Effect of solvent removal technique on the matrix characteristics of polylactide/glycolide microspheres for peptide delivery

Porous salmon calcitonin (sCT)-loaded PLGA microspheres (size range 35-140 mu m) of varying matrix characteristics were prepared by an aqueous emulsification process using either a temperature gradient (Tmp) or dilution (Dill of the continuous phase (CP). The Tmp technique resulted in microspheres with a hollow internal core and a porous wall. The core size and thickness of the porous wall were dependent on the temperature gradient used. A rapid ramp of temperature from 15 to 40 degrees C resulted in a large core and a thin wall, while a gradual temperature rise resulted in a smaller core. The Dil technique produced microspheres with a uniform, honeycomb like pore structure without a core, pore size being dependent on the dilution volume used. The specific surface area was higher and bulk density lower for microspheres prepared by the Tmp technique while there was no significant difference in the peptide load (3.2-4.5%) between both techniques. A rapid removal of CH2Cl2 was observed in case of the Tmp technique while the Dil technique facilitated a slower and gradual CH2Cl2 removal. Residual CH2Cl2 was approximately <10-20 ppm for microspheres prepared by the Tmp technique while the levels were 20-130 ppm for microspheres produced by the Dil technique. Higher retention of methanol (similar to 15-50%) was observed in the droplet formation stage with the Tmp technique, subsequent removal of which affected the core size. In the Dil technique, very low levels of methanol (<2%) were retained in the droplets soon after dispersion resulting in a uniform porous structure without core. Slower removal of methanol from the microspheres was partly responsible for the core formation.