Category: Formulation and Quality
Purpose: Poor solubility of oral formulations and the formulation challenges associated with it has been a concern in drug development and design. The aim was to investigate the influence of polymer on supersaturation profile and compare the dissolution performance of amorphous solid dispersions (ASDs) prepared by spray drying technique using -L, -M and -H grades of HPMCAS polymer in Simulated Intestinal fluid w/o enzyme (USP SIF, pH 6.8) media and Fasted Simulated Intestinal Fluid-V2 (FaSSIF-V2, pH 6.5) media.
Methods: Spray drying solutions were prepared by dissolving itraconazole and HPMCAS in 2:1 (w/w) dichloromethane: methanol with 20% drug load. Spray drying was performed on Buchi Mini Spray Dryer with inlet temperature maintained at 55 degC and aspirator at 100%. USP SIF media was prepared as per USP procotol and FaSSIF-V2 media was prepared by reconstitution of powder obtained from biorelevant.com (UK). A standard curve was prepared by adding different concentration of ITZ DMSO stock solution to dissolution media (USP SIF and FaSSIF-V2) which was previously equilibrated with 0.05% (w/v) polymer. The validation of in situ fiber optics was performed by assessing the linearity of standard curve. Dissolution testing were performed on Sporonax capsules (n=6) using both the automated in situ fiber optics and manual sampling method. The dissolution experiments for ASD were performed at RT at 100(±3) rpm using µDISS Profiler™ dissolution apparatus (Pion Inc.). The spray dried samples (6mg of ASD) were pre-wet for one minute and 10 ml of dissolution media was added to each vial. Drug concentrations were measured at various time points with the in situ fiber optics. The precipitation was observed by change in shift of baseline in second derivative UV spectrum. These testing were performed for ASDs from all three grades -L, -M, and -H of HPMCAS, in both the dissolution media.
Results: The dissolution profiles were similar (f2 ≥ 50) for both dissolutions performed with manual and automated in situ fiber optics method. Itraconazole tend to precipitate in intestinal fluids and polymers tend to provide the stabilizing effect. A high mean concentration of about 80 ug/ml and faster initial dissolution was obtained with HPMCAS -L in USP SIF media. Although the extent of supersaturation was high in HPMCAS -L grade, HPMCAS -M grade was able to maintain supersaturation of 60 ug/ml for a longer period without precipitation. The dissolution performance in FaSSIF-V2 biorelevant media was similar to dissolution in USP SIF for both HPMCAS -M and -H grades. However, two-fold increase in supersaturation was obtained in cases of HPMCAS -L in biorelevant FaSSIF-V2 media.
Conclusion: Amorphous solid dispersions of itraconazole and HPMCAS -L and -M grades were able to initiate and maintain higher supersaturation as compared to H grade. Results point the more readily available succinoyl group in L and M grades contributing to the better dissolution performance for itraconazole. Overall, dissolution of amorphous solid dispersion was impacted by HPMCAS polymer and was highest for -L followed by -M and lowest for -H grade.
James Polli– Professor and Ralph F. Shangraw/Noxell Endowed Chair in Industrial Pharmacy and Pharmaceutics, University of Maryland School of Pharmacy, Baltimore, Maryland