Thermodynamic Analysis of the Solubility of Sulfadiazine in (Acetonitrile 1-Propanol) Cosolvent Mixtures from 278.15 K to 318.15 K
, Fredy Angarita-Reina 3, Mauricio Herrera 1, Claudia Patria Ortiz 4, Rossember Edén Cardenas-Torres 5, Fleming Martinez 6 and Daniel Ricardo Delgado 1,*Round 1
Reviewer 1 Report
This is an interesting manuscript. It reports carefully conducted measurements of sulfadiazine solubility in the solvent mixture of 1-prpanol and acetonitrile, over a temperature range. The derived solution and mixing thermodynamic quantities and the data interpretation are also interesting. An attempt was made to elucidate the interactions involved and their role in the dissolution process.
This is a fairly complex system. The solution process involves “melting” and solvation/mixing sub-processes and, on top of it, the mixing enthalpy of the solvent pair is relatively large (positive). Thus, the solution quantities are the outcome of the interplay of various factors and it is not easy to decipher the numbers and extract process mechanism.
The mixing quantities, on the other hand, seem to be somehow simpler to interpret in terms of intermolecular interactions. Quite often, when two solvents do not very much like each other, their mixture may offer a miscibility “window” to a third compound, insoluble in the pure solvents. When the third compound is marginally soluble in the pure solvents, the above miscibility “window” appears as a solubility “spike” in a mixture composition.
I am wondering if this is the case here in the w = 0.85 mixture composition.
The heat of mixing drug/solvent is negative in acetonitrile-rich solvents. The authors indicate that the drug sees acetonitrile as a base. Thus, the negative heat of mixing may just be the result of the (Lewis) acid – base solute-solvent interactions in this region of solvent concentrations. In fact, the negative mixing entropy also implies order formation, which may indicate hydrogen-bond or acid-base interactions. In contrast, propanol prefers to self-associate rather than to cross-associate with the drug (stronger OH—OH interactions) and, this contributes to the positive heat of mixing in the propanol-rich solvent case.
At w = 0.85, there is a synergism of two factors contributing to the minimum in the mixing enthalpy: the above mentioned “spike” and the acid-base (drug-acetonitrile) interaction.
Do the authors agree with such a picture of the involved intermolecular interactions? If yes, they could, probably, rephrase parts of their data interpretation accordingly.
The entropy units in the tables should change: kJ should be replaced by J.
Author Response
Dear Reviewer,
The authors would like to thank you for your careful, helpful and constructive comments, which all have improved the quality of the manuscript.
A summary of how we have addressed the comments is presented below (Note: in black are the reviewer comments, and immediately below, in red, is our response and summary of changes made to the manuscript).
Point 1: The mixing quantities, on the other hand, seem to be somehow simpler to interpret in terms of intermolecular interactions. Quite often, when two solvents do not very much like each other, their mixture may offer a miscibility “window” to a third compound, insoluble in the pure solvents. When the third compound is marginally soluble in the pure solvents, the above miscibility “window” appears as a solubility “spike” in a mixture composition.
I am wondering if this is the case here in the w = 0.85 mixture composition.
The heat of mixing drug/solvent is negative in acetonitrile-rich solvents. The authors indicate that the drug sees acetonitrile as a base. Thus, the negative heat of mixing may just be the result of the (Lewis) acid – base solute-solvent interactions in this region of solvent concentrations. In fact, the negative mixing entropy also implies order formation, which may indicate hydrogen-bond or acid-base interactions. In contrast, propanol prefers to self-associate rather than to cross-associate with the drug (stronger OH—OH interactions) and, this contributes to the positive heat of mixing in the propanol-rich solvent case.
At w1 = 0.85, there is a synergism of two factors contributing to the minimum in the mixing enthalpy: the above mentioned “spike” and the acid-base (drug-acetonitrile) interaction.
Do the authors agree with such a picture of the involved intermolecular interactions? If yes, they could, probably, rephrase parts of their data interpretation accordingly.
Response 1: We agree with the reviewer on the possible acid-base (Lewis) interactions between solute and solvent, which are consistent with the increase in the solubility of SD in mixtures rich in MeCN. However, in this case there is no peak (solubility maximum) for the mixture w1=0.85, but the lowest mixing enthalpy value, which indicates a benefit to the mixing process and therefore to the solution process.
The phenomenon described by the reviewer usually occurs in cosolvent mixtures where the drug solubility parameter is between the parameters of pure solvents.
Point 2: The entropy units in the tables should change: kJ should be replaced by J.
Response 2: Entropy units were replaced in tables (from kJ to J)
Author Response File: 
Author Response.docx
Reviewer 2 Report
Comments:
This paper presents solubility data of sulfadiazine (SD) in cosolvent mixtures {acetonitrile + 1-propanol} at temperatures (278.15 K-318.15 K) and a thermodynamic analysis of the solubility of sulfadiazine (SD) in the solvents studied.
My main notes follow.
#1:
In 2.2. Preparation of Solvent Mixtures
Line 51 “…For each concentration, 3 samples of 10.00±0.00 g each were prepared.”
I have doubts about the mass weighted 10.00+-0.00g (4 decimal places), due to the analytical balance (RADWAG AS 220.R2, Poland) of 4 decimal places (sensitivity ±0.0001 g).
#2
In 2.3. Solubility Determination
In line 60 “…the concentration of the solution was measured by UV/Vis spectrophotometry.”
Spectrophotometer characteristics are missing.
#3
In 3.1. Experimental mole fraction solubility (x3)
Figure 2 is unnecessary; the information can be seen in table 2.
In lines 74 – 77 “…considering the three-dimensional solubility parameter[24], i.e. dispersion (d), polar (p) and hydrogen bonding (h) forces, the solvents show a greater difference in δd 14.1 MPa1/2 and 10.3 MPa1/2 for 1-PrOH and MeCN, respectively. Therefore, the dispersion forces between MeCN and SD would favor the increase of solubility”
The authors only mention the dispersion parameter solubility as a factor that influences the solubility of (SD). The other two-solubility parameter should be mentioned and how it can influence the solubility of (SD) in the cosolvents studied.
Typos
Line 134 “…soluto”. Solute
Figure 6. “acetonitrilo”. acetonitrile
Comments for author File: Comments.docx
Author Response
Dear Reviewer,
The authors would like to thank you for your careful, helpful and constructive comments, which all have improved the quality of the manuscript.
A summary of how we have addressed the comments is presented below (Note: in black are the reviewer comments, and immediately below, in red, is our response and summary of changes made to the manuscript).
Point 1: In 2.2. Preparation of Solvent Mixtures
Line 51 “…For each concentration, 3 samples of 10.00±0.00 g each were prepared.”
I have doubts about the mass weighted 10.00±0.00g (4 decimal places), due to the analytical balance (RADWAG AS 220.R2, Poland) of 4 decimal places (sensitivity ±0.0001 g).
Response 1: An approximate mass of the prepared cosolvent mixture sample was actually presented, since once saturated only aliquots were taken to determine the SD solubility. Therefore, only two decimal places were reported.
Point 2: In 2.3. Solubility Determination
In line 60 “…the concentration of the solution was measured by UV/Vis spectrophotometry.”
Spectrophotometer characteristics are missing.
Response 2: The equipment specifications were reported.
Point 3: In 3.1. Experimental mole fraction solubility (x3)
Figure 2 is unnecessary; the information can be seen in table 2
Response 3: Figure 2 was removed from the manuscript.
Point 4: In 3.1. Experimental mole fraction solubility (x3)
In lines 74 – 77 “…considering the three-dimensional solubility parameter[24], i.e. dispersion (d), polar (p) and hydrogen bonding (h) forces, the solvents show a greater difference in δd 14.1 MPa1/2 and 10.3 MPa1/2 for 1-PrOH and MeCN, respectively. Therefore, the dispersion forces between MeCN and SD would favor the increase of solubility”
The authors only mention the dispersion parameter solubility as a factor that influences the solubility of (SD). The other two-solubility parameter should be mentioned and how it can influence the solubility of (SD) in the cosolvents studied.
Response 4: An improved formulation of the idea is presented in the manuscript according to the reviewer's suggestion:
Concerning the cosolvent effect, solubility usually depends on the polarity of the solvent, so the maximum solute solubility is reached in the solvent or cosolvent mixture with a solubility parameter similar to the solute. In this case, the solubility parameter of MeCN and PrOH are similar, so it is complex to elucidate the relationship between the polarity of the solvent medium (quasi-constant solubility parameter; between 24.8 and 24.9 MPa1/2) and the SD (28.89 MPa1/2). Therefore, regarding the solubility parameter, one alternative is to consider the three-dimensional solubility parameter [24], which means, the dispersion force (d), polar force (p), and hydrogen bonding force (h). In this way PrOH (δd=14.1 MPa1/2, δp= 10.1 MPa1/2, δh=17.1 MPa1/2) differs the most with MeCN (δd=10.3 MPa1/2, δp= 11.1 MPa1/2, δh=19. 6 MPa1/2) in δd, so the increase in SD solubility with increasing PrOH concentration in the cosolvent mixture is possibly due to the increase in non-polar interactions between PrOH and SD.
Point 5: Typos
Line 134 “…soluto”. Solute
Figure 6. “acetonitrilo”. acetonitrile
Response 5: Typos were corrected (the entire document was proofread).
Author Response File: Author Response.docx
Round 2
Reviewer 2 Report
The suggestions and questions mentioned in report 1 were clarified and introduced correctly.
