Variable-Temperature NMR Analysis of the Thermodynamics of Polymer Partitioning between Aqueous and Drug-Rich Phases and Its Significance for Amorphous Formulations.
Mol Pharm
; 19(1): 100-114, 2022 01 03.
Article
en En
| MEDLINE
| ID: mdl-34702040
ABSTRACT
We previously reported that the polymers used in amorphous solid dispersion (ASD) formulations, such as polyvinylpyrrolidone (PVP), polyvinylpyrrolidone/vinyl acetate (PVP-VA), and hypromellose (HPMC), distribute into the drug-rich phase of ibuprofen (IBP) formed by liquid-liquid phase separation, resulting in a reduction in the maximum drug supersaturation in the aqueous phase. Herein, the mechanism underlying the partitioning of the polymer into the drug-rich phase was investigated from a thermodynamic perspective. The dissolved IBP concentration in the aqueous phase and the amount of polymer distributed into the IBP-rich phase were quantitatively analyzed in IBP-supersaturated solutions containing different polymers using variable-temperature solution-state nuclear magnetic resonance (NMR) spectroscopy. The polymer weight ratio in the IBP-rich phase increased at higher temperatures, leading to a more notable reduction of IBP amorphous solubility. Among the polymers, the amorphous solubility reduction was the greatest for the PVP-VA solution at lower temperatures, while HPMC reduced the amorphous solubility to the greatest extent at higher temperatures. The change in the order of polymer impact on the amorphous solubility resulted from the differences in the temperature dependency of polymer partitioning. The van't Hoff plot of the polymer partition coefficient revealed that both enthalpy and entropy changes for polymer transfer into the IBP-rich phase from the aqueous phase (ΔHaqueousâIBP-rich and ΔSaqueousâIBP-rich) gave positive values for most of the measured temperature range, indicating that polymer partitioning into the IBP-rich phase was an endothermic but entropically favorable process. The polymer transfer into the IBP-rich phase was more endothermic for HPMC than for PVP and PVP-VA. The solid-state NMR analysis of the IBP/polymer ASD implied that the newly formed IBP/polymer interactions in the IBP-rich phase upon polymer incorporation were weaker for HPMC, providing a rationale for the larger positive transfer enthalpy for HPMC. The change in Gibbs free energy for polymer transfer (ΔGaqueousâIBP-rich) showed negative values across the experimental temperature range, decreasing with an increase in temperature, indicating that the distribution of the polymer into the IBP-rich phase is favored at higher temperatures. Moreover, ΔGaqueousâIBP-rich for HPMC showed the greatest decrease with the temperature, likely reflecting the temperature-induced dehydration of HPMC in the aqueous phase. This study contributes fundamental insights into the phenomenon of polymer partitioning into drug-rich phases, furthering the understanding of achievable supersaturation levels and ultimately providing information on polymer selection for ASD formulations.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Polímeros
/
Espectroscopía de Resonancia Magnética
/
Composición de Medicamentos
Idioma:
En
Revista:
Mol Pharm
Asunto de la revista:
BIOLOGIA MOLECULAR
/
FARMACIA
/
FARMACOLOGIA
Año:
2022
Tipo del documento:
Article
País de afiliación:
Japón