Transcript 《药剂学》课程双语教学方法建设的工作进展

Chapter 5 Capsules
2007.1.28
1
Introduction - The definition of
capsules
Capsules are solid dosage forms in which medicinal
agents and/or inert substances are enclosed within
a small shell of gelatin. Gelatin capsule shells may
be hard or soft depending on their composition.
Administration route of capsules
orally (whole or mixed with food or drink after
opening capsules)
2
Introduction – Advantages of
capsules for oral administration
1. conveniently carried
2. readily identified
3. easily taken
4. prescribing flexibility
5. Efficiently and productively manufactured
6. Packaged and shipped at lower cost and with less
breakage
7. More stable and have a longer shelf-life
8. Empty hard gelatin capsules are often used in the
extemporaneous compounding of prescriptions.
9. Tablets and capsules are sometimes used as the source
of a medicinal agent when it is not otherwise available.
3
Introduction - Dosage forms that
must be left intact
Dosage forms that must be left intact include:
enteric coated tablets
extended/controlled release dosage forms
sublingual or buccal tablets
In instances in which a patient is unable to swallow an
intact solid dosage form, an alternative product may
be employed, such as chewable tablet, instant
dissolving tablet, oral liquid, suppository or injection.
4
Types of capsules
Gelatin capsule shells may be hard or soft depending
on their composition.
 Hard gelatin capsules
 Soft gelatin capsules
5
Hard gelatin capsules
The application of hard gelatin capsules
 used to manufacture most medicated agents
 employed in clinical trials
 used in the extemporaneous compounding
The empty capsule shells consist of
gelatin, sugar, water, colorants (various dyes),
and opaquants遮光剂 (titanium dioxide).
6
Hard gelatin capsules
The main quality control item of gelatin (continuned)
 viscosity degradation (粘度下降)
 moisture (水分)
 transparency (透明度)
 ash (灰分)
 pH value
 Iron: Its concentration depends on the iron content
of the water used in its manufacture. ≤15ppm for
gelatin used in soft gelatin capsules.
7
Hard gelatin capsules
Normally, hard gelatin capsules contain between 13 to 16% of
moisture.
additional moisture is absorbed: become distorted and lose their rigid shape
lose their contained moisture: become brittle and crumble when handled
desiccant (dried silica gel, clay, and activated carbon)→in vitro
dissolution→bioavailability.
The solubility property of gelatin:
Insoluble in cold water, soften through the absorption of up to ten times
its weight of water; soluble in hot water and in warm gastric fluid.
Gelatin, being a protein, is digested by proteolytic enzymes.
8
Two methods used to track the
passage of capsules and tablets
through the gastrointestinal tract


Gamma scintigraphy(闪烁照相)
Heidelberg capsule
9
The manufacture of hard
gelatin capsule shells
The shell consists of two parts, the capsule body(囊体) and
the capsule cap(囊帽).
The process of capsule shell production with the peg/pin
method:
dipping(蘸胶) → drying → stripping(脱模) → trimming(截割) → joining
a) The thickness of the gelatin walls must be strictly controlled.
b) The caps are slightly larger in diameter than the bodies.
10
The manufacture of hard
gelatin capsule shells
Some improvements to hard gelatin capsule shells



capsule-making pegs (body-making or cap-making pegs):
general rounded shape pegs → tapered pegs
tapered rims, indentations and locking grooves:
straight-walled capsule shell → tapered rim capsule shell with
indentations and locking grooves (see page 25)
a) The tapered rims avoid splitting;
b) The indentations prevent premature opening;
c) The grooves lock the two capsule parts together after the capsule
has been filled.
extension capsule cap (CONI-SNAP SUPRO) (see page 26)
increase the security of the contents and the integrity of the capsule
11
The manufacture of hard
gelatin capsule shells
Tamper-evident sealing and imprinting


Tamper-evident sealing (显窃启密封): through various
capsule sealing techniques
Imprinting
which signals will be imprinted on finished capsules?
a) names and monograms of the manufacturer
b) the assigned national drug code (NDC) number
c) other markings making the product identifiable and
distinguishable from other products
12
Capsule sizes

How to select capsule size?
1) the amount of fill material to be encapsulated
2) the density and compressibility of the fill
3) The final determination largely may be the result of trial.

The sizes of empty capsules
For human use: 000(the largest), 00, 0, 1, 2, 3, 4, 5 (the smallest)
For veterinary use: Larger capsules are available.
13
Preparation of filled hard
gelatin capsules

The general steps of preparation
1) developing and preparing the formulation and selecting
the size of capsule.
2) filling the capsule shells.
3) capsule sealing (optional).
4) cleansing and polishing the filled capsules.
14
Developing the formulation and
selection of capsule size
The goal of developing a capsule formulation is to
prepare a capsule with
How to get to the goal?
1) pharmaceutical processing(工艺)
2) pharmaceutical excipient(辅料)
15
Developing the formulation and
selection of capsule size
The pharmaceutical processing in the
preparation of filled hard gelatin capsules
1) blending: → uniform powder mix, uniform drug
distribution
2) comminution/milling: 50~100 microns, suitable
for a drug of low dose (10mg or greater)
3) micronization: 10~20 microns, suitable for drugs
of lower dose
16
Developing the formulation and
selection of capsule size
The pharmaceutical excipient in the preparation of
filled hard gelatin capsules
1) diluent/filler: to produce the proper capsule fill volume; to
provide cohesion to the powders,
e.g. lactose, microcrystalline cellulose and starch
2) disintegrants/disintegration agents: to assist the break-up
and distribution of the capsule contents
e.g. pregelatinized starch (预胶化淀粉), croscarmellose (交联羧甲基
纤维素) , and sodium starch glycolate (羟基乙酸淀粉钠)
17
Developing the formulation and
selection of capsule size
The pharmaceutical excipient in the preparation of
filled hard gelatin capsules (continued)
3) lubricant or glidant: to enhance the flow properties of the
powder mix
e.g. fumed silicon dioxide, magnesium stearate, calcium
stearate, stearic acid, or talc
#: magnesium stearate, water-proofing characteristics,
retard penetration of the GI fluids, delay drug dissolution and
absorption
4) wetting agents: to facilitate wetting of the dry powder
e.g. surfactants, as sodium lauryl sulfate
18
Developing the formulation and
selection of capsule size
The form of filling material in capsules:
1) powder or granulate
2) pellet mixture
3) paste or wetted mass: the mixture of liquid and an inert powder
4) capsule
5) tablet
4 and 5 are employed to separate chemically incompatible agents or to add
premeasured (as tablets) amounts of potent drug substances
6) liquids: fixed or volatile oils (locking or sealed gelatin capsules)
7) eutectic mixtures: mixed with a diluent or absorbent to separate the
interacting agents and to absorb any liquefied material
19
Developing the formulation and
selection of capsule size
The selection of capsule size


For a commercial product: during the product development
stage
In the extemporaneous compounding of prescriptions
20
Developing the formulation and
selection of capsule size
Examples of filled hard gelatin capsules
1) Tetracycline capsules
Active ingredient: Tetracycline hydrochloride, 250 mg
Filler:
Lactose
Lubricant/glidant:
Magnesium stearate
Capsule colorants: omitted
Capsule opaquant: Titanium dioxide
21
Filling hard capsule shells
1. The “punch” method
suitable for filling a small number of capsules in the pharmacy
1) placing the powder on paper
2) forming the powder mix into a cake
3) punching the empty capsule body into the powder cake
1) nonpotent drugs: The first filled capsules should be weighed.
The other capsules should be weighed periodically.
2) potent drugs: Each capsules should be weighed.
22
Filling hard capsule shells
2. The pouring method
suitable for filling a small number of capsules in the
pharmacy
suitable for granular material
23
Filling hard capsule shells
3. Hand-operated capsule filling machines
consist of a couple of plates
24
Filling hard capsule shells
4. Machines for industrial use
The process of working:
separating the caps from
empty capsules → filling the
bodies → scraping the excess
powder → replacing the caps
→ sealing the capsules →
cleaning the outside of the
filled capsules
165,000 capsules per hour
SCF-10半自动胶囊充填机
25
Capsule sealing
make the capsules tamper-evident (显窃启)
1) sealing with a colored band of gelatin
2) heat welding
3) Thermally bonding at 40-45℃ with the help
of a melting-point-lowering liquid wetting
agent
4) extemporaneously, by lightly coating the
inner surface of the cap with a warm gelatin
solution
26
Cleaning and polishing
capsules
Small amount of powder may adhere to the
outside of capsules after filling.
1) On a small scale, cleaning with a clean
gauze or cloth.
2) On a large scale, cleaning vacuum
27
Soft gelatin capsules
The definition of soft gelatin capsules
Soft gelatin capsules are made of gelatin, glycerin (or a
polyhydric alcohol such as sorbitol) and water etc. to
hermetically seal and encapsulate liquids, suspensions, pasty
materials, dry powders and even preformed granules, pellets,
tablets. They may be manufactured to be oblong, oval or round
in shape.
The advantages of soft gelatin capsules
1) pharmaceutically elegant
2) easily swallowed by the patient
Turn to 34
Turn to 35
28
Turn to 33
29
Soft gelatin capsules
The pharmaceutical applications of soft gelatin
capsules are
1) as an oral dosage form
2) as a suppository dosage form
3) as a specialty package in tube form, for human and
veterinary single dose application of topical, ophthalmic,
and otic preparations, and rectal ointments.
30
Soft gelatin capsules
The components of soft gelatin capsules
1) gelatin
2) glycerin or polyhydric alcohol
3) water/moisture
4) preservative
5) colorant
6) markings
7) opaquants
8) Flavors may be added and up to 5% sucrose may be included
for its sweetness and to produce a chewable shell.
31
Preparation of soft gelatin
capsules
1. The plate process钢板模压法 (using a set of molds)
The plates contain die pockets.
1) placing a warm sheet of gelatin on the bottom plate
2) pouring the liquid-containing medications
3) placing the second sheet of gelatin
4) putting the top plate of the mold into place
5) pressing the mold to form, fill, and seal the capsules
simultaneously
6) removing and washing the capsule
Today, this equipment can no longer be purchased.
32
Preparation of soft gelatin
capsules
2. The rotary die process(旋转模压法 1933, R. P. Scherer)
more efficient and productive
1) Liquid gelatin is formed into two ribbons
2) The two ribbons are brought together
3) Metered fill material is injected between the ribbons
4) These pockets of fill-containing gelatin are sealed
33
34
Rotary die soft capsule
machine
The dies for production of soft
capsule
35
Preparation of soft gelatin
capsules
3. The reciprocating die process (往复模压法 1949, Norton
company)
is similar to the rotary process in that ribbons of gelatin are
formed and used to encapsulate the fill, but it differs in the
actual encapsulating process.
1) A set of vertical dies continually open and close to form rows of
pockets in the gelatin ribbons.
2) These pockets are filled with the medication and are sealed,
shaped, and cut out of the film.
3) The capsules fall into refrigerated tanks which prevent the
capsules from adhering to one another.
36
Preparation of soft gelatin
capsules
4. The Accogel
machine (1949,
Cyanamid comcany)
This equipment is
unique in that it is the
only equipment that
accurately fills
powdered dry solids.
5. Dripping method(滴制
法)
37
The nature of soft gelatin
capsule shell
1) The gelatin is pharmacopoeial grade with additional
specifications required by the capsule manufacturer.
a) Bloom strength:
b) viscosity:
Generally, 25 to 45 millipoise is acceptable.
c) iron: ≤15ppm
38
The nature of soft gelatin
capsule shell
2) Plasticizers
glycerin or sorbitol or combinations of these
The ratio by weight of dry plasticizer to dry gelatin determines
the “hardness” of the gelatin shell.
0.4/1 hard
0.6/1 medium
0.8/1 soft
The ratio by weight of water to dry gelatin can vary from 0.71.3 to 1.0.
3) The color of the gelatin shell
39
The fill material of soft gelatin
capsules
1) liquids
a) water-immiscible volatile and nonvolatile liquids
b) water-miscible, nonvolatile liquids
c) water-miscible and relatively nonvolatile liquids
e.g. propylene glycol, isopropyl alcohol
d) Liquids that can easily migrate through the capsule shell
cannot be encapsulated into soft gelatin capsules
2) solids (solutions, suspensions, pasty mass, dry powders,
granules, pellets, or small tablets.)
40
Compendial requirements for
capsules
The requirements for added substances
1) are harmless in the quantities used
2) do not exceed the maximum amounts required to
provide their intended effect
3) do not impair the product’s bioavailability, therapeutic
efficacy or safety
4) do not interfere with requisite compendial assays and
tests
41
The container and preservation
condition described in USP
containers
1) light resistant container(避光):
2) well-closed container(密闭):
3) tight container(密封):
4) Hermetic Container (熔封或严封):
Preservation conditions
1) Freezer: -25 ~ -10 ℃;
2) Cold: <8 ℃;
3) Cool: 8 ~ 15 ℃;
4) Room Temperature: The temperature prevailing in a working area.
5) Controlled Room Temperature: 20 ~ 25 ℃; 6) Warm: 30 ~ 40 ℃;
7) Excessive Heat: >40 ℃;
8) Protection from Freezing: (breakage of the container, loss of strength or
potency, destructive alteration of its characteristics)
42
Compendial requirements for
capsules
Disintegration test for capsules
1) Method
The capsules are placed in the basket-rack assembly,
which is repeatedly immersed 30 times per minute into a
thermostatically controlled fluid at 37 ℃ and observed
over the time described in the individual monograph.
2) To fully satisfy the test, the capsules disintegrate
completely into a soft mass having no palpably firm core,
and only some fragments of the gelatin shell.
43
Compendial requirements for
capsules
Dissolution test for capsules
1) The apparatus, dissolution media and test is the same
as that for uncoated and plain coated tablets.
2) Generally, when a dissolution test is applied to an
existing capsule product, the disintegration test is
unnecessary.
44
Compendial requirements for
capsules
Weight variation and content uniformity show the uniformity of dosage units.

Weight variation
Wcapsule – Wemptied shell = Wcontent 10 capsules
labeled amount or average amount, ±10%
1) For hard capsules
#1: Wcapsule should match Wemptied shell.
2) For soft capsules
#1: evaporating the washing solvent over 30 mins
#2: avoid uptake or loss of moisture

Content uniformity
The amount of active ingredient should be within the range of 85% to 115%
of the label amount for 9 of 10 capsules, with no unit outside the range of
70% to 125% of label amount.
45
Compendial requirements for
capsules
Other requirements:
1) content labeling: the quantity of each active
ingredient
2) stability testing
method: long-term stability testing, accelerated
stability test
aim: storage condition, shelf life
3) moisture permeation test: unit dose container
46
Inspecting, counting, packaging,
and storing capsules
1) Inspecting
visual or electronic inspection → uniform in
appearance
2) Counting
a) counting tray;
b) counting and filling machines
3) Packaging
unit dose and strip packaging (sanitary,
identifiable, safe)
4) Storing
in tightly capped container in a cool, dry place
47