Use of Raman Spectroscopy to Characterize Hydrogenation Reactions Venkat S. Tumuluri, ² Mark S. Kemper, ‡ Anjaneyulu Sheri, § Seoung-Ryoung Choi, § Ian R. Lewis, ‡ Mitchell A. Avery, § and Bonnie A. Avery* ,² Department of Pharmaceutics, UniVersity of Mississippi, UniVersity, Mississippi 38677, U.S.A., Kaiser Optical Systems, Ann Arbor, Michigan, U.S.A., and Department of Medicinal Chemistry, UniVersity of Mississippi, UniVersity, Mississippi 38677, U.S.A. Abstract: Raman spectroscopy was used to characterize hydrogenation reactions involving single-step and two-step processes. The Raman technique was shown to be well-suited for endpoint determination as well as process optimization. In this investiga- tion, hydrogenation of cyclohexene to produce cyclohexane was used as a model system. Conditions were varied to determine the effect of catalyst loading, solvent ratios, and reactant concentrations. Four catalysts were evaluated. The kinetic profiles of each reaction process were determined for each of the catalysts. In one case, a side reaction leading to an intermediate was observed for the hydrogenation reaction when run under hydrogen-starved conditions. After these cyclohexene hydrogenations were characterized, Raman spectroscopy was applied to the conversion of carvone to tetrahydrocarvone and the hydrogenation of 2-(4-hydroxyphenyl) propionate. Raman was used to characterize the kinetics of these reactions and was also used to prove that two-step hydrogenation mechanisms occurred in each. Raman was shown to be useful for process understanding, process optimization, process monitoring, and endpoint determination. Accomplishment of these goals leads to better process controls upon transfer of the procedure to a process environment. This ultimately leads, in turn, to the mitigation of risk of making out-of-specification product in manufacturing. Introduction Hydrogenation reactions are ubiquitous in chemical manufacturing processes. In the pharmaceutical industry, they are quite commonly used in multistep procedures employed in the synthesis of active pharmaceutical ingredients (APIs). 1 In fact, hydrogenation reactions account for about 10% to 20% of all reactions employed by API manufacturers. 1 This class of reactions is also used in the chemical industry for general synthetic procedures. Hydrogenations can be performed to accomplish several types of chemical transformations, but they are often used to convert olefinic bonds to aliphatic bonds. 2 Other common conversions include transformation of nitro compounds to amines, functional group deprotection procedures, and other processes. 3,4 With any synthetic reaction carried out on an industrial scale, it is useful to perform in-process checks in order to ascertain the progress of the reaction and know when the endpoint has been reached. In the case of hydrogenations, many of the reactions are inherently highly exothermic. Ineffective heat removal can result in thermal runaway leading to an explosion. 5 In these cases, monitoring of the progress of the reaction to avoid such events is essential. Real-time feedback through a monitoring scheme that allows for process adjustments is preferred. In the pharmaceutical industry, active ingredient synthesis is often referred to as primary processing. The Process Analytical Technology (PAT) initiative proposed by the United States Food and Drug Administration (USFDA) has produced much activity in the realm of process chemistry amongst pharmaceutical companies. 6 The premise of this is that better understanding necessarily leads to the ability to impose better controls. In turn, a better control regime mitigates the risk of making product that is out-of-specifica- tion. Such a result provides benefits for both the consumer and the manufacturer. In the case of the manufacturer, benefits are realized by a reduction of scrapped materials and wasted production capacity as well as the reduction or elimination of costly product recalls. For the consumer, the benefit is the assurance that the product they use was manufactured to the highest standards for purity, safety, and efficacy as the processes are monitored in real time. Vibrational spectroscopic techniques such as Fourier transform infrared (FT-IR) spectroscopy, near-infrared (NIR) spectroscopy and Raman spectroscopy are extremely valuable tools for many process situations. Various groups have experimented with NIR in the area of reaction monitoring. For example, hydrogenation of itaconic to methyl succinic acid was carried out by Wood et al. 7 Fermentation was monitored by Lendl et al. 8 Pharmaceutical companies have * To whom correspondence should be addressed. E-mail: bavery@olemiss.edu. Dr. Bonnie A. Avery, Associate Professor, 107 Faser Hall, Department of Pharmaceutics, University of Mississippi, University, MS 38677. Telephone: 662-915-5163. Fax: 662-915-1177. ² Department of Pharmaceutics, University of Mississippi. ‡ Kaiser Optical Systems. § Department of Medicinal Chemistry, University of Mississippi. (1) Pavlenko, N. V.; Tripolskii, A. I. L. V. Res. Chem. Kinetics 1995, 207- 258. (2) Dyson, P. J.; Zhao, D. Hydrogenation. Multiphase Homogeneous Catalysis 2005, 2, 494-511. (3) An Leeuwen, P. W. N. M.; Van Koten, G. Catalysis 1993, 79, 199-248. (4) Jacobson, S. E. Catalytic hydrogenolysis of organic thiocyanates and disulfides to thiols. PCT Int. Appl. 1997, 17 pp. (5) Rylander P. N. Catalysts, Reactors, and Reaction Parameters. Hydrogena- tion methods; Academic Press: Orlando, FL, 1985. (6) Guidance for Industry PAT sA Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. Center for Drug Evaluation and Research, Division of Food and Drug Administration. 2003 (7) Wood, J.; Turner, P. Appl. Spectrosc. 2003, 57 (3), 293-8. Organic Process Research & Development 2006, 10, 927-933 10.1021/op0600355 CCC: $33.50 © 2006 American Chemical Society Vol. 10, No. 5, 2006 / Organic Process Research & Development • 927 Published on Web 07/14/2006