Understanding the Formation of IndomethacinâSaccharin Cocrystals

Article pubs.acs.org/crystal

Understanding the Formation of Indomethacin−Saccharin Cocrystals by Anti-Solvent Crystallization Min-Jeong Lee,† Nan-Hee Chun,‡ In-Chun Wang,† J. Jay Liu,§ Myung-Yung Jeong,∥ and Guang J. Choi*,‡ †

Department Department § Department ∥ Department ‡

of of of of

Smart Food & Drugs, Inje University, Gimhae, Gyeongnam 621-749, South Korea Pharmaceutical Engineering, Soon Chun Hyang University, Asan, Chungnam 336-745, South Korea Chemical Engineering, Pukyong National University, 365 Sinseon-ro, Nam-gu, Busan, 608-739, South Korea Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735, South Korea

ABSTRACT: Pharmaceutical cocrystals are a novel drug form with the potential to enhance pharmaceutical properties, including the solubility and dissolution behavior for BCS class II drug substances such as indomethacin (IMC). Recently, we reported that pure indomethacin−saccharin (IMC−SAC) cocrystals were prepared via anti-solvent crystallization. In this study, we investigated the solubility behavior of IMC−SAC cocrystals and individual components in methanol−water cosolvent. Also, the phase solubility diagram (PSD) of the cocrystal was determined to increase our understanding of cocrystallization. The criterion for pure IMC−SAC cocrystal formation was proposed and verified through supporting experiments performed with different concentrations. We also found that Scocrystal and Scocrystal/Sdrug are critical factors for the design of the cocrystallization process via antisolvent addition. Real-time monitoring of the cocrystallization process was performed using an in-line near-infrared (NIR) system. Principal component analysis (PCA) was applied to NIR spectral analysis. Based on the PCA results, distinct differences were observed in the pathways of IMC−SAC cocrystal formation depending on the initial concentrations. interactions with the solvent.22 The cocrystal solubility product indicates that high coformer concentrations are associated with low drug concentrations, similar to the common ion effect.26 Models for the solubility trend of cocrystals with different stoichiometries have been derived based on the solubility product and the solution complexation characteristics.23,24 Phase diagrams are used to show thermodynamically stable phases and predict the phase transformation of a substance at different temperatures, pressures, and compositions. In cocrystal research, the phase diagram determines the stable region of cocrystals depending on their phase composition at a fixed temperature and pressure.23 Cocrystal transition or eutectic point is a critical parameter that establishes the thermodynamically stable regions of cocrystals relative to components in the phase solubility diagram (PSD).17,25−27 This is an immutable point where two solid phases (e.g., drug and cocrystal) coexist in equilibrium with solution at a constant temperature.26 The concentrations of cocrystal components at the transition point and the solubilities of individual components can be used to determine whether the cocrystals are congruently or incongruently saturating in a particular solvent and at a particular temperature.21,26,27 Therefore, PSDs

1. INTRODUCTION In the pharmaceutical industry, improving drug solubility is an important challenge because it can enhance the bioavailability of poorly soluble drugs. Many techniques have been used to increase the solubility of drugs, including salt formation, micronization, emulsification, and complexation.1−6 Recently, there has been great interest in the design of pharmaceutical cocrystals, which have emerged as potential additives to modify physicochemical properties of active pharmaceutical ingredients (APIs), such as solubility, dissolution rate, stability, flowability, and compressibility.7−11 Pharmaceutical cocrystals are stoichiometric molecular complexes that contain an API and coformer in a crystal lattice via noncovalent interactions, predominantly hydrogen bonds.12,13 To date, a number of pharmaceutical cocrystals have been reported, and some APIs can produce as many as 50 cocrystals.14 Various methods have been used to prepare pharmaceutical cocrystals, such as solvent evaporation, cooling, reaction crystallization, grinding, supercritical fluid crystallization (SCF), twin screw extrusion, and spray drying.15−21 Recently, studies on the solubility behavior of cocrystals have revealed the dependence of cocrystal solubility on the coformer concentration.22−26 The dissociation of cocrystals in solution is demonstrated by the solubility product (Ksp), defined as the product of the drug and coformer concentrations. Ksp is a constant that represents the strength of solid phase cocrystal interactions between the drug and coformer relative to © 2013 American Chemical Society

Received: January 24, 2013 Revised: March 6, 2013 Published: March 8, 2013 2067

dx.doi.org/10.1021/cg400135a | Cryst. Growth Des. 2013, 13, 2067−2074

Crystal Growth & Design

Article

subsequent analysis were withdrawn and filtered with syringe filters (Whatman, 0.45 μm nylon membrane). The aliquot was diluted as required, and concentrations were measured using high-performance liquid chromatography (HPLC; Shimadzu UFLC, Japan) with a ZORBAX SB-C18 column (Agilent, 4.6 × 250 mm, 5 μm). The solid phases remaining in suspension were filtered, dried, and subsequently analyzed using PXRD to determine whether a solid-state transition occurred. 2.4. Transition Point Determination. The transition point for IMC−SAC cocrystals was determined in MeOH−water 2:1 cosolvent at 25 ± 0.5 °C. This was achieved by adding IMC−SAC cocrystal to a suspension containing excess solid IMC. The suspension was magnetically stirred until two solid phases (cocrystal and IMC) coexisted in equilibrium for at least 24 h. IMC and SAC concentrations were measured by HPLC as described above. The solid phases at equilibrium were confirmed by PXRD. 2.5. Anti-Solvent Cocrystallization. The anti-solvent cocrystallization processes at constant temperature were performed in a 1 L double jacketed reactor, as shown in Figure 1. Predetermined amounts

are important for increasing the efficiency of cocrystal screening and preparation and for understanding cocrystal behavior. The US FDA has promoted process innovation in the pharmaceutical industry through process understanding achieved using quality by design (QbD) and process analytical technology (PAT). Process analyzers are an important constituent of the PAT framework.28 Recently, spectroscopic methods, such as attenuated total reflectance (ATR) Fourier transform infrared (FTIR), near-infrared (NIR), Raman, and focused beam reflectance measurement (FBRM), have been used for online process monitoring and quality control of crystallization processes.29−32 For cocrystallization, the analyzers were mostly used for screening studies rather than process monitoring. In a recent study, NIR spectroscopy was used to monitor the formation of ibuprofen and nicotinamide cocrystals during extrusion based solvent free continuous cocrystallization (SFCC).33 Real-time process monitoring was performed using a high temperature NIR probe in the extruder die. It was concluded that NIR spectroscopy was sensitive to cocrystal formation and could be used to monitor cocrystal purity on an industrial scale. Gagniere et al. investigated the mechanisms of carbamazepine (CBZ)−nicotinamide (NCT) cocrystallization using two in situ process analytical technologies including a FBRM probe and a video probe.34 They reported that a solution mediated phase transition from CBZ to the cocrystal was initiated by the addition of NCT, and it was possible to discriminate between two solid phases using two sensors. In our previous study, we applied an anti-solvent crystallization process for indomethacin−saccharin (IMC− SAC) cocrystals.35 Anti-solvent crystallization would require less energy than a solvent evaporation process and can be performed at ambient temperatures. Thus, it has been widely used to crystallize pharmaceutical substances that are generally sensitive to heating. Because it is difficult to control the particle characteristics using this approach, it is important to monitor critical quality attributes of the process, such as solute concentration and particle size. The aims of the current study were (1) to generate the PSD of IMC−SAC cocrystals in methanol−water cosolvent, (2) to establish optimal conditions for formation of pure cocrystal by understanding the solubility behavior, and (3) to employ NIR spectroscopy for in-line monitoring of cocrystallization.

Figure 1. Experimental apparatus for anti-solvent cocrystallization process. of IMC and SAC were fully dissolved in methanol (300 mL), and 150 mL of purified water as anti-solvent was added to the solution using a peristaltic pump under 500 rpm agitation at constant temperature (25 °C). The process was performed for 30 min; subsequently the solution was filtered using vacuum filtration with filter paper (Whatman 2.5 μm grade). The collected solid was dried in a vacuum oven at 25 °C overnight prior to subsequent characterization. The filtrate was diluted as required and filtered with a syringe filter (Whatman 0.45 μm nylon membrane) prior to HPLC analysis. All experiments were carried out in duplicate to verify the reproducibility. 2.6. NIR Spectroscopy. Off-line NIR spectra were measured for IMC a-form, cocrystal, and final products obtained by multiple experiments. The cocrystallization processes were monitored with 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 and an InGaAs diode array detector. A diffusive reflectance probe (FOCON FO; ABB Bomem) was integrated into the spectrophotometer using a 3 m long fiber-optic cable. NIR spectra were continuously collected in the wavenumber range from 4000 to 14,000 cm−1 at a resolution of 64 cm−1. Each spectrum was recorded by averaging 32 scans, which took approximately 6 s. All NIR spectra were acquired using GRAMS/AI 7.00 software (Galactic Ind., Salem, NH), and subsequent preprocessing and principal component analysis (PCA) were performed using Unscrambler (CAMO Software AS, Oslo, Norway). 2.7. Powder Characterization. The crystalline structures of collected powders were determined using a powder X-ray diffractometer (Rigaku DMAX-2200, Japan) with Cu Kα radiation source (λ = 1.54 Å at 40 kV/40 mA). The PXRD pattern for each powder

2. MATERIALS AND METHODS 2.1. Materials. Indomethacin (IMC; r-form) and saccharin (SAC) were purchased from Tokyo Chemical Industry (Tokyo, Japan) and Sigma Aldrich Co. (St. Louis, MO, USA), respectively. Methanol (MeOH) and ethyl acetate (EtAc) were supplied by Merck Millipore (EMSURE, Darmstadt, Germany). Water was purified using a deionizer (Human Corp., Seoul, Korea) prior to use. 2.2. Preparation of IMC−SAC Cocrystal by Evaporation. IMC (0.01 M) and SAC (0.01 M) were dissolved in 200 mL of EtAc, and the solution was agitated at room temperature (∼25 °C). After the solution evaporated, the flask was placed in a vacuum oven at 25 °C overnight to ensure complete dryness. The prepared powder was verified by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). 2.3. Solubility of Cocrystal and Cocrystal Components in MeOH−Water 2:1 Cosolvent. The solubility measurements of IMC, SAC, and IMC−SAC cocrystal at several concentrations of SAC (0− 0.01M) in methanol−water 2:1 cosolvent were determined at 25 ± 0.5 °C. The known amount of powder was added to 30 mL of cosolvent, and the suspensions were magnetically stirred for 24 h. Samples for 2068



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sample was acquired at a Bragg angle (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 along with a blank pan as a reference. DSC measurements were performed at 25−250 °C with 10 °C/min heating rate under a nitrogen atmosphere. Solid powder morphology was observed using optical microscopy (Olympus CKX 41, Tokyo, Japan).

IMCsolution + SACsolution ↔ IMC−SACsolution

And the cocrystal solubility can be expressed as [IMC]total =

Figure 2. Solubility of IMC−SAC cocrystals at 25 °C as a function of SAC concentration in methanol and MeOH−water 2:1 cosolvent. Solid line represents the predicted cocrystal solubility in MeOH− water 2:1 cosolvent according to eq 3 with a solubility product Ksp = 3.845 × 10−5 M2. Horizontal dotted line represents the IMC solubility. ▲ and ○ are measurement points. Solubility curves of cocrystal and IMC in methanol are slightly modified from ref 25.

the solubilities of IMC−SAC cocrystals and IMC at 25 °C as a function of total SAC concentration in MeOH−water 2:1 cosolvent. The solubility behavior in methanol was presented for comparison, which was reported in a previous study.25 The mathematical models already described in the earlier study were used to predict the cocrystal solubility.22 The equilibrium reaction for IMC−SAC cocrystal can be written as K sp

(1)

Then, the solubility product can be given as K sp = [IMC][SAC]

At equilibrium, the cocrystal solubility is given by K sp [IMC]total = [SAC]total

(2)

(3)

If the 1:1 solution complex is in equilibrium, the equilibrium reaction can be written as K sp

IMC−SACsolid ← → IMCsolution + SACsolution

K sp [SAC]total

+ K11K sp

(6)

The solubility product of IMC−SAC cocrystal in MeOH− water 2:1 cosolvent was determined to be Ksp = 3.845 × 10−5 M2 by plotting [IMC]total versus 1/[SAC]total according to eq 7. K11, the binding constant for the 1:1 complex formed in solution, was calculated from the y-intercept, which was close to zero. The PSD showed that IMC−SAC cocrystal solubility decreases as the SAC concentration increases in solution, similar to other cocrystal systems. Compared to the methanol conditions, drug (IMC) solubility decreased more significantly (about 1/10) than the conformer (SAC) solubility (about 1/ 2.5). As a result, the solubility of SAC (0.105 M) was about 28 times higher than the solubility of IMC (0.0037 M). Coformers with a 10-fold greater solubility than the drug resulted in incongruently saturating cocrystals. For incongruent systems, the concentration of coformers at the transition point ([SAC]tr), where cocrystals and drugs coexisted in equilibrium with solution, was higher than the concentration of the drug ([IMC]tr).26 As shown in Figure 2, [IMC]tr was lower than [SAC]tr in MeOH−water cosolvent compared to methanol alone. Thus, IMC−SAC cocrystals are incongruently saturating in MeOH−water 2:1 cosolvent. In congruently saturating systems, the cocrystal components have similar solubilities in solvent, and the cocrystal is thermodynamically stable during slurrying. Therefore, cocrystals can be produced with equimolar components (for 1:1 cocrystal) in solution-based cocrystallization. For incongruently saturating systems, the drug is less soluble than the coformer, and the cocrystal can be transformed into a more stable solid form during slurrying. Accordingly, nonequivalent concentrations of cocrystal components (for 1:1 cocrystal) should be used to approach the cocrystal stability region.17,21,36 Because the IMC−SAC cocrystal is an incongruent system in MeOH− water cosolvent, nonequimolar concentrations of IMC and SAC are required to prepare the cocrystal using anti-solvent crystallization. 3.2. Understanding Cocrystal Formation. The PSD relates solubility to the thermodynamic stability of cocrystals and is a useful tool for cocrystal scale-up because it provides insight into the pathway of cocrystal formation.17,37 Transition concentrations play a key role in predicting solubility and stability; they also provide valuable information on cocrystal design and formulation.38 Here, we propose a method and standard that can predict whether pure cocrystals are formed based on the relationship between transition concentrations and differences in the initial concentrations of the two components. Figure 3 presents a portion of the PSD and illustrates an expected pathway during cocrystallization. The driving force for crystallization is supersaturation, i.e., the difference between the initial reactant concentration and the equilibrium concentration. When cocrystals are formed, the concentration of coformer (SAC) is reduced during the process, which causes changes in the equilibrium point. We predicted the SAC concentration of the equilibrium point using simple calculations.

3. RESULTS AND DISCUSSION 3.1. Solubility Behavior of IMC−SAC Cocrystal in MeOH−Water Cosolvent. In cocrystallization studies, knowledge of cocrystal solubility behavior is essential for rational and efficient cocrystal screening and preparation. Figure 2 shows

IMC−SACsolid ← → IMCsolution + SACsolution

(5)

(4) 2069



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[SAC]n

= [SAC]0 − [IMC]0 + f ([SAC]n − 1 )

[SAC]n + 1 =

[SAC]0 − [IMC]0 + f ([SAC]n )

Because [SAC]n > [SAC]0 − [IMC]0 and f([SAC]n) < f([SAC]0 − [IMC]0), [SAC]0 − [IMC]0 < [SAC]n + 1 < [SAC]0 − [IMC]0 + f ([SAC]0 − [IMC]0 )

which can be rewritten as [SAC]0 − [IMC]0 < [SAC]equil < [SAC]0 − [IMC]0 + f ([SAC]0 − [IMC]0 )

(7)

This approach is based on the creation of cocrystals, but drug (IMC) crystals can also be produced by adding anti-solvent during the actual process. Considering the solubility, the cocrystal remains when [SAC]equil is higher than [SAC]tr. If [SAC]tr = [SAC]0 − [IMC]0, an inequation (7) is given by [SAC]tr < [SAC]equil < [SAC]tr + f ([SAC]tr )

Figure 3. A portion of the phase solubility diagram shown in Figure 2 and an expected pathway from initial point (A0) to equilibrium point.

(8)

Thus, we can predict that the pure cocrystal is created if [SAC]tr ≤ [SAC]0 − [IMC]0. This inequation can be generalized as [coformer]tr ≤ [coformer]0 − [drug]0, and it can be employed to develop other 1:1 cocrystal system using anti-solvent crystallization. To confirm this hypothesis, several experiments were performed at different initial concentrations. The SAC concentration at transition point was determined to be about 0.01 M. Therefore, we choose the concentration of cocrystal components according to [SAC]0 − [IMC]0 ≥ 0.01 M. Table 1

Let [SAC]0 and [IMC]0 be the concentrations of SAC and IMC in the cosolvent, respectively (A0). Also, let [IMC]1 be the concentration of IMC in equilibrium with the cocrystal when [SAC]1 is equal to [SAC]0 (A1). The formation of cocrystal is induced by supersaturation, corresponding to the difference between [IMC]0 and [IMC]1. The concentration of SAC in cosolvent is reduced as cocrystal is created. Here, we presume that cocrystal is produced as [IMC]0 − [IMC]1. Then, the concentration of SAC in cosolvent changes to [SAC]2, and the cocrystal solubility becomes [IMC]2 at [SAC]2 (A2). Because the cocrystal solubility at point A2 is higher than at point A1, some cocrystal will dissolve and the concentration of SAC will increase (A3). If the formation and dissociation of cocrystal is repeated in accordance with the cocrystal solubility curve, as explained above, the concentration at each point can be calculated as follows. Let f be the function of the cocrystal solubility curve shown in Figure 3.

Table 1. Concentration Conditions and Final Solid Phases of Anti-Solvent Cocrystallization

A 0 = ([SAC]0 , [IMC]0 ) A1 = ([SAC]1 , [IMC]1 ): [SAC]1 = [SAC]0 , [IMC]1 = f([SAC]1 ) A 2 = ([SAC]2 , [IMC]2 ): [SAC]2 = [SAC]0 − ([IMC]0 − [IMC]1 ), [IMC]2 = f ([SAC]2 )

exp no.

[SAC]0

[IMC]0

Scocrystal

Sdrug

Scocrystal/ Sdrug

1

0.035

0.025

4.77

6.25

0.76

2

0.036

0.025

4.84

6.25

0.77

3

0.038

0.025

4.97

6.25

0.79

4 5

0.04 0.04

0.025 0.03

5.10 5.58

6.25 7.5

0.82 0.74

6 7

0.04 0.05

0.02 0.025

4.56 5.70

5 6.25

0.91 0.91

final solid phase cocrystal/IMC a-form cocrystal/IMC a-form cocrystal/IMC a-form cocrystal cocrystal/IMC a-form cocrystal cocrystal

summarizes the experimental conditions and resulting solid phases. The initial supersaturation ratio of IMC−SAC cocrystal (Scocrystal) was calculated with the following equation:39

A3 = ([SAC]3 , [IMC]3 ): [SAC]3 = [SAC]0 − ([IMC]0 − [IMC]2 ), [IMC]3 = f ([SAC]3 )

⎡ [IMC]·[SAC] ⎤1/2 ⎥ Scocrystal = ⎢ K sp ⎢⎣ ⎥⎦

A4 = ([SAC]4 , [IMC]4 ): [SAC]4 = [SAC]0 − ([IMC]0 − [IMC]3 ), [IMC]4 = f ([SAC]4 )

(9)

As shown in Table 1, the initial supersaturation ratio of IMC (Sdrug) was always greater than that of the cocrystal, suggesting that IMC crystal can be created together with cocrystals at any rate. Considering the solubilities of the two solid phases, only IMC−SAC cocrystal would be present. Figure 4a shows the PXRD patterns of powders prepared by exp 1−4. Contrary to our expectations, pure cocrystal was only formed in exp 4, whereas mixtures of IMC a-form and cocrystal

⋮ A n = ([SAC]n , [IMC]n ): [SAC]n = [SAC]0 − ([IMC]0 − [IMC]n − 1 ), [IMC]n = f ([SAC]n )

[SAC]n and [SAC]n+1 can be written as 2070



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Figure 5. Powder X-ray diffraction patterns for different solid phases prepared by exp 4, 5, 6, and 7.

assumed that pure cocrystal was more easily formed as Scocrystal/ Sdrug increased. This was verified by exp 6. The Scocrystal of exp 6 was lowest, but Scocrystal/Sdrug was highest among the experiments. Naturally, pure cocrystal was generated. Overall, Scocrystal played a role in cocrystal nucleation, and Scocrystal/Sdrug affected the phase transformation of IMC a-form. Experiment 7 was conducted with the same Scocrystal/Sdrug as exp 6 but with higher Scocrystal than exp 6. Typical microscopy images of cocrystal powders acquired via exp 6 and 7 are shown in Figure 6. Both cocrystal powders had columnar structures, while the cocrystals prepared by exp 7 were much larger. This may be caused by differences in the procedure of cocrystal formation between the two experiments. The nucleation and growth of IMC a-form were observed visually during exp 6, similar to other experiments. However, for exp 7, we found that only cocrystal particles were formed and grown, gradually. It is possible that the nucleation and growth of IMC a-form were inhibited by the rapid nucleation of cocrystals, and cocrystal growth occurred during this process. More detailed pathways of cocrystal formation will be explored in a future study. 3.3. NIR Monitoring. Figure 7 shows the off-line NIR spectra of IMC a-form and cocrystal, which were collected 20 times; the spectra were preprocessed using the second derivative method. The NIR spectra of SAC powder were not measured because only two solid phases of IMC a-form and cocrystal were generated using anti-solvent cocrystallization. In the region of 4900−5400 cm−1, the combination of O−H stretching and the second overtone of CO stretching are observed. The first overtone of O−H stretching is represented in the range of 7000−7300 cm−1. Hydrogen bonding results in peak shift and decrease of peak intensity in these absorption bands. The IMC−SAC cocrystal structure is characterized that carboxylic acid dimer interacts with imide dimer synthon through weak hydrogen bond.15 As shown in Figure 7, the spectra of cocrystal containing hydrogen bonding in the crystal lattice had lower peak intensity and a slight peak shift compared to the spectra of IMC a-form. Also, a new peak near 5150 cm−1 was observed in the cocrystal spectra. Therefore, the region of 4900−7500 cm−1 was chosen for PCA. Principal component analysis (PCA) is a data compression method that reduces multivariable data sets to a simpler set of new variables, generally referred to as principal components (PCs). Since the PCs are extracted in order, the first few PCs retain most of the information present in the

Figure 4. (a) Powder X-ray diffraction patterns for different solid phases prepared by exp 1−4. (b) DSC thermograms for solid phases created by exp 3 and 4.

were produced in all other experiments. For exp 3, although the peak corresponding to IMC a-form was not observed in the PXRD result, a small peak was detected in DSC analysis (Figure 4b). Although pure cocrystal was not created (excluding exp 4), it was confirmed that the formation of cocrystal increased as Scocrystal increased. It is well-known that the supersaturation ratio affects nucleation and crystal growth. An increment in Scocrystal led to an increase in cocrystal nucleation. This may be associated with the relative reduction of IMC crystal nucleation, and the phase transformation of IMC to cocrystal would take place more quickly. Also, it appeared that pure cocrystals could be obtained by exp 1, 2, and 3 if the process time was extended. Experiments 5 and 6 were carried out with the same SAC concentration as exp 4 but with different IMC concentrations. Figure 5 shows the results of PXRD analysis. The small peaks corresponding to IMC a-form were observed in exp 5, which was confirmed using a DSC thermogram (data not shown). While the [SAC]0 − [IMC]0 of exp 5 was equal to that of exp 1, the result was approximate to pure cocrystal. It was because the Scocrystal of exp 5 was much higher than that of exp 1, as explained above. However, pure cocrystal was not produced because Sdrug also increased. Thus, both Sdrug and Scocrystal should be evaluated for cocrystal creation. We calculated the Scocrystal/ Sdrug ratio to evaluate the effect of Sdrug. As a result, it was 2071



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Figure 6. Microscopy images of IMC−SAC cocrystals prepared by exp 6 and 7.

formation increased. Because the PC1 explained 99% of the total spectral variation, we presumed that the PC1 is related to creation of cocrystal. Thus, the pathway of cocrystal formation by anti-solvent cocrystallization could be identified via PCA. We selected exp 1, 6, and 7 as model processes for in-line NIR monitoring. Figure 9 displays the PC score plots of the entire process. The direction of arrows represents the change of process time. All data points were collected continuously during each experiment. PCA was performed using about 1000 spectra (3 batches) with the same procedure as described above. Since the PC1 explained 98% of the total spectral variation, we expected that the PC1 is related to creation of solid phases. The score distributions of three experiments appeared similar for a while after addition of anti-solvent, but the pathways varied with the formation of crystals. For exp 6, it could be seen that the changing shape of the pathway was very dynamic. This pathway could be divided into two steps; the first step corresponded to the initial state of crystallization, which was similar to the pathway of exp 1 having the U-form from right to left. Considering the final solid phase of exp 1 was a mixture of IMC a-form and cocrystal, it resulted from the nucleation and growth of the drug and cocrystal. Afterward, the direction of the pathway drastically changed to the lower left and was modified again to the right. Because pure cocrystals were generated by exp 6, the second step could be described as the transformation of IMC a-form (toward the lower left) and the growth of pure cocrystals (toward the right). Although pure cocrystals were created by both exp 7 and 6, the score plots of the two experiments showed a distinct difference. This suggested that the pathway of cocrystal formation could be altered depending on the initial supersaturation ratio, as discussed above. To confirm that, the process was terminated at a designated time, and the product was characterized. Figure 10 shows the PXRD patterns of each solid phase. When the process duration was 5 min, mixtures of cocrystal and IMC a-form were obtained in exp 6. In exp 7, we did not observe peaks corresponding to IMC a-form. We verified that the nucleation and growth of IMC a-form were inhibited as both Scocrystal and Scocrystal/Sdrug increased. We also confirmed the phase transition of IMC a-form to cocrystal. In exp 6, mixtures of cocrystal and IMC a-form were generated when the process time was 15 min. However, the ratio of IMC a-form decreased significantly. This phenomenon was detected via microscopy, as shown in Figure 11. The IMC a-form had a typical needle-like shape, and the cocrystal formed a columnar structure. It appeared as though the IMC a-form and cocrystals grew together, and a subsequent phase transition

Figure 7. Second derivatives of NIR spectra for IMC a-form and IMC−SAC cocrystal collected off-line.

original data. Each sample has a score value on each PC, and it can be visualized in score plots. This made it possible to determine patterns, trends, and outliers present in the data sets.40 Figure 8 shows the results of PCA performed with the NIR spectra of the final products obtained by exp 1−4. The NIR data of solid powders were measured 20 times and were preprocessed as described above. The results showed that each experiment was distinct but became closer to exp 4 as cocrystal

Figure 8. PC score plots of final products obtained by exp 1, 2, 3, and 4. 2072



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Figure 9. PC score plots of entire process for exp 1, 6, and 7.

from IMC to cocrystal occurred. Consequently, IMC−SAC cocrystals remained present and continued to grow.

4. CONCLUSION We determined the PSD of IMC−SAC cocrystal in MeOH− water 2:1 cosolvent. The solubility of cocrystal decreased as the SAC concentration increased in cosolvent. The solubility behaviors of cocrystal and individual components indicated that IMC−SAC cocrystal was an incongruently saturating system in cosolvent. We also proposed a model to create pure cocrystal, which was expressed by the relationship between the transition concentration and the difference in initial concentrations of two components. This approach can be applied to develop other cocrystals using anti-solvent crystallization. In addition, we confirmed that the IMC−SAC cocrystal formation was affected by the Scocrystal/Sdrug ratio, as well as Scocrystal. Based on PCA with off-line characterization via PXRD, DSC, and optical microscopy, a reasonable interpretation for the various pathways of cocrystallization was established. The results demonstrated that NIR spectroscopy can be implemented to monitor the cocrystallization process.

Figure 10. Powder X-ray diffraction patterns for solid phases obtained at designated process times of exp 6 and 7.

Figure 11. Microscopy images of solid phases obtained with different process times for exp 6. 2073



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AUTHOR INFORMATION

Corresponding Author

*22 Soonchunhyang-ro, Asan, Chungnam 336-745, South Korea. Tel: +82-41-530-4864. Fax: +82-41-530-3085. E-mail: [email protected]. 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 (20120008212).

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