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Quality Risk Management and Quality by Design for the Development of Diclofenac Sodium Intra-articular Gelatin Microspheres

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Abstract

The aim of the present study was to evaluate the development of an intra-articular nonsteroidal anti-inflammatory drug gelatin microsphere formulation based on quality risk management and quality by design approaches. Specifically, after setting the quality target product profile and the critical quality attributes, risk assessment was performed by constructing Ishikawa fishbone diagrams based on preliminary hazard analysis. A Plackett–Burman screening experimental design was applied in order to identify the factors (previously classified by risk assessment analysis as having high risk of failure) having a statistically significant impact on the formation of gelatin microspheres. Particle size, polydispersity index, and drug loading were used as responses, while diclofenac sodium was selected as a model drug. All drug-loaded gelatin microspheres were prepared by emulsion-crosslinking process. Screening results showed that gelatin type, surfactant type and quantity, oil phase type, emulsification speed, and glutaraldehyde’s concentration had a statistically significant impact on microsphere’s final and intermediate critical quality attributes. A design space was then constructed based on central composite design overlaying contour plots, while verification experiments for the optimum suggested formulation (derived from a set control strategy) showed good agreement between the predicted and the experimentally observed results. In addition, the physicochemical characterization of the optimum formulation showed the formation of significant molecular interactions between the drug and the gelatin matrix, leading to the complete amorphization of diclofenac within the microsphere structure, while dissolution release experiments showed a biphasic release profile which extended the drug’s release for up to 30 days, governed by a Fickian diffusion release mechanism.

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Acknowledgments

The authors would like to acknowledge the School of Chemical Engineering, Aristotle University of Thessaloniki, Greece, for providing access to the XRD instrument and Mr. Anastasios Palladas for the analysis, as well as Ass. Prof. Christos Chatzidoukas for providing access to the particle size analyzer (Malvern Mastersizer 2000). Also, the authors would like to thank the School of Physics, Department of Solid State Physics for providing access to the scanning electron microscope.

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Authors and Affiliations

  1. Laboratory of Organic Chemistry, School of Chemical Engineering, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece

    Alexandros Nakas, Athanasia M. Dalatsi, Konstantinos N. Kontogiannopoulos & Andreana N. Assimopoulou

  2. NatPro-AUTH, Center for Interdisciplinary Research and Innovation (CIRI-AUTH), 57001, Thessaloniki, Greece

    Alexandros Nakas, Konstantinos N. Kontogiannopoulos, Andreana N. Assimopoulou & Panagiotis Barmpalexis

  3. Department of Pharmaceutical Technology, School of Pharmacy, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece

    Afroditi Kapourani & Panagiotis Barmpalexis

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  1. Alexandros Nakas
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Nakas, A., Dalatsi, A.M., Kapourani, A. et al. Quality Risk Management and Quality by Design for the Development of Diclofenac Sodium Intra-articular Gelatin Microspheres. AAPS PharmSciTech 21, 127 (2020). https://doi.org/10.1208/s12249-020-01678-0

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