Crosslinking: An avenue to develop stable amorphous solid dispersion with high drug loading and tailored physical stability

• Published in: Journal of controlled release 2019-10, Vol.311-312, p.212-224
• Main Authors: Sahoo, Anasuya, Kumar, N.S. Krishna, Suryanarayanan, Raj
• Format: Article
• Language: English
• Subjects: Amorphous solid dispersion (ASD); Crosslinking; High drug loading (95% w/w); Molecular mobility; Tailored physical stability; Viscosity
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2019.09.007

Influence of crosslinking (crosslinker concentration and crosslinking condition) on molecular mobility and physical stability of ketoconazole (KTZ) solid dispersions was investigated over a wide temperature range in the supercooled state. Amorphous solid dispersions (ASDs) with very high drug loading (95% w/w) were prepared by thermal crosslinking. As the crosslinker concentration increased (from 0.25–1.0% w/w), there was a progressive decrease in molecular mobility as evident from both the longer α-relaxation time, and higher viscosity values. Consequently, there was progressive enhancement in physical stability (crystallization inhibition). At 1.0% w/w crosslinker concentration, when compared with the drug alone, there was ~4 orders of magnitude increase in both viscosity and α-relaxation times. Elevating the crosslinking temperature, by increasing the crosslinking density, provided a second avenue to enhance physical stability. Hence, crosslinking density offers a simple method to enhance physical stability and control drug release. We have formulated ASDs: (i) with very high drug loading (95% w/w), and (ii) pronounced stability even when exposed to elevated temperatures and water vapor pressure. Also, during dissolution study, the degree of supersaturation in the dissolution medium generated by the crosslinked systems gradually increased and maintained the supersaturation for a longer period. A series of amorphous solid dispersions (ASDs) were designed and formulated (i) with very high drug loading (95% w/w), and (ii) pronounced stability even under “harsh” conditions (no crystallization when heated to 170 °C or when stored at 90% RH/25 °C). The ASDS showed a prolonged supersaturation compared to amorphous drug. Unlike chemical crosslinking, in our approach, amorphous solid dispersions (ASDs) were prepared by thermal crosslinking. Hence, ASDs with 95% drug loading whereas in chemical crosslinking the drug loading is limited to ~30%. [Display omitted] •Stable amorphous solid dispersions with exceptionally high drug loading (95% w/w)•Mechanism of stabilization discerned from molecular mobility measurement.•Crosslinking density provides an avenue to modulate physical stability.•Crosslinker concentration and reaction temperature modulate crosslinking density.•Ability to avoid rapid attainment of supersaturation