Volume 52, Number 1, 1998 APPLIED SPECTROSCOPY 170003-7028 / 98 / 5201-0017$2.00 / 0q 1998 Society for Applied Spectroscopy

On-Line Determination of Reaction Completion in aClosed-Loop Hydrogenator Using NIR Spectroscopy

HOWARD W. WARD II, S. SONJA SEKULIC, MICHAEL J. WHEELER,GERALDINE TABER, FRANK J. URBANSKI, FRANK E. SISTARE,TIMOTHY NORRIS, and PAUL K. ALDRIDGE*P® zer Central Research (H.W.W., S.S.S., T.N., P.K.A.) and P® zer U.S. Pharmaceutical Group (M.J.W., G.T., F.J.U., F.E.S.),Eastern Point Road, Groton Connecticut 06340

An on-line near-infrared (NIR) spectroscopic method has been de-veloped to determine in situ the endpoint of a bulk pharmaceuticalhydrogenation reaction in a loop hydrogenator. This hydrogenationemploys a 5% palladium-on-carbon catalyst with tetrahydrofuran(THF) as the reaction solvent. The traditional test for monitoringthe endpoint of the hydrogenation is a gas chromatographic pro-cedure that requires an estimated 60 min from the time a sampleis taken to the point where the analysis results become available.The use of NIR spectroscopy in an on-line mode of operation allowsspectra to be collected every 2 min and thereby signi® cantly im-proves response time and result availability. The need for obtainingresults in `̀ real time’’ stems from the creation of undesired sideproducts if the reaction is allowed to continue past the optimal end-point. If the reaction is not stopped before these side products reacha level of approximately 0.8% (wt/wt), the batch requires additionalpuri® cation at considerable time and cost. A partial least-squaresmodel was constructed , validated, and successfully used to deter-mine the endpoint of subsequent batches.

Index Headings: NIR; Near-IR; Near-infrared; Pharmaceutical; Hy-drogenation; Multivariate calibration; PLS.

INTRODUCTION

Opportunities for the utilization of near-infrared (NIR)spectroscopy in the pharmaceutical industry are becom-ing evident as this technology becomes more widely ac-cepted. For example, the analysis of intact tablets1 andblister-packed clinical supplies2 has been performed byusing NIR spectroscopy. Similarly, off-line experimentshave shown that NIR spectroscopy may be used to de-termine the homogeneity of simple powder mixtures.3

On-line NIR applications include coupling NIR spectros-copy with ® ber optics to monitor blend homogeneity withdynamic data collection.4 In other related applications,NIR spectroscopy has been used to monitor the percentconversion of polymerization reactions in situ5 and tomonitor the progress of polymer processes.6 In this study,we have developed an NIR spectroscopic method for de-termining the endpoint of a hydrogenation reaction whichemploys a 5% palladium-on-carbon catalyst in tetrahy-drofuran (THF). This paper describes the implementationof an on-line NIR monitoring system in a hydrogenationreactor and presents the conclusions reached from thisstudy.

Typically, the determination of the endpoint of the hy-drogenation reaction requires a time-consuming series ofsteps to be performed. Samples are removed at speci® edtimes throughout the reaction and analyzed by traditional

Received 24 January 1997; accepted 12 August 1997.* Author to whom correspondence should be sent.

methods such as ultraviolet-visible (UV-vis) spectroscopyor high-performance liquid chromatography (HPLC).7

From these results, the rate of reaction may be deter-mined and the endpoint of the reaction estimated by ex-trapolation of the data. A sample is then removed at theestimated endpoint and the hydrogen supply secured. Ifresults from this sample indicate that the reaction hasreached the desired endpoint, a ® nal con® rmatory sampleis taken and no further steps are necessary. If the end-point has not yet been reached, the reaction is restartedand allowed to continue for another period of time, whichis estimated from the previous sample and the resultsplot. This procedure is repeated until the reaction hasreached or progressed beyond the optimal endpoint. Stop-ping the reaction at the desired endpoint is therefore high-ly dependent on the time required to complete the aboveanalysis sequence. The traditional test for monitoring theend of the hydrogenation is a gas chromatographic (GC)procedure that requires an estimated 60 min from the timea sample is taken to the point where the analysis resultsbecome available.

The use of NIR spectroscopy in an on-line mode ofoperation allows spectra to be collected every 2 min andproduces results in `̀ real time’ ’ . The desire for obtainingresults in real time stems from the formation of undesiredside products if the reaction is allowed to continue pastthe optimal endpoint. Towards the reaction endpoint, thedesired product can undergo hydrogenolysis to give amixture of undesired side products. If the hydrogenationis continued past this endpoint and the side productsreach a certain level, the batch requires additional puri-® cation at appreciable time and cost. For maximum pro-cess ef® ciency, the undesired side products should not begreater than 0.8% (wt/wt) of the ® nal reaction composi-tion. Ideally, at the end of the reaction, the compositionshown in Table I should be present.

This NIR method improves the ef® ciency of the re-action by allowing the reaction to be stopped prior to theformation of the undesired products, thereby precludingthe need to perform additional puri® cation steps in theprocess. Since the need to wait for laboratory results iseliminated, the turn-around time between batches is re-duced and batch-to-batch productivity increased. The re-duction in the number of samples taken for laboratoryanalysis results in decreased analytical test time and cost,as well as minimization of handling of THF-containingsamples.

INSTRUMENTAL

A modi® ed NIRSystems process 5000 spectrophotom-eter (NIRSystems, Silver Spring, MD) was used in this

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TABLE I. Desired composition at the end of hydrogenation.

Component Weight %

Starting compoundDesired productUndesired side products

, 1%. 98%, 0.8%

FIG. 2. Expanded view of the trans¯ ectance ® ber-optic probe.

FIG. 3. Schematic diagram of slipstream con® guration and NIR ® ber-optic probe installation.

FIG. 1. The NIRSystems Model 5000 spectrophotometer shownmounted on the instrument cart with the operational control unit (OCU).

study. The modi® cations encompass out® tting the unit formobile operations. This procedure includes shock mount-ing the instrument on a cart and connecting an Opera-tional Control Unit (OCU) to the spectrophotometer, asshown in Fig. 1. The OCU was included to enable op-eration in a variety of hazardous environments by pro-viding a nitrogen purge for both the spectrophotometerand the OCU container, together with a pressure sensor,time delays, and a door interlock sensor connected to apower override switch.

The spectrophotometer is connected to a 12 in. (1 in.O.D.) sampling probe via a 3 m ® ber-optic bundle. Thebundle is a 210/210 con® guration, which indicates thatthere are 210 ® bers taking light from the source to theprobe tip and there are 210 ® bers taking the responselight back to the detector. The trans¯ ectance probe sleeveis attached to the end of the probe with a pathlength of0.5 mm set with a feeler gauge. The short pathlength isrequired so that the dynamic range of the instrument isnot exceeded while data are collected on a reaction matrixcontaining a carbon catalyst. The trans¯ ectance probecon® guration is shown in Fig. 2. Reference scans werecollected through a shunt ® ber bundle approximately 1/4m in length. This con® guration eliminates the need forremoving the probe from the process to acquire a refer-ence spectrum.

The controlling computer was a Toshiba 6400DX486/33 (Toshiba America Information Systems Inc., Ir-vine, CA), which was placed in a control room adjacentto the building containing the reactor vessel. Communi-cation with the instrument was achieved with a ® ber-opticcommunication link. One hundred meters of dual ® ber-optical cable (Siecor Optical Cable, 110/140 m m, TypeOFNR, Optelecom, Gaithersburg, MD) was installedthrough conduit from the control room to the instrument.The ® ber was connected to the instrument and the com-

puter by using ® ber-optic full duplex data modems (Mod-el 4131AS-S-SM, Optelecom, Gaithersburg, MD).

Near Infrared Spectral Analysis Software (NSAS) Ver-sion 3.30 (NIRSystems, Silver Springs, MD) was usedfor spectral data collection. Data analysis was carried outin Pirouette Version 1.2 (Infometrix Inc., Seattle, WA)and Matlab Version 4.2c.1 (The MathWorks Inc., Natick,MA).

EXPERIMENTAL

During installation of the NIR spectrophotometer inthe loop reactor, installation quali® cation (IQ) tests wereperformed to determine that all necessary hardware andsoftware were in place and to ensure that all safety con-siderations had been addressed. Operation quali® cation(OQ) tests were also carried out to ensure that the hard-ware, software, and communication links were perform-ing as required. Performance quali® cation (PQ) tests werethen performed to test the functioning of the Process5000 mobile spectrophotometer as a complete unit, withthe intended application requirements taken into consid-eration.

The 1 in. o.d. trans¯ ectance probe was installed witha Swagelokt ® tting in the lower end of a gas± liquid sep-aration chamber in a slipstream, which was placed acrossthe system pump as shown in Fig. 3. The separation

APPLIED SPECTROSCOPY 19

FIG. 4. Typical trans¯ ectance spectra for an entire reaction over the1400 ± 1900 nm range.

FIG. 5. Second-derivative spectra for an entire reaction showing thetwo regions with the greatest amount of variability.

FIG. 6. An expanded view of the 1530 nm region, which is generallyattributed to the ® rst N± H stretch overtone. Arrows indicate reactionprogress.

chamber provided a means for removing the entrainedgas from the stream prior to its traversing the probe. Theslipstream from the main process loop enters the side ofa separation chamber, which provides both top and bot-tom exit streams. A restriction on the bottom end of thechamber, along with a valve, creates a back pressure topartially ® ll the chamber with liquid while providing anescape through the top exit for the liquid over¯ ow andthe less dense gas. After the liquid stream has left thechamber, it converges with the gas and over¯ ow streamand returns to the main process stream. A valve placedin this stream immediately prior to its return to the mainstream was used to control ¯ ow rates, which were mon-itored indirectly via a pressure gauge (i.e., the larger thepressure drop across the slipstream, the higher the ¯ owrate). The ¯ ow rate through the slipstream was optimizedby incrementally changing the ¯ ow rate and examiningthe stability of the predictions over a period of 10 min.Predictions remain stable over approximately a 208change in the valve setting.

After the nitrogen-purged hydrogenation loop wascharged with the reaction matrix, the reactor was pres-surized with hydrogen and the pump started to initiatethe reaction. Spectra were collected every 2 min over the1100 to 2500 nm wavelength range with a 2 nm interval.Samples were withdrawn throughout the reaction, and thecorresponding spectrum for each sample was recorded.The removed samples were analyzed by GC to providethe concentration values for the reaction components ofinterest.

RESULTS AND DISCUSSION

The hydrogenation reaction involves the conversion ofan imine functionality to the cis and trans isomers of theamine. Near the end of the reaction, the compound canundergo hydrogenolysis to give a mixture of undesiredside products. The typical spectra collected over the du-ration of one such hydrogenation reaction are shown inFig. 4. The arrow indicates the order of spectrum collec-tion, i.e., the progress of the reaction. In order to mini-mize the spectral features induced by the physical char-acteristics of the sample, in this case the turbidity and thepresence of the carbon-based catalyst, a second derivativeof the collected spectra is calculated. The resultant secondderivatives are shown in Fig. 5 over the wavelength re-

gion of 1400 to 1900 nm. Two regions have been boxedin this ® gure to indicate spectral changes that re¯ ect prod-uct formation in the reaction mixture. The ® rst regionoccurs around 1530 nm and is expanded in Fig. 6, wherethe arrows indicate the progress of the reaction. This re-gion is generally attributed to the ® rst overtone of a N±H bond stretch and is consistent with the expected reac-tion chemistry. The second region, shown more clearlyin Fig. 7, occurs at approximately 1660 nm. This regionis typically assigned to the ® rst overtone of an a C± Hbond stretch. Again, the arrow indicates the progress ofthe reaction. Note that at the start of the reaction thespectra do not change signi® cantly in this region; i.e., thespectra are superimposed on top of each other. Thechanges appear to occur toward the later part of the re-action. This observation is consistent with the GC resultsfor the production of the undesired side products, whichtend to increase in concentration only toward the laterpart of the reaction.

The initial data exploration was carried out by usingprincipal component analysis (PCA). The spectral datawere mean centered and derivatized (13-point-gap second

20 Volume 52, Number 1, 1998

FIG. 7. Expanded view of the 1660 nm region, which is generallyattributed to the region of the ® rst C± H stretch overtone. Arrows indi-cate reaction progress.

FIG. 9. A correlation plot of the actual GC vs. NIR predicted valuesof the desired product concentration for the validation set with a modelconstructed by using a separate calibration set.

FIG. 10. A correlation plot of the actual GC vs. NIR predicted valuesof the undesired side products concentrations for the validation set witha model constructed by using a separate calibration set.

FIG. 8. The second score vector for the PCA decomposition of threereactions. Arrows indicate reaction progress.

derivatives) covering the wavelength region of 1400 to1900 nm. Figure 8 shows the resultant score vector ofthe second principal component for three reactions. Thearrows are used to indicate the progress of the reaction.The clustering at the end of the arrows is representativeof the end point of the reaction, where little change oc-curs. This pattern indicates that the behavior of the spec-tral data is reproducible from reaction run to reaction run.

Multivariate calibration tools available in the softwarepackage Pirouette were then used to construct a calibra-tion model that would be used for prediction of the con-centration of (1) the desired product formation and (2)the undesired side products.

The spectra from 16 batches were divided into a cali-bration set containing 90 spectra from eleven batches anda validation set containing 44 spectra from ® ve batches.Each set contained a variety of batches produced by usinga number of different catalyst lots, starting material lots,and reaction temperatures. No batch was common to boththe calibration and validation sets. A 4-latent-variablespartial least-squares (PLS) model was constructed in Pir-ouette with the use of the mean-centered and derivatized

(13-point-gap second derivatives) calibration spectra.This model was then used to predict the constituents ofthe validation set.

Figure 9 shows the prediction results for the concen-tration of the desired product formation of the validationset. As can be seen, the correlation coef® cient is 0.998and the root mean squared error of prediction (RMSEP)is calculated to be 0.75; i.e., on the average, the error inthe prediction would be 6 1.5% relative at a con® dencelevel of 95%. The predictive ability of the model is de-pendent on process variables such as the temperature, thetypes and concentrations of reactants used, and the ¯ owrate through the slipstream. As these variables arechanged, the model is re-evaluated for robustness andvalidity.

For the concentration of the undesired side products,the same preprocessing and parameters discussed abovefor the desired compound were used. Figure 10 showsthe predicted concentration against the measured GC con-centrations. For this case, the correlation coef® cient iscalculated to be only 0.64, while the RMSEP value is

APPLIED SPECTROSCOPY 21

approximately 0.11. The GC method used for the sideproducts is the same as that for the main reaction prod-ucts with relative errors on the order of 3%. Thus, it ishighly unlikely that the error in Fig. 10 is due to error inthe GC method. The nonlinearity of the undesired prod-uct spectra, possibly due to back-protonation of the prod-uct by HCl, together with the low concentrations of theseconstituents and a reaction matrix containing a carboncatalyst, leads to the poor predictive ability of this modelfor these particular reaction components.

CONCLUSION

NIR spectroscopy can be used to monitor in situ theendpoint of the closed-loop hydrogenation reaction,which uses a 5% palladium-on-carbon catalyst. With theaid of multivariate calibration tools and data analysistechniques, a system model has been constructed to mon-itor and predict the concentration of the desired productat any point in the reaction sequence. This model was

successfully used to determine on-line the endpoint ofsequential batches in a production campaign of a bulkpharmaceutical compound.

ACKNOWLEDGMENTS

We take this opportunity to thank the chemical operators, engineers, andlaboratory personnel involved with the implementation of this project.

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