The physical stability of block copolymer micelles is important because the early release of the drug into the bloodstream as a result of the disassembly of copolymer chains results in insufficient accumulation of the drug at the target site. It is critical that the copolymer micelles possess sufficient stability to remain intact in the circulation. The thermodynamic tendency for micelles to disassemble into individual chains is reflected by the critical micelle concentration (CMC) of the copolymer. Below the CMC, the copolymer is in the form of single polymer chains or unimers, and above the CMC, the copolymer exists as micelles in equilibrium with a small population of single chains. In this way, the CMC represents an important parameter as it determines the thermo-dynamic stability of the micelles during dilution.23 Small molecule surfactants form micelles that tend to have higher CMC values that make them more susceptible to disassembly following dilution. In contrast, amphiphilic block copolymers tend to be more thermodynamically stable with lower CMC values in the range of 10k7-10~6 M.3,24,25

The CMC has been found to be dependent on the nature and length of the hydrophobic block, the length of the hydrophilic block, and the total molecular weight of the copolymer.26,27 Specifically, increasing the hydrophobicity of the core-forming block reduces the CMC and, in turn, improves the thermodynamic stability of the micelles. For example, Leroux et al. have demonstrated that increasing the hydrophobic PDLLA block from 27 to 55 mol% in a series of PVP-b-PDLLA-b-PVP copolymers results in a decrease in the CMC from 19.9 to 5.1 mg/L.28 In contrast, when the hydrophilic block length is increased and the hydrophobic block is kept constant, the CMC increases as has been shown for the Pluronicw copolymers.29

Even at concentrations below the CMC, micelles can remain kinetically stable for extended periods of time depending on their glass transition temperature (Tg) and/or Tm if the core-forming block is semicrystalline. Micelles with a core-forming block that has a lower Tg (below 37°C) will tend to disassemble at a faster rate than those with a higher Tg as a result of the free motion of the core-forming polymer chains at temperatures above the Tg. For example, Kataoka et al. found a dramatic increase in the CMC of PEG-b-PDLLA micelles at a temperature above the Tg of the hydrophobic PDLLA polymer that suggested a decrease in the kinetic stability of the system. Kang et al. improved the kinetic stability of PEG-b-poly(lactide) (PLA) block copolymer micelles by blending equimolar mixtures of PEG-b-poly(D-lactide) (PDLA) and PEG-b-poly(L-lactide) (PLLA) enantiomeric copolymers. They reported superior kinetic stability as a result of the increased van der Waals interactions between the PLA polymer chains that promoted a denser packing and a tighter conformation.31 Finally, the presence of the hydrophobic drug in the core has also been shown to promote kinetic stability of the formulation.32

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