In Situ Monitoring of Antisolvent Cocrystallization by Combining Near

Article pubs.acs.org/crystal

In Situ Monitoring of Antisolvent Cocrystallization by Combining Near-Infrared and Raman Spectroscopies Min-Jeong Lee, Nan-Hee Chun,† Min-Ju Kim, Paul Kim, Keon-Hyoung Song, and Guang J. Choi* Department of Pharmaceutical Engineering, Soon Chun Hyang University, Asan, Chungnam 336-745, South Korea

Downloaded by UNIV OF NEBRASKA-LINCOLN on August 31, 2015 | http://pubs.acs.org Publication Date (Web): August 12, 2015 | doi: 10.1021/acs.cgd.5b00700

S Supporting Information *

ABSTRACT: In situ monitoring techniques are essential for the control and optimization of the cocrystallization process. In our previous study, we successfully monitored indomethacin−saccharin (IMC−SAC) cocrystallization by antisolvent addition using a method based on near-infrared principal component analysis (NIR−PCA). In this study, a calibration model was developed to predict the solute concentration of the two components. Several samples withdrawn from five sets of experiments were used to develop the calibration model. The actual concentrations of the two components were determined using UV−vis spectroscopy and high performance liquid chromatography (HPLC). The amount of solid-phase material in suspension was calculated from these solute concentration data. Correlations between NIR spectra and solid concentrations were evaluated using partial least-squares (PLS) regression analyses. Reasonably good calibration models with determination coefficients (R2) higher than 0.979 were obtained. Process monitoring was performed using in situ NIR and Raman spectroscopies to predict the concentrations of both IMC and SAC in solution and to identify the solid-phase materials, respectively. The calibration models were deemed suitable, with reasonable accuracy and precision, for in situ concentration monitoring of the antisolvent crystallization of IMC− SAC cocrystals. This combination of NIR and Raman spectroscopies was able to detect the formation and phase transition of the resulting cocrystal.

1. INTRODUCTION Many promising drugs are limited by low solubility. Pharmaceutical cocrystallization has attracted enormous attention as a means of modifying the physicochemical properties of drug substances including solubility/dissolution rate, stability, and compressibility.1−3 Pharmaceutical cocrystals are stoichiometric molecular complexes that contain an active pharmaceutical ingredient (API) and a coformer in a crystal lattice via noncovalent interactions, predominantly hydrogen bonds.4,5 Various methods have been used to prepare pharmaceutical cocrystals, e.g., solvent evaporation, cooling, reaction crystallization, grinding, and antisolvent crystallization.6−8 Although cocrystallization has been one of the hottest topics in the pharmaceutical industry for over a decade, commercialized drug products based on cocrystal entities are rare. In addition to the significant difference in how pharmaceutical cocrystals are defined by the United States Food and Drug Administration and EU European Medicines Agency, the paucity of pharmacokinetics data on publicized cocrystal materials has been identified as one of the main impediments to commercialization.9 The crystallization process is well-known as one of the highest-risk steps in pharmaceutical development. Therefore, in situ or in-line monitoring cannot be overemphasized as a means of attaining a desired quality. A variety of physicochemical analytical tools, including in situ near-infrared spectroscopy © XXXX American Chemical Society

(NIRS), Raman spectroscopy, attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR), focused beam reflectance measurement (FBRM), and particle vision measurement (PVM), have attracted enormous attention as process analytical technologies (PATs) for diverse pharmaceutical processes.10 There are, however, relatively few reports that detail the monitoring of pharmaceutical cocrystallization. The formation of ibuprofen and nicotinamide cocrystals during an extrusion-based, solvent-free, continuous cocrystallization was monitored using a high-temperature NIR probe in the extruder die.11 The cocrystal conversion correlated strongly with the appearance of new peaks and peak shifts, particularly in the 4800−5200 cm−1 region. A contour plot can be used to provide a clear picture of the physicochemical changes occurring during the cocrystallization of furosemide and adenine by evaporation.12 The preparation of salicylic acid and 4,4′-dipyridyl cocrystals upon cooling was monitored via in situ Raman spectroscopy.13 The nucleation and growth of cocrystals from solution were successfully monitored by quantifying the intensity of certain Raman bands. An in situ ATR-FTIR spectroscopic method was used to estimate the solute concentrations of both carbamazepine and nicotinaReceived: May 21, 2015 Revised: July 21, 2015

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DOI: 10.1021/acs.cgd.5b00700 Cryst. Growth Des. XXXX, XXX, XXX−XXX


Crystal Growth & Design

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mide.14 In a study to determine the design space of a caffeineglutaric acid cocrystallization process,15 solute concentrations in suspension were measured via ATR-FTIR spectroscopy. PVMs were combined to detect the formation of polymorphic cocrystals. Combination of analytical tools were shown reliable when studying the in situ formation of solid phases during a solution-mediated phase transition from carbamazepine crystals to cocrystals.16 PVM is often thought to be the best tool for obtaining a qualitative understanding of the cocrystallization process until the solid content becomes too high. In these cases, FBRM can serve a complementary role since it is best applied under the high concentrations of solid material as in a slurry. X-rays may be used to penetrate the milling vessel, and powder X-ray diffraction (PXRD) has been used for in situ, noninvasive monitoring of the mechanochemical cocrystallization of carbamazepine and saccharin.17 Previously unseen intermediates were detected, especially in fast liquid-assisted grinding processes. For antisolvent crystallization processes, the concentration of sodium scutellarein in solution has been monitored via NIRS.18 Good calibration statistics were obtained, and PLS-based calibration models were established. A dynamic, model multicomponent antisolvent crystallization system involving naproxen was monitored in real time using NIRS.19 The acquired spectra processed via PCA to construct a process trajectory. From a comprehensive analysis of the relationship between nucleation induction time and supersaturation ratio, the mechanisms of homogeneous and heterogeneous nucleation were clarified for low and high supersaturation regions. Through a series of studies,20−22 it was also demonstrated that cocrystallization by antisolvent addition can be efficiently monitored via in situ NIRS. On the basis of PCA results, it was shown that the initial supersaturation of the cocrystal (Scocrystal) and its ratio over the supersaturation of the drug, Scocrystal/Sdrug are critical factors in the design of a cocrystallization process.20 Antisolvent cocrystallization pathways, in terms of nucleation timing and crystalline composition, have been successfully characterized using in situ NIRS data.21 In particular, the presence or absence of transient α-IMC during the antisolvent cocrystallization of indomethacin and saccharin was verified. NIRS was employed to monitor the progress of antisolvent cocrystallization in a midscale (4.5 L) setup for synthesizing carbamazepine-saccharin cocrystals.22 On the basis of analyses of in situ NIRS spectra, the nucleation of cocrystals and the polymorphic transformation during cocrystallization were clearly detected. As discussed above, few studies describe the in situ NIRS monitoring of antisolvent cocrystallization processes. In addition to qualitative analyses, a means of quantitatively monitoring cocrystallization would be necessary in order to more precisely control and optimize the process. This study describes the development of a calibration model based on in situ NIRS measurements that provides real-time concentrations of both IMC and SAC in solution. In situ Raman spectra were also acquired to identify the solid phases present in suspension and to evaluate and validate the predictive capabilities of NIRS. The effect of supersaturation ratio is also taken into account as a critical process parameter for the nucleation and growth of cocrystals and phase transformations.

Sigma-Aldrich Co. (St. Louis, MO, USA), respectively. Methanol (MeOH) was purchased from Merck Millipore (EMSURE, Darmstadt, Germany), and water was purified prior to use with a deionizer (Human Corp., Seoul, Korea). 2.2. Antisolvent Cocrystallization. Antisolvent cocrystallization was performed in a 2 L double-jacketed reactor at constant temperature as shown in Figure 1. Predetermined amounts of IMC

Figure 1. A schematic of the experimental setup consisting of in situ NIR and Raman spectroscopic analyzers. and SAC were completely dissolved in methanol (900 mL), and 450 mL of purified water was added to the solution as an antisolvent using a peristaltic pump under agitation at 1000 rpm at constant temperature (25 °C). Each calibration batch (Table 1) was allowed to continue for

Table 1. Batch Crystallization Conditions calibration batch

monitoring batch

exp no.

[SAC]0

[IMC]0

1 2 3 4 5 6 7 8

0.045 0.045 0.045 0.035 0.035 0.040 0.030 0.040

0.035 0.025 0.015 0.025 0.015 0.020 0.015 0.030

60 min. During the process, several samples were withdrawn at prearranged time intervals after nucleation and subsequently passed through filter paper (Whatman 2.5 μm grade) by vacuum filtration. The collected solids were dried overnight in a vacuum oven at 25 °C prior to characterization. The filtrates were diluted as required and passed through a syringe filter (Whatman 0.45 μm nylon membrane) prior to HPLC and UV−vis spectroscopic analyses. SAC concentrations were measured by HPLC (Shimadzu UFLC, Japan) with a ZORBAX SB-C18 column (Agilent, 4.6 × 250 mm, 5 μm). IMC concentrations were determined by measuring the absorbance of the samples at 320 nm using a UV−vis spectrometer (Shimadzu, Japan). 2.3. NIR Spectroscopy. The cocrystallization process was monitored using a NIR probe immersed in the reactor (Figure 1). The NIR spectrometer (FTPA 2000-260; ABB Bomem, Quebec, Canada) was equipped with a tungsten-halogen source, an InGaAs diode array detector, and a diffusive reflectance probe (FOCON FO; ABB Bomem). NIR spectra were continuously collected from 4000 to

2. MATERIALS AND METHODS 2.1. Materials. Indomethacin (IMC; γ-form) and saccharin (SAC) were supplied by Tokyo Chemical Industry (Tokyo, Japan) and B




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14 000 cm−1 at a resolution of 32 cm−1. Each spectrum was recorded by averaging 25 scans, requiring approximately 6 s per spectrum. All NIR spectra were acquired using GRAMS/AI 7.00 software (Galactic Ind., Salem, NH), and subsequent preprocessing and multivariate analyses were performed using Unscrambler (CAMO Software AS, Oslo, Norway). 2.4. Raman Spectroscopy. A Raman RXN2 HYBRID analyzer (Kaiser Optical Systems, Inc., Ann Arbor MI, USA) was used for inline measurements of cocrystal formation in solution. Raman spectra were recorded on an RXN system equipped with an Invictus 785 nm NIR laser as an excitation source and an immersed probe. Spectra were collected from 100 to 1890 cm−1 at 2 min intervals with a 1 cm−1 spectral width and 20 s exposures. iC Raman software (Kaiser Optical Systems, Inc., Ann Arbor MI, USA) was used in combination with this system. 2.5. Powder Characterization. The crystalline structures of the collected powders were determined using a powder X-ray diffractometer (Rigaku DMAX-2200, Japan) with Cu Kα radiation source (λ = 1.54 Å @ 40 kV/40 mA). Diffractograms were acquired at Bragg angles (2θ) of 5−30° with a step size of 0.05° and a count time per step of 3 s. Thermal analyses of the samples were performed with a DSC-60 (Shimadzu, Japan). Each specimen (5 mg) was loaded in an aluminum pan alongside an empty pan as reference. Thermograms were acquired between 25 and 250 °C at a 10 °C/min heating rate in a nitrogen atmosphere. The morphologies of cocrystal powders were observed by optical microscopy (Olympus CKX 41, Tokyo, Japan).

3. RESULTS AND DISCUSSION 3.1. Development of a Batch Calibration Model. In order to monitor quantitative changes in crystallization process, relevant calibration models describing the correlation between spectroscopic data and solution concentrations are required. In practice, every calibration involves a wide range of variation to account for the actual process.23 Calibration experiments are typically performed under saturated conditions to avoid nucleation effects on spectra.24 However, this is difficult in cocrystallizations because the solubility of the cocrystal is lower than that of the drug, and decreases as the coformer concentration increases. As shown in Figure 2a, especially, the solubility of the IMC−SAC cocrystal and IMC in MeOH− water 2:1 cosolvent at 25 °C expressed as a function of SAC concentration was very low. Therefore, it was practically impossible to prepare undersaturated solutions. Our previous study20 showed that NIR spectra collected in diffuse reflectance mode changed as solid phases were created and transformed. In this work, NIR spectra collected during the actual antisolvent cocrystallization process were used to develop the calibration model. Table 1 summarizes the initial concentration conditions of the calibration and the monitoring batches. The initial concentrations in the monitoring experiments were determined based on a previous study.20 Figure 2a shows the positions of each component in a phase solubility diagram at 25 °C. The phase solubility diagram is a powerful tool when determining thermodynamically stable phases and critical regions for the formation of pure cocrystal, so it could lead to a better understanding of the cocrystallization pathway.25−28 There are two pathways available to create a solid phase. One is parallel to the 1:1 line, starting from the transition point for the formation of pure cocrystals. The other is vertical for the creation of pure drug crystals. The pathway of the actual process may exist between these two extremes. Initial conditions spanning these extremes were chosen for calibration batches.

Figure 2. (a) The experimental range in a phase solubility diagram of IMC−SAC cocrystal (slightly modified from ref 20; used by permission. Copyright 2013 American Chemical Society). The solid line and horizontal dotted line represent the predicted cocrystal solubility and the IMC solubility in MeOH−water 2:1 cosolvent, respectively (●: calibration batches and ▲: monitoring batches). (b) Solid-phase concentration profiles for the calibration model.

During the calibration reactions, several samples were taken at predetermined time intervals after nucleation. A total of 52 samples was collected from five calibration batches. Solute concentrations of the two components were determined by UV−vis and HPLC analyses. Since diffuse reflectance NIR spectroscopy is more sensitive to solid phases than to dissolved materials, the amounts of solid materials that can exist in suspension were calculated from solute concentration data. These data were used to build calibration models. Figure 2b shows the solid phase concentrations of IMC and SAC in suspension. Data points on the y-axis indicate the presence of only IMC crystals in suspension. In our previous study, we confirmed that the solubility of SAC was 0.105 M in MeOH− water 2:1 cosolvent.20 Considering the experimental conditions used herein for cocrystallization, the SAC crystal cannot exist alone in suspension. Therefore, the concentration of solid SAC should correspond to that of the IMC−SAC cocrystal, and data points on the stoichiometric 1:1 line can suggest the presence of only IMC−SAC cocrystals in suspension. Consequently, the concentration of SAC solid phase stands for that of cocrystal, whereas the concentration of IMC solid phase represents those C




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Figure 3. Correlation plots of solid concentration predicted by NIR spectra versus measured solid concentrations of (a) SAC and (b) IMC (blue “x” = calibration data and red “x” = validation data).

Table 2. Statistical Evaluation of Calibration Models predicted variable

factor

RMSEC

RMSECV

R2

SAC solid phase IMC solid phase

7 7

0.00111 0.00106

0.00154 0.00127

0.9885 0.9796

of the cocrystal and IMC crystal. These solid concentration profiles were used to develop a quantitative calibration model. Three spectra corresponding to each sampling time were acquired. The resulting 156 spectra were preprocessed by taking the second derivative between 4900 and 7500 cm−1 as described previously.20 It was confirmed that the spectral change was closely associated with the composition of two solid phases (Supporting Information, Figure S1). A partial leastsquares (PLS) regression method was used to establish the quantitative calibration model, and a full cross validation was performed to determine the optimum number of factors. The root-mean-square error of calibration (RMSEC) and the rootmean-square error of cross-validation (RMSECV) were used to statistically assess the quality of the model. Figure 3a,b presents the relationships between the measured and predicted solid concentrations of IMC and SAC, respectively. Representative calibration models were obtained with determination coefficients (R2) greater than 0.979, and the statistical results (Table 2) show that these PLS models can be used to accurately predict the concentrations of IMC and SAC.

Figure 4. (a) Solid phase and (b) solute concentration profiles of SAC and IMC for Exp 6 (red = SAC and blue = IMC), (c) DSC thermogram, and (d) optical micrograph of sample #1.

3.2. In Situ Process Monitoring Using NIR and Raman. Table 3 summarizes the results of the monitoring experiments. D



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Table 3. Summary of Monitoring Experiments no.

Scocrystal

Sdrug

induction time (min)

primary nucleated form

Scocrystal after primary nucleation (approximately)

final product

6 7 8

4.56 3.42 5.58

5 3.75 7.5

8 25 3

cocrystal cocrystal IMC α-form

3.2 2 3

cocrystal cocrystal cocrystal

peaks near 1690 and 1650 cm−1.29,30 Figure 5 shows Raman spectra collected during Exp 6 from 1550 to 1800 cm−1. There are no peaks corresponding to IMC, only those corresponding to IMC−SAC cocrystals. This indicates the formation of pure cocrystals as predicted by the NIR spectra. The formation of cocrystals was characterized by the appearance of two peaks at 1683 and 1717 cm−1 as shown in Figure S2a. Both peaks began to emerge approximately 7 min, and their intensities increased as a function of time. Phase equilibrium was attained after 30 min (Supporting Information, Figure S2b). In a previous study, we observed a phase transition from IMC α-form to cocrystals under the same concentration conditions as those used in Exp 6. In the current study, however, only IMC−SAC cocrystals were generated and grown. This suggests differences in reactivity as a function of batch scale. The current study was run with 3-fold more material than the previous study. When the antisolvent was added slowly, the local supersaturation of SAC and IMC may have been relatively low. As a result, nucleation of the most unstable phase, IMC αform, was suppressed, allowing cocrystal embryos to form. Thus, the rate at which antisolvent is added played a key role in the formation of pure cocrystals. We recently showed that the addition rate of antisolvent had a decisive effect on determining the polymorph of CBZ−SAC cocrystals as a function of reaction scale.22 Figure 6a,b shows the solid and solute concentrations, respectively, that were predicted using the calibration models for Exp 7. The concentration profiles of both SAC and IMC were similar to those predicted in Exp 6. Thus, it is likely that cocrystals were formed and grew alone. The results of DSC and microscopy analyses of the first sample drawn after nucleation, shown in Figure 6c,d, supported this conclusion. Exp 7 was conducted with the same Scocrystal/Sdrug ratio as in Exp 6, but with a lower Scocrystal. According to our previous study, the phase transition from IMC α-form to cocrystals should occur under these conditions. The phase transition was not observed, however, primarily because the nucleation of IMC α-form was suppressed and the nucleation of cocrystals was favored instead as described above. Therefore, controlling the nucleation of IMC α-form is essential for IMC−SAC cocrystallization by antisolvent addition. Figure 7 shows Raman spectra from 1550 to 1800 cm−1 acquired over the course of Exp 7. As in Exp 6, only peaks corresponding to cocrystals were observed. The cocrystals were formed at about 25 min, and phase equilibrium was reached after 75 min (Supporting Information, Figure S3). These data agree with the predictions made based on NIR spectra. Relative to Exp 6, the time required to induce nucleation and reach steady state was considerably greater. In accordance with the classical theory of nucleation, primary nucleation occurred earlier with a higher supersaturation ratio. Figure 8a,b shows the supersaturation ratios of Experiments 6 and 7, respectively, as a function of time. The initial supersaturation ratio of Exp 6 was higher than that of Exp 7, corresponding to the rapid formation of cocrystals. In both experiments, the supersaturation ratio of IMC (Sdrug) prior to nucleation was

Figure 5. Raman spectra acquired during Exp 6.

Figure 4a shows the predicted amount of solid-phase material in suspension using the calibration models for Exp 6. The solid concentration profiles of SAC and IMC were the same following the addition of the antisolvent. The stoichiometric ratio of IMC−SAC cocrystals is 1:1. Therefore, these data indicate the formation of cocrystals. Figure 4b presents the solute concentration profiles of both SAC and IMC, calculated from the predicted amounts of solidphase material, and shows the results of off-line measurements on samples collected during the cocrystallization process. Suspension samples were withdrawn every 10 min following nucleation as observed with the naked eye. This ensured that sampling did not affect spontaneous nucleation. As shown in Figure 4b, there was a close relationship between measured and predicted concentrations. Therefore, the calibration models developed with diffuse reflectance NIR spectra were able to accurately monitor the solute concentrations of the two components. The solute concentration profiles in Exp 6 maintained identical trends until decreasing sharply about 8 min after the water addition. A burst of nucleation was also observed at this time. These decreases were attributed to identical levels of consumption for both SAC and IMC, corresponding to IMC− SAC cocrystal formation (from A to B). After the sharp decrease, the concentrations of both components steadily declined until stabilizing at about 35 min (from B to C). This stage was indicative of phase equilibrium within the cocrystal suspension. Thus, cocrystals were formed and grew only from the early stages of nucleation in Exp 6. The differential scanning calorimetry (DSC) thermogram and optical micrograph of the first sample collected after nucleation (Figure 4c,d) confirm that only cocrystals were produced. In situ Raman analysis was used to identify the solid phase in suspension. According to previous studies, Raman peaks near 1720 and 1684 cm−1 indicate the presence of IMC−SAC cocrystals. A distinct peak at 1699 cm−1 indicates the γ-form of IMC. The α-form of IMC is indicated by the appearance of E




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Figure 8. Supersaturation ratio trajectories for (a) Exp 6 and (b) Exp 7 (red = Scocrystal and blue = Sdrug).

was initialized. This change indicates the continuous growth of cocrystal, which dominated the reaction mixture. The supersaturation ratio of cocrystal in Exp 7, however, decreased to less than 2. Considering that the driving force for crystal growth is also supersaturation, the cocrystal growth rate in Exp 7 should be lower than that of Exp 6. It is possible that the time required for phase equilibrium after primary nucleation was dependent on the supersaturation ratio. 3.3. Heterogeneous Nucleation of IMC−SAC Cocrystals. Figure 9a shows the solid concentration profiles for Exp 8 as predicted by the calibration models. These profiles were converted to solute concentrations, as shown in Figure 9b.

Figure 6. (a) Solid phase and (b) solute concentration profiles of SAC and IMC for Exp 7 (red = SAC and blue = IMC), (c) DSC thermogram, and (d) optical micrograph of sample #1.

consistently slightly greater than that of the cocrystal (Scocrystal). Surprisingly, this trend changed dramatically after nucleation F




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Figure 9. (a) Solid phase and (b) solute concentration profiles of SAC and IMC in Exp 8 (red = SAC and blue = IMC).

After nucleation, a good agreement was observed between the predicted and measured concentrations. Interestingly, the changes in the component concentration were significantly different from those of the two previous experiments. It signifies that the cocrystal in Exp 8 was created in a different way from Exp 6 and 7. As shown in Figure 9b, solute concentrations of IMC and SAC decreased sharply at about 3 min after the water addition was complete. A burst of nucleation was observed at this time (point A). Strangely enough, solute concentration of SAC increased abruptly and returned to the initial concentration (point B). We presumed at first that cocrystals were created and dissipated rapidly in the early stages of nucleation because the changes in the SAC concentration were caused by the formation of cocrystals as mentioned above. If the cocrystals were generated, they should exist consistently in the suspension because the cocrystal form is thermodynamically more stable than the α-form of IMC. However, there was no evidence that the cocrystals have been formed. Instead, we found that the preprocessed NIR spectra of IMC α-form acquired at low concentration of solid phase were similar to those of cocrystals (Supporting Information, Figure S4). Therefore, the decrease in the concentration of SAC in the initial stage of nucleation was not associated with the formation of cocrystals.

Figure 10. (a) DSC thermograms and (b) optical micrographs of samples #2−#7 for Exp 8.

At about 25 min (point C), the SAC solute concentration decreased slightly and then gradually declined after 35 min (point D). This suggests that while cocrystals nucleated and grew, the IMC α-form in suspension began to be consumed. These data also suggest that the plateau in concentrations following nucleation of the cocrystal result from competition between freshly formed cocrystal and existing IMC α-form. The transformation of solid IMC α-form to a mixture of cocrystals and IMC α-form, a mixture to pure cocrystals, was confirmed by DSC and microscopic data shown in Figure 10a,b. We presumed that the transformation from the IMC α-form to the IMC−SAC cocrystal phase can occur through either one of two processes in solution: (i) a solid−solid transformation process in which the heterogeneous nucleation and epitaxial growth of cocrystals are achieved on IMC α-form surfaces or (ii) a solvent-mediated transformation process where the IMC αform dissolves to make up the necessary supersaturation for the nucleation and growth of cocrystals. If the latter mechanism was responsible for the transformation, the concentration of G




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formation and the minority of IMC α-form prior to the complete disappearance of IMC. Figure 11 shows the supersaturation ratio profiles for Exp 8. The supersaturation ratios of IMC (Sdrug) and cocrystal (Scocrystal) were reversed as the IMC α-form was created, becoming similar again at point E. Moreover, the supersaturation ratio of cocrystal (Scocrystal) was only about 1.7, indicating that the remaining IMC α-form could not be quickly transformed to cocrystal. After approximately 65 min, only IMC−SAC cocrystals were observed. Figure 12 shows the Raman spectra collected during the course of Exp 8. There are two apparent peaks around 1650 and 1790 cm−1 that can be attributed to the presence of the IMC α-form. These peaks were not apparent in spectra acquired during Experiments 6 and 7. As the reaction progressed, those two peaks disappeared, and new peaks appeared at 1717 and 1683 cm−1, corresponding to the cocrystal. The formation of cocrystal began around 26 min, and the IMC α-form disappeared completely after about 55 min (Supporting Information,Figure S5). These times were included in sections C−D and E−F of the NIR predictions, respectively. These data support the prior hypotheses regarding cocrystal formation and phase transitions. Hence, both quantitative and qualitative analyses of the cocrystallization were performed simultaneously by exploiting the complementary nature of NIR and Raman spectroscopies.

Figure 11. Supersaturation ratio trajectories for Exp 8 (red = Scocrystal and blue = Sdrug).

4. CONCLUSIONS A calibration-based approach employing NIR and Raman spectroscopic analyses was proposed and applied to study antisolvent cocrystallization. The stoichiometric consumption of dissolved IMC and SAC resulted in the formation of pure cocrystals. Competition for nucleation between pure IMC crystals and cocrystals was highly controlled by the process operating parameters such as the initial concentrations, the antisolvent addition rate, and the supersaturation levels. The relatively unstable IMC solid crystallized initially under low Scocrystal/Sdrug conditions and then transformed to stable cocrystals. In addition, the nucleation and growth of cocrystals was affected by the existence of α-form IMC. Process monitoring via a combination of in situ NIR and Raman spectroscopies allowed predictions of solute concentrations and identification of solid materials, respectively, and showed that the calibration models developed herein were suitable for examining the antisolvent crystallization of IMC−SAC cocrystals. In addition, the predictive accuracy of the calibration models can be improved by employing a wider range of concentration data. This combined approach, which utilizes two complementary technologies, is an efficient means of understanding and controlling pharmaceutical antisolvent cocrystallization.


IMC would have been increased as well as the supersaturation ratio of the cocrystal. As shown in Figure 9b and Figure 11, however, the solute concentration of IMC and the supersaturation of cocrystal remained constant until the cocrystals were generated. Thus, we can suggest that cocrystals were produced in Exp 8 through a heterogeneous nucleation and epitaxial growth process. Previous studies on polymorphic transition have shown that the heterogeneous nucleation of a stable form can be accomplished through an ordering of prenucleation aggregates on the surface of unstable form, metastable form or hetero nuclei.31−35 Figure 10b shows needle-shaped agglomerates of the IMC α-form together with or near columnar cocrystals. The agglomerate’s structure resembles that of the cocrystal. Consequently, the IMC αform is very likely to act as a heterogeneous nucleation substrate for IMC−SAC cocrystals, which grow epitaxially on the IMC α-form. Such an epitaxial relationship between the cocrystal formation and drug substances has been described previously.36 Solute concentrations of both SAC and IMC decreased progressively in accordance with the formation of cocrystals and then increased slightly after 50 min (from E to F). This effect likely resulted from competition between cocrystal

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S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.5b00700. Additional NIR and Raman spectra (PDF)

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Corresponding Author

*Address: 22 Soonchunhyang-ro, Asan, Chungnam 336-745, South Korea. Tel.: +82-41-530-4864. Fax: +82-41-530-3085. Email: [email protected]. H



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(23) Han, B.; Sha, Z.; Qu, H.; Louhi-Kultanen, M.; Wang, X. CrystEngComm 2009, 11, 827−831. (24) Kadam, S. S.; Mesbah, A.; van der Windt, E.; Kramer, H. J. M. Chem. Eng. Res. Des. 2011, 89, 995−1005. (25) Chadwick, K.; Davey, R.; Sadiq, G.; Cross, W.; Pritchard, R. CrystEngComm 2009, 11, 412−414. (26) Yu, Z. Q.; Chow, P. S.; Tan, R. B. H. Cryst. Growth Des. 2010, 10 (5), 2382−2387. (27) Nehm, S. J.; Rodriguez-Spong, B.; Rodriguez-Hornedo, N. Cryst. Growth Des. 2006, 6, 592−600. (28) Good, D. J.; Rodriguez-Hornedo, N. Cryst. Growth Des. 2009, 9, 2252−2264. (29) Allesø, M.; Velaga, S.; Alhalaweh, A.; Cornett, C.; Rasmussen, M. A.; van den Berg, F.; Lopez de Diego, H.; Rantanen, J. Anal. Chem. 2008, 80, 7755−7764. (30) Heinz, A.; Savolainen, M.; Rades, T.; Strachan, C. J. Eur. J. Pharm. Sci. 2007, 32, 182−192. (31) Rodriguez-Hornedo, N.; Murphy, D. J. Pharm. Sci. 1999, 88 (7), 651−660. (32) Bobrovs, R.; Seton, L.; Actiņs,̌ A. CrystEngComm 2014, 16, 10581−10591. (33) Croker, D.; Hodnett, B. K. Cryst. Growth Des. 2010, 10, 2806− 2816. (34) Chadwick, K.; Myerson, A.; Trout, B. CrystEngComm 2011, 13, 6625−6627. (35) Chadwick, K.; Chen, J.; Myerson, A.; Trout, B. Cryst. Growth Des. 2012, 12, 1159−1166. (36) Gagniere, E.; Mangin, D.; Puel, F.; Rivoire, A.; Monnier, O.; Garcia, E.; Klein, J. P. J. Cryst. Growth 2009, 311, 2689−2695.

†

(N.H.C.) Unimed Pharm Inc., Asan, Chungnam, South Korea.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science, and Technology (NRF-2014R1A1A2056702).


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