Samra, Raya M.; (2003) Characterization of terfenadine as a model of a hydrophobic amorphous form of a drug and preparation and characterization of some of its derivatives. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Terfenadine was used as a model hydrophobic drug from which an amorphous form was prepared by melting followed by slow or quench-cooling. It was not possible to crystallize amorphous terfenadine at elevated RH either in the isothermal microcalorimeter or the Dynamic Vapour Sorption apparatus. Amorphous terfenadine samples crystallized completely in 95 % ethanol in the DVS. SEM showed crystallization to start at pores and/or cracks on the surface of the amorphous beads with enlargement of the pores during crystallization resulting in diffusion of more organic vapours and complete crystallization. Long term storage at elevated RH (up to 2 years) resulted in slow crystallization. This was followed by crystallization of the remainder amorphous content by use of a mixture of organic liquids in the isothermal microcalorimeter. Crystallization rates over these storage periods were slow with linear regression analysis showing that very long timeis needed for complete crystallization. SEM showed that crystallization starts at cracks and/or pores on the surface of the beads while sealing the pores with crystalline material once crystallization started. This limited the access of water and prevented further crystallization of the samples. Homologous salts of terfenadine were prepared by reacting terfenadine (basic drug) with a series of dicarboxylic acids. The salts were proven to be ammonium salts of terfenadine reacting in equimolar ratio (1 mole of terfenadine: 1 mole of dicarboxylic acid). Terfenadine oxalate, succinate and glutarate were found to be hydrates. These hydrates collapsed into their amorphous forms after prolonged drying under vacuum. Amorphous forms of the terfenadine salts were prepared by melting and slow cooling. The amorphous forms showed a decrease in Tg going from the oxalate to the adipate salt. Amorphous terfenadine glutarate did not crystallize in the presence of either humidity or ethanol while terfenadine adipate crystallized in the presence of ethanol in the DVS. The results show an agreement with Tm/Tg ratios where lower Tm/Tg ratios suggest lower crystallization potential. Solubility of amorphous and crystalline forms of terfenadine and its salts at pH 2 and pH 6 was investigated. The amorphous forms showed higher apparent solubility than their crystalline counterparts. The interesting thing was that an increase in solubility accompanied an increase in physical stability of the amorphous forms. This observation indicated the possibility of enhancing the physical stability of a compound while at the same time enhancing the rate and/or extent of solution through the preparation of salts with the correct Tm/Tg ratio.

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