Byrne, Jonathan and Wyraz, Anke and Velasco-Torrijos, Trinidad and Reinhardt, Robert (2016) Formulation factors affecting the isomerization rate of betamethasone-17-valerate in a developmental hydrophilic cream – a HPLC and microscopy based stability study. Pharmaceutical Development and Technology, 22 (4). pp. 537-544. ISSN 1097-9867

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Abstract

The formulation of betamethasone-17-valerate (BV) into topical medicines presents a significant challenge for the formulation chemist. The substance is susceptible to acid and base catalyzed isomerization in aqueous environments, which results in valerate transesterification from carbon 17 to carbon 21 of the steroid ring system. This acyl migration process is of significant clinical importance since the 21-valerate ester possesses only a fraction of the potency of the 17-valerate parent compound. Isomerization of BV should therefore be reduced to a minimum through design of a suitable drug vehicle. In this study, the effect of varying the concentration of several excipient components on the isomerization rate of betamethasone valerate in a model hydrophilic cream has been investigated. These excipients include the emulsifier macrogolstearylether-20/21, the co-emulsifier cetylstearyl alcohol and the thickening agent hydroxyl propyl methylcellulose. Additionally, the influence of pH, the presence of the antioxidant, alpha-tocopherol, as well as the chelating agent, disodium edetate, on the stability of the formulation have been investigated. Trial drug product formulations, which were designed to investigate the influence of the above-mentioned components/parameters were manufactured and their stability was tested according to current ICH Guidelines. The content, purity and crystalline structure of the active substance in these formulations was analyzed by a combination of HPLC and microscopy techniques. The study demonstrates that the rate of isomerization of betamethasone valerate depends significantly on the concentration of emulsifier used in the cream formulation. At higher concentrations of emulsifier the isomerization proceeds rapidly with significant degradation over a period of weeks, whereas at lower concentrations significant degradation may not be observed, even after several years’ storage. The influence of the emulsifier has been shown to be independent of the pH value of the aqueous phase of the cream. These findings have not been reported in previous literature reports on this topic, which have tended to focus on the influence of pH. The results are likely to be of interest to pharmaceutical chemists working on the formulation of glucocorticoids as well as to local- and hospital pharmacists who carry out the practice of dilution of proprietary corticoid preparations, where the choice of diluent is likely to be critical for ensuring the stability of the diluted product.

Item Type:	Article
Additional Information:	Cite as: Jonathan Byrne, Anke Wyraz, Trinidad Velasco-Torrijos & Robert Reinhardt (2017) Formulation factors affecting the isomerization rate of betamethasone-17-valerate in a developmental hydrophilic cream – a HPLC and microscopy based stability study, Pharmaceutical Development and Technology, 22:4, 537-544, DOI: 10.3109/10837450.2016.1143003
Keywords:	Chromatography; corticosteroid; emulsifier; isomerization; pH; topical formulation;
Academic Unit:	Faculty of Science and Engineering > Chemistry
Item ID:	10738
Identification Number:	https://doi.org/10.3109/10837450.2016.1143003
Depositing User:	Dr. Trinidad Velasco-Torrijos
Date Deposited:	23 Apr 2019 13:59
Journal or Publication Title:	Pharmaceutical Development and Technology
Publisher:	Taylor & Francis
Refereed:	Yes
URI:	https://www.tandfonline.com
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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