Article pubs.acs.org/IECR
Gelation Phenomenon during Antisolvent Crystallization of Cefotaxime Sodium Yongheng Yin,† Zhenguo Gao,† Ying Bao,*,†,‡ Baohong Hou,† Hongxun Hao,†,‡ Dong Liu,§ and Yongli Wang†,‡ †
School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, People’s Republic of China Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency, Tianjin University, Tianjin, 300072, People’s Republic of China § Huabei Pharmaceutical Co., Ltd., Shijia Zhuang, Hebei, 050015, People’s Republic of China ‡
S Supporting Information *
ABSTRACT: In this paper, gelation phenomenon during the crystallization process of cefotaxime sodium (CTX) is systematically studied. First, the gelation process is monitored using a nanoparticle size analyzer; the gel and xerogel are studied by different characterization tools to speculate the gelation mechanism. It is found that the gelation is driven by the crystallization of CTX and the nanoparticles act as gelators before they can be seen by the naked eye. Moreover, the solid-solution interfacial tension used to predict the rate of crystal growth is calculated using the induction periods and solvents are classified using the Hansen solubility parameters method, according to whether it can be gelated by CTX. It is shown that the strong polar interaction between solvent molecules and the carboxyl, amine, or acyl groups exposed on the CTX crystal surface is the key factor for gelation.
1. INTRODUCTION Solution crystallization is a common method for drug purification. In order to improve the crystal quality of drugs, much research has been carried out regarding the effects of nucleation and crystal growth on crystal size, crystal size distribution, crystal morphology, etc.1−3 During crystallization, the supersaturated solution will first nucleate and crystal growth follows. For systems with a fast growth rate, nuclei gradually become visible crystals and form a good solid−liquid two-phase suspension. If the growth rate is slow, crystals of nanometer or micrometer size will form a colloidal suspension, which is thermodynamically unstable and may further form a gel. Gel is a form of colloid and can be divided into “flowing” or “nonflowing” gel qualitatively.4,5 Many drugs themselves can form gels. Xu et al.6,7 reported the first antibiotic gelator, vancomycin pyrene, which can form hydrogel via hydrophobic interaction and hydrogen bonding. Wang8 reported that a simple drug compound, 4-oxo-4-(2-pyridinylamino) butanoic acid, is able to gel water during its cooling crystallization. However, for drug purification, gelation is undesirable during the crystallization process. There are two indispensable conditions for gelation: (i) the presence of a gelator and (ii) the interaction between gelators or between the gelator and the solvent. Regarding the first condition, gelators can be nanometer- or micrometer-sized particles, polymers, and low-molecular-weight gelators (LMWGs). In solution crystallization, nanometer- or micrometer-sized crystals can serve as the gelator. Zhang and Zhu9,10 both have reported that, during the antisolvent crystallization of cefotaxime sodium (CTX) and tobramycin, gelation occurs after certain amounts of antisolvent have been added into the solution. Regarding the second condition, a three-dimensional © 2013 American Chemical Society
(3-D) network is formed by gelators using weak interactions such as hydrogen bonding, hydrophobic interactions, van der Waals forces, dipole−dipole interactions, electrostatic interactions, and π-stacking interactions, to trap the solvent via surface tension and capillary force. Hydrogen bonding based on carboxyl groups, hydroxy groups, or the ion pairs of the LMWG molecules is the main driving force for the formation of 3-D networks.11−15 For rather soluble salts, the forces acting between particles are electrostatic attractive forces, which make the particles coalesce irreversibly during the crystallization.16 For example, the strong electrostatic attraction between the positive charged nitrogen atom of clopidogrel base and the negative charged oxygen atom of hydrogen sulfate is the reason why clopidogrel hydrogen sulfate crystals aggregate and form gels.17 Usually, the gelation process is followed and monitored by Fourier transform infrared (FTIR) spectroscopy, fluorescence technique, densitometry, etc.18−20 The gelation mechanism can be revealed by the characterization of gel microstructure.21−23 Through the use of nuclear magnetic resonance (NMR), rheological measurements, atomic force microscopy (AFM), differential scanning calorimetry (DSC), and light scattering, Lee et al.24 proposed that crystallization drives the gelation of copolymers by forming crystalline fibrils. Ide et al.25 reported that gelation is caused by aggregation via noncovalent interactions between molecules. Nagarkar et al.26 reported that nucleation and growth lead to gelation. Received: Revised: Accepted: Published: 1286
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mechanism of CTX gelation is speculated based on the above characterizations and analysis.
CTX is a third-generation cephalosporin; its structure is depicted in Figure 1. It is an organic acid salt, and its appears as
2. EXPERIMENTAL SECTION 2.1. Materials. Cefotaxime acid (molecular formula: C16H17N5O7S2, purity >98.5%) was supplied by Huabei Pharmaceutical Co., Ltd. of China. Sodium acetate, deionized water, and all the organic solvents (analytical reagent grade) were purchased from Tianjin Kewei Chemical Co., Ltd. of China and used without further purification. 2.2. Tracking of the Gelation Process. CTX solution was obtained via the reaction of cefotaxime acid with a sodium acetate solution at 283.15 ± 0.05 K (controlled by a thermostatic water-circulator bath, 501 A, Shanghai Laboratory Instrument Works, China). The reaction step required ∼15 min and the concentration of CTX after reaction was 0.3 g/mL. Antisolvent was added, with stirring, into the solution at a constant rate of 10 mL/min, using a peristaltic pump (Model BT100-1F, Baoding Longer, China). Samples were taken at half minute intervals for particle size and zeta potential measurements (using a ZetaPlus nanoparticle size analyzer, Brookhaven Instruments, USA) until gelation occurred. 2.3. Characterization of Gel and Xerogel. The gel was dissolved in predetermined amounts of N,N-dimethylformamide (DMF), and its water content was measured by volumetric Karl Fischer titration (Model V20/V30, Mettler− Toledo, Switzerland). The CTX content was measured by attenuated total reflection (ATR) Fourier transform infrared (FTIR) spectroscopy (React IR TM45, Mettler−Toledo, Switzerland). Drying the gel at room temperature under normal pressure yielded the xerogel. The gel and xerogel were analyzed using a
Figure 1. Molecular structure of cefotaxime sodium (CTX).
a white or almost-white crystalline powder. During the crystallization process of CTX, gelation often occurs. To the authors’ knowledge, there are few reports on the gelation phenomenon in the pharmaceutical crystallization process, and, to date, the gelation mechanism of pharmaceutical drugs has not been discussed and reported. The gelation phenomenon has been studied for the purpose of understanding the relationship between gelation and the crystallization of CTX. First, the gelation process is monitored using a nanoparticle size analyzer. The gel and xerogel are characterized by the polarized light microscopy (PLM), scanning electron microscopy (SEM), and powder X-ray diffraction (PXRD). The solid-solution interfacial tension then is calculated by induction periods. Moreover, solvent classification is carried out using the Hansen solubility parameters method, and the crystallization of CTX can be enhanced by a proper screening of solvents. Finally, the
Figure 2. Nanoparticle size distributions after the addition of various amounts ((a) 5, (b) 10, (c) 15, and (d) 20 mL) of antisolvent (2-propanol) into the CTX solution. 1287
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Figure 3. Pictures of CTX at different stages: (a) microscopic picture of CTX solution before gelation; (b) photograph of gel formed in the crystallizer; (c) photograph of gel after the removal of nongelled solvent.
flocculent deposit appears (see Figure 3b). An opaque gel is obtained after the removal of nongelled solution (Figure 3c). The phenomenon indicates that nanometer- and micrometersized particles aggregate after being crystallized out of the solution. The zeta potential values obtained at different times in Figure 2 are shown in Table 1; these data suggest that the addition of
polarized light microscopy system (Model BX51, Olympus, Japan) that was equipped with a hot plate (Model LTS350/ TMS94, Linkam Scientific Instruments Limited, U.K.); analyses via powder X-ray diffraction (Model D/MAX 2500, Rigaku, Japan) and scanning electron microscopy (Model S-4800, Rigaku, Japan) were also performed. 2.4. Measurement of the Induction Period. The setup used to measure the induction period is shown in Figure S1 in the Supporting Information. A saturated solution of CTX was prepared, first according to solubility data in the literature.27 The solution was stirred in a jacketed glass vessel at 283.00 ± 0.05 K for 0.5 h, and then predetermined amounts of antisolvent, which was thermally controlled at the same temperature, was quickly added into the vessel. The stirrer was set at a suitable speed to ensure that the solution would be mixed well soon and avoid bubble forming. The solution was monitored with a laser system (Model JSW3-300, Peking University, China) until primary nuclei appeared, which was the point at which the intensity of the laser penetrating through the solution had a sudden decrease. The period from antisolvent addition to the formation of the primary nuclei is called the induction period. 2.5. Classification of Solvents. A small amount (0.05 g) of CTX powder was added into 20 mL of solvent to be tested. The suspension was shaken in a shaking water bath (Model WE-1, Honor, China) at 20 °C with a constant speed of 140 rpm for 30 min. The solvents in which CTX could not be dissolved thoroughly were classified as insoluble solvents. For homogeneous solutions formed in other solvents, each solution (30 mL) was taken for antisolvent crystallization experiments as described in section 2.2. If gelation happened, the solvents would be classified as gelling solvents; otherwise, the solvents were classified as soluble solvents.
Table 1. Zeta Potential of the CTX Solution at Different Times volume of antisolvent (mL)
zeta potential (mV)
5 10 15 20
17.00 7.15 4.02 3.11
the antisolvent leads to lower zeta potentials. Generally speaking, a lower zeta potential means that the repulsive force between particles is weaker and the probability of aggregation is larger.28,29 The zeta potential is 3.11 mV after 20 mL of antisolvent is added, which suggests that the colloidal dispersion becomes unstable and gelation will happen soon.30 3.2. Characterization of Gel and Xerogel. The compositions of gel and nongelled solution are listed in Table 2. Each value is the average of three independent Table 2. Proportions of H2O, 2-Propanol, and CTX in the Gel and in the Nongelled Solution
3. RESULTS AND DISCUSSION 3.1. Gelation Process Tracking and Analysis. The solution formed through the reaction of cefotaxime acid with sodium acetate is homogeneous and clear. It exhibits an obvious Tyndall effect after adding 5 mL of 2-propanol as an antisolvent. As shown in Figure.2a, nanoparticles 50 nm in size appear, although they cannot be seen by the naked eye. The nanoparticle size exhibits a tendency to increase as more 2propanol is added, which can be seen in Figures 2b−d. The solution becomes cloudy when 20 mL of 2-propanol is added. After 25 mL of 2-propanol is fed into solution, many small spherical particles can be observed (Figure 3a) and then a
component
H2O (wt %)
2-propanol (wt %)
CTX (wt %)
gel nongelled solution total system
15.5 6.2 7.1
48.2 93.2 87.1
36.3 0.6 5.8
measurements. It can be found that the mass ratio of water to 2-propanol in the gel is much greater than that in the nongelled solution, which means that the crystals selectively gelate water molecules. Microscopic pictures of CTX gel on a hot plate are shown in Figure 4. At room temperature, birefringent domains can be seen in the polarized light view (Figure 4a), which shows that gelation is driven by the crystallization of nanometer- and micrometer-sized crystals. There is not a clear view of those particles, because of their small sizes (approximately a few hundred nanometers) and certain thickness of the gel. During 1288
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Figure 4. Microscopic pictures of CTX gel at different temperatures: (a) microscope image at 30 °C, viewed under polarized light; (b) optical microscope image at 70 °C; and (c) optical microscope image at 150 °C.
Figure 5. Powder X-ray diffraction (PXRD) patterns of (a) CTX gel, (b) CTX xerogel, and (c) CTX crystal.
the heating process, solvent evaporates gradually (Figure 4b) and solid is precipitated afterward. An obvious collapse of solid can be seen at 150 °C (Figure 4c) and no further changes occur in the following process. PXRD patterns of the gel, xerogel, and CTX crystal are shown in Figure 5. PXRD analysis of the gel (Figure 5a) exhibits one characteristic peak (at 2θ ≈ 9°), in addition to a halo shape pattern, meaning the presence of crystalline materials.31 The pattern of xerogel (Figure 5b) is same as that of CTX crystal (Figure 5c), which demonstrates that the microcrystals in the gel grow into highly orderly crystals after solvent removal. Note that, although the xerogel exhibits a crystal structure, its drug qualitiessuch as color, purity, and yieldsare reduced significantly. Micromorphological investigations of the xerogel are also carried out via SEM techniques. A highly entangled fibrillar-like 3-D network is observed in the xerogel (Figure 6), and the presence of cavities is caused by evaporation of solvent encapsulated in this network. It is indicated that the network is formed through the aggregation of nanometer- and micrometer-sized particles. The particles play a role of gelator, which is one of the two conditions responsible for gelation. 3.3. Solid-Solution Interfacial Tension. The solidsolution interfacial tension is often used to reflect the interaction between solid surface and liquid molecules. It can be estimated by the induction period values. According to classical nucleation theory, the nucleation rate can be expressed as32 ⎛ ΔG ⎞ ⎟ B = A p exp⎜ − ⎝ kT ⎠
Figure 6. Scanning electron microscopy (SEM) image of CTX xerogel.
where B is the primary nucleation rate, ΔG the critical nucleation free energy, T the absolute temperature, k the Boltzmann constant, and Ap the pre-exponential factor. ΔG is given by the expression32 ΔG =
16πVm 2γ 3 3υ2k 2T 2 ln 2 S
(2)
where Vm is the volume of molecule, γ the solid-solution interfacial tension, υ the number of moles of ions per mole of
(1) 1289
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solute, and S the supersaturation ratio. Substituting eq 2 into eq 1 gives ⎛ 16πγ 3V 2 ⎞ B = A p exp⎜ − 2 3 3 m 2 ⎟ ⎝ 3υ k T ln S ⎠
solubility parameters method is used to investigate the gelation phenomena of CTX in different solvents. The solvents tested are divided into three categories, according to the experiments described in section 2.5. Results are shown in Table 4. The Hansen solubility parameters of
(3)
Table 4. Results of the Solvent Classification Experimentsa
The induction period is inversely proportional to nucleation rate, so the induction period can be expressed as ln t ind = ln K +
No.
16πγ 3Vm 2 3υ2k3T 3 ln 2 S
(4)
The relationship between ln tind and 1/ln2 S can be obtained by a straight line, on the basis of the slope of line α; the solidsolution interfacial tension (γ) can be calculated by ⎛ 3αυ2k3T 3 ⎞1/3 ⎟ γ=⎜ 2 ⎝ 16πVm ⎠
No.
toluene methyl acetate dichloromethane methanol
I I I S
2 4 6 8
9
acetone + methanol (n:n = 9:1) 2-propanol + methanol (n:n = 8:2) dimethylsulfoxide 2-propanol + H2O (n:n = 2:8)
S
10
S
12
G G
14 16
11
The surface entropy factor (ζ), which is very important to explore the mechanism of crystal growth, can be determined by33
13 15
4γVm 2/3 kT
groupb
1 3 5 7
(5)
ζ=
solvent
solvent ethyl acetate diethyl ether 2-propanol ethanol + methanol (n:n = 9:1) 2-propanol + methanol (n:n = 9:1) H2O formamide ethanol + H2O (n:n = 2:8)
groupb I I I S S G G G
a
Note: n:n means molar ratio. bG = gelling solvents, I = insolube solvents, S = soluble solvents.
(6)
Briefly, if ζ < 3, it means the crystal surface is rough and allows continuous growth to proceed. When ζ is between 3 and 5, the most probable mode of growth is birth and spread growth. For ζ > 5, a smooth surface is indicated and spiral growth will occur.32,34 The induction periods of CTX over a range of supersaturation at 283.15 K under different mole fractions of the antisolvent xd are shown in Figure S2 in the Supporting Information. A good correlation is obtained between ln tind and 1/ln2 S, which indicates that homogeneous nucleation prefers to occur because of high supersaturation.34 According to eqs 5 and 6, the solid-solution interfacial tension (γ) and the surface entropy factor (ζ) are calculated and shown in Table 3. The
solvents found in the literature39 are plotted in a 3-D diagram shown in Figure 7. Each solvent point has three coordinates:
Table 3. Solid-Solution Interfacial Tension and Surface Entropy Factor of CTX Crystal xd
interfacial tension, γ (J/mol)
surface entropy factor, ζ
0.4 0.5 0.6
0.01087 0.009933 0.009595
7.952 7.267 7.020
Figure 7. Hansen space for solvents tested (axes: δh, hydrogen bonds; δp, polar interactions; and δd, dispersive interactions). Legend: red ball represents insoluble solvents (I); blue ball represents soluble solvents (S); green ball represents gelling solvents (G); red star represents the center of the I sphere; blue star represents the center of the S sphere; and green star represents the center of the G sphere.
high interfacial tension implies the interaction between crystal surface and solvent molecules is strong. The desolvation is difficult and thus the arrangement of CTX molecules on crystal surface is hindered. Surface entropy factor ζ is usually used to identify the growth mechanism of crystal. As shown in Table 3, for CTX, ζ > 5, which indicates that the growth mechanism of CTX is spiral dislocation growth and the growth of “primary nuclei” is very slow. That is the reason why a colloidal suspension is formed and then nanoparticles aggregate. 3.4. Classification of the Solvents. It is well-known that the gelation tendency of a gelator can be indicated by some solubility indicators, such as Kamlet−Taft parameters, the Hildebrandt solubility parameter, Hansen solubility parameters, etc.35−37 Among them, Hansen solubility parameters are one of the most accurate indicators to investigate the gelling power of gelators and select proper solvents.38 In this study, the Hansen
polar interactions (δp), hydrogen bonds (δh), and dispersive interactions (δd). For δp, the solvents clearly have the following ranking: gelling solvents (G) > soluble solvents (S) > insoluble solvents (I)
This indicates that the stronger polar interactions between solvent molecules and CTX crystal surface, which has strong polar carboxyl, amine, and acyl groups, are responsible for gelation. 1290
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For all the solvents tested, the points for I, S, and G solvents tend to cluster in their respective special regions in Hansen space. The center and radius of the I solvents sphere (RI) are determined first; then, it can be found that I solvents lie inside the sphere, most of the S and G solvents lie outside the sphere. The distances between all solvents and the center of the I solvents are calculated, and the results are plotted in Figure 8a.
Figure 9. PXRD pattern of CTX crystals using 2-methoxyethanol as solvent.
amounts of nanometer- and micrometer-sized crystals form a thermodynamically unstable colloidal dispersion. The crystals are easy to aggregate in solution and form a 3-D network. The strong polar groups exposed on the crystal face selectively adsorb the strong polar solvent molecules and finally gelation occurs. In a word, gelation is driven by the crystallization of nanometer- and micrometer-sized crystals, enhanced by the strong polar interaction between solvent molecules and CTX molecules.
4. CONCLUSIONS The gelation phenomenon of cefotaxime sodium (CTX) is systematically studied by monitoring gelation process and using different characterization tools. The mechanism of gelation during CTX crystallization is speculated in the present work. First, it is indicated from induction periods that high solidsolution interfacial tension causes the slow growth rate of the nanometer- and micrometer-sized crystals that form an unstable colloidal system. Then, the crystals aggregate and form a threedimensional (3-D) network. Since polar groups are distributed on the crystal surface, the crystals selectively adsorb polar solvent molecules and finally form a gel. Through solvent selection on the basis of Hansen space, crystallization process can be enhanced and drug crystals of CTX can be prepared successfully.
Figure 8. Distances in Hansen space between solvents (a) to the center of the I sphere (RI = 8.9) and (b) to the center of the S sphere (RS = 7.5). Legend: blue ball represents S solvents, and green ball represents G solvents.
The center and radius of the S solvents are determined in the same way (Figure 8b). The results are also satisfactory: S solvents lie inside the radius of the S solvents (RS), while most other solvents are excluded. Based on the results, gelation tendency can be predicted. If an untested solvent falls outside the radii RI and RS, then CTX in this solvent is likely to gelate. Here, two solvents are tested, and the predictions are consistent with the experimental results. One is 2-methoxyethanol, which is predicted to be a soluble solvent, and the other is N,Ndimethylformamide (DMF), which is predicted to be a gelling solvent. Experiments show that crystalline CTX powders are obtained in 2-methoxyethanol and gelation is avoided. The PXRD pattern is shown in Figure 9. For DMF, gelation occurs. This method can be used successfully to enhance the CTX crystallization process by choosing the proper solvents. 3.5. Mechanism of Gelation. Based on the above analysis, the gelation mechanism of CTX is speculated. With the addition of antisolvent, nanometer- and micrometer-sized crystals are precipitated gradually. Because of the slow growth rate caused by high solid-solution interfacial tension, large
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ASSOCIATED CONTENT
S Supporting Information *
Setup for the measurement of induction period and the induction period values are shown as Supporting Information. This information is available free of charge via the Internet at http://pubs.acs.org/.
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AUTHOR INFORMATION
Corresponding Author
*Tel.: +86-22-27405754. Fax: +86-22-27374971. E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors gratefully acknowledge financial support from the Tianjin Municipal Natural Science Foundation (No. 1291
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13JCZDJC28400) and Huabei Pharmaceutical Co., Ltd. of China for supplying cefotaxime acid.
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dx.doi.org/10.1021/ie403539d | Ind. Eng. Chem. Res. 2014, 53, 1286−1292
