Crystal defects cause nitrosamine formation in ranitidine under accelerated storage conditions

Area of Science:

• Pharmaceutical Science
• Chemical Engineering
• Materials Science

Background:

• Nitrosamine impurities, such as N-nitrosodimethylamine (NDMA), are potent carcinogens found in pharmaceutical products like ranitidine hydrochloride (RAN).
• Previous research indicated a correlation between ranitidine hydrochloride's crystal morphology and its degradation rate into NDMA.
• Public health concerns and product recalls have been driven by the presence of these harmful impurities.

Purpose of the Study:

• To investigate the role of solid-state reactive species (SSRS) in NDMA formation within ranitidine hydrochloride.
• To establish a quantitative relationship between SSRS levels and NDMA generation under controlled conditions.
• To assess the impact of manufacturing processes on SSRS introduction and subsequent drug degradation.

Main Methods:

• Systematic introduction of SSRS into ranitidine hydrochloride using cryogenic milling.
• Stability testing of ranitidine hydrochloride at 60 °C and 0% relative humidity (RH).
• Quantification of NDMA formation in relation to SSRS concentration and manufacturing methods (e.g., milling, tablet preparation).

Main Results:

• A direct correlation was observed between the amount of SSRS in ranitidine hydrochloride and the extent of NDMA formed during stability studies.
• Cryogenically milled samples, containing higher SSRS levels, exhibited NDMA formation rates up to two orders of magnitude greater than unprocessed samples.
• Ranitidine hydrochloride tablets manufactured with increased SSRS also demonstrated accelerated NDMA formation.

Conclusions:

• NDMA formation in ranitidine hydrochloride is significantly driven by solid-state reactive species (SSRS) generated during manufacturing processes.
• Controlling and mitigating SSRS in drug substances and products is essential for ensuring pharmaceutical quality and patient safety.
• This study highlights the critical need to address SSRS during pharmaceutical manufacturing to prevent impurity formation and associated health risks.