Recent Advances in Biocompatible Ionic Liquids in Drug Formulation and Delivery

Round 1

Reviewer 1 Report

The paper submitted for review entitled "Recent advances in Biocompatible Ionic Liquids in Drug Formulation and Delivery" is very interesting and up-to-date. It is prepared very carefully. The drawings prepared by the authors deserve special mention. As a reviewer of this work, I recommend it for publication. However, before publication, I suggest a few corrections that, in my opinion, will improve the perception of this work.

1. I suggest you prepare a diagram that will explain and illustrate the selection of chapters and subchapters. It is not clear when the authors write about ILs as ingredients of pharmaceutical preparations, and when they describe the use of ILs for the synthesis of drugs or obtaining them from natural sources. For instance the following parts:

-“The pharmaceutical industry faces significant challenges when developing new  drugs. In particular, many drugs exhibit poor bioavailability, which is attributed to their  limited solubility in physiological fluids/water, poor permeability and inadequate absorption in the gastrointestinal tract, rapid metabolism, and/or degradation during systemic  circulation [1,2]. Several organic solvents, including acetone, ethanol, isopropyl alcohol,  dimethyl sulfoxide, dimethylformamide, and pyridine, are commonly used to solubilize  these drug molecules.”- I do not understand the point of text. Are these solvents used to solubilize drugs in human organism?

-“However, organic solvents present in pharmaceutical products are not accepted by regulatory authorities because they have severe adverse effects on the  human body, including acute toxicity and carcinogenicity [2,3]. “- What kind of solvents present in pharmaceutical formulations do you mean?

-Line 45-72- I do not understand the point of these part of the manuscript. At the beginning the authors write about processes belonging to ADME and after that they give the examples of IL such as 1-butyl-3-methylimidazolium tetra- fluoroborate and 1-butyl-3-methylimidazolium hexafluorophosphate. It means that these ILs can be added as solvents to pharmaceutical formulations? Please give examples of such formulations.

2. Authors should mention in the introduction e.g. Where did the sources used to prepare this review come from; what period of time they took into account when collecting the materials. I understand that this is a non-systematic review and should also be mentioned.

-“In addition,  this review will provide an information-based tool to bridge the gap between commonly used ILs and biocompatible ILs in fields ranging from chemical synthesis to biomedicine, which underpins the advancement of biocompatible IL-based drug delivery systems.”-This sentence is obscure. Please give reasonable reasons of this review and define the review’ kind, the sources of discussed papers.

3. I understand that although the article is about ionic liquids, I should write briefly about the difference between ILs and DES, as it is not always understandable.

4. The authors should also expand on the future perspectives section. Many bio-ILs are synthesized, and so far they have not found specific applications in pharmacy. If I can suggest a few works that might be considered, they are as follows:

Natural terpene derivatives as new structural task-specific ionic liquids to enhance the enantiorecognition of acidic enantiomers on teicoplanin-based stationary phase by high-performance liquid chromatography. [AUT.] JOLANTA FLIEGER*, JOANNA FEDER-KUBIS, MAŁGORZATA TATARCZAK-MICHALEWSKA, ANITA PŁAZIŃSKA, ANNA MADEJSKA, MARTA SWATKO-OSSOR. J. Sep. Sci. [online] 2017 vol. 40 nr 11 s. 2374-2381, http://onlinelibrary.wiley.com/doi/10.1002/jssc.201700197/full. DOI: 10.1002/jssc.201700197 

Renewable sources from plants as the starting material for designing new terpene chiral ionic liquids used for the chromatographic separation of acidic enantiomers. [AUT.] JOANNA FEDER-KUBIS*, JOLANTA FLIEGER, MAŁGORZATA TATARCZAK-MICHALEWSKA, ANITA PŁAZIŃSKA, ANNA MADEJSKA, MARTA SWATKO-OSSOR. RSC Adv. 2017 vol. 7 nr 51 s. 32344-32356,. DOI: 10.1039/c7ra03310a 

5. Since this is an overview I suggest you write a short section on chiral ILs. I have an overview of this, although you can find other examples in the literature as well. The choice is up to the authors.

Flieger J, Feder-Kubis J, Tatarczak-Michalewska M. Chiral Ionic Liquids: Structural Diversity, Properties and Applications in Selected Separation Techniques. Int J Mol Sci. 2020 Jun 15;21(12):4253. doi: 10.3390/ijms21124253.

Author Response

Dear Reviewer,

Thank you very much for your valuable comments on our manuscript. Please see the attached file for a point-by-point response to the reviewer's comments. 

Author Response File: Author Response.docx

Reviewer 2 Report

A systematic analysis is made on the advances in the use of biocompatible ionic liquids in the development of pharmaceutical formulations and drug delivery. 

The review is complete, the research works consulted guarantee the quality of the information contained in the document. Except for some formal corrections and clarifications necessary to improve the understanding of the text, the document is of sufficient quality to be considered for publication. 

1. Line 36. the correct word is "dissolve", "solubilize" implies the use of surfactants. 

2. Line 47: "melting point of 100 °C or lower and are liquids at room temperature" If the melting temperature is 100 °C, how can they be liquid at room temperature?

3. Line 74 Writing in the third person 

4. It is recommended to modify figure 1. Remove component A. 

5.  Describe in a clear and detailed way how ionic liquids affect Pharmacokinetics and Pharmacodynamics, in particular Pharmacokinetics (what the body does to the drug).

6. Separate figures 2, 3, 5 and 6. The information contained is not related. 

Author Response

Dear Reviewer,

Thank you very much for your valuable comments on our manuscript. Please see the attached file for a point-by-point response to the reviewer's comments.

Author Response File: Author Response.docx

Reviewer 3 Report

The review entitled "Recent advances in Biocompatible Ionic Liquids in Drug For-2 mulation and Delivery" comprehensively brings together all recent applications of ILs in drug delivery and formulations. The authors include some of the leading experts in this field, and this is reflected in the quality of the work. Therefore, I suggest the publication of the work only after two minor reviews.

 

Some references in the opening part of the introduction are dated. For example, 10.1007/s12551-018-0419-2, 10.1007/s11356-023-25562-z, 10.1016/j.molliq.2019.112038 can also be added.

 

In captions, the specific reference of the image taken should be put after each "letter" and not at the end. This makes it faster to trace directly back to the source of the image.

 

In some cases, the read L of the abbreviation ILs results in lower case (e.g., line 73 and 75)

 

Recently, a study employing ILs based on betaine and carnitine esters as solubilizing and stabilizing agents for the formulation of antimicrobial eye drops containing diacerein was reported. Betaine is a derivative of glycine and for this reason could be , for example, included in section 2.3.

 

 

Author Response

Dear Reviewer,

Thank you very much for your valuable comments on our manuscript. Please see the attached file for a point-by-point response to the reviewer's comments.

Author Response File: Author Response.docx