Combined application of extrusion-spheronization and hot-melt coating technologies for improving...

PHARMACEUTICAL TECHNOLOGY

Combined Application of Extrusion-Spheronization andHot-Melt Coating Technologies for ImprovingMoisture-Proofing of Herbal Extracts

HAO CHEN, SHUAI SHI, AINA LIU, XING TANG

College of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road, No. 103, Shenyang 110016, PR China

Received 26 May 2009; revised 20 August 2009; accepted 29 September 2009

Published online 4 November 2009 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21990

CorrespondeFax: þ86-24-239E-mail: tangpha

Journal of Pharm

� 2009 Wiley-Liss

2444 JOURN

ABSTRACT: The aim of this research was to investigate the moisture-proofing effect and itsmechanism for herbal extracts using extrusion-spheronization combined with hot-melt coating.Guizhi Fuling (GF) compound herbal extract with high hygroscopicity was used as a model drug.In the process of extrusion-spheronization, pellets containing 100% GF were prepared, and thencoated with hot-melt coating material using a traditional coating pan. The moisture sorptiondata for GF were determined by storage at a series of different relative humidities. When thepellets were coated with a 96:4 mixture of stearic acid and polyethylene glycol 6000, thecumulative drug release was over 90% at 45 min while the moisture content was 4.9% at75% RH within 10 days. These pellets have better moisture-proofing than those coated withOpadry AMB at the same coating level due to a different moisture sorption mechanism. Themoisture sorption behavior of the hot-melt coating can be attributed to water vapor diffusion viaa porous matrix system, while the Opadry AMB coating system involved a swelling controlledsystem. The Higuchi model was the best fit for the moisture sorption of the hot-melt coating in allformulations whereas the Opadry AMB coating fitted the Nuttanan model. � 2009 Wiley-Liss, Inc.

and the American Pharmacists Association J Pharm Sci 99:2444–2454, 2010

Keywords: Guizhi Fuling; extrusion-sph
eronization; hot-melt coating; hygroscopicity;dissolution
INTRODUCTION

Herbal extracts, especially Traditional Chinese Med-icines (TCM), have been used to treat diseases forthousands of years. Unlike Western medicines,herbal dry extracts always have a complex composi-tion and contain a number of active components andseveral hydrophilic ingredients, such as carbohy-drates and organic acids.1 Carbohydrates, as a majoringredient of herbs, are soluble in the water or water–ethanol solvent systems which are always used forherbal extraction. The highly hygroscopic nature ofthe herbal materials may be attributed to theirhydrophilic ingredients.2 The moisture sorption canexert significant effects on the physicochemical and

nce to: Xing Tang (Telephone: þ86-24-23986343;11736;[email protected])

aceutical Sciences, Vol. 99, 2444–2454 (2010)

, Inc. and the American Pharmacists Association

AL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 5, MAY 201

technological properties as well as the biopharma-ceutical parameters of the extracts. Thus, it is auniversal problem to incorporate medicinal herbalextracts into safe, efficacious, consistent and stableoral solid dosage forms (e.g., tablets, granules,capsules, pellets).

Guizhi Fuling (GF) has been used in China for thetreatment of gynecological blood stasis for a long time.It consists of five herbal extracts, namely, CassiaTwig, Poria Cocos, Cortex Moutan, Red Peony Rootand Peach Seed. GF dry extracts, like most herbal drypowders are by nature very hygroscopic.3 Thus, it wasused as a model drug in this study.

Granulation technology and coating technology arecurrently being widely used to improve the moisture-proofing technology of herbal extracts.4,5 For largedoses of drugs, such as the herbal compound extractswe studied, the method of extrusion-spheronization isoften selected.6,7 Furthermore, the extrusion-spher-onization technique can provide an excellent sphe-rical shape which is considered important8 since thespherical pellets can be packed more uniformly and

0

MOISTURE-PROOFING OF HERBAL EXTRACTS 2445

provides the best conditions for film-coating toprovide an anti-hygroscopic effect.

A variety of coatings are currently used to improvethe moisture-proofing effect of herbal extracts. Arange of moisture-barrier film coatings materials,including Eudragit L30 D-55, acrylic resin andOpadry AMB, are available for drugs with highhygroscopicity.9,10 However, water, organic solvent ora mixture of these are always required for the film-coating processes mentioned above and these cancause environmental problems, involving disposal ofthe solvent residues, and can also prolong the coatingpossess. The hot-melt coating technology couldeffectively overcome these problems. A suitablematerial for hot-melt coating is one having a meltingpoint typically within the range of 50–1008C. A lowermelting point could carry a risk of melting orsoftening of the binder during handling and storage,whereas a higher melting point could cause degrada-tion of the drugs during the process of hot-meltcoating. Although hot-melt coating technology hasthe disadvantage of needing a suitable temperature tomelt the coating materials, this temperature rangewould not affect the stability of herbal extractsbecause most herbal extracts are thermally stable.Therefore, hot-melt coating would be a suitablemethod for controlling the moisture sorption of herbalextracts.

A coating material can be composed of a hydrophilicor hydrophobic substance or a combination of these.Many hydrophobic materials containing fatty acids,natural waxes and glycerides have been used for thesustained release of matrix tablets and pellets.11,12 Abarrier that resists the penetration of moisture isprovided by the above carriers because of theirhydrophobic nature. For improving drug release, ahydrophilic material is also necessary. Polyethyleneglycols (PEGs) of a hydrophilic nature have beenwidely used as binders for melt pelletization.13,14

They are also often used as a pore-forming agentto control drug release.15,16 The viscosity of materialsis an important factor in hot-melt coating since lowerviscosity coating materials prevent the agglomerationof pellets during the coating process. Therefore, thesubstances investigated as coating materials in thisstudy were selected on the basis of their viscosity andmelting point (50–1008C).

Opadry AMB [poly(vinylalcohol)-based formula-tion] is an aqueous coating material with a commer-cial moisture-barrier film coating and has a goodmoisture-protective ability,9 and it was selected forcomparison with the hot-melt coating process. Thepurpose of this study was to investigate the moisture-proofing mechanism and effect of herbal pelletsprepared by extrusion-spheronization combined withhot-melt coating. The moisture sorption data for GFwere determined by storage at a series of different

DOI 10.1002/jps

relative humidities. In addition, the dissolutionbehavior was investigated in a classic dissolution test.

MATERIALS AND METHODS

Materials

Guizhi Fuling herbal compound extracts weredonated by Kanion Pharmaceutical Co., Ltd. Jiangsu,China. The 95% (v/v) ethanol solution was supplied byShenyang Fukang disinfectant preparation factory.Glyceryl monostearate and stearic acid were pur-chased from Tianjin Bodi Chemical Holding Co., Ltd.Tianjin, China. Carnauba wax and beeswax weresupplied by Hebei Cangzou Senlin Wax Industry Co.,Ltd. Hebei, China. Compritol 888 ATO (USP-NFglyceryl behenate) was a gift from Gattefosse’ (SaintPriest, F). PEG 1500, PEG 3000, PEG 6000, and PEG10000 were all purchased from Tianjin KermelChemical Reagent Co., Ltd. Tianjin, China. Magne-sium stearate, used as an anti-cohesive agent, wasalso purchased from Tianjin Bodi Chemical HoldingCo., Ltd. Opadry AMB dispersion was donated byShanghai Colorcon Coating Technology Ltd. Shang-hai, China. Color-variable silica gel (0% RH), LiCl(11% RH), MgCl2 (33% RH), NaBr (57% RH), NaCl(75% RH), and KCl (84% RH), used to provide a rangeof relative humidities in a closed system at 23� 28C,were purchased from Tianjin Kermel ChemicalReagent Co., Ltd.

Preparation of Herbal Extract Pellets byExtrusion-Spheronization

The ethanol solution and distilled water were used toprepare a 50% (v/v) aqueous ethanolic solution as abinder. Also, 50 mL of this binder was mixed with100 g GF powder samples to obtain a wet mass. Then,the wet mass was extruded through a 1.0 mm screenusing a Granulator (WL350, Wenzhou PharmacyEquipment Factory, Zhejiang, China). The extrudedmaterial was collected and spheronized in a spher-onizer (WL350, Wenzhou Pharmacy EquipmentFactory) at a speed of 300 rpm for 10 min. Finally,the pellets were dried overnight in a hot air oven at408C.

Viscosity and Melting Point Determinations

The viscosities of the molten materials were studiedusing an NDJ-7 rotary rheometer (Shanghai PreciseScientific Equipment Inc. Shanghai, China), and themolten viscosity was determined at 908C. The meltingpoints were determined by X-4 Melting-point Appa-ratus with Microscope (Gongyi City Yuhua Instru-ment Co., Ltd., Hennan, China).

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 5, MAY 2010

2446 CHEN ET AL.

Hot-Melt Coating of Herbal Extract Pellets

Molten wax spread on the surface of the pellets formsa moisture-barrier film coating to improve themoisture-proofing effect of herbal extracts. In thisstudy, stearic acid and mixtures of stearic acid andPEG 6000 at different ratios were used as coatingmaterials as shown in Table 1. The mixtures werewell mixed by passing them through a 100 mesh sievethree times. A traditional coating pan (B-300 CoatingPan, Baoji JianHua CO. Ltd. Shanxi, China) was usedfor hot-melt coating. The rotation speed of the coatingpan was set at 30 rpm and the temperature of the hotair blower of the coating pan was set at 808C (inlettemperature, and the outlet temperature was 408C) toensure the molten state of the coating material. A500 g batch of GF pellets of 1.06–1.59 mm wastransferred to the coating pan, and the pellets wererotated in the pan until the temperature of theparticles reached approximately 708C. Then, thecoating material was gradually added to the coatingpan. It melted quickly and rolled over with theparticles, coating them uniformly. The coatingmaterial was divided into several batches. One batchwas added at a constant rate for nearly 30 s. When onebatch had melted completely, the hot air blower of thecoating pan was stopped, and the coating pan waskept rotating for 1 min to avoid agglomeration ofmelting coating material. Then, the hot air blowerwas turned on again, but the next batch was notadded until the temperature of the coating panreached 808C. The amount of coating material wascontrolled by the weight gain of the pellets. Generally,about a 5% level (w/w of pellets) of coating materialwas added over 15 min at a constant rate. After all thecoating material had been added and had melted,rolling was continued for an additional 10 min, andthen the heating apparatus, including the hot airblower, was turned off. Then, magnesium stearateused as anti-cohesive agent was added gradually toavoid particle aggregation. According to the cohesionof the pellets, 1–2% (w/w of pellets) magnesiumstearate was needed. The hot-melt coated pellets werecollected after cooling to room temperature.

Table 1. Formulations for Hot-Melt Coating of a 500 gBatch of Drug-Loaded Pellets

Abbreviation

Coating Material

CoatingLevel (%)

StearicAcid (%)

PEG6000 (%)

SA 100 — 456

SA/P (9.7:0.3) 97 3 5SA/P (9.6:0.4) 96 4 5SA/P (9.5:0.5) 95 5 5


Opadry AMB Coating of Herbal Extract Pellets

Based on polymer weight, a 10% polymer aqueousdispersion of Opadry AMB was the recommendedcoating and this was carried out in a fluidize bedcoater (FD MP-10, Powrex CO. Ltd., Hyogo, Japan) inthe bottom-spray mode. The coating conditions wereas follows. The temperature was set at 40–458Caccording to the manufacturer’s instructions; thepressure of the spray gun was set at 1 bar, and therotation speed of the peristaltic pump ranged from 0.8to 1.2 g/min. After coating, the pellets were dried at608C for 12 h.

Dissolution Test

The in vitro dissolution test was carried out accordingto the USP31 dissolution apparatus I procedure (ZRS-8G Intelligence Dissolve Apparatus, Tianda TianfaTechnology Co., LTD, Tianjin, China). The rotatingbasket method was used, with 1000 mL water as thedissolution medium, and a rotation speed of 100 rpm/min at 37� 0.58C. For each formulation, six replicateswere carried out with weighed amounts of pellets,equal to 100 mg GF powder, depending on theformulation. Approximately 4 mL of filtered samplewas taken at 5, 10, 15, 20, 30, 45, 90, and 120 min. Therelease rate was determined by ultraviolet spectro-photometry at a wavelength of 268 nm (Fig. 1) and theabsorbance of the GF powder was used as acomparison. The cumulative drug release wasobtained using Eq. (1), where At is the filtered sampleof pellets taken at time t, and Apowders is theabsorbance of the GF powder

Accumulated Drug release ð%Þ

¼ At

Apowders� 100% (1)

Hygroscopicity Test

Water adsorption was measured gravimetrically. Theapparatus used for hygroscopicity measurementsconsisted of six humidity chambers and an electricalbalance (FA1104, Shanghai Minqiao Medical Appli-ance Ltd. Shanghai, China). This method is based onthe use of a saturated salt solution put into a chamberto maintain a fixed relative humidity.17 The transferbetween the product and saturated air was by naturaldiffusion of water vapor. Color-variable silica gel,LiCl, MgCl2, NaBr, NaCl, and KCl were chosen toprovide relative humidities of 0%, 11%, 33%, 57%,75%, and 84%. The chamber was set at roomtemperature (23� 28C) and the moisture contentwas determined on an electrical balance with a

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Figure 1. The UV spectrum of the GF herbal extract.


sensitivity of 0.1 mg. The dried samples wereequilibrated in color-variable silica gel until theweight change was not more than 2.0 mg at dailyintervals according to USP31. Then, the abovesamples were placed in sample pans to give a layerof 2–3 mm, weighed at 2.0� 0.1 g, and then trans-ferred to the chambers. The samples were weighed atdaily intervals and the measured weight changeswere converted to percentage changes compared withthe initial weight. The formula used was as follows:

Mt ð%Þ ¼ Wt � W0

W0� 100% (2)

where Mt is the amount of moisture sorption at time t,Wt is the weight of sample at time t, and W0 is theweight of the dried sample.

Light Microscopy Studies of the Coating Film

The mixtures of stearic acid and PEG 6000 atdifferent ratios in Table 1 were heated to 808C on athermostatically controlled water bath until molten.Films were obtained by pouring the above materialinto a mold, and allowing the molten wax to cool overthe mold to form a uniform film. The films obtainedhad an average thickness of 80–100mm, measuredusing a Motic DMBA 450 microscope (Motic ChinaGroup Co. Ltd., Beijing, China). Therefore, the film

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obtained had a mean thickness of 89.6mm. Then, thefilms were transferred to distilled water at 378C for30 min to observe the pores that PEG 6000 formed.The microscopic assessment was carried out using aMotic DMBA 450 microscope. The films wereinvestigated at 100-fold magnification. The pore sizeof each film was obtained from the average size of 20porous channels.

Physical Characteristics of Pellets

The electron micrographs of the pellets were obtainedfrom gold sputtered samples, using scanning electronmicroscopy (Model SHIMADZA SSX-550, Japan). Thesurface and the cross-sectional view of the uncoatedpellets, hot-melt coated pellets, and Opadry AMBcoated pellets were examined. The particle sizedistribution was determined by sieve analysis. Theresultant pellets were put on the top of the sieve witha series of openings ranging from 1.59, 1.41, 1.27, to1.06 mm (16, 18, 20, to 24 mesh). The results werereported as the percentage of the weight retained oneach sieve. The bulk density and tapped density weredetermined from the weight of 50 g resultant pelletsplaced in a 100-mL glass graduated cylinder, and thevolume was recorded. Then, the pellets were tappeduntil a constant volume was obtained. The former isthe bulk density and the latter is the tapped density ofpellets. The flow properties were characterized interms of the angle of repose. The resultant pelletswere poured gently down the walls of a funnel with a6-mm internal stem diameter, which was fixed in aposition such that its lower tip was exactly 2 cm abovea hard surface. The pellets were poured until theupper tip of the pile surface touched the lower tip ofthe funnel. The tan�1 of the (height of the pile/radiusof its base) gave the angle of repose.18

RESULTS AND DISCUSSION

Selection of Hot-Melt Coating Materials

The materials for hot-melt coating were selected bytheir viscosity and melting point. Five hydrophobicmaterials with suitable melting points, glycerylmonostearate, Compritol ATO 888, stearic acid,carnauba wax and beeswax, were investigated. Inthis study, GF pellets were prepared by hot-meltcoating using a traditional coating pan, a faster andcheaper technique, to reduce moisture sorption. Thistechnique needs molten material with a low viscosityto improve the efficiency and feasibility of the hot-melt coating process. As shown in Table 2, stearic acidhas the lowest viscosity and it was selected as thehydrophobic coating material. Meanwhile, hydrophi-lic materials are also needed to improve the drug


Table 2. The Viscosities and Melting Points of Hydrophobic and Hydrophilic MoltenMaterials

Hydrophobic Materials Melting Point (8C) Viscosity (cP) at 908C

Glyceryl monostearate 62–67 22Glyceryl behenate (Compritol 888) 68–73 23Stearic acid 61–66 9Carnauba wax 75–83 43Beeswax 61–64 15Hydrophilic materials (PEGs)

PEG 1500 44–48 37PEG 3000 47–58 123PEG 6000 55–63 459PEG 10000 52–64 1490

2448 CHEN ET AL.

release. Polyethylene glycols (PEGs) containing PEG1500, PEG 3000, PEG 6000, and PEG 10000 wereused as hydrophilic materials in this study. Due to thesmall proportion of polyethylene glycols used in theformulation, a similar melting point to the hydro-phobic materials is more important than the viscosity.This is because a material with a similar meltingpoint will mix evenly during the coating process. Asshown in Table 2, PEG 6000 has a similar meltingpoint to stearic acid. Furthermore, it has been widelyused as a pore-forming agent for drug release andabsorbs very little moisture when stored at less than80% relative humidity.19 Therefore, stearic acid andPEG 6000 were selected as the coating materials inthis study.

Dissolution of GF Pellets

As we can see in Figure 2, the drug release from theuncoated pellets was rapid. The cumulative drugrelease was 95% at 10 min and the drug was almostcompletely released within 20 min. However, whenpellets were coated with stearic acid, complete drugrelease could not be achieved within a short period.

Figure 2. The influence of pellets coated with stearic acid


GF release from pellets coated with stearic acid at a6% level was only about 50% at 45 min. Even after120 min, only 60% of the drug was released. Thecumulative release from pellets with a 5% and 4%coating was 60% and 70% at 45 min, and these valuesdid not change during the late period of dissolution.This is mainly because of the hydrophobic nature ofstearic acid. The higher the stearic acid coating, themore the hot-melt coating material adhered to thepellets. Finally, a barrier was formed between pelletsand water, which retarded drug release from thecores.

In order to improve the cumulative drug release ofpellets with hot-melt coating, a combination of PEG6000 and stearic acid was used. Adding PEG 6000 tothe coating material had a significant effect on drugrelease as confirmed by the dissolution profiles. InTable 1, different proportion mixtures of stearic acid(SA) and PEG 6000 (P) were used as hot-melt coatingmaterials. The data for the drug release profiles ofpellets coated with SA/P (9.7:0.3), SA/P (9.6:0.4), andSA/P (9.5:0.5) are shown in Figure 3. It is clear thatthe rates of release of these pellets were markedlyhigher than those only coated with SA at the samecoating level (Fig. 2). As shown in Figure 3, thecumulative drug release of pellets coated with SA/P(9.6:0.4) was more than 80% at 20 min. Also, thepellets coated with SA/P (9.5:0.5) exhibited a releaseof over 90% at 20 min and release was complete within45 min. It can be concluded that PEG 6000 is a keyfactor for immediate release, and the amount of PEG6000 had a significant effect on the cumulativerelease of coating pellets. In comparison, the drugrelease behavior of pellets coated with Opadry AMBat a 5% level was similar to that of pellets coated withSA/P (9.5:0.5). Also, the cumulative drug release ofSA/P (9.6:0.4) was less than Opadry AMB during theinitial period, however, the cumulative drug releaseof both was more than 90% within 45 min. Thisphenomenon indicated that, while adding 4% PEG6000, the hot-melt coating pellets could exhibitedgood release behavior.

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Figure 3. The influence of pellets coated with differentcoating materials at a 5% level (w/w) on drug release (&)Opadry AMB, (~) SA/P (9.5:0.5), (^) SA/P (9.6:0.4), (�) SA/P (9.7:0.3).

Figure 4. Effect of pellets with a 5% coating weight gainon water vapor sorption patterns when stored at 75% RH. &Uncoated, & coated with Opadry AMB, ~ coated with SA/P(9.5:0.5), & coated with SA/P (9.6:0.4), & coated with SA/P(9.7:0.3), * coated with SA.


Hygroscopicity of Pellets

The moisture curve of GF was obtained from thepercentage weight change following storage at 75%RH for 10 days according to the hygroscopicity test ofthe Chinese Pharmacopoeia 2005 (Chp 2005). If themoisture content of the drug was less than 5% within10 days, it qualified. Stearic acid used as a coatingmaterial is very effective in retarding moisturesorption. However, it also clearly slowed the drugrelease. The contradiction between moisture retard-ing and drug dissolution were resolved followingaddition of PEG 6000. The moisture sorption profile ofthe pellets is shown in Figure 4. The uncoated pelletsachieved a hygroscopic balance in only 2 days and therate of moisture absorption of the coated pellets wasmarkedly slower than that of uncoated ones. Incomparison with uncoated pellets, the moistureresistance of the pellets was obviously improved.The amount of moisture sorption within 10 days was12.1%, 8.1%, 6.9%, 4.9%, 2.3%, and 2.2% weightchanges of uncoated pellets and pellets coated withOpadry AMB, SA/P (9.5:0.5), SA/P (9.6:0.4), SA/P(9.7:0.3), and SA at a 5% coating level, respectively.This indicates that the pellets coated with SA/P(9.6:0.4) exhibited a good moisture-proofing effect andcould meet the requirement of the hygroscopicity testof the Chp 2005. However, the moisture content of thepellets coated with Opadry AMB was 8.1%, and thisdid not meet the requirement. Meanwhile, thecumulative drug release of pellets coated with SA/P(9.6:0.4) and Opadry AMB were both over 90% at45 min as discussed above. This demonstrated that, atthe same coating level, pellets with a hot-melt coatinghave better moisture-proofing than pellets coatedwith Opadry AMB. Pellets were coated with Opadry

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AMB at another three coating levels, 7%, 10%, 12%,and the moisture sorption within 10 days was 7.2%,5.8% and 4.7%, respectively. This result indicatedthat the requirements were met until the pellets werecoated at a 12% level. Therefore, to achieve the samemoisture-proofing effect, more Opadry AMB wasneeded in comparison with hot-melt coating material.The application of SA/P (9.6:0.4) as a hot-melt coatingmaterial was superior to Opadry AMB in resolvingthe problem of the moisture sorption of herbalextracts.

In order to explain the different moisture sorptionbehavior of hot-melt coating and Opadry AMB coat-ing, four classical models such as zero-order, first-order, Higuchi-order and the Nuttanan model20 wereinvestigated to determine the most suitable moisturesorption model.21 The results of the hygroscopicitytests were fitted to Eqs. (3)–(6)

Mt

M1¼ Kt (3)

lnMt

M1

� �¼ Kt (4)

Mt

M1¼ Kt1=2 (5)

lnMt

M1

� �¼ �K

t(6)

where Mt is the percentage moisture sorption at timet, M1 is the percentage equilibrium moisture sorptionof core, and K is a constant. The correlation coeffi-cients, R, of the fits of moisture sorption data todifferent kinetic models are shown in Table 3. Thisshows that the Higuchi equation gives the best


Table 3. Moisture Sorption Rate Constants (K) and Correlation Coefficients (R2) Obtained from Data Corresponding toPellets Coated With SA, SA/P (9.7:0.3), SA/P (9.6:0.4), SA/P (9.5:0.5), and Opadry AMB With a 5% Level

Model SA SA/P (9.7:0.3) SA/P (9.6:0.4) SA/P (9.5:0.5) Opadry AMB

Zero orderR2 0.8457 0.9583 0.9655 0.8258 0.6685K 0.0008 0.0007 0.0016 0.002 0.0021

First orderR2 0.8556 0.8831 0.8835 0.8264 0.6234K 0.0069 0.0059 0.0065 0.0038 0.0028

Higuchi orderR2 0.9780 0.9880 0.9830 0.9787 0.8925K 0.0128 0.0133 0.0282 0.0371 0.0419

Nuttanan modelR2 0.9212 0.9040 0.9163 0.9537 0.9957K 44.989 37.821 41.377 25.685 22.563

The bold was used in order to emphasize Higuchi order and Nuttanan model. However, it can not affect the expression of the article withoutthe bold.

2450 CHEN ET AL.

correlation (R2> 0.9780) and was the most appro-priate model for the hot-melt coating pellets. How-ever, the moisture sorption profile of pellets withOpadry AMB coating did not satisfy this model, butthe Nuttanan model did.

This phenomenon could be attributed to thedifferent moisture sorption mechanisms of hot-meltcoating and Opadry AMB coating. In actual fact, thecharacteristics of the coating material and thepreparation technology are the main factors. Thehot-melt coating materials consisted of a waxymaterial (stearic acid) and hydrophilic gel matrix(PEG 6000). The amount of PEG 6000 had asignificant effect on the K value of the Higuchi modelas shown in Table 3. The K value of SA/P (9.7:0.3), SA/P (9.6:0.4), and SA/P (9.5:0.5) was 0.0133, 0.0282, and0.0371, respectively. The K value can be designated asa ‘‘diffusion constant,’’ which implies that the largerthe K value of the Higuchi model, the more watervapor diffuses into the cores. It was found that Klinearly increased with PEG 6000 as shown inFigure 5. The finding shows that the more PEG

Figure 5. Relationship between the K value of the Higu-chi model and the proportion of PEG 6000.


6000 added to the wax coating, the greater the Kvalue, leading to an increase in moisture sorption.This is mainly because the PEG 6000 was in the formof channels or pores in the hot-melt coating film, andthe moisture sorption behavior meant that watervapor could diffuse into the cores via these channelsor pores. In order to investigate the form of PEG 6000present in the coating film, SA/P (9.5:0.5), SA/P(9.6:0.4), and SA/P (9.7:0.3) films were formed. PEG6000 could dissolve in water while stearic acid couldnot. Therefore, the above films were put into water.After a few minutes, the porous channels formed inthe film were observed by microscopy as shown inFigure 6. This result proved that the PEG 6000 was inthe form of channels and pores in the coating film. Theaverage pore size of SA/P (9.5:0.5), SA/P (9.6:0.4), andSA/P (9.7:0.3) was 212, 113, and 48mm, respectively.As more PEG 6000 was added, the larger the poresizes formed in the coating film. Hence, the amount ofPEG 6000 had a significant effect on the moisturesorption of hot-melt coating pellets.

However, the K value of SA/P (9.7:0.3) and SA didnot exhibit any significant differences. In otherwords, adding 3% PEG 6000 to the coating materialdid not affect the moisture sorption behavior. Thisphenomenon could be due to the preparation technol-ogy. The coating materials were divided into anumber of batches during the hot-melt coatingprocess. The coating temperature decreased whenone batch had completely melted, which avoided theagglomeration of the melting coating material. Thepellets kept on rolling in the coating pan until thecoating materials had dispersed evenly on the pellets.This batch of molten solid moved as dropletsand solidified into spherical pellets. The next batchwas added until the coating pan reached the coatingtemperature. This process was continued until all thebatches of coating material had been added. Conse-

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Figure 6. Microscope photos of hot-melt coating films. (A) SA/P¼ 95:5 film. (B) SA/P¼ 96:4film. (C) SA/P¼ 97:3 film.


quently, the pellets were hot-melt coated withsolidified particles layer by layer as shown inFigure 7A. As discussed above, the moisture sorptionbehavior was influenced by the pore size of PEG 6000on the coating films. However, the layer by layerstructure of the coating barriers could cover thesurface of some cores. The minor proportion of PEG6000 as a pore-forming agent produced a small poresize, and coating the pellets with barriers layer bylayer could cover up these small pores. Hence, SA/P(9.7:0.3) produced almost no change in diffusion withSA. As the PEG 6000 was increased to over 4%, thepore size increased and it could not be covered by themulti-layer barriers. Therefore, a multi-layer barrierwas formed and porous channels existed at theoverlapping layers. A porous matrix system wassuccessfully formed by combined use of stearic acidand PEG 6000. The Higuchi model was proposed todescribe the release of a drug from an insolublematrix.22 Many studies have reported that theHiguchi model suitably describes porous matrixsystems.23,24 The Higuchi model is based on Fickiandiffusion,25 which has always been used for thediffusion behavior of moisture sorption.9,26 Therefore,the moisture sorption behavior of the hot-melt coatingpellets could be explained as water vapor diffusion viathe porous matrix system.

The moisture sorption profile of pellets with OpadryAMB coating, however, did not fit the Higuchi model.

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The Opadry AMB aqueous dispersion was sprayedonto the pellets using a fluid bed coating technique.As the water evaporated, a continuous, homogeneousmembrane was formed (Fig. 7B). It was found that themore Opadry AMB used to coat the pellets, the lessmoisture sorption was achieved in this study. Thisagrees with the research on the water sorptionbehavior of Opadry AMB films showing that thethicker the film, the less moisture was absorbed.27

Opadry AMB is a polyvinylalcohol (PVA) and xanthangum-based preformulated coating system. There arecomparatively great numbers of –OH groups in theconstituent polymers.26 Also, there is significantinteraction between water and the free hydroxylgroups in Opadry AMB via hydrogen bonding.28 Thewater molecules in the Opadry AMB film exhibitlower mobility but a high plasticizing efficiency and,hence, they disrupt interchain hydrogen bonding andinduce polymer chain relaxation and swelling.26

Therefore, the moisture sorption through the OpadryAMB coating membranes is based on the swellingcontrolled system diffusion. Also, the moisture sorp-tion model of Opadry AMB coating was not thesame as that of the hot-melt coating. It can beconcluded that the different mechanisms of moistureresistance between the Opadry AMB coating and hot-melt coating resulted in different moisture sorptionmodels between Opadry AMB coating and hot-meltcoating.


Figure 7. SEM photograph of a cross sectional view of GFpellets with hot-melt coating (A) and Opadry AMB coating(B).

Figure 8. Water vapor adsorption isotherms of GF at theseventh day (^) powders, (&) uncoated pellets, (*) pelletscoated with Opadry AMB, (~) pellets coated with SA/P(9.6:0.4).

2452 CHEN ET AL.

Moisture Sorption Behavior Under Different RelativeHumidities

GF powders, uncoated pellets and the pellets coatedwith SA/P (9.6:0.4) and Opadry AMB at a 5% coatinglevel were maintained under a relative humidity (RH)of 11%, 33%, 57%, 75%, and 84% for 7 days to estimatetheir moisture sorption behaviors. As is shown inFigure 8, GF powders have a high moisture sorptioncontent at each relative humidity In comparison withGF powders, the moisture absorption content of theuncoated pellets was lower than that of the powdersat a high relative humidity (33–84%). The explana-

Table 4. Particle Size Distributions of Pelle

Weight Percentage 1.59 mm

Hot-melt coating pellets 49.2%Opadry AMB coating pellets 41.4%


tion for this phenomenon was that uncoated pellets,compared with powders, had a smaller specificsurface area and a higher density. The moisturesorption content of coated formulations was notablylower than that of uncoated pellets/powders, indicat-ing that the coated pellets have a higher resistance tomoisture uptake, as the coating material can form amoisture-retarding barrier. While the pellets werecoated with SA/P (9.6:0.4) and Opadry AMB at thesame coating level, pellets with the hot-melt coatinghad a better moisture-proofing effect at a highrelative humidity (75–84%). Therefore, followingcombined application of the extrusion-spheronizationand hot-melt coating technologies, the moisturesorption content of GF was markedly reduced overthe entire range of relative humidity.

Physical Characteristics of Pellets

In this study, pellets containing GF with a narrowparticle size distribution and a spherical form weresuccessfully prepared. The particle size distributionof the resultant pellets is shown in Table 4, and it canbe seen that the weight percentages of the pellets withhot-melt coating and Opadry AMB coating over the

ts

1.41 mm 1.27 mm 1.06 mm

30.6% 11.3% 0.2%39.1% 8.1% 0.6%

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Table 5. Bulk Density and Tapped Density of Pellets

Bulk Density (g/mL) Tapped Density (g/mL)

Hot-melt coating pellets 0.76 0.81Opadry AMB coating pellets 0.80 0.84


size range of 1.06–1.59 mm were 91.3% and 89.2%,respectively. As shown in Table 5, the bulk densityand tapped density of the hot-melt coating pelletswere both lower than those of the Opadry AMBcoating at the same level and this may be due to thelower density of the hot-melt coating materials. Hot-melt coating pellets and Opadry AMB coating pelletsboth possessed a smoother surface than uncoatedpellets (Fig. 9). However, the angles of repose of thehot-melt coating pellets and Opadry AMB coatingpellets were 17.18 and 20.68, respectively. Thisindicated that pellets with the hot-melt coating havea better fluidity than those with the Opadry AMBcoating. The phenomenon might be attributed to theuse of the traditional coating pan for the hot-meltcoating process. The molten materials uniformly

Figure 9. SEM photograph of uncoated pelletsAMB coated pellets (C).

DOI 10.1002/jps

filled the holes of the drug-loaded pellets while rollingover in the coating pan, making the surface of thepellets extremely smooth.

CONCLUSION

In conclusion, the hot-melt coating technique usingthe traditional coating pan is a valuable method forproducing moisture-proof pellets. Pellets coated withSA/P (9.6:0.4) at a 5% level effectively slowedmoisture sorption into the pellet cores. Also, hot-meltcoating materials using a suitable mixture of stearicacid and PEG 6000 exhibit good release behavior incomparison with the use of stearic acid alone. Hot-melt coating using the traditional coating pan was

(A), hot-melt coated pellets (B), and Opadry


2454 CHEN ET AL.

initially used to prevent moisture. This technique issolvent-free and can save time, protect the environ-ment and reduce production costs. The hot-meltcoated pellets have a better moisture-proofing effectthan pellets coated with Opadry AMB at the samecoating level. Therefore, the hot-melt coating processis ideal for preparing moisture-proof pellets of herbalextracts.

ACKNOWLEDGMENTS

Dr. David B. Jack is gratefully thanked for correctingthe manuscript.

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