Crystalline forms of Losartan Potassium
Field of the Invention
The invention in general relates to novel crystalline forms of Losartan potassium. More particularly, the present invention is directed to novel crystalline form VI, VII, VIII, IX, X of Losartan potassium and the process for preparing the same. Further, the present invention is also directed to novel processes for the preparation of anhydrous crystalline Losartan potassium Form I, Form II, Form III, Form V solvate and amorphous Losartan potassium.
Background of the Invention
Losartan potassium, a non-peptide molecule, is chemically described as 2-butyl-4-chloro-l-[[2'-(lH-tetrazol-5-yl)[l,r-biphenyl]-4-yl]methyl]-lH-imidazole-5-methanol mono potassium salt (I).

I
Losartan potassium is an angiotensin II (All) inhibitor useful in the treatment of angiotensin-dependent hypertension. Losartan potassium is also useful in the treatment of hypercholesterolemia, as it decreases total cholesterol. Furthermore, the administration of Losartan potassium in combination with a diuretic enhances the antihypertensive effect, while keeping the anti-atherosclerotic and hypocholesterolemizing activities.

The synthesis of Losartan is first disclosed in US 5,138.069. The advantages provided by pharmaceutical products in the crystalline form in term of easiness of processes for the preparation of related medicaments are well known. Crystalline compounds are in fact known to be more suited to the formulation of galenic forms because of their flowability in the form of powders or granulates, and to the surface properties of the crystals which promote adhesion, for example during the preparation of tablets. Furthermore, the solubility of crystalline compounds in aqueous solutions, in particular in the gastric juices, can also be significantly different than that of the corresponding amorphous compounds. There is therefore the need to discriminate between crystalline and the amorphous forms of biologically active compounds, so as to fulfill the various pharmaceutical requirements.
A number of crystalline and amorphous forms of Losartan potassium are known from US 5,608,075, US20040097568 and US20040006237. US 5,608,075 discloses two polymorphic forms of Losartan potassium (Form I and Form II) and according to US 5,608,075, crystalline Losartan potassium is prepared by salification of acid Losartan with an alkali hydroxide. The Losartan potassium aqueous solution is then added to isopropanol-cyclohexane azeotropic mixture under reflux, followed by removal of water by azeotropic distillation of the resulting water-isopropanol-cyclohexane ternary mixture, which boils at 64°C. When the solution is anhydrous, the head temperature rises to 69°C and Losartan potassium crystallizes. US20040097568 describes a further polymorphic form of Losartan potassium, referred to as Form III. US20040006237 discloses two further Losartan potassium solvate forms (Form IV and Form V), and a hydrated form. WO2004039352 claims Losartan potassium in the amorphous form.
It has now been found that Losartan potassium can exist, in addition to the above mentioned crystalline forms, also in novel crystalline forms stable at room temperature, herein referred to as crystalline form VI, VII, VIII, IX. Therefore, the invention relates to said crystalline forms, process for preparing the same and novel processes for the preparation of anhyurous crystalline Losartan potassium Form I, Form II, Form III, Form V solvate and amorphous Losartan potassium.

Summary of the Invention
It is the principal aspect of the present invention to provide novel crystalline forms of Losartan potassium, referred to as crystalline Form VI, VII, VIII, IX and X characterized by Infrared absorption spectrum, X-ray powder diffraction pattern, thermo gravimetric analysis (TGA), differential scanning calorimetry (DSC), moisture content and/or melting point.
Furthermore, the present invention is also directed to the process for the preparation of novel crystalline Losartan potassium Form VI, VII, VIII, IX and X by using different solvent system and conditions.
In accordance with one preferred embodiment of the present invention is also directed to novel processes for the preparation of anhydrous crystalline Losartan potassium Form I, Form II, Form IIL Form V solvate and amorphous Losartan potassium.
Brief Description of the Drawings
Fig 1 shows a characteristic X-ray powder diffraction pattern for crystalline Losartan
potassium Form VI.
Fig 2 shows a charucicristic X-ray powder diffraction pattern for crystalline Losartan
potassium Form VII.
Fig 3 shows a characteristic X-ray powder diffraction pattern for crystalline Losartan
potassium Form V m.
Fig 4 shows a characteristic X-ray powder diffraction pattern for crystalline Losartan
potassium Form IX.
Fig 5 shows a characteristic X-ray powder diffraction pattern for crystalline Losartan
potassium Form X.
Jetailed Description of the Invention
The present invention describes the crystalline Losartan potassium Form VI, VII, VIII, IX and Form X. Crystalline Losartan potassium Form VI, VII, VIII, IX and X differ from each other in their physical properties, spectral data and methods of preparation and

characterized by their X-ray powder diffraction patterns, Thermo gravimetric analysis, differential scanning calorimetry (DSC), moisture content and/or melting point.
The present invention also provides a process for preparing Losartan potassium Form VI comprising the steps of suspending Losartan potassium in a solvent selected from the group consisting of lower alcohols, chlorinated solvents, ethers, lower aliphatic ketones, or mixtures thereof, filtering off the solid residue formed and allowing the filtrate for slow evaporation and recovering the isolated crystalline Losartan potassium Form VI.
In another aspect, the present invention provides a process for preparing crystalline Losartan potassium Form VII comprising the step of heating a crystalline form of Losartan potassium Form V.
In another aspect, the present invention provides a process for preparing crystalline Losartan potassium Form VIII comprising the steps of crystallizing Losartan potassium from a solvent DMF using the methods of slow and fast evaporation and recovering the isolated crystalline Losartan potassium Form VIII.
In another aspect, the present invention provides a process for preparing crystalline Losartan potassium Form IX comprising the steps of crystallizing Losartan potassium from a solvent DMSO using the methods of slow and fast evaporation and recovering the isolated crystalline Losartan potassium Form IX.
In another aspect, the present invention provides a process for preparing crystalline Losartan potassium Form X comprising the steps of suspending Losartan potassium in a polar solvent, filtering off the solid residue formed and allowing the filtrate for slow evaporation and recovering the isolated crystalline Losartan potassium Form X.
In yet another aspect, the present invention provides a process for preparing crystalline Losartan potassium Form I, II, III, V solvate and amorphous form.

In another aspect, the present invention provides a process for preparing crystalline Losartan potassium Form I, comprising the steps of suspending the Losartan potassium in a solvent selected from the group consisting of aprotic polar solvents, alcohols, chlorinated solvents, ethers, esters, lower aliphatic ketones, amides, carbonates or mixtures thereof using the slurry, anti-solvent and slow crystallization methods and recovering the crystalline Losartan potassium Form I.
In another aspect, the present invention provides a process for preparing crystalline Losartan potassium Form I, comprising the step of heating crystalline Losartan potassium Form VI, Form VIII or Imrm X.
In another aspect, the present invention provides a process for preparing crystalline Los.rtan potassium Form II comprising the step of heating crystalline Losartan potassium Form VI, Form VIII or Form X above 250°C.
In another aspect, the present invention provides a process for preparing crystalline Losartan potassium Form III comprising the steps of preparing a solution of Losartan pot; ssium from a suitable solvent selected from the group consisting of lower alkanol, chkmnated solvent, aliphatic hydrocarbons or mixtures thereof, followed by seeding with crysulline Form 111 und ^covering the isolated crystalline Losartan potassium Form III.
In ;.:other aspect, the present invention provides a process for preparing crystalline Lo.,. rtan potassium Form V solvate comprising the steps of preparing a solution of Los. rtan potassium lVom a solvent, such as ethanol, adding xylene to form a mixture, and recovering the isolated ciystalline Losartan potassium Form V solvate.
In ■ other aspect, the present invention provides a process for preparing amorphous Lo. tan potassium comprising the steps of preparing a solution of Losartan potassium fro: a suitable solveu; elected from the group consisting of lower alkanol, chlorinated ervh (>nt nr mivtnrM thpn>r»f fnllowerl hv seeding with Form VI and Form II of Losartan

po' sium obtained as (inscribed above and recovering the isolated amorphous Losartan po: sium.
While the present invention has been described in terms of its specific embodiments, cerv :i modifications and equivalents will be apparent to those skilled in the art and are int led to be include; . ithin the scope of the present invention.