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Thursday, September 13
Thu, Sep 13, 2:45 PM - 4:00 PM
Thurgood Marshall South
CMC1In Vitro Testing

Predicting Dissolution of a Suspension Product Based on Particle Size (300679)

Stan Altan, Janssen R&D 
*Wim Van Der Elst, Janssen, LLD 

Recent discussions of clinically relevant specifications (Suarez, 2012) have attracted increasing attention to the role of particle size distribution (PSD) of drug substance and its relationship to dissolution properties of a drug product. Dissolution is considered in many cases a surrogate for bioavailability as well as a product performance quality attribute, so how dissolution is affected by particle size is an important consideration. It’s desirable for the particle size distribution to fall within a relatively narrow range or controlled through appropriate specifications (Sun et al, 2010). The details of the latter are outside the scope of this discussion other than to say that a careful assessment of the effects of a range of PSDs is necessary to develop a PSD specification. The goal is to assure consistent quality in the manufacture of drug product. We present a case study of the prediction of dissolution at multiple stability time points (time 0 up to time 0 + 26 months) for a suspension product based on particle size distribution (measured at time 0 only). A two-stage modelling approach is proposed. In Stage 1, Weibull models are fitted to the dissolution profiles for each batch by stability time point combination. In Stage 2, the Weibull model parameters (obtained in Stage 1) are predicted based on the particle sizes of the batch (at time 0) and the stability time point of interest. The obtained model allows for the straightforward prediction of IVR profiles at different stability time point based on the particle size of a batch at time 0. Some advantages and limitations of the proposed model are discussed along with other potential modeling approaches.