Experimental and Hirshfeld Surface Investigations for Unexpected Aminophenazone Cocrystal Formation under Thiourea Reaction Conditions via Possible Enamine Assisted Rearrangement

Round 1

Reviewer 1 Report

The paper presents the synthesis and structural crystallization of one new, original and relevant co-crystal. I recommend this article for print after minor corrections.

The abstract contains more than 200 words and does not follow the Crystals journal instructions. It contains redundant information about Hirshfeld surface analysis results, which can be reduced.

There are unexplained abbreviations as well API, NSAID, 4-AAP, PABA, CAF and XRD.

The introduction provides relevant background and unfortunately includes old references that should be refilled positions for 2018-2021. Now, only 19% of references are in the range of this period.

Please add the names and references to the aminophenazone co-crystals in Figure 2. Only the CSD reference is welcome.

In the text, there are two spellings of the word co-crystal (co-crystal and cocrystal) and the compound numbering (4&5 and 4 and 5). Please choose only one.

The X-ray structure is poorly described. Nothing is written about S…H and π…π stacking interactions. What rings are stacked? Are co-crystal molecules linked to each other by hydrogen bonds? What do they form? Please add more information about the structure and packing of molecules in the crystal. Figure 6 needs updating. Important atoms have been omitted and presented H-bonds look odd.

Please check punctuation throughout the text.

The Hirshfeld surface analysis section should be shortened. Please keep the discussion of predominant contacts only and cut down on contacts with less than 5.0% contribution that do not add relevant material to your paper. Figure 10 is redundant, remove it. Mark in Figure 8 the bow-tie pattern which is the signature of C…C contacts in the structure. Is your compound soluble in polar solvents? The higher contribution of polar interactions compared to non-polar ones suggests a high degree of interaction of this co-crystal with polar solvents [https://0-doi-org.brum.beds.ac.uk/10.1039/C6CE01838F; https://0-doi-org.brum.beds.ac.uk/10.1007/s10973-022-11263-1].

Please add missing information to reference 36 and unify all references. Some of them have doi and others do not.

Some stylistic inaccuracies should be corrected:

“4-aminiphenazone” → “4-aminophenazone”

“Hirshfeld” (keyword) → “Hirshfeld surface analysis”

“…we here in report…” → “…we here report…”

“…only eleven molecular salts of 4-AAP have yet been reported, of which two are simple salts…” → “…only eleven molecular salts of 4-AAP have been reported, two of which are simple salts…”

“The most important interaction is…” → “The predominant interactions/contacts…”

Comments for author File: Comments.pdf

Author Response

Reviewer 1:

 Comments and Suggestions for Authors

The paper presents the synthesis and structural crystallization of one new, original and relevant co-crystal. I recommend this article for print after minor corrections.

The abstract contains more than 200 words and does not follow the Crystals journal instructions. It contains redundant information about Hirshfeld surface analysis results, which can be reduced.

Authors Reply:

We acknowledge the referee for her/his comments.

The changes and modifications in the abstract have been highlighted in red in the revised manuscript version. Overall, the abstract volume has been reduced taking into consideration the suggestion by the respected reviewer.

There are unexplained abbreviations as well API, NSAID, 4-AAP, PABA, CAF and XRD.

Authors Reply:

API abbreviation used for Active pharmaceutical ingredient

NSAID abbreviation used for Non-steroidal anti-inflammatory drug

4-AAP abbreviation used for 4-Aminoantipyrine

PABA abbreviation used for Para amino benzoic acid which can also be mentioned as 4-aminobenzoic acid (The abbreviation was used as it is from the source manuscript quoting the caffeine structure). Sorry for inconvenience. In revision correction has been inserted. Thank You for bringing attention to important point.

CAF abbreviation used for Caffeine (The abbreviation was used as it is from the source manuscript quoting the caffeine structure). Sorry for inconvenience. In revision correction has been inserted. Thank You for bringing attention to important point.

XRD abbreviation used for Single-crystal X-ray Diffraction. It is a non-destructive analytical technique which provides detailed information about the internal lattice of crystalline substances, including unit cell dimensions, bond-lengths, bond-angles, and details of site-ordering.

The introduction provides relevant background and unfortunately includes old references that should be refilled positions for 2018-2021. Now, only 19% of references are in the range of this period.

Authors Reply:

We acknowledge the referee for her/his comments. The meaning of abbreviations pointed out have been added in the revised manuscript with red highlight. Moreover, reviewer’s suggestion of using references in said time domain have been considered and modifications accordingly have been made in the revised version by red highlight in both the reference list and in reference numbering throughout the manuscript as superscripts. Respected Sir, in some cases the reference has all together has been replaced by the latest reference, while in other cases old references has been retained along with addition of new ones for serving the purpose by quoting references as a and b sub parts.. Thank You.

Please add the names and references to the aminophenazone co-crystals in Figure 2. Only the CSD reference is welcome.

Authors Reply:

We acknowledge the referee for her/his comments. CSD references have been added as reference 33 in the revised version of manuscript with red highlight as below.

33. Smith, M. G.; Lemmerer, A. Novel crystal forms of 4-aminoantipyrine and its derivatives: co-crystallizing areluctant molecule. J. Mol. Struct. 2019, 1175 (5), 307-313. (i). Database Identifier: IFEGEI, Deposition Number: 1586523; (ii). Database Identifier: IFEFIL, Deposition Number: 1586519; (iii). Database Identifier: IFEGAE, Deposition Number: 1586522.

Further to add the third example of cocrystal in fig 2 has been replaced by another cocrystal set due to non- availability of CSD reference for it. (aminophenazone and saccharine cocrystal have been replaced cocrystal set (III) in fig 2 by aminophenazone and 2-amino benzoic acid).

In the text, there are two spellings of the word co-crystal (co-crystal and cocrystal) and the compound numbering (4&5 and 4 and 5). Please choose only one.

Authors Reply:

We acknowledge the referee for her/his comments. These errors have been fixed in the corrected version throughout the manuscript.

The comments on X-ray crystallography and Hirshfeld surface analysis parts (Sections 3.3 and 3.4) have been addressed

the Figures 5 and 6 have been replaced with the newly drawn ones by giving two figures as Figs. 6a and 6b for Fig. 6.

changed the above-mentioned sections by taking into accounts the referees' comments on the sections and marked them in red colour.

Please check punctuation throughout the text.

Authors Reply:

The manuscript has been well checked about punctuations and corrections have been done where required.

The comments of the referee on the X-ray crystallography and Hirshfeld surface analysis parts (Sections 3.3 and 3.4) are addressed

The Figures 5 and 6 were replaced with the newly drawn ones by giving two figures as Figs. 6a and 6b for Fig. 6.

The above mentioned sections have been changed by taking into accounts the referees' comments on the sections and marked in red colour.

Please add missing information to reference 36 and unify all references. Some of them have doi and others do not.

Authors Reply:

The missing information to reference 36 has been added with red highlight in revised manuscript with red highlight as below. Thank You for bringing attention to it.

36. Khurshid, A.; Saeed, A.; Ashraf, Z.; Abbas, Q.; Hassan, M. Understanding the enzymatic inhibition of intestinal alkaline phosphatase by aminophenazone‑derived aryl thioureas with aided computational molecular dynamics simulations: synthesis, characterization, SAR, and kinetic profiling. Mol. Divers. 2020, 25(3), 1701-1715.

Moreover, to keep uniformity of reference styles keeping in view the journal specific reference styles the doi’s have been removed from the reference list to bring uniformity. Further the whole reference list has been revised again with view of raised points/corrections and in general (as a whole) with corrections in red highlight in revised version.

Some stylistic inaccuracies should be corrected:

“4-aminiphenazone” → “4-aminophenazone” Corrected

“Hirshfeld” (keyword) → “Hirshfeld surface analysis” Corrected

“…we here in report…” → “…we here report…” Corrected

“…only eleven molecular salts of 4-AAP have yet been reported, of which two are simple salts…” → “…only eleven molecular salts of 4-AAP have been reported, two of which are simple salts…” Corrected

Authors Reply:

The authors acknowledge the referee for her/his comments. These errors have been fixed in the corrected version

Reviewer 2 Report

The article reports the preparation, characterization and study of a new cocrystal. It is well documented and substantiated and it fits in the scope of the journal.

But it is poorly written and, in order to publish it,  a major revision of the  English lenguage has to be done throughout the article. On my opinion, authors should seek professional help to write in English.  There are  mistakes and confusing expresions and it is hard to understand some paragraphs.

Some other points to consider:

• Check the format o the adresses of the authors: department, university, postal code, city, country, e-mail
• API (line 58) has to be defined.

References: It is necessary to review all references so all them are written in the same format.

• The initials ot the title of the articles sometimes are written in lover case and other times are written in capital letters.
• After the title sometimes the authors put a period (.) and other times they put a comma (,).
• The name of the journal should be written in italics.
• DOI is given in some references and in others it is not given.
• Put the initial and final page.
• In particular, check the references 20, 25, 30, 33, 34, 38, 44, 45, 46.

Author Response

The article reports the preparation, characterization, and study of a new cocrystal. It is well documented and substantiated, and it fits in the scope of the journal.

But it is poorly written and, to publish it, a major revision of the English language has to be done throughout the article. On my opinion, authors should seek professional help to write in English.  There are mistakes and confusing expressions and it is hard to understand some paragraphs.

Authors Reply:

Respected Reviewer, the whole manuscript has been reconsidered by the authors with respect to improvement of English language with changes or corrections/modifications highlighted in revised version as red highlight.

Some other points to consider:

Check the format of the addresses of the authors: department, university, postal code, city, country, e-mail

Authors Reply:

Thank You for bringing attention to the useful aspect. Corrections have been inserted where required taking into consideration the mentioned points by the reviewer and journal pattern in that regard.

API (line 58) has to be defined.

Authors Reply:

Thank You for pointing important aspect to remove the confusion from the manuscript. The line has been modified in the revision to avoid confusion (which has been squeezed to line 56 and 57) as below

Cocrystalline materials possess non-covalent interactions such as ionic interactions, hydrogen bonding and Van der Waals interactions between the active pharmaceutical ingredient (API) i.e., the active cocrystal component and its conformer

References: It is necessary to review all references so all them are written in the same format.

Authors Reply:

The authors acknowledge the referee for her/his comments. The whole reference list has been revised again with view of raised points/corrections and in general also with corrections in red highlight in revised version.

The initials of the title of the articles sometimes are written in lover case and other times are written in capital letters. After the title sometimes the authors put a period (.) and other times they put a comma (,).

Authors Reply:

Sorry for the mistake and thank You for bringing attention to it. The article title has been corrected as per reviewer suggestion. Punctuations has also been corrected.

The name of the journal should be written in italics.

Authors Reply:

The authors acknowledge the referee for her/his comments. Journal name have been made italics in the reference list where required in the revised manuscript.

DOI is given in some references and in others it is not given. Put the initial and final page. In particular, check the references 20, 25, 30, 33, 34, 38, 44, 45, 46.

Authors Reply:

The authors acknowledge the referee for her/his comments. DOI have been removed in the revised manuscript version in reference list to keep uniformity while keeping in mind the journal style for references. Moreover, the page numbers (initial and last) have been added as corrections in the suggested references i.e., 20, 25, 30, 33, 34, 38, 44, 45, 46. Further the whole reference list has been revised again with view of raised points/corrections and in general also with corrections in red highlight in revised version.

Round 2

Reviewer 1 Report

The crystal structure section is underdeveloped, poorly described, and does not correspond with the Crystal Journal level.

The authors provide a lot of Hirshfeld Surface Analysis data but do not show a correlation between them and the X-ray crystal study, which makes it unclear the importance of this section in the article.

Some punctuation marks are still missing in the text.

Author Response

Reviewer 1: The crystal structure section is underdeveloped, poorly described, and does not correspond with the Crystal Journal level.

The authors provide a lot of Hirshfeld Surface Analysis data but do not show a correlation between them and the X-ray crystal study, which makes it unclear the importance of this section in the article.

Authors reply: The authors have improved the crystal structure section 3.3 with view to show the relevance with Hirshfeld surface analysis (3.4) and to make it more appropriate in the manuscript (red highlights).

Reviewer 1: Some punctuation marks are still missing in the text.

Authors Reply: Punctuation marks have been added throughout 

Reviewer 2 Report

The work is nice. My concern is about English language.

Author Response

The work is nice. My concern is about English language.

Response. The language and spelling have been checked and revised throughout to make it understandable. The changes/corrections are marked in red font