Isolation of a Degradation Product of Ranitidine Hydrochloride Using the Waters Analytical Scale Purification System

Význam tématu

Understanding and isolating degradation products in pharmaceutical development is essential for ensuring drug safety, efficacy and consistent product quality. Forced-degradation studies reveal potential impurities that may form during storage or processing. Isolating these products enables detailed structural characterization, supports formulation optimization and upholds regulatory standards.

Cíle a přehled studie / článku

This application note demonstrates the selective isolation of a major basic-degradation product of ranitidine hydrochloride using the Waters Analytical Scale Purification System. Key objectives include:

• Perform forced-degradation under basic, acidic and thermal stress conditions.
• Develop an analytical LC method to detect a degradation product at m/z 302.
• Scale up the method to preparative conditions and collect high-purity fractions.
• Validate the purity and assess loading capacity for increased yield.

Použitá metodika a instrumentace

Forced-degradation solutions of ranitidine drug substance and tablet extracts (1 mg/mL) were treated with 0.5 M NaOH, 0.5 M HCl or heat at 55 °C for up to 24 h. Samples were neutralized, diluted to 0.1 mg/mL and analyzed by HPLC–PDA–MS. The analytical separation used an Arc Premier System with a 4.6×50 mm, 3.5 µm XBridge Premier BEH C18 column at 30 °C, gradient elution (0.1% formic acid in water/methanol) and ESI+ detection (m/z 50–350). Preparative isolation employed the Waters Analytical Scale Purification System with two QSM-R pumps, 3767 Sample Manager, PDA and ACQUITY QDa II detectors, a 10×50 mm, 3.5 µm XBridge Premier Peptide BEH C18 column, and MassLynx/FractionLynx software for automated fraction collection.

• Analytical system: Arc Premier LC, 2998 PDA, ACQUITY QDa II Mass Detector.
• Preparative system: Waters Analytical Scale Purification System, 3767 Sample Manager, ISM, CM-30S Column Manager.
• Software: Empower 3.8.0 (analytical), MassLynx 4.2 with FractionLynx (preparative).

Hlavní výsledky a diskuse

A significant degradation product at m/z 302 formed under basic stress. Analytical LC baseline-resolved this impurity from the ranitidine API. Scale-up to a preparative column with identical L/dp ratio maintained resolution while increasing load. MS- and UV-directed fraction collection selectively trapped the m/z 302 peak. Purity assessment by analytical re-injection showed:

• Chromatographic purity: 99.7% area by HPLC–PDA.
• Spectral purity: homogenous UV spectrum (purity angle below threshold) and single mass signal at m/z 302.
• Loading study: injection volumes up to 600 µL (8.5× scale) yielded 96.3–97.5% purity, demonstrating robustness of preparative method.

Přínosy a praktické využití metody

The workflow offers:

• Rapid method scale-up via matched column chemistry and L/dp ratio.
• Efficient isolation using sub-5 µm preparative columns at high pressure (up to 9500 psi).
• Automated, mass- and UV-triggered fraction collection to enhance selectivity.
• High-purity material suitable for structural elucidation, toxicology and formulation studies.

Budoucí trendy a možnosti využití

Future developments may integrate high-throughput purification, advanced detectors (e.g. high-resolution MS), and predictive software for real-time fraction optimization. Emerging micro- and preparative techniques can further accelerate impurity profiling and support continuous manufacturing platforms in pharmaceutics.

Závěr

The Waters Analytical Scale Purification System successfully isolated a ranitidine degradation product with high purity (>99.7%) and scalable loading capacity. Matched analytical and preparative column design, combined with automated MS/UV fraction collection, streamlines impurity isolation workflows critical to pharmaceutical research and quality control.

Reference

• United States Pharmacopeia. General Chapter <1086> Impurities in Drug Substances and Drug Products. USP 40-NF 35, 2015.
• Dhangar KR, Jagtap RB, Surana SJ, Shirkhedkar AA. Impurity Profiling of Drugs: Theory and Practice. J. Chil. Chem. Soc. 62(2):2017.
• Alsante KM, Hatajik TD, Lohr LL, Sharp TR. Isolation and Identification of Process Related Impurities. Pfizer R&D, 2001.
• ICH Q1A. Stability Testing of New Drug Substances and Products. EMA, 2003.
• Jablonski J. 5 Rules of Scaling LC Purification. Waters Corp., 2024.
• Waters Analytical Scale Purification System. Waters Corp., Product Brochure.