A chemometric model for the quantitative determination of isotopic impurities in d3-methylamine hydrochloride by Fourier-transform infrared spectroscopy.

Deuterated drug molecules are of increasing interest to the pharmaceutical industry due to their capacity to slow metabolism and the potential for improved pharmacokinetics or improved pharmacodynamics they may offer over their non-deuterated counterparts. The desired level of deuteration or isotopic purity is a critical quality attribute for these compounds that can be essential for drug efficacy or patient safety. Deuterated reagents are often used to introduce a deuterated moiety into the drug substance; as such, isotopic impurities in these deuterated input materials need to be tightly controlled. A novel Fourier-transform infrared (FTIR) spectroscopic method was developed and evaluated as a fast and straightforward technique to quantify low-level isotopic impurities in the deuterated reagent d3-methylamine hydrochloride. Using data acquired through LC-MS analysis, the resulting chemometric model was validated according to ICH Q2(R1) guidelines achieving limits of quantitation of 0.31, 0.31, and 0.34 wt% for d0-, d1- and d2-methylamine hydrochloride impurities respectively.

Installing the "magic methyl"- C-H methylation in synthesis.

The selective and efficient C-H methylation of sp2 and sp3 carbon centres has become a powerful transformation in the synthetic toolbox. Due to the potential for profound changes to physicochemical properties attributed to the installation of a "Magic Methyl" group at a strategic site in a lead compound, such techniques have become highly desirable in modern drug discovery and synthesis programmes. This review will cover the diverse techniques that have been employed to enable the selective installation of the C-Me bond in a wide range of chemical structures, from simple building blocks to complex drug-like architectures.