Category: Formulation and Quality
Purpose: The aim of the study was to investigate the impact of the polymer molecular weight on the drug solubility of powdered, HPC-stabilized nano-suspensions produced by spray drying. Itraconazole (BCS Class II, solubility 1-4 ng/L) was used as a model API in this study.
Methods: Hydroxypropyl cellulose (HPC) with molecular weights 10,000 (NISSO HPC-UL), 40,000 (NISSO HPC-SSL) and 100,000 (NISSO HPC-SL) was provided from Nippon Soda, Japan. Itraconazole (TCI, Germany) was used as a model drug. Planetary ball mill Pulverisette 7 (Fritsch, Germany) provided with 0.3-0.4 mm YTZ® grinding beads (yttrium stabilized ZrO2) was used for the milling process. IR spectrum in KBr tablets (Excalibur FTS 3100, Varian, Germany), SEM (Gemini Ultra 55, Carl Zeiss, Germany) and X-Ray diffractometer (D8 Advance, Bruker, USA) were used for characterization. Mini spray dryer BÜCHI B-290 (BÜCHI, Switzerland) was used to prepare the spray dried suspensions. USP II method (paddle) in simulated gastric fluid (SGF without pepsin) at non-sink conditions was used for drug dissolution testing.
Results: The milling of Itraconazole (ITZ) in presence of HPC in aqueous environment depends on the polymer concentration and milling time. HPC concentrations > 12.5 g/L are necessary to achieve the target particle size of X90,3 < 1.0 µm. Only the ultra-low molecular weight HPC-UL could be used at high concentration (50 g/L) without foam formation. The optimal milling time with all HPC grades was between 90 and 180 min. The spray drying of the itraconazole nano-suspensions produced dry powders with ITZ/HPC ratio of 61.5/38.5 and average particle size of 0.1 µm. The dissolution profiles of the dry nanosuspension containing 100 mg ITZ in simulated gastric fluid (SGF without pepsin, non-sink conditions) revealed a strong dependence on the used HPC molecular weight. The highest dissolution rate was observed with the ultra-low molecular weight HPC-UL followed by SSL and SL (Figure 1). No re-crystallization of the drug during the dissolution test was observed.
Conclusion: With a challenging API as itraconazole, the ultra-low molecular grade HPC-UL demonstrated the highest efficiency as milling adjuvant and super-saturation stabilizer. The nanomilling process of itraconazole in aqueous solution and presence of HPC depends on the polymer concentration and milling time: concentration > 12.5 g/L and milling time > 90 min are necessary to achieve the target particle size of X90,3 < 1.0 µm.