Los cocristales farmacéuticos: Conceptos generales.

Pharmaceutical co-crystals emerge as a possibility to improve the biopharmaceutical properties and pharmacotechnical of an Active Pharmaceutical Ingredient (API). Theco-crystalsare crystalline solids composed of an API and a former, which are located in the same crystal cell. The search for new pharmaceutical co-crystals is the responsibility of supramolecular chemistry, since the formerand the API are held together by non-covalent interactions. Solution and solid state methods are employed for the formation of cocrystals. In addition, this field offers a possibility of intellectual development due to the patentability of products, without neglecting the regulatory aspects. This work presents the main concepts considered for the study of these pharmaceutical solids.Los cocristales farmacéuticos surgen como una posibilidad para mejorar las propiedades biofarmacéuticas y farmacotécnicas de un IFA (Ingrediente Farmacéutico Activo). Los cocristales farmacéuticos son sólidos cristalinos constituidos por un IFA y un formador, los cuales se encuentran en la misma celda cristalina. La búsqueda de nuevos cocristales farmacéuticos es competencia de la química supramolecular, ya que el IFA y el formador se mantienen juntos mediante interacciones no covalentes. Existen métodos en solución y en sólidos para la formación de cocristales. Además, este campo ofrece una posibilidad de desarrollo intelectual debido a la posibilidad de patentar los productos, considerando los parámetros regulatorios. Este trabajo presenta los principales conceptos que se consideran para el estudio de estos sólidos farmacéuticos

Investigation of the role of stereoelectronic effects in the conformation of piperidones by NMR spectroscopy and X-ray diffraction

This paper reports the synthesis of a series of piperidones 1–8 by the Mannich reaction and analysis of their structures and conformations in solution by NMR and mass spectrometry. The six-membered rings in 2,4,6,8-tetraphenyl-3,7-diazabicyclo[3.3.1]nonan-9-ones, compounds 1 and 2, adopt a chair–boat conformation, while those in 2,4-diphenyl-3-azabicyclo[3.3.1]nonan-9-ones, compounds 3–8, adopt a chair–chair conformation because of stereoelectronic effects. These stereoelectronic effects were analyzed by the 1JC–H coupling constants, which were measured in the 13C satellites of the 1H NMR spectra obtained with the hetero-dqf pulse sequence. In the solid state, these stereoelectronic effects were investigated by measurement of X-ray diffraction data, the molecular geometry (torsional bond angles and bond distances), and inter- and intramolecular interactions, and by natural bond orbital analysis, which was performed using density functional theory at the ωB97XD/6311++G(d,p) level. We found that one of the main factors influencing the conformational stability of 3–8 is the interaction between the lone-pair electrons of nitrogen and the antibonding sigma orbital of C(7)–Heq (nN→σ*C–H(7)eq), a type of hyperconjugative interaction

Mechanochemical Synthesis of the Catechol-Theophylline Cocrystal: Spectroscopic Characterization and Molecular Structure

Pharmaceutical cocrystallization offers the possibility to modify the physicochemical and biopharmaceutical properties of active pharmaceutical ingredients. The mechanochemical synthesis and spectroscopic characterization of the catechol-theophylline (CAT-TEO) cocrystal is reported. The cocrystal was prepared by the solvent-assisted grinding method. The ATR-IR spectroscopy study allowed to determine the formation of the cocrystal because the O-H and C=O stretching bands in the CAT-TEO cocrystal were shifted with respect to the starting materials, suggesting the formation of the C=O···H-O hydrogen bond interaction. Infrared spectroscopy also allowed to discard hydration of the cocrystal, and polymorphic transitions of the starting products as a consequence of the mechanochemical grinding. The X-ray powder diffraction and thermal studies confirmed the formation of a new solid phase. In the solid state 13C NMR spectra of the cocrystal, the signals were shifted with respect to the starting products. The 13C NMR chemical shifts of the CAT-TEO cocrystal were simulated by using the gauge including the atomic orbital (GIAO) method. These results showed a good correlation between the experimental and calculated 13C NMR results. Theoretical calculations and natural bonding orbital analysis (NBO) at a B3LYP/6-31G(d,p) level of theory were performed to obtain structural information of the cocrystal

NMR Structural Study of the Prototropic Equilibrium in Solution of Schiff Bases as Model Compounds

An NMR titration method has been used to simultaneously measure the acid dissociation constant (pKa) and the intramolecular NHO prototropic constant ΔKNHO on a set of Schiff bases. The model compounds were synthesized from benzylamine and substituted ortho-hydroxyaldehydes, appropriately substituted with electron-donating and electron-withdrawing groups to modulate the acidity of the intramolecular NHO hydrogen bond. The structure in solution was established by 1H-, 13C- and 15N-NMR spectroscopy. The physicochemical parameters of the intramolecular NHO hydrogen bond (pKa, ΔKNHO and ΔΔG°) were obtained from 1H-NMR titration data and pH measurements. The Henderson–Hasselbalch data analysis indicated that the systems are weakly acidic, and the predominant NHO equilibrium was established using Polster–Lachmann δ-diagram analysis and Perrin model data linearization