Carbon dioxide extraction of residual solvents in poly(lactide-co-glycolide) microparticles.
A process for the reduction of residual solvents in spray-dried poly(lactide-co-glycolide) (PLGA)-darbepoetin alfa microparticles was developed using carbon dioxide (CO(2)) as an extraction solvent. CO(2) was investigated in two phase states, liquid and gas. Detrimental effects on encapsulated protein integrity and microparticle morphology were observed with liquid CO(2) exposure. Extraction with CO(2) gas at <100 psig reduced residual solvent concentration and particle agglomeration was limited. Extraction rates and particle agglomeration increased with higher CO(2) gas pressures. The CO(2) pressures below which particles of polylactide (PLA) and PLGA microparticles significantly agglomerated were determined and the data used to develop extraction cycles. Extraction cycles were developed in which CO(2) gas pressure was increased as residual solvent concentration decreased in order to keep extraction rates high throughout the cycle. Spray dried darbepoetin alfa-PLGA microparticles were extracted with CO(2) gas and characterized for residual solvent concentration, process yield, particle size distribution, morphology, and protein integrity. The results indicated CO(2) gas may be used to reduce residual solvent to approximately 200 ppm with no significant detrimental effects on protein integrity or microparticle morphology.
Herberger
John
J
Drug Product Process Development, Amgen, Inc, One Amgen Ctr Dr, Thousand Oaks, CA 91320-1799, USA. johnh@amgen.com
Murphy
Keith
K
Munyakazi
Louis
L
Cordia
Jon
J
Westhaus
Eric
E
D002245:Carbon Dioxide / Q000032:analysis* / Q000737:chemistry; D008863:Microspheres; D011098:Polyglactin 910 / Q000032:analysis* / Q000737:chemistry; D012997:Solvents / Q000032:analysis* / Q000737:chemistry; D013678:Technology, Pharmaceutical / Q000295:instrumentation / Q000379:methods*
D012997:Solvents; D002245:Carbon Dioxide; D011098:Polyglactin 910