Structural characterization of novel hydrolytic and oxidative degradation products of acalabrutinib by LC-Q-TOF-MS, H/D exchange and NMR.

The drug substance, acalabrutinib was subjected to hydrolytic (acid, base and neutral) and oxidative stress degradation as per ICH recommendations. Degradation products (DPs) generated from the drug substance were separated on a Shimadzu Shim-pak C-8 column utilizing a mobile phase composed of methanol: acetonitrile (90:10 v/v) and ammonium acetate buffer (10 mM, pH 3.80) in a gradient elution mode. Acalabrutinib was found to be labile under acid, basic, neutral and oxidative conditions. A total of eighteen DPs of drug substance were formed in hydrolytic (fourteen DPs) and oxidative degradation conditions (four DPs). All the DPs were characterized by comparing the LC-Q-TOF mass spectrometric fragmentation pathway of the drug substance with DPs. Further, hydrogen/deuterium (H/D) exchange studies were also carried out on the DPs to confirm the presence of labile hydrogens in their structures. Four DPs (H-12, O-2, O-3 and O-4) were isolated for chemical structural elucidation by NMR. Probable mechanisms involved in degradation of acalabrutinib were also postulated.

Molecular encapsulation of andrographolide in 2-hydroxypropyl-ß-cyclodextrin cavity: synthesis, characterization, pharmacokinetic and in vitro antiviral activity analysis against SARS-CoV-2.

In present investigation, AND-2-HyP-ß-CYD (Andrographolide-2-Hydroxypropyl-ß-cyclodextrin) complex was synthesized and characterized for antiviral and pharmacokinetic profile. The linear host-guest relation suggested synthesis of a 1:1 complex of AND with 2-HyP-ß-CYD by inclusion mode. The Kc, stability constant of the two phase system of AND with 2-HyP-ß-CYD computed to be 38.60 x 10-3M. 1H NMR spectrum of AND indicated the presence of triplet at 6.63-ppm which was up-fielded in AND-2-HyP-ß-CYD complex at 6.60-ppm (doublet) confirmed the insertion of AND in cavity of 2-HyP-ß-CYD through lactone ring. AND-2-HyP-ß-CYD complex exhibited the IC50 of 0.1-µg.mL-1 (E gene) and 0.29-µg.mL-1 (N gene) against SARS-CoV-2 infected Vero6 cells. Moreover, a 1.5-fold increment in extent of absorption of AND was noticed post complexation. The bioavailability was estimated to be 15.87 ± 3.84% and 23.84 ± 5.46%, respectively for AND and AND-2-HyP-ß-CYD complex. AND-2-HyP-ß-CYD complex may be a prospective candidate for further studies to evolve as a clinically viable formulation against SARS-CoV-2.