Pharmaceutical Mixing Processes

Mixing

• Mixing is the most widely used unit operation in pharmaceutical manufacturing.
• Mixing is defined as an operation in which two or more components in separate or roughly mixed condition are treated so each particle lies as nearly as possible in contact with a particle of each of the other ingredients.

Objectives of Mixing

• Simple Physical Mixture: Production of a blend of two or more miscible liquids or uniformly divided solids. Low efficiency of mixing is sufficient.
• Physical Change: Example: Solution of a soluble substance. Low efficiency of mixing is often enough.
• Dispersion: Includes the dispersion of two immiscible liquids to form an emulsion or the dispersion of a solid in a liquid to give a suspension or paste. Good mixing is crucial for stability.
• Promotion of Reaction: Mixing encourages chemical reactions, ensuring uniform products.

Types of Mixtures

• Positive Mixtures: Formed from materials like gases or miscible liquids. Irreversible mixing occurs by diffusion, without significant energy. These mixtures present no mixing problems.
• Negative Mixtures: Examples are suspensions of solids in liquids requiring work during formation; compounds tend to separate unless continuously mixed. Higher mixing efficiency is required for these mixtures.
• Neutral Mixtures: Components have no tendency to spontaneously mix. Many pharmaceutical products, like pastes, ointments, and mixed powders, fall into this category.

Mixing Process

• Perfect Mix: Ideal state where each particle is adjacent to a particle of the other component. This is practically impossible.
• Random Mix: The probability of selecting a particular particle type is the same at all positions in the mix.
• Scale of Scrutiny (SOS): The weight/volume of the dosage unit; dictates how closely the dosage unit must be analyzed to insure correct dose/concentration.
• SOS Example: 200mg tablet=200mg sample to see if the mixing is adequate.
• The number of particles in the scale of scrutiny depends on sample weight, particle size, and particle density.

Problem: Low Strength Potent Drugs

• Low proportion of active component in a mixture makes it difficult to achieve an acceptably low deviation in active content.
• More particles in a dose / scale of scrutiny result in lower deviation in content.
• Increasing the number of particles can be addressed by decreasing particle size (milling).

Mathematical Treatment of the Mixing Process

• Aim is to minimize variation in mixing to acceptable levels using appropriate SOS, particle size, and mixing procedure.
• Standard Deviation (SD): Formula: √p(1-p)/n where p = proportion of the component in the total mix, n = total number of particles in the sample. As 'n' increases SD decreases, and conversely, as 'p' decreases. 
• Percentage Coefficient of Variation (CV): A more useful parameter, represents deviation as a percentage of mean amount of active component in the sample. Formula; [Content SD / mean content (p)] x100

Evaluation of Degree of Mixing

• Indicates degree/extent of mixing.
• Follows mixing processes.
• Indicates when sufficient mixing has occurred.
• Assesses mixing efficiency of mixers.
• Determines mixing time required for a particular process.

Mixing Index

• Mixing Index (M) is calculated by dividing the standard deviation (SD) of samples from the mix under investigation (Sact) by the standard deviation (SD) of samples from a fully random mix (SR).
• M = SR/Sact.  At the beginning, Sact will be high and M will be low, but as mixing occurs Sact will decrease and M will approach 1 (indicating a completely random mix).

Requirements for Evaluating a Mixing Process

• Sufficient number of representative samples (at least 10) taken from different depths of the mix.
• Suitable and valid analytical techniques.

Mechanisms of Mixing and Demixing

• Powders:

  • Convective mixing: Occurs via transfer of larger groups of particles from one part of a powder bed to another—contributing significantly to microscopic mixing but usually quickly.
  • Shear mixing: Occurs when one layer of a substance moves over another. This may happen due to removal of a mass in convective mixing which can result in the unstable shear/slip plane and the powder bed collapsing or high shear mixers where action of mixer induces velocity gradients.
  • Diffusion mixing: A true random mix where indivisible particles move close together. This occurs because when forced to move, the powder expands (increasing volume), becomes loosely packed, and creates air spaces or voids. Particles then fall under gravity via these void spaces.

  Low rate of mixing is a disadvantage. Multiple mechanisms may occur in a mixing process depending on mixer type, mixing conditions, and powder flowability.

• Liquids:

  • Bulk transport: Analogous to convective mixing; involves the movement of large amounts of material; tends to create a large degree of mixing quickly.
  • Turbulent mixing: Arises from haphazard movement of molecules when forced to move; causes small parts of molecules to remain unmixed within the resultant eddies near container surfaces. 

• Molecular Diffusion: Occurs in miscible fluids when a concentration gradient is present.  May take a great amount of time. All three mechanisms often happen at once in most mixers

Powder Segregation (Demixing)

• Opposite of Mixing
• Components tend to separate.
• Non-random mix may cause variations in content uniformity in tablets and weight/dose variations in capsules.
• Particle size, shape, and density may affect the occurrence of demixing.
• Particle size may cause segregation of particles due to difference in size: Smaller particles fall through the voids of larger ones creating a layer at the bottom of the mass. Segregation may also occur in static powder beds, but to a higher degree when the bed is disturbed e.g. in cereal.

Particle Size (Causes of Segregation)

• Percolation segregation: Smaller particles fall through the voids of larger ones. May occur in static or disturbed powder beds.
• Trajectory segregation: Larger particles have greater kinetic energy due to their masses causing them to travel farther distances compared to smaller particles. This difference in particle distances causes different sized particles to separate.
• Elutriation segregation: Dust (very fine particles) may be blown upward by air and settle at the top.

Particle Density (Causes of Segregation)

• More dense materials tend to move downwards, even with smaller sizes.

Particle Shape (Causes of Segregation)

• Spherical particles are more freely mixed but may also segregate easily. Irregular or needle shaped particles tend to get interlocked, thus decreasing segregation. Non-spherical particles also have a greater surface area or contact surface area (SA) and tend to decrease segregation by increasing cohesive forces.
  • Non-segregating mixes will become uniformly mixed over time with increased mixing time.

Approaches to Correct Segregation

• Selection of a particular particle size range
• Milling of components
• Controlled crystallization during the production of drugs/excipients for particular shape or size ranges.
• Selecting excipients with similar density to the active pharmaceutical ingredient (API).
• Granulation.
• Reduce extent of vibration/movement after mixing.
• Use filling machine hoppers to decrease time of residence
• Using equipment where several operations can occur without transferring the mix. (e.g. high-speed mixer granulator).
• Production of an ordered mix—in this case, smaller particles are adsorbed to the active sites on larger carrier particles, and the process minimizes segregation and maintains good flow properties.

Powder Mixing Equipment (Tumbling/Blenders)

• Used to mix granules and free-flowing powders.
• Rotating containers.
• Intermediate bulk containers (IBCs) can be used.

Different Types of Powder Mixers

• Tumbling Mixers/Blenders:
  • Used for mixing granules and free-flowing powders
• High-Speed Mixer-Granulator:
  • Can mix and granulate simultaneously; reduces segregation.
• Fluidized Bed Mixer:
  • Mainly used for drying, coating, or mixing powders before granulation in the same vessel.
• Agitator Mixer: (Planetary, Ribbon, Nautamixer etc.) Convective mixing (motion of a blade or paddle through the product), centrifugal force, and shearing actions happen
• Proppeller mixer: used for liquids.
• Turbine mixer: used for more viscous fluids (e.g. o/w or w/o emulsions).
• Sigma-blade mixer: robust, handles stiff pastes and ointments.

Mixing of Semisolid

• Semisolid mixtures are difficult to mix because they do not flow readily. 
• Suitable mixers need rotating elements and narrow clearances with the vessel walls to produce sufficient shearing force for thorough mixing.

Explore the essential concepts of mixing in pharmaceutical manufacturing. This quiz covers the objectives of mixing, types of mixtures, and their significance in producing uniform and stable products. Test your understanding of mixing operations and their applications.