Phase Behavior of the Quaternary Poly(dl-lactide-co-glycolide)/Monoolein/1-Methyl-2-pyrrolidinone/Water System:  An Experimental and Theoretical Study

Abstract

The phase behavior of the poly(dl-lactide-co-glycolide) (PLG)/monoolein (MO)/1-methyl-2-pyrrolidinone (NMP)/water system has been studied. The particular system was selected because it was a candidate for being a suitable system for creation of lipid−polymer hybrid particles. Phase diagrams of the four ternary subsystems, as well as phase behaviors of selected quaternary mixtures, have been determined. The PLG/NMP/water system exhibits a behavior similar to a polymer/solvent/nonsolvent system, and the PLG/MO/NMP system shows a segregative behavior similar to a polymer 1/polymer 2 (or surfactant)/solvent system. The ternary MO/NMP/water subsystem exhibits a rich, mainly mesomorphic phase behavior, including lamellar and cubic phases, and offers thus possibilities to create both liposomes and cubosomes. At high NMP content, the system gives rise to several liquid phases, such as a sponge phase and MO-poor and MO-rich liquid phases. Addition of PLG to the MO/NMP/water subsystem reveals that both liquid crystals and liquid phases may exist in equilibrium with PLG-rich liquids, the latter being highly viscous. At high water content, the PLG phase may be caught in a glassy state at room temperature. The Flory−Huggins theory has been used to model three of the ternary subsystems and some parts of the quaternary system.

Long-Acting Injectable Hormonal Dosage Forms for Contraception

“…In situ forming depot systems appeared in the field of controlled drug release as an alternative to microspheres in order to overcome the disadvantages noticed for microspheres such as the need of reconstitution, the possibility of microsphere migration after injection, and high fabrication cost, low encapsulation efficiency for some APIs (87)(88)(89)(90). These in situ forming depot systems generally are injectable polymer or lipid solutions/suspensions having low viscosity before injection, and solidify into semi-solid or solid depots after administration into the body (91).…”

Segregation of Lipid and Polymer in Emulsion Droplets Captured by Confocal Laser Scanning Microscopy

“…It will be demonstrated that the phase behavior, of the system used for the encapsulation process, is of main importance, in particular when particles are created by a slow process such as emulsification. At least one other quaternary system containing a biocompatible solvent (1-methyl-2-pyrrolidinone) has been explored before . The system reported in ref is of general interest even though emulsification in aqueous solution is practically unworkable due to the instantaneous diffusion of NMP out to the water phase.…”

The 1-Monooleoyl-rac-glycerol/n-Octyl-β-d-Glucoside/Water System. Phase Diagram and Phase Structures Determined by NMR and X-ray Diffraction

“…22,23 The technical grade has been used as an emulsifying agent and a food additive since the 1950s, and it has also been utilized as a coamphiphile in pharmaceutical applications. 24 The liquid crystalline structures formed by MO have been proposed to be utilized as alternatives to lipid vesicles for administration of drugs, providing slow release [25][26][27][28] and stabilization of sensitive substances. 27,[29][30][31] Another potentially interesting application for these compounds is the use of them in electrochemical biosensors based on enzymes entrapped in a cubic phase.…”

“…36 To fully utilize these applications, several aspects must be thoroughly studied and a detailed knowledge of the phase behavior must be obtained. Several more or less complete ternary systems involving MO can be found in the literature, and they may contain from small-and medium-sized molecules and ions [37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52] to polymers 28,53,54 and proteins. [29][30][31][32][55][56][57][58][59] Generally, inorganic ions 37 and small molecules such as urea 37 and sugars 37,38,46 can be incorporated in substantial amounts (mol/L) into the cubic phases without causing major structural changes.…”

“…1-Monooleoyl- rac -glycerol (MO) is an amphiphilic lipid that is almost insoluble in water, and a rich phase behavior, including lamellar, hexagonal, as well as cubic structures, is observed. , The technical grade has been used as an emulsifying agent and a food additive since the 1950s, and it has also been utilized as a coamphiphile in pharmaceutical applications . The liquid crystalline structures formed by MO have been proposed to be utilized as alternatives to lipid vesicles for administration of drugs, providing slow release − and stabilization of sensitive substances. ,− Another potentially interesting application for these compounds is the use of them in electrochemical biosensors based on enzymes entrapped in a cubic phase . The cubic phase can be dispersed in excess water, producing a suspension of so-called cubosomes. , A stabilization of the cubic phase can be obtained by a polymerization of the lipids building up the cubic structure .…”