Mixing and size reduction Flashcards
What is a powder? What does particle reduction do?
Mix of dry particles disperesed in a matrix
- Powder can be free flowing (un-sticky) or cohesive (sticky forming aggeregates)
- Particle reduction increases the chance of cohesiveness
Explain when powder mixing and size reduction occurs and what it achieves
- Occurs during process of drug manufacturing and formulation
- Purposes of powder mixing and size reduction –> ensure optimum quality of final product
- Form a uniform composition so that when a sample is withdrawn from a bulk –> it represents overall composition of bulk
- Obtaining uniformity in final product is crucial for proper dosing
- Different powders can be mixed to form a random mixture, an ordered mixture or an interactive mixture
- Powder mixture may contain particles of same or different size, denisty and shape
What is random mixing?
Probability of selecting a particle of the mix is the same at all locations of the mix and is equal to the proportion of such particles in the mixture
- For example, a 50:50 powder mix should contain two adjacent particles with each half occupying the mix
What is required for random mixing to occur
At rest: particles are in spatial equilibrium
to enable mixing to occur
- The powder has bed to be expanded
- Sufficient shearing force needed to be applied to achieve relative moment of the particles in the powder bed
What are the types of mixing force (random mixing)?
- Pure tension: Separates particles but does not change their relative position
- Pure compression: compresses particles but does not change relative location
- Shear: causes relative particle movement
What is the process of powder mixing?
- Expansion of the powder bed
- Application of adequate shear forces
- Providing sufficient time for proper mixing
- Prevention of segregation (demixing)
What are some forces and factors that control the process of of powder mixing?
Forces
- Electrostatic
- Van der Waals forces
Factors
- Particle size
- Particle density
- Particle shape
What are the components of ordered powder system?
- Surface active force (e.g. Van der Waals) as well as adsorbed films used
- Particle size, density and shape
- Particle adhesion and compatibility
Describe pharmaceutical requirements for random mixing and the equation associated with it
Where samples are taken from a random mix of the same particle size, shape and density:
SD = [p (1-p)/n]½
p = proportion of active ingredient
n = number of particles in the sample
What is a common measure of the degree of mixing?
degree of mixing can be achieved by the following equation:
M = SR/SM
Where:
ØSR = standard deviation of a random mix
ØSM = standard deviation from samples
- As mixing continues, the value of M should approach 1
- More mixing is carried out = smaller the standard deviation becomes
Ordered powder mixing process –> discuss cohesiveness
- Cohesiveness may occur if different powder particles have different size, shape and density
- When powder mix has significant particle-particle interactions, cohesiveness is most likely to occur
- Increased SA = cohesiveness
- Segregation most likely will not occur when fine powders were adsorbed onto host crystals –> results in ordered powder mixtures
How does an ordered mix coarse?
- For an ordered mix to occur as coarse (usually excipient compount) –> it is coated with fine particles adsorbed to the surface
- Ordered mix gives higher degree of homogeneity than random mix
- Ordered powder mix can also be obtained if the active ingredient is dissolved in a solvent which then evaporates (heated) while mixing a coarse excipient
Requirements for formation of a perfect ordered system?
- Very fine mono-sized cohesive drug
- Coarse mono-size diluent (excipient)
- Mono-particular dispersion of the drug
- Saturation of surface sites on diluent by the drug
- Adequate mixing forces to achieve these requirements
- High adhesional stability
- Coarse component breaks up cohesive aggregates of fine powder form
- When sufficient mixing forces operate, mixing occurs rapidly (often less than 10 minutes)
- If higher homogeneity than a random mix –> often indicates some ordered mixing has occurred
- Larger sized components needs to be in large excess and only a limited number of sites are likely to adsorb the active principle.
- Hence only low amounts of drugs can be adsorbed.
What are some problems with the ordered powder mixing process
Segregation
- Occurs when the coarse phase has a variable size distribution
- Weight of drug adsorbed is directly related to the surface area
Mixing forces: must be sufficient to break up aggregates of the fine component but not to rupture the adhesive bond structure
>Saturation of adsorption sites leaving excess powder as small aggregates that segregate
What is preferntial adsorption?
Where an ordered mixture has been achieved and a second fine component is added: It may preferentially adsorb displacing the original particles
- A third component can strip the adsorbed component from the coarse material without itself being adsorbed
- Charging particles may improve the stability of an ordered mix
- Moisture content can also influence the stability of a mixture
Provide an example of a common problem with ordered powder mixture
- Salicylic acid (0.2%) produced an ordered mixture (when mixed with sucrose particles) so the additron of 4% magnesium stearate caused separation of the ordered mixture without itself being adsorbed
What are some things to consider when mixing powder?
- Powder movement should be 3D and random to avoid ‘dead’ regions
- Mixing process depends on the motion of a blade or paddle through the product
- Shear mixing involves slip planes in 3 dimensions where applicable
- Diffusive mixing involves particles rolling over each other down a powder slope with the greatest velocity being at the surface
- For a powder to be adequately mixed, a shearing force needs to be applied following by expansion to the powder bed for sufficient time
What are the types of mixers, their mechanisms, their uses and issues
What is size reduction
- Breaking large particles/units into samall ones, thus, reducing their size (also known as comminution)
- Achieved by either mechanical force (attrition, cutting, crushing, pealing) or other forces (thermal, pressure, chemical interactions)
- Common methods are compression, impact, attrition, cutting
What does a size crusher need to have?
- Wide crushing capacity
- Well-controlled power input per unit mass or particle
- Be efficient in terms of power/enery consumption
- Produce small variation in size of final product
What are some of the instruments and devices that can be used for size reduction?
- Crushers (primary and secondary)
- Grinders
- Cutters
Crushers (eg jaw crushers): Break large particles. Primary crushers reduce large particles into smaller size (around 200mm), while secondary crushers reduce particles together
Grinders (e.g. hammer mills): Reduce the size further into a few mm in diameter
Cutters (eg dicers and cutters): Produce particles with defined shape and size and with less size variation
What are the advantages and disadvantages of size reduction?
Advantages
- Increase SA (better dissolution)
- Improved extraction rate, drying, formation of final product and the manufacturing process
- Final product homogeneity and uniformity of dose
- Improve physical appearance
- Improve stability in some pharmaceutical products
Disadvatanges
- Changes in state of the particles or polymorphism
- Drug degradation or compromised stability
- Decrease in density which may compromise flow properties
- Change in particle charge
What is the energy needed to reduce the size of particles?
Kicks Law: energy required for crushing materials is proportional to the ratio of the size reduction
Rittingers Law: energy required for crushing materials is proportional to the surface area sheared
