4 research outputs found
Pharmaceutical Salts of Biologically Active Hydrazone Compound Salinazid: Crystallographic, Solubility, and Thermodynamic Aspects
The crystal structures of salts of
the active pharmaceutical ingredient
(API) called salinazid with dicarboxylic acids and acesulfame were
determined by single-crystal X-ray diffraction method. The crystals
contain hydrogen bond motifs of different structure and complexity,
the energies of which were estimated by using the quantum theory of
atoms in molecules and crystals (QTAIMC) methodology. It was found
that the driving force for facile the oxalate and malate salts formation
is the bifurcated N<sup>+</sup>âH···O<sup>â</sup> and N<sup>+</sup>âH···O hydrogen bond synthon,
while salinazid malonate is mainly stabilized via a âclassicâ
pyridinium-carboxylate heterosynthon. The oxalate and acesulfame salts
of salinazid were found to be stable during aqueous dissolution experiments,
providing a substantial solubility improvement compared to pure API
(33 and 18 times, respectively). However, the malonate and malate
salts dissolved incongruently and rapidly underwent a solution-mediated
transformation to form pure salinazid. Based on the solubility data
of the stable salts and of the pure components, the Gibbs free energy
of the salts formation were calculated to be â21.2 kJ·mol<sup>â1</sup> for salinazid oxalate and â22.6 kJ·mol<sup>â1</sup> for salinazid acesulfame
Weak Interactions Cause Packing Polymorphism in Pharmaceutical Two-Component Crystals. The Case Study of the Salicylamide Cocrystal
Two
polymorphs of the salicylamide cocrystal with oxalic acid have
been obtained and described. Form I of the cocrystal was prepared
by three alternative methods in various solvents, while formation
of form II was achieved only by a special crystallization procedure.
Single-crystal X-ray analysis has revealed that polymorphs consist
of conformationally identical salicylamide and oxalic acid molecules,
which are assembled into supramolecular units connected via a network
of very similar hydrogen bonds. The packing arrangements of the cocrystal
polymorphs, however, were found to be different, suggesting a rare
example of packing polymorphism. The stability relationship between
the polymorphs has been rationalized by using a number of experimental
methods, including thermochemical analysis, solubility, and solution
calorimetry measurements. Similarities and differences in intermolecular
contacts across two polymorphs have been visualized using the Hirshfeld
surface analysis. The Bader analysis of the theoretical electron density
has enabled us to quantify the pattern of noncovalent interactions
in the considered cocrystals. Applicability of different theoretical
schemes for evaluation of the lattice energy of the two-component
organic crystals has been discussed
Evaluation of the Lattice Energy of the Two-Component Molecular Crystals Using Solid-State Density Functional Theory
The lattice energy <i>E</i><sub>latt</sub> of the two-component
crystals (three co-crystals, a salt, and a hydrate) is evaluated using
two schemes. The first one is based on the total energy of the crystal
and its components computed using the solid-state density functional
theory method with the plane-wave basis set. The second approach explores
intermolecular energies estimated using the bond critical point parameters
obtained from the Bader analysis of crystalline electron density or
the pairwise potentials. The <i>E</i><sub>latt</sub> values
of two-component crystals are found to be lower or equal to the sum
of the absolute sublimation enthalpies of the pure components. The
computed energies of the supramolecular synthons vary from âŒ80
to âŒ30 kJ/mol and decrease in the following order: acidâamide
> acidâpyridine > hydroxylâacid > amideâamide
> hydroxylâpyridine. The contributions from different types
of noncovalent interactions to the <i>E</i><sub>latt</sub> value are analyzed. We found that at least 50% of the lattice energy
comes from the heterosynthon and a few relatively strong H-bonds between
the heterodimer and the adjacent molecules
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