In Situ Monitoring of the Solvent-Mediated Transformation of

Aug 27, 2013 - Pseudopolymorphism has come to denote those crystal systems for which ... of the stable form (C*stable), R=C*metastable/C*stable.16 We ...
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In Situ Monitoring of the Solvent-Mediated Transformation of Cefadroxil DMF Solvate into Monohydrate Xuemei Wang,† Songgu Wu,† Weibing Dong,‡ and Junbo Gong*,† †

School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, Tianjin University, Tianjin 300072, People’s Republic of China ‡ Tianjin Key Laboratory of Modern Drug Delivery and High Efficiency, Tianjin University, Tianjin 30072, People’s Republic of China ABSTRACT: In situ monitoring phase transformation process is of great importance to control the quality of crystalline products. In this paper, the transformation of N,N-dimethylformamide (DMF) solvate into monohydrate of cefadroxil was studied in DMF-water mixtures. The solvates were characterized by several offline methods such as Powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and scanning electron microscope (SEM). Thermodynamic stability of DMF solvate and monohydrate of cefadroxil in DMF-water mixtures were investigated to analyze the relationship between solubility ratio and transformation kinetics at different temperatures, water content and stirring speeds. Results indicate that solubility ratio increases with temperature and water content, which leads to less transformation time. Transformation rate is governed by the growth of cefadroxil monohydrate and process parameters must be controlled based on in situ techniques to prepare high quality products. According to process analysis results by SEM, the mechanism of transformation was interpreted as the surface nucleation of monohydrate.

1. INTRODUCTION Pseudopolymorphism has come to denote those crystal systems for which a substance can exist in structures characterized by different unit cells where these unit cells differ in their elemental composition through the inclusion of one or more molecules of solvent.1 The different pseudopolymorphs of a given substance exhibit different physicochemical properties due to difference in their crystal structure. Such properties, including density, solubility, stability, dissolution rate, and so on, can affect the bioavailability and product performance.2 Therefore it is essential to identify the properties of pseudopolymorphs and study their transformation behaviours.3 Characterization techniques used to elucidate the transformation process comprise offline and in situ methods. Offline techniques, PXRD, DSC, TGA and SEM, are used to identify the polymorphs, which is the qualitative analysis for the process.4 In situ techniques, such as Fourier transform infrared (FTIR), Raman spectroscopy, focused beam reflectance measurement (FBRM), online PXRD can be applied to analyze the transformation kinetics, which is the quantitative analysis for the process; and particle vision measurement (PVM) can be used to observe the evolution of crystal morphology during the process.5−9 In recent years, these PAT tools have widely been used to monitor and control the transformation process during crystallization, especially in the pharmaceutical and fine chemical industries.10,11 Cefadroxil, a first-generation cephalosporin antibiotic, is used to treat urinary tract infections, skin structure infections, and respiratory tract infections.12,13 The molecular structure of cefadroxil is shown in Figure 1. It has a variety of crystal forms, including monohydrate, hemihydrate, N,N-dimethylformamide (DMF) solvate, N,N-dimethylacetamide (DMA) solvate, and N-methylformamide (NMF) solvate.14 Marketed cefadroxil generally refers to monohydrate, which can be produced by © 2013 American Chemical Society

Figure 1. Sketch of the molecular structure of cefadroxil.

chemical synthesis or enzymatic synthesis.15 The process of chemical synthesis is applied widely now. 7-Aminocephalosporanic acid (7-ACA) is used as the raw material to prepare DMF solvate of cefadroxil. Then the DMF solvate transforms into the monohydrate of cefadroxil. In this work, the transformation process of DMF solvate into the monohydrate in DMF−water binary mixtures was investigated to control the quality of the product. The solubilities of DMF solvate and monohydrate were measured. To explain the relationship between thermodynamics and phase transformation, the solubility ratio (R) was introduced, which is defined as the ratio between the solubility of the metastable form (C*metastable) and the solubility of the stable form (C*stable), R = C*metastable/C*stable.16 We also combined FTIR and PVM to monitor the concentration of cefadroxil in the solution and to make images of the particles. The transformation experiments were conducted with different operation parameters in terms of temperature, water content, and stirring speed. Moreover, the mechanism of the transformation process was investigated. The results obtained in this work hold a great significance toward understanding the process of the transformation of cefadroxil, which provides a theoretical guidance for the Received: June 20, 2013 Published: August 27, 2013 1110

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production of the monohydrate of cefadroxil and other similar pharmaceuticals.

Table 1. Experimental conditions used for investigating the transformation kinetics

2. EXPERIMENTAL SECTION 2.1. Materials. Cefadroxil DMF solvate (99 wt % supplied from Northern China Beta Pharmaceutical Co. Ltd.) was used. It was characterized by PXRD, DSC, TGA, and SEM. DMF used in the experiments was analytical grade. Double-distilled water was prepared in our lab. 2.2. Characterization of Cefadroxil DMF Solvate and Monohydrate. The PXRD spectra of the solvate were obtained by a D/MAX 2500 diffractometer (Cu Kα radiation, λKα1 = 1.5406 Å) at 100 mA and 40 kV. The samples were recorded between 2 and 50° in 2θ with a step size of 0.02° and a scanning rate of 8°/min. The differential scanning calorimetry (DSC) curve was acquired by a Mettler Toledo DSC 1/500. The thermogravimetric analysis was operated on a Mettler Toledo TGA/DSC 1/SF. The samples were both heated from 298.15 K to 513.15 K at a rate of 5 K/min. The scanning electron microscope (SEM) was operated at the voltage of 15 kV by a Hitachi TM3000. The sample was sprayed gold with a thickness of 10 nm. 2.3. Solubility Measurements. The solubilities of cefadroxil DMF solvate and monohydrate in DMF−water mixtures were measured by a synthetic method at 288.15 K, 293.15 K, 298.15 K, 303.15 K, and 308.15 K, respectively.17 The experiments were carried out in a jacketed glass vessel of about 50 mL, which was maintained at the desired temperature by circulating water from a thermostatically controlled water bath (Sunny Instruments, CH1015, China). The actual value of the temperature was measured by a mercury thermometer (with an uncertainty of 0.05 K) inserted into the inner chamber of the vessel. Continuous stirring was achieved by a magnetic stir bar. A laser monitoring system, which includes a laser generator, a photoelectric transformer, and a light intensity display, was employed to determine the disappearance of the last solute in the solvent. During the experiments, predetermined amounts of solute and solvent with known composition were placed in the inner chamber of the vessel. In the early stage of the experiment, the solute was completely dissolved, and the solution was clear, so that the intensity of the laser beam penetrating the vessel reached the maximum. Then a certain amount of solute was added into the vessel. If the solute dissolved completely, another amount of solute was added. This procedure was repeated until the last addition could not be dissolved completely. The total amount of solute consumed was recorded. The same solubility experiment was conducted three times. 2.4. In Situ PVM and FTIR Measurements. The solventmediated transformation process was monitored by using an ATR-FTIR React IR 45m reaction analysis system coupled with iC IR 4.2 software from Mettler Toledo equipped with Duradisc DiComp probe. The characteristic peak used was at 1765 cm−1 with an interval of 60 s. PVM (model V819) images were taken at an interval of 60 s. Experimental conditions can be seen in Table 1. 2.5. Experiments on the Mechanism of Phase Transformation. A conical flask (200 mL) with the solvent mixture (water content: 0.8) was put into an incubator shaker (HNY211B, Tianjin) with a stirring speed of 400 rpm. Excessive DMF solvate of cefadroxil was added into the solvent mixture until the temperature reached 303.15 K. The solution was

temp (K)

water content (Vwater/Vtotal)

stir speed (rpm)

293.15 298.15 303.15 298.15 298.15 298.15 298.15

0.80 0.80 0.80 0.85 0.90 0.80 0.80

400 400 400 400 400 200 600

sampled every 5 min, followed by 8 h of drying at 313.15 K. Then it was analyzed by SEM and PXRD.

3. RESULTS AND DISCUSSION 3.1. Characterization of DMF Solvate and Monohydrate of Cefadroxil. DSC and TGA curves of DMF solvate and monohydrate are shown in Figure 2. As shown in Figure 2a, the DSC curve of the DMF solvate exhibits two clear peaks. The first one at 444.80 K is attributed to the melt of the sample. It corresponds to the weight loss of 32.72% in Figure 2b. According to the mass loss, two DMF molecules escaped per one molecule of DMF solvate. The second peak at 446.07 K results from the decomposition of samples. While the DSC scan of cefadroxil monohydrate displays only one clear peak at 487.99 K, because the sample melted and decomposed. Figure 2c revealed the PXRD results of DMF solvate and monohydrate of cefadroxil. Characterization peaks are at 9.670, 11.928, 14.247 for monohydrate and 6.979, 15.961, 20.939 for DMF solvate of cefadroxil. SEM images in Figure 2d show that the DMF solvate of cefadroxil has a needlelike shape and the monohydrate has a hexahedron shape. 3.2. Driving force for DMF Solvate Transforming into Monohydrate. In order to investigate the driving force of transformation, the solubilities of DMF solvate and monohydrate in DMF−water were measured, which are presented in Figure 3. It can be seen that the solubility of DMF solvate increases with temperature. While it exhibits one peak as the increase of water content, this phenomenon is termed cosolvency.18 Monohydrate of cefadroxil exhibits the same tendency as shown in Figure 3b. The typical thermodynamic relationship between DMF solvate and monohydrate is shown Figure 4a. The intersection of the solubility curves of DMF solvate and monohydrate represents the transition points of the two forms. As reported, the state of the hydrate depends on the water content in the solvent mixture at a given temperature,19 and thus, there exists an equilibrium water content x* at which the solubilities of the DMF solvate and the monohydrate are identical. The dependency of the equilibrium water content on the temperature for the DMF solvate and the monohydrate is shown in Figure 4b. The equilibrium water content decreases with the increase of temperature. Any deviation from the equilibrium water content will result in phase transformation. For example, the DMF solvate can transform into the monohydrate at higher water content, and the monohydrate will transform into the DMF solvate if the water content is lower than the equilibrium value. To further explain the influence of process parameters on transformation driving force, the relationship between solubility ratio (R = C*DMF solvate/C*monohydrate) and temperature, water content was shown in Figure 5. The ratio increases with 1111

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Figure 2. (a) DSC curves and (b) TGA curves of cefadroxil. (c) PXRD patterns of cefadroxil. (d) SEM photos of DMF solvate and monohydrate of cefadroxil.

the transition point, so DMF solvate of cefadroxil can transform into monohydrate. 3.3. In Situ Monitoring of Phase Transformation. As can be seen in Figure 6, the process of solvent-mediated transformation includes three phases: (1) dissolving of DMF solvate of cefadroxil, (2) nucleation of monohydrate, (3) growth of monohydrate.20 Figure 6 reveals the evolvement of particle morphology during the transformation experiment at 298.15 K. First, the concentration of solution moves up rapidly to a plateau, where the solution is saturated for DMF solvate of cefadroxil. This corresponds to the dissolving of DMF solvate. During the second phase, the concentration of solution remains almost constant. Actually, the dissolving of DMF solvate and nucleation and growth of monohydrate all takes place at this stage. As can be seen in Figure 7, DMF solvate and monohydrate of cefadroxil exist at the same time during this phase. This illustrates that the dissolving rate of DMF solvate equals the nucleation and growth rate of monohydrate. The third phase starts with the decline of solution concentration owing to the growth of monohydrate of cefadroxil. At this phase, DMF solvate disappears completely corresponding to image f in Figure 7. Finally, the solution concentration approaches the solubility of monohydrate of cefadroxil. After stage (2) is completed, there is no metastable phase in the solution. Thus, we define this point as the terminal point of transformation. 3.3.1. Influence of Temperature on the Transformation Kinetics. The time-dependent evolution of cefadroxil concentration in Figure 8a shows that the dissolving of DMF solvate to a plateau was finished in 10 min at 293.15 K. DMF solvate completely transforms to monohydrate after 112 min. The concentration does not reach equilibrium with monohydrate until 195 min. This demonstrates that the total rate of

Figure 3. Measured solubility of (a) DMF solvate and (b) monohydrate (black solid lined) as a function of solvent composition and temperature.

increasing temperature and also increases as water content increases. This can explain the curve tendency shown in Figure 4b. At higher temperature, the driving force for transformation is bigger, so the water content needed is smaller. The transformation experiments in this work were designed above 1112

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Figure 5. Effect of (a) temperature and (b) water fraction on solubility ratio.

Figure 4. (a) Typical thermodynamic relationship between DMF solvate and monohydrate of cefadroxil at 298.15 K and (b) water content x* at which DMF solvate and monohydrate are in equilibrium in DMF−water mixtures.

dissolution is much faster than the total rate of growth. In addition, the energy required for nucleation is very low because of the existing solid of DMF solvate. Thus, the transformation of DMF solvate into monohydrate is controlled by the growth of the monohydrate.16 Comparing three curves in Figure 8a, we can conclude that the rate of transformation becomes faster as the temperature increases under the same water content and the same stirring speed. According to the transformation time defined above, a curve has been plotted of solubility ratio vs transformation time, which is also shown in Figure 8a. It can be seen that the process is finished in 112 min at 293.15 K, while it takes only 25 min at 303.15 K. This can be explained by the curve in Figure 5a where at increasing temperature, the solubility ratio increases, and hence, the transformation driving force increases. The SEM photos shown in Figure 8b indicate that the product coalesces at 303.15 K and has a wide size distribution at 293.15 K. The reason lies in the fact that when the transformation process happens too quickly, monohydrate of cefadroxil tends to nucleate on the surface of DMF solvate. Whereas, when the process takes too much time, product formed at the early stage is much bigger than at a later stage, so that it exhibits a wide size distribution. 3.3.2. Influence of Water Content on the Transformation Kinetics. The second step of transformation is the reaction between cefadroxil and water, because water plays an important role in the transformation process.19,21,22 For example, in Figure 4a, when the water content exceeds 0.747 and the

Figure 6. Typical time-dependent evolution of cefadroxil concentration during phase transformation process from DMF solvate to monohydrate.

solubility ratio is greater than one, the DMF solvate of cefadroxil can transform to the monohydrate. When the water content is less than 0.747 and the solubility ratio is smaller than one, the monohydrate of cefadroxil can transform to DMF solvate. Figure 9 reveals that the transformation time becomes shorter as water content increases. This phenomenon can be explained from two aspects. On one hand, the driving force of the transformation is the solubility ratio, and the ratio increases with water content as shown in Figure 5b. On the other hand, the water content has a great effect on the nucleation and growth rate of the monohydrate. In Figure 4b, it shows that there exists an equilibrium water content x* at a given temperature. When the water content is higher than the 1113

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Figure 9. Effect of water content on the transformation at 298.15 K and a stir speed of 400 rpm.

Figure 7. PVM images of suspensions during the transformation with an initial water content of 0.80, a temperature of 298.15 K, and a stirring speed of 400 rpm.

Figure 10. Effect of stirring speed on transformation at 298.15 K and an initial water content of 0.80.

process of transformation was completed in 65 min. However, when the stirring speed was 600 rpm, it only took about 35 min to finish the process. The reason lies in the fact that the process of solvent-mediated transformation comprises desolvation and solvation. It is obvious that stirring speed has a great effect on the convective mass transfer, which will influence the reaction rate of desolvation and solvation.23 By increasing the stirring speed, solvent and solvate can be blended more sufficiently, and the probability to contact is larger, so that the process of transformation can be finished more quickly. 3.4. Mechanism of Phase Transformation. In slurry transformation experiments, dissolution of the metastable form and nucleation of the stable form always take place simultaneously. In order to observe the mechanism of transformation more clearly, the experiment was undertaken at a relatively high transformation rate; as a result, the product has a poor quality. PXRD patterns shown in Figure 11a demonstrate that DMF solvate and monohydrate solid exist at the same time in the solution. The relative intensities of the characteristic peaks of monohydrate increase with the time, and the intensity of the DMF solvate peak decreases. Additionally, it is obvious that monohydrate of cefadroxil nucleates on the surface of DMF solvate as shown in Figure 11b. The final product is of needlelike shape, composed by a hexahedron shape. This illustrates that the existing surface of the metastable phase facilitates the nucleation of the stable phase. The

Figure 8. (a) Effect of temperature on the transformation at an initial water content of 0.80 and a stirring speed of 400 rpm. (b) SEM photos of products at 293.15 K, 298.15 K, and 303.15 K.

equilibrium water content, the DMF solvate can transform into monohydrate. The difference between them can also be considered as the driving force of transformation. It is obvious that x − x* increases with the increase of x at a given temperature. Therefore, we can conclude that transformation time decreases with the increase of water content. The product reveals the same properties as is shown in Figure 8b. 3.3.3. Influence of Stirring Speed on the Transformation Kinetics. Figure 10 exhibits the influence of stirring speed on the transformation. When the stirring speed was 200 rpm, the 1114

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The SEM result proves that the mechanism of transformation is surface nucleation, and PXRD patterns show that the transformation was from DMF solvate to monohydrate of cefadroxil. The results obtained in this work have a great significance in understanding the process of solvent-mediated pseudopolymorph transformation. The driving force of transformation is determined by the thermodynamic issue, while the transformation kinetics is determined by both thermodynamics and fluid dynamics. As is shown in Figure 8b, in order to obtain high-quality product, we should keep the transformation rate at an appropriate level through controlling the process parameters to adjust the solubility ratio and mass transfer rate. This conclusion can also be applied to the solvent-mediated transformation of similar pharmaceuticals.

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AUTHOR INFORMATION

Corresponding Author

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

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for the financial support of the National Natural Science Foundation of China (No. NNSFC 21176173), Tianjin Municipal Natural Science Foundation (No. 11JCZDJC 20700), and National High Technology Research and Development Program (863 Program No.2012AA021202).

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Figure 11. (a) Powder diffraction patterns of the slurry for the crystal form transformation during crystallization and (b) SEM photos of cefadroxil during the transformation with an initial water content of 0.80, a temperature of 303.15 K, and a stirring speed of 400 rpm.

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occurrence of this phenomenon results from two possible reasons. The local supersaturation close to the surface of the dissolving DMF solvate is higher than the solution, and also the existing surface of DMF solvate decrease the energy required for nucleation.24,25

4. CONCLUSIONS In this work, the driving force, kinetics, and mechanism of solvent-mediated transformation from DMF solvate to the monohydrate of cefadroxil were investigated. The solubilities of DMF solvate and monohydrate from 288.15 K to 308.15 K in DMF−water mixtures were measured with the result of threedimensional phase graphs. The solubility ratios were also calculated according to the definition above. DMF solvate can transform into monohydrate if the ratio exceeds one. Vice versa, monohydrate will transform into DMF solvate in the case where the ratio is less than one. Transformation kinetics at different temperature, water content, and stirring speed were evaluated by in situ PVM and FTIR spectroscopy. The growth of monohydrate was the rate-controlling step during transformation. Increasing temperature, water content, and stirring speed resulted in the decrease of transformation time, because transformation kinetics are determined by the solubility ratio and the mass transfer rate. Higher temperature and higher water content increased the solubility ratio, and the mass transfer rate improved with the increase of stirring speed. 1115

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(21) Tian, F.; Qu, H.; Zimmermann, A.; Munk, T.; Jørgensen, A. C.; Rantanen, J. J. Pharm. Pharmacol. 2010, 62, 1534. (22) Wang, X.; Dang, L.; Black, S.; Zhang, X.; Wei, H. Ind. Eng. Chem. Res. 2012, 51, 2789. (23) Wang, Z.; Wang, J.; Dang, L.; Zhang, M. Ind. Eng. Chem. Res. 2007, 46, 1851. (24) Croker, D.; Hodnett, B. Cryst. Growth Des. 2010, 10, 2806. (25) Kumashiro, M.; Saitoh, S.; Kobayakawa, A.; Hirasawa, I. J. Chem. Eng. Jpn. 2011, 44, 187.

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