Preparation of carbamazepine-Soluplus? solid dispersions by hot-melt extrusion, and prediction of drug-polymer miscibility by thermodynamic model fitting

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• 作者：Jelena Djuris^a ; ^{jelena.djuris@pharmacy.bg.ac.rs} ; Ioannis Nikolakakis^b ; Svetlana Ibric^a ; Zorica Djuric^a ; Kyriakos Kachrimanis^b
• 关键词：ATR ; attenuated total reflectance ; CBZ ; carbamazepine ; DSC ; differential scanning calorimetry ; FTIR ; Fourier-transform infrared ; HME ; hot-melt extrusion ; HSM ; hot stage microscopy ; MW ; molecular weight ; PM ; physical mixtures ; PRU ; polymer repeat units ; SL
• 刊名：European Journal of Pharmaceutics and Biopharmaceutics
• 出版年：2013
• 出版时间：May, 2013
• 年：2013
• 卷：84
• 期：1
• 页码：228-237
• 全文大小：1333 K

文摘

Hot-melt extrusion (HME) is a dust- and solvent-free continuous process enabling the preparation of a variety of solid dosage forms containing solid dispersions of poorly soluble drugs into thermoplastic polymers. Miscibility of drug and polymer is a prerequisite for stable solid dispersion formation. The present study investigates the feasibility of forming solid dispersions of carbamazepine (CBZ) into polyethyleneglycol-polyvinyl caprolactam-polyvinyl acetate grafted copolymer (Soluplus?) by hot-melt extrusion. Physicochemical properties of the raw materials, extrudates, co-melted products, and corresponding physical mixtures were characterized by thermo-gravimetric analysis (TGA), differential scanning calorimetry (DSC), attenuated total reflectance infrared (ATR-FTIR) spectroscopy and hot stage microscopy (HSM), while miscibility of CBZ and Soluplus? was estimated on the basis of the Flory-Huggins theory, Hansen solubility parameters, and solid-liquid equilibrium equation. It was found that hot-melt extrusion of carbamazepine and Soluplus? is feasible on a single-screw hot-melt extruder without the addition of plasticizers. DSC analysis and FTIR spectroscopy revealed that a molecular dispersion is formed when the content of CBZ does not exceed ¡«5 % w/w while higher CBZ content results in a microcrystalline dispersion of CBZ form III crystals, with the molecularly dispersed percentage increasing with extrusion temperature, at the risk of inducing transformation to the undesirable form I of CBZ. Thermodynamic modeling elucidated potential limitations and temperature dependence of solubility/dispersibility of carbamazepine in Soluplus? hot-melt extrudates. The results obtained by thermodynamic models are in agreement with the findings of the HME processing, encouraging therefore their further application in the HME process development.