Tendency of blends for segregation How to study it? Methods for measuring the segregation potential Louk Peffer 1
Outline/Themes Blends unmix Theory or reality Visual inspection Segregation mechanisms Validation blend quality Sampling equipment Representative sampling Investigation techniques / quantifying segregation Reducing segregation 2
Mixing Unit operations Conveying / transport Storage (charge / discharge) Filling / tableting Blend homogeneity? Validity Segregation tendency? Investigation of representative lots 3
50%/50% 50% Theoretically Gaussian distribution Error still 1 pellet 4
Reality? 3D simulation discrete elements (DEM) 50.000 grains Even if particles are originally mixed, they will tend to unmix (segregate) on handling e.g. transport, pouring, conveying, processing. De-mixing or segregation is mainly caused by differences in size and shape of constituent particles but also density. Particle size and (bio) chemical composition of the product may be off specification e.g. blends of pharmaceuticals, food, feed, chemicals. 5
Visual Inspection Segregation visible? Steak seasoning Medicine Animal Nutrition 6
Washing Powder 7
15 Vitamins B 6 preparations API (standard requirement <6%) mg mg analyzed Difference [%] 8 of 15 Difference > 10% 2.8 0.0 100 1.4 1.1 21 20 13 35 25 31 24 25 32 28 10 85 750 80 91 14 80 112 40 8
Mechanism of Segregation Rhodes, Johanson, Schulze Sifting Angle of Repose Air Entrainment Impact Fluidization Brazil nut effect Fine particles sift down through a matrix or grid of coarse particles Piles formed during charge or discharge concentrate large particles at the slope of the pile Entrained air with a falling stream of particles dislodges fine particles A (semi)-fluidized state coarse and heavy particles penetrate in fluffy powder Very large particles rise by shocks 9
Justification of Blend Sample Sizes and Acceptance Criteria Number of Sampling Locations At least 10 locations should be used for tumbling mixers to adequately map blender At least 20 locations should be used for convection mixers, which are more likely to have dead spots Replicates Per Location At least 3 samples/location required to perform component variance analysis to detect the presence of sampling error tumbling convection 10
Blend: 10 locations 3 samples per location Assay 1 sample per location Blend Validation Fail Assay 2nd and 3rd blend samples from each location Acceptance Criteria: RSD 5.0% All individuals within +/- 10% of mean Pass Proceed to Stage 1 Dosage Unit Testing Mixing problem identified Yes No Blend is not uniform. Go back to development Investigation points to sampling bias or some other attributable cause Proceed to Stage 2 Dosage Unit Testing 11
Sampling probes sample thiefs bulk interior Pos: easy Neg: operator bias perturbs bulk appropriate for granular, dry, flowable solids End & side samplers 12
Sampling probes during discharge Small hopper angles > mass flow sampling 13
Off-line sample preparation Cube Mixer Mixing constituents Representative sampling Rotary riffling 14
Representative lots Rotary Riffler 2-1600 L Max. 2-5 L Micro 15
Representativeness sampling methods Allen 1981 16
Differential volume / % Fluidization Segregation Simulates the top-to-bottom segregation effects of gas flow through a bulk material Mechanism - upon filling a bin, - rapid blending, - pneumatic conveying Fresh sample Top fraction - density 1.5429 g/cm3 Bottom fraction - density 1.5849 g/cm3 Segregation factor 1.97 Allows comparison of one material to another 0.1 1 10 100 1000 Particle diameter / micrometer 17
Differential volume / % Fluidization Segregation Fresh sample Top fraction - density 1.5429 g/cm3 Bottom fraction - density 1.5849 g/cm3 Segregation factor 1.97 True density Top 1.5429 g/cm 3 Bottom 1.5849 g/cm 3 Segregation factor 1.97 0.1 1 10 100 1000 Particle diameter / micrometer 18
Sifting Segregation Simulates the core flow hopper effect during discharge [μm] First sample Last sample D 10 302 446 D 50 821 972 D 90 1481 1568 Mode 1007 1118 Binary mixture Mass flow hopper Core flow hopper Segregation diminish 20 Fractions 19
Segregation coefficient (k 0 ) Active ingredient(s), ratio between fractions Fraction 1 Fraction 2 Fraction n k 0 = C f1 n C 0 C 0 = target concentration C f = concentration fractions 1 K 0 1 20
Vibration chute Accelerated testing of powder blends for component segregation. Suitable: - Pharmaceuticals, - Food, - Cosmetics, - Chemical formulations. 21 dosing 10 g helical form ramp output chute e.g. 10 units 1 g base agitator angle 7.5 column V shape channel control adjustable amplitude and frequency
Determination of degree of segregation Collected unit doses Particle size distribution (Bio)Chemical assay Pharmaceuticals e.g. API (standard requirement <6%) Food e.g. composition Feed e.g. minerals, vitamins, nutrients True density Visual inspection e.g. color Taste e.g. powder drink mixes 22
Hosokawa Mixing Sensor On-line insight in powder mixing Light - Transmission - Absorption - Reflection 23
Light Reflection Determined refractive index absorption index - Particle size - Colour - Roughness, porosity 24
Hosokawa Mixing Sensor Applications Determination of end of mixing Analysis of residence time Blend ready in x minutes Quality control Detection of segregation Detection of malfunctioning of mixer, Even when there are no visual changes during mixing Inline monitoring 25
Sifting segregation, Angle of Repose, Reflectance spectroscopy Material Flow Solutions Visible NIR 26
Process Validation During compression/filling, sample from at least 20 locations, taking at least 7 dosage units per location Assay at least 3 dosage units per location Acceptance Criteria: RSD of all individuals 6.0% Each location mean within 90-110% target potency All individual within 75-125% target potency Fail Assay at least 4 additional dosage units per location Pass Process Validated Acceptance Criteria: RSD of all individuals 6.0% Each location mean within 90-110% target potency All individual within 75-125% target potency Pass Fail Blend is not uniform or post-blending practices cause segregation 27
Investigation Segregation Off-line study In-line study Minimum amount of blend 10 g, 80 ml, 1L Formulation Quality control Homogeneous Blend! Run the complete process Loss of product Assay of the final product Sampling at different unit operations Formulation 28
Reduction of Segregation As similar as possible the size distribution of constituents Reducing the span (broadness) of the particle size distribution Reduction of particle size to < 30 μm (interparticle forces) Van der Waals, electrostatic, humidity Addition of small quantities of liquid binder (reduced mobility) Water Maltodextrine in water Vegetable oil Modifying unit operation Measures may lead to flow problems! 29
30 Thank you for your attention!