HK40001832A - Ferric citrate dosage forms - Google Patents

Description

Ferric citrate dosage forms

The application is a divisional application of a Chinese patent application with the original application date of 2010, 07-21.8. 201080041895.3 and the invention name of ferric citrate dosage form.

Cross reference to related applications

The present patent cooperation treaty patent application claims priority from U.S. provisional patent application No. 61/227,124, filed on 7/21/2009, which is incorporated herein by reference in its entirety for all purposes.

Technical Field

The field of the invention generally relates to pharmaceutical compositions of ferric citrate, methods of their use for treating medical conditions, and methods of their manufacture.

Background

US 5,753,706 discloses ferric citrate compounds that can be used to control phosphate metabolism and prevent metabolic acidosis in a patient. The content of US 5,753,706 is incorporated herein by reference in its entirety. The ferric citrate compound may be used in patients suffering from renal failure with hyperphosphatemia, or patients susceptible to the hyperphosphatemia condition. Ferric citrate is also used as a dietary supplement and additive. Ferric citrate is characterized as a light brown to beige powder, odorless and slightly iron-tasting. According to the Merck Index (Merck Index), ferric citrate is slowly but completely soluble in cold water and readily soluble in hot water, but the solubility diminishes with age.

US 6,903,235 discloses commercially available ferric citrate in the form of a combination of iron and citric acid of indeterminate composition. The content of US 6,903,235 is incorporated herein by reference in its entirety. The' 235 patent explains that the uncertain composition may be due to difficulties encountered in its preparation, but those skilled in the art understand and must recognize: commercially available ferric citrate contains iron and citric acid in different molar ratios and also contains varying amounts of hydrates.

WO 2004/074444 discloses a method of manufacturing ferric organic compounds such as ferric citrate with enhanced dissolution rate. WO 2007/022435 is a partially subsequent application to WO 2004/074444 and discloses a process for the manufacture of ferric organic compounds which are soluble over a wide pH range and have a large surface area. WO 2007089577 relates to a method of treating soft tissue calcification using ferric organic compounds such as ferric citrate compounds. WO 2007089571 relates to a method of treating chronic kidney disease using ferric organic compounds such as ferric citrate compounds.

Disclosure of Invention

In one aspect, the invention relates to a tablet comprising ferric citrate. In some embodiments, the tablet may include at least 65 weight percent ferric citrate.

In another aspect, the invention relates to a tablet comprising granules. The particles comprise ferric citrate and a binder, and the average surface area to mass ratio of the particles is equal to or greater than 1 square meter per gram (m)²In terms of/g). In specific examples, the particles have an average surface area to mass ratio of 5m or greater²G or 10m²/g。

In another aspect, the tablet can include at least 70 weight percent ferric citrate, at least 80 weight percent ferric citrate, or at least 90 weight percent ferric citrate.

In another aspect, the binder may be one or more of hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium alginate, alginic acid, guar gum (guar gum), acacia gum (acacia gum), xanthan gum (xanthan gum), carbomer (carbopol), cellulose gum (carboxymethyl cellulose), ethyl cellulose, maltodextrin, PVP/VA, povidone (povidone), microcrystalline cellulose, starch (partially or fully pregelatinized starch), and methyl cellulose.

In another aspect, the tablet may include various other components including, for example, one or more disintegrants and/or one or more lubricants. The disintegrant may be one or more of microcrystalline cellulose, croscarmellose sodium, crospovidone, sodium starch glycolate, and starch. The lubricant may be one or more of magnesium stearate, calcium stearate, sodium stearyl fumarate, polyethylene glycol (molecular weight greater than 3350), sodium lauryl sulfate, talc, mineral oil, leucine, and poloxamer (poloxamer). In some embodiments, the tablet may include about 65% to 92% ferric citrate, about 4.5% to 30% binder, and 0.5% to 3% lubricant. The binder may have disintegrant properties. The binder may be a pregelatinized starch.

In another aspect, the tablet may have about 65% to 92% ferric citrate, about 4.5% to 30% binder, about 1.5% to 15% disintegrant, and 0.5% to 3% lubricant.

Various other components in the tablet may include microcrystalline cellulose, pregelatinized starch, and sodium stearyl fumarate. In one embodiment, the ferric citrate may be present at about 85 weight percent, the microcrystalline cellulose at about 4 weight percent, the pregelatinized starch at about 9 weight percent, and the sodium stearyl fumarate at about 2 weight percent.

In another aspect, the tablet may have about 10% to 60% ferric citrate (dissolved in about 15 minutes), about 30% to 90% ferric citrate (dissolved in about 30 minutes), and at least about 60% ferric citrate (dissolved in about 60 minutes) in a dissolution test according to test method USP <711 >. In the dissolution test according to test method USP <711>, a tablet can be at least 90% dissolved in 30 minutes. In the dissolution test according to test method USP <711>, a tablet may show at least 90% dissolution within 60 minutes.

In a disintegration test according to test method USP <701>, the tablet may show a disintegration time of less than 30 minutes. In a disintegration test according to test method USP <701>, the tablet may show a disintegration time of more than 30 minutes.

The tablet may include about 1000mg ferric citrate, about 667mg ferric citrate, about 500mg ferric citrate, about 250mg ferric citrate, or about 125mg ferric citrate.

In various aspects, the LOD (loss on drying)% of water in the tablet is less than 20% (water w/w). In other aspects, the LOD% of tablet water is less than 15% (water w/w). In other aspects, the LOD% of tablet water is less than 10% (water w/w).

In various aspects, at least 80% of the ferric citrate in the tablet dissolves in 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 may be selected from one or more of microcrystalline cellulose, croscarmellose sodium, crospovidone, sodium starch glycolate, and starch.

In another aspect, the tablet includes a lubricant. In certain embodiments, the lubricant may be selected from one or more of magnesium stearate, calcium stearate, and sodium stearyl fumarate.

In another aspect, the invention relates to a method of preparing a ferric citrate tablet. The method includes mixing ferric citrate with one or more binders to form ferric citrate granules under conditions such that the LOD% of water does not exceed 25%. Granulation (e.g., fluid bed granulation or high shear granulation) can be performed by any method known in the art. The ferric citrate granules were then pastillated.

In another aspect, the tablet is heated to above 50 ℃ after tableting.

The tablets may be used for the prevention or treatment of a variety of diseases or disease conditions, including, but not limited to, hyperphosphatemia.

Particular examples of the method may include one or more of the features described above or herein.

Various embodiments are described in detail in the accompanying drawings and the following description. The features and advantages of various embodiments are apparent from the description, drawings, and claims.

Drawings

Fig. 1 is a graph showing the relationship of hardness to compressive force for formulations 1-5.

Fig. 2 is a graph showing brittleness versus compressive force for formulations 1-5.

Fig. 3 is a graph showing the relationship of disintegration time to compression force for formulations 1-5.

Fig. 4 is a graph showing the dissolution times of formulation 1 and formulations 3-5.

Fig. 5 is a graph showing the relationship of hardness to compressive force for formulations 6-8 and formulation 11.

Fig. 6 is a graph showing brittleness versus compressive force for formulations 6-8 and formulation 11.

Fig. 7 is a graph showing the relationship of disintegration time to compression force for formulations 6-8 and formulation 11.

Fig. 8 is a graph showing dissolution times of formulations 6 to 8 and 11.

Fig. 9 shows the dissolution times of the different tablets before and after drying.

Detailed Description

Those skilled in the art will appreciate that the drawings described herein are for illustration purposes only. The drawings are not intended to limit the scope of the invention.

Tablets containing ferric citrate are disclosed herein. In various embodiments, the tablet includes a ferric citrate formulation that meets certain dissolution, tableting, and disintegration criteria. In various aspects, the tablet formulation may include ferric citrate as an active ingredient, and a binder. The formulation may also include a lubricant and/or a disintegrant (which may be the same as the binder in some embodiments).

Tablet formulation

In one aspect, the formulation is a tablet comprising ferric citrate and a binder. As used herein, a "tablet" is a substance that is manufactured using a compression force, such as with a pastillator. In other embodiments, the formulation or tablet may include ferric citrate, a binder, a lubricant, and a disintegrant. The tablets or formulations can be used to prevent or treat hyperphosphatemia by administering an effective amount or amounts of the tablets or formulations known in the art.

The formulation is characterized by a high drug loading of ferric citrate present in the formulation, with values greater than about 65% by weight of the formulation, greater than about 70% by weight of the formulation, and up to about 92% of the formulation. Intermediate values such as about 80 wt.% ferric citrate, about 85 wt.% ferric citrate, and about 90 wt.% ferric citrate may also be used in the ferric citrate formulation. The characteristics of tablets manufactured in accordance with these high drug loading weight percentages are controlled depending on variables such as the binder, binder amount, disintegrant amount, formulation method used (e.g., granulation, direct compression), tableting parameters, and the like. Thus, if a tablet has been manufactured and has a low number of laminations or top cracks, the laminations or top cracks can be corrected by varying one or more of the variables.

In various embodiments, the tablet formulation contains one or more components selected from one or more binders, one or more lubricants, and one or more disintegrants.

The binder can be any binder known in the art. Examples of binders may include, but are not limited to, one or more of hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium alginate, alginic acid, guar gum, acacia gum, xanthan gum, carbomer, cellulose gum (hydroxymethyl cellulose), ethyl cellulose, maltodextrin, PVP/VA, povidone, microcrystalline cellulose, starch (partially or fully pregelatinized starch), and methyl cellulose. Maltodextrin, PVP/VA and methylcellulose act as an immediate release binder when used in ferric citrate formulations.

It should also be appreciated that combinations of adhesives may be used to control and modify the effect of the adhesive. For example, the binder system may consist of hydroxypropyl cellulose and polyvinylpyrrolidone (povidone) with or without microcrystalline cellulose. One or both of hydroxypropyl cellulose and povidone may be replaced with pregelatinized starch.

In various aspects, the tablet may include a lubricant. As examples of lubricants for ferric citrate formulations, magnesium stearate, calcium stearate, sodium stearyl fumarate, and combinations may be used. Other suitable lubricants include one or more of polyethylene glycol (molecular weight higher than 3350), sodium lauryl sulfate, talc, mineral oil, leucine, and poloxamer.

In various aspects, the tablet may include a disintegrant. Disintegrants may be included in the formulation. The disintegrant and binder may be the same or different. For example, but not limited to, microcrystalline cellulose has both binder and disintegrant properties, and microcrystalline cellulose may be used as the only binder/disintegrant in the formulation. Other examples of suitable disintegrants include croscarmellose sodium, crospovidone, sodium starch glycolate and starch.

The amount of binder present in the formulation may range from about 4.5 wt% to about 30 wt%. The amount of disintegrant present in the formulation may range from about 1.5% to about 15% by weight. In particular examples, some non-starch disintegrants in a lower range (e.g., as low as 0.25%) are typically used, and thus, the disintegrant present in the formulation may be as low as 0.25% under some conditions.

The amount of lubricant present in the formulation may range from about 0.5 wt% to about 3 wt%. It will be appreciated that some components, such as microcrystalline cellulose, may have disintegrant and binder properties.

The weight of the individual tablets may depend on the final dose to be manufactured; for example 125mg, 250mg, 500mg, 667mg, 750mg and 1,000mg of ferric citrate.

In specific examples, tablets were coated with Opadry suspension or equivalent in a perforated pan coater until weight gain of about 2% to 5%. As noted above, the calcium stearate and Opadry violet may be replaced by or used with different lubricants or coating systems, respectively.

High surface area per unit mass tablet

In one variation, the disclosed tablets contain particles having an average surface area per unit mass that is significantly higher than previous ferric citrate formulations. It has been found that an increase in surface area per unit volume results in an immediate release dissolution time (greater than 80% 60 minutes after administration as determined by United States Pharmacopeia testing <711> as described in United States Pharmacopeia compandium of Standards, USP 30NF 25, Vol.1, p.276-284 (2007), which is incorporated herein by reference in its entirety). Without wishing to be bound by a particular theory or mode of action, an increase in the particle surface area of the particles in the tablet may cause an increase in the amount of ferric citrate exposed to the solvent. With reduced tablet size, the immediate release dissolution time is significantly reduced.

In other variations, the tablets disclosed herein can be designed to have an average particle surface area to mass ratio equal to or greater than 1 square meter per gram. In other variations, the tablet may have an average particle surface area to mass ratio equal to or greater than 2 square meters per gram. In other variations, the formulation has an average particle surface area to mass ratio equal to or greater than 4 square meters per gram. In other variations, the formulation has an average particle surface area to mass ratio equal to or greater than 6 square meters per gram. In other variations, the formulation has an average particle surface area to mass ratio equal to or greater than 8 square meters per gram. In other variations, the formulation has an average particle surface area to mass ratio equal to or greater than 10 square meters per gram. In other variations, the formulation has an average particle surface area to mass ratio equal to or greater than 15 square meters per gram. In other variations, the average particle surface area to mass ratio of the formulation is equal to or greater than 20 square meters per gram. In other variations, the average particle surface area to mass ratio of the formulation is equal to or greater than 30 square meters per gram. In other variations, the average particle surface area to mass ratio of the formulation is equal to or greater than 40 square meters per gram. In other variations, the average particle surface area to mass ratio of the formulation is equal to or greater than 50 square meters per gram. The increase in surface area of each granule in the tablet causes a significant increase in dissolution rate.

In other variations, the water content of the tablet is reduced. In one embodiment, the water content of the particles, in terms of LOD%, is less than 20%. In another embodiment, the water content of the particles, in LOD%, is less than 19%. In another embodiment, the water content of the particles, in LOD%, is less than 18%. In another embodiment, the water content of the particles in LOD% is less than 17%. In another embodiment, the water content of the particles in LOD% is less than 16%. In another embodiment, the water content of the particles in LOD% is less than 15%. In another embodiment, the water content of the particles in LOD% is less than 14%. In another embodiment, the water content of the particles in LOD% is less than 13%. In another embodiment, the water content of the particles in LOD% is less than 12%. In another embodiment, the water content of the particles in LOD% is less than 11%. In another embodiment, the water content of the particles in LOD% is less than 10%. In another embodiment, the water content of the particles in LOD% is less than 9%. In another embodiment, the water content of the particles in LOD% is less than 8%. In another embodiment, the water content of the particles in LOD% is less than 7%. In another embodiment, the water content of the particles in LOD% is less than 6%. In another embodiment, the water content of the particles in LOD% is less than 5%.

As will be appreciated by those skilled in the art, in various embodiments, LOD is the thermogravimetric moisture determination method: in the thermogravimetric process, the moisture of a substance comprises a substance that volatilizes during heating and thus results in a loss of mass of the substance. Besides water, alcohols or decomposition products may also be included. When using thermogravimetric methods (using infrared, halogen, microwave or oven drying), there is no difference between water and other volatile components.

Degree of brittleness

Friability is typically a measure of the mechanical strength of a tablet. Tablets may lose some weight during coating, transport, packaging and other processes. To measure weight loss, the samples were counted and weighed.

In various embodiments, the brittleness test is performed as described in United States Pharmacopeia compandium of Standards (2007), which is incorporated herein by reference in its entirety.

Method for producing tablet

In the tableting method, tablets may be prepared in three steps. First granules of ferric citrate and binder are formed. Second, the lubricant is added to the formulation, followed by pastillation. Third, after optionally performing the coating step, the tablets are dried.

Granulating

Ferric citrate (such as pharmaceutical-grade ferric citrate, e.g., as described in U.S. patent No. 6,903,235B 2) can be granulated by any method known in the art. Exemplary methods of granulation include fluid bed granulation, high shear granulation, and direct compression granulation.

In specific examples, reaching levels of moisture above 25% LOD at any point in the formulation greatly reduces the surface area per gram of particle. This can be achieved, for example, by limiting the amount of water introduced or by blowing air and monitoring the water content in the formulation.

To increase the surface area to mass ratio of the ferric citrate particles to greater than 1 m/g, or in other embodiments greater than 10 m/g, the moisture content of the particles is maintained below 25% LOD throughout the particle formation process. In certain variations, the moisture content of the granules is maintained below 24% LOD, 23% LOD, 22% LOD, 21% LOD, or 20% LOD throughout the granule formation process.

Without wishing to be bound by a particular mechanism or mode of action, it is hypothesized that keeping the water content below 25% LOD during granulation will maintain a high surface area to mass ratio for the particles. The addition of a greater amount of water at any time during the granulation process results in larger granules having a lower average surface area to mass ratio. Lower surface area to mass ratios will reduce the dissolution rate below that of the immediate release formulation. The lower average surface area to mass ratio of the particles measured resulted in slower dissolution and release characteristics.

In particular examples, it has been noted that the surface area to weight ratio reduction of the ferric citrate formulation is irreversible after adding moisture above 25% LOD. Thus, in particular examples, the water percentage is kept below 25% during granulation.

Blending

In various embodiments, one or more lubricants may be blended with the particles. In specific examples, a non-limiting list of lubricants includes stearates, such as calcium and magnesium stearate, sodium stearyl fumarate, stearic acid, talc, polyethylene glycol, hydrogenated vegetable oils, aluminum stearate, sodium benzoate, sodium acetate, sodium chloride, leucine, Carbowax (Carbowax), and magnesium lauryl sulfate. Certain starches, such as starch 1500, may also be considered lubricants because of some lubricant properties when used in direct compression applications. Any lubricant known in the art may be used, including any of those disclosed in the Handbook of Pharmaceutical Excipients, fifth edition, which is incorporated herein by reference in its entirety. Multiple lubricants may be combined.

In certain embodiments, the amount of lubricant used may be greater than the amounts commonly used in the art. It has been surprisingly found that the amount of lubricant must be higher than what is recommended or known in the industry to reduce the amount of sticking of the ferric citrate tablets.

In certain variations, magnesium or calcium stearate and sodium stearyl fumarate are used in combination as a lubricant. In other embodiments, the lubricant is a combination of calcium stearate and sodium stearyl fumarate. In particular examples, the amount of calcium stearate used may be greater than recommended in the art. The recommended amount of calcium stearate is at most 1.0% (w/w), as described in Handbook of pharmaceutical excipients, fifth edition. In one embodiment, the amount of calcium stearate is equal to or greater than 2.0% (w/w). In another embodiment, the amount of calcium stearate is equal to or greater than 2.2% (w/w). In another embodiment, the amount of calcium stearate is equal to or greater than 2.4% (w/w).

Also, in particular examples, sodium stearyl fumarate can be used in amounts greater than the recommended concentration of 0.5 to 2.0% (w/w). In a specific example, the amount of sodium stearyl fumarate is greater than or equal to 2.1% (w/w). In another specific example, the amount of sodium stearyl fumarate is greater than or equal to 2.2% (w/w). In another specific example, the amount of sodium stearyl fumarate is greater than or equal to 2.3% (w/w). In another specific example, the amount of sodium stearyl fumarate is greater than or equal to 2.4% (w/w). In another specific example, the amount of sodium stearyl fumarate is greater than or equal to 2.5% (w/w). In another specific example, the amount of sodium stearyl fumarate is greater than or equal to 2.6% (w/w). In another specific example, the amount of sodium stearyl fumarate is greater than or equal to 2.7% (w/w).

Drying after ingot making

The drying step may be performed after the pastillation. Without drying the tablets after the tablets, the dissolution rate of the tablets was found to increase with time. Drying maintains the immediate release characteristics of the ferric citrate tablets as disclosed herein. Without being bound by a particular mechanism or mode of action, it is believed that particle size increases due to the presence of residual water, and that the drying step maintains a large surface area per unit weight of the original particles.

In one embodiment, the final particle water content in LOD% is less than 20%. In another embodiment, the final particle water content in LOD% is less than 19%. In another embodiment, the final particle water content in LOD% is less than 18%. In another embodiment, the final particle water content in LOD% is less than 17%. In another embodiment, the final particle water content in LOD% is less than 16%. In another embodiment, the final particle water content in LOD% is less than 15%. In another embodiment, the final particle water content in LOD% is less than 14%. In another embodiment, the final particle water content in LOD% is less than 13%. In another embodiment, the final particle water content in LOD% is less than 12%. In another embodiment, the final particle water content in LOD% is less than 11%. In another embodiment, the final particle water content in LOD% is less than 10%. In another embodiment, the final particle water content in LOD% is less than 9%. In another embodiment, the final particle water content in LOD% is less than 8%. In another embodiment, the final particle water content in LOD% is less than 7%. In another embodiment, the final particle water content in LOD% is less than 6%. In another embodiment, the final particle water content in LOD% is less than 5%.

Examples

The following examples describe the preparation and characteristics of various dosage forms and methods described herein. It will be apparent to those skilled in the art that various modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

Example 1

The following exemplary formulations and formulation techniques of ferric citrate provide data showing the characteristics of the formulation or tablet, including data such as dissolution, disintegration, and friability.

Some sources of material include: ferric citrate from Biovectra; silicified microcrystalline cellulose (Prosolv SMCC 50 and Prosolv SMCC HD90, consisting of microcrystalline cellulose (NF) and colloidal silicon dioxide (NF), available from JRS Pharma); pregelatinized starch (NF) from Colorcon (starch 1500); povidone (NF) available from ISP (Plasdone K-29/32); hydroxypropyl cellulose (NF) (Klucel EF) available from Hercules; croscarmellose sodium (NF) (Ac-Di-Sol SD-711) purchased from FMC Biopolymer; and magnesium stearate (NF) available from Mallinckrodt.

An apparatus for formulation comprising: FLM1 fluidized bed available from Vector Corporation, Marion, IA; comil cone Mills available from Quadro Engineering, Millburn, N.J.; a GMX high shear granulator, 4L bowl, available from Vector Corporation, Marion, IA; a blender model 2qtv available from Patterson Kelley, East Stroudsburg, Pa; XL100Pro ingot-making machine available from Korsch, South Easton, MA; a capsule shaped tool purchased from Elizabeth Carbide, Lexington, NC; and a sound screen separator available from Advantech Manufacturing, New Berlin, Wis.

An apparatus for analyzing a test formulation comprising: an 8M tablet tester (hardness tester) available from dr, schleuniger, Manchester, NH; brittleness determination apparatus available from VanKel, Palo Alto, CA; flodex from Hanson Research, Chatsworth, CA; model 3106 and Evolution 6100 anhydrous bath disintegration systems available from Distek, North Brunswick, NJ; and Uv-Vis model 8453 from Agilent, Santa Clara, Calif.

High shear granulation

A series of experiments were conducted to determine the ability to use a high shear granulator to produce a tablet blend with suitable characteristics. Formulations 1 to 3 are shown in tables 1 to 3 below.

TABLE 1 (formulation 1)

TABLE 2 (formulation 2)

TABLE 3 (formulation 3)

The procedure for making formulations 1-3 was as follows.

The milled ferric citrate, hydroxypropyl cellulose, silicified microcrystalline cellulose, and croscarmellose sodium were mixed in a 4L bowl of a GMX high shear granulator at 500rpm for 2 minutes. Deionized water was added at a rate of about 18g/min over 10 minutes while mixing at a rate of 900rpm, with a chopper speed of 1500 rpm. The final (peak) moisture content was measured as 24.3%, 23.8% and 24.4%, respectively. The particles were dried in a FLM1 fluidized bed at an inlet temperature of 65 ℃ for 5 to 8 minutes. 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, followed by a 25 mesh hand screen to remove oversized granules and clumps. Magnesium stearate was screened through a 25 mesh hand screen. The granules and magnesium stearate were blended in a 2 quart (quart) v blender for 2 minutes. The ingot making was performed on a Korsch ingot maker with a capsule tool.

The resulting tablet blend was found to exhibit poor flow through the hopper due to irregular particle shapes. Nevertheless, excellent tablets can be manufactured using an ingot making apparatus.

Example 2:

another series of experiments was performed to determine whether tablets could be formulated using the fluid bed granulation method:

TABLE 4 (formulation 4 and formulation 5)

Components	Milligram/tablet	％w/w
			Milled ferric citrate	1190.7	90.0
Pregelatinized starch	119.1	9.0
			Magnesium stearate	13.2	1.0
Total of	1323.0	100.0

The manufacturing procedures for formulation 4 and formulation 5 described in table 4 are provided below:

the milled ferric citrate was added to the FLM1 fluid bed granulator. For formulation 4, a 10% (w/w) solution of pregelatinized starch was added at a spray rate that increased from 24g/min to 52g/min over the duration of the run. [ inlet temperature ═ 64 ℃ to 77 ℃; the product temperature is 25 ℃ to 35 ℃; process air 29 to 35CFM ]. The final (peak) moisture content was measured to be 32.5%.

For formulation 5, a 10% (w/w) solution of pregelatinized starch was added at an average spray rate of 40.8 g/min. [ inlet temperature ═ 69 ℃ to 75 ℃; the product temperature is 25 ℃ to 35 ℃; process air 24 to 38CFM ]. The final (peak) moisture content was measured to be 30.0%.

The granules were dried at an inlet temperature of 65 ℃ for 7 to 10 minutes. The moisture content after drying was measured to be 15.5% and 16.7%. The particles were milled at 1500rpm through a Comil equipped with a 45R screen and a square impeller. Magnesium stearate was screened through a 25 mesh hand screen. The granules and magnesium stearate were blended in a 2 quart v blender for two minutes. The ingot making was performed on a Korsch ingot maker with a capsule tool.

The main difference between the tablets of formulation 4 and formulation 5 was the disintegration time. The tablets of formulation 5 disintegrated slower than the tablets of formulation 4. These prototypes have no flow problems during ingot making.

The powder properties of formulations 1-5 were characterized as shown in tables 5 and 6. All blends had excellent flow characteristics as measured by Flodex.

TABLE 5 powder characteristics of high shear blends

Measurement of	Formulation 1	Formulation 2	Formulation 3
				Bulk density	0.772g/mL	0.618g/mL	0.679g/mL
Flodex	4	5	10

TABLE 6 powder characteristics of the fluidized bed blends

Measurement of	Formulation 4	Formulation 5
			Bulk density	0.647g/mL	0.578g/mL
Flodex	4	4

Experimental formulations of formulation 1 and formulation 5 were examined by Scanning Electron Microscopy (SEM), and both samples had similar particle size ranges. Although the particles of formulation 1 appeared to have a bimodal distribution, both samples had different particle morphologies. Formulation 1 prepared by high shear granulation had more pronounced oblong particles. Formulation 5, prepared by fluid bed granulation, had softer spherical particles. It is believed that this difference has an effect on the flow characteristics observed during ingot making.

Tablet properties of formulations 1-5 were characterized as shown in table 7 and table 8. The compaction characteristics consisted of the representations presented graphically in fig. 1 (hardness), fig. 2 (brittleness) and fig. 3 (disintegration). Only the characteristic data of the tablets prepared with the highest compression force are presented. The compressive force is measured in kilonewtons (kilo newtons). The dissolution results for formulation 1 and formulations 3 through 5 are presented graphically in fig. 4.

For hardness testing, the tablets were tested for hardness/breaking strength according to USP <1217 >. For the friability test, tablets were tested for friability following USP <1216 >. For the disintegration test, 6 tablets were tested in deionized water at 37 ℃ using a disintegration apparatus. For the dissolution test, the dissolution characteristics of 6 tablets were tested according to the conditions listed below. Tablet dissolution results were scaled up to report 100% dissolution at a 1000mg dose, corrected for actual average tablet weight as necessary.

Dissolution conditions:

dissolution apparatus: distek Evolution 6100

Culture medium: McIlvaine buffer solution with pH of 4.0

USP apparatus: device II (paddle method); 100rpm

Temperature: 37 +/-0.5 DEG C

Time: samples were taken at 5, 15, 30 and 60 minutes

UV-Vis Instrument: agilent 8453 UV-Vis; background correction at 360nm and 600 nm.

TABLE 7 characteristics of high shear test (formulation 1 to formulation 3)

TABLE 8 tablet characteristics for the fluid bed experiment (examples 4 and 5)

For the high shear prototype (formulation 1 to formulation 3), the combination of increased silicified microcrystalline cellulose (formulation 1 and formulation 2) improved compressibility as indicated by the low compressive force required to achieve equivalent hardness. The incorporation of increased hydroxypropyl cellulose (formulation 1, formulation 2, and formulation 3) also improved compressibility as indicated by the low compressive force required to achieve equivalent hardness.

Example 3

Other developments were made to strike a balance between dissolution characteristics and acceptable tablet properties. The use of pregelatinized starch gradually changes the fluid bed granulation spray rate, showing that the moisture content plays a role in the dissolution profile and tablet properties.

Fluidized bed granulation with starch

Batches of formulation 6 to formulation 11 shown in tables 9 and 10 were prepared in target batches of 1.0kg using pregelatinized starch.

TABLE 9 formulation of formulation 6 to formulation 8

Components	Milligram/tablet	％w/w
			Milled ferric citrate	1190.7	90.0
Pregelatinized starch	119.1	9.0
			Magnesium stearate	13.2	1.0
Total of	1323.0	100.0

TABLE 10 formulation of formulation 9 to formulation 11

Components	Milligram/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 of	1470.2	100.0

Formulations 6 to 11 were made as follows:

the milled ferric citrate was added to the FLM1 fluid bed granulator. A10% (w/w) solution of pregelatinized starch was added using the granulation and drying parameters in Table 11. All batches were dried at an inlet temperature of 65 ℃.

TABLE 11 granulation parameters

The granules of formulation 6, formulation 7, formulation 9 and formulation 10 were screened through a 20 mesh hand screen. The granules of formulation 8 and formulation 11 were milled at 1500rpm through a Comil equipped with a 45R sieve and a square impeller, then sieved through a 20 mesh hand sieve.

Two blends were prepared by various granulation methods. In the first blend, magnesium stearate was screened through a 25 mesh hand screen. The granules and magnesium stearate were blended in a 2 quart v blender for two minutes. In the second blend, the magnesium stearate was screened through a 25 mesh hand screen. The granules, silicified microcrystalline cellulose and magnesium stearate were blended in a 2 quart v blender for two minutes.

Several of the blends prepared were pastilled using a capsule tool on a Korsch pastiller.

The flow characteristics of the resulting tablets of formulation 6 and formulation 9 were a Hausner ratio (Hausner ratio value) equal to or less than 1.25 and/or a Carr index value (Carr index value) equal to or less than 25. In particular examples, the hausner ratio is equal to or less than 1.20. In other specific examples, the hausner ratio is equal to or less than 1.20. In particular examples, the carr index is less than 25. In other specific examples, the carr index is equal to or less than 20.

Excellent fluidity: the hausner ratio is about 1.20 or less than 1.20 and the karl index value is less than 20, but evidence indicates that additional lubrication is required to achieve better ingot results. The resulting tablets of formulation 7, formulation 8, formulation 10 and formulation 11 had excellent flow characteristics and were successful tablets.

The powder properties of formulations 6-11 were characterized as shown in table 12 and table 13. The flow characteristics of formulations 7, 8, 10 and 11 were hausner ratio equal to or less than 1.20 and a karl index value less than 20, as measured by Flodex, assuming higher injection rates due to their experiments. The bulk density of the starch granulation experiments increased with increasing spray rate.

TABLE 12 powder characteristics of the fluidized bed experiment

Tablet properties of formulations 6-8 and 11 were characterized as shown in table 13 and table 14. The compaction characteristics of each formulation were obtained and presented as a graph in fig. 5 (hardness), fig. 6 (friability) and fig. 7 (disintegration). Only the characteristic data of the tablets prepared with the highest compression force are presented. The dissolution results for formulations 6-8 and 11 are presented graphically in fig. 8.

TABLE 13 tablet characteristics of high shear formulation 6 and formulation 7

Measurement of	Formulation 6	Formulation 7
			Difference in weight	Average 1126.9mg (0.4% RSD)	Average 1272.8mg (0.4% RSD)
Thickness of	Average 7.74mm (0.2% RSD)	Average 8.00mm (0.5% RSD)
			Hardness of	Average 11.2kP (28.7% RSD)	27.2kP(8.9％RSD)
Degree of brittleness	2.23％	0.36％
			Disintegration	Average 1.8 minutes	Average 3.9 minutes
Dissolution	99.9 percent in 60 minutes	95.7 percent in 60 minutes

TABLE 14 tablet characteristics of fluidized bed formulation 8 and formulation 11

Measurement of	Formulation 8	Formulation 11
			Difference in weight	Average 1332.0mg (0.3% RSD)	Average 1497.7mg (0.3% RSD)
Thickness of	Average 7.94mm (0.1% RSD)	Average 8.72mm (0.1% RSD)
			Hardness of	Average 21.1kP (2.8% RSD)	26.1kP(2.9％RSD)
Degree of brittleness	0.28％	0.15％
			Disintegration	Average 11.7 minutes	Average 8.3 minutes
Dissolution	55.8 percent in 60 minutes	65.6 percent in 60 minutes

Milled ferric citrate and croscarmellose sodium were added to the FLM1 fluidized bed. Granules were made using the granulation and drying parameters in table 15 with the addition of 30% (w/w) solution of povidone (formulation 12) and 20% (w/w) solution (formulation 13). Drying is not required.

TABLE 15 granulation parameters

Parameter(s)	Formulation 12	Formulation 13
			Injection rate	22.9g/min	30.0g/min
Inlet temperature	55-60℃	52-58℃
			Temperature of the product	31-37℃	22-30℃
Process air	31-36CFM	35-38CFM
			Final (peak) moisture	13.0％	17.3％

The granules were screened through a 20 mesh hand screen. Magnesium stearate was screened through a 25 mesh hand screen. The granules and magnesium stearate were blended in a 2 quart v blender for two minutes.

Ingot making was performed on a Korsch ingot maker. During the ingot making process, there is excessive adhesion to the tool. It is believed that this adhesion can be handled by using different tools or by changing ingot making parameters.

Example 4

Other examples were formulated and analyzed. A summary of the results is provided in tables 16 and 17 below. Table 16 provides a summary of the results for formulations 14 through 20 obtained using the direct compression formulation. Table 17 provides a summary of the results for formulations 21 through 29 obtained using fluid bed granulation. These various formulations exhibit a variety of properties that are applicable depending on the application, such as immediate release, extended release, and delayed release, with some formulations requiring a small amount of additional experimentation to ensure that a suitable tablet is formed.

TABLE 16 qualitative results for direct compression formulations

TABLE 17 qualitative results for fluidized bed granulation formulations

Example 5

Tables 18a and 18b provide formulations 30 and 31 for exemplary ferric citrate drugs.

Table 18a. formulation 30 of ferric citrate drug

Purified water was removed during drying.

Table 18 b: formula 31 of ferric citrate medicine

Table 19 provides suggested ferric citrate pharmaceutical formulations that can be used in the manufacturing methods described below.

TABLE 19 formulation 32

Removing purified water

(1) Or other adhesives listed in the patent

(2) Or other lubricants listed in the patent

(3) Or other coating systems listed in the patent

Example 6 pharmaceutical tablets were made using fluid bed granulation of a binder suspension of screened API and pregelatinized starch, with a target moisture content of about 13 to 20% after granulation. The granular active is then blended with the screened calcium stearate and the mixture is compressed to form the tablet core. The tablet is firm, has a friability equal to or less than 1.0% (w/w), a hardness of 8 to 20kP, a disintegration time equal to or less than 15 minutes and a compression force of about 3.5 to 5.0kN, and a main pressure of 5 to 20 kN. It will be recognized that multiple embodiments are within the scope of one or more of these various parameters.

The weight of the individual tablets may depend on the final dose to be manufactured; for example 125mg, 250mg, 500mg, 667mg, 750mg and 1,000mg of ferric citrate. The method enables consistent manufacturing of tablets within a target + -5% specification. The tablet thickness and hardness meet specific acceptance criteria. Tablets were coated in a pan-orifice coater with Opadry suspension or equivalent to achieve a weight gain of about 2% to 5%.

The manufacturing results show that the selected formulation and method can produce robust tablets that meet specific criteria. First, ferric citrate was passed through a sieve mill. The granular drug binder suspension was then prepared by adding purified water to a stainless steel mixing kettle, followed by addition of pregelatinized starch to the purified water and mixing. The ferric citrate was screened through a fluid granulator to form granular granules. The pregelatinized starch binder suspension is sprayed into the fluidized product bed. Upon completion of the binder addition, the granules were dried.

The dried granules were filled into a diffusion mixer. Calcium stearate was screened and added to the granules in the diffusion mixer. Mixing the granules with a lubricant.

The lubricated granules were compressed into tablets. The tablets were collected in an intermediate bulk container. Aqueous film coating suspensions were prepared in a stainless steel kettle and mixer. The tablets were filled into a full-bore pan coater and the coating suspension was sprayed onto the cascade product bed. After the spraying step was completed, the tablets were dried. The film coated tablets were discharged into an intermediate bulk container. The film coated tablets were packaged in HPDE bottles with desiccant and child resistant aluminum foil closures.

Example 7

The ferric citrate tablets were formulated as described above. Tablet formulations 33 and 34 are described in table 20 and table 21.

Table 20: formulation 33

(1) Calcium stearate or sodium stearyl fumarate was used as lubricant.

Purified water was removed.

Table 21: formulation 34

(1) Calcium stearate or sodium stearyl fumarate was used as lubricant.

Purified water was removed.

Example 8

Ferric citrate tablets were made under granulation conditions that increased the LOD water% above 25%.

Pharmaceutical-grade ferric citrate is added to a fluid bed granulator. A pre-gelatinized starch binder suspension (pre-gelatinized starch + water) is sprayed into the fluidized product bed. The moisture content of the formulation was made to exceed 25% (measured as LOD (loss on drying)).

In specific examples, reaching levels of moisture above 25% LOD at any point in the formulation greatly reduces the surface area per gram of particle.

Referring to table 22, the moisture gain obtained during manufacture increased above 20% at 120 minutes and to 27.87% at 170 minutes.

TABLE 22 granulation operating parameters

Table 23 describes the measured surface areas of two samples prepared using the above formulations. The surface area of the formulation was 0.12m²G and 0.20m²/g。

TABLE 23

The average surface area to unit mass ratios of the two samples were 0.12 and 0.20m, respectively²/g。

Example 9

Ferric citrate tablets were prepared by keeping the LOD% water content of the granules less than 25% during granulation.

Pharmaceutical-grade ferric citrate is added to a fluid bed granulator. A pre-gelatinized starch binder suspension (pre-gelatinized starch + water) is sprayed into the fluidized product bed. Referring to table 24, the moisture content of the formulation was maintained below 20% (in LOD (loss on drying)) throughout the spraying process. The resulting formulation has a surface area greater than 10 square meters per gram.

Watch 24

The results show a reduction in surface area between the pre-granulated material and the post-granulated material (see table 25). The results are described in table 25 in sample 1. Table 25 samples 2 and 3 also show surface areas greater than 10m²(iv)/g, which corresponds to the rapid immediate release formulation characteristics as described herein. For particles prepared with increased water (in LOD%), the difference in particle size is almost two orders of magnitude.

TABLE 25

A significant increase in particle surface area corresponds to a decrease in particle size. The tablets have a higher particle surface area and a faster dissolution rate (compared to tablets prepared with a lower surface area per unit weight).

Calcium stearate and sodium stearyl fumarate are added as lubricants. The amounts used in the formulations exceed those recommended in the art (e.g., Handbook of Pharmaceutical Excipients, fifth edition). 0.5% (w/w) sodium stearyl fumarate or 2.4% (w/w) calcium stearate was used.

Example 10

Ferric citrate tablets were manufactured for clinical studies as described above. The amounts of the tablet components are described in table 26.

Watch 26

The pregelatinized starch is sprayed into a chamber maintained at an inlet temperature and a product temperature. The LOD% of water at each preparation stage was maintained below 20%. The parameters used during the compounding are disclosed in table 27.

Watch 27

The moisture content was 19.66% (LOD), reaching a target peak moisture between 19% and 20% (LOD). Tables 28 and 29 summarize the physical properties after the granulation step and after the pastillation and drying steps.

Table 28: granulation characteristics

Sieve number	Retention%
		35(500μm)	0.0
45(355μm)	1.3
		60(250μm)	11.1
80(180μm)	16.2
		120(125μm)	19.4
170(90μm)	16.0
		230(63μm)	16.3
Dish	18.8

Table 29: characteristics of the final blend (after pastillation and drying)

Bulk Density (g/ml)	0.460
		Tightness of knock (g/ml)	0.566
Haosnabis	1.23
		Karl index	19

Tables 30 and 31 summarize the final blend characteristics of the formulations.

Table 30: characteristics of the final blend

Sieve number	Retention%
		35(500μm)	0.0
45(355μm)	0.8
		60(250μm)	10.8
80(180μm)	16.6
		120(125μm)	20.3
170(90μm)	17.2
		230(63μm)	15.6
Dish	17.0

Table 31: test results

Bulk Density (g/ml)	0.436
		Tightness of knock (g/ml)	0.573
Haosnabis	1.31
		Karl index	24

Table 32:

properties or settings	Initiation of	Intermediate (II)	End up
				Main pressure (kN)	9.9	9.9	-
Pre-pressure (kN)	3.5	4.0	-
				Pressing speed (rpm)	28.69	28.69	-
Degree of brittleness (%)	0.2	-	-
				Disintegration (second)	88	95	105

Watch 33

Feature(s)	Weight (D)	Thickness of	Hardness of
				Mean value of	1161	7.709	15.7
Standard deviation of	9.39	0.029	1.13
				Individual tablet minimum	1150	7.680	13.8
Maximum of individual tablets	1186	7.800	18.0
				RSD	0.81	0.38	7.20
Cpk	1.88	2.21	1.26

The compression data shows that the formulations and methods of the present invention are capable of producing robust tablets that disintegrate at a fast rate. Cpk values for individual tablet weights indicate that the process is capable of consistently producing tablets within the ± 5% specification of the target. The tablet thickness and tablet hardness meet certain acceptance criteria.

Coating and drying operating parameters:

an Opadry coating suspension was prepared with a solids content of 15 wt.%. The theoretical weight gain of the target batch was 3%. The film coating is a non-functional component used only for aesthetic purposes and therefore the actual weight gain is not critical for the efficacy of the drug. The spraying method is directed to a theoretical amount of coating suspension, rather than a specific weight gain (without using an efficiency factor). The average coated tablet weight after drying was 1110 mg.

The operating parameters in table 34 were used during the coating process:

watch 34

The operating parameters in table 35 were used during the final tablet drying process:

watch 35

Dissolution profiles indicate that higher tablet moisture levels will cause the dissolution rate to decrease over time. High moisture content tablets exposed to high temperatures experience an accelerated decrease in dissolution rate. The tablets after drying with a final moisture content of 8.84% (LOD) did not experience the same reduction in dissolution rate. Tablets containing high moisture content and calcium stearate experienced the greatest decrease in dissolution rate.

The moisture content of the core and coated tablets containing calcium stearate was slightly higher (about 15% LOD) than the core tablet containing sodium stearyl fumarate (about 14% LOD). Without wishing to be bound by a particular theory or mode of action, this may cause a difference in the observed dissolution rates. The final moisture content of the tablet and the 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 characteristics of the tablet stability before and after drying were measured. Stability included conditions of 25 ℃/60% RH and 40 ℃/75% RH. All samples were placed in HDPE bottles (0.025% wall thickness) with aluminum foil flaps, and a small portion of the study included bottles with desiccant. The following figures outline informal stability data.

Referring to fig. 9, the immediate dissolution rate of the tablets exposed to the post-drying treatment (greater than 80% 60 minutes after administration) was maintained. In the absence of post-drying treatment, the dissolution rate decreased significantly after one week.

Example 11: clinical study of ferric citrate dosage forms

A protocol for performing a clinical study of a ferric citrate drug formulation as described above is provided below.

The protocol includes a 6 week feasibility test of a novel formulation of KRX-0502 (ferric citrate) on End Stage Renal Disease (ESRD) patients. The study was aimed at determining the potential efficacy of KRX-0502 (ferric citrate) as a dietary phosphate binder and tolerability of serum phosphorus levels in patients with end-stage renal disease (ESRD) and monitoring changes in serum phosphorus from baseline to the end of treatment following four weeks of treatment.

The study design included drug studies on ESRD patients dialyzed three times a week. Approximately 24 patients (12 diabetic and 12 non-diabetic) began taking study medication for two to three weeks.

The study consisted of 5 sessions: screening, eliminating, studying the initial administration of the drug, treating and finally follow-up. A six-week treatment period follows the two-week washout period. The clinical trial is about three to four months in duration, with about two to three weeks allocated for patient screening, clearance and study drug start-up.

The study population included three hemodialysis sessions per week for at least three months prior to follow-up (follow-up 3) after study drug administration, with at least three tablets/capsules of calcium acetate, calcium carbonate, lanthanum carbonate, or sevelamer (hydrochloride or carbonate), or any combination of these agents, currently administered daily, and all ESRD patients eligible were enrolled. About 12 patients will be diabetic and 12 patients will be non-diabetic. About 24 to 48 patients were screened so that about 24 patients began taking study medication. All patients will be recruited from 2 to 4 sites.

The dosing study included having about 24 patients begin to take KRX-0502 (ferric citrate) after the two-week washout period of their current phosphate binder, and monitoring serum phosphorus levels during the study. The target serum phosphorus level is about 3.5 to 5.5 mg/dL. Serum phosphorus levels were checked weekly during clearance and during follow-up 4, follow-up 5, follow-up 6 and final follow-up (follow-up 7) of the treatment period.

The dose of KRX-0502 was determined as follows: all patients were started on study medication at a fixed dose of 6 tablets per day, with each ferric citrate tablet containing 210mg of ferric iron in the ferric citrate form (about 720mg of ferric iron in the ferric citrate form) and the patient's blood samples were titrated at visit 4, visit 5 and visit 6 as follows:

if the serum phosphorus content of the blood is 3.5 to 5.5mgs/dL, no treatment is required, if it is raised to >5.6 to 6.9mgm/dL, the drug dose is increased by one tablet per day, and if it is raised to 6.9mg/d, the dose is increased by three tablets per day up to 12 tablets per day.

The patient orally took the study medication with the meal or snack or within one hour of their meal or snack. If more than one hour has passed after ingestion of their meal or snack, the patient is instructed not to take study medication. Some patients may have different tablet assignments on a given day due to snacks or meals errors. For example, if the patient receives an initial dose of 6 grams per day, the patient may take 2 tablets with breakfast, 2 with lunch and 2 with dinner, and may change to 1 with breakfast, 1 with lunch and 2 with dinner (if the meal needs).

The second phase of the study in the statistical program (drug efficacy study) was to evaluate the tolerability and safety of the study drug. Drug safety was assessed by recording and monitoring adverse events, documenting concomitant drug use, performing simple physical examinations (body weight, blood pressure and heart rate), and obtaining continuous blood chemistry including serum phosphorus, serum calcium and selected iron parameters, and the rate of adverse events and changes in laboratory parameters.

While several particular forms of the invention have been illustrated and described, it will be apparent that various modifications and combinations of the contents described in the text and drawings can be made without departing from the spirit and scope of the invention. For example, references to construction materials, construction methods, particular dimensions, shapes, utilities, or applications are not intended to be limiting in any way, and other materials and dimensions may be substituted and still fall within the spirit and scope of the present invention.

Claims (26)

1. A tablet comprising granules comprising ferric citrate and a binder, wherein the granules have an average surface area to mass ratio equal to or greater than 1 m/g.

2. The tablet according to claim 1, wherein the average surface area to mass ratio of the granules is equal to or greater than 5 m/g.

3. The tablet according to claim 1, wherein the average surface area to mass ratio of the granules is equal to or greater than 10 m/g.

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

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

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

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

8. The tablet according to claim 1, wherein the LOD% of water in the tablet is less than 20% (water w/w).

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

10. The tablet of claim 1, wherein the LOD% of water in 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.

13. The tablet according to claim 1, wherein the tablet comprises:

about 65% to 92% ferric citrate;

about 4.5% to 30% binder; and

0.5% to 3% of a lubricant.

14. The tablet according to 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 according to claim 1, wherein at least 80% of the ferric citrate in the tablet dissolves in less than or equal to 60 minutes as measured by test method USP <711 >.

17. The tablet according to claim 1, wherein the tablet comprises about 1000mg ferric citrate.

18. The tablet according to claim 1, wherein the tablet comprises about 667mg of ferric citrate.

19. The tablet according to claim 1, wherein the tablet comprises about 500mg ferric citrate.

20. A method of making the tablet of claim 1, the method comprising:

mixing ferric citrate with one or more binders to form ferric citrate granules, under conditions wherein the LOD% of water does not exceed 25%;

the ferric citrate granules were tableted to form tablets.

21. The method of claim 20, wherein the particles have an average surface area to mass ratio greater than 1 m/g.

22. The method of claim 21, wherein the particles have an average surface area to mass ratio equal to or greater than 10 m/g.

23. The method of claim 18, wherein the mixing step comprises fluid bed granulation.

24. The method of claim 18, wherein the mixing step comprises high shear granulation.

25. The method of claim 20, further comprising heating the tablet to above 50 ℃.

26. A method of preventing or treating hyperphosphatemia comprising administering the tablet of claim 1.