Date of Award
Doctor of Philosophy in Pharmaceutical Sciences
Christopher T. Rhodes
Interaction of beta-cyclodextrin with ampicillin, phenobarbitone, and phenytoin was studied and complexation was observed with all three drugs. Analytical methods for the quantification of these drugs were validated. In order to obtain an inclusion compound in the solid powdered form, a variety of methods (freeze drying, spray drying, kneading, and solvent evaporation) was evaluated. Among these methods freeze drying was the most feasible and reproducible method from a laboratory scale to a pilot scale and to the manufacturing level. Methods using an industrial model freeze drier were developed which resulted in an increase in yield from 53% to more than 90%. However, because of ampicillin instability in freezing conditions, it was not possible to obtain an inclusion compound in the solid powdered form.
Physico-chemical properties of the inclusion complexes were evaluated by a variety of methods such as stability, solubility, X-ray diffractometry, differential scanning calorimetry, infrared and proton magnetic resonance spectroscopies, photomicrographs, etc. The stability of ampicillin in an acidic medium (pH 2.0) was considerably improved by complex formation with beta-cyclodextrin. The observed apparent pseudo-first order rate constants (hr-1) of ampicillin were 1. 8 x 10-2, 1.2 x 10-2, and 1.1 x 10-2 for ratios of .1:0.0 and 1:1.0, 1:0.0 and 1:1.5 and 1:0.0 and 2.0 of ampicillin to beta-cyclodextrin, respectively. Furthermore, it was estimated that the complex degrades nine times slower than the drug itself, and the apparent stability constant was found to be 458.46M-1. Aqueous solubility of phenobarbitone and phenytoin beta-cyclodextrin complexes were five and eleven fold larger than that of phenobarbitone and phenytoin alone, respectively. A phase solubility diagram was constructed and the apparent stability constants were calculated for phenobarbitone and phenytoin beta-cyclodextrin complexes. The calculated stability constants were 4.54 X 10 3M-l and 766M-l for phenobarbitone and phenytoin complexes respectively. Thus, the formation and presence of the inclusion complex were confirmed by stability and solubility analysis. Furthermore, the proton magnetic resonance spectra of phenobarbitone beta-cyclodextrin complex strongly indicated the presence of the inclusion complex in the liquid phase. The mode of interaction and elucidation of the presence of the inclusion complex in the solid phase were studied by X-ray diffraction, differential scanning calorimetry, infrared spectra photomicrographs, etc. The X-ray diffraction spectra and differential scanning calorimetry thermograms clearly suggested the presence of the inclusion complex in the freeze dried material but not in the physical mixture. The infrared spectra and photomicrographs evaluations were such that a definitive, unambiguous interpretation could not be made; however, they were useful to some extent to show the interaction with beta-cyclodextrin.
A solution was prepared from the phenobarbitone beta-cyclodextrin complex. Unlike an official USP preparation, the solution prepared from the complex did not require the addition of alcohol to keep the phenobarbitone in solution. Four months' physical and one month's chemical stability data indicated a considerable potential especially for pediatric use. It was possible to prepare a pharmaceutically elegant suspension from the phenytoin beta-cyclodextrin complex. The suspense on possessed desirable qualities of a pharmaceutically elegant suspension, such as ease of dispersion, high sedimentation volume, etc.; in addition, the suspension had a low viscosity. Physical stability was good even in freezing conditions and a syr ingeability study suggested a potential for intramuscular use.
A flow study was designed using a recording flowmeter with small quantities of material in an attempt to predict the flow rate during large scale operations. The data indicated that the flowmeter was sensitive enough that a small quantity of material could be used to predict the flow rate, effect of formulation and processing variables on production scale quantities. The flow study, and the bulk properties of beta-cyclodextrin suggested that the material was fairly free flowing and compressible. The freeze dried phenytoin beta-cyclodextrin complex lacked flowability and compressibility; neverthless, it was possible to compress tablets of a suitable size and weight using the wet granulation method. All the properties of tablets were measured and found to be within the USP standards. Dissolution studies in different test media strongly suggested that the dissolution rate. for phenytoin beta-cyclodextrin complex tablets was superior to all other phenytoin formulations or preparations. Furthermore, due to in situ complexation in the dissolution medium, the dissolution rate of the physical mixture of the freeze dried phenytoin and beta-cyclodextrin was found to be similar to the dissolution rate of the freeze dried complex.
Hegde, Ramachandra P., "DRUG- CYCLODEXTRIN INCLUSION COMPOUNDS. STUDIES OF THE FORMULATION OF PHARMACEUTICAL PRODUCTS CONTAINING CYCLODEXTRINS." (1985). Open Access Dissertations. Paper 174.