German L. Perlovich

Thermodynamics of solutions. II. Flurbiprofen and diflunisal as models for studying solvation of drug substances

Three independent methods (sublimation, solubility and solution calorimetry) were used to study the dissolution and solvation processes of diflunisal (DIF) and flurbiprofen (FBP). Thermodynamic functions for the sublimation of DIF and FBP were obtained. Concentrations of saturated solutions and standard solution enthalpies of DIF and FBP in aliphatic alcohols and individual organic solvents were measured. Correlation analysis between: (a) the thermodynamic functions for a substance in various solvents, and (b) the same functions for different compounds was carried out. The investigated substances can be arranged with increasing Gibbs energy of solvation as follows: benzoic acid<DIF<FBP. Enthalpy is found to be the major driving force of the solvation process for all the studied compounds. The ratio of specific and nonspecific solute-solvent interaction in terms of enthalpies (epsilon (H)) and in terms of entropies (epsilon (S)) was analyzed. Based on the experimental data, a compensation effect of thermodynamic solubility functions of the investigated substances both in alcohols and in organic solvents was found.

Solvation of Drugs as a Key for Understanding Partitioning and Passive Transport Exemplified by NSAIDs

Passive transport properties of drug molecules are of utmost importance for their pharmacological and biopharmaceutical effectiveness. Diffusion in different media and through lipid bilayers is in many cases the rate-determining step for the distribution in the body. In the present review an attempt is made to demonstrate the importance of solvation of drug molecules for the diffusion and partition/distribution in phases of different lipophilicity. Different approaches known in the literature to describe solvation of compounds with flexible conformation are discussed as well as the experimental methods to directly measure the energy of solvation. NSAIDs are chosen as an example of a class of drugs of different molecular structures that have already been studied thoroughly in many aspects, and a set of aliphatic alcohols can be used as a model for compartments of different lipophilic/hydrophilic properties. Thermodynamic characteristics of solvation of the drug molecules yielded by independent classical experimental methods (Gibbs energy, enthalpic and entropic terms of Gibbs energy) are studied in order to better understand diffusion and distribution properties. Correlations between in-vitro-data (partition coefficient, enthalpy of solvation) with biopharmaceutically relevant characteristics (plasma half-life) are also discussed.

Solvation and hydration characteristics of ibuprofen and acetylsalicylic acid

Ibuprofen and acetylsalicylic acid were studied by thermoanalytical methods: sublimation calorimetry, solution calorimetry, and with respect to solubility. Upon measuring the temperature dependences of the saturated vapor pressure, enthalpies of sublimation, ΔHsub0, as well as the entropies of sublimation, ΔHsub0, and their respective relative fractions in the total process were calculated. The Gibbs energy of solvation in aliphatic alcohols as well as the enthalpic and entropic fractions thereof were also studied and compared with the respective properties of model substances and other nonsteroidal antiinflammatory drugs (benzoic acid, diflunisal, flurbiprofen, ketoprofen, and naproxen). In all cases, enthalpy was found to be the driving force of the solvation process. Correlations were derived between Gibbs energy of solvation in octanol, ΔGsolvOct, and the transfer Gibbs energy from water to octanol, ΔGtr0. Influence of mutual octanol and water solubilities on the driving force of partitioning is discussed. An enthalpy-entropy-compensation effect in octanol was observed, and consequences of deviation from the general trend are also discussed.

Salicylamide Cocrystals: Screening, Crystal Structure, Sublimation Thermodynamics, Dissolution, and Solid-State DFT Calculations

A new cocrystal of 2-hydroxybenzamide (A) with 4-acetamidobenzoic acid (B) has been obtained by the DSC screening method. Thermophysical analysis of the aggregate [A:B] has been conducted and a fusion diagram has been plotted. Cocrystal formation from melts was studied by using thermomicroscopy. A cocrystal single-crystal was grown and its crystal structure was determined. The pattern of noncovalent interactions has been quantified using the solid-state DFT computations coupled with the Bader analysis of the periodic electron density. The sublimation processes of A-B cocrystal have been studied and its thermodynamic functions have been calculated. The classical method of substance transfer by inert gas-carrier was chosen to investigate sublimation processes experimentally. The lattice energy is found to be 143 ± 4 kJ/mol. It is lower than the sum of the corresponding values of the cocrystal pure components. The theoretical value of the lattice energy, 156 kJ/mol, is in reasonable agreement with the experimental one. A ternary phase diagram of solubility (A-B-ethanol) has been plotted and the areas with solutions for growing thermodynamically stable cocrystals have been determined.

Cocrystal screening of hydroxybenzamides with benzoic acid derivatives: A comparative study of thermal and solution-based methods

The main problem occurring at the early stages of cocrystal search is the choice of an effective screening technique. Among the most popular techniques of obtaining cocrystals are crystallization from solution, crystallization from melt and solvent-drop grinding. This paper represents a comparative analysis of the following screening techniques: DSC cocrystal screening method, thermal microscopy and saturation temperature method. The efficiency of different techniques of cocrystal screening was checked in 18 systems. Benzamide and benzoic acid derivatives were chosen as model systems due to their ability to form acid-amide supramolecular heterosynthon. The screening has confirmed the formation of 6 new cocrystals. The screening by the saturation temperature method has the highest screen-out rate but the smallest range of application. DSC screening has a satisfactory accuracy and allows screening over a short time. Thermal microscopy is most efficient as an additional technique used to interpret ambiguous DSC screening results. The study also included an analysis of the influence of solvent type and component solubility on cocrystal formation.

N-(4-Chloro­phen­yl)benzene­sulfonamide

The crystal structure of the title compound, C12H10ClNO2S, has been determined. The molecules of the substance form chains with adjacent molecules by means of hydrogen bonds, which create infinite helicoids along the b axis. The hydrogen-bond network can be described by the graph-set as C(4) (infinite chain with four atoms in the repeat pattern).

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.

Thermodynamic characteristics of cocrystal formation and melting points for rational design of pharmaceutical two-component systems

A database containing the fusion temperatures of two-component molecular cocrystals and individual compounds has been built based on literature analysis. Correlation equations were obtained connecting the fusion temperatures of cocrystals and individual components, which made it possible to design cocrystals with predictable fusion temperatures. An approach has been developed to estimate cocrystal sublimation thermodynamic characteristics. Thermodynamic functions of 79 cocrystals have been obtained and analyzed by the diagram method.

Volumetric properties of tetraphenylporphine, their metallo-complexes and some substituted tetraphenylporphines in benzene solution

Densities, apparent molar volumes and partial molar volumes of benzene solutions of tetraphenylporphine, H2TPP, tetraphenylporphine metallo-complexes, MTPP (where M=Ni,Cu,Zn,Pd,Ag, and Cd), and some substituted tetraphenylporphines H2T(i-R)PP (where i=2–4 and R=−Cl,−CH3,−OCH3) H2T(i-F)PP (where i-2,3), H2T(3-Br)PP, and H2T(3-I)PP were determined at 25°C. It was found that the partial molar volumes of the studied compounds correlate linearly with the first ionization potential of the corresponding metal atom. The calculated values of the surface and volume accessible to the solvent, and the solvent-excluded volume for different conformations of H2TPP, were compared with experimental data. The volume per molecule for different crystalline forms of H2TPP and MTPP were compared with the partial molar volumes of the corresponding compounds in benzene solutions. The correlation between the partial molar volumes of H2T(3-R)PP and their Van der Waals volumes are presented for R=−H, −F,−CH3,−Cl,−Br,−OCH3, and −I. The experimental data are rationalized in terms of differences in the conformational states of the molecules.