RESUMEN
Amorphous solid dispersions (ASDs) are single-phase amorphous systems, where drug molecules are molecularly dispersed (dissolved) in a polymer matrix. The molecular dispersion of the drug molecules is responsible for their improved dissolution properties. Unambiguously establishing the phase behavior of the ASDs is of utmost importance. In this paper, we focused on the complementary nature of (modulated) differential scanning calorimetry ((m)DSC) and X-ray powder diffraction (XRPD) to elucidate the phase behavior of ASDs as demonstrated by a critical discussion of practical real-life examples observed in our research group. The ASDs were manufactured by either applying a solvent-based technique (spray drying), a heat-based technique (hot melt extrusion) or mechanochemical activation (cryo-milling). The encountered limiting factors of XRPD were the lack of sensitivity for small traces of crystallinity, the impossibility to differentiate between distinct amorphous phases and its impossibility to detect nanocrystals in a polymer matrix. In addition, the limiting factors of (m)DSC were defined as the well-described heat-induced sample alteration upon heating, the interfering of residual solvent evaporation with other thermal events and the coinciding of enthalpy recovery with melting events. In all of these cases, the application of a single analytical technique would have led to erroneous conclusions, whilst the combination of (m)DSC and XRPD elucidated the true phases of the ASD.
Asunto(s)
Polímeros/química , Polvos/química , Rastreo Diferencial de Calorimetría/métodos , Química Farmacéutica/métodos , Cristalización/métodos , Calor , Nanopartículas/química , Sensibilidad y Especificidad , Solubilidad/efectos de los fármacos , Solventes/química , Tecnología Farmacéutica/métodos , Difracción de Rayos X/métodosRESUMEN
In spite of the large research efforts in the past two decades, it is still difficult, if possible at all, to predict what manufacturing technology will lead to the best amorphous solid dispersions (ASDs) in terms of drug to polymer ratio ("drug loading") and physical stability. In general, ASDs can be prepared by solvent based methods, heat based methods and mechanochemical activation. In the current study, one manufacturing technique per category was selected: spray drying, hot melt extrusion and cryo-milling, respectively. These processes were compared for their capability to formulate high drug loaded ASDs. High drug loadings may allow decreasing the pill burden and/or reducing dosage size, which both increase the therapeutic compliance. A fast crystallizer, naproxen, in combination with PVP K25, PVP-VA64, HPMC and HPMC-AS was used as a model system. Clear differences in the physical structure of the ASDs were observed. Our data indicate that not only the drug loading is dependent on the manufacturing process, but also the carrier that is able to incorporate the highest drug loading. This suggests that a carrier should be selected not only as function of the API, but also as function of the manufacturing process. Overall, hot melt extrusion showed to be most suited to reach high drug loadings for these naproxen-polymer combinations. This was in agreement with our finding that heat is an important energy input for mixing.