RESUMO
Four aromatic acid compounds: benzoic acid (Bz), 4-hydroxyphenylpropionic acid (HPPA), gallic acid (GA) and 4-aminobenzoic acid (PABA) were covalently bonded to chitosan in order to improve water solubility at neutral pH. The synthesis was performed via a radical redox reaction in heterogeneous phase by employing ascorbic acid and hydrogen peroxide (AA/H2O2) as radical initiators in ethanol. The analysis of chemical structure and conformational changes on acetylated chitosan was also the focus of this research. Grafted samples exhibited as high as 0.46 M degree of substitution (MS) and excellent solubility in water at neutral pH. Results showed a correlation between the disruption of C3-C5 (O3 O5) hydrogen bonds with increasing solubility in grafted samples. Spectroscopic techniques such as FT-IR and 1H and 13C NMR showed modifications in both glucosamine and N-Acetyl-glucosamine units by ester and amide linkage at C2, C3 and C6 position, respectively. Finally, loss of crystalline structure of 2-helical conformation of chitosan after grafting was observed by XRD and correlated with 13C CP-MAS-NMR analyses.
RESUMO
A new polymorphic form of the title compound, C12H10O4, is described in the ortho-rhom-bic space group Pbca and Z = 8, as compared to polymorph I, which crystallizes in the monoclinic space group C2/c and Z = 8 [Li et al. (2012). Chin. J. Struct. Chem. 31, 1003-1007.]. In polymorph II, the coumarin ring system is almost planar (r.m.s. deviation = 0.00129â Å). In the crystal, mol-ecules are connected by Csp 3-Hâ¯O and Car-Hâ¯O hydrogen bonds, forming mol-ecular sheets linked into zigzag shaped layers along the b-axis direction. The three-dimensional lattice is assembled through stacking of the zigzag layers by π-π inter-actions with a centroid-to-centroid distance of 3.600â (9)â Å and anti-parallel C=Oâ¯C=O inter-actions with a distance of 3.1986â (17)â Å, which give rise to a helical supra-molecular architecture.
RESUMO
Mebendazole (MBZ), designated as a WHO essential drug, can exist in diverse solid forms and presents low absorption at the gastrointestinal level. Considering the potential of cyclodextrins to enhance the solubility and permeability of drugs, inclusion complexes of polymorphs A and C of MBZ with ßcyclodextrin were obtained. The characterization of the complexes in solid state was performed by using a combination of experimental techniques including Fourier transform infrared spectroscopy, powder X-ray diffractometry and solid state nuclear magnetic resonance. Moreover, the effect of the binary complexes on their physical stability was evaluated. In addition, for a complete characterization of polymorphs A and C, one dimensional spectra and correlation nuclear magnetic resonance experiments were employed. Our physical studies showed that the inclusion complexes were new crystalline forms that induced shifts and broadening in the infrared and nuclear spectra. A molecular modelling analysis performed on the inclusion modes, demonstrated that the most favourable structure for the complex was the head down orientation. Moreover, the intermolecular interactions calculated for the complex with the atoms in molecules theory are in good agreement with the spectroscopic results. The inclusion complexes exhibited an increment of solubility in simulated physiological media. Furthermore, it was demonstrated that the complex formation did not affect the physical stability of the polymorphs.
Assuntos
Anti-Helmínticos/química , Mebendazol/química , beta-Ciclodextrinas/química , Cristalização , Modelos MolecularesRESUMO
Current regulations command to properly characterize pharmaceutically relevant solid systems. Chemometrics comprise a range of valuable tools, suitable to process large amounts of data and extract valuable information hidden in their structure. This review aims to detail the results of the fruitful association between analytical techniques and chemometrics methods, focusing on those which help to gain insight into the characteristics of drug polymorphism as an important aspect of the solid state of bulk drugs and drug products. Hence, the combination of Raman, terahertz, mid- and near- infrared spectroscopies, as well as instrumental signals resulting from X-ray powder diffraction, 13C solid state nuclear magnetic resonance spectroscopy and thermal methods with quali-and quantitative chemometrics methodologies are examined. The main issues reviewed, concerning pharmaceutical drug polymorphism, include the use of chemometrics-based approaches to perform polymorph classification and assignment of polymorphic identity, as well as the determination of given polymorphs in simple mixtures and complex systems. Aspects such as the solvation/desolvation of solids, phase transformation, crystallinity and the recrystallization from the amorphous state are also discussed. A brief perspective of the field for the next future is provided, based on the developments of the last decade and the current state of the art of analytical instrumentation and chemometrics methodologies.
Assuntos
Química Farmacêutica/métodos , Cristalização/métodos , Espectroscopia de Ressonância Magnética/métodos , Preparações Farmacêuticas/análise , Análise Espectral Raman/métodos , Preparações Farmacêuticas/química , Difração de Raios X/métodosRESUMO
Progesterone is a natural hormone steroid used in humans for several treatments and in livestock for artificial insemination, which exhibits two polymorphic forms at ambient conditions: form 1 and form 2. Form 2 is metastable and more soluble than form 1; however, it is not suitable to use as powder raw material because it transforms into form 1 by the effects of grinding. A polymorphic screening of progesterone based on polymer-induced heteronucleation method was performed as an alternative to prepare the metastable form. Polyvinyl alcohol, hydroxypropyl methylcellulose (HPMC), dextran, gelatin, polyisoprene (PI) and acrylonitrile-butadiene (NBR) copolymer were used. Crystals were prepared from 0.5, 10 and 40 mg/mL solutions in acetone at room temperature by solvent evaporation. The samples were characterized by X-ray powder diffraction, differential scanning calorimetry (DSC), scanning electron microcopy and attenuated total reflectance infrared Fourier transform spectroscopy. Form 1 was nucleated from 40 mg/mL solutions on the six polymers and from 10 mg/mL solutions on PI and NBR. The mixture of form 1 and form 2 was obtained from 10 mg/mL solution on HPMC, dextran and gelatin and from 0.5 mg/mL solution crystallizations. Therefore, the polymeric devices, which crystallized the metastable and more soluble polymorph (2) of progesterone, would be a promissory alternative for the pharmaceutical applications.
Assuntos
Polímeros/química , Progesterona/química , Progestinas/química , Varredura Diferencial de Calorimetria , Química Farmacêutica/métodos , Cristalização , Estabilidade de Medicamentos , Microscopia Eletrônica de Varredura , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios XRESUMO
Se explica lo que es un sólido cristalino y el polimorfismo en general. Se muestra la relación estructura cristalina/propiedades físicas y químicas a partir del átomo de carbono. Se entrega la definición de polimorfismo de la FDA. Se muestra el polimorfismo del paracetamol y se dan algunas cifras relativas a la existencia del polimorfismo en principios activos de medicamentos. Se explica que la consecuencia más importante para los polimorfos farmacéuticos es la diferencia de solubilidad y cómo eso afecta propiedades como la biodisponibilidad y la bioequivalencia, entre otras. Se muestra la dificultad de elaboración de formas farmacéuticas a partir de polimorfos específicos a través del caso emblemático del medicamento Ritonavir. Se muestran las consecuencias económicas y de salud pública en América Latina a partir de una experiencia en países vecinos como Brasil y Argentina y se informa de una Resolución del ISP en Chile que reconoce la existencia de los polimorfos y su importancia en la estabilidad y Bio-Disponibilidad de los productos farmacéuticos.
An explanation is given of crystalline solids and polymorphism in general. The crystal structure/chemical and physical properties relation is illustrated for the element carbon. The FDA's definition of polymorphism is given. The polymorphism of phenacetin (para-acetylaminophenol) is shown and some figures are given for the existence of polymorphism in medicinal active principles. The fact that solubility difference is the most important consequence of pharmaceutical polymorphs is stated, and how it affects properties like bioavailability and bioactivity, among others, is explained. The difficulty of making pharmaceutical preparations from specific polymorphs is illustrated by means of the emblematic case of the drug Ritonavir. The economic and public health consequences in Latin America are shown using the experience of neighboring countries like Brazil and Argentina, and a Resolution of the Public Health Institute (ISP) of Chile in relation to the polymorphism is reported.