Srinivas Basavoju

Indomethacin-saccharin cocrystal: design, synthesis and preliminary pharmaceutical characterization.

PurposeTo design and prepare cocrystals of indomethacin using crystal engineering approaches, with the ultimate objective of improving the physical properties of indomethacin, especially solubility and dissolution rate.Materials and MethodsVarious cocrystal formers, including saccharin, were used in endeavours to obtain indomethacin cocrystals by slow evaporation from a series of solvents. The melting point of crystalline phases was determined. The potential cocrystalline phase was characterized by DSC, IR, Raman and PXRD techniques. The indomethacin–saccharin cocrystal (hereafter IND–SAC cocrystal) structure was determined from single crystal X-ray diffraction data. Pharmaceutically relevant properties such as the dissolution rate and dynamic vapour sorption (DVS) of the IND–SAC cocrystal were evaluated. Solid state and liquid-assisted (solvent-drop) cogrinding methods were also applied to indomethacin and saccharin.ResultsThe IND–SAC cocrystals were obtained from ethyl acetate. Physical characterization showed that the IND–SAC cocrystal is unique vis-à-vis thermal, spectroscopic and X-ray diffraction properties. The cocrystals were obtained in a 1:1 ratio with a carboxylic acid and imide dimer synthons. The dissolution rate of IND–SAC cocrystal system was considerably faster than that of the stable indomethacin γ-form. DVS studies indicated that the cocrystals gained less than 0.05% in weight at 98%RH. IND–SAC cocrystal was also obtained by solid state and liquid-assisted cogrinding methods.ConclusionsThe IND–SAC cocrystal was formed with a unique and interesting carboxylic acid and imide dimer synthons interconnected by weak N−H⋯O hydrogen bonds. The cocrystals were non-hygroscopic and were associated with a significantly faster dissolution rate than indomethacin (γ-form).

Tape and layer structures in cocrystals of some di- and tricarboxylic acids with 4,4′-bipyridines and isonicotinamide. From binary to ternary cocrystals

Linear, zigzag tapes and flat, corrugated sheet structures are described in binary cocrystals 1–9 of some di- and tricarboxylic acids with 4,4′-bipyridine bases and isonicotinamide. Carboxylic acid⋯pyridine O–H⋯N, its proton transfer form N+–H⋯O−, carboxamide dimer N–H⋯O, and extended motifs are present in these crystal structures. Our results show modular expansion of carboxylic acid dimer in neutral cocrystals with pyridine type bases. Even as the structures of these aggregates can be understood from the molecular constituents in a straightforward manner, the nature of acid⋯pyridine synthon, i.e. neutral or ionic, is difficult to anticipate from their ΔpKa values. We modify the ΔpKa (pKa conjugate acid of pyridine base – pKa carboxylic acid) rule in COOH–pyridine cocrystals: ΔpKa 3.75 results in proton migration to the ionic interaction N+–H⋯O−. Proton transfer results in the assembly of a supramolecular 3-connected node of cyclohexane tricarboxylate and these anions form chair cyclohexane or parquet grid sheets in 10 and 11. The length of bipyridinium cation plays a role in the overall structure. A novel approach to three-component adducts is crystallization of 1,3cis,5cis-cyclohexane tricarboxylic acid with 4,4′-bipyridine and 4,4′-bipyridine-N-oxide bases of different strengths, which results in a ternary cocrystal 12 sustained via O–H⋯N and O–H⋯O− hydrogen bonds.

Pharmaceutical cocrystals of nitrofurantoin: screening, characterization and crystal structure analysis

The objective of this study was to screen and prepare cocrystals of the poorly soluble drug nitrofurantoin (NTF) with the aim of increasing its solubility. Screening for cocrystals of NTF using 47 coformers was performed by high-throughput (HT) screening using liquid assisted grinding (LAG) methods. Raman spectroscopy and powder X-ray diffraction (PXRD) were used as the primary analytical tools to identify the new crystalline solid forms. Manual LAG and reaction crystallization (RC) experiments were carried out to confirm and scale-up the hits. Seven hits were confirmed to be cocrystals. The cocrystals were characterized by PXRD, Raman and IR spectroscopy, thermal analysis (DSC and TGA) and liquid-state NMR or elemental analysis. The solution stability of the scaled-up cocrystals in water was tested by slurrying the cocrystals at 25 °C for one week. NTF forms cocrystals with a 1:1 stoichiometric ratio with urea (1), 4-hydroxybenzoic acid (2), nicotinamide (3), citric acid (4), L-proline (5) and vanillic acid (6). In addition, NTF forms a 1:2 cocrystal with vanillin (7). All but one of the NTF cocrystals transformed (dissociated) in water, resulting in NTF hydrate crystalline material or NTF hydrate plus the coformer, which indicates that the transforming cocrystals have a higher solubility than the NTF hydrate under these conditions. The crystal structures of 1:1 NTF-citric acid (4) and 1:2 NTF-vanillin (7) were solved by single-crystal X-ray diffraction. The crystal structures of these two cocrystals were analyzed in terms of their supramolecular synthons.

Host–guest and network structures of some tetraphenylmethane derivatives

Dinitro and tetracyano derivatives of tetraphenylmethane (TPM) are identified as new host materials that include THF, water and MeCN. The crystal structures of the host–guest complexes are reminiscent to those of the related host compound tetranitrotetraphenylmethane (TNTPM) studied by us previously. Guest loss has been measured quantitatively. The crystal structures are characterized by O–H⋯O, C–H⋯O, C–H⋯N and C–H⋯π interactions. It is interesting to note that while the unsubstituted TPM and some of its other derivatives form guest-free crystals, the nitro and cyano derivatives form more open structures.

Synthesis, characterization and biological evaluation of fused thiazolo[3,2-a]pyrimidine derivatives

A series of fused thiazolo[3,2-a]pyrimidines (7a–g, 8a–f, 11a–g and 12a,b) have been synthesized in good yields by reaction of fused 3,4-dihydropyrimidin-2(1H)-thiones (4a–g) with phenacyl bromides (5,6)/3-(2-bromoacetyl)coumarins (9,10) under conventional heating in acetic acid. Analytical and spectral studies as well as single crystal X-ray diffraction data on the representative compound 8e confirmed the structure of all the reaction products. All the synthesized compounds were screened for their antibacterial, antioxidant and DNA cleavage activities. The compound 7e against Escherichia coli, 8a and 8c–e against Pseudomonas aeruginosa have shown prominent antibacterial activity compared to the standard drug Penicillin with MIC 9.375 μg mL−1, whereas the compounds 11c, 12a and 12b have shown very good antioxidant activity compared to the standard drug Trolox with IC50 values 12.36, 11.12 and 13.88 μM respectively. Compounds 11f and 12b have completely cleaved the DNA even at 50 μg mL−1 concentration and the remaining compounds have partially cleaved the DNA.

Pharmaceutical Salts of Fluoroquinolone Antibacterial Drugs with Acesulfame Sweetener

Novel organic salts of norfloxacin and ciprofloxacin with artificial sweeteners such as saccharin and acesulfame were prepared. The two salts 1 and 2 were characterized by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). Finally, the crystal structures were solved by single crystal X-ray diffraction data and the structures were analyzed in terms of supramolecular synthons. In norfloxacin acesulfamate 1, two norfloxacin cations and two acesulfame anions form an eight membered cyclic tetramer supramolecular synthon. The salt, ciprofloxacin acesulfamate 2, has a similar structure as salt 1. This study contributes the importance of crystal engineering and supramolecular chemistry to the pharmaceutical applications in terms of interactions and structural correlations in the design of new solid phases. Supplemental materials are available for this article. Go to the publishers online edition of Molecular Crystals and Liquid Crystals to view the free supplemental file.

Ultrasound-assisted rapid and efficient one-pot synthesis of furanyl spirooxindolo and spiroquinoxalinopyrrolizidines by 1,3-dipolar cycloaddition: a green protocol

Efficient synthesis of novel spirooxindolo and spiroquinoxalinopyrrolizidine derivatives was expediently accomplished with regioselectivity via one-pot, three-component 1,3-dipolar cycloaddition using ultrasonication. Chalcones derived from both heteroaryl methyl ketones and furfural were used as dipolarophiles in these reactions. The synthesized compounds were analyzed by 1H and 13C nuclear magnetic resonance (NMR), mass spectrometry, and elemental (CHN) analysis. Single-crystal X-ray diffraction studies of one of the compounds (11d) proved the structure and regiochemistry of the cycloaddition. The ultrasound methodology is clearly advantageous, and the desired products were obtained in moderate to good yield in shorter reaction time compared with conventional heating and fusion methods.

Crystal Structure Analysis of Betti Base 1-((2-hydroxynaphthalen-1-yl)(2-hydroxyphenyl)methyl)urea•2DMF Solvate

A novel Betti base compound, 1-((2-hydroxynaphthalen-1-yl)(2-hydroxyphenyl)methyl)urea, UBB, was synthesized and characterized by spectral, structural and thermal studies. Single crystal X-ray diffraction studies reveal that the racemic mixture of the compound, when crystallized from DMF, yields R-isomer preferentially (prismatic crystals), whereas, when crystallized from 5:1 (v/v) mixture of DMF-THF, it yields S-isomer (rectangular shaped crystals) with two molecules of DMF, included in both the cases. The crystal structure is discussed in terms of supramolecular interactions and molecular modeling. Both R and S enantiomeric DMF solvate crystals are in their chiral triclinic P1 space group.

Crystal Structure Analysis of Ethyl 7-Phenyl-5- p-tolylpyrazolo[1,5-a]pyrimidine-3-carboxylate

The title compound, C22H19N3O2, was prepared from the three-component reaction. The structure of the title compound was established by single-crystal X-ray diffraction. The molecular structure shows that the phenyl ring is not coplanar with the pyrimidine ring. The torsion angle between the phenyl ring and pyrimidine ring is 147.01(15)°. The glide related molecules form one-dimensional corrugated tape-like structure via C–H···O hydrogen bonds along the crystallographic b-axis. These one-dimensional layers stack along the a-axis and form a corrugated layered structure and these layers are further stabilized by the weak C–H···π interactions. Also, it was found that the pyrazole moiety and p-toluyl groups of glide-related molecules are stacked through π···π interactions.

Crystal Structure Analysis and Conformational Isomerism of 2,2′-(4,4′-oxybis(4,1-phenylene)bis(azan-1-yl-1-ylidene))bis(methan-1-yl-1-ylidene)dinaphthalen-1-ol

A helicate Schiff base ligand 2,2′-(4,4′-oxybis(4,1-phenylene)bis(azan-1-yl-1-ylidene))bis(methan-1-yl-1-ylidene)dinaphthalen-1-ol (NDADPE) was synthesized from 1-hydroxynaphthalene-2-carbaldehyde and 4-(4-aminophenoxy)benzenamine. The compound (NDADPE) was characterized by FT-IR, 1H NMR, and mass spectroscopic and elemental analyses. The structure of NDADPE was solved by single crystal X-ray diffraction method. The crystal structure reveals that there are two conformers (A and B). Conformer A forms a supramolecular dimer with bifurcated C‒H···O hydrogen bond synthon, whereas conformer B forms a supramolecular helix due to bifurcated C‒H···O hydrogen bond synthons. Hirshfeld surface analyses were carried out on the two conformers to explain the conformational isomerism.