Prediction of the changes in drug dissolution from an immediate-release tablet containing two active pharmaceutical ingredients using an accelerated stability assessment program (ASAPprime®)

Hanlin Li,Andrew Kuzmission,Christopher M Riley,David Nadig

doi:10.1186/s41120-016-0010-5

Hanlin Li, Andrew Kuzmission + Show 2 more

Open Access

https://doi.org/10.1186/s41120-016-0010-5

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Journal: AAPS Open	Publication Date: Nov 3, 2016
Citations: 17	License type: CC BY 4.0

Affiliation: Vertex Pharmaceuticals (United States)

Abstract

The computer program ASAPprime® has been used successfully for some time to predict the stability of active pharmaceutical ingredients (APIs) in solid-dosage forms. In this study, we have demonstrated that the ASAPprime® program can also be used to predict the slow-down in dissolution of two APIs in an immediate release tablet. The tablets were pre-equilibrated at 25 °C at different relative humidities (30–75 %), sealed in aluminum pouches and stored at temperatures ranging from 50–60 °C for 3, 7 or 14 days. The storage times were selected to encompass the time needed to produce a slowdown in dissolution such that the amount of the two APIs fell below the acceptance criteria of no less than 80 % dissolved in 20 min. Up to 6 months of stability data from a 40 °C/75%RH open dish study were also included in the modeling. The effects of temperature (T in °K) and relative humidity (RH) were then shown to be related to the isoconversion (IC) time by an empirical, modified Arrhenius equations, where IC is the time for the amount dissolved to equal 80 % of the label claim. These studies showed that while the slowdown in dissolution of API 2 was influenced more by the relative humidity than API 1, the overall slowdown in dissolution was more sensitive to changes in temperature than changes in relative humidity. In addition to showing that ASAPprime® could be used to model the effects of temperature and relative humidity on dissolution, the software was also used to demonstrate that no special precautions were necessary to protect the tablets from moisture and they could be stored in Aclar blisters®. It was also shown that the water content of the tablet was not a critical quality attribute and need not be included in the drug product specification.

Highlights

The use of accelerated stability studies is a wella established technique that has been widely used for more than 60 years to predict the shelf life and storage conditions of drugs and drug products (Baertschi 2007; Huynh-Ba 2008; Karstensen 1990; Waterman & Carella2007)
Slowdown in dissolution of both Active pharmaceutical ingredient (API) was observed for tablets stored at highly elevated temperature and relative humidity conditions, likely due to physical changes of the solid dosage forms (SDF), no chemical degradation of either API was observed under these conditions
The dissolution of API 1 decreased to 79.9 % after storage in an open dish for 7 days at 60 °C/ 65 % relative humidity (RH) and 76.8 % after 3 days at 60 °C/75 % RH

Summary

Introduction

The use of accelerated stability studies is a wella established technique that has been widely used for more than 60 years to predict the shelf life and storage conditions of drugs and drug products (Baertschi 2007; Huynh-Ba 2008; Karstensen 1990; Waterman & Carella2007). Whereas the experimental approaches may vary between studies, the general principles are the same and are based on the extrapolation of the rate of degradation at two or more temperatures above the intended condition, using the Arrhenius Relationship (Eq 1). The Arrhenius relationship is less reliable over larger temperature ranges when the dependency of A and Ea on T described by Eyring (Stella, 2000) results in non-linear relationships between ln k and 1/T. Another important source of error arises from extrapolation of the data because the confidence interval of the predicted value increases as the difference between the measured and predicted values increases

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