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Crystal nucleation of poorly soluble drugs in aqueous solutionsLennart Lindfors, Preformulation/Experimental Formulation, AstraZeneca R&D Mölndal, Sweden A significant proportion of drugs on the market are poorly soluble in water and it is expected that this will be even more pronounced in the future. Formulations of poorly water-soluble compounds offers a challenge to the formulation scientist, from the early discovery phase through the development to the launch of the pharmaceutical product. In formulations of poorly soluble compounds drug particle size are often reduced in order to facilitate drug dissolution. An interesting alternative are formulations where the API are in metastable state, for example in solid dispersions or when a salt of the API is used. The metastability offers an increased driving force for drug absorption. However, for the same reason crystallization to a less soluble state may occur. In the presentation crystallization of a model compound, bicalutamide, in the absence and presence of a polymer polyvinylpyrrolidone (PVP) will be discussed. Results showed that PVP decreased the crystallization rate significantly in a system with PVP concentrations as low as 0.01 %(w/w), without changing the polymorph formed. Furthermore, in experiments designed to specifically study crystal nucleation, the same nucleation rate was found in the absence and presence of PVP. Instead, PVP adsorbs to the crystals formed in solution and by doing so, the crystal growth rate is reduced. This was confirmed in separate experiments using bicalutamide nanocrystals. By combining theories describing classical nucleation and crystal growth, with some modifications, a consistent description of several independent experiments performed in polymer-free systems was obtained. From these experiments a crystal-water interfacial tension of 22.1 mN/m was extracted. The interfacial tension of other crystalline organic solids in water was also analysed and shown to be high in general for poorly soluble compounds and proportional to the logarithm of the solubility. |
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