2 Introduction Wet granulation is used to improve . . . Flow Topiramate TabletsIntroductionWet granulation is used to improve . . .FlowCompressibilityBio-availabilityHomogeneityElectrostatic propertiesStability07/24/2000
3 Factors in High shear wet granulation DensificationAgglomerationShearing and compressing action of the impellerMixing, granulation and wet massingPossibility of overgranulation due to excessive wettingPossibility of producing low porosity granulesLiquid bridgesCoalescenceBreakage of the bondsSpecific surface areaMoisture contentIntragranular porosityHeatingEvaporationMean granule size
4 Granule GrowthGranule formation and growth can be described by two mechanismsNucleation of particlesCoalescence between agglomerates
5 Coalescence Plastic deformation upon collision Surface water Absolute moisture content vs. Liquid saturationH (1 – ε) ρS =εH: Moisture content on dry basisε: Granular porosityρ : Particle density of the feed material
7 Effect of feed material on Granule growth in high shear mixer From: Hand book of Pharmaceutical granulation Page 162
8 Granule growth in high shear mixer This demonstrates the characteristic features of the agglomeration of insoluble, cohesive powders in high shear mixers. The growth rate is very sensitive to the amount of liquid phase and to processing conditions, in particular the impeller rotation speed and processing time.
9 Critical moisture content Granulation process development of a cohesive, fine, water insoluble materialDecreasing Intragranular porosityLiquid addition phase(3 minutes)Kneading phase(7 minutes)Granule growth by nucleationCoalescence/DensificationCritical moisture content
10 High shear Granulation Granulation properties are influenced by:Apparatus variablesProcess variablesProduct variables
11 Apparatus variablesShear forces in a high shear mixer are very dependent on the mixer constructionBowl designImpeller designChopper designWhile the fluidized state in a fluidized bed granulator is nearly independent of the construction of the apparatus, shear forces in a high shear mixer are very dependent on the mixer construction. Consequently, apparatus variables are more essential when using high shear mixers. Size and shape of the mixing chamber, impeller and chopper differ in different high shear mixers.A small change in shape, size or inclination of the blade tips have a significant effect on the impact of the mass.
12 Apparatus variablesRelative Swept volume: The volume swept out per second by the impellor divided by the volume of the mixer.The relative swept volume has considered to relate to the work input on the material which is assumed to provide densification of the wet mass.
13 Relative swept volumeFrom: Pharm. Ind. 48, 1083 (1986)The relative swept volume seems to be an appropriate parameter when comparing the effect of size and construction of the mixing tools.
14 Process Variables Impeller rotation speed Chopper rotation speed Load of the mixerLiquid addition methodLiquid flow rateWet massing time
15 Product variables Characteristics of the feed materials Particle size and size distributionSolubility in the liquid binderWettabilityPacking propertiesAmount of liquid binderCharacteristics of liquid binderSurface tensionViscosity
16 Granulation end point Target particle size mean What is the end point? When you stop your mixer!Target particle size meanTarget particle size distributionTarget granule viscosityTarget granule densityPrinciple of equifinalityDetermining the end point, and then reproducibility arriving at that same end point as equipment size and model changes are encountered, has been a continual challenge for the formulation scientist
18 Granulation end point determination Hand testQualitativeSubjectiveInconsistentEmerging methodsAcoustic Emission (Int. J. Pharm 205, – 71)Image processing (Powder Tech. 115, – 130)Off line methodsTorque Rheology (Mass consistency)Granulation particle sizeIn line instrumentationMain impeller motor amperageMain impeller motor powerMain impeller shaft torque
21 Forces in high shear Granulation Acceleration F1Frictional F2Centripetal F3Centrifugal F4
22 Forces in high shear Granulation From: Hand book of granulation technology page191The data on centrifugal acceleration reveal that one might expect higher compaction forces in smaller machines at the same level of tip speed.
23 relative swept volume blade tip speed Froude number Fr = n2 d / g scale-up approach 1 from Horsthius et al.(1993)relative swept volumeblade tip speedFroude numberFr = n2 d / gn - impeller speed [T-1]d - impeller diameter [L]g - gravitational constant [LT-2]They concluded that maintaining an equal Froude’s number at different scales resulted in comparable particle size distribution.
24 Use of Froude Numbers for mixers comparison Being dimensionless it is independent of machine sizeRatio of centrifugal force to gravitational forceCan be a criterion of dynamic similarity of mixersIn a recent publication by Michael Levin different mixers have been compared by the range of Froude number they can produce. “ A matching range of Froude numbers would indicate the possibility of scale-up even for the mixers that are not geometrically similar”.
30 All corresponding dimensions have same ratio Kinematic similarity scale-up approach 3, Using power number correlations Landin, M., P. York, M.J. Cliff(1996)Dependent of the concept of similarityGeometric similarityAll corresponding dimensions have same ratioKinematic similarityAll velocities at corresponding points have same ratioDynamic similarityAll forces at corresponding points have same ratio
31 Ne = P / ( n3 d5) Newton (power) Fr = n2 d / g Froude scale-up approach 3, Using power number correlationsDimensionless numbersNe = P / ( n3 d5) Newton (power)Fr = n2 d / g FroudeRe = d2 n / ReynoldsP - power consumption [ML2T-5] - specific density of particles [M L-5]n - impeller speed [T-1]d - impeller diameter [L]g - gravitational constant [LT-2] - dynamic viscosity [M L-1 T-1]Being dimensionless, the relationship becomes general for a series of geometrically similar high shear mixers regardless of their scale.
32 D = Diameter scale-up approach 3, Using power number correlations Power number relationshipNe = K(Re.Fr. h/D)n h = height of powder bedD = Diameter
33 Experimental procedure scale-up approach 3, Using power number correlationsExperimental procedureCharge powders and switch on mixerNote power readingAdd water at constant rateAt specific water contents note power reading and take sampleMeasure density of sampleMeasure viscosity of sampleCalculate Power, Reynolds and Froude numbersPlot Power number relationship
34 scale-up approach 3, Using power number correlations scale-up strategyPerform experiments on small scale to define master curve for the formulationIdentify viscosity and density of wet mass that produces optimum granulesUse these values plus machine variables to calculate power needed on desired large scale mixerRun large scale mixer at the defined settingCheck mass using the mixer torque rheometer
35 Conclusion/Recommendations Design a process friendly formulation.Make sure the process on the small scale is understood controlled.Attempt to develop formulation/process in the same mixer model as the production scale (Geometric similarity)Use the Froude number as an indication of the possibility of scale-up between two different mixer.Try to work with slow impeller speed during development work in the lab scale mixers to simulate production scale mixers.Use relative swept volume as a good indication of how much work will be done on the granulate.Establish an END POINT based on a reliable response factor and characterize the granulation and tablet properties at the same end point.Do an intentional overgranulation and undergrnulation and characterize granulation/tabletting properties.In most cases Granulation liquid can be scaled up linearly.Try to keep the mixer load ratio consistent in the small and large scale mixers.
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