Article

In-Line and Real-Time Process Monitoring of a Freeze Drying Process Using Raman and NIR Spectroscopy as Complementary Process Analytical Technology (PAT) Tools

Laboratory of Pharmaceutical Chemistry and Drug Analysis, Department of Pharmaceutical Analysis, Ghent University, Harelbekestraat 72, B-9000 Gent, Belgium.
Journal of Pharmaceutical Sciences (Impact Factor: 3.01). 09/2009; 98(9):3430-46. DOI: 10.1002/jps.21633
Source: PubMed

ABSTRACT The aim of the present study was to examine the complementary properties of Raman and near infrared (NIR) spectroscopy as PAT tools for the fast, noninvasive, nondestructive and in-line process monitoring of a freeze drying process. Therefore, Raman and NIR probes were built in the freeze dryer chamber, allowing simultaneous process monitoring. A 5% (w/v) mannitol solution was used as model for freeze drying. Raman and NIR spectra were continuously collected during freeze drying (one Raman and NIR spectrum/min) and the spectra were analyzed using principal component analysis (PCA) and multivariate curve resolution (MCR). Raman spectroscopy was able to supply information about (i) the mannitol solid state throughout the entire process, (ii) the endpoint of freezing (endpoint of mannitol crystallization), and (iii) several physical and chemical phenomena occurring during the process (onset of ice nucleation, onset of mannitol crystallization). NIR spectroscopy proved to be a more sensitive tool to monitor the critical aspects during drying: (i) endpoint of ice sublimation and (ii) monitoring the release of hydrate water during storage. Furthermore, via NIR spectroscopy some Raman observations were confirmed: start of ice nucleation, end of mannitol crystallization and solid state characteristics of the end product. When Raman and NIR monitoring were performed on the same vial, the Raman signal was saturated during the freezing step caused by reflected NIR light reaching the Raman detector. Therefore, NIR and Raman measurements were done on a different vial. Also the importance of the position of the probes (Raman probe above the vial and NIR probe at the bottom of the sidewall of the vial) in order to obtain all required critical information is outlined. Combining Raman and NIR spectroscopy for the simultaneous monitoring of freeze drying allows monitoring almost all critical freeze drying process aspects. Both techniques do not only complement each other, they also provided mutual confirmation of specific conclusions.

0 Followers
 · 
151 Views
 · 
0 Downloads
  • Source
    • "This is a well-known variable reduction method and has proven to be a highly efficient method for extracting physicochemical information from large and complex multivariate datasets collected during freeze-drying [11] [17]. PCA is a multivariate data analysis technique [25], widely used for spectroscopic process monitoring [11] [17]. PCA produces orthogonal bilinear data matrix decomposition, where principal components (PCs) are obtained in a sequential way to explain maximum variance: "
    [Show abstract] [Hide abstract]
    ABSTRACT: Freeze drying is a complex, time consuming and thus expensive process, hence creating a need for understanding the material behaviour in the process environment and for process optimization. Near-infrared (NIR) spectroscopy offers the opportunity to monitor physicochemical changes of the formulation during freeze-drying. The aim of this work was to examine whether NIR spectroscopy allows in-line monitoring of all components during the entire freeze-drying process of a multi-component pharmaceutical formulation (a solution of fenofibrate and mannitol in a mixture of tertiary-butyl alcohol, and water). To extract useful information of all components in the formulation from the large multivariate data-sets obtained during in-line spectroscopic monitoring, several spectral pre-processing techniques and spectral data analysis techniques such as the mean of selected wavenumbers (Mws), the correlation coefficient (CorrCoef) and principal component analysis (PCA) have been evaluated and compared. To find out whether these chemometric techniques are also able to differentiate between changes in the process settings influencing the freeze-drying process of the formulation, freeze-drying processes were performed at four different conditions. Results demonstrated that in-line measurements using NIR spectroscopy were possible in an icy environment and that a further process understanding could be obtained. Data-analysis revealed the crystallization behaviour of each of the four components. In addition, using the three pre-processing techniques allowed observe the sublimation of the solvents. Mws and CorrCoef have proven to be adequate methods for monitoring the main physicochemical changes of product during the processes; this affirmation was confirmed by observing the outputs of PCA for entire processes.
    Journal of pharmaceutical and biomedical analysis 04/2014; 97C:39-46. DOI:10.1016/j.jpba.2014.04.010 · 2.83 Impact Factor
  • Source
    • "This is a well-known variable reduction method and has proven to be a highly efficient method for extracting physicochemical information from large and complex multivariate datasets collected during freeze-drying [11] [17]. PCA is a multivariate data analysis technique [25], widely used for spectroscopic process monitoring [11] [17]. PCA produces orthogonal bilinear data matrix decomposition, where principal components (PCs) are obtained in a sequential way to explain maximum variance: "
  • Source
    • "Luypaert et al. reviewed more than 40 applications of NIR for moisture reported until 2007 [16]. Since then, more applications of NIR spectroscopy for the determination of water in pharmaceutical products have been published [17] [18] [19] [20]. Although the major pharmacopoeias have generally adopted NIR techniques (the European [25] and United States Pharmacopoeia [26] both contain a general chapter on near-infrared spectrometry and spectrophotometry, respectively), NIR has traditionally not been considered an amenable technique for quality control (QC release methods). "
    [Show abstract] [Hide abstract]
    ABSTRACT: In this paper we demonstrate the feasibility of replacing KF for water content testing in bulk powders and tablets with at-line near infrared (NIR) or microwave resonance (MR) methods. Accurate NIR and MR prediction models were developed with a minimalistic approach to calibration. The NIR method can accurately predict water content in bulk powders in the range of 0.5-5% w/w. Results from this method were compared to a MR method. We demonstrated excellent agreement of both NIR and MR methods for powders vs. the reference KF method. These methods are applicable to in-process control or quality control environments. One of the aims of this study was to determine if a calibration developed for a particular product could be used to predict the water content of another product (with related composition) but containing a different active pharmaceutical ingredient (API). We demonstrated that, contrary to the NIR method, a general MR method can be used to predict water content in two different types of blends. Finally, we demonstrated that a MR method can be developed for at-line moisture determination in tablets.
    Analytica chimica acta 06/2011; 696(1-2):84-93. DOI:10.1016/j.aca.2011.03.048 · 4.52 Impact Factor
Show more