Investigation of solid-state stability of selected bioactive compounds

Wei Xu, Purdue University

Abstract

Chemical stability is a critical issue in the drug development process. Since a vast majority of drug products are administered as solid dosage forms, understanding the molecular details of a solid-state reaction becomes very important to the pharmaceutical industry. The following thesis describes the studies of two common solid-state degradation reactions. The first study investigates the UV-induced oxidation of small methionine-containing peptides in the solid state. scDL-Ala- scDL-Met, N-formyl-Met-Leu-Phe methyl ester, and Met-Enkephalin acetate salt were chosen as models to examine the effect of sample crystallinity and moisture on a solid-gas reaction. This study shows that the amorphous forms are more susceptible to methionine oxidation than the corresponding crystalline forms. A correlation between reactivity and the looseness of molecular packing is indicated. Additionally, this study shows that moisture can influence the oxidation rate by inducing physical changes in the solid sample. The second study investigates the solid-state cyclization of two model N-carboxyalkyl dipeptide ACE inhibitors--spirapril hydrochloride and quinapril hydrochloride. The temperature dependence of the cyclization rate of the crystalline and amorphous forms of the compounds was examined. The cyclization rates of the amorphous forms with different water contents were also measured. This study shows that: (1) amorphous forms are more reactive and have a lower activation energy than their crystalline counterparts; and (2) increasing the water content lowers the glass transition temperature of the amorphous forms and accelerates the reaction. The results indicate the importance of molecular mobility in this solid-state intramolecular reaction. $\sp{13}$C solid-state NMR is also exploited in this study to investigate mobility in the model compounds and to further examine the relationship between mobility and reactivity. A preliminary study utilizing a combination of pulse techniques indicates different mobility in the phenyl ring between the crystalline and amorphous forms. Variable temperature $\sp{13}$C $T\sb1$ measurements were performed to probe large amplitude motion near the reaction site, and a correlation between glass transition and MHz frequency motion is indicated.

Degree

Ph.D.

Advisors

Byrn, Purdue University.

Subject Area

Pharmacology

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