cg060742p

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

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 acceptablecarboxylic acids. Forming cocrystals of piroxicam can potentially result in solid forms with increased bioavailability. A total of 50unique cocrystals containing piroxicam and a guest carboxylic acid were identified in screening experiments. Each of the 23 guestmolecules 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 aredifferentiated by the piroxicam tautomer present in the cocrystal and the presence or absence of a strong hydrogen bond donorinteracting 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 awell-ordered host containing disordered guest compounds. Crystal structures of eight piroxicam cocrystals and a dioxane solvate ofpiroxicam are reported. All carboxylic acid guest compounds are non-ionized in the cocrystals, and piroxicam is present as thenon-ionized or zwitterionic tautomer. Of special interest are two 1:1 piroxicam/4-hydroxybenzoic acid cocrystal polymorphs. Whilethe unit cell contents are identical, one polymorph contains the non-ionized piroxicam tautomer plus the guest, while the othercontains the zwitterionic tautomer plus the guest. In a related phenomenon, a 4:1 piroxicam/fumaric acid cocrystal is reported thatcontains 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 ingre-dients (APIs) in the form of molecular crystals. During thedevelopment of these drugs, one of the early decisions to bemade concerns the crystalline form that will be used to deliverthe API in an oral dosage form. Physical properties of this solidform can dramatically affect the efficacy of the drug. Dissolutionrate, solubility, hygroscopicity, and chemical stability are someof the more important factors that must be considered. Thearrangement of molecules at the atomic scale affects the physicalproperties on the macroscopic level,1 and manipulating physicalproperties by rearranging the molecules in the solid state throughthe formation of different crystal structures is common practicein the pharmaceutical industry.

Crystallizing the API as a multicomponent crystal has beenan accepted approach to generating form and physical propertydiversity. Hydrate and salt formation2 are the most commonapplications of this concept if the API and salt former areconsidered to be two independent molecular components thatform an ionic complex. Traditionally, any additional molecularcomponent introduced into a pharmaceutical dosage form hasbeen limited to water, possibly a nontoxic solvent such asethanol, or a salt former. Along with a polymorph screen, thishas been considered to be a complete approach to solid formscreening. However, the diversity of solid forms obtainablethrough these approaches is limited.3 Crystal engineeringconcepts4 applied to pharmaceuticals provides a new path forthe systematic discovery of a wider range of multicomponentstructures containing the API by reconsidering the types ofmolecules and intermolecular interactions that can be used toform crystalline complexes with pharmaceuticals.

A cocrystal is a crystalline material made up of two or morecomponents, usually in a stoichiometric ratio, each component

being an atom, ionic compound, or molecule. Cocrystals relyprimarily on the use of hydrogen bonds to form an API/guestmolecular complex in the solid state. The pharmaceuticalsciences has provided a venue for the practical application ofcrystal engineering and supramolecular synthesis, and althoughit is still an emerging area of research, cultivating cocrystals5

is becoming an accepted approach for creating solid dosageforms.6 Here we report the results of a crystal engineeringapproach to generating cocrystals of piroxicam.

Piroxicam (Figure 1) is a nonsteroidal anti-inflammatory drug(NSAID).7 Piroxicam is an enolic acid used in the symptomaticrelief of rheumatoid arthritis and osteoarthritis.8 Piroxicam haslow solubility at physiological pH and is classified as a ClassII API (low solubility and high permeability) based on theBiopharmaceutics Classification System (BCS).9 It takes morethan 2 h for piroxicam to reach the maximum concentrationafter being administered orally.10 A more rapid onset andincreased bioavailability is desirable for analgesics of this typeand formulation and delivery of piroxicam with improvedbioavailability has been the goal of a number of research studies.A cocrystal screen of piroxicam is relevant because we haveshown that cocrystals of Class II compounds can provideincreased bioavailability.11

There are a large number of multicomponent solid forms ofpiroxicam that have been studied. A cocrystal of piroxicamcontaining saccharin as the guest has been reported12 and saltsof piroxicam have been formed with pharmaceutically accept-able bases such asL-arginine,13 ethanolamine, triethanolamine,

* 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.

CRYSTALGROWTH& DESIGN

2007VOL.7,NO.7

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

and diethanolamine.14 A number of metal complexes areknown,15 and beta-cyclodextrin inclusion complexes containingthe zwitterion, the sodium salt monohydrate and other piroxicamcomplexes have been studied.16 A variety of noncrystallinemulticomponent piroxicam systems have also been consideredin efforts to improve the bioavailability of piroxicam, includingdispersions of piroxicam in polymers,17 lipids,18 nicotinamide,19

maltodextrin,20 and urea.21

The cocrystals reported here are only one type of multicom-ponent solid form that can be considered in the process ofselecting the best solid dosage form of piroxicam but animportant one because these solid forms represent an emergingfield within the pharmaceutical sciences. Although the conceptof cocrystals is well-known in the academic literature, thecocrystallization of an API is a new option in the pharmaceuticalsolid form selection process that is finding a voice in industrialresearch programs and steadily gaining acceptance within thepharmaceutical industry.

Experimental Procedures

Piroxicam and 23 carboxylic acids were purchased from the SigmaChemical Company, St. Louis, MO, and used as received withoutfurther purification.

Solution-Based Cocrystal Screen of Piroxicam.A cocrystal screenof piroxicam was performed by generating two duplicate 96-well platesin 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 mixturewith the same piroxicam/guest combination. Four wells functioned ascontrol experiments and contained only piroxicam in four unique solventmixtures. The solutions were allowed to evaporate to dryness at roomtemperature. The first plate was allowed to evaporate faster, over thecourse of about 8 h, while the second plate evaporated more slowlyover 3-5 days. Solids were examined by microscopy. Raman spec-troscopic 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 96wells in plate 2. Infrared (IR) data were obtained from 18 selectedwells in plate 1.

Solid-State Grinding Cocrystal Screen of Piroxicam.Physicalmixtures of piroxicam with 20 carboxylic acids were generated bycombining weighed amounts of each API/guest acid combination inan agate grinding vial in 1:2 and/or 1:1 API/guest molar ratios. Thephysical mixtures were ground in 3-5 min cycles in a Retsch mm200mixer mill at 80% power, and the solids were examined after eachgrinding cycle. Solids were scraped from the side of the vial betweencycles. Raman spectra were obtained from the sample at the end ofeach cycle. Samples were initially ground dry (no solvent) for up tothree cycles. The solid form based on the Raman spectra wasdetermined, and then a drop of solvent was added to the grinding jar.One drop was typically used for 25-50 mg of material. Solvents usedwere 2,2,2-trifluoroethanol, methanol, or acetonitrile. Up to three cyclesof grinding with the added solvent were performed, and the resultingsolid form was identified by Raman spectroscopy. At least twoexperiments were performed for each API/guest combination. A totalof 52 experiments were performed. The Raman spectra of the groundproducts was compared to the data obtained from the solution screento determine the identity of the solid form after grinding. XRPD datawere obtained on new solid forms identified by Raman spectroscopybut not obtained in the solution screen.

Raman Spectroscopy Data Acquisition.Raman spectra werecollected with a Chromex Sentinel dispersive Raman unit equippedwith a 785 nm, 70 mW excitation laser and a TE cooled CCD (1024× 256 pixels,< 0.1e - /pixel/s). A fiber-optically coupled filteringprobe was used to collect data in a spectral range of 300 cm-1 to 2180cm-1 at a resolution of 4 cm-1. Each spectrum is a result of two ormore co-added 20 s scans. The unit has continuous automatic calibrationusing an internal standard. The data were collected by SentinelSoftdata acquisition software and processed in GRAMS/AI V.7.

Infrared (IR) Spectroscopy Data Acquisition. IR spectra wereacquired on a Magna-IR 860 Fourier transform infrared (FTIR)

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 totalreflectance (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 spectralresolution of 4 cm-1. A background data set was acquired with a cleanGe crystal. Log 1/R (R ) reflectance) spectra were acquired by takinga ratio of these two data sets against each other. Wavelength calibrationwas performed using polystyrene.

X-ray Powder Diffraction. X-ray powder diffraction (XRPD)analyses were performed using a Bruker D-8 Discover diffractometerand Bruker’s general area diffraction detection system (GADDS, v.4.1.20). An incident beam of Cu KR radiation was produced using afine-focus tube (40 kV, 40 mA), a Go¨bel mirror, and a 0.5 mm double-pinhole collimator. Some samples were packed between 3-micron thickfilms to form a portable disc-shaped specimen. The prepared specimenwas loaded in a holder secured to a translation stage and analyzed intransmission geometry. The incident beam was scanned and rasteredto optimize orientation statistics. A beam-stop was used to minimizeair scatter from the incident beam at low angles. Samples contained inwellplates were positioned for analysis by securing the well plate to atranslation stage and moving each sample to intersect the incident beam.The samples were analyzed using a transmission geometry. The incidentbeam was scanned and rastered over the sample during the analysis tooptimize orientation statistics. A beam-stop was used to minimize airscatter from the incident beam at low angles. Diffraction patterns werecollected using a Hi-Star area detector located 15 cm from the sampleand processed using GADDS. The intensity in the GADDS image ofthe diffraction pattern was integrated using a step size of 0.04° 2θ.The integrated patterns display diffraction intensity as a function of2θ. Prior to the analysis, a silicon standard was analyzed to verify theSi 111 peak position.

Single-Crystal X-ray Diffraction. Suitable crystals of each solidform sample were coated with Paratone N oil, suspended in a smallfiber loop, and placed in a cooled nitrogen gas stream at 173 K on aBruker D8 sealed tube diffractometer. Diffraction intensities fromsamples11A2, 11B, and4B were obtained using graphite monochro-mated MoKR (0.71073 Å) radiation and an APEX I CCD detector. Thedata were measured using a series of combinations of phi and omegascans with 10-30 s frame exposures and 0.3° frame widths. Datacollection, indexing, and initial cell refinements were all carried outusing SMART22 software. Frame integration and final cell refinementswere done using SAINT23 software. For samples7A1, 17A, 20A, 3B,and 24B, the diffraction intensities were obtained using graphitemonochromated CuKR (1.54178 Å) radiation. Data were measured withan APEX II CCD detector by using a series of combinations of phiand omega scans with 10-30 s frame exposures and 0.5° frame widths.Data collection, indexing, and initial cell refinements were all carriedout using APEX II24 software. Frame integration and final cellrefinements were done using SAINT software. The SADABS25 programwas used to carry out absorption corrections on all samples.

All solid-state structures were solved using Direct methods anddifference Fourier techniques (SHELXTL, V6.14).26 Hydrogen atomswere placed on their expected chemical positions using the HFIXcommand or obtained from difference Fourier maps and were includedin the final cycles of least-squares with isotropicUij’s. All non-hydrogenatoms were refined anisotropically except for sample17A; only the N,O, and S atoms were refined anisotropically for that structure. Scatteringfactors and anomalous dispersion corrections are taken from theInternational Tables for X-ray Crystallography.27 Structure solution,refinement, and generation of publication materials were performedby using SHELXTL, V6.14 software. Graphics for publication weregenerated using X-Seed software.28 Additional details of data collectionand structure refinement are given in Tables 1 and 2.

Single crystals were grown by generating an array of slow evapora-tion experiments. Four different solvent compositions were used foreach 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 appropriatevolumes of stock solutions into the vials. The vials were sealed with aplastic cap that contained one small hole. The solutions evaporatedover the course of two to three weeks at room temperature. All potentialsingle crystals were screened by collecting Raman spectra on theindividual single crystals before mounting on the diffractometer. The

1292 Crystal Growth & Design, Vol. 7, No. 7, 2007 Childs and Hardcastle

experimental conditions used to generate each single-crystal sampleare as follows:

2:1 Piroxicam/Succinic Acid (7A1).A single crystal was formedby slow evaporation in a wellplate during screening experiments. Thesolvent system was 2:1 tetrahydrofuran (THF)/2-propanol.

1:1 Piroxicam/1-Hydroxy-2-Naphthoic Acid (17A).Single crystalswere recovered from a slow evaporation of a 2:1 THF/2-propanolsolution containing an equimolar mixture of piroxicam and 1-hydroxy-2-naphthoic acid.

1:1 Piroxicam/Caprylic Acid (20A). Single crystals were grownby saturating a sample of caprylic acid with piroxicam at 50°C. Thesolution was seeded with a cocrystal sample obtained in the wellplateevaporative experiments. The sample was allowed to cool to roomtemperature, and single crystals formed overnight.

Piroxicam/Malonic Acid (14C). Single crystals were grown froma slow evaporation of a 1:1 mixture of trifluoroethanol and acetonitrile.

1:1 Piroxicam/4-Hydroxybenzoic Acid, Form 1 (11A2).A 1:1methanol/acetonitrile solution containing a 1:1 mixture of piroxicam/4-hydroxybenzoic acid was allowed to evaporate slowly at roomtemperature. Rectangular colorless blocks were recovered from thesolution before all of the solvent evaporated.

1:1 Piroxicam/4-Hydroxybenzoic Acid, Form 2 (11B). Slowevaporation of a 3:1 trifluoroethanol (TFE)/methanol solution containinga 1:1 mixture of piroxicam/4-hydroxybenzoic acid resulted in a mixedproduct containing primarily piroxicam form I as long needles. Yellowblocks of11B of adequate size for structure determination grew at theevaporation front. This product was not observed in the screeningexperiments and was only isolated from the single-crystal experimentsand characterized by Raman spectroscopy and single-crystal X-raydiffraction.

4:1 Piroxicam/Fumaric Acid (4B). Slow evaporation of a 3:1 TFE/methanol solution containing a 2:1 mixture of piroxicam:fumaric acidresulted in a mixed product containing piroxicam form I, fumaric acid,and4B as tiny needles. At the evaporation front, small clusters of platesof 4B grew as a minor (<2%) product. This product was not observedin the screening experiments and was only isolated from the single-crystal experiments and characterized by Raman spectroscopy andsingle-crystal X-ray diffraction.

1:1 Piroxicam/Benzoic Acid (3B). A single crystal was recov-ered from a sample generated by slow evaporation in a wellplateduring screening experiments. The solvent system was 1:1 methanol/acetonitrile.

Table 1. Crystallographic Data for Cocrystals 7A1, 17A, 20A, 14C, and 11A2

7A1 17A 20A 14C 11A2

2:1 piroxicam/succinicacid

1:1 piroxicam/1-hydroxy-2-naphthoicacid

1:1 piroxicam/caprylicacid

piroxicam/malonicacid

1:1 piroxicam/4-hydroxy-benzoicacid, form 1

empirical formula C17H16N3O6S C26H21N3O7S C23H29N3O6S C30H26N6O8S2 C22H19N3O7Sformula weight 390.39 519.52 475.55 662.69 469.46temperature, K 173(2) 173(2) 173(2) 173(2) 173(2)wavelength, Å 1.54178 1.54178 1.54178 1.54178 0.71073crystal system triclinic triclinic triclinic monoclinic monoclinicspace group P1h P1h P1h P21/c P21/nunit cell

dimensionsa, Å

7.7069(2) 6.9743(6) 8.4286(6) 15.692(8) 9.3201(10)

b, Å 8.4282(2) 12.3558(9) 9.7241(6) 16.195(7) 16.4366(17)c, Å 14.4344(3) 14.9892(14) 15.2060(9) 6.999(3) 14.2134(15)R, deg 79.6380(10) 114.045(6) 94.674(3) 90 90â, deg 74.9870(10) 92.672(7) 105.723(3) 101.720(11) 100.561(2)γ, deg 72.6160(10) 95.105(6) 97.953(3) 90 90

volume, Å3 858.87(4) 1170.02(17) 1178.83(13) 1741.7(14) 2140.5(4)Z 2 2 2 2 4density (calc),

Mg/m31.510 1.475 1.340 1.264 1.457

abs coef, mm-1 2.061 1.704 1.595 1.852 0.202F(000) 406 540 504 688 976crystal size, mm3 0.37× 0.24× 0.18 0.17× 0.07× 0.04 0.41× 0.18× 0.18 0.10× 0.03× 0.01 0.33× 0.26× 0.25theta range for

data collection8.15-65.76 3.24-37.63 3.04-65.95 8.47-45.17 1.91-28.34

index ranges -8 e h e 8-9 e k e 8-4 e l e 16

-4 e h e 5-9 e k e 9-11 e l e 11

-9 e h e 8-11 e k e 10-17 e l e 17

-14 e h e 14-13 e k e 14-6 e l e 6

-12 e h e 12-21 e k e 21-18 e 1 e 18

reflections collected 4356 1772 9047 5129 31316independent

reflections2162

[R(int) )0.0122]

1052[R(int) )0.0258]

3182[R(int) )0.0214]

1364[R(int) )0.1371]

5328[R(int) )0.0421]

completeness, % 73.0 85.9 77.6 95.7 99.7absorption

correctionsemiempirical from

equivalentssemiempirical from




equivalentsmax and min

transmission0.7079 and 0.5160 0.9350 and 0.7605 0.7623 and 0.5609 0.9817 and 0.8365 0.9511 and 0.9362

refinement method full-matrixleast-squaresonF2

full-matrixleast-squaresonF2




data/restraints/parameters

2162/0/309 1052/0/212 3182/0/303 1364/0/212 5328/0/302

goodness-of-fiton F2

1.058 1.058 1.075 1.057 1.070

final R indices[I > 2σ(I)]

R1 ) 0.0296,wR2 ) 0.0817

R1 ) 0.0480,wR2 ) 0.1240

R1 ) 0.0855,wR2 ) 0.2029

R1 ) 0.0853,wR2 ) 0.2426

R1 ) 0.0508,wR2 ) 0.1166

R indices (all data) R1) 0.0300,wR2 ) 0.0822

R1 ) 0.0632,wR2 ) 0.1447

R1 ) 0.1379,wR2 ) 0.2715

R1 ) 0.1243,wR2 ) 0.2641

R1 ) 0.0573,wR2 ) 0.1205

largest diff peakand hole,e‚Å-3

0.276 and-0.312 0.232 and-0.237 0.836 and-1.441 0.354 and-0.401 0.515 and-0.344

Cocrystals of Piroxicam Crystal Growth & Design, Vol. 7, No. 7, 20071293

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

Results and Discussion

The cocrystal data reported here resulted from a research anddevelopment program to study the cocrystallization behaviorof piroxicam and carboxylic acids that are generally consideredto be pharmaceutically acceptable salt formers.29 A total of 50multicomponent crystalline forms containing piroxicam and anon-ionized carboxylic acid guest molecule were generated using23 carboxylic acid guests in evaporative and solid-state grindingscreening experiments. The molecular structure of the guestcompounds and the number of multicomponent crystalline solidsidentified that contain piroxicam and each guest are listed inTable 3. Of the 23 guest molecules in the screen, 6 formed 1unique multicomponent solid form, while 9 guests formed 2, 6guests formed 3, and 2 guests formed 4 unique piroxicamcocrystals. The 50 unique solid phases were identified usingRaman spectroscopy, IR spectroscopy, and/or X-ray powderdiffraction. Single-crystal structures are reported for eight ofthe cocrystals (Tables 1 and 2) and are dissussed below.

Raman Spectroscopy.Raman spectroscopy has been usedto effectively characterize solid forms of piroxicam.16a,30Raman

spectra were collected on all solids obtained from evaporativeexperiments, grinding experiments, and on individual crystalsisolated from experiments performed to obtain single crystalsfor structure determination. The spectra were analyzed usingproprietary in-house software developed at SSCI to compareand sort XRPD and vibrational data.31

The spectra from the solid forms obtained in screeningexperiments were compared with patterns of the known poly-morphs of piroxicam and patterns from an in-house databasecontaining Raman spectra of solid forms of pharmaceuticallyacceptable guest compounds. The spectra of the new solid formswere sorted using an envelope matching algorithm. The den-drogram from the results of wellplate experiments indicated thatthe new solid forms could be sorted into one of three clearlydelineated clusters (Figure 2). We arbitrarily labeled theseclusters of Raman patterns Group A, Group B, and Group C.Twenty solid forms involving 17 guests could be classified asGroup C. Seventeen Group B solids were formed from 12guests, and 13 Group A forms were identified using 10 differentguests (Table 4). Many guests formed structures in more thanone Raman group (Table 3). The numbering scheme used toidentify the piroxicam cocrystals begins with an arbitrarynumber associated with the guest molecule followed by a letter(A, B, or C) designating the Raman group for that solid form.

Table 2. Crystallographic Data for 11B, 4B, 3B, and 24B

11B 4B 3B 24B

1:1 piroxicam/4-hydroxybenzoicacid, form 2

4:1 piroxicam/fumaric acid

1:1 piroxicam/benzoic acid

4:1 piroxicam/p-dioxane

empirical formula C22H19N3O7S C32H28N6O10S2 C22H19N3O6S C16H15N3O4.5Sformula weight 469.46 720.72 453.46 353.37temperature, K 173(2) 173(2) 173(2) 173(2)wavelength, Å 0.71073 0.71073 1.54178 1.54178crystal system triclinic triclinic monoclinic triclinicspace group P1h P1h P21/c P1hunit cell dimensions

a, Å7.4086(10) 8.7433(12) 10.5790(8) 10.5355(13)

b, Å 10.9004(15) 10.9557(15) 21.0495(16) 12.7289(14)c, Å 12.9268(17) 16.633(2) 9.2413(8) 13.1794(14)R, deg 95.965(3) 86.335(3) 90 102.048(6)â, deg 100.576(3) 89.030(2) 95.152(4) 99.758(7)γ, deg 96.858(2) 84.809(3) 90 109.836(8)

volume, Å3 1010.3(2) 1583.3(4) 2049.6(3) 1569.5(3)Z 2 2 4 4density (calc), Mg/m3 1.543 1.512 1.470 1.495abs coef, mm-1 0.214 0.239 1.816 2.117F(000) 488 748 944 736crystal size, mm3 0.40× 0.19× 0.09 0.66× 0.31× 0.07 0.35× 0.03× 0.03 0.25× 0.19× 0.09theta range for data collection 1.62-29.91 1.87-28.33 4.20-44.64 3.55-65.65index ranges -10 e h e 10

-15 e k e 15-18 e l e 18

-11 e h e 11-14 e k e 14-22e l e 22

-9 e h e 9-18 e k e 19-8 e l e 8

-11 e h e 11-14 e k e 14-15 e l e 14

reflections collected 14367 23468 6147 8090independent reflections 5252

[R(int) )0.0403]

7870[R(int) )0.0351]

1537[R(int) )0.1135]

4300[R(int) )0.0393]

completeness, % 89.6 99.6 94.2 79.2absorption correction semiempirical from




equivalentsmax and min transmission 0.9812 and 0.9191 0.9835 and 0.8582 0.9475 and 0.5690 0.8323 and 0.6197refinement method full-matrix

least-squaresonF2




data/restraints/parameters 5252/0/302 7870/0/470 1537/0/299 4300/0/438goodness-of-fit on F2 1.132 1.031 1.003 1.115final R indices [I > 2 σ(I)] R1 ) 0.0532,

wR2 ) 0.1388R1 ) 0.0481,

wR2 ) 0.1138R1 ) 0.0395,

wR2 ) 0.0920R1 ) 0.0584,

wR2 ) 0.1828R indices (all data) R1) 0.0669,

wR2 ) 0.1468R1 ) 0.0592,

wR2 ) 0.1200R1 ) 0.0645,

wR2 ) 0.1040R1 ) 0.1053,

wR2 ) 0.2303largest diff peak

and hole, e.Å-30.584 and-0.468 0.603 and-0.358 0.152 and-0.187 0.529 and-0.649


If more than one cocrystal form was observed for a guest withinone Raman group, then the forms have an additional sequentialnumber appended as shown in Table 3. The single-crystalstructures 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 thesesolids are colorless, while the Group B forms are yellow andthe spectral features are very different from Groups A and C.The solvo-chromism of piroxicam is well documented, and ithas been shown that the colorless piroxicam polymorphscontaining non-ionized molecules and the yellow piroxicammonohydrate containing zwitterionic molecules can readily be

distinguished from each other based on Raman spectra.32

Colorless solids correspond to the non-ionized tautomer ofpiroxicam, and the yellow color is due to the zwitterionictautomer (Figure 3).

The presence of the zwitterionic tautomer of piroxicam caneasily be determined based on the presence of the strong Ramanband at∼1410 cm-1. However, while it is easy to distinguishcomplexes that contain a zwitterionic tautomer from onecontaining only the non-ionized tautomer using Raman spec-troscopy, the differences between the similar Group A andGroup C products are more difficult to discern (Figure 4). Theexistence of these two distinct groups based on envelope

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

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


matching prompted us to look closely at the characteristics ofthe Raman spectra to identify the underlying reason for theformation 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 Chas been assigned to the amide I mode (V CdO stretchingvibration).30b That peak is not present in Group A spectra. If

the amide carbonyl group is involved in a strong intermolecularhydrogen bond, that peak is expected to be shifted to lowerfrequencies and also broaden.33 This assignment suggests thatthe difference between Group A and Group C spectra can becorrelated with the hydrogen bonding of the amide carbonylgroup. The conformation of the non-ionized tautomer requiresone intramolecular hydrogen bond to the amide carbonyl oxygenatom from the enolic acid, but the carbonyl group is still ableto accept an additional hydrogen bond from a neighboringmolecule. Specifically, when the carbonyl group is accepting astrong hydrogen bond, the solid form will be in Group A. Ifthat group is not involved in a strong hydrogen bond, it will bein Group C.

Crystal structure data support the hypothesis concerning theamide carbonyl group and its involvement in a strong hydrogenbond. The crystal structures are described in detail in asubsequent section of this paper. Three structures from GroupA for which crystal structures have been solved, the 1-hydroxy-2-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 anidentical intermolecular hydrogen bond pairing motif that is notpresent in any of the Group C crystal structures. In the4-hydroxybenzoic acid cocrystal (11A2) and the malonic acidcocrystal (14C) the amide carbonyl group is not involved in anintermolecular hydrogen bond, and the peak at∼1610 cm-1 ispresent. The crystal structures of polymorphs I and II alsosupport these conclusions because the Raman band in questionis present and the amide group is not involved in a stronghydrogen bond in these structures.

IR Spectroscopy.Infrared (IR) spectroscopy has been usedto study piroxicam in the solid state.37 IR data were obtainedon 18 of the piroxicam cocrystals, the three known piroxicampolymorphs, and thep-dioxane solvate of piroxicam. It ispossible to classify the IR spectra in a manner similar to theRaman groupings, although the groupings are not as clear withIR data. As with Raman, distinguishing between the non-ionizedand zwitterion tautomers is possible, but the greater variationin IR spectra makes it much more difficult to discern betweenGroup A and Group C forms.

XRPD Data. XRPD data were used along with the Ramanspectra to determine the identity of the solid forms obtained inthe screening experiments. Although the XRPD patterns cannotdistinguish between the different groups identified using theRaman data, they confirmed the unique crystalline structurepresent in each piroxicam cocrystal. In addition, the XRPD dataindicated that there is a group of similar structures that form asubcategory of the Group C structures (Figure 5). The single-crystal structure of one of those, cocrystal14C, will be discussedin the following section. The XRPD patterns obtained from thepiroxicam cocrystals are available in Supporting Information.

Single-Crystal Structures. Single-crystal structures arereported for 8 of the 50 piroxicam cocrystals and also for thedioxane solvate of piroxicam. Two of the single-crystal datasetswere obtained by recovering single crystals from samplesgenerated in the 96-well plates. The rest of the single-crystalsamples were generated by very slow evaporation on a largerscale. The intent of these experiments was not to determine thecrystal structure of every piroxicam cocrystal that was identifiedbut rather to generate a representative number of crystalstructures to illustrate the structural features of this system.

All of the single-crystal structures contain piroxicam mol-ecules in the form of the non-ionized or zwitterionic tautomer(Figure 3). There are two strong hydrogen bond donors on each

Figure 2. The dendrogram of Raman data from wellplate experimentssorted by an envelope matching algorithm.

Table 4. Piroxicam Cocrystal Screening Results Sorted by RamanGroup

number of unique forms

guest acid Group A Group B Group C

L-tartaric acid 1citric acid 1fumaric acid 3 1adipic acid 1 1succinic acid 1L-malic acid 1 1 1glutaric acid 1 1DL-malic acid 1 1 1oxalic acid 2(+)-camphoric acid 1ketoglutaric acid 1 2benzoic acid 1 14-hydroxybenzoic acid 2 1 1malonic acid 1 1salicylic acid 3glycolic acid 21-hydroxy-2-naphthoic acid 1 1gentisic acid 2 1dL-tartaric acid 1 2maleic acid 1 1caprylic acid 1hippuric acid 1 1L-pyroglutamic acid 1

total forms per group 13 17 20


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

intermolecular hydrogen bond in addition to the relatively weakintramolecular interaction.

In the zwitterionic tautomer, the enolic acid proton is locatedon the pyridine base. Two six-membered intramolecular hydrogen-bonded rings are formed as the amide N-H is hydrogen bondedto the enolate anion and the protonated pyridine N-H ishydrogen bonded to the amide oxygen atom. The formation ofthe intramolecular hydrogen bonds is a dominant influence onthe conformation of both tautomers of piroxicam. The inter-conversion of the non-ionized to the zwitterionic tautomerrequires a proton transfer from the enolic acid to the pyridinebase and also the rotation of two single bonds that leave theenol and pyridine groups in the same relative location but rotatethe amide moiety by 180° (Figure 3).

Both tautomers of piroxicam have excess hydrogen bondacceptor sites available. The availability of the pyridine acceptorsite on the non-ionized tautomer and the lack of additional strongdonors create favorable conditions for hetero-synthon formationbetween piroxicam and carboxylic acids. For instance, all ofthe crystal structures obtained from Groups A and C containthe acid-pyridine hetero-synthon. Likewise, the accessibility ofthe enolic anion on the zwitterionic tautomer creates a favorableacceptor site for the carboxylic acid guests.

All known crystal structures (those reported here plus thosein the CSD) were used to compare conformations of piroxicamin the non-ionized and zwitterion tautomeric conformation.Piroxicam polymorphs and multicomponent structures contain-ing non-ionized guest molecules are included in the conforma-tion overlay diagrams shown in Figure 6. Salt forms and metalcomplexes of piroxicam were not included. For structures withmore than one piroxicam molecule in the asymmetric unit, 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 toRaman groups A and C, and these solid forms are colorless. The zwitterionic tautomer is present in the Raman group B solid forms. Solid formscontaining the zwitterionic tautomer are yellow.

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

Figure 5. XRPD patterns for the structurally similar piroxicamcocrystals1C (a), 14C (b), 10C2 (c), 13C (d), 9C (e), and8C (f).These structures are a subset of Group C forms as grouped by Ramandata.


conformer was considered independently. When the conforma-tions are overlaid, it is clear that differences within groups ofidentical tautomers are due primarily to the pyridine ringmovement, while the central ring containing the sulfonamideremains essentially superimposable. The variable position of thepryidine ring is presumably due to crystal packing forces anddoes not represent any preferred orientation of that group. Thereis no correlation between the classification in the Raman groupsand the conformation of the molecule or location of thesubstituted pyridine ring, indicating that intermolecular interac-tions rather than intramolecular interactions are responsible forthe differences between Group A and Group C. Additionaldetails on the specific intramolecular interactions that give riseto the Raman groupings are discussed in the context of specificcrystal structures below.

2:1 Piroxicam/Succinic Acid (7A1). The 2:1 piroxicam/succinic acid cocrystal (7A1) contains one non-ionized piroxi-cam molecule and one-half of a succinic acid molecule in theasymmetric unit. The succinic acid guest molecule is locatedon an inversion center and links two piroxicam moleculesthrough hydrogen bonding. The conformation of the non-ionizedpiroxicam tautomer leaves the amide N-H donor and thepyridine acceptor positioned in a way that provides an excellentinteraction site for the carboxylic acid group (Figure 7). Thepiroxicam molecule also interacts with a neighboring piroxicamby forming hydrogen bonds between two enolic acid donorsand two amide carbonyl acceptors across an inversion center.Even though the enolic acid proton is involved in an intramo-lecular hydrogen bond with the amide carbonyl on the same

molecule, it is also able to form an interaction with the amidecarbonyl group on a neighboring molecule. These two interac-tions result in a one-dimensional (1D) hydrogen-bonded motifthat extends along theb-c bisector.

1:1 Piroxicam/1-Hydroxy-2-naphthoic Acid (17A) and 1:1Piroxicam/Caprylic Acid (20A). The hydrogen-bonding motifsin the 1:1 piroxicam/1-hydroxy-2-naphthoic acid cocrystal(17A), and the 1:1 piroxicam/caprylic acid cocrystal (20A) aresimilar to the hydrogen bonding in the succinic acid cocrystal(7A1). The acid group on the guest molecule is hydrogen bondedto the pyridine acceptor site on the piroxicam, and the enolicacid forms an interaction with the amide oxygen atom throughintra- and intermolecular interactions across an inversion center.Instead of the continuous 1D motif formed by7A1, 17A, and20A each forms a zero-dimensional aggregate of four indepen-dent molecules as shown in Figure 8.7A1, 17A, and20A allbelong to Raman Group A and contain the same generalhydrogen-bonded motifs. The presence of the centrosymmetricenol-enol interaction in Group A cocrystals is the central featurethat distinguishes the Group A and Group C cocrystals basedon Raman data.

1:1 Piroxicam/Malonic Acid (14C). The 1:1 piroxicam/malonic acid cocrystal (14C) forms a clathrate type structurein which a non-ionized piroxicam creates a host framework withchannels along thec-axis. There are six isostructural cocrystalsidentified with this motif based on XRPD data (Figure 5). Inaddition to the structure of14C, unit cell data were obtainedfor two other cocrystals identified by XRPD as having theclathrate motif (Table 5). The unit cell data matched the 1:1piroxicam/malonic acid unit cell closely, which provides ad-ditional evidence that the six patterns in Figure 5 representstructurally similar forms. The occurrence of this isostructuralhost framework in the presence of six different guest moleculessuggests that it is a robust packing motif.

The host framework is formed by two alternating layers ofpiroxicam molecules that form an open linear channel ap-proximately 7 Å in diameter (Figure 9). The piroxicam moleculeis well ordered, while the guest acid is highly disordered in thechannel. The orientation of the pyridine acceptor site and theamide N-H donor pointing directly into the channel suggests

Figure 6. Conformations of piroxicam from all known single-crystalstructures 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 acidcocrystal (7A1).

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


that these sites play an integral role in stabilizing the carboxylicacid in the channel, although the exact nature of the acid topiroxicam interaction could not be determined due to thedisorder of the malonic acid guest in14C. Attempts to refinethe structure by modeling the disordered guest in the channelwere unsuccessful. To refine the structure, a new set of F2 (hkl)values were generated with the residual electron density in thechannel removed using SQUEEZE.34 The resulting structurecontains the ordered piroxicam and empty channels.

1:1 Piroxicam/4-Hydroxybenzoic Acid, Form 1 (11A2) and1:1 Piroxicam/4-Hydroxybenzoic Acid, Form 2 (11B).Crystalstructures for two polymorphs of 1:1 piroxicam/4-hydroxyben-zoic acid (11A2and11B) were obtained. These two polymorphsboth contain one molecule of piroxicam and one molecule of4-hydroxybenzoic acid in the asymmetric unit; however, theyare very unusual polymorphs because in11B the piroxicam is

present as the zwitterion tautomer and in11A2 the piroxicammolecule is present as the non-ionized tautomer.

In the case of the 1:1 piroxicam/4-hydroxybenzoic acidcocrystal polymorph containing the non-ionized tautomer (11A2,

Figure 9. The 1:1 piroxicam/malonic acid structure (14C) contains disordered guest molecules. Only the coordinates of the piroxicam moleculein 14C, which forms a host structure with linear cavities, are shown. The available hydrogen bond donors and acceptors are shown as spheres thatare pointing into the empty channels that run along thec-axis (a). A view down thec-axis is shown as a space filling diagram (b) to highlight thechannel structure. The view down theb-axis (c) shows the coplanar aromatic groups.

Table 5. Unit Cell Data from Three Indexed Single Crystalsa

spacegroup guest a, Å b, Å c, Å

R,deg

â,deg

γ,deg

(a) P2(1)/c malonicacid(14C)

15.692 16.195 6.999 90 101.72 90

(b) P2(1)/c DL-malicacid

15.674 16.169 6.997 90 101.73 90

(c) P1h L-malicacid

15.672 16.215 7.088 82.62 98.81 96.36

a Unit cell (a) is from the piroxicam/malonic cocrystal structure(14C).

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

guest grinding result

benzoic acid 3B, 3Cadipic acid 6Csuccinic acid 7A(+)-camphoric acid 8CL-malic acid 9B, 9Cketoglutaric acid 10C14-hydroxybenzoic acid 11Bglutaric acid 12A, 12CDL-malic acid 13Amalonic acid 14Bsalicylic acid 15B21-hydroxy-2-naphthoic acid 17Agentisic acid 18Coxalic acid 19B1hippuric acid 21BL-tartaric acid no reactioncitric acid no reactionfumaric acid no reactionglycolic acid no reactionDL-tartaric acid no reactionmaleic acid not testedcaprylic acid not testedL-pyroglutamic acid not tested

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


form 1), the carboxylic acid guest forms an unexpectedhydrogen-bonded dimer (Figure 10). The expected interaction35

of the strongest donor (the carboxylic acid) with the bestacceptor (the pyridine site) is not observed. Instead, the phenolichydroxy group acts as a donor to the pyridine and an acceptorfor the amide N-H.

The 1:1 piroxicam/4-hydroxybenzoic acid cocrystal poly-morph that contains a zwitterionic piroxicam (11B) also containssome unexpected interactions. The phenolic hydroxy group onthe guest forms a hydrogen bond to the enolate oxygen (Figure11), again in contrast to the general observation that the strongestdonor interacts with the strongest acceptor. The carboxylic acidforms a hydrogen bond to the sulfonyl group on one API andalso accepts a hydrogen bond from a protonated pyridine N-Hlocated on a neighboring API.

4:1 Piroxicam/Fumaric Acid (4B). While it is unusual tofind a zwitterion tautomer and a non-ionized piroxicam tautomerin a pair of polymorphic cocrystals, it is perhaps even moreunexpected to find both tautomers in the same cocrystalstructure. The 4:1 piroxicam/fumaric acid cocrystal (4B) containsone zwitterionic piroxicam, one non-ionized piroxicam, and one-half of a fumaric acid in the asymmetric unit.

The zwitterionic piroxicam molecule is hydrogen-bonded toanother identical zwitterion through an intermolecular interactioninvolving the protonated pyridine and the amide carbonylacceptor as well as a C-H‚‚‚O interaction (2.34 Å) betweenan aromatic C-H donor and the sulfonamide nitrogen (Figure12b). The non-ionized piroxicam is hydrogen bonded to thefumaric acid, and the 2:1 aggregate is shown in Figure 12a.The non-ionized 2:1 piroxicam/fumaric acid cluster is similarto the aggregate formed in the succinic acid cocrystal (7A1).When observed down thea-axis, the packing of this structuresuggests that the association of the zwitterionic aggregate andthe 2:1 non-ionized piroxicam/guest aggregate can be viewed

as an arrangement of convenience. Each set of non-ionized andzwitterionic aggregates pack neatly side by side and layer bylayer. The aggregates are formed with strong hydrogen bondsbut interact with each other only through C-H‚‚‚O and vander Waals interactions.

1:1 Piroxicam/Benzoic Acid (3B). The 1:1 piroxicam/benzoic acid cocrystal (3B) has one zwitterionic piroxicam andone non-ionized benzoic acid in the asymmetric unit. Thecarboxylic acid guest forms a hydrogen bond with the enolateanion acceptor site. The protonated pyridine donor forms abifurcated interaction, forming inter- and intramolecular interac-tions with the amide carbonyl group. The tetramer in3B formedby the strong hydrogen bonds as well as the weaker C-H‚‚‚Ointeractions is shown in Figure 13. C-H‚‚‚O interactionsinvolving aromatic C-H donors and the benzoic acid carbonyl(2.29 Å) as well as the sulfonamide nitrogen (2.40 Å) appearto play a supporting role in the stabilization of this aggregate.All distances are non-normallized.

4:1 Piroxicam/Dioxane Solvate (24B).When the XRPD andRaman data from the wellplate screening was initially examined,it was believed that the monohydrate was identified in a numberof wells because the XRPD pattern was a close match to theknown pattern of piroxicam monohydrate (Figure 14). Thisassignment was suspect because water was not introduced as asolvent in those wells and would have to be absorbed from theair. Closer inspection revealed that the Raman and XRPD

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

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

Figure 12. In the 4:1 piroxicam/fumaric acid (4B), there is an aggregateof two non-ionized piroxicam molecules and one fumaric acid (a) plusan aggregate of two zwitterionic piroxicam molecules (b). The packingof 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 thea-axis.


patterns were slightly different than the known patterns of themonohydrate, but the form could not be identified. This mysterywas allowed to linger until large crystals were obtained fromsingle-crystal experiments that matched the Raman pattern ofthe suspect monohydrate pattern obtained in the wellplate. Thevolume of the unit cell obtained was nearly identical to themonohydrate (CSD refcode CIDYAP) except it was slightlylarger,∼1570 Å3 vs ∼1540 Å.3 The structure was determinedto be a 4:1 piroxicam/dioxane solvate with one dioxane takingthe place of a quartet of water molecules that are present in themonohydrate. The 4:1 piroxicam/dioxane solvate is essentiallyisostructural with the monohydrate; however, in the monohy-drate, a water is hydrogen bonded to the piroxicam enolateanion, while in the dioxane structure there are no hydrogenbonding interactions involving the dioxane molecule andpiroxicam.

The detection of the dioxane solvate in this study might havebeen missed if the only analytical technique used was XRPD.The calculated XRPD patterns of the monohydrate and thedioxane solvate are so similar that the broad peaks in theexperimental data make it difficult to recognize that the patternrepresents something other than the known monohydrate (Figure14). The Raman data for these forms, however, indicate that

the dominant peak in the dioxane solvate spectrum is signifi-cantly shifted compared to the monohydrate (1400 cm-1 forthe known hydrate and 1393 cm-1 for the dioxane solvate). Thepeak at 1400 cm-1 has been assigned as theV CO antisymmetricstretching mode for the enolate anion in the monohydrate,30c

and the significant change in intermolecular hydrogen bondingfor that group in the hydrate compared to the dioxane solvateleads to the observed peak shift.

Polymorphism of Piroxicam. The polymorphism of piroxi-cam has been well studied,36 and three piroxicam polymorphsand one hydrate have been reported in the literature.37 Threepolymorphs of piroxicam and ap-dioxane solvate were identifiedduring the screen; XRPD patterns are shown in Figure 15 andRaman spectra of the three polymorphs are shown in Figure16. Forms I, II, and III have been best described in the literatureby Vrecer.36 Form I of piroxicam has previously been describedin the literature as the beta polymorph (CSD refcodes BIYSEH38

and BIYSEH0139a) and form II as the alpha polymorph (CSDrefcode BIYSEH0239). Piroxicam is also known to form a

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

Figure 14. Distinguishing between the piroxicam monohydrate and the 4:1 piroxicam/dioxane solvate (24B) can be difficult because these twostructures are nearly identical. XRPD data (left): (e) calculated pattern for piroxicam monohydrate (CSD refcode CIDYAP), (d) calculated patternof 24B, and (a-c) three XRPD patterns obtained from the cocrystal screen. Raman data (right) for piroxicam monohydrate (a) and24B (b) aresimilar, although the strong peak shown in the inset is significantly shifted.

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


monohydrate (CSD refcode CIDYAP40). Redeterminations offorms I and II were recently reported by Sheth.36i Of particularinterest is the fact that we obtained form III from evaporationat room temperature of a solvent mixture of 1:1:2 propionitrile/t-butyl-alcohol/p-dioxane, whereas Vrecer, et al. reported itsproduction by either pouring a hot, saturated solution of absoluteethanol over dry ice or spray drying.

Solid-State Grinding. Solution based crystallization experi-ments produced 47 of the 50 piroxicam cocrystals reported here.However, the use of nontraditional synthesis techniques alsoplays an important role in the search for cocrystals. Thesetechniques complement solution experiments because they canoften form cocrystal phases that are not readily obtainable fromtraditional solution-based experiments.41 Twenty of the 23 guestsused in the wellplate experiments were selected for solid-stategrinding experiments. Eighteen unique solid forms were ob-tained from grinding experiments based on Raman data (Table6). Three of the cocrystals obtained by grinding were notobtained in the solution experiments (Table 4). XRPD patternsof these three new ground products indicated that these wereindeed unique solid forms.

The role of solvent in grinding experiments has been thesubject of recent discussion in the literature.42 It is oftennecessary to add a small amount of solvent to the grindingexperiment to promote cocrystal formation, a technique that isgenerally referred to as “solvent drop grinding”. For example,a 1:1 molar ratio of adipic acid and piroxicam ground dry for4 min gave no reaction, but addition of acetonitrile andsubsequent grinding for 2 min resulted in complete conversionto 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 samesolvent is used in every grinding experiment. We started withdry grinding of the piroxicam/guest mixture, identified theproduct using Raman spectroscopy, and then added a drop ofsolvent to this product and ground the sample once more,identifying the product again by Raman spectroscopy. In thecase of a 1:1 benzoic acid/piroxicam mixture, dry grinding for3 cycles of 3 min resulted in one cocrystal. Addition of 1 dropof trifluoroethanol (TFE) or methanol plus additional grindingresulted in the formation of a different cocrystal form (identicalto the single-crystal structure of the 1:1 benzoic acid:piroxicam

cocrystal (3B) reported here). In another example, a 1:1 drygrind of malonic acid and piroxicam resulted in no reaction,while addition of acetonitrile and subsequent grinding resultedin a previously unobserved cocrystal form.

The ratio of the components in the grinding experiment canalter the product significantly. For example, a 1:1 molecularratio of glutaric acid and piroxicam ground with a drop of TFEproduced one colorless solid form containing the non-ionizedpiroxicam tautomer, while a 2:1 mixture ground with a drop ofTFE produced a second colorless solid form. Both of theseproducts were obtained in solution experiments, but the resultsof the grinding experiments are indicative of the componentratio that the product contains.

Five of the 20 guests used did not produce a multicomponentform in grinding experiments; however, solution experimentsyielded new solid forms for these piroxicam/guest combinations.The solution-based experiments produced a much wider varietyof forms for each guest compared to grinding. Our resultssuggest that grinding experiments are a good complement totraditional solution based experiments because they can identifyforms not readily obtained from solution, but they are not asubstitute for solution experiments. Our results emphasize theneed to use multiple experimental techniques when screeningfor cocrystals.

Conclusions

Piroxicam is a Class II compound according to the BCS (lowsolubility and high permeability). We have shown in a previouspaper that the bioavailability of Class II compounds can beimproved by cocrystallizing the API with a pharmaceuticallyacceptable guest molecule.11 We investigated the cocrystalli-zation behavior of piroxicam using a crystal engineeringapproach with the goal of identifying new cocrystal forms thatcould potentially be used to improve bioavailability.

The pharmaceutical sciences present an opportunity for thepractical application of crystal engineering and cocrystallization,although this opportunity comes with a few limitations. Perhapsthe most significant is that the guest compounds used ascocrystal formers must meet the restrictive set of requirementsthat are used to select the acids and bases commonly used asAPI salt formers. There are roughly 100 commonly used salt

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


formers in the tables of acids and bases provided in theHandbook of Pharmaceutical Saltsby Stahl and Wermuth29a

that are considered to be “pharmaceutically acceptable”, mean-ing that they are present in a dosage form previously approvedby regulatory agency. Pharmaceutical companies, with very fewexceptions, will select API salts using counterions from thislist and are reticent to explore alternative salt formers becauseof the risk and expense associated with selecting a salt formerthat has never been included in an approved dosage form. Forthis reason, we populated our guest list with carboxylic acidsthat have been included, with the exception of 4-hydrocybenzoicacid, in FDA-approved dosage forms.

The discovery of 50 cocrystals of piroxicam with 23carboxylic acids demonstrates a remarkable ability of this APIto accommodate a variety of guests in multicomponent solidforms. At least one cocrystal was found for every guest tested,and 17 of the 23 guests produced more than one unique cocrystalform. The two tautomers of piroxicam play a key role in thissystem because the unique molecular conformations and dif-ferent hydrogen bonding requirements for each tautomer providealternative packing options and hydrogen-bonding possibilities,which results in increased potential for cocrystal formation.

Cocrystal screening is rapidly becoming an accepted part ofthe solid-state screening strategy in many pharmaceuticalresearch labs. Although no approved drug has been deliberatelyformulated as a cocrystal to the best of our knowledge, webelieve that it is just a matter of time before the benefits ofcocrystallization yield an FDA-approved drug containing acocrystal.

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 thismanuscript.

Supporting Information Available: X-ray crystallographic infor-mation files (CIF) for the nine crystal structures, comparisons of XRPDand Raman data for piroxicam form 3, and figures showing all availableIR, Raman, and XRPD data for each cocrystal is available free of chargevia the Internet at http://pubs.acs.org.

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CG060742P


cg060742p

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cocrystals of piroxicam

nonionized piroxicam

piroxicam tautomer present

piroxicam forms awell

known polymorphs of

nonionized tautomer

guest carboxylic acid

zwitterionic tautomer