Thermally induced solid-state transformation of cimetidine. A multi-spectroscopic/chemometrics determination of the kinetics of the process and structural elucidation of one of the products as a stable N3-enamino tautomer.

Exposure of cimetidine (CIM) to dry heat (160-180°C) afforded, upon cooling, a glassy solid containing new and hitherto unknown products. The kinetics of this process was studied by a second order chemometrics-assisted multi-spectroscopic approach. Proton and carbon-13 nuclear magnetic resonance (NMR), as well as ultraviolet and infrared spectroscopic data were jointly used, whereas multivariate curve resolution with alternating least squares (MCR-ALS) was employed as the chemometrics method to extract process information. It was established that drug degradation follows a first order kinetics. One of the products was structurally characterized by mono- and bi-dimensional NMR experiments. It was found to be the N3-enamino tautomer (TAU) of CIM, resulting from the thermal isomerization of the double bond of the cyanoguanidine moiety of the drug, from the imine form to its N3-enamine state. The thus generated tautomer demonstrated to be stable for months in the glassy solid and in methanolic solutions. A theoretical study of CIM and TAU revealed that the latter is less stable; however, the energy barrier for tautomer interconversion is high enough, precluding the process to proceed rapidly at room temperature.

A PCA-based chemometrics-assisted ATR-FTIR approach for the classification of polymorphs of cimetidine: application to physical mixtures and tablets.

The identity of the polymorphic form of an active pharmaceutical ingredient is an important parameter that may affect the performance of the drug formulation. This calls for special techniques, able to classify crystal forms or assign the polymorphic identity to a given solid in a mixture. In order to develop a method to determine which of the relevant polymorphs of Cimetidine (CIM) is present in commercial tablet samples, authentic forms A, B, D and M1 of the drug were prepared, structurally characterized and employed as standards. Thus, attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) was coupled to Principal Component Analysis (PCA) and used for the classification of physical mixtures of CIM and excipients, as well as laboratory-made and commercial tablets, according to their polymorphic composition. It was demonstrated that two principal components (PCs) suffice to classify the samples of the four forms of CIM into distinct groups, and that method performance is optimum when the second and third PCs are used for the classification process. The application of the method to commercial tablets of CIM also gave good results, confirming they were prepared employing the correct polymorph (form A).

A dynamic thermal ATR-FTIR/chemometric approach to the analysis of polymorphic interconversions. Cimetidine as a model drug.

Crystal polymorphism of active ingredients is relevant to the pharmaceutical industry, since polymorphic changes taking place during manufacture or storage of pharmaceutical formulations can affect critical properties of the products. Cimetidine (CIM) has several relevant solid state forms, including four polymorphs (A, B, C and D), an amorphous form (AM) and a monohydrate (M1). Dehydration of M1 has been reported to yield mixtures of polymorphs A, B and C or just a single form. Standards of the solid forms of CIM were prepared and unequivocally characterized by FTIR spectroscopy, digital microscopy, differential scanning calorimetry and solid state (13)C NMR spectroscopy. Multivariate curve resolution with alternating least squares (MCR-ALS) was coupled to variable temperature attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) to dynamically characterize the behavior of form M1 of CIM over a temperature range from ambient to 160°C, without sample pretreatment. MCR-ALS analysis of ATR-FTIR spectra obtained from the tested solid under variable temperature conditions unveiled the pure spectra of the species involved in the polymorphic transitions. This allowed the simultaneous observation of thermochemical and thermophysical events associated to the changes involved in the solid forms, enabling their unequivocal identification and improving the understanding of their thermal behavior. It was demonstrated that under the experimental conditions, dehydration of M1 initially results in the formation of polymorph B; after melting and upon cooling, the latter yields an amorphous solid (AM). It was concluded that the ATR-FTIR/MCR association is a promising and useful technique for monitoring solid-state phase transformations.

Determinación de un Polimorfo de la Cimetidina mediante la calorimetría diferencial de barrido / Determination of a cimetidine polymorph by differential scanning calorimetry

Se estableció la diferencia entre 2 sustancias de masa molecular similar -la cimetidina A y la B-, pero de estructuras internas distintas, mediante el empleo de la técnica de calorimetría diferencial de barrido donde solamente una de ellas, la cimetidina B, posee la actividad farmacológica requerida, es decir, cumple con las especificaciones de la farmacopea(AU)

Determinación de un Polimorfo de la Cimetidina mediante la calorimetría diferencial de barrido / Determination of a cimetidine polymorph by differential scanning calorimetry

Se estableció la diferencia entre 2 sustancias de masa molecular similar -la cimetidina A y la B-, pero de estructuras internas distintas, mediante el empleo de la técnica de calorimetría diferencial de barrido donde solamente una de ellas, la cimetidina B, posee la actividad farmacológica requerida, es decir, cumple con las especificaciones de la farmacopea

[Theoretical conformation study of tiotidine and nizatidine, two strong histamine H2-receptor antagonists]. / Estudio teórico conformacional de tiotidina y nizatidina, dos potentes antagonistas en los receptores H2 de histamina.

A conformational study of two potent histamine H2-receptor antagonists, tiotidine and nizatidine, have been made. The geometry of cyanoguanidine and guanidinothiazol in tiotidine and diaminonitroetane in nizatidine was obtained using MNDO calculations. On the other hand, the conformations of the molecules, under study were obtained using a empirical atom-atom potential that stimulates the drug behavior in aqueous solution at 37 degrees C. For both molecules, folded and very rigid conformations, with a substantial parallelism between the planes of the rings and the polar groups, were obtained. All the possibilities of the configurational isomerism on the polar groups of this molecules was taken into account. The results obtained show that the polar group can adopt just staggered forms (Z,E and E,Z). These results agree with experimental and theoretical studies made on the polar group. The type of conformations found in tiotidine and nizatidine are very similar to those previously found for metiamide, cimetidine, ranitidine and etintidine. These results would permit us to propose that these conformations play a determinant role in the histamine H2-receptor recognition.

Estudio teorico conformacional de tiotidina y nizatidina, dos potentes antagonistas en los receptores H2 de histamina / Theoretical conformation study of tiotidine and nizatidine, two strong histamine H2-receptors antagonists

Se realizó un estudio conformacional de dos potentes antagonistas en los receptores de H2 de histamina, tiodidina y nizatidina. Las geometrías de los grupos cianoguanidina y guanidinotiazol de tiotidina y el grupo diaminonitroetano de nizatidina fueron calculadas utilizando técnicas MNDO de la química cuántica. Mientras que las conformaciones de las moléculas en estudio se obtuvieron empleando un potencial átomo-átomo empírico que simula el comportamiento de las drogas en solución acuosa a 37-C. Para ambas moléculas se obtuvieron conformaciones plegadas, muy rígidas con un marcado paralelismo entre el plano de los anillos y el de los grupos polares. En las dos moleculas en estudio todas las posibilidades de isomerismo configuracional de los grupos polares fueron tenidas en cuenta: encontrándose que las únicas conformaciones posible son aquellas que tienen los grupos polares en la forma de los isómeros cruzados (Z-E o E-Z). Estos resultados están totalmente de acuerdo con los estudios experimentales y teóricos realizados en estos grupos polares. El tipo de conformaciones encontradas por totidina y nizatidina son muy similares a las encontradas previamente para metiamida, cimetidina, ranitidina y etintidina. Estos resultados nos permitirían proponer que este tipo de conformaciones juegan un rol determinante en el reconocimiento del receptor H2 de histamina