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. 2020 Oct 29;12(11):1034.
doi: 10.3390/pharmaceutics12111034.

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

Ezinwa Elele  1 , Yueyang Shen  1 , Rajyalakshmi Boppana  1 , Afolawemi Afolabi  1 , Ecevit Bilgili  1 , Boris Khusid  1
Affiliations

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

Ezinwa Elele et al. Pharmaceutics. .

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.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Suspension shear viscosity vs. shear rate.
Figure 2
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 σ=2πfε0ε”, where f is the field frequency in Hz and ε0=8.85×10−12F/m is the vacuum permittivity.
Figure 3
Figure 3
EHD DOD concept: (a) printing device: 1, infused fluid volume vi; 2, insulating nozzle; 3, energized electrode; 4, suspension, 5, porous polymer film; 6, insulator; 7, ground electrode; 8, 3D-movable stage; 2ROD, the nozzle outer diameter; H, the separation between the electrodes; h, the film thickness, and Up, tp 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
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
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
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
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
Figure 8
Release profiles of griseofulvin from (a) six porous (20.4±0.4)-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
Figure 9
Mean drug content predicted by Equation (3) vs. the measured mean drug content in the printed films. Note that Nd×Vd 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 Nd−Vd pairs in the experiments.
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