A Combination of Virtual and Experimental Screening Tools for the Prediction of Nitrofurantoin Multicomponent Crystals with Pyridine Derivatives

Round 1

Reviewer 1 Report

The manuscript reports a combined virtual and experimental screening of 34 binary systems containing antibacterial drug nitrofurantoin (NFT) and pyridine derivatives resulted in discovery of three novel cocrystals. The structures of these 3 cocrystals have been fully characterized by single crystals X-ray analyses. In the cocrystal [NFT+3AmPy] (1:1), there is a disordered of the 3AmPy molecule which has been corrected treated.

I have no special comments on the X-ray work which could be published as it is

Author Response

Thanks for your appreciation of our work.

Reviewer 2 Report

The MS by Manin et al. (crystals-2470537) builds on the most recent (and interesting) paper 10.1021/acs.cgd.2c00044 from the same group. The MS presents a comprehensive experimental/computational study of the polymorphism of a charged compound, and in principle is suitable for Crystals. Perhaps it might add into an ongoing debate of suitability or not of partitioning molecule...molecule interactions into atom...atom interactions (10.1039/d0ce00270d).

I've checked the coordinates of new structures to see they correctly open in the Materials Studio. However, the MS requires a major revision to remove parts based on the flawed assumption of a possibility of the formation of just one hydrogen bond by a donor atom; the sentence at p. 10:

"While donors, unlike acceptors, can only participate in one hydrogen bond (excluding rather rare cases of bifurcated hydrogen bonds, which are weaker than ordinary two-center hydrogen bonds [79])." 

should be contrasted with something recent dealing with bifurcated hydrogen bonding, e.g., doi.org/10.1002/chem.202203577). In short, Part 3.2.3 is bogus.

Minor points:
1. Recent important investigations into hydrogen bonding should be mentioned (10.1021/jacs.3c00802).
2. Please provide table of contents in the beginning of the Supporting Materials file.

The English should be checked carefully to remove mistakes like "contributing almost equal" at l. 676 of p. 17.

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Reviewer 3 Report

In this interesting manuscript the authors analyzed 34 binary systems of nitrofurantoin with pyridine derivatives by combining virtual (molecular complementarity prediction and hydrogen bond propensity calculations) and experimental (liquid-assisted grinding) screening methods. The authors propose a new modification of the hydrogen bond propensity calculation method to improve the efficiency. The authors discovered new cocrystals of nitrofurantoin with 3-aminopyridine and 2-(1H-Imidazol-2-yl)pyridine were discovered. They found that the nitrofurantoin cocrystal with 3-aminopyridine exists in two polymorphic modifications. The origins of the different stability of the polymorphic forms were rationalized by the authors both in terms of total lattice enthalpy and free energy derived from periodic DFT-D3 calculations.

My opinion is that this manuscript is very interesting, it has been competently done and it is technically correct. The topic is interesting and adequate the readership of this journal. The conclusions are well supported by the results. Therefore, I recommend publication after one minor point is considered by the authors:

1) The authors used the equation of Mata et al for the calculation of the HB energies that is based in Gb value at the BCP. The authors may consider to compare with other methods for deriving the energies based on other parameters like Vb or ρ in some case to compare.

2) Revise reference 82

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

I feel at this point the work by Manin et al. (crystals-2470537) should be presented to the Crystals readers.

Remaining issues (like what appears to be a lost "and" at l. 394 (p. 10) during editing) can be handled by the MDPI language editors.

Author Response

The manuscript has been rechecked and appropriate changes have been made.