Solubilizing Temperature of Crystalline Drug in Polymer Carrier: A Rheological Investigation on a Posaconazole-Copovidone System with Low Drug Load

Eur J Pharm Biopharm. 2021 Apr 22:S0939-6411(21)00107-7. doi: 10.1016/j.ejpb.2021.04.015. Online ahead of print.


Measuring the solubility of a crystalline active pharmaceutical ingredient (API) in a polymer-rich system is challenging due to the high viscosity of the polymer which kinetically impedes reaching the solubility equilibrium. In this study, a rheological approach of determining the solubilizing temperature of a crystalline API in a polymeric carrier has been developed. To validate the method, a model physical mixture of crystalline posaconazole and copovidone with a relatively low API load (25wt%) was utilized. First, a comparison between conventional differential scanning calorimetry (DSC) and a rheological temperature ramp was conducted to illustrate that the rheological method could capture the melting point depression behavior similarly to the more well-known DSC technique. Second, to further understand the dissolution process of the crystalline posaconazole into the copovidone carrier and precisely measure the solubilizing temperature, a series of isothermal rheological time sweeps were carried out at various temperatures selected based on the rheological temperature sweep. Because the dissolved API molecule imparted a plasticizing effect to the polymeric carrier, the complex viscosity of the API-polymer system decreased gradually over time and correlated well to an exponential decay function. Moreover, dependent on the applied temperature, the API-polymer system eventually accomplished distinct equilibrium states (complex viscosities) within different time frames. The obtained time constants at different temperatures were fitted to the Arrhenius equation, allowing the determination of the activation energy of the mixing process. The results indicated that once the processing temperature exceeded a critical point below the melting point of the crystalline API, the API-polymer solubilization process switched from a surface dominated dispersive mechanism to a molecular-level solubilization mode, manifested by the significantly increased activation energy. To the best of our knowledge, the currently developed rheological approach was the first successful measurement of the solubilizing temperature of a crystalline drug in a polymer-rich system.

PMID:33895292 | DOI:10.1016/j.ejpb.2021.04.015