ISBN 9783843936552

978-3-8439-3655-2, Reihe Thermodynamik

Christian Marc Lübbert
Phase separation and crystallization in pharmaceutical formulations

189 Seiten, Dissertation Technische Universität Dortmund (2018), Softcover, A5

Zusammenfassung / Abstract

The bioavailability of poorly-water-soluble active pharmaceutical ingredients (APIs) can be significantly improved by formulation as so-called amorphous solid dispersion (ASD). However, the long-term stability of ASDs might be impaired by API crystallization and/or amorphous phase separation (APS). In this study, the phase behavior (solubility and APS) and glass-transition temperatures of the model APIs ibuprofen and felodipine in polymeric excipients were investigated by means of hot-stage microscopy (HSM), differential scanning calorimetry (DSC) and Raman spectroscopy. APS was found in water-free ibuprofen/ poly (lactic-co-glycolic acid) formulations. The influence of temperature, monomer composition (ratio of DL-lactic acid to glycolic acid) and polymer architecture (linear vs. star-shaped) on APS was investigated. Phase-separation kinetics as well as the compositions of the two amorphous phases evolving due to APS were quantitatively determined for the first time via Raman spectroscopy. DSC, HSM and Raman mapping measurements agreed nicely providing a consistent and cross-validated phase diagram of ASD systems. Based on a successful modeling of the crystallization behavior using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT), the occurrence of APS was predicted in agreement with experimental findings.

During the pharmaceutical development of new formulations, stability studies via storage at certain temperature and relative humidity (RH) conditions have to be carried out to verify the long-term stability of these formulations against unwanted crystallization and moisture-induced amorphous-amorphous phase separation (MIAPS). The mutual impact of water sorption, API solubility, and MIAPS in the above-mentioned formulations at humid conditions was predicted in perfect agreement with the results of three-year lasting stability studies at 25 °C/ 60% RH and 40 °C/ 75% RH. The crystallization kinetics in spray-dried nifedipine/ poly(vinyl acetate) ASDs was investigated only by measuring the time-dependent water sorption. By coupling water sorption measurements with PC-SAFT water sorption predictions and mass balances, the crystallization kinetics in the ASD could be directly estimated without any calibration.

This work showed that the long-term stability of ASDs can be predicted correctly at early stages of formulation development via thermodynamic modeling.