Solubility of Small-Molecule Crystals in Polymers: d-Mannitol in PVP, Indomethacin in PVP/VA, and Nifedipine in PVP/VA

Abstract

A DSC method was developed for measuring the solubility of crystalline drugs in polymers. Cryomilling the components prior to DSC analysis improved the uniformity of the mixtures and facilitated the determination of dissolution endpoints. This method has the potential of providing useful data for designing physically stable formulations of amorphous drugs.

Physical stability of solid dispersions with respect to thermodynamic solubility of tadalafil in PVP-VA

“…Utilization of solid dispersions instead of physical mixtures in the evaluation of drug-polymer solubility is one of the features that distinguishes this method from other commonly used, based on melting point depression [18,17]. However, the applicability of this approach depends strongly on the type of a solid dispersion which must reveal an amorphous and supersaturated character and good miscibility between components at the molecular level.…”

“…4). Thus, thermal degradation of Td and PVP-VA, even at a heating rate of 10 °C/min, prevents the use of conventional methods for solubility assessment, which requires reliable measurements of the melting events of the drug [13,18,17]. …”

“…While conventional methods employed to determine solubility of drugs in polymer typically use slow heating rates [18,17] to attain solubility equilibrium as close as practically achievable, this is not always possible especially when the drug (or polymer) is known to thermally decompose. On the other hand, by applying fast heating rates decomposition upon/after melting can be diminished or eliminated [14].…”

“…Apart from thermal degradation, the biggest drawback of this method is the risk of solubility underestimation caused by low molecular mobility in a viscous polymer and an inadequate shift of the endotherm. Modifications involving initial milling of physical mixtures, annealing and different heating rates improve the protocol but significantly extend the analysis [18,17].…”

Molecular Modeling as a Predictive Tool for the Development of Solid Dispersions

“…The interactions between small molecule drugs and polymers in a polymeric matrix system determines the nature of the drug loading inside the polymer matrix, such as oversaturated or under saturated, thus play a vital role in determining the long-term stability of the formulated product. Therefore, the characterisation and prediction of drug-polymer miscibility and more importantly drug solubility at various conditions has become an emerging topic in pharmaceutical research for the development of solid dispersions [1][2][3] . The dispersion of a small drug molecule being miscible into a polymer matrix is mechanistically a complex process.…”