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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.

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.

Many pharmaceutical bulk powders are known to have various solid states, such as polymorphic forms, solvates, and amorphous forms. The amorphous form is known to be recrystallized by absorbing various solvent vapors depending on the chemical properties. It is possible to perform a search for polymorphs of drugs by utilizing this property. In this study, the solvent properties of solvent vapor by using amorphous indomethacin (A-IMC) as a model drug were measured using X-ray diffraction (XRD) in terms of the effect on crystallization. A-IMC was exposed for 2 h at 30 °C in a sealed container with normal alcohols with different carbon number (ethanol, 1-propanol, 1-butanol, 1-pentanol, and 1-octanol), and changed to the stable crystalline form (γ-IMC) and the metastable form (α-IMC). Exposure to alcohol vapor with a long alkyl chain provided a high yield of the γ-form and a long induction period. It was considered that the rapid generation of crystal nuclei was performed by increasing the polarity of alcohol. [ABSTRACT FROM AUTHOR]

Amorphous indomethacin was prepared by melting the γ-form of indomethacin, spatially confined within microcontainers (inner diameter of 223 μm), followed by cooling of the melt at a rate of 14, 23 or 36 K/min. The physical stability of the amorphous indomethacin within microcontainers was investigated using Raman microscopy. Furthermore, the dissolution behaviour of confined amorphous indomethacin was evaluated in biorelevant intestinal media at pH 6.5. After 30 days of storage, 10.3 ± 1.2 % of the amorphous indomethacin cooled at 14 K/min and confined within microcontainers was found to be crystalline. When the melt of indomethacin was cooled at 23 or 36 K/min, 20.7 ± 1.5 and 31.0 ± 2.6 % of the indomethacin were found to be crystalline after storage for 30 days. Scanning electron microscopy showed a smooth surface of amorphous indomethacin within the microcontainers when cooling the melt at 14 K/min, whereas cracks and an uneven surface were observed when cooling at rates of 23 and 36 K/min. The uneven surface is hypothesised to be the main reason for the lower physical stability, as the cracks could act as nucleation sites for crystal growth. The rate of cooling was not seen to have any effect on the dissolution of amorphous indomethacin from the microcontainers. [ABSTRACT FROM AUTHOR]