Weak Interactions in Cocrystals of Isoniazid with Glycolic and Mandelic Acids

Round 1

Reviewer 1 Report

The paper ‘Weak interactions in cocrystals of isoniazid and some α-hydroxycarboxylic acids’ consist a wide structural analysis of intermolecular interactions observed in crystal structures.
In my opinion the paper could be published but require extended work. 
First, the title suggest that we will get a series of new cocrystals but there are only two. Maybe it would be proper to make title more consistent to the issue of publication? Moreover, it is not clear how the carboxylic acids for cocrystallization were selected. What changes in the supramolecular structure of the co-crystal did the authors expect? These questions require clarification. 
Second, the refinement process is not complete. Why are the weight parameters not refined?
Publication requires a lot of editorial work. Boldings in the text are used very inconsistently. There are a lot of typos that need to be improved. In the caption of Figure 7 there should be "Asymmetric unit". In addition, the drawings are not carefully prepared and their style needs to be standardized.

Author Response

First of all, we would like to thank this reviewer for his/her careful reading of the manuscript, corrections and suggestions. We have taken into consideration his/her concerns and revised the manuscript accordingly, as detailed below. The changes have been marked using blue colored font whenever possible.

Comments:

The paper ‘Weak interactions in cocrystals of isoniazid and some α-hydroxycarboxylic acids’ consist a wide structural analysis of intermolecular interactions observed in crystal structures.

In my opinion the paper could be published but require extended work.

First, the title suggest that we will get a series of new cocrystals but there are only two. Maybe it would be proper to make title more consistent to the issue of publication?

Reply: The title has been changed including the name of the alpha-hydroxycarboxylic acids used.

Moreover, it is not clear how the carboxylic acids for cocrystallization were selected. What changes in the supramolecular structure of the co-crystal did the authors expect? These questions require clarification.

Reply: In the text, some considerations are included clarifying these issues.

Second, the refinement process is not complete. Why are the weight parameters not refined?

Reply: As usual, in each structure, the refinement has been completed when Shift/ESD = 0.000, but new refinements have been made. New CHECKCIF included.

Publication requires a lot of editorial work.

Reply: done as requested whenever possible

Boldings in the text are used very inconsistently.

Reply: The style of the bold source of abbreviations has been suppressed.

There are a lot of typos that need to be improved.

Reply: A new revision of the text has been performed and eliminated some typographical errors.

In the caption of Figure 7 there should be "Asymmetric unit".

Reply: Corrected, thanks!

In addition, the drawings are not carefully prepared and their style needs to be standardized.

Reply: thank you for this suggestion. Please note that it is not possible to standardize the style of the figures by the different programs used in the structural analysis and in Hirshfeld Surface Analysis and DFT Calculations. I ask the referee to allow us to use the current setting, since it does not affect the scientific content of the manuscript.

Reviewer 2 Report

The authors report three cocrystals of isoniazid with glycolic and mandelic acids. The main attention has been paid to the role of hydrogen bonding in these crystals.

My main concern relates to the numerical values of the N-H and H-O distances shown in Figures 1 and 4 and Table 2. Please explain in details how these values have been estimated with the reported accuracy.

Cocrystals containing heterocyclic nitrogen bases have been widely studied. Readers will find it helpful if the introduction to this article discusses their general properties:

1. DOI: 10.1515/zkri-2017-2136
2. DOI: 10.1021/cg900873t
3. DOI: 10.1002/mrc.946
4. DOI: 10.1107/S0108270198013766

There are however many more publications on this topic. These publications should be used to explain the novelty of the work presented.

The energies of specific interactions in the crystals studied in this paper were calculated theoretically. It is important to mention, that these energies can be measured experimentally. Such studies are available:

1. DOI: 10.1021/acs.cgd.0c01287
2. 10.1021/jacs.0c06035
3. DOI: 10.1524/zpch.2013.0400
4. DOI: 10.1021/cr990112c

The authors should compare their theoretical estimates with experimental data obtained for similar interactions and discuss the result.

In general, the paper is difficult to read because figures are too small and overloaded with data.

Author Response

First of all, we would like to thank this reviewer for his/her careful reading of the manuscript, corrections and suggestions. We have taken into consideration his/her concerns and revised the manuscript accordingly, as detailed below. The changes have been marked using blue colored font whenever possible.

Comments:

The authors report three cocrystals of isoniazid with glycolic and mandelic acids. The main attention has been paid to the role of hydrogen bonding in these crystals.

My main concern relates to the numerical values of the N-H and H-O distances shown in Figures 1 and 4 and Table 2. Please explain in details how these values have been estimated with the reported accuracy.

Reply: In 2.2 Crystallography (Pag. 3) is indicated: “Hydrogen atoms were located in difference maps and refined isotropically, but those bonded to carbon atoms were included as fixed contributions riding on attached atoms”. Then, as the positions of the hydrogen atoms bonded to N and O were isotropically refined, all geometric parameters and U_iso are affected by their esd and, consequently, also the bond lengths and angles.

Cocrystals containing heterocyclic nitrogen bases have been widely studied. Readers will find it helpful if the introduction to this article discusses their general properties:

DOI: 10.1515/zkri-2017-2136

DOI: 10.1021/cg900873t

DOI: 10.1002/mrc.946

DOI: 10.1107/S0108270198013766

There are however many more publications on this topic. These publications should be used to explain the novelty of the work presented.

Reply: The introduction has been modified as suggested.

The energies of specific interactions in the crystals studied in this paper were calculated theoretically. It is important to mention, that these energies can be measured experimentally. Such studies are available:

DOI: 10.1021/acs.cgd.0c01287

10.1021/jacs.0c06035

DOI: 10.1524/zpch.2013.0400

DOI: 10.1021/cr990112c

The authors should compare their theoretical estimates with experimental data obtained for similar interactions and discuss the result.

Reply: Thank you for this suggestion. The references have been cited and the energies compared in a new section of the manuscript. See section 3.3.4

In general, the paper is difficult to read because figures are too small and overloaded with data.

Reply: We have enlarged some of the figures. In any case the editorial team must adjust the size of the figures according to the format of the article.

 

Round 2

Reviewer 1 Report

Thank you for considering my comments, I believe they helped to make the publication more attractive.

I wrote that the drawings style needs to be standardized and I should be more precise. I agree that the drawing style depends on the program in which it is prepared. However, I meant that in drawings composed of several parts, they are sometimes marked as "a)" "b)" ... and other times as "(a)", "(b)”…

Besides, in Figure 2 it is not clear what is marked as "c)".

Please correct the captions of Figures 1 and Figures 4 - it should be „Asymmetric unit”.

Author Response

We would like to thank this reviewer for his/her careful second reading of the manuscript, corrections and suggestions. We have taken into consideration his/her concerns and revised the manuscript accordingly, as detailed below:

 

Comments:

I wrote that the drawings style needs to be standardized and I should be more precise. I agree that the drawing style depends on the program in which it is prepared. However, I meant that in drawings composed of several parts, they are sometimes marked as "a)" "b)" ... and other times as "(a)", "(b)”…

Reply: Done, Thanks for the clarification

Besides, in Figure 2 it is not clear what is marked as "c)".

Reply: Fixed. A new Figure has been provided

Please correct the captions of Figures 1 and Figures 4 - it should be „Asymmetric unit”.

Reply: Done

Reviewer 2 Report

The reviewer's comments have been answered satisfactorily. I have no other important questions for the article or suggestions for improving it.

Author Response

Thank you for endorsing publication