Solid Dispersions of Fenbendazole with Polymers and Succinic Acid Obtained via Methods of Mechanochemistry: Their Chemical Stability and Anthelmintic Efficiency
, Ekaterina A. Khakina 1, Marat S. Khalikov 1 and Anastasiya I. Varlamova 2Round 1
Reviewer 1 Report
Comments and Suggestions for Authors
The work entitled „Preparations based on fenbendazole obtained by methods of mechanochemistry, their stability and efficacy” presents the possible bioavailability of fenbendazole through mechanochemical route. Because of several issues the manuscript needs some additions and explanations before it could be accepted, so the reviewer recommend its major revision.
Some detailed comments are listed below:
1. It is not clear what is the novelty of presented manuscript as compared to the cited in introduction references no 1-7. Please present it clearly and also discuss and compare later presenting current results. What more the ref. no 7 have a wrong bibliographic data.
2. Check the correctness of used chemicals’ names and also the English throughout the manuscript. It contains several mistakes, e.g. the sentence in line 70-72 lost the verb.
3. The analysis of all NMR spectra presented in the manuscript is not sufficient. Please show the integrals of corresponding signals and discuss them in manuscript. The lack of AG’s proton signals is unconvincingly explained, especially that the FBZ:AG ration in mixture is 1:9. Please provide the spectra in other solvents. In line 156-157 authors stated that no evidence of FBZ oxidation products are present. Please discuss in detail what product could be expected and how they would be manifested. Some information are given later, but it should be discussed in detail at this part of manuscript.
4. In figs 1&2 the NMR and LC/MS of SD FBZ:AG are presented but later in lines 166-167 authors concluded about the mixtures of FBZ with PVP? Based on what evidence?
5. Lines 175-177 authors write about the increased solubility of FBZ:SA”PVP and FBZ:SA:AG but not present any results. If it was some old results, please express that clearly and again as in point 1 this is the result of the poor definition of manuscript novelty as compared to the previous works.
6. In fig. 3 in the MS spectrum of SA at m/z 257.1 is a strong not assigned signal with the half intensity of the molecular peak of SA+H. Please comment.
7. Lines 191-194 authors mentioned about the possible increased solubility of AG in the presence of SA, but on the spectrum no signals coming from AG are visible, even that present in fig. 1 between 4 and 5.5 ppm.
8. Fig. 5 and lines 203-205. How was the concentration determined? Looking on the LC/MS the area of the peaks do not correspond with presented concentration.
9. The NMR and LC/MS of FBZ:SA milled in two other solvents (Product II and III) should be also included in the manuscript or supplementary materials.
10. The table 1 that define the prepared and investigated compositions must be placed in paragraph 2. Materials and Methods which would make the manuscript reading more convenient.
11. The FBZ concentration presented in table 1 and in manuscript lines 211-214 are different.
Comments on the Quality of English Language
as above
Author Response
In accordance with the comments of Reviewer 1, changes have been made to the abstract, introduction, and all subsequent sections, including references. All changes are marked by fields and green background.
In accordance with the comments of Reviewer 1 (p. 3 ; p. 4), the file “ESI_Powders 2362414” has been prepared.
In accordance with the comments of Reviewer 1 (p. 5), table 1 has been added to the text of the article.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for Authors
In this submitted manuscript, Dr. Khalikov and coworkers studied the preparation of solid dispersions with fenbendazole and other components through a mechanochemistry strategy. The solubility and stability of fenbendazole are always an issue for applications in anthelmintic drugs, while through the mechanical treatment of fenbendazole in the presence of polymeric substances, the solid dispersions were formed and the solubility and anthelmintic activity were improved.
It is important to develop novel approaches to solve the problems of applying fenbendazole in anthelmintic drugs efficiently, however, it is recommended to take some necessary revisions before further consideration.
1. The language of the manuscript should be thoroughly revised and improved. For example, the title of this manuscript, which is one of the most important sections, is not a correct sentence and has grammatical errors. Another wrong sentence was found on lines 52-53.
2. It is unclear why the low solubility of fenbendazole in water would lead to the overestimated content in drug preparation on lines 14-15.
3. It is not a professional way to cite the reference in the way the authors used, like on line 38, the sentence “So, for example, in [4], by mechanical processing…”. Please rewrite the sentences in this type throughout the manuscript, like on lines 69, 232, and 235.
4. The discussion on previous reports is not sufficient in the Introduction section. More examples and literature should be discussed to help the readers better understand this research project.
5. The novelty of this report is another aspect that the authors should highlight in the Introduction section.
6. The chemical structures of all targeted compounds were missed. At least one scheme should be provided to show the chemicals and polymeric solid dispersions studied in this report.
7. The format of the unit should be correctly followed, like “ml” should be “mL” for volume, and “1H NMR” should be “1H NMR” with 1 being superscript. The methyl group should be “-CH3” on line 144.
8. Some of the figures are of low quality, and higher resolution pictures are recommended, like Fig 1, Fig 2, Fig 4,
9. The singlet peak at 7.5 ppm in Fig 1 for SD FBZ-AG is very ambiguous. It is hard to tell if there is a singlet peak at that position based on the spectrum provided in the manuscript.
10. Please properly use punctuation in the manuscript. It is not correct to write “88.4; 97.3 and 100%” on line 247. The same issue was found on line 248 as well.
Comments on the Quality of English Language
The language of the manuscript should be thoroughly revised and improved.
Author Response
In accordance with the questions and comments of Reviewer 2, changes have been made to the abstract, introduction, and all subsequent sections, including references. All changes are marked by fields and green background.
Reviewer 2 is provided with answers strictly by the numbers of their questions or notes.
Author Response File: Author Response.pdf
Reviewer 3 Report
Comments and Suggestions for Authors
The manuscript by Khalikov and colleagues contains remarkable data and provides information on the stability of fenbendazole. Long-term stability data for both native and different fenbendazole formulations are crucial to the development of more effective drug products. The aqueous solubility of bendazoles is always a principal challenge for formulation scientists, and there are no general solutions for this active substance.
Despite detailed descriptions and data analysis, the current version is unsuitable for publication yet. Due to the need for rewriting the text and intensive revision of the reference section, the referee recommends a major revision, even though only sporadic typos or unusual sentence structure would not require it. A native English language check would also seem necessary before resubmission.
The referee outlines the principal concerns that need corrections.
- In section 2.2, the authors cited a literature method of the preparation for the two-component dispersions - probably based on their previous publication. It is unclear whether it is identical to the description in this paragraph for the three-component versions or if there are differences between the two types. The expectation that readers should be up-to-date with a previous publication is exaggerated. So, if the preparation method is identical to the described one, they should mention it. But, if it is different, they should insert a summary of the already published procedure in the experimental section.
Line 71 contains a typo or an unknown component.
Although the calculation of the reagent/ball mass ratio is necessary, the volume ratio of the solid to the vessel is at least as informative in ball milling. Please provide this information in the description.
The referent assumes that machining is not the correct word for milling/grinding/treatment.
The description of the HPLC method is incomplete. The authors have omitted to indicate the detection wavelength(s).
- In the 2.4 section, the authors describe another HPLC method. The referee recommends showing the various HPLC methods in one subsection.
- In line 85 (and in line 97), the referee found a new(?) abbreviation for fenbendazole. As that version occurs once more later, the referee must ask the authors for the differences between FBZ’ and FBZ. In particular, because the first version does not appear after line 97.
- Line 93 contains a typo.
- It does not affect the manuscript quality, but is the light pink color a native property of FBZ or caused by impurities?
- The title of the 2.5 section (line 123) may not contain the appropriate word (Learning).
- The spectrum identifiers of NMR figures (Figs. 1 and 4) are misleading. Since the spectrum titles are directly below the previous spectrum line, at the top of the spectra, reading them requires more concentration to figure out which is which. Please place the names closer to the corresponding spectrum lines for clarity.
- The referee would also recommend a tabulated version of the NMR assignment because the information inside the text makes the reading more difficult.
- Usually, peak integration of an LC/MS chromatogram not always provides the correct values. Did the authors compare the integrals of UV and MS detections?
- Lines 196-202 must be in the Experimental section but not in the current location.
Besides this, the sentence in lines 201-203 needs some polishing.
- The sentence starting in line 221 needs a reformulation, as the number of sulfides is hard to interpret.
- In line 232, the authors repeatedly cite ref. 8, which emphasizes the necessity of a summary of the applied method described in the referenced publication.
- The referee would suggest replacing the title of the first column of Table 2. The identifier or sample might sound better.
- The referee assumes that the authors unintentionally left the template message in lines 284 and 288.
- The references contain many flaws.
If the journal is not abbreviated, the dot between the journal name and the year is unnecessary (Refs. 3, 7, and eventually 13).
Ref. 3 does not contain dots in the abbreviated name.
Refs. 6 and 13 are not abbreviated, while the ref. 14 contains an incorrect version.
Comments on the Quality of English Language
Spellcheck and language control of a native English chemist seem necessary before resubmission.
Author Response
In accordance with the questions and comments of Reviewer 3, changes have been made to the abstract, introduction, and all subsequent sections, including references. All changes are marked by fields and green background.
Reviewer 3 is provided with answers strictly by the numbers of their questions or notes.
Author Response File: Author Response.pdf
Round 2
Reviewer 1 Report
Comments and Suggestions for Authors
Revised manuscript can be accepted in current form.
Author Response
-
Reviewer 2 Report
Comments and Suggestions for Authors
In the revised manuscript, the authors have provided detailed explanations and made careful revisions based on the comments and suggestions from the reviewers. The quality of the manuscript has been improved and I would recommend accepting it after a minor revision, as it is clear that the chemical structure of FBZ in section 2.1 was stretched, please revise it before publication.
Author Response
We express our gratitude for the valuable comments and suggestions of the Reviewers.
Reviewer 3 Report
Comments and Suggestions for Authors
The authors have given correct feedback to the referees' concerns. The actual format of the manuscript is eligible for publication.
Only one minor problem is in the structure of FBZ. It is unclear whether it is an issue of the conversion or the word processor caused the distortion. Presumably, if the authors upload a MOL or ChemDraw file, the final molding of the manuscript will result in an undistorted version.
Comments on the Quality of English Language
The language conforms to scientific standards.
Author Response
The chemical structure of FBZ in section 2.1 was revised.
