Prediction of Sublimation Functions of Molecular Crystals Based on Melting Points: Cocrystal Formation Thermodynamics Application

On the basis of the values contained in the literature published in 1900–2016, we have developed an experimental database including sublimation Gibbs energies, enthalpies, and melting temperatures of 1515 compounds. We have also suggested an algorithm of database fragmentation which includes groups/clusters with structurally similar compounds. For this aim we used Tanimoto similarity coefficients. Clusterization was carried out for each substance of the test set. All the points within a cluster were smoothed by a linear function in the coordinates of Gibbs energy vs melting temperature. Using the training and test sets, it has been shown that the algorithm suggested by us describes experimental data well (rms = 3.89 kJ·mol^–1). We have developed quantitative structure–property relationship models based on HYBOT physicochemical descriptors and melting points in order to predict sublimation Gibbs energies and enthalpies of molecular crystals. The developed approach was applied to determine cocrystal formation thermodynamics. Twenty nine out of 30 seven cocrystals selected in the literature have been predicted correctly (78% of the correct matches)

Thermodynamic Approaches to the Challenges of Solubility in Drug Discovery and Development

This paper considers fundamental aspects determining the processes of drug compound dissolution and distribution in solvents/systems modeling biological media. Special attention is paid to the complex analysis of thermodynamic functions of sublimation and solvation/hydration processes during structural modification of lead/hit compounds and their influence on dissolution processes. The paper shows that at the first stages of drug design it is necessary to develop algorithms of optimizing the properties determining absorption, distribution, metabolism, and excretion (ADME) characteristics of molecules: in particular, diffusion flux density through lipophilic membranes. Using sulfonamides and nonsteroidal anti-inflammatory drugs (NSAIDs) as an example, we have demonstrated the efficiency of approaches to manipulating thermodynamic functions of the basic processes that result from delivering compounds to the points of their operation. We have formulated several criteria of compound selection for further tests

Three Polymorphic Forms of Ciprofloxacin Maleate: Formation Pathways, Crystal Structures, Calculations, and Thermodynamic Stability Aspects

Polymorphism of the pharmaceutical salt of ciprofloxacin with maleic acid has been investigated. Ciprofloxacin maleate was found to exist in three polymorphic forms and one hydrate. The formation pathways of the salt polymorphs were elucidated by using solvent screening of the mechanochemical synthesis. It has been found that the mechanochemical reaction of the salt formation consists of two steps, including the formation of a kinetic polymorph as a transitional stage and its conversion into a thermodynamically favorable form. The thermodynamic relationships between the polymorphs were rationalized based on solubility and solution calorimetry measurements. The pattern of intermolecular interactions and crystal lattice energies of the polymorphs were quantified by solid-state density functional theory followed by Bader analysis of periodic electron density

New Solid Forms of the Antiviral Drug Arbidol: Crystal Structures, Thermodynamic Stability, and Solubility

Salts of the antiviral drug Arbidol (umifenovir) with pharmaceutically relevant benzoate and salicylate anions were obtained, and their crystal structures were described. For Arbidol salicylate, an unstable solvate with acetonitrile was also found and characterized. Analysis of the conformational preferences of the Arbidol molecule in the crystal structures showed that it adopts two types of conformations, namely “open” and “closed”, both of which correspond to local conformational energy minima of the isolated molecule. Thermal stability of the Arbidol salicylate solvates with chloroform and acetonitrile was analyzed by means of differential scanning calorimetry and thermogravimetric analysis. The standard thermodynamic functions of the salt formation were determined. The Gibbs energy change of the process was found to be negative, indicating that the formation of the salts from individual components is a spontaneous process. The dissolution study of the Arbidol salts performed in aqueous buffer solutions with pH 1.2 and 6.8 showed that both salts dissolve incongruently to form an Arbidol hydrochloride monohydrate at pH 1.2 and an Arbidol base at pH 6.8, respectively

Hydrogen Bond Donor/Acceptor Ratios of the Coformers: Do They Really Matter for the Prediction of Molecular Packing in Cocrystals? The Case of Benzamide Derivatives with Dicarboxylic Acids

Seven new 4-aminobenzamide cocrystals/salts with dicarboxylic acids and one 4-hydroxybenzamide/malonic acid 1:1 cocrystal have been obtained and characterized. Analysis of the Cambridge Structural Database of para-substituted benzamide derivatives cocrystals with dicarboxylic acids has been carried out to understand the influence of hydrogen bond donor/acceptor ratios of the coformers on molecular packing similarity in cocrystals. The concept of supramolecular constructs has been used to compare 37 benzamide derivatives cocrystals/salts. Common zero- to three-dimensional structure fragments have been identified and discussed. Two types of zero-dimensional and two types of one-dimensional fragments of closely para-substituted benzamide derivatives have been identified as the dominating motifs. It has been identified that a deviation from the ratio of hydrogen bond donors and acceptors in cocrystal formers increases the probability of formation of multicomponent crystal solvates. In a number of groups of similarly packed crystals, the minimal values of dissimilarity index X (which means maximal likelihood) are observed for the pairs of structures with halogen-substituted benzamide cocrystals. This study is helpful for understanding cocrystal formation mechanisms and has a high significance for crystal engineering

Cocrystal and Coamorphous Solid Forms of Enzalutamide with Saccharin: Structural Characterization and Dissolution Studies

Cocrystallization and coamorphization are similar yet independent approaches toward modifying various pharmaceutically relevant properties of modern drug compounds, in particular, solubility, dissolution rate, and the associated bioavailability. In this work, both strategies were applied to enzalutamide (Enz), a poorly soluble nonsteroidal antiandrogen drug, which led to the development of new multicomponent crystalline and amorphous solid forms of the drug with saccharin (Schr) in a 1:1 molar ratio. The structural analysis of the cocrystal formed by Enz and Schr revealed multiple intermolecular interactions between the components. Both Enz···Enz and Schr···Schr interactions were observed in the crystal packing. With the aid of N–H···O, C–H···O, C–H···N, and C–H···S hydrogen bonds, the molecules were aggregated into a three-dimensional hydrogen-bonded network. In the coamorphous composition, however, the components do not seem to involve in any strong intermolecular interactions and undergo recrystallization separately upon storage at room and elevated temperatures. The thermodynamic solubility of the cocrystal, evaluated using eutectic concentrations of the components, was found to be higher than that of the parent enzalutamide over an entire range of physiological pH values. The advantages and drawbacks of both formulation methods were analyzed and discussed, taking into account a tradeoff between physical stability and dissolution performance of the considered coamorphous composition and the cocrystal

Crystallization and Polymorphism of Felodipine

Two previously known polymorphs (forms I and II) and two new polymorphs (forms III and IV) of the calcium-channel blocker felodipine were obtained during attempts to cocrystallize the compound with a variety of potential cocrystal formers. A correlation was observed between the polymorphic outcome and the effective pH value in the presence of the cocrystal former, and it was possible subsequently to produce the four polymorphs by pH adjustment using H₂SO₄(aq) or NaOH­(aq). This suggests that there is no distinct “structure-directing” role for the molecular additives present during the cocrystallization trials. The crystal structures of the new forms III and IV were determined using single-crystal X-ray diffraction. Forms I, II, and III were obtained in bulk form and characterized by a variety of analytical methods, including thermal analysis, solution calorimetry, intrinsic dissolution rate measurement, and solubility measurement. Form IV could be obtained only as a few isolated single crystals, and its crystallization could not be reproduced. On the basis of the measured thermochemical data and solubility studies, form I appears to be the thermodynamically most stable phase at ambient conditions, although the new form III is practically isoenergetic. Form II shows the highest solubility and intrinsic dissolution rate, consistent with the lowest thermodynamic stability. Forms I, II, and III are all monotropically related

Novel Spiro-Derivatives of 1,3-Thiazine Molecular Crystals: Structural and Thermodynamic Aspects

Crystal structures of 10 spiro-derivatives of 1,3-thiazine were determined by X-ray diffraction technique. Molecular conformational states, packing architecture, and hydrogen bond networks were studied using graph set notations. Selected compounds were grouped within two classes with chains and dimer crystal structure organization. The sublimation thermodynamic aspects of the spiro-derivatives of 1,3-thiazine were investigated via temperature dependence of vapor pressure using the transpiration method. Thermophysical study of fusion processes of the molecular crystals was carried out and relationships between thermodynamic characteristics of sublimation (fusion) processes and crystal structure parameters were obtained. The influence of various molecular fragments on packing crystal energy was analyzed

Novel Spiro-Derivatives of 1,3-Thiazine Molecular Crystals: Structural and Thermodynamic Aspects

Crystal structures of 10 spiro-derivatives of 1,3-thiazine were determined by X-ray diffraction technique. Molecular conformational states, packing architecture, and hydrogen bond networks were studied using graph set notations. Selected compounds were grouped within two classes with chains and dimer crystal structure organization. The sublimation thermodynamic aspects of the spiro-derivatives of 1,3-thiazine were investigated via temperature dependence of vapor pressure using the transpiration method. Thermophysical study of fusion processes of the molecular crystals was carried out and relationships between thermodynamic characteristics of sublimation (fusion) processes and crystal structure parameters were obtained. The influence of various molecular fragments on packing crystal energy was analyzed

Scarabaeus sp.

Crystal structures of 10 spiro-derivatives of 1,3-thiazine were determined by X-ray diffraction technique. Molecular conformational states, packing architecture, and hydrogen bond networks were studied using graph set notations. Selected compounds were grouped within two classes with chains and dimer crystal structure organization. The sublimation thermodynamic aspects of the spiro-derivatives of 1,3-thiazine were investigated via temperature dependence of vapor pressure using the transpiration method. Thermophysical study of fusion processes of the molecular crystals was carried out and relationships between thermodynamic characteristics of sublimation (fusion) processes and crystal structure parameters were obtained. The influence of various molecular fragments on packing crystal energy was analyzed