Multicomponent Solids of DL-2-Hydroxy-2-phenylacetic Acid and Pyridinecarboxamides

Round 1

Reviewer 1 Report

The manuscript entitled “Multicomponent solids of DL-2-Hydroxy-2-phenylacetic acid with pyridinecarboxamides” submitted by Alfonso Castiñeiras et. al. discusses the nature of different cocrystals of D/L-2-Hydroxy-2-phenylacetic acid with picolinamide / nicotinamide / isonicotinamide. The manuscript is well written and present a very interesting methodological discussion and analysis. The aims are clearly formulated and the discussion of the results follows the logical sequence of these aims. The topic of the present study is of great importance, especially because of its medicinal applications. Beside the experimental work, the manuscript also includes theoretical investigations about the nature of different intermolecular bindings between different crystal constituents. Nonetheless there are several issues that have to be resolved before publication of this material. My greatest concerns are listed below:

1. Theoretical calculations. The energies of hydrogen bond interactions were estimated using empirical approach proposed by Vener derived the QTAIM analysis. The crystal motifs were adopted directly from the crystal structures. However, I have not found information (neither in discussion nor experimental section) on the hydrogen atoms treatment. It should be stressed that the C-H, O-H and N-H bonds should be elongated to the standard neutron values prior calculations. Otherwise the obtained results are significantly flawed. I also recommend to optimize the positions of the hydrogen atoms from OH and NH groups that participate in hydrogen bond interactions. As the positions of other atoms should be frozen, such calculations are usually very fast and allow to provide correct positions of hydrogen atoms in the selected motifs. I also recommend to compare QTAIM-derived interaction energies with the results obtained from the counterpoise procedure. As far as I understand, the counterpoise procedure was only applied for π-π stacking dimers, whereas the calculation methodology should be uniform. The interaction energies should be gathered in table to improve the presentation of the results.
2. Single crystal X-ray diffraction studies. The quality of the single-crystal diffraction data is acceptable. The discussed bond lengths and angles should be provided with experimental errors. The .cif files should be provided as separate supplementary material.
3. PXRD analysis. The presented PXRD data for inam-LH2ma cocrystal is hardly interpretable (Figure 11 – blue line). In addition the axis scope should match the experimental data (please note that the negative theta angles are senseless). Please improve the presentation. Please also note that the overlay of experimental and simulated PXRD patterns are presented on Fig S5 and S6, not on Fig S1, as it is claimed in the text. I also recommend to provide legends to the Figures S5 and S6.
4. FT-IR spectroscopy. Please improve the quality of IR spectra (Figure 14). In its current form the line maxima are unreadable. I also recommend to remove Figure 14 to SI, whilst Figures S3 and S4 should be shown in main article.
5. NMR analysis. According to the abstract, the obtained cocrystals were characterized by 1H and 13C NMR spectroscopy. 13C NMR spectral data is neither provided nor discussed. Please clarify. Please also improve the presentation of the 1H NMR data (Figures S1 and S2) . Each signal should be integrated and chemical shifts should be indicated.

Minor corrections:

1. Sentences starting from lines 407 and 410 provide essentially the same information.
2. Sentence “The phase purity of the as..” (line 442) seems out of place. There is no Fig S10 in SI.
3. Conclusions: authors claim that the synthesis of four cocrystal is reported, while there are only two new cocrystal studied in the current paper.
4. Please also provide descriptions for all figures presented in SI.
5. Figures 10, 11. Figure labels (a,b,c) are missing.
6. Please check scheme numbering (Scheme 1 appears as scheme 2)
7. Line 310: "nitocotinamide".

Overall, I consider that the present manuscript is suitable for publishing in the Crystals MPDI after major revision.

Author Response

crystals-1527152

REVIEWER REPORT(S):

Referee: 1

Comments to the Author

1. Theoretical calculations. The energies of hydrogen bond interactions were estimated using empirical approach proposed by Vener derived the QTAIM analysis. The crystal motifs were adopted directly from the crystal structures. However, I have not found information (neither in discussion nor experimental section) on the hydrogen atoms treatment. It should be stressed that the C-H, O-H and N-H bonds should be elongated to the standard neutron values prior calculations. Otherwise the obtained results are significantly flawed. I also recommend to optimize the positions of the hydrogen atoms from OH and NH groups that participate in hydrogen bond interactions. As the positions of other atoms should be frozen, such calculations are usually very fast and allow to provide correct positions of hydrogen atoms in the selected motifs. I also recommend to compare QTAIM-derived interaction energies with the results obtained from the counterpoise procedure. As far as I understand, the counterpoise procedure was only applied for π-π stacking dimers, whereas the calculation methodology should be uniform. The interaction energies should be gathered in table to improve the presentation of the results.

Reply: For the theoretical study, we have optimized the position of all H-atoms using DFT calculations while the rest of the atoms are freeze. This is our standard procedure; however we did not indicate this in the theoretical methods of our original manuscript. This has been clarified in the revised version. As suggested by the referee, we have compared the energies derived from QTAIM from those using BSSE corrected energies. A new Table has been added (new Table 4) and the results compared. A new paragraph has introduced in Page 15

2. Single crystal X-ray diffraction studies. The quality of the single-crystal diffraction data is acceptable. The discussed bond lengths and angles should be provided with experimental errors. The .cif files should be provided as separate supplementary material.

Reply: Experimental errors have been included in the discussion on bond distances and angles and CIFs are included as Supplementary Material.

3. PXRD analysis. The presented PXRD data for inam-LH2ma cocrystal is hardly interpretable (Figure 11 – blue line). In addition the axis scope should match the experimental data (please note that the negative theta angles are senseless). Please improve the presentation. Please also note that the overlay of experimental and simulated PXRD patterns are presented on Fig S5 and S6, not on Fig S1, as it is claimed in the text. I also recommend to provide legends to the Figures S5 and S6.

Reply: Figure 11 has been improved according to the Referee's suggestions and legends have been included in all the figures contained in the Supplementary Material.

4. FT-IR spectroscopy. Please improve the quality of IR spectra (Figure 14). In its current form the line maxima are unreadable. I also recommend to remove Figure 14 to SI, whilst Figures S3 and S4 should be shown in main article.

Reply: Figure 14 has been improved and has been changed to S3 and S4 contained in the Supplementary Material.

5. NMR analysis. According to the abstract, the obtained cocrystals were characterized by 1H and 13C NMR spectroscopy. 13C NMR spectral data is neither provided nor discussed. Please clarify. Please also improve the presentation of the 1H NMR data (Figures S1 and S2). Each signal should be integrated and chemical shifts should be indicated.

Reply: In the Supplementary Material the representations of the 1H NMR spectra have been improved and the 13C NMR spectra have been included. Each signal has also been integrated and the chemical shift has been indicated.

6. Minor corrections:

Sentences starting from lines 407 and 410 provide essentially the same information.

Sentence “The phase purity of the as..” (line 442) seems out of place. There is no Fig S10 in SI.

Conclusions: authors claim that the synthesis of four cocrystal is reported, while there are only two new cocrystal studied in the current paper.

Please also provide descriptions for all figures presented in SI.

Figures 10, 11. Figure labels (a,b,c) are missing.

Please check scheme numbering (Scheme 1 appears as scheme 2)

Line 310: "nitocotinamide".

Reply: All omissions and typos have been corrected.

 

Referee: 2

Comments to the Author

1. General:

Please review the manuscript to correct some minor typing issues: e.g., physic-chemical properties; min–1; 1H. Page 9 “que se extienden en el plano “ca” semejando un zig-zag that”

Reply: All omissions and typos have been corrected.

In the introduction section, when discussing heterosynthons to obtain cocrystals, the work of Swift et al. can be cited (e.g., https://doi.org/10.1021/acs.cgd.5b01039; https://doi.org/10.1021/acs.cgd.7b00922).

Reply: Swift publications have been included as references [5] and [6]

To better understanding which cocrystals are new and which data are from the literature, please inform previously the compounds number in a illustrative form to clarity. For example, in table 1, which compound/cocrystal is HOGGOB [36] JILZOU [37] JILZOU01 (2) [38]? In the results section compounds 2a and 2b are presented. During the manuscript, compounds are mentioned as (pic)-(D-H2ma), (nam)-(L-H2ma) and (inam)-(L-H2ma) and using the numbers, please review and standardize. At conclusions section it is mentioned four new cocrystals. The authors should present at the beginning how many forms are reported in a clear and concise form, with respective numbers/code, to improve clarity for the reader.

Reply: The nomenclature of co-crystals has been modified.

The authors could reduce the length of the article, some parts can be removed to improve the reading, e.g., the beginning of the results and discussion section repeats experimental information, same in other subtopics.

Reply: Some paragraphs have been removed and some subtopics have been moved to Supplemental Information.

Indicate in the ESI, which PXRD pattern is the simulated and which is experimental.

Reply: This information has been included in the figure caption in the Supplementary Information.

2. Experimental:

 

Which solvent was used to obtain the cocrystals in the solvent-drop grinding process?

Reply: Ethyl acetate. This information has been included in the Experimental Part.

The suitable single crystals were obtained by slow evaporation of solvent? It is mentioned by the author that in other solvents the yield was lower to form single crystals, but was still possible to obtain suitable single crystals to be measured?

Reply: Yes. This information is contained in Co-crystal Screening.

The single crystals were measured in room temperature? The same phase was observed?

Reply: The single crystals were measured at 100 K, but the powder diffractograms were obtained at room temperature. The PXRD pattern simulated and experimental indicates that it is the same phase.

Differences in the hydrogen atoms refinement can lead to different forms/interactions? For example, leading to a salt or cocrystal form?

Reply: No.

1. Results and Discussion:

Table 2 could be sent to ESI, since these geometric data doesn’t bring so relevant information when comparing with the whole manuscript. The energetic data and intermolecular interactions of the main proposed nucleus must be highlighted.

Reply: Table 2 has been moved to Supplementary Information, and the energetic data is included in a new Table.

Page 8, line 210. How was determined the mentioned “This weak packing”? or is a qualitative mention?

Reply: It is a qualitative mention that has been corrected.

It is interesting the proposed tetramer showed in figures 1 and 3. The heterodimer or the tetramer can be identified in solution? Using concentration-dependent 1H NMR experiments, for example, or by calculating the different/main dimers in these crystalline phases? (e.g, see 10.1021/acsomega.8b01801; https://doi.org/10.1021/acs.cgd.1c00600). The authors believe that this tetramer is the first stable nucleus to be formed during the crystallization process? If yes, this is an important finding to be mentioned in the conclusions section.

Reply: To date, the authors do not know of studies using concentration-dependent 1H NMR experiments applied to the systems of the present manuscript. In the discussion of results and in the section of conclusions, an estimated proposal of crystallization mechanism for the formation of tetramers has been incorporated.

Instead of showing motifs in figure 2, 4, and 6, it would be more interesting to see a general view of each crystal phase, for example, a supramolecular cluster (first coordination sphere). To observe the similarities/differences in each phase.

Reply: The motifs are now mentioned in the text and a subtopic on Supramolecular synthons has been included.

Table 3 which discuss the molecular torsions could be presented first.

Reply: Done.

It is observed during the manuscript the abbreviation XRPD and PXRD, please standardize

Reply: The abbreviation has been corrected as XRPD.

Figure 11 must be edited to show mandelic acid full diffractogram pattern. The ‘baseline’ is not showed.

Reply: The Figure has been modified in these terms.

The total stabilization energy data of all crystalline phases could be furnished to discuss the supramolecular stability differences.

Reply: That information has been included in a Table.

Page 15, line 416: this is the first time NCR term appears, please review.

Reply: The error has been corrected.

Table 4: of coformers*; what means *? All data from Table 4 was obtained by DSC?

Reply: * is an informative call to the "foot of the Table" that indicates where the values of the melting points of mandelic acid and pyridinecarboxamides were obtained.

Author Response File: Author Response.pdf

Reviewer 2 Report

Dear Editor,

The manuscript ID crystals-1527152, titled “Multicomponent Solids of DL-2-Hydroxy-2-Phenylacetic Acid With Pyridinecarboxamides”, report co-crystals of DL-2-Hydroxy-2-phenylacetic acid (D, L-H2ma) with pyridinecarboxamides. The co-crystals were fully characterized, and the main interactions were described by means of geometric analysis and using DFT calculations including NCI Plot and QTAIM analysis.

In general, it is an interesting peace of chemistry, since covers an important matter sustained by straightforward and well conducted experiments. This manuscript furnishes new cocrystals with full characterization and reasonable discussion regarding its supramolecular environment, and for that reason I recommend this manuscript for publication, if the following questions/recommendations are answered.

 

1. General:

Please review the manuscript to correct some minor typing issues: e.g., physic-chemical properties; min–1; 1H. Page 9 “que se extienden en el plano “ca” semejando un zig-zag that”

In the introduction section, when discussing heterosynthons to obtain cocrystals, the work of Swift et al. can be cited (e.g., https://doi.org/10.1021/acs.cgd.5b01039; https://doi.org/10.1021/acs.cgd.7b00922).

To better understanding which cocrystals are new and which data are from the literature, please inform previously the compounds number in a illustrative form to clarity. For example, in table 1, which compound/cocrystal is HOGGOB [36] JILZOU [37] JILZOU01 (2) [38]? In the results section compounds 2a and 2b are presented. During the manuscript, compounds are mentioned as (pic)-(D-H2ma), (nam)-(L-H2ma) and (inam)-(L-H2ma) and using the numbers, please review and standardize. At conclusions section it is mentioned four new cocrystals. The authors should present at the beginning how many forms are reported in a clear and concise form, with respective numbers/code, to improve clarity for the reader.

The authors could reduce the length of the article, some parts can be removed to improve the reading, e.g., the beginning of the results and discussion section repeats experimental information, same in other subtopics.

Indicate in the ESI, which PXRD pattern is the simulated and which is experimental.

 

2. Experimental:

Which solvent was used to obtain the cocrystals in the solvent-drop grinding process?

The suitable single crystals were obtained by slow evaporation of solvent? It is mentioned by the author that in other solvents the yield was lower to form single crystals, but was still possible to obtain suitable single crystals to be measured?

The single crystals were measured in room temperature? The same phase was observed?

Differences in the hydrogen atoms refinement can lead to different forms/interactions? For example, leading to a salt or cocrystal form?

 

3. Results and Discussion:

Table 2 could be sent to ESI, since these geometric data doesn’t bring so relevant information when comparing with the whole manuscript. The energetic data and intermolecular interactions of the main proposed nucleus must be highlighted.

Page 8, line 210. How was determined the mentioned “This weak packing”? or is a qualitative mention?

It is interesting the proposed tetramer showed in figures 1 and 3. The heterodimer or the tetramer can be identified in solution? Using concentration-dependent 1H NMR experiments, for example, or by calculating the different/main dimers in these crystalline phases? (e.g, see 10.1021/acsomega.8b01801; https://doi.org/10.1021/acs.cgd.1c00600). The authors believe that this tetramer is the first stable nucleus to be formed during the crystallization process? If yes, this is an important finding to be mentioned in the conclusions section.

Instead of showing motifs in figure 2, 4, and 6, it would be more interesting to see a general view of each crystal phase, for example, a supramolecular cluster (first coordination sphere). To observe the similarities/differences in each phase.

Table 3 which discuss the molecular torsions could be presented first.

It is observed during the manuscript the abbreviation XRPD and PXRD, please standardize.

Figure 11 must be edited to show mandelic acid full diffractogram pattern. The ‘baseline’ is not showed.

The total stabilization energy data of all crystalline phases could be furnished to discuss the supramolecular stability differences.

Page 15, line 416: this is the first time NCR term appears, please review.

Table 4: of coformers*; what means *? All data from Table 4 was obtained by DSC?

 

Comments for author File: Comments.pdf

Author Response

"Please see the attachment."

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Authors have taken into account all my concerns. I do not have any further comments. The article can be accepted in its present form.