Enthalpy–Entropy Compensation in the Structure-Dependent Effect of Nonsteroidal Anti-inflammatory Drugs on the Aqueous Solubility of Diltiazem

Abstract

Certain combinations of acidic and basic drugs can cause significant changes in physicochemical properties through the formation of ionic liquids, eutectic mixtures, or deep eutectic solvents. In particular, combining indomethacin and lidocaine is known to result in apparent increases in both the partition coefficients (hydrophobicity) and aqueous solubilities (hydrophilicity). The physicochemical interactions between drugs change the water solubility of the drugs and affect the bio-availability of active pharmaceutical ingredients. Therefore, we need to clarify the mechanism of changes of water solubility of drugs through the physicochemical interactions. In the present study, we identified a thermodynamic factor that regulates the dissolution of a basic drug, in the presence of various acidic nonsteroidal anti-inflammatory drugs. The results demonstrated that enthalpy-entropy compensation plays a key role in the dissolution of drug mixtures and that relevant thermodynamic conditions should be considered.

Quantification of crystallinity during indomethacin crystalline transformation from α- to γ-polymorphic forms and of the thermodynamic contribution to dissolution in aqueous buffer and solutions of solubilizer

“…There was a large difference between the polymorphs in the ATR-FTIR spectra, especially in the 1800-1600 cm −1 range, corresponding to the differential C]O stretching vibration depending on the hydrogen bonds in the crystal. 27,53,54 Both the thermograms and spectra of the samples were in good agreement with previously reported data on the aand g-forms, indicating that two pure polymorphic forms of INM were obtained. The measured and published XRPD diffractograms of the aand g-forms are conrmed as described in Materials and Methods in Fig.…”

“…Chatani et al 23 reported that the solubility of a drug is influenced by buffer components, such as phosphate, Britton–Robinson universal prescription, imidazolium salt, and a variety of Good's buffers. Kinoshita et al 27 claimed the entropy-enthalpy compensation of variable combinations of solubilizers to prevent the formation of a soluble complex. Hereafter, it is expected to yield a solution under the conditions of a thermodynamically homogeneous solute dissolved from heterogeneous polymorphic crystals.…”

“…In previous studies, [22][23][24][25][26][27][28] indomethacin (INM) (see Scheme 1 for its chemical structure) was used as a poorly water-soluble API model to analyze its thermodynamic and dissolution properties. With regard to INM, its most stable g-form (Form I, T m = 433 K) and a metastable a-form (Form II, T m = 426 K) are frequently studied in terms of the mechanisms of polymorph formation for the selective recovery of specic polymorphs, [32][33][34][35][36][37] and several other polymorphs and solvates are reported.…”

“…As a result, the balance between the dissolution enthalpy and dissolution entropy of acidic drugs is maintained in the presence and absence of basic drugs DTZ and LDC, supporting the establishment of enthalpy-entropy compensation. 27 We have reported various basic drugs, such as LDC, other local anesthetics, 25,27 DTZ, 25,26 cimetidine, famotidine, arginine, antipyrine, and imidazole, 24 that increase or decrease INM solubility. L-Carnosine (CNS) is a dipeptide consisting of b-alanyl and histidine moieties that maintain structural commonality with imidazole, antipyrine, cimetidine, and famotidine 24 which have ve-membered heterocycles.…”

“…Any unexpected modication of solubility and dissolution kinetics might occasionally involve risks of overdose or loss of therapeutic efficacy. [22][23][24] To overcome these shortcomings, the goal of our series of studies [22][23][24][25][26][27][28][29][30][31] is to establish a rational indexation of physicochemical properties to strike a balance between the solubility of solid-state APIs and the solubility required for controlled release. This study aims to enhance APIs' bioavailability, expecting to improve solubility by taking advantage of thermodynamic rationality.…”