Mechanoradical-induced degradation in a pharmaceutical blend during high-shear processing.
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.
Polizzi
Mark A
MA
Pfizer Global Research and Development, Groton, Connecticut 06340, USA. mark.polizzi@pfizer.com
Singhal
Dharmendra
D
Colvin
Joshua
J
D002482:Cellulose / Q000737:chemistry; D004339:Drug Compounding / Q000379:methods*; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry*; D005609:Free Radicals / Q000737:chemistry*; D007785:Lactose / Q000737:chemistry; D055595:Mechanical Phenomena; D009025:Morpholines / Q000737:chemistry; D010084:Oxidation-Reduction; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D012822:Silicon Dioxide / Q000737:chemistry; D013213:Starch / Q000031:analogs & derivatives / Q000737:chemistry; D013440:Sulfides / Q000737:chemistry; D013454:Sulfoxides / Q000737:chemistry; D014961:X-Ray Diffraction
D005079:Excipients; D005609:Free Radicals; D009025:Morpholines; D004364:Pharmaceutical Preparations; D013440:Sulfides; D013454:Sulfoxides; D012822:Silicon Dioxide; D002482:Cellulose; D013213:Starch; C048390:sodium starch glycolate; D007785:Lactose; C109691:microcrystalline cellulose