Application of laminar jet break-up to the preparation of monodisperse poly(ester) microparticles

Rahman, Mohammad Mizanur (2007). Application of laminar jet break-up to the preparation of monodisperse poly(ester) microparticles MPhil Thesis, School of Pharmacy, University of Queensland.

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Author Rahman, Mohammad Mizanur
Thesis Title Application of laminar jet break-up to the preparation of monodisperse poly(ester) microparticles
School, Centre or Institute School of Pharmacy
Institution University of Queensland
Publication date 2007
Thesis type MPhil Thesis
Supervisor Dr Nigel Davies
Subjects 3611 Pharmacy
Abstract/Summary Poly(ester) drug-loaded microspheres are most commonly prepared by emulsion solvent evaporation/extraction in which the polymer is dissolved in an organic solvent which is dispersed in an aqueous continuous phase. Typically, the o/w or more complex w/o/w (required for encapsulation of hydrophilic actives) emulsions are produced by homogenization, sonication or high speed stirring which yield microspheres with wide size distributions. Standard deviations of 25-50% of the mean diameter are not uncommon for microspheres prepared by such technologies. This lack of control and predictability are limitations of the current technologies. Particle size is a primary determinant of drug release and particle deposition following in vivo administration. Any variation in the size of particles will lead to sub-optimal delivery in which release kinetics are difficult to control. A long-sought after goal in particulate drug delivery technologies has therefore been to precisely control the size of the particles. Many theoretical and experimental studies have shown that uniformly sized liquid-liquid dispersions can be formed by laminar jet break-up. However, to date nobody has used the resulting dispersions for the preparation of drug loaded polymeric microparticles. The aim of this project was therefore to investigate the application of laminar jet break-up for the preparation of o/w dispersions for the fabrication of monodisperse biodegradable microparticles of controlled and predictable size. In this study, poly(@-caprolactone) was used as the polymer and was dissolved in an organic solvent (initially and mainly, dichloromethane). The organic polymer solution was loaded into a high precision syringe pump and pumped through orifices of different diameters into an aqueous phase containing poly(vinyl alcohol) as surfactant. The dispersions were subsequently stirred to facilitate solvent removal leading to polymer precipitation and microparticle formation. Resulting microparticles were characterized by optical microscopy and low angle laser light scattering. In the first series of investigations (Chapter 2), the effect of orifice diameter, flow rate (particularly within the laminar jet region), type of organic solvent and polymer/surfactant concentrations on the size and polydispersity of the microparticles were investigated. Uniformly sized microspheres (polydispersity index < 0.5) were observed to form in both the dripping and laminar jet flow regions. Microspheres formed in the laminar region were however smaller and there was a trend of decreasing particle size and polydispersity upon approaching the flow velocity resulting in maximum jet-length. In the dewaving region, polydispersity of the particles was found to increase. Consequently, all further studies were undertaken in the laminar jet region using the flow rate yielding maximum jet length. Polydispersity as well as size of micrparticles was influenced by concentration of poly(vinylalcohol) in the continuous aqueous phase (used as viscosity modifier and surfactant). A concentration of 0.91 % w/v poly(vinylalcohol) was found most suitable with higher/lower concentrations resulting in increased polydispersity as a result of viscosity and interfacial effects. Size and polydispersity of microspheres was found to be also influenced by the organic solvent used to dissolve the poly(ester) with dichloromethane yielding the smallest and most uniformly dispersed microspheres. Size of microspheres produced from dispersions prepared by laminar jet break-up not surprisingly increased with both the size of the orifice used for jetting and the concentration of polymer. In chapter 3, a factorial designed study combined with mathematical modelling was used to investigate whether a relationship existed between the response variable of particle size and these two independent process variables (nozzle orifice diameter and polymer concentration) for microspheres prepared under conditions based on the results of chapter 2 (namely jetting at a velocity yielding maximum jet length, using dichloromethane as the organic solvent and using a poly(vinylalcohol) concentration of 0.91 % w/v in the aqueous phase). Based on the results of four trials (22 factorial design), a linear, algebraic first-degree polynomial correlation was predicted to describe the effects of nozzle orifice diameter, polymer concentration and their interaction on the mean particle size of microspheres. The model was validated by 11 experimental results within the factor space. It was found that the predicted values of ten experiments (means, n=3) were within ±5.5% of the calculated values. Only one experimental result deviated by greater than 10% from that predicted. The model thus allows a prescribed size of particles to be prepared by selecting the appropriate nozzle orifice size and polymer concentration.

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