Research Article: Optimising poly(lactic-co-glycolic acid) microparticle fabrication using a Taguchi orthogonal array design-of-experiment approach

Date Published: September 26, 2019

Publisher: Public Library of Science

Author(s): R. A. Mensah, S. B. Kirton, M. T. Cook, I. D. Styliari, V. Hutter, D. Y. S. Chau, Bing Xu.


The objective of this study was to identify, understand and generate a Taguchi orthogonal array model for the formation of 10–50 μm microparticles with applications in topical/ocular controlled drug delivery. Poly(lactic-co-glycolic acid) (PLGA) microparticles were fabricated by the single emulsion oil-in-water method and the particle size was characterized using laser diffraction and scanning electronic microscopy (SEM). Sequential Taguchi L12 and L18 orthogonal array (OA) designs were employed to study the influence of ten and eight parameters, respectively, on microparticle size (response). The first optimization step using the L12 design showed that all parameters significantly influenced the particle size of the prepared PLGA microparticles with exception of the concentration of poly(vinyl alcohol) (PVA) in the hardening bath. The smallest mean particle size obtained from the L12 design was 54.39 μm. A subsequent L18 design showed that the molecular weight of PLGA does not significantly affect the particle size. An experimental run comprising of defined parameters including molecular weight of PLGA (89 kDa), concentration of PLGA (20% w/v), concentration of PVA in the emulsion (0.8% w/v), solvent type (ethyl acetate), organic/aqeuous phase ratio (1:1 v/v), vortexing speed (9), vortexing duration (60 seconds), concentration of PVA in hardening bath (0.8% w/v), stirring speed of hardening bath (1200 rpm) and solvent evaporation duration (24 hours) resulted in the lowest mean particle size of 23.51 μm which was predicted and confirmed by the L18 array. A comparable size was demonstrated during the fabrication of BSA-incorporated microparticles. Taguchi OA design proved to be a valuable tool in determining the combination of process parameters that can provide the optimal condition for microparticle formulation. Taguchi OA design can be used to correctly predict the size of microparticles fabricated by the single emulsion process and can therefore, ultimately, save time and costs during the manufacturing process of drug delivery formulations by minimising experimental runs.

Partial Text

Microparticles (MPs) may be designed to allow precise delivery of small quantities of potent drug and increase the local concentration of the drugs in the target tissue [1, 2]. MPs for use in drug delivery may be manufactured to provide controlled and sustained release, provide stability to the encapsulated drug and may reduce the side-effects of the drug [2–4]. The fabrication of MPs depends on the choice of suitable polymeric materials. An ideal polymeric material must be non-toxic, biodegradable and biocompatible [4]. In this work, poly(lactic-co-glycolic acid) (PLGA) was chosen for MP fabrication as it possesses the suitable properties, is readily available and approved by regulatory authorities (i.e. FDA) for clinical use in humans [5]. In the body, PLGA undergoes hydrolysis to generate lactic and glycolic acid which do not cause carrier toxicity or immunological response and explains the success of PLGA as a biodegradable polymeric material [6, 7]. When used for drug delivery, this hydrolysis leads to the degradation of the PLGA matrix and any drug incorporated within is liberated in a time-dependent fashion, typically over several weeks.

The solvent evaporation method has been used widely to encapsulate drugs in polymer matrices to form delivery systems and involves many processing parameters which influence the properties and quality of the final MPs product [12–16]. Optimising this process one variable at a time is impractical. As such, this study employed the use of a Taguchi orthogonal arrays design of experiment protocol to assess the optimal conditions required for the fabrication of 10–50 μm sized MPs and to identify the parameters that deemed to most significantly influence PLGA MP size.

In this study, Taguchi OA design proved to be a valuable tool in the optimization of several processing parameters in solvent evaporation technique with complex interrelationship with few experiments. The design was efficient for identifying the parameters which had significant effect on microparticles size More precisely, vortexing speed, concentration of PLGA, organic/aqueous phase ratio, stirring speed, concentration of PVA in primary emulsion, vortexing duration were significant whereas the molecular weight of PVA and concentration of PVA in hardening bath were proven to be not important parameters with regard to PLGA microparticle size. The optimal model formulation was established as molecular weight of PVA = 89,00 Da, concentration of PLGA = 20 w/v %, organic/aqueous phase ratio = 1:1, vortexing speed = 9, vortexing duration = 60 s, stirring speed for hardening process = 1200 rpm and solvent evaporation duration = 24 h. These optimum levels of the parameters were useful in the fabrication of PLGA microparticles with the minimum particle size of 23.51 μm. A model drug (BSA) was successfully incorporated into the optimised microparticles, which had no statistically significant impact on size.