Implementation of Raman Signal Feedback to Perform Controlled

Article pubs.acs.org/OPRD

Implementation of Raman Signal Feedback to Perform Controlled Crystallization of Carvedilol Hajnalka Pataki,*,† Istvan Csontos,† Zsombor K. Nagy,† Balazs Vajna,† Milan Molnar,‡ Laszlo Katona,‡ and Gyorgy Marosi† †

Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, H-1111 Budapest, Hungary Department of Control Engineering and Information Technology, Budapest University of Technology and Economics, H-1111 Budapest, Hungary

‡

ABSTRACT: This study indicates that real-time Raman spectroscopy is more than just an effective tool for monitoring drug crystallizations. The results verify that fibre-optic-coupled Raman spectroscopy can be used not only for monitoring processes but also for ensuring the production of the desired polymorphs by continuous feedback of the polymorph signal in the course of crystallization procedures. Cooling crystallization of an active pharmaceutical ingredient was performed to test the feedback method, during which the kinetically preferred and desired Form II crystal structure was produced. If, however, a thermodynamically stable undesired polymorph is present as an impurity, it will influence the characteristics of the end product. The aim of the control, based on Raman-signal feedback, was to ensure that the quality of the drugs was maintained in crystallization processes, despite such disturbing influences. The feedback control was based on the development of communication between a Raman spectroscope and a programmable logic controller. The control was performed with the aid of the ratio of two Raman intensities, characteristic of the two polymorphs (Form I and Form II). In addition, the control was able to handle the changes in Raman intensity caused by crystal size alteration. The developed model demonstrates a new way to meet the recent FDA directives concerning Process Analytical Technology (PAT). ment (PVM),11,12 ultrasound spectroscopy,13,14 and bulk video imaging.15−18 In addition, these PAT tools can be also used for real-time feedback control during crystallization or chemical reactions to ensure the formation of the desired polymorph or particular crystal properties. Feedback control of concentration has already been successfully performed by ATR-FTIR,19−23 ATR-UV/vis,24,25 and NIR.26 The automated direct nucleation control (ADNC) approach was made possible by feedback FBRM control.27,28 Within this list, Raman spectroscopy is the most effective analytical tool to qualify and quantify different polymorphs in crystallization mediums, although it is sensitive to the alteration of crystal size. This method is adaptable to monitor the crystallization process closely, by applying either noninvasive or invasive inline methods. Although the control of crystallizations through feedback from real-time Raman spectra is very promising, no detailed discussion of an example has been published so far. Several studies demonstrate, however, the notable success of process monitoring by Raman spectroscopy; for example solvent-mediated polymorphic changes can be detected, allowing investigation of crystallizations from kinetic and thermodynamic points of view.29−31 There is a statement in the patent literature concerning the use of feedback from Raman signals in a controlling process regarding the maintenance of the carbonate/bicarbonate concentration ratio. According to the description of this patent, the exact

1. INTRODUCTION The applications of automated reactor systems are essential in the contemporary chemical industry to improve product quality, increase yield, ensure process safety, and reduce the impact on the environment. The control of batch and semibatch crystallizations is very challenging because of the constantly changing characteristics of such dynamic systems. Modern control approaches are required to meet the requirements outlined above.1,2 Crystallization is a critical segment of batch processes in the pharmaceutical industry because of product sensitivity to process parameters. For example, crystal morphology can be influenced by temperature, stirring conditions, concentration, solvent properties, impurities, etc. The suitable design of crystal morphology (i.e., polymorphism, crystal size, crystal size distribution) is essential for subsequent production procedures. These characteristics can affect the processes and parameters used for formulation, as well as the solubility characteristics of the drug. Thus, it can modify the bioavailability of pharmaceutical compounds as well. Consideration of the principles of Process Analytical Technology (PAT) is useful when contemplating the control of crystallization processes. According to the FDA directives, PAT requires “controlling manufacturing during timely measurements, with the goal to ensuring final product quality”.3 This concept supports the application of real-time analytical sensors to characterize crystal properties during crystallization or other reactions. The methods adapted for crystallization tracking include attenuated total reflectance Fourier transformation infrared spectroscopy (ATR-FTIR)4,5 near-infrared spectroscopy (NIR),6,7 Raman spectroscopy,8,9 focused beam reflectance measurement, (FBRM),10 particle vision measure© XXXX American Chemical Society

Special Issue: Polymorphism and Crystallization 2013 Received: March 9, 2012

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dx.doi.org/10.1021/op300062t | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

Yokogawa (Japan) and a monofluid thermostat developed in our Department. A Eurostar power control-visc type stirrer, made by IKA (Germany), was also controlled by the PLC. Noninvasive Raman spectra were collected by a fibre-opticcoupled Raman probe connecting to the Horiba Jobin Yvon Raman spectrometer. 2.3. Methods. Carvedilol Form II polymorph (13.8 g) was dissolved in 100 mL of ethyl acetate, after which the suspension was heated to the boiling point of the solvent (77 °C). The drug solution was cooled at a rate of 0.096 °C/min and stirred at 200 rpm. At 73 °C the solution was seeded with the thermodynamically stable Form I polymorph. The filtration of the end product was performed at 0 °C, after it was dried at room temperature and atmospheric pressure. Noninvasive Raman spectrometry was used to monitor the whole process from dissolution until the end of crystallization. Real-time Raman spectra were fixed in 292−1540 cm−1 spectral range with a 300 mW laser (785 nm) source and air-cooled CCD detector. Exposition time was 90 s, while the accumulation number during cooling crystallizations was 2. Exact quantification of the raw spectra was obtained with the aid of the LabSpec programme and the Classical Least Square (CLS) method. Supersaturation measurements were performed by taking samples every 10 °C. The samples were filtered with microfilters (0.2 μm) before being diluted. The concentrations were identified with UV/vis spectroscopy at 332 nm. Supersaturation values were calculated from the difference of measured and equilibrium concentrations (c − c*). The Raman spectra were evaluated using the CLS method, which is a bilinear model. CLS is based on the assumption that mixture spectra are linear combinations of the spectra of the pure components.34 (Equations and the explanation can be found in the cited reference.) In the case of postevaluation of the experiment, the percent values show the rates of phase formations in the slurry and not the exact concentrations. Therefore, the calculated concentration values will be referred

concentration values were calculated from real-time Raman spectra using chemometrics. The process conditions of the applied programmable logic controller (PLC) were modified, using the results of calculations, to maintain the required concentration ratio. The procedure was used in carbon dioxide absorption technology for the regeneration process of carbonate/bicarbonate.32 The present report gives a description of feedback control applied to the cooling crystallization of an active pharmaceutical ingredient by Raman intensity ratios. It also introduces the operation of a proprietary laboratory reactor system developed for implementing PAT crystallization technology. The model drug selected for this purpose is carvedilol, which is a nonselective beta blocker, used in the treatment of mild to moderate congestive heart failure.

2. EXPERIMENTAL METHODS 2.1. Materials. Carvedilol ((±)-[3-(9H-carbazol-4-yloxy)-2hydroxypropyl][2-(2-methoxypheoxy)ethyl] amine) (Scheme 1), was obtained from Sigma Aldrich, while the solvent Scheme 1. Molecular structure of carvedilol

employed was ethyl acetate. Two polymorphs were used for all experiments; thermodynamically stable Form I and kinetically preferred Form II, which have a monotropic relationship.33 2.2. Equipment. Crystallizations were performed in a computer-controlled laboratory reactor system, developed by the authors, which contained the following main parts. The reactor unit of the system was a partly duplicated 150-mL glass vessel, produced by Normag (Germany). The temperature was controlled using a Stardom FCN-type PLC manufactured by

Figure 1. Feedback control scheme for cooling crystallization. B



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Figure 2. Raman spectra of ethyl acetate and carvedilol, Form I and Form II.

to as “spectral concentrations” to avoid confusion with the real concentration values.

thermodynamically stable crystal structure in this crystallization circumstanceis present as an impurity, it will seed the crystallization medium, determining the morphology of the end product. This phenomenon was used to test the efficiency of the feedback control. Thus, the experiments modeled this case, where the thermodynamically stable polymorph, used as an impurity, would prevent the production of the desired crystal structure. First of all, it was necessary to study the real-time Raman monitoring of the cooling crystallization process to implement successful feedback control. Examining the changes in Raman spectra was necessary during the process to apply the principles of control-based Raman intensity ratios. The process parameters (cooling rate, stirring speed, antisolvent addition rate) can be changed at any time during crystallization as this will alter the quality of the product correspondingly. The drug solution was heated from 0 to 77 °C. A low level of supersaturation could be ensured with a slow cooling rate (slow cooling in metastable zones produces bigger crystals). At the saturation point of Form I (73 °C) the solution was seeded with 1% Form I polymorph. If the control objective is to produce Form II, an intensity ratio threshold of the characteristic peaks of the two polymorphs (Form I and Form II) has to be determined. Form I polymorph is described by the peak at 753 cm−1, while Form II is characterized by the peak at 727 cm−1. The solvent, ethyl acetate, does not absorb at this wavenumber range (713−778 cm−1); thus, the composition of solid phase can be identified (Figure 2). The feedback control was designed to be based upon the intensity ratio of the peaks of Form I (753 cm−1) and Form II (727 cm−1), because neither the solvent nor the saturated solution have any significant signs at these wavenumbers. The intensity values in these Raman shifts have to be corrected with the actual baseline, because the baseline can fluctuate during crystallization. Therefore, only the relative intensity values are definitive and should be used for accurate control of the process. Furthermore, such control is not sensitive for Raman intensity changes caused by particle size alteration. Con-

3. RESULTS AND DISCUSSION Numerous developments have improved Raman-based process control. Software modules of the PLC were written in Structured Text (ST), Function Block Diagram (FBD), and Sequential Function Charts (SFC) languages, which are defined in the IEC 61131-3 standard. A robust temperature control was created and tested. The cascade regulation system consisted of a primary control loop for the crystallization medium, and a secondary control loop for the jacket. The control loops used an enhanced PID algorithm to reduce the overshot when the set point changed quickly. Heating and cooling profiles could be programmed so that it could simulate industrial crystallizers. The Raman spectrometer and PLC were connected through a serial line. The Raman spectrometer operation was controlled by a Visual Basic program using the ActiveX interface of the spectrometer. This program received the exposition parameters and the requested wavenumbers, made the Raman measurement, stored the raw data for subsequent evaluation, and sent the corresponding intensity data to the PLC (Figure 1). The continuous acquisition of the Raman spectra with time stamp was significant, because all the Raman intensity data from the whole spectral range were needed for the accurate, subsequent quantitative evaluation of processes. The goal was to produce carvedilol Form II polymorph during cooling crystallization. The control approach ensures the production of the desired Form II polymorph. However, there were several disturbing factors to which the control had to react properly. Thus, the control reaction could be tested with deliberately induced disturbances. Normally, in the case of cooling without seeding, the kinetically preferred Form II polymorph is crystallized from ethyl acetate solution. The presence of the thermodynamically stable polymorph in the crystallization medium can be a significant disturbing factor. If Form I polymorphwhich has a C



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Figure 3. Development of the intensity values of Form I and Form II during cooling crystallization without Raman feedback control.

Figure 4. Real-time Raman spectra during cooling crystallization of carvedilol without Raman feedback control.

sequently, Raman intensity at 743 cm−1 was chosen as a baseline to subtract from both characteristic intensities (753 cm−1, 727 cm−1). In the subsequent parts of this report the intensitiescharacteristic of the two formswill represent the baseline-corrected intensity values. The peak intensity of Form I is larger than the peak intensity of Form II (IForm I > IForm II) only when unwanted Form I crystal structure is growing in the reactor. This is confirmed by Figure 3, where the alteration of the intensity values can be observed in the case of a manually controlled experiment. The heating period was started without Raman feedback control, with a spectral concentration of just 39% Form I. Real-time Raman spectra from selected points in the experiment are shown in Figure 4, where the main stages of crystallization can be identified. When Raman feedback control crystallization was performed, the realized control strategy can be seen in Figure 5. The SFC program starts with the initial setting of program variables, followed by heating. A cooling phase starts after complete

dissolution of the solid phase (at 77 °C), accompanied with continuous Raman monitoring. If the peak intensity of Form I is larger than the peak intensity of Form II during the cooling stage (i.e., unwanted Form I polymorph appears in the suspension), the crystallization process can be altered so that the desired path is taken. This is done through changing the process parameters. The cooling crystallization process can be affected by varying the temperature; hence, an SFC program is used in the PLC to select the required temperature profiles (see Figure 5). Thus, in case of formation of Form I polymorph, the controller increases the temperature up to 77 °C achieving complete solution), and the crystallization process will restart. As two pathways are possible during the cooling phase, the controller program has to be able to handle both cases. The details of the overall approach are shown in Figure 5. If formation of unwanted Form I is identified (i.e., intensity of Form I peak exceeds the Raman intensity of Form II), the SFC program will automatically respond and reheat the suspension. D



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Figure 5. SFC program module of the PLC for Raman feedback control of cooling crystallization of carvedilol.

Figure 6. Raman spectra of Raman feedback control crystallization of carvedilol.

The complete dissolution of the drug was confirmed by the diminishing quantity of Form II. The clear solution formed at 26 °C. The undesired Form I polymorph started to crystallize at 62 °C following seeding (73 °C); the continued increase of its spectral concentration as it can be seen in Figure 7. At 56.7 °C the spectral concentration of Form I increased to 12%, so that the peak intensity characteristic of Form I was larger than the peak intensity of Form II. At that time the PLC started

The reheating period must ensure the complete dissolution of Form I, which is considered an impurity in this crystallization medium. If desired Form II appears, cooling will continue until a temperature of 0 °C is reached. At the end of the heating and cooling stages the “holding temperature” action is initiated. The real-time Raman spectra from Raman feedback control crystallization can be observed in Figure 6. The first time Form II polymorph was identified from Raman spectra was at 0 °C. E



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Figure 7. Quantitative evaluation of the Raman feedback control crystallization.

Figure 8. Supersaturation profile of Raman feedback control crystallization.

to automatically heat the suspension above the saturation point of the system. The solution was stirred for 25 min to reach complete dissolution at 77 °C, before repetition of the cooling phase with a modified rate. In the second cooling phase Form II crystals started to grow at 53 °C, complete crystallization took place in nearly 2 h. The supersaturation profiles of Form I and Form II polymorphs can be seen in Figure 8 during Raman feedback control crystallization. The crystallization medium was supersaturated only with Form I after seeding at 74 °C. Crystallization seemed to start at 60 °C, based on visual observation and the supersaturation curve. The quantity of Form I increased with decreasing temperature from 57.8 °C until 12% spectral concentration. At the feedback moment, the supersaturation of Form I decreased to zero; thus, the measured drug concentration of the solution reached the equilibrium solubility. The crystallization of Form II polymorph was indicated by a steep supersaturation profile. Form I and Form II of carvedilol have a monotropic relationship in ethanol; consequently, both forms can be produced during cooling crystallization by seeding with the

desired form and selecting suitable process conditions. The control algorithm can be modified easily on the basis of the desired target crystal structure. If production of Form I is desired, only minor alterations to the conditions should be made. It requires the same control algorithm, and it would operate on the same principle. In this case, reheating should be initiated, when the ratio of the Raman intensities of Form I and Form II fell below 1 at 54 °C.

4. CONCLUSIONS The experimental work described in this report performed controlled crystallization based on feedback of real-time Raman signals. As far as the authors are aware, no similar crystallization process has been previously documented. The control was realized in a specially designed laboratory reactor system, controlled by a PLC (as it was developed in the authors’ laboratory). The model process was cooling crystallization of carvedilol (a nonselective beta blocker) in ethyl acetate. The control principle is based on the ratio of two Raman intensities, which are characteristic of the two monotropic polymorphs F



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(16) Simon, L. L.; Nagy, Z. K.; Hungerbuhler, K. Org. Process Res. Dev. 2009, 13, 1254−1261. (17) Simon, L. L.; Oucherif, K. A.; Nagy, Z. K.; Hungerbuhler, K. Ind. Eng. Chem. Res. 2010, 49, 9932−9944. (18) Simon, L. L.; Nagy, Z. K.; Hungerbuhler, K. Chem. Eng. Sci. 2009, 64, 3344−3351. (19) Liotta, V.; Sabesan, V. Org. Process Res. Dev. 2004, 8, 488−494. (20) Ma, C. Y.; Wang, X. Z. J. Process Control. 2012, 22, 72−81. (21) Doki, N.; Seki, H.; Takano, K.; Asatani, H.; Yokota, M.; Kubota, N. Cryst. Growth Des. 2004, 4, 949−953. (22) Kee, N. C. S.; Tan, R. B. H.; Braatz, R. D. Cryst Growth Des. 2009, 9, 3044−3051. (23) Kee, N. C. S.; Arendt, P. D.; Tan, R. B. H.; Braatz, R. D. Cryst Growth Des. 2009, 9, 3052−3061. (24) Saleemi, A. N.; Rielly, C. D.; Nagy, Z. K. Cryst. Growth Des. 2012, 12, 1792−1807. (25) Abu Bakar, M. R.; Nagy, Z. K.; Rielly, C. D. Org. Process. Res. Dev. 2009, 13, 1343−1356. (26) Cervera-Padrell, A. E.; Nielsen, J. P.; Pederson, M. J.; Christensen, K. M; Mortensen, A. R.; Skovby, T.; Dam-Johansen, K.; Kiil, S.; Gernaey, K. V. Org. Process Res. Dev. 2012, 16, 901−914. (27) Saleemi, A.; Rielly, C.; Nagy, Z. K. CrystEngComm 2012, 14, 2196−2203. (28) Abu Bakar, M. R.; Nagy, Z. K.; Saleemi, A. N.; Rielly, C. D. Cryst. Growth Des. 2009, 9, 1378−1384. (29) Chen, Z. P.; Fevotte, G.; Caillet, A.; Littlejohn, D.; Morris, J. Anal. Chem. 2008, 80, 6658−6665. (30) Qu, H.; Louhi-Kultanen, M.; Rantanen, J.; Kallas, J. Cryst. Growth Des. 2006, 6, 2053−2060. (31) Herman, C.; Haut, B.; Douieb, S.; Larcy, A.; Vermylen, V.; Leyssens, T. Org. Process Res. Dev. 2012, 16, 49−56. (32) Bosco, R., Grandjean, B.: WO/2010/014583 A1, 2010 (33) Beyer, P.; Reinholz, E.: EP 0893440A1, 1999 (34) Gendrin, C.; Roggo, Y.; Collet, C. J. Pharm. Biomed. Anal. 2008, 48, 533−553.

(thermodynamically stable Form I and kinetically preferred Form II). The capacity to manufacture the Form II polymorph had to be ensured in the presence of a small mass of thermodynamically stable Form I, so that only the formation of the desired product occurred despite the disturbance caused by the presence of Form I. The control is not sensitive for Raman intensity changes caused by particle size alteration, because the relation of intensities (IForm I > IForm II) is used for process control instead of exact intensity values. The control also eliminates the baseline alteration by working with relative peak intensities. The baseline is continuously subtracted from characteristic Raman peaks to supply relative peak intensities. The control algorithm can be modified easily depending on the desired target crystal structure. For production of Form I, the same control algorithm can be applied with some minor alterations. The described Raman feedback control can be considered as a realized PAT technology, in line with current pharmaceutical development ambitions. The application of this work is not limited to cooling crystallization or to the studied polymorphs, as any Raman-sensitive systems and processes can be controlled with the aid of the developed connection of PLC and Raman spectroscopy.

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AUTHOR INFORMATION

Corresponding Author

*[email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Yokogawa Hungária Kft. for putting the PLC and its software at our disposal. REFERENCES

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Implementation of Raman Signal Feedback to Perform Controlled

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