Rubén M. Maggio

PCA-CR analysis of dissolution profiles. A chemometric approach to probe the polymorphic form of the active pharmaceutical ingredient in a drug product

A simple chemometric approach to differentiate among the three crystalline polymorphs of the model drug Furosemide (FUR) in a pharmaceutical dosage form is presented. The proposed method is based on the principal component analysis with confidence regions (PCA-CR) comparison of the dissolution profiles of the test pharmaceutical formulation, and formulations containing the different polymorphs, employed as the corresponding references. For the elaboration of the references, FUR polymorphs I, II and III were prepared, characterized and compounded with the excipients found in the test commercial formulation. The dissolutions were carried out in a discriminating HCl-KCl dissolution medium (pH 2.2), and the corresponding profiles were constructed from the absorbances (274 nm) of the dissolution samples. PCA-CR was able to differentiate among the three crystalline polymorphs of FUR and to confirm the presence of polymorph I in the test sample, with 99% statistical confidence. The PCA-CR results were compared with those obtained by a bootstrap-mediated implementation of Moore and Flanners difference factor (f(2)). The same conclusion was reached employing an f(2)-based comparison, despite its inability to differentiate between polymorphs II and III. Therefore, PCA-CR may be considered a complementary and useful tool for probing the polymorphic form present in a pharmaceutical formulation.

Mebendazole crystal forms in tablet formulations. An ATR-FTIR/chemometrics approach to polymorph assignment

Structural polymorphism of active pharmaceutical ingredients (API) is a relevant concern for the modern pharmaceutical industry, since different polymorphic forms may display dissimilar properties, critically affecting the performance of the corresponding drug products. Mebendazole (MEB) is a widely used broad spectrum anthelmintic drug of the benzimidazole class, which exhibits structural polymorphism (Forms A-C). Form C, which displays the best pharmaceutical profile, is the recommended one for clinical use. The polymorphs of MEB were prepared and characterized by spectroscopic, calorimetric and microscopic means. The polymorphs were employed to develop a suitable chemometrics-assisted sample display model based on the first two principal components of their ATR-FTIR spectra in the 4000-600 cm(-1) region. The model was internally and externally validated employing the leave-one-out procedure and an external validation set, respectively. Its suitability for revealing the polymorphic identity of MEB in tablets was successfully assessed analyzing commercial tablets under different physical forms (whole, powdered, dried, sieved and aged). It was concluded that the ATR-FTIR/PCA (principal component analysis) association is a fast, efficient and non-destructive technique for assigning the solid-state forms of MEB in its drug products, with minimum sample pre-treatment.

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).

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.

An eco-friendly strategy, using on-line monitoring and dilution coupled to a second-order chemometric method, for the construction of dissolution curves of combined pharmaceutical associations

A simple, precise, economic and minimally operator-dependent method was developed under green analytical chemistry principles, for the simultaneous construction of the dissolution curves of a pharmaceutical association in short time and without employing organic solvents, allowing important savings of labor and resources. The carvedilol (CAR) and hydrochlorothiazide (HCT) combined formulation was employed as a model. The method (OD/UV-MCR) involves on-line sample dilution (OD) and UV detection of the analytes, coupled to multivariate curve resolution with alternating least squares (MCR-ALS). OD/UV-MCR proved to be robust and was successfully validated in accordance to ICH guidelines, fulfilling acceptance criteria for specificity (r(2) of spectral correlation>0.950), linearity [r>0.999 (N=25) in the ranges 1.00-31.1mg l(-1) and 0.51-15.2mg l(-1) for CAR and HCT, respectively] and precision (RSD<2%). Accuracy was assessed by point-to-point comparison between the dissolution profiles furnished by the proposed method with those provided by HPLC analysis, evidencing the usefulness of this monitoring system. In addition, OD/UV-MCR was successfully employed for the comparative analysis of three lots of commercial formulations of the CAR-HCT pharmaceutical association, belonging to a couple of different brands, employing Moore and Flanners f2 similarity indicator.

Chemometrics-assisted study of the interconversion between the crystalline forms of nimodipine

HIGHLIGHTSNimodipine Mode I and Mode II forms were prepared and exhaustively characterized.Subtle differences in the infrared spectra of the nimodipine polymorphs were found.The behavior of the polymorphs of nimodipine to thermal stress stimuli was examined.An ATR‐FTIR/MCR‐ALS method was developed and used to monitor NIM form transitions.The chemometrics‐assisted method enabled observation of Mode II in commercial sample. ABSTRACT Nimodipine (NIM) is a calcium channel‐blocking agent, which in the solid state exhibits two crystalline modifications, Mode I and Mode II. The first one is a racemic mixture, while the second is a conglomerate. Because the drug has poor aqueous solubility and Mode I is twice as soluble as Mode II, the former is widely preferred for the development of pharmaceutical forms. In order to study the effect of thermal stimuli on the behavior of NIM, an analytical method was developed coupling ATR‐FTIR spectroscopy to Multivariate Curve Resolution with Alternating Least Squares (MCR‐ALS). The method allowed to monitor the transformations of each polymorph, their respective mixtures and commercial samples, during the thermal treatment. It was observed that Mode II experienced changes during the experiments and the chemometric technique provided the abundance profile and the pure spectra of the different species involved. In this way, it was established that Mode II has two transitions, at 116.8°C and 131.9°C, which reflect that Mode II is first transformed into Mode I, which then melts. The liquid phase solidifies to give an amorphous (AM) vitreous solid, which does not revert to the crystalline state. The analysis of a commercial sample of NIM exhibited the similar transformations than Mode II; however, a pronounced decrease was noted in the first transition temperature (95°C), whereas the second remained essentially unchanged (131.6°C). This could be a result of the presence of mixtures of Mode I and Mode II (0.32:0.68) in the bulk solid, as confirmed by the analysis of a physical mixture of crystals of Modes I and II. Therefore, it was concluded that the developed ATR‐FTIR/MCR‐ALS method is suitable for the detailed analysis of the crystalline forms of NIM in bulk drug and enables de study of their possible thermally promoted interconversions.