Cápsulas / Capsules - Universidad de Navarra

Farmacia y Tecnología Farmacéutica 

Universidad de Navarra 

Cápsulas / Capsules 

Formas Sólidas Oral: cápsulas 

Juan M. Irache 

1.2. Tipos de cápsulas 

Cápsulas 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. Cápsulas: Introducción 

1.1. Definiciones Farmacopea 

Preparaciones 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 cubiertas 

de 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 

ENSAYOS 

Uniformidad 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. 



1.3. 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 capsules 

made from animal derived components 




Juan M. Irache

Hard Gelatin vs Soft Gelatin "Softgels" Capsules 

Criterion Soft gelatin 

Hard Gelatin 

Capsules 

Capsules 

Shell Plasticized (glycerin, 

propylene glycol, sorbitol) 

Not plasticized 

Content Usually liquids or suspensions Usually dry solids (liquids/ 

(dry solids possible) semi-solid matrices possible) 

Manufacture Formed/filled in one Shells made in one operation 

operation 

and filled in a separate 

process 

Closure Hermetically sealed Traditional friction-fit; 

(inherent) 

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) 



2.1. Hard capsules: sizes and capacities 

Size Volume Capacity 

(mL) (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. Hard gelatin capsules 

Advantages of Hard Gelatin Capsules 

Rapid drug release possible 

Flexibility 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 problem 

Filling equipment slower than tableting 

Generally more costly than tablets, but judge on a case-by-case basis 

Concern over maintaining proper shell moisture content 

- Shell should have moisture content of 13-15% 

If too dry – become brittle/easily fractured 

It 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 



2.2. Composition of Hard Gelatin Shells 



Composition hard capsules 

a. 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 cohesive 

strength of gelatin film 

The weight in g required to depress a plunger 12.7 mm diameter 4 mm into 

a 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. Water 

c. Dyes and other colorants: 

http://www.capsugel.com/amer/color/catalog.php 

d. Opaquing agent (TiO 2 ) 

e. Preservative: 

no necessary if work under GMP conditions 

water content of 13-16%: no possibility for microbial contamination 




Juan M. Irache

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 bath 

b. A film of gelatin is formed around 

c. Dry process of gelatin 

d. Extraction 

e. Cutting at the desiring size 

f. Sealing and positive closure 

Tamper resistance/tamper evidence 

Prevents inadvertent separation on 

handling/shipping 

Makes liquid/semi-solid filling of hard 

gelatin capsules possible 

Sealed capsules are excellent barriers to O2 

Shionogi Qualicaps 

Capsugel div. Pfizer 

Pharmaphil (Canada) 



Types of hard gelatin capsules: mechanically 

interlocking Caps and Bodies 



Interlocking rings or bumps molded into the cap and body side-walls 

Posilok (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) 


Juan M. Irache



Types of hard capsules 



Quali-V® (HPMC) Shionogi Qualicaps / VCaps (Capsugel): multifunctional twopiece 

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 doubleblind 

clinical trials. The shorter length facilitates ease of swallowing. 

DBcaps Licaps Press-fit 









Sealing and Welding Methods 

Banding 

Original banded hard gelatin capsule - Parke Davis' "Kapseal" 

Modern banding process - Shionogi's Qualiseal 

Liquid sealing 

Capsugel's Licaps 



Licaps 


Juan M. Irache

2.4. Formulation of hard capsules 

Active Ingredient 

Highly 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 and 

capsules. 

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 large 

percent of soluble filler in the formulation has slowed the dissolution of a soluble drug. 

Possible incompatibilities 

Classic example: Tetracycline formulated with calcium phosphate. 





2.5. Manufacturing steps 





Lubricants 

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

Optimum concentration generally



Dosing Disc Principle 



Dosator Principle 





MG2 Futura 

Dosator Machine 

36,000 caps/h 



Bosch 

GKF 1500 

Dosing Disc 

Machine 

90,000/h 






Juan M. Irache

Capsule-filling 

machine 



2.6. Ensayos cápsulas 

Banding 

machine 



Disgregación 

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). 





2.5.2. Manual coaters 





3. Soft gelatin capsules (Softgels) 



Similar to hard gelatin shell, except plasticizer is 

incorporated (sorbitol, propylene glycol, glycerin) 

Usually filled with liquids or suspensions (dry solids 

are 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 


Juan M. Irache

Disadvantages of Soft Gelatin Capsules 

Generally, product is contracted out to a limited number of 

specialty houses,e.g. Scherer, Banner. 

Generally more costly to produce than tablets or hard shell 

capsules 

More intimate contact between the shell and contents than with 

dry-filled hard shell capsules - stability a concern. 

Not adaptable to incorporation of more than one kind of fill into 

the same capsule (compare with hard shell capsules) 





Softgel sizes and shapes 



3.1. Formulation of soft capsules 



Gelatin: Bloom strength 150 - 200 bloom grams 

Pure 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 




Juan M. Irache

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 gelatin 

melting 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 tanks 

gelatin mass should be kept at 65º C 

c. Spreader Boxes - The gelatin mass is applied to both sides of the machine 

simultaneously by a set of spreader boxes which regulates the gelatin thickness 

from 0.6 to 0.7 mm as it is spread on the cooling drum. The gelatin is cooled while 

the 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 





Rotary Die process 





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 and 

lubricated, they meet together at the forming and filling station. Dies that contain small 

pockets in the shape and size of the capsule to be made help form and seal. While the 

capsule 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 



Referencias 

1. Gelatin ribbon 

2. Rotary die 

3. Filling Wedge 

4. Filled capsule 

5. Webbing 

6. Pumping mechanism 



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 




Juan M. Irache

Referencias 

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 




Juan M. Irache

Cápsulas / Capsules - Universidad de Navarra

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