Alexander P. Voronin

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.

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.

Influence of Secondary Interactions on the Structure, Sublimation Thermodynamics, and Solubility of Salicylate:4-Hydroxybenzamide Cocrystals. Combined Experimental and Theoretical Study.

Cocrystal screening of 4-hydroxybenzamide with a number of salicylates (salicylic acid, SA; 4-aminosalicylic acid, PASA; acetylsalicylic acid, ASA; and salicylsalicylic acid, SSA) was conducted to confirm the formation of two cocrystals, [SA+4-OHBZA] (1:1) and [PASA+4-OHBZA] (1:1). Their structures were determined using single-crystal X-ray diffraction, and the hydrogen-bond network topology was studied. Thermodynamic characteristics of salicylic acid cocrystal sublimation were obtained experimentally. It was proved that PASA cocrystallization with 4-OHBZA makes the drug more stable and prevents the irreversible process of decarboxylation of PASA resulting in formation of toxic 3-aminophenol. The pattern of non-covalent interactions in the cocrystals is described quantitatively using solid-state density functional theory followed by Bader analysis of the periodic electron density. It has been found that the total energy of secondary interactions between synthon atoms and the side hydroxyl group of the acid molecule in [SA+4-OHBZA] (1:1) and [PASA+4-OHBZA] (1:1) cocrystals is comparable to the energy of the primary acid-amide heterosynthon. The theoretical value of the sublimation enthalpy of [SA+4-OHBZA], 231 kJ/mol, agrees fairly well with the experimental one, 272 kJ/mol. The dissolution experiments with [SA+4-OHBZA] have proved that the relatively large cocrystal stability in relation to the stability of its components has a negative effect on the dissolution rate and equilibrium solubility. The [PASA+4-OHBZA] (1:1) cocrystal showed an enhancement of apparent solubility compared to that of the corresponding pure active pharmaceutical ingredient, while their intrinsic dissolution rates are comparable.

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.

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 .

Structural and energetic aspects of adamantane and memantine derivatives of sulfonamide molecular crystals: experimental and theoretical characterisation

A number of new sulfonamide compounds with adamantane and memantine fragments were synthesised and characterised. Their single crystals were grown and crystal structures were determined. XPac analysis has revealed three sets of isostructural crystals based on adamantane/memantine-specific hydrogen bond patterns. The use of QTAIMC and Hirshfeld surface analysis allowed elucidating the influence of functional groups and molecular arrangement on the strength of inter- and intramolecular non-covalent interactions in crystals and overall packing efficiency. It was found that the bulky memantine fragment hinders the formation of C(4) hydrogen-bonded chains, leading to the formation of dimeric structures with lower stabilisation energy. The layered packing of hydrophobic fragments in the group of isostructural crystals was found to be the most effective for a group of adamantane derivatives of P21/c symmetry.

Diversity of crystal structures and physicochemical properties of ciprofloxacin and norfloxacin salts with fumaric acid

The crystallization of norfloxacin and ciprofloxacin – antibacterial fluoroquinolone compounds – with fumaric acid resulted in the isolation of six distinct solid forms of the drugs with different stoichiometries and hydration levels. Each salt can be selectively obtained by mechanochemical treatment in the presence of water/organic mixtures of a particular composition. The new phases were analysed using TG, DSC and PXRD, and their structural parameters were determined using single crystal X-ray diffraction. Despite having the same counterion, the ciprofloxacin and norfloxacin fumarates crystallise to form distinct crystal structures, which consequently determine the differences in the relative stability and the corresponding physicochemical properties of the solid forms. The influence of water activity (aw) on the solid form stability and transformation pathways of anhydrous and hydrated fumarates was elucidated. The solubility and phase stability of the salts were also investigated in pharmaceutically relevant buffer solutions with pH 6.8 and pH 1.2. The largest solubility improvement relative to the parent drug (≈33 times) in the pH 6.8 medium was observed in the case of ciprofloxacin hemifumarate sesquihydrate. In turn, the norfloxacin fumarates showed a moderate 3-fold enhancement in solubility.

Specific features of supramolecular organisation and hydrogen bonding in proline cocrystals: a case study of fenamates and diclofenac

New zwitterionic cocrystals of fenamate drugs and diclofenac with the naturally occurring amino acid L-proline have been obtained and thoroughly characterised by a variety of experimental and theoretical techniques. A crystal structure analysis and a CSD survey allowed us to establish a distinct supramolecular motif formed by the double chain arrangement of proline entities, which was found to play the structure-directing role in the proline zwitterionic cocrystals. Special graph set notation has been introduced to describe the particular type of the bifurcated H-bond observed in the crystal structures of proline with different APIs. Solid state DFT calculations enabled us to quantify different intermolecular interactions in the new cocrystals obtained, to interpret specific features of supramolecular organisation, and to explain the reasons for selective cocrystallisation of L-proline with fenamates. Cocrystallisation of the diclofenac and fenamate APIs with L-proline improved the solubility of these drugs in comparison with the parent drugs. The cocrystal solubility advantage values determined from eutectic concentrations at pH 6.8 and 25.0 °C were found to be in the range from 9 to 25.

Pharmaceutical salts of emoxypine with di­carb­ox­ylic acids

New salt forms of the antioxidant drug emoxypine (EMX, 2-ethyl-6-methylpyridin-3-ol) with pharmaceutically acceptable maleic (Mlt), malonic (Mln) and adipic (Adp) acids were obtained {emoxypinium maleate, C8H12NO+·C4H3O4-, [EMX+Mlt], emoxypinium malonate, C8H12NO+·C3H3O4-, [EMX+Mln], and emoxypinium adipate, C8H12NO+·C6H9O4-, [EMX+Adp]} and their crystal structures determined. The molecular packing in the three EMX salts was studied by means of solid-state density functional theory (DFT), followed by QTAIMC (quantum theory of atoms in molecules and crystals) analysis. It was found that the major contribution to the packing energy comes from pyridine-carboxylate and hydroxy-carboxylate heterosynthons forming infinite one-dimensional ribbons, with [EMX+Adp] additionally stabilized by hydrogen-bonded C(9) chains of Adp- ions. The melting processes of the [EMX+Mlt] (1:1), [EMX+Mln] (1:1) and [EMX+Adp] (1:1) salts were studied and the fusion enthalpy was found to increase with the increase of the calculated lattice energy. The dissolution process of the EMX salts in buffer (pH 7.4) was also studied. It was found that the formation of binary crystals of EMX with dicarboxylic acids increases the EMX solubility by more than 30 times compared to its pure form.