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Phase separation of poly(lactide) (PLA) and poly(lactide-co-glycolide) (PLGA), often called "coacervation" in the pharmaceutical field, is one of the classical methods for peptide drug microencapsulation in biodegradable polyesters. Although numerous studies have used this technique, the underlying physicochemical mechanisms of polyester coacervation under conditions of microsphere production have not been well-described yet. Moreover, the quality of microencapsulation in terms of drug loading efficiency and residual organic solvents is often not entirely satisfactory and depends greatly on the specific drug and polymer used. The first part of this contribution reviews briefly the scientific and patent literature on PLA/PLGA coacervation. Then, the underlying physicochemical principles of polyester coacervation are discussed and relevant thermodynamic models presented. More specifically, attempts were made to clarify the necessary characteristics of polymers, solvents, and coacervating and hardening agents for successful phase separation and microsphere formation. These basic considerations may contribute to a better understanding of the boundary conditions crucial for efficient drug microencapsulation by polyester coacervation.

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Phase separation (frequently called coacervation) of poly(lactide) (PLA) and poly(lactide-co-glycolide) (PLGA) is a classical method for drug microencapsulation. Here, attempts have been made to describe this process in the light of thermodynamics. Different PLA/PLGAs were dissolved in either dichloromethane or ethyl acetate, phase separated by addition of the coacervating agent silicone oil (PDMS), and hardened in either octamethylcyclotetrasiloxane or hexane. Various stages of phase separation were defined microscopically, and the coacervate and continuous phases characterized with respect to volume, composition, polymer molecular weight, and rheological behavior. The optimal amount of PDMS was inversely proportional to the polymer molecular weight and hydrophilicity, and a coacervate viscosity of above 5-10 Pa s was required for stable coacervate droplets. The composition and, consequently, viscosity of the coacervate and continuous phases depended on the polymer-solvent-PDMS interactions, as analyzed by the parameters chi (Flory), delta (Hildebrand), and delta(int)E (Hô). In general, the lattice model of FIory and Scott describing polymer-polymer incompatibility best explained the results. The interaction parameters and viscosity of the phases were also helpful to explain microsphere characteristics such as residual solvent and particle size. The data suggest that microsphere formation by polyester coacervation is primarily driven by molecular interactions between polymer, solvents, and coacervating agent.

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