Electro-Hydrodynamic Drop-on-Demand Printing of Aqueous Suspensions of Drug Nanoparticles

Abstract

We demonstrate the ability to fabricate dosage forms of a poorly water-soluble drug by using wet stirred media milling of a drug powder to produce an aqueous suspension of nanoparticles and then print it onto a porous biocompatible film. Contrary to conventional printing technologies, a deposited material is pulled out from the nozzle. This feature enables printing highly viscous materials with a precise control over the printed volume. Drug (griseofulvin) nanosuspensions prepared by wet media milling were printed onto porous hydroxypropyl methylcellulose films prepared by freeze-drying. The drug particles retained crystallinity and polymorphic form in the course of milling and printing. The versatility of this technique was demonstrated by printing the same amount of nanoparticles onto a film with droplets of different sizes. The mean drug content (0.19-3.80 mg) in the printed films was predicted by the number of droplets (5-100) and droplet volume (0.2-1.0 µL) (R² = 0.9994, p-value < 10^-4). Our results also suggest that for any targeted drug content, the number-volume of droplets could be modulated to achieve acceptable drug content uniformity. Analysis of the model-independent difference and similarity factors showed consistency of drug release profiles from films with a printed suspension. Zero-order kinetics described the griseofulvin release rate from 1.8% up to 82%. Overall, this study has successfully demonstrated that the electro-hydrodynamic drop-on-demand printing of an aqueous drug nanosuspension enables accurate and controllable drug dosing in porous polymer films, which exhibited acceptable content uniformity and reproducible drug release.

Keywords: biocompatible films; drop-on-demand printing; drug release profile; nanoparticles; poorly water-soluble drugs; precision dosage form.

Figure 1

Suspension shear viscosity vs. shear rate.

Figure 2

Frequency dependence of the suspension electric properties: (a) real part of complex permittivity ɛ’; (b) imaginary part of complex permittivity ɛ”; (c) specific conductivity $\sigma =2{\mathsf{\pi }\mathrm{f}\mathsf{\epsilon }}_0\mathsf{\epsilon }”$, where f is the field frequency in Hz and ${\mathsf{\epsilon }}_0=8.85\times {10}^{-12}\mathrm{F}/\mathrm{m}$ is the vacuum permittivity.

Figure 3

EHD DOD concept: (a) printing device: 1, infused fluid volume v_i; 2, insulating nozzle; 3, energized electrode; 4, suspension, 5, porous polymer film; 6, insulator; 7, ground electrode; 8, 3D-movable stage; 2R_OD, the nozzle outer diameter; H, the separation between the electrodes; h, the film thickness, and U_p, t_p are the peak and length of a voltage pulse applied to the electrodes. (b) Three-step printing process: (1) a fluid volume is infused into the nozzle to form a pendant droplet, (2) an electric force generated by an applied voltage stretches the droplet to form a liquid bridge anchored to the nozzle exit and the film, (3) the liquid bridge breaks up, creating a sessile droplet on the film and the other hanging from the nozzle. Adapted with permission from [19], Elsevier, 2012.

Figure 4

Printing 0.5-μL droplets of 2.5% HPMC-griseofulvin suspension onto 92%-porous HPMC film: (a) dispensing of a droplet, (b) 20.6-mg porous HPMC film before (left) and after (right) printing of fifty 0.5-μL droplets.

Figure 5

DSC curves of specimens overlaid on the temperature range 200–240 °C: (a) as-received griseofulvin powder (0.5 mg); (b) 3.5-mg porous HPMC film with five printed 0.5-µL droplets of 2.5% HPMC-griseofulvin-suspension (calculated griseofulvin content 0.45 mg); (c) porous HPMC film (3 mg) without the suspension.

Figure 6

X-ray diffractograms: (a) griseofulvin reference pattern in the instrument library; (b) as-received griseofulvin powder (4.5 mg); (c) 20-mg porous HPMC film with 50 printed 0.5-µL droplets of 2.5% HPMC-griseofulvin suspension (calculated griseofulvin content 4.51 mg); (d) porous HPMC film (20 mg) without the suspension.

Figure 7

Curves of the HPMC matrix weight percentage vs. temperature for (1–3) (2.5 ± 0.3)-mg porous films with 5 printed 0.5-µL droplets of 2.5% HPMC-griseofulvin suspension (calculated griseofulvin content 0.45 mg) after overnight storage in a desiccator at room temperature and for (4–6) (2.5 ± 0.3)-mg porous films without the suspension.

Figure 8

Release profiles of griseofulvin from (a) six porous $\left(20.4\pm 0.4\right)$-mg HPMC films, each loaded with 25 µL of 2.5% HPMC-griseofulvin suspension by printing fifty 0.5-µL droplets, and (b) six 25-µL specimens of the same griseofulvin suspension.

Figure 9

Mean drug content predicted by Equation (3) vs. the measured mean drug content in the printed films. Note that ${\mathrm{N}}_{\mathrm{d}}{\times \mathrm{V}}_{\mathrm{d}}$ was set at 1, 2, 4, 8, 12, 16, and 20 µL to attain 7 different levels of drug content presented in the figure. The variability observed along the horizontal direction is associated with the use of 29 different ${\mathrm{N}}_{\mathrm{d}}-{\mathrm{V}}_{\mathrm{d}}$ pairs in the experiments.