Pharmacy Milling and Mixing Processes
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Questions and Answers

What are three synonyms for the term 'milling' in the context of pharmaceutical manufacturing?

Grinding, comminution, and particle size reduction.

Besides improved dissolution rate, give one reason why particle size reduction may be necessary for topical preparations?

To improve the feel of the preparation when applied to the skin.

What is the typical range of aerodynamic particle diameter required for an aerosol intended for oral inhalation?

0.5 to 5 micrometers.

Explain how increasing the surface area of a poorly soluble drug affects its dissolution rate?

<p>Increasing the surface area generally increases the dissolution rate.</p> Signup and view all the answers

Why is particle size reduction important for topical preparations that are intended to be absorbed through the skin?

<p>To increase the contact area with the skin.</p> Signup and view all the answers

In the context of oral inhalation aerosols, what happens if the particle size is not between 0.5 and 5 micrometers, as mentioned in the text?

<p>The drug may not reach deep into the lungs.</p> Signup and view all the answers

Why is dissolution rate important in pharmaceutical manufacturing?

<p>It impacts how quickly the API becomes available for absorption by the body.</p> Signup and view all the answers

Name two unit processes discussed so far, from the Pharmaceutical Manufacturing train?

<p>Milling and mixing</p> Signup and view all the answers

What happens to stress energy in reversible deformation before the yield point?

<p>It manifests as heat.</p> Signup and view all the answers

Why should care be taken with the amount of grinding force applied to thermosensitive materials?

<p>The heat generated may be detrimental to the material.</p> Signup and view all the answers

What is one major difference in how ductile and brittle materials behave under stress?

<p>Ductile materials experience extensive plastic deformation before breaking, while brittle materials fracture quickly.</p> Signup and view all the answers

In a material with flaws, where does fracture or failure tend to start?

<p>Fracture or failure will be concentrated initially at any natural flaws or cracks present in the material.</p> Signup and view all the answers

What type of stress involves applying a force slowly towards the center of a particle, causing size reduction?

<p>Compressive stress</p> Signup and view all the answers

Why does fracture occur at flaw lines?

<p>Stress concentrates in the vicinity of the flaw, leading to fracture.</p> Signup and view all the answers

Is it common for crystalline materials to be perfectly formed, without any natural cracks or flaws?

<p>No, it's rare to have a whole batch of crystals perfectly formed without natural cracks or flaws.</p> Signup and view all the answers

How is impact stress different from compression stress in particle size reduction?

<p>Impact stress is applied instantaneously and perpendicular to the particle's surface whereas compression is applied slowly.</p> Signup and view all the answers

What kind of stress is associated with ripping a material apart by applying force away from the center?

<p>Tensile stress</p> Signup and view all the answers

How does the presence of more flaws affect size reduction?

<p>More flaws make size reduction easier, because fracture propagates along these flaws.</p> Signup and view all the answers

What is a key advantage of wet grinding compared to dry grinding regarding energy consumption?

<p>Wet grinding is typically a lower energy process than dry grinding.</p> Signup and view all the answers

Why does it become more difficult to achieve further size reduction as the grinding process progresses?

<p>The natural failure or flaw lines are consumed or used up.</p> Signup and view all the answers

In the context of grinding, how is shear stress applied to reduce particle size?

<p>Shear stress is applied in a direction parallel to the particle surface.</p> Signup and view all the answers

Besides lower energy requirements, what is another advantage of wet grinding?

<p>Easier material handling and elimination of dust hazards.</p> Signup and view all the answers

What is attrition, and how does it lead to particle size reduction?

<p>Attrition is a type of shear stress resulting from particle-particle contact which causes particle size reduction as particles shear against each other.</p> Signup and view all the answers

What is a potential disadvantage of wet grinding that may not exist in dry grinding?

<p>The need for a drying step after grinding.</p> Signup and view all the answers

What is a common characteristic about stress types in grinding processes?

<p>A mixture of different types of stress is often present., although one may be predominant</p> Signup and view all the answers

What is the primary difference between mixing and demixing?

<p>Mixing brings ingredients together, whereas demixing separates them.</p> Signup and view all the answers

When is very fine grinding expected in a grinding process with different types of stress?

<p>When there is a lot of attrition.</p> Signup and view all the answers

What is the term used to describe the operation where ingredients are treated such that each particle or molecule is adjacent to another of a different ingredient?

<p>Mixing or blending.</p> Signup and view all the answers

What are the two categories listed that comminution or grinding can be?

<p>Free or packed process.</p> Signup and view all the answers

Why might a lab-scale investigation with tools like mortars and pestles be important before large-scale size reduction?

<p>To understand how a material will behave on size reduction.</p> Signup and view all the answers

If a material is suspended in a liquid in which it won't dissolve, what is the resulting mixture called in wet grinding?

<p>A slurry or a concentrated suspension.</p> Signup and view all the answers

What wear and tear issue is mentioned as a disadvantage of wet grinding?

<p>More wear and tear on the equipment.</p> Signup and view all the answers

Why is it important to have a uniform mix in pharmaceutical products?

<p>To ensure uniform composition in the formulation, which will give uniform dosing.</p> Signup and view all the answers

Besides uniformity, what is another purpose of mixing?

<p>To promote physical or chemical reactions such as crystallization or dissolution.</p> Signup and view all the answers

What does 'point uniformity' mean in the context of solid mixing?

<p>Every particle is surrounded on all sides by a particle of the other component.</p> Signup and view all the answers

Why is a perfect mix with point uniformity virtually impossible to achieve in practice?

<p>Achieving perfect adjacency of all particles is extremely difficult.</p> Signup and view all the answers

What constitutes a 'random mix' in solid-solid mixing?

<p>The probability of finding a particle type at any point equals its proportion in the system.</p> Signup and view all the answers

In a 50/50 random mix, what is the expected ratio when sampling "largeish" sections?

<p>Approximately a 50/50 ratio.</p> Signup and view all the answers

If a mix has a 70% API and 30% excipient, what would be the expected ratio of particles when sampling in a random mix?

<p>Approximately a 70/30 ratio.</p> Signup and view all the answers

Is point uniformity or random mix more achievable in real-world pharmaceutical processing?

<p>Random mix.</p> Signup and view all the answers

What is the primary issue that powder segregation can cause in solid blending?

<p>It can change an already formed random mix into a non-random mix, or prevent a random mix from ever being achieved.</p> Signup and view all the answers

Name the three main mechanisms of mixing used in pharmaceutical mixers or blenders.

<p>Convective, diffusive, and shear mixing.</p> Signup and view all the answers

Describe the movement of particles during convective mixing.

<p>Groups of adjacent particles or molecules are transferred together.</p> Signup and view all the answers

What type of mixing is particularly essential for achieving a good random mix, especially at a small scale?

<p>Diffusive mixing.</p> Signup and view all the answers

How does shear mixing occur?

<p>Shear mixing occurs through the displacement of two regions relative to each other, causing a slip plane.</p> Signup and view all the answers

For solid materials that tend to aggregate, what additional process might be needed along with mixing?

<p>Grinding may be required simultaneously, in order to overcome aggregation.</p> Signup and view all the answers

What two characteristics describe a good mix?

<p>Random and homogenous.</p> Signup and view all the answers

What is the main reason additional force may be required for solid mixing processes?

<p>Solid materials tend to aggregate, and impact/attrition may be needed to facilitate the mixing process.</p> Signup and view all the answers

Flashcards

Milling

The process of reducing the size of particles in a solid material. It can also be called grinding, comminution, or particle size reduction.

Dissolution Rate

The rate at which a solid substance dissolves in a liquid.

Surface Area

The amount of surface area of a material exposed to its surroundings per unit of weight or volume.

Aerodynamic Particle Diameter

The size of a particle as measured in air, considering its shape and ability to move through the air.

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Topical Preparation

A type of medication that is applied to the skin.

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Aerosol for Oral Inhalation

A medication that is inhaled into the lungs.

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Poorly Soluble Drug

A drug that is not easily dissolved in liquids.

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API

The active ingredient in a medication.

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Impact stress

A force applied perpendicular to the surface of a particle, causing it to break apart. Think of hitting a rock with a hammer.

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Compressive stress

A force applied slowly in a direction towards the center of a particle, causing it to break apart. Think of crushing a can with your hand.

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Shear stress

A force applied in a direction parallel to the surface of a particle, causing it to break apart. Think of using a knife to cut through a piece of paper.

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Attrition

A type of shear stress where particles rub against each other, causing them to break apart. Think of sand being rubbed between your hands.

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Tensile stress

A force applied away from the center of a particle, trying to pull it apart. Think of pulling a piece of string until it breaks.

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Free crushing

A grinding process where particles are free to move and collide individually.

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Packed crushing

A grinding process where particles are packed together and crushed collectively.

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Wet Grinding

A process where a solid material is reduced in size by suspending it in a liquid.

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Slurry

A concentrated suspension of solid material in a liquid.

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Size Reduction

A process where solid particles are reduced in size by applying mechanical force.

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Ductile

A type of solid material that is easily deformed.

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Brittle

A type of solid material that is hard and easily breaks.

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Demixing

A process where a mixture separates into its individual components.

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Hardness

A measure of the resistance of a material to deformation.

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Stress energy and heat in reversible deformation

The energy applied during reversible deformation before a material reaches its yield point is released as heat. This is particularly relevant for materials that are sensitive to temperature changes, as excessive heat can damage them.

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Heat generation in grinding

In a grinding process, the force applied to break down a material often generates heat. This heat can be detrimental to thermo-sensitive materials, which are easily affected by temperature.

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Ductile vs. Brittle Materials

Materials can be broadly classified into two categories based on their behavior under stress: ductile and brittle. Ductile materials experience significant plastic deformation before fracturing, while brittle materials break with little to no deformation.

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Fracture initiation at flaws

In size reduction of materials, fractures often start at pre-existing flaws or cracks within the material. Stress concentrates around these flaws, making them the primary points of failure.

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Difficulty in size reduction

The initial size reduction is the easiest because the material breaks along existing flaws. As the grinding progresses, these flaws are consumed, making further size reduction more difficult.

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Imperfections in materials

Most materials contain imperfections such as natural cracks or flaws. These imperfections weaken the material, making it easier to break down during size reduction.

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Role of flaws in Size Reduction

The process of size reduction relies on these naturally present cracks or flaws. As grinding progresses, these flaws act as points of weakness, allowing the material to break into smaller particles.

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Fracture propagation in size reduction

Fracture propagation occurs along existing flaw lines, leading to the disintegration of a single particle into smaller ones. This process continues with the smaller particles until the desired size is achieved.

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Powder segregation

A process where particles of different sizes or densities separate within a mixture, resulting in an uneven distribution of components.

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Convective mixing

A type of mixing where groups of particles or molecules move together from one area to another.

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Diffusive mixing

A type of mixing where individual particles or molecules spread out and move independently throughout the mixture.

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Point Uniformity in Solid Mixing

A blend of components where each individual particle is surrounded by particles of the other component, leading to a uniform distribution.

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Shear mixing

A type of mixing where two regions of the mixture slide past each other, creating a shearing force that helps to mix the components.

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Random Mix in Solids

A blend of components where the probability of finding a specific particle at any point is equal to its proportion in the mixture.

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Grinding

A process of breaking down solid particles by applying a force to cause them to split or fragment.

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Uniform Composition in Pharmaceuticals

The consistency of the active pharmaceutical ingredient (API) and excipients throughout the formulation, ensuring uniform drug delivery.

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Excipients

Substances other than the active ingredient (API) used in a pharmaceutical formulation to help with processing, stability, or delivery.

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Mixing for Reactions

The process of combining ingredients to promote physical or chemical reactions, like crystallization or dissolution.

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Study Notes

Milling, Mixing

  • Milling, also known as grinding or comminution, reduces particle size
  • Reasons for particle size reduction include: topical preparations, aerosols, suspension formulations, drying processes, blending powders, and tinted preparations.
  • Particle size reduction is often required for drug dissolution rate enhancement
  • Particle size reduction impacts on the surface area that is in contact with the dissolution medium. Poorly soluble drugs benefit greatly from smaller particle size.
  • Particle size is critical for aerosol oral inhalations; particle diameter needs to be between 0.5 - 5 micrometers
  • There are different types of stress used in milling include: compression, tensile, and shear
  • Particle size reduction involves applying a force or stress to the material.
  • Stress applied to material results in strain, which is demonstrated by a stress-strain curve.
  • Elastic behavior: stress removal results in fully recoverable strain
  • Plastic deformation: beyond the elastic limit; stress removal results in non-recoverable strain. A point will be reached when fracture or failure of the material occurs.
  • Heat generation is a possible side effect of milling and is important in thermo-sensitive or thermo-labile materials
  • Materials in milling can be classified into ductile materials or brittle materials based on the amount of strain absorbed before breaking
  • Fracture or failure begins in the defects or cracks in the material
  • There are different types of grinding processes: free crushing and packed crushing
  • Free crushing is a continuous process for size reduction, while packed crushing involves continuous stress on the crushed particles.
  • Milling can be done wet or dry.

Reasons for Particle Size Reduction

  • Particle size reduction is often required for clinical or formulation performance reasons
  • Particle size reduction may be needed for materials with poor flow properties - and moisture content can influence this greatly
  • If using topical preparations the surface area of the material should be increased when in contact with the skin to increase the absorption of the material

Types of Stress

  • Compressive stress
  • Tensile stress
  • Shear stress
  • Attrition
  • Impact(a type of compressive stress)

Mechanisms of Particle Size Reduction

  • Elastic behavior
  • Plastic deformation
  • Fracture or failure
  • Heat

Classification of Mixing

  • Positive mixing: spontaneously and irreversibly mixes by diffusional processes; examples include miscible fluids
  • Negative mixing: systems undergo phase separation; requires continuous input of energy (agitation); examples include solid suspensions
  • Neutral mixing: neither positive or negative mixing; requires force to mix; examples include mixtures of solids

Reasons for Mixing

  • Produce uniform composition of mixed system for uniform dosing
  • Promote physical or chemical reactions (e.g., crystallisation, dissolution)

Solid-Solid Mixing

  • Point uniformity
  • Random mix

Scale of Scrutiny

  • Sampling is critical for determining the degree of mixing
  • Sample size depends on the scale of scrutiny
  • An appropriate scale of scrutiny determines the minimum sample size required for the mix to be considered sufficiently mixed

Degree of Mixing

  • Degree of mixing is measured by the statistical variation in composition within samples taken during the process
  • Variance plot measures variance in composition to monitor mixing over time.  Ideal mixing process will show minimal variance
  • Index of mixing measures ratio of mixing achieved to the maximum possible achieved, with an ideal value approaching 1

Powder Segregation

  • Powder segregation is a problem that can occur during mixing; it can lead to non-random mixes
  • Segregation starts before a random mix is achieved

Mechanisms of Mixing

  • Convective mixing
  • Diffusive mixing
  • Shear mixing

Properties of Materials that Affect Mixing

  • Particle size, density
  • Relative density, shape, stickiness
  • Viscosity, density, relative density, miscibility

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Milling, Mixing PDF

Description

This quiz reviews the essential concepts of milling and mixing in pharmacy, focusing on particle size reduction and its significance in drug formulation. Understand the forces involved in milling, the required particle sizes for various formulations, and the impact on drug dissolution and effectiveness.

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