J. Chem.

Thermodynamics 57 (2013) 913

Contents lists available at SciVerse ScienceDirect

J. Chem. Thermodynamics
journal homepage: www.elsevier.com/locate/jct

Measurement and correlation of solubility of Tetracycline hydrochloride in six

organic solvents
Yan Zhao, Yongli Wang
School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, Peoples Republic of China

a r t i c l e

i n f o

Article history:
Received 10 April 2012
Received in revised form 26 May 2012
Accepted 11 August 2012
Available online 30 August 2012
Keywords:
Tetracycline hydrochloride
Solubility
Modied Apelblat
NRTL
UNIQUAC

a b s t r a c t
The solubility of Tetracycline hydrochloride (TCH) in methanol, ethanol, 1-propanol, 1-butanol, acetone,
and acetonitrile, was measured using a static method from (283.15 to 318.15) K. The solubility of TCH
decreased in the order of methanol, ethanol, 1-propanol, 1-butanol, acetone, and acetonitrile. With
increasing temperature, the solubility of TCH increased in ethanol, 1-propanol, 1-butanol, acetone, and
acetonitrile but decreased in methanol. Moreover, the experimental solubility data were correlated by
the modied Apelblat equation, NRTL and UNIQUAC models, respectively. And the calculated data by
NRTL model showed better agreement with experimental values than the modied Apelblat equation
and UNIQUAC model.
2012 Elsevier Ltd. All rights reserved.

1. Introduction
Tetracycline hydrochloride (TCH, C22H24N2O8HCl, CAS RN
64-75-5) is a broad-spectrum antibiotic which can be used in the
treatment of disease caused by gram-negative and gram-positive
microorganisms and so on [1]. Besides its antibiotics property, it
can also affect immunomodulation, angiogenesis, inammation
and cell proliferation [2]. Moreover, during past decades, this medicine has been widely used as a model drug for the research of drug
delivery system [3]. The chemical structure of TCH is shown in
gure 1.
In industrial production, TCH was produced through reactive
crystallization of tetracycline urea complex (C22H24N2O8CO(NH2)2) and concentrated hydrochloric acid in 1-butanol. This
reactive crystallization process was traditionally composed of
two steps: rstly, the tetracycline urea complex was decomposed
into urea and tetracycline; secondly, TCH was generated by the
reaction between tetracycline and concentrated hydrochloric acid
and meanwhile the crystallization process of TCH took place. One
of the most serious issue existed in the process was the low purity
(always less than 98%) of nal products. Therefore, the purity of
TCH should be improved through the optimization of reactive crystallization of TCH. Literatures related to this work have seldom
been reported so far.
Generally, the crystallization process is much slow compared
with the reaction [4], which makes it become the rate-controlling
Corresponding author. Tel.: +86 22 27405754; fax: +86 22 27374971.
E-mail address: yliwang@tju.edu.cn (Y. Wang).
0021-9614/$ - see front matter 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.jct.2012.08.007

step of the reactive crystallization process. And it would have a

great effect on the quality of nal products. Among all the factors
inuencing the reactive crystallization process, solvent has a crucial impact on the crystal morphology, crystal size, purity and yield
and so on [5]. It is necessary to select an appropriate solvent for the
optimization of this process. The most basic information for solving
solvent selection problem is the basic physical properties and solubility data. Therefore, this present work aims to measure and correlate the solubility data of TCH in different solvents, which can be
used for the selection of desirable solvent and the optimization of
reactive crystallization process.
In the previous work, Marrucho [6] had measured the solubility
of TCH in water, ethanol, 2-proposal and acetone. However, there
are no experimental data in the literatures for the solubility of
TCH in methanol, 1-propanol, 1-butanol and acetonitrile at temperatures ranging from (283.15 to 318.15) K. Therefore, we determined the solubility of TCH in these four solvent systems,
ethanol as well as acetone by using the static method. On the basis
of the physicochemical properties of each component, the modied
Apelblat equation, NRTL model and UNIQUAC model were used for
correlating and predicting the solubility of TCH in different
solvents.
2. Experimental section
2.1. Materials
All the materials and their purities are listed in table 1. TCH was
precipitated via reaction of tetracycline and concentrated

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Y. Zhao, Y. Wang / J. Chem. Thermodynamics 57 (2013) 913

OH

OH

To verify the reliability of the method of measurement, the

experimental results of TCH were compared with the known results reported in the literature [6]. As seen from gure 2, our experimental results were in good agreement with accessible literature
data and the deviation was less than 1%.

OH
NH2

HCl
H
HO

CH3

OH

H
N

CH3

H3C
FIGURE 1. Chemical structure of Tetracycline hydrochloride.

hydrochloric acid (the molar ratio is 1:1) in 1-butanol. The reaction

was carried out at the temperature of 35 C for 4 h until tetracycline was completely converted into TCH. In our laboratory, the
purity of TCH determined by High Performance Liquid Chromatograph (HPLC) was no less than 98.5% (mass fraction). The high purity is mainly because the tetracycline urea complex was puried
for several times before the reaction. However, the purication
process of this complex is not commonly used in large-scale production due to the economic reasons and only prepared for special
needs.
2.2. Experimental procedure
The solubility of TCH in methanol, ethanol, 1-propanol, 1-butanol, acetone and acetonitrile were determined in a temperature
range of (283.15 to 303.15) K. Firstly, pure solvents and excess solute were added into sealed conical asks at a constant temperature. A shaking table (Julabo SW 23, Germany) was used to
promote the dissolving process and control the experimental temperature with 0.05 K uncertainty. For temperature from (288.25
to 303.15) K, 6 h is sufcient for the phase equilibrium [6]. While
between the temperatures (308.15 and 313.15) K, the experimental time should be about (4 to 5) h, since it is sufcient for TCH
to achieve the equilibrium concentration before it decomposed.
The concentrations of TCH in the liquid phase were then determined by UV spectroscopy (U-3010, HITACH, Japan) at the wavelength with the maximum absorbance, 265 cm1, after which,
the results can be calculated through the calibration curve measured in corresponding solvents. High performance liquid chromatograph (HPLC) was employed to analyze the components in
liquid phase at (308.15 and 313.15) K before and after the equilibrium. The results showed that there existed no newly-formed compounds in liquid phase after the equilibrium. Hence, we can make
sure that there is no degradation during the dissolution process of
TCH.

3. Thermodynamic theory
3.1. Modied Apelblat equation
Modied Apelblat equation has been extensively used in the
correlation and prediction of solubility data of different substances
due to its simplicity. Hence, the temperature dependence of solubility of TCH in pure solvents was predicted by this semiempirical
equation [7]:

where a, b, and c are the empirical parameters. The values of a

and b stand for the variation in the solution activity and the solution behavior resulting from the nonidealities of solution. The value of c represents the relationship between the temperatures
and the enthalpy of fusion.
3.2. Local composition models
Considering the solidliquid equilibrium for the system solid
TCH(1)/pure solvent(2), the solubility (x1) of TCH at different temperatures can be expressed by [8].





Dfus Hm;1 1
1
DC p
T m;1 T m;1


ln

1 ;
T m;1 T
R
R
T
T

lnx1 c1

where c1 is the activity coefcient of solid, x1 is the mole fraction solubility, Tm,1 represents the melting temperature, DfusHm,1
refers to the fusion enthalpy at the melting temperature, and DCp
is the heat capacity difference. Generally, the second term of equation (2) can be neglected due to its very small value. Thus, the
equation (2) can be transformed as [8]:

ln x1



Dfus Hm;1
1
1
 ln c1 ;

T m;1 T
R

where the values of DfusHm,1 and Tm,1 should be determined before the correlation. After that, the activity coefcient can be calculated by the NRTL [9] and UNIQUAC [10] models.
3.2.1. NRTL model
There are three parameters in this model in each binary interaction, the activity coefcients can be calculated by the following
equation:

"
ln c1

TABLE 1
The mass purities and resource of materials.

b
c ln T;
T

ln x1 a

x22

s21 G221

x1 x2 G21 2

s12 G12
x2 x1 G12 2

#
;

where s12, s21, G12 and G21 can be calculated as follows:

Materials

Mass
fraction
purity

Sources

G12 expa12 s12 G21 expa21 s21 ;

Tetracycline urea complex

P0.850

s12

Concentrated hydrochloric acid

Tetracycline hydrochloride crystal
Methanol
Ethanol
1-Propanol
1-Butanol
Acetonitrile
Acetone

P0.385
P0.985
P0.995
P0.995
P0.995
P0.995
P0.995
P0.995

North China Pharmaceutical

Group Corporation
Tianjin Kewei Chemical Co.
Prepared in laboratory
Tianjin Kewei Chemical Co.
Tianjin Kewei Chemical Co.
Tianjin Kewei Chemical Co.
Tianjin Kewei Chemical Co.
Tianjin Kewei Chemical Co.
Tianjin Kewei Chemical Co.

g 12  g 22 Dg 12

RT
RT

s21

g 21  g 11 Dg 21

;
RT
RT

5
6

where Dg12 = g12  g22 and Dg21 = g21  g11 represent the cross
interaction energy, and a is the parameter that reects the nonrandomness in the mixture. All these three parameters can be regressed from the solubility data [11].
3.2.2. UNIQUAC model
In binary systems, the activity coefcients can be expressed as:

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215728

Title
Measurement and correlation of solubility of Tetracycline hydrochloride in six organic solvents

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