Article pubs.acs.org/jced
Determination and Correlation of Solubility of Cephradine and Cefprozil Monohydrate in Water As a Function of pH Hua Sun,†,‡ Cuiyuan Jiang,† Baoshu Liu,*,†,‡ and Junli zhang§ †
College of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang, Hebei Province 050018, People’s Republic of China ‡ Hebei Research Center of Pharmaceutical and Chemical Engineering, Shijiazhuang, Hebei Province 050018, People’s Republic of China § NCPC Hebei Huamin Pharmaceutical Company, Ltd., Shijiazhang, Hebei Province 052160, People’s Republic of China S Supporting Information *
ABSTRACT: The objective of this study is to report the solubility of cephradine form 1 in 0.5% sodium bisulfate (W/ V) solution and cefprozil monohydrate in water, as a function of pH, at temperatures of 283.15, 298.15, and 308.15 K. The experiment was conducted by using a dynamic laser monitoring technique under atmospheric pressure at pH values ranging from 1.45 to 8.57. The solubility data were correlated with two transformational theoretical models. The results show that the pH value has a significant effect on the solubility; as the pH value increased, the solubility of cephradine form 1 and cefprozil monohydrate in water initially decreased before increasing. Additionally, it has a minimum value at the isoelectric point. The effect of temperature, however, was not particularly apparent; the increase of temperature from 283.15 to 308.15 K only improved the solubility slightly. The distribution curves for the species of cephradine form 1 and cefprozil monohydrate in this study were obtained.
1. INTRODUCTION Cephradine (CAS Registry No. 38821-53-3), whose structural formula is shown in Figure 1, is a semisynthetic cephalosporin
Figure 2. Molecular structure of cefprozil monohydrate.
treatment of upper and lower respiratory tract infections as well as skin and soft tissue infections caused by sensitive bacteria. During the production process, cephradine form 1 and cefprozil monohydrate should be purified by crystallization. The crystallization of them is a reaction crystallization because the minimum solubility of them is at the isoelectric point. The solubility of chemicals is a significant property that needs to be determined before production and purification processes are undertaken,6−8 and the aqueous solubility date of drugs is important for their discovery and development.9 There are currently no experimental data on the solubility of cephradine form 1 or cefprozil monohydrate in water as a function of pH. Therefore, in order to design an optimum crystallization plan for cephradine form 1 and cefprozil monohydrate, it is vital to
Figure 1. Molecular structure of cephradine form 1.
antibiotic developed at the Squibb Institute for medical research, and it is a first generation of cephalosporin.1,2 It exhibits broad-spectrum antibacterial activity against Grampositive and Gram-negative microorganisms by inhibiting bacterial cell wall synthesis.3 Cephradine form 1 is effective for respiratory tract infections, otitis media, urinary tract infections, and soft tissue, skin, and skin structure infections with strong antibacterial force, and it caused few adverse reactions. As a basic medicine, cephradine form 1 is used extensively in clinical applications,4,5 and it has the potential to be utilized even more extensively. Cefprozil monohydrate (CAS Registry No. 121123-17-9), whose structural formula is shown in Figure 2, is a second generation of cephalosporin antibiotics widely used in the © 2017 American Chemical Society
Received: May 17, 2017 Accepted: July 26, 2017 Published: August 9, 2017 3423
DOI: 10.1021/acs.jced.7b00446 J. Chem. Eng. Data 2017, 62, 3423−3430
Journal of Chemical & Engineering Data
Article
Figure 3. Ionization balance of cephradine form 1 and cefprozil monohydrate.
ions as well as the zwitter ions, and it can be expressed as the following;22
obtain these data. Since that cephradine form 1 is easily oxidized and its antioxidant is used in industrial synthesis and crystallization, we added 0.5% sodium bisulfate (W/V) to water in this study.4,10 This study aims to obtain an applicable equation for the solubility of cephradine form 1 and cefprozil monohydrate in water as a function of pH and to provide a theoretical foundation for the crystallization of cephradine form 1 and cefprozil monohydrate.11−14 A simple and widely used method for the experimental determination of solubility is the laser monitoring observation technique, which has proved to be accurate and sensitive.15−19 In this work, this method was used to determine the solubility of cephradine form 1 and cefprozil monohydrate.
xA = x A± + x A+ + x A−
In the above equation, xi represents the mole fraction solubility of component i. xA =
(1)
K 2 = α A−αH+/α A±
(2)
mA /MA mA /MA + mB /MB
(4)
where xA is the mole fraction solubility of cephradine form 1 or cefprozil monohydrate, mA and mB are the masses of cephradine form 1 (or cefprozil monohydrate) and water, respectively, and MA and MB represent the molar masses of cephradine form 1 (or cefprozil monohydrate) and water, respectively. The following equations were used by Tsuji et al. to correlate the solubility data of several antibiotics in water as a function of pH.23−25
2. THEORETICAL FRAMEWORK Both cephradine form 1 and cefprozil monohydrate contain amino and carboxyl acid groups; the ionization balance20,21 between them can be expressed in Figure 3. K1 and K2 in Figure 3 represent the dissociation constants for the carboxyl and amino groups of cephradine form 1 or cefprozil monohydrate, respectively. K1 = α A±αH+/α A+
(3)
⎛a + K ⎞ CT = C 0 ⎜ H + 1 + 2 ⎟ a H+ ⎠ ⎝ K1
(5)
In this equation, C0 is the intrinsic solubility of amphoteric cephalosporins with the electrically neutral zwitterion A±, whose unit is milligrams per milliliter, and aH+ is the hydrogen ion activity of the solution. The isoelectric point value can be written as the following:
In the two above equations, αi represents the mole fraction of component i. The apparent solubility of cephradine form 1 or cefprozil monohydrate is the sum of the positive and negative
pI = 3424
1 (pK1 + pK 2) 2
(6) DOI: 10.1021/acs.jced.7b00446 J. Chem. Eng. Data 2017, 62, 3423−3430
Journal of Chemical & Engineering Data
Article
Table 1. Detailed Information about All of the Materials Used in This Study
a
chemicals
CAS registry no.
molar mass (g·mol−1)
source
mass fraction purity (%)
cephradine form 1 cefprozil monohydrate hydrochloric acid ammonia−water sodium bisulfite deionized water
38821-53-3 121123-17-9 7647-01-0 1336-21-6 7631-90-5 7732-18-5
349.40 407.4 36.47 35.05 104.06 18.02
North China Pharmaceutical Co., Ltd. Zhejiang Puluodebang Pharmaceutical Co., Ltd. Shijiazhuang Reagent Co., Ltd. Shijiazhuang Reagent Co., Ltd. Tianjin Yongda Chemical Reagent Co., Ltd. laboratory-made
>99a >99a 37 25−28 ≥58.5 (based on SO2)
Determined by HPLC.
However, the solubility data do not correlate well with eq 5 in their study. −pH
a H = 10
(7)
pK i = −log K i
(8)
+
Δ ln xA = ln x A n+1 − ln x A n ⎡⎛ Cn*+1 ⎢⎜ M = ln⎢⎜ * A C 1 n + ⎢⎜⎝ M + ⎣ A
C0 ⎞ ⎛ ⎟ ⎜ MA ρT ⎟ / ⎜ C0 + MB ⎠ ⎝ MA
⎛C + ⎞ ⎟ CT ⎜ 0 ρ0 ⎟ = C0 ⎜⎜ CT + MB ⎠ ⎝
⎞ MB ⎟ ρT MA ⎟ ⎟ MB ⎠ ρ0 MA
m B0 VB0
and ρT =
m BT VBT
B
ρ0 MA
Δ ln xA = ln
, and mB0 and mBT
MB
, CT <
99% was supplied by North China Pharmaceutical Co., Ltd., Cefprozil monohydrate with a mass fraction purity of >99% was purchased from Zhejiang Puluodebang Pharmaceutical Co., Ltd. The purities of cephradine form 1 and cefprozil monohydrate were determined by high-performance liquid chromatography (HPLC).27 The secondary deionized water was purified in the laboratory. Hydrochloric acid and ammonia−water were purchased from Shijiazhuang Reagent Co., Ltd., China, and their mass fractions were 37% and 25− 28%, respectively. Sodium bisulfite was purchased from Tianjin Yongda Chemical Reagent Co., Ltd. All of the materials were used without further purification. Detailed information about the materials are listed in Table 1. 3.2. Equipment and Procedures. A laser monitoring observation technique was used to determine the solubility of cephradine form 1 and cefprozil monohydrate.15−19 We dissolved the materials in a glass jacketed vessel with a valid volume of 100 mL. A pH meter, with an accuracy of ±0.01, and a calibrated thermometer, with an uncertainty accuracy of ±0.01 K, were both immersed in the solution to measure the pH value and temperature, respectively. A glass buret was used to carefully add ammonia−water and hydrochloric acid to adjust and maintain the pH of the experimental solution.28 The temperature was controlled to an accuracy of ±0.05 K by circulating water from a super thermostat water bath. All of the mass in the experiment was determined by using an electronic analytical balance with an accuracy of ±0.0001 g, and a
(10)
(11)
(12)
Here, C* is the total solubility of 6-APA in water, and the unit is grams per g of solvent. In order to make the correlation more apparent, d ln C* and d pH were replaced by Δ ln C* and ΔpH in this study, respectively. (ln 10)[K1K 2(102pH) − 1] Δ ln C* = ΔpH 1 + K1(10 pH) + K1K 2(102pH)
(16)
, thus, eq 9
Previously, Nezhad used an equation to correlate the solubility data of 6-APA in water as a function of pH.26 (ln 10)[K1K 2(102pH) − 1] d ln C* = d pH 1 + K1(10 pH) + K1K 2(102pH)
(15)
Δ ln xA (ln 10)[K1K 2(102pH) − 1] = ΔpH 1 + K1(10 pH) + K1K 2(102pH)
where xA and xA0 represent the total and intrinsic mole fraction solubility of cephradine form 1 or cefprozil monohydrate, respectively. By combining eq 5 with eqs 7−10, we can get the following equation: xA = x A 0[10(pK1− pH) + 10(pH − pK 2) + 1]
Cn*+ 1 = Δ ln C* Cn*
A combination of eq 13 and eq 15 leads to the following:
can be expressed as the following: CT /C0 = xA /x A 0
B
can be expressed as the following:
represent the mass of water at the isoelectric point value and the mass of water at other pH value, respectively; VB0 and VBT represent the volume of water at the isoelectric point value and the volume of water at other pH value, respectively. To the dilute solution C0 <
