Increasing the Equilibrium Solubility of Meloxicam in Aqueous Media by Using Dimethyl Sulfoxide as a Cosolvent: Correlation, Dissolution Thermodynamics and Preferential Solvation

Round 1

Reviewer 1 Report

The paper is devoted to solubility studies of Meloxicam (an analgesic and anti-inflammatory drug) in (Water DMSO) mixtures at different temperatures (from 273.15 up to 313.15K. To interpret the experimental data the authors applied various approached and models: Jouyban-Acree model, the van’t Hoff and Gibbs equations, the inverse Kirkwood-Buff integrals method. The paper is well written with clear presentation and interpretation of the experimental and theoretical data. The paper should be published in the Journal without doubts.

 

I have some comments for improvement of the paper (I hope)

 

1) line 214

“524.0 K”

It should be presented experimental error.

 

2) Fig. 5

It will be useful inserting in Fig. 5 modeled diffractogram for Form I Meloxicam (from the single crystal data)

 

3) Eq(6)

It should be presented errors for the correlation coefficients.

 

4) Eq(8)

It should be presented errors for the correlation coefficients.

 

5) Eq(9)

It should be presented errors for the correlation coefficients.

 

6) Eq(10)

It should be presented errors for the correlation coefficients.

 

7) Eq(11)

It should be presented errors for the correlation coefficients.

 

8) line 471

Should be “drug-alike”

 

9) Caption for Fig. 7.

Instead of "entropy"

Should be "energy Gibbs"

 

10) Eq(31)

It should be presented errors for the correlation coefficients.

 

11) Table 11.

It should be evaluated and mentioned errors of the presented in Table 6 parameters/functions (at the footnote, for example).

 

Author Response

The paper is devoted to solubility studies of Meloxicam (an analgesic and anti-inflammatory drug) in (Water DMSO) mixtures at different temperatures (from 273.15 up to 313.15K. To interpret the experimental data the authors applied various approached and models: Jouyban-Acree model, the van’t Hoff and Gibbs equations, the inverse Kirkwood-Buff integrals method. The paper is well written with clear presentation and interpretation of the experimental and theoretical data. The paper should be published in the Journal without doubts.

Response: Response: Many thanks for your nice and constructive suggestions.

I have some comments for improvement of the paper (I hope)

1) line 214. “524.0 K”. It should be presented experimental error. Response: This sentence has been remove because of suggestion of another reviewer.

2) Fig. 5. It will be useful inserting in Fig. 5 modeled diffractogram for Form I Meloxicam (from the single crystal data). Response: A new tables summarizing the most significant peaks has been added.

3) Eq(6). It should be presented errors for the correlation coefficients. Response: F and R values were added.

4) Eq(8). It should be presented errors for the correlation coefficients. Response: F and R values were added in the text.

5) Eq(9). It should be presented errors for the correlation coefficients. Response: F and R values were added in the text.

6) Eq(10). It should be presented errors for the correlation coefficients. Response: Statistical information has been reported in Reference 56.

7) Eq(11). It should be presented errors for the correlation coefficients. Response: Statistical information has been reported in Reference 56.

8) line 471. Should be “drug-alike”. Response: corrected.

9) Caption for Fig. 7. Instead of "entropy" Should be "energy Gibbs". Response: The caption has been expanded to make it more clear.

10) Eq(31). It should be presented errors for the correlation coefficients. Response: Added.

11) Table 11. It should be evaluated and mentioned errors of the presented in Table 6 parameters/functions (at the footnote, for example). Response: No table 11 is shown but it could be referred to new table 7. If this is the case, in the case is indicated that dx1,3 are significant for preferential solvation effects if they are higher than 0.01 as absolute values.

Reviewer 2 Report

In this work it is reported an interesting, clear, and complete analysis on solubility of Meloxicam in Aqueus - Dimethyl Sulfoxide mixtures.

I regard that the present manuscript is clearly suitable to publish in Liquids, after taking into consideration minor comments

 

·         Melting point of MLX have been reported in many previous works. It is not a real contribution in this work. I suggest removing this paragraph and figure 3 from the text.

·         Why solubility values in neat water were taken from reference [32]? Authors says: “ The  observed differences in solubility values could be attributed to several reasons like different polymorphic states, different saturation times, or different analytical procedures, among others, …” Solubility determinations in reference 32 and in this work are different. Moreover, melting point in this work is 535.4 K, and, in reference 32 it is 536.7 K. So, I recommend determining the solubility of meloxicam in neat water and using these results in the models.

·         e33 is written with different formats in the text

·         In my opinion the expression: “This demonstrates the energetic predominance in almost all these dissolution processes, with the exception of neat water and the mixture of x1 = 0.10, where ζH = 0.224 and 0.177, respectively, and thus, the entropy is the dominant function in these both cases” could be written for better comprehension, for example in the next form:

“This demonstrates that in almost all the mixtures the main contributor to this positive standard molar Gibbs energy of solution of meloxicam (reflected in the low solubility) is the enthalpy except for neat water and the mixture of x1 = 0.10, where ζH = 0.224 and 0.177, respectively, and thus, the entropy is the dominant function in these both cases”

 

 

Author Response

In this work it is reported an interesting, clear, and complete analysis on solubility of Meloxicam in Aqueus - Dimethyl Sulfoxide mixtures.

I regard that the present manuscript is clearly suitable to publish in Liquids, after taking into consideration minor comments

Response: Response: Many thanks for your nice and constructive suggestions.

• Melting point of MLX have been reported in many previous works. It is not a real contribution in this work. I suggest removing this paragraph and figure 3 from the text. Response: The respective paragraph and figures were remove.
• Why solubility values in neat water were taken from reference [32]? Authors says: “ The  observed differences in solubility values could be attributed to several reasons like different polymorphic states, different saturation times, or different analytical procedures, among others, …” Solubility determinations in reference 32 and in this work are different. Moreover, melting point in this work is 535.4 K, and, in reference 32 it is 536.7 K. So, I recommend determining the solubility of meloxicam in neat water and using these results in the models. Response: The literature values were obtained by our research group following the same procedures with the same reagent sample and if considering the uncertainty in temperature of fusion (+/- 0.5 K) it could be considered that no significant difference is observed.
• e33 is written with different formats in the text. Response: it was corrected.
• In my opinion the expression: “This demonstrates the energetic predominance in almost all these dissolution processes, with the exception of neat water and the mixture of x1 = 0.10, where ζH = 0.224 and 0.177, respectively, and thus, the entropy is the dominant function in these both cases” could be written for better comprehension, for example in the next form:

“This demonstrates that in almost all the mixtures the main contributor to this positive standard molar Gibbs energy of solution of meloxicam (reflected in the low solubility) is the enthalpy except for neat water and the mixture of x1 = 0.10, where ζH = 0.224 and 0.177, respectively, and thus, the entropy is the dominant function in these both cases”

Response: It was modified as suggested.

Reviewer 3 Report

the presented paper is generally well prepared and can be accepted after minor revision:

introduction is relatively short and can be extended.

The novelty of the paper is to be clearly stated

More descriptions are needed for the material and methods.

The unit of the heat flow is to be indicated in Fig. 3

The y-scale values are missing in Figs 3 to 5.

The used range of temperature is to be justified.

The measurement uncertainties are to be discussed.

The following paper may be added to the literature review:

 https://doi.org/10.1016/j.aej.2020.10.019

 

Author Response

the presented paper is generally well prepared and can be accepted after minor revision:

Response: Many thanks for your nice concept and constructive suggestions.

introduction is relatively short and can be extended.

The novelty of the paper is to be clearly stated. Response: It was mentioned that a cosolvent of high cosolvent power is studied here.

More descriptions are needed for the material and methods. Response: More detail have been added.

The unit of the heat flow is to be indicated in Fig. 3. Response: This figure has been removed because the suggestion of another reviewer.

The y-scale values are missing in Figs 3 to 5. Response: arbitrary units have been noted. 

The used range of temperature is to be justified. Response: A sentence has been added to justify the temperature interval studied.

The measurement uncertainties are to be discussed. Response: uncertainty in solubility values is in concordance with obtained in other similar studies. This has been added.

The following paper may be added to the literature review:  https://doi.org/10.1016/j.aej.2020.10.019. Response: the suggested article has been added.

Reviewer 4 Report

The manuscript “liquids-1841671” investigated the equilibrium solubility of Meloxicam in DMSO-aqueous solvent systems, the solubility data were further correlated with several thermodynamic models. Apparent standard dissolution, mixing thermodynamic parameters and the preferential solvation parameters of meloxicam in DMSO-aqueous solvent systems were studied. The paper was overall well written and it deserves publication in Liquids, but there are some minor mistakes which need to be modified before it can finally be accepted for publication.

(1)  The full name should be indicated when abbreviations appear for the first time in the abstract.

(2)  “It is noteworthy that very good meloxicam solubility-increasing has been reported, reaching more than 1000-fold in some cases.” Citations of data require specific references to be given.

(3)  Restrict the number of references cited in the text to the minimum. Cite only those references which are necessary to under the contents.

(4)  It is recommended that application of DMSO as a solvent model should be introduced more instead of other applications in the second paragraph of the introduction.

Comments for author File: Comments.pdf

Author Response

The manuscript “liquids-1841671” investigated the equilibrium solubility of Meloxicam in DMSO-aqueous solvent systems, the solubility data were further correlated with several thermodynamic models. Apparent standard dissolution, mixing thermodynamic parameters and the preferential solvation parameters of meloxicam in DMSO-aqueous solvent systems were studied. The paper was overall well written and it deserves publication in Liquids, but there are some minor mistakes which need to be modified before it can finally be accepted for publication.

Response: Many thanks for your nice and constructive suggestions.

(1)  The full name should be indicated when abbreviations appear for the first time in the abstract. Response: It has been done.

(2)  “It is noteworthy that very good meloxicam solubility-increasing has been reported, reaching more than 1000-fold in some cases.” Citations of data require specific references to be given. Response: Specific values and references have been added.

(3)  Restrict the number of references cited in the text to the minimum. Cite only those references which are necessary to under the contents. Response: Some references have been remove regarding melting properties as suggested by another reviewer.

(4)  It is recommended that application of DMSO as a solvent model should be introduced more instead of other applications in the second paragraph of the introduction. Response: More information has been added.

Reviewer 5 Report

Overall, this is a very nice manuscript. I enjoyed reading it very much. The work is excellent in that they provide experimental measurements, and then attempt to extract as much information as possible from the data. From other experimental papers I have read, this is rare. I emphasize that this would be an excellent contribution to the journal. I have a series of minor comments. Please know that the comments are not criticisms, but come from an interested reader. 

1) "3.3. Activity Coefficients in Mixed Solvents". Please clearly explain how xideal is computed. 

2) I do not understand equation (2) and see how it is related to intermolecular interactions. Please explain and provide justification. As it appears to me, the first three terms in parenthesis all look like constants that can be lumped together.

3) Okay, I have a question about equation (13). I am a thermodynamics researcher and work with modeling solutions of mixtures. But I have not previously compute what you label as property chances upon solution. So first, could you give a physical description of what a property change upon solution means? Also, I am a little hesitant about the application of equation 13. So:

ln x3 = - ln gamma3 + ln xid 

Where ln xid = ln f3S/f30 (the ratio of the fugacity of the pure solid relative to the pure subcooled liquid), which is equal to (G3S-G30)/RT, the difference in Gibbs free energy divided by RT. So now going back to our equation, we could write the differential then as a sum with respect to the differential of -ln gamma3 and ln xid. I have no issues with the differential of ln xid since it is a property of pure component 3 and should give the enthalpic contribution via the Gibbs-Helmholtz equation. What is not clear to me is the differential of -ln gamma3. ln gamma3 is equivalent to the partial molar excess Gibbs free energy. Where I am puzzled, is the solubility is changing at each temperature, so the values of ln gamma3 are not at the same composition as you be required to obtain the partial molar excess enthalpy via the Gibbs-Helmholtz equation.

Please let me be clear that I am not questioning your work nor questioning if it is correct. The question comes from a very interested reader that wants to make sure he fully understands your work and the meaning. This is a very important part of your work, and I want to make sure it is fully grasped. This will better help my understanding of your discussion of the values.

4) Equation 16 and 17. Why use the absolute value of each term in the denominator, as compared to the absolute value of the sum? Aren't you interested in the fraction of the Gibbs free energy due to each contribution?

5) Okay, coming back to my comment 3. Reading you introduce us to equations 18 and 19. But really, this does not help clarify things for me. 

6) Equations 20 and 21. Please be sure to state your assumption of constant Cp value.

7) I question the correctness of equation 30. I believe that you should use mass or molar concentrations (mass/volume or moles/volume), and not mole fractions.

Author Response

Overall, this is a very nice manuscript. I enjoyed reading it very much. The work is excellent in that they provide experimental measurements, and then attempt to extract as much information as possible from the data. From other experimental papers I have read, this is rare. I emphasize that this would be an excellent contribution to the journal. I have a series of minor comments. Please know that the comments are not criticisms, but come from an interested reader. 

Response: Many thanks for your nice and constructive suggestions.

1) "3.3. Activity Coefficients in Mixed Solvents". Please clearly explain how xideal is computed. Response: A new sentence has been added as ". It is noteworthy that ideal solubilities were taken from the literature [32]." 

2) I do not understand equation (2) and see how it is related to intermolecular interactions. Please explain and provide justification. As it appears to me, the first three terms in parenthesis all look like constants that can be lumped together. Response: It indicates that deviations to ideal solubility are as consequence of differences among solvent-solvent, solute-solute and solvent-solute interactions energies and depend on the mixtures composition.

3) Okay, I have a question about equation (13). I am a thermodynamics researcher and work with modeling solutions of mixtures. But I have not previously compute what you label as property chances upon solution. So first, could you give a physical description of what a property change upon solution means? Also, I am a little hesitant about the application of equation 13. So:

ln x3 = - ln gamma3 + ln xid 

Where ln xid = ln f3S/f30 (the ratio of the fugacity of the pure solid relative to the pure subcooled liquid), which is equal to (G3S-G30)/RT, the difference in Gibbs free energy divided by RT. So now going back to our equation, we could write the differential then as a sum with respect to the differential of -ln gamma3 and ln xid. I have no issues with the differential of ln xid since it is a property of pure component 3 and should give the enthalpic contribution via the Gibbs-Helmholtz equation. What is not clear to me is the differential of -ln gamma3. ln gamma3 is equivalent to the partial molar excess Gibbs free energy. Where I am puzzled, is the solubility is changing at each temperature, so the values of ln gamma3 are not at the same composition as you be required to obtain the partial molar excess enthalpy via the Gibbs-Helmholtz equation.

Please let me be clear that I am not questioning your work nor questioning if it is correct. The question comes from a very interested reader that wants to make sure he fully understands your work and the meaning. This is a very important part of your work, and I want to make sure it is fully grasped. This will better help my understanding of your discussion of the values.

Response: All reported thermodynamic quantities imply the equilibrium state at saturation. What we consider the change are the differences between saturated solution and the solute and solvents before the dissolution.

4) Equation 16 and 17. Why use the absolute value of each term in the denominator, as compared to the absolute value of the sum? Aren't you interested in the fraction of the Gibbs free energy due to each contribution? Response: This sentence has been modified to indicate the respective magnitude contributions.

5) Okay, coming back to my comment 3. Reading you introduce us to equations 18 and 19. But really, this does not help clarify things for me. Response: this treatment assume the mixing of both liquids, i.e. solvent mixture and hypothetically melted solute (after the solute melting).

6) Equations 20 and 21. Please be sure to state your assumption of constant Cp value. Response: This sentence has been added to clarify it: where DC_p denotes the difference of heat capacities of liquid and solid states at the temperature of melting. Owing the difficulties in DC_p experimental determinations the entropy of fusion (DS_f) is used instead [66]. 

7) I question the correctness of equation 30. I believe that you should use mass or molar concentrations (mass/volume or moles/volume), and not mole fractions. Response: It is expressed in mole fraction as required by the inverse Kirkwood-Buff integrals method as reported earlier in the literature.