Conformational Polymorphism in Sulfonylurea Drugs: Electronic

Aug 18, 2010 - (35) The general trend is that less polar solvents lead to structures similar to SLU-1, whereas polar ...... Struct: THEOCHEM 2009, 897...
0 downloads 0 Views 4MB Size
Download PDF
J. Phys. Chem. B 2010, 114, 11603–11611

11603

Conformational Polymorphism in Sulfonylurea Drugs: Electronic Structure Analysis Yoganjaneyulu Kasetti, Nikunj K. Patel, Sandeep Sundriyal, and Prasad V. Bharatam* Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar 160 062, Punjab, India ReceiVed: February 11, 2010; ReVised Manuscript ReceiVed: July 30, 2010

Quantum chemical calculations have been performed using HF, B3LYP, and MP2 methods on the model sulfonylurea PhSO2NHC(dO)NHMe to understand the conformational and tautomeric preferences. The results indicate that a conformer with intramolecular hydrogen bond SLU-1 (hitherto not considered) is more stable than the conformer SLU-2 (which is generally considered) for sulfonylureas. The energy difference between these two conformers is about 4 kcal/mol in the gas phase; however, the energy differences between the two rotamers become negligible in the solvent phase. Iminol tautomeric forms of sulfonylurea (which were also not studied until now) are only about 5-6 kcal/mol higher in energy as per both gas-phase and solvent-phase analyses, indicating easy accessibility of tautomeric states in sulfonylureas. Quantum chemical analysis has also been carried out on the possible dimeric structures of these three important isomers of sulfonylurea, and correlations have been made to the known crystal structures of polymorphic states of sulfonylurea drugs. Introduction Sulfonylurea (SU) derivatives are the most valuable drug molecules among all existing antidiabetic drug molecules.1 Initially sulfonylureas were expected to have potential chemotherapeutic action because of their structural resemblance to the sulfanilamide molecule.2 Deaths caused by 2-(p-aminobenzenesulfonamido)-5-isopropyl-thiadiazole [IPTD] due to hypoglycemia during the treatment of typhoid fever in 1940s limelighted the antidiabetic action of sulfonylureas.3 Carbutamide and tolbutamide are the antidiabetic drug molecules which initially entered the market from the sulfonylurea class in the 1950s.4 Antidiabetic SU drugs which are currently in market are divided mainly into three categories based on their structure, potency, safety, and time of invention: first generation SU drugs (acetohexamide, chlorpropamide, tolbutamide, tolazamide); second generation SU drugs (glibenclamide, glipizide, gliclazide); third generation (glimepiride) (Figure 1).5 Second and third generation SU drugs require less dosage, show longer duration of action, and have larger R1 groups in their structure in comparison with first generation SU drugs.6,7 In addition to antidiabetic effects, sulfonylureas are proven to have wide range of therapeutic applications such as antihypertensive,6 anticancer,8 antimalarial,9 antibacterial,10 herbicidal,11 and so forth. SU hypoglycemic drugs are sparingly soluble in water and cannot be converted to salts to increase the bioavailability.12 SU compounds are very potent, and small variations in bioavailability can significantly affect the pharmacokinetics and pharmacodynamics (PKPD) of the drug.13 Scientists working in molecular pharmaceutics are interested in developing polymorphs of SU which show an improved bioavailability profile.14-16 Atomic level information related to the arrangement of molecular units is helpful in understanding the differences in various polymorphs. Crystallographic analyses of sulfonylureas were extensively carried out to get an insight regarding the intermolecular interactions in the solid state.17-27 * Corresponding author: Prasad V. Bharatam, Ph.D. Phone: +91-1722292018. Fax: +91-172-2214692; alt: +91-9417503172. E-mail: [email protected].

The physical properties like polymorphic preferences and their influence on the therapeutic activity of SU hypoglycemics have been reported over the decades. In the 1970s Burger classified five polymorphic forms for the SU analogue tolbutamide (form I to V)20 based on their thermodynamic stability which are reevaluated further by Kimura et al.21 On the basis of FT-IR structural analysis Takla and Dakas18 reported that the polymorphic states in acetohexamide are due to keto-enol tautomerism (structural polymorphism). Stephenson et al.24 rejected the possibility of enol form in any of the polymorphs of acetohexamide but proposed two polymorphic states acetohexamide A and B based on the relative arrangement of the adjacent molecules (crystal packing polymorphism) based on 13C NMR technique and crystal structure. Subsequently, Stephenson reported that more stable acetohexamide A exists in parallel, while acetohexamide B exists in antiparallel arrangement.25 Chakravarty et al. reported that, for tolbutamide, the form III polymorph is similar to acetohexamide A and comparatively more stable than form I based on solubility and dissolution experiments.16 Boldyreva and co-workers have extensively studied polymorphism in chorpropamide using crystal structure analysis and proposed four polymorphs (R, β, γ, and δ) based on variations in the alkyl side chain.14,15,23 Ueda and co-workers have reported two polymorphs of glimepiride and their temperature-mediated transition behavior.22 Crystal structures for other SU drugs like torasemide,28 glibenclamide,29 glisentide,30 and tolbutamide21 have also been reported in literature. Unlike sulfonamide derivatives, SU derivatives exhibit polymorphism not only because of differences in packing arrangements but also because of the conformational preferences. Many studies have been carried out to understand conformational preferences of SU and to estimate the lowest energy conformation (LEC). Lins et al. utilized the semiempirical method with simplex minimization for conformational analysis of the gliquidone molecule.31 They claimed U-shaped conformation as the LEC under the gas-phase condition in which both hydrophobic rings are at the end of the U-shaped structure with urea amide nitrogen at the bottom of U-shape. This gas-phase study using the force field method may have a limitation, as

10.1021/jp101327k  2010 American Chemical Society Published on Web 08/18/2010

11604

J. Phys. Chem. B, Vol. 114, No. 35, 2010

Kasetti et al. Lins is the LEC in vacuo, but explicit aqueous solvent conditions stabilized the extended conformation more than the U-shaped conformation. It was suggested that the availability of good H-bond donors and acceptors in sulfonylurea analogues prefer the extended form in water, while under gas-phase conditions hydrophobic interactions prevail to prefer U-shape. Remko reported the theoretical studies on the structure of a few sulfonylurea based hypoglycemic agents.35 Geometries, energies, physicochemical properties (ex. XLOGP2), and solvent effects were studied; however, conformational preferences have not been evaluated. Intramolecular hydrogen bonds are reported on the basis of distances, which is not a sufficient condition for intramolecular hydrogen bonds.35 Though many computational studies, as above, are taken up on SU derivatives, no attempt has been made to understand electronic structure of SU moiety and correlate it to the intermolecular interactions. In the present study we carried out quantum chemical analysis of SU moiety including its tautomeric preferences and its various chemically feasible dimeric molecular arrangements so as to understand the electronic structure as well as intermolecular interactions using ab initio MO (molecular orbital)36 and DFT (density functional theory)37 quantum chemical methods. In most of medicinal chemistry literature SU drugs are written as in I. Structure II represents the crystal structure conformation of most SU drugs, while structure III is a conformation found in the crystal structure glimepiride, the latest second generation SU on the market (Figure 2). Electronically I suffers from lone pair-lone pair repulsion between amide oxygen and sulfoxide oxygens, while conformation II is a simplistic representation which maintains the trans arrangement across both of the amide bonds and is partially devoid of repulsive interactions in comparison to I. In III, one of the amide bonds adopts a cis arrangement (which usually is not the preferred arrangement), but it is characterized by a stabilizing intramolecular hydrogen bond. Our preliminary semiempirical quantum chemical analysis of I, II, and III using PM338 method suggested III to be more stable than the generally written structure I and the crystal structure conformation II of many SU drugs. The abovementioned background work prompted us to carry out the extensive conformational and tautomeric analysis of this privileged sulfonylurea moiety. Quantum chemical analysis has been performed on the model sulfonylurea PhSO2NH-C(dO)NH-CH3 (SLU).

Figure 1. Different generations of sulfonylurea antidiabetic drug molecules.

these methods are known to overestimate the hydrophobic forces arising from the proximity of the cyclohexyl and aromatic ring in a U-shaped conformation (Liao et al.).32 Grell et al. employed the ab initio Hartee-Fock method (HF/6-31G*) for calculating energies of U-shaped conformation and the extended conformations of selected SU drugs. It was found that the U-shaped conformation is 1.3 and 2.1 kcal/mol less stable than the extended conformation for glibenclamide and glimepiride, respectively.33 Yuriev et al. used the Monte Carlo conformational analysis of glibenclamide analogues in vacuo and in explicit aqueous solution to find out the LEC.34 However, they mainly emphasized on the ethyl linker and benzamide group of the side chain of glibenclamide molecule to find out the stability of U-shaped conformation versus the extended conformation. During the systematic Monte Carlo search, they have ignored the torsional freedom across the SU moiety because both the amide bonds of SU moiety are found in the expected trans arrangement in the crystal structures of most of the SU drugs. They concluded that the U-shaped conformation proposed by

Computational Details Ab initio MO and DFT calculations have been carried out using the GAUSSIAN03 software package.39 Complete optimizations have been performed on various rotamers and tautomers (SLU-1 to SLU-11), transition states, and various dimeric arrangements of conformers of the model SU moiety using HF (Hartree-Fock), B3LYP (Becke3, Lee, Yang, Parr), and MP2 (Moeller-Plesset perturbation) methods with the 6-31+G(d,p) basis set. Solvent level optimization studies (using RMIN ) 0.5, OFAC ) 0.8) have been performed using the integral equation formalism versions of the polarizable continuum model (IEFPCM) method40 at 6-31+G(d,p) basis set. Frequencies were computed analytically for all of the optimized monomeric species at all levels to characterize each stationary point as a minimum or a transition state. A few representative drugs of first and second generation SU have also been optimized using the B3LYP/6-31+G(d,p) method to understand the differences in the conformational preferences in the crystal structure of both of the generations. Intramolecular H-bonding is confirmed by AIM (atoms in molecules)41 calculations using

Conformational Polymorphism in Sulfonylurea Drugs

J. Phys. Chem. B, Vol. 114, No. 35, 2010 11605

Figure 2. Three important conformations of sulfonylurea.

Figure 3. (a) 2D structures of conformers of the model SU moiety. (b) Optimized 3D geometries of SLU-1 to SLU-11; intramolecular hydrogen bond distances are given in Å units.

AIM2000 software package;41e NBO (natural bond orbital)42 analysis has been employed in the estimation of partial atomic charges. NICS (nuclear independent chemical shift)43 values were obtained using the GIAO44 method using B3LYP/631+G(d,p) geometries to get the extent of electronic delocalization in the ring-forming conformations. The energy and geometric parameters used in the discussion are from the B3LYP/6-31+G(d,p) method unless otherwise specifically mentioned. Results and Discussion Electronic Structure and Conformational Analysis. 3-(Phenyl)-sulfonyl-1-methylurea, SLU, has been considered as a model for antidiabetic sulfonylurea derivatives. Around 20 rotamers and tautomers based on chemically feasible 3D geometries were considered for SLU in the present study. Initially, semiempirical PM3 method was used for geometry optimization. After excluding conformers with very high energy and chemically unimportant structures at PM3 level, 14 conformers were selected for further analysis using more accurate HF, B3LYP, and MP2 methods. The higher level quantum chemical analysis led to the identification of 11 relevant conformers (SLU-1 to SLU-11, Figure 3a) 3D structures of which are displayed in

Figure 3b, with their relative energies listed in Table 1. SLU-1 is the global minimum conformation as per all of the quantum chemical methods in the study. Surprisingly, this conformation was not given any consideration in the previous computational conformational analyses30,31 and in other computational analyses.33-35 SLU-1 is more stable than the generally considered structure SLU-2 by 4.44 kcal/mol at the MP2 level. SLU-1 is characterized by intramolecular hydrogen bonds (N3-H · · · O7S5) with the H-bond length of 2.09, 2.05, and 2.12 Å at HF, B3LYP, and MP2 levels, respectively. The S-O bond involved in intramolecular hydrogen bonding is almost coplanar with N3-C2-N4-S5 frame of SLU-1. This particular arrangement is associated with relatively unfavorable cis conformation across the peptide bond in SLU-1 (H-N4-C2-O1) indicating that the strength of the intramolecular hydrogen bond in the gas phase is strong enough to overcome this unfavorable interaction. AIM calculation also confirmed the presence of intramolecular hydrogen bonds in SLU-1, which is shown by a bond path connecting O7 and H-N3; bond critical point (BCP) is characterized by parameters typical to an intramolecular hydrogen bond, F ) 0.222 × 10-1, 32F ) 0.69 × 10-1, and ε ) 0.675 × 10-1. There is also a ring critical point (RCP) (F ) 0.118 × 10-1) corresponding to a six-membered ring formed due to an

11606

J. Phys. Chem. B, Vol. 114, No. 35, 2010

Kasetti et al.

TABLE 1: Relative Energies of Various Conformers of Model Sulfonyl Urea SLU (in kcal/mol)a,b,c solvent phased water

chloroform

ethanol

conformer

structural description

HF

gas phase MP2

B3LYP

B3LYP

B3LYP

B3LYP

SLU-1 SLU-2 SLU-3 SLU-4 SLU-5 SLU-6 SLU-7 SLU-8 SLU-9 SLU-10 SLU-11 SLU-TS1 SLU-TS2 SLU-TS3

C2-N4 rotamer of SLU-2 generally referred SU structure C2-N3 rotamer of SLU-2 N4-O1 enol of SLU-2 C2-N3 rotamer of SLU-4 C2-N3 rotamer of SLU-1 1,3-H shift tautomer of SLU-1 N4-S5 rotamer of SLU-2 C2-N3 rotamer of SLU-7 N3-O1 enol of SLU-2 C2-N3 rotamer of SLU-9 O1-H(N4) torsional angle is 73° O1-H(N4) torsional angle is 242° transition state for 1,3-H shift in SLU-1

0.00 2.78 4.48 5.59 6.58 8.66 8.27 9.65 11.74 20.44 26.70 ----

0.00 4.44 5.58 6.84 8.19 5.67 9.88 10.18 11.84 17.85 23.18 ----

0.00 4.12 5.01 5.07 5.89 7.39 8.15 9.87 11.30 18.26 23.28 11.24 9.86 34.91

0.00 -1.78 1.64 6.33 6.74 4.66 6.52 0.19 -19.00 23.07 5.00 6.06 39.98

0.00 0.37 2.77 5.98 6. 19 5.26 6.24 1.53 7.22 19.30 24.42 7.24 7.50 38.00

0.00 -1.33 2.24 6.24 6.59 4.86 6.76 1.09 -20.46 -----

a The basis set used for all optimizations is 6-31+G(d,p). b All relative energies are corrected for zero-point vibrational energy. c The ZPE corrected absolute energy values are given as Supporting Information in Tables S1 and S2. d Implicit solvent analysis using the IEFPCM method at B3LYP/6-31+G(d,p) level.

Figure 4. NBO atomic charges of SLU-1.

intramolecular hydrogen bond in SLU-1. No intramolecular hydrogen bond is noticed between S-O · · · H-N4 in any structure SLU-1 to SLU-11 (which was highlighted by Remko35), though the distance is in the range of 2.5 Å as reported earlier.35 NBO charges on sulfoxide oxygen are more negative than on carbonyl oxygen (Figure 4). O7 which is involved in intramolecular hydrogen bond is more negative compared to O6. A partial atomic negative charge (NBO) on N4 (-0.950) is more than that of N3 (-0.697). Two amide bonds (C2-N3 and C2-N4) are present in SLU1; the bond lengths across the two are not equal. The C2-N3 bond length (1.355 Å) is much shorter than the C2-N4 bond length (1.425 Å). Both of the bonds are characterized by the nN f π*CO resonance (second-order electron delocalization) as in urea and thiourea.45 NBO analysis shows that the nN3 f π*CO (E(2) ) 56.81 kcal/mol) is much stronger than the nN4 f π*CO (E(2) ) 23.40 kcal/mol), that is, resonance across C2-N3 bond is much stronger in comparison with the C2-N4 bond, leading to the observed differences in their bond lengths. The weaker resonance across the C2-N4 bond is also reflected in its rotational barrier (7.9 kcal/mol) in comparison to that across the C2-N3 bond (16.32 kcal/mol). The electron occupancy on the lone pairs at N3 (1.717) and N4 (1.807) are much less than two, supporting the resonance across the C2-N3 and C2-N4 bonds: the smaller value at N3 reflects greater delocalization from this atom in comparison to N4. The SO2Ph group at N4 is an electron-withdrawing group, and it reduces electron density at N4; thus, the second-order delocalization from N4 is weaker, and the C2-N4 bond length is longer. The N3-C2-N4-

S5-O7-H ring in SLU-1 also is characterized by partial aromatic character as indicated by the relatively strong nuclear independent chemical shift (NICS) value (-3.43) at the center of the ring; this aromaticity is probably associated with the resonance assisted hydrogen bond in the ring.46 SLU-2, the most referred to structure of SU, is the C2-N4 rotamer of the global minimum structure SLU-1. SLU-2 is characterized by favorable trans arrangement of both peptide bonds of SU moiety but lacks the stabilizing intramolecular hydrogen bonding in contrast to SLU-1. The energy difference between SLU-1 and SLU-2 is only about 4 kcal/mol; it is worth exploring the energy barrier for the interconversion of these rotamers. Complete optimizations have also been performed on the transition states between the two medicinally important rotamers SLU-1 and SLU-2. Two transition states have been identified on the C2-N4 rotational path in SLU-1, with 11.24 and 9.86 kcal/mol barriers, indicating that interconversion between SLU-1 and SLU-2 is an energetically favorable process (Figure 5). In the aqueous phase, however, the energy difference between SLU-1 and SLU-2 is quite small (i.e., ∼1.78 kcal/mol; SCRF calculation using IEFPCM (solvent ) water) method and B3LYP/6-31+G(d,p) quantum chemical method), favoring SLU-2. The rotational barrier has been found to be 6.06 kcal/ mol in aqueous phase; thus in the solution phase, an equilibrium between the two structures, SLU-1 and SLU-2, can be expected. In chloroform medium, SLU-1 is only marginally more stable (0.37 kcal/mol) with ∼7.5 kcal/mol barrier for SLU-1 to SLU-2 interconversion. This data indicate that the intramolecular hydrogen bond in SLU-1 becomes quite weak in the solution phase with an increase in the dielectric constant of the medium, and the strength of the intramolecular hydrogen bond gets weakened, leading to the observed reversal of relative stabilities in aqueous phase (Figure 5). Second-order delocalization energy for nN3 f π*CO (E(2) ) 31.71 kcal/mol) in SLU-2 is much lower in comparison to that of SLU-1 (E(2) ) 56.81 kcal/mol), while for nN4 f π*CO second-order energy delocalization is weaker (E(2) ) 23.40 kcal/mol). This is further supported by the larger C2-N3 bond length (1.369 Å) in SLU-2 in comparison to that in SLU-1 (1.355 Å). SLU-3 is a C2-N3 rotamer of SLU-2; it is marginally less stable because of increased intramolecular steric interactions.

Conformational Polymorphism in Sulfonylurea Drugs

Figure 5. Potential energy surface along the C2-N4 rotational path between SLU-1 and SLU-2 in gas and solvent phases. The torsional angles noted as per gas phase calculations are given along the X-axis; the deviations in other media are minimal.

SLU-4 and SLU-5 are iminol tautomers (N4----O1) of SLU-2; these are characterized by intramolecular hydrogen bonds of 1.65 Å and 1.63 Å, respectively, at B3LYP level. These tautomers respectively are only about 5.07 and 5.87 kcal/mol less stable than SLU-1; they are quite competitive alternatives to the structures SLU-1 and SLU-2 on the potential energy surface. As per the SCRF calculations (in water) these tautomers are (SLU-4 and SLU-5) 6.33 and 6.74 kcal/mol less stable than SLU-1, indicating that the possibility of tautomerism is quite high in gas phase as well as in solvent phase. Tautomerism arising from the proton on N3 appears to be difficult because the resulting tautomers (SLU-10 and SLU-11) are higher energy (> 18 kcal/mol) isomers. Intramolecular hydrogen bonding in structures SLU-4, SLU-5, SLU-7, SLU-10, and SLU-11 is also confirmed using the AIM method as they are characterized by corresponding BCPs and RCPs. Sulfoxide enol tautotmers with S-OH units are not minima at B3LYP and MP2 methods and optimized to corresponding ketone enols (SLU-4 and SLU-5). In HF method, sulfur enols are optimized as minima but at relatively very high energy. N3-O1 enols (SLU-10 and SLU11) are relatively less stable as compared to N4-O1 enols (SLU-4 and SLU-5). This can be attributed to the stronger intramolecular hydrogen bonding interactions in SLU-4 and SLU-5. The tautomer SLU-7 (an iminol tautomer of SLU-1) is also a relatively high energy tautomer. The tautomerism in sulfonylureas might be taking place through the 1,3-H shift. Under gas-phase conditions, the tautomerization of the SLU-1 to SLU-7 is having the 1,3-H shift transition state barrier of 34.91 kcal/mol. Under solvent conditions the transition state barrier is increased to 38.00 kcal/ mol in chloroform solvent, whereas in water medium the barrier is higher (40.05 kcal/mol). Since these barriers are high, the bimolecular pathway involving proton exchange may be associated with the tautomerization. The deprotonation energy from N4 in SLU-1 has been estimated to be 331.07 kcal/mol. The anion SLU-a is characterized by two lone pairs of electrons on N4. HOMO and HOMO-1 are lone pairs of electrons; NLMO analysis shows the two lone pairs to be fully populated with two electrons, whereas NBO analysis shows that HOMO and HOMO-1 contain 1.872 and 1.640 electron densities, respectively. The deprotonation energy in SLU-1 from N4 (331.07

J. Phys. Chem. B, Vol. 114, No. 35, 2010 11607 kcal/mol) is much smaller than that of the deprotonation energy from N3 (345.82 kcal/mol), suggesting that a bimolecular process also prefers tautomerization arising from N4 rather than N3. It is intriguing to note that the deprotonation energy at N4 position is (331.07 kcal/mol) much less than that of acetic acid (344.44 kcal/mol), indicating that the proton at N4 is highly acidic. The high acidity at N4 position may be attributed to the resonance stabilization of the corresponding anion. The isomers SLU-6 to SLU-9 are slightly high energy rotamers of SLU-1; they may have an only transient existence on the potential energy surface of SLU. A computationally estimated dipole moment in the SLU-1 conformer is 4.6 D, and the dipole moment of the SLU-2 conformer is 5.3 D, which indicates that SLU-2 will be highly stable in polar media like water, in comparison with the SLU-1 conformer. Because of the larger dipole moment of SLU-2, it undergoes higher solvation with a more polar solvent. It has been observed that both solvents, chloroform and water, can better solvate SLU-2 than SLU-1; this is because of the extended structure of the SLU-2 conformer. Conformations of SU Drugs. Gas-phase geometry optimizations have been performed on several SU drugs at the B3LYP/ 6-31+G(d,p) level to obtain their isomeric preferences. In all cases, the structure with intramolecular hydrogen bond (similar to that in SLU-1) has been found to be more stable. In all of the cases, the next preferred conformation is only slightly less stable: acetohexamide (3.93 kcal/mol), carbutamide (4.68 kcal/ mol), chlorpropamide (3.89 kcal/mol), gliburide (4.97 kcal/mol), gliclazide (3.54 kcal/mol), glimepiride (4.67 kcal/mol), gliquidone (4.76 kcal/mol), and tolbutamide (4.14 kcal/mol). Further solvent effect data of acetohexamide clearly indicate that the preference for a SLU-1 type structure gets reduced with an increase in the dielectric constant of the medium: gas phase (3.93 kcal/mol), chloroform (0.80 kcal/mol), ethanol (-1.56 kcal/mol), and water (-1.36 kcal/mol). This data indicate that the isomeric preferences in SU drugs are quite delicately balanced as a function of solvent medium and thus are responsible for the observed several polymorphic states of this class of drugs.35 The general trend is that less polar solvents lead to structures similar to SLU-1, whereas polar solvents prefer structures similar to SLU-2. The 3D structures of the above drug molecules obtained using the B3LYP/6-31+G(d,p) method and their energies are given in Supporting Information (SI: Table S4, Table S5, and Figure S1). The SU drugs tolbutamide, gliclazide, glimepiride, glipizide, and glibenclamide are shown to be weakly acidic with pKa values of 5.3, 5.8, 6.2, 5.9, and 6.0, respectively.47 Also, they are shown to exist in ionic state in solution, wherein ionization is expected to originate from the N4 position. The above quantum chemical analysis clearly supports the observation. Intermolecular Interactions in Dimers and Their Possible Contribution to Polymorphism. The above electronic structure study revealed that the isomers SLU-1 to SLU-5 can exist in equilibrium in the gas phase. However, in the solid state, molecules with similar conformation exist in close proximity to each other; hence we have to consider bulk properties and intermolecular interactions to extrapolate the above analyses to crystal structure stability by understanding the intermolecular arrangements of similar conformations. SU derivatives demonstrate two types of polymorphism, that is, conformational and packing arrangement. As per the available crystal structure data, acetohexamide24,25 and chlorpropamide14,15 exist in different packing arrangements of SLU-2 conformation. Tolazamide48 exhibits SLU-3 conformation, and glimepiride49 exhibits SLU-1

11608

J. Phys. Chem. B, Vol. 114, No. 35, 2010

Kasetti et al.

Figure 6. Optimized 3D structures of D1-D12 with inter- and intramolecular hydrogen bond distances given in Å.

conformation. Acetohexamide exhibits two polymorphs based on differences in packing arrangements: form A (parallel arranged SLU-2) and form B (antiparallel SLU-2). The limited structural analysis carried out on various polymorphic states did not yet provided any simple atomic level description. To address this issue, we have computationally generated 12 chemically significant and feasible dimeric molecular arrangements of model SU moiety from the four LECs (SLU-1, SLU-2, SLU3, and SLU-4) (Figure S3 of the SI and Figure 6) with their relative energies mentioned in Table 2. Although this analysis is not exhaustive, it provides some relevant atomic level details. D1-D4 are dimers which can be formed from SLU-1. The most stable dimer under gas-phase conditions is D1 with an anti arrangement across the two monomers (Table 2). D2 differs from D1 in terms of stereochemistry at the S atom; it is relatively less stable by 1.05 kcal/mol. On the other hand, the syn isomers D3 and D4 are much less stable with relative energies 4.96 and 8.20 kcal/mol. Table 2 lists the relative energies of dimers

D1-D12 as well as stabilization energy due to dimer formation from the monomers, estimated using the B3LYP/6-31+G(d,p) level. The D1 formation leads to a stabilization of up to 13.38 kcal/mol. D1 is characterized by two intermolecular hydrogen bonds and two strong intramolecular hydrogen bonds. AIM calculations indicated the presence of two BCPs and one RCP between the two monomeric units. The intermolecular hydrogen bond length between two monomers is 1.81 Å, indicating a very strong hydrogen bond. The F ) 0.0343 positive laplacian 32F ) 0.1020 and the ellipticity ε ) 0.0391 at the intermolecular BCP in D1 are clearly indicative of a typical hydrogen bond. The intramolecular hydrogen bond in the SLU-1 unit in D1 is 1.98 Å, which is smaller than that in SLU-1 (2.05 Å), indicating that this intramolecular interaction becomes stronger upon dimerization. D5, D6, and D7 are possible dimers of SLU-2; D8 could not be located on the PE surface (the structure got distorted upon complete optimization). On a relative scale, D5 is much less

Conformational Polymorphism in Sulfonylurea Drugs TABLE 2: Relative Energies (Gas Phase) of Dimeric SLUs (D1-D12) and Their Stabilization Energies Obtained Using the B3LYP/6-31+G (d,p) Methoda relative energyb (kcal/mol) solvent phased dimer

gas phase

water

chloroform

molecular unit

D1 D2 D3 D4 D5 D6 D7 D8e D9 D10 D11 D12

0.00 1.05 4.96 8.20 9.52 9.88 12.06 -10.44 11.42 20.25 23.18

0.00 -1.14 3.09 -2.85 -2.35 -1.29 -2.75 4.01 -16.25

0.00 -1.54 3.87 0.90 1.75 2.77 -5.57 5.95 -18.09

SLU-1 SLU-1 SLU-1 SLU-1 SLU-2 SLU-2 SLU-2 SLU-2 SLU-3 SLU-3 SLU-4 SLU-4

gas phase stabilization energyc (kcal/mol) 13.38 12.33 8.42 5.18 12.10 11.74 9.55 12.97 11.99 3.26 0.34

a The ZPE corrected absolute energy values are given as SI in Table S3. b Relative energies of D1-D12. c Gas-phase stabilization energy due to dimer formation from various SLUs. d Implicit solvent analysis using the IEFPCM level using the B3LYP/ 6-31+G(d,p) method. e D8 structure is distorted during the optimization of the sulfonylurea dimer (see SI, Figure S3).

stable compared to D1 by 9.52 kcal/mol, indicating that dimer formation from isomer SLU-1 should be more thermodynamically favorable in the gas phase. The calculated stabilization energy due to the formation of D5 from its monomer units in the gas phase is 12.10 kcal/mol. There are three intermolecular hydrogen bonds in D5 (Figure 6), with bond lengths 1.91, 2.33, and 2.36 Å; the longer ones are due to bifurcated hydrogen bonding interactions. AIM calculations also support the presence of three intermolecular hydrogen bonds in D5. Though there are three intermolecular hydrogen bonds in D5, overall strength appears to be weaker than the two intermolecular hydrogen bonds in D1. This observation provides strong evidence that varying hydrogen bond strengths play an important role in the polymorphic preferences of sulfonylurea derivatives. D6 and D7 are marginally less preferred than D5 but are much less preferred in comparison to D1 in terms of relative energy. D9-D10 are dimers originating from SLU-3. These dimers are also characterized by two intermolecular hydrogen bonds but no intramolecular hydrogen bonds. The two intermolecular hydrogen bonds in D9 are very strong as per geometric as well as AIM analysis. On a relative energy scale, D9 and D10 are about 10.44 and 11.42 kcal/mol less stable than D1 in the gas phase at the B3LYP/6-31+G(d,p) level. The stabilization energy due to the formation of D9 and D10 from SLU-3 are 12.97 and 11.99 kcal/mol, respectively, at the B3LYP/6-31+G(d,p) level. These energetic parameters are quite comparable to that of D5-D7. D11 and D12 are dimers of SLU-4; they are high energy dimers with 20.25 and 23.18 kcal/mol relative energy in comparison to D1. The stabilization energy due to their formation is very small, -3.26 kcal/mol for D11 and 0.34 kcal/ mol for D12. These values clearly indicate the formation of the dimers, and hence the polymorphs with such an arrangement (D11, D12) should not be possible. This result is in accordance with the suggestion by Stephenson et al.,24,25 who proposed that the polymorphism in acetohexamide cannot originate from the tautomeric states of sulfonylurea derivatives. Recent crystallographic analysis22,49 showed that solvent plays an important role in the crystal structure of SU. The crystallization was carried out in an ethanol-water preferred structure similar to SLU-2,22 whereas crystal structure obtained using chloroform preferred a structure similar to SLU-1 for the

J. Phys. Chem. B, Vol. 114, No. 35, 2010 11609 glimepiride compound.49 SCRF calculations using water and chloroform indicated different energetic preferences between SLU-1 and SLU-2. The relative energies of D1, D5, and D9 in chloroform are 0.00, 0.89, and 5.56 kcal/mol, respectively. These values are much smaller than the relative energies reported in the gas phase, indicating that solvents strongly influence the relative preferences of dimers. The relative energies of D1, D5, and D9 in water medium are 0.00, -2.84, and 2.74 kcal/mol, respectively. D5 becomes relatively more stable than D1 in water. D1 and D5 show exchanged dimer preferences in chloroform and water (also applies to D6, D7). This is in accordance with the observed structural differences of glimepiride in these two media. Experimental hydrogen bond lengths of dimers can be compared with the hydrogen bond lengths of theoretical studies. According to solvent phase calculations in the chloroform phase, the intermolecular hydrogen bond lengths of D1 (when two SLU-1 monomers were making complex) are ∼1.8 Å which is in accordance to the experimental studies.49 According to solvent-phase calculations in aqueous phase, the intermolecular hydrogen bond lengths of D5 when two SLU-2 monomers were making a complex are also comparable to experimental studies. This indicates that the polymorphic states of SU drugs are highly susceptible to solvents employed in the study. Also small energetic differences can lead to large structural differences in the polymorphs. This analysis also suggests that the polymorphic differences can be traced to atomic level details with the help of quantum chemical methods, and thus quantum chemical methods can be employed to predict the polymorphic differences of drugs successfully. Conclusions Quantum chemical analysis of the SU moiety was carried out to understand conformational preferences in the gas phase and extrapolated to solid state stability. Calculations on the model system PhSO2NHC(dO)NHMe indicated that the most preferred conformation, SLU-1, is characterized by intramolecular hydrogen bonds. Surprisingly, this conformation was not considered in the previous studies on the conformational analysis of SU derivatives. Rotamer SLU-2, which was always considered as the best conformer in the previous studies, has been found to be about 4.12 kcal/mol less stable in the gas phase; however, the energy difference between the two rotamers gets reduced in solvent media. In chloroform medium, SLU-1 is more stable by 0.37 kcal/mol, and in water medium, SLU-2 is more stable by 1.78 kcal/mol. B3LYP/6-31+G(d,p) calculations on many known drugs of SU class confirmed this pattern, thus explaining the observed structural differences from the crystal structure analyses. Rotational barriers across the potential energy curve for the interconversion of SLU-1 and SLU-2 are 11.24 and 9.86 kcal/mol through two different transition states. This barrier can be easily overcome under solvent conditions; hence, there is a delicate balance of conformational preferences in the solution phase. SUs may adopt the tautomeric state in equilibrium because enol tautomers SLU-4 and SLU-5 have been shown to be low energy isomers of SLU-1 in both the gas phase and the solvent phase. The dimeric D1 (antiparallel SLU-1) arrangement is thermodynamically most stable. Thus, SLU-1 is the preferred conformation in a single molecule as well as in the dimeric state. Solvent-level calculations show that an aprotic, moderately polar solvent like chloroform prefers SLU-1, while a polar protic solvent like water prefers SLU-2 conformation. The differences observed in the molecular interactions in the dimers D1 and D5 provide a clear understanding of the observed polymorphic differences in the

11610

J. Phys. Chem. B, Vol. 114, No. 35, 2010

sulfonylurea drug glimepiride crystallized from two different media. The present study estimated D1, which is arranged antiparallel of SLU-1 to be the most stable dimeric arrangement in all of the possible dimeric arrangements considered. This more thermodynamic stability of D1 in comparison with D5 provides an explanation for the poor solubility of glimepiride form I as compared to form II in phosphate buffer. Acknowledgment. P.V.B. thanks the Department of Science and Technology (DST), Nano mission, New Delhi and NIPER, S. A. S. Nagar for financial support. Y.K. thanks the Council of Scientific and Industrial Research (CSIR), New Delhi for financial support. Supporting Information Available: Tables S1-S22 with absolute energies of species under consideration and secondorder perturbation analysis using NBO analysis as well as the Cartesian coordinates of all geometry optimized molecules reported in the paper. This material is available free of charge via the Internet at http://pubs.acs.org. References and Notes (1) Bolen, S.; Feldman, L.; Vassy, J.; Wilson, L.; Yeh, H. C.; Marinopoulos, S.; Wiley, C.; Selvin, E.; Wilson, R.; Bass, E. B. Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann. Intern. Med. 2007, 147, 386–399. (2) Kurzer, F. Sulfonylureas and Sulfonylthioureas. Chem. ReV. 1952, 50, 1–46. (3) Janbon, M.; Chaptal, J.; Vedel, A.; Schaap, J. Accidents hypoglyce´miques graves par un sulfamidothiodiazol (le VK 57 ou 2254 RP). Montpellier Med. 1942, 21, 441–444. (4) Fonseca, V. A. Clinical diabetes: translating research into practice, illustrated ed.; Elsevier Health Sciences: Philadelphia, PA, 2006; pp 293304. (5) Luna, B.; Feinglos, M. N. Oral Agents In The Management of Type 2 Diabetes Mellitus. Am. Fam. Physician 2001, 63, 1747–1756. (6) Deprez, P.; Heckmann, B.; Corbier, A. Balanced AT1 and AT2 Angiotensin Antagonists. I. New Orally Active 5-Corboxyl Imidazolyl Biphenyl Sulfonylureas. Bioorg. Med. Chem. Lett. 1995, 5, 2605–2610. (7) Moller, D. E. New Drug Targets for Type 2 Diabetes and The Metabolic Syndrome. Nature 2001, 414, 821–827. (8) Mohamadi, F.; Spees, M. M.; Grindey, G. B. Sulfonylureas: a new class of cancer chemotherapeutic agents. J. Med. Chem. 1992, 35, 3012– 3016. (9) Leo´n, C.; Rodrigues, J.; Gamboa de Domınguez, N.; Charris, J.; Gut, J.; Rosenthal, P. J.; Domınguez, J. N. Synthesis and evaluation of sulfonylurea derivatives as novel antimalarials. Eur. J. Med. Chem. 2007, 42, 735–742. (10) Wang, J.; Xiao, Y.; Li, Y.; Ma, Y.; Li, Z. Identification of Some Novel AHAS Inhibitors via Molecular Docking and Virtual Screening Approach. Bioorg. Med. Chem. 2007, 15, 374–380. (11) LaRossa, R. A.; Schloss, J. V. The sulfonylurea herbicide sulfometuron methyl is an extremely potent and selective inhibitor of acetolactate synthase in Salmonella typhimurium. J. Biol. Chem. 1984, 259, 8753–8757. (12) Yokoyama, T.; Umeda, T.; Kuroda, K.; Sato, K.; Takagishi, Y. Studies on drug nonequivalence. VII. Bioavailability of acetohexamide polymorphs. Chem. Pharm. Bull. 1879, 27, 1476–1478. (13) Melander, A.; Bitzen, P. O.; Faber, O.; Groop, L. Sulphonylurea Antidiabetic Drugs An Update of Their Clinical Pharmacology and Rational Therapeutic Use. Drugs 1989, 37, 58–72. (14) Drebushchak, T. N.; Chukanov, N. V.; Boldyreva, E. V. A New Polymorph of Chlorpropamide: 4-chloro-N-(propylaminocarbonyl)benzenesulfonamide. Acta Crystallogr., Sect. E: Struct. Rep. Online 2006, E62, o4393–o4395. (15) Drebushchak, T. N.; Chukanov, N. V.; Boldyreva, E. V. A New γ-Polymorph of Chlorpropamide: 4-chloro-N-(propylaminocarbonyl)benzenesulfonamide. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2007, C63, o355–o357. (16) Chakravarty, P.; Alexander, K. S.; Riga, A. T.; Chatterjee, K. Crystal Forms of Tolbutamide from Acetonitrile and 1-octanol: Effect of Solvent, Humidity and Compression Pressure. Int. J. Pharm. 2005, 288, 335–348. (17) Takla, P. G.; Chroneos, I. The Polymorphism of Acetohexamide. J. Pharm. Pharmacol. 1977, 29, 640–642. (18) Takla, P. G.; Dakas, C. J. An Infrared Study of Tautomerism in Acetohexamide Polymorphs. J. Pharm. Pharmacol. 1989, 41, 227–230. (19) Rowe, E. L.; Anderson, B. D. Thermodynamic Studies of Tolbutamide Polymorphs. J. Pharm. Sci. 1984, 73, 1673–1675.

Kasetti et al. (20) Burger, A. Zur polymorphie oraler antidiabetika. Sci. Pharm. 1975, 43, 161–168. (21) Kimura, K.; Hirayama, F.; Uekama, K. Characterization of Tolbutamide Polymorphs (Burger’s Forms II and IV) and Polymorphic Transition Behavior. J. Pharm. Sci. 1999, 88, 385–391. (22) Endo, T.; Iwata, M.; Nagase, H.; Shiro, M.; Ueda, H. Polymorphism of Glimepiride: Crystallographic Study, Thermal Transitions Behavior and Dissolution Study. STP Pharma Sci. 2003, 13, 281–286. (23) Boldyreva, E. V.; Dmitriev, V.; Hancock, B. C. Effect of Pressure up to 5.5 GPa on Dry Powder Samples of Chlorpropamide Form-A. Int. J. Pharm. 2006, 327, 51–57. (24) Stephenson, G. A.; Pfeiffer, R. R.; Byrn, S. R. Solid-State Investigation of The Tautomerism of Acetohexamide. Int. J. Pharm. 1997, 146, 93–97. (25) Stephenson, G. A. Structure Determination from Conventional Powder Diffraction Data: Application to Hydrates, Hydrochloride Salts and Metastable Polymorphs. J. Pharm. Sci. 2000, 89, 958–966. (26) Wildfong, P. L. D.; Morris, K. R.; Anderson, C. A.; Short, S. M. Demonstration of a Shear-Based Solid-State Phase Transformation in a Small Molecular Organic System: Chlorpropamide. J. Pharm. Sci. 2007, 96, 1100–1113. (27) Moller, D. E. New Drug Targets for Type 2 Diabetes and The Metabolic Syndrome. Nature 2001, 414, 821–827. (28) Rollinger, J. M.; Gstrein, E. M.; Burger, A. Crystal forms of torasemide: new insights. Eur. J. Pharm. Biopharm. 2002, 53, 75–86. (29) Panagopoulou-Kaplani, A.; Malamataris, S. Preparation and Characterization of a New Insoluble Polymorph Form of Glibenclamide. Int. J. Pharm. 2000, 195, 239–246. (30) Zornoza, A.; de No, C.; Martin, C.; Goni, M. M.; Martinez Oharriz, M. C.; Velaz, I. Evidence for Polymorphism in Glisentide. Int. J. Pharm. 1999, 186, 199–204. (31) Lins, L.; Brasseur, R.; Malaisse, W. J. Pharmacology of The Hypoglycaemic Sulphonylurea Gliquidone III. Conformational Analysis. Pharmacol. Res. 1996, 34, 9–10. (32) Liao, C.; Xie, A.; Zhou, J.; Shi, L.; Li, Z.; Lu, X.-P. 3D QSAR Studies on Peroxisome Proliferator-Activated Receptor γ Agonists Using CoMFA and CoMSIA. J. Mol. Model. 2004, 10, 165–177. (33) Grell, W.; Hurnaus, R.; Griss, G.; Sauter, R.; Rupprecht, E.; Mark, M.; Luger, P.; Nar, H.; Wittneben, H.; Muller, P. Repaglinide and Related Hypoglycemic Benzoic Acid Derivatives. J. Med. Chem. 1998, 41, 5219– 5246. (34) Yuriev, E.; Kong, D. C. M.; Iskander, M. N. Investigation of Structure-Activity Relationships in a Series of Glibenclamide Analogues. Eur. J. Med. Chem. 2004, 39, 835–847. (35) Remko, M. Theoretical study of molecular structure, pKa, lipophilicity, solubility, absorption, and polar surface area of some hypoglycemic agents. J. Mol. Struct: THEOCHEM 2009, 897, 73–82. (36) (a) Hehre, W. J.; Radom, L.; Schleyer, P. V. R.; Pople, J. A. Ab Initio Molecular Orbital Theory; Wiley: New York, 1985. (b) Foresman, J. B.; Frisch, Æ. Exploring Chemistry with Electronic Structure Methods; Gaussian Inc.: Pittsburgh, PA, 1998. (c) Ochterski, J. W. Thermochemistry in Gaussian. http:// Gaussian.com/g_whitepap/thermo.htm (accessed Feb 11, 2010). (37) (a) Parr, R. G.; Yang, W. Density Functional Theory of Atoms and Molecules; Oxford University Press: New York, 1989. (b) Bartolotti, L. J.; Fluchick, K. In ReViews in Computational Chemistry; Lipkowitz, K. B., Boyd, D. B., Eds.; VCH Publishers: New York, 1996; Vol. 7, pp 187216. (38) (a) Stewart, J. J. P. Optimization of parameters for semiempirical methods I. Method. J. Comput. Chem. 1989, 10, 209–220. Stewart, J. J. P. Optimization of parameters for semiempirical methods II. Applications. J. Comput. Chem. 1989, 10, 221–264. (39) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A.; Vreven, T., Jr.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian-03 suite of programs; Gaussian, Inc.: Pittsburgh, PA, 2003. (40) Cance`s, M. T.; Mennucci, B.; Tomasi, J. Evaluation of solvent effects in isotropic and anisotropic dielectrics, and in ionic solutions with a unified integral equation method: theoretical bases, computational implementation and numerical applications. J. Chem. Phys. 1997, 107, 3032– 3041.

Conformational Polymorphism in Sulfonylurea Drugs (41) (a) Popelier, P. Atoms in Molecules, An Introduction; Prentice Hall, Pearson Education Limited: New York, 2000. (b) Koch, U.; Popelier, P. L. A. Characterization of CHO hydrogen bonds on the basis of the charge density. J. Phys. Chem. 1995, 99, 9747–9754. (c) Bader, R. F. W. Atom in Molecules. A Quantum Theory; Oxford University Press: Oxford, U.K., 1992. (d) Bader, R. F. W. A quantum theory of molecular structure and its applications. Chem. ReV. 1991, 91, 893–928. (e) Biegler-Ko¨nig, F.; Scho¨nbohm, J.; Bayles, D. J. Comput. Chem. 2001, 22, 545–559; http:// www.aim2000.de. (42) (a) Reed, A. E.; Weinstock, R. B.; Weinhold, F. J. Chem. Phys. 1985, 83, 735–746. (b) Reed, A. E.; Weinhold, F.; Curtiss, L. A. Intermolecular interactions from a natural bond orbital, donor-acceptor viewpoint. Chem. ReV. 1988, 88, 899–926. (43) (a) Schleyer, P. V. R.; Maerker, C.; Dransfeld, A.; Jiao, H. Nucleusindependent chemical shifts: a simple and efficient aromaticity probe. J. Am. Chem. Soc. 1996, 118, 6317–6318. (b) Jiao, H.; Schleyer, P. v. R.; Mo, Y.; McAllister, M. A.; Tidwell, T. T. J. Magnetic Evidence for the Aromaticity and Antiaromaticity of Charged Fluorenyl, Indenyl, and Cyclopentadienyl Systems. J. Am. Chem. Soc. 1997, 119, 7075–7083. (44) London, F. Quantum theory of interatomic currents in aromatic compounds. J. Phys. Radium 1937, 8, 397–409. (45) (a) Bharatam, P. V.; Uppal, P.; Bassi, P. S. Barrier to C-N rotation in selenoformamide: an ab initio study. Chem. Phys. Lett. 1997, 276, 31– 38. (b) Bharatam, P. V.; Moudgil, R.; Kaur, D. Se-N interactions in Selenohydroxyalamine: A Theoretical Study. J. Chem. Soc., Perkin Trans. 2 2000, 2469–2474. (c) Moudgil, R.; Kaur, D.; Vashisht, R.; Bharatam, P. V. Theoretical studies on the conformations of selenamides. J. Chem.

J. Phys. Chem. B, Vol. 114, No. 35, 2010 11611 Sci. 2000, 112, 623–629. (d) Bharatam, P. V.; Moudgil, R.; Kaur, D. Electron delocalization in isocyanates, formamides, and ureas: Importance of orbital interactions. J. Phys. Chem. A 2003, 107, 1627–1634. (46) (a) Krygowski, T. M. Crystallographic studies of inter and intramolecular interactions reflected in aromatic character of electron systems. J. Chem. Inf. Comput. Sci. 1993, 33, 70–78. (b) Gilli, G.; Bellucci, F.; Ferretti, V.; Bertolasi, V. Evidence for resonance-assisted hydrogen bonding from crystal-structure correlations on the enol form of the β-diketone fragment. J. Am. Chem. Soc. 1989, 111, 1023–1028. (47) (a) AbuRuz, S.; Millership, J.; McElnay, J. The development and validation of liquid chromatography method for the simultaneous determination of metformin and glipizide, gliclazide, glibenclamide or glimperide in plasma. J. Chromatogr. B 2005, 817, 277–286. (b) Winters, C. S.; Shields, L.; Timmins, P.; York, P. Solid-state properties and crystal structure of gliclazide. J. Pharm. Sci. 1994, 83, 300–304. (c) Maserrel, B.; Lebrun, P.; Dogno, J. M.; de Tullio, P.; Pirotte, B.; Pochet, L.; Diouf, O.; Delarge, J. Tetrahedron Lett. 1996, 37, 7253–7254. (d) Wishart, D. S.; Knox, C.; Guo, A. C.; Shrivastava, S.; Hassanali, M.; Stothard, P.; Chang, Z.; Woolsey, J. DrugBank: a comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res. 2006, 34, D668–D672. (48) Koo, C. H.; Suh, J. S.; Yeon, Y. H.; Watanabe, T. The crystal and molecular structure of 1-(Hexahydro-1H-azepin-1-yl)-3-(p-tolylsulfonyl) Urea: Tolazamide (C14H21N3O3S). Arch. Pharm. Res. 1988, 11, 74–79. (49) Iwata, M.; Nagase, H.; Endo, T.; Ueda, H. Glimepiride. Acta Crystallogr. 1997, C53, 329–331.

JP101327K