Development of 1H qNMR Analytical Procedure for Purity Determination of Imazosulfuron and 1,4-BTMSB-d4 for ISO 17034 Accreditation.

Abstract

Background: Quantitative NMR spectroscopy (qNMR) can be used to determine chemical purity. This applies to the resonating nuclei of all the present chemical species, enabling quantitation of the analyte against chemically nonidentical calibrator molecules.

Objective: Validation approaches for determining chemical purity with qNMR are being endorsed by major pharmacopoeias and other standard-setting bodies. In this study, we investigated the purity determination, uncertainty evaluation, and method validation of imazosulfuron using qNMR to gain ISO 17034 accreditation.

Methods: We ensured the NIST traceability of imazosulfuron by calibrating 1,4-BTMSB-d4 (determining its purity and uncertainty) using NIST PS 1 and then calibrating imazosulfuron using the calibrated 1,4-BTMSB-d4. Purity and uncertainty determinations were performed using qNMR, as per the proposed revisions to the USP General Chapters <761> and <1761>. Method development and validation were performed as described in these chapters using the principles of Analytical Quality by Design (AQbD).

Results: First, we defined a target measurement uncertainty of ±2.0% (k = 2) as the Analytical Target Profile (ATP). Next, we established robust operating parameters for qNMR and determined the purity and uncertainty of 1,4-BTMSB-d4. Subsequently, we determined the purity and uncertainty of imazosulfuron using the calibrated 1,4-BTMSB-d4 to verify that the qNMR method produced reportable values that met the ATP criteria.

Conclusions: The purity and uncertainty of imazosulfuron were 98.2% ± 1.2% (k = 2), meeting the ATP criteria. We then moved on to the next stage to monitor and ensure that the qNMR method remains properly controlled and to satisfy the ATP criteria during routine use. Based on the above, we established a validation scheme that meets the requirements of ISO 17034 by leveraging AQbD considerations.

Highlights: The AQbD principles shift the focus of method validation toward procedure design and development, resulting in more rational design, efficient development, and validation.