Purpose: Biorelevant media (BRM) simulate the gastrointestinal fluids by including the physiological surfactants, bile salts and lecithin. BRM are predominantly important for the development of poorly soluble drugs since these surfactants can significantly increase drug solubility. FeSSIF aids formulation scientists for obtaining solubility and dissolution profiles of a drug in their formulations in vitro in media simulating fed state intestinal fluids. The purpose of this study was to compare the equilibrium solubility and dissolution profiles of weakly acidic and weakly basic BCS class II drug substances (ibuprofen and ketoconazole) in FeSSIF-V2 (made from commercial powder and scratch) and corresponding USP buffer. Comparing solubility values of drugs in FeSSIF with corresponding pH buffer will give an indication on how the drug solubility is affected by the presence of bile salts and lecithin. The effect of various factors including different preparation methods of the BRM on the dissolution performance of the study drugs were evaluated by comparing the dissolution in FeSSIF-V2 prepared from scratch (ScrFeSSIF-V2) and in media prepared from lyophilized powder (from biorelevant.com).
Methods: IR ketoconazole tablets (200-mg, Lot 303339) and IR ibuprofen tablets (200-mg, Lot P97327) were studied. The BRM used in the studies are Fed State Simulated Intestinal Fluid (FeSSIF-V2 – pH 5.8) prepared from biorelevant.com powder (1) or from scratch using Dressman et al’s procedure (2). USP buffer used in the studies was pH 5.8 phosphate buffer. The solubility studies were carried out at room temperature and 37 ºC for 24h and the stability chamber was used to maintain the temperature. Appropriate amount of media and excess amount of drug were placed in vials and were agitated at same speed using magnetic stirrer bar, followed by filtration using syringe filters of 450-nm pore size. The dissolution tests were performed in 500ml of BRM as well as USP buffer using USP apparatus 2 for 75 minutes and sampling was done at 10, 20, 30, 45, 60 and 75 min (infinity time point). An isocratic reverse phase high performance liquid chromatography with UV detection (HPLC-UV-Waters Inc.) was used for the quantitation of solubility and dissolution samples.
Results: As can be seen from Table 1, ibuprofen and ketoconazole both showed significantly higher equilibrium solubility in both FeSSIF-V2 compared to USP buffer and dissolution profiles of ketoconazole confirms the same effect (Figure 2). The differences in solubility were attributed to the presence of high amount of bile salts and lecithin in the FeSSIF-V2. The dissolution profiles of ibuprofen (Figure 1) shows a lower rate of dissolution in buffer at earlier time points compared to both FeSSIF-V2, but the end point is 100% complete dissolution in all three media because of the high drug solubility. Solubility of drugs in ScrFeSSIF-V2 was overall slightly higher than the FeSSIF-V2 due to slightly higher (approx. 1.1%) surfactant concentration in media made from scratch. However, dissolution profiles of drugs in both types of FeSSIF-V2 were similar for both drugs (Figure 1 and Figure 2).
Conclusion: Evaluating solubility and dissolution profiles of poorly soluble drugs and drug products in BRM can help identify issues early on that may be later observed in vivo. The solubility of ibuprofen and ketoconazole in both FeSSIF-V2 and pH 5.8 USP buffer were reported at room temperature as well as at 37 ºC. The dissolution profiles in each of the medium made from scratch and the commercial powder were similar. Thus, it is practical to switch from the more labor-intensive preparation method to the use of standardized lyophilized instant powders for preparing biorelevant media without affecting dissolution results.
Ibuprofen and ketoconazole showed 7-fold and 15-fold higher solubility in both FeSSIF-V2, respectively, compared to USP pH 5.8 buffer. Dissolution profiles of ketoconazole reflect the difference in solubility observed between BRM and buffer. This indicates that in vitro solubilization and dissolution results can be considerably affected in the presence of lecithin and bile salts. To conclude, the physiological solubility of these BCS class II drugs may be largely underestimated in in vitro solubility assays in buffer medium.
2. Jantratid E, Janssen N, Reppas C, Dressman JB. “Dissolution media simulating conditions in the proximal human gastrointestinal tract: an update.” Pharm Res. 2008 Jul;25(7):1663-76. Doi:10.1007/s11095-008-9569-4. Epub 2008 Apr 11.
3. Katerina S, Zahari V, Slavka T. “Improving Ibuprofen solubility by surfactant-facilitated self-assemblyinto mixed micelles” Journal of Drug Delivery Science and Technology 36 (2016) 208-215.
4. Masashi A, Yuta H, Kosuke K, Hidemasa K, Toshiyasu S, Manabu N, Koichi W, Akira Y. “Improved dissolution and absorption of ketoconazole in the presence of organic acids as pH-modifiers” European Journal of Pharmaceutical Sciences 76 (2015) 225–230.
Rusha Sardhara– Long Island University
Rusha Sardhara– Long Island University
Kenneth Morris– Director, Lachman Institute for Pharmaceutical Analysis, New York
Arzu Selen– Associate Director, USFDA, Maryland
Zongming Gao– Research Scientist, US Food and Drug Administration, Saint Louis
Akhtar Siddiqui– FDA
Poonam Delvadia– Acting Biopharmaceutics Lead, USFDA, Silver Spring, Maryland
Ting Xu– Long Island University
Harsh Shah– Research Assistant, Long Island University
Rushaben Sardhara– Graduate Assistant, Long Island University, Brooklyn