' The present invention relates to the new crystalline Forms of Losartan potassium and processes for producing them. More particularly the invention relates to the preparation of these crystalline Forms herein after referred to as Losartan Form A and Losartan Form B; and to the isolation of this compound in these new crystalline Forms; as well as to pharmaceutical compositions containing them.
2-butyl-4-chloro-1-[(2'-tetrazol-5-yl)-biphenyl-4-yl]methyl]-5-(hydroxymethyl) imidazole potassium salt is well known as Losartan potassium. Losartan potassium has been shown to be useful in the treatment of hypertension. Losartan is disclosed in U.S. Pat. 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 inhibits the action of the hormone angiotensin II 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 All. 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, blood pressure is reduced. Losartan potassium also is useful for the treatment of congestive heart failure.
The crystalline Losartan Form I and II, and the process for morphologically homogenous Losartan are disclosed in US Pat. No. 5,608,075. It has now been discovered that Losartan potassium can exist in more different crystalline Forms, which differ from each other by their stability, their spectral characteristics and process of preparation.
Accordingly, in one general aspect the present invention provides Losartan Form A.
In another general aspect it provides process for the preparation of Losartan Form A.
In another general aspect it provides pharmaceutical Formulations comprising Losartan Form A.
In another general aspect it provides Losartan Form B.
In another general aspect it provides process for the preparation of Losartan Form B.
In yet another general aspect it provides pharmaceutical Formulations comprising Losartan Form B.
The present invention relates to two new crystalline Forms namely Losartan Form A and Losartan Form B represented by the following chemical structure, the crystalline Forms being characterized by the peaks appearing in the powder X-ray diffraction pattern and Infrared absorption spectra in potassium bromide.
(Structure removed)

Method, and Condition of the Measurement of X-ray Diffraction Patterns
(1) Method of the Measurement X-ray diffraction patterns were measured on each 100 mg of the samples by the following condition.
* (2) Condition of the Measurement
Target Cu Filter monochro
Voltage — 40 KV Current— 100 mA Slit DS1.RS 0.15, SS 1 Scan speed — 27 min. Step/Sample — 0.02°
Method and Condition of the Measurement of Infrared Absorption
Infrared absorption spectra in potassium bromide were measured according to the general method recorded in the United States Pharmacopoeia.
(1) Losartan Form A
Losartan Form A, according to the present invention, is characterized in providing an X-ray powder diffraction pattern, as in FIG. 1, exhibiting substantially the following d-values and intensities:
(Table removed)
Losartan Form A according to the present invention is further characterized by IR data as given in Fig -2. Wave numbers (cm '1) of infrared absorption spectra in potassium bromide are:
1640; 1562; 1576; 1460; 1426; 1408; 1359; 1259; 1208; 1146; 1126; 1105; 1072; 1072; 1027; 1012; 992; 931; 879; 831; 799; 784; 761 cm"1.
(2) Losartan Form B
Losartan Form B, according to the present invention, is characterized in providing an X-
* ray powder diffraction pattern, as in FIG. 3, exhibiting substantially the following d-values and intensities:
(Table removed)

Losartan Form B according to the present invention is further characterized by IR data as given in Fig -4. Wave numbers (cm"1) of infrared absorption spectra in potassium bromide are: 840; 1637; 1576; 1562; 1506; 1497; 1459; 1426; 1422; 1408; 1377; 1357; 1307; 1207; 1258; 1128; 1105; 1073; 1145; 1007; 993; 932; 840; 788; 762 cm-1.
The X-ray powder diffractogram data as well as the IR data for Losartan Form A are different compared to Losartan Form B. Losartan Form A can thereby be distinguished from Losartan Form B, using X-ray powder diffraction. Form A shows characteristic band at 2 theta 17.9 and 15.7, however Form B shows characteristic band at 2 theta 19.2 and 15.9.
Losartan Form A can also be characterized by IR data, where Losartan Form A is characterized by the absence of a band at 840 cm"1, which is observed for Losartan 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" 1band) is <1 for Losartan Form A, while the ratio is >1 for Losartan Form B. Similarly the ratio (intensity of 1426 cm"1 band/intensity of 1408 cm"1 band) is <1 for Losartan Form A, while the ratio is >1 for Losartan Form B.
Detailed processes for preparing the new Forms are as follows.
In these processes, "Losartan" means Losartan potassium, i.e., potassium salt of 2-butyl-4-chloro-1- [(2'-tetrazol-5-yl)-biphenyl-4-yl] methyl]-5-(hydroxymethyl) imidazole. Losartan may be prepared using the reactions and techniques described in US Pat. No. 5,138,069, O 93/10106 or one of its three US counterparts, US Pat. No. 5,130,439 and US Pat No. 5,206,374; and US Pat No. 5,608,075 which are incorporated herein as reference.
Losartan Form A and B can be prepared by using anyone of the following methods: (i) Heating the amorphous Losartan potassium, (ii) Heating and humidifying the amorphous Losartan potassium, (iii) Heating the Losartan potassium Form 'A'.
In one of the embodiments Losartan "Form A" was prepared by spray drying the aqueous solution of Losartan Form I (Losartan Form -I was prepared by the process
given in US Pat No. 5,608,075; spray drying process as disclosed in our co-pending Indian patent application 1095/DEL/2002). The amorphous Losartan potassium so obtained was subjected to heating and humidification (at 40°C/75% RH) for 24 hours to give Losartan Form A.
In another embodiment Losartan "Form A" was prepared by spray drying the methanolic solution of Losartan Form I (Losartan Form-I was prepared by the process given in US Pat No. 5,608,075; spray drying process as disclosed in our co-pending application Indian patent application 1095/DEL/2002). The amorphous Losartan potassium so obtained was subjected to heating and humidification (at 40°C/75% RH) for 24 hours to give Losartan Form A.
In yet another embodiment Losartan Form A obtained from water spray dried amorphous Losartan potassium was heated at 40°C for 24 hours to give Losartan Form B.
The following examples further illustrate the preparation of the Losartan Torm A' and 'Form B are not be considered or construed as limiting the invention recited in the appended claims.
Example-1
20 gm of the Losartan potassium Form I was dissolved in 100 ml water at 20°C. The solution was spray dried using Lab Plant spray drier to afford about 16gm of amorphous Losartan potassium. This material was kept for 24 hours at 40°C temperature under 75% relative humidity. About 15 gm of the Losartan Form 'A' was obtained.
Example-2
50 gm of the Losartan potassium Form I was dissolved in 500 ml methanol at 20°C. The solution was spray dried using Lab Plant spray drier to afford about 40 gm of amorphous Losartan potassium. This material was kept for 24 hours at 40°C temperature under 75% relative humidity. About 38gm of the Losartan Form 'A' was obtained.
Example-3
5 gm of the Losartan potassium Form 'A' of Example-1 was heated at 80°C for 24 hours. About 4 gm of the Losartan Form 'B' was obtained.
Example-4
10 gm of the Losartan Form 'A' of Example-2 was heated at 80°C for 24 hours. About 8 gm of the Losartan Form T was obtained.
From the X-ray diffraction and IR spectra, it is evident that two new crystalline Forms of Losartan are Formed, a metastable pseudomorph (Form 'A') and a true polymorph (Form 'B').
The crystalline Forms of this invention 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 example, administration can be oral, parenteral, i.e., subcutaneous, intravenous, intramuscular or intra peritoneal or transdermal.
The compounds 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.
For the purpose 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 dosage administered will be dependent on the age, health and weight of the recipient, the extent of disease, kind of concurrent treatment, if any, frequency of treatment and the nature of the effect desired. Usually, a daily dosage of active ingredient compound will be from about 1-500 milligrams per day. Ordinarily, from 10 to 100 milligrams per day in one or more applications is effective to obtain desired results. These dosages are the effective amounts both for treatment of hypertension and for treatment of congestive heart failure, i.e., for lowering blood pressure and for correcting
"the hemodynamic burden on the heart to relieve the congestion.
Losartan Form A and B can be administered orally in solid dosage Forms, such as capsules, tablets, and powders, or in liquid dosage Forms, such as elixirs syrups, and suspensions. These can also be administered parenterally, in sterile liquid dosage Forms.
Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
Liquid dosage Forms for oral administration can contain coloring and flavoring to increase patient acceptance.
In general, water, suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl or propyl paraben, and chlorobutanol.
Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences.

CLAIM:
1. Losartan potassium Form 'A' which has characteristic bands at 2 theta = 5.6; 6.8; 8.9; 13.2; 15.7; 17.3; 17.9; 19.9; 20.9; 23.5; 24.7; 26.6 and 27.7.
2. Losartan Potassium Form 'A' according to claim 1 wherein Form A is further characterized by I.R. spectra having spectral absorbance at 1640; 1562; 1576; 1460; 1426; 1408; 1359; 1259; 1208; 1146; 1126; 1105; 1072; 1072; 1027; 1012; 992; 931; 879; 831; 799; 784; 761 cm"1.
3. Losartan potassium Form B which has characteristic bands at 2 theta = 7.3; 11.1; 14.2; 15.9; 19.0; 19.2; 22.0; 22.1; 23.9; 24.1; 24.4; 24.8; 26.6; 27.4.
4. Losartan Potassium Form 'B' according to claim 3 wherein Form B is further characterized by I.R. spectra having spectral absorbance at 840; 1637; 1576; 1562; 1506; 1497; 1459; 1426; 1422; 1408; 1377; 1357; 1307; 1207; 1258; 1128; 1105; 1073; 1145; 1007; 993; 932; 840; 788; 762 cm-1.
5. A process for the preparation of Losartan Form 'A' according to claim 1 comprising the step of heating the amorphous Losartan potassium.
6. The process for the preparation of Losartan Form 'A' according to claim 1 comprising the steps of heating and humidifying the amorphous Losartan potassium.
7. The process according to claims 5-6 wherein amorphous Losartan potassium is prepared from Losartan potassium Form -I.
8. The process according to claim 7 wherein amorphous Losartan potassium is prepared by spray drying an aqueous solution of Losartan Form I.
9. The process according to claim 7 wherein amorphous Losartan potassium is prepared by spray drying methanolic solution of Losartan Form I.
10. The process according to claim 6 wherein amorphous Form of Losartan potassium is heated at 40°C under 75% relative humidity for 24 hours.

11. A process for the preparation of Losartan Form 'B' according to claim 3 comprising the step of heating the Losartan potassium Form 'A'.
12. The process according to claim 11 wherein heating is done at 80°C for up to 24 hours.
13. The process according to claim 11 wherein heating is done at 80°C for 24 hours.
14. A method of treatment of hypertension which comprises administration of a therapeutically effective amount of Losartan Form A according to claim 1 in patients suffering from hypertension.
15. A pharmaceutical Formulation comprising Losartan Form A according to claim 1 in admixture with pharmaceutical excipient.
16. A method of treatment of hypertension which comprises administration of a therapeutically effective amount of Losartan Form B according to claim 3 in patients suffering from hypertension.
17. A pharmaceutical Formulation comprising Losartan Form B according to claim 3 in admixture with pharmaceutical excipient.