Kristallisation polymorpher Arzneimittel in Nanoporen
Zusammenfassung der Projektergebnisse
We could show that different polymorphic states of pharmaceuticals like acetaminophen, ibuprofen or D-mannitol and other polymorphic substances like n-tetracosan can be rationally produced in nanoporous host systems like controlled porous glass (CPG) with continuous sponge-like pore systems or anodic aluminum oxide (AAO) membranes containing discrete and straight cylindrical pores. Polymorphic states metastable or transient in bulk systems can be stabilized in both nanoporous host systems under investigation, despite their different pore morphologies. The range of parameters that determine how crystallization occurs and which polymorph forms includes not only thermal history and presence/absence of a bulk guest layer on the top surface of nanoporous membranes, but also the pore morphology of the latter. We could demonstrate that significant modification of the surface energy of the pore walls by silanization and calcination leads in the case of pharmaceuticals in CPGs to limited changes in polymorphic state and crystallization behavior. This was originally a surprise but can be explained by the existence of a non-crystallizable drug layer with a thickness of a few nanometers at the pore walls which is preserved in case of moderate surface modification. The layer thickness was calculated from a geometrical two phase model based on melting enthalpies, pore geometry and mass of guest molecules in the host systems. The existence of a non-crystalline layer is supported by 1H NMR experiments on CPGs filled with acetaminophen. The presence of amorphous guest layers on the host pore walls is probably related to strong interactions between (partly) hydrophilic pore walls and guest systems, which are able to form hydrogen bonds. Hence, nanocrystals growing inside the pores never have direct contact with the pore walls. The relevant surface energy crystal-to-amorphous layer is not significantly changing if the pore walls of the host are modified. For AAO modified with ODPA and infiltrated with n-tetracosan, pore wall modification apparently stabilized triclinic crystals and suppressed the formation of rotator phases. This result indicates that the ordering of compounds either capable of crystallization or of mesophase formation can be indeed influenced by contact to the moieties of a coupling agent attached to the walls of the containers. We developed a thermodynamic model rationalizing the growth of commonly metastable polymorphic states in nanopores based on differences in the overall surface energy between the polymorphs. Due to the significant contributions of surface energy to the overall Gibbs free energy of nanocrystals this is a potential reason for the stabilization of polymorphs that are metastable in bulk systems. This model also rationalizes the transient appearance of metastable polymorphs during early stages of bulk crystal growth observed already more than 100 years ago and summarized in Ostwalds’s step role of stages. One striking advantage of crystallization experiments in nanopores is that nanocrystals seldom and transient in bulk systems can be stabilized and studied. Highly oriented form II/form III crystals form in isolated, cylindrical AAO nanopores by oriented crystallization related to a kinetic selection mechanism, which results in the dominance of crystals having their direction of fastest growth aligned with the pore axes. This mechanism is suppressed in the highly tortuous CPG pore systems, where form I crystals are observed under similar conditions. Hence, the pore morphology influences which polymorph forms. The existence of oriented form II/form III crystals with rough high-energy surfaces normal to the pore axes was confirmed by X-ray texture analysis. An interesting consequence of this orientation effect is that only highly soluble rough crystal faces are exposed to the environment. Tentative results revealed that correspondingly oriented crystals exhibit solubilities matching that of amorphous acetaminophen. Highly soluble crystalline drugs that show long-term stability are advantageous with respect to amorphous drugs because the properties of the latter are changed by aging and cold crystallization. In general, the results of this project underline nicely that mesoscopic crystal engineering in nanoconfinement is a promising approach to rationally design nanoscale systems containing polymorphic substances. Different strategies to control the polymorphic state have been tested and predictive models have been developed. This seems to be a useful starting point for advanced activities towards pharmaceutical applications or applications in other fields where polymorph control is of major importance. A related project incorporating companies working in relevant fields is planned in the near future.
Projektbezogene Publikationen (Auswahl)
- Size-dependent growth of polymorphs in nanopores and Ostwald’s step rule of stages, Phys. Chem. Chem. Phys. 13 (2011) 21367-21374
G.T. Rengarajan, D. Enke, M. Steinhart, M. Beiner
- Suppression of Phase Transitions in a Confined Rodlike Liquid Crystal, ACS Nano 5 (2011) 9208-9215
C. Grigoriadis, H. Duran, M. Steinhart, M. Kappl, H.J. Butt, G. Floudas
- Characterization of pore filling of mesoporous host systems by means of positronium annihilation lifetime spectroscopy (PALS), Optica Applicata 42 (2012) 281-286
J. Kullmann, D. Enke, S. Thränert, R. Krause-Rehberg, M. Beiner
- Imprinting macropore arrays into mesoporous silica monoliths. J. Mater. Chem. 22 (2012), 9490-9493
S. Grimm, A. Lange, D. Enke, M. Steinhart
(Siehe online unter https://doi.org/10.1039/c2jm31245j) - Preparation of Porous Glass Monoliths with an Aligned Pore System via Stretch Forming, Journal of the American Ceramic Society 95 (2012) 3013-3015
A. Barascu, J. Kullmann, B. Reinhardt, T. Rainer, H. Roggendorf, M. Dubiel, D. Enke
- Properties and Cross-Link Density of Styrene-Butadiene Model Composites Containing Fillers with Bimodal Particle Size Distribution, Macromolecules 45 (2012) 6504-6515
A. Mujtaba, M. Keller, S. Ilisch, H.-J. Radusch, T. Thurn-Albrecht, K. Saalwächter, M. Beiner
(Siehe online unter https://doi.org/10.1021/ma300925p) - Silica Monoliths with Hierarchical Porosity obtained from Porous Glasses, Chem Soc Rev 42 (2013) 3753-3764
A. Inayat, B. Reinhardt, H. Uhlig, W.-D. Einicke, D. Enke
- Morphology of porous hosts determines which polymorph confined pharmaceuticals preferentially form, Crystal Growth & Design 14 (2014) 78-86
G. Graubner, G. T. Rengarajan, N. Anders, N. Sonnenberger, D. Enke, M. Beiner, M. Steinhart
(Siehe online unter https://doi.org/10.1021/cg401170m) - Inverse gas chromatography (IGC) as a tool for an energetic characterisation of porous materials, Microporous and Mesoporous Materials 209 (2015), 99- 104
M. Rückriem, D. Enke, T. Hahn
(Siehe online unter https://doi.org/10.1016/j.micromeso.2014.08.053)
