Solid-state investigations of crystalline and amorphous lisinopril and stabilization of amorphous lisinopril and quinapril hydrochloride
Abstract
Chemical stability of drug substances in the solid state is critical to the efficacy and safety of the solid dosage forms. Different forms of a solid drug may differ in chemical stability. For drugs in the amorphous state the chemical instability is often a major concern and may override the benefits of the amorphous state, which include enhanced solubility, faster dissolution, and better bioavailability. In the current research, emphasis is placed upon studying the controlling factors for the chemical stability of the selected amorphous dipeptide angiotensin-converting enzyme (ACE) inhibitors, which leads to the development of the stabilization strategies. In addition, many large peptides and proteins exist in the amorphous form in the solid state. The study may also provide insight into how to stabilize the large peptides and proteins against chemical instability. Amorphous lisinopril is much less stable than its crystalline counterpart. The temperature-dependence of the reactivity of the amorphous lisinopril correlates very well with that of the structural relaxation time. Moisture plasticizes the amorphous form and significantly decreases the chemical stability. In addition, amorphous lisinopril, with a higher Tg, shows better chemical stability than structurally similar compounds (e.g. quinapril hydrochloride and spirapril hydrochloride). We conclude that the Tg and the structural-relaxation time are closely related to the chemical stability of amorphous lisinopril. The chemical stability of amorphous lisinopril and quinapril hydrochloride is improved by preparing the binary amorphous molecular mixtures (solid molecular dispersions) with certain excipients. PVP, which has only proton acceptors for H-bonding, destabilizes amorphous lisinopril but stabilizes amorphous quinapril HCl. On the other hand, dextrans and trehalose, which have both proton acceptors and donors, were found to stabilize amorphous lisinopril. Glass transition temperature does not correlate with the chemical stability of the drugs in their binary amorphous mixtures with the excipients. Specific molecular interactions (H-bonding) between the drugs and excipients have to be considered. It is postulated that the local mobility relevant to the cyclization reaction is more important than the bulk mobility to the chemical stability of the compounds. In addition, six other crystalline forms of lisinopril besides the dihydrate are characterized in this research.
Degree
Ph.D.
Advisors
Byrn, Purdue University.
Subject Area
Pharmacology
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