The present invention relates to a process for the preparation of novel amorphous form of losartan potassium.
Losartan potassium is chemically, 2-butyl-4-chloro-l-[[2'-(lH-tetrazol-5-yl)[l,l'-biphenyl]-4-yl]methyl]-lH-imida. zole-5-methanol and has structural Formula I, as shown in the accompanied drawings. It is disclosed in US patent No. 5,138,069 assigned to Du Pont. Losartan potassium is a substituted imidazoles useful as angiotensin II blockers. It is known for treating hypertension and congestive heart failure.
The difference in the activity of different polymorphic forms of a given drug has drawn the attention of many workers in recent years. This has especially become very interesting after observing that many antibiotics, antibacterials, tranquilizers etc. exhibit polymorphism and some of the polymorphic forms of a given drug exhibit superior bioavailabiltiy and consequently show much higher activity compared to the polymorphs. The term polymorphism includes different physical forms, crystal forms, crystalline / liquid crystalline / non-crystalline (amorphous) forms.
It has also been disclosed that the amorphous forms in the number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form [Konne T. Chem Pharm Bull 38, 2003 (1990)]. For some therapeutic indications one bioavailability pattern may be favoured over another. Cefuroxime axetil is the classical example of amorphous form exhibiting higher bioavailibility than the crystalline form. Host of patents have been granted on a number of drugs exhibiting polymorphism.
US Patent No. 5,608,075 discloses novel crystalline forms of losartan potassium and reports two novel polymorphic forms, differing from one another in respect of their physical properties, stability, spectral data. They are designated Form I and Form II. However, there is no teaching of the amorphous form of losartan potassium in the known prior art.
We reasoned that the amorphous form of losartan potassium would have an even better intrinsic dissolution and therefore, set out to prepare in this invention, hitherto unknown, solid amorphous form of losartan potassium.
The present invention relates to a new losartan potassium, the amorphous form and a process for the preparation thereof. The present process uses conditions which are convenient to perform on a commercial scale, operationally safe and provide the product in pure form . The process provides obvious benefits with respect to safety, health and environmental consideration.
Accordingly, the present invention provides an amorphous form of losaratan potassium and a process for preparation thereof. The process comprises dissolving losartan potassium in a suitable solvent(s), water or mixtures thereof and recovering amorphous form by a conventional technique. Such conventional techniques include, but are not limited to distillation, distillation under vacuum, evaporation spray drying, freeze drying etc.
In a preferred embodiment of the invention losartan potassium is recovered from solution in an amorphous form using a spray drying technique. The mini-spray dryer (Model : Buchi type) which is used, operates on the principle of nozzle spraying in a parallel flow i.e. spray product and drying gas flow in the same direction. The drying gas carbon air or inert gas car be air or inert gases such as nitrogen, argon and carbon dioxide. Nitrogen is preferred in this case.
The term "suitable solvent" means lower alkanols, ketones, chlorinated solvents or mixtures thereof. Lower alkanols include those primary, secondary and tertiary alcohols having one to six carbon atoms preferably selected from primary, secondary and tertiary alcohols having one to four carbon atoms such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, isobutanol, n-butanol, t-butanol or mixtures thereof.
In a more preferred embodiment methanol is used.
The process of the said invention also includes various solvates of losartan potassium and its conversion to amorphous losartan potassium
Figure 1 is an infrared spectrum showing peaks characteristic of amorphous losartan potassium. Figure 2 is an X- ray powder diffraction (XRD) pattern of amorphous losartan potassium.
Figure 3 is an infrared spectrum showing peaks characteristic of crystalline form I and form II of losartan potassium from 1150 cm1 to 600 cm1 obtained per U.S. patent No. 5,608,075: (A) Form I and (B) Form II.
Figure 4 is an infrared spectrum showing peaks characteristic of crystalline form I and form II of losartan potassium frpm 1800 cm1 to 1150 cm1 obtained per U.S. patent No. 5,608,075: (A) Form I and (B) Form II.
Figure 5 is an XRD pattern characteristic of crystalline form I and form II of losartan potassium obtained per U.S. patent No. 5,608,075 : (A) Form I and (B) Form II.
Figure 2 shows no peak which are characteristic of crystalline losartan potassium form I and form II ( Figure 5 and 6 of the accompanied drawings) showing the form to be an amorphous one.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE
A suspension was made from crystalline losartan potassium (10 g) in methanol (300 ml) at ambient temperature. The resulting solution was slowly heated to 45-47°C for 30 minutes to get a clear solution which was subjected to spray drying on 190 Mini Spray Dryer (Buchi make) at a temperature of 67-68°C using nitrogen gas. The losartan potassium in an amorphous form was collected. It was further dried at 45-50°C for 8 hours under vacuum to yield was found to be amorphous.
X- ray powder diffraction (XRD) pattern (Figure 2) does not exhibit any peak and shows a plain halo thus demonstrating the amorphous nature of the product. Infrared spectrum in KBr (Figure 1) is different than one obtained for crystalline form of losartan potassium.

WE CLAIM:
1. A process for the preparation of losartan potassium in amorphous form which comprises
dissolving crystalline losartan potassium in suitable solvent(s), water or mixtures thereof
and recovering losartan potassium in the amorphous form from the solution thereof.
2. The process of claim 1 wherein suitable solvent(s) is selected from lower alkanols, ,
ketones, chlorinated solvents or mixtures thereof.
3. The process of claim 2 wherein lower alkanols includes primary, secondary and tertiary
alcohols having from one to six carbon atoms.
4. The process of claim 2 wherein lower alkanols includes primary, secondary and tertiary
alcohols having from one to four carbon atoms.
5. The process of claim 4 wherein lower alkanols is selected from methanol, ethanol, n-
propyl alcohol, iso propyl alcohol, iso butanol, n-butanol, t-butanol or mixtures thereof.
6. The process of claim 5 wherein the solvent is methanol.
7. The process of claim 1 wherein the solvent is removed by a conventional technique.
8. The process of claim 7 wherein the conventional technique includes distillation,
distillation under vacuum, evaporation, spray drying or freeze drying.
9. The process of claim 8 wherein losartan potassium in an amorphous form is recovered by
spray drying.
10. The process of claim 9 wherein the spray drying is effected in the presence of nitrogen
gas.

11. The process of claim 1 wherein the product obtained is further dried.
12. A process for the preparation of losartan potassium in amorphous form of structural formula I shown in the accompanied drawings substantially described herein and exemplified by the example