PHARMACEUTICS, PREFORMULATION ANDDRUG DELIVERY

Relationships between Structural and Thermal Properties ofAnhydrous and Solvated Crystalline Forms of Brodimoprim

MINO R. CAIRA,1 GIAMPIERO BETTINETTI,2 MILENA SORRENTI,2 LAURA CATENACCI2

1Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa

2Dipartimento di Chimica Farmaceutica, Universita di Pavia, Viale Taramelli 12, I-27100 PV, Italy

Received 4 May 2006; accepted 5 July 2006

Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.20934

ABSTRACT: The isolation and physicochemical characterization of four crystallinemodifications of brodimoprim (5-[(4-bromo-3,5-dimethoxyphenyl)methyl]-2,4-pyrimidi-nediamine, hereinafter BMP), a structural analog of trimethoprim (TMP), are reported.These phases include an unsolvated form of BMP, a hemihydrate (BMP�0.5H2O), a1:1 solvate containing isopropanol (BMP�C3H7OH(iso)), and a hemichloroformate(BMP�0.5CHCl3). Unsolvated BMP was isolated both by recrystallization from a rangeof common solvents as well as by thermal decomposition of the above solvates and noevidence for polymorphism was found. PXRD data indicated that the three solvatescrystallize in different arrangements. Data from thermal analysis (thermogravimetry(TGA), hot stage microscopy (HSM), differential scanning calorimetry (DSC)) of thesolvates containing water and iso-propanol were interpreted on the basis of their single-crystal X-ray structures which revealed that the modes of solvent inclusion inBMP�0.5H2O and BMP�C3H7OH(iso) may be described as ‘isolated site’ and ‘latticechannel’ type inclusions, respectively. � 2007 Wiley-Liss, Inc. and the American Pharmacists

Association J Pharm Sci 96:996–1007, 2007

Keywords: brodimoprim; drug solvates; thermal analysis; X-ray diffraction

INTRODUCTION

In our previous studies on the solid-stateproperties of tetroxoprim (5-[[3,5-dimethoxy-4-(2-methoxyethoxy)phenyl]methyl]-2,4-pyrimidine-diamine, TXP) (Fig. 1(I)), one of the most activestructural analogs of trimethoprim (TMP)(Fig. 1(II)) for the competitive inhibition ofbacterial dehydrofolate reductase, alterations of

physical properties such as melting point andaqueous solubility due to the substitution of the4-methoxy group of TMP with a methoxyethoxygroup in TXP were interpreted in terms of crystalpacking, hydrogen bonding, and moleculardisorder.1 Another structural analog of TMP isthe brominated compound brodimoprim, 5-[(4-bromo-3,5-dimethoxyphenyl)methyl]-2,4-pyrimi-dinediamine, BMP (Fig. 1(III)), a long actingbroad spectrum antibacterial agent which is usedmainly in upper respiratory tract infections.2 Theefficacy and tolerability of BMP in the treatmentof acute uncomplicated bacterial cystitis3 and theadditive antimicrobial effects of its combinationwith epiroprim4,5 have also been reported.

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Correspondence to: Mino R. Caira (Telephone: þ27 21 6503071; Fax: þ27 21 689 7499;E-mail: xraymino@science.uct.ac.za)

Journal of Pharmaceutical Sciences, Vol. 96, 996–1007 (2007)� 2007 Wiley-Liss, Inc. and the American Pharmacists Association

To our knowledge, the unique experimentaldatum available in the pharmaceutical literatureon the solid-state properties of BMP is a meltingpoint of 225–2288C for the crystals frommethanol6 or ethanol.7 In this paper an analogousinvestigation to that carried out for TXP was per-formed on BMP samples prepared by recrystalli-zation from various solvents. Single-crystal andpowder X-ray diffractometry (XRD), differentialscanning calorimetry (DSC), thermogravimetry(TGA), and hot stagemicroscopy (HSM) were usedfor structural and thermal characterization of thecrystalline forms of BMP. Solid–solid transforma-tions between solvates and anhydrous BMPunderambient atmosphere were also studied. The effectof the presence of the bromine atom in themolecule, which makes BMP more hydrophobicand more active than TMP against Gram-positivebacteria,8,9 on the increase in melting point byabout 258C (and consequent decrease of aqueoussolubility) was related to crystal packing andhydrogen bonds.

EXPERIMENTAL

Preparation of BMP Samples

Samples were prepared by recrystallization ofcommercial BMP (Helsinn Chemicals SA, Biasca,Switzerland) (mp 232.78C) from solutions inthe solvents (analytical reagent grade) and atthe concentrations indicated in Table 1 at therespective boiling points. The solutions werefiltered and allowed to recrystallize by sponta-neously cooling to room temperature. The pro-ducts were filtered and the intact crystals withoutcrushing dried in air and analyzed just after

drying. The solid-state forms of the crystalsand the stoichiometry of the solvates wereassessed by DSC and TGA (see below).The isolated crystalline forms of BMP, namelyanhydrous BMP, BMP�0.5H2O, BMP�CH3OH,BMP�C3H7OH(iso), and BMP�0.5CHCl3, weresieved collecting the <180 mm granulometricfraction and 1.5 g samples of each form spreadon Petri dishes were exposed to ambient atmo-sphere (�228C, �45% relative humidity (RH)).Samples (3–7 mg) were taken out at appropriateintervals and checked for the solid phase composi-tion by DSC and TGA (see below).

Preliminary Characterization of Anhydrous andSolvated BMP Crystals

Anhydrous BMP (from ethanol: Anal. Calc.C13H15BrN4O2: C, 46.03; H, 4.46; N, 16.52%.Found: C, 46.24; H, 4.43; N, 16.60%) crystallizedas colorless prisms (Fig. 2a). BMP�0.5H2O (fromwater/ethanol 1/1 (v/v): calc. mass loss 2.59%;TGA mass loss 2.3� 0.3%, n¼ 4) crystallizedas striated laths (Fig. 2b). BMP�0.5H2O can alsobe obtained from anhydrous BMP by prolongedexposure (�2 months) to ambient atmosphere(�228C, �45% RH). Crystals of the chloroformsolvate (BMP�0.5CHCl3: calc. mass loss 14.82%;TGAmass loss 14.85�0.07%, n¼ 3) were obtainedas irregular laminae (Fig. 2c). A progressivedarkening of the crystal along parallel linesrapidly occurs under ambient conditions(see Fig. 2c’). BMP�C3H7OH(iso) (calc. mass loss15.05%; TG mass loss 15.3� 0.7%, n¼ 3)crystallized as laths similar to those ofBMP�0.5H2O (Fig. 2d). BMP�CH3OH (calc. massloss 8.62%; TGA mass loss 8.5� 0.4%, n¼ 4)

Table 1. BMP Samples Isolated by Recrystallizationfrom the Tested Solutions

SolventmL per1 gBMP Sample

Ethanol 120 Anhydrous BMPEthyl acetate 300 Anhydrous BMPAcetone 130 Anhydrous BMPDimethylsulfoxide 50 Anhydrous BMPWater 3500 BMP�0.5H2OWater/ethanol 1/1 (v/v) 70 BMP�0.5H2OWater/methanol 1/1 (v/v) 270 BMP�0.5H2OMethanol 300 BMP�CH3OHIsopropanol 200 BMP�C3H7OH(iso)Chloroform 250 BMP�0.5CHCl3

Figure 1. Chemical structure of TXP (I), TMP (II),and BMP (III).

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was obtained in the form of extremely thinwhiskers (Fig. 2e).

HSM

Microscopic observation of the sample morpho-logy and thermal events on heating were carriedout under a Reichert polarized light microscopeequipped with a Mettler FP82HT/FP80 systemat a heating rate of 10 K min�1. Images weretransferred by a Moticam 2000 to a computerfor elaboration (Adobe Photoshop 7.0) andprinting.

DSC

Temperature and enthalpy values were measuredwith a METTLER STARe system equipped witha DSC821e Module on 3–5 mg (Mettler M3Microbalance) samples in standard aluminiumpans with pierced lids under static air. An emptypan was used as reference. The heating rate was10 Kmin�1 over the 30–3008C temperature range.

TGA

Mass losses were recorded with a Mettler TA4000 apparatus equipped with a TGA 50 cell at a

Figure 2. Morphological features of BMP crystalline forms. Key: (a) anhydrousBMP (from acetone); (b) BMP�0.5H2O (from water/ethanol 1/1 (v/v)); (c) BMP�0.5CHCl3;(c’) sample (c) after exposure to ambient atmosphere for 2 min; (d) BMP�C3H7OH(iso);(e) BMP�CH3OH.

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heating rate of 10 Kmin�1 on 7–10 mg samples inopen alumina crucibles over the temperaturerange 30–3008C under static air.

XRD Studies

Of the species listed in Table 1 unsolvated BMP(from acetone) and BMP�C3H7OH(iso) affordedcrystals suitable for X-ray analysis (see Fig. 2),while BMP�0.5H2O crystals obtained by exposureof anhydrous BMP to ambient atmosphere wereused for structural investigations. Preliminarysurveys of the X-ray diffraction patterns collectedon a Nonius Kappa CCD diffractometer revealedLaue symmetry �1 for all three crystals, indicatingthe triclinic crystal system. Intensity data werecollected using MoKa radiation (l¼ 0.71073 A)with the crystal specimens coated in Paratone oil(Exxon Chemical Co., Houston, TX) and cooled ina stream of N2 vapour. The crystal data andrefinement parameters are reported in Table 2.The data-collection strategy indicated by theprogram COLLECT10 involved suitable combina-tions of f- and o-scans. Program DENZO-SMN11

was used for unit cell refinement and datareduction. Intensity statistics indicated thecentric space group P1 in all cases. The structureswere solved by direct methods using programSHELXS8612 and refined by full-matrix least-squares using program SHELX-97.13 Molecularparameters were calculated with PLATON.14

Programs ORTEP15 and WebLab ViewerPro3.716 were used for illustrations.

RESULTS AND DISCUSSION

Thermal Analysis

In the DSC trace of anhydrous BMP (fromacetone) there is an endothermal effect with apeak maximum temperature at 232.2� 0.98C(n¼ 3) due to fusion (DHfus¼ 147� 4 J g�1) whichis followed by an exothermal effect peaking at�2808C attributable to sample decomposition(Fig. 3, curve a). Thermogravimetry of anhydrousBMP revealed no weight loss from the samplesover the 30–2408C temperature range and totalweight loss over the 240–3008C temperaturerange of the DSC exothermal effect, confirminga complete decomposition of the BMPmelt (Fig. 4,curve a). By stopping a DSC run of anhydrousBMP just after melting, cooling down to roomtemperature, and rescanning, a sharp endother-mal effect with substantially the same tempera-ture and enthalpy parameters as those forthe original sample are recorded (data notshown). Gravimetric, thermal, and calorimetricdata for BMP�0.5H2O (prepared by exposure ofanhydrous BMP to ambient atmosphere),BMP�0.5CHCl3, BMP�C3H7OH(iso), and BMP�CH3OH are presented in Table 3. The onset

Table 2. Crystal Data and Details of Refinement

Parameter Anhydrous BMP BMP�0.5H2O BMP�C3H7OH(iso)

Chemical formula C13H15BrN4O2 C13H16BrN4O2.5 C16H23BrN4O3

Formula weight 339.19 348.21 399.29Dcalc (g cm�3) 1.657 1.612 1.450Crystal system Triclinic Triclinic TriclinicSpace group P1 P1 P1a (A) 7.6740(1) 7.5809(2) 8.3130(1)b (A) 8.2254(1) 11.6935(4) 8.8187(1)c (A) 11.3822(2) 17.6428(6) 13.3105(2)a (8) 88.741(1) 96.181(1) 88.700(1)b (8) 71.178(1) 100.409(2) 81.248(1)g (8) 88.346(1) 108.633(2) 71.552(1)V (A3) 679.70(2) 1434.48(8) 914.53(3)

Formula units, Z 2 4 2m (MoKa) (mm�1) 3.031 2.877 2.269T (K) 113 193 193Reflections 3106 6307 4341R1 (on F> 4sF) 0.0179 0.0390 0.0353wR2 (on F2, F> 4sF) 0.0422 0.0743 0.0719Goodness-of fit, S 1.062 1.071 1.050

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temperatures of desolvation gradually increasedfrom BMP�0.5H2O to BMP�CH3OH, indicating adifferent binding strength of the various solventsin the crystal. All solvents were lost in one stepand the desolvation product was anhydrous BMPin all cases. The percentage mass loss measuredover the TGA desolvation step of each solvate(DmS%) was related to the enthalpy changecalculated over the corresponding DSC desolva-tion endotherm (DHS,exp, in J g�1) as in Eq. 1:

DHs ¼DHs;exp � 100

Dms%

� ��Ms ð1Þ

where DHS (in J mol�1) is the heat of vaporizationof the BPM-bound solvent and MS the molecularweight of the solvent, and the results arepresented in Table 3. On comparison of the DHS

values with the heats of vaporization for the pure

Figure 3. DSC curves of BMP crystalline forms. Key:(a) anhydrous BMP (from acetone); (b) BMP�0.5H2O(by exposure to ambient atmosphere of anhydrousBMP); (c) BMP�0.5CHCl3; (d) BMP�C3H7OH(iso);(e) BMP�CH3OH.

Figure 4. TGA and DTG (derivative thermogravime-try) curves of BMP crystalline forms. Key: (a) anhydrousBMP (from acetone); (b) BMP�0.5H2O (by exposure toambient atmosphere of anhydrous BMP); (c) BMP�0.5CHCl3; (d) BMP�C3H7OH(iso); (e) BMP�CH3OH.

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solvents,17 stronger interactions with BMP hostthan those in the respective pure liquid can bededuced for BMP�0.5CHCl3, BMP�C3H7OH(iso),and BMP�CH3OH solvates. On the other hand,these data suggest that the water molecules arenot tightly bound in the crystals of the BMPhemihydrate. No structural data are available forBMP�0.5CHCl3, but the relative sharpness of theDSC endotherm for desolvation suggests that thesolvent molecules are tightly bound in isolatedsites in the solvated crystals. It is noted that aBMP�0.5CHCl3 crystal under a microscope showsa progressive darkening along parallel lines (seeFig. 2c’), which may represent channels forsolvent escape within the crystal. BMP hemi-chloroformate, isopropanolate, and methanolatetended to transform into anhydrous BMP underambient conditions (�228C, �45% RH) at arate in the rank order BMP�0.5CHCl3 >>BMP�C3H7OH(iso) > BMP�CH3OH. AnhydrousBMP tended to absorb water from the atmosphereat a much slower rate, transforming intoBMP�0.5H2O.

The results of HSM for the BMP crystallineforms whose structures were solved are presentedin Figure 5. HSM observations of crystals immers-ed in silicone oil showed that the prismatic crystalof anhydrous BMP maintained its transparencyand shape up to the melting point (Fig. 5a). At thecenter of the curved crystal of BMP�0.5H2O,bubble formation at 788C and solvent escape fromthe top and the bottom between 85 and 968C areevident (Fig. 5b). The crystal starts to becomeround, shrinks at�2318Cand thenmelts at 2348C.The acicular crystal of BMP�C3H7OH(iso) startsto lose its transparency at �628C and darkenscompletely at 2008C, with no change in its originalshape and no apparent bubble evolution beforemelting (Fig. 5c).

Powder XRD

As shown in Figure 6, the crystalline forms ofBMP are readily distinguishable from theirpowder X-ray diffraction (PXRD) patterns. It isnoted, however, that due to the crystallitemorphologies (especially in the cases ofBMP�0.5H2O and BMP�C3H7OH(iso), Fig. 2), theexperimental peak intensities are significantlyaffected by preferred orientation in the samples.This was evident from comparison of the experi-mental traces with those computed from therefined single-crystal X-ray structures. Peaks inT

able

3.

Thermog

ravim

etricandCalorimetricData

forBMPSolvates(Standard

Dev

iation

sin

Parentheses

Refer

totheLast

Digit)

Solvate

Desolvation

Onset

Tem

perature

(8C)

Desolvation

Enthalpy

ChangeDH

S,exp(J

g�1)

PercentMass

Loss,

Dm

S%

Hea

tof

Vaporization

ofthe

Bou

ndSolven

tDH

S(kJmol

�1)

Hea

tof

Vaporization

ofthe

Pure

Solven

tDH

PS(kJmol

�1)

BMP�0.5H

2O

51(9)

32(7)

1.7(3)

34(9)

40.7

BMP�0.5CHCl 3

58(2)

83(2)

14.8(2)

67(2)

31.4

BMP�C

3H

7OH(iso)

66(3)

105(4)

12(1)

52(5)

42.1

BMP�CH

3OH

91(6)

139(8)

8.1(2)

55(3)

39.2

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Figure 5. Photomicrographs of BMP solvates at various temperatures recorded byhot stage microscopy. Key: (a) anhydrous BMP (from acetone); (b) BMP�0.5H2O (fromwater/ethanol 1/1 (v/v)); (c) BMP�C3H7OH(iso).

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the latter traces (not shown) had angular valuesin close agreement with those of the correspond-ing experimental traces, but the intensities weregenerally in poor agreement.

Single-Crystal XRD

The asymmetric units in the crystals of anhy-drous BMP, BMP�0.5H2O, and BMP�C3H7OH(iso)(Fig. 7), respectively, comprise a single moleculeof BMP, two independent molecules of BMP and awater molecule, and a single molecule of BMPwith one molecule of isopropanol. A noteworthyfeature in Figure 7b is the pseudo-inversion

Figure 6. Experimental PXRD patterns for BMPcrystalline forms. Key: (a) anhydrous BMP (fromacetone); (b) BMP�0.5H2O (by exposure to ambientatmosphere of anhydrous BMP); (c) BMP�0.5CHCl3;(d) BMP�C3H7OH(iso); (e) BMP�CH3OH.

Figure 7. The asymmetric units in the crystals of(a) anhydrous BMP; (b) BMP�0.5H2O; (c) BMP�C3H7

OH(iso). Thermal ellipsoids are drawn at the 50% level.

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center between the two independent BMP mole-cules, reflected in a close fit of one molecule on theinverted form of the other (rms fit �0.16 A). InBMP�C3H7OH(iso), the C atoms of the solventmolecule are disordered over two sites each, onlythe dominant conformer (site-occupancy 0.68)being shown in Figure 7c. The molecules ofBMP adopt similar conformations in BMP andBMP�0.5H2O (Tab. 4), significantly different fromthat induced by inclusion of iso-propanol. Aprimary aim of this study was to attempt toreconcile thermal behavior of the various BMP

crystal forms with their crystal structures. In thecase of anhydrous BMP, analysis of the crystalpacking revealed infinite ribbons of base triples(Fig. 8), similar to those found in the crystal ofTMP18 in which each 2,4-diaminopyrimidinering is hydrogen bonded to two others, theribbon-generators being centers of inversion.However, whereas the two unique N�H���Nhydrogen bonds in the TMP crystal are equallystrong (N���N 3.059(2), 3.036(2) A), in BMP one ofthese is much weaker (Tab. 5, Fig. 8). The highermelting point of BMP is evidently associated withadditional intermolecular interactions in its crys-tal, namely p�p stacking with centroid���centroiddistances <4 A (3.691, 3.950 A) that are absentin crystals of TMP.18 Stereoviews illustratingthe detailed modes of solvent inclusion inBMP�0.5H2O and BMP�C3H7OH(iso) are shownin Figure 9. In the hemihydrate, the BMPmolecules associate via strong base-paired hydro-gen bonds. The water molecules occur in pairs(one such pair being shown in the center ofFigure 9a, which is a view parallel to the a-axis)with O���O 3.424 A. Identical pairs are therefore

Table 4. Principal Torsion Angles (Deg.) Describingthe Conformations of BMP Molecules

Crystal Phaset1:

C4-C5-C9-C10t2:

C5-C9-C10-C15

BMP (anhydrous) �71.5(2) 122.6(1)BMP�0.5H2O

a �71.2(4) 119.9(3)68.2(4) �125.5(3)

BMP�C3H7OH(iso) �88.2(3) 157.4(2)

aTwo independent molecules.

Figure 8. (100) Projection of the crystal structure of unsolvated BMP showingmolecular association via two distinct types of base-pairing hydrogen bonds.

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located regularly above and below those shown,with periodicity a¼ 7.581 A, such that the nearestO���O distance from a member of one pair to thatof the next is 4.965 A. Further examination ofthe same projection with the water moleculesomitted and with the BMP molecules representedin space-filling mode shows a continuousfissure parallel to the a-axis with minimum andmaximum dimensions 1.3 and 5.6 A, whoserelaxation could therefore provide a dehydrationpathway on heating the crystal. This hydrate istherefore intermediate between type 1 (‘isolatedlattice sites’) and type 2 (‘lattice channels’)according to the classification of Morris.19 Theappearance of the dehydration endotherm inFigure 3b, whose gradual onset leads to a broadpeak, is consistent with this model. It should benoted that the X-ray analysis was performed atrelatively low temperature in order to localisesolvent molecules accurately. Certainly, at 193Keach water molecule is tightly bound to the hoststructure, engaging in four hydrogen bonds withatoms of three neighbouring BMP molecules(Fig. 9a, Tab. 5). Presumably at room tempera-ture, and close to the relatively low desolvationtemperature, the hydrogen bonds are fluxional,accounting for the broad desolvation endotherm.

In the crystal of BMP�C3H7OH(iso), the extent ofbase-paired hydrogen bonding between BMPmolecules is significantly less than that observedin the preceding structures, the basic motif beinga hydrogen-bonded BMP dimer (Fig. 9b). Thesedimers are interconnected through hydrogenbonding mediated by the included isopropanolmolecules, each of which is tethered to the BMPframework via three hydrogen bonds (Tab. 5).Analysis of the mode of inclusion of isopropanol inthe crystal showed that the solvent van der Waalsenvelopes are in contact in the y-direction (hor-izontal in Fig. 9b), with centers of inversionseparating one solvent molecule from thenext. BMP�C3H7OH(iso) is therefore a solvate oftype 2 (‘lattice channels’).19 Such solvates areexpected to show broader desolvation endothermsthan those typical of type 1 solvates, with earlyonset of desolvation, and Figure 3e reflects thisbehavior.

CONCLUSIONS

This study revealed no evidence for polymorphismof unsolvated BMP. It was confirmed that thecrystal forms obtained by recrystallization and bycooling of the melt are identical. A possibleexplanation for the difference in the meltingpoints of BMP and TMP was found, based onknown differences in their crystal structures.BMP does, however, have a tendency to formsolvates, and pertinent characterization data forBMP solvates containing water, isopropanol,and chloroform have been presented. Whereasprevious studies revealed isostructurality forsolvates of TXP, X-ray analysis of the BMPsolvates with water and isopropanol showedthat they crystallize in distinctly differentarrangements. Comparison of PXRD patternsconfirms that the hemichloroformate adoptsyet a third arrangement. These differences incrystal structure precluded the type of direct,quantitative comparison of thermal data thatwas previously possible for the isostructuralsolvates of TXP. Nevertheless, the modes ofsolvent inclusion in the BMP solvates examinedwere precisely determined and classified interms of ‘isolated site’ or ‘lattice channel’ typeinclusions. Finally, examination of the topology ofinclusion of water molecules in BMP�0.5H2Osuggested a possible pathway for dehydration.This is important in the context of formulation

Table 5. Geometrical Data* for Principal HydrogenBonds

D–H���A D���A/A H���A/AD–H���A/

Deg.

BMP (anhydrous)N8-H8B���N3i 3.101(2) 2.24 165N7-H7A���N1ii 3.427(2) 2.58 177

BMP�0.5H2ON7-H7A���N21iii 3.246(4) 2.43 155N8-H8A���N3iv 3.075(3) 2.21 169N27-H27A���N1v 3.068(3) 2.24 156O41-H41A���O36 2.899(3) 1.90 175O41-H41B���N23vi 2.865(3) 1.96 149N27-H27B���O41vii 3.016(3) 2.19 156N28-H28A���O41vi 3.063(3) 2.30 145

BMP�C3H7OH(iso)N7-H7A���N3viii 3.076(3) 2.31 145N7-H7B���O21ix 2.918(3) 2.22 136N8-H8B���O21ix 3.069(3) 2.20 169O21-H21���N1 2.776(2) 1.96 172N8-H8A���Br18iv 3.557(2) 2.83 141

Symmetry codes: (i)�x, 2�y, 1�z; (ii),�1�x, 1�y, 1�z; (iii),�1þx, 1þy, z; (iv), 1�x, 2�y, 1�z; (v), 1þx, �1þy, z; (vi), 2�x,1�y, 2�z; (vii), x,�1þy, z; (viii),�x, 2�y,�z; (ix),�x, 1�y,�z;(x), x, 1þy, z.

*Estimated standard deviations are in the range 0.002–0.004 A for distances involving nonhydrogen atoms.

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design where solvate stability at atmosphericpressure has implications at both biopharma-ceutical (dissolution rate, bioavailability) andtechnological levels.

SUPPORTING INFORMATION

The CIF files for the three single crystal X-raystructures described have been deposited at the

Cambridge Crystallographic Data Centre (CCDC287342–287344).

ACKNOWLEDGMENTS

MRC thanks the University of Cape Town and theNRF (Pretoria) for supporting this work.

Figure 9. Stereoviews showing details of the inclusion modes of (a) water (b) iso-propanol in the corresponding solvates of BMP. Hydrogen bonds are drawn as dashedlines.

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DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007