OBJECTIVE The purpose of this study was to stabilize the vinca alkaloids, vincristine sulfate (VCR) and vinblastine sulfate (VBL), in poly(lactide-co-glycolide) (PLGA) microspheres and to release the drugs in a sustained manner for more than a month. METHODS An oil-in-oil emulsion-solvent extraction method was used to encapsulate VCR and VBL in PLGA50/50 microspheres. Stability and release kinetics of the drugs during the incubation at 37 degrees C in PBS/Tween 80 were assessed by HPLC. Degradation products were identified with HPLC-MS. RESULTS VCR and VBL were encapsulated in PLGA microspheres unchanged. During the microsphere incubation, however, VCR degraded inside the particles with a t1/2 approximately 7.5 days. The degradation product was identified by LC-MS as the deformyl derivative, commonly formed at acidic pH. VBL, which differs only by a stable methyl group in place of the N-formyl group in VCR, was completely stable in the PLGA microclimate. The neutralization of acidic PLGA microclimate by addition of 3-10% Mg(OH)2 completely inhibited deformylation of VCR during release. but introduced a new degradation product formed under the more alkaline conditions used during the preparation. The substitution of Mg(OH)2 with a weaker base, ZnCO3, inhibited the formation of both degradation products resulting in VCR stabilization of >92% for 4 weeks. The optimal formulations of VCR (containing ZnCO3) and VBL (no additives) slowly and continuously released stable drugs for over a month. CONCLUSIONS VCR and VBL were successfully stabilized and released in a sustained manner from PLGA microspheres. Co-encapsulation of ZnCO3 stabilizes VCR against acid-catalyzed degradation during release from the polymer and minimizes VCR decomposition during encapsulation.