Method for controlling encapsulation efficiency and burst release of water soluble molecules from nanoparticles and microparticles produced by inverse flash nanoprecipitation

A method of forming a polymer inverse nanoparticle that encapsulates a water soluble active to maximize or optimize encapsulation efficiency and/or to minimize or optimize burst fraction, comprising:

• dissolving the water soluble active at a concentration and a block copolymer at a concentration in an amount of a process solvent to form a process solution;
• and
• continuously mixing the process solution with an amount of a nonprocess solvent at a process temperature to form a first nanoparticle solution comprising polymer inverse nanoparticles having a core and a shell and a first nanoparticle solvent;
• wherein the block copolymer comprises a hydrophilic block and a hydrophobic block having a glass transition temperature (Tg),
• wherein the hydrophilic block is soluble in the process solvent and is insoluble in the nonprocess solvent,
• wherein the hydrophobic block is insoluble in the process solvent and is soluble in the nonprocess solvent,
• wherein the process solution is more polar than the nonprocess solvent,
• wherein the water soluble active and the hydrophilic block are in the core and the hydrophobic block is in the shell, and
• wherein the encapsulation efficiency is maximized or optimized by
• (a) selecting the process solvent, so that the hydrophilic block is close to a solubility limit in the process solution for the concentration of the block copolymer, and/or
• (b) crosslinking the hydrophilic block in the core, and/or
• (c) selecting the hydrophilic block to have bonding interactions with the water soluble active in the core, and/or
• (d) selecting the hydrophobic block to have a molecular weight of at least 10 kDa, 20 kDa, 30 kDa, 40 kDa, 50 kDa, 70 kDa, or 100 kDa, and/or
• (e) selecting the process temperature and/or the hydrophobic block, so that the process temperature is less than the hydrophobic block glass transition temperature (Tg), and/or
• (f) selecting the process solvent to have high osmolarity (e.g., by dissolving a salt in the process solvent), and/or
• (g) adding a supplemental hydrophobic compound to the process solvent and/or to the nonprocess solvent to increase the bulk of hydrophobic material in the shell,
• and/or
• wherein the burst fraction is minimized or optimized by
• (aa) crosslinking the hydrophilic block in the core, and/or
• (bb) increasing the hydrophobic block glass transition temperature (Tg), and/or
• (cc) adding a supplemental hydrophobic compound to the process solvent and/or to the nonprocess solvent to increase the bulk of hydrophobic material in the shell.