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

Abstract

Differential scanning calorimetry and Raman spectroscopy were used to study the nonisothermal and isothermal crystallization behavior of amorphous indomethacin powders (with particle sizes ranging from 50 to 1000 µm) and their dependence on long-term storage conditions, either 0–100 days stored freely at laboratory ambient temperatures and humidity or placed in a desiccator at 10 °C. Whereas the γ-form polymorph always dominated, the accelerated formation of the α-form was observed in situations of heightened mobility (higher temperature and heating rate), increased amounts of mechanically induced defects, and prolonged free-surface nucleation. A complex crystallization behavior with two separated crystal growth modes (originating from either the mechanical defects or the free surface) was identified both isothermally and nonisothermally. The diffusionless glass–crystal (GC) crystal growth was found to proceed during the long-term storage at 10 °C and zero humidity, at the rate of ~100 µm of the γ-form surface crystalline layer being formed in 100 days. Storage at the laboratory temperature (still below the glass transition temperature) and humidity led only to a negligible/nondetectable GC growth for the fine indomethacin powders (particle size below ~150 µm), indicating a marked suppression of GC growth by the high density of mechanical defects under these conditions. The freely stored bulk material with no mechanical damage and a smooth surface exhibited zero traces of GC growth (as confirmed by microscopy) after >150 days of storage. The accuracy of the kinetic predictions of the indomethacin crystallization behavior was rather poor due to the combined influences of the mechanical defects, competing nucleation, and crystal growth processes of the two polymorphic phases as well as the GC growth complex dependence on the storage conditions within the vicinity of the glass transition temperature. Performing paired isothermal and nonisothermal kinetic measurements is thus highly recommended in macroscopic crystallization studies of drugs with similarly complicated crystal growth behaviors.

How the Presence of Crystalline Phase Affects Structural Relaxation in Molecular Liquids: The Case of Amorphous Indomethacin

“…Apart from the T g -related information (which will be introduced in detail later in this section), the DSC curves from Figure 2 also provide a very interesting insight into the crystallization behavior of amorphous and partially crystalline IMC. The coarse powder (300-500 µm) shows a relatively common behavior consistent with previous research conducted in this field [20,65]-i.e., the presence of the low-T-crystallized α polymorphic phase accelerates the crystal growth during the consequent secondary crystallization step (depicted in Figure 2B). On the contrary, in the case of the finely ground IMC powder (Figure 2A), the development of the crystallization behavior with the increasing content of the initially present crystalline phase is rather complex.…”

Thermo-Structural Characterization of Phase Transitions in Amorphous Griseofulvin: From Sub-Tg Relaxation and Crystal Growth to High-Temperature Decomposition

“…Note that the majority of known GSF polymorphs form from solution [42]. The widened onset and endset parts of the melting peak measured at higher q + can be attributed to the larger variety of crystallite sizes (which is in correspondence with a broad range of powder size distributions)-this is in contrast to the results measured for narrow size distributions in [38,43]. Also, GSF is the only drug, out of the three discussed, that exhibited T g -induced crystallization, which may be associated with GSF having one of the fastest surface diffusions (compared to bulk diffusion at T g ) [20]-more on this in the next paragraphs.…”

“…The results are listed in the Supplementary Materials. Overall, the very high correlation coefficients in the case of the main crystallization peaks indicate sufficient precision and accuracy for the data to be used in the kinetic modeling and predictions [43,70]. The significantly worse correlation coefficients obtained in the case of the crystallization pre-peaks (especially those obtained at high q + ) can be attributed to the overlap with the glass transition effect, where the subtraction of the thermo-kinetic background was not precise enough.…”

“…For these data, the simplified modeling/prediction approach based only on the E and A values would be recommended [70]. The most important conclusion resulting from the tabulated sc-MKA data is that the crystal growth mechanism is significantly temperature-dependent, and for the kinetic predictions extrapolated to the lower temperatures, the mathematic description determined for the q + = 0.5 • C•min −1 would be the most relevant and accurate to use [43,70].…”

Indole Derivatives: Unveiling New Frontiers in Medicinal and Synthetic Organic Chemistry

“…The kinetic predictions for indomethacin crystallization were limited due to complex factors such as mechanical defects, competing nucleation, crystal growth processes, and the dependence of GC growth on storage conditions near the glass transition temperature. The study emphasizes the importance of conducting isothermal and nonisothermal measurements in comprehensive studies of drugs with complex crystal growth behaviors [ 14 ].…”