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.
Highlights
Amorphous solid dispersions of drug molecules in a polymer matrix are a well-established approach to achieve both controlled release or solubilization.1 The amorphous form of most small molecule drugs is inherently unstable, and the physical stability of such systems is determined by the thermodynamic equilibrium solubility level of the drug in the polymer, which determines the maximum drug load that can be molecularly dispersed in the polymer matrix without risk of phase separation over time
A 50% w/w olanzapine−poly(lactic-co-glycolic acid) (PLGA) microparticle solid dispersion was annealed at a range of temperatures, and the the DSC demixing (Tg) was subsequently measured on reheating following cooling under controlled conditions
The new method was validated by comparison to an established differential scanning calorimetry (DSC) demixing (Tg) method, and the two protocols were found to calculate very similar olanzapine−PLGA solubility levels at a temperature of interest
Summary
Amorphous solid dispersions of drug molecules in a polymer matrix are a well-established approach to achieve both controlled release or solubilization. The amorphous form of most small molecule drugs is inherently unstable, and the physical stability of such systems is determined by the thermodynamic equilibrium solubility level of the drug in the polymer, which determines the maximum drug load that can be molecularly dispersed in the polymer matrix without risk of phase separation over time. Amorphous solid dispersions of drug molecules in a polymer matrix are a well-established approach to achieve both controlled release or solubilization.. The amorphous form of most small molecule drugs is inherently unstable, and the physical stability of such systems is determined by the thermodynamic equilibrium solubility level of the drug in the polymer, which determines the maximum drug load that can be molecularly dispersed in the polymer matrix without risk of phase separation over time. The capability to understand the physical stability of a formulation is essential as changes in the physical state of the drug, such as crystallization, can significantly affect the release performance of the solid dispersion, which makes determining the solubility of the drug in the polymer of critical importance..
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