Structural and Energetic Aspects of Entacapone-Theophylline-Water Cocrystal

Round 1

Reviewer 1 Report

This is a very interesting manuscript dealing with the preparation and characterization of hydrated co-crystals of entacapone and theophylline. Experimental techniques like XRDA, FTIR, DSC, TGA and hot stage microscopy were used for characterization. Moreover, several theoretical studies were also performed to evaluate the possibility of predicting physical behavior of co-crystals as well as to understand the respective intermolecular interactions in co-crystals formation. In my opinion the manuscript could be accepted after checking some minor points as shown in the attached pdf, in particular the following:

1. There are some typo mistakes as shown.
2. Please check carefully the adequate use of italics for physicochemical symbols in equations, text, tables and figures. It is important the uniformity thorough the document.
3. Table 1: Please check the expressions for P2.
4. Line 414: Here is better to use "insoluble" than "immiscible".
5. Line 458: It is "solubility parameter" rather than "solubility".
6. Table 2: Please add the total solubility parameter calculated as the square root of the summation of squares.
7. Line 521 (and other places): Is it referred to interactions between two functional groups of the same molecule? Please check it.
8. Lines 767-768: Please check this sentence because it is not clear

Comments for author File: Comments.pdf

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

In the paper the authors described the investigation of structural and energetic aspects of the entacapone-theophylline-water cocrystal. The paper is well written and the results are interesting. However, it is very extensive and some results were related to routine characterization of the cocrystal system and did not contribute to the understanding of the structural and energetic aspects of the cocrystal. In my opinion the authors should review the paper and include the characterization techniques as supplementary materials.

Furthermore, the authors should observe:

• In the Materials and Methods, the authors should focus on the obtention of the cocrystal that was studied, the liquid-assisted grinding (page 3, line 106) is not important in this work.
• Review the methodology of the DSC technique (page 4, line 131), the range of the temperature is different in the results (figure 4, page 11);
• Why did the authors include the physical mixture in the ATR-FTIR, XRPD, DSC and HSM results (pages 8-11)? This point needs to be explained and the preparation of the physical mixture must be included in the methodology.
• The figure 3 (page 9) needs to be improved, the bands were not clearly visible; besides, the sharp stretching band at 2218 cm^-1 of the ENT is not clear.
• The results of the HSM and Cocrystal Screening Methods (page 11-14) are not crucial for the aim of the work. They could be excluded or be presented as Supplementary Materials.
• The authors must connect the results of the Dehydration Study of the cocrystal (page 23-26) with the others results. Why these results are important?

Author Response

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Author Response File: Author Response.pdf

Reviewer 3 Report

-          use subscripts in the formula of P2O5 (p. 3, l. 104)

-          p. 5, l. 190. Correct FAILL for FAIL.

-          use spaces around the equality sign (p. 7, l. 300)

-          p. 5, l. 305: correctly dα/dt?

-          p. 8, l. 325. Equation 8 is dubious as written now. Is the shorter fraction line a negative sign or is it simply the fraction line split? This is of importance, since the quantity represented by this fraction is minimised, thus a negative sign will change the meaning entirely.

-          p. 8, l. 327. What does ``Ea,a’’ denote in in Eq. 9?

-          p. 9, Fig. 2. I have serious doubts regarding the assignment of the SE (ENT-THP-HYD) phase in this Figure. Should this phase contain some (equimolar) amounts of ENT, its diffraction(s) around 9.5 degrees of 2theta should be visible in the cocrystal, yet, it is totally absent (while it remained visible in all other mixtures). Noteworthy/strange is also the fact, that the very first diffraction becomes shifted significantly with respect both to THP and its monohydrate form. Since the SE phase remained in solution for 4-5 days, this raises the serious question whether the two reactants did not undergo a slow chemical reaction upon standing and whether we do not actually see the record of a different molecule in the diffractogram. This assumption is strengthened further by the DSC record, as the one provided in the current work is quite different from the one in ref [31]. The best practice would be to compute the theoretical powder pattern from single-crystal data and correlate it with the experimentally obtained record.

-          p. 12, l. 434. The authors assign the melting temperature 155 °C to entacapone, but in ref. [31] this value is given as 162 °C. This is a serious difference.

-          p. 15. The arguing about the role of hydrogen bridges and pi-pi stacking is reasonable, but the authors did not consider other possible interactions, line anion--pi, cation--pi and lone-pair--pi. Is it totally sure that such are not present in the current system? Thanks to its structure, THP provides numerous such opportunities.

-          p. 18, l. 648. Correct the missing superscript in the Laplacian. Also it should be made clear in this section, that Bond Critical Points are being discussed (this becomes clean only one page later). The DOI of reference [87] should be of the article itself and not of its supplemental file.

•          p. 25, caption of Table 8. The caption of the table is misleading, as the values under consideration are actually anticorrelating. Probably the absolute values of the correlation coefficients > 0.98 were meant to be marked by red.
•  

Author Response

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Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

The authors reformulated the manuscript in accordance with the reviewers’ suggestions, making it more clear and better for the readers. Furthermore, the routine characterization of the cocrystal was included as a Supplementary Materials. 

Reviewer 3 Report

The current version of the manuscript is a very nice piece of work and this referee is happy to congratulate the authors for conducting a valuable research.