UNGAP best practice for improving solubility data quality of orally administered drugs.

An important goal of the European Cooperation in Science and Technology (COST) Action UNGAP (UNderstanding Gastrointestinal Absorption-related Processes, www.ungap.eu) is to improve standardization of methods relating to the study of oral drug absorption. Solubility is a general term that refers to the maximum achievable concentration of a compound dissolved in a liquid medium. For orally administered drugs, relevant information on drug properties is crucial during drug (product) development and at the regulatory level. Collection of reliable and reproducible solubility data requires careful application and understanding of the limitations of the selected experimental method. In addition, the purity of a compound and its solid state form, as well as experimental parameters such as temperature of experimentation, media related factors, and sample handling procedures can affect data quality. In this paper, an international consensus developed by the COST UNGAP network on recommendations for collecting high quality solubility data for the development of orally administered drugs is proposed.

A combined experimental and theoretical study of miconazole salts and cocrystals: crystal structures, DFT computations, formation thermodynamics and solubility improvement.

Experimental and theoretical screening of multi-component crystal forms of miconazole (MCL), an antifungal drug, with ten aliphatic dicarboxylic acids was performed. Seven multi-component molecular crystals were isolated and identified by different analytical techniques, including the powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TG), and solubility methods. The crystal structures of the MCL hemihydrate, two cocrystals with succinic ([MCL + SucAc] (2 : 1)) and fumaric acids ([MCL + FumAc] (2 : 1)) and one salt with maleic acid ([MCL + MleAc] (1 : 1)) were redetermined. The new cocrystal of MCL with adipic acid ([MCL + AdpAc] (2 : 1)) was investigated by single crystal X-ray diffractometry. It was found that the AdpAc molecule in the cocrystal has an unusual anticlinal conformation. The combination of periodic density functional theory (DFT) computations and quantum topology analysis confirmed the structure-directing role of the acid-imidazole heterosynthon for the considered crystals. The melting temperatures of all the studied multi-component crystals are between the values of the corresponding individual components except [MCL + MleAc] (1 : 1). A thermal analysis has shown that the thermodynamic and thermophysical characteristics of the considered two-component molecular crystals are strongly dependent both on specific interactions (presence of sites of donor-acceptor interactions and hydrogen bond formation) and on nonspecific interactions - molecule polarizability. Based on the sublimation thermodynamics database of molecular crystals, the standard sublimation thermodynamic functions of MCL were evaluated. The thermodynamic functions of multi-component crystal formation based on MCL were calculated and analyzed. Solubility experiments on the MCL multi-component crystals were carried out in isotonic aqueous buffer solutions at pH 1.2 and 6.8 and compared with the solubility of the MCL free base and its nitrate salt. It was found that the salt/cocrystal formation of MCL with dicarboxylic acids considerably increased the MCL solubility in pH 6.8 buffer. The biggest MCL solubility enhancement was observed in the [MCL + TartAc] (1 : 1) salt. The solubility value of MCL in the [MCL + TartAc] (1 : 1) salt is commensurate with the commercial MCL nitrate salt.

Crystal structure of a 1:1 salt of 4-amino-benzoic acid (vitamin B10) with pyrazinoic acid.

The title 1:1 salt, C7H8NO2 +·C5H3N2O2 - (systematic name: 4-carb-oxy-anilinium pyrazine-2-carboxyl-ate), was synthesized successfully by slow evaporation of a saturated solution from water-ethanol (1:1 v/v) mixture and characterized by X-ray diffraction (SCXRD, PXRD) and calorimetry (DSC). The crystal structure of the salt was solved and refined at 150 and 293 K. The salt crystallizes with one mol-ecule of 4-amino-benzoic acid (PABA) and one mol-ecule of pyrazinoic acid (POA) in the asymmetric unit. In the crystal, the PABA and POA mol-ecules are associated via COOH⋯Narom heterosynthons, which are connected by N-H⋯O hydrogen bonds, creating zigzag chains. The chains are further linked by N-H⋯O hydrogen bonds and π-π stacking inter-actions along the b axis [centroid-to-centroid distances = 3.7377 (13) and 3.8034 (13) Šat 150 and 293 K, respectively] to form a layered three-dimensional structure.

Towards the rational design of novel drugs based on solubility, partitioning/distribution, biomimetic permeability and biological activity exemplified by 1,2,4-thiadiazole derivatives.

Novel 1,2,4-thiadiazole derivatives as potent neuroprotectors were synthesized and identified. Their ability to inhibit the glutamate stimulated Ca2+ uptake was investigated. The solubility of thiadiazoles was measured in a buffer solution (pH 7.4) at 298 K. The distribution coefficients in 1-octanol/buffer (pH 7.4) and 1-hexane/buffer (pH 7.4) immiscible phases as model systems imitating the gastrointestinal tract epithelium and the blood-brain barrier were determined. Permeation experiments the new Permeapad™ barrier using Franz diffusion cells were conducted and the apparent permeability coefficients were obtained. The influence of the compound structure on the physicochemical properties determining the bioavailability of drug-like substances was revealed. Solubility-permeability interplay has been assessed to evaluate potential bioavailability of the compounds studied.

Adamantane derivatives of sulfonamides: sublimation, solubility, solvation and transfer processes in biologically relevant solvents.

Eight adamantane derivatives of sulfonamides were synthesized and characterized. Temperature dependencies of saturation vapor pressure were obtained using the transpiration method and thermodynamic functions of the sublimation processes were calculated. Solubility values of the selected compounds in buffer (pH 7.4), 1-octanol and 1-hexane were determined at different temperatures using the isothermal saturation method. Thermophysical characteristics of fusion processes (melting points and fusion enthalpies) of the substances were studied using the DSC method. Transfer processes from buffer to 1-octanol, from buffer to 1-hexane and 1-hexane to 1-octanol were analyzed. The impact of the molecules' structural modification on sublimation, solubility and solvation/hydration processes in the solvents was studied. Correlation equations connecting the thermodynamic functions with physicochemical descriptors were obtained.

The impact of structural modification of 1,2,4-thiadiazole derivatives on thermodynamics of solubility and hydration processes.

The influence of a structural modification on thermodynamic aspects of solubility and hydration processes of 1,2,4-thiadiazole drug-like compounds was investigated. A substitution in the phenyl ring of the 1,2,4-thiadiazole molecule leads to a significant decrease of the solubility of these compounds. In order to rationalize the relationship between the structures of 1,2,4-thiadiazoles and their solubility, the latter was considered in terms of two fundamental processes: sublimation and hydration. It was found that for most of the compounds solubility decline is a result of a differently directed action of the sublimation and hydration contributions, i.e., the introduction of substituents leads to the simultaneous growth of the sublimation Gibbs energy and decrease in the hydration Gibbs energy.

Physicochemical properties/descriptors governing the solubility and partitioning of chemicals in water-solvent-gas systems. Part 2. Solubility in 1-octanol.

On the basis of octanol solubility data (log S(o)) for 218 structurally diverse solid chemicals it was shown that the exclusive consideration of melting points did not provide satisfactory results in the quantitative prediction of this parameter (s = 0.92). The application of HYBOT physicochemical descriptors separately (s = 0.94) and together with melting points (s = 0.70) in the framework of a common regression model also was not successful, although contributions of volume-related and H-bond terms to solubility in octanol were identified. It was proposed that the main reason for such behaviour was the different crystal lattice interaction of different classes of chemicals. Successful calculations of the solubility in octanol of chemicals of interest were performed on the basis of the experimental solubility of structurally/physicochemically/numerically similar nearest neighbours with consideration of their difference in physicochemical parameters (molecular polarisability, H-bond acceptor and donor factors (s = 0.66)) and of these descriptors together with melting point differences (s = 0.38). Good results were obtained for all compounds having nearest neighbours with sufficient similarity, expressed by Tanimoto indexes, and by distances in the scaled 3D descriptor space. Obviously the success of this approach depends on the size of the database.