Solubility Measurement and Stability Study of Sodium Cefuroxime

Article pubs.acs.org/jced

Solubility Measurement and Stability Study of Sodium Cefuroxime Wen J. Liu,† Cai Y. Ma,† Sheng X. Feng,§ and Xue Z. Wang*,‡,† †

Institute of Particle Science and Engineering, School of Process, Environmental and Materials Engineering, University of Leeds, Leeds LS2 9JT, United Kingdom ‡ School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, Guangdong, PR China 510640 § Sinopharm Weiqida Pharmaceutical Co. Ltd, Economic & Technological Development Zone, Datong, Shanxi, PR China 037300 ABSTRACT: The stability of sodium cefuroxime has been a major concern since it was invented as a valuable antibiotic. In this study, online attenuated total reflection-fourier transform infrared spectroscopy was applied to monitor the change in supersaturation and optimize the solvent flow rate in antisolvent recrystallization experiments of sodium cefuroxime. The solubility of sodium cefuroxime under various temperatures T, pH values, and solvents was measured and correlated in models. The effect of the antisolvent (79.1 % ethanol) flow rate on crystallinity was examined, and the products were analyzed by X-ray diffraction, scanning electron microscopy, and stability test. The results showed that appropriate mean particle size, uniform particle size distribution, and good crystalline state could improve the stability of sodium cefuroxime. The optimum antisolvent flow rate for this recrystallization process under these operating conditions was found to be 2 mL·min−1.

1. INTRODUCTION Cefuroxime is a valuable broad spectrum antibiotic, which has high activity against a wide range of gram-positive and gramnegative micro-organisms.1,2 The sodium salt of cefuroxime, a nontoxic derivative, is well suited to administration by injection because of good solubility in water.3 As one of the secondgeneration cephalosporins, due to its superior lactamase stability, even beyond cefoperazone, the third-generation, sodium cefuroxime always plays an important role in clinical practice. Since being developed by Glaxo in 1976,4 sodium cefuroxime has been widely used. However, its poor stability has been a cause of widespread concern during industrial production. In the storage and transportation processes, its color tends to deepen, solubility and liquidity are reduced, and it becomes sticky.5 In fact, much research has been done to improve its production process as well as the purification process. At present, there are four main methods of sodium cefuroxime production in line with Pharmacopoeia requirements: (a) Acid cefuroxime is dissolved in the mixed solvent of water and acetone, then active carbon is added into the solvent mixture for bleaching. After filtration, sodium salt (sodium lactate, sodium acetate, and sodium ethylhexanoate) is added for crystallization to produce sodium cefuroxime.6−9 (b) Acetonitrile is added and acid cefuroxime forms a solvent compound first, then follows method (a).10,11 (c) N,N-benzyl acetamide is added and acid cefuroxime forms a salt first, and then sodium salt is added to the mixture of acetone, methanol, acetonitrile, and tetrahydrofuran to precipitate out sodium cefuroxime.3,4 (d) Crude sodium cefuroxime is dissolved in water first, then active carbon is added into the solvent mixture for bleaching. After filtration, © 2014 American Chemical Society

water miscible organic solvent (acetone, isopropyl alcohol, and ethanol) is dropped to precipitate out sodium cefuroxime.12−14 The first three methods use different reaction paths, reaction conditions, or solvents to improve the process. The last one is a method for purification by the recrystallization process. In these patents,3,4,7−14 most researchers focused on the purity or the yield of this drug, the stability test is only mentioned as a means of detection, few of them were concerned about the impact of various process parameters on stability, not to mention the crystallinity.15,16 As a drug produced through either the reaction crystallization process or a recrystallization process, the change of the crystalline form can not only affect the drug’s external appearance without altering its internal structure, but also reduce its effectiveness, or even endanger the safety of the consumers of the drug. The stability of a drug can be characterized by its chemical stability and physical stability. Although most studies on drug stability focused on the chemical stability, such as the pathway of chemical degradation and the disadvantage of molecular structure,17,18 the physical stability, such as the crystalline state of the drug is also of critical importance.19,20 Sodium cefuroxime has been described as a predominantly amorphous material in Pharmacopoeia. It is generally accepted that the stability of a drug is lower in amorphous form than in crystalline form. For example, the relationship between degradation rate and crystallinity determined from heats of dissolution for ß-lactam antibiotics, such as sodium cefazolin, indicates that a Received: October 24, 2013 Accepted: February 4, 2014 Published: February 17, 2014 807

dx.doi.org/10.1021/je400938a | J. Chem. Eng. Data 2014, 59, 807−816

Journal of Chemical & Engineering Data

Article

data in mixtures of water and ethanol of different ratios, at varied temperatures, and pH values. Commercial sodium cefuroxime, batch no. 11112062, was dissolved in this solvent, and the mixture was filtered through Whatman Qualitative Circles FDH-300-130T filter paper using a Vacuubrand MZ 2C+2AK vacuum pump. The clear filtrate was evaporated to dryness in a DZF-6030B vacuum oven at approximate 35 °C with a ABF 63/4c-7RQ vacuum pump within half an hour (to prevent sodium cefuroxime from degradation), and the remaining solid was weighed using an AND GX-200 balance. Each measurement was weighed twice at 5 min interval. If the two measurements gave the same weight, it indicated that the sample was dry. Then the solution solubility was calculated using the following equation:

drug with low crystallinity tends to have decreased chemical stability.21,22 Therefore it is likely that an increase of its crystallinity via improved crystallization process could improve its stability. To study the relationship between the crystallinity and the stability, we selected the recrystallization process, which can avoid interference from the various reaction parameters such as reaction temperature and solvent effect. Recrystallization is a valuable technique because it is one of the methods used most often for purification of drugs or the acquisition of activity components.23,24 Other techniques for purifying solids such as sublimation and extraction chromatography are more complicated. The process of recrystallization involves the dissolution of solid in an appropriate solvent and the subsequent reformation of crystals upon cooling or the antisolvent process, so the impurities contained in the crystal will remain in the solution. Even though the recrystallization process cannot remove all impurities, it can help to mend the defective crystalline structure. The recrystallization process is seldom used in the organic laboratory because the crystals often form a viscous oily substance containing impurities, as a result of which it is difficult to separate the desired pure solid.7 Therefore, supersaturation monitoring seems to be indispensable because both the nucleation and growth of crystals are driven thermodynamically by supersaturation. Infrared spectroscopy is now established as a simple and reliable technique for dynamic measurement of solution concentration. Specifically, attenuated total reflection-fourier transform infrared (ATR-FTIR) spectroscopy has been successfully used in online solution concentration and supersaturation monitoring.25 In this paper, the solubility of sodium cefuroxime under various temperatures T, pH values, and solvents was investigated for constructing a model to predict supersaturation in the reactor. The recrystallization process was used to purify the commercial sodium cefuroxime products to obtain improved drug stability. The ATR-FTIR spectroscopy was employed to optimize the process by monitoring supersaturation to obtain an optimized solvent flow rate.

x=

W1/kg − W2/kg W3/kg − W4 /kg

(1)

where x is the solubility of the solute in mass solid per weigh of solvent, W1 is the total weight of the dry residue and sampling bottle, W2 is the weight of the sampling bottle, W3 is the total weight of the sampling bottle and solution (after filtering), and W4 is the weight of the sampling bottle plus dry residue. The relative standard uncertainty ur can be calculated using the following equation: u r (x ) =

u(x) , |x |

for x ≠ 0

(2)

To minimize the uncertainty in obtaining the experimental data of solubility, at a given temperature T and a pH value, for a given solvent (either water, ethanol, or mixture of water and ethanol at a defined ratio), solubility of sodium cefuroxime was measured in three parallel experiments conducted in parallel. The averaged value of the three parallel experiments is regarded as the solubility at that T and pH and in that solvent (Table 1). The above-described procedure of measuring the solubility of sodium cefuroxime has assumed that the precipitates are only sodium cefuroxime without containing the precipitate of acid cefuroxime. When a salt dissolves in aqueous solution, a dissociation equilibrium between the ionized and the nonionized species is attained.27 It is therefore important to make sure that in the pH range studied in the present work (pH 5 to 7), the solid that precipitated out from the process is a pure salt, rather than a mixture of the salt and the free acid (sodium cefuroxime and acid cefuroxime). According to Wozniak and Hicks (1991),28 sodium cefuroxime is freely soluble in buffer solvents of pH = 7.0, 4.5, and 1.2. To further confirm that there is no free acid in the precipitated solids, we have also performed XRD analysis of the precipitate (Figure 1). Also plotted in the figure is the XRD pattern we obtained for pure acid cefuroxime. The XRD pattern of the precipitate did not show any sign of containing acid cefuroxime. For example, the two peaks of acid cefuroxime (blue line) between the 2θ values of 15° to 17° did not show any appearance in the precipitate XRD plot. (The characteristic peaks of sodium cefuroxime crystals were observed at 2θ values of 9° to 10.5° (the main peak), 10.5° to 13° and 14° to 15°). The Jouyban−Acree model29 is expressed as

2. EXPERIMENTAL SECTION 2.1. Materials. Commercial sodium cefuroxime (C16H15N4NaO8S, 446.37 kg·mol−1, (6R,7R)-3-{[(aminocarbonyl)oxy]methyl}-7-{[(2Z)-2-(2-furyl)-2-(methoxyimino) acetyl]amino}8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic sodium, batch no. 11112062, > 92 %, water content < 0.24 %) was obtained from a pharmaceutical company, ethanol (79.1 %) was obtained from Fisher Scientific UK Ltd., acetic acid (≥ 99.8 %) was obtained from Sigma, and distilled water produced in our laboratory was also used in the process. 2.2. Methods and Apparatus. 2.2.1. Solubility Determination. The gravimetric method was used for measuring the solubility of sodium cefuroxime in solvents. It involves the following steps. First, the solubility of sodium cefuroxime in water was measured and correlated, and then solubility of sodium cefuroxime in ethanol was also measured and correlated under the same temperature and pH conditions. To estimate the solubility of sodium cefuroxime in a mixture of water and ethanol, the Jouyban−Acree model26 was employed since it was considered as one of the most accurate models to represent the solubility of a drugs in a mixed solvent. In the Jouyban−Acree model, there are three constants that need to be determined. Therefore experiments were also conducted to obtain solubility

log(103x3) = φ1 log(103x1) + φ2 log(103x 2) 2

+ φ1φ2 ∑ i=0

808

Ji (φ1 − φ2)i T /K

(3)



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Table 1. Mass Fraction of Solubility w of Sodium Cefuroxime (3) at Temperature T, pH Values, and Mass Fraction of Water (w) for the Solvent Mixture of Water (1) and Ethanol (2) at Pressure p = 0.1 MPaa T/°C 24

25

26

27

28

29

31 33 35 24

25

26

27 a

w1 pH = 7 1.0 0.8 0.4 0.2 1.0 0.8 0.4 0.2 1.0 0.8 0.4 0.2 1.0 0.8 0.4 0.2 1.0 0.8 0.4 0.2 1.0 0.8 0.4 0.2 1.0 1.0 1.0 pH = 6 1.0 0.8 0.4 0.2 1.0 0.8 0.4 0.2 1.0 0.8 0.4 0.2 1.0 0.8

T/°C

w3 0.2202 0.1125 0.0477 0.0083 0.2227 0.1222 0.0488 0.0142 0.2272 0.1282 0.0555 0.0158 0.2343 0.1352 0.0571 0.0221 0.2414 0.1404 0.0606 0.0223 0.2519 0.1503 0.0644 0.0274 0.2623 0.2791 0.2930

28

29

31 33 35 24

25

26

27

0.2111 0.1027 0.0443 0.0081 0.2128 0.1209 0.0458 0.0138 0.2141 0.1241 0.0549 0.0144 0.2182 0.1295

28

29

31 33 35

w1 pH = 6 0.4 0.2 1.0 0.8 0.4 0.2 1.0 0.8 0.4 0.2 1.0 1.0 1.0 pH = 5 1.0 0.8 0.4 0.2 1.0 0.8 0.4 0.2 1.0 0.8 0.4 0.2 1.0 0.8 0.4 0.2 1.0 0.8 0.4 0.2 1.0 0.8 0.4 0.2 1.0 1.0 1.0

w3 0.0556 0.0187 0.2300 0.1370 0.0587 0.0218 0.2406 0.1455 0.0605 0.0256 0.2501 0.2620 0.2784 0.1856 0.0967 0.0411 0.0080 0.1907 0.1086 0.0458 0.0122 0.1990 0.1188 0.0533 0.0126 0.2089 0.1203 0.0542 0.0162 0.2168 0.1293 0.0558 0.0187 0.2268 0.1363 0.0579 0.0215 0.2381 0.2430 0.2577

Standard uncertainties u are u(p) = 0.015 kPa, u(T) = 0.01 °C, u(w1) = 0.0001, u(pH) = 0.01, and u(w3) = 0.004.

where x1, x2, and x3 are the solubility of the solute in water, cosolvent, and solvent mixture at a fixed temperature, T. Ji is the model constant. φ1 and φ2 refer to the volume fraction of water and cosolvent in the binary solvents without solute. 2.2.2. The Antisolvent Recrystallization Process. The equipment for the antisolvent recrystallization process is illustrated in Figure 2. Considering the size of the reactor (1 L), the experimental program was that 150 g of commercial sodium cefuroxime (batch no. 11112062) was dissolved in 550 g of distilled water, and then filtered into the reactor with a stirring speed between 80 rpm and 100 rpm. Then 550 g of 79.1 % ethanol was added by means of a WATSON MARLOW SCI 400 peristaltic pump for flow rate control.

A ReactIR 4000 probe (Mettler Toledo Co., Ltd., is an Fourier transform infrared-based in situ reaction analysis system designed specifically for the organic process); a turbidimeter, a thermostat Julabo circulator, and a pH meter (JENWAY 3510) were used to monitor this process. After this recrystallization process, the product was washed using 79.1 % ethanol until the pH value reached 8 and was then dried in the DZF-6030B vacuum oven for 24 h. 2.2.3. Product Characterization. X-ray diffraction data were collected using a Bruker D8 Advance (Cu Kα1, λ = 1.540598 Å) diffractometer. Yttria (Y2O3) was used as standard for the estimation of instrumental peak broadening. Samples prepared for scanning electron microscopy (SEM) (Carl Zeiss EVO MA15) were coated with gold using an EMSCOPE 809



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Figure 3. The solubility profiles of sodium cefuroxime (w3) in pure water under different temperatures (T): ◆, pH = 7; ■, pH = 6; ▲, pH = 5.

Figure 1. The XRD pattern of sodium cefuroxime (red line) and acid cefuroxime (blue line).

sodium cefuroxime decreased with the decrease of temperature, but the extent of decrease was relatively limited, indicating that the cooling crystallization process was not suitable for the recrystallization of sodium cefuroxime. On the other hand, the solubility of sodium cefuroxime reduced with the increase of pH values indicating that it was a weak basic drug. Therefore, it is not feasible to recrystallize sodium cefuroxime by changing pH because a weak basic drug is unstable in the acidic environment. Because the solubility of sodium cefuroxime is sensitive to the different solvents, the antisolvent method was found to be the best for the recrystallization purification process. Subsequently, the solubility of sodium cefuroxime in 79.1 % ethanol was investigated under the same conditions. It was found that sodium cefuroxime was slightly soluble in pure ethanol (0.05 %), but the solubility in 79.1 % ethanol was 1.14 g/100 g solvent, at 25 °C and pH 7. It was found from the experiments that the solubility in 79.1 % ethanol had little change with the temperature and pH values in 79.1 % ethanol, so compared with the solubility in the water, the change can be ignored. The solubility of sodium cefuroxime in 100 g 79.1 % ethanol was treated as a constant of 1.14 g in the following formula fitting.

SC500 gold sputter. Color grade data were obtained by a drug accelerated test using a stability chamber (Labonce-60GS).

3. RESULTS AND DISCUSSION 3.1. Solubility of Sodium Cefuroxime. In Pharmacopeia, sodium cefuroxime is freely soluble in water and buffer solvent (pH 7.0, pH 4.5, and pH 1.2),28 soluble in methanol, and very slightly soluble in ethyl acetate, diethyl ether, octanol, benzene, and chloroform. Therefore, water was chosen to be one of the solvents. However, there was research focused on neither the influence of pH value on solubility of sodium cefuroxime nor provided any data. To investigate the effect of both temperature and pH value on the solubility of sodium cefuroxime, on the basis of the conditions of industrial production, the test temperature range was set to be (24 to 35) °C, and the test pH value range was 5 to 7. Acetic acid was used to adjust the pH value because it showed no effect on sodium cefuroxime. It can be seen from Figure 3 that for 10 °C of temperature change, the solubility varied about 6 % but for one pH value change, solubility changed around 2 %. The solubility of

Figure 2. The equipment of the antisolvent recrystallization process. 810



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3.2. Solubility of Sodium Cefuroxime in Binary Solvent. Zhao et al.30,31 studied the thermodynamics and kinetics of sodium cefuroxime in binary solvents during antisolvent crystallization processes. The antisolvents they used were acetone, ethanol, and propan-2-ol, but acetone was selected as the preferred antisolvent because the hydrogen bond between solvents enhanced its solubility, leading to the maximum yield being obtained. However, besides the solubility and yield, the influence of an antisolvent on the final product quality is also a very important factor affecting the selection of an antisolvent. Acetone has already been found not to be an ideal choice because it can deepen the color of the final product.14 According to the data provided by Zhao et al. and the color requirement of the product, ethanol was found to be more appropriate. The use of 79.1 % ethanol instead of pure ethanol was due to 79.1 % ethanol being much cheaper and more easily obtained in industrial production. The method to determine the solubility of sodium cefuroxime in the solvent mixture by the Jouyban−Acree model only gave us the correlation among the temperature, the solvent ratio, and the solubility. However, in the present study, due to the solubility of sodium cefuroxime being strongly influenced by pH value and that the environmental pH value was changed by the amount of acid cefuroxime solution, the process also required the pH value effect. Therefore, the solubility data under different pH values were measured for fitting corresponding formula (as shown in Figure 4). The test temperature range was (24 to 29) °C. The results showed that with the increase in the percentage of water in the mixed solvent, the solubility of sodium cefuroxime increased at different degrees. When the percentage of water was less than 0.5, the solvent polarity was lower and the slower solubility increased. When the percentage of water was greater than 0.5, the polarity of the solvent was enhanced together with the accelerated performance of hydrogen bonds in a water-rich environment and solubility grew rapidly. On the other hand, with decreasing pH value, the growing trend of solubility became less obvious, which possibly resulted from (a) the decline of the pH value making the solubility decline overall and/or (b) the decreasing pH value leading to the ammonia being protonated and unable to form hydrogen bonds due to the existence of amino hydrogen in the sodium cefuroxime molecule. The least-squares method (first described by Carl Friedrich Gauss around 1794) was used to construct the predictive model: β = (XTX )−1XTy

Figure 4. The experimental solubility profiles of sodium cefuroxime (w3) in a binary solvent of water (w1) and ethanol: (a) pH = 7; (b) pH = 6; (c) pH = 5. (◆, T = 24 °C; ■, T = 25 °C; ▲, T = 26 °C; +, T = 27 °C; ∗, T = 28 °C; ●, T = 29 °C).

Table 2. The Fitting Results of the Jouyban−Acree Model

(4)

where β is a matrix of coefficients, X is a matrix of predictors, and Y is a matrix of responses. Table 2 showed the fitting results using eq 4. To verify the accuracy of the fitting, three contrasts can be seen in Figure 5. The results showed that most of the simulation data were located around the experimental data which means that the model worked effectively, especially for the percentage of water lower than 0.5. 3.3. Calibration Experiment of Online ATR-FTIR. The calibration data used in this work contained 38 spectra (Table 3), which included spectra from solutions with different proportions (100 % to 50 %), and the concentration ranged from 0 g to the solubility of sodium cefuroxime in the corresponding solvent. The selection of 50 % as the lower limit occurred because the recrystallization process took a long time and during this

pH

J0

J1

J2

7 6 5

68.8 65.4 73.3

472.5 484.8 510.1

1156.4 1136 1213.7

period, sodium cefuroxime degraded easily in water. If the proportion of the antisolvent is too high, the unstable sodium cefuroxime will be crystallized, hence affecting the product quality. As the other characteristic peaks were not in the measurement range of our ATR-FTIR instrument, the characteristic peak, wavenumber 1758 cm−1 (CO stretch, β-lactam) was selected to perform the calibration. Figure 6 provided the absorption curves of sodium cefuroxime in pure water and 50 % water at 25 °C and pH 7. It can be seen that the absorption of 811



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Figure 5. The contrast diagram of sodium cefuroxime solubility (w3) in a binary solvent of water (w1) and ethanol between experimental and simulation data (Jouyban−Acree model): ◆, measurement at pH = 5, T = 29 °C; round dot line, simulation at pH = 5, T = 29 °C; ▲, measurement at pH = 6, T = 27 °C; dash line, simulation at pH = 6, T = 27 °C; ■, measurement at pH = 7, T = 25 °C; long dash line, simulation at pH = 7, T = 25 °C.

IR spectra at the wavenumber 1758 cm−1 was proportional to the value of solution concentration. Subsequently, the IR absorption spectra of sodium cefuroxime in other different proportions were done under the same conditions. In Table 3, the spectra data highlighted with bold-face italic font were used to construct the ATR-FTIR calibration model, and the remainder of the data in Table 3 were used for the model validation. The concentration of sodium cefuroxime during the recrystallization process was then calculated with the model. The partial least-squares regression method (PLS)32,33 was used to construct this predictive model. The general underlying model of multivariate PLS is X = LPT + E

(5)

Y = LQT + F

(6)

Figure 6. The ATR-FTIR absorption spectra of sodium cefuroxime at 25 °C and pH 7. Pure water (a): solution concentrations of (0.0, 2.5, 5.0, 7.5, 10.0, 13.0, 15.0, 17.5, 20.0, and 22.2) %; binary solvent with 50 % water (b): solution concentrations of (0.0, 2.5, 5.0, and 7.5) %.

3.4. Monitoring the Antisolvent Recrystallization Process. The solubility prediction model (eq 3) was used to predict the solubility of sodium cefuroxime during the recrystallization process, and the ATR-FTIR calibration models (eq 5 and 6) were used to calculate the concentration of sodium cefuroxime during the recrystallization process. In the following work, supersaturation was used to optimize the recrystallization process. As the temperature did not vary very much in the antisolvent recrystallization processes, the antisolvent flow rate became the main focus of our investigations such as 2 mL·min−1 for batch no. 20120223 and 8 mL·min−1 for batch no. 20120224. The selection of different flow rates was a dilemma. On one hand, lower flow rate could make the crystal grow slowly, thereby reducing the crystal defect and the chance of impurity intrusion. However, on the other hand, if the flow rate is too slow, the residence time of sodium cefuroxime in water will be long, which increases the risk of the degradation of product quality.

where X is an n × m matrix of predictors, Y is an n × p matrix of responses, L is an n × l matrix, P and Q are, respectively, m × l and p × l loading matrices, and matrices E and F are the error terms. The prediction results of the test data were plotted in Figure 7. The actual values were compared with the predicted ones, with the diagonal line being the ideal prediction. It can be concluded that most of the predicted data are located around the diagonal which means that the model works effectively. Table 3. The Spectrum Data for ATR-FTIR Calibrationa solvent w1

w2

1.0 0.9 0.8 0.7 0.6 0.5

0.0 0.1 0.2 0.3 0.4 0.5

sodium cefuroxime 0 0 0 0 0 0

g g g g g g

0.5 g 0.5 g 0.5 g 0.5 g 0.5 g 0.5 g

1.0 g 1.0 g 1.0 g 1.0 g 1.0 g 1.0 g

2.0 g 2.0 g 2.0 g 2.0 g 1.9 g

1.5 g 1.5 g 1.5 g 1.5 g 1.5 g 1.5 g

2.5 2.5 2.5 2.2

g g g g

3.0 g 2.8 g

3.5 g

4.0 g

4.4 g

a

Note: (1) For each solution made, three spectra were taken, and the average of the three measurements is regarded as the spectrum at that concentration. (2) Bold-face italic data points were used for training the model, while normal font data points were used for test the model. 812



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Figure 9. The relative supersaturation (σ) diagram: solid line, supersaturation monitoring in a slow antisolvent experiment (2 mL·min−1); round dot line, supersaturation monitoring in a rapid antisolvent experiment (8 mL·min−1).

Figure 7. The calibration model of online ATR-FTIR prediction performance.

Figure 10. The XRD patterns of sodium cefuroxime: no. 20120224 ((a) blue line) and no. 20120223 ((b) red line) are obtained via recrystallization process and show better crystallinity than no. 11112062 ((c) black line) which was the crystals used in the recrystallization process.

Figure 8. Profiles of variables in antisolvent recrystallization experiment: ethanol (E), temperature (T), turbidity (TU), pH, solution concentration (C), solubility (S), and supersaturation (Δc = concentration C − solubility S) during the antisolvent recrystallization process: (a) parameter monitoring in a slow antisolvent experiment (2 mL·min−1); (b) parameter monitoring in a rapid antisolvent experiment (8 mL· min−1) (solid red, percentage of ethanol; round dot green, temperature; square dot purple, pH value; dash dark blue, turbidity; dash dot orange, solution concentration; long dash light blue, solubility; long dash dot pink, supersaturation).

less than the concentration, resulting in generation of the supersaturation. Because the decline rate of solubility is greater than the decline rate of the concentration, supersaturation started to increase. However, because of the metastable zone, where spontaneous crystallization was improbable, the turbidity remained the same, which indicated no crystal generation, and the supersaturation continued rising. Once the crystal began to precipitate, the turbidity began to decline and the supersaturation, as the driving force promoting the continuation of this precipitation, also began to decline after a period of time, where the inflection point appeared. After experiencing a continuous decline to a certain extent, the supersaturation entered into the metastable zone again. When the antisolvent was stopped, due to the slow deposition rate, we considered that precipitation of the crystal stopped. The result showed that this process was not an obviously endothermic or exothermic process, and the inflection point of the supersaturation was the key to the effect of the crystallinity on the product.

From Figure 8, it can be seen that under both flow rates, the results showed mostly similar phenomenon during the whole recrystallization process except the supersaturation, which will be further discussed in the next paragraph. The temperature had the smallest fluctuation, the concentration and solubility decreased with the increase of ethanol in the various degrees. However, the supersaturation experienced first an increasing and then a decreasing process. At the start, with the increase of the antisolvent, the concentration of the solution remained unchanged, while the solubility decreased rapidly until it was 813



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Table 5. Stability Test Data of Sodium Cefuroximea color grade (40 oC) batch no.

0d

3d

6d

10 d

11112062 20120223

< Y-2# < Y-2#

< Y-7# < Y-4#

< Y-7# < Y-5#

< Y-8# < Y-5#

a

(1) Y means the color grade yellow; (2) batch no. 11112062 refers to the original crystals that are used in recrystallization, batch no. 20120223 refers crystals obtained from recrystallization.

degradation in water will only lead to more crystal structure defects. 3.5. Physical Properties Analyses. As indicated by Yoshioka and Stella in their book entitled “Stability of Drugs and Dosage Forms”,34 the factors that affect a crystalline drug’s stability can include crystallinity, impurity, water content, purity, size distribution, and shape, etc. Some of these factors are often correlated. The general view is that increased crystallinity often means higher purity and lower impurity content, leading to improved stability. The crystalline state of these three samples (batch no. 11112062, 21210223, 20120224) was characterized using XRD and the patterns were compared (Figure 10). The characteristic peak of sodium cefuroxime crystals were observed at 2θ values of 9° to 10.5° (the main peak), 10.5° to 13°, and 14° to 15°.35 The results showed that the crystalline state of batch no. 20120223 (the main peak > 20 000) was much better than that of batch no. 20120224 (the main peak ≈ 18 000), which means that the rapid flow rate did little good to the product quality. However, both of them were better than the original batch (no. 11112062) with the main peak < 10 000, which meant that even if the samples were obtained under a relatively rapid recrystallization process, the purpose of reducing the impurities and mending the crystal structure during this antisolvent recrystallization process can be partly achieved. The SEM results (Figure 11) showed that sodium cefuroxime had serious aggregation phenomenon. As is wellknown, serious aggregation is usually considered as a significant problem for rapid crystallization. Like ceftriaxone sodium,36 as a result of the lamellar habit, it was hard to completely avoid aggregation in this antisolvent recrystallization process. However, after this recrystallization process, batch no. 20120223 had a smaller mean particle size and more uniform size distribution. Appropriate mean size and uniform size distribution are also important for higher stability. The best particle mean size of sodium cefuroxime for injection is (75 to 150) μm.35 Compared with the crystal size distribution of batch no. 11112062, a more uniform crystal size distribution is obtained with a slow crystallization rate (batch no. 20120223). Other physical properties were also analyzed to further verify the product stability. As can be seen in Table 4, the water content was reduced and the content of sodium cefuroxime was increased in batch no. 20120223, which meant that the impurity decreased in sodium cefuroxime crystals after the

Figure 11. The SEM images of sodium cefuroxime: (a) batch no. 11112062 (mean size = 184.5 μm); (b) batch no. 20120223 (mean size = 77.4 μm).

From Figure 9, the difference between these two flow rates on the supersaturation curves can be more clearly seen. The rapid flow rate made the inflection point of the supersaturate appear and reduce earlier. This was because it caused the distribution of the supersaturation to be uneven, resulting in the partial excessive supersaturation which caused the first crystal precipitation. Once the crystal generated, the supersaturation began to decline. In contrast, the slower flow rate can produce not only a higher inflection point, but also fewer fluctuations, which means the crystal can be produced in a more uniform environment; therefore better crystal structure and size distribution can be obtained. The idea that the sodium cefuroxime precipitates as soon as possible to prevent Table 4. Physical Data of Sodium Cefuroximea batch no.

water mass fraction

color grade

specific volume/m3·kg−1

absorbance

sodium cefuroxime mass fraction in product measured by HPLC

11112062 20120223

0.239 0.226

< Y-2# < Y-2#

1.8 3

383 392

0.9496 0.9523

a

(1) Y means the color grade yellow; (2) batch no. 11112062 refers to the original crystals that are used in recrystallization, batch no. 20120223 refers crystals obtained from recrystallization. 814



Article

(11) Zheng, Y. L.; Li, J. W.; Guan, H. Y.; Xue, M. H.; Qin, J. Preparation of cefuroxime sodium. CN Pat. 101955492 A, Jan 26, 2011. (12) Stables, H. C. Crystallization process. US Pat. 4,298,732, Nov 3, 1981. (13) Cai, Z. W.; Li, M. C.; Yang, J. The synthesis process of cefuroxime sodium. CN Pat. 101054386 A, Oct 17, 2007. (14) Hu, Y. R.; Wang, G. S.; Hu, L. M.; Tan, Q. Z.; Dong, W. C.; Wang, C. J. Recrystallization of cefuroxime sodium CN Pat. 101967156 A, Feb 9, 2011. (15) Crisp, H. A.; Clayton, J. C.; Elliott, L. G.; Wilson, E. M. Process for preparing cefuroxime axetil. US Pat. 5,013,833, May 7, 1991. (16) Crisp, H. A.; Clayton, J. C.; Wilson, E. M. Process for preparation of cefuroxime axetil. US Pat. 4,994,567, Feb 19, 1991. (17) Khan, A. A. P.; Asiri, A. M.; Khan, A.; Azum, N.; Rub, M. A.; Rahman, M. M.; Khan, S. B.; Siddiqi, K. S.; Alamry, K. A. Mechanistic investigation of the oxidation of cefuroxime by hexacyanoferrate(III) in alkaline conditions. J. Ind. Eng. Chem 2013, 19 (2), 595−600. (18) Zhao, L. S.; Li, Q.; Liu, Z. Z.; Su, J.; Chen, X. H.; Bi, K. S. Degradation kinetics of cefuroxime lysine in aqueous solution by LC− MS. Curr. Pharm. Anal 2012, 8 (4), 409−414. (19) Crisp, H. A.; Clayton, J. C. Amorphous form of cefuroxime ester. US Pat. 4,562,181, Dec 31, 1985. (20) Crisp, H. A.; Clayton, J. C.; Elliott, L. G.; Wilson, E. M. Preparation of a highly pure, substantially amorphous form of cefuroxime axetil. US Pat. 4,820,833, Apr 11, 1989. (21) Pikal, M. J.; Lukes, A. L.; Lang, J. E.; Gaines, K. Quantitative crystallinity determinations for β-lactam antibiotics by solution calorimetry: Correlations with stability. J. Pharm. Sci. 1978, 67, 767−773. (22) Siviero, E.; Cabri, W.; Terrassan, D. M. Process for the preparation of β-lactam derivatives. US Pat. 6,458,558 B1, Oct 1, 2002. (23) Huttenrauch, R.; Keiner, I. Effect of pressing power on recrystallization of activated powders during tabletting molecular galenicals. Pharmazie 1978, 33 (9), 610−610. (24) Nagy, J.; Decsi, L.; Simon, L. Recrystallization from ether causes unusual changes in the convulsant activity of pentylenetetrazol. Acta Physiol. Hung 1985, 65 (1), 95−99. (25) Borissova, A.; Khan, S.; Mahmud, T.; Roberts, K. J.; Andrews, J.; Dallin, P.; Chen, Z. P.; Morris, J. In situ measurement of solution concentration during the batch cooling crystallization of L-glutamic acid using ATR-FTIR spectroscopy coupled with chemometrics. Cryst. Growth Des 2009, 9 (2), 692−706. (26) Acree, W. E. Mathematical representation of thermodynamic properties: Part 2. Derivation of the combined nearly ideal binary solvent (NIBS)/Redlich-Kister mathematical representation from a two-body and three-body interactional mixing model. Thermochim. Acta 1992, 198 (1), 71−79. (27) Stahl, P. H.; Wermuth, C. G., Handbook of Pharmaceutical Salts: Properties, Selection, and Use. Wiley-VCH: Weinheim; Chichester, 2002. (28) Wozniak, T. J.; Hicks, J. R. Analytical Profile of Cefuroxime Sodium. In Analytical Profiles of Drug Substances; Florey, K., Ed.; Elselvier B.V.: The Netherlands, 1992; pp 209−236. (29) Jouyban, A.; Acree, W. E. In silico prediction of drug solubility in water−ethanol mixtures using Jouyban−Acree model. J. Pharm. Pharmaceut. Sci. 2006, 9 (2), 262−269. (30) Zhao, Y. Y.; Hou, B. H.; Jiang, X. B.; Liu, C.; Wang, J. K. Determination of thermodynamics in various solvents and kinetics of cefuroxime sodium during antisolvent crystallization. J. Chem. Eng. Data 2012, 57 (3), 952−956. (31) Zhao, Y. Y.; Jiang, X. B.; Hou, B. H. Measurement and correlation of solubility of cefuroxime acid in pure and binary solvents at various temperatures. J. Chem. Eng. Data 2010, 55, 3369−3372. (32) Abbasi, M.; Abduli, M. A.; Omidvar, B.; Baghvand, A. Forecasting municipal solid waste generation by hybrid support vector machine and partial least square model. Int. J. Environ. Res 2013, 7 (1), 27−38.

recrystallization process. These changes further proved that the crystallinity has been improved. Better crystallinity can reduce the defect of the crystal and reduce the moisture and impurities wrapped in the crystal growth process as well. The stability test data results (Table 5) proved that the stability improved in batch no. 20120223, indicating that a good crystalline state can improve the stability of the product. The antisolvent recrystallization method can produce the desired product quality, so it is an ideal method for high quality seed production.

4. CONCLUSIONS The solubility of sodium cefuroxime in water, ethanol, and a mixture of water and ethanol was measured at varied temperatures and pH values, and was correlated in models. The derived solubility models were applied together with an online ATR-FTIR probe to monitor in real-time the supersaturation during the recrystallization process of cefuroxime sodium. This provided a means for studying the effect of operating parameters on the crystal quality. It was found that the antisolvent flow rate of 2 mL·min−1 can be considered as the optimum value. Recrystallization under the optimized operational condition has improved crystallinity as characterized by XRD patterns. The positive relationship between the stability of sodium cefuroxime and the crystallinity was also observed.

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AUTHOR INFORMATION

Corresponding Author

*Tel: +86 20 8711 4000. Fax: +86 20 8711 4050. E-mail: [email protected]. Funding

Financial Support from UK Engineering and Physical Sciences Research Council (EP/H008012/1, EP/H008853/1) by China Scholarship Council (CSC) and funding of the China One Thousand Talents Scheme are gratefully acknowledged. Notes

The authors declare no competing financial interest.

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REFERENCES

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Solubility Measurement and Stability Study of Sodium Cefuroxime

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