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THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10; rule 13}
1. Title of the Invention : "PROCESS OF MAKING CALCIUM CARBONATE GRANULES AND COMPOSITIONS THEREOF "
2. Applicant(s)

(a) NAME : IDEAL CURES PVT. LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS : A-223-229, 2nd floor, Virwani Industrial Estate, Off. Western Ex press Highway, Goregaon (East), Mumbai - 400 063. E-mail- patent@idealcures.co.in
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Title:- PROCESS OF MAKING CALCIUM CARBONATE GRANULES AND COMPOSITIONS THEREOF
Field of the Invention
The present invention relates to novel excipient composition of brittle compounds like calcium salts for manufacture of pharmaceutical solid dosage forms such as microsphere(s), tablets, capsule fillers, suspended solid particles and variant thereof. Present invention also relates to process of making novel excipient granule, sphere of plurality of sizes. Further invention relates to process of manufacturing solid dosage form with novel excipient composition of present invention, along with active pharmaceutical ingredient.
Background or Information on Art
Manufacturing a solid oral dosage in tablet form is typically obtained through mixing active pharmaceutical ingredient and excipient. Generally, a mixture is converted to tablet form by way of compression. To qualify for stability standards and application tablet should remain intact during entire processing, it should have stability in terms of activity and physical appearance during storage and transportation. Changes in any property can affect API activity and bioavailability, which will eventually affect its release profile and reproducible results will not come.
A commonly used excipient class is of Calcium salts, wherein Calcium carbonate (CaC03) being highly acceptable by animal body including human body without any side-effects. However, the use of Calcium Carbonate has two major disadvantages. First, Calcium Carbonate has an extremely low compressibility along with brittleness, which makes it difficult to form suitable tablets by direct compression. Further, Calcium Carbonate is physically abrasive, lending an undesirable mouth feel to

tablets, as well as leading to increased wear and tear of tableting punches or drug loading process.
It is well-known in the art that calcium carbonate lacks the ability to form intact mass, and therefore, it must be converted into small granules to form more suitable for tablet manufacturing. Commonly, a process to convert abrasive/brittle compounds into granules involves the addition of compounds with adhesive properties leading to binding of all components. Granulation methods in state of the art include wet granulation, dry granulation, and fluid bed granulation. Among these, wet granulation is the most widely used process to make granules of desired size.
PCT Patent application WO2007065441 discloses process for making partly film-coated and/or granulated calcium containing compounds, after compression resulted tablets having a very high load of elemental calcium and a conveniently small size. In accordance with publication formulation comprising 1250 mg calcium carbonate, 133.5 mg xylitol, 16 mg Povidone 30, 0.5 mg Sucralose prepared in fluid bed granulator.
U.S. Patent No. 4,744,987 illustrates the granules of processed microcrystalline cellulose and calcium carbonate composition, publication illustrate individual components having maximum weight ratio of 75:25. However publication fails to provide process and method to give granules of weight ratio more than 75:25.
Patent application WO2006092727 discloses a process for producing a particulate material comprising a calcium-containing compound, the process comprises granulating and/or coating a powder mixture, which comprises the calcium-containing compound together with one or more pharmaceutically acceptable excipients in a continuous fluid bed apparatus.

There is a continuing need for granulations of brittle compounds, having high compressibility. Accordingly, it is an object of the invention to provide granules and process for granulation of brittle compounds such as Calcium salts and like, that can be compressed into solid dosage forms. Further, it is an object of the invention to provide formulations and processes for preparing granulations.
There is therefore, a need for a universal excipient composition of improved Calcium salt solid formulation excipient that provides sufficient compressibility.
Summary of Invention
In accordance with the foregoing objectives, the present invention provides micronized granule of brittle compound(s) with a polymer, a binder, a surfactant/stabilizer and process for making thereof. In one of the embodiment micronized granules can optionally have an active pharmaceutical ingredient, colorant(s), sweetener(s) and other pharmaceutically acceptable ingredients compositions and process for making thereof.
The present invention also aims to provide solid formulation(s) made by micronized product /granule(s)/sphere(s) of present invention also the formulations made by encapsulation/coating/layering/center-filling/gel/cosmetic product or like by resultant sphere granules of present invention.
In one of the aspect, present invention also provides composition of granule having Calcium salt(s) with at least one binder like polyvinylpyrrolidone or variant thereof, at least one polymer like HPMC, at least one surfactant like tween-80, SLS or variant thereof.
In another aspect, the present invention also provides spray drying process for making granules having Calcium carbonate.

In another aspect of the present invention provides process of making granules or sphere of calcium carbonate comprising calcium carbonate 60-90% w/w; HPMC 0.01-20% w/w; polyvinylpyrrolidone 0.01-10% w/w; and tween-80 0.01-5% w/w, wherein all components are adjusted and blended together, reconstituted in pharmaceutically acceptable solvent and spray dried at desirable pressure and temperature.
The details of one or more embodiments in the practice of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the appended examples and claims.
Detailed description
Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described. To describe the invention, certain terms are defined herein specifically as follows.
Unless stated to the contrary, any of the words "having" "including," "includes," "comprising," and "comprises" mean "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims.
Present invention provides highly dense and highly compactable granulation compositions. In accordance with objective of invention micronized product of the invention is prepared through process of spray drying. In one of the embodiment

and preferred method, the granulation compositions comprise calcium salts. The fine granule size of the micronized product have a particle size of a No. 60 to 120 sieve, preferably 80 to 120 sieve, therefore having a median particle size in the range of from 125 microns to 250 microns or 125 microns, preferably 125 microns to 180 microns respectively. Variety of sources are available for commercial grade calcium carbonate prepared from mineralized rock, chemical process, bones etc. exhibiting large range of particle sizes.
According to objective of invention 'brittle compound' includes but not limited to salts of calcium and variant thereof, like calcium phosphate, calcium carbonate, heavy calcium carbonate, or any physical or chemical form of calcium salt acceptable to animal administration including human.
Granules of brittle compounds like Calcium salts can be prepared by novel process. Granules can be singular or adhere together in plurality of numbers e.g. monomer, dimer, irregular mass and they could be separated by other means.
To adhere with composition binder is used having adhesive property, binder molecule bind brittle compound to other components of composition to make an intact form. Binders are selected from synthetic polymers, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, either alone or in combination thereof.
To make a polymeric coalescence with composition, polymer is used having polymeric capabilities, polymer molecule coalesce with brittle compound to other components of composition to make an intimate form. Polymer are selected from hydroxypropyl methylceJlulose (HPMC) (e.g. HPMC E5 / E15,HPMC K4M / K100 or like)sodium carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, In one of the preferred embodiment inventors have exemplified objective of invention by using HPMC K100 and/or HPMC E15 as polymer.

Surfacetant stabIizer is a material which enhances the surface wetting of the poorly soluble material like calcium carbonate and granules/sphere produced thereby. It was observed that addition of such surfactant produces the granules / spheres which are much easier to process further either for direct compression into compressed tablets or used for drug loading. Surfactant(s) that are included in the formulation are but not limited to Tween-20, Tween-40, Tween-60, Tween-80, sodium lauryl sulphate either alone or in combinations thereof.
In accordance of the present invention a coalesced granules is provided comprising brittle compound like calcium carbonate and polymer with binders, produced granules of present invention is defined as 'micronized product'. Additionally the term coalesced would mean physical processing of brittle compound with polymer and binder in accordance with process of present invention providing enhanced physical properties to generated granules which were not exhibited by either brittle compound or binder alone or by simple blends of dry mixture of them.
The spray drying step may likewise include any spray drying technique that is known for or otherwise suitable for use in the production of granules or spheres. Many different spray drying methods and techniques are known like spray-drying, flame-spray, low-pressure spraying, electro-spray etc. for use in the granulation or spheronization field, all of which are theoretically suitable for use in the manufacture of the granules or spheres herein.
It was surprisingly found by inventors that by the use of novel composition, sphere or granules of brittle compounds can be easily prepared which can then be further processed very easily to form compressed tablets or for drug loading. It is well known in the art that, brittle compounds cannot be used efficiently in tableting or drug loading. Invention thereby solves the problem in efficient manner and improves API loading on granules.

According to one of the main embodiment of the present Invention brittle compound is mixed with polymer and binder in pharmaceutically acceptable liquid and spray dried at desirable pressure and temperature. In another embodiment of present invention brittle compound is calcium carbonate, polymer is hydroxypropylmethyl cellulose and binder is polyvinylpyrrolidone in pharmaceutically acceptable liquid is water, and all are mixed to prepare slurry. In yet another embodiment brittle compound is mixed with polymer, binder and surfactant to generate slurry. Further in accordance with inventive process slurry generated is dried by spry drying method to get micronized product. Therefore micronized product comprises brittle compound, polymer and binder, or calcium carbonate, hydroxypropyl methylcellulose and polyvinylpyrrolidone. In some of the embodiment of present invention brittle compound and polymer are in ratio of about 88:12 to 86:14, or about, it is to be noted by skilled artisan other ratios may also provide satisfactory micronized product based on choice of components used for brittle compound, polymer, binder, surfactant etc.
In yet another embodiment micronized product comprise brittle compound in 60-90% w/w; polymer preferably in 0.01-20% w/w; binder preferably in 0.01-10% w/w; and surfactant preferably in 0.01-5% w/w of dry weight of slurry. In one of the embodiment weight ratio of polymer to brittle compound is in the range of from 88:12 to 86:14 and weight ratio of binder to brittle compound is in the range of from 93:7 to 95:5.
In an embodiment micronized product comprise heavy calcium carbonate in range of 60-90% w/w; hydroxypropyl methyl cellulose preferably in range of 0.01-20% w/w; polyvinylpyrrolidone preferably in range of 0.01-10% w/w; and surfactant preferably in range of 0.01-5% w/w of dry weight, in one of the embodiment weight

ratio of polymer to calcium carbonate is in the range of from 88:12 to 86:14 and weight ratio of binder to calcium carbonate is in the range of from 93:7 to 95:5.
In accordance with the objective micronized product spry dry method is used to get desired granules of brittle compound. It is to be noted that co-processed micronized granules of brittle compound, polymer and binder are coalesced and fused together to form a physical complex of intimate association. Surprisingly inventors observed that such physical complex is not seen when dry blending or other granulation methods were used for generating equivalent micronized product.
In one of the embodiment process of manufacturing micronized product granule or sphere of brittle compound comprises, brittle compounds in range of 60 to 90% w/w; polymer in range of 0.01 to 20% w/w; binder in range of 0.01 to 10% w/w; and surfactant in range of 0.01 to 5%, wherein all components are blended together, reconstituted in pharmaceutically acceptable liquid and spray dried at desirable pressure and temperature.
In one of the embodiment process of manufacturing micronized product granule or sphere of brittle compound comprises heavy calcium carbonate in range of 65 to 82% w/w; HPMC in range of 0.5 to 20% w/w; polyvinylpyrrolidone K-30 selected in range of 1 to 10% w/w; and at least one surfactant like tween-80 selected from range of 0.5 to 3% w/w, wherein all components are blended together, reconstituted in pharmaceutically acceptable liquid and spray dried at desirable pressure and temperature.
The ingredients of novel composition are mixed in water or other pharmaceutically suitable liquid to provide slurry or semi-solid liquid or liquid slurry of spray able acceptable viscosity. Alternatively Novel compositions are mixed in dried state and there after mixed in water or other suitable liquid to provide slurry or semi-solid

liquid or liquid slurry. Subsequently slurry like substance obtained above is maintained in range of 25 to 40% of solid content preferably 30 to 35% of solid content. Such liquids or slurry from the composition described herein are used as feeder solution to Spray drier. In accordance with such methods, the liquids may be supplied to Spray-drier in a controlled manner (with pre-defined rates and solids content) as needed to provide the desired characteristics of granules or spheres, most typically in the form of peristaltic motion, continuous stream with or without air pressure. Slurry purging volumes adjusted according to requirements typically per hour volume which can go as high as 1000 kg/hour. In one of the embodiment of lab scale size feeding rate was 5 Kg per hour. Accordingly Inlet temperature of spray dryer can be adjusted according to requirements typically temperature varies upto 500°C. Accordingly outlet temperature of spray dryer can be adjusted according to requirements typically temperature varies upto 500°C. Accordingly Evaporation rate of spray dryer can be adjusted according to requirements could be varied upto 24 Hours.
In one of the preferred embodiments of invention inlet-outlet temperature and evaporation rate of spray dryer was adjusted according to Table 1.
Table 1. Spray dryer physical parameters at production scale.

SN. Inlet Spray dryer temperature (°C) Outlet Spray dryer temperature (°C) Evaporation rate (Kg)
1 180 80 300-350
2 225 100 350-400
Micronized product or granules produced by spray drying process could be plurality of mesh sizes, in one of the embodiment of present invention preferable mesh size varies from 60 to 120. In preferred aspects, the granule size of micronized product

have a median particle size of less than about 250 microns, preferably less than about 180 microns and most preferably in range of 125 to 180 microns. In one of the embodiment micronized product have at least 99% of particles with dimensions less than about 250 microns, most preferably at least 82% of particles has less than about 180 microns. In accordance with spray dry process in one of the embodiment micronized product generated are characterized by having about 15 to 19 % of 180 to 250 microns, about 35 to 39 % of 150 to 180 microns, about 22 to 28% of 125 to 150 microns and about 18 to 20% of less than 125 microns. In order to evaluate integrity of the micronized product friability test was performed and related integrity of granules prepared is represented as percentage of granule weight loss after 400 strokes per minutes in a Electrolab Granule Friabilator. Micronized product granules were having friability of 0.1 to 0.2%, it is well known in the art that solid substrates having friability in range of about 0% to 3% is useful for pharmaceutical purpose.
\n accordance with the methods of manufacture herein, it is preferred that all of the compositions are spray dried as describe herein. Solid granules prepared through spray drying may be further be coated by a known techniques, suitable for preparing pharmaceutically acceptable coating and/or formulating coated granules.
Invention provides enhanced granules/spheres having strong integrity, stability, shock absorbance, strong holding capacity within composition. Granules and Sphere made by composition have good holding capacity for pharmaceutically acceptable API.
Suitable APIs that can be used with the present invention include, but are not limited to: adrenergic blocking agent; acetyl-choline-esterase inhibitor; analgesic or antipyretics; angiotensin modulator; anthelmintic agents; anti-anxiety agent; antibacterial; antibiotic; anticoagulant; anticonvulsant; antidepressant; antifungal;

antihistamine; antimalarial; antimicrobial agent; antipsychotic agent; Antiviral agents; blood glucose lowering drug; calcium channel modulator; diuretic; erectile dysfunction; gastric acid secretion inhibitor; histamine H2-receptor antagonist; inhibitor of steroid Type II 5[alpha]- reductase including; lipid regulating agents; selective HI- receptor antagonist; vasodilator; vitamins.
In one of embodiment the micronized product is particularly useful as an excipient in processes involving roller compaction, granulation, and/or tabletting.
For example, the micronized product may be utilized in the following process: The micronized product is used to load API or blended with an API with other pharmaceutical excipients; alternatively micronized product is used to load API by standard means and generated granules are further supplemented with other pharmaceutical ingredients to be filled in standard capsule. For the purpose of creating solid oral dosage forms like tablets etc micronized product is blended with API and other pharmaceutical excipient this blend is compacted using a roller compactor or similar function device, if required to reduce sticking on the compaction rolled lubricant can be added to form tablets.
Following examples are offered to more fully illustrate the invention, but are not to be construed as limiting the scope thereof.
Example 1. Manufacturing granules of calcium carbonate in tray dryer.
Table 2

Component Percentage Quantity
CaC03 81.5%
HPMCE15 10%
HPMC K100 0.5%
Polyvinylpyrrolidone 6%
Tween 80 2%

Dry blending of calcium carbonate, HPMC in the rapid mix granulator to get a uniform mix. Prepare a dispersion by dissolving polyvinylpyrrolidone in water. Subsequently add the binding solution to calcium carbonate rapid mix granulated powder blend and granulate the mixture. Further generated wet mass is thoroughly dried in the tray dryer. After drying resultant dry mass is sieved through #80, #120 and other mesh size sieves to generate granules. It was noted that granules obtained by above tray dry process were average conditions for drug loading having problems of granule breaking, melting and fractures.
Example 2 Manufacturing # 80 size granules of calcium carbonate in tray dryer.
Table 3

Component Percentage Quantity
CaC03 74%
HPMCE15 17.5%
HPMCK100 0.5%
polyvinylpyrrolidone 6%
Tween 80 2%
Dry blending of calcium carbonate, HPMC in the rapid mix granulator to get a uniform mix. Prepare a dispersion by dissolving polyvinylpyrrolidone in water. Subsequently add the binding solution to calcium carbonate rapid mix granulated powder blend and granulate the mixture. Further generated wet mass is thoroughly dried in the tray dryer. After drying resultant dry mass is sieved through #80, #120 and other mesh size sieves to generate granules. It was noted that granules obtained by above tray dry process were average conditions for drug loading having problems of granule breaking, melting and fractures.

Example 3 Manufacturing #60, #80, #120 mesh size granules of calcium carbonate by spray drying
Table 4

Component Percentage Quantity Quantity (Kg)
CaC03 71.5% 71.5
HPMCE15 20% 20.0
HPMCK100 0.5% 0.5
polyvinylpyrrolidone 6% 6.0
Tween 80 2% 2.0
TOTAL 100.0
In order to generate coalesced micronized product, table 4 ingredients were taken as calcium carbonate is blended with polymer hydroxypropyl methylcellulose and binder polyvinylpyrrolidone and slurry is prepared with sufficient amount of de-mineralized water at 60°C. Subsequently slurry like substance obtained above is maintained for 33% of solid content. As explained in description many state of the art spraying techniques can be utilized to spray dry slurry thus prepared. Spray drier having rotatory disc atomizer is used to prepare micronized product or granules with inlet temperature of about 180±5 °C and outlet temperature of about 80±5 °C along with feeding rate of 5 Kg per hour and evaporation rate of 5 Kg per hour at laboratory scale. Example yields granules of sizes in range of 125 to 250 microns wherein more than 60% were in range of 125 to 180 microns and have friability of less than 0.20%, and found to be good for API loaded/coated solid dosage manufacturing, additionally granules/spheres exhibit excellent stability during API loading/coating.
Example 4 Manufacturing #60, #80, #120 mesh size granules of calcium carbonate in Spray dryer.

Table 5

Component Percentage Quantity Quantity (Kg)
CaC03 81.5% 815
HPMCE15 10% 100
HPMCK100 0.5% 5
polyvinylpyrrolidone 6% 60
Tween 80 2% 20
Total 1000
In order to generate coalesced micronized product, table 5 ingredients were taken as calcium carbonate is blended with polymer hydroxypropyl methylcellulose and binder polyvinylpyrrolidone and slurry is prepared with sufficient amount of de-mineralized water at 60°C. Subsequently slurry like substance obtained above is maintained for 33% of solid content. As explained in description many state of the art spraying techniques can be utilized to spray dry slurry thus prepared. Spray drier having rotatory disc atomizer is used to prepare micronized product or granules with inlet temperature of about 180±5 °C and outlet temperature of about 80±5 °C along with feeding rate of 300 Kg per hour and evaporation rate of 300 Kg per hour at commercial scale. Example yields granules of sizes in range of 125 to 250 microns wherein more than 60% were in range of 125 to 180 microns and found to be fine for API loaded/coated solid dosage manufacturing, additionally granules/spheres exhibit good stability during API loading/coating.
Example 5 Manufacturing #60, #80, #120 mesh size granules of calcium carbonate by spray drying

Table 6

Component Percentage Quantity Quantity (Kg)
CaC03 71.5% 715
HPMC E15 20% 200
HPMC K100 0.5% 5
polyvinylpyrrolidone 6% 60
Tween 80 2% 20
Total 1000
In order to generate coalesced micronized product, table 6 ingredients were taken as calcium carbonate is blended with polymer hydroxypropyl methylcellulose and binder polyvinylpyrrolidone and slurry is prepared with sufficient amount of de-mineralized water at 60°C. Subsequently slurry like substance obtained above is maintained for 33% of solid content. As explained in description many state of the art spraying techniques can be utilized to spray dry slurry thus prepared. Spray drier having rotatory disc atomizer is used to prepare micronized product or granules with inlet temperature of about 180±5 °C and outlet temperature of about 80±5 °C along with feeding rate .of 400 Kg per hour and evaporation rate of 400 Kg per hour at commercial scale. Example yields granules of sizes in range of 125 to 250 microns wherein more than 60% were in range of 125 to 180 microns and have friability of less than 0.20%, and found to be good for API loaded/coated solid dosage manufacturing, additionally granules/spheres exhibit excellent stability during API loading/coating.

We Claim,
1. A coalesced micronized product comprising brittle compound in the range of 60-90%, polymer in the range of 0.01 to 20%, binder in the range of 0.01 to 10%, surfactant in range of 0.01 to 5%.
2. The granules of claim 1, wherein the micronized product is obtained by forming a slurry of brittle compound, binder, polymer, surfactant and spray drying the slurry.
3. A coalesced micronized product comprising brittle compound, polymer, binder and surfactant, wherein the micronized product of 125 -250 microns is obtained by spray drying.
4. The coalesced micronized product of claim 1 and 3, wherein brittle compound is selected from salts of calcium, calcium phosphate, calcium carbonate, heavy calcium carbonate and variant thereof, any physical or chemical form of calcium salt acceptable to animal administration including human.
5. The coalesced micronized product of claim 1 and 3, wherein binder is selected from group comprising polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, either alone or in combination thereof.
6. The coalesced micronized product of claim 1 and 3, wherein polymer is selected from group comprising hydroxypropyl methylcellulose (HPMC) or its variants, sodium carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, either alone or in combination thereof.
7. The coalesced micronized product of claim 1 and 3, wherein surfactant is selected from group comprising polysorbate-20, polysorbate -40, polysorbate -60, polysorbate -65, polysorbate -80, sodium lauryl sulphate either alone or in combinations thereof.
8. The coalesced micronized product of claim 1 and 3, wherein at least one calcium salt is in the range of from 88:12 to 86:14 and weight ratio of binder to calcium salt is in the range of from 93:7 to 95:5.
9. The coalesced micronized product of claim 1, wherein the at least one micronized granule has a mean diameter measured by sieve analysis, between 125 and 250 microns.

10. A granulate or tablet formulation comprising the micronized product of claim 1 and at least one drug molecule.
11. Process of manufacturing micronized product according to claim 1, comprising stages:

I) preparing a slurry of brittle compound, polymer, binder, surfactant in water;
II) feeding slurry of step I in spray drier;

III) controlling the air inlet temperature of the spray drier to 180±5 °C;
IV) controlling the air outlet temperature of the spray drier to 80±5 °C;
V) continuous spraying of slurry from step I;
f) atomization and cooling of micronized product to get dry granules.
12. A process for preparing micronized granule useful as a pharmaceutical excipient,
which comprises forming a well-dispersed aqueous slurry of calcium carbonate, a
polymer with binder, and drying the aqueous slurry by removing water therefrom to
yield a particulate micronized product, in which the weight ratio of polymer to
calcium salt is in the range of from 88:12 to 86:14 and weight ratio of binder to
calcium salt is in the range of from 93:7 to 95:5.