FORM 2

THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10, rule 13)
1. Title of the invention
"Salts of Biguanide"
2. Applicants)

Name
U$V Limited

Nationality
Indian company incorporated under Companies Act, 1956

Address
Ajvind Vitthal Gandhi Chowk, B.S.D. Marg, Govandi, Mumbai-400 088, Maharashtra, India.

3. Preamble to the description
The following specification particularly describes the invention and the manner in which it is to be performed.

Field of invention:
The present invention relates to a process for preparation of Metformin embonate/pamoate Form I or Form II, substantially flee of other polymorphic forms. The present invention further relates to novel polymorphic forms of Metformin pamoate/ embonate and processes for preparation thereof.

Background of invention:
Metformin, a biguanide is the first choice of drug among oral anti-diabetic drugs. The antidiabetic drug Metformin acts by stimulating AMPK leading to reduced glucose production in the liver and reduced insulin resistance in the muscle. AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme that plays a role in cellular energy homeostasis. The free base form of Metformin is pharmaceutically useful, but has low stability. For this reason, Metformin is administered in the form of its pharmaceutically acceptable acid addition salt. It is marketed in the form of its hydrochloride, under the brand name GLUCOPHAGE® by Bristol-Myers Squibb. It is also marketed in the form of its pamoate/embonate salt under the brand name STAGID®in France, Portugal and Philippines.
Metformin pamoate/embonate is chemically designated as N,N-dimethylimido dicarbonimidic diamide pamoate/embonate or 1,1-dimethyl biguanide pamoate/ embonate. Each STAGID® Tablet for oral administration contains 700 mg of Metformin pamoate equivalent to 280 mg of Metformin. It is administered as 3 tablets daily in three divided doses. STAGID® is a prescription drug used to treat Type II Diabetes meliitus. . Additional therapeutic indication includes Type I Diabetes. Metformin hydrochloride, Metformin embonate and Metformin chlorophenoxyacetate are available, but Metformin hydrochloride is by far the most commonly used salt. However, Metformin hydrochloride is highly soluble in water and hardly permeates the lower gastrointestinal tract and thus most of the drug gets absorbed at the upper gastrointestinal tract. As a result, Metformin

hydrochloride is poorly absorbed throughout the entire GI tract.
US6031004 discloses that Metformin hydrochloride is a cohesive white powder which is highly soluble in water (>300 mg/ml at ambient temperature), has a hygroscopicity measured at 95% relative humidity/25°C of greater than 20% moisture uptake at 6 hours, and a high compaction susceptibility. Accordingly, handling of Metformin hydrochloride in a pharmaceutical manufacturing facility could present problems, especially in high humidity environments.
As per the available literature, Pamoate/Embonate salt is one of the pharmaceutically acceptable salts. However, it should only be considered for an extended release formulation since these salts are almost always poorly soluble in water or stomach acid. The formation of a pamoate/embonate salt is used to decrease the solubility of basic drugs. These salts are prepared for retarding the dissolution of basic drugs. Handbook of Pharmaceutical Salts: Properties, Selection and Use, ed. P. H. Stahl and C. G. Wermuth, Wiley-VCH/VHCA, Weinheim/Zurich, 2002, mentions the pamoate/embonate salts of amitriptyline, benzphetamine, chlorpromazine, cyclguanyl, difenidol, dothiepin, imipramine, levomepromazine, metformin, noscapine, pamaquine, phendimetrazine, promazine, pyrantel, pyrvinium and rhodoquine.
FR2037002 discloses that pamoate salt has remarkable delay effect (release and absorption). FR2037002 also discloses the process for preparation of Metformin pamoate. Pamoate salts are useful as hypoglycemic drug having longer duration of action. Their delayed action makes it possible to decrease daily dose, number of daily intake of the tablet and thus improves the digestive tolerance.
Polymorphism is the ability of a compound to exhibit more than one orientation or conformation of molecules within the crystal lattice. Drug substance may exist in various polymorphic forms, which may differ from each other in terms of stability, solubility, compressibility, flowability and spectroscopic properties thus affecting dissolution, bio-availability and handling characteristics of the substance. Polymorphism is not reported for Metformin pamoate/embonate.
The present invention provides a process for preparation of Metformin pamoate/embonate Form I or Form II, substantially free of other polymorphic forms. The present invention

further provides novel polymorphic forms of Metformin pamoate/embonate and processes for preparation thereof. Novel polymorphic forms provides a large repertoire of materials that a formulation scientist can use for formulation optimization. Polymorphic forms of Metformin pamoate of the present invention have the desired physicochemical properties such as solubility, stability and hygroscopicity thus making them amenable to large scale pharmaceutical processing and formulation.
Object of the invention:
An object of the present invention is to provide a simple, consistent, industrially feasible and reproducible process for preparation of Metformin pamoate/embonate Form I or Form II, substantially free of other polymorphic forms.
Another object of the present invention is to provide novel polymorphic forms of Metformin pamoate/embonate selected from Form II, Form III, Form IV, Form V or Form VI and processes for preparation thereof.
Another object of the present invention is to provide substantially pure Metformin pamoate/embonate Form I.
Summary of the invention:
The present invention provides a process for preparation of Metformin embonate/pamoate Form I, substantially free of other polymorphic forms, comprising treating Metformin salt with an aqueous solution of disodium pamoate, wherein the reaction medium contains water in an amount of about 9 to 13 volumes with respect to the weight of disodium pamoate. Preferably, said treatment is carried out at a temperature of about 10°C to 70 °C. Preferably, said Metformin salt is Metformin hydrochloride. Preferably, said Metformin embonate Form I is substantially free of Form II.
Another aspect of the present invention provides a process for preparation of Metformin embonate/pamoate Form II, substantially free of other polymorphic forms, comprising treating Metformin salt with an aqueous solution of disodium pamoate, wherein the reaction medium contains atleast about 11 volumes of water with respect to the weight of disodium pamoate. Preferably, said treatment is carried out at a temperature of about 30°C or less than about 30°C. Preferably, said Metformin salt is Metformin hydrochloride. Preferably, said Metformin embonate Form II is substantially

free of Form I.
Another aspect of the present invention provides a process for preparation of Metformin embonate/ pamoate polymorph, comprising the steps of,
a) treating Metformin embonate/pamoate with a first solvent to obtain a first mixture;
b) optionally treating the first mixture with a second solvent to obtain a second mixture; and
c) isolating Metformin embonate polymorph from the first mixture or the second mixture.
Preferably, for polymorphic Form I, the first solvent is selected from methanol, ethanol, ethyl acetate, acetone, methylene dichloride, 1,4-dioxane or tetrahydrofuran and second solvent is selected from diisopropyl ether, n-hexane, methanol, diethyl ether or toluene; for polymorphic Form II, the first solvent is selected from methanol, ethanol, n-propanol, isopropanol or water; for polymorphic Form III, the first solvent is selected from dimethyl formamide or dimethyl acetamide and the second solvent is selected from diisopropyl ether, isopropanol, ethyl acetate or methylene dichloride; for polymorphic Form IV, the first solvent is selected from dimethyl formamide or dimethyl acetamide and second solvent is selected from acetone or methyl ethyl ketone.
Another aspect of the present invention provides a process for preparation of Metformin pamoate/embonate comprising the steps of,
a) treating Metformin base with an organic solvent to obtain a first mixture;
b) treating the first mixture with pamoic acid or disodium pamoate to obtain a second mixture; and
c) isolating Metformin pamoate from the second mixture.
Preferably, said Metformin pamoate is Form I and said organic solvent is selected from methylene dichloride, acetonitrile or isopropanol; said Metformin pamoate is Form II and said organic solvent is selected from methanol, ethanol, n-propanol or isopropanol; said Metformin pamoate is Form IV and said organic solvent is selected from acetone or methyl ethyl ketone; said Metformin pamoate is Form V and said organic solvent is selected from 1,4-dioxane or THF; and said Metformin pamoate is Form VI and said organic solvent is selected from ethyl acetate, methyl acetate or isopropyl acetate.
Yet another aspect of the present invention provides Metformin embonate polymorph

selected from a group consisting of Form II, Form III, Form IV, Form V and Form VI.
Brief Description of the Drawings:
Fig. 1: X-ray diffraction pattern of Metformin pamoate/embonate Form I obtained
according to the present invention. Fig. 2: X-ray diffraction pattern of Metformin pamoate/embonate Form II. Fig. 3: X-ray diffraction pattern of Metformin pamoate/embonate Form III. Fig. 4: X-ray diffraction pattern of Metformin pamoate/embonate Form IV. Fig. 5: X-ray diffraction pattern of Metformin pamoate/embonate Form V. Fig. 6: X-ray diffraction pattern of Metformin pamoate/embonate Form VI.
Detailed description of the invention:
The present invention provides a process for preparation of Metformin pamoate/embonate comprising treating Metformin salt, in particular Metformin hydrochloride, with an aqueous solution of disodium pamoate followed by isolation of Metformin pamoate/embonate.
Any other acid addition salt of Metformin can be used in the place of Metformin hydrochloride.
A preferred embodiment of the present invention provides a process for preparation of Metformin embonate/pamoate Form I, substantially free of other polymorphic forms, in particular Form II, comprising treating Metformin hydrochloride with an aqueous solution of disodium pamoate wherein the reaction medium contains water in an amount of about 9 to 13 volumes with respect to the weight of disodium pamoate. The reaction is carried out at a temperature of about 10°C to 70°C, preferably 20°C to 50°C, more preferably 25°Cto35°C.
Another preferred embodiment of the present invention provides a process for preparation of Metformin embonate/pamoate Form II substantially free of other polymorphic forms, in particular Form I, comprising treating Metformin hydrochloride with an aqueous solution of disodium pamoate wherein the reaction medium contains atleast about 11 volumes of water with respect to the weight of disodium pamoate. The reaction is carried out at a temperature of about 30°C or less than about 30°C. It has been observed by the inventors of the present invention that Form I and Form II of

Metformin embonate can be obtained from water. Since water can be used for producing both these Forms, it is important to understand the conditions which lead to the formation of Form I or Form II.
Another embodiment of the present invention provides a method to study the effect of water on polymorphism of Metformin embonate/pamoate, wherein the method comprises varying the volume of water required to prepare disodium pamoate solution while keeping the volume of water required to prepare Metformin hydrochloride solution constant.
In a preferred embodiment, experiments are performed where the volume of water required to prepare a solution of Metformin hydrochloride is kept constant and the volume of water required to prepare disodium pamoate solution is varied. 5.96 gm of disodium pamoate is dissolved in varying amounts of water under stirring at 25°C to obtain a solution. 5 gm of Metformin hydrochloride is dissolved in 23.84 ml of water at the same temperature. The obtained Metformin hydrochloride solution is charged to the above disodium pamoate solution to obtain a mixture. The obtained mixture is maintained under stirring at 25 to 30CC for 4 hours. The solid obtained is isolated, dried at 60°C and is used to study the effect of water on polymorphism. The results are shown in Table 1,
Table 1

Wtof
Metformin
HCl(gm) Wtof
disodium
pamoate (gm) Total vol of
water for reaction (ml) Vol of water used for disodium
pamoate (ml) Vol of water used for
Metformin HCI (ml) Polymorphic form
5 5.96 53.64 29.8 23.84 Form I
5 5.96 59.6 35.76 23.84 Form I
5 5.96 65.56 41.72 23.84 Form I with slight
contamination of Form
II
5 5.96 71.52 47.68 23.84 Form I with slight
contamination of Form
II
5 5.96 77.48 53.64 23.84 Form I with slight
contamination of Form
II
5 5.96 83.44 59.6 23.84 Form II
5 5.96 89.4 65.56 23.84 Form II
5 5.96 95.36 71.52 23.84 Form II

5 5.96 101.32 77.48 23.84 Form II
5 5.96 107.28 83.44 23.84 Form II
5 5.96 113.24 89.4 23.84 Form II
It is observed that when the reaction medium contains about 9 to 10 volumes of water with respect to the weight of disodium pamoate, pure Metformin pamoate Form I is obtained, whereas when the reaction medium contains about 11 to 13 volumes of water with respect to the weight of disodium pamoate, Metformin pamoate Form I with slight contamination of Metformin pamoate Form II is obtained. However, when the reaction medium contains water in an amount of about 14 volumes or above with respect to the weight of disodium pamoate, pure Metformin pamoate Form II is obtained.
For dissolving disodium pamoate, minimum 9 volumes of solvent is required. If less than 9 volumes of solvent is used for dissolution of disodium pamoate, then heating is required to obtain a clear solution, however solid may precipitate out during filtration. The disodium pamoate solution and Metformin hydrochloride solution are preferably filtered to remove any residual matter which may affect the quality of the final product.
Another embodiment of the present invention provides the effect of time on the polymorphic form of Metformin embonate/pamoate. It is observed that when the reaction medium contains about 11 to 13 volumes of water with respect to the weight of disodium pamoate, pure Metformin pamoate Form I is formed, if the reaction mixture is maintained with or without stirring for about 2 hours or less than 2 hours. Said reaction mixture is obtained by treating Metformin hydrochloride with disodium embonate. If this reaction mixture is maintained for a longer duration, Form II or its mixture with Form I is obtained.
Another embodiment of the present invention provides a method to study the effect of temperature on polymorphism of Metformin pamoate/embonate.
In a preferred embodiment, 5.96 gm of disodium pamoate is dissolved in 53.64 ml water under stirring at 40-45°C to obtain a solution. 5 gm of Metformin hydrochloride is dissolved in 23.84 ml water at the same temperature. The obtained Metformin hydrochloride solution is charged to the above disodium pamoate solution to obtain a mixture. The obtained mixture is maintained under stirring at different temperatures for

4 hours. The solid obtained is isolated, dried at 60°C and is used to study the effect of temperature on polymorphism. The result is shown in Table 2 below,
Table 2:

Wtof
Metformin
HCI(gm) Wtofdisodium pamoate (gm) Vol of solvent w.r.t. wt of disodium pamoate Temp
(°C) Crystalline polymorphic form
5 5.96 13 30 Form I with slight contamination of Form II
5 5.96 13 40 Pure Form I
5 5.96 13 50 Pure Form I
5 5.96 13 60 Pure Form I
5 5.96 13 70 Pure Form I
It is observed that at a temperature of 30°C and below, Metformin pamoate/embonate Form I with slight contamination of Metformin pamoate/embonate Form II is obtained, whereas at a temperature of 40°C and above, pure Metformin pamoate/embonate Form I is obtained. Further it is observed that even when the reaction temperature is about 30°C or less than about 30°C, pure Metformin pamoate Form I is obtained, if the reaction mixture is maintained with or without stirring for about 2 hours or less than about 2 hours. Said reaction mixture is obtained by treating Metformin hydrochloride with disodium embonate. If this reaction mixture is maintained for a longer duration, Form II or its mixture with Form I is obtained.
In a preferred embodiment, disodium pamoate is dissolved in water at 30-50°C, preferably at 40-45°C to obtain a clear solution. Metformin hydrochloride is dissolved in water at 30-60°C, preferably at 45-55°C to obtain Metformin hydrochloride solution. The obtained Metformin hydrochloride solution is treated with the above solution of disodium pamoate at the same temperature to obtain a mixture. The obtained mixture is maintained at the same temperature for 3-5 hours, preferably for 4 hours followed by cooling at 25-30°C to obtain Metformin pamoate/embonate Form I. Metformin pamoate/embonate Form I thus obtained is isolated and dried.
In a preferred embodiment, disodium pamoate is dissolved in water at 25-30°C to obtain a clear solution. Metformin hydrochloride is dissolved in water at 25-30°C to obtain Metformin hydrochloride solution. The obtained Metformin hydrochloride solution is treated with the above solution of disodium pamoate at the same temperature to obtain a

mixture. The obtained mixture is maintained at the same temperature for 3-5 hours, preferably for 4 hours to obtain Metformin pamoate Form II. Metformin pamoate Form II thus obtained is isolated and dried.
In a preferred embodiment, disodium pamoate is dissolved in water at 50 to 70°C, preferably 55 to 65°C to obtain a solution. An aqueous solution of Metformin hydrochloride is added to the obtained disodium pamoate solution at a temperature of about 10 to 70°C, preferably 20 to 50°C, more preferably 25 to 35°C to obtain a mixture. This mixture was maintained at the same temperature for about 2 hours. The solid which precipitated out was filtered and dried to obtain pure Metformin pamoate Form I.
It has been observed that reaction temperature has an effect on the particles of Metformin pamoate Form I. When the reaction is performed at a lower temperature, spherical shaped particles are obtained, whereas when the reaction is performed at a higher temperature, needle shaped particles are obtained.
The present invention provides novel polymorphic forms of Metformin embonate/ pamoate selected from Form II, III, IV, V or VI. The present invention further provides substantially pure Metformin embonate/pamoate Form I.
FR2037002 discloses the process for preparation of Metformin pamoate by reacting Metformin hydrochloride with disodium pamoate in an aqueous medium at room temperature for 24 hours followed by recrystallization from boiling water. It further discloses that Metformin pamoate is soluble in boiling water, acetone or alcohol and is insoluble in chloroform or ether. The inventors of the present invention have observed that various polymorphic forms of the Metformin pamoate can be obtained by using different solvents. Polymorphic forms of Metformin pamoate obtained by the process of present invention have better physicochemical properties as compared to the prior art form.
One embodiment of the present invention provides a novel polymorphic form of Metformin embonate/pamoate designated as Form II, characterized by X-ray diffraction pattern having peaks expressed as 2-theta at about 6.73, 7.52, 11.53, 13.17, 17.81, 20.35, 20.67 and 24.67 degrees. It is further characterized by X-ray diffraction pattern having peaks expressed as 2-theta at about 9.93, 11.38, 13.73, 15.08, 15.76, 16.06, 16.55, 17.15,

18.97, 19.49, 19.98, 22.11, 22.71, 23.76, 24.02, 24.17, 25.19, 26.44, 27.10, 27.39, 27.89, 28.72, 28.97, 30.44, 31.01, 31.67, 32.45, 33.01, 34.21, 34.91, 35.27, 36.61, 37.50, 37.91, 38.38, 39.63 and 45.38 degrees. X-ray diffraction pattern of Metformin embonate/pamoate Form II is as shown in Fig. 2.
Another embodiment of the present invention provides a novel polymorphic form of Metformin embonate/pamoate, designated as Form III, characterized by X-ray diffraction pattern having peaks expressed as 2-theta at about 8.31, 11.36, 11.79, 16.66, 17.21, 17.88,
19.06, 19.46, 20.19, 20.44, 21.69, 22.45, 22.80, 23.69, 24.43, 26.12 and 26.49 degrees. It
is further characterized by X-ray diffraction pattern as shown in Fig. 3.
Another embodiment of the present invention provides a novel polymorphic form of Metformin pamoate/embonate, designated as Form IV, characterized by X-ray diffraction pattern having peaks expressed as 2-theta at about 6.14, 8.38, 11.56, 12.26, 16.81, 17.53, 18.27, 18,95, 19.35, 19.94, 21.23, 21.48, 21.73, 22.55, 23.01, 23.24, 23.88, 25.74, 26.13, 27.05 and 30.12 degrees. It is further characterized by X-ray diffraction pattern as shown in Fig. 4.
Another embodiment of the present invention provides a novel polymorphic form of Metformin pamoate/embonate, designated as Form V characterized by X-ray diffraction pattern having peaks expressed as 2-theta at about 7.59, 11.68, 12.24, 14.96, 16.09,
17.07, 17.77, 18.28, 18.53, 18.94, 19.30, 20.55, 20.94, 21.66, 22.65, 23.47, 23.82, 25.48
and 26.07 degrees. It is further characterized by X-ray diffraction pattern as shown
in Fig. 5.
Another embodiment of the present invention provides a novel polymorphic form of Metformin pamoate/embonate, designated as Form VI characterized by X-ray diffraction pattern having peaks expressed as 2-theta at about 6.16, 10.65, 11.80, 12.93, 14.73,16.47, 17.20, 19.30, 20.16, 21.05, 23.10, 23.64, 25.97 and 29.74 degrees, It is further characterized by X-ray diffraction pattern as shown in Fig. 6.
X-ray diffraction pattern of Metformin embonate/pamoate obtained by following the process disclosed in Example 3 of FR2037002 is as shown in Fig. 1 and is designated as Form I. Metformin pamoate Form I is characterized by X-ray diffraction pattern having peaks expressed as 2-theta at about 5.66, 7.04, 7.81, 10.13, 11.35, 11.73, 13.82, 15.07,

15.70, 16.59, 17.07, 18.03, 19.28, 20.56, 20.85, 21.42, 22.24, 22.93, 23.67, 24.20, 25.67, 26.22, 26.73, 27.88, 28.73, 29.31, 29.93, 30.72, 31.74, 32.84, 33.81, 34.83, 35.38, 37.28, 40.70,43.47, 44.14 and 45.38 degrees.
According to another embodiment of the present invention, there is provided a process for preparation of Metformin embonate/pamoate polymorph comprising the steps of,
a) treating Metformin embonate/pamoate with a first solvent to obtain a first mixture;
b) optionally treating the first mixture obtained in step a) with a second solvent to obtain a second mixture; and
c) isolating Metformin embonate/pamoate polymorph from the first mixture or the second mixture.
In a preferred embodiment, Metformin pamoate/embonate is treated with a first solvent selected from methanol, ethanol, ethyl acetate, acetone, methylene dichloride, 1,4-dioxane, tetrahydrofuran (THF) or mixture thereof to obtain a first mixture. The first mixture is heated to a temperature of about 40-100°C, preferably about 50-80X. This mixture is cooled to about 5 to 30°C followed by optionally treating the obtained mixture with a second solvent selected from diisopropyl ether, n-hexane, diethyl ether or toluene to obtain a second mixture. Metformin pamoate/embonate Form I is isolated from the first mixture or the second mixture.
In a preferred embodiment, Metformin embonate is treated with a first solvent selected from methanol, ethanol, n-propanol, isopropanol, water or mixture thereof to obtain a first mixture. The first mixture is heated to a temperature of 40 to 100°C preferably 50 to 80°C. This mixture is cooled to a temperature of about 5 to 10°C and is maintained at the same temperature for about 1 to 24 hours to obtain Metformin embonate/pamoate Form II. The product thus obtained is isolated and dried.
In a preferred embodiment, Metformin pamoate/embonate is treated with a first solvent selected from dimethyl formamide (DMF) or dimethyl acetamide (DMA) at room temperature, preferably 25 to 30°C to obtain a first mixture. The first mixture is treated with a second solvent selected from diisopropyl ether, isopropanol, ethyl acetate or methylene dichloride to obtain a second mixture. The second mixture is stirred for 2 to 30 hours, preferably for 4 to 24 hours to obtain Metformin embonate/pamoate Form III. The

product thus obtained is isolated and dried.
In a preferred embodiment, Metformin pamoate/embonate is treated with a first solvent selected from dimethyl formamide (DMF) or dimethyl acetamide (DMA) at room temperature, preferably 25 to 30°C to obtain a first mixture. The first mixture is treated with a second solvent selected from acetone or methyl ethyl ketone to obtain a second mixture. The second mixture is stirred for 2 to 10 hours, preferably for 4 to 6 hours to obtain Metformin pamoate/embonate Form IV. The product thus obtained is isolated and dried.
Metformin pamoate used for the preparation of novel polymorphic forms can be selected from Form I or its mixture with other polymorphic forms, in particular its mixture with Form II.
According to another embodiment of the present invention, there is provided a process for preparation of Metformin pamoate/embonate, comprising the steps of,
a) treating Metformin base with an organic solvent to obtain a first mixture;
b) treating the first mixture with pamoic acid or disodium pamoate to obtain a second mixture; and
c) isolating Metformin pamoate from the second mixture.
In a preferred embodiment, Metformin base is treated with a solvent selected from methylene dichloride, acetonitrile, isopropanol or mixture thereof at room temperature, preferably at 25 to 30°C to obtain a first mixture. The first mixture is optionally heated to obtain a clear solution. The first mixture is then treated with pamoic acid to obtain a second mixture. The second mixture is maintained at the same temperature for 5 to 30 hours, preferably for 6 to 24 hours under stirring to obtain Metformin pamoate/embonate Form I. The product thus obtained is isolated and dried.
In a preferred embodiment, Metformin base is treated with a solvent selected from methanol, ethanol, n-propanol, isopropanol or mixture thereof at room temperature, preferably at 25°C to obtain a first mixture. The first mixture is treated with pamoic acid to obtain a second mixture. The second mixture is maintained at the same temperature for 20 to 30 hours, preferably for 24 hours under stirring to obtain Metformin pamoate Form II. The product thus obtained is isolated and dried.

In a preferred embodiment, Metformin base is treated with a solvent selected from acetone, methyl ethyl ketone or mixture thereof at room temperature, preferably at 25 to 30°C to obtain a first mixture. The first mixture is treated with pamoic acid to obtain a second mixture. The second mixture is maintained at the same temperature for 20 to 30 hours, preferably for 24 hours under stirring to obtain Metformin pamoate Form IV. The product thus obtained is isolated and dried.
In a preferred embodiment, Metformin base is treated with a solvent selected from 1,4-dioxane or THF to obtain a first mixture. The first mixture is optionally heated to obtain a clear solution. The first mixture is treated with pamoic acid to obtain a second mixture. This second mixture is maintained at the same temperature for 20 to 30 hours, preferably for 24 hours under stirring to obtain Metformin pamoate Form V. The product thus obtained is isolated and dried.
In a preferred embodiment, Metformin base is treated with a solvent selected from ethyl acetate, methyl acetate, isopropyl acetate or mixture thereof at room temperature, preferably at 25 to 30°C to obtain a first mixture. The first mixture is treated with pamoic acid to obtain a second mixture. The second mixture is maintained at the same temperature for 20 to 30 hours, preferably for 24 hours under stirring to obtain Metformin pamoate Form VI. The product thus obtained is isolated and dried.
Metformin base, Metformin hydrochloride and Metformin pamoate used in the above processes can be obtained by the methods known in the art or by the process described herein. Metformin free base can be prepared by neutralization of Metformin salts such as hydrochloride or pamoate.
Metformin HC1 can be prepared by any method known in the art. In a preferred embodiment Metformin hydrochloride is prepared by a process comprising the steps of, charging DMF in a round bottom flask followed by addition of dimethylamine HC1 and dicyandiamide under stirring to obtain a mixture. DMF is further charged to the above mixture followed by heating the mixture to 65°C. The heating of the mixture is stopped after the temperature reaches 65°C and the mixture is maintained for 30 min at 70-80°C to obtain a solution. The obtained solution is filtered into another RB flask and to this is charged 10 ml isopropanol followed by heating this mixture to 120°C. The heating of the mixture is stopped after the temperature reaches 120°C. Isopropanol distills out at 120 to

125°C. After the distillation ceases, the mixture is maintained at 140-160°C for 4 hours followed by cooling the mixture to 30-35°C. The solid obtained is filtered and dried. The solid is washed with dimethyl formamide and dried. The solid is further washed with isopropanol and dried at 80-90°C to obtain Metformin HC1.
In a preferred embodiment, Metformin pamoate/embonate Form III, Form IV, Form V and Form VI exists as solvates.
Polymorphic forms differ in their physicochemical properties such as solubility, dissolution rate etc. which influence the performance of pharmaceutical products. Various conditions in the crystallization process are responsible for the generation of different polymorphic forms. These conditions include solvent effects, impurities, level of supersaturation, temperature at which crystallization is carried out and change in stirring conditions.
Pre-formulation study involves investigation of the physical and chemical properties of the drug substance alone or when combined with the excipients. The aim of pre-formulation testing is to generate information useful to develop a stable and bioavailable dosage form. The commonly investigated preformulation parameters include Bulk Density/Tapped Density, Carr's index and Hausner ratio. The above mentioned parameters affect the flow properties of a molecule. A Hausner ratio greater than 1.25 is considered to be an indication of poor flowability. Carr's index greater than 25 is considered to be an indication of poor flowability,
Metformin pamoate Form I is lemon yellow in colour whereas Metformin pamoate Form II is off-white in colour. The Hausner ratio of Metformin pamoate Form I is 1.937 whereas that of Metformin pamote Form II is 1.650 indicating that Metformin pamoate Form II has better flowability as compared to Form I. Carr's index of Metformin pamoate Form I is 48.38 and that of Metformin pamoate Form II is 39.39 indicating that Metformin pamoate Form II has better flowability as compared to Form I. Bulk density of Metformin pamoate Form I is 0.1612 and that of Metformin pamoate Form II is 0.303. Tapped density of Metformin pamoate Form I is 0.3125 and that of Metformin pamoate Form II is 0.5. Metformin pamoate or polymorphic forms thereof obtained by the process of the present invention is more than about 99% pure, preferably more than about 99.9%

pure, with impurities less than about 0.1%.
According to another embodiment, the present invention provides pharmaceutical compositions comprising Metformin pamoate or polymorphs thereof and at least one pharmaceutically acceptable excipient.
The pharmaceutical compositions may be in the form of tablet, capsules, powder, syrup, solution, suspension or the like. The pharmaceutical compositions may comprise Metformin pamoate in the range of 70% to about 90% by weight of the total composition. Suitable pharmaceutically acceptable excipient include diluent, binder, disintegrant, lubricant, coating agent and others. Diluent may be used in an amount of about 5% to about 25% by weight of total composition. Binder may be used in an amount of about 1.5% to about 10% by weight of total composition. Disintegrant may be used in an amount of about 0.5% to about 10% by weight of tota/ composition. Lubricant may be used in an amount of about 0.5% to about 10% by weight of total composition.
Diluent may be selected from microcrystalline cellulose, lactose monohydrate, maltodextrin and the like. Binder may be selected from hydroxypropyl methyl cellulose, PVPK-30, hydroxypropyl cellulose and the like. Disintegrant may be selected from crospovidone, sodium starch glycolate, croscarmellose sodium and the like. Lubricant may be selected from magnesium stearate, stearic acid and the like.
The pharmaceutical compositions of the present invention may be prepared according to any of the conventional methods including wet granulation method, dry granulation method and direct compression method. The tablets may be optionally film coated. The coating can be performed according to any of the conventional coating methods.
In a preferred embodiment, Metformin pamoate/embonate, Sodium Starch Glycolate, Polyethylene Glycol 4000 and Polyethylene Glycol 6000 are sifted and mixed in a Fluid Bed Processor for 10 minutes to obtain a mixture. PVP-K-30 is dissolved in water under stirring to obtain a binder solution. The mixture is granulated using the binder solution in the Fluid Bed Processor to obtain granules. The obtained granules are dried and the dried granules are mixed with sifted Sodium Starch Glycolate to obtain a blend. The obtained blend is lubricated with magnesium stearate and the lubricated blend is compressed to obtain tablets.

Unless otherwise indicated, the following definitions are set forth to illustrate and define
the meaning and scope of the various terms used to describe the invention herein.
The term "Metformin embonate" or "Metformin pamoate" is used interchangeably in the
specification.
The term "pharmaceutically acceptable" means that which is useful in preparing a
pharmaceutical composition that is generally non-toxic and is not biologically undesirable
and includes that which is acceptable for human pharmaceutical use.
As used herein, the term "room temperature" means a temperature from about 10°C to
45°C, preferably 20°C to 40°C.
The term "substantially free" or "substantially pure" as used herein means Metformin
embonate/pamoate Form I or Metformin embonate/parnoate Form II containing less than
about 1% , preferably less than about 0.5%, more preferably less than about 0.1% of
undesired compounds including other polymorphic forrns.
Identification of solid obtained by the present invention can be made by methods known in the art such as X-Ray powder diffraction pattern (XRPD), Infra red spectrum (IR) or Differential scanning calorimetry (DSC).
X-ray powder diffraction pattern is obtained on Xpert'pRO, PANalytical, diffractometer equipped with accelerator detector using Copper Ka (n = 1.5406 A) radiation with scanning range between 2-theta 4-50° at a scanning speed of 2°/min.
The following examples are for illustrative purposes only and are not intended, nor should they be interpreted, to limit the scope of the invention in any manner.
Examples
Example 1: Preparation of Metformin HC1
67.5 ml of dimethyl formamide was taken in a 500 ml RB flask followed by addition of 50 gm of dimethylamine HC1 and 46.33 gm of Dicyandiamide under stirring to obtain a mixture. 66.7 ml of dimethyl formamide was further charged to the obtained mixture followed by heating the mixture to 65°C. The heating of the mixture was stopped after the temperature reached 65°C and the mixture was maintained for 30 min at 70-80°C to obtain a solution. The obtained solution was filtered into another RB flask and to this was charged 10 ml isopropanol followed by heating this mixture to 120°C. The heating of the mixture was stopped after the temperature reached 120°C. Isopropanol distilled out at 120

to 125°C. After the distillation ceases, the mixture was maintained at 140-160°C for 4 hours followed by cooling the mixture to 30-35°C. The solid obtained was filtered and dried. The solid was washed with 71.5 ml of dimethyl formamide and dried. The solid was further washed with 43 ml of isopropanol and dried at 80-90°C in a Fluidized Bed Dryer (FBD) to obtain Metformin HC1. Yield: 72.5 - 82.5 gm
Example 2: Preparation of Metformin pamoate Form I
59.5 gm of disodium pamoate was dissolved in 535 ml of purified water at 40-45°C to obtain a solution. The obtained solution was filtered through 0.45 micron/hyflo bed. The filtrate was transferred to a RB flask and heated to 55°C. 50 gm of Metformin hydrochloride was dissolved in 238 ml of purified water at 55°C to obtain a solution of Metformin hydrochloride. The obtained Metformin hydrochloride solution was charged to the above solution of disodium pamoate at 55°C to obtain a mixture. The obtained mixture was maintained at the same temperature for 4 hours followed by cooling to 25 - 30°C. The solid obtained was filtered, washed with 100 ml water and dried in Air Tray Dryer (ATD) at 65-70°C to obtain Metformin pamoate Form I. Yield: 70-75 gm
Example 3: Preparation of Metformin pamoate Form I
25gm of disodium pamoate was dissolved in 200ml of water at 55-65°C to obtain a solution. The obtained hot solution was filtered through 0.45 micron/hyflo bed. The clear solution was cooled to 10°C. To this, was added a solution of 20.84gm Metformin hydrochloride in 73ml of water to obtain a mixture. This mixture was maintained at the same temperature for about 2 hours. The solid which precipitated out was filtered and dried to obtain 34g of Metformin pamoate Form I as spherical particles.
Example 4: Preparation of Metformin pamoate Form I
25gm of disodium pamoate was dissolved in 200ml of water at 55-65°C to obtain a solution. The obtained hot solution was filtered through 0.45 micron/hyflo bed. The clear solution was cooled to 25°C. To this, was added a solution of 20.84gm Metformin hydrochloride in 73ml of water to obtain a mixture. This mixture was maintained at the same temperature for about 2 hours. The solid which precipitated out was filtered and dried to obtain 33.9g of Metformin pamoate Form I as spherical particles.

Example 5: Preparation of Metformin pamoate Form I
25gm of disodium pamoate was dissolved in 200ml of water at 55-65°C to obtain a solution. The obtained hot solution was filtered through 0.45 micron/hyflo bed. The clear solution was cooled to 35°C. To this, was added a solution of 20.84gm Metformin hydrochloride in 73ml of water to obtain a mixture. This mixture was maintained at the same temperature for about 2 hours. The solid which precipitated out was filtered and dried to obtain 33.7g of Metformin pamoate Form I as spherical particles.
Example 6: Preparation of Metformin pamoate Form I
25gm of disodium pamoate was dissolved in 200ml of water at 55-65°C to obtain a solution. The obtained hot solution was filtered through 0.45 micron/hyflo bed. The clear solution was cooled to 45°C. To this, was added a solution of 20.84gm Metformin hydrochloride in 73ml of water to obtain a mixture. This mixture was maintained at the same temperature for about 2 hours. The solid which precipitated out was filtered and dried to obtain 34. lg of Metformin pamoate Form I as needle shaped particles.
Example 7: Preparation of Metformin pamoate Form II
59.5 gm of disodium pamoate was dissolved in 952 ml of purified water at 25-30°C to obtain a solution. The obtained solution was filtered through 0.45 micron/hyflo bed. The filtrate was transferred to a RB flask. 50 gm of Metformin hydrochloride was dissolved in 238 ml of purified water at 25-30°C to obtain a solution of Metformin hydrochloride. The obtained Metformin hydrochloride solution was charged to the above solution of disodium pamoate at 25- 30°C to obtain a mixture. The obtained mixture was maintained at the same temperature for 4 hours. The solid obtained was filtered, washed with 100 ml water and dried in Air Tray Dryer (ATD) at 65-70°C to obtain Metformin pamoate Form II. Yield: 70-75 gm
Example 8: Preparation of Metformin pamoate Form II
59.5 gm of disodium pamoate was dissolved in 1547 ml of purified water at 25-30°C to obtain a solution. The obtained solution was filtered through 0.45 micron/hyflo bed. The filtrate was transferred to a RB flask. 50 gm of Metformin hydrochloride was dissolved in 238 ml of purified water at 25-30°C to obtain a solution of Metformin hydrochloride. The obtained Metformin hydrochloride solution was charged to the above solution of disodium pamoate at 25-30°C to obtain a mixture. The obtained mixture was maintained

at the same temperature for 4 hours. The solid obtained was filtered, washed with 100 ml water and dried in Air Tray Dryer (ATD) at 65-70°C to obtain Metformin pamoate Form II. Yield: 70-75 gm
Example 9: Preparation of Metformin pamoate Form I
0.5g of Metformin pamoate was dissolved in 5ml of methanol at 50°C to obtain a solution. The solution was cooled to 25-30°C followed by addition of 10 ml of diisopropyl ether (DIPE) in a drop wise manner under stirring to obtain a mixture. The obtained mixture was maintained at the same temperature for 1 to 4 hours to obtain a solid. The solid thus obtained was isolated by filtration and dried at 50-60°C to obtain Metformin pamoate Form I. Yield: 0.3gm; Purity: greater than 99.9%
Example 10: Preparation of Metformin pamoate Form I
0.5g of Metformin pamoate was dissolved in 5ml of methanol at 50°C to obtain a solution. The solution was cooled to 5-10°C. This cold solution was added in a drop wise manner under stirring to 10 ml of cold DIPE to obtain a mixture. The obtained mixture was maintained at the same temperature for 2 to 4 hours to obtain a solid. The solid thus obtained was isolated by filtration and dried at 50-60°C to obtain Metformin pamoate Form I. Yield: 0.3 lgm; Purity: greater than 99.9%
Example 11: Preparation of Metformin pamoate Form I
0.5g of Metformin pamoate was dissolved in 25 ml of ethanol at 60°C to obtain a solution. The solution was cooled to 25-30°C followed by addition of 25 ml of n-hexane in a drop wise manner under stirring to obtain a mixture. The obtained mixture was maintained at the same temperature for 1 to 4 hours to obtain a solid. The solid thus obtained was isolated by filtration and dried at 50-60°C to obtain Metformin pamoate Form I. Yield: 0.26 gm; Purity: greater than 99.9%
Example 12: Preparation of Metformin pamoate Form I
0.5g of Metformin pamoate was suspended in 50 ml of ethyl acetate at 70°C to obtain a suspension. 15 ml of methanol was added to the obtained suspension in a drop wise manner under stirring at the same temperature to get a clear solution. The solution was filtered and the filtrate was cooled to 20-2 5 °C. The filtrate was maintained at the same temperature for 1 to 4 hours to obtain a solid. The solid thus obtained was isolated by

filtration and dried at 50-60°C to obtain Metformin pamoate Form I. Yield: 0.37 gm; Purity: greater than 99.9%
Example 13: Preparation of Metformin pamoate Form I
0.5g of Metformin pamoate was suspended in 20 ml of acetone at 55 °C to obtain a suspension. 8 ml of methanol was added to the obtained suspension in a drop wise manner under stirring at the same temperature to get a clear solution. The solution was filtered and the filtrate was cooled to 20-25°C. The filtrate was maintained at the same temperature for 1 to 4 hours to obtain a solid. The solid thus obtained was isolated by filtration and dried at 50-60°C to obtain Metformin pamoate Form I. Yield: 0.26gm; Purity: greater than 99.9%
Example 14: Preparation of Metformin pamoate Form I
0.5g of Metformin pamoate was suspended in 50 ml of Methylene dich/oride (MDC) at 55°C to obtain a suspension. 8 ml of methanol was added to the obtained suspension in a drop wise manner under stirring at the same temperature to get a clear solution. The solution was filtered and the filtrate was cooled to 20-25°C. The filtrate was maintained at the same temperature for 1 to 4 hours to obtain a solid. The solid thus obtained was isolated by filtration and dried at 50-60°C to obtain Metformin pamoate Form I. Yield: 0.32gm; Purity: greater than 99.9%
Example 15: Preparation of Metformin pamoate Form I
0.5g of Metformin pamoate was suspended in 50 ml of 1,4-dioxane at 55°C to obtain a suspension. 15 ml of methanol was added to the obtained suspension in a drop wise manner under stirring at the same temperature to get a clear solution. The solution was filtered and the filtrate was cooled to 20-25°C. The filtrate was maintained at the same temperature for 1 to 4 hours to obtain a solid. The solid thus obtained was isolated by filtration and dried at 50-60°C to obtain Metformin pamoate Form I. Yield: 0.26 gm; Purity: greater than 99.9%
Example 16: Preparation of Metformin pamoate Form I
0.5g of Metformin pamoate was suspended in 50 ml of Tetrahydrofuran (THF) at 55°C to obtain a suspension. 15 ml of methanol was added to the obtained suspension in a drop wise manner under stirring at the same temperature to get a clear solution. The solution

was filtered and the filtrate was cooled to 20-25°C. The filtrate was maintained at the same temperature for 1 to 4 hours to obtain a solid. The solid thus obtained was isolated by filtration and dried at 50-6CTC to obtain Metformin pamoate Form I. Yield: 0.23gm; Purity: greater than 99.9%
Example 17: Preparation of Metformin pamoate Form I
0.5g of Metformin base was suspended in 30 ml of Methylene dichloride(MDC) at 25°C to obtain a suspension. 0.65g of Pamoic acid was added to the suspension at the same temperature. The suspension was maintained at the same temperature for 24 hours under stirring to obtain a solid. The solid thus obtained was isolated by filtration and dried at 50-60°C to obtain Metformin pamoate Form I. Yield: 0.61gm; Purity: greater than 99.9%
Example 18: Preparation of Metformin pamoate Form I
0.5g of Metformin base was suspended in 10 ml acetonitrile at 25°C to obtain a suspension. The obtained suspension was heated at 55-60°C to get a clear solution. The solution was filtered and the filtrate was cooled to 25°C. 0.65g of Pamoic acid was added to the filtrate at the same temperature. The solid which precipitated out was added to 10ml acetonitrile to obtain a mixture. This mixture was maintained at the same temperature for 6 hours under stirring to obtain a solid. The solid thus obtained was isolated by filtration and dried at 50-60°C to obtain Metformin pamoate Form I. Yield: 0.82gm; Purity: greater than 99.9%
Example 19: Preparation of Metformin pamoate Form I
0.5g of Metformin base was suspended in 20 ml of isopropanol at 25°C to obtain a suspension. The obtained suspension was heated to 55-60° to get a clear solution. The solution was filtered and the filtrate was cooled to 25°C. 0.65g of Pamoic acid was added to the filtrate at the same temperature to obtain a mixture. This mixture was maintained at the same temperature for 24 hours under stirring to obtain a solid. The solid thus obtained was isolated by filtration and dried at 50-60°C to obtain Metformin pamoate Form I. Yield: 0.62gm; Purity: greater than 99.9%
Example 20: Preparation of Metformin pamoate Form II
0.75g of Metformin pamoate was dissolved in 5 ml of methanol at 55°C to obtain a clear solution. The solution was filtered and the filtrate was cooled to 5-10°C. The filtrate was

maintained at the same temperature for 1 to 4 hours to obtain a solid. The solid thus obtained was isolated by filtration and dried at 50~60°C to obtain Metformin pamoate Form II. Yield: 0.42gm; Purity: greater than 99.9%
Example 21: Preparation of Metformin pamoate Form II
0.5g of Metformin pamoate was dissolved in 14 ml of water at 75-80°C to obtain a clear solution. The solution was filtered and the filtrate was cooled to 5-10°C. The filtrate was maintained at the same temperature for 4 to 24 hours to obtain a solid. The solid thus obtained was isolated by filtration and dried at 50-60°C to obtain Metformin pamoate Form II. Yield: 0.26gm; Purity;greater than 99.9%
Example 22: Preparation of Metformin pamoate Form II
0.5g of Metformin pamoate was treated with 50 ml of isopropanol at 70°C to obtain a suspension. The obtained suspension was treated with 6 ml of water to obtain a clear solution. The solution was filtered and the filtrate was cooled to 5-10°C. The filtrate was maintained at the same temperature for 1 to 6 hours to obtain a solid. The solid thus obtained was isolated by filtration and dried at 50-60°C to obtain Metformin pamoate Form II. Yield: 0.21gm; Purity: greater than 99.9%
Example 23: Preparation of Metformin pamoate Form II
0.5 g of Metformin pamoate was treated with 50 ml of isopropanol at 70°C to obtain a suspension. The obtained suspension was treated with 25 ml of methanol to obtain a clear solution. The solution was filtered and the filtrate was cooled to 5-10°C. The filtrate was maintained at the same temperature for 1 to 6 hours to obtain a solid. The solid thus obtained was isolated by filtration and dried at 50-60°C to obtain Metformin pamoate Form II. Yield: 0.27gm; Purity; greater than 99.9%
Example 24: Preparation of Metformin pamoate Form II
0.5g of Metformin base was dissolved in 7 ml of methanol at 25°C to obtain a solution. 0.65g of pamoic acid was added to the obtained solution at the same temperature to obtain a mixture. The mixture was filtered and the filtrate was maintained at 25-30°C under stirring for 24 hours to obtain a solid. The solid thus obtained was isolated by filtration and dried at 50-60°C to obtain Metformin pamoate Form II. Yield: 0.58gm; Purity: greater than 99.9%

Example 25: Preparation of Metformin pamoate Form III
0.5g of Metformin pamoate was dissolved in 5 ml of dimethyl formamide at 25-30°C to obtain a clear solution. The obtained solution was filtered and 10 ml diisopropyl ether was added to the filtrate to obtain an oily layer. The obtained oily layer was stirred for 24 hours to obtain a solid. The solid thus obtained was isolated by filtration and dried at 50-60°C to obtain Metformin pamoate Form III. Yield: 0.28 gm; Purity: greater than 99.9%
Example 26: Preparation of Metformin pamoate Form III
0.5 gm of Metformin pamoate was dissolved in 5ml dimethyl formamide at 25-30°C to obtain a clear solution. The solution was filtered and 30 ml isopropanol was added to the filtrate to obtain a mixture. The mixture was stirred for 24 hours to obtain a solid. The solid thus obtained was isolated by filtration and dried at 50-60°C to obtain Metformin pamoate Form III. Yield: 0.29gm; Purity: greater than 99.9%
Example 27: Preparation of Metformin pamoate Form III
0.5gm of Metformin pamoate was dissolved in 5ml dimethyl formamide at 25-30°C to obtain a clear solution. The solution was filtered and 30 ml ethyl acetate was added to the filtrate to obtain a mixture. The mixture was stirred for 4 hours to obtain a solid. The solid thus obtained was isolated by filtration and dried at 50-60°C to obtain Metformin pamoate Form III. Yield: 0.33 gm; Purity: greater than 99.9%
Example 28: Preparation of Metformin pamoate Form III
0.5gm of Metformin pamoate was dissolved in 5ml of dimethyl formamide at 25-30°C to obtain a clear solution. The solution was filtered and 30 ml methylene dichloride was added to the filtrate to obtain a mixture. The mixture was stirred for 4 hours to obtain a solid. The solid thus obtained was isolated by filtration and dried at 50-60°C to obtain Metformin pamoate Form III. Yield: 0.38 gm; Purity: greater than 99.9%
Example 29: Preparation of Metformin pamoate Form IV
0.5gm of Metformin pamoate was dissolved in 5ml dimethyl formamide at 25-30°C to obtain a clear solution. The solution was filtered and was treated with 20 ml acetone to obtain a mixture. The mixture was stirred for 4 hours to obtain a solid. The solid thus obtained was isolated by filtration and dried at 50-60°C to obtain Metformin pamoate Form IV. Yield : 0.31 gm; Purity: greater than 99.9%

Example 30: Preparation of Metformin pamoate Form IV
0.5gm of Metformin base was suspended in 30 ml acetone at 25-30°C to obtain a suspension. 0.65gm of pamoic acid was added to the obtained suspension and the suspension was maintained under stirring for 24 hours at the same temperature to obtain a solid. The solid thus obtained was isolated by filtration and dried at 50-60°C to obtain Metformin pamoate Form IV. Yield: 0.8 gm; Purity; greater than 99.9%
Example 31: Preparation of Metformin pamoate Form V
0.5gm of Metformin base was dissolved in 20 ml 1,4-dioxane at 50-60°C to obtain a clear solution. The solution was filtered and 0.65gm of pamoic acid was added to the filtrate to obtain a sticky mass. The obtained sticky mass was maintained under stirring for 24 hours at 25-30°C to obtain a solid. The solid thus obtained was isolated by filtration and dried at 50-60°C to obtain Metformin pamoate Form V. Yield: 0.71 gm; Purity: more than 99.9%
Example 32: Preparation of Metformin pamoate Form VI
0.5gm of Metformin base was suspended in 30 ml of ethyl acetate at 25-30°C to obtain a suspension, 0.65gm of pamoic acid was added to the obtained suspension at the same temperature. The colour of the suspension changed from orange to yellow. The yellow coloured suspension was maintained under stirring for 24 hours at 25-30°C to obtain a solid. The solid thus obtained was isolated by filtration and dried at 50-60°C to obtain Metformin pamoate Form VI. Yield: 0.72 gm; Purity: greater than 99.9%
Example 33:
700gm of Metformin pamoate, 25gm of Sodium Starch Glycolate, 2.5gm of Polyethylene Glycol 4000 and 2.5gm of Polyethylene Glycol 6000 were sifted and mixed in a Fluid Bed Processor for 10 minutes to obtain a mixture. 22.5 gm of PVP-K-30 was dissolved in water under stirring to obtain a binder solution. The mixture was granulated using the binder solution in the Fluid Bed Processor to obtain granules. The obtained granules were dried and the dried granules were mixed with 20 gm of sifted Sodium Starch Glycolate to obtain a blend. The obtained blend was lubricated with 7.5 gm of magnesium stearate and the lubricated blend was compressed to obtain tablets.

We claim,
1. A process for preparation of Metformin embonate/pamoate Form I, substantially free of other polymorphic forms, comprising treating Metformin salt with an aqueous solution of disodium pamoate, wherein the reaction medium contains water in an amount of about 9 to 13 volumes with respect to the weight-of disodium pamoate.
2. The process as claimed in claim 1, wherein said treatment is carried out at a temperature of about 10°C to 70 °C and wherein said Metformin salt is Metformin hydrochloride.
3. A process for preparation of Metformin embonate Form II, substantially free of other polymorphic forms, comprising treating Metformin salt with an aqueous solution of disodium pamoate, wherein the reaction medium contains atleast about 11 volumes of water with respect to the weight of disodium pamoate.
4. The process as claimed in claim 3, wherein said treatment is carried out at a temperature of about 30°C or less than about 30°C and wherein said Metformin salt is Metformin hydrochloride.
5. A process for preparation of Metformin embonate/pamoate polymorph comprising the steps of,

a) treating Metformin embonate/pamoate with a first solvent to obtain a first mixture;
b) optionally treating the first mixture with a second solvent to obtain a second mixture; and
c) isolating Metformin embonate polymorph from the first mixture or the second mixture.
6. The process as claimed in claim 5, wherein for Form I, the first solvent is selected
from methanol, ethanol, ethyl acetate, acetone, methylene dichloride, 1,4-dioxane
or tetrahydrofuran and second solvent is selected from diisopropyl ether, n-hexane,
methanol, diethyl ether or toluene; for Form II, the first solvent is selected from
methanol, ethanol, n-propanol, isopropanol or water; for Form III, the first solvent

is selected from dimethyl formamide or dimethyl acetamide and the second solvent is selected from diisopropyl ether, isopropanol, ethyl acetate or methylene dichloride; for Form IV, the first solvent is selected from dimethyl formamide or dimethyl acetamide and second solvent is selected from acetone or methyl ethyl ketone.
7. A process for preparation of Metformin pamoate/embonate comprising the
steps of,
a) treating Metformin base with an organic solvent to obtain a first mixture;
b) treating the first mixture with pamoic acid or disodium pamoate to obtain a second mixture; and
c) isolating Metformin pamoate/embonate from the second mixture.

8. The process as claimed in claim 7, wherein said Metformin pamoate is Form I and said organic solvent is selected from methylene dichloride, acetonitrile or isopropanol; wherein said Metformin pamoate is Form II and said organic solvent is selected from methanol, ethanol, n-propanol or isopropanol; wherein said Metformin pamoate is Form IV and said organic solvent is selected from acetone or methyl ethyl ketone; wherein said Metformin pamoate is Form V and said organic solvent is selected from 1,4-dioxane or THF; and wherein said Metformin pamoate is Form VI and said organic solvent is Selected from ethyl acetate, methyl acetate or isopropyl acetate.
9. Metformin embonate polymorph selected from a group consisting of
Form II characterized by X-ray diffraction pattern having peaks expressed as
2-theta at about 6.73, 7.52,11.53, 13.17, 17.81,20.35, 20.67 and 24.67 degrees;
Form III characterized by X-ray diffraction pattern having peaks expressed as
2-theta at about 8.31, 11.36, 11.79, 16.66, 17.21, 17.88, 19.06, 19.46,20.19,20.44,
21.69,22.45, 22.80,23.69, 24.43, 26.12 and 26.49 degrees;
Form IV characterized by X-ray diffraction pattern having peaks expressed as
2-theta at about 6.14, 8.38, 11.56, 12.26, 16.81, 17.53, 18.27, 18.95, 19.35, 19.94,
21.23, 21.48, 21.73, 22.55, 23.01, 23.24, 2.3.88, 25.74, 26.13, 27.05 and
30.12 degrees;
Form V characterized by X-ray diffraction pattern having peaks expressed as

2-theta at about 7.59, 11.68,12.24,14.96,16.09, 17.07, 17.77,18.28,18.53, 18.94, 19.30, 20.55, 20.94, 21.66, 22.65, 23.47,23.82,25.48 and 26.07 degrees; and Form VI characterized by X-ray diffraction pattern having peaks expressed as 2-theta at about 6.16, 10.65, 11.80, 12.93, 14.73, 16.47, 17.20, 19.30, 20.16, 21.05, 23,10,23.64,25.97 and 29.74 degrees.
10. The process as claimed in claim 1 or claim 3, wherein said Metformin embonate/pamoate is formulated with excipients to obtain a pharmaceutical formulation.