cg201510n

Cocrystal Systems of Pharmaceutical Interest: 2010Harry G. Brittain*

Center for Pharmaceutical Physics, 10 Charles Road, Milford, New Jersey 08848, United States

ABSTRACT: The literature published during 2010 whose subject matterencompasses the cocrystallization of organic compounds having particularinterest to pharmaceutical scientists has been summarized in an annualreview. The papers cited in this review were drawn from the major physical,crystallographic, and pharmaceutical journals. After a brief introduction,the review is divided into sections that cover articles of general interest, thepreparation of cocrystal systems and methodologies for their character-ization, and more detailed discussion of cocrystal systems containingpharmaceutically relevant compounds. A brief summary of the state of theart of pharmaceutical cocrystals is also included, which poses an issue that isof great importance to the field.

1. INTRODUCTIONPharmaceutical scientists are always interested in improving thephysical properties of drug substances, and hence have delvedinto the scope of solid-state structural variations that can beobtained through the cocrystallization of several molecules in asingle lattice structure.13 Along these lines, workers haveresearched the assembly of supramolecular synthons and crystalengineering in ever-increasing efforts to produce materials havingnew and useful properties.4 In the present review, the definitionof a cocrystal proposed by Aakeroy will be used, namely, wherecocrystal formation from supramolecular synthons is to beconsidered as forming from discrete neutral molecular speciesthat are solids at ambient temperatures, and where the cocrystalis a structurally homogeneous crystalline material that containsthe building blocks in definite stoichiometric amounts.1

Actually, the cocrystal field has a long history, but historicallymixed crystals were identified under other names, such asmolecular complexes, association species, donoracceptorcomplexes, and the like. Stahly has provided a history ofcocrystals that were reported in the literature prior to 2000 andwhich contained only organic components, discussing theirdiscovery and history, and illustrating principles of cocrystalchemistry through the use of illustrative examples.5 The presentreview continues the annual surveys corresponding to theliterature published in 2007, 2008,6 and 2009,7 and willsummarize literature published during 2010.Although primary attention will be given to cocrystal systems

having pharmaceutical interest, related papers that are ofparticular significance to the field will be discussed as well. Theliterature cited in the present review has been drawn from themajor physical, crystallographic, and pharmaceutical journals,and consequently the coverage cannot be represented as beingencyclopedic or comprehensive. Apologies are presented inadvance to any scientist in the field whose works have beeninadvertently omitted.

2. ARTICLES OF GENERAL INTERESTA very useful review has been published that summarizes recentdevelopments in the utility of cocrystals as means to improvethe physical properties of pharmaceutical drug substances,including enhancement of drug solubility and dissolution rates,stability toward thermal and humidity stress, and materialcompressibility during tablet formation.8 Some of the othertopics covered in this article include the design of supra-molecular synthons, and the conduct of screening studies toevaluate stoichiometric variations in cocrystal composition. Itwas concluded that reliable strategies for the synthesis anddesign of cocrystal systems are effectively established, as well asthe potential of cocrystallization for improvement of the solid-state properties of drug substances. The authors reportedthat workers in the field are seeking to develop a betterunderstanding of cocrystal structureproperty relationshipsthrough the conduct of systematic structural and computationalstudies.Supramolecular synthons represent the fundamental building

block of cocrystal systems, and the development in under-standing of the scope and boundaries of the interactionsresponsible for formation of these synthons has been reviewedin detail.9 In this article, catemer and dimer HOCOHOCO and COHN motifs were discussed, butmore discussion was placed on interactions involving fluorine.Hence, the coverage of aggregation of organo-fluorinecompounds, and supramolecular synthons based on CFHor CF interactions, was extensive. Finally, the current stateof crystal structure prediction was addressed in context withhighly developed crystallization methodologies and the neededimprovements in computational models.The degree of proton transference in a hydrogen-bonded

synthon determines whether a particular solid should be

Received: November 16, 2011Published: December 21, 2011

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classified as a cocrystal or as a salt, and hence discussions of thecontinuum between salts and cocrystals retain their importance.The degree of transfer between substituted pyridine derivativesand a series of carboxylic acids has been evaluated usingmolecular electrostatic potential surface calculations, and it wasreported that the calculated charges on the N-heterocyclic base-bond acceptor could be used to predict the existence of a salt ora cocrystal.10 Formation of the salt was inevitable once thecharge on the hydrogen-bond acceptor exceeded a critical value,while the intended cocrystal could not form if the charge wastoo low.In another study, Hammett substituent constants were used

as the basis to model the formation of cocrystal products.11

During the attempted cocrystallization of 32 acid/acidcombinations of substituted benzoic acids, it was found that90% of the systems formed cocrystals if the Hammett constantsof the coformers were of opposite sign, while only 25% of thesystems where the constants were of the same sign yieldedcocrystals. It was noted in the paper that a direct relationshipexists between the Hammett constant and the ionizationconstant of the carboxylic acids, and hence systems charac-terized by large differences in substituent constants (and, byextension, large differences in pKa) would be predicted to yieldsalts instead of cocrystals.The formation of nicotinamide/salicylic acid and nicotinamide/

oxalic acid cocrystal products was anticipated by principlesof crystal engineering and trends in ionization constants, andthe charge density distribution in these cocrystals has beenstudied.12 In these structures, the CHO interactions werenoted to provide support for the directional OHO andNHO hydrogen bonding. The two ionizations inherent tochloranilic acid were exploited to form both salt and cocrystalspecies with a variety of organic bases, characterized by sixdistinct motifs of hydrogen bonding.13 Since the structurescontained protonated base functionalities, the dominantinteraction was the N+HO hydrogen bond.Another approach for studying the salt-cocrystal continuum

has involved the evaluation of protonation states using X-rayphotoelectron spectroscopy, where the shifting in energy of thenitrogen 1s spectrum of theophylline has been used to evaluatethe degree of proton transfer. Conventional methods wereused to demonstrate the formation of an adduct with citric acid,and the equivalence in energies of the nitrogen 1s spectra intheophylline and its citric acid adduct was taken as proof of theexistence of a cocrystal and the lack of salt formation.14 Thisresult is what one would have expected on the basis of thepKa rule. In a related study, the same methodology wasused to demonstrate the formation of a theophylline cocrystalwith oxalic acid, but only the formation of a salt species with5-sulfosalicylic acid.15

One of the important rationales for modifying the propertiesof a drug substance is to improve its solubility and dissolutionrate. Cocrystal eutectic constants, calculated as the ratio of thesolution-phase concentrations at the eutectic point of thecompounds making up a cocrystal species, have been found toserve as indicators of phase behavior.16 These constants wereshown capable of providing guidance to the selection andsynthesis of cocrystal systems. Hansen solubility parametershave been used as part of an interaction study of 30 coformerswith indomethacin, and their use was demonstrated to be auseful tool to improve the efficiency of cocrystal screening.17

The micellar solubilization of cocrystals has been found tofollow a nonlinear dependence on surfactant concentration,

which was in turn related to the differential solubilization of thecocrystal components.18

In a double-blind study involving 10 systems, the ability toobtain accurate structures of cocrystals using high-resolutionpowder diffraction has been demonstrated.19 Even thoughconduct of the powder refinement methodology was signifi-cantly more difficult relative to the single-crystal method, theability to obtain reliable structures of systems that do not yieldadequate crystals is a great advantage in crystal engineering.Dividing hydrates of cocrystal systems into four categories

based upon thermal stability properties (i.e., water is lost attemperatures less than 100 C, water is lost between 100 and120 C, water is lost at temperatures exceeding 120 C, andwhere dehydration occurs concurrently with the meltingtransition), the implications for crystal engineering of water incocrystals have been considered.20 An analysis of structures inthe Cambridge Structural Database revealed the existence ofconsiderable diversity in the types of heterosynthons formed bywater in the formation of hydrogen bonds with carboxylic acidsor alcohols. It was concluded that the variability in supra-molecular synthons involving water molecules is the factor thatcauses their unpredictable thermal stability.

3. PREPARATION OF COCRYSTAL SYSTEMS ANDMETHODOLOGIES FOR CHARACTERIZATION

Brittain has continued to develop vibrational spectroscopicselection rules for the recognition of salts and cocrystals,studying the sodium salt formation of benzoic acid, phenylaceticacid, hydrocinnamic acid, and 4-phenylbutanoic acid and in the1:1 cocrystal products formed by the free acids and sodiumsalts.21 It was deduced from these studies that for salt andcocrystal systems involving carboxylic acid groups, the energy ofthe antisymmetric stretching mode of the carbonyl group couldbe used to identify the nature of the species formed. When thefree acid absorption band (approximate frequency range of16801690 cm1) disappeared entirely and became replaced bythe corresponding anion band (approximate frequency range of15501600 cm1), a salt has been formed. On the other hand,when the free acid absorption band undergoes a small shifttoward higher energy (approximate frequency range of 17001730 cm1), one has observed the formation of a cocrystal.These trends are illustrated in Figure 1 for the phenylacetatesystem.Several characterization techniques have been used to study

the cocrystal products formed by salicylic acid with nicotinicacid, phenylalanine, and 6-hydroxynicotinic acid, as well as thecocrystal formed by 3,4-dihydroxybenzoic acid and oxalic acid.22

By completely assigning the Raman spectra of the cocrystals, adeeper understanding was obtained into the perturbation ofvibrational mode frequencies upon formation of the supra-molecular synthons. The use of in situ Raman spectroscopy hasbeen reported, and shown to be an effective observation toolin the high-throughput screening of slurries containing indo-methacin and 46 potential cocrystal formers.23 It was reportedthat savings in cost and time could be used using the reportedmethodology, as the spectroscopic information could be rapidlyobtained and analyzed during the course of the studies.The utility of cocrystallization as a means to develop new

routes for the crystallization of organic compounds has beendemonstrated for the cinnamic acid3-nitrobenzamide sys-tem.24 The isolation of cinnamic acid from fermentationfeedstocks was facilitated by formation of the cocrystal, as thereaction product formed at mole fractions that were seven times

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less than the solubility of the pure acid. Using a simulated fed-batch system, it was shown that the cinnamic acid producedduring the fermentation could be transformed into the less-soluble cocrystal. Eventually, a stationary state was obtainedwhere the process could be operated near the 3-phaseequilibrium point (i.e., between cocrystals, coformer solids,and dissolved solutes in solution).The importance of phase diagrams to process technology has

been demonstrated in two publications. Although little solutionphase interaction between benzoic acid and isonicotinamide wasdetected in 95% ethanol solutions, trends in the ternary phasediagram suggested differing crystal growth characteristics thatwere a function of composition.25 In particular, excess benzoicacid appeared to increase the metastable zone width (yieldingsmaller crystals) and excess isonicotinamide decreased themetastable zone width (yielding larger crystals). A completetemperature-dependent ternary phase diagram was developed forthe caffeineglutaric acidacetonitrile system, and subsequentlyused to develop a cooling cocrystallization process.26 In thiswork, it was shown that cocrystal purity could be compromisedwhen the crystallization took place outside of the defined safeoperating region.It has been shown that when one of the cocrystal formers

has the ability to modulate the activity of water, modulation ofthe anhydratehydrate composition of the product can beobtained.27 In particular, the effects of solution compositionand water activity were studied for the theophylline/citric acidsystem, where it was reported that the critical water activity forthe anhydroushydrate cocrystal equaled 0.8. In this work, itwas also shown that the activities of both water and coformerdetermined the relative phase stability, and that excipients ableto modify water activity could affect the eutectic points andphase stability. Finally, when cocrystals contain highly water-soluble coformers, these products will be prone toward phase

transformations owing to the moisture uptake and deliques-cence of the coformer.The use of mixed solvent mixtures to suppress the formation

of solvates during solution-phase cocrystallization has beendemonstrated for the carbamazepine/saccharin system.28 Usingup to nine different solvate-forming solvents, and 18 knowncocrystal formers of carbamazepine, it was reported that theprobability of obtaining a nonsolvated product increased withthe number of solvents used during the crystallization. Theextreme method to obtain nonsolvated cocrystals is to generatethe products either by a solvent-free reaction (or by a thermallyinduced combination of solid reactants) has been demonstratedfor the systems formed by phenazine or acridine with vanillin.29

Interestingly, while the phenazine/vanillin cocrystal wasobtained by a solid-state reaction, the acridine/vanillin cocrystalcould only be obtained from the melt.While most cocrystal products are obtained on the small scale

by solution-phase, mechanical, or solvent-drop methods, theuse of alternate technologies continues to be investigated.An ultrasound-assisted solution-phase cocrystallization methodhas been studied for the noncongruently soluble system of caffeineand maleic acid.30 Conventional methods yielded mixtures ofcaffeine and the 2:1 caffeine/maleic acid cocrystal in varyingamounts, while only the ultrasound-assisted method yielded thepure 2:1 cocrystal product.A supercritical fluid enhanced atomization process was

used to produce cocrystals of various drug substances withsaccharin.31 Cocrystal products with indomethacin, theophyl-line, caffeine, sulfamethazine, aspirin, and carbamazepine wereproduced from ethanol solutions using supercritical carbondioxide as the atomization enhancing fluid, and the work servedto demonstrate the utility of supercritical fluid technology as ameans to obtain cocrystals of pharmaceutically importantcompounds. The authors also reported the formation of a 1:2cocrystal of theophylline with saccharin that had not beenpreviously reported.Cocrystals of six model systems were produced by spray

drying, where the spray drying of solutions containingincongruently saturating solutes generated pure cocrystalproducts.32 It was suggested that the formation of cocrystalsby spray drying represented a kinetically controlled route thatminimized the effects of thermodynamics, namely, byproceeding through a noncrystalline form of the material. Inanother work, these same authors concluded that with sufficientunderstanding of the mechanism, the spray-drying process couldbe scaled up to a more useful level.33

For cocrystals to achieve pharmaceutically significance,methods must be developed that enable the products to bemanufactured on a commercial scale. One approach has been touse a solvent-free extrusion process, where enhanced surfacecontact between the cocrystal formers was achieved by a high-mixing screw design.34 The utility of this method wascommunicated for the 2:1 caffeine/oxalic acid system, and fora 1:1 cocrystal of sorbic acid with an experimental compound.Spherically agglomerated 1:1 cocrystals of ibuprofen andnicotinamide were produced using a hot-melt extrusionprocedure, where the effect of operating parameters (temper-ature, applied shear, and residence time) on the productproperties was investigated using a number of techniques.35 Itwas reported the process yield was improved by increases inmixing and shear intensity, with processing above eutectic pointbeing required for cocrystallization to occur.

Figure 1. Infrared absorption spectra in the fingerprint region ofphenylacetic acid (blue trace), sodium phenylacetate (green trace),and their 1:1 salt-cocrystal product (red trace) (adapted from ref 21).



4. COCRYSTAL SYSTEMS HAVING PHARMACEUTICALINTEREST

As cocrystal systems achieve more and more interest aspotential solid-state forms of active pharmaceutical ingredients,the research conducted on such systems continues. In thissection, the considerable amount of published work which hasbeen conducted on cocrystal systems having direct interest topharmaceutical scientists will be discussed.An interesting cocrystal of acetaminophen:

with 2,4-pyridinedicarboxylic acid has been reported, wherealthough both coformer ingredients were white in color, thecocrystal product was red in color.36 Analysis of the crystalstructure revealed that the pyridinedicarboxylic acid convertedto a zwitterionic form in the cocrystal, and that the coformersassembled to form a three-dimensional hydrogen-bondedframework that featured a pronounced two-dimensionalstructure. Using density function calculations, it was concludedthat the red color of the cocrystal was associated with adecrease in the bandgap separation between the highest-occupied and lowest-unoccupied molecular orbitals (i.e., the* separation) of the components in the supramolecularsynthon relative to the analogous separation of the individualcomponents.Using solvent drop grinding procedures, 20 cocrystal formers

have been combined with acetazolamide:

with these being identified by their X-ray powder diffractionpatterns.37 Single-crystal structural analysis was then used tostudy the hydrogen-bonding patterns in the products, and itwas reported that while 4-hydroxybenzoic acid bound to thethiadiazole acetamide fragment of acetazolamide via C(N)-NHHOOC and OHN interactions, nicotinamide boundvia NHN and NHO interactions. Phase stability assayswere conducted in water at physiological pH values, and it wasreported that while come cocrystal products were stable, othersunderwent gradual transformations.The heterosynthons present in the crystal structures of series

of cocrystals and salts of alprazolam:

with carboxylic acids, boric acid, boronic acids, and phenolshave been reported.38 It was reported that the triazole ringacted as a hydrogen bond acceptor with the acidic coformers,and the resulting structures contained a variety of hydrogenbonding patterns. Alprazolam was found to form hydratedstructures when cocrystallized with aliphatic dicarboxylic acidswhere the waters of hydration played significant roles in thenature of the crystal structure. It was also reported that thetriazole ring formed two different heterosynthons in itscocrystal with boric acid, while boronic acids formed non-centrosymmetric cyclic synthons and phenols formed OHNhydrogen bonds with the triazole ring.

While the relatively insoluble antimalarial drug artemisinin:

has found pharmaceutical utility, its lack of accessibleionizations has precluded salt formation as a means to enhanceits solubility. However, using a mechanochemical screeningprocedure, cocrystal products of artemisinin have beenformed with resorcinol (1,3-dihydroxybenzene) and orcinol(5-methylbenzene-1,3-diol).39 Molecular descriptors derivedfrom the Cambridge Structural Database were used to deducewhether cocrystals could be formed with artemisinin and 74potential coformers, and it was found that 33 of the coformerswould not be predicted to form a cocrystal product, thusenabling the use of a more focused screening process.In spite of the large amount of work conducted on cocrystals

of carbamazepine:

the compound continues to provide fertile ground for research.The structure of the isonicotinamide cocrystal Form-II was solvedusing powder diffraction data and found to be isostructural withthe carbamazepinenicotinamide cocrystal.40 However, picolin-amide did not form a cocrystal with carbamazepine, and socomputed crystal energy landscapes and binary and ternary phasediagrams were used to explain this finding. It was concluded thatthe lattice energies of predicted carbamazepinepicolinamidecocrystal structures would be less than the lattice energies of theseparated components, which was explained in terms of availableintermolecular hydrogen-bonding capabilities.Another cocrystal former that has received considerable

interest is caffeine:

The energies of the known cocrystals of caffeine with 2- and3-hydroxybenzoic acids were shown to be more stable relative totheir separate components, as was the instability of any possiblecocrystal between caffeine and the more stable conformer of3-hydroxybenzoic acid. The ability of caffeine to form a stablecocrystal with 4-hydroxybenzoic acid was confirmed in thisstudy, and the same cocrystal system was studied in greaterdetail in a separate study conducted by different authors.41 Inthis latter work, the use of differing initial concentration ratiosyielded cocrystals of differing stoichiometry, suggesting that themicroscopic intermolecular interactions determined in thesolution state could serve as qualitative and predictive indicatorsfor the final crystalline products. In another study, sonochem-istry and a surfactant were used to produce nanosized cocrystalproducts of caffeine with 2,4-dihydroxybenzoic acid.42

A 1:1 cocrystal of caffeine with 2-hydroxy-1-naphthoic acidwas isolated upon execution of a screening procedure that wasbased on solution-mediated phase transformation.43 Thecomponents were connected by means of hydrogen bondingthat involved both an intermolecular OHN hydrogen bond



and an intramolecular OHO hydrogen bond. In anotherstudy, cocrystals with maleic acid having 1:1 and 2:1stoichiometry have been obtained, and characterized throughmeasurement of the binary and ternary phase diagrams.44 Thediffering cocrystal products formed by caffeine with mono-hydroxybenzoic acids have been studied as to their computedcrystal energy landscapes to rationalize the diversity.45

The structures and properties have been reported for threecocrystals formed by dicarboxylic acids with cytosine:

have been reported.46 Solvent-drop grinding and solution-phase crystallization procedures were used to obtain the 4:1cocrystal of cytosine with oxalic acid, the 2:1 cocrystal ofcytosine with malonic acid, and the 2:1 cocrystal of cytosinewith succinic acid. The same R2

2(12) structural motif wasdetected in the three products, which was formed by a pair ofNHO hydrogen bonds within a dimer of cytosine.Various solid-state conformations of efavirenz:

were found in its pure crystal form, its cyclohexanesolvatomorph, and in cocrystals with 1,4-cyclohexanedioneand 4,4-bipyridine.47 The formation of cocrystal products bythis drug substance proved to be unpredictable, as only the twococrystals were obtained after performance of at least 27screening experiments. Two distinct heterosynthons wereidentified in the structure of the 4,4-bipyridine cocrystal: oneof the efavirenz molecules interacts with the bipyridine throughcyclic NHN/CHO hydrogen bonds, and the otherefavirenz molecule is joined to the other end of the bipyridinemolecule through a single-point NHN hydrogen bond.Two enantiotropically related polymorphic forms of the 1:1

cocrystal formed by ethylmalonic acid with ethenzamide:

have been reported and characterized by a variety of analyticaltechniques.48 The single-crystal X-ray diffraction study revealedthat in both polymorphs the ethylmalonic acid coformermolecules adopted different molecular conformations eventhough the same hydrogen-bonding motif was present in bothcrystal types. In another study, the 1:1 cocrystal of ethenzamidewith 3,5-dinitrobenzoic acid has been shown to exist in twononsolvated polymorphs and in a series of solvates.49 In astatistical study with structures filed in the Cambridge StructuralDatabase, it was deduced that the tendency to formsolvatomorphs was significantly higher for cocrystals as comparedto the crystalline solvatomorphs of a single solid component.The carboxylate OHNarom heterosynthon of fluconazole:

was exploited in a cocrystal design strategy in order toimprove the physicochemical properties of this antifungalagent.50 Cocrystal products were obtained of fluconazole withmaleic, fumaric, and glutaric acids upon solvent evaporation,and the results of single-crystal structural analysis were used tounderstand the intermolecular connectivities in the respectivesupramolecular synthons. In the maleic acid product, evidencefor proton transfer from the acid to fluconazole was obtainedeven through the pK difference between the coformers was lessthan that expected for salt formation.The first reported example of cocrystal solid solutions for a

system containing enantiomers of opposite chirality has beenreported for the 1:2 product formed by 4,4-dipyridyl andibuprofen:51

The enantiomeric mixtures of (ibuprofen)2(4,4-dipyridyl)cocrystals were obtained as a Roozeboom type-II solid solution,with the crystal structures of the solids being similar to those oftheir corresponding enantiomorphic and racemic coformers. Itwas found that the cocrystal products exhibited significantlyhigher melting temperatures and enthalpies of fusion relative totheir parent ibuprofen chiral crystals, and the solid solutionscould be crystallized to obtain a chiral enrichment. This latterfeature suggested that cocrystallization could be used to obtainalternate methods for the chiral resolution of racemiccompounds.Since the cocrystal of saccharin with indomethacin:

has been shown to exhibit more solubility than indomethacinalone all pH values, a study was conducted to evaluate the invitro dissolution and in vivo bioavailability of the cocrystalproduct relative a simple physical mixture and a commercialproduct.52 It was reported that the dissolution rate associatedwith the cocrystals was higher relative to that of other simplerforms of indomethacin, and that the in bioavailability in dogswas also higher for the of the indomethacinsaccharin cocrystal.This study is one of the few that has provided a case studywhere the properties of a poorly soluble drug substance wereimproved upon formation of a pharmaceutically acceptablecocrystal.The structures of a series of cocrystals of the antituberculosis

drug isoniazid:

with 4-hydroxybenzoic acid, 2,4-dihydroxybenzoic acid,malonic acid, succinic acid, glutaric acid, adipic acid, andpimelic acid have been reported.53 A search of literature cited inthe Cambridge Structural Database revealed the scope ofpossible homosynthons and heterosynthons that would be mostplausible in cocrystals of isoniazid with mono- and dicarboxylicacids. In the cocrystal systems of isoniazid, the dominantinteraction was the COOHN hydrogen bond, which wasidentified in the structures of all seven cocrystals of this study.



Cocrystal, salt, and solvatomorph formation has been tried inefforts to improve the solubility of lamotrigine:54

This work featured structural studies of two polymorphicforms of the 1:1 lamotrigine/methylparaben cocrystal, the 1:1lamotrigine/nicotinamide cocrystal and its monohydrate, the1:1 saccharin salt of lamotrigine, the 2:1 adipate and malatesalts of lamotrigine, the dimethanol solvate of lamotriginenicotinate, as well as the dimethanol and ethanol monohydratesolvatomorphs of lamotrigine. Some of the more promisingcrystal forms were further characterized as to their dissolutionrate, solubility, and pharmacokinetic behavior.The temperaturecomposition phase diagram of the (L)-

menthol binary system with lidocaine:

has been obtained as a means to understand the dynamics ofthe cocrystal formation process.55 It was learned that the onlyway to construct a phase diagram was to prepare the binarymixtures from the 1:1 cocrystal. This knowledge enabled thedevelopment of a process that maintains the cocrystal productin its thermodynamically stable state throughout its prepara-tion, manufacture, and storage.It is known that the nonsolvated form of mefloquine

hydrochloride:

is more soluble than its hydrated crystal form, and so oneof the goals associated with its formulation has been attemptsto prevent formation of hydrates. However, it has been foundthat formation of several cocrystals of mefloquine hydro-chloride with different coformers results in products thatexhibit enhanced solubility and dissolution rate.56 In addition,the cocrystals were shown to be stable over a period of 6months and also resisted conversion of the anhydrate to thehydrate.A total of 19 cocrystals (including one cocrystal of a salt)

containing meloxicam:

have been prepared using either solid-state or solution-phase methods.57 The pK differences between the co-formers was used as a reference to determine whetherproducts were cocrystals or salts. In the six reported single-crystal structures, the two-point carboxylic acidazole/NHsupramolecular heterosynthon was observed, and themeloxicam dimer unit was found to exist in five out of thesix structures. As part of the continuous development, theresulting meloxicam cocrystal forms will be further inves-tigated to explore improved physicochemical and pharmaco-logical properties.

The attempted cocrystallization of minoxidil:

with a number of potential pharmaceutically acceptablecocrystal formers has been carried out, with the synthesesyielding seven salts and one cocrystal with benzoic acid.58 In allof the products, the drug substance and the coformers wereconnected through charge-assisted carboxylate/N-hydroxidesynthon (or its neutral analogue), which demonstrated thestrength of this interaction even in the presence of other typesof hydrogen-bonding interactions moieties. It was reported thateven through the amino-pyridine and piperidine moieties areknown to be effective hydrogen-bond acceptors, there was noevidence for these groups forming hydrogen-bonds with acarboxylic acid group.The nutraceutical compound pterostilbene

is thought to exhibit anticancer, antihypercholesterolemia, andantihypertriglyceridemia properties, and its ability to form 1:1cocrystals with caffeine and carbamazepine has been inves-tigated.59 It was reported that the carbamazepinepterostilbenecocrystal was stable when suspended in water for 3 days,permitting an equilibrium solubility determination that thecocrystal was seven times less soluble than carbamazepinedihydrate and 2.5 times less soluble than pterostilbene. Owingto precipitation issues, only kinetic solubility data could beobtained for the caffeinepterostilbene cocrystal, but it wasreported that after 5 h of suspension in water, the concentrationof the cocrystal was 33 times lower than the solubility of caffeinehydrate and 27 times higher than the solubility of pterostilbeneitself.A structural characterization has been reported of the

cocrystal formed by pyrazine with nifedipine:60

In the monoclinic (nifedipine)2(pyrazine) cocrystal, thecenter of the pyrazine ring lies on an inversion center, with thepyrazine molecules being organized in the structure through vander Waals interactions. The nifedipine molecules are linked intochains along the c-axis through chains of NHO hydrogenbonds.A systematic study has been reported of the effects associated

with the positional isomerism of various dihydroxybenzoic acidson the cocrystals formed with piracetam:61

In this work, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, and 3,5-dihydroxy-benzoic acids were used as the cocrystal formers, and the 1:1



products were obtained by crystallization from acetonitrile.Interestingly, a cocrystal could not be obtained with 2,6-dihydroxybenzoic acid, which was ascribed to steric effects ofthe hydroxyl groups and preferred intramolecular hydrogenbonding between the hydroxyl group and the carboxylic acidgroup. Structural and infrared spectroscopic analyses of thefive cocrystal products indicated that the patterns of hydrogenbonding in the various products were quite different.The applicability of the OHN heterosynthon for

synthesis of cocrystals was examined for the case of methylparaben and quinidine:

In this work, the authors introduced the concept of amolecular hook to describe how methyl paraben picked itstarget site of interaction via hydrogen-bond-mediated molecularrecognition.62 The local conformation and hydrogen-bondingpatterns were derived from advanced multinuclear solid-statenuclear magnetic resonance techniques, where the interpreta-tion of the NMR data was supported by density-functionquantum-chemical calculations. One interesting finding of thestudy was that the molecular specificity of methyl parabenenabled the stereoselective separation of quinidine from itsquinine stereoisomer.The hemihydrate, and the dehydrated form, of the 1:1

cocrystal formed by saccharin and spironolactone:

have been studied, as well as the in vitro dissolution of thehemihydrate.63 Structural analysis indicated that the hemi-hydrate water resides in linear channels, and also that thehemihydrate and its anhydrate were isostructural. Single-crystalX-ray diffraction using the cocrystal anhydrate prepared fromsingle-crystal to single-crystal dehydration confirmed theisostructural relationship, and showed the retention of thechannels and shrinkage of the unit cell upon dehydration. Whilethe hydrated cocrystal demonstrated improved solubilityrelative to spironolactone Form-II (the most stable form),over time the solubility decreased upon formation of thepreviously unreported spironolactone 0.33-hydrate.The cocrystal formed by benzamide with salicylic acid:

has been studied by a series of physical measurements, and itwas determined that Raman spectroscopy was particularlyuseful for the characterization of the products and for a study ofthe nature of the interactions in the cocrystallized product.64

Changes in the intensities of the amide and the carboxylic acidvibrational modes were noted to accompany formation of the

cocrystal, and new vibrational bands were identified in thecocrystal product that could be used as identifiers of cocrystalformation.The 1:1 cocrystal formed by methyl gallate and theophylline:

has been studied, as well as the tabletting performance of thecocrystal and its coformers.65 While it was found thatcocrystallization improved the tabletability of methyl gallate,it was found to significantly deteriorate the tabletability oftheophylline, a difference ascribed to the dissimilar degrees ofcrystal plasticity and elasticity. In another work, the 1:2cocrystal formed by theophylline and sulfamethazine wasobtained using dry cogrinding, solvent-drop grinding, andslow evaporation procedures.66 The structure was obtainedusing single crystal X-ray diffraction data, showing that thesulfamethazine molecules form a dimer through intermolecularhydrogen bonding (OHN) and that two intermolecularhydrogen bonds (OHN and NHN) attach theophyllineto the dimer. The product formed by cocrystallization of with5-sulfosalicylic acid studied by X-ray photoelectron spectros-copy (XPS) was identified as a salt, with the XPS method beingused to determine the protonation state of the nitrogenfunctional groups on the theophylline moiety.67

5. PHARMACEUTICAL COCRYSTALS: STATE OF THEART

Over the past few years, work in the pharmaceutical communityhas begun to change the image of cocrystals from that ofcrystallographic curiosities to viable and useful forms of drugsubstances. Given that many new drug substances underdevelopment exhibit solubility limitations, workers have begunto successfully use cocrystallization as a means to enhancesolubility and dissolution rate. Others have noted that the use ofappropriate cocrystal forms can enhance the stability of a drugsubstance in the solid state and have exploited this feature toimprove the long-term quality of an active pharmaceuticalingredient. Areas yet to be explored concern how cocrystallizeddrug substances will facilitate the formulation of such materialsinto viable dosage form, but there is no doubt that such workwill follow.As of yet, the regulatory hurdle toward the use of cocrystals

in pharmaceutical products remains to be resolved. Whileagencies view polymorphs and solvatomorphs as alternate solid-state forms of drug substance and routinely accept their use indosage forms, new issues are generated by the fact thatcocrystallization necessarily results in a material in which theactive pharmaceutical ingredient and another substance are inintimate contact at the molecular level. Therefore, the questionto be addressed is whether a cocrystal should be defined as aphysical mixture (and thus possibly being able to be classifiedwithin current compendial guidelines), or whether a cocrystal isactually a new chemical entity that requires as much safety andtoxicology testing as would any other new chemical entity. It isfairly certain that investigators seeking to use cocrystals inpharmaceutical dosage forms will have to face this situation atsome point during a regulatory review process, and thispossibility may require some degree of intestinal fortitude andcourage on the part of the company filing the drug application.



Nevertheless, if the benefits of cocrystallization are sufficient,one should be able to overcome any additional regulatory issues.

AUTHOR INFORMATIONCorresponding Author*E-mail: [email protected].

REFERENCES(1) Aakeroy, C. B.; Salmon, D. J. Building Cocrystals with MolecularSense and Supramolecular Sensibility. CrystEngComm 2005, 7, 439448.(2) Vishweshwar, P.; McMahon, J. A.; Bis, J. A.; Zaworotko, M. J.Pharmaceutical Cocrystals. J. Pharm. Sci. 2006, 95, 499516.(3) Shan, N.; Zaworotko, M. J. The Role of Cocrystals inPharmaceutical Science. Drug Discovery Today 2008, 13, 440446.(4) Desiraju, G. R. Supramolecular Synthons in Crystal Engineering:A New Organic Synthesis. Angew. Chem., Int. Ed. 1995, 34, 23112327.(5) Stahly, G. P. A Survey of Cocrystals Reported Prior to 2000.Cryst. Growth Des. 2009, 9, 42124229.(6) Brittain, H. G. Cocrystal Systems of Pharmaceutical Interest:20072008. Profiles of Drug Substances, Excipients, and RelatedMethodology; Brittain, H. G., Ed.; Elsevier Academic Press:Amsterdam, 2010; Vol. 35; pp 373390.(7) Brittain, H. G. Cocrystal Systems of Pharmaceutical Interest:2009. Profiles of Drug Substances, Excipients, and Related Methodology;Brittain, H. G., Ed.; Elsevier Academic Press: Amsterdam, 2010; Vol.36; pp 361381.(8) Frisc ic, T.; Jones, W. Benefits of Cocrystallization inPharmaceutical Materials Science: An Update. J. Pharm. Pharmacol.2010, 62, 15471559.(9) Merz, K.; Vasylyeva, V. Development and Boundaries in the Fieldof Supramolecular Synthons. CrystEngComm 2010, 12, 39894002.(10) Aakeroy, C. B.; Rajbanshi, A.; Li, Z. J.; Desper, J. Mapping outthe Synthetic Landscape for Recrystallization, Cocrystallization, andSalt Formation. CrystEngComm 2010, 12, 42314239.(11) Seaton, C. G.; Chadwick, K.; Sadiq, G.; Guo, K.; Davey, R. J.Designing Acid/Acid Cocrystals through the Application of HammettSubstituent Constants. Cryst. Growth Des. 2010, 10, 726733.(12) Hathwar, V. R.; Pal, R.; Row, T. N. G. Charge Density Analysisof Crystals of Nicotinamide with Salicylic Acid and Oxalic Acid: AnInsight into the Salt to Cocrystal Continuum. Cryst. Growth Des. 2010,10, 33063310.(13) Molcanov, K.; Kojic-Prodic, B. Salt and Cocrystals of ChloranilicAcid with Organic Bases: Is it Possible to Predict Salt Formation?CrystEngComm 2010, 12, 925939.(14) Stevens, J. S.; Byard, S. J.; Schroeder, S. L. M. Characterizationof Proton Transfer by X-Ray Photoelectron Spectroscopy. Cryst.Growth Des. 2010, 10, 14351442.(15) Stevens, J. S.; Byard, S. J.; Schroeder, S. L. M. Salt or Cocrystal?Determination of Protonation State by X-Ray Photoelectron Spec-troscopy. J. Pharm. Sci. 2010, 99, 44534457.(16) Good, D. J.; Rodrguez-Hornedo, N. Cocrystal EutecticConstants and Prediction of Solubility Behavior. Cryst. Growth Des.2010, 10, 10281032.(17) Mohammad, M. A.; Alhalaweh, A.; Bashimam, M.; Al-Mardini,M. A.; Velaga, S. Utility of Hansen Solubility Parameters in theCocrystal Screening. J. Pharm. Pharmacol. 2010, 62, 13601362.(18) Huang, N.; Rodrguez-Hornedo, N. Effect of MicellarSolubilization on Cocrystal Solubility and Stability. Cryst. GrowthDes. 2010, 10, 20502053.(19) Lapidus, S. H.; Stephens, P. W.; Arora, K. K.; Shattock, T. R.;Zaworotko, M. J. A Comparison of Cocrystal Structure Solutions fromPowder and Single Crystal Techniques. Cryst. Growth Des. 2010, 10,46304637.(20) Clarke, H. D.; Arora, K. K.; Bass, H.; Kavusu, P.; Ong, T. T.;Pujari, T.; Wojtas, L.; Zaworotko, M. J. Structure-Stability Relation-ships in Cocrystal Hydrates: Does the Promiscuity of Water make

Crystalline Hydrates the Nemesis of Crystal Engineering? Cryst.Growth Des. 2010, 10, 21522167.(21) Brittain, H. G. Vibrational Spectroscopic Studies of Cocrystalsand Salts. 3. Cocrystal Products formed by Benzenecarboxylic Acidsand their Sodium Salts. Cryst. Growth Des. 2010, 10, 19902003.(22) Elbagerma, M. A.; Edwards, H. G. M.; Munshi, T.; Hargreaves,M. D.; Matousek, P.; Scowen, I. J. Characterization of New Cocrystalsby Raman Spectroscopy, Powder X-ray Diffraction, DifferentialScanning Calorimetry, and Transmission Raman Spectroscopy. Cryst.Growth Des. 2010, 10, 23602371.(23) Kojima, T.; Tsutsumi, S.; Yamamoto, K.; Ikeda, Y.; Moriwaki, T.High-Throughput Cocrystal Slurry Screening by use of in situ RamanMicroscopy and Multi-Well Plate. Int. J. Pharm. 2010, 399, 5259.(24) Urbanus, J.; Roelands, C. P. M.; Verdoes, D.; Jansens, P. J.; terHorst, J. H. Cocrystallization as a Separation Technology: ControllingProduct Concentrations by Cocrystals. Cryst. Growth Des. 2010, 10,11711179.(25) Boyd, S.; Back, K.; Chadwick, K.; Davey, R. J.; Seaton, C. C.Solubility, Metastable Zone Width Measurement and Crystal Growthof the 1:1 Benzoic Acid/Isonicotinamide Cocrystal in Solutions ofVariable Stoichiometry. J. Pharm. Sci. 2010, 99, 37793786.(26) Yu, Z. Q.; Chow, P. S.; Tan, R. B. H. Operating Regions inCooling Cocrystallization of Caffeine and Glutaric Acid in Acetonitrile.Cryst. Growth Des. 2010, 10, 23822387.(27) Jayasankar, A.; Roy, L.; Rodrguez-Hornedo, N. TransformationPathways of Cocrystal Hydrates when Coformer Modulates WaterActivity. J. Pharm. Sci. 2010, 99, 39773985.(28) Rager, T.; Hilfiker, R. Cocrystal Formation from SolventMixtures. Cryst. Growth Des. 2010, 10, 32373241.(29) Braga, D.; Grepioni, F.; Maini, L.; Mazzeo, P. P.; Rubini, K.Solvent-Free Preparation of Cocrystals of Phenazine and Acridine withVanillin. Thermochim. Acta 2010, 507508, 18.(30) Aher, S.; Dhumal, R.; Mahadik, K.; Paradkar, A.; York, P.Ultrasound Assisted Cocrystallization from Solution (USSC)Containing a Non-Congruently Soluble Cocrystal Component Pair:Caffeine/Maleic Acid. Eur. J. Pharm. Sci. 2010, 41, 597602.(31) Padrela, L.; Rodrigues, M. A.; Velaga, S. P.; Fernandes, A. C.;Matos, H. A.; de Azevedo, E. G. Screening for PharmaceuticalCocrystals Using the Supercritical Fluid Enhanced AtomizationProcess. J. Supercrit. Fluids 2010, 53, 156164.(32) Alhalaweh, A.; Velaga, S. P. Formation of Cocrystals fromStoichiometric Solutions of Incongruently Saturating Systems by SprayDrying. Cryst. Growth Des. 2010, 10, 33023305.(33) Alhalaweh, A; Velaga, S. P. Formation of Cocrystals by SprayDrying. J. Pharm. Pharmacol. 2010, 62, 13321333.(34) Medina, C.; Daurio, D.; Nagapudi, K.; Alvarez-Nunez, F.Manufacture of Pharmaceutical Cocrystals using Twin ScrewExtrusion: A Solvent-Less and Scalable Process. J. Pharm. Sci. 2010,99, 16931696.(35) Dhumal, R. S.; Kelly, A. L.; York, P.; Coates, P. D.; Paradkar, A.Cocrystallization and Simultaneous Agglomeration Using Hot MeltExtrusion. Pharm. Res. 2010, 27, 27252733.(36) Sander, J. R. G.; Bucar, D.-K.; Henry, R. F.; Baltrusaitis, J.;Zhang, G. G. Z.; MacGillivray, L. R. A Red Zwitterionic Cocrystal ofAcetaminophen and 2,4-Pyridine-dicarboxylic Acid. J. Pharm. Sci.2010, 99, 36763683.(37) Arenas-Garcia, J. I.; Herrera-Ruiz, D.; Mondragon-Vasquez, K.;Morales-Rojas, H.; Hopfl, H. Cocrystals of Active PharmaceuticalIngredients Acetazolamide. Cryst. Growth Des. 2010, 10, 37323742.(38) Varughese, S.; Azim, Y.; Desiraju, G. R. Molecular Complexes ofAlprazolam with Carboxylic Acids, Boric Acid, Boronic Acids, andPhenols. Evaluation of Supramolecular Heterosynthons Mediated by aTriazole Ring. J. Pharm. Sci. 2010, 99, 37433753.(39) Karki, S.; Friscic, T.; Fabian, L.; Jones, W. New Solid Forms ofArtemisinin Obtained Through Cocrystallization. CrystEngComm2010, 12, 40384041.(40) Habgood, M.; Deij, M. A.; Mazurek, J.; Price, S. L.; ter Horst,J. H. Carbamazepine Cocrystallization with Pyridine Carboxamides:



Rationalization by Complementary Phase Diagrams and CrystalEnergy Landscapes. Cryst. Growth Des. 2010, 10, 903912.(41) He, G.; Chow, P. S.; Tan, R. B. H. Investigating theIntermolecular Interactions in Concentration-Dependent SolutionCocrystallization of Caffeine and p-Hydroxybenzoic Acid. Cryst.Growth Des. 2010, 10, 37633769.(42) Sander, G. Jr.; Bucar, D.-K.; Henry, R. F.; Zhang, G. G. Z.;MacGillivray, L. R. Pharmaceutical Nano-Cocrystals: SonochemicalSynthesis by Solvent Selection and Use of a Surfactant. Angew. Chem.,Int. Edn. 2010, 49, 72847288.(43) Bucar, D. K.; Henry, R. F.; Duerst, R. W.; Lou, X.; MacGillivray,L. R.; Zhang, G. G. Z. A 1:1 Cocrystal of Caffeine and 2-Hydroxy-1-Naphthoic Acid Obtained via a Slurry Screening Method. J. Chem.Cryst. 2010, 40, 933939.(44) Guo, K.; Sadiq, G.; Seaton, C.; Davey, R. J.; Yin, Q.Cocrystallization in the Caffeine/Maleic Acid System: Lessons fromPhase Equilibria. Cryst. Growth Des. 2010, 10, 268273.(45) Habgood, M.; Price, S. L. Isomers, Conformers, and CocrystalStoichiometry: Insights from the Crystal Energy Landscapes ofCaffeine with the Hydroxybenzoic Acids. Cryst. Growth Des. 2010,10, 32633272.(46) Lee, T.; Wang, P. Y. Screening, Manufacturing, Photo-luminescence, and Molecular Recognition of Co-Crystals: Cytosinewith Dicarboxylic Acids. Cryst. Growth Des. 2010, 10, 14191434.(47) Mahapatra, S.; Thakur, T. S.; Joseph, S.; Varughese, S.; Desiraju,G. R. 2010. New Solid State Forms of the Anti-HIV Drug Efavirenz:Conformational Flexibility and High Z Issues. Cryst. Growth Des. 201010, 3191-3202.(48) Aitipamula, S.; Chow, P. S.; Tan, R. B. H. Conformational andEnantiotropic Polymorphism of a 1:1 Cocrystal Involving Ethenz-amide and Ethylmalonic Acid. CrystEngComm 2010, 12, 36913697.(49) Aitipamula, S.; Chow, P. S.; Tan, R. B. H. Polymorphs andSolvates of a Cocrystal Involving an Analgesic Drug, Ethenzamide, and3,5-Dinitrobenzoic Acid. Cryst. Growth Des. 2010, 10, 22292238.(50) Kastelic, J.; Hodnik, Z.; Sket, P.; Plavec, J.; Lah, N.; Leban, I.;Pajk, M.; Planinsek, O.; Kikelj, D. Fluconazole Cocrystals withDicarboxylic Acids. Cryst. Growth Des. 2010, 10, 49434953.(51) Chen, S.; Xi, H.; Henry, R. F.; Marsden, I.; Zhang, G. G. Z.Chiral Cocrystal Solid Solution: Structures, Melting Point PhaseDiagram, and Chiral Enrichment of (ibuprofen)2(4,4-dipyridyl).CrystEngComm 2010, 12, 14851493.(52) Jung, M.-S.; Kim, J.-S.; Kim, M.-S.; Alhalaweh, A.; Cho, W.;Hwang, S.-J.; Velaga, S. P. Bioavailability of Indomethacin-SaccharinCocrystals. J. Pharm. Pharmacol. 2010, 62, 15601568.(53) Lemmerer, A.; Bernstein, J.; Kahlenberg, V. One-Pot Covalentand Supramolecular Synthesis of Pharmaceutical Co-Crystals Usingthe API Isoniazid: A Potential Supramolecular Reagent. CrystEngComm2010, 12, 28562864.(54) Cheney, M. L.; Shan, N.; Healey, E. R.; Hanna, M.; Wojtas, L.;Zaworotko, M. J.; Sava, V.; Song, S.; Sanchez-Ramos, J. R. Effects ofCrystal Form on Solubility and Pharmacokinetics: A CrystalEngineering Case Study of Lamotrigine. Cryst. Growth Des. 2010, 10,394405.(55) Corvis, Y.; Negrier, P.; Lazerges, M.; Massip, S.; Leger, J.-M.;Espeau, P. Lidocaine/L-Menthol Binary System: Cocrystallizationversus Solid-State Immiscibility. J. Phys. Chem. B 2010, 114, 54205426.(56) Yadav, A. V.; Dabke, A. P.; Shete, A. S. Crystal Engineering toImprove Physicochemical Properties of Mefloquine Hydrochloride.Drug Dev. Ind. Pharm. 2010, 36, 10361045.(57) Cheney, M. L.; Weyna, D. R.; Shan, N.; Hanna, M.; Wojtas, L.;Zaworotko, M. J. Supramolecular Architectures of MeloxicamCarboxylic Acid Cocrystals, A Crystal Engineering Case Study. Cryst.Growth Des. 2010, 10, 44014413.(58) Schultheiss, N.; Lorimer, K.; Wolfe, S.; Desper, J. AttemptedConstruction of Minoxidil: Carboxylic Acid Cocrystals; 7 Salts and 1Cocrystal Resulted. CrystEngComm 2010, 12, 742749.

(59) Schultheiss, N.; Bethune, S.; Henck, J.-O. Nutraceuticalcocrystals: utilizing pterostilbene as a cocrystal former. CrystEngComm2010, 12, 24362442.(60) Schultheiss, N.; Roe, M.; Smit, J. P. Nifedipine-Pyrazine (2/1).Acta Crystallogr. 2010, E66, o2297o2298.(61) Liao, X.; Gautam, M.; Grill, A.; Zhu, H. J. Effect of PositionIsomerism on the Formation and Physicochemical Properties ofPharmaceutical Cocrystals. J. Pharm. Sci. 2010, 99, 246254.(62) Khan, M.; Enkelmann, V.; Brunklaus, G. Crystal Engineering ofPharmaceutical Co-crystals: Application of Methyl Paraben asMolecular Hook. J. Am. Chem. Soc. 2010, 132, 52545263.(63) Takata, N.; Takano, R.; Uekusa, H.; Hayashi, Y.; Terada, K.A Spironolactone-Saccharin 1:1 Cocrystal Hemihydrate. Cryst. GrowthDes. 2010, 10, 21162122.(64) Elbagerma, M. A.; Edwards, H. G. M.; Munshi, T.; Scowen, I. J.Identification of a new cocrystal of salicylic acid and benzamide ofpharmaceutical relevance. Anal. Bioanal. Chem. 2010, 397, 137146.(65) Chattoraj, S.; Shi, L.; Sun, C. C. Understanding the Relationshipbetween Crystal Structure, Plasticity and Compaction Behavior ofTheophylline, Methyl Gallate, and their 1:1 Cocrystal. CrystEngComm2010, 12, 24662472.(66) Lu, J.; Rohani, S. Synthesis and Preliminary Characterization ofSulfamethazine-Theophylline Cocrystal. J. Pharm. Sci. 2010, 99, 40424047.(67) Stevens, J. S.; Byard, S. J.; Muryn, C. A.; Schroeder, S. L. M.Identification of Protonation State by XPS, Solid-State NMR, andDFT: Characterization of the Nature of a New Theophylline Complexby Experimental and Computational Methods. J. Phys. Chem. B 2010,114, 1396113969.



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