Method for evaluating the solubility of a crystalline substance in a polymer
View Patent ↗A viable strategy to enhance the bioavailability of poorly soluble drugs is to use amorphous solids in place of the more commonly used crystalline solids in pharmaceutical formulations. However, amorphous solids are physically meta-stable and tend to revert back to their crystalline counterpart. An effective approach to stabilizing an amorphous drug against crystallization is to disperse it in a polymer matrix. The drug's solubility in the chosen polymer defines the upper limit of drug loading without any risk of crystallization. Measuring the solubility of a drug in a polymer has been a scientific and technological challenge because the high viscosity of polymers makes achieving solubility equilibrium difficult and because pharmaceutically important drug/polymer dispersions are glasses, which undergo structural relaxation over time. The invention provides a method based on Differential Scanning calorimetry (DSC) for measuring the solubility of crystalline drugs in polymeric matrices. The method relies on the detection of the dissolution endpoint of a drug/polymer mixture prepared by cryomilling.
1. A method for evaluating the solubility of a crystalline substance in a polymer, comprising
a) providing an intimate non-amorphous mixture of the crystalline substance and the polymer,
b) heating the intimate non-amorphous mixture while recording the DSC dissolution endotherm of the mixture,
c) determining an endset temperature of dissolution T end from the DSC dissolution endotherm,
d) taking T end as the temperature at which the crystalline substance dissolves completely in the polymer.
2. The method of claim 1 , wherein the intimate non-amorphous mixture is obtained by joint cryo-milling of the crystalline substance and the polymer.
3. The method of claim 1 , comprising recording the DSC dissolution endotherm at a plurality of heating rates and extrapolating T end to zero heating rate.
4. A method for evaluating the solubility of a crystalline substance in a polymer as a function of temperature, comprising
a) providing a plurality of intimate non-amorphous mixtures of crystalline substance and polymer having different compositions,
b) determining T end of each of the intimate non-amorphous mixtures by the method of claim 1 ,
c) plotting T end over the composition of the mixtures.
5. A method for evaluating the solubility of a crystalline substance in a polymer at the glass transition temperature Tg, comprising
a) establishing the solubility of the crystalline substance in the polymer as a function of temperature by the method of claim 4 ,
b) providing a plurality of crystalline substance and polymer non-amorphous mixtures having different compositions and determining Tg of a liquid formed by melting each of the non-amorphous mixtures,
c) plotting Tg over the composition of the non-amorphous mixtures, d) determining the solubility at Tg as the intersection of the T end plot and the Tg plot.
6. The method of claim 5 , wherein Tg is determined by a DSC method.
7. The method of claim 5 , wherein the crystalline substance is a pharmaceutically active ingredient.
8. The method of claim 1 , wherein the intimate non-amorphous mixture of the crystalline substance and the polymer is a powder mixture.