Mebendazole mesylate monohydrate: A new route to improve the solubility of mebendazole polymorphs

Article abstract of DOI:10.1002/jps.23658

Mebendazole mesylate monohydrate, a new stable salt of mebendazole (MBZ), has been synthesized and fully characterized. It was obtained from recrystallization of MBZ forms A, B, or C in diverse solvents with the addition of methyl sulfonic acid solution. The crystal packing is first organized as a two-dimensional array consisting of rows of alternating MBZ molecules linked to columns of mesylate ions by hydrogen bonds. The three-dimensional structure is further developed by classical intermolecular interactions involving water molecules. In addition, nonclassical contacts are also found. The vibrational behavior is consistent with the crystal structure, the most important functional groups showing shifts to lower or higher frequencies in relation to the MBZ polymorphs. Thermal analysis indicates that the compound is stable up to 50°C. Decomposition occurs in five steps. Solubility studies show that the title compound presents a significant higher performance than polymorph C.

Full text of DOI:10.1002/jps.23658

RESEARCH ARTICLE – Drug Discovery-Development Interface
Mebendazole Mesylate Monohydrate: A New Route to Improve
the Solubility of Mebendazole Polymorphs
1
2
2
2
1
´
KARINA DE PAULA, GERARDO E. CAMI, ELENA V. BRUSAU, GRISELDA E. NARDA, JAVIER ELLENA
1Physics Instituto of Sa˜o Carlos, Universidade of Sa˜o Paulo, CP 369, 13560-970, Sa˜o Carlos, SP, Brazil
2INTEQUI-CCT-CONICET, Qu´ımica Inorga´nica, Departamento de Qu´ımica, Facultad de Qu´ımica, Bioqu´ımica y Farmacia,
Universidad Nacional de San Luis Chacabuco 917, San Luis, 5700, Argentina
Received 15 February 2013; revised 27 May 2013; accepted 11 June 2013
Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.23658
ABSTRACT: Mebendazole mesylate monohydrate, a new stable salt of mebendazole (MBZ), has been synthesized and fully characterized.
It was obtained from recrystallization of MBZ forms A, B, or C in diverse solvents with the addition of methyl sulfonic acid solution. The
crystal packing is first organized as a two-dimensional array consisting of rows of alternating MBZ molecules linked to columns of mesylate
ions by hydrogen bonds. The three-dimensional structure is further developed by classical intermolecular interactions involving water
molecules. In addition, nonclassical contacts are also found. The vibrational behavior is consistent with the crystal structure, the most
important functional groups showing shifts to lower or higher frequencies in relation to the MBZ polymorphs. Thermal analysis indicates
that the compound is stable up to 50◦C. Decomposition occurs in five steps. Solubility studies show that the title compound presents a
ꢀC
significant higher performance than polymorph C. 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci
Keywords: mebendazole mesylate; solid state; crystal structure; FTIR–Raman spectroscopy; thermal stability; dissolution
INTRODUCTION
authors agree that form A is the most abundant and stable
and then the least soluble one.1,2,8 Thus, form C is the phar-
maceutically preferred on the basis of both its stability and
solubility properties even though its oral bioavailability is less
than 10%.4,6,11
Mebendazole
[(5-benzoyl-1H-benzimidazole-2-yl)-carbamic
acid methyl ester, MBZ] is a broad-spectrum anthelmintic
that demonstrated to be efficacious in the oral treatment
of ascariasis, uncinariasis, oxyuriasis, and trichuriasis. It is
recommended for the treatment of nonsurgical cases and as a
supplementary therapy before and after surgery. Like other
benzimidazole anthelmintics, MBZ primary mechanism of
action is consistent with tubulin binding.1–6
Three polymorphic forms (A, B, and C) of MBZ displaying dis-
tinctive physical–chemical properties have been identified and
characterized.3,7,8 They have been mainly studied in relation
to their thermal stability and dissolution behavior in several
solvents. On the contrary, their crystal structures remained
unknown up to recent times because MBZ polymorphs are usu-
ally hard to crystallize as single crystals. Lately, the complete
structural data for the form C was determined by single-crystal
X-ray diffraction, whereas the structure of the polymorph A was
solved using synchrotron powder X-ray diffraction (PXRD) and
refined by the Rietveld method.9,10
Different strategies are constantly in progress to overcome
the MBZ low aqueous solubility by altering its physical prop-
erties; for example, new and better formulations that enhance
the activity of the anthelmintics have been generated.12 An-
other effective alternative is to interfere at the molecular level
by incorporating pharmaceutically acceptable coformers into a
unique crystal lattice without altering the covalent bonding of
the active pharmaceutical ingredient. This approach focuses in
the preparation of salts and cocrystals that are applied in the
development of new dosage forms of BCS class II drugs.13
The crystal structures of several MBZ salts and cocrystals
were also reported. Mebendazole hydrobromide was found to
crystallize in a monoclinic space group, P21/c14; recrystalliza-
tion of MBZ in propionic acid yields a 1:1 molecular complex
crystallizing in the noncentrosymmetric triclinic space group,
P1,15 whereas a stable salt, mebendazole hydrochloride (or-
thorhombic, space group Cmc21), was also fully characterized
by vibrational and thermal analyses.16 Structural and thermal
information as well as stability and dissolution studies were
recently reported for some MBZ salts and cocrystals involv-
ing dicarboxylic acids as coformers.17 Two new MBZ solvates
with N,N-dimethyl acetamide (MBZ-DMA) and N,N-dimethyl
formamide (MBZ-DMF) were obtained as microcrystalline
forms, and other techniques such as optical and polarized
microscopy, Fourier transformed infrared (FTIR) spec-
troscopy, thermal analysis, and PXRD were applied to their
characterization.18
Regarding the solubility properties of the MBZ polymorphs,
their significantly different solubility values in water condition
the therapeutic effects, thus indicating the high polymorphism
dependence of the anthelmintic efficacy. MBZ belongs to class
II (low solubility/high permeability) of the Biopharmaceutics
Classification System (BCS).
Even though some discrepancies concerning the relative sol-
ubility of forms B and C are reported in the literature, all the
Correspondence to: Griselda E. Narda (Telephone: +54-266-4424689;
Fax: +54-266-4430224; E-mail: gnarda@unsl.edu.ar)
This article contains supplementary material available from the authors upon
request or via the Internet at http://onlinelibrary.wiley.com/.
In an attempt to increase the solubility and subsequent
bioavailability of not only MBZ C form but also the nonphar-
maceutically preferred MBZ polymorph A, we have synthesized
Journal of Pharmaceutical Sciences
ꢀ
C
2013 Wiley Periodicals, Inc. and the American Pharmacists Association
Paula et al, JOURNAL OF PHARMACEUTICAL SCIENCES
1

2
RESEARCH ARTICLE – Drug Discovery-Development Interface
was carried out with SHELXL-97.27 All non-hydrogen atoms
were anisotropically refined. The C–H hydrogen atoms were
stereochemically positioned, and were refined with fixed indi-
a new salt by incorporating a pharmaceutically acceptable
coformer.
The present study reports the synthesis of mebendazole me-
sylate monohydrate (MBZ M) obtained from recrystallization
of MBZ polymorphs A, B, or C in methyl sulfonic acid solutions.
Its crystalline structure was solved by single-crystal X-ray
diffraction while a complete physical–chemical characteriza-
tion of the compound by solid-state techniques such as FTIR,
Raman, variable-temperature FTIR (VT-FTIR), PXRD, differ-
ential thermal analysis (DTA), and thermogravimetric analysis
(TGA) was also carried out. Solubility properties were investi-
gated, and a comparative analysis taking into account MBZ
polymorphs and previously reported salts is presented.
vidual displacement parameters [Uiso (H) = 1.2 Ueq(Csp2) or
3
–
1.5 U eq (Csp )] using a riding model with aromatic C H bond
˚
length of 0.93 A. The N-bound H atom was located by difference
Fourier synthesis, and its position was fixed as initially found,
with U iso (H) = 1.2 U eq (N). Geometrical calculations were
carried out with PARST.28,29 Table 1 summarizes the structural
and refinement parameters of MBZ M.
The analysis of the intramolecular geometrical parameters
of MBZ in the salt was performed with MOGUL31 by applying
the following filters: R factor less than 5% and the exclusion of
metal-organic compounds. This program was developed in 2004
and includes structural information that gives quick access to
values of bond lengths, valence, and torsion angles of structures
with similar geometries and molecular conformation, deposited
in the Cambridge Structural Database (CSD),32 which contains
the results of 600,000 (up to January 2012) crystal-structure
determinations of organic and metal-organic compounds.
The crystallographic information file (CIF) loading the data
sets (excluding the structure factors) for MBZ M has been de-
posited with the CSD under deposit code CCDC 934635 (copies
of these data may be obtained free of charge from The Direc-
tor, CCDC, Cambridge CB2 1EZ, UK, Fax: +44-123-336-033;
E-mail: deposit@ccdc.cam.ac.uk or http:www.ccdc.cam.ac.uk).
Powder X-ray diffraction diagrams were obtained with a
Rigaku D-MAX-IIIC diffractometer (Rigaku Company, Tokyo,
Japan) using CuK" radiation (Ni filter) and NaCl and quartz
as external calibration standards.
Fourier transformed infrared spectra were recorded on a
Nicolet Prote´ge´ 460 spectrometer (Nicolet Instrument Corpo-
ration, Madison, Wisconsin) provided with a CsI beamsplitter
in the 4000 –225 cm−1 range with 32 scans and spectral reso-
lution of 4 cm−1, using the KBr pellet technique. The spectra
at controlled increasing temperatures were recorded by plac-
ing the pellet in a variable-temperature IR cell in the range
25◦C–250◦C. The Raman spectrum was obtained with a Bruker
66 spectrophotometer (Bruker Corporation, MA) provided with
the FRA 106 Bruker accessory, using 1064 nm excitation line.
Thermogravimetric analysis and DTA curves were ob-
tained with Shimadzu TGA-51 and DTA-50 thermal analyzers
(Shimadzu Inc., Kyoto, Japan), using platinum pans, flowing
air at 50 mL min−1, and a heating rate of 10◦C min−1 from RT
to 1000◦C.
EXPERIMENTAL
Materials
All chemicals used were of analytical grade. The polymorphs A
and C were kindly provided by the Laboratorio de Control de
Calidad de Medicamentos, Universidad Nacional de San Luis,
Argentina, whereas polymorph B was obtained by recrystalliza-
tion of form C in acetonitrile. These samples were previously
tested by comparing the corresponding powder X-ray diffrac-
tograms and IR spectra with those reported in the literature
for the different MBZ polymorphs.
Salt Formation
A suspension containing 100 mg (0.34 mmol) of polymorph A
(or B or C) and 50 mL of absolute ethanol was prepared at
25◦C under stirring. Then, 0.5 mL (7.6 mmol) of methyl sulfonic
acid (99.5%) was slowly added until complete dissolution of the
solid. The solutions were kept about 2 weeks at 15◦C, yielding
colorless prismatic crystals, suitable for the crystallographic
determination, in all cases. The habit of MBZ M crystals is
shown in Figure S1 (see Supporting Information). As it can be
seen, the single crystals show a highly breakable needle shape.
In addition, all polymorphs yielded a polycrystalline form
by dissolution in other organic solvents such as acetonitrile or
methanol with further addition of methyl sulfonic acid solution.
The obtained products were filtered, washed with a hexane–
ethanol mixture (20:1), and dried under room conditions for
further characterization.
Methods
A suitable-sized clear crystal was selected for the single-
crystal X-ray diffraction experiment. Intensity data were mea-
Solubility Determination
sured at room temperature (RT) (293 K) with MoK" radia-
˚
tion (8 = 0.71073 A) from a graphite monochromator, using an The dissolution experiments for MBZ polymorphs A and C as
Enraf-Nonius Kappa-CCD diffractometer (Enraf-Nonius, Delft, reference drugs, and both salts (MBZ M and MBZ·HCl) were
The Netherlands).
conducted under nonsink conditions and without surfactant ad-
Crystal detector distance was fixed at 40 mm, and a to- dition. This is considered as the most appropriate approach in
tal of 346 images were collected using the oscillation method, developing a biorelevant dissolution method for a poorly water-
with scan angle by frame 2◦ oscillation and 120 s exposure soluble drug such as MBZ.33–35 For obtaining the dissolution
time by image. Data collection strategy was calculated with profiles, an amount of 200 mg of MBZ M, MBZ A, MBZ C, and
the program collect.19 Data reduction and cell refinement were MBZ·HCl was compressed at a pressure of 300 kg cm−2 for
performed with the software HKL Denzo and Scalepack.20 5 min using a hydraulic press into disks of 13.1 mm diameter
Tables were generated by WinGX,21 ORTEP-3,22 MERCURY,23 and 1.15 mm thickness. The disks were suspended in 500 mL
enCIFer,24 and PLATON25 programs were employed to prepare of pH 1 dissolution medium (0.1 M HCl solution) at 37◦C us-
material for publication.
ing a Hanson SR8 dissolution equipment (Hanson Corporation,
The crystal structure was solved by direct methods using CA) with paddles rotating at 120 rpm, which allows smoothly
the program SIR-97.26 Anisotropic least-squares refinement stirring conditions without significant wobble (Method 2 of the
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DOI 10.1002/jps.23658

RESEARCH ARTICLE – Drug Discovery-Development Interface
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Table 1. Crystal Data and Structure Refinement for MBZ M
Empirical formula
Temperature (K)
C17H19N3O7S
293(2)
409.41
0.71073
Formula weight (g.mol−1
)
˚
Wavelength (A)
Crystal system
Space group
Unit cell dimensions (A;
Triclinic
P1
¯
◦
˚
)
a = 6.8339(2)
" = 86.948(2)
$ = 86.577(2)
( = 80.693(2)
b = 9.3030(3)
c = 14.6869(4)
3
˚
Volume (A )
918.89(5)
Z
2
Density (calculated) (mg/m3)
Absorption coefficient (mm−1
F(000)
1.480
0.223
428
)
Crystal size (mm)
Theta range for data collection
Index ranges
0.73 × 0.14 × 0.11
3.02◦–27.48◦
−8 ≤ h ≤ 8, −11≤ k ≤ 11, −19 ≤ l ≤ 18
7568
Collected Reflections
Independent reflections
Completeness to theta = 27.48◦
Refinement method
Absorption correction
Data/restraints/parameters
Goodness-of-fit on F2
4137 [Rint = 0.0287]
98.5%
Full-matrix least squares on F2
Gaussian 30
4137/0/255
1.066
Final R indices [I > 2F(I)]
R indices (all data)
Largest difference peak and hole (e. A
R1 = 0.0537, wR2 = 0.1439
R1 = 0.0689, wR2 = 0.1569
0.284 and −0.525
−3
˚
)
USP 29, modified).1,36 Samples were taken every 5 min during
the first 75 min, then every 15 min up to 120 min, and finally,
the sampling time was 60 min in the range 120 –780 min.
Intrinsic dissolution rate experiments were conducted in a
rotating disk apparatus under the same experimental condi-
tions by using disks prepared as described previously. The ab-
sorbance measurements at 283 nm for each sample were per-
formed with a Shimadzu UV–Vis 1603 (Shimadzu Inc.). The
absorbance values were converted into solution concentration
ones by means of a calibration curve for MBZ (Fig. S2, Support-
ing Information). Experimental results were the average of five
replicated experiments.
Figure 1. ORTEP–3 view of the asymmetric unit of MBZ M showing
the atoms labeling, the 50% probability ellipsoids, and the intramolecu-
lar interactions. Nonclassical interactions are indicated in blue dashed
lines.
RESULTS AND DISCUSSION
Crystal Structure
Table 2. Geometrical Parameters of the Intramolecular Interactions
(with estimated standard deviations in Parenthesis)
The experimental PXRD diagram can be satisfactorily com-
pared with the theoretical one obtained by simulation with
MERCURY23 inputting the MBZ M CIF file created after the
structural refinement (see Fig. S3, Supporting Information). In
addition, PXRD patterns and FTIR spectra of the crystalline
powders confirmed that different solvents render the same salt
of MBZ.
◦
˚
˚
˚
–
–
–
D H•••A
D H (A) D•••A (A) H•••A (A) D H•••A ( )
–
N(3) H(3)•••O(2)
0.990
0.960
0.930
0.930
2.724(2)
2.680(3)
2.758(3)
2.802(3)
2.117
2.565
2.440
2.542
117.76(9)
86.30(13)
99.99(13)
96.35(14)
–
C(1) H(1c)•••O(2)
–
C(7) H(7)•••O(3)
–
C(16) H(16)•••O(3)
Figure 1 shows an ORTEP-322 view of the asymmetric unit
of MBZ M, which contains one MBZ molecule, one mesylate ion,
and one water molecule. The MBZ M presents the azolic nitro-
The
–
classical
intramolecular
hydrogen
bond
gen located on N(3), unlike other compounds, such as MBZ·HCl, [N(3) H(3)•••O(2)] between the carbonyl of the carba-
where the azolic nitrogen is positioned on N(2).16
mate group and the nitrogen atom N3 of the heterocycle
The analysis of the molecular conformation reveals classical closes chelating six-membered system. This H-bond
and nonclassical intramolecular hydrogen bonds whose respec- is stabilized by a resonance effect involving the atoms
a
–
–
–
–
–
tive distances and angles are shown in Table 2.
H(3) N(3) C(3) N(1) C(2) O(2). This electron delocalization
DOI 10.1002/jps.23658
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RESEARCH ARTICLE – Drug Discovery-Development Interface
Table 3. Bond Length Values Involved in the Resonance-Assisted
Hydrogen Bond Compared with the Respective Values Obtained by
MOGUL31 (with estimated standard deviations in Parenthesis)
participates in three intermolecular interactions, two of them
involving two mesylate groups and the remaining one with a
MBZ molecule (Fig. 3).
–
The N(1) H(1)•••O(6) hydrogen bond connects the nitro-
˚
˚
Fragment
Bond Length (A)
Average Value (A)
gen of the carbamate group with the oxygen of the mesy-
late ion. Furthermore, the nitrogen N(3) of the benzimida-
zole group is also hydrogen bonded to the O(4) from another
mesylate ion. This same oxygen atom also acts as an accep-
tor in a nonclassical intermolecular interaction with a car-
–
N(3) C(3)
1.341(2)
1.355(2)
1.381(2)
1.195(2)
1.349
1.336
1.374
1.211
–
C(3) N(1)
–
N(1) C(2)
–
C(2) O(2)
–
bon atom of the benzimidazole group, C(6) H(6)•••O(4). These
three mentioned intermolecular interactions lead to the for-
mation of infinite chains along the b axis (Fig. 4, Table 4).
These chains form two-dimensional arrays in which succes-
sive chains are rotated 180◦ along the b axis, which places
the phenyl groups of a chain toward the corresponding ones
belonging to the adjacent chain. These two-dimensional arrays
are linked together through intermolecular interactions involv-
ing water molecules allowing the development of the three-
dimensional packing. Thus, each mesylate ion interacts with
two different water molecules through strong hydrogen bonds
effect is called resonance-assisted hydrogen bond (RAHB),37,38
and is characterized by an interaction between a hydro-
gen atom connected to an electronegative atom (N or NH)
and to another electronegative atom of the same molecule
=
= – = –
( O) connected to a B-conjugated system (O C C C OH,
= – = –
= – = –
O C C C NH, or O C N C NH). This electron delocal-
ization effect is of great importance for the stabilization of
the intramolecular interaction (RAHB effect). This resonant
effect influences the bond lengths of the atoms involved as
–
–
O(1w) H(11W)•••O(5) and O(1w) H(12w)•••O(6). In turn, wa-
ter molecules behave as acceptors for other classical hydrogen
bonds involving the nitrogen atom N(2) from the benzimidazole
–
–
can be seen from the N(3) C(3) and C(2) O(2) bond distances
–
–
that get shorter, whereas the C(3) N(1) and N(1) C(2) ones
become longer than the mean value for this kind of compounds.
Table 3 displays the bond length values involved in the hybrid
resonance according to the program MOGUL.31 The highest
deviation from the least-squares plane passing through the
–
group, N(2) H(2)•••O(1w).
As it was already mentioned, B−B stacking interactions are
also present in the crystal packing of MBZ M. In this type of
interaction, the rings are arranged so as to position themselves
parallel to each other but exhibiting an offset of their centroids
in the ring plane, thus leading to a decrease in the electron
repulsion. Although weak, these interactions represent a sig-
nificant contribution to the aggregate of molecules that form a
crystal, thereby decreasing the crystalline energy. In the B−B
˚
above-mentioned six cyclic atoms is − 0.0113(5) A (root mean
square deviation).
The crystal structure presents a three-dimensional packing
stabilized by classical and nonclassical intermolecular inter-
actions. The different interactions originate hydrophilic chan-
nels in which the mesylate ions and water molecules are dis-
tributed (Fig. 2a). The packing consists of rows of alternating
MBZ molecules linked through hydrogen bonds to columns of
mesylate ions (Fig. 2b).
˚
stacking interactions, the centroids are separated by 3.743 A,
with a displacement between centroids of 26.33◦ (Fig. S4, Sup-
porting Information).
Each molecule of MBZ participates in three intermolecular
Statistical Analysis of Molecular Parameters
–
interactions, all of them belonging to the N H•••O type, two
of them to mesylate ions, and the remaining one to a water The analysis of the MBZ M geometrical parameters performed
molecule. No classical intermolecular interactions are found with the MOGUL program31 shows important deviations for
between MBZ molecules. Furthermore, each mesylate group several parameters when compared with the expected values
–
participates in four intermolecular interactions involving two (see Table 5). The major disagreements involve the C(7) C(8)
=
MBZ and two water molecules. Finally, each water molecule and O(2) C(2) bond lengths. The difference found in the former
Figure 2. (a) MBZ M crystal packing showing the hydrophilic channels containing the mesylate ions and water molecules; (b) view of the rows
interspersed by MBZ and mesylate ions along the [100] direction.
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RESEARCH ARTICLE – Drug Discovery-Development Interface
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Figure 3. Classical intermolecular interactions in the MBZ M crystal structure.
Figure 4. Intermolecular interactions in MBZ M along the [010] direction. Classical intermolecular interactions are outlined in blue lines and
the nonclassical ones in purple.
DOI 10.1002/jps.23658
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RESEARCH ARTICLE – Drug Discovery-Development Interface
Table 4. Selected Intermolecular Interactions Parameters (with estimated standard deviations in Parenthesis)
◦
˚
˚
˚
–
–
–
D H•••A
D H (A)
D•••A (A)
H•••A (A)
D H•••A ( )
a
–
N(2) H(2)•••O1w
0.951
0.955
0.984
0.990
0.820
0.930
2.679(2)
2.776(2)
2.728(2)
2.755(2)
2.879(2)
3.227(3)
1.785
1.823
1.744
1.959
2.076
2.614
155.3(1)
175.9(1)
177.7(1)
135.6(1)
166.2(1)
123.9(1)
b
c
–
O(1w) H(11w)•••O(5)
a
–
N(1) H(1)•••O(6)
b
–
N(3) H(3)•••O(4)
–
O(1w) H(12w)•••O(6)
b
–
C(6) H(6)•••O(4)
Symmetry operations: a−x + 1,−y,−z; b−x + 1,−y + 1,−z; cx + 1,y,z.
one is a consequence of the participation of the C(7) in the in- a trans-conformation, whereas in MBZ·HCl, they adopt a cis-
tramolecular interaction with oxygen O(3), as previously de- conformation.16 These differences in the conformation of the
scribed. The difference in the second bond length is because carbamate group are characterized by rotations about the
–
–
of the presence of the resonance-assisted interaction involv- C(2) N(1) and N(1) C(3) bonds.
–
–
–
–
–
ing atoms H(3) N(3) C(3) N(1) C(2) O(2). This effect leads to
a redistribution of the electron charge density that decreases
Vibrational Spectra
=
the O(2) C(2) bond length, when compared with the average
value. The other bonds that are also involved in resonance show
similar deviations.
The FTIR and Raman spectra of MBZ M are presented in Fig-
ures S5 and S6 (see Supporting Information), respectively. VT-
FTIR spectra are gathered in Figure S7 (see Supporting Infor-
mation). Table 6 shows the assignment of the vibrational modes
performed on the basis of the most important functional groups
such as carbonyl, NH, CN, SO, and OH. The main differences
among the vibrational behavior of MBZ polymorphs, MBZ·HCl
and MBZ M are also analyzed.
–
Figure 5 depicts the histograms for the O3 C10 bond dis-
tance and the O3 C10 C11 bond angle as well as for the
–
–
–
–
–
O3 C10 C8 C9 torsion angle. It is worthy to note that for the
torsion angle, there are two preferred values for the same frag-
ment. These parameters were chosen because they all lie in the
region of the phenyl and benzimidazole groups, that is, in a re-
gion where the oxygen atom participates in two intramolecular
NH and OH Modes
–
interactions of the C H•••O type, these interactions being re-
Three intense bands at 3475, 3370, and 3210 cm−1 are iden-
tified in the high-frequency region in the MBZ M spectrum.
sponsible for the stabilization of the phenyl ring conformation.
–
Thus, these interactions lead to an increase in the O3 C10 bond
length and to a contraction in the O3 C10 C11 valence angle.
The relatively broad band at 3210 cm−1 is assigned to the N H
–
–
–
stretching mode. For MBZ·HCl, the <N–H bands are observed
at 3216 and 3144 cm−1, the last one being associated to the
Comparison with Others Solid Forms of MBZ
–
Nazolic H(HCl). The considerably stronger hydrogen bonds de-
Figure 6 shows the overlap of the MBZ moiety in the MBZ M rived from the basicity of the mesylate and chloride anions
molecule with the corresponding one in the other MBZ solid could explain the shifting to lower frequencies of this mode
forms reported by us. The overlap of the molecular conforma- when comparing with the MBZ polymorphs.1,5
tions indicates that the main differences involve the phenyl
The bands centered at 3475 and 3370 cm−1 are assigned
ring and the carbamate group. In all of them, the carbamate to the <O–H mode of crystallization water. This assignment
group is coplanar with the benzimidazole ring (within ex- is justified by their disappearance in the VT-FTIR spectra at
perimental error). For MBZ·HCl, a satisfactory overlap was temperatures consistent with dehydration (Fig. S7, Supporting
not possible to obtain because of the particular molecular Information).
conformation of the MBZ related to the conformational F
The imine and carbamate NH bending modes occur in the IR
(Sigma) binding between nitrogen and oxygen of the carba- and Raman spectra at 1650, 1635, and 1600 cm−1. Furthermore,
mate group. In MBZ M, methoxy and benzoyl group are in the band at 1650 cm−1 presents another component associated
◦
˚
Table 5. Selected Disagreement Values for Bond Lengths (A) and Angles ( ) Obtained with the MOGUL Program
Value in Query
Statistics Total
Mean
Median
Standard Deviation
l z–Score l
Bond
–
C7 C8
1.406
1.195
1.501
1.226
2417
1373
450
1.389
1.211
1.490
1.227
1.390
1.212
1.491
1.223
0.011
0.011
0.010
0.014
1.536
1.510
1.183
0.044
–
O2 C2
–
C11 C10
–
O3 C10
960
Torsion angle
–
–
–
–
C6 C7 C8
122.775
116.203
116.949
117.436
123.627
118.351
2684
744
714
714
714
450
120.791
120.054
120.577
120.577
120.577
119.878
120.771
120.640
120.767
120.767
120.767
119.945
0.951
1.798
1.993
1.993
1.993
1.520
2.086
2.142
1.821
1.576
1.530
1.004
–
C7 C6 C5
–
C7 C8 C10
–
–
–
–
C16 C11 C10
–
C12 C11 C10
–
O3 C10 C11
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RESEARCH ARTICLE – Drug Discovery-Development Interface
7
–
–
–
–
–
–
Figure 5. Histograms obtained by the MOGUL program for (a) O3 C10 bond length, (b) O3 C10 C11 bond angle, and (c) O3 C10 C8 C9
torsion angle.
with the <C O(ketonic) mode, whereas the band at 1600 cm−1 and 1700 cm−1, respectively;1,5 for MBZ·HCl it is observed at
=
involves the *H2O mode because it is progressively modified 1767 cm−1 (IR) and 1760 cm−1 (Raman).16
when temperature raises from RT to 150◦C.
The bands at 1365 cm−1 (IR) and 1370 cm−1 (Raman) have
– –
been attributed to the C O C stretching mode in accordance
with the reference values.39–41
CO Modes
Both carbonyl groups in MBZ M are involved in two intramolec-
CN Modes
ular H-bonds each one. The IR and Raman spectra exhibit the
characteristic band of the <C O(carbamic) mode at 1750 cm−1
Polymorphs A, B and C present this mode at 1730, 1720, *N H mode, both in IR and Raman spectra, and at 1565 cm
.
The <C N mode is identified at 1635 cm overlapped with t−h1e
−1
=
–
–
.
Figure 6. Superposition of the MBZ moiety of the different MBZ solid forms reported by us in the literature (MBZ M in blue): (a) MBZ·HCl
(orange) and (b) form C (green).
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8
RESEARCH ARTICLE – Drug Discovery-Development Interface
Table 6. Selected Vibrational Modes of the Raman and FTIR
Spectra of MBZ M
An analysis of the thermal data indicates that MBZ M degra-
dation occurs in five steps. The first stage involves a mass
decay of 4.6% (calculated: 4.4%, onset: 50◦C) associated with
an endothermic DTA signal. This fact was confirmed by the
VT-FTIR spectra (Fig. S7, Supporting Information) that show
the disappearance of the bands derived from water molecules.
The corresponding anhydrous compound remains stable up to
150◦C without undergoing through phase transitions or melt-
ing process. The second step is also endothermic in nature and
accounts for the breakdown of the carbamate moiety16 with
further elimination of CO2, the weight loss being 16.1% (cal-
culated: 14.17%, onset: 215◦C). This fact is supported by the
absence of the IR bands located at 1750 and 3210 cm−1 in the
spectrum recorded at 200◦C (Fig. S7, Supporting Information).
The following three mass decays consist of successive events
with no stability plateau among them; the first two stages of
–27.6% (calculated: −25.67%; onset 330◦C and 400◦C) are as-
sociated with relatively weak and complex DTA signals. In an
attempt to elucidate these processes, a small amount of sam-
ple was heated at 400◦C and then, the corresponding FTIR
spectrum was recorded. The decrease in the intensity of the
1650 cm−1 band and the disappearance of high- and medium-
Mode
FTIR
Raman
Wavenumbers (cm−1
)
Wavenumbers (cm−1
)
<OH (water)
<NH Modes
*NH + <C = O
(ketone)
3475 (m), 3370 (m)
3210 (m)
1650 (s)
*NH + <CN
*NH + *H2O
<CN
1635 (w)
1600 (m)
1565 (m), 1505 (w)
1650 (sh)
1635 (m)
1599 (m)
1565 (w), 1500 (vw)
<C = O
1750 (s)
(carbamate)
–
–
<C O C
1370 (w)
1290 (w)
1750 (w)
1369 (m)
–
<C C
SO Modes
<
asSO
1240 (s), 1155 (s)
1040 (s)
<sSO
1240 (w), 1150 (w)
1050 (w)
<CH (aromatic)
3100 (m), 3070 (m),
3060 (m)
3099 (vw), 3074 (w),
3064 (sh), 3011
(vw)
–
frequency bands assigned to the C H modes are observed.
<CH (aliphatic)
2955 (m)
These evidences suggest the elimination of the benzoyl moiety.
The final step involves a 51.7% weight loss (calculated: 55.51%;
onset 450◦C) accompanied with an important exothermic sig-
nal, resulting in the complete decomposition of the compound.
The thermal evolution of MBZ M is substantially different
from those of MBZ·HCl16 or MBZ polymorphs8; the presence
of a coformer with high thermal stability could explain this
observation.
s, Strong; m, media; w, weak; vw, very weak; sh, shoulder; d, doublet; <,
stretching; *, deformation; D, rocking; s, symmetric; as, antisymmetric.
=
The higher frequency band could be assigned to the C N bond
of the benzimidazole ring; this band is shifted to lower fre-
39–41
=
quency regarding the corresponding C N frequency values
and reveals losing of the double bond character in the benzim-
idazole ring. The lower frequency band is associated with the
–
carbamate C N simple bond.
Solubility Studies
Thermal Studies
Solubility at a defined temperature and pressure is the satu-
Figure 7 displays the TGA and DTA curves for MBZ M. The ration concentration of the dissolved drug in equilibrium with
proposed thermal decomposition of the compound is shown in the solid drug. Aqueous solubility of drugs is traditionally de-
Scheme 1.
termined using the equilibrium solubility method that involved
Figure 7. TGA and DTA curves for MBZ M. (Inset) Zoom in the RT to 270◦C range.
Paula et al, JOURNAL OF PHARMACEUTICAL SCIENCES
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RESEARCH ARTICLE – Drug Discovery-Development Interface
9
suspending an excess amount of a solid drug in a selected aque- CONCLUSIONS
ous medium.
The use of methyl sulfonic acid as a coformer leads to a new
MBZ salt, which is able to improve significantly the poor
MBZ solubility. The crystal structure of a new salt, MBZ M,
shows a two-dimensional array consisting of MBZ molecules
and mesylate ions with further development of the three-
dimensional packing via intermolecular H-bonds involving the
water molecules. Other weak interactions also contribute to
the solid-phase stabilization. Unlike other MBZ solid forms,
MBZ M presents a rich intramolecular interactions pattern
with formation of four rings, one of them being stabilized by
the RAHB effect that affects the involved bond distances. The
vibrational behavior is consistent with the structural findings.
Thermal studies indicate that the salt dehydrates at 50◦C and
further continues its thermal evolution without converting to
any solid form of MBZ because of the high stability of the mesy-
late moiety on heating. Finally, solubility experiments at pH 1
demonstrated that MBZ M exhibits a much better performance
than MBZ polymorphs A and C.
The dissolution profiles in comparison with those of MBZ
polymorphs A and C and MBZ·HCl are shown in Figure 8a,
whereas the intrinsic dissolution rate curves are displayed in
Figure 8b.
The maximum solubility values for the forms A and C and
both salts are given in Supporting Information (Table S1).
These values indicate that MBZ M is 3.1 and 19.2 times as large
as that of polymorphs C and A, respectively, whereas MBZ·HCl
is 1.2 times more soluble than MBZ M.
Both salts exhibit an important increase in solubility and
dissolution rate as compared with MBZ forms A and C; in addi-
tion, they are even more soluble than the MBZ-oxalate mono-
hydrate and the MBZ-maleate salts reported by Chen et al.,17
with reference to the corresponding form C solubility values in
all cases.
The maintenance of the initial form for each compound as-
sayed was confirmed at the end of the dissolution experiments
by FTIR spectrometry, showing that no solution-mediated
transformation was observed during the reported period.
The solubility profiles are promising because higher concen-
tration of the drug can be achieved at a faster rate through salt
formation.
ACKNOWLEDGMENTS
The authors thank the Brazilian agencies CNPq, CAPES, and
FAPESP and Argentinian ones CONICET (PIP 2008-01360)
and SECyT-UNSL for financial support. G.E.N. is a member of
the CONICET.
Scheme 1. Proposed thermal degradation of MBZ M.
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10
RESEARCH ARTICLE – Drug Discovery-Development Interface
Figure 8. Dissolution profiles of MBZ M in comparison with those of MBZ polymorphs A and C and MBZ·HCl for (a) 780 min and (b) 35 min.
Intrinsic dissolution rates (mg mL−1 min−1 cm−2): A, 4.4 × 10−6 (R2 = 0.8); C, 3.5 × 10−5 (R2 = 0.99); MBZ·HCl, 6.94 × 10−5 (R2 = 0.99); MBZ
M 5.6 × 10−5 (R2 = 0.98).
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