http://wwwcourses.sens.buffalo.edu/ce435/Riess03.pdf

Micellization of block copolymers

https://nathan.instras.com/documentDB/paper-311.pdf

Poly(ethylene oxide)-poly(propylene oxide )-poly (ethylene oxide) block copolymer surfactants in aqueous solutions and at interfaces: thermodynamics, structure, dynamics, and modeling

Pluronic® block copolymers as novel polymer therapeutics for drug and gene delivery

Nano-engineering block copolymer aggregates for drug delivery

Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.

Strategies to Address Low Drug Solubility in Discovery and Development

Solubilization of polycyclic aromatic hydrocarbons by poly(ethylene oxide-propylene oxide) block copolymer micelles: effects of polymer structure

A self-consistent mean-field lattice theory used to model the solubilization of polycyclic aromatic hydrocarbons in poly(ethylene oxide)-poly(propylene oxide) block copolymer micelles is able to reproduce the experimental finding that the micelle-water partition coefficient of naphthalene increases with an increase in the poly(propylene oxide) content of the polymer and with polymer molecular weight. With the polycyclic aromatic hydrocarbons treated as flexible benzene chains, the model indicated a strong correlation between the micelle-water partition coefficient and the octanol-water partition coefficient of the solute, which was also observed experimentally. Linear, triblock copolymers and starlike, branched copolymers were studied. It was found that the linear polymers formed larger micelles with a more hydrophobic core environment, resulting in higher micelle-water partition coefficients.

Molecular modeling of micelle formation and solubilization in block copolymer micelles. 1. A self-consistent mean-field lattice theory.

A self-consistent mean-field lattice theory of the micellization and solubilization properties of poly(ethylene oxide)-poly(propylene oxide) block copolymers is described. The polymer segments are allowed to assume both polar and nonpolar conformations (corresponding to the gauche and trans rotations of the C-C and C-O bonds), which permits the dependence of the segment-segment interactions on temperature and composition to be accounted for in a physically realistic manner. The phase diagrams of poly(ethylene oxide) and poly(propylene oxide) in water, both of which exhibit lower critical solution temperatures, can be reproduced semiquantitatively. The predictions of the theory compare favorably with published light scattering results on the aggregation behavior of block copolymers and with the authors experimental results for the solubilization of naphthalene in these micelles as a function of polymer composition and molecular weight. The dependence of the micelle-water partition coefficient on polymer composition is not simply related to the proportion of the hydrophobic constituent but depends on the detailed micelle structure. The strong effect of the molecular weight and PPO content of the polymer on the amount of naphthalene solubilized observed experimentally was interpreted in terms of the model results.

Molecular modeling of micelle formation and solubilization in block copolymer micelles. 2. Lattice theory for monomers with internal degrees of freedom

The phase equilibria distribution of naphthalene between CO 2 , water, and poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) block copolymer micelle phases is examined experi mentally and predicted semiquantitatively using a molecular thermodynamic model. The predictions treat the poly(propylene oxide) micelle core as a «pseudophase» resembling an ether. The favorable distribution coefficients at pressures as low as 70 bar suggest that CO 2 is appropriate for regenerating block copolymer micelles used for concentration of trace organics in dilute aqueous solutions

Patricia N. Hurter

Papers

Solubilization of polycyclic aromatic hydrocarbons by poly(ethylene oxide-propylene oxide) block copolymer micelles: effects of polymer structure

Molecular modeling of micelle formation and solubilization in block copolymer micelles. 1. A self-consistent mean-field lattice theory.

Molecular modeling of micelle formation and solubilization in block copolymer micelles. 2. Lattice theory for monomers with internal degrees of freedom

Carbon dioxide regeneration of block copolymer micelles used for extraction and concentration of trace organics