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DOI: 10.1039/C6RA15387A (Communication) RSC Adv., 2016, 6, 77174-77178

Janus particle synthesis via aligned non-concentric angular nozzles and electrohydrodynamic co-flow for tunable drug release†

Chunchen Zhangab, Ming-Wei Chang*ab, Yudong Lia, Yuankai Qia, Jingwen Wua, Zeeshan Ahmadc and Jing-Song Lia
aKey Laboratory for Biomedical Engineering of Education Ministry of China, Hangzhou, 310027, P. R. China. E-mail: mwchang@zju.edu.cn
bZhejiang Provincial Key Laboratory of Cardio-Cerebral Vascular Detection Technology and Medicinal Effectiveness Appraisal, Hangzhou, 310027, P. R. China
cLeicester School of Pharmacy, De Montfort University, The Gateway, Leicester, LE1 9BH, UK

Received 14th June 2016 , Accepted 9th August 2016

First published on 10th August 2016

Abstract

A novel non-concentric, symmetrical spinneret possessing aligned nozzles with angular outlets was designed and manufactured. The device was used to synthesize Janus particles by atomizing co-flowing formulations at relatively high electric fields (up to ∼15 kV). By manipulating the nozzle outlet angle (θ), the maximum applied voltage permitting stable co-jetting was enhanced; enabling the production of finer droplets and, thus, microparticles. Furthermore, non-concentric co-flow, process optimization and stable atomization yielded Janus particles with distinct morphological features which were then used to demonstrate tunable drug release.

Janus particles have attracted appreciable attention during the past decade because of their prospective applications in catalysis, optical engineering, drug delivery science and as potential actuators.1–4 Numerous approaches have been investigated and developed to fabricate Janus particles (e.g., masking, bottom-up assembly, microfluidic and electrohydrodynamic (EHD) co-jetting).5–11 EHD atomization (or electrospraying) is a liquid disintegration process where an electrically conductive solution is exposed to a strong electric field; forming a fine liquid jet which subsequently breaks-up into small droplets. Atomized droplets then undergo the solidification process via rapid solvent evaporation, giving rise to particles on the micro/nano scale.12 The EHD co-jetting technique is advantageous as it is facile, an ambient temperature operation and cost effective when compared to other particle synthesis techniques. However, the method is yet to be explored in greater depth when considering particle tunability and drug release kinetics.2,6,13–15

While the structure of Janus particles may display two different chemical or morphological characteristics, their overall size is crucial when considering them as drug carriers.16–18 Particle size impacts drug loading, release and accumulation (e.g. in organs).17 The production of finer particles via conventional EHD co-jetting setup is challenging when using two parallel nozzles with flat outlets. The electrospraying atomization scaling law; where the mean diameter of synthesized particles is inversely proportional to the applied voltage19,20 is also applicable to the co-jetting process (eqn (1)).10

 
r ∼ Δσy0/2ηv (1)

In eqn (1), y0 is channel radius, η is viscosity of the continuous phase, v is the linear velocity of the continuous phase at the junction, Δσ is the effective interfacial tension and r is the droplet radius. When y0, η and v are kept constant, according to the equation, Δσ decreases as the applied voltage increases, this leads to a reduction in droplet radius. For a typical EHD co-jetting process, once the applied voltage exceeds the threshold value stable jetting is no longer attainable and multiple jets often form. Multi-jet formation is associated with variations in particle size and morphology (when processed via EHD) and this phenomenon is more apparent when working with liquids possessing appreciable electrical conductivity (e.g. >600 μS m−1). In this work, novel non-concentric angular EHD spraying nozzles with varying tip angles were designed and utilized for the synthesis of drug loaded Janus particles. The effect of nozzle tip angle on maximum applied voltage (for stable jetting) was explored with a view to reduce particle size. Janus particles possessing two phases, each with distinct drug loading volume, were explored for tunable drug release using model dye (Sudan Red G, SRG) and drug (indomethacin, INM).

The modified EHD setup used in this work is shown in Fig. 1. The system included two syringe pumps, a high voltage power supply (supplying up to ∼30 kV) and a novel non-concentric angular aligned nozzle system. The nozzle comprised two aligned conducting needles (for media inflow) with each possessing a slanted exit (inclination angle = θ) as indicated in Fig. 1. A high speed camera was used to observe jetting behavior. Precision syringe pumps were used to perfuse individual polymeric solutions (in controlled fashion) from pre-filled syringes directly into the nozzle. The nozzle was connected to the high power voltage supply, and a metallic ring was used as the ground electrode. The high voltage power supply was used to generate a static electric field between the nozzle and the grounded electrode. Generated particles were collected on glass slides and aluminum film. Samples were subsequently analyzed using SEM and FTIR, and further assessments were performed to assess drug release from Janus particles (ESI†).


image file: c6ra15387a-f1.tif
Fig. 1 A schematic diagram of the modified non-concentric symmetric nozzle with inclination angle (θ) used for EHD co-jetting.

The effect of inclination angle (θ) on stable-jet formation was explored. For this, a series of experiments were performed using polymeric solutions incorporating two pigments. The first solution comprised 6 wt% polycaprolactone (PCL) and 0.22 wt% TiO2 dissolved in dichloromethane (DCM). The second solution comprised 6 wt% PCL and 0.22 wt% carbon black, both dissolved in DCM. Under optimized conditions (fixed working distance = 30 cm and flow rate = 12 ml h−1 for both infusions), the EHD transition from dripping to jetting modes were obtained using a series of nozzles with varying outlet angles (θ = 0, 30 and 60°) as a function of applied voltage as shown in Fig. 2. From digital images it is apparent that stable co-flowing cone-jets are obtainable at a broader applied voltage range when the nozzle outlet angle is increased (from 0° to 60°). In addition, the macroaxis of the co-flow jetting contact area gets notably longer (the lengths of macroaxis for 0, 30 and 60° was 1.49, 2.90 and 3.97 mm, respectively) at a constant applied voltage of 12 kV. When the applied voltage exceeds the threshold (>15 kV), individual flows contributing towards the non-concentric co-flowing jet (generated using all angular nozzles with varying θ values) repel mutually due to coulombic force.21 At this point, multi-jets are formed which are closely related to the nozzle angle (θ). Examining jetting patterns at a constant applied voltage, where multiple jets are formed and comparable (e.g. 15 kV), the impact of nozzle angle (θ) becomes clear. Increasing θ from 0 to 60° demonstrates this variation. For example two separate non-contacting jets are formed at 0°. At 30°, minimal contact at the cone region is observed which is appreciably away from the apex. Finally, a stable jet with continuous co-flow and breakup at the apex is observed at 60°. The latter also possesses a much longer macroaxis (5.36 mm). In this regard, a greater nozzle angle outlet enables non-concentric co-flow stability during EHD co-jetting which is valuable for Janus particle synthesis. In addition, larger θ values permit a broader stable jetting window at increased applied voltages; which are often used to generate finer particles. Enhanced co-flow and jetting stability due to larger θ values are attributed to a greater contact area on the angular nozzle outlet. This provides an increased interface for chain entanglement or interfacial interactions between the two polymeric solutions.22


image file: c6ra15387a-f2.tif
Fig. 2 Digital images of dripping, stable and repulsive jetting modes from nozzles with varying outlet angles (θ) as a function of the applied voltage.

Therefore, based on co-jetting stability at elevated applied voltages (for the production of finer Janus particles) utilization of nozzles with outlet angles of 60° are most suitable. In addition, the operating window for stable co-flowing jets is broader, which provides further control on particle diameter through voltage manipulation over a narrow window.23 To demonstrate Janus particle production and application in controlled drug delivery, a nozzle outlet possessing an inclined angle of θ = 60° was selected for further experiments.

To assess the feasibility of the modified angular nozzle system for the fabrication of Janus particles, aforementioned polymeric solutions were used with varying flow rate ratios for the EHD co-jetting process. Optical micrographs (reflected light) of pigment-loaded particles fabricated using co-flowing ratios of (for PCL/TiO2[thin space (1/6-em)]:[thin space (1/6-em)]PCL/carbon) 1[thin space (1/6-em)]:[thin space (1/6-em)]2, 1[thin space (1/6-em)]:[thin space (1/6-em)]1 and 2[thin space (1/6-em)]:[thin space (1/6-em)]1 are shown in Fig. 3(a)–(c), respectively. The total flow rate of both solutions was maintained at 24 ml h−1. The bright blue regions in Fig. 3(a)–(c) indicate Janus particle compartments encapsulated with TiO2, while the remainder of particles indicates the loading of carbon black (see ESI†). The difference in blue color intensity (encapsulated pigment) and volume distribution shows modified nozzles can be used readily to tailor the volume ratio of individual compartments through flow rate ratio manipulation. Furthermore, analysis of optical images (Fig. 3(a)–(c)) using Image-pro plus (software) also confirms the mean ratio of blue area[thin space (1/6-em)]:[thin space (1/6-em)]black area, which was 1[thin space (1/6-em)]:[thin space (1/6-em)]2.28, 1[thin space (1/6-em)]:[thin space (1/6-em)]1.05 and 2.21[thin space (1/6-em)]:[thin space (1/6-em)]1 for each particle type, respectively. The images also reveal a clear interface between the two compartments. Furthermore, higher flow rates of PCL/TiO2 result in Janus particles with relatively larger compartment volumes (Fig. 3(c)). These findings confirm the successful preparation of Janus structures for compartmentalized loading.


image file: c6ra15387a-f3.tif
Fig. 3 Optical micrographs of pigment loaded Janus particles fabricated at different flow rate ratios. The flow rate ratio of TiO2 loaded solution to carbon black loaded solution in (a)–(c) is 1[thin space (1/6-em)]:[thin space (1/6-em)]2, 1[thin space (1/6-em)]:[thin space (1/6-em)]1 and 2[thin space (1/6-em)]:[thin space (1/6-em)]1, respectively. Micrographs of (d)–(f) are the corresponding images of (a)–(c), respectively. The bright compartment contains TiO2 while the dark compartment contains carbon black. Micrographs in (a)–(c) are taken under reflected light while (d)–(f) are taken under transmitted light using the same microscope and magnification.

Fig. 3(d)–(f) are corresponding micrographs of Fig. 3(a)–(c) obtained using transmitted light. Spherical monolithic particles were afforded using angular nozzles under stable EHD co-jetting with particles exhibiting variable volume ratios. The near monodisperse nature of microparticles is also noteworthy, indicating another potential benefit of angular nozzles for single step production of uniform particles. Janus particles prepared using identical processing conditions are uniform and possess approximately equal blue to black area ratios within each sample. Co-flowing jets achieved through angular nozzles appear more stable for Janus particle production when compared to their conventional (flat) counterparts.

Dual-drug encapsulation and release behavior from Janus particles was explored. Polymeric solutions were loaded with the anti-inflammatory drug indomethacin (INM) and model dye Sudan Red G (SRG). The first polymeric solution comprised 6 wt% PCL and 0.03 wt% INM dissolved in DCM. The second solution comprised 6 wt% PCL and variable quantities of SRG dissolved in DCM to achieve model drug/probe mass ratios of (SRG[thin space (1/6-em)]:[thin space (1/6-em)]INM) 1[thin space (1/6-em)]:[thin space (1/6-em)]4, 2[thin space (1/6-em)]:[thin space (1/6-em)]4 and 4[thin space (1/6-em)]:[thin space (1/6-em)]4.

FTIR analysis was used to confirm the presence of various components of Janus particles (PCL, INM and SRG). Fig. 4 shows FTIR transmittance spectra of various (raw and atomized) particle components and drug loaded Janus particles. The FTIR spectrum of pure PCL particles shows a prominent peak at 1730 cm−1 due to –C[double bond, length as m-dash]O stretching and the peaks at 2868 and 2947 cm−1 are related to C–H bond of saturated carbons.24 The characteristic bands of pure SRG are 1500, 1484, 1252 and 1206 cm−1.25 For Pure INM strong C[double bond, length as m-dash]O bond stretches were observed at 1718 and 1692 cm−1.26 The characteristic bands of PCL, SRG and INM were observed in the spectra of all Janus particles (with varying SRG[thin space (1/6-em)]:[thin space (1/6-em)]INM mass ratio). Bands for the dual-drug loaded Janus particles were observed at ∼600 cm−1, which confirmed the presence of INM and ∼750 cm−1 and ∼835 cm−1 indicated the encapsulation of SRG. The peak at ∼835 cm−1 intensified when the mass ratio of SRG to INM was increased, while the peak at ∼600 cm−1 remained unchanged. The FTIR spectra indicate successful encapsulation of model active and probe into synthesized Janus particles in a single step via the modified EHD co-jetting process.


image file: c6ra15387a-f4.tif
Fig. 4 FTIR transmittance spectra of individual components and dual-drug loaded Janus particles with varying mass ratios (SRG[thin space (1/6-em)]:[thin space (1/6-em)]INM of 1[thin space (1/6-em)]:[thin space (1/6-em)]4, 2[thin space (1/6-em)]:[thin space (1/6-em)]4 and 4[thin space (1/6-em)]:[thin space (1/6-em)]4).

Fig. 5(a)–(c), show electron micrographs of near monodisperse Janus particles which were successfully synthesized using the EHD process. The mean particle diameter for formulation mass ratios of SRG to INM (1[thin space (1/6-em)]:[thin space (1/6-em)]4, 2[thin space (1/6-em)]:[thin space (1/6-em)]4 and 4[thin space (1/6-em)]:[thin space (1/6-em)]4) was 46.5 ± 7.1, 48.9 ± 8.1 and 41.2 ± 7.5 μm, respectively. The surface morphology of all dual-drug loaded Janus particles are identical and display pyramid-like structures which is due to rapid solvent evaporation of solvent (during the jetting process). The solvent evaporation rate in this instance is much faster at the surface when compared to the central region of droplet forming particles which explains the presence of concave features on the resulting Janus particle surface.27


image file: c6ra15387a-f5.tif
Fig. 5 SEM images of dual-drug loaded Janus particles with varying mass ratios of SRG[thin space (1/6-em)]:[thin space (1/6-em)]INM (a) 1[thin space (1/6-em)]:[thin space (1/6-em)]4 (b) 2[thin space (1/6-em)]:[thin space (1/6-em)]4 and (c) 4[thin space (1/6-em)]:[thin space (1/6-em)]4, and the corresponding release behavior of (d) 1[thin space (1/6-em)]:[thin space (1/6-em)]4, and (e) 2[thin space (1/6-em)]:[thin space (1/6-em)]4, and (f) 4[thin space (1/6-em)]:[thin space (1/6-em)]4, ratio based particles.

Fig. 5(d)–(f) show drug and probe release profiles from Janus particles with varying SRG and INM loading ratios (SRG[thin space (1/6-em)]:[thin space (1/6-em)]INM was 1[thin space (1/6-em)]:[thin space (1/6-em)]4, 2[thin space (1/6-em)]:[thin space (1/6-em)]4 and 4[thin space (1/6-em)]:[thin space (1/6-em)]4) measured using a UV-Vis spectrometer. The general release pattern from all particle types was similar and typical of matrix based systems; a sharp burst followed by a sustained release phase and then indication (variable between SRG and INM) of polymer swelling which results in a second enhanced release phase of drug. INM release behavior is comparable regardless of SRG loading quantity during the first 8 hours. The enhanced release (72–96 hours) is caused by intrinsic properties of INM and the PCL polymer matrix. During the first 8 hours, INM on and near the particle surface detaches from the carrier system with little change to the polymeric matrix. The remaining INM, which is deeper within the polymeric matrix, diffuses slowly towards the particle surface and eventually into the release medium (12–72 h). During this time the release medium is also diffusing in the opposite direction and interacting with the polymeric matrix. Around 72–96 hours the particle system has undergone 'swelling', where release medium has penetrated through polymeric chains in matrix providing a much greater interface for INM diffusion into the surrounding release medium. At this stage greater quantities of INM are able to diffuse out of the polymeric system; as polymeric chains are less-rigidly bound and more liquid medium is interfacing the drug in the polymeric matrix.28 After 168 hours, the total quantity of INM released reaches 260.7, 298.3 and 204.0 μg from Janus particles with SRG[thin space (1/6-em)]:[thin space (1/6-em)]INM ratios of 1[thin space (1/6-em)]:[thin space (1/6-em)]4, 2[thin space (1/6-em)]:[thin space (1/6-em)]4 and 4[thin space (1/6-em)]:[thin space (1/6-em)]4, respectively.

In contrast, SRG release is more varied between the three Janus particles. A rapid burst release is observed during the first 8 hours, after which sustained release of the probe is observed. After 168 hours, the quantities of SRG released from Janus particles with SRG[thin space (1/6-em)]:[thin space (1/6-em)]INM ratios of 1[thin space (1/6-em)]:[thin space (1/6-em)]4, 2[thin space (1/6-em)]:[thin space (1/6-em)]4, and 4[thin space (1/6-em)]:[thin space (1/6-em)]4 was 129.7, 190.1 and 377.3 μg, respectively. INM clearly exhibits tri-phasic release kinetics (burst release, sustained and then rapid release). SRG, in general, shows simple biphasic release; a burst phase followed by a slow release phase; although there is a slight increase in SRG release at the end of each experiment (at 148 hours and onwards). This is less apparent when compared to INM release kinetics. The difference in INM and SRG release kinetics is most likely due to the chemical structure and nature of the model materials. INM possesses a greater molecular weight (∼358 g mol−1) than SRG (∼278 g mol−1) which automatically suggests the latter has greater diffusion potential. Furthermore, the chemical structure of INM is more likely to sterically hinder movement of adjacent drug molecules when compared to SRG, which also limits movement within the PCL polymeric matrix. Finally, the various functional groups present on INM are more likely to enhance molecular interactions between the drug (INM–INM) and between compounds (PCL–INM). INM is known to dimerize when it is in the amorphous state and when it is in a polymeric matrix possessing hydrogen bonding capability.29 One of the benefits of the EHD process is the ability to fabricate structures in the amorphous state in situ.30 In this regard, it is suggested the dimerization of INM is facilitated during this process, which further stabilizes the diffusive behavior of the molecule. Secondly, molecular interactions arising between INM and PCL also stabilize movement of the drug. However, when there is sufficient swelling of the PCL matrix, polymeric chains are no longer held together rigidly and the free movement of release medium causes drug to detach from the matrix, and thus released.

Both SRG and INM were successfully encapsulated in to Janus particles and released. There is potential to control drug delivery using the novel nozzle system. Furthermore, the findings suggest the cumulative release of both SRG and INM were independent, and drug loading in to Janus particles can be selectively controlled by varying infusion rate of co-jetting liquid formulations.

It should be noted; while individual release is independent the potential to use such a system for co-therapy is clear. In such cases, the release rate of both drugs can be tailored by varying the quantity of drug incorporated in formulated jetting solutions.

In this article, the impact of nozzle outlet angle θ for co-flowing media on enhancing stable jetting of the EHD co-flow process is shown. Furthermore, using the same system distinctive microparticle compartments can be synthesized. By manipulating the flow rate and mass ratio of model agents, tunable drug and probe release is achievable with great potential in co-therapy of actives. Further explorations will now focus on exploiting this new approach to fabricate advanced Janus structures for smart and stimuli responsive dual-drug delivery.

Acknowledgements

This work was financially supported by the National Nature Science Foundation of China (No. 81301304), the Key Technologies R&D Program of Zhejiang Province (2015C02G2010104; 2015C02035)​ and the Research Fund for The Doctoral Program of Higher Education of China (20130101120170).

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra15387a
This journal is © The Royal Society of Chemistry 2016
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