J. MICROENCAPSULATION,
1991, VOL. 8, NO, 3, 401-406
Eudragit E microspheres containing bacampicillin: preparation by solvent removal methods M. BOGATAJ, A. MRHAR, A. KRISTL and F. KOZJEK Faculty of Natural Sciences and Technology, Department of Pharmacy, University of Ljubljana, ASkerEeva 9, 61000 Ljubljana, Yugoslavia
Journal of Microencapsulation Downloaded from informahealthcare.com by McMaster University on 11/06/14 For personal use only.
(Received 1 February 1991; accepted 19 February 1991)
Eudragit E microspheres containing bacampicillin hydrochloride were prepared by solvent evaporation and solvent extraction methods. Three different systems of solvents were used: methyl acetate, acetone and methanol/liquid paraffin. The success of the procedures depended mostly on the lipophilicity of the solvent. The particle size of microspheres was determined by sieve analysis. The results showed that the average size of microspheres is influenced greatly by the type of solvent. Scanning electron microscopy was used for observation of the shape of microspheres. Microspheres prepared by the solvent evaporation method in systems with acetone and methyl acetate were all of a regular spherical shape. The surface of all other microspheres was folded. The influence of magnesium stearate content in microspheres was also studied in terms of different methods, solvents and processing conditions.
Introduction Solvent removal methods are used frequently for the preparation of microspheres in laboratory conditions; the most important are the solvent evaporation and solvent extraction methods. Although these procedures are very simple, many variables can influence the physicochemical and biopharmaceutic properties of the final product. T h e influence of the type of organic solvent, temperature, polymer and drug concentration, surfactant type and concentration, etc. is described in literature (Bodmeier and McGinity 1987,1988, Sat0 et al. 1988). When applying one of these methods the following systems of solvents are most widely used: water/methylene chloride, usually for the preparation of polylactide microspheres (Bodmeier and McGinity 1987) and liquid paraffin/acetone (Goto et al. 1986 a, b). In our laboratory microspheres with bacampicillin hydrochloride were prepared using Eudragit E as polymer and the solvents acetone, methyl acetate and methanol/liquid paraffin. We have recently reported the preparation of microspheres by solvent evaporation method (Bogataj et al. 1989). In the present work the preparation of microspheres by the solvent extraction method is represented and compared to the evaporation procedure. T h e influence of the method, the system of solvents, the temperature of evaporation and the rate of unsolvent adding on the properties of the final product are described.
Experimental Materials Bacampicillin hydrochloride was supplied by Lek, Ljubljana, Yugoslavia (quality corresponds to USP XXI). Eudragit E was purchased from Rohm Pharma, Darmstadt, Germany and magnesium stearate from Merck, Darmstadt, Germany. Solvents were all of analytical grade. 0265-2048/91 $3.00 0 1991 Taylor & Francis Ltd.
M . Bogataj et al.
402
Journal of Microencapsulation Downloaded from informahealthcare.com by McMaster University on 11/06/14 For personal use only.
Table 1 . The signatures of the samples and conditions of preparation of microspheres. Sample
Method
Solvent
Temperature of evaporation; rate of unsolvent adding
TA40 TA50 TA60 TMA40 TM40
Solvent evaporation Solvent evaporation Solvent evaporation Solvent evaporation Solvent evaporation
Acetone Acetone Acetone Methyl acetate Methanol
40°C 50°C 60°C 40°C 40°C
NA60 NA12 NA6 NMA12
Solvent extraction Solvent extraction Solvent extraction Solvent extraction
Acetone Acetone Acetone Methyl acetate
60 ml min12 ml min6 mlmin-' 12 ml min-
'
Preparation of microspheres Eudragit E (3.2g) was dissolved completely in 10.4ml of the solvent (methanol, acetone or methyl acetate) and 0-3g of magnesium stearate was added; 1.6g of bacampicillin was dispersed separately in 10.4 ml of the same solvent previously cooled to 5"C, and this dispersion was added to Eudragit solution. T h e mixture obtained was stirred at 5°C for 10min and then poured slowly with stirring (250 rpm) into 80 ml of liquid paraffin. T h e solvent was removed by evaporation or by extraction with n-hexane. T h e temperature of evaporation was 40,50 or 60°C and the rate of unsolvent adding 6, 12 or 60 ml min- Microspheres were separated by filtration, washed with n-hexane and dried at room temperature under reduced pressure overnight. T h e signatures of the samples and the conditions of preparation are shown in' table 1. Sieve analysis Particle size distribution was determined by sieve analysis. Apparatus Vibrations-Priifsiebmaschine Thyr 2, Germany, was used. We chose screens with different mesh sizes and the chi-square test for log-normal distribution of particles was performed subsequently. We used 3 g samples and a sifting time of 10 min. T h e procedure was carried out twice for each product. Electron microscopy Surface characteristics were examined by means of a scanning electron microscope. T h e microspheres were coated with C Au/Pd using a vacuum evaporator (Jeol). Samples were examined with a scanning electron microscope (Jeol SM2) at accelerating voltage 10 kV using a secondary electron technique. Tilt was 45" and working distance 12 mm.
+
Determination of magnesium stearate content T h e method according to N F XVI was modified and used for determination of magnesium stearate content in microspheres. An appropriate amount of microspheres containing approximately 5 mg of magnesium stearate was accurately weighed and boiled with 10 ml of 0.1 N sulphuric acid. During 30-40 min of boiling, stearic acid separated as a clear layer and the resulting emulsion was cooled and neutralized with 1 N sodium hydroxide. Ammonia-ammonium chloride buffer
Preparation of Eudragit E microspheres by solvent removal
403
( 0 5 ml) and 100 mg of eriochrome black were added and the mixture was titrated with 0.01 M disodium ethylenediaminetetra-acetateto a blue endpoint. T h e standard samples containing the physical mixture of bacampicillin, Eudragit and magnesium stearate were also prepared and the magnesium stearate content was determined. The magnesium stearate content in microspheres was calculated by comparison of the results obtained for microspheres with those obtained for the standard samples.
Journal of Microencapsulation Downloaded from informahealthcare.com by McMaster University on 11/06/14 For personal use only.
Results and discussion Microspheres loaded with bacampicillin were prepared by a solvent evaporation and solvent extraction method using three different systems of solvents. It was reported earlier that methyl acetate is partly miscible with liquid paraffin, so liquid paraffin has to be saturated with methyl acetate before the evaporation procedure (Bogataj et al. 1989). T h e flocculation of emulsive drops also occurred when the extraction process was performed; therefore the addition of methyl acetate was also necessary in this case. Consequently the diffusion of methyl acetate from the emulsive drops into continuous phase was decreased and the agglomeration of microspheres was prevented. Microspheres were prepared by a solvent extraction . method only in systems with acetone ( ~ = 2 0 . 7 )and methyl acetate ( ~ = 6 . 7 )When n-hexane was added to the system with methanol its diffusion into the emulsive droplets was hindered, since methanol is a more hydrophylic solvent ( E = 32.6). It is also assumed that the partition of methanol into the continuous phase was prevented; consequently the precipitation of the polymer in the droplets was not observed. We can therefore conclude that the solvents which are partly miscible with liquid paraffin could be used for the preparation of microspheres by solvent evaporation and solvent extraction methods if liquid paraffin is saturated with the solvent before the microencapsulation procedure. When preparing the microspheres by a solvent extraction method in liquid paraffin the solvents should not be too hydrophilic; the upper limit for their dielectric constant is between 20 and 30. All products obtained were free-flowing powders; no agglomeration of particles was observed. T h e yields of the procedures were high for all types of microspheres: 80% for the methanol microspheres prepared by the evaporation method, 85-95% for acetone and 100% for methyl acetate microspheres. T h e yields for acetone and methyl acetate microspheres did not differ between the methods used for preparation. T h e particle size of microspheres was determined by sieve analysis. As shown in figure 1 the average size is influenced mostly by the type of solvent. T h e influence of the method is less important and depends on the solvent used. Temperature of evaporation and rate of unsolvent adding do not affect the average size of microspheres. We assume that the lipophilicity of the solvent greatly influences particle size of microspheres. After bacampicillin containing Eudragit E solution was added in liquid paraffin the solvent diffused from the emulsive droplets into liquid paraffin. T h e diffusion of the solvent, and consequently the precipitation of the polymer at the droplet surface, is faster when a more lipophilic solvent is used. T h e emulsive droplets with precipitated polymer on their surface cannot be dispersed to smaller size by stirring, and microspheres with higher particle size are obtained. T h e influence of lipophilicity (dielectric constant) of the solvent on the particle size of microspheres is shown in figure 2. Other parameters that influence the particle size of microspheres are viscosity and surface tension of the solvent, as well as the presence
M. Bogataj et al.
404
NMAl2 *TMALO
700600500
-
Journal of Microencapsulation Downloaded from informahealthcare.com by McMaster University on 11/06/14 For personal use only.
m-
40 6
50
@
33
60
T of evaporation i0c 1 R a t e o f umolvent adding ( m l .rnin-I 1
Figure 1. Influence of different processing parameters on the particle size of microspheres.
dl urn 1 7w I
400-
300200100-
4
Figure 2.
I
,
8
I
,
I2
I
I
16
TM4O I
1
20
I
I
24
L
I
28
I
,
32
I
36
Influence of dielectric constant ( E ) of the solvent on the particle size of microspheres.
of undissolved bacampicillin particles in acetone and methyl acetate. Additionally sieve analysis showed that the particle sizes of microspheres follows log-normal distribution in all systems. Scanning electron microscopy was used for observation of the shape of microspheres. Microspheres prepared by a solvent evaporation method in systems with acetone and methyl acetate were all of regular spherical shape. T h e surface of all other microspheres was folded. Both parameters, particle size and shape of microspheres, affect surface area; consequently an influence on biopharmaceutic properties can be expected. Scanning electron micrographs are shown in figure 3.
Journal of Microencapsulation Downloaded from informahealthcare.com by McMaster University on 11/06/14 For personal use only.
Figuire 3 . Scanning electron micrographs of microspheres prepared in methyl acetate by solvent evaporation (a) and by the solvent extraction method ( b ) , in acetone b y evaporation (c) and extraction ( d )and in methanol by the evaporation method ( e ) .
406
Journal of Microencapsulation Downloaded from informahealthcare.com by McMaster University on 11/06/14 For personal use only.
Table 2.
Preparation of Eudragit E microspheres by solvent removal Magnesium stearate content in microspheres (%) and standard deviations (SD). Sample
Percentage of Mg stearate
SD
TA40 TA50 TA60 TMA40 TM40
3.95 3.10 2.48 3.77 3.39
0.21 0.52 0.66 0.44 0.07
NA60 NA12 NA6 NMAl2
4.55 491 476 469
0.13 0.08 0.29 0.1 5
T h e influence of method, solvent and processing conditions on magnesium stearate content in microspheres was also investigated. Magnesium stearate was used to prevent agglomeration of microspheres. T h e quantity of magnesium stearate used for the preparation of microspheres was equal in all systems, but the quantity of magnesium stearate incorporated in microspheres depended on the different processing conditions, as shown in table 2 . T h e magnesium stearate content in microspheres prepared by a solvent extraction method at room temperature is the highest, and is not dependent on type of solvent or rate of unsolvent adding. Microspheres prepared by the solvent evaporation method contain less magnesium stearate; magnesium stearate content in these microspheres is decreased by raising the temperature of evaporation. We assume that the sohbility of magnesium stearate in liquid paraffin is increased at higher temperatures; therefore less magnesium stearate is incorporated into microspheres. Solvent evaporation and solvent extraction methods used for the preparation of Eudragit E microspheres with bacampicillin hydrochloride proved to be efficient methods from the technological point of view. T h e success of the procedures depends mostly on the lipophilicity of the solvent. T h e technological properties of the resulting microspheres are influenced greatly by the method and the system of solvents used for preparation. Future studies will investigate the influence of preparation procedures on microsphere biopharmaceutic properties.
References RODMEIER,R., and MCGINITY, J. W., 1987, Polylactic acid microspheres containing quinidine base and quinidine sulphate prepared by the solvent evaporation technique. 11. Some process parameters influencing the preparation and properties of microspheres. Journal of Microencapsulatiun, 4, 289-297. BODMEIER, R., and MCGINITY, J. W., 1988, Solvent selection in the preparation of PO~Y(DLlactide) microspheres prepared by solvent evaporation method. International Journal of Pharmaceutics, 43, 179-186. BOGATAJ, M., MRHAR, A., KRIsrL, A., and KOZJEK, F., 1989, Preparation and evaluation of Eudragit E microspheres containing bacampicillin. Drug Development and Industrial Pharmacy, 15, 2295-2313. GOTO, S., KAWATA, M., NAKAMURA, M., MAEKAWA, K., and AOYAMA, T., 1986 a, Eudragit RS and R L (acrylic resins) microcapsules as pH insensitive and sustained release preparations of ketoprofen. Journal of Microencapsulation, 3, 293-304. COTO, s.,KAWATA, h/2., NAKARKJRA,M., MABKAWA, K . , and AOYAILIA, T., 1986 b, Eudragit E, L and S (acrylic resins) microcapsules as pH sensitive release preparations of ketoprofen. Journal of Microencapsulation, 3, 305-3 16. SATO, T., KANKE, M., SCHROEDER, H. G., and DELUCA, P. P., 1988, Porous biodegradable microspheres for controlled drug delivery. I. Assessment of processing conditions and solvent removal techniques. Pharmaceutical Research, 5, 21-30.
1991, VOL. 8, NO, 3, 401-406
Eudragit E microspheres containing bacampicillin: preparation by solvent removal methods M. BOGATAJ, A. MRHAR, A. KRISTL and F. KOZJEK Faculty of Natural Sciences and Technology, Department of Pharmacy, University of Ljubljana, ASkerEeva 9, 61000 Ljubljana, Yugoslavia
Journal of Microencapsulation Downloaded from informahealthcare.com by McMaster University on 11/06/14 For personal use only.
(Received 1 February 1991; accepted 19 February 1991)
Eudragit E microspheres containing bacampicillin hydrochloride were prepared by solvent evaporation and solvent extraction methods. Three different systems of solvents were used: methyl acetate, acetone and methanol/liquid paraffin. The success of the procedures depended mostly on the lipophilicity of the solvent. The particle size of microspheres was determined by sieve analysis. The results showed that the average size of microspheres is influenced greatly by the type of solvent. Scanning electron microscopy was used for observation of the shape of microspheres. Microspheres prepared by the solvent evaporation method in systems with acetone and methyl acetate were all of a regular spherical shape. The surface of all other microspheres was folded. The influence of magnesium stearate content in microspheres was also studied in terms of different methods, solvents and processing conditions.
Introduction Solvent removal methods are used frequently for the preparation of microspheres in laboratory conditions; the most important are the solvent evaporation and solvent extraction methods. Although these procedures are very simple, many variables can influence the physicochemical and biopharmaceutic properties of the final product. T h e influence of the type of organic solvent, temperature, polymer and drug concentration, surfactant type and concentration, etc. is described in literature (Bodmeier and McGinity 1987,1988, Sat0 et al. 1988). When applying one of these methods the following systems of solvents are most widely used: water/methylene chloride, usually for the preparation of polylactide microspheres (Bodmeier and McGinity 1987) and liquid paraffin/acetone (Goto et al. 1986 a, b). In our laboratory microspheres with bacampicillin hydrochloride were prepared using Eudragit E as polymer and the solvents acetone, methyl acetate and methanol/liquid paraffin. We have recently reported the preparation of microspheres by solvent evaporation method (Bogataj et al. 1989). In the present work the preparation of microspheres by the solvent extraction method is represented and compared to the evaporation procedure. T h e influence of the method, the system of solvents, the temperature of evaporation and the rate of unsolvent adding on the properties of the final product are described.
Experimental Materials Bacampicillin hydrochloride was supplied by Lek, Ljubljana, Yugoslavia (quality corresponds to USP XXI). Eudragit E was purchased from Rohm Pharma, Darmstadt, Germany and magnesium stearate from Merck, Darmstadt, Germany. Solvents were all of analytical grade. 0265-2048/91 $3.00 0 1991 Taylor & Francis Ltd.
M . Bogataj et al.
402
Journal of Microencapsulation Downloaded from informahealthcare.com by McMaster University on 11/06/14 For personal use only.
Table 1 . The signatures of the samples and conditions of preparation of microspheres. Sample
Method
Solvent
Temperature of evaporation; rate of unsolvent adding
TA40 TA50 TA60 TMA40 TM40
Solvent evaporation Solvent evaporation Solvent evaporation Solvent evaporation Solvent evaporation
Acetone Acetone Acetone Methyl acetate Methanol
40°C 50°C 60°C 40°C 40°C
NA60 NA12 NA6 NMA12
Solvent extraction Solvent extraction Solvent extraction Solvent extraction
Acetone Acetone Acetone Methyl acetate
60 ml min12 ml min6 mlmin-' 12 ml min-
'
Preparation of microspheres Eudragit E (3.2g) was dissolved completely in 10.4ml of the solvent (methanol, acetone or methyl acetate) and 0-3g of magnesium stearate was added; 1.6g of bacampicillin was dispersed separately in 10.4 ml of the same solvent previously cooled to 5"C, and this dispersion was added to Eudragit solution. T h e mixture obtained was stirred at 5°C for 10min and then poured slowly with stirring (250 rpm) into 80 ml of liquid paraffin. T h e solvent was removed by evaporation or by extraction with n-hexane. T h e temperature of evaporation was 40,50 or 60°C and the rate of unsolvent adding 6, 12 or 60 ml min- Microspheres were separated by filtration, washed with n-hexane and dried at room temperature under reduced pressure overnight. T h e signatures of the samples and the conditions of preparation are shown in' table 1. Sieve analysis Particle size distribution was determined by sieve analysis. Apparatus Vibrations-Priifsiebmaschine Thyr 2, Germany, was used. We chose screens with different mesh sizes and the chi-square test for log-normal distribution of particles was performed subsequently. We used 3 g samples and a sifting time of 10 min. T h e procedure was carried out twice for each product. Electron microscopy Surface characteristics were examined by means of a scanning electron microscope. T h e microspheres were coated with C Au/Pd using a vacuum evaporator (Jeol). Samples were examined with a scanning electron microscope (Jeol SM2) at accelerating voltage 10 kV using a secondary electron technique. Tilt was 45" and working distance 12 mm.
+
Determination of magnesium stearate content T h e method according to N F XVI was modified and used for determination of magnesium stearate content in microspheres. An appropriate amount of microspheres containing approximately 5 mg of magnesium stearate was accurately weighed and boiled with 10 ml of 0.1 N sulphuric acid. During 30-40 min of boiling, stearic acid separated as a clear layer and the resulting emulsion was cooled and neutralized with 1 N sodium hydroxide. Ammonia-ammonium chloride buffer
Preparation of Eudragit E microspheres by solvent removal
403
( 0 5 ml) and 100 mg of eriochrome black were added and the mixture was titrated with 0.01 M disodium ethylenediaminetetra-acetateto a blue endpoint. T h e standard samples containing the physical mixture of bacampicillin, Eudragit and magnesium stearate were also prepared and the magnesium stearate content was determined. The magnesium stearate content in microspheres was calculated by comparison of the results obtained for microspheres with those obtained for the standard samples.
Journal of Microencapsulation Downloaded from informahealthcare.com by McMaster University on 11/06/14 For personal use only.
Results and discussion Microspheres loaded with bacampicillin were prepared by a solvent evaporation and solvent extraction method using three different systems of solvents. It was reported earlier that methyl acetate is partly miscible with liquid paraffin, so liquid paraffin has to be saturated with methyl acetate before the evaporation procedure (Bogataj et al. 1989). T h e flocculation of emulsive drops also occurred when the extraction process was performed; therefore the addition of methyl acetate was also necessary in this case. Consequently the diffusion of methyl acetate from the emulsive drops into continuous phase was decreased and the agglomeration of microspheres was prevented. Microspheres were prepared by a solvent extraction . method only in systems with acetone ( ~ = 2 0 . 7 )and methyl acetate ( ~ = 6 . 7 )When n-hexane was added to the system with methanol its diffusion into the emulsive droplets was hindered, since methanol is a more hydrophylic solvent ( E = 32.6). It is also assumed that the partition of methanol into the continuous phase was prevented; consequently the precipitation of the polymer in the droplets was not observed. We can therefore conclude that the solvents which are partly miscible with liquid paraffin could be used for the preparation of microspheres by solvent evaporation and solvent extraction methods if liquid paraffin is saturated with the solvent before the microencapsulation procedure. When preparing the microspheres by a solvent extraction method in liquid paraffin the solvents should not be too hydrophilic; the upper limit for their dielectric constant is between 20 and 30. All products obtained were free-flowing powders; no agglomeration of particles was observed. T h e yields of the procedures were high for all types of microspheres: 80% for the methanol microspheres prepared by the evaporation method, 85-95% for acetone and 100% for methyl acetate microspheres. T h e yields for acetone and methyl acetate microspheres did not differ between the methods used for preparation. T h e particle size of microspheres was determined by sieve analysis. As shown in figure 1 the average size is influenced mostly by the type of solvent. T h e influence of the method is less important and depends on the solvent used. Temperature of evaporation and rate of unsolvent adding do not affect the average size of microspheres. We assume that the lipophilicity of the solvent greatly influences particle size of microspheres. After bacampicillin containing Eudragit E solution was added in liquid paraffin the solvent diffused from the emulsive droplets into liquid paraffin. T h e diffusion of the solvent, and consequently the precipitation of the polymer at the droplet surface, is faster when a more lipophilic solvent is used. T h e emulsive droplets with precipitated polymer on their surface cannot be dispersed to smaller size by stirring, and microspheres with higher particle size are obtained. T h e influence of lipophilicity (dielectric constant) of the solvent on the particle size of microspheres is shown in figure 2. Other parameters that influence the particle size of microspheres are viscosity and surface tension of the solvent, as well as the presence
M. Bogataj et al.
404
NMAl2 *TMALO
700600500
-
Journal of Microencapsulation Downloaded from informahealthcare.com by McMaster University on 11/06/14 For personal use only.
m-
40 6
50
@
33
60
T of evaporation i0c 1 R a t e o f umolvent adding ( m l .rnin-I 1
Figure 1. Influence of different processing parameters on the particle size of microspheres.
dl urn 1 7w I
400-
300200100-
4
Figure 2.
I
,
8
I
,
I2
I
I
16
TM4O I
1
20
I
I
24
L
I
28
I
,
32
I
36
Influence of dielectric constant ( E ) of the solvent on the particle size of microspheres.
of undissolved bacampicillin particles in acetone and methyl acetate. Additionally sieve analysis showed that the particle sizes of microspheres follows log-normal distribution in all systems. Scanning electron microscopy was used for observation of the shape of microspheres. Microspheres prepared by a solvent evaporation method in systems with acetone and methyl acetate were all of regular spherical shape. T h e surface of all other microspheres was folded. Both parameters, particle size and shape of microspheres, affect surface area; consequently an influence on biopharmaceutic properties can be expected. Scanning electron micrographs are shown in figure 3.
Journal of Microencapsulation Downloaded from informahealthcare.com by McMaster University on 11/06/14 For personal use only.
Figuire 3 . Scanning electron micrographs of microspheres prepared in methyl acetate by solvent evaporation (a) and by the solvent extraction method ( b ) , in acetone b y evaporation (c) and extraction ( d )and in methanol by the evaporation method ( e ) .
406
Journal of Microencapsulation Downloaded from informahealthcare.com by McMaster University on 11/06/14 For personal use only.
Table 2.
Preparation of Eudragit E microspheres by solvent removal Magnesium stearate content in microspheres (%) and standard deviations (SD). Sample
Percentage of Mg stearate
SD
TA40 TA50 TA60 TMA40 TM40
3.95 3.10 2.48 3.77 3.39
0.21 0.52 0.66 0.44 0.07
NA60 NA12 NA6 NMAl2
4.55 491 476 469
0.13 0.08 0.29 0.1 5
T h e influence of method, solvent and processing conditions on magnesium stearate content in microspheres was also investigated. Magnesium stearate was used to prevent agglomeration of microspheres. T h e quantity of magnesium stearate used for the preparation of microspheres was equal in all systems, but the quantity of magnesium stearate incorporated in microspheres depended on the different processing conditions, as shown in table 2 . T h e magnesium stearate content in microspheres prepared by a solvent extraction method at room temperature is the highest, and is not dependent on type of solvent or rate of unsolvent adding. Microspheres prepared by the solvent evaporation method contain less magnesium stearate; magnesium stearate content in these microspheres is decreased by raising the temperature of evaporation. We assume that the sohbility of magnesium stearate in liquid paraffin is increased at higher temperatures; therefore less magnesium stearate is incorporated into microspheres. Solvent evaporation and solvent extraction methods used for the preparation of Eudragit E microspheres with bacampicillin hydrochloride proved to be efficient methods from the technological point of view. T h e success of the procedures depends mostly on the lipophilicity of the solvent. T h e technological properties of the resulting microspheres are influenced greatly by the method and the system of solvents used for preparation. Future studies will investigate the influence of preparation procedures on microsphere biopharmaceutic properties.
References RODMEIER,R., and MCGINITY, J. W., 1987, Polylactic acid microspheres containing quinidine base and quinidine sulphate prepared by the solvent evaporation technique. 11. Some process parameters influencing the preparation and properties of microspheres. Journal of Microencapsulatiun, 4, 289-297. BODMEIER, R., and MCGINITY, J. W., 1988, Solvent selection in the preparation of PO~Y(DLlactide) microspheres prepared by solvent evaporation method. International Journal of Pharmaceutics, 43, 179-186. BOGATAJ, M., MRHAR, A., KRIsrL, A., and KOZJEK, F., 1989, Preparation and evaluation of Eudragit E microspheres containing bacampicillin. Drug Development and Industrial Pharmacy, 15, 2295-2313. GOTO, S., KAWATA, M., NAKAMURA, M., MAEKAWA, K., and AOYAMA, T., 1986 a, Eudragit RS and R L (acrylic resins) microcapsules as pH insensitive and sustained release preparations of ketoprofen. Journal of Microencapsulation, 3, 293-304. COTO, s.,KAWATA, h/2., NAKARKJRA,M., MABKAWA, K . , and AOYAILIA, T., 1986 b, Eudragit E, L and S (acrylic resins) microcapsules as pH sensitive release preparations of ketoprofen. Journal of Microencapsulation, 3, 305-3 16. SATO, T., KANKE, M., SCHROEDER, H. G., and DELUCA, P. P., 1988, Porous biodegradable microspheres for controlled drug delivery. I. Assessment of processing conditions and solvent removal techniques. Pharmaceutical Research, 5, 21-30.
