J. of Supercritical Fluids 51 (2010) 376–383 Contents lists available at ScienceDirect The Journal of Supercritical Fluids journal homepage: www.elsevier.com/locate/supflu Influence of polydispersity of poly(lactic acid) on particle formation by rapid expansion of supercritical CO 2 solutions Muhammad Imran ul-haq, Alberto Acosta-Ramírez, Parisa Mehrkhodavandi, Ruth Signorell ∗ Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC, V6T 1Z1, Canada article info Article history: Received 10 July 2009 Received in revised form 23 October 2009 Accepted 24 October 2009 Keywords: Poly(lactic acid) RESS Supercritical CO2 Nanoscale particles and infrared spectroscopy abstract Poly(lactic acid) (PLA) particles were generated by rapid expansion of supercritical PLA/CO 2 solutions (RESS). Two different PLA samples, one with high (PDI = 2.4) and the other one with low (PDI = 1.4) polydis- persity but similar number average molecular weight, were compared. After micronization, the polymers were analysed by rapid-scan infrared spectroscopy, scanning electron microscopy, size-exclusion chro- matography, differential scanning calorimetry, and NMR spectroscopy. Our investigation reveals that the polydispersity of the polymers strongly affects the size but not the shape of the particles. We found larger particles (∼730 nm) for the PLA with high polydispersity than for the PLA with low polydispersity (∼270 nm). In both cases, spherical particles were formed. Moreover, our results clearly show that PLA with high polydispersity is less suitable for RESS processing because the low-molecular weight chains are depleted over time and process conditions are thus not constant. © 2009 Elsevier B.V. All rights reserved. 1. Introduction Poly(lactic acid) (PLA) and its copolymers are widely used for medical and pharmaceutical applications. Because of their bio- compatibility and biodegradability, these polymers are ideal base materials to produce parenteral drug delivery systems, such as microparticles, nanoparticles, slabs, pellets, and in situ formed implants [1–7]. Rapid expansion of supercritical CO 2 solutions (RESS) is an attractive method to produce submicron-sized particulate drug delivery systems [8–22]. The process conditions are comparatively mild and the particles are generated free from solvent residues. Sev- eral previous investigations were devoted to the micronization of l-poly(lactic acid) and dl-poly(lactic acid) by RESS [8–11] as well as to the formation of particulate drug delivery systems contain- ing PLA [9,12,17–22]. In these drug delivery systems, PLA is either mixed with the drug or coats the drug particles. The goal of using a polymer in combination with the drug is twofold. The presence of the polymer can enable controlled drug release. Furthermore, PLA is used to stabilize the drug particles. Small drug particles are prone to agglomeration and coagulation, which reduces the effects gained by the micronization. As has been demonstrated for various pharmaceuticals (phytosterol, naproxen, and lovastatin) [9,19–21], coating with PLA strongly reduces agglomeration and coagulation. A comparison of the properties of the PLA particles among the vari- ∗ Corresponding author. Tel.: +1 604 822 9064; fax: +1 604 822 2847. E-mail address: signorell@chem.ubc.ca (R. Signorell). ous RESS studies reveals major differences in the appearance of the particles (size and shape). A likely explanation for these deviations is the use of different PLA samples with varying molecular weights and polydispersities. The studies reported so far used commer- cially available PLA samples, which usually have broad molecular weight distributions (polydispersity indices between 2 and 4) as a result of the synthetic techniques employed (polycondensation or ring-opening polymerization of lactides with stannous octanoate (Sn(Oct 2 )). The aim of the present contribution is to investigate the influ- ence of the polydispersity of PLA on particle formation by RESS. To our knowledge this is the first systematic study of this kind. We compare commercially available PLA of high polydispersity with PLA of low polydispersity produced by living polymerization [23,24] to study the influence of the polydispersity on the parti- cle size distribution, on the particle shape, and on the temporal stability of the particle generation process. 2. Experimental 2.1. Materials In the present contribution we compare two different types of dl-poly(lactic acid) (dl-PLA). Commercially available poly(lactic acid) (PLA1) with a number average molecular weight M n = 30,000 g/mol and a polydispersity index of PDI = 2.40 was purchased from Sigma–Aldrich. Polymers with low polydispersity are not available commercially and had thus to be synthesized for the present study. PLA2 with a number average molecular 0896-8446/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.supflu.2009.10.010