Solubility estimation and rapid structural characterization of small molecule drugs in polymers

Amorphous solid dispersions are known to enhance solubility of poorly aqueous-soluble drugs and subsequently improve their bioavailability. However, this formulation strategy is limited due to the physical instability of amorphous form arising from its crystallization. It is important to assess the drug solubility in the polymeric carrier at a relatively low temperature to allow it would not crystallize out of the solid dispersion at certain storage temperature. The routine industry methods indirectly determine the drug solubility in the polymer in solid state. An accurate estimation of a drug compound solubility in the polymer will provide its maximum drug loading when designing an amorphous solid dispersion formulation without concerns of re-crystallization. A mixed solvent method was established based on co-solvency models, where the degree of polymerization can be quantitatively treated as a deviation from ideal mixing behavior. In our approach, a low-molecule analogue, N-ethyl-2-pyrrolidone (NEP) and three grades of poly(vinylpyrrolidone) (PVP) were investigated as the mixed solvent. The solubility of several pharmaceutical model compounds was determined by conventional assay method – high performance liquid chromatography (HPLC). The mixed solvent approach provides an athermal mixture suitable for analysis based on co-solvency log linear models. The solubility profiles as a function of polymer concentration of the model drugs fall into two distinct categories. One of very high initial solubility that remains high even as the degree of polymerization in the solvent mixture increases. The other of low initial solubility that falls very sharply as the degree of polymerization increases. The solubilization profile provides a strong indicator of the suitability of an API to produce an amorphous dispersion of acceptable stability. The high solubility group is populated by compounds that produce relatively stable dispersions (ritonavir). The second group is populated by drugs that cannot produce stable dispersions at pharmaceutically meaningful drug loads. Even though experimentally more elaborate than traditional HPLC, the assay method employed here can be readily implemented in a typical analytical laboratory. Structural characterization by synchrotron x-ray at the Advanced Photon Source of Argonne National Laboratory was applied to the generation process of a variety of drugs with detailed in-situ measurements. Amorphous and nanocrystalline pharmaceutical compounds and solid dispersions were generated from evaporating the supersaturated solutions containerlessly by acoustic levitation. This technology provides a fast screening method for selecting polymers that best stabilize a solid dispersion, especially for the investigation of spray drying process. Finally, a case study of efavirenz amorphous solid dispersion was included as an example of achieving dose reduction by this formulation strategy. Polymers selection was based on both synchrotron x-ray results and traditional powder x-ray diffraction. A final formulation of efavirenz HPMC-AS (1:1) with 5% Span 80 amorphous solid dispersion showed promising dissolution enhancement and is potentially able to reduce the dosage from 600 mg to 509 mg