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The influence of functionality parameters on the quality of finished dosagesDr. Bhushan ThekedarField Marketing Manager, Asia PCSOverview High Functional Excipients Excipients for Direct Compression Mannitol for Direct Compression Excipient for Wet Granulation Directly Compressible Magnesium Excipient for Orally Disintegrating Tablets Lubricants with Added Value2B. Thekedar, June 2012High Functional Excipients3B. Thekedar, June 2012Functional Particle EngineeringPhysical characteristics in addition to chemistry determine the quality of your products.4B. Thekedar, June 2012 Flowability Particle size distribution for the active(s) in the formulation Hygroscopicity Compressibility Drug loading capacity Friability Stability Mouthfeel Content uniformity of finished dosage Disintegration time of final dosage Dissolution of drug substanceFunctional Particle EngineeringKey Physical Characteristics of an Solid Formulation Excipient 5B. Thekedar, June 2012Filler/matrix polymerGlidantBinderDisintegrantAPILubricantFunctional Excipients of Tablets6B. Thekedar, June 2012GlidantMultifunctional DC-excipientAPILubricantMultifunctional DC-Excipients7B. Thekedar, June 2012Properties of an ideal DC-excipient .It should have a outstanding flowabilityIt should have a particle 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 form 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 heatIt 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 and compressibilityIt should make the validation of the tabletting process easy8B. Thekedar, June 2012Excipients for Direct Compression9B. Thekedar, June 2012Tablet Manufacturing by Direct Compression Process Flow ChartDC-ExcipientsTabletsMixingDirect CompressionAPI (s)MixtureMixingLubricant10B. Thekedar, June 2012Wet granulationPotential reduction of 6 additional steps Total cost reduction up to 3 timesCompression to tablets 1. Weighing of ingredients2. Blending of ingredients3. 4. 5. -6. -7. -8. - TOTAL Direct Compression0.4 1.00 /kg0.2 1.50 /kg0.5 0.75 /kg1.0 2.00 /kg0.3 0.70 /kg1.5 3.00 /kg0.3 0.70 /kg0.3 0.70 /kg4.7 10.35 /kgProcess cost(/kg)0.4 1.00 /kg0.2 1.50 /kg - - - - 1.6 4.50 /kgProcess cost(Estimative)1. Weighing of ingredients2. Blending of ingredients3. Prep. granulation fluid4. Granulation5. Wet sieving6. Drying process7. Dry sieving process8. Add. of external phase TOTAL Cost Break Down11B. Thekedar, June 2012Ideal RequirementsAdvantagesLimitationsFlowabilityCost effective productionsSegregationCompressibilityBetter stability of APIVariation in functionalityDilution potentialFaster dissolutionLow dilution potentialReworkabilityLess wear & tear of punchesReworkabilityStabilitySimplified validationPoor compressibility of APIControlled particle sizeLower microbial contaminationLubricant sensitivityWhat are the best Excipients for DC ?12B. Thekedar, June 2012B. Thekedar, June 201213Mannitol for DC: Parteck MMannitol Positioning Less reactive than lactoses (no Maillard-reaction: threat to API) Less hygroscopic than lactoses and MCC Recommended for people with lactose intolerance Vegetarian: No BSE/TSE safety risk Derived from inexhaustible resources (sugar or starch) Sugar“-free so ideal for diabetic patients Parteck M : Mannitol for DC14B. Thekedar, June 2012Parteck M : A unique productUnique characteristics Directly compressible Mannitol Unique particle properties High compactibility at low compression forces Rapid disintegration and dissolution High dilution potential Excellent flow Exceptionally low specified level of reducing sugars Two grades available Guaranteed Merck KGaA quality15B. Thekedar, June 2012Granular Mannitol Spray dried Mannitol (Parteck M) Different Types of Mannitol16B. Thekedar, June 2012Polymorph and BET-surfaceProductPolymorphappr. BET (m/g)QualityParteck M 200beta3Spray driedParteck M 300beta3Spray driedPearlitol SD 100alpha0,6Spray driedPearlitol SD 200alpha0,5Spray driedPearlitol 300 DCbeta0,5GranulatedPearlitol 400 DCbeta0,4GranulatedPearlitol 500 DCbeta0,3GranulatedMannogem EZalpha0,5Spray driedMannogem Granularbeta0,3GranulatedMannogem 2080beta0,5GranulatedMannogem 3215beta0,4Granulated17B. Thekedar, June 2012Supplier ASupplier BParteck M: Compressibilitytablet hardnessN010020030040005101520253035compression force kNParteck M 200Mannitol SDGran. MannitolMethodFormulation: 99% test material + 1% magnesium stearate; 5 min. mixingCompression: single punch press (Korsch EK0 DMS, rpm:54, punch: 11mm, flat, facetted)Tablet weight: 500 mg (rel. S.D.:0.5)18B. Thekedar, June 20125010015020025051525Compression force kNtablet hardness NParteck M 200Mannitol SDGran. mannitolMethodFormulation: 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 SD is commercially available spray-dried mannitolGranular mannitol is commercially available pre-granulated mannitolParteck M: High dilution potential 19B. Thekedar, June 2012020406080Parteck MDC-MannitolLactose/starch-granulesTablettosetablet hardness (N)Parteck M: Fast Disintegration Formulation: 98,5% Mannit; 1,5% Mg-Stearat, Compr. Force 15 KN | 99% Lactose, 1% Mg-Stearat, Compr. Force 15 KN20B. Thekedar, June 20120102030Parteck MDC-Mannitol Lactose/starch-granulesTablettoseDisintegration time (min)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 21B. Thekedar, June 2012Parteck M: Excellent flowability MaterialAngle of reposeQualityParteck M 20025.3Spray driedCompetitor B GR30.0GranulatedCompetitor B GR28.4GranulatedCompetitor B GR30.7GranulatedCompetitor A SD27.0Spray dried22B. Thekedar, June 201200,511,522,533,544,55Parteck M 200Parteck M 300DC-Lactose(anhydrous)DC-SucroseDC-DextroseWater content %55%68%76%86%rel. humidityx1x2x31= 7.22= 9.33= 12.5Parteck M: No water-uptake 23B. Thekedar, June 2012 No significant 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 presses Content uniformity was in defined range (+/- 1,8 %)Parteck M: DC with low dose actives 40.000/h80.000/hTablet weight120.1 mg (rel.sd.: 0.6%)118.8 (rel.sd.: 0,9%)Hardness178 N (rel.sd. 4.1%)173 N (rel. sd: 4.1)Disintegration325322Scale up24B. Thekedar, June 2012Parteck M: Reducing 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 browning25B. Thekedar, June 2012Excipient for Wet Granulation:Parteck Delta M26B. Thekedar, June 2012Tablet Manufacturing by Wet GranulationProcess Flow ChartExcipientsMixingAPI (s)Addition of Binder SolutionWet GranulationDryingTabletsCompression27B. Thekedar, June 2012Tablet Manufacturing by Wet GranulationProcess Flow ChartExcipientsMixingAPI (s)Addition of Binder SolutionWet GranulationDryingTabletsCompressionWith Parteck Delta M you do not need additional binder!28B. Thekedar, June 2012Properties of Parteck Delta M Unique Mannitol crystals 90 % delta polymorphic Large surface after granulation Excellent binding properties Accelerated disintegration DMF available Merck KGaA quality29B. Thekedar, June 2012Parteck 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-polymorph 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 volume30B. Thekedar, June 2012Parteck Delta M : Unique Mannitol Crystals (continued) In customer specific formulations this conversion resulted in Enhancement of compression properties Shortening of disintegration time Shortening of in-vitro drug release Harder tablets are achieved by Decrease in elastic deformation Increase in particle binding sites31B. Thekedar, June 2012SEMs of beta-mannitolBefore wet granulationAfter wet granulation32B. Thekedar, June 2012SEMs of delta-mannitolBefore wet granulationAfter wet granulation33B. Thekedar, June 2012Parteck Delta M : Surface-area BET - Method34B. Thekedar, June 2012Parteck Delta M : Compression profileMannitol was granulated with 15% water and 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 mg35B. Thekedar, June 2012Parteck Delta M : Accelerated Disintegration36B. Thekedar, June 2012B. Thekedar, June 201237Directly Compressible Mg: Parteck Mg DCParteck 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 industry are fulfilled A high BET surface38B. Thekedar, June 2012Parteck 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 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 action39B. Thekedar, June 2012Parteck Mg DC: Solid Dose Applications Swallowed tablets ODT formulations Effervescent tablets Chewable tablets Combination with other ingredients like vitamins minerals micro minerals functional additives APIs40B. Thekedar, June 2012Parteck Mg DC: Unique, Functional ParticleSEM of Parteck Mg DC2500 xSEM of Parteck Mg DC25000 x41B. Thekedar, June 2012Parteck Mg DC: BET Surface Area 42B. Thekedar, June 2012Parteck Mg DC: Compression Profile (I)Parteck Mg DC is superior in hardness to all other pure DC Mg-Carbonates 43B. Thekedar, June 2012Korsch EK DMS Tabletting machine, Parteck Mg DC/ Competitors + 1% Mg Stearate, 500mg Tablets, diameter 11 mm, facetted, Hardness by ERWEKA TBH 30 MDParteck Mg DC: Compression Profile (II)Parteck Mg DC is as hard as the best starch containing DC Mg-Carbonates 44B. Thekedar, June 2012Korsch EK DMS Tabletting machine, Parteck Mg DC/ Competitors + 1% Mg Stearate, 500mg Tablets, diameter 11 mm, facetted, Hardness by ERWEKA TBH 30 MDParteck Mg DC: FriabilityParteck Mg DC leads to lower friability than all other pure DC Mg-Carbonates45B. Thekedar, June 2012Korsch EK DMS Tabletting machine, Parteck Mg DC tablets / Competitors + 1% Mg Stearate, 500mg Tablets, diameter 11 mm, facetted, Friability by ERWEKA TA 420Excipient for Orally Disintegrating Tablets: Parteck ODT46B. Thekedar, June 2012What is ODT?ODT = Orally Disintegrating TabletsDefinitions Definition by US Food and 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. 2 m2/g)Reg. StatusFunctionQuantityExcipientThe unique surface structure leads to exceptional compressionbehaviour and fast disintegration49B. Thekedar, June 2012Parteck ODT or mechanical mixture? Parteck ODTDC Mannitol A + 5% Na-CMCDC Mannitol B + 5% Na-CMCDC Mannitol C + 5% Na-CMCDC Mannitol D + 5% Na-CMCParteck ODT shows better compressibility & faster disintegration than mechanical mixtures with DC-Mannitols !50B. Thekedar, June 2012Parteck ODT: Direct Compression Profile Parteck ODT shows excellent tabletting behaviour Good tablet quality could be achieved by very low compression forces Friability of Parteck ODT tablets good flow99% 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 Profile 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 MD51B. Thekedar, June 2012Parteck ODT: Disintegration time Parteck ODT tablets disintegrate in less than 40 sec Increased physical stability of the tablets does not compromise disintegration time313 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 + 200 mg Ibuprofen + 1 % SiO2 + 1 % Mg-stearateKorsch EK 0 DMS, 500 mg tablets, diameter 11 mm, flat, facetted, USP disintegration in water at 37 C52B. Thekedar, June 2012Features of Parteck ODT Parteck ODT shows excellent tabletting behaviour Friability of Parteck ODT tablets 0,4 % Angle of repose: 33-38 (good flow) Parteck ODT tablets disintegrate in less than 40 sec Rapid disintegration Fast release Pleasant mouthfeel No royalties, fees or license payments required Applicable in Neutraceuticals as well Global regulatory acceptance ( USP, Ph. Eur, JP) 5353B. Thekedar, June 2012B. Thekedar, June 201254Lubricants with Added Value: Parteck LubricantsParteck LubricantsLubricants with added value Magnesium Stearate Calcium Stearate European Pharmacopeia Specific surface area: (2.9.26, Method I) Determine the specific surface area in the P/P0 range of 0.05 to 0.15 Sample outgasing: 2 h at 40 C Merck has adopted functionality test since 04/04 for MST and lately for CaSTFunctionality test recommended55B. Thekedar, June 2012Merck Lubricants Features Approved Functionality Specified particle size and surface area Vegetable origin Excellent batch to batch consistency Multi-compendial56B. Thekedar, June 2012SummaryOptimizing manufacturing processes Producing tablets by direct compression using directly compressible Excipients Using Excipients with multiple functionality: diluent, sweetener, disintegrants & binders Compressible polyols with good flowability can be used to increase production capacity of tablets Highly compressible polyols enable smaller tablet production Excipients 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”57B. Thekedar, June 2012
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