《药剂学》课程双语教学方法建设的工作进展ppt课件

1、Chapter 3 Powders and granules 2007.1.14.Definition of powdersConnotation(涵义) 1, the physical form of a material a dry substance composed of finely divided particles The use of powdered substances in the preparation of other dosage forms is extensive. For example, a. tablets and capsules; b. liquid

2、dosage forms (solutions or suspensions); c. ointments and creams. Connotation 2, a type of pharmaceutical preparation a medicated powder intended for internal (i.e., oral powder) or external (i.e., topical powder) use The use of medicated powders per se in therapeutics is limited.Definition of granu

3、lesGranules are prepared agglomerates of powdered materials, and may be used per se for the medicinal value of their content or they may be used for pharmaceutical purposes, as in tableting.The chemical and physical features of solid materials used in the preparation of pharmaceutical products1. mor

4、phology (形状学)2. purity (纯度)3. solubility (溶解度)4. stability (稳定性)5. particle size (粒径)6. uniformity (均一性)7. compatibility (相容性) with any other formulation componentschemical and pharmaceutical processingefficient production of a finished dosage formand optimum therapeutic efficacyThe requirements for

5、 the material of solid dosage formMixing thoroughlyFlowabilityFilling property .Particle size and analysisThe particle size gradation in USPVery coarse最粗粉Coarse粗粉Moderately coarse中粉Fine细粉Very fine最细粉This gradation system is based on sieving method筛分法, and is related to the proportion of powder that

6、is capable of passing through the opening of standardized sieves of varying dimensions in a specified time period under shaking.Particle size and analysistypical particle size of granules: 4- to 12- sieveGranules fall within the range of 12- to 20- sieve are sometimes used in tablet making.The purpo

7、se of particle size analysis in pharmacy is to obtain quantitative data on the size, size distribution, and shapes of drug and nondrug components to be used in pharmaceutical formulations.Particle size and analysisParticle size can influence a variety of important factors:Dissolution rate (particle

8、size surface area)Suspendability(混悬性) (suspensions; 0.5-10 m)Uniform distribution to ensure dose-to-dose content uniformity (powders, granules and tablets)Penetrability (inhalers; 1-5 m, deposition deep in the respiratory tract)Nongrittiness(无砂砾感) (dermal ointments, creams, and ophthalmic(眼科) prepar

9、ations; 50-100 m).Particle size and analysisThe methods used for the determination of particle sizeSieving 40 to 9500 mMicroscopy 0.2 to 100 m provide information of shapeSedimentation rate 0.8 to 300 m Light energy diffraction or light scattering 0.2 to 500 m laser scattering 0.02 to 2000 m photon

10、correlation spectrumLaser Holography 1.4 to 100 m provide information of shapeCascade impaction (级联撞击) A combination of the above methods and others is often preferred to provide greater assurance of size and shape parameters. .Particle size and analysisStokes law/relationv: velocity of the sediment

11、ation in cm/secr: particle radius in cm D: particle diameter in cmd1: density of the particle in g/ml d2: density of the liquid in g/mlg=gravitational constant=980.7 cmsec-2the viscosity of the medium in poises, i.e., gcm-1sec-1 (poise) in cgs unitsIncidentally, the water at 20 has a viscosity of ap

12、proximately one centipoises (0.01 poise).1 gcm-1sec-1 = 1 p = 100 cp =0.1Pas 1 cp =1 mPas .On micromeritics (微粒学,粉粒学)Micromeritics is the science of small particles; a particle is any unit of matter having defined physical dimensions.Micromeritics includes a number of characteristics including parti

13、cle size, particle size distribution, particle shape, angle of repose(休止角), porosity(空隙率), true volume(真实体积), bulk volume(总体积、松容积), apparent density(松密度) and bulkiness(膨松度) .A reduction in a powders particle size increases the number of particles and the powders total surface area.particle sizedeter

14、mined by microscopic methodsize group of counted particles/mMiddle value m“d”Number of particles per group “n”“nd”40-60501575060-807025175080-10090958550100-12011014015400120-1401308010400n=355nd=36850.particle sizedetermined by sieving methodSeive numberArithmetic mean opening (mm)Weight retained (

15、G)%Retained%RetainedMean opening20/400.63015.514.39.00940/600.33525.823.77.93960/800.21448.344.49.50280/1000.16315.614.32.330100/1200.1352108.7100.029.232.Angle of repose休止角The angle of repose is a parameter used to estimate the flowability of a powder.hrPowders with low angles of repose w

16、ill flow freely and powders with high angles of repose will flow poorly.A number of factors, including shape and size, determine the flowability of powders.Shape: Spherical particles flow better than needles.Size: Very fine particles do not flow as freely as large particles. a) 250-2000 m: flow free

17、ly if the shape is amenable b) 75-250 m: may flow freely or cause problems, depending on shape and other factors c) less than 100 m: Flow is problem with most substances. .Other characteristics of micromeritics.Comminution(粉碎) of drugsDefinitionComminution is the process of reducing the particle siz

18、e of a solid substance to a finer state of subdivisions. It is used toa) facilitate crude drug extraction, b) increase the dissolution rates of a drug,c) aid in the formulation of pharmaceutically acceptable dosage forms, andd) enhance the absorption of drugs.Comminution(粉碎) of drugsMechanism of com

19、minution isovercoming the internal adhering force(内聚力) with mechanical action including: a) impaction(冲击力) b) compression(紧缩力) c) cuttiing/shearing(剪切力) d) bending(弯曲力) e) rubbing(研磨力) .Comminution(粉碎) of drugsTrituration研磨:the process of grinding(磨碎) a drug in a mortar to reduce its particle size.

20、Tools: mortar (研钵) and pestle (研杵) Application: on a small scaleOn a large scaleTools: ball mills(球磨机), colloid mills(胶体磨), impact mills(冲击式粉碎机) and fluid-energy mills(流能磨) .Comminution(粉碎) of drugs.Comminution(粉碎) of drugs流能磨的优点：1、能耗低；2、同时完成微粉碎和微粉分选；3、磨损小，由于主要粉碎作用是粒子相互冲击碰撞，高速粒子与壁面很少碰撞，可适用粉碎硬度较大的物料；

21、4、粉碎粒度小，在d5m；5、物料在气流带动下本身碰撞粉碎，不带入介质,无污染;6、不用停机即可控制产品的细度，且细粉能全部回收，不污染环境；7、不升温，由于物料是在气体膨胀形状下粉碎，所以粉碎腔体温度控制在常温形状，温度不会升高；8、对易燃、易爆物料可用惰性气体作介质粉碎。.Comminution(粉碎) of drugsLevigation水飞,液中研磨: combining the powder material and a small amount of liquid the levigating agent: mineral oil and glycerinin which the

22、powder is insoluble, then triturating the mixture to reduce the particle size and grittiness of added powders (a paste is produced), this process is termed levigation.Tools: mortar, pestle or an ointment tileApplication: the small-scale preparation of ointments .Comminution(粉碎) of drugsWhat is ointm

23、ent tile, and how to use it?It is a flat rectangular or square slab of glass or porcelain. It is also an excellent work surface for triturating and levitating small amounts of ointments and suppository masses. The ointment tile should never be scratched and should be cleaned and stored when not in u

24、se. .Blending powdersThe mechanism of blending convective mixing; shear mixing; diffusive mixingThe methods of blending:Spatulation (调拌)Trituration (研磨)Sifting (过筛)Tumbling (翻转)Stirring (搅拌).Blending powdersThe methods of blending 1. Spatulation (调拌)Spatulation is a method by which small amounts of

25、powders may be blended by the movement of a spatula through the powders on a sheet of paper or an ointment tile.Features: little compression or compacting of the powderNot suitable for: large quantities of powders or for powders containing potent substances.Suitable for: the mixing of solid substanc

26、es that form eutectic mixtures (being dampened or liquify) when in close and prolonged contact with one another.Blending powdersHow to avoid forming eutectic mixtures(低共熔混合物)?mixing in the presence of an inert diluent such as light magnesium oxide or magnesium carbonateSubstances that form eutectic

27、mixtures when combined include chloral hydrate(水合氯醛), phenol, camphor(樟脑), menthol, thymol(麝香草酚), aspirin(乙酰水杨酸), phenylsalicylate(苯基水杨酸) and other similar chemicals. .Blending powdersHow to blend materials containing eutectic mixtures?Method 1: avoid forming eutectic mixturesMethod 2: by forming eu

28、tectic mixturesTake the effect of eutectic mixtures on the pharmacological action into account: a) pharmacological action: method 2 b) pharmacological action: method 1 c) pharmacological action: method 1 or 2.Blending powdersThe methods of blending 2. Trituration (研磨)Features: may be employed both t

29、o comminute and to mix powdersGeometric dilution method: The potent drug is placed on an approximately equal volume of the diluent in a mortar and mixed thoroughly by trituration. Then a second portion of diluent equal in volume to the mixture is added, and the trituration repeated. This process is

30、continued by adding equal volumes of diluent to the powder mixture and repeating until all of the diluent is incorporated.Suitable for the mixing of a small amount of a potent drug with a large amount of diluent, in particular, the potent and the nonpotent ingredients being of the same color.Blendin

31、g powdersThe methods of blending 3. Sifting (过筛)Features: resulting in a light fluffy product; not acceptable for the incorporation of potent drugs into a diluent powder.Blending powdersThe methods of blending 4. tumbling (翻转)Features: tumbling the powder enclosed in a rotating container (V-shape, c

32、ube, cylinder etc.);motorized powder blenders (large-scale) widely employed in industryMixing is thorough, although time-consumingThe methods of blending 5. stirring (搅拌)also frequently used on large scale.Medicated powdersApplicationinternally (with blue label) a. taken orally after mixing with wat

33、er b. inhaled into the lungs c. packaged with a liquid solvent or vehicle for constitution (orally, as an injection, as a vaginal douche: A stream of water, often containing medicinal or cleansing agents, that is applied to a body part or cavity for hygienic or therapeutic purposes.) eg. antibiotics

34、 for pediatric use externally (with red label, externally use only or topical) a. sifter-type(筛罐) container b. a powder aerosol.Medicated powdersthe advantage and disadvantage of medicated powderadvantages a. suitable for patients who have difficulty swallowing solid dosage forms b. faster rates of

35、dissolution and absorption than solid dosage forms (oral powders for systemic use) disadvantage a. the undesirable taste of the drug.Aerosolized powdersVarious application formPressurized aerosols To make the powder deposit deep into the lungs, the particle size of the micronized medication is prepa

36、red in the range of 1 m to 6 m in diameter.Mechanical devices (SPINHALER) for the delivery of powders in a capsules Powder blowers or insufflators.The definition of aerosols(气雾剂)DefinitionAn aerosol is defined as a system that depend on the power of a compressed or liquefied gas to expel the content

37、s from the container with special valve system.An aerosol product consists of the following component parts: a. propellants(抛射剂) b. container c. valve (阀门) and actuator (推进钮) d. therapeutic agent and pharmaceutical excipients(辅料).Advantages of aerosolsAdvantages over other dosage forms a. contaminat

38、ion b. Stability c. Sterility d. delivered in a desired form e. Irritation f. ease and convenience of application g. application of medication in a thin layer .The classification of aerosols1. according to administration route 1)inhalation aerosols(吸入气雾剂): 2)non-inhalation aerosols(非吸入气雾剂): 3)topica

39、l aerosols(外用气雾剂):2. according to the working way of valve 1)metered dose aerosols(定量气雾剂) 2)non-metered dose aerosols(非定量气雾剂) .The classification of aerosols(continued)3. according to dispersion system 1)solution aerosols(溶液型气雾剂): 2)emulsion aerosols(乳剂型气雾剂): 3)suspension aerosols(混悬型气雾剂):4. accordi

40、ng to the number of phases 1)two phases aerosols(二相气雾剂) 2)three phases aerosols(三相气雾剂) .The components of aerosolsAn aerosol product consists of the following component parts: a. propellants(抛射剂)(The fluorinated hydrocarbons find widespread use in most aerosols. Other propellants includes hydrocarbo

41、ns including propane, butane, and isobutane, and compressed gases such as nitrogen, carbon dioxide, and nitrous oxide(N2O).) b. container (tinplate(镀锡铁皮), aluminum, stainless steel, glass) c. valve (阀门) and actuator (推进钮) d. therapeutic agent and pharmaceutical excipients (辅料) including diluents, an

42、tioxidants and suspending agents.c. valve and actuator c1. continuous spray valves c2. metering valvesThe valves consist of the following parts: 1) ferrule(套圈) or mounting cup(固定杯) 2) stem(阀门杆) 3) valve body(阀体) or housing(小室) 4) gasket(垫圈、封圈) 5) spring(弹簧) 6) dip tube(浸入管) Actuator(推进钮)The componen

43、ts of aerosols(continued).The formulation(处方) of aerosolsTypes of pharmaceutical aerosolsSolution system (two-phase system)Suspension systemsFoam/emulsion systems a. aqueous stable foams b. nonaqueous stable foams c. quick-breaking foams d. thermal foams.Types of pharmaceutical aerosolsSolution syst

44、em (two-phase system: consists of a vapor and liquid phase) Example1: weight/% isoproterenol(异丙肾上腺素) HCl 0.25 ascorbic acid(Vc) 0.10 ethanol 35.75 propellant 12 63.90In order to reduce the pressure, the addition of propellant 114 is recommended. Ethanol is a cosolvent. Ascorbic acid is antioxidant.

45、The formulation(处方) of aerosols.Types of pharmaceutical aerosolsSolution system Example2: weight/% active ingredients up to 10-15 solvents (ethanol etc.) up to 10-15 distilled water 10-15 hydrocarbon propellant A-46 55-70Hydrocarbons are often used in topical aerosol.Depending on the amount of water

46、 present, the final product may be a solution or a three-phase system.The formulation(处方) of aerosols.Types of pharmaceutical aerosolsSuspension systems Example3 weight/% epinephrine(肾上腺素) bitartrate (within 1 to 5 microns) 0.50 sorbitan trioleate(spans-85) 0.50 propellant 114 49.50 propellant 12 49

47、.50sorbitan trioleate: surfactants/suspending agents, to decrease the rate of settling of the dispersed particles.The epinephrine bitartrate has a minimum solubility in the propellant system, but is sufficiently soluble in the fluids in the lungs to exert a therapeutic activity. The formulation(处方)

48、of aerosols.Types of pharmaceutical aerosolsSuspension systemsThe physical stability of an aerosol dispersion can be increased by a) control of moisture content, b) use of derivatives of active ingredients having minimum solubility in propellant system, c) reduction of initial particle size to less

49、than 5 microns, d) adjustment of density of propellant and/or suspensoid(悬胶体) so that they are equalized, and e) use of dispersing agents.The formulation(处方) of aerosols.Types of pharmaceutical aerosolsFoam/emulsion systems a. aqueous stable foams b. nonaqueous stable foams (using various glycols, s

50、uch as PEG) c. quick-breaking foams d. thermal foamsThe formulation(处方) of aerosols.a. aqueous stable foamscan be formulated as follows: % w/w Active ingredientsOil-waxeso/w surfactantWaterHydrocarbon propellant95.0-96.53.5-5.01) Oil-waxes: myristic acid, stearic acid, cetyl alcohol, lanolin, etc.2)

51、 Hydrocarbon propellant can be replaced by compressed gas.3) As the amount of propellant increases, a stiffer and dryer foam is produced. Lower propellant concentrations yield wetter foams.4) Surfactants that showed some solubility in the propellants are preferable.The formulation(处方) of aerosols.a.

52、 nonaqueous stable foamscan be formulated as follows: % w/w Glycol 91.092.5 Emulsifying agent 4.0Hydrocarbon propellant 3.55.01) The most effective emulsifying agents are glycol esters, namely, myrijs.The formulation(处方) of aerosols.Manufacture of pharmaceutical aerosolsStep1: manufacture of concent

53、rate (general procedure and condition)Step2: addition of propellantThe filling methods: cold filling: -40。F; restricted to nonaqueous products and to those products not adversely affected by low temperatures pressure filling: preferable for solution, emulsions, suspensions; less danger of contaminat

54、ion of the product with moisture; high production speeds; less propellant loss.Testing of pharmaceutical aerosolsA. Flammability(可燃性) and combustibility(熄灭性) 1. Flash point(闪点) of limited value 2. Flame extension(火焰延伸), including flashback(闪回)B. Physicochemical characteristics 1. vapor pressure: pre

55、ssure gauge(压力计), water bath, pressure variation from container to container; 2. density: hydrometer(液体比重计) 3. moisture content: Karl Fisher method, GC 4. identification of propellants: GC, IR 5. concentrate-propellant ratio: GC.Testing of pharmaceutical aerosols(continued)C. Performance(性能) 1. Aero

56、sol valve discharge rate(排空率): W1-W0 g/s 2. spray pattern(喷雾方式): spray on a paper treated with a dye-talc mixture 3. dosage with metered valves: 1)reproducibility of dosage each time the valve is depressed:a) one or two doses of discharge; b) left amount. 2)amount of medication actually received by

57、the patient:a) hard to determine; b)artificial respiratory system 4. net contents(净含量): Wtotal-Wcontainer 5. foam stability: visual evaluation, rotational viscometer, rod falling, mass penetration.Testing of pharmaceutical aerosols (continued) 6. particle size determination: cascade impactor(级联撞击器):

58、0.130 microns light scatter decay: Tyndall beam 7. leakage D. biologic characteristics 1. therapeutic effect 2. toxicity.Packaging of powdersBulk powders limited to nonpotent substances such as a) antacid powders and laxative powders b) douche powders c) medicated powders for external application an

59、tiinfectives or antifungals d) powder containing nutritional supplementsDivided powders a) weigh each portion separately for potent drug b) block-and-divide method for nonpotent drug approximate each portion.granulesPreparation of granules1. wet methods 1) basic wet method a) moistening the powder mixture (paste-like mass) b) granulation by screening (wet granules) c) drying (dry granules) d) sizing the granules by screening (finished granules) 2) fluid-bed processing Particles are vigorously dispersed and suspended while a liquid excipient is sprayed on