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.

Keywords: amorphous indomethacin; crystallization; kinetic prediction; particle size; storage.

Figure 1

(A) Glass-forming classification experiment performed using DSC for amorphous IMC. Exothermic signals evolve in the upwards direction. (B) Partial crystallinity acceleration test performed for amorphous IMC. (C) Example of the series of kinetic measurements performed as simple DSC heating scans of the amorphous IMC powder at different q⁺.

Figure 2

Example DSC curves obtained at 1 and 10 °C·min⁻¹ for various IMC powders with defined particle sizes. Each row of graphs corresponds to particular time and temperature storage conditions (powders were stored at laboratory temperature unless otherwise stated). Exothermic signals evolve in the upwards direction.

Figure 3

(A,B) Comparison of the DSC curves for the bulk IMC samples stored at either the laboratory temperature or at 10 °C. Exothermic signals evolve in the upwards direction. (C,D) Comparison of selected DSC curves for the IMC powders stored for 14 days at 10 °C and prepared either by gentle tapping or by forced grinding.

Figure 4

(A–C) Raman spectra of IMC powders stored for 0, 14, and 100 days at laboratory temperature and humidity. The notation of the spectra is as follows: (A) 20–50 µm, (B) 50–125 µm, (C) 125–180 µm, (D) 180–250 µm, (E) 250–300 µm, (F) 300–500 µm, (G) bulk (~500–1000 µm), (H) true bulk IMC formed as a droplet of molten IMC being allowed to cool/freeze-in on a microscopy slide, and (I) initial as-purchased IMC powder used to prepare the amorphous IMC. In graph (C), two spectra are displayed for sample H—one for the formed crystal and one for the free smooth surface. (D) Optical micrograph of a bulk sample stored for 100 days at 10 °C. The sample was then gently broken; the micrograph shows two pieces on the cross-section. The pale/white parts represent the surface crystalline layer formed by the GC growth mechanism.

Figure 5

Base characteristic quantities (glass transition temperature T_g—(A), the onset temperature of the crystallization peak T_onset—(B), the peak temperature of the crystallization peak T_p—(C), and crystallization enthalpy ΔH_c—(D) obtained at chosen q⁺ for the IMC powders stored under different conditions.

Figure 6

Graphs showing T_m,1, (A) T_m,2, (B) and the corresponding melting enthalpies ΔH_m,1 (C) and ΔH_m,2 (D) obtained at chosen q⁺ for the IMC powders stored under different conditions.

Figure 7

Kissinger plots for the IMC powders stored under different conditions. Each graph displays data for one time period: 0 days = as-prepared (A), 14 days (B), and 100 days (C).

Figure 8

(A) Activation energy of the crystallization process E_c determined using Equation (2) from the Kissinger dependencies displayed in Figure 7. (B) Values of the degree of conversion corresponding to the maxima of the characteristic kinetic functions z(α), see Equation (3), determined for the IMC powders stored under various conditions. The dashed horizontal lines indicate the applicability range of the JMA kinetic model.

Figure 9

DSC curves for the isothermal crystallization experiments that exhibited detectable and reproducible signals—generally, fine powders annealed at higher temperatures. Exothermic signals evolve in the upwards direction.

Figure 10

Tests of the kinetic prediction accuracy for isothermal crystallization based on the description of nonisothermal DSC data—the kinetic parameters of this description are listed in Table 1. For each of the two tested powders (50–125 µm and 250–300 µm), two annealing temperatures were selected and the corresponding isothermal crystallization experiments performed—solid lines represent the α–t data. For each of these four isothermal experiments, two theoretical predictions were made using the kinetic parameters obtained from the nonisothermal crystallization data measured at 0.5 and 20 °C·min⁻¹.