13. Disperse Systems13. Disperse Systems(( 分散体系）分散体系）

Contents Contents

Suspensions Suspensions （混悬剂）（混悬剂） Emulsions Emulsions （乳剂）（乳剂） Gels and magmas Gels and magmas （凝胶剂和乳浆剂）（凝胶剂和乳浆剂） Proper administration and use of disProper administration and use of disperse systems perse systems （分散体系的正确给药和（分散体系的正确给药和使用）使用） Aerosols Aerosols （气雾剂）（气雾剂）

Liquid preparations contaLiquid preparations containing undissolved or immiining undissolved or immiscible drug distributed thrscible drug distributed throughout a vehicle.oughout a vehicle. In these preparations, the In these preparations, the substance distributed is resubstance distributed is referred to as ferred to as dispersed phadispersed phasese, and the vehicle is term, and the vehicle is termed ed the dispersing phase or the dispersing phase or dispersion medium.dispersion medium. Together, they produce a Together, they produce a dispersed systemdispersed system..

The particles of the dispersed phase are The particles of the dispersed phase are vary widely in size.vary widely in size.

Dispersions containing coarse Dispersions containing coarse particles, usually particles, usually 10 to 50 10 to 50 mm, are , are referred to as referred to as coarse dispersionscoarse dispersions; they ; they include the suspensions and include the suspensions and emulsions.emulsions.

Dispersions containing particles of Dispersions containing particles of smaller size are termed smaller size are termed fine fine dispersions (0.5dispersions (0.5~10~10m).m).

If the particles are in the colloidal If the particles are in the colloidal range, range, colloidal dispersionscolloidal dispersions..

Magmas and gels are fine dispersions.Magmas and gels are fine dispersions.

Suspensions Suspensions Suspensions may be defined as prepaSuspensions may be defined as preparations containing finely divided drurations containing finely divided drug particles distributed somewhat unig particles distributed somewhat uniformly throughout a vehicle in whicformly throughout a vehicle in which the drug exhibits a minimum degreh the drug exhibits a minimum degree of solubility.e of solubility. 混悬剂系指难溶性固体药物以微粒状态分混悬剂系指难溶性固体药物以微粒状态分散于分散介质中形成的多相分散体系。散于分散介质中形成的多相分散体系。

Some suspensions are available in ready-to-Some suspensions are available in ready-to-use form, that is, already distributed througuse form, that is, already distributed through a liquid vehicle with or without stabilizers h a liquid vehicle with or without stabilizers and other additives. and other additives. （一些混悬剂在有或无稳定（一些混悬剂在有或无稳定剂和其他药用添加剂的情况下分散在液体介子中而剂和其他药用添加剂的情况下分散在液体介子中而供使用）供使用）

Other preparations are available as dry Other preparations are available as dry powders intended for suspension in liqpowders intended for suspension in liquid vehicles. uid vehicles. （其他制剂还有分散到液体介（其他制剂还有分散到液体介质中能形成混悬剂的干粉）。质中能形成混悬剂的干粉）。 This type of product generally is a powThis type of product generally is a powder mixture containing the drug and suder mixture containing the drug and suitable suspending and dispersing agentitable suspending and dispersing agents to be diluted and agitated with a specis to be diluted and agitated with a specified quantity of vehicle, generally puriffied quantity of vehicle, generally purified water.ied water.

醋酸甲地孕酮口服混悬剂

Reasons for SuspensionsReasons for SuspensionsThere are several reasons for prepariThere are several reasons for preparing suspensions.ng suspensions.

11 ）） The suspension ensures chemical The suspension ensures chemical stability while permitting liquid therstability while permitting liquid therapy.apy. （（混悬剂以液体形式给药保证了药物混悬剂以液体形式给药保证了药物的化学稳定性。）的化学稳定性。）

22 ）） For many patients, the liquid form For many patients, the liquid form is preferred to the solid form of the sis preferred to the solid form of the same drug because of the ease of swalame drug because of the ease of swallowing liquids and the flexibility in alowing liquids and the flexibility in administration of a range of doses.dministration of a range of doses.（对许多病人来说，服用同一种药物的液（对许多病人来说，服用同一种药物的液体制剂比固体制剂更容易接受，这是因为体制剂比固体制剂更容易接受，这是因为液体便于吞服并能在一定范围内很方便的液体便于吞服并能在一定范围内很方便的改变给药剂量）。改变给药剂量）。

33 ）） The disadvantage of a disagreeablThe disadvantage of a disagreeable taste of certain drugs in solution foe taste of certain drugs in solution form is overcome when the drug is adrm is overcome when the drug is administered as undissolved particles oministered as undissolved particles of an oral suspension.f an oral suspension.（当药物在口服混悬剂中以不溶粒子的形式（当药物在口服混悬剂中以不溶粒子的形式给药时可克服某些药物以溶液剂给药时具给药时可克服某些药物以溶液剂给药时具有不良气味的缺点）。有不良气味的缺点）。

Features Desired in a Features Desired in a Pharmaceutical SuspensionPharmaceutical Suspension

There are many considerations in the There are many considerations in the development and preparation of a phdevelopment and preparation of a pharmaceutically elegant suspension.armaceutically elegant suspension.1.1. A properly prepared pharmaceutical A properly prepared pharmaceutical suspension should settle slowly and ssuspension should settle slowly and should be readily redispersed upon gehould be readily redispersed upon gentle shaking of the container. ntle shaking of the container. （正确制备的药物混悬剂应沉降缓慢，且（正确制备的药物混悬剂应沉降缓慢，且轻微振摇容器后能重新分散）轻微振摇容器后能重新分散）

2.2. The particle size of the suspensoid sThe particle size of the suspensoid should remain fairly constant throughould remain fairly constant throughout long periods of undisturbed sthout long periods of undisturbed standing. anding. （混悬剂应具有长时间放置后（混悬剂应具有长时间放置后其混悬粒子大小保持不变的特性）其混悬粒子大小保持不变的特性）3.3. The suspension should pour readily The suspension should pour readily and evenly from its container. and evenly from its container. （混（混悬剂应易于从容器中均匀倒出）悬剂应易于从容器中均匀倒出）

Sedimentation Rate of the Sedimentation Rate of the Particles of a SuspensionParticles of a Suspension

Stokes’ EquationStokes’ Equation dx/dt=ddx/dt=d22((ii--ee)g/18)g/18where where

- dx/dt is the rate of settingdx/dt is the rate of setting- d is the diameter of the particles,d is the diameter of the particles, i i is the density of the particle,is the density of the particle, e e is the density of the medium,is the density of the medium,- g is the gravitational constant,g is the gravitational constant, is the viscosity of the mediumis the viscosity of the medium

A number of factors can be adjusted to A number of factors can be adjusted to enhance the physical stability of a suenhance the physical stability of a suspension, including spension, including the diameter of the particles,the diameter of the particles, the density, the density, viscosity of the medium.viscosity of the medium.为了减少微粒的沉降速度，可采用的措施有：为了减少微粒的沉降速度，可采用的措施有：①① 减小微粒的半径，减小微粒的半径，②② 加入助悬剂加入助悬剂

Stokes’ equation does not apply Stokes’ equation does not apply precisely to the usual precisely to the usual pharmaceutical suspension is pharmaceutical suspension is irregularly shaped and of various irregularly shaped and of various particle diameters,particle diameters,

in which the fall of the particles in which the fall of the particles does result in both turbulence and does result in both turbulence and collision, and also in which the collision, and also in which the particles may have some affinity for particles may have some affinity for the suspension medium.the suspension medium.

The basic concepts of the equation do give The basic concepts of the equation do give a valid indication of the factors that are a valid indication of the factors that are important to suspension of the particles important to suspension of the particles and a clue to the possible adjustments and a clue to the possible adjustments that can be made to a formulation to that can be made to a formulation to decrease the rate of sedimentation.decrease the rate of sedimentation.

For the most part, the physical stability of For the most part, the physical stability of a pharmaceutical suspension appears to a pharmaceutical suspension appears to be most appropriately adjusted by an be most appropriately adjusted by an alteration in the dispersed phase rather alteration in the dispersed phase rather than through great changes in the than through great changes in the dispersion medium.dispersion medium.

Physical Features of the Physical Features of the Dispersed Phase of a Dispersed Phase of a

SuspensionSuspension The most important single The most important single

consideration in a discussion of consideration in a discussion of suspensions is the suspensions is the size of the size of the particles.particles.

In most good pharmaceutical In most good pharmaceutical suspensions, the particle diameter is suspensions, the particle diameter is 1 to 50 1 to 50 m.m.

Particle size reduction is generally Particle size reduction is generally accomplished by accomplished by dry millingdry milling prior to prior to incorporation of the dispersed phase incorporation of the dispersed phase into the dispersion medium.into the dispersion medium.

One of the most rapid, convenient,anOne of the most rapid, convenient,and inexpensive methods of producing d inexpensive methods of producing fine drug powders of about 10 to 50 fine drug powders of about 10 to 50 m size is m size is micropulverization.micropulverization. For still finer particles, under 10 For still finer particles, under 10 m, m, fluid energy grinding (jet milling or fluid energy grinding (jet milling or micronizing),micronizing), is quite effective. is quite effective. Particles of extremely small dimensiParticles of extremely small dimensions may also be produced by ons may also be produced by spray-dspray-drying.rying.

The reduction in the particle size of a suThe reduction in the particle size of a suspensoid is beneficial to the stability of tspensoid is beneficial to the stability of the suspension.he suspension. However, one should avoid reducing the However, one should avoid reducing the particle size too much, since fine particlparticle size too much, since fine particles have a tendency to form a compact caes have a tendency to form a compact cake upon settling to the bottom of the conke upon settling to the bottom of the container.tainer. To avoid formation of a cake, it is necessTo avoid formation of a cake, it is necessary to prevent agglomeration of the partiary to prevent agglomeration of the particles into larger crystals or into masses.cles into larger crystals or into masses.

One common method of preventing riOne common method of preventing rigid cohesion of small particles of a sugid cohesion of small particles of a suspension is intentional formation of a spension is intentional formation of a less rigidless rigid or or loose aggregationloose aggregation of the of the particles held together by comparativparticles held together by comparatively ely weak particle-to-particle bonds.weak particle-to-particle bonds. Such an aggregation of particles is terSuch an aggregation of particles is termed med a floc or a floccule.a floc or a floccule.

絮凝与反絮凝 絮凝与反絮凝 向混悬剂中加入电解质，向混悬剂中加入电解质， ζζ 电位降低到一电位降低到一定程度后，混悬剂中的微粒形成疏松的絮定程度后，混悬剂中的微粒形成疏松的絮状聚集体的过程称为絮凝，加入的电解质状聚集体的过程称为絮凝，加入的电解质称为絮凝剂。称为絮凝剂。 向絮凝状态的混悬剂中加入电解质，使絮向絮凝状态的混悬剂中加入电解质，使絮凝状态变为非絮凝状态的过程称为反絮凝，凝状态变为非絮凝状态的过程称为反絮凝，加入的电解质称为反絮凝剂。 加入的电解质称为反絮凝剂。

The flocs settle to form The flocs settle to form a a higher sediment volumehigher sediment volume than unflo than unflocculated particles, cculated particles, the loose structure of which permits the loose structure of which permits the aggregates to the aggregates to break up easilybreak up easily and and distribute readilydistribute readily with a small a with a small amount of agitation.mount of agitation.

There are There are several methodsseveral methods of preparain of preparaing flocculated suspensions,g flocculated suspensions, For an oral suspension of drug, clays suFor an oral suspension of drug, clays such as ch as diluted bentonite magmadiluted bentonite magma （皂土乳（皂土乳浆）浆） are commonly employed.are commonly employed. In a parenteral suspension, frequently In a parenteral suspension, frequently a floc of the dispersed phase can be proa floc of the dispersed phase can be produced by duced by an alteration in the pH of the an alteration in the pH of the preparationpreparation..

ElectrolytesElectrolytes can also act as flocculati can also act as flocculating agents.ng agents. The carefully determined concentratThe carefully determined concentration of ion of surfactants surfactants can also induce flocan also induce flocculation of particles in suspension acculation of particles in suspension and increase the sedimentation volumnd increase the sedimentation volume.e.

Dispersion mediumDispersion medium Oftentimes, as with highly flocculateOftentimes, as with highly flocculated suspensions, the particles of a suspd suspensions, the particles of a suspension settel too rapidly to be consistension settel too rapidly to be consistent with what might be termed a phaent with what might be termed a pharmaceutically elegant preparation. rmaceutically elegant preparation. （当混悬剂高度絮凝时，即使是药剂角度（当混悬剂高度絮凝时，即使是药剂角度上优质的制剂其粒子的沉降速度也很快）。上优质的制剂其粒子的沉降速度也很快）。 In many commercial suspensions, In many commercial suspensions, sususpending agentsspending agents are added to the dis are added to the dispersion medium to lend it structure.persion medium to lend it structure.

The following suspending agents are cThe following suspending agents are commonly usedommonly used CarboxymethylcelluloseCarboxymethylcellulose MethylcelluloseMethylcellulose Microcrystalline celluloseMicrocrystalline cellulose Polyvinyl pyrrolidonePolyvinyl pyrrolidone Xanthan gumXanthan gum （黄原胶）（黄原胶） Bentonite Bentonite （皂土）（皂土）

为增加混悬剂的稳定性，可适当加入稳定为增加混悬剂的稳定性，可适当加入稳定剂包括：剂包括： 湿润剂湿润剂（如聚山梨酯类、聚氧乙烯脂肪醇（如聚山梨酯类、聚氧乙烯脂肪醇醚类、聚氧乙烯蓖麻油类、磷脂类、泊洛醚类、聚氧乙烯蓖麻油类、磷脂类、泊洛沙姆等）、沙姆等）、 助悬剂助悬剂（甘油、糖浆剂、阿拉伯胶、西黄（甘油、糖浆剂、阿拉伯胶、西黄蓍胶、桃胶、海藻酸钠等）、蓍胶、桃胶、海藻酸钠等）、 絮凝剂和反絮凝剂絮凝剂和反絮凝剂（絮凝剂和反絮凝剂往（絮凝剂和反絮凝剂往往是同一种电解质，只是由于用量不同而往是同一种电解质，只是由于用量不同而产生不同的作用）。产生不同的作用）。

Preparation of Preparation of SuspensionsSuspensions

In the preparation of a suspension, the In the preparation of a suspension, the pharmacist must be acquainted with pharmacist must be acquainted with the characteristics of both the the characteristics of both the intended dispersed phase and the intended dispersed phase and the dispersion medium.dispersion medium.

Some drugs are not penetrated easily Some drugs are not penetrated easily by the vehicle and have a tendency to by the vehicle and have a tendency to clump together or to float on top of clump together or to float on top of the vehicle.the vehicle.

In this case, the powder must first In this case, the powder must first be wetted by a “be wetted by a “wetting agentwetting agent” to ” to make the powder more penetrable make the powder more penetrable by the dispersion medium.by the dispersion medium.

Alcohol, glycerin, and other Alcohol, glycerin, and other hygroscopic liquidshygroscopic liquids are employed are employed as wetting agents when an as wetting agents when an aqueous vehicle is to be used as aqueous vehicle is to be used as the dispersion phase.the dispersion phase.

In the large-scale preparation of In the large-scale preparation of suspensions the wetting agents are suspensions the wetting agents are mixed with the particles by an mixed with the particles by an apparatus such as a apparatus such as a colloid mill.colloid mill.

On a small scale in the pharmacy, On a small scale in the pharmacy, they are mixed with they are mixed with a mortar and a mortar and pestlepestle..

Once the powder is wetted, the Once the powder is wetted, the dispersion medium is added in dispersion medium is added in portions to the powder, and the portions to the powder, and the mixture is thoroughly blended before mixture is thoroughly blended before subsequent additions of vehicle.subsequent additions of vehicle.

A portion of the vehicle is used to wasA portion of the vehicle is used to wash the mixing equipment free of suspeh the mixing equipment free of suspensoid, and this portion is used to brinnsoid, and this portion is used to bring the suspension contains the desired g the suspension contains the desired concentration of solid matter.concentration of solid matter. The final product is then passed throThe final product is then passed through a colloid mill or final product is tugh a colloid mill or final product is then passed through a colloid mill or hen passed through a colloid mill or other blender or mixing device to insother blender or mixing device to insure uniformity.ure uniformity.

An example formula for an oral suspension follAn example formula for an oral suspension follows:ows: Aluminum hydroxide compressed gelAluminum hydroxide compressed gel 326.326.8 g8 g Sorbitol solutionSorbitol solution 282.0 ml282.0 ml Syrup Syrup 93.0 ml93.0 ml GlycerinGlycerin 25.0 ml25.0 ml MethylparabenMethylparaben 0.9 g0.9 g PropylparabenPropylparaben 0.3 g0.3 g FlavorFlavor q.s.q.s. Purified water, to make 1000.0 mlPurified water, to make 1000.0 ml

Extemporaneous Extemporaneous Compounding of Compounding of

SuspensionsSuspensions Handbook of Extemporaneous Handbook of Extemporaneous

Formulations Formulations When formulating an extemporaneous When formulating an extemporaneous

suspension, the contents of a capsule are suspension, the contents of a capsule are emptied into a mortar or the tablets of the emptied into a mortar or the tablets of the drug crushed in a mortar with a pestle.drug crushed in a mortar with a pestle.

The selected vehicle is then slowly added The selected vehicle is then slowly added to and mixed with the powder to create a to and mixed with the powder to create a paste and then diluted to the desired paste and then diluted to the desired volume.volume.

Packaging and Storage of Packaging and Storage of SuspensionsSuspensions

All suspensions should be packaged in All suspensions should be packaged in wide mouth containerswide mouth containers having adequate having adequate airspace above the liquid to permit airspace above the liquid to permit adequate shakingadequate shaking and and ease of pouringease of pouring..

Most suspensions should be stored in Most suspensions should be stored in tight containers protected from tight containers protected from freezing,freezing, excessive heat, and light.excessive heat, and light.

It is important that suspensions be It is important that suspensions be shaken before each use to ensure a shaken before each use to ensure a uniform distribution of solid in the uniform distribution of solid in the vehicle.vehicle.

Examples of Oral SuspensionExamples of Oral Suspension

Antacid oral suspensionsAntacid oral suspensions Antacids are intended to Antacids are intended to

counteract the effects of gastric counteract the effects of gastric hyperacidity and as such are hyperacidity and as such are employed by persons, as peptic employed by persons, as peptic ulcer patients, who must reduce ulcer patients, who must reduce the level of acidity in the the level of acidity in the stomach.stomach.

Antibacterial oral suspensionsAntibacterial oral suspensionsThe antibacterial oral suspensions incluThe antibacterial oral suspensions include preparations of de preparations of antibiotic substances (chloramphenicoantibiotic substances (chloramphenicol palmitate, erythromycin derivatives, tl palmitate, erythromycin derivatives, tetracycline and its derivatives),etracycline and its derivatives), Sulfonamides (e.g., sulfamethoxazoleSulfonamides (e.g., sulfamethoxazole磺胺甲磺胺甲噁噁唑唑 , , sulfisoxazole acetylsulfisoxazole acetyl 乙酰磺胺乙酰磺胺异异噁噁唑唑 ),), Other chemotherapeutic agents (e.g. mOther chemotherapeutic agents (e.g. methenamine mandelate ethenamine mandelate 乌洛托品扁桃酸乌洛托品扁桃酸酯酯 and nitrofurantoinand nitrofurantoin 硝基呋喃硝基呋喃 ))

Dry Powders for Oral Dry Powders for Oral SuspensionSuspension

A number of official and commercial A number of official and commercial preparations consist of dry powder preparations consist of dry powder mixtures or granules, which are mixtures or granules, which are intended to be suspended in water or intended to be suspended in water or some other vehicle prior to oral some other vehicle prior to oral administration.administration.

The majority of drugs prepared as a The majority of drugs prepared as a dry mix for oral suspension are dry mix for oral suspension are antibiotics.antibiotics.

The dry products are prepared commercially The dry products are prepared commercially to containto contain the antibiotic drug,the antibiotic drug, colorants,colorants, flavorants, flavorants, sweeteners (as sucrose or sodium saccharin),sweeteners (as sucrose or sodium saccharin), stabilizing agents (as citric acid, sodium citrastabilizing agents (as citric acid, sodium citrate), te), suspending agents (as guar gum, xanthan gususpending agents (as guar gum, xanthan gum, methylcellulose),m, methylcellulose), preserving agents (as methylparaben, sodiupreserving agents (as methylparaben, sodium benzoate).m benzoate).

教学重点、难点和知识点：教学重点、难点和知识点：1.1. 掌握下列基本概念：掌握下列基本概念： suspension, dispersuspension, dispersed system, floc or sed system, floc or floccule.floccule.2.2. 重点掌握重点掌握 stokestoke 定律及为了减少微粒的沉定律及为了减少微粒的沉降速度，可采用的措施。 降速度，可采用的措施。 3.3. 掌握增加混悬剂稳定性的方法。掌握增加混悬剂稳定性的方法。4.4. 熟悉混悬剂的制备、包装和储存。熟悉混悬剂的制备、包装和储存。

Emulsions Emulsions An emulsion is a dispersion in which An emulsion is a dispersion in which the dispersed phase is composed of sthe dispersed phase is composed of small globules of a liquid distributed tmall globules of a liquid distributed throughout a vehicle in which it is imhroughout a vehicle in which it is immiscible.miscible. 乳剂系指互不相溶的两相液体混合，其中乳剂系指互不相溶的两相液体混合，其中一相以液滴状态分散于另一相中形成的非一相以液滴状态分散于另一相中形成的非均匀分散液体制剂。均匀分散液体制剂。

In emulsion terminology, the dispersIn emulsion terminology, the dispersed phase is referred to as the internal ed phase is referred to as the internal phase, and the dispersion medium as phase, and the dispersion medium as the external or continuous phase.the external or continuous phase. Emulsions having an oleaginous interEmulsions having an oleaginous internal phase and an aqueous external phnal phase and an aqueous external phase are referred to as oil-in-water emase are referred to as oil-in-water emulsions, and are commonly designateulsions, and are commonly designated as “o/w”emulsions.d as “o/w”emulsions.

To prepare a stable emulsion, a third To prepare a stable emulsion, a third phase is necessary, that being an phase is necessary, that being an ememulsifying agentulsifying agent..

Purpose of EmulsionsPurpose of Emulsions The process of emulsification enables The process of emulsification enables

the pharmacist to prepare relatively the pharmacist to prepare relatively stable and homogeneous mixtures of stable and homogeneous mixtures of two immiscible liquids.two immiscible liquids.

It permits the administration of a It permits the administration of a liquid drug in the form of minute liquid drug in the form of minute globules rather than in bulk.globules rather than in bulk.

The reduced particle size of the oil The reduced particle size of the oil globules may render the oil more globules may render the oil more digestible and more readily digestible and more readily absorbed.absorbed.

Theories of Theories of EmulsificationEmulsification

1)1) the surface-tension theory the surface-tension theory （表面张（表面张力理论）力理论）2)2) the oriented-wedge theorythe oriented-wedge theory （定向楔（定向楔理论）理论）3)3) the plastic- or interfacial-film theorthe plastic- or interfacial-film theory y （塑性或界面膜理论）（塑性或界面膜理论）

1) the surface-tension theory1) the surface-tension theory According to the surface-tension theoAccording to the surface-tension theory of emulsification, the use of surfacry of emulsification, the use of surfactants as emulsifiers and stabilizers retants as emulsifiers and stabilizers results in the sults in the lowering of the interfacial tension of lowering of the interfacial tension of the two immiscible liquids,the two immiscible liquids, reducing the repellent force between reducing the repellent force between the liquidsthe liquids and diminishing each liquid’s attracand diminishing each liquid’s attraction for its own molecules.tion for its own molecules.

The surfactants facilitate the breakinThe surfactants facilitate the breaking up of large globules into smaller ong up of large globules into smaller ones, which then have a lesser than usues, which then have a lesser than usual tendency to reunite or coalesce. al tendency to reunite or coalesce. （表面活性剂可促进大液滴分散成小液滴，（表面活性剂可促进大液滴分散成小液滴，减弱再结合或合并的趋势）减弱再结合或合并的趋势）

22 ）） The oriented-wedge theoryThe oriented-wedge theory assum assumes monomolecular layers of emulsifyes monomolecular layers of emulsifying agent curved around a droplet of ing agent curved around a droplet of the internal phase of the emulsion. the internal phase of the emulsion. （定向楔理论是假设乳化剂的单分子层在（定向楔理论是假设乳化剂的单分子层在乳剂内相的液滴表面环绕排列）乳剂内相的液滴表面环绕排列） The theory is based on the presumptiThe theory is based on the presumption that certain emulsifying agents oron that certain emulsifying agents orient themselves about and within a liient themselves about and within a liquid in a manner reflective of their squid in a manner reflective of their solubility in that particular liquid.olubility in that particular liquid.

3) The plastic- or interfacial-film theory3) The plastic- or interfacial-film theory places the emulsifying agent at the intplaces the emulsifying agent at the interface between the oil and water, surrerface between the oil and water, surrounding the droplets of the internal pounding the droplets of the internal phase as a thin layer of film adsorbed ohase as a thin layer of film adsorbed on the surface of the drops. n the surface of the drops. （（塑性或界塑性或界面膜理论认为：乳化剂存在于油和水的界面，面膜理论认为：乳化剂存在于油和水的界面，以薄膜的形式吸附于内相液滴的表面）以薄膜的形式吸附于内相液滴的表面） The film prevents the contact and coaThe film prevents the contact and coalescing of the dispersed phase; the tolescing of the dispersed phase; the tougher and more pliable the film, the gugher and more pliable the film, the greater the stability of the emulsion.reater the stability of the emulsion.

Preparation of EmulsionsPreparation of Emulsions 1) Emulsifying agents1) Emulsifying agents

To be useful in a pharmaceutical To be useful in a pharmaceutical preparation, the emulsifying agent preparation, the emulsifying agent must possess certain qualities.must possess certain qualities.

compatiblecompatible stablestable nontoxicnontoxic possess little odor, taste, or colorpossess little odor, taste, or color

Of prime importance is the capabilitOf prime importance is the capability of the emulsifying agent to promoty of the emulsifying agent to promote emulsification and to maintain the e emulsification and to maintain the stability of the emulsion for the intenstability of the emulsion for the intended shelf life of the product. ded shelf life of the product. （最重要（最重要的是乳化剂促进乳化作用和在保存期内保的是乳化剂促进乳化作用和在保存期内保持乳剂稳定性的能力。）持乳剂稳定性的能力。）

Among the emulsifiers and stabilizers foAmong the emulsifiers and stabilizers for pharmaceutical systems are the followir pharmaceutical systems are the following:ng: Carbohydrate materials such as the natuCarbohydrate materials such as the naturally occuring agents acacia, tragacanth, rally occuring agents acacia, tragacanth, agar, chondrus, and pectin. agar, chondrus, and pectin. （碳水化合物（碳水化合物类如自然界中的阿拉伯胶、西黄蓍胶、琼脂、类如自然界中的阿拉伯胶、西黄蓍胶、琼脂、角叉菜和果胶）角叉菜和果胶） Protein substances such as gelatin, egg yProtein substances such as gelatin, egg yolk, and casein. olk, and casein. （蛋白质类如明胶、蛋黄和（蛋白质类如明胶、蛋黄和酪蛋白）酪蛋白）

High molecule weight alcohols such as High molecule weight alcohols such as stearyl alcohol, cetyl alcohol, and glycestearyl alcohol, cetyl alcohol, and glyceryl monostearate. ryl monostearate. （高分子量的醇类如硬（高分子量的醇类如硬脂酰醇、鲸蜡醇和单硬脂酸甘油酯）脂酰醇、鲸蜡醇和单硬脂酸甘油酯） Wetting agents, which may be anionic, Wetting agents, which may be anionic, cationic, or nonionic.cationic, or nonionic. Finely divided solids such as colloidal cFinely divided solids such as colloidal clays including bentonite, magnesium hlays including bentonite, magnesium hydroxide, and aluminum hydroxide. ydroxide, and aluminum hydroxide.

33 ．常用的乳化剂有：．常用的乳化剂有：（（ 11）表面活性剂类乳化剂）表面活性剂类乳化剂 阴离子型（如硬脂酸钠、十二烷基硫酸钠阴离子型（如硬脂酸钠、十二烷基硫酸钠等）等）非离子型（如聚甘油油酸酯、聚山梨酯类非离子型（如聚甘油油酸酯、聚山梨酯类等）等）

（（ 22）天然乳化剂）天然乳化剂 如阿拉伯胶、西黄蓍胶、明胶、卵磷脂等。如阿拉伯胶、西黄蓍胶、明胶、卵磷脂等。

（（ 33）固体微粒乳化剂）固体微粒乳化剂 形成形成 O/WO/W 类乳剂的有：氢氧化镁、氢氧化类乳剂的有：氢氧化镁、氢氧化铝、二氧化硅、皂土等；铝、二氧化硅、皂土等；形成形成 W/OW/O 类乳剂的有：氢氧化钙、氢氧化类乳剂的有：氢氧化钙、氢氧化锌、硬脂酸镁等。锌、硬脂酸镁等。（（ 44）辅助乳化剂 ）辅助乳化剂 增加乳剂粘度从而增加乳剂稳定性的附加增加乳剂粘度从而增加乳剂稳定性的附加剂，如甲基纤维素、羧甲基纤维素钠、羟剂，如甲基纤维素、羧甲基纤维素钠、羟丙甲纤维素等增加水相粘度的辅助乳化剂丙甲纤维素等增加水相粘度的辅助乳化剂和鲸蜡醇、蜂蜡、单硬脂酸甘油酯等增加和鲸蜡醇、蜂蜡、单硬脂酸甘油酯等增加油相粘度的辅助乳化剂。油相粘度的辅助乳化剂。

2) The HLB system2) The HLB system Emulsifying or surface-active agents Emulsifying or surface-active agents may be categoried on the basis of theimay be categoried on the basis of their chemical make-up as to their hydropr chemical make-up as to their hydrophile-lipophile balance or “HLB”hile-lipophile balance or “HLB” By this method, each agent is assigned By this method, each agent is assigned an HLB value or number which is indian HLB value or number which is indicative of the substance’s polarity.cative of the substance’s polarity.

The usual range of HLB is between 1 and The usual range of HLB is between 1 and 20.20. Generally, those surface-active agents haGenerally, those surface-active agents having an assigned HLB value of from ving an assigned HLB value of from 3 to 63 to 6 are greatlyare greatly lipophilic lipophilic and produce and produce water-water-in-oil emulsions, in-oil emulsions, and those agents have HLB values of froand those agents have HLB values of from about m about 8 to 188 to 18 produce oil-in-water emu produce oil-in-water emulsions.lsions.

3) Methods of emulsion preparation3) Methods of emulsion preparationa. Continental or dry gum methoda. Continental or dry gum method （大（大陆法或干胶法）陆法或干胶法）b. English or wet gum method b. English or wet gum method （英国法（英国法或湿胶法）或湿胶法）c. Bottle or forbes bottle methodc. Bottle or forbes bottle method （（瓶法瓶法或或 ForbesForbes 瓶法）瓶法）d. Auxiliary methodsd. Auxiliary methods （辅助法）（辅助法）e. In situ soap methode. In situ soap method （新生皂法）（新生皂法）

a)a) Continental or dry gum methodContinental or dry gum method （大（大陆法或干胶法）陆法或干胶法） This method is also referred to as the This method is also referred to as the “4:2:1” method because for every 4 “4:2:1” method because for every 4 parts (volumes) of oil, 2 parts of wateparts (volumes) of oil, 2 parts of water and 1 part of gum are added in prepr and 1 part of gum are added in preparing the initial or primary emulsion.aring the initial or primary emulsion.

b) English or wet gum methodb) English or wet gum method （英国法（英国法或湿胶法）或湿胶法） Generally a mucilage of the gum is preGenerally a mucilage of the gum is prepared by triturating granular acacia wipared by triturating granular acacia with twice its weight of water in a mortar.th twice its weight of water in a mortar. （通常可将阿拉伯胶颗粒与两倍于其重量的（通常可将阿拉伯胶颗粒与两倍于其重量的水在研体中研碎来形成胶浆剂）水在研体中研碎来形成胶浆剂） The oil is then added slowly in portionThe oil is then added slowly in portions, and the mixture is triturated to emuls, and the mixture is triturated to emulsify the oil.sify the oil.

After all of the oil has been added, thAfter all of the oil has been added, the mixture is thoroughly mixed for see mixture is thoroughly mixed for several minutes to insure uniformity.veral minutes to insure uniformity. The emulsion is transferred to a gradThe emulsion is transferred to a graduate and made to volume with water.uate and made to volume with water.

c. Bottle or forbes bottle methodc. Bottle or forbes bottle method （（瓶法瓶法或或 ForbesForbes 瓶法）瓶法） In this method, powdered acacia is plIn this method, powdered acacia is placed in a dry bottle, two parts of oil araced in a dry bottle, two parts of oil are then added, and the mixture is thoroe then added, and the mixture is thoroughly shaken in the capped container.ughly shaken in the capped container. A volume of water appoximately equal A volume of water appoximately equal to the oil is then added in portions, thto the oil is then added in portions, the mixture being thoroughly shaken afte mixture being thoroughly shaken after each addition.er each addition.

When all of the water has been addeWhen all of the water has been added, the primary emulsion thus formed d, the primary emulsion thus formed may be diluted to the proper volume may be diluted to the proper volume with water or an aqueous solution of with water or an aqueous solution of other formulative agents.other formulative agents.

d. Auxiliary methodsd. Auxiliary methods （辅助法）（辅助法） An emulsion prepared by either the wet An emulsion prepared by either the wet gum or the dry gum methods can genergum or the dry gum methods can generally be increased in quality by passing it ally be increased in quality by passing it through a hand homogenizer through a hand homogenizer （手动匀浆（手动匀浆机）机） .. In this apparatus, the pumping action oIn this apparatus, the pumping action of the handle forces the emulsion througf the handle forces the emulsion through a very small orifice which reduces the h a very small orifice which reduces the globules of the internal phase to about 5 globules of the internal phase to about 5

m and sometimes less.m and sometimes less.

乳剂的制备方法乳剂的制备方法 （（ 11）油中乳化剂法：）油中乳化剂法：先将乳化剂分散于油中研匀，按油、水、先将乳化剂分散于油中研匀，按油、水、乳化剂乳化剂 44 ：： 22：： 11 的比例加水，用力研成的比例加水，用力研成初乳，再加水稀释至全量。初乳，再加水稀释至全量。

（（ 22）水中乳化剂法：）水中乳化剂法：先将乳化剂分散于水中研匀，按油、水、先将乳化剂分散于水中研匀，按油、水、乳化剂乳化剂 44 ：： 22：： 11 的比例加油，用力研成的比例加油，用力研成初乳，再加水稀释至全量。初乳，再加水稀释至全量。

（（ 33 ）机械法：）机械法：将油、水、乳化剂混合后用乳化机械制成将油、水、乳化剂混合后用乳化机械制成乳剂。乳剂。

乳化机械主要有：乳化机械主要有：①① 搅拌乳化设备：如高速搅拌乳化设备；搅拌乳化设备：如高速搅拌乳化设备；②乳匀机；②乳匀机；③③ 胶体磨；胶体磨；④④ 超声乳化设备。超声乳化设备。

Stability of EmulsionsStability of EmulsionsAn emulsion is considered to be phAn emulsion is considered to be physically unstable ifysically unstable if

(a)(a) the internal or dispersed phase upothe internal or dispersed phase upon standing tends to form aggregates n standing tends to form aggregates of globules,of globules,(b)(b) large globules or aggregates of globlarge globules or aggregates of globules rise to the top or fall to the bottules rise to the top or fall to the bottom of the emulsion to form a conceom of the emulsion to form a concentrated layer of the internal phase,ntrated layer of the internal phase,

c) If all or part of the liquid of the interc) If all or part of the liquid of the internal phase separates and forms a distinal phase separates and forms a distinct layer on the top or bottom of the nct layer on the top or bottom of the emulsion as a result of the coalescing emulsion as a result of the coalescing of the globules of the internal phase.of the globules of the internal phase.

Aggregation and CoalescenceAggregation and Coalescence Aggregates of globules of the internal Aggregates of globules of the internal phase have a greater tendency than do phase have a greater tendency than do individual particles to rise to the top of individual particles to rise to the top of the emulsion or fall to the bottom. Sucthe emulsion or fall to the bottom. Such a preparation of the globules is termh a preparation of the globules is termed the ed the creaming of the emulsioncreaming of the emulsion ，， and and provided coalescence is absent, it is reprovided coalescence is absent, it is reversible process. versible process. （内相液滴的聚集体比其单个颗粒具有更大的（内相液滴的聚集体比其单个颗粒具有更大的趋势上浮到乳剂顶部或下沉到底部，这种聚趋势上浮到乳剂顶部或下沉到底部，这种聚集体的形成称为集体的形成称为乳剂的分层。当未发生合并乳剂的分层。当未发生合并时，是一可逆过程。时，是一可逆过程。） ）

Of greater destruction to an emulsion thaOf greater destruction to an emulsion than creaming is the n creaming is the coalescence coalescence of the globof the globules of the internal phase and the separatiules of the internal phase and the separation of that phase into a layer. The separation of that phase into a layer. The separation of the internal phase from the emulsioon of the internal phase from the emulsion is called the “breaking” of the emulsion is called the “breaking” of the emulsion, and the emulsion is described as being n, and the emulsion is described as being “cracked” or “broken.” this is irrevers“cracked” or “broken.” this is irreversible.ible. 比分层更具有破坏性的是乳剂内相液滴的比分层更具有破坏性的是乳剂内相液滴的合并，合并，从而产从而产生相分离形成不同的液层。乳剂中内相的分离称为乳剂生相分离形成不同的液层。乳剂中内相的分离称为乳剂的“破坏”，此时乳剂则被描述成“破裂”。这是不可的“破坏”，此时乳剂则被描述成“破裂”。这是不可逆的变化。逆的变化。

Generally, care must be taken to protect Generally, care must be taken to protect emulsions against the extremes of emulsions against the extremes of cold cold and heat.and heat. Because other enviromental conditions Because other enviromental conditions such as the presence of such as the presence of light, air, and colight, air, and contaminating microorganismsntaminating microorganisms can adver can adversely affect the stability of an emulsion, asely affect the stability of an emulsion, appropriate formulative and packaging sppropriate formulative and packaging steps are usually taken to minimize such teps are usually taken to minimize such possible hazards to product stability.possible hazards to product stability.

乳剂的不稳定性指乳剂的不稳定性指化学不稳定性化学不稳定性和和物理不物理不稳定性，稳定性， 化学不稳定性是指化学不稳定性是指乳剂易发生氧化或受微乳剂易发生氧化或受微生物作用而腐败，生物作用而腐败， 物理不稳定性包括物理不稳定性包括分层、絮凝、转相、合分层、絮凝、转相、合并与破坏。 并与破坏。

To increase the stability of an emulsion,To increase the stability of an emulsion, The globule or particle size should be rThe globule or particle size should be reduced as fine as practically possible.educed as fine as practically possible. The density difference between the intThe density difference between the internal and external phases should be mernal and external phases should be minimal,inimal, The viscosity of the external phase shoThe viscosity of the external phase should be reasonably high.uld be reasonably high.Thickeners such as tragacanth and miThickeners such as tragacanth and microcrystalline cellulose are frequently crocrystalline cellulose are frequently added to emulsions to increase the visadded to emulsions to increase the viscosity of the external phase.cosity of the external phase.

教学重点、难点和知识点：教学重点、难点和知识点：1.1. 掌握下列基本概念：掌握下列基本概念： emulsion,emulsion, HLB value,HLB value, creaming of the emulsion and creaming of the emulsion and coalesccoalescence ence of theof the emulsion emulsion..2.2. 重点掌握乳剂形成的理论。 重点掌握乳剂形成的理论。 3.3. 掌握增加乳剂稳定性的方法。掌握增加乳剂稳定性的方法。4.4. 熟悉乳剂的制备和物理不稳定性。熟悉乳剂的制备和物理不稳定性。

Gels and MagmasGels and Magmas Gels are defined as semisolid systemGels are defined as semisolid systems consisting of dispersions made up os consisting of dispersions made up of either small inorganic particles or lf either small inorganic particles or large organic molecules enclosing anarge organic molecules enclosing and interpenetrated by a liquid. d interpenetrated by a liquid. （凝胶剂是由微细无机颗粒或有极大分子（凝胶剂是由微细无机颗粒或有极大分子被液体包围并渗透组成的分散体系所构成被液体包围并渗透组成的分散体系所构成的半固体系统）的半固体系统）

Gels are also defined as semirigid sysGels are also defined as semirigid systems in which the movement of the dtems in which the movement of the dispersing medium is restricted by an ispersing medium is restricted by an interlacing three-dimensional netwointerlacing three-dimensional network of particles or solvated macromolrk of particles or solvated macromolecules of the dispersef phase.ecules of the dispersef phase.（凝胶剂亦被定义为分散介质的运动被分散（凝胶剂亦被定义为分散介质的运动被分散相中的粒子或溶解的大分子形成的三维交相中的粒子或溶解的大分子形成的三维交叉网状结构所限制的半刚性系统叉网状结构所限制的半刚性系统 ))

凝胶剂有单相分散系统和双相分散系统之凝胶剂有单相分散系统和双相分散系统之分。分。 属双相分散系统的凝胶剂使小分子无机药属双相分散系统的凝胶剂使小分子无机药物胶体微粒一网状结构存在于液体中，具物胶体微粒一网状结构存在于液体中，具有触变性，也称混悬凝胶剂。有触变性，也称混悬凝胶剂。 局部应用的凝胶剂系单相分散系统，又分局部应用的凝胶剂系单相分散系统，又分为水性凝胶剂和油性凝胶剂。 为水性凝胶剂和油性凝胶剂。

水性凝胶剂的基质一般由水性凝胶剂的基质一般由 西黄芪胶、西黄芪胶、 明胶、明胶、 淀粉、淀粉、 纤维素衍生物、纤维素衍生物、 聚羧乙烯聚羧乙烯 海藻酸钠海藻酸钠加水、甘油或丙二醇等制成。加水、甘油或丙二醇等制成。

油性凝胶剂的基质常由液状石与聚氧乙烯油性凝胶剂的基质常由液状石与聚氧乙烯或脂肪油与胶体硅或铝皂、锌皂构成。或脂肪油与胶体硅或铝皂、锌皂构成。

Colloidal dispersionsColloidal dispersions Sol is a general term to designate a diSol is a general term to designate a dispersion of a solid substance in a liquspersion of a solid substance in a liquid, solid or gaseous medium. id, solid or gaseous medium. （溶胶（溶胶是指固体物质在液体、固体或气体是指固体物质在液体、固体或气体分散介质中形成的分散体系，但它一般是分散介质中形成的分散体系，但它一般是指固液分散体系）指固液分散体系）

hydrosol hydrosol 水溶胶水溶胶 alcosol alcosol 醇溶胶醇溶胶 The term The term aerosolaerosol indicate a dispersio indicate a dispersion of a solid or a liquid in a gaseous pn of a solid or a liquid in a gaseous phase. hase. （术语气溶胶则表示固体或液体在（术语气溶胶则表示固体或液体在气相中形成的分散体系。气相中形成的分散体系。 A substance is said to be colloidal whA substance is said to be colloidal when its particles fall between 1 nm and en its particles fall between 1 nm and 0.5 0.5 m.m.

A third type of colloidal sol, termed aA third type of colloidal sol, termed an n association orassociation or amphiphilic colloidamphiphilic colloid, , is formed by grouping or association is formed by grouping or association of molecules that exhibit both lyophiof molecules that exhibit both lyophilic and lyophobic properties. lic and lyophobic properties. （第三种溶胶类型被称为缔合胶体或两性胶（第三种溶胶类型被称为缔合胶体或两性胶体，由分子的聚合或交联形成，既有亲液体，由分子的聚合或交联形成，既有亲液性也有疏液性）性也有疏液性）

Terminology Related to Terminology Related to GelsGels

Imbibition Imbibition （吸入）（吸入） is taking up of a ceis taking up of a certain amount of liquid without a measurtain amount of liquid without a measurable increase in volume.rable increase in volume. SwellingSwelling （溶胀）（溶胀） is the taking up of a liis the taking up of a liquid by a gel with an increase in volumquid by a gel with an increase in volume.e. SyneresisSyneresis （收缩）（收缩） is when the interactiis when the interaction between particles of the dispersed pon between particles of the dispersed phase becomes so great that on standing,hase becomes so great that on standing, the dispersing medium is squeezed out the dispersing medium is squeezed out in droplets and the gel shrinks.in droplets and the gel shrinks.

ThixotropyThixotropy （触变胶）（触变胶） is a reversible is a reversible gel-sol formation with no change in vgel-sol formation with no change in volume or temperature-a type of non-olume or temperature-a type of non-Newtonian flow.Newtonian flow. Xerogel Xerogel （干凝胶）（干凝胶） is formed when this formed when the liquid is removed from a gel and one liquid is removed from a gel and only the framework remains.ly the framework remains.

Classification and Types of Classification and Types of GelsGels

The first scheme divides gels into The first scheme divides gels into “inor“inorganic” and “organic.”ganic” and “organic.” Inorganic hydrogelsInorganic hydrogels are usually two-ph are usually two-phase systems such as ase systems such as Aluminum HydroxiAluminum Hydroxide Gel de Gel andand Bentonite Magma Bentonite Magma （皂土乳（皂土乳浆）浆） .. Organic gelsOrganic gels are usually single-phase sy are usually single-phase systems and may include such gelling agestems and may include such gelling agents as nts as carbomer and tragacenthcarbomer and tragacenth and tho and those that contain an organic liquid, such ase that contain an organic liquid, such as Plastibase.s Plastibase.

The second classification scheme divideThe second classification scheme divides gels into s gels into hydrogels and organogelshydrogels and organogels wit with some additional subcategories.h some additional subcategories. HydrogelsHydrogels include ingredients that are d include ingredients that are dispersible as colloidals or soluble in watispersible as colloidals or soluble in water and include organic hydrogels, naturer and include organic hydrogels, natural and synthetic gums and inorganic hydal and synthetic gums and inorganic hydrogels.rogels.水凝胶包括在水中可分散的（如：胶体）和可水凝胶包括在水中可分散的（如：胶体）和可溶解的，包括：有机水凝胶、天然和合成的胶溶解的，包括：有机水凝胶、天然和合成的胶质、无机水凝胶。质、无机水凝胶。

Preparation of Magmas and Preparation of Magmas and GelsGels

Some magmas and gels (inorganic) arSome magmas and gels (inorganic) are prepared by freshly precipitating the prepared by freshly precipitating the disperse phase in order to achieve a e disperse phase in order to achieve a fine degree of subdivision of the partifine degree of subdivision of the particles and a gelatinous character to thocles and a gelatinous character to those particles. se particles. （某些乳浆剂和凝胶剂可通过将分散相沉淀以（某些乳浆剂和凝胶剂可通过将分散相沉淀以得到更加精细的粒子和使粒子具有凝胶性得到更加精细的粒子和使粒子具有凝胶性质。）质。）

Other magmas and gels may be prepOther magmas and gels may be prepared by the direct hydration in water ared by the direct hydration in water of the inorganic chemical, the hydratof the inorganic chemical, the hydrated form constituting the disperse phed form constituting the disperse phase of the dispersion. ase of the dispersion. （其它乳浆剂和凝胶剂可将无机化合物直接（其它乳浆剂和凝胶剂可将无机化合物直接加水进行水合来制得，其水合物构成分散加水进行水合来制得，其水合物构成分散体系的分散相。）体系的分散相。）

Examples of Gelling AgentsExamples of Gelling Agents

Examples of gelling agents include Examples of gelling agents include acacia, acacia, alginic acid, alginic acid, bentonite, bentonite, carbomer,carbomer, carboxymethylcellulose sodium,carboxymethylcellulose sodium, colloidal silicon dioxide, etc.colloidal silicon dioxide, etc.

Aerosol Aerosol Pharmaceutical aerosols are pressuriPharmaceutical aerosols are pressurized dosage forms containing one or mzed dosage forms containing one or more active ingredients which upon actore active ingredients which upon actuaton emit a fine dispersion of liquid uaton emit a fine dispersion of liquid and/or solid materials in a gaseous mand/or solid materials in a gaseous medium.edium. 药物气雾剂为一种或多种活性成分的压缩剂药物气雾剂为一种或多种活性成分的压缩剂型，可通过喷出在气态介质中形成液体和型，可通过喷出在气态介质中形成液体和（或）固体物质的细小分散体系。（或）固体物质的细小分散体系。

Advantages of the Aerosol Advantages of the Aerosol Dosage formsDosage forms

1.1. A portion of medication may be A portion of medication may be easily withdrawn from the easily withdrawn from the package without contamination package without contamination or exposure to the remaining or exposure to the remaining material.material.

2.2. By virtue of its hermetic By virtue of its hermetic character, the aerosol container character, the aerosol container protects medicinal agents protects medicinal agents adversely affected by adversely affected by atmospheric oxygen and atmospheric oxygen and moisture. moisture. Being opaque, the usual aerosol Being opaque, the usual aerosol container also protects drugs container also protects drugs adversely affected by light. adversely affected by light.

3. Topical medication may be applied in a 3. Topical medication may be applied in a uniform, thin layer to the skin, without touniform, thin layer to the skin, without touching the affected area.uching the affected area.4. By proper formulation and valve control,4. By proper formulation and valve control, the physical form and the particle size of the physical form and the particle size of the emitted product may be controlled wthe emitted product may be controlled which may contribute to the efficacy of a dhich may contribute to the efficacy of a drug.rug.5. Aerosol application is a “clean” proces5. Aerosol application is a “clean” process, requiring little or no “wash-up” by ths, requiring little or no “wash-up” by the user.e user.

气雾剂的优点：气雾剂的优点：①① 药物直接到达作用部位，分布均匀，起效药物直接到达作用部位，分布均匀，起效快。快。②② 药物密闭于不透明的容器中不易被污染，药物密闭于不透明的容器中不易被污染，不与空气中的氧或水分接触，提高了药物不与空气中的氧或水分接触，提高了药物的稳定性。的稳定性。③③ 不经过胃肠道系统，可以完全避免胃肠道不经过胃肠道系统，可以完全避免胃肠道的破坏作用和肝脏的首过效应，提高药物的破坏作用和肝脏的首过效应，提高药物的生物利用度。的生物利用度。

④④ 由于气雾剂中的药物是以雾状喷出的，所由于气雾剂中的药物是以雾状喷出的，所以可减少 对创面的刺激性。以可减少 对创面的刺激性。⑤⑤ 定量阀门控制剂量比较准确，并可以单剂定量阀门控制剂量比较准确，并可以单剂量或多剂量给药。量或多剂量给药。

The Aerosol PrincipleThe Aerosol Principle An aerosol formulation consists of tAn aerosol formulation consists of two compoment parts, the wo compoment parts, the product coproduct concentrate and the propellant. ncentrate and the propellant.

active ingredientantioxidantssurface-active agentssolventsProduct Product concentrateconcentrate

Propellant Propellant Liquefied gasA mixture of liquefied gases

chlorofluorocarbons

Aerosol SystemsAerosol Systems

The pressure of an aerosol is critical to its performance.It can be controlled by:(a) the type and amount of propellant(b) the nature and amount of product concentrate.

Space sprays generally contain a greater proportion of propellant than do aerosols intended for surface coating;

hence they are released with greater pressure, and the resultant particles are projected more violently from the valve.

Foam aerosols may be considered to be emulsions, because the liquefied propellant is partially emulsified with the product concentrate rather than being dissolved in it.

The use of surfactants or emulsifiers in the formulation encourages the mixing of the two components to enhance the emulsion.

When the aerosol valve is activated, the mixture is expelled to the atmosphere, where the propellant globules vaporize rapidly, leaving the active ingredient in the form of a foam.

Blends of the various liquefied gas propellants are generally used in pharmaceutical aerosols to achieve the desired vapor pressure and to provide the proper solvent features for a given product.

Some propellants are eliminated from use in certain products because of their reactivity with other formulative materials or with the proposed container or valve components.

The physiologic effect of the propellant must also be considered in formulating an aerosol to ensure safety of the product in its intended use.

Even though an individual propellant or propellant blend and the active ingredient of a formulation are nontoxic when tested individually, the use of the combination in aerosol form may have undesirable features.

(1) Two-Phase systems(1) Two-Phase systems

the liquid phase

the vapor phase

the liquefied propellant

the product concentrate

(2) Three-Phase Systems(2) Three-Phase Systems

The three-phase system consists of a layer of water-immiscible liquid

propellant, a layer of highly aqueous product

concentrate, and the vapor phase.

(3) Compressed Gas (3) Compressed Gas SystemsSystems

The pressure of the compressed gas in the head space of the aerosol container forces the product concentrate up the dip tube and out of the valve.

The use of gases that are insoluble in the product concentrate, as is nitrogen, will result in emission of a product in essentially the same form as it was placed in the container.

An advantage of nitrogen as a propellant is

its inert behavior toward other formulative components and

its protective influence on products subject to oxidation.

Other gases, such as carbon dioxide and nitrous oxide, which are slightly soluble in the liquid phase of aerosol products,

may be employed when their expulsion with the product concentrate is desired to achieve spraying or foaming.

Unlike aerosols prepared with liquefied gas propellants, compressed gas filled aerosols have no reservoir of propellant. Thus higher gas pressures are required in these systems, and the pressure in these aerosols diminishes as the product is used.

常用抛射剂常用抛射剂11 ．氟氯烷烃类．氟氯烷烃类 俗称氟里昂，为药用气雾剂最常用的抛射俗称氟里昂，为药用气雾剂最常用的抛射剂。氟里昂常温下蒸气压略高于大气压，剂。氟里昂常温下蒸气压略高于大气压，故对容器的耐压性要求不高，而气化产生故对容器的耐压性要求不高，而气化产生的动力又足以达到要求，化学性质稳定，的动力又足以达到要求，化学性质稳定，毒性较小，基本无臭无味。毒性较小，基本无臭无味。 常用常用 F11F11 、、 F12F12 和和 F114F114 三种。以三种。以 F12F12 为基为基本抛射剂，加一定比例的本抛射剂，加一定比例的 F11F11 和和 F114F114 ，以，以达到不同产品的基本要求。达到不同产品的基本要求。

注意氟里昂在大气层受紫外线照射可分解出注意氟里昂在大气层受紫外线照射可分解出高活性的元素氯，并与臭氧反应而破坏臭氧高活性的元素氯，并与臭氧反应而破坏臭氧层。层。 由由 140140 个国家签定的蒙特利尔条约要求在个国家签定的蒙特利尔条约要求在 20020055 年全面禁止使用氟氯烷烃抛射剂。年全面禁止使用氟氯烷烃抛射剂。 非定量气雾剂一般不用氟里昂做抛射剂。非定量气雾剂一般不用氟里昂做抛射剂。22 ．碳氢化合物类．碳氢化合物类 主要是丙烷、正丁烷和异丁烷，局部气雾剂主要是丙烷、正丁烷和异丁烷，局部气雾剂用。用。 特点：价廉、稳定、无毒、不含卤素、不存特点：价廉、稳定、无毒、不含卤素、不存在环境保护问题，最大缺点是易燃易爆。在环境保护问题，最大缺点是易燃易爆。

33 ．氢氟氯烷烃类和氢氟烃类．氢氟氯烷烃类和氢氟烃类 由于氟里昂的环境保护问题，一些新型的抛射剂由于氟里昂的环境保护问题，一些新型的抛射剂不断研制出来，其中比较好的就是不断研制出来，其中比较好的就是氢氟烷烃类氢氟烷烃类和和氢氟烃类氢氟烃类。。 氢氟氯烷烃类是由一个或多个氢氟氯烷烃类是由一个或多个 HH原子取代氯原子。原子取代氯原子。氢氟烃类不含氯原子，对环境污染较少。常用三氢氟烃类不含氯原子，对环境污染较少。常用三氟一氯乙烷、七氟丙烷和一氯二氟乙烷等。氟一氯乙烷、七氟丙烷和一氯二氟乙烷等。44 ．混合抛射剂．混合抛射剂 在实际应用中，单一的抛射剂往往很难达到要求在实际应用中，单一的抛射剂往往很难达到要求而选择混合抛射剂可以取长补短。而选择混合抛射剂可以取长补短。 F11F11、、 F12F12和和F114F114 常混合使用。碳氢化合物和氟里昂类也混常混合使用。碳氢化合物和氟里昂类也混合使用。合使用。

药物与附加剂药物与附加剂 氢氟氯烷烃类是非极性的，相当一部分药氢氟氯烷烃类是非极性的，相当一部分药物难于混溶其中，要加入一些潜溶剂用以物难于混溶其中，要加入一些潜溶剂用以增加药物的溶解度。如乙醇、甘油等。增加药物的溶解度。如乙醇、甘油等。 当药物分子不溶于抛射剂或抛射剂和潜溶当药物分子不溶于抛射剂或抛射剂和潜溶剂的混合溶剂时，可制成混悬型气雾剂，剂的混合溶剂时，可制成混悬型气雾剂，但需加入表面活性剂和分散剂。但需加入表面活性剂和分散剂。 加入适宜的表面活性剂和分散剂有利于药加入适宜的表面活性剂和分散剂有利于药物的均匀分散。如聚山梨酯等。物的均匀分散。如聚山梨酯等。 常用分散剂：肉豆蔻异丙酯或矿物油。常用分散剂：肉豆蔻异丙酯或矿物油。

乳剂型气雾剂的主要组成：乳剂型气雾剂的主要组成： 药物、抛射剂、表面活性剂、水性和油性药物、抛射剂、表面活性剂、水性和油性介质。介质。 O/WO/W 型，抛射剂为内相，喷出剂为泡沫状。型，抛射剂为内相，喷出剂为泡沫状。W/OW/O 型，抛射剂为外相，喷出剂为雾状。型，抛射剂为外相，喷出剂为雾状。 OO/W/W 型较常用，常用的表面活性剂有聚山梨型较常用，常用的表面活性剂有聚山梨酯类、脂肪酸山梨坦、月桂醇硫酸钠等。酯类、脂肪酸山梨坦、月桂醇硫酸钠等。

Aerosol Container and Aerosol Container and Valve AssemblyValve Assembly

The effectiveness of a pharmaceutical aerosol depends on

achieving the proper combination of formulation,

container, and valve assembly.

The formulation must not

chemically interact with the container or valve components,

interfere with the stability of the

formulation or with the integrity, and operation of the container and valve assembly.

The container and valve must be capable of withstanding the pressure required by the product, it must resist corrosion, and the valve must contribute to the form of the product to be emitted.

(1) Containers(1) Containers

Various materials have been used in the manufacture of aerosol containers, including:

(a) glass, uncoated or plastic coated(b) metal, including tin-plated steel, alu

minum, and stainless steel(c) plastics

The selection of the container for an aerosol product is based on

its adaptability to production methods, compatibility with formulation componen

ts, ability to sustain the pressure intended fo

r the product, the interest in design and aesthetic appeal

on the part of the manufacturer, and cost.

Glass presents fewer problems with respect to chemical compatibility with the formula than do metal containers,

Glass is not subjuct to corrosion, Glass is also more adaptive to creativi

ty in design.

Plastic coatings are commonly applied to the outer surface of galss containers to render them more resistant to accidental breakage, When required, the inner surface of galss containers may be coated to render them more chemically resistant to formulation materials.

Tin-plated steel containers are the most widely used metal containers for aerosols.

Most aluminum containers are manufactured by extrusion or by other methods that make them seamless.

Stainless steel is employed to produce containers for certain small-volume aerosols in which a great deal of chemical resistance is required.

Plastic containers have met with varying success in the packaging of aerosols because of their inherent problem of being permeated by the vapor within the container.

Also, certain drug-plastic interactions affect the release of drug from the container and reduce the efficacy of the product.

(2) Valve Assembly(2) Valve Assembly

The function of the valve assembly is The function of the valve assembly is to permit expulsion of the contents oto permit expulsion of the contents of the can f the can in the desired form, in the desired form, at the desired rate, at the desired rate, and in the case of metered valves, in and in the case of metered valves, in the proper amount or dose.the proper amount or dose.

Among the materials used in the maAmong the materials used in the manufacture of the various valve parts anufacture of the various valve parts are re plastic, plastic, rubber, rubber, aluminum, aluminum, and stainless steel. and stainless steel.

The usual aerosol valve assembly is cThe usual aerosol valve assembly is composed of the following parts:omposed of the following parts:1) Actuator1) Actuator （揿动钮）（揿动钮） :: The button the u The button the user presses to activate the valve assemser presses to activate the valve assembly for emission of the product. The ably for emission of the product. The actuator permits easy opening and closctuator permits easy opening and closing of the valve.ing of the valve.2) Stem2) Stem （阀杆）（阀杆） :: Supports the actuator Supports the actuator and delivers the formulation in the prand delivers the formulation in the proper form to the chamber of the actuaoper form to the chamber of the actuator.tor.

3) Gasket3) Gasket （垫圈）（垫圈） :: Placed snugly with t Placed snugly with the stem, prevents leakage of the formhe stem, prevents leakage of the formulation when the valve is closed.ulation when the valve is closed.4) Spring4) Spring （弹簧）（弹簧） :: Holds the gasket in Holds the gasket in place and is the mechanism by which place and is the mechanism by which the actuator retracts when pressure is the actuator retracts when pressure is released, returning the valve to the clreleased, returning the valve to the closed position.osed position.5) Mounting cup5) Mounting cup （固定帽）（固定帽） :: Attached t Attached to the aerosol can or container, holds to the aerosol can or container, holds the valve in place. he valve in place.

6) Housing6) Housing （支架）（支架） :: Directly below the Directly below the mounting cup, the housing links the dimounting cup, the housing links the dip tube and the stem and actuator. With p tube and the stem and actuator. With the stem, its orifice helps to determine the stem, its orifice helps to determine the delivery rate and the form in which the delivery rate and the form in which the product is emitted.the product is emitted.7) Dip tube7) Dip tube （浸入管）（浸入管） :: Extends from the Extends from the housing down into the product; brings housing down into the product; brings the formulation from the container to tthe formulation from the container to the valve.he valve.

Metered Dose InhalersMetered Dose Inhalers Metering valves Metering valves

are employed are employed when the when the formulation is formulation is a potent a potent medication, as medication, as in inhalation in inhalation therapy.therapy.

Depression of the actuaDepression of the actuator causes tor causes a simultaneous reversal a simultaneous reversal of positionsof positions （同时使密（同时使密封位置逆转）封位置逆转） ; ; the chamber becomes othe chamber becomes open to the atmosphere, pen to the atmosphere, releasing its contents, releasing its contents, at the same time becomat the same time becoming sealed from the coning sealed from the contents of the container.tents of the container.

气雾剂的吸收气雾剂的吸收（一）肺部吸收（一）肺部吸收 吸入气雾剂通过肺部吸收，吸收速度是很吸入气雾剂通过肺部吸收，吸收速度是很快的，不亚于静脉注射。如异丙肾上腺素快的，不亚于静脉注射。如异丙肾上腺素气雾剂每次喷射一个剂量，吸入后气雾剂每次喷射一个剂量，吸入后 1-21-2 分分钟即起平喘作用。肺部吸收迅速的原因是钟即起平喘作用。肺部吸收迅速的原因是由于由于11 ．肺部具有巨大的可供吸收的表面积．肺部具有巨大的可供吸收的表面积 肺泡是人体进行气血交换的场所。人的肺肺泡是人体进行气血交换的场所。人的肺泡总量有泡总量有 3-43-4 亿个，肺泡总面积达亿个，肺泡总面积达 140m2140m2 。。

22 ．具有十分丰富的毛细血管．具有十分丰富的毛细血管 和肺泡接触的毛细血管总面积达和肺泡接触的毛细血管总面积达 100m2100m2 ，，肺泡表面到毛细血管的距离肺泡表面到毛细血管的距离 0.50.5~~1μm1μm 。。33 ．血液通过肺循环的量很大．血液通过肺循环的量很大 自心脏输出的血液几乎全部通过肺。自心脏输出的血液几乎全部通过肺。

（二）影响药物在呼吸系统分布的因素（二）影响药物在呼吸系统分布的因素11 ．呼吸的气流．呼吸的气流 粒子的沉积率与呼吸量成正 粒子的沉积率与呼吸量成正比与频率成反比。比与频率成反比。22 ．微粒大小．微粒大小 微粒大小是主要影响因素。粒子（或雾微粒大小是主要影响因素。粒子（或雾滴）太大容易沉积在呼吸道粘膜上，吸收滴）太大容易沉积在呼吸道粘膜上，吸收少而慢；则随呼气排出，在肺部的沉积率少而慢；则随呼气排出，在肺部的沉积率很低。很低。 一般吸入型气雾剂的粒子大小在一般吸入型气雾剂的粒子大小在 0.50.5~~10μm10μm较好，发挥全身治疗作用的粒子较好，发挥全身治疗作用的粒子 0.10.1~~1μm1μm为好。为好。

33 ．药物的性质．药物的性质 药物在肺部的吸收属于被动扩散，药物分药物在肺部的吸收属于被动扩散，药物分子的脂溶性在其中起着重要作用，油子的脂溶性在其中起着重要作用，油 // 水水分配系数大的脂溶性药物吸收迅速。分配系数大的脂溶性药物吸收迅速。 肺部的吸收还与分子量有关，一般分子量肺部的吸收还与分子量有关，一般分子量小的 药物吸收较快。若药物吸湿性大，微小的 药物吸收较快。若药物吸湿性大，微粒通过湿度很高的呼吸道时会聚结，妨碍粒通过湿度很高的呼吸道时会聚结，妨碍药物的吸收。药物的吸收。

Filling OperationsFilling Operations

Fluorinated hydrocarbon gases may Fluorinated hydrocarbon gases may be liquefied by cooling below their be liquefied by cooling below their boiling point or by compressing the boiling point or by compressing the gas at room temperature.gas at room temperature.

These two features are used in the These two features are used in the filling of aerosol containers with filling of aerosol containers with propellant.propellant.

(1) Cold Filling(1) Cold Filling In the cold method, both the product In the cold method, both the product

concentrate and the propellant must be concentrate and the propellant must be cooled to -34.5℃ to -40℃. This temperature cooled to -34.5℃ to -40℃. This temperature is necessary to liquefy the propellant gas.is necessary to liquefy the propellant gas.

After the chilled product concentrate has After the chilled product concentrate has been quantitatively metered into an equally been quantitatively metered into an equally cold aerosol container, the liquefied gas is cold aerosol container, the liquefied gas is added.added.

The heavy vapors of the cold liquid propellThe heavy vapors of the cold liquid propellant generally displace the air in the contaiant generally displace the air in the container.ner. When sufficient propellant has been addeWhen sufficient propellant has been added, the valve assembly is inserted and crimd, the valve assembly is inserted and crimped into place.ped into place. For nonaqueous systems, some moisture uFor nonaqueous systems, some moisture usually appears in the final product due to tsually appears in the final product due to the condensation of atmospheric moisture he condensation of atmospheric moisture within the cold containers.within the cold containers.

(2) Pressure Filling(2) Pressure Filling By the pressure method, the By the pressure method, the

product concentrate is product concentrate is quantitatively placed in the aerosol quantitatively placed in the aerosol container,container,

the valve assembly is inserted and the valve assembly is inserted and crimped into place,crimped into place,

and the liquefied gas, under and the liquefied gas, under pressure, is metered into the valve pressure, is metered into the valve stem from a pressure burette.stem from a pressure burette.

The desired amount of The desired amount of propellant is allowed to enter propellant is allowed to enter the container under its own the container under its own vapor pressure.vapor pressure.

When the pressure in the When the pressure in the container equals that in the container equals that in the burette, the propellant stops burette, the propellant stops flowing.flowing.

Additional propellant may be added Additional propellant may be added by increasing the pressure in the filliby increasing the pressure in the filling apparatus through the use of comng apparatus through the use of compressed air or nitrogen gas.pressed air or nitrogen gas. After the container is filled with suffiAfter the container is filled with sufficient propellant, the valve actuator icient propellant, the valve actuator is tested for proper function.s tested for proper function.

Pressure filling is used for most Pressure filling is used for most pharmaceutical aerosols. pharmaceutical aerosols.

It has two advantages over cold filling: It has two advantages over cold filling: there is less danger of moisture there is less danger of moisture

contamination of the product, contamination of the product, and less propellant is lost in the and less propellant is lost in the

process.process.

(3) Testing the Filled (3) Testing the Filled ContainersContainers

The aerosol container is tested under The aerosol container is tested under various environmental conditions for various environmental conditions for leaks or weakness in the valve leaks or weakness in the valve assembly or container.assembly or container.

Filled aerosol containers are also Filled aerosol containers are also tested for proper function of the valve.tested for proper function of the valve.

Aerosols may be tested Aerosols may be tested for their spray patterns,for their spray patterns, for particle size distribution of the for particle size distribution of the

spray, spray, and for accuracy and reproducibility and for accuracy and reproducibility

of dosage when using metered valves.of dosage when using metered valves.

Packaging, Labeling, and Packaging, Labeling, and StorageStorage

Most aerosol products have a Most aerosol products have a protective cap or coverprotective cap or cover that fits that fits snugly over the valve and snugly over the valve and mounting cup.mounting cup.

This protects the valve This protects the valve against against contamination with dust and dirt. contamination with dust and dirt.

In addition to the usual labeling requIn addition to the usual labeling requirements for pharmaceutical producirements for pharmaceutical products, aerosols have special requirementts, aerosols have special requirements for use and storage.s for use and storage.For safety, For safety, labels must warn users not to punctulabels must warn users not to puncture pressurized containers, re pressurized containers, not to use or store them near heat or not to use or store them near heat or an open flame, an open flame, and not to incinerate them.and not to incinerate them.

Aerosols should be maintained with tAerosols should be maintained with the protective caps in place he protective caps in place

to prevent accidental activation of thto prevent accidental activation of the valve assembly e valve assembly

or contamination by dust and other for contamination by dust and other foreign materials.oreign materials.

Proper Administration and Use Proper Administration and Use of Pharmaceutical Aerosolsof Pharmaceutical Aerosols

The patient should be instructed to holThe patient should be instructed to hold the breath for several seconds or as ld the breath for several seconds or as long as possible to gain the maximum bong as possible to gain the maximum benefit from the medication, enefit from the medication,

then remove the inhaler from the moutthen remove the inhaler from the mouth and exhale slowly through pursed liph and exhale slowly through pursed lips. s.

To ensure continuity of therapy it is To ensure continuity of therapy it is wise for the pharmacist to share with wise for the pharmacist to share with the patient ways to assess how much the patient ways to assess how much medication is left in the canister.medication is left in the canister.

This is important to ensure continuity This is important to ensure continuity of therapy, especially for those who of therapy, especially for those who have respiratory illness and may need have respiratory illness and may need their medication on a moment’s their medication on a moment’s notice.notice.

For topical administration of aerosol For topical administration of aerosol dosage forms, the patient should firsdosage forms, the patient should first clean the affected area gently and pt clean the affected area gently and pat it dry.at it dry.

本章要求本章要求11 ．了解气雾剂制备方法、常用设备、质量要．了解气雾剂制备方法、常用设备、质量要求、包装与贮存。求、包装与贮存。22 ．掌握气雾剂的基本概念、术语、特点、常．掌握气雾剂的基本概念、术语、特点、常用基质的种类、性质、特点及应用。气雾用基质的种类、性质、特点及应用。气雾剂的组成、分类、特点、制备工艺、质量剂的组成、分类、特点、制备工艺、质量评价等。评价等。

QuestionsQuestions 1.1. What is the Stokes’ equation and how to imWhat is the Stokes’ equation and how to improve stability of pharmaceutical suspensioprove stability of pharmaceutical suspension?n?2.2. Why emulsions were prepared?Why emulsions were prepared?3.3. What is the HLB system?What is the HLB system?4.4. How many different methods of emulsion prHow many different methods of emulsion preparation? Explain shortly.eparation? Explain shortly.5.5. What are the common gelling agents used in What are the common gelling agents used in the preparation of gel?the preparation of gel?6.6. What are the advantages of the aerosol dosaWhat are the advantages of the aerosol dosage form?ge form?7.7. What are the differences between cold fillinWhat are the differences between cold filling and pressure filling in the filling operationg and pressure filling in the filling operations?s?