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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 efficient 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 profile via cooling and/or antisolvent addition. The concept, procedure, and benefits 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 Differences 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 affects the kinetics of these processes is supersaturation, a measure which relates the realtime batch concentration to the system’s solubility and is the driving force for crystallization. The FDA’s 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 specificity, 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 effects,4 and spectroscopic methods such as NIR (sensitive to particle size and chemical composition).5 However, focused beam reflec© 2013 American Chemical Society

tance measurement (FBRM) is the online method most commonly applied for determining a PSD (more specifically, 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.1,9−17 Combining these features creates a powerful tool that enables process information to be garnered efficiently. The benefit of that tool for process evaluation, development, and risk assessment is significantly 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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dx.doi.org/10.1021/op400187h | Org. Process Res. Dev. 2013, 17, 1320−1329

Small crystals of paracetamol tend to agglomerate and form a substandard final product with highly variable dissolution rates. however. glass vessel with a custom lid. reported the results of an antisolvent crystallization via feedback control of the supersaturation. Jiang et al. procedures (A detailed explanation on automation has not been included. and concentration control. EXPERIMENTAL SECTION Materials. seed size.2 It is usually performed in a semibatch manner. and MK-B for “fed batch” crystallization. they developed a process that minimized nucleation and prevented agglomeration. user-friendly.Organic Process Research & Development practitioners to operate many apparatuses coherently with PAT tools. an online FBRM. The crystallizer temperature was controlled by a chiller dx. Because the formation. MO. Among reported literature. When a portion of the previous batch is left as the seed bed.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. 2013. Fujiwara et al. n-heptane (ACS grade). which is often unavailable and/or difficult to obtain.org/10. 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.30 studied a paracetamol−acetone−water system for the effects of supersaturation control on the mean particle size. Fujiwara. a chiller/bath. where antisolvent is pumped into the crystallizer at a flow rate which can be manipulated to modulate performance. Grol et al. 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. Several active pharmaceutical ingredients of drug candidates made in-house at Merck were used in the case studies.27 and Fujiwara et al. closed-loop (feedback) control of supersaturation enables crystallization control to be implemented without the requirement of kinetic knowledge.31 in which carrying out crystallization at different supersaturation levels resulted in products with different PSD and required different amounts of time to complete crystallization. By accurately measuring the liquid composition in the presence of crystals18−22 with online FTIR. In order to achieve this goal. By controlling the concentration. 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. and agitation speed.25 used process monitoring and process control to optimize the size distribution of paracetamol crystals formed in a batch process.32−34 on using systems integrated with FTIR and FBRM for studies on feedback control of crystallization processes. MK-A for crystallization via antisolvent addition.1021/op400187h | Org. Deionized water was used to prepare the solutions. this is referred to as a “heel” process. and an online FTIR. and distortion of crystals depend heavily on the degree of supersaturation in the crystallizing solution. two dosing pumps.doi. Dev. 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.15. a heat controller for heat-tracing the IR probe. 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. size distribution. The results of the numerical simulations agreed well with the corresponding experimental results and assisted in the design of a suitable crystallization process.28 have also demonstrated successfully the feedback control strategy for cooling crystallization. and feedback control crystallizations via cooling or antisolvent addition. and overall batch time in seeded and unseeded antisolvent crystallization. solubility measurement.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. measures concentration and solubility. and conventional chemicals (ACS grade) were all obtained from Sigma-Aldrich. antisolvent addition. The integrated crystallization platform (Figure 1) operates on the basis of a set of automation ■ Figure 1. Feng et al. Solvents such as ethanol (HPLC grade). Schematic of apparatus and instrument setup. et al. and can be applied for process evaluation or feedback control crystallization achieved via cooling. Louis. 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. one may apply a “fed batch” crystallization in which the batch is added as a hot solution into a lower-temperature seed bed. They are etoricoxib for cooling crystallization. 1320−1329 . toluene (ACS grade). and intelligent platform that calibrates IR automatically. 1321 Article There have been numerous reports14. Process Res. Liotta and Sabesan. measurement of solubility and concentration. and “fed-batch” hot batch addition. Experimental Setup.10 In a similar manner. They developed a simple method to design antisolvent addition crystallization by using a numerical simulation.24 used inline IR to reduce the uncertainties in mean crystal size and yield of final products stemming from variations in kinetics and solubility. Nagy et al. Grön et al. St.) for automatic data collection. acetic acid and sodium acetate (both ACS grade). It consists of a 500-mL jacketed. Built on top of the initial work with Professor Braatz31 is described an automated. Crystallization via antisolvent addition has proved to be the most common technique for the separation and purification of many heat-sensitive pharmaceuticals and agrochemicals. an overhead mechanical stirrer. There are a number of examples of online measurement of solution concentration applied successfully to feedback control of cooling crystallizations. modification. 17.

g. 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. Holliston. e. evaluating processes via one-factor-at-a-time or via design of experiment (DOE).org/10. MD) was used to measure the liquid-phase concentration of the solute. 1320−1329 . and temperature at which they were collected. Lasentec FBRM (model S400 by Mettler-Toledo AutoChem. concentration profile. Process Res. MA). and solvents were delivered by programmable syringe pumps (PHD 4400 by Harvard Apparatus. this platform enables users to accurately follow the true solute concentration in realtime during the operation with minimal user intervention. During operation. dx. 17.1021/op400187h | Org. In addition. and FBRM and was used to control the chiller and charge pumps. localized crystallization on the IR probe. such a system has played an important role in routine operations. Germany).35 to correlate the IR spectra to the 1322 corresponding solvent compositions. Columbia. 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. enabling efficient experiments with better data management and treatment. and agitation control together with PAT tools. Columbia. FTIR.Organic Process Research & Development Article Figure 2. built in-house at Merck. solvent addition. The Visual Basic interface called a program written in MATLAB for calibration model development using partial least-squares (PLS) regression methods. The FTIR with a diamond ATR probe (ReactIR4000 by Mettler-Toledo AutoChem. The crystallization procedures were enabled on a graphical user interface written in Microsoft Visual Basic Net on a control PC. Spectral resolution of 4 cm−1. (Unistat 705 by Peter Huber Kal ̈ temaschinenbau GmbH. cooling−heating. Diagrams of automatic calibration procedures for (a) cooling or (b) antisolvent B addition to solvent A at a constant temperature. solute concentrations. Each spectrum was composed of 64 coadded scans. It shows the temperature profile. (a) Schematic of an integrated walkup system and (b) process profiles of a cooling crystallization of in toluene obtained with this walkup platform. Figure 2b is an illustration of a cooling crystallization of etoricoxib in toluene being monitored on this walkup platform. Figure 3. Figure 2a shows the user interface for the workup system of this platform. spectral region of 4000−650 cm−1. The spectra of nitrogen gas at room temperature were used as background. The control PC received signals from the thermocouple. and an MCT detector were used. The FTIR was calibrated by using chemometric techniques31. online FTIR and FBRM. 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. apodization of HappGenzel. has effectively served this purpose as the working platform for the study of crystallization process development. Some of such lab systems have consolidated all the equipment and analyzers in one place on one platform. Walkup Operation. Dev. with the special capability of automated calibration of online FTIR. An integrated “walkup” system. Offenburg. 2013. MD) was employed to measure the chord length distribution profiles or to check for the presence of crystals during the process. In many pharmaceutical laboratories.doi.

Thus. After sequentially adding the antisolvent and solvent to the crystallizer according to this procedure. 1323 Similarly. the solution is diluted by the automated addition of solvent to give a lower concentration C2 and heated to T2 to achieve full dissolution. the slurry is held to allow the liquid and solid phases to reach equilibrium. It starts with a clear solution of known composition of API plus a specific amount of solvent A. during cooling. Meanwhile. temperature. In order to obtain a reliable calibration model. 1320−1329 . Solubility is obtained through a program that automatically collects IR spectra for slurries at different temperatures (Figure 4a) or different solvent compositions (Figure 4b). for antisolvent addition crystallization. spectra of clear solutions are collected with known concentrations and temperatures. the sequence will jump to and continue with the next step.doi. 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.Organic Process Research & Development Article Figure 4. 17. the solution at T1 and concentration C1 is cooled at a constant rate until the appearance of nucleation (or a preset wide default difference of temperature when metastable zone width (MSWZ) is relatively wide). After being heated to the high temperature T1 to achieve total dissolution. and heating. At each temperature stage. along the path of the solubility curve. the automated procedures are designed in such a way that allows the collection of spectra from clear solutions with known solute concentration. In the case of cooling crystallization in Figure 3a. Diagram for the automated collection of slurry spectra for solubility vs (a) temperature or (b) solvent composition. stepping down to the end of the operating range of interest.36 the calibration procedure is defined with a simulated Excel spreadsheet table populated along the targeted points of dilution pictured in Figure3b. dilution. Once representative spectra across a wide range of solute concentrations and temperature or solvent compositions are obtained. representative spectra are collected throughout the temperature and concentration ranges that cover the intended scope of application. and solvent composition. Figure 5. dx. Solubility Measurement via Cooling and Antisolvent Addition. the batch starts with the slurry of API solute in solvent A and is heated stepwise to different temperatures. Automated Calibration for Cooling or Antisolvent Addition Crystallization. and then the cooling is repeated. and the procedure is repeated. Dev. IR spectra of clear solutions with known solute concentrations and solvent compositions are collected automatically. as the procedure moves from the point of T1 and C1 to the lowest concentration via cooling. Solvent A is then added again until the solute dissolves. and chord length data on a single plot so that the impact of system changes can be readily appreciated. After the nucleation point. the batch starts with a solution of known concentration of API and solvent(s). If FBRM detects the presence of particles. a reliable calibration model is built automatically with the partial leastsquares regression in MATLAB. Solvent B (antisolvent) is then added while IR data is collected. Process Res. supersaturation profile.org/10.1021/op400187h | Org. 2013. For cooling crystallization.

1320−1329 . if the batch concentration is above the operation line. then %A set = %A set end if sum = sum + e dx. it is a constant in absolute SS control. The process is repeated until spectra are collected for six stages at different temperatures covering the range of interest. %Aset. leading to reduction of batch temperature Else if e ≥ 0 then Tset = Tset end if sum = sum + e where K and τ are the constants of control. the control algorithm will add antisolvent to move the batch toward the operation line. IR spectra and temperature measurements collected at real-time are used to calculate the real-time concentration of API. In Figure 5a for a cooling crystallization with preset supersaturation target.. the controller will slow the cooling so that the rate of supersaturation relief can catch up to the rate of supersaturation generation. the batch is cooled rapidly by 15−20 °C to crash out crystals36 (Figure 4b) and then heated back to target measurement temperature to dissolve the material and reach equilibrium. At the end of each stage. As to supersaturation (SS). five spectra are collected and used for determining solubility. (b) PLS model performance. In order to speed up the protocol by taking advantage of the fact that crystal dissolution is typically faster than crystal growth.org/10. Process Res. if the batch concentration is above the operation line. SS is the supersaturation. sum and e are the differences between batch concentration and targeted concentration. and Δt is the interval of logic timer in seconds. once the supersaturation is set.Organic Process Research & Development Article Figure 6. On the other hand. the controller will slow the antisolvent addition rate so that the batch can move to the operation line as supersaturation is relieved. g/L) or a relative percentage of supersaturation. Dev. At the end of each stage.1021/op400187h | Org.37−39 Feedback Control via Cooling and Antisolvent Addition. 1324 Cset = Csat(T ) + SS e = Ccurrent − Cset If e < 0. 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 confirm that the solid phase is exclusively the polymorph of interest. in Figure 5b for crystallization via antisolvent addition. When the batch concentration is below the curve. one can start the crystallization process in a controlled manner based on controlling either an absolute supersaturation (e. 17. Similarly. 2013. A brief description of algorithm for antisolvent addition crystallization is as following: at constant T and given a solvent A percentage. On the other hand. 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. the process trajectory will be programmed to proceed along the projected line of operation defined by the solubility curve and supersaturation target. but a function of Csat(T) in relative SS control. (a) Selected spectra of solution at different concentrations of at different temperatures. A brief description of algorithm for cooling crystallization is as following: given the current T. then %A set = %A set + K (e + Δt *sum/τ ).g. 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. During the entire process. Cset = Csat(%A set ) + SS e = Ccurrent − Cset If e < 0.doi. leading to add antisolvent B Else if e ≥ 0. the system automatically collects and saves five spectra for solubility determination. the process proceeds along the projected line of operation defined by the solubility curve and supersaturation target. allowing the batch to move toward the operation line. The process is repeated until spectra are collected for six stages with targeted levels of solvent A. For the antisolvent addition crystallization. the control algorithm will cool the batch at a faster rate to move toward the operation line (Cset). after each antisolvent addition step. When the batch concentration (Ccurrent) is below the set-point curve. and solubility curves are available. then Tset = Tset + K (e + Δt *sum/τ ). Once the calibration models have been constructed.

. numerous calibration models were constructed. SS is the supersaturation. which show spectral features changing as the level of etoricoxib and temperature vary. By using the automated procedure for antisolvent addition crystallization.1021/op400187h | Org. two batches were carried out in this automated manner with absolute supersaturation at 9.35 Since the extent of agglomeration is often controlled by the supersaturation level. 1325 The feedback control crystallization of etoricoxib in toluene proceeded with the real-time measurement of temperature and concentration.5 g/L etoricoxib. the goal was to manage the supersaturation level during the course of crystallization in order to minimize agglomeration. each batch closely followed the preset supersaturation value.5 g/L and 29 g/L etoricoxib. These studies were initiated by collecting representative solution spectra as a function of API solute composition and temperature. When this model was dx. Following the calibration work. a nonlinear temperature profile was obtained to achieve the desired supersaturation profile. temperature and batch concentration profiles are presented in Figure 8b. Process Res. b is 0. Meanwhile. Calibration models were constructed based on the spectra depicted in Figure 6a. a subloop on the number of PLS factors (e. To demonstrate the bene fi ts of this integrated platform. a solubility curve (Figures 7) was obtained and best fitted as: Y = e(aX + bX + c) 2 ■ RESULTS AND DISCUSSION Figure 7.g. for each spectral window. the left side shifts one step to right (∼20 cm−1) with a new finite window of 100 cm−1. totally 7*N calibration models could be constructed. which was generated and charged as a 10 wt % slurry in 60/40 v/v. As shown in Figure 8a. 1320−1329 .0265855 and c is 3. As an example demonstrating polymorph control capabilities. water/ethanol.000191172. all possible spectral regions (totally N regions) could be used to build calibration models. has been evaluated using the procedure for antisolvent addition crystallization. Article Cooling Crystallization for Etoricoxib. 1−7) will be checked. As to supersaturation (SS). For the feedback control with a constant absolute supersaturation of 9.5 g/L etoricoxib did not have noticeable agglomerates and the PSD was better controlled (see Figure 9 for details). water is added as the antisolvent. As one of the platform’s key outputs of feedback control. the cooling crystallization of etoricoxib in toluene. By using a Matlab routine which loops stepwise across the entire spectral range and the number of PLS factors. A PLS calibration was built for determining liquid phase concentration from the spectra of slurries where solids are suspended in a liquid phase. The optimum calibration model is then chosen as the one with the lowest RMSEV.51 mg/mL across the concentration range of 0−200 g/L and solvent composition range of 30−70 vol % A (ethanol/(etanol + water)). 20 cm−1 in one step) to the right side of the window until it reaches the end of right side. Different PSDs of crystals were also obtained with these two processes. has been evaluated using this protocol. and Δt is the interval of logic timer in seconds. During the crystallization. Figure 6b shows the plots of SECV of models built with different number of PLS factors in different spectral region and with temperature incorporated.doi.g. The seed used for the controlled crystallization studies was media-milled Form II with a size of ∼2 μm. sum and e are the differences between batch concentration and targeted concentration.) Each batch was carried out with 7% seed and aged for 30 min at a constant temperature prior to cooling. a Merck drug candidate with a kinetically favored metastable Form I and thermodynamically stable Form II available. Also included is the MSZW window at the cooling rate of −0. resulting in a RMSEV for each calibration model. This nonlinear temperature profile could be used to enable process scale-up. sorted. When the calibration model was applied to this data. a system known to be highly prone to agglomeration. 100 cm−1). (Crystallization with constant relative supersaturation control was not tested in this case. By looping all the possible combinations. As a result. 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. respectively. it is a constant in absolute SS control. and repeats above operations. It starts from left side with a finite spectral window (e. PLS calculation of leave-one-out cross validation has been performed. and evaluated based on the value of their corresponding RMSEVs (root mean standard error of validation or SECV).. The R2 value obtained with this model was 0. where a is 0. 17. As a result of online monitoring and control of the process with FTIR..Organic Process Research & Development where K and τ are the constants of control.g.org/10. A metastable zone width for this system was also generated and is presented in Figure 7.9956 and the SECV was 0. MK-A. For each calibration model with a given spectral region and a number of PLS factors.4 °C/min.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. Then. A PLS calibration model built using five factors in the 1267−1521 cm−1 spectral region together with temperature incorporated was chosen as the optimum. 2013. This Matlab routine first loops across spectral region.31 g/L. but a function of Csat(%A) in relative SS control. Solubility curve of etoricoxib as a function of temperature in toluene. 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. Dev. an optimum PLS model was built in the spectral region 1800−1000 cm−1 with a standard error of cross validation (SECV) of 0.24339. and goes to next by adding another spectral region (e. Antisolvent Addition Crystallization of MK-A.

1021/op400187h | Org. Form II was isolated at the exclusion of metastable Form I. (a) Solubility curve and crystallization profiles at preset supersaturations at 9. 2013. Microscope image of crystallized slurry at the end of a feedback controlled crystallization batch with supersaturation at (a) 29 g/L and (b) 9. such that initial efforts to isolate Form II always resulted in a mixture of the two forms which was very slow to convert to the target Form II. The batch started with 10% media milled seed of Form II.6591X − 0. (b) Temperature and batch concentration profiles of feedback control with absolute supersaturation of 9. 17. The addition rate of hot batch is controlled on the basis of the feedback of measured concentration against a preset value. With a robust calibration model and a solubility curve available. feedback control crystallization proceeded with the real-time measurement of temperature. Dev.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. Process Res. the corresponding nonlinear antisolvent profile is also presented in Figure 10d. applied to solubility spectra collected per the previously described approach.doi. Figure 10a presents the concentration and solvent composition profiles during the course of this antisolvent addition. and then 1326 proceeded to antisolvent crystallization at a constant temperature with a relative supersaturation maintained at 33%.4601 + 5.2121X2 − 0.5 g/L . solubility curves (Figure 10a) were obtained and best fitted as: Y = 10. was aged for approximately 1 h.6974X − 0.0033X3 for form I Y = −49. API concentration. The hot batch stream of API dissolved in 45 °C n-heptane is fed slowly to the crystallizer. indicating clearly that the batch concentration stayed safely below the solubility curve of Form I while closely following the preset supersaturation value.5 and/or 29 g/L of via feedback control of temperature.Organic Process Research & Development Article Figure 8.5447 + 2. This crystallization process starts with a ‘heel’ seed bed of API slurried in n-heptane at 20 °C. and solvent composition. MK-B.1811X2 − 0. 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.org/10. Different from the dx. For the consideration of potential process scale-up. the addition of the hot batch stream creates supersaturation that drives crystallization. Therefore. 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. 1320−1329 . “Fed Batch” Heel Crystallization.5 g/L etoricoxib. Figure 9. Due to the difference in solubility of API in n-heptane between 20 and 45 °C. a drug candidate at Merck. The FBRM profiles (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.

17. When implementing the “fed batch” crystallization. 1320−1329 . then pump rate = pump rate + K (e + Δt *sum/τ ). Instead of adding antisolvent to the batch when the concentration is below the preset value.Organic Process Research & Development Article Figure 10. then pump rate = 0. an approach similar to the automated protocol of antisolvent addition crystallization has been adopted. 1327 where SS is a constant. the “fed batch” heel crystallization operates around one solubility point which is determined by the solvent and batch temperature (Figure 11). leading to add “hot” batch Else if e ≥ 0. sodium acetate) and antisolvent (water). the hot batch is added to raise the concentration to the set-point.doi. acetic acid. crystallizations of both cooling and antisolvent addition. 2013. K and τ are the constants of control.org/10. Process Res. and crystallization profiles for MK-A via feedback-controlled addition of water to maintain a relative supersaturation of 33% under 65 °C. Cset = Csat+SS e = Ccurrent − Cset If e < 0. (a) (b) Solubility curve of Forms I and II of MK-A in solvent mixture (ethanol. (c) corresponding FBRM PSD profiles and (d) water addition profile for this crystallization.1021/op400187h | Org. sum and e are the differences between batch concentration and dx. Diagrams of process progress and control for the heel crystallization via feedback control. A brief description of the algorithm for “fed batch” crystallization is as the following: at fixed T and solvent composition. Dev. or at a reduced rate end if sum = sum + e Figure 11.

REFERENCES (1) Yu. Thomas. G. Arrivo. Braatz. A.. 2001. D.doi. S. collaboration. R. 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. A follow-up experiment at higher supersaturation reduced cycle time to ∼4 h while maintaining desired API attributes. J. Cryst. C. H. Rev. R.001055. P. 349. 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. dx. A. 2013.. Goetz. P. the addition rate was in high gear to establish the predefined supersaturation. Adv.. We thank Drs. 7..com Notes The authors declare no competing financial interest. S. The hot feed was carried out at a constant crystallizer temperature of 20 °C with a relative supersaturation maintained at 21%. R. Process Res. 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 scientific understanding. L. suggesting that particle growth was predominant while nucleation was not significant. ■ Y = e(aX 2 + bX + c) where a is 0. Templeton. expanding the scope of this platform to another category of application. W. Pharm. As illustrated in Figure 13. A. 1989. and c is 2. 49. Thurau.9691. 3.org/10. Wu. information-rich manner. Chem.. D. D. Nagy. Wilkinson. 1328 . the heel seed bed. 2004. a solubility curve (Figure 11a) was obtained and best fitted as: Article addition rate dialed down and reached a steady rate for the duration of the crystallization process. Bowen. (5) Higgins. A. Green.. Robert Guenard and Gert Thurau of Merck for their support and helpful discussions in this work. B..mt. Z. optimization. J. Int. AUTHOR INFORMATION Corresponding Author *E-mail: george_zhou@merck. 1777. 64. Drug Delivery Rev. S. J. A. Hussain.Organic Process Research & Development targeted concentration. G. b is 0. L.. Growth Des. Sys. Lionberger. Cindy Starbuck. Skagerberg. Chemom. solubility measurement. N... R. 75. We also are very grateful to Michael Wismer of Merck for his dedicated contribution to this work.. 1992. Intell. R. S. N. D’Costa. A. 92. Chem. A. the total counts of fines (1−5 and 10−24 μm/s) went down. Lab.html (9) Saleemi. The FBRM profiles in Figure 12 show that at this level of supersaturation. Biomol. In order to further improve the efficiency of the method. 55. and control of robust crystallization processes has been described. When this model is used to predict the spectra from solutions of which API is in equilibrium between the liquid and solid phases. one can achieve robust and efficient crystallization processes to ensure isolation of the desired polymorph at target particle size in a resource-sparing. (6) Brown.. Eng. Raw. (3) Mougin. Reed. (2) Nagy. and Δt is the interval of logic timer in seconds. By utilizing such an integrated API platform.. Profiles of hot batch addition and addition rate for the “fed batch” crystallization with 21% supersaturation of MK-B via feedback control.. Chem. Anal. L.003595. Adv. and insight on the development of the technology described in this manuscript. Z. L.. K.24 g/L API in n-heptane across the spectral range of 1812− 1215 cm−1 and temperature range of 5−28 °C was attained for this model. a new approach has been developed and demonstrated for the “fed batch” crystallization. 2002. S. 2012. In addition. Profiles of MK-B concentration and PSD during the course of “fed batch” crystallization via feedback control. 56. 430. 56. Hsien-Hsin Tung and Professor Richard Braatz for the initial work.. 17. ■ Figure 12.. A.. M. Zhihong Ge.. Dev. X. Lange. P.com/us/ en/home/products/L1_AutochemProducts. Freeman.. 2002. Bear. Blank. K. Kettaneh-Wold. (7) Wold. Pedge. 1320−1329 Figure 13. 227. A standard error of cross validation (SECV) of 0. when the feedback control started. (4) Dukhin.1021/op400187h | Org. Annu. 73. Colloid Interface Sci.. 2012. 2. In order to develop a robust calibration model for feedback control. A. 53. S. T.. This versatile tool empowers the user with the integrated platform for automated calibration. Anal. (8) Synthesis workstation of Mettler Toledo: http://us.. Q. D. N. 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. Steele. while large ones (28−90 and 95−270 μm/s) increased as the process proceeded. a PLS model was built with spectra collected from the solutions with known composition around the crystallization temperature. R. Then the ■ ■ ACKNOWLEDGMENTS We greatly appreciate Dr..

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