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

Abstract

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.

Keywords:

• mechanoradicals
• stability
• oxidation
• high-shear mixing
• API morphology

ACKNOWLEDGMENTS

The authors gratefully acknowledge the assistance of Dr Dinos Santafianos for the synthesis of the oxidative degradant and Dr Ken Waterman and Dr Sheri Shamblin for data interpretation and useful discussions.