08 Capsulas

Cpsulas / Capsules
Farmacia y Tecnologa Farmacutica

Universidad de Navarra
Formas Slidas Oral: cpsulas
Juan M. Irache
1. Cpsulas: Introduccin
1.1. Definiciones Farmacopea
Preparaciones slidas, con una cubierta que puede ser dura o blanda y tener forma y
capacidad variables, y que generalmente contienen una nica dosis de un p.a. Las cubiertas
de las cpsulas son de gelatina u otras sustancias, cuya consistencia puede adaptarse por
adicin de sustancias como glicerol o sorbitol. Tambin pueden aadirse otros como
tensioactivos, opacificantes, conservantes, edulcorantes, colorantes y aromatizantes. Las
cpsulas pueden llevar inscripciones en su superficie. El contenido puede ser de
consistencia slida, lquida o pastosa. Est constituido por uno o ms p.a.(s), con o sin
excipientes tales como disolventes, diluyentes, lubricantes y disgregantes. El contenido no
causa deterioro de la cubierta. sta, sin embargo, es atacada por los jugos digestivos,
liberando el contenido. Se pueden distinguir varios tipos:
- cpsulas duras
- cpsulas blandas
- cpsulas gastrorresistentes
- cpsulas de liberacin modificada
ENSAYOS
Uniformidad de contenido: Salvo indicacin contraria o excepcin justificada y autorizada,
las cpsulas 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
Disolucin: Si se prescribe un ensayo de disolucin, puede no ser necesario ensayo de
disgregacin.
ETIQUETADO: indicar el nombre de conservantes antimicrobianos que se hayan aadido.
CONSERVACIN: En envase bien cerrado, a una temperatura no superior a 30 C.
Juan M. Irache
1.2. Tipos de cpsulas
Cpsulas duras: cubiertas formadas por dos partes cilndricas prefabricadas, en
las cuales uno de los extremos es redondeado y est cerrado y el otro est abierto.
El principio o pa(s), generalmente en forma slida (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.
Cpsulas blandas: cubiertas ms gruesas que las de cubierta dura. Las cubiertas
constan de una sola pieza y son de formas variadas. La fabricacin de las cpsulas,
el llenado y el cierre se realizan normalmente en una sola operacin. El material de
que se compone la cubierta puede contener un p.a. Los lquidos pueden
encapsularse directamente; los slidos generalmente se disuelven/dispersan en un
excipiente adecuado, para dar una disolucin o suspensin de consistencia ms o
menos pastosa. Dependiendo naturaleza de los materiales y de las superficies en
contacto, puede producirse una migracin parcial del contenido hacia la cubierta y
viceversa.
Cpsulas gastrorresistentes: Se preparan llenando las cpsulas con
granulados o partculas que tengan una cubierta gastrorresistente o bien
recubriendo cpsulas duras o blandas con una cubierta gastrorresistente
(cpsulas entricas).
Cpsulas de liberacin modificada: Las cpsulas de liberacin modificada
incluyen cpsulas de liberacin prolongada y cpsulas de liberacin retardada.
Juan M. Irache
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
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)

Juan M. Irache
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
Juan M. Irache
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
Juan M. Irache
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)
Juan M. Irache
Juan M. Irache
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
Juan M. Irache
Coni-Snap (Capsugel)
Juan M. Irache
Juan M. Irache
Juan M. Irache
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.
PCcapsCapsules: 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
Juan M. Irache
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.
Juan M. Irache
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)
Juan M. Irache
2.5. Manufacturing steps
Juan M. Irache
2.5.1. 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
Juan M. Irache
Dosator Principle
Juan M. Irache
MG2 Futura
Dosator Machine
36,000 caps/h
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Dosing Disc Principle
Juan M. Irache
Bosch
GKF 1500
Dosing Disc
Machine
90,000/h
Juan M. Irache
Banding
machine
Capsule-filling
machine
Juan M. Irache
2.5.2. Manual coaters
Juan M. Irache
2.6. Ensayos cpsulas
Disgregacin
Cpsulas duras: Utilizar agua R. Si justificado, puede emplearse cido clorhdrico 0,1 M, o jugo
gstrico artificial R. Si las cpsulas flotan en la superficie del agua, puede aadirse disco. Hacer
funcionar aparato durante 30 min, salvo excepcin, y examinar el estado de las cpsulas. Las
cpsulas satisfacen el ensayo si las 6 se disgregran.
Cpsulas blandas: Utilizar agua R. Si justificado, puede emplearse HCl 0,1 M, o jugo gstrico
artificial R. Aadir un disco a cada tubo. Hacer funcionar el aparato durante 30 min, salvo
excepcin, y examinar el estado de las cpsulas. Si las cpsulas no satisfacen el ensayo debido a
que se adhieren a los discos, repetir el ensayo en otras 6, omitiendo los discos. Las cpsulas
satisfacen el ensayo si las 6 se disgregran.
Cpsulas gastroresistentes: Utilizar HCl 0,1 M y hacer funcionar el aparato durante 2 h sin los
discos. Examinar el estado de las cpsulas. El tiempo que las cpsulas resisten el medio cido
vara dependiendo formulacin, siendo su valor normal 2-3 h. Nunca menor de 1 h. Ninguna
cpsula muestra seales de disgregacin o fisuras que permitan la salida de su contenido.
Reemplazar por disolucin tampn de fosfato a pH 6,8 R. Cuando se justifique, puede emplearse
una disolucin tampn a pH 6,8 con polvo de pncreas (Ej., 0,35 g de polvo de pncreas R por 100
ml). Aadir un disco a cada tubo. Hacer funcionar el aparato durante 60 min y examinar el estado
de las cpsulas. Si las cpsulas no satisfacen el ensayo debido a que se adhieren a los discos,
repetir el ensayo omitiendo los discos. Las cpsulas satisfacen el ensayo si se disgregran las 6.
Disolucin.
Cpsulas gastroresistentes: Para cpsulas preparadas a partir de granulados o partculas con
recubrimiento gastrorresistente, se efecta ensayo adecuado que demuestre liberacin del p.a(s).
Juan M. Irache
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)
Juan M. Irache
Softgel sizes and shapes
Juan M. Irache
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 < 35C
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 65 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
Juan M. Irache
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
Juan M. Irache
Rotary Die process
Juan M. Irache
Referencias
Textos Generales
Vila Jato, J. L. (1997). Tecnologa Farmacutica. Formas
Farmacuticas. Vol. II, Ed. Sntesis, Madrid.
Aulton, M.E. (1988). Pharmaceutics. The science of dosage form
design. Churchill Livingstone, New York
Real Farmacopea Espaola. 2005.
Cpsulas
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
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 Qumica, 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
Juan M. Irache
Mquinas para dosificacin de cpsulas
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
Juan M. Irache

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