00686nas a2200181 4500008004100000022001400041245006200055210006200117260000800179300000900187490000700196653012600203100002400329700001800353700001900371700002000390856009400410 2014 eng d a2053-273300aSupramolecular synthon hierarchy in bumetanide cocrystals0 aSupramolecular synthon hierarchy in bumetanide cocrystals cFEB aC7210 v7010aNovel cocrystals of sulfonamide drug Bumetanide with carboxamides are developed based on supramolecular synthons approach1 aAllu, Suryanarayana1 aBolla, Geetha1 aTothadi, Srinu1 aNangia, Ashwini uhttps://library.ncl.res.in/content/supramolecular-synthon-hierarchy-bumetanide-cocrystals02338nas a2200157 4500008004100000022001400041245004800055210004700103260011000150300001400260490000700274520178300281100001802064700002002082856007802102 2016 eng d a1359-734500aPharmaceutical cocrystals: walking the talk0 aPharmaceutical cocrystals walking the talk aTHOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLANDbROYAL SOC CHEMISTRYcMAY a8342-83600 v523 a

Pharmaceutical cocrystals belong to a sub-class of cocrystals wherein one of the components is a drug molecule (or an active pharmaceutical ingredient, API) and the second is a benign food or drug grade additive (generally regarded as safe, GRAS). The two components are hydrogen-bonded in a fixed stoichiometric ratio in the crystal lattice. In the past decade, pharmaceutical cocrystals have demonstrated significant promise in their ability to modify the physicochemical and pharmacokinetic properties of drug substances, such as the solubility and dissolution rate, bioavailability, particle morphology and size, tableting and compaction, melting point, physical form, biochemical and hydration stability, and permeability. In this feature review, we highlight some prominent examples of drug cocrystals which exhibit variable hardness/softness and elasticity/plasticity depending on coformer selection, improvement of solubility and permeability in the same cocrystal, increase of the melting point for solid formulation, enhanced color performance, photostability and hydration stability, and a longer half-life. Cocrystals of flavanoids and polyphenols can make improved pharmaceuticals and also extend to the larger class of nutraceuticals. The application of crystal engineering to assemble ternary cocrystals expands this field to drug-drug cocrystals which may be useful in multi-drug resistance, mitigating side effects of drugs, or attenuating/enhancing drug action synergistically by rational selection. The advent of new techniques for structural characterization beyond the standard X-ray diffraction will provide a better understanding of drug phases which are at the borderline of crystalline-amorphous nature and even newer opportunities in the future.

1 aBolla, Geetha1 aNangia, Ashwini uhttps://library.ncl.res.in/content/pharmaceutical-cocrystals-walking-talk02150nas a2200157 4500008004100000245006500041210006300106260000800169300001200177490000600189520163800195100001801833700002501851700002001876856009601896 2017 eng d00a Acemetacin cocrystal structures by powder X-ray diffraction0 aAcemetacin cocrystal structures by powder Xray diffraction cMAY a206-2140 v43 aCocrystals of acemetacin drug (ACM) with nicotinamide (NAM), p-aminobenzoic acid (PABA), valerolactam (VLM) and 2-pyridone (2HP) were prepared by melt crystallization and their X-ray crystal structures determined by high-resolution powder X-ray diffraction. The powerful technique of structure determination from powder data (SDPD) provided details of molecular packing and hydrogen bonding in pharmaceutical cocrystals of acemetacin. ACM-NAM occurs in anhydrate and hydrate forms, whereas the other structures crystallized in a single crystalline form. The carboxylic acid group of ACM forms theacid-amide dimer three-point synthon R-3(2)(9) R-2(2)(8) R-3(2)(9) with three different syn amides (VLM, 2HP and caprolactam). The conformations of the ACM molecule observed in the crystal structures differ mainly in the mutual orientation of chlorobenzene fragment and the neighboring methyl group, being anti (type I) or syn (type II). ACM hydrate, ACM-NAM, ACM-NAM-hydrate and the piperazine salt of ACM exhibit the type I conformation, whereas ACM polymorphs and other cocrystals adopt the ACM type II conformation. Hydrogen-bond interactions in all the crystal structures were quantified by calculating their molecular electrostatic potential (MEP) surfaces. Hirshfeld surface analysis of the cocrystal surfaces shows that about 50% of the contribution is due to a combination of strong and weak O center dot center dot center dot H, N center dot center dot center dot H, Cl center dot center dot center dot H and C center dot center dot center dot H interactions. The physicochemical properties of these cocrystals are under study.1 aBolla, Geetha1 aChernyshev, Vladimir1 aNangia, Ashwini uhttps://library.ncl.res.in/content/acemetacin-cocrystal-structures-powder-x-ray-diffraction01861nas a2200169 4500008004100000245007400041210006900115260000800184300001400192490000700206520129100213100002401504700001801528700001901546700002001565856010601585 2017 eng d00aSupramolecular synthons in bumetanide cocrystals and ternary products0 aSupramolecular synthons in bumetanide cocrystals and ternary pro cAUG a4225-42360 v173 aA novel design strategy for cocrystals of the diuretic sulfonamide drug bumetanide (BUM) with carboxamides is reported based on reliable supramolecular synthons. Binary cocrystals of BUM with pyridine carboxamides, pyridones, and cytosine were obtained by solvent assisted grinding followed by solution crystallization. All cocrystal structures exhibit hydrogen bonding of the coformer with the carboxylic acid group of BUM via heterosynthons which replace the acid homodimer in the drug crystal structure. Pyridones are inserted as N-H center dot center dot center dot O dimers which are in turn bonded to the acid group of BUM, while the pyridine amide coformers interact via the acid amide heterosynthon. Cocrystal polymorphs were obtained for bumetanide isonicotinamide cocrystal structure with the sulfonamide pyridine and sulfonamide acid synthons. Careful crystal packing analysis of BUM structure and nine new binary adducts gave an idea for the design ternary cocrystals, and subsequently four new ternary crystalline products were crystallized. Whereas the binary cocrystal structures were confirmed by single crystal diffraction, the ternary combinations were chatacterized by their unique powder X-ray diffraction patterns as well as by thermal and spectroscopic techniques.1 aAllu, Suryanarayana1 aBolla, Geetha1 aTothadi, Srinu1 aNangia, Ashwini uhttps://library.ncl.res.in/content/supramolecular-synthons-bumetanide-cocrystals-and-ternary-products01736nas a2200145 4500008004100000245004700041210004600088260000800134300001500142490000700157520131000164100001801474700002001492856007801512 2018 eng d00a Novel pharmaceutical salts of albendazole0 aNovel pharmaceutical salts of albendazole cNOV a 6394-64050 v203 aAlbendazole (ABZ) is a class II safe and effective antihelmintic drug in the benzimidazole group according to the BCS (Biopharmaceutics Classification System) with low solubility (9 mg L-1) and high permeability (log P 2.54). Novel salts and salt hydrates of ABZ are reported with benzene and p-toluene sulfonic acid (BSA, PTSA), as well as carboxylic acids such as oxalic acid (OA), maleic acid (MLE), L-tartaric acid (LTA), 2,6-dihydroxybenzoic acid (2,6-DHBA), and 2,4,6-trihydroxybenzoic acid (2,4,6-THBA). The products ABZ-BSA, ABZ-BSA-H, ABZ-PTSA, ABZ-PTSA-H, ABZ-OA-H and ABZ-2,6-DHBA were confirmed by single crystal X-ray diffraction. In the hydrate structures (designated as -H), the water molecule acts as a bridge in the hydrogen bonding network. The salt formation of ABZ-MLE, ABZ-LTA, and ABZ-2,4,6-THBA was confirmed by N-15 ss-NMR based on the chemical shift change of ca. 50 ppm. The sulfonate salt hydrates exhibit 2D isostructurality, and position disorder in the thiopropyl group in the drug crystal structure was not observed in the salts. Crystal lattice energies were calculated for the MLE, LTA, and 2,4,6-THBA complexes of ABZ to confirm the molecular salt formation. The cocrystals of ABZ with the hydroxybenzene carboxylic acids are novel salts in the benzimidazole drugs class.1 aBolla, Geetha1 aNangia, Ashwini uhttps://library.ncl.res.in/content/novel-pharmaceutical-salts-albendazole01119nas a2200193 4500008004100000022001400041245009400055210006900149260000900218300001400227490000700241520045000248100002400698700002000722700001800742700002800760700002000788856011700808 2019 eng d a1466-803300aRole of hydrogen bonding in cocrystals and coamorphous solids: indapamide as a case study0 aRole of hydrogen bonding in cocrystals and coamorphous solids in cAPR  a2043-20480 v213 a

The stronger sulfonamide-pyridine (SO2NH2 center dot center dot center dot N-Py) and sulfonamide-carboxamide (SO2NH2 center dot center dot center dot O = C-NH) hydrogen bonds direct the formation of cocrystals, while the weaker sulfonamide-amine (SO2NH2 center dot center dot center dot N-H) hydrogen bond results in coamorphous products. IDP-PIP and IDP-ARG coamorphous solids exhibit remarkable stability under accelerated conditions.

1 aAllu, Suryanarayana1 aSuresh, Kuthuru1 aBolla, Geetha1 aMannava, M., K. Chaitan1 aNangia, Ashwini uhttps://library.ncl.res.in/content/role-hydrogen-bonding-cocrystals-and-coamorphous-solids-indapamide-case-study01899nas a2200217 4500008004100000022001400041245009200055210006900147260000800216300001200224490000600236520118300242653001501425653002401440653001701464653002801481653001501509100001801524700002001542856011901562 2019 eng d a2052-252500aSupramolecular synthon hierarchy in sulfonamide cocrystals with syn-amides and N-oxides0 aSupramolecular synthon hierarchy in sulfonamide cocrystals with  cJUL a751-7600 v63 a

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 carboxylic 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, hydrochlorothiazide 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.

10acocrystals10acrystal engineering10asulfonamides10asupramolecular synthons10asyn-amides1 aBolla, Geetha1 aNangia, Ashwini uhttps://library.ncl.res.in/content/supramolecular-synthon-hierarchy-sulfonamide-cocrystals-syn-amides-and-n-oxides01824nas a2200181 4500008004100000022001400041245006000055210006000115260000800175300001200183490000700195520126300202100002401465700001801489700001901507700002401526856009201550 2020 eng d a1528-748300aNovel pharmaceutical cocrystals and salts of bumetanide0 aNovel pharmaceutical cocrystals and salts of bumetanide cFEB a793-8030 v203 a

New crystalline forms of bumetanide, namely, four cocrystals, two salts, and one salt-cocrystal were crystallized. Urea and lactams such as valerolactam, caprolactam, and N-methyl caprolactam formed cocrystals with bumetanide, whereas 4-aminopyridine gave a salt. Piperazine afforded a salt hydrate, and 5-fluorocytosine gave a salt-cocrystal. The supramolecular synthons in bumetanide-lactam cocrystals are an amide dimer between drug and coformer, and acid homo dimer between bumetanide molecules. In bumetanide salts, the acid proton is transferred from bumetanide to coformer amine, whereas in bumetanide salt-cocrystal proton transfer and free acid were observed in the crystal structure. Similarly, the cytosine salt-cocrystal of bumetanide and fluorocytosine also gave a salt-cocrystal adduct. The acid proton of bumetanide is transferred to the 2-amino pyridine base of cytosine as a salt, and on the other side of the drug molecule the sulfonamide interacts with the syn amide part of cytosine. Furthermore, solubility, dissolution, and diffusion membrane permeability experiments were performed on all new solid forms. The piperazine salt shows high dissolution and permeability crossover when compared to other binary forms of bumetanide.

1 aAllu, Suryanarayana1 aBolla, Geetha1 aTothadi, Srinu1 aNangia, Ashwini, K. uhttps://library.ncl.res.in/content/novel-pharmaceutical-cocrystals-and-salts-bumetanide