Çözünürlüğü ve Çözünme Hızı Artırılmış Selekoksib Formülasyonlarının Tasarımı, Optimizasyonu ve İn Vitro/İn Vivo Değerlendirilmesi

Abstract

Dry co-milling is a technology that has been widely used in recent years and can be applied in the pharmaceutical industry to improve the solubility and dissolution rate of poorly soluble active substances. Quality by Design is a systematic approach that uses statistical, analytical and risk management methodology with predefined objectives. The aim of this thesis is to develop submicron/nano-sized compositions of celecoxib, which has low solubility in water and physiological environments, prepared by dry co-milling technology, with a quality by design approach and to characterize them in vitro/in vivo. The most suitable excipients for dry milling with celecoxib were determined by preliminary screening experiments. Different experimental designs were used to understand the effects of processing and formulation factors on the critical quality properties of co-milled celecoxib compositions. Potential risk factors were determined with Ishikawa diagram, important risk factors were selected with Plackett-Burman experimental design, and celecoxib compositions were optimized with central composite and Bayesian optimization. Optimized co-milled celecoxib compositions were characterized by FTIR, XRD, DSC, SEM, IDR, solubility and stability studies. Dissolution tests and permeability studies of the optimum formulation developed with this composition were carried out. Oral pharmacokinetic studies of the optimum formulation and reference product were performed in rats. As a result of these studies, optimum factors for the design of celecoxib compositions with increased solubility and dissolution rate at submicron/nano-sized were determined with the quality by design approach. Results of in vitro and in vivo studies have demonstrated the development of celecoxib compositions with improved solubility, dissolution rate, and oral pharmacokinetic profile.