Ethanol Effects on Apparent Solubility of Poorly Soluble Drugs in Simulated Intestinal Fluid

Abstract

Ethanol intake can lead to an unexpected and possibly problematic increase in the bioavailability of druglike compounds. In this work we investigated the effect of ethanol on the apparent solubility and dissolution rate of poorly soluble compounds in simulated intestinal fluid representing a preprandial state. A series of 22 structurally diverse, poorly soluble compounds were measured for apparent solubility and intrinsic dissolution rate (37 °C) in phosphate buffer pH 6.5 (PhB6.5) and fasted state simulated intestinal fluid (FaSSIF, pH 6.5) with and without ethanol at 5% v/v or 20% v/v. The obtained data were used to understand for which molecules ethanol results in an increased apparent solubility and, therefore, may increase the amount of drug absorbed. In FaSSIF20%ethanol 59% of the compounds displayed >3-fold higher apparent solubility than in pure FaSSIF, whereas the effects of 5% ethanol on solubility, in most cases, were negligible. Acidic and neutral compounds were more solubilized by the addition of ethanol than by lecithin/taurocholate aggregates, whereas bases showed a more substance-specific response to the additives in the buffer. The stronger solubilizing capacity of ethanol as compared to the mixed lipid aggregates in FaSSIF was further identified through Spearman rank analyses, which showed a stronger relationship between FaSSIF20%ethanol and PhB6.5,20%ethanol (rS of 0.97) than FaSSIF20%ethanol and FaSSIF (rS of 0.86). No relationships were found between solubility changes in media containing ethanol and single physicochemical properties, but multivariate data analysis showed that inclusion of ethanol significantly reduced the negative effect of compound lipophilicity on solubility. For this data set the higher concentration of ethanol gave a dose number (Do) <1 for 30% of the compounds that showed incomplete dissolution in FaSSIF. Significant differences were shown in the melting point, lipophilicity, and dose profiles between the compounds having a Do < 1 and Do > 1, with the latter having higher absolute values in all three parameters. In conclusion, this study showed that significant effects of ethanol on apparent solubility in the preprandial state can be expected for lipophilic compounds. The results herein indicate that acidic and neutral compounds are more sensitive to the addition of ethanol than to the mixed lipid aggregates present in the fasted intestine.

Concomitant intake of alcohol may increase the absorption of poorly soluble drugs

“…2) (Fagerberg et al, 2012). The data set included three acidic compounds (indomethacin, indoprofen and tolfenamic acid), three non-ionizable compounds (felodipine, griseofulvin and progesterone), and three weak bases (cinnarizine, dipyridamole and terfenadine); these compounds were selected to cover both charged and non-ionizable compounds with a diversity in physicochemical properties (Table 1).…”

“…The number of rotatable bonds was calculated with Admet Predictor 6.5 (Simulations Plus, CA); molecular weight (MW), melting temperature (Tm) (O'Neil, 2001;Persson et al, 2013), disassociation constant (pKa) of ionizable groups at 37°C (Fagerberg et al, 2012). b a denotes acidic, n denotes neutral and b denotes basic function.…”

“…The particles may either dissolve or grow; dissolved material may partition into the bile salt micelles or is absorbed through the intestinal wall. Intestinal solubility, represented by previously reported S app in phosphate buffer pH 6.5 and FaSSIF (Fagerberg et al, 2012(Fagerberg et al, , 2010, was used as input for the concentration in the intestinal compartment. The pH-dependent solubility of an ionizable compound is traditionally calculated in GI-Sim according to the Henderson-Hasselbalch equation and the physiological pH in each GI compartment.…”

“…Indomethacin, indoprofen and tolfenamic acid are weak acids with pKa values > 3.9 (Fagerberg et al, 2012); therefore at pH 2.5, they are predominantly neutral. This is reflected in the low S app in NaCl pH2.5 .…”

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“…Based on literature survey, polarity and solubility 9,10 of CIN many preliminary trials were carried out for selection of mobile phase composition, some are tabulated in Table 3. Densitogram obtained using these optimised chromatographic conditions for CIN is shown in Fig.3, R f value for CIN was found to be 0.72.…”