Cocrystals of Piroxicam with Carboxylic Acids - ACS Publications

CRYSTAL GROWTH & DESIGN

Cocrystals of Piroxicam with Carboxylic Acids Scott L. Childs*,‡ and Kenneth I. Hardcastle§ SSCI, Inc., 3065 Kent AVenue, West Lafayette, Indiana 47906, and Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30306

2007 VOL. 7, NO. 7 1291-1304

ReceiVed October 23, 2006; ReVised Manuscript ReceiVed February 20, 2007

ABSTRACT: A crystal engineering method was used to investigate cocrystal formation of piroxicam with pharmaceutically acceptable carboxylic acids. Forming cocrystals of piroxicam can potentially result in solid forms with increased bioavailability. A total of 50 unique cocrystals containing piroxicam and a guest carboxylic acid were identified in screening experiments. Each of the 23 guest molecules tested formed at least one cocrystal with piroxicam. In addition, the three known polymorphs of piroxicam were observed. Raman data for the piroxicam cocrystals can be sorted into three distinct groups based on spectral similarity. These groups are differentiated by the piroxicam tautomer present in the cocrystal and the presence or absence of a strong hydrogen bond donor interacting with piroxicam’s amide carbonyl group. X-ray powder diffraction data revealed six isostructural piroxicam cocrystals. Single-crystal structure determination revealed that this isostructural series is a host-guest system in which the piroxicam forms a well-ordered host containing disordered guest compounds. Crystal structures of eight piroxicam cocrystals and a dioxane solvate of piroxicam are reported. All carboxylic acid guest compounds are non-ionized in the cocrystals, and piroxicam is present as the non-ionized or zwitterionic tautomer. Of special interest are two 1:1 piroxicam/4-hydroxybenzoic acid cocrystal polymorphs. While the unit cell contents are identical, one polymorph contains the non-ionized piroxicam tautomer plus the guest, while the other contains the zwitterionic tautomer plus the guest. In a related phenomenon, a 4:1 piroxicam/fumaric acid cocrystal is reported that contains one zwitterionic tautomer, one non-ionized tautomer, and one-half of a non-ionized fumaric acid in the asymmetric unit. Introduction Most pharmaceuticals contain active pharmaceutical ingredients (APIs) in the form of molecular crystals. During the development of these drugs, one of the early decisions to be made concerns the crystalline form that will be used to deliver the API in an oral dosage form. Physical properties of this solid form can dramatically affect the efficacy of the drug. Dissolution rate, solubility, hygroscopicity, and chemical stability are some of the more important factors that must be considered. The arrangement of molecules at the atomic scale affects the physical properties on the macroscopic level,1 and manipulating physical properties by rearranging the molecules in the solid state through the formation of different crystal structures is common practice in the pharmaceutical industry. Crystallizing the API as a multicomponent crystal has been an accepted approach to generating form and physical property diversity. Hydrate and salt formation2 are the most common applications of this concept if the API and salt former are considered to be two independent molecular components that form an ionic complex. Traditionally, any additional molecular component introduced into a pharmaceutical dosage form has been limited to water, possibly a nontoxic solvent such as ethanol, or a salt former. Along with a polymorph screen, this has been considered to be a complete approach to solid form screening. However, the diversity of solid forms obtainable through these approaches is limited.3 Crystal engineering concepts4 applied to pharmaceuticals provides a new path for the systematic discovery of a wider range of multicomponent structures containing the API by reconsidering the types of molecules and intermolecular interactions that can be used to form crystalline complexes with pharmaceuticals. A cocrystal is a crystalline material made up of two or more components, usually in a stoichiometric ratio, each component * Corresponding author. Fax: 404 712-9357. Phone: 404 377-7876. E-mail: [email protected]. ‡ SSCI, Inc. § Emory University.

Figure 1. The molecular structure of piroxicam.

being an atom, ionic compound, or molecule. Cocrystals rely primarily on the use of hydrogen bonds to form an API/guest molecular complex in the solid state. The pharmaceutical sciences has provided a venue for the practical application of crystal engineering and supramolecular synthesis, and although it is still an emerging area of research, cultivating cocrystals5 is becoming an accepted approach for creating solid dosage forms.6 Here we report the results of a crystal engineering approach to generating cocrystals of piroxicam. Piroxicam (Figure 1) is a nonsteroidal anti-inflammatory drug (NSAID).7 Piroxicam is an enolic acid used in the symptomatic relief of rheumatoid arthritis and osteoarthritis.8 Piroxicam has low solubility at physiological pH and is classified as a Class II API (low solubility and high permeability) based on the Biopharmaceutics Classification System (BCS).9 It takes more than 2 h for piroxicam to reach the maximum concentration after being administered orally.10 A more rapid onset and increased bioavailability is desirable for analgesics of this type and formulation and delivery of piroxicam with improved bioavailability has been the goal of a number of research studies. A cocrystal screen of piroxicam is relevant because we have shown that cocrystals of Class II compounds can provide increased bioavailability.11 There are a large number of multicomponent solid forms of piroxicam that have been studied. A cocrystal of piroxicam containing saccharin as the guest has been reported12 and salts of piroxicam have been formed with pharmaceutically acceptable bases such as L-arginine,13 ethanolamine, triethanolamine,

10.1021/cg060742p CCC: $37.00 © 2007 American Chemical Society Published on Web 05/31/2007

1292 Crystal Growth & Design, Vol. 7, No. 7, 2007

and diethanolamine.14 A number of metal complexes are known,15 and beta-cyclodextrin inclusion complexes containing the zwitterion, the sodium salt monohydrate and other piroxicam complexes have been studied.16 A variety of noncrystalline multicomponent piroxicam systems have also been considered in efforts to improve the bioavailability of piroxicam, including dispersions of piroxicam in polymers,17 lipids,18 nicotinamide,19 maltodextrin,20 and urea.21 The cocrystals reported here are only one type of multicomponent solid form that can be considered in the process of selecting the best solid dosage form of piroxicam but an important one because these solid forms represent an emerging field within the pharmaceutical sciences. Although the concept of cocrystals is well-known in the academic literature, the cocrystallization of an API is a new option in the pharmaceutical solid form selection process that is finding a voice in industrial research programs and steadily gaining acceptance within the pharmaceutical industry. Experimental Procedures Piroxicam and 23 carboxylic acids were purchased from the Sigma Chemical Company, St. Louis, MO, and used as received without further purification. Solution-Based Cocrystal Screen of Piroxicam. A cocrystal screen of piroxicam was performed by generating two duplicate 96-well plates in which piroxicam was combined, in solution, with 23 different “guest” carboxylic acids. Four experiments per acid were prepared in each plate. Each of these four experiments contained a unique solvent mixture with the same piroxicam/guest combination. Four wells functioned as control experiments and contained only piroxicam in four unique solvent mixtures. The solutions were allowed to evaporate to dryness at room temperature. The first plate was allowed to evaporate faster, over the course of about 8 h, while the second plate evaporated more slowly over 3-5 days. Solids were examined by microscopy. Raman spectroscopic data were obtained on samples in all 96 wells in both plates. Multiple spectra were obtained from unique domains in selected wells. XRPD data were obtained from selected wells in plate 1 and all 96 wells in plate 2. Infrared (IR) data were obtained from 18 selected wells in plate 1. Solid-State Grinding Cocrystal Screen of Piroxicam. Physical mixtures of piroxicam with 20 carboxylic acids were generated by combining weighed amounts of each API/guest acid combination in an agate grinding vial in 1:2 and/or 1:1 API/guest molar ratios. The physical mixtures were ground in 3-5 min cycles in a Retsch mm200 mixer mill at 80% power, and the solids were examined after each grinding cycle. Solids were scraped from the side of the vial between cycles. Raman spectra were obtained from the sample at the end of each cycle. Samples were initially ground dry (no solvent) for up to three cycles. The solid form based on the Raman spectra was determined, and then a drop of solvent was added to the grinding jar. One drop was typically used for 25-50 mg of material. Solvents used were 2,2,2-trifluoroethanol, methanol, or acetonitrile. Up to three cycles of grinding with the added solvent were performed, and the resulting solid form was identified by Raman spectroscopy. At least two experiments were performed for each API/guest combination. A total of 52 experiments were performed. The Raman spectra of the ground products was compared to the data obtained from the solution screen to determine the identity of the solid form after grinding. XRPD data were obtained on new solid forms identified by Raman spectroscopy but not obtained in the solution screen. Raman Spectroscopy Data Acquisition. Raman spectra were collected with a Chromex Sentinel dispersive Raman unit equipped with a 785 nm, 70 mW excitation laser and a TE cooled CCD (1024 × 256 pixels, < 0.1e - /pixel/s). A fiber-optically coupled filtering probe was used to collect data in a spectral range of 300 cm-1 to 2180 cm-1 at a resolution of 4 cm-1. Each spectrum is a result of two or more co-added 20 s scans. The unit has continuous automatic calibration using an internal standard. The data were collected by SentinelSoft data acquisition software and processed in GRAMS/AI V.7. Infrared (IR) Spectroscopy Data Acquisition. IR spectra were acquired on a Magna-IR 860 Fourier transform infrared (FTIR)

Childs and Hardcastle spectrophotometer (Thermo Nicolet) equipped with an Ever-Glo mid/ far IR source, an extended range potassium bromide (KBr) beamsplitter, and a deuterated triglycine sulfate (DTGS) detector. An attenuated total reflectance (ATR) accessory (Thunderdome, Thermo Spectra-Tech), with a germanium (Ge) crystal was used for data acquisition. Generally, the spectra represent 256 co-added scans collected at a spectral resolution of 4 cm-1. A background data set was acquired with a clean Ge crystal. Log 1/R (R ) reflectance) spectra were acquired by taking a ratio of these two data sets against each other. Wavelength calibration was performed using polystyrene. X-ray Powder Diffraction. X-ray powder diffraction (XRPD) analyses were performed using a Bruker D-8 Discover diffractometer and Bruker’s general area diffraction detection system (GADDS, v. 4.1.20). An incident beam of Cu KR radiation was produced using a fine-focus tube (40 kV, 40 mA), a Go¨bel mirror, and a 0.5 mm doublepinhole collimator. Some samples were packed between 3-micron thick films to form a portable disc-shaped specimen. The prepared specimen was loaded in a holder secured to a translation stage and analyzed in transmission geometry. The incident beam was scanned and rastered to optimize orientation statistics. A beam-stop was used to minimize air scatter from the incident beam at low angles. Samples contained in wellplates were positioned for analysis by securing the well plate to a translation stage and moving each sample to intersect the incident beam. The samples were analyzed using a transmission geometry. The incident beam was scanned and rastered over the sample during the analysis to optimize orientation statistics. A beam-stop was used to minimize air scatter from the incident beam at low angles. Diffraction patterns were collected using a Hi-Star area detector located 15 cm from the sample and processed using GADDS. The intensity in the GADDS image of the diffraction pattern was integrated using a step size of 0.04° 2θ. The integrated patterns display diffraction intensity as a function of 2θ. Prior to the analysis, a silicon standard was analyzed to verify the Si 111 peak position. Single-Crystal X-ray Diffraction. Suitable crystals of each solid form sample were coated with Paratone N oil, suspended in a small fiber loop, and placed in a cooled nitrogen gas stream at 173 K on a Bruker D8 sealed tube diffractometer. Diffraction intensities from samples 11A2, 11B, and 4B were obtained using graphite monochromated MoKR (0.71073 Å) radiation and an APEX I CCD detector. The data were measured using a series of combinations of phi and omega scans with 10-30 s frame exposures and 0.3° frame widths. Data collection, indexing, and initial cell refinements were all carried out using SMART22 software. Frame integration and final cell refinements were done using SAINT23 software. For samples 7A1, 17A, 20A, 3B, and 24B, the diffraction intensities were obtained using graphite monochromated CuKR (1.54178 Å) radiation. Data were measured with an APEX II CCD detector by using a series of combinations of phi and omega scans with 10-30 s frame exposures and 0.5° frame widths. Data collection, indexing, and initial cell refinements were all carried out using APEX II24 software. Frame integration and final cell refinements were done using SAINT software. The SADABS25 program was used to carry out absorption corrections on all samples. All solid-state structures were solved using Direct methods and difference Fourier techniques (SHELXTL, V6.14).26 Hydrogen atoms were placed on their expected chemical positions using the HFIX command or obtained from difference Fourier maps and were included in the final cycles of least-squares with isotropic Uij’s. All non-hydrogen atoms were refined anisotropically except for sample 17A; only the N, O, and S atoms were refined anisotropically for that structure. Scattering factors and anomalous dispersion corrections are taken from the International Tables for X-ray Crystallography.27 Structure solution, refinement, and generation of publication materials were performed by using SHELXTL, V6.14 software. Graphics for publication were generated using X-Seed software.28 Additional details of data collection and structure refinement are given in Tables 1 and 2. Single crystals were grown by generating an array of slow evaporation experiments. Four different solvent compositions were used for each of 10 selected guest compounds for a total of 40 experiments. API and guest were added in 1:1 or 2:1 ratios by delivering appropriate volumes of stock solutions into the vials. The vials were sealed with a plastic cap that contained one small hole. The solutions evaporated over the course of two to three weeks at room temperature. All potential single crystals were screened by collecting Raman spectra on the individual single crystals before mounting on the diffractometer. The

Cocrystals of Piroxicam

Crystal Growth & Design, Vol. 7, No. 7, 2007 1293 Table 1. Crystallographic Data for Cocrystals 7A1, 17A, 20A, 14C, and 11A2 7A1 2:1 piroxicam/ succinic acid

empirical formula formula weight temperature, K wavelength, Å crystal system space group unit cell dimensions a, Å b, Å c, Å R, deg β, deg γ, deg volume, Å3 Z density (calc), Mg/m3 abs coef, mm-1 F(000) crystal size, mm3 theta range for data collection index ranges reflections collected independent reflections completeness, % absorption correction max and min transmission refinement method data/restraints/ parameters goodness-of-fit on F2 final R indices [I > 2σ(I)] R indices (all data) largest diff peak and hole, e‚Å-3

17A

20A

14C

11A2

1:1 piroxicam/ caprylic acid

piroxicam/ malonic acid

C17H16N3O6S 390.39 173(2) 1.54178 triclinic P1h 7.7069(2)

1:1 piroxicam/ 1-hydroxy2-naphthoic acid C26H21N3O7S 519.52 173(2) 1.54178 triclinic P1h 6.9743(6)

C23H29N3O6S 475.55 173(2) 1.54178 triclinic P1h 8.4286(6)

C30H26N6O8S2 662.69 173(2) 1.54178 monoclinic P21/c 15.692(8)

1:1 piroxicam/ 4-hydroxybenzoic acid, form 1 C22H19N3O7S 469.46 173(2) 0.71073 monoclinic P21/n 9.3201(10)

8.4282(2) 14.4344(3) 79.6380(10) 74.9870(10) 72.6160(10) 858.87(4) 2 1.510

12.3558(9) 14.9892(14) 114.045(6) 92.672(7) 95.105(6) 1170.02(17) 2 1.475

9.7241(6) 15.2060(9) 94.674(3) 105.723(3) 97.953(3) 1178.83(13) 2 1.340

16.195(7) 6.999(3) 90 101.720(11) 90 1741.7(14) 2 1.264

16.4366(17) 14.2134(15) 90 100.561(2) 90 2140.5(4) 4 1.457

2.061 406 0.37 × 0.24 × 0.18 8.15-65.76

1.704 540 0.17 × 0.07 × 0.04 3.24-37.63

1.595 504 0.41 × 0.18 × 0.18 3.04-65.95

1.852 688 0.10 × 0.03 × 0.01 8.47-45.17

0.202 976 0.33 × 0.26 × 0.25 1.91-28.34

-8 e h e 8 -9 e k e 8 -4 e l e 16 4356 2162 [R(int) ) 0.0122] 73.0 semiempirical from equivalents 0.7079 and 0.5160




-12 e h e 12 -21 e k e 21 -18 e 1 e 18 31316 5328 [R(int) ) 0.0421] 99.7 semiempirical from equivalents 0.9511 and 0.9362

full-matrix least-squares on F2 2162/0/309





1.058

1.058

1.075

1.057

1.070

R1 ) 0.0296, wR2 ) 0.0817 R1 ) 0.0300, wR2 ) 0.0822 0.276 and -0.312

R1 ) 0.0480, wR2 ) 0.1240 R1 ) 0.0632, wR2 ) 0.1447 0.232 and -0.237

R1 ) 0.0855, wR2 ) 0.2029 R1 ) 0.1379, wR2 ) 0.2715 0.836 and -1.441

R1 ) 0.0853, wR2 ) 0.2426 R1 ) 0.1243, wR2 ) 0.2641 0.354 and -0.401

R1 ) 0.0508, wR2 ) 0.1166 R1 ) 0.0573, wR2 ) 0.1205 0.515 and -0.344

experimental conditions used to generate each single-crystal sample are as follows: 2:1 Piroxicam/Succinic Acid (7A1). A single crystal was formed by slow evaporation in a wellplate during screening experiments. The solvent system was 2:1 tetrahydrofuran (THF)/2-propanol. 1:1 Piroxicam/1-Hydroxy-2-Naphthoic Acid (17A). Single crystals were recovered from a slow evaporation of a 2:1 THF/2-propanol solution containing an equimolar mixture of piroxicam and 1-hydroxy2-naphthoic acid. 1:1 Piroxicam/Caprylic Acid (20A). Single crystals were grown by saturating a sample of caprylic acid with piroxicam at 50 °C. The solution was seeded with a cocrystal sample obtained in the wellplate evaporative experiments. The sample was allowed to cool to room temperature, and single crystals formed overnight. Piroxicam/Malonic Acid (14C). Single crystals were grown from a slow evaporation of a 1:1 mixture of trifluoroethanol and acetonitrile. 1:1 Piroxicam/4-Hydroxybenzoic Acid, Form 1 (11A2). A 1:1 methanol/acetonitrile solution containing a 1:1 mixture of piroxicam/ 4-hydroxybenzoic acid was allowed to evaporate slowly at room temperature. Rectangular colorless blocks were recovered from the solution before all of the solvent evaporated.

1:1 Piroxicam/4-Hydroxybenzoic Acid, Form 2 (11B). Slow evaporation of a 3:1 trifluoroethanol (TFE)/methanol solution containing a 1:1 mixture of piroxicam/4-hydroxybenzoic acid resulted in a mixed product containing primarily piroxicam form I as long needles. Yellow blocks of 11B of adequate size for structure determination grew at the evaporation front. This product was not observed in the screening experiments and was only isolated from the single-crystal experiments and characterized by Raman spectroscopy and single-crystal X-ray diffraction. 4:1 Piroxicam/Fumaric Acid (4B). Slow evaporation of a 3:1 TFE/ methanol solution containing a 2:1 mixture of piroxicam:fumaric acid resulted in a mixed product containing piroxicam form I, fumaric acid, and 4B as tiny needles. At the evaporation front, small clusters of plates of 4B grew as a minor ( 2 σ(I)] R indices (all data) largest diff peak and hole, e.Å-3

4B

3B

24B

1:1 piroxicam/ 4-hydroxybenzoic acid, form 2 C22H19N3O7S 469.46 173(2) 0.71073 triclinic P1h 7.4086(10)

4:1 piroxicam/ fumaric acid

1:1 piroxicam/ benzoic acid

4:1 piroxicam/ p-dioxane

C32H28N6O10S2 720.72 173(2) 0.71073 triclinic P1h 8.7433(12)

C22H19N3O6S 453.46 173(2) 1.54178 monoclinic P21/c 10.5790(8)

C16H15N3O4.5S 353.37 173(2) 1.54178 triclinic P1h 10.5355(13)

10.9004(15) 12.9268(17) 95.965(3) 100.576(3) 96.858(2) 1010.3(2) 2 1.543 0.214 488 0.40 × 0.19 × 0.09 1.62-29.91 -10 e h e 10 -15 e k e 15 -18 e l e 18 14367 5252 [R(int) ) 0.0403] 89.6 semiempirical from equivalents 0.9812 and 0.9191 full-matrix least-squares on F2 5252/0/302 1.132 R1 ) 0.0532, wR2 ) 0.1388 R1 ) 0.0669, wR2 ) 0.1468 0.584 and -0.468

10.9557(15) 16.633(2) 86.335(3) 89.030(2) 84.809(3) 1583.3(4) 2 1.512 0.239 748 0.66 × 0.31 × 0.07 1.87-28.33 -11 e h e 11 -14 e k e 14 -22e l e 22 23468 7870 [R(int) ) 0.0351] 99.6 semiempirical from equivalents 0.9835 and 0.8582 full-matrix least-squares on F2 7870/0/470 1.031 R1 ) 0.0481, wR2 ) 0.1138 R1 ) 0.0592, wR2 ) 0.1200 0.603 and -0.358

21.0495(16) 9.2413(8) 90 95.152(4) 90 2049.6(3) 4 1.470 1.816 944 0.35 × 0.03 × 0.03 4.20-44.64 -9 e h e 9 -18 e k e 19 -8 e l e 8 6147 1537 [R(int) ) 0.1135] 94.2 semiempirical from equivalents 0.9475 and 0.5690 full-matrix least-squares on F2 1537/0/299 1.003 R1 ) 0.0395, wR2 ) 0.0920 R1 ) 0.0645, wR2 ) 0.1040 0.152 and -0.187

12.7289(14) 13.1794(14) 102.048(6) 99.758(7) 109.836(8) 1569.5(3) 4 1.495 2.117 736 0.25 × 0.19 × 0.09 3.55-65.65 -11 e h e 11 -14 e k e 14 -15 e l e 14 8090 4300 [R(int) ) 0.0393] 79.2 semiempirical from equivalents 0.8323 and 0.6197 full-matrix least-squares on F2 4300/0/438 1.115 R1 ) 0.0584, wR2 ) 0.1828 R1 ) 0.1053, wR2 ) 0.2303 0.529 and -0.649

4:1 Piroxicam/p-Dioxane (24B). Large single crystals were obtained from a slow evaporation of a saturated solution of piroxicam in 1:4 methanol/dioxane.

Results and Discussion The cocrystal data reported here resulted from a research and development program to study the cocrystallization behavior of piroxicam and carboxylic acids that are generally considered to be pharmaceutically acceptable salt formers.29 A total of 50 multicomponent crystalline forms containing piroxicam and a non-ionized carboxylic acid guest molecule were generated using 23 carboxylic acid guests in evaporative and solid-state grinding screening experiments. The molecular structure of the guest compounds and the number of multicomponent crystalline solids identified that contain piroxicam and each guest are listed in Table 3. Of the 23 guest molecules in the screen, 6 formed 1 unique multicomponent solid form, while 9 guests formed 2, 6 guests formed 3, and 2 guests formed 4 unique piroxicam cocrystals. The 50 unique solid phases were identified using Raman spectroscopy, IR spectroscopy, and/or X-ray powder diffraction. Single-crystal structures are reported for eight of the cocrystals (Tables 1 and 2) and are dissussed below. Raman Spectroscopy. Raman spectroscopy has been used to effectively characterize solid forms of piroxicam.16a,30 Raman

spectra were collected on all solids obtained from evaporative experiments, grinding experiments, and on individual crystals isolated from experiments performed to obtain single crystals for structure determination. The spectra were analyzed using proprietary in-house software developed at SSCI to compare and sort XRPD and vibrational data.31 The spectra from the solid forms obtained in screening experiments were compared with patterns of the known polymorphs of piroxicam and patterns from an in-house database containing Raman spectra of solid forms of pharmaceutically acceptable guest compounds. The spectra of the new solid forms were sorted using an envelope matching algorithm. The dendrogram from the results of wellplate experiments indicated that the new solid forms could be sorted into one of three clearly delineated clusters (Figure 2). We arbitrarily labeled these clusters of Raman patterns Group A, Group B, and Group C. Twenty solid forms involving 17 guests could be classified as Group C. Seventeen Group B solids were formed from 12 guests, and 13 Group A forms were identified using 10 different guests (Table 4). Many guests formed structures in more than one Raman group (Table 3). The numbering scheme used to identify the piroxicam cocrystals begins with an arbitrary number associated with the guest molecule followed by a letter (A, B, or C) designating the Raman group for that solid form.


Crystal Growth & Design, Vol. 7, No. 7, 2007 1295

Table 3. Twenty-Three Carboxylic Acid Guest Compounds Used in the Cocrystal Screen of Piroxicam and the Total Number of Cocrystals Formed with That Guest and Piroxicama

a

Letter codes in the “cocrystal forms” column correspond to the Raman group assigned to each cocrystal.

If more than one cocrystal form was observed for a guest within one Raman group, then the forms have an additional sequential number appended as shown in Table 3. The single-crystal structures also use this numbering scheme as well as the Raman, IR, and XRPD data available in Supporting Information. The Group A and Group C patterns are similar and these solids are colorless, while the Group B forms are yellow and the spectral features are very different from Groups A and C. The solvo-chromism of piroxicam is well documented, and it has been shown that the colorless piroxicam polymorphs containing non-ionized molecules and the yellow piroxicam monohydrate containing zwitterionic molecules can readily be

distinguished from each other based on Raman spectra.32 Colorless solids correspond to the non-ionized tautomer of piroxicam, and the yellow color is due to the zwitterionic tautomer (Figure 3). The presence of the zwitterionic tautomer of piroxicam can easily be determined based on the presence of the strong Raman band at ∼1410 cm-1. However, while it is easy to distinguish complexes that contain a zwitterionic tautomer from one containing only the non-ionized tautomer using Raman spectroscopy, the differences between the similar Group A and Group C products are more difficult to discern (Figure 4). The existence of these two distinct groups based on envelope


Childs and Hardcastle

Figure 2. The dendrogram of Raman data from wellplate experiments sorted by an envelope matching algorithm. Table 4. Piroxicam Cocrystal Screening Results Sorted by Raman Group number of unique forms guest acid acid citric acid fumaric acid adipic acid succinic acid L-malic acid glutaric acid DL-malic acid oxalic acid (+)-camphoric acid ketoglutaric acid benzoic acid 4-hydroxybenzoic acid malonic acid salicylic acid glycolic acid 1-hydroxy-2-naphthoic acid gentisic acid dL-tartaric acid maleic acid caprylic acid hippuric acid L-pyroglutamic acid

Group A

Group B

L-tartaric

total forms per group

Group C 1 1

3 1 1 1 1 1

1 1 1 1 2

1 2

1 1 1 3

1 1 1 1 2 1 1 1 2

1

1 2 1 1

1 2 1

1

13

1

1 1

17

20

matching prompted us to look closely at the characteristics of the Raman spectra to identify the underlying reason for the formation of these two Raman groups. Group C spectra contain a characteristic peak at ∼1610 cm-1 and more intense peaks than Group A forms at 1537, 1335, and 1365 cm-1. The strong band at ∼1610 cm-1 in Group C has been assigned to the amide I mode (V CdO stretching vibration).30b That peak is not present in Group A spectra. If

the amide carbonyl group is involved in a strong intermolecular hydrogen bond, that peak is expected to be shifted to lower frequencies and also broaden.33 This assignment suggests that the difference between Group A and Group C spectra can be correlated with the hydrogen bonding of the amide carbonyl group. The conformation of the non-ionized tautomer requires one intramolecular hydrogen bond to the amide carbonyl oxygen atom from the enolic acid, but the carbonyl group is still able to accept an additional hydrogen bond from a neighboring molecule. Specifically, when the carbonyl group is accepting a strong hydrogen bond, the solid form will be in Group A. If that group is not involved in a strong hydrogen bond, it will be in Group C. Crystal structure data support the hypothesis concerning the amide carbonyl group and its involvement in a strong hydrogen bond. The crystal structures are described in detail in a subsequent section of this paper. Three structures from Group A for which crystal structures have been solved, the 1-hydroxy2-naphthoic acid cocrystal (17A), the caprylic acid cocrystal (20A), and the succinic acid cocrystal (7A1), lack the amide I (V CdO) peak at ∼1610 cm-1. These three structures have an identical intermolecular hydrogen bond pairing motif that is not present in any of the Group C crystal structures. In the 4-hydroxybenzoic acid cocrystal (11A2) and the malonic acid cocrystal (14C) the amide carbonyl group is not involved in an intermolecular hydrogen bond, and the peak at ∼1610 cm-1 is present. The crystal structures of polymorphs I and II also support these conclusions because the Raman band in question is present and the amide group is not involved in a strong hydrogen bond in these structures. IR Spectroscopy. Infrared (IR) spectroscopy has been used to study piroxicam in the solid state.37 IR data were obtained on 18 of the piroxicam cocrystals, the three known piroxicam polymorphs, and the p-dioxane solvate of piroxicam. It is possible to classify the IR spectra in a manner similar to the Raman groupings, although the groupings are not as clear with IR data. As with Raman, distinguishing between the non-ionized and zwitterion tautomers is possible, but the greater variation in IR spectra makes it much more difficult to discern between Group A and Group C forms. XRPD Data. XRPD data were used along with the Raman spectra to determine the identity of the solid forms obtained in the screening experiments. Although the XRPD patterns cannot distinguish between the different groups identified using the Raman data, they confirmed the unique crystalline structure present in each piroxicam cocrystal. In addition, the XRPD data indicated that there is a group of similar structures that form a subcategory of the Group C structures (Figure 5). The singlecrystal structure of one of those, cocrystal 14C, will be discussed in the following section. The XRPD patterns obtained from the piroxicam cocrystals are available in Supporting Information. Single-Crystal Structures. Single-crystal structures are reported for 8 of the 50 piroxicam cocrystals and also for the dioxane solvate of piroxicam. Two of the single-crystal datasets were obtained by recovering single crystals from samples generated in the 96-well plates. The rest of the single-crystal samples were generated by very slow evaporation on a larger scale. The intent of these experiments was not to determine the crystal structure of every piroxicam cocrystal that was identified but rather to generate a representative number of crystal structures to illustrate the structural features of this system. All of the single-crystal structures contain piroxicam molecules in the form of the non-ionized or zwitterionic tautomer (Figure 3). There are two strong hydrogen bond donors on each



Figure 3. Piroxicam is present in one of two tautomeric forms in the solid state. The non-ionized tautomer is present in solid forms belonging to Raman groups A and C, and these solid forms are colorless. The zwitterionic tautomer is present in the Raman group B solid forms. Solid forms containing the zwitterionic tautomer are yellow.

Figure 5. XRPD patterns for the structurally similar piroxicam cocrystals 1C (a), 14C (b), 10C2 (c), 13C (d), 9C (e), and 8C (f). These structures are a subset of Group C forms as grouped by Raman data.

Figure 4. Multiple Raman spectra from each Raman group are shown overlaid to indicate the high correlation of spectra within each group. Spectra representing Groups A (blue) and C (red) are shown to highlight the spectral differences between these two groups.

tautomer, and they both engage in intramolecular hydrogen bonding. In the non-ionized tautomer, the enolic acid forms a stable six-membered ring by hydrogen bonding to the amide oxygen atom, and the amide N-H donor forms a weaker but viable five-membered ring involving the sulfonamide nitrogen atom. This amide N-H donor is also available to form an

intermolecular hydrogen bond in addition to the relatively weak intramolecular interaction. In the zwitterionic tautomer, the enolic acid proton is located on the pyridine base. Two six-membered intramolecular hydrogenbonded rings are formed as the amide N-H is hydrogen bonded to the enolate anion and the protonated pyridine N-H is hydrogen bonded to the amide oxygen atom. The formation of the intramolecular hydrogen bonds is a dominant influence on the conformation of both tautomers of piroxicam. The interconversion of the non-ionized to the zwitterionic tautomer requires a proton transfer from the enolic acid to the pyridine base and also the rotation of two single bonds that leave the enol and pyridine groups in the same relative location but rotate the amide moiety by 180° (Figure 3). Both tautomers of piroxicam have excess hydrogen bond acceptor sites available. The availability of the pyridine acceptor site on the non-ionized tautomer and the lack of additional strong donors create favorable conditions for hetero-synthon formation between piroxicam and carboxylic acids. For instance, all of the crystal structures obtained from Groups A and C contain the acid-pyridine hetero-synthon. Likewise, the accessibility of the enolic anion on the zwitterionic tautomer creates a favorable acceptor site for the carboxylic acid guests. All known crystal structures (those reported here plus those in the CSD) were used to compare conformations of piroxicam in the non-ionized and zwitterion tautomeric conformation. Piroxicam polymorphs and multicomponent structures containing non-ionized guest molecules are included in the conformation overlay diagrams shown in Figure 6. Salt forms and metal complexes of piroxicam were not included. For structures with more than one piroxicam molecule in the asymmetric unit, each


Figure 6. Conformations of piroxicam from all known single-crystal structures are shown in these overlay plots. The non-ionized tautomer (a) and the zwitterionic tautomer (b) are shown.

Figure 7. Hydrogen-bonding motif in the 2:1 piroxicam/succinic acid cocrystal (7A1).

conformer was considered independently. When the conformations are overlaid, it is clear that differences within groups of identical tautomers are due primarily to the pyridine ring movement, while the central ring containing the sulfonamide remains essentially superimposable. The variable position of the pryidine ring is presumably due to crystal packing forces and does not represent any preferred orientation of that group. There is no correlation between the classification in the Raman groups and the conformation of the molecule or location of the substituted pyridine ring, indicating that intermolecular interactions rather than intramolecular interactions are responsible for the differences between Group A and Group C. Additional details on the specific intramolecular interactions that give rise to the Raman groupings are discussed in the context of specific crystal structures below. 2:1 Piroxicam/Succinic Acid (7A1). The 2:1 piroxicam/ succinic acid cocrystal (7A1) contains one non-ionized piroxicam molecule and one-half of a succinic acid molecule in the asymmetric unit. The succinic acid guest molecule is located on an inversion center and links two piroxicam molecules through hydrogen bonding. The conformation of the non-ionized piroxicam tautomer leaves the amide N-H donor and the pyridine acceptor positioned in a way that provides an excellent interaction site for the carboxylic acid group (Figure 7). The piroxicam molecule also interacts with a neighboring piroxicam by forming hydrogen bonds between two enolic acid donors and two amide carbonyl acceptors across an inversion center. Even though the enolic acid proton is involved in an intramolecular hydrogen bond with the amide carbonyl on the same


Figure 8. Hydrogen bonding in the 1:1 piroxicam/1-hydroxy-2naphthoic acid structure (17A), (a) and 1:1 piroxicam/caprylic acid structure (20A) (b).

molecule, it is also able to form an interaction with the amide carbonyl group on a neighboring molecule. These two interactions result in a one-dimensional (1D) hydrogen-bonded motif that extends along the b-c bisector. 1:1 Piroxicam/1-Hydroxy-2-naphthoic Acid (17A) and 1:1 Piroxicam/Caprylic Acid (20A). The hydrogen-bonding motifs in the 1:1 piroxicam/1-hydroxy-2-naphthoic acid cocrystal (17A), and the 1:1 piroxicam/caprylic acid cocrystal (20A) are similar to the hydrogen bonding in the succinic acid cocrystal (7A1). The acid group on the guest molecule is hydrogen bonded to the pyridine acceptor site on the piroxicam, and the enolic acid forms an interaction with the amide oxygen atom through intra- and intermolecular interactions across an inversion center. Instead of the continuous 1D motif formed by 7A1, 17A, and 20A each forms a zero-dimensional aggregate of four independent molecules as shown in Figure 8. 7A1, 17A, and 20A all belong to Raman Group A and contain the same general hydrogen-bonded motifs. The presence of the centrosymmetric enol-enol interaction in Group A cocrystals is the central feature that distinguishes the Group A and Group C cocrystals based on Raman data. 1:1 Piroxicam/Malonic Acid (14C). The 1:1 piroxicam/ malonic acid cocrystal (14C) forms a clathrate type structure in which a non-ionized piroxicam creates a host framework with channels along the c-axis. There are six isostructural cocrystals identified with this motif based on XRPD data (Figure 5). In addition to the structure of 14C, unit cell data were obtained for two other cocrystals identified by XRPD as having the clathrate motif (Table 5). The unit cell data matched the 1:1 piroxicam/malonic acid unit cell closely, which provides additional evidence that the six patterns in Figure 5 represent structurally similar forms. The occurrence of this isostructural host framework in the presence of six different guest molecules suggests that it is a robust packing motif. The host framework is formed by two alternating layers of piroxicam molecules that form an open linear channel approximately 7 Å in diameter (Figure 9). The piroxicam molecule is well ordered, while the guest acid is highly disordered in the channel. The orientation of the pyridine acceptor site and the amide N-H donor pointing directly into the channel suggests



Figure 9. The 1:1 piroxicam/malonic acid structure (14C) contains disordered guest molecules. Only the coordinates of the piroxicam molecule in 14C, which forms a host structure with linear cavities, are shown. The available hydrogen bond donors and acceptors are shown as spheres that are pointing into the empty channels that run along the c-axis (a). A view down the c-axis is shown as a space filling diagram (b) to highlight the channel structure. The view down the b-axis (c) shows the coplanar aromatic groups. Table 5. Unit Cell Data from Three Indexed Single Crystalsa space group

guest

a, Å

b, Å

c, Å

R, deg

β, deg

γ, deg

(a) P2(1)/c malonic 15.692 16.195 6.999 90 101.72 90 acid (14C) (b) P2(1)/c DL-malic 15.674 16.169 6.997 90 101.73 90 acid (c) P1h L-malic 15.672 16.215 7.088 82.62 98.81 96.36 acid a Unit cell (a) is from the piroxicam/malonic cocrystal structure (14C).

that these sites play an integral role in stabilizing the carboxylic acid in the channel, although the exact nature of the acid to piroxicam interaction could not be determined due to the disorder of the malonic acid guest in 14C. Attempts to refine the structure by modeling the disordered guest in the channel were unsuccessful. To refine the structure, a new set of F2 (hkl) values were generated with the residual electron density in the channel removed using SQUEEZE.34 The resulting structure contains the ordered piroxicam and empty channels. 1:1 Piroxicam/4-Hydroxybenzoic Acid, Form 1 (11A2) and 1:1 Piroxicam/4-Hydroxybenzoic Acid, Form 2 (11B). Crystal structures for two polymorphs of 1:1 piroxicam/4-hydroxybenzoic acid (11A2 and 11B) were obtained. These two polymorphs both contain one molecule of piroxicam and one molecule of 4-hydroxybenzoic acid in the asymmetric unit; however, they are very unusual polymorphs because in 11B the piroxicam is

Table 6. Solid-State Grinding Results for Piroxicam with 23 Carboxylic Acidsa guest

grinding result

benzoic acid adipic acid succinic acid (+)-camphoric acid L-malic acid ketoglutaric acid 4-hydroxybenzoic acid glutaric acid DL-malic acid malonic acid salicylic acid 1-hydroxy-2-naphthoic acid gentisic acid oxalic acid hippuric acid L-tartaric acid citric acid fumaric acid glycolic acid DL-tartaric acid maleic acid caprylic acid L-pyroglutamic acid

3B, 3C 6C 7A 8C 9B, 9C 10C1 11B 12A, 12C 13A 14B 15B2 17A 18C 19B1 21B no reaction no reaction no reaction no reaction no reaction not tested not tested not tested

a Forms shown in bold indicate a solid form not identified in the solutionbased high-throughput experiments.

present as the zwitterion tautomer and in 11A2 the piroxicam molecule is present as the non-ionized tautomer. In the case of the 1:1 piroxicam/4-hydroxybenzoic acid cocrystal polymorph containing the non-ionized tautomer (11A2,



Figure 10. Hydrogen bonding in the 1:1 piroxicam/4-hydroxybenzoic acid cocrystal (form 1) (11A2).

Figure 11. 1:1 Piroxicam/4-hydroxybenzoic acid (form 2) (11B). Only the sulfonamide group that is accepting a hydrogen bond from the carboxylic acid of the guest molecule is shown for clarity.

form 1), the carboxylic acid guest forms an unexpected hydrogen-bonded dimer (Figure 10). The expected interaction35 of the strongest donor (the carboxylic acid) with the best acceptor (the pyridine site) is not observed. Instead, the phenolic hydroxy group acts as a donor to the pyridine and an acceptor for the amide N-H. The 1:1 piroxicam/4-hydroxybenzoic acid cocrystal polymorph that contains a zwitterionic piroxicam (11B) also contains some unexpected interactions. The phenolic hydroxy group on the guest forms a hydrogen bond to the enolate oxygen (Figure 11), again in contrast to the general observation that the strongest donor interacts with the strongest acceptor. The carboxylic acid forms a hydrogen bond to the sulfonyl group on one API and also accepts a hydrogen bond from a protonated pyridine N-H located on a neighboring API. 4:1 Piroxicam/Fumaric Acid (4B). While it is unusual to find a zwitterion tautomer and a non-ionized piroxicam tautomer in a pair of polymorphic cocrystals, it is perhaps even more unexpected to find both tautomers in the same cocrystal structure. The 4:1 piroxicam/fumaric acid cocrystal (4B) contains one zwitterionic piroxicam, one non-ionized piroxicam, and onehalf of a fumaric acid in the asymmetric unit. The zwitterionic piroxicam molecule is hydrogen-bonded to another identical zwitterion through an intermolecular interaction involving the protonated pyridine and the amide carbonyl acceptor as well as a C-H‚‚‚O interaction (2.34 Å) between an aromatic C-H donor and the sulfonamide nitrogen (Figure 12b). The non-ionized piroxicam is hydrogen bonded to the fumaric acid, and the 2:1 aggregate is shown in Figure 12a. The non-ionized 2:1 piroxicam/fumaric acid cluster is similar to the aggregate formed in the succinic acid cocrystal (7A1). When observed down the a-axis, the packing of this structure suggests that the association of the zwitterionic aggregate and the 2:1 non-ionized piroxicam/guest aggregate can be viewed

Figure 12. In the 4:1 piroxicam/fumaric acid (4B), there is an aggregate of two non-ionized piroxicam molecules and one fumaric acid (a) plus an aggregate of two zwitterionic piroxicam molecules (b). The packing of these aggregates is shown in (c). Non-ionized aggregates are in blue, and the zwitterion pairs are in green. The view in (c) is down the a-axis.

as an arrangement of convenience. Each set of non-ionized and zwitterionic aggregates pack neatly side by side and layer by layer. The aggregates are formed with strong hydrogen bonds but interact with each other only through C-H‚‚‚O and van der Waals interactions. 1:1 Piroxicam/Benzoic Acid (3B). The 1:1 piroxicam/ benzoic acid cocrystal (3B) has one zwitterionic piroxicam and one non-ionized benzoic acid in the asymmetric unit. The carboxylic acid guest forms a hydrogen bond with the enolate anion acceptor site. The protonated pyridine donor forms a bifurcated interaction, forming inter- and intramolecular interactions with the amide carbonyl group. The tetramer in 3B formed by the strong hydrogen bonds as well as the weaker C-H‚‚‚O interactions is shown in Figure 13. C-H‚‚‚O interactions involving aromatic C-H donors and the benzoic acid carbonyl (2.29 Å) as well as the sulfonamide nitrogen (2.40 Å) appear to play a supporting role in the stabilization of this aggregate. All distances are non-normallized. 4:1 Piroxicam/Dioxane Solvate (24B). When the XRPD and Raman data from the wellplate screening was initially examined, it was believed that the monohydrate was identified in a number of wells because the XRPD pattern was a close match to the known pattern of piroxicam monohydrate (Figure 14). This assignment was suspect because water was not introduced as a solvent in those wells and would have to be absorbed from the air. Closer inspection revealed that the Raman and XRPD



Figure 13. Four molecules form an aggregate through hydrogen bonding in the structure of 1:1 piroxicam/benzoic acid (3B). C-H‚‚‚O interactions are shown as dashed lines.

patterns were slightly different than the known patterns of the monohydrate, but the form could not be identified. This mystery was allowed to linger until large crystals were obtained from single-crystal experiments that matched the Raman pattern of the suspect monohydrate pattern obtained in the wellplate. The volume of the unit cell obtained was nearly identical to the monohydrate (CSD refcode CIDYAP) except it was slightly larger, ∼1570 Å3 vs ∼1540 Å.3 The structure was determined to be a 4:1 piroxicam/dioxane solvate with one dioxane taking the place of a quartet of water molecules that are present in the monohydrate. The 4:1 piroxicam/dioxane solvate is essentially isostructural with the monohydrate; however, in the monohydrate, a water is hydrogen bonded to the piroxicam enolate anion, while in the dioxane structure there are no hydrogen bonding interactions involving the dioxane molecule and piroxicam. The detection of the dioxane solvate in this study might have been missed if the only analytical technique used was XRPD. The calculated XRPD patterns of the monohydrate and the dioxane solvate are so similar that the broad peaks in the experimental data make it difficult to recognize that the pattern represents something other than the known monohydrate (Figure 14). The Raman data for these forms, however, indicate that

Figure 15. XRPD data for three piroxicam polymorphs and the dioxane solvate of piroxicam, form I (a), form II (b), form III (c), and the dioxane solvate (d).

the dominant peak in the dioxane solvate spectrum is significantly shifted compared to the monohydrate (1400 cm-1 for the known hydrate and 1393 cm-1 for the dioxane solvate). The peak at 1400 cm-1 has been assigned as the V CO antisymmetric stretching mode for the enolate anion in the monohydrate,30c and the significant change in intermolecular hydrogen bonding for that group in the hydrate compared to the dioxane solvate leads to the observed peak shift. Polymorphism of Piroxicam. The polymorphism of piroxicam has been well studied,36 and three piroxicam polymorphs and one hydrate have been reported in the literature.37 Three polymorphs of piroxicam and a p-dioxane solvate were identified during the screen; XRPD patterns are shown in Figure 15 and Raman spectra of the three polymorphs are shown in Figure 16. Forms I, II, and III have been best described in the literature by Vrecer.36 Form I of piroxicam has previously been described in the literature as the beta polymorph (CSD refcodes BIYSEH38 and BIYSEH0139a) and form II as the alpha polymorph (CSD refcode BIYSEH0239). Piroxicam is also known to form a

Figure 14. Distinguishing between the piroxicam monohydrate and the 4:1 piroxicam/dioxane solvate (24B) can be difficult because these two structures are nearly identical. XRPD data (left): (e) calculated pattern for piroxicam monohydrate (CSD refcode CIDYAP), (d) calculated pattern of 24B, and (a-c) three XRPD patterns obtained from the cocrystal screen. Raman data (right) for piroxicam monohydrate (a) and 24B (b) are similar, although the strong peak shown in the inset is significantly shifted.



Figure 16. Raman spectra for the three forms of piroxicam, form I (a), form II (b), form III (c).

monohydrate (CSD refcode CIDYAP40). Redeterminations of forms I and II were recently reported by Sheth.36i Of particular interest is the fact that we obtained form III from evaporation at room temperature of a solvent mixture of 1:1:2 propionitrile/ t-butyl-alcohol/p-dioxane, whereas Vrecer, et al. reported its production by either pouring a hot, saturated solution of absolute ethanol over dry ice or spray drying. Solid-State Grinding. Solution based crystallization experiments produced 47 of the 50 piroxicam cocrystals reported here. However, the use of nontraditional synthesis techniques also plays an important role in the search for cocrystals. These techniques complement solution experiments because they can often form cocrystal phases that are not readily obtainable from traditional solution-based experiments.41 Twenty of the 23 guests used in the wellplate experiments were selected for solid-state grinding experiments. Eighteen unique solid forms were obtained from grinding experiments based on Raman data (Table 6). Three of the cocrystals obtained by grinding were not obtained in the solution experiments (Table 4). XRPD patterns of these three new ground products indicated that these were indeed unique solid forms. The role of solvent in grinding experiments has been the subject of recent discussion in the literature.42 It is often necessary to add a small amount of solvent to the grinding experiment to promote cocrystal formation, a technique that is generally referred to as “solvent drop grinding”. For example, a 1:1 molar ratio of adipic acid and piroxicam ground dry for 4 min gave no reaction, but addition of acetonitrile and subsequent grinding for 2 min resulted in complete conversion to a cocrystal form. Solvent is not necessary for a reaction to occur in some cases, and some cocrystal forms may not be observed if the same solvent is used in every grinding experiment. We started with dry grinding of the piroxicam/guest mixture, identified the product using Raman spectroscopy, and then added a drop of solvent to this product and ground the sample once more, identifying the product again by Raman spectroscopy. In the case of a 1:1 benzoic acid/piroxicam mixture, dry grinding for 3 cycles of 3 min resulted in one cocrystal. Addition of 1 drop of trifluoroethanol (TFE) or methanol plus additional grinding resulted in the formation of a different cocrystal form (identical to the single-crystal structure of the 1:1 benzoic acid:piroxicam

cocrystal (3B) reported here). In another example, a 1:1 dry grind of malonic acid and piroxicam resulted in no reaction, while addition of acetonitrile and subsequent grinding resulted in a previously unobserved cocrystal form. The ratio of the components in the grinding experiment can alter the product significantly. For example, a 1:1 molecular ratio of glutaric acid and piroxicam ground with a drop of TFE produced one colorless solid form containing the non-ionized piroxicam tautomer, while a 2:1 mixture ground with a drop of TFE produced a second colorless solid form. Both of these products were obtained in solution experiments, but the results of the grinding experiments are indicative of the component ratio that the product contains. Five of the 20 guests used did not produce a multicomponent form in grinding experiments; however, solution experiments yielded new solid forms for these piroxicam/guest combinations. The solution-based experiments produced a much wider variety of forms for each guest compared to grinding. Our results suggest that grinding experiments are a good complement to traditional solution based experiments because they can identify forms not readily obtained from solution, but they are not a substitute for solution experiments. Our results emphasize the need to use multiple experimental techniques when screening for cocrystals. Conclusions Piroxicam is a Class II compound according to the BCS (low solubility and high permeability). We have shown in a previous paper that the bioavailability of Class II compounds can be improved by cocrystallizing the API with a pharmaceutically acceptable guest molecule.11 We investigated the cocrystallization behavior of piroxicam using a crystal engineering approach with the goal of identifying new cocrystal forms that could potentially be used to improve bioavailability. The pharmaceutical sciences present an opportunity for the practical application of crystal engineering and cocrystallization, although this opportunity comes with a few limitations. Perhaps the most significant is that the guest compounds used as cocrystal formers must meet the restrictive set of requirements that are used to select the acids and bases commonly used as API salt formers. There are roughly 100 commonly used salt



formers in the tables of acids and bases provided in the Handbook of Pharmaceutical Salts by Stahl and Wermuth29a that are considered to be “pharmaceutically acceptable”, meaning that they are present in a dosage form previously approved by regulatory agency. Pharmaceutical companies, with very few exceptions, will select API salts using counterions from this list and are reticent to explore alternative salt formers because of the risk and expense associated with selecting a salt former that has never been included in an approved dosage form. For this reason, we populated our guest list with carboxylic acids that have been included, with the exception of 4-hydrocybenzoic acid, in FDA-approved dosage forms. The discovery of 50 cocrystals of piroxicam with 23 carboxylic acids demonstrates a remarkable ability of this API to accommodate a variety of guests in multicomponent solid forms. At least one cocrystal was found for every guest tested, and 17 of the 23 guests produced more than one unique cocrystal form. The two tautomers of piroxicam play a key role in this system because the unique molecular conformations and different hydrogen bonding requirements for each tautomer provide alternative packing options and hydrogen-bonding possibilities, which results in increased potential for cocrystal formation. Cocrystal screening is rapidly becoming an accepted part of the solid-state screening strategy in many pharmaceutical research labs. Although no approved drug has been deliberately formulated as a cocrystal to the best of our knowledge, we believe that it is just a matter of time before the benefits of cocrystallization yield an FDA-approved drug containing a cocrystal. Acknowledgment. We thank Dr. Barbara Stahly, Dr. G. Patrick Stahly, Dr. Pamela Smith, and Dr. Aeri Park from SSCI, Inc. for helpful discussions during the preparation of this manuscript. Supporting Information Available: X-ray crystallographic information files (CIF) for the nine crystal structures, comparisons of XRPD and Raman data for piroxicam form 3, and figures showing all available IR, Raman, and XRPD data for each cocrystal is available free of charge via the Internet at http://pubs.acs.org.

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Cocrystals of Piroxicam with Carboxylic Acids - ACS Publications

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