1、1,Chapter 3 Powders and granules,2007.1.14,2,Definition of powders,Connotation(涵义) 1, the physical form of a materiala dry substance composed of finely divided particlesThe 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 preparationa medicated powder intended for internal (i.e., oral powder) or external (i.e., topical powder) useThe use of medicated powders per se in therapeutics is limited,3,Definition of granu
3、les,Granules 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.,4,The chemical and physical features of solid materials used in the preparation of pharmaceutical products,1
4、. morphology (形态学) 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 components,efficient production of a finished dosage form and optimum therapeutic efficacy,The requirements for the material of solid d
5、osage form Mixing thoroughly Flowability Filling property,5,Particle size and analysis,The particle size gradation in USP Very 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 i
6、s capable of passing through the opening of standardized sieves of varying dimensions in a specified time period under shaking.,6,Particle size and analysis,typical particle size of granules: 4- to 12- sieve Granules fall within the range of 12- to 20- sieve are sometimes used in tablet making. The
7、purpose 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,7,Particle size and analysis,Particle size can influence a variety of important factors: Dissolution rate (
8、particle 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 ophthalm
9、ic(眼科) preparations; 50-100 m),8,Particle size and analysis,The methods used for the determination of particle size Sieving 40 to 9500 m Microscopy 0.2 to 100 m provide information of shape Sedimentation rate 0.8 to 300 m Light energy diffraction or light scattering0.2 to 500 m laser scattering 0.02
10、 to 2000 m photon correlation spectrum Laser Holography 1.4 to 100 m provide information of shape Cascade 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.,9,Particle size and analysis,Stokes law/relation,v: v
11、elocity of the sedimentation in cm/sec r: particle radius in cm D: particle diameter in cm d1: density of the particle in g/ml d2: density of the liquid in g/ml g=gravitational constant=980.7 cmsec-2 the viscosity of the medium in poises, i.e., gcm-1sec-1 (poise) in cgs units Incidentally, the water
12、 at 20 has a viscosity of approximately one centipoises (0.01 poise). 1 gcm-1sec-1 = 1 p = 100 cp =0.1Pas 1 cp =1 mPas,10,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 o
13、f characteristics including particle 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 tot
14、al surface area.,11,particle size,determined by microscopic method,12,particle size,determined by sieving method,13,Angle of repose（休止角）,The angle of repose is a parameter used to estimate the flowability of a powder.,Powders with low angles of repose will flow freely and powders with high angles of
15、 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 freely if the shape is amenableb) 75-250 m: may f
16、low freely or cause problems, depending on shape and other factorsc) less than 100 m: Flow is problem with most substances.,14,Other characteristics of micromeritics,15,Comminution(粉碎) of drugs,Definition Comminution is the process of reducing the particle size of a solid substance to a finer state
17、of subdivisions. It is used to a) facilitate crude drug extraction, b) increase the dissolution rates of a drug, c) aid in the formulation of pharmaceutically acceptable dosage forms, and d) enhance the absorption of drugs.,16,Comminution(粉碎) of drugs,Mechanism of comminution is overcoming the inter
18、nal adhering force(内聚力) with mechanical action including:a) impaction(冲击力) b) compression(压缩力) c) cuttiing/shearing(剪切力) d) bending(弯曲力) e) rubbing(研磨力),17,Comminution(粉碎) of drugs,Trituration（研磨）:the process of grinding(磨碎) a drug in a mortar to reduce its particle size.Tools: mortar (研钵) and pestl
19、e (研杵) Application: on a small scale On a large scale Tools: 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),18,Comminution(粉碎) of drugs,19,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； 4、粉碎粒度小，在d5m； 5、
20、物料在气流带动下自身碰撞粉碎，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状态下粉碎，所以粉碎腔体温度控制在常温状态，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。,20,Comminution(粉碎) of drugs,Levigation（水飞,液中研磨）: combining the powder material and a small amount of liquid （the levigating agent: mineral oil and glycerin）in which the powd
21、er 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 tile Application: the small-scale preparation of ointments,21,Comminution(粉碎) of drugs,What is oint
22、ment 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
23、 use.,22,Blending powders,The mechanism of blendingconvective mixing; shear mixing; diffusive mixing The methods of blending: Spatulation (调拌) Trituration (研磨) Sifting (过筛) Tumbling (翻转) Stirring (搅拌),23,Blending powders,The methods of blending 1. Spatulation (调拌) Spatulation is a method by which sm
24、all amounts of 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 powder Not suitable for: large quantities of powders or for powders containing potent substances. Suitable for: the mixing
25、 of solid substances that form eutectic mixtures (being dampened or liquify) when in close and prolonged contact with one another.,24,Blending powders,How 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 carbonate Subst
26、ances that form eutectic 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.,25,Blending powders,How to blend materials containing eutectic mixtures? Method 1: avoid forming eutectic mi
27、xtures Method 2: by forming eutectic mixtures Take the effect of eutectic mixtures on the pharmacological action into account:a) pharmacological action: method 2b) pharmacological action: method 1c) pharmacological action: method 1 or 2,26,Blending powders,The methods of blending 2. Trituration (研磨)
28、 Features: may be employed both to comminute and to mix powders Geometric 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 trit
29、uration repeated. This process is 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 ingredie
30、nts being of the same color.,27,Blending powders,The 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,28,Blending powders,The methods of blending 4. tumbling (翻转) Features: tumbling the powder
31、 enclosed in a rotating container (V-shape, cube, cylinder etc.); motorized powder blenders (large-scale) widely employed in industry Mixing is thorough, although time-consuming The methods of blending 5. stirring (搅拌) also frequently used on large scale.,29,Medicated powders,Application internally
32、(with blue label)a. taken orally after mixing with waterb. inhaled into the lungsc. 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 fo
33、r hygienic or therapeutic purposes.)eg. antibiotics for pediatric use externally (with red label, externally use only or topical)a. sifter-type(筛罐) containerb. a powder aerosol,30,Medicated powders,the advantage and disadvantage of medicated powder advantagesa. suitable for patients who have difficu
34、lty swallowing solid dosage formsb. faster rates of dissolution and absorption than solid dosage forms (oral powders for systemic use) disadvantagea. the undesirable taste of the drug,31,Aerosolized powders,Various application form Pressurized aerosolsTo make the powder deposit deep into the lungs,
35、the particle size of the micronized medication is prepared 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,32,The definition of aerosols(气雾剂),Definition An aerosol is defined as a system that depend on the
36、 power of a compressed or liquefied gas to expel the contents from the container with special valve system.,An aerosol product consists of the following component parts:a. propellants(抛射剂) b. containerc. valve (阀门) and actuator (推动钮) d. therapeutic agent and pharmaceutical excipients(辅料),33,Advantag
37、es of aerosols,Advantages over other dosage formsa. contaminationb. Stabilityc. Sterilityd. delivered in a desired forme. Irritationf. ease and convenience of applicationg. application of medication in a thin layer,34,The classification of aerosols,1. according to administration route1)inhalation ae
38、rosols(吸入气雾剂):2)non-inhalation aerosols(非吸入气雾剂):3)topical aerosols(外用气雾剂): 2. according to the working way of valve1)metered dose aerosols(定量气雾剂)2)non-metered dose aerosols(非定量气雾剂),35,The classification of aerosols (continued),3. according to dispersion system1)solution aerosols(溶液型气雾剂):2)emulsion a
39、erosols(乳剂型气雾剂):3)suspension aerosols(混悬型气雾剂): 4. according to the number of phases1)two phases aerosols(二相气雾剂)2)three phases aerosols(三相气雾剂),36,The components of aerosols,An aerosol product consists of the following component parts:a. propellants(抛射剂)(The fluorinated hydrocarbons find widespread us
40、e in most aerosols. Other propellants includes hydrocarbons 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 (推动钮) d. therapeutic agent an
41、d pharmaceutical excipients (辅料) including diluents, antioxidants and suspending agents,37,c. valve and actuatorc1. continuous spray valvesc2. metering valves The 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)
42、spring(弹簧)6) dip tube(浸入管) Actuator(推动钮),The components of aerosols (continued),38,The formulation(处方) of aerosols,Types of pharmaceutical aerosols Solution system (two-phase system) Suspension systems Foam/emulsion systemsa. aqueous stable foamsb. nonaqueous stable foamsc. quick-breaking foamsd. th
43、ermal foams,39,Types of pharmaceutical aerosolsSolution system (two-phase system: consists of a vapor and liquid phase) Example1: weight/%isoproterenol(异丙肾上腺素) HCl 0.25ascorbic acid(Vc) 0.10ethanol 35.75propellant 12 63.90 In order to reduce the pressure, the addition of propellant 114 is recommende
44、d. Ethanol is a cosolvent. Ascorbic acid is antioxidant.,The formulation(处方) of aerosols,40,Types of pharmaceutical aerosolsSolution system Example2: weight/%active ingredients up to 10-15solvents (ethanol etc.) up to 10-15distilled water 10-15hydrocarbon propellant A-46 55-70 Hydrocarbons are often
45、 used in topical aerosol. Depending on the amount of water present, the final product may be a solution or a three-phase system.,The formulation(处方) of aerosols,41,Types of pharmaceutical aerosolsSuspension systemsExample3 weight/%epinephrine(肾上腺素) bitartrate(within 1 to 5 microns) 0.50 sorbitan tri
46、oleate(spans-85) 0.50propellant 114 49.50propellant 12 49.50 sorbitan 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
47、lungs to exert a therapeutic activity.,The formulation(处方) of aerosols,42,Types of pharmaceutical aerosolsSuspension systems The physical stability of an aerosol dispersion can be increased bya) control of moisture content,b) use of derivatives of active ingredients having minimum solubility in prop
48、ellant system,c) reduction of initial particle size to less than 5 microns,d) adjustment of density of propellant and/or suspensoid(悬胶体) so that they are equalized, ande) use of dispersing agents.,The formulation(处方) of aerosols,43,Types of pharmaceutical aerosolsFoam/emulsion systemsa. aqueous stab
49、le foamsb. nonaqueous stable foams (using various glycols, such as PEG)c. quick-breaking foamsd. thermal foams,The formulation(处方) of aerosols,44,a. aqueous stable foams can be formulated as follows: % w/w,Active ingredients Oil-waxes o/w surfactant Water Hydrocarbon propellant,95.0-96.5,3.5-5.0,1)
50、Oil-waxes: myristic acid, stearic acid, cetyl alcohol, lanolin, etc. 2) 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.,
