DSC, TGA-FTIR and FTIR Assisted by Chemometric Factor Analysis and PXRD in Assessing the Incompatibility of the Antiviral Drug Arbidol Hydrochloride with Pharmaceutical Excipients.

Arbidol hydrochloride is an antiviral product widely used in Russia and China for the treatment of, among other diseases, influenza. In recent years, it has turned out to be highly effective against COVID-19. However, there is little knowledge about its physicochemical properties and its behavior in the presence of various pharmaceutical excipients, which could be useful in the development of new preparations by increasing its solubility and bioavailability. For this reason, binary mixtures composed of arbidol hydrochloride and selected pharmaceutical excipients such as chitosan, polyvinylpyrrolione K-30 and magnesium stearate were prepared and subjected to differential scanning calorimetry (DSC), thermogravimetry combined with Fourier transform infrared spectrometry (TGA-FTIR) and Fourier transform infrared spectrometry (FTIR) analyses. In order to obtain clarity in the interpretation of the outcomes, chemometric calculations with factor analysis (FA) were used. Additionally, a powder X-ray diffraction (PXRD) and an intrinsic dissolution rate study were performed for arbidol hydrochloride itself and in the presence of excipients. As a result of the study, it was revealed that arbidol hydrochloride may undergo polymorphic transformations and be incompatible with chitosan and magnesium stearate. However, mixing arbidol hydrochloride with polyvinylpyrrolidone K-30 guarantees the obtaining of durable and safe pharmaceutical preparations.

FTIR, Raman spectroscopy and HT-XRD in compatibility study between naproxen and excipients.

Detection of incompatibility between an active pharmaceutical ingredient (API) and excipients, including the selection of the most biopharmaceutical advantageous excipients is extremely important in the pre-formulation process of developing a solid dosage form technology. Therefore, having fast and reliable methods for identifying incompatibility is fundamental in pharmaceutical technology. For this purpose, combined Fourier transform infrared (FTIR) and Raman spectroscopy as well as high-temperature X-ray diffraction (HT-XRD) were used as a new approach for incompatibility detection, whereas differential scanning calorimetry (DSC) was applied as a reference method. In addition, to facilitate the interpretation of FTIR and Raman data, a multivariate analysis was used - hierarchical cluster analysis (HCA). The tests were carried out in mixtures of naproxen (NPX) with eight selected polymer excipients, mixed at a 1:1 ratio. The results of spectroscopic analyses have shown the physical incompatibility of NPX with methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), sodium starch glycolate (SSG) and sodium carboxymethylcellulose (CMC). HT-XRD studies performed when these mixtures were heated to 156 °C and then cooled to 25 °C showed a decrease in naproxen crystallinity in these mixtures. Furthermore, the results obtained with spectroscopic methods were confirmed by DSC tests and an intrinsic dissolution rate study.

Quantification of Compatibility Between Polymeric Excipients and Atenolol Using Principal Component Analysis and Hierarchical Cluster Analysis.

An important challenge to overcome in the solid dosage forms technology is the selection of the most biopharmaceutically efficient polymeric excipients. The excipients can be selected, among others, by compatibility studies since incompatibilities between ingredients of the drug formulations adversely affect their bioavailability, stability, efficacy, and safety. Therefore, new, fast, and reliable methods for detecting incompatibility are constantly being sought. Hence, the purpose of this work was to assess the usefulness of a heating, cooling, and reheating differential scanning calorimetry (DSC) program for detecting potential incompatibilities between atenolol, an active pharmaceutical ingredient (API), and polymeric excipients. Hot-stage microscopy (HSM), Fourier transform infrared (FTIR) spectroscopy, and powder X-ray diffraction (PXRD) were used as supporting techniques. Additionally, principal component analysis (PCA) and hierarchical cluster analysis (HCA) served as tools to support the interpretation of the data acquired from the DSC curves and FTIR spectra. As the alterations in the shape of the DSC peak of atenolol which are indicative of incompatibility are visible only on the cooling and reheating curves of the mixtures, the DSC heating-cooling-reheating program was found to be very useful for identifying potential incompatibilities in the binary mixtures of atenolol and polymeric excipients. The melting and recrystallization of atenolol alone and in its mixtures were also confirmed by HSM, while FTIR displayed changes in the spectra of mixtures due to incompatibility. These studies revealed that atenolol is incompatible with hydroxyethylcellulose, hypromellose, and methylcellulose. PXRD measurements at room temperature revealed that the crystallinity of atenolol did not change in these mixtures. However, its crystallinity was reduced in the mixtures previously heated up to 155 °C and then cooled to 25 °C.

FTIR and TG analyses coupled with factor analysis in a compatibility study of acetazolamide with excipients.

A compatibility study of drug substance with excipients is a crucial step in the drug development process in order to generate potent final drug formulations for efficient and safe therapy for various diseases. Thus, the development of new methods for compatibility studies is a great challenge. For this reason, a new approach based on improvement of FTIR spectra and TG curves interpretation using factor analysis (FA) was developed as a screening technique for assessing the compatibility of acetazolamide with selected excipients. This multivariate method demonstrates that in some cases acetazolamide and mixtures with high acetazolamide content formed one cluster, while a second cluster consisted of excipient and mixtures with high excipient content. Such clustering of the analyzed samples (drug substance, excipient and their mixtures) demonstrates the compatibility between ingredients. This in turn means that the FTIR spectra and TG curves of mixtures are the sum of absorption bands or of the thermal profiles of ingredients. In the case of incompatibility, the FTIR spectra and TG curves of mixtures differ from those of ingredients. The FA score scatter plot shows that clusters consist of mixtures which differ with respect to ingredient content. In conclusion, FA proved the incompatibility of acetazolamide mixtures with ß-cyclodextrin, chitosan, lactose, mannitol, meglumine and starch. This was also confirmed by complementary techniques such as DSC and PXRD. Hence, the application of FA can be helpful for better comprehension of data obtained from FTIR spectra and TG curves.

Detection of compatibility between baclofen and excipients with aid of infrared spectroscopy and chemometry.

In the paper infrared (IR) spectroscopy and multivariate exploration techniques: principal component analysis (PCA) and cluster analysis (CA) were applied as supportive methods for the detection of physicochemical incompatibilities between baclofen and excipients. In the course of research, the most useful rotational strategy in PCA proved to be varimax normalized, while in CA Ward's hierarchical agglomeration with Euclidean distance measure enabled to yield the most interpretable results. Chemometrical calculations confirmed the suitability of PCA and CA as the auxiliary methods for interpretation of infrared spectra in order to recognize whether compatibilities or incompatibilities between active substance and excipients occur. On the basis of IR spectra and the results of PCA and CA it was possible to demonstrate that the presence of lactose, ß-cyclodextrin and meglumine in binary mixtures produce interactions with baclofen. The results were verified using differential scanning calorimetry, differential thermal analysis, thermogravimetry/differential thermogravimetry and X-ray powder diffraction analyses.

Application of chemometrically processed thermogravimetric data for identification of baclofen-excipient interactions.

Studies are constantly being conducted on the elaboration of efficient methods to confirm the compatibility of active pharmaceutical ingredients (APIs) and excipients, since medicinal products, apart from their APIs, also contain numerous excipients that not only have important functions in pharmaceutical preparations but can also initiate or participate in interactions with drug substances, which eventually lead to a decline in drug quality. With this in mind, research was undertaken to evaluate two of the most often applied pattern recognition methods, hierarchical cluster analysis (HCA) and principal component analysis (PCA), as supporting techniques in the identification of potential physicochemical interactions that may occur during the preformulation of solid dosage forms. The investigation performed with the use of baclofen and selected excipients has shown that with thermogravimetric analysis, HCA and PCA fulfill their role as supporting techniques in the interpretation of the data obtained. Based on these methods, it is possible to detect incompatibilities between baclofen and excipients, and the data obtained concur strongly with the results of differential scanning calorimetry and IR spectrometry analyses.