The present invention describes the nature of the invention in the manner in which it has to be performed:

PHARMACEUTICAL FORMULATIONS COMPRISING IRBESARTAN
BACKGROUND OF THE INVENTION
The present application relates to a stable pharmaceutical formulation comprising irbesartan alone or in combination with hydrochlorothiazide.
Irbesartan  a compound having the chemical name 2-butyl-3-[p-(o-1H- tetrazol-5-ylphenyl)benzyl]-1  3-diazaspiro[4.4]non-1-en-4-one  is a potent  long- acting angiotensin Il receptor antagonist is described in US Patent No. 5  270  317.
Irbesartan is commercially available as 75mg  150mg  or 300mg tablets  which are sold under the trade name AVAPRO® in USA.
The combination formulation of irbesartan and hydrochlorothiazide is commercially available as 150/12.5 mg  300/12.5mg  or 300/25 mg tablets  which are sold under the trade name AVALIDE® in USA.
Fluffy nature of irbesartan makes it difficult to formulate a large amount of the drug into a small tablet due to undesirable flow characteristics  such that it adheres to surfaces of tablet punch faces and dies. Low aqueous solubility of irbesartan presents a challenge for providing a rapid and complete drug release since in a small size of tablet only limited amounts of the excipients. Further in case of addition of hydrochlorothiazide which adds to the poor flow characteristics it is still more challenging to prepare a small tablet having desired drug release characteristics  and therefore the excipients needs to be selected more carefully. Thus it is desired that these effects be achieved in a pharmaceutical formulation wherein the pharmaceutical formulation has an improved processability  improved stability and includes excipients  which are easily available at low cost. It is further desired that such pharmaceutical formulation be prepared using economically preferable technical processes.
US Patent No. 6 342 247 discloses pharmaceutical compositions containing irbesartan  alone or in combination with a diuretic  providing tablets with a high relative amount of active agent and excellent wetting and disintegration properties. The said patent further discloses that the intragranular: extragranular placement ratio of the disintegrant croscarmellose sodium as 1:1; and the poloxamer surfactant improves the aqueous granulation of irbesartan (which is hydrophobic)  eases the ejection of tablets after compression and accelerates the dissolution of the irbesartan active agent.
US Patent No 5 994 348 discloses a pharmaceutical composition comprising  based on weight: (a) from about 20 to about 70% irbesartan or a pharmaceutically acceptable salt thereof  and (b) about 2 to about 33% hydrochlorothiazide  wherein the total weight % of irbesartan or salt thereof and hydrochlorothiazide does not exceed about 85%  said composition being free of povidone and poloxamer. The said patent discloses that the use of pregelatinized starch as a binder was found to impart greater stability to hydrochlorothiazide than  for example  povidone (which resulted in the formation of quantities of the free amine degradant). Poloxamer was also found to increase the degradation of hydrochlorothiazide  and therefore  was not a preferred component for the irbesartan/hydrochlorothiazide compositions.
U. S. Patent Application Publication nos. 20090030052 and 20110045097 provide pharmaceutical compositions of Irbesartan that are free of surfactant. U. S. Patent Application Publication no. 20100104640 provides pharmaceutical compositions of Irbesartan having improved dissolution properties wherein the compositions do not include silicon containing antiadherent. U. S. Patent Application Publication no. 20090136571 provides pharmaceutical compositions of irbesartan characterized in that it includes maltose. International Patent Application Publication Nos. WO2011010316 and WO2006013545 and U. S. Patent Application Publication no. 20050271720 covers pharmaceutical compositions wherein the amount of Irbesartan is more than 65% by weight. U. S. Patent Application Publication no. US20090220597 cover pharmaceutical composition  of Irbesartan having a low-substituted hydroxypropyl cellulose. International Patent Application Publication No. WO2009115301 covers a solid pharmaceutical composition comprising at least two layers and the composition is free of disintegrants. International Patent Application Publication No WO2006067601  U. S. Patent Application Publication no. 20100092549 relates to a stable oral pharmaceutical composition comprising irbesartan and hydrochlorothiazide  wherein the irbesartan and hydrochlorothiazide are present as distinct portions within the composition. U. S. Patent Application Publication no. 20100204292 covers a pharmaceutical composition containing antiadherent element in the intragranular as well as extragranular portion and the intragranular portion is substantially free of a diluent element.
Irbesartan exists in more than one polymorph forms. Polymorph forms A and B are disclosed in U. S. Patent No. 6 800 761 and 5 629 331 respectively. International Patent Application Publication No. WO 03/050110 discloses an amorphous form of irbesartan
Chemical and polymorphic stability of the active ingredients present in the formulations is of utmost importance in case of pharmaceutical formulations. Chemical instability may result in loss of potency and formation of impurities  which is undesirable. Similarly  a formulation is expected to retain the polymorphic nature of an active ingredient during manufacturing and shelf life of the product. Change or conversion of a polymorph to other forms is highly undesirable as it may result in altered dissolution  bioavailability and efficacy in general. Irbesartan is prone to undergo polymorphic conversions when exposed to environmental conditions The importance of polymorphic stability of irbesartan can be appreciated from the fact that  the sponsor of the currently marketed tablet formulation containing combination of irbesartan and hydrochlorothiazide i.e. AVALIDE®  had to recall the product from the market in January 2011 because of polymorphic contamination of irbesartan. Compositions containing polymorph A of irbesartan are disclosed in U. S. Patent Application Publication No. 2009/0220597; however  this document does mention about polymorphic stability of irbesartan. None of the prior art references have demonstrated the polymorphic stability of the pharmaceutical formulations therein.
Hence there is still a need for improved formulations containing irbesartan alone or in combination with hydrochlorothiazide wherein chemical and polymorphic stability of the formulation is retained.
Thus the present invention provides stable pharmaceutical formulations of irbesartan alone or in combination with hydrochlorothiazide possessing desired drug release characteristics.

SUMMARY OF THE INVENTION
Aspects of the present application relate to a stable pharmaceutical formulation comprising irbesartan alone or in combination with hydrochlorothiazide.
In an aspect  the present application provides a stable pharmaceutical formulation comprising irbesartan alone or in combination with hydrochlorothiazide  and at least one vinyl-2-pyrrolidinone containing polymeric compound.
In aspects the present application relates to a stable pharmaceutical formulation comprising irbesartan alone or in combination with hydrochlorothiazide wherein irbesartan is present in polymorphic Form A.
In an aspect  the present application provides a stable pharmaceutical formulation comprising irbesartan Form A alone or in combination with hydrochlorothiazide  and at least one vinyl-2-pyrrolidinone containing polymeric compound wherein the vinyl-2-pyrrolidinone containing polymeric compound is present in intragranular portions  extragranular portions or both.
In aspects  the present invention provides a stable pharmaceutical formulation comprising irbesartan Form A alone or in combination with hydrochlorothiazide have total related substances of Irbesartan as less than about 5%  or less than about 2% by weight of the labeled amount of irbesartan when stored at the temperature of 40°C and relative humidity of 75% for at least 3 months.
In aspects  the present invention provides a stable pharmaceutical formulation comprising irbesartan Form A in combination with hydrochlorothiazide have total related substances of hydrochlorothiazide as less than about 5%  or less than about 2% by weight of the labeled amount of irbesartan when stored at the temperature of 40°C and relative humidity of 75% for at least 3 months
In other aspects  the present application provides stable pharmaceutical formulations comprising irbesartan Form A alone or in combination with hydrochlorothiazide  which retains the polymorphic state of irbesartan when stored at the temperature of 40°C and relative humidity of 75% for at least 3 months.
The applicants of the present application have surprisingly found that vinyl-2-pyrrolidinone containing polymeric compounds impart stability to of irbesartan.
In an aspect  the present application provides a stable pharmaceutical formulation comprising irbesartan Form A alone or in combination with hydrochlorothiazide  and at least one vinyl-2-pyrrolidinone containing polymeric compound  wherein the concentration of vinyl-2-pyrrolidinone containing polymeric compound with respect to irbesartan is selected from the range of 0.1 to 50% by weight  preferably  the from the range of 1 to 30% by weight.
In an aspect  the present application provides a stable pharmaceutical formulation comprising irbesartan Form A alone or in combination with hydrochlorothiazide  and at least one vinyl-2-pyrrolidinone containing polymeric compound wherein the vinyl-2-pyrrolidinone containing polymeric compound is present in intragranular as well as extragranular portions in a weight ratio ranging from 1:0.1 to 1:10.
In an aspect  the present application provides stable pharmaceutical formulations comprising irbesartan Form A alone or in combination with hydrochlorothiazide  and at least one vinyl-2-pyrrolidinone containing polymeric compound selected from the group containing of linear polyvinylpyrrolidone  cross-linked polyvinylpyrrolidone  polyvinylpyrrolidone-vinyl acetate copolymer and mixtures thereof.
In one aspect the present application provides a stable pharmaceutical formulation comprising irbesartan Form A alone or in combination with hydrochlorothiazide  wherein the pharmaceutical formulation provides a dissolution profile of Irbesartan such that not less than about 65% or not less than about 85% of the drug is released within 30 minutes.
In another aspect the present application provides stable pharmaceutical formulations comprising irbesartan Form A in combination with hydrochlorothiazide  wherein the pharmaceutical formulations provide a dissolution profile of hydrochlorothiazide such that not less than about 65% or not less than about 85% of the drug is released within 30 minutes.
In another aspect  the present application provides a process of preparation of a stable pharmaceutical formulation comprising irbesartan Form A alone or in combination with hydrochlorothiazide.
In aspect  the present application provides a stable pharmaceutical formulation comprising irbesartan Form A alone or in combination with hydrochlorothiazide that is useful in treating a disease or disorder comprising orally administering such formulation to the subject in need thereof.

BRIEF DESCRIPTION OF FIGURES
Figure 1 shows X-ray diffraction pattern (PXRD) data of Irbesartan (A)  formulation of Example 1H (B) and a placebo formulation prepared similar to Example 1H (C) at initial time point.
Figure 2 shows X-ray diffraction pattern (PXRD) data of Irbesartan (A) formulation of Example 1H (B) and a placebo formulation prepared similar to Example 1H (C) packed in HDPE container and stored at conditions of temperature of 40°C and 75% of relative humidity for a period of 3 months.
Figure 3 shows X-ray diffraction pattern (PXRD) data of Irbesartan (A) formulation of Example 1H (B) and a placebo formulation prepared similar to Example 1H (C) packed in PVC-PVDC container and stored at conditions of temperature of 40°C and 75% of relative humidity for a period of 3 months
Figure 4 shows X-ray diffraction pattern (PXRD) data of Irbesartan (A) formulation of Example 1H (B) and a placebo formulation prepared similar to Example 1H (C) packed in Alu-Alu blister packs and stored at conditions of temperature of 40°C and 75% of relative humidity for a period of 3 months
Figure 5 shows X-ray diffraction pattern (PXRD) data of Irbesartan (A)  a placebo formulation prepared similar to Example 4A (B) and a formulation of Example 4A (C) at initial time point.
Figure 6 shows X-ray diffraction pattern (PXRD) data of a formulation of Example 4A as initial (A)  and as packed in Alu-Alu blister packs stored at conditions of temperature of 25°C and 60% of relative humidity for a period of 3 months (B) and 6 months (C); and; as packed in Alu-Alu blister packs stored at conditions of temperature of 40°C and 75% of relative humidity for a period of 3 months (D) and 6 months (E).
Figure 7 shows X-ray diffraction pattern (PXRD) data of a formulation of Example 4A as initial (A)  and as packed in PVC-PVDC blister packs stored at conditions of temperature of 25°C and 60% of relative humidity for a period of 3 months (B) and 6 months (C); and; as packed in PVC-PVDC blister packs stored at conditions of temperature of 40°C and 75% of relative humidity for a period of 3 months (D) and 6 months (E).

DETAILED DESCRIPTION
The present application relates to a stable pharmaceutical formulation comprising irbesartan alone or in combination with hydrochlorothiazide.
The term ‘irbesartan’ includes irbesartan or any of its pharmaceutically acceptable salts  solvates  esters and derivatives thereof.
The term ‘stable’ means physicochemical as well as thermodynamic stability. The parameters that determine stability includes polymorphic stability and degradation products.
In an aspect  the present application provides a stable pharmaceutical formulation comprising irbesartan alone or in combination with hydrochlorothiazide  and at least one vinyl-2-pyrrolidinone containing polymeric compound.
In an aspect  the present application provides a stable pharmaceutical formulation comprising irbesartan alone or in combination with hydrochlorothiazide  and at least one vinyl-2-pyrrolidinone containing polymeric compound wherein the vinyl-2-pyrrolidinone containing polymeric compound is present in intragranular portions  extragranular portions or both.
In aspects  a stable pharmaceutical formulation comprising irbesartan alone or in combination with hydrochlorothiazide have total related substances of Irbesartan as less than about 5%  or less than about 2% by weight of the labeled amount of irbesartan when stored at the temperature of 40°C and relative humidity of 75% for at least 3 months.
In aspects  a stable pharmaceutical formulation comprising irbesartan in combination with hydrochlorothiazide have total related substances of hydrochlorothiazide as less than about 5%  or less than about 2% by weight of the labeled amount of hydrochlorothiazide when stored at the temperature of 40°C and relative humidity of 75% for a period of at least 3 months.
Irbesartan exhibits polymorphism  i.e. it may exist in more than one arrangements and/or conformations of the molecules in the crystal lattice. Form A of irbesartan is preferred because of its higher solubility and stability. However  Form A may undergo polymorphic conversion to other forms and in particular  may convert to Form B. Such conversions of one polymorph to other polymorph(s) are undesirable as it may result in altered dissolution  bioavailability and efficacy in general.
In one aspect a pharmaceutical formulation according to the present application comprises irbesartan in any polymorphic form or amorphous form  polymorphic Form A  polymorphic form B or in a mixtures thereof.
In another aspect a stable pharmaceutical formulation of the present application comprises irbesartan in polymorphic Form A.
To assess the polymorphic behavior of irbesartan Form A  soaking studies were performed as follows 
1. 3g of irbesartan Form A was soaked in 300 ml of water and kept for stirring for 24 hrs at 200 rpm rotation.
2. After 24 hrs flasks were removed  filtered & dried under vacuum.
3. The sample so obtained was subjected to XRD analysis.
All X-ray powder diffraction pattern data provided herein  were obtained using
a PANalytical Axe D8 Advance Powder X-ray Diffractometer. XRPD pattern was recorded at wavelength 1.5418 A using Cu K α radiation.
XRD analysis confirmed that Form A of irbesartan  when subjected to the soaking study as described above  was converted to Form B and only traces of Form A were observed. This confirmed the role of moisture in the polymorphic conversion of Irbesartan. Therefore  it is important that formulations containing polymorph A of irbesartan retain the polymorphic state of the active ingredient.
In aspects  the present application provides a stable pharmaceutical formulation comprising irbesartan alone or in combination with hydrochlorothiazide  which retains the polymorphic state of irbesartan when stored at the temperature of 40°C and relative humidity of 75% for a period of at least 3 months.
In aspects  a stable pharmaceutical formulation of irbesartan Form A alone or
in combination with hydrochlorothiazide constituted of intragranular and extragranular portions and comprises at least one 2-vinyl pyrrolidone containing polymeric compound wherein the 2-vinyl pyrrolidone containing polymeric compound is present in intragranular portion or extragranular portion or both.
In aspects  a stable pharmaceutical formulation comprising irbesartan Form A alone or in combination with hydrochlorothiazide have total related substances of Irbesartan as less than about 5%  or less than about 2% by weight of the labeled amount of irbesartan when stored at the temperature of 40°C and relative humidity of 75% for at least 3 months.
In aspects  a stable pharmaceutical formulation comprising irbesartan Form A in combination with hydrochlorothiazide have total related substances of hydrochlorothiazide as less than about 5%  or less than about 2% by weight of the labeled amount of hydrochlorothiazide when stored at the temperature of 40°C and relative humidity of 75% for a period of at least 3 months.
In aspects  the present application provides a stable pharmaceutical formulation comprising irbesartan Form A alone or in combination with hydrochlorothiazide  which retains the polymorphic state of irbesartan when stored at the temperature of 40°C and relative humidity of 75% for a period of at least 3 months.
The applicants of the present application have surprisingly found that vinyl-2-pyrrolidinone containing polymeric compounds impart stability to of irbesartan.
In an aspect  the present application provides a stable pharmaceutical formulation comprising irbesartan alone or in combination with hydrochlorothiazide  and at least one vinyl-2-pyrrolidinone containing polymeric compound  wherein the concentration of vinyl-2-pyrrolidinone containing polymeric compound with respect to irbesartan is selected from the range of 0.1 to 50% by weight  preferably  the from the range of 1 to 30% by weight. In a preferred embodiment of this aspect irbesartan is present as polymorphic Form A.
In aspects  the present application relates to a pharmaceutical formulation comprising 20 to 90% by weight  preferably 40 to 70% by weight  in particular 50 to 60% by weight  of irbesartan and 0.1 to 50% by weight  preferably 1 to 30% by weight  more preferably 1 to 20% by weight of an vinyl-2-pyrrolidinone containing polymeric compound  optionally containing other pharmaceutically acceptable excipients. In a preferred embodiment of this aspect irbesartan is present as polymorphic Form A.
In an aspect  the present application provides a stable pharmaceutical formulation comprising irbesartan alone or in combination with hydrochlorothiazide  and at least one vinyl-2-pyrrolidinone containing polymeric compound wherein the vinyl-2-pyrrolidinone containing polymeric compound is present in intragranular as well as extragranular portions in a weight ratio ranging from 1:0.1 to 1:10. In a preferred embodiment of this aspect irbesartan is present as polymorphic Form A.
By "vinyl-2-pyrrolidinone containing polymeric compound" as used herein is meant a pharmaceutically acceptable polymeric compound containing  either linear and/ or crosslinked homopolymers of N-vinyl-2-pyrrolidinone as a moiety  where ‘N’ is the number of repeating units; and; copolymers thereof.
Examples of vinyl-2-pyrrolidinone containing polymeric compound include  but are not limited to  linear or cross-linked polyvinylpyrrolidone (PVP). Other polymeric compounds  which are co-polymers containing vinylpyrrolidone monomer units are also useful in the formulations of the subject application. The term "copolymer" as used herein includes polymers that include two or more distinct monomeric units. An example of such a copolymer containing vinylpyrrolidone monomer units is a copolymer of vinylpyrrolidone monomer units and vinyl acetate monomer units (polyvinylpyrrolidone-vinyl acetate copolymer)  such as copolyvidone or copovidone.
It is to be understood that the vinyl-2-pyrrolidinone containing polymeric compound useful to provide stabilized pharmaceutical formulations in accordance with the present application are not to be construed as limited to the foregoing exemplary polymers. Thus  any pharmaceutically acceptable vinyl-2-pyrrolidinone containing polymeric compound that provides a stabilized pharmaceutical formulation of the present application may be employed. Such pharmaceutical acceptable vinyl-2-pyrrolidinone containing polymeric compound are commercially available. For example  polyvinylpyrrolidone (PVP  Povidone) polymers are commercially available  for example  under the trade names Kollidon® and Plasdone®  cross-linked polyvinylpyrrolidone polymers are commercially available  for example  under the trade names Kollidon CL®  Polyplasdone XL®  Polyplasdone XL-10® and Polyplasdone INF-10®; and polyvinylpyrrolidone-vinyl acetate copolymer are commercially available  for example  under the trade name of Kollidon VA64®. Kollidon® K-30 is a particularly preferred polyvinylpyrrolidone polymer useful in the stabilized pharmaceutical formulations of the present application.
Polyvinylpyrrolidone  cross-linked polyvinylpyrrolidone  and copolymers containing vinylpyrrolidone monomer units provide an additional advantage in that such compounds can also function in the stabilized pharmaceutical formulations of the present application in their conventional roles as excipients; for example  as binders  thickeners and disintegrants. Thus  when such vinyl-2-pyrrolidinone containing polymeric compounds are used in the pharmaceutical formulations  need to use separate fillers and disintegrants may be reduced or even eliminated.
In an aspect  the present application provides a stable pharmaceutical formulation comprising irbesartan alone or in combination with hydrochlorothiazide  and at least one vinyl-2-pyrrolidinone containing polymeric compound selected from the group comprising of linear polyvinylpyrrolidone  cross-linked polyvinylpyrrolidone  polyvinylpyrrolidone-vinyl acetate copolymer and mixtures thereof.
In one aspect the present application provides a stable pharmaceutical formulation comprising irbesartan alone or in combination with hydrochlorothiazide  wherein the pharmaceutical formulations are devoid of a surfactant. In further embodiment of the same aspect the pharmaceutical formulations are devoid of particularly poloxamer.
The pharmaceutical formulation of the present application may contain additional pharmaceutically acceptable excipients.
Useful pharmaceutically acceptable excipients according to the present application include  for example  any one or more of diluents  binders  stabilizers  lubricants  glidants  disintegrating agents  surfactants  and any other additives that are commonly used in solid pharmaceutical dosage form preparations. One or more useful filers or diluents according the present application include  but are not limited to starches  lactose  mannitol (e.g. Pearlitol™ SD200)  cellulose and its derivatives  confectioner’s sugar and the like. Different grades of lactose include but are not limited to lactose monohydrate  lactose DT (direct tableting)  lactose anhydrous  Flowlac™ (available from Meggle Products)  Pharmatose™ (available from DMV) and others. Different starches include but are not limited to maize starch  potato starch  rice starch  wheat starch  pregelatinized starch (commercially available as PCS PC10 from Signet Chemical Corporation) and starch 1500  starch 1500 LM grade (low moisture content grade) from Colorcon  fully pregelatinized starch (commercially available as National 78-1551 from Essex Grain Products)  and others. Different cellulose compounds that can be used include crystalline cellulose and powdered cellulose. Examples of crystalline compounds include  but are not limited to Ceolus™ KG801  Avicel™ PH101  PH102  PH301  PH302  PH-F20  PH112  microcrystalline cellulose 114 and microcrystalline cellulose 112.
Other useful diluents include  but are not limited to  carmellose  sugar alcohols such as mannitol  sorbitol and xylitol  calcium carbonate  magnesium carbonate  dibasic calcium phosphate  and tribasic calcium phosphate.
One or more useful binders according to the present application include but are not limited to hydroxypropylcellulose  also called HPC (e.g. Klucel™ LF  Klucel™ EXF) and various grades of hydroxypropylmethylcellulose  also called as hypromellose (e.g. Methocel™ products) and various grades of polyvinylpyrrolidones or povidones (such as grades PVP-K25  PVP-K29  PVP-K30 and PVP-K90)  copovidone (e.g. Plasdone™ S 630)  powdered acacia  gelatin  guar gum  carbomers (e.g.  Carbopol® products)  methylcelluloses  polymethacrylates  and starches.
One or more useful disintegrants include  but are not limited to  carmellose calcium (Gotoku Yakuhin Co. ltd.)  carboxymethyl starch sodium (Matsutani Kagaku Co. Ltd.  Kimura Sangyo Co. Ltd.)  croscarmellose sodium (Ac-di-sol™ from FMC-Asahi Chemical Industry Co. Ltd.)  crospovidone (crosslinked povidones  Kollidone® CL manufactured by BAS (Germany)  Polyplasdone™ XL  XL-10 and INF-10 manufactured by ISP Inc. (USA) and low-substituted hydroxypropylcelluloses. Examples of low-substituted hydroxypropylcelluloses include  but are not limited to  low-substituted hydroxypropylcellulose LH11  LH21  LH31  LH22  LH32  LH20  LH30  LH32 and LH33 (all manufactured by Shin-Etsu Chemical Co.  Ltd.). Other useful disintegrants include sodium starch glycolate  colloidal silicon dioxide  and starches.
One or more lubricants include magnesium stearate  glyceryl monostearates  palmitic acid  talc  carnauba wax  calcium stearate sodium  sodium or magnesium lauryl sulfate  calcium soaps  zinc stearate  polyoxyethylene monostearates  calcium silicate  silicon dioxide  hydrogenated vegetable oils and fats  stearic acid.
One or more glidant materials  which improve the flow of powder blends  pellets or mini-tablets and minimize dosage form weight variations  can be used. Useful glidants include  but are not limited to  silicon dioxide  talc.
Coloring agents can be used to colour code the formulations  for example  to indicate the type and dosage of the therapeutic agent therein. Coloring agents can also be used to differentiate the varied fractions of multiparticulates comprised in a unit dosage form such as a capsule. One or more suitable coloring agents include  without limitation  natural and/or artificial compounds such as FD&C coloring agents  natural juice concentrates  pigments such as titanium oxide  silicon dioxide  iron oxides  zinc oxide.
The selection of appropriate particles sizes of irbesartan  as well as of excipients  is within the scope of the application. D(10)  D(50) and D(90)  values are useful ways for indicating a particle size distribution. D(90) is the size value where at least 90 volume percent of the particles have sizes smaller than the value. Likewise  a D(10) value refers to 10 volume percent of the particles having sizes smaller than the value. A D(50) value refers to 50 volume percent of the particles having sizes smaller than the value  and a D [4 3] value refers to the mean particle size. Methods for determining D(10)  D(50)  D(90)  and D[4 3] include laser diffraction techniques  such as using equipment made available by Malvern Instruments Ltd.  Malvern  Worcestershire  United Kingdom  or by Horiba.
In aspects  the pharmaceutical formulation of the present application are prepared using irbesartan having particle size distribution such that D(90) is less than about 500 µm  or less than about 250 µm  or less than about 100 µm; and D(50) is less than about 200 µm  or less than about 100 µm  or less than about 50 µm. In aspects  D(10) is less than about 50 µm.
In certain specific aspects  the pharmaceutical formulation of the present application are prepared using irbesartan having particle size distribution such that D(90) is less than about 70 µm  and D(50) is less than about 40 µm. In aspects  D(10) is less than about 10 µm.
In aspects  the present application provides a process of preparation of a stable pharmaceutical formulation comprising irbesartan or pharmaceutically acceptable salts thereof  alone or in combination with hydrochlorothiazide.
In aspects  pharmaceutical formulations of irbesartan are prepared using a direct compression  dry granulation  or wet granulation method.
Equipment suitable for processing the pharmaceutical formulations of the present application include any one or more of rapid mixer granulators  planetary mixers  mass mixers  ribbon mixers  fluid bed processors  mechanical sifters  blenders  roller compacters  extrusion-spheronizers  compression machines  capsule filling machines  rotating bowls or coating pans  tray dryers  fluid bed dryers  rotary cone vacuum dryers  and the like  multimills  fluid energy mills  ball mills  colloid mills  roller mills  hammer mills  and the like  equipped with a suitable screen.
In aspects  the present application provides a process of preparation of a stable pharmaceutical formulation comprising irbesartan alone or in combination with hydrochlorothiazide wherein the process comprises:
a) Sifting irbesartan and other intragranular excipients and mixing them
together.
b) Granulating the blend using a binder solution (or a granulating agent).
c) Drying the granules and milling them
d) Sifting and mixing extragranular excipients and mixing them with the
granules.
e) Compressing the tablets of the blend using suitable tooling.
f) Coating the tablets using a coating solution.
In a preferred embodiment of this aspect irbesartan is present as polymorphic Form A.
Various solvents can be used in a process of preparation of a pharmaceutical formulation of the present application including  but are not limited to  water  methanol  ethanol  acidified ethanol  acetone  diacetone  polyols  polyethers  oils  esters  alkyl ketones  methylene chloride  isopropyl alcohol  butyl alcohol  methyl acetate  ethyl acetate  isopropyl acetate  castor oil  ethylene glycol monoethyl ether  diethylene glycol monobutyl ether  diethylene glycol monoethyl ether  dimethylsulphoxide  N N-dimethylformamide  tetrahydrofuran  and mixtures thereof.
The dosage forms of the present application can be subjected to in-vitro dissolution testing  such as according to Test 711 “Dissolution” in United States Pharmacopeia 32  United States Pharmacopeial Convention  Inc.  Rockville  Maryland  2009 (“USP”)  to determine the rate at which the active substance is released from the dosage forms  and content of active substance can be determined in dissolution media using techniques such as high performance liquid chromatography (HPLC).
In one aspect the present application provides a stable pharmaceutical formulation comprising irbesartan alone or in combination with hydrochlorothiazide  wherein the pharmaceutical formulations provide a dissolution profile of Irbesartan such that not less than about 65% or not less than about 85% of the drug is released within 30 minutes. In a preferred embodiment of this aspect irbesartan is present as polymorphic Form A.
In another aspect the present application provides a stable pharmaceutical formulation comprising irbesartan in combination with hydrochlorothiazide  wherein the pharmaceutical formulations provide a dissolution profile of hydrochlorothiazide such that not less than about 65% or not less than about 85% of the drug is released within 30 minutes. In a preferred embodiment of this aspect irbesartan is present as polymorphic Form A.
In aspect  the present application provides a stable pharmaceutical
formulation comprising irbesartan alone or in combination with hydrochlorothiazide that is useful in treating a disease or disorder comprising administering to the subject in need thereof such formulation. In a preferred embodiment of this aspect irbesartan is present as polymorphic Form A.
In aspects  the pharmaceutical formulations of the present application are intended for oral administration to a subject in need thereof.
In aspects  the pharmaceutical formulations of the present application are tablets.
In certain specific aspect the present application provided using illustrative examples which should not be construes as limiting the scope of the disclosure.

EXAMPLES
Example 1: Irbesartan Tablet formulation
Ingredient 1A 1B 1C 1D 1E 1F 1G 1H
mg/tablet
Intragranular
Irbesartan Form A 300 300 300 300 300 300 300 300
Lactose 140 140 140 140 140 140 140 140
Microcrystalline
cellulose -- 47 47 47 47 47 47 47
Crospovidone -- -- -- 15.5 15.5 15.5 15.5 15.5
Povidone K-30 -- -- 18 18 18 18 -- 18
Purified Water* q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.
Extragranular
Crospovidone -- -- -- 13.5 13.5 13.5 13.5 13.5
Silicon dioxide -- -- -- -- 5 5 5 5
Mag. Stearate -- -- -- -- 5 5 5
Core Tab Weight 440 487 505 534 539 544 526 544
Coating
Opadry II White -- -- -- -- -- -- 16 16
Final Tab Weight 440 487 505 534 539 544 542 560
*Evaporates during processing.
Manufacturing process:
1. Irbesartan  lactose monohydrate  crospovidone and microcrystalline
cellulose were sifted and mixed thoroughly.
2. Povidone was dissolved in purified water to prepare a binder solution
(except for examples 1A and 1B where water is a granulating agent)
3. The blend of step 1 was granulated with the granulating agent of step
2.
4. The granules of step 3 were dried and milled and sifted.
5. The extragranular excipients were sifted and blended and added to the
granules of step 5.
6. The tablets of blend of step 6 were compressed using suitable tooling.
7. The tablets of step 6 were coated using aqueous coating solution.
Tablet formulations of Example 1 were soaked (10 tablets eq. to 3g API in 300 ml of purified water) and kept for stirring for 24 hrs at 200 rpm rotation. Flasks were removed after 24 hrs  filtered & dried under vacuum and the resultant samples were subjected to PXRD analysis to determine the polymorphic stability of irbesartan Form A and presence of Form B. In tablets of Examples 1C to 1H irbesartan Form A was retained and Form B was not observed whereas in tablets of Examples 1A and 1B that are devoid of vinyl-2-pyrrolidinone containing polymeric compounds irbesartan Form A was converted to irbesartan Form B.
The tablets of example 1H were packed in HDPE containers and stored under the accelerated stability conditions of 40°C and 75% RH for 3 months. The tablets were then evaluated for potency  related substances and in-vitro dissolution. The in-vitro dissolution of tablets was determined as % of drug released at 20 minutes in 1000 ml of 0.1N HCl by using paddle (USP type II) method at 50 rpm. The results are tabulated in table 1.
Table 1
Parameters Analyzed Time period
Initial 3 Months
Potency 101.6 97.1
Related substances Compound A 0.03 0
Maximum unknown impurity 0.01 0.03
Total impurities 0.04 0.13
In-vitro dissolution
(% of drug released at 20 minutes) 98.0 97.0
Polymorphic conversion None None

It is evident from the results that the tablets prepared according to the present invention retains the polymorphic nature of the irbesartan  maintains the chemical stability and produces consistent in-vitro dissolution.

Example 2: Irbesartan tablet formulation
Ingredients 2A 2B 2C
mg/tab % w/w mg/tab % w/w mg/tab % w/w
Irbesartan
Form A 300 97.1 300 94.3 300 91.7
Povidone K-30 9 2.9 18 5.7 27 8.3
Purified Water* q.s. -- q.s. -- q.s. --
Core Tab Weight 309 100 318 100 327 100
*Evaporates during processing.
Manufacturing process:
1. irbesartan and povidone K-30 were sifted through sieves of appropriate
mesh.
2. Povidone K-30 was dissolved in purified water.
3. Irbesartan was granulated with the solution of step 2.
4. The granules of step 3 were dried and milled.
5. The blend of step 4 was compressed into tablets using suitable tooling.
Tablets of Example 2 were subjected to soaking studies and PXRD analysis similar to those of Example 1. In tablets of Examples 2A-2C irbesartan Form A was retained and Form B was not observed.

Example 3: Irbesartan tablet formulation
Ingredient 1A 1B 1C 1D 1E 1F
mg/tablet
Intragranular
Irbesartan Form A 300 300 300 300 300 300
Lactose monohydrate 39.5 124.5 138 114 83 138
Microcrystalline Cellulose 118.5 31 47 83 111 47
Crospovidone 13 24 15.5 -- 3 --
Copovidone 12 4.0 -- -- -- --
PVP k30 -- -- 18 20 20 18
Propylene Glycol -- 0.5 -- -- -- --
Purified water* q.s. q.s. q.s. q.s. q.s. q.s.
Extragranular
Crospovidone 7 6 8.5 10 10 --
Croscarmellose Sodium -- -- -- -- -- 8.5
Silica colloidal anhydrous 8 8 10 10 10 10
Magnesium stearate 6 6 7 7 7 7
Core tablet wt. 504 504 544 544 554 544
Film Coating
Instacoat aqua white
(ICG A 10099) 12 12 12 -- -- --
Lactose monohydrate 4 4 4 -- -- --
Opadry white - - - 16 16 16
Coated tablet wt. 520 520 560 560 560 560
*Evaporates during processing.
The tablets were prepared using the process as described in example 1.

Example 4: Irbesartan tablet formulation
Ingredients 4A 4B 4C 4D
mg/tablet
Intragranular
Irbesartan Form A 300 300 300 150
Hydrochlorothiazide 25 12.5 12.5 12.5
Lactose monohydrate 26.2 26.2 26.2 13.1
Microcrystalline cellulose 93.8 106 106 46.9
Crospovidone NF 12 12 12 6
Povidone (PVP K30) 20 20 -- 10
Copovidone -- -- 20 -
Purified water* q.s. q.s. q.s. q.s.
Extragranular
Crospovidone 20 20 20 10
Colloidal silicon dioxide 6 6 6 3
Magnesium stearate NF 6 6 6 3
Core tablet weight 509 509 509 254.5
Film coating
Opadry II Brown 32F565000 16 -- -- -
Opadry II Pink 32F540012 -- 16 16 -
Opadry II Pink 32F540014 -- -- -- 8
Purified water USP q.s.
Coated tablet weight 525 525 525 262.5
*Evaporates during processing.
Manufacturing process:
1. Irbesartan  hydrochlorothiazide  lactose monohydrate 
crospovidone and microcrystalline cellulose were sifted and mixed thoroughly.
2. Povidone(example 4A  4B and 4D) or copovidone (example
4C) was dissolve in purified water to prepare a binder solution.
3. The blend of step 1 was d with the granulating agent of step 2.
4. The granules of step 3 were dried  milled and sifted.
5. The extragranular excipients were sifted and blended and added to the
granules of step 5.
6. The tablets of blend of step 6 were compressed using suitable tooling.
7. The tablets of step 6 were coated using aqueous coating solution.
The resultant tablets of examples 4A and 4D were packed in HDPE containers and Alu-Alu blisters and stored under accelerated stability conditions of 40°C and 75% RH and analyzed for related substances and polymorphic stability. The results are tabulated below 
Related Substances Example 4A Example 4D
Initial 3 Months
(HDPE) 3 Months (Alu-Alu blisters) Initial 3 Months
(HDPE) 3 Months (Alu-Alu blisters)
Irbesartan related substances
Impurity A 0.01 0.01 0.01 0.01 0.01 0.02
Any individual unspecified impurity 0.02 0.04 0.03 0.02 0.03 0.03
Total Impurities 0.08 0.1 0.11 0.09 0.1 0.13
Hydrochlorothiazide related substances
Chlorothiazide Impurity ND ND ND ND ND ND
Benzothiadiazine Related Compound 0.04 0.05 0.09 0.04 0.04 0.08
Any individual unspecified impurity 0.01 0.04 0.02 0.01 0.02 0.02
Total Impurities 0.06 0.09 0.14 0.06 0.06 0.1

In-vitro dissolution (% of drug released at 30 minutes)
Irbesartan 99 98 99 99 98 98
Hydrochlorothiazide 101 101 101 102 102 102

It was found that the tablets of example 4 were stable and there was no significant increase in the levels of related substances. Further  PXRD analysis confirmed that Irbesartan Form A used in the examples 4A and 4D did not undergo any polymorphic conversion during manufacturing and upon stability.