Formulation parameters of crystalline nanosuspensions on spray drying processing: A DoE approach

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• 作者：Sumit Kumar^a ; Xiaoming Xu^a ; ¹ ; Rajeev Gokhale^b ; Diane J. Burgess^a ; ^{d.burgess@uconn.edu" class="auth_mail}
• 关键词：ANOVA ; analysis of variance ; API ; active pharmaceutical ingredient ; BCS ; biopharmaceutical classification system ; CQA ; critical quality attributes ; Ct Pt ; center point ; DoE ; design of experiment ; DSC ; differential scanning calorimeter ; PDI ; polydispersity index ; PXRD ; powder X-ray diffraction ; Tg ; glass transition temperature ; Tm ; melting temperature
• 刊名：International Journal of Pharmaceutics
• 出版年：10 April, 2014
• 年：2014
• 卷：464
• 期：1-2
• 页码：34-45
• 全文大小：2962 K

文摘

Nanocrystalline suspensions offer a promising approach to improve dissolution of BCS class II/IV compounds. Spray drying was utilized as a downstream process to improve the physical and chemical stability of dried nanocrystals. The effect of nanocrystalline suspension formulation variables on spray-drying processing was investigated. Naproxen and indomethacin nanocrystalline formulations were formulated with either Dowfax 2A1 (small molecule) or HPMC E15 (high molecular weight polymer) and spray drying was performed. A DoE approach was utilized to understand the effect of critical formulation variables, i.e. type of stabilizer, type of drug, ratio of drug-to-stabilizer and drug concentration. The powders were analyzed for particle size, moisture content, powder X-ray diffraction and dissolution. A dialysis sac adapter for USP apparatus II was developed which provided good discrimination between aggregated and non-aggregated formulations. Nanocrystal aggregation was dependent on the drug-to-stabilizer ratio. The glass transition temperature and the charge effect played a dominant role on spray-dried powder yield. Those formulations with low drug-to-excipient ratios were less aggregating and showed faster dissolution compared to those formulations with high drug-to-excipient ratios. All stable (less aggregated) formulations were subjected to accelerated storage stability testing. The Flory-Huggins interaction parameter (between drug and excipients) correlated with the spray-dried nanocrystal formulations stability.