(T1330-02-12) Fed State Intestinal Drug Solubility: The Behaviour of Acidic Drugs

Purpose: In the gastrointestinal tract, drug solubility can be influenced by intestinal fluid components such as bile salts, lecithin, food digestion products and gastrointestinal luminal fluid pH. In order to evaluate how these components affect the solubility of different drugs, previous design of experiment (DoE) approaches using simulated intestinal fluids [1-4]studied the influence of eight media components (bile salt, lecithin, buffer, salt, pH, enzyme, fatty acid and monoglyceride) on drug solubility for the fasted and fed state. These approaches determined that for both states, pH was the most significant factor affecting the solubility of acidic drugs with a twenty times greater standardised effect on solubility than any of the other media components. A recent fasted state study [5]applied nine bioequivalent media recipes to evaluate the solubility behaviour of a group of drugs. Acidic drugs behaviour was consistent with the previous fasted state DoE  and confirmed that acidic drug solubility in the fasted state is controlled by media pH. In the present study, a similar approach was performed using nine simulated media recipes representative of the fed state. These simulated media recipes resulted from a multidimensional mathematical analysis of fed intestinal fluids obtained from human volunteers, and the media covers more than 90% of fed state human intestinal fluid composition variation [6]. The equilibrium solubity range of nine acidic drugs (naproxen, piroxicam, indomethacin, phenytoin, zafirlukast, ibuprofen, mefenamic acid, furosemide and valsartan) was measured and the solubility ranges were analysed to determine if the behaviour is consistent with previously reported studies.

Methods: The nine media recipes were prepared by combining different concentrations of bile salts, phospholipid, free fatty acid, cholesterol, buffer and salt in a 15ml centrifuge tube [7]. An excess of solid drug was added the pH adjusted to the required value and made to a final volume (4ml) with water. Samples were agitated for an hour at room temperature, pH was readjusted, and then incubated for 24 hours at 37 ºC and 240 rpm using an orbital mixer. After incubation, the tubes were checked for the presence of solid drug, 1 ml of each solution centrifuged (10,000 rpm for 15 minutes) and the supernatant analysed by HPLC for drug content (with reference to a standard curve) and the equilibrium solubility calculated[7].

Results: The majority of drugs, with the exception of piroxicam and phenytoin, have pKa values below the lowest media pH (5.97) and thus in these systems ionised drug is predominant. The equilibrium solubility of each drug plotted against media pH highlights that solubility increases with media pH and that the drugs generally display a similar behaviour. Some minor variations in the ranking of points with close pH values are evident and probably due to the influence of other media components that are present at higher concentrations in the fed state when compared to the fasted. This behaviour is consistent with the previous DoE approaches [1-4]and with the published nine media fasted study [5]. In 8 out of 9 cases (89%) media number 2 (with the highest pH value (6.59)) provides the highest solubility values. In 5 out of 9 cases (56%) media number 1 provides the lowest solubility and in 3 out of 9 cases (33.3%) media number 7 provides the lowest solubility. Media number 1 and 7 have the lowest pH value of 5.97, with the major difference the concentration of amphiphiles present (media 7 > media 1). It is note that the drugs with higher pKa (phenytoin and piroxicam) or lower intrinsic solubility (zafirlukast) register in media 7 rather than media 1, possibly indicating solubilisation by micellar components.

Conclusion: The solubility behaviour of the acidic drugs in this fed state study is directly linked to media pH, which is in agreement with previous studies. The highest solubility can be determined in media 2 with more than 80% frequency and the lowest solubility can be determined with media 1 and/or media 7 with a greater than 90% frequency. These media (1,7 and 2) could be used instead of the full nine media to identify in vitro maximum and minimum solubility limits for acidic drugs that should be applicable in vivo in the fed state. Therefore, the nine fed simulated media could be applied during drug formulation and development to provide a solubility range with fewer measurements that still represent the best and worst case scenario for drug solubility.

References: 1. Ainousah, B.E., et al., Dual Level Statistical Investigation of Equilibrium Solubility in Simulated Fasted and Fed Intestinal Fluid. Mol Pharm, 2017. 14(12): p. 4170-4180.
2. Khadra, I., et al., Statistical investigation of simulated intestinal fluid composition on the equilibrium solubility of biopharmaceutics classification system class II drugs. Eur J Pharm Sci, 2015. 67: p. 65-75.
3. Perrier, J., et al., Statistical investigation of the full concentration range of fasted and fed simulated intestinal fluid on the equilibrium solubility of oral drugs. Eur J Pharm Sci, 2018. 111: p. 247-256.
4. Zhou, Z., et al., Statistical investigation of simulated fed intestinal media composition on the equilibrium solubility of oral drugs. Eur J Pharm Sci, 2017. 99: p. 95-104.
5. Abuhassan, Q., et al., Structured solubility behaviour in bioequivalent fasted simulated intestinal fluids. European Journal of Pharmaceutics and Biopharmaceutics, 2022. 176: p. 108-121.
6. Pyper, K., et al., Multidimensional analysis of human intestinal fluid composition. Eur J Pharm Biopharm, 2020. 153: p. 226-240.
7. Inês Silva, M., et al., Small scale in vitro method to determine a potential bioequivalent equilibrium solubility range for fed human intestinal fluid. European Journal of Pharmaceutics and Biopharmaceutics, 2022. 177: p. 126-134.

Acknowledgments: MIS is funded by Medical Research Scotland, PHD-50074-2019. GWH is funded by Cancer Research UK (C149/A20496).