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MARCO B. PRANZO,1 DYANNE CRUICKSHANK,2 MASSIMO CORUZZI,1 MINO R. CAIRA,2 RUGGERO BETTINI1
1
Department of Pharmacy, University of Parma, Viale G.P. Usberti 27/A, 43124 Parma, Italy
2
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
ABSTRACT: In the present study we report the solid-state properties of albendazole (ABZ)
re-crystallized from different solvents for comparison with the commercially available form.
Crystalline phases were characterized as to thermal behavior, X-ray diffractometry, both on
powder and single crystal, and solubility in methanol or 0.1 N HCl. The relevant thermodynamic
parameters were calculated from solubility measurements at different temperatures. The re-
crystallization of ABZ both from methanol and N,N-dimethylformamide afforded a new stable
polymorph form (Form II) enantiotropically related to the commercially available ABZ (Form I),
the latter being the metastable form at ambient temperature. Both forms proved to be physically
quite stable, likely due to a high-energy barrier for the activation of the interconversion. ABZ in
the solid state represents a rather complex system in which the molecular structural differences
that could be associated with the polymorphism are of at least four possible types, or combina-
tions of these: (a) tautomeric; (b) different conformations of either or both of the side-chains
attached to the bicyclic ring system; (c) the occurrence of molecular disorder or its absence; (d) no
essential difference in molecular structure but different hydrogen bonding arrangements in
the two polymorphs. ß 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci
99:3731–3742, 2010
Keywords: albendazole; polymorphism; enantiotropy; crystal structure; solid state
Despite the fact that ABZ was discovered more than Single Crystal X-Ray Analysis of Form II of ABZ
35 years ago and its use in therapy is well established,
Microscopic examination of many batches of ABZ
no reports are presently available on its solid-state
obtained by re-crystallization from methanol and
characterization nor on its possible polymorphism.
DMF revealed a constant crystal morphology, namely
The aim of the present work was to study the solid-
poorly formed laminae with typical thickness only
state properties of ABZ re-crystallized from different
10 mm. A specimen viewed normal to the thin
solvents for comparison with the commercially
section is shown in Figure 1. Eventually, a specimen
available form.
with thickness 0.06 mm was identified and cut to a
Crystalline phases were characterized as to ther-
more equant shape (0.18 mm 0.18 mm 0.06 mm)
mal behavior, X-ray diffractometry, both on powder
to minimize X-ray absorption error and ensure suffi-
and single crystal, and solubility in methanol or 0.1 N
cient volume for adequate X-ray diffraction intensity.
HCl. The relevant thermodynamic parameters were
This was mounted on a cryoloop with Paratone oil
calculated from solubility measurements at different
(Exxon Chemical Co., Houston, TX), placed on a
temperatures.
Nonius Kappa CCD four-circle diffractometer and
cooled in a stream of nitrogen vapor to 213(2) K using
MATERIALS AND METHODS an Oxford Cryostream cooler (Oxford Cryosystems,
Oxford, UK) to ensure a rigid mount. No phase change
ABZ Crystallization accompanied the cooling process.
Data collection (COLLECT software20) with Mo
An amount corresponding to about 100 mg of ABZ
Ka-radiation (l ¼ 0.71073 Å) involved a combination
(Sigma, Steinheim, Germany) was dissolved in
of f- and v-scans of 1.008 and 0.508, respectively. All
100 mL of methanol, (HPLC grade, 99.9% minimum
data were corrected for Lorentz-polarization effects.
assay, Carlo Erba Reagents, Milan, Italy) or N,N-
Absorption effects were negligible for the specimen
dimethylformamide, DMF, (99.8% assay, Fluka
used (transmission range 0.9555–0.9858). Unit cell
Chemie GmBH, Buchs, Switzerland) and stirred at
refinement and data-reduction were performed using
408C until a clear solution was obtained. The filtered
DENZO-SMN and SCALEPACK.21 The monoclinic
solution was allowed to spontaneously evaporate
crystal system was established from the Laue
under ambient conditions until ABZ crystallization
symmetry (2/m) and the space group C2/c from
was complete. Colorless crystals formed after a few
systematic absences, centrosymmetry being indicated
days from methanol, whereas light brown crystals
by the hE2 1i value of 0.922.
were collected after about 1 month from DMF.
The structure was solved using direct methods
(program SHELXS-9722) and refined by full-matrix
Thermal Analysis
least-squares against F2 (program SHELXL-9723).
Differential scanning calorimetry (DSC) was per- After location of the nonhydrogen atoms of the
formed on an indium calibrated Mettler DSC 821e asymmetric unit (a single molecule of ABZ), it was
(Mettler Toledo, Columbus, OH) driven by STARe noted that the propylthio-chain was disordered over
software (Mettler Toledo). DSC traces were recorded two chemically equivalent positions. Each component
by placing precisely weighed quantities (1–5 mg) in a was modeled with a fixed site occupancy of 0.5, based
sealed and pierced 40 mL aluminium pan. Scans were on very similar electron densities for the atoms
performed between 30 and 2258C at 5 K min1 or comprising the two side-chains as well as intermo-
between 30 and 2708C at 40 K min1 under a flux of lecular distance constraints. Following treatment of
dry nitrogen (100 mL min1). Each powder sample the non-H atoms, special care was exercised in the
was analyzed at least in triplicate. location of hydrogen atoms, given the possibility of
Thermogravimetric analysis (TG 50, Mettler
Toledo) was carried out on ABZ samples placed in
70 mL alumina pans with a pierced cover. Samples
were heated under a flux of dry nitrogen
(100 mL min1) at 5 K min1 in the 30–2258C tem-
perature range.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 9, SEPTEMBER 2010 DOI 10.1002/jps
ENANTIOTROPICALLY RELATED ALBENDAZOLE POLYMORPHS 3733
tautomerism for this molecule. All H atoms were Table 1. Crystal Data and Refinement Parameters for
located unequivocally in difference Fourier electron Form II of Albendazole
density maps. In particular, both N atoms of the
Parameter Form II
imidazole ring were found to bear H atoms, while no
electron density attributable to a hydrogen atom was Chemical formula C12H15N3O2S
found on the exocyclic N atom. Figure 2a shows the Formula weight 265.33
Dcalc (g cm3) 1.401
conventional structural diagram for ABZ and
Crystal system Monoclinic
Figure 2b the structure of the tautomer found in Space group C2/c
the crystal of Form II. The disordered model was a (Å) 23.934(5)
completed with half-atoms of hydrogen added at b (Å) 5.440(1)
positions C7, C8 of the phenyl ring. Except for one of c (Å) 19.586(6)
a (8) 90.0
the atoms of a disordered chain component (C18A), all
b (8) 99.29(1)
non-H atoms refined anisotropically. H atoms were g (8) 90.0
generally added in a riding model at idealized V (Å3) 2516.6(10)
positions based on their stereochemistries, clearly Formula units (Z) 8
established from electron density maps, and were m (Mo Ka) (mm1) 0.255
T (K) 213(2)
assigned isotropic thermal parameters 1.2–1.3 times
Reflections 2157
those of their parent atoms. Crystal data and Parameters 204
refinement parameters are reported in Table 1. Completeness (%) 97.8
Molecular parameters were calculated with program R1 (on F > 4s ( F)) 0.0723
PLATON.24 wR2 (on F2, F > 4s ( F)) 0.1547
Goodness-of fit (S) 1.033
Final D/s <0.001
Solubility Determination Dr min.; max. (e Å3) 0.257; 0.259
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 9, SEPTEMBER 2010
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ENANTIOTROPICALLY RELATED ALBENDAZOLE POLYMORPHS 3735
1st Peak, 8C DH 1st Peak, J g1 2nd Peak, 8C DH 2nd Peak, J g1
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ENANTIOTROPICALLY RELATED ALBENDAZOLE POLYMORPHS 3737
Solubility in Solubility in
Methanol HCl 0.1 N
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3738 PRANZO ET AL.
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ENANTIOTROPICALLY RELATED ALBENDAZOLE POLYMORPHS 3739
Table 4. Selected Molecular Parameters for Form II of Table 5. Hydrogen Bond Data for Form II of Albendazole
Albendazole
D–H A D–H (Å) H A (Å) D A (Å) D–H A (8)
Bond Distances (Å) a
N1–H1 N10 0.87 1.96 2.816(5) 168
N1–C2 1.348(5) N3–C2 1.344(5) N3–H3 O12b 0.87 2.20 2.928(4) 140
N10–C2 1.330(5) N3–C4 1.396(5) N3–H3 O12 0.87 2.25 2.735(5) 115
N1–C5 1.394(5) N10–C11 1.345(5) a
1/2 x, 5/2 y, 2 z.
C11–O12 1.221(5) C11–O13 1.364(5) b
1/2 x, 1/2 þ y, 3/2 z.
Bond angles (8)
C5–N1–C2 109.0(3) C4–N3–C2 109.2(3)
N1–C2–N3 108.2(4) N1–C2–N10 120.9(4)
N3–C2–N10 130.8(4) C2–N10–C11 118.7(3) due to formation of a six-membered ring as a result of
intramolecular hydrogen bonding (N3–H3 O12,
Tab. 5). Atom H3 is in fact involved in an inter-
structural refinement proceeded reasonably well, all molecular H-bond as well, as described below. The
parameters converging satisfactorily and no abnor- formal bonding pattern C2 – N10–C11 occurring in
mal residual electron density being evident. this tautomer is also easily distinguished from the
The most significant molecular features are the alternative tautomeric possibility C2–N10(H)–C11 by
locations of the H atoms on N1 and N3, and the the value of the bond angle subtended at N10
twofold disorder of the propylthio-chain. As expected, (118.7(3)8 in the present case), which is the same as
the atoms of the side-chains display significantly the reported value of 118.5(4)8 in N-(2-benzimidazo-
higher thermal vibration than the rest of the lyl)-O-methyl carbamate. Instead, in benzimidazole
molecule. The five-membered ring is symmetrical, analogues in which N10 bears a hydrogen atom, and
the bond distances N1–C2 and N3–C2 being equal either one or both endocyclic N atoms bear a hydrogen
and longer than N10–C2 (Tab. 4), in accord with atom, the angle subtended at N10 is significantly
the formal bond orders indicated in Figure 2b. The larger (range 121.8–123.78 in the closely related
corresponding N–C and N – – C distances in N-(2- molecules BEWLOF,35 BMCBIB,36 QESBOG37).
benzimidazolyl)-O-methyl carbamate (refcode SED- Thus, there is ample evidence from the present X-
ZUW34), which has the same formal bonding arrange- ray structure that the ABZ tautomer in Form II
ment, are respectively 1.352(4), 1.364(6), and corresponds to that shown in Figure 2b.
1.328(5) Å. These values do not differ significantly Molecular association via intermolecular hydrogen
from their counterparts listed in Table 4. Further ring bonding is extensive, with two well-defined motifs
symmetry is indicated in the present study by the occurring, one finite and the other infinite. The
equality of the endocyclic angles at N1 and N3. The former is a centrosymmetric dimer with graph set R22
bond angle N3–C2–N10 exceeds N1–C2–N10 by 108 (8),38 shown at the top of Figure 10, in which the
Figure 10. Stereoview showing details of the primary hydrogen bonding motifs and
the generation of nonparallel molecular stacks in the crystal structure of albendazole,
Form II.
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 9, SEPTEMBER 2010
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ENANTIOTROPICALLY RELATED ALBENDAZOLE POLYMORPHS 3741
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3742 PRANZO ET AL.
24. Spek AL. 1990. PLATON: A multipurpose crystallographic tool. 33. Bettini R, Bonassi L, Castoro V, Rossi A, Zema L, Gazzaniga A,
Acta Crystallogr A46:C34. Giordano F. 2001. Solubility and conversion of carbamazepine
25. 2008. Monograph 01/2008:1386. European Pharmacopoeia 6.0, polymorphs in supercritical carbon dioxide. Eur J Pharm Sci
ed. Strasbourg, France: EDQM. pp. 1122–1123. 13:281–286.
26. Alanazi FK, El-Badry M, Ahmed MO, Alsarra IA. 2007. 34. Sokol VI, Davydov VV, Porai-Koshits MA, Zaitsev BE, Palish-
Improvement of albendazole dissolution by preparing micro- kin MV, Sheban GV, Pakhomov VI, Kukalenko SS. 1988.
particles using spray-drying technique. Sci Pharm 75:63–79. Crystal and molecular structure of N-(2-benzimidazolyl)-O-
27. Moriwaki C, Costa GL, Ferracini CN, de Moraes FF, Zanin GM, alkyl carbamates. Izv Akad Nauk SSSR Ser Khim (Russ) (Russ
Pineda EAG, Matioli G. 2008. Enhancement of solubility of Chem Bull) 37:1306–1311.
albendazole by complexation with b-cyclodextrin. Brazilan J 35. Iriepa I, Villasante FJ, Galvez E, Bellanato J, Martin A,
Che Eng 25:255–267. Gomez-Sal P. 2004. Synthesis, spectroscopic and crystallo-
28. Kalaiselvan R, Mohanta GP, Manna PK, Manavalan R. 2006. graphic study of some carbamates from an azabicyclic chlor-
Studies on mechanism of enhanced dissolution of albendazole oformate and primary heterocyclic amines. New J Chem
solid dispersions with crystalline carriers. Indian J Pharm Sci 28:618–624.
68:599–607. 36. Blaton NM, Peeters OM, De Ranter CJ. 1980. (5-Benzoyl-1H-
29. Kalaiselvan R, Mohantha GP, Manna PK, Manavalan R. 2006. benzimidazol-2-yl)carbamic acid methyl ester hydrobromide
Multicoponent system of albendazole with cyclodextrins and (Mebendazole.HBr), C16H14BrN3O3. Cryst Struct Commun
hydroxyacids. Acta Pharm Sci 48:19–33. 9:181–186.
30. Aguiar AJ, Zelmer JE. 1969. Dissolution behavior of poly- 37. Sepassi K, Nichol GS, Yalkowsky SH. 2006. The napsylate salt
morphs of chloramphenicol palmitate andmefenamic acid. of carbendazim. 2-(Methoxycarbonylamino)benzimidazolium
J Pharm Sci 58:983–987. naphthalene-1-sulfonate. Acta Crystallogr Sect E: Struct Rep
31. Carstensen JT. 2001. Polymorphism. In: Carstensen JT, Online E62:o5172–o5173.
editor. Advanced Pharmaceutical Solids, ed. New York: Marcel 38. Etter MC. 1990. Encoding and decoding hydrogen bond
Dekker. pp. 117–131. patterns of organic compounds. Acc Chem Res 12:120–
32. Brittain HG, Grant DJW. 1999. Effect of polymorphism and 126.
solid-state solvation on solubility and dissolution rate. In: 39. Yvon K, Jeitschko W, Parthe E. 1977. LAZY PULVERIX: A
Brittain HG, editor. Polymorphism in pharmaceutical solids, computer program for calculating X-ray and neutron diffrac-
ed. New York: Marcel Dekker. pp. 291–329. tion powder patterns. J Appl Crystallogr 10:73–74.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 9, SEPTEMBER 2010 DOI 10.1002/jps