Journal of the Taiwan Institute of Chemical Engineers

Solution thermodynamics and preferential solvation of sulfamethazine in ethylene

glycol + water mixtures
--Manuscript Draft--

Manuscript Number: JTICE-D-20-01519R1

Article Type: Original Paper

Section/Category: Chemical and Biomolecular Science and Technology

Keywords: Sulfamethazine; solubility; Preferential solvation; vat´n Hoff; solution

thermodynamics,

Corresponding Author: Daniel Ricardo Delgado, Ph.D

Universidad Cooperativa de Colombia - Neiva
Neiva, Huila COLOMBIA

First Author: Abdelkarim Aydi, Ph.D

Order of Authors: Abdelkarim Aydi, Ph.D

Claudia Patricia Ortiz, M.Sc

Diego Ivan Caviedes Rubio, M.Sc

Cherifa Ayadi, Ph.D

Souhaira Hbaieb, Ph.D

Daniel Ricardo Delgado, Ph.D

Abstract: <p>&nbsp;</p> <p class="MDPI17abstract" style="line-height:200%"><span lang="EN-

US" style="font-size:12.0pt;line-height:200%;font-family:&quot;Times New
Roman&quot;,serif">The solubility of sulfamethazine (SMT) in ethylene glycol (EG) +
water (W) cosolvent mixtures was determined at nine temperatures (278.15, 283.15,
288.15, 293.15, 298.15, 303.15, 308.15, 313.15 and 318.15 K) by means of the stirring
method. From the solubility data, the thermodynamic functions of solution, transfer and
mixing were calculated using the Gibbs and van´t Hoff equations. On the other hand,
the preferential solvation parameters of SMT were determined by means of the method
of the inverse integrals of Kirkwood-Buff (IKBI),<o:p></o:p></span></p> <p
class="MDPI17abstract" style="line-height:200%"><span lang="EN-US" style="font-
size:12.0pt;line-height:200%;font-family:&quot;Times New Roman&quot;,serif">In
general terms, the solubility of SMT is favored by the increase in temperature and the
decrease in the polarity of the cosolvent system, thus the maximum solubility is
reached in pure EG at 318.15 K and the minimum in pure water at 278.15 K. Gibbs
energy is positive in all cases, with a higher contribution from the energy component
(enthalpy of solution). Regarding enthalpy-entropic compensation, the process is
driven in all cases by the enthalpy of solution. Finally, SMT is preferentially solvated by
water in mixtures with higher polarity and by EG in less polar mixtures.</span><span
lang="EN-US" style="font-size:12.0pt;line-height:200%;font-family:&quot;Times New
Roman&quot;,serif; color:windowtext"><o:p></o:p></span></p>

Suggested Reviewers: William Acree, Ph.D

Professor, Associate Chair and Undergraduate Advisor, University of North Texas
[email protected]
Dr Acree is an expert in solution thermodynamics

Abolghasem Jouyban, Ph.D

Professor, Tabriz University of Medical Sciences
[email protected]
Dr. Jouyban is an expert in solution thermodynamics and mathematical models

Lioua Kolsi, Ph.D

Professor, University of Hail
[email protected]
Dr. Kolsi is an expert in solution chemistry

María Ángeles Peña Fernández, Ph.D

Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation
 Professor, Universidad de Alcalá de Henares: Universidad de Alcala de Henares
[email protected]
Dra. Peña is an expert in solution thermodynamics and cosolvency

Opposed Reviewers:

Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation
Cover Letter

Calle 11 No. 1-51

Universidad Cooperativa de Colombia
Neiva-Huila

December 25, 2020

Professor Heng-Kwong Tsao

Editors in Chief, Journal of the Taiwan Institute of Chemical Engineers

Dear Prof.
Please find attached the corrected version of the manuscript “ Solution thermodynamics and preferential solvation
of sulfamethazine in ethylene glycol + water mixtures” (Ref: JTICE-D-20-01519), written by Abdelkarim Aydi,
Claudia Patricia Ortiz, Diego Ivan Caviedes Rubio Cherifa Ayadi, Souhaira Hbaieb and Daniel Ricardo Delgado.
First, we would like to thank you and the reviewers for the helpful suggestions. This new version was arranged in
line with the suggestions made by the reviewers. It is important to note that these changes allowed us to improve our
work. All the changes have been indicated in red font in the new version.
Comments from the editors and reviewers:

Reviewer #1:

1. In the Abstract part, line 13, ". . . van Hoff equations" should be written as ". . . van´t Hoff equations". Also,
in the Keywords, the phrase "solution thermodynamic" should be corrected. There are other typical errors
throughout the manuscript so it needs revising.
Response: Words and phrases were corrected, and the document was reviewed (Page 2)
2. Above the Fig. 1, line 17, please write the full form of abbreviation LD50.
Response: The abbreviation has been replaced by the full form (Page 3)
3. It is stated in section 3.1, line 5, that the dissolution data of SMT in water were taken from Ref. [3]. Why
didn‘t the authors obtain the data themselves so that they could compare their own data with it.
Response: The water solubility data was not determined experimentally, because these data were determined
and published by the research group. Reference 3 corresponds to an article published by the authors of this
manuscript.
4. Present Tables 2 and 5 in a single page. The way the author present the Table 2, the figures are not well
readable. It should be corrected.
Response: Tables 2 and 5 were presented on a single page, table 2 was modified to give greater clarity to the
data. (Pages 7 and 17)
5. Above the Fig. 2, line 24-25, what solvent does the "pure PG" stand for?
Response: The abbreviation "PG" was changed to "EG" (Page 8)
6. In the paragraph below the Fig. 2, figures 27.42 Mpa1∕2 (SMT), (Ethanol: 26.1 MPa1∕2 , n-propanol: 24.9
MPa1∕2 , Acetonitrile: 24.8 MPa1∕2 ) does not represent the polarity! They are probably Hildbrands’ solubility
parameter. The authors should check and modify the related sentence.
Response: We agree with the reviewer, therefore, the expression "polarity" is changed to "solubility parameter"
(Pages 8 and 9)
7. In the paragraph below the Fig. 3, lines 35-37, explain the "sodium phase"?
Response: The word "sodium" was replaced by "solid" (Page 10)
8. Figs. 4 and 5 are unclear. The authors should give more explanations about these Figs to clarify them for the
reader.
Response: The results presented in Figures 4 and 5 are described in more detail. (Pages 14, 15 and 19)
9. In the paragraph above the Fig. 6, lines 15-18, "positive slope" and "entropic conduction" are probably
incorrect, because they are in contradiction to what is claimed in lines 6-9.
Response: The reviewer’s assessment is correct, the conduction is enthalpy. (Page 20)
 10. In the ref. part, the number of self-citations for "Delgado DR" are pretty much (8 vs 40 or 20% of all refs.).
Response: The percentage of self-citation was reduced from 20% to 13%.

Reviewer #3: In discussing the differential scanning calorimetric data the authors stated "However, in the present
study the thermograms show a similar endothermic peak in all DSC analyses, which indicates that in the MeCN +
water cosolvent mixtures, as in MeCN + N cosolvent mixtures [3] these transitions or solvates do not appear." I think
that there are several errors in the statement. For one thing the mixtures that are being studied are aqueous-ethylene
glycol cosolvent mixtures, and not MeCN + water. Second, I am not sure what chemical the " + N" is referring to in
the second binary mixture.

Also, in the manuscript text immediately below Figure 3, the authors mention a sodium phase in equilibrium with
water . . . . . . .. Is this text correct? What does a sodium phase have to do with the experimental solubility study?

Response: The first cosolvent mixture was corrected, modifying "MeCN + W" by "EG + W", the letter "N" was
also changed to "W" (water) in the second cosolvent mixture. Finally, the phrase "sodium phase" was modified to
"solid phase" (Pages 9 and 10)

Sincerely,

Prof. Daniel Ricardo Delgado PhD

Universidad Cooperativa de Colombia
[email protected]

2
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Detailed Response to Reviewers

Calle 11 No. 1-51

Universidad Cooperativa de Colombia
Neiva-Huila

December 25, 2020

Reviewers
Journal of the Taiwan Institute of Chemical Engineers

Dear Reviewers
Next, I present the corrections suggested by each of the reviewers (1 and 3) to the manuscript: Solution thermody-
namics and preferential solvation of sulfamethazine in ethylene glycol + water mixtures, (Ref: JTICE-D-20-
01519).
The authors, we appreciate the valuable contribution of the reviewers to our manuscript.
This new version was arranged in line with the suggestions made by the reviewers. It is important to note that these
changes allowed us to improve our work. All the changes have been indicated in red font in the new version.
Comments from the editors and reviewers:

Reviewer #1:

1. In the Abstract part, line 13, ". . . van Hoff equations" should be written as ". . . van´t Hoff equations". Also,
in the Keywords, the phrase "solution thermodynamic" should be corrected. There are other typical errors
throughout the manuscript so it needs revising.
Response: Words and phrases were corrected, and the document was reviewed (Page 2)
2. Above the Fig. 1, line 17, please write the full form of abbreviation LD50.
Response: The abbreviation has been replaced by the full form (Page 3)
3. It is stated in section 3.1, line 5, that the dissolution data of SMT in water were taken from Ref. [3]. Why
didn‘t the authors obtain the data themselves so that they could compare their own data with it.
Response: The water solubility data was not determined experimentally, because these data were determined
and published by the research group. Reference 3 corresponds to an article published by the authors of this
manuscript.
4. Present Tables 2 and 5 in a single page. The way the author present the Table 2, the figures are not well
readable. It should be corrected.
Response: Tables 2 and 5 were presented on a single page, table 2 was modified to give greater clarity to the
data. (Pages 7 and 17)
5. Above the Fig. 2, line 24-25, what solvent does the "pure PG" stand for?
Response: The abbreviation "PG" was changed to "EG" (Page 8)
6. In the paragraph below the Fig. 2, figures 27.42 Mpa1∕2 (SMT), (Ethanol: 26.1 MPa1∕2 , n-propanol: 24.9
MPa1∕2 , Acetonitrile: 24.8 MPa1∕2 ) does not represent the polarity! They are probably Hildbrands’ solubility
parameter. The authors should check and modify the related sentence.
Response: We agree with the reviewer, therefore, the expression "polarity" is changed to "solubility parameter"
(Pages 8 and 9)
7. In the paragraph below the Fig. 3, lines 35-37, explain the "sodium phase"?
Response: The word "sodium" was replaced by "solid" (Page 10)
8. Figs. 4 and 5 are unclear. The authors should give more explanations about these Figs to clarify them for the
reader.
Response: The results presented in Figures 4 and 5 are described in more detail. (Pages 14, 15 and 19)
9. In the paragraph above the Fig. 6, lines 15-18, "positive slope" and "entropic conduction" are probably
incorrect, because they are in contradiction to what is claimed in lines 6-9.
Response: The reviewer’s assessment is correct, the conduction is enthalpy. (Page 20)
 10. In the ref. part, the number of self-citations for "Delgado DR" are pretty much (8 vs 40 or 20% of all refs.).
Response: The percentage of self-citation was reduced from 20% to 13%.

Reviewer #3: In discussing the differential scanning calorimetric data the authors stated "However, in the present
study the thermograms show a similar endothermic peak in all DSC analyses, which indicates that in the MeCN +
water cosolvent mixtures, as in MeCN + N cosolvent mixtures [3] these transitions or solvates do not appear." I think
that there are several errors in the statement. For one thing the mixtures that are being studied are aqueous-ethylene
glycol cosolvent mixtures, and not MeCN + water. Second, I am not sure what chemical the " + N" is referring to in
the second binary mixture.

Also, in the manuscript text immediately below Figure 3, the authors mention a sodium phase in equilibrium with
water . . . . . . .. Is this text correct? What does a sodium phase have to do with the experimental solubility study?

Response: The first cosolvent mixture was corrected, modifying "MeCN + W" by "EG + W", the letter "N" was
also changed to "W" (water) in the second cosolvent mixture. Finally, the phrase "sodium phase" was modified to
"solid phase" (Pages 9 and 10)

Sincerely,

Prof. Daniel Ricardo Delgado PhD

Universidad Cooperativa de Colombia
[email protected]

2
Highlight (for review)

Highlights:

 The decrease in the polarity of the system leads to an increase in the solubility of
sulfamethazine.
 The sulfamethazine solution process is endothermic.
 The analysis of DSC, show that there are no polymorphic transitions in the different
cosolvent mixtures
 Ethylene glycol has a positive cosolvent effect in the solubility of sulfamethazine.
 sulfamethazine is preferentially solvated by ethylene glycol in less polar mixtures.
Manuscript Click here to view linked References

Solution thermodynamics and preferential solvation of sulfamethazine in ethylene

1
2 glycol + water mixtures
3
4
5 Abdelkarim Aydi1,2, Claudia Patricia Ortiz3, Diego Ivan Caviedes Rubio4 Cherifa
6
7
8 Ayadi5,6, Souhaira Hbaieb7 and Daniel Ricardo Delgado4*
9
10
11
1
Université Paris-Sud, LETIAM, Lip (Sys)2, IUT d’Orsay, Plateau de Moulon, 91400
12
13 Orsay, France
14
15 2
16
Laboratory of Materials Molecules and Applications, Preparatory Institute for Scientific
17
18 and Technical Studies, University of Carthage, Tunisia.
19
20 3
Corporación Universitaria Minuto de Dios-UNIMINUTO, Programa de Administración
21
22
23 en Seguridad y Salud en el Trabajo, Grupo de Investigación en Seguridad y Salud en el
24
25 Trabajo, Neiva, Huila, Colombia.
26
27 4
28 Universidad Cooperativa de Colombia, Sede Neiva, Facultad de Ingeniería, Programa de
29
30 Ingeniería Industrial, Grupo de Investigaciones GRIAUCC, Calle 11 No. 1-51, Neiva-
31
32
33 Huila, Colombia.
34
5
35 Laboratory of Materials, Treatment and Analysis (LMTA), National Institute of Research
36
37
38
and Physicochemical Analysis (INRAP), BiotechPole Sidi-Thabet, Ariana 2020,
39
40 Tunisia.
41
42 6
Faculté des Sciences de Tunis, Université Tunis El Manar, Campus Universitaire El
43
44
45 Manar, Tunis 2092, Tunisia
46
47 7
Université Tunis El Manar, Faculté des Sciences de Tunis, LR/18/ES/08
48
49
50 "Caractérisations, Applications et Modélisation de Matériaux", 2092, Tunisia.
51
*
52 Corresponding autor: [email protected]
53
54
55
56
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58
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60
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 Abstract
1
2
3 The solubility of sulfamethazine (SMT) in ethylene glycol (EG) + water (W) cosolvent
4
5
6 mixtures was determined at nine temperatures (278.15, 283.15, 288.15, 293.15, 298.15,
7
8 303.15, 308.15, 313.15 and 318.15 K) by means of the stirring method. From the solubility
9
10
11 data, the thermodynamic functions of solution, transfer and mixing were calculated using
12
13 the Gibbs and van´t Hoff equations. On the other hand, the preferential solvation parameters
14
15
16
of SMT were determined by means of the method of the inverse integrals of Kirkwood-Buff
17
18 (IKBI). In general terms, the solubility of SMT is favored by the increase in temperature
19
20 and the decrease in the polarity of the cosolvent system, thus the maximum solubility is
21
22
23 reached in pure EG at 318.15 K and the minimum in pure water at 278.15 K. Gibbs energy
24
25 is positive in all cases, with a higher contribution from the energy component (enthalpy of
26
27
28 solution). Regarding enthalpy-entropic compensation, the process is driven in all cases by
29
30 the enthalpy of solution. Finally, SMT is preferentially solvated by water in mixtures with
31
32
33 higher polarity and by EG in less polar mixtures.
34
35
36 Keywords: Sulfamethazine; solubility; preferential solvation, van´t Hoff, solution
37
38
39
thermodynamics.
40
41
42 1. Introduction
43
44
45
46
Sulfamethazine (Figure 1) (4-amino-N-(4,6-dimethylpyrimidin-2-
47
48 yl)benzenesulfonamide; (C12H14N4O2S; CAS: 57-68-1), is a long-acting bacteriostatic agent,
49
50 used both in human and animal therapy[1,2] due to its wide spectrum against Gram positive
51
52
53 and Gran negative bacteria[3]. Its massive use, especially in veterinary products, has made
54
55 SMT an emerging, highly dangerous contaminant[4], which has led to develop studies that
56
57
58 point to the development of more efficient industrial processes and the generation of
59
60 information for the treatment of these pollutants.
61
62
63
64
65
 In this sense, one of the most relevant studies that provides essential data for the optimization
1
2 of processes in the pharmaceutical industry are solubility studies, since these intervene in
3
4
5 formulation, pre-formulation, crystallization, dosage, stability processes, among others[5]; in
6
7 addition, these data are essential for the development of mathematical models, which are the
8
9
10 best tool for optimizing processes, tending to reduce the use of resources, therefore, leading
11
12 on reducing the potential environmental impact generated by the pharmaceutical industry.
13
14
15
Moreover, the solubility data are implemented in the development of models that allow the
16
17 calculation of data such as bioavailability, lethal dose 50%, and partition coefficient, which
18
19 have great biological and environmental importance[5,6].
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37 Figure 1. Molecular structure of the sulfamethazine
38
39
40 In this order of ideas, thermodynamic analysis from solubility data is another important line
41
42
43 of research, which leads to rationalize industrial processes, thus, the calculation of
44
45 thermodynamic functions, through Gibbs and van´t Hoff equations, allow us to understand
46
47
48
the molecular interactions that occur between the solute and the solvent. Deepening the
49
50 understanding of molecular interactions, the analysis of solvation preferences through the
51
52 inverse integrals of Kirkwood-Buff (IKBI) allows understanding the molecular interactions
53
54
55 from a perspective of the close environment of the solute molecule, understanding how it
56
57 interacts preferentially with one or more solvents[7–9].
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 In this context, the objective of this research is to present the solubility data of SMT in
1
2 ethylene glycol + water co-solvent mixtures at 9 temperatures, performing a thermodynamic
3
4
5 analysis and solvation preferences, thus strengthening the theoretical bases regarding the
6
7 physicochemical properties of the solution’s process of this drug.
8
9
10
11 2. Materials and Methods
12
13
14 2.1. Reagents.
15
16
17
18 In this study, SMT (Sigma-Aldrich, USA; compound 3; with purities of at least 0.990 in mass
19
20 fraction), Ethylene glycol (Sigma-Aldrich, USA; the solvent component 1, purity of at least
21
22
23
0.998 in mass fraction), and distilled water with conductivity <2 μS cm–1 (solvent component
24
25 2) were used. Table 1 summarizes the sources and purities of the compounds studied.
26
27
28
29 Table 1. Source and purities of the compounds used in this research.
30
31 Chemical Molar mass/ Purity in Analytic
32 CASa Formula –1
Source
name g mol mass fraction techniqueb
33
34 Sulfametaz Sigma-
57-68-1 C12H14N4O2S 278.33 >0.990 HPLC
35 ine (SMT) Aldrich, USA
36 Ethylene Sigma-
37 107-21-1 HOCH2CH2OH 62.07 0.998 GC
38 glycol Aldrich, USA
39 7732-18- Obtained by
40 Water H 2O 18.02 >0.999 -
5 distillation
41
42 a
43
Chemical Abstracts Service Registry Number.
44
45 b
HPLC is high-liquid-performance chromatography; GC is gas chromatography.
46
47
48
49
50 2.2. Preparation of solvent mixtures
51
52
53 The procedure is similar to that used in other investigations of the research group[3], So all
54
55
56 {EG (1) + water (2)} solvent mixtures were prepared by mass in quantities of 20.00 g, using
57
58 an analytical balance with sensitivity ± 0.1 mg (RADWAG AS 220.R2, Poland). The mass
59
60
61 fractions of (1), w1, of the nine mixtures prepared varied by 0.05 from 0.05 to 0.95.
62
63
64
65
 2.3. Solubility determination
1
2
3 The procedure is similar to the one developed in previous work by the research group[10].
4
5 The Higuchi and Connors[11] flask shaking method was implemented. Thus, adding an
6
7
8 amount of SMT to 20 ml of solvent or co-solvent mixture, until obtaining a solid phase of
9
10 the drug in equilibrium with the saturated solution after having subjected the system to
11
12
13 ultrasound for at least 30 minutes. The equilibrium time at each study temperature was 36
14
15 hours. The determination of solubility was carried out by UV/vis spectrophotometry, taking
16
17
a sample of each drug, filtering this sample through membranes with a pore size of 0.45 µm
18
19
20 (Millipore Corp. Swinnex-13, USA) and making the respective dilutions with NaOH at 0.1
21
22 to avoid drug precipitation.
23
24
25 2.4. Calorimetric study
26
27
28
29 The temperature and melting enthalpy of five SMT samples were determined using
30
31 differential scanning calorimetric (DSC) (DSC 204 F1 Phoenix, Germany) (original sample,
32
33
34 solid phase in equilibrium with saturated water, solid phase in equilibrium with saturated EG,
35
36 and solid phase in equilibrium with saturated mixture of w1 = 0.50).
37
38
39 The samples were weighed using 5–10 mg of the drug in an aluminum crucible and placed
40
41
42
inside the calorimeter with nitrogen current (10 mL/min). The samples were subjected to a
43
44 temperature program in which they were heated from an initial temperature of 303.15 K to a
45
46 temperature 480.15 K above the melting point of the analyzed drug, a heating rate of 10
47
48
49 K·min-1. The equipment was calibrated using 99.99% pure Indium.
50
51
52
53
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55
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 3. Results
1
2
3 3.1. Solubility of SMT in EG + W cosolvent mixtures
4
5
6 In Table 2, the solubility of SMT in co-solvent EG+W mixtures is presented at nine
7
8 temperatures (278.15, 283.15, 288.15, 293.15, 298.15, 303.15, 308.15, 313.15 and 318.15
9
10
11 K). The solubility data for SMT in water were taken from Blanco et al[3].
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
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49
50
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15
16
17
18
19
20
21
22 Table 2. Experimental solubility of SMT (3) in EG (1) + W (2) cosolvent mixtures expressed in mole fraction (104x3) at different temperatures.
23 Experimental pressure p: 0.1 MPaa.
24
25 Temperature /K
26 x1 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15
27 d d d d d
28 0.00 0.1138±0.0029 0.1317±0.0018 0.1744±0.0032 0.222±0.001 0.281±0.001 0.367±0.003 0.433±0.001 0.555±0.004 0.6612±0.009
29 0.05 0.1275±0.0023 0.148±0.004 0.1766±0.0020 0.242±0.005 0.307±0.005 0.377±0.010 0.460±0.005 0.562±0.002 0.655±0.020
30
31 0.10 0.154±0.005 0.199±0.002 0.249±0.005 0.315±0.005 0.383±0.001 0.441±0.005 0.539±0.013 0.629±0.017 0.748±0.002
32 0.15 0.2037±0.0016 0.260±0.006 0.321±0.008 0.389±0.010 0.413±0.006 0.545±0.019 0.631±0.020 0.750±0.031 0.972±0.026
33
34 0.20 0.2437±0.0006 0.294±0.005 0.357±0.006 0.434±0.008 0.480±0.006 0.628±0.012 0.748±0.009 0.890±0.030 1.00±0.06
35 0.25 0.2839±0.0031 0.355±0.009 0.416±0.004 0.519±0.010 0.579±0.002 0.729±0.019 0.867±0.022 0.972±0.011 1.23±0.04
36
37 0.30 0.362±0.009 0.423±0.011 0.498±0.023 0.637±0.013 0.687±0.011 0.883±0.016 1.06±0.04 1.25±0.05 1.43±0.03
38 0.35 0.436±0.011 0.538±0.009 0.626±0.013 0.789±0.014 0.871±0.023 1.104±0.020 1.34±0.05 1.499±0.016 1.63±0.03
39
40 0.40 0.558±0.019 0.627±0.008 0.738±0.027 0.921±0.020 1.12±0.06 1.35±0.06 1.50±0.07 1.833±0.024 2.00±0.06
41 0.45 0.670±0.017 0.873±0.014 1.034±0.023 1.251±0.033 1.280±0.033 1.71±0.04 1.96±0.06 2.30±0.04 2.56±0.04
42
0.50 0.851±0.017 1.026±0.027 1.212±0.020 1.461±0.025 1.62±0.06 2.09±0.07 2.29±0.04 2.84±0.08 3.048±0.009
43
44 0.55 1.08±0.04 1.281±0.024 1.584±0.037 1.842±0.033 1.96±0.05 2.60±0.09 2.81±0.10 3.46±0.04 4.05±0.07
45
0.60 1.284±0.033 1.62±0.08 1.87±0.06 2.09±0.03 2.31±0.07 3.01±0.04 3.47±0.06 4.13±0.11 4.78±0.14
46
47 0.65 1.69±0.08 1.96±0.09 2.62±0.07 2.74±0.05 3.01±0.07 4.02±0.17 4.62±0.08 5.48±0.12 5.93±0.27
48
0.70 2.24±0.09 2.53±0.06 3.04±0.12 3.33±0.11 3.86±0.13 4.89±0.05 5.58±0.11 6.61±0.16 7.46±0.05
49
50 0.75 3.23±0.06 3.39±0.05 3.78±0.13 4.49±0.08 5.55±0.08 6.26±0.08 7.30±0.10 8.70±0.20 9.36±0.019
51 0.80 4.12±0.05 5.11±0.13 5.53±0.12 6.50±0.08 7.40±0.10 8.43±0.15 9.30±0.16 10.14±0.24 11.37±0.09
52
53 0.85 5.25±0.11 6.08±0.10 7.08±0.06 7.67±0.20 9.06±0.29 9.98±0.05 11.26±0.31 12.56±0.14 13.5±0.4
54 0.90 6.849±0.033 8.09±0.10 9.31±0.11 10.05±0.16 11.141±0.014 12.77±0.26 13.75±0.14 15.57±0.26 16.91±0.12
55
56 0.95 13.085±0.013 14.29±0.20 15.6±0.3 17.36±0.18 20.0±0.6 21.9±0.6 24.6±0.6 27.4±0.4 29.9±0.9
57 1.00 18.50±0.31 20.6±0.4 22.08±0.21 24.3±0.4 27.8±0.7 31.6±0.7 35.5±0.3 39.1±0.4 40.53±0.06
58
a b
59 The experimental pressure was about 0.096 MPa, a standard uncertainties u(P)= 0.001. w1 is the mass fraction of EG (1) in the EG (1) + W (2)
60 mixtures free of SMT (3). cT is the absolute temperature, Standard uncertainties u is u(T)=0.05 K. dValues from reference[3]
61
62
63
64
65
 1
2
3 The solubility of SMT (Figura 2) rise with increasing temperature, indicating an endothermic
4
5 process, and also increases as the concentration of EG in the mixture increases. Thus, the
6
7
8 lowest solubility is obtained in pure water at 278.15 K and the highest at 318.15 K in pure
9
10 EG
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36 Figure 2. Solubility of sulfamerazine (3) expressed in mole fraction (104x3) in EG (1) + W
37
38
39 (2) cosolvent mixtures as a function of mass fraction of EG at different temperatures. ○:
40
41
42 278.15; ♦: 288.15 K; ●: 298.15 K; ■: 308.15 K and ▲: 318.15 K.
43
44
45
46
47 Delgado et al, have reported the solubility of SMT in different cosolvent systems, among
48
49
50 which are methanol + water[12], ethanol + water[13], n-propanol + water[14],
51
52 acetonitrile + water[3], propylene glycol + water[15]. On co-solvent mixtures where the
53
54
55 solubility parameter of the SMT (27.42 MPa1/2) is greater than the one of the organic
56
57 solvent (Ethanol: 26.1 MPa1/2, n-propanol: 24.9 MPa1/2, Acetonitrile: 24.8 MPa1/2 [16])
58
59
60
the maximum solubility of the drug is reached in a cosolvent mixture with a solubility
61
62 parameter similar to that of the drug; and in mixtures where the solubility parameter of
63
64
65
 the SMT is lower than that of the organic solvent (Methanol: 29.7 MPa1/2 and propylene
1
2 glycol: 30.7 MPa1/2[16]), the maximum solubility is reached in the organic solvent, as
3
4
5 reported on this research. In the EG + W mixture, the maximum solubility is reached in
6
7 the pure EG whose solubility parameter is 34.9 MPa1/2 [16].
8
9
10
11 Figure 3 shows the DSC thermograms of the original SMT sample and of the solid phases
12
13 in equilibrium with the solutions saturated in pure water, w1 = 0.50, and pure EG.
14
15
16
According to previous reports[3], Maury et al., Sorrenti et al., and Zhang et al. reported
17
18 polymorphic transitions and/or solvate formations[17–19]. However, in the present
19
20 study, the thermograms show a similar endothermic peak in all DSC analyses, which
21
22
23 indicates that in EG + W cosolvent mixtures, as in MeCN + W cosolvent mixtures[3]
24
25 these transitions or solvates do not appear.
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59 Figure 3. DSC thermograms of sulfamethazine (Original sample, Pure water, w1 = 0.50,
60
61 and pure EG).
62
63
64
65
 Thus the temperature and enthalpy of fusion of the original sample, the solid phase in
1
2 equilibrium with water, the solid phase in equilibrium with w0.5 and the solid phase in
3
4
5 equilibrium with the EG are 198.3±0.5 °C; 33.9±0.5 kJ.mol-1, 198.5±0.5 °C-34.1±0.5
6
7 kJ.mol-1, 198.3±0.5 °C; 34.0±0.5 kJ.mol-1, 197.9±0.5 °C; 33.8±0.5 kJ.mol-1 y
8
9
10 respectively. The data of the original sample, coincide with those reported by Blanco et
11
12 al. (198.4±0.5 °C; 34.1±0.5 kJ.mol-1)[3]
13
14
15
16
On the other hand, the values presented in this work are similar to those reported by other
17
18 researchers. So, Delgado et al 196.1±0.2 °C; 34.1±0.5 kJ.mol-1[12]; Hamada et al
19
20 200±0.3 °C; 33.96 kJ.mol-1[20], Sunwoo and Eisen 198.45 °C; 31.12 kJ.mol-1 [21],
21
22
23 Bustamante et al 198.5 °C; 31.12 kJ.mol-1 [22], Martínez and Gómez 195.85 °C; 39.22
24
25 kJ.mol-1 [23], Khattab 195.45 °C; 44.81 kJ.mol-1[24], Maury et al. 197-198 °C [17] and
26
27
28 Lu and Rohani, 199.05 °C[25]
29
30
31 3.2. Activity coefficients
32
33
34
35 The activity coefficients (Table 3) are a measure of the deviation from the ideality of
36
37
38 the process[26], which is calculated using equation 1. From the activity coefficients,
39
40
41
it is possible to infer about the solute-solvent molecular interactions using equation
42
43 2.
44
45
46
47 𝛾3 = 𝑥3id 𝑥3−1 (1)
48
49
50
51 ln 𝛾3 = (𝑒11 + 𝑒33 − 2𝑒13 )(𝑉3 𝜙12 ⁄𝑅𝑇) (2)
52
53
54
55
56 x3id is the ideal solubility, which was taken from the literature [4]; x 3 is the
57
58
59
experimental solubility (Table 2); e11, e33 and e13 represent the molecular interactions
60
61 solvent-solvent, solute-solute and solute-solvent respectively[27]. V3 represents the
62
63
64
65
 molar volume of the sub-cooled solute (cm3/mol) and ϕ1 is the volume fraction of the
1
2
3 solvent. Thus, e11 and e33 are factors that disadvantage the SMT solution process,
4
5
6 while e13 favors the solution process.
7
8
9 According to the data presented on Table 3, the activity coefficients decrease as the
10
11
12 EG concentration increases, in addition it also decreases due to the increase in
13
14
15 temperature. Therefore, the addition of EG favors the solute-solvent iterations,
16
17
18 possibly because there is a better affinity between SMT and EG. Although in water-
19
20
21 rich mixtures, the activity coefficients are very large, possibly due to the structuring
22
23 of the water around the non-polar groups of the SMT[28], from w1 = 0.5, there is a
24
25
26 significant decrease in the coefficients of activity, until reaching a value very close
27
28
29 to unity in pure EG, indicating an almost ideal behavior.
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
 Table 3. Coefficient activity of SMT (3) in EG (1) + W (2) cosolvent mixtures at
1
2
3 different temperatures and pressure p = 0.096 MPaa.
4
5
6 Temperature/Kc
7 w1 b
8 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15
9 0.00 242.3 249.3 223.3 207.6 193.5 174.3 173.3 158.2 166.1
10
11 0.05 216.3 221.6 220.6 190.1 176.9 169.6 163.2 156.2 156.5
12 0.10 178.8 165.0 156.7 146.4 142.0 144.9 139.3 139.5 137.0
13
14 0.15 135.4 126.4 121.4 118.4 131.5 117.3 119.0 117.1 105.4
15 0.20 113.2 111.8 109.0 106.2 113.2 101.8 100.4 98.7 100.1
16
17
0.25 97.2 92.4 93.6 88.9 93.9 87.7 86.5 90.4 83.1
18 0.30 76.1 77.6 78.1 72.3 79.1 72.4 71.1 70.1 71.6
19 0.35 63.3 61.1 62.3 58.4 62.4 57.9 56.1 58.6 63.1
20
21 0.40 49.4 52.4 52.8 50.0 48.3 47.5 49.9 47.9 51.3
22 0.45 41.2 37.6 37.7 36.8 42.5 37.3 38.3 38.1 40.0
23
24 0.50 32.4 32.0 32.1 31.5 33.6 30.7 32.7 31.0 33.6
25 0.55 25.5 25.6 24.6 25.0 27.7 24.6 26.7 25.4 25.3
26
27
0.60 21.5 20.3 20.8 22.0 23.6 21.3 21.6 21.3 21.4
28 0.65 16.3 16.7 14.9 16.8 18.0 15.9 16.2 16.0 17.3
29 0.70 12.3 13.0 12.8 13.8 14.1 13.1 13.4 13.3 13.7
30
31 0.75 8.5 9.7 10.3 10.3 9.8 10.2 10.3 10.1 11.0
32 0.80 6.7 6.4 7.0 7.1 7.3 7.6 8.1 8.7 9.0
33
34 0.85 5.3 5.4 5.5 6.0 6.0 6.4 6.7 7.0 7.6
35 0.90 4.0 4.1 4.2 4.6 4.9 5.0 5.5 5.6 6.1
36
37
0.95 2.1 2.3 2.5 2.7 2.7 2.9 3.0 3.2 3.4
38 1.00 1.5 1.6 1.8 1.9 2.0 2.0 2.1 2.2 2.5
39
40 a
The experimental pressure was about 0.096 MPa, a standard uncertainties u(P)=
41
42
43 0.001.
44
45
46 w1 is the mass fraction of EG (1) in the EG (1) + W (2) mixtures free of SMT (3).
b

47
48
49
c
T is the absolute temperature, Standard uncertainties u is u(T)=0.05 K.
50
51
52
53
54
55 3.3. Thermodynamic functions of solution
56
57
58 From the experimental solubility data (Table 2), the solution thermodynamic functions are
59
60 calculated, using the equations proposed by Gibbs and van´t Hoff, modified by Krug[29,30]:
61
62
63
64
65
 𝜕 ln 𝑥3 (3)
1 Δsoln 𝐻 𝑜 = −𝑅 −1 )
2 𝜕(𝑇 −1 − 𝑇hm
3
4
5
6
Δsoln 𝐺 𝑜 = −𝑅𝑇hm × intercept (4)
7
8
−1
9 Δsoln 𝑆 𝑜 = (Δsoln 𝐻 𝑜 − Δsoln 𝐺 𝑜 )𝑇hm (5)
10
11
12
13 𝜉𝐻 = |Δsoln 𝐻 𝑜 |[|Δsoln 𝐻 𝑜 | + |𝑇Δsoln 𝑆 𝑜 |]−1 (6)
14
15
16 𝜉𝑇𝑆 = |𝑇Δsoln 𝑆 𝑜 |[|Δsoln 𝐻 𝑜 | + |𝑇Δsoln 𝑆 𝑜 |]−1 (7)
17
18
19
20 Where G, H and S are the Gibbs energy, the enthalpy, and the entropy respectively, Thm is
21
22 the harmonic mean of the study temperatures and R is the gas constant. ξH y ξTS are the
23
24
25
contributions of the enthalpy and entropy to the Gibbs energy of solution.
26
27
28
Table 4 shows the thermodynamic functions of solution of the SMT in the EG + W cosolvent
29
30 system. The Gibbs energy is positive in all cases, decreasing from water to pure EG, due to
31
32 the positive cosolvent effect of EG on SMT solubility. As for the standard enthalpy of
33
34
35 solution, it is positive in all cases indicating an endothermic process, unlike what usually
36
37 occurs in organic solvent + water systems where an initial increase of enthalpy occurs,
38
39
40 possibly due to the structuring of the water around the non-polar groups of the SMT[3,13];
41
42 in this case, the enthalpy decreases from pure water to pure EG.
43
44
45 The solution entropy decreases from pure water to the co-solvent mixture w1=0.9 where it
46
47
48
reaches negative values, from this mass fraction of EG to pure EG there is an increase in
49
50 entropy. Finally, from equations 6 and 7 it can be inferred that the greatest contributor to
51
52 Gibbs energy is the energy factor (enthalpy of solution), which in most cases is greater than
53
54
55 82%.
56
57
58
59
60
61
62
63
64
65
 Table 4. Thermodynamic functions of solution of SMT (3) in EG (1) + W (2) cosolvent
1
2 mixtures at 297.6 K and pressure p = 0.096 MPaa.
3
4
5 ΔsonlGo/kJ mol- ΔsonlHo/kJ mol- ΔsonlSo/J mol-1K- TΔsonlSo/kJ mol-
6 w1 b 1 1 1 1 ξH ξTS
7
8 0.00 26.0±0.2 32.9±0.4 23.3±0.4 6.91±0.11 0.826 0.174
9
10 0.05 25.8±0.5 31.7±0.5 19.6±0.5 5.84±0.14 0.844 0.156
11 0.10 25.3±0.4 28.7±0.4 11.25±0.24 3.35±0.07 0.895 0.105
12 0.15 24.8±0.6 27.3±0.6 8.31±0.27 2.47±0.08 0.917 0.083
13
14 0.20 24.5±0.5 26.6±0.4 7.11±0.19 2.12±0.06 0.920 0.080
15 0.25 24.1±0.4 26.3±0.4 7.35±0.17 2.19±0.05 0.923 0.077
16
17 0.30 23.6±0.7 25.9±0.5 7.93±0.26 2.36±0.08 0.917 0.083
18 0.35 23.1±0.5 25.1±0.4 6.69±0.19 1.99±0.06 0.926 0.074
19
20 0.40 22.6±0.7 24.9±0.5 7.57±0.29 2.25±0.09 0.917 0.083
21 0.45 22.0±0.5 24.2±0.5 7.62±0.24 2.27±0.07 0.915 0.085
22
0.50 21.5±0.5 24.0±0.4 8.45±0.23 2.52±0.07 0.905 0.095
23
24 0.55 20.9±0.5 23.9±0.5 10.02±0.32 2.98±0.10 0.889 0.111
25 0.60 20.5±0.6 23.7±0.6 10.6±0.4 3.16±0.11 0.882 0.118
26
27 0.65 19.9±0.6 23.6±0.7 12.5±0.5 3.73±0.16 0.863 0.137
28 0.70 19.3±0.5 22.8±0.5 11.7±0.4 3.47±0.12 0.868 0.132
29
30 0.75 18.6±0.3 21.4±0.6 9.32±0.30 2.77±0.09 0.885 0.115
31 0.80 17.91±0.31 18.25±0.32 1.136±0.028 0.338±0.008 0.982 0.018
32
0.85 17.4±0.3 17.59±0.27 0.548±0.014 0.163±0.004 0.991 0.009
33
34 0.90 16.82±0.19 16.22±0.24 -2.03±0.04 -0.605±0.011 0.964 0.036
35 0.95 15.41±0.29 15.68±0.29 0.893±0.024 0.266±0.007 0.983 0.017
36
37 1.00 14.56±0.21 15.4±0.3 2.87±0.08 0.855±0.022 0.947 0.053
38
a
39 The experimental pressure was about 0.096 MPa, a standard uncertainties u(P)= 0.001.
40
41 b
42 w1 is the mass fraction of EG (1) in the EG (1) + W (2) mixtures free of SMT (3).
43
44 A graph that allows verifying the results obtained through equations 6 and 7 is the one
45
46
47 presented by Pércovich et al[31,32] (Figure 4), which consists of a plot (T∆solnSo vs ∆solnHo)
48
49 of 8 triangular sectors; four sectors (I, IV, V and VIII) where the absolute value of ∆solnHo is
50
51
52 greater than the absolute value of T∆solnSo, indicating enthalpy conduction, and four other
53
54 sectors (II, III, VI and VII) where the absolute value of ∆solnHo is less than the value absolute
55
56
57 of T∆solnSo, indicating entropy conduction
58
59
60
61
62
63
64
65
 1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28 Figure 4. Relation between enthalpy (∆solnHo) and entropy (T∆solnSo) terms of the process of
29
30 SMT solution in EG (1) + water (2) cosolvent mixtures at 297.6 K. The isoenergetic curves
31
32
33 for ∆solnGo are represented by dotted lines
34
35
36 Thus, from pure water to w1=0.85 and from w1=0.95 to pure EG (Sector I: (∆solnHo>
37
38
39 T∆solnSo>0) the process is driven by enthalpy as is the point w1=0.90, unique negative point
40
41
42 located in sector VIII (∆solnHo<0, T∆solnSo<0, |∆solnHo|>|T∆solnSo|).
43
44
45 This is due to the fact that the absolute value of the ∆solnHo is greater than the absolute value
46
47
48 of T∆solnSo, so that the values of the Gibbs energy of solution depend in greater proportion
49
50
51 of the enthalpy[32].
52
53
54 3.4. Thermodynamic transfer functions
55
56
57
58 From the thermodynamic transfer functions, the cosolvent effect of EG on the
59
60
61 solubility of SMT can be identified. Starting from a hypothetical process of transfer
62
63
64
65
 from a higher polarity system to a lower polarity system, expressed
1
2
3 mathematically as[33]:
4
5
6 𝑜 𝑜
7 𝛥𝑡𝑟 𝑓 𝑜 = 𝛥soln 𝑓less polar − 𝛥soln 𝑓more polar (8)
8
9
10
11
12
13
14 Being f, the solution functions (Gibbs Energy, Enthalpy or Entropy).
15
16
17
18
19
20 Table 5 shows the transfer functions of the SMT, in all cases the Gibbs energy of
21
22
transfer is negative, indicating the affinity of the SMT by less polar means, which
23
24
25 implies that the EG has a positive cosolvent effect. Thus from w0.00→ w0.25 the transfer
26
27
28 process is favored by enthalpy, but presents entropic disadvantage, w0.25→ w0.30, the
29
30
31 transfer process is favored by enthalpy and entropy, w0.30→ w0.35, again presents
32
33
34 enthalpy favoring and entropic disadvantage, w0.35→ w0.65 the process presents
35
36
37 enthalpic and entropic favoring, w0.65→ w0.90, the transfer process is favored by
38
39
40 enthalpy but presents entropic disadvantage, finally w0.90→ w1.0 again the process is
41
42
43 favored by both enthalpy and entropy.
44
45
Thus, in all cases, enthalpy promotes the transfer of SMT from the more polar
46
47
48 solvent or cosolvent mixture to the lower polarity medium. As the entropy presents
49
50
51 an intermittent favoring, however, it is clear the influence of the enthalpy allows the
52
53
54 transfer process to occur.
55
56
57
58
59
60
61
62
63
64
65
 1 Table 5. Thermodynamic functions of transfer of SMT (3) in EG (1) + W (2) cosolvent
2
3
4 mixtures at 297.6 K and pressure p = 0.096 MPaa.
5
6 More polar→less TΔtrSo/kJ mol-
7 ΔtrGo/kJ mol-1 ΔtrHo/kJ mol-1 ΔtrSo/J mol-1K-1
polar 1
8
bw0.00→ w0.25 -1.9±0.5 -6.7±0.6 -15.9±0.4 -4.73±0.09
9
10 w0.25→ w0.30 -0.5±0.8 -0.3±0.6 0.58±0.31 0.17±0.09
11
12 w0.30→ w0.35 -0.5±0.8 -0.9±0.6 -1.24±0.32 -0.37±0.10
13 w0.35→ w0.65 -3.2±0.8 -15±0.5 5.8±0.6 1.74±0.17
14
15
w0.65→ w0.90 -3.0±0.7 -7.4±0.7 -14.6±0.5 -4.33±0.16
16 w0.90→ w1.0 -2.26±0.28 -0.8±0.4 4.91±0.08 1.46±0.03
17
18 a
The experimental pressure was about 0.096 MPa, a standard uncertainties u(P)=
19
20
21 0.001.
22
23
24 w1 is the mass fraction of EG (1) in the EG (1) + W (2) mixtures free of SMT (3).
b

25
26
27 3.5. Thermodynamic mixing functions
28
29
30
31
Hypothetical stages of the SMT dissolution process is: [14].
32
33
34 Solute(solid) at T → Solute(solid) at Tfus → Solute(liquid) at Tfus → Solute(liquid) at T → Solute(solution)
35
36 at T
37
38
39 Thus, the solution process can be expressed mathematically as:
40
41
42 𝛥soln 𝑓 𝑜 = 𝛥𝑓 𝑓 𝑜 + 𝛥mix 𝑓 𝑜 (9)
43
44
45
46 Where f, represents the thermodynamic functions G, H or S, and the subscripts f and mix
47
48
49 indicate fusion and mixing, respectively.
50
51
52 Table 6 shows the thermodynamic mixing functions, in all cases the mixing Gibbs energy is
53
54
55 positive, so the solution process is driven by the fusion functions. Bearing in mind that for
56
57
58 the mixing process to occur, the solvent molecules must be reorganized to form a cavity that
59
60
61 houses the solute, a process that is endothermic, since energy must be supplied to counteract
62
63
64
65
 1 the cohesive forces of the solvent molecules, thus The decrease in the values of both the
2
3
4 Gibbs energy and the enthalpy, indicate that the addition of EG promotes the formation of
5
6
7
the cavity, which is consistent with the increase in the solubility of SMT as the concentration
8
9 of EG increases, this It also implies that the solvent-solvent molecular interactions (e11)
10
11
12 decrease with the addition of EG, just as the solute-solvent interactions (e13) increase.
13
14
15 In general, from pure water up to w1=0.45, both the enthalpy and the entropy of the mixture
16
17
18 disfavor the solution process, from w1=0.45 to the pure EG, the enthalpy of the mixture favors
19
20
21 the solution process, however, entropic disadvantage continues.
22
23
24 Table 6. Thermodynamic functions of mixing SMT (3) in EG (1) + W (2) cosolvent
25
26
27 mixtures at 297.6 K and pressure p = 0.096 MPaa.
28
29 w1 b ΔmixGo/kJ mol-1 ΔmixHo/kJ mol-1 ΔmixSo/J mol-1K-1 TΔmixSo/kJ mol-1
30 0.00 13.06±0.06 8.8±05 -14.4±0.5 -4.30±0.14
31 0.05 12.9±0.5 7.5±0.6 -18.1±0.6 -5.38±0.17
32
0.10 12.4±0.5 4.5±0.4 -26.5±0.4 -7.87±0.12
33
34 0.15 11.9±0.6 3.1±0.6 -29.4±0.4 -8.75±0.12
35 0.20 11.5±0.5 2.4±0.5 -30.6±0.4 -9.11±0.11
36 0.25 11.1±0.4 2.1±0.4 -30.4±0.4 -9.03±0.11
37 0.30 10.7±0.7 1.8±0.5 -29.8±0.4 -8.86±0.12
38
39
0.35 10.1±0.5 0.9±0.5 -31.0±0.4 -9.23±0.11
40 0.40 9.7±0.7 0.7±0.5 -30.1±0.4 -8.97±0.13
41 0.45 9.1±0.5 0.1±0.6 -30.1±0.4 -8.96±0.12
42 0.50 8.6±0.5 -0.1±0.4 -29.3±0.4 -8.71±0.12
43 0.55 8.0±0.5 -0.2±0.5 -27.7±0.4 -8.24±0.13
44
45 0.60 7.6±0.6 -0.5±0.6 -27.1±0.5 -8.07±0.15
46 0.65 6.9±0.6 -0.6±0.7 -25.2±0.6 -7.49±0.18
47 0.70 6.4±0.5 -1.4±0.5 -26.1±0.5 -7.75±0.15
48 0.75 5.7±0.4 -2.8±0.6 -28.4±0.4 -8.45±0.13
49
50
0.80 4.99±0.31 -5.9±0.4 -36.57±0.31 -10.88±0.09
51 0.85 4.5±0.3 -6.56±0.32 -37.16±0.31 -11.06±0.09
52 0.90 3.90±0.20 -7.93±0.29 -39.74±0.31 -11.83±0.09
53 0.95 2.49±0.30 -8.5±0.3 -36.81±0.31 -10.96±0.09
54 1.00 1.63±0.21 -8.7±0.4 -34.84±0.32 -10.37±0.10
55
56 a
57
The experimental pressure was about 0.096 MPa, a standard uncertainties u(P)= 0.001.
58
59 b
w1 is the mass fraction of EG (1) in the EG (1) + W (2) mixtures free of SMT (3).
60
61
62
63
64
65
 1 According to the Perlovich graph (Figure 5), in the mixing process, from water to
2
3
4 w1=0.05 the greatest contributor is the standard mixing enthalpy, because the
5
6
7
absolute value of the enthalpy of mixture is greater than the absolute value of the
8
9 entropy term (Sector VIII: ΔmixHo<0, TΔmixSo<0, |ΔmixHo |>| TΔmixSo |), from w1=0.10
10
11
12 to w1=0.45 (sector VII: ΔmixHo< TΔmixSo, |ΔmixHo |<| TΔmixSo |) the mixing process is
13
14
15 driven by entropy and finally from w1=0.50 to the pure EG (sector VI: ΔmixHo<0,
16
17
18 TΔmixSo<0, |ΔmixHo |<| TΔmixSo |) again the process is driven by entropy, In both
19
20
21 sectors VI and VII, the absolute value of TΔmixSo is greater than the absolute value of
22
23
24 ΔmixHo.[34].
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54 Figure 5. Relationship between the enthalpy (ΔmixHo) and entropy (TΔmixSo) terms
55
56
57 of the mixing process of SMT at 297.6 K. The isoenergetic curves of ΔmixGo are
58
59
60 represented by dotted lines.
61
62
63
64
65
 1
2
3
4 3.6. Enthalpy-entropic compensation
5
6
7
8 The enthalpy-entropic compensation analysis allows identifying the mechanisms involved in
9
10
11
the cosolvent action. Furthermore, this analysis allows us to recognize the thermodynamic
12
13 consequences of the formation of solute-solvent bonds, where the hydrogen bond is the most
14
15
16 important interaction[35–37].
17
18
19 This analysis is performed by plotting ΔsolnHo vs ΔSolnGo, where negative slopes indicate
20
21
22 processes driven by entropy and positive slopes indicate processes driven by enthalpy[38,39].
23
24
25 Figure 6 presents the enthalpy-entropic compensation of the SMT solution process in EG +
26
27
28 W co-solvent mixtures. A non-linear behavior with a positive slope can be observed in all
29
30
31 cases, indicating an enthalpy conduction of the solution process.
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55 Figure 6 Enthalpy-entropy compensation plot for the solubility of SMT (3) in EG (1) + W
56
57
58 (2) mixtures at Thm = 297.6 K.
59
60
61
62
63
64
65
 3.7. Preferential solvation
1
2
3
4 Preferential solvation analysis allows identifying the local composition of the solvation
5
6
7 sphere surrounding the solute molecule. Ben-Naim, presents an approach called Inverse
8
9
Integrals of Kirkwood-Buff integral (IKBI), which assesses solvation as a function of the
10
11
12 preferential solvation parameter δx1,3[40,41]
13
14
15 The mathematical development of the IKBI approach is presented as:
16
17 −1
18 𝛿𝑥1,3 = [𝑥1 (1 − 𝑥1 )(𝐺1,3 − 𝐺2,3 )][𝑥1 𝐺1,3 + (1 − 𝑥1 )𝐺2,3 + 𝑉𝑐𝑜𝑟 ] (10)
19
20
21
22 𝐺1,3 = 𝑅𝑇𝜅𝑇 − 𝑉3 + (1 − 𝑥1 )𝑉2 𝐷𝑄 −1 (11)
23
24
25 𝐺2,3 = 𝑅𝑇𝜅𝑇 − 𝑉3 + 𝑥1 𝑉1 𝐷𝑄 −1 (12)
26
27
28
29 3
3
𝐿 𝐿
30 𝑉cor = 2522.5 [𝑟3 − 0.1363 √(𝑥1,3 𝑉1 ) + (𝑥2,3 𝑉2 ) − 0.085] (13)
31
32
33
34
35 𝑉1 = 𝑉 + 𝑥2 𝑑𝑉 ⁄𝑑𝑥1 (14)
36
37
38 𝑉2 = 𝑉 + 𝑥1 𝑑𝑉 ⁄𝑑𝑥2 (15)
39
40
41 𝑜
42 𝑄 = 𝑑𝛥𝑡 𝐺3,2→1+2 ⁄𝑑𝑥1 (16)
43
44
45 𝐸 ⁄
46 𝐷 = 𝑅𝑇𝑥1 (1 − 𝑥1 )(𝑑 2 𝐺1,2 𝑑𝑥22 ) (17)
47
48
49
50
51
52 Where G1,3 y G2,3 are the Kirkwood-Buff integrals (in cm3.mol-1) calculated from the
53
54
55 thermodynamic data using equations 11 and 12, Vcor is the volume of correlation around the
56
57
58 SMT (in this case) where preferential solvation occurs. In equations 11 and 12 (κT-W=0.457
59
60
61 GPa-1, κT-W=0.392 GPa-1[42]), V3 is the partial molar volume of the solute (179.0 cm3.mol-1),
62
63
64
65
 1 and V1 y V2 are those of the solutes (in cm3.mol-1), calculated using equations 14 and 15 from
2
3
4 the density of the solute-free cosolvent mixtures reported by Egorov et al. [43], D and Q (in
5
6
7
kJ.mol-1 as well as RT) are parameters calculated from Go3,22 which is the Gibbs energy of
8
9 solute transfer (SMT) (Eq. 18) (Figure 7) and GE1,2 is the excess Gibbs energy of the solute-
10
11
12 free cosolvent mixture (Eq. 19[41]).
13
14
𝑜
15 𝛥𝑡 𝐺3,2→1+2 = −8.255𝑥13 + 19.944 − 23.195𝑥1 − 0.0502 (18)
16
17
𝐸
18
19
𝐺1,2 = 𝑥1 𝑥2 [−558 + 164(1 − 2𝑥1 ) − 189(1 − 2𝑥1 )2 ] (19)
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44 Figure 7. Gibbs energy of SMT transfer from pure water to coving mixtures at 298.15 K.
45
46
47
48 Table 8 shows some relevant data corresponding to the calculations necessary to
49
50
51
determine the preferential solvation parameter of SMT in EG + W cosolvent
52
53 mixtures. Figure 8 shows the trend of x1,3.
54
55
56 In this way, SMT is solvated preferentially by water from x1=0.00 hasta x1=0.20, this
57
58
59 behavior usually occurs in aqueous cosolvent mixtures, and is possibly due to the structuring
60
61
62
63
64
65
 1 of water around the non-polar groups of SMT (hydration hydrophobic), however, since
2
3
4 x1,3<0.01 solvation by water is negligible[41]. From x1=0.20 to x1=1.00, the values of x1,3
5
6
7
are positive and in intermediate mixtures x1,3>0.01, indicating a clear solvation of the SMT
8
9 by the EG. In principle, SMT would behave like a Lewis base in mixtures rich in water due
10
11
12 to the pair of free electrons of its groups –SO2–, NH2 and =N– in addition to the fact that
13
14
15 water is more acidic than EG according to to the acid and basicity parameters of Kamlet-Taft
16
17
18 (αW=1.017±0.0236, αEG=0.792±0.004[44], βW=0.14 βEG=0.51[45], and as a Lewis acid in
19
20
21 intermediate and rich mixtures in EG due to the hydrogen of its groups –NH2 and –NH–,
22
23
24 besides the fact that EG is more basic than water (see β parameters).
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
 Table 8. Some properties associated to preferential solvation of SMT (3) in EG (1) +
1
2
3 W (2)} mixtures at 298.15 K
4
5
6 D/ Q/ G1,3 / Vcor /
V1 / V2 / G2,3 / 100
7 x1 a kJ.mol– kJ.mol– cm3.mol cm3.mol–
8 1 1 cm3.mol–1 cm3.mol–1 –1 cm3.mol–1 1 x1,3
9
10 0.00 -23.20 2.479 53.97 18.08 -347.0 -177.9 890.4 0.000
11 0.05 -21.26 2.559 54.26 18.07 -320.5 -200.4 949.8 -0.751
12 0.10 -19.45 2.605 54.53 18.05 -299.2 -218.6 1012.3 -0.889
13
14 0.15 -17.77 2.627 54.76 18.02 -281.5 -233.5 1075.6 -0.698
15 0.20 -16.21 2.633 54.97 17.97 -266.4 -245.6 1138.0 -0.354
16 0.25 -14.77 2.631 55.15 17.92 -253.4 -255.3 1199.2 0.036
17
18
0.30 -13.46 2.627 55.31 17.86 -241.9 -262.9 1258.7 0.409
19 0.35 -12.27 2.626 55.44 17.80 -232.0 -268.6 1316.5 0.729
20 0.40 -11.20 2.631 55.56 17.73 -223.2 -272.6 1372.6 0.979
21
0.45 -10.26 2.643 55.65 17.66 -215.6 -275.2 1426.9 1.155
22
23 0.50 -9.44 2.663 55.73 17.59 -209.1 -276.7 1479.9 1.260
24 0.55 -8.75 2.692 55.79 17.52 -203.6 -277.7 1531.5 1.304
25 0.60 -8.18 2.725 55.84 17.46 -198.9 -278.5 1582.1 1.299
26
27 0.65 -7.73 2.760 55.87 17.40 -195.0 -279.7 1631.5 1.256
28 0.70 -7.41 2.793 55.90 17.35 -191.8 -281.8 1680.4 1.184
29 0.75 -7.21 2.816 55.91 17.31 -189.1 -285.4 1728.4 1.089
30
31 0.80 -7.13 2.822 55.92 17.28 -186.7 -291.1 1775.9 0.972
32 0.85 -7.18 2.803 55.92 17.26 -184.6 -299.8 1822.6 0.826
33 0.90 -7.36 2.747 55.93 17.26 -182.6 -312.8 1869.1 0.637
34
35 0.95 -7.65 2.643 55.92 17.27 -180.5 -331.8 1914.5 0.379
36 1.00 -8.07 2.479 55.92 17.30 -178.0 -360.1 1959.2 0.000
37 a
x1 is the mole fraction of ethylene glycol (1) in the EG (1) + W (2)} mixtures free of
38
39
40 SMT (3).
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
 1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Figure. 8. δx1,3 values of SMT (3) in EG (1) + W (2) mixtures at 298.15 K.
22
23
24
25 4. Conclusions
26
27
28
The solubility of SMT is an endothermic process, strongly influenced by the polarity of the
29
30
31 cosolvent system that decreases as the concentration of EG increases, which favors the
32
33 solubility of SMT. The Gibbs energy of solution is positive in all cases and its value depends
34
35
36 more on the enthalpy of solution. Regarding the thermodynamic transfer functions, the Gibbs
37
38 energy is negative for which it can be inferred that the SMT prefers less polar systems than
39
40
41 water.
42
43
44 From the mixing functions, it can be inferred that the solution process is favored by the fusion
45
46 process, and that as the EG proportion increases, the solute-solvent molecular interactions
47
48
49
increase favoring the solubility of the SMT. Finally, regarding the preferential solvation
50
51 process, SMT is solvated profferentially by water in mixtures rich in water and is solvated
52
53 preferably by EG in intermediate and EG-rich mixtures.
54
55
56 Acknowledgments
57
58
59 We would like to express our gratitude to the National Directorate of Research and National
60
61
62 Committee for Research Development of the Universidad Cooperativa de Colombia for
63
64
65
 providing financial support for this study with code INV2929. Furthermore, we thank the
1
2 Universidad Cooperativa de Colombia at Neiva for facilitating the supply of laboratories and
3
4
5 equipment.
6
7
8 Conflicts of Interest
9
10
11 The authors declare no conflict of interest.
12
13
14 References
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 Click here to
CH3
access/download;Figure;
O
O
S N

N
H
N
H2 N
CH3
 Click here to access/download;Figure;Figure2.pdf
45

40

35

30
Solubility /104 x3

25

20

15

10

0
0.0 0.2 0.4 0.6 0.8 1.0
w1
 Click here to access/download;Figure;Figure3.pdf
Original sample
Water
w1 :0.50
Ethylene glycol
Heat Flow (W/g)

100 120 140 160 180 200 220 240 250

Temperature (o C)
 Click here to access/download;Figure;Figure4.pdf
∆soln Go /KJ.mol−1
15 20 25
10
Sector III Sector II
Water
0.05
5
0.65
0.10
T ∆soln S o /kJ.mol−1

0.75 0.15
Sector IV EG Sector I
0.80
0
Sector V 0.90 Sector VIII

-5

Sector VI Sector VII

-10
-10 -5 0 5 10 15 20 25 30 35
∆soln H o /kJ.mol−1
 Click here to access/download;Figure;Figure5.pdf
∆mix Go /kJ.mol−1
5 10 15
0
Sector V Sector VIII

Water
-5
T ∆mix S o /kJ.mol−1

0.05

0.65
0.10

-10 EG

0.90

Sector VI Sector VII

-15
-10 -5 0 5 10 15
∆mix H o /KJ.mol−1
 Click here to access/download;Figure;Figure6.pdf
35
Water

30 0.05
0.10
∆soln H o /kJ.mol−1

25 0.65 0.35

0.75
20

0.80
EG 0.90
15
13
13 15 20 25 30
∆soln Go /kJ.mol−1
 Click here to access/download;Figure;Figure7.pdf
0
∆tr Go3,2−>1+2 /kJ.mol−1

-5

-10

-14
0.0 0.2 0.4 0.6 0.8 1.0
x1
 Click here to access/download;Figure;Figure8.pdf
1.5

1.0

0.5
100δ1,3

-0.5

-1
0.0 0.2 0.4 0.6 0.8 1.0
x1
Graphical Abstract

20
ln x3
o = −RT
ln γ3 =
e11 + ∆ solnG
e22 − 2 CH3
e12 V3 ϕ12 O
RT O
15 S N

N
G 2,3 )
G 1,3 − +V corr H ∂ ln x
Solubility, 104 x3

x1x2( 3 ∆soln H o
+x 2 G 2 ∂T =
,3
= x 1 G 1,3 N RT 2
δ x 1,3 H2 N
10 CH3

0
278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15
Temperature/K
Declaration of Interest Statement

Declaration of interests

☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.

☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: