Investigation of Solution-Mediated Phase Transformation of

Article pubs.acs.org/OPRD

Investigation of Solution-Mediated Phase Transformation of Cefuroxime Acid to Its Acetonitrile Solvate Guan Wang,† Youguang Ma,† Yongli Wang,*,†,‡ Hongxun Hao,*,†,‡ and Yang Jiang§ †

School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China § School of Chemistry and Chemical Engineering, University of Jinan, Shandong, Jinan 250022, China ‡

ABSTRACT: The cefuroxime acid and its acetonitrile solvate were characterized by using a series of methods, such as optical microscopy, powder X-ray diffraction, thermogravimetric analysis, Fourier transform infrared spectroscopy, and Raman spectroscopy. The solvation profile of cefuroxime acid in acetonitrile and water mixture was determined at 303.15 K by phase transformation experiments. The solution-mediated phase transformation from cefuroxime acid to its acetonitrile solvate was in situ investigated with the help of Raman spectroscopy and PVM. It was found that the nucleation process of acetonitrile solvate was the limiting step of the transformation process. Furthermore, kinetic parameters of the transformation process at different temperatures were obtained using the Johnson−Mehl−Avrami equation. The influence of different operating parameters on the transformation process was also investigated to better understand the process.

1. INTRODUCTION Solvate, also called pseudopolymorph, is an important solidstate formation in pharmaceutical industry.1,2 Due to the inclusion of solvent molecules, solvate exhibits many different physical properties when compared with its unsolvate formation, such as density, solubility, dissolution rate, stability, hygroscopicity, and so on.3,4 Because of these differences, solvate has been attracting attentions of many researchers who to identify and evaluate its properties and transformation behaviors.5−8 The solution-mediated phase transformation is one of the most commonly used methods to investigate the formation of a certain compound’s solvate. As previously described by Wikström et al.,9 the solution-mediated phase transformation process commonly can be divided into three essential steps: dissolution of metastable solid, self-recognition of the molecular units to nucleate a more stable solid phase, and growth of the stable phase. Each step can be affected by operating parameters, such as temperature, solvent content, solid loading, agitation speed, and so on. Hence, it is very important to investigate the effect of these parameters to optimize and control the transformation process, which is crucial to obtain ideal product in pharmaceutical industry. The solution-mediated phase transformations of polymorphs have been widely investigated by many scientists and engineers.10−14 However, little has been done to investigate the solution-mediated phase transformation of solvates to find out how the transformation would happen and what operating parameters would affect the transformation process. With this background, the main objective of this work is to investigate the phase transformation of one compound’s unsolvate to its solvate in the solutions. To achieve this aim, cefuroxime acid (Figure 1), an active pharmaceutical ingredient (API),15 is selected to be the model compound since it can form unsolvate form and acetonitrile solvate form. The mechanism and the kinetics of the transformation between © XXXX American Chemical Society

Figure 1. Chemical structure of cefuroxime acid.

cefuroxime acid and its acetonitrile solvate were studied to better understand the transformation phenomenon of solvate. To better investigate the solution-mediated phase transformation process, Raman spectroscopy and PVM which are both commonly used process analytical technologies (PAT) in pharmaceutical industry were applied for in situ monitoring of the transformation process.16−19 Furthermore, the solvation profile of cefuroxime acid was also determined by phase transformation experiments.

2. EXPERIMENTAL SECTION 2.1. Materials. Cefuroxime acid was supplied by North China Pharmaceutical Group Corp. (Shijiazhuang, China) and Special Issue: Polymorphism & Crystallisation 2015 Received: September 20, 2014

A

DOI: 10.1021/op500304u Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Organic Process Research & Development

formation. The details of the experimental conditions are listed in Table 1.

used without further purification. Cefuroxime acid acetonitrile solvate was obtained by recrystallization of cefuroxime acid in acetonitrile solution. Acetonitrile (analytical reagent grade) was used without further treatment. Distilled deionized water was used throughout. 2.2. Characterizations of Cefuroxime Acid and Its Acetonitrile Solvate. The characterization techniques used in this study include optical microscopy, powder X-ray diffraction (PXRD), TGA, Fourier transform infrared (FT-IR) spectroscopy, and Raman spectroscopy. The crystal morphology was observed by using an optical microscope of Nikon Eclipse E200 with a magnification of 100×. PXRD was determined by using a Rigaku D/max-2500 X-ray powder diffractometer (Rigaku Co., Japan) with Cu Kα radiation (λ = 1.541845 Å). The measurements were carried out in 2θ range of 2−40° at a scanning rate of 1 step/s. TGA was carried out on a Mettler-Toledo model TGA 1/SF thermogravimetric analysis system (Mettler-Toledo, Swizerland) from 303.15 to 460.15 K. The heating rate was set at 10 K min−1, and the flow rate of nitrogen gas was set at 100 mL min−1. FT-IR spectra were recorded (3800−400 cm−1) by using KBr disks method on a Nicolet 380 FT-IR spectrometer (Thermo Nicolet Corporation, USA). The Raman spectra were collected with a Raman RXN2 system (Kaiser Optical Systems, Inc., USA). 2.3. Determination of the Solvation Profile. The solution-mediated phase transformation of cefuroxime acid to its acetonitrile solvate at 303.15 K was carried out to determine the mass fraction of acetonitrile in water−acetonitrile mixed solvents where cefuroxime acid would transform to its acetonitrile solvate. The mass fraction of acetonitrile (XA) in water−acetonitrile mixed solvents was calculated as follows: XA =

mA mA + mW

Table 1. Details of experimental conditions for cefuroxime acid transformation number

T/K

acetonitrile:water (w:w)

solid loadings/g

agitation speed/rpm

1 2 3 4 5 6 7 8 9 10

293.15 303.15 313.15 303.15 303.15 303.15 303.15 303.15 303.15 303.15

4:1 4:1 4:1 1:1 8:1 acetonitrile 4:1 4:1 4:1 4:1

4 4 4 4 4 4 1 4 4 4

100 100 100 100 100 100 100 200 300 400

2.5. Calibration of Raman Spectra for Quantitative Analysis. Although slurring can be applied to improve the mixing and homogeneity of the polymorphic mixtures, it is not applicable to unsolvate/solvate systems since finding a solvent that will not alter the solid state of the unsolvate/solvate mixtures is difficult.22 In this study, the calibration of Raman spectra for quantitative analysis was done by using the method published in literature.23−25 Eleven dry powder mixtures of cefuroxime acid and its acetonitrile solvate were used for building up the calibration model. The mixtures were prepared by manually mixing pure cefuroxime acid and its acetonitrile solvate powders, and the fraction of cefuroxime acid was calculated on the basis of the amount of cefuroxime acid and its acetonitrile solvate used in the mixing. Then the mixtures were analyzed with Raman spectra immediately after preparation. All the samples were double-sampled. To build the calibration curve, the peak heights of characteristic Raman peaks of cefuroxime acid (HC) and characteristic Raman peaks of acetonitrile solvate (HA) were selected to represent the solid phase of cefuroxime acid and acetonitrile solvate, respectively. The calibration curve was set up by correlating the relative peak height HC/(HC + HA) with the fraction of cefuroxime acid in the mixtures.

(1)

where mA is the mass of acetonitrile and mW is the mass of water in the solvents. The experiment procedure was similar to that described in the literature.20,21 A range of binary solvent mixtures of acetonitrile + water were prepared (e.g., XA = 0, 0.1, 0.2, 0.3, ..., 0.9, 1). Cefuroxime acid was added into 20 g mixtures of acetonitrile and water so that cefuroxime acid was in excess of the saturation concentration by at least 0.1 g/g at 303.15 K. To reach the equilibrium state, the mixtures were constantly stirred for 2−3 days with a magnetic stirrer (the minimum time for reaching the equilibrium state was identified as 2 days by our experiments). The excess solid phases were then analyzed by PXRD. 2.4. In Situ Monitoring of Solution-Mediated Phase Transformation. The transformation experiments of cefuroxime acid to its acetonitrile solvate were carried out in a 100 mL jacketed glass crystallizer. The initial suspended solutions with temperature of 293.15, 303.15, and 313.15 K were prepared by adding 1−4 g cefuroxime acid into 50 g saturated acetonitrile + water solution (w/w: 1:1−8:1) or pure acetonitrile solvent of cefuroxime acid, respectively. The Raman probe was immersed into the solution to in situ monitor the solid form composition and the solid form transformation behavior. The PVM (model 800 L, Mettler-Toledo, Swizerland) was also used to record the real-time morphology of the particles during the trans-

3. RESULTS AND DISCUSSION 3.1. Characterizations of Cefuroxime Acid and Its Acetonitrile Solvate. The crystal habits and PXRD patterns of cefuroxime acid and its acetonitrile solvate are shown in Figure 2. It is relatively easy to identify the two forms by their shapes, as the solvate exhibits a needle-like shape. Also, the characteristic PXRD peaks of cefuroxime acid are also different from those of acetonitrile solvate.26 Obviously, these differences are resulted from the inclusion of acetonitrile in the crystal structure. The results of TGA measurement shown in Figure 3 also agree with this conclusion. As shown in Figure 3, the TGA curve of cefuroxime acid shows a big mass loss at 440 K, which is due to the decomposition of cefuroxime acid. The TGA curve of acetonitrile solvate shows two mass losses at 305 and 400 K, respectively. The first mass loss at 305 K is due to the loss of the two acetonitrile molecules, considering that the mass loss is about 15.1% (16.2% in theory), while the second mass loss at 400 K is due to the decomposition of cefuroxime acid. On the basis the above results, the solvent loss of acetonitrile solvate will cause the change of its thermodynamic properties. B


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cefuroxime acid and acetonitrile solvate (Figure 5) occur at 982 and 958 cm−1, respectively.

Figure 2. PXRD patterns and the habits of cefuroxime acid (black line) and its acetonitrile solvate (red line). Figure 5. Raman spectra of cefuroxime acid (black line) and its acetonitrile solvate (red line).

3.2. Determination of the Solvation Profile. The solvation profile of cefuroxime acid in acetonitrile and water at 303.15 K are plotted in Figure 6. When the XA is lower than

Figure 3. TG curves of cefuroxime acid (black line) and its acetonitrile solvate (red line).

From Figure 4 which shows the FT-IR data of cefuroxime acid and its acetonitrile solvate, it can be seen that the FT-IR

Figure 6. Phase diagram after 3 days for cefuroxime acid in acetonitrile and water solutions with different mass fractions of acetonitrile (XA) at 303.15 K.

0.41, only the solid state cefuroxime acid exists in the solution after 3 days. On the contrary, only the solid state acetonitrile solvate exists when XA is higher than 0.41. The point of XA = 0.41 should be the critical point of transformation between cefuroxime acid and its acetonitrile solvate. The transformation process would become very slow near the critical point, which means that the system may take as long as several weeks to reach the phase equilibrium state. According to this, the following solution-mediated phase transformation experiments were carried out in the solutions where XA is higher than 0.41. 3.3. In Situ Monitoring of Solution Mediated Phase Transformation. The phase transformation from the cefuroxime acid to the acetonitrile solvate was carried out by adding 4 g of cefuroxime acid into 50 g of acetonitrile + water saturated solution (w/w: 4/1) at 303.15 K, which was in situ monitored by the Raman spectroscopy and PVM. The results are shown in Figure 7. As described in the section of introduction, the solution-mediated phase transformation process usually contains three steps. It is common to identify the controlling step

Figure 4. FT-IR spectra of cefuroxime acid (black line) and its acetonitrile solvate (red line).

spectrum of cefuroxime acid is similar to that of acetonitrile solvate. But the absorption band at 2250 cm−1, which is due to the −CN stretching vibration,27 could be identified as the characteristic absorption band of acetonitrile solvate. In addition, the different bands in the Raman spectra of C


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cefuroxime acid acetonitrile solvate, this type transformation is classified as the nucleation controlled polymorphic transformation. 3.4. Calibration Curve of Solid State Raman Data. The peak heights of characteristic Raman peak of cefuroxime acid at 982 cm−1 (HC) and characteristic Raman peak of acetonitrile solvate at 958 cm−1 (HA) were selected to represent the solid phase of cefuroxime acid and acetonitrile solvate, respectively. The calibration result is plotted in Figure 8. The correlation

Figure 7. (a) Relative intensities of Raman peak at 982 cm−1 for cefuroxime acid (black line) and Raman peak at 958 cm−1 for acetonitrile solvate (red line) and the concentration of solution (blue line) and (b) PVM images of particles in the solution during the transformation of cefuroxime acid to acetonitrile solvate at 303.15 K.

Figure 8. Calibration model of Raman spectra of cefuroxime acid fraction.

curve in Figure 8 shows an R2 value close to 1, which means that the calculated mass fraction of cefuroxime acid is pretty close to the actual mass fraction of cefuroxime acid in the solid phase. 3.5. Kinetics of Phase Transformation. To investigate the kinetics of the solution-mediated phase transformation, the experiments were carried out by adding 4 g of cefuroxime acid into 50 g of acetonitrile + water saturated solution (w/w: 4/1) at 293.15, 303.15, and 313.15 K, respectively. The solid compositions detected with elapsed time of solution-mediated phase transformation in slurry at various temperatures are plotted in Figure 9. As shown in Figure 9, the induction time decreases with the increasing of temperature. This result can be well-explained by the classical nucleation theory since the increasing temperature will accelerate the molecular motion and decrease the interfacial energy between the solid and liquid phases. Thus, higher

of transformation by comparing the real time profiles of solid and liquid phase composition during the transformation. The solution concentration profile (based on cefuroxime acid) was measured as the following procedure. Solution samples were taken through a syringe filter with 0.22 μm pore size during the transformation experiment. Then the sample was dried in vacuum oven until only cefuroxime acid left, which was verified by the PXRD. The results of concentration profile are also plotted in Figure 7. As shown in Figure 7, during the initial period of 120 min, the solution concentration remains at the solubility of cefuroxime acid as shown in Figure 7a. Only cefuroxime acid crystals can be seen from the Raman data in Figure 7a, and the PVM images shown in Figure 7b while the acetonitrile solvate crystals (represented by the Raman data in Figure 7a) are not detected. This period is the induction time of the acetonitrile solvate nucleation during which solute and solvent molecules undergo molecular recognition process to build solvate clusters. Upon reaching the induction limit, the solution concentration and the amount of cefuroxime acid crystals (represented by the Raman data in Figure 7a) continuously decrease after the nucleation of cefuroxime acid acetonitrile solvate crystals. This phase continues for another 120 min or so until all the cefuroxime acid crystals dissolve and a large amount of needlelike acetonitrile solvates crystals appear in the solution (Figure 7b). By that time, the solute concentration almost reduces the solubility of acetonitrile solvate, and the remaining supersaturation is quickly consumed by further growth of cefuroxime acid acetonitrile solvate. Then the amount of acetonitrile solvate crystals stay constant, and the transformation process is ended. The similar solution-mediated phase transformation process was also found in the system of tolbutamide by Thirunahari et al.28 As the plateau region in the transformation profile is resulted from the induction time for nucleation of the

Figure 9. Transformation profiles at different temperatures in acetonitrile and water mixtures. D


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cefuroxime acid to its acetonitrile solvate is strongly influenced by acetonitrile content. This result is also consistent with the above theory in the section of solvation profile. The solvate form is the more stable phase when the acetonitrile content is higher than the critical point of acetonitrile content of the transition point. In addition, the higher content of acetonitrile in the solution leads to the shorter total transformation time in the above experiments. 3.7. Influence of Solid Loading. Since the solid loading in the slurry may also affect the process, the solution-mediated phase transformation experiments were performed by adding 1 g and 4 g of cefuroxime acid into 50 g of acetonitrile + water saturated solution (w/w: 4:1) at 303.15 K. The results are shown in Figure 11. As shown in this figure, the transformation

temperature will result in faster nucleation and consequently shorter induction time. As the kinetic model for the transformation would be useful for the design and controlling of the crystallization process of the acetonitrile solvate, the Johnson−Mehl−Avrami (JMA) equation was used to model the kinetics of phase transformation as follows:29 x(t ) = 1 − exp{−K (t − t ind)n }

(2)

where x(t) is the fraction of transformation at time t, referred as mass fraction of cefuroxime acid; tind is the induction time for acetonitrile solvate formation; K is nucleation and growth ratedependent constant; and n is the order of the transformation. The kinetic parameters of eq 2 for the solution-mediated phase transformation at the above temperatures are also listed in Table 2. As revealed in Table 2, the value of K increases with Table 2. Results of kinetic parameters for cefuroxime acid transformation condition

tind/h

K/h−3

n

R2

293.15 K, 100 rpm, 4:1 (A:W), 4 g 303.15 K, 100 rpm, 4:1(A:W), 4 g 313.15 K, 100 rpm, 4:1 (A:W), 4 g

2.70 1.56 0.43

0.691 0.937 3.54

3.53 2.16 1.96

0.9880 0.9840 0.9721

the increasing of temperature. All the values of R2 are higher than 0.97, which means that the transformation process can be well-described by the JMA equation. 3.6. Influence of the Acetonitrile Content on the Transformation. The crystallization of solvate is different from that of an unsolvate compound. In unsolvate compound crystallization, the solute molecules solely experience the phase changing from solution to solid through nucleation and crystal growth. For solvate crystallization, the solvent molecules have to be incorporated with the solute molecules to form the growth unit cell of the solvate crystalline. The solvent composition in the solution plays an important role in the solution-mediated phase transformation process.30,31 To reveal the influence of acetonitrile content on the solution-mediated phase transformation process, a series of experiments were performed by adding 4 g of cefuroxime acid into 50 g of different acetonitrile + water saturated solution (w/ w: 1:1, 4:1, 8:1) and pure acetonitrile saturated solution at 303.15 K, respectively. The transformation results are plotted in Figure 10. It can be clearly seen that the transition from

Figure 11. Effect of solid loadings on the transformation process at 303.15 K.

time is much shorter in the experiments with the higher loading of cefuroxime acid. Since the larger solid loading will increase the possibility of the nucleation of the acetonitrile solvate and the transformation process is governed by the nucleation of the acetonitrile solvate, it is not strange that a higher solid loading will lead to a shorter transformation process. 3.8. Influence of Agitation Speed. To study the influence of the agitation speed, the solution-mediated phase transformation experiments were carried out by adding 4 g of cefuroxime acid into 50 g of acetonitrile + water saturated solution (w/w: 4:1) with agitation speeds of 100, 200, 300, and 400 rpm, respectively. The results are shown in Figure 12. It is

Figure 10. Effect of acetonitrile content on the transformation process at 303.15 K.

Figure 12. Effect of agitation speed on the transformation process at 303.15 K. E


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very interesting that the agitation speed does not obviously affect the transformation process. As referred in literature,30 increasing the agitation rate not only will increase the interaction between solute and solvent, but also will accelerate the breakage of the solid due to the development of the contacted surface. When both effects are equal to each other, the agitation rate will cause no obvious effect on solutionmediated phase transformation process.

4. CONCLUSIONS The solution-mediated phase transformation from cefuroxime acid to its acetonitrile solvate was investigated. The transformation controlling step was identified as the nucleation of acetonitrile solvate. The kinetic models of phase transformation at different temperatures were built with the JMA equation. Moreover, it was found that operating parameters, such as temperature, solvent composition, and solid loading, will affect the transformation process significantly, while the agitation speed has no obvious effect on the process. In addition, the transition point between cefuroxime acid and it acetonitrile solvate in acetonitrile and water mixtures was found to be XA = 0.41 by a series of the phase transformation experiments.

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AUTHOR INFORMATION

Corresponding Authors

*Tel.: +86-22-27405754. Fax: +86-22-27374971. E-mail: [email protected]. *E-mail: [email protected] Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research is financially supported by National Natural Science Foundation of China (no. 21376165) and Key Project of Tianjin Science and Technology Supporting Program (no. 13ZCZDNC02000).

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REFERENCES

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