Pharmaceutical Nanotechnology
Haloperidol-loaded PLGA nanoparticles: Systematic study of particle size and drug content

https://doi.org/10.1016/j.ijpharm.2006.11.061Get rights and content

Abstract

We have produced haloperidol-loaded PLGA/PLA nanoparticles by using two emulsification-solvent evaporation methods: homogenization and sonication. We have established how five independent processing parameters and two materials characteristics control the particle size and drug content. The interdependencies between processing and materials parameters and the subsequent nanoparticle characteristics are discussed in terms of underlying scientific principles that are broadly applicable to the production of drug-loaded polymer nanoparticles. This level of understanding should quicken the pace of designing protocols for making new drug-PLGA nanoparticles. It was determined that the particle size of haloperidol-loaded PLGA/PLA nanoparticles is effectively controlled by the amount of shear stress transferred from the energy source to the organic phase, which is strongly correlated to the following parameters: type of applied energy, aqueous phase volume, and polymer concentration in the organic solvent. The drug content of these nanoparticles is controlled by reducing the diffusion of the drug from the organic to the aqueous phase during the solvent evaporation stage of the preparation and by increasing the drug–polymer interactions. The following significantly inhibit drug diffusion: large particle size, higher polymer concentration and polymer molecular weight, and reducing the drug solubility in the aqueous phase by adjusting the pH. Specific drug–polymer interactions are engineered by optimizing the lactide to glycolide ratio (L:G ratio) and including specific polymer end groups. When optimized, the drug-loaded PLGA/PLA nanoparticles contain as much as 2.5% haloperidol.

Introduction

Controlled drug delivery systems use biodegradable polymers to release pharmaceutical drugs at a controlled rate for days, weeks or months. PLGA microparticles and nanoparticles have been widely studied for extended release of hydrophobic drugs. The controlled release of a model hydrophobic drug from PLGA nanoparticles depends on the characteristics of the particles, including particle size, size distribution, drug content, incorporation and surface morphology (Gabor et al., 1999). The particle size and drug content are particularly important characteristics that determine drug release. These characteristics depend on the specific fabrication parameters employed to make the particles in the system (Seo et al., 2003). To control these characteristics, it is vital to isolate and establish the effect of each processing and materials parameter on particle size and drug content noting that the effects may vary with different drugs.

The aim of this research is to develop a systematic methodology to control particle size and drug content and to employ scientific principles that link the various processing parameters to the nanoparticle characteristics. The broad scientific principles enable both the control of particle size and drug content and the extension of our results from the haloperidol-PLGA system to other hydrophobic drugs encapsulated in PLGA/PLA nanoparticles.

The general emulsification-solvent evaporation method employed to produce nanoparticles involves a number of processing and materials parameters: power and duration of energy applied, aqueous phase volume, pH of the aqueous phase, polymer and drug concentration in the organic phase, polymer molecular weight, polymer L:G ratio, polymer end groups, solvent volume, and surfactant concentration. Each of these processing and materials parameters influences the size and/or the drug content of the nanoparticles, which can be understood by applying appropriate scientific principles, as summarized here.

In a typical emulsification-solvent evaporation process employed to produce PLGA/PLA nanoparticles, the nanoparticles are formed as a result of shrinkage of the emulsion nanodroplets (containing the polymer and drug dissolved in organic solvent) and the size of the final nanoparticles (formed upon solvent evaporation from the emulsion nanodroplets) correlates with the size of nanodroplets (Desgouilles et al., 2003, Galindo-Rodriguez et al., 2004). The basic scientific principle governing the size of nanodroplets is that the external energy source provides shear stresses to the organic phase, which results in the formation of nanodroplets. The size of the droplets is inversely correlated to the magnitude of shear stresses. Any change in processing or materials parameters that reduces these shear stresses will increase the nanodroplet size. The most direct influence on the shear stresses in the organic phase is exercised by the energy density (external energy applied per unit total volume). Increasing the energy density directly increases the shear stresses and results in more efficient droplet breakdown and hence a reduction in nanodroplet size. The viscous forces in the organic and aqueous phase oppose the shear stresses in the organic phase. Reducing the organic phase viscosity reduces the viscous forces, which results in a net increase in shear stress felt by the organic phase. This decreases the nanodroplet size.

The drug molecules are trapped inside the nanoparticles as a result of solidification of the nanodroplets. Bodmeier and McGinity (1987) have shown that for a PLGA-quinidine base system there is no drug loss once the polymer starts solidifying from the surface to the core. Thus the entire drug loss occurs during the transition of nanodroplets to nanoparticles due to diffusion of drug from the nanodroplets to the surrounding aqueous phase. Any change in processing or polymer parameters that hinders drug diffusion from the nanodroplets to the aqueous phase will result in increased drug content in the nanoparticles. For example, diffusion can be hindered if we (i) reduce the diffusion time of the drug, (ii) increase the diffusional resistance to the drug molecules, and/or (iii) reduce the drug solubility in the aqueous phase. Another principle that can be used to increase the drug content is to increase the drug–polymer interactions. We can use the above principles to understand and methodically vary the size and drug content of the nanoparticles.

In this study, we developed a method of emulsification-solvent evaporation using sonication, which gives unimodal particle population for a wide range of processing parameters. This provides a constant particle size while probing the effect of various processing parameters on drug content, thereby eliminating interference from changing particle size on drug content. The technique of sonication is first optimized and then utilized to establish the effect of varying the processing parameters and polymer characteristics on particle size and drug content. The characteristics of particles obtained from sonication are also compared with those of particles obtained from homogenization and nanoprecipitation under similar conditions. The technique of nanoprecipitation is used only for comparison purposes because the drug content is too low to be practical. This study demonstrates that sonication effectively produces small (∼220 nm) particles with narrow size distributions in which the drug content can be increased by careful manipulation of various parameters including polymer concentration, initial haloperidol concentration, solvent volume and polymer type. These results are discussed in terms of the scientific principles outlined above.

Section snippets

Materials

Poly(d,l-lactic-co-glycolic acid) (PLGA) 50:50 DL (molecular weight, 7 kDa), 50:50 DL (14 kDa), 50:50 DL (24 kDa), 50:50 DL (48 kDa), 50:50 DL (63 kDa), 65:35 (114 kDa), 75:25 (92 kDa) 100:0 (109 kDa) were purchased from Alkermes, USA. Polyvinyl alcohol (PVA) (MW, 25,000, 88% hydrolyzed) was purchased from Polysciences Inc., USA. Haloperidol, phosphate buffered saline (PBS), ammonium acetate, 1-Piperazineethane sulfonic acid, 4-(2-hydroxyethyl)-monosodium salt (HEPES) were purchased from Sigma, USA.

Effect of polymer concentration in the organic phase

Fig. 1a shows the effect of polymer concentration in the organic phase on the mean diameter of two batches of nanoparticles produced by sonication. The polymer concentration is varied from 5 to 66.6 mg/ml while keeping other processing parameters at standard conditions. Increasing the polymer concentration leads to a gradual increase in nanoparticle diameter while maintaining a unimodal size distribution. In contrast, our homogenization method at these concentrations produced bimodal size

Conclusions

We used homogenization or sonication in our emulsification-solvent evaporation method to produce haloperidol-loaded PLGA/PLA nanoparticles and compared the results with the nanoprecipitation method. Particles produced by nanoprecipitation had small size (∼185 nm) but the technique was not pursued because of very low drug content (∼0.15%). For nanoparticles produced by homogenization or sonication, we examined the scientific principles controlling particle size and drug content. Table 1

Acknowledgements

This research was supported by financial assistance from the Commonwealth of Pennsylvania through the Nanotechnology Institute. We are thankful to Prof. Anthony Lowman for providing laboratory facilities and to Meredith Hans (Drexel University) and Yuling Liang (University of Pennsylvania) for their invaluable help with the experiments.

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