1H NMR Relaxation Study to Evaluate the Crystalline State of Active Pharmaceutical Ingredients Containing Solid Dosage Forms Using Time Domain NMR

Abstract

The aim of this study was to demonstrate the usefulness of the time domain nuclear magnetic resonance (TD-NMR) method to characterize the crystalline state of active pharmaceutical ingredients (APIs) containing solid dosage forms. In this study, carbamazepine and indomethacin are used as models for poorly water-soluble APIs. First, we measured the T 1 and T 2 relaxation behavior of crystalline and amorphous APIs. From the results, we were able to confirm that the T 1 relaxation time measured by TD-NMR is an effective parameter for distinguishing between crystalline and amorphous states in powdered APIs. We then examined physical mixtures of APIs with polyvinylpyrrolidone and their solid dispersion. The results indicated that TD-NMR allows the evaluation of not only the crystalline form of APIs but also the miscibility of APIs and polymers. In the final phase of the study, we conducted continuous monitoring of the crystalline state of APIs incorporated into physical mixtures during the thermal stress test. Conversion to crystalline forms of the APIs was successfully monitored based on the T 1 relaxation behavior. Our findings led us to conclude that TD-NMR is useful as a new approach to evaluate the crystalline state of APIs.

Exploring molecular reorientations in amorphous and recrystallized felodipine at the microscopic level

“…One can suppose that it is related to the reconstruction of the bifurcated hydrogen bond network in crystalline sample. 14 Bi-exponential recovery of magnetization was previously observed in cyclodextrin with diazepam, 48 drugs in silica matrices, [49][50][51] drugs with polymers, 23,52 or in the process of recrystallization of FLD of different grain sizes 42 of amorphous API. 53 The measurement 14 weeks aer amorphization showed a one-exponential magnetization recovery in all temperature range.…”

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

“…Various technical approaches have been applied in the pharmaceutical industry to improve the solubility of active pharmaceutical ingredients (APIs). [1][2][3][4][5] Amorphization using the solid dispersion (SD) technique is regarded as a promising pharmaceutical technology. 5) We recently used the timedomain NMR (TD-NMR) method to evaluate the crystalline state of APIs incorporated into solid oral dosage forms including amorphous SDs.…”

“…[1][2][3][4][5] Amorphization using the solid dispersion (SD) technique is regarded as a promising pharmaceutical technology. 5) We recently used the timedomain NMR (TD-NMR) method to evaluate the crystalline state of APIs incorporated into solid oral dosage forms including amorphous SDs. 6,7) TD-NMR is a benchtop instrument used for measuring the 1 H-NMR relaxation.…”

A Novel Approach to Evaluate Amorphous-to-Crystalline Transformation of Active Pharmaceutical Ingredients in Solid Dispersion Using Time-Domain NMR

“…For the development of solid-dispersion formulations, maintaining the amorphous state throughout the shelflife period is still a huge challenge. 11) Thus, it is important to investigate the crystalline state of APIs in solid dispersions in more detail.…”