Abstract
A novel experimental approach describing the integration of drug substance and drug production design using particle engineering techniques such as sonocrystallization, high shear wet milling (HSWM) and dry impact (hammer) milling were used to manufacture samples of an active pharmaceutical ingredient (API) with diverse particle size and size distributions. The API instability was addressed using particle engineering and through judicious selection of excipients to reduce degradation reactions. API produced using a conventional batch cooling crystallization process resulted in content uniformity issues. Hammer milling increased fine particle formation resulting in reduced content uniformity and increased degradation compared to sonocrystallized and HSWM API in the formulation. To ensure at least a 2-year shelf life based on predictions using an Accelerated Stability Assessment Program, this API should have a D [v, 0.1] of 55 μm and a D [v, 0.5] of 140 μm. The particle size of the chief excipient in the drug product formulation needed to be close to that of the API to avoid content uniformity and stability issues but large enough to reduce lactam formation. The novel methodology described here has potential for application to other APIs.
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Acknowledgements
The authors would like to thank Neil Dawson for particle size distribution characterisation support and Lisa Taylor for supporting dry milling studies. We also acknowledge Florence Colin and Sally Grieb for analytical assistance and Kate Boxell for conducting the segregation studies.
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This research project is funded by the Netherlands Organization for Scientific Research (NWO, The Hague, project number: 411-02-163)
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Kougoulos, E., Smales, I. & Verrier, H.M. Towards Integrated Drug Substance and Drug Product Design for an Active Pharmaceutical Ingredient Using Particle Engineering. AAPS PharmSciTech 12, 287–294 (2011). https://doi.org/10.1208/s12249-011-9582-5
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DOI: https://doi.org/10.1208/s12249-011-9582-5