Characterization of the Salt and Free Base of Active Pharmaceutical Ingredients Based on NMR Relaxometry Measured by Time Domain NMR

Abstract

NMR relaxometry measurement by time domain NMR (TD-NMR) is a promising technique for characterizing the properties of active pharmaceutical ingredients (APIs). This study is dedicated to identifying the salt and free base of APIs by NMR relaxometry measured by the TD-NMR technique. Procaine (PC) and tetracaine (TC) were selected as model APIs to be tested. By using conventional methods including powder X-ray diffraction and differential scanning calorimetry, this study first confirmed that the salt and free base of the tested APIs differ from each other in their crystalline form. Subsequently, measurements of T 1 and T 2 relaxation were performed on the tested APIs using TD-NMR. The results demonstrated that these NMR relaxometry measurements have sufficient capacity to distinguish the difference between the free base and salt of the tested APIs. Furthermore, quantification of the composition of the binary powder blends consisting of salt and free bases was conducted by analyzing the acquired T 1 and T 2 relaxation curves. The analysis of the T 1 relaxation curves provided a partly acceptable estimation: a good estimation of the composition was observed from PC powders, whereas for TC powders the estimation accuracy changed with the free base content in the binary blends. For the analysis on T 2 relaxation curves, a precise estimation of the composition was observed from all the samples. From these findings, the NMR relaxometry measurement by TD-NMR, in particular the T 2 relaxation measurement, is effective for evaluating the properties of APIs having different crystalline forms.

Determination of Hardness of a Pharmaceutical Oral Jelly by Using <i>T</i>₂ Relaxation Behavior Measured by Time-Domain NMR

“…The spin-lattice relaxation time, T 1 , is the time constant with which the net magnetization of the spin ensemble returns to equilibrium by rearranging with the external magnetic field, whereas the spin-spin relaxation time, T 2 , reflects the fact that the transverse relaxation is the time constant with which the transverse polarization of the spin ensemble returns to its zero equilibrium value after excitation by a radiofrequency pulse. [9][10][11][12] These NMR parameters represent the molecular mobility of the measured substances. In particular, it is known that T 2 becomes monotonically shorter with molecular mobility restriction.…”

“…Furthermore, the measurement time for the T 2 relaxation time is much shorter than for T 1 . 12) To date, numerous technical reports show that the T 2 values of jellies and hydrogels are negatively correlated with their hardness. The tested samples contained hydrolysatepolysaccharide gel, 8) gelatin hydrogels cross-linked by cellulose nanowhiskers, 6) myofibrillar gels, 3,5) and polyvinyl alcohol cryogel.…”

“…The applications have also expanded into the fields of chemistry, 14,15) food, [16][17][18] and plants. 19,20) We applied TD-NMR analysis to evaluate characteristics of pharmaceuticals such as the crystalline state of active pharmaceutical ingredients in solid dosage forms, 12,21) the state of water incorporated in wet granules, 22) the dispersion state of pharmaceutical nanosuspensions, 23,24) and the hygroscopic behavior of disintegrants. 25) The jellies tested in this study were prepared with different compositions using ternary gel-forming agents.…”

NMR Longitudinal Rotating Frame Relaxation Time (T1ρ) with a Weak Spin Locking Field as an Approach to Characterize Solid-State Active Pharmaceutical Ingredients: Proof of Concept

“…The authors also performed T 2 -based investigations to evaluate the crystalline state of indomethacin in solid dispersions. 7 Chiba et al 9 (2022) evaluated the use of T 1 and T 2 relaxation times to characterize salt and free base of procaine and tetracaine API. Sinyavsky and Mershiev (2023) 23 evaluated the molecular dynamics of paracetamol and sulfanilamide polymorphs using T 1 and T 2 relaxation times.…”

“…Only recently, applications of TD-NMR have shown an increase in pharmaceutical practices. − Amongst them, studies have focused on use of TD-NMR to characterize solid-state active pharmaceutical ingredients (APIs). − These applications offer new opportunities to investigate the structural and dynamic characteristics of API solid forms in terms of various physical and chemical properties, impacting API bioavailability and efficacy.…”