Acyclovir chemical kinetics with the discovery and identification of newly reported degradants and degradation pathways involving formaldehyde as a degradant and reactant intermediate |
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Authors: | Bhanu C. Bejgum Paul R. Johnson William C. Stagner |
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Affiliation: | 1. Campbell University, College of Pharmacy & Health Sciences, Department of Pharmaceutical Sciences, PO Box 1090, Buies Creek, NC 27506, USA;2. Campbell University, College of Pharmacy & Health Sciences, Pharmaceutical Education & Research Center, 130 Burt Street, Buies Creek, NC 27506, USA |
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Abstract: | The purpose of this research was to determine acyclovir (ACV) acidic degradation kinetics which is relevant to gastric retentive device product design. A stability-indicating method revealed two unknown degradation products which have been identified by mass spectrometry as ACV and guanine formaldehyde adducts. In addition to the formation of these adducts, a proposed degradation scheme identifies the formation of methyl acetal ethylene glycol, formaldehyde, ethylene glycol, and guanine as additional ACV degradation products. pH-rate profiles were explained by using a rate law which assumed acid-catalyzed hydrolysis of protonated and unprotonated ACV. The predicted and observed rate constants were in good agreement. Data-driven excipient selection recommendations were based on the chemical kinetic study results, degradation scheme, and pH-rate profiles. The average activation energy for the degradation reaction was determined to be 31.3 ± 1.6 kcal/mol. The predicted ACV t90% at 37 °C and pH 1.2 was calculated to be 7.2 days. As a first approximation, this suggests that ACV gastric retentive devices designed to deliver drug for 7 days should have acceptable drug product stability in the stomach. |
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Keywords: | Acyclovir (PubChem CID: 2022) Guanine (PubChem CID: 764) Formaldehyde (PubChem CID: 712) Ethylene glycol (PubChem CID: 174) Chemical stability Stability-indicating method Degradation pathway Mass spectroscopy |
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