Journal
DRUG DESIGN DEVELOPMENT AND THERAPY
Volume 11, Issue -, Pages 733-746Publisher
DOVE MEDICAL PRESS LTD
DOI: 10.2147/DDDT.S125323
Keywords
pharmaceutical development; quality by design; failure mode effects analysis; Ishikawa diagram; fish-bone diagram; hydrophilic matrix
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Funding
- Romanian National Authority for Scientific Research and Innovation, CNCS - UEFISCDI [PN-II-RU-TE-2014-4-1862]
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This study focuses on the development of a drug product based on a risk assessment-based approach, within the quality by design paradigm. A prolonged release system was proposed for paliperidone (Pal) delivery, containing Kollidon (R) SR as an insoluble matrix agent and hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), or sodium carboxymethyl cellulose as a hydrophilic polymer. The experimental part was preceded by the identification of potential sources of variability through Ishikawa diagrams, and failure mode and effects analysis was used to deliver the critical process parameters that were further optimized by design of experiments. A D-optimal design was used to investigate the effects of Kollidon SR ratio (X-1), the type of hydrophilic polymer (X-2), and the percentage of hydrophilic polymer (X-3) on the percentages of dissolved Pal over 24 h (Y-1-Y-9). Effects expressed as regression coefficients and response surfaces were generated, along with a design space for the preparation of a target formulation in an experimental area with low error risk. The optimal formulation contained 27.62% Kollidon SR and 8.73% HPMC and achieved the prolonged release of Pal, with low burst effect, at ratios that were very close to the ones predicted by the model. Thus, the parameters with the highest impact on the final product quality were studied, and safe ranges were established for their variations. Finally, a risk mitigation and control strategy was proposed to assure the quality of the system, by constant process monitoring.
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