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1、The influence of functionality parameters on the quality of finished dosagesDr.Bhushan ThekedarField Marketing Manager,Asia PCS,Overview,High Functional ExcipientsExcipients for Direct CompressionMannitol for Direct Compression Excipient for Wet GranulationDirectly Compressible MagnesiumExcipient fo
2、r Orally Disintegrating TabletsLubricants with Added Value,2,B.Thekedar,June 2012,High Functional Excipients,3,B.Thekedar,June 2012,Functional Particle Engineering,Physical characteristics in addition to chemistry determine the quality of your products.,4,B.Thekedar,June 2012,Functional Particle Eng
3、ineering,Key Physical Characteristics of an Solid Formulation Excipient,5,B.Thekedar,June 2012,Functional Excipients of Tablets,6,B.Thekedar,June 2012,Multifunctional DC-Excipients,7,B.Thekedar,June 2012,Properties of an ideal DC-excipient.,It should have a outstanding flowabilityIt should have a pa
4、rticle size distribution appropriate for the active(s)in the formulationIt should be not/little hygroscopicIt should have a high compressibilityIt shold have a high drug loading capacity It should have an excellent pressure-hardness profileIt should result in tablets with low friabilityIt should for
5、m tablets with short disintegration time and fast drug dissolutionIt should result in tablets with excellent content uniformityIt should be unsusceptible to lubricantsIt should be physiologically inert It should be compatible with all types of ingredientsIt should be stable to air,moisture and heatI
6、t must not show any physical or chemical change on agingIt should be colourless and tastelessIt should accept colourants uniformlyIt should be inexpensiveIt should pocess a proper mouthfeelIt should not interfere with the biological availability of activesIt should be reworkable without loss of flow
7、 and compressibilityIt should make the validation of the tabletting process easy,8,B.Thekedar,June 2012,Excipients for Direct Compression,9,B.Thekedar,June 2012,Tablet Manufacturing by Direct Compression Process Flow Chart,DC-Excipients,Tablets,Mixing,Direct Compression,API(s),Mixture,Mixing,Lubrica
8、nt,10,B.Thekedar,June 2012,Wet granulation,Potential reduction of 6 additional steps Total cost reduction up to 3 times,1.Weighing of ingredients2.Blending of ingredients3.4.5.-6.-7.-8.-TOTAL,Direct Compression,1.Weighing of ingredients2.Blending of ingredients3.Prep.granulation fluid4.Granulation5.
9、Wet sieving6.Drying process7.Dry sieving process8.Add.of external phase TOTAL,Cost Break Down,11,B.Thekedar,June 2012,What are the best Excipients for DC?,12,B.Thekedar,June 2012,B.Thekedar,June 2012,13,Mannitol for DC:Parteck M,Mannitol Positioning,Less reactive than lactoses(no Maillard-reaction:t
10、hreat to API)Less hygroscopic than lactoses and MCCRecommended for people with lactose intoleranceVegetarian:No BSE/TSE safety riskDerived from inexhaustible resources(sugar or starch)Sugar“-free so ideal for diabetic patients,Parteck M:Mannitol for DC,14,B.Thekedar,June 2012,Parteck M:A unique prod
11、uct,Unique characteristicsDirectly compressible MannitolUnique particle propertiesHigh compactibility at low compression forcesRapid disintegration and dissolutionHigh dilution potentialExcellent flowExceptionally low specified level of reducing sugarsTwo grades availableGuaranteed Merck KGaA qualit
12、y,15,B.Thekedar,June 2012,Granular Mannitol,Spray dried Mannitol(Parteck M),Different Types of Mannitol,16,B.Thekedar,June 2012,Polymorph and BET-surface,17,B.Thekedar,June 2012,Supplier A,Supplier B,Parteck M:Compressibility,MethodFormulation:99%test material+1%magnesium stearate;5 min.mixingCompre
13、ssion:single punch press(Korsch EK0 DMS,rpm:54,punch:11mm,flat,facetted)Tablet weight:500 mg(rel.S.D.:0.5),18,B.Thekedar,June 2012,MethodFormulation:25%Ascorbic acid,74%test material,1%Mg stearateTablet press:Kilian LX 28A,30 rpm,Punch:9/16 diameter concave bevel edgeTablet weight:1000 mg,Mannitol S
14、D is commercially available spray-dried mannitolGranular mannitol is commercially available pre-granulated mannitol,Parteck M:High dilution potential,19,B.Thekedar,June 2012,Parteck M:Fast Disintegration,Formulation:98,5%Mannit;1,5%Mg-Stearat,Compr.Force 15 KN|99%Lactose,1%Mg-Stearat,Compr.Force 15
15、KN,20,B.Thekedar,June 2012,Parteck M:Fast Disintegration,Formulation:98,5%Mannit;1,5%Mg-Stearat,Compr.Force 15 KN|99%Lactose,1%Mg-Stearat,Compr.Force 15 KN,21,B.Thekedar,June 2012,Parteck M:Excellent flowability,22,B.Thekedar,June 2012,Parteck M:No water-uptake,23,B.Thekedar,June 2012,No significant
16、 deviations in tablet weight and hardnesses were observed The good flow and compressibility of Parteck M is ideal for high-through put production on fast rotary pressesContent uniformity was in defined range(+/-1,8%),Parteck M:DC with low dose actives,Scale up,24,B.Thekedar,June 2012,Parteck M:Reduc
17、ing sugars,Commercial standardPh.Eur.0,20%USP 0,30%Parteck MLimit 0,05%(actual values 50%of limit)Additionally specified:total residual sugar 0,4%,Cause for instability and browning,25,B.Thekedar,June 2012,Excipient for Wet Granulation:Parteck Delta M,26,B.Thekedar,June 2012,Tablet Manufacturing by
18、Wet GranulationProcess Flow Chart,Excipients,Mixing,API(s),Addition of Binder Solution,Wet Granulation,Drying,Tablets,Compression,27,B.Thekedar,June 2012,Tablet Manufacturing by Wet GranulationProcess Flow Chart,Excipients,Mixing,API(s),Addition of Binder Solution,Wet Granulation,Drying,Tablets,Comp
19、ression,With Parteck Delta M you do not need additional binder!,28,B.Thekedar,June 2012,Properties of Parteck Delta M,Unique Mannitol crystals 90%delta polymorphic Large surface after granulation Excellent binding properties Accelerated disintegration DMF available Merck KGaA quality,29,B.Thekedar,J
20、une 2012,Parteck Delta M:Unique Mannitol Crystals,Several polymorphic forms of Mannitol have been classified(Walter-Levy 1968)Commercially available crystalline Mannitol is in beta form Beta crystals are the most stable form Parteck Delta M has delta()crystals During wet granulation the delta-polymo
21、rph transforms into beta These beta crystals are aggregates of fine crystalline primary particles with a large surface area This conversion is connected with a considerable increase in surface area and pore volume,30,B.Thekedar,June 2012,Parteck Delta M:Unique Mannitol Crystals(continued),In custome
22、r specific formulations this conversion resulted inEnhancement of compression propertiesShortening of disintegration timeShortening of in-vitro drug release Harder tablets are achieved by Decrease in elastic deformationIncrease in particle binding sites,31,B.Thekedar,June 2012,SEMs of beta-mannitol,
23、Before wet granulation,After wet granulation,32,B.Thekedar,June 2012,SEMs of delta-mannitol,Before wet granulation,After wet granulation,33,B.Thekedar,June 2012,Parteck Delta M:Surface-area BET-Method,34,B.Thekedar,June 2012,Parteck Delta M:Compression profile,Mannitol was granulated with 15%water a
24、nd dried in a fluidized bed.Granules larger than 1 mm were removed.Granules were mixed for 5 min with 1.5%MST and compressed on a single punch press at various compression forces(Korsch EKO DMS)Punch Tablet weight 11 mm,flat,facetted400 mg,35,B.Thekedar,June 2012,Parteck Delta M:Accelerated Disinteg
25、ration,36,B.Thekedar,June 2012,B.Thekedar,June 2012,37,Directly Compressible Mg:Parteck Mg DC,Parteck Mg DC,Direct Compressible Excipient Parteck Mg DC 100%Magnesium carbonate Without any additives Declaration of Pharmacopoeias PH EUR,BP,USP,E 504 available Purity requirements of the food and pharma
26、 industry are fulfilled A high BET surface,38,B.Thekedar,June 2012,Parteck Mg DC:Benefits for the Customer,Direct compressibility:facilitates formulation work and reduces production costs High compactibility even at low compression forces:reduces stress on tabletting presses and tooling No need for
27、extra binder:simplifies formulation work and the regulatory effort High mineral content:due to lack of binder allows for smaller tablet sizes and/or more additional formulation components No license agreement or payment required:saves time Fast disintegration time:leads to fast dissolution and fast
28、action,39,B.Thekedar,June 2012,Parteck Mg DC:Solid Dose Applications,Swallowed tablets ODT formulations Effervescent tablets Chewable tablets Combination with other ingredients likevitamins minerals micro minerals functional additives APIs,40,B.Thekedar,June 2012,Parteck Mg DC:Unique,Functional Part
29、icle,SEM of Parteck Mg DC2500 x,SEM of Parteck Mg DC25000 x,41,B.Thekedar,June 2012,Parteck Mg DC:BET Surface Area,42,B.Thekedar,June 2012,Parteck Mg DC:Compression Profile(I),43,B.Thekedar,June 2012,Korsch EK DMS Tabletting machine,Parteck Mg DC/Competitors+1%Mg Stearate,500mg Tablets,diameter 11 m
30、m,facetted,Hardness by ERWEKA TBH 30 MD,Parteck Mg DC:Compression Profile(II),44,B.Thekedar,June 2012,Korsch EK DMS Tabletting machine,Parteck Mg DC/Competitors+1%Mg Stearate,500mg Tablets,diameter 11 mm,facetted,Hardness by ERWEKA TBH 30 MD,Parteck Mg DC:Friability,45,B.Thekedar,June 2012,Korsch EK
31、 DMS Tabletting machine,Parteck Mg DC tablets/Competitors+1%Mg Stearate,500mg Tablets,diameter 11 mm,facetted,Friability by ERWEKA TA 420,Excipient for Orally Disintegrating Tablets:Parteck ODT,46,B.Thekedar,June 2012,What is ODT?,ODT=Orally Disintegrating TabletsDefinitionsDefinition by US Food and
32、 Drug Administration Center for Drug Evaluation and Research(CDER)A solid dosage form containing medicinal substances,which disintegrates rapidly(USP 30 s)Definition EPOrodisperse=a tablet that can be placed in the mouth where is dispersed rapidly before swallowing.(Ph.Eur.180 s),47,B.Thekedar,June
33、2012,Benefits of ODT Products,Patient valuesConvenience and ease of use makes ODTs beneficial for children,elderly and disabled peopleEffective in case of diseases that can restrict swallowing(Parkinson,AIDs and cancer)Convenient for travellers(no water necessary)Marketing valuesCost-effective devel
34、opment(direct compression)Creation of branded,differentiated line extensions(protection of market share)Using new(ODT)technology to extent patent life of an established drug,48,B.Thekedar,June 2012,Parteck ODTIntroduction composition,production,regulatory,EP,USP,JP,super-disintegrant,5%,Croscarmello
35、se sodium,EP,USP,JP,Filler,binder,slightly sweet taste,95%,Mannitol(spray dried,BET 2 m2/g),Reg.Status,Function,Quantity,Excipient,The unique surface structure leads to exceptional compressionbehaviour and fast disintegration,49,B.Thekedar,June 2012,Parteck ODT or mechanical mixture?,Parteck ODT,DC
36、Mannitol A+5%Na-CMC,DC Mannitol B+5%Na-CMC,DC Mannitol C+5%Na-CMC,DC Mannitol D+5%Na-CMC,Parteck ODT shows better compressibility&faster disintegration than mechanical mixtures with DC-Mannitols!,50,B.Thekedar,June 2012,Parteck ODT:Direct Compression Profile,Parteck ODT shows excellent tabletting be
37、haviourGood tablet quality could be achieved by very low compression forcesFriability of Parteck ODT tablets good flow,99%test material and 1%magnesium stearate,mixed and compressed on 500 mg tablets,diameter 11 mm,facetted,single punch EK 0 DMS Hardness by ERWEKA TBH 30 MD,Placebo Compression Profi
38、le of Parteck ODT vs.Competitors+1%Mg-stearateKorsch EK 0 DMS,500 mg tablets,diameter 11 mm,flat,facetted,tablet hardness by ERWEKA TBH 30 MD,51,B.Thekedar,June 2012,Parteck ODT:Disintegration time,Parteck ODT tablets disintegrate in less than 40 sec Increased physical stability of the tablets does
39、not compromise disintegration time,313 mg Parteck ODT with 80 mg ascorbic acid,1%magnesium stearate,0.5%orange flavor,0.2%sucralose on 400 mg tablets,diameter 11 mm,facetted,single punch EK 0 DMS Hardness by ERWEKA TBH 30 MD,Disintegration Profile of API Formulation with Parteck ODT vs.Competitors+2
40、00 mg Ibuprofen+1%SiO2+1%Mg-stearateKorsch EK 0 DMS,500 mg tablets,diameter 11 mm,flat,facetted,USP disintegration in water at 37 C,52,B.Thekedar,June 2012,Features of Parteck ODT,Parteck ODT shows excellent tabletting behaviourFriability of Parteck ODT tablets 0,4%Angle of repose:33-38(good flow)Pa
41、rteck ODT tablets disintegrate in less than 40 sec Rapid disintegrationFast releasePleasant mouthfeel No royalties,fees or license payments requiredApplicable in Neutraceuticals as wellGlobal regulatory acceptance(USP,Ph.Eur,JP),53,53,B.Thekedar,June 2012,B.Thekedar,June 2012,54,Lubricants with Adde
42、d Value:Parteck Lubricants,Parteck LubricantsLubricants with added value,Magnesium StearateCalcium Stearate,European PharmacopeiaSpecific surface area:(2.9.26,Method I)Determine the specific surface area in the P/P0 range of 0.05 to 0.15Sample outgasing:2 h at 40 CMerck has adopted functionality tes
43、t since 04/04 for MST and lately for CaST,Functionality test recommended,55,B.Thekedar,June 2012,Merck Lubricants Features,Approved FunctionalitySpecified particle size and surface areaVegetable originExcellent batch to batch consistencyMulti-compendial,56,B.Thekedar,June 2012,Summary,Optimizing man
44、ufacturing processesProducing tablets by direct compression using directly compressible ExcipientsUsing Excipients with multiple functionality:diluent,sweetener,disintegrants&bindersCompressible polyols with good flowability can be used to increase production capacity of tabletsHighly compressible polyols enable smaller tablet productionExcipients can improve safety of a drug(Emprove concept)Stability and storage of a medicine can be improved by using the right Excipient Excipients can enhance drug availability and effectiveness key word“bioavailability”,57,B.Thekedar,June 2012,
