Preformulation - Bulk Powder Properties PDF

**Preformulation -- Bulk Powder Properties** flow uniformly -- obsessively important! **Powder Packing** sit together - Powders can take up a variety of packing states - Loosely packed powders -- contain a **maximum** of airspace between particles and **minimum** of contact points useful...

**Preformulation -- Bulk Powder Properties** flow uniformly -- obsessively important! **Powder Packing** sit together - Powders can take up a variety of packing states - Loosely packed powders -- contain a **maximum** of airspace between particles and **minimum** of contact points useful information -- don't want particles to be contacted too closely - Tightly packed powders -- **minimum** air entrapped & **maximum** interparticulate contact (large particles/small particles -- problem with particles stick together) - Powders expand and contract between these limits - Term 'porosity' how much air is present refers to relative amount of air entrapped between particles - Porosity depends on shape and size (small particles fill voids empty spaces between large particles) - Roughly 75% coarse and 25% fine gives densest packing arrangement - **Cubical packing** - Loosely packed - Porosity approx. 48% - **Rhombohedral packing** - Most densely packed - Porosity approx. 26% **Influence of shapes (cubes)**  **Coarse & fine particles** A diagram of blue circles with black dots Description automatically generated = decrease the porosity ! **Determination of Porosity** - Powder placed in measuring cylinder without any vibration or disturbance -- loosest packing state - This volume known as 'poured bulk volume' or 'maximum bulk volume' = [*V*~*b*~ (cm^3^cm^3^)]{.math.inline} - Assume particles have no internal pores or capillaries - Void volume = [*v*~*b*~ − *v*~*p*~]{.math.inline} where [*v*~*p*~]{.math.inline} is the particle volume [(cm^3^/*g*]{.math.inline}, assuming solid particle -- no pores/capillaries) - Porosity given by; 1. **True density** -- density of material 2. **Particle density** -- mass/volume of single particle - lower than the true density 3. **Bulk density** -- density of lots of particles together - Lower than the true? particle? density Particles are solid -- not accurate (cracks and pores in them) - Porosity often expressed as % - Since often don't know if particles have internal pores/capillaries, ε (porosity) better termed 'apparent porosity' -- True density is difficult to assess **Determination of tapped density** A measuring cylinder and clamp Description automatically generated **Bulk density**  Consolidation = Packed (can't get any closer) 1. Powders placed in cylinder on tapping volumeter 2. Tapped until volume constant 3. Rotating cam at base lifts cylinder then drops it down 4. During fall, particles will have all interparticulate forces removed and hence rearrange position - Final volume = 'minimum bulk volume' or 'tapped volume' = [*V*~*t*~]{.math.inline} - Reciprocal values will be 'maximum bulk density' or 'tapped density' = [*ρ*~*t*~]{.math.inline} - Use to measure dynamic powder packing i.e. monitor change of packing density with time (no. of taps) **Powder flow properties** - Packing and flow are closely related - Interparticulate forces (Van der Waals, electrostatics, etc) will give: - A larger difference between poured and tapped densities - Increase in number of taps required to give tightest packing state - **Carr's compressibility index** and **Hausner ratio** use powder packing data to estimate powder flow - [*ρ*~Bmax~]{.math.inline} *= tapped density* - [*ρ*~Bmin~]{.math.inline} *= bulk density* - ***Carr's compressibility index*** we use this !  *\* Fair-passable may be improved by glidant -- e.g. 0.2% Aerosil* - ***Hausner ratio*** less information A black text on a white background Description automatically generated - *Value less than 1.25 indicates **good** flow (= 20% Carr)* - *Value greater than 1.5 indicates **poor** flow (= 33% Carr)* - *Between 1.25-1.5, added **glidant** normally improves flow* - *\> 1.5 added glidant doesn't improve flow* - ***Examples***  *MCC; common excipient/CI; Carr's Index* *Table 1. Bulk powder characteristics (n=3). 100 g used for bulk measurements.* - ***Description of results in table 1*** - *Lactose -- good flow and others poor* give the pressure → flattened (not good)/mixing works better - *Corn starch has 35% drop in volume on tapping suggests cohesive powder (low aspect ratio)* - *Lactose has low volume drop and particles large enough not to be cohesive (i.e. too large for attractive focuses to be significant. Also lactose not hygroscopic -- moisture not influencing flow)* - *Microcrystalline cellulose has 33% volume drop, probably due to rod shaped particles (**AR \> 1.7*** problem alert!!*) -- gives characterised as 'bulky' (anything \< 0.4 g/ml)* - *This gives low tapped or maximum bulk density (0.42 g/ml), therefore may not be suitable for e.g. capsule filling* - **Angle of Repose** -- direct method for measuring flow - The angle of repose only applies to free-flowing materials - The maximum angle between the surface of a pile of powder and horizontal plane - Either fixed cone height or fixed base diameter - tan α = h/r where h = height of cone and r is radius of cone base - The rougher and more irregular the surface of the particles, the higher will be the angle of repose - Lower values indicating better flow characteristics a. Less than 20° -- excellent flow b. Between 20-30° -- good flow c. Between 30-40° -- pass flow d. Greater than 40° -- poor flow - **Hopper design** - **Flow from hopper** - Two main types of flow through orifice from hopper a. funnel flow b. mass flow - With **funnel flow**, some powder remains stationary - Rat holing occurs - Typical in hoppers with shallow angle of orifice - Stagnant (no flow) powder may cause segregation & powder remains in hopper (stability problems) - Less height required for hopper - Rat holing - Segregating solids - First in/last out - Time consolidation effects can be severe Not gonna uniformly flow - With **mass flow**, all powder in motion - No segregation - Powder leaves uniformly with constant density - Steep orifice angle - Better but more expensive & specifically manufactured for particular powder systems Make a hopper (done the experiments) to fit the powder inside -- gets expensive - **Arch formation and rat holing in hoppers**  Rat holing -- form a rat hole by the powder flow -- stop moving - **Inadequate emptying** - Usually occurs in funnel flow silos (tower) where the cone angle is insufficient to allow self-draining of the bulk solid A drawing of a beam Description automatically generated  - **Factors affecting flow rate through orifice relating to hopper** - Hopper design: a. **Hopper width** b. **Powder depth** c. **Hopper wall angle** d. **Orifice diameter** - **Critical orifice diameter** -- powder just flows without arching/rat holing. Depends on particle size and flow properties. - Flow rate depends on ratio between orifice diameter [*D*~*O*~]{.math.inline} and mean particle diameter [*D*~*p*~]{.math.inline} - When [*D*~*O*~/*D*~*p*~ \ - **Flow through circular orifice diameter,** [**D**~**0**~]{.math.inline} plot this graph in TBL ! A diagram of a flow chart Description automatically generated [*D*~*O*~/*D*~*p*~]{.math.inline} ⇒ particles are too big/small -- agglomerate tgt **Flow improvement** - **Particle properties** - Size, shape - Charge - Moisture (capillary bonding) - **Formulation** - Glidants smooth the surface? -- improve the flow of particles - **Equipment** - Hoppers - Aeration - Force feeders - Vacuum **Flow induced by aeration of powder in hopper**  air = pushing the particles apart, freely moving particles available **Flow induction by mechanical screw feeders** A drawing of a screwdriver and a screwdriver Description automatically generated **Flow induction by vacuum**  **Powder transport from hopper A to machine (vessel B)** **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**: Achieve a homogeneous distribution of the single components in the powder bulk - **Components of a powder mix**: a. Particles of different powders (drugs, excipients) b. Particle size fractions of the same powder -- get good flow - **Importance of powder mixing (examples)**: a. Granulation/tabletting/direct compression (granule -- next year !) b. Capsule/sachet filling c. Vial filling for injections **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 **Mixing terminology** - **Dry mixing** -- Mixing of powders without the addition of a liquid phase pick up moisture - **Wet mixing** -- Granulation i.e. powder mixed with a liquid binder - **Pre-mixing** -- Used for mixtures with less than 5% w/w drug. Mix them 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 mins) coat sits on the outside **Tumbler mixers** - For free-flowing powders tumble the powders around -- powders flow - Rotating vessels of various shapes e.g. Y-cone, cylinder gets into powder -- make powders tumble - Rotation causes particles to tumble over each other on mixture surface - Advantages: a. No particle attrition (damage -- rubbing off -- losing some powders/reduction in numbers/size) b. Useful for adding lubricants and glidants to granules - Disadvantage: a. Prone to particle **segregation**, but fitting of internal impellers/prongs reduces segregation **Cube, cone and V mixers** A blue arrow pointing to a hexagon Description automatically generated  A blue arrow pointing to a heart Description automatically generated **Turbula mixer** next year !  **\ Double cone mixer** A machine with a large cylinder Description automatically generated with medium confidence **Convective mixers** - Mixer vessel is fixed, not in rotation - Internal impeller moves around groups of particles from one location to another within the powder bulk - Advantage: a. Less fine particle segregation - Disadvantages: a. Dead spaces, where powder hardly moved or not moved at all b. Adhesion to blades and inside surface of vessel stick to the vessel -- no good c. Shear forces created at impeller surfaces can shatter powder particles = powder breakage d. Rarely used for dry powder mixing use for wet mixing ! **Planetary** **mixing**  **Nauta® mixer** A close-up of a machine Description automatically generated **Impaction & high shear mixers** - Increase in energy input into a mix need high energy to 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 A drawing of a mechanical device Description automatically generated with medium confidence  **impaction & high shear mixers** **Impaction mixer** spinning at really high speed -- break up agglomerates ㄴEx) Dry powders for the lung **Fluidised bed mixers** - Powder subjected to flowing gas stream - Weight of particles counter-balanced by their ability to float in an air stream (buoyancy) - Particle mobility is increased - Turbulence - Efficient and fast **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: a. Tumbling mixers 25-35% b. Convective mixers 50-80% c. Fluidised bed mixers 20-30% - Distribution of particles in all 3 dimensions of space beware particle attrition and overmixing! - Temperature change! **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** (industry obsessed with this topic !) charging: - all particles charged - Surfaces involved - Mixer speed - Relative humidity of environment **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: (**briefly** mentioned) 1. **Diffusion** -- random movement of [individual] particles in powder system, sometimes called 'micro-mixing' 2. **Convection** -- transfer of groups of particles, sometimes called 'macromixing' 3. **Shear** -- layers of particles move by **sliding**, so called 'slip planes' - 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. Nauta® mixer -- convective mixing (upward transport by screw), diffusive mixing -- particles percolate through mass - High shear mixers -- very cohesive, agglomerated powders **Interactive powder mixtures ('ordered mixtures')** -- briefly mentioned again!! - Cohesive, fine powders (\ - 'Ordered unit segregation' due to size differences of carrier - 'Displacement segregation' due to 3^rd^ component - 'Saturation segregation' due to finite number of sites for adhering coating particles. Often results in agglomerates existing alongside ordered units **Free-flowing mixtures ('random mixtures')** - No interparticulate forces - Individual particles are able to move around - Formation is governed by stochastic ('statistical') process - Complete random mixture achieved only if all components identical is size, shape, and density - Median size \ 20 μm - Used for direct compression **Perfect/random mixtures**  - Perfect = each particle lies adjacent to particle of other component - For 100 particles (50:50), chance of perfect mix = 1 in [10^30^]{.math.inline} - 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%) **Factors affecting segregation** - Particle size - Particle density - Particle shape - Electrostatic charging - Powder handling **\ ** **If segregation is a problem...** - Particle size too small -- stick all tgt/too long -- don't flow - Select similar sized drug & excipient (narrow size distribution) - Mill components -- give structural mix (may agglomerate & take longer to reach satisfactory mix) - Granulate (form granules -- expensive step to do !) the mix - Produce an ordered mix high-shear mix - Particle density & shape - Select excipients of similar density to drug → change in formulation - Control crystallisation process for shape - Electrostatic charging - difficult/tricky - Change surface contact materials smtg charged → not flow properly → find which surface is charged... - Powder handling - Use equipment so that several operations can be done without transfer, limit vibration of mix sampling -- next year ! **Effect of particle size on drug distribution during mixing** A diagram of different types of drugs Description automatically generated **Testing for drug content uniformity** next year bit ! - Random samples taking samples -- very hard - Analysis for drug content - Inspection of results - Standard deviation - Coefficient of variation - Compare with pharmacopeial tests - Effect of mixing variables