TY - JOUR
T1 - Implications of phase solubility/miscibility and drug-rich phase formation on the performance of co-amorphous materials
T2 - The case of Darunavir co-amorphous materials with Ritonavir and Indomethacin as co-formers
AU - Shete, Sushant
AU - Reddy, Sai Charan
AU - Lakshman, Yarlagadda Dani
AU - Vullendula, Sai Krishna Anand
AU - Mehta, Chetan Hasmukh
AU - Nayak, Usha Yogendra
AU - Dengale, Swapnil
N1 - Funding Information:
The authors would want to thank Manipal College of Pharmaceutical Sciences (MCOPS), Manipal Academy of Higher Education (MAHE) for providing the research infrastructure to execute the project. Further, the kind help of Dr. Lalit Kumar, Assistant Professor-selection grade, MCOPS in recording AT-FTIR spectra is also acknowledged.
Publisher Copyright:
© 2021 Elsevier B.V.
PY - 2021/10/25
Y1 - 2021/10/25
N2 - The present study was designed to investigate the contribution of solid-state and the impact of composite drug-rich phase generated as a consequence of pH shift on the maximum achievable supersaturation of co-amorphous formulations. The co-amorphous phases of weak base-weak base-pair i.e. Ritonavir and Darunavir were prepared in anticipation of studying the effect of drug-rich phase consequent to pH shift. While the co-amorphous phases of weak base-Weak acid pair i.e. Darunavir and Indomethacin were studied to understand the manifestation of the solid-state drug: co-former miscibility in the absence of drug rich phase. Thermodynamically, the lowering of the supersaturation was found commensurate with the mole fraction of the respective component (Drug/Co-former) within the co-amorphous materials for both Darunavir: Ritonavir and Darunavir: Indomethacin pair. Kinetically, for Darunavir: Ritonavir co-amorphous materials, the shift in the pH from acidic to the neutral side led to the generation of drug-rich phase and subsequent LLPS. The free drug concentration achieved in the bulk of the solution was found dependent upon the mole fraction of the respective component within the drug-rich phase. The relative mole fraction of each component within the composite drug-rich phase is dictated by pH-dependent solubility and molecular weight of the individual components.
AB - The present study was designed to investigate the contribution of solid-state and the impact of composite drug-rich phase generated as a consequence of pH shift on the maximum achievable supersaturation of co-amorphous formulations. The co-amorphous phases of weak base-weak base-pair i.e. Ritonavir and Darunavir were prepared in anticipation of studying the effect of drug-rich phase consequent to pH shift. While the co-amorphous phases of weak base-Weak acid pair i.e. Darunavir and Indomethacin were studied to understand the manifestation of the solid-state drug: co-former miscibility in the absence of drug rich phase. Thermodynamically, the lowering of the supersaturation was found commensurate with the mole fraction of the respective component (Drug/Co-former) within the co-amorphous materials for both Darunavir: Ritonavir and Darunavir: Indomethacin pair. Kinetically, for Darunavir: Ritonavir co-amorphous materials, the shift in the pH from acidic to the neutral side led to the generation of drug-rich phase and subsequent LLPS. The free drug concentration achieved in the bulk of the solution was found dependent upon the mole fraction of the respective component within the drug-rich phase. The relative mole fraction of each component within the composite drug-rich phase is dictated by pH-dependent solubility and molecular weight of the individual components.
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U2 - 10.1016/j.ijpharm.2021.121119
DO - 10.1016/j.ijpharm.2021.121119
M3 - Article
AN - SCOPUS:85115978174
SN - 0378-5173
VL - 608
JO - International Journal of Pharmaceutics
JF - International Journal of Pharmaceutics
M1 - 121119
ER -