Quantitative in-line monitoring of solvent-mediated polymorphic transformation of sulfamerazine by near-infrared spectroscopy.

The in-line monitoring of pharmaceutical processes with high risk, such as crystallization, has been one of the most popular research topics in recent years. Sulfamerazine (SMZ), a well-known sulfonamide antibacterial agent was investigated to examine the mechanism of polymorphic conversion by solvent-mediated polymorphic transformation (SMPT). The primary purpose of this study is to monitor the polymorphic transformation through in-line near-infrared (NIR) measurements and concurrently interpret the whole process quantitatively with off-line characterizations. Samples taken at every hour during SMPT were analyzed by X-ray diffractometry (XRD) and differential scanning calorimetry (DSC). NIR spectra in the range of 7500-4900 cm(-1) were taken into account for multivariate analysis, which included partial least square (PLS) regression and principal component analysis (PCA). In brief, the form II content was estimated very accurately and reproducibly during the SMPT process not only by XRD but also by the DSC measurements. In addition, the form II content values were predicted very accurately by separate experiments at two designated time points. In a separate study, it was demonstrated that PCA could be employed to explain a complicated process such as SMPT mechanistically by several stages.

Polymorph transformation in paracetamol monitored by in-line NIR spectroscopy during a cooling crystallization process.

The reliable in-line monitoring of pharmaceutical processes has been regarded as a key tool toward the full implementation of process analytical technology. In this study, near-infrared (NIR) spectroscopy was examined for use as an in-line monitoring method of the paracetamol cooling crystallization process. The drug powder was dissolved in ethanol-based cosolvent at 60°C and was cooled by 1°C/min for crystallization. NIR spectra acquired by in-line measurement were interpreted by principal component analysis combined with off-line characterizations via X-ray diffraction, optical microscopy, and transmission electron microscopy. The whole crystallization process appeared to take place in three steps. A metastable form II polymorph of paracetamol was formed and transformed into the stable form I polymorph on the way to the growth of pure form I by cooling crystallization. These observations are consistent with a previous focused beam reflectance method-based study (Barthe et al., Cryst Growth Des 8:3316-3322, 2008).

In line NIR quantification of film thickness on pharmaceutical pellets during a fluid bed coating process.

Along with the risk-based approach, process analytical technology (PAT) has emerged as one of the key elements to fully implement QbD (quality-by-design). Near-infrared (NIR) spectroscopy has been extensively applied as an in-line/on-line analytical tool in biomedical and chemical industries. In this study, the film thickness on pharmaceutical pellets was examined for quantification using in-line NIR spectroscopy during a fluid-bed coating process. A precise monitoring of coating thickness and its prediction with a suitable control strategy is crucial to the quality assurance of solid dosage forms including dissolution characteristics. Pellets of a test formulation were manufactured and coated in a fluid-bed by spraying a hydroxypropyl methylcellulose (HPMC) coating solution. NIR spectra were acquired via a fiber-optic probe during the coating process, followed by multivariate analysis utilizing partial least squares (PLS) calibration models. The actual coating thickness of pellets was measured by two separate methods, confocal laser scanning microscopy (CLSM) and laser diffraction particle size analysis (LD-PSA). Both characterization methods gave superb correlation results, and all determination coefficient (R(2)) values exceeded 0.995. In addition, a prediction coating experiment for 70min demonstrated that the end-point can be accurately designated via NIR in-line monitoring with appropriate calibration models. In conclusion, our approach combining in-line NIR monitoring with CLSM and LD-PSA can be applied as an effective PAT tool for fluid-bed pellet coating processes.