国生 国生一 Concepts Concepts ④Micromeritics粉体学：science and Micromeritics technology of small particles ·Powdert粉：100um ·Primary particle一级粒子 ·Second particle二级粒子 国生三 Particle size Characteristics:compare with solid,liquid and gas Knowledge and control of particle sine is very There are many types of analyses for +Flowability南动性 important in pharmacy. particle characterization.Each method will result in a unique measure of particle size and distribution,since a real sample ·Anti女rmablity抗变形往 exhibits a range of shapes and size.It is ·Tble片剂 important to distinguish between different ·Suspension匹混巷剂 methods,and to use the same type of analysis when comparing lots of raw material. 国生 Particle size Particle size Particle size Ge 几何学较子径 m三径 (Stoke's dimndet,EBed diander) ④Sieving diameter筛分径 ,Fee dumde定方向接线径D, ·(a,+b) ,边in dunder定方内等分径D K定方最大 D=ab D,=4+6 ·ywood dumde等权面面积同相当竖O 2 wdt6缸女等表到积相当径， 1
1 Micromeritics School of Pharmacy Chen Jian 2012.2 chenjian@sjtu.edu.cn Shanghai Jiao Tong University Concepts Primary properties • Particle size and size distribution • Morphology and specific surface area Second properties • Density and porosity • Flowability and packability • Moisture absorption and wetting • Adhesion and cohesion • Compact characterization Shanghai Jiao Tong University Concepts Micromeritics粉体学: science and technology of small particles • Powder粉: ＜100μm • Particles粒:＞100μm • Primary particle一级粒子 • Second particle 二级粒子 Shanghai Jiao Tong University Characteristics: compare with solid, liquid and gas • Flowability 流动性 • Compressibility 可压缩性 • Anti-deformability 抗变形性 Shanghai Jiao Tong University Knowledge and control of particle size is very important in pharmacy. • Powders散剂 • Capsules胶囊 • Tablets片剂 • Suspensions混悬剂 Shanghai Jiao Tong University Particle size There are many types of analyses for particle characterization. Each method will result in a unique measure of particle size and distribution, since a real sample exhibits a range of shapes and size. It is important to distinguish between different methods, and to use the same type of analysis when comparing lots of raw material. Shanghai Jiao Tong University Geometric diameter 几何学粒子径 • Diameter of the three dimensions三轴径 • Projected diameter投影径 • Feret diameter定方向接线径DF • Martin diameter定方向等分径DM • Krummbein diameter定方向最大径DK • Heywood diameter 等投影面积圆相当径DH • Equivalent perimeter diameter等投影面周长圆相当径DL • Equivalent volume diameter 等体积球相当径DV • Equivalent surface diameter 等表面积相当径DS • Equivalent specific surface diameter 等比表面积相当径DSV Particle size Shanghai Jiao Tong University Settling velocity diameter 沉降速度相当径 (Stoke’s diameter, Effect diameter) Particle size t h g D p l stk ( ) 18 Shanghai Jiao Tong University Particle size Sieving diameter筛分径 • (-a, +b) D a b A D ab A 2
©t生Particle size distribution ④生Particle size distrbution 国a生Particle size distrbution Particle size distribution Particle size distribution Particle size distribution ·Fre问uency size distribution频率分布 ·Normal distribution正态分布 ·Count basis个数基准 ·Cumulative size distrbution累积分布 ·Log-normal distributon对数正态分布 Mass basis 质量基准 ·Surface basis面积基准 ·Volume basis体积基准 ·Length basis长度基准 ,Undersize distribution痛上分布 ·Oversize distribution暗下分布 国生一 Morphology Mean diameter 式 Methods used to determine particle size ∑d1∑n ·3 icrcopic method是微镜法 The shape affects the flow and packing ,Co点r coumer ethod库尔特计数法 properties of a powder,as well as having 烟验录多的龄子直登 ·mchd态光射法 ·mem沉法 some influence on the surface area. 紧积中饲值《D) ·Specificsuface ea mcthod此表面积法 ∑dI∑ 围Shape index形状指数 面积长皮平尚轻 ·Sieving methodi游分法 ·动日 ∑nd1∑u 国Shape factor}形状系数 ∑nd1∑m Specific surface area ©t生Specific surface area 图Specific surface area 象Volume specific surface area体积比表面积 象Gas adsorption method气体吸附法 ©Gas permeability method气体透过法 S.=42400602x100 14AP.1c2 ④Weight specific surface area重量比表面积 pVn-L·Q1-s)2 1,C-1.卫 6 V(P-P)V.C+V 2
2 Shanghai Jiao Tong University Particle size distribution Particle size distribution • Frequency size distribution频率分布 • Cumulative size distribution累积分布 • Undersize distribution筛上分布 • Oversize distribution筛下分布 频率百分数 % Shanghai Jiao Tong University Particle size distribution Particle size distribution • Normal distribution 正态分布 • Log-normal distribution 对数正态分布 Shanghai Jiao Tong University Particle size distribution Particle size distribution • Count basis 个数基准 • Mass basis 质量基准 • Surface basis 面积基准 • Volume basis 体积基准 • Length basis 长度基准 Shanghai Jiao Tong University 名称 公式 算术平均径 Arithmetic mean diameter 众数径 Mode diameter 频数最多的粒子直径 中位径 Medium diameter 累积中间值（D50） 面积-长度平均径 Surface length mean diameter 体面积平均径 Volume surface mean diameter 重量平均径 Weight mean diameter nd nd 2 / nd nd 4 3 / nd nd 3 2 / nd n / Mean diameter Shanghai Jiao Tong University Methods used to determine particle size • Microscopic method显微镜法 • Coulter counter method库尔特计数法 • Photon correlation spectroscopy method动态光散射法 • Sedimentation method沉降法 • Specific surface area method比表面积法 • Sieving method筛分法 • Mush目 Shanghai Jiao Tong University Morphology The shape affects the flow and packing properties of a powder, as well as having some influence on the surface area. Shape index形状指数 Shape factor形状系数 Shanghai Jiao Tong University Specific surface area Volume specific surface area体积比表面积 Weight specific surface area 重量比表面积 S s v d n d n d v 2 3 6 6 S s w d n d n d w 2 3 6 6 Shanghai Jiao Tong University Specific surface area Gas adsorption method气体吸附法 23 6.02 10 22400 m w V S A 0 0 1 1 ( ) p p V C V p p V C p m m Shanghai Jiao Tong University Specific surface area Gas permeability method气体透过法 2 2 (1 ) 14 L Q A P t Sw
国生 Density 国生 Density 国生 Density Methods to determine true density and Methods to determine density ©True density 真密度 granule density ·Liquid immersion method液浸法 ·Liquid immersion method液浸法 ©Granule density颗粒密度 ·Gas pressure method乐力比较法 且 (%-%A ©Bulk density松密度 Methods to determine bulk density P= ·Tapping method轻薇法 (m-%)-(m-m) 丝_Density ©a生_Density 国生一 Porosity Methods to determine density Methods to determine bulk density ●Porosity空豫率 ·Gasp四essure method压力比较法 ·Tapping method轻敲法 内=1-巳 5m=1-巳 Pe 58=1-巳 Flowability Flowability Flowability ©Angle of repose休止角 ©Flow velocity流出速度 @Compressibility压缩度 电@ c=P-Pex1o0(%) 3
3 Shanghai Jiao Tong University Density True density 真密度 Granule density 颗粒密度 Bulk density 松密度 Shanghai Jiao Tong University Density Methods to determine true density and granule density • Liquid immersion method液浸法 • Gas pressure method压力比较法 Methods to determine bulk density • Tapping method轻敲法 Shanghai Jiao Tong University Density Methods to determine density • Liquid immersion method液浸法 ( ) ( ) ( ) 0 0 L aL S S l t m m m m m m Shanghai Jiao Tong University Density Methods to determine density • Gas pressure method压力比较法 Shanghai Jiao Tong University Density Methods to determine bulk density • Tapping method轻敲法 Shanghai Jiao Tong University Porosity Porosity空隙率 t g 内 1 g b 间 1 t b 总 1 Shanghai Jiao Tong University Flowability Angle of repose休止角 Shanghai Jiao Tong University Flowability Flow velocity流出速度 Shanghai Jiao Tong University Flowability Compressibility压缩度 100(%) 0 f f c
国生 Flowability 国生 Packability(充填性) 国a生Moisture absorption Methods to improve flowability 和性导位发量)周本体裂 Increase particle size Smooth particle surface .Reduce moisture 空比 兰 ·Add glidant 体明真样装与后情之比 7777 ④4生Moisture absorption ®24线Moisture absorption 国生一Wetting润湿性 Water soluble materials ©Contact angle接触角 ,CRH:critical relative humidity在界相对漫度 ,Humidity湿度 ,Relative humidity相对湿度H办 ·CRH一CRH~CRH Water insoluble materials Water soluble drugs Water insoluble drugs 国生 Wetting ©Contact angle Adhesion粘附性： 体层 attract force between different kinds of molecules rYI COs0 t 2n 体吸入高度 需凝聚性： .attract force between se kind of molecules 4
4 Shanghai Jiao Tong University Flowability Methods to improve flowability • Increase particle size • Smooth particle surface • Reduce moisture • Add glidant Shanghai Jiao Tong University Packability(充填性) 松比容 Specific volume 粉体单位质量（1g）所占体积 ν=V/W 松密度 Bulk density 粉体单位体积（cm3）的质量 ρ=W/V 空隙率 Porosity 粉体的松体积中空隙所占体积比 ε=(V-Vt )/V 空隙比 Void ratio 空隙体积与粉体真体积之比 e=（V-Vt ）/Vt 充填率 Packing fraction 粉体的真体积与松体积之比 g=Vt /V=1-ε 配位数 Coordination number 一个粒子周围相邻的其它粒子个数 Shanghai Jiao Tong University Moisture absorption Shanghai Jiao Tong University Moisture absorption Water soluble materials • CRH: critical relative humidity临界相对湿度 • Humidity湿度 • Relative humidity相对湿度 RH=p/ps • CRHAB=CRHA·CRHB Water insoluble materials P p p H 0.622 Shanghai Jiao Tong University Moisture absorption Water soluble drugs Water insoluble drugs Shanghai Jiao Tong University Wetting润湿性 Contact angle接触角 S SL L cos Shanghai Jiao Tong University Wetting Contact angle t r h l 2 cos 2 Shanghai Jiao Tong University Adhesion粘附性: • attract force between different kinds of molecules Cohesion凝聚性: • attract force between same kind of molecules Shanghai Jiao Tong University Compact characterization Compressibility 可压缩性 Compactibility 可成型性 Tabletability 可压片性
®日stic deformation弹性变形 Upper punch force,u上冲力 Lower punch foree,Fi下冲力 Pas deforation塑性变形 画Radical force,Fa径向力 专Doe wall friction force,下a模壁摩候力 ®Brittle deformation脆性变形 图4生Learning Objectives 图丝一Learning Objectives Advantages and disadvantages ©Types specific surfce True density,Granule density, TABLETS Tablet excipients Hulk densiry,Angle of repose,Porosity,cntical relative humidity,Contactae Methods of preparation ®Evalution Packaging and Storage mmersion method,Gas pressure method Variables which effect quality Coating ®Tablet Types Oral tablets for ingestion ©Advantages eOr包tabletsfor s Standard compressed tablets 份Coued tahlets农片 h泡秀片 Tablesainsd by other routes Chewable tablets咀第片 Dispersible tablets分敢片 ©Disadvantages Release tablet缓释片 Unsuitable for those can't swallow ®Controlled Release tablets控释片 .Problems with biouvalabiliry @Multilayer tablets多层片 +Loos of vo山tile coe世pone 口聚速崩/速溶片 5
5 Shanghai Jiao Tong University Compact characterization Elastic deformation 弹性变形 Plastic deformation 塑性变形 Brittle deformation 脆性变形 Shanghai Jiao Tong University Compact characterization Upper punch force, FU 上冲力 Lower punch force, FL 下冲力 Radical force, FR 径向力 Die wall friction force, FD 模壁摩擦力 Ejection force, FE 推出力 Shanghai Jiao Tong University Compact characterization Compression cycle 压缩循环图 Shanghai Jiao Tong University Learning Objectives Frequency size distribution, Cumulative size distribution, Medium diameter, Volume specific surface area, Weight specific surface area , True density, Granule density, Bulk density, Angle of repose, Porosity, critical relative humidity, Contact angle Coulter counter method, Sedimentation method, Gas adsorption method, Gas permeability method, Liquid immersion method, Gas pressure method TABLETS School of Pharmacy Chen Jian 2012.2 chenjian@sjtu.edu.cn Shanghai Jiao Tong University Learning Objectives Advantages and disadvantages Types Tablet excipients Methods of preparation Evaluation Packaging and Storage Variables which effect quality Coating Shanghai Jiao Tong University Advantages • Accurate and uniform • Stable • Convenient • Suitable for large-scale production • Able to develop special release properties Disadvantages • Unsuitable for those can’t swallow • Problems with bioavailability • Loss of volatile component Shanghai Jiao Tong University Tablet Types Oral tablets for ingestion Tablets used in the oral cavity Tablets administered by other routes Shanghai Jiao Tong University Oral tablets for ingestion Standard compressed tablets Coated tablets包衣片 Effervescent tablets泡腾片 Chewable tablets咀嚼片 Dispersible tablets分散片 Sustained Release tablets缓释片 Controlled Release tablets控释片 Multilayer tablets 多层片 Orally disintegrating/dissolving tablets 口服速崩/速溶片
国生 Coated tablets 国4生Effervescent tablets 国生 Tablets used in the oral cavity ©Sugar Coated Tablets糖农片 ·Sublingual tablets话下片 ,Troches合片 ©Film Coated Tablets薄膜衣片 ·B证e:比口腔贴片 ©Enteric coaed tablets肠溶农片 国生 国2生Excipients Excipients Perform a varicty of functions Tablets administered by other routes Providingesse mamacturing techology Any component other than the active functioes ·Soutic可溶片 pharmaceutical ingredient(s)intentionallyaded ,Vaginal tahle别道片 to the formulation of a dosage form. Optimizing o modifying drug release ·Enhancingstabiliy Excipients 国生 Excipients 国生Diluents(fillers)) Physically and chemically stable 多Dilues稀释剂(les填充利 Designed to make up the required bulk f taets when Moistening thedugto puduce of ®Nontoxic ●Disinteg态喇解剂 Physiologically inert ©Lubricants润滑剂 Oxchers: ,&g于rminda ·010g Cheap variable. 6
6 Shanghai Jiao Tong University Coated tablets Sugar Coated Tablets糖衣片 Film Coated Tablets薄膜衣片 Enteric coated tablets肠溶衣片 Shanghai Jiao Tong University Effervescent tablets Shanghai Jiao Tong University Tablets used in the oral cavity • Sublingual tablets舌下片 • Troches含片 • Buccal tablets口腔贴片 Shanghai Jiao Tong University Tablets administered by other routes • Solution tablets可溶片 • Vaginal tablet 阴道片 Shanghai Jiao Tong University Excipients Any component other than the active pharmaceutical ingredient(s) intentionally added to the formulation of a dosage form. Shanghai Jiao Tong University Excipients Perform a variety of functions • Providing essential manufacturing technology functions • Enhancing patient acceptance • Providing aid in product identification • Optimizing or modifying drug release • Enhancing stability Shanghai Jiao Tong University Excipients Physically and chemically stable Nontoxic Physiologically inert Commercially available Cheap Shanghai Jiao Tong University Excipients Diluents稀释剂 (fillers填充剂) Moistening agents润湿剂 and adhesives黏合剂 Disintegrants崩解剂 Lubricants润滑剂 Others: • Absorbents吸收剂, • Coloring agents着色剂, • Flavoring agents矫味剂, • …… Shanghai Jiao Tong University Diluents (fillers) Designed to make up the required bulk of tablets when the drug dosage amount is inadequate to produce of adequate weight and size. • 6 or 7 mm diameter • 80 to 100 mg They also improve compressibility and reduce dose variable
国生 Types of diluents 国生 Moistening agents 国生一Adhesives(Binders) 争Starch淀粉 角Sucro蓝额 Moistening agents are used to moisten the Be added either liquid or in dry form during 国Lactos乳糖 wet granulation to form granules or to promote ·Wad @Microcrystalline cellulose(MCC)微品纤雏素 tablets. Inorganic salts Mannitol and s0 rbitol甘露醇和山梨醇 Adhesives 国生三 Disintegrants 国生一Mechanism ofs Capillay action nd Added to tablet formulstions to 308. faclae disintegration Sweling 。CC-吸甲5纤重素销 落 ”5 ewhwat. ,C乙新杆m素 of the tablet when Hest of wetting 用PV伊豪淮围 contacts water. 一 Gas release PEG聚Z 多S正糖 都 t生Types of disintegrants ©生Disintergrants adding method 生Lubricants ●D叮rh干淀粉 Inragbe added during granultion 多CM心N甲淀粉钠 争Gida助液剂peomtof the tabletg2 nulation added after granulation ⊕L-HC低取代是丙基纤米素 Mixed mode07%ntragraeular ●CCNa文联投甲纤鉴素销 PVPP交联聚 die and poch. Effervescem disimegr2nt泡爵解剂 舍Die wall达ricant润清剂educes friction betwen the 多Surfctae表面话性剂 7
7 Shanghai Jiao Tong University Types of diluents Starch淀粉 Sucrose 蔗糖 Dextrin糊精 Lactose乳糖 Pregelatinized starch预胶化淀粉 Microcrystalline cellulose (MCC)微晶纤维素 Inorganic salts Mannitol and sorbitol甘露醇和山梨醇 Shanghai Jiao Tong University Moistening agents Moistening agents are used to moisten the power and induce its stickiness. • Water • Alcohol Shanghai Jiao Tong University Adhesives (Binders) Be added either liquid or in dry form during wet granulation to form granules or to promote cohesive compact for directly compressed tablets. Shanghai Jiao Tong University Adhesives Starch paste 淀粉浆 Cellulose and its derivatives • MC甲基纤维素 • HPC羟丙基纤维素 • HPMC羟丙甲纤维素 • CMC-Na羧甲基纤维素钠 • EC乙基纤维素 PVP 聚维酮 Gelatin明胶 PEG聚乙二醇 Sucrose蔗糖 Shanghai Jiao Tong University Disintegrants Added to tablet formulations to facilitate disintegration of the tablet when it contacts water. Shanghai Jiao Tong University Mechanism of disintegrants Capillary action • Enhance the action of capillary forces in producing a rapid uptake of aqueous. Swelling • Swell on contact with water. Heat of wetting • The heat of wetting makes the entrapped air swell. Gas release • Effervescent salts are added to tablet to release gases to disrupt the tablet structure Shanghai Jiao Tong University Types of disintegrants Dry starch干淀粉 CMS-Na羧甲淀粉钠 L-HPC低取代羟丙基纤维素 CCNa交联羧甲纤维素钠 PVPP交联聚维酮 Effervescent disintegrants泡腾崩解剂 Surfactants表面活性剂 Shanghai Jiao Tong University Disintergrants adding method Intragranular: be added during granulation Extragranular: be added after granulation Mixed mode: 50~75% intragranular 25~50% extragranular Shanghai Jiao Tong University Lubricants Glidant助流剂 promotes flow of the tablet granulation by reducing friction between them. Antiadherent抗黏剂 reduces sticking of the tablet to the die and punch. Die wall lubricant润滑剂reduces friction between the tablet and the walls of the die cavity
国生 Lubricants 国生Types of ubricants 国丝生 ®Absorbents The lubricant activity of magnesium stearate is Be capae of retaininglargeofwithout becoming wet. 多Aa0s微粉硅胶 ®Colorants 多Tle滑石粉 ·Prodact identification ·Surface areas ·Production ofa moree女prodact ·Suppliers 象PEG聚乙二醇 Flavors .Usually limited to chewable ublets ·Micing time 多Sodium lauryl suifate月柱醇顾酸销 inended to dissolve io mouth. ④Sweeteners 国生 Excipients 国4 Excipients An incompatbility in dosge form can result in Excipient compatibality any of the following changes: change in color/acpearance: .Excipienes and their concertration in a formulaion Methods of Preparation areseetadhsedaonlyontherfincaianadlis, .changes to dissolution performance; but also on the compatibiliny between the druz and excipients. loss through sublimation; .increasein degradtion peoducts 国生一 国生Methods of Prep BRECT COMPSON Factors affecting tablet formation ®Wet granulation湿法制粒压片 ·Flowability ©Dry granulation干法制粒压片 ·Compressibility 需Direct compre粉末直接压片 ·Lubricability 需半干式飘粒压片法 8
8 Shanghai Jiao Tong University Lubricants The lubricant activity of magnesium stearate is related to • Surface areas • Suppliers • Mixing time Shanghai Jiao Tong University Types of lubricants Magnesium stearate硬脂酸镁 Aerosil微粉硅胶 Talc 滑石粉 Hydrogenated vegetable oil氢化植物油 PEG聚乙二醇 Sodium lauryl sulfate月桂醇硫酸钠 Shanghai Jiao Tong University Absorbents • Be capable of retaining large quantities of liquids without becoming wet. Colorants • Product identification • Production of a more elegant product Flavors • Usually limited to chewable tablets or other tablets intended to dissolve in mouth. Sweeteners • Are added to tablet formulation to improve the taste of chewable tablets. Shanghai Jiao Tong University Excipients Excipient compatibility • Excipients and their concentration in a formulation are selected based not only on their functionality, but also on the compatibility between the drug and excipients. Shanghai Jiao Tong University Excipients An incompatibility in dosage form can result in any of the following changes: • change in color/appearance; • loss in mechanical properties (e.g., tablet hardness) • changes to dissolution performance; • physical form conversion; • loss through sublimation; • a decrease in potency • increase in degradation products. Methods of Preparation Shanghai Jiao Tong University Factors affecting tablet formation • Flowability • Compressibility • Lubricability Shanghai Jiao Tong University Methods of Preparation Wet granulation湿法制粒压片 Dry granulation干法制粒压片 Direct compression粉末直接压片 半干式颗粒压片法 WET GRANULATION DRY GRANULATION DIRECT COMPRESSION 1. Milling and mixing of drugs and excipients 1. Milling and mixing of drugs and excipients 1. Milling and mixing of drugs and excipients 2. Preparation of binder solution 2. Compression into slugs or roll compaction 2. Compression of tablet 3. Wet massing by addition of binder solution 3. Milling and screening of slugs and compacted powder 4. Screening of wet mass into granules 4. Add disintegrants 5. Drying of the wet granules 5. Lubrication and blending 6. Screening of dry granules 6. Compression of tablet 7. Add disintegrants 8. Lubrication and blending 9.Compression of tablet
国生 生Disadvantages of Crushing Possibly change in polymorphic form Operations involved in raw material treatment Affect stability ·Crushing粉碎 Promotes better mixture May cause flow problem ·Sieving过箱 May inhibit wettability of the drug ·Mxmg混合 Du Explode ④4生Mechanism of Crushing Energy needed for crushing 国生一nsrusof Crushing 豐 盟分的安 edinsieredtcn amuch higher rate than would be predicted from Mortar ®BmL This lost'energy is consumed in Elastic deformatiooof the particle ©l回gm山 ®uid-energy mill Cutting Bending Rub地ies Noise 国生Instruments of Crushing 国生一Ming 愈Convective mixing对流混合 303a 雪Shear mixing剪切混合 3-3 我特8体 甲号一视三号得氢55玉号为妈8妈原人槽A号得 ®Diffusive mixing扩散混合 冲社式和单 陆力 大军好高再私 5n中 a知思品 9
9 Shanghai Jiao Tong University Operations involved in raw material treatment • Crushing 粉碎 • Sieving 过筛 • Mixing 混合 Shanghai Jiao Tong University Advantages of Crushing Increases bioavailability. Promotes better mixture Improves content uniformity Improves flow properties Shanghai Jiao Tong University Disadvantages of Crushing Possibly change in polymorphic form Affect stability May cause flow problem May inhibit wettability of the drug Dust Explode Shanghai Jiao Tong University Mechanism of Crushing Impact Compression Cutting Bending Rubbing Shanghai Jiao Tong University Energy needed for crushing Size reduction obviously requires energy input but the energy is consumed in size reduction apparatus at a much higher rate than would be predicted from the new surface area created, by a factor of about 1000. This 'lost' energy is consumed in • Elastic deformation of the particle • Movement of particles • friction between particles • Elastic deformation of milling surfaces • Noise Shanghai Jiao Tong University Instruments of Crushing Mortar Ball mill Impact mill Fluid-energy mill Shanghai Jiao Tong University Instruments of Crushing 粉碎机类型 粉碎作用 粉碎品的粒度 适应物料 球磨机 磨碎 冲击 20~200μm 可研磨性物料 滚压机 压缩 剪切 20~200μm 软性粉体 冲击式粉碎机 冲击力 4~325μm 大部分医药品 胶体磨 磨碎 20~200μm 软性纤维状 气流粉碎机 撞击 研磨 1~30μm 中度硬物质 Shanghai Jiao Tong University Sieving Makes the size distribution more uniform 筛 号 一号筛 二号筛 三号筛 四号筛 五号筛 六号筛 七号筛 八号筛 九号筛 筛孔平均内径 （μm） 2000 ±70 850 ±29 355 ±13 250 ±9.9 180 ±7.6 150 ±6.6 125 ±5.8 90 ±4.6 75 ±4.1 Shanghai Jiao Tong University Mixing Convective mixing对流混合 Shear mixing 剪切混合 Diffusive mixing 扩散混合
国生 Mixing 国生 Wet Granulation 国生一 Factors which affect the mixing Widely employed method for the production of 1.Milling and mixing of drugs ad evcipieres Properties of ingredients Proportion ofeach ingrediest Milling and mixing of dngs and excipients 2 Preparaticn of binder soltioe .Preparic ofbinder soluice Density and Hthe dnm wabetnces is affected by water wc a nosagucoun hindo ·Cobesive and charge the wet mass granules. 金支Wet massing byiofbinderotion 间inaddedt te roda mittane Drying of the wet granules .Eutectie mixture Overudting cama gaues that ae too baod 。Underweing e i bc a业 ·Apparatuses ·Operations .Lubrication and blending. ·Compressiontt 国生一_strfor 通Estoder 5.Drying of the wet granules 角Ramg 9.Tableting Eld Bedgrnulor 6.Screenng of dry gsamlles e Comples mode ‘ a。the e cty SphencalCosallsation h ©生Mechanism of wet granution ©生Drying of the wet granules 国生Drying of the wet granules ®Property of wet air 0 ·We bulb temperature漫球度 兰末母汽化 ·ldha ·Humidity混度 Meaniolieldinhn H-a62。 ,Relative humidity相对度 10
10 Shanghai Jiao Tong University Mixing Factors which affect the mixing • Properties of ingredients • Proportion of each ingredient • Density and particle size • Cohesive and charge • Liquid or hygroscopic material • Eutectic mixture • Apparatuses • Operations Shanghai Jiao Tong University Wet Granulation Widely employed method for the production of compressed tablets • Milling and mixing of drugs and excipients • Preparation of binder solution • Wet massing by addition of binder solution • Screening the wet mass into granules. • Drying of the wet granules • Screening of dry granules • Add disintegrants • Lubrication and blending. • Compression of tablet Shanghai Jiao Tong University 1. Milling and mixing of drugs and excipients • The active ingredient and excipients are milled and weighed, then mixed thoroughly. 2. Preparation of binder solution • The adhesives are solved in suitable solvent to make binder solution • If the drug substances is affected by water use a nonaqueous binder 3. Wet massing by addition of binder solution • A binder solution is added to the powder mixture • Overwetting causes granules that are too hard • Underwetting results in tablets that are too soft and friable Shanghai Jiao Tong University 4. Screening the wet mass into granules • Pass the wet mass through a sieve or screen, wet granules are obtained. 5. Drying of the wet granules • Temperature • Residual moisture content • Instruments 6. Screening of dry granules • After the granules are dried, pass through a screen of smaller size than the one used for the wet mass. This process is necessary to select granules of uniform size to allow even fill in the die cavity. Shanghai Jiao Tong University 7. Add disintegrants • Add (a part of) disintegrants into the dry granules. 8. Lubrication and blending • A dry lubricant, antiadherent and glidant are added to the granules. 9. Tableting • Content of the drug in the mixture is determined and tablet weight is calculated • Wtablet=labeled dose/Cgranule • The granule/lubricant mix is fed through a hopper in the die cavity and then compressed between a lower and an upper punch. Shanghai Jiao Tong University Instruments for granulation Extruder Roll granulator High-shear granulator Fluid Bed granulator Complex mode Spray-dryer Spherical Crystallization Shanghai Jiao Tong University Mechanism of wet granulation Interparticulate bonds • Attractive forces between solid particles • Interfacial forces and capillary pressure at freely movable liquid surfaces • Adhesion forces caused by the immobile liquid films • Solid bridges • Mechanical interlocking bonds Shanghai Jiao Tong University Drying of the wet granules Shanghai Jiao Tong University Drying of the wet granules Property of wet air • Dry bulb temperature干球温度 • Wet bulb temperature湿球温度 • Humidity湿度 • Relative humidity相对湿度 P p p H 0.622
