Measurement, analysis and prediction of amoxicillin oral dose stability from integrated molecular description approach and accelerated predictive stability (APS)

Abstract

BackgroundStability of low amoxicillin oral dosage form (5 mg) used in reintroduction drug test was not fully documented. Furthermore, the impact of (1) salt moiety of amoxicillin and (2) amoxicillin – excipient interactions upon the antibiotic formulation stability during the storage was not characterized so that the estimation of the pharmaceutical expiration date from shelf-life was uncertain. Thus, the main goal of this study was to estimate the shelf-life of two formulations of amoxicillin, using a semi-predictive methodology.MethodsAmoxicillin sodium (AS) and amoxicillin trihydrate (ATH), corresponding to 5-mg amoxicillin, were compounded with microcrystalline cellulose (MCC) in oral hard capsules which were, then, submitted to four environmental conditions (25 °C / 60% or 80% relative humidity (RH); 40 °C / 75% RH; 60 °C / 5% RH) in climatic chambers for 45 and 84 days. Therefore, the characterization of amoxicillin-MCC mixture was assessed by attenuated total reflectance Fourier-transform infrared spectroscopy (ATR-FTIR) The profiles of amoxicillin content (determined by stability indicating chromatographic method) as a function of storage time, temperature and RH were fitted to pre-defined kinetic models performed by accelerated predictive stability (APS).ResultsATR-FTIR analysis of AS, ATH, MCC and bulk specimens stored in heated and humid atmosphere confirmed water sorption to cellulose described by a broad and unresolved 3600 to 3000 cm−1 band associated with (1) general intramolecular and intermolecular hydrogen bonding between water and hydroxyl groups of the cellulose, and with (2) free hydroxyl in cellulose. Moreover, a dramatic decrease of absorption at 1776 and 1687 cm−1 respectively characteristic of the β-lactam ring (νC=O) and amide group (νC=O), was revealed as a consequence of AS and ATH degradation caused by moisturization of bulk. Amoxicillin degradation was established by chromatographic analysis showing faster AS degradation than ATH throughout time exposure. The combined effects of temperature – RH were successfully modeled by APS, where AS and ATH showed accelerated (auto-catalysis degradation mechanism) and linear degradation, respectively. The faster AS degradation was assumed to be linked to lower hydrogen donor to hydrogen acceptor count ratio and polar surface than ATH, increasing the probability of AS hydrolysis by water adsorption to AS-MCC solid dispersion (e.g., by reduction of protective intramolecular hydrogen bonds between AS molecules). Furthermore, the compounding which involved a drastic homogenization of solids may have affected the crystalline degree of MCC with an increase of amorphous phase more sensitive to water adsorption.ConclusionsThe improvement of amoxicillin compounding for oral dose forms might be rationalized by taking into account the molecular descriptors of salt moiety and excipients, improved by the choice of an appropriate process of production, characterized from infrared vibrational spectroscopy and chromatographic analysis and finally predicted from accelerated stability assays.

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“…FTIR spectra of amoxycillin trihydrate showed that the characteristic peak of the drug is present in the peak (12). The infrared spectrum of the Amoxycillin trihydrate showed strong absorption at 1,776 cm −1 , characteristic of the β-lactam ring 28 .…”

“…The comparison was carried out between 3700 cm -1 and 2400 cm -1 and between 1800 cm -1 and 1000 cm -1 . Alkenyl (>C=C); 3,020-3,100 cm -1 ; and amide (>NH; 1,000-1,250 cm -1 ) Phenolic (-OH; 970-1,250 cm-1 ) and ketone (>C=O; 1,710-1,720 cm -1 ) stretches are the primary functional groupings in charge of certain areas 28,29 . The FTIR data reveals the formation of weak to medium intensity bonds, which may be caused by the development of Vander Waal forces and dipole moments due to the interaction of the drug and excipient.…”

Medicine Identification New Database (MIND): A quick, simple and accurate tool for the identification of unlabelled medication in hospital pharmacies

“…The infrared spectrum was recorded using an ATR/FT-IR spectrometer (3800-400 cm −1 , 10 cm optical path, 32 scans with spectral resolution of 4 cm −1 , Nicolet ® iS 50 FT-IR spectrometer, Thermo Fisher Scientific). 2,3 The ATR/ FT-IR spectrum obtained was compared to the MIND ATR/FT-IR spectrum module database. Finally, a multi-component deconvolution of the initial spectrum was carried out to identify up to four individual components of the unknown crushed pellets.…”

Predictive stability, novel HPLC-MS analysis and semi-automatic compounding process for the emergency implementation of a production line of pancuronium in injectable solution.

“…The stability-indicating quantitative analytical method was used to study the stability of the compounded formulation. In an emergency context, two methods were applied to assess the stability: a semi-predictive method (based on the Arrhenius equation and the kinetics equations developed during the 20 th century), allowing a very fast assessment, and a prospective method (classical method) as a confirmation of the prediction ( Šesták and Berggren, 1971 , Waterman and Adami, 2005 , Merienne et al, 2020 , Clénet, 2018 ).…”