Development of a Stability-Indicating Purity Method for Ubrogepant through Stress Degradation Analysis, Extraction, and Characterization of Unidentified Degradation Products Using Flash Chromatography, NMR, IR, and LC-MS.

BACKGROUND: Ubrogepant is a prescription medication used to prevent migraine headaches. It is currently available in tablet form. OBJECTIVE: The goal of this work is to investigate the drug degradation profile of Ubrogepant, as well as to isolate and characterize undiscovered Ubrogepant degradation products by utilizing LC-MS, NMR, and IR spectroscopic analytical techniques. Furthermore, to develop a high resolution, sensitive, stability-indicating analytical approach for detecting and quantifying Ubrogepant degradation products in its pharmaceutical formulation. METHOD: To identify and quantify the degradation products of Ubrogepant in pharmaceutical products, a novel gradient reverse-phase HPLC (RP-HPLC) technique with a PDA detector was developed by utilizing a C18 stationary phase column. The eluent comprised a mixture of acetonitrile and water with 0.1% v/v ortho-phosphoric acid. To establish the intrinsic stability of Ubrogepant pharmaceutical product, it was stress tested under various degrading circumstances, including water, alkaline, acid hydrolysis, photolytic, oxidative, and thermal. Flash chromatography was used to isolate the two major degradants, and the structures were determined using NMR (1H , 13C, DEPT 135), IR, and LC-MS methods. RESULTS: The Ubrogepant medication was relatively more degradable in alkaline and acidic circumstances, and two unique degradation products were discovered. Based on spectroscopic and chromatographic evidence, it was conclusively demonstrated that these unique compounds were Ubrogepant hydrolysis products. All degradation products have been separated with a resolution greater than 2.0. The peak purity data shown that the Ubrogepant peak in all of the stress samples examined was pure. Under all stress environments, Ubrogepant achieved a minimum mass balance of 95%. The validated developed approach was sensitive enough to quantify Ubrogepant degradation products at 0.03% of the Ubrogepant test concentration. CONCLUSIONS: The proposed method was found to be stability-indicating since it fits all of the regulatory authorities' typical requirements. This method is highly efficient for detecting and quantifying impurities in Ubrogepant drug substances and drug products in QC laboratories. HIGHLIGHTS: Two new degradation products of Ubrogepant were successfully extracted and characterized using NMR, IR, and LC-MS spectroscopic methods. The proposed HPLC method can accurately quantify the degradation products of Ubrogepant in pharmaceutical products and is sensitive enough to detect degradation products of Ubrogepant as low as 0.17 µg/mL.

QbD-Based UPLC Method for Quantification of Brexpiprazole in Presence of Impurities and Application to In Vitro Dissolution.

Quality-by-design-based UPLC method was developed for chromatographic separation to quantify the antischizophrenic drug brexpiprazole in the presence of impurities. Research findings from pH-scouting studies were used as control variables which influence the chromatographic separation. The peak tailing and resolution are the response variables and established the design-space by DoE-study for selection of suitable chromatographic conditions. Separation was achieved with lower particle size stationary phase and buffer pH 2.0 in the mobile phase. The present method developed through C18 50 × 2.1 mm, Ethylene-Bridged-Hybrid technology column with 1.7 µm particles, mobile phase consists of pH 2.0 buffer and acetonitrile (67:33 v/v), flow rate of 0.5 mL min-1 and detection wavelength at 215 nm. The retention time of brexpiprazole is 0.6 min and all impurities were eluted within 2 min. The method linearity ranges were 20.4-61.3 µg mL-1 for assay and 0.88-6.59 µg mL-1 for dissolution with correlation-coefficients of 0.9999 and 0.9998 for assay and dissolution, respectively. The recovery values were found in between 99.3 and 100.9%. The method shows stability-indicating on the basis of noninterference of placebo, and impurities from forced-degradation studies. Method validation was carried out according to ICH guideline Q2 (R1).

Design, synthesis and anti-tumour activity of new pyrimidine-pyrrole appended triazoles.

The new pyrimidine-pyrrole scaffolds (7a-7m) with substituted 1,2,3-traizole moiety were synthesized in good to mild yields and subjected for anti-cancer activity against melanoma and breast cancer cell lines using MTT assay. The compounds 7f and 7m exhibited highest anti-cancer activity against both the tested cell lines in in vitro assay. The molecular docking analysis provided the insights of binding orientation of pyrimidine-pyrrole nucleus of current ligands and their crucial interactions with Cys797 and other residues of the EGFR tyrosine kinase active site. The interactions of triazole and its various substituted groups with EGFR tyrosine kinase have been discussed.