Thermodynamics and Crystallization of the TheophyllineâGlutaric

Article pubs.acs.org/crystal

Thermodynamics and Crystallization of the Theophylline−Glutaric Acid Cocrystal Published as part of the Crystal Growth and Design virtual special issue of selected papers presented at the 10th International Workshop on the Crystal Growth of Organic Materials (CGOM10) Shuo Zhang† and Åke C. Rasmuson*,†,‡ †

Department of Chemical Engineering and Technology, Royal Institute of Technology (KTH), SE-100 44 Stockholm, Sweden Department of Chemical and Environmental Science, Materials and Surface Science Institute, Solid State Pharmaceutical Cluster, University of Limerick, Limerick, Ireland

‡

ABSTRACT: This work investigates the thermodynamics and crystallization of the theophylline−glutaric acid 1:1 cocrystal. It is found that the cocrystal physically decomposes at 120 °C (i.e., in the range between the melting points of the two pure compounds). The solubility of the cocrystal and pure compounds has been determined in chloroform and acetonitrile. In chloroform, the theophylline concentration of the saturated solution over the cocrystal is clearly higher than that in the saturated solution over pure theophylline I/II, while for glutaric acid the situation is the opposite. With the solubility data, the Gibbs free energy of the formation of the cocrystal from solid theophylline II and solid β-glutaric acid at 30 °C can be estimated to −0.39 kJ mol−1. The work reveals that polymorphism in the pure components of a cocrystal can dramatically influence the phase diagram and shift an incongruently dissolving case into a kinetically stabilized congruent case. In chloroform, the cocrystal dissolves incongruently with respect to the stable form I of theophylline but congruently with respect to the metastable theophylline II. However, the cocrystal is stable in a stoichiometric solution for more than 2 weeks. Given sufficient time, the system should transform into a solid phase being a mixture of cocrystal and stable theophylline I, in equilibrium with a solution that has the composition of the corresponding invariant point. In acetonitrile, where the glutaric acid solubility is much higher than that of theophylline II, the cocrystal dissolves, clearly incongruently. The region where the cocrystal is the only solid stable phase is clearly shifted toward the glutaric acid side and is fairly narrow. In both solvents the cocrystal can readily be produced by isothermal slurry conversion crystallization to a reasonable level of productivity, as long as the process is operated in a region of the phase diagram where the cocrystal is the only stable (or reasonably metastable) solid phase.

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the cocrystal.10 The cocrystal may dissolve congruently in one solvent but incongruently in another.10 The stability zone can also be altered if the solubility of one of the components is changed by other means (e.g., by micellar solubilization or ionization).11 Attempts have been made to model the phase diagram.12 The phase diagram provides the basis for the design of processes for manufacturing of cocrystals. The desired crystallization conditions can be generated by cooling the mixture, and supersaturation feedback control may be used to help crystallize the desired polymorph.13−15,25 Alternatively, the process can start from a nonstoichiometric solution to which is added one of the cocrystal components as a solid phase.15,16 In either process, the product can become a mixture of cocrystal with one cocrystal component if the kinetic pathway falls out of the cocrystal region. The cocrystal can also be prepared by slurry conversion crystallization, where both components are added as pure solid phase to a solution of suitable composition and under agitation transforms into the cocrystal.22 In this

INTRODUCTION Cocrystallization has become an important research area in the recent years for the great potential of fine-tuning the physical properties of the active pharmaceutical ingredient (API) as well as the ability of API separation.1 The ternary phase diagrams of a cocrystal system contains important information about the system behavior required for selection of a coformer for tailoring of product properties and for design of a crystallization process for manufacturing. Most phase diagrams reported so far describe cocrystal systems in which the cocrystal is dissolving congruently (i.e., the cocrystal can establish equilibrium with a solution of stoichiometric composition).2−4 However, there are systems described where the cocrystal dissolved incongruently (i.e., during the dissolution of the cocrystal another solid phase forms and the solution is no longer stoichiometric).5,6 In some cases, there could be several cocrystals of different compositions or polymorphs of one cocrystal in one cocrystal system (e.g., a 2A−B cocrystal and an A−B cocrystal) and each cocrystal has its own stability region in the phase diagram.2,7−9 In addition, the solvent does not only change the overall solubility of the cocrystal but may also change the overall appearance of the phase diagram and thus the stability zone of © XXXX American Chemical Society

Received: October 11, 2012 Revised: December 19, 2012

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dx.doi.org/10.1021/cg3014859 | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

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carried out on a UV-2550/SHIMADZU and a Cary 300 Bio UV−vis/ Varian. Preparation of Cocrystal. The very first batch of cocrystal was prepared by grinding stoichiometric amounts of solid theophylline II and β-glutaric acid without liquid assistance by hand for 30 min. Larger quantities of cocrystal materials were prepared by cooling crystallization of an unseeded chloroform solution of a concentration of 0.07 mol/L for both compounds, from 50 to 5 °C at a constant cooling rate of 0.75 °C min−1. Isothermal slurry conversion crystallization was also used for cocrystal manufacture. Solvent Selection. A strategy of the work was to investigate the behavior of the cocrystal system in different solvents, significantly altering the appearance of the phase diagram. Rough solvent screening experiments were carried out on the basis that if the pure components have about equal solubility in the solvent, we expect to find a symmetric diagram where the cocrystal dissolves congruently. If one of the components has a much higher solubility, we expect the phase diagram to be shifted toward that corner such that the cocrystal dissolves incongruently with the low solubility compound invariant lying on the high solubility side of the stoichiometric line. The experiments were performed as follows: 0.2 g β-glutaric acid or theophylline II was added to the test tube. Then, the solvent was added slowly drop by drop as the test tube was shaken, until the solid phase dissolved completely. The maximum volume of the added solvent was 10 mL. The volume of the solvent added was recorded, and the solubility of the β-glutaric acid or theophylline II in the solvent was estimated. The solvents used in this experiment were acetone, 1propanol, methanol, toluene, cyclohexane, and acetonitrile. On the basis of the outcome, chloroform and acetonitrile were selected for further work. Solubility Measurement and Phase Diagram Determination. The solubility of pure theophylline II, β-glutaric acid, and the cocrystal in chloroform were measured from 20 to 50 °C by the gravimetric method described previously.22 Further points in the ternary phase diagram of theophylline/glutaric acid/solvent were determined by finding the solution composition in nonstoichiometric slurries and the corresponding solid phases. The cocrystal together with one of the cocrystal components was added into chloroform or acetonitrile to form slurries. The slurry was agitated by magnetic stir bars at 400 rpm for at least 12 h to reach equilibrium at 30 °C. Then, the slurry was filtered, and the solid material was examined by XRD or DSC. Determining the invariant points E1 and E2 is of key importance. In accordance with the Gibbs phase rule, in both congruent and incongruent cases, if the solid phase is either pure A or B, the solution composition has to be on the curve A-E1 or E2-B, respectively (Figure 2). If the solid phase is the pure cocrystal, the solution composition has to be on the curve E1-C/I-E2. If the solid phase is the mixture of the cocrystal together with either A or B, the solution composition must represent the invariant point E1 or E2, respectively. The saturated solution filtered out from the slurry was diluted by the pure solvent and examined by UV−vis. For the diluted solution, the maximum UV absorbance around 270 nm caused by theophylline was linearly proportional to the theophylline concentration. Thus, the amount of theophylline in the solution was determined from a calibration line. The absorbance peak of glutaric acid overlapped with that of the solvent. Therefore, the concentration of glutaric acid was calculated from the total amount of the solute in the solution, determined by the gravimetric method and the spectoscopically determined theophylline concentration. Isothermal Slurry Conversion Crystallization. Guided by the determined ternary phase diagram, isothermal slurry conversion crystallizations have been carried out in chloroform and in acetonitrile at 30 °C. In these experiments, solid material of the pure components is added to a solution. The pure material dissolves and the cocrystal crystallizes in a slurry conversion process. A number of experiments have been carried out in 100 mL scale in 250 mL glass bottles, agitated by magnetic stir bars at 400 rpm, along three different lines. Crystallization 1: stoichiometric amounts of theophylline II (9 g) and β-glutaric acid (6.6 g) were added into ca. 100 mL chloroform. This crystallization was carried out along the green line in Figure 2a.

work, the theophylline−glutaric acid cocrystal was selected as a model system to investigate not only the ternary phase diagram but also the crystallization (see Figure 1 for structures).

Figure 1. Chemical structure of theophylline and glutaric acid.

Theophylline is an FDA-approved API for asthma treatment, which forms cocrystals with oxalic acid, maleic acid, glutaric acid, phthalic acid, etc.17,18 So far, three polymorphs of theophylline have been reported with determined crystal structures.19−21 The commonly used polymorph (theophylline II), which is commercially available, is metastable at room temperature but stable at higher temperatures.22 The stable form at room temperature, theophylline I, is enantiotropically related to theophylline II.22 Glutaric acid is a commonly used cocrystal coformer (CCF); it can form cocrystals with several APIs. It is also an FDA-approved compound.8,12,13,23−30 There are five records of glutaric acid in the Cambridge Structure Database (CSD). The records with code GLURAC, GLURAC03, and GLURAC04 describe the β-polymorph. GLURAC02 is also regarded as β-polymorph because of the similarity of the unit cell information with the other beta-polymorph structures. GLURAC01 is the alpha-polymorph. The betapolymorph is stable at room temperature, while the alphapolymorph is stable at high temperature.31 The transition temperature is at 70−80 °C. In this work, the physical properties of the cocrystal and the cocrystal components are characterized and compared. The ternary phase diagram is determined in chloroform and in acetonitrile, and crystallizations are carried out. To our knowledge, we are able to report for the first time a system that is thermodynamically incongruent but for sufficient time behaves as congruent as a result of polymorphism in one of the cocrystal components. This work further shows that the solvent can have a dramatic influence on the phase diagram of a particular cocrystal. However, it is also shown that the cocrystal can be readily produced whether or not the phase diagram is congruent or incongruent.

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EXPERIMENTAL WORK

Materials. Theophylline (anhydrous, >99%) (Form II) and glutaric acid (99%) were purchased from Sigma-Aldrich. Chloroform (for HPLC, >99.9%) and acetonitrile (>99.8%) were purchased from VWR/Merck. All the chemicals except glutaric acid were used as received. The color of the purchased glutaric acid is not white but green, probably because of impurities. Thus, the glutaric acid was recrystallized in acetonitrile and examined by X-ray diffraction (XRD) for polymorph determination before usage. Equipment. A METTLER AE 240 was used for weighing. Crystallization experiments were carried out in 250 mL glass bottles with magnetic stir bars. Differential scanning calorimetry (DSC) data was collected by a TA Instruments DSC2920 using a 5 °C min−1 ramp rate from room temperature to 300 °C. Hot-stage microscope images were captured using a 1 °C min−1 ramp by a Mettler FP82 and an OLYMPUS BH-2. X-ray diffraction powder patterns were determined by a PANalytical XPert Pro powder diffractormeter with Cu Kα radiation. Crystal images were captured by a scanning electron microscopy (SEM) using a Hitachi SU-70. UV−vis spectroscopy was B



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RESULTS AND DISCUSSION Solid Phase Characterization. The glutaric acid recrystallized from acetonitrile in this work was always the βpolymorph. The theophylline used in this work includes two polymorphs with known structures: the stable form (theophylline I, CSD reference code BAPLOT02) and a metastable form (theophylline II, CSD reference code BAPLOT01). The latter is the form of the purchased material. The XRD result shows that the cocrystal obtained is the 1:1 theophylline−glutaric acid cocrystal and corresponds to the CSD reference code XEJXIU. Figure 3 shows the experimental

Figure 3. Experimental and calculated powder XRD pattern of the 1:1 theophylline−glutaric acid cocrystal.

XRD pattern and the one calculated by Mercury, using the crystal structure data. Figure 4 shows the crystal structure from two different angles obtained using Mercury. Similar to the theophylline−oxalic acid cocrystal, the hydrogen bonding Figure 2. Schematic ternary phase diagram of theophylline/glutaric acid/solvent. The green line is the operation line of cocrystallization used in the slurry conversion experiments of this work.

The solid phase was sampled every 15 min and examined by XRD or DSC. After 5 h, this frequent sampling was terminated. The slurry was kept agitated and thermostatted for 2 additional weeks and then analyzed by XRD and DSC again. Crystallization 2: certain amounts of theophylline II and β-glutaric acid were dissolved into 100 mL chloroform to prepare a solution with composition on the curve E1-E2 of Figure 2a, near the invariant point E1, where the concentration of theophylline is higher than that of glutaric acid. Then, stoichiometric amounts of pure solid cocrystal components were added to form the slurry for cocrystallization. After 1.5 h, the slurry was sampled and the separated solid phase was examined by XRD and DSC. Crystallization 3: certain amounts of theophylline II and β-glutaric acid were added into 100 mL acetonitrile to prepare a solution with a composition corresponding to point I on the curve E1-E2 of Figure 2b. Then, stoichiometric amounts of the pure components, 9 g theophylline II and 6.6 g β-glutaric acid, were added into the solution to form a slurry. The solid phase in the slurry was sampled every 15 min and examined by XRD or DSC. Five hours later, the slurry was filtered (the first batch). The solution collected from the filtration, approximately 80 mL, was used for a second slurry conversion experiment (the second batch). Eighteen grams (0.1 mol) of solid theophylline II and 13.2 g (0.1 mol) of solid β-glutaric acid were added into the solution and agitated for several hours. The solid phase in the slurry was sampled from time to time and examined by XRD or DSC. The slurry conversion process was carried out through the green line in Figure 2b.

Figure 4. The crystal structure of 1:1 theophylline−glutaric acid cocrystal. C



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although strongly agglomerated. At 120 °C, cocrystal agglomerates are opaque, indicating a destruction of the original crystal structure. At 150 °C, crystals are encapsulated in liquid droplets. In the following pictures we focus on the upper left corner on a large droplet. At 175 °C, the vision switches to the upper left for the large liquid droplets. The microscopy magnification remains the same. The crystals in the droplets are transparent and larger than they were at 150 °C. At higher temperatures, the crystals gradually dissolve. With a knowledge of the melting temperatures of glutaric acid and theophylline, it can be suggested that at 120 °C, the cocrystal decomposes into a glutaric acid melt in which theophylline crystals are formed. As the temperature rises, the theophylline crystals gradually dissolve in the melt. Solubility and Ternary Phase Diagram. An asymmetric ternary phase diagram describing an incongruent cocrystal system requires a large solubility difference between the two cocrystal components, even though a too large solubility difference may result where the cocrystal region disappears completely.12 In the solvent selection experiment, the results show that β-glutaric acid has a comparatively high solubility (higher than 200 g L−1) in acetone, 1-propanol, and methanol, a very low solubility in toluene and cyclohexane, and a medium solubility in acetonitrile. Compared with glutaric acid, theophylline has a relatively low solubility in all these solvents. Thus, acetonitrile is selected for investigation of an asymmetric phase diagram to be compared with the rather symmetric one in chloroform. The solubility of theophylline II, β-glutaric acid, and the cocrystal in chloroform from 20 to 50 °C is shown in Table 1. As can be deduced from our previous analysis,22 the Gibbs free energy of the formation of the cocrystal from the pure solid components can be calculated by:

between theophylline and glutaric acid is formed between the basic N atom of theophylline and the hydroxyl H of glutaric acid, and two theophylline molecules also form a hydrogenbonded dimer in a cyclic motif. However, unlike the 2:1 theophylline−oxalic acid cocrystal in which both hydroxyl Hs of oxalic acid are connected to a theophylline, in this 1:1 cocrystal, only one of the hydroxyl Hs of glutaric acid is connected to theophylline, while the other one is connected to another glutaric acid molecule. An SEM image of the cocrystal obtained from an isothermal slurry conversion crystallization in chloroform is shown in Figure 5. Most of the particles are rounded, but a few of them have a more clear hexagonal shape.

Figure 5. Theophylline−glutaric acid cocrystals obtained by isothermal slurry conversion crystallization in chloroform.

Figure 6 shows the DSC curves of theophylline II, β-glutaric acid, and the cocrystal. The melting point of theophylline is at

ΔG 0form = −RT ln

aliqA, +aliqB, + aliqAaliqB

(1)

B,+ Here aA,+ liq and aliq are the activity of solute in the solution when the solution is in equilibrium with the pure cocrystal components respectively, while aAliq and aBliq are the activity of the cocrystal components in the solution when in equilibrium with the pure cocrystal. Neglecting the differences in the activity coefficients for each component and approximating activities by mol L−1 concentrations, the free energy of cocrystal formation from the metastable theophylline II and β-glutaric acid receives a value of −0.39 kJ mol−1 at 30 °C. Accordingly, this formation of the cocrystal should be a spontaneous process. In case of formation from the stable theophylline I and βglutaric acid, ΔG0form receives the value of −0.061 kJ mol−1. The solubility data of Table 1 in the unit of mole solute per liter solvent are plotted in Figure 8. The theophylline concentration of the saturated solution over the cocrystal is clearly higher than that in the saturated solution over pure theophylline II, while for glutaric acid the concentration in the saturated solution over the cocrystal is clearly lower than that over the pure β-glutaric acid. In Table 2 is listed the solution mole fraction composition of solutions in equilibrium with various solid phases in chloroform at 30 °C. The corresponding ternary phase diagram is plotted in Figure 9 a. As can be read from the table and is illustrated in this figure, the invariant point between theophylline and the cocrystal is dramatically influenced by the nature of the theophylline polymorph. When the solid phase in the slurry is a

Figure 6. DSC graphs of theophylline II, β-glutaric acid, and the cocrystal.

274 °C. There are two endothermic peaks in the curve for pure glutaric acid, the first and shallower one at 74 °C is the transition peak of β-glutaric acid to α-glutaric acid, and the second and deeper one at 97 °C is the melting peak of αglutaric acid.32 The endothermic peak at 120 °C in the cocrystal curve indicates a decomposition of the cocrystal. Figure 7 shows the hot stage microscope images of the cocrystal sample. At 113 °C, the cocrystals are translucent, D



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Figure 7. Hot stage microscopy images upon heating the cocrystal from 100 to 215 °C. From 175 °C, the view is moved toward the upper left corner (highlighted), however, with the same magnification.

Table 1. Solubility of Theophylline II, β-Glutaric Acid, and the Cocrystal in Chloroform g solute/kg solvent (standard deviation/number of sample) temperature (°C) 20.00 25.00 30.00 35.00 40.00 45.00 50.00

theophylline II 5.21 5.40 5.47 5.71 5.88 6.13 6.24

[0.14/4] [0.16/4] [0.24/4] [0.08/4] [0.08/4] [0.16/4] [0.04/4]

glutaric acid 5.43 8.32 11.58 19.07 23.33 36.26 49.14

[0.19/4] [0.30/4] [0.80/4] [0.21/4] [0.03/3] [0.43/4] [0.42/2]

mol/L

theophylline−glutaric acid in equilibrium with cocrystala 10.38 11.57 14.44 15.77 17.85 21.76 26.79

[0.29/4] [0.27/4] [0.18/4] [0.27/4] [0.41/4] [0.39/4] [0.08/4]

theophylline II

glutaric acid

theophylline−glutaric acid in equilibrium with cocrystalb

0.0429 0.0444 0.0449 0.0470 0.0484 0.0505 0.0514

0.0610 0.0933 0.1299 0.2140 0.2619 0.4070 0.5516

0.0493 0.0550 0.0686 0.0749 0.0847 0.1033 0.1272

a

The numbers represent the total mass of glutaric acid and theophylline in a stoichiometric solution in equilibrium with the cocrystal. bThe numbers represent mol/L of each of glutaric acid and theophylline in a stoichiometric solution in equilibrium with the cocrystal.

mixture of theophylline II and the cocrystal at the “equilibrium” state, the composition of the saturated invariant solution is given by the green triangle point (E1′), and the phase diagram of theophylline II/glutaric acid/chloroform describes a congruently dissolving cocrystal. When the solid phase in the slurry is a mixture of theophylline I and the cocrystal, the invariant point moves to E1, given by the blue upside down triangle. Accordingly, the phase diagram of theophylline I/

glutaric acid/chloroform describes an incongruently dissolving cocrystal. Figure 9b shows a schematic view of the whole phase diagram. This is confirmed by XRD analyses of the solid phases when the system is at the invariant point. Figure 10a shows the XRD of the solid phase from invariant point E1′ compared with the pure cocrystal XRD spectra and the pure theophylline II XRD spectra, the latter two being calculated spectra from the single crystal structural data using Mercury. The invariant E



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Figure 8. Solution concentrations in equilibrium with the cocrystal and the pure solids, respectively. Figure 9. (a) Experimental determinations in the ternary phase diagram of theophylline/β-glutaric acid/chloroform. (b) Schematic complete diagram showing the influence of the polymorphism of theophylline. E1′ is a metastable invariant point.

Table 2. Equilibrium Solution Compositions of Various Solid Phases in Chloroform at 30 °C mole fraction composition of solid phases

theophylline

glutaric acid

chloroform

theophylline I theophylline II theophylline II and cocrystala (E1′) theophylline I and cocrystal (E1) cocrystal cocrystal and glutaric acid (E2) pure glutaric acid

0.00317 0.00361 0.00598 0.00359 0.00324 0.00584 0

0 0 0.00311 0.00620 0.00324 0.02435 0.01036

0.99683 0.99639 0.99091 0.99021 0.99351 0.96981 0.98964

a

dramatic. Rigorously speaking, the phase diagram in chloroform shows an incongruently dissolving cocrystal, but because of the nucleation barrier for appearance of the theophylline I, the system can remain in a metastable state for sufficient time for the pure cocrystal solubility to be determined and produced in the slurry crystallization experiments described below. In acetonitrile, the solubility of both components is lower. The glutaric acid solubility is reduced to half of its value in chloroform, and the theophylline solubility is reduced to 15%. Hence, the ratio of the mole fraction solubility of glutaric acid:theophylline changes from 2.9 in chloroform to 10 in acetonitrile, which leads to a phase diagram in the latter solvent that is clearly incongruent. Equilibrium data for the theophylline/glutaric acid/acetonitrile system are given in Table 3 and are plotted in Figure 11a. Figure 11a shows an incongruently dissolving cocrystal with a narrow stability region. The point marked with E1′ is the theophylline II/cocrystal eutectic, E1 is the theophylline I/cocrystal invariant, and E2 is the β-glutaric acid/cocrystal eutectic. Figure 11b shows a schematic over the whole phase diagram. The XRD spectra in Figure 12 verify the solid phase compositions at the invariant points. In comparison with the phase diagram in Figure 9, the cocrystal region in

Metastable equilibrium.

mixture is a mixture of cocrystal and theophylline form II. Figure 10b shows the comparison for the solid phase at invariant point E1, with the pure cocrystal XRD spectra and the pure theophylline form I spectra, verifying that the solid phase mixture contains a cocrystal and theophylline form I. Figure 10c compares the XRD spectra of the solid phase at invariant point E2 with those of the pure cocrystal and of pure β-glutaric acid and verifies that the invariant point solid phase is a mixture of these two solid phases. The solubility of theophylline I is only 0.68 g/kg lower than that of theophylline II. However, the influence on the general features of the phase diagram is F



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Table 3. Equilibrium Solution Composition of Various Solid Phases in Acetonitrile at 30 °C mole fraction composition of solid phases pure theophylline I pure theophylline II cocrystal and theophylline IIa (E1′) cocrystal and theophylline I (E1) pure cocrystal

cocrystal and glutaric acid pure glutaric acid a

theophylline

glutaric acid

acetonitrile

0.00038 0.00054 0.00113

0 0 0.01367

0.99962 0.99946 0.98520

0.00114 9.02 × 10−04 9.57 × 10−04 9.39 × 10−04 0.00105 0.00134 0.00116 8.10 × 10−04 9.72 × 10−04 0.00101 0.00114 0.00104 0

0.01336 0.01467 0.04865 0.04418 0.05406 0.05492 0.04805 0.01874 0.03009 0.03886 0.05766 0.05665 0.05431

0.98550 0.98443 0.95039 0.95488 0.94489 0.94375 0.95079 0.98045 0.96894 0.96013 0.94120 0.94231 0.94569

Metastable equilibrium.

Isothermal Slurry Conversion Crystallization. In slurry conversion crystallization 1, the XRD results confirmed that the pure cocrystal formed. The DSC result shows that the solid phase converted into a pure cocrystal completely after 15 min of agitation (i.e., even without seeding by cocrystals). The production of the cocrystal is approximately 12 g, according to 120 g/L. The sample taken from the slurry 2 weeks later was confirmed to be pure cocrystal as before. Although the cocrystal only exists in chloroform as a metastable stable phase, this metastable status can exist for at least two weeks. This experiment confirms that the cocrystal can actually be produced if the cocrystallization is operated through the green line of the phase diagram, Figure 2a, when there are stoichiometric amounts of theophylline II and β-glutaric acid in the slurry. Slurry conversion crystallization 2 is similar to crystallization 1 but changes the condition of the starting point. The XRD and DSC results show that the solid phase in the slurry is the pure cocrystal. Although this crystallization is not operated through the middle line of the phase diagram, it is still in the cocrystal region. In acetonitrile, the cocrystal dissolves incongruently. In the slurry conversion crystallization 3, the following point was selected for preparation of the solution: 0.03009:0.96894:9.73 × 10−04 glutaric acid:acetonitrile:theophylline. Therefore, the starting point of the slurry conversion was at the saturation curve of the cocrystal region in the phase diagram, schematically illustrated by point I in Figure 2b. When stoichiometric amounts of pure solid theophylline II and β-glutaric acid are added into the solution, the cocrystal forms and the total composition of the system moves toward the point M. In this way, the operation was locked in the cocrystal region. The DSC results of the solid phase samples showed that the cocrystal components transformed to the cocrystal gradually in 2 h. For the first batch, the yield was approximately 16 g, according to 160 g/L. The starting point of the second batch falls on the cocrystal curve of the phase diagram automatically. Because of too much solid phase, the agitation was inadequate. But, the cocrystal components still had transformed into a cocrystal 5 h

Figure 10. Comparison of invariant point solid phases from chloroform with pure compound XRD spectra. (a) Solid phase from E1′, (b) solid phase from E1, and (c) solid phase from E2.

Figure 11 is smaller and located closer to the glutaric acid side. Obviously, the solvent has a dramatic influence on the general appearance of the phase diagram, and proper selection is an important part in process design. G



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Figure 11. (a) Experimental determinations in the ternary phase diagram of theophylline/β-glutaric acid/acetonitrile. (b) Corresponding schematic complete phase diagram. Please note that in reality, region 4 is fairly narrow as given by the data shown in (a).

Figure 12. Comparison of invariant point solid phases from acetonitrile with pure compound XRD spectra. (a) Solid phase E1′, (b) solid phase from E1, and (c) solid phase from E2.

diagram can be used to design a successful process for the manufacturing of cocrystals. The time to complete the transformation in crystallization experiment 2 is clearly shorter than in crystallization experiment 3. Since similar properties and amount of solid reactant material were used, and the experiments were performed in the same equipment at comparable experimental conditions, this suggests that the transformation is faster in chloroform than in acetonitrile. An important reason for this is probably that the pure compound solubilities are higher in chloroform, in particular the solubility of theophylline.

later. The yield was approximately 33 g in total. For both batches, all the added pure component materials transformed completely into a cocrystal. Therefore, the crystallization experiments 2 and 3 confirm that, with the knowledge of the ternary phase diagram, cocrystals can be prepared by slurry conversion crystallization whether or not the phase diagram shows congruent or incongruent dissolution. By creating a solution at the start, placing the system at or close to saturation in the sector of the cocrystal region of the phase diagram, the total composition of the system upon addition of stoichiometric amounts of pure solid cocrystal component material and crystallization of the cocrystal will be maintained inside the cocrystal region. Furthermore, after removal of the product cocrystal material, the remaining solution of course is a saturated solution in the cocrystal region sector and as such will be suitable to use as the starting point for the next slurry conversion batch. These experiments confirm that the phase

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CONCLUSIONS This work reveals that polymorphism in the pure components of a cocrystal can dramatically influence the ternary phase diagram, and even shift an incongruent case into a congruently dissolving system. When the 1:1 cocrystal of theophylline and H



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glutaric acid is dissolved in chloroform, it behaves like a congruently dissolving phase, and the solubility of the cocrystal in the stoichiometric solution can be determined. However, it is shown that this represents a metastable equilibrium which relies on the non-nucleation of the stable form I of theophylline. At the stable equilibrium, the cocrystal dissolves incongruently (i.e., the phase diagram describes incongruent dissolution of the cocrystal with respect to the stable polymorph I of theophylline) but congruent dissolution of the cocrystal with respect to the metastable form II. In acetonitrile at 30 °C, the region where the cocrystal is the only stable solid phase is clearly shifted toward the glutaric acid side because of the much higher solubility of β-glutaric acid relative to theophylline. The cocrystal dissolves incongruently, and the cocrystal region is fairly narrow. The cocrystal physically decomposes at 120 °C, which is higher than the melting temperature of glutaric acid but lower than the melting temperature of theophylline. In chloroform, the theophylline concentration of the saturated solution over the cocrystal is clearly higher than that in the saturated solution over pure theophylline I/II, while for glutaric acid, the concentration over the cocrystal is clearly lower than that over the pure glutaric acid. With the solubility of the cocrystal in chloroform and the corresponding solubility of the pure compounds, the Gibbs free energy of the formation of the cocrystal from solid theophylline II and solid β-glutaric acid at 30 °C can be estimated to −0.39 kJ mol−1. In both solvents, the cocrystal can readily be produced by isothermal slurry conversion crystallization with adequate productivity, as long as the process is operated in the region of the phase diagram where the cocrystal is the only stable (or reasonably metastable) solid phase. At comparable conditions, the slurry conversion in chloroform is much faster than in acetonitrile.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected], [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS

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REFERENCES

The financial support of the Swedish Research Council is gratefully acknowledged.

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