Study on the Mechanism Responsible for the Incompatibility of Enalapril Maleate with Sodium Starch Glycolate

Merel Rachel Bout; Herman Vromans

doi:10.1016/j.xphs.2020.11.037

Study on the Mechanism Responsible for the Incompatibility of Enalapril Maleate with Sodium Starch Glycolate

J Pharm Sci. 2021 May;110(5):2074-2082. doi: 10.1016/j.xphs.2020.11.037. Epub 2020 Dec 8.

Authors

Merel Rachel Bout¹, Herman Vromans²

Affiliations

¹ Research and Development Department, Tiofarma B.V., Hermanus Boerhaavestraat 1, 3261 ME Oud-Beijerland, the Netherlands. Electronic address: mbout@tiofarma.nl.
² Research and Development Department, Tiofarma B.V., Hermanus Boerhaavestraat 1, 3261 ME Oud-Beijerland, the Netherlands; Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, the Netherlands.

PMID: 33307043
DOI: 10.1016/j.xphs.2020.11.037

Abstract

Enalapril maleate (EM) is known to suffer from incompatibilities in the solid state. This study investigates the destabilizing effect of sodium starch glycolate (SSG) on EM. This was done by varying the mixing ratio and moisture content of binary mixtures. Differential scanning calorimetry and microscopy show a loss of crystallinity of EM at the contact surface with SSG. It is shown that this is followed by decomposition of E to diketopiperazine (DKP). These phenomena are modulated by moisture. The environmental pH turned out to be crucial; when the zwitterion is formed at the appropriate pH, ring closure into DKP is promoted.

Keywords: Diketopiperazine; Drug-excipient interaction; Enalapril maleate; Physicochemical properties; Sodium starch glycolate; Solid-state stability.

MeSH terms

Calorimetry, Differential Scanning
Diketopiperazines
Enalapril*
Starch* / analogs & derivatives

Substances

Diketopiperazines
Enalapril
Starch
sodium starch glycolate