Solution thermodynamics of ceftezole in seven pure solvents and two binary solvent mixtures

Journal Pre-proof Solution thermodynamics of ceftezole in seven pure solvents and two binary solvent mixtures

Lingling Zeng, Baohong Hou, Beiqian Tian, Xin Li, Hao Wu, Kui Chen, Jinyue Yang, Hongxun Hao PII:

S0167-7322(19)36671-1

DOI:

https://doi.org/10.1016/j.molliq.2020.112476

Reference:

MOLLIQ 112476

To appear in:

Journal of Molecular Liquids

Received date:

4 December 2019

Revised date:

4 January 2020

Accepted date:

7 January 2020

Please cite this article as: L. Zeng, B. Hou, B. Tian, et al., Solution thermodynamics of ceftezole in seven pure solvents and two binary solvent mixtures, Journal of Molecular Liquids(2020), https://doi.org/10.1016/j.molliq.2020.112476

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

© 2020 Published by Elsevier.

Journal Pre-proof

Solution thermodynamics of ceftezole in seven pure solvents and two binary solvent mixtures Lingling Zenga, Baohong Houa,b,*, Beiqian Tiana, Xin Lia, Hao Wua, Kui Chena, Jinyue Yanga, Hongxun Haoa,b,* a

National Engineering Research Center of Industrial Crystallization Technology,

School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin),

of

b

-p

ro

Tianjin 300072, China

re

* Corresponding Author

Hongxun Hao:

lP

Tel: 86-22-27405754. Fax: +86-22-27374971.

Baohong Hou:

na

E-mail: [email protected]

Abstract

Jo ur

E-mail: [email protected]

In this work, solubility data of ceftezole in seven pure solvents and two binary solvent systems were experimentally measured via a static gravimetric method in the temperature range from 278.15 K to 313.15 K under atmospheric pressure. The results indicated that the solubility of ceftezole in all the selected pure and binary solvent systems increased with the rising of temperature. It was also found that the solubility order of ceftezole in the seven mono-solvents was generally ranked as: 1

Journal Pre-proof

water
acetate
The

Apelblat model and the NRTL model were used to correlate the experimental solubility data of ceftezole in pure solvents, and the modified Apelblat equation, the CNIBS/R-K model and the combined version of the Jouyban−Acree were applied for binary solvents. The calculation results agreed fairly well with the experimental data. Finally,

of

the mixing and dissolution thermodynamic properties of ceftezole in all the tested

ro

solvents were calculated based on the NRTL model and the experimental solubility

-p

data.

re

Keywords: Ceftezole; Solubility; Mixing thermodynamic properties; Dissolution

1. Introduction

lP

thermodynamic properties.

na

Ceftezole (C13H12N8O4S3, CAS registry No: 26973-24-0, Figure.1), a

Jo ur

semi-synthetic cephalosporin derivative, has been reported to have an extremely strong bactericidal effect on a variety of gram-positive bacteria and gram-negative bacteria. Because of its high antibacterial activity and low side effects, ceftezole is widely used in the treatment of respiratory system infection, urinary system infection, septicemia, peritonitis and other diseases[1,2]. In the production process of ceftezole, crystallization is the key step that directly determines the quality of the final product. In order to ensure the reliability and stability of ceftezole in the crystallization process, it is of great significance to understand the thermodynamic parameters such as solubility and enthalpy of dissolution. Furthermore, in the production process of ceftezole sodium 2

Journal Pre-proof

and other ceftezole salts, ceftezole is usually used as the raw material and needs to be dissolved first. Therefore, the solubility data of ceftezole are also essential for the salt production with high quality. Although ceftezole has been on the market for a long time, no detailed thermodynamic data such as solubility of ceftezole in different solvents have been reported. Thus, the investigation on solubility data and other thermodynamic

re

-p

ro

of

properties of ceftezole is highly demanded.

(b)

lP

(a)

Fig.1. chemical structure (a) and three-dimensional structure (b) of ceftezole

na

In this work, the solubility data of ceftezole in seven pure organic solvents (water,

Jo ur

methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, acetone) and two binary solvent systems (acetone + water, acetone + ethanol) were measured under atmosphere pressure (0.1 MPa) from 278.15 K to 313.15 K by using gravimetric method. And the modified Apelblat equation, the CNIBS/R-K model, the combined version of the Jouyban−Acree and the NRTL model were chosen to correlate the solubility data of ceftezole in different solvents[3, 4]. Furthermore, in order to analyze and predict the dissolution process better, the mixing and dissolution thermodynamic data including the enthalpy, the entropy and the Gibbs free energy were obtained through the NRTL model and the experimental data[5]. 3

Journal Pre-proof

2. Experimental section

2.1 Chemicals Ceftezole (mass fraction > 0.996) was supplied by Shandong Lukang Pharmaceutical Co., Ltd., China. Methanol, ethanol, isopropanol, acetonitrile and ethyl acetate were purchased from Kemiou Chemical Reagent Co., Ltd., Tianjin, China. And

of

acetone was purchased from Guangda Pharmaceutical Co., Ltd., Tianjin, China.

ro

Deionized water was utilized for all experiments. More details of all materials used in

re

-p

this work are depicted in Table 1.

Table 1. The sources and mass fraction purity of chemicals used in this work.a.b.c Chemical

lP

Source

name

Shandong Lukang Pharmaceutical Co.,

Ceftezole acid

na

Ltd., Jining, China

Kemiou Chemical Reagent Co.,

Isopropanol

Ethanol Acetonitrile

Kemiou Chemical Reagent Co.,

Jo ur

Methanol

Ltd.,Tianjin, China Ltd.,Tianjin, China

Kemiou Chemical Reagent Co., Ltd.,Tianjin, China

Kemiou Chemical Reagent Co., Ltd.,Tianjin, China Kemiou Chemical Reagent Co.,

Ethyl Acetate Acetone a

Ltd.,Tianjin, China Guangda Pharmaceutical Co.,Ltd., Tianjin, China

Mass

Purification

Analysis

purity

method

method

>0.996

None

HPLCa

≥0.997

None

GCb

≥0.998

None

GCb

≥0.997

None

GCb

≥0.995

None

GCb

≥0.995

None

GCb

≥0.995

None

GCc

High-performance liquid chromatography, conducted by Shandong Lukang Pharmaceutical Co.,

Ltd., Jining, China. b

Gas chromatography, conducted by Kemiou Chemical Reagent Co., Ltd., Tianjin, China.

c

Gas chromatography, conducted by Guangda Pharmaceutical Co., Ltd., Tianjin, China.

2.2 Characterization of ceftezole 4

Journal Pre-proof

The X-ray powder diffraction (XRPD) measurements were carried out to identify the crystal form of ceftezole before and after solubility measuring experiments. The XRPD data were collected with an X-ray powder diffractometer (model D/max-2500, Rigaku) over a diffraction angle (2θ) range of 2-40° with scanning rate of 0.067°·s-1 and step size of 0.02°. All the XRPD experiments were performed at about 293 K. analysis

(Mettler

Toledo

TGA/DSC/SF,

Greifensee,

of

Thermogravimetric

ro

Switzerland) was conducted to estimate whether ceftezole would decompose or not at

-p

the melting point. Samples (5–10 mg) of ceftezole were treated with a heating rate of 10

re

K/min under the protection of nitrogen atmosphere.

lP

2.3 Solubility measurements

The solubility data of ceftezole in seven pure solvents and two binary solvent

na

systems were measured by gravimetric method, which has been reported in detail in

Jo ur

previous literatures[6, 7]. In order to further verify the reliability of the method used in this paper, the solubility data of tris-(2,4-ditert-butylphenyl)-phosphite in acetone were measured by using the same method in this work and the experimental data were compared with the data from reference[8]. The results are graphically showed in Fig.2 and it can be observed that the experimental data are consistent with the data from the literature, proving the reliability of the method used in this paper. This process could be briefly depicted as follows: firstly, excess amount of solid ceftezole was put into 50 mL conical flasks which contained moderate solvents. Then, the temperature of solution was controlled by a thermostatic mechanical shaker (Tianjin Ounuo 5

Journal Pre-proof

Instrument Co. Ltd., China). Next, the hermetic conical flasks in the thermostatic mechanical shaker were agitated for at least 24 h at a given temperature to ensure that the solid−liquid equilibrium was reached. Afterwards, the agitation was stopped and the solution was kept static for 8 h to allow the undissolved particles to settle down. Then, the supernatant liquid was rapidly taken out by a pre-heated (or pre-cooled)

of

syringe with a 0.22 μm organic membrane and transferred into a pre-weighted beaker.

ro

The total weight of the filtrate and the beaker was immediately measured using an

-p

electronic analytic balance (Mettler Toledo ML204, Switzerland) with an uncertainty

re

of ±0.0001 g. Finally, the beaker was placed into a vacuum oven at 313.15 K for about

lP

48 h until the total weight of filtrate and beaker did not change anymore. For each solubility point, the above-mentioned process was repeated at least three times and the

na

average value was used as the result. During the measurements, the wet solids which

Jo ur

did not dissolve were analyzed by XRPD to make sure that they were identical with the original material. The mole fraction solubility (𝑥1 ) of ceftezole in pure solvents and binary solvent systems can be calculated through the following equations[9].

𝑥1 =

𝑥1 =

𝑚1 ⁄𝑀1 #(1) 𝑚1 ⁄𝑀1 + 𝑚2 ⁄𝑀2

𝑚1 ⁄𝑀1 #(2) 𝑚1 ⁄𝑀1 + 𝑚2 ⁄𝑀2 + 𝑚3 ⁄𝑀3

where 𝑚1 , 𝑚2 and 𝑚3 represent the mass of ceftezole and solvents, respectively. 𝑀1 , 𝑀2 and 𝑀3 represent the molar mass of ceftezole and solvents, respectively.

6

-p

ro

of

Journal Pre-proof

re

Fig.2. The comparison of the mole fraction solubility (x) of tris-(2,4-ditert-butylphenyl)-phosphite

na

3. Thermodynamic models

lP

in acetone: ●, this work; ■, Ref. [8].

3.1 Modified Apelblat equation

Jo ur

The modified Apelblat equation, also known as ABC equation, was derived from Clausius-Clapeyron equation. It is a widely used semi-empirical model, which can be used to simulate the relationship between solute mole fraction and temperature[10]. The equation is shown as follows: 𝑙𝑛 𝑥1 = 𝐴 +

𝐵 + 𝐶 𝑙𝑛 𝑇 #(3) 𝑇

Where 𝑥1 represents the mole fraction solubility of ceftezole, T is the absolute temperature. A, B and C are semi-empirical constants, among which A and B can represent the change of activity coefficient in solution, while C refers to the influence of temperature on the fusion enthalpy[11]. The modified Apelblat equation is both 7

Journal Pre-proof

applicable in pure solvents and binary mixed solvent systems.

3.2 CNIBS/R–K model The CNIBS/R–K model was employed to correlate the solubility against the proportion of binary solvent mixtures at specific temperatures[12, 13] . It can be expressed as follows: 𝑁

+

𝑥30 𝑙𝑛 𝑋3

+

𝑥20 𝑥30 ∑ 𝑆𝑖 𝑖=0

(𝑥20 − 𝑥30 )𝑖 #(4)

of

𝑙𝑛 𝑥1 =

𝑥20 𝑙𝑛 𝑋2

ro

where 𝑥20 and 𝑥30 are the initial mole fractions of organic solvents (acetone and water

-p

or ethanol) in a binary mixed solvent system in the absence of solute, respectively. 𝑋2

re

and 𝑋3 represent the saturated mole fraction solubility of ceftezole in pure acetone and

lP

pure organic solvent (water or ethanol), respectively. 𝑆𝑖 represents the model constant

na

and N refers to the number of the solvents. For a binary solvent system, N = 2 and 𝑥30 = 1 − 𝑥20 . Therefore, this equation can be simplified as:

Jo ur

𝑙𝑛 𝑥1 = (𝑙𝑛 𝑥2 − 𝑙𝑛 𝑥3 + 𝑆0 − 𝑆1 + 𝑆2 )𝑥20 + (−𝑆0 + 3𝑆1 − 5𝑆2 )(𝑥20 )2 +(−2𝑆1 + 8𝑆2 )(𝑥20 )3 + (−4𝑆2 )(𝑥20 )4 + 𝑙𝑛 𝑋3 #(5) This equation can be further simplified into a polynomial form as: 𝑙𝑛 𝑥1 = 𝐵0 + 𝐵1 𝑥20 + 𝐵2 (𝑥20 )2 + 𝐵3 (𝑥20 )3 + 𝐵4 (𝑥20 )4 #(6)

where 𝐵0 , 𝐵1 , 𝐵2 , 𝐵3 , and 𝐵4 are model parameters and they can be acquired by least-squares regression.

3.3 Jouyban–Acree model The Jouyban−Acree model, proposed by Jouyban Gharamaleki and his co-workers in 1988, could estimate the solute solubility with respect to both 8

Journal Pre-proof

temperature and solvent composition of binary solvent mixtures in a fairly simple way[14]. The model is expressed as follows [15, 16]. 𝑁

𝑙𝑛 𝑥1 =

𝑥20 𝑙𝑛 𝑋2

+

𝑥30

𝑙𝑛 𝑋3 +

𝑥20 𝑥30

∑ 𝑖=0

𝐽𝑖 (𝑥20 − 𝑥30 )𝑖 #(7) 𝑇

where 𝐽𝑖 terms are model constants. T is the absolute temperature of solution. The other symbols represent the same meanings as Eq. (4).

of

Mole fraction solubility of ceftezole in pure solvents, 𝑋2 and 𝑋3 , can be

-p

𝑏2 + 𝑐2 𝑙𝑛 𝑇 #(8) 𝑇 𝑏3 + 𝑐3 𝑙𝑛 𝑇 #(9) 𝑇

re

𝑙𝑛 𝑋2 = 𝑎2 +

ro

calculated by the modified Apelblat equation and expressed as follows:

lP

𝑙𝑛 𝑋3 = 𝑎3 +

as:

𝑏2 𝑥20 + 𝑐2 𝑙𝑛 𝑇 + (𝑎2 − 𝑎3 )𝑥20 + (𝑏2 − 𝑏3 + 𝐽0 − 𝐽1 + 𝐽2 ) 𝑇 𝑇 0 0 2 3 (𝑥2 ) (𝑥2 ) +(3𝐽1 − 𝐽0 − 5𝐽2 ) + (8𝐽2 − 2𝐽1 ) 𝑇 𝑇 0 4 (𝑥2 ) +(−4𝐽2 ) + (𝑐2 − 𝑐3 )𝑥20 𝑙𝑛 𝑇 #(10) 𝑇

Jo ur

𝑙𝑛 𝑥1 = 𝑎2 +

na

In the same way, N = 2 and 𝑥30 = 1 − 𝑥20 . Therefore, the eq. (7) can be transformed

When introducing constant terms, the eq. (10) can be further simplified as follows: (𝑥20 )2 (𝑥20 )3 (𝑥20 )4 𝐴2 𝑥20 0 𝑙𝑛 𝑥1 = 𝐴1 + + 𝐴3 𝑙𝑛 𝑇 + 𝐴4 𝑥2 + 𝐴5 + 𝐴6 + 𝐴7 + 𝐴8 𝑇 𝑇 𝑇 𝑇 𝑇 +𝐴9 𝑥20 𝑙𝑛 𝑇 #(11)

where 𝐴1 to 𝐴9 are the model parameters. The other symbols denote the same meanings as in eq 4. 9

Journal Pre-proof

3.4 NRTL model The equation which can calculate the solubility data after simplification is shown as[17] : 𝑙𝑛 𝑥𝑖 =

∆𝑓𝑢𝑠 𝐻 1 1 ( − ) − 𝑙𝑛 𝛾𝑖 #(12) 𝑅 𝑇𝑚 𝑇

Where 𝑥𝑖 is the mole fraction solubility of ceftezole and 𝛾𝑖 is the activity coefficient

of

of solute in solution. Besides, ∆𝑓𝑢𝑠 𝐻 , 𝑅 and 𝑇𝑚 represent the fusion enthalpy of

ro

solute, the gas constant and the melting temperature of solute.

-p

Based on the solid-liquid phase equilibrium theory, the NRTL model can be used

re

to calculate the activity coefficient in nonideal solution by using a local composition

lP

model. For the binary system (ceftezole + pure solvent) and the ternary system (ceftezole + binary mixed solvent system), based on NRTL model, the activity

na

coefficient 𝛾𝑖 can be acquired using eq. (13) and eq. (14), respectively [18]. 𝜏𝑗𝑖 𝐺𝑗𝑖2

(𝑥𝑖 + 𝐺𝑗𝑖 𝑥𝑗 )

Jo ur

𝑙𝑛 𝛾𝑖 = 𝑥𝑗2 [

𝑙𝑛 𝛾𝑖 =

2+

𝜏𝑖𝑗 𝐺𝑖𝑗2 (𝑥𝑗 + 𝐺𝑖𝑗 𝑥𝑖 )

2 ] #(13)

∑𝑗 𝜏𝑗𝑖 𝐺𝑗𝑖 𝑥𝑗 ∑𝑙 𝜏𝑙𝑗 𝐺𝑙𝑗 𝑥𝑙 𝐺𝑗𝑖 𝑥𝑗 +∑ (𝜏𝑖𝑗 − ) #(14) ∑𝑘 𝐺𝑘𝑖 𝑥𝑘 ∑𝑘 𝐺𝑘𝑗 𝑥𝑘 𝐺𝑘𝑖 𝑥𝑘 𝑗

where i, j, k and l stand for each component of the solution system, separately. 𝐺𝑖𝑗 and 𝜏𝑖𝑗 are the parameters of NRTL model, which can be expressed as below: 𝐺𝑖𝑗 = 𝑒𝑥𝑝(−𝛼𝑖𝑗 𝜏𝑖𝑗 ) #(15) 𝜏𝑖𝑗 =

𝑔𝑖𝑗 − 𝑔𝑗𝑗 ∆𝑔𝑖𝑗 = #(16) 𝑅𝑇 𝑅𝑇

𝛼𝑖𝑗 = 𝛼𝑗𝑖 , 𝑖, 𝑗 = 1,2,3#(17) Where ∆𝑔𝑖𝑗 , as the parameter of this model, reflects the cross-interaction energy. 𝛼𝑖𝑗 is 10

Journal Pre-proof

an empirical parameter that reflects the non-randomness of the system[8]. In this work, different thermodynamic models were selected for the correlation of solubility. To evaluate the fitting effect of the above models, the average relative deviation (ARD) and the root-mean-square deviation (RMSD) were employed and are defined as follows: 𝑁

of

1 𝑥𝑖𝑒𝑥𝑝 − 𝑥𝑖𝑐𝑎𝑙 𝐴𝑅𝐷 = ∑ | | #(18) 𝑁 𝑥𝑖𝑒𝑥𝑝 𝑖=1

1⁄2

𝑁

ro

1 2 𝑅𝑀𝑆𝐷 = [ ∑(𝑥𝑖𝑒𝑥𝑝 − 𝑥𝑖𝑐𝑎𝑙 ) ] 𝑁

-p

𝑖=1

#(19)

re

Where N refers to the total number of solubility data points in this work; the superscript

lP

exp and cal stand for the experimental value and calculated value of the mole fraction solubility of ceftezole, respectively.

na

3.5 Thermodynamic properties of the mixing and dissolution processes

Jo ur

In order to better understand the mixing process of a non-ideal solution, the mixing Gibbs free energy (∆𝑚𝑖𝑥 𝐺), mixing enthalpy (∆𝑚𝑖𝑥 𝐻) and mixing entropy (∆𝑚𝑖𝑥 𝑆) of ceftezole in different pure or binary solvents, were calculated by the following equations: ∆𝑚𝑖𝑥 𝐺 = 𝐺 𝐸 + ∆𝑚𝑖𝑥 𝐺 𝑖𝑑 #(20) ∆𝑚𝑖𝑥 𝐻 = 𝐻 𝐸 + ∆𝑚𝑖𝑥 𝐻 𝑖𝑑 #(21) ∆𝑚𝑖𝑥 𝑆 = 𝑆 𝐸 + ∆𝑚𝑖𝑥 𝑆 𝑖𝑑 #(22) Where ∆𝑚𝑖𝑥 𝐺, ∆𝑚𝑖𝑥 𝐻 and ∆𝑚𝑖𝑥 𝑆 refer to the mixing thermodynamic properties of real solution; 𝐺 𝐸 , 𝐻 𝐸 and 𝑆 𝐸 represent the excess properties of the real solution; 11

Journal Pre-proof

∆𝑚𝑖𝑥 𝐺 𝑖𝑑 , ∆𝑚𝑖𝑥 𝐻 𝑖𝑑 and ∆𝑚𝑖𝑥 𝑆 𝑖𝑑 demonstrate the mixing thermodynamic properties of an ideal solution, which can be calculated through Eq. (23)-(25). 𝑛

∆𝑚𝑖𝑥 𝐺

𝑖𝑑

= 𝑅𝑇 ∑ 𝑥𝑖 𝑙𝑛 𝑥𝑖 #(23) 𝑖=1

∆𝑚𝑖𝑥 𝐻 𝑖𝑑 = 0#(24) 𝑛

∆𝑚𝑖𝑥 𝑆

𝑖𝑑

∆𝑚𝑖𝑥 𝐺 𝑖𝑑 =− = −𝑅 ∑ 𝑥𝑖 𝑙𝑛 𝑥𝑖 #(25) 𝑇

of

𝑖=1

ro

Where 𝑥𝑖 stands for the mole fraction of component i in solution. In this work, for the

re

binary mixed solvent system), n = 3

-p

binary system (ceftezole + pure solvent), n= 2 and for the ternary system (ceftezole +

lP

As for the excess properties of the real solution system, they can be calculated by Eq. (26)-(28).

na

𝐺 𝐸 = 𝑅𝑇 𝑙𝑛 𝛾𝑖 #(26)

Jo ur

𝐺𝐸 𝑛 𝜕( 𝑇 ) 𝜕 𝑙𝑛 𝛾𝑖 𝐻 𝐸 = −𝑇 2 [ ] = −𝑅𝑇 2 ∑ 𝑥𝑖 ( ) #(27) 𝜕𝑇 𝜕𝑇 𝑝.𝑥 𝑖=1

𝑆𝐸 =

𝐻𝐸 − 𝐺 𝐸 #(28) 𝑇

Where 𝛾𝑖 means the activity coefficient of component i in real solution and can be calculated by the NRTL model. For a non-ideal solution, the dissolution process of the solute in the solvent can be generally divided into four steps: heating, melting, cooling and mixing processes[19] , which can be illustrated as follows.

heating fusion  Solute(liquid) at Tm Solute(solid) at T  Solute(solid) at Tm  12

Journal Pre-proof mixing cooling Solute(liquid) at T  Solute(solution) at T     Thus, the whole dissolution thermodynamics (∆𝑑𝑖𝑠 𝑀) of Ceftezole in solvents can be obtained by Eq. (29). ∆𝑑𝑖𝑠 𝑀 = 𝑥(∆ℎ𝑒𝑎𝑡 𝑀 + ∆𝑓𝑢𝑠 𝑀 + ∆𝑐𝑜𝑜𝑙 𝑀) + ∆𝑚𝑖𝑥 𝑀#(29) Where M refers to the Gibbs free energy (G), enthalpy (H) or entropy(S). x is the mole

of

fraction solubility of ceftezole; ∆𝑓𝑢𝑠 𝑀 stands for the fusion thermodynamic properties

ro

of ceftezole.

-p

The values of ∆ℎ𝑒𝑎𝑡 𝐻 , ∆𝑐𝑜𝑜𝑙 𝐻 , ∆ℎ𝑒𝑎𝑡 𝑆 and ∆𝑐𝑜𝑜𝑙 𝑆 can be calculated by Eq.

re

(30)-(33).

lP

∆ℎ𝑒𝑎𝑡 𝐻 = 𝐶𝑝(𝑠) (𝑇𝑚 − 𝑇)#(30) ∆𝑐𝑜𝑜𝑙 𝐻 = 𝐶𝑝(𝑙) (𝑇 − 𝑇𝑚 )#(31) 𝑇𝑚 #(32) 𝑇 𝑇 ∆𝑐𝑜𝑜𝑙 𝑆 = 𝐶𝑝(𝑙) 𝑙𝑛 #(33) 𝑇𝑚

Jo ur

na

∆ℎ𝑒𝑎𝑡 𝑆 = 𝐶𝑝(𝑠) 𝑙𝑛

Where 𝐶𝑝(𝑠) and 𝐶𝑝(𝑙) stand for the heat capacity of solid and liquid, respectively. Generally, for enthalpy and entropy, the sum of (∆ℎ𝑒𝑎𝑡 𝑀 +∆𝑐𝑜𝑜𝑙 𝑀) can be ignored due to their very low values compared with the corresponding thermodynamic properties of the fusion process [20] . Therefore, the dissolution thermodynamic properties can be calculated by the following equations: ∆𝑑𝑖𝑠 𝐻 = 𝑥∆𝑓𝑢𝑠 𝐻 + ∆𝑚𝑖𝑥 𝐻#(34) ∆𝑑𝑖𝑠 𝑆 = 𝑥∆𝑓𝑢𝑠 𝑆 + ∆𝑚𝑖𝑥 𝑆#(35) 13

Journal Pre-proof

∆𝑑𝑖𝑠 𝐺 = ∆𝑑𝑖𝑠 𝐻 − 𝑇∆𝑑𝑖𝑠 𝑆#(36) Apparently, the fusion properties and mixing properties are essential to the calculation of the dissolution properties.

4. Results and discussion

4.1 Thermal analysis (DSC/TGA).

of

As can be seen from the TGA curve in Figure.3, the sample begins to lose weight

ro

at about 437.15 K, and at this temperature point, there is an obvious exothermic peak at

-p

the corresponding point on the DSC curve. In general, melting is an endothermic

re

process and the weight of the sample remains the same during this process. Therefore,

lP

the exothermic peak on the DSC curve in Figure.3 should be caused by the

na

decomposition of ceftezole during heating. For decomposed solids before complete melting, enthalpy of fusion and melting temperature can't be accurately obtained by

Jo ur

general thermal analysis method. In order to get enthalpy of fusion and melting temperature of ceftezole, a model proposed by Akash Jain et al [21, 22] that combined the additive group contributions and non-additive molecular parameters was applied to estimate the 𝑇𝑚 , ∆𝑓𝑢𝑠 𝐻 and ∆𝑓𝑢𝑠 𝑆 . This model has been applied to over 2200 compounds including a few pharmaceuticals with complex structures[21]. Its reliability and accuracy have been verified by these compounds. The equations for this model can be described as follows: 𝑇𝑚 = ∆𝑓𝑢𝑠 𝐻 ⁄∆𝑓𝑢𝑠 𝑆 #(37) ∆𝑓𝑢𝑠 𝐻 = ∑ 𝑛𝑖 𝑚𝑖 + ∑ 𝑛𝑗 𝑚𝑗 #(38) 14

Journal Pre-proof

∆𝑓𝑢𝑠 𝑆 = 50 − 8.314 𝑙𝑛 𝜎 + 7.382𝜏#(39) 𝜏 = 𝑆𝑃3 + 0.5𝑆𝑃2 + 0.5𝑅𝐼𝑁𝐺 − 1#(40) Where ∆𝑓𝑢𝑠 𝐻 and ∆𝑓𝑢𝑠 𝑆 represent the fusion enthalpy and the fusion entropy, respectively; 𝑛𝑖 and 𝑛𝑗 represent the number of group i and proximity factor j that occur in a substance, respectively. 𝑚𝑖 and 𝑚𝑗 represent the contribution of

of

corresponding groups to the enthalpy of melting, respectively. 𝜎 is the rotational

ro

symmetry value and 𝜏 is an adjustable number or effective number of the torsion angle.

-p

SP3 represents the number of non-ring and non-terminal atoms that undergo sp3

re

hybridization, such as CH2, CH, C, NH, N, O and S atoms. SP2 represents the number

lP

of sp2 hybridization of non-ring and non-terminal atoms, such as =CH, =C, =N and C=O. RING represents the number of single or fused aromatic rings. For aliphatic

na

compounds, the -1 in the formula becomes -3.

Jo ur

By using this method, the melting point was calculated to be 611.782 K, while the fusion enthalpy was calculated to be 53.170 kJ/mol.

15

-p

ro

of

Journal Pre-proof

Jo ur

na

lP

re

Fig.3. Thermal analysis (TGA/DSC) data of ceftezole

Fig.4. X-ray powder diffraction patterns of ceftezole : (a) black : raw material;（b）red: materials after the solubility measurements.

4.2 X-ray powder diffraction analysis. The raw material and residual ceftezole solids in all experimental conditions were 16

Journal Pre-proof

collected for XRPD testing. The XRPD patterns of all ceftezole samples were found to be the same before and after experiments, which is shown in Fig. 4. It confirms that all the samples of ceftezole used in this work are the same crystalline form and no polymorphic transformation was observed during solubility experiments.

4.3 Solubility data of ceftezole in pure solvent systems

of

In this work, the solubility data of ceftezole from 278.15 K to 313.15 K in water,

ro

methanol, ethanol, isopropanol, acetonitrile, ethyl acetate and acetone were measured

-p

by static gravimetric method. The results are shown in Table 2. It can be observed that

re

the solubility of ceftezole increases with the increasing of temperature in the all

lP

selected pure solvents. Furthermore, by comparing the solubility data of ceftezole in Table 2, it can be found that the solubility of ceftezole in the seven solvents can be

na

ranked as water < methanol < ethanol < isopropanol < acetonitrile < ethyl

Jo ur

acetate < acetone. In order to better illustrate the difference of solubility data in the studied solvents, some physical properties of the seven pure solvents including Hidebrand solubility parameters (δH), dipole moments (μ), dielectric constants (ε) , polarities and summation of the hydrogen bond donor propensities of the solvent (∑ 𝛼) are listed in table 3[23, 24]. It can be found that the polarity order of the chosen solvents is water > methanol > ethanol > isopropanol > acetonitrile > acetone > ethyl acetate. It can be seen that the polarity order of the solvent is the opposite of the solubility order of ceftezole in the solvent except for ethyl acetate, which is reasonable if considering that the polarity of ceftezole is not particularly high. It can be also 17

Journal Pre-proof

explained by the fact that dissolution is a complex process and is not only influenced by the polarity of solution, but also affected by some other factors such as molecular size and the ability to form hydrogen bond. From the point of view of forming intermolecular hydrogen bonds, the amide group in ceftezole molecule can act as hydrogen bond donor, while the carbonyl group in acetone can act as hydrogen bond

of

acceptor. The formation of hydrogen bonds between acetone and ceftezole may

ro

accelerate the dissolution of ceftezole in acetone. In addition, it can be seen from table

-p

3 that alcohol solvents and water show strong hydrogen bond donor capacity, and the

re

equally strong hydrogen bond donors of ceftezole and solvent molecules is not

lP

conducive to the formation of hydrogen bond, which may lead to its low solubility in

na

these solvents.

Table 2. Experimental and calculated mole fraction solubility of ceftezole in seven pure solvents

T/K Isopropanol

Jo ur

from 278.15K to 313.15 K (p = 101.3 kPa). a,b 𝑒𝑥𝑝

105𝑥1

ABC

5 𝑐𝑎𝑙

10 𝑥1

NRTL

T/K

5 𝑐𝑎𝑙

10 𝑥1

𝑒𝑥𝑝

105𝑥1

ABC 5 𝑐𝑎𝑙

NRTL

10 𝑥1

105𝑥1𝑐𝑎𝑙

Ethanol

278.15

6.43

6.26

5.78

278.15

4.85

4.94

4.55

283.15

6.82

6.90

6.75

283.15

5.92

5.66

5.42

288.15

7.37

7.69

7.85

288.15

6.49

6.53

6.53

293.15

8.59

8.68

9.00

293.15

7.26

7.60

7.83

298.15

10.4

9.89

10.2

298.15

9.45

8.91

9.10

303.15

11.4

11.4

11.7

303.15

10.4

10.5

10.8

308.15

13.4

13.2

13.3

308.15

12.2

12.5

12.7

313.15

15.2

15.5

15.0

313.15

15.2

14.9

14.6

Methanol

Water

278.15

1.20

1.18

1.09

278.15

1.04

1.04

0.909

283.15

1.50

1.51

1.46

283.15

1.27

1.28

1.20

288.15

1.92

1.94

1.94

288.15

1.64

1.59

1.57

293.15

2.43

2.50

2.55

293.15

1.92

1.99

2.03

18

Journal Pre-proof 298.15

3.26

3.23

3.32

298.15

2.51

2.52

2.61

303.15

4.34

4.18

4.26

303.15

3.24

3.23

3.33

308.15

5.48

5.41

5.44

308.15

4.27

4.16

4.21

313.15

6.84

7.00

6.87

313.15

5.32

5.40

5.28

Ethyl Acetate 12.4

12.5

11.5

278.15

18.8

18.8

17.7

283.15

13.7

13.7

13.2

283.15

21.7

21.6

21.0

288.15

15.9

15.1

14.9

288.15

24.2

24.9

25.0

293.15

16.4

16.9

17.6

293.15

30.0

28.8

28.7

298.15

18.4

19.0

20.1

298.15

34.2

33.2

33.5

303.15

21.9

21.6

22.2

303.15

37.1

38.4

39.7

308.15

25.3

24.8

24.8

308.15

43.3

44.5

45.5

313.15

28.4

28.6

27.9

313.15

53.0

51.6

50.5

278.15

153

156

152

298.15

170

172

175

283.15

156

155

154

303.15

184

184

187

288.15

161

157

159

308.15

193

201

201

293.15

165

163

166

313.15

230

222

219

Standard uncertainty is u(T) = 0.05 K, u(p) = 0.3 kPa. Relative standard uncertainty is ur(x1) =

re

a

0.05. 𝑒𝑥𝑝

𝑥1

is the experimental mole fraction solubility, 𝑥1𝑐𝑎𝑙 is the calculated mole fraction solubility

lP

b

-p

Acetone

of

278.15

ro

Acetonitrile

of ceftezole.

na

Table 3. Physical properties of the selected solventsa. δH

（298K)/(cal1/2∙cm-

Jo ur

Solvent names

μ(298K)/D

ε(293K)/F∙ m-1

polarity(water100)

∑𝛼

3/2

)

Acetone

10

2.9

20.6

35.5

0.04

9.1

1.7

6.02

23

0

11.9

3.2

37.5

46

0.07

2-propanol

11.5

1.66

18.3

54.6

0.33

Ethanol

13.4

1.7

22.4

65.4

0.37

Methanol

14.5

1.7

32.6

76.2

0.43

water

23.4

1.87

79.7

100

1.17

Ethyl acetate Acetonitrile

a

Taken from Ref [23,24].

Furthermore, among the selected seven pure solvents, it can be seen that ceftezole has the highest solubility in acetone and the lowest solubility in water. And the solubility in acetone is about 20 times higher than that in water. Therefore, acetone can 19

Journal Pre-proof

be used as a solvent for the crystallization of ceftezole in the industry. To extent the application range of the solubility data, the modified Apelblat equation and NRTL model were adopted to correlate the solubility of ceftezole in single solvents. The correlated solubility data are also tabulated in Table 2. The average relative deviation (ARD%) and the root-mean-square deviations (RMSD) were applied to evaluate the

of

applicability of the model and the results are listed in Table 4 and Table 5. It can be

ro

observed from Table 4 and Table 5 that the ARD% values of two models are both below

-p

5%, indicating that the fitting effect is good. Besides, compared to the NRTL model, the

re

Apelblat model gives better correlation results and the data correlated by the Apelblat

lP

model are also graphically showed in the Figs. 5 and 6.

Table 4. Model parameters and deviations of the modified Apelblat model for ceftezole in seven pure solvents (p = 101.3 kPa). a,b

C

ARD%

105RMSD

-345.2809

12900.91

51.38831

2.160

0.2631

-293.2469

10177.52

43.84058

2.767

0.2786

-233.3873

6054.121

35.58366

1.901

0.09260

-395.8832

13499.78

59.67740

1.587

0.05855

-313.8532

11715.20

46.68498

2.123

0.4597

-145.3946

3921.997

21.80401

2.415

1.008

Acetone

-450.3172

18830.86

66.83374

1.839

4.358

Average ARD%

2.113

Average 106RMSD

0.9312

Isopropanol Ethanol Methanol Water Acetonitrile Ethyl Acetate

Jo ur

A

na

B

Parameters

a

A, B and C are the parameters of the Apelblat equation.

b

Standard uncertainty is u(p) = 0.3 kPa.

Table 5. Model parameters and deviations of the NRTL model for ceftezole in seven pure solvents (p = 101.3 kPa). a, b Parameters

10-4Δg12

10-4Δg21

ARD%

104RMSD

Isopropanol

-2.291551

1.791460

3.766

3.642

20

Journal Pre-proof Ethanol

-0.2992002

-0.7233930

4.833

4.387

Methanol

-0.3192910

-0.9037941

2.719

0.7079

Water

-0.1988999

-0.8164337

4.683

0.8943

Acetonitrile

-0.2976921

-0.8819748

4.835

9.369

Ethyl Acetate

-0.2408457

-1.352852

4.506

16.68

Acetone

-1.232391

2.191603

2.176

0.5337

Average ARD%

3.931

Average 106RMSD

5.173

Δg12 and Δg21 are the parameters of the NRTL model.

b

Standard uncertainty is u(p) = 0.3 kPa.

Jo ur

na

lP

re

-p

ro

of

a

Fig.5. Mole fraction solubility of ceftezole in four pure solvents from 278.15 K to 313.15 K.

21

-p

ro

of

Journal Pre-proof

re

Fig.6. Mole fraction solubility of ceftezole in three pure solvents from 278.15 K to 313.15 K.

lP

4.4 Solubility data of ceftezole in binary solvent systems

na

The experimental solubility of ceftezole in mixtures of acetone and water/ethanol

Jo ur

are listed in Table 6 and graphically shown in Figure. 7 and 8. The results indicate that the solubility of ceftezole in the binary solvent mixtures is a function of both the temperature and solvent composition. From Table 6, it can be seen that the solubility data of ceftezole in both binary solvent systems increase with the rise of temperature. At a fixed temperature, the solubility of ceftezole in binary acetone + water solvent mixtures increase with the increase of the initial molar fraction of acetone. However, the solubility in acetone + ethanol system exhibits a different trend. In acetone + ethanol system when the temperature is constant, the molar solubility of ceftezole first increases with the increase of the molar fraction of acetone in the mixed solvent. When

22

Journal Pre-proof

x = 0.649, the solubility of ceftezole in the mixed solvent reaches the maximum. After that, the solubility of ceftezole starts to decrease with the increase of acetone molar fraction. It is worth noting that the maximum point of solubility does not change with the variation of temperature. This phenomenon can be explained by cosolvency, as reported in the previous experiments[25, 26]. Cosolvency is a complicated process,

of

which may be affected by many factors such as the dielectric constant, ionization

ro

constant surface tension of the different solvents, and so on.

Table 6. Experimental and calculated mole fraction solubility of ceftezole in binary solvent 278.15

283.15

288.15

293.15

298.15

303.15

308.15

313.15

K

K

K

K

K

K

K

K

3.79

4.99

7.14

11.0

16.7

1.82

2.49

2.85

0.0720

3.65

4.17

5.34

6.96

9.22

12.7

19.0

27.5

0.117

6.90

8.40

11.3

14.6

19.7

27.7

38.9

61.5

0.171

15.5

18.8

25.8

34.0

45.4

61.3

93.4

132

0.237

37.0

45.8

59.4

74.6

107

142

187

253

0.318

83.7

96.0

130

164

196

247

322

430

0.419

161

198

232

290

333

417

512

652

0.554

237

306

313

336

439

566

643

760

0.736

334

367

389

445

499

571

666

796

2.28

2.86

3.76

5.14

7.32

10.8

16.5

Jo ur

5 𝐴⁄𝑊,𝐴𝐵𝐶

lP

10 𝑥1 0.0334

na

5 𝐴⁄𝑊,𝑒𝑥𝑝

re

𝑥20

-p

mixtures of acetone+ water and acetone+ ethanol from 278.15 K to 313.15 K (p = 101.3 kPa).a,b

10 𝑥1 0.0334

1.91

0.0720

3.61

4.28

5.31

6.87

9.25

12.9

18.6

27.7

0.117

6.93

8.54

10.9

14.5

19.8

27.8

40.3

59.7

0.171

15.4

19.4

25.1

33.4

45.6

63.6

90.8

132

0.237

36.5

46.3

59.6

77.9

103

138

188

257

0.318

82.4

101

125

157

199

254

326

422

0.419

164

194

233

281

342

419

517

642

0.554

244

276

316

368

436

523

635

781

0.736

337

361

395

440

499

574

669

792

5 𝐴⁄𝑊,𝑅𝐾

10 𝑥1

0.0334

1.59

2.54

2.25

4.41

4.22

5.75

9.58

16.0

0.0720

3.21

4.61

4.88

7.68

9.39

13.1

20.4

31.8

23

Journal Pre-proof 0.117

6.93

9.08

11.1

15.0

21.2

29.5

43.7

64.1

0.171

15.8

19.3

25.9

32.5

47.3

64.8

91.4

129

0.237

37.2

43.5

60.3

74.8

102

134

182

249

0.318

83.4

97.7

129

165

199

253

328

437

0.419

161

198

232

290

331

415

509

649

0.554

237

306

313

336

440

566

644

761

0.736

334

367

389

445

499

571

666

796

10 𝑥1 0.0334

1.62

2.06

2.72

3.71

5.22

7.56

11.2

17.2

0.0720

3.31

4.15

5.38

7.21

10.0

14.2

20.7

30.9

0.117

7.26

8.95

11.4

15.0

20.3

28.3

40.3

58.8

0.171

16.8

20.4

25.6

32.9

43.6

59.1

82.1

116

0.237

40.1

47.8

58.6

73.8

95.2

126

169

233

0.318

90.4

106

127

156

196

252

328

436

0.419

171

198

233

279

0.554

237

271

313

367

0.736

310

350

397

452

ro

of

5 𝐴⁄𝑊,𝐽𝐴

423

534

683

436

523

635

778

518

596

688

797

27.2

30.7

38.3

44.6

52.4

54.1

62.0

74.2

81.6

97.8

94.9

97.9

127

136

155

5 𝐴⁄𝐸 ,𝑒𝑥𝑝

-p

341

22.5

23.8

24.6

0.166

44.4

46.1

48.2

0.254

66.4

71.8

85.3

0.346

134

143

153

167

181

198

208

224

0.443

206

210

220

222

243

252

277

288

0.543

265

267

271

300

320

343

364

0.649

296

316

321

329

347

352

366

379

0.760

276

303

315

320

335

339

345

353

0.877

191

lP

na

10 𝑥1

283

199

222

242

258

271

313

324

23.3

25.0

27.6

31.4

36.6

43.8

53.6

46.0

49.6

54.6

61.6

70.7

82.8

98.7

76.1

84.1

93.7

105

119

136

156

Jo ur

5 𝐴⁄𝐸 ,𝐴𝐵𝐶

re

10 𝑥1 0.0814

0.0814

22.5

0.166

43.8

0.254

69.5

0.346

133

144

155

167

180

194

209

225

0.443

206

211

218

227

239

254

271

291

0.543

264

267

274

285

299

317

340

368

0.649

299

310

321

332

344

355

366

378

0.760

280

297

312

324

334

342

347

350

0.877

189

204

220

238

258

279

303

328

10 𝑥1 0.0814

19.9

19.6

19.2

24.3

27.4

38.3

46.2

57.5

0.166

40.9

45.0

47.7

54.6

59.7

75.3

81.0

94.8

0.254

77.3

85.5

92.8

101

109

128

135

151

0.346

132

140

150

159

172

192

205

223

5 𝐴⁄𝐸 ,𝑅𝐾

24

Journal Pre-proof 0.443

202

206

215

224

242

259

282

299

0.543

267

271

276

285

305

317

341

357

0.649

299

317

321

327

345

351

364

377

0.760

273

301

314

321

335

340

347

358

0.877

192

200

222

242

259

271

312

323

10 𝑥1 0.0814

21.9

23.3

25.4

28.3

32.1

37.0

43.6

52.0

0.166

43.9

46.3

49.9

54.7

61.1

69.3

79.8

93.2

0.254

79.8

83.8

89.4

97.0

107

119

134

153

0.346

131

137

145

156

169

186

206

230

0.443

194

202

213

227

243

262

286

313

0.543

252

263

276

292

310

330

353

380

0.649

284

298

313

329

346

365

385

406

0.760

270

285

300

315

330

344

358

372

0.877

208

222

235

247

275

282

c

ro

267

Standard uncertainty is u(T) = 0.05 K, u(p) = 0.3 kPa. Relative standard uncertainty is ur(𝑥1 ) =

0.05. b

258

-p

a

of

5 𝐴⁄𝐸 ,𝐽𝐴

𝑥20 is the initial mole fraction of acetone in the binary solvents. 𝐴⁄𝑊,𝑒𝑥𝑝

𝐴⁄𝐸,𝑒𝑥𝑝

⁄

⁄

re

𝑥1 and 𝑥1 are the experimental mole fraction solubility of ceftezole in binary solvents of acetone + water and acetone + ethanol.

e

𝐴⁄𝑊,𝑅𝐾

𝐴⁄𝐸,𝑅𝐾

lP

𝑥1𝐴 𝑊,𝐴𝐵𝐶 and 𝑥1𝐴 𝐸,𝐴𝐵𝐶 are the calculated mole fraction solubility of ceftezole in binary solvents of acetone + water and acetone + ethanol by ABC model. d

⁄

⁄

na

𝑥1 and 𝑥1 are the calculated mole fraction solubility of ceftezole in binary solvents of acetone + water and acetone + ethanol by CNIBS/R-K model. 𝑥1𝐴 𝑊,𝐽𝐴 and 𝑥1𝐴 𝐸,𝐽𝐴 are the calculated mole fraction solubility of ceftezole in binary solvents of acetone + water and acetone + ethanol by JA model.

Jo ur

e

Fig.7. Mole fraction solubility of ceftezole in acetone and water mixtures from 278.15 K to 313.15 K.

25

of

Journal Pre-proof

Fig.8. Mole fraction solubility of ceftezole in acetone and ethanol mixtures from 278.15 K to

ro

313.15 K.

Table 7. Model parameters and deviations of the modified Apelblat model for ceftezole in binary

A

B

ARD%

105RMSD

178.0878

2.867

0.1472

C

Acetone+Water

re

𝑥20

-p

solvent mixtures (p = 101.3 kPa). a,b

-1182.712

47156.59

0.0720

-1106.823

44085.34

166.6793

1.218

0.1594

0.117

-951.5281

37026.68

143.7117

1.660

0.8124

0.171

-792.4080

30053.88

2.015

1.319

0.237

-511.3223

18110.82

77.87526

1.868

2.631

0.318

-387.0307

13333.68

58.98777

2.726

5.272

0.419

-321.7709

1.624

6.425

0.554

-463.4920

17740.75

69.95121

4.492

23.35

0.736

-473.0542

18818.44

71.01868

0.8150

4.117

na

120.0354

11043.29

48.97742

0.0814

Jo ur

lP

0.0334

-746.7545

30744.53

111.5504

1.975

0.8587

0.166

-583.5582

23692.78

87.17696

1.660

1.476

0.254

-272.8569

10020.61

40.78770

2.633

3.986

0.346

-47.72957

711.2942

6.849446

0.7785

1.625

0.443

-230.3893

9158.026

33.98594

1.189

3.527

0.543

-293.9989

12008.29

43.51142

0.7081

2.470

0.649

-12.07912

-211.8676

1.249039

0.8204

3.218

0.760

167.0770

-8089.968

-25.56243

1.073

3.681

0.877

-79.28864

2062.970

11.65557

1.700

5.461

Acetone+Ethanol

a

A, B and C are the parameters of the Apelblat equation.

b

Standard uncertainty is u(p) = 0.3 kPa.

26

Journal Pre-proof Table 8. Model parameters and deviations of the CNIBS/R-K model for ceftezole in binary solvent mixtures (p = 101.3 kPa).a,b T/K

B0

B1

B2

B3

B4

ARD%

105RMSD

Acetone+Water 19.24782

-8.066258

-31.55524

29.86536

3.091

0.2207

283.15

-11.09836

15.53694

1.742768

-38.59751

28.96903

3.421

1.045

288.15

-11.42434

22.35811

-21.05801

-12.61911

19.96044

3.789

0.4981

293.15

-10.47951

12.80759

22.41965

-92.60715

69.56811

3.881

0.6597

298.15

-10.84780

24.45206

-37.43305

20.22693

-0.8020044

3.967

2.224

303.15

-10.58030

26.04632

-48.97955

45.37463

-18.10641

4.777

3.620

308.15

-9.998811

23.66823

-40.88429

30.22318

-7.960328

4.482

3.379

313.15

-9.403465

20.82587

-29.83273

9.747939

3.527

of

-11.68040

3.345

278.15

-9.327335

10.51294

-8.061633

1.012260

-1.062252

4.404

3.993

283.15

-9.620759

15.31375

-27.24137

29.88472

-15.60378

4.114

3.807

288.15

-9.785706

17.66079

-34.53806

38.03974

-18.43440

4.283

4.107

293.15

-9.388687

15.11635

-27.21070

28.22112

-13.52449

2.789

3.544

298.15

-9.194962

13.91448

-22.75555

-p

278.15

21.36172

-9.926463

3.749

5.344

303.15

-8.722875

11.90965

-18.69145

16.77211

-7.727026

1.123

3.514

308.15

-8.271288

7.457549

-1.627036

-9.350985

5.953132

1.149

2.413

313.15

-7.973036

6.308773

0.4762251

-11.33171

6.729405

2.758

5.475

lP

re

ro

Acetone+Ethanol

5.165886

B0, B1, B2, B3 and B4 are the parameters of the CNIBS/R-K model.

b

Standard uncertainty is u(p) = 0.3 kPa.

na

a

Jo ur

Table 9. Model parameters and deviations of the Jouyban–Acree model for ceftezole in binary solvent mixtures (p = 101.3 kPa).a,b Parameters

Acetone+Water

Acetone+Ethanol

-1005.532

-617.3409

38658.31

24756.00

151.8934

92.23662

A4

1085.748

844.4658

A5

-40004.56

-33508.41

A6

-1858.667

-2720.720

A7

-10295.24

1007.686

A8

9439.657

-503.9095

A9

163.9044

-126.7757

ARD%

4.960

4.099

1.203

1.188

A1 A2 A3

4

10 RMSD a

A1, A2, A3, A4, A5, A6, A7, A8 and A9 are the parameters of the Jouyban–Acree model.

b

Standard uncertainty is u(p) = 0.3 kPa.

27

Journal Pre-proof

The modified Apelblat equation, CNIBS/R–K model and Jouyban–Acree model were adopted to correlate the solubility of ceftezole in the above binary solvent systems and the results are given in Table 6. In the meantime, the values of the model parameters and the calculated accuracies of the corresponding models are listed in Tables 7-9. It can be observed from Table 7-9 that the ARD% and RMSD values of three

of

models in all the measured binary solvent systems are all below 5% and 0.025%,

ro

separately, indicating that the three models have decent fitting effect and can be utilized

-p

to accurately predict the experimental data. Therefore, the data presented here can be

re

used for the design and optimization of the crystallization process for ceftezole.

lP

4.5 Mixing and dissolution thermodynamic properties The mixing and dissolution thermodynamic properties of ceftezole in all the tested

na

solvent systems were calculated by the NRTL model from the experimental solubility

Jo ur

data and the results are listed in Tables 10-15. It can be found that the values of ΔmixG are negative while the values of ΔmixH are positive, which means that the mixing processes of ceftezole in all the studied solvent systems are spontaneous and endothermic. Similar results can be found for the dissolution processes. From Table 11 and Table 14-15, negative ΔdisG and positive ΔdisH confirm that the dissolution processes are also spontaneous and endothermic. In addition, the positive values of ΔmixH and ΔdisH are also consistent with the experimental rule that the solubility data of ceftezole in the studied solvent systems increase with the increasing temperature.

28

Journal Pre-proof Table 10. The mixing thermodynamic properties of ceftezole in pure solvents (p = 101.3 kPa).a,b T(K)

∆mixG(J·mol-1)

∆mixS(J·K-1·mol-1)

∆mixH(kJ·mol-1)

Isopropanol 278.15

-3.8852

4.8503

1.3452

283.15

-4.1731

5.1905

1.4655

288.15

-4.5897

5.7226

1.6444

293.15

-5.5728

7.1328

2.0854

298.15

-7.1920

9.5797

2.8490

303.15

-8.0423

10.793

3.2639

308.15

-10.005

13.843

4.2558

313.15

-11.931

16.853

5.2656

of

Ethanol -2.7434

3.6278

1.0063

283.15

-3.4810

4.8045

1.3569

288.15

-3.8836

5.3713

293.15

-4.4364

6.1982

1.8126

298.15

-6.1856

303.15

-6.9759

308.15

-8.5770

313.15

-11.433

1.5438

9.2676

2.7570

10.512

3.1796

13.309

4.0927

18.597

5.8124

re

-p

ro

278.15

lP

Methanol

-0.51282

0.18737

0.051604

283.15

-0.64582

0.23793

0.066723

-0.83545

0.31221

0.089129

-1.0629

0.40351

0.11722

-1.4482

0.56629

0.16739

-1.9596

0.79322

0.23850

-2.5225

1.0531

0.32199

-3.2285

1.3941

0.43333

-0.44338

0.20576

0.056789

283.15

-0.54713

0.25681

0.072169

288.15

-0.70934

0.34182

0.097787

293.15

-0.83664

0.40716

0.11852

298.15

-1.0976

0.55619

0.16473

303.15

-1.4313

0.75957

0.22883

308.15

-1.9134

1.0794

0.33071

313.15

-2.4194

1.4340

0.44665

293.15 298.15 303.15 308.15 313.15 278.15

Jo ur

288.15

na

278.15

Water

Acetonitrile 278.15

-10.807

23.089

6.4115

283.15

-12.314

26.296

7.4333

288.15

-15.038

32.499

9.3496

29

Journal Pre-proof 293.15

-15.439

32.725

9.5778

298.15

-17.844

37.892

11.280

303.15

-22.879

49.431

14.962

308.15

-27.840

60.548

18.630

313.15

-32.727

71.203

22.264

Ethyl Acetate -14.258

23.728

6.5857

283.15

-17.187

29.105

8.2239

288.15

-19.787

33.723

9.6976

293.15

-26.563

46.878

13.716

298.15

-31.752

56.585

16.839

303.15

-35.279

62.664

18.961

308.15

-43.815

78.808

24.241

313.15

-58.394

106.84

33.398

Acetone 283.15

-48.193

288.15

-48.949

293.15

-49.498

298.15

-50.516

303.15

-53.912

308.15 313.15

22.182 22.181

77.666

22.331

76.455

22.363

76.009

22.611

79.347

24.000

-55.872

80.219

24.664

-65.089

92.254

28.824

lP

re

78.508

na

mixG, mixS and mixH are the mixing Gibbs free energy, mixing entropy and mixing enthalpy,

respectively. b

79.920

-p

-47.765

The combined expanded uncertainties U are Uc(Hm) = 0.060Hm, Uc(Sm) = 0.065Sm,

Jo ur

a

278.15

ro

of

278.15

Uc(Gm) = 0.065Gm (0.95 level of confidence). Table 11. The dissolution thermodynamic properties of ceftezole in pure solvents (p = 101.3 kPa).a,b T(K)

∆disG(J·mol-1)

∆disS(J·K-1·mol-1)

∆disH(kJ·mol-1)

Isopropanol 278.15

-2.0222

4.8559

1.3486

283.15

-2.2248

5.1964

1.4691

288.15

-2.5156

5.7290

1.6483

293.15

-3.1929

7.1403

2.0900

298.15

-4.3445

9.5888

2.8545

303.15

-4.9881

10.803

3.2700

308.15

-6.4730

13.855

4.2629

313.15

-7.9802

16.866

5.2737

3.6320

1.0089

Ethanol 278.15

-1.3379 30

Journal Pre-proof 283.15

-1.7910

4.8097

1.3601

288.15

-2.0569

5.3769

1.5473

293.15

-2.4266

6.2045

1.8164

298.15

-3.6108

9.2758

2.7620

303.15

-4.1832

10.521

3.1852

308.15

-5.3514

13.320

4.0992

313.15

-7.4963

18.611

5.8204

Methanol -0.16625

0.18841

0.052240

283.15

-0.21839

0.23923

0.067518

288.15

-0.29455

0.31389

0.090152

293.15

-0.39137

0.40561

0.11851

298.15

-0.55830

0.56913

0.16913

303.15

-0.79474

0.79699

0.24081

308.15

-1.0772

1.0579

313.15

-1.4539

1.4000

0.43697

0.32491

0.20666

0.057340

0.25792

0.072846

0.34325

0.098661

0.40884

0.11955

-0.41394

0.55837

0.16606

303.15

-0.56230

0.76238

0.23055

308.15

-0.78568

1.0831

0.33299

-1.0384

1.4387

0.44948

-7.2178

23.100

6.4180

-8.3931

26.308

7.4406

-10.555

32.513

9.3581

-10.887

32.739

9.5866

-12.841

37.908

11.289

303.15

-16.997

49.450

14.974

308.15

-21.175

60.570

18.644

313.15

-25.354

71.227

22.279

-p

ro

of

278.15

-0.14308

283.15

-0.18367

288.15

-0.24720

293.15

-0.30357

298.15

278.15 283.15 288.15 293.15 298.15

na

Acetonitrile

Jo ur

313.15

lP

278.15

re

Water

Ethyl Acetate 278.15

-8.8040

23.744

6.5957

283.15

-10.988

29.124

8.2354

288.15

-12.980

33.744

9.7105

293.15

-18.256

46.904

13.732

298.15

-22.424

56.614

16.857

303.15

-25.327

62.696

18.981

308.15

-32.378

78.845

24.264

31

Journal Pre-proof 313.15

-44.643

106.88

33.426

Acetone

a

278.15

-3.4150

80.053

22.263

283.15

-3.5326

78.644

22.265

288.15

-3.7064

77.806

22.416

293.15

-3.9370

76.598

22.451

298.15

-4.2249

76.156

22.702

303.15

-4.5793

79.507

24.098

308.15

-4.9990

80.387

24.766

313.15

-5.4949

92.454

28.946

disG, disS and disH are the dissolution Gibbs free energy, dissolution entropy and dissolution

b

of

enthalpy, respectively. The combined expanded uncertainties U are Uc(Hd) = 0.060Hd, Uc(Sd) = 0.065Sd, Uc(Gd)

ro

= 0.065Gd (0.95 level of confidence).

𝑥20

∆mixG(J·mol-1)

∆mixS(J·K-1·mol-1)

re

acetone+water (p = 101.3 kPa).a,b

-p

Table 12. The mixing thermodynamic properties of ceftezole in binary solvent mixtures of ∆mixH(kJ·mol-1)

T=278.15 K

-150.26

-120.37

-33.630

0.0720

-214.32

-145.70

-40.741

0.117

-253.49

-81.537

-22.933

0.171

-284.79

61.826

16.912

-322.41

267.87

74.185

-380.71

504.75

140.01

-470.94

721.44

200.20

-584.12

825.19

228.94

-670.16

682.90

189.28

-149.90

-131.36

-37.346

-212.36

-168.39

-47.891

0.117

-250.20

-115.25

-32.883

0.171

-280.55

19.108

5.1299

0.237

-318.61

219.92

61.952

0.318

-377.26

455.23

128.52

0.419

-474.58

679.80

192.01

0.554

-598.29

799.14

225.68

0.736

-679.81

667.07

188.20

0.419 0.554 0.736 0.0334 0.0720

na

0.318

Jo ur

0.237

lP

0.0334

T=283.15 K

T=288.15 K 0.0334

-149.79

-141.78

-41.004

0.0720

-211.18

-189.88

-54.925

0.117

-248.11

-147.26

-42.680

32

Journal Pre-proof 0.171

-278.35

-21.269

-6.4069

0.237

-317.21

174.48

49.960

0.318

-381.03

411.56

118.21

0.419

-478.18

638.07

183.38

0.554

-596.19

760.84

218.64

0.736

-686.88

649.06

186.34

T=293.15 K -150.15

-151.61

-44.594

0.0720

-210.68

-210.28

-61.854

0.117

-246.89

-177.81

-52.371

0.171

-277.38

-59.893

-17.835

0.237

-317.22

130.79

38.025

0.318

-385.50

368.71

107.70

0.419

-489.25

601.97

175.98

0.554

-599.07

725.97

0.736

-703.51

637.85

186.28

212.22

-160.91

-48.127

-229.64

-68.678

-206.78

-61.897

-96.525

-29.057

-322.80

91.791

27.045

0.318

-390.31

326.39

96.923

0.419

-496.80

563.05

167.38

-624.56

707.58

210.34

-720.22

626.57

186.09

-152.10

-169.69

-51.594

-211.91

-247.96

-75.380

-248.31

-234.11

-71.220

-280.84

-130.99

-39.992

0.237

-330.02

54.561

16.210

0.318

-401.26

288.99

87.207

0.419

-516.19

533.06

161.08

0.554

-655.98

693.53

209.59

0.736

-741.70

618.67

186.81

-p

ro

of

0.0334

-150.87

0.0720

-210.88

0.117

-246.88

0.171

-278.09

0.237

0.0334 0.0720 0.117 0.171

na

0.736

Jo ur

0.554

lP

0.0334

re

T=298.15 K

T=303.15 K

T=308.15 K 0.0334

-154.03

-177.94

-54.987

0.0720

-214.12

-265.16

-81.922

0.117

-251.21

-259.84

-80.321

0.171

-288.58

-161.43

-50.032

0.237

-340.44

20.189

5.8808

33

Journal Pre-proof 0.318

-419.08

256.98

78.769

0.419

-538.56

505.06

155.10

0.554

-674.39

669.49

205.63

0.736

-769.25

615.17

188.79

T=313.15 K -185.69

-58.307

0.0720

-217.34

-281.33

-88.316

0.117

-257.64

-282.90

-88.849

0.171

-298.44

-189.74

-59.716

0.237

-356.79

-9.3665

-3.2899

0.318

-445.61

231.69

72.107

0.419

-572.89

485.96

151.61

0.554

-703.36

652.99

203.78

0.736

-805.99

618.47

192.87

of

-156.65

ro

a

0.0334

mixG, mixS and mixH are the mixing Gibbs free energy, mixing entropy and mixing enthalpy,

b

-p

respectively.

The combined expanded uncertainties U are Uc(Hm) = 0.060Hm, Uc(Sm) = 0.065Sm, Uc(Gm)

re

= 0.065Gm (0.95 level of confidence).

acetone+ethanol (p = 101.3 kPa).a,b 𝑥20

lP

Table 13. The mixing thermodynamic properties of ceftezole in binary solvent mixtures of ∆mixG(J·mol-1)

∆mixS(J·K-1·mol-1)

∆mixH(kJ·mol-1)

na

T=278.15 K

-3883.6

3146.5

871.31

0.166

-6368.7

5957.0

1650.6

0.254

-7875.4

7989.5

2214.4

-8594.0

9119.1

2527.9

-8640.7

9343.6

2590.3

-8090.7

8729.2

2419.9

-6977.4

7368.7

2042.6

-5325.5

5390.9

1494.2

-3083.9

2895.6

802.32

0.346 0.443 0.543 0.649 0.760 0.877

Jo ur

0.0814

T=283.15 K 0.0814

-3835.3

3065.2

864.07

0.166

-6301.7

5827.3

1643.7

0.254

-7809.4

7849.7

2214.8

0.346

-8537.4

8989.4

2536.8

0.443

-8601.3

9240.5

2607.8

0.543

-8074.6

8664.6

2445.3

0.649

-6991.8

7355.8

2075.8

0.760

-5363.8

5414.6

1527.8

0.877

-3124.5

2922.2

824.30

34

Journal Pre-proof T=288.15 K 0.0814

-3789.5

2987.6

857.09

0.166

-6238.1

5702.9

1637.0

0.254

-7745.9

7713.2

2214.8

0.346

-8483.5

8863.5

2545.5

0.443

-8564.6

9142.1

2625.7

0.543

-8060.0

8601.4

2470.4

0.649

-7004.6

7335.6

2106.8

0.760

-5401.8

5433.2

1560.2

0.877

-3170.3

2957.1

848.92

-3746.7

2914.0

0.166

-6178.4

5585.0

1631.1

0.254

-7685.5

7581.8

2214.9

0.346

-8432.3

8742.2

0.443

-8528.1

ro

2554.3

9041.3

2641.9

0.543

-8047.9

8542.7

2496.3

0.649

-7018.8

7317.4

2138.1

0.760

-5439.6

5449.1

1592.0

0.877

-3219.4

2994.0

874.49

re

of

0.0814

-p

T=293.15 K 850.49

-3706.4

0.166

-6121.9

0.254

-7626.3

0.346 0.443 0.649 0.760 0.877

844.20

5472.2

1625.4

7451.3

2214.0

-8383.5

8624.1

2562.9

-8496.9

8951.9

2660.5

-8038.2

8487.7

2522.6

-7035.9

7304.2

2170.7

-5480.0

5469.5

1625.2

-3271.0

3032.2

900.78

Jo ur

0.543

2843.9

na

0.0814

lP

T=298.15 K

T=303.15 K

0.0814

-3669.2

2777.6

838.37

0.166

-6068.9

5365.0

1620.3

0.254

-7574.9

7336.7

2216.5

0.346

-8336.8

8509.3

2571.2

0.443

-8464.9

8857.8

2676.8

0.543

-8030.4

8434.8

2549.0

0.649

-7051.8

7285.5

2201.6

0.760

-5519.6

5485.6

1657.5

0.877

-3324.5

3070.7

927.57

T=308.15 K 0.0814

-3633.5

2713.8 35

832.61

Journal Pre-proof 0.166

-6017.1

5259.5

1614.7

0.254

-7521.0

7215.0

2215.8

0.346

-8290.8

8393.8

2578.3

0.443

-8437.4

8773.1

2695.0

0.543

-8024.4

8383.7

2575.4

0.649

-7070.0

7270.8

2233.4

0.760

-5560.0

5502.8

1690.1

0.877

-3386.7

3123.7

959.18

2652.7

827.10

0.166

-5969.3

5160.8

1610.1

0.254

-7471.4

7101.6

2216.4

0.346

-8247.7

8283.7

2585.8

0.443

-8408.9

8683.2

2710.7

0.543

-8019.6

8332.8

0.649

-7089.2

ro

2601.4

7256.2

2265.2

0.760

-5601.3

5520.5

1723.2

0.877

-3448.8

3169.4

989.05

of

-3599.9

mixG, mixS and mixH are the mixing Gibbs free energy, mixing entropy and mixing enthalpy,

re

a

0.0814

-p

T=313.15 K

respectively.

The combined expanded uncertainties U are Uc(Hm) = 0.060Hm, Uc(Sm) = 0.065Sm, Uc(Gm)

lP

b

na

= 0.065Gm (0.95 level of confidence).

Table 14. The dissolution thermodynamic properties of ceftezole in binary solvent mixtures of acetone+water (p = 101.3 kPa).a,b

0.0334

∆disG(J·mol-1)

Jo ur

𝑥20

∆disS(J·K-1·mol-1)

∆disH(kJ·mol-1)

T=278.15 K

-149.73

-120.37

-33.629

-213.26

-145.70

-40.739

-251.49

-81.531

-22.929

-280.29

61.839

16.920

0.237

-311.67

267.90

74.205

0.318

-356.44

504.82

140.06

0.419

-424.25

721.58

200.28

0.554

-515.44

825.40

229.07

0.736

-573.17

683.19

189.46

0.0720 0.117 0.171

T=283.15 K 0.0334

-149.19

-131.36

-37.345

0.0720

-211.17

-168.38

-47.889

0.117

-247.80

-115.24

-32.878

0.171

-275.19

19.124

5.1398

0.237

-305.52

219.96

61.977

36

Journal Pre-proof 0.318

-349.83

455.31

128.57

0.419

-417.99

679.97

192.11

0.554

-511.03

799.41

225.84

0.736

-574.91

667.39

188.40

T=288.15 K -148.99

-141.78

-41.002

0.0720

-209.68

-189.88

-54.923

0.117

-244.93

-147.25

-42.674

0.171

-271.09

-21.246

-6.3932

0.237

-300.49

174.53

49.991

0.318

-344.37

411.67

118.28

0.419

-412.94

638.27

183.51

0.554

-508.14

761.11

218.81

0.736

-577.49

649.40

186.55

ro

of

0.0334

-149.10

-151.61

-44.592

0.0720

-208.76

-210.27

-61.851

0.117

-242.85

-177.79

-52.363

0.171

-267.95

-59.864

-17.817

0.237

-296.55

130.86

38.065

0.318

-340.09

368.85

107.79

0.419

-408.93

602.22

176.13

0.554

-506.07

726.26

212.40

0.736

-580.38

638.23

186.52

lP

na

T=298.15 K -160.91

-48.124

-208.37

-229.63

-68.673

-241.51

-206.76

-61.887

-265.73

-96.486

-29.033

-293.69

91.883

27.101

-336.96

326.56

97.027

0.419

-406.12

563.34

167.55

0.554

-504.80

707.96

210.57

0.736

-584.07

627.00

186.36

0.0720 0.117 0.171 0.237 0.318

-149.51

Jo ur

0.0334

re

0.0334

-p

T=293.15 K

T=303.15 K 0.0334

-150.19

-169.68

-51.590

0.072

-208.50

-247.95

-75.373

0.117

-240.89

-234.09

-71.205

0.171

-264.40

-130.94

-39.959

0.237

-291.84

54.684

16.286

0.318

-334.95

289.21

87.338

0.419

-404.30

533.42

161.30

37

Journal Pre-proof 0.554

-504.26

694.02

209.89

0.736

-588.45

619.17

187.11

T=308.15 K -151.13

-177.93

-54.981

0.0720

-209.12

-265.14

-81.912

0.117

-240.96

-259.81

-80.300

0.171

-263.93

-161.34

-49.982

0.237

-290.99

20.352

5.9804

0.318

-334.01

257.26

78.941

0.419

-403.53

505.51

155.37

0.554

-504.73

670.04

205.97

0.736

-593.56

615.75

189.15

-152.32

-185.68

0.0720

-210.20

-281.31

-88.301

0.117

-241.68

-282.85

-88.816

0.171

-264.26

-189.63

-59.646

0.237

-291.07

-9.1464

-3.1553

0.318

-334.01

232.06

72.336

0.419

-403.61

486.53

151.95

0.554

-506.05

653.65

204.18

0.736

-599.42

619.16

193.29

lP

re

ro

0.0334

-p

T=313.15 K

of

0.0334

-58.298

disG, disS and disH are the dissolution Gibbs free energy, dissolution entropy and dissolution enthalpy, respectively. b

na

a

The combined expanded uncertainties U are Uc(Hd) = 0.060Hd, Uc(Sd) = 0.065Sd, Uc(Gd)

Jo ur

= 0.065Gd (0.95 level of confidence).

Table 15. The dissolution thermodynamic properties of ceftezole in binary solvent mixtures of acetone+ethanol (p = 101.3 kPa).a,b 𝑥20

∆disG(J·mol-1)

∆disS(J·K-1·mol-1)

∆disH(kJ·mol-1)

T=278.15 K

0.0814

-3877.1

3146.5

871.32

0.166

-6355.9

5957.0

1650.6

0.254

-7855.5

7989.6

2214.5

0.346

-8555.1

9119.3

2528.0

0.443

-8581.0

9343.8

2590.4

0.543

-8013.8

8729.5

2420.1

0.649

-6891.4

7369.0

2042.8

0.760

-5245.5

5391.1

1494.3

0.877

-3028.5

2895.7

802.42

T=283.15 K 0.0814

-3828.5

3065.2 38

864.09

Journal Pre-proof 0.166

-6288.5

5827.3

1643.7

0.254

-7787.2

7849.7

2214.9

0.346

-8496.6

8989.6

2536.9

0.443

-8541.1

9240.7

2608.0

0.543

-7998.3

8664.8

2445.4

0.649

-6901.4

7356.0

2076.0

0.760

-5277.2

5414.9

1527.9

0.877

-3067.7

2922.4

824.41

T=288.15 K -3782.6

2987.6

857.10

0.166

-6224.5

5702.9

1637.1

0.254

-7721.9

7713.2

2214.8

0.346

-8440.4

8863.6

2545.6

0.443

-8502.7

9142.2

2625.8

0.543

-7983.7

8601.6

0.649

-6914.4

7335.9

2106.9

0.760

-5313.2

0.877

-3108.0

2957.3

849.04

ro

2470.6

-p

of

0.0814

5433.5

1560.4

2914.0

850.51

5585.0

1631.1

7581.9

2215.0

8742.3

2554.4

9041.5

2642.1

-7969.5

8543.0

2496.4

-6927.7

7317.7

2138.3

-5350.9

5449.4

1592.1

-3152.4

2994.3

874.61

0.166

-6163.4

0.254

-7659.2

0.346

-8386.2

0.443

-8466.6

0.543 0.649 0.877 0.0814

Jo ur

0.760

lP

-3739.2

na

0.0814

re

T=293.15 K

T=298.15 K

-3698.1

2843.9

844.21

-6105.0

5472.2

1625.4

0.254

-7599.7

7451.3

2214.0

0.346

-8334.0

8624.3

2563.0

0.443

-8430.6

8952.1

2660.7

0.543

-7956.3

8488.0

2522.7

0.649

-6941.2

7304.5

2170.9

0.760

-5388.7

5469.8

1625.4

0.877

-3200.6

3032.4

900.91

0.166

T=303.15 K 0.0814

-3658.9

2777.7

838.39

0.166

-6049.0

5365.1

1620.4

0.254

-7540.8

7336.8

2216.6

39

Journal Pre-proof 0.346

-8283.8

8509.4

2571.3

0.443

-8397.4

8858.0

2676.9

0.543

-7944.4

8435.1

2549.1

0.649

-6957.4

7285.8

2201.7

0.760

-5428.8

5485.9

1657.6

0.877

-3251.7

3071.0

927.71

-3621.7

2713.8

832.64

0.166

-5995.5

5259.6

1614.8

0.254

-7485.3

7215.1

2215.8

0.346

-8236.0

8394.0

2578.4

0.443

-8364.4

8773.3

2695.1

0.543

-7934.0

8384.0

2575.6

0.649

-6973.4

7271.1

2233.6

0.760

-5469.0

5503.1

0.877

-3304.1

ro

1690.3

3124.0

959.34

2652.8

827.13

5160.9

1610.2

7101.7

2216.5

8283.9

2585.9

8683.5

2710.9

8333.1

2601.6

7256.5

2265.4

of

0.0814

-p

T=308.15 K

T=313.15 K 0.166

-5943.9

0.254

-7431.1

0.346

-8189.5

0.443

-8334.1

0.543

-7925.2

0.649

-6990.7

0.760

-5509.7

5520.9

1723.3

0.877

-3364.7

3169.7

989.22

na

lP

re

-3586.3

Jo ur

a

0.0814

disG, disS and disH are the dissolution Gibbs free energy, dissolution entropy and dissolution

enthalpy, respectively. b

The combined expanded uncertainties U are Uc(Hd) = 0.060Hd, Uc(Sd) = 0.065Sd, Uc(Gd)

= 0.065Gd (0.95 level of confidence).

5. Conclusions In this study, the solubility data of ceftezole in water, methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, acetone, acetone+ water, acetone +ethanol were measured by a static gravimetric method in the temperature range from 278.15 K to 313.15 K. In pure solvents, the solubility values of ceftezole at a given temperature can be ranked as: water＜methanol＜ethanol＜isopropanol＜acetonitrile＜ethyl acetate＜ 40

Journal Pre-proof

acetone. In all tested solvents, the solubility data of ceftezole increase with the increasing of temperature. At the fixed temperature, the solubility data of ceftezole increase with the increasing of the fraction of acetone in acetone + water mixtures. However, co-solvency phenomenon was observed in acetone + ethanol mixtures and the solubility data of ceftezole reach the maximum when the mole fraction of acetone is

of

about 0.649. The experimental data of ceftezole in pure solvents were well correlated

ro

by the modified Apelblat equation and the NRTL model while the experimental data of

-p

ceftezole in binary solvent mixtures were well correlated by the modified Apelblat

effects.

Finally,

mixing and dissolution

lP

can give satisfactory correlation

re

equation, the CNIBS/R–K model and the Jouyban–Acree model. And all these models

thermodynamic properties of ceftezole in pure solvents and binary solvent mixtures

na

were calculated by the NRTL model and the results indicate that both the mixing and

Jo ur

dissolution process in all studied solvents are spontaneous and endothermic.

Acknowledgements

This research is financially supported by the National Natural Science Foundation of China (No.51478308)

References [1] D.-S. Lee, J.-M. Lee, S.-U. Kim, K.-T. Chang, S.-H. Lee, Ceftezole, a cephem antibiotic, is an α-glucosidase inhibitor with in vivo anti-diabetic activity, Int J Mol Med. (2007). 41

Journal Pre-proof

https://doi.org/10.3892/ijmm.20.3.379. [2] J.A. García-Rodríguez, J.L. Muñoz Bellido, J.E. García Sánchez, Oral cephalosporins: current perspectives, International Journal of Antimicrobial Agents. 5 (1995) 231–243. https://doi.org/10.1016/0924-8579(95)00015-Z. [3] J. Wang, C. Xie, Q. Yin, L. Tao, J. Lv, Y. Wang, F. He, H. Hao, Measurement and correlation of

of

Chemical

Thermodynamics.

95

(2016)

63–71.

ro

Journal

of

solubility of cefmenoxime hydrochloride in pure solvents and binary solvent mixtures, The

-p

https://doi.org/10.1016/j.jct.2015.11.024.

re

[4] X. Li, X. Huang, Y. Luan, J. Li, N. Wang, X. Zhang, S. Ferguson, X. Meng, H. Hao, Solubility

lP

and thermodynamic properties of 5-nitrofurazone form gamma in mono-solvents and binary solvent mixtures (vol 275, pg 815, 2019), JOURNAL OF MOLECULAR LIQUIDS. 280 (2019)

na

173–174. https://doi.org/10.1016/j.molliq.2019.01.158.

Jo ur

[5] H. Wu, J. Wang, Y. Zhou, N. Guo, Q. Liu, S. Zong, Y. Bao, H. Hao, Solid–liquid phase equilibrium and dissolution properties of ethyl vanillin in pure solvents, The Journal of Chemical Thermodynamics. 105 (2017) 345–351. https://doi.org/10.1016/j.jct.2016.10.029. [6] G. Wang, Y. Wang, X. Hu, Y. Ma, H. Hao, Determination and correlation of cefoperazone solubility in different pure solvents and binary mixture, Fluid Phase Equilibria. 361 (2014) 223–228. https://doi.org/10.1016/j.fluid.2013.11.005. [7] S. Zong, J. Wang, Y. Xiao, H. Wu, Y. Zhou, Y. Guo, X. Huang, H. Hao, Solubility and dissolution thermodynamic properties of lansoprazole in pure solvents, Journal of Molecular Liquids. 241 (2017) 399–406. https://doi.org/10.1016/j.molliq.2017.06.037.

42

Journal Pre-proof

[8] J. Yang, B. Hou, J. Huang, X. Li, B. Tian, N. Wang, J. Bi, H. Hao, Solution thermodynamics of tris-(2,4-ditert-butylphenyl)-phosphite in a series of pure solvents, Journal of Molecular Liquids. 283 (2019) 713–724. https://doi.org/10.1016/j.molliq.2019.03.122. [9] X. Zhang, Y. Wang, X. Huang, X. Meng, L. Luo, X. Li, B. Sakoth, H. Hao, Solubility and thermodynamic properties of azlocillin in pure and binary solvent systems, Journal of

Apelblat,

E.

Manzurola,

Solubilities

of

o-acetylsalicylic,

4-aminosalicylic,

ro

[10] A.

of

Molecular Liquids. 286 (2019) 110897. https://doi.org/10.1016/j.molliq.2019.110897.

-p

3,5-dinitrosalicylic, and p-toluic acid, and magnesium-DL- aspartate in water from T s ( 278 to

re

348) K, (n.d.) 7.

lP

[11] H. Hojjati, S. Rohani, Measurement and prediction of solubility of paracetamol in water-isopropanol solution. Part 1. Measurement and data analysis, ORGANIC PROCESS

na

RESEARCH & DEVELOPMENT. 10 (2006) 1101–1109. https://doi.org/10.1021/op060073o.

Jo ur

[12] A. Jouyban, B. Clark, Describing solubility of polymorphs in mixed solvents by CNIBS/R-K equation, PHARMAZIE. 57 (2002) 861–862. [13] M. Barzegar-Jalali, A. Jouyban-Gharamaleki, A general model from theoretical cosolvency models,

International

Journal

of

Pharmaceutics.

152

(1997)

247–250.

https://doi.org/10.1016/S0378-5173(97)04922-3. [14] M. del Mar Muñoz, D.R. Delgado, M.Á. Peña, A. Jouyban, F. Martínez, Solubility and preferential solvation of sulfadiazine, sulfamerazine and sulfamethazine in propylene glycol+water mixtures at 298.15K, Journal of Molecular Liquids. 204 (2015) 132–136. https://doi.org/10.1016/j.molliq.2015.01.047.

43

Journal Pre-proof

[15] A. Jouyban, Review of the cosolvency models for predicting solubility of drugs in water-cosolvent mixtures, J Pharm Pharm Sci. 11 (2008) 32. https://doi.org/10.18433/J3PP4K. [16] S. Vahdati, A. Shayanfar, J. Hanaee, F. Martínez, W.E. Acree, A. Jouyban, Solubility of Carvedilol in Ethanol + Propylene Glycol Mixtures at Various Temperatures, Ind. Eng. Chem. Res. 52 (2013) 16630–16636. https://doi.org/10.1021/ie403054z.

of

[17] Y. Guo, Y. Hao, Y. Zhou, Z. Han, C. Xie, W. Su, H. Hao, Solubility and thermodynamic

ro

properties of vanillyl alcohol in some pure solvents, JOURNAL OF CHEMICAL

-p

THERMODYNAMICS. 106 (2017) 276–284. https://doi.org/10.1016/j.jct.2016.11.030.

re

[18] H. Renon, J.M. Prausnitz, Local compositions in thermodynamic excess functions for liquid

lP

mixtures, AIChE J. 14 (1968) 135–144. https://doi.org/10.1002/aic.690140124. [19] M.A. Ruidiaz, D.R. Delgado, F. Martínez, Y. Marcus, Solubility and preferential solvation of

na

indomethacin in 1,4-dioxane+water solvent mixtures, Fluid Phase Equilibria. 299 (2010) 259–

Jo ur

265. https://doi.org/10.1016/j.fluid.2010.09.027. [20] Y. Zhou, J. Wang, B. Fang, N. Guo, Y. Xiao, H. Hao, Y. Bao, X. Huang, Solubility and dissolution thermodynamic properties of 2-Cyano-4′-methylbiphenyl in binary solvent mixtures,

Journal

of

Molecular

Liquids.

236

(2017)

298–307.

https://doi.org/10.1016/j.molliq.2017.04.049. [21] A. Jain, S.H. Yalkowsky, Estimation of Melting Points of Organic Compounds-II, Journal of Pharmaceutical Sciences. 95 (2006) 2562–2618. https://doi.org/10.1002/jps.20634. [22] A. Jain, G. Yang, S.H. Yalkowsky, Estimation of Total Entropy of Melting of Organic Compounds, Ind. Eng. Chem. Res. 43 (2004) 4376–4379. https://doi.org/10.1021/ie0497745.

44

Journal Pre-proof

[23] C.-H. Gu, H. Li, R.B. Gandhi, K. Raghavan, Grouping solvents by statistical analysis of solvent property parameters: implication to polymorph screening, International Journal of Pharmaceutics. 283 (2004) 117–125. https://doi.org/10.1016/j.ijpharm.2004.06.021. [24] I.M. Smallwood, Handbook of organic solvent properties, Arnold ; Halsted Press, London : New York, 1996.

of

[25] U. Domanska, Solubility of benzoyl-substituted naphthols in mixtures of hexane and 1-butanol,

ro

Ind. Eng. Chem. Res. 29 (1990) 470–475. https://doi.org/10.1021/ie00099a026.

-p

[26] L. Lin, K. Zhao, B. Yu, H. Wang, M. Chen, J. Gong, Measurement and Correlation of Solubility

re

of Cefathiamidine in Water + (Acetone, Ethanol, or 2-Propanol) from (278.15 to 308.15) K, J.

Jo ur

na

lP

Chem. Eng. Data. 61 (2016) 412–419. https://doi.org/10.1021/acs.jced.5b00617.

45

Journal Pre-proof

Author statement Lingling Zeng: design, writing, review and editing; Baohong Hou: conception and supervision; Beiqian Tian: analysis of data; Xin Li: software;

of

Hao Wu: supervision;

Jo ur

na

lP

Hongxun Hao: writing and editing.

re

Jinyue Yang: revision;

-p

ro

Kui Chen: investigation;

46

Journal Pre-proof

Conflict of interest Notes

Jo ur

na

lP

re

-p

ro

of

The authors declare no competing financial interest.

47

Journal Pre-proof Highlights 

Solubility data of ceftezole in different solvents were measured.



The experimental solubility data were correlated by different models.



The mixing and dissolution thermodynamic properties of ceftezole were

Jo ur

na

lP

re

-p

ro

of

calculated.

48