6. Capsules
Characters
1) orally, conveniently carried, readily
identified, and easily taken
2) compared with equivalent doses of a
liquid medication, accurate dosing,
most tasteless when swallowed
3) readily identified
4) Prescribing flexibility (a variety of
dosage strengths)
5) from a pharmaceutic standpoint,
solid dosage forms are
• efficiently and productively
manufactured
• packaged and shipped by
manufacturers at lower cost and with
less breakage than comparable liquid
forms
• more stable, have a longer shelf-life
than their liquid counterparts.
I. Capsules
1. Hard gelatin capsules
2. Soft gelatin capsules
3. Compendial requirements for
capsules
4. Official and commercially
available capsules
5. Inspecting, counting, packaging,
and storing capsules
Capsules are solid dosage forms in
which medicinal agents and/or inert
substances are enclosed in a small shell
of gelatin. Gelatin capsule shells may
be hard or soft, depending on their
composition.
1. Hard gelatin capsules
• Hard gelatin capsule shells are used in
most commercial medicated capsules.
• The empty capsule shells are made of
gelatin, sugar, and water.
• They can be clear, colorless, and
essentially tasteless; or they may be
colored with various dyes.
• Most commercially available medicated
capsules contain combinations of
colorants and opaquants to make them
distinctive, many with caps and bodies
of different colors.
• Gelatin is obtained by the partial
hydrolysis of collagen obtained from the
skin, white connective tissue, and bones
of animals.
• It is desirable to maintain hard gelatin
capsules in an environment free from
excessive humidity or dryness.
• Many capsules are packaged along with a
small packet of a desiccant material to
protect against the absorption of
atmospheric moisture. The desiccant
materials most used are dried silica gel,
clay, and activated charcoal.
• A number of methods have been
developed to track the passage of
capsules and tablets through the
gastrointestinal tract to map their transit
time and drug release patterns.
• Among these is gamma scintigraphy, a
noninvasive procedure that entails use of
a gamma ray-emitting radiotracer
incorporated into the formulation with a
gamma camera coupled to a data
recording system.
When scintigraph is combined with
pharmacokinetic studies, the resultant
pharmacoscintographic evaluation provides
information about the transit and drug
release patterns of the dosage form as well
as the rate of drug absorption from the
various regions of the gastrointestinal tract.
This method is particularly useful in
(a) determining whether a correlation
exists between in vitro and in vivo
bioavailability for immediate-release
products,
(b)assessing the integrity and transit
time of enteric coated tablets through
the stomach en route to the intestines,
(c) drug and dosage form evaluation in new
product development.
1) The manufacture of hard
gelatin capsule shells
• Hard gelatin capsule shells are
manufactured in two sections, the
capsule body and a shorter cap.
• The shells are produced industrially by
the mechanical dipping of pins or pegs
of the desired shape and diameter
into
a
temperature-controlled
reservoir of melted gelatin mixture.
• The pegs submerged to the desired depth
and maintained for the desired period to
achieve the proper length and thickness
of coating.
• The pegs are slowly lifted from the bath
and the gelatin dried by a gentle flow of
temperature- and humidity-controlled air.
• When dried, each capsule part trimmed
mechanically to the proper length and
removed from the pegs, and the capsule
bodies and caps are joined together.
空胶囊的制备工艺：
• 溶胶
蘸胶
干燥
拔壳
切割
整理
• 一般由自动化生产线完成，生产环境洁
净度应达10000级，温度1025C，相对
湿度3545%。
2) Capsule sizes
• Empty gelatin capsules are manufactured in
various lengths, diameters, and capacities.
• The size selected for use is determined by
the amount of fill material to be
encapsulated.
• The density and compressibility of the fill
will largely determine to what extent it may
be packed into a capsule shell.
3) Preparation of filled hard
gelatin capsules
• Developing and preparing the
formulation and selecting the size
capsule
• Filling the capsule shells
• Capsule sealing (optional)
• Cleaning and polishing the filled
capsules
4) Developing the formulation
and selection of capsule size
In developing a capsule formulation,
the goal is to prepare a capsule
with
• accurate dosage,
• good bioavailability,
• ease of filling and production,
stability, and elegance.
• In dry formulations, the active and
inactive components must be blended
thoroughly to ensure a uniform powder
mix for the fill.
• A
diluent
or
filler
(lactose,
microcrystalline cellulose and starch)
may be added to the formulation to
produce the proper capsule fill volume.
• Disintegrants
(pregelatinized
starch,
croscarmellose 交 联 羟 甲 纤 维 素 , and sodium
starch glycolate 羟 基 乙 酸 淀 粉 钠 ) are
frequently included in a capsule formulation
to assist the breakup and distribution of
the capsule’s contents in the stomach.
• To achieve uniform drug distribution, it is
advantageous if the density and particle
size of the drug and nondrug components
are similar.
• The addition of a lubricant or glidant
such as fumed silicon dioxide,
magnesium stearate, calcium stearate,
stearic acid, or talc (about 0.25-1%) to
the powder mix enhances flow
properties.
• A surface-active agent, such as sodium
lauryl sulfate（硫酸月桂醇钠）, is used
to
facilitate
wetting
by
the
gastrointestinal fluids.
• Gelatin
aqueous
gelatin
resulting
capsules are unsuitable for
liquids because water softens
and distorts the capsules,
in leakage of the contents.
• A liquid may be mixed with an inert
powder to make a wet mass or paste,
which may then be placed in capsules in
the usual manner.
• Eutectic mixtures of drugs, or mixtures
of agents that have a propensity to
liquefy when admixed, may be mixed
with a diluent or absorbent to separate
the interacting agents and to absorb any
liquefied material that may form.
药物的填充
胶囊内容物的配方研究
1）粉末的流动性
粉末流动性会影响到装量的准确性，流动
性差针晶或引湿性粉末，可加适量润滑剂、
助流剂。用量0.1%.
2）粉末的分散与湿润
疏水性药物遇体液时会结块，加惰性亲水
性辅料如甲基纤维素，可增加药物的分散
与湿润性，从而提高生物利用度。
3）药物的释放
难溶性药物，粒径减少可增加药物的溶出。
但有些药物粒径小的粉末由于空隙小，液体
不易渗入。加表面活性剂或亲水性辅料，加
速药物的溶出。
4）液体、半固体药物的填装
- 用于填充液体或半固体类药物的胶囊应采用
锁口胶囊；
- 液体药物以可选用适当的辅料，制成糊状物，
用泵压法填充。
选择辅料的基本原则是：
1）不与主药发生物理、化学变化；
2）与主药混合后具有较好的流动性；
3）遇水后具有一定分散性，不会粘结成团而
影响药物的溶出。
The selection of the capsule size
• Hard gelatin capsules are used to
encapsulate between about 65 mg and 1
g of powdered material.
• The smallest capsule (No. 5) may be
expected to hold 65 mg of powder or
more, depending on the characteristics
of the powder substance.
An example of commercially available
capsule:
• Active ingredient: tetracycline
hydrochloride 250 mg
• Filler: lactose
• Lubricant/glidant: magnesium stearate
• Capsule colorants: FD&C Yellow No. 6
• Capsule opaquant: Titanium dioxide
5) Filling hard capsule shells
填充药物有手工法和自动填充机法两种：
1）手工填充法
药尘飞扬严重，装量误差大，生产效率低。
2）自动填充机法：
a. 螺旋钻压进药物
b. 栓塞上下往复将药物压进
c. 药粉自由流动，要求物料具有良好的流动
性，常需制粒才能达到。
d. 由捣棒在填充管内先将药物压成一定量后
再填充于胶囊中，适用于聚集性较强的针
状结晶或吸湿性药物。
6) Capsule sealing
• Sealed with gelatin
• Sealed through a heat welding process that
fuses the capsule cap to the body through
the double wall thickness at their juncture
• Utilized a melting-point-lowering liquid
wetting agent in the contact areas of the
capsule’s cap and body and then thermally
bonds the two parts using low temperatures
(40-45C).
7) Cleaning and polishing
capsules
• On a small scale, capsules may be
cleaned individually or in small numbers
by rubbing them with a clean gauze or
cloth.
• On a large scale, many capsule-filling
machines are affixed with a cleaning
vacuum that removes any extraneous
material from the capsules as they exit
the equipment.
2. Soft gelatin capsules
• Soft gelatin capsules are made of gelatin
to which glycerin or a polyhydric alcohol
such as sorbitol has been added.
• Soft gelatin capsules, which contain more
moisture than hard capsules, may have a
preservative,
such as methylparaben
and/or propylparaben, to retard microbial
growth.
• Soft gelatin capsules may be oblong, oval,
or round.
软胶囊剂的主要特点有：
- 装量均匀准确
- 软胶囊完全密封，其厚度可防氧进入；
挥发性药物，遇空气容易变质的药物
- 适合盛装难以压片或贮存中会变形的低熔
点固体药物
- 药物溶解或分散在可与水混溶的溶剂或油
状液体后再装胶囊，这样药物分散面大，
生物利用度也高。
1) Preparation of soft gelatin
capsules
Soft gelatin capsules may be prepared
• by the plate process, using a set of molds to
form the capsules.
• by the rotary（旋转） or reciprocating（往返
式） die processes by which they are
produced, filled, and sealed in a continuous
operation.
• Most soft gelatin capsules are prepared by
the rotary die process.
By the plate process,
1) A warm sheet of plain or colored gelatin
is placed on the bottom plate of the mold
and the liquid-containing medication is
evenly poured on it.
2) A second sheet of gelatin is carefully
placed on top of the medication and the
top plate of the mold is put into place.
3) Pressure is then applied to the mold to
form, fill, and seal the capsules
simultaneously
4) The capsules are removed and washed
with a solvent harmless to the capsules.
By the rotary die process,
1) Liquid gelatin flowing from an overhead
tank is formed into two continuous
ribbons by the rotary die machine and
brought together between twin rotating
dies.
2) At the same time, metered fill
material is injected between the
ribbons precisely at the moment that
the dies form pockets of the gelatin
ribbons.
3) These pockets of fill-containing
gelatin are sealed by pressure and
heat and then severed from the
ribbon.
4) Use of ribbons of two different
colors results in bicolored capsules.
The reciprocating die process 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) The gelatin ribbons are fed between a set of
vertical dies that 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
films.
3) As the capsules are cut from the ribbons, they
fall into refrigerated tanks which prevent the
capsules from adhering to one another.
软胶囊剂的生产工艺
1、滴制法：
系将明胶溶液与油状药物通过滴丸机的喷
头使夹层内的两种液体按不同速度喷出，
这样，外层明胶液将定量的内层油状液包
裹后，滴入另一种不相混溶的冷却液中，
明胶液在冷却液中因表面张力作用而形成
球形，并逐渐凝固成球形软胶囊剂。
滴制法制备软胶囊剂的生产工艺流程：
（1）胶液的准备
明胶
加热至7080C
水和甘油
混匀
熔融
保温过滤
保温12小时
待用
（2）药液的提取或炼制
（3）制胶丸
将药液明胶液经滴丸机特制的喷头滴入冷却液中，
由收集器收集而成。
①明胶的处方
明胶:甘油:水为1:(0.30.4):(0.71.4)为宜。
②液体的密度
一定的沉降速度和足够的冷却成型时间
制备鱼肝油胶丸时，药液:胶液:冷却液
=0.9g/ml:1.12g/ml:0.86g/ml。
③温度
胶液和药液均应保持在60C，喷头处应
保持在80C，冷却液为1317C。
（4）整丸与干燥
纱布
室温冷风干燥
制得的胶丸
3035C烘干
水份达到12%15%
石油醚洗涤两次
95%乙醇洗涤一次
（5）检查与包装
2、压制法
将明胶、甘油、水等溶解后制成胶皮，再
将药物置于两块胶皮之间，用钢模压制而
成。
2) Utilization of soft gelatin
capsules
• Soft gelatin capsules are prepared to
contain a variety of liquid, paste, and
dry fills.
• Liquids that may be encapsulated into
soft gelatin capsules include the
following:
- water-immiscible
volatile
and
nonvolatile liquids such as vegetable
and aromatic oils, aromatic and
aliphatic hydrocarbons, chlorinated
hydrocarbons,
ethers,
esters,
alcohols and organic acids.
- water-miscible, nonvolatile liquids,
such as polyethylene glycols, and
nonionic surface active agents as
polysorbate 80.
- water-miscible
and
relatively
nonvolatile
compounds,
as
propylene glycol and isopropyl
alcohol, depending on factors as
concentration used and packaging
conditions.
• Liquids are not suitable for soft
gelatin capsules. These materials
include
- water above 5%
- low molecular weight water-soluble and
volatile organic compounds such as
alcohols, ketones, acids, amines, and
esters.
3. Compendial requirements
for capsules
1) Requirements for added substances
- Harmless
- Do not impair the product’s bioavailability,
therapeutic efficacy or safety
- Do
not
interfere
with
requisite
compendial assays and tests
- Do not exceed the minimum amounts
required to provide their intended effect
2) Containers for dispensing capsules
The container may be required to be tight,
well-closed, and light resistant.
3) Disintegration tests for capsules
 The capsules are placed in the basket rack
assembly, which is immersed 30 times per
minute into a thermostatically controlled
fluid at 37C.
 The capsules disintegrate completely into a
soft mass.
4) Dissolution test for capsules
The dissolution test for capsules uses the
same apparatus, dissolution medium, and
test as that for uncoated and plain coated
tablets.
5) Weight variation
The uniformity of dosage units may be
demonstrated
by
determining
weight
variation and/or content uniformity.
- hard capsules
- Soft capsules
HARD CAPSULES:
• Ten capsules are individually weighed and
the contents removed.
• The emptied shells are individually weighed
and the net weight of the contents
calculated by subtraction.
• From the results of an assay performed as
directed in the indidual monograph, the
content of active ingredient in each of the
capsules is determined.
SOFT CAPSULES:
• The gross weight of 10 intact capsules is
determined individually.
• Each capsule is cut open with a scissors or a
sharp open blade, and the contents removed by
washing with a suitable solvent.
• The solvent is allowed to evaporate at room
temperature over a period of about 30 minutes,
taking precautions to avoid uptake or loss of
moisture.
• The individual shells are weighed and the net
contents calculated.
• From the results of the assay directed in the
individual monograph, the content of active
ingredient in each of the capsules is determined.
6) Content uniformity
- The
amount
of
active
ingredient,
determined by assay, is within the range
of 85% to 115% of the label claim for 9
of 10 dosage units assayed, with no unit
outside the range of 70% to 125% of
label claim.
- Additional tests are prescribed when two
or three dosage units are outside of the
desired range but within the stated
extremes.
7) Content labeling requirement
All official capsules must be labeled to
express the quantity of each active
ingredient in each dosage unit.
8) Stability testing
Stability testing of capsules is performed
to determine
- the intrinsic stability of the active drug
molecule,
- the influence of environmental factors as
- temperature,
- humidity,
- light,
- formulative compounds
- the containers/closure system.
The battery of
• stress testing,
• long-term stability
• and accelerated stability tests
help determine the appropriate
conditions for storage and the
product’s anticipated shelf-life.
9) Moisture permeation test
The degree and rate of moisturepenetration of containers are determined
- by packaging the dosage unit together
with a color-revealing desiccant pellet,
- exposing the packaged unit to known
relative humidity over a specified time,
- observing the desiccant pellet for color
change (indicating absorption of moisture)
- comparing the pre- and post-weight of
the packaged unit.
胶囊剂的质量检查与包装贮存
1、质量检查
胶囊剂的质量应符合《中国药典》2005
年版二部附录I “制剂通则”项下对胶囊
剂的要求：
1）外观
胶囊剂外观应整洁，不得有粘结、变形、
渗漏或囊壳破裂现象，并应无异臭。
2） 装量差异
胶囊剂装量差异，应符合下列规定
平均装量
装量差异限度
0.30g 以下
10%
0.30g 及0.30g以上
7.5%
检查法
• 取供试品20粒，分别精密称定重量后，倾出内
容物（不得损失囊壳），硬胶囊用小刷或其他
适宜用具试净，软胶囊用乙醚等易挥发性溶剂
洗净，置通风处使溶剂自然挥尽，再分别精密
称定囊壳重量，求出每粒内容物的装量与平均
装量。
• 每粒的装量与平均装量相比较，超出装量差异
限度的不得多于2粒，并不得有一粒超出限度
一倍。
• 凡规定检查含量均匀度的胶囊剂，可不进行装
量差异的检查。
3）崩解时限
• 取供试品6粒，按《中国药典》2005年版
二部附录XA进行崩解时限检查（如胶囊
浮于液面，可加挡板）。
• 硬胶囊应在30min内全部崩解，软胶囊应
在1h内全部崩解。
• 如有一粒不能完全崩解，应另取6粒复试，
均应符合规定。
2）包装和储存
• 一般来说，高温、高湿（相对湿度60%）
对胶囊剂可产生不良的影响，不仅会使
胶囊吸湿、软化、变粘、膨胀、内容物
结团，而且会造成微生物滋生。
• 一般应选用密封性能良好的玻璃容器、
透湿系数小的塑料容器和泡罩式包装，
在<25C、相对湿度<60%的干燥阴凉处，
密闭贮藏。
4. Official and commercially
available capsules
• There are approximately 200 officially
recognized medications in capsule form
in the USP.
• However commercially, there are many
fold this number of capsule products
available from various manufactures
for various drugs and in various dosage
strengths.
5. Inspecting, packaging and
storing capsules
• Capsules produced on a small or large
scale should be uniform in appearance.
• Visual or electronic inspection should be
undertaken to detect any flaws in the
integrity and appearance of the capsules.
• Capsules are packaged in glass or in
plastic containers, some containing
packets of a desiccant to prevent the
absorption of excessive moisture.
• Capsules should be stored in tightly
capped containers in a cool, dry place.
Questions
1．How to manufacture the hard gelatin
capsules？
2．How to select the hard gelatin capsule
sizes？
3．Describe the preparation of filled hard
gelatin capsules?
4．How to prepare soft gelatin capsules?
5．How many compendial requirements for
capsule？simply describe them.