Selection of Optimal Hydrate/Solvate Forms of a Fibrinogen Receptor Antagonist for Solid Dosage Development

• Published in: Pharmaceutical development and technology Vol. 4; no. 1; pp. 81 - 87
• Main Authors: Bray, Michelle L., Jahansouz, Hossain, Kaufman, Michael J.
• Format: Journal Article
• Language: English
• Published: New York, NY Informa UK Ltd 1999; Taylor & Francis; Informa Healthcare
• Subjects: Administration, Oral; Azepines - administration & dosage; Azepines - chemistry; Biological and medical sciences; Calorimetry, Differential Scanning; Chromatography, High Pressure Liquid; Crystallinity; Crystallization; Drug Stability; Fibrinogen receptor antagonist; Fibrinolytic Agents - administration & dosage; Fibrinolytic Agents - chemistry; General pharmacology; Humidity; Hydrate; Hygroscopicity; Medical sciences; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Platelet Glycoprotein GPIIb-IIIa Complex - antagonists & inhibitors; Polymorphism; Powder x-ray diffractometry; Solubility; Stability; Sulfonamides - administration & dosage; Sulfonamides - chemistry; Thermogravimetry; X-Ray Diffraction; Hygroscopicity; Pharmaceutical technology; Chemical stability; Fibrinogen; Dosage form; Oral form; Antagonist; Crystalline state; Hydrates; Polymorphism; Biological receptor; Physical structure
• ISSN: 1083-7450; 1097-9867
• DOI: 10.1080/10837459908984227

ABSTRACT The objective of this work was to compare the physicochemical properties of four crystalline forms of the fibrinogen receptor antagonist L-738,167 [2(S)-[p-toluenesulfonyl amino]-3-[[[5,6,7,8-tetrahydro-4-oxo-5-[2-(piperidin-4-yl)ethyl]-4-H-pyrazolo[1,5-a][1,4]diazepin-2-yl]carbonyl]amino]-propionic acid] to determine the best form for use in the development of oral dosage formulations. Four crystalline forms [form A (trihydrate), form B (pentahydrate), form C, and form D] were compared using x-ray powder diffractometry, thermal analysis, and moisture sorption studies. The trihydrate, form A, was demonstrated to hydrate upon exposure to relative humidity (RH) above 50% at room temperature (25°C) with conversion to the pentahydrate. The pentahydrate, form B, converted to the trihydrate at room temperature when exposed to humidity levels below 25% RH. The crystalline pentahydrate was shown to be stable to dehydration upon storage at 30°C/60% RH and 40°C/75% RH for 3 months. The suspension of form A or form D in water resulted in conversion to form B, the stable hydrated form in an aqueous environment. Form C has a unique crystalline structure that is stable in an aqueous environment and not subject to hydration/dehydration with changes in relative humidity and thus may offer some advantages in pharmaceutical development.