Effect of manufacturing conditions on the formation of double-walled polymer microspheres

Abstract

This paper discusses the optimization of the solvent evaporation process to produce double-walled (DW) microspheres in a single-step. Five process variables were studied: polymer solution concentration, polymer weight ratio, polymer solution volume ratios, encapsulation temperature, and air flow rate across the top of the encapsulation vessel. The effects of these variables on the process efficiency (defined here as the percentage of microspheres with a DW configuration compared to the total number of microspheres) were examined. Total polymer concentrations of less than 20% (w/v) produced microspheres with high efficiency, with phase separation consistent across all size fractions in each batch. Changing the volume ratio of the two polymer solutions had no significant effect on the process efficiency. The weight ratio of the polymers greatly influenced the process efficiency, resulting in a low 63% efficiency for the 1:3 Poly-L-lactide (PLLA): Poly(carboxyphenoxypropane-co-sebacic)anhydride 20:80 (P(CPP:SA 20:80)) weight ratio and 0% for the 3:1 weight ratio. The 1:3 weight ratio also caused the polymers to reverse their orientation, although the efficiency for this switch was still relatively low. The temperature of the non-solvent bath affected the efficiency of certain pairs of polymers, but not all. The PLLA/Poly(lactide-co-glycolide) 50:50 (PLGA) pair was most sensitive to temperature, due to the chemical similarity of the two polymers which narrowed the range of acceptable conditions for encapsulation. Pairs of polymers which phase separated readily (e.g. polystyrene and PLLA) were the least sensitive to temperature changes. Process yield and size distribution show no clear trends with respect to air flow rate across the top of the reaction vessel. The efficiency of the process to produce DW microspheres increased and the process time decreased with increasing air flow across the surface of the encapsulation vessel.

Manipulation of process parameters to achieve different ternary phase microparticle configurations

“…As compared with other earlier attempts where prefabricated microspheres were further coated using a hot melt technique, pan coating or fluidized beds to produce double walled microparticles [10], the solvent evaporation technique is a onestep process that gave double walled microparticles with higher yields, uniform wall thickness and a controllable particle size within the range 20-1000 lm. Subsequently, Leach et al [11] studied the effect of fabrication conditions such as weight ratio, polymer solution concentration, temperature and air flow on the formation efficiency of double walled microspheres.…”

Microspheres for Drug Delivery

“…One of the first studies consisted of adding two separate polymers dropwise to an aqueous phase and controlling precipitation rates such that one polymer has ample time to spread on the other [96,97,99,122,132]. Another technique utilized the phase separation of PLG and PLL at certain concentrations [103][104].…”

Tunable Release of Proteins with Polymer–Inorganic Nanocomposite Microspheres

“…[26] In this study, high molecular weight PLLA was chosen as a shell material because it would degrade very slowly as compared to PLGA, and it would naturally envelope PLGA upon phase separation, resulting in microspheres with PLLA-rich shell and PLGA-rich core. [24,25] Although this phase separation phenomenon [21][22][23][24][25] and other techniques [26][27][28] have previously been employed in the synthesis of double-walled microspheres, no tunable delayed release profiles were reported with those formula- tions. In fact, in several cases, the core/shell structure only served to reduce the initial burst and prolong the protein release.…”

“…[21][22][23][24][25] As the solvent was removed from the oil-in-water emulsion, the polymers concentration in the oil droplets would increase, which eventually led to a phase separation when the total polymers concentration exceeded a critical level. This phase separation between polymers could be described using thermodynamic calculations.…”