Indomethacin: The Interplay between Structural Relaxation, Viscous Flow and Crystal Growth

Abstract

Non-isothermal differential scanning calorimetry (DSC) was used to study the influences of particle size (daver) and heating rate (q+) on the structural relaxation, crystal growth and decomposition kinetics of amorphous indomethacin. The structural relaxation and decomposition processes exhibited daver-independent kinetics, with the q+ dependences based on the apparent activation energies of 342 and 106 kJ·mol−1, respectively. The DSC-measured crystal growth kinetics played a dominant role in the nucleation throughout the total macroscopic amorphous-to-crystalline transformation: the change from the zero-order to the autocatalytic mechanism with increasing q+, the significant alteration of kinetics, with the storage below the glass transition temperature, and the accelerated crystallization due to mechanically induced defects. Whereas slow q+ led to the formation of the thermodynamically stable γ polymorph, fast q+ produced a significant amount of the metastable α polymorph. Mutual correlations between the macroscopic and microscopic crystal growth processes, and between the viscous flow and structural relaxation motions, were discussed based on the values of the corresponding activation energies. Notably, this approach helped us to distinguish between particular crystal growth modes in the case of the powdered indomethacin materials. Ediger’s decoupling parameter was used to quantify the relationship between the viscosity and crystal growth. The link between the cooperativity of structural domains, parameters of the Tool-Narayanaswamy-Moynihan relaxation model and microscopic crystal growth was proposed.

Indomethacin: Effect of Diffusionless Crystal Growth on Thermal Stability during Long-Term Storage

“…The third basic feature of the IMC crystallization behavior is shown in Figure 1 C. This graph demonstrates the kinetics of the base thermokinetic phenomena initiated by the heating of the amorphous phase; the 300–500 µm powder fraction heated at different q + was chosen as an example. The endothermic glass transition signal at 45–50 °C only slightly shifts with increasing q + , which indicates a high activation energy for this process—in [ 25 ], this value was found to be 342 ± 7 kJ·mol −1 . The second effect on the DSC curves is exothermic and corresponds to the macroscopic manifestation of crystal growth.…”

“…The main goal of this paper was to explore the crystallization behavior of IMC with respect to the particle size and aging (long-term storage) conditions—the majority of the corresponding DSC data are summarized in Figure 2 . However, before interpreting the DSC data from Figure 2 , some basic facts [ 25 , 28 , 29 ] about the IMC polymorphic behavior need to be introduced: Nucleation below 55 °C dominantly produces the γ-IMC form, whereas, above 55 °C, the α-IMC nucleation is preferential. The crystal growth rate of the α-IMC form starts to exceed that of the γ-IMC form above 50 °C; the difference increases with rising T. The metastable α-IMC polymorph has lower interfacial energy σ (compared to the γ-IMC) [ 30 ], which results in preferential formation of the α-IMC nuclei in the cases of high molecular mobility [ 28 , 31 ].…”

“…Amorphous indomethacin was prepared using the melt-quenching routine [ 25 ] from 5N crystalline material (Sigma-Aldrich). Amorphous product was powdered into the following fractions: 20–50, 50–125, 125–180, 180–250, 250–300, and 300–500 µm.…”

“…The calorimetric crystallization data were obtained through differential scanning calorimetry (DSC), performed using a heat flow DSC instrument (Q2000, TA Instruments, New Castle, DE, USA). [ 25 ] The DSC heating scans were performed in the 20–180 °C range at heating rates (q + ) of 0.5, 1, 2, 5, 10, and 20 °C·min −1 . Sample masses were approximately 2 mg (accurately weighted to 0.01 mg); hermetically sealed low-mass T-zero DSC pans were used.…”

“…This paper is a sequel to the previous paper, which included more theoretical work on the general thermokinetic characterization of IMC [ 25 ], described all thermally induced phenomena observable in IMC, and introduced the hypotheses about their mutual relationships. This paper focuses on practical questions associated with the processing, and short- and long-term storage of various forms of amorphous IMC.…”