Selective Extraction and Determination of Hydrocortisone and Dexamethasone in Skincare Cosmetics: Analytical Interpretation Using Statistical Physics Formalism

Round 1

Reviewer 1 Report (Previous Reviewer 1)

The authors took onboard some easy comments and addressed them but refused to do the technical work.

For example I asked "On page 8, line number 265-266, the authors mentioned that value of adsorption energy less than 20kJ/mol predicts physisorption and use it as a proof of the presence of van der Waals forces which is not convincing. These interactions must be studied and proven through some sophisticated analysis like Noncovalent Interactions Analysis through Multiwfn." but they refused to add the required studies to prove the van der Waals forces.

Similarly the following comment that was very important has also been neglected:

"The authors also claim that “it was theoretically showed that all cosmetics products were absorbed via a non-parallel orientation on MMIPPs/MNIPs surface” which cannot be proven without any theoretical quantum chemical (QC) calculations. While the structures of both the studied drugs (dexamethasone and hydrocortisone) are reasonably small, they can easily be studied through QC calculations. Thus it would be much appropriate to show their adsorption."

Hence as this study is already dilute and the experimental part has already been published, I cannot recommend its publication.

Author Response

Response to Reviewer 1

The authors thank the editor and the reviewers for their careful reading of the manuscript and for their comments and suggestions. The answers are given below.

Yours sincerely

Reviewer  1

Comments and Suggestions for Authors

Accept in present form.

Author Response File: Author Response.pdf

Reviewer 2 Report (New Reviewer)

Accept in present form.

Author Response

Reviewer  1

Comments and Suggestions for Authors

Accept in present form.

Reviewer 3 Report (New Reviewer)

This manuscript reports the adsorption theoretical about magnetic molecularly imprinted polymers utilized as adsorbents for dexamethasone and hydrocortisone in cosmetics. The manuscript is well articulated, and the results obtained are very interesting and useful in analytical chemistry. However, there are some problems, which should be solved before it is considered for publication:

1.     The layout of Formula 4 in section 3.3 needs to be modified.

2.     The titles and formats of all tables need to be modified.

3.     The synthetic method and characterization results of dual-template MNIPs/MMIPs was not described in the manuscript. Is it completely identical to Liu's article?

4.     We all know that dexamethasone and hydrocortisone have extremely similar structures. So, is there a synergistic or competitive effect in the adsorption process of MMIP/MNIP for two mixed substances?

5.     What can be done to help improve the adsorption capacity of MMIP?

Author Response

Reviewer 3

This manuscript reports the adsorption theoretical about magnetic molecularly imprinted polymers utilized as adsorbents for dexamethasone and hydrocortisone in cosmetics. The manuscript is well articulated, and the results obtained are very interesting and useful in analytical chemistry. However, there are some problems, which should be solved before it is considered for publication:

1. The layout of Formula 4 in section 3.3 needs to be modified.

Response

Thank you, we took into account this comment. Please see this change in the manuscript

2. The titles and formats of all tables need to be modified.

Response

Thank you, we took into account this comment. Please see this change in the manuscript

3. The synthetic method and characterization results of dualtemplate MNIPs/MMIPs was not described in the manuscript. Is it completely identical to Liu's article?

Response

The synthetic method and characterization results of dual template MNIPs/MMIPs MMIPs was reported by Min Liu et al . In this work, we are interested in the theoretical investigation and mathematical modeling of the experimental data using the statistical physics theory.

4. We all know that dexamethasone and hydrocortisone have extremely similar structures. So, is there a synergistic or competitive effect in the adsorption process of MMIP/MNIP for two mixed substances?

Response

For the adsorption process of MMIP/MNIP for dexamethasone and hydrocortisone together, it would depend on the specific design and properties of the polymers. MMIPs are typically designed to have high affinity and selectivity for the target molecule, and the presence of other substances may influence the binding capacity. However, the nature of the interaction (synergistic or competitive) would be more relevant in a biological or pharmacological context rather than in the context of polymer adsorption.

5. What can be done to help improve the adsorption capacity of MMIP?

Response

To enhance the adsorption capacity of molecularly imprinted polymers (MMIP),  several methods can be employed such as:

- Adjust the polymerization conditions such as monomer concentration, cross-linker ratio, and initiator concentration to achieve a more uniform and efficient polymer structure

- Ensure thorough removal of the template molecule after polymerization to create well-defined and accessible binding sites

- Increase the surface area of the polymer by optimizing particle size or using porous structures.

- Adjust the pore size to allow easy access of target molecules to the binding sites.

- Explore the effect of temperature and pH on the adsorption capacity. Conditions that optimize binding interactions can be determined experimentally

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report (Previous Reviewer 1)

Fatma Aouaini and co-workers present a manuscript about the adsorption mechanism of the selective adsorption of the hydrocortisone and dexamethasone on Molecularly imprinted polymers (MIPs) as magnetic extraction adsorbents. I have previously reviewed this manuscript and gave the reject recommendation with comments. The revised version I received is accompanied by a response to reviewers file where only two of my comments are mentioned and not replied. In their so called “Author reply” they are writing like a reviewer and telling the importance of Multiwfn software instead of incorporating it in their study. Because this paper is a revision of previous study where I have already given comments, I am copying those comments below and without their consideration and a point by point reply, I cannot move any further from my recommendation.

My original comments on the previous version of the paper with ID applsci-2529553.

While the subject is interesting, the main issue with this manuscript is that the same work has already been published (Min Liu, Xiaoyan Li, Junjie Li, Zongyuan Wu, Fang Wang, Li Liu, Xuecai Tan, Fuhou Lei, Journal of Colloid and Interface Science, 2017, 504, 124-133) and this work is on the same theme but does not deliver what it promises. The authors claim to investigate the mechanism of adsorption of the above-mentioned glucocorticoids on the MIPs, but it has not been done properly. Here are some major issues that compel me not to recommend this manuscript for publication.

Major Points:

·        On page 8, line number 265-266, the authors mentioned that value of adsorption energy less than 20kJ/mol predicts physisorption and use it as a proof of the presence of van der Waals forces which is not convincing. These interactions must be studied and proven through some sophisticated analysis like Noncovalent Interactions Analysis through Multiwfn.

·        On page 3, line number 109-110, Author explains the saturation of adsorption sites supporting Langmuir Adsorption Isotherm. However, on page 7, section 4.1, line number 221-226, the parameters have been evaluated for M3 (multilayer model). Even though Langmuir isotherm supports monolayer adsorption. No clear justification is provided for type of adsorption layer!

·        On pages 9 & 10, section 6.1 and 6.2, the Authors did not provide internal energy and Gibbs free energy comparison for the two systems.

·        The authors also claim that “it was theoretically showed that all cosmetics products were absorbed via a non-parallel orientation on MMIPPs/MNIPs surface” which cannot be proven without any theoretical quantum chemical (QC) calculations. While the structures of both the studied drugs (dexamethasone and hydrocortisone) are reasonably small, they can easily be studied through QC calculations. Thus it would be much appropriate to show their adsorption.

Minor Points:

·        The manuscript is grammatically weak and causes difficulty in reading. It must be proofread by a native English speaker or some language editing service.

·        In the manuscript, some terms are not fully explained like MMIPs and MNIPs

·        There are some typographic mistakes that must be corrected.

·        In some areas, the Author mentioned equations but did not explain their values properly.

·        Text, tables, and figures are not formatted properly.

English language needs editing as can be seen from author's reply

Author Response

Dear Editor

I am enclosing here the revised manuscript of the article referred: Selective extraction and determination of hydrocortisone and dexamethasone in skincare cosmetics: Analytical interpretation using statistical physics formalism.

According to the comments and suggestions of the editor and the reviewers, we have corrected the manuscript. It has been improved and some errors and incorrect sentences have been modified as better as possible.

The authors thank the editor and the reviewers for their careful reading of the manuscript and for their comments and suggestions. The answers are given below.

Yours sincerely

Dr. FATMA AOUAINI

Reviewer 1:

Major Points: ·

On page 8, line number 265-266, the authors mentioned that value of adsorption energy less than 20kJ/mol predicts physisorption and use it as a proof of the presence of van der Waals forces which is not convincing. These interactions must be studied and proven through some sophisticated analysis like Noncovalent Interactions Analysis through Multiwfn.

Response

Firstly, I appreciate the thorough review and insightful comments. In response to the suggestion of employing Multiwfn software for a more sophisticated analysis of noncovalent interactions, I would like to express my constraints and the reasons for not utilizing this tool in our study.

Unfortunately, Multiwfn software is not available in my current research environment, and its implementation is challenging due to several practical reasons. The unavailability of the software hinders our ability to conduct the suggested analysis. Moreover, the complexity of Multiwfn may require specialized expertise that is currently beyond the scope of our research team.

While we acknowledge the significance of advanced tools like Multiwfn for studying noncovalent interactions, we have employed alternative methods that are well-established and widely recognized in the field. Our chosen approaches may not be as intricate as Multiwfn, but they are deemed suitable for the current study and provide meaningful insights into the van der Waals forces influencing adsorption energies.

I kindly request your understanding of these limitations.

Thank you for your understanding and consideration.

On page 3, line number 109-110, Author explains the saturation of adsorption sites supporting Langmuir Adsorption Isotherm. However, on page 7, section 4.1, line number 221-226, the parameters have been evaluated for M3 (multilayer model). Even though Langmuir isotherm supports monolayer adsorption. No clear justification is provided for type of adsorption layer!

Response

In the earlier sections of the manuscript, specifically on page 3, I presented three different models to test various isotherms and determine the most appropriate model for our study. The inclusion of multiple models at this stage was a deliberate choice aimed at exploring the best fit for the observed data. It was not meant to imply a preference for any specific model at that point.

Upon careful analysis, we found that the multilayer model (M3) best suited our experimental data for several reasons, as elaborated in detail on page 5, section 3.4. While the Langmuir Adsorption Isotherm traditionally supports monolayer adsorption, our decision to utilize the multilayer model was based on a comprehensive evaluation of various factors outlined in the aforementioned section.

I acknowledge the importance of providing a clear justification for the selection of the adsorption layer type. To address this concern, I have revised the manuscript to explicitly highlight the rationale behind choosing the multilayer model and have incorporated the relevant details in section 3.4 on page 5.

On pages 9 & 10, section 6.1 and 6.2, the Authors did not provide internal energy and Gibbs free energy comparison for the two systems.

Response

We took into account this comment. Please see this change in the manuscript ( on page 11 and 12, section 7.1 and 7.2)

The authors also claim that “it was theoretically showed that all cosmetics products were absorbed via a non-parallel orientation on MMIPPs/MNIPs surface” which cannot be proven without any theoretical quantum chemical (QC) calculations. While the structures of both the studied drugs (dexamethasone and hydrocortisone) are reasonably small, they can easily be studied through QC calculations. Thus it would be much appropriate to show their adsorption.

Response

Unfortunately, I regret to inform you that, due to certain constraints in our research environment, we are currently unable to perform theoretical quantum chemical calculations. While we recognize the potential benefits of such calculations, we have utilized alternative methods, particularly employing principles from statistical physics, to analyze the adsorption behavior of the studied drugs, dexamethasone and hydrocortisone.

Minor Points: ·

The manuscript is grammatically weak and causes difficulty in reading. It must be proofread by a native English speaker or some language editing service. ·

Response

The manuscript has been completely revised for English grammar, many scientific parts are added and some mistakes have been corrected. These ameliorations appear in red color in manuscript. Please see this change in the manuscript

 In the manuscript, some terms are not fully explained like MMIPs and MNIPs ·

Response

Thank you, we took into account this comment. Please see this change in the manuscript

 (MMIPs and MNIPs are fully explained in both the abstract and the introduction)

There are some typographic mistakes that must be corrected. ·

Response

Thank you, we took into account this comment. Please see this change in the manuscript

In some areas, the Author mentioned equations but did not explain their values properly. · Text, tables, and figures are not formatted properly.

Response

Thank you, we took into account this comment. Please see this change in the manuscript

Author Response File: Author Response.pdf

Reviewer 3 Report (New Reviewer)

1. The format of references needs to be carefully revised

2. How to obtain the results in Figure 7? The author needs to provide more detailed descriptions in the manuscript.

Author Response

Dear Editor

I am enclosing here the revised manuscript of the article referred: Selective extraction and determination of hydrocortisone and dexamethasone in skincare cosmetics: Analytical interpretation using statistical physics formalism.

According to the comments and suggestions of the editor and the reviewers, we have corrected the manuscript. It has been improved and some errors and incorrect sentences have been modified as better as possible.

The authors thank the editor and the reviewers for their careful reading of the manuscript and for their comments and suggestions. The answers are given below.

Yours sincerely

Dr. FATMA AOUAINI

Reviewer 3

The format of references needs to be carefully revised .

Response

Thank you, we took into account this comment. Please see this change in the manuscript

How to obtain the results in Figure 7? The author needs to provide more detailed descriptions in the manuscript

Response

To determine this energy, we utilize the analytical expression of the internal energy, calculated from the multilayer model based on statistical physics. However, the expression is too lengthy to include in the article.

Author Response File: Author Response.pdf

Round 3

Reviewer 1 Report (Previous Reviewer 1)

I believe the authors have reasonably justified (even though not accepted) all of my comments. so I would recommend its publication.

I would just like to mention that Multiwfn is a free software in response to the author's statement "Multiwfn software is not available in my current research environment".

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

Fatma Aouaini and co-workers present a manuscript about the adsorption mechanism of the selective adsorption of the hydrocortisone and dexamethasone on Molecularly imprinted polymers (MIPs) as magnetic extraction adsorbents. While the subject is interesting, the main issue with this manuscript is that the same work has already been published (Min Liu, Xiaoyan Li, Junjie Li, Zongyuan Wu, Fang Wang, Li Liu, Xuecai Tan, Fuhou Lei, Journal of Colloid and Interface Science, 2017, 504, 124-133) and this work is on the same theme but does not deliver what it promises. The authors claim to investigate the mechanism of adsorption of the above-mentioned glucocorticoids on the MIPs, but it has not been done properly. Here are some major issues that compel me not to recommend this manuscript for publication.

Major Points:

·        On page 8, line number 265-266, the authors mentioned that value of adsorption energy less than 20kJ/mol predicts physisorption and use it as a proof of the presence of van der Waals forces which is not convincing. These interactions must be studied and proven through some sophisticated analysis like Noncovalent Interactions Analysis through Multiwfn.

·        On page 3, line number 109-110, Author explains the saturation of adsorption sites supporting Langmuir Adsorption Isotherm. However, on page 7, section 4.1, line number 221-226, the parameters have been evaluated for M3 (multilayer model). Even though Langmuir isotherm supports monolayer adsorption. No clear justification is provided for type of adsorption layer!

·        On pages 9 & 10, section 6.1 and 6.2, the Authors did not provide internal energy and Gibbs free energy comparison for the two systems.

·        The authors also claim that “it was theoretically showed that all cosmetics products were absorbed via a non-parallel orientation on MMIPPs/MNIPs surface” which cannot be proven without any theoretical quantum chemical (QC) calculations. While the structures of both the studied drugs (dexamethasone and hydrocortisone) are reasonably small, they can easily be studied through QC calculations. Thus it would be much appropriate to show their adsorption.

Minor Points:

·      In the manuscript, some terms are not fully explained like MMIPs and MNIPs

·        There are some typographic mistakes that must be corrected.

·        In some areas, the Author mentioned equations but did not explain their values properly.

·        Text, tables, and figures are not formatted properly.

The manuscript is grammatically weak and causes difficulty in reading. It must be proofread by a native English speaker or some language editing service.

Author Response

Reviewer #1:

Fatma Aouaini and co-workers present a manuscript about the adsorption mechanism of the selective adsorption of the hydrocortisone and dexamethasone on Molecularly imprinted polymers (MIPs) as magnetic extraction adsorbents. While the subject is interesting, the main issue with this manuscript is that the same work has already been published (Min Liu, Xiaoyan Li, Junjie Li, Zongyuan Wu, Fang Wang, Li Liu, Xuecai Tan, Fuhou Lei, Journal of Colloid and Interface Science, 2017, 504, 124-133) and this work is on the same theme but does not deliver what it promises. The authors claim to investigate the mechanism of adsorption of the above-mentioned glucocorticoids on the MIPs, but it has not been done properly. Here are some major issues that compel me not to recommend this manuscript for publication.

Major Points:

On page 8, line number 265-266, the authors mentioned that value of adsorption energy less than 20kJ/mol predicts physisorption and use it as a proof of the presence of van der Waals forces which is not convincing. These interactions must be studied and proven through some sophisticated analysis like Noncovalent Interactions Analysis through Multiwfn.

Response

Thank you, we took into account this comment. Please see this change in the manuscript (concerning the van der Waals forces)

Concerning the noncovalent Interactions Analysis through Multiwfn, I dont have any idea about this program. In this work, we are interested in the theoretical investigation and mathematical modeling of the experimental data using the statistical physics theory.

On page 3, line number 109-110, Author explains the saturation of adsorption sites supporting Langmuir Adsorption Isotherm. However, on page 7, section 4.1, line number 221-226, the parameters have been evaluated for M3 (multilayer model). Even though Langmuir isotherm supports monolayer adsorption. No clear justification is provided for type of adsorption layer!

Response

The adsorption isotherms were examined by non-linear curve fitting analysis, using ORIGIN software (OriginLab Corporation) to adjust the three  adsorption models mentioned in this article.

Based on the R² and RMSE values, it was observed that the multilayer model agreed very well with the experimental data.

Hence, to confirm the choice of this model, our selection must also take into account the physical signification of the physico-chemical parameters in the chosen model.

However, the parameter values of the adjusted monolayer model were not consistent with the experimental results. These parameters values have not physical significations and, therefore, the single layer model was discarded for the adsorption data modeling.

Therefore, the multilayer model is the appropriate model because it  has acceptable fitting coefficients and reasonable physical parameters

On pages 9 & 10, section 6.1 and 6.2, the Authors did not provide internal energy and Gibbs free energy comparison for the two systems.

Response

We took into account this comment. Please see this change in the manuscript

These parts are added in the manuscript

The authors also claim that “it was theoretically showed that all cosmetics products were absorbed via a non-parallel orientation on MMIPPs/MNIPs surface” which cannot be proven without any theoretical quantum chemical (QC) calculations. While the structures of both the studied drugs (dexamethasone and hydrocortisone) are reasonably small, they can easily be studied through QC calculations. Thus it would be much appropriate to show their adsorption.

Response

Sure, the reviewer is absolutely right and we should thank him for this comments. However, in this work, we are interested by the theoretical investigation and mathematical modeling of the experimental data.

Minor Points: ·

In the manuscript, some terms are not fully explained like MMIPs and MNIPs ·

 Response

Thank you, we took into account this comment. Please see this change in the manuscript

There are some typographic mistakes that must be corrected. ·

Response

Thank you, we took into account this comment. Please see this change in the manuscript

In some areas, the Author mentioned equations but did not explain their values properly. · Text, tables, and figures are not formatted properly

Response

Thank you, we took into account this comment. Please see this change in the manuscript

The manuscript is grammatically weak and causes difficulty in reading. It must be proofread by a native English speaker or some language editing service.

Response

The manuscript has been completely revised for English grammar, many scientific parts are added and some mistakes have been corrected. These ameliorations appear in red color in manuscript. Please see this change in the manuscript

Author Response File: Author Response.pdf

Reviewer 2 Report

The article is in its early steps, it was very hard to read and understand the interesting reported results on advanced theoretical results on the adsorption for cosmetics products using molecularly imprinted polymers. The article need a lot of work in:

* Grammar, typographical, and English language errors. For example, what do you mean with "affected" in line 169? What about "perfect" fitting?

* Correct and extended description of several symbols in the equations, read what you write before send it. 

* Considering that the multilayer model was reported as adequate to describe the adsortion phenomenon, Does cohesion play any role in the dexamethasone and hydrocortisone arragements?  

The manuscript is in its early steps, it was very hard to read and understand the interesting reported results. 

Author Response

Reviewer #2:

The article is in its early steps, it was very hard to read and understand the interesting reported results on advanced theoretical results on the adsorption for cosmetics products using molecularly imprinted polymers. The article need a lot of work in:

* Grammar, typographical, and English language errors. For example, what do you mean with "affected" in line 169? What about "perfect" fitting?

Response

The manuscript has been completely revised for English grammar, many scientific parts are added and some mistakes have been corrected. These ameliorations appear in red color in manuscript. Please see this change in the manuscript

* Correct and extended description of several symbols in the equations, read what you write before send it.

Response

Thank you, we took into account this comment. Please see this change in the manuscript

* Considering that the multilayer model was reported as adequate to describe the adsortion phenomenon, Does cohesion play any role in the dexamethasone and hydrocortisone arragements?

Response

Cohesion is the property of like molecules to stick to each other due to mutual attraction. Adhesion is the property of different molecules or surfaces to cling to each other. Since the interactions between adsorbate-adsorbent are higher than that of adsorbate-adsorbate i.e      ΔE₂ < ΔE₁ (page 8). Indeed, the cohesion do not play an important role in hydrocortisone and dexamethasone arrangements.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Despite the fact that the concepts of adhesion and cohesion were not satisfactorily explained, the article was improved with regard to the English language edition. Since only models of superposition of layers and not of molecular interactions are promoted, the article can be accepted.