Search Results (6)

Non-isothermal differential scanning calorimetry (DSC) and Raman microscopy were used to study the crystallization behavior of the 20–50 μm amorphous nifedipine (NIF) powder. In particular, the study was focused on the diffusionless glass-crystal (GC) growth mode occurring below the glass transition temperature (T_g). The exothermic signal associated with the GC growth was indeed directly and reproducibly recorded at heating rates q⁺ ≤ 0.5 °C·min⁻¹. During the GC growth, the α_p polymorphic phase was exclusively formed, as confirmed via Raman microscopy. In addition to the freshly prepared NIF samples, the crystallization of the powders annealed for 7 h at 20 °C was also monitored—approx. 50–60% crystallinity was achieved. For the annealed NIF powders, the confocal Raman microscopy verified a proportional absence of the crystalline phase on the sample surface (indicating its dominant formation along the internal micro-cracks, which is characteristic of the GC growth). All DSC data were modeled in terms of the solid-state kinetic equation paired with the autocatalytic model; the kinetic complexity was described via reaction mechanism based on the overlap of 3–4 independent processes. The kinetic trends associated with decreasing q⁺ were identified, confirming the temperature-dependent kinetic behavior, and used to calculate a theoretical kinetic prediction conformable to the experimentally performed 7 h annealing at 20 °C. The theoretical model slightly underestimated the true extent of the GC growth, predicting the crystallinity to be 35–40% after 7 h (such accuracy is still extremely good in comparison with the standard kinetic approaches nowadays). Further research in the field of kinetic analysis should thus focus on the methodological ways of increasing the accuracy of considerably extrapolated kinetic predictions. Full article

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 α_p and β_p polymorphs, enantiotropic β_p → β_p′ transformation, and β_p/β_p′ → α_p 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. Full article

Co-amorphous drug–drug systems have been developed with the overall aim of improving the physical stability of two or more amorphous drugs. Co-amorphous systems often show good physical stability, and higher solubility and dissolution rates compared to their crystalline counterparts. The aim of this study is to determine if eutectic mixtures of two drugs can form stable co-amorphous systems. Three drug–drug mixtures, indomethacin–naproxen (IND−NAP), nifedipine–paracetamol (NIF−PAR), and paracetamol–celecoxib (PAR−CCX), were investigated for their eutectic and co-amorphization behavior as well as their physical stability in the co-amorphous form. The phase diagrams of the crystalline mixtures and the thermal behavior of the co-amorphous systems were analyzed by differential scanning calorimetry. The solid-state form and physical stability of the co-amorphous systems were analyzed using X-ray powder diffractometry during storage at room temperature at dry conditions. Initial eutectic screening using nifedipine (NIF), paracetamol (PAR), and celecoxib (CCX) indicated that IND−NAP, NIF−PAR, and PAR−CCX can form eutectic mixtures. Phase diagrams were then constructed using theoretical and experimental values. These systems, at different drug-to-drug ratios, were melted and cooled to form binary mixtures. Most mixtures were found to be co-amorphous systems, as they were amorphous and exhibited a single glass transition temperature. The stability study of the co-amorphous systems indicated differences in their physical stability. Comparing the phase diagrams with the physical stability of the co-amorphous mixtures, it was evident that the respective drug–drug ratio that forms the eutectic point also forms the most stable co-amorphous system. The eutectic behavior of drug–drug systems can thus be used to predict drug ratios that form the most stable co-amorphous systems. Full article

Nifedipine (NIF) is a 1,4-dihydropyridine-based calcium channel blocker with poor solubility, whose bioavailability is highly dependent on the type of formulation. Dry powder mixtures of 20% w/w NIF with microcrystalline cellulose (MCC) and its high surface area nanocellulose analogue, which is namely Cladophora (CLAD) cellulose, were produced by heating at the melting temperature of the drug for 1 h. Non-heated samples were used as a reference. The solid-state properties of the mixtures were characterized by scanning electron microscopy, differential scanning calorimetry and X-ray diffraction. The drug release was studied in biorelevant media, including simulated gastric fluid (SGF), fasted-state simulated intestinal fluid (FaSIF) and fed-state simulated intestinal fluid (FeSIF). An enhanced apparent solubility and faster dissolution rate of NIF were observed in the heated mixture of NIF with CLAD-H in all tested biorelevant media (i.e., SGF, FaSIF and FeSIF), which was due to NIF amorphization in the high surface area nanocellulose powder. Ordinary MCC, which is essentially non-porous, did not produce an enhancement of a similar magnitude. The results of the study suggest that dry powder formulation using high surface area nanocellulose is a facile new strategy for formulating calcium channel blocker drugs, which could potentially be a viable alternative to currently used soft gel liquid capsules. Full article

The high index of simultaneous incidence of hypertension and hypercholesterolemia in the population of many countries demands the preparation of more efficient drugs. Therefore, there is a significant area of opportunity to provide as many alternatives as possible to treat these illnesses. Taking advantage of the solubility enhancement that can be achieved when an active pharmaceutical ingredient (API) is obtained and stabilized in its amorphous state, in the present work, new drug-drug co-amorphous formulations (Simvastatin SIM- Nifedipine NIF) with enhanced solubility and stability were prepared and characterized. Results show that the co-amorphous system (molar ratio 1:1) is more soluble than the pure commercial APIs studied separately. Aqueous dissolution profiles showed increments of solubility of 3.7 and 1.7 times for SIM and NIF, correspondingly, in the co-amorphous system. The new co-amorphous formulations, monitored in time, (molar fractions 0.3, 0.5 and 0.7 of SIM) remained stable in the amorphous state for more than one year when stored at room temperature and did not show any signs of crystallization when re-heating. Inspection on the remainder of a sample after six hours of dissolution showed no recrystallization, confirming the stability of co-amorphous system. The enhanced solubility of the co-amorphous formulations makes them promising for simultaneously targeting of hypertension and hypercholesterolemia through combination therapy. Full article

The amorphous state is of particular interest in the pharmaceutical industry due to the higher solubility that amorphous active pharmaceutical ingredients show compared to their respective crystalline forms. Due to their thermodynamic instability, drugs in the amorphous state tend to recrystallize; in order to avoid crystallization, it has been a common strategy to add a second component to hinder the crystalline state and form a thermally stable co-amorphous system, that is to say, an amorphous binary system which retains its amorphous structure. The second component can be a small molecule excipient (such as a sugar or an aminoacid) or a second drug, with the advantage that a second active pharmaceutical ingredient could be used for complementary or combined therapeutic purposes. In most cases, the compositions studied are limited to 1:1, 2:1 and 1:2 molar ratios, leaving a gap of information about phase transitions and stability on the amorphous state in a wider range of compositions. In the present work, a study of novel co–amorphous formulations in which the selection of the active pharmaceutical ingredients was made according to the therapeutic effect is presented. Resistance against crystallization and behavior of glass transition temperature ( $T_{\mathrm{g}}$ were studied through calorimetric measurements as a function of composition and shelf time. It was found that binary formulations with $T_{\mathrm{g}}$ temperatures higher than those of pure components presented long-term thermal stability. In addition, significant increments of $T_{\mathrm{g}}$ values, of as much as 15 ${}^{\circ }$ C, were detected as a result of glass relaxation at room temperature during storage time; this behavior of glass transition has not been previously reported for co-amorphous drugs. Based on these results, it can be concluded that monitoring behavior of $T_{\mathrm{g}}$ and relaxation processes during the first weeks of storage leads to a more objective evaluation of the thermomechanical stability of an amorphous formulation. Full article