Solubility of Sulfamerazine in Acetonitrile + Ethanol Cosolvent Mixtures: Thermodynamics and Modeling

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Ms.No: Molecules-3253515

Ortiz C.P. et al.: Solubility of sulfamerazine in acetonitrile + water cosolvent mixtures: Thermodynamics and modeling

The title contains misprint since the study was conducted in MeCN + EtOH not in MeCN + water. But it reflects the fact also that the work is a next part of a very long series of papers of corresponding author devoted to the thermodynamics and modelling of SMR solubility in different cosolvent systems [e.g. ref 21, 24, 27, 29, 30, etc]. Authors use the same methodology as in the previous papers and the construction of the manuscript is the same, moreover figures (e.g.: Fig. 6) and used equations also. The conclusions are very similar.

The main shortcoming of the manuscript is an overall evaluation pointing out what added this study to the previous findings. The used cosolvent system is very similar to MeCN + MeOH cosolvent [ref 27] and MeCN + water [ref 29]. What is the novelty of the study?

On the other hand, the work (as former ones) is well designed and nicely presented, logical study. So, its publication in a more specified journal would be reasonable.

Line 60: delete one of the two solubility words

Line 103: delete y between the names

Table 5: check the notes, they refer to Table 4

Line 184: correct iteration to interaction

 

Author Response

We are grateful for your thoughtful review of our manuscript. All your comments have been taken into account and changes have been made accordingly. Changes have been highlighted in red for ease of review. Thank you again for your time in reviewing the manuscript. 

1. What is the novelty of the study
The following paragraph has been added to the introduction: The following research aims to further develop the evaluation of the solubility of structurally related drugs such as sulfadiazine (SD), sulfamerazine (SMR) and sulfamethazine (SMT) in cosolvent mixtures of industrial interest with structurally related solvents such as the linear alcohols methanol, ethanol and propanol. In this context, in addition to generating useful information for industry, we also seek to elucidate the possible molecular interactions that govern the solubility of these drugs. A complete data set that systematically relates a structural change allows the development of models that explain solubility behaviour in a more rational way.

2. delete one of the two solubility words
Reviewed and corrected
3. Line 103: delete y between the names
Reviewed and corrected
4. Table 5: check the notes, they refer to Table 4
Reviewed and corrected
5. Line 184: correct iteration to interaction
Reviewed and corrected

 

Reviewer 2 Report

Comments and Suggestions for Authors

Comments:

1. The description of polymorph and nonclassical crystal nucleation and growth theories in Introduction is too verbose and could be slightly abridged.

2. On page 7, lines 33-38, the manuscript mentions that the distinct conformational energy of α-/β-glu is defined by the rotation of the C(sp3)-C(sp3) bond represented by the χ1and χ2 corresponding to the N-C2-C3-C4 and C2-C3-C4-C5 . Can you further explain what the χ1 and χ2 symbols represent and the specific atomic labeling corresponding to α-/β-glu?

3. Page 9, lines 48-60, the mass fraction of α-glu increases with increasing additive concentration. So how was the mass fraction of α-glu/β-glu quantitatively determined, please elaborate.

4. Some parts of the conclusion were repeated several times. For example, page 11, lines 1-5 and 25-28, and this was reflected elsewhere in the paper, so please check carefully and revise.

5. There are parts of the dot line chart where the dots are not exactly on the line. Such as, Fig4, Fig8, Fig9.

Comments on the Quality of English Language

In this paper, the thermodynamics and modeling of sulfadiazine in acetonitrile + water co-solvent mixtures have been carried out, which provides important information for the study of drugs in these two solvents.

        1.        A period is missing at the end of line 34.

2.        “^a Standard uncertainty in pressure u(p)=0.001MPa” There is no period at the end of the sentence.

3.        Figure 2 Missing period at the end of the comment sentence.

4.        The paragraphs on lines 133 and 139 are not capitalized.

5.        The first letter of line 141 is not capitalized and the end of line 142 is missing.

6.        Picture 5 Incorrect punctuation at the end of the comment sentence.

7.        Incorrect position of the Arabic numeral 8 on line 164.

8.        Paragraphs 166, 205 and 216 are not capitalized.

9.        A period is missing at the end of lines 238, 239, 241, 248, and 249.

 

Author Response

We are grateful for your thoughtful review of our manuscript. All your comments have been taken into account and changes have been made accordingly. Changes have been highlighted in red for ease of review. Thank you again for your time in reviewing the manuscript. 

 

1. The description of polymorph and nonclassical crystal nucleation and growth theories in Introduction is too verbose and could be slightly abridged.
2. On page 7, lines 33-38, the manuscript mentions that the distinct conformational energy of $\alpha$-/$\beta$-glu is defined by the rotation of the C(sp3)-C(sp3) bond represented by the x1 and x2 corresponding to the N-C2-C3-C4 and C2-C3-C4-C5 . Can you further explain what the x1 and x2 symbols represent and the specific atomic labeling corresponding to $\alpha$-/$\beta$-glu?
3.  Page 9, lines 48-60, the mass fraction of $\alpha$-glu increases with increasing additive concentration. So how was the mass fraction of $\alpha$-glu/$\beta$-glu quantitatively determined, please elaborate.
4. Some parts of the conclusion were repeated several times. For example, page 11, lines 1-5 and 25-28, and this was reflected elsewhere in the paper, so please check carefully and revise.
5. There are parts of the dot line chart where the dots are not exactly on the line. Such as, Fig4, Fig8, Fig9.   

Dear esteemed reviewer, the first remarks do not correspond to the manuscript. Example: There is no figure 9

 

1. A period is missing at the end of line 34.
   Reviewed and corrected
2. “a Standard uncertainty in pressure u(p)=0.001MPa” There is no period at the end of the sentence. Reviewed and corrected
3. Figure 2 Missing period at the end of the comment sentence. Reviewed and corrected
4. The paragraphs on lines 133 and 139 are not capitalized. Reviewed and corrected
5. The first letter of line 141 is not capitalized and the end of line 142 is missing. Reviewed and corrected
6. Picture 5 Incorrect punctuation at the end of the comment sentence. Reviewed and corrected
7. Incorrect position of the Arabic numeral 8 on line 164. Reviewed and corrected
8. Paragraphs 166, 205 and 216 are not capitalized. Reviewed and corrected
9. A period is missing at the end of lines 238, 239, 241, 248, and 249. Reviewed and corrected
   
   

Reviewer 3 Report

Comments and Suggestions for Authors

The solubility measurements presented are a continuation of previous measurements by the group and represent useful experimental data. I was surprised that the title of the manuscript does not fit to the content. According to the title the solvent was acetonitrile plus water, whereas in the manuscript measurements in acetonitrile plus ethanol are described.

Author Response

Title corrected 
Solubility of sulfamerazine in acetonitrile + ethanol cosolvent mixtures: Thermodynamics and modeling.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Authors refined the manuscript. The introduction is extended with a paragraph what clarifies how the aim of this work fits to the previous research. It helps a lot.

However, they neglected the fundamental critical remak: "The main shortcoming of the manuscript is an overall evaluation pointing out what added this study to the previous findings. The used cosolvent system is very similar to MeCN + MeOH cosolvent [ref 27] and MeCN + water [ref 29]. What is the novelty of the study?" 

Such evaluation is still missing from the conclusion.

Author Response

We would like to thank the reviewer again for his valuable comments on our manuscript. Regarding the reviewer's comments, we draw a conclusion that correlates with previous studies and emphasize the important information provided by this work, which allows conclusions to be drawn about the influence of the carbon number of the alcohol involved.

"Taking into account the works related to the solubility of SMR in MeCN + MeOH and MeCN-PrOH, an influence of the aliphatic chain of the alcohols can be observed in the solubility behavior of SMR, in MeCN + MeOH (one -CH₃ group) the solubility tendency of SMR seems to be more related to the solubility parameter of the cosolvent mixtures, in this cosolvent system the maximum solubility is reached in a cosolvent mixture with a solubility parameter similar to that of SMR, in MeCN + EtOH (one -CH₂- group and one -CH₃- group) and MeCN-PrOH (two -CH₂- groups and one -CH₃- group) the solubility tendency seems to be more related to the acid/base character of the solvents, therefore, this work allows to conclude that the change in the number of carbons of the aliphatic chain of the alcohol in the MeCN-alcohol cosolvent mixture induces changes in the mechanisms involved in the solubility of the SMR, highlighting the difficulty of developing mathematical models that allow predicting solubility, since this property clearly does not follow a predictable pattern in this case."