, wherein 60-90% of the R substituents are hydrogen and 10-40% are ethylene crosslinks between two nitrogens of the crosslinked amine polymer.

10. The pharmaceutical composition of any one of claims 1-3, wherein 65-90% of the R substituents are hydrogen and 10-35% are ethylene crosslinks between two nitrogens of the crosslinked amine polymer.

11. The pharmaceutical composition of any one of claims 1-3, wherein 70-90% of the R substituents are hydrogen and 10-30% are ethylene crosslinks between two nitrogens of the crosslinked amine polymer.

12. The pharmaceutical composition of any one of claims 1-3, wherein 75-85% of the R substituents are hydrogen and 15-25% are ethylene crosslinks between two nitrogens of the crosslinked amine polymer.

13. The pharmaceutical composition of any one of claims 1-3, wherein 80-85% of the R substituents are hydrogen and 15-20% are ethylene crosslinks between two nitrogens of the crosslinked amine polymer.

14. The pharmaceutical composition of any one of claims 1-3, wherein 81% of the R substituents are hydrogen and 19% are ethylene crosslinks. ​ 15. The pharmaceutical composition of any one of claims 1-3, administered orally.

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