Losartan

Losartan, a potassium salt and an orally active antihypertensive agent, exhibits polymorphism with two known forms (Raghavan et al. 1993). When losartan is crystallized from solution (usually a mixture of cyclohexane, isopropanol, and water), only one anhydrous form (Form I) is observed. Variations in the solvents, temperature I 80 C and lower), and rate of crystallization appear to have no effect on the nature of the solid phase. 

When the solvent-isolated losartan was subjected to DSC characterization, the DSC curve (Fig. 3-5, curve A) showed a minor endotherm at an extrapolation onset temperature of about 229°C (10°C/min) and a major melting endotherm at an extrapolation onset temperature of about 273°C (10°C/min). When a sample of Form I was heated to 255°C and then cooled back to room temperature, the subsequent DSC curve showed only the high-temperature endotherm (Fig. 3-5, curve B). Chemical analysis (HPLC) and solution NMR showed no change in the material heated to 255°C and cooled back to room temperature. However, XRPD indicated a change in the crystal structure. Therefore, it was concluded that the minor endotherm corresponded to a kinetically irreversible enantiotropic polymorphic transition and that the losartan system was not under complete thermodynamic control. Form I is the low-temperature stable form, up to the transition point, and the high-temperature stable form was 

The solubility measurements of the two losartan forms (Form II prepared by heating) in isopropanol and ethyl acetate at 25 C and with overnight equilibration resulted in the conversion of Form U to Form I and no change in the initial Form I. The observed solubilities were 35 to 0.3 mg/g, respectively. However, in isopropyl acetate, no conversion of either form was observed after overnight equilibration at 25°C. The resulting solubihties were 18 and 41 mcg/gm for Forms I and II, respectively. More extensive solubility data, in methyl ethyl ketone at temperatures ranging from 25 to 65 C with shorter equilibration times that did not result in any conversions, showed Form I, once again, to have the lower measured values (Crocker and McCauley 1997). Extrapolation (Fig. 3-6) of the methyl ethyl ketone data indicated that the two solubility-temperature curves cross at a temperature of about 192 C, which is consistent with the enantiotropic transition seen in the DSC curves for Form I. The solubility data confirm that Form I is the more thermodynamically stable form at room temperature. 

Comprehensive spectral analysis including solid state FTIR, solid state Raman, and solid state C NMR by Raghavan et al. (1993), resulted in the following conclusion, particularly from sohd state C NMR ... spectral characteristics of Form I were interpreted in terms of the presence of more than one orientation for the n-butyl side chain and the imidazole ring. In addition, the spectral characteristics of Form II were consistent with a large molecular motion of the n-butyl side chain. Although spectral differences were observed, no conclusions about relative thermodynamic stabihty could be or were made from the spectral data, leaving those conclusions to the more traditional methods of thermal analysis (DSC) and solubihty measurements. 

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At Merck Research Laboratories, the imidazole ring ia losartan (81, K = n — butyl), a novel clinical candidate against hypertension, was replaced with a pyrazole ring (52). Some of the best compounds are represented by formula (82), where K = n — butyl and R = 2,6-dichlorophenyl, 2-chlorophenyl, or... 

P-gp (ABCB1) Verapamil, digoxin, mitoxantrone, vinblastine, doxorubicin, losartan, talinolol, cortisol, dexamethasone, colchicine, loperamide, domperidone, indinavir, erythromycin, tetracycline, itraconazole, cyclosporine, methotrexate, amitryptyline, phenobarbital, morphine, cimetidine, and others... 

Angiotensin II receptor antagonists—for example, irbesartan (Avapro), losartan (Cozaar), and valsar-tan (Diovan)... 

Hydroserpine 2 Tablets—hydrochbrothiazide, reserpine Hyzaar—hydrochlorothiazide, losartan potassium Inderide—hydrochlorotliiazide, propranolol HC1 Inderide LA—hydrochlorotliiazide, propranolol HC1 Lexxel Extended-Release—enalapril maleate, felodipine Lopressor—hydrochlorothiazide, metoprolol Lotensin HCT—hydrochlorothiazide, benazepril Lotrel—amlodopine, benazepril... 

C22H22C1N,0 114772-55-3) see Losartan potassium tert-butyl chloroformate (C5H9CIO2 24608-52-4) see Cefalexin 2-butyl-4-chloro-5-hydroxymethyiimidazole (CSII13CIN2O 79047-41-9) see Losartan potassium 2-butyl-4-cbloro-lif-imidazole-5-carboxaldehyde (CnHiiClNjO 83857-96-9) see Eprosartan Losartan potassium... 

C4 H35C1N 0 120568-18-5) see Losartan potassium tert-butyl (4R,6S)-2-(6-cyanomethyl-2,2-dimcthyl-13-di-oxan-4-yl)acetale... 

C9H21BO3 5419-55-6) see Losartan potassium Rofecoxib triisopropyl phosphite... 

C,7H 5CI 76-83-5) see Candesartan cilexetil Cefotaxime Ceftazidime Indeloxacine Losartan potassium Remoxipride Zidovudine... 

C24H2,BN402 144873-97-2) see Losartan potassium 5 -0-(triphenylmethyl)thymidine 3 -methanesulfonate (CjoH,0N2O7S 42214-24-4) see Zidovudine... 

Angiotensin converting enzyme inhibitors, atracurium, P-lactams, heparin, iron (parenteral), losartan, and streptokinase... 

Joint National Committee Seventh Report Losartan Intervention For Endpoint reduction in hypertension study... 

Valproic acid/salts Losartan Meglumine antimoniate Piroxicam Procainamide Salicylates Sodium stibogluconate Zalcitabine... 

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