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liquid filled hard gelatine capsules

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8/16/2019 liquid filled hard gelatine capsules http://slidepdf.com/reader/full/liquid-filled-hard-gelatine-capsules 1/12 Liquid lled and sealed hard gelatin capsules Ewart T.C O LE The World's Leader in Two- Piece Capsules Your Natural Partner
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    Liquid lledand sealedhard gelatin

    capsules

    Ew art T.C O LE

    The World's Leader in Two- Piece Capsules ™

    Your Natural Partner ™

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    It is g enerally accep ted that m any o f today’sN C E’s are p oorly w ater so luble and the c lassicalm ethods, such as red uction in particle size a re nolong er adeq ua te to achieve satisfac tory d rug ad -sorption from a solid oral dosag e form .

    U ntil recently if liquid /sem i-so lid form ulationsw ere necessary the soft gelatin capsule w as theonly d rug form availab le in w hich to en capsulatesuch poorly w ater solub le drug form ulations.

    This p resentation w ill describe the use of hardgelatin capsules as an alternative for liquid/sem i-so-lid form ulations. A screening program has been de-veloped from w hich a list of functional excip ientsw hich are com patible w ith the gelatin shell has b eendraw n up . O nce com patibility has been estab lishedthe capsules are filled and then sealed by sp rayinga sm all am oun t of a w ater/etha no l m ixture at thecap and body interface follow ed by a gen tle w ar-m ing to fuse the tw o capsule p arts together. Theadvantages offered by the LEM S (Liquid Encapsu-lation b y M icro S pray) process over capsule b an-

    ding w ill be d iscussed.It is considered that this techno logy can m ake a

    signi cant contribution to the developm ent of ef ca-cious pha rm aceu tica l p rod uc ts b y p rovid ing the exibility to rap idly develop and test in-house form u-lations w hen only sm all quantities of drug substanceis availab le. The process can be scaled -up and alsokept in-house in a sim ilar w ay to the o perations oftabletting or pow der/pellet lling of hard g elatin cap-sules.

    Ew art T.C O LE

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    1. IntroductionThe hard gelatin capsule has been conventionally

    used as a dosage form for R x and O TC drugs andherba l products, w hich are form ulated either aspow der or pe llets. Va rious categ ories of d rugs,how ever, dem and new and different w ays of form u-lation and the m arket dem ands that these p rod uctsare d evelop ed and launched in an ever decreasingtim e period.

    This article w ill review how liquids filled into hardgelatin cap sules can fulfill som e o f these d em andsand in particular w ill review the categories of drugsfor w hich the liquid and sem i-solid filled capsule isparticularly relevant, exam ine the com patibility is-sues associated w ith excipients, com pare the liquid lled and sealed hard gelatin cap sule w ith soft gela-tin cap sules and also describe a n ew process forsealing hard gelatin capsules.

    2. Drug categories

    Figure 1 show s the different categories of drugsfor w hich a conventional dry pow der dosage formm ay be either unsuitab le or im practical.

    2.1. Poor bioavailabilityG hirardi et al. (1) reported in 1977 that the bio-

    availability of the poorly w ater so luble drug digoxincould be signi cantly enhanced w hen form ulated asa liquid in a soft gelatin cap sule, w hich at the tim ew as the only availab le w ay to form ulate a liquid unitdosage form . It w as no t until the early 80‘s w hen

    w orkers rep orted stud ies in w hich hard gelatin cap-sules can be filled w ith m olten form ulations of drugsubstances (2-7) that an alternative to so ft gelatincap sules becam e a reality. O ne of the rst com m er-cial products to be d eveloped as a liquid filled hardgelatin capsule w as the p oorly w ater so lub le cal-cium antagonist nifed ipine as described by Lahr (8).B ioeq uivalence w ith a drop solution and a so ft gela-tin capsule w as achieved (9) and the prod uct w asm arketed in G erm any as A prical ®.

    S ince the early 80’s the n um ber of poorly w atersolub le drug s exiting from screening program s hasincreased sh arp ly. Lip inski (10) recently reportedthat 35% of N C E’s from the current P zer screeningprogram are p oorly so lub le w hich ag rees w ith theestim ate given by R obinson (11).

    Liquid lled and sealedhard gelatin capsules

    Ewa rt T. C OLE

    Capsugel Division,Wa rner-Lam bert Co .,4144 Arles he im/B a sel,Switzerland

    Enhancement ofBioavailability

    Low MeltingPoints

    Low Dose /High P otencyActive Substance

    CriticalStability

    SustainedRelease

    Figure 1: Reasons for form ulating drugs as liquid or semi-solid d osage forms.

    Originally published in GattefosséBulletin nr 92 (199 9) and reprinted with the kind perm ission of Gattefossé.

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    Fo rm ulation of m icroem ulsions is a techn ique ,

    w hich has alread y been u sed (12 , 13 ) to im provethe bioavailability of poorly w ater so luble drugs anda continuation of this approach can be expected .

    2.2. Low melting pointM aterials w hich have low m elting points or are li-

    quid at room tem perature present difficu lties w henform ulating a s dry pow ders, often req uiring h ighconcentrations of excipien t to avoid processing pro-blem s.

    The product P iasc led ine ® 300, w hich w as origi-nally m arketed in France as a tab let, is a good

    exam ple of ho w a m anufacturing p rocess can b econsiderably sim plified by filling as a hot m elt into ahard gelatin cap sule. The product co ntains a m ix-ture of oils of avocado and soya for the treatm ent ofskin d isorders and the five step process to m anu-facture a tab let w as reduced to a sim ple m ixing andfilling operation. C onsum er acceptance w as alsoenhanced due to the sm aller size of the nal dosageform .

    O ther actives w ith low m elting points, w hichco uld ben efit from this p roce ss include ibup rofen(14) and the oily vitam ins.

    2.3. Low dose / High potencyD rug s in this ca teg ory prese nt tw o m ain cha l-

    lenges; ho w to achieve acceptab le content un ifor-m ity and ho w to control cross-con tam ination andw orker protection.

    2.3.1. Content uniformityD uerr et al. (5) and C ad é et al. (15) have reported

    that the liquid filling operation is capable of achie-ving fill w eight variations o f < 1% . If a drug sub-stance is in so lution or is uniform ly d isp ersed in a li-quid vehicle then it follow s that good drug co ntentuniform ity can also be achieved as has b een repor-ted by W alker et al. (3) for the m odel drug triam te-rene at a d ose level of 25µg .

    2.3.2. Cross-contaminationC om pa nies m anu facturing solid d osag e form s of

    ho rm on es and cytotoxic ag ents from p ow d ers areforced to install extrem ely elaborate system s to re-duce co ntam ination. Inco rporation o f the highly po-tent agent into a liquid for filling into a hard gelatincap sule ca n red uce the da ng ers w hen w orking w ith

    suc h drug s. A stud y carried out by B ow tle (16) using

    phenacetin as a m od el drug , dem on strated that in asw ab test of the b ushing s o n a c ap su le filling m a-chine op erating w ith liquids, no d etectab le level ofphe na ce tin w as foun d . Tho se fam iliar w ith capsulefilling operations w ill realize that su ch clean condi-tions rarely exist w hen w orking w ith dry p ow ders.

    2.4. Critical stabilityS ensitivity to m oisture is an asp ect of form ulation

    w hich can b e m inim ized b y inc orporating the d rugin to either a hyd ro p hilic o r lip op hilic m atrix. Fo rexam ple, the antibiotic vanco m ycin h ydroch loride ishighly hygroscopic an d to achieve acceptab le stab ilityit ne ed ed to be form ulated as a lyophilized pow derfor reconstitution. B ow tle et al. (17) su ccessfully d e-veloped a hard g elatin capsule lled w ith a P EG 60 00m atrix o f the drug . This cap sule form ulation producedfaec al, p lasm a and urine levels o f the an tib iotic thatw ere sim ilar to those obtained w ith the so lution (18)an d is m arketed by E li Lilly as Van co cin ® H C L .

    2.5. Sustained releaseB y choosing an appropriate excipien t the release

    rate o f an ac tive c an b e m od ified . Fo r exa m p leG elucire, w hich is available as a sem i-solid w ith a

    range o f m elting points an d H LB values, can bem ixed to obtain different drug release rates (19).

    Seta et al. (20) com pared the bioavailability of anoily sem i-so lid m atrix o f captopril in hard gelatincapsules w ith that of a tab let. They conclud ed thatthe oily sem i-solid m atrix o f cap topril containingsoybean o il and glyceryl m onostearate b .i.d. provi-ded antihyp ertensive action that w as com parab le tothe conventional tab let t.i.d ., the total daily d osebeing eq ual. This product is m arketed by Sankyo inJap an as C aptoril ®‚ and provides the patient w ith am ore convenient dosag e regim e.

    3. The empty hard gelatin capsuleand comparison to soft gelatincapsules

    The hard gelatin capsule for liquid filling is identi-cal in com position to the c apsu le u sed for fillingpow ders and co m prises gelatin, w ater, co louringand opacifying ag en ts. For an efficient sealing pro-cess, how ever, it is im portant that the fill m aterialdoes no t penetrate into the zone b etw een the b od yand cap before the sealing operation.

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    A capsule w ith a special co nfiguration has b eendesigned to elim inate this problem and the range ofcapsule sizes available is given in Tab le 1 .

    In co ntrast to the h ard g elatin c ap su le the so ftgelatin capsu le contains a p lasticizer in add ition togelatin and w ater. U su ally g lycero l at a level of ap-prox. 30 % is used . A s d escribed by B auer (21), them oisture uptake of so ft gelatin cap sules plasticizedw ith glycerol is considerably higher than that for hardgelatin capsu les. A nother effect of the plasticizer hasbee n rep orted by A rm strong et al. (22). They foundthat m igration of a drug into the shell of a so ft gelatin

    capsule can o ccur w hich m ay resu lt in d rug deg ra-dation an d dif cu lties in assay.

    O ne basic d ifferen ce exists b etw een the ha rdan d so ft gelatin enca psulation p rocesses. In thehard gelatin capsule process, the capsule is p re-fa-bricated and supplied em pty, w he reas in the softgelatin cap sule process the encapsulation and llingtake p lace sim ultaneously. The m oisture content ofthe gelatin/p lasticizer m ass at this stage can bearound 50% , the equilib rium m oisture level onlybeing reached after several days storage on trays. Itis conceivable that this is the m ost critical periodduring w hich m igration and degradation o f m oisture

    sensitive drugs, w hich are readily so luble in glycerol,can occur.

    H om et al. (23) rep orted that the o xygen trans-m ission rate of a soft gelatin cap sule lm decreasedw ith the level of glycerol in the lm and also w ith them oisture co ntent. A s the hard gelatin capsule w allcontains no plasticizer one m ay exp ect that the per-m eability of the hard gelatin capsule w all w ill be lo-w er than that of a soft gelatin capsule. C ad é et al.(15) rep orted on the sm ell assessm ent of soft andhard gelatin cap sules containing the highly odorousproducts sh oil, valerian and garlic oil. Their resu lts

    ag ree w ith the conclusions of H om et al. (23), in thatthe perm eability o f the gelatin shell w ithout plastici-zer w as found to be low er than that of the soft gela-tin capsule w ith plasticizer. This higher perm eabilityco uld ha ve c on seq uenc es for oxyge n sen sitivedrugs lled into soft gelatin capsules.

    The soft gelatin encapsulation process is in thehand s o f a few contract m anufacturers, and rarely,due to the com plexities o f the process, do pharm a-ceutica l com panies get involved in this operation.This m eans, tha t from an early stag e o f develop -m en t, once it has been estab lished that a unit li-

    quid/sem i-solid dosage form is necessary, all deve-lopm en t ac tivities m ust be contrac ted out. M an ycom panies w ould prefer to keep these activities in-house for reasons of con dentiality, co ntrol over thedevelopm ent process, availab ility of drug substanceat the ea rly stag es o f developm en t an d no t leastcontrol over costs.

    The asp ects of hard and soft gelatin capsules aresum m arized in Table 2 .

    4. Suitability of ll materials

    A s the ten dency for poorly w ater solub le d rug sto en ter the p ipeline increases so does the chal-lenge to find innovative w ays of developing bioavai-lab le and stab le d osage form s.

    Excipien t suppliers, enco uraged by the potentialopportunities in this eld, are developing new m ate-rials com prising m ixtures of functional exc ipients.A n e xam ple is the introd uction of S M E D D S (S elfEm ulsifying D rug D elivery S ystem ) by G attefossé.U nd oub ted ly this approach w as stim ulated by thew ork perform ed by Sand oz, on the m icroem ulsionform ulation of cyclosporin A (12, 13).

    Sizes and volumes of hard gelatin capsules for liquid lling (Licaps™ (1) )

    Size Approx. volume Approx. availableml volume (2) ml

    00el 0.92 0.83

    00 0.85 0.77

    0 0.61 0.55

    1 0.45 0.41

    2 0.34 0.31

    (1) Licap s is a registered trade m ark of the C apsug el D ivision o f W arner-Lam be rt C om pany.

    (2) A com plete lling of the cap sule bod y is no t possible becau se of the risk of sp illag e during the lling op eration.Th is value a ssum es a lling level of 90 % of the a vailab le vo lum e.

    Table 1 .

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    Th e a rea of contact betw een the capsule sh elland a liquid fill m aterial is greater than is the case

    w ith a pow der filled capsule. The potential for inter-actions m ust therefore b e checked.

    4.1. Moisture exchange ll-shell

    A hard ge latin capsule co ntains 1 4-16% m ois-ture, w hich acts as a plasticizer for gelatin. A hygro-scopic m aterial, w hen filled into the capsule, couldextract m oisture from the shell thereby inducing em -brittlem ent.

    The p otential for this is checked by storing cap-su les filled w ith the product under various condi-tions o f relative hum idity from 2.5 to 65% and m ea-suring the w eight change as already described byC adé and M adit (24 ).

    The accep tan ce criteria h ave bee n set at achange in w eight of plus or m inus 2% .

    4.2. Mechanical properties

    The relationship betw een relative hum idity duringstorag e, gelatin m oisture content and capsule p ro-perties w as rep orted by B ond et al. (25) an d isshow n in Figure 2 .

    The change in capsu le b rittleness w ith relativehu m id ity has a lso b een stud ied by K on tny an dM ulski (26). It follow s that m onitoring of the m echa-nical properties o f capsules stored at various rela-tive hum idities is o f critical im portance in determ i-ning com patibility b etw een the fill m aterial and thecapsule shell. The m ethodology to d eterm ine this isdescribed by C adé and M ad it (24 ). Acceptance cri-teria proposed are that significant capsule brittle-ness shou ld no t be d etected in cap sules stored at30 % and 5 0% relative hum idity for four w eeks.

    4.3. Dissolution stability indicator

    The potential for interaction of an excipien t or ac-tive w ith the cap su le shell w hich can resu lt in achange in d issolution b ehaviour has been d escribedby D ey et al. (27) for capsules filled w ith p ow ders.D isso lution of gelatin capsules w as also the topic ofan FD A /Industry W orking G roup and a m od i ed d is-so lution testing procedure allow ing the use of en -zym es has b een accepted w hen a delay in d issolu-tion is a resu lt o f p ellicle form ation (28). N orelevance to the in vivo beh aviour of the cap sulesw as estab lished (29, 30).

    Comparison of hard and soft gelatin capsules

    Aspect Hard gelatin Soft gelatin

    capsule capsuleIn house developm ent and m anufacture Yes D if cult

    A bility to m anufacture sm all batches Yes N o

    S cale-up S im ple and in-house R equires large quantitiesof drug sub stanceand m ust be outsourced

    Tem perature of ll M ax. ~ 70°C M ax. ~ 35°C

    P lasticizer in shell N o Yes

    R isk of drug m igration Low H igh for drugs solublein plasticizer

    P erm eability of shell to oxygen Low H igh due to plasticizerVaries w ith m oisture content

    S ensitivity to heat and hum idity Low H igh due to plasticizer

    Lim itation on excipients for form ulation H igh concentrations of H ygroscopic excipientshygroscopic excipients such can be tolerated due toas glycerol m ust be avoided presence of plasticizer

    in shell

    C apsule dim ensions C onstant M ay vary

    Table 2 .

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    C ertain exc ipients used in the form ulation of liquidfilled ca p su les m ay h ave , o r m ay g en erate d uringstorag e, low leve ls of aldeh yd es, w hich can p oten -tially rea ct w ith gelatin. A s a m ea ns to evaluate p o-tential interactions w ith the gelatin sh ell, cap su lesare filled w ith the test m aterial and stored in closedH D P E bottles at 40 °/75 % R H for period s of up to sixm onths. A fter the appropriate tim e h as e lap sed thecap sules are em ptied and clean ed . A cetam ino phenis use d as a d isso lution referen ce m aterial and isfilled into the capsules w hich ha ve been stored an dthe d isso lution rate d eterm ine d using the U S P m e-tho d 2. C om parison of the ace tam ino phen d issolu-tion p rofiles from the stored an d from a reference

    capsu le g ives an ind ication of a p otential interactionbetw een the ll m aterial an d the capsule sh ell.

    Particularly in the case of hot m elt fills the effectof m elting tem perature and tim e held at this tem pe-rature o n the p otential for form ation of aldehydesneeds to b e investigated .

    The rate of cooling can also have an in uence onthe structure of certain excipien ts w hich in turn m aym odify the drug relea se ch aracteristics from them atrix itself (31).

    4.4. Recommended Properties

    (Temperature And Viscosity) of FillMaterials

    The im portan t factors to bear in m ind during a li-quid filling operation are tem perature and viscosityof fill m aterial and in the case of a susp ension theparticle size of the suspen ded d rug . W he reas inprinciple any excipien t found to be com patible w iththe gelatin shell can be used, in practice in a m anu-facturing environm ent the viscosity of the ll m aterialis im portant. If the viscosity is too low sp lash ing ofthe b ushing s m ay occur w hich cou ld contam inatethe area o f overlap betw een the cap sule bod y andcap and prevent a good seal from being form ed.

    A bsence of a clean break d uring dosing (“strin-ging”) can have the sam e effect.

    The guidelines for problem free lling are g iven inTable 3 .

    4.5. Excipients compatible withhard gelatin capsules

    The m aterials listed have been tested acco rdingto the p rocedures desc rib ed ab ove. E xcip ien tsw hich , from the aspec t of co m patibility, can consi-dered to be suitab le for form ulation of drugs intoha rd gelatin ca psules, are sho w n in Tables 4 , 5 and 6 . They have b een classi ed into three arbitrarygroups:

    • Lipophilic liquid vehicles• S em i-solid lipophilic vehicles/viscosity m odi-

    ers for lipophilic liquid vehicles

    • S olubilizing agents, su rfactants, em ulsifyingagents and adsorption enhancers

    E xcipien ts show n in Tab le 7 are considered to b eincom patible w ith hard gelatin capsules and sho uld beavo ided at high co ncen tration s. They m ay, ho w ever,

    be u sed in m ixed system s, in w hich case the criticalco nc en tration, ab ove w hich co m patib ility co uld be-com e an issue, m ust be d eterm ined exp erim entally.

    It appears that the incom patibility of the m ediumchain m onoglycerides m ay be d ue to the presenceof quantities of glycerol rem aining from the synthe-sis of these products. If the M C M ’s are to b e consi-dered the glycerol level m ust be < 5% .

    The co m patibility screening of the final form ula-tion includ ing the drug sub stance m ust be m onito-red as part of the routine developm ent process.

    5 10 15 20 25 30 35 40

    CAPSULE SHELLSHELLSOFTENS

    SHELL CHARACTERISTICSSATISFACTORY

    SHELLFRACTURES

    ACCEPTABLERH FOR SHELL

    45 50 55 60 65 70 75 800

    0

    5

    67

    8

    9

    10

    11

    12

    13

    14

    15

    16

    17

    18

    19

    20

    M o

    i s t u r e c o n

    t e n

    t %

    Relative humidity

    Figure 2: Equilibrium moisture content of emp ty ge- latin capsule shells stored at various relative hum idi- ties for two w eeks a t 20°C.

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    Lipophilic liquid vehicles

    Rened speciality oils MCT’s (1) and related estersArachis oil Akom ed EC astor oil Akom ed RC ottonseed oil C aptex 355M aize (corn) oil Labrafac C CO live oil Labrafac P GSesam e oil Lauroglycol FC CSoybean oil M iglyol 810Sun ow er oil M iglyol 812

    M iglyol 829M iglyol 840Softisan 645

    Q uality m ay vary betw een d ifferent sup pliers and also from batch to b atch and sh ou ld b e routine ly checked .Th e the rm al history of excipients du ring m anufacture sho uld b e recorded.

    (1) M ed ium chain triglycerides.

    Semi-solid lipop hilic vehicles / Viscositymodiers for lipophilic liquid vehicles

    H ydrogenated speciality oilsA rachis o il: G roundnu t 36C astor oil: C utina H RC ottonseed oil: S terotexP alm oil: S oftisan 154S oyb ean oil: A kosol 40 7

    A erosil

    C etosteryl alcoho lC etyl alcoho lG elucires 33 /01 , 39 /01 , 43 /01G lyceryl behenate (C om pritol 88 8 ATO )G lyceryl palm itostearate (P recirol ATO 5)S oftisans 100 , 14 2, 37 8, 64 9S teryl alco ho l

    Q uality m ay vary betw een d ifferent sup pliers and also from ba tch tobatch and sho uld b e routinely checked . Th e therm al history of exci-pients during m anu facture shou ld be reco rded.

    Solubilizing agents, surfactants,emulsifying agents adsorption enhancers

    C apryol 90G elucire 44/14, 50/13C rem ophor R H 40Im w itor 19 1, 30 8 (1) , 380, 742, 78 0 K , 928, 988Labra l M 1944 CS , M 2125 CSLauroglyco l 90

    P EG M W > 4000P lurol O leique C C 49 7P oloxam er 124 and 188S oftigen 70 1, 76 7Tagat TOTw een 80

    (1) G lycerin co ntent < 5%

    Q uality m ay vary betw een d ifferent supp liers and also from ba tch tobatch and sho uld b e routinely checked . Th e therm al history of exci-pients during m anu facture shou ld be reco rded.

    Table 4: Excipients com patible w ith hard gelatin capsu le shells.

    Table 5: Excipients com patible w ith hard gelatin capsule shells.

    Table 6: Excipients com patible w ith hard gelatin capsule shells.

    Recommended guidelines for dosing liquids/semi-solids into hard gelatin capsules

    Parameter RecommendationTem perature of ll m aterial M ax. ~ 70°C

    Viscosity at the tem perature of dosing 0.1 - 1 P a s

    Visco properties C lean break from dosing nozzleA bsence o f “stringing”

    Particle size of suspended drug < 50 µm

    Table 3 .

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    5. Filling and sealing equipment

    5.1. Capsule Filling Machines

    M ost of the m od ern Europ ean capsule lling m a-chine s can b e m odified to a llow hard gelatin cap -sules to be filled w ith hot or cold liquids. The m a-

    ch ine req uirem en ts to allow an industrialm anufacture of liquid lled capsules are rep orted byC ole (32) an d the m od els availab le a re g iven inTable 8 .

    5.2. Equipment for sealinghard gelatin capsules

    An essential part of a liquid lling operation is theability to e ffectively seal the capsule. Various m e-thods a re availab le to seal hard g elatin cap su lesand these have b een review ed by W ittw er (33 ). The

    tw o m ost stud ied m ethods are band ing using a ge-latin band and sealing using a hydroalcoholic solu-tion and both m ethods are described in the G eneralInform ation section of the U SP on capsules (34).

    5.2.1. Hard gelatin capsulebanding technology

    The ban ding of hard gelatin capsules is a pro-cess w hich has been com m only used and w as ori-gina lly developed to prevent sep aration o f pow derfilled capsules prior to the invention of capsule loc-king system s. The c apsules are first rectified andthe n p asse d o nce o r tw ice o ver a w he el tha t re-volves in a gelatin bath. A quantity of gelatin is p ic-ked up by the serrated w heel and ap plied to thejunction o f the cap and body. The capsules rem ainin individual carriers for drying. It is generally accep-ted that the industrial banding operation is capitalintensive and not user friendly.

    European automatic capsule-lling machines for liquid lling

    M achine type N um ber of capsules/segm ent Approxim ate lling rate

    (capsules/H )

    Robert Bosch GmbHG K F 400 L 3 10,000G K F 800 L 6 30,000G K F 1500 L (2 pum ps) 6 60,000

    Harro Hoeiger GmbHK FM III-I 1 3,500K FM III 3 10,000

    IMA Zanasi DivisionZ 12 2 12,000Z 48 P lus 6 36,000Z 85 P lus 11 70,000

    MG2C om pact C ontinuous m otion 4,000 - 34,000Futura C ontinuous m otion 4,000 - 70,000

    Table 8 .

    At the 100% level the fo llowing excipients are incompatible w ith hard gelatin capsule shells

    Ethanol P EG ’s of M W < 4000G lycerin P harm asolveG lycofurol 75 P ropylene glycolM C M ’s S pan 80–A koline M C M , C apm ul M C M , Im w itor 308 (1) Transcutol P

    (1) G lycerin content > 5%

    M ixtures w ith com pa tible exc ipients m ay allow these to be u sed in low er concen tration s. Lim it m ust be d eterm ined experim entally.

    Table 7: Excipients for liquid/sem i-solid formulations.

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    Stages of the hard gelatin capsule sealing process

    Stage Process1. M oisturizing 50:50 w ater/ethanol m ixture sprayed onto join and capillary

    action draw s liqu id into the space betw een bo dy and cap .

    Excess uid rem oved by suction. M elting point of gelatinlow ered by presence of w ater.

    2. W arm ing Application of gentle heat of approx. 45°C com p letes them elting over a period of about one m inute and the tw ogelatin layers are fused together to form a com plete 360° seal.

    3. S etting G elatin setting or hardening process is com pleted w hile theproduct returns to room tem perature. This process is bestcarried out on trays.

    Table 9 .

    Capillary Actiondraw s fluid upbetween the ca pand the body

    Spray fluid ontojoin betweenca psule ha lves

    Magnify

    Directedfluid jet

    Figure 3: Illustration of sp raying p rocess tomoisturize the space betw een cap and bo dy of the cap sule.

    Figure 4: LEMS™ 30 m achine for sealing hardgelatin capsules.

    Comparison of the hard gelatin capsule sealing and banding t echnologies

    Aspect Capsule sealing Capsule bandingusing LEMS™

    Installation and start-up Easy, Q uick D if cult, Tim e consum ing

    M achine operation U ser friendly U ser unfriendly

    Initial capital costs Low H igh

    Tim e for size change ~ 1 hour ~ 8 hours

    C apsule recti cation N o Yes

    C leaning Tim e 2 - 3 hours ~ 12 hours

    S ealed area Large Sm all area of band

    G elatin handling N o YesC urrent m axim um m achine output 30,000 / hour 80,000 / hour

    S olvent exhaust Yes N o

    Table 10.

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    5.2.2. Hard gelatin capsule sealing

    technology by microsprayThe capsule se aling p roce ss, w hich w as first

    desc ribed by W ittw er (33) and sub seq uently byC adé et al. (15), uses the principle of low ering of them elting point of gelatin by the applica tion of m ois-ture to the area betw een the capsule bod y and cap .

    The first m achine deve loped to sea l capsules,described by C ad é et al. (15) involved dipping thecapsules into a bath of liquid and drying in a fluidi-zed bed cham ber. D uring this process the cap sulesw ere su bjec ted to considerable stress. In contrastto this, in the red esigned process every cap sule isindividually sprayed w ith a m icro am ount of sealingfluid at the b ody an d cap jun ction a s show n in

    Figure 3 . D rying takes place by gently tum bling thecapsules in a rotating drum . The various stages ofthe process are outlined in Tab le 9 .

    C ontrol of the filled and sealed capsules is car-ried out as follow s:

    • Inspection on trays after 24 hours.

    • Inspection after depression test at - 0.8 bar for20 m inutes.

    •Inspection after 18 hours at 45°C after coolingto room tem perature.

    B y inco rporation of a d ye tracer into the sealing uid and observation of the liquid in the overlap pingsp ace it could be verified that the se aling liquiddoes not pass beyond the interlocking rings of a Li-caps capsule.

    The m ach ine for industrially sealing hard gelatincap sules, sho w n in Figure 4 , is com m ercially avai-lable and is m arketed under the nam e LEM S 30 (1)

    (Liquid E ncapsulation by M icroSpray).

    The m achine is free standing and in prac tice isconnected to the output of a capsule lling m achineby m eans of a conveyor.

    N um erous com panies fam iliar w ith the hard gela-tin cap sule ban ding o peration have eva luated thecapsule sealing technology using LEM S and overa p eriod of tim e a neutral co m parison o f the tw oprocesses has been p ossible. This com parison isshow n in Table 10 .

    6. ConclusionThe ability to be able to ll liquids and sem i-solids

    into h ard gelatin cap sules h as b een an o ption forseveral years. The tech nology p otentially p rovidesthe ind ustry w ith an in-ho use p rocess to developdrugs w hich are poorly w ater solub le, have low m el-ting points, are h ighly potent or low dosed or have acritical stability issue, into bioavailable, stable andsafe dosag e form s.

    O ne p rob lem w hich has prevented w ider accep -tance of this techno logy w as the fact tha t the cap-sules had to b e banded using a p rocess w hich isdifficult to operate and capital intensive. D evelop -m ent of the LEM S techno logy provides a m eansto effectively seal hard gelatin capsules using a pro-cess w hich is easy to co ntrol.

    Liquid filling and sealing of hard gelatin capsulesthus becom es a m uch m ore feasible option. It pro-vides the form ulation scien tist w ith an in-house op-tion to rap id ly develop p roducts for clinical trialsw hen drug substance is at a prem ium and also p ro-vides an easy route to scale-up and production.

    7. References1. P. G hirardi, G . C aten azzo , O . M an tero, G .C . M erotti

    and A . M arzo. “B ioava ilab ility of D igoxin in a N ew S o-lub le P ha rm ac eu tica l Form ulation in C ap su les .” J .Pharm. Sci. 66 (2): 267-269 (1977).

    2. A . C uiné et al., “D as Einb ringen visko ser Loesun genvon A ktivstoffen in H artgelatinekapseln.” Pharm. Ind.40 (6): 654-657 (1987).

    3. S .E. W alker et al., “The Filling of M olten and ThixotropicFo rm ulations into H ard G elatin C ap sules.” J. Pharm.Pharmacol. 32 : 38 9-393 (19 80 ).

    4. S .E . W alker, K . B ed ford, an d T. Eaves, B ritish patent1.572.226, 30 July 1980 .

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    von R ezep turen un d Verfah ren zur Ab fuellun g vonfluessigen M assen in H artgelatine kapseln un ter Pro-du ktionsbedingungen. “ Acta Pharm. Technol. 29 (3):245-251 (1983).

    6. C . M cTaggart et al., “The Evalua tion of an A utom aticS ystem for Filling Liquids into H ard G elatin C ap sules.”J. Pharm. Pharmacol. 36 : 119-121 (1984).

    7. C . D oelker et al., “The Inco rporation an d In V itro R e-lease P rofile of Liquid. D eliquescent or U nstab le D rugsw ith Fusible E xcipien ts in H ard G elatin C ap sules.” Drug Dev. Ind. Pharm. 12 (10 ): 15 53 -15 65 (19 86 ).

    (1) LE M S is a reg istered trad e m ark of the C ap suge l D ivision o f W arner-Lam bert C om pany.

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    8. W . Lahr, “Fluess ig B efuellte H artgelatineka pse ln,”

    Pharm. Ztg. 131 (15): 871-874 (1986).9. R . H errm an n, “B ioverfueg barkeit zw eier neuer N ifed i-

    pin-Form ulierungen ,” Pharm. Ztg. 131 (15): 869-870(1986).

    10. C .A . Lipinski, S trategies for O ptim izing O ral D rug D eli-very, K obe, April 19-21, 1999.

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    12. J.M . K ovarik, E.A . M ue ller, J-B . Van -Bree , W . Tetzloffan d K . K utz, “R ed uced inter- and intraindividual varia-bility in cyclosp orin pharm acokinetics from a m icro-em ulsion form ulation.” J. Pharm. Sci. 83 : 44 4-446(1994).

    13. Patent, “O il-Free Pharm aceu tica l co m positions co ntai-ning cyclosporin A ”, W O 93 /20 83 3, 19 93 .

    14. A .R . H aw ley, G . R ow ley, W .J. Loug h, S .M . C hatham“P hysical and chem ical ch aracterisation of therm osof-ten ed bases for m olten filled hard gelatin cap sule for-m ulations” Drug Devel. Ind. Pharm. 18 (16): 1719(1992).

    15 . D . C ad é, E.T. C ole, J-Ph . M aye r and F. W ittw er. “Li-quid Filled and S ealed H ard G elatin C ap sules” Acta Pharm. Technol. 33 (2): 97-100 (1987).

    16 . W . J. B ow tle, P rivate C om m unication , 19 97 .

    17 . W . J. B ow tle, N .J. B arker, and J . W od ham s. “A N ew

    A pproa ch to V an co m ycin F orm ulation U sing FillingTechn ology for S em iso lid M atrix C ap sules.” Pharm.Technol. 12 (6): 86-97 (1988).

    18 . R .A . Lu cas, W .J. B ow tle, R . R yden , “D isp osition ofvanco m ycin in h ea lthy volun tee rs from oral so lutionand sem i-solid m atrix capsules”, J. Clinical Pharmacy and Therapeutics , 12 : 27 -31 (19 87 ).

    19 . J.R . H ow ard and P.L. G ou ld, “D rug R elease from Ther-m osetting Fatty Vehicles Filled into H ard G elatin C ap -su les,” Drug Dev. Ind. Pharm . 13 (6): 103 1-10 45(1987).

    20. Y. Seta et al., “D esign of C ap topril S ustained -ReleaseP rep aration w ith O ily S em iso lid M atrix Intend ed for

    U se in H um an S ub jects.” Int. J. Pharm. 41 : 26 3-269(1988).

    21. K .H . B auer, “D ie H erstellung von H art- und W eichgela-tinekapseln.”In D ie K ap sel. W . Fahrig and U .H . H ofer,Eds., Wissensc haftliche Verlags GmbH, Stuttg art , pp.58 -82 (1983).

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    M igration into S oft G elatin C ap sule S hells and its E f-fect on In-Vitro Availability.” J. Pharm. Pharmacol , 36 :361-365 (1984).

    23 . F.S . H om , S .A . Ve resh and W .R . Ebert “S oft G elatinC ap sules II: O xyge n P erm eab ility S tud y o f C ap suleS hells.” J. Pharm. Sci. 64 (5): 851-857 (1975).

    24. D . C ad é an d N . M ad it, “Liquid Filling in H ard G elatinC apsules –Prelim inary Steps”, Bulletin Techniq ue Gat- tefossé , 1996.

    25 . C .M . B ond , K .A . Lees, J.L. Packing ton, “C ephalexin:A new oral broad -spectrum an tibiotic”, Pharm. J. 205 :210-214 (1970).

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    27 . M . D ey, R . Enever, M . K ram l, D .G . P rue, D . S m ith andR . W eierstall, “The D issolution and B ioavailability o fE tod olac from C ap sules E xpo sed to C on dition s o fH igh R elative H um idity and Tem peratures”, Pharm.Res. 10 : 1295 -1300 (1993).

    28 . P harm acop eial Fo rum , “C ollab orative D evelop m ent ofTw o-Tier D isso lution Testing for G elatin C ap sules andG elatin-C oated Tablets using Enzym e-C ontaining M e-dia”, 24 (5): 70 45 -70 50 (19 98 ).

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    A .B . S trau ghn , L. Le sko an d R .L. W illiam s. “The ef-fects of cross-linking in gelatin capsules on the bioe-quivalence of acetam ino phen”. Pharm. Res. 14 (11):3251 (19 97).

    30. J. B row n, N . M ad it. E .T. C o le, I.R . W ild ing an d D .C ad é. The effec t of cross-linking on the in vivo disinte-gration of hard gelatin capsules. Pharm. Res. 15 (7):1026-1030 (1998).

    31 . S .M . C hatham , “The U se o f B ases in S em i-S olid M a-trix F o rm ulations,” S.T.P. Phar ma. 3 (7 ): 575-58 2(1987).

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    33. F. W ittw er, “N ew D evelopm ents in H erm etic S ealing ofH ard G elatin C ap su les.” Pharm. Manuf . 2 : 24 -27(1985).

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