Spherical Crystallization for Lean Solid-Dose Manufacturing by Initial Solvent Screening: The Study of Phenylbutazone

Drug discovery and development process was a long and expensive process. The average cost for a drug from laboratory to market was about USD 500 to USD 880 million and it takes ten to fifteen years to complete the whole process. In this thesis, the final target was to establish fast, convenient and systematic method to improve the efficiency, and money-saving for scale up in drug development stage. Firstly, a useful engineering data bank of solubility, polymorphism, crystallinity, crystal habit and Form Space by solvent screening for phenylbutazone would be established and a robust, miniature solvent screening method would be introduced. In the meantime, the new polymorph, Form F, was discovered in the crystals precipitated in n-butyl alcohol and benzyl alcohol by temperature cooling respectively. Secondly, the study of phenylbutazone in spherical crystallization for lean solid manufacturing was carried out through 136 solvent combinations derived from the Form Space. A successful solvent combination giving the best yield, sphericity, and friability for scale-up in the pharmaceutical industry was acetonitrile-water-n-heptane. Besides, with spherical crystallization, Form E was produced in a fast, energy saving and easy way compared with literatures. Phenylbutazone was chosen as the active pharmaceutical ingredient (API) because of the abundance in literatures about the characterization of phenylbutazone and its polymorphs. By the initial solvent screening methods in this thesis could also be applied to some other APIs or drug candidates or simple organic materials.