Category: Formulation and Quality
Purpose: Over the past 20 years, various biorelevant media have been developed for in vitro tests to simulate the dissolution behavior of drugs in the human small intestine1,2. The question arises as to which media best represents human fasted state intestinal fluid (HIF) in a performance test? In this work, dissolution tests with three different neutral agents in three versions of fasted state simulating intestinal fluid (FaSSIF) were performed and the results compared with the solubility of the respective active ingredient in HIF.
Methods: All chemicals used in the experiments were of analytical grade. Instant powders of biorelevant media FaSSIF V1, FaSSIF V2 and FaSSIF V3 were kindly donated by biorelevant.com (London, UK). Carbamazepine 200 - 1a Pharma® (Carbamazepine), Danol® 100mg capsules (Danazol) and Cil® 160mg capsules (Fenofibrate) were ordered from Pheonix Pharma SE (Mannheim, Germany). Media were prepared according to the instructions from biorelevant.com or the literature2.
Dissolution tests were performed in USP apparatus II (paddle, DT 720 by Erweka GmbH, Heusenstamm, Germany) with n = 6 vessels and 500mL medium per vessel. The paddle speed was set to 75 rpm and the temperature of the medium was maintained at 37 ± 0.5°C. The test duration was set to 120 minutes with nine sampling points and analytics were performed by HPLC.
Results: Carbamazepine: Carbamazepine showed marginally higher dissolution in FaSSIF V2 than in FaSSIF V1 and FaSSIF V3. Within the test period of 120 minutes, between 50% - 60% (200 - 240 µg/mL) of the carbamazepine was released from the 1A tablets (Fig. 1a). The maximum concentration achieved in all three FaSSIF versions fell within the range of the thermodynamic solubility of carbamazepine in HIF (range 170.0µg/mL - 336.0µg/mL)3.
Danazol: The dissolution of danazol was most extensive in FaSSIF V1 and had not reached a plateau by 120 minutes. That said, less than 5% of the danazol dose was released from the Danol® capsules during the test. The extent of dissolution was lower in FaSSIF V2 than in FaSSIF V3, and in both media a plateau had been reached by 30min (Fig. 1b). Since danazol solubility in HIF appears to be quite variable, the solubilities and maximum concentrations in the dissolution tests in all three FaSSIF versions were within the range reported in HIF (2.04µg/mL - 13.2µg/mL)3.
Fenofibrate: The dissolution of fenofibrate was highest in FaSSIF V1, with dissolution in FaSSIF V2 and V3 less extensive but similar to each other. A plateau was not reached in any of the FaSSIF versions (Fig. 1c). Less than 6% fenofibrate was released from the Cil® capsules within 120min in any of the FaSSIF versions. Only the dissolution in FaSSIF V1 yielded results commensurate with the thermodynamic solubility in HIF (reported range: 11.9µg/mL -19.7µg/mL)3.
Conclusion: The different FaSSIF versions are mostly able to achieve similar values in dissolution test as the solubility in HIF. However, the composition of the FaSSIF versions has an influence on the release. In comparison with the other two versions, FaSSIF V1 appears to correspond best with the HIF data. This work is currently being extended to weak acids and weak bases to obtain a better overview of the relative merits of the three versions for simulation of in vivo results.
References: 1 Jantratid E.; Janssen, N.; Reppas, C. and Dressman, J. Dissolution media simulating conditions in the proximal human gastrointestinal tract: an update, Pharmaceutical Research, Vol. 25, No 7, (2008)
2 Fuchs A. Entwicklung einer neuen Generation von Biorelevanten Medien zur Simulation des nüchternen humanen Dünndarms –FaSSIFV3, Dissertation (2015)
3 Fuchs, A.; Leigh, M.; Kloefer, B. and Dressman, J. Advances in the design of fasted state simulating intestinal fluids: FaSSIF-V3. European Journal of Pharmaceutics and Biopharmaceutics, 94, 229-240 (2015)
Jennifer Dressman– Goethe University, Frankfurt am Main, Hessen, Germany