PHARMACEUTICAL TECHNOLOGY
Combined Application of Extrusion-Spheronization and Hot-Melt Coating Technologies for Improving
Moisture-Proofing of Herbal Extracts
HAO CHEN,SHUAI SHI,AINA LIU,XING TANG
College of Pharmacy,Shenyang Pharmaceutical University,Wenhua Road,No.103,Shenyang110016,PR China Received26May2009;revid20August2009;accepted29September2009
Published online4November2009in Wiley InterScience(www.).DOI10.1002/jps.21990
ABSTRACT:The aim of this rearch was to investigate the moisture-proofing effect and its
mechanism for herbal extracts using extrusion-spheronization combined with hot-melt coating.
全身荨麻疹Guizhi Fuling(GF)compound herbal extract with high hygroscopicity was ud as a model drug.
In the process of extrusion-spheronization,pellets containing100%GF were prepared,and then
coated with hot-melt coating material using a traditional coating pan.The moisture sorption
data for GF were determined by storage at a ries of different relative humidities.When the
pellets were coated with a96:4mixture of stearic acid and polyethylene glycol6000,the
cumulative drug relea was over90%at45min while the moisture content was4.9%at
75%RH within10days.The pellets have better moisture-proofing than tho coated with
Opadry AMB at the same coating level due to a different moisture sorption mechanism.The
moisture sorption behavior of the hot-melt coating can be attributed to water vapor diffusion via
热水器安装高度a porous matrix system,while the Opadry AMB coating system involved a swelling controlled
system.The Higuchi model was the bestfit for the moisture sorption of the hot-melt coating in all
formulations whereas the Opadry AMB coatingfitted the Nuttanan model.ß2009Wiley-Liss,Inc.
四字成语寓言故事
and the American Pharmacists Association J Pharm Sci99:2444–2454,2010
Keywords:Guizhi Fuling;extrusion-spheronization;hot-melt coating;hygroscopicity;
dissolution
INTRODUCTION
Herbal extracts,especially Traditional Chine Med-icines(TCM),have been ud to treat dias for thousands of years.Unlike Western medicines, herbal dry extracts always have a complex composi-tion and contain a number of active components and veral hydrophilic ingredients,such as carbohy-drates and organic acids.1Carbohydrates,as a major ingredient of herbs,are soluble in the water or water–ethanol solvent systems which are always ud for herbal extraction.The highly hygroscopic nature of the herbal materials may be attributed to their hydrophilic ingredients.2The moisture sorption can exert significant effects on the physicochemical and technological properties as well as the biopharma-ceutical parameters of the extracts.Thus,it is a universal problem to incorporate medicinal herbal extracts into safe,efficacious,consistent and stable oral solid dosage ,tablets,granules, capsules,pellets).
Guizhi Fuling(GF)has been ud in China for the treatment of gynecological blood stasis for a long time. It consists offive herbal extracts,namely,Cassia Twig,Poria Cocos,Cortex Moutan,Red Peony Root and Peach Seed.GF dry extracts,like most herbal dry powders are by nature very hygroscopic.3Thus,it was ud as a model drug in this study.
Granulation technology and coating technology are currently being widely ud to improve the moisture-proofing technology of herbal extracts.4,5For large dos of drugs,such as the herbal compound extracts we studied,the method of extrusion-spheronization is often lected.6,7Furthermore,the extrusion-spher-onization technique can provide an excellent sphe-rical shape which is considered important8since the spherical pellets can be
Correspondence to:Xing Tang(Telephone:þ86-24-23986343;
Fax:þ86-24-23911736;
E-mail:)
少女心的手抄报
Journal of Pharmaceutical Sciences,Vol.99,2444–2454(2010)
ß2009Wiley-Liss,Inc.and the American Pharmacists Association
2444JOURNAL OF PHARMACEUTICAL SCIENCES,VOL.99,NO.5,MAY2010
provides the best conditions forfilm-coating to provide an anti-hygroscopic effect.
A variety of coatings are currently ud to improve the moisture-proofing effect of herbal extracts.A range of moisture-barrierfilm coatings materials, including Eudragit L30D-55,acrylic resin and Opadry AMB,are available for drugs with high hygroscopicity.9,10However,water,organic solvent or a mixture of the are always required for thefilm-coating process mentioned above and the can cau environmental problems,involving disposal of the solvent residues,and can also prolong the coating posss.The hot-melt coating technology could effectively overcome the problems.A suitable material for hot-melt coating is one having a melting point typically within the range of50–1008C.A lower melting point could carry a risk of melting or softening of the binder during handling and storage, whereas a higher melting point could cau degrada-tion of the drugs during the process of hot-melt coating.Although hot-melt coating technology has the disadvantage of needing a suitable temperature to melt the coating materials,this temperature range would not affect the stabilit
y of herbal extracts becau most herbal extracts are thermally stable. Therefore,hot-melt coating would be a suitable method for controlling the moisture sorption of herbal extracts.
A coating material can be compod of a hydrophilic or hydrophobic substance or a combination of the. Many hydrophobic materials containing fatty acids, natural waxes and glycerides have been ud for the sustained relea of matrix tablets and pellets.11,12A barrier that resists the penetration of moisture is provided by the above carriers becau of their hydrophobic nature.For improving drug relea,a hydrophilic material is also necessary.Polyethylene glycols(PEGs)of a hydrophilic nature have been widely ud as binders for melt pelletization.13,14 They are also often ud as a pore-forming agent to control drug relea.15,16The viscosity of materials is an important factor in hot-melt coating since lower viscosity coating materials prevent the agglomeration of pellets during the coating process.Therefore,the substances investigated as coating materials in this study were lected on the basis of their viscosity and melting point(50–1008C).
Opadry AMB[poly(vinylalcohol)-bad formula-tion]is an aqueous coating material with a commer-cial moisture-barrierfilm coating and has a good moisture-protective ability,9and it was lected for comparison with the hot-melt coating process.The purpo of this study was to investigate the moisture-proofing mechanism and effect of herbal pellets prepared by extrusion-spheronization com
bined with hot-melt coating.The moisture sorption data for GF were determined by storage at a ries of different relative humidities.In addition,the dissolution behavior was investigated in a classic dissolution test. MATERIALS AND METHODS
Materials
Guizhi Fuling herbal compound extracts were donated by Kanion Pharmaceutical Co.,Ltd.Jiangsu, China.The95%(v/v)ethanol solution was supplied by Shenyang Fukang disinfectant preparation factory. Glyceryl monostearate and stearic acid were pur-chad from Tianjin Bodi Chemical Holding Co.,Ltd. Tianjin,China.Carnauba wax and beeswax were supplied by Hebei Cangzou Senlin Wax Industry Co., Ltd.Hebei,China.Compritol888ATO(USP-NF glyceryl behenate)was a gift from Gattefos’(Saint Priest,F).PEG1500,PEG3000,PEG6000,and PEG 10000were all purchad from Tianjin Kermel Chemical Reagent Co.,Ltd.Tianjin,China.Magne-sium stearate,ud as an anti-cohesive agent,was also purchad from Tianjin Bodi Chemical Holding Co.,Ltd.Opadry AMB dispersion was donated by Shanghai 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),ud to provide a range of relative humidities in a clod system at23Æ28C, were purchad from Tianjin Kermel Chemical Reagent Co.,Ltd.
Preparation of Herbal Extract Pellets by
Extrusion-Spheronization
The ethanol solution and distilled water were ud to prepare a50%(v/v)aqueous ethanolic solution as a binder.Also,50mL of this binder was mixed with 100g GF powder samples to obtain a wet mass.Then, the wet mass was extruded through a1.0mm screen using a Granulator(WL350,Wenzhou Pharmacy Equipment Factory,Zhejiang,China).The extruded material was collected and spheronized in a spher-onizer(WL350,Wenzhou Pharmacy Equipment Factory)at a speed of300rpm for10min.Finally, the pellets were dried overnight in a hot air oven at 408C.
Viscosity and Melting Point Determinations
The viscosities of the molten materials were studied using an NDJ-7rotary rheometer(Shanghai Preci Scientific Equipment Inc.Shanghai,China),and the molten viscosity was determined at908C.The melting points were determined by X-4Melting-point Appa-ratus with Microscope(Gongyi City Yuhua Instru-ment Co.,Ltd.,Hennan,China).
DOI10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES,VOL.99,NO.5,MAY2010
MOISTURE-PROOFING OF HERBAL EXTRACTS2445
Hot-Melt Coating of Herbal Extract Pellets
白羊座的幸运数字Molten wax spread on the surface of the pellets forms a moisture-barrierfilm coating to improve the moisture-proofing effect of herbal extracts.In this study,stearic acid and mixtures of stearic acid and PEG6000at different ratios were ud as coating materials as shown in Table1.The mixtures were well mixed by passing them through a100mesh sieve three times.A traditional coating pan(B-300Coating Pan,Baoji JianHua CO.Ltd.Shanxi,China)was ud for hot-melt coating.The rotation speed of the coating pan was t at30rpm and the temperature of the hot air blower of the coating pan was t at808C(inlet temperature,and the outlet temperature was408C)to ensure the molten state of the coating material.A 500g batch of GF pellets of 1.06–1.59mm was transferred to the coating pan,and the pellets were rotated in the pan until the temperature of the particles reached approximately708C.Then,the coating material was gradually added to the coating pan.It melted quickly and rolled over with the particles,coating them uniformly.The coating material was divided into veral batches.One batch was added at a constant rate for nearly30s.When one batch had melted completely,the hot air blower of the coating pan was stopped,and the coating pan was kept rotating for1min to avoid agglomeration of melting coating material.Then,the hot air blower was turne
d on again,but the next batch was not added until the temperature of the coating pan reached808C.The amount of coating material was controlled by the weight gain of the pellets.Generally, about a5%level(w/w of pellets)of coating material was added over15min at a constant rate.After all the coating material had been added and had melted, rolling was continued for an additional10min,and then the heating apparatus,including the hot air blower,was turned off.Then,magnesium stearate ud as anti-cohesive agent was added gradually to avoid particle aggregation.According to the cohesion of the pellets,1–2%(w/w of pellets)magnesium stearate was needed.The hot-melt coated pellets were collected after cooling to room temperature.Opadry AMB Coating of Herbal Extract Pellets
Bad on polymer weight,a10%polymer aqueous dispersion of Opadry AMB was the recommended coating and this was carried out in afluidize bed coater(FD MP-10,Powrex CO.Ltd.,Hyogo,Japan)in the bottom-spray mode.The coating conditions were as follows.The temperature was t at40–458C according to the manufacturer’s instructions;the pressure of the spray gun was t at1bar,and the rotation speed of the peristaltic pump ranged from0.8 to1.2g/min.After coating,the pellets were dried at 608C for12h.
Dissolution Test
The in vitro dissolution test was carried out according to the USP31dissolution apparatus I procedure(ZRS-8G Intelligence Dissolve Apparatus,Tianda Tianfa Technology Co.,LTD,Tianjin,China).The rotating basket method was ud,with1000mL water as the dissolution medium,and a rotation speed of100rpm/ min at37Æ0.58C.For each formulation,six replicates were carried out with weighed amounts of pellets, equal to100mg GF powder,depending on the formulation.Approximately4mL offiltered sample was taken at5,10,15,20,30,45,90,and120min.The relea rate was determined by ultraviolet spectro-photometry at a wavelength of268nm(Fig.1)and the absorbance of the GF powder was ud as a comparison.The cumulative drug relea was obtained using Eq.(1),where A t is thefiltered sample of pellets taken at time t,and A powders is the absorbance of the GF powder
Accumulated Drug releað%Þ
¼
A t
A powders
Â100%(1)
Hygroscopicity Test
Water adsorption was measured gravimetrically.The apparatus ud for hygroscopicity measurements consisted of six humidity chambers and an electrical balance(FA1104,Shanghai Minqiao Medical Appli-ance Ltd.Shanghai,China).This method is bad on the u of a saturated salt solution put into a chamber to maintain afixed relative humidity.17The transfer between the product and saturated air was by natural diffusion of water vapor.Color-variable silica gel, LiCl,MgCl2,NaBr,NaCl,and KCl were chon to provide relative humidities of0%,11%,33%,57%, 75%,and84%.The chamber was t at room temperature(23Æ28C)and the moisture content was determined on an electrical balance with a
木兰诗拼音版Table1.Formulations for Hot-Melt Coating of a500g Batch of Drug-Loaded Pellets
Abbreviation
Coating Material
Coating
Level(%) Stearic
Acid(%)
PEG
6000(%)
SA100—4
5
6
SA/P(9.7:0.3)9735
SA/P(9.6:0.4)9645
SA/P(9.5:0.5)9555
JOURNAL OF PHARMACEUTICAL SCIENCES,VOL.99,NO.5,MAY2010DOI10.1002/jps 2446CHEN ET AL.
nsitivity of0.1mg.The dried samples were equilibrated in color-variable silica gel until the weight change was not more than2.0mg at daily intervals according to USP31.Then,the above samples were placed in sample pans to give a layer of2–3mm,weighed at2.0Æ0.1g,and then trans-ferred to the chambers.The samples were weighed at daily intervals and the measured weight changes were converted to percentage changes compared with the initial weight.The formula ud was as follows:
M tð%Þ¼W tÀW0
W0
Â100%(2)
where M t is the amount of moisture sorption at time t, W t is the weight of sample at time t,and W0is the weight of the dried sample.
Light Microscopy Studies of the Coating Film
The mixtures of stearic acid and PEG6000at different ratios in Table1were heated to808C on a thermostatically controlled water bath until molten. Films were obtained by pouring the above material into a mold,and allowing the molten wax to cool over the mold to form a uniformfilm.Thefilm
s obtained had an average thickness of80–100m m,measured using a Motic DMBA450microscope(Motic China Group Co.Ltd.,Beijing,China).Therefore,thefilm obtained had a mean thickness of89.6m m.Then,the films were transferred to distilled water at378C for 30min to obrve the pores that PEG6000formed. The microscopic asssment was carried out using a Motic DMBA450microscope.Thefilms were investigated at100-fold magnification.The pore size of eachfilm was obtained from the average size of20 porous channels.
Physical Characteristics of Pellets黑胡椒牛柳意面
The electron micrographs of the pellets were obtained from gold sputtered samples,using scanning electron microscopy(Model SHIMADZA SSX-550,Japan).The surface and the cross-ctional view of the uncoated pellets,hot-melt coated pellets,and Opadry AMB coated pellets were examined.The particle size distribution was determined by sieve analysis.The resultant pellets were put on the top of the sieve with
a ries of openings ranging from1.59,1.41,1.27,to
1.06mm(16,18,20,to24mesh).The results were reported as the percentage of the weight retained on each sieve.The bulk density and tapped density were determined from the weight of50g resultant pel
lets placed in a100-mL glass graduated cylinder,and the volume was recorded.Then,the pellets were tapped until a constant volume was obtained.The former is the bulk density and the latter is the tapped density of pellets.Theflow properties were characterized in terms of the angle of repo.The resultant pellets were poured gently down the walls of a funnel with a 6-mm internal stem diameter,which wasfixed in a position such that its lower tip was exactly2cm above a hard surface.The pellets were poured until the upper tip of the pile surface touched the lower tip of the funnel.The tanÀ1of the(height of the pile/radius of its ba)gave the angle of repo.18
RESULTS AND DISCUSSION
Selection of Hot-Melt Coating Materials
The materials for hot-melt coating were lected by their viscosity and melting point.Five hydrophobic materials with suitable melting points,glyceryl monostearate,Compritol ATO888,stearic acid, carnauba wax and beeswax,were investigated.In this study,GF pellets were prepared by hot-melt coating using a traditional coating pan,a faster and cheaper technique,to reduce moisture sorption.This technique needs molten material with a low viscosity to improve the efficiency and feasibility of the hot-melt coating process.As shown in Table2,stearic acid has the lowest viscosity an
d it was lected as the hydrophobic coating material.Meanwhile,hydrophi-lic materials are also needed to improve the
drug Figure1.The UV spectrum of the GF herbal extract.
DOI10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES,VOL.99,NO.5,MAY2010
MOISTURE-PROOFING OF HERBAL EXTRACTS2447
relea.Polyethylene glycols(PEGs)containing PEG 1500,PEG3000,PEG6000,and PEG10000were ud as hydrophilic materials in this study.Due to the small proportion of polyethylene glycols ud in the formulation,a similar melting point to the hydro-phobic materials is more important than the viscosity. This is becau a material with a similar melting point will mix evenly during the coating process.As shown in Table2,PEG6000has a similar melting point to stearic acid.Furthermore,it has been widely ud as a pore-forming agent for drug relea and absorbs very little moisture when stored at less than 80%relative humidity.19Therefore,stearic acid and PEG6000were lected as the coating materials in this study.
Dissolution of GF Pellets
As we can e in Figure2,the drug relea from the uncoated pellets was rapid.The cumulative drug relea was95%at10min and the drug was almost completely relead within20min.However,when p
ellets were coated with stearic acid,complete drug relea could not be achieved within a short period.GF relea from pellets coated with stearic acid at a 6%level was only about50%at45min.Even after 120min,only60%of the drug was relead.The cumulative relea from pellets with a5%and4% coating was60%and70%at45min,and the values did not change during the late period of dissolution. This is mainly becau of the hydrophobic nature of stearic acid.The higher the stearic acid coating,the more the hot-melt coating material adhered to the pellets.Finally,a barrier was formed between pellets and water,which retarded drug relea from the cores.
In order to improve the cumulative drug relea of pellets with hot-melt coating,a combination of PEG 6000and stearic acid was ud.Adding PEG6000to the coating material had a significant effect on drug relea as confirmed by the dissolution profiles.In Table1,different proportion mixtures of stearic acid (SA)and PEG6000(P)were ud as hot-melt coating materials.The data for the drug relea profiles of pellets coated with SA/P(9.7:0.3),SA/P(9.6:0.4),and SA/P(9.5:0.5)are shown in Figure3.It is clear that the rates of relea of the pellets were markedly higher than tho only coated with SA at the same coating level(Fig.2).As shown in Figure3,the cumulative drug relea of pellets coated with SA/P (9.6:0.4)was more than80%at20min.Also,the pellets coated with SA/P(9.5:0.5)exhibited a relea of over90%at20min and relea was complete within 45min.It can
be concluded that PEG6000is a key factor for immediate relea,and the amount of PEG 6000had a significant effect on the cumulative relea of coating pellets.In comparison,the drug relea behavior of pellets coated with Opadry AMB at a5%level was similar to that of pellets coated with SA/P(9.5:0.5).Also,the cumulative drug relea of SA/P(9.6:0.4)was less than Opadry AMB during the initial period,however,the cumulative drug relea of both was more than90%within45min.This phenomenon indicated that,while adding4%PEG 6000,the hot-melt coating pellets could exhibited good relea behavior.
Table2.The Viscosities and Melting Points of Hydrophobic and Hydrophilic Molten Materials蜜蜂虾
Hydrophobic Materials Melting Point(8C)Viscosity(cP)at908C Glyceryl monostearate62–6722 Glyceryl behenate(Compritol888)68–7323
Stearic acid61–669 Carnauba wax75–8343 Beeswax61–6415 Hydrophilic materials(PEGs)
PEG150044–4837
PEG300047–58123
PEG600055–63459
PEG1000052–64
1490
