A process analytical tool

There is an increasing demand for new approaches to understand the chemical and physical phenomena that occur during pharmaceutical unit operations. Obtaining real-time information from processes opens new perspectives for safer manufacture of pharmaceuticals. Raman spectroscopy provides a molecular level insight into processing and it is therefore a promising process analytical tool.

Gathering relevant information from multicomponent systems, such as pharmaceutical unit operations, is not a straightforward task. Consider a typical solid dosage form with numerous sequential processing steps. There are many possible pitfalls during processing that may critically affect the final product performance. For example, active pharmaceutical ingredient or excipient may be stressed in an aqueous environment or they may be stressed thermally during processing. Focusing analysis on the end product will not enable the early detection of problems or further, the complex relations between them. Recently, the U.S. FDA introduced a guidance to address this issue¹.

Process analytical technology (PAT) is a system for developing and implementing new efficient tools for use during pharmaceutical development, manufacturing and quality assurance, while maintaining or improving the current level of product quality assurance. This guideline categorises PAT tools in five groups: multivariate tools for design; data acquisition and analysis; process analysers; process control tools and continuous improvement and knowledge management tools. Raman spectroscopy provides a molecular level insight into processing and therefore offers a new way to understand our unit operations. The basic principle of Raman spectroscopy is to irradiate a substance with monochromatic light and to detect the scattered light with different wavelength to the incident beam. The differences in the frequencies result in characteristic Raman shifts. The Raman effect is inherently very weak and, in addition to intense excitation source, good filters are needed to remove the excitation line from the collected radiation. Utilisation of this phenomenon has been relatively limited in the field of pharmaceutical processing due to the high price of instrumentation and difficulties in process interfacing. Recent developments in the fields of optoelectronics, computer technology, data transfer and data analysis methods have enabled the real-time and non-invasive Raman analysis of pharmaceutical unit operations and, by this means, a molecular level insight into processing. This will enable process understanding for scientific, risk-managed pharmaceutical development, manufacture and quality assurance in accordance with the PAT ideology.

Raman spectroscopy within pharmaceutical unit operations

There are an increasing number of published studies on the utilisation of Raman spectroscopy in the process environment. Vankeirsbilck et al. have recently reviewed the use of Raman in the field of pharmaceutics, with attention paid to comparison of FT-Raman and dispersive instruments2. Threlfall3 and Bugay4 have reviewed the use of spectroscopic tools for solid-state analysis and in these reviews they relate Raman to the other tools available. Issues related to quantitative analysis with Raman are well described in a tutorial by Pelletier5. This chapter summarises the possibilities of Raman spectroscopy to the process analysis of pharmaceutical unit operations related to solid dosage forms. Discussion starts from the synthesis phase and concludes with the film coating process. Svensson et al. used Raman spectroscopy for reaction monitoring in combination with multivariate techniques6. To avoid problems related to spectral overlapping, they recommend the use of effective preprocessing (standard normal variate and derivatives) together with principal component analysis (PCA) and partial least squares (PLS). They achieved a rate constant with a model system, with good agreement with published values. The subsequent processing step is crystallization of material. This critical unit operation is performed to produce purified material with desired purity, polymorphic composition, surface properties and particle size and shape distributions. It is crucial to have an in-depth process signature from crystallization phase, as a failure in crystallization results in major difficulties in secondary manufacturing steps (mixing, granulation, tableting, coating). Crystallization is not a well understood nor controlled unit operation. The recent case of ritonavir really underlines the need for new tools in the process analysis and control of crystallization and in the implementation of a polymorph screening step7. However, the number of published works on real-time analysis of crystallization with pharmaceutics is relatively limited. Schwartz monitored in situ lysozyme concentration changes in hanging drop crystallization8. Changes in polymorphic composition has been monitored and quantified with in-line Raman spectroscopy9-14. Falcon and Berglund reported the use of Raman for real time monitoring of phenomena related to antisolvent addition13. Recently, Hu et al. reported simultaneous monitoring of solution concentration in conjunction with information about the polymorphic outcome of the crystallization event and further, solvent-mediated transformations of the model system14. Raman spectroscopy can also be used to understand the mechanisms of the phase transitions15. Batch crystallizations of pharmaceutics are quite often performed in aqueous media, so Raman spectroscopy is an extremely promising tool for process control and monitoring purposes. In the solid state quantification of polymorphic form, Raman spectroscopy is an ideal candidate. Minimal sample preparation combined with sensitivity to polymorphism opens new perspectives for fast and reliable solid state analysis16-22. Both univariate and multivariate methods have been used for development of quantitative models. In addition, the use of Raman for quantification of crystallinity has been reported23. Recently, Raman has been combined with high-throughput (HTS) polymorph screening ideology 24,25. There is an increasing demand for early screening of solid-state forms and further identification of the most stable form. After a case related to polymorphism of ritonavir, high-throughput crystallization experiments were carried out to explore the diversity of ritonavir solid state forms26. One of the least understood unit operations within solid dosage forms is the mixing of powders. Vergote et al. have reported the use of Raman for in-line monitoring of the blending process27. Raman mapping in combination with near IR spectral mapping can be used to describe heterogeneous mixtures in more detail28. The granulation step – and in some cases wet granulation – is a process step needed for many products. In this unit operation, material may undergo phase transformation after exposure to solvent29. Possible phase transitions are polymorphic transformations; solvate formation and dehydration of solvate; production of amorphous regions and crystallization of amorphous material. The use of Raman for at-line30 and in-line31 analysis of hydrate formation during wet granulation has been reported. Wikström et al. used the real time information to verify a model for predicting the transformation kinetics of hydrate formation. Raman spectroscopy also provides an insight into water-solid interactions in the formulation and further can be used to understand the role of excipients in the early development phase. Taylor et al. investigated the nature of water-polymer interactions for polymers of pharmaceutical interest32. Airaksinen et al. has reported the use of Raman to detect hydrate formation in presence of excipients and the role of excipients in the phase transformation33. FT-Raman has been utilised in evaluating the potential of carrageens to protect drugs from polymorphic transformations34. Schmidt et al. reported the detection of both recrystallization of amorphous component and dehydration after the tabletting process. Fechner et al. utilised Raman in the extrusion-spheronization process environment35. They explained the effect of water on the structure of cellulose during this unit operation. One of the most attractive possibilities of Raman and other possible PAT sensors is to utilise them for the real time assay of tablets and capsules. Moving into a situation where we can analyse, for example, every tenth tablet during production, will open up totally new perspectives for quality assurance. Raman has been used for quantification of components in antacid tablets36. Wang et al. reported the use of Raman for direct assay of acetylsalicylic acid and also the analysis of the major degradation product, salicylic acid37. Niemczyk et al. utilised this technique for quantitative analysis of intact gel capsules and they also reported the analysis of capsules through blister packs38. Vergote et al. investigated the role of excipients in quantification of diltiazem hydrochloride39. Folestad and Johansson have recently discussed the use of Raman for monitoring the tableting process40. One application area for Raman is the fast analysis of prohibited substances from seized tablets, as reported by Bell et al. for analysis of ecstasy (MDMA, N-methyl-3,4-methylenedioxyamphetamine and its near analogues). Another potential consideration is the use of Raman for fast analysis of possible processing-induced transformation during the tableting process. It could also be used for fast verification of the polymorphic form of a drug in final tablets21,42. Again, solid state properties of both excipients and active pharmaceutical ingredients can be followed non-invasively. In many cases, following unit operation is the coating process, usually performed using an aqueous polymer solution. Raman spectroscopy has been utilised in various other areas for analysis of film coatings, but not widely in the field of pharmaceutics. Ringqvist et al. has reported the use of confocal Raman for analysis of the chemical composition in selected small areas of the coating surface43.

Challenges in process analysis

One fundamental question concerning process measurements with Raman is interfacing into process, as it is with all process analytical tools. The basic problem is obviously to keep the insight into a process clean, to measure a representative part of the material and to have the moving sample in focus. A Raman probe can be mounted invasively using an immersion probe, or process monitoring can be performed non-invasively using non-contact optics. Another problem related to Raman is the small sampling area. The penetration depth of the lasers used is relatively small, resulting in a small effective sample volume. This can be affected with optics, by increasing the area that is being measured. Wikström et al. has recently evaluated different sampling devices for in-line measurements44. Sample heating is a widely recognised problem in Raman spectroscopy. Moving the sample being measured, which is automatically the case in process analysis, can minimise problems related to heating. Johansson et al. investigated the sample heating of pharmaceutical materials and developed a model to predict the rotation speed needed to minimise the heating45. With some materials, an intense fluorescence background is observed. This can be affected by selecting the appropriate excitation wavelength.

Conclusions

Raman spectroscopy has matured into an effective tool for ensuring safe and efficient manufacturing of pharmaceutics. Much has happened since Chandrasekhara Venkata Raman visited Europe in the summer of 1921, when he formulated his first ideas related to this phenomena whilst observing the blue opalescence of the Mediterranean Sea46 At the moment, we have instruments ready for non-invasive process measurements. Recent developments in the fields of optoelectronics, computer technology, data transfer and data analysis methods have enabled the real-time and non-invasive Raman analysis of pharmaceutical unit operations and, by this means, a molecular level insight into processing. More research is needed to understand the full potential of Raman as a process analytical tool.

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