This Article reports the solvent-free synthesis and characterization of a number of different crystal forms of niclosamide (HNic), which is an API belonging to the Salicilamide class. The synthesized compounds are four new salt cocrystals (KNic·HNic·H 2 O, KNic·HNic·3H 2 O, NaNic· HNic·3H 2 O, NaNic·HNic·2H 2 O), a classic cocrystal with imidazole (IM) (HNic·IM), and two sodium salts, (NaNic· DMSO·H 2 O and NaNic·DMSO·2H 2 O). The peculiarity of these salt cocrystals is the API's concomitant presence as both a neutral component and as a salt coformer and the fact that they interact via hydrogen bond formation. HNic's poor aqueous solubility makes the enhancement of its dissolution rate via the modulation of its physical properties extremely important. All samples have been investigated using a combination of solid-state experimental techniques which provide complementary information on powdered samples. These techniques are X-ray powder diffraction, solid-state NMR, IR, and Raman. Single crystals were only obtained for KNic·HNic·H 2 O and NaNic·DMSO·2H 2 O. The nature of the adducts (whether salt or cocrystal), their stoichiometry and the presence of independent molecules in the unit cell of the other samples were thus all determined by means of solid-state NMR and the comparative analysis of 13 C and 15 N CPMAS (Cross-Polarization Magic Angle Spinning) and 1 H MAS spectra. Furthermore, differential scanning calorimetry, thermogravimetric analysis and intrinsic dissolution rate measurements completed the characterization and enabled us to evaluate the effects of microscopic changes (molecular packing, weak interactions, conformations, etc.) on the macroscopic properties (thermal stability and bioavailability) of the multicomponent forms. The results obtained indicate that the formation of salt cocrystals provides a reliable method with which to improve the HNic intrinsic dissolution rate.
Four lidocaine molecular salts of dicarboxylic acids (oxalic, fumaric, malonic, and succinic) were synthesized and characterized by a combined use of X-ray powder and single-crystal diffraction, differential scanning calorimetry, Fourier transform infrared spectroscopy (FT-IR), and solidstate NMR ( 1 H MAS and CRAMPS, and 13 C and 15 N CPMAS): all molecular salts show a dramatic increase in their melting point with respect to both lidocaine and lidocaine hydrochloride, and a higher dissolution rate and thermodynamic solubility in physiological solution with respect to the free base.
The variety of crystal forms that may be associated with one specific molecule of interest can be extremely large: in addition to polymorphs, all sorts of crystalline solids can be obtained, from molecular and ionic co-crystals to hydrates/solvates, to, needless to say, polymorphs of all these new crystal forms. Lack of predictability of crystallization experiments, far from representing a failure or a nuisance, should encourage in the crystal maker the same attitude shown by the three princes of Serendip (who were making unexpected discoveries by virtue of their "sagacity and readiness of mind") to be ready to pick new avenues as the crystal experiments will yield something unplanned for.
The possibility of
decreasing the solubility of the antidepressant
drug venlafaxine hydrochloride by formation of molecular salts with
organic acids accepted by the Pharmacopeia has been successfully investigated.
Reacting venlafaxine with coumaric, ferulic, oxalic, salicylic, fumaric,
and citric acids results in the protonation of the amino group and
formation of the corresponding 1:1 molecular salts. All compounds
have been characterized by a combination of solid state techniques,
i.e., single crystal and powder X-ray diffraction, thermogravimetric
analysis, differential scanning calorimetry, Fourier transform infrared
spectroscopy and solid-state NMR (1H MAS, 13C and 15N CPMAS, 1H DQ MAS, two-dimensional
(2D) 13C–1H HETCOR, and 2D 14N–1H J-HMQC) spectroscopy. Intrinsic dissolution
tests were performed on the pure salts, and suitable candidates were
selected for the preparation of solid formulations with excipients;
dissolution profiles for the solid formulations were measured in water
and sodium chloride solution, and compared with that of the commercial
form of venlafaxine, showing that the coumarate salt might represent
an improvement for extended release administrations.
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