辅料功能性指标对制剂质量的影响_默克.ppt

The influence of functionality parameters on the quality of finished dosages Dr. Bhushan Thekedar Field Marketing Manager, Asia PCS Overview 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 Value 2B. Thekedar, June 2012 High Functional Excipients 3B. Thekedar, June 2012 Functional Particle Engineering Physical 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 substance Functional Particle Engineering Key Physical Characteristics of an Solid Formulation Excipient 5B. Thekedar, June 2012 Filler/matrix polymer Glidant Binder Disintegrant API Lubricant Functional Excipients of Tablets 6B. Thekedar, June 2012 GlidantMultifunctional DC- excipient API Lubricant Multifunctional DC-Excipients 7B. Thekedar, June 2012 Properties of an ideal DC-excipient . It should have a outstanding flowability It should have a particle size distribution appropriate for the active(s) in the formulation It should be not/little hygroscopic It should have a high compressibility It shold have a high drug loading capacity It should have an excellent pressure-hardness profile It should result in tablets with low friability It should form tablets with short disintegration time and fast drug dissolution It should result in tablets with excellent content uniformity It should be unsusceptible to lubricants It should be physiologically inert It should be compatible with all types of ingredients It should be stable to air, moisture and heat It must not show any physical or chemical change on aging It should be colourless and tasteless It should accept colourants uniformly It should be inexpensive It should pocess a proper mouthfeel It should not interfere with the biological availability of actives It should be reworkable without loss of flow and compressibility It should make the validation of the tabletting process easy 8B. Thekedar, June 2012 Excipients for Direct Compression 9B. Thekedar, June 2012 Tablet Manufacturing by Direct Compression Process Flow Chart DC-Excipients Tablets Mixing Direct Compression API (s) Mixture Mixing Lubricant 10B. Thekedar, June 2012 Wet granulation Potential reduction of 6 additional steps Total cost reduction up to 3 times Compression to tablets 1. Weighing of ingredients 2. Blending of ingredients 3. 4. 5. - 6. - 7. - 8. - TOTAL Direct Compression 0.4 1.00 /kg 0.2 1.50 /kg 0.5 0.75 /kg 1.0 2.00 /kg 0.3 0.70 /kg 1.5 3.00 /kg 0.3 0.70 /kg 0.3 0.70 /kg 4.7 10.35 /kg Process cost (/kg) 0.4 1.00 /kg 0.2 1.50 /kg - - - - - - 1.6 4.50 /kg Process cost (Estimative) 1. Weighing of ingredients 2. Blending of ingredients 3. Prep. granulation fluid 4. Granulation 5. Wet sieving 6. Drying process 7. Dry sieving process 8. Add. of external phase TOTAL Cost Break Down 11B. Thekedar, June 2012 Ideal RequirementsAdvantagesLimitations FlowabilityCost effective productionsSegregation CompressibilityBetter stability of APIVariation in functionality Dilution potentialFaster dissolutionLow dilution potential ReworkabilityLess wear 5 min. mixing Compression: single punch press (Korsch EK0 DMS, rpm:54, punch: 11mm, flat, facetted) Tablet weight: 500 mg (rel. S.D.:0.5) 18B. Thekedar, June 2012 50 100 150 200 250 51525 Compression force kN tablet hardness N Parteck M 200 Mannitol SD Gran. mannitol Method Formulation: 25 % Ascorbic acid, 74 % test material, 1% Mg stearate Tablet press: Kilian LX 28A, 30 rpm, Punch: 9/16 diameter concave bevel edge Tablet weight: 1000 mg, Mannitol SD is commercially available spray- dried mannitol Granular mannitol is commercially available pre- granulated mannitol Parteck M: High dilution potential 19B. Thekedar, June 2012 0 20 40 60 80 Parteck MDC-MannitolLactose/starch- granules Tablettose tablet 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 KN 20B. Thekedar, June 2012 0 10 20 30 Parteck MDC-Mannitol Lactose/starch- granules Tablettose Disintegration 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 2012 Parteck M: Excellent flowability MaterialAngle of reposeQuality Parteck M 20025.3Spray dried Competitor B GR30.0Granulated Competitor B GR28.4Granulated Competitor B GR30.7Granulated Competitor A SD27.0Spray dried 22B. Thekedar, June 2012 0 0,5 1 1,5 2 2,5 3 3,5 4 4,5 5 Parteck M 200Parteck M 300DC-Lactose (anhydrous) DC-SucroseDC-Dextrose Water content % 55% 68% 76% 86% rel. humidity x 1 x2x3 1= 7.2 2= 9.3 3= 12.5 Parteck 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/h Tablet 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) Disintegration325322 Scale up 24B. Thekedar, June 2012 Parteck M: Reducing sugars Commercial standard Ph. Eur. 0,20 % USP 0,30 % Parteck M Limit 2 m2/g) Reg. StatusFunctionQuantityExcipient The unique surface structure leads to exceptional compression behaviour and fast disintegration 49B. Thekedar, June 2012 Parteck ODT or mechanical mixture? Parteck ODT DC 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 ! 50B. Thekedar, June 2012 Parteck 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 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 Profile of Parteck ODT vs. Competitors + 1 % Mg-stearate Korsch EK 0 DMS, 500 mg tablets, diameter 11 mm, flat, facetted, tablet hardness by ERWEKA TBH 30 MD 51B. Thekedar, June 2012 Parteck ODT: Disintegration time Parteck ODT tablets disintegrate in less than 40 sec Increased physical stability of the tablets does 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 + 200 mg Ibuprofen + 1 % SiO2 + 1 % Mg-stearate Korsch EK 0 DMS, 500 mg tablets, diameter 11 mm, flat, facetted, USP disintegration in water at 37 C 52B. Thekedar, June 2012 Features 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) 53 53B. Thekedar, June 2012 B. Thekedar, June 201254 Lubricants with Added Value: Parteck Lubricants Parteck Lubricants Lubricants 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 04/0