Pharmaceutical cocrystals and a nitrate salt of voriconazole

Article abstract of DOI:10.1039/c3ce42324g

Voriconazole ((2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1- (1H-1,2,4-triazol-1-yl)butan-2-ol, VZL) is an antifungal drug with low aqueous solubility of 0.71 mg mL^-1 and a BCS class II drug (Biopharmaceutics Classification System) of the azole family. We have prepared a nitrate salt and three cocrystals of VZL with p-hydroxybenzoic acid, p-aminobenzoic acid (both are GRAS compounds) and m-nitrobenzoic acid coformers to improve the physicochemical properties. All four multi-component crystals of voriconazole were obtained by solution crystallization as well as solid-state grinding and their structures were confirmed by X-ray diffraction, FT-IR, Raman and NMR spectroscopy, and thermal techniques. VZL-PHBA and VZL-PABA are isostructural based on XPac calculations and molecular packing arrangement. A notable result from a crystal engineering viewpoint is that the supramolecular synthon between the basic drug and the acidic coformer undergoes a switch based on the pK _a of the acid.

Full text of DOI:10.1039/c3ce42324g

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Submitted to the Special Theme issue of CEC on India IYCr Celebration
Pharmaceutical Cocrystals and a Nitrate Salt of Voriconazole
S. Sudalai Kumar, Ranjit Thakuria, and Ashwini Nangia*
School of Chemistry, University of Hyderabad, Central University PO, Prof. C. R. Rao Road,
Gachibowli, Hyderabad 500 046, India
Eꢀmail: ashwini.nangia@gmail.com
Abstract
Voriconazole ((2R,3S)ꢀ2ꢀ(2,4ꢀdifluorophenyl)ꢀ3ꢀ(5ꢀfluoropyrimidinꢀ4ꢀyl)ꢀ1ꢀ(lHꢀl,2,4ꢀtriazolꢀlꢀ
yl)butanꢀ2ꢀol, VZL) is an antifungal drug with low aqueous solubility of 0.71 mg/mL and it is a
BCS class II drug (Biopharmaceutics Classification System) of the azole family. We have
prepared a nitrate salt and three cocrystals of VZL with pꢀhydroxybenzoic acid, pꢀaminobenzoic
acid (both are GRAS compounds) and mꢀnitrobenzoic acid coformers to improve the
physicochemical properties. All four multiꢀcomponent crystals of voriconazole were obtained by
solution crystallization as well as solidꢀstate grinding and their structures were confirmed by Xꢀ
ray diffraction, FTꢀIR, Raman, and NMR spectroscopy, and thermal techniques. VZL–PHBA
and VZL–PABA are isostructual by XPac calculations and molecular packing arrangement. A
notable result from a crystal engineering viewpoint is that the supramolecular synthon between
the basic drug and the acidic coformer undergoes a switch based on the pKa of the acid.
† Electronic Supplementary Information available with this paper. Comparison of calculated and
experimental PXRD plots (Fig. S1), FTꢀIR and Raman spectra (Fig. S2 and S3), PXRD plots of
cocrystals and salt after slurry (Fig. S4), List of experiments for VZL solid forms search (Table
13
S1), Hydrogen bonds in crystal structures (Table S2), C chemical shift values in ppm (Table
S3), and IR, Raman peaks (Table S4 and S5), CSD Refcodes (Table S6), and crystallographic
.cif files (CCDC Nos. 971867ꢀ971870).
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Introduction
Cocrystals are multiꢀcomponent systems consisting of two or more neutral, solid compounds
held together by hydrogen bonds in a definite stoichiometry.1 To be a pharmaceutical cocrystal,
one of the components (drug) must be an active pharmaceutical ingredient (API) and the other
(coformer) should be a safe compound from the GRAS list (generally regarded as safe by the
USꢀFDA).2 The idea of preparing pharmaceutical cocrystals is to alter the physicochemical
properties, most often solubility and dissolution rate, of a drug without modifying its chemical
structure.1,3 Itraconazole4 and fluoxetine hydrochloride cocrystals5 are early examples of
pharmaceutical cocrystals, a trail that has been followed up with several hundred publications
and several excellent reviews.3 There are three examples of drug cocrystals in the market:
caffeineꢀcitric acid/citrate,6a and escitalopramꢀoxalic acid/oxalate, and valproic acid/Naꢀ
valproate.6b,c A few more cocrystals are in clinical stage.6d
Results and Discussion
Voriconazole (VFEND®, Pfizer) is an antifungal drug administered intravenously or in oral
dosage formulation.7 Two other antifungal drugs of the azole family, itraconazole and
fluconazole, have been studied for salts, cocrystals and metal complexes.4,8 A guest free form9a
and a camphor sulfonate salt9b of voriconazole are reported along with nanoꢀindentation study of
the pure API.9c VZL has low aqueous solubility (0.71 mg/mL) and is unstable in water due to a
retroꢀaldol reaction.10 Due to the presence of less basic triazole and pyrimidine rings,
voriconazole is able to form salts with strong acids only, whereas with moderate organic acids it
can possibly form cocrystals11 (Table 1). A complete list of coformers and crystallization
experiments attempted is listed in Table S1 (ESI†). The successful nitrate salt and a few
cocrystals are reported (Scheme 1) with the objective to analyze Xꢀray crystal structures and
improve the physicoꢀchemical profile of voriconazole.
2

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3
N
1
2
N
R
F
N
CH3
S
COOH
COOH
COOH
HO
5
F
N
N
4
NO2
HNO3
Nitric acid
OH
NH2
F
3-NBA
PABA
PHBA
Voriconazole, VZL
(a)
N
N
N
N
N
F
N
CH3
S
F
R
O
H
O
+
N
N
F
F
N
N
F
F
(b)
Scheme 1 (a) Voriconazole and successful coformers; (b) Retroꢀaldol degradation pathway of
voriconazole in the aqueous medium.
Table 1 ∆pKa value of voriconazole and coformers.
a
API/Coformer
pKa
Cocrystal/salt ∆pKa (COOH with
N5ꢀ and N3ꢀVZL)
VZL
2.27 (N3)
0.43 (N5)
–1.30
ꢀ
ꢀ
HNO3
VZL–HNO3
3.57, 1.73
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PHBA
PABA
3ꢀNBA
3.57 (COOH)
4.87 (COOH)
3.49
VZL–PHBA
VZL–PABA
VZL–3ꢀNBA
–1.30, –3.14
–2.60, –4.44
–1.22, –3.06
a pKa values for VZL are calculated from ChemAxon software. The pKa values for VZL are those
for the conjugate acid of the heterocycle N.
Structural analysis
Voriconazole dinitrate salt (1:2): Voriconazole dinitrate salt was prepared by dissolving 50 mg
of voriconazole in 10 mL ethanol followed by the addition of 1ꢀ2 drops of 1N HNO3 acid
solution. The mixture was boiled for a few minutes and then kept for slow evaporation at
ambient conditions. Colorless plate shaped crystals were obtained whose Xꢀray crystal structure
was solved in the orthorhombic space group P212121 with one voriconazolium and two nitrate
ions in the asymmetric unit. Protons from two different nitric acid molecules are transferred to
triazole N3 and pyrimidine N5 (partial transfer) of the voriconazole molecule. The fully ionized
nitrate ion is sandwiched between the layers of voriconazole connected through bifurcated
N3+−H3AꢁꢁꢁO2– and N3+−H3AꢁꢁꢁO3– (1.72 Å, 171° and 2.33 Å, 126°) hydrogen bonds (Table S2,
2
ESI†) to make of graph set motifs of notation12 R1 (3) (Figure 1a). The second nitrate ion is
connected to N5 pyrimidine through N5+−H6AꢁꢁꢁO6– interaction and a second molecule of
voriconazole through weak van der Waal interactions in a zigzag tape (Figure 1b).
4

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(a)
(b)
Figure 1 (a) Nitrate ions form strong ionic N+−HꢁꢁꢁO– and weak C−HꢁꢁꢁO hydrogen bonds with
voriconazole molecules, and (b) C−HꢁꢁꢁO hydrogen bonds in the zigzag tapes of VZL molecules
connected via nitrate ions.
Voriconazole–pꢀhydroxybenzoic acid (1:1): VZL–PHBA 1:1 cocrystal was prepared by
mixing the components (0.30 mmol each) in 10 mL methanol and kept for slow evaporation.
Colorless plateꢀshape crystals were solved in the monoclinic space group P21. VZL and PHBA
are connected in a helical chain through O−HꢁꢁꢁN hydrogen bonds (Figure 2). The carboxyl group
of PHBA forms a twoꢀpoint synthon with the pyrimidine N5 of VZL rather than the N3 of
triazole. The pKa values of the two N positions suggest a strong hydrogen bond between the
carboxylic acid donor and N3 of triazole as acceptor based on ꢀpKa (Table 1). The triazole N3
(pKa of conjugate acid 2.72) is a stronger base than pyrimidine N5 (pKa NH+ 0.43). Etter’s
rule12a,b of strong hydrogen bond donor−acceptor pairing does not seem to be followed in this
system. The tertiary OH group pKa is very high (12.71) for any kind of ionization at
physiological conditions. The hydroxyl group of PHBA forms O−HꢁꢁꢁN hydrogen bond to
triazole N3.
Voriconazole is a multiple acidic/basic site molecule, and accurately determining the pKa
of each N atom is very difficult. A survey of the literature afforded two different sets of pKa
values for voriconazole. Buchanan et al.13a reported 4.98 and 12.0, and Reddy et al.13b reported
2.72 and 11.54. It is clear that the higher value of 11ꢀ12 refers to the OH group pKa.13c It was not
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mentioned in the above papers whether the 2nd pKa number refers to that of azole N or the
pyrimidine N. We then searched the pKa of a related azole drug without the pyrimidine ring, and
the values for fluconazole are 11.01, 2.94, 2.65.13d Therefore the value of 2.72 taken for triazole
N is the correct assignment. The pyrimidine N basicity may be severely attenuated by the metaꢀ
fluoro group and so triazole N is the more basic site in voriconazole.
Figure 2 VZL forms strong O−HꢁꢁꢁN and weak C−HꢁꢁꢁO hydrogen bonds with PHBA.
Voriconazole–pꢀaminobenzoic acid (1:1): VZL–PABA cocrystal was crystallized from a 1:1
solution of methanol and ethanol. The colorless plates of VZL–PABA 1:1 cocrystal were solved
in the monoclinic space group P21 with a helix of VZL and PABA connected via O−HꢁꢁꢁN and
N−HꢁꢁꢁN hydrogen bonds (Figure 3). Similar to the VZL–PHBA, VZL–PABA also is assembled
via carboxylic acidꢀpyrimidine twoꢀpoint synthon and oneꢀpoint N−HꢁꢁꢁN hydrogen bond
between the amino group of PABA and triazole N3 of VZL.
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Figure 3 The strong acidꢀpyrimidine twoꢀpoint synthon and aminoꢀtriazole oneꢀpoint synthon is
shown along with weak interactions between VZL and PABA.
The structures of VZL–PHBA and VZL–PABA have similar hydrogen bond motifs with
O−H/ N−H exchange for the coformers PHBA and PABA. They are isomorphous structures
(Table 2). The isostructurality of single component and multiꢀcomponent systems (cocrystals,
solvates, and complexes) by chloroꢀmethyl, C−H/ N−H, N−H/ O−H, C−H/ O−H, halogen
exchange are well represented.14 The XPac dissimilarity15 index value of 2.9 (a small number) is
indicative of 3D isostructurality between PHBA and PABA cocrystals of VZL (Figure 4).
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(a)
(b)
Figure 4 (a) The XPac dissimilarity index of 2.9 indicates similarity between PHBA and PABA
cocrystals, (b) 3D supramolecular construct in VZL–PABA and VZL–PHBA.
4. Voriconazole–3ꢀnitrobenzoic acid (1:1): VZL–3ꢀNBA 1:1 cocrystal was prepared by
dissolving a 1:1 mixture of voriconazole (100 mg) and 3ꢀnitrobenzoic acid (48 mg) in
8

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acetonitrile and kept for slow evaporation at ambient conditions. Thin plate shaped colorless
crystals were solved in the monoclinic space group P21. The carboxylic acid group of 3ꢀNBA is
hydrogen bonded to triazole N3 via O−HꢁꢁꢁN and C−HꢁꢁꢁO twoꢀpoint synthon, consistent with
Etter’s12 hydrogen bond pairing rule (Figure 5). The O−H donor of VZL makes bifurcated H
bonds with N4 of pyrimidine (intramolecular hydrogen bond) and triazole N2 of the next
molecule in an infinite chain.
Figure 5 The triazole ring of VZL forms strong O−HꢁꢁꢁN and weak C−HꢁꢁꢁO hydrogen bonds
with 3ꢀNBA.
Table 2 Crystallographic detail of VZL complexes
Compound
Solid forms
Empirical
formula
VZL–HNO3
Salt
VZL–PHBA VZL–PABA
Cocrystal Cocrystal
VZL–3ꢀNBA VZL
Cocrystal Ref 9a
C16H16F3N7O7
C23H20F3N5O4 C23H21F3N6 O3 C23H19F3N6O5 C16H14F3N5O
Formula weight 475.36
487.44
486.46
516.44
349.32
Crystal system
Space group
a (Å)
Orthorhombic
Monoclinic
P21
Monoclinic
P21
Monoclinic
P21
Monoclinic
P21
P212121
9.1515(9)
13.1275(13)
16.1908(16)
90
13.7102(5)
6.04623(17)
14.2265(5)
90
13.674(11)
6.085(5)
14.196(11)
90
11.5743(5)
6.7286(2)
14.9073(6)
90
7.5332 (19)
8.349 (2)
12.989 (3)
90
b (Å)
c (Å)
α (°)
β (°)
90
107.314(4)
106.543(12)
97.526(4)
100.062 (4)
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90
90
90
90
90
γ (°)
V (Å3)
Dcalcd (g cm–3) 1.623
ꢁ (mm–1)
1945.1(3)
1125.87(7)
1.438
1132.4(15)
1.427
1150.96(8)
1.490
804.4 (3)
1.442
0.12
25.0
ꢀꢀ
0.147
0.117
0.114
0.124
2.00ꢀ26.06
2.93ꢀ 24.96
2/1
2.44ꢀ22.71
2/1
2.75ꢀ26.31
2/1
θ range (º)
Z/Z′
4/1
Range h
ꢀ11 to 11
ꢀ16 to 16
ꢀ19 to 19
ꢀ16 to 10
ꢀ6 to 6
ꢀ16 to 16
ꢀ7 to 7
ꢀ13 to 14
ꢀ7 to 8
ꢀ18 to 17
ꢀꢀ
Range k
ꢀꢀ
Range l
ꢀ16 to 16
ꢀ17 to 17
ꢀꢀ
Reflections
collected
Observed
reflections
Total
20312
3830
3753
3814
3071
2831
11761
4474
3718
5175
3868
2649
7364
1529
1398
reflections
R1 [I > 2 σ(I)]
wR2 (all)
0.0305
0.0768
0.0345
0.0933
1.086
0.0540
0.1123
1.137
0.0384
0.0750
0.911
0.0509
ꢀ
Goodnessꢀofꢀfit 1.059
ꢀ
T (K)
100
298
298
298
294
Oxford
Xcalibur
Gemini
Bruker
SMART
APEX
Oxford
Xcalibur
Gemini
Xꢀray
Bruker SMART
APEX
Bruker
diffractometer
SMART APEX
Supramolecular synthon and CSD search:
From the four crystal structures and the reported sulphonate salt it was observed that there is a
synthon switch depending on the pKa value of the coformer. The strongly acidic 3ꢀNO2ꢀ
PhCOOH preferentially forms the acid−triazole synthon (eg. VZL–3ꢀNBA cocrystal) whereas
weaker acids make the acidꢀpyrimidine synthon (e.g. as in VZL–PHBA and VZL–PABA). Both
types of heterosynthons are twoꢀpoint and assembled via O–HꢁꢁꢁN and C–HꢁꢁꢁO hydrogen bonds,
and so it difficult to rationalize this switch. The very strong nitric acid gives a dinitrate with both
azole and pyrimidine N being protonated. A search of the Cambridge Structural Database16a for
carboxylic acid−pyrimidine and acid−triazole twoꢀpoint synthon gave only 2 hits for
acid−triazole and 5 hits for acid−pyrimidine (Scheme 2 and Table 3). The number of archived
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crystal structures with the given motif is too small to extract a pKa dependent synthon trend.
Related searches on protonated triazole and acid−triazole single O−HꢁꢁꢁN hydrogen bond gave 38
and 18 hits respectively (see details in Table S5, ESI†). The difficulty in making cocrystals of
azole drugs with COOH is contrary to pKa prediction, but nonetheless a fact known from the
literature,4,9b and the few CSD hits (Table 3).
WALCUJ
UPOQIA
N
N
N
N
N
N
N
F
N
N
(CH2)8
HO
COOH
F
H2O
N
N
N
HOOC
COOH
HOOC
COOH
Scheme 2 Chemical structures of CSD Refcodes with acid–triazole twoꢀ
point O–HꢁꢁꢁN and C–HꢁꢁꢁO synthon.
Table 3 CSD refcodes for the acid−traiazole synthon and calculated pKa values.a
pKa of triazole nitrogen ∆pKa (= NH+ – acid)
(NH+) and acid
Carboxylic acid–triazole twoꢀ
point synthon (2 hits)
UPOQIA
2.03, 4.32
1.99, 4.55
–2.29
–2.56
WACLUJ
Carboxylic
twoꢀpoint synthon (5 hits)
ABIWIT
pKa of pyrimidine nitrogen ∆pKa (= NH+ – acid)
acid–pyrimidine
(NH+) and acid
1.78, 3.15
1.58, 4.14
–0.28, 3.80
1.99, 4.37
1.19, 4.37
–1.57
–2.56
–4.08
–2.38
–3.18
POFPEF
XAQNOT
LEJMOE
TENSIQ
a pKa values are calculated from ChemAxon software
Conformation of VZL
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The presence of flexible methylene group between the heterocycle ring and the chiral
center results in two clusters of conformations for voriconazole in the solidꢀstate (Figure 6). The
free base and the dinitrate salt have a similar conformation whereas the cocrystals overlay in a
different orientation for the triazole ring (see Table 4 for torsion angles).
N
1
N
4 CH3
F
N
5
1
3
2
OH
N
N
F
11
F
(a)
(b)
Figure 6 (a) Molecular structure of VZL with atom labeling considered for conformation
analysis, and (b) Molecular overlay of different conformers of VZL in crystal structures.
Table 4 Torsion angle values of voriconazole salt and cocrystals.
Solid forms
Torsion angle (°)
Torsion angle (°)
Torsion angle (°)
τ2 (C11−C2−C3−C5)
τ3 (C1−C2−C3−C4)
τ1 (C11−C2−C1−N1)
55.6(4)
VZL (ref 9a)
VZL–HNO3
VZL–PHBA
VZL–PABA
VZL–3ꢀNBA
175.6(3)
179.6(1)
168.4(2)
169.1(2)
169.3(2)
175.0(3)
179.8(1)
164.6(2)
165.2(2)
167.5(2)
61.7(2)
173.4(2)
170.5(2)
175.18(19)
Characterization of VZL crystalline forms
Voriconazole salt and cocrystals were prepared for spectroscopic and thermal
characterization by neat and liquid assisted grinding (LAG).16b The PXRD of the materials match
13
well with the calculated powder pattern from the crystal structure (Fig S1, ESI†). C ssꢀNMR,
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FTꢀIR, FTꢀRaman (Fig S2ꢀS3, ESI†) and differential scanning calorimetry (DSC) confirmed the
bulk purity of the crystalline products (Table S3ꢀS5, ESI†).16c,d,e
Figure 7 13C ssꢀNMR spectra of VZL dinitrate salt and cocrystals.
Thermal analysis confirms the formation of VZL salt and cocrystals. Though VZL–
PABA and VZL–PHBA are isomorphous, there is a large difference in their melting points (152
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°C, 120 °). This difference might be due to the presence of two hydrogen bond donors in pꢀ
aminobenzoic acid that has the additional hydrogen bond (N6−H6AꢁꢁꢁO3) in the crystal structure
of VZL−PABA with a molecule in the adjacent layer compared to VZLꢀPHBA which lacks this
stabilizing interaction. Their crystal density is comparable (VZL−PHBA 1.43 g cm–3
,
VZL−PABA 1.42 g cm–3). The similarity in the molecular confirmation of these two isostructural
cocrystals suggests that the additional interaction in VZL−PABA is responsible for the higher in
the melting point. VZL–3ꢀNBA has a low melting point of 95 °C. The conformation of this
cocrystal is slightly different from other two cocrystals of PABA and PHBA in the overlay of
molecular conformations17 (Figure 6). Molecular conformation and melting point of carboxylic
acids have been correlated in the recent literature.18 DSC thermograms of VZL complexes are
shown in Figure 8. The dinitrate salt melts at 151° C and the large exotherm in DSC indicates
decomposition of the salt at 154° C.
Figure 8 DSC of VZL adducts.
Table 5 Melting temperatures of solid forms of VZL
Solid forms
m.p. of
m.p. of
Density
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(g cm–3)
1.442
1.623
1.438
1.427
1.490
cocrystal/salt (°C) Coformers (°C)
VZL
129.6
151.0
119.9
152.0
94.46
ꢀ
VZL–HNO3
VZL–PHBA
VZL–PABA
VZL–3ꢀNBA
ꢀ
215
188
140
Solubility and Dissolution study
Solubility and dissolution behavior of voriconazole salt and cocrystals were measured in 0.1 N
HCl. The advantage of salt preparation with respect to cocrystal is well established in the
literature.19 However, due to the presence of less basic groups (N3 of triazole and N5 of
pyrimidine) in voriconazole, salt preparation is difficult and proton transfer occurred only with
the strong HNO3. The dinitrate salt of voriconazole is about 10 times more soluble (2.5 mg/ mL)
than the free base (0.26 mg/ mL) in 0.1 N HCl. The cocrystals with EAFUS coformers2 (PABA
and PHBA) and 3ꢀNBA have lower solubility (1.16, 0.35 and 0.39 mg/ mL). It is noteworthy that
the isomorphous VZL–PABA cocrystal is ~ 3 times more soluble than VZL–PHBA. The reason
for the higher solubility of PABA cocrystal is due to the higher solubility of the coformer PABA
(6.11 mg/mL) compared to PHBA (4.89 mg/mL) and the presence of NH2 (two Hꢀbond donors)
compared to OH (one Hꢀbond donor) group, which will lead to greater hydration in solution.20
The intrinsic dissolution21 data follows similar trends (Table 6). The nitrate salt has ~ 3
times faster IDR compared to VZL base (Figure 9). The materials were found to be stable as
confirmed by PXRD of the residue at the end of the solubility and dissolution measurements
(Figure S4, ESI†).
Table 6 Solubility and Intrinsic dissolution rate of VZL solid forms
Solid forms
λmax (nm) Absorption coefficient
(ε), (Mꢀ1 cmꢀ1)
IDR in 0.1N HCl
Solubility in 0.1N
(X
10ꢀ2 mg/cm2)
3.27
HCl (mg/mL)
0.26
VZL
257
259
258
257
318.37
141.91
547.70
187.05
VZL–HNO3
VZL–PHBA
VZL–PABA
9.18
2.57
3.86
0.35
5.20
1.16
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VZL–3ꢀNBA
258
337.13
3.95
0.39
Figure 9 Dissolution profile of voriconazole pure base and its solid forms in 0.1N HCl solution
in 4 h.
Conclusions
A nitrate salt and three cocrystals of voriconazole with PHBA, PABA and 3ꢀNBA were
prepared in bulk as well by solution crystallization. All the multiꢀcomponent structures of
voriconazole were characterized using solidꢀstate characterization techniques. Overall, the
success rate for cocrystal/ salt formation was found to be very difficult from the 30 or so
conformers/ salt formers attempted. From the solved crystal structures it was observed that there
is a synthon switch from acid−pyrimidine to acid−triazole synthon depending on the strength of
the coformer acid. The weaker PABA and PHBA are sustained by acid−pyrimidine whereas
stronger 3ꢀNBA cocrystal contains acid−triazole synthon. Both the pyrimidine and triazole N are
protonated in the dinitrate salt. The occurrence of these synthons is compared with CSD
statistics. There are very few reports for these two synthons and the present analysis adds
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structural data to the less known acid–triazole and acid–pyrimidine twoꢀpoint synthons. The
isostructurality between PHBA and PABA cocrystals of voriconazole was quantified by XPac.
The good solubility and dissolution of VZL–PABA cocrystal is encouraging along with the
dinitrate salt of voriconazole for formulation development.
Experimental Section
Materials
Voriconazole was purchased from Shanghai Xunxin Chemical Co., Ltd., China and was used
without any further purification. All other coformers were of analytical or chromatographic
grade and were purchased from SigmaꢀAldrich (Hyderabad, India). Water altered through a
doubleꢀdeionized purification system (Milli Q Plus Water System from Millipore Co., Billerica,
Massachusetts) was used in all the experiments. Melting points were measured on a FisherꢀJohns
melting point apparatus. Single crystals were obtained via slow evaporation of stoichiometric
amounts of starting materials in appropriate organic solvents after solid state and liquid assisted
grinding in a mortarꢀpestle. Cocrystals and salt were characterized by FTꢀIR, Raman, 13C ssꢀ
NMR spectroscopy techniques, DSC, PXRD and single crystal Xꢀray diffraction (SCꢀXRD).
Preparation of cocrystals by liquid (solvent drop) assisted grinding
1. Voriconazole (VZL)
Voriconazole crystals were obtained from organic alcoholic solvents and the ground material of
these crystals was used in the comparison of analysis and characterizations with the new solid
forms. m.p. 130ꢀ132 °C.
2. VZL–PHBA (1:1) cocrystal
100 mg (0.28 mmol) voriconazole and 38.5 mg (0.28 mmol) pꢀhydroxybenzoic acid were
ground in mortarꢀpestle for 15 min after adding 5 drops of EtOH, and then kept for
crystallization in 10 mL ethanol. Suitable plate type crystals appeared at ambient condition after
3ꢀ4 days. m.p. 120ꢀ122 °C.
3. VZL–PABA (1:1) cocrystal
100 mg (0.28 mmol) voriconazole and 39.2 mg (0.28 mmol) pꢀaminobenzoic acid were ground
in mortarꢀpestle for 15 min after adding 5 drops of EtOH, and then kept for crystallization in 10
mL ethanol. Suitable thick plate crystals were harvested at ambient condition after 3ꢀ4 days. m.p.
150ꢀ153 °C.
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4. VZL−3NBA (1:1) cocrystal
100 mg (0.28 mmol) voriconazole and 47.8 mg (0.28 mmol) PABA was ground in mortarꢀpestle
for 15 min after adding 5 drops of EtOH/CH3CN, and then kept for crystallization in 10 mL
ethanol. Suitable block and plate type crystals were harvested at ambient condition after 3ꢀ4
days. m.p. 94ꢀ96 °C.
5. VZL–HNO3 (1:2) salt
100 mg (0.28 mmol) voriconazole is dissolved in 10 mL of ethanol and boiled on a hot plate to
reach the homogeneous solution. Few drops of diluted nitric acid solution is added into the
homogeneous solution of voriconazole, boiled for 2ꢀ3 minutes and allowed for evaporation under
room temperature condition. Suitable plate type crystals were harvested at ambient condition
after 3ꢀ4 days. m.p. 152ꢀ154 °C.
Xꢀray Crystallography. Xꢀray reflections for voriconazole dinitrate salt (LT data) and
voriconazole:pꢀhydroxybenzoic acid (RT data) were collected on a Bruker SMART APEX CCD
diffractometer equipped with a graphite monochromator and MoꢀKα fineꢀfocus sealed tube (λ =
0.71073 Å). Data integration was done using SAINT.22a Intensities for absorption were corrected
22b
using SADABS.
Structure solution and refinement were carried out using Bruker SHELXꢀ
TL.22c Xꢀray reflections for voriconazole:pꢀaminobenzoic acid and voriconazole:3ꢀnitrobenzoic
acid (RT data) were collected on an Oxford Xcalibur Gemini Eos CCD diffractometer using Moꢀ
Kα, radiation. Data reduction was performed using CrysAlisPro (version 1.171.33.55).22d
OLEX2ꢀ1.0 and SHELXꢀTL 97 were used to solve and refine the data.22e All nonꢀhydrogen
atoms were refined anisotropically, and C−H hydrogens were fixed. In case of VZLꢀHNO3, the
N–H location in pyimidine ring was not stable in mapping as the proton is only partially
protonated from HNO3 to the pyrimidine ring. The reason for this partial proton transfer is due to
the less basic nature of pyrimidine N compared to triazole. O–H and N–H protons were located
from difference electron density maps and C–H hydrogens were fixed. Hydrogen bond distances
were neutron normalized using WingGXꢀPLATON.22f Packing diagrams were prepared in Xꢀ
Seed.22g Crystallographic .cif files (CCDC Nos. 971867ꢀ971870) are available at
www.ccdc.cam.ac.uk/data_request/cif or as part of the Supporting Information.
CSD Search. All organic compounds, with “triazole” and pyrimidine” with the intermolecular
distance of 1ꢀ3 Å with “carboxylic acid” in the qualifier, and entries for which 3D coordinates
are determined were searched in Cambridge Structural Database, ver. 5.34, ConQuest 1.15,
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November 2012 release, May 2013 update. Two hits for triazole−carboxylic acid and five hits for
pyrimidine−carboxylic acid two point synthon of O−HꢁꢁꢁN and C−HꢁꢁꢁO hydrogen bonds were
retrieved. The combination search of both triazole and pyrimidine synthons in the same distance
range with carboxylic acid gave 0 hits. These data and Refcodes for CSD search are summarized
in Table 3.
Vibrational Spectroscopy. Nicolet 6700 FTꢀIR spectrometer with an NXR FTꢀRaman module
was used to record IR spectra. IR spectra were recorded on samples dispersed in KBr pellets.
Raman spectra were recorded with the pellet of samples.
13C ssꢀNMR Spectroscopy. Solidꢀstate NMR spectra were recorded on a Bruker Advance
13
spectrometer operating at 400 MHz (100 MHz for C nucleus). ssꢀNMR spectra were recorded
on a Bruker 4 mm double resonance CPꢀMAS probe in zirconia rotors at 5.0 kHz spin rate with a
crossꢀpolarization contact time of 2.5 ms and a recycle delay of 8 s. 13C CPꢀMAS spectra
recorded at 100 MHz were referenced to the methylene carbon of glycine and then the chemical
shifts were recalculated to the TMS scale (δglycine = 43.3 ppm).
Thermal Analysis. DSC was performed on Mettler Toledo DSC 822e module. Samples were
placed in crimped but vented aluminum sample pans. The typical sample size was 3ꢀ4 mg, and
the temperature range was 30ꢀ200°C at heating rate of 5 °C/min. Samples were purged by a
stream of dry nitrogen flowing at 150 mL/min.
Dissolution and Solubility Measurements. Intrinsic dissolution rate (IDR) and solubility
measurements were carried out on a USP certified Electrolab TDTꢀ08 L dissolution tester
(Electrolab, Mumbai, MH, India). A calibration curve was obtained for all the solid forms by
plotting absorbance vs. concentration UVꢀvis spectra curves on a Thermo Scientific Evolution
EV300 UVꢀvis spectrometer (Waltham, MA) for known concentration solutions in 0.1N HCl
solutions medium. The slope of the plot from the standard curve gave the molar extinction
coefficient (ε) by applying the BeerꢀLambert’s law. Equilibrium solubility was determined in
0.1N HCl solutions medium using the shakeꢀflask method. To obtain equilibrium solubility, 15ꢀ
200 mg of each solid material was stirred for 24 h in 5ꢀ10 mL of 0.1N HCl solutions at 37 °C,
and the absorbance was measured at 257ꢀ260 nm. The concentration of the saturated solution
was calculated at 24 h, which is referred to as the equilibrium solubility of the stable solid form.
The dissolution rates are obtained from the IDR experiments.
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Powder Xꢀray Diffraction. PXRDs were recorded on a SMART Bruker D8 Advance Xꢀray
diffractometer (BrukerꢀAXS, Karlsruhe, Germany) in the BraggꢀBrentano geometry using Cuꢀ
Kα Xꢀradiation (λ = 1.5406 Å) at 40 kV and 30 mA. Diffraction patterns were collected over the
2θ range of 5ꢀ50° at a scan rate of 1°/min. The appearance of new solid phases was monitored by
the appearance of new diffraction peaks when comparing with the starting materials. Powder
Cell 2.35921h was used for overlaying the experimental XRPD pattern on the calculated lines
from the crystal structure.
Melting Point. FisherꢀScientific instrument is used for the determination of melting points of
VZL and its solid forms. Samples were taken in less than 1 mg quantity for this study.
Acknowledgement: This research was funded by J. C. Bose fellowship (SERBꢀDST
SR/S2/JCBꢀ06/2009), research scheme Novel solidꢀstate forms of APIs (SERBꢀDST SR/S1/OCꢀ
37/2011), and Pharmaceutical Cocrystals (CSIR 01ꢀ2410/10/EMRꢀII). DST (IRPHA) and
University Grants Commission (UGCꢀPURSE grant) are thanked for providing instrumentation
and infrastructure facilities. SSK and RT thank the CSIR and UGC for fellowship and
contingency grant.
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Graphical abstract
Novel crystalline forms of Voriconazole drug are identified with improved aqueous solubility.
The dinitrate salt of voriconazole exhibited 10 fold higher solubility and 3 times faster
dissolution rate in 0.1 N HCl medium compared to the reference drug.
24