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.

In-line monitoring and interpretation of an indomethacin anti-solvent crystallization process by near-infrared spectroscopy (NIRS).

PAT (process analytical technology) has been emphasized as one of key elements for the full implementation of QbD (quality-by-design) in the pharmaceutical area. NIRS (near-infrared spectroscopy) has been studied intensively as an in-line/on-line monitoring tool in chemical and biomedical industries. A precise and reliable monitoring of the particle characteristics during crystallization along with a suitable control strategy should be highly encouraged for the conformance to new quality system of pharmaceutical products. In this study, the anti-solvent crystallization process of indomethacin (IMC) was monitored using an in-line NIRS. IMC powders were produced via anti-solvent crystallization using two schemes; 'S-to-A' (solvent-to-antisolvent) and 'A-to-S' (antisolvent-to-solvent). In-line NIR spectra were analyzed by a PCA (principal component analysis) method. Although pure α-form IMC powder was resulted under A-to-S scheme, a mixture of the α-form and γ-form was produced for S-to-A case. By integrating the PCA results with off-line characterization (SEM, XRD, DSC) data, the crystallization process under each scheme was elucidated by three distinct consecutive steps. It was demonstrated that in-line NIRS, combined with PCA, can be very useful to monitor in real time and interpret the anti-solvent crystallization process with respect to the polymorphism and particle size.

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.

Preparation and characterization of salmon calcitonin-sodium triphosphate ionic complex for oral delivery.

Even though salmon calcitonin (sCT) has been known as a potent hypocalcemic agent, only injection or nasal spray products are available on the market. In order to develop oral delivery system of the agent, a novel sCT-sodium tripolyphosphate (STPP) ionic complex was fabricated and also characterized. For the optimization of the ionic complexation, the effect of incubation time and molar ratio between sCT and STPP was evaluated. Particle size of the ionic complex in aqueous media, SEM images, DSC, FT-IR, in vitro release test, stability within the simulated intestinal fluid, and hypocalcemic effect were evaluated. The optimal molar complexation ratio of sCT to STPP was ranged from 1:5 to 1:10 and the complexation efficiency was about 95%. The SEM image has shown that the freeze dried ionic complex has rough morphology in their surface and the particle size in PBS (pH 7.4) was about 220nm. The DSC and FT-IR results provided evidences for ionic interaction between -NH(2) groups and -P horizontal lineO groups of sCT and STPP, respectively. The sCT ionic complex has shown sustained sCT releasing characteristics for 3weeks. The sCT-STPP ionic complex was protective to enzymatic attack and in vivo animal data revealed that the present ionic complex would show continuous hypocalcemic effect. Conclusively, the present sCT-STPP ionic complex formulation thought to be a novel oral delivery candidate for the treatment of osteoporosis.