Potential for pharmaceutical excipients to impact absorption: A mechanistic review for BCS Class 1 and 3 drugs

The potential for certain excipients to impact drug absorption is the subject of numerous publications. Reflecting this, current Biopharmaceutics Classification System (BCS) guidelines place restrictions on the level of change in excipients to be eligible for a BCS biowaiver. The degree of change permitted between test and reference formulations varies between BCS Class 1 and 3, and also across different regulatory authorities. This article reviews the literature evidence for excipients to impact drug absorption, with a particular focus on identifying effects which may be important for BCS Class 1 and 3 compounds and formulations. Literature examples were categorised according to the mechanism by which the excipient was believed to impact drug absorption, and the relevance of these mechanisms for compounds within BCS Class 1 and 3 was assessed. The likelihood of using the excipient in solid oral immediate release formulations (i.e. formulation types which would be eligible for BCS biowaivers) was also considered. Using this mechanistic and risk-based approach, potential critical excipients for BCS Class 1 and 3 compounds were identified. Based on the literature data, there are only a limited number of mechanisms by which excipients could affect the absorption of a BCS Class 3 drug. For BCS1, absorption is very unlikely to be affected by excipient changes. For many of these excipients, there is no in vivo evidence of such an effect having occurred. The risk can be mitigated to a large extent by applying some compound-specific understanding of the absorption site, rate and mechanism of the particular API under consideration.