Drug Substance and Former Structure Property Relationships in 15 Diverse Pharmaceutical Co-Crystals

Mary K. Stanton, Sunita Tufekcic, Carrie Morgan, and Annette Bak*

Department of Pharmaceutics, Amgen Inc., Cambridge, Massachusetts 02139 ReceiVed May 14, 2008; ReVised Manuscript ReceiVed NoVember 14, 2008

CRYSTAL GROWTH & DESIGN 2009 VOL. 9, NO. 3 13441352

ABSTRACT: The pharmaceutical co-crystal approach can be used to modify physicochemical properties of new chemical entities. However, methodical studies of how co-crystal former selection inuences properties of the resulting co-crystal, such as melting point and solubility, are needed. Consequently, we investigated 15 co-crystals of AMG 517 and three related molecules using diand triacids as well as amides as co-crystal formers. Fourteen co-crystals and one partial salt were prepared as judged by pKa values and single crystal data. In addition, we found that our ability to form co-crystals was signicantly inuenced by even minor changes to the chemical structure of the drug substance. Furthermore, we discovered that all AMG 517 co-crystals, which we obtained single crystal structure for, utilize the same hydrogen bond donor (amide) and acceptor (benzothiazole) on the drug substance. Additional hydrogen bonds were observed in all of the co-crystals. In this study, we found little correlation between the melting point of the co-crystal former and the co-crystal, and no correlation between the melting point and solubility of the co-crystals, although some correlations within specic classes were found. Therefore, as the diversity of co-crystal formers increases, rational design of AMG 517 co-crystals becomes more difcult, and obtaining the desired physicochemical properties would still have to involve experimental testing. Introduction Because of dramatic changes in the drug discovery strategy over the last 20 years, physicochemical properties of new chemical entities (NCEs) selected for development have changed signicantly. Consequently, candidates are becoming more lipophilic and have less aqueous solubility.1 Formation of salts is a frequently used approach to change the dissolution rate without changing covalent bonds in the molecule itself. A recent study investigated the trend in counterion selection over time. The authors found that the diversity of counterions has increased over the years for oral drugs, indicating an increasing need to improve physicochemical properties of NCEs. The same article reports that 53.2% of drug candidates in the orange book database are present as nonsalt forms.2 This may reect that the drug form is sufciently soluble, that the molecules do not contain an ionizable moiety, or that a suitable salt form could not be found. The formation of pharmaceutical co-crystals has recently been proposed as an alternate strategy to salt selection for dealing with poor physicochemical properties.3,4 The method has also been reported to work in cases where salts are physically unstable or the NCE contains no pKa within the physiological range.5,6 To assess the multicomponent crystals discussed, we will use a recently published denition, stating that pharmaceutical co-crystals are formed between a drug substance and a co-crystal former, which is a solid under ambient conditions, and are not limited to two components. The components of the crystal interact by hydrogen bonding or other noncovalent and nonionic interactions.3,4 Available co-crystal cases, for which pharmaceutical properties have been studied, are relatively few as recently reviewed by several sets of authors.4,5,7,8 A melting point is frequently reported, since it is an important pharmaceutical property related to solubility, as discussed later in this article, but it also has a signicant impact on pharmaceutical processability.8 As with any other crystal engineering approach, forming a co-crystal
* Author to whom correspondence should be addressed. E-mail: anjabak@ verizon.net.

can change the melting point of the resulting structure. For example, for carbamazepine and nicotinamide or carbamazepine and saccharin co-crystals the melting points of the co-crystals were reported between the melting point of the co-crystal former and the API.8,9 This corresponds well to another study, where melting points of six out of seven co-crystals of 2-acetaminopyridine with diacids were reported to lie between the cocrystal former and the API.10 Consequently, one may be able to engineer a co-crystal with a certain melting point by selecting the co-crystal former appropriately. Active pharmaceutical ingredients (API) with poor physicochemical properties, such as solubility and dissolution, can be problematic for clinical development, cause failure of the candidate, and therefore be very expensive for the company.11,12 Therefore, not surprisingly, several co-crystal cases evolve around testing solubility and dissolution. For example, 2:1 co-crystals of uoxetine hydrochloride with succinic and fumaric acid were reported to have greater solubility than uoxetine hydrochloride.13 Also, we previously reported on a succinic acid co-crystal that initially had higher solubility than the parent free base in a buffer with pH relevant for oral aborption.5 Furthermore, co-crystals of itraconazole, and several diacids (e.g., fumaric acid and succinic acid) have been reported. The co-crystals achieved a better dissolution prole (i.e., 4-20-fold higher concentrations) than the crystalline form and a similar dissolution prole to the marketed amorphous form of the itraconazole.14 In addition, a glutaric acid co-crystal of a sodium channel blocker had an 18-fold increase in the dissolution rate over the sodium channel blocker itself. This translated into a 3-fold increase in exposure of the co-crystal over the parent compound in a dog pharmacokinetic (PK) study.15 Other researchers reported on an L-tartaric acid co-crystal of a phosphodiesterase-IV inhibitor that exhibited higher solubility than the free base form. Consequently, a 20-fold increase in exposure over the free base was seen in a monkey PK study, when dosing the hemitartrate co-crystal.16 Finally, a comparison of the marketed form of carbamazepine and a

10.1021/cg8005019 CCC: $40.75 2009 American Chemical Society Published on Web 01/29/2009

Structure Property Relationships in Co-Crystals

Crystal Growth & Design, Vol. 9, No. 3, 2009 1345

Figure 1. Structures of TRPV1 antagonists used for co-crystal formation22 (1a) AMG 517, (1b) AMG 831664, (1c) AMG 678809, (1d) AMG 670129, (1e) AMG 677902, (1f) AMG 676826, (1g) AMG 831790.

saccharin co-crystal found the co-crystal to be a viable alternative. Dissolution data indicated that the aqueous solubility of carbamazepine was not affected by co-crystal formation, and oral bioavailability from dog PK studies was comparable to the marketed form.17 These case studies illustrate that co-crystals may successfully be used to circumvent poor physicochemical properties of pharmaceuticals. However, systematic studies covering a larger number of pharmaceutical co-crystals are still lacking. We have previously reported using a pharmaceutical cocrystal to resolve the solubility limited absorption for AMG 517 as shown in rat PK studies.6 AMG 517 is a small molecule transient receptor potential vanilliod 1 (TRPV1) antagonist that was being developed for the treatment of chronic pain.18 Discussing the target is outside the scope of this article, but Julius and Basbaum19 can be consulted for a review of TRPV1. In a second study we investigated 10 1:1 co-crystals of AMG 517 with commercially available acids. Within this series rational design of AMG 517 co-crystals with select physicochemical properties is possible, since we observed a 78% correlation between melting point of the cocrystal former and the melting point of the co-crystal. In addition, a 55% correlation between the melting point and the Log solubility of the co-crystals were reported.20 Theoretically, the diversity possible with co-crystals is large, since the presence of a hydrogen bond donor and an acceptor is the only structural prerequisite. Therefore, restricting cocrystal former selection to acids commonly used for salt selection21 is limiting. Consequently, in the present work, we are investigating AMG 517 co-crystals with amides. In addition, we are expanding the acid diversity to also include other diacids and triacids commonly used in pharmaceutically acceptable salts.21 Furthermore, we are also reporting on three sorbic acid co-crystals of similar TRPV1 antagonists with the intent to gain an understanding of the compound features needed for co-crystal formation. The structures of AMG 517 and the six other TRPV1 compounds studied are shown in

Figure 1. The structures of the co-crystal formers used are shown in Figure 2. Materials and Methods
Materials. Co-crystal formers were purchased from Sigma-Aldrich (benzamide, cinnamamide, propionamide, L-(-)-malic acid, and adipic acid), Fluka (malonic acid), TCI (n-capronamide), EM Science (maleic acid), Alfa Aesar (valeramide, citric acid, and succinic acid) and EMD chemicals (sorbic acid). Drug substance was synthesized in-house.22 Milling. Drug substance and co-crystal former were ball milled with or without 20 L of isopropyl alcohol, acetone, or ethyl acetate in a mixer mill MM301 (Retsch Inc., Newton, PA) in a 1:1.2 ratio of drug substance to co-crystal former in a 1.5 mL stainless steel grinding jar containing a 5 mm stainless steel grinding ball for 2 min. Crystallization. Crystallizations were carried out by slow cooling a saturated solution. Drug substance and co-crystal former were dissolved in a 1:1.2 ratio in isopropyl alcohol, isopropyl acetate, acetone, methanol, ethyl acetate, acetonitrile, dichloromethane, 1,2-dichloroethane, or 2-butanol at 50 C, or at the solvents boiling point if it is less than 50 C, and then cooled at 2 C/min in an Imperial V oven (Labline Instruments Inc., Melrose Park, IL). If crystallization did not occur within 48-72 h, slow evaporation was utilized until crystallization occurred. Due to the low solubility of AMG 831664 co-crystal was formed from slurry in acetone or methanol. Thermal Analysis. Differential scanning calorimetry (DSC) was performed on a Q100 (TA Instruments, New Castle, DE) at 2 or 10 C/min from 30 to 250 C in an open, aluminum pan. Thermal gravimetric analysis (TGA) was performed on a Q500 (TA Instruments) at 2 or 10 C/min from 30 to 300 C in a platinum pan. X-Ray Powder Diffractometry. X-ray diffraction (XRPD) patterns were obtained on an XPert PRO X-ray diffraction system (PANalytical, Almelo, The Netherlands). Samples were scanned in continuous mode from 5-45 (2) with step size of 0.0334 on a spinning stage at 45 kV and 40 mA with Cu KR radiation (1.54 ). The incident beam path was equipped with a 0.02 rad soller slit, 15 mm mask, 4 xed antiscatter slit and a programmable divergence slit. The diffracted beam was equipped with a 0.02 rad soller slit, programmable antiscatter slit and a 0.02 mm nickel lter. Detection was accomplished with an RTMS detector (XCellerator). Particle Size. Particle size was determined by laser diffraction on the HELOS/BF with a CUVETTE disperser (Sympatec GmbH, Clausthal-Zellerfeld). Samples were suspended in 2% hydroxypropyl methylcellulose 1% Tween 80 by vortexing. The suspension was

1346 Crystal Growth & Design, Vol. 9, No. 3, 2009

Stanton et al.

Figure 2. Structures of co-crystal formers used for co-crystal formation (2a) sorbic acid, (2b) citric acid, (2c) maleic acid, (2d) L-malic acid, (2e) malonic acid, (2f) adipic acid, (2g) succinic acid, (2h) benzamide, (2i) capronamide, (2j) cinnamamide, (2k) propionamide, (2l) valeramide. then added dropwise to the 50 mL cuvette containing 40 mL of water until a 5-15% optical concentration was achieved. Measurements were taken for 10 s using R3 or R5 lens while mixing at 500 rpm. NMR. 1H nuclear magnetic resonance (NMR) analysis was performed on a Bruker 400 MHz NMR (Bruker BioSpin GmbH, Germany) in DMSO-d6 or chloroform-d at 25 C. Hygroscopicity. Hygroscopicity was determined by dynamic vapor sorption on the DVS Advantage (Surface Measurement Systems Ltd., London). Measurements were taken from 0 to 90-0% RH at 25 C with 10% RH per step with equilibration set to dm/dt (0.002%/ min for 5 min or 120 min/step (minimum 10 min/step). All samples reached equilibration at each step before the 120 min maximum set point was reached. Solubility. Solubility was measured from slurry (3.33 mg/mL) in fasted simulated intestinal uid (FaSIF - 5 mM taurocholic acid sodium and 1.5 mM lecithin in pH 6.8 phosphate buffer) with samples taken at 1, 15, 30, 45, 60, 90, 120, 240, and 1440 min at 25 C. Particle size control was not attempted nor was particle size measured during the experiment. Samples were ltered through a 0.2 m PTFE syringe lter. Analysis was performed by HPLC-UV on an Agilent 1100 series HPLC (Agilent Technologies, Palo Alto, CA) equipped with a binary pump (G1312A), DAD detector (G1315B), auto sampler (G1329A) and a 4.5 150 mm, 8 nm pore size, 5 m particle size, YMC ProC18 column (Waters Corporation, Milford, MA). Elution was achieved by a gradient method from 10 to 95% of acetonitrile 0.1% triouroacetic acid at 1 mL/min for 8 min. Standards were prepared in 50% acetonitrile at 0.05 mg/mL and injected at 1, 5, 10, and 15 L. All of the AMG 517 co-crystals with acid co-crystal formers (except the citric acid co-crystal) as well as the AMG 678809, AMG 831664, and AMG 670129 sorbic acid co-crystals were run in duplicate. AMG 517 tartaric acid and AMG 517 malonic acid (2:1) co-crystals were not analyzed due to insufcient quantity. Stability. Stability samples, 10-20 mg in 4 mL clear glass vials, were placed into a stability chamber (Hotpack, model 435305) at 40 C/75% RH uncapped for 1 month. Samples were analyzed by DSC and XRPD as described above. X-Ray Single Crystal Structure. The single crystal structure of AMG 517 and AMG 517 sorbic acid co-crystal has been published previously.6 Single crystal structures for all other co-crystals and free bases with suitable single crystals were determined by Dr. Richard J. Staples at Harvard University (Cambridge, MA). Data were collected using a Bruker SMART APEX CCD (charge coupled device) based diffractometer equipped with an Oxford Cryostream low-temperature apparatus operating at 193 K. Data were measured using omega scans of 0.3 per frame for 45 s, such that a hemisphere was collected. A total of 1221-1850 frames were collected with a maximum resolution of 0.76-0.90 . The rst 50 frames were recollected at the end of data collection to monitor for decay. Cell parameters were retrieved using SMART software and rened using SAINT on all observed reections. Data reduction was performed using the SAINT software which corrects for Lp and decay. The structures were solved by the direct method using the SHELXS-97 program and rened by least-squares method on F2, SHELXL-97, incorporated in SHELXTL-PC V 6.10. pKa Determination. AMG 670129 pKa was determined at Amgen Inc. The sample was titrated using a pH-metric technique on the Sirius GlpKa instrument (Sirius Analytical Instruments Ltd.) in various methanol/water ratios (63.0% - 41.9% methanol) in three triple titrations, over a total pH range of pH 1.8 to pH 6.0 with sample concentrations of 5-7.1 m. Some precipitation was observed after titration and the data was extrapolated back to zero percent cosolvent by the YasudaShedlovsky procedure.

Results and Discussion Fifteen crystalline co-crystals were prepared and the composition was conrmed by TGA and 1H NMR. DSC and XRPD were conducted on all co-crystals and assessed to be different than that of the parent free base and the co-crystal former. The

Structure Property Relationships in Co-Crystals

Crystal Growth & Design, Vol. 9, No. 3, 2009 1347

Table 1. Physicochemical Properties of 15 Co-Crystals of AMG 517 and Related TRPV1 Compounds ACD pKaa co-crystal
AMG AMG AMG AMG AMG AMG AMG AMG AMG AMG AMG AMG AMG AMG AMG 517 - adipic acid 517 - citric acide 517 - maleic acid 517 - L-malic acid 517 - malonic acid 517 - malonic acid 517 - succinic acid 517 - benzamide 517 - capronamide 517 - cinnamamide 517 - propionamide 517 - valeramide 678809 - sorbic acid 831664 - sorbic acid 670129 - sorbic acid

pKa former (acid2)d

5.13 4.24 4.79 4.82 5.61 5.61 5.52 NA NA NA NA NA NA NA NA

melting onsets (C)f former

152 155 141 103 135 135 185 125 101 147 80 104 134 134 134

free baseb
0.68 0.68 0.68 0.68 0.68 0.68 0.68 0.68 0.68 0.68 0.68 0.68 3.05 0.68 3.58

former (acid1)c
4.39 2.93 3.15 3.61 2.92 2.92 4.24 16.00 16.76 15.65 16.60 16.68 4.59 4.59 4.59

(base-former)
-3.71/-4.45 -2.25/-3.56 -2.47/-4.11 -2.93/-4.14 -2.24/-4.93 -2.24/-4.93 -3.56/-4.84 -15.32 -16.08 -14.97 -15.92 -16.00 -1.54 -3.91 -1.01

co-crystal
199 169 187 218 186 197 180 164 119 184 126 123 152 164 138

free base
230 230 230 230 230 230 230 230 230 230 230 230 246 206 214

TGA weight %
15.5 18.0 10.8 15.0 19.2 11.0 16.9 21.7 20.7 26.1 15.0 18.3 22.2 18.6 22.2

crystalinity by XRPDg
crystalline crystalline crystalline crystalline crystalline crystalline crystalline crystalline crystalline crystalline crystalline crystalline crystalline crystalline crystalline

molar ratioh
2:1 2:1 2:1 2:1 1:1 2:1 2:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1

a pKa value calculated using ACD software.23 b Amino benzothiazole group pKa. c Lowest/only pKa value. d Highest pKa value. e Citric acid has three pKa values, the third pKa is 5.09. f Melting onset of the endotherm associated with the loss of co-crystal former on TGA. g Crystallinity was determined by XRPD. h Molar ratio was determined by TGA and 1H NMR; NA: not relevant.

melting points of the co-crystal former, free base, and resulting co-crystals as well as calculated pKa values,23 percent weight loss by TGA, crystallinity, and molar ratio are shown in Table 1 (see Supporting Information for the data). Are the 15 multicomponent crystals listed in Table 1 co-crystals? AMG 517, AMG 678809, AMG 831664, AMG 670129, and all co-crystal formers are solids at room temperature (i.e., 25 C - see Table 1), therefore qualifying as co-crystals based on the physical state of the pure isolated solids.4 In Table 1, we have also shown pKa (pKa base - pKa acid) values where a range from -1.01 to -16.08 was found. According to a recent publication a pKa < 0 almost exclusively results in co-crystal formation.24 Consequently, based on pKa values it appears that co-crystals rather than salts were formed in all 15 cases. It also has been argued that a distinction between salts and co-crystals can be made based on DC-O distances (i.e., carbon oxygen distances in the acid carbonyl group) determined from single crystal structures. A carboxyl anion possesses two similar DC-O values, whereas a neutral carboxyl group possesses two distinctively different DC-O values. For 2-aminopyrimidine systems, it was concluded that complexes with DC-O < 0.03 are salts, and complexes with DC-O > 0.08 are co-crystals.10,24 The single crystal structure of 10 co-crystals and their parent free bases were determined. The structure of AMG 831664 free base and the remaining co-crystals could not be solved due to lack of sufcient quality crystals. Table 2 shows the crystallographic data (crystallographic data for AMG 517 and its sorbic acid co-crystal has been previously published and is therefore not included in this table).6 Table 3 shows the DC-O distances for the co-crystals in Table 2 that are formed between an acid and the parent free base. As mentioned, it appears that all six multicomponent crystals listed in Table 3 qualify as co-crystals based on pKa. However, based on bond distances in the acid carbonyl groups, it appears that the AMG 670129 sorbic acid multicomponent crystal may have some salt character. To investigate this apparent discrepancy, the actual pKa value of AMG 670129 was determined to be 5.63 rather than the calculated value of 3.5823 listed in Table 1 giving rise to a pKa of only 1.04. Therefore, the AMG 670129 multicomponent co-crystal may indeed have some salt character. When the hydrogen bonding in the co-crystals was studied, we found seven of the eight co-crystals listed in Table 2 had a different network than their parent free bases. This comparison was not made for AMG 831664 and the sorbic acid co-crystal of AMG 831664, since the crystal structure of the free base

was not determined. Furthermore, all co-crystal formers interact with the drug substance through similar heterosynthons as shown in Figure 3. We observed hydrogen bonds from the amide or amine proton on the drug substance to the carbonyl group on the acid or amide co-crystal former and from the hydroxyl group or the amide proton on the co-crystal former to the benzothiazole or quinolone nitrogen on the drug substance. The AMG 517 sorbic acid co-crystal6 and two other 1:1 co-crystals with AMG 517 were also shown to interact via heterosynthon 3a.20 In addition to the hydrogen bonds in heterosynthon 3b, capronamide forms a third hydrogen bond with the pyrimidine nitrogen in a neighboring AMG 517 molecule resulting in a continuous chain of drug substance and former, while the propionamide co-crystal forms a third hydrogen bond with the carbonyl group in a neighboring propionamide molecule (Figure 4). The adipic, citric, maleic, malic, malonic, and succinic dior triacids form 2:1 co-crystals (i.e., drug substance to acid) with AMG 517. However, we were only able to determine single crystal structures of the 2:1 adipic, succinic, and malonic acid co-crystals. The hydrogen bonding networks of these co-crystals are shown in Figure 5. All three of these diacids form heterosynthon 3a with AMG 517. Succinic and adipic acid form heterosynthon 3a with both acid groups, thereby bridging two molecules of AMG 517 and giving rise to the 2:1 stoichiometry. The malonic acid forms a carboxylic acid homosynthon with another malonic acid before forming heterosynthon 3a with a second molecule of AMG 517. Malonic acid is the smallest of the diacids, and this arrangement may be required in order to span the distance to the second AMG 517 molecule. This would appear to be a 1:1 co-crystal; however for each of these interconnected tetramers, there are two other molecules of AMG 517 that do not form hydrogen bonds with the malonic acid. From Table 2 it is evident that the density of the 2:1 AMG 517 malonic acid co-crystal is signicantly lower than that of other diacid co-crystals. Not surprisingly, correlation between density and packing coefcient has been reported.25 Therefore, this arrangement appears not to allow for the most efcient packing among the diacids. From Table 1 it is seen that malonic acid forms both 1:1 and 2:1 (i.e., AMG 517 to acid) co-crystals. We were unable to scale up the 2:1 co-crystal in sufcient amount to generate solubility data indicating that the 1:1 form is preferred under the conditions tested. We have previously published two other 1:1 co-crystals of AMG 517 with diacids (glutaric and tartaric acid)22 and are currently investigating the details of why certain diacids form both 2:1 and 1:1 co-crystals

1348 Crystal Growth & Design, Vol. 9, No. 3, 2009

C27H23F3N4O4S 1:1 556.55 monoclinic C2/c 44.787(6) 4.773(6) 24.110(3) 90.000 93.544(3) 90.000 5143.7(11) 1.44 8 0.91 to 22.50 3359/0/355 193(2) 0.0795 0.1350 AMG 831664 sorbic acid

Stanton et al.

and certain diacids exclusively 1:1 co-crystals with AMG 517. Other diacids bridging two API molecules have been reported previously. For example, it was reported that succinic acid spanned two itraconazole molecules;14 that succinic acid bridged two molecules of uoxetine hydrochloride entities;13 and that oxalic acid interconnected two caffeine molecules.26 All these cases give rise to 2:1 co-crystals in a similar fashion to what we are reporting here. As discussed, we successfully formed sorbic acid co-crystals with three additional TRPV1 compounds (i.e., AMG 670129, AMG 678809, and AMG 831664, see Figure 1 for structures). In all three co-crystals we observed heterosynthon 3a or 3c as previously described. The AMG 670129 co-crystal forms heterosynthon 3c and contains an additional hydrogen bond from the quinolone amine on the drug substance to the carboxyl group on the co-crystal former (see Figure 6b). The AMG 678809 co-crystal forms heterosynthon 3a and also contains one additional intermolecular hydrogen bond from the amino benzothiazole amine on the drug substance to the pyrimidine nitrogen on the drug substance (see Figure 6d). In both cases, this arrangement gives rise to tetramers consisting of two molecules of AMG 678809 or AMG 670129 and two molecules of sorbic acid. AMG 831664 sorbic acid co-crystal hydrogen bonds via heterosynthon 3a with no additional hydrogen bonds. A compounds hydrogen bonding network has an impact on physicochemical properties such as solubility and melting point.27,28 At the melting point, the free energy of transition is zero, and the melting point can be determined from the ratio of the enthalpy of fusion to the entropy of fusion.27 The melting onsets of the AMG 517, AMG 678809, AMG 831664, and AMG 670129 co-crystals are listed in Table 1. It is evident that the melting point of all co-crystals, with the exception of the succinic acid co-crystal falls between that of the co-crystal former and the drug substance. However, the melting point of the succinic acid co-crystal may be affected by the excess succinic acid present in the sample. Solubility has been cited to depend on the enthalpy of fusion, temperature of the solvent, melting point of the solid, hydrogen bonding in the solid and solvent, and other polar and nonpolar forces in both the solvent and the solute.28 We determined solubility of the co-crystals in FaSIF as opposed to water or other media due to stability, solubility, and biorelevance considerations.6,20 The solubility (Smax), particle size, and conversion patterns in FaSIF are captured in Table 4 for 14 of the 15 co-crystals along with the associated free base solubility. For co-crystal cases where the solubility prole was determined in duplicate (see Materials and Methods), the average is reported in Table 4. Previously, we investigated 10 1:1 co-crystals of AMG 517 with commercially available acids, and we found a 78% correlation between melting point of the co-crystal former and the melting point of the co-crystal. In the same article we also found a 55% correlation between the melting point of the cocrystal and log Smax for a set of nine 1:1 co-crystals of AMG 517. As discussed this solubility correlation is using melting point data rather than enthalpy of fusion data. Therefore, implied in the correlation is the assumption that the entropy of fusion follows Waldens rule29 and is a constant. From data presented in Table 4, we found signicantly less correlation between melting point of the co-crystal former and the co-crystal for all co-crystals (i.e., only 23%). In addition, we found no correlation between melting point and log Smax of the co-crystals (i.e., only 8%). These observations are not surprising given a signicantly more diverse set of co-crystal formers, and co-crystal hydrogen bonding networks described here. Better correlation was found

AMG 670129 sorbic acid AMG 670129 Table 2. Crystallographic Data for Eight Co-Crystals and Two Free Bases AMG 678809 sorbic acid AMG 678809 AMG 517 propionamide AMG 517 capronamide AMG 517 adipic acid AMG 517 malonic acid AMG 517 succinic acid parameter

formula stoichiometry formula weight crystal system space group a () b () c () R (deg) (deg) (deg) volume (3) calc density (g cm-3) Z range (deg) data/restraints/params T (K) R1 wR2

C22H16F3N4O4S 2:1 489.45 triclinic j P1 10.302(2) 12.794(3) 17.004(4) 104.026(4) 99.473(4) 91.595(4) 2139.4(8) 1.52 4 1.25 to 25.00 7460/222/617 193(2) 0.0785 0.1609

C33H45F3N4O8S 2:1 714.79 triclinic j P1 11.582(2) 12.275(2) 16.184(3) 97.183(4) 108.818(4) 98.030(4) 2120.7(7) 1.12 2 1.35 to 25.00 7386/0/608 193(2) 0.0607 0.0827

C23H18F3N4O4S 2:1 503.47 monoclinic P2(1)/n 10.559(2) 9.528(2) 22.396(5) 90.000 97.098(4) 90.000 2235.8(9) 1.50 4 1.83 to 27.92 5338/0/388 193(2) 0.0574 0.1446

C26H26F3N5O3S 1:1 545.58 monoclinic P2(1)/n 5.233(14) 20.056(6) 25.014(7) 90.000 93.300(6) 90.000 2620.8(12) 1.38 4 1.3 to 25.00 4619/0/345 193(2) 0.0677 0.1757

C23H20F3N5O3S 1:1 503.5 triclinic j P1 5.102(8) 10.128(17) 23.009(4) 102.072(3) 93.711(3) 98.007(3) 2120.7(7) 1.46 2 0.91 to 27.90 5417/0/318 193(2) 0.0534 0.1331

C18H11F3N4OS 1 388.37 triclinic j P1 9.862(15) 12.958(19) 13.551(19) 98.915(3) 90.638(3) 93.451(3) 1707.3(4) 1.51 4 1.52 to 27.89 7890/0/575 193(2) 0.0996 0.1606

C24H19F3N4O3S 1:1 500.49 triclinic j P1 11.917(3) 12.426(3) 16.430(4) 83.330(4) 76.227(4) 78.659(4) 2310.8(11) 1.44 4 1.28 to 27.91 10949/0/783 193(2) 0.0585 0.1341

C20H14F3N4O 1 383.35 triclinic j P1 10.269(2) 13.135(3) 13.325(3) 107.245(3) 98.368(4) 91.498(4) 1693.8(6) 1.50 4 1.62 to 27.90 7876/0/507 193(2) 0.0857 0.2607

C26H21F3N4O3 1:1 494.47 monoclinic P2(1)/n 5.206(8) 25.720(4) 17.027(3) 90.000 93.981(3) 90.000 2274.2(6) 1.44 4 1.44 to 25.02 4004/0/326 193(2) 0.1634 0.0473

Structure Property Relationships in Co-Crystals

Crystal Growth & Design, Vol. 9, No. 3, 2009 1349

Table 3. DC-O Distances for Six Co-Crystals with an Acid Co-Crystal Former compound AMG AMG AMG AMG AMG AMG
a

former succinic acid malonic acid adipic acid sorbic acid sorbic acid sorbic acid

DC-01 () 1.212 1.222 1.202 1.212 1.216 1.235

DC-02 () 1.307 1.294 1.306 1.310 1.324 1.256

DC-03 () 1.208 1.199 1.202 NA NA NA

DC-04 () 1.304 1.326 1.306 NA NA NA

DC-O (1)a 0.095 0.072 0.104 0.098 0.108 0.021

DC-O (2)b 0.096 0.127 0.104 NA NA NA

517 517 517 831664 678809 670129

DC-O2 - DC-O1. b DC-O4 - DC-O3; NA: not relevant.

Figure 3. Heterosynthons observed in (3a) AMG 517, AMG 831664, and AMG 678809 acid co-crystals, (3b) AMG 517 amide co-crystals, and the (3c) AMG 670129 sorbic acid co-crystal (R ) H, COCH3, or COCH2CH3).

for some subclasses such as the amide co-crystals. However, the data sets are too small to warrant presentation and an extensive discussion. Finally, when a correlation analysis30 was performed on the numerical parameters listed in Table 4 (data not shown), no overall correlation was found between the starting particle size and any other numerical parameter. This does not indicate that major differences in particle size may not have inuenced the rate of conversion differences between certain co-crystals as discussed below. The majority of the co-crystals reach a maximum solubility (Smax) within 1-2 h and then decrease over time. This is shown in Figure 7 for six AMG 517 acid co-crystals, in Figure 8 for ve amide co-crystals, and in Figure 9 for three sorbic acid co-crystals of other TRPV1 compounds and the corresponding free bases. The bell-shaped prole can be explained by the dissolution of the co-crystal followed by conversion to the free base or free base hydrate, as determined by XRPD (see Table 4). A similar conversion has previously been reported for the AMG 517 sorbic acid co-crystal6 and for ve other 1:1 cocrystals with AMG 517.20 By comparing the data in Table 4 and Figures 7 and 8 it is seen that two acid co-crystals (i.e., succinic and adipic) and one amide co-crystal (i.e., cinnamamide) have comparable or lower solubility than AMG 517 free base. This may reect the different hydrogen bonding networks. Since the experiments are describing kinetic solubility, particle size may potentially play a role. However, when data from Table 4 for the acid co-crystal with the largest particle size, AMG 517 citric acid co-crystal (X50 ) 512 m), is compared to the co-crystal with the lowest particle size, AMG 517 malonic acid co-crystal (X50 ) 31 m), it is apparent that the two co-crystals have almost identical Smax (8.4 versus 8.1 g/mL, respectively), and consequently the starting particle size does not have an obvious impact on solubility for these co-crystals. From Table 4 it is seen that two co-crystals (i.e., cinnamamide and benzamide) do not convert to a form of the free base during the solubility experiment. The cinnamamide co-crystal is the least soluble amide co-crystal (<6 g/mL), so it is possible that 24 h is not sufcient time for conversion to occur. The cinnamide co-crystal has the smallest starting particle size among the amide co-crystals (i.e., 134 m); thus, the lack of conversion may not be explained by particle size. Usually, smaller particle size gives rise to a faster rate of conversion.31 However, the benzamide co-crystal has signicant solubility, a bell-shaped solubility prole, but yet no conversion was found. The details

on what governs the formation and conversion of AMG 517 co-crystals of various stoichiometries will be investigated and hopefully will be the subject of a future communication. By comparing the data in Table 4 and Figure 9 with previously published records,20 it is seen that most sorbic acid co-crystals of other TRPV1 compounds have lower solubility than the AMG 517 sorbic acid co-crystal (Smax 12 g/mL). The only exception is the AMG 670129 sorbic acid co-crystal, but as discussed previously, this co-crystal may have salt character. In addition the Smax of AMG 678809 and AMG 670129 sorbic acid co-crystal was improved over the respective free base. However, the AMG 831664 sorbic acid co-crystal showed no signicant improvement in solubility over the free base. As evident from Figure 1 the structures of AMG 517 and AMG 831664 are similar, and as discussed previously the corresponding co-crystals have identical hydrogen bonding network. However, the AMG 831664 sorbic acid co-crystal crystallizes in a different crystal system and space group (i.e., monoclinic and C2/C, respectively) than the AMG 517 sorbic acid co-crystal j, respectively). Whether this explains the (i.e., triclinic and P1 solubility differences would need to be investigated further to reach a conclusion. The AMG 670129 sorbic acid co-crystal converts to the free base within 4 h with a resulting drop in solubility over time. AMG 678809 sorbic acid co-crystal, however, does not share this prole. This co-crystal maintains constant solubility for at least 24 h. However, examination of the solids at 24 h time point by XRPD shows that the co-crystal has started to convert to the free base. This slower rate of conversion may be due to the previously described different hydrogen bonding pattern in the tetramers of the two co-crystals. Alternatively, it could be explained by the large particle size of the AMG 678809 sorbic acid co-crystal (see Table 4). The same increase in surface area (i.e., smaller particle size) that allows for faster dissolution may also increase the rate of form change.31 In this research we found that all but two co-crystals convert to a form of the free base during the solubility experiment. This has previously been described for the AMG 517 sorbic acid co-crystal and several other 1:1 co-crystal of AMG 517.6,20 As discussed the initial solubility advantage may drive the exposure advantage that we reported for the sorbic acid co-crystal,6 but the disproportionation may also give rise to physical stability concerns. Consequently, physical stability of the solid samples of all 15 co-crystals at 40 C/75%RH was also monitored for 1 month. No signicant changes were observed in any of the samples by XRPD indicating that all samples were stable at these conditions. It is evident from Table 1 that we successfully formed sorbic acid co-crystals of four out of seven compounds listed in Figure 1. It has been discussed that method diversity is crucial for nding co-crystals,7,32 and consequently we employed both solution crystallization methods and solvent drop grinding methods to generate co-crystals. Using these two approaches, we were not able to form sorbic acid co-crystals of AMG 677902, AMG 676826, and AMG 831790. Consequently, it

1350 Crystal Growth & Design, Vol. 9, No. 3, 2009

Stanton et al.

Figure 4. Hydrogen bonding of (4a) AMG 517 sorbic acid,6 (4b) AMG 517 capronamide, and (4c) AMG 517 propionamide co-crystals (view chosen to highlight hydrogen bonding).

Figure 5. Hydrogen bonding of (5a) AMG 517 malonic acid, (5b) AMG 517 succinic acid, and (5c) AMG 517 adipic acid co-crystals (view chosen to highlight hydrogen bonding).

Figure 6. Hydrogen bonding of (6a) AMG 670129 free base, (6b) AMG 670129 sorbic acid co-crystal, (6c) AMG 678809 free base, and (6d) AMG 678809 sorbic acid co-crystal (view chosen to highlight hydrogen bonding).

appears that completely removing (i.e., AMG 678809) or extending the chain on the amide proton donor (i.e., AMG 831664) had no effect on co-crystal formation. Next, removing the amide proton donor responsible for hydrogen bonding to the carboxyl group on the co-crystal former (i.e., AMG 676826) apparently inhibited co-crystal formation. Amides are strong hydrogen bond donors,33 and this bond may have been signicant in holding the crystal together, which may potentially explain our inability to form a AMG 676826 sorbic acid cocrystal. Furthermore, we were unable to form the AMG 831790 sorbic acid co-crystal after multiple attempts. Structurally AMG 831790 is identical to AMG 517 except having a pyridine rather than a pyrimidine, which, in AMG 517 sorbic acid co-crystal, is not responsible for hydrogen bonding to the co-crystal former. Unfortunately, we were not able to obtain a single crystal structure of the AMG 831790 free base. However, the melting points of the two compounds, AMG 831790 and AMG 517, are quite different. AMG 517 melts at 230 C while AMG 831790 has a much higher melting point at 291 C, which is an indication of strong intermolecular bonding.34 This may poten-

tially explain our inability to form a sorbic acid co-crystal with AMG 831790. Finally, changing the core from an amino benzothiazole in AMG 517 to a quinoline group in AMG 677902 resulted only in unsuccessful attempts to form a sorbic acid co-crystal. However, we were able to form a co-crystal with AMG 670129, which also contains a quinoline group. As discussed AMG 670129 sorbic acid co-crystal may have salt character. This may potentially explain why we are able to form a multicomponent complex of AMG 670129 but not AMG 677902, since ionic bonds are in general stronger than hydrogen bonds.34 Conclusion As the drug discovery strategy in the pharmaceutical industry is changing, the need for new approaches to deal with increasingly poor physicochemical properties of NCEs has become evident. The research presented here illustrates that pharmaceutical co-crystals can be successfully used to alter physicochemical properties, such as solubility and melting points, of NCEs. We investigated 12 co-

Structure Property Relationships in Co-Crystals

Crystal Growth & Design, Vol. 9, No. 3, 2009 1351

Table 4. Solubility (Smax),a Particle Size, and Potential Conversion of 14 Co-Crystals melting onsets (C) co-crystal AMG AMG AMG AMG AMG AMG AMG AMG AMG AMG AMG AMG AMG AMG
c

solubility Smax (g/mL) molar ratio 2:1 2:1 2:1 2:1 1:1 2:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 free baseb 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 0.4 0.6 0.9 co-crystal 2.1 8.4 21.5 24.0 8.1 3.5 12.6 14.5 6.3 14.3 15.3 8.2 1.7 14.8 log Smax co-crystal 0.32 0.92 1.33 1.38 0.91 0.54 1.11 1.18 0.78 1.15 1.18 0.91 0.23 1.17 conversion during experimentc some FB hydrate some FB hydrate some FB hydrate some FB hydrate some FB hydrate some FB hydrate no some FB hydrate no some FB hydrate some FB hydrate some FB some FB some FB

particle size X50 (m) co-crystal 118 512 59 64 31 93 170 138 134 299 428 758 131 263 free base 3 3 3 3 3 3 3 3 3 3 3 9 83 37

former 152 155 141 103 135 185 125 101 147 80 104 134 134 134

co-crystal 199 169 187 218 186 180 164 119 184 126 123 152 164 138

517 - adipic acid 517 - citric acid 517 - maleic acid 517 - L-malic acid 517 - malonic acid 517 - succinic acid 517 - benzamide 517 - capronamide 517 - cinnamamide 517 - propionamide 517 - valeramide 678809 - sorbic acid 831664 - sorbic acid 670129 - sorbic acid

a Smax: the max solubility observed in the solubility over time prole. b No conversion of the parent free bases were observed during the experiment; Co-crystal conversion was assessed by XRPD; FB: free base.

Figure 7. Solubility proles of six AMG 517 co-crystals with acids in FaSIF.

Figure 9. Solubility proles of three sorbic acid co-crystals with other TRPV1 compounds and their corresponding free bases in FaSIF.

Figure 8. Solubility proles of ve AMG 517 co-crystals with amides in FaSIF.

crystals of AMG 517 with diverse acids and amides, and three sorbic acid co-crystals with other related TRPV1 compounds. We could not obtain single crystal structures of all co-crystals, but the eight obtained showed the same two hydrogen bonds, connecting the co-crystal former and the API, as previously described for the AMG 517 sorbic acid co-crystal.6 Since all the co-crystal formers and APIs had multiple hydrogen bond donors and/or acceptors, additional hydrogen bonds were also observed. Hydrogen bonding network is related to physicochemical properties, and given the diversity of formers and APIs employed in this study we found

low correlation between the melting point of the co-crystal former and the melting point of the co-crystal, and no correlation between the melting point and the Log solubility of the co-crystals across all 15 co-crystals. We previously reported that design of co-crystals were possible by considering certain properties of the co-crystal former and the co-crystal within a series of 10 1:1 co-crystal of AMG 517.20 This present work indicates that the co-crystals need to be very similar for such design to be possible. In addition, this article highlights the importance of the API in co-crystal design. We found that our ability to form co-crystals was sensitive to minor changes in the chemical structure of the drug substance. The present work also illustrates the range of physicochemical properties possible when diverse acids and amides are used as cocrystal formers for AMG 517. We previously reported on the serendipitous discovery of the AMG 517 sorbic acid co-crystal6 and nine 1:1 co-crystals with AMG 517 and mono- and diacids.20 However, as described in this research other classes of formers such as amides almost exclusively gave rise to higher solubility than the AMG 517 sorbic acid co-crystal. Therefore, it would be valuable to explore expanding the list of pharmaceutically acceptable co-crystals formers. This discussion is ongoing, should be cross-functional, will require involvement of disciplines other than physical chemistry (e.g., legal, regulatory, and safety assessment), but is outside the scope of this article on crystal engineering. As discussed, the case studies where the pharmacokinetics of pharmaceutical co-crystals has been tested are few and far in between. Physicochemical properties are just one of many

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factors such as permeability and metabolism that inuence the absorption of drugs.35 Therefore, future work within this area should attempt to illuminate pharmacokinetic properties of pharmaceutical co-crystals. Acknowledgment. We wish to acknowledge Drazen Ostovic and Beata Sweryda-Krawiec for helpful discussions, Richard Staples for conducting the single crystal structure analysis, and Krawiec Lee for editing assistance. In addition, we would like to thank Dennis Lei and Janan Jona for determining the actual pKa value for AMG 670129.
Supporting Information Available: 1H NMR, XRPD, DSC, and TGA data and X-ray crystallographic information les (.cif) are available. This material is available free of charge via the Internet at http:// pubs.acs.org.

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