Preparation of Electrosprayed Poly(caprolactone) Microparticles Based on Green Solvents and Related Investigations on the Effects of Solution Properties as Well as Operating Parameters
Round 1
Reviewer 1 Report
The paper dealt with the evaluation of 4 green solvents as alternative to chloroform to electrospray PCL. The topic is very hot and of course of interest for many readers and the authors investigated many parameters, identifying in the ethyl acetate a possible alternative to the chloroform.
Before the publication it would be interesting to check the deposition of an homogeneous coating of PCL in ethyl acetate and to show to the readers the possible applications of it. In particular, electrospray parameters for the deposition of an homogeneous coating and its characterization in terms of adhesion (resistance to delamination) will complete this study.
Author Response
Answers to Reviewer # 1
Before the publication it would be interesting to check the deposition of an homogeneous coating of PCL in ethyl acetate and to show to the readers the possible applications of it. In particular, electrospray parameters for the deposition of an homogeneous coating and its characterization in terms of adhesion (resistance to delamination) will complete this study.
Thank you very much for this suggestion. For the moment we have not explored this avenue, but we will do so in the future. The objective of this paper was to determine the main process and formulation parameters influencing the formation of PCL-based microparticles. To do this, we decided to select 4 green solvents for the writing of this article to replace the chlorinated solvents usually used.
In addition, the formation of a film in a solution containing liquids is very different from that at the particle interface, particularly in electrospraying. We are not entirely convinced that this exploratory approach is appropriate for our study. We take into consideration that adhesion is a fundamental phenomenon in the structuring of particles, but for all that, the analysis of this from an experimental point of view is very difficult to implement, especially at the microscopic level. These adhesion phenomena require very specific manipulations, and in our case will be addressed from a theoretical point of view in the future.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
In this work, entitled ‘’ Preparation of Electrosprayed Poly(caprolactone)Microparticles Based on Green Solvents and Related Investigations on The Effects of Solution Properties as well as Operating Parameters” , the authors verify the effect of electrical conductivity and surface tension of solvents used to electrospray microparticles. This is a very interesting and detailed study with well-organized descriptions.
The authors may also add the following references and discuss them too to cover the full picture of solvent effect regarding their most important properties.
For example the high surface tension of water with controlled electrospraying by avoiding a cone relaxation due to the space charge effect created by the charged droplets between the jet and the counter electrode, more in the reference: Journal of Aerosol Science 41 (10), 963-973- Single event electrospraying of water, by U Stachewicz, CU Yurteri, JF Dijksman, JCM Marijnissen. Additionally, the important aspects for this study are clarified in the ref: Journal of Fluid Mechanics 260, 155-184- The current emitted by highly conducting Taylor cones, by JF De La Mora and IG Loscertales. In case of highly conductive solutions discuss this key paper: J. Aerosol Sci 25 (6), 1093-1119- Generation of monodisperse droplets 0.3 to 4 µm in diameter from electrified cone–jets of highly conducting and viscous liquids by J Rosell-Llompart and J Fernandez de la Mora.
Author Response
Answers to Reviewer # 2
The authors may also add the following references and discuss them too to cover the full picture of solvent effect regarding their most important properties.
For example the high surface tension of water with controlled electrospraying by avoiding a cone relaxation due to the space charge effect created by the charged droplets between the jet and the counter electrode, more in the reference: Journal of Aerosol Science 41 (10), 963-973- Single event electrospraying of water, by U Stachewicz, CU Yurteri, JF Dijksman, JCM Marijnissen. Additionally, the important aspects for this study are clarified in the ref: Journal of Fluid Mechanics 260, 155-184- The current emitted by highly conducting Taylor cones, by JF De La Mora and IG Loscertales. In case of highly conductive solutions discuss this key paper: J. Aerosol Sci 25 (6), 1093-1119- Generation of monodisperse droplets 0.3 to 4 µm in diameter from electrified cone–jets of highly conducting and viscous liquids by J Rosell-Llompart and J Fernandez de la Mora.
Thank you for this useful coment, we have taken in account the above reference to write the new version of this article. Modifications are made in the introduction part (line 74 to 85).
For instance, as the resistance of the formation of Taylor cone, low surface tension (lower than 50 mN/m) makes the stable cone-jet mode more accessible. Thus, under high surface tension, intermittent cone–jet is obtained due to the cone relaxation resulted from space charge. According to Stachewicz et al., the electrospraying of high surface tension liquid (i.e., water) will be carried out under stable cone-jet when using single event electrospraying (SEE) to avoid cone relaxation based on pulse-controlled liquid deposition [20]. Meanwhile, the charge transfer in electrified liquid cones as well as related relationships among solution properties, liquid flow rate, emit currents and jet diameter were closely related to the electrical conductivity of working liquid [21]. Also, Rosell-Llompart et al. found that the formation of a stable cone-jet mode is obtained under the minimum liquid flow rate [22]. The mean diameter, as well as the size distribution of electrosprayed droplets, mainly depends on flow rate of liquid, electrical conductivity of liquid and viscosity of the liquid.
Reviewer 3 Report
The manuscript titled "Preparation of Electrosprayed Poly(caprolactone) Microparticles Based on Green Solvents and Related Investigations on The Effects of Solution Properties as well as Operating Parameters” presents a study for fabrication of polymeric nano particle via electrospraying technique. The manuscript is connected with interesting and modern scientific problem for electrospraying; the paper is written legible English and from scientific point of view is modern and interesting. The manuscript could be ready for publication after minor revision.
- Authors need to justify the novelty of their study by providing more literature review. Also, it is recommended to provide more comparison with other similar studies.
- stats methods need to be described in the results tables.
- the written info in figures are not legible
Author Response
Answers to Reviewer # 3
- Authors need to justify the novelty of their study by providing more literature review. Also, it is recommended to provide more comparison with other similar studies.
The introduction part was completed, and the aim of this study was well specified.
Line 106 to 124
There had been some papers publishing some simple relationships among structure as well as the morphology of electrosprayed particles, solution properties and operating parameters [1,12,38]. However, these conditions to determine the formation and shape of Taylor cone are still superficial and unclear. Meanwhile, the suitable operating parameters for achieving cone-jet also strictly depend on the solution properties. Furthermore, as a multi-physical process, the effects coming from operating parameters and solution properties on electrospraying are complex and interactional. The relationships among solution properties, operating parameters and structural characteristics of electrosprayed particles are also different based on different solvent systems. Therefore, the suitable solvent properties as well as operating parameters to develop electrosprayed particles with satisfied size, as well as morphology, also needs further investigations. Also, although some green solvents (i.e., anisole and acetone) had been introduced to prepare PCL microspheres, their applications in PCL electrospraying is still unreported [35,39].
In order to clarify the effects of solvent properties on electrospraying and obtain appropriate green solvent used for PCL electrospraying, the study aimed to prepare PCL microparticles using four green solvents (ethyl acetate, acetone, anisole and glacial acetic acid) according to the direction of REACH (Registration, Evaluation, and Authorization of Chemicals) and the regulation of European Pharmacopoeia (belonging to the Class 3), to find the best possible alternative to the chlorinated solvents commonly used in this process [35,40].
- stats methods need to be described in the results tables.
Stats methods were revised and explained in the Materials and Methods part. To avoid overloading the tables, we have chosen to include them in this section. For example in line 174 to 176 : The obtained data were statistically analyzed in a spreadsheet (Microsoft Excel 2011) to calculate the mean diameter as well as the particle size distribution.
Furthermore, standard deviations were added in all the tables.
- the written info in figures are not legible
All the figures were revised according to your useful comment. Thank a lot.
Figure 1. Images of Taylor cone obtained with anisole, ethyl acetate, chloroform, acetic acid and acetone at three PCL concentrations (1, 5 and 10 wt%) (working parameters: working distance 17 cm, dripping time: 5 s (excepted for anisole: 93 s)).
Figure 2. Images of Taylor cone obtained with anisole, ethyl acetate, chloroform, acetic acid and acetone at three working distances (9, 17 and 23 cm) at 5 wt% PCL concentrations for a dripping time of 5 s excepted for anisole (93 s).
Figure 3. Images of Taylor cone obtained with anisole, ethyl acetate, chloroform, acetic acid and acetone at three dripping times (129, 93, and 45 s) at 5 wt% PCL concentrations and a fixed working distance of 17 cm.
Figure 4. Mean diameter and size distribution of PCL electrosprayed microparticles obtained from ethyl acetate (a)), chloroform (b)), anisole (c)), acetic acid (e)), and acetone (f) for a working distance of 17 cm, an applied voltage of 3.75 kV (excepted for acetone: 4.75 kV, and glacial acetic acid: 5.25 kV), and a dripping time of 5 s (excepted for anisole, 93 s)).
Figure 5. Mean diameter and size distribution of PCL electrosprayed microparticles obtained from ethyl acetate (a)), chloroform (b)), anisole (c)), acetic acid (e)), and acetone (f) for various working distances (9, 13, 17, 21; and 25 cm), at 5 wt% PCL concentration for an applied voltage of 3.75 kV (excepted for acetone: 4.75 kV, and glacial acetic acid: 5.25 kV), and a dripping time of 5 s (excepted for anisole, 93 s)).
Figure 6. Mean diameter and size distribution of PCL electrosprayed microparticles obtained from ethyl acetate (a)), chloroform (b)), anisole (c)), acetic acid (e)), and acetone (f) for various dripping times, at 5 wt% PCL concentration for an applied voltage of 3.75 kV (excepted for acetone: 4.75 kV, and glacial acetic acid: 5.25 kV), and a working distance of 17 cm.
Figure 7. Mean diameter and size distribution of PCL electrosprayed microparticles obtained from ethyl acetate (a)), chloroform (b)), anisole (c)), acetic acid (e)), and acetone (f) for a dripping time of 5 s (excepted for anisole, 93 s), at various applied voltages, and a working distance of 17 cm.
Figure 8. SEM images of PCL microparticles obtained from different solvent and different operating parameters (the caption in each figure presents the experimental conditions. For example, ethyl acetate-5wt%-425px-5s presents that the solvent system is ethyl acetate; PCL concentration is 5wt%; working distance is 425px; dripping time for one droplet is 5s. For figures a1-a4, c1-c4 and e, the applied voltage is 3.75 kV. For figure b1-b4, the applied voltage is 4.75 kV. For figure d1-d3, the applied voltage is 5.25kv. Scale bar: 100 µm)
Author Response File: Author Response.pdf
Round 2
Reviewer 1 Report
The manuscript has been revised according to the Reviewer's comments. In particular, the Authors introduced the required revisions. The manuscript is now acceptable for publication.
Reviewer 3 Report
Authors applied my comments and the manuscript is ready to be submitted for publication.
