Modularity and three-dimensional isostructurality of novel synthons in sulfonamide-lactam cocrystals.
ABSTRACT: The design of novel supramolecular synthons for functional groups relevant to drugs is an essential prerequisite for applying crystal engineering in the development of novel pharmaceutical cocrystals. It has been convincingly shown over the past decade that molecular level control and modulation can influence the physicochemical properties of drug cocrystals. Whereas considerable advances have been reported on the design of cocrystals for carboxylic acids and carboxamide functional groups, the sulfonamide group, which is a cornerstone of sulfa drugs, is relatively unexplored for reproducible heterosynthon-directed crystal engineering. The occurrence of synthons and isostructurality in sulfonamide-lactam cocrystals (SO2NH2?CONH hydrogen bonding) is analyzed to define a strategy for amide-type GRAS (generally recognized as safe) coformers with sulfonamides. Three types of supramolecular synthons are identified for the N-H donor of sulfonamide hydrogen bonding to the C=O acceptor of amide. Synthon 1: catemer synthon C 2 (1)(4) chain motif, synthon 2: dimer-cyclic ring synthon R 2 (2)(8)R 4 (2)(8) motifs, and synthon 3: dimer-catemer synthon of R 2 (2)(8)C 1 (1)(4)D notation. These heterosynthons of the cocrystals observed in this study are compared with the N-H?O dimer R 2 (2)(8) ring and C(4) chain motifs of the individual sulfonamide structures. The X-ray crystal structures of sulfonamide-lactam cocrystals exhibit interesting isostructurality trends with the same synthon being present. One-dimensional, two-dimensional and three-dimensional isostructurality in crystal structures is associated with isosynthons and due to their recurrence, novel heterosynthons for sulfonamide cocrystals are added to the crystal engineer's toolkit. With the predominance of sulfa drugs in medicine, these new synthons provide rational strategies for the design of binary and potentially ternary cocrystals of sulfonamides.
Project description:A novel design strategy for cocrystals of a sulfonamide drug with pyridine carboxamides and cyclic amides is developed based on synthon identification as well as size and shape match of coformers. Binary adducts of acetazolamide (ACZ) with lactams (valerolactam and caprolactam, VLM, CPR), cyclic amides (2-pyridone, labeled as 2HP and its derivatives MeHP, OMeHP) and pyridine amides (nicotinamide and picolinamide, NAM, PAM) were obtained by manual grinding, and their single crystals by solution crystallization. The heterosynthons in the binary cocrystals of ACZ with these coformers suggested a ternary combination for ACZ with pyridone and nicotinamide. Novel supramolecular synthons of ACZ with lactams and pyridine carboxamides are reported together with binary and ternary cocrystals for a sulfonamide drug. This crystal engineering study resulted in the first ternary cocrystal of acetazolamide with amide coformers, ACZ-NAM-2HP (1:1:1).
Project description:The disposition of functional groups can induce variations in the nature and type of interactions and hence affect the molecular recognition and self-assembly mechanism in cocrystals. To better understand the formation of cocrystals on a molecular level, the effects of disposition of functional groups on the formation of cocrystals were systematically and comprehensively investigated using cresol isomers (o-, m-, p-cresol) as model compounds. Consistency and variability in these cocrystals containing positional isomers were found and analyzed. The structures, molecular recognition and self-assembly mechanism of supramolecular synthons in solution and in their corresponding cocrystals were verified by a combined experimental and theoretical calculation approach. It was found that the heterosynthons (heterotrimer or heterodimer) combined with O-H?N hydrogen bonding played a significant role. Hirshfeld surface analysis and computed interaction energy values were used to determine the hierarchical ordering of the weak interactions. The quantitative analyses of charge transfers and molecular electrostatic potential were also applied to reveal and verify the reasons for consistency and variability. Finally, the molecular recognition, self-assembly and evolution process of the supramolecular synthons in solution were investigated. The results confirm that the supramolecular synthon structures formed initially in solution would be carried over to the final cocrystals, and the supramolecular synthon structures are the precursors of cocrystals and the information memory of the cocrystallization process, which is evidence for classical nucleation theory.
Project description:Sulfonamide drugs are well known antibacterial and antimicrobial molecules for pharmaceutical development. Building a library of suitable supramolecular synthons for the sulfonamide functional group and understanding their crystal structures with partner coformer molecules continues to be a challenge in crystal engineering. Although a few sulfonamide cocrystals with amides and N-oxides have been reported, the body of work on sulfonamide synthons is limited compared with those that have carb-oxy-lic acids and carboxamides. To address this structural gap, the present work is primarily focused on sulfonamide-lactam and sulfonamide-syn-amide synthons with drugs such as celecoxib, hydro-chloro-thia-zide and furosemide. Furthermore, the electrostatic potential of previously reported cocrystals has been recalculated to show that the negative electrostatic potential on the lactam and syn-amide O atom is higher compared with the charge on carboxamide and pyridine N-oxide O atoms. The potential of sulfonamide molecules to form cocrystals with syn-amides and lactams are evaluated in terms of the electrostatic potential energy for the designed supramolecular synthons.
Project description:The crystallization of 28 binary and ternary cocrystals of quercetin with dibasic coformers is analyzed in terms of a combinatorial selection from a solution of preferred molecular conformations and supramolecular synthons. The crystal structures are characterized by distinctive O-H?N and O-H?O based synthons and are classified as nonporous, porous and helical. Variability in molecular conformation and synthon structure led to an increase in the energetic and structural space around the crystallization event. This space is the crystal structure landscape of the compound and is explored by fine-tuning the experimental conditions of crystallization. In the landscape context, we develop a strategy for the isolation of ternary cocrystals with the use of auxiliary template molecules to reduce the molecular and supramolecular 'confusion' that is inherent in a molecule like quercetin. The absence of concomitant polymorphism in this study highlights the selectivity in conformation and synthon choice from the virtual combinatorial library in solution.
Project description:Four novel xanthohumol (XN) cocrystals with pharmaceutically acceptable coformers, such as nicotinamide (NIC), glutarimide (GA), acetamide (AC), and caffeine (CF) in the 1:1 stoichiometry were obtained by the slow evaporation solution growth technique. The structure of the cocrystals was determined by single crystal X-ray diffraction. The analysis of packing and interactions in the crystal lattice revealed that molecules in the target cocrystals were packed into almost flat layers, formed by the O-HO, O-HN, and N-HO-type contacts between the xanthohumol and coformer molecules. The results provided details about synthons responsible for crystal net stabilization and all hydrogen bonds observed in the crystal lattice. The main synthon was formed via the hydrogen bond between the hydroxyl group in the B ring of XN and coformers. The three-dimensional crystal lattice was stabilized by the hydrogen XN-XN interactions whereas the ?-? stacking interactions played an additional role in layer binding, with the exception of low quality cocrystals formed with caffeine. Application of FTIR and Raman spectroscopy confirmed that the crystalline phase of obtained cocrystals was not a simple combination of individual components and completely different crystal phases resulted from the effect of intermolecular interactions. The multivariate analysis showed the changes in the spectra, and this technique can be applied in a combination with vibrational spectroscopy for fast screening of new crystal phases. Additionally, the solubility studies of pure XN and its cocrystals exhibited a 2.6-fold enhancement in XN solubility in aqueous solution for XN-AC and, to a lesser extent, for other cocrystals.
Project description:Polymorphism in the orcinol:4,4'-bipyridine cocrystal system is analyzed in terms of a robust convergent modular phenol?pyridine supramolecular synthon. Employing the Synthon Based Fragments Approach (SBFA) to transfer the multipole charge density parameters, it is demonstrated that the crystal landscape can be quantified in terms of intermolecular interaction energies in the five crystal forms so far isolated in this complex system. There are five crystal forms. The first has an open, divergent O-H?N based structure with alternating orcinol and bipyridine molecules. The other four polymorphs have different three-dimensional packing but all of them are similar at an interaction level, and are based on a modular O-H?N mediated supramolecular synthon that consists of two orcinol and two bipyridine molecules in a closed, convergent structure. The SBFA method, which depends on the modularity of synthons, provides good agreement between experiment and theory because it takes into account the supramolecular contribution to charge density. The existence of five crystal forms in this system shows that polymorphism in cocrystals need not be considered to be an unusual phenomenon. Studies of the crystal landscape could lead to an understanding of the kinetic pathways that control the crystallization processes, in other words the valleys in the landscape. These pathways are traditionally not considered in exercises pertaining to computational crystal structure prediction, which rather monitors the thermodynamics of the various stable forms in the system, in other words the peaks in the landscape.
Project description:Acemetacin (ACM) is a non-steroidal anti-inflammatory drug (NSAID), which causes reduced gastric damage compared with indomethacin. However, acemetacin has a tendency to form a less soluble hydrate in the aqueous medium. We noted difficulties in the preparation of cocrystals and salts of acemetacin by mechanochemical methods, because this drug tends to form a hydrate during any kind of solution-based processing. With the objective to discover a solid form of acemetacin that is stable in the aqueous medium, binary adducts were prepared by the melt method to avoid hydration. The coformers/salt formers reported are pyridine carboxamides [nicotinamide (NAM), isonicotinamide (INA), and picolinamide (PAM)], caprolactam (CPR), p-aminobenzoic acid (PABA), and piperazine (PPZ). The structures of an ACM-INA cocrystal and a binary adduct ACM-PABA were solved using single-crystal X-ray diffraction. Other ACM cocrystals, ACM-PAM and ACM-CPR, and the piperazine salt ACM-PPZ were solved from high-resolution powder X-ray diffraction data. The ACM-INA cocrystal is sustained by the acid?pyridine heterosynthon and N-H?O catemer hydrogen bonds involving the amide group. The acid?amide heterosynthon is present in the ACM-PAM cocrystal, while ACM-CPR contains carboxamide dimers of caprolactam along with acid-carbonyl (ACM) hydrogen bonds. The cocrystals ACM-INA, ACM-PAM and ACM-CPR are three-dimensional isostructural. The carboxyl?carboxyl synthon in ACM-PABA posed difficulty in assigning the position of the H atom, which may indicate proton disorder. In terms of stability, the salts were found to be relatively stable in pH 7 buffer medium over 24?h, but the cocrystals dissociated to give ACM hydrate during the same time period. The ACM-PPZ salt and ACM-nicotinamide cocrystal dissolve five times faster than the stable hydrate form, whereas the ACM-PABA adduct has 2.5 times faster dissolution rate. The pharmaceutically acceptable piperazine salt of acemetacin exhibits superior stability, faster dissolution rate and is able to overcome the hydration tendency of the reference drug.
Project description:Aniline-phenol recognition is studied in the crystal engineering context in several 1:1 cocrystals that contain a closed cyclic hydrogen-bonded [?O-H?N-H?]2 tetramer supramolecular synthon (II). Twelve cocrystals of 3,4,5- and 2,3,4-trichlorophenol with one of eight halogenated anilines have been characterized. Ten of these cocrystals contain an extended octamer synthon that is assembled with hydrogen bonding and ??? stacking that defines a Long-Range Synthon Aufbau Module (LSAM). The design strategy is, therefore, based on the construction and transferability of the LSAM, which is a dimer of tetramers. Using the LSAM concept, two short cell axes in the crystal structures can be predicted. Whilst one of them is dictated by synthon II, the other one is dominated by ??? interactions. The third cell axis can also be predicted, in some cases, by systematic tuning of the halogen bonds. The design strategy is also verified in cocrystals of non-halogenated precursors. The observation of this large synthon in so many structures points to its stability and possible existence in solution. To this end, one-dimensional (1)H and (15)N NMR studies, performed on the 3,4,5-trichlorophenol-3,5-dichloroaniline cocrystal in CDCl3, show characteristic downfield shifts that point to a ??? stacked structure and to the robustness of the hydrogen-bonded aggregates. Nuclear Overhauser effects point to hydrogen bonding between aniline and phenol molecules in the aggregates. Diffusion-ordered spectroscopy and T 1 inversion recovery experiments show that stacking is present in concentrated solution and lost at a certain dilution. A sequence of events is therefore established: molecules of the aniline and the phenol associate via hydrogen bonding to form tetramers, and tetramers subsequently stack to form octamers.
Project description:BACKGROUND:Co-crystal is a structurally homogeneous crystalline material that contains two or more neutral building blocks that are present in definite stoichiometric amounts. The main advantage of co-crystals is their ability to generate a variety of solid forms of a drug that have distinct physicochemical properties from the solid co-crystal components. In the present investigation, five co-crystals containing 2-amino-6-chloropyridine (AMPY) moiety were synthesized and characterized. RESULTS:The crystal structure of 2-amino-6-chloropyridine (AMPY) (I), and the robustness of pyridine-acid supramolecular synthon were discussed in four stoichiometry co-crystals of AMPY…BA (II), AMPY…2ABA (III), AMPY…3CLBA (IV) and AMPY…4NBA (V). The abbreviated designations used are benzoic acid (BA), 2-aminobenzoic acid (2ABA), 3-chlorobenzoic acid (3CLBA) and 4-nitrobenzoic acid (4NBA). All the crystalline materials have been characterized by (1)HNMR, (13)CNMR, IR, photoluminescence, TEM analysis and X-ray diffraction. The supramolecular assembly of each co-crystal is analyzed and discussed. CONCLUSIONS:Extensive N---H?·?·?·?N/N---H?·?·?·?O/O---H?·?·?·?N hydrogen bonds are found in (I-V), featuring different supramolecular synthons. In the crystal structure, for compound (I), the 2-amino-6-chloropyridine molecules are linked together into centrosymmetric dimers by hydrogen bonds to form homosynthon, whereas for compounds (II-V), the carboxylic group of the respective acids (benzoic acid, 2-aminobenzoic acid, 3-chlorobenzoic acid and 4-nitrobenzoic acid) interacts with pyridine molecule in a linear fashion through a pair of N---H?·?·?·?O and O---H?·?·?·?N hydrogen bonds, generating cyclic hydrogen-bonded motifs with the graph-set notation [Formula: see text] , to form heterosynthon. In compound (II), another intermolecular N---H?·?·?·?O hydrogen bonds further link these heterosynthons into zig-zag chains. Whereas in compounds (IV) and (V), these heterosynthons are centrosymmetrically paired via N---H?·?·?·?O hydrogen bonds and each forms a complementary DADA [D?=?donor and A?=?acceptor] array of quadruple hydrogen bonds, with graph-set notation [Formula: see text], [Formula: see text] and [Formula: see text].
Project description:Specific isoforms from the carbonic anhydrase (CA) family of zinc metalloenzymes have been associated with a variety of diseases. Isoform-specific carbonic anhydrase inhibitors (CAIs) are therefore a major focus of attention for specific disease treatments. Classical CAIs, primarily sulfonamide-based compounds and their bioisosteres, are examined as antiglaucoma, antiepileptic, antiobesity, antineuropathic pain and anticancer compounds. However, many sulfonamide compounds inhibit all CA isoforms nonspecifically, diluting drug effectiveness and causing undesired side effects due to off-target inhibition. In addition, a small but significant percentage of the general population cannot be treated with sulfonamide-based compounds due to a sulfa allergy. Therefore, CAIs must be developed that are not only isoform specific, but also non-classical, i.e. not based on sulfonamides, sulfamates, or sulfamides. This review covers the classes of non-classical CAIs and the recent advances in the development of isoform-specific inhibitors based on phenols, polyamines, coumarins and their derivatives.