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Microencapsulation of Drugs with Aqueous Colloidal Polymer Dispersions
Microencapsulation of Drugs with Aqueous Colloidal Polymer Dispersions ROLAND60DMElERX AND JIJUN WANG Received December 23, 1991, from the College of Pharmacy, The University of Texas at Austin, Austin, T X 78712-1074. publication June 29, 1992. Abstract 0 Sustained-release polymer particles containing drugs with various solubility characteristics (ibuprofen, theophylline, guaifenesin, and pseudoephedrine HCI) were prepared with colloidal polymer dispersions in a completely aqueous environment as an alternative to conventional microencapsulation techniques, which use organic solvents. Spherical particles were prepared by spraying or dropping dilute sodium alginate solutions (0.67%, whrv) containing the dissolved or dispersed drug and colloidal polymer particles into calcium chloride solutions. The gelled particles, which formed by ionotropic gelation of the polysaccharide with calcium ions, were dried and cured at 60 "C to cause fusion of the colloidal polymer particles into a homogeneous matrix system.Actual drug contents close to 50%and encapsulation efficienciesof between 80 and 98% were achieved with all drugs. Guaifenesin and ibuprofen acted as plasticizers for the ethyl cellulose pseudolatex, whereas with theophylline and pseudoephedrine HCI, dibutyl sebacate had to be added as a plasticizer to yield a nondisintegrating polymer matrix. The stirring time before separation of the particles from the gelation medium had to be minimized with the water-soluble drugs to maximize drug loading; however, it was not critical with the water-insoluble drugs. Drug release was a function of the solubility of the drug, drug loading, and the type of polymer dispersion used.
Accepted for
propyl methylcellulose with water-insoluble polymers in the form of colloidal polymer dispersions and a subsequent curing step to induce the fusion of colloidal polymer particles into a homogeneous matrix. In this paper, the term latex is used synonymously for colloidal polymer dispersions without further distinction between true latexes or pseudolatexes.
Experimental Section
Materials-The following materials were used as received from commercial suppliers: calcium chloride, guaifenesin, ibuprofen, pseudoephedrine HCI, and sodium alginate (accordingto the supplier, the viscosity of a 2% aqueous solution at 25 "C was 3500 cps; (allfrom Sigma Chemical Co., St. Louis, MO); theophylline (Boehringer Ingelheim, Ingelheim, Germany); chitosan [Protan Laboratories, Redmond, WA, according to the supplier, the viscosity of a 1% (w/w) solution in 1% (v/v) acetic acid at 25 "Cwas 2790 cps, and the degree of deacetylation was 80.4%1; E t h e l STD 10 Premium (ethyl cellulose; Dow Chemical Co., Midland, MI); dibutyl sebacate (Eastman Kodak Co., Rochester, NY); Aquacoat (ethyl cellulose; FMC Corp., Newark, DE); Surelease (ethyl cellulose; Colorcon Inc., West Point, PA); and Eudragit L 30D [poly(methacrylic acid-ethyl aaylate)l, Eudragit NE 30D [poly(ethyl acrylate-methyl methacrylate)], and Eudragit RS 30D or RL 30D [poly(ethyl acrylatemethyl methacrylate-trimethylammonioethyl methacrylate chloride)] (allfrom Riihm Microencapsulation techniques based on water-insoluble Pharma, Darmstadt, Germany). polymer carriers (e.g., solvent evaporation or organic phase Preparation of Microparticles-The drug (0.51g) was dissolved or separation methods) require organic solvents to solubilize the dispersed in an aqueous solution of sodium alginate t2 g; 2% (w/w)l polymers.1-3 However, the safety hazards, toxicity, and high and added to the polymer dispersion [4 g; 30 % (w/w) solids, including 20% (w/w) plasticizer, based on polymer solids, if required]. The costs associated with organic solvents make the use of organic drug-containing particles were formed by dropping the bubble-free solvent-free systems desirable. These concerns led to the dispersions through a disposable syringe into gently agitated calcium objective of this study: to entrap drugs with various solubility chloride [1% (w/w)] solutions (40 mL). The gelled beads were sepacharacteristics within water-insoluble polymers in an aquerated after 1-2 min by filtration, rinsed with distilled water, and ous, organic solvent-free environment. dried under vacuum at 60 "C for 12 h. The 18/20US.standard screen Aqueous colloidal polymer dispersions (latexes or pseudolasize fraction was used for further studies. texes) have been developed to replace organic solvents in the The followingformulation and process variables were investigated: coating of solid dosage forms with water-soluble palymers.4~~ (1)concentration of sodium alginate L0.17,0.34, and 0.67% (w/w) in During the coating and drying process, the colloidal polymer the aqueous sodium alginate-latex-drug mixture, corresponding to 0.57, 1.14,and 2.29% (w/w) total solids], (2)drug content [10-50% particles coalesce and fuse into a homogeneous film.- In this (w/w),in 10% increments; the amount of polymer was kept constantl, study, the preparation of drug-containing microparticles was (3) the stirring time before separation of the gelled particles (1,2.5, based on this principle of coalescence of colloidal polymer 5,10,30, and 60 min), (4) the volume of the external calcium chloride particles. (10, 25, 50, and 100 mL), (5) different types of polymer phase The microparticles were prepared without organic solvents dispersions (Aquacoat,Surelease, and Eudragit NE 30D, L 30D, or Rs by use of water-insoluble polymers in the form of aqueous 30D or RL 30D), and (6)different drugs (guaifenesin, ibuprofen, colloidal dispersions and ionotropic gelation of the anionic pseudoephedrine HCI, and theophylline). The theoretical drug conpolysaccharide sodium alginate with oppositely charged caltent of these formulations was 30% (w/w) unless stated otherwise. cium ions to form the microparticles. Dilute solutions of The drug content of the beads was determined spectrophotometrically afterextractingand dissolving the beads in methanol (ibuprofen charged polysaccharides such as sodium alginate or chitosan at 221 nm, theophylline at 273 nm, guaifenesin at 272 nm, and form gelled particles when sprayed into solutions of counter pseudoephedrine HC1at 256 nm). Allmicroparticles were prepared in ions such as calcium or tripolyphosphate.gJO In a previoud duplicate. The reproducibility of the method was excellent; generally, study, a sustained-release multiple-unit delivery system were observed between the two differences in drug content of ~ 0 . 5 % based on the water-soluble carrier hydroxypropyl methylcelreplicates. lulose was prepared by injecting dispersions of drugs in Solubility Study-The solubility of each drug in a calcium chloride heated aqueous hydroxypropyl methylcellulose containing solution [I% (w/v)] was determined by adding excess drug to the sodium alginate into calcium chloride solutions and then medium-containing vials and shaking the vials in a constantdrying the gelled droplets.11The same principle was used in temperature water bath for 3 days [22"C;n = 2;model 127 shaker this study, the differences being the replacement of hydroxywater bath (Fisher Co., Pittsburgh, Pa.)]. The samples were filtered, 0022-3549/93/0200-0191$02.50/0 0 1993, American Pharmaceutical Association
Journal of Pharmaceutical Sciences1 191 Vol. 82, No. 2, February 1993
diluted with water, if necessary, and assayed spectrophotometrically. Dissolution Study-The USP XXI rotating-paddle method KO.10.5 g of beads; 37 "C; 50 rpm; 500 mL of 0.1 M (pH 7.4) phosphate buffer; n = 3; coefficient of variation, <5%] was used to study drug release from the polymer microparticles.Two milliliter samples were withdrawn at specified time intervals and assayed by W spectrophotometry. The drug content of the particles obtained after dissolution studies and the amount of drug released matched the original drug content to within 5%.
Results and Discussion To prepare polymer microparticles in a n organic solventfree environment, we dropped a mixture of a colloidal polymer dispersion, dissolved drug (guaifenesin and pseudoephedrine HCl) or dissolved, dispersed drug (ibuprofen and theophylline), and sodium alginate into solutions of calcium chloride. The droplets instantaneously formed gelled spheres through the interaction of sodium alginate with calcium ions. Smaller particles could be prepared by forcing the mixture with compressed air through a nozzle into the gelation medium.12 The droplet size could be varied by adjusting the air pressure. The gelled particles were separated and dried. The colloidal polymer particles fused into a polymer matrix during drying and water removal, with the drug being dissolved or dissolved and dispersed in the latex. Various colloidal polymer dispersions that are commercially available for pharmaceutical applications were evaluated as carrier materials for ibuprofen, theophylline, guaifenesin, and pseudoephedrine HCl (Table I). Actual loadings were close to the theoretical loading of 30%, with encapsulation efficiencies 1100% x (actual drug loadinghheoretical drug 10ading)l being mostly >go%. Drug loading was not affected by the dispersion selected, except with Eudragit L 30D, as indicated by similar drug loadings. The polymer dispersions studied were based on either cellulosic (Aquacoat and Surelease) or acrylic (Eudragit NE 30D, Eudragit RS 30D or RL 30D, and Eudragit L 30D) polymers. A prerequisite for the successful preparation of the particles was the compatibility among the polymer dispersion, the drug, and sodium alginate. Colloidal polymer dispersions are stabilized against premature flocculation and coalescence or settling during storage by either anionic or nonionic surfactants or by charged groups present in polymer side chains. The colloidal polymer particles had to be neutral or negatively charged to be compatible with the negatively charged sodium alginate. The ethyl cellulose dispersions Aquacoat and Surelease are stabilized with the anionic surfactants sodium lauryl sulfate and ammonium oleate, respectively, and Eudragit NE 30D, latex is stabilized with nonionic surfactants; hence, these dispersions were compatible with sodium alginate. On the contrary, Eudragit RS 30D and RL 30D latexes are stabilized by quaternary ammonium groups present on the polymer side chains. The addition of sodium alginate to these latexes resulted in immediate flocculation or precipitation and no particle formation after injection of these dispersions into calcium chloride solutions. Beads could be formed with the cationic Eudragit RS 30D and RL 30D latexes when sodium alginate and calcium chloride were replaced with chitosan, a Table 1-Actual
cationic polysaccharide, and tripolyphosphate as the gelling system.10 Besides polymer dispersion-polysaccharide incompatibilities, interactions between the drug and dispersion or the drug and sodium alginate could also affect this microencapsulation method. For example, the addition of chlorpheniramine maleate, a cationic drug, to the sodium alginate solution caused the formation of a n insoluble complex, and particles could not be formed by ionotropic gelation. In contrast, pseudoephedrine HCI did not result in an insoluble complex, possibly because of its higher water solubility. Various formulation and process variables were investigated to maximize the drug loading of the polymer particles. The effect of theoretical drug loading [lo-50% (w/w)] on actual drug loading and encapsulation efficiency is shown in Figure 1.As expected, actual loading increased with increasing theoretical loading. The actual loading was close to the theoretical loading for ibuprofen and theophylline, which are insoluble and moderately soluble in water, respectively. The encapsulation efficiency was almost independent of the theoretical loading, except for a slight decrease with pseudoephedrine HCl particles with increasing theoretical loading, possibly because of the high solubility or osmotic effects of this drug (Figure 1B). A constant drug fraction was lost from the gelled particles to the external aqueous phase before separation, resulting in similar encapsulation efficiencies at different theoretical loadings. Guaifenesin loading was insensitive to the volume of the external calcium chloride phase and the concentration of sodium alginate in the range investigated. Saturation of the external aqueous phase with drug was not a factor, because the amount of drug dropped or sprayed into the gelation medium was small compared with the amount of drug soluble in the external aqueous phase. Sufficiently strong, gelled beads were obtained at all sodium alginate concentrations evaluated. The beads did not rupture during separation from the external aqueous phase during filtration. The three concentrations tested corresponded to solids contents of only 0.57,1.14, and 2.29%(wlw)in the microparticles. The amount of sodium alginate in the microparticles (assuming no diffusion of sodium alginate into the external CaC1, solution) was minimal. The only purpose for the inclusion of the polysaccharide was for the formation of the microparticles. Drug loading as a function of stirring time before separation of the particles from the gelation medium for ibuprofen, theophylline, guaifenesin, and pseudoephedrine HC1is shown in Figure 2. The loading depended on the solubility of the drug in the external aqueous phase, and the stirring time became more critical with drugs that were more soluble in the gelation medium. The actual loading was close to the theoretical loading (30%) for ibuprofen, a water-insoluble drug, but decreased as a function of time for the water-soluble drugs pseudoephedrine HCl and guaifenesin. The rank order in drug loading corresponded to solubility of the drug in 1%(wlv) calcium chloride solution, with pseudoephedrine HC1 (733 mg/mL) having the highest solubility and being followed by guaifenesin (46 mg/mL), theophylline (8.8 mg/mL), and ibu-
Drug Loading (Encapsulatlon Efliciency) 01 Drugs Encapsulated with Different Colloidal Polymer Dispersions'
Drug
Ibuprofen Theophylline Guaifenesin Pseudoephedrine HCI
% Actual Drug
Aquacoat
Surelease
29.4 (98.0) 29.0 (96.7) 27.1 (90.3) 25.1 (83.7)
29.2 28.5 27.6 26.9
(97.3) (95.0) (92.0) (89.7)
Thirty percent theoretical loading. Eudragit. -, No particle formation. 192 I Journal of Pharmaceutical Sciences Vol. 82, No. 2, February 1993
Loading (Encapsulation Efficiency) with: NE 30Db
L 30Db
28.3 (94.3) 28.8 (96.0) 27.3 (91.O) 26.9 (89.6)
25.5 (85.0) 26.6 (88.7)
-
24.5 (81.7)
RL 30D or RS 30Db
1
0
I
1
30
40
50
30
I0
1
I
10
20
theoretical drug loading, %
0
20
10
theoretical drug loading, %
50
Flgure 1-Effect of theoretical drug loading on actual drug loading (A) and encapsulation efficiency (6)of ethyl cellulose (Aquacoat)microparticles. Key: (U) ibuprofen; (0)theophylline; (A)guaifenesin;(A) pseudoephedrine HCI.
"1
coat) microparticles (plasticized in the case of pseudoephedrine HCl and theophylline) in 0.1 M (pH 7.4) phosphate buffer is shown in Figure 3.Again, the rank order in drug release corresponded to the solubility of the drug in the dissolution medium, with pseudoephedrine HCl having the highest solubility and hence the fastest release. The particles were initially prepared without the addition of plasticizers. The latexes, which have a minimum film formation temperature above the drying temperature, generally required the addition of a plasticizer to induce fusion of the colloidal polymer particles into a nondisintegrating matrix during oven drying. Pseudoephedrine HCl and theophylline microparticles prepared without a plasticizer disintegrated rapidly. Dibutyl sebacate had to be added as a plasticizer [20% (w/w), based on polymer solids] to enhance the fusion of the colloidal polymer particles into nondisintegrating microparticles. In contrast, guaifenesin and ibuprofen microparticles did not disintegrate, even without the use of a plasticizer, indicating a plasticizing effect of the drugs on the polymer. The plasticization was probably aided by the low melting point of the drugs. The plasticizing action wm confirmed with a simple mechanical test (bending between fingers) on solvent-cast ethyl cellulose-drug films (ethyl cellulose, 350 mg; drug, 150 mg; acetone, 7 mL; cast into an aluminum dish). Guaifenesin and ibuprofen films were flexible and clear (the drugs were dissolved in the polymer), while pseudoephedrine HC1 and theophylline films were very brittle and opaque, with visible drug crystals on the film surface, indicating little polymerdrug compatibility. The release of theophylline from microparticles prepared from different polymer dispersions is shown in Figure 4. Surelease is a preplasticized ethyl cellulose dispersion, and Eudragit NE 30D has a minimum film formation temperature below room temperature; they did not require the addition of plasticizers. Eudragit L 30D is based on an enteric acrylic polymer; rapid drug release with this polymer dispersion could be explained by the dissolution and disintegration of the microparticles in pH 7.4 buffer. The trend in release profiles seen with theophylline was also seen with the other drugs. Drug release also increased with increasing drug loading (data not shown). Some of the investigated polymer dispersions contain high levels of surfactants (e.g., Aquacoat contains 4% sodium lauryl sulfate, relative to ethyl cellulose). The presence of these surfactants in the particles certainly enhanced drug release, and a reduction in release probably could have been obtained with lower levels of surfactants or different stabilizers (e.g., stabilizers of a polymer nature). In conclusion, sustained-release particles containing waterloo
8 0
0
10
20
30
40
50
60
stirring time, min Flgure 2-Effect of stirring time before separation of the particles from the external aqueous phase on the drug loading of ethyl cellulose (Aquacoat) microparticles. Key: (H) ibuprofen; (0)theophylline; (A) guaifenesin; (A) pseudoephedrine HCI.
CI)
225
U
0
profen (0.07 mg/mL). The contact or stirring time therefore was not critical with water-insoluble drugs but had to be kept to a minimum to maximize drug loading with water-soluble drugs. The release of the four drugs from ethyl cellulose (Aqua-
0
2
I
time, hours
8
Figure %Drug release from ethyl cellulose (Aquacoat)microparticles in 0.1 M (pH 7.4) phosphate buffer. Key: (H) pseudoephedrine HCI; (0) guaifenesin; (A)theophylline; (A) ibuprofen. Journal of PharmaceuticalSciences I 193 Vol. 82, No. 2, February 7993
efficiencies. Considering the final dosage form, the particles could be administered as prepared, be placed in capsules, or possibly compressed into tablets.
bp
i 1 E 0
References and Notes 1. Deaay, P. B. Microencapsulation and Related Drug Processes; Marcel Dekker: New York, 1984.
2. Kondo, A. Microcapsule h c e s s i n g and Technology; Marcel Dekker: New York, 1979. 3. Bodmeier, R.; Chen, H. J. Controlled Release 1991, 15, 65-77. 4. Lehmann, K.0. R. In. ueous Pol meric Coatin s or Pharmaceutical Aoolzcatzons: M%initv... J. . Ed.:, Marce5 Ifekker: New York, 1986; pp 153-245. 5. Steuernagel, C. R. In Aqueous Polymeric Coatings for Pharmaceutical Applicaizons; McGinity, J. W., Ed.; Marcel Dekker: New York, 1989; pp 1-61. 6. Vanderhoff,J. W. J.Polym. Sci. Polym. Symp. 1973,41,155-174. 7. Kast, H. Makromol. Chem. Suppl. 1985,10l11,447461. 8. Bodmeier, R.; Paeratakul, 0. Int. J. Pharm. 1991, 70, 59-68. 9. Lim, F. In Biomedical Ap lications of Microencapsulation; Lim, F., Ed.; CRC Press: Boca %,aton, FL, 1984; pp 137-154. 10. Bodmeier, R.; Oh, K.-H.; Pramar, Y. Drug Dev. Id. Pharm. 1989,
f.:
I
0
2
I
I
I
8
i
8
time, h Flgure 4-Theophylline release from micropanicles prepared from different polymer dispersions in 0.1 M (pH 7.4) phosphate buffer. Key: (m) Eudragit L 30D;(0)Surelease; (A)Aquacoat; (A) Eudragit NE 30D.
soluble and water-insoluble drugs within water-insoluble polymers were prepared with colloidal polymer dispersions in a completely aqueous environment,with high encapsulation
194 I Journal of Pharmaceutical Sciences VOI.82, NO.2, February 1993
15,1475-1494. 11. Bodmeier, R.; Paeratakul, 0. Carbohydr. PoZym. 1991,16, 399-
408. 12. Bodmeier, R.; Paeratakul, 0. J. Pharm. Sci. 1989, 78, 964-967.
Accepted for
propyl methylcellulose with water-insoluble polymers in the form of colloidal polymer dispersions and a subsequent curing step to induce the fusion of colloidal polymer particles into a homogeneous matrix. In this paper, the term latex is used synonymously for colloidal polymer dispersions without further distinction between true latexes or pseudolatexes.
Experimental Section
Materials-The following materials were used as received from commercial suppliers: calcium chloride, guaifenesin, ibuprofen, pseudoephedrine HCI, and sodium alginate (accordingto the supplier, the viscosity of a 2% aqueous solution at 25 "C was 3500 cps; (allfrom Sigma Chemical Co., St. Louis, MO); theophylline (Boehringer Ingelheim, Ingelheim, Germany); chitosan [Protan Laboratories, Redmond, WA, according to the supplier, the viscosity of a 1% (w/w) solution in 1% (v/v) acetic acid at 25 "Cwas 2790 cps, and the degree of deacetylation was 80.4%1; E t h e l STD 10 Premium (ethyl cellulose; Dow Chemical Co., Midland, MI); dibutyl sebacate (Eastman Kodak Co., Rochester, NY); Aquacoat (ethyl cellulose; FMC Corp., Newark, DE); Surelease (ethyl cellulose; Colorcon Inc., West Point, PA); and Eudragit L 30D [poly(methacrylic acid-ethyl aaylate)l, Eudragit NE 30D [poly(ethyl acrylate-methyl methacrylate)], and Eudragit RS 30D or RL 30D [poly(ethyl acrylatemethyl methacrylate-trimethylammonioethyl methacrylate chloride)] (allfrom Riihm Microencapsulation techniques based on water-insoluble Pharma, Darmstadt, Germany). polymer carriers (e.g., solvent evaporation or organic phase Preparation of Microparticles-The drug (0.51g) was dissolved or separation methods) require organic solvents to solubilize the dispersed in an aqueous solution of sodium alginate t2 g; 2% (w/w)l polymers.1-3 However, the safety hazards, toxicity, and high and added to the polymer dispersion [4 g; 30 % (w/w) solids, including 20% (w/w) plasticizer, based on polymer solids, if required]. The costs associated with organic solvents make the use of organic drug-containing particles were formed by dropping the bubble-free solvent-free systems desirable. These concerns led to the dispersions through a disposable syringe into gently agitated calcium objective of this study: to entrap drugs with various solubility chloride [1% (w/w)] solutions (40 mL). The gelled beads were sepacharacteristics within water-insoluble polymers in an aquerated after 1-2 min by filtration, rinsed with distilled water, and ous, organic solvent-free environment. dried under vacuum at 60 "C for 12 h. The 18/20US.standard screen Aqueous colloidal polymer dispersions (latexes or pseudolasize fraction was used for further studies. texes) have been developed to replace organic solvents in the The followingformulation and process variables were investigated: coating of solid dosage forms with water-soluble palymers.4~~ (1)concentration of sodium alginate L0.17,0.34, and 0.67% (w/w) in During the coating and drying process, the colloidal polymer the aqueous sodium alginate-latex-drug mixture, corresponding to 0.57, 1.14,and 2.29% (w/w) total solids], (2)drug content [10-50% particles coalesce and fuse into a homogeneous film.- In this (w/w),in 10% increments; the amount of polymer was kept constantl, study, the preparation of drug-containing microparticles was (3) the stirring time before separation of the gelled particles (1,2.5, based on this principle of coalescence of colloidal polymer 5,10,30, and 60 min), (4) the volume of the external calcium chloride particles. (10, 25, 50, and 100 mL), (5) different types of polymer phase The microparticles were prepared without organic solvents dispersions (Aquacoat,Surelease, and Eudragit NE 30D, L 30D, or Rs by use of water-insoluble polymers in the form of aqueous 30D or RL 30D), and (6)different drugs (guaifenesin, ibuprofen, colloidal dispersions and ionotropic gelation of the anionic pseudoephedrine HCI, and theophylline). The theoretical drug conpolysaccharide sodium alginate with oppositely charged caltent of these formulations was 30% (w/w) unless stated otherwise. cium ions to form the microparticles. Dilute solutions of The drug content of the beads was determined spectrophotometrically afterextractingand dissolving the beads in methanol (ibuprofen charged polysaccharides such as sodium alginate or chitosan at 221 nm, theophylline at 273 nm, guaifenesin at 272 nm, and form gelled particles when sprayed into solutions of counter pseudoephedrine HC1at 256 nm). Allmicroparticles were prepared in ions such as calcium or tripolyphosphate.gJO In a previoud duplicate. The reproducibility of the method was excellent; generally, study, a sustained-release multiple-unit delivery system were observed between the two differences in drug content of ~ 0 . 5 % based on the water-soluble carrier hydroxypropyl methylcelreplicates. lulose was prepared by injecting dispersions of drugs in Solubility Study-The solubility of each drug in a calcium chloride heated aqueous hydroxypropyl methylcellulose containing solution [I% (w/v)] was determined by adding excess drug to the sodium alginate into calcium chloride solutions and then medium-containing vials and shaking the vials in a constantdrying the gelled droplets.11The same principle was used in temperature water bath for 3 days [22"C;n = 2;model 127 shaker this study, the differences being the replacement of hydroxywater bath (Fisher Co., Pittsburgh, Pa.)]. The samples were filtered, 0022-3549/93/0200-0191$02.50/0 0 1993, American Pharmaceutical Association
Journal of Pharmaceutical Sciences1 191 Vol. 82, No. 2, February 1993
diluted with water, if necessary, and assayed spectrophotometrically. Dissolution Study-The USP XXI rotating-paddle method KO.10.5 g of beads; 37 "C; 50 rpm; 500 mL of 0.1 M (pH 7.4) phosphate buffer; n = 3; coefficient of variation, <5%] was used to study drug release from the polymer microparticles.Two milliliter samples were withdrawn at specified time intervals and assayed by W spectrophotometry. The drug content of the particles obtained after dissolution studies and the amount of drug released matched the original drug content to within 5%.
Results and Discussion To prepare polymer microparticles in a n organic solventfree environment, we dropped a mixture of a colloidal polymer dispersion, dissolved drug (guaifenesin and pseudoephedrine HCl) or dissolved, dispersed drug (ibuprofen and theophylline), and sodium alginate into solutions of calcium chloride. The droplets instantaneously formed gelled spheres through the interaction of sodium alginate with calcium ions. Smaller particles could be prepared by forcing the mixture with compressed air through a nozzle into the gelation medium.12 The droplet size could be varied by adjusting the air pressure. The gelled particles were separated and dried. The colloidal polymer particles fused into a polymer matrix during drying and water removal, with the drug being dissolved or dissolved and dispersed in the latex. Various colloidal polymer dispersions that are commercially available for pharmaceutical applications were evaluated as carrier materials for ibuprofen, theophylline, guaifenesin, and pseudoephedrine HCl (Table I). Actual loadings were close to the theoretical loading of 30%, with encapsulation efficiencies 1100% x (actual drug loadinghheoretical drug 10ading)l being mostly >go%. Drug loading was not affected by the dispersion selected, except with Eudragit L 30D, as indicated by similar drug loadings. The polymer dispersions studied were based on either cellulosic (Aquacoat and Surelease) or acrylic (Eudragit NE 30D, Eudragit RS 30D or RL 30D, and Eudragit L 30D) polymers. A prerequisite for the successful preparation of the particles was the compatibility among the polymer dispersion, the drug, and sodium alginate. Colloidal polymer dispersions are stabilized against premature flocculation and coalescence or settling during storage by either anionic or nonionic surfactants or by charged groups present in polymer side chains. The colloidal polymer particles had to be neutral or negatively charged to be compatible with the negatively charged sodium alginate. The ethyl cellulose dispersions Aquacoat and Surelease are stabilized with the anionic surfactants sodium lauryl sulfate and ammonium oleate, respectively, and Eudragit NE 30D, latex is stabilized with nonionic surfactants; hence, these dispersions were compatible with sodium alginate. On the contrary, Eudragit RS 30D and RL 30D latexes are stabilized by quaternary ammonium groups present on the polymer side chains. The addition of sodium alginate to these latexes resulted in immediate flocculation or precipitation and no particle formation after injection of these dispersions into calcium chloride solutions. Beads could be formed with the cationic Eudragit RS 30D and RL 30D latexes when sodium alginate and calcium chloride were replaced with chitosan, a Table 1-Actual
cationic polysaccharide, and tripolyphosphate as the gelling system.10 Besides polymer dispersion-polysaccharide incompatibilities, interactions between the drug and dispersion or the drug and sodium alginate could also affect this microencapsulation method. For example, the addition of chlorpheniramine maleate, a cationic drug, to the sodium alginate solution caused the formation of a n insoluble complex, and particles could not be formed by ionotropic gelation. In contrast, pseudoephedrine HCI did not result in an insoluble complex, possibly because of its higher water solubility. Various formulation and process variables were investigated to maximize the drug loading of the polymer particles. The effect of theoretical drug loading [lo-50% (w/w)] on actual drug loading and encapsulation efficiency is shown in Figure 1.As expected, actual loading increased with increasing theoretical loading. The actual loading was close to the theoretical loading for ibuprofen and theophylline, which are insoluble and moderately soluble in water, respectively. The encapsulation efficiency was almost independent of the theoretical loading, except for a slight decrease with pseudoephedrine HCl particles with increasing theoretical loading, possibly because of the high solubility or osmotic effects of this drug (Figure 1B). A constant drug fraction was lost from the gelled particles to the external aqueous phase before separation, resulting in similar encapsulation efficiencies at different theoretical loadings. Guaifenesin loading was insensitive to the volume of the external calcium chloride phase and the concentration of sodium alginate in the range investigated. Saturation of the external aqueous phase with drug was not a factor, because the amount of drug dropped or sprayed into the gelation medium was small compared with the amount of drug soluble in the external aqueous phase. Sufficiently strong, gelled beads were obtained at all sodium alginate concentrations evaluated. The beads did not rupture during separation from the external aqueous phase during filtration. The three concentrations tested corresponded to solids contents of only 0.57,1.14, and 2.29%(wlw)in the microparticles. The amount of sodium alginate in the microparticles (assuming no diffusion of sodium alginate into the external CaC1, solution) was minimal. The only purpose for the inclusion of the polysaccharide was for the formation of the microparticles. Drug loading as a function of stirring time before separation of the particles from the gelation medium for ibuprofen, theophylline, guaifenesin, and pseudoephedrine HC1is shown in Figure 2. The loading depended on the solubility of the drug in the external aqueous phase, and the stirring time became more critical with drugs that were more soluble in the gelation medium. The actual loading was close to the theoretical loading (30%) for ibuprofen, a water-insoluble drug, but decreased as a function of time for the water-soluble drugs pseudoephedrine HCl and guaifenesin. The rank order in drug loading corresponded to solubility of the drug in 1%(wlv) calcium chloride solution, with pseudoephedrine HC1 (733 mg/mL) having the highest solubility and being followed by guaifenesin (46 mg/mL), theophylline (8.8 mg/mL), and ibu-
Drug Loading (Encapsulatlon Efliciency) 01 Drugs Encapsulated with Different Colloidal Polymer Dispersions'
Drug
Ibuprofen Theophylline Guaifenesin Pseudoephedrine HCI
% Actual Drug
Aquacoat
Surelease
29.4 (98.0) 29.0 (96.7) 27.1 (90.3) 25.1 (83.7)
29.2 28.5 27.6 26.9
(97.3) (95.0) (92.0) (89.7)
Thirty percent theoretical loading. Eudragit. -, No particle formation. 192 I Journal of Pharmaceutical Sciences Vol. 82, No. 2, February 1993
Loading (Encapsulation Efficiency) with: NE 30Db
L 30Db
28.3 (94.3) 28.8 (96.0) 27.3 (91.O) 26.9 (89.6)
25.5 (85.0) 26.6 (88.7)
-
24.5 (81.7)
RL 30D or RS 30Db
1
0
I
1
30
40
50
30
I0
1
I
10
20
theoretical drug loading, %
0
20
10
theoretical drug loading, %
50
Flgure 1-Effect of theoretical drug loading on actual drug loading (A) and encapsulation efficiency (6)of ethyl cellulose (Aquacoat)microparticles. Key: (U) ibuprofen; (0)theophylline; (A)guaifenesin;(A) pseudoephedrine HCI.
"1
coat) microparticles (plasticized in the case of pseudoephedrine HCl and theophylline) in 0.1 M (pH 7.4) phosphate buffer is shown in Figure 3.Again, the rank order in drug release corresponded to the solubility of the drug in the dissolution medium, with pseudoephedrine HCl having the highest solubility and hence the fastest release. The particles were initially prepared without the addition of plasticizers. The latexes, which have a minimum film formation temperature above the drying temperature, generally required the addition of a plasticizer to induce fusion of the colloidal polymer particles into a nondisintegrating matrix during oven drying. Pseudoephedrine HCl and theophylline microparticles prepared without a plasticizer disintegrated rapidly. Dibutyl sebacate had to be added as a plasticizer [20% (w/w), based on polymer solids] to enhance the fusion of the colloidal polymer particles into nondisintegrating microparticles. In contrast, guaifenesin and ibuprofen microparticles did not disintegrate, even without the use of a plasticizer, indicating a plasticizing effect of the drugs on the polymer. The plasticization was probably aided by the low melting point of the drugs. The plasticizing action wm confirmed with a simple mechanical test (bending between fingers) on solvent-cast ethyl cellulose-drug films (ethyl cellulose, 350 mg; drug, 150 mg; acetone, 7 mL; cast into an aluminum dish). Guaifenesin and ibuprofen films were flexible and clear (the drugs were dissolved in the polymer), while pseudoephedrine HC1 and theophylline films were very brittle and opaque, with visible drug crystals on the film surface, indicating little polymerdrug compatibility. The release of theophylline from microparticles prepared from different polymer dispersions is shown in Figure 4. Surelease is a preplasticized ethyl cellulose dispersion, and Eudragit NE 30D has a minimum film formation temperature below room temperature; they did not require the addition of plasticizers. Eudragit L 30D is based on an enteric acrylic polymer; rapid drug release with this polymer dispersion could be explained by the dissolution and disintegration of the microparticles in pH 7.4 buffer. The trend in release profiles seen with theophylline was also seen with the other drugs. Drug release also increased with increasing drug loading (data not shown). Some of the investigated polymer dispersions contain high levels of surfactants (e.g., Aquacoat contains 4% sodium lauryl sulfate, relative to ethyl cellulose). The presence of these surfactants in the particles certainly enhanced drug release, and a reduction in release probably could have been obtained with lower levels of surfactants or different stabilizers (e.g., stabilizers of a polymer nature). In conclusion, sustained-release particles containing waterloo
8 0
0
10
20
30
40
50
60
stirring time, min Flgure 2-Effect of stirring time before separation of the particles from the external aqueous phase on the drug loading of ethyl cellulose (Aquacoat) microparticles. Key: (H) ibuprofen; (0)theophylline; (A) guaifenesin; (A) pseudoephedrine HCI.
CI)
225
U
0
profen (0.07 mg/mL). The contact or stirring time therefore was not critical with water-insoluble drugs but had to be kept to a minimum to maximize drug loading with water-soluble drugs. The release of the four drugs from ethyl cellulose (Aqua-
0
2
I
time, hours
8
Figure %Drug release from ethyl cellulose (Aquacoat)microparticles in 0.1 M (pH 7.4) phosphate buffer. Key: (H) pseudoephedrine HCI; (0) guaifenesin; (A)theophylline; (A) ibuprofen. Journal of PharmaceuticalSciences I 193 Vol. 82, No. 2, February 7993
efficiencies. Considering the final dosage form, the particles could be administered as prepared, be placed in capsules, or possibly compressed into tablets.
bp
i 1 E 0
References and Notes 1. Deaay, P. B. Microencapsulation and Related Drug Processes; Marcel Dekker: New York, 1984.
2. Kondo, A. Microcapsule h c e s s i n g and Technology; Marcel Dekker: New York, 1979. 3. Bodmeier, R.; Chen, H. J. Controlled Release 1991, 15, 65-77. 4. Lehmann, K.0. R. In. ueous Pol meric Coatin s or Pharmaceutical Aoolzcatzons: M%initv... J. . Ed.:, Marce5 Ifekker: New York, 1986; pp 153-245. 5. Steuernagel, C. R. In Aqueous Polymeric Coatings for Pharmaceutical Applicaizons; McGinity, J. W., Ed.; Marcel Dekker: New York, 1989; pp 1-61. 6. Vanderhoff,J. W. J.Polym. Sci. Polym. Symp. 1973,41,155-174. 7. Kast, H. Makromol. Chem. Suppl. 1985,10l11,447461. 8. Bodmeier, R.; Paeratakul, 0. Int. J. Pharm. 1991, 70, 59-68. 9. Lim, F. In Biomedical Ap lications of Microencapsulation; Lim, F., Ed.; CRC Press: Boca %,aton, FL, 1984; pp 137-154. 10. Bodmeier, R.; Oh, K.-H.; Pramar, Y. Drug Dev. Id. Pharm. 1989,
f.:
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0
2
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8
i
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time, h Flgure 4-Theophylline release from micropanicles prepared from different polymer dispersions in 0.1 M (pH 7.4) phosphate buffer. Key: (m) Eudragit L 30D;(0)Surelease; (A)Aquacoat; (A) Eudragit NE 30D.
soluble and water-insoluble drugs within water-insoluble polymers were prepared with colloidal polymer dispersions in a completely aqueous environment,with high encapsulation
194 I Journal of Pharmaceutical Sciences VOI.82, NO.2, February 1993
15,1475-1494. 11. Bodmeier, R.; Paeratakul, 0. Carbohydr. PoZym. 1991,16, 399-
408. 12. Bodmeier, R.; Paeratakul, 0. J. Pharm. Sci. 1989, 78, 964-967.