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Effect of three types of additives in poor solvent on preparation of sustained-release nitrendipine microspheres by the quasi-emulsion solvent diffusion method
J. DRUG DEL. SCI. TECH., 15 (2) 129-135 2005
Effect of three types of additives in poor solvent on preparation of sustained-release nitrendipine microspheres by the quasi-emulsion solvent diffusion method M. Yang1, F. Cui1*, Y. Fan1, B. You1, K. Ren1, H. Feng1, Y. Kawashima2 Department of Pharmaceutics, School of Pharmaceutical Science, Shenyang Pharmaceutical University, No.103, Wenhua Road, Shenyang 110016, China 2 Gifu Pharmaceutical University, 5-6-1 Mitahora-Higashi, Gifu 502, Japan *Correspondence: [email protected]
1
Sustained-release microspheres of nitrendipine with hydroxypropylmethylcellulose phthalate (HP-55) having a solid dispersion structure were prepared by using the quasi-emulsion solvent diffusion method of the spherical crystallization technique. To investigate the effect of the additives in poor solvent on the preparation of the nitrendipine microspheres, three types of additives, i.e. C12H25NaO4S (sodium dodecyl sulfate), NaOH, and KH2PO4/NaOH mixture, were chosen. The resultant microspheres were evaluated with respect to their recoveries, micromeritic properties and release rates. The mechanisms involved in the effect of different poor solvents on formation of the microspheres are discussed. The sustained-release nitrendipine microspheres could not be prepared without using any additives added to the poor solvent. The additives dissolved in poor solvent could affect the micromeritic properties and the release profiles of the resultant microspheres. On increasing the amount of additives, the total recoveries of microspheres were increased and the average diameter of the microspheres was reduced. It was found that a dissociation of HP-55 in poor solvent contributed to the formation of sustained-release nitrendipine microspheres. The release rate of the microspheres prepared with sodium dodecyl sulfate aqueous solution was slower than that of the other two additives, due to the more dense structure formed. Since HP-55, a pH-dependent polymer, was formulated in the present microspheres, the pH value of dissolution medium was one of critical factors to determine the dissolution rate. Key words: Poor solvent – Nitrendipine – Sustained-release microspheres – Quasi-emulsion solvent diffusion method.
The spherical crystallization technique has advantages over conventional microsphere preparation methods [1]. Also, it has been accepted as a useful technique for particle design in pharmaceutics [2]. The agglomeration mechanisms of this technique are classified mainly as involving two methods i.e. the wet agglomeration method and the quasi-emulsion solvent diffusion method [3]. Recently, the quasi-emulsion solvent diffusion method has been widely employed to prepare functional drug delivery devices such as sustained-release microspheres for water soluble drugs [4] and poorly water soluble drugs [5], immediate-release microspheres for water insoluble drugs in solid dispersions [6], and biodegradable nanospheres [7]. In this process, the crystallization and agglomeration can be carried out simultaneously in a two (i.e., poor solvent and bridging liquid) or three (i.e., poor solvent, good solvent and bridging liquid) solvent system. Drug and polymers are firstly dissolved in either good solvent or a mixed solution of good solvent and bridging liquid and then the resultant solution of drug and polymer is poured into poor solvent under agitation. The solution is instantly dispersed into fine quasi-emulsion droplets. Along with the diffusion of the good solvent out of the droplets, the drug and polymers are coprecipitated in the droplets. This results in the solidification of the droplets and the formation of the microspheres. Nitrendipine, a dihydropyridine calcium antagonist, is a water insoluble drug which has a very low bioavailability in vivo [8]. Since the solid dispersion technique is one of the effective methods to improve the dissolution rate of insoluble drugs, leading to high bioavailability [9], in our previous research [10], a form of sustained-release nitrendipine microsphere having
a solid dispersion structure was designed by combining the microsphere preparation and the solid dispersion in one step. In this formulation, to enhance the drug releasing and absorption in intestinal tract, hydroxypropylmethylmethylcellulose phthalate, a pH-dependent polymer, which can be dissolved in the intestinal juice at a pH above 5.5, was formulated as a solid dispersion carrier. The acrylic resins, i.e. Eudragit RS PO and ethylcellulose were chosen as retarding agents and also formulated in the microspheres to control the release rate of the drug. All of these polymers exhibited a high viscosity during the formation of coacervation droplets. This resulted in the droplets often agglomerating into an irregular mass or adhering to the propeller and the vessel wall during the preparation process. A great deal of tests have been carried out to resolve the above problem, such as adding antiadhesion agents, adjusting the solvent system or changing the temperature and agitation speed. It was found that the conglutination of the emulsion droplets could be prevented effectively by introducing suitable additives in poor solvent. After screening many excipients, three types of additives, i.e. sodium dodecyl sulfate (SDS), NaOH, and a KH2PO4/NaOH mixture, were chosen as model additives of poor solvent to prepare the microspheres. In this study, the selection process for the additives is briefly described and then the formation mechanism of the microspheres in poor solvent, containing the above three types of additives, is explained in detail. The recovery, micromeritic properties and the release profiles of the resultant microspheres in three types of poor solvent are reported. Finally, the effects of pH value of dissolution medium on the release behavior of microspheres are also investigated. 129
J. DRUG DEL. SCI. TECH., 15 (2) 129-135 2005
Effect of three types of additives in poor solvent on preparation of sustained-release nitrendipine microspheres by the quasi-emulsion solvent diffusion method M. Yang, F. Cui, Y. Fan, B. You, K. Ren, H. Feng, Y. Kawashima
loaded powders. The particle size distribution was determined by the sieving method using the standard sieve stipulated in the Chinese pharmacopoeia 2000 Ed. (Ch. P. 2000 Ed.). The bulk density of the microspheres was measured by the tapping method. The morphology of the microspheres was investigated using a scanning electron microscope (Jeol Co. Ltd., Japan).
I. MATERIALS AND METHODS 1. Materials
Nitrendipine (Nanjing Pharmaceutical Factory, China) was used as a water insoluble model drug, hydroxypropylmethylcellulose phthalate (HP-55, Shin-Etsu Chemical Ind. Co. Ltd., Japan) was chosen as a solid dispersing carrier, the acrylic resins Eudragit RS PO (EuRS PO, Röhm Pharma. Germany) and ethylcellulose (EC, Dow Chemical Company, United States) were used as retarding agents, and light anhydrous silicic acid (Aerosil, D50 = 28.34 µm, Guangzhou People Chemical Plant, China) was used as the drug dispersing and antiadhesion agent. The additives for the poor solvent employed in this study were C12H25NaO4S (SDS) or NaOH and KH2PO4/NaOH mixture. It was found that a solution of ethanol and acetone mixed in a suitable ratio was good solvent for dissolving both nitrendipine and the above polymers. Distilled water was used as poor solvent, inducing coprecipitation of both the drug and the polymers. Dichloromethane was selected as bridging liquid due to its good linkage ability between the drug and the polymers, and for its immiscibility in poor solvent. In the dissolution test, SDS was added to the dissolution medium to improve the wetting of the microspheres and create sink conditions for the drug. All chemicals were of analytical grade.
4. Release behavior of microspheres
The drug release tests on the microspheres were carried out for 12 h at 100 rpm using the paddle method specified in the Ch. P. 2000 Ed. The temperature of the dissolution medium was controlled at 37 ± 0.5°C. The microspheres were fractionated to -20+60 mesh (280~900 µm) and weighed to obtain an equivalent to 20 mg nitrendipine. The dissolution medium was 900 ml distilled water containing SDS (0.5% (w/v)) to maintain sink conditions for the drug. Five milliliters of the dissolution medium was sampled at specified intervals, and fresh dissolution medium was immediately added to the apparatus to keep the volume constant. Each withdrawn sample was passed through a membrane filter (0.8 µm) and the filtrate was scanned at 358 nm to determine the dissolved drug concentration using a spectrophotometer (Shanghai Third Analytical Instrument Plant, China).
5. Effect of pH value of dissolution medium on the release behavior of microspheres
2. Preparation of sustained-release microspheres of nitrendipine
To investigate the effect of pH value of dissolution medium on the release behavior of microspheres, the microspheres prepared in 2.08 mM SDS solution was selected as model microspheres due to its more dense structure. The 0.1 N HCl and phosphate buffer solution of different pH value were employed as the dissolution mediums, which corresponding pH values are 1.0, 4.0, 5.0, 5.5, 6.0 and 6.8. Because nitrendipine is a practically insoluble drug, 3% Tween 80 was added in phosphate buffer to maintain sink conditions for the drug. The other dissolution test conditions and the measurement method of released drug were the same as for the method described in section I.4.
The microspheres were prepared using the quasi-emulsion solvent diffusion method involving the spherical crystallization technique. Nitrendipine (1.0 g), HP-55 (2.5 g), EuRS PO (1.0 g) and EC (0.75 g) were dissolved in a mixed organic solution containing 7.5 ml ethanol, 10 ml acetone and 10 ml dichloromethane. The Aerosil (4.0 g) was suspended uniformly in the solution of drug-polymers under agitation. Then, the resultant drug-polymer-Aerosil suspension was poured into poor solvent (150 ml) thermally controlled at 25°C with agitation (750 rpm) using a propeller-type stirrer in a cylindrical vessel (500 ml) with three baffles. After agitating the system for 10 min, another 200 ml poor solvent was added to the vessel and agitation was continued for 30 min until the quasi-emulsion droplets changed into opaque pellets. The resultant products were decanted, filtered and dried in an oven at 50°C for 6 h. The experimental parameters were varied as follows: 1) concentration of SDS in distilled water: 0.69, 1.39, 2.08, 2.77, 3.46 and 5.20 mM; 2) concentration of NaOH in distilled water: 0.03, 0.10, 0.32, 1.00 and 3.16 mM. The corresponding pH value of NaOH solution is 9, 10, 11, 12 and 13, respectively; 3) to maintain the pH of the mixed solution of KH2PO4/NaOH 6.8 ± 0.1, the amount of KH2PO4 and NaOH were added to the distilled water at the same mixing ratio. The concentration of KH2PO4 in distilled water was 0.42, 0.62, 1.25, 2.50, 5.00 and 10.00 mM and the corresponding concentration of NaOH was 0.19, 0.28, 0.56, 1.12, 2.24 and 4.48 mM.
II. RESULTS AND DISCUSSION 1. Screening of the additives
The recovery of the microspheres was selected as the main evaluation index to screen the additives to poor solvent. As shown in Figure 1, when the drug-polymer-Aerosil suspension was poured into poor solvent without any additives, no microspheres could be recovered, because the suspension could not be dispersed into stable quasi-emulsion droplets. The polymers usually agglomerated into an irregular mass or adhered to the propeller paddle and the vessel wall. To solve the above problem, different types of surfactants were initially tested for adding to the poor solvent during the manufacturing process, and the products were evaluated by measuring the recovery. The results showed that most anionic surfactants and nonionic surfactants could not effectively reduce the adhesion of the microspheres, with the exception of SDS. Although microspheres could sometimes be collected in several surfactant solutions, such as gum arabic, PVA and Tween 80 solution, the product particles were usually large in size and the recovery was low. However, it was found that the addition of
3. Measurement of micromeritic properties of microspheres
The recovery of the microspheres was determined from the ratio of the amount of microspheres to that of the total amount of 130
Effect of three types of additives in poor solvent on preparation of sustained-release nitrendipine microspheres by the quasi-emulsion solvent diffusion method M. Yang, F. Cui, Y. Fan, B. You, K. Ren, H. Feng, Y. Kawashima
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cationic surfactants, such as quaternary ammonium salts, contribute to the reduction in adhesion between the microspheres. The particle size of the microspheres decreased dramatically on increasing the concentration of cationic surfactants in poor solvent, while the resultant poor solvent was usually turbid and most of the Aerosil separated from the microspheres. In general, the recovery of microspheres was very low. This was believed to be due to the dissolution of HP-55 in an alkaline poor solvent, which was attributed to the dissociation of quaternary ammonium salt surfactants in distilled water. Also, the results suggest that alkaline conditions in poor solvent contribute to the formation of microspheres. Then, several alkalis, such as KOH and NaOH, were tested for adding to poor solvent to prepare microspheres, and similar results were observed. This showed that a slight dissolution of HP-55 in poor solvent contributed to the formation of nitrendipine microspheres. Finally, different buffer solutions were also used as the poor solvent to prepare microspheres. The results obtained showed that microspheres could be produced at a high pH buffer solution, while the drug-polymer-Aerosil suspension could not be dispersed into quasi-emulsion droplets when a low pH buffer solution was employed. In order to investigate the formation mechanism of microspheres in different poor solvents, three types of additives, i.e. SDS, NaOH, and KH2PO4/NaOH mixture, were chosen. Figure 1 illustrates the recovery of microspheres in these different poor solvents. The results show that the total recovery of microspheres increased on increasing the concentration of the three types of additives in poor solvent. This shows that these three types of additives contribute to the formation of microspheres.
J. DRUG DEL. SCI. TECH., 15 (2) 129-135 2005
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The detailed preparation of sustained-release nitrendipine microspheres has been presented in another of our papers [10]. It was found that the dispersed and stable quasi-emulsion droplets formed in the initial stage of preparation is an essential condition for the quasi-emulsion solvent diffusion method. As a surfactant and emulsifying agent, SDS contributed to the fine dispersion of emulsion droplets in poor solvent. On increasing the concentration of SDS, the interfacial tension of the emulsion droplets could be effectively reduced. The microspheres with a defined particle size were formed by the balance between the interfacial tension of the emulsion droplets and the shearing force applied to the droplets under agitation. The addition of SDS contributes not only to the dispersion but also to the stability of emulsion droplets in poor solvent. It was found that the agglomeration and conglutination of droplets could be avoided effectively when SDS was added to distilled water. As far as the reason for the formation of microspheres in NaOH or KH2PO4/NaOH solution is concerned, it appears that the formation of microspheres was due to a slight dissolution of HP-55 in poor solvent following the addition of these additives. As a pH-dependent polymer, HP-55 can be dissolved in solutions of pH above 5.5. In this system, the pH of the KH2PO4/NaOH mixed solution was 6.8 ± 0.1 and the NaOH solution was alkaline (pH ≥ 9.0). The HP-55 dissolved slightly
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2. Formation of microspheres in poor solvent containing different additives
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Figure 1 - Recoveries and average diameters of microspheres as a function of the concentration of additives in poor solvent. ▲, total recovery; ■, recovery of -20+60 mesh; ●, average diameter.
in these poor solvents, and the solubility increased on increasing the concentration of these additives in distilled water. Then, the hydrophilic group, -COOH, of HP-55 molecule would be hydrated with the poor solvent and dissociated into -COO- and H+, which resulted in the quasi-emulsion droplets formed carrying a negative charge, and the stability of the droplets was improved by the electrostatic repulsive force. Also, the dissociation of -COOH contributed to improving the hydrophilicity of the quasi-emulsion droplets, which then contributed to the reduction in the interfacial tension between the droplets and the poor solvent. 131
J. DRUG DEL. SCI. TECH., 15 (2) 129-135 2005
Effect of three types of additives in poor solvent on preparation of sustained-release nitrendipine microspheres by the quasi-emulsion solvent diffusion method M. Yang, F. Cui, Y. Fan, B. You, K. Ren, H. Feng, Y. Kawashima
mainly dependent on the concentration of SDS in the distilled water. On increasing the concentration of SDS, the size of the microspheres decreased. In either NaOH or KH2PO4/NaOH poor solvent, the average diameter of the microspheres was also reduced on increasing the concentration of additives. This was probably due to the increase in the dissolution of HP-55 in the poor solvent, which was responsible for increasing the ζ potential of quasi-emulsion droplets and increasing the dispersion of the droplets in the poor solvent. As illustrated in Figure 1, the recoveries of -20+60 mesh reached a maximum (i.e. 69.9% at 2.08 mM SDS, 62.8% at 1.00 mM NaOH, 71.1% at 5.00 mM KH2PO4) and then decreased slightly. This is mainly due to the reduction in the particle size of the microspheres on increasing the amount of additives in poor solvent. Some small microspheres passed through the 60 mesh and were unrecovered. In addition, it should be pointed out here that the effect of concentration of NaOH in distilled water on the recovery and particle size of microspheres reflected the effect of pH value of the poor solvent on these properties, because the pH value of the poor solvent was changed with adjusting the amount of NaOH added in distilled water. Consequently, the results in Figure 1 also indicated that when the NaOH solution, which has no buffer capacity, was employed as the poor solvent, the recovery of microspheres was improved with increasing the pH value of the poor solvent. But microspheres were difficult to be prepared when the pH value of NaOH solution is less than 9 or acidic solution was employed as the poor solvent, because drug-polymer-Aerosil suspension could not be dispersed into stable emulsion droplets when it was poured into the poor solvent. At the same time, the mean diameter of microspheres was decreased with increasing in the pH value of the poor solvent. However, when KH2PO4/NaOH mixed solution, i.e. a buffer solution, was employed the pH value of which was 6.8 ± 0.1 (less than 8 but higher than 5.5), with an increase in the concentration of the buffer solution, the recovery of microspheres was improved while the mean diameter of microspheres was decreased. It was clear that the pH value was not changed in this case. These findings suggested that pH value of poor solvent could affect the recovery and the properties of microspheres, but it was not the essential reason, whereas the slight dissolving of HP-55 in poor solvent was a critical factor which contributed the formation of microspheres. Figure 2 illustrates the wetting properties of HP-55 (166.7 mg) in KH2PO4/NaOH phosphate buffer solution (10 ml) with different concentration, of which the pH value is constant. The concentration of buffer solution was represented with that of KH2PO4 i.e. 50.0, 10.0, 5.0, 2.5, 1.25, 0.62 and 0.42 mM. It can be seen that with a decrease in the concentration of KH2PO4/NaOH buffer solution, HP-55 shows a hydrophobic characteristic in the aqueous solvent. It indicated that the dissolution of HP-55 was reduced, which caused the decrease in the dissociation of hydrophilic group (-COOH) of HP-55. This results in the decrease in ζ potential of the quasiemulsion droplets and leads to coalescence of the droplets and increase in the average diameter of microspheres.
In order to prove the above hypothesis, we attempted to measure the ζ potential of quasi-emulsion droplets in poor solvent. However, the droplets were too large, heavy and viscous to be measured by usual methods. Agglomeration always occurred without agitation, and this influenced the results measured. Emulsion droplets (≤ 50 µm) of the same formulation were then prepared using the same manufacturing process, except that the concentration of the drug-polymer-Aerosil suspension was reduced by increasing the amount of organic solvent (i.e. good solvent and bridging liquid). Its ζ potential was measured by capillary electrophoresis (Shanghai Measure Instrument Plant, China). The results confirmed the above speculation that the emulsion droplets carried a negative charge. However, on increasing the concentration of the additives in distilled water, the change in the data was not reproducible (not shown here). This was probably due to the viscosity of the emulsion droplets. In addition, it was found that the drug-polymer-Aerosil suspension could not be dispersed into quasi-emulsion droplets when it was poured into an acidic poor solvent. Also, the quasiemulsion droplets agglomerated into an irregular mass when a small amount of hydrochloric acid was added to an alkaline poor solvent, even though it had been dispersed well in poor solvent. This appeared to be a flocculation phenomenon. They could not be redispersed. The pH of the resultant poor solvent was usually below 4.0~4.5. This could be due to the neutralization of the negative charges of droplets by H+, which caused a reduction in the stability of the system. However, such a phenomenon was not observed in the manufacturing process involving only EuRS PO or EC microspheres without HP-55 being formulated. These findings suggest that the proper dissolution of HP-55 in poor solvent contributed to the formation of the dispersed and stable quasi-emulsion droplets during the initial stage of the preparation process. Also, the reason why SDS was more effective than other anionic surfactants and nonionic surfactants was believed to be due to its mild alkaline properties. However, cationic surfactants, which are usually strongly alkaline, were not selected in this study due to their toxicity. These findings suggest that the pH of poor solvent affected the formation of microspheres formulated with HP-55. Moreover, the dissolution of HP-55 could be minimized by controlling the concentration of the additives in the poor solvent.
3. Effect of the additive concentration in poor solvent on the particle size of microspheres
Many papers have reported that the particle size of microspheres is controlled mainly by the agitation speed of the system [11]. We obtained similar results in a previous study [10]. In the present study, it was found that the particle size of the microspheres was also influenced by the concentration of additives in the distilled water (Figure 1). As shown in Figure 1, on increasing the concentration of SDS in distilled water, the average size of the microspheres reduced. It was shown earlier that the interfacial energy of this system was reduced on increasing the amount of SDS in poor solvent, which resulted in a reduction in the particle size of the quasi-emulsion droplets. When the agitation speed of the system was fixed, the size of the quasi-emulsion droplets was
4. Drug release behavior of microspheres
Usually the release rate of a drug from the microspheres depends on the concentration of the polymers formulated. In 132
Effect of three types of additives in poor solvent on preparation of sustained-release nitrendipine microspheres by the quasi-emulsion solvent diffusion method M. Yang, F. Cui, Y. Fan, B. You, K. Ren, H. Feng, Y. Kawashima
this study, the drug release rate from microspheres increased on increasing the amount of solid dispersion carriers (HP-55), and decreased on increasing the amount of retarding agents (ethyl cellulose and EuRS PO). Whereas, it was found that the release rate of microspheres was also dependent on the types of additives added to the poor solvent. As shown in Figure 3, although three types of microspheres were prepared using the same formulation, the drug release rate of the microspheres prepared in SDS solution was slower than that of the other two types of microspheres. The microspheres used in the dissolution tests have the same particle size range (280~900 µm). To explain these findings, the bulk density of the microspheres prepared with different types of additives was measured (Figure 4), and the morphology of the microspheres was also examined by SEM (Figure 5). Figure 4 shows the comparison data of the bulk density of the microspheres prepared with different additives, measured in the same particle size range. It was seen that the bulk density of the microspheres of SDS was larger than that of the other two. Also, there was no obvious difference in bulk density between the other two. This implies that the slower release rate of microspheres of SDS was due to its denser structure. To further confirm this conclusion, the surface and cross section of three types of microspheres were also observed using SEM technique (Figure 5). The results showed that the microspheres of SDS had a more dense structure as compared with that of the other two. Although all three types of microspheres have an inner hollow structure, the inner wall of SDS microspheres was much thicker and compacted than those of the other two. Moreover, the interstices on the surface of the microspheres prepared with SDS were smaller and less than those of the other two. This was probably due to the dissolution and loss of HP-55 in NaOH or KH2PO4/NaOH mixture solution, which led to the formation of more interstices on the surface of these microspheres. This was responsible for the increase in the release rate of drug from the microspheres. These findings could explain why the drug release rate of microspheres prepared with SDS was slower than that of the other two types of microspheres. This shows that the additives in poor solvent had clear influence on the micromeritic properties and structure of microspheres formulated with HP-55 and affected the release behavior of the microspheres.
J. DRUG DEL. SCI. TECH., 15 (2) 129-135 2005
Figure 2 - Wetting properties of HP-55 in KH2PO4/NaOH phosphate buffer solution with different concentration. Note: the concentration of buffer solution is represented with that of KH2PO4 (mM).
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5. Effect of pH value of dissolution medium on release behavior of microspheres
Because the dissolution of HP-55 depends on the pH value of solution, the pH value of dissolution medium is one of important factors to determine the dissolution rate. The effect of pH value of dissolution medium on release behaviors of microspheres is illustrated in Figure 6. It can be seen that the drug release rate increased with increasing the pH value of phosphate buffer from 4.0 to 6.8. This was believed to be due to the increase in the dissolution rate of HP-55 with increasing the pH value of phosphate buffer. However, the release rate of nitrendipine from microspheres was not reduced when the pH value of dissolution medium was adjusted from 4.0 to 1.0 i.e. 0.1 N HCl solution. It indicated that the pH value of the dissolution medium had less effect on the release rate of the microspheres when dissolution medium of low pH value
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Figure 4 - The bulk density of microspheres as a function of various additives. ▲, SDS; ●, KH2PO4; ■, NaOH.
was employed. This indicated that HP-55 started to dissolve only after the pH of the solution exceeded a critical value. The release curves in Figure 6 suggested that such a critical range of pH value was between 4.0 and 5.0. 133
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Effect of three types of additives in poor solvent on preparation of sustained-release nitrendipine microspheres by the quasi-emulsion solvent diffusion method M. Yang, F. Cui, Y. Fan, B. You, K. Ren, H. Feng, Y. Kawashima
Figure 5 - Scanning electron microphotograph of microspheres. A, Microsphere prepared in SDS solution (2.08 mM); B, Microsphere prepared in KH2PO4/NaOH solution (5.00 mM/2.24 mM); C, Microsphere prepared in NaOH solution (1.00 mM); 1, whole image (x 75); 2, cross section (x 75).
by the quasi-emulsion solvent diffusion method. Suitable microspheres could also be obtained by choosing an appropriate type and concentration of additive in poor solvent.
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REFERENCES
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Time (h) Figure 6 - Release profiles of nitrendipine from microspheres in different pH dissolution medium. ■, pH = 1.2; ●, pH = 4.0; ▲, pH = 5.0; ▼, pH = 5.5; ◆, pH = 6.0; +, pH = 6.8.
3. 4.
* * * In this study, no microspheres could be recovered without any additives added to the poor solvent. However, good microspheres could be obtained by adding certain additives to distilled water, i.e. SDS, NaOH, or a KH2PO4/NaOH mixture. The findings in this study suggest that the slight dissociation of HP-55 contributed to the formation of sustained-release nitrendipine microspheres. The micromeritic properties and release behaviors of microspheres were affected by the different additives added and pH of poor solvent. This shows that the effects of the additives in poor solvent on the microsphere properties should be considered when preparing microspheres
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Effect of three types of additives in poor solvent on preparation of sustained-release nitrendipine microspheres by the quasi-emulsion solvent diffusion method M. Yang, F. Cui, Y. Fan, B. You, K. Ren, H. Feng, Y. Kawashima
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ACKNOWLEDGMENTS
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This work was funded by the ‘9.5’ National Science and Technology Foundation of China. The authors would like to thank Ms. Xiaoyan Wang for the measuring the SEM, and RÖhm Pharma. Co. and Shanghai Colorcon Coating Tech., Ltd for kindly supplying EuRS PO and EC.
MANUSCRIPT Received 22 June 2004, accepted for publication 30 August 2004.
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Effect of three types of additives in poor solvent on preparation of sustained-release nitrendipine microspheres by the quasi-emulsion solvent diffusion method M. Yang1, F. Cui1*, Y. Fan1, B. You1, K. Ren1, H. Feng1, Y. Kawashima2 Department of Pharmaceutics, School of Pharmaceutical Science, Shenyang Pharmaceutical University, No.103, Wenhua Road, Shenyang 110016, China 2 Gifu Pharmaceutical University, 5-6-1 Mitahora-Higashi, Gifu 502, Japan *Correspondence: [email protected]
1
Sustained-release microspheres of nitrendipine with hydroxypropylmethylcellulose phthalate (HP-55) having a solid dispersion structure were prepared by using the quasi-emulsion solvent diffusion method of the spherical crystallization technique. To investigate the effect of the additives in poor solvent on the preparation of the nitrendipine microspheres, three types of additives, i.e. C12H25NaO4S (sodium dodecyl sulfate), NaOH, and KH2PO4/NaOH mixture, were chosen. The resultant microspheres were evaluated with respect to their recoveries, micromeritic properties and release rates. The mechanisms involved in the effect of different poor solvents on formation of the microspheres are discussed. The sustained-release nitrendipine microspheres could not be prepared without using any additives added to the poor solvent. The additives dissolved in poor solvent could affect the micromeritic properties and the release profiles of the resultant microspheres. On increasing the amount of additives, the total recoveries of microspheres were increased and the average diameter of the microspheres was reduced. It was found that a dissociation of HP-55 in poor solvent contributed to the formation of sustained-release nitrendipine microspheres. The release rate of the microspheres prepared with sodium dodecyl sulfate aqueous solution was slower than that of the other two additives, due to the more dense structure formed. Since HP-55, a pH-dependent polymer, was formulated in the present microspheres, the pH value of dissolution medium was one of critical factors to determine the dissolution rate. Key words: Poor solvent – Nitrendipine – Sustained-release microspheres – Quasi-emulsion solvent diffusion method.
The spherical crystallization technique has advantages over conventional microsphere preparation methods [1]. Also, it has been accepted as a useful technique for particle design in pharmaceutics [2]. The agglomeration mechanisms of this technique are classified mainly as involving two methods i.e. the wet agglomeration method and the quasi-emulsion solvent diffusion method [3]. Recently, the quasi-emulsion solvent diffusion method has been widely employed to prepare functional drug delivery devices such as sustained-release microspheres for water soluble drugs [4] and poorly water soluble drugs [5], immediate-release microspheres for water insoluble drugs in solid dispersions [6], and biodegradable nanospheres [7]. In this process, the crystallization and agglomeration can be carried out simultaneously in a two (i.e., poor solvent and bridging liquid) or three (i.e., poor solvent, good solvent and bridging liquid) solvent system. Drug and polymers are firstly dissolved in either good solvent or a mixed solution of good solvent and bridging liquid and then the resultant solution of drug and polymer is poured into poor solvent under agitation. The solution is instantly dispersed into fine quasi-emulsion droplets. Along with the diffusion of the good solvent out of the droplets, the drug and polymers are coprecipitated in the droplets. This results in the solidification of the droplets and the formation of the microspheres. Nitrendipine, a dihydropyridine calcium antagonist, is a water insoluble drug which has a very low bioavailability in vivo [8]. Since the solid dispersion technique is one of the effective methods to improve the dissolution rate of insoluble drugs, leading to high bioavailability [9], in our previous research [10], a form of sustained-release nitrendipine microsphere having
a solid dispersion structure was designed by combining the microsphere preparation and the solid dispersion in one step. In this formulation, to enhance the drug releasing and absorption in intestinal tract, hydroxypropylmethylmethylcellulose phthalate, a pH-dependent polymer, which can be dissolved in the intestinal juice at a pH above 5.5, was formulated as a solid dispersion carrier. The acrylic resins, i.e. Eudragit RS PO and ethylcellulose were chosen as retarding agents and also formulated in the microspheres to control the release rate of the drug. All of these polymers exhibited a high viscosity during the formation of coacervation droplets. This resulted in the droplets often agglomerating into an irregular mass or adhering to the propeller and the vessel wall during the preparation process. A great deal of tests have been carried out to resolve the above problem, such as adding antiadhesion agents, adjusting the solvent system or changing the temperature and agitation speed. It was found that the conglutination of the emulsion droplets could be prevented effectively by introducing suitable additives in poor solvent. After screening many excipients, three types of additives, i.e. sodium dodecyl sulfate (SDS), NaOH, and a KH2PO4/NaOH mixture, were chosen as model additives of poor solvent to prepare the microspheres. In this study, the selection process for the additives is briefly described and then the formation mechanism of the microspheres in poor solvent, containing the above three types of additives, is explained in detail. The recovery, micromeritic properties and the release profiles of the resultant microspheres in three types of poor solvent are reported. Finally, the effects of pH value of dissolution medium on the release behavior of microspheres are also investigated. 129
J. DRUG DEL. SCI. TECH., 15 (2) 129-135 2005
Effect of three types of additives in poor solvent on preparation of sustained-release nitrendipine microspheres by the quasi-emulsion solvent diffusion method M. Yang, F. Cui, Y. Fan, B. You, K. Ren, H. Feng, Y. Kawashima
loaded powders. The particle size distribution was determined by the sieving method using the standard sieve stipulated in the Chinese pharmacopoeia 2000 Ed. (Ch. P. 2000 Ed.). The bulk density of the microspheres was measured by the tapping method. The morphology of the microspheres was investigated using a scanning electron microscope (Jeol Co. Ltd., Japan).
I. MATERIALS AND METHODS 1. Materials
Nitrendipine (Nanjing Pharmaceutical Factory, China) was used as a water insoluble model drug, hydroxypropylmethylcellulose phthalate (HP-55, Shin-Etsu Chemical Ind. Co. Ltd., Japan) was chosen as a solid dispersing carrier, the acrylic resins Eudragit RS PO (EuRS PO, Röhm Pharma. Germany) and ethylcellulose (EC, Dow Chemical Company, United States) were used as retarding agents, and light anhydrous silicic acid (Aerosil, D50 = 28.34 µm, Guangzhou People Chemical Plant, China) was used as the drug dispersing and antiadhesion agent. The additives for the poor solvent employed in this study were C12H25NaO4S (SDS) or NaOH and KH2PO4/NaOH mixture. It was found that a solution of ethanol and acetone mixed in a suitable ratio was good solvent for dissolving both nitrendipine and the above polymers. Distilled water was used as poor solvent, inducing coprecipitation of both the drug and the polymers. Dichloromethane was selected as bridging liquid due to its good linkage ability between the drug and the polymers, and for its immiscibility in poor solvent. In the dissolution test, SDS was added to the dissolution medium to improve the wetting of the microspheres and create sink conditions for the drug. All chemicals were of analytical grade.
4. Release behavior of microspheres
The drug release tests on the microspheres were carried out for 12 h at 100 rpm using the paddle method specified in the Ch. P. 2000 Ed. The temperature of the dissolution medium was controlled at 37 ± 0.5°C. The microspheres were fractionated to -20+60 mesh (280~900 µm) and weighed to obtain an equivalent to 20 mg nitrendipine. The dissolution medium was 900 ml distilled water containing SDS (0.5% (w/v)) to maintain sink conditions for the drug. Five milliliters of the dissolution medium was sampled at specified intervals, and fresh dissolution medium was immediately added to the apparatus to keep the volume constant. Each withdrawn sample was passed through a membrane filter (0.8 µm) and the filtrate was scanned at 358 nm to determine the dissolved drug concentration using a spectrophotometer (Shanghai Third Analytical Instrument Plant, China).
5. Effect of pH value of dissolution medium on the release behavior of microspheres
2. Preparation of sustained-release microspheres of nitrendipine
To investigate the effect of pH value of dissolution medium on the release behavior of microspheres, the microspheres prepared in 2.08 mM SDS solution was selected as model microspheres due to its more dense structure. The 0.1 N HCl and phosphate buffer solution of different pH value were employed as the dissolution mediums, which corresponding pH values are 1.0, 4.0, 5.0, 5.5, 6.0 and 6.8. Because nitrendipine is a practically insoluble drug, 3% Tween 80 was added in phosphate buffer to maintain sink conditions for the drug. The other dissolution test conditions and the measurement method of released drug were the same as for the method described in section I.4.
The microspheres were prepared using the quasi-emulsion solvent diffusion method involving the spherical crystallization technique. Nitrendipine (1.0 g), HP-55 (2.5 g), EuRS PO (1.0 g) and EC (0.75 g) were dissolved in a mixed organic solution containing 7.5 ml ethanol, 10 ml acetone and 10 ml dichloromethane. The Aerosil (4.0 g) was suspended uniformly in the solution of drug-polymers under agitation. Then, the resultant drug-polymer-Aerosil suspension was poured into poor solvent (150 ml) thermally controlled at 25°C with agitation (750 rpm) using a propeller-type stirrer in a cylindrical vessel (500 ml) with three baffles. After agitating the system for 10 min, another 200 ml poor solvent was added to the vessel and agitation was continued for 30 min until the quasi-emulsion droplets changed into opaque pellets. The resultant products were decanted, filtered and dried in an oven at 50°C for 6 h. The experimental parameters were varied as follows: 1) concentration of SDS in distilled water: 0.69, 1.39, 2.08, 2.77, 3.46 and 5.20 mM; 2) concentration of NaOH in distilled water: 0.03, 0.10, 0.32, 1.00 and 3.16 mM. The corresponding pH value of NaOH solution is 9, 10, 11, 12 and 13, respectively; 3) to maintain the pH of the mixed solution of KH2PO4/NaOH 6.8 ± 0.1, the amount of KH2PO4 and NaOH were added to the distilled water at the same mixing ratio. The concentration of KH2PO4 in distilled water was 0.42, 0.62, 1.25, 2.50, 5.00 and 10.00 mM and the corresponding concentration of NaOH was 0.19, 0.28, 0.56, 1.12, 2.24 and 4.48 mM.
II. RESULTS AND DISCUSSION 1. Screening of the additives
The recovery of the microspheres was selected as the main evaluation index to screen the additives to poor solvent. As shown in Figure 1, when the drug-polymer-Aerosil suspension was poured into poor solvent without any additives, no microspheres could be recovered, because the suspension could not be dispersed into stable quasi-emulsion droplets. The polymers usually agglomerated into an irregular mass or adhered to the propeller paddle and the vessel wall. To solve the above problem, different types of surfactants were initially tested for adding to the poor solvent during the manufacturing process, and the products were evaluated by measuring the recovery. The results showed that most anionic surfactants and nonionic surfactants could not effectively reduce the adhesion of the microspheres, with the exception of SDS. Although microspheres could sometimes be collected in several surfactant solutions, such as gum arabic, PVA and Tween 80 solution, the product particles were usually large in size and the recovery was low. However, it was found that the addition of
3. Measurement of micromeritic properties of microspheres
The recovery of the microspheres was determined from the ratio of the amount of microspheres to that of the total amount of 130
Effect of three types of additives in poor solvent on preparation of sustained-release nitrendipine microspheres by the quasi-emulsion solvent diffusion method M. Yang, F. Cui, Y. Fan, B. You, K. Ren, H. Feng, Y. Kawashima
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cationic surfactants, such as quaternary ammonium salts, contribute to the reduction in adhesion between the microspheres. The particle size of the microspheres decreased dramatically on increasing the concentration of cationic surfactants in poor solvent, while the resultant poor solvent was usually turbid and most of the Aerosil separated from the microspheres. In general, the recovery of microspheres was very low. This was believed to be due to the dissolution of HP-55 in an alkaline poor solvent, which was attributed to the dissociation of quaternary ammonium salt surfactants in distilled water. Also, the results suggest that alkaline conditions in poor solvent contribute to the formation of microspheres. Then, several alkalis, such as KOH and NaOH, were tested for adding to poor solvent to prepare microspheres, and similar results were observed. This showed that a slight dissolution of HP-55 in poor solvent contributed to the formation of nitrendipine microspheres. Finally, different buffer solutions were also used as the poor solvent to prepare microspheres. The results obtained showed that microspheres could be produced at a high pH buffer solution, while the drug-polymer-Aerosil suspension could not be dispersed into quasi-emulsion droplets when a low pH buffer solution was employed. In order to investigate the formation mechanism of microspheres in different poor solvents, three types of additives, i.e. SDS, NaOH, and KH2PO4/NaOH mixture, were chosen. Figure 1 illustrates the recovery of microspheres in these different poor solvents. The results show that the total recovery of microspheres increased on increasing the concentration of the three types of additives in poor solvent. This shows that these three types of additives contribute to the formation of microspheres.
J. DRUG DEL. SCI. TECH., 15 (2) 129-135 2005
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The detailed preparation of sustained-release nitrendipine microspheres has been presented in another of our papers [10]. It was found that the dispersed and stable quasi-emulsion droplets formed in the initial stage of preparation is an essential condition for the quasi-emulsion solvent diffusion method. As a surfactant and emulsifying agent, SDS contributed to the fine dispersion of emulsion droplets in poor solvent. On increasing the concentration of SDS, the interfacial tension of the emulsion droplets could be effectively reduced. The microspheres with a defined particle size were formed by the balance between the interfacial tension of the emulsion droplets and the shearing force applied to the droplets under agitation. The addition of SDS contributes not only to the dispersion but also to the stability of emulsion droplets in poor solvent. It was found that the agglomeration and conglutination of droplets could be avoided effectively when SDS was added to distilled water. As far as the reason for the formation of microspheres in NaOH or KH2PO4/NaOH solution is concerned, it appears that the formation of microspheres was due to a slight dissolution of HP-55 in poor solvent following the addition of these additives. As a pH-dependent polymer, HP-55 can be dissolved in solutions of pH above 5.5. In this system, the pH of the KH2PO4/NaOH mixed solution was 6.8 ± 0.1 and the NaOH solution was alkaline (pH ≥ 9.0). The HP-55 dissolved slightly
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2. Formation of microspheres in poor solvent containing different additives
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Figure 1 - Recoveries and average diameters of microspheres as a function of the concentration of additives in poor solvent. ▲, total recovery; ■, recovery of -20+60 mesh; ●, average diameter.
in these poor solvents, and the solubility increased on increasing the concentration of these additives in distilled water. Then, the hydrophilic group, -COOH, of HP-55 molecule would be hydrated with the poor solvent and dissociated into -COO- and H+, which resulted in the quasi-emulsion droplets formed carrying a negative charge, and the stability of the droplets was improved by the electrostatic repulsive force. Also, the dissociation of -COOH contributed to improving the hydrophilicity of the quasi-emulsion droplets, which then contributed to the reduction in the interfacial tension between the droplets and the poor solvent. 131
J. DRUG DEL. SCI. TECH., 15 (2) 129-135 2005
Effect of three types of additives in poor solvent on preparation of sustained-release nitrendipine microspheres by the quasi-emulsion solvent diffusion method M. Yang, F. Cui, Y. Fan, B. You, K. Ren, H. Feng, Y. Kawashima
mainly dependent on the concentration of SDS in the distilled water. On increasing the concentration of SDS, the size of the microspheres decreased. In either NaOH or KH2PO4/NaOH poor solvent, the average diameter of the microspheres was also reduced on increasing the concentration of additives. This was probably due to the increase in the dissolution of HP-55 in the poor solvent, which was responsible for increasing the ζ potential of quasi-emulsion droplets and increasing the dispersion of the droplets in the poor solvent. As illustrated in Figure 1, the recoveries of -20+60 mesh reached a maximum (i.e. 69.9% at 2.08 mM SDS, 62.8% at 1.00 mM NaOH, 71.1% at 5.00 mM KH2PO4) and then decreased slightly. This is mainly due to the reduction in the particle size of the microspheres on increasing the amount of additives in poor solvent. Some small microspheres passed through the 60 mesh and were unrecovered. In addition, it should be pointed out here that the effect of concentration of NaOH in distilled water on the recovery and particle size of microspheres reflected the effect of pH value of the poor solvent on these properties, because the pH value of the poor solvent was changed with adjusting the amount of NaOH added in distilled water. Consequently, the results in Figure 1 also indicated that when the NaOH solution, which has no buffer capacity, was employed as the poor solvent, the recovery of microspheres was improved with increasing the pH value of the poor solvent. But microspheres were difficult to be prepared when the pH value of NaOH solution is less than 9 or acidic solution was employed as the poor solvent, because drug-polymer-Aerosil suspension could not be dispersed into stable emulsion droplets when it was poured into the poor solvent. At the same time, the mean diameter of microspheres was decreased with increasing in the pH value of the poor solvent. However, when KH2PO4/NaOH mixed solution, i.e. a buffer solution, was employed the pH value of which was 6.8 ± 0.1 (less than 8 but higher than 5.5), with an increase in the concentration of the buffer solution, the recovery of microspheres was improved while the mean diameter of microspheres was decreased. It was clear that the pH value was not changed in this case. These findings suggested that pH value of poor solvent could affect the recovery and the properties of microspheres, but it was not the essential reason, whereas the slight dissolving of HP-55 in poor solvent was a critical factor which contributed the formation of microspheres. Figure 2 illustrates the wetting properties of HP-55 (166.7 mg) in KH2PO4/NaOH phosphate buffer solution (10 ml) with different concentration, of which the pH value is constant. The concentration of buffer solution was represented with that of KH2PO4 i.e. 50.0, 10.0, 5.0, 2.5, 1.25, 0.62 and 0.42 mM. It can be seen that with a decrease in the concentration of KH2PO4/NaOH buffer solution, HP-55 shows a hydrophobic characteristic in the aqueous solvent. It indicated that the dissolution of HP-55 was reduced, which caused the decrease in the dissociation of hydrophilic group (-COOH) of HP-55. This results in the decrease in ζ potential of the quasiemulsion droplets and leads to coalescence of the droplets and increase in the average diameter of microspheres.
In order to prove the above hypothesis, we attempted to measure the ζ potential of quasi-emulsion droplets in poor solvent. However, the droplets were too large, heavy and viscous to be measured by usual methods. Agglomeration always occurred without agitation, and this influenced the results measured. Emulsion droplets (≤ 50 µm) of the same formulation were then prepared using the same manufacturing process, except that the concentration of the drug-polymer-Aerosil suspension was reduced by increasing the amount of organic solvent (i.e. good solvent and bridging liquid). Its ζ potential was measured by capillary electrophoresis (Shanghai Measure Instrument Plant, China). The results confirmed the above speculation that the emulsion droplets carried a negative charge. However, on increasing the concentration of the additives in distilled water, the change in the data was not reproducible (not shown here). This was probably due to the viscosity of the emulsion droplets. In addition, it was found that the drug-polymer-Aerosil suspension could not be dispersed into quasi-emulsion droplets when it was poured into an acidic poor solvent. Also, the quasiemulsion droplets agglomerated into an irregular mass when a small amount of hydrochloric acid was added to an alkaline poor solvent, even though it had been dispersed well in poor solvent. This appeared to be a flocculation phenomenon. They could not be redispersed. The pH of the resultant poor solvent was usually below 4.0~4.5. This could be due to the neutralization of the negative charges of droplets by H+, which caused a reduction in the stability of the system. However, such a phenomenon was not observed in the manufacturing process involving only EuRS PO or EC microspheres without HP-55 being formulated. These findings suggest that the proper dissolution of HP-55 in poor solvent contributed to the formation of the dispersed and stable quasi-emulsion droplets during the initial stage of the preparation process. Also, the reason why SDS was more effective than other anionic surfactants and nonionic surfactants was believed to be due to its mild alkaline properties. However, cationic surfactants, which are usually strongly alkaline, were not selected in this study due to their toxicity. These findings suggest that the pH of poor solvent affected the formation of microspheres formulated with HP-55. Moreover, the dissolution of HP-55 could be minimized by controlling the concentration of the additives in the poor solvent.
3. Effect of the additive concentration in poor solvent on the particle size of microspheres
Many papers have reported that the particle size of microspheres is controlled mainly by the agitation speed of the system [11]. We obtained similar results in a previous study [10]. In the present study, it was found that the particle size of the microspheres was also influenced by the concentration of additives in the distilled water (Figure 1). As shown in Figure 1, on increasing the concentration of SDS in distilled water, the average size of the microspheres reduced. It was shown earlier that the interfacial energy of this system was reduced on increasing the amount of SDS in poor solvent, which resulted in a reduction in the particle size of the quasi-emulsion droplets. When the agitation speed of the system was fixed, the size of the quasi-emulsion droplets was
4. Drug release behavior of microspheres
Usually the release rate of a drug from the microspheres depends on the concentration of the polymers formulated. In 132
Effect of three types of additives in poor solvent on preparation of sustained-release nitrendipine microspheres by the quasi-emulsion solvent diffusion method M. Yang, F. Cui, Y. Fan, B. You, K. Ren, H. Feng, Y. Kawashima
this study, the drug release rate from microspheres increased on increasing the amount of solid dispersion carriers (HP-55), and decreased on increasing the amount of retarding agents (ethyl cellulose and EuRS PO). Whereas, it was found that the release rate of microspheres was also dependent on the types of additives added to the poor solvent. As shown in Figure 3, although three types of microspheres were prepared using the same formulation, the drug release rate of the microspheres prepared in SDS solution was slower than that of the other two types of microspheres. The microspheres used in the dissolution tests have the same particle size range (280~900 µm). To explain these findings, the bulk density of the microspheres prepared with different types of additives was measured (Figure 4), and the morphology of the microspheres was also examined by SEM (Figure 5). Figure 4 shows the comparison data of the bulk density of the microspheres prepared with different additives, measured in the same particle size range. It was seen that the bulk density of the microspheres of SDS was larger than that of the other two. Also, there was no obvious difference in bulk density between the other two. This implies that the slower release rate of microspheres of SDS was due to its denser structure. To further confirm this conclusion, the surface and cross section of three types of microspheres were also observed using SEM technique (Figure 5). The results showed that the microspheres of SDS had a more dense structure as compared with that of the other two. Although all three types of microspheres have an inner hollow structure, the inner wall of SDS microspheres was much thicker and compacted than those of the other two. Moreover, the interstices on the surface of the microspheres prepared with SDS were smaller and less than those of the other two. This was probably due to the dissolution and loss of HP-55 in NaOH or KH2PO4/NaOH mixture solution, which led to the formation of more interstices on the surface of these microspheres. This was responsible for the increase in the release rate of drug from the microspheres. These findings could explain why the drug release rate of microspheres prepared with SDS was slower than that of the other two types of microspheres. This shows that the additives in poor solvent had clear influence on the micromeritic properties and structure of microspheres formulated with HP-55 and affected the release behavior of the microspheres.
J. DRUG DEL. SCI. TECH., 15 (2) 129-135 2005
Figure 2 - Wetting properties of HP-55 in KH2PO4/NaOH phosphate buffer solution with different concentration. Note: the concentration of buffer solution is represented with that of KH2PO4 (mM).
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5. Effect of pH value of dissolution medium on release behavior of microspheres
Because the dissolution of HP-55 depends on the pH value of solution, the pH value of dissolution medium is one of important factors to determine the dissolution rate. The effect of pH value of dissolution medium on release behaviors of microspheres is illustrated in Figure 6. It can be seen that the drug release rate increased with increasing the pH value of phosphate buffer from 4.0 to 6.8. This was believed to be due to the increase in the dissolution rate of HP-55 with increasing the pH value of phosphate buffer. However, the release rate of nitrendipine from microspheres was not reduced when the pH value of dissolution medium was adjusted from 4.0 to 1.0 i.e. 0.1 N HCl solution. It indicated that the pH value of the dissolution medium had less effect on the release rate of the microspheres when dissolution medium of low pH value
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Figure 4 - The bulk density of microspheres as a function of various additives. ▲, SDS; ●, KH2PO4; ■, NaOH.
was employed. This indicated that HP-55 started to dissolve only after the pH of the solution exceeded a critical value. The release curves in Figure 6 suggested that such a critical range of pH value was between 4.0 and 5.0. 133
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Effect of three types of additives in poor solvent on preparation of sustained-release nitrendipine microspheres by the quasi-emulsion solvent diffusion method M. Yang, F. Cui, Y. Fan, B. You, K. Ren, H. Feng, Y. Kawashima
Figure 5 - Scanning electron microphotograph of microspheres. A, Microsphere prepared in SDS solution (2.08 mM); B, Microsphere prepared in KH2PO4/NaOH solution (5.00 mM/2.24 mM); C, Microsphere prepared in NaOH solution (1.00 mM); 1, whole image (x 75); 2, cross section (x 75).
by the quasi-emulsion solvent diffusion method. Suitable microspheres could also be obtained by choosing an appropriate type and concentration of additive in poor solvent.
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REFERENCES
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Time (h) Figure 6 - Release profiles of nitrendipine from microspheres in different pH dissolution medium. ■, pH = 1.2; ●, pH = 4.0; ▲, pH = 5.0; ▼, pH = 5.5; ◆, pH = 6.0; +, pH = 6.8.
3. 4.
* * * In this study, no microspheres could be recovered without any additives added to the poor solvent. However, good microspheres could be obtained by adding certain additives to distilled water, i.e. SDS, NaOH, or a KH2PO4/NaOH mixture. The findings in this study suggest that the slight dissociation of HP-55 contributed to the formation of sustained-release nitrendipine microspheres. The micromeritic properties and release behaviors of microspheres were affected by the different additives added and pH of poor solvent. This shows that the effects of the additives in poor solvent on the microsphere properties should be considered when preparing microspheres
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Effect of three types of additives in poor solvent on preparation of sustained-release nitrendipine microspheres by the quasi-emulsion solvent diffusion method M. Yang, F. Cui, Y. Fan, B. You, K. Ren, H. Feng, Y. Kawashima
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ACKNOWLEDGMENTS
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This work was funded by the ‘9.5’ National Science and Technology Foundation of China. The authors would like to thank Ms. Xiaoyan Wang for the measuring the SEM, and RÖhm Pharma. Co. and Shanghai Colorcon Coating Tech., Ltd for kindly supplying EuRS PO and EC.
MANUSCRIPT Received 22 June 2004, accepted for publication 30 August 2004.
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