3. Powder mixing

lejigolo's version from 2018-01-10 10:17

Section 1

Question Answer
what aspects of solid dosage forms does the quality of mixing influenceefficacy, properties (right site, right rate), appearance, cost
definition of powder mixingunit operatin aiming to treat two or more components so that each particle lies as nearly as possible in contact with a particle of each of the other components
what is a perfect mix?a mix of two or more components where each particle lies as nearly as possible in contact with a particle of each of the other components
when is getting close to an ideal mix important?small amount of potent drug
when is getting close to an ideal mix not important?mixing in lubricants
what is a positive mix?materials which mix spontaneously and irreversibly by diffusion e.g. gas/ miscible liquids. No energy required IF time is unlimited
what is a negative mix?components tend to separate unless energy is continuously input e.g. suspensions like calamine lotion. Or they tend to separate very slowly e.g. creams. Harder to form/ maintain and require higher mixing efficiency
what is a neutral mix?static in behaviour, no tendency to mix/de mix e.g. ointments
what is a random mix?a mix where the PROBABILITY of selecting a particular type of particle is the same at all positions, and is equal to the proportions of such particles in the mix
what is the scale of scrutiny?to determine whether a random mix has been achieved and each dosage unit contains the right amounts an amount equal to the dosage unit is sampled.
what determines the number of particles in the scale of scrutiny?sample weight, particle size, particle density
the greater the no. of particles and the greater the % of active the greater chance f obtaining the correct dose. Therefore what mixes are harder to mix?components with large drug particles, very low dose drugs

Section 2

Question Answer
how is composition variation minimised during formulation and processing?appropriate dosage unit size, particle size control, mixing procedures (mixer)
An idea of how well a powder blend is mixed can by found by...analysing several samples then calculation standard deviation, smaller the sd the better
what can be more useful than standard deviation?%coefficient of variance (%CoV) = [sd*100]/mean
what is assessment of homogeneity?assessment of a mixing process
how is homogeneity assessed?several samples taken at different time points, analysed and sd calculated
what is SDact?content standard deviation of samples from a partially mixed system
what is SDr?standard deviation of a random mix. As system is mixed SDact gets closer to SDr but might not be acheived
what is SDt/SDe?A theoretical acceptable standard deviation [%active in formulation x (acceptable variation/100)]
what is required to adequately analyse powder mixes?suitable analytical technique to determine drug content, samples must be taken from diff positions in mixer, sufficient samples must be taken

Section 3

Question Answer
what is convective mixing?transfer of rel. large groups of particles from one part (e.g powder bed) to another (moved by blade/paddle)
what is shear mixing?when a layer of material moves/flows over another e.g. when convective mixing creates an unstable shear/ slip plane and the powder collapses
what kind of mixes do convective/ shear mixing produce?move large groups of particles so create rough mixes but local groups of particles may remain unmixed
what is diffusive mixing?when particles tumble over one another (tumbling mixers) gravitational forces cause the material to fall and a velocity gradient causes the top layer to move fastest
how does mixing occur?differences in particle velocity (shear), falling through void spaces due to gravity as the mix dilates, size of voids increasing (tumbling)
What is the extent to which each each mixing type occurs dependant on?mixer type, process conditions (load, speed), material properties
In terms of mixing what happens if a material forms aggregates?form units and cannot be mixed on a particulate scale therefore a random mix cannot be acheived, mixer choice is v. important in this situation
In terms of mixing what happens if a powder segregates?may change from random to non random or may never become random. this equilibrium sets the quality limit

Section 4

Question Answer
How does very small particle size (dust) affect segregation?gets blown up and may form layer on top when mixer stops, can be minimised by reducing speed- elutriation segregation
How does small particle size affect segregation?smaller particles fall through voids between larger masses- percolation segregation. Increases as powder dilates, typical causes are vibration transport, tablet making
How does large particle size affect segregation?when powder bed is moved they have greater kinetic energy so move further before coming to rest (e.g. when poured into hopper)- trajectory segregation
How does particle density affect segregation?more dense tend to move downwards, trajectory segregation may also occur with particles of same size but diff. density
How does particle shape affect segregation?spherical more easily mixed but segregate more easily, needles may become interlocked decreasing tendency to segregate, they also have greater SA so more cohesive increasing dusting out.

Section 5

Question Answer
how does selecting particular size fractions affect segregation?removes dust/fines and lumps
how does milling of components affect segregation?if all <30┬Ám do not generally segregate
how does controlling crystallisation affect segregation?gives particular shape/size
how does selecting excipients of similar density to active affect segregation?reduces it
how does granulation affect segregation?so large numbers of particles are evenly distributed in each granule. however unless granules monosized smaller ones can fall to the bottom of the hopper, these will have a larger bulk density (less void) causing weight variation
how does reducing vibration/transport affect segregation?reduces it
how does powder hopper design affect segregation?use hoppers designed so sloping surfaces do not form and powder resistance time is minimised
how does using multiple operations affect segregation?use equiptment where several operations can be carried out without transferring the mix e.g. fluid bed drier, high speed mixer/granulator
how does the production of an ordered mix affect segregation?if one powder is sufficiently small it may be come adsorbed onto the 'active sites' of a larger 'carrier' therefore segregation of fines can be minimised
ordered mixing is important in what kind of formulations?direct compression, potent drugs, dry powder inhalation
how may segregation still occur in ordered mixes?carrier particle diff sizes (if diff. sized carriers separate causing ordered unit segregation), another component competes for sites on the carrier and displaces adsorbed material (displacement segregation, this may occur when magnesium stearate is added), insufficient carrier particles (saturation segregation)

Section 6

Question Answer
what are the 3 main types of powder mixers?tumbling, high speed, agitator. Tumbling mixers commonly used for mixing granules/powders with little tendency to segregate
what different designs of tumbling mixers are there?Y cone, double cone, twin shell, cube, drum
how do tumbling mixers work?container generally mounted so it can rotate about an axis, material tumbles causing diffusive and shear mixing, addition of 'prongs'/baffles causes convective mixing
advantage of tumbling mixers?good for free-flowing powders/granules
disadvantage of tumbling mixers?poor for cohesive material as encourages aggregates without sufficient shear to break them up
efficiency of tumbling mixers is dependent on?rotation speed, too slow shear and diffusive do not occur sufficiently, too fast centrifugal forces hold the powder towards to side of the mixer
what are tumbling mixers commonly used for? blending lubricants with granules, mixing direct compression formulations, producing ordered mixes (though v. slow), can also double up as a hopper removing a stage
how do high speed mixer/granulators work?impeller blade mounted at bottom of mixer rotates at high speed, chopper blades on side to help break up over-large granules
how does mixing occur in high speed mixer/granulators?v. quickly due to high shear and diffusive (large increase in void volume).
why are high speed mixer/granulators useful for cohesive materials?can quickly achieve a high degree of mixing, can break apart aggregates. However care in needed if the material fractures easily
what are high speed mixer/granulators often used for?if wanting to granulate as does both.
How do agitator mixers work?depend on movement of a blade/paddle through the mix e.g. ribbon mixer (like Archimedes screw)
how does mixing occur in agitator mixers?mainly convective and shear and may therefore be useful if you have a segregating mix/ poor flow
how useful?not extensively used for pharmaceutical powders since not very efficient

Section 7

Question Answer
what needs to be taken into consideration with volumes of non segregating mixes?enough so sufficient bed dilation can occur, overfilling may reduce mixing efficacy
what is the doubling up technique?the order of mixing
for segregting mixes how should a mixer be chosen?one that establishes an equilibrium between mixing and segregation which gives a mix of the right quality
mixers should be...easily cleanable, dust tight and allow complete discharge
process should be checked by...removing and analysing representative samples after different mixing intervals- determine optimum mixing time etc.
process should not...damage powders e.g. by attrition (break down)
why should build up of surface charges be minimised?results in clumping, causes material to adhere to machine