(M1030-09-60) Influence of the Biorelevant Media on the Solubility of Benzthiazide, Isoxicam, and Piroxicam in the Presence of Several Excipients

Purpose: The bioavailability of a drug depends, among other parameters, on solubility. Only a drug in a solution can be absorbed through the gastrointestinal tract; however, a high number of drug candidates are poorly soluble not only in water itself but also in the presence of gastrointestinal medium components. One of the strategies used to enhance the solubility of sparingly soluble drugs is the use of excipients, as the excipients can interact with the drug by increasing its solubility and/or stabilizing supersaturated solutions. However, to have a better predictive bioavailability of the drug, solubility measurements must mimic in vivo conditions. Due to this, biorelevant media are used to simulate gastrointestinal fluids in fasted and fed states. The main purpose of this work is to evaluate the influence of the biorelevant media (fasted and fed states) on the solubility of three pharmaceutical compounds (benzthiazide, isoxicam, and piroxicam) in the presence of five excipients: two cyclodextrins (Captisol and Cavasol) and three hydrophilic polymers (Klucel, Kollidon, and Plasdone-S630). Additionally, the intrinsic solubility (S₀) and the capacity of the drugs to form supersaturated solutions were compared with aqueous conditions.

Methods: The S₀ was determined potentiometrically (CheqSol method) using the SiriusT3 (Pion Inc). The fasted (FaSSiF) and fed (FeSSiF) states were prepared following www.biorelevant.com guides. The ratio of drug:excipient selected for this study was 1:1, and the starting concentration was between 8.5 - 18.9 mM. All titrations started at pH 12.0 and titrated to a low pH where precipitation was detected by a UV–turbidity probe. After precipitation, base and acid titrants were alternately added to drive the sample back and forth across the equilibrium solubility of the neutral species (S₀). All solubilities were determined at least in quadruplicate at the average ionic strength of 0.17 M (KCl), under argon atmosphere at a 25.0 ± 0.1◦C. The data was processed using RefineT3 v2.0 software.

Results: The CheqSol method provides the intrinsic solubility (S₀) and evaluates the supersaturated state using the extent of the supersaturation (C_max) and the duration of the supersaturation (t_s): the time that the supersaturation state remains in solution before the equilibrium is reached (S₀), Figure1A. The intrinsic solubility (S₀) in biorelevant media of the three compounds studied is shown in Table1. Figure1B shows the effect of the biorelevant media (without excipient) on benzthiazide in comparison with water conditions [ref1]. Due to the effect of the biorelevant conditions, an increase is observed in the C_max and the solubility of benzthiazide increases 2.3 and 3.5 times in FaSSiF and FeSSiF respectively. However, this behavior is not observed for the oxicams drugs, where the effect of the SiF slightly impact on the solubility, obtaining the maximum effect with the use of FeSSiF (Table1). The use of cyclodextrins does not result in significant differences on the solubility of the oxicam drugs in comparison with aqueous conditions (Table1). However, the solubility of benzthiazide is enhanced in SiF media and an increase of the C_max is also observed. Figure2A shows that the enhancement of the solubility in SiF media for benzthiazide is the same as the enhancement observed without the excipients (Figure1B); meaning that the biorelevant media is promoting the solubility and not the excipient. The use of hydrophilic excipients has more influence in the supersaturation process [ref1]. Figure 2B shows the effect of the media for benzthiazide without and with the hydrophilic excipients in SiF media. All excipients enhance the supersaturation state (C_max) of the drugs in SiF conditions, showing the greatest effect in FeSSIF media. The extent of the supersaturation solutions in FeSSiF media increases for kollidon and plasdone-S630 with 3.2-fold and 3.8-fold respectively, in comparison with aqueous media. However, it was observed that there was a 2-fold decrease on the duration of the supersaturation (t_s). It seems that the SiF media did not have a significant influence on the solubility of the oxicam drugs. Only slight increases in solubility were observed for piroxicam in FeSSiF, and for isoxicam; in FaSSiF in the presence of klucel and plasdone-S630.

Conclusion: The CheqSol method was used for the study of the effect of the biorelevant media (fasted and fed states) with two cyclodextrins and three hydrophilic polymers on the solubility and the capacity to form supersaturated solutions of three acidic drugs. In the presence of cyclodextrins, it was observed that there was an increase in the solubility for benzthiazide in SiF media but not a significant effect on the oxicam drugs. In the case of hydrophilic excipients, it is observed the influence of the SiF media on benzthiazide enhancing the solubility and increasing the C_max of supersaturation solutions decreasing the duration of the supersaturation. On the contrary, it was not observed a significant influence of the biorelevant media on the oxicam compounds, just a slight increase for piroxicam in FeSSiF media.

References: [1] Influence of Ionization and the Addition of Cyclodextrins and Hydrophilic Excipients on the Solubility of Benzthiazide, Isoxicam, and Piroxicam. Diego Lucero-Borja, Rebeca Ruiz, Elisabet Fuguet and Clara Ràfols. Pharmaceutics 2025, 17, 571.

Figure 1. Concentration of the neutral species vs time plots for: (A) Isoxicam;
(B) Benzthiazide without excipients in aqueous (blue), FaSSiF (orange) and FeSSiF (red) media


Figure 2: Concentration of the neutral species vs time plots for (A) cyclodextrines; FaSSiF-without excipient (orange) FeSSiF- without excipient (red), cavasol- FaSSiF (light green), cavasol- FeSSiF (green) , captisol- FaSSiF (light purple), captisol- FeSSiF (purple) and (B) hydrophilic excipients; FaSSiF-without excipient (orange) FeSSiF- without excipient (red), klucel-FaSSiF (light green), klucel-FeSSiF (green) , kollidon-FaSSiF (yellow), kollidon-FeSSiF (brown), plasdone-S630- FaSSiF (light purple), plasdone-S630- FeSSiF (purple).

Table 1. Intrinsic solubility (S0) obtained through the CheqSol method in biorelevant media and in aqueous media [ref 1].