1062 J. Chem. Eng.

Data 2006, 51, 1062-1065

Solubility of Erythromycin A Dihydrate in Different Pure Solvents and Acetone +

Water Binary Mixtures between 293 K and 323 K

Zhanzhong Wang, Jingkang Wang,* Meijing Zhang, and Leping Dang

School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, People’s Republic of China

The solubility of erythromycin A dihydrate in pure ethanol, propan-2-ol, methanol, acetone, chloroform, and
acetone + water was measured by a synthetic method at temperature ranging from 293.20 K to 323.00 K at
atmosphere pressure. The laser monitoring observation technique was used to determine the disappearance of the
solid phase in a solid + liquid mixture. The results of these measurements were correlated by a semiempirical
Apelblat equation.

Introduction Experimental Section

Erythromycin is a mixture of macrolide antibiotics produced Materials. Erythromycin A dihydrate (Figure 1, molecular
by Streptomyces erythreus. The major component is erythro- weight 769.94) had a mass fraction purity of 99.4 %. It was
mycin A, which is the most active antimicrobial agent in obtained by purifying commercial erythromycin, which was
erythromycin mixtures.1 Treatment with this antibiotic drug in obtained from Xi’an Rejoy Pharmaceutical Co. Ltd. of China.
human and veterinary practice is still very common because of First, 20.0 g of erythromycin A dihydrate was dissolved in 80
the high activity against gram-positive and a few gram-negative mL of acetone at a temperature of 45 °C. Then, 160 mL of
strains. In addition, erythromycin is useful as an intermediate water was added to the mixture and stirred at 45 °C for 2 h.
for the preparation of roxithromycin, azithromycin, and clarithro- The wet crystals of erythromycin obtained by filtration were
mycin, and commercial erythromycin is usually available as the washed in 50 °C purified water for 30 min. The crystals were
dihydrate. then filtered off and dried at 45 °C to obtain erythromycin A
Chemical solubility data are of great technical interest. dihydrate. Acetone used for the experiments was of analytical
Crystallization processes are the critical steps that determine reagent grade. Distilled deionized water of HPLC grade was
the quality of final product, and crystallization in aqueous and used.
organic solvents and solvent mixtures is often employed in the Method and Apparatus. The melting point of erythromycin
manufacturing of pharmaceuticals. The solubility of solid A dihydrate was measured with a differential scanning calo-
compounds in pure solvents and solvent mixtures plays a crucial rimeter (Netzsch DSC-204) that was equipped with a data station
role in the development and operation of crystallization pro- (TA analysis) to analyze the result. The temperature axis and
cesses. Therefore, knowing the solubility of the product is a the cell constant of the DSC cell were calibrated with indium.
necessary procedure in designing the crystallization process A sample of 5 mg in a punctured aluminum pan was heated at
properly. In industrial manufacturing, erythromycin is crystal- a rate of 10 K/min under a nitrogen purge of 45 mL/min to 55
lized from solution in the purification step. To determine the mL/min. The range of temperature was from 298 K to 573 K.
proper solvent and to design an optimized crystallizer, it is A thermogravimetric analyzer (Netzsch TG 209) was employed
necessary to know its solubility in different solvent systems. to measure the water content. Measurements were carried out
The published works relating to erythromycin are mainly at a rate of 85 mL/min-1 under a dynamic atmosphere of dry
concerned with synthesis, degradation, and clinical study. nitrogen. The temperature range was ambient to 673 K at a
Investigations of solubility are relatively rare. Huang and Wu heating rate of 10 K/min. The runs were performed using an
studied the solubility of erythromycin in an aqueous acetone alumina crucible containing 4.4 mg of sample, and the alumina
solution from 273.00 K to 293.00 K.2 However, the solubility crucible was used as a reference material. Three experiments
of erythromycin between 293.20 K and 323.00 K is needed in were conducted, and nearly identical results were obtained.
industrial crystallization processes. A systematic study of the Solubility was measured by the synthetic method.3-5 The
solubility of this drug in different solvent systems between apparatus for the solubility measurement (Figure 2) is the same
293.20 K and 323.00 K has not been reported in the literature. as that described in the literature.6,7 The solubility of erythro-
In the present study, the solubility of erythromycin A mycin A dihydrate was measured by the last crystal disappear-
dihydrate in various organic solvents and acetone + water was ance method. The laser monitoring observation technique was
measured in the temperature range from 293.20 K to 323.00 K used to determine the disappearance of the last crystal in the
at atmosphere pressure by a laser monitoring observation solid + liquid mixtures. The system consisted of a laser
technique, and the modified Apelblat equation was used for the generator, a photoelectric transformer, and a light-intensity
correlation of the solubility of erythromycin A dihydrate in display. The equilibrium cell is a cylindrical double-jacketed
different solvents and acetone + water binary mixtures. glass vessel. A constant desired temperature was maintained
by circulating water through the outer jacket from a thermostat.
* To whom correspondence should be addressed. E-mail: The uncertainty in the temperature was ( 0.05 K. Continuous
wzz7698@sohu.com. Fax: 86-22-27374971. stirring was achieved with a magnetic stir bar. A condenser was
10.1021/je0505265 CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/09/2006
 Journal of Chemical and Engineering Data, Vol. 51, No. 3, 2006 1063

Figure 1. Structure of erythromycin A dihydrate. Figure 3. Mole fraction solubility of erythromycin A dihydrate (x1) in
different pure solvents: *, ethanol; 4, acetone; open triangle with point
facing left, chloroform; open triangle with point facing right, methanol; g,
propan-2-ol.

Table 1. Mole Fraction Solubility of Erythromycin A Dihydrate (1)

in Different Pure Solvents from 293.20 K to 323.00 K
100(x1 - x1,calcd) 100(x1 - x1,calcd) 100(x1 - x1,calcd)
T/K 102x1 x1 102x1 x1 102x1 x1
Propan-2-ol Methanol Acetone
293.20 0.3000 2.19 1.162 -0.81 0.9140 -9.39
298.00 0.4012 -0.29 1.432 0.89 1.310 -8.18
303.15 0.5560 -0.92 1.789 2.77 2.170 4.77
308.00 0.7542 -1.32 2.154 1.43 2.930 1.74
313.10 0.9953 -5.62 2.534 -0.95 4.330 3.16
318.00 1.430 0.63 3.050 -1.07 5.420 -3.37
323.00 1.940 0.86 3.730 0.26 8.040 6.23
Chloroform Ethanol Water
293.20 0.3914 5.67 1.483 4.19 0.0054 5.56
298.00 0.5399 -5.39 1.919 1.00 0.0047 -2.13
303.15 0.8749 -2.43 2.544 -1.59 0.0042 -7.14
Figure 2. Schematic setup for the solubility determination: 1, laser 308.00 1.341 -1.61 3.383 -1.62 0.0040 -5.00
generator; 2, dissolution kettle; 3, condenser; 4, injector; 5, inlet for solid; 313.10 2.159 2.81 4.600 -0.51 0.0038 0.00
6, digital display; 7, photoelectric switch; 8, superthermostatic bath; 9, 318.00 3.129 -0.71 6.200 1.25 0.0035 0.00
magnetic stirrer; 10, stir bar; 11, thermometer. 323.00 4.734 0.00 8.100 -0.30 0.0034 8.82

connected to the vessel to prevent the solvent from evaporating. system, mA, mB represent the masses of solute and solvents,
A mercury-in-glass thermometer was inserted into the inner MA, MB are the molecular weights of solute and solvents, and
chambers of the vessel for the measurement of the temperature. mC ) 0. The same solubility experiment was performed three
The temperature had an uncertainty of ( 0.05 K. The masses times. The uncertainty in the solubility values is estimated to
of the solvent and solute were weighed using an analytical be 0.5 %.
balance (type TG 332A, China) with an accuracy of ( 0.0001
g. Results and Discussion
During the measurement, predetermined excess amounts of The melting point of erythromycin A dihydrate measured by
solute and various solvents or binary solvents of known masses differential scanning calorimetry is 410.80 K, and the literature
were transferred to the equilibrium vessel. The contents of the value is 407.00 K to 411.00 K.8 The loss of 4.8 % of the sample
vessel were stirred continuously at an invariable, required weight by thermogravimetric analysis (4.7 % in theory) corre-
temperature for 30 min. Then, additional solvent of known mass sponds to two water molecule in an erythromycin A molecule.
was introduced into the cell. When the last portion of solute The measured solubility of erythromycin A dihydrate in pure
just disappeared, the intensity of the laser beam penetrating the methanol, ethanol, acetone, propan-2-ol, and chloroform at
vessel reached the maximum, and the solvent mass consumed different temperatures is listed in Table 1 and plotted in Figure
in the measurement was recorded. Together with the mass of 3. The temperature dependence of the erythromycin A dihydrate
solute, the solubility was obtained. The saturated mole fraction solubility in pure solvents is described by a modified Apelblat
solubility of the solute (xA) in different pure solvents and binary equation9
acetone + water solvent mixtures can be obtained as follows
B
mA/MA ln x ) A + + C ln T (2)
xA ) (1) T
mA/MA + mB/MB + mC/MC
where x is the mole fraction solubility of erythromycin A
in which mA, mB, and mC represent the masses of solute, acetone, dihydrate, T is the absolute temperature, and A, B, and C are
and water. MA, MB, and MC are the molecular weights of solute, the model parameters. The calculated solubility values of
acetone, and water, respectively. With regard to pure solvents erythromycin A dihydrate are also given in Table 1. The values
1064 Journal of Chemical and Engineering Data, Vol. 51, No. 3, 2006

Table 3. Solubility Data of Erythromycin A Dihydrate (1) in

Acetone (2) + Water (3)
100(x1 - x1,calcd) 100(x1 - x1,calcd) 100(x1 - x1,calcd)
T/K 104x1 x1 104x1 x1 104x1 x1
x3 ) 0.2649 x3 ) 0.4465 x3 ) 0.5935
293.20 60.00 0.28 34.10 5.90 18.10 0.15
298.00 82.00 -3.35 47.10 5.87 23.89 -5.55
303.15 126.4 3.67 63.20 1.65 34.90 -1.10
308.00 170.0 0.23 82.80 -2.35 49.20 3.46
313.10 246.4 3.50 118.3 -1.57 63.80 0.14
318.00 309.7 -5.41 148.9 -5.33 82.70 -0.40
323.00 453.6 1.50 215.5 2.11 106.9 -0.11
x3 ) 0.6827 x3 ) 0.7636 x3 ) 0.8273
293.20 8.240 -5.91 3.621 -1.91 2.501 -3.89
298.00 11.77 -3.50 5.021 -1.59 3.312 -0.04
303.15 17.21 1.02 7.320 3.70 4.298 2.03
Figure 4. ], Solubility of erythromycin A dihydrate in water (x1,w); 4, 308.00 24.30 5.85 9.612 2.62 5.359 3.35
solubility of erythromycin A dihydrate in pure acetone (x1,a); ×, solubility 313.10 30.10 -1.56 11.90 -3.79 6.182 -2.25
in the literature.2 318.00 38.90 -1.90 15.80 -0.10 7.386 -1.90
323.00 51.10 0.67 20.10 0.55 8.953 1.14
Table 2. Parameters of Equation 1 for Erythromycin A Dihydrate x3 ) 0.8826 x3 ) 0.9290 x3 ) 0.9668
in Different Pure Solvents 293.20 1.914 2.46 1.434 3.35 0.5854 4.00
298.00 2.166 3.00 1.409 -0.65 0.5098 -2.51
solvents A B C 102rmsd
303.15 2.323 -0.90 1.407 -1.91 0.4667 -2.49
acetone -120.30 -76.628 21.222 0.11 308.00 2.483 -3.20 1.400 -2.23 0.4186 -4.15
ethanol -121.41 887.84 20.900 0.05 313.10 2.718 -1.96 1.388 -1.70 0.3857 -1.63
propan-2-ol -108.14 -157.08 18.914 0.02 318.00 2.899 -1.70 1.380 0.14 0.3623 3.12
methanol -110.05 -1995.6 18.206 0.03 323.00 3.205 3.25 1.376 3.26 0.3267 4.74
chloroform -105.23 -2079.5 19.596 0.03
Table 4. Parameters of Equation 1 for Erythromycin A Dihydrate
(1) in Acetone (2) + Water (3)
of parameters A, B, and C and the root deviation (rmsd) are
listed in Table 2. The rmsd is defined as water mole
fraction (x3) A B C 104rmsd

{∑ }
N 1/2 0.2649 -3.9815 -5024.2 4.4375 7.8
1 -3448.9 -16.243
rmsd ) (xcalcd - xiexptl)2 (3) 0.4465 148.597 3.8
N
i 0.5935 251.89 -16 152 -34.133 0.84
i)1
0.6827 292.14 -17 979 -40.250 0.69
0.7636 311.85 -18 721 -43.426 0.23
where N is the number of experimental points, xcalcd i represents 0.8273 310.17 -17 421 -43.971 0.12
the solubility calculated from eq 2, and xexptl represents the 0.8826 307.47 -15 386 -44.776 0.06
i 0.9290 305.49 -13 840 -45.408 0.03
experimental solubility values. The solubility in all five solvents 0.9668 303.04 -12 292 -46.065 0.01
increases with temperature. It can be seen from Table 1 that
ethanol and acetone are relatively good solvents for the title solvents. The temperature dependence of erythromycin A
compound. Because the throughput is a very important target dihydrate solubility in acetone + water is also described by the
for industrial interest, relatively high solubility of the compound modified Apelblat equation. The calculated solubility is listed
is needed. By further comparison of the solubility of erythro- in Table 3. Values of parameters A, B, and C and the root
mycin A dihydrate in ethanol and acetone, it is found that deviations (rmsd values) are listed in Table 4. From the data
acetone can be a more appropriate solvent because of its more listed in Table 3, it can be concluded that when x3 < 0.9290,
obvious dependence on temperature. Because erythromycin A the solubility values of erythromycin A dihydrate increase with
dihydrate in pure water is slightly soluble, acetone + water can increasing temperature in acetone + water mixtures in the
be an ideal system for the dilution crystallization of erythro- temperature range from 293.20 K to 323.00 K. When x3 >
mycin. The solubility of erythromycin A dihydrate in acetone 0.9290, the solubility values of erythromycin A dihydrate
+ water was also experimentally measured. decrease slightly with increasing temperature in the temperature
Figure 4 is a plot of the solubility of erythromycin A dihydrate range from 293.20 K to 323.00 K. At a fixed temperature, the
in pure acetone and distilled water between 293.20 K and 323.00 solubility data of erythromycin A dihydrate in acetone + water
K. From Figure 4, it can be seen that the solubility of decreases with increasing water content.
erythromycin A dihydrate decreases with increasing temperature
in pure water, whereas solubility rapidly rises with increasing Conclusions
temperature in pure acetone. There is an inverse dependence of
the solubility in pure water on temperature, which is in good From Tables 1 to 4 and Figure 3, we can draw the following
agreement with the literature.10 conclusions: (1) For all pure solvent systems, solubility is a
On the basis of the above results, it can be expected that function of temperature, and solubility increases with increasing
there should be two contrary tendencies for solubility in acetone temperature. The best solubility of erythromycin A dihydrate
+ water, and it can be inferred that these two tendencies with is shown in acetone. (2) For acetone + water binary mixtures,
respect to solubility will be equal at a certain acetone mole x3 ) 0.9290 is the mole fraction where the solubility of
fraction. erythromycin A dihydrate in acetone + water is essentially
The solubility data of erythromycin A dihydrate in acetone independent of temperature. When x3 < 0.9290, the solubility
+ water in the temperature range from 293.20 K to 323.00 K of erythromycin A dihydrate increases with increasing temper-
are listed in Table 3, confirming the above conclusions. X3 refers ature in the temperature range from 293.20 K to 323.00 K. When
to the initial mole fraction composition of water in the binary x3 > 0.9290, the solubility values of erythromycin A dihydrate
 Journal of Chemical and Engineering Data, Vol. 51, No. 3, 2006 1065

decrease slightly with increasing temperature in the temperature (5) Jiang, Q.; Gao, G.-H.; Yu, Y.-X.; Qin, Y. Solubility of Sodium
range from 293.20 K to 323.00 K. Dimethyl Isophthalate-5-sulfonate in Water and in Water + Methanol
Containing Sodium Sulfate. J. Chem. Eng. Data 2000, 45, 292-294.
The calculated solubility shows good agreement with the (6) Li, D.-Q.; Liu, D.-Z.; Wang, F.-A. Solubilities of Terephthaladehydic,
experimental values. The experimental solubility and correlation p-Toluic, Benzoic, Terephthalic, and Isophthalic Acids in N-Methy-
equation presented can be used as essential data and models in 2-pyrrolidone from 295.65 K to 371.35 K. J. Chem. Eng. Data 2001,
46, 172-173.
the process of the resolution of erythromycin A dihydrate. (7) Li, D.-Q.; Liu, D.-Z.; Wang, F.-A. Solubility of 4-Methylbenzoic Acid
between 288 K and 370 K. J. Chem. Eng. Data 2001, 46, 234-236.
Literature Cited (8) Happy, A.; Rose. Erythromycin and Some of Its Derivations. Cryst.
Data 1954, 26, 938-939
(1) Kiyoshi, T.; John, H. R. Determination of Erythromycin and Its (9) Liu, C. W.; Fu, A. W. Solubility of Niacin in 3-Picolin + Water from
Derivatives by Gas-Liquid Chromatography. Anal. Chem. 1971, 43, 287.65 to 359.15 K. J. Chem. Eng. Data 2004, 49, 155-156.
818-821. (10) Yoshinobu, F.; Yomoaki, F.; Yuko, Y.; Yasue, S.; Yoshinobo, K.;
(2) Huang, A.; Wu, X. Y. Solubility of Erythromycin in Acetone-water Yoshikazu, T. Physical Characterization of Erythromycin Dihydrate,
Solution. Chin. J. Antibiot. 1999, 24, 415-416. Anhydrate and Amorphous Solid and Their Dissolution Properties.
(3) Nyvlt, J. Solid-Liquid Equilibria; Czechoslovak Academia of Sci- Chem. Pharm. Bull. 1983, 31, 4029-4039
ences: Praha, Czechoslovakia, 1997.
(4) Roberts, K. L.; Rousseau, R. W.; Teja, A. S. Solubility of Long-Chain Received for review December 16, 2005. Accepted February 14, 2006.
n-Alkanes in Heptane between 280 and 350 K. J. Chem. Eng. Data
1994, 39, 793-795. JE0505265