Operating Regions in Cooling Cocrystallization of Caffeine and

Mar 25, 2010 - Rodriguez-Hornedo , N.; Nehru , S. J.; Seefeldt , K. F.; Pagan-Torres , Y.; Falkiewicz , C. J. Reaction crystallization of pharmaceutic...
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DOI: 10.1021/cg100198u

Operating Regions in Cooling Cocrystallization of Caffeine and Glutaric Acid in Acetonitrile

2010, Vol. 10 2382–2387

Zai Qun Yu,*,† Pui Shan Chow,† and Reginald B. H. Tan*,†,‡ †

Institute of Chemical & Engineering Sciences Ltd., A*STAR (Agency for Science, Technology and Research), 1 Pesek Road, Jurong Island, Singapore 627833, and ‡Department of Chemical & Biomolecular Engineering, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260 Received February 9, 2010; Revised Manuscript Received March 12, 2010

ABSTRACT: A complete temperature-dependent solute-solute-solvent phase diagram is an essential starting point for cooling cocrystallization process development. In this study, the phase diagram of caffeine-glutaric acid-acetonitrile in the temperature range of 10-35 °C was charted using attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy to measure concentrations in situ. Solution-mediated phase transformation was exploited to locate the eutectic points. The operating region was then prescribed according to the stoichiometry of the cocrystal, and the boundary of stability zones at the initial and final temperatures of cooling crystallization. It was demonstrated that cocrystal purity could be compromised when crystallization occurs outside the safe operating region. The complete phase diagram has laid the foundation for further cocrystallization process development of the model system.

Introduction Research on pharmaceutical cocrystals has yielded fruitful results in the past decade. Increasingly, more cocrystals with improved physiochemical properties have been reported for a number of active pharmaceutical ingredients (API)1 such as caffeine,2 carbamazapine,3 theophylline,4 etc. Various methods are emerging for the fast screening of coformers to obtain cocrystals with desired property enhancements.5 Among them, solution-mediated phase transformation (SMPT) has proved very effective and efficient.5-8 ter Horst and co-workers9 proposed to assess the possibility of cocrystal formation by measuring the saturation temperature at a composition corresponding to the solubilities of constituent components at a convenient reference temperature. On the basis of a ternary phase diagram, Chiarella et al.10 rationalized the failure of cocrystal formation from solutions of appropriate stoichiometry in some cases and thus highlighted the importance of covering a wide range of compositions in cocrystal screening through solution crystallization.11 It has also been demonstrated that cocrystal can be formed spontaneously by simply mixing solids reactants.12 Spectroscopic analysis of solutions including nuclear magnetic resonance (NMR) and Raman and Fourier transform infrared (FTIR) spectroscopy provides information on intermolecular interactions before crystallization and offers a better understanding of the solution chemistry involved.13,14 Structure-determining instruments and molecular modeling software provide detailed intermolecular interactions in the solid state.15 All these advances point to a promising alternative to traditional solid forms of APIs.16,17 Amid this encouraging progress, however, studies on process development of cocrytallization are sorely lacking. Among the major preparation methods of cocrystals, slow evaporative crystallization and solvent drop grinding are most widely used.18 They are simple and easy to implement in laboratories under ambient conditions. At a large scale, however, these methods suffer from numerous practical limitations. *To whom correspondence should be addressed. E-mail: yu_zaiqun@ ices.a-star.edu.sg (Z.Q.Y.); [email protected] (R.B.H.T.). pubs.acs.org/crystal

Published on Web 03/25/2010

SMPT utilizes the conversion relationship of different solid phases (crystals of constituent single components and cocrystals) in slurries.19 When crystals of both constituent single components are in excess with respect to their solubility in a suspension, their cocrystal (if there is any) will form spontaneously. In spite of its efficiency in coformer screening, SMPT may be problematic upon scale-up beyond research studies because of possible incomplete or hindered transformation of undesired solid phases. Being the most widely used purification method in the pharmaceutical industry, cooling crystallization seems to be the best choice for industrial cocrystal production. The same crystallization equipment as conventional cooling crystallization can be used, provided that the more complex design and operational space are well-understood. Sheikh et al. proposed a framework for conceptualization of cocrystallization process development with carbamazepine-nicotinamide (CBZNIC) cocrystal as the model system.18 Gagniere et al. tracked the crystallization pathway of CBZ-NIC cocrystal in ethanol using in situ attenuated total reflectance (ATR) FTIR and showed that the proportion of different solid phases formed could be deduced by performing mass balance.20 In spite of the importance of solubility behavior at different temperatures, data were reported only at 25 °C in these studies. A complete phase diagram at different temperatures is essential to the understanding of cocrystallization operations. Such a phase diagram has two important implications. First, a robust operating region for the production of pure cocrystal can be determined reliably. Solubility data at the initial or final temperature alone are not sufficient to ensure consistent production of pure cocrystal product. Second, supersaturation at various temperatures can be monitored and controlled accurately to obtain quality products.21,22 Calculation of supersaturation demands solubility information at continuous temperatures. One potentially time-consuming part of phase diagram construction is to locate the eutectic points at which two thermodynamically stable solid phases, that is, cocrystal and crystal of either single component, coexist in equilibrium with r 2010 American Chemical Society

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the suspension.5,23 In this study, SMPT will be exploited to locate these eutectic points and solute concentrations will be measured online by ATR-FTIR. Then the solubility data will be fitted using the solubility product of cocrystal and solution complexation constants. After phase diagram construction, two runs of cocrystallization will be conducted and monitored. The model system used for this study is caffeine, glutaric acid, and acetonitrile. Caffeine and glutaric acid can form a 1:1 cocrystal which has two polymorphs,24 with polymorph Form I as the metastable form and polymorph Form II as the stable form.2 Trask et al.2 has demonstrated that Form II exhibits remarkable resistance to hydration in high relative humidity. Form II has been harvested consistently in this study. Theory Nehm et al.25 and Jayasankar et al.19 reported that the solubility of cocrystal can be described by solubility product and complexation constants. In their model, three equilibriums exist in liquid and solid phases: Dissociation of the A-B cocrystal (solid phase) into single components in the liquid phase: KSP

ABS T AL þ BL with KSP ¼ ½A½B

ð1Þ

where subscripts S and L denote solid and liquid phases, respectively. [A] and [B] stand for the molar concentration of components A and B in liquid phase, respectively. KSP is the solubility product of A-B cocrystal in an ideal solution, with the assumption that the activity of solid ABS is equal to 1. First order complex (1:1) formation in liquid phase between two single components K11

AL þ BL T ABL with K11 ¼

½AB KSP

ð2Þ

K11 is the first-order complexation constant. Second-order complex (1:2) formation in the liquid phase K12

ABL þ BL T AB2, L

ð3Þ

½AB2  K11 KSP ½B

ð4Þ

with K12 ¼

K12 is the second-order complexation constant. Note that A in solution exists in three forms, that is, individual molecules of A, complex AB, and complex AB2. Therefore, the total concentration of A, [A]T, can be expressed as ½AT ¼ ½A þ ½AB þ ½AB2 

ð5Þ

Similarly, ½BT ¼ ½B þ ½AB þ 2½AB2 

ð6Þ

The relationship between [A]T and [B]T can be derived as ½AT ¼

KSP ð1 þ 2K11 K12 KSP Þ þ K11 KSP ½BT - K11 KSP

þ

K11 K12 KSP ð½BT - K11 KSP Þ 1 þ 2K11 K12 KSP

ð7Þ

If second-order complexation does not have a measurable effect on the solubility curve, or in other words, K12 is close to

Figure 1. Experimental setup for cocrystallization.

zero, the resulting model equation is ill-conditioned and the estimated parameters will have questionable values with unacceptable large estimated variances.26 In this case, secondorder complexation must be excluded (K12 is forced to be 0) to obtain reasonable modeling results, yielding a simplified expression for [A]T: ½AT ¼

KSP þ K11 KSP ½BT - K11 KSP

ð8Þ

Only [A]T and [B]T can be measured by ATR-FTIR. The values of KSP, K11, and K12 (if applicable) will be obtained by fitting experimental data at each temperature with eqs 7 or 8 as appropriate. Experimental Section Chemicals. Anhydrous caffeine of 99% purity was obtained from Fluka, glutaric acid of 99% purity from Alfa Aesar, HPLC grade acetonitrile from Fisher Chemical. Experimental Setup. The experimental setup is shown schematically in Figure 1. The main vessel was a 1-L flat-bottomed glass crystallizer with an inner diameter of 100 mm. It was fitted with four built-in glass baffles on the inner wall. A marine-type impeller made of stainless steel with a diameter of 42 mm rotating at 400 rpm was used to provide agitation. Temperature in the crystallization was controlled by a heating and cooling circulator (Julabo FP50-HL). Absorbance spectra were collected with a resolution of 4 cm-1 on a Nicolet 4700 spectrophotometer (Nicolet Instrument Co.) equipped with a Dipper-210 ATR immersion probe (Axiom Analytical Inc.). Every spectrum was the average of 64 scans in the range of 600 to 4000 cm-1. Calibration of ATR-FTIR. Calibration of the ATR-FTIR measurements followed the procedure developed by Togkalidou et al.27 A total of 49 calibration runs were conducted. Around 220 g of solvent was used in each run. After appropriate amounts of caffeine and glutaric acid were added to the solvent at room temperature, the suspension was heated to dissolve all solids. Following that, the solution was cooled down at 0.5 °C/min, while FTIR spectra were collected continuously at an interval of 2 min until nucleation took place. Temperature was also recorded along with spectra. Therefore, the spectra in each calibration run spanned undersaturated and supersaturated states of the solution at a constant concentration combination of caffeine and glutaric acid. The concentration range of caffeine for calibration was 0-3.41 mol/kg, and the concentration range of caffeine was 0-0.46 mol/kg. The overall temperature range for calibration was 10-35 °C. In all, 346 spectra were collected at different temperatures. Principal component regression was employed to correlate the concentrations of caffeine and glutaric acid respectively with temperature and the absorbance in the wavenumber range of 800-1800 cm-1. The prediction error for caffeine concentration was less than 210-3 mol/kg

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Figure 2. A generalized solubility curve of 1:1 cocrystal at a certain temperature. [A] and [B] stand for the molar concentration of components A and B, respectively. Concentration SA on the x-axis and concentration SB on the y-axis (open circles) stand for the solubility of component A and B in solvent, respectively. E1 (open square) denotes the eutectic point where the solid-state component B coexists with cocrystal. The concentration of component A at E1 is CA. Likewise, E2 (open square) denotes the eutectic point where solid-state component A coexists with cocrystal. The concentration of component B at E2 is CB. The dashed line bisects the coordinate system with which lines bc and de are parallel. and for glutaric acid was less than 10-2 mol/kg. Such accuracy is sufficient for engineering purposes. Solubility Measurement of Single Components in Acetonitrile. Excess solid caffeine or glutaric acid was added to acetonitrile at a constant controlled temperature. The concentration was measured every 5 min by ATR-FTIR. It was found that after 11/2 h, the concentration readings did not change significantly anymore. The readings taken in the next 1/2 h were averaged as the solubility at this temperature. Locating Eutectic Points by SMPT and Solubility Measurement of Cocrystal. A generalized solubility curve of a 1:1 cocrystal at a certain temperature is shown in Figure 2. The x-axis refers to the equilibrium concentration of component A and y-axis to component B. SA on the x-axis and SB on the y-axis denote the solubility of pure components A and B, respectively. E2 and E1 are the eutectic points on the solubility curve of cocrystal with the concentration of component A at E1 equal to CA and the concentration of component B at E2 equal to CB. The dashed line bisects the coordinate system. Suppose we start from point a on the solubility curve. If excess B is added, the system state moves to point b. Nucleation of cocrystal may occur spontaneously or growth of cocrystal can be initiated by seeding in this zone. The system state then moves along a pathway parallel to the bisecting line according to the stoichiometric consumption of the two molecular species. Eventually, cocrystallization stops when the system reaches point c on the solubility curve. If more solid B is added, the system state moves to point d and then to point e on the solubility curve due to cocrystallization. If sufficient solid B is put in, the system state will eventually move to the eutectic point E1 wherein solid B and A-B cocrystal coexist in the suspension and both are in equilibrium with the liquid phase. Likewise, eutectic point E2 can be located by successively adding in excess solid A. The process will be monitored by ATR-FTIR to ascertain the eutectic points. Between successive additions of solids A or B, the suspension is allowed to stand for a period of 40 min which was found to be sufficient for the system to reach new equilibrium (stable measurement readings). The measurements in the last 20 min were averaged as the equilibrium concentration. Powder X-ray Diffraction (PXRD). The PXRD patterns of raw materials and cocrystal products harvested in this study were collected using a D8 Advance powder X-ray diffractometer (Bruker AXS GmbH, Germany), with Cu KR radiation (λ = 1.54056 A˚). The voltage and current applied were 35 kV and 40 mA, respectively. The samples were scanned within a range of 2-50° 2θ at a scan rate of 2°/min. The sample was deemed as pure cocrystal if the characteristic peaks of caffeine and glutaric disappeared in its diffraction pattern. Tiwari et al.28 has shown that the limit of detection of PXRD can be as high as 0.4% for polymorphic mixtures after calibration.

Yu et al.

Figure 3. Concentration profiles of caffeine and glutaric acid in cocrystal solubility measurements at 30 °C. Left y-axis is for glutaric acid and the right y-axis is for caffeine. Note that at time 1 glutaric acid was added, followed by consecutive additions of caffeine solids (marked by dashed lines). The dashed line numbered as 2 signifies that the eutectic point for caffeine/cocrystal has been reached. It was followed by consecutive additions of glutaric acid solids (marked by dot-dash lines). The line numbered as 3 signifies that the eutectic point for glutaric acid/cocrystal has been reached.

Results and Discussion Typical Concentration Profiles. Shown in Figure 3 is a typical concentration profile of caffeine and glutaric acid recorded by ATR-FTIR during solubility measurement of cocrystal at 30 °C. The left y-axis is for glutaric acid and the right y-axis is for caffeine. At the start, a given amount of solid glutaric acid was added to acetonitrile and dissolved completely. Then an excess amount of solid caffeine was added to the stirred solution and partially dissolved. As an additional amount of glutaric acid was introduced into the suspension at time 1 and began dissolving, the excess solid caffeine started to dissolve and its concentration increased. The suspension was supersaturated with respect to cocrystal, and cocrystallization occurred shortly as indicated by the simultaneous decrease in the concentration of both caffeine and glutaric acid. As more solid caffeine was successively added to the suspension (marked by dashed lines), the caffeine concentration underwent gradual increase, while glutaric acid concentration went down monotonously until time 2. The concentration of both components did not change any more with the addition of solid caffeine from then on, which signified that the eutectic point for caffeine/cocrystal was reached. After that, appropriate amounts of solid glutaric acid were added successively as marked by dot-dash lines in Figure 3. It can be seen that the caffeine concentration continually changed with higher glutaric acid concentration until time 3 when the eutectic point for glutaric acid/cocrystal was approached. Phase Diagram. The phase diagram at different temperatures is presented in Figure 4. Notice that different scales are adopted for the x and y axis to make variations in caffeine concentration more visible. Equilibrium concentrations at each temperature are joined together by a dotted line. The solubility data of pure caffeine and pure glutaric acid lie on the y-axis and x-axis, respectively. Their solubility data are also shown in Table 1 for reference. It has been found in this study that the HPLC method agrees well with the ATRFTIR method in the solubility measurement of caffeine, which verifies the reliability of the ATR-FTIR method.20 Eutectic points for caffeine/cocrystal and for glutaric acid/ cocrystal at different temperatures are linked together by two

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red bold lines, which mark the two boundaries of the stability zone of the caffeine-glutaric acid cocrystal. On its left is the stability zone for caffeine and on its right is that for glutaric acid. Fitting of Cocrystal Solubility Data. Before fitting solubility curves, it is necessary to assess the extent of second-order complexation, that is, the value of K12. Nehm et al.25 have demonstrated that the solubility of the A-B cocrystal decreases with increasing concentration of B first and then increases with a further increase in the concentration of B if K12 is significantly larger than zero. On the other hand, if K12 is close to zero, the solubility of cocrystal A-B decreases monotonously and levels off with increasing concentration of B. On the basis of the observed trends in measured solubility data in Figure 4, eq 7 was used to fit data at 25, 30, and 35 °C, while eq 8 was used to fit data at 10, 15, and 20 °C. Regression tools in Excel and SigmaPlot were used to fit the solubility data at each temperature according to eq 7 and the blue solid lines in Figure 4 represent the best fit curves. The parameter estimation is summarized in Table 2. It can be seen that the fitting curves agree well with the measured data, as also evidenced by the high values of coefficients of determination R2 in Table 2. The overall

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fit for eq 8 (at 10, 15, and 20 °C) is slightly poorer than eq 7 (at 25, 30, and 35 °C), due to the exclusion of one of the three parameters. The solubility model and its parameter estimates can be exploited to interpolate the solubility of cocrystal at any temperatures between 10 and 35 °C in future studies on process optimization and control of cocrystallization. Operating Region of Cocrystallization. With a complete phase diagram in hand, the operating region for cocrystal production can be delineated by considering the stoichiometry of the cocrystal system, and the stability zones at the initial and final temperatures for cooling crystallization. A relatively narrow operating region is obtained if the initial and final temperatures are set at 35 and 10 °C, respectively, as shown in Figure 5. The shaded operating region is sandwiched between the left boundary of the stability zone of cocrystal and the green straight line whose slope corresponds to the stoichiometry of the caffeine-glutaric acid cocrystal. The green straight line passes through the eutectic point for glutaric acid/cocrystal at 10 °C and represents a critical operating line for cooling cocrystallization of caffeineglutaric acid. The composition of starting solutions must be within this narrow region to obtain pure cocrystal. It should be noted that merely relying on solubility data at the final temperature is not sufficient to chart a “safe” operating region. To illustrate how the full phase diagram as shown in Figure 5 can be used to design cocrystallization processes, two crystallization runs were performed. One is labeled by “þ” operating within the shaded operating region (Run 1) and the other by “” running outside the shaded operating region (Run 2). Both starting solutions were saturated at

Figure 4. Phase diagram of the caffeine-glutaric acid-acetonitrile system at different temperatures. Note that different scales are adopted by x-axis and y-axis. Equilibrium concentrations of caffeine and glutaric acid at different temperatures are marked by different legends. Data at each temperature are joined together by a dotted line for easy reference. Solubility of cocrystal at 25, 30, and 35 °C is fitted with eq 7 (blue solid lines). Solubility of cocrystal at 10, 15, and 20 °C is fitted with eq 8 (blue solid lines). Eutectic points for caffeine/cocrystal and for glutaric acid/cocrystal at different temperatures are connected by two bold red lines. Table 1. Solubilities of Pure Caffeine and Pure Glutaric Acid in Acetonitrile Measured by ATR-FTIRa temperature, °C

35

30

25

20

15

10

caffeine, mol/kg 0.2075 0.1789 0.1535 0.1318 0.1142 0.09841 glutaric acid, mol/kg 2.2311 1.5570 1.1068 0.8040 0.5881 0.4539 a Note: the prediction error of ATR-FTIR measurements for caffeine was less than 2  10-3 mol/kg and for glutaric acid was less than 10-2 mol/kg.

Figure 5. The operating region (shaded) of cocrystallization between 35 and 10 °C. Solubility data at 20 °C are also presented. The operating region is sandwiched between the left boundary of the stability zone of cocrystal and the green straight line. The green straight line passes through the eutectic point for glutaric acid/ cocrystal at 10 °C with a slope corresponding to the stoichiometry of the caffeine-glutaric acid cocrystal. The trajectories of two crystallization runs are also shown. The starting position of the two runs is marked by a filled square respectively. Run 1 falls in the operating region, while Run 2 stays outside the operating region.

Table 2. Parameter Estimation for eqs 7 and 8 temperature, °C

KSP, (mol/kg)2

K11, (mol/kg)-1

K12, (mol/kg)-1

R2 , -

model

35 30 25 20 15 10

0.0838 ( 0.0061 0.0571 ( 0.0019 0.0315 ( 0.0028 0.0147 ( 0.003 0.0132 ( 0.002 0.0158 ( 0.001

1.53 ( 0.26 1.42 ( 0.13 2.22 ( 0.51 5.10 ( 1.3 3.47 ( 1.0 0.384 ( 0.30

0.693 ( 0.11 0.851 ( 0.083 0.624 ( 0.19

0.993 0.999 0.998 0.927 0.952 0.990

eq 7 eq 7 eq 7 eq 8 eq 8 eq 8

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35 °C but with different compositions (marked by filled squares). They were cooled down to 34 °C quickly, and cocrystal seeds were added to avoid uncontrolled nucleation. After a few minutes, the suspensions were cooled further down to 10 at 0.2 °C/min and changes in concentration were recorded by ATR-FTIR. It can be seen that the path of Run 1 is parallel to the green straight line throughout the operation, indicating the stoichiometric consumption of caffeine and glutaric acid concentrations and thus the production of phase pure cocrystal. The path of Run 2 was also parallel with the green straight line in the beginning. After briefly breaching the right boundary of the stability zone of cocrystal, it deviated sharply to rejoin the stability zone boundary for glutaric acid. Initially, the solution of Run 2 was supersaturated with respect to cocrystal only, resulting in the generation of pure cocrystal. After breaching the stability zone boundary, the solution became supersaturated with respect to glutaric acid. As a result of supersaturation buildup, nucleation of glutaric acid took place and then the growth of pure glutaric acid crystals commenced. The growth of cocrystal continued at the same time with further cooling. Since there were excess glutaric acid and cocrystal solids in the suspension, the system was close to triple equilibrium which included three phases, that is, two solid phases and one liquid phase. Gagniere and co-workers20 observed a similar path deflection in the phase diagram with the cabamazapinenicotinamide-ethanol system.

Figure 6. The concentration profiles of caffeine and glutaric acid in Run 2 along with temperature profile.

Yu et al.

Some interesting features can be observed in the concentration profiles of caffeine and glutaric acid in Figure 6 for Run 2. The concentration profiles correspond to the path marked by the “” symbol in Figure 5. At time t1 in Figure 6, the operating path breached the boundary, and it rejoined the boundary at time t2. After t1, cocrystal growth, as indicated by a parallel decrease in the concentrations of caffeine and glutaric acid, persisted until a sharp drop in glutaric acid concentration occurred. It can be seen that there was no obvious dissolution of cocrystal between t1 and t2 because the increase in caffeine concentration was marginal. Upon reaching the boundary at time t1, further cooling rendered the liquid phase supersaturated with respect to both cocrystal and glutaric acid. Therefore, glutaric acid molecules were expected to come out of liquid phase as pure glutaric acid crystals so that the path could turn and trace the boundary of the stability zone. However, crystallization of pure glutaric acid could not happen until its supersaturation was built up to such a level as to induce primary nucleation. Consequently, the boundary was breached and the composition of liquid phase quickly rejoined the boundary through nucleation and growth of glutaric acid. To determine the composition of solid phases from Runs 1 and 2, PXRD analysis was conducted. Simulated PXRD pattern of Form II of caffeine-glutaric acid cocrystal by software Mercury 2.3 is shown in Figure 7a. The crystal structure data (CSD refcode EXUQUJ) acquired by Trask et al.24 was adopted for the calculation. The measured PXRD patterns of the products from these two runs are shown in Figure 7b,c, respectively, along with those of caffeine (d) and glutaric acid (e). It can be seen that Figure 7b has all the major characteristic peaks present in Figure 7a except that the simulated pattern exhibits a noticeable peak shift at high 2θ values. Trask et al.24 have observed a similar peak shift for caffeineglutaric acid cocrystal and explained that it was a result of crystal lattice contraction at the low temperature used for single crystal X-ray diffraction (XRD) data collection. The presence of characteristic peaks confirms that cocrystal of Form II was obtained from Run 1. At the same time, the characteristic peaks of glutaric acid in Figure 7d and those of caffeine in Figure 7e are not visible in Figure 7b, indicating that the product from Run 1 is free from the contamination

Figure 7. PXRD patterns of (a) simulated pattern of caffeine-glutaric acid cocrystal of Form II from Mercury 2.3, (b) product from Run 1, (c) product from Run 2, (d) glutaric acid, and (e) caffeine.

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by caffeine and glutaric acid within the detection limit of PXRD. On the contrary, characteristic peaks of glutaric acid appear in Figure 7c apart from those of caffeine-glutaric acid cocrystal of Form II, and two of them are circled. It can be deduced that the product from Run 2 was a mixture of cocrystal and glutaric acid, as expected. With the understanding based on the complete phase diagram obtained so far, more research can be done on the optimization and control of cocrystallization processes, for example, manipulation of particle size, polymorph, and rectification of cocrystal purity when the crystallization path goes stray.

(9) (10) (11) (12)

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Conclusion A complete temperature-dependent solute-solute-solvent phase diagram of the caffeine-glutaric acid-acetonitrile system in the temperature range of 10-35 °C has been obtained using ATR-FTIR. The eutectic points in the phase diagram have been located through SMPT. The operating region of cooling cocrystallization has been prescribed according to the stoichiometry of cocrystal, and the stability zone of cocrystal at the initial and final temperatures. Operation outside the prescribed operating region has been shown to result in the production of impure cocrystals. The solubility data of cocrystal at different temperatures can be fitted well in a simple model based on solubility product of cocrystal and complexation constants. The solubility model and parameter estimates can be exploited for supersaturation calculation in real-time control of cocrystallization as a useful extension of this study. Acknowledgment. The authors wish to thank two colleagues, Ang Wei Han and Annie Wong, for their technical support in the research.

References (1) Schultheiss, N.; Newman, A. Pharmaceutical cocrystals and their physicochemical properties. Cryst. Growth Des. 2009, 9, 2950– 2967. (2) Trask, A. V.; Motherwell, W. D. S.; Jones, W. Pharmaceutical cocrystallization: Engineering a remedy for caffeine hydration. Cryst. Growth Des. 2005, 5, 1013–1021. (3) Chieng, N.; Hubert, M.; Saville, D.; Rades, T.; Aaltonen, J. Formation kinetics and stability of carbamazepine-nicotinamide cocrystals prepared by mechanical activation. Cryst. Growth Des. 2009, 9, 2377–2386. (4) Trask, A. V.; Motherwell, W. D. S.; Jones, W. Physical stability enhancement of theophylline via cocrystallization. Int. J. Pharm. 2006, 320, 114–123. (5) Childs, S. L.; Rodriguez-Hornedo, N.; Reddy, L. S.; Jayasankar, A.; Maheshwari, C.; McCausland, L.; Shipplett, R.; Stahly, B. C. Screening strategies based on solubility and solution composition generate pharmaceutically acceptable cocrystals of carbamazepine. CrystEngComm 2008, 10, 856–864. (6) Rodriguez-Hornedo, N.; Nehru, S. J.; Seefeldt, K. F.; PaganTorres, Y.; Falkiewicz, C. J. Reaction crystallization of pharmaceutical molecular complexes. Mol. Pharmaceutics 2006, 3, 362– 367. (7) Zhang, G. G. Z.; Henry, R. F.; Borchardt, T. B.; Lou, X. C. Efficient co-crystal screening using solution-mediated phase transformation. J. Pharm. Sci. 2007, 96, 990–995. (8) Bucar, D. K.; Henry, R. F.; Lou, X. C.; Duerst, R. W.; MacGillivray, L. R.; Zhang, G. G. Z. Cocrystals of caffeine and hydroxybenzoic acids composed of multiple supramolecular

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