Cyclosporine A: Solubilization, solid dispersion and solid -state transformation

Yunlong Zhou, Purdue University

Abstract

The objective of this research was to explore two formulation strategies—hydrotropic solubilization and solid dispersion—for poorly water soluble drugs using cyclosporine A (CyA) as a model compound and to characterize several crystal forms of CyA. Using nicotinamide as the hydrotropic agent and a phase solubility technique, the present study showed that hydrotropic solubilization of large, nonaromatic compounds such as CyA is possible. In 4.5 M nicotinamide the solubility of CyA was increased almost 500-fold as compared to that in water. Moreover, it was proposed from the log-linear solubilization profiles displayed by CyA in the presence of nicotinamide that cosolvency was the mechanism responsible for the solubilization. The second part focused on solid dispersion technology, using the dispersion of CyA in d-α-tocopherol polyethylene glycol 1000 succinate (TPGS). By following the dissolution rates of both CyA and TPGS, it was determined that the dissolution of the dispersion was primarily controlled by the swell-erosion of TPGS and to a lesser extent by CyA through an osmotic stress in the gel layer. Secondly, the TPGS/CyA dispersion was found to be unstable and CyA undergoes recrystallization in the dispersion. A stabilized dispersion was developed by incorporating PEG 4600 into TPGS at a 10% level. The treatment has resulted in a dispersion that was stable after 16 weeks of storage at room temperature. The third part of the study focused on characterizing the various crystal forms of CyA using PXRD, thermal analysis and moisture adsorption techniques. It was determined that CyA exists in five modifications: form I (anhydrate, mp 109°C, heat of fusion 2.65 kJ mol−1 ), form II (variable hydrate with maximum hydration level of one), form III (monohydrate), form IV (dehydrated hydrate of form II, mp 175°C, heat of fusion 52.3 kJ mol−1), form V (dehydrated hydrate of form III, mp 127°C, heat of fusion 1.0 IV mol−1). Under normal condition, both forms IV and V transform into forms II and III, respectively. Forms I and V are enantiotropically related whereas form N is monotropically related to both forms I and V.

Degree

Ph.D.

Advisors

Kildsig, Purdue University.

Subject Area

Pharmaceuticals

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