WO2004076442A1

WO2004076442A1 - Polymorphs of losartan

Info

Publication number: WO2004076442A1
Application number: PCT/IB2004/000516
Authority: WO
Inventors: Pananchukunnath Manoj Kumar; Ramalingam Manikandan; Romi Barat Singh; Vishnubhotla Nagaprasad; Rajiv Malik
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2003-02-28
Filing date: 2004-02-27
Publication date: 2004-09-10

Abstract

The invention relates to polymorphic forms of losartan potassium. The invention also relates to processes for producing them. More particularly, it relates to the preparation of two polymorphic forms of losartan potassium, referred to as 'Form A' and 'Form B' and pharmaceutical compositions that include the 'Form A' and 'Form B'.

Description

POLYMORPHS OF LOSARTAN

Field of the Invention

The field of the invention relates to polymorphic forms of losartan potassium. The invention also relates to processes for producing them. More particularly, it relates to the preparation of two polymorphic forms of losartan potassium, referred to as 'Form A' and 'Form B' and pharmaceutical compositions that include the 'Form A' and 'Form B'.

Background of the Invention

Chemically, losartan potassium is 2-butyl-4-chloro-l-[(2'-tetrazol-5-yl)-biphenyl-4- yl]methyl]-5-(hydroxymethyl) imidazole potassium salt and has structural Formula I

Formula I

Losartan potassium is known to be useful in the treatment of hypertension and congestive heart failure. It is disclosed in U.S. Patent No. 5,138,069 and has been demonstrated to be an orally active angiotensin II (All) antagonist, selective for the ATi receptor subtype.

Losartan potassium is known to inhibit the action of the hormone angiotensin II (All) and is useful therefore in alleviating angiotensin-induced hypertension. The enzyme renin acts on a blood plasma alpha 2-globulin, angiotensinogen, to produce angiotensin I, which is then converted by angiotensin converting-enzyme to AIL The latter substance is a powerful vasopressor agent that has been implicated as a causative agent for producing high blood pressure in various mammalian species, such as the rat, dog, and man. Losartan potassium inhibits the action of All at its receptors on target cells and thus prevents the increase in blood pressure produced by this hormone-receptor interaction. By administering losartan potassium to a species of mammal with hypertension due to All, the blood pressure is reduced.

U.S. Patent No. 5,608,075 discloses crystalline forms of losartan potassium and describes two polymorphic forms, differing from one another in respect of their stability, physical properties, and spectral characteristics. They are designated Form I and Form II. It is known that different morphs of biologically active compounds may have different absorption profile in vivo and consequently different pharmacokinetic profile.

Summary of the Invention

In one general aspect there are provided two polymoφhic forms of losartan potassium, 'Form A' and 'Form B'.

The Form A of losartan potassium may have the X-ray diffraction pattern of Figure 1 and the infrared spectrum of Figure 2.

hi another general aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of Form A of losartan potassium; and one or more pharmaceutically acceptable carriers, excipients or diluents.

hi another general aspect there is provided a process for the preparation of Form A of losartan potassium. The process includes heating the amorphous form of losartan potassium.

In another general aspect there is provided a method of treating hypertension in a warm-blooded animal, the method comprising providing a pharmaceutical composition to the warm-blooded animal that includes Form A of losartan potassium.

The Form B of losartan potassium may have the X-ray diffraction pattern of Figure 3 and the infrared spectrum of Figure 4.

hi another general aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of Form B of losartan potassium; and one or more pharmaceutically acceptable carriers, excipients or diluents. In another general aspect there is provided a process for the preparation of Form B of losartan potassium. The process includes heating the Form A of losartan potassium.

In another general aspect there is provided a method of treating hypertension in a warm-blooded animal, the method comprising providing a pharmaceutical composition to the warm-blooded animal that includes Form B of losartan potassium.

The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.

Description of the Drawings

Figure 1 is X- ray powder diffraction pattern of Form A of losartan potassium.

Figure 2 is an infrared spectrum in KBr of Form A of losartan potassium.

Figure 3 is X- ray powder diffraction pattern of Form B of losartan potassium.

Figure 4 is an infrared spectrum in KBr of Form B of losartan potassium.

Detailed Description of the Invention

The inventors have found two new polymoφhic forms of losartan potassium, referred to as 'Form A³ and 'Form B\ The new polymoφhic forms are characterized by their X-ray powder diffraction patterns as shown in Figures 1 and 3 and infrared spectra as shown in Figures 2 and 4, respectively. The inventors also have developed processes for the preparation of the new polymoφhic forms of losartan potassium. The inventors also have developed pharmaceutical compositions that contain Form A and/or Form B of the losartan potassium, in admixture with one or more solid or liquid pharmaceutical diluents, carriers, and/or excipients.

Losartan potassium may be prepared using the reactions and techniques described in U.S. Patent No. 5,138,069, WO 93/10106 or one of its three U.S. counteφarts, U.S. Patent Nos. 5,130,439; 5,206,374; and 5,608,075 which are incoφorated herein as reference.

In general, the new polymoφhic form of losartan potassium, Form A may be prepared by heating the amoφhous form of losartan potassium. Alternatively, Form A of losartan potassium may be prepared by heating and humidifying the amoφhous form of losartan potassium.

The amoφhous form of losartan potassium may be heated from about 25- 45°C, for example from about 30- 40°C. It may be humidified at about 50% to about 80% relative humidity, for example at about 60% to about 75% relative humidity.

In one aspect, Form A of losartan potassium may be prepared by heating the amoφhous form of losartan potassium at about 40°C and humidifying at about 75% relative humidity for about 24 hours.

In another aspect, Form B of losartan potassium may be prepared by heating Form A of losartan potassium. Form A may be heated at a temperature from about 45- 85°C, for example, from about 60-80°C.

The losartan potassium in amoφhous form may be obtained from an aqueous or methanolic solution of losartan potassium using a spray drying technique. In particular, it was prepared according to the process disclosed in our co-pending PCT Patent Application Serial No. PCT/IB03/04873.

If crystalline losartan potassium is used as a starting material for the preparation of amoφhous form of losartan potassium it may be in the form of any of the various polymoφhic forms known in the prior art including solvates, hydrates, anhydrous or any other polymoφhic forms of losartan potassium. In particular, the crystalline Form I of losartan potassium was prepared according to the process disclosed in U.S. Patent No. 5,608,075.

The two polymoφhic forms of losartan potassium, Form A and Form B prepared by any of the processes disclosed above were characterized by X-ray diffraction patterns and infrared spectral analyses. X-Ray Powder Diffraction

X-ray powder diffraction patterns were recorded using the instrumental parameters listed in Table 1.

Table 1. XRD Parameters

X-ray diffraction patterns of Form A and Form B of losartan potassium are shown in Figure 1 and Figure 3, respectively. X-ray diffraction patterns of Form A and Form B of losartan potassium in terms of diffraction angles and relative intensities are shown in Table 2 and Table 3, respectively.

Table 2. X-ray diffraction pattern of Form A

Infrared Spectra

Infrared spectral analyses of Form A and Form B of losartan potassium in potassium bromide was carried out according to the general method mentioned in United States Pharmacopoeia.

Form A was characterized by specific infrared spectral bands at 1640, 1562, 1576, 1460, 1426, 1408, 1359, 1259, 1208, 1146, 1126, 1105, 1072, 1072, 1027, 1012, 992, 931, 879, 831, 799, 784 and 761 cm^"1.

Form B was characterized by specific infrared spectral bands at 1637, 1576, 1562, 1506, 1497, 1459, 1426, 1422, 1408, 1377, 1357, 1307, 1207, 1258, 1128, 1105, 1073, 1145, 1007, 993, 932, 840, 788 and 762 cm^"1.

The X-ray diffraction data as well as the infrared spectral data for Form A and Form B reveal that the two polymoφhic forms are different.

Form A of losartan potassium can be distinguished from Form B, using X-ray powder diffraction. Form A shows characteristic peaks at 15.7, 16.3, 17.9, 22.9 and 28.4 degrees 2 theta. Form B shows characteristic peaks at 7.3, 11.1, 15.9 and 19.0 degrees 2 theta.

Form A can also be distinguished from Form B by infrared spectral data. Form A is characterized by the absence of a band at 840 cm^"1, which is observed for Form B, and by the ratio of the relative intensities of the 1562 and 1576 cm^"1 bands; and 1426 and 1408 cm^"1 bands. The ratio (intensity of 1562 cm-1 band/intensity of 1576 cm^band) is <1 for Form A, while the ratio is >1 for Form B. Similarly, the ratio (intensity of 1426 cm^"1 band/intensity of 1408 cm^"1 band) is <1 for Form A, while the ratio is >1 for Form B.

The resulting polymoφhic forms of losartan potassium, Form A and Form B can be administered by any conventional means alone or in a combination with other therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The polymoφhic forms of losartan potassium, Form A and Form B may be formulated into ordinary dosage forms such as, for example, tablets, capsules, pills, solutions, etc. In these cases, the medicaments can be prepared by conventional methods with conventional pharmaceutical excipients.

The compositions include dosage forms suitable for oral, buccal, rectal, and parenteral (including subcutaneous, intramuscular, and ophthalmic) administration. The oral dosage forms may include solid dosage forms, like powder, tablets, capsules, suppositories, sachets, troches and lozenges as well as liquid suspensions, emulsions, pastes and elixirs. Parenteral dosage forms may include intravenous infusions, sterile solutions for intramuscular, subcutaneous or intravenous administration, dry powders to be reconstituted with sterile water for parenteral administration, and the like.

The polymoφhic forms of losartan potassium, Form A and Form B can be administered for the treatment of hypertension by any means that effects contact of the active ingredient compound with the site of action in the body of a warm-blooded animal.

For the puφose of this disclosure, a warm-blooded animal is a member of the animal kingdom possessed of a homeostatic mechanism and includes mammals and birds.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and are not intended to limit the scope of the invention. Although the examples are directed to the two polymoφhic forms of losartan potassium, 'Form A' and 'Form B', the principles described in these examples can be applied to other salts of losartan.

Example 1

20 gm of losartan potassium Form I was dissolved in 100 ml water at 20°C. The solution was spray dried using Lab Plant spray drier to yield about 16gm of amoφhous losartan potassium. This material was kept for 24 hours at 40°C temperature and 75% relative humidity. About 15 gm of Form 'A' of losartan was obtained. Example 2 50 gm of losartan potassium Form I was dissolved in 500 ml methanol at 20°C. The solution was spray dried using Lab Plant spray drier to yield about 40 gm of amoφhous losartan potassium. This material was kept for 24 hours at 40°C temperature and 75% relative humidity. About 38 gm of Form 'A' of losartan was obtained.

Example 3 5 gm of Form A of losartan potassium of Example 1 was heated at 80°C for 24 hours. About 4 gm of Form 'B' of losartan was obtained.

Example 4 10 gm of Form 'A' of losartan of Example 2 was heated at 80°C for 24 hours. About 8 gm of Form B of losartan was obtained.

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.

Claims

CLAIM: 1. 'Form A' losartan potassium.

2. The Form A of claim 1 , wherein the losartan potassium has the X-ray diffraction pattern of Figure 1.

3. The Form A of claim 1 , wherein the losartan potassium has the infrared spectrum of Figure 2.

4. Form A losartan potassium characterized by X-ray diffraction pattern having peaks at about 15.7, 16.3, 17.9, 22.9 and 28.4 degrees 2 theta.

5. Form A losartan potassium of claim 4 further characterized by IR bands at 1640, 1562, 1576, 1460, 1426, 1408, 1359, 1259, 1208, 1146, 1126, 1105, 1072, 1072, 1027, 1012, 992, 931, 879, 831, 799, 784 and 761 cm^"1.

6. A pharmaceutical composition comprising:

a therapeutically effective amount of Form A losartan potassium;

and one or more pharmaceutically acceptable carriers, excipients or diluents.

7. The pharmaceutical composition of claim 6, wherein the losartan potassium has the X-ray diffraction pattern of Figure 1.

8. The pharmaceutical composition of claim 6, wherein the losartan potassium has the infrared spectrum of Figure 2.

9. A process for the preparation of the Form A losartan potassium, the process comprising heating the amoφhous form of losartan potassium.

10. The process of claim 9, wherein the amoφhous form of losartan potassium is heated at a temperature from about 25- 45°C.

11. The process of claim 10, wherein the temperature is from about 30- 40°C.

12. The process of claim 9, wherein the process further comprising humidifying the amoφhous form of losartan potassium.

13. The process of claim 12, wherein the amoφhous form of losartan potassium is humidified at about 50- 80% relative humidity.

14. The process of claim 13, wherein the amoφhous form of losartan potassium is , humidified at about 60- 75% relative humidity.

15. The process of claim 12, wherein the process comprising heating and humidifying the amoφhous form of losartan potassium at about 45°C and at about 75% relative humidity.

16. The process of claim 9, wherein the amoφhous form of losartan potassium is prepared from Form I of losartan potassium.

17. The process of claim 16, wherein the amoφhous form of losartan potassium is prepared by spray drying an aqueous solution of Form I of losartan potassium.

18. The process of claim 16, wherein the amoφhous form of losartan potassium is prepared by spray drying a methanolic solution of Form I of losartan potassium.

19. A method of treating hypertension in a warm-blooded animal comprising administering a pharmaceutical composition that includes Form A losartan potassium.

20. 'Form B' losartan potassium.

21. The Form B of claim 20, wherein the losartan potassium has the X-ray diffraction pattern of Figure 3.

22. The Form B of claim 20, wherein the losartan potassium has the infrared spectrum of Figure 4.

23. Form B losartan potassium characterized by X-ray diffraction pattern having peaks at about 7.3, 11.1, 15.9 and 19.0 degrees 2 theta.

24. Form B losartan potassium of claim 23 further characterized by TR bands at 1637, 1576, 1562, 1506, 1497, 1459, 1426, 1422, 1408, 1377, 1357, 1307, 1207, 1258, 1128, 1105, 1073, 1145, 1007, 993, 932, 840, 788 and 762 cm^"1.

25. A process for the preparation of the Form B losartan potassium, the process comprising heating the Form A losartan potassium.

26. The process of claim 25, wherein the Form A losartan potassium is heated at a temperature from about 45- 85°C.

27. The process of claim 26, wherein the temperature is from about 60- 80°C.

28. The process of claim 25, wherein the heating is carried out at about 80°C for about 24 hours.

29. A pharmaceutical composition comprising:

a therapeutically effective amount of Form B losartan potassium;

and one or more pharmaceutically acceptable carriers, excipients or diluents.

30. The pharmaceutical composition of claim 29, wherein the losartan potassium has the

X-ray diffraction pattern of Figure 3.

31. The pharmaceutical composition of claim 29, wherein the losartan potassium has the infrared spectrum of Figure 4.

32. A method of treating hypertension in a warm-blooded animal comprising administering a pharmaceutical composition that includes Form B losartan potassium.