Mechanoradical-Induced Degradation in a Pharmaceutical Blend during High-Shear Processing

• Published in: Pharmaceutical development and technology Vol. 13; no. 6; pp. 457 - 462
• Main Authors: Polizzi, Mark A., Singhal, Dharmendra, Colvin, Joshua
• Format: Journal Article
• Language: English
• Published: New York, NY Informa UK Ltd 01-01-2008; Taylor & Francis; Informa Healthcare
• Subjects: API morphology; Biological and medical sciences; Cellulose - chemistry; Drug Compounding - methods; Drug Stability; Excipients - chemistry; Free Radicals - chemistry; General pharmacology; high-shear mixing; Lactose - chemistry; Mechanical Phenomena; mechanoradicals; Medical sciences; Morpholines - chemistry; oxidation; Oxidation-Reduction; Pharmaceutical Preparations - chemistry; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Silicon Dioxide - chemistry; stability; Starch - analogs & derivatives; Starch - chemistry; Sulfides - chemistry; Sulfoxides - chemistry; X-Ray Diffraction; Mixing; Shear; Stability; Pharmaceutical technology; Metabolism; Formulation; Morphology; Mechanical degradation; Oxidative degradation; Oxidation; API morphology; high-shear mixing; Pharmacokinetics; mechanoradicals; Physicochemical properties
• ISSN: 1083-7450; 1097-9867
• DOI: 10.1080/10837450802328869

Mechanically generated radicals were shown to affect short-term stability of a model pharmaceutical formulation during high-shear processing. A formulation containing an oxidatively sensitive drug, either amorphous or crystalline, and a polymeric excipient was high-shear mixed and the resulting short-term degradation was determined with HPLC. High-shear mixing of the excipients was also carried out before drug addition to isolate effects on excipients versus those directly on the drug. Short-term drug stability was found to be strongly dependent on the amount of shear added to excipients prior to drug addition, regardless of morphology. A mechanism for the observed degradation based on mechanically generated radicals from microcrystalline cellulose is proposed. These results indicate that excipient high-shear exposure needs to be considered in regards to drug stability.