Discovering New Co-Crystals - American Chemical Society

CRYSTAL GROWTH & DESIGN

Discovering New Co-Crystals J. H. ter Horst,*,† M. A. Deij,‡ and P. W. Cains‡ Intensified Reaction and Separation Systems, Process & Energy Department, Delft UniVersity of Technology, Leeghwaterstraat 44, 2628 CA Delft, The Netherlands, and AVantium Technologies BV, Zekeringstraat 29, 1014 BV Amsterdam, The Netherlands

2009 VOL. 9, NO. 3 1531–1537

ReceiVed October 26, 2008; ReVised Manuscript ReceiVed December 4, 2008

ABSTRACT: A new and systematic method for co-crystal screening has been developed, based on improvements in the understanding of the thermodynamic factors that influence co-crystal formation. This method works from the premise that pure component solubilities determine the concentration regions to screen for new co-crystals, rather than the stoichiometry of the co-crystal. An extended phase diagram screen gives the composition ranges in which the co-crystal is the stable crystalline form. The method is based on the measurement of saturation temperatures which are experimentally easily accessible using standard laboratory equipment. The method has been validated using both carbamazepine and cinnamic acid with a number of co-formers in ethanol solvent. New co-crystals of carbamazepine with isonicotinamide, benzamide and 3-nitrobenzamide, and of cinnamic acid with 3-nitrobenzamide have been discovered. Introduction 1

Crystal engineering has been identified by pharmaceutical scientists as a means of improving and tailoring the physicochemical properties of active pharmaceutical ingredients (APIs). Traditionally, the properties of an API may be modified by forming salts with a limited number of available counterions.2 Co-crystals offer potential for exploring the phase-space of API properties more extensively by using a much larger range of co-crystallizing components (co-formers). Much recent work on solid form preparation has focused on preparing co-crystals. The discovery and preparation of new co-crystals, however, is still based on trial and error. A co-crystal is defined as a crystal that is built up out of two or more organic compounds that are, in their pure forms, solid at ambient conditions.3 Properties such as shelf life,4 dissolution rate5,6 and bioavailability7,8 can be improved using co-crystals, and the development of new, patentable co-crystal forms is expected to impact the intellectual property landscape of pharmaceutical products.9 Co-crystals have been prepared by solution methods6,10,11 and by solid-state grinding,4,9,12 but uncertainty remains about the key factors that determine their formation, and as to why some methods work and others do not in specific cases.13 As a method of first choice, co-crystals of a given molar stoichiometry are conventionally crystallized from clear solutions of the same composition, using cooling and evaporative techniques. We believe that a significant number of co-crystals are missed experimentally in this way, because the range of experimental conditions tested is not optimal and thermodynamic information is neglected. This paper describes a systematic and effective method to discover new co-crystal forms based on easily determined solubility data of the pure components. The method consists of 3 steps combining solubility data and X-ray powder diffraction (XRPD), testing a pair of components on their ability to form stable co-crystals in a certain solvent. For a successful pair of * Corresponding author. E-mail: [email protected]. † Delft University of Technology. ‡ Avantium Technologies BV.

components a solution composition range to be used in single crystal preparation is given. Co-Crystals and the Saturation Temperature Two recent articles have led to an improved thermodynamic understanding of co-crystallizing systems. Nehm et al.14 have suggested that co-crystal solubility can be represented as a product of the component concentrations. If the co-crystal is more stable than its components, then its solubility (representing the free energy of formation) will be lower than the combination of its constituents, provided an appropriate solvent has been selected. At a constant temperature, the product of the component concentrations should therefore exceed a certain value to achieve a driving force for co-crystallization. Chiarella et al.15 have shown that crystallization from solutions using the stoichiometry of the co-crystal will not lead a priori to co-crystals, because the region of the phase diagram most favorable to co-crystal formation may be missed. They concluded that the relative solubilities of the two components is a better starting point for preparation than the co-crystal stoichiometry. Figure 1 shows a simplified schematic phase diagram of a co-crystal system of API A, co-former B and solvent where the mole fraction xA of A is plotted against the mole fraction xB of B. The equilibrium (solubility) lines for temperatures T1 and T2 > T1 are shown. To simplify the representation, we have assumed (1) that at constant temperature the solubilities xA*, xB* of the pure components are unaffected by the presence of the second component, except where co-crystals form, and (2) that the solubility product (xA · xB)* of the co-crystal AB is approximately constant. This results in straight vertical and horizontal lines for the solubilities of the pure components A and B respectively. As we will demonstrate below, the efficacy of the method is not dependent on these conditions being met. For a stable co-crystal, the solubility product (xA · xB)* is smaller than the product of the pure component solubilities xA* · xB* to reflect the lower chemical potential. The solubility line of a stable co-crystal is thus curved and intersects the rectangular envelope of the pure component solubilities xA*(T1) and xB*(T1) below its upper right point with composition (xA*(T1),xB*(T1)). We therefore propose that, at temperature T1 with corresponding component solubilities xA*(T1) and xB*(T1), a solution

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Figure 2. The subsequent steps in the co-crystal screening method.

Figure 1. A schematic phase diagram of a 1:1 AB co-crystal at two temperatures T1 and T2 in solution. The pure component solubilities xA* and xB* and the co-crystal solubility product (xA · xB)* are constant at a certain temperature. The dashed line indicates 1:1 stoichiometry. Note from the position of the stoichiometry line that the molar solubility of B is larger than that of A (xB*(T1) > xA*(T1)). Crystallization from 1:1 stoichiometric solutions (dashed line) would result in pure component A. The red point (xA*(T1),xB*(T1)) is optimum for cocrystallization at temperature T1. Temperature T2 > T1 is the saturation temperature of this point (xA*(T1),xB*(T1)) and thus of the co-crystal phase.

with overall composition (xA*(T1),xB*(T1)) will generally be well-positioned in the co-crystal region. For co-crystal screening, a solution with composition (xA*(T1),xB*(T1)) will have a saturation temperature T2 > T1 determined by the solubility of the co-crystal phase. These saturation temperatures are experimentally easily accessible with commercially available high throughput equipment and analysis. Experimental Section Solubility. The Crystal16 equipment of Avantium Technologies BV16 has been used to determine the solubilities of pure components and co-crystals in ethanol. In the Crystal16, cloud points and clear points of sixteen 1 mL solution aliquots can be measured in parallel and automatically, based on turbidity. The temperature at the point the suspension becomes a clear solution upon heating (at 0.3 °C per minute) was taken as the saturation temperature of the measured sample, of which the composition was established beforehand. The maximum error (overshoot) in the saturation temperature measured in this way, because the conditions are not strictly at equilibrium, has been determined as T which is above the reference temperature T. In step 2 of the screening procedure the pair of components is tested for its ability to co-crystallize. In step 3 a combination of phase diagram screening and XRPD gives further information on the conditions suitable for co-crystal formation. The phase diagram can be constructed using this information, and will indicate the optimum solution composition to use for single crystal structure preparation. We have searched for new co-crystals of carbamazepine (CBZ) as well as cinnamic acid (CA). In case of CBZ we used the three isomeric pyridine carboxamides, isonicotinamide (INA), nicotinamide (NA) and picolinamide (PA), and also benzamide (BA), 3-nitrobenzamide (NBA) and 2-ethoxybenzamide (EBA) as possible co-formers. For CA we tested the co-formers INA, PA, EBA and NBA. CBZ10 and INA17 are relatively simple compounds that have been workhorses of cocrystallization research, mainly because they possess active cocrystal forming functionalities (amide groups) with otherwise simple molecular structures for which structural information can be interpreted easily. Pure Component Solubilities. As a first step in the procedure, the solubilities of the pure components in ethanol were determined over the temperature range 10-50 °C. As shown in Figure 3 all these solubilities could be well correlated by the van’t Hoff equation

Discovering New Co-Crystals

ln x ) -

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(

∆H 1 1 R T T0

)

(1)

where x is the component mol fraction, ∆H is the dissolution enthalpy, T0 is a set-point temperature and T is the saturation temperature of the mole fraction x. Usually this equation is adequate to describe the solubility in a sufficiently narrow temperature range. The van’t Hoff parameters ∆H and T0 can then be used to interpolate or extrapolate the solubilities at other temperatures. Saturation Temperatures of Mixed Compositions. Using the CBZ-INA combination to demonstrate the subsequent methodology, at 25 °C the solubilities of CBZ and INA in ethanol are respectively xCBZ* ) 5.67 and xINA* ) 33.3 mmol/ mol. The second step is to determine the saturation temperature of solutions with composition (xCBZ*,xINA*) after dissolution and recrystallization. It is known, Figure 1, that a solution with composition xCBZ* ) 5.67 and xINA* ) 33.3 mmol/mol at 25 °C is likely to be positioned in a stable co-crystal region if one exists. Measuring the saturation temperature gives a value of Ts ) 42.0 °C (see Table 1). This is significantly higher than the pure component saturation temperature T ) 25 °C and indicates that a more stable and thus less soluble co-crystal phase was recrystallized. We conclude that CBZ and INA can probably form co-crystals. Note that a large molar excess of INA (solventfree mole fraction of CBZ, yCBZ ≈ 0.13) is needed to successfully co-crystallize. This is because the (molar) solubility of INA is much higher than that of CBZ. Measurements taken in this way using a range of starting temperatures are given in Table 1. Figure 4 gives a graphical representation of the CBZ-INA data from table 1 by plotting the difference (Ts - T) between the saturation temperature Ts of the mixture and the starting temperature T against temperature T. The figure additionally contains the experimental data for the CBZ-NA, CBZ-PA, CBZ-BA, CBZ-NBA and CBZ-EBA combinations in ethanol as well. The substantial positive (Ts - T) values of 15 to 30 °C for the CBZ-INA, CBZ-NA, CBZ-BA and CBZ-NBA combinations are indicative of co-crystal formation, as will be established below. CBZ-PA and CBZ-EBA recorded a small, negative (Ts - T) suggesting that no stable co-crystals were formed for this combination. This difference becomes slightly more negative at higher temperatures. These nonzero values and variations in (Ts - T) for CBZ-PA and CBZ-EBA under conditions where no co-crystals form probably represent nonideal behavior of the mixed component solutions. Figure 4 (and Table 1) also shows that, for all these examples, the starting temperature T does not affect the outcomes, and may therefore be chosen for experimental convenience. Similarly, Figure 5 shows the results for the systems with CA for which the co-formers INA, PA, NBA and EBA were Table 1. Measured Saturation Temperatures Ts of CBZ-INA at a Range of Starting Temperatures Ta T [°C]

xCBZ*(T) [mmol/mol]

xINA*(T) [mmol/mol]

yCBZ

Ts [°C]

Ts - T [°C]

10 15 20 25

2.93 3.68 4.59 5.67

21.8 25.2 29.0 33.3

0.12 0.13 0.13 0.14

26.8 34.2 36.9 42.0

16.8 19.2 16.9 17.0

a The pure component solubilities of carbamazepine xCBZ* and isonicotinamide xINA* are taken from Figure 3, and the solvent-free mole fraction yCBZ ) xCBZ*/[xCBZ* + xINA*] is calculated. The significantly higher Ts compared to T indicates a co-crystal phase. Note from yCBZ that the system is automatically sampled under highly nonstoichiometric conditions. Temperatures T and Ts correspond to temperatures T1 and T2 in Figure 1.

Figure 4. Discovering new co-crystals of carbamazepine (CBZ) with isonicotinamide (INA), nicotinamide (NA), picolinamide (PA), benzamide (BA), 3-nitrobenzamide (NBA) and 2-ethoxy benzamide (EBA). The temperature difference (Ts - T) between the measured saturation temperature Ts of samples with composition (xA*(T),xB*(T)) versus the reference temperature T with pure component solubilities xA*(T) and xB*(T). A substantially positive value of (Ts - T) indicates likely formation of stable co-crystals; for (Ts - T) ≈ 0 the formation of cocrystals is unlikely.

Figure 5. Discovering new co-crystals of cinnamic acid (CA) with isonicotinamide (INA), picolinamide (PA), 3-nitrobenzamide (NBA) and 2-ethoxy benzamide (EBA).

tested. The figure shows that for the combinations CA-INA and CA-NBA high temperature differences (Ts - T) were measured. The temperature difference for CA-NBA was a little more than 30 °C while CA-INA resulted in temperature differences up to 60 °C, indicating that possibly a very stable co-crystal was formed. The combinations CA-PA and CA-EBA showed values of (Ts - T) between 0 and -15 °C making it unlikely that co-crystals are formed. Co-Crystal Identification: XRPD. After the saturation temperature experiments, the crystalline residues were collected by filtration and dried, after which they were analyzed using XRPD. The XRPD patterns of CBZ-EBA, CA-EBA and CA-PA did not show indications of the formation of co-crystals or any other new solid phases, as the reflections recorded could all be assigned to polymorphs of CBZ, CA and the co-former. Figure 6 shows XRPD patterns of the other crystalline residues that contained new features. CBZ can crystallize in 4 polymorphic forms,18-21 INA in 2 forms.22 Figure 6 shows the two distinct patterns found for the CBZ-INA system that are different from all CBZ and INA forms known. It indicates that CBZ-INA can form two differently structured co-crystals, as we reported recently.11 Figure 6 shows the two XRPD patterns for CBZ-INA cocrystals as well as the distinct patterns found in the systems CBZ-NA and CBZ-BA. The pattern for CBZ-INA form II

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Figure 6. Typical XRPD patterns from co-crystallized residues of systems containing both CBZ and co-former. The XRPD patterns indicate two distinct co-crystalline structures for CBZ-INA (CBZ-INA I and CBZ-INA II).11 The pattern for CBZ-NA is similar to the pattern generated using the crystal structure reported in the literature10 while the patterns of CBZ-INA II and CBZ-BA resemble the CBZ-NA pattern. Also CBZ-NBA gives a distinct XRPD pattern. Only mixtures of a possible co-crystal CBZ-PA and PA were obtained (CBZ-PA+PA), although we have not yet fully established the presence or absence of a CBZ-PA co-crystal. Also the patterns of CA-INA and CA-NBA co-crystals are given.

is very similar to the pattern found for CBZ-NA as well as CBZ-BA. A distinct pattern was also found for the CBZ-NBA system. The crystallized pure component PA showed two distinct XRPD patterns indicating dimorphism of PA. Comparing these XRPD patterns of PA with the CBZ-PA system showed some characteristics of one of the PA forms. However, a feature distinct from both PA forms is present at 2θ ) 8.74°. Although this is close to the position of a feature of CBZ form II, the possibility of an alternative solid form or even a co-crystal cannot be entirely ruled out. This XRPD pattern in Figure 6 is indicated as CBZ-PA+PA. Co-Crystal Identification: Phase Diagrams. We want to systematically screen the phase diagram to establish the existence and the size of the co-crystal region. The phase diagram provides valuable information to use in single crystal preparation, co-crystallization optimization and process scale up. Figure 7 shows an isothermal co-crystallization phase diagram as in Figure 1 with regions corresponding to a stable co-crystal AB and the two components, the API A and the co-former B. Figure 7 shows the presence of small amounts of each component enhancing the solubility of the other component outside the cocrystal region. When screening, it is generally not known whether an AB-phase is present. The pure component solubilities xA*(T) and xB*(T), however, are easily determined. The system then can be systematically sampled at compositions along the dashed line in Figure 7. This line is described by

xB xA )1xB * (T) xA * (T)

(2)

When the saturation temperatures of samples along this dashed line are determined, figures such as those in Figure 7b may be constructed. Here the saturation temperature is plotted against the solvent-excluded mole fraction yA ) xA/(xA + xB) of component A. At a value of yA ) 1 the solution only contains compound A in a concentration xA* so that a saturation temperature Ts ) T is measured. Similarly, at yA ) 0, the solution only contains compound B in a concentration xB* and the saturation temperature is again Ts ) T. When proceeding

along the abscissa, that is, along the yA-axis from yA ) 0 to 1 the concentration of A increases from 0 to xA* while that of B decreases from xB* to 0. At values of yA near yA ) 0 a Ts < T will be measured because there is no co-crystal formation, and the saturation of the solution is dominated by the more abundant component B, the proportion of which is decreasing. Similarly, at values of yA near yA ) 1 a Ts < T will be measured because xA < xA*(T). However, at intermediate yA values the AB-phase will at some point become the more stable phase and will have a lower solubility. At this point the saturation temperatures will begin to rise, and the curve in the co-crystal region will be discontinuous with the pure component trend lines close to the axes. For the CBZ-INA combination the results of such a phase diagram screening are shown in Figure 8a. At T ) 40 °C the solubilities of CBZ and INA in ethanol are respectively xCBZ* ) 10.2 and xINA* ) 48.8 mmol/mol. The sample compositions have been located on a rectilinear xCBZ-xINA diagram like Figure 7, on a straight construction line from xCBZ* ) 10.2 to xINA* ) 48.8 mmol/mol using eq 2. The saturation temperature measured at yA ) 0 and 1 is about 40 °C as expected, and increasing yA from 0 initially decreases the saturation temperature. This is because INA determines the solubility under these conditions, and the amount of INA decreases with increasing yA. Similarly, decreasing yA from 1 also decreases the saturation temperature due to the decreasing amount of CBZ in the samples. Between yA ) 0.07 and 0.35 the saturation temperature increases from a little under 30 °C to about 40 °C and then decreases again. The saturation temperatures in this region deviate from the predictions for the single components, and represent the solubility of the co-crystal phase. The co-crystal is more stable than the pure components, is therefore less soluble and exhibits a higher saturation temperature. The temperature dependent co-crystal solubility product obtained from the data in table 1 was used to construct co-crystal saturation temperature lines as a function of the solvent excluded molar CBZ fraction yCBZ, shown as a solid line in Figure 8a. The measured saturation temperatures for the co-crystal show a systematic deviation from this line which indicates nonideal solubility behavior (e.g., speciation effects). Despite this deviation, the principle still accurately predicts the optimal solution composition for cocrystal formation. Similar co-crystal regions are shown in Figure 8 for CBZ-NA, CBZ-BA and CBZ-NBA. For CBZ-NA the reference pure component solubilities were chosen at 40 °C. Between yA ) 0.05 and 0.45 the saturation temperatures are higher and even go up to 50 °C. For the CBZ-BA system the reference pure component solubilities were chosen at 30 °C. Between yA ) 0.05 and 0.45 the saturation temperatures are higher, indicating CBZ-BA co-crystals. In this case the saturation temperatures go up to as high as 43 °C. This probably indicates relatively stable co-crystals that are correspondingly less soluble than the components. It can furthermore be seen that the BA purecomponent saturation temperature (at yA < 0.05) decreases more sharply than indicated by the solid line constructed using the van’t Hoff parameters of BA. This higher than expected solubility might indicate that CBZ and BA form complexes together in ethanol, which has also been reported for CBZ-NA.10 A closer inspection of our CBZ-NA results did show some indications for higher than expected solubilities of NA in the presence of CBZ. Speciation or complexation might also explain the deviation of the experimental points from the curved line representing the solubility product of the co-crystal. This latter line is constructed from the temperature dependent

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Figure 7. (a) A phase diagram of a ternary system of API A, co-former B and solvent at constant temperature T, plotted using the same system of variables as in Figure 1. The phase diagram is probed by determining the saturation temperature Ts of samples with compositions along the broken line joining the solubilities of the single components in this representation. The region between the two intersections of this sampling line and the curve representing co-crystal stability is where co-crystals may be expected to form, and where the Ts > T results as in Table 1 and Figure 4 can be expected. (b) The saturation temperature profile obtained as a function of the solvent-excluded mole fraction yA when measuring along the dashed line in Figure 7a.

Figure 8. The saturation temperature as a function of the solvent-excluded mole fraction yA of CBZ with the co-formers INA (a), NA (b), PA (c), BA (d), EBA (e) and NBA (f). The saturation temperatures of the single-component API and co-former predicted using the van’t Hoff parameters are shown as solid lines from the pure-component axes. The solid line rising to a maximum is a fit to the van’t Hoff equation of the co-crystal based on the notion of a solubility product. The increased saturation temperature indicates that there is a stable co-crystal region in the phase diagram. CBZ-PA and CBZ-EBA seem to indicate that no stable co-crystals form.

solubility product from the CBZ-BA data in Figure 4. For the CBZ-NBA system the saturation temperatures are higher than the expected pure component saturation temperatures between 0.16 < yA < 0.75. The CBZ-PA and the CBZ-EBA systems in Figure 8 do not indicate a region where a co-crystal is more stable than the pure components. The saturation temperatures decrease toward the minimum at yA ) 0.16 for CBZ-PA and yA ) 0.41 for CBZ-EBA. Figure 9 shows the saturation temperatures for CA-INA and CA-NBA in ethanol. Both show elevated saturation tempera-

tures compared to the pure component saturation temperatures, which indicates a co-crystal region. In order to translate the phase diagram screen data to an isothermal phase diagram, a sound model incorporating speciation and temperature effects should be used. We are currently working on this. Educate guesses of the isothermal phase diagram are shown in Figure 10 for the systems CBZ-NBA, CBZ-EBA and CA-INA in ethanol at 20, 30 and 40 °C. The lines are constructed by determining the van’t Hoff parameters of the co-crystal for the points in Figure 4 and Figure 5. The van’t Hoff parameters in turn can be used to determine the

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Figure 9. The saturation temperature Ts as a function of the solvent-excluded mole fraction yA of CA with the co-formers INA (left) and NBA (right).

Figure 10. The phase diagram of CBZ-NBA (left), CBZ-EBA and CA-INA (right) at T ) 40 (yellow), 30 (red) and 20 °C (blue). The curved part of the line gives the co-crystal solubility. CBZ-EBA does not form co-crystals in ethanol. Table 2. Summary of the Detection of Co-Crystals Using Saturation Temperature Measurements (Ts - T), XRPD Analysis, and Phase Diagram Screening (PhDia) compound A

B

Ts - T

XRPD

PhDia

overall

CBZ CBZ CBZ CBZ CBZ CBZ CA CA CA CA

INA NA PA BA NBA EBA INA PA NBA EBA

+ + + + + + -

+ + +/+ + + + -

+ + + + +

+ + -? + + + + -

+

solubility product at a certain temperature. The phase diagram of CBZ-NBA shows a substantial co-crystal region. The CA-INA co-crystal is very stable: only small amounts of INA are needed to enter the co-crystal region using a saturated CA-solution. The system CBZ-EBA in ethanol is a typical system that does not form co-crystals and therefore does not contain a co-crystal region as is indicated by the straight horizontal and vertical lines. By constructing these phase diagrams compositions for single crystal determination well within the co-crystal region can be chosen so that the probability of forming a co-crystal is maximal. Discussion Saturation temperature measurements, XRPD and a phase diagram screening all separately indicate whether co-crystals are formed. Table 2 summarizes the results for all combinations of API and co-former tested. For CBZ the co-formers INA, NA, BA and NBA while for CA the co-formers INA and NBA resulted in co-crystals.

Since this research deals primarily with the validation of a screening method, not all the co-crystals reported are newly discovered. A recent in-depth crystallization study of CBZ and INA revealed two polymorphic 1:1 co-crystals.11 The stable 1:1 CBZ-INA co-crystal structure (form I) consists of packed alternating chains of CBZ and INA dimers, each of which is independently hydrogen bonded together by the familiar R22(8) diamide motif. We also identified a second polymorph, CBZ-INA form II, with a powder pattern similar to that reported for CBZ-NA (see below), and probably isostructural with the latter. CBZ-INA form II transformed to form I via a solvent-mediated transformation over a period of around 30 min at room temperature, indicating that form II is metastable in respect to form I at room temperature.11 Although the pyridine group of INA is capable of forming hydrogen bonds, it does not participate in bonding as such in either CBZ-INA co-crystal structure. CBZ-NA forms a co-crystal that has already been reported.10 This 1:1 CBZ-NA co-crystal consists of CBZ dimers hydrogenbonded laterally to NA on both sides.10 We recorded a very similar XRPD pattern for CBZ-NA. The stable co-crystal of CBZ-INA (I) has the same stoichiometry but is differently packed to the co-crystal of CBZ-NA. The NA molecules form hydrogen bonded chains along the crystallographic direction [100], with each NA molecule connected to a dimer. To our knowledge the CBZ-BA co-crystal is as yet unreported. The pattern of CBZ-BA is again quite similar to CBZ-NA and CBZ-INA form II, indicating that CBZ-BA is probably isostructural to these. Figure 11 shows the experimentally observed morphologies of CBZ-INA form II, CBZ-NA and CBZ-BA obtained by crystallization from ethanol. The isostructural CBZ-INA form II, CBZ-NA and CBZ-BA co-crystals all have extreme needle-like morpholo-

Discovering New Co-Crystals

Figure 11. The crystal morphology of the co-crystals. Note the similar extreme needle morphology of CBZ-INA form II, CBZ-NA and CBZ-BA.

gies. High resolution XRPD data suggests that CBZ-INA form II, CBZ-NA and CBZ-BA are indeed isostructural. The cocrystal of CBZ-NBA is to our knowledge not reported. Currently we are pursuing to grow single crystals to determine the co-crystal structures of the unreported co-crystals. The saturation temperature measurement and the phase diagram screening did not indicate the occurrence of a CBZ-PA co-crystal. The XRPD patterns, however, included a feature that was not present in any known forms of CBZ or PA. We are therefore unable to rule out entirely the possibility of a solid arising from an interaction between the two components, but we believe the evidence is well short of that required to establish the presence of a new solid phase. We are continuing to search for a CBZ-PA co-crystal along with our work to prepare and characterize further new co-crystals. In PA the pyridine heteronitrogen is ortho with respect to the carboxamide group, and the molecule is able to form zwitterions, and this may be the reason that a stable co-crystal between CBZ and PA does not seem to form. It is possible that CBZ and PA may form cocrystals more readily in a less polar solvent in which the zwitterion is energetically less favored. This is also under investigation. In 9 out of the 10 systems tested (the exception being CBZ-PA, where some uncertainties remain) the temperature difference (Ts - T) gives a good indication whether co-crystals form. Furthermore, in all cases where a positive temperature difference was measured, this was because of the formation of a new co-crystalline phase. These temperature difference measurements can be done reliably, rapidly and simply in commercially available equipment. This method is therefore highly effective for discovering new co-crystals of an API by testing with a large number of co-formers. Conclusions We have developed a systematic screening method for discovering co-crystalline materials that is soundly based on thermodynamic principles. Starting with the solubilities of the components, possible co-crystal formation can be initially assessed by measuring the saturation temperature at a composition corresponding to saturation with respect to both components at a convenient reference temperature. If the measured saturation temperature is significantly higher (>10 °C) than the reference, there is a good chance that a co-crystal has formed. Matching solution composition to the co-crystal stoichiometry should not be used in an initial co-crystal screen. An initial positive result obtained by the above method can be followed up by saturation temperature measurements across a range of compositions bounded by the solubilities of the two components at a convenient temperature. The resulting plots will locate the composition regions in which co-crystals may

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be formed. Measurement of saturation temperature is simple and straightforward, and these methods can be easily adapted to high-throughput platforms. A combination with XRPD gives a more definitive proof of co-crystal formation. We have applied the systematic screening method to cocrystal screening of carbamazepine and cinnamic acid with a number of co-formers. We have identified co-crystals of carbamazepine with isonicotinamide, nicotinamide, benzamide and 3-nitrobenzamide and of cinnamic acid with isonicotinamide and 3-nitrobenzamide. We believe we have developed an interesting, successful and fast screening method for discovering new co-crystals. Acknowledgment. This research was made possible by a Casimir grant obtained from NWO (Netherlands Organisation for Scientific Research). J.H.t.H. gratefully acknowledges the hospitality that he enjoyed at Avantium Technologies during the Casimir project. The authors would like to thank Gerda van Rosmalen for stimulating discussions. Sulivan Djamad, Sara Kraus, Christine van Zuylen, Jan Harm Urbanus and Nandlal Dokhale are thanked for their experimental help in discovering the co-crystals.

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CG801200H