Artem O. Surov

Pharmaceutical Cocrystals of Diflunisal and Diclofenac with Theophylline

Pharmaceutical cocrystals of nonsteroidal anti-inflammatory drugs diflunisal (DIF) and diclofenac (DIC) with theophylline (THP) were obtained, and their crystal structures were determined. In both of the crystal structures, molecules form a hydrogen bonded supramolecular unit consisting of a centrosymmetric dimer of THP and two molecules of active pharmaceutical ingredient (API). Crystal lattice energy calculations showed that the packing energy gain of the [DIC + THP] cocrystal is derived mainly from the dispersion energy, which dominates the structures of the cocrystals. The enthalpies of cocrystal formation were estimated by solution calorimetry, and their thermal stability was studied by differential scanning calorimetry. The cocrystals showed an enhancement of apparent solubility compared to the corresponding pure APIs, while the intrinsic dissolution rates are comparable. Both cocrystals demonstrated physical stability upon storing at different relative humidity.

Thermodynamic and structural study of tolfenamic acid polymorphs.

The article deals with the study of two polymorphic modifications in the space groups P2(1)/c (white form) and P2(1)/n (yellow form) of the tolfenamic acid. It also describes how the white form vapor pressure temperature dependence was determined by using the transpiration method and how thermodynamic parameters of the sublimation process were calculated. We have estimated the difference between the crystal lattice energies of the two polymorphic forms by solution calorimetry and found that the crystal lattice energy of the yellow form is 6.7+/-1.2 kJ mol(-1) higher than that of the white form, whereas Gibbs free energies of the forms obtained from the vapor pressure temperature dependence are practically the same. The modifications under consideration are monotropically related. From the practical point of view, the white form is more preferable due to its lower crystal lattice energy and better performing procedure. We have also studied the solubility, solvation and transfer processes of the tolfenamic acid white form in buffers (with various values of pH and ionic strengths), n-hexane and n-octanol. The thermodynamic parameters of the investigated processes have been discussed and compared with those determined for others fenamates. In the study we estimated specific and non-specific contributions of the solvation enthalpic term of the fenamate molecules with the solvents as well. The driving forces of the transfer processes from the buffers with pH 7.4 and different ionic strengths to n-octanol were analyzed. It was found that the relationship between the enthalpic and entropic terms depends essentially on the ionic strength. For the considered fenamates the transfer processes of the neutral molecules and the ionic forms are enthalpy-determined, whereas for the niflumic acid this process is entropy-determined.

Pharmaceutical salts of ciprofloxacin with dicarboxylic acids

New salts of antibiotic drug ciprofloxacin (CIP) with pharmaceutically acceptable maleic (Mlt), fumaric (Fum) and adipic (Adp) acids were obtained and their crystal structures were determined. The crystal lattices of the fumarate and adipate salts were found to accommodate the water molecules, while the maleate salt was anhydrous. The dehydration and melting processes were analyzed by means of differential scanning calorimetry and thermogravimetric analysis. Solubility and intrinsic dissolution rates of the salts were measured in pharmaceutically relevant buffer solutions with pH 1.2 and pH 6.8. Under acidic conditions, the salts were found to be less soluble than the parent form of drug, while the [CIP+Fum+H2O] and [CIP+Mlt] solids showed enhanced dissolution rate when compared to a commercially available ciprofloxacin hydrochloride hydrate. In the pH 6.8 solution, all the salts demonstrated solubility improvement and faster dissolution rate with respect to pure CIP.

Crystal architecture and physicochemical properties of felodipine solvates

Solvates of the calcium-channel blocking agent felodipine with three structurally related high-boiling point solvents, dimethylacetamide (DMAA), dimethylethyleneurea (DMEU) and tetramethylurea (TMU), are described. The solvates can be formed either by solution crystallisation or solvent-drop mechanical grinding. In all of the crystal structures, the solvent molecule accepts an N–H⋯O hydrogen bond from felodipine. Analysis of the conformational preferences of the felodipine molecule in the crystal structures shows that it adopts a higher-energy conformation in the solvate with TMU. Hot-stage microscopy shows that the solvates decompose below the boiling point of the solvent, then the solvent condenses and dissolves the desolvated felodipine. The decomposition temperature of the solvate is correlated with the van der Waals molecular volume for the solvent molecule within the crystal structure. Measurements of the aqueous dissolution rate show that the concentration of felodipine during the first hour is increased by 4–6 times for dissolution of the solvates compared to pure felodipine.

Cocrystals of the antiandrogenic drug bicalutamide: screening, crystal structures, formation thermodynamics and lattice energies

Two new cocrystals of the non-steroidal anti-androgen drug bicalutamide (Bic) are reported with benzamide (BZA) and salicylamide (2OHBZA), both in a 1 :  1 molar ratio. X-ray crystal structure analysis shows that both cocrystals contain a folded molecular conformation of bicalutamide, similar to that seen in polymorph II of the pure drug. Calculations of intermolecular interaction energies using the PIXEL approach indicate closely comparable total lattice energies for [Bic + BZA] and [Bic + 2OHBZA]. The structures are dominated by dispersion interactions, with a significant contribution also from the coulombic interactions, particularly in [Bic + BZA]. The main difference between the two cocrystals is seen for the bicalutamide–cocrystal former interaction energy, which is calculated to be slightly more stabilizing in [Bic + BZA]. The melting temperatures of the cocrystals (132 °C for [Bic + BZA] and 157 °C for [Bic + 2OHBZA]) are significantly lower than that of the pure API (193 °C). In general, the melting temperatures of all known bicalutamide cocrystals are shown to increase with an increase of the total van der Waals volume (Vvdw) of the molecules in the asymmetric unit of the crystal. The thermodynamic functions of the cocrystal formation were estimated from the solubility of the cocrystals and the corresponding solubility of the pure compounds in chloroform at various temperatures. In both cases, the Gibbs energy of formation was found to be small: −3.4 kJ mol–1 for [Bic + BZA] and −2.2 kJ mol−1 for [Bic + 2OHBZA]. The most significant contribution to the Gibbs energy is provided by the exothermic enthalpy of formation. However, the cocrystal formation is accompanied by a considerable decrease of the system entropy, which diminishes the overall driving force of the process. Both cocrystals demonstrated a classical “spring and parachute” behavior during aqueous dissolution, providing an increased concentration level of Bic compared to that of the parent drug for several hours.

Saccharin salts of biologically active hydrazone derivatives

The crystal structures of two saccharin salts with derivatives of an anti-tubercular drug isoniazid, namely vanillin isoniazid saccharinate (salt I) and salinazid saccharinate (salt II), were obtained in a X-ray diffraction experiment. The pattern of intermolecular interactions in the crystals was quantified by solid-state DFT followed by the Bader analysis of periodic electron density. It was established that ca. 42% of lattice energy is contributed by C–H⋯O contacts, while conventional hydrogen bonds have only ca. 28%. Salt I was found to show a 12-fold aqueous solubility improvement compared to pure API, whereas salt II is approximately 20 times more soluble than the starting salinazid. 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 most significant contribution to the Gibbs energy is provided by the enthalpy term, while the entropy change of the process has a negative value, introducing a positive contribution to .

Polymorphism of felodipine co-crystals with 4,4′-bipyridine

The calcium-channel blocking agent felodipine (Fel) forms co-crystals with 4,4′-bipyridine (BP) with 1 : 1 and 2 : 1 molar ratios. The [Fel + BP] (1 : 1) co-crystal exists in two polymorphic forms. Differential scanning calorimetry and solution calorimetry show that form I of the [Fel + BP] (1 : 1) co-crystal is the most thermodynamically stable phase. The difference in the crystal lattice energies between different polymorphs of the co-crystal is found to be comparable with that between the polymorphic forms of pure felodipine. The enthalpies of formation of the co-crystals are small, which indicates that the packing energy gain originates from only weak van der Waals interactions. Analysis of Hirshfeld surfaces of the felodipine molecule shows a similar distribution of intermolecular contacts in the co-crystals and pure felodipine.

Novel 1,2,4-thiadiazole derivatives: crystal structure, conformational analysis, hydrogen bond networks, calculations, and thermodynamic characteristics of crystal lattices.

The results of X-ray crystallographic and computational studies of twelve 1,2,4-thiadiazole derivatives are reported. The effect of orientation of different parts of the molecules on crystal organization and hydrogen bond network were studied. DFT calculations were carried out in order to explore conformational preferences of the molecules inside and outside of crystal environment. The role of hydrogen bonds was found to be essential for the stabilization of conformationally strained molecules as well as for the packing density of such molecules in a crystal. Thermodynamic aspects of sublimation processes of the studied compounds were analyzed using temperature dependencies of their vapor pressure. Thermophysical characteristics of the molecular crystals were obtained and compared with the sublimation enthalpy and the structural parameters. The influence of crystal structure features on the sublimation enthalpy and on the melting temperature was analyzed.

Diversity of felodipine solvates: structure and physicochemical properties

Solvates of the calcium-channel blocking agent felodipine with three structurally related common organic solvents, acetone (ATN), dimethyl sulfoxide (DMSO) and acetophenone (APN), are described. A relationship between the felodipine packing arrangement in all known solvates and the van der Waals volume of the solvent molecule is established. Intermolecular interaction energies in the crystals are examined using the PIXEL approach in order to rationalize the difference between alternative molecule packing arrangements. DSC studies show that the desolvation onset temperatures of the solvates are closely comparable, despite the large difference in the boiling points of the solvent molecules. The enthalpies of formation derived from the calorimetric data for the solvates are also found to be similar, despite the difference in the van der Waals volume of the solvent molecules.

Crystal structure analysis and sublimation thermodynamics of bicyclo derivatives of a neuroprotector family

The crystal structures of three new structurally related drug-like bicyclo derivatives are correlated with measured thermodynamic quantities for their sublimation and melting processes. The sublimation thermodynamics are determined using the temperature dependencies of the vapour pressure, and the melting processes are examined using differential scanning calorimetry. The three compounds contain a common N-(3-thia-1-azabicyclo[3.3.1]non-2-ylidene)aniline core, with either a CH3, F or CF3 substituent at the 4-position of the aniline ring. Lattice energy calculations are made using both the PIXEL and Coulomb-London-Pauli (CLP) models, and the conformational flexibility of the molecules is examined using gas-phase density functional theory (DFT) calculations. The experimentally measured crystal lattice energies (ΔH(0)sub) decrease in the order: CH3 > F > CF3. The calculated lattice energies using the PIXEL approach are in good agreement with the experimental values, and the partitioned intermolecular interaction energies suggest that dispersion contributions dominate the crystal structures of all three compounds. The sublimation energies and melting points are inversely correlated for the three molecules, with the melting points increasing in the order CF3 < F < CH3.