tema08 cápsulas

Cápsulas / Capsules

Farmacia y Tecnología FarmacéuticaUniversidad de Navarra

Formas Sólidas Oral: cápsulasJuan M. Irache

1. Cápsulas: Introducción1.1. Definiciones FarmacopeaPreparaciones sólidas, con una cubierta que puede ser dura o blanda y tener forma y capacidad variables, y que generalmente contienen una única dosis de un p.a. Las cubiertasde las cápsulas son de gelatina u otras sustancias, cuya consistencia puede adaptarse por adición de sustancias como glicerol o sorbitol. También pueden añadirse otros como tensioactivos, opacificantes, conservantes, edulcorantes, colorantes y aromatizantes. Las cápsulas pueden llevar inscripciones en su superficie. El contenido puede ser de consistencia sólida, líquida o pastosa. Está constituido por uno o más p.a.(s), con o sin excipientes tales como disolventes, diluyentes, lubricantes y disgregantes. El contenido no causa deterioro de la cubierta. Ésta, sin embargo, es atacada por los jugos digestivos, liberando el contenido. Se pueden distinguir varios tipos:

- cápsulas duras- cápsulas blandas- cápsulas gastrorresistentes- cápsulas de liberación modificada

ENSAYOSUniformidad de contenido: Salvo indicación contraria o excepción justificada y autorizada, las cápsulas cuyo contenido de p.a. sea menor que 2 mg o menor que el 2% de la masa total satisfacen el ensayo B de uniformidad de contenido para preparaciones en dosis unitarias.Uniformidad de masa Disolución: Si se prescribe un ensayo de disolución, puede no ser necesario ensayo de disgregación.ETIQUETADO: indicar el nombre de conservantes antimicrobianos que se hayan añadido.CONSERVACIÓN: En envase bien cerrado, a una temperatura no superior a 30 ºC.



1.2. Tipos de cápsulasCápsulas duras: cubiertas formadas por dos partes cilíndricas prefabricadas, en las cuales uno de los extremos es redondeado y está cerrado y el otro está abierto. El principio o pa(s), generalmente en forma sólida (en polvo o granulados) se introducen en una de las partes de la cubierta, que se cierra por deslizamiento sobre ella de la otra parte. La seguridad del cierre puede reforzarse por medios adecuados.

Cápsulas blandas: cubiertas más gruesas que las de cubierta dura. Las cubiertas constan de una sola pieza y son de formas variadas. La fabricación de las cápsulas, el llenado y el cierre se realizan normalmente en una sola operación. El material de que se compone la cubierta puede contener un p.a. Los líquidos pueden encapsularse directamente; los sólidos generalmente se disuelven/dispersan en un excipiente adecuado, para dar una disolución o suspensión de consistencia más o menos pastosa. Dependiendo naturaleza de los materiales y de las superficies en contacto, puede producirse una migración parcial del contenido hacia la cubierta y viceversa.

Cápsulas gastrorresistentes: Se preparan llenando las cápsulas con granulados o partículas que tengan una cubierta gastrorresistente o bien recubriendo cápsulas duras o blandas con una cubierta gastrorresistente(cápsulas entéricas).Cápsulas de liberación modificada: Las cápsulas de liberación modificada incluyen cápsulas de liberación prolongada y cápsulas de liberación retardada.



1.3. Capsules: generalities

��The capsule can be viewed as a container dosage form...- Odorless- Tasteless- Easily swallowed- Elegant

��Gelatin capsules (hard or soft)

��Some shell capsules are made from materials other than gelatin...- Starch hydrolysate: "Capill"- Hydroxypropyl methyl cellulose ("Vegicaps" and others)

Such alternatives to gelatin will be of interest to those who,for religious, cultural or other reasons wish to avoid capsulesmade from animal derived components



Hard Gelatin vs Soft Gelatin "Softgels" CapsulesCriterion

Soft gelatin Capsules

Hard Gelatin Capsules

Shell

Plasticized (glycerin, propylene glycol, sorbitol)

Not plasticized

Content

Usually liquids or suspensions (dry solids possible)

Usually dry solids (liquids/ semi-solid matrices possible)

Manufacture

Formed/filled in one operation

Shells made in one operation and filled in a separate

process Closure

Hermetically sealed

(inherent) Traditional friction-fit; mechanical interlock,

banding and liquid sealing possible

Sizes and Shapes

Many Limited

Formulation Technology

Liquids Solids

Fill Accuracy 1-3% 2-5% (with modern automatic machines)



2. Hard gelatin capsules��Advantages of Hard Gelatin Capsules

Rapid drug release possibleFlexibility of formulation

- Easily compounded- No need to form a compact that must stand up to handling- Unique mixed fills possible- Role in drug development / Role in clinical tests

Sealed HGCs are good barriers to atmospheric oxygen.��Disadvantages of Hard Gelatin Capsules

Very bulky materials are a problemFilling equipment slower than tabletingGenerally more costly than tablets, but judge on a case-by-case basisConcern over maintaining proper shell moisture content

- Shell should have moisture content of 13-15%If too dry – become brittle/easily fracturedIt to moist – become too soft and can get sticky

- Unprotected capsules are best stored at 45-65% RH- Caution using strongly hygroscopic drugs

Cross-linking can affect soft/hard gelatin capsules, gelatin coated tablets



2.1. Hard capsules: sizes and capacities

Size Volume (mL)

Capacity (mg)

000 1.37 1096 00 0.91 728 0 0.68 554 1 0.50 400 2 0.37 296 3 0.30 240 4 0.21 168 5 0.10 104

Capacity (mg) at packing density=0.8 g/mL Specials “containers” 00el: 1.02 mL, 816 mg 0el: 0.78 mL, 624 mg



2.2. Composition of Hard Gelatin Shells��Composition hard capsulesa. Gelatin

Bone Gelatin (Type B, alcaline gelatin; pI: 4.7-5.1)Skin Gelatin (Type A, acidic gelatin; pI: 7-9)

Bloom strength (Poder gelificante): a measure of relevance to cohesivestrength of gelatin filmThe weight in g required to depress a plunger 12.7 mm diameter 4 mm intoa 6.67% gel held for 17 hours at 10 degrees (O.T. Bloom, 1925)

Typically for hard capsules: 200-260 "bloom-grams"Viscosity: single most important factor controlling shell thickness

Capillary viscometer; 6.67% soln.Typical range 25-45 millipoise.

b. Waterc. Dyes and other colorants: http://www.capsugel.com/amer/color/catalog.phpd. Opaquing agent (TiO2)e. Preservative:

no necessary if work under GMP conditionswater content of 13-16%: no possibility for microbial contamination



2.3. Hard capsules manufacture

The Dipping Process of Making Hard Gelatin Capsules: similar process to that patented in 1846

a. Metalic mouds are dipped in a warm gelatin bathb. A film of gelatin is formed aroundc. Dry process of gelatind. Extractione. Cutting at the desiring sizef. Sealing and positive closure

Tamper resistance/tamper evidencePrevents inadvertent separation on

handling/shippingMakes liquid/semi-solid filling of hard

gelatin capsules possibleSealed capsules are excellent barriers to O2

Shionogi QualicapsCapsugel div. PfizerPharmaphil (Canada)





Types of hard gelatin capsules: mechanicallyinterlocking Caps and Bodies

Interlocking rings or bumps molded into the cap and body side-wallsPosilok (Shionogi): two-piece gelatin capsule with its mechanical lock made by indentations in the cap and body. The vented cap indentation allows air to escape when capsule is closed on high-speed filling machines. Snap-Fit and Coni-Snap® (Capsugel)Lox-it (Pharmaphil)

Traditional Prefit Locked



Coni-Snap® (Capsugel)







Types of hard capsules��Quali-V® (HPMC) Shionogi Qualicaps / VCaps (Capsugel): multifunctional two-piece hard shell capsule derived from non-animal sources, which satisfy vegetarian and cultural needs. Additional benefits: chemical stability and low moisture content –making it an attractive alternative for hygroscopic formulations.��Licaps® Capsules: gelatin capsules for containment of liquids and semi-solids.��PCcaps™ Capsules: very small size gelatin capsules that are ideal for oral dosage to rodents in pre-clinical studies.��Press-fit® Gelcaps: high-gloss gelatin coating that encases a caplet core. They combine the best qualities of a gelatin capsule with the density of a tablet. ��DBcaps® Capsules: two-piece gelatin capsules that are designed for double-blind clinical trials. The shorter length facilitates ease of swallowing.

DBcaps Licaps Press-fit



Sealing and Welding MethodsBanding

Original banded hard gelatin capsule - Parke Davis' "Kapseal"Modern banding process - Shionogi's Qualiseal

Liquid sealingCapsugel's Licaps

Licaps



2.4. Formulation of hard capsules

Active IngredientHighly water soluble drugs exhibit few formulation problems in terms of drug release from either tablets or capsules.Micronization of poorly soluble drugs can improve dissolution from tablets andcapsules.

Affect on flow and mixing– Adsorption to surfaces of filler particles (a form ordered mixing) may help

Effective surface area may be reduced by agglomeration of micronized particles– Addition of a wetting agents (surfactants) may help.

Filler (Diluent)Fillers include lactose, starch, dicalcium phosphate, Starch 1500

Forms modified for direct compression tableting are useful for flow/compactibility- especially important for plug forming machines.

Consideration the solubility of drug in selecting a filler.Water soluble fillers are preferred for poorly soluble drugs: In certain instances, a largepercent of soluble filler in the formulation has slowed the dissolution of a soluble drug.

Possible incompatibilitiesClassic example: Tetracycline formulated with calcium phosphate.



LubricantsGlidants (colloidal silicas such as Cab-O-Sil, Aerosil)

Optimum concentration generally <1%, typically 0.25-5.0%.True Lubricants and Antiadherents (e.g. Metallic stearates, stearic acid)

Best lubricants are hydrophobic– Increasing concentrations usually retard dissolution.– Blending time an issue with laminar lubricants.avoid overmixing

Effect is exacerebated at higher degrees of compaction.

Disintegrants (4-8%): sodium starch glycolate; croscarmellose sodiumSpeed up drug dissolution by... Promoting liquid penetration (wicking)

Promoting deaggregationEfficiency often improves with increased tamping force.

Crospovidone not as effective in capsules at equivalent concentrations

Surfactants: sodium docusate (0.1-0.5%); sodium lauryl sulfate (1-2%)Speed up dissolution by... Increasing wetting of powder mass (can overcome thewaterproofing effect of hydrophobic lubricants)



2.5. Manufacturing steps



2.5.1. Capsule filling machines

Output Capacities of Some Capsule Filling MachinesSemi-automatic No. 8 Machine 120,000-140,000/ShiftFully Automatic Zanasi Z-5000/R3 150,000/h

MG2 G100 100,000/hBosch GKF 3000 180,000/hOsaka R-180 165,000/h

TODAY, HARD GELATIN CAPSULES ARE MOST OFTENFILLED BY AUTOMATIC MACHINES WHICH RESEMBLETABLET PRESSES TO THE EXTENT THAT -THEY FORM POWDER PLUGS BY COMPRESSION, AND EJECT THEM INTO EMPTY CAPSULE BODIES



Dosator Principle



MG2 FuturaDosator Machine36,000 caps/h



Dosing Disc Principle



BoschGKF 1500Dosing DiscMachine90,000/h



Bandingmachine

Capsule-fillingmachine



2.5.2. Manual coaters



2.6. Ensayos cápsulasDisgregación Cápsulas duras: Utilizar agua R. Si justificado, puede emplearse ácido clorhídrico 0,1 M, o jugo gástrico artificial R. Si las cápsulas flotan en la superficie del agua, puede añadirse disco. Hacer funcionar aparato durante 30 min, salvo excepción, y examinar el estado de las cápsulas. Las cápsulas satisfacen el ensayo si las 6 se disgregran.Cápsulas blandas: Utilizar agua R. Si justificado, puede emplearse HCl 0,1 M, o jugo gástrico artificial R. Añadir un disco a cada tubo. Hacer funcionar el aparato durante 30 min, salvo excepción, y examinar el estado de las cápsulas. Si las cápsulas no satisfacen el ensayo debido a que se adhieren a los discos, repetir el ensayo en otras 6, omitiendo los discos. Las cápsulas satisfacen el ensayo si las 6 se disgregran.Cápsulas gastroresistentes: Utilizar HCl 0,1 M y hacer funcionar el aparato durante 2 h sin los discos. Examinar el estado de las cápsulas. El tiempo que las cápsulas resisten el medio ácido varía dependiendo formulación, siendo su valor normal 2-3 h. Nunca menor de 1 h. Ninguna cápsula muestra señales de disgregación o fisuras que permitan la salida de su contenido. Reemplazar por disolución tampón de fosfato a pH 6,8 R. Cuando se justifique, puede emplearse una disolución tampón a pH 6,8 con polvo de páncreas (Ej., 0,35 g de polvo de páncreas R por 100 ml). Añadir un disco a cada tubo. Hacer funcionar el aparato durante 60 min y examinar el estado de las cápsulas. Si las cápsulas no satisfacen el ensayo debido a que se adhieren a los discos, repetir el ensayo omitiendo los discos. Las cápsulas satisfacen el ensayo si se disgregran las 6.

Disolución. Cápsulas gastroresistentes: Para cápsulas preparadas a partir de granulados o partículas con recubrimiento gastrorresistente, se efectúa ensayo adecuado que demuestre liberación del p.a(s).



3. Soft gelatin capsules (Softgels)

� �� Similar to hard gelatin shell, except plasticizer isincorporated (sorbitol, propylene glycol, glycerin)

� �� Usually filled with liquids or suspensions (dry solidsare possible)

��Advantages of Soft Gelatin Capsules� �� High Accuracy/precision possible� �� Hermetically sealed (inherently)� �� Possible bioavailability advantages� �� Reduced dustiness; lack of compression stage in

manufacture� �� Possible reduced gastric irritancy compared to

tablets and hard shell capsules� �� Special packages available



Disadvantages of Soft Gelatin Capsules

� �Generally, product is contracted out to a limited number ofspecialty houses,e.g. Scherer, Banner.

� �Generally more costly to produce than tablets or hard shellcapsules

� �More intimate contact between the shell and contents than withdry-filled hard shell capsules - stability a concern.

� �Not adaptable to incorporation of more than one kind of fill intothe same capsule (compare with hard shell capsules)



Softgel sizes and shapes



3.1. Formulation of soft capsules

� �Gelatin: Bloom strength 150 - 200 bloom gramsPure liquids, mixtures of miscible liquids, or solids dissoved or suspended in a liquid vehicle.� �Vehicles

� Water immiscible non-volatile liquids� �� vegetable oils� �� Mineral oil not recommended for drug formulations.

� Water-miscible, non-volatile liquids� �� Low molecular weight PEG's� �� Nonionic surfactants such as polysorbate 80

Limitations of liquid contents� �Water can not exceed 5% of contents� �pH must be between 2.5 and 7.5� �Low molecular weight water soluble and volatile compounds must be

excluded� �Aldehydes, in general, must be excluded (Cause cross-linking)� �Contents must flow under gravity at < 35ºC



3.2. Soft capsules manufacture

� �Original Rotary Die Process (R.P. Scherer: 1933)� Only for pumpable fills

� �Accogel Process (Stern Machine) - Lederle: 1948� A rotary die process for filling powders/granules into soft capsules

a. Blending powdered gelatin and other ingredients with warm water in a gelatinmelting tank:

after hydration the powder becomes a thick “syrup” called a gelatin mass. the key to mixing gelatin is to heat, blend and deaerate quickly

b. Filtration and store in portable heated stainless steel tanksgelatin mass should be kept at 65º C

c. Spreader Boxes - The gelatin mass is applied to both sides of the machinesimultaneously by a set of spreader boxes which regulates the gelatin thicknessfrom 0.6 to 0.7 mm as it is spread on the cooling drum. The gelatin is cooled whilethe thin layer of gelatin rotates with the cooling drum. d. Lubrication System – Prior to encapsulation the ribbon must be coated with a thin layer of oil to prevent sticking during the filling and sealing process.

lubricants are: digestible mineral oil, fractionated coconut oil, Miglyol 812



e. Medicine Filling Pump: Before the capsule can be formed and sealed, it must be filled. The material to be filled flows by gravity and is injected between dies

Individual plungers pull a precise amount of material f. Capsule Forming & Filling – After the 2 halves of gelatin have been cooled andlubricated, they meet together at the forming and filling station. Dies that contain smallpockets in the shape and size of the capsule to be made help form and seal. While thecapsule is being filled, it is also simultaneously being sealed and cut from the ribbon.g. Drying: capsules are very soft due to the high moisture content. Reduce to 6-10% h. Polishing (for printing) i. Packaging: bulk containers, bottles or blister packaging

1. Gelatin ribbon2. Rotary die3. Filling Wedge4. Filled capsule5. Webbing6. Pumping mechanism



Rotary Die process



Referencias

Textos Generales– Vila Jato, J. L. (1997). Tecnología Farmacéutica. Formas

Farmacéuticas. Vol. II, Ed. Síntesis, Madrid.– Aulton, M.E. (1988). Pharmaceutics. The science of dosage form

design. Churchill Livingstone, New York– Real Farmacopea Española. 2005.

Cápsulas– Shionogi Qualicaps: http://www.qualicaps.com/– Capsugel: http://www.capsugel.com/– Pharmaphil: http://www.pharmaphil.ca/– Laboratorios Juste: http://www.juste.es/

Aparatos para ensayos– Electrolab: http://www.scientificdealers.com/electrolab/ – Erweka: http://www.erweka.com/EN/index.php– PharmaAlliance: http://www.pharma-alliance.net/index.php– Quantachrome Instruments:

http://www.quantachrome.com/index.htm– Sotax: http://www.sotax.com/index3.html



Excipientes – Basf Pharma: http://www.basf-pharma.com/ – Beghin-Say: http://www.beghin-say.fr/pharmafr/– Borculo Domo Ingredients: http://www.borculodomo.com/milk/lactosaesp/– Brenntag NV: http://www.brenntag.be/– Colorcon: http://www.colorcon.com/– Degussa Pharma: http://www.degussa4pharma.com/

http://www.aerosil.com– DMV International: http://www.dmv-international.com/default.asp– FMC Biopolymer: http://www.fmcbiopolymer.com/– Friesland Foods Domo: http://www.domo.nl/– International Specialty Products (ISP): http://www.ispcorp.com/– JRS Pharma: http://www.jrspharma.com/– Merck Farma y Química, SA:

http://www.merck.de/servlet/PB/menu/1378040/index.html– Meggle Pharma: http://www.meggle-pharma.de/es/– PFormulate: http://www.pformulate.com/– Roquette Pharma: http://www.roquette-pharma.com/

Referencias



• Máquinas para dosificación de cápsulas– Axus: http://www.axus.cc/– Bosch: http://www.boschpackaging.com/site/home/index.aspx– CapPlus Technologies: http://www.capplustech.com/ – Torpac: http://www.torpac.com/filling_machines.htm– Karisma Pharma Machines: http://www.karishmapharmamachines.com/– Health Star:

http://images.google.com/imgres?imgurl=http://www.healthstar.net/images/UsedMachines/Large/28352-289-01.jpg

– Zhejiang Fuchang Machinery: http://www.chinafuchang.com– Maneklal: http://www.maneklalexports.com/English/PharmaMc.htm

Referencias



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