Effect of Solid State Transition on the Physical Stability of Suspensions Containing Bupivacaine Lipid Microparticles

Abstract

Bupivacaine lipid microparticles were prepared and evaluated as a parenteral sustained-release dosage form for postoperative pain management. Bupivacaine free base was incorporated into a molten tristearin matrix and lipid microparticles were subsequently formed from this molten mixture by a spray-congealing process. A 3% injectable bupivacaine lipid microparticle suspension was prepared by dispersing 30% bupivacaine lipid microparticles in an aqueous medium containing carboxymethylcellulose (CMC), mannitol, and Tween 80. Upon room temperature storage, the fluid suspension gradually changed into a nonflowing semisolid (gelation) as a result of crystal growth of bupivacaine. However, suspensions prepared with bupivacaine lipid microparticles that were previously annealed at an elevated temperature remained fluid upon long-term storage. Differential scanning calorimetry (DSC), x-ray powder diffraction (XRPD), and isoperibol solution calorimetry were used to investigate the changes in the solid-state properties of tristearin and bupivacaine in the lipid microparticles before and after the heat treatment. The DSC and XRPD results indicate that after 24 hours of heating at 40°C, tristearin was completely converted from the unstable α form to the stable β form. Using the isoperibol solution calorimetric method, bupivacaine was found to transform into a more stable form after the lipid microparticles were heated at 60°C for 24 hours. The generation of the unstable solid forms of tristearin and bupivacaine was attributed to the resolidification of both components from the molten mixture during the spray-congealing process.