Continuous Monitoring of the Agglomeration and Sedimentation of Indomethacin Nanosuspensions Using T₂ Relaxation Time with Time-Domain NMR

The time-domain NMR technique was utilized to monitor precisely the physicochemical stability of indomethacin (IMC) nanosuspensions using T₂ relaxation time (T₂). We investigated whether T₂ values can distinguish between agglomeration and sedimentation. Nanosuspensions of IMC were prepared using aqueous wet bead milling with polyvinylpyrrolidone as a stabilizer. Prepared nanosuspensions were divided into two fractions: one was stored in the NMR equipment for continuous T₂ measurements and the other was stored in the dispersion analyzer. Measurements of both nanosuspensions were carried out, without dilution, over a period of 24h at 10-min intervals. Transmission profiles based on multilight scattering technology showed that agglomeration predominantly occurred at 25 and 35°C immediately after wet bead milling up to 4h, followed by sedimentation from 4 to 24h. Upon measuring the T₂ relaxation, T₂ values at both 25 and 35°C showed a two-step change—there was a significant prolongation in T₂ values immediately after preparation of nanosuspensions up to approx. 4h and a gradual prolongation in T₂ values from approx. 4 to 24h. Considering the results of transmission profiles, these two-step T₂ changes correspond to agglomeration and sedimentation. In other words, this study established that monitoring the T₂ values of nanosuspensions could be used to evaluate the agglomeration and sedimentation of contained drug particles. This technique does not directly observe the nanoparticles themselves, but the water molecules. Thus, measurement of T₂ relaxation is considered to be a general-purpose technique, independent of the type of drug or polymer.