Investigation of Solid-State Hydrate-Anhydrous Phase Transformations of Dabigatran Etexilate Hemi-Edisylate

Round 1

Reviewer 1 Report

The authors do not refer to the previously reported investigation done on Dabigatran etexilate hemi-edisylate described in the patent KR102147600B1 where the crystal structure of monohydrate, powder X-ray diffraction and DSC patterns of monohydrate and anhydrate were published. The same pictures are used. Therefore, I miss the novelty and recommend to reject the article or to make a major revision to emphasize the novelty in comparison with the patent. Link: 

https://worldwide.espacenet.com/patent/search/family/072242082/publication/KR102147600B1?q=dabigatran%20edisylate

Author Response

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Reviewer 2 Report

The paper reports the structure and hydrate−anhydrous phase transformations of a salt prepared by the reaction with dabigatran etexilate (DBG) and edisilic acid.

The experiment work is of good quality but in my opinion the process has to be described as hydrate−anhydrous phase transformations than “solid-state polymorphic transformation” following the IUPAC raccomandation ( https://goldbook.iupac.org/terms/view/P04748 ). In the present case the two phases did not possess the “same chemical composition.”

The manuscript in my opinion has to be changed accordingly before the final acceptance, as just few examples:

- pag 9 lines: “So, it could be confirmed that there was no decomposition of DBE in drying and the DBE anhydrate was a polymorph of DBE.”

- Pag 9 lines 260-266 The concept of this sentence is repeated twice: “Thin and fragile properties of DBE anhydrate might be assumed to be a reason for the difficulties in preparation of single crystal.”

Also the authors stated that the transformation to the anhydrous phase is irreversible based on hygroscopic tests. Did they tried to add one equivalent of water to the anhydrous compound?

Other minor points:

Pag. 6 lines 186-187: “The crystal structure of DBE monohydrate consists of the two dabigatran etexilate (DBG), one edisilic acid, and two water molecules.” In the structure, there is no edisilic acid but a edisylate molecule.

Pag 12 line 369: “the edisilic acid forming an ionic bonding” … again there is no edisilic acid but a edisylate molecule. Please rephrase.

Please add the hydrogen atoms bonded to nitrogen atoms in order to visualize better the hydrogen bonds in Figure 2a.

In conclusion, the paper could be accepted for publication after the revision suggested.

Author Response

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Reviewer 3 Report

The manuscript “Investigation of Solid-State Polymorphic Transformation of 2 Dabigatran Etexilate hemi-edisylate” presents a relevant purpose of investigation the transition between the monohydrate and anhydrous form of Dabigatran Etexilate hemi-edisylate.

However, in my opinion, the manuscript can only be considered for publication in Crystals if a major and thorough revision is performed.

The manuscript presents several formatting major errors, from repetition of words (see, for example, in line 92, “anhydrate” is present twice), to the lack of title in table 2 (page 4, which is supposed to be table 1) and including section 2.4, which is repeated three times!

Nonetheless, my main concern is the terminology presented in the manuscript. As the authors might be aware, solvates or, in particular, hydrate forms, are not polymorphic forms of the anhydrous forms. Moreover, according to IUPAC, a polymorphic transition is a transition of a solid crystalline phase to another phase of the same chemical composition with a different crystal structure. In this work, the authors claim that the reported monohydrated and the anhydrate forms are polymorphs, which is not scientifically correct. The authors also claim that “the polymorphic transformation from monohydrate to amorphous to anhydrate is the de-hydration of water molecules”; hence, if the polymorphic transformation involves a modification of the chemical composition in the crystal structure, the transformation cannot be, by definition, a polymorphic one.

To conclude, in my opinion, the manuscript needs to be modified accordingly before it can be considered for publication.

Author Response

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Reviewer 4 Report

In this manuscript, a new salt form of dabigatran DBE was prepared by the reaction crystallization of dabigatran DBG and edisilic acid. Also, the hot stage microscopy showed that the DBE monohydrate was transformed to DBE amorphous solid and then finally shifted to the DBE anhydrate in solid-state. The polymorphic transformation of DBE monohydrate to DBE anhydrate was irreversible. This is an interesting study and subsequently deserves publication, however after addressing the following concerns.

1. Line 119,129, and 136, why are there three “2.4. Differential Scanning Calorimetry (DSC)” ?

2. Line 177-182, after hygroscopic test, PXRD should have been conducted for the resulting solids to determine if crystallinity remains/form change.

3. Line 186-187, what are the components in the asymmetric unit of crystal structure of DBE monohydrate?

4. Solubility plays an important role in pharma. Since DBG is a commonly used drug, is it possible to increase its aqueous solubility by forming DBE monohydrate/anhydrate? Could you measure the approximate solubility in water or pH buffers of your salts? Please check the following reference for solubility estimation:

https://doi.org/10.1021/acs.cgd.0c01197

Author Response

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Round 2

Reviewer 1 Report

The authors did not meet my expectations and recommendations. They did not differentiate the results significantly against the previously published patent and I do not see the novelty for publishing in such high rating journal. The same figures and pictures are used in the patent and in the manuscript. Crystal structure and cell parameters of the dabigatran salt were mentioned in the patent.

Author Response

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Reviewer 2 Report

The paper could be accepted in the present form

Author Response

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Reviewer 3 Report

In my opinion, the manuscript needs to be further improved in order to be considered for publication.
The terminology issue addressed in my first revision has not been totally corrected.

In the introduction, the authors kept several sentences about polymorphism, when this is not the central topic of the manuscript.

In the main text, there also remains statements like "So, these result supported the polymorphic transformation of the DBE mono-291 hydrate to the DBE anhydrate." that, has we have seen previously, are not scientifically correct.
Hence, a further revision to correct these issues need to be performed before for this manuscript to be considered for publication.

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Reviewer 4 Report

The study synthesized dabigatran etexilate edisylate (DBE) and analyzed its structure, phase transformations and stability, revealing that the phase transformation from DBE monohydrate to DBE anhydrate was irreversible and that DBE anhydrate was the most stable phase. This manuscript could be considered for publication after addressing the following concerns:

1. Line 32, in the first paragraph, The references that have been cited appear to be somewhat outdated. It is requested that more recent sources be utilized such as:

1) https://doi.org/10.1021/acs.chemmater.9b00441

2) https://doi.org/10.1021/acs.chemrev.1c00987

3) https://doi.org/10.1021/acs.cgd.0c01197

4) https://doi.org/10.1016/j.drudis.2020.11.016

5) https://doi.org/10.1021/acs.cgd.9b00914

2. Line 89, delete one of the following two expressions - "two grams" or "2g".

3. Stability test of your salts should also be studied.

Author Response

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Round 3

Reviewer 1 Report

The revised form of the manuscript is acceptable. The authors tried to differentiate the results from the data in the discussed patent.

Author Response

Reviewer 1

The revised form of the manuscript is acceptable. The authors tried to differentiate the results from the data in the discussed patent.

• We thank the reviewer for the kind comment.

Sincerely yours,

Ji-Hun An, Ph.D.

CEO

Unicel Lab

Uiwang, Gyeonggi, 16079, Republic of Korea

E-mail: [email protected]

Reviewer 3 Report

In the abstract of the manuscript, innacurate statements about polymorphism and polymorphic transformation are still present. Furthermore, these terms are also still present in the keywords. These must be corrected.
Sentences like "Among DBM polymorphs including the hydrate form, the form-I was used for medication" must also be corrected accordingly.
The sentence "Through the polymorph investigation studies, information regarding the crystal structure, shape as well as the physico-chemical characteristics are obtained." does not make sense in this manuscript either.

Please find every "polymorph" terms in the manuscript and correct them before the manuscript can be considered for publication.

Author Response

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