02013nas a2200229 4500008004100000245011400041210006900155260000800224300001400232490000700246520121200253100002301465700002401488700002101512700001901533700001701552700001901569700002101588700002401609700002401633856012601657 2022 eng d00aNovel crystal forms of Entresto: a supramolecular complex of trisodium sacubitril/valsartan hemi-pentahydrate0 aNovel crystal forms of Entresto a supramolecular complex of tris cOCT a7387-73930 v243 a

Entresto is a salt-cocrystal supramolecular complex with the chemical name trisodium sacubitril/valsartan hemi-pentahydrate for treating chronic heart failure and was approved by the US FDA in 2015. This multidrug complex was synthesized in our laboratory to investigate its polymorphic behavior. Different crystallization conditions, including various solvent systems, yielded different novel solid forms of Entresto (Form-I to Form-VI), including the reported form. All the novel solids are solvent-dependent and were reproducibly crystallized on a 10 g scale quantity. The 1H NMR spectra confirmed the 1 : 1 stoichiometry of the two drugs, namely, sacubitril and valsartan, in all the solid forms of the crystalline products. Powder X-ray diffraction and DSC analysis of the crystalline solids established that they are distinct crystalline forms. Stability studies under ambient conditions carried out over a one-year period showed higher stability for Form-I and Form-III compared to the other forms, including the innovator crystal form (labelled as Form-II). The novel crystal forms (notably Form-I and Form-III) exhibit higher stability and less hygroscopicity than the reported Form-II.

1 aShaikh, Tabrez, R.1 aGeorge, Christy, P.1 aBhukya, Priyanka1 aShelke, Nikita1 aPawar, Komal1 aGarai, Abhijit1 aDandela, Rambabu1 aGonnade, Rajesh, G.1 aNangia, Ashwini, K. uhttps://library.ncl.res.in/content/novel-crystal-forms-entresto-supramolecular-complex-trisodium-sacubitrilvalsartan-hemi02461nas a2200169 4500008004100000245011900041210006900160260000800229300001600237490000700253520180700260100002402067700001902091700002902110700002402139856012802163 2022 eng d00aSynthesis of ternary cocrystals, salts, and hydrates of acefylline with enhanced dissolution and high permeability0 aSynthesis of ternary cocrystals salts and hydrates of acefylline cJUN a4165–41810 v223 a

Acefylline (ACF) is a stimulant xanthine derivative drug, which is formulated as a piperazine salt for the treatment of bronchial asthma. ACF falls under BCS class IV category of low solubility and poor permeability, which together limit the bioavailability and efficacy of the drug. In this work, ACF binary and ternary cocrystals, salts–cocrystals, and their polymorphs are synthesized by cocrystallization with several coformers. Two different methods were adopted for the supramolecular assembly of the ternary systems A.B.C: (1) first, binary adducts A.B or A.C were crystallized by grinding a slurry of the components in a suitable solvent and then C was added and grinding was continued; and (2) all three components were taken in a solvent slurry and ground together. The former method was found to be superior in affording the ternary salt/cocrystal. The role of laboratory seeding is implicated to explain the variation in crystallization results at different stages of the project. Crystal structures of the product’s binary and ternary systems were solved by single-crystal X-ray diffraction and powder X-ray diffraction data for structure solution. The crystal structures show the recurrence of carboxylate–pyridinium and imidazole–acid heterosynthons in the binary and ternary adducts. The intermolecular interactions between ACF and the coformer are analyzed by Hirshfeld surfaces, 2D fingerprint plots, and an energy framework. The permeability of ACF increases in binary and ternary systems with selected coformers. The fast dissolution and high permeability of ACF-PIP make this salt an improved crystalline formulation of acefylline.

1 aAllu, Suryanarayana1 aGarai, Abhijit1 aChernyshev, Vladimir, V.1 aNangia, Ashwini, K. uhttps://library.ncl.res.in/content/synthesis-ternary-cocrystals-salts-and-hydrates-acefylline-enhanced-dissolution-and-high