- Email: [email protected]
Preparation and characterization of uniform drug particles: Dehydrocholic acid
Journal of Colloid and Interface Science 368 (2012) 625–628
Contents lists available at SciVerse ScienceDirect
Journal of Colloid and Interface Science www.elsevier.com/locate/jcis
Preparation and characterization of uniform drug particles: Dehydrocholic acid Amr Ali Mohamed a,b, Egon Matijevic´ a,⇑ a b
Center for Advanced Materials Processing, Clarkson University, Potsdam, NY 13699-5814, USA Ain Shams University, Faculty of Science, Cairo, Egypt
a r t i c l e
i n f o
Article history: Received 8 September 2011 Accepted 2 November 2011 Available online 11 November 2011 Keywords: Colloidal drugs Dehydrocholic acid Drug particles
a b s t r a c t Two methods for the preparation of uniform dispersions of dehydrocholic acid of different morphologies are described. In the first case, the drug was dissolved in acetone and then re-precipitated by adding a non-solvent (either water or an aqueous stabilizer solution), which yielded rod-like particles. In the second procedure, spheres, consisting of small elongated subunits, were obtained by acidification of basic aqueous solutions of the drug. The resulting particles were characterized in terms of their structure and surface charge characteristics. Ó 2011 Elsevier Inc. All rights reserved.
1. Introduction Any approved drug must be of exact chemical composition. However, the functionality of the same medication also depends in a significant way on its physical state. In an extensive review article, Rouhi [1] describes in much detail the effects of the morphology of drug particles on their efficiency. For this reason, it is essential for the performance of a medication to be in the most effective and stable form. Several approaches are available to obtain finely dispersed drugs. Obviously, the most common process is grinding. However, even special mills would not yield truly uniform particles, and their shape cannot be controlled. A number of drug dispersions were prepared by supercritical fluid technique, as reviewed by Yasuji et al. [2]. In most cases, the particles so obtained were of irregular shape [3–6], although some appeared as rods [5,6]. In the emulsion process, either water in oil or oil in water systems yielded polydispersed rod-like [7], irregular spherical [8] or aggregated particles [9]. Drugs were also micronized by the spray-dry (aerosol) technique [10], which produced either rods or irregular particles of broad size dispersions.
⇑ Corresponding author. E-mail address: [email protected] (E. Matijevic´). 0021-9797/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.jcis.2011.11.005
The most versatile process to generate finely dispersed material is by precipitation in solutions. There are several avenues of approach in this method, which may be summarized as: 1. Forming a sparingly soluble salt of an ionizable drug in an aqueous solution. 2. Precipitating the drug in a solution by changing the pH. 3. Adding a miscible non-solvent to the drug in a solvent (solvent shifting). 4. Vaporizing the more volatile solvent of the drug in a solution of two miscible liquids, one being a non-solvent. While precipitation has been generally employed in the preparation of drugs, unless controlled procedures were taken, the resulting particles were of irregular size and shape [11,12]. Recently, well-defined dispersions of a number of drugs were obtained by various modifications of the precipitation procedures listed above [13–19]. Indeed, in many cases, the same medication was produced as uniform particles in different shapes by adjusting the experimental conditions. Furthermore, most of the resulting particles consisted as aggregates of smaller subunits. This study describes the precipitation of dehydrocholic acid (C24H34O5), which is the only artificial bile acid [20]. This compound is the main component in many drugs, especially those used for cholestatic liver disease and for dissolving cholesterol gallstones [21,22]. It is also employed to protect hepatocytes and other cell types from apoptosis [23,24], and as antimicrobial [25,26]. This study describes the preparation of this drug in two forms of uniform particles, one consisting of needles and the other of spheres. The latter is composed of tiny rods.
A.A. Mohamed, E. Matijevic´ / Journal of Colloid and Interface Science 368 (2012) 625–628
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2. Experimental 2.1. Materials and methods Dehydrocholic acid (Alfa Aesar) of the composition
2.2.2. The precipitation method In this process, 8.0 mg of dehydrocholic acid was dissolved in 2 cm3 of a 0.015 mol dm 3 NaOH solution of pH 8. The latter was then combined with 5 cm3 or water or a 0.1 wt.% surfactant solution. Finally, 0.1 mol dm 3 HCl solution was slowly added under magnetic stirring to the drug solution until pH 5. The precipitated drug particles were then washed with water and dried. 3. Results
was used without further purification. Two surfactants, i.e., Igepal CO 630 95% pure (Rhodia Novecare) and hydroxypropyl cellulose (HPC-SL, Nisso Chemical, lot DL-0881), were employed in the preparation of uniform particles of this drug. These surfactants are already found in pharmaceutical applications. The samples were examined with either JEOL JSM-6300 scanning or JEOL JSM-7400F field emission scanning electron microscopes, and their crystallinity was evaluated with a Bruker D8 Axis X-ray diffractometer. Electrophoretic measurements of dehydrocholic acid dispersions were studied with the BIC ZetaPlus analyzer over the pH range 2–6. The pH was adjusted with HCl or NaOH solutions.
2.2. Preparation and characterization of drug particles The dehydrocholic acid particles were prepared by two different methods. The first was based on the difference of the drug solubility in organic solvents and miscible non-solvents (i.e. either water or aqueous solutions of stabilizers). The second method takes advantage of the carboxylic group in the molecule. Thus, the drug was dissolved in sodium hydroxide solutions and then acidified to form a precipitate.
Electron micrographs in Fig. 1 illustrate drug particles as received (Fig. 1a) and re-precipitated as described in Section 2.2.1 (Fig. 1b). In both cases, dispersions consist of partially aggregated rods and irregular in size and surfaces, although less so in the treated sample. Using the same method, but in the presence of surfactants, resulted in considerably thinner, less irregular, but somewhat aggregated needles (Fig. 2). The second method, described in Section 2.2.2, yielded drug particles consisting of smaller needle-type subunits (Fig. 3). In the absence of a stabilizer, a rather large cluster is produced (Fig. 3a), while the addition of Igepal resulted in reasonably uniform spheres of aggregated thin rods (Fig. 3b). The same kind of dispersions was obtained when other stabilizers, such as hydroxypropyl cellulose, were added instead of Igepal. Fig. 4 displays the X-ray diffractograms of the commercial drug, of the aggregated needle-shaped particles in Fig. 2a and b, as well as the spheres in Fig. 3b. It is clear that the XRD patterns for these samples are nearly the same, which indicates that all particles have the same crystal structure. The amorphous background shown in the XRD patterns of the prepared particles is due to the presence of the amorphous polymeric stabilizers (Igepal or hydroxypropyl cellulose). It is hard to remove these additives from the precipitated particles. Fig. 5 shows the XRD patterns after the background is removed. The electrophoretic measurements were carried out on two different dispersions, i.e., needles shown in Fig. 2a and of spheres in Fig. 3b. The change in the f-potential as a function of the pH is shown in Fig. 6. 4. Discussion
2.2.1. The solvent–non-solvent method In this procedure, 20 cm3 either of water or of a 0.1 wt.% surfactant solution was added to 5 cm3 of a 0.02 mol dm 3 solution of dehydrocholic acid in acetone under magnetic stirring, until turbidity appeared. After 10 min, the drug precipitate was filtered through 1-lm pore-size polycarbonate membranes and dried in vacuum.
This paper shows that the same drug can be obtained as uniform particles of two different morphologies by modifications of the precipitation process in homogenous solutions. In both cases, primary particles were of rod-like shape, the larger ones being fully dispersed, while the small ones aggregated into monodispersed spheres. Thus, it is of interest to assess parameters affecting the
Fig. 1. Scanning electron micrographs (SEMs) of dehydrocholic acid particles as (a) received and (b) precipitated by adding 20 cm3 of a 0.02 mol dm acetone, as described in Section 2.2.1.
3
solution of the drug in
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627
Fig. 2. Scanning electron micrographs (SEMs) of dehydrocholic acid particles precipitated by adding 20 cm3 of 0.1 wt.% either of Igepal CO 630 (a) or of hydroxypropyl cellulose (b) to 5 cm3 of a 0.02 mol dm 3 solution of the drug in acetone as described in Section 2.2.1.
Fig. 3. Scanning electron micrographs (SEMs) of dehydrocholic acid particles precipitated by the acidification of a drug solution in NaOH as described in the method in Section 2.2.2 in the absence of a surfactant (a) and in the presence of Igepal CO 630 as a stabilizer (b).
Fig. 4. XRD spectra of the drug particles shown in Fig. 2a (a), in Fig. 2b (b), in Fig. 3b (c), and as received (d).
Fig. 5. XRD spectra of the drug particles shown in Fig. 2a (a), in Fig. 2b (b), in Fig. 3b (c), after removing the amorphous background from the spectra and as received (d).
precipitation processes to yield such morphologically diverse dispersions. The single rod-like particles were formed in an acetone–water mixture in the presence of a stabilizer, while the composite spheres were obtained by acidification of the basic aqueous solutions of the drug without any additives. In order to account for these differences, one needs to consider the effects of the solvent properties in terms of the dielectric constant, pH, ionic strength, and of the surface charge on the resulting drug particles. The electrokinetic data showed that the f-potential of both solids as a function of the pH was essentially the same. With regard
to the dielectric constant, one would expect the system in the mixed solvent to be less stable [27]. However, in the studied samples, this is not the case, because the particles in the acetone/water solution were well dispersed, while in the aqueous solution they were aggregated. The last effect is due to the high electrolyte concentration of the dispersion, resulting in ionic strength l = 10 2 mol dm 3. This concentration of singly charged counterions normally causes the onset of rapid coagulation of lyophobic colloids. Due to the small size of subunits, the aggregation resulted in the formation of composite spheres.
628
A.A. Mohamed, E. Matijevic´ / Journal of Colloid and Interface Science 368 (2012) 625–628
is dependent on the solvents. The molecules in the first case should yield longer chains, resulting in hydrated straight rod-like particles. In contrast, the solutes in the b-form would produce small rods, which at the high ionic strength aggregate to spheres. Acknowledgments The financial support for this project and the fellowship for Amr Ali Mohamed from the Ministry of Higher Education, Egypt, are gratefully acknowledged. The authors appreciate the useful interactions with Dr. Bill Bosch and Prof. Don Rasmussen on this project. References Fig. 6. Zeta potential as a function of the pH of aqueous dispersions of the drug particles shown in Fig. 2a (a), and in Fig. 3b (b).
Dehydrocholic acid can appear in two morphologies.
[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22]
The a-form (needle shaped as particles prepared using the first method) is usually obtained when this drug is precipitated in a water–acetone system, while the b-form of the spherical shape may be obtained through a solvent-mediated transformation by a prolonged contact of the solid a-form in a water–HCl solution (which is similar to the particles prepared using the second method in this study) [28]. The different size of the primary particles may be affected by the conformation of the drug particles in solution, which
[23] [24]
[25] [26] [27] [28]
A.M. Rouhi, Chem. Eng. News 81 (2003) 32. T. Yasuji, H. Takeuchi, Y. Kawashima, Adv. Drug Delivery Rev. 60 (2008) 388. A.Z. Hezave, F. Esmaeilzadeh, J. Cryst. Growth 312 (2010) 3373. Z. Huang, G.B. Sun, Y.C. Chiew, S. Kawi, Powder Technol. 160 (2005) 127. Y. Hakuta, H. Hayashi, K. Arai, Curr. Opin. Solid State Mater. 7 (2003) 341. P. Chattopadhyay, R.B. Gupta, Int. J. Pharm. 228 (2001) 19. X. Xu, L. Yang, X. Xu, X. Wang, X. Chen, Q. Liang, J. Zeng, X. Jing, J. Controlled Release 108 (2005) 33. Z.B. Zhang, Z.G. Shen, J.X. Wang, H.X. Zhang, H. Zhao, J.F. Chen, J. Yun, Int. J. Pharm. 376 (2009) 116. Q.P. Huang, J.X. Wang, Z.B. Zhang, Z.G. Shen, J.F. Chen, J. Yun, Int. J. Pharm. 368 (2009) 160. H. Zhao, Y. Le, H. Liu, T. Hu, Z. Shen, J. Yun, J.F. Chen, Powder Technol. 194 (2009) 81. Z. Wang, J.F. Chen, Y. Le, Z.G. Shen, Ind. Eng. Chem. Res. 46 (2007) 4839. Q.P. Huang, J.X. Wang, G.Z. Chen, Z.G. Shen, J.F. Chen, J. Yun, Int. J. Pharm. 360 (2008) 58. G.A. Pozarnsky, E. Matijevic´, Colloid Surf. A 125 (1997) 47. C. Goia, E. Matijevic´, J. Colloid Interface Sci. 206 (1998) 583. F. Ruch, E. Matijevic´, J. Colloid Interface Sci. 229 (2000) 207. L. Joguet, I. Sondi, E. Matijevic´, J. Colloid Interface Sci. 251 (2002) 284. L. Joguet, E. Matijevic´, J. Colloid Interface Sci. 250 (2002) 503. S.D. Škapin, E. Matijevic´, J. Colloid Interface Sci. 272 (2004) 90. H.W. Bosch, S.D. Škapin, E. Matijevic´, Colloid Surf. A 250 (2004) 43. G. Cravotto, A. Binello, L. Boffa, O. Rosati, M. Boccalini, S. Chimichi, Steroids 71 (2006) 469. G. Tomer, B. Shneider, Gastroenterol. Clin. North America 32 (2003) 839. W.M. Duan, C.M.P. Rodrigures, L.R. Zhao, C.J. Steer, W.C. Low, Cell Transplant. 11 (2002) 195. A.P. Rolo, C.M. Palmeira, G.M. Holy, K.B. Wallace, Toxicol. Sci. 79 (2004) 196. M.H. Schoemaker, L. Conde de la Rosa, M. Buist-Homan, T.E. Vreken, R. Havinga, K. Poelstra, H.J. Haisma, P.L.M. Jansen, H. Moshage, Hepatology 39 (2004) 1563. P.B. Savage, C. Li, Expert Opin. Invest. Drugs 9 (2000) 263. H.M. Willemen, L.C. de Smet, A. Koudijs, M.C. Stuart, I.G. Heikamp-de Jong, A.T. Marcelis, E.J.R. Sudhölter, Angew. Chem. 41 (2002) 4275. J.P. Kratohvil, M. Orhanovic´, E. Matijevic´, J. Phys. Chem. 64 (1960) 1216. G. Fantin, M. Fogagnolo, O. Bortolini, N. Masciocchi, S. Galli, A. Sironi, New J. Chem. 27 (2003) 1794.
Contents lists available at SciVerse ScienceDirect
Journal of Colloid and Interface Science www.elsevier.com/locate/jcis
Preparation and characterization of uniform drug particles: Dehydrocholic acid Amr Ali Mohamed a,b, Egon Matijevic´ a,⇑ a b
Center for Advanced Materials Processing, Clarkson University, Potsdam, NY 13699-5814, USA Ain Shams University, Faculty of Science, Cairo, Egypt
a r t i c l e
i n f o
Article history: Received 8 September 2011 Accepted 2 November 2011 Available online 11 November 2011 Keywords: Colloidal drugs Dehydrocholic acid Drug particles
a b s t r a c t Two methods for the preparation of uniform dispersions of dehydrocholic acid of different morphologies are described. In the first case, the drug was dissolved in acetone and then re-precipitated by adding a non-solvent (either water or an aqueous stabilizer solution), which yielded rod-like particles. In the second procedure, spheres, consisting of small elongated subunits, were obtained by acidification of basic aqueous solutions of the drug. The resulting particles were characterized in terms of their structure and surface charge characteristics. Ó 2011 Elsevier Inc. All rights reserved.
1. Introduction Any approved drug must be of exact chemical composition. However, the functionality of the same medication also depends in a significant way on its physical state. In an extensive review article, Rouhi [1] describes in much detail the effects of the morphology of drug particles on their efficiency. For this reason, it is essential for the performance of a medication to be in the most effective and stable form. Several approaches are available to obtain finely dispersed drugs. Obviously, the most common process is grinding. However, even special mills would not yield truly uniform particles, and their shape cannot be controlled. A number of drug dispersions were prepared by supercritical fluid technique, as reviewed by Yasuji et al. [2]. In most cases, the particles so obtained were of irregular shape [3–6], although some appeared as rods [5,6]. In the emulsion process, either water in oil or oil in water systems yielded polydispersed rod-like [7], irregular spherical [8] or aggregated particles [9]. Drugs were also micronized by the spray-dry (aerosol) technique [10], which produced either rods or irregular particles of broad size dispersions.
⇑ Corresponding author. E-mail address: [email protected] (E. Matijevic´). 0021-9797/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.jcis.2011.11.005
The most versatile process to generate finely dispersed material is by precipitation in solutions. There are several avenues of approach in this method, which may be summarized as: 1. Forming a sparingly soluble salt of an ionizable drug in an aqueous solution. 2. Precipitating the drug in a solution by changing the pH. 3. Adding a miscible non-solvent to the drug in a solvent (solvent shifting). 4. Vaporizing the more volatile solvent of the drug in a solution of two miscible liquids, one being a non-solvent. While precipitation has been generally employed in the preparation of drugs, unless controlled procedures were taken, the resulting particles were of irregular size and shape [11,12]. Recently, well-defined dispersions of a number of drugs were obtained by various modifications of the precipitation procedures listed above [13–19]. Indeed, in many cases, the same medication was produced as uniform particles in different shapes by adjusting the experimental conditions. Furthermore, most of the resulting particles consisted as aggregates of smaller subunits. This study describes the precipitation of dehydrocholic acid (C24H34O5), which is the only artificial bile acid [20]. This compound is the main component in many drugs, especially those used for cholestatic liver disease and for dissolving cholesterol gallstones [21,22]. It is also employed to protect hepatocytes and other cell types from apoptosis [23,24], and as antimicrobial [25,26]. This study describes the preparation of this drug in two forms of uniform particles, one consisting of needles and the other of spheres. The latter is composed of tiny rods.
A.A. Mohamed, E. Matijevic´ / Journal of Colloid and Interface Science 368 (2012) 625–628
626
2. Experimental 2.1. Materials and methods Dehydrocholic acid (Alfa Aesar) of the composition
2.2.2. The precipitation method In this process, 8.0 mg of dehydrocholic acid was dissolved in 2 cm3 of a 0.015 mol dm 3 NaOH solution of pH 8. The latter was then combined with 5 cm3 or water or a 0.1 wt.% surfactant solution. Finally, 0.1 mol dm 3 HCl solution was slowly added under magnetic stirring to the drug solution until pH 5. The precipitated drug particles were then washed with water and dried. 3. Results
was used without further purification. Two surfactants, i.e., Igepal CO 630 95% pure (Rhodia Novecare) and hydroxypropyl cellulose (HPC-SL, Nisso Chemical, lot DL-0881), were employed in the preparation of uniform particles of this drug. These surfactants are already found in pharmaceutical applications. The samples were examined with either JEOL JSM-6300 scanning or JEOL JSM-7400F field emission scanning electron microscopes, and their crystallinity was evaluated with a Bruker D8 Axis X-ray diffractometer. Electrophoretic measurements of dehydrocholic acid dispersions were studied with the BIC ZetaPlus analyzer over the pH range 2–6. The pH was adjusted with HCl or NaOH solutions.
2.2. Preparation and characterization of drug particles The dehydrocholic acid particles were prepared by two different methods. The first was based on the difference of the drug solubility in organic solvents and miscible non-solvents (i.e. either water or aqueous solutions of stabilizers). The second method takes advantage of the carboxylic group in the molecule. Thus, the drug was dissolved in sodium hydroxide solutions and then acidified to form a precipitate.
Electron micrographs in Fig. 1 illustrate drug particles as received (Fig. 1a) and re-precipitated as described in Section 2.2.1 (Fig. 1b). In both cases, dispersions consist of partially aggregated rods and irregular in size and surfaces, although less so in the treated sample. Using the same method, but in the presence of surfactants, resulted in considerably thinner, less irregular, but somewhat aggregated needles (Fig. 2). The second method, described in Section 2.2.2, yielded drug particles consisting of smaller needle-type subunits (Fig. 3). In the absence of a stabilizer, a rather large cluster is produced (Fig. 3a), while the addition of Igepal resulted in reasonably uniform spheres of aggregated thin rods (Fig. 3b). The same kind of dispersions was obtained when other stabilizers, such as hydroxypropyl cellulose, were added instead of Igepal. Fig. 4 displays the X-ray diffractograms of the commercial drug, of the aggregated needle-shaped particles in Fig. 2a and b, as well as the spheres in Fig. 3b. It is clear that the XRD patterns for these samples are nearly the same, which indicates that all particles have the same crystal structure. The amorphous background shown in the XRD patterns of the prepared particles is due to the presence of the amorphous polymeric stabilizers (Igepal or hydroxypropyl cellulose). It is hard to remove these additives from the precipitated particles. Fig. 5 shows the XRD patterns after the background is removed. The electrophoretic measurements were carried out on two different dispersions, i.e., needles shown in Fig. 2a and of spheres in Fig. 3b. The change in the f-potential as a function of the pH is shown in Fig. 6. 4. Discussion
2.2.1. The solvent–non-solvent method In this procedure, 20 cm3 either of water or of a 0.1 wt.% surfactant solution was added to 5 cm3 of a 0.02 mol dm 3 solution of dehydrocholic acid in acetone under magnetic stirring, until turbidity appeared. After 10 min, the drug precipitate was filtered through 1-lm pore-size polycarbonate membranes and dried in vacuum.
This paper shows that the same drug can be obtained as uniform particles of two different morphologies by modifications of the precipitation process in homogenous solutions. In both cases, primary particles were of rod-like shape, the larger ones being fully dispersed, while the small ones aggregated into monodispersed spheres. Thus, it is of interest to assess parameters affecting the
Fig. 1. Scanning electron micrographs (SEMs) of dehydrocholic acid particles as (a) received and (b) precipitated by adding 20 cm3 of a 0.02 mol dm acetone, as described in Section 2.2.1.
3
solution of the drug in
A.A. Mohamed, E. Matijevic´ / Journal of Colloid and Interface Science 368 (2012) 625–628
627
Fig. 2. Scanning electron micrographs (SEMs) of dehydrocholic acid particles precipitated by adding 20 cm3 of 0.1 wt.% either of Igepal CO 630 (a) or of hydroxypropyl cellulose (b) to 5 cm3 of a 0.02 mol dm 3 solution of the drug in acetone as described in Section 2.2.1.
Fig. 3. Scanning electron micrographs (SEMs) of dehydrocholic acid particles precipitated by the acidification of a drug solution in NaOH as described in the method in Section 2.2.2 in the absence of a surfactant (a) and in the presence of Igepal CO 630 as a stabilizer (b).
Fig. 4. XRD spectra of the drug particles shown in Fig. 2a (a), in Fig. 2b (b), in Fig. 3b (c), and as received (d).
Fig. 5. XRD spectra of the drug particles shown in Fig. 2a (a), in Fig. 2b (b), in Fig. 3b (c), after removing the amorphous background from the spectra and as received (d).
precipitation processes to yield such morphologically diverse dispersions. The single rod-like particles were formed in an acetone–water mixture in the presence of a stabilizer, while the composite spheres were obtained by acidification of the basic aqueous solutions of the drug without any additives. In order to account for these differences, one needs to consider the effects of the solvent properties in terms of the dielectric constant, pH, ionic strength, and of the surface charge on the resulting drug particles. The electrokinetic data showed that the f-potential of both solids as a function of the pH was essentially the same. With regard
to the dielectric constant, one would expect the system in the mixed solvent to be less stable [27]. However, in the studied samples, this is not the case, because the particles in the acetone/water solution were well dispersed, while in the aqueous solution they were aggregated. The last effect is due to the high electrolyte concentration of the dispersion, resulting in ionic strength l = 10 2 mol dm 3. This concentration of singly charged counterions normally causes the onset of rapid coagulation of lyophobic colloids. Due to the small size of subunits, the aggregation resulted in the formation of composite spheres.
628
A.A. Mohamed, E. Matijevic´ / Journal of Colloid and Interface Science 368 (2012) 625–628
is dependent on the solvents. The molecules in the first case should yield longer chains, resulting in hydrated straight rod-like particles. In contrast, the solutes in the b-form would produce small rods, which at the high ionic strength aggregate to spheres. Acknowledgments The financial support for this project and the fellowship for Amr Ali Mohamed from the Ministry of Higher Education, Egypt, are gratefully acknowledged. The authors appreciate the useful interactions with Dr. Bill Bosch and Prof. Don Rasmussen on this project. References Fig. 6. Zeta potential as a function of the pH of aqueous dispersions of the drug particles shown in Fig. 2a (a), and in Fig. 3b (b).
Dehydrocholic acid can appear in two morphologies.
[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22]
The a-form (needle shaped as particles prepared using the first method) is usually obtained when this drug is precipitated in a water–acetone system, while the b-form of the spherical shape may be obtained through a solvent-mediated transformation by a prolonged contact of the solid a-form in a water–HCl solution (which is similar to the particles prepared using the second method in this study) [28]. The different size of the primary particles may be affected by the conformation of the drug particles in solution, which
[23] [24]
[25] [26] [27] [28]
A.M. Rouhi, Chem. Eng. News 81 (2003) 32. T. Yasuji, H. Takeuchi, Y. Kawashima, Adv. Drug Delivery Rev. 60 (2008) 388. A.Z. Hezave, F. Esmaeilzadeh, J. Cryst. Growth 312 (2010) 3373. Z. Huang, G.B. Sun, Y.C. Chiew, S. Kawi, Powder Technol. 160 (2005) 127. Y. Hakuta, H. Hayashi, K. Arai, Curr. Opin. Solid State Mater. 7 (2003) 341. P. Chattopadhyay, R.B. Gupta, Int. J. Pharm. 228 (2001) 19. X. Xu, L. Yang, X. Xu, X. Wang, X. Chen, Q. Liang, J. Zeng, X. Jing, J. Controlled Release 108 (2005) 33. Z.B. Zhang, Z.G. Shen, J.X. Wang, H.X. Zhang, H. Zhao, J.F. Chen, J. Yun, Int. J. Pharm. 376 (2009) 116. Q.P. Huang, J.X. Wang, Z.B. Zhang, Z.G. Shen, J.F. Chen, J. Yun, Int. J. Pharm. 368 (2009) 160. H. Zhao, Y. Le, H. Liu, T. Hu, Z. Shen, J. Yun, J.F. Chen, Powder Technol. 194 (2009) 81. Z. Wang, J.F. Chen, Y. Le, Z.G. Shen, Ind. Eng. Chem. Res. 46 (2007) 4839. Q.P. Huang, J.X. Wang, G.Z. Chen, Z.G. Shen, J.F. Chen, J. Yun, Int. J. Pharm. 360 (2008) 58. G.A. Pozarnsky, E. Matijevic´, Colloid Surf. A 125 (1997) 47. C. Goia, E. Matijevic´, J. Colloid Interface Sci. 206 (1998) 583. F. Ruch, E. Matijevic´, J. Colloid Interface Sci. 229 (2000) 207. L. Joguet, I. Sondi, E. Matijevic´, J. Colloid Interface Sci. 251 (2002) 284. L. Joguet, E. Matijevic´, J. Colloid Interface Sci. 250 (2002) 503. S.D. Škapin, E. Matijevic´, J. Colloid Interface Sci. 272 (2004) 90. H.W. Bosch, S.D. Škapin, E. Matijevic´, Colloid Surf. A 250 (2004) 43. G. Cravotto, A. Binello, L. Boffa, O. Rosati, M. Boccalini, S. Chimichi, Steroids 71 (2006) 469. G. Tomer, B. Shneider, Gastroenterol. Clin. North America 32 (2003) 839. W.M. Duan, C.M.P. Rodrigures, L.R. Zhao, C.J. Steer, W.C. Low, Cell Transplant. 11 (2002) 195. A.P. Rolo, C.M. Palmeira, G.M. Holy, K.B. Wallace, Toxicol. Sci. 79 (2004) 196. M.H. Schoemaker, L. Conde de la Rosa, M. Buist-Homan, T.E. Vreken, R. Havinga, K. Poelstra, H.J. Haisma, P.L.M. Jansen, H. Moshage, Hepatology 39 (2004) 1563. P.B. Savage, C. Li, Expert Opin. Invest. Drugs 9 (2000) 263. H.M. Willemen, L.C. de Smet, A. Koudijs, M.C. Stuart, I.G. Heikamp-de Jong, A.T. Marcelis, E.J.R. Sudhölter, Angew. Chem. 41 (2002) 4275. J.P. Kratohvil, M. Orhanovic´, E. Matijevic´, J. Phys. Chem. 64 (1960) 1216. G. Fantin, M. Fogagnolo, O. Bortolini, N. Masciocchi, S. Galli, A. Sironi, New J. Chem. 27 (2003) 1794.