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Title: In vitro and physiologically based pharmacokinetic models for pharmaceutical cocrystals
Author: Tomaszewska, Irena
Awarding Body: University of Bath
Current Institution: University of Bath
Date of Award: 2013
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About 30% of commercial and developmental drugs exhibit poor solubility and thus poor bioavailability. Strategies that enhance solubility of such compounds have become more popular. Cocrystallisation is one of these strategies, so characterisation of in vitro performance of cocrystals is essential. Conventional dissolution systems (USP apparatus 1 and USP apparatus 2) are often not suitable for testing poorly soluble drugs due to failure in providing sink conditions and inability to change the media during the experiment. This project involves designing appropriate dissolution methods that will help understand the mechanism of dissolution of cocrystals. Successful dissolution methods were used to test marketed formulations of Carbamazepine (CBZ) (IR and PR Tegretol® tablets) and Indomethacin (IND) (IR Indocid® capsules). Flow-through cell (USP 4) apparatus proved to be more suitable to test poorly soluble formulations than basket (USP 1) apparatus. Formulations and their cocrystals were tested in four combinations of media: compendial (SGF/SIF), modified I (MGM/MIM-I), modified (MGM/MIM-II) and biorelevant media (FaSSGF/FaSSIF-V2). USP apparatus 4 allowed capturing and quantifying the precipitation of IND samples upon the media change. All Indomethacin formulations exhibited precipitation; however, this occurred into the smaller extent in biorelevant media. The greatest enhancement in CBZ dissolution was observed for Saccharin cocrystals of CBZ. On the other hand, Nicotinamide cocrystal of IND improved dissolution of IND greater than Saccharin cocrystal. Dissolution profiles with physicochemical and pharmacokinetic parameters were used to develop a Physiologically Based Pharmacokinetic (PBPK) model using in silico program Simcyp®. Successful models were then used to predict in vivo performance of cocrystals. Successful PBPK models were developed for IR and PR formulations of Tegretol® tablets and IR Indocid® capsules using dissolution data tested in biorelevant media using dissolution USP apparatus 4. It was found that in vivo absorption of CBZ from cocrystals did not increase dramatically. An overall 2 % increment was observed when compared against the CBZsp sample. However, the rate of absorption for CBZ-SACss samples was significantly faster than the rate of CBZsp absorption. API and cocrystals of IND completely absorbed within 3 hours and IND-NICss cocrystal were found to absorb slightly faster than the other cocrystals. Absorption was 8% higher at 1 h in comparison to IND. However, overall the improvement was not statistically significant. In summary, this research demonstrates that selection of appropriate medium and apparatus is essential to build a successful PBPK model.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available