FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENT RULES, 2003
•
COMPLETE SPECIFICATION (Section 10 and Rule 13)
"STABLE PHARMACEUTICAL COMPOSITION COMPRISING EPROSARTAN MESYLATE"
Glenmark Generics Limited
an Indian Company, registered under the Indian company's Act 1957
and having its registered office at
B/2, Mahalaxmi Chambers, 22 Bhulabhai Desai Road,
Mumbai - 400 026
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 stable pharmaceutical composition comprising Eprosartan mesylate, substantially in an anhydrous form, and process of preparation thereof.
BACKGROUND OF THE INVENTION:
Eprosartan mesylate is an angiotensin II receptor (ATI) antagonist and it is approved as Teveten® for the treatment of essential hypertension. Chemically Eprosartan mesylate is (E)-[alpha]-[2-n-butyl-l-[(4-carboxyphenyl) methyl]- lH-imidazol-5-yl] methylene-2-thiophene-propionic acid monomethanesulfonate.
Eprosartan has a very low bioavailability, approximately 13%, and the reason for such low bioavailability is its low solubility and low permeability across the intestinal epithelium. Because of such low bioavailability, it becomes essential to administer high dose of Eprosartan mesylate to achieve the desired therapeutic effect, which eventually results into the finished dosage form of higher weight and size.
Eprosartan and its Mesylate salt was first disclosed in U.S. Patent No. 5185351, however patent '351 doesn't provide any information with respect to its polymorphic nature. Subsequently, inventors of European Patents EP0991647 and EP0889880 described the various polymorphic forms of Eprosartan and the process of making them. Inventors of Patents '647 and '880 states that, the existing anhydrous form, if moistened prior to storage in a container, converts to the hydrated form more particularly to the dihydrate form. However it is said that, the hydrated form thus produced is not a stable form and generally converts back to the other polymorphic forms such as anhydrous or monohydrate, based on the extent and duration of vacuum drying. Hence inventors of the reference European patents predicted the possibility of getting a mixture of a monohydrate, a dihydrate and an anhydrate form depending upon the length or severity of vacuum drying, while preparing the drug product comprising Eprosartan mesylate. In order to avoid the formation of mixtures of various polymorphic forms, the inventors of patent '647 and '880 has proposed the complete conversion of anhydrous form of eprosartan mesylate into dihydrate form, by wet granulating a dry blend comprising anhydrous Eprosartan mesylate, with

water. However, if desired the said granulate comprising Eprosartan mesylate dihydrate, can be further converted into monohydrate by means of vacuum drying.
The in-situ processes of making dihydrate or monohydrate forms of Eprosartan mesylate during wet granulation stage and/or drying stage, provided in patent '647 and '880, are highly sensitive with respect to its process parameters like quantity of water used, extent and duration of granulation, and extent and duration of drying processes. A minor error in any of these process parameters may affect the quality of final drug product either immediately or during the stability. Moreover the inventors of patent '647 and '880 did not provide the appropriate drying temperature requirement for the production of Eprosartan mesylate dihydrate or Eprosartan mesylate monohydrate specifically. In absence of such guidance on accurate drying temperatures, the possibility of formation of mixture of different polymorphic form in a drug product comprising Eprosartan mesylate can't be neglected.
The stability or uniformity of polymorphic form of an active ingredient in a drug product is an essential quality parameter, because the polymorphic nature of active ingredient affects the solubility, which in turn affects the bioavailability of active ingredient. US FDA's guidance for industry for the polymorphism in drug product (published in July 2007), also identify the following three ways, by which polymorphism influence the drug substance and drug product:
i) Influence on solubility, dissolution and Bioavailability (BA) and Bioequivalence (BE)
ii) Influence on the manufacturing of the drug product, and
iii) Influence on stability
Further the guideline; suggest that the polymorphic forms of the drug substance can undergo phase conversion when exposed to a range of manufacturing processes, such as drying, milling, micronization, wet granulation, spray-drying, and compaction. Exposure to environmental conditions such as humidity and temperature can also induce polymorph conversion.
Hence as stated above, in the absence of proper control over the all critical process parameters, there is a possibility of formation of Drug product, having Eprosartan mesylate as a mixture of anhydrous, monohydrate and dihydrate form (as also reported in EP0991647), that may lead to

variation in aqueous solubility and dissolution rates, ultimately affecting bioavailability of the drug product. Hence it is highly desired to develop a stable pharmaceutical composition comprising Eprosartan mesylate, substantially in an anhydrous form, which do not convert to other hydrate form during the course of stability.
In addition to abovesaid prior arts, there are quite a few references that teach the pharmaceutical compositions of Eprosartan base or its mesylate salt. Inventors of SmithKline's patent W09925321 surprisingly found that unlike Eprosartan Mesylate, Eprosartan base does not form a Hydrate during the wet granulation process, which in fact allows the preparation of reduced size, high drug load tablet of anhydrous Eprosartan base. In addition to this, the Patent applications filed by Lek Pharmaceuticals WO2009124982, WO2009124983 and WO2009124984 describes a special dry granulation process termed as NAMADG (Non-aqueous moisture activated dry granulation) which doesn't affect the polymorphic form of Eprosartan mesylate. The NAMADG referred in Lek's patent uses non-aqueous liquid excipient preferably liquid surfactants such as polysorbates, poloxamer and liquid polyethylene glycol of low molecular weight.
However, none of the prior arts adequately addresses the issue of polymorphism in the pharmaceutical composition comprising Eprosartan mesylate.
SUMMARY OF THE INVENTION:
The present invention provides a stable pharmaceutical composition comprising, Eprosartan mesylate substantially in the anhydrous form and at-least one pharmaceutically acceptable carrier.
In an another embodiment, the present invention provides, a stable pharmaceutical composition comprising, Eprosartan mesylate substantially in the anhydrous form and at-least one pharmaceutically acceptable carrier, that releases at-least 75% of Eprosartan mesylate within 30 minutes, in USP type II apparatus, at 50 rpm, in 1000 ml of Phosphate buffer at pH of 7.5.

In another preferred embodiment, the present invention provides a stable pharmaceutical composition comprising Eprosartan mesylate substantially in the anhydrous form, prepared by a non-aqueous granulation process.
BRIEF DESCRIPTION OF THE FIGURES:
Figure 1 depicts comparative XRPD diffractogram of Eprosartan mesylate API, un-lubricated granule and coated tablet with their corresponding placebo.
Figure 2 & 3 respectively depicts DSC thermogram of un-lubricated granule and coated tablet Figure 4 &5, respectively depicts TGA thermogram of un-lubricated granule and coated tablet.
DETAILED DESCRIPTION OF INVENTION:
Eprosartan mesylate is unstable with respect to its polymorphic form and the anhydrous form if moistened prior to storage in a container, can convert to hydrate form, preferably into dihydrate form. Additionally, the dihydrate form was also found to be obtained during wet granulation of anhydrous Eprosartan mesylate with water. Further the dihydrate form, being unstable may convert back to monohydrate form during vacuum drying step of the formulation process. So there is the possibility of getting a mixture of different hydrate forms in the final dosage form comprising Eprosartan mesylate. The present invention addresses the problem pertaining to the conversion of polymorphic forms of eprosartan mesylate, and provides pharmaceutical compositions, comprising Eprosartan mesylate substantially in anhydrous form. For the purpose of present invention, the term "substantially in anhydrous form" means that the Eprosartan mesylate, in the pharmaceutical composition of present invention, largely exists in an anhydrous form, whereby the other hydrate forms will not exceed more than 5% of total Eprosartan mesylate.
The anhydrous and hydrate forms of Eprosartan mesylate, can be distinguished and differentiated by means of x-ray powder diffraction patterns (XRPD), thermograms (DSC or TGA), infrared spectra (IR). Anhydrous, dihydrate and monohydrate, forms of Eprosartan mesylate, are characterized in European patents, EP0889880 and EP0991647 of SmithKline, the content of

which is incorporated herein by reference. As per the disclosures of patent, EP0889880, the powder X-ray diffraction pattern of anhydrous form exhibits characteristic diffraction lines at 20 values 7.15, 13.90, 18.9, 22.2, 24.35 and 28.95°. Similarly, the differential scanning calorimetric, hereinafter DSC thermogram of anhydrous form exhibits a single thermal event, a melting endotherm at about 250°C associated with a weight loss, suggesting that melting is followed by decomposition of the drug substance. Further, EP0889880 discloses that Thermogravimetric analysis (TGA) of anhydrous Eprosartan mesylate does not exhibit significant weight loss prior to melting, indicating that this compound does not contain significant quantities of surface adsorbed water and/or residual solvents and thereby confirming the anhydrous nature of Eprosartan mesylate.
A stable pharmaceutical composition of present invention comprises Eprosartan mesylate substantially in anhydrous form, wherein the undesired conversion of anhydrous form to other hydrate form of Eprosartan mesylate are controlled.
In a preferred aspect, the present invention provides a stable pharmaceutical composition of Eprosartan mesylate substantially in an anhydrous form, which shows a characteristic peak at 7.15, 18.9, 20.45, 22.2, 24.35 and 34.2 ±0.2° in powder X-ray diffraction.
In an additional aspect, the pharmaceutical compositions of the present invention, does not show any significant moisture loss in the temperature range of 25-125°C, which is characteristic of anhydrous form, in contrast to that of hydrate forms of Eprosartan mesylate.
In one of the aspects, the present invention also provides the pharmaceutical composition comprising Eprosartan Mesylate, substantially in an anhydrous form, which shows a sharp endotherm at about 250° C.
The present invention also provides a pharmaceutical composition comprising Eprosartan mesylate, substantially in anhydrous form, which exhibits one or more of the following characteristics, after subjecting the said compositions to the 40 Deg C Temperature /75% Relative humidity, for the period of three months:

1. Characteristic peaks at 7.15, 18.9, 20.45, 22.2, 24.35 and 34.2 ±0.2° in powder X-ray diffraction.
2. No significant moisture loss in the temperature range of 25-125°C,
3. a sharp endotherm at about 250°C.
The present invention also provides a tablet comprising Eprosartan mesylate, substantially in an anhydrous form, which exhibits one or more of the following characteristics, after subjecting the said compositions to the 40 Deg C Temperature /75% Relative humidity, for the period of three months:
1. Characteristic peaks at 7.15, 18.9, 20.45, 22.2, 24.35 and 34.2 ±0.2° in powder X-ray diffraction.
2. No significant moisture loss in the temperature range of 25-125°C,
3. a sharp endotherm at about 250°C.
In a preferred aspect, the pharmaceutical composition of present invention comprises Eprosartan mesylate, which is equivalent to the 300 mg to 600 mg of Eprosartan base. Apart from Eprosartan mesylate, the pharmaceutical composition of present invention, also comprises one or more diluent, one or more disintegrant, one or more binder, and one or more lubricant, optionally with other excipients like stabilizers, flowing aids, antiadherents or glidants.
The pharmaceutical composition of present invention may be a tablet, capsule, granules, powder, or pellets etc. however the tablet form is more preferred.
The pharmaceutical compositions comprising a high drug dose, faces some additional complexities while manufacturing and hence it becomes crucial to select an appropriate formulation process, which will result into a pharmaceutical composition, having sufficient hardness and a size comfortable for administration to a patient. In case of Eprosaratan mesylate, the therapeutically effective dose is high; hence a dry granulation process results in a tablet of low hardness and high friability. The present invention provides, pharmaceutical composition comprising Eprosartan mesylate, prepared by the non-aqueous granulation process, which

prevents any undesired conversion to the hydrate forms of Eprosartan mesylate, and provides Eprosartan mesylate tablet, having adequate hardness, and disintegration time properties.
The stable pharmaceutical composition comprising Eprosartan mesylate substantially in anhydrous form, is prepared by dry mixing anhydrous Eprosartan mesylate with diluent(s) and disintegrant(s); granulating the blend with binder solution prepared by dissolving a binder in a non-aqueous solvent; drying the granulated mass, and optionally mixing with extra-granular material and finally lubricating and compressing the blend.
The term "non aqueous granulation" used in the present application includes physical adherence achieved, by means of a solvent that is neither a water nor an aqueous solution of any organic solvent. Apart from, maintaining anhydrous nature of Eprosartan mesylate, the proper nonaqueous granulation solvent of present invention, improves the binding between the dry powders, and helps to produce the granules suitable with respect to the flow, blend homogeneity, and high speed compression of tablets. More particularly, the combination of appropriate non-aqueous solvent and drying conditions provides a suitable environment which maintains the anhydrous nature of the drug Eprosartan mesylate in the pharmaceutical composition.
The type and quantity of non-aqueous solvent used in above-said non aqueous granulation process is crucial to maintain the anhydrous nature of Eprosartan mesylate in the finished dosage form. For the purpose of present invention, the non-aqueous granulating solvent comprises Isopropyl alcohol, methylene dichloride, ethanol, acetone and the likes; whereas Isopropyl alcohol being more preferred. However, it is well within the scope of present invention to use a mixture of more than one non-aqueous solvent in various proportions e.g. 50:50 mixtures (v/v) of Isopropyl alcohol and methylene dichloride.
In an aspect of the present invention, the quantity of non-aqueous solvent used for wet granulation is 15-25 % of the weight of dry mix blend.
The composition thus prepared in accordance with the said invention, is found to be stable after three months exposure at the accelerated stability storage conditions, wherein the pharmaceutical

composition is found to contain Eprosartan mesylate largely in an anhydrous form, having not more than 5% of other hydrate forms of Eprosartan mesylate.
In a more preferred aspect, the tablet prepared in accordance with the said invention, is found to be stable after three months exposure at the accelerated stability storage conditions, wherein the tablet is found to contain Eprosartan mesylate largely in an anhydrous form, having not more than 5% of other hydrate forms of Eprosartan mesylate.
The polymorphic uniformity of Eprosartan mesylate in the pharmaceutical composition of present invention reduces the possibility of variation in drug release from the dosage form. In a preferred embodiment, drug release from the dosage form is found uniform with at-least 75% of Eprosartan mesylate released from the pharmaceutical composition within 30 minutes, as measured in USP type II apparatus, at 50 rpm, in 1000 ml of Phosphate buffer at pH of 7.5.
The stable pharmaceutical composition of present invention is a tablet that comprises, Eprosartan mesylate substantially in an anhydrous form, a diluent in an amount of about 5 to 50 wt. % of composition, binder in an amount of about 0.5 to 15 wt. % of composition, disintegrant in an amount of about 0.5 to 15 wt. % of composition, and lubricant in an amount of about 0.1 to 10 wt. of composition, optionally a film coat enclosing core of the tablet. The film coat of present invention varies in range of 0.5- 5 wt % of the total weight of core tablet.
In an another aspect, the stable pharmaceutical composition is a tablet dosage form comprising Eprosartan mesylate substantially in the anhydrous form and a diluent in an amount of about 5 to 50 wt. % of composition, binder in an amount of about 0.5 to 15 wt. % of composition, disintegrant in an amount of about 0.5 to 15 wt. % of composition, and lubricant in an amount of about 0.1 to 10 wt. of composition, optionally a film coat enclosing core of the, tablet; wherein the said tablet is prepared by a non-aqueous granulation process.
In an another aspect, the stable pharmaceutical composition is a tablet dosage form comprising Eprosartan mesylate substantially in the anhydrous form and a diluent in an amount of about 5 to 50 wt. % of composition, binder in an amount of about 0.5 to 15 wt. % of composition,

disintegrant in an amount of about 0.5 to 15 wt. % of composition, and lubricant in an amount of about 0.1 to 10 wt. of composition, wherein the non-aqueous solvent used for granulation is Isopropyl alcohol.
In yet another aspect, the stable pharmaceutical composition is a tablet dosage form, comprising Eprosartan mesylate substantially in the anhydrous form and a diluent in an amount of about 5 to 50 wt. % of composition, binder in an amount of about 0.5 to 15 wt. % of composition, disintegrant in an amount of about 0.5 to 15 wt. % of composition, and lubricant in an amount of about 0.1 to 10 wt. of composition, wherein the said tablet is prepared by using Isopropyl alcohol in range of about 15-25 % of the weight of dry mix blend.
The prepared granulated mass is then dried at a temperature of about 50 - 60°C for a time period, sufficient to maintain the loss on drying (LOD) not more than 2%. Drying is carried out either under vacuum or through the circulation of warm dry air. The control of drying temperature for adequate time period prevents the conversion of anhydrous Eprosartan mesylate into any other form during the formulation process. In a preferred aspect, the granulated mass is dried at 60°C for about 60 minutes.
In an aspect of the present invention, the tablet as per the present invention comprises, anhydrous Eprosartan mesylate in amount of about 75 wt % of the composition, with remaining 25 wt % of the composition comprising pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients may comprise diluent(s) in an amount of about 15 wt % of the composition, a disintegrant(s) in an amount of about 5 wt. % of the composition and binder in an amount of about 5 wt. % of the composition. The non-aqueous solvent is used in an amount of about 20 % of the dry mix weight. Additional extra-granular material selected from diluent, disintegrant and lubricant may constitute 5 wt. % of the composition. The tablet core may then be coated with a film coating solution resulting in weight gain of the core by about 3 wt. %.
The tablet as per the above description is prepared by non-aqueous granulation process comprising the steps of dry mixing anhydrous Eprosartan mesylate with diluent(s) and disintegrant(s); granulating the blend with binder solution prepared by dissolving binder in non-

aqueous solvent which is 15-25 % of the dry mix to obtain the granules. The granulated mass is dried at 50 - 60°C for time sufficient to maintain loss on drying (LOD) not more than 2% and optionally mixing extra-granular material with excipients including lubricant and finally compressing the lubricated granule into core tablet, which may optionally be coated with a film coating.
In another aspect of the present invention, the stable pharmaceutical composition comprising Eprosartan mesylate substantially in the anhydrous form comprises:
i) diluent(s) selected from the group comprising of, but not limited to lactose monohydrate, lactose, sugar, starches, modified starches, mannitol, sorbitol, inorganic salts like dicalcium phosphate, cellulose derivatives (e.g. microcrystalline cellulose), calcium sulfate, xylitol, lactitol and the likes.
ii) Binder(s) selected from the group comprising of, but not limited to, polyvinylpyrrolidone, lactose, starches, modified starches, sugars, gum acacia, gum tragacanth, guar gum, pectin, wax binders, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, crospovidone, polyethylene glycol, polyvinyl alcohol, gelatin, sodium alginate, copolymers of acrylic and methacrylic acid esters and the likes.
iii) Disintegrant(s) selected from the group comprising of, but not limited to cross linked polyvinylpyrollidone (crospovidone), crosscarmallose sodium, polyvinylpyrrolidone, starch, modified starch, sodium starch glycolate, microcrystalline cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose and the likes.
iv) Lubricant(s) selected from the group comprising of, but not limited to, magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax, hydrogenated vegetable oils, mineral oil, polyethylene glycols, sodium stearyl fumarate and the likes.
In a preferred aspect of the present invention, the granules are prepared by dry mixing anhydrous Eprosartan mesylate in an amount of about 75 wt. % of the composition with one or more

diluent(s) present in an amount of about 15 wt. % of the composition and selected from Lactose monohydrate & microcrystalline cellulose along with one or more disintegrant(s) in an amount of about 5 wt. % of the composition and selected from Pregelatinized starch & croscarmellose sodium. The resulting dry mix is granulated with a binder solution prepared by dissolving a binder present in an amount of about 5 wt. % of the composition and selected from polyvinylpyrrolidone (PVP) in a non-aqueous solvent. The non-aqueous solvent is added in an amount of about 20 wt. % of the dry mix blend and is selected from Isopropyl alcohol or a mixture of isopropyl alcohol and methylene dichloride in a ratio of 50:50. The resulting granulated mass is then dried at a temperature of about 60°C for a time period of about 60 minutes, till the loss on drying (LOD) of "not more than 2 %" is achieved. The dried granulated mass is then, optionally mixed with extra-granular material comprising a diluent and disintegrated and the final blend is lubricated with a lubricant present in amount of about 1 wt. % of the composition and selected from magnesium stearate.
The lubricated granules are finally compressed into tablet core which may optionally be coated with a film coating selected from Opadry film coating system of Colorcon™. The film coating results in a weight gain of the tablet core by 3 wt %. The composition formulated according to the above description is found to contain Eprosartan mesylate substantially in anhydrous form with not more than 5 % of other hydrate forms. This polymorphic uniformity of the drug substance, results in uniform release of at-least 75% Eprosartan mesylate from the tablet in 30 minutes, as measured in USP type II apparatus, at 50 rpm, in 1000 ml of Phosphate buffer at pH of7.5.
While the present invention is disclosed by reference to the preferred embodiments and example below, it is understood that these example are intended in an illustrative rather than in a limiting sense. It is contemplated that modifications and combinations will readily occur to those skilled in the art, which modifications and combinations will be within the spirit of the invention and the scope of the following claims.
Throughout this specification it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted

inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
EXAMPLE-1: In a preferred embodiment, below examples illustrates a tablet composition comprising anhydrous Eprosartan mesylate (Equivalent to 600 mg of Eprosartan):
Table-1:

S.No. Ingredient Qty/Tab.(mg) Function of each Excipients
A Dry Mix
01 Eprosartan mesylate 735.848 Active
02 Lactose monohydrate 97.152 Diluent
03 Microcrystalline cellulose 11.5 Diluent
04 Starch 10.0 Disintegrant
05 Crosslinked polyvinylpyrrolidone 10.0 Disintegrant
B Binder
06 Poly vinyl pyrrolidone 50.0 Binder
07 Isopropyl alcohol q.s. Solvents
C Extra-granular
08 Micro crystalline cellulose 25.5 Diluent
09 Sodium starch glycolate 20.0 Disintegrant
D Lubrication
10 Magnesium stearate 10.0 Lubricant
Total 970.00
E Coating
11 Opadry White ® (20A28671) 30.0 Film coating material
12 Isopropyl alcohol q.s. Solvents
13 Methylene chloride q.s. Solvents
Total weight 1000.00

PROCESS:
Anhydrous Eprosartan mesylate, lactose monohydrate, microcrystalline cellulose, starch and Cross linked polyvinyl pyrrolidone were sifted through suitable sieve and dry mixed in rapid mixer granulator. The required quantity of polyvinylpyrrolidone was dissolved in the nonaqueous solvent (Isopropyl alcohol) and was used to granulate the dry mixture of step (i) in a rapid mixer granulator. The granulated mass was shifted to fluid bed processor and was dried such that the loss on drying (LOD) is not more than 2%.
The granules obtained were passed through suitable sieve to get the granules of desired size. Extra-granular excipients including microcrystalline cellulose and Sodium starch glycolate were shifted, blended and mixed with the granules. The blend was lubricated with magnesium stearate. The lubricated blend was then compressed into tablet using suitable compression machine, which may further be film coated with Opadry white to get the final stable dosage form.
The tablet compositions as illustrated in table-1 is stable, with substantial amount of anhydrous Eprosartan mesylate found intact in the final dosage form. To ascertain the polymorphic nature of Eprosartan mesylate, inventors of the present invention analyzed different samples of the composition prepared, through analytical tools like XRPD, DSC and TGA. Further the tablet prepared as per the present invention is tested for its physical parameters and dissolution profile and the results obtained were compared with the respective data of marketed product Teveten®.
Un-lubricated granule of Eprosartan mesylate and coated tablet of Eprosartan mesylate, from example no. 1, were subjected to polymorphic test such as Powder X-ray Diffraction (XRPD), Differential scanning calorimetry (DSC) and Thermo gravimetric analyzer (TGA). The results obtained were compared with the reported data of anhydrous, monohydrate and dihydrate form of Eprosartan mesylate.
# Figure 1 depicts comparative XRPD diffractogram of Eprosartan mesylate API, un-lubricated granule and coated tablet with their corresponding placebo. The peaks of anhydrous Eprosartan mesylate at 7.15, 18.9, 20.45, 22.2, 24.35 and 34.2 ±0.2° were found to be present in the samples of un-lubricated granule and the coated tablet comprising Eprosartan mesylate. Further the

characteristic peak of monohydrate form at 9.4 ±0.2° and dihydrate form at 9.95 ±0.2° were absent in the two samples containing Eprosartan mesylate.
Figure 2 & 3 respectively depicts DSC thermogram of un-lubricated granule and coated tablet of the present invention, whereby the endothermic peak at about 250°C (characteristics of anhydrous form) was found to be present in both the samples.
Figure 4 &5, respectively depicts TGA thermogram of un-lubricated granule and coated tablet. Both the thermograms does not show any significant moisture loss in the temperature range of 25-125°C, which are characteristics of monohydrate and dihydrate form. Absence of moisture loss in the temperature range of 25-125°C indicates that Eprosartan mesylate present in the sample does not contain monohydrate form and dihydrate form.
The above analytical test (XRPD, DSC and TGA) confirms that Eprosartan mesylate in the un-lubricated granules and film coated tablet prepared by the non-aqueous granulation process as described in the instant application is present substantially in anhydrous form. This suggest that the anhydrous Eprosartan mesylate when formulated into a pharmaceutical composition employing non-aqueous granulation process with processing parameters controlled as illustrated in the present application, does not convert to other hydrate form (monohydrate or dihydrate) during formulation process and in the stability course of drug product.
The said composition after subjecting to the accelerated stability conditions, of 40 Deg C Temperature and 75% RH, for three months, doesn't show any evidence of the undesired conversion into other hydrate forms and maintains the Eprosartan mesylate in substantially in an anhydrous form.
The tablet prepared in example-1, were tested for its physical parameters like, hardness, friability and disintegration time and the same was compared with marketed product Teveten®. The result depicted in table-2 below, suggest that the tablet prepared as per present invention have physical parameters comparable to that of the marketed product Teveten®.

Table 2:

Parameters tested Eprosartan Tablet 600 mg Teveten Eprosartan Tablet 600 mg (of present invention)
Disintegration Time (minute) 8-9 8-9
Tablet Hardness(KP) 24-25 22-25 Kp
Friability at 100 Revolutions NA Less than 0.1 %
Friability at 500 Revolutions NA Less than 0.5%
The tablets of Example-1 don't show any retardation or delay with respect to its disintegration time in due course of stability.
Subsequently, Eprosartan mesylate tablet 600 mg of Example-1, were compared with that of marketed product Teveten® 600 mg; with respect to its Dissolution profiles in USP type II apparatus, at 50 rpm, in 1000 ml of Phosphate buffer at pH of 7.5. The result depicted in table-3 below, suggest that the tablet prepared as per present invention has dissolution profile similar to the marketed product Teveten®.
Table-3: Dissolution Profile

Time in Minute Teveten® 600 mg Eprosartan Tablet 600 mg (of present invention)
0 0 0
5 30 29
10 67 70
15 82 87
20 87 89
30 93 91
45 95 95
60 95 98
REC 96 102

Claims:
We claim
1. A stable pharmaceutical composition comprising Eprosartan mesylate substantially in the anhydrous form and at-least one pharmaceutically acceptable carrier.
2. A stable pharmaceutical composition of claim 1, comprising not more than 5% Eprosartan mesylate in hydrate form.
3. A stable pharmaceutical composition of claim 1, in the form of a film coated tablet comprising Eprosartan mesylate substantially in an anhydrous form in an amount of about 75 %, a diluent in an amount of about 5 to 50 %, a binder in an amount of about 0.5 to 15 %, a disintegrant in an amount of about 0.5 to 15 %, and a lubricant in an amount of about 0.1 to 10 % by weight of the composition, optionally coated with a film coat surrounding the core.
4. A stable pharmaceutical composition of claim 1, comprising Eprosartan mesylate substantially in an anhydrous form, which exhibits one or more of the following characteristics after subjecting to accelerated stability condition of 40° C temperature and 75% relative humidity:

a) characteristic 29 peaks at 7.15, 18.9, 20.45, 22.2, 24.35 and 34.2 ±0.2° in powder X-ray diffraction.
b) no significant moisture loss in the temperature range of 25-125 C as measured by thermo-gravimetric analysis.
c) a sharp endotherm at about 250°C as measured by differential scanning calorimetry.
5. A stable pharmaceutical composition of claim 1, wherein at-least 75% of Eprosartan
mesylate is released from the pharmaceutical composition within 30 minutes, as
measured in USP type II apparatus, at 50 rpm, in 1000 ml of Phosphate buffer at pH 7.5.

6. A stable pharmaceutical composition of claim 1, prepared by a non-aqueous granulation process, comprising the steps of dry mixing anhydrous Eprosartan mesylate with a diluent(s) and a disintegrant(s); granulating the dry blend with binder solution prepared by dissolving a binder in a non-aqueous solvent; drying the granulated mass; optionally mixing with extra-granular material; and then lubricating and compressing the blend into core tablet which is optionally coated with a film coat.


Fig. 1: Comparative XRPD Diffractogram of Eprosartan mesylate API, un-Iubricated granule and coated tablet and their corresponding placbo


Fig. -2: DSC thermogram of Un-lubricated Granules

Fig. -3: DSC thermogram of coated tablet


Fig. -4: TGA Thermogram of un-lubricated granules