Preparation and studies of the co-crystals of meloxicam with carboxylic acids

Russian Chemical Bulletin, International Edition, Vol. 61, No. 9, pp. 1798—1809, September, 2012

1798

Preparation and studies of the coꢀcrystals of meloxicam

with carboxylic acids

S. A. Myz,^a,bT. P. Shakhtshneider,^a,bN. A. Tumanov,^band E. V. Boldyreva^a,b

^aInstitute of Chemistry of Solid State and Mechanochemistry,

Siberian Branch of the Russian Academy of Sciences,

18 ul. Kutateladze, 630128 Novosibirsk, Russian Federation.

Fax: +7 (383) 332 2847. Eꢀmail: apenina@solid.nsc.ru

^bScientific Educational Center "Molecular Design and Environmentally Friendly Technologies",

Novosibirsk State University,

2 ul. Pirogova, 630090 Novosibirsk, Russian Federation.

Fax: +7 (383) 339 3142

Mechanical treatment with addition of some liquid, crystallization from solutions, and

heating of the mixture components preliminary subjected to mechanical treatment were the

methods used for the preparation of the coꢀcrystals of 4ꢀhydroxyꢀ2ꢀmethylꢀNꢀ(5ꢀmethylthiꢀ

azolꢀ2ꢀyl)ꢀ2Hꢀ1,2ꢀbenzothiazinꢀ3ꢀcarboxamide 1,1ꢀdioxide (meloxicam) with carboxylic acꢀ

ids. It was shown that preliminary mechanical treatment plays significant role for the synthesis,

whereas the addition of small amounts of solvents accelerates the process. The coꢀcrystals were

obtained for 17 mixtures of meloxicam—carboxylic acid. The use of the coꢀcrystals of meloxiꢀ

cam in the compositions of improved pharmaceutical forms was found promising, which was

attributable to the fact that the dissolution rate and the solubility of the coꢀcrystals of meloxiꢀ

cam with the carboxylic acids under study are higher than those for meloxicam itself.

Key words: coꢀcrystals, meloxicam, carboxylic acids, mechanochemical synthesis, solubiliꢀ

zation of medicines.

Lately, coꢀcrystals of medicines, in which together with

This method frequently allow one to avoid formation of

solvate forms, as well as gives a possibility to obtain coꢀ

crystals, whose formation from solutions or melts is imꢀ

possible.^1,23Addition of a small amount of solvent during

mechanical treatment can accelerate the process of obꢀ

taining coꢀcrystals and keep formation of polymorphous

modifications of coꢀcrystals under control.^24,25It is not

quite clear how the liquid added influences the process.

One of the possible reasons for this influence can be the

fact that the process proceeds through the dissolution of at

least one of the reagents in the solvent with subsequent

crystallization of the coꢀcrystal from the solution.^26—31

Meloxicam (MOC), 4ꢀhydroxyꢀ2ꢀmethylꢀNꢀ(5ꢀmethylꢀ

2ꢀthiazolyl)ꢀ2Hꢀ1,2ꢀbenzothiazineꢀ3ꢀcarboxamide 1,1ꢀdiꢀ

oxide, is modern nonsteroid antiinflammatory drug.³²Deꢀ

pending on conditions, it crystallizes in different tautoꢀ

meric forms: anionic, enol, cationic, and zwitterionic.

molecules of active pharmaceutical ingredient (API) other

molecules are present, attract very much attention. In conꢀ

trast to solid solutions, the alternation of molecules of

different components is strictly regular in them. The forꢀ

mation of coꢀcrystals is not accompanied by such subꢀ

stantial redistribution of charges between molecules as it

happens in salts, so one cannot suggest formation of catꢀ

ions and anions. The coꢀcrystals allow one to, first, conꢀ

siderably increase the number of forms existing for a cerꢀ

tain API (salts, different polymorphous modifications,

amorphous forms, hydrates/solvates), which is of great

importance for solving the problems related to the patent

protection of a certain medicines based on a certain API,

and second, improve clinically important physicochemiꢀ

cal properties of drugs, for example, solubility, the dissoꢀ

lution rate, stability on storage. Coꢀcrystals can also have

technological advantages: behave better on filtration and

crystallization, possess lower hygroscopicity and higher

stability on treatment.¹Mechanochemical method is one

of the most widely used approaches to the preparation of

coꢀcrystals of organic compounds.^1—20Mechanochemiꢀ

cal method is environmentally friendly, since it does not

require the use of organic solvents on a large scale.^4,21,22

Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1782—1793, September, 2012.

Coꢀcrystals of meloxicam with carboxylic acids

Russ.Chem.Bull., Int.Ed., Vol. 61, No. 9, September, 2012

1799

Earlier,³³we have used mechanochemical methods for

the first preparation of coꢀcrystals of meloxicam with carꢀ

boxylic acids: succinic and maleic. In continuation of these

works, we obtained the coꢀcrystals of meloxicam with anꢀ

other fifteen carboxylic acids^34,35(Table 1). The literature

described³⁶the preparation of coꢀcrystals of meloxicam

with a number of carboxylic acids by three methods: crysꢀ

tallization from solution, crystallization from a suspenꢀ

sion of reagents in solvent, and mechanochemically with

addition of small amounts of liquid. Besides acids given in

Table 1, the authors of the work³⁶reported preparation of

coꢀcrystals of meloxicam with 1ꢀhydroxyꢀ2ꢀnaphthoic,

Lꢀmalic, gentisic, 4ꢀhydroxybenzoic, DLꢀmalic, (+)ꢀcamꢀ

phoric, glycolic, and hydrocinnamic acids. The crystal

structures were determined for the coꢀcrystals of meloxiꢀ

cam with succinic, fumaric, glutaric, salicylic, 1ꢀhydroxyꢀ

2ꢀnaphthoic, and ^Lꢀmalic acids.³⁶The structure of the

coꢀcrystal of meloxicam with succinic acid given in the

work³⁶is the same as that independently determined by

us,^37—39CCDC 796926 (Fig. 1). Earlier, we have shown

that mechanochemical method for the preparation of coꢀ

crystals of carboxylic acids with piroxicam (compound

related to meloxicam in the structure and having similar

therapeutic effect) was more promising than cocrystalliꢀ

zation from solutions or from melts.¹

mechanochemical method, including that with addition

of small amounts of various liquids, differing in the ability

to dissolve both meloxicam and carboxylic acids), as well

as to study the coꢀcrystals obtained by a combination of

physicochemical methods.

Results and Discussion

The results of crystallization from solutions, heating of

the mixture components preliminary subjected to mechanꢀ

ical treatment, as well as of mechanical treatment of mixꢀ

tures of meloxicam and carboxylic acids, including that

with addition of small amounts of liquids, are summarized

in Table 1.

The crystallization from solutions allowed us to obtain

crystals with various ratios of meloxicam : carboxylic acid

(2 : 1, 1 : 1, 1 : 2, 1 : 3, and 1 : 4). As it was mentioned

previously, the structure of MOC—1 was found to be the

same as reported in the work³⁶for the structure of coꢀ

crystal of the same composition. The structures of MOC—2

and MOC—3 have been described by us earlier.³⁸A comꢀ

parison of the powder diffraction motives showed that the

coꢀcrystals MOC—2, MOC—6, MOC—12, and MOC—13

are identical to those obtained in the work.³⁶The structure

of MOC—13 was described³⁶based on the single crystal

studies, whose calculated diffraction motive matched the

experimental one (the present work), that indicated the

monophase nature of our sample.

Upon isothermal heating of the mixtures (Table 2),

three kinds of coꢀcrystals were isolated, whose powder

diffraction motives matched the diffraction motives of coꢀ

crystals obtained by mechanochemical method and from

solutions. We mainly chose temperatures of heating close

to the sublimation temperature, but below melting points.

It turned out that the synthesis was possible before the

acid melted and even at the temperature below the subliꢀ

mation point, which was, for example, 0.8 subl.t.

Preliminary mechanical treatment of mixtures of reꢀ

agents without addition of solvent allowed us to increase

the efficiency of formation of coꢀcrystals with subsequent

heating of the mixtures, though no formation of coꢀcrysꢀ

tals was observed upon direct mechanical treatment of the

same mixtures in the absence of solvent. Heating of simple

physical mixture of components did not lead to coꢀcrysꢀ

tals, either.

The purpose of the present work was to compare

a possibility of preparation of coꢀcrystals of meloxicam

with carboxylic acids using various methods (crystallizaꢀ

tion from solutions, heating of the mixture components

preliminary subjected to mechanical treatment, as well as

O(2)

O(1)

C(5)

S(1)

C(4)

C(1)

C(9)

C(7)

C(2)

C(10)

C(11)

C(3)

C(8)

C(13)

C(6)

C(14)

N(2)

N(3)

O(3)

N(1)

C(12)

S(2)

O(5)

O(6)

C(15)

C(16)

O(4)

C(16)

C(15)

O(4)

O(5)

O(3)

N(3)

O(6)

Mechanical treatment of mixtures of meloxicam with

carboxylic acids in the absence of liquid leads neither to

the polymorphous transitions in separate components, nor

to the formation of new phases, however, after addition of

small amount of liquid (0.2 mL of liquid per 0.1 g of the

mixture) the mixtures rapidly lose the yellow color, turnꢀ

ing colorless. At the same time, new reflections appear on

the diffraction motives, which indicate the formation of

a new phase with the crystalline structure differing from

the structure of the starting components. This can be conꢀ

C(12)

C(11)

N(1)

C(13)

C(8)

N(2)

C(4)

C(14)

C(6)

C(3)

C(2)

C(1)

C(10)

C(5)

O(1)

C(7)

O(2)

C(9)

S(1)

Fig. 1. The structureꢀforming fragment in the coꢀcrystal of

meloxicam with succinic acid (typical of the coꢀcrystals of

meloxicam).

1800

Russ.Chem.Bull., Int.Ed., Vol. 61, No. 9, September, 2012

Myz et al.

Table 1. The coꢀcrystals of meloxicam (MOC) with carboxylic acids 1—17

Acid

Methods of the preparation of the coꢀcrystals and their composition

Trituration

with acetone

Crystallization

from solution

Heating after preliminary

mechanical activation

Succinic³⁶(1)^a

Adipic³⁶(2)^a

Terephthalic (3)

Oxalic (4)

Malonic³⁶(5)

Maleic³⁶(6)^a

Fumaric³⁶(7)

Glutaric³⁶(8)

Pimelic (9)

MOC—1 (2 : 1)

MOC—2 (2 : 1)^с

MOC—3 (2 : 1)

MOC—4 (1 : 1)

MOC—5 (1 : 3)

MOC—6 (1 : 2)

MOC—7 (1 : 1)

MOC—8 (1 : 2)

MOC—9 (1 : 4)

MOC—10 (1 : 1)

MOC—11 (1 : 1)

MOC—12 (1 : 1)

MOC—13 (1 : 1)

MOC—14 (1 : 1)

MOC—15 (1 : 1)

MOC—16 (1 : 4)

MOC—17 (1 : 2)

MOC—1 (2 : 1)^b

—

MOC—2 (2 : 1)^c

MOC—3 (2 : 1)^b

—

MOC—6 (1 : 2)

—

MOC—8 (1 : 2)

—

Suberic (10)

Sebacic (11)

Benzoic³⁶(12)^a

Salicylic³⁶(13)^a

Isophthalic (14)

Trimesic (15)

Phenylsuccinic (16)

Citric acid hydrate (17)

—

MOC—4 (1 : 1)

—

^aThe phases of the coꢀcrystals matched with those obtained in the work.³⁶

^bThe structure was determined in the present work.

^cThe structure was determined in the present work and different polymorphous modifications were obtained.

sidered as an evidence for the formation of the coꢀcrystal.

A procedure of the phase indexing is described in the

Experimental. Analysis of the Xꢀray diffraction data

showed that the samples obtained by us by mechanical

treatment of mixtures of meloxicam with benzoic, adipic,

succinic, maleic, and salicylic acids with addition of aceꢀ

tone are identical to those reported earlier³⁶for the coꢀ

crystals of meloxicam with these acids. In the case of

benzoic, adipic, and maleic acids, the comparison was

performed using Xꢀray powder diffraction motives, for sucꢀ

cinic and salicylic, using the data of the single crystals

analysis. It should be noted that in the work,³⁶other solꢀ

vents were used: THF for the preparation of the coꢀcrysꢀ

tals with benzoic, adipic, succinic, maleic acids and ethyl

acetate in the case of salicylic acid. At the same time, the

Xꢀray powder diffraction motives of the samples obtained

by mechanical treatment of the mixtures of meloxicam

with malonic, fumaric, and glutaric acids considerably

differed from the diffraction motives given in the work,³⁶

that indicated that different phases were formed in these

systems upon mechanical treatment in our experiments

and in experiments described earlier.³⁶One of the possible

reasons for such discrepancies is the use of additives of

different liquids, which, as it is known, can influence the

composition, stoichiometry, and crystalline structure of

the products of mechanical synthesis.⁴⁰When the same

liquids were used, the phases coincided with those deꢀ

scribed earlier.³⁶More in detail discussion on the influꢀ

ence of liquids on the results of mechanosynthesis in the

mixtures of meloxicam with carboxylic acids will follow

below. In the present work, we for the first time obtained

the coꢀcrystals of meloxicam with pimelic, suberic, sebacic,

oxalic, isophthalic, terephthalic, trimesic, and phenylsucꢀ

cinic acids. Despite the fact that no coꢀcrystals were obꢀ

tained upon mechanical treatment of dry mixtures of

Table 2. Melting points and sublimation temperatures of carboxꢀ

ylic acids and temperatures of heating of mixtures of acids with

meloxicam

Acid*

M.p./subl.t.

Temperature of heating

С

Oxalic (4)

166/125

135.6/—

185/130—140

139/—

130, 160

90

130, 180

120

170

90

140

90

130

Malonic (5)

Succinic (1)

Maleic* (6)

Fumaric (7)

Glutaric* (8)

Adipic (2)

296/165

98/—

153/130

105.5/—

122.4/—

348/160

300/165

380/300

Adipic(9)

Benzoic (12)

Isophthalic* (14)

Terephthalic (3)

Trimesic (15)

130

* The coꢀcrystals were obtained with this acid upon heating.

Coꢀcrystals of meloxicam with carboxylic acids

Russ.Chem.Bull., Int.Ed., Vol. 61, No. 9, September, 2012

1801

meloxicam with citric acid,³³the coꢀcrystal was obꢀ

tained by trituration of meloxicam with citric acid monoꢀ

hydrate with addition of acetone. No formation of coꢀ

crystals was observed either upon mechanical treatment of

mixtures of meloxicam with 3ꢀ(4ꢀhydroxyphenyl)proꢀ

pionic and 3ꢀ(3,4ꢀdihydroxyphenyl)propionic acids. Like

in the works,^33,36no coꢀcrystals of meloxicam with ascorꢀ

bic or tartaric acid were obtained by the synthetic method

chosen.

For the coꢀcrystals with three acids, viz., succinic, adꢀ

ipic, and terephthalic, single crystals were grown from

solutions in THF, toluene, and ethanol, respectively, by

a slow evaporation in air. Comparison of the powder difꢀ

fraction motives, which were calculated based on the

models obtained by the decoding of the diffractional data

for single crystals and the powder diffraction motive meaꢀ

sured for the products of mechanochemical synthesis

showed that the powders of the products have the monoꢀ

phase nature and the crystalline structures of the single

crystals coincide with the crystalline structures of polyꢀ

crystalline samples.

of terephthalic acid is 300 C). It is seen that the coꢀcrysꢀ

tals of meloxicam have different melting points, while forꢀ

mation of the coꢀcrystals suppresses the sublimation and

decomposition of carboxylic acids up to the coꢀcrystal

melting point.

The mechanochemical method of synthesis has proved

more efficient for the preparation of coꢀcrystals of melꢀ

oxicam with carboxylic acids than crystallization from soꢀ

lutions or heating mixtures. The same behavior was obꢀ

served for the coꢀcrystals of piroxicam:¹from the six methꢀ

ods used (coꢀmelting of components, evaporation of solꢀ

vent, rapid and slow cooling of solution, salting out of

solution, and mechanochemical), the mechanochemical

method turned out to be the most productive for the crysꢀ

tallization of coꢀcrystals. At the same time, to effect the

mechanochemical synthesis of the majority of the sysꢀ

tems, the presence in the system of at least a small amount

of liquid is still necessary, without which the process does

not take place or proceeds so slowly that is not detected

within a real duration of the experiment.

The influence of liquid on the process of synthesis of

coꢀcrystals upon mechanical treatment was studied more

in detail using the systems meloxicam—succinic acid and

meloxicam—adipic acid as examples. The results for the

system meloxicam—succinic acid are compared in Table

3, where the molar solubility of meloxicam also is given.⁴¹

There is no unambiguous correlation between the solubilꢀ

ities of the starting components in the liquid added and

the possibility of the formation of the coꢀcrystals. For

example, the coꢀcrystals were formed upon addition of

both the liquids dissolving both components (acetone,

ethanol, isopropanol) and the liquids, in which one of the

components (succinic acid) was virtually insoluble (chloroꢀ

form, toluene, benzene, ethyl acetate). In the case of solꢀ

vents, in which neither of the components is soluble (hexꢀ

ane, cyclohexane), no coꢀcrystals were obtained. At the

same time, the coꢀcrystals were not formed upon addition

of water, though both starting components were soluble in

it. In the equilibrium crystallization, a necessary condiꢀ

tion for the formation of coꢀcrystals is a lower solubility of

the coꢀcrystal obtained as compared to the solubility of

separate components in the solvent used. Formation of

coꢀcrystals often is a nonequilibrium process and is obꢀ

served in such cases, when in a certain solvent the crystalꢀ

lization of coꢀcrystals occurs faster than crystallization of

the individual phases. We have observed that the mechaꢀ

nochemical synthesis frequently gives products correꢀ

sponding to the rapid crystallization. Thus, it has been

shown earlier for the system glycine—oxalic acid that the

mechanical coꢀtreatment of a mixture of glycine and oxꢀ

alic acid dihydrate initially and very fast led to the formaꢀ

tion of bisꢀglycinium oxalate (the same product as in the

rapid spontaneous crystallization from aqueous solutions

upon precipitation with acetone), which on further meꢀ

chanical treatment was transformed to glycinium semiꢀ

Thermoanalytical studies of mechanically activated

mixtures of meloxicam with acids in those case when the

mechanical treatment was interrupted, without the reacꢀ

tion reaching completion, showed the presence of thermal

effects characteristic of the melting of the separate comꢀ

ponents and the product, i.e., the coꢀcrystal. The meltꢀ

ing points of the coꢀcrystals can be registered on their

DSCꢀcurves. The results of the DSCꢀmeasurements of

coꢀcrystals of meloxicam with adipic and terephthalic acꢀ

ids are given in Fig. 2. An endothermic thermal effect was

detected in both samples, which can be attributed to the

melting of the coꢀcrystals, followed by the endoꢀ and exoꢀ

thermic effects apparently related to the sublimation of

acids and decomposition of the samples. The coꢀcrysꢀ

tal of meloxicam with adipic acid melts at 195 C (m.p.

of meloxicam and adipic acid are 260 and 153 C, respecꢀ

tively). For the coꢀcrystal with terephthalic acid, the

endothermic process of melting is observed at 255 C (m.p.

DSC/mW mg^–1

2

exo

70

60

50

40

30

1

20

10

0

–10

160 180 200 220 240 260 280 T/С

Fig. 2. The DSC curves for the coꢀcrystals of meloxicam with

adipic (1) and terephthalic (2) acids.

1802

Russ.Chem.Bull., Int.Ed., Vol. 61, No. 9, September, 2012

Myz et al.

Table 3. Solubility of succinic acid and meloxicam in various solvents and the products formed

Solvent

Solubility of

succinic acid

Molar

solubility of

meloxicam⁴¹

Product of

mechanochemical

synthesis

Product of

synthesis

from solution

Chloroform

Dioxane

Acetone

Toluene

Benzene

Carbon tetrachloride

Propanꢀ1ꢀol

Ethanol

Propanꢀ2ꢀol

Ethyl acetate

Water

—

0.001814

0.001796

MOC—1 (2 : 1)

—

MOC—1 (2 : 1)

—

MOC—1 (2 : 1)

—

+

—

0.0006055

0.0001698

0.0001612

6.166•10^–5

5.562•10^–5

4.582•10^–5

3.93•10^–5

3.476•10^–5

1.023•10^–5

7.701•10^–6

4.474•10^–6

MOC—1 (2 : 1)

—

+

—

+

MOC—1 (2 : 1)

—

Hexane

Cyclohexane

—

oxalate (i.e., to the product of slow crystallization upon

evaporation of the aqueous solution).^42,43In the present

work, in the system of meloxicam—succinic acid the forꢀ

mation of the coꢀcrystals upon crystallization from the

solution in acetone, isopropyl alcohol, ethyl acetate also

was observed only in such a case, when the solution was

subjected to the rapid evaporation, as in the grinding case,

whereas the starting components were crystallized upon

slow evaporation.

ground when dry.³³The role of mixing the components

during preliminary mechanical treatment of dry mixture

should not be underestimated, either.

We compared the preparation of the coꢀcrystals of

meloxicam with adipic acid upon mechanical treatment

with addition of a small amount of dioxane or toluene, as

well as upon slow coꢀcrystallization from solutions of these

solvents. The use of different solvents led to the formation

of compounds with different crystalline structure by both

slow crystallization from solutions and grinding with

addition of small amounts of the same solvents (Fig. 4). In

this case, the slow crystallization from solution of a cerꢀ

tain solvent and mechanical treatment with addition of

the same solvent gave the same result. In order to deterꢀ

mine whether the compounds obtained were solvates or

coꢀcrystals with different stoichiometry, we performed elꢀ

emental analysis. The results showed that the coꢀcrystals

obtained are not solvates but, obviously, different polyꢀ

morphous modifications of the same coꢀcrystal meloxiꢀ

cam—adipic acid with the ratio of components 2 : 1.

For the practical use of meloxicam as medicinal preꢀ

paration, it is of importance to develop forms, in which

the dissolution rate and solubility would be higher. These

properties are characteristic, at least, of some of the coꢀ

crystals synthesized in the present work: with succinic,

oxalic, isophthalic, benzoic, and terephthalic acids (Fig. 5).

Except oxalic acid, all the acids listed have no harmful

effects on the organism and are permitted by pharmaꢀ

copoeia for the introduction in the composition of medicꢀ

inal forms.⁴⁴Therefore, the coꢀcrystals listed (except the

coꢀcrystal with oxalic acid) can be considered as promising

for the application in the composition of pharmaceutical

forms as alternatives to the individual compound.

The role of solvents was also demonstrated in the series

of experiments, the results of which are shown in Fig. 3.

On the Xꢀray diffraction motive 2, the reflections related

to the coꢀcrystal of meloxicam with succinic acid are

marked. It is seen that shortꢀtime treatment with addition

of the solvent resulted in the incomplete formation of the

coꢀcrystal. Mechanical treatment after evaporation of

the solvent did not lead to further formation of the coꢀ

crystal (Xꢀray diffraction motive 3). It can be concluded

that the presence of solvent is necessary for the process to

take place. After addition of a solvent to a preliminary

ground mixture, the product was obtained almost inꢀ

stantly (Xꢀray diffraction motives 4 and 5). At the same

time, the addition of a solvent to the mixture of compoꢀ

nents ground separately led to the formation of only

insignificant amount of the product (Xꢀray diffraction

motive 6). To sum up, in the case of meloxicam with

succinic acid mechanical coꢀtreatment of the mixture of

components plays an important role in the formation of

the mixed crystal, whereas addition of solvent, apparently,

accelerates the process. The influence of preliminary meꢀ

chanical activation, possibly, consists in the fact that meꢀ

chanical treatment leads to the formation of nuclei of the

product, which then, upon addition of the solvent, beꢀ

come the centers of its crystallization. This was confirmed,

for example, by the fact that meloxicam could react with

maleic acid upon heating, if the mixture was preliminary

The most important characteristics of solid medicinal

compound is its crystalline structure. The detailed comꢀ

parative analysis of the crystalline structures of coꢀcrystals

Coꢀcrystals of meloxicam with carboxylic acids

Russ.Chem.Bull., Int.Ed., Vol. 61, No. 9, September, 2012

1803

I (rel. units)

6

5

4

3

2

1

10

20

30

40

2/deg

Fig. 3. Xꢀray diffraction patterns of mixtures of meloxicam with succinic acid (2 : 1): the mixture ground during 3 min without solvent (1)

or with solvent (2), the preceding mixture ground during 15 min after evaporation of the solvent (3), the preceding mixture ground for

another 20 s with the solvent (4); a mixture ground during 9 min without solvent and then 20 s with the solvent (5); a mixture of

components ground separately during 9 min, which was ground with addition of the solvent during 20 s (6).

of meloxicam is given in the work.³⁸Meloxicam in the

coꢀcrystal exists in the enol prototropic form in such

a configuration that the oxygen atoms of the hydroxyl and

keto groups are on the same side of the molecule. The

O—H...O hydrogen bond is formed between the oxygen

atoms of these groups, which stabilizes this conformation.

Due to the rigid enough geometry of the molecule, paraꢀ

meters of this intramolecular hydrogen bond cannot conꢀ

siderably vary and lie in the same range as in other strucꢀ

tures with meloxicam in similar conformation.

In the known structures of coꢀcrystals of meloxicam

with acids, no proton transfer from the carboxyl group of

the acid to the thiazole ring of meloxicam takes place,

except for the coꢀcrystal with ^Lꢀmalic acid. However, it is

obvious that the formation of the hydrogen bond between

the nitrogen and the hydrogen atoms leads to the weakenꢀ

ing of the conjugation of the lone pair of electron on the

nitrogen with the ring and the disappearing of the color of

the compound.

through the hydrogen bonds N—H...O and O—H...N, reꢀ

spectively. This motive was observed in all the known by

now structures of the coꢀcrystals of meloxicam with carbꢀ

oxylic acids. Thus, the main structural fragment is formed

consisting of one molecule of the corresponding acid and

two molecules of meloxicam.³⁸These structural fragments

form planar layers, as it is shown in Fig. 6, a. In the coꢀ

crystals with succinic, fumaric, and ^Lꢀmalic acids, the

planar layers are formed from similar structural fragments.

In the case of adipic and terephthalic acids, the distance

between the meloxicam molecules happens to be enough

for the meloxicam molecule of one fragment to be placed

between two molecules of meloxicam of another fragment,

so that the fragments are "hooked" to each other, though

forming no dimers (see Fig. 6, a). In the coꢀcrystals with

succinic, fumaric, and ^Lꢀmalic acids, the distance between

the meloxicam molecules in one fragment is smaller and

not enough for the meloxicam molecule of the neighborꢀ

ing fragment to be placed between them (Fig. 6, b succinic

acid was taken as an example). In this case, the structural

fragments are arranged in such a way that the formation of

Each carboxyl group of dicarboxylic acid is bonded to

the NH group and the thiazole group of meloxicam

1804

Russ.Chem.Bull., Int.Ed., Vol. 61, No. 9, September, 2012

Myz et al.

I (rel. units)

6

4

5

3

2

1

10

20

30

40

2/deg

Fig. 4. Xꢀray diffraction motives of the starting meloxicam (1), the starting adipic acid (2), the coꢀcrystal obtained by grinding with

toluene (3) or dioxane (4) and obtained from the solution by a slow evaporation from toluene (5) or dioxane (6).

C/mg mL^–1

3.5

C/mg mL^–1

3.0

a

b

2

3

2

3

3.0

2.5

2.0

1.5

1.0

0.5

2.5

2.0

1.5

1.0

0.5

4

1

5

10

15

20 t/min

5

10

15

20 t/min

Fig. 5. Curves of dissolution of the coꢀcrystals of meloxicam with carboxylic acids as compared to the individual meloxicam (1): (a):

with succinic (2), oxalic (3), and isophthalic acid (4); (b): with benzoic (2) and terephthalic acid (3).

Coꢀcrystals of meloxicam with carboxylic acids

Russ.Chem.Bull., Int.Ed., Vol. 61, No. 9, September, 2012

a

1805

b

Fig. 6. The motive of planar layers in the structure of the coꢀcrystals of meloxicam with adipic (a) and succinic acids (b).

molecular pairs (pseudodimers) of meloxicam becomes

possible, in which the molecules are situated close to each

other, though are not bonded by hydrogen bonds. Such

a motive can also be found in the crystalline structures of

meloxicam hydrogen sulfate hydrate³²and benzene solꢀ

vate of transꢀdichloro(²ꢀethylene)(meloxicam)platinꢀ

1806

Russ.Chem.Bull., Int.Ed., Vol. 61, No. 9, September, 2012

Myz et al.

um(^II)⁴⁵. For the comparison, in the structure of the inꢀ

dividual meloxicam the molecules are bonded by strong

hydrogen bonds to true dimers. A suggestion³⁸has been

made that this is destruction of dimers in the coꢀcrystals

based on medicinal compound which can be the reason of

the increased rate of their dissolution as compared to the

crystals of the individual medicinal compound.

It was of interest to compare the crystalline structures

of coꢀcrystals of meloxicam—carboxylic acid with the strucꢀ

tures of the coꢀcrystals of piroxicam with the same acids

determined in Ref. 46. Piroxicam has molecular structure

similar to that of meloxicam, but has a pyridine fragment

instead of the thiazolyl group. At least two polymorphous

modifications are known for piroxicam, which differ in

the molecular packing. In both polymorphous modificaꢀ

tions of piroxicam no formation of dimers, analogous to

the dimers in compounds of meloxicam, was observed,

whereas in the structures of crystals containing piroxicam

with such a configuration where the oxygen atoms of the

hydroxyl and keto groups are on the same side of the molꢀ

ecule, such dimers are formed. The structures of the coꢀ

crystals of piroxicam with 1ꢀhydroxyꢀ2ꢀnaphthoic and sucꢀ

cinic acids are similar to the structures of the coꢀcrystals

of meloxicam with the same acids, whereas the structures

of the coꢀcrystals with malonic and fumaric acids in the

cases of meloxicam and piroxicam considerably differ, that

can be attributed to the influence of the pyridyl group.

The motive in the form of planar infinite chains, similar to

that present in the structures of the coꢀcrystals of melꢀ

oxicam with adipic and terephthalic acids, in the coꢀcrysꢀ

tals of piroxicam with carboxylic acids was not observed,

that can also be explained by the specifics of the pyridyl

group. Conformations of the piroxicam molecule in the

coꢀcrystals are distinguished by a greater variety as comꢀ

pared to those of meloxicam. Note that as of the present

moment, no formation of the coꢀcrystals of piroxicam

with terephthalic acid is described in contrast to meloxiꢀ

cam, but piroxicam is known to form three coꢀcrystals

with adipic acid (while meloxicam forms only two coꢀ

crystals). Such a difference for the structurally close comꢀ

pounds cannot be explained only from the standpoint of

crystallochemical analysis.

Investigation of vibration spectra gives an additional

information about the interactions in the structure of coꢀ

crystals. The vibration bands of the meloxicam molecule

in the IR spectra of coꢀcrystals and an individual pharmaꢀ

ceutical compound have different positions (Fig. 7).

A strong peak at 3290 cm^–1corresponding to the stretchꢀ

A

1

2

3

4

3250 3000

2000

1800

1600

1400

1200

1000 /cm^–1

Fig. 7. IR absorption spectra of meloxicam (1) and the coꢀcrystals of meloxicam with succinic (2), adipic (3), and terephthalic

acids (4).

Coꢀcrystals of meloxicam with carboxylic acids

Russ.Chem.Bull., Int.Ed., Vol. 61, No. 9, September, 2012

1807

ing vibration (N—H) in the molecule of meloxicam is

shifted toward the lower frequencies in the IR spectrum of

coꢀcrystals, whereas its intensity decreases. At the same

time, the amide II and amide III vibration bands, which

are a combination of vibrations (C—N) + (NH), are

displaced toward higher frequencies. These changes corꢀ

respond to the strengthening of the NH...O hydrogen

bonds when the homomolecular dimers in meloxicam

are replaced with the heteromolecular clusters meloxiꢀ

cam—carboxylic acid in coꢀcrystals. In the spectra of the

coꢀcrystals, the band, which corresponds to the stretching

vibration of the C=O group involved in the individual

meloxicam in the formation of intramolecular hydrogen

bond and short contacts in the molecular pairs (pseudoꢀ

dimers),³⁸is slightly shifted toward the highꢀfrequency

region, that indicates the "loosening" or the absence (deꢀ

pending on the type of packing) of molecular pairs. The

IR spectra of coꢀcrystals with different types of molecular

packing also differ. In the spectra of the coꢀcrystals of

meloxicam with adipic and terephthalic acids, where

a chainꢀlike motive of packing is effected and molecules

are bonded through a short contact with participation of

the oxygen atom of the SO₂group, the band correspondꢀ

ing to the stretching vibration _as(SO₂) virtually does not

change its position, whereas upon formation of the coꢀ

crystal with succinic acid, the distruction of the dimers

existing in the starting meloxicam bonded by hydrogen

bonds with participation of the SO₂group, leads to the

shift of the band toward higher frequencies.

The strengthening of heteromolecular hydrogen bonds

in the coꢀcrystals as compared to the homomolecular ones

in the individual meloxicam, from the one hand, allows

one to explain formation of the coꢀcrystals, rather than

the phases of individual components on coꢀcrystallization,

but, from the other hand, causes a question about the

reasons of the higher dissolution rate of coꢀcrystals as comꢀ

pared to the individual meloxicam. Apparently, as it was

suggested in the work,³⁸the dissolution rate is influenced

not only by the energy of intermolecular interactions in

the crystal, but also by the easiness of the attack of the

molecule in the crystal by the solvent molecules, which is

defined by the crystalline structure. If in the heteromolecꢀ

ular clusters the two molecules of meloxicam are connectꢀ

ed by the carboxylic acid bridge, the solvation of the

meloxicam molecules can take place easier than if the

molecules of meloxicam are bonded to each other in

a dimer by hydrogen bonds.

treatment, allowed us to obtain different polymorphous

modifications of the coꢀcrystals of meloxicam. It was

shown that the dissolution rate and the solubility of meloxiꢀ

cam in the case of the coꢀcrystals with the carboxylic acids

under study was higher than the dissolution rate of the

starting medicinal compound, that makes it promising to

use the coꢀcrystals of meloxicam for solubilization of meꢀ

dicinal forms based on it.

Experimental

Meloxicam was purchased from ChemꢀEast Ltd. (Hungary).

Carboxylic acids (see Table 1) purchased from Hebei Welcome

Pharmaceutical Co., Ltd (China) and solvents (see Table 2) purꢀ

chased from Reakhim (Russia) and Sigma—Aldrich (USA) were

used without additional purification.

IR spectra of frustrated total internal reflection (FTIR) in

the range of frequencies 4000—580 cm^–1with the resolution of

4 cm^–1were recorded on a Digilab Excalibur 3100 Fourierꢀ

transform IR spectrometer (USA) using an FTIR (Pike) appliꢀ

ance with a ZnSe crystal without special preparation of samples.

Elemental analysis was performed on an EAꢀ3000 (HEKAtech

GmbH, Germany) elemental analyzer. Thermoanalytical meaꢀ

surements were performed on a DSCꢀ204 (Netzsch) calorimeꢀ

ter, the rate of heating was 6 K min^–1, masses of samples were

5.1 and 4.6 mg for the coꢀcrystals of meloxicam with terephthalic

and adipic acids, respectively.

Xꢀray powder analysis. Xꢀray powder analysis was performed

on D8 DISCOVER (Bruker, Germany, CuꢀK irradiation) and

STADI MP (STOE & Cie GmbH, Germany, CuꢀK irradiaꢀ

1

tion) diffractometers. The diffraction motives obtained were anꢀ

alyzed using the WinXPOW software.⁴⁷In the cases when only

peaks from new phases could be identified, the diffraction moꢀ

tives were indexed. Stoichiometry of a compound obtained was

determined proceeding from the volume of a unit cell and apꢀ

proximate volumes of molecules of meloxicam and the correꢀ

sponding acid. Product was considered as having a monophase

nature, when no peaks from the starting reagents remained in its

diffraction motive and all the peaks in the diffraction motive of

the product were indexed.

Mechanochemical synthesis of coꢀcrystals (general procedure).

Mechanical treatment of mixtures of meloxicam with carboxylic

acids in different molar ratios was carried out in an agate mortar

(the time of treatment 20—30 min) or in a SPEX 8000 roller mill

(CertiPrep Inc., USA, 40ꢀmL steel cans, steel balls 6 mm in

diameter, the proportion of the compound weight to the weight

of the balls 1 : 100, the load on the ball 8—10 g, the time of

treatment 15 min). Dry treatment was used initially, then liquid

was added (acetone, 0.2 mL of liquid per 0.1 g of the mixture).

Experiments with the variations of liquids were carried out in

a mortar, adding solvents (see Table 2) to a preliminary triturated

dry mixture of meloxicam with succinic acid in the molar ratio of

2 : 1. Dioxane and toluene were used in the case of adipic acid. For

the product of mechanical treatment of the mixture of meloxiꢀ

cam with adipic acid in the presence of dioxane: found (%):

C, 48.86; H, 5.23; N, 6.46; S, 9.85. For the mixture triturated

with toluene: found (%): C, 48.96; H, 5.20; N, 6.72; S, 10.50.

C₂₆H₃₃N₃S₂O₁₂. Calculated (%): C, 48.47; H, 5.13; N, 6.52; S, 9.96.

Synthesis of coꢀcrystals by crystallization from solutions. The

coꢀcrystals of meloxicam with succinic acid (2 : 1) were obtained

In conclusion, in the present work coꢀcrystals of

meloxicam with 17 different carboxylic acids were obꢀ

tained using various methods. It was shown that prelimiꢀ

nary mechanical treatment plays a significant role in efꢀ

fecting the synthesis, whereas addition of small amount of

solvent accelerates the process. Varying the liquids, from

which crystallization was carried out or which were added

to the mixtures of powders during their mechanical coꢀ

1808

Russ.Chem.Bull., Int.Ed., Vol. 61, No. 9, September, 2012

Myz et al.

by crystallization from a THF solution. A preliminary triturated

mixture of meloxicam with succinic acid (2 : 1) was dissolved at

40 C in the solvent (15 mL). The solution was subjected to the

slow evaporation (using a cap with a small opening) at 20 C.

The coꢀcrystals of meloxicam—adipic acid were obtained from

the solution in toluene saturated at 50 C with the mixture of

meloxicam with adipic acid (2 : 1) by cooling to 20 C. The

coꢀcrystals of meloxicam with terephthalic acid were obtained

from the solution in ethanol saturated at 50 C with the mixture

of meloxicam with terephthalic acid (2 : 1) by cooling to 5 C.

The coꢀcrystals of meloxicam with glutaric acid were obtained

from the solution in benzene subjected to a slow evaporation

at 20 C.

ing Scientific Schools of the Russian Federation, Grant

NShꢀ221.2012.3).

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This work was financially supported by the Civilian

Research and Development Foundation (Grant RUX0ꢀ

008ꢀNOꢀ06), the Russian Foundation for Basic Research

(Project Nos 10ꢀ03ꢀ00252 and 11ꢀ03ꢀ00684), the Presidiꢀ

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and Materials Science of the Russian Academy of Sciences

(Program "Chemistry and Physical Chemistry of Suꢀ

pramolecular Systems and Atomic Clusters", Project

No. 5.6.4), the Council on Grants at the President of the

Russian Federation (Program of State Support for Leadꢀ

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Received March 29, 2011;

in revised form July 3, 2012

Article Doi

Preparation and studies of the co-crystals of meloxicam with carboxylic acids

DOI: 10.1007/s11172-012-0248-6

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Authors:

Article abstract of DOI:10.1007/s11172-012-0248-6

Full text of DOI:10.1007/s11172-012-0248-6

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