Transcript chapter 5

5. Powders and Granules
Contents
I.
II.
III.
Powders
Medicated powders
Granules
I. Powders
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A dry substance composed of finely
divided particles
A medicated powder intended for internal
(i.e. oral powder) or external (i.e., topical
powder) use.
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Powders are intimate mixtures of dry,
finely divided drugs and /or chemicals
that may be intended for internal or
external use.
e.g. tablets, capsules, liquid dosage forms,
ointments and creams.
Granules
are prepared agglomerates of powdered
materials, may be used per se for the
medicinal value of their content or they
may be used for pharmaceutical purposes,
as in making tablets.
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Before their use in the preparation of
pharmaceutical products, solid materials first
are characterized to determine their chemical
and physical features including their
morphology,
purity,
solubility,
stability,
particle size,
uniformity,
compatibility with any other formulation
components.
一、Particle size and analysis
Powders of vegetable and animal drugs
are officially defined as follows:
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Very coarse (No. 8): All particles pass
through a No. 8 sieve (2.36 mm) and not
more than 20% through a No. 60 sieve
(250 m).
Coarse (No. 20): All particles pass through
a No. 20 sieve (850 m) and not more than
40% through a No. 60 sieve.
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Moderately coarse (No. 40):
All particles pass through a No. 40 sieve
(425 m) and not more than 40% through
a No.80 sieve (180 m).
Fine (No. 60):
All particles pass through a No. 60 sieve
(250 m) and not more than 40% through
a No. 100 sieve (150 m).
Very fine (or a No. 80):
All particles pass through a No. 80 sieve.
There is no limit to greater fineness.
The powder fineness for chemicals is
defined as follows
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Course (or a No. 20) powder-All particles
pass through a No. 20 sieve and not more
than 60% through a No. 40 sieve.
Moderately Course (or a No. 40) powderAll particles pass through a No. 40 sieve
and not more than 60% through a No. 60
sieve.
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Fine (or a No 80) powder-All particles
pass through a No. 80 sieve. There is no
limit as to greater fineness.
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Very fine (or a No. 120) powder-All
particles pass through a No. 120 sieve.
There is no limit as to greater fineness.
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Granules typically fall within the range of
4（4.75 mm) to 12-sieve size, although
granulations of powders prepared in the
12- to 20-sieve (850 m) range are
sometimes used in tablet making.
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The purpose of particle size analysis in
pharmacy is to obtain quantitative data on
the size, distribution, and shapes of drug
and nondrug components to be used in
pharmaceutical formulations.
Particle size can influence a variety of
important factors, including the
following:
1) Dissolution rate of particles intended to
dissolve; drug micronization can
increase the rate of drug dissolution and
its bioavailability.
2) Suspendability of particles intended to
remain undissolved but uniformly
dispersed in a liquid vehicle (e.g., fine
dispersions have particles approximately
0.5-10 m).
3) Uniform distribution of a drug substance
in a powder mixture or solid dosage form
to ensure dose-to-dose content uniformity.
4) Penetrability of particles intended to be
inhaled for deposition deep in the
respiratory tract (e.g., 1-5 m).
5) Lack of grittiness of solid particles in
dermal ointments, creams, and
ophthalmic preparations (e.g., fine
powders may be 50-100 m in size).
A number of methods exist for the
determination of particle size
1) Sieving
Particles are passed by mechanical shaking
through a series of sieves of known and
successively smaller size and the
determination of the proportion of powder
passing through or being withheld on each
sieve (range about 40-9500m, depending
upon sieve sizes).
2) Microscopy
in which the particles are sized through
the use of a calibrated grid background
or other measuring device. (range
0.2100m)
3) Sedimentation rate
in which particle size is determined by
measuring the terminal settling velocity of
particles through a liquid medium in a
gravitational or centrifugal
environment.(range:0.8-300microns)
4) Light energy diffraction or light scattering
In which particle size is determined by the
reduction in light reaching the sensor as the
particle, dispersed in a liquid or gas, passes
through the sensing zone (range 0.2500
microns).
5) Laser holography （激光全息照相术）
In which a pulsed laser is fired through
an aerosolized particle spray and
photographed in three dimensions with a
holographic
camera,
allowing
the
particles to be individually imaged and
sized (range:1.4100micros).
用一束激光通过雾化粒子流，用全息照相术
拍三维照片，观察到粒子的形态和大小。
6) Cascade impaction （阶式碰撞）
is based on the principle that a particle,
driven by an airstream, will impact on a
surface in its path, provided that its
inertia （惯性） is sufficient to overcome
the drag force that tends to keep it in the
airstream.
当粒子用空气流输送时会撞击到一表面，假
定其惯性大于其向内的拉力，粒子流则会在
不同速率的空气流驱动下按不同的粒径分离。
Micromeritics （粉体学）
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Micromeritics is the science of small
particles.
It is important to study particles because the
majority of drug dosage forms are solids.
Solids are not “static” systems-the physical
state of particles can be altered by physical
manipulation and particle characteristics can
alter therapeutic effectiveness.
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Micromeritics includes a number of
charateristics including
particle size
particle size distribution
shape
angle of repose
porosity
true volume
bulk volume
apparent density and bulkiness
Particle Size
The microscopic method can include counting not
fewer than 200 particles in a single plane using a
calibrated ocular on a microscope.
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The sieving method entails using a set of
U.S. standard sieves in the size range desired.
A stack of sieves is arranged in order, the powder
placed in the top sieve, the stack shaken, the
quantity of powder resting on each sieve weighed,
and this calculation performed:
Angle of repose
 The angle of repose is a relatively simple
technique for estimating the flow properties of
a powder.
 It can easily be determined by allowing a
powder to flow through a funnel and fall freely
onto a surface
 The height and diameter of the resulting cone
are measured and the angle of repose
calculated from this equation:
tan=h/r
where h is the height of the powder cone
r is the radius of the powder cone.
Porosity, void, and bulk volume
The characteristics used to describe powders
include porosity, true volume, bulk volume,
apparent density, true density, and bulkiness.
Porosity is void 100%
This value should be determined
experimentally by measuring the volume
occupied by a selected weight of a powder,
Vbulk.
The true volume, V, of a powder is the space
occupied by the powder exclusive of spaces
greater than the intramolecular space.
Void can be defined as
(Vbulk-V)/Vbulk
therefore, porosity is (Vbulk-V)/Vbulk100%
the bulk volume is
true volume + porosity
Apparent density, true density, and
bulkiness
The apparent density, a, is
Weight of the sample/Vbulk
The true density, , is
Weight of the sample/V
The bulkiness, B, is the reciprocal of the
apparent density,
B=1/a
二、Comminution of drugs
 Grinding a drug in a mortar to reduce its
particle size is termed trituration（研碎）.
 Mills and Pulverizers
 Levigation is commonly used in small-scale
preparation of ointments to reduce the
particle size and grittiness of added
powders.
Mineral oil and glycerin are commonly used
levigating agents.
Particle size reduction
1. Increase in number of particles
If a powder consists of cubes 1mm on edge
and it is reduced to particles 10m on edge,
what is the number of particles produced?
1) 1mm equals 1000m
2) 1000m/10m=100 pieces produced on
each edge; that is, if the cube is sliced into
100 pieces on the x-axis, each 10m long,
100 pieces result.
If this is repeated on the y- and z-axes, the
result is 100100100=1 million particles
produced, each 10 m on edge, for each
original particle 1 mm on edge. This can
also be written [(102)3=106].
2. Increase in surface area
What increase in the surface area of the
powder is produced by decreasing the
particle size from 1mm to 10m?
1) The 1mm cube has 6 surfaces, each 1mm
on edge. Each face has a surface area of
1mm2. Because there are 6 faces, this is 6
mm2 surface area per particle.
3)
2) Each 10 m cube has 6 surfaces, each 10
m on edge. Each face has a surface area of
1010=100m2. because there are 6 faces,
this is 6100m2, or 600m2 surface area per
particle. Since 106particles resulted from
comminuting the 1mm cube, each 10m on
edge, the surface are now is 600 m2106, or
6108 m2.
3) To get everything in the same units for
ease of comparison, convert the 6108m2
into square millimeters as follows.
4) Since there are 1000 m=1mm, there must
This is more appropriately expressed as 106
m2=mm2.
6108m2/106m2/mm2=6102mm2
The surface areas have been increased from
6 mm2 to 600 mm2 by the reduction in particle
size of cubes 1 mm on edge to cubes 10 m
on edge, a hundredfold increase in surface
area.
This can have a significant increase in the
rate of dissolution of a drug product.
三、Blending powders
Powders may be blended by spatulation
（搅拌法）, trituration（研磨法）, sifting
（过筛法）, and tumbling（滚动法）.
1) Spatulation is blending small amounts of
powders by movement of a spatula through
them on a sheet of paper or an ointment tile.
Substances that form eutectic mixtures
when combined include phenol, camphor,
menthol, aspirin, phenyl salicylate, and
other similar chemicals.
2）Trituration may be employed both to
comminute and to mix powders.
Geometric dilution method:
- By this method, the potent drug is placed on an
approximately equal volume of the diluent in a
mortar and mixed thoroughly by trituration.
- Then the second portion of diluent equal in
volume to the mixture is added, and the
trituration repeated.
- This process is continued by adding equal
volumes of diluent to the powder mixture and
repeating until all of the diluent is incorporated.
This method
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is used to ensure the uniform distribution of
the potent drug.
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is especially indicated when the potent and
other ingredients are the same color and a
visible sign of mixing is lacking.
3）Sifting
 Sifting results in a light fluffy product.
 This process is not acceptable for the
incorporation of potent drugs into a diluent
powder.
4) Tumbling
 Mixing by this method is thorough.
 are widely employed in industry.
II. Medicated powders
1) Internally (taken orally after mixing with
water)
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Local effects (laxatives)
Systemic effects (e.g., analgesics)
2) Externally (injection, vaginal douche)
3) Inhaled for local and systemic effects
散剂的特点：
1）不受剂量的限制
2）便于服用
3）奏效快
4）易于分散
5）分剂量灵活，便于用药个体化。
6）制药方法简单，价格低廉，包装、贮藏、运
输方便。
缺点：
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掩味作用差；
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吸湿性强；
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不利于药物的稳定性。
散剂的分类
1. 按用途分：内服和外用
外用散剂又分为：
撒布散剂（皮肤）；
吹入散剂（体内腔道）；
牙用散剂：牙粉
2. 按组成分：单散剂和复方散剂
3. 按剂量分：分剂量散剂和不分剂量散剂
1.
Aerosol powders (粉雾剂）
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Some medicated powders are
administered by inhalation
with the aid of dry-powder
inhalers, which deliver
micronized particles of
medication in metered
quantities.
Therapeutic agent
Inert propellants
Pharmaceutical diluents
The particle size of the
micronized medication is
prepared in the range of 1 to
6 m in diameter
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2. Bulk and divided powders （多剂量和
分剂量散剂）
1) Bulk powders
 Antacids (sodium bicarbonate) and laxatives
(psyllium,车前子);
 Douch powders, dissolved in warm water by
the patient for vaginal use;
 Medicated powders for external application to
the skin, usually topical anti-infectives (e.g.,
bacitracin zinc and polymyxin B sulfate) or
antifungals (e.g., tolnaftate托萘酯);
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Brewer’s yeast powder containing B-complex
vitamins and other nutritional supplements.
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Dispensing powder medication in bulk
quantities is limited to nonpotent substances.
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Powders containing substances that should
be administered in controlled dosage are
supplied to the patient in divided amounts in
folded papers or packets.
2) Divided powders
After a powder has been properly blended, it
may be divided into individual dosing units
based on the amount to be taken or used at a
single time.
Each divided portion of powder may be
placed on a small piece of paper that is
folded to enclose the medication.
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The selection of the type of paper is based
primarily on the nature of the powder.
If the powder contains hygroscopic or
deliquescent materials, a water-proof or a
waxed paper should be used.
Powders containing volatile components
should be wrapped in waxed or in glassine
papers.
Powders containing neither volatile
components nor ingredients adversely affected
by air or moisture are usually wrapped in white
bond paper.
A number of commercially prepared
premeasured products are available in folded
papers or packets, including
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headache powders
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powdered laxatives
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douche powders
散剂的制备
1．物料前处理
2．粉碎与筛分
- 干法粉碎是将药物干燥到一定程度（一般是使水
分小于5％）后粉碎的方法
- 湿法粉碎, 在药物粉末中加入适量的水或其他液
体再研磨粉碎的方法
- 过筛是保证所的粉末的均匀性，一般可过6号筛，
儿科和外用过7号筛，眼科用过9号筛。
3．混合与分剂量
1）混合方法：搅拌混合、研磨混合和过筛
混合。
2）影响混合效果的因素及防止混合不匀的
措施
数量差异悬殊、组分比例
相差过大时，应采用等量递加混合法（又称
配研法）混合，即量小药物研细后，加入等
体积其它药物细粉混匀，如此倍量增加混合
至全部混匀，再过筛混合即成。
①组分的比例
密度差异较大时，应将密度
小（质轻）者先放入混合容器中，再放入密度大
（质重）者，这样可避免密度小者浮于上面或飞
扬，密度大者沉于底部而不易混匀。
②组分的密度
应将量大且不易
吸附的药粉或辅料垫底，量少且易吸附者后加入。
因混合摩擦而带电的粉末常阻碍均匀混合，通常
可加少量表面活性剂克服，也有人用润滑剂作抗
静电剂。
③组分的吸附性与带电性
④含液体或易吸湿性的组分
如处方中有液体
组分时，可用处方中其它组分吸收该液体，若液
体组分量太多，宜用吸收剂吸收至不显润湿为止，
常用吸收剂有磷酸钙、白陶土、蔗糖和葡萄糖等。
若有易吸湿性组分，则应针对吸湿原因加以解决：
a. 如含结晶水，则可用等摩尔无水物代替；
b. 若是吸湿性很强的药物，则可在低于其临
界相对湿度条件下，迅速混合，并密封防潮包
装；
c. 若组分因混合引起吸湿，则不应混合，可
分别包装。
⑤含可形成低共熔混合物的组分
将二种或二种以上药物按一定比例混合时，在
室温条件下，出现的润湿与液化现象，称做低
共熔现象。
常见的可发生低共熔现象的药物有水合氯醛、萨
罗（水杨酸苄酯）、樟脑、麝香草酚等，它们以
一定比例混合研磨时极易润湿、液化。
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若该复方散剂不影响药物疗效，可直接使用；
若增加疗效，可适当减少剂量；
若影响疗效，可分别与其他辅料混合分别包装使
用。
3）分剂量 将混合均匀的散剂，按重量要求
分成等重份数的过程叫分剂量。
（1）重量法：
是用天平进行准确称量，将所称出的每个单个剂
量进行单独包装。
特点：分剂量准确，适于含有细料或毒剧药物的
散剂分剂量。
但操作麻烦，效率低，不适于大生产。
（2）容量法：
是将所制的散剂填入一定容积的容器中进行分剂
量，容器的容积相当于一个剂量的散剂的体积。
特点：分剂量快速，可连续操作。
缺点：分剂量不准确，散剂的物理性质以及分剂
量的速度均影响准确性。
散剂的质量检查与包装贮存
1．质量检查
1）含量测定与均匀度
单散剂要测定该散剂中药物的含量，复方散剂要
对处方中各种成分的含量都进行测定。
取供试品适量置光滑纸上平铺约5 cm2，将其表
面压平，在亮处观察，应呈现均匀色泽，无花纹、
色斑。
2）细度
过筛法、显微镜法、沉降法、气体吸附法
3）水分
按药典规定水分测定法测定，除特殊规定外，
不得超过9％。
4）装量差异
单剂量、一日剂量包
装的散剂，装量差异
限度应符合规定（表3
一2）
取散剂10包（瓶），
分别精密称定每包
（瓶）的重量。
2．包装贮存
散剂的包装与贮存要注意密闭、温度、湿度、光
线和微生物等的影响。
散剂包装与储存的重点在于防潮，散剂的吸湿特
性及防止吸湿措施成为控制散剂质量的重要内容。
散剂采取防潮包装成密封包装，避免高温和光照，
并贮存于干燥、阴凉处。
III. Granules
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Granules are prepared agglomerates of
smaller particles of powder.
Granules are prepared by wet methods and
dry methods.
Moisten
Powder or
powder mixture
Screen
granules
Dry powder
Roll compactor
Granulating
machine
granules
compression
Powder
Powder mixture
Large tablets
slugs
Granulated into
the desired
particle size
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Granules flow well compared to powders. For
comparison, consider the pouring/flowing
characteristics of granulated sugar versus
powdered sugar.
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Because of their flow properties, granulations
are commonly used in tablet-making to
facilitate the free flow of material from the
feeding container into the tableting presses.
In addition to being free-flowing, granules
have other important characteristics.
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The surface area is less than a comparable
volume of powder, granules are usually more
stable to the effects of atmospheric humidity
and are less likely to cake or harden upon
standing.
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Granules also are more easily “wetted” by
liquids than are certain light and fluffy
powders.
Granulated commercial products
 Antibiotics
 Laxative Senokot granules (Purdue Frederick)
 Alka-Seltzer (Bayer)
1. Effervescent granulated salts
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A medicinal agent
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Sodium bicarbonate
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Citric acid
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Tartaric acid
1) Fusion method
other powder
citric acid crystals
granules
powdered
a sieve
mixing
oven at 34C to 40C
2) Wet method
- The wet method differs from the fusion
method in that the source of binding
agent is not the water of crystallization
from the citric acid but water added to
alcohol as the moistening agent, forming
the pliable mass for granulation.
- In this method, all of the powders may be
anhydrous as long as water is added to
the moistening liquid.
Questions
1. Why is particle size analysis important in
pharmaceutical formulation？
2. How are powders of chemical drugs officially
defined?
3. What are the methods for determination of
particle size？
4. How to comminute the particle size of drugs？
5. How to blend powders? Simply describe each
method.
6. What are medicated powders and how to apply
them to the medication?
7. What are granules？How to prepare granules?