02373nas a2200193 4500008004100000022001400041245007200055210006900127260000900196300001400205490000700219520174100226100002801967700002101995700001902016700001902035700002402054856010102078 2020 eng d a1528-748300aNaftopidil molecular salts with improved dissolution and permeation0 aNaftopidil molecular salts with improved dissolution and permeat cMAY  a3064-30760 v203 a

Naftopidil (NFPD) is a alpha 1 adrenoceptor antagonist drug. Low solubility and low permeability are the major drawbacks of this drug. The synthesis of multicomponent crystalline forms of this amine functional group drug with carboxylic acid coformers, both achiral and chiral acids, provides a solution to improve its solubility as well as permeability. Nine molecular salts were crystallized by liquid-assisted grinding followed by isothermal crystallization. Single-crystal X-ray diffraction analysis of the molecular salts showed that the structures are stabilized by strong N-H center dot center dot center dot O and O-H center dot center dot center dot O and weak C-H center dot center dot center dot O hydrogen bonds in the solid state. The bulk phase purity of new solid forms was confirmed by powder X-ray diffraction (PXRD), and the crystalline products were further characterized by IR spectroscopy and thermal analytical techniques (differential scanning calorimetry). The molecular salts exhibit superior dissolution rates compared to pure NFPD. However, during dissolution, NFPD showed decrease in concentration after 60 min for all salts due to precipitation. The supersaturation occurred due to salt disproportionation, which generates insoluble NFPD, as confirmed by PXRD of the residue. The salts reach high saturation concentration before 60 min, which is indicative of immediate release formulation to achieve fast onset of therapeutic activity. Moreover, the salts exhibit high saturation in phosphate buffer saline media and improved permeability compared to the pure drug. Finally, the D,L-malic acid racemate of NFPD shows enhanced dissolution and permeability compared to all other salts and pure NFPD.

1 aMannava, M., K. Chaitan1 aDandela, Rambabu1 aTothadi, Srinu1 aSolomon, Anand1 aNangia, Ashwini, K. uhttp://library.ncl.res.in/content/naftopidil-molecular-salts-improved-dissolution-and-permeation01823nas a2200181 4500008004100000022001400041245006000055210006000115260000800175300001200183490000700195520126300202100002401465700001801489700001901507700002401526856009101550 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. uhttp://library.ncl.res.in/content/novel-pharmaceutical-cocrystals-and-salts-bumetanide01779nas a2200205 4500008004100000245010700041210006900148260000800217300000700225490000700232520105500239653002001294653003001314653001801344653002701362100001701389700001901406700001901425856012901444 2022 eng d00aNucleophilic substitution at a coordinatively saturated five-membered NHC center dot haloborane centre0 aNucleophilic substitution at a coordinatively saturated fivememb cJUL a970 v103 a

In this paper, we have used a saturated five-membered N-Heterocyclic carbene (5SIDipp = 1,3-bis-(2,6-diisopropylphenyl)imidazolin-2-ylidine) for the synthesis of SNHC-haloboranes adducts and their further nucleophilic substitutions to put unusual functional groups at the central boron atom. The reaction of 5-SIDipp with RBCl2 yields Lewis-base adducts, 5-SIDipp center dot RBCl2 [R = H (1), Ph (2)]. The hydrolysis of 1 gives the NHC stabilized boric acid, 5-SIDipp center dot B(OH)(3) (3), selectively. Replacement of chlorine atoms from 1 and 2 with one equivalent of AgOTf led to the formation of 5-SIDipp center dot HBCl(OTf) (4) and 5-SIDipp center dot PhBCl(OTf) (5a), where all the substituents on the boron atoms are different. The addition of two equivalents of AgNO3 to 2 leads to the formation of rare di-nitro substituted 5-SIDipp center dot BPh(NO3)(2) (6). Further, the reaction of 5-SIDipp with B(C6F5)(3) in tetrahydrofuran and diethyl ether shows a frustrated Lewis pair type small molecule activated products, 7 and 8.

10aNHC-haloboranes10anucleophilic substitution10asaturated NHC10atetra-coordinate boron1 aKundu, Gargi1 aTothadi, Srinu1 aSen, Sakya, S. uhttp://library.ncl.res.in/content/nucleophilic-substitution-coordinatively-saturated-five-membered-nhc-center-dot-haloborane