AU2014218455A1 - Ferric Citrate Dosage Forms - Google Patents

Abstract

The disclosure relates to ferric citrate tablets and dosage forms. - 37 - WO 2011/011541 PCT/US2010/042788 HARDNESS VS. COMPRESSION FORCE $ 15.0 C/3 Lu -V- EXAMPLE 1 -+- EXAMPLE 2 --o- EXAMPLE 4 --A- EXAMPLE 5 0.0- i i i I 0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 COMPRESSION FORCE

Description

FERRIC CITRATE DOSAGE FORMS CROSS REFERENCE TO RELATED APPLICATIONS This application is a divisional of Australian Patent Application No. 2010276242, the entire content of which is incorporated herein by reference. 5 FIELD The field of the disclosure generally relates to pharmaceutical compositions of ferric citrate, methods for their use in treating medical conditions, and processes for their manufacture. BACKGROUND 0 US 5,753,706 discloses that ferric citrate compounds can be used to control phosphate metabolism and prevent metabolic acidosis in patients. The contents of US 5,753,706 are incorporated herein in its entirety by reference. Ferric citrate compounds can be used with patients suffering from renal failure associated with hyperphosphatemia or patients predisposed to development of a hyperphosphatemic condition. Ferric citrate also is used as 5 a food supplement and additive. Ferric citrate is characterized as a light brown to beige powder, odorless and slightly ferruginous tasting. According to the Merck Index, ferric citrate is slowly but completely soluble in cold water and readily soluble in hot water but diminishes in solubility with age. US 6,903,235 discloses that ferric citrate is commercially available in the form of a .0 combination of iron and citric acid of indefinite composition. The contents of US 6,903,235 are incorporated herein in its entirety by reference. The '235 Patent explains that the indefinite composition is likely due to difficulties encountered in its preparation but that those knowledgeable in the art understand and necessarily accept that commercially available ferric citrate contains different molar ratios of iron and citric acid and also contains different 25 amounts of hydrate. WO 2004/074444 discloses processes for making ferric organic compounds, such as ferric citrate, with enhanced dissolution rates. WO 2007/022435 is a continuation-in-part of WO 2004/074444 and discloses processes for making ferric organic compounds soluble over a wide pH range and having a large surface area. WO 2007089577 is directed to methods of 30 treating soft tissue calcification using ferric organic compounds, such as a ferric citrate compound. WO 2007089571 is directed to methods of treating chronic kidney disease using ferric organic compounds, such as ferric citrate compounds. - 1 - SUMMARY In one aspect, the disclosure is directed to a tablet including ferric citrate. In some embodiments, the tablet can include at least 65 weight percent ferric citrate. In another aspect, the disclosure is directed to a tablet comprising granule particles. 5 The granule particles include ferric citrate and a binder, and the mean surface area to mass ratio of the granule particles is equal to or greater than 1 m2 per gram. In various embodiments, the mean surface area to mass ratio of said granule particles is equal to or greater than 5 m2 per gram or 10 m2 per gram. In another aspect, the tablet can include at least 70 weight percent ferric citrate, at 0 least 80 weight percent ferric citrate, or at least 90 weight percent ferric citrate. In another aspect, the binder can be one or more of hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), sodium alginate, alginic acid, guar gum, acacia gum, xanthan gum, carbolpol, cellulose gum (carboxymethyl cellulose), ethyl cellulose, maltodextrin, PVP/VA, povidone, microcrystalline cellulose, starch (partially or fully 5 pregelatinized starch) and methyl cellulose. In another aspect, the tablet can include various additional components including, for example, one or more disintegrants and/or one or more lubricants. The disintegrant can be one or more of microcrystalline cellulose, croscarmellose sodium, crospovidone, sodium starch glycolate, and starch. The lubricant can be one or more of magnesium stearate, .0 calcium stearate, sodium stearyl fumarate, polyethylene glycol (molecular weight above 3350), sodium lauryl sulfate, talc, mineral oil, leucine, and poloxamer. In some embodiments, the tablet can include between approximately 65% and 92% ferric citrate, between approximately 4.5% and 30% binder, and between 0.5% and 3% lubricant. The binder can have disintegrant properties. The binder can be pregelatinized starch. 25 In another aspect, the tablet can be between approximately 65% and 92% ferric citrate, between approximately 4.5% and 30% binder, between approximately 1.5% and 15% disintegrant, and between 0.5% and 3% lubricant. Various additional components in the tablet can include microcrystalline cellulose, pregelatinized starch and sodium stearyl fumarate. In one embodiment, the ferric citrate can 30 be present at approximately 85 weight percent, the microcrystalline cellulose present at approximately 4 weight percent, the pregelatinized starch present at approximately 9 weight percent, and the sodium stearyl fumarate present at approximately 2 weight percent. In another aspect, the tablet can have between approximately 10% and 60% of ferric citrate dissolved in about 15 minutes, between approximately 30% and 90% of ferric citrate -2dissolved in about 30 minutes and at least approximately 60% of the ferric citrate dissolved in about 60 minutes in a dissolution test according to test method USP <711>. The tablet can have a dissolution of at least 90% within 30 minutes in a dissolution test according to test method USP <711>. The tablet can show a dissolution of at least 90% within 60 minutes in a 5 dissolution test according to test method USP <711>. The tablet can show a disintegration time of less than 30 minutes in a disintegration test according to test method USP <701>. The tablet can show a disintegration time of greater than 30 minutes in a disintegration test according to test method USP <701>. The tablet can include approximately 1000 mg of ferric citrate, approximately 667 mg 0 of ferric citrate, approximately 500 mg of ferric citrate, approximately 250 mg of ferric citrate, or approximately 125 mg of ferric citrate. In various aspects, the LOD (loss on dried) % water in the tablet is less than 20% water w/w. In other aspects, the LOD % water of the tablet is less than 15% water w/w. In still other aspects, the LOD % water of the tablet is less than 10% water w/w. 5 In various aspects, at least 80% of the ferric citrate in the tablet is dissolved in a time less than or equal to 60 minutes as measured by test method USP <711>. In another aspect, the tablet includes a disintegrant. In certain embodiments, the disintegrant can be selected from one or more of microcrystalline cellulose, croscarmellose sodium, crospovidone, sodium starch glycolate, and starch. .0 In another aspect, the tablet includes a lubricant. In certain embodiments, the lubricant can be selected from one or more of magnesium stearate, calcium stearate, and sodium stearyl fumarate. In another aspect, the disclosure is directed to a method of preparing a ferric citrate tablet. The method includes mixing the ferric citrate with one or more binders under 25 conditions in which the LOD % water does not exceed 25% to form ferric citrate granules. Granulation can be performed by any method known in the art (e.g. fluid bed granulation or high shear granulation). The ferric citrate granules are then tableted. In another aspect, the tablets are heated to above 50'C after tableting. The tablets can be used for the prophylaxis or treatment of a variety of diseases or 30 disease states, including, but not limited to, hyperphosphatemia. Embodiments of the method can include one or more of the features described above or herein. -3- The details of various embodiments are set forth in the accompanying drawings and the description below. Features and advantages of various embodiments are apparent from the description, the drawings, and the claims. DESCRIPTION OF THE DRAWINGS 5 Those skilled in the art will understand that the drawings, described herein, are for illustration purposes only. The drawings are not intended to limit the scope of the present disclosure. Fig. 1 is a chart showing hardness as a function of compression force for Formulations 1-5. 0 Fig. 2 is a chart showing friability as a function of compression force for Formulations 1-5. Fig. 3 is a chart showing disintegration time as a function of compression force for Formulations 1-5. Fig. 4 is a chart showing dissolution time for Formulations 1 and 3-5. 5 Fig. 5 is a chart showing hardness as a function of compression force for Formulations 6-8 and 11. Fig. 6 is a chart showing friability as a function of compression force for Formulations 6-8 and 11. Fig. 7 is a chart showing disintegration time as a function of compression force for .0 Formulations 6-8 and 11. Fig. 8 is a chart showing dissolution time for Formulations 6-8 and 11. Fig. 9 shows the dissolution time different tablets that were pre-dried and post-dried. DETAILED DESCRIPTION Disclosed herein are ferric citrate-containing tablets. In various embodiments, the 25 tablets include ferric citrate formulations that meet certain dissolution, tableting and disintegration standards. In various aspects, the tablet formulations can include ferric citrate as the active ingredient and a binder. The formulations also can include a lubricant and/or a disintegrant (which, in some embodiments, can be the same as the binder). Tablets 30 In one aspect, the formulation is a tablet that includes ferric citrate and a binder. As is used herein, a "tablet" is a material produced by compression force, such as with a tableting machine. In other embodiments the formulation or tablet can include ferric citrate, a binder, a lubricant and a disintegrant. The tablet or formulation can be used as a prophylaxis or -4treatment for hyperphosphatemia by administering the tablet or formulation in an effective amount or amounts known in the art. The formulation can be characterized as highly drug loaded with the ferric citrate present in the formulation at values of greater than approximately 65 % by weight of the 5 formulation, greater than approximately 70% by weight of the formulation and as high as approximately 92% of the formulation. Intermediate values such as approximately 80% by weight ferric citrate, approximately 85% by weight ferric citrate and approximately 90% by weight ferric citrate also can be used in the ferric citrate formulation. The characteristics of the tablet produced at these highly loaded weight percentages are controlled by variables such 0 as binder, binder amount, disintegrant, disintegrant amount, formulation method used (e.g., granulation, direct compression), tableting parameters, etc. Thus if a tablet is made and it has a slight amount of lamination or capping, by varying one or more of the above variables, the lamination or capping can be corrected. In various embodiments, the tablet formulation contains one or more components 5 selected from among one or more binders, one or more lubricants, and one or more disintegrants. The binder can be any binder known in the art. Without limitation, examples of the binder can include one or more of hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), sodium alginate, alginic acid, guar gum, acacia gum, xanthan gum, .0 carbolpol, cellulose gum (carboxy methyl cellulose), ethyl cellulose, maltodextrin, PVP/VA, povidone, microcrystalline cellulose, starch (partially or fully pregelatinized starch) and methyl cellulose. The maltodextrin, PVP/VA, and methyl cellulose function as immediate release binders when used in the ferric citrate formulations. It also should be understood that combinations of binders can be used to control and 25 vary the effect of the binder. For example, a binder system can be made up of hydroxypropyl cellulose and polyvinyl pyrrolidone (povidone) with or without microcrystalline cellulose. One or both of the hydroxypropyl cellulose and povidone can be replaced with pregelatinized starch. In various aspects, the tablet can include a lubricant. As an example of a lubricant for 30 the ferric citrate formulations, magnesium stearate, calcium stearate, sodium stearyl fumarate and combinations can be used. Other suitable lubricants include one or more of polyethylene glycol (molecular weight above 3350), sodium lauryl sulfate, talc, mineral oil, leucine, and poloxamer. -5- In various aspects, the tablet can include a disintegrant. The disintegrant can be included in the formulation. The disintegrant can be the same as or different from the binder. By way of example and not limitation, microcrystalline cellulose has both binder and disintegrant properties and microcrystalline cellulose can be use as the sole 5 binder/disintegrant in the formulation. Examples of other suitable disintegrants include croscarmellose sodium, crospovidone, sodium starch glycolate, and starch. The binder can be present in the formulation in an amount ranging from approximately 4.5% by weight to approximately 30% by weight. The disintegrant can be present in the formulation in an amount ranging from approximately 1.5% by weight to 0 approximately 15% by weight. In various embodiments, some non-starch disintegrants are often used at lower ranges, e.g., as low as 0.25% and thus the disintegrant present in the formulation can be as low as 0.25% in some conditions. The lubricant can be present in the formulation in an amount ranging from approximately 0.5% by weight to approximately 3% by weight. It should be understood that 5 some components, such as microcrystalline cellulose, can function with both disintegrant and binder properties. The weight of individual tablets can depend upon the final dosage to be produced; e.g. 125mg, 250mg, 500mg, 667mg, 750mg and 1,000mg of Ferric citrate. In various embodiments, tablets are coated to a weight gain of approximately 2% to .0 5% using an Opadry suspension or equivalent in a perforated pan coater. As noted above, calcium stearate and Opadry purple can be replaced with or used with a different lubricant or coating system, respectively. Tablets Having High Surface Area Per Unit Mass In one variation, the disclosed tablets contain granule particle size having a 25 significantly higher mean surface area per unit mass than previous ferric citrate formulations. It has been discovered that the increased surface area per unit volume results in immediate release dissolution times (greater than 80% at 60 minutes after administration as determined by United States Pharmacopeia (USP) test <711, described in United States Pharmacopeia Compendium of Standards, USP 30 NF 25, Vol. 1 p. 276-284 (2007), which is incorporated 30 herein by reference in its entirety). Without wishing to be limited to a specific theory or mode of action, the increased granular surface area of granules in the tablet results in an increased amount of ferric citrate exposed to the solvent. The immediate release dissolution times are significantly reduced in a reduced tablet size. -6- In additional variations, the tablets disclosed herein can be designed to have a mean granule particle surface area to mass ratio equal to or greater than 1 square meter per gram. In further variations, the tablet has a mean granule particle surface area to mass ratio equal to or greater than 2 square meters per gram. In further variations, the formulation has a mean 5 granule particle surface area to mass ratio equal to or greater than 4 square meters per gram. In further variations, the formulation has a mean granule particle surface area to mass ratio equal to or greater than 6 square meters per gram. In further variations, the formulation has a mean granule particle surface area to mass ratio equal to or greater than 8 square meters per gram. In further variations, the formulation has a mean granule particle surface area to mass 0 ratio equal to or greater than 10 square meters per gram. In further variations, the formulation has a mean granule particle surface area to mass ratio equal to or greater than 15 square meters per gram. In further variations, the formulation has a mean granule particle surface area to mass ratio equal to or greater than 20 square meters per gram. In further variations, the formulation has a mean granule particle surface area to mass ratio equal to or 5 greater than 30 square meters per gram. In further variations, the formulation has a mean granule particle surface area to mass ratio equal to or greater than 40 square meters per gram. In further variations, the formulation has a mean granule particle surface area to mass ratio equal to or greater than 50 square meters per gram. The increased surface area per particle in a tablet resulted in a significantly increased dissolution rate. .0 In other variations, the tablets have reduced water content. In one embodiment, the granular water content as measured by LOD % is less than 20%. In another embodiment, the granular water content as measured by LOD % is less than 19%. In another embodiment, the granular water content as measured by LOD % is less than 18%. In another embodiment, the granular water content as measured by LOD % is less than 17%. In another embodiment, the 25 granular water content as measured by LOD % is less than 16%. In another embodiment, the granular water content as measured by LOD % is less than 15%. In another embodiment, the granular water content as measured by LOD % is less than 14%. In another embodiment, the granular water content as measured by LOD % is less than 13%. In another embodiment, the granular water content as measured by LOD % is less than 12%. In another embodiment, the 30 granular water content as measured by LOD % is less than 11%. In another embodiment, the granular water content as measured by LOD % is less than 10%. In another embodiment, the granular water content as measured by LOD % is less than 9%. In another embodiment, the granular water content as measured by LOD % is less than 8%. In another embodiment, the granular water content as measured by LOD % is less than 7%. In another embodiment, the -7granular water content as measured by LOD % is less than 6%. In another embodiment, the granular water content as measured by LOD % is less than 5%. As will be understood to those of skill in the art, in various embodiments LOD is a method of thermogravimetric moisture determination: In thermogravimetric processes the 5 moisture of a material includes substances that volatilize during warming, and therefore contribute to the material's loss of mass. Alongside water this may also include alcohol or decomposition products. When using thermogravimetric measurement methods (drying using infrared, halogen, microwaves or ovens) no distinction is made between water and other volatile components. 0 Friability Friability generally measures the mechanical strength of tablets. During the process of coating, transportation ,packing, and other processes. tablets can lose some weight. To measure the weight loss the samples are counted and weighed. In various embodiments, friability test is performed as described in United States 5 Pharmacopeia Compendium of Standards (2007), which is incorporated herein by reference in its entirety. Method of Making Tablets In one tableting method, the tablets can be prepared in three steps. First, granules of ferric citrate and binder are formed. Second, a lubricant is added to the formulation before .0 tableting. Third, the tablet is dried after an optional coating step. Granulation Ferric Citrate, such as pharmaceutical grade ferric citrate described, for example, in US patent# 6,903,235 B2, can be granulated by any method known in the art. Exemplary methods of granulation include fluid bed granulation, high shear granulation and direct 25 compression granulation. In embodiments in which the moisture of the formulation was brought to the level above 25% LOD at any point resulted in a substantially lower surface area per gram of particle. This can be accomplished, for example, by limiting the quantity of water introduced, or by air blowing and monitoring the amount of water in a formulation. 30 To increase the surface area to mass ratio of ferric citrate particles to greater than 1 square meter per gram, or in other embodiments greater than 10 square meter per gram, the moister content of the granules is maintained at below 25% LOD throughout formation of granules. In certain variations, the moister content of the granules is maintained at below -8- 24% LOD, 23% LOD, 22% LOD, 21% LOD, or 20% LOD, throughout formation of granules. Without wishing to be held to a particular mechanism or mode of action, it is hypothesized that keeping the amount of water below 25% LOD during granulation maintains 5 granules with a high surface area per mass ratio. The addition of water in higher amounts at any time during the granulation process results in formation of larger granules with a lower mean surface area to mass ratio. The lower surface area to mass reduces the dissolution rate below the rate for an immediate release formulation. The measured lower mean surface area to mass ratio of granules results in slower dissolution, and release characteristics. 0 In various embodiments, it has been observed that the reduced surface area to weight ratio of the ferric citrate formulation is irreversible after addition of moisture at above 25% LOD. Accordingly, the percent water is kept below 25% during granulation in various embodiments. Blending 5 In various embodiments, one or more lubricants can be blended with the granules. In various embodiments, a non-limiting list of lubricants includes stearates such as calcium stearate and magnesium stearate, sodium stearyl fumarate, stearic acid, talc, polyethylene glycol, hydrogenated vegetable oils, aluminum stearate, sodium benzoate, sodium acetate, sodium chloride, leucine, Carbowax, and Magnesium Lauryl Sulfate. Certain starches, such .0 as starch 1500, can also be considered lubricants, as they have some lubricant properties when used in direct compression application. Any lubricant known in the art can be used, including any of those disclosed in the Handbook of Pharmaceutical Excipients fifth edition, incorporated herein by reference in its entirety. Multiple lubricants can be combined. In certain embodiments, a greater quantity of lubricant than is ordinarily used in the 25 art can be used. It has been discovered that surprisingly, the quantity of lubricant must be higher than recommended or understood in the industry to reduce the quantity of sticking in the ferric citrate tablets. In certain variations, a combination of magnesium or calcium stearate and sodium stearyl fumarate is used as a lubricant. In further embodiments, the lubricant is a 30 combination of calcium stearate and sodium stearyl fumarate. In various embodiments, a greater quantity of calcium stearate than is recommended in the art can be used. As described in the Handbook of Pharmaceutical Excipients fifth edition, the recommended quantity of calcium stearate is a maximum of 1.0% w/w. In one embodiment, the quantity of calcium stearate is equal to or greater than 2.0% w/w. In another embodiment, the quantity of -9calcium stearate is equal to or greater than 2.2% w/w. In another embodiment, the quantity of calcium stearate is equal to or greater than 2.4% w/w. Likewise, in various embodiments, a greater quantity of sodium stearyl fumarate than the recommended 0.5 - 2.0% w/w concentration can be used. In one embodiment, the 5 quantity of sodium stearyl fumarate is greater than or equal to 2.1% w/w. In another embodiment, the quantity of sodium stearyl fumarate is greater than or equal to 2.2% w/w. In another embodiment, the quantity of sodium stearyl fumarate is greater than or equal to 2.3% w/w. In another embodiment, the quantity of sodium stearyl fumarate is greater than or equal to 2.4% w/w. In another embodiment, the quantity of sodium stearyl fumarate is greater than 0 or equal to 2.5% w/w. In another embodiment, the quantity of sodium stearyl fumarate is greater than or equal to 2.6% w/w. In another embodiment, the quantity of sodium stearyl fumarate is greater than or equal to 2.7% w/w. Post-Tableting Drying A drying step can be performed after tableting. In the absence of drying the tablet 5 after tableting, it was discovered that the dissolution rate of tablets increased over time. Drying maintained the immediate release characteristics of the ferric citrate tablets as disclosed herein. Without being limited to a specific mechanism or mode of action, it is believed that granule size increases due to the presence of residual water, and the drying step maintains the large surface area per unit weight of the original granules. .0 In one embodiment, the final granular water content as measured by LOD % is less than 20%. In another embodiment, the final granular water content as measured by LOD % is less than 19%. In another embodiment, the final granular water content as measured by LOD % is less than 18%. In another embodiment, the final granular water content as measured by LOD % is less than 17%. In another embodiment, the final granular water 25 content as measured by LOD % is less than 16%. In another embodiment, the final granular water content as measured by LOD % is less than 15%. In another embodiment, the final granular water content as measured by LOD % is less than 14%. In another embodiment, the final granular water content as measured by LOD % is less than 13%. In another embodiment, the final granular water content as measured by LOD % is less than 12%. In 30 another embodiment, the final granular water content as measured by LOD % is less than 11%. In another embodiment, the final granular water content as measured by LOD % is less than 10%. In another embodiment, the final granular water content as measured by LOD % is less than 9%. In another embodiment, the final granular water content as measured by LOD % is less than 8%. In another embodiment, the final granular water content as - 10 measured by LOD % is less than 7%. In another embodiment, the final granular water content as measured by LOD % is less than 6%. In another embodiment, the final granular water content as measured by LOD % is less than 5%. Examples 5 The following examples describe the preparation and properties of various dosage forms and methods described herein. It will be apparent to those skilled in the art that many modifications, both to materials and methods, can be practiced without departing from the scope of the disclosure. Example 1 0 The following exemplary formulations and formulation techniques for ferric citrate provide data showing characteristics for the formulations or tablets, including data such as dissolution, disintegration, and friability. The sources for some of the materials included: ferric citrate from Biovectra; silicified microcrystalline cellulose (Prosolv SMCC 50 and Prosolv SMCC HD90 which is 5 composed of microcrystalline cellulose, NF and colloidal silicon dioxide, NF) from JRS Pharma; pregelatinized starch, NF (Starch 1500) from Colorcon; Povidone, NF (Plasdone K 29/32) from ISP; hydroxypropyl cellulose, NF (Klucel EF) from Hercules; croscarmellose sodium, NF (Ac-Di-Sol SD-7 11) from FMC Biopolymer; and magnesium stearate, NF from Mallinckrodt. .0 The equipment used for the formulations included: FLM1 fluid bed from Vector Corporation of Marion, IA; Comil conical mill from Quadro Engineering of Millburn, NJ; GMX high shear granulator 4L bowl from Vector Corporation of Marion, IA; 2qt v-blender from Patterson Kelley of East Stroudsburg, PA; XL100 Pro tablet press from Korsch of South Easton, MA; capsule-shaped tooling from Elizabeth Carbide of Lexington, NC; and Sonic 25 sifter separator from Advantech Manufacturing of New Berlin, WI. The equipment used for the analytical testing of the formulations included: 8M Tablet Tester (hardness tester) from Dr. Schleuniger of Manchester, NH; Friabilator from VanKel of Palo Alto, CA; Flodex from Hanson Research of Chatsworth, CA; Bathless Disintegration System, Model 3106 and Bathless Dissolution System, Evolution 6100 from Distek of North 30 Brunswick, NJ; and Model 8453 Uv-Vis from Agilent of Santa Clara, CA. High Shear Granulation A series of experiments were conducted to determine the ability to use a high shear granulator to make a tablet blend having suitable characteristics. Formulations 1-3 are shown below in Tables 1-3. - 11 - Table 1 (Formulation 1) Component mg/tablet %w/w Milled Ferric Citrate 1190.3 75.0 Silicified microcrystalline 238.1 15.0 cellulose (Prosolv SMCC 50) Croscarmellose sodium 47.6 3.0 Hydroxypropyl cellulose 95.2 6.0 Magnesium stearate 15.9 1.0 Total 1587.0 100.0 Table 2 (Formulation 2) Component mg/tablet %w/w Milled Ferric Citrate 1190.4 60.0 Silicified microcrystalline 595.2 30.0 cellulose (Prosolv SMCC 50) Croscarmellose sodium 59.5 3.0 Hydroxypropyl cellulose 119.0 6.0 Magnesium stearate 19.8 1.0 Total 1984.0 100.0 Table 3 (Formulation 3) Component mg/tablet %w/w Milled Ferric Citrate 1190.3 69.0 Silicified microcrystalline 258.8 15.0 cellulose (Prosolv SMCC 50) Croscarmellose sodium 86.3 5.0 Hydroxypropyl cellulose 172.5 10.0 Magnesium stearate 17.3 1.0 Total 1725.0 100.0 The manufacturing procedure for the Formulations 1-3 were as follows. 5 Milled ferric citrate, hydroxypropyl cellulose, silicified microcrystalline cellulose, and croscarmellose sodium were mixed for 2 minutes at 500 rpm in a GMX high shear granulator 4 L bowl. Deionized water was added at an approximate rate of 18 g/min over 10 minutes, while mixing at a rate of 900 rpm with a chopper speed of 1500 rpm. The final (peak) moisture content was measured to be 24.3%, 23.8%, and 24.4%, respectively. The granules 10 were dried in a FLM1 fluid bed for 5-8 minutes at an inlet temperature of 65'C. The moisture content after drying was measured to be 14.3%, 15.5%, and 15.9%, respectively. The granules were screened through a 16 mesh hand-screen, then through a 25 mesh hand screen to remove over-sized granules and clumps. The magnesium stearate was screened - 12 through a 25 mesh hand-screen. Granules and magnesium stearate were blended for 2 minutes in a 2 quart v-blender. Tableting was performed on a Korsch tablet press with capsule shaped tooling. It was found that the resulting tablet blends demonstrated poor flow through the 5 hopper due to the irregular particle shape of the granules. Nonetheless, excellent tablets were able to be made using the tableting equipment. Example 2: Another series of experiments were conducted to determine whether a tablet could be formulated using a fluid bed granulation process: 0 Table 4 (Formulations 4 and 5) Component mg/tablet %w/w Milled Ferric Citrate 1190.7 90.0 Pregelatinized starch 119.1 9.0 Magnesium stearate 13.2 1.0 Total 1323.0 100.0 Manufacturing Procedure for Formulations 4 and 5 depicted in Table 4 are provided below as follows: Milled ferric citrate was added to a FLM1 fluid bed granulator. For Formulation 4, pregelatinized starch was added as a 10% w/w solution at a spray rate that increased from 24 5 g/min to 52 g/min over the duration of the run. [Inlet Temp = 64-77'C; Product Temp = 25 35'C; Process Air = 29-35 CFM]. The final (peak) moisture content was measured to be 32.5%. For Formulation 5, pregelatinized starch was added as a 10% w/w solution at an average spray rate of 40.8 g/min. [Inlet Temp = 69-75'C; Product Temp = 25-35'C; Process 20 Air = 24-38 CFM]. The final (peak) moisture content was measured to be 30.0%. The granules were dried for 7-10 minutes at an inlet temperature of 65'C. The moisture content after drying was measured to be 15.5% and 16.7%. Granules were milled through a Comil equipped with a 45R screen and square impeller at 1500 rpm. The magnesium stearate was screened through a 25 mesh hand-screen. Granules and magnesium 25 stearate were blended for two minutes in a two quart V-blended. Tableting was performed on a Korsch tablet press with capsule shaped tooling. - 13 - The primary difference between the tablets of Formulations 4 and 5 was the disintegration time. The tablets of Formulation 5 had a slower disintegration time than the tablets of Formulation 4. These prototypes had no flow problems during tableting. The powder properties of Formulations 1-5 were characterized as shown in Tables 5 5 and 6. All blends have excellent flow properties as measured by the Flodex. Table 5. Powder Characterization of High Shear Blends Measurement Formulation 1 Formulation Formulation 3 2 Bulk density 0.772 g/mL 0.618 g/mL 0.679 g/mL Flodex 4 5 10 Table 6. Powder Characterization of Fluid Bed Blends Measurement Formulation 4 Formulation 5 Bulk density 0.647 g/mL 0.578 g/mL Flodex 4 4 Experimental formulations of Formulations 1 and 5 were examined by Scanning 0 Electron Microscopy (SEM) and both samples have a similar particle size range. While the particles of Formulation 1 appeared to have a bimodal distribution, both samples have distinct particle morphologies. Formulation 1, which was prepared by high shear granulation, has more sharp, oblong particles. Formulation 5, prepared by fluid bed granulation, has more soft, round particles. This difference is believed to have an impact on the flow properties 5 observed during tableting. The tablet properties of Formulations 1-5 were characterized as shown in Table 7 and Table 8. Compaction profiles were made of each formulation, graphically presented in Figure 1 (hardness), Figure 2 (friability), and Figure 3 (disintegration). Characterization data is presented only of the tablets prepared at the highest compaction force. Compression force 20 is measured in kilo Newtons. Dissolution results are graphically presented in Figure 4 for Formulations 1 and 3-5. For the hardness testing, the tablets were tested according to USP <1217> for hardness/breaking strength. For the friability testing, the tablets were tested following USP <1216> for friability. For the disintegration testing, six tablets were tested using a 25 disintegration apparatus in deionized water at 37'C. For the dissolution testing, six tablets were tested for dissolution properties according to the conditions listed below. Tablet dissolution results were scaled to report 100% dissolution as a 1000 mg dose, correcting for actual average tablet weight, as needed. - 14 - Dissolution Conditions: Dissolution Instrument: Distek Evolution 6100 Medium: pH 4.0 McIlvaine buffer Apparatus USP: Apparatus II (paddle method); 100 rpm 5 Temperature: 37'C ± 0.5'C Time: Samples taken at 5, 15, 30, and 60 minutes UV-Vis Instrument: Agilent 8453 UV-Vis; 360 nm with 600 nm background correction. Table 7. Characterization of High Shear Experiments (Formulations 1-3) Measurement Formulation 1 Formulation 2 Formulation 3 Weight Average 1580.8 mg Average 1485.6 mg Average 1518.4 mg variation (0.5% RSD) (0.4% RSD) (0.7% RSD) Thickness Average 8.59 mm Average 8.37 mm Average 8.69 mm (0.2% RSD) (0.2% RSD) (0.4% RSD) Hardness 18.1 kP 19.5 kP 21.5 kP (2.6% RSD) (2.3% RSD) (3.8% RSD) Friability 0.19% 0.22% 0.26% Disintegration Average 5.8 Average 19.8 Average 3.0 minutes minutes minutes Dissolution 48.2% in 60 --- 49.7% in 60 minutes minutes 0 Table 8. Tablet Characterization of Fluid Bed Experiments (Examples 4 and 5) Measurement Formulation 4 Formulation 5 Weight variation Average 1286.5 mg Average 1313.2 mg (0.3% RSD) (0.4% RSD) Thickness Average 7.18 mm Average 7.24 mm (0.2% RSD) (0.2% RSD) Hardness Average 19.3 kP 20.5 kP (3.2% RSD) (7.4% RSD) Friability 0.20% 0.23% Disintegration Average 7.7 minutes Average 36.3 minutes Dissolution 50.4% in 60 minutes 42.5% in 60 minutes For the high shear prototypes (Formulations 1-3) incorporation of increased silicified microcrystalline cellulose (Formulation 1 and Formulation 2) improved compactibility, as shown by reduced compression forces required to achieve equivalent hardness. Also, incorporation of increased hydroxypropyl cellulose (Formulations 1, 2, and 3) improved 15 compactibility, as shown by reduced compression forces required to achieve equivalent hardness. - 15 - Example 4 Additional development was conducted to achieve a balance between dissolution profile and acceptable tablet properties. The fluid bed granulation spray rate was varied step wise using pregelatinized starch, which showed that in-process moisture content plays a role 5 in dissolution profile and tablet properties. Fluid Bed Granulation with Starch Batches of Formulations 6-11 shown in Tables 9 and 10 were prepared using pregelatinized starch with target batch sizes of 1.0 kg. Table 9. Formulation Formulations 6-8 Component mg/tablet %w/w Milled Ferric Citrate 1190.7 90.0 Pregelatinized starch 119.1 9.0 Magnesium stearate 13.2 1.0 Total 1323.0 100.0 0 Table 10. Formulation Formulations 9-11 Component mg/tablet %w/w Milled Ferric Citrate 1190.7 80.9 Pregelatinized starch 119.1 8.1 Silicified microcrystalline cellulose 147.2 10.0 Magnesium stearate 13.2 1.0 Total 1470.2 100.0 Formulations 6-11 were manufactured as follows: Milled Ferric Citrate was added to a FLM 1 fluid bed granulator. Pregelatinized starch was added as a 10% w/w solution using the granulation and drying parameters in Table 11. 15 All batches were dried at an inlet temperature of 65'C. Table 11. Granulation Parameters Parameter Formulation 6 Formulations Formulations and9 7and10 8and11 Spray rate 24.0 g/min 32.5 g/min 37.5 g/min Inlet temp 69-79 0 C 72-75 0 C 69-76 0 C Product temp 26-35 0 C 26-36 0 C 26-35 0 C Process air 31-36 CFM 32-38 CFM 36-39 CFM Final (peak) moisture 17.3% 23.4% 25.7% Moisture after drying 14.8% 16.1% 17.5% Drying time 2 minutes 5 minutes 7 minutes - 16 - Granules from Formulations 6, 7, 9 and 10 were screened through a 20 mesh hand screen. Granules from Formulations 8 and 11 were milled through a Comil equipped with a 45R screen and square impeller at 1500 rpm, then screened through a 20 mesh hand-screen. Two blends were prepared from each granulation. In the first blend, the magnesium 5 stearate was screened through a 25 mesh hand-screen. Granules and magnesium stearate were blended for two minutes in a two quart V-blender. In the second blend, the magnesium stearate was screened through a 25 mesh hand-screen. Granules, silicified microcrystalline cellulose, and magnesium stearate were blended for two minutes in a two quart V-blender. Tableting was performed on a Korsch tablet press with capsule shaped tooling on 0 several of the prepared blends. The resulting tablets of Formulations 6 and 9 had flow properties with Hausner ratio values equal to or less than 1.25 and/or Carr index values equal to or less than 25. In various embodiments, the Hauser ratio is equal to or less than 1.20. In further embodiments, the Hauser ratio is equal to or less than 1.20. In various embodiments, the Carr index is less than 5 25. In further embodiments, the Carr index is equal to or less than 20. Excellent flow: Hausner ration values about or less than 1.20 and Carr index values less than 20)but showed evidence that additional lubrication was needed to achieve better tableting results. The resulting tablets of Formulations 7, 8, 10 and 11 had excellent flow properties and made successful tablets. .0 The powder properties of Formulations 6-11 were characterized as shown in Tables 12 and 13. Formulations 7, 8, 10 and 11 have flow properties with Hauser ratios equal to or less than 1.20 and Carr index values less than 20 as measured by the Flodex, presumably due to the higher spray rates of those experiments. The bulk density of the starch granulation experiments increased as the spray rate increased. 25 Table 12. Powder Characterization of Fluid Bed Experiments Measurement Formulations 6 Formulations 7 Formulations 8 and9 and 10 and11 Bulk density 0.475 g/mL 0.531 g/mL 0.698 g/mL Flodex 7 4 4 The tablet properties of Formulations 6-8 and 11 were characterized as shown in Table 13 and 14. Compaction profiles were made for each formulation and are graphically presented in Figure 5 (hardness), Figure 6 (friability) and Figure 7 (disintegration). 30 Characterization data is presented only of the tablets prepared at the highest compaction force. Dissolution results are graphically presented in Figure 8 for Formulations 6-8 and 11. - 17 - Table 13. Tablet Characterization of High Shear Formulations 6 and 7 Measurement Formulation 6 Formulation 7 Weight variation Average 1126.9 mg (0.4% Average 1272.8 mg (0.4% RSD) RSD) Thickness Average 7.74 mm (0.2% RSD) Average 8.00 mm (0.5% RSD) Hardness Average 11.2 kP (28.7% RSD) 27.2 kP (8.9% RSD) Friability 2.23% 0.36% Disintegration Average 1.8 minutes Average 3.9 minutes Dissolution 99.9% in 60 minutes 95.7% in 60 minutes Table 14. Tablet Characterization of Fluid Bed Formulations 8 and 11 Measurement Formulation 8 Formulation 11 Weight variation Average 1332.0 mg (0.3% RSD) Average 1497.7 mg (0.3% RSD) Thickness Average 7.94 mm (0.1% RSD) Average 8.72 mm (0.1% RSD) Hardness Average 21.1 kP (2.8% RSD) 26.1 kP (2.9% RSD) Friability 0.28% 0.15% Disintegration Average 11.7 minutes Average 8.3 minutes Dissolution 55.8% in 60 minutes 65.6% in 60 minutes 5 Milled Ferric Citrate and croscarmellose sodium were added to a FLM1 fluid bed. Povidone was added as a 30% w/w solution (Formulation 12) and 20% w/w solution (Formulation 13) using the granulation and drying parameters in Table 15 to make granules. No drying was required. Table 15. Granulation Parameters Parameter Formulation 12 Formulation 13 Spray rate 22.9 g/min 30.0 g/min Inlet temp 55-60 0 C 52-58 0 C Product temp 31-37 0 C 22-30 0 C Process air 31-36 CFM 35-38 CFM Final (peak) moisture 13.0% 17.3% 10 Granules were screened through a 20 mesh hand-screen. The magnesium stearate was screened through a 25 mesh hand-screen. Granules and magnesium stearate were blended for two minutes in a two quart V-blender. Tableting was performed on a Korsch tablet press. During the tableting process, there was excessive sticking to the tooling. This sticking was believed to be addressable by use of 15 different tooling or by varying the tableting parameters. - 18 - Example 6 Additional examples were formulated and analyzed. A summary of the results are provided below in Tables 16 and 17. Table 16 provides a summary of results for Formulations 14-20 using direct compression of the formulations. Table 17 provides a 5 summary of results for Formulations 21-29 using fluid bed granulation. These various formulations showed a variety of ranges of properties that could be useful depending upon the application, e.g., immediate release, extended release, and delayed release, with a minor amount of additional experimentation required for some of the formulations to ensure that suitable tablets are formed. - 19 - Table 16. Qualitative Results for Direct Compression Formulations Experiment Dose Formulation Summary Results and Observations Reference Target Formulation 667 mg 91.9% Ferric Citrate, Tablets had some lamination, 14 7.3% Prosolv SMCC 50, achieved 12.5 kP average 0.8% Magnesium Stearate hardness Formulation 667 mg 91.9% Ferric Citrate, Friability equal to or less than 15 7.3% Prosolv HD 90, 1.0% w/w. 0.8% Magnesium Stearate Formulation 667 mg 87.0% Ferric Citrate, Friability equal to or less than 16 7.3% Prosolv SMCC 50, 1.0% w/w. 4.9% Povidone K-29/32, 0.8% Magnesium Stearate Formulation 500 mg 90.7% Ferric Citrate, Tablets show capping and 17 8.5% Prosolv HD 90, lamination addressable with 0.8% Magnesium Stearate additional binder or varying the tableting parameters Formulation 500 mg 90.7% Ferric Citrate, Tablets show capping and 18 8.0% Prosolv HD 90, lamination addressable with 0.5% Povidone K-29/32, additional binder or varying the 0.8% Magnesium Stearate tableting parameters; long disintegration times Formulation 500 mg 88.0% Ferric Citrate, Tablets show capping and 19 7.0% Avicel PH 200, lamination addressable with 2.7% Povidone K-29/32, additional binder or varying the 1.5% Crospovidone XL, tableting parameters; 0.8% Magnesium Stearate disintegration time reduced to 1-3 minutes suitable for immediate release applications Formulation 500 mg 87.0% Ferric Citrate, Tablets show reduced lamination 20 7.0% Avicel PH 200, that was addressable with 3.7% Povidone K-29/32, additional binder or varying the 1.5% Crospovidone XL, tableting parameters, 0.8% Magnesium Stearate disintegration time 3-5 minutes suitable for immediate release I applications - 20 - Table 17. Qualitative Results for Fluid Bed Granulation Formulations Experiment Dose Formulation Summary Results and Observations Reference Target Formulation 500 mg 90.0% Ferric Citrate, Friability equal to or less than 21 2.0% Povidone K-29/32, 1.0% w/w. 2.0% Starch 1500, 5.2% Avicel PH 102, 0.8% Magnesium Stearate Formulation 500 mg 90.0% Ferric Citrate, Acceptable tablet properties with 22 4.0% Starch 1500, additional development work 5.2% Avicel PH 102, needed for tablet integrity 0.8% Magnesium Stearate Formulation 500 mg 90.0% Ferric Citrate, Tablets have disintegration to be 23 9.0% Starch 1500, more than 15 minutes. 1.0% Magnesium Stearate Formulation 500 mg 90.0% Ferric Citrate, Tablets have disintegration to be 24 4.0% Starch 1500, more than 15 minutes. 5.2% Avicel PH 102, 0.8% Magnesium Stearate Formulation 500 mg 80.0% Ferric Citrate, Tablets have disintegration to be 25 8.0% Starch 1500, more than 15 minutes. 11.0% Avicel PH 200, 1.0% Magnesium Stearate Formulation 500 mg 90.0% Ferric Citrate, Tablets have disintegration to be 26 9.0% Starch 1500, more than 15 minutes. 1.0% Magnesium Stearate Formulation 500 mg 85.0% Ferric Citrate, Tablets have disintegration to be 27 8.5% Starch 1500, more than 15 minutes. 5.5% Avicel PH 200, 1.0% Magnesium Stearate Formulation 1000 84.9% Ferric Citrate, Granulation very dense 28 mg 5.6% Starch 1500, 8.6% Avicel PH 200, 1.0% Magnesium Stearate Formulation 1000 89.5% Ferric Citrate, Acceptable tablet properties with 29 mg 5.9% Starch 1500, tableting and coating successful 3.6% Avicel PH 200, 1 1 1 ___1.0% Magnesium Stearate 1 Example 7 Tables 18a and 18b provide Formulation 29 and 30 for an exemplary ferric citrate 5 drug product. - 21 - Table 18a. Formulation for a Ferric Citrate Drug Product Material Description Theetical % w/w Ferric Citrate 14.89 87.6 Pregelatinized Starch 1.70 10.0 Calcium Stearate 0.406 2.4 Purified Water 15.30* N/A** Core Tablet Total 17.00 100.0 Opadry Purple 03K100000 0.51 15.0 Purified Water 2.89* 85.0** Coated Tablet Total 17.5 100.0 *Purified water is removed during the drying phase. 5 Table 18b: Formulation for a Ferric Citrate Drug Product Material Description Theoretical % w/w Ferric Citrate 14.87 85.0 Silicified Microcrystalline 0.70 4.0 Cellulose Pregelatinized Starch 1.58 9.0 Calcium Stearate 0.35 2.0 Purified Water 14.18 N/A* Core Tablet Total 17.5 100.0 Opadry Purple 03K100000 0.51* 15.0 Purified Water 2.89* 85.0** Coated Tablet Total 18.0 100.0 Table 19 provides a proposed ferric citrate drug product formulation that can be used in the manufacturing process described below. 10 Table 19. Formulation 31 Material Theoretical % w/w to Core % w/w Coated Description 100 kg/Lot Tablet Tablet Ferric Citrate 80.0 - 90.0 80.0 - 90.0 76.2 - 88.2 Pregelatinized 8.0-15.0 8.0-15.0 7.6-14.7 Starch Calcium Stearate 2.0-3.0 2.0-3.0 1.9-2.9 Purified Water N/A* N/A* N/A* Core Tablet Total 100.0 100.0 N/A* Opadry Purple 5.3 15.0 2.0-5.0 03K100000 Purified Water 30.0* 85.0* N/A* Coated Tablet 35.3 100.0 100.0 Total *Purified water is removed - 22 - (1) or other binders as listed in the patent (2) or other lubricants as listed in the patent (3) or other coating system as listed in the patent 5 Example 8 The drug product tablet was produced using fluid bed granulation of the screened API with a binder suspension of pregelatinized starch, targeting for a moisture content after granulation of approximately 13-20%. The granulated active was subsequently blended with 0 screened calcium stearate and the mix compressed to form a tablet core. The tablet was robust with friability equal to or less than 1.0% w/w, hardness from 8 - 20 kP, disintegration equal to or less than 15 min, and compression force about 3.5 - 5.0 kN, with a main force 5 20 kN. It will be recognized that various embodiments are within the ranges of one or more of each of these parameters. 5 The weight of individual tablets can depend upon the final dosage to be produced; e.g., 125mg, 250mg, 500mg, 667mg, 750mg and 1,000mg of Ferric citrate. The process is capable of consistently producing tablets within a specification of ± 5 % of target. The tablet thickness and hardness meet the specified acceptance criteria. The tablets are coated to a target weight gain of approximately 2% to 5% using an Opadry suspension or equivalent in a .0 perforated pan coater. The production results demonstrate the selected formulation and process is capable of producing robust tablets meeting the specified criteria. First, ferric citrate was passed through a screening mill. A granulation drug binder suspension was then prepared by adding purified water to a stainless steel mixing kettle, then adding pregelatinized starch to the 25 purified water and mix. Granulated particles were formed by screening ferric citrate through a fluid granulator. The pregelatinized starch binder suspension was sprayed into the fluidized product bed. At the completion of binder addition the granulation is dried. The dried granules were charged into a diffusion mixer. Calcium stearate was screened and added to the granulation in the diffusion mixer. The granules and lubricant were 30 mixed. The lubricated granules were compressed into tablets. Tablets were collected in intermediate bulk containers. An aqueous film coating suspension was prepared in a stainless steel kettle and mixer,. The tablets were charged into a fully perforated pan coater, and the coating suspension was sprayed onto the cascading product bed. Upon completion of the 35 spraying step the tablets were dried. Film coated tablets were discharged into intermediate - 23 bulk containers. The film coated tablets were packaged in HPDE bottles with desiccant and child resistant foil induction seal cap. Example 9 Ferric citrate tablets were formulated as described above. Tablet formulations 32 and 33 are 5 depicted in Tables 20 and 21. Table 20: Formulation 32 % w/w % w/w Coated Material Description kg/Batch T0 orial Individual Tablet Ferric Citrate 14.9 80.0 - 90.0 80.0 - 90.0 76.2 - 88.2 Pregelatinized Starch 1.7 8.0-15.0 8.0-15.0 7.6-14.7 Calcium Stearate (1) 0.4 1.0-3.0 1.0-3.0 0.9-2.9 OR - Sodium Stearyl 0.4 2.0-3.0 2.0-3.0 1.9-2.9 Fumarate (1) Purified Water 15.3* 72.0-135.0* * * Core Tablet Total 17.0 100.0 100.0 N/A* Opadry Purple 0.9 5.3 15.0 2.0-5.0 Purified Water 5.1* 30.0* 85.0* N/A* Coated Tablet Total 17.5 to 17.9 35.3 100.0 100.0 (1) - use either calcium stearate or sodium stearyl fumarate as lubricant *Purified water is removed - 24 - Table 21: Formulation 32 % w/w % w/w Coated Material Description kg/Batch T0 orial Individual Tablet Ferric Citrate 14.9 80.0 - 90.0 80.0 - 90.0 76.2 - 88.2 Pregelatinized Starch 1.6 8.0-12.0 8.0-12.0 7.6-11.5 Silicified Microcrystalline 0.7 3.0 - 5.0 3.0 - 5.0 2.5 - 4.5 Cellulose Calcium Stearate (1) 0.4 1.0-3.0 1.0-3.0 0.9-2.9 OR - Sodium Stearyl 0.4 2.0-3.0 2.0-3.0 1.9-2.9 Fumarate (1) Purified Water 15.3* 72.0-135.0* * * Core Tablet Total 17. 6 to 18.0 100.0 100.0 N/A* Opadry Purple 03K100000 0.9 5.3 15.0 2.0-5.0 Purified Water 5.1* 30.0* 85.0* N/A* Coated Tablet Total 17.8 to 18.9 35.3 100.0 100.0 (1) - use either calcium stearate or sodium stearyl fumarate as lubricant *Purified water is removed 5 Example 10 A ferric citrate tablet was made under conditions in which granulation was conducted by allowing the LOD water % to increase above 25%. Pharmaceutical grade ferric citrate was added into a fluid bed granulator. Pregelatinized starch binder suspension (Pregelatinized starch + water) was sprayed into the fluidized 10 product bed. The water moisture level of the formulation was allowed to exceed 25% by LOD (loss on dried method). In embodiments in which the moisture of the formulation was brought to the level above 25% LOD at any point resulted in a substantially lower surface area per gram of particle. Referring Table 22, the increase the moisture provided during manufacturing 15 increased above 20% at 120 minutes, increased to 27.87% at 170 minutes. - 25 - Table 22 Granulation Operating Parameters Time Rate Pump Inlet Inlet Product Atom LOD Exhaust (g/min) Speed Air Temp Temp Air (%) Temp (rpm) (scfm) (C) ( 0 C) (psi) ( 0 C) 0 - - 145 42 35.8 65.0 11.85 30.6 10 87.7 30 150 61.6 30.0 65.0 12.82 28.4 20 71.2 30 153 63.5 28.2 65.0 13.02 26.6 30 76.2 30 153 63.1 27.5 64.7 13.18 25.8 40 77.7 30 144 63 27.1 65.1 15.19 25.4 50 75.9 30 146 63.1 27.0 65.1 15.7.0 25.3 60 79.6 30 147 63.0 26.8 65.1 15.74 25.2 71 80.0 30 144 62.9 26.7 65.1 - 25.1 80 83.4 33 149 63.0 26.7 65.1 17.31 25.1 90 90.5 33 151 63.0 26.5 65.1 18.49 25.0 100 90.4 33 152 63.0 26.5 65.1 18.64 24.9 110 90.5 33 153 63.0 26.4 65.1 18.99 24.8 120 90.5 33 150 63.0 26.4 65.1 22.89 24.8 130 90.4 33 144 63.0 26.3 65.1 22.47 24.8 141 91.1 33 153 63.0 26.3 65.1 24.25 24.7 150 90.2 33 152 63.0 26.2 65.1 25.41 24.7 160 91.8 33 153 62.9 26.2 65.0 26.03 24.7 170 89.6 33 154 63.0 26.2 65.1 27.89 24.7 180 90.7 33 149 63.0 26.2 65.1 27.47 24.7 190 - - 147 63.0 26.4 - 26.76 24.7 200 - - 150 63.0 26.8 - 25.00 25.0 210 - - 154 63.1 27.2 - 22.37 25.1 220 - - 153 63.1 27.8 - 21.32 25.2 230 - - 149 63.1 29.0 - 18.68 25.7 240 - - 153 63.1 30.7 - 17.55 26.5 Final 16.69 LOD The measured surface area of two samples prepared using the above formulation is 5 depicted in Table 23. The surface areas of the formulations were 0.12 m 2 /g and 0.20 m 2 /g. Table 23 Sample Sample 1 BET Sample 2 BET Surface Area (m 2/g) Surface Area (m 2 /g) Pre- 27.99 32.34 granulation(API+ProSolv) PostGranulation 0.12 0.20 10 The mean surface area per unit mass ratios of the two samples was 0.12 and 0.20 m2 respectively. - 26 - Example 11 A ferric citrate tablet was prepared by keeping granules at an LOD % water concentration less than 25% during granulation. Pharmaceutical grade ferric citrate was added into a fluid bed granulator. 5 Pregelatinized starch binder suspension (Pregelatinized starch + water) was sprayed into the fluidized product bed. With reference to Table 24, the moisture level of the formulation was maintained at below 20% by LOD (loss on dried method) at all times during the spraying process. The surface area of the resulting formulation was greater than 10 square meters per gram. 0 Table 24 Time Spray Pump Inlet Inlet Product Atom Exhaus LOD (min) Rate Speed Air Temp Temp (C) Air t Temp (%) (g/min) (rpm) (SCFM) (-C) (psi) (OC) 0 - - 149 55.4 39.8 - 44.5 12.05 10 86.1 31 153 70.3 36.0 65.0 39.6 12.44 20 88.2 31 152 70.1 32.0 64.9 35.4 13.01 30 87.9 31 146 69.8 30.0 65.1 36.6 13.38 40 90.1 31 153 70.0 28.9 64.8 30.6 13.80 50 85.2 31 151 70.0 28.6 65.1 29.8 14.36 60 87.5 31 144 70.0 28.2 65.1 28.9 15.03 70 89.0 31 153 72.5 28.1 65.1 28.4 16.49 80 87.0 31 145 75.9 28.4 65.1 28.3 16.34 90 88.7 31 153 78.5 28.9 65.1 28.5 17.25 100 94.0 31 149 80.3 29.2 64.9 28.5 17.43 110 82.5 31 153 80.2 29.2 65.1 28.4 19.60 120 78.3 25 152 79.9 30.0 64.9 28.9 19.08 130 66.4 25 153 79.9 29.2 64.9 28.4 19.24 141 66.3 25 152 79.8 29.8 65.1 28.6 19.29 150 66.1 25 153 80.2 29.7 64.9 28.7 18.44 160 65.7 25 152 80.1 29.6 65.1 28.5 18.43 170 66.1 25 153 80.1 30.0 65.1 28.8 18.85 181 57.7 25 152 79.9 29.4 64.8 28.4 191 76.9 25 154 80.0 29.4 65.0 28.3 16.70 200 63.9 25 153 80.0 30.2 65.0 28.7 18.64 210 - - 150 74.6 31.0 - 28.0 16.97 220 - - 150 80.7 37.1 - 31.7 14.95 Final 13.30 LOD= The results showed a reduced surface area between the pre-granulated and granulated materials (see the Table 25). The results are depicted in Table 25, Sample 1. Table 25, 15 samples 2 and 3 also show a surface area of over 10 m 2/g, which corresponds to rapid - 27 immediate release formulation characteristics as described herein. The difference in granule particle size is nearly two orders of magnitude over granules that were prepared with increased water as measured by LOD%. Table 25 Sample Sample 1 BET Sample 2 BET Sample 3 BET Surface Area (m 2/g) Surface Area (m 2 /g) Surface Area (m 2 /g) Pre- 28.87 28.87 28.87 granulation(API+ProSolv) PostGranulation 11.85 14.03 10.18 PTLReportNumber 19005 19005 19005 5 A significant increase in particle surface area corresponding to a reduction in particle size. Tablets with higher granular surface area faster dissolution rate when compared to tablets prepared with a lower surface area per unit weight. Calcium stearate and sodium stearyl fumarate were added as lubricants. The quantity 0 used in the formula are beyond the quantities recommended in the art (e.g. Handbook of Pharmaceutical Excipients fifth edition). 0.5% w/w of sodium stearyl fumarate 2.4% w/w of calcium stearate was used. Example 12 5 A ferric citrate tablet was produced for clinical study as described above. The quantities of tablet components used are depicted in Table 26. Table 26 Material Description Target kg/Batch % w/w Individual Ferric Citrate 14.89 87.6 Pregelatinized Starch 1.70 10.0 Calcium Stearate (1) 0.406 2.4 Purified Water 15.30 N/A Core Tablet Total 17. 00 100.0 Opadry Purple 0.51 15.0 Purified Water 2.89 85.0 Coated Tablet Total 17.5 100.0 - 28 - Pregelatinized starch was sprayed into a chamber maintained at inlet temperature and product temperature. The LOD % water at every stage of preparation was maintained under 20%. The parameters used during the formulation are disclosed in Table 27. Table 27 Tim Spray Pump Inlet Inlet Product Atom Exhaus LOD e Rate Speed Air Temp Temp (C) Air t Temp (%) (min (g/min) (rpm) (SCF (-C) (psi) (OC) M) 0 - 38 150 61.5 42.6 60 11.24 41.3 10 107.6 38 151 63.0 31.3 60 12.4 34.5 20 109.1 38 151 63.1 27.1 60 13.32 29.5 30 109.5 38 150 63.0 26.1 60 14.37 27.5 40 109.5 38 151 63.0 25.5 60 15.64 26.4 50 109.6 38 151 62.9 25.3 60 16.99 25.7 60 109.5 38 152 69.4 25.9 60 17.66 25.5 71 109.9 38 153 72.8 26.9 60 19.35 26.3 80 94.7 30 153 72.3 26.9 60 17.05 26.3 90 91.0 35 151 71.7 27 60 19.66 26.3 100 88.5 30 152 72.1 27.1 60 19.57 26.3 110 81.7 30 150 73.3 27.4 60 18.88 26.4 120 85.7 33 153 73.2 27.7 60 16.39 26.6 130 97.9 35 149 72.4 27.4 60 18.87 26.5 141 94.5 33 152 72.0 27.4 60 18.78 26.3 150 93.3 34 153 71.9 27.3 60 18.62 26.3 160 93.4 34 152 71.8 27.5 60 18.30 26.3 170 95.6 34 154 72.2 27.5 60 19.49 26.4 180 - - 151 71.9 29.5 - 16.71 26.8 5 The targeted peak moisture between 19 - 20 % (LOD) was achieved with a moisture content of 19.66% (LOD). Table 28 and Table 29 summarize the physical properties after the granulation step and after the tableting and drying steps. 10 Table 28: Granulation Characteristics ScreenSize %Retained 35(500[tm) 0.0 45(355 [m) 1.3 60(250[tm) 11.1 80(180 [m) 16.2 120(125 [m) 19.4 170(90 jm) 16.0 230(63 jm) 16.3 Pan 18.8 -29 - Table 29: Final blend (post-tableting and drying) characteristics BulkDensity(g/ml) 0.460 TappedDensity(g/ml) 0.566 HausnerRatio 1.23 Carrlndex 19 Table 30and Table 31 summarize the final blend characteristics of the formulations. 5 Table 30: Final Blend Characteristics ScreenSize % Retained 35(500[tm) 0.0 45(355 [m) 0.8 60(250 [m) 10.8 80(180jm) 16.6 120(125 [m) 20.3 170(90 jm) 17.2 230(63 [m) 15.6 Pan 17.0 Table 31: Test Results BulkDensity(g/ml) 0.436 TappedDensity(g/ml) 0.573 HausnerRatio 1.31 Carrlndex 24 Table 32: AttributeorSetting Start Middle End PressMainForce(kN) 9.9 9.9 PressPreForce(kN) 3.5 4.0 PressSpeed(rpm) 28.69 28.69 Friability(%) 0.2 - Disintegration(seconds) 88 95 105 10 Table 33 Characteristic Weight Thickness Hardness Mean 1161 7.709 15.7 StandardDeviation 9.39 0.029 1.13 MinIndividual 1150 7.680 13.8 MaxIndividual 1186 7.800 18.0 RSD 0.81 0.38 7.20 Cpk 1.88 2.21 1.26 The compression data demonstrates that the subject formulation and process were capable of producing a robust tablet with rapid disintegration. The Cpk value for individual tablet weight 15 demonstrates the process was capable of consistently producing tablets within a specification of ± 5 % of target. The tablet thickness and tablet hardness met the specified acceptance criteria. -30- Coating and Drying Operating Parameters: The Opadry coating suspension was prepared to 15 % solids content by weight. The theoretical weight gain for the subject batch was 3 %. The film coating was a non-functional component used for aesthetics purposes only and therefore the actual weight gain was not 5 critical to drug performance. The process sprayed to the theoretical quantity of coating suspension and not to a specific weight gain (an efficiency factor was not used). The average coated tablet weight post drying 1110 mg. The operating parameters in Table 34 were used during the coating process: Table 34 Time AirFlow Inlet Dew Exhaust Spray Atom Pan (min.) (cfm) Temp Point Temp ('C) Rate Air Speed

(

0 C) ( 0 C) (g/min) (psi) (rpm) 0 308 55.0 4.9 33.2 45 37 10 15 317 46.0 5.6 36.4 48 37 10 30 307 45.1 6.3 37.3 44 37 10 45 309 50.4 7.6 34.6 40 37 10 60 307 44.4 7.6 36.7 51 37 10 75 310 52.9 7.5 37.3 53 37 10 0 The operating parameters in Table 35 were used during the final tablet drying process: Table 35 Time (min) Air Flow Inlet Temp DewPoint Exhaust %Water (cfm) ( 0 C) ( 0 C) Temp( 0 C) (LOD) 0 503 70.2 7.3 50.6 13.19 15 504 69.7 7.2 63.3 11.93 30 494 69.6 7.2 65.4 11.33 45 502 69.6 7.0 66.3 11.14 60 500 70.4 6.8 67.0 10.14 75 502 80.1 7.0 73.0 9.73 90 501 80.2 7.0 74.5 9.59 105 505 79.7 6.8 75.4 8.96 120 509 81.1 6.8 75.7 8.78 135 510 81.2 6.6 76.2 8.21 150 505 81.1 6.7 76.5 7.88 15 The dissolution profiles demonstrate that higher moisture levels in the tablet can reduce the dissolution rate over time. Tablets with high moisture content exposed to high temperature experienced accelerated reductions in dissolution rate. The post dried tablet, which had an end moisture content of 8.84 % (LOD), did not experience the same reduction in dissolution rate. The tablets containing high moisture level and calcium stearate 20 experienced the greatest reduction in dissolution rate. -31 - The core and coated tablets containing calcium stearate had slightly higher moisture contents (-15 % LOD) when compared to the core tablets containing sodium stearyl fumarate (~14 % LOD). Without wishing to be held to a particular theory or mode of action, this could be contributing to the difference in the observed dissolution rates. The final moisture content 5 of the tablet and moisture in the tablet during manufacture appear to contribute to the immediate release characteristics and long term stability of the tablet. The one month stability profile of pre-dried and post dried tablets stability were measured. The stability included both 25'C/60 % RH and 40'C/75% RH conditions. All samples were placed into HDPE bottles (0.025" wall thickness) with a foil induction seal cap, 0 and a small portion of the study included bottles with desiccants. The following charts summarize the informal stability data. With reference to Figure 9, the immediate dissolution rate (greater than 80% at 60 minutes after administration) of tablets exposed to the post-dry process was maintained. The dissolution rate reduced dramatically after one week at in the absence of the post-dry process. 5 Example 13: Clinical Study of Ferric Citrate Dosage Forms A protocol for performing clinical studies of a ferric citrate drug formulation as described above is provided as follows. The protocol includes a 6-Week Feasibility Trial of a New Formulation of KRX-0502 (Ferric Citrate) in Patients with End-Stage Renal Disease (ESRD). The objective of the study .0 is to determine the potential efficacy as a dietary phosphate binder and tolerability of KRX 0502 (ferric citrate) in controlling and managing serum phosphorus levels in patients with end-stage renal disease (ESRD) and monitoring the change in serum phosphorus from baseline to end of treatment after a four week treatment period. The study design includes conducting the study of the drug in patients with ESRD on 25 thrice weekly hemodialysis. Approximately 24 patients (twelve diabetic and twelve non diabetic patients) will be initiated on study drug over two to three weeks. The study consists of five periods: Screening, Washout, Study Drug Initiation, Treatment, and Final Visit. The two-week washout period is immediately followed by a six week treatment period. The duration of the clinical trial is approximately three to four 30 months with approximately two to three weeks being allocated for patient screening, washout, and initiation of the study drug. The study population includes all ESRD patients on thrice weekly hemodialysis for at least three months prior to the Study Drug Initiation Visit (Visit 3) who are currently taking at least three tablets/capsules per day of calcium acetate, calcium carbonate, lanthanum - 32 carbonate or sevelamer (hydrochloride or carbonate) or any combination of these agents will be eligible for enrollment. Approximately twelve patients will be diabetic and twelve patients will be non-diabetic. Approximately 24 to 48 patients will be screened to initiate approximately 24 patients on study drug. All patients will be recruited from 2-4 sites. 5 The study for the drug administration includes initiating approximately 24 patients on KRX-0502 (ferric citrate) following a two week washout period from their current phosphate binder and monitoring the serum phosphorus level during the study. The target level of serum phosphorus is approximately 3.5 to 5.5 mg/dL. The serum phosphorus levels will be checked weekly during the washout period and during the visits 4, 5, 6, and at the Final Visit 0 (Visit 7) of the treatment period The KRX-0502 dosage is determined by initiating all patients on the study drug with a fixed dosage of 6 tablets per day with each tablet of ferric citrate containing 210 mg of ferric iron as ferric citrate (approximately 720 mg of ferric iron as ferric citrate) and titrating the blood samples of the patients at Visits 4, 5, and 6 as follows: 5 For a serum phosphorus level from 3.5-5.5 mgs/dL of the blood, no action is required, for a rise to > 5.6-6.9mgm/dL, the drug dosage is increased by one tablet per day and for a rise to 6.9 mg/d, the dosage is increased to 3 tablets per day to a maximum of 12 tablets/day. Patients take the study drug orally with meals or snacks or within one hour after their meals or snacks. Patients are instructed not to take the study drug if greater than one hour .0 has passed since the ingestion of their meals or snacks. Some patients can require a different distribution in tablets in a given day due to snacks or missed meals. For example, if the patient is receiving a starting dose of 6 g/day that patient can be taking 2 tablets with breakfast, 2 with lunch, and 2 with dinner and can be switched to 1 with breakfast, 1 with a morning snack, 1 with lunch, 1 with a afternoon snack and 2 with dinner if diet dictates. 25 The second phase of the study in the statistical plan, the drug efficacy study, assesses the tolerability and safety of the study drug. Drug safety is assessed by recording and monitoring adverse events, reviewing concomitant medication use, conducting brief physical examinations (weight, blood pressure and heart rate), and obtaining sequential blood chemistries (including serum phosphorus, serum calcium and selected iron parameters) and 30 rates of adverse events and changes in laboratory parameters. While several particular forms of the disclosure have been illustrated and described, it will be apparent that various modifications and combinations of the disclosure detailed in the text and drawings can be made without departing from the spirit and scope of the disclosure. For example, references to materials of construction, methods of construction, specific - 33 dimensions, shapes, utilities or applications are also not intended to be limiting in any manner and other materials and dimensions could be substituted and remain within the spirit and scope of the disclosure. Throughout this specification and the claims which follow, unless the context requires 5 otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an 0 acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates. - 34 -

Claims (26)

1. A tablet comprising granule particles, said granule particles comprising ferric citrate and a binder, wherein the mean surface area to mass ratio of said granule particles is equal to or greater than 1 m 2 per gram.

2. The tablet of claim 1, wherein the mean surface area to mass ratio of said granule particles is equal to or greater than 5 m2 per gram.

3. The tablet of claim 1 wherein the mean surface area to mass ratio of said granule particles is equal to or greater than 10 m2 per gram.

4. The tablet of claim 1 wherein the tablet comprises at least 70 weight percent ferric citrate.

5. The tablet of claim 1 wherein the tablet comprises at least 80 weight percent ferric citrate.

6. The tablet of claim 1 wherein the tablet comprises at least 90 weight percent ferric citrate.

7. The tablet of claim 1 wherein the binder comprises one or more of hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), sodium alginate, alginic acid, guar gum, acacia gum, xanthan gum, carbolpol, cellulose gum (carboxymethyl cellulose), ethyl cellulose, maltodextrin, PVP/VA, povidone, 5 microcrystalline cellulose, starch (partially or fully pregelatinized starch) and methyl cellulose.

8. The tablet of claim 1, wherein the LOD % water of the tablet is less than 20% water w/w.

9. The tablet of claim 1, wherein the LOD % water of the tablet is less than 15% water w/w.

10. The tablet of claim 1, wherein the LOD % water of the tablet is less than 10% water w/w.

11. The tablet of claim 1 further comprising a disintegrant selected from one or more of microcrystalline cellulose, croscarmellose sodium, crospovidone, sodium starch glycolate, and starch.

12. The tablet of claim 1 further comprising a lubricant selected from one or more of magnesium stearate, calcium stearate, and sodium stearyl fumarate. - 35 -

13. The tablet of claim 1 wherein the tablet comprises: between approximately 65% and 92% ferric citrate; between approximately 4.5% and 30% binder; and between 0.5% and 3% lubricant.

14. The tablet of claim 1 wherein the binder comprises pregelatinized starch.

15. The tablet of claim 12, wherein the lubricant comprises calcium stearate, and sodium stearyl fumarate.

16. The tablet of claim 1 wherein at least 80% of the ferric citrate in the tablet is dissolved in a time less than or equal to 60 minutes as measured by test method USP <711>.

17. The tablet of claim 1 wherein the tablet comprises approximately 1000 mg of ferric citrate.

18. The tablet of claim 1 wherein the tablet comprises approximately 667 mg of ferric citrate.

19. The tablet of claim 1 wherein the tablet comprises approximately 500 mg of ferric citrate.

20. A method of preparing a tablet according to claim 1, the method comprising: mixing the ferric citrate with one or more binders under conditions in which the LOD % water does not exceed 25% to form ferric citrate granules; 5 tableting the ferric citrate granules to form a tablet.

21. The method according to claim 20, wherein said granule particles have a mean surface area to mass ratio greater than 1 m2 per gram.

22. The method according to claim 21, wherein the mean surface area to mass ratio of said granule particles is equal to or greater than 10 m2 per gram.

23. The process of clam 18, wherein the mixing step comprises fluid bed granulation.

24. The process of clam 18, wherein the mixing step comprises high shear granulation.

25. The method according to claim 20, further comprising heating said tablet above 50'C.

26. A method for the prophylaxis or treatment of hyperphosphatemia comprising administering the tablet of claim 1. - 36 -