Purpose: Re-crystallization of amorphous drug is one of the biggest risks on physical instability in amorphous solid dispersions (ASD), which may negatively affect solubility, dissolution and bioavailability. Purpose of this work was to assess the impact of level of crystallinity on dissolution of amorphous solid dispersions by engineering ASD samples.
Methods: Amorphous solid dispersions of itraconazole (ITR) and hypromellose acetyl succinate (AFFINISOL™ HPMCAS 716G, Dow Chemical Company) in 1:3 ratio of drug:polymer, were prepared by hot melt extrusion (HME) using a twin-screw extruder (Pharma 11, Thermo Fisher). The HME process was carried out at 3-7g/min feed rate, 100 rpm screw speed and 170°C target process temperature. The extrudates were air-cooled, pelletized and milled into powder using 500 µm screen (ZM 200, Retsch).
Physical Mixture (PM) of crystalline itraconazole and AFFINISOL™ 716G were prepared, also in 1:3 ratio of drug:polymer, through simple blending. Samples containing different levels of crystallinity were engineered by blending PM and ASD in different ratios (Table 1). All samples were characterized using powder X-ray diffraction (XRD) and thermal analysis (differential scanning calorimetry, DSC). Dissolution behavior of all the samples in 1000 mL of phosphate buffer pH 6.8 at 37°C, with USP apparatus II at 75 rpm, were evaluated. Aliquots were evaluated spectrophotometrically at 257 nm.
Results: XRD and DSC were not able to detect crystallinity in engineered samples C, D, E and F due to low levels in the samples and sensitivity of the equipment. However, Sample F showed two glass transition (Tg) events in DSC. First Tg corresponded to itraconazole and second Tg represented the ASD. Dissolution results demonstrated reduction in release rate for first 30 minutes. Incorporation of 5% (sample D), 10% (sample E) and 20% (sample F) crystalline API in the engineered samples resulted in equivalent percentage reduction in drug release (Figure 1).
Conclusion: XRD and DSC were not able to detect crystallinity in engineered samples C, D, E and F due to low levels in the samples and sensitivity of the equipment. However, Sample F showed two glass transition (Tg) events in DSC. First Tg corresponded to itraconazole and second Tg represented the ASD. Dissolution results demonstrated reduction in release rate for first 30 minutes. Incorporation of 5% (sample D), 10% (sample E) and 20% (sample F) crystalline API in the engineered samples resulted in equivalent percentage reduction in drug release (Figure 1).
Manish Rane
– Product Development Manager, Colorcon Inc, HARLEYSVILLEManjeet Pimparade
– Research Scientist, Colorcon, Inc.Lawrence Martin
– Senior Research Scientist, Colorcon, Inc., HARLEYSVILLE, PennsylvaniaAli Rajabi-Siahboomi
– CSO and VP Technical, Colorcon, Inc., Harleysville, PennsylvaniaAli Rajabi-Siahboomi
– CSO and VP Technical, Colorcon, Inc., Harleysville, PennsylvaniaManish Rane
– Product Development Manager, Colorcon Inc, HARLEYSVILLE288 Views