Tf3 15 ff-oral-capsulas

Cápsulas / Capsules
Juan M. Irache
Farmacia y Tecnología Farmacéutica
Universidad de Navarra
I. Formas Destinadas a la Vía Oral

1. Cápsulas: Introducción
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.

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.
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.
Sellos: preparaciones sólidas que consisten en una cubierta dura que contiene una
dosis única de uno o más principios activos. La cubierta del sello es de pan ácimo
generalmente de harina de arroz y consiste en 2 secciones cilíndricas planas
prefabricadas. Antes de su administración, los sellos se sumergen en agua durante
unos cuantos segundos, se colocan en la lengua y se tragan con un sorbo de agua.

2. 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

Hard Gelatin vs Soft Gelatin "Softgels" Capsules
Criterion 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)

3. 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

3.1. 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

3.2. 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 (TiO2)
e. Preservative:
no necessary if work under GMP conditions
water content of 13-16%: no possibility for microbial contamination

3.3. 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
Qualicaps Group
Capsugel

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

Pre-locked
position
Sealed
position
Coni-Snap® (Capsugel)

Types of hard capsules
Quali-V® (HPMC) Shionogi Qualicaps / VCaps (HPMC; Capsugel): 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

Types of hard capsules
DRcaps Gastro Resistant Capsules: HPMC capsules resistants to the acidic
conditions of the stomach without the addition of any type of coatings.
NPcaps Pullulan Capsules: from pullulan, a water-soluble polysaccharide.
Capsules highly impermeable to oxygen transmission.
OceanCaps Fish Gelatin Capsules: marine-based capsule.
Pearlcaps Pearlescent Capsules: shiny, iridescent capsules. Differentiate your
products, ideally suited for the cosmeceutical market. Available in gelatin and HPMC
capsules.

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

3.4. 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.

3.4. Formulation of hard capsules
Lubricants
Glidants (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 sodium
Speed up drug dissolution by... Promoting liquid penetration (wicking)
Promoting deaggregation
Efficiency 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 the
waterproofing effect of hydrophobic lubricants)

3.5. Manufacturing steps

3.6. Capsule filling machines
Output Capacities of Some Capsule Filling Machines
Semi-automatic No. 8 Machine 120,000-140,000/Shift
Fully Automatic Zanasi Z-5000/R3 150,000/h
MG2 G100 100,000/h
Bosch GKF 3000 180,000/h
Osaka R-180 165,000/h
TODAY, HARD GELATIN CAPSULES ARE MOST OFTEN
FILLED BY AUTOMATIC MACHINES WHICH RESEMBLE
TABLET PRESSES TO THE EXTENT THAT -
THEY FORM POWDER PLUGS BY COMPRESSION,
AND EJECT THEM INTO EMPTY CAPSULE BODIES

Dosator Principle

Dosing Disc Principle

MG2 Futura
Dosator Machine
36,000 caps/h

Banding
machine
Capsule-filling
machine

Manual filling machine
https://www.youtube.com/watch?v=fF1bJ6jaZw8

Semi automatic filling
machine
Manual filling machine
https://www.youtube.com/watch?v=26OIri_HEBo
https://www.youtube.com/watch?v=9rzoHH8nlvQ

Mini beads Granules Liquids
Mini tabs Semi-solids Powders

3.7. Ensayos cápsulas
Disgregación
Cápsulas duras: Utilizar agua R. Si está justificado, puede emplearse ácido
clorhídrico 0,1 M, o bien jugo gástrico artificial R. Hacer funcionar aparato durante 30
min y examinar el estado de las cápsulas. Las cápsulas satisfacen el ensayo si las 6
se disgregran.
Cápsulas blandas: Utilizar agua R. Si está justificado, puede emplearse HCl 0,1 M,
o bien jugo gástrico artificial R. Hacer funcionar el aparato durante 30 min y examinar
el estado de las cápsulas. 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, o cualquier otro tiempo que se autorice. El tiempo que las cápsulas resisten el
medio ácido varía entre 2-3 h. Nunca menor de 1 h. Ninguna cápsula muestra
señales de disgregación o fisuras que permitan la salida de su contenido.
Reemplazar el ácido 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.
Hacer funcionar el aparato durante 60 min y examinar el estado de las cápsulas. 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).

4. 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

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

6.5.1. 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

6.5.2. Soft capsules manufacture
Original Rotary Die Process (R.P. Scherer: 1933); troquel rotatorio
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

http://www.kwangdah.com/kde-300.htm
Rotary Die process

6.5.2. Soft capsules manufacture
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
1. Gelatin ribbon
2. Rotary die
3. Filling Wedge
4. Filled capsule
5. Webbing
6. Pumping mechanism

Bibliografía complementaria
• Cápsulas
– Qualicaps: http://www.qualicaps.com/about/default.aspx
– Capsugel: http://www.capsugel.com/
– Laboratorios Juste: http://www.juste.es/
– Banner: http://banpharm.com/
• 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/

• 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
• 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
Bibliografía complementaria

Tf3 15 ff-oral-capsulas

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