Supersaturation, nucleation, and crystal growth during single- and biphasic dissolution of amorphous solid dispersions: Polymer effects and implications for oral bioavailability enhancement of poorly water soluble drugs

作者：Sarode Ashish L; Wang Peng; Obara Sakae; Worthen David R^*

来源：European Journal of Pharmaceutics and Biopharmaceutics, 2014, 86(3): 351-360.

DOI：10.1016/j.ejpb.2013.10.005

• Amorphous
• Solid dispersion
• Biphasic dissolution
• Supersaturation
• Nucleation and growth
• Bioavailability
• Hot melt extrusion
• Drug polymer interaction

The influence of polymers on the dissolution, supersaturation, Crystallization, and partitioning of poorly water soluble compounds in biphasic media was evaluated. Amorphous solid dispersions (ASDs) containing felodipine (FLD) and itraconazole (ITZ) were prepared by hot melt mixing (HMM) using various polymers. The ASDs were analyzed using powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and HPLC. Amorphous drug conversion was confirmed using DSC and PXRD, and drug stability by HPLC. Single- and biphasic dissolution studies of the ASDs with concurrent dynamic light scattering (DLS) and polarized light microscopic (PLM) analysis of precipitated drugs were performed. HPLC revealed no HMM-induced drug degradation. Maximum partitioning into the organic phase was dependent upon the degree of supersaturation. Although the highest supersaturation of FLD was attained using Eudragit (R) EPO and AQOAT (R) AS-LF with better nucleation and crystal growth inhibition using the latter, higher partitioning of the drug into the organic phase was achieved using Pharmacoat (R) 603 and Kollidon (R) VA-64 by maintaining supersaturation below critical nucleation. Critical supersaturation for ITZ was surpassed using all of the polymers, and partitioning was dependent upon nucleation and crystal growth inhibition in the order of Pharmacoat (R) 603 %26gt; Eudragit (R) L-100-55 %26gt; AQOAT (R) AS-LF. HMM drug-polymer systems that prevent drug nucleation by staying below critical supersaturation are more effective for partitioning than those that achieve the highest supersaturation.

• 出版日期2014-4