Real-Time Raman During Development and Manufacturing

One of the common methods used to identify and characterize active ingredients and excipients is Raman spectroscopy. Both qualitative and quantitative analysis can be performed with this technique. Raman spectroscopy is based on the inelastic scattering of laser radiation with loss of vibrational energy by the compound. A vibrational mode is Raman active when there is a change in the polarizability during the vibration. Symmetric modes tend to be Raman-active. For example, vibrations about bonds between the same atoms can be observed by Raman spectroscopy.

Raman spectroscopy can be very useful for research particularly during various stages of development and manufacturing. The technique may allow one to identify polymorphs (1-2), follow salt/co-crystal formation (3) and monitor real-time processes (4). During formulation, active ingredients can be monitored via their Raman bands without significant interference from the excipients (5). Amounts of active ingredient as low as 0.1% can be detected and monitored by Raman (6).

Traditionally analytical techniques are implemented in an off-line fashion, where samples have to be removed from the reaction or process, in order to obtain information about chemical composition or interactions. With offline techniques one obtains information on a few data points in time, but the nagging question always remains: Have I missed something?

Crystalline with through the vial analytical capabilities (turbidity, particle visualization and Raman) offers you the possibility to easily follow crystallization processes and to study polymorph conversions, hydration or the formation of solvates in slurries. Chemical interactions like co-crystal and salt formation can be studied effortlessly during the process. This hassle-free tool enables you not only to screen many solvents, counter-ions or co-formers on a small amount of compound but also monitor your process. The Crystalline instrument gives you valuable answers much earlier on in the process and in short time. Your tool for solving process related problems!


(1) Kulkarni S.A., McGarrity E.S., Meekes H. and ter Horst J.H., Isonicotinamide self-association: the link between solvent and polymorph nucleation, Chem. Commun., 2012, 48, 4983.
(2) Ono T., ter Horst J.H., Jansens P.J., Quantitative measurement of the polymorphic transformation of L-glutamic acid using in-situ Raman spectroscopy, Crystal Growth & Design, 2004, 4 (3), 465.
(3) Horst J.H., Cains P.W., Co-crystal polymorphs from a solvent-mediated transformation, Crystal Growth and Design, 2008, 8 (7), 2537.
(4) Feth M.P., Nagel N., Baumgartner B., Brockelman M., Rigal D., Otto B., Spitzenberg M., Schulz M., Becker B., Fischer F., Petzoldt C., Challenges in the development of hydrate phases as active pharmaceutical ingredients- An example, European Journal of PharmaceuticalSciences, 2011, 42, 116.
(5) Sasic A., A Raman mapping of low-content API pharmaceutical formulations. I.Mapping of Alprazolam in Alprazolam/Xanax tablet, Pharm Res., 2007, 24, 58.
(6) Hausman D.S., Cambron R.T., Sakr A., Application of Raman spectroscopy for on-line monitoring of low dose blend uniformity, Int. J. Pharm., 2005, 298, 80.