Article pubs.acs.

org/OPRD

Evolution and Application of an Automated Platform for the Development of Crystallization Processes
George Zhou,*, Aaron Moment, Stephanie Yaung, Aaron Cote, and Tseng-En Hu

Merck Sharp & Dohme Corp., P.O. Box 2000 RY818-C306, Rahway, New Jersey 07065, United States Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States ABSTRACT: An automated crystallization platform enabled by FTIR and FBRM in combination with automation and chemometrics has provided a versatile tool for ecient crystallization process development. This system allows users to perform a walkup operation for routine process evaluation and also execute automated feedback control of crystallization based on a preset supersaturation prole via cooling and/or antisolvent addition. The concept, procedure, and benets of the PAT-enabled crystallization platform are presented in general terms and then illustrated through several case studies where feedback control is applied to cooling, antisolvent addition, and fed batch (hot batch solution charged to lower-temperature seed bed) crystallization.

INTRODUCTION Dierences in particle size distribution (PSD), crystal shape, and polymorphic form of the active pharmaceutical ingredient (API) can have an impact on drug substance processability, as well as drug product quality and performance, including stability, dissolution, and bioavailability. Thus, it becomes vital to have a robust crystallization process that consistently produces the desired polymorphic form and PSD of the bulk API. For APIs with multiple polymorphic forms, thermodynamic data are required to rationally design the crystallization to deliver the target API solid phase. However, kinetic factors are also critical and should be taken into consideration. For many processes, the key aspects that impact product attributes are the rates of nucleation, growth, and agglomeration of the crystals. The main variable that aects the kinetics of these processes is supersaturation, a measure which relates the realtime batch concentration to the systems solubility and is the driving force for crystallization. The FDAs process analytical technology (PAT) initiative encourages the application of online process measurement in the pharmaceutical industry to allow a paradigm shift towards quality by design to enhance process understanding and ensure quality through optimal design, continuous monitoring, and feedback control. For a crystallization process, it is important to know at real-time the stories of PSD, crystal form, and the solution-phase concentration of API,1 and with recent advances in technology, more online analytical tools have become available for these measurements.2 There are many ways to measure the concentration of an API in the liquid phase in a crystallization process, including chromatographic and spectroscopic methods; however, FTIR or mid-IR with an in situ ATR probe is the method of choice because of its high specicity, quick response, and ease of sampling. There are also a number of ways to measure particle size at real-time including acoustic attenuation of sound waves,3 electroacoustic eects,4 and spectroscopic methods such as NIR (sensitive to particle size and chemical composition).5 However, focused beam reec 2013 American Chemical Society

tance measurement (FBRM) is the online method most commonly applied for determining a PSD (more specically, chord length distribution) in the crystallization processes,26 and this is the technology that was applied in the work described herein. In addition to recent advances in hardware, our ability to properly construct robust calibration models allows us to accurately calculate real-time liquid-phase concentration and supersaturation when using FTIR with an in situ ATR probe. Although in some cases, simple calibration can be achieved with peak height or peak area of an API compound, for better accuracy and robustness, a multivariate calibration approach is often needed to account for the variation of API, solvents, impurities, temperature, etc. Calibration models can be developed with multiple linear regression (MLR), principle component regression (PCR), and/or partial least-squares (PLS).6 There are numerous software packages that employ these and other methods. Regardless of the algorithm used, there is high value in developing a universal approach to build calibration models automatically in order to cover the variety of situations one may encounter. As such, a multivariate calibration approach such as PLS can be considered.7 There are integrated systems where instrument control and PAT tools work together for user-friendly operation, including commercially available units.8 In addition, calibration of FTIR and feedback control of crystallization have been achieved for process development in the lab and, in some cases, at the pilotplant scale.1,917 Combining these features creates a powerful tool that enables process information to be garnered eciently. The benet of that tool for process evaluation, development, and risk assessment is signicantly enhanced by establishing the capability as a walkup system that allows nonexpert
Special Issue: Engineering Contributions to Chemical Process Development Received: July 12, 2013 Published: September 12, 2013
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Organic Process Research & Development practitioners to operate many apparatuses coherently with PAT tools. By accurately measuring the liquid composition in the presence of crystals1822 with online FTIR, closed-loop (feedback) control of supersaturation enables crystallization control to be implemented without the requirement of kinetic knowledge, which is often unavailable and/or dicult to obtain. There are a number of examples of online measurement of solution concentration applied successfully to feedback control of cooling crystallizations. Feng et al.23 studied and obtained optimal cooling curves for crystallization of succinic acid by maintaining the solute concentration close to the solubility curve and intentionally altering seed loadings, seed size, and agitation speed. Nagy et al.24 used inline IR to reduce the uncertainties in mean crystal size and yield of nal products stemming from variations in kinetics and solubility. Fujiwara et al.25 used process monitoring and process control to optimize the size distribution of paracetamol crystals formed in a batch process. Small crystals of paracetamol tend to agglomerate and form a substandard nal product with highly variable dissolution rates. By controlling the concentration, they developed a process that minimized nucleation and prevented agglomeration. Gron et al.26 applied constant supersaturation control for crystal growth in the unseeded cooling crystallization of monosodium glutamate from aqueous solution and produced more uniform crystals than with uncontrolled isothermal operation. Liotta and Sabesan,27 and Fujiwara et al.28 have also demonstrated successfully the feedback control strategy for cooling crystallization. Crystallization via antisolvent addition has proved to be the most common technique for the separation and purication of many heat-sensitive pharmaceuticals and agrochemicals.2 It is usually performed in a semibatch manner, where antisolvent is pumped into the crystallizer at a ow rate which can be manipulated to modulate performance. Among reported literature, Gabas and Laguer ie29 achieved constant supersaturation in the antisolvent crystallization of D-xylose using an immersion refractometer to measure the solute concentration in situ. Grol et al.30 studied a paracetamolacetonewater system for the eects of supersaturation control on the mean particle size, size distribution, and overall batch time in seeded and unseeded antisolvent crystallization. They developed a simple method to design antisolvent addition crystallization by using a numerical simulation. The results of the numerical simulations agreed well with the corresponding experimental results and assisted in the design of a suitable crystallization process. Fujiwara, et al. reported the results of an antisolvent crystallization via feedback control of the supersaturation,31 in which carrying out crystallization at dierent supersaturation levels resulted in products with dierent PSD and required dierent amounts of time to complete crystallization. Jiang et al. reported using dual impinging jets combining hot and cold streams in a semicontinuous crystallizer to generate uniform seed which grew into large size crystals in the crystallizer with online FTIR and FBRM.10 In a similar manner, one may apply a fed batch crystallization in which the batch is added as a hot solution into a lower-temperature seed bed. The outcome of the crystallization process can be tuned by controlling the supersaturation of API through adjustment to the addition rate of hot batch to give product with the desired PSD and crystal form. When a portion of the previous batch is left as the seed bed, this is referred to as a heel process.
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There have been numerous reports14,15,3234 on using systems integrated with FTIR and FBRM for studies on feedback control of crystallization processes; however, there is no report on such an integrated API platform that not only can perform the walkup activities but can also execute automatically the tasks of calibration of IR, measurement of solubility and concentration, and feedback control crystallizations via cooling or antisolvent addition. Because the formation, modication, and distortion of crystals depend heavily on the degree of supersaturation in the crystallizing solution, an automated and integrated system that can monitor and control supersaturation is of particular interest for evaluating current processes and developing new processes to obtain the desired form and PSD. In order to achieve this goal, a special platform which enables the measurement of both liquid and solid phases and a methodology that guides the experiment and collects process information are desirable. Built on top of the initial work with Professor Braatz31 is described an automated, user-friendly, and intelligent platform that calibrates IR automatically, measures concentration and solubility, and can be applied for process evaluation or feedback control crystallization achieved via cooling, antisolvent addition, and fed-batch hot batch addition.

EXPERIMENTAL SECTION Materials. Several active pharmaceutical ingredients of drug candidates made in-house at Merck were used in the case studies. They are etoricoxib for cooling crystallization, MK-A for crystallization via antisolvent addition, and MK-B for fed batch crystallization. Solvents such as ethanol (HPLC grade), n-heptane (ACS grade), toluene (ACS grade), acetic acid and sodium acetate (both ACS grade), and conventional chemicals (ACS grade) were all obtained from Sigma-Aldrich, St. Louis, MO. Deionized water was used to prepare the solutions. Experimental Setup. The integrated crystallization platform (Figure 1) operates on the basis of a set of automation

Figure 1. Schematic of apparatus and instrument setup.

procedures (A detailed explanation on automation has not been included.) for automatic data collection, solubility measurement, and concentration control. It consists of a 500-mL jacketed, glass vessel with a custom lid, a chiller/bath, two dosing pumps, a heat controller for heat-tracing the IR probe, an overhead mechanical stirrer, an online FBRM, and an online FTIR. The crystallizer temperature was controlled by a chiller
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Figure 2. (a) Schematic of an integrated walkup system and (b) process proles of a cooling crystallization of in toluene obtained with this walkup platform.

Figure 3. Diagrams of automatic calibration procedures for (a) cooling or (b) antisolvent B addition to solvent A at a constant temperature.

(Unistat 705 by Peter Huber Kal temaschinenbau GmbH, Oenburg, Germany), and solvents were delivered by programmable syringe pumps (PHD 4400 by Harvard Apparatus, Holliston, MA). The control PC received signals from the thermocouple, FTIR, and FBRM and was used to control the chiller and charge pumps. The crystallization procedures were enabled on a graphical user interface written in Microsoft Visual Basic Net on a control PC. The Visual Basic interface called a program written in MATLAB for calibration model development using partial least-squares (PLS) regression methods. Lasentec FBRM (model S400 by Mettler-Toledo AutoChem, Columbia, MD) was employed to measure the chord length distribution proles or to check for the presence of crystals during the process. The FTIR with a diamond ATR probe (ReactIR4000 by Mettler-Toledo AutoChem, Columbia, MD) was used to measure the liquid-phase concentration of the solute. Spectral resolution of 4 cm1, apodization of HappGenzel, spectral region of 4000650 cm1, and an MCT detector were used. Each spectrum was composed of 64 coadded scans. The spectra of nitrogen gas at room temperature were used as background. During operation, the IR probe was heat-traced so that its temperature could be matched in real-time to the crystallizer temperature in order to prevent unwanted coating or premature, localized crystallization on the IR probe. The FTIR was calibrated by using chemometric techniques31,35 to correlate the IR spectra to the
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corresponding solvent compositions, solute concentrations, and temperature at which they were collected. Walkup Operation. The majority of experiments for process scouting and optimization can be carried out in the lab on a setup integrated with operations such as pumping, coolingheating, solvent addition, and agitation control together with PAT tools, e.g. online FTIR and FBRM. In many pharmaceutical laboratories, such a system has played an important role in routine operations, evaluating processes via one-factor-at-a-time or via design of experiment (DOE). Some of such lab systems have consolidated all the equipment and analyzers in one place on one platform, enabling ecient experiments with better data management and treatment. An integrated walkup system, built in-house at Merck, has eectively served this purpose as the working platform for the study of crystallization process development. Figure 2a shows the user interface for the workup system of this platform. This platform provides users the ability to run an experiment automatically, by controlling all the instruments and logging the data in an integrated manner for subsequent analysis and presentation. In addition, with the special capability of automated calibration of online FTIR, this platform enables users to accurately follow the true solute concentration in realtime during the operation with minimal user intervention. Figure 2b is an illustration of a cooling crystallization of etoricoxib in toluene being monitored on this walkup platform. It shows the temperature prole, concentration prole,
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Figure 4. Diagram for the automated collection of slurry spectra for solubility vs (a) temperature or (b) solvent composition.

Figure 5. Progressive diagram for the feedback control crystallization via (a) cooling or (b) antisolvent addition where A is the solvent being diluted by the antisolvent as the crystallization proceeds.

supersaturation prole, and chord length data on a single plot so that the impact of system changes can be readily appreciated. Automated Calibration for Cooling or Antisolvent Addition Crystallization. In order to obtain a reliable calibration model, the automated procedures are designed in such a way that allows the collection of spectra from clear solutions with known solute concentration, temperature, and solvent composition, along the path of the solubility curve. In the case of cooling crystallization in Figure 3a, the batch starts with a solution of known concentration of API and solvent(s). After being heated to the high temperature T1 to achieve total dissolution, the solution at T1 and concentration C1 is cooled at a constant rate until the appearance of nucleation (or a preset wide default dierence of temperature when metastable zone width (MSWZ) is relatively wide). Meanwhile, during cooling, spectra of clear solutions are collected with known concentrations and temperatures. After the nucleation point, the solution is diluted by the automated addition of solvent to give a lower concentration C2 and heated to T2 to achieve full dissolution, and then the cooling is repeated. Thus, as the procedure moves from the point of T1 and C1 to the lowest concentration via cooling, dilution, and heating, representative spectra are collected throughout the temperature and concentration ranges that cover the intended scope of application.
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Similarly, for antisolvent addition crystallization,36 the calibration procedure is dened with a simulated Excel spreadsheet table populated along the targeted points of dilution pictured in Figure3b. It starts with a clear solution of known composition of API plus a specic amount of solvent A. Solvent B (antisolvent) is then added while IR data is collected. If FBRM detects the presence of particles, the sequence will jump to and continue with the next step. Solvent A is then added again until the solute dissolves, and the procedure is repeated, stepping down to the end of the operating range of interest. After sequentially adding the antisolvent and solvent to the crystallizer according to this procedure, IR spectra of clear solutions with known solute concentrations and solvent compositions are collected automatically. Once representative spectra across a wide range of solute concentrations and temperature or solvent compositions are obtained, a reliable calibration model is built automatically with the partial leastsquares regression in MATLAB. Solubility Measurement via Cooling and Antisolvent Addition. Solubility is obtained through a program that automatically collects IR spectra for slurries at dierent temperatures (Figure 4a) or dierent solvent compositions (Figure 4b). For cooling crystallization, the batch starts with the slurry of API solute in solvent A and is heated stepwise to dierent temperatures. At each temperature stage, the slurry is held to allow the liquid and solid phases to reach equilibrium.
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Figure 6. (a) Selected spectra of solution at dierent concentrations of at dierent temperatures, (b) PLS model performance.

At the end of each stage, ve spectra are collected and used for determining solubility. The process is repeated until spectra are collected for six stages at dierent temperatures covering the range of interest. For the antisolvent addition crystallization, the batch starts by adding solvent B incrementally to the slurry of API solute in solvent A and is aged at each stage for an adequate time to allow the liquid and solid phases to reach equilibrium. At the end of each stage, the system automatically collects and saves ve spectra for solubility determination. The process is repeated until spectra are collected for six stages with targeted levels of solvent A. In order to speed up the protocol by taking advantage of the fact that crystal dissolution is typically faster than crystal growth, after each antisolvent addition step, the batch is cooled rapidly by 1520 C to crash out crystals36 (Figure 4b) and then heated back to target measurement temperature to dissolve the material and reach equilibrium. In case there is a risk of crystallizing out the wrong form (the kinetically favorable form) during the cool-down, a Raman spectrometer with an in situ probe could be used to conrm that the solid phase is exclusively the polymorph of interest.3739 Feedback Control via Cooling and Antisolvent Addition. Once the calibration models have been constructed, and solubility curves are available, one can start the crystallization process in a controlled manner based on controlling either an absolute supersaturation (e.g., g/L) or a relative percentage of supersaturation. During the entire process, IR spectra and temperature measurements collected at real-time are used to calculate the real-time concentration of API. These concentration values are then compared to the calculated solubility value at the measured temperature and/or known solvent composition in order to determine the real-time supersaturation. In Figure 5a for a cooling crystallization with preset supersaturation target, the process trajectory will be programmed to proceed along the projected line of operation dened by the solubility curve and supersaturation target. When the batch concentration (Ccurrent) is below the set-point curve, the control algorithm will cool the batch at a faster rate to move toward the operation line (Cset). On the other hand, if the batch concentration is above the operation line, the controller will slow the cooling so that the rate of supersaturation relief can catch up to the rate of supersaturation generation, allowing the batch to move toward the operation line. A brief description of algorithm for cooling crystallization is as following: given the current T,
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Cset = Csat(T ) + SS

e = Ccurrent Cset
If e < 0, then
Tset = Tset + K (e + t *sum/ ), leading to reduction of batch temperature
Else if e 0

then Tset = Tset

end if sum = sum + e

where K and are the constants of control, sum and e are the dierences between batch concentration and targeted concentration, and t is the interval of logic timer in seconds. SS is the supersaturation. As to supersaturation (SS), it is a constant in absolute SS control, but a function of Csat(T) in relative SS control. Similarly, in Figure 5b for crystallization via antisolvent addition, once the supersaturation is set, the process proceeds along the projected line of operation dened by the solubility curve and supersaturation target. When the batch concentration is below the curve, the control algorithm will add antisolvent to move the batch toward the operation line. On the other hand, if the batch concentration is above the operation line, the controller will slow the antisolvent addition rate so that the batch can move to the operation line as supersaturation is relieved. A brief description of algorithm for antisolvent addition crystallization is as following: at constant T and given a solvent A percentage, %Aset,
Cset = Csat(%A set ) + SS

e = Ccurrent Cset
If e < 0, then
%A set = %A set + K (e + t *sum/ ), leading to add antisolvent B

Else if e 0,
then %A set = %A set
end if sum = sum + e
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Organic Process Research & Development where K and are the constants of control, sum and e are the dierences between batch concentration and targeted concentration, and t is the interval of logic timer in seconds. SS is the supersaturation. As to supersaturation (SS), it is a constant in absolute SS control, but a function of Csat(%A) in relative SS control.

Article

Cooling Crystallization for Etoricoxib. To demonstrate the bene ts of this integrated platform, the cooling crystallization of etoricoxib in toluene, a system known to be highly prone to agglomeration, has been evaluated using this protocol.35 Since the extent of agglomeration is often controlled by the supersaturation level, the goal was to manage the supersaturation level during the course of crystallization in order to minimize agglomeration. These studies were initiated by collecting representative solution spectra as a function of API solute composition and temperature. A PLS calibration was built for determining liquid phase concentration from the spectra of slurries where solids are suspended in a liquid phase. Calibration models were constructed based on the spectra depicted in Figure 6a, which show spectral features changing as the level of etoricoxib and temperature vary. By using a Matlab routine which loops stepwise across the entire spectral range and the number of PLS factors, numerous calibration models were constructed, sorted, and evaluated based on the value of their corresponding RMSEVs (root mean standard error of validation or SECV). This Matlab routine rst loops across spectral region. It starts from left side with a nite spectral window (e.g., 100 cm1), and goes to next by adding another spectral region (e.g., 20 cm1 in one step) to the right side of the window until it reaches the end of right side. Then, the left side shifts one step to right (20 cm1) with a new nite window of 100 cm1, and repeats above operations. By looping all the possible combinations, all possible spectral regions (totally N regions) could be used to build calibration models. Meanwhile, for each spectral window, a subloop on the number of PLS factors (e.g., 17) will be checked. As a result, totally 7*N calibration models could be constructed. For each calibration model with a given spectral region and a number of PLS factors, PLS calculation of leave-one-out cross validation has been performed, resulting in a RMSEV for each calibration model. The optimum calibration model is then chosen as the one with the lowest RMSEV. Figure 6b shows the plots of SECV of models built with dierent number of PLS factors in dierent spectral region and with temperature incorporated. A PLS calibration model built using ve factors in the 12671521 cm1 spectral region together with temperature incorporated was chosen as the optimum. The R2 value obtained with this model was 0.9956 and the SECV was 0.31 g/L. Following the calibration work, a series of spectra were collected as solids were allowed to equilibrate with the liquid across a range of temperatures, as described generically earlier in this paper. When the calibration model was applied to this data, a solubility curve (Figures 7) was obtained and best tted as:
Y = e(aX + bX + c)
2

RESULTS AND DISCUSSION

Figure 7. Solubility curve of etoricoxib as a function of temperature in toluene. Also included is the MSZW window at the cooling rate of 0.4 C/min.

where a is 0.000191172, b is 0.0265855 and c is 3.24339. A metastable zone width for this system was also generated and is presented in Figure 7.
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The feedback control crystallization of etoricoxib in toluene proceeded with the real-time measurement of temperature and concentration. As shown in Figure 8a, two batches were carried out in this automated manner with absolute supersaturation at 9.5 g/L and 29 g/L etoricoxib, respectively. (Crystallization with constant relative supersaturation control was not tested in this case.) Each batch was carried out with 7% seed and aged for 30 min at a constant temperature prior to cooling. As a result of online monitoring and control of the process with FTIR, each batch closely followed the preset supersaturation value. As one of the platforms key outputs of feedback control, a nonlinear temperature prole was obtained to achieve the desired supersaturation prole. For the feedback control with a constant absolute supersaturation of 9.5 g/L etoricoxib, temperature and batch concentration proles are presented in Figure 8b. This nonlinear temperature prole could be used to enable process scale-up. Dierent PSDs of crystals were also obtained with these two processes. The one with supersaturation at 29 g/L etoricoxib revealed the presence of typically observed agglomerates and wide PSD while the one with supersaturation at 9.5 g/L etoricoxib did not have noticeable agglomerates and the PSD was better controlled (see Figure 9 for details). Antisolvent Addition Crystallization of MK-A. As an example demonstrating polymorph control capabilities, MK-A, a Merck drug candidate with a kinetically favored metastable Form I and thermodynamically stable Form II available, has been evaluated using the procedure for antisolvent addition crystallization.36 This crystallization process follows immediately after a quenching reaction in which sodium ethoxide is quenched with acetic acid to give a solution (referred to as solvent A) of API in ethanol with sodium acetate and excess acetic acid. During the crystallization, water is added as the antisolvent. The seed used for the controlled crystallization studies was media-milled Form II with a size of 2 m, which was generated and charged as a 10 wt % slurry in 60/40 v/v, water/ethanol. By using the automated procedure for antisolvent addition crystallization, an optimum PLS model was built in the spectral region 18001000 cm1 with a standard error of cross validation (SECV) of 0.51 mg/mL across the concentration range of 0200 g/L and solvent composition range of 3070 vol % A (ethanol/(etanol + water)). When this model was
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Figure 8. (a) Solubility curve and crystallization proles at preset supersaturations at 9.5 and/or 29 g/L of via feedback control of temperature; (b) Temperature and batch concentration proles of feedback control with absolute supersaturation of 9.5 g/L .

Figure 9. Microscope image of crystallized slurry at the end of a feedback controlled crystallization batch with supersaturation at (a) 29 g/L and (b) 9.5 g/L etoricoxib.

applied to solubility spectra collected per the previously described approach, solubility curves (Figure 10a) were obtained and best tted as:
Y = 10.5447 + 2.6974X 0.1811X2 0.0033X3 for form I
Y = 49.4601 + 5.6591X 0.2121X2 0.0028X3 for form II

where X is the percentage of ethanol ratio (VEtOH/(Vwater + VEtOH)) This was a particularly challenging system because the undesired metastable Form I nucleated readily when the concentration exceeded the Form I solubility, such that initial eorts to isolate Form II always resulted in a mixture of the two forms which was very slow to convert to the target Form II. Therefore, a strategy was conceived by which Form I crystallization could be avoided by operating at a liquid phase concentration that resides above Form II solubility (thus creating a driving force for Form II crystallization) but below the Form I solubility. With a robust calibration model and a solubility curve available, feedback control crystallization proceeded with the real-time measurement of temperature, API concentration, and solvent composition. The batch started with 10% media milled seed of Form II, was aged for approximately 1 h, and then
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proceeded to antisolvent crystallization at a constant temperature with a relative supersaturation maintained at 33%. Figure 10a presents the concentration and solvent composition proles during the course of this antisolvent addition, indicating clearly that the batch concentration stayed safely below the solubility curve of Form I while closely following the preset supersaturation value. The FBRM proles (Figure 10c) show that at this level of supersaturation crystal growth took place dominantly and nucleation event was minimized which allowed for growth on seed to a predictable target PSD.36 As expected, Form II was isolated at the exclusion of metastable Form I. For the consideration of potential process scale-up, the corresponding nonlinear antisolvent prole is also presented in Figure 10d. Fed Batch Heel Crystallization. MK-B, a drug candidate at Merck, has been evaluated using the protocol for a fed batch crystallization in which a hot API solution is fed to lower-temperature crystallizer-containing seed bed, where the seed bed for Batch (N + 1) is the residual heel from Batch N. This crystallization process starts with a heel seed bed of API slurried in n-heptane at 20 C. The hot batch stream of API dissolved in 45 C n-heptane is fed slowly to the crystallizer. Due to the dierence in solubility of API in n-heptane between 20 and 45 C, the addition of the hot batch stream creates supersaturation that drives crystallization. The addition rate of hot batch is controlled on the basis of the feedback of measured concentration against a preset value. Dierent from the
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Figure 10. (a) (b) Solubility curve of Forms I and II of MK-A in solvent mixture (ethanol, acetic acid, sodium acetate) and antisolvent (water), and crystallization proles for MK-A via feedback-controlled addition of water to maintain a relative supersaturation of 33% under 65 C; (c) corresponding FBRM PSD proles and (d) water addition prole for this crystallization.

crystallizations of both cooling and antisolvent addition, the fed batch heel crystallization operates around one solubility point which is determined by the solvent and batch temperature (Figure 11).

When implementing the fed batch crystallization, an approach similar to the automated protocol of antisolvent addition crystallization has been adopted. Instead of adding antisolvent to the batch when the concentration is below the preset value, the hot batch is added to raise the concentration to the set-point. A brief description of the algorithm for fed batch crystallization is as the following: at xed T and solvent composition,
Cset = Csat+SS

e = Ccurrent Cset
If e < 0, then
pump rate = pump rate + K (e + t *sum/ ), leading to add hot batch

Else if e 0,
then pump rate = 0, or at a reduced rate

end if sum = sum + e

Figure 11. Diagrams of process progress and control for the heel crystallization via feedback control.
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where SS is a constant, K and are the constants of control, sum and e are the dierences between batch concentration and
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Organic Process Research & Development targeted concentration, and t is the interval of logic timer in seconds. In order to develop a robust calibration model for feedback control, a PLS model was built with spectra collected from the solutions with known composition around the crystallization temperature. A standard error of cross validation (SECV) of 0.24 g/L API in n-heptane across the spectral range of 1812 1215 cm1 and temperature range of 528 C was attained for this model. When this model is used to predict the spectra from solutions of which API is in equilibrium between the liquid and solid phases, a solubility curve (Figure 11a) was obtained and best tted as:

Article

addition rate dialed down and reached a steady rate for the duration of the crystallization process. The FBRM proles in Figure 12 show that at this level of supersaturation, the total counts of nes (15 and 1024 m/s) went down, while large ones (2890 and 95270 m/s) increased as the process proceeded, suggesting that particle growth was predominant while nucleation was not signicant. A follow-up experiment at higher supersaturation reduced cycle time to 4 h while maintaining desired API attributes.

Y = e(aX

+ bX + c)

where a is 0.001055, b is 0.003595, and c is 2.9691. Figure 12 shows the fed batch crystallization trajectory achieved by feedback controlling the addition of hot batch into

CONCLUSION The application of a walkup PAT-enabled API platform to the development, optimization, and control of robust crystallization processes has been described. This versatile tool empowers the user with the integrated platform for automated calibration, solubility measurement, and feedback control of crystallizations via cooling or antisolvent addition with all the data collected and synchronized together in a way that enables facile data analysis toward better scientic understanding. In addition, a new approach has been developed and demonstrated for the fed batch crystallization, expanding the scope of this platform to another category of application. In order to further improve the eciency of the method, a robust routine for the automated selection of spectral region and number of PLS factors to attain the optimum calibration model has also been developed and implemented. By utilizing such an integrated API platform, one can achieve robust and ecient crystallization processes to ensure isolation of the desired polymorph at target particle size in a resource-sparing, information-rich manner.

Figure 12. Proles of MK-B concentration and PSD during the course of fed batch crystallization via feedback control.

AUTHOR INFORMATION

Corresponding Author

*E-mail: george_zhou@merck.com
Notes

The authors declare no competing nancial interest.

the heel seed bed. The batch started with 5% heel seed bed of Form I that was aged for approximately 30 min prior to initiating the hot batch feed. The hot feed was carried out at a constant crystallizer temperature of 20 C with a relative supersaturation maintained at 21%. As illustrated in Figure 13, when the feedback control started, the addition rate was in high gear to establish the predened supersaturation. Then the

ACKNOWLEDGMENTS We greatly appreciate Dr. Hsien-Hsin Tung and Professor Richard Braatz for the initial work, collaboration, and insight on the development of the technology described in this manuscript. We thank Drs. Cindy Starbuck, Zhihong Ge, Robert Guenard and Gert Thurau of Merck for their support and helpful discussions in this work. We also are very grateful to Michael Wismer of Merck for his dedicated contribution to this work. REFERENCES
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Figure 13. Proles of hot batch addition and addition rate for the fed batch crystallization with 21% supersaturation of MK-B via feedback control.
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