<i>T</i>₂ Relaxation Study to Evaluate the Crystalline State of Indomethacin Containing Solid Dispersions Using Time-Domain NMR

Abstract

The aim of this study was to demonstrate the usefulness of T 2 measurements conducted with a timedomain NMR (TD-NMR) for the characterization of active pharmaceutical ingredients (APIs) containing solid dosage forms. A solid dispersion (SD) and a physical mixture (PM) consisting of indomethacin (IMC) and polyvinylpyrrolidone (PVP) were prepared at different weight ratios as test samples, and then their T 2 relaxation curves were measured by TD-NMR. The T 2 relaxation curve of IMC was quite different from that of PVP by nature. T 2 values of the SD and PM samples became gradually shortened with increasing IMC content. No difference in T 2 relaxation curves was observed between SD and PM. By analyzing the T 2 relaxation curves in detail, we succeeded in precisely quantifying the IMC contents incorporated in the samples. Next, this study evaluated the T 2 relaxation curves of amorphous and crystalline states of powdered IMC. T 2 relaxation rate of crystalline IMC was slightly but significantly higher than that of amorphous IMC, proving that the T 2 measurement was sensitive enough to detect these differences. Finally, a thermal stress was imposed on SD and PM samples at 60°C for 7 d, and then an amorphous-to-crystalline transformation occurred in IMC in the PM sample and was successfully monitored by T 2 measurement. We believe that T 2 measurement by TD-NMR is a promising analysis for the characterization of APIs in solid dosage forms, including SD-based pharmaceuticals.

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

“…We have already demonstrated this analysis by testing two different binary blends consisting of IMC (a model API) and polyvinylpyrrolidone (PVP) (a model additive) 14) and consisting of amorphous and crystalline IMC. 13) Table 2 shows the free base contents estimated from the T 2 relaxation curves by using Eq. ( 5).…”

“…We also investigated the crystalline state of APIs by using TD-NMR. [13][14][15] In previous studies, we demonstrated that the T 1 and T 2 relaxation curves measured by TD-NMR could be applied to identify differences between amorphous and crystalline APIs: amorphous APIs showed shorter T 1 and longer T 2 than crystalline APIs because of the higher molecular mobility.…”

Low-Field NMR to Characterize the Crystalline State of Ibuprofen Confined in Ordered or Nonordered Mesoporous Silica

“…The development of a technology that can evaluate the drug itself regardless of the functional group was desired. Therefore, we decided to measure the 1 H-NMR relaxation of the drug by NMR and report the dissolution profile of the drug, noting that the drug has 1 H and silica has almost no 1 H. The T 1 relaxation of solid drugs shows a larger difference between crystalline and amorphous than the T 2 relaxation 16) ; therefore, the T 1 relaxation was mainly measured and its behavior was compared between IBU-loaded T 1 (ms) T 1(short) (ms) T 1(long) (ms) P 1(short) (%) P SBA, IBU-loaded SYL, and IBU-loaded AER. First, we will discuss the NMR relaxation of IBU-loaded SBA that generated supersaturated solutions.…”

“…In particular, we characterized the IBU-loaded SBA by its T 1 relaxation because the difference of T 1 values between amorphous and crystalline for solid samples is larger than that of T 2 relaxation. 16) Using this feature, the crystalline states of the drugs in SYL and AER could be distinguished as T 1(short) and T 1(long) values. It is also worth noting that a benchtop and low-field instrument was applied in this study.…”

“…To date, measuring NMR relaxation can evaluate the crystalline state of drug powder. [16][17][18][19] While the drug molecule has protons, silica has few protons; therefore, the crystalline state of the drug-loaded silica can be evaluated by 1 H-NMR relaxation. In the present study, NMR relaxation was measured using low-field time-domain NMR (TD-NMR).…”