Daniela Košťálová

Purpose: Amorphous active pharmaceutical ingredients (APIs) are generally considered to have significantly higher bioavailability, compared to their crystalline counterpart, due to the enhanced solubility of the disordered phase. However, an akin functionality can be also adopted by the particle size of the powdered API. In this case study, a detailed investigation of the particle-size-influenced properties of amorphous griseofulvin powders will be introduced. Methods: The crystallization of amorphous griseofulvin powders in the range 20 – 1000 μm (+ 2 – 10 μm only for crystalline form) was studied calorimetrically, spectroscopically, and microscopically. Dissolution profiles of pharmaceutical tablets with incorporated either amorphous or crystalline griseofulvin were obtained under conditions simulating the path through the gastrointestinal tract. Results: Standard crystal growth regime was accompanied by the rapid diffusionless growth mode, which was detected at low heating rates for the finest griseofulvin powders. The dissolution profiles of the pharmaceutical tablets with incorporated individual griseofulvin powder fractions were described in terms of the Korsmeyer-Peppas model (indicating the release by super case II transport). Conclusion: Particle size was found to play dominant role in the dissolution kinetics, whereas the difference in the dissolution rates of the crystalline and amorphous particles was rather negligible. This is a beneficial finding, considering the very low stability of finely powdered amorphous griseofulvin, but at the same time, it negates the primary purpose of amorphization. Main benefit is thus that of the coarse amorphous griseofulvin powder, which can be utilized to fine-tune the dissolution profile due to its delayed dissolution.

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 (d_aver) and heating rate (q⁺) on the structural relaxation, crystal growth and decomposition kinetics of amorphous indomethacin. The structural relaxation and decomposition processes exhibited d_aver-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.