Powder Mixing PHA114 2024 PDF

MPharm Programme Powder Mixing Dr Paul Carter Slide 1 of 38 Powder Mixing  Powder Mixing Definition: Two or more powder components are treated so that each particle of one component lies as...

MPharm Programme Powder Mixing Dr Paul Carter Slide 1 of 38 Powder Mixing  Powder Mixing Definition: Two or more powder components are treated so that each particle of one component lies as nearly as possible in contact to one particle of each additional component. Aim: to achieve a homogeneous distribution of the single components in the powder bulk components of a powder mix: particles of different powders (drugs, excipients), particle size fractions of the same powder Importance of powder mixing (examples): granulation/tabletting/direct compression capsule/sachet filling vial filling for injections Slide 2 of 38 MPH116 Powder Mixing  Mixing and solid dosage forms Drug and excipient(s) have different physicochemical properties mixing affects: homogeneity of drug distribution in dosage form mechanical properties (e.g. of the tablet) bioavailability of the drug Slide 2 of 38 Powder Mixing  Mixing terminology Dry mixing: mixing of powders without the addition of a liquid phase Wet mixing: granulation i.e. powder mixed with a liquid binder Pre-mixing: used for mixtures with less than 5 % w/w drug. Mix then further deagglomerated by e.g. sieving Post-mixing: addition of an external phase such as a lubricant or glidant. Relative short mixing times (3-5 min) Slide 4 of 38 Powder Mixing  Tumbler mixers For free flowing powders Rotating vessels of various shapes e.g. Y-cone, cylinder Rotation causes particles to tumble over each other on mixture surface disadvantage: prone to particle segregation, but fitting of internal impellers/prongs reduces segregation advantages: no particle attrition useful for adding lubricants and glidants to granules Slide 5 of 38 Powder Mixing  Cube, cone and v mixers Slide 6 of 38 Powder Mixing  Turbula mixer Slide 7 of 38 Powder Mixing  Double cone mixer Slide 8 of 38 Powder Mixing  Convective mixers Mixer vessel is fixed, not in rotation internal impeller moves groups of particles from one location to another within the powder bulk advantage: less fine particle segregation disadvantages: dead spaces, where powder hardly moved adhesion to blades and inside surface of vessel shear forces created at impeller surfaces can shatter powder particles rarely used for dry powder mixing Slide 9 of 38 Powder Mixing  Planetary mixing Slide 10 of 38 Powder Mixing  Nautamixer Slide 11 of 38 MPharm Powder Mixing  Impaction & high shear mixers increase in energy input into a mix impaction mixers have blades rotating at 2000-3000 rpm in static vessel blade may be introduced along axis of rotation of tumbling mixer high shear mixers subject powder to very high shear that will break most aggregates – usually after convective/tumbling mixing. Rotating impeller – centrifugal forces Slide 12 of 38 MPharm Powder Mixing  Impaction mixer Slide 13 of 38 MPharm Powder Mixing  Impaction & high shear mixers (Goris & van der Well, Chem. Eng, March 2003) Slide 14 of 38 MPharm Powder Mixing  Fluidised bed mixers powder subjected to flowing gas stream weight of particles counterbalanced by their ability to float in an air stream (buoyancy) particle mobility is increased turbulence efficient and fast Slide 15of 38 MPharm Powder Mixing  Choice of mixer: physical considerations particles are in motion: more space required, mixing vessel cannot to filled completely optimal loading ratio with respect to vessel volume: tumbling mixers 25-35% convective mixers 50-80% fluidised bed mixers 20-30% distribution of particles in all 3 dimensions of space beware particle attrition and overmixing! temperature change! Slide 16 of 38 MPharm Powder Mixing  Choice of mixer: economical and safety considerations Energy consumption Mixing time Continuous mixing or batch approach Time to fill, empty and clean Dust emission Explosion hazard due to electrostatic charging: Surfaces involved Mixer speed Relative humidity of environment Scottsbluff, NE 1996 - sugar refinery explosion Slide 17 of 38 MPharm Powder Mixing  Mixing mechanisms Expansion of powder bed to permit movement of particles Agitation for sufficient period for satisfactory mix and avoidance of segregation Maintenance of adequate mix during further handling and processing. Segregation to be avoided Large differences in particle size, shape and density could lead to segregation. When mixing, movement of particles by 3 mechanisms: Diffusion – random movement of individual particles in powder system, sometimes called ‘micromixing’ Convection – transfer of groups of particles, sometimes called ‘macromixing’ Shear – layers of particles move by sliding, so called ‘slip planes’ Slide 18 of 38 MPharm Powder Mixing  Mixing mechanisms Diffusion - random movement of individual particles Convection - movement of groups of particles Shear - movement of particles by slip planes Slide 19 of 38 MPharm Powder Mixing  Mixing mechanisms Predominant mechanism dependent on mixer design and an efficient mixer will incorporate all three mechanisms. Simple tumbling mixers – free flowing powders Low shear blade/paddle mixers – moderately cohesive powders e.g. Nautamixer – convective mixing (upward transport by screw, diffusive mixing – particles percolate through mass High shear mixers – very cohesive, agglomerated powders Slide 20 of 38 MPharm Powder Mixing  Interactive powder mixtures (‘ordered mixtures’) Cohesive, fine powders ( 20µm Used for direct compression Slide 29 of 38 MPharm Powder Mixing  Perfect/random mixtures Perfect/random mixtures Perfect mix Random mix Slide 30 of 38 MPharm Powder Mixing  Perfect/random mixtures Perfect = each particle lies adjacent to particle of other component For 100 particles (50:50), chance of perfect mix = 1 in 1030 Random = - random distribution - maximum disorder - unable to predict particle type from knowledge of neighbour - probability of finding a component is the same at all parts of the mix Chance of picking 2 blue particles = 1 in 4 (25 %) Chance of picking 2 white particles = 1 in 4 (25 %) Chance of picking one of each = 1 in 2 (50 %) Slide 31of 38 MPharm Powder Mixing  Factors affecting segregation Particle size Particle density Particle shape Electrostatic charging Powder handling Slide 32 of 38 MPharm Powder Mixing  if segregation a problem… Particle size select similar sized drug & excipient (narrow size distribution) mill components – give structural mix (may agglomerate & take longer to reach satisfactory mix) granulate the mix produce an ordered mix Particle density & shape select excipients of similar density to drug control crystallisation process for shape Electrostatic charging change surface contact materials Powder handling use equipment so that several operations can be done without transfer, limit vibration of mix Slide 33 of 38 MPharm Powder Mixing  Effect of particle size on drug distribution during mixing Large drug particles - Particle size reduction - poor distribution good drug distribution Particle agglomeration - poor distribution Slide 34 of 38 MPharm Powder Mixing  Testing for drug content uniformity Random samples Analysis for drug content Inspection of results  standard deviation  coefficient of variation Compare with pharmacopoeial tests Effect of mixing variables Slide 35 of 38 MPharm Powder Mixing