Thermokinetic characterization of amorphous carbamazepine was performed utilizing non-isothermal differential scanning calorimetry (DSC) and thermogravimetry (TGA). Structural relaxation of the amorphous matrix was described in terms of the Tool-Narayanaswamy-Moynihan model with the following parameters: Δh* ≈ 200-300 kJ·mol-1, β = 0.57, x = 0.44. The crystallization of the amorphous phase was modeled using complex Šesták-Berggren kinetics, which incorporates temperature-dependent activation energy and degree of autocatalysis. The activation energy of the crystal growth was determined to be >320 kJ·mol-1 at the glass transition temperature (Tg). Owing to such a high value, the amorphous carbamazepine is stable at Tg, allowing for extensive processing of the amorphous phase (e.g., self-healing of the quench-induced mechanical defects or internal stress). A discussion was conducted regarding the converse relation between the activation energies of relaxation and crystal growth, which is possibly responsible for the absence of sub-Tg crystal growth modes. The high-temperature thermal decomposition of carbamazepine proceeds via multistep kinetics, identically in both an inert and an oxidizing atmosphere. A complex reaction mechanism, consisting of a series of consecutive and competing reactions, was proposed to explain the second decomposition step, which exhibited a temporary mass increase. Whereas a negligible degree of carbamazepine degradation was predicted for the temperature characteristic of the pharmaceutical hot-melt extrusion (~150 °C), the degradation risk during the pharmaceutical 3D printing was calculated to be considerably higher (1-2% mass loss at temperatures 190-200 °C).

• Klíčová slova
• carbamazepine, crystal growth, structural relaxation, thermal decomposition,
• MeSH
• diferenciální skenovací kalorimetrie MeSH
• karbamazepin * chemie   MeSH
• kinetika MeSH
• krystalizace MeSH
• teplota MeSH
• termogravimetrie MeSH
• tranzitní teplota MeSH
• vysoká teplota MeSH
• změna skupenství * MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• karbamazepin * MeSH

The particle size-dependent processes of structural relaxation and crystal growth in amorphous nifedipine were studied by means of non-isothermal differential scanning calorimetry (DSC) and Raman microscopy. The enthalpy relaxation was described in terms of the Tool-Narayanaswamy-Moynihan model, with the relaxation motions exhibiting the activation energy of 279 kJ·mol-1 for the temperature shift, but with a significantly higher value of ~500 kJ·mol-1 being obtained for the rapid transition from the glassy to the undercooled liquid state (the latter is in agreement with the activation energy of the viscous flow). This may suggest different types of relaxation kinetics manifesting during slow and rapid heating, with only a certain portion of the relaxation motions occurring that are dependent on the parameters of a given temperature range and time frame. The DSC-recorded crystallization was found to be complex, consisting of four sub-processes: primary crystal growth of αp and βp polymorphs, enantiotropic βp → βp' transformation, and βp/βp' → αp recrystallization. Overall, nifedipine was found to be prone to the rapid glass-crystal growth that occurs below the glass transition temperature; a tendency of low-temperature degradation of the amorphous phase markedly increased with decreasing particle size (the main reason being the increased number of surface and bulk micro-cracks and mechanically induced defects). The activation energies of the DSC-monitored crystallization processes varied in the 100-125 kJ·mol-1 range, which is in agreement with the microscopically measured activation energies of crystal growth. Considering the potential correlations between the structural relaxation and crystal growth processes interpreted within the Transition Zone Theory, a certain threshold in the complexity and magnitude of the cooperating regions (as determined from the structural relaxation) may exist, which can lead to a slow-down of the crystal growth if exceeded.

• Klíčová slova
• DSC, Raman microscopy, amorphous nifedipine, crystal growth, structural relaxation,
• Publikační typ
• časopisecké články MeSH

The performance of in situ Raman microscopy (IRM) in monitoring the crystallization kinetics of amorphous drugs (griseofulvin and indomethacin) was evaluated using a comparison with the data obtained via differential scanning calorimetry (DSC). IRM was found to accurately and sensitively detect the initial stages of the crystal growth processes, including the rapid glass-crystal surface growth or recrystallization between polymorphic phases, with the reliable localized identification of the particular polymorphs being the main advantage of IRM over DSC. However, from the quantitative point of view, the reproducibility of the IRM measurements was found to be potentially significantly hindered due to inaccurate temperature recording and calibration, variability in the Raman spectra corresponding to the fully amorphous and crystalline phases, and an overly limited number of spectra possible to collect during acceptable experimental timescales because of the applied heating rates. Since theoretical simulations showed that, from the kinetics point of view, the constant density of collected data points per kinetic effect results in the smallest distortions, only the employment of the fast Raman mapping functions could advance the performance of IRM above that of calorimetric measurements.

• Klíčová slova
• DSC, amorphous drugs, crystal growth kinetics, in situ Raman microscopy,
• Publikační typ
• časopisecké články MeSH

The nonexponentiality and nonlinearity are two essential features of the structural relaxation in any glass-forming material, which seem to be inextricably bound together by the material time. It is shown that the temperature down-jump and up-jump experiments of the same magnitude ΔT = T0 - T to the same temperature T provide a clue for their separation. The isothermal structural relaxation can be quantified using the stabilization period on the logarithmic time scale log(tm/t0). It is described as the sum of the nonexponentiality term 1.181/ß and the nonlinearity term (σ/2.303)ΔT for the temperature down-jump, and as their difference for the temperature up-jump. The material parameter σ = -(∂lnτ/∂Tf)i quantifies variation of the relaxation time with structural changes at the inflection point of the relaxation curve and is formulated for the most widely used phenomenological models. The asymmetry of approach to equilibrium after the temperature down-jump and up-jump was first described by Kovacs in 1963. A detailed analysis of this asymmetry is provided, and a simple method for the estimation of the parameters characterizing the nonexponentiality (ß) and nonlinearity (σ) is proposed. The applicability of this method is tested using previously reported isothermal experimental data as well as calculated data for aging of polymers and other glass-forming materials. This concept illuminates differences in structural relaxation kinetics in a simple and consistent way that can be useful in the design of novel materials and the evaluation of their physical aging treatment.

• Publikační typ
• časopisecké články MeSH

The processes of structural relaxation, crystal growth, and thermal decomposition were studied for amorphous griseofulvin (GSF) by means of thermo-analytical, microscopic, spectroscopic, and diffraction techniques. The activation energy of ~395 kJ·mol-1 can be attributed to the structural relaxation motions described in terms of the Tool-Narayanaswamy-Moynihan model. Whereas the bulk amorphous GSF is very stable, the presence of mechanical defects and micro-cracks results in partial crystallization initiated by the transition from the glassy to the under-cooled liquid state (at ~80 °C). A key aspect of this crystal growth mode is the presence of a sufficiently nucleated vicinity of the disrupted amorphous phase; the crystal growth itself is a rate-determining step. The main macroscopic (calorimetrically observed) crystallization process occurs in amorphous GSF at 115-135 °C. In both cases, the common polymorph I is dominantly formed. Whereas the macroscopic crystallization of coarse GSF powder exhibits similar activation energy (~235 kJ·mol-1) as that of microscopically observed growth in bulk material, the activation energy of the fine GSF powder macroscopic crystallization gradually changes (as temperature and/or heating rate increase) from the activation energy of microscopic surface growth (~105 kJ·mol-1) to that observed for the growth in bulk GSF. The macroscopic crystal growth kinetics can be accurately described in terms of the complex mechanism, utilizing two independent autocatalytic Šesták-Berggren processes. Thermal decomposition of GSF proceeds identically in N2 and in air atmospheres with the activation energy of ~105 kJ·mol-1. The coincidence of the GSF melting temperature and the onset of decomposition (both at 200 °C) indicates that evaporation may initiate or compete with the decomposition process.

• Klíčová slova
• DSC, amorphous griseofulvin, crystal growth, particle size, structural relaxation,
• Publikační typ
• časopisecké články MeSH

The influence of partial crystallinity on the structural relaxation behavior of low-molecular organic glasses is, contrary to, e.g., polymeric materials, a largely unexplored territory. In the present study, differential scanning calorimetry was used to prepare a series of amorphous indomethacin powders crystallized to various extents. The preparations stemmed from the two distinct particle size fractions: 50-125 µm and 300-500 µm. The structural relaxation data from the cyclic calorimetric measurements were described in terms of the phenomenological Tool-Narayanaswamy-Moynihan model. For the 300-500 µm powder, the crystalline phase forming dominantly on the surface led to a monotonous decrease in the glass transition by ~6 °C in the 0-70% crystallinity range. The activation energy of the relaxation motions and the degree of heterogeneity within the relaxing matrix were not influenced by the increasing crystallinity, while the interconnectivity slightly increased. This behavior was attributed to the release of the quenched-in stresses and to the consequent slight increase in the structural interconnectivity. For the 50-125 µm powder, distinctly different relaxation dynamics were observed. This leads to a conclusion that the crystalline phase grows throughout the bulk glassy matrix along the internal micro-cracks. At higher crystallinity, a sharp increase in Tg, an increase in interconnectivity, and an increase in the variability of structural units engaged in the relaxation motions were observed.

• Klíčová slova
• TNM model, crystallinity, indomethacin, structural relaxation,
• MeSH
• diferenciální skenovací kalorimetrie MeSH
• indomethacin * chemie   MeSH
• krystalizace MeSH
• prášky, zásypy, pudry MeSH
• teplota MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• indomethacin * MeSH
• prášky, zásypy, pudry MeSH

PURPOSE: Affinisol HPMC HME is a new popular form of hypromellose specifically designed for the hot melt extrusion and 3D printing of pharmaceutical products. However, reports of its thermal stability include only data obtained under inert N2 atmosphere, which is not consistent with the common pharmaceutical practice. Therefore, detailed investigation of its real-life thermal stability in air is paramount for identification of potential risks and limitations during its high-temperature processing. METHODS: In this work, the Affinisol HPMC HME 15LV powder as well as extruded filaments will be investigated by means of thermogravimetry, differential scanning calorimetry and infrared spectroscopy with respect to its thermal stability. RESULTS: The decomposition in N2 was proceeded in accordance with the literature data and manufacturer's specifications: onset at ~260°C at 0.5°C·min-1, single-step mass loss of 90-95%. However, in laboratory or industrial practice, high-temperature processing is performed in the air, where oxidation-induced degradation drastically changes. The thermogravimetric mass loss in air proceeded in three stages: ~ 5% mass loss with onset at 150°C, ~ 70% mass loss at 200°C, and ~ 15% mass loss at 380°C. Diffusion of O2 into the Affinisol material was identified as the rate-determining step. CONCLUSION: For extrusion temperatures ≥170°C, Affinisol exhibits a significant degree of degradation within the 5 min extruder retention time. Hot melt extrusion of pure Affinisol can be comfortably performed below this temperature. Utilization of plasticizers may be necessary for safe 3D printing.

• Klíčová slova
• DSC, TGA, affinisol, hot melt extrusion, thermal degradation,
• MeSH
• 3D tisk MeSH
• farmaceutická chemie * metody   MeSH
• rozpustnost MeSH
• technologie extruze tavenin * MeSH
• teplota MeSH
• vysoká teplota MeSH
• Publikační typ
• časopisecké články MeSH

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.

• Klíčová slova
• amorphous indomethacin, crystallization, kinetic prediction, particle size, storage,
• MeSH
• diferenciální skenovací kalorimetrie MeSH
• indomethacin * chemie   MeSH
• krystalizace MeSH
• teplota MeSH
• tranzitní teplota MeSH
• velikost částic MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• indomethacin * MeSH