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The Development of Quasi-isothermal Calorimetry for the Measurement of DrugPolymer Miscibility and Crystallization Kinetics: Olanzapine-Loaded PLGA Microparticles

Askin, S; Zhao, M; Gonçalves, AD; Gaisford, S; Craig, DQM; (2018) The Development of Quasi-isothermal Calorimetry for the Measurement of DrugPolymer Miscibility and Crystallization Kinetics: Olanzapine-Loaded PLGA Microparticles. Molecular Pharmaceutics , 15 (8) pp. 3332-3342. 10.1021/acs.molpharmaceut.8b00364. Green open access

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Abstract

The assessment of drug–polymer equilibrium solubility is of critical importance for predicting suitable loading and physical stability of solid dispersion formulations. However, quantitative measurement of this parameter is nontrivial due to the difficulties associated with ascertaining equilibrium values in systems that are prone to supersaturation and are simultaneously highly viscous, thereby slowing the equilibration process considerably; no standard methodology has yet been agreed for such measurements. In this study, we propose a new approach involving quasi-isothermal modulated temperature DSC (QiMTDSC), whereby unsaturated and supersaturated samples are held at defined temperatures and subject to a sinusoidal heating signal at a zero underpinning heating rate, thereby allowing the heat capacity of the sample to be measured as a function of time and temperature. We are not only able to ascertain whether equilibrium has been reached by monitoring the time-dependent heat capacity signal, but we can also measure solubility as a function of temperature via the absolute heat capacity values of the components. We are also able to measure the kinetics of recrystallization from the supersaturated systems. Dispersions of olanzapine in PLGA at concentrations up to 50% w/w, prepared by spray drying, were prepared and characterized using conventional and QiMTDSC as well as hot stage microscopy. The new QiMTDSC protocol was successfully able to determine olanzapine solubility in PLGA at 90 °C to be 23.1 ± 6.1% w/w, which was comparable to the values calculated using other established methods at this temperature, while a temperature/solubility profile was obtained using the method at a range of temperatures. Drug crystallization kinetics from the solid dispersions could also be modeled directly from the QiMTDSC data using the Avrami approach, thereby allowing the effect of drug loading on the rate of crystallization and the effective completion of crystallization to be investigated. Overall, an alternative protocol for measuring drug–polymer solubility has been developed and validated via comparison to established methods, the approach allowing solubility as a function of temperature, identification of equilibrium following demixing, and kinetic analysis of crystallization to be performed within one set of experiments.

Type: Article
Title: The Development of Quasi-isothermal Calorimetry for the Measurement of DrugPolymer Miscibility and Crystallization Kinetics: Olanzapine-Loaded PLGA Microparticles
Open access status: An open access version is available from UCL Discovery
DOI: 10.1021/acs.molpharmaceut.8b00364
Publisher version: https://doi.org/10.1021/acs.molpharmaceut.8b00364
Language: English
Additional information: Copyright © 2018 American Chemical Society. This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Keywords: drug−polymer solubility, amorphous solid dispersion, PLGA, microparticles, olanzapine, crystallization, crystallization kinetics, differential scanning calorimetry, quasi-isothermal modulated temperature differential scanning calorimetry, polarized light microscopy, physical stability, demixing
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmaceutics
URI: https://discovery.ucl.ac.uk/id/eprint/10052171
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