Qualitative in situ analysis of multiple solid-state forms using spectroscopy and partial least squares discriminant modeling.

This study used in situ spectroscopy to reveal the multiple solid-state forms that appear during isothermal dehydration. Hydrate forms of piroxicam and carbamazepine (CBZ) were investigated on hot-stage at different temperatures using near-infrared (NIR) and Raman spectroscopy combined with multivariate modeling. Variable temperature X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis, and Karl Fisher titrimetry were used as reference methods. Partial least squares discriminant analysis (PLS-DA) was performed to qualitatively evaluate the phase transition. It was shown that the constructed PLS-DA models, where spectral differences were directly correlated to solid-state modifications, enabled differentiation between the multiple forms. Qualitative analysis revealed that during dehydration, hydrates, such as CBZ dihydrate, may go through several solid-state forms, which must be considered in quantitative model construction. This study demonstrates that in situ analysis can be used to monitor the dehydration and reveal associated solid-state forms prior to quantification. The utility of the complementary spectroscopic techniques, NIR and Raman, have been shown.

Hyphenated spectroscopy as a polymorph screening tool.

Polymorph screening of a model compound (nitrofurantoin) was performed. Nitrofurantoin was crystallized from acetone-water mixtures with varying process parameters. Two anhydrate forms (alpha and beta) and one monohydrate form (II) were crystallized in the polymorph screen. The solid forms were analyzed with three complementary spectroscopic techniques: near-infrared (NIR) spectroscopy, Raman spectroscopy and terahertz pulsed spectroscopy (TPS), and the results of the solid phase analysis were verified with X-ray powder diffraction (XRPD). NIR and Raman spectroscopy were coupled to achieve a rapid and comprehensive method of solid phase analysis. The hyphenated NIR/Raman spectroscopic data were analyzed with a multivariate method, principal component analysis (PCA). The combination was found effective in screening solid forms due to the complementary characteristics of the methods. NIR spectroscopy is powerful in differentiating between anhydrate and hydrate forms and intermolecular features, whereas Raman spectroscopy is sensitive to intramolecular alterations in the molecular backbone.

IR spectroscopy together with multivariate data analysis as a process analytical tool for in-line monitoring of crystallization process and solid-state analysis of crystalline product.

Crystalline product should exist in optimal polymorphic form. Robust and reliable method for polymorph characterization is of great importance. In this work, infra red (IR) spectroscopy is applied for monitoring of crystallization process in situ. The results show that attenuated total reflection Fourier transform infra red (ATR-FTIR) spectroscopy provides valuable information on process, which can be utilized for more controlled crystallization processes. Diffuse reflectance Fourier transform infra red (DRIFT-IR) is applied for polymorphic characterization of crystalline product using X-ray powder diffraction (XRPD) as a reference technique. In order to fully utilize DRIFT, the application of multivariate techniques are needed, e.g., multivariate statistical process control (MSPC), principal component analysis (PCA) and partial least squares (PLS). The results demonstrate that multivariate techniques provide the powerful tool for rapid evaluation of spectral data and also enable more reliable quantification of polymorphic composition of samples being mixtures of two or more polymorphs. This opens new perspectives for understanding crystallization processes and increases the level of safety within the manufacture of pharmaceutics.

An insight into water of crystallization during processing using vibrational spectroscopy.

Many organic molecules used as drugs can incorporate water into their crystal lattice. These compounds are also prone to processing-induced transformations (PITs) because processing often exposes the compounds to moisture, heat and mechanical stress. The aim of this review is to provide an overview of the possibilities for following and understanding hydrate/anhydrate transformations using vibrational spectroscopy (mid-infrared, near-infrared, Raman and terahertz). The review begins with a general section on hydrates, followed by considerations on the impact of these on drug products and a description of transformation mechanisms of hydrates. Moreover, a general introduction is given for the spectroscopic techniques together with a discussion of critical issues for quantification models. Unit operations that may induce transformations in hydrate systems are discussed with focus on the published work on the use of spectroscopy to derive information from these processes. Finally, the effect of excipients on PITs is discussed.

Establishing quantitative in-line analysis of multiple solid-state transformations during dehydration.

The aim of the study was to conduct quantitative solid phase analysis of piroxicam (PRX) and carbamazepine (CBZ) during isothermal dehydration in situ, and additionally exploit the constructed quantitative models to analyze the solid-state forms in-line during fluidized bed drying. Vibrational spectroscopy (near-infrared (NIR), Raman) was employed for monitoring the dehydration and the quantitative model was based on partial least squares (PLS) regression. PLS quantification was confirmed experimentally using isothermal thermogravimetric analysis (TGA) and X-ray powder diffractometry (XRPD). To appraise the quality of quantitative models several model parameters were evaluated. The hot-stage spectroscopy quantification results were found to be in reasonable agreement with TGA and XRPD results. Quantification of PRX forms showed complementary results with both spectroscopic techniques. The solid-state forms observed during CBZ dihydrate dehydration were quantified with Raman spectroscopy, but NIR spectroscopy failed to differentiate between the anhydrous solid-state forms of CBZ. In addition to in situ dehydration quantification, Raman spectroscopy in combination with PLS regression enabled in-line analysis of the solid-state transformations of CBZ during dehydration in a fluidized bed dryer.

Batch cooling crystallization and pressure filtration of sulphathiazole: the influence of solvent composition.

Currently there is a great interest in new process analytical approaches to increase the process understanding of pharmaceutical unit operations. In the present study, the influence of the solvent composition on the material properties and, further, on the filtration characteristics, of different crystal suspensions obtained through an unseeded batch-cooling-crystallization process was studied. Sulphathiazole, which is an antibiotic agent with multiple polymorphic forms, was produced by performing laboratory-scale cooling crystallization experiments from five different mixtures of water and propan-1-ol (n-propanol). The size, shape and polymorphic composition of the crystals produced were characterized with a scanning electron microscope, with a novel automated image analyser and with an X-ray powder diffractometer. All of the monitored crystal properties were found to clearly differ between the samples obtained from different solvents. The crystals produced in the batch-cooling-crystallization experiments were separated from the crystallizing solvents using a batch-type pressure Nutsche filter, and the filtration characteristics of the suspensions were evaluated on the basis of average filter-cake porosities and average specific cake resistances, which were determined from the experimentally obtained filtration data. Comparison between the calculated filtration characteristics revealed that considerable differences existed between the different suspensions, and it could therefore be concluded that the pressure-filtration process was influenced by the composition of the crystallizing solvent. The filterability of all the studied sulphathiazole suspensions was considered to be rather good on the basis of the relatively low cake porosities (0.51-0.63), which were accompanied with low average specific cake resistances [(8.7 x 10(7))-(1.2 x 10(9)) m/kg].