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Effect of Shear Rate on the Aggregation Behavior of Self-Aggregated Glycyrrhizin Micelles by MesoDyn
WORLD SCIENCE AND TECHNOLOGY MODERNIZATION OF TRADITIONAL CHINESE MEDICINE AND MATERIA MEDICA
Volume 14, Issue 1, February 2012 Online English edition of the Chinese language journal Cite this article as: Mode Tradit Chin Med Mater Med, 2012, 14(1): 1201–1205
RESEARCH
Effect of Shear Rate on the Aggregation Behavior of Self-Aggregated Glycyrrhizin Micelles by MesoDyn Wang Yuguang1, Shi Xinyuan2*, Qiao Yanjiang2* 1 2
School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, China Research Center of TCM-Information Engineering, Beijing University of Chinese Medicine, Beijing 100102, China
Abstract: MesoDyn has been carried out to elaborate the micellar properties of natural surfactant glycyrrhizin which is frequently used in traditional Chinese medicine (TCM). The effect of shear rate on the aggregation behavior of glycyrrhizin has been investigated. The results showed that the critical micelle concentration (CMC) of glycyrrhizin increased with the addition of shear rate. And the glycyrrhizin aggregation transformed from spherical micelle to cylindrical micelle as the increase of shear rate. Furthermore, the aggregation behavior of the as-formed micelle was not stable to the change of shear rate. Removal of shear rate was unable to recover the micelle completely in the changing process of shear rate. The simulation results provide mesoscopic information for the solubilization of poorly water-soluble drug, and at the same time provide guidance for high efficient experiments. Key Words: Glycyrrhizin, mesoscopic simulation, solubilization, aggregation behavior, shear rate
1
Introduction
The solubilization of poorly water-soluble drugs is one of the difficult and hot spots of pharmacy [1]. Recent years, the emergence of various solubilization methods, such as micellar solubilization, solid dispersion, cyclodextrin inclusion and microemulsion technique, makes the problem of low aqueous solubility to be solved to some extent [2-5]. However, the addition of pharmaceutical excipients has been reported to be responsible for some adverse effects, which bring potential safety hazard to clinical treatment [6]. Prescriptions of traditional Chinese medicine (TCM) emphasize the unification of drugs and pharmaceutical excipients. It is reported that the solubility of some poorly watersoluble drugs can be increased through prescription compatibility [7]. The solubilization through prescription compatibility, which is in conformity with the characteristics of TCM, is expected to be a proper method to increase the solubility of poorly water-soluble drugs and eliminate the side effects caused by pharmaceutical excipients. Glycyrrhizin, the main active component of Glycyrrhiza uralensis which is frequently used in Chinese prescriptions, can be used as a kind of natural surfactant to increase the solubilization of poorly water-soluble drugs for the formation of micelles in aqueous solution [8]. The solubilizing properties of glycyrrhizin depend on the aggregation behavior and affected by concentration, temperature, shear rate, etc [9-12]. As the
formation of micelle completed within several milliseconds and the micelle size is in mesoscopic scale, although many characteristics can be investigated by experiments, the underlying solubilization mechanism and micellar properties still need to be further studied. Mesoscopic simulation makes it possible to study the process of micelle formation and provides a powerful tool for the investigation of aggregation behavior [13]. MesoDyn introduced by Fraaije [14-15] and Dissipative particle dynamics (DPD) by Groot and Warren [16-17] are the main methods in mesoscopic simulation. In our previous work, mesoscopic simulation was carried out to study the effect of concentration and temperature on the aggregation behaviors of P188 and glycyrrhizin [18-19]. In this work, MesoDyn were employed to the investigation of shear rate on the aggregation behavior of glycyrrhizin micelles, in order to provide scientific foundation for the solubilization of poorly water-soluble drugs in mesoscopic scale.
2 2.1
Experiment MesoDyn theory
The basic idea of MesoDyn is the mean-field density functional theory that the free energy F of an inhomogeneous liquid is a function of the local density function . All thermodynamic functions can be derived from the free energy to study the characteristics of the system. In MesoDyn, the
Received date: 14 February 2012 *Corresponding author. Tel.:+86-10-84738621; E-mail: [email protected], [email protected] Foundation item: Supported by the National Nature Science Foundation of China (No. 81073058/H2806), and the Subsidized Project on Young and Middle-aged Teachers in Beijing University of Chinese Medicine (2009JYB22-JS036). Copyright © 2012, World Science and Technology Press. Published by Elsevier BV. All rights reserved.
Wang Yuguang / Mode Tradit Chin Med Mater Med, 2012, 14(1): 1201–1205
molecules are defined on a course-grained level and represented by bead-spring model [20]. Bead is the minimum structural unit and represents one or some structural units of a polymer chain. The interactions for the intra molecular interactions are described by harmonic oscillator potentials and a mean field potential for the other interactions [21]. The coarse-grained process permits a larger time step and makes it possible to the simulation of most physical processes. 2.2
Coarse-grained models and interaction parameters
Coarse-grained models and interaction parameters are two of the important parameters in mesoscopic simulation. In the coarse-grained process, glycyrrhizin was represented by beads A and B. Water molecule was coarse grained by bead W. The topologies of glycyrrhizin and water were defined to be A 2 B 5 and W 1 (Fig.1). The interaction parameters among different beads can be obtained from atomistic simulation, empirical value, experimental data such as vapor pressure and light scattering [2223]. In this work, the interaction parameters were calculated via Blends module in Materials Studio 4.1 (Accelys Inc.) (Tab.1). 2.3
Simulation parameters
The mesoscopic simulation was calculated in a cubic box with periodic boundary condition and the dimensitions of the simulation lattice were 32 nm × 32 nm × 32 nm. The bond length was set to be 1.1543 nm and bead diffusion coefficient was 1.0×10-7 cm2/s. Noise parameter was taken to be 75.002. In order to ensure the completeness of the simulation process, time step was set
Fig.1 Coarse-grained models Tab. 1 Interaction parameters in MesoDyn (unit: KJ/mol)
A
B
W
A
0
23.8347
5.4081
B
23.8347
0
23.3561
W
5.4081
23.3561
0
to be 50.0 ns and the simulation time was 2.5 ms.
3
Results and discussion
3.1 Effect of shear rate on the micellar properties of glycyrrhizin The solubilization properties are depended on the aggregation behavior and affected by concentration, temperature, shear rate, etc. In mesoscopic simulation, the effect of external force to the aggregation behavior in the preparation course was simulated by the addition of shear rate. We discussed the effect of shear rate on the micellar properties in two aspects as follows. 3.1.1 Effect of shear rate on the critical micelle concentration (CMC) of glycyrrhizin Order parameter, defined by the mean-squared deviation from homogeneity in a system, shows the time evolution of phase separation of a system. The separation of order parameters indicates the occurrence of the phase separation. Large values of order parameter indicate strong phase separation, while very small values indicate a mixed system. Thus, order parameter provides a simple and intuitive way to reflect the effect of shear rate on the micellar properties [18-19, 24]. Glycyrrhizin can form spherical micelles in concentration of 0.9% without shear rate. In order to investigate the effect of shear rate on the aggregation behavior of glycyrrhizin, four kinds of shear rate, 0.0005 (1/ns), 0.001 (1/ns), 0.0015 (1/ns) and 0.002 (1/ns) were set to the system in the beginning of the simulation, respectively. With the addition of shear rate, the order parameters were nearly unchanged and no phase separation happened in the whole simulation process. The order parameters of the system with the shear rate of 0.0005 (1/ns) were shown (Fig.2). The order parameters with the addition of the other three kinds of shear rate were similar to figure 2. The order parameters indicated that the system was in a homogeneous state and no micelles formed. The addition of shear rate increased CMC of glycyrrhizin. Further investigation showed that the addition of the four kinds of shear rate above increased the CMC to 1.0%, and the time needed for system balance prolonged with the increase of shear rate, as shown in figure 3. The addition of shear rate in the beginning of the simulation made the phase separation more difficult. 3.1.2 Effect of shear rate to the aggregation behavior of glycyrrhizin micelle The addition of shear rate affected the aggregation behavior of glycyrrhizin micelle (Fig.4). To a system in concentration of 1.0%, spherical micelle formed without shear rate (Fig.4a). With the addition of shear rate, micelles extended in the direction of shear rate and the degree of extension became larger with the increase of shear rate (Fig.4b-e). Rod micelles formed in the system with the shear rate of 0.002 (1/ns) (Fig.4e).
Wang Yuguang / Mode Tradit Chin Med Mater Med, 2012, 14(1): 1201–1205
3.2 Stability of glycyrrhizin micelle to the change of shear rate In order to investigate the stability of glycyrrhizin micelle to the change of shear rate, a dynamic process of shear rate was set to the 0.9% glycyrrhizin/water system. To the spherical micelles formed in the system without shear rate (Fig.5a, Fig.5d), the addition of shear rate, 0.001(1/ns), extended the micelles in the direction of shear rate (Fig.5b, 5e). The removal of shear rate from the system of figure 5b could not recover the shape of the micelles completely. The micelles were extended in the direction of shear rate and the aggregation behavior did not change as the simulation time prolonged. On the other hand, the aggregation behavior of glycyrrhizin was affected by the addition time of shear rate. To the 0.9% glycyrrhizin/water system, no phase separation was observed during the whole simulation process with 0.001 (1/ns) shear rate added in the beginning of the mesoscopic simulation. While the spherical micelles formed in 0.9% glycyrrhizin/water system were not destroyed after the addition of 0.001(1/ns) shear rate during the simulation process.
Fig.4 Effect of shear rate on the aggregation behavior of 1.0% glycyrrhizin/water system Note: (a): Phase diagram of the system in concentration of 1.0% without shear rate; (b), (c), (d) and (e): Phase diagrams of the systems at the concentration of 1.0% with shear rate of 0.0005 (1/ns), 0.001 (1/ns), 0.0015 (1/ns) and 0.002 (1/ns), respectively.
Fig.5 Effect of shear rate on the stability of glycyrrhizin micelle Note: (a): Phase diagram of glycyrrhizin/water system in concentration of 0.9% without shear rate; (b): Phase diagram after a shear rate of 0.001(1/ns) added to (a) system; (c): Phase diagram after a removal of shear rate from (b) system; (d), (e) and (f): Slices of the micelles of (a), (b) and (c), respectively.
Fig.2 Order parameters of 0.9% glycyrrhizin/water system with the addition of shear rate of 0.0005 (1/ns)
Fig.3 Effect of shear rate to the time needed for system balance
4
Conclusions
Mesoscopic simulation provided a simple and intuitive way to investigate the aggregation behavior of glycyrrhizin and the effect of external conditions. Through mesoscopic simulation, the dynamic process of the micelle formation could be reflected and we could obtain more detailed information for the solubilization of poorly water-soluble drugs from mesoscopic scale. In our previous work, we investigated the effect of concentration, temperature to the aggregation behavior and validated by experiments [18-19, 25]. In this work, we further investigated the effect of shear rate to the aggregation behavior of glycyrrhizin. The addition of shear rate increased the CMC of glycyrrhizin and affected the aggregation behavior of glycyrrhizin micelle, which reflected that the external force in the preparation course affected the micellar properties of glycyrrhizin,
Wang Yuguang / Mode Tradit Chin Med Mater Med, 2012, 14(1): 1201–1205
and provided mesoscopic information to the solubilization mechanism of glycyrrhizin. With the guidance of mesoscopic simulation, further experiment is needed in order to provide scientific basis for the design of preparation technology and the improvement of TCM quality.
Phys 1997, 107(11): 4423-4435. [14] Lam YM, Goldbeck-Wood G. Mesoscale simulation of block copolymers in aqueous solution: parameterization, micelle growth kinetics and the effect of temperature and concentration morphology. Polymer 2003, 44(12): 3593-3605. [15] Chen HY, Wu JH, Luo SJ et al. MesoDyn and experimental
References
approach to the structural fabrication and pore-size adjust-
[1]
ment of SBA-15 molecular sieves. Adsorpt. Sci. Technol.
Alsenz J, Kansy M. High throughput solubility measurement in drug discovery and development. Adv Drug Deliv Rev 2007, 59(7): 546-567.
[2]
Borisov OV, Zhulina EB. Reentrant morphological transitions
self-assembled paclitaxel structures: templates for hierarchi-
in copolymer micelles with pH-sensitive corona. Langmuir
cal block copolymer assemblies and sustained drug release.
2005, 21(8): 3229-3231. [3]
[17] Yamamoto S, Maruyama Y, Hyodo SA. Dissipative particle
into a microemulsion. J. Phys. Chem. B 2010, 114(50):
dynamics study of spontaneous vesicle formation of amphi-
Nasongkla N, Wiedmann AF, Bruening A et al. Enhancement
[6]
[7]
[8]
cal micelle concentration of poloxamer 188. World Science
dextrin inclusion complexes. Pharm. Res. 2003, 20(10):
and Technology-Modernization of Traditional Chinese Medicine and Materia Medica 2008, 10(5): 126-129.
Betageri GV, Makarla KR. Enhancement of dissolution of
[19] Liu NC, Shi XY, Qiao YJ. Mesoscopic simulation study on
glyburide by solid dispersion and lyophilization techniques.
the aggregation behavior of poloxamer 188 and cholalic acid.
Int. J. Pharm 1995, 126(1-2): 155-160.
Scientia Sinica Chimica 2011, 41(3): 500-508.
Siderov J, Prasad P, De Boer R et al. Safe administration of
[20] Xu ZJ, Meakin P. A phase-field approach to no-slip boundary
etoposide phosphate after hypersensitivity reaction to intra-
conditions in dissipative particle dynamics and other particle
venous etoposide. Br. J. Cancer 2002, 86(1): 12-13.
models for fluid flow in geometrically complex confined
Güçlü-Üstünda Ö, Mazza G. Saponins: properties, applica-
systems. J. Chem. Phys. 2009, 130(23): 234103-234110.
tions and processing. Crit. Rev. Food Sci. Nutr. 2007, 47(3):
[21] Bai GY, Nichifor M, Lopes A et al. Thermodynamic charac-
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terization of the interaction behavior of a hydrophobically
Sasaki Y, Mizutani K, Kasai R et al. Solubilizing properties
modified polyelectrolyte and oppositely charged surfactants
of glycyrrhizin and its derivatives: solubilization of saiko-
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of solubility and bioavailability of -lapachone using cyclo1626-1633. [5]
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Nir I, Aserin A, Libster D et al. Solubilization of a dendrimer 16723-16730.
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Phys. Chem. B 2005, 109(1): 518-525. [22] Honeycutt JD. A general simulation method for computing
Mitra S, Dungan SR. Micellar properties of quillaja saponin.
conformational properties of single polymer chains. Comput.
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Theor. Polym. Sci. 1998, 8(1-2): 1-8.
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[23] Vlimmeren BAC, Martis NM, Zvelindovsky AV, et al. Si-
[10] Mitra S, Dungan SR. Micellar properties of quillaja sapo-
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[11] Li YM, Xu GY, Wu D et al. The aggregation behavior be-
and (Propylene Oxide)19 (Ethylene Oxide)33 (Propylene Ox-
tween anionic carboxymethylchitosan and cetyltrimethyl-
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[24] Zheng LS, Yang YQ, Guo XD et al. Mesoscopic simulations
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on the aggregation behavior of pH-responsive polymeric
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363(1): 114-121. [25] Maskarinec SA, Hannig J, Lee RC, et al. Direct observation of poloxamer 188 insertion into lipid monolayers. Biophys J. 2002, 82(3): 1453-1459.
Volume 14, Issue 1, February 2012 Online English edition of the Chinese language journal Cite this article as: Mode Tradit Chin Med Mater Med, 2012, 14(1): 1201–1205
RESEARCH
Effect of Shear Rate on the Aggregation Behavior of Self-Aggregated Glycyrrhizin Micelles by MesoDyn Wang Yuguang1, Shi Xinyuan2*, Qiao Yanjiang2* 1 2
School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, China Research Center of TCM-Information Engineering, Beijing University of Chinese Medicine, Beijing 100102, China
Abstract: MesoDyn has been carried out to elaborate the micellar properties of natural surfactant glycyrrhizin which is frequently used in traditional Chinese medicine (TCM). The effect of shear rate on the aggregation behavior of glycyrrhizin has been investigated. The results showed that the critical micelle concentration (CMC) of glycyrrhizin increased with the addition of shear rate. And the glycyrrhizin aggregation transformed from spherical micelle to cylindrical micelle as the increase of shear rate. Furthermore, the aggregation behavior of the as-formed micelle was not stable to the change of shear rate. Removal of shear rate was unable to recover the micelle completely in the changing process of shear rate. The simulation results provide mesoscopic information for the solubilization of poorly water-soluble drug, and at the same time provide guidance for high efficient experiments. Key Words: Glycyrrhizin, mesoscopic simulation, solubilization, aggregation behavior, shear rate
1
Introduction
The solubilization of poorly water-soluble drugs is one of the difficult and hot spots of pharmacy [1]. Recent years, the emergence of various solubilization methods, such as micellar solubilization, solid dispersion, cyclodextrin inclusion and microemulsion technique, makes the problem of low aqueous solubility to be solved to some extent [2-5]. However, the addition of pharmaceutical excipients has been reported to be responsible for some adverse effects, which bring potential safety hazard to clinical treatment [6]. Prescriptions of traditional Chinese medicine (TCM) emphasize the unification of drugs and pharmaceutical excipients. It is reported that the solubility of some poorly watersoluble drugs can be increased through prescription compatibility [7]. The solubilization through prescription compatibility, which is in conformity with the characteristics of TCM, is expected to be a proper method to increase the solubility of poorly water-soluble drugs and eliminate the side effects caused by pharmaceutical excipients. Glycyrrhizin, the main active component of Glycyrrhiza uralensis which is frequently used in Chinese prescriptions, can be used as a kind of natural surfactant to increase the solubilization of poorly water-soluble drugs for the formation of micelles in aqueous solution [8]. The solubilizing properties of glycyrrhizin depend on the aggregation behavior and affected by concentration, temperature, shear rate, etc [9-12]. As the
formation of micelle completed within several milliseconds and the micelle size is in mesoscopic scale, although many characteristics can be investigated by experiments, the underlying solubilization mechanism and micellar properties still need to be further studied. Mesoscopic simulation makes it possible to study the process of micelle formation and provides a powerful tool for the investigation of aggregation behavior [13]. MesoDyn introduced by Fraaije [14-15] and Dissipative particle dynamics (DPD) by Groot and Warren [16-17] are the main methods in mesoscopic simulation. In our previous work, mesoscopic simulation was carried out to study the effect of concentration and temperature on the aggregation behaviors of P188 and glycyrrhizin [18-19]. In this work, MesoDyn were employed to the investigation of shear rate on the aggregation behavior of glycyrrhizin micelles, in order to provide scientific foundation for the solubilization of poorly water-soluble drugs in mesoscopic scale.
2 2.1
Experiment MesoDyn theory
The basic idea of MesoDyn is the mean-field density functional theory that the free energy F of an inhomogeneous liquid is a function of the local density function . All thermodynamic functions can be derived from the free energy to study the characteristics of the system. In MesoDyn, the
Received date: 14 February 2012 *Corresponding author. Tel.:+86-10-84738621; E-mail: [email protected], [email protected] Foundation item: Supported by the National Nature Science Foundation of China (No. 81073058/H2806), and the Subsidized Project on Young and Middle-aged Teachers in Beijing University of Chinese Medicine (2009JYB22-JS036). Copyright © 2012, World Science and Technology Press. Published by Elsevier BV. All rights reserved.
Wang Yuguang / Mode Tradit Chin Med Mater Med, 2012, 14(1): 1201–1205
molecules are defined on a course-grained level and represented by bead-spring model [20]. Bead is the minimum structural unit and represents one or some structural units of a polymer chain. The interactions for the intra molecular interactions are described by harmonic oscillator potentials and a mean field potential for the other interactions [21]. The coarse-grained process permits a larger time step and makes it possible to the simulation of most physical processes. 2.2
Coarse-grained models and interaction parameters
Coarse-grained models and interaction parameters are two of the important parameters in mesoscopic simulation. In the coarse-grained process, glycyrrhizin was represented by beads A and B. Water molecule was coarse grained by bead W. The topologies of glycyrrhizin and water were defined to be A 2 B 5 and W 1 (Fig.1). The interaction parameters among different beads can be obtained from atomistic simulation, empirical value, experimental data such as vapor pressure and light scattering [2223]. In this work, the interaction parameters were calculated via Blends module in Materials Studio 4.1 (Accelys Inc.) (Tab.1). 2.3
Simulation parameters
The mesoscopic simulation was calculated in a cubic box with periodic boundary condition and the dimensitions of the simulation lattice were 32 nm × 32 nm × 32 nm. The bond length was set to be 1.1543 nm and bead diffusion coefficient was 1.0×10-7 cm2/s. Noise parameter was taken to be 75.002. In order to ensure the completeness of the simulation process, time step was set
Fig.1 Coarse-grained models Tab. 1 Interaction parameters in MesoDyn (unit: KJ/mol)
A
B
W
A
0
23.8347
5.4081
B
23.8347
0
23.3561
W
5.4081
23.3561
0
to be 50.0 ns and the simulation time was 2.5 ms.
3
Results and discussion
3.1 Effect of shear rate on the micellar properties of glycyrrhizin The solubilization properties are depended on the aggregation behavior and affected by concentration, temperature, shear rate, etc. In mesoscopic simulation, the effect of external force to the aggregation behavior in the preparation course was simulated by the addition of shear rate. We discussed the effect of shear rate on the micellar properties in two aspects as follows. 3.1.1 Effect of shear rate on the critical micelle concentration (CMC) of glycyrrhizin Order parameter, defined by the mean-squared deviation from homogeneity in a system, shows the time evolution of phase separation of a system. The separation of order parameters indicates the occurrence of the phase separation. Large values of order parameter indicate strong phase separation, while very small values indicate a mixed system. Thus, order parameter provides a simple and intuitive way to reflect the effect of shear rate on the micellar properties [18-19, 24]. Glycyrrhizin can form spherical micelles in concentration of 0.9% without shear rate. In order to investigate the effect of shear rate on the aggregation behavior of glycyrrhizin, four kinds of shear rate, 0.0005 (1/ns), 0.001 (1/ns), 0.0015 (1/ns) and 0.002 (1/ns) were set to the system in the beginning of the simulation, respectively. With the addition of shear rate, the order parameters were nearly unchanged and no phase separation happened in the whole simulation process. The order parameters of the system with the shear rate of 0.0005 (1/ns) were shown (Fig.2). The order parameters with the addition of the other three kinds of shear rate were similar to figure 2. The order parameters indicated that the system was in a homogeneous state and no micelles formed. The addition of shear rate increased CMC of glycyrrhizin. Further investigation showed that the addition of the four kinds of shear rate above increased the CMC to 1.0%, and the time needed for system balance prolonged with the increase of shear rate, as shown in figure 3. The addition of shear rate in the beginning of the simulation made the phase separation more difficult. 3.1.2 Effect of shear rate to the aggregation behavior of glycyrrhizin micelle The addition of shear rate affected the aggregation behavior of glycyrrhizin micelle (Fig.4). To a system in concentration of 1.0%, spherical micelle formed without shear rate (Fig.4a). With the addition of shear rate, micelles extended in the direction of shear rate and the degree of extension became larger with the increase of shear rate (Fig.4b-e). Rod micelles formed in the system with the shear rate of 0.002 (1/ns) (Fig.4e).
Wang Yuguang / Mode Tradit Chin Med Mater Med, 2012, 14(1): 1201–1205
3.2 Stability of glycyrrhizin micelle to the change of shear rate In order to investigate the stability of glycyrrhizin micelle to the change of shear rate, a dynamic process of shear rate was set to the 0.9% glycyrrhizin/water system. To the spherical micelles formed in the system without shear rate (Fig.5a, Fig.5d), the addition of shear rate, 0.001(1/ns), extended the micelles in the direction of shear rate (Fig.5b, 5e). The removal of shear rate from the system of figure 5b could not recover the shape of the micelles completely. The micelles were extended in the direction of shear rate and the aggregation behavior did not change as the simulation time prolonged. On the other hand, the aggregation behavior of glycyrrhizin was affected by the addition time of shear rate. To the 0.9% glycyrrhizin/water system, no phase separation was observed during the whole simulation process with 0.001 (1/ns) shear rate added in the beginning of the mesoscopic simulation. While the spherical micelles formed in 0.9% glycyrrhizin/water system were not destroyed after the addition of 0.001(1/ns) shear rate during the simulation process.
Fig.4 Effect of shear rate on the aggregation behavior of 1.0% glycyrrhizin/water system Note: (a): Phase diagram of the system in concentration of 1.0% without shear rate; (b), (c), (d) and (e): Phase diagrams of the systems at the concentration of 1.0% with shear rate of 0.0005 (1/ns), 0.001 (1/ns), 0.0015 (1/ns) and 0.002 (1/ns), respectively.
Fig.5 Effect of shear rate on the stability of glycyrrhizin micelle Note: (a): Phase diagram of glycyrrhizin/water system in concentration of 0.9% without shear rate; (b): Phase diagram after a shear rate of 0.001(1/ns) added to (a) system; (c): Phase diagram after a removal of shear rate from (b) system; (d), (e) and (f): Slices of the micelles of (a), (b) and (c), respectively.
Fig.2 Order parameters of 0.9% glycyrrhizin/water system with the addition of shear rate of 0.0005 (1/ns)
Fig.3 Effect of shear rate to the time needed for system balance
4
Conclusions
Mesoscopic simulation provided a simple and intuitive way to investigate the aggregation behavior of glycyrrhizin and the effect of external conditions. Through mesoscopic simulation, the dynamic process of the micelle formation could be reflected and we could obtain more detailed information for the solubilization of poorly water-soluble drugs from mesoscopic scale. In our previous work, we investigated the effect of concentration, temperature to the aggregation behavior and validated by experiments [18-19, 25]. In this work, we further investigated the effect of shear rate to the aggregation behavior of glycyrrhizin. The addition of shear rate increased the CMC of glycyrrhizin and affected the aggregation behavior of glycyrrhizin micelle, which reflected that the external force in the preparation course affected the micellar properties of glycyrrhizin,
Wang Yuguang / Mode Tradit Chin Med Mater Med, 2012, 14(1): 1201–1205
and provided mesoscopic information to the solubilization mechanism of glycyrrhizin. With the guidance of mesoscopic simulation, further experiment is needed in order to provide scientific basis for the design of preparation technology and the improvement of TCM quality.
Phys 1997, 107(11): 4423-4435. [14] Lam YM, Goldbeck-Wood G. Mesoscale simulation of block copolymers in aqueous solution: parameterization, micelle growth kinetics and the effect of temperature and concentration morphology. Polymer 2003, 44(12): 3593-3605. [15] Chen HY, Wu JH, Luo SJ et al. MesoDyn and experimental
References
approach to the structural fabrication and pore-size adjust-
[1]
ment of SBA-15 molecular sieves. Adsorpt. Sci. Technol.
Alsenz J, Kansy M. High throughput solubility measurement in drug discovery and development. Adv Drug Deliv Rev 2007, 59(7): 546-567.
[2]
Borisov OV, Zhulina EB. Reentrant morphological transitions
self-assembled paclitaxel structures: templates for hierarchi-
in copolymer micelles with pH-sensitive corona. Langmuir
cal block copolymer assemblies and sustained drug release.
2005, 21(8): 3229-3231. [3]
[17] Yamamoto S, Maruyama Y, Hyodo SA. Dissipative particle
into a microemulsion. J. Phys. Chem. B 2010, 114(50):
dynamics study of spontaneous vesicle formation of amphi-
Nasongkla N, Wiedmann AF, Bruening A et al. Enhancement
[6]
[7]
[8]
cal micelle concentration of poloxamer 188. World Science
dextrin inclusion complexes. Pharm. Res. 2003, 20(10):
and Technology-Modernization of Traditional Chinese Medicine and Materia Medica 2008, 10(5): 126-129.
Betageri GV, Makarla KR. Enhancement of dissolution of
[19] Liu NC, Shi XY, Qiao YJ. Mesoscopic simulation study on
glyburide by solid dispersion and lyophilization techniques.
the aggregation behavior of poloxamer 188 and cholalic acid.
Int. J. Pharm 1995, 126(1-2): 155-160.
Scientia Sinica Chimica 2011, 41(3): 500-508.
Siderov J, Prasad P, De Boer R et al. Safe administration of
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