Investigation of Crystallization and Salt Formation of Poorly Water-Soluble Telmisartan for Enhanced Solubility

Method: In my   previous comment, "How is the composition ratio of drug and acid? If the   salt is formed by method III, composition ratio of drug and salt should be   calculated. And determine by analytical technique."

There is still   no information in the manuscript.

Author answered   that the composition was 1:1, but not mentioned in the method. And my   question is not for preparation, what is the actual ratio of drug and HCl in   "salt form"? Also, the detail for preparation method of method   I-III should be described. As it is, no one can reproduce.

Thank you for your pinpointing. We have   added detailed description about preparation method in the method section   (Method I, II, III). In the previous version of manuscript, we didn’t mention   about any filtration process for obtaining exact salt forms of TEL. As   mentioned in 2.2.1.3, final salt forms of TEL were retained by 1:1 ratio with   HCl. Amount of TEL and TEL/HCl required for LC/MS quantitative analysis are   described. In addition, we have added the detailed information about preparation   method of salt form and crystalline form of TEL. When a TEL salt form is prepared,   it is theoretically estimated that the molecules are formed as non-covalent   bonds with weak interactions. As a result, the amount of TEL contained in the   obtained powder with TEl/HCl was quantitatively calculated by LC/MS analysis.

MS analysis: Me   previous comment

"The   purpose of MS analysis is uncertain. Why the fragmentation was different   between TEL and salt form? Just pH condition of the sample solution? Please   check same pH condition. Under solution state, if the salt dissolved   completely, MS spectrum of TEL salt can be corresponding to that of TEL   crystal because HCL is disconnected from salt form under solution state. If   so, this evaluation makes no sense for confirmation of salt formation."   Author's answer was not adequate.  

Thank you for your suggestion. In order to   correspond to what you pointed out, more detailed descriptions of the LC/MS   analysis methods and results for TEL and TEL/HCl, with similar relative   absorbances in relation to the mass spectrum have been explained. Salt   formation and dissociation to the corresponding free acid or base form is the   function of the pH (pH_max). In our study, appearance of the peaks   at m/z 167 and m/z 391 indicated the retention of the salt form of TEL under   the experimental solution state. The solubility and stability data further   confirmed the stable salt form of TEL/HCL under tested conditions.   

In the   manuscript, the purpose of the study is still unclear, and discussion is not   sufficient. There is no evidence for the different fragmentation (What is the   relation of hydrogen bonds?). Please, revise again.

Thank you for your pinpointing. We have revised   the manuscript by supplementing detailed information. In case of salt   formation, the non-covalent bond is connected through the hydrogen action   between the drug and the salt. Structure and molecular weight of fragmented   ions generated from TEL and TEL/HCl sample prepared during LC/MS analysis at   the same concentration confirmed the formation of hydrogen bond interaction   between the ions of TEL and HCl.

1.      Authors   are encouraged to emphasize the novelty of current work in introduction by   adding related formulation literature.

Thank you for your comment. We have added   the sentence for emphasizing the novelty of current work (Line 72-83). We   have further addressed the issue of stability and solubility that has not   been achieved in previous studies.

2.      English   can be improved throughout the manuscript, e.g., Page 1 Line 29-30; Page 2   Line54-55; Page 2 Line 70-72;…

Thank you for your comment. We have   improved the English throughout the manuscript.

3.  How do you define ‘quite stable’? Page 1   Line 33

Thank you for your comment. We have changed   the term of ‘quite stable’ and modified the sentence.

4. The   pharmacokinetic behaviors and the clinical properties of TEL have been   reported [14]’, please add the summary of what has been reported to complete   this sentence.

Thank you for your comment. We have added   the sentence to explain about the pharmacokinetic behaviors and the clinical   properties of TEL (Line 62-64)

5. Page 2   Line73, correct it to ‘…examined via ….’

Thank you. We have corrected it to ‘examined   via’ as per your comment.

6. Page 2 Line   74, were broken up? Please clarify

Thank you for your comment. We have   clarified the meaning of sentence.

7. Please add   DSC nitrogen purging flow rate (not critical)

Thank you for your comment. We have added   the information about DSC nitrogen purging flow rate. Flow rate of purging   gas with nitrogen was 50ml/min.  

8. Plotting the   DSC curves together is not sound to draw a conclusion. Please add melting   enthalpy and onset temperature for all your DSC results in Figures 1, 4.

Thank you for your comment. We have added   the enthalpy and onset temperature of all DSC curves in Figure 1 and 4.

9.      Is it expected that salt form would   enhance the drug solubility?

Thank you for your comment. Based on figure   8, we have proved that our TEL/HCl improve the solubility according to three   bioequivalent solvents (pH 1.2, pH 6.8 buffer and distilled water). Salt   formation is a common and effective method of increasing solubility and   dissolution rates of acidic and basic drugs.