Modulation of morphology and efficacy of new CB1 receptor antagonist using simple and benign polymeric additives

1014-1021The compound 1, [(1H-[1]benzoxepino[5,4-c]pyrazole-3-carboxamide, 8-chloro-1-(2,4-dichlorophenyl)-4,5-dihydro-N- 1-piperidinyl], a known CB1 modulator has been synthesized and characterized by IR, NMR and single Crystal X-ray study. The single crystal study of 1 displays a number of halogen bonds leading to 1-D network along with other weak noncovalent interactions. The CB1 modulator 1 inherently possesses extremely low solubility in water, which makes its application as drug difficult, and this may be attributed to multiple halogen bonds present in the crystal structure. A series of polymer additives, which are Generally Regarded As Safe (GRAS), have been explored to investigate whether they can modulate the halogen bond present in 1 through formation of various non-bonded interactions. Surprisingly, these polymers are found to change crystal morphology, crystal packing while retaining efficacy and bioavailability. The polymer molecular weight is found to play a significant role in crystal morphology modification especially in case of polyethylene glycol (PEG). The formation of new polymorphic forms of 1 and modification of halogen bond has been established using powder X-ray diffraction and IR study, respectively, in case of PEG 4000, PVPK-30, PVA polymers and compound 1 adducts

Modulation of morphology and efficacy of new CB1 receptor antagonist using simple and benign polymeric additives

The compound 1, [(1H-[1]benzoxepino[5,4-c]pyrazole-3-carboxamide, 8-chloro-1-(2,4-dichlorophenyl)-4,5-dihydro-N-1-piperidinyl], a known CB1 modulator has been synthesized and characterized by IR, NMR and single Crystal X-ray study. The single crystal study of 1 displays a number of halogen bonds leading to 1-D network along with other weak non-covalent interactions. The CB1 modulator 1 inherently possesses extremely low solubility in water, which makes its application as drug difficult, and this may be attributed to multiple halogen bonds present in the crystal structure. A series of polymer additives, which are Generally Regarded As Safe (GRAS), have been explored to investigate whether they can modulate the halogen bond present in 1 through formation of various non-bonded interactions. Surprisingly, these polymers are found to change crystal morphology, crystal packing while retaining efficacy and bioavailability. The polymer molecular weight is found to play a significant role in crystal morphology modification especially in case of polyethylene glycol (PEG). The formation of new polymorphic forms of 1 and modification of halogen bond has been established using powder X-ray diffraction and IR study, respectively, in case of PEG 4000, PVPK-30, PVA polymers and compound 1 adducts.

Facile preparation and structure–property correlation of low molecular mass organic gelators derived from simple organic salts

Secondary ammonium salts namely dicyclohexylammonium 4-nitrocinnamate 1, 3-nitrocinnamate 2, 2-nitrocinnamate 3 and the corresponding benzoate salts namely dicyclohexylammonium 4-nitrobenzoate 4, 3-nitrobenzoate 5 and 2-nitrobenzoate 6 have been prepared and scanned for gelation. Salts 1 and 2 display excellent gelation properties. Structure–property correlations of these salts based on various X-ray diffraction data have been attempted and compared with the earlier results reported by our group. Single crystal structures of the gelator dicyclohexylammonium 3-bromocinnamate 7 reported earlier by us, and 4- and 2-methylbenzoate 8 and 10, both nongelators, have also been reported in the context of drawing important conclusions on structure–property correlations of dicyclohexylammonium cinnamate based gelators

Structures and gelation properties of a series of salts derived from an alicyclic dicarboxylic acid and n-alkyl primary amines

Structures and the gelation property of a series of primary ammonium hydrogen dicarboxylate salts derived from cyclobutane-1,1-dicarboxylic acid and n-alkyl amines, that is, Me-(CH_n)₂-NH₂ (n = 3−15, reacted in 1:1 molar ratio) have been studied systematically as a function of alkyl chain length. While salts with n < 11 did not show any gelation ability, salts with n > 11 could gel a number of solvents including commercial fuels such as kerosene. On the basis of the single crystal, powder X-ray diffraction and data from various microscopies (scanning electron and optical microscopy), a structure−property correlation has been attempted. The results revealed that a two-dimensional hydrogen bonding network and nearly identical crystal packing are present in the crystal structures of the salts (n = 3, 8−15) reported herein displaying the inability of imparting hydrogen bond isomerism because of alkyl−alkyl interactions. Existence of microcrystals of thin plate like morphology directly obtained from gel as well as dilute solution demonstrated the meta-stable nature of the gel forming network

Supramolecular assemblies in salts and co-crystals of imidazoles with dicarboxylic acids

Two new salts 2-phenyl imidazolium hydrogen cyclobutane-1,1-dicarboxylate 1, imidazolium hydrogen malonate 2, and two new co-crystals benzimidazole/succinic acid co-crystal (1 ∶ 1) 3 and benzimidazole/isophthalic acid co-crystal (1 ∶ 1) 4 were synthesized and characterized by X-ray crystallography in order to analyze their supramolecular architecture. The results are examined and compared with the structures present in the Cambridge Structural Database

Structural studies of a new low molecular mass organic gelator for organic liquids based on simple salt

A series of easy to prepare organic salt based on imidazole derivatives and cyclobutane-1,1-dicarboxylic acid have been studied for their gelation behavior after it was found that imidazolium hydrogen cyclobutane-1,1-dicarboxylate (1) can harden few organic liquids. 1 forms remarkably stable gel (remains intact for several months in an open container, gel dissociation temp TGel = 66 °C) with nitrobenzene at a very low concentration of 0.137 wt %, whereas bis-imidazolium cyclobutane-1,1-dicarboxylate (2) resulted in a weak and unstable gel with nitrobenzene, indicating the importance of the free COOH group in 1 in gel formation. Molecular packing in the primary assembly unit (fibers) of xerogel of 1/nitrobenzene is successfully established based on single-crystal X-ray and X-ray powder diffraction data. The morph responsible for gel formation of 1 with nitrobenzene is found to be different from that of its xerogel. Substitution on the imidazole moiety results in nongelators

Ascertaining the 1D hydrogen-bonded network in organic ionic solids

Crystal engineering concepts are exploited to generate a 1D hydrogen-bonded network in a series of organic salts (9−18) derived from dicyclohexylamine and various dicarboxylic acids (1−7) having linear as well as twisted/angular functional topology. It is clearly demonstrated that the cyclic 0D hydrogen-bonded network involving corresponding cations and anions in a secondary ammonium monocarboxylate salt (synthon B or C) can indeed be transformed into a 1D network in 1:2 (acid/amine) dicarboxylate systems (9−12). The effects of the twisted/angular functional topology of the anion moiety on the resultant supramolecular architectures in the corresponding 1:2 (acid/amine) salts (13−15) are examined. The 1:1 salts (16−18) of the dicarboxylic acids having twisted/angular functional topology also display a 1D network

New series of organogelators derived from a combinatorial library of primary ammonium monocarboxylate salts

A crystal engineering approach has been adopted to generate a combinatorial library of 40 primary ammonium monocarboxylate salts derived from 10 cinnamic acid derivatives and 4 n-alkyl primary amines, as potential organic gelators. It is observed that 4-Cl, 4-Me, and 4-Br cinnamate salts of CH3(CH2)n−NH2 (n = 15) are gelators. A systematic study of 4-Br cinnamate salts of n-alkylamine with varying chain lengths indicates that the alkyl chain length has a profound effect on gelation. A structure−property correlation study has been attempted on the basis of single-crystal and powder X-ray diffraction data of the salts

Noncovalent syntheses of supramolecular organo gelators

Four new organo gelators, namely, dicyclohexylammonium hydrogen cyclobutane-1,1-dicarboxylate (1), dicyclohexylammonium cyclobutane-1,1-dicarboxylate (2), dibenzylammonium hydrogen cyclobutane-1,1-dicarboxylate (3), and dibenzylammonium cyclobutane-1,1-dicarboxylate (4), have been noncovalently synthesized. Single-crystal structures of all the gelators were determined to make an attempt to correlate their structure with their properties (gelation). The results support the conclusion that a one-dimensional hydrogen-bonded network in the crystal structure appears to be one of the prerequisites for gelation behavior