Characterization and Structure Analysis of Cefodizime Sodium

Feb 3, 2014 - Fushun Research Institute of Petroleum and Petrochemical, SINOPEC, ... Organic Process Research & Development 2016 20 (4), 780-785...
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Characterization and Structure Analysis of Cefodizime Sodium Solvates Crystallized from Water and Ethanol Binary Solvent Mixtures Zengkun Liu,† Qiuxiang Yin,†,‡ Xinwei Zhang,†,§ Junbo Gong,†,‡ and Chuang Xie*,† †

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 300072, People’s Republic of China § Fushun Research Institute of Petroleum and Petrochemical, SINOPEC, Fushun 113001, People’s Republic of China ABSTRACT: Only a few studies of heterosolvate are reported in the literature. In this article, heterosolvates of cefodizime sodium were prepared in water/ethanol binary solvent mixtures and characterized. Through thermal analysis and composition determination, we deduced that both water and ethanol molecules participated in the forming of crystal lattice. The general chemical name of heterosolvates may be defined as cefodizime sesquihydrate sesquiethanolate. Then, the studies on infrared ATR and Raman spectroscopy provided a strong evidence of intermolecular hydrogen bonds. Further, the crystal structure of solvates was analyzed by the powder X-ray diffraction data. The results indicated that the structure differences between solvate and raw material were mainly caused by the solvent effect, leading to forming solvation through intermolecular hydrogen bonding.



from various solvent.12−18 Cefodizime sodium, as the model compound in the present work, is a third generation cephalosporin with a high antibacterial activity in the treatment of lower respiratory tract infections.19 Cefodizime sodium can easily form solvate and hydrate due to its donor-rich cephalosporin mother nucleus structure (Figure 2). Industrially, cefodizime sodium is crystallized from its aqueous solution with ethanol as antisolvent. In this process, cefodizime sodium always combines with water and ethanol to produce complicated solvates with two different solvent molecules. The objectives of this study were to (1) characterize cefodizime sodium heterosolvates prepared in water/ethanol binary solvent system, (2) develop a mechanistic understanding of typical solvate formation based on the crystal structure analysis, and (3) determine the roles of solvents playing in this solvate formation. In order to achieve these goals, a number of analytical techniques such as thermal analysis (thermogravimetric and differential thermal analysis, TG/DTA; differential scanning calorimetry, DSC; hot stage microscopy, HSM), infrared spectroscopy (IR), Raman spectroscopy, and powder X-ray diffraction (PXRD) were applied.

INTRODUCTION The formation of solvates is one of the most common phenomenon especially for pharmaceutical materials.1−8 Investigation on structures with solvent molecules incorporated in the crystal lattice has drawn significant interests because solvate formation often leads to different physical properties, stability and bioavailability. Therefore, the possibility of solvate formation should be considered in the crystallization of pharmaceutical materials. However, only a few studies of heterosolvate are reported in the literature.9,10 Cephalosporin, as a kind of semisynthetic antibiotic with a broad spectrum, has many advantages such as broad antimicrobial spectrum, strong bactericidal effects, and a little anaphylaxis compared with other antibiotics.11 In their mother nucleus structures shown in Figure 1, there are many groups with strong donors, such as acylamino (−CONH−) and carboxyl (−COOH), which are easy to form hydrogen bonding with the solvent molecules, so solvate formation has been widely observed in cephalosporins. Much literature have reported that cefatrizine, cefazolin, ceftriaxone sodium, cefoperazone, cefixime, cefazolin sodium, etc. can form solvates



EXPERIMENTAL SECTION Materials. Solvent-free cefodizime sodium was provided by Shandong Lukang Pharmaceutical Group Co., Ltd., with a purity of 0.99 in mass fraction. Distilled deionized water of high performance liquid chromatography grade was used. Ethanol Received: Revised: Accepted: Published:

Figure 1. Molecular structure of cephalosporins. © 2014 American Chemical Society

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Figure 2. Chemical structure of cefodizime sodium.

Morphology. The morphology of cefodizime sodium solvate was characterized by polarized light microscope (PLM, Olympus BX51) and scanning electron microscope (SEM, Hitachi X650).

was purchased from Tianjin Kewei Chemical Ltd. with analytical reagent grade. Preparation of Cefodizime Sodium Solvate. The experimental apparatus consisted of three parts: reagent feeding system, crystallizer with temperature control, and mixing system, the details of which are given elsewhere.20 Cefodizime sodium solvates were prepared by a batch antisolvent crystallization process through the following procedure. First, the raw materials (i.e., solvent-free cefodizime sodium) were dissolved in the water at 20 °C; second, the solution was discolored through adding active carbon, and the filtrate was returned to the clear crystallizer; third, the ethanol was added into the resulting solution at a proper rate, and the solution rested for 30 min after the solutes were crystallized; fourth, the rest of ethanol continued to be added into the slurry, which was then cooled to 5 °C; finally, after the system reached equilibrium for enough time, the products were filtered and dried in a vacuum oven at 45 °C. Thermal Analysis. Thermogravimetric and differential thermal analysis (TG/DTA) was conducted on a Rigaku PTC-10A instrument; the sample (5−10 mg) was heated at a rate of 10 °C/min and the TG/DTA curve was recorded from 25 to 300 °C under a dry nitrogen atmosphere with a flux of 90 mL/min. Differential scanning calorimetry (DSC) was carried out on a Netzsch DSC 204 instrument with a nitrogen purge rate of 90 mL/min, and the temperature range of the experiment was from 25 to 300 °C with a heating rate of 10 °C/min. The desolvation behavior of solvates was studied under hot stage microscope (HSM, Olympus UMAD3) at a heating rate of 10 °C/min between 30 and 300 °C. Composition. The water content in the solvate crystals was analyzed through a Mettler Toledo V20 Volumetric Karl Fischer titrator. The ethanol content in the solvates was determined by gas chromatography analysis, which was carried out on an Angilent 7890A instrument. Spectroscopy. Infrared spectra of solvates and raw materials were recorded on a Nexus 670 infrared instrument (Thermo Inc.) with attenuated total reflectance accessory. The scanning range was 4000−400 cm−1. Raman spectra were collected using a RamanRXN2 spectrometer (Kaiser Optical Systems, Inc.). Powder X-ray Diffraction (PXRD). The crystallinity of solvated cefodizime sodium was analyzed through using PXRD analysis. The samples were gently ground to a fine powder prior to analysis. Data were collected with a Rigaku D/max-2500 powder X-ray diffractometer, operated at 40 kV and 100 mA; Cu Kα radiation was utilized in the measurements. The PXRD pattern was made over a range of 5−50° with a step size of 0.02°.



RESULTS AND DISCUSSION Thermal Analysis and Composition. The TG/DTA results (Figure 3) showed that the samples prepared from the

Figure 3. TG/DTA results for desolvation of cefodizime sodium solvate.

water and ethanol solution of cefodizime sodium went through an obvious procedure of desolvation, indicating that these corresponding samples formed the solvates crystallized from the binary solvent mixtures. Three-step desolvations of the samples were confirmed via three DTA endothermic peaks: first, free solvent was removed at 30 °C; then, the solvent which had entered into the lattice was removed at 56 and 95 °C, respectively. The decreases in mass of 7.7% in the first desolvation, 6.9% in the second desolvation, and 9.0% in the third desolvation clearly indicated that the solvents existed either in free form or by entering into the crystal lattice. The needle-like solvated crystals packed in compression and was dried at low temperature, so the existence of free solvent was possible.21 By comparison, the mass loss, when the samples were raw material and solvent was removed from the surfaces, was about 7.2%. From the DSC data as shown in Figure 4, the resulting samples (solvate run 1) also exhibited an obvious desolvation peak at 75 °C and the decomposition temperature of the solvates was higher than that of amorphous raw material. In order to prove solvate formation, the experiment on the solvate in which cyclic DSC analysis was performed in the temperature regime: heating from 25 to 100 °C, cooling to 20 °C, second heating 300 °C. The result showed that the endotherm at 75 3374

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Figure 4. DSC results of cefodizime sodium solvate and raw material. Solvate run 1: heating from 25 to 100 °C; solvate run 2: second heating from 25 to 300 °C after heating from 25 to 100 °C and then cooling to 20 °C.

Figure 6. Infrared ATR results of cefodizime sodium solvate and raw material.

hydrogen bond at the carbonyl groups between solvate and raw material, giving rise to distinct changes in the 1500−1800 cm−1 region of the spectrum. In the solvate, there were two peaks at 1756 and 1594 cm−1, while the peaks at 1767 and 1589 cm−1 (with a small shoulder) were seen in the raw material. Moreover, the combined −NH− and −OH stretch was found in the 3100−3500 cm−1 region, and the intensity of characteristic peak in the solvate became stronger than that in the raw material. These differences in the spectra indicated that solvent molecules formed the intermolecular hydrogen bonds with the acylamino (−CONH−) and the carboxylate group (−COO−) of cefodizime sodium, respectively. In our previously reported work, we drew a conclusion that the carboxylic ion (−COO−) of one cefodizime sodium molecule and the amino group (−NH2) of another cefodizime sodium molecule, combined simultaneously with the hydroxyl group (−OH) of ethanol to yield a six-membered hydrogen bond framework, corresponding to the peaks of Raman spectra between 1340 and 1430 cm−1.20 From the evidence of spectroscopy study, we deduced that one water molecule with −NH− of the acylamino group (a) and two water molecules (b) formed intermolecular hydrogen bonds and −OH of one ethanol molecule formed a six-membered hydrogen bond framework with −COO− and −NH2 of thiazole (c) (Figure 7). These results indicated that the crystal structure formation of the solvate was mainly determined by the intermolecular hydrogen bonds. Powder X-ray Diffraction Data. PXRD was used to examine the structure of crystals prepared from the water and

°C disappeared during the second heating run (solvate run 2). Figure 5 showed graphs of typical samples of crystals of cefodizime sodium solvate during desolvation under hot stage microscopy. The removal of solvent led the crystal diaphaneity to decline with increased temperatures. In the late stage of desolvation, needle-shaped crystals have been bent. The water content in the solvate crystals was 4.1 ± 0.9 (mean ± standard deviation) wt % using Karl Fischer method. The ethanol content was confirmed as (10.0 ± 1.2) wt %, performed through gas chromatography determination for a crystallization product. Further, a simplified molar ratio in the solvates was determined as cefodizime sodium/water/ethanol = 1/(1.3− 2.1)/(1.4−1.8). Thus we could find that the results were statistically significant, and the composition of solvate essentially matched with the thermal analysis results. Through above analysis, it clearly showed that the solvents had been incorporated into the cefodizime sodium crystals, and the intermolecular hydrogen bondings were formed between cefodizime sodium and solvent molecules. According to the simplified molar ratio, the general chemical name of the obtained solvate may be defined as cefodizime sesquihydrate sesquiethanolate. Infrared ATR and Raman Spectroscopy. As shown in Figure 2, cefodizime sodium molecule contained many functional groups, −NH2, −COO−, and −CONH−, which had the ability to form hydrogen bonds with solvent molecules. ATR spectra shown in Figure 6 revealed the differences in

Figure 5. Images of hot stage microscopy during desolvation. 3375

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Figure 7. Intermolecular hydrogen bonding scheme (a−c) in cefodizime sodium solvate.

ethanol solution of cefodizime sodium and thus determined whether the resulting samples, which were thought to be solvates, had distinct crystal structures. As shown in Figure 8,

Figure 8. PXRD patterns of cefodizime sodium solvate and raw material.

Figure 9. (a) PLM photo: cefodizime sodium solvate. (b) SEM photo: cefodizime sodium solvate. (c and d) SEM photo: raw material.

the diffractograms produced from the solvate exhibited sharp, distinct peaks, which are indicative of a high degree of crystallinity; on the other hand, the samples obtained from the raw material were amorphous according to the PXRD pattern. Obviously, the differences resulted from the solvation. The PLM and SEM photos of typical samples were showed in Figure 9. The solvated crystals exhibited needle-like shapes, while the samples of raw material were an agglomeration of irregular shapes with porous structures. This further illustrated that the effect of solvent on the shape of cefodizime sodium crystals in comparison to the solvent-free samples was remarkable. Figure 10 indicated that the intensity of diffraction peaks decreased with the increasing temperature; and a small diffraction peak also existed in the last photo. This is evidence

that the solvent molecules participated in the forming of crystal lattice and played an important part in supporting the structures.



CONCLUSION Cefodizime sodium heterosolvate was prepared from water/ ethanol binary solvent mixtures. Through thermal analysis and composition determination, we deduced that the solvents had been incorporated into the cefodizime sodium solvate crystals and intermolecular hydrogen bonds were formed. The general chemical name of the obtained solvate may be defined as cefodizime sesquihydrate sesquiethanolate. Then, the studies on ATR and Raman spectroscopy provided strong evidence of 3376

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(6) Caira, M. R.; Stieger, N.; Liebenberg, W.; De Villiers, M. M.; Samsodien, H. Solvent inclusion by the anti-HIV drug nevivapine: Xray structures and thermal decomposition of representative solvates. Cryst. Growth Des. 2008, 8, 17−23. (7) Renou, L.; Coste, S.; Cartigny, Y.; Petit, M. N.; Vincent, C.; Schneider, J. M.; Coquerel, G. Mechanism of Hydration and Dehydration of Ciclopirox Ethanolamine (1:1). Cryst. Growth Des. 2009, 9, 3918−3927. (8) Andre, V.; Braga, D.; Grepioni, F.; Duarte, M. T. Crystal molecular forms of the antibiotic 4-aminosalicylic acid: Solvates and molecular salts with dioxane, morpholine, and piperazine. Cryst. Growth Des. 2009, 9, 5108−5116. (9) Görbitz, C. H.; Hersleth, H. P. On the inclusion of solvent molecules in the crystal structures of organic compounds. Acta Crystallogr. 2000, B56, 526−534. (10) Detoisien, T.; Arnoux, M.; Taulelle, P.; Colson, D.; Klein, J. P.; Veesler, S. Thermal analysis: A further step in characterizing solid forms obtained by screening crystallization of an API. Int. J. Pharm. 2011, 403, 29−36. (11) Kelkheim, W. M. Process for the preparation of cefodizime sodium. US 5126445, 1992. (12) Coenen, S.; Ferech, M.; Dvorakova, K. European surveillance of antimicrobial consumption (ESAC): outpatient cephalosporin use in Europe. J. Antimicrob. Chemother. 2006, 58, 413−417. (13) Deshpand, P. B.; Catangler, B. P.; Gurusamy, K.; Konda, R. A. Method for producing 3-allyl cephalosporins solvate in DMF. CN 02829831.4, 2005. (14) Zhang, C. T.; Wang, J. K.; Wang, Y. L. Non-isothermal dehydration kinetics of ceftriaxone disodium hemiheptahydrate. Ind. Eng. Chem. Res. 2005, 44, 7057−7061. (15) Hou, B. Z.; Hu, C. Q.; Wei, R. P. Process for the preparation of a novel cefoperazone sodium. CN 200510086950, 2007. (16) Zhou, Y. J.; Meng, H.; Zhao P. A method for producing cefixime. CN 200510013537.2, 2005. (17) Wang, J. K.; Qian, Y. X.; Zhang, M. J. Study on crystal structure of cefazolin sodium pentahydrate and its molecular assembly. CN 200510016123, 2006. (18) Hilfiker, R. Polymorphism: in the pharmaceutical industry; Wiley: New York, 2006; Vol. 211, pp 216−227. (19) Marunaka, T.; Matsushima, E.; Minami, Y. Acidic degradation of cefodizime (THR-221) and structural elucidation of the products. I. Chem. Pharm. Bull. 1989, 37, 367−372. (20) Cui, P. L.; Zhang, X. W.; Yin, Q. X.; Gong, J. B. Evidence of Hydrogen-Bond Formation during Crystallization of Cefodizime Sodium from Induction-Time Measurements and In Situ Raman Spectroscopy. Ind. Eng. Chem. Res. 2012, 51, 13663−13669. (21) Lekhal, A.; Girard, K. P.; Brown, M. A.; Kiang, S.; Khinast, J. G.; Glasser, B. J. The effect of agitated drying on the morphology of Lthreonine (needle-like) crystals. Int. J. Pharm. 2004, 270, 263−277.

Figure 10. PXRD patterns for desolvation process of cefodizime sodium solvate.

intermolecular hydrogen bonds between cefodizime sodium and solvent. More specifically, one water molecule with −NH− of the acylamino group and two water molecules formed intermolecular hydrogen bonds; a six-membered hydrogen bond framework was formed involving in −OH of one ethanol molecule, −COO−, and −NH2 of thiazole. Finally, PXRD was used to examine the crystal structure of solvate and raw material, which indicated that the differences were mainly caused by the solvent effect. Both water and ethanol led to forming solvation with cefodizime sodium through intermolecular hydrogen bonds.



AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone: 86-22-27405754. Fax: 8622-27314971. Notes

The authors declare no competing financial interest.



ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (No. 2117617) and the Tianjin Municipal Natural Science Foundation (Nos. 10JCYBJC14200 and 11JCZDJC20700). The analysis tools used in this study were supported by the State Key Laboratory of Chemical Engineering (No. SKL-ChE-11B02).



REFERENCES

(1) Kim, Y. B.; Park, I. Y.; Lah, W. R. The crystal structure of naproxen sodium, (C14H13O3Na), a non-steroidal antiinflammatoryagent. Arch. Pharm. Res. 1990, 13, 166−173. (2) Kim, Y. S.; Rousseau, R. W. Characterization and solid-state transformation of the pseudopolymorphic forms of sodium naproxen. Cryst. Growth Des. 2004, 4, 1211−1216. (3) Kim, Y. S.; Paskow, H. C.; Rousseau, R. W. Propagation of solidstate transformations by dehydration and stabilizaiton of pseudopolymorphic crystals of sodium naproxen. Cryst. Growth Des. 2005, 5, 1623−1632. (4) Tanaka, K.; Wada, S.; Caira, M. R. Inclusion crystals of 2,2′,7,7′,9,9′ - hexahalo - 9,9′ - bisfluorenyl derivatives: A new family of polyhalo arylhosts. Tetrahedron 2007, 63, 9213−9220. (5) Van de Streek, J. All series of multiple solvates (including hydrates) from the Cambridge Structural Database. Cryst. Eng. Commun. 2007, 9, 350−352. 3377

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