Comparison between aqueous and non-aqueous solvent evaporation methods for microencapsulation of...

12
International Journal of Pharmaceutics 173 (1998) 171 – 182 Comparison between aqueous and non-aqueous solvent evaporation methods for microencapsulation of drug – resin complexes Dolores Torres *, Lina Boado, Dolores Blanco, Jose ´ L. Vila-Jato Department of Pharmaceutical Technology, Faculty of Pharmacy, Uni6ersity of Santiago de Compostela, 15706 Santiago de Compostela, Spain Received 23 February 1998; received in revised form 18 June 1998; accepted 3 July 1998 Abstract Terbutaline-loaded ion-exchange resins were entrapped within cellulose acetate butyrate (CAB) microcapsules using either an aqueous (O/W) or a non-aqueous (O/O) solvent evaporation method. Scanning electron micrographs of the cross-sections of microcapsules prepared by both techniques revealed that the degree of multinucleation was dependent on the polymer concentration. A low polymer concentration led to a typical mononucleated reservoir structure whereas more multicore microcapsules were formed at high polymer concentrations. These differences on the inner structure affected the in vitro terbutaline release profiles. Terbutaline released very rapidly from the mononucleated microcapsules, however its release was controlled from the multinucleated systems. In addition, terbutaline release was influenced by the microencapsulation method. Using the higher CAB concentrations, the O/O technique produced microcapsules which adequately controlled the release of terbutaline; in contrast, microcapsules obtained by the O/W method showed a biphasic behaviour, with an initial burst effect followed by stabilization of the drug release, which became finally incomplete. With the aim of elucidating the main causes which were responsible for the differences in drug release, CAB films were obtained by casting the polymeric solutions prepared with the solvents used in each encapsulation procedure, acetone and methylene chloride for O/O and O/W methods, respectively. Thermal properties of the polymer in films and microcapsules were compared, and terbutaline diffusion studies through the films were performed. Results revealed that the polymer solvent was a key factor that determined the structure of the polymer wall formed, and thereby the in vitro release properties of the polymer films. After an initial rapid permeation step in both films, the CAB film cast from acetone allowed a faster permeation of terbutaline by diffusion through the pores, whereas the diffusion through the polymer chains was probably the only possible mechanism of drug release in the dense film formed from methylene chloride polymer solutions, this process being extremely slow for terbutaline. © 1998 Elsevier Science B.V. All rights reserved. Keywords: Microencapsulation; Ion-exchange resins; Controlled release; Solvent evaporation method; Cellulose acetate butyrate; Terbutaline * Corresponding author. Departamento de Farmacia y Tecnologı ´a Farmace ´utica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15706 Santiago de Compostela, Spain. Tel.: +34 981 594627; fax: +34 981 547148; e-mail: [email protected] 0378-5173/98/$ - see front matter © 1998 Elsevier Science B.V. All rights reserved. PII S0378-5173(98)00224-5

Transcript of Comparison between aqueous and non-aqueous solvent evaporation methods for microencapsulation of...

Page 1: Comparison between aqueous and non-aqueous solvent evaporation methods for microencapsulation of drug–resin complexes

International Journal of Pharmaceutics 173 (1998) 171–182

Comparison between aqueous and non-aqueous solventevaporation methods for microencapsulation of

drug–resin complexes

Dolores Torres *, Lina Boado, Dolores Blanco, Jose L. Vila-Jato

Department of Pharmaceutical Technology, Faculty of Pharmacy, Uni6ersity of Santiago de Compostela,15706 Santiago de Compostela, Spain

Received 23 February 1998; received in revised form 18 June 1998; accepted 3 July 1998

Abstract

Terbutaline-loaded ion-exchange resins were entrapped within cellulose acetate butyrate (CAB) microcapsules usingeither an aqueous (O/W) or a non-aqueous (O/O) solvent evaporation method. Scanning electron micrographs of thecross-sections of microcapsules prepared by both techniques revealed that the degree of multinucleation wasdependent on the polymer concentration. A low polymer concentration led to a typical mononucleated reservoirstructure whereas more multicore microcapsules were formed at high polymer concentrations. These differences onthe inner structure affected the in vitro terbutaline release profiles. Terbutaline released very rapidly from themononucleated microcapsules, however its release was controlled from the multinucleated systems. In addition,terbutaline release was influenced by the microencapsulation method. Using the higher CAB concentrations, the O/Otechnique produced microcapsules which adequately controlled the release of terbutaline; in contrast, microcapsulesobtained by the O/W method showed a biphasic behaviour, with an initial burst effect followed by stabilization ofthe drug release, which became finally incomplete. With the aim of elucidating the main causes which were responsiblefor the differences in drug release, CAB films were obtained by casting the polymeric solutions prepared with thesolvents used in each encapsulation procedure, acetone and methylene chloride for O/O and O/W methods,respectively. Thermal properties of the polymer in films and microcapsules were compared, and terbutaline diffusionstudies through the films were performed. Results revealed that the polymer solvent was a key factor that determinedthe structure of the polymer wall formed, and thereby the in vitro release properties of the polymer films. After aninitial rapid permeation step in both films, the CAB film cast from acetone allowed a faster permeation of terbutalineby diffusion through the pores, whereas the diffusion through the polymer chains was probably the only possiblemechanism of drug release in the dense film formed from methylene chloride polymer solutions, this process beingextremely slow for terbutaline. © 1998 Elsevier Science B.V. All rights reserved.

Keywords: Microencapsulation; Ion-exchange resins; Controlled release; Solvent evaporation method; Celluloseacetate butyrate; Terbutaline

* Corresponding author. Departamento de Farmacia y Tecnologıa Farmaceutica, Facultad de Farmacia, Universidad de Santiagode Compostela, 15706 Santiago de Compostela, Spain. Tel.: +34 981 594627; fax: +34 981 547148; e-mail: [email protected]

0378-5173/98/$ - see front matter © 1998 Elsevier Science B.V. All rights reserved.

PII S0378-5173(98)00224-5

Page 2: Comparison between aqueous and non-aqueous solvent evaporation methods for microencapsulation of drug–resin complexes

D. Torres et al. / International Journal of Pharmaceutics 173 (1998) 171–182172

1. Introduction

Most of the oral controlled-release productsare available as solid forms, however, liquid sus-pensions are especially preferred in particularsituations, for example in the pediatric or geri-atric populations, because of their ease of swal-lowing and the flexibility of adjusting dosages.Attempts to develop liquid oral controlled-re-lease formulations are generally based on multi-particulates, such as coated pellets ormicroparticles, but due to the drawbacks associ-ated to their development, there are to date fewsuitable suspensions available on the market.These difficulties deal essentially with the leach-ing of the drug into the aqueous suspendingmedium and the interactions with the liquidcontents, often changing the original propertiesduring storage.

Ion-exchange resins offer one of very usablesystems for achieving ready-made liquid prod-ucts with prolonged release properties. Thedrug–resin complexes can be suspended in anion-free aqueous medium without any apprecia-ble drug leaching occurring during storage,whereas the drug release will be only promotedupon administration by the presence of compet-ing ions in the gastrointestinal fluids. If theproperties of the drug–resin complex do notgive the desired sustained-release rate, coatingthe particles with a rate-controlling membraneoften achieves the targeted bioavailability. Withthis aim, different polymers, mainly hydrophobiccompounds, and coating or microencapsulationprocesses have been used to encapsulate drug–resin beads. In addition to the typical air coat-ing methods as is described in the mostcommon application of this technology—thePennkinetic system, developed by the PennwaltCorporation (Raghunathan, 1980)—a variety ofmicroencapsulation methods have been appliedto obtain resin containing hydrophobic mi-croparticles. Organic phase separation methods,such as the solvent/non solvent evaporationmethod (Motycka et al., 1985; Moldenhauer andNairn, 1990, 1991), were used to explore thepossibilities of ethylcellulose in the microencap-

sulation of resin cores. Taking into accountsome of the critical steps involved in the mi-croencapsulation of resin beads, such as the dis-persion of the solid cores in the coating mediumor the rate of polymer precipitation, the abovementioned authors concentrated their work onthe study of the main factors related to thesesteps, allowing mononucleated and uniformlycoated microcapsules to be formed. The protec-tive colloid polyisobutylene was considered es-sential in the microencapsulation process inorder to prevent microcapsule multinucleationby altering phase changes in the ethylcellulosesolution. Also the rate of solvent evaporationwas found to be an important factor to be con-trolled, as it affects the type of coat formed.

Drug–resin complexes were also microencap-sulated with water-insoluble polymers, such ascellulose acetate butyrate and polymethylmetacrylate, using emulsion-solvent evaporationmethods in an oily phase (Sprockel and Price,1989, 1990). However, the resulting microparti-cles prepared by these techniques presentedsome problems, such as their large particle sizedistribution or the long time required for manu-facture. The inclusion of emulsion stabilizers inthe external phase (i.e. magnesium stearate), al-lowed to some extent the reduction of the parti-cle size although the technique continued to bea time-consuming process.

Whereas, the non-aqueous phase methodshave generally been applied for encapsulatingdrug–resin complexes, the use of typical solventevaporation methods in an aqueous phase hasnot yet been reported for this purpose. Thepresent work deals with the comparison ofaqueous and non-aqueous solvent evaporationtechniques for microencapsulation of drug–resincomplexes with cellulose acetate butyrate. In ad-dition to the type of method, several formula-tion variables were included in the study todisclose their influence on microcapsule structureand coat characteristics. The anti-asthmaticterbutaline, a highly water soluble drug, waschosen to evaluate the feasibility of the twotypes of microencapsulation methods to obtain aliquid controlled-release product.

Page 3: Comparison between aqueous and non-aqueous solvent evaporation methods for microencapsulation of drug–resin complexes

D. Torres et al. / International Journal of Pharmaceutics 173 (1998) 171–182 173

2. Materials and methods

2.1. Materials

The following chemicals were obtained fromcommercial sources and used as received: celluloseacetate butyrate (CAB 171-15S: 29.5% w/w acetyl,17% w/w butyryl and 1.5% w/w hydroxyl content;MW=65000) (Eastman Chemical, Kingsport,TN); poly(j-caprolactone) (PjCL) (Aldrich,Madrid, Spain); sulfonic acid cation-exchangeresins in the H+ form (Dowex® 50W-X4, 200–400 mesh), terbutaline hemisulphate, silicone (an-tifoam A concentrate), poly(vinyl alcohol) (PVA)(MW=30000–70000) and propylene glycol (PG)(Sigma, St. Louis, MO); liquid paraffin (viscos-ity=110–230 mPa; Merck, Darmstadt, Ger-many); sorbitan trioleate (Span® 85) andpolyethylene glycol 400 and 4000 (PEG 400 andPEG 4000) (Fluka, Madrid, Spain); acetone,methylene chloride and n-hexane of HPLC grade(Romil, Cambridge, UK). All other chemicalswere of analytical grade.

2.2. Purification of the ion-exchange resins

The resins were purified by rinsing about 10 gof wet resin with 3×50 ml portions of deion-izated water, 1×50 ml of 95% ethanol, 1×50 mlof 50% ethanol and 1×50 ml of deionized water.Each stage of treatment lasted 1 h under magneticstirring. The resin was then conditioned by recy-cling the ion exchanger twice between the H+ andthe Na+ form, with 60 ml of 2 M NaOH and 60ml of 2 M HCl, and washing with deionized waterafter each treatment. Finally, the resin in the Na+

form was recovered by vacuum filtration, washedthoroughly with deionizated water and dried toconstant weight at 50°C in an electronic moisturebalance (Shimadzu model EB-280 MOC, Kyoto,Japan).

2.3. Loading of the resins

The terbutaline–resin complex (TRC) wasformed by a batch process, in which the previ-ously purified resin (5 g dry weight) was sus-pended in a 0.1 M solution of terbutaline sulphate

(250 ml) and stirred at room temperature for 1 h.The complex was separated from the supernatantby vacuum filtration, washed with deionized waterto remove any unreacted drug, dried to constantweight and placed in a dessicator. Two batches ofTRC were prepared.

The terbutaline content of the complex wasdetermined in duplicate by placing 25 mg of thedry complex into centrifugal basket stirrers with400 mesh wire screens, which were introducedinto 1000 ml of acidic buffer (HCl/NaCl, pH 1.2,m=0.1), and rotated at 1000 rpm (IKA stirringmotor RW DZM, IKA Labortechnik, Staufen,Germany) at 37°C. The acidic medium was re-placed every hour until the concentration ofterbutaline was negligible (B0.01 mg/ml). Thesolutions from each sample were accumulated andanalyzed by HPLC for terbutaline (HPLC condi-tions are below described). From the amount ofterbutaline that was eluted from each batch ofTRC, the actual drug loading (%) was calculatedas the (amount of drug (mg)/amount of TRC(mg))×100. The value for this parameter was55.5792.57.

2.4. Microencapsulation process

The terbutaline-loaded resins were encapsulatedby the O/O or O/W solvent evaporation methods.In the O/O method, the resin particles (coat tocore ratio: 2:1 or 3:1) were suspended in 15 ml ofa solution of the polymer (0.6, 0.9 or 1.2 g) inacetone followed by emulsification of this phase in100 ml of liquid paraffin containing 1% w/w Span85 and 0.1% w/w silicone. The resulting emulsionwas maintained at 25°C and agitated at 1300 rpmwith a propeller stirrer (IKA stirring motor RWDZM, IKA Labortechnik, Staufen, Germany) un-til the complete evaporation of acetone was ac-complished (3 h). After that, the microcapsuleswere collected by vacuum filtration, washed withthree portions of 75 ml of n-hexane and air driedfor 24 h. In the O/W method, the resin particles(coat to core ratio: 2:1) were suspended in 10 mlof a solution of the polymer (0.3 or 0.6 g) inmethylene chloride followed by emulsification in100 ml of a 0.25% w/v aqueous solution ofpoly(vinyl alcohol). The emulsion was stirred at

Page 4: Comparison between aqueous and non-aqueous solvent evaporation methods for microencapsulation of drug–resin complexes

D. Torres et al. / International Journal of Pharmaceutics 173 (1998) 171–182174

700 rpm (25°C, 3 h) to evaporate the solvent. Themicrocapsules were recovered by vacuum filtra-tion, washed with 200 ml of deionized water anddried at 50°C in oven for 24 h. Two batches weremade for each formulation.

The terbutaline content of the microcapsuleswas determined in duplicate for each batch for-mulation after dissolving the polymer coat of themicrocapsules (50 mg dry weight) in 10 ml ofacetone. The remaining resin particles were thenvacuum filtered, dried to constant weight andplaced (25 mg) into centrifugal basket stirrers todetermine the drug content by allowing the com-plete elution of terbutaline as previously describedfor the terbutaline–resin complex.

2.5. Morphological and particle size analysis ofCAB microcapsules

The surface and the cross-section of the micro-capsules was examined by scanning electron mi-croscopy (Jeol model JSM-6400, Tokyo, Japan).Samples were gold sputter coated (BAL-TECSCD 004, Lichenstein) for 165 s at 15 mA underan argon atmosphere. The cross-sections of themicrocapsules were obtained by cryofracture. Themicrocapsules were suspended in water, frozenand cross-sectioned using an ultra-microtome (Ul-tracut Reichert-Jung, Austria).

The particle size distribution of the resin parti-cles and the microcapsules was measured by aCoulter counter (Multisizer II, Coulter Electron-ics, Northwell, UK). The particle size was ex-pressed as the equivalent volume diameter andtwo replicates were performed for each batch ofmicrocapsules.

2.6. Drug release studies

In vitro terbutaline release was determined witha continuous flow-through apparatus (Sotax,Basel, Switzerland), where 25 mg of dry resincomplex or microcapsules were placed in the sam-ple cells. The dissolution media (HCl/NaCl, pH1.2, m=0.1; or NaH2PO4/Na2HPO4, pH 6.8, m=0.1) were pumped at 20 ml/min and the systemwas maintained at 37°C. Samples were taken outby an automatic fraction collector (Model FC

204, Gilson, Middleton, WI) at specific time inter-vals for 12 h and then assayed by HPLC forterbutaline content. Two replicates were per-formed for each batch of terbutaline–resin com-plex or microcapsules (n=4).

2.7. X-ray diffraction studies

X-ray diffraction experiments were performedin a Philips PW 1710 X-ray diffractometer(Philips Export; Eindhoven, The Netherlands) us-ing Cu Ka2 rays with a voltage of 40 kV and acurrent of 30 mA. Samples were scanned from 5to 80° 2u at a scanning rate of 1.5° 2u/min.Diffraction patterns for polymer and both typesof CAB microcapsules were obtained.

2.8. Films preparation

Cast films were prepared from 6% w/v CABsolutions in acetone and methylene chloride. A5-ml sample of solution was poured onto analuminium dish (63 mm diameter×17.5 mmheight; Fisher Scientific and Pacisa, Madrid,Spain) and the solvent was allowed to evaporateat room temperature for 48 h. Following thecomplete evaporation of the solvent, the filmswere carefully removed and stored in a desiccatorfor at least 24 h (approximate dry film thick-ness=77 mm).

2.9. Thermal analysis

Thermograms of the CAB films and microcap-sules were obtained using a Shimadzu differentialscanning calorimeter (DSC-50 model, Kyoto,Japan). Samples (5 mg) were scanned in alu-minium pans over the temperature range between30–250°C (first run) and 100–200°C (second run)at a scanning rate of 10°/min. The glass transitiontemperature (Tg) of the polymeric samples wasdetermined after a repeat run from the onsettemperature values. All tests were carried out induplicate.

2.10. Terbutaline diffusion from the films

Diffusion experiments were performed using a

Page 5: Comparison between aqueous and non-aqueous solvent evaporation methods for microencapsulation of drug–resin complexes

D. Torres et al. / International Journal of Pharmaceutics 173 (1998) 171–182 175

horizontal side-by-side diffusion cell (CrownGlass, Somerville, NJ). CAB films were clampedbetween two compartments of equal volume (3ml; 37°C; diffusion area 78 cm2). A saturatedsolution of terbutaline in acidic medium (HCl/NaCl, pH 1.2, m=0.1) was placed in the donorcompartment while acidic medium was placed inthe receptor. Samples of 500 m l were taken fromthe receptor cell and replaced with fresh mediumat predetermined time intervals. The amount ofterbutaline diffused through the films was deter-mined by HPLC and each experiment was re-peated twice.

2.11. HPLC conditions

The HPLC system consisted of a solvent de-livery pump (Model P 1500, Spectra Physics,San Jose, CA), a variable UV absorbance detec-tor (Model UV 1000, Spectra Physics, San Jose,CA) and an automatic injector (Kontron au-tosampler 460, Zurich, Switzerland). The detec-tion wavelength was set at 276 nm and theseparation was achieved using a reverse phasecolumn (Spherisorb ODS 2, 10 mm particle size,15×0.46 cm; Tecknokroma, Barcelona, Spain)at 35°C. The mobile phase consisted of an ace-tonitrile/0.15% v/v o-phosphoric acid aqueoussolution (12:88 v/v; pH 2.5) and the flow ratewas 1 ml/min.

2.12. Statistical analysis

The statistical significance of the differencesbetween formulations was tested by the analysisof the variance (ANOVA) or the non-parametricKruskal-Wallis test. The least significant differ-ence (LSD) test or Siegel and Castellan (1988)test were applied for multiple comparison be-tween formulations. Reference to a significantdifference in the subsequent test refers to a levelof pB0.01.

3. Results and discussion

Cellulose acetate butyrate (CAB) microcap-

sules containing terbutaline-loaded resins wereobtained by aqueous and non-aqueous solventevaporation methods. Differences between themicrocapsules in their surface porosity, innerstructure and particle size were evaluated andrelated to the drug release profiles. The modifiedO/O solvent evaporation technique presentedhere led to discrete microcapsules of less than200 mm in diameter, adequate to be suspendedin an aqueous medium. The time required toform the microparticles was reduced from 12 to3 h by adjusting the viscosity of the externalphase, the stirring rate and by adding siliconeand Span® 85 to the external phase. As an alter-native, in this report, the use of the O/W solventevaporation method for the microencapsulationof resin particles is also presented. This proce-dure is more economical and desirable, since theoil phase is replaced by an aqueous solution,and the use of solvents in the final cleaning-upstep is eliminated.

3.1. Morphological and physicochemicalcharacterization of CAB microcapsulescontaining terbutaline-loaded resins

The effect of the preparation method, coat/core ratio and polymer concentration on terbu-taline loading and particle size of the resincontaining microcapsules is shown in Table 1.The drug loading was closely related to the ini-tial coat/core ratio, and ranged from 17–19%when the coat/core ratio was 2:1, to 12–13%when it was 3:1 (encapsulation efficiency: be-tween 92–103% and 86–94%, respectively). Themean particle size of microcapsules prepared bythe O/O method was mainly determined by thepolymer concentration (Fig. 1a, b). As the vis-cosity increased (Fig. 2), the difficulty in obtain-ing a good dispersion of the resin particlesbefore the polymer deposition become moredifficult, thus producing more multinucleatedparticles and a less homogeneous population insize. This fact was also corroborated by the ex-amination of the inner structure of the mi-croparticles. Scanning electron micrographs ofcross-sections of microcapsules (Fig. 3c, d; Fig.

Page 6: Comparison between aqueous and non-aqueous solvent evaporation methods for microencapsulation of drug–resin complexes

D. Torres et al. / International Journal of Pharmaceutics 173 (1998) 171–182176

Table 1Mean values9standard deviations of drug loading and particle size (n=4) of CAB microcapsules containing terbutaline-loadedresins prepared by different solvent evaporation methods

Coat/core ratio Drug loading (%)Method Particle size (mm)CAB conc. (% w/v)

2:1O/O 18.1591.684 114.7297.944 3:1 13.0790.69 112.5296.59

2:1 19.4091.116 145.4293.063:1 11.9790.826 138.8592.98

8 2:1 16.9691.20 191.20910.953:1 12.8490.20 172.07910.738

2:1O/W 17.4090.043 53.1790.726 2:1 19.1591.65 143.4896.75

2:1 18.7492.17 125.05915.756a

2:1 18.4190.956b 149.7199.66

a CAB/PjCL (50:50) polymer mixture.b CAB/PjCL (25:75) polymer mixture.

4c, d) revealed that the multinucleation degreeincreased with increasing polymer concentrations,this trend being more pronounced for the aqueousmethod. At the lower CAB concentration, themicrocapsules formed a very homogeneous popu-lation, the mean particle size being fairly similarto that the resin particles (theoretical particle size:37–74 mm, data from the supplier), which evi-denced the existence of a uniform population ofmononucleated microcapsules with a typical reser-voir structure (Fig. 4c).

The scanning electron micrographs of the mi-croparticles prepared by both the O/O and O/Wmethods (Fig. 3a, b; Fig. 4a, b) evidenced thehigher porosity of the microcapsules prepared inan aqueous medium.

3.2. In 6itro release studies of CAB microcapsulescontaining terbutaline-loaded resins

The dissolution profiles of terbutaline from theresin containing CAB microcapsules prepared byboth the O/O and the O/W methods are depictedin Fig. 5a–c. It can be noted that terbutalinereleased immediately from the uncoated complex,while the CAB coating effectively retarded thedrug release in most of the formulations. CABmicrocapsules made using the O/O method exhib-ited adequate controlled-release profiles whenhigher CAB concentrations (6 and 8%) were used,

however the lowest concentration hardly showedany additional control on the drug release fromthe resin complex, particularly for the 2:1 coat/core ratio. CAB concentration and coat/core ratiowere found to be significant factors when theparameter dissolution efficiency was statisticallyanalyzed (F(2,18)=38.97 and F(2,18)=21.55; pB0.01), the multiple comparison test distinguishingfor each coat/core ratio the formulation preparedat the lowest polymer concentration from theothers. The microcapsules made using the O/Wmethod, in contrast, did not adequately controlthe release of terbutaline from the ionic complex.They showed quite different biphasic release profi-les, with an initial burst effect depending on theconcentration of CAB, followed by a very slowrelease of drug until the end of the dissolutionstudy. This led finally to an incomplete drugrelease, especially for the microcapsules made ofthe higher CAB concentration, which only re-leased about 35% of drug fixed onto the resincomplex after 12 h. This slow release rate did notagree well with the higher porosity of these micro-capsules evidenced in the scanning electronmicrographs.

3.3. CAB-PjCL microcapsules containingterbutaline-loaded resins

With the objective of increasing drug release

Page 7: Comparison between aqueous and non-aqueous solvent evaporation methods for microencapsulation of drug–resin complexes

D. Torres et al. / International Journal of Pharmaceutics 173 (1998) 171–182 177

from the microcapsules made in the aqueousmedium, two formulations were prepared at thehigher polymer concentration by combining CABwith a more permeable polymer, the poly(j-caprolactone) (PjCL), in the proportions 50:50and 25:75 (CAB/PjCL). Neither particle size norterbutaline loading of the formulations (Table 1)were affected by the incorporation of PjCL (drugloading efficiency was about 100%). These resultswere a contrast to the important decreases in drugloading efficiencies described in similar formula-tions, such as those of diltiazem pectate-loadedCAB microcapsules, when CAB was partially sub-

Fig. 2. Viscosity of the acetone and methylene chloride CABsolutions used in the microencapsulation procedures.

Fig. 1. Effect of polymer concentration on the particle sizedistribution of CAB microcapsules prepared by the (a) O/Oand (b) O/W solvent evaporation methods.

stituted by PjCL (Shah and Chafetz, 1994); in-creasing PjCL proportions increased the drugloss (about 34–42%) due to the partition to theexternal aqueous phase, even in this particularcase where diltiazem was formulated as pectate, asparingly soluble salt. This drug loss, attributed toa slower precipitation rate of PjCL during pro-cessing, did not occur in our case when the terbu-taline was fixed on the ion-exchange resins,because the drug leaching was avoided in anion-free medium. Drug release profiles for CAB-PjCL microcapsules (Fig. 6) revealed a significantdifference in the burst effect followed by similardissolution rates, when compared to the sameformulation made of CAB. The higher burst effectwas correlated to the increased porosity and irreg-ularity of the surface of the microcapsules, as seenin the scanning electron micrograph (Fig. 7).Therefore, the combination of CAB with PjCLdid not permit an adequate control of terbutalinerelease.

3.4. Global comparison of methods by using CABfilms and microcapsules

From the comparison of both the O/O andO/W methods at higher polymer concentrations,it can be appreciated that the first method allowsan adequate control of terbutaline release,whereas the microcapsules made in aqueousmedium led to a very slow and incomplete drug

Page 8: Comparison between aqueous and non-aqueous solvent evaporation methods for microencapsulation of drug–resin complexes

D. Torres et al. / International Journal of Pharmaceutics 173 (1998) 171–182178

Fig. 3. Scanning electron micrographs of CAB microcapsules prepared by the O/O solvent evaporation method (coat to core ratio:2:1). (a) General view; (b) detail of the surface, and (c, d) cross-sections of those prepared at 4 and 8% CAB concentration,respectively.

release. These differences in the release behaviourcould not be explained on the basis of the differ-ences in their inner structure—as it was verysimilar—or in their wall porosity, as the morpho-logical characteristics suggested exactly the oppo-site result. Therefore, with the aim of obtainingadditional information about the microcapsuleswall characteristics while avoiding other factorsrelated to the microencapsulation methods (i.e.nature of external phase, solvent diffusion rate orpresence of additives), CAB films were preparedby solvent casting (Nixon and Wong, 1990). Theterbutaline diffusion through the films prepared atthe same polymer concentration (6% w/v) wasevaluated, and the thermal properties of the CABfilms and microcapsules were analyzed in order toelucidate the possible structural changes caused

by the solvent or the method used.The thermal properties, determined by differen-

tial scanning calorimetry, were the glass transitiontemperature (Tg) and the melting temperature(Tm). It has been reported that repeated differen-tial runs are recommended to minimize erraticresults caused by the appearance of broad en-dotherms (Sakellariou et al., 1985), usually due tothe water or typically seen with some polymerssuch as the cellulose esters. In this study, a secondrun was necessary to clearly distinguish the Tg ofCAB samples. The results (Table 2) showed thatthe Tg values of the polymer were very similar formicrocapsules and films made with the same sol-vent. However, significant differences betweengroups were observed when formulations madeusing acetone were compared with those made

Page 9: Comparison between aqueous and non-aqueous solvent evaporation methods for microencapsulation of drug–resin complexes

D. Torres et al. / International Journal of Pharmaceutics 173 (1998) 171–182 179

Fig. 4. Scanning electron micrographs of CAB microcapsules prepared by the O/W solvent evaporation method. (a) General view;(b) detail of the surface, and (c, d) cross-sections of those prepared at 3 and 6% CAB concentration, respectively.

from methylene chloride solutions (F(1,4)=44.57,pB0.01). Additionally, it was observed that theTm values were significantly higher when acetonewas the polymer solvent employed, either for mi-crocapsules or films (F(1,4)=7730.90, pB0.01). Asboth products, microcapsules and films, showedsimilar changes, the possibility that some additiveincluded in the microencapsulation process wasresponsible for the observed variations, was im-mediately excluded. Therefore, it was thought thatthe Tg and Tm changes recorded could be relatedto some physicochemical change occurring in thepolymer during solvent evaporation from the twodifferent CAB solutions. These changes couldhave had effects on the crystallinity degree of thepolymer, but no modifications were found afterexamining the X-ray diffractograms of the rawpolymer and microcapsules prepared by the two

microencapsulation methods (Fig. 8). They didnot show any appreciable change when theseproducts were compared, thus indicating that thesolvent evaporation process did not modify thecrystallinity of polymer.

Finally, the terbutaline permeation through dif-ferent CAB films was evaluated (Fig. 9). Theinformation from this study on the particulardiffusion characteristics of the drug through eachfilm was in agreement with some previous reportswhich indicated the important role of the solventon the film properties (Narisawa et al., 1994;Jones and Medlicott, 1995). The present dataindicated that terbutaline permeated fasterthrough the CAB film cast from acetone, whereasthe drug diffusion through the film cast frommethylene chloride was very slow. The initialrapid permeation rate observed in both films de-

Page 10: Comparison between aqueous and non-aqueous solvent evaporation methods for microencapsulation of drug–resin complexes

D. Torres et al. / International Journal of Pharmaceutics 173 (1998) 171–182180

creased with time as the films became saturatedwith the drug. However, after a few hours, theterbutaline continued to diffuse progressivelythrough the CAB film cast from acetone but no

Fig. 6. In vitro terbutaline release profiles of microcapsulesprepared from CAB/PjCL blends by the O/W method. (Datashown are the mean9standard deviation, n=4).

Fig. 5. Effect of polymer concentration on the terbutalinerelease from the CAB microcapsules prepared by the differentsolvent-evaporation methods. (a) O/O method, coat/core: 2:1;(b) O/O method, coat/core: 3:1 and (c) O/W method, coat/core: 2:1. (Data shown are the mean9standard deviation,n=4).

diffusion was observed through the CAB film castfrom the methylene chloride solution. These re-sults suggest that drug transport through the CABfilm produced from the methylene chloride solu-tion occurs principally by simple molecular diffu-sion, whereas in the film cast from the acetonicsolution, the drug diffusion occurs through theliquid-filled pores rather than by partitioning intothe polymeric membrane.

These discrepancies in permeability are at-tributable to differences in the density/porosity ofthe CAB films resulting from the two castingsolvents. When methylene chloride was the sol-vent used, the resulting film was nearly transpar-

Fig. 7. Scanning electron micrograph of CAB/PjCL (25:75)microcapsules prepared by the O/W method.

Page 11: Comparison between aqueous and non-aqueous solvent evaporation methods for microencapsulation of drug–resin complexes

D. Torres et al. / International Journal of Pharmaceutics 173 (1998) 171–182 181

Table 2Mean values9standard deviations (n=2) of glass transition(Tg) and melting (Tm) temperatures of raw polymer, and CABmicrocapsules and films prepared from polymer solutions inacetone and methylene chloride

FormulationPolymer sol- Tg (°C) Tm (°C)vent

151.3391.34Raw polymer 190.2490.88

Microcap-Acetone 148.0091.38 227.8690.47sules

143.4690.30 238.5790.36Film

Microcap- 190.4390.24Methylene 158.5492.36chloride sules

151.2692.59 189.7291.12FilmFig. 9. Diffusion of terbutaline through CAB films preparedby casting from acetone and methylene chloride solutions.(Data shown are the mean9standard deviation, n=2).

ent and flexible, suggesting that a very homoge-neous film was formed. In contrast, the film pre-pared from the acetonic solution was opaque,slightly whitish and brittle, corresponding to amore heterogeneous and porous structure. Thesedifferences in the film structures may be explainedby the conformation of the polymer in the solu-tion prior to the casting process (Banker, 1966;Isihara and Guth, 1968). When thermodynami-cally good solvents are used, upon solvent evapo-

ration, the intermolecular forces between chainsegments of the polymer molecule and also be-tween chain segments of neighbouring polymermolecules become increasingly effective and, thus,the resulting film is a homogeneous dense struc-ture with strong interpenetrating chains(methylene chloride case). In dilute solutions ofpoor solvents, the polymer coils are compact andonly superficially interact when the solvent evapo-rates. The resulting film is distinctly heteroge-neous in structure due to the presence ofmicrovoids (acetone case).

Although these results do not exactly describethe case of microcapsules, they could explain, to acertain degree, the differences observed betweenmicrocapsules prepared by the O/O and O/Wmethods. Therefore, it could be interpreted thatthe structure of the polymer wall obtained by theO/O method allows a rapid exchange betweenterbutaline and ions present in the dissolutionmedium whereas the density of the coat producedin the O/W method hinders the penetration orions, and thus the release of terbutaline. Thehigher apparent porosity of the microcapsulesprepared by this latter method is only related tothe observed burst effect (resin particles entrappednear the surface), however the diffusion studiesindicate that the drug release process was defin-itely conditioned by the dense structure of thepolymer wall formed.

Fig. 8. X-ray diffraction patterns of raw polymer and CABmicrocapsules prepared by the O/O and O/W solvent evapora-tion methods.

Page 12: Comparison between aqueous and non-aqueous solvent evaporation methods for microencapsulation of drug–resin complexes

D. Torres et al. / International Journal of Pharmaceutics 173 (1998) 171–182182

Acknowledgements

This work was supported by the Xunta deGalicia (XUGA 20315 B91) and the SpanishCommission of Science and Technology (CICYT-SAF 92-0601). The authors wish to thank Profes-sor M.J. Alonso for her advice and contributionto the discussion of this work.

References

Banker, G.S., 1966. Film coating theory and practice. J.Pharm. Sci. 55, 81–89.

Isihara, A., Guth, E., 1968. Theory of dilute macromolecularsolutions. Adv. Polym. Sci. 5, 233–260.

Jones, D.S., Medlicott, N.J., 1995. Casting solvent controlledrelease of chlorhexidine from ethylcellulose films preparedby solvent evaporation. Int. J. Pharm. 114, 257–261.

Moldenhauer, M.G., Nairn, J.G., 1990. Formulation parame-ters affecting the preparation and properties of microen-capsulated ion-exchange resins containing theophylline. J.Pharm. Sci. 79, 659–666.

Moldenhauer, M.G., Nairn, J.G., 1991. The effect of rate ofevaporation on the coat structure of methylcellulose micro-capsules. J. Control. Release 17, 49–60.

Motycka, S., Newth, C.J.L., Nairn, J.G., 1985. Preparationand evaluation of microencapsulated and coated ion-ex-

change resin beads containing theophylline. J. Pharm. Sci.74, 643–646.

Narisawa, S., Yoshino, H., Hirakawa, Y., Noda, K., 1994.Porosity-controlled ethylcellulose film coating. II. Sponta-neous porous film formation in the spraying process and itssolute permeability. Int. J. Pharm. 104, 95–106.

Nixon, J.R., Wong, K.T., 1990. Evaluation of drug perme-ation through polymeric membranes as a model for release(II) ethylcellulose-walled microcapsules. Int. J. Pharm. 58,31–40.

Raghunathan, Y., 1980. US Patent 4,221,778 (to PennwaltCorporation).

Sakellariou, P., Rowe, R.C., White, E.F.T., 1985. The ther-momechanical properties and glass transition temperaturesof some cellulose derivatives used in film coating. Int. J.Pharm. 27, 267–277.

Shah, K.P., Chafetz, L., 1994. Use of sparingly soluble salts toprepare oral sustained release suspensions. Int. J. Pharm.109, 271–281.

Siegel, S., Castellan, N.J., 1988. Non-Parametric Statistics forthe Behavioural Sciences, 2nd ed. McGraw-Hill, NewYork.

Sprockel, O.L., Price, J.C., 1989. Evaluation of sustainedrelease aqueous suspensions containing microencapsulateddrug-resin complexes. Drug Dev. Ind. Pharm. 15, 1275–1287.

Sprockel, O.L., Price, J.C., 1990. Development of an emulsion-solvent evaporation technique for microencapsulation ofdrug–resin complexes. Drug Dev. Ind. Pharm. 16, 361–376.

.

.