WO2019012553A1

WO2019012553A1 - Process for preparation of compositions of ferric organic compounds

Info

Publication number: WO2019012553A1
Application number: PCT/IN2018/050442
Authority: WO
Inventors: Thilek Kumar Muniyappan; Rama Chandra Rao MOLLETI; Balaji PANDYA
Original assignee: RA Chem Pharma Ltd
Current assignee: RA Chem Pharma Ltd
Priority date: 2017-07-12
Filing date: 2018-07-07
Publication date: 2019-01-17
Anticipated expiration: 2020-01-12

Abstract

The invention relates to oral pharmaceutical compositions of ferric citrate comprising dry granulation, wherein ferric citrate is combined with dry binder or disintegrant, and a lubricant, which is roller compacted, and then mixed with extra granular material comprising disintegrant, and lubricant, wherein the amounts of said ingredients being such as to provide a disintegration time for the tablet in the order of 15 minutes or less.

Description

Process for Preparation of Compositions of Ferric Organic Compounds

This invention relates to process for preparation of pharmaceutical compositions of pharmaceutical grade ferric organic compounds, such as Ferric citrate.

Ferric iron containing compounds are useful in the treatment of a number of disorders, including, but not limited to, hyperphosphatemia and metabolic acidosis. Ferric iron containing compounds existing in the art are for example Ferric chloride, Ferric oxide, Ferric fluoride, and Ferric citrate. Elevated amounts of phosphate in the blood can be removed by administering compounds such as Ferric citrate. Once in solution, the ferric iron binds phosphate, and the ferric phosphate compounds precipitate in the gastrointestinal tract, resulting in effective removal of dietary phosphate from the body. It is also believed that the absorbed citrate from Ferric citrate is converted to bicarbonate which corrects metabolic acidosis, a condition common in renal failure patients.

Ferric citrate has the following structure, and can be referred to as FCT.

The novel form of Ferric citrate has the formula C₆H₅O₇Fe and has novel physical properties as determined by dissolution rates, and has a molecular weight of 244.94 g/mole. Ferric citrate is approved in 2014 in USA, and the NDA applicant is Keryx Pharmaceuticals. Pharmaceutical grade Ferric citrate is suitable for treating hyperphosphatemia, or other disorders characterized by high serum phosphate levels. Specifically, for treating subjects or patients with various renal diseases; e.g., End Stage Renal Diseases (ESRD), Chronic Kidney Disease (CKD) or other related kidney diseases, or subjects and patients who are on dialysis but not limited to hemodialysis. 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 5,753,706 discloses that Ferric citrate compounds can be used to control phosphate metabolism and prevent metabolic acidosis in patients. 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 a food supplement and additive. US 6,903,235 discloses that Ferric citrate is commercially available in the form of a combination of iron and citric acid of indefinite composition. It 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 amounts of water.

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 2007/089577 is directed to methods of treating soft tissue calcification using Ferric organic compounds, such as a Ferric citrate. WO 2007/089571 is directed to methods of treating chronic kidney disease using Ferric organic compounds, such as Ferric citrate. Where in US 7,767,851 relates to Ferric citrate having intrinsic dissolution of 1.9 to 4 mg/cm²/min, US 8,299,298 B2/ US 8,754,258 B2 relate to Ferric citrate having BET active surface area of at least 16 sq. m/g, US 8,338,642 B2/ US 8,901,349 B2/ US 8,609,896 B2 relate to Ferric citrate having BET active surface area greater than 16 sq. m/g. US 8,754,257 B2, US 9,328,133 and US 8,093,423 relate to FCT having intrinsic dissolution rate of 1.88-4.0 mg/cm²/min. US 8,754,258 B2/ US 8,846,976 B2/ US 9,050,316 B2 relate to FCT having intrinsic dissolution rate of at least 1.88 mg/cm²/min.

US 9,387,191/US 2013/274328 A1/US 2016/0263075 A relates to a composition of Ferric citrate comprising Pregelatinized starch, a lubricant and coating. IN 2016/28011726 which is an equivalent of US 9,387,191 relates to Ferric citrate tablet wherein the mean surface area to mass ratio of said granule particles is equal to or greater than 1 m²/g. IN 305/MUMNP/2012 which is an equivalent of US 9,387,191 relates to a tablet containing Ferric citrate with a mean surface area to mass ratio of 1 m²/g, and a binder, with LOD limitation. US 2016/0263038 which is assigned to Keryx pharma relates to FCT composition containing Pregelatinized starch. US 2009/0186939 which is an equivalent of US 7,767,851 relates to Ferric citrate having BET surface area ≥16m²/g. WO2016/162794 relates to FCT tablet, wherein Ferric citrate having a specific surface area less than 16m²/g. WO2016/162888 relates to Ferric citrate having a BET active surface area of less than 16 m²/g. WO 2015/110968 relates to Ferric citrate having a BET active surface area in the range of 1-15 m²/g. WO 2015/198304 discloses FCT tablet preparation and process for preparation FCT composition using wet granulation. IN241/MUM/2014 / IN 201627024694 relates to Ferric citrate having a BET active surface area in the range of 1-15 m²/gm. IN 996/DEL/2015 relates to pharmaceutical grade Ferric citrate having a BET active surface area of less than 16 m²/g and a mean dissolution rate of 4 to 9 mg/cm²/min. IN 253106 which is an equivalent of WO 2007/022435 relates to Ferric citrate having intrinsic dissolution of 1.9 to 4 mg/cm²/min, and BET active surface area greater than 16 m²/g.

Accordingly, there exists a need for improved/technologically advanced/economically feasible/scalable compositions of Ferric organic compounds or Ferric citrate for human use.

The main aspect of the invention is to provide an improved process for the preparation of pharmaceutical composition comprising Ferric citrate, along with pharmaceutically acceptable excipients, wherein the composition is prepared by dry granulation technique. According to other object of invention, the composition disintegrates within 15 minutes, and the BET surface area of Ferric citrate of the composition is the in the range of 6-12 m²/g.

The other aspect of the present invention is to provide a process for the preparation of an oral pharmaceutical composition comprising Ferric organic compound such as Ferric citrate using dry granulation.

In another aspect, the invention provides a pharmaceutical composition comprising:
a) Ferric organic compound; b) a binder; c) a disintegrant; d) a lubricant, and other optional excipients.

In another aspect, the invention provides a pharmaceutical composition in the form of a tablet that comprises Ferric organic compound, and one or more pharmaceutically acceptable excipients, for example, a disintegrant, a binder, and a lubricant or any combination thereof.

In yet another aspect, the invention provides a pharmaceutical composition consisting of a tablet that comprises a powder blend or granules comprising ferric organic compound; and, one or more pharmaceutically acceptable excipients, for example, a disintegrant, a binder, and a lubricant using dry granulation technology.

In another aspect the pharmaceutical composition of the invention disintegrates within 15 minutes.

In another aspect, the pharmaceutical composition is directed to a tablet comprising Ferric citrate having a BET surface area in the range of 6-12 m²/g.
Description of the Embodiments

The present invention relates to process for the preparation of pharmaceutical composition of ferric organic compound.

Disclosed herein are pharmaceutical compositions and process for preparation of compositions containing ferric organic compounds which can include Ferric Citrate, Iron Sucrose, Sucroferric Oxyhydroxide, preferably Ferric Citrate.

According to one embodiment of invention, the pharmaceutical composition is a tablet that includes ferric citrate and a binder or disintegrant and one or more pharmaceutically acceptable excipients.

According to the other embodiment of the present invention the pharmaceutically acceptable excipients are selected from a glidant, a binder, a diluent/filler, a lubricant, a disintegrant, etc.

As used herein, the term “glidant” is intended to mean an agent used in tablet and capsule formulations to promote flowability of the granulation. Such compounds include, by way of example and without limitation, colloidal silica, cornstarch, talc, calcium silicate, magnesium silicate, silicon hydrogel and other materials known to one of ordinary skill in the art.

According to one aspect, “binder” can be one or more of acacia, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, low substituted hydroxypropylcellulose, dextrin, gelatin, guar gum, hydroxypropyl methylcellulose, magnesium aluminum silicate, maltodextrin, methylcellulose, polyethylene oxide, polymethacrylates, povidone, sodium alginate, starches and zein and other materials known to one of ordinary skill in the art.

As used herein, the term “diluent” or “filler” is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of tablets and capsules. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, lactose, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, and starch and other materials known to one of ordinary skill in the art.

As used herein, the term “lubricant” is intended to mean a substance used in the instant formulations to reduce friction during compression or other processing. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, and zinc stearate and other materials known to one of ordinary skill in the art.

As used herein, the term “disintegrant” is intended to mean a compound used in solid pharmaceutical compositions to promote the disruption of the solid mass into smaller particles that are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, corn starch, potato starch, pre-gelatinized and modified starches thereof, microcrystalline cellulose, croscarmellose sodium, cross linked cellulose, low substituted hydroxypropyl Cellulose, cellulose polyacrilin potassium, alginates, sodium starch glycolate, crospovidone and other materials known to one of ordinary skill in the art.

Pharmaceutical-grade ferric citrate contains a definite composition and a definite hydrate.

The other embodiment of the present invention provides the method wherein an effective amount of pharmaceutical-grade ferric citrate is administered in the form of a tablet, a powder, a capsule, a lozenge, a granule, a troche, or a pill.

In one embodiment, the composition can be prepared by dry granulation. The ferric organic compound is ferric citrate. The invention provides a process for making the pharmaceutical compositions described herein by roller compaction process comprising the steps of weighing ferric organic compound and excipients; screening, blending ferric organic compound and excipients; roller compacting the blend into ribbons and milling the ribbons into granules; blending the granules with extra-granular excipients for a suitable amount of time; compressing the blend into tablets; coating the tablet.

Roller compactor is widely used as one of dry granulation processes. Most of the dry granulation processes do not use solvents, and thus do not cause problems of picking and sticking in which uneven spots occur on the surface of tablets.

The other methods commonly used in the pharmaceutical industry, such as wet granulation has been proven to be disadvantageous mainly because the solvents needed in the granule and tablet manufacturing process often have an adverse effect on the characteristics of the active pharmaceutical ingredients (APIs) and/or on the end product such as a tablet. Dry granulation is usually described as a method of controlled crushing of precompacted powders densified by either slugging or passing the material between two counter-rotating rolls. More specifically, powdered components that may contain very fine particles are typically mixed prior to being compacted to yield hard slugs which are then milled and sieved before the addition of other ingredients and final compression to form tablets. Because substantially no solvents are used in the dry granulation process, the issues related to wet granulation are avoided. Although dry granulation would in many cases appear to be the best way to produce products such as tablets containing APIs, it has been relatively little used because of the challenges in producing the desired particle size of granules as well as managing the granulated material in the manufacturing process. Known dry granulation methods, as well as the known issues related to them are well described in scientific articles, such as the review article "Roll compaction / dry granulation: pharmaceutical applications" written by Peter Kleinebudde and published in European Journal of Pharmaceutics and Biopharmaceutics 58 (2004) at pages 317-326.

According to another aspect, the invention provides a process for making the pharmaceutical compositions described herein by roller compaction process comprising the steps of weighing ferric organic compound and excipients; screening, blending ferric organic compound and excipients for a suitable amount of time; roller compacting the blend into ribbons and milling the ribbons into granules; blending the granules with extra-granular excipients for a suitable amount of time; compressing the blend into tablets; coating the tablets.

According to yet another embodiment, the method for producing a pharmaceutical composition comprises providing an admixture of solid forms, e.g. an admixture of powdered ingredients, the admixture comprising ferric organic compound and one or more excipients selected from: a binder, a glidant, a diluent, a lubricant, a disintegrant, and a filler; mixing the admixture until the admixture is substantially homogenous, and compressing/compacting the admixture into a slugs/compacts using a roller compactor using a dry granulation composition as set forth in the Examples below. Pharmaceutical formulations, for example a tablet as described herein, can be made using the granules prepared incorporating ferric organic compound in addition to the selected excipients described herein.

According to yet another aspect, process for preparing a tablet, which comprises:

(a) Sifting and blending a ferric organic compound, with one or more excipients selected from a binder, a glidant, a diluent, a lubricant, a disintegrant, a filler, and other pharmaceutically acceptable excipients.

(b) Roller compacting the formulation prepared during step (a) followed by milling to get desired particle size of granules.

(c) Compressing the formulation prepared during step (b) to form the compressed tablet.

The present inventors have conducted extensive studies to overcome the above-described problems occurring in wet granulation and ensuring flowability by a dry granulation process using a roller compactor.

According some embodiments, roller compaction is a granulation process comprising highly intensive mechanical compacting of one or more substances. In some embodiments, a pharmaceutical composition comprising an admixture of powders is pressed, that is roller compacted, between two counter rotating rollers to make a solid sheet which is subsequently crushed in a sieve to form a particulate matter. In this particulate matter, a close mechanical contact between the ingredients can be obtained. An example of roller compaction equipment is Minipactor® a Gerteis 3W-Polygran from Gerteis Maschinen+Processengineering AG, Chilsonator roll compactor machine manufactured by Fitzpatrick.

According to another embodiment, the admixture comprises a composition of ferric organic compound, and any combination of: a binder, a glidant, a diluent, a surfactant, a lubricant, a disintegrant, and filler and other pharmaceutically acceptable excipients.

According to yet another embodiment, the ferric organic compound formulation which disintegrates in less than 15 minutes in the USP disintegration test carried out over the anticipated viscosity range in the stomach.

Ferric citrate according to the present invention has the BET surface area of 6-12 m²/g. Brunauer–Emmett–Teller (BET) theory relates to the physical adsorption of gas molecules on a solid surface and serves as the basis for an important analysis technique for the measurement of the specific surface area of materials.

BET analysis provides precise specific surface area evaluation of materials by nitrogen multilayer adsorption measured as a function of relative pressure using a fully automated analyser. The technique encompasses external area and pore area evaluations to determine the total specific surface area in m²/g yielding important information in studying the effects of surface porosity and particle size in many applications.

The analysis of active surface area is based on BET theory which describes the phenomenon of mass and energy interaction and phase changes during gas adsorption onto solid surfaces and in pore spaces. In BET active surface area measurement, the volume of a monolayer of gas is determined which allows the surface area of the sample to be determined using the area occupied by a single layer of adsorbed gas molecule.

According to some embodiments, tablets comprising a pharmaceutical composition as described herein can be optionally coated with a film coating.

The following examples illustrate various aspects of the present invention. They are not to be construed to limit the claims in any manner whatsoever.

Examples

Example 1: Ferric citrate formulation was prepared by using dry granulation technique, where L-HPC has been used as the disintegrant.

Excipients	mg/unit	% w/w
Core Tablet
Ferric citrate	1000.0	88.50
L-HPC	20.0	1.77
Calcium Stearate	10.0	0.88
Extragranular Part
L-HPC	80.0	7.08
Calcium Stearate	20.0	1.77
Tablet weight	1130	100.00
Film coating
Opadry	20.0
Purified water	QS
Total	1150.0	100.00

Example 2: Ferric citrate formulation was prepared by using dry granulation technique, where Crospovidone has been used as the disintegrant.

Excipients	mg/unit	% w/w
Core Tablet
Ferric citrate	1000.0	88.50
Hydroxypropyl methyl cellulose	20.0	1.77
Magnesium Stearate	10.0	0.88
Extragranular Part
Crospovidone	80.0	7.08
Magnesium Stearate	20.0	1.77
Tablet weight	1130	100.00
Film coating
Opadry	20.0
Purified water	QS
Total	1150.0	100.00

Example 3: Ferric citrate formulation was prepared by using dry granulation technique, where Croscarmellose sodium has been used as the disintegrant.

Excipients	mg/unit	% w/w
Core Tablet
Ferric citrate	1000.0	88.50
Hydroxypropyl methyl cellulose	20.0	1.77
Magnesium Stearate	10.0	0.88
Extragranular Part
Croscarmellose sodium	80.0	7.08
Magnesium Stearate	20.0	1.77
Tablet weight	1130	100.00
Film coating
Opadry	20.0
Purified water	QS
Total	1150.0	100.00

Example 4: Ferric citrate formulation was prepared by using dry granulation technique, where L-HPC has been used as the disintegrant.

Excipients	mg/unit	% w/w
Core Tablet
Ferric citrate	1000.0	88.50
Hydroxypropyl cellulose	20.0	1.77
Magnesium Stearate	10.0	0.88
Extragranular Part
L-HPC	80.0	7.08
Magnesium Stearate	20.0	1.77
Tablet weight	1130	100.00
Film coating
Opadry	20.0
Purified water	QS
Total	1150.0	100.00

Manufacturing Process:
a) The drug substance and dry binder were sifted and loaded into blender and blended for about 10 min,
b) The intragranular lubricant was sifted and added to above step and blended for about 5 min,
c) The above material was loaded into hopper of Compactor and compacted with suitable hardness of ribbons with preset roller RPM, GAP, Vertical and horizontal feeder screw speed.
d) The above flakes were milled in multimill fitted with suitable screen at suitable speed and suitable direction,
e) The milled material was sifted using suitable ASTM mesh. The compaction followed by milling process will be continued till desired particle size of granules obtained.
f) The above material loaded in blender and blended for 5 min,
g) The extragranular material was sifted through # 40 ASTM and loaded to above step and blended for 5 min,
h) The above lubricated material compressed into tablets with suitable punches,
i) The core tablets are coated with opadry and evaluated for physicochemical properties.

Claims

A process for preparation of a pharmaceutical composition comprising ferric organic compound, and one or more pharmaceutically acceptable excipients using dry granulation technique.
A process for preparation of a pharmaceutical composition comprising ferric organic compound, and one or more pharmaceutically acceptable excipients, wherein the finished product disintegrates within 15 minutes.
Ferric organic compound of claim 1 is selected from the group comprising of Ferric Citrate, Iron Sucrose, Sucroferric Oxyhydroxide, preferably Ferric Citrate.
Process according to claim 1 wherein the dry granulation involves use of roller compaction or slugging by using compression machine.
A process for preparation of a composition comprising ferric citrate for use in forming a pharmaceutical composition, wherein the process comprises:
(a) sifting and blending ferric citrate, dry binder or disintegrant and lubricant
(b) compacting and milling the compacted material
(c) adding the extra granular material comprising disintegrant, and lubricant to step b compacted material, and compressing into tablets.
(d) the compressed tablets of step c are optionally coated with a film coating material.
The process according to claim 5, wherein the binder is selected from group consisting of acacia, carboxymethylcellulose, hydroxyethylcellulose, low substituted hydroxypropyl cellulose, hydroxypropylcellulose, dextrin, gelatin, guar gum, hydroxypropyl methylcellulose, magnesium aluminum silicate, maltodextrin, methylcellulose, polyethylene oxide, polymethacrylates, povidone, sodium alginate, starches and zein or any combinations thereof.
The process according to claim 5, wherein the lubricant is selected from one or more of magnesium stearate, calcium stearate, sodium stearyl fumarate, polyethylene glycol, talc.
The process according to claim 5, wherein the disintegrant is selected from corn starch, potato starch, pre-gelatinized and modified starches thereof, microcrystalline cellulose, croscarmellose sodium, cross linked cellulose, low substituted hydroxypropyl Cellulose, cellulose polyacrilin potassium, alginates, sodium starch glycolate, crospovidone.
A solid pharmaceutical composition comprising ferric citrate having BET surface area of 6-12 m²/g, wherein the composition is prepared by dry granulation using roller compaction, and the finished product disintegrates within 15 minutes.
A solid pharmaceutical composition comprising ferric citrate prepared by dry granulation technique having BET surface area of 6-12 m²/g.