The Influence of Thermal and Mechanical Preparative Techniques on the Amorphous State of Four Poorly Soluble Compounds

• Published in: Journal of pharmaceutical sciences Vol. 94; no. 9; pp. 1998 - 2012
• Main Authors: Patterson, James E., James, Michael B., Forster, Angus H., Lancaster, Robert W., Butler, James M., Rades, Thomas
• Format: Journal Article
• Language: English
• Published: Hoboken Elsevier Inc 01.09.2005; Wiley Subscription Services, Inc., A Wiley Company; Wiley; American Pharmaceutical Association
• Subjects: amorphous; Biological and medical sciences; carbamazepine; Carbamazepine - chemistry; Chemistry, Pharmaceutical; Crystallization; dipyridamole; Dipyridamole - chemistry; Drug Stability; General pharmacology; glibenclamide; Glyburide - chemistry; indomethacin; Indomethacin - chemistry; Medical sciences; melting; milling; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; polymorphism; Powder Diffraction; solid state; Solubility; Spectroscopy, Fourier Transform Infrared; Technology, Pharmaceutical - methods; Temperature; Thermogravimetry; X-Ray Diffraction; amorphous; dipyridamole; polymorphism; melting; glibenclamide; milling; solid state; carbamazepine; indomethacin; Sulfanilamide derivatives; Antianginal agent; Prostaglandin-endoperoxide synthase; Coronary vasodilator agent; Indometacin; Anticonvulsant; Tocolytic; Hypoglycemic agent; Mood stabilizer; Indoleacetic acid derivatives; Glibenclamide; Melting; Pharmaceutical technology; Enzyme; Dipyridamole; Enzyme inhibitor; Amorphous state; Tricyclic compound; Carbamazepine; Antiplatelet agent; Non steroidal antiinflammatory agent; Solid state; Sulfonylureas; Soluble compound; Oxidoreductases; Polymorphism
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.20424

A number of studies in the literature have reported on the use of different preparative techniques to convert crystalline pharmaceutical compounds into the amorphous form. However, very few direct comparisons of different preparative techniques using the same drugs are available. The purpose of this study was to determine the influence of two techniques: quench cooling and ball milling on four structurally diverse pharmaceutical drugs. Dipyridamole, carbamazepine, glibenclamide, and indomethacin were converted to the amorphous form by (a) quench cooling of the drug melt and (b) ball milling. The chemical purity and physical form of the products was determined using diffractometric, spectroscopic, and thermal analytical techniques. Products were analysed immediately post preparation and after storage under different stability conditions. Quench cooling of the melt resulted in amorphous conversion of all four compounds. However with glibenclamide, quench cooling resulted in unacceptable chemical degradation whereas ball milling of glibenclamide resulted in a change in the keto–enol tautomerism at the aryl amide moiety of this drug. Ball milling resulted in predominantly amorphous products for all compounds except carbamazepine. Ball milling of carbamazepine resulted in a polymorphic transition of the starting material to form III. Physical stability studies showed that irrespective of preparative technique and storage conditions all samples showed at least partial reversion to the crystalline state after storage. Quench cooling of drug melts may be of use as a preparative technique however it can result in chemical degradation. Ball milling may also be of use as a preparative technique however its effectiveness is dependent on the unit cell structure of the compound. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association.