ADVANCEMENT IN MANUFACTURING OF NON-GELATIN CAPSULE SHELL-A REVIEW

Author Name: - Daga !"e Ra#!$ ra %&' (a)a*e Ar+ha$a D' Maha)a$ Va$ a$a (' ,o-h! Ma$!-ha H. A//!*!at!o$:01 Daga !"e Ra#!$ ra %& 2 Author 31 (a)a*e Ar+ha$a D 2 Gu! e 41 Maha)a$' Va$ a$a ( 2 Co gu! e 51 ,o-h! Ma$!-ha H 2 Co gu! e Dr.V.P.P.Co**ege o/ Pharma+"' Pa!tha$ roa ' Aura$ga6a ' Mahara-htra Corre-7o$ e$+e Deta!*-:-r!+8"ra#!$ ra9gma!*.+om& A re--: - N-3' L-5-04:;' Ram$agar' CIDCO' Aura$ga6a ' Mahara-htra' 540<<=.

Co$ta+t $o:->?0?5345=@;5=.

A6-tra+t:The gelatin cap-sule shell may be soft or hard depending on their formulation. Capsules are intended to be swallowed whole by the patient. In instances where patients (especially children) are unable to swallow capsules, the contents of the capsule can be removed and added (e.g., sprinkled) on soft food immediately before ingestion. In the manufacture of pharmaceuticals, encapsulation refers to a range of techni ues used to enclose medicines in a relatively stable shell known as a capsule, allowing them to, for e!ample, be taken orally or be used as suppositories. "ard-shelled capsules, which are normally used for dry, powdered ingredients or miniature pellets, #oth of these classes of capsules are made from a ueous solutions of gelling agents like$%nimal protein mainly gelatine %nd &on-gelatin such as 'lant polysaccharides or their derivatives like carrageenans and modified forms of starch and cellulose. (espite the great advantages, of gelatin capsules), gelatin has several drawbacks that limit its use for capsules. The animal source of gelatin can be a problem for certain consumers such as vegetarians or vegans and religious or ethnic groups, *ince unmodified gelatin is prone to cross linking when in contact with aldehydes, solubility problems might be e!pected with certain fill formulations. The non-gelatin capsule shells are made up of such as *tarch, "'+C, ',%, and %lginate. (e" Aor -: - -elatin.&on--elatin +aterial, capsule shell, *tarch, "'+C, ',%, %lginate.

GELATIN:NON-GELATIN CAPSULE SHELL

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INTRODUCTION Capsules are solid dosage forms in which the drug is enclosed within either a hard or soft soluble container or /shell.0 The shells are usually formed from gelatin1 however, they also may be made from starch or other suitable substances. 234 The gelatin capsule shell may be soft or hard depending on their formulation. Capsules are intended to be swallowed whole by the patient. In instances where patients (especially children) are unable to swallow capsules, the contents of the capsule can be removed and added (e.g., sprinkled) on soft food immediately before ingestion. In this case, capsules are used as a vehicle to deliver premeasured medicinal powder.
254

In the manufacture of

pharmaceuticals, encapsulation refers to a range of techni ues used to enclose medicines in a relatively stable shell known as a capsule, allowing them to, for e!ample, be taken orally or be used as suppositories. The two main types of capsules are$ "ard-shelled capsules, which are normally used for dry, powdered ingredients or miniature pellets (also called beads that are made by the process of 6!trusion and *pheroni7ation) - or mini tablets1 *oft-shelled capsules, primarily used for oils and for active ingredients that are dissolved or suspended in oil. #oth of these classes of capsules are made from a ueous solutions of gelling agents like$
%nimal protein mainly gelatin1 'lant polysaccharides or their derivatives like carrageenans and modified forms of starch and

cellulose. 8ther ingredients can be added to the gelling agent solution like plastici7ers such as glycerine and.or sorbitol to decrease the capsule9s hardness, colouring agents, preservatives, disintegrants, lubricants and surface treatment.
TBPES OF CAPSULES

Ge*at!$ +a7-u*e-, informally called ge* +a7- or ge*+a7-, are composed of gelatin manufactured from the collagen of animal skin or bone. (-elatin is not derivable from ungulate hooves, which are composed of a different protein, keratin.)

Vegeta6*e +a7-u*e- are composed of hypromellose, a polymer formulated from cellulose.2:4 There are two types of capsules, /hard0 and /soft0. The hard capsule is also called /two pieces0 as it consists of two pieces in the form of small cylinders closed at one end, the shorter piece is called the /cap0 which fits over the open end of the longer piece, called the /body0. The soft gelatin capsule is also called as /one piece0. Capsules are available in many
3

si7es to provide dosing fle!ibility. ;npleasant drug tastes and odours can be masked by the tasteless gelatin shell. The administration of li uid and solid drugs enclosed in hard gelatin capsules is one of the most fre uently utili7ed dosage forms. A #a$tage- o/ Ca7-u*eCapsules mask the taste and odour of unpleasant drugs and can be easily administered. They are attractive in appearance They are slippery when moist and, hence, easy to swallow with a draught of water. %s compared to tablets less ad<uncts are re uired. The shells are physiologically inert and easily and uickly digested in the gastrointestinal tract. They are economical They are easy to handle and carry. The shells can be opacified (with titanium dio!ide) or colored, to give protection from light. D!-a #a$tage- o/ Ca7-u*eThe drugs which are hygroscopic absorb water from the capsule shell making it brittle and hence are not suitable for filling into capsules. The concentrated solutions which re uire previous dilution are unsuitable for capsules because if administered as such lead to irritation of stomach.2=423>4

Sta$ ar -!Ce- o/ tAo-7!e+e CAPSULES D4E

4

S!Ce ? = : 5 3 @ @6 @@ @@@ 3: 35 35el 33 3@ > *u@>

Vo*ume Fm*1 @.3: @.53 @.: @.:> @.? @.CB @.> @.A? 3.:> :.5 ? >.? 3@ 3B 5= 5B

Lo+8e *e$gth Fmm1 33.3 3=.: 3?.A 3B 3A.= 53.> 5:.3 5:.: 5C.3= :@ =@.? ?> =>.? C= >B BB.?

EGter$a* !ameter Fmm1 =.A3 ?.:3 ?.B5 C.:? C.A3 >.C? >.C? B.?: A.A3 3?.: 3?.: 3?.? 5@.A 5:.= 5:.= 5:.=

RaA mater!a*- u-e /or +a7-u*e -he** ma$u/a+tur!$g GELATIN CAPSULE SHELL De#e*o7me$t o/ +a7-u*e -he** 6" Ge*at!$:-elatin is the ma<or component of the capsules and has been the material from which they have traditionally been made. -elatin has been the raw material of choice because of the ability of a solution to gel to form a solid at a temperature <ust above ambient temperate conditions, which enables a homogeneous film to be formed rapidly on a mould pin. The reason for this is that gelatin possesses the following basic properties$ It is non-to!ic, widely used in foodstuffs and acceptable for use worldwide. It is readily soluble in biological fluids at body temperature. It is good film-forming material, producing a strong fle!ible film The gelatin films are homogeneous in structure, which gives them strength. *ome of the disadvantages with using gelatin for hard capsules include$ it has a high moisture content, which is essential because this is the plastici7er for the film and, under International Conference on "armoni7ation of Technical De uirements for Degistration of 'harmaceuticals for "uman ;se (IC") conditions for accelerated storage testing, gelatin
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undergoes a cross linking reaction that reduces its solubility. -elatin is a translucent brittle solid substance, colourless or slightly yellow, nearly tasteless and odourless, which is created by prolonged boiling of animal skin connective tissue or bones. Type % gelatin is derived from an acid-treated precursor and e!hibits an isoelectric point in the region of p" A, whereas type # gelatin is from an alkali-treated precursor and has its isoelectric 7one in the region of p" =.>. Capsules may be made from either type of gelatin, but mostly a mi!ture of both types is used considering availability and cost. (ifference in the physical properties of finished capsules as a function of the type of gelatin used is slight. #lends of bone and pork skin gelatins of relatively high strength are normally used for hard capsule production. The bone gelatin produces a tough, firm film, but tends to be ha7y and brittle. The pork skin gelatin contributes plasticity and clarity to the blend, thereby reducing ha7e or cloudiness in the finished capsule.2=423>4 I - HARD GELATIN CAPSULES The ma<ority of capsule products are made of hard gelatin capsules. "ard gelatin capsules are made of two shells$ the capsule body and a shorter cap. The cap fits snugly over the open end of the capsule body. The basic hard gelatin capsule shells are made from mi!tures of gelatin, sugar, and water. They are clear, colourless, and essentially tasteless. -elatin is a product obtained by partial hydrolysis of collagen ac uired from the skin, white connective tissue, and bones of animals. -elatin is a protein which is soluble in warm (or hot) water, but insoluble in cold water. %t low temperatures, gelatin dissolved in water becomes a gel (which is insoluble in water). This property is used to prepare Eello and other gelatin deserts. -elatin capsules become dissolved in warm gastric fluid and release the contents. &ormally, hard gelatin capsules contain 3:F3CG of moisture. If additional moisture is absorbed when stored in a high relative humidity environment, hard gelatin capsule shell may lose their rigid shape and become distorted. In an opposite environment of e!treme dryness, capsules may become too brittle and may crumble during handling. *ince moisture can be absorbed or released by the gelatin capsules, capsules containing moisture-sensitive drugs are usually packaged in containers. -elatin for making hard shells is of bone origin and has 55@F5B@ g bloom strength (the weight re uired to depress a standard plunger = mm into the gel).2?423?4 +%&;H%CT;DI&- 8H "%D( C%'*;I6* *ome of the ma<or suppliers of empty gelatin capsules are$ 6li Iilly and Company, Jarner Iambert)s Capsugel (formerly 'ark (avis) and D. '. *cherer Corporation.

The metal moulds at room temperature are dipped into a hot gelatin solution, which gels to form a film. This is dried, cut to length, removed from the moulds and the two parts are <oined together, these processes are carried out as a continuous process in large machines. The completely automatic machine most commonly used for capsule production consists of mechanisms for automatically dipping, spinning, drying, stripping, trimming, and <oining the capsules. K *tainless steel pins are used on which the capsule is formed and controls some of the final critical dimensions of the capsule. K 8ne hundred and fifty pairs of these pins are dipped in to gelatin sol of carefully controlled viscosity to form caps and bodies simultaneously. The pins are usually rotated to distribute the gelatin uniformly, during which time the gelatin may be set or gelled by a blast of cool air. K The pins are moved through a series of controlled air drying kilns for the gradual and precisely controlled removal of water. The capsules are striped from the pins by bron7e <aws and trimmed to length by stationary knives while the capsule halves are being spun in chuks or collets. %fter being trimmed to e!act length, the cap and body sections are <oined and e<ected from the machine. The entire cycle of the machine lasts appro!imately =? min. K Thickness of the capsule wall is controlled by the viscosity of the gelatin solution and the speed and time of dipping. +old pin dimensions, precise drying, and machine control relating to cut lengths are matters that are critical to the final dimensions. 'recise control of drying conditions is essential to the ultimate uality of the cast film. The in-process uality controls include periodic monitoring, and ad<ustment when re uired, of film thickness, cut lengths of cap and body, colour, and moisture content. Inspection processes to remove imperfect capsules which were previously done visually, have recently been automated following the development and patenting of a practical electronic sorting mechanism by 6li Iilly and Company. This e uipment mechanically orients the capsules and transports them past a series of optical scanners, at which time those having detectable visual imperfections are automatically re<ected. 2?4

EG+!7!e$t- o/ Har ge*at!$ +a7-u*e %) -elatin #) Colour L 8pecifying agent C) 'reservatives (methyl paraben, propyl paraben, butylated hy-dro!yaniline, 6(T%, sodium ben7oate) () (yes, pigments, 6) H) p"-ad<usting additive Hlavour and fragrance

II- SOFT GELATIN CAPSULES *oft gelatin (also called softgel or soft elastic) capsules consist of one-piece hermetically-sealed soft shells. *oft gelatin capsules are prepared by adding a plastici7er, such as glycerine or polyhydric alcohol (e.g., sorbitol), to gelatin. The plastici7er makes gelatin elastic. *oft gelatin capsules come in various shapes such as spherical, elliptical, oblong, and special tube shapes with and without twist off (see Higure :.B). They can contain non-a ueous li uids, suspensions, pasty materials, or dry powders. They are especially important to contain volatile drug substances or drug materials susceptible to deterioration in the presence of air. +%&;H%CT;DI&- 8H *8HT C%'*;I6* There are several procedures to prepare soft gelatin capsules, such as the plate process, the rotary die process, and reciprocating die process. +ost soft gelatin capsules produced in industry are prepared by the rotary-die process (see Higures :.A and :.3@). In this process, two continuous gelatin ribbons are brought together between twin rotating dies. %t the moment that the dies form pockets of the gelatin ribbons, metered-fill material is in<ected between the ribbons. Then the pockets of fill-containing gelatin are sealed by pressure and heat. The capsules are subse uently severed from the ribbon. %s the capsules are cut from the ribbons, they may be collected in a refrigerated tank to prevent capsules from adhering to one another and from getting dull. *oft gelatin capsules contain more moisture than the hard capsules. *ince gelatin is sub<ect to microbic decomposition when it becomes moist, soft gelatin capsules may be prepared with preservatives to prevent the growth of fungi. -elatin used for making soft capsules is usually of bone and skin origin and has 3?@F3>? g bloom strength.2?42C4 D33E
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Ta6*e:-6!amples of commercial products prepared in soft gelatin capsules 6thchlorvynol ('lacidylM, %bbott) (emeclocycline "Cl ((eclomycinM, Iederle) Chlortrianisene (T%C6M, +arion +errell (ow) (igo!in (Iano!icapsM, #urroughs Jellcome) (ocusate calcium (*urfakM, ;p<ohn) ,itamin 6 (%cesM, E.D. Carlson Iab.) &eoralM capsule NantacM -eldose capsule 'rocardiaM capsule ('6- based) %dvilM li uicapsule

F!gure' *chematic drawing of rotary-die soft gelatin capsule filler (D.'. *cherer$ (etroit, +I). EG+!7!e$t- o/ So/tge*- D=E D@E -elatin *oftener (plastici7er)$ sorbitol, !ylose, maltitol, glycerin, '6-, wa-ter)

'reservatives (methyl paraben, propyl paraben, butylated hy-dro!yaniline, 6(T%, sodium ben7oate) (yes, pigments, *olvent

o 'olar$ glycerin, '6-, '6- =@@, '6- ::?@, ethanol, ''-, water o &onpolar$ beeswa!, coconut oil, triglycerin, corn oil, mineral oil, soybean oil, (,I-Otocopherol p"-ad<usting additive flavor and fragrance 'igment$ titanium o!ide, ferric o!ide %nticaking agent$ *ilicone dio!ide "umectant$ polyol Im7orta$t Fa+tor- !$ So/t Ge*at!$ Ca7-u*eD=ED@E *olubility 'ermeability 8rganic solubility

o Common organic solvents$ (+*8 o %cceptable softgel e!cipients$ fatty li uids, '6-s, propylene glycol, surfactants (rug-e!cipient compatibility o Chemical stability o 'hysical stability$ (rug migration into shell, gelatin disintegration, recrystalli7ation of gelatin o 'olymorphism A #a$tage- o/ So/t Ge*at!$ Ca7-u*e- D=ED@E 6ase of swallowing (osage accuracy.uniformity$ 'recise fill volume of li uid fill unit delivers a greater degree of accuracy and consistency from capsule-to-capsule and lot-to-lot. Consistent manufacturing re uirements$ +ore accurate compound-ing, blending, and dispensing of li uid fill facilitates manufacturing. Ii uid blends are more homogeneous. Increase in bioavailability$ %bsorption and bioavailability can be enhanced by formulating compounds in solution including solubili7ers and absorption enhancers, if necessary. Jaterinsoluble drugs may be formulated in a softgel. Clinical studies have shown enhanced
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absorption and bioavailability with softgel forms. 6!amples are tema7epam (*alonen et al., 3ABC) and ibuprofen (*aano et al., 3AA3). 6nhanced stability and security$ The tight hermetical sealing protects fill from air and environmental contamination. -elatin shell can be formulated to block out ultraviolet light. *treamlined, one-piece design is tamper-evident. 'liable shell$ soft gel shell allows for custom shapes and si7es appropriate for oral, topical, chewable and suppository delivery. 'ortability$ 6ncapsulated li uid dosage formulations become highly portable for consumers.patients.23>4 RaA mater!a*- u-e /or +a7-u*e -he** ma$u/a+tur!$g NON-GELATIN CAPSULE SHELL De#e*o7me$t o/ No$-ge*at!$ +a7-u*eTraditionally, gelatin has been used almost e!clusively as shell-forming material of soft capsules. This is due to its legal status and its uni ue physicochemical properties, namely its o!ygen impermeability and the combination of film forming capability and thermo reversible sol.gel formation that favour its use for the industrial capsule production especially in the rotary die process. (espite these great advantages, which have been described in detail in the section above on P*oft gelatin capsules), gelatin has several drawbacks that limit its use for capsules$ The animal source of gelatin can be a problem for certain consumers such as vegetarians or vegans and religious or ethnic groups (Eews, +uslims, "indus, etc.) who observe dietary laws that forbid the use of certain animal products. *ince unmodified gelatin is prone to cross linking when in contact with aldehydes, solubility problems might be e!pected with certain fill formulations. Transparent low-colour capsules are difficult to produce owing to the effect of the intrinsic +aillard reaction on gelatin colour. The temperature and moisture sensitivity of gelatin-based soft capsules is an issue that complicates the use of soft gelatin capsules in very hot and humid regions and re uires special packaging and storage conditions to ensure product stability. Hor low-price health and nutrition products, pricing of commercially available gelatin might be an additional problem.

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To address these concerns, there has been a great interest in the soft capsule industry in looking for gelatin substitutes. Indeed, several concepts based on synthetic polymers and.or plant-derived hydrocolloids have been described in the patent literature. 2C4
A) DEVELOPMENT OF S TARCH CAPSULES

'D8'6DTI6* 8H *T%DC" +oisture content$+oisture content in starch capsule lies between 35G to 3=G w.w, with more than ?@G being tightly bound to starch. The presence of this bound moisture indicates that starch capsules may provide better stability properties and reduces susceptibilities to change on storage. (issolution *imilar to that of gelatine capsules. %dvantages$Deady for filling immediately following manufacturing. 8ffer greater resistance to humidity and heat than gelatin and allow easy filling as they are non-static. (issolution is independent of p". -ood surface finish. Coating of hard gelatine capsule with a ueous spray formulations can lead to softening of gelatin shell or gelatin shell may become brittle due to water evaporation and drying. 6specially at the onset of coating. 8n the contrary, the coating of starch capsules seems to be less problematic because of smooth seal of the filled unit, together with the higher bulk density of the capsules, which provide a more uniform coating bed. +%&;H%CT;DI&- 8H *T%DC" "%D( C%'*;I6* "ard gelatin capsules have been used most widely. Decently, however, starch capsules have been used in various controlled-release products as well as in general use as demands for non-animal based products increase. *tarch capsules are more easily coated than gelatin capsules. -elatin shells may soften and solubilise when sprayed with a ueous dispersion of coatings and can become brittle during the drying stage. The higher bulk density of the starch capsule provides for a more uniform coating bed. *tarch capsules are manufactured by an in<ection molding process that yields e!act dimensions and provides an e!cellent seal between /top0 and /bottom.0 The filling and

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sealing process is simultaneous, resulting in a finished product that is well-sealed, secure and relatively resistant to further manipulation. *tarch and "'+C are good candidates for making not only hard but also soft gelatin capsules. 8ne of the limitations of using them is the initial high capital investment 2>4 23?4 D5:4
B) DEVELOPMENT CAPSULES OF HBDROHB PROPBL METHBL CELLULOSE FHPMC1

"ypromellose (I&&), short for hydro!ypropyl methylcellulose ("'+C), is a semisynthetic, inert, viscoelastic polymer used as an ophthalmic lubricant, as well as an e!cipient and controlled-delivery component in oral medicaments, found in a variety of commercial products. Pro u+t eta!*-:-DIE Other $ame"ydro!ypropyl methylcellulose1 hydro!ypropyl methyl cellulose1 "'+C1 CAS $um6er Chem S7! er UNII Mo*e+u*ar /ormu*a Mo*ar ma-Pro7ert!e-: %ppearance$ "'+C is white or similar to white fiber or granular powder1 8dourless. 'roperties$ %lmost insoluble in ethanol, ether and acetone1 Quickly dispersed in B@-A@ centigrade water1 % ueous solution is very stable in room temperature1 "as good wetting . dispersing . adhesive . thickening . emulsifying . water preserving.film-forming properties1 Can prevent the infiltration of grease1 Hilm formed has e!cellent fle!ibility and transparency1 "as good compatibility with other emulsifier1 6asy salting-out. Its solution is stable with p" 5-35. %pparent density$ @.:@-@.>@g.cm:, density is 3.:-.cm:. 6=C= A@@=-C?-: 535=3BC: :C*HJ5EN@J ,ariable ,ariable

D!--o*#!$g 7ro+e--

13

"'+C will agglomerate when directly added to water and then dissolve. In this way it dissolves very slow and hard. *uggested methods as followers$ 0. !$ hot Aater. "'+C does not dissolve in hot water. The primary "'+C can be uniformly disperse in hot water. Then cool down in two ways$ %) %dd hot water in container and heated to over >@ centigrade. %dd "'+C gradually while slowly, stir. %t the beginning, "'+C float on the top of water, then turns into slurry state stir and cool down. #) %dd water in container to 3.: or 5.: of its content. "eated to over >@ centigrade add "'+C by se uence of a). +ake it disperse to form slurry state. %dd cool water or ice to the residual content, stir and cool down the mi!ture. 3. PoA er +om6!$at!o$. +i! "'+C with identical volume of other powder, disperses them sufficiently then add water to the. D?E (espite the fact that most of pharmaceutical capsules available in market are made of gelatin, several "'+C capsules for powdered herbs and dietary supplements have been available in recent years. +any investigational new drugs with "'+C encapsulation are in clinical trials. "'+C capsules may offer attractive alternative to gelatine capsules because of its vegetable source. The cross linking of gelatin and drug incompatibilities and the strict regulations regarding the use of animal derived gelatin re uiring the absence of bovine spongiform encephalopathy (#*6). transmissible spongiform encephalopathy (T*6) have encouraged the search for gelatin replacement. Deligious, cultural and personal issues may affect patients) preference towards the medications presented in capsule dosage forms. ,egetarians for e!ample are becoming increasingly aware of the capsule shell materials which also encouraged the companies to search for alternatives. %s a result, the first vegetable capsules with the trademark ,egicaps made of "'+C were produced in 3ABA by - * Technologies Inc. (now D.'. *cherer Technologies ownership).23@4 +%&;H%CT;DI&- 8H ("'+C) C%'*;I6* The results from the search were filtered to use information regarding the two-piece capsules (hard capsules) only1 since there are the soft capsules such as ,egicaps *oft (Catalent 'harma *olutions), "'+C based soft capsules, which are available as alternative to soft gelatin capsules. "ard gelatin and "'+C capsules are manufactured using similar e uipments developed by 6li Iilly (5@).

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In hard gelatin capsule manufacturing, pins (molds for making the capsules) at 55RC are dipped in a dip pan or pot that holds a fi!ed uantity of gelatin at a constant temperature, between =?R and ??RC. The level of solution is maintained automatically by a feed from the holding hopper. 8nce the molds are dipped a film will be formed on them by gelling since they are at lower temperature. The slowly withdrawn pins from the dipping pan are rotated to maintain uniform film thickness, where they are passed through a series of drying kilns at controlled temperature and humidity. The dried films (shells) are stripped of the pins, cut to the correct length and the two pieces (cap and body) are <oined together. The pins are then cleaned and lubricated to start the ne!t cycle.

The manufacture of "'+C based capsules necessitates some modification to the molding machine or to the formulation of the shell materials. "'+C gelling from solution occurs when the temperature is raised while it is converted to its original solution as the temperature is lowered, unlike gelatin solution. This means that the pins immersed in the dip pan containing the "'+C solution must be of higher temperature (>@RC) in order for the film to be formed. To avoid li uefaction of the films formed on the pins, the temperature of the pins must be further maintained post-dip to facilitate gelation until the films dry out in the kilns (53-5=).

#ecause "'+C shell walls are much weaker than gelatin made shells, removal of the capsule from the pins and subse uent handling and filling are in <eopardy. To overcome these problems, three approaches were adapted. These approaches were to use a stripper <aw with depressions on the inner surface, increase the formed "'+C film thickness and the use of gelling agents. The following gelling agents were e!perimented$ tamarind seed polysaccharide, carrageenan, pectin, curdlan, gellan gum and furcellaran.

C) DEVELOPMENT OF PVA C OPOLYMER CAPSULES

"ard capsules have been developed as an edible container to mask the taste and odour of medicines. Traditionally used for powder or granulated formulations, capsules have also been adapted to contain oily li uids, tablets and even powders for inhalation. They are popular because of their relative ease of manufacture (compared with other dosage forms such as tablets) and their fle!ibility to accommodate a range of fill weights. %dditionally, capsules readily demonstrate bioe uivalence between different strengths of the same formulation. The solubility of many compounds used in potential new drugs is very low because they are selected for their affinity to receptors, which increases as the lipophilicity of a compound increases. %lthough these compounds are e!pected to have a high clinical performance, they

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often fail to become new drug entities because of their low absorption in the gastro-intestinal (-I) tract - a result of poor dissolution. This suggests that pharmaceutical manufacturers could develop dosage forms of insoluble drugs with macrogol =@@, improving the solubility of such entities. #ecause the formulations and manufacturing processes are simple, no scale-up studies would be re uired - possibly reducing drug development times. #ecause of the large potential of capsules that can hold macrogol =@@, the developed new capsules, synthesi7ing materials that are suitable as capsule shells. #y copolymeri7ing acrylic acid (%%) and methyl methacrylate (++%) on ',% as a skeleton and then using the obtained ',% copolymer as capsule shells, the successfully developed capsules that can be filled with macrogol =@@.5,: In this paper, the physical properties of the ',% copolymer, and the characteristics and pharmaceutical applications of ',% copolymer capsules, are given. 23=4 Ne+e--!t" o/ $eA mater!a*-:Initially, e!amined why conventional capsule shells do not tolerate macrogol =@@. Jhen gelatin capsules were filled with macrogol =@@, they became brittle and broke easily because the moisture in the shell was absorbed by the macrogol. Jhen hydro!ypropyl methylcellulose ("'+C) capsules were filled with macrogol =@@, the agent oo7ed out through the capsule shell. It is believed that new synthetic polymers would be more suitable for capsule shell materials rather than natural polymers or polysaccharides. Thus, different polymers were synthesi7ed, using styrene resin, polyurethane, acrylic polymer and chitosan as a skeleton. Pro u+t I$/ormat!o$:- D0;E Chem!+a* Name Commo !t" Name Categor" Mo*e+u*ar /ormu*a Mo*e+u*ar At. H.S.Co e CAS No. HaCar C*a-UN No. Pa+8!$g Grou7: Te+h$!+a* S7e+!/!+at!o$:-D0;E A77eara$+e V!-+o-!t" 6" mPa.A*+oho* egree 6" ":FG>"1 G 0<<J Jhite granular 5>.@S :5.@ AB.@S AA.@
16

'olyvinyl %lcohol ',% Iinear polymer with hydro!yl group (C":C"C88C":)!(C"5C"8")y n.a :A@?:@@@@@ A@@5-BA-? n.a n.a n.a

So !um A+etate 6" At J Vo*at!*e 6" At J A-h 6" At J 7H #a*ue Part!+*e -!Ce 6" me-h +%&;H%CT;DI&- 8H (',%) C%'*;I6* (issolution of ',% copolymer$-

5.? ma! ?.@ ma! @.> ma! ?S > about 3?

Capsules made only of ',% are available, although they are easily softened by surrounding moisture. In the ',% copolymer, ++% was used to increase the hardness of the capsule shell1 however, increasing the amount of ++% decreases the polymer solubility. Thus, %% was copolymeri7ed to increase the solubility at neutral p". The composition ratios of ',%, %% and ++% in the ',% copolymer can be modified1 the best copolymer is formed when the levels of ',%, %% and ++% are >@FB@G, 5.?F?.@G and 3?F5?G, respectively.

(rug capsules should dissolve in purified water, as well as in simulated gastric fluid (p" 3.5) and simulated intestinal fluid (p" C.B) of the disintegration test method listed in the Eapanese 'harmacopoeia (E'). The dissolution of ',% copolymer cast film in the above media was e!amined. The result showed that the film was soluble in all three fluids, indicating that the copolymer has suitable dissolution characteristics. The film showed no erosion, swelling or dissolution in macrogol =@@. Hilm strength$-

',% copolymer film was formed in 3@@ Tm thickness using the casting method. The breaking strength and elongation rate of =@:3@ mm film segments were e!amined, which showed the breaking strength of the ',% copolymer film to be :5.5 &.mm5. The value was slightly lower than that of gelatin film (??.B &.mm5), but comparable to that of "'+C film (:@.B &.mm5)1 therefore, the ',% copolymer film was considered acceptable for practical use.

Jhen the ',% copolymer film was moistened in a chamber (5? RC.>?G relative humidity 2D"4), its strength decreased by appro!imately 5?G. -elatin and "'+C specimens showed larger reductions (more than ?@G) in strength when moistened at the same condition.

%lthough the gelatin and "'+C films showed a low elongation rate before and after moistening, the ',% copolymer film showed a markedly higher rate before and particularly after moistening (:35G of the original rate). -as permeability of the film$-

17

The 3@@ Tm thick film was also used to e!amine gas permeability by the %merican *ociety for Testing and +aterials (%*T+) method. Jater vapour permeability through ',% copolymer film at 5? RC.A@G D" was :5:.5 g.m5.5= h, which was between the values of the gelatin and "'+C films. There was no marked difference in water vapour permeability between the three films. In contrast, o!ygen permeability through ',% copolymer was significantly less than through gelatin and "'+C films, indicating that it should be impermeable to the ',% copolymer film.

+oisture absorption and desorption isotherm. -enerally, water-soluble polymers start to absorb moisture when relative moisture increases by more than >@G and the absorption rate dramatically increases when relative moisture e!ceeds B@G. The moisture absorption isotherm curve of ',% copolymer is similar to that of gelatin. The moisture desorption of ',% copolymer is similar to its absorption isotherm curve, whereas, for gelatin film, the desorption rate is slower than its absorption rate. 'hysical properties

',% copolymer capsules were prepared by the dipping and forming method. Carrageenan (@.@?-@.?G) was added as a gelling agent and potassium chloride (@.@?-@.?G) was added as a gelling promoter. This method re uires no additional investment for capsule manufacturers because conventional gelatin capsule manufacturing machines can be used. 'rototype ',% copolymer capsules were coloured showed a good gloss and were not different from conventional capsules. D!-!$tegrat!o$ a$ !--o*ut!o$:-

'rototype ',% copolymer capsules (si7e U@) were filled with macrogol =@@ and the time taken for the contents to begin to leak out was measured (Table I,). The capsules were filled with the disintegrate croscarmellose sodium and the paddle method (?@ rpm) was used to measure the disintegration time as an inde! of the start of dissolution. The capsules opened in less than 3@ min in all the media. Ca7-u*e har $e--:The relationships between the brittleness and moisture content of ',% copolymer, gelatin and "'+C capsules were compared using a hardness tester (*hionogi Qualicaps, Eapan). % ?@ g weight was dropped at a height of 3@ cm onto a capsule and the percentage of broken capsule was determined (Higure :). %t a water content of BG, the gelatin capsules became brittle and the percentage of broken capsules was 3@@G. The "'+C capsules did not break, even at 3G water content. ',% copolymer capsules became brittle when water content was less than =G, but were less brittle compared with gelatin capsules. ',% copolymer capsules
18

did not become brittle or break easily, even when filled with macrogol =@@ (which absorbs moisture from the capsule shell) or silica gel grains (desiccant). The authors concluded that these test conditions were too severe to estimate capsule brittleness. To evaluate capsule deformation, the load re uired to deform each capsule by ?@G was measured using a load cell. The results illustrate that ',% copolymer capsules can be deformed by moisture absorption, but this can be prevented by controlling the water content of the filling and the humidity of the environment, or with moisture-proof packaging. F!**!$g !--o*ut!o$$Jhen dissolution testing ',% copolymer capsules (si7e U5) filled with macrogol =@@, the bottom of the capsules uickly dissolved (5 min) in purified water, E' 3st fluid (p" 3.5) and E' 5nd fluid (p" C.B), with the macrogol =@@ leaking out from the bottom. Two sets of capsules for the insoluble drugs tolbutamide and indomethacin were prepared. 8ne capsule was filled with the drug as a solution of macrogol =@@ and the other was filled with a mi!ture of the drug, lactose (as filler) and croscarmellose sodium (as a disintegrant). The dissolution behaviour of the capsules was compared using the E' paddle method (?@ rpm). The tolbutamide.macrogol =@@ capsules almost dissolved completely in 3@ min in all the test solutions. "owever, for the capsules filled with the drug, filler and disintegrant, only B@G of the drug had dissolved after C@ min. %bsorption of indomethacin in rats. Indomethacin ',% copolymer capsules were prepared using either a solution of macrogol =@@ or a mi!ed powder formulated with lactose and croscarmellose sodium. #oth sets were filled into mini-capsules (si7e UA) and administered to rats to compare the plasma profiles of the drug .= The results illustrate that between 3B@-:C@ min, the capsule containing the drug as a solution of macrogol =@@ demonstrated a higher plasma concentration (B Tg.mI) compared with the capsules containing the mi!ed powder (3 Tg.mI). The data suggest that ',% copolymer capsules filled with macrogol =@@ improve the bioavailability of insoluble drugs. Tolerance of ',% copolymer capsules. The solubilising agents macrogol =@@, Tween B@ and Iabrasol were filled into ',% copolymer capsules and stored in accelerating conditions (=@ RC.>?G D") in a sealed container to e!amine the tolerance of the capsules to the agents. The capsules showed no change in appearance after C months. Jhen a solubilising agent with high water content is filled into a capsule, the moisture causes the capsule shell to soften and.or deform. This can be prevented by controlling the water content of the agent and the humidity of the manufacturing environment, and by using moisture-proof packaging, as done for conventional capsules.23C423?423B4
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D) DEVELOPMENT OF ALGINATE CAPSULES

;tili7ing a novel patented process based on one of H+C core #iopolymers (alginate) this technology provides a uni ue seamless, enteric, vegetarian alternative to gelatin soft capsules in one unit process for pharmaceutical and nutraceutical applications. A*g!$ate +a7-u*e- a #a$tage-lobally acceptable regulatory compliance with ,egetarian (gelatin-free) Capsules easier to swallow$ *maller Capsule$ *eamless thinner capsule shell, allowing for capsules :@G smaller than traditional gelatin for a given fill volume &o Hish #urps$ &aturally enteric providing superior gastro resistant and enteric release properties to film coated alternatives *uperior elegance - high shell transparency *ugar and gluten free +anufacture of capsules easier$ Havourable unit cost - process does not produce waste ribbon as seen in traditional rotary die processes and eliminates need.cost of enteric film coating ma!imi7ing production efficiency 'rocess designed to provide o!idation protection Qb( development philosophy 'atented product and process enables product life cycle enhancement.23A4 A*g!$ate Ca7-u*e- %a-!+ Formu*at!o$ 6mulsion Voil VCaCl5K5"58 Vemulsifier Vwater -elling bath V%lginate Jashing VJater W 'lastici7er W Degulatory evaluation of shell components$
20

V%ll of the e!cipients used in the algicaps shell are established e!cipients for use in oral dose forms at levels used. A*g!$ate Ca7-u*e- - F!*m th!+8$e--

Thinner films than conventional soft capsules, in the range of hard Capsules V3@@-3?@ micron after drying VIow film thickness variations VConventional seam variations avoided V*maller capsules V6asier to swallow V+ore product per capsule VHilm thickness determined by formulation and process conditions V%mount of Ca5X used V%mount of alginate used V-elling temperature V-elling time Ma$u/a+tur!$g o/ a*g!$ate +a7-u*e-:-D3<E 3. 5. :. interface. =. ?. C. The capsule shell wall is formed with the same thickness all around. Jashing and drying. (ry capsule with transparent shell and transparent core. *teps involved in alginate capsule shell formation$6!trude formation of 6mulsion. Introduce emulsion fragments into alginate bath. CaCl5 diffuses through the emulsion and react with sodium alginate at the

21

F!g. %lginate capsule shell manufacturing process Co$t!$uou- +a7-u*e -he** ma$u/a+tur!$g 7ro+e--:-

F!g. Continuous %lginate capsule shell manufacturing process.

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Re/ere$+e:1) http$..www.pharmacopeia.cn%rticalG5@capsule.-eneralG5@ChaptersYG5@Y33?3Y

G5@'"%D+%C6;TIC%IG5@(8*%-6G5@H8D+*G5@-G5@C%'*;I6*.mht 5) I% %ugsburger /"ard and soft gelatin capsules0 in +odern 'harmaceutics -* #anker L CT Dhodes, (3AA?) ,6ds., +arcel (ekker, Inc.$ &ew Zork, &Z, pp :A?F==@.
3) http$..en.wikipedia.org.wiki.Capsule(pharmacy)

=) (r. #.#hatt,'rof. *.*. %grawal ['harmaceutical Technology Capsules(5=-@>-5@@>)[ (elhi Institute of 'harmaceutical *cience and Desearch *ector F :, ,'ushp ,ihar ,&ew (elhi,page no $-3 to 5C. ?) 8gura T, Huruya Z, +atuura *. /"'+C capsules$ an alternative to gelatin.0 'harm Tech 6urope, 3AAB1 3@(33)$ :5-=5. C) +* 'atel, H** +orton, L " *eager /%dvances in softgel formulation technology (3ABA)0 +anuf Chem, Euly 5CF5B. >) + *alonen, 6 %antaa, I %altonen, + "ovi-,iander, L E \anto /% comparison of the soft gelatin capsule and the tablet form of tema7epam(3ABC)0 %cta 'harmacol To!icol ?B ,page no$-=AF?=.
8) http$..en.wikipedia.org.wiki."ypromellose 9) http$..kehongchem.en.made-in-china.com.product.obrnI,t+Cdk(.China-"ydro!ypropyl-

+ethyl-Cellulose-"'+C-+"'C-.html 3@) +. +oawia . %l-Tabakha,0 "'+C Capsules$ Current *tatus and Huture 'rospects0, College of 'harmacy, %l %in ;niversity of *cience and Technology, %l-%in, ;.%.6.,E 'harm 'harmaceut *ci (www.cspsCanada.org) 3:(:) , 5@3@,=5B F ==5. 33) +. *herry \ua,Jeiyi Iia,,Jendy (ulina, Hran (onahuea, (omini ue Cadeb, "assan #enameurb, \eith "utchison,0 'erformance Qualification of a &ew "ypromellose Capsule0, 'harmaceutical (evelopment, Jyeth Desearch, =@3 &. +iddletown Doad, 'earl Diver, &Z 3@AC?, ;*%. 35) Z. 6l-+alah1 *.&a77al1Carey #. #ottom0"ard -elatin and "ypromellose ("'+C) Capsules$ 6stimation of Dupture Time by Deal-time (issolution *pectroscopy0.'ublished in$(rug (evelopment and Industrial 'harmacy, ,olume ::, Issue 3 Eanuary 5@@> , pages 5> - :=
13)

https://data.epo.org/publication-

server/rest/v1.0/publicationdates/20081224/patents/EP169 0!6"#$1/docu%ent.ht%l 3=) &."oshi, *.;ramatsu, T.*himamoto, T.8gura,0 (evelopment of ',% Copolymer Capsules0, 'harmaceutical Technology 6urope, %pr 3, 5@@=.
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http$..www.lukem.cn.en.'roduct*how.asp]I(^C5
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16)

http$..www.pharmtech.com.pharmtech.DawX+aterials.(evelopment-of-',%-

Copolymer-Capsules.%rticleIong.%rticle.detail.A5=>A]conte!tCategoryId^5?A5Lref^5? 3>) Ieon Iachman.,[The Theory and 'ractice of Industrial 'harmacy[,varghese publication house,mumbay,page no$-:>=-==5.
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http$..www.capsugel.com

3A) +agenta oral dosage formulation /Introduction to the &ovel %lginate Capsules Technology0, H+C.
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55) www.li uidcapsules.com 5:) http$..www.google.com.patents.;*???=:B?.pd

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