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5. Powders and Granules

5. Powders and Granules. Contents I. Powders II. Medicated powders III. Granules

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Page 1: 5. Powders and Granules. Contents I. Powders II. Medicated powders III. Granules

5. Powders and Granules

Page 2: 5. Powders and Granules. Contents I. Powders II. Medicated powders III. Granules

Contents

I. Powders

II. Medicated powders

III. Granules

Page 3: 5. Powders and Granules. Contents I. Powders II. Medicated powders III. Granules

I. Powders

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.

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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.

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一、 Particle size and analysis

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Powders of vegetable and animal drugs are officially defined as follows:

- 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.

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The powder fineness for chemicals is defined as follows

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) powder-All 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.

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.

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.

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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).

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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).

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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 40-9500m, depending upon sieve sizes).

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2) Microscopy

in which the particles are sized through the use of a calibrated grid background or other measuring device. (range 0.2100m)

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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 0.2500 microns).

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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:1.4100micros).

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。

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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。

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Micromeritics (粉体学)

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

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Particle SizeThe microscopic method can include counting not fe

wer 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:

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Angle of repose The angle of repose is a relatively simple tec

hnique 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/rwhere h is the height of the powder cone

r is the radius of the powder cone.

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Porosity, void, and bulk volumeThe 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 spacesgreater than the intramolecular space.

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Void can be defined as

(Vbulk-V)/Vbulk

therefore, porosity is (Vbulk-V)/Vbulk100%

the bulk volume is

true volume + porosity

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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

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二、 Comminution of drugs Grinding a drug in a mortar to reduce its par

ticle 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.

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Particle size reduction

1. Increase in number of particles

If a powder consists of cubes 1mm on edge and it is reduced to particles 10m on edge, what is the number of particles produced?

1) 1mm equals 1000m

2) 1000m/10m=100 pieces produced on each edge; that is, if the cube is sliced into 100 pieces on the x-axis, each 10m long, 100 pieces result.

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3) If this is repeated on the y- and z-axes, the result is 100100100=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 areaWhat increase in the surface area of the powder is produced by decreasing the particle size from 1mm to 10m?

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.

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2) Each 10 m cube has 6 surfaces, each 10 m on edge. Each face has a surface area of 1010=100m2. because there are 6 faces, this is 6100m2, or 600m2 surface area per particle. Since 106particles resulted from comminuting the 1mm cube, each 10m on edge, the surface are now is 600 m2106, or 6108 m2.

3) To get everything in the same units for ease of comparison, convert the 6108m2 into square millimeters as follows.

4) Since there are 1000 m=1mm, there must

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This is more appropriately expressed as 106 m2=mm2.

6108m2/106m2/mm2=6102mm2

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.

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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.

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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.

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This method

- is used to ensure the uniform distribution of the potent drug.

- is especially indicated when the potent and other ingredients are the same color and a visible sign of mixing is lacking.

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3 ) Sifting Sifting results in a light fluffy product. This process is not acceptable for the incorpo

ration of potent drugs into a diluent powder.

4) Tumbling Mixing by this method is thorough. are widely employed in industry.

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II. Medicated powders

1) Internally (taken orally after mixing with water)

- Local effects (laxatives)- Systemic effects (e.g., analgesics)

2) Externally (injection, vaginal douche)

3) Inhaled for local and systemic effects

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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。

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缺点:- 掩味作用差;- 吸湿性强;- 不利于药物的稳定性。

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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

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1. Aerosol powders ( 粉雾剂)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 t

he 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.

Dispensing powder medication in bulk quantit

ies is limited to nonpotent substances.

Powders containing substances that should be administered in controlled dosage are supplied to the patient in divided amounts in folded papers or packets.

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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.

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A number of commercially prepared premeasured products are available in folded papers or packets, including

headache powders

powdered laxatives

douche powders

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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。

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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

①组分的比例 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。

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②组分的密度 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。

③组分的吸附性与带电性 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。

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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;

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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。

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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。

- 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。

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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。

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( 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。

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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。

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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%。

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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。

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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。

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III. Granules

Granules are prepared agglomerates of smaller particles of powder.

Granules are prepared by wet methods and dry methods.

Powder or powder mixture

Moisten

Screen granules

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Dry powder Roll compactorGranulating

machine

granules

PowderPowder mixture

compression

Large tabletsslugs

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.

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.

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In addition to being free-flowing, granules have other important characteristics.

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.

Granules also are more easily “wetted” by liquids than are certain light and fluffy powders.

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Granulated commercial products Antibiotics Laxative Senokot granules (Purdue Frederic

k) Alka-Seltzer (Bayer)

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1. Effervescent granulated salts A medicinal agent Sodium bicarbonate Citric acid Tartaric acid

1) Fusion method

citric acid crystals powdered

other powder

mixing

oven at 34C to 40Ca sievegranules

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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.

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Questions 1. Why is particle size analysis important in pharm

aceutical formulation ?2. How are powders of chemical drugs officially de

fined? 3. What are the methods for determination of partic

le size ?4. How to comminute the particle size of drugs ?5. How to blend powders? Simply describe each m

ethod.6. What are medicated powders and how to apply t

hem to the medication?7. What are granules ? How to prepare granules?