CLIAMS:1. A process of preparing stable pharmaceutical composition comprising linagliptin or salt thereof, metformin or salt thereof wherein the process comprises steps of:
(a) preparing granules comprising linagliptin or salt thereof, metformin or salt thereof and one or more alkalizer/s;
(b) drying and sizing the granules;
(c) optionally mixing extra-granular excipients with granules, and
(d) formulating the granules or mixture of granules and extra-granular excipient(s) in a solid oral dosage form.

2. The process of claim 1, wherein the alkalizer are selected sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate, sodium bicarbonate, calcium carbonate, magnesium oxide, magnesium carbonate, magnesium hydrogen carbonate, aluminum hydroxide, magnesium silicate, sodium citrate, magnesium aluminate, aluminum magnesium hydroxide, tribasic calcium phosphate or mixtures thereof.

3. The process of claim 1, wherein the alkalizer is magnesium oxide, sodium citrate or mixture thereof.

4. The process of claim 1, 2 or 3, wherein the amount of alkalizer ranges from about 0.25% w/w to about 5% w/w of the composition.

5. The process of claim 1, wherein the binder is povidone.

6. The process of claim 1, wherein the solid dosage form is a tablet.

7. The process of claim 1, wherein the solid oral dosage form is further coated with one or more coats.

8. The process of claim 1, wherein composition retains at least 90% w/w of the total potency of linagliptin and metformin or salts thereof when stored at 40°C and 75% relative humidity over a period of at least 3 months.
,TagSPECI:DESCRIPTION

The present invention relates to a process of preparing a pharmaceutical composition of metformin and linagliptin or salt thereof. In particular, the present invention relates to a process of preparing stable oral pharmaceutical composition comprising fixed dose combination of metformin and linagliptin or salt thereof. By using an alkalizer, it is possible to achieve the stable pharmaceutical composition of metformin and linagliptin. The invention further relates to use of such composition in the treatment of diabetes mellitus.

Diabetes mellitus affecting approximately 7.5 million people in the United States. It is characterized by its clinical manifestations, namely the non-insulin-dependent or maturity onset form, also known as Type 2 diabetes and the insulin-dependent or juvenile onset form, also known as Type 1 diabetes. The manifestations of clinical symptoms of Type 2 diabetes and the underlying obesity usually appear at an age over 40. In contrast, Type 1 diabetes usually shows a rapid onset of the disease often before 30. The disease is a metabolic disorder in humans with a prevalence of approximately one percent in the general population, with one-fourth of these being Type 1 and three-fourth of these being Type 2 diabetes. Type 2 diabetes is a disease characterized by high-circulating blood glucose, insulin and corticosteroid levels

As therapeutic agents for diabetes mellitus, those which promote insulin secretion such as sulfonylurea agent and sulfonylamide agent, those which promote insulin resistance such as thiazolidione agent and biguanide agent, those which improve postcibal hyperglycemia such as. Alpha-glucosidase inhibitor, and the like have been known, and for the treatment of diabetes mellitus, these agents are used either solely or in combination.

Dipeptidyl-peptidase-IV (DPP-4) inhibitors are an oral drug class that was introduced in 2006 and that seems easy to use and do not require regular glucose monitoring or dose adjustments. Their mode of action based on incretin physiology.

Linagliptin is an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme and is designated chemically as 8-[(3R)-3-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1H-purine-2,6-dione.

Linagliptin is having a molecular formula of C25H28N8O2 and has a molecular weight of 472.54 g/mol with the following structural formula:

Linagliptin is a white to yellowish, not or only slightly hygroscopic solid substance. It is very slightly soluble in water. Linagliptin is soluble in methanol, sparingly soluble in ethanol, very slightly soluble in isopropanol, and very slightly soluble in acetone.

Linagliptin inhibits the enzymatic activity of DPP-4 in a competitive and reversible manner with a slow rate of dissociation from the active center of the DPP-4 molecule. It is developed and marketed by Boehringer Ingelheim Pharmaceuticals under brand name Tradjenta®.

Metformin is the member of the biguanide class of an oral antihyperglycemics and available in various salt forms, e.g. hydrochloride. Metformin is used in the management of type 2 diabetes mellitus. It is an antihyperglycemic agent, which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Chemically, metformin hydrochloride is 1-carbamimidamido-N,N-dimethylmethanimidamide hydrochloride with the following structure:

Pharmacologic mechanism of action of metformin is different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects, except in special circumstances) and does not cause hyperinsulinemia.

A combination therapy of Linagliptin with metformin HCI (a well established active ingredient of diabetes management) provides even more effective treatment of type II diabetes. Although metformin is effective at lowering blood glucose levels, its use is associated with gastrointestinal (GI) adverse effects, particularly diarrhea and nausea. These adverse effects may limit the tolerated dose of metformin and cause patients to discontinue the therapy. Linagliptin in combination with Metformin is marketed in the United States under the brand name Jentadueto® by Boehringer Ingelheim.

U.S. Patent No. 7,407,955 discloses Linagliptin, related compounds, and their pharmaceutical compositions containing comprising one or more inert carriers or diluents. Further, it describes a process for the preparation of Linagliptin wherein tert-butyloxy carbonyl protected Linagliptin is deprotected using 5-6M isopropanolic hydrochloric acid followed by purification using chromatography.

U.S. Patent Application No. US 20130122089 discloses pharmaceutical composition comprising linagliptin with mannitol, pregelatinized starch, copovidone, cornstarch, and magnesium stearate.

The biguanide antidiabetic agent metformin is disclosed in U.S. Pat. No. 3,174,901. The preparation of metformin (dimethyldiguanide) and its hydrochloride salt is state of the art and was disclosed first by Emil A. Werner and James Bell, J. Chem. Soc. 121, 1922, 1790-1794. Other pharmaceutically acceptable salts of metformin can be found in U.S. application Ser. No. 09/262,526 or U.S. Pat. No. 3,174,901.

U.S. Patent Application Nos. US 20110206766 discloses fixed dose combinations of a DPP-4 inhibitor drug such as linagliptin and a partner drug such as metformin. The composition further comprising one or more pharmaceutical excipients, basic agent such as buffering agent for stabilizing said DPP-4 inhibitor against degradation.

Prior art teaches that DPP-IV inhibitors with a primary or secondary amino group are unstable and show incompatibilities, degradation problems, or extraction problems with a number of customary excipients such as microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, tartaric acid, citric acid, glucose, fructose, saccharose, lactose, maltodextrines. When packaged in the form of tablets, powders, granules, or within capsules, the compounds may be further destabilized by reaction between the amino group with reducing sugars and with other reactive carbonyl groups and with carboxylic acid functional groups formed for example at the surface of microcrystalline cellulose by oxidation. Since pharmaceutical dosage components such as binders, diluents, antiadherents, surfactants and the like may adversely interact with the compound, a stabilizing means is required for effective pharmaceutical dosage form.

Therefore, it is an object of the present invention to provide a stable oral pharmaceutical composition of linagliptin and metformin or salt thereof comprising one or more alkalizer/s as an stabilizer, one can overcome problems like incompatibility, poor stability, decomposition (which may be caused by reaction (e.g. by acylation, urea formation or Maillard reaction, or the like) of free base of linagliptin when combined with an incompatible other drug, or its impurity product and/or a pharmaceutical excipient having such functional group (such as a reducing end of a sugar or an acyl group).

The inventors of the present invention have surprisingly found that by use of nucleophilic and/or basic agent other than amino acids, it may be possible to provide a stable oral pharmaceutical composition and solve these problems associated with the unexpected potency of selected DPP-IV inhibitor.

In particular, it has been found that by the use of amino sugar and/or alkalizer as a stabilizer, within these pharmaceutical compositions one can overcome these problems. Therefore, by the use of a suitable amino sugars and/or alkalizer within these pharmaceutical compositions, protection against decomposition and degradation can be achieved.

In one general aspect, there is provided pharmaceutical composition comprising DPP-IV inhibitors such as linagliptin and metformin or salts thereof wherein the composition comprises one or more alkalizer/s. The pharmaceutical composition according to the invention is preferably a solid pharmaceutical composition, for example a solid pharmaceutical composition for oral administration.

In another general aspect, there is provided a stable oral pharmaceutical composition of linagliptin or salt thereof, optionally metformin, one or more alkalizer/s and one or more pharmaceutical acceptable excipients.

In another general aspect, there is provided a stable oral pharmaceutical composition of linagliptin or salt thereof, optionally metformin, one or more alkalizer/s and one or more pharmaceutical acceptable excipients, wherein the composition is devoid of amino acid.

In another general aspect, there is provided a stable fixed dose oral pharmaceutical composition comprising DPP-IV inhibitors such as linagliptin, metformin or salts thereof, one or more alkalizer/s and one or more pharmaceutical acceptable excipients.

In another general aspect, there is provided stable oral fixed dose combination of DPP-IV inhibitors such as linagliptin and metformin or salts thereof comprising one or more amino sugar/s and/or alkaline earth metal salt/s and pharmaceutical acceptable excipients.

In another general aspect, there is provided pharmaceutical composition comprising DPP-IV inhibitors such as linagliptin or salts thereof in combination with metformin, wherein the composition is intended for the treatment of diabetes mellitus.

In another general aspect, there is provided an stable oral pharmaceutical composition comprising DPP-IV inhibitors such as linagliptin or salts thereof, wherein the alkalizer/alkaline earth metal salts are selected, but not limited to sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate, sodium bicarbonate, calcium carbonate, magnesium oxide, magnesium carbonate, magnesium hydrogen carbonate, aluminum hydroxide, magnesium hydroxide, magnesium silicate, magnesium aluminate or aluminum magnesium hydroxide, sodium citrate, pharmaceutically acceptable salts of phosphoric acid such as tribasic calcium phosphate or mixtures thereof.

In another general aspect, the total amount of linagliptin or salts thereof and metformin or salts thereof in the pharmaceutical composition ranges from about 0.01 % w/w to about 90.0% w/w of the composition.

In another general aspect, there is provided a stable oral pharmaceutical composition comprising linagliptin or salts thereof, wherein the amount of one or more alkaline earth metal salt/s ranges from about 0.25% w/w to about 85.50% w/w of the total composition. Preferably, the amount of alkalizer in the composition ranges from about 0.25% w/w to about 5% w/w of the composition

In another general aspect, the stable oral pharmaceutical composition comprises a core which comprises of:
(a) linagliptin or salts thereof;
(b) metformin or salts thereof
(c) one or more alkalizer/s, and
(d) pharmaceutically acceptable excipients,
whereby said pharmaceutically acceptable excipients and drug are combined by a granulation process and further compressed into solid oral dosage form.

In another general aspect, the stable oral pharmaceutical composition comprises a core which comprises of:
(a) linagliptin or salts thereof;
(b) one or more alkalizer/s, and
(c) pharmaceutically acceptable excipients,
whereby said pharmaceutically acceptable excipients and said linagliptin are combined by granulation process and further compressed into solid oral dosage form.

In another general aspect, the present invention provides a process for the preparation of a stable oral pharmaceutical composition according to the invention comprising one or more granulation processes wherein the one or two active pharmaceutical ingredients are granulated together with one or more excipients.

In another general aspect, the granulation step is carried out in a rapid mixer granulator, fluidized bed processor or one-pot granulation. Preferred method is rapid mixer granulator.

In a further general aspect, pharmaceutically acceptable solvents used for granulation process may be selected from aqueous or non-aqueous solvents. The solvents comprise, but not limited to, water, isopropyl alcohol, acetone, ethanol, methylene chloride or combination thereof.

In another general aspect, the oral pharmaceutical composition may be in the form of powder, tablets, pellets, capsules, granules or pellets filled in capsule, tablet in capsule, multilayer tablet, a bilayer tablet, a trilayer tablet, or premixed powder filled in capsule. Preferred oral solid dosage form is tablet.

In another general aspect, the oral solid dosage form is further transformed into film coated solid dosage form by coating the cores with the coating suspension using a standard coating apparatus.

In another general aspect, the oral solid dosage form is further coated with one or more coating comprising pharmaceutically acceptable excipients.

Alternatively, for preparing film-coated tablets of this invention the film coating suspension is prepared by using commercially available film coating pre-mixtures such as Opadry™. The single ingredients of the film-coat or the commercially available premixture such as Opadry™ is suspended or dissolved in the film coating solvent, preferably purified water at room temperature, for preparing the film-coating suspension

In another general aspect, pharmaceutical acceptable excipients used in the present invention are selected from the group consisting of diluents, binders, fillers, disintegrants, glidants, lubricants, film coating agents, plasticizers, flavors and others.

In another general aspect, there is provided a stable oral pharmaceutical composition comprising linagliptin and metformin or salts thereof, wherein the amount of binder in the composition ranges from 0.5% w/w to about 15% w/w of the composition.

In another general aspect, there is provided a stable oral pharmaceutical composition comprising linagliptin and metformin or salts thereof, wherein the amount of diluent in the composition ranges from 2.5% w/w to about 85.50% w/w of the composition.

In another general aspect, there is provided a stable oral pharmaceutical composition comprising linagliptin and metformin or salts thereof, wherein the amount of disintegrants in the composition ranges from 2.5% w/w to about 75.50% w/w of the composition.

In another general aspect, there is provided a stable oral pharmaceutical composition comprising linagliptin or salts thereof, wherein the amount of lubricant in the composition ranges from 0.25% w/w to about 5.75% w/w of the composition.

Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Exemplary binders for solid pharmaceutical compositions include, but are not limited to, polyvinylpyrrolidon, hydroxypropyl methylcellulose, hydroxypropylcellulose, pregelatinized starch, low-substituted hydroxypropylcellulose, copovidone and povidone being preferred.

Diluents increase the bulk of a solid pharmaceutical composition. Exemplary diluents for solid compositions include, but are not limited to, microfine cellulose (e.g. microcrystalline cellulose), starch, pregelatinized starch, kaolin, mannitol, polymethacrylates, potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.

The disintegrants that can be used in the pharmaceutical compositions according to the present invention can be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, crospovidone, hydroxypropyl cellulose, methyl cellulose, chitosan, cornstarch, starch, pregelatinized starch or the combinations thereof.

The lubricants that can be used in the pharmaceutical compositions according to the present invention can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate or combinations thereof.

The glidants that can be used in the pharmaceutical compositions according to the present invention can be selected from but not limited to colloidal silicon dioxide, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc and the like or combinations thereof.

In another general aspect, the composition retains at least 90% w/w of the total potency of linagliptin and metformin or salts thereof when stored at 40°C and 75% relative humidity over a period of at least 3 months.

In another general aspect, the process of preparing the solid oral pharmaceutical composition of linagliptin or salt thereof comprises steps of preparing a core containing linagliptin or salt thereof and pharmaceutical acceptable excipients, drying the granules, sizing the dried granules, optionally adding the extra-granular excipient(s), and formulating it further in a suitable solid oral dosage form.

In another general aspect, the pharmaceutical composition of the present invention can be produced by one of the methods of wet granulation, dry granulation, dry blending. In the pharmaceutical compositions of the present invention, the active agents can be formulated separately according to any production methods in the prior art; though, they can also be formulated together by using the same production method.

In the wet granulation process the granulation liquid is a solvent such as methanol, isopropanol, acetone, water, ethanol, preferably purified water, and contains a binder such as povidone. The solvent is a volatile component, which does not remain in the final product. The active ingredient and the other excipients with exception of the lubricant are premixed and granulated with the aqueous granulation liquid using a granulator. The wet granulation step is followed by an optional wet sieving step, drying and dry sieving of the granules.

The dried granules are sieved through an appropriate sieve. After addition of the other excipients with exception of the lubricant the mixture is blended in a suitable conventional blender followed by addition of the lubricant such as magnesium stearate and final blending in the blender.

In another general aspect, there is provided a method of treating diabetes mellitus in a patient in need thereof, which method comprises of administering the stable pharmaceutical composition of linagliptin or salts thereof in accordance with the present invention.

In another general aspect, the stable oral pharmaceutical composition comprising linagliptin or salt thereof and optionally metformin, further comprises intragranular portion and extragranular portion.

The term “linagliptin” as used throughout the specification refers to not only linagliptin per se, but also its other pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.

The term “metformin” as used throughout the specification refers to all forms of metformin or pharmaceutically acceptable salts, esters, solvates, hydrates, metabolites, prodrugs or isomers thereof. The most preferred form is metformin hydrochloride

The term 'pharmaceutically acceptable excipient(s)' used in pharmaceutical compositions of invention comprise but not limited to diluents, binders, pH stabilizing agents, disintegrants, surfactants, glidants and lubricants.

The term "core" defined to mean a solid vehicle in which at least one active drug is uniformly or non-uniformly dispersed with pharmaceutically acceptable excipients which can be in the form of powder, beads, microgranules, tablet, minitablet, compact, pellets, granules, microcapsules, spheroid, particles and the like.

The term "layer", "coat" or "coating" as used herein are used interchangeably and are defined to mean a process in which the whole surface of a core is covered with a coating composition.

The term "solid dosage form" as used herein includes dosage forms for oral administration such as tablet, capsule, and the like.

The term "tablet" comprises tablets without a coating and tablets with one or more coatings. Furthermore the "term" tablet comprises tablets having one, two, three or even more layers and press-coated tablets, wherein each of the before mentioned types of tablets may be without or with one or more coatings. The term "tablet" also comprises mini, melt, chewable, effervescent and orally disintegrating tablets.

In an embodiment, the stable oral pharmaceutical composition comprising DPP-IV inhibitors such as linagliptin or salts thereof wherein the composition comprises one or more alkalizer/s and one or more pharmaceutical acceptable excipients.

In an embodiment, the stable oral pharmaceutical composition comprising DPP-IV inhibitors such as linagliptin or salts thereof in combination with metformin, wherein the composition comprises one or more alkalizer/s and one or more pharmaceutical acceptable excipients.

In another embodiment, the stable oral stable oral pharmaceutical composition a DPP-IV inhibitor such as linagliptin or salt thereof and pharmaceutical acceptable excipients intended for the treatment of diabetes mellitus.

In another embodiment of the present invention, said DPP-IV inhibitor is at least one selected from the group comprising of denagliptin, alogliptin, linagliptin, trelagliptin, saxagliptin and sitagliptin.

In another embodiment, the total amount of linagliptin or salts thereof and metformin or salts thereof in the pharmaceutical composition ranges from about 0.01 % w/w to about 90.0% w/w of the composition.

In another embodiment, the stable oral pharmaceutical composition comprises a core which comprises of:
(a) linagliptin or salts thereof;
(b) one or more alkalizer/s, and
(c) pharmaceutically acceptable excipients,
whereby said pharmaceutically acceptable excipients and said linagliptin are combined by granulation process and further compressed into solid oral dosage form.

In another embodiment, the stable oral pharmaceutical composition comprises a core which comprises of:
(a) linagliptin or salts thereof;
(b) metformin
(c) one or more alkalizer/s, and
(d) pharmaceutically acceptable excipients,

In another embodiment, the stable oral pharmaceutical composition of linagliptin or salt thereof and optionally metformin further comprising an intragranular portion and extragranular portion.

In another embodiment, the stable oral pharmaceutical composition of linagliptin or salt thereof and optionally metformin further comprises an intragranular portion containing linagliptin or salt thereof, diluent, binder, one or more alkalizer/s and an extragranular portion containing a lubricant (particularly magnesium stearate).

In another embodiment, the stable oral pharmaceutical composition comprises an intragranular portion containing linagliptin or salt thereof, one or more diluent, one or more binder, one or more alkalizer/s and an extragranular portion containing a lubricant (particularly magnesium stearate).

In another embodiment of the present invention, the stable oral pharmaceutical composition comprises essentially of: an intragranular portion containing linagliptin or salt thereof, a diluent which are mannitol, maize starch, a disintegrant which is crospovidone, a alkalizer/s which is magnesium oxide and a binder which is povidone; and an extragranular portion containing a lubricant which is magnesium stearate.

In another embodiment, the granulation step is carried out in a rapid mixer granulator, fluidized bed processor or one-pot granulation.

In another embodiment, pharmaceutically acceptable solvents used for granulation process may be selected from aqueous or non-aqueous solvents.

In another embodiment, the stable solid oral pharmaceutical composition may be in the form of powder, tablets, pellets, capsules, granules or pellets filled in capsule, tablet in capsule, multilayer tablet, a bilayer tablet, a trilayer tablet, or premixed powder filled in capsule. Preferred oral solid dosage form is tablet.

In another embodiment, pharmaceutical acceptable excipients used in the present invention are selected from the group consisting of diluents, binders, fillers, disintegrants, glidants, lubricants, film coating agents, plasticizers, flavors and others.

In another embodiment, the stable oral pharmaceutical composition comprising linagliptin or salts thereof, wherein the amount of binder in the composition ranges from 0.5% w/w to about 15% w/w of the composition.

In another embodiment, the stable oral pharmaceutical composition comprising linagliptin or salts thereof and metformin, wherein the amount of diluent in the composition ranges from 2.5% w/w to about 85.50% w/w of the composition.

In another embodiment, the stable oral pharmaceutical composition comprising linagliptin or salts thereof and metformin, wherein the amount of disintegrants in the composition ranges from 2.5% w/w to about 75.50% w/w of the composition.

In another embodiment, the stable oral pharmaceutical composition comprising linagliptin or salts thereof in combination with metformin, wherein the amount of alkalizer/s in the composition ranges from 0.25% w/w to about 85.50% w/w of the composition.

In another embodiment, the amount of alkalizer/s in the present composition is more than 10%w/w of the total weight of composition.

In another embodiment, the stable oral pharmaceutical composition comprising linagliptin or salts thereof, wherein the amount of lubricant in the composition ranges from 0.25% w/w to about 5.75% w/w of the composition.

In another embodiment, the process of preparing the solid oral pharmaceutical composition of linagliptin or salt thereof and metformin or salt thereof further comprises steps of preparing a core containing linagliptin or salt thereof, metformin or salt thereof and pharmaceutical acceptable excipients, drying the granules, sizing the dried granules, optionally adding the extra-granular excipient(s), and formulating it further in a suitable solid oral dosage form.

The invention further provides a method of treating diabetes mellitus in a human in need thereof, wherein method comprises of administering the stable oral pharmaceutical composition as described herein.

Unless otherwise defined, 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.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

The invention now will be described in particularity with the following illustrative examples; however, the scope of the present invention is not intended to be, and shall not be, limited to the exemplified embodiments below.

Example 1: Linagliptin + Metformin Tablets
Table 1
Sr. No Ingredient mg/Tab
Intragranular part
1 Metformin hydrochloride 1000.00
2 Corn starch 55.50
Binder composition
3 Magnesium oxide/Sodium citrate 13.00
4 Linagliptin 2.50
5 Copovidone 95.00
6 Purified water qs
Extragranular part
7 Colloidal anhydrous silica 5.00
8 Magnesium stearate 10.00
Core tablet weight 1180.00
9 Film coating agent 18.00
10 Purified water qs
Coated tablet weight 1198.00

Process:
Intragranular materials were sifted through sieve and were mixed in rapid mixer granulator. Binder solution was prepared in purified water. Then wet granulation of pre-sifted intragranular materials was done with binder solution. Granules were then dried and sifted through sieve. Extragranular materials were sifted through sieve separately. Lubrication of dried granules of intragranular and extragranular materials was carried out in a blender. The blend was then compressed to form the tablets. The tablets were then coated using film coating agent.