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DEVELOPMENT OF SUPERSATURATED MATRIX SYSTEMS FOR POORLY WATER-SOLUBLE COMPOUNDS BASED ON SPRAY-DRIED SOLID DISPERSIONS
Lu, Zheng
Lu, Zheng
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Thesis/Dissertation
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2017
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Pharmaceutical Sciences
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http://dx.doi.org/10.34944/dspace/1760
Abstract
The objective of this study was to design, develop and evaluate an amorphous solid dispersion (ASD)-loaded controlled release (CR) matrix system for poorly water-soluble drug in order to enhance its solubility and dissolution rate while maintaining the stability of the supersaturated state during and after dissolution. Two types of polymeric carriers, namely hydroxypropyl methylcellulose acetate succinate (HPMCAS) and copovidone S-630, were used in spary-dried dispersion (SDD) formulations. Weak acid drugs glipizide and gliclazide which tend to have limited solubility and dissolution rate were chosen as poorly soluble model compounds representing Class-II drugs according to the FDA adopted Biopharmaceutics Classification Scheme. The unique features of the hydrating CR matrix system consisting of amorphous drug dispersion that provides supersaturation and probable mechanisms to inhibit precipitation are investigated. SDD-loaded CR matrix tablets prepared in this study were based on use of automated spray dryer and compaction simulator with optimized process parameters in order to control the critical quality attributes (CQAs) of final formulations. A 3×4 full factorial design was conducted to understand the effect of drug loading level and polymer type on the performance of SDD products for both glipizide and gliclazide. Drug loading level and succinoyl content % of HPMCAS were identified as two critical factors for meeting goals set to achieve maximum concentration under non-sink condition referred to as Cmax. Compliance to Cmax limit is assured by selecting drug loading level and type of HPMCAS within design space. Spray-dried dispersions (SDDs) of glipizide and gliclazide were prepared using HPMCAS (H, M and L grades) and copovidone as amorphous matrix forming polymer in order to improve the solubility and dissolution rate of the drug. The SDDs appeared as a single amorphous phase with up to 60% drug loading level as revealed by X-ray powder diffraction (XRPD), modulated differential scanning calorimetry (mDSC) and scanning electron microscopy (SEM). Supersaturated micro-dissolution testing of SDD powders in fasted state simulated intestinal fluid showed prolonged supersaturation state (up to 180 minutes) with significant solubility increase relative to crystalline drug under same conditions. Moreover, plot of relative dissolution AUCs (AUC (SDD) /AUC (crystalline)) versus stable supersaturated concentration ratio (C180/Cmax) was provided as an appropriate formulation strategy for selecting SDDs with improved solubility and supersaturation stability. Selected SDDs were formulated into matrix tablet with rate-controlling hydrophilic polymer, hydroxypropylmethylcellulose (HPMC) and other excipients. Dissolution data based on standard USP paddle method indicated that SDD-loaded CR tablets provide stable supersaturated concentration within the hydrated matrix with increased rate and extent of drug dissolution. Co-existence of HPMCAS and HPMC within the hydrating matrix showed strong suppression of drug crystallization and allowed achievement of zero-order and slow-first order release kinetics. In conclusion, results of this study indicate that use of HPMCAS as drug carrier in spray-drying process is able to produce homogeneous single phase SDDs which are stable and promising for inclusion into CR systems in development of CR dosage forms of poorly water-soluble drugs.
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