Unit Processes - Science of Medicines 2 PDF

Unit Processes Science of Medicines 2 Dr Abdullah Mrad Lecturer in Pharmaceuticals [email protected] 1 Unit Processes The production of pharmaceutical dosage forms involves many processes. Some of the processes which are required for the production of...

Unit Processes Science of Medicines 2 Dr Abdullah Mrad Lecturer in Pharmaceuticals [email protected] 1 Unit Processes The production of pharmaceutical dosage forms involves many processes. Some of the processes which are required for the production of solid dosage forms: Particle size reduction and size separation Mixing Granulation Drying 2 Particles’ Size Reduction Process LOs By the end of this session, you should be able to: Describe the importance of particles’ size reduction as a pharmaceutical process Describe the impact of size reduction on powder properties Outline the main methods of particles’ size reduction Evaluate factors associated with the chosen size reduction method Describe the particles’ size separation process List the main methods of particles’ size separation 3 Reasons for reducing particle size Influence of Particle Size in Pharmaceutical Powders o Flow properties, mixing properties, uniformity of content, dissolution rate, etc,. Importance of Size Reduction in Powder Manufacturing Needs to make sure that you break down particles if they Initial Powder Size: aggregate together o Typically, larger than pharmaceutical requirements, small particles aggregate during storage Size Reduction: o Essential for manufacturing progress o Controls properties of final products 4 Aims of Particle size reduction The particle size has a direct link with many physiochemical properties. Reducing particles size can improve mixing. Decreasing particle sizes will increase the total surface area which affects the powder’s flow properties and dissolution rate. The quality and stability of some formulations (i.e., suspensions) is affected by particles sizes. The impact of particle sizes on organoleptic properties is clearer with semi-solids such as pastes. Size reduction not only affects the mean particle size but also the distribution of the sizes of the powdered material. 5 Size reduction & size distribution Large particles should disappear Small particles multimodal distribution Size reduction process of a unimodal powder bed. Represented from Aulton M.E, Taylor K.M.G. Aulton’s Pharmaceutics 5th edition. Chapter 34: Soft capsules. Elsevier publishers, 2018. 6 Size reduction & size distribution Size reduction process of a unimodal powder bed. Represented from Aulton M.E, Taylor K.M.G. Aulton’s Pharmaceutics 5th edition. Chapter 34: Soft capsules. Elsevier publishers, 2018. 7 Concepts & definitions During the particle size reduction process, different behaviours can be identified. Terms such as Toughness, Hardness, Brittle, Tough, Plastic & Elastic, etc. are useful to describe those behaviours. Toughness is the ability of a material to absorb the applied energy and deform without fracturing. o Or Toughness is the strength with which the material opposes rupture. It is hard to break tough materials, so it is difficult to reduce the size of a tough materials. Tough materials (i.e., steel, iron) undergo plastic deformation and absorb a lot of energy before breaking. Brittle materials (i.e., glass, ceramic) experience breakage easily. They have little elasticity and do not stretch easily. Tough materials break through crack propagation Hardness is different from Toughness Tough materials are resistant to fracturing, measured by the amount of breaking energy they can withstand. While, Hardness is how much a material can withstand scratches, cuts, or other abrasions, as well as plastic deformation. 8 Concepts & definitions Hardness is the ability of a material to resist deformation, which is determined by a standard test where the surface resistance to indentation is measured. A mineral's hardness is a measure of its relative resistance to scratching, measured by scratching the mineral against another substance of known hardness on the Mohs Hardness Scale. Mohs scale is used to help identify minerals. Diamonds, with Mohs scale 10, are at the top of the table Talc, with Mohs scale 1, is at the bottom. Mohs hardness scale. 9 National Park Service Concepts & definitions Elasticity is the property of a solid material that allows it to restore its shape after an external load is removed. Plasticity is the property of a solid substance that allows it to keep its deformed shape even when the external load is removed. Reversible vs irreversible deformation For example, rubber string and steel string. Which one will show elastic behaviour? Elastic materials that are subject to external stresses beyond the elastic limit, will not return to the original shape. Ductile materials are easily stretched and clearly show plastic deformation under pressure. Brittle materials, experience little elastic or plastic deformation. they break through crack propagation rather than stretch. Elastic materials such as rubber, are extremely soft yet difficult to size-reduce. 10 Figure 1: A Stress Strain Curve for a Ductile Material Influence of material properties Size reduction of solid materials occurs by a process of crack propagation, whereby localized stresses produce strains in the particles that are large enough to cause bond rupture and thus propagate the crack. It is hard to break (reduce particle sizes) tough materials. It is hard to break (reduce particle sizes) hard materials. How about soft materials? Materials such as rubber that are soft under ambient conditions, waxy substances such as stearic acid that soften when heated, and ‘sticky’ materials such as gums… all these materials are capable of absorbing large amounts of energy through elastic and plastic deformation without crack initiation and propagation. These materials can be more easily size-reduced when temperatures are lowered below the glass transition point of the material. At these lower temperatures the material undergoes a transition from plastic to brittle behaviour, and crack propagation is facilitated. The glass transition point is the temperature at which a material change in properties. Below this temperature, the material is brittle. While above this temperature, the material is rubbery. 11 Particle size reduction: methods There are different types of size reduction techniques. The principles associated with those techniques are: Cutting Compression Impact Combined impact and attrition 12 Cutter mills Size reduction method: Cutting Particles are fractured between two sets of knives. A stationary set on the mill casing and a set attached to the rotor The size reduction range is 500 to 50,000 microns Can stop the process anytime if you think its enough, so you can control it. Size reduction process via cutter mill. Represented from Aulton M.E, Taylor K.M.G. Aulton’s Pharmaceutics 5th edition. Chapter 34: Soft capsules. Elsevier publishers, 2018. 13 Roller mill Size reduction method: Compression A form of compression mill uses two cylindrical rollers mounted horizontally and rotated about their long axes The size reduction range is 1,000 to 100,000 microns Figure 1. Size reduction via compression using Roller mill. Reproduced from Stedman, Size Reduction Equipment Manufacturer. 14 End-runner mill Size reduction method: Compression Powder is compressed using mortar and pestle The size reduction range is 50 to 10,000 microns Size reduction processes via compression method. Represented from Aulton M.E, Taylor K.M.G. Aulton’s Pharmaceutics 5th edition. Chapter 34: Soft capsules. Elsevier publishers, 2018. 15 Hammer mill Size reduction method: Impact Particle size is reduced upon impact driven by 4 (or more) rotating hammers The size reduction range is 50 to 10,000 microns Hammer mill. Pharmapproach online platform. www. Pharmapproach.com 16 Vibration mill Size reduction method: Impact A cylinder filled to 80% with porcelain or stainless-steel balls. Particle size is reduced upon repeat impact driven by vibration of the whole body of the mill. The size reduction range is 1 to 1,000 micron Size reduction processes via impact method. Illustration of the vibration mill on the right. Represented from Aulton M.E, Taylor K.M.G. Aulton’s Pharmaceutics 5th edition. Chapter 34: Soft capsules. Elsevier publishers, 2018. 17  Ball mill Size reduction method: combined impact & attrition A rotating cylinder filled to 30-50% with balls. The mill can be filled with a variety of ball sizes to improve the size reduction process. The size reduction range is 1 to 100 micron ✓ Tumbler ball mills ✓ Vibratory mills ✓ Planetary mills Slow rotation speed Fast rotation speed Correct cascade action Size reduction processes via Ball mill. Reproduced from pharmacygyan, Independent Peer-reviewed Medical Website. 18 Fluid energy mill Size reduction method: combined impact & attrition Air is injected at a high-pressure, creating turbulence which will lead particles to collide with other particles and with the wall of the mill. The size reduction range is 1 to 50,000 microns 19 Pin mill Size reduction method: combined impact & attrition Two metal discs with closely spaced pins rotate against one another at high speeds. Particle size reduction occurs by impaction with the pins and by attrition between pins as the particles travel outwards under the influence of centrifugal force. The size reduction range is 10 to 10,000 microns Size reduction processes via impact and attrition methods. Represented from Size reduction process via Pin mill Aulton M.E, Taylor K.M.G. Aulton’s Pharmaceutics 5th edition. Chapter 34: Soft capsules. Elsevier publishers, 2018. 20 Size reduction method consideration The purpose of size reduction The required particle size range Fine particles, size distribution Costs of the process Particle properties (i.e. toughness and hardness) Special requirements…costs! 21 22 Size separation Size separation vs size analysis Size analysis: information on the size characteristics of a powder Size separation is an integral part of a production process and results in a product powder of a given particle size range that is available for separate handling or subsequent processing. Size separation aims to: Separate particles based on sizes Remove powder particles from other gases and liquids 23 Size separation ❖ Size separation by sieving Based on mechanical disturbances of the powder bed and include the following methods: agitation, brushing, and Centrifugation Table1. Particle size classification Powder classification Sieve diameter (µm) Sieve diameter through which no more than 40% of powder must pass(µm) Coarse 1700 355 Moderately Coarse 710 250 Moderately fine 355 180 Fine 180 - Very fine 125 - 24 Size separation ❖ Size separation by Sedimentation Separating particles based on the differences in settling velocities of particles with different diameters ❖ Size separation by Elutriation moving in opposite directions In sedimentation methods the fluid is stationary and the separation of particles of various sizes depends solely on particle velocity. In Elutriation, almost same principle. However, there is a fluid flow in the opposite direction to the sedimentation movement so that in gravitational elutriators particles move vertically downwards while the fluid travels vertically upwards. Size separation via Elutriation 25 Unit Processes- Mixing The production of pharmaceutical dosage forms involves many processes. Some of the processes which are required for the production of solid dosage forms: Particle size reduction and size separation Mixing Granulation Drying 26 Mixing learning outcomes By the end of this session, you should be able to: Describe the importance and aims of mixing Differentiate between the perfect mix and ordered mix Discuss the differences between positive, negative and neutral mixtures Describe the powder mixing mechanisms Define de-mixing/segregation Discuss the different types of size-based segregation Describe the ordered mixing Discuss approaches to avoid segregation 27 Mixing key points The vast majority of dosage forms are composed of a mixture of different ingredients (API & excipients). Products with more than one component, a mixing or blending stage will be required to ensure: o an even distribution of the active component(s) Ensure uniformity of content o even appearance o the dosage form releases the drug at the correct site and at the desired rate Mixing is therefore involved at some stage in the production of practically every pharmaceutical preparation and control of mixing processes is of critical importance in assuring the quality of pharmaceutical products. Solutions.. Easy to mix Semisolids…more difficult Powders? Fine particles with coarse ones? Stay mixed? 28 Mixing Almost all pharmaceutical dosage forms include mixtures. For example: Tablets, capsules, dry powder inhalers… mixtures of solid particles Linctuses… mixtures of miscible liquids Emulsion, creams, ointments… mixtures of immiscible liquids Suspensions… mixtures of solids in liquids Pastes… mixtures of solids in semi-solids 29 Definition and objectives of mixing Mixing may be defined as a unit process which aims to treat two or more components so that the density of each type of particle is constant throughout the entire volume. The previous state is called the “Ideal mixing” or the “Perfect mix” The perfect mix is not normally practicable, is process, and is sometimes undesirable. For example: Potent drugs/ small-dose drugs requires the best possible mixing order to ensure a consistent dose. Dispersing immiscible liquids or dispersing solids in a liquid, a good mixing is required to ensure product homogeneity. In the case of mixing lubricants with granules during tablet production, there is a danger of ‘overmixing’ and the subsequent production of a weak tablet with an increased disintegration time. Mixing is commonly a random process, and this randomness will give some regions within our blend more of a certain type of particles than others. Considering potent drugs 30 Types of mixing Mixtures may be categorized into three types that differ fundamentally in their behaviour. Positive mixtures Form spontaneously Positive mixtures are formed from materials such as gases or miscible liquids which mix spontaneously and irreversibly by diffusion and tend to approach a perfect mix. There is no input of energy required with positive mixtures. Input of energy will shorten the time required to obtain the desired degree of mixing. No energy Energy will be required to separate a component out of the mix. Usually, materials which mix by positive mixing do not present any problems during product manufacture. Negative mixtures Need energy to be formed Components will tend to separate out (quickly, or slowly) spontaneously. Slowly, such as emulsions, creams and viscous suspensions Quickly such as a suspension of solids in a liquid of low viscosity (energy must be continuously input to keep the components adequately dispersed) Negative mixtures are generally more difficult to form and to maintain and require a higher degree of mixing efficiency than do positive mixtures. 31 Types of mixing Neutral mixtures Components have no tendency to mix spontaneously or segregate spontaneously once work has been input to mix them. For example: mixed powders. Neutral mixes are capable of demixing, but this requires energy input. PS. It should be noted that the type of mixture can change during processing. For example, if the viscosity increases sufficiently, a mixture may change from a negative to a neutral mixture. Similarly, if the particle size, degree of wetting or liquid surface tension changes, the mixture type may also change. 32  Mixing process To discuss the principles of the mixing process, a situation will be considered where there are equal quantities of two powdered components of the same size, shape and density that are required to be mixed, the only difference between them being their colour. This situation will not, of course, occur practically but it will serve to simplify the discussion of the mixing process. Check this diagram, the components are represented by coloured cubes, these are representation of the completely segregation, perfect mixing, and random mix state. Perfect mix occurs when each particle lies adjacent to a particle of the other component Random mix is a mix where the probability of selecting a particular type of particle is the same at all positions in the mix and is equal to the proportion of such particles in the total mix. Aim in the pharmaceutical industry is the random mix Figure 2. Different states of powder mixing. (a) Complete segregation. (b) An ideal or ‘perfect’ mix. (c) A random mix. 33 Mixing process To discuss the principles of the mixing process, a situation will be considered where there are equal quantities of two powdered components of the same size, shape and density that are required to be mixed, the only difference between them being their colour. This situation will not, of course, occur practically but it will serve to simplify the discussion of the mixing process. Check this diagram, the components are represented by coloured cubes, these are representation of the completely segregation, perfect mixing, and random mix state. Perfect mix occurs when each particle lies adjacent to a particle of the other component Random mix is a mix where the probability of selecting a particular type of particle is the same at all positions in the mix and is equal to the proportion of such particles in the total mix. Figure 2. Different states of powder mixing. (a) Complete segregation. (b) An ideal or ‘perfect’ mix. (c) A random mix. 34 Mixing mechanisms Powder particles need to move relative to each other to get mixed. There are three main mechanisms by which powder mixing occurs: namely, convection, shear and diffusion. Liquids use different methods for mixing such as bulk transport, turbulent mixing and molecular diffusion. We will describe the powder mixing methods as they are related to the production of solid dosage forms. 35 Convection mixing Convection mixing occurs when large group of particles move from one part of the powder bed to another, e.g. when a mixer blade or paddle moves through the mix Planetary mixer uses convection mixing method Convection mixing is a quick process & provides good mixing to powders with poor-flow properties Convection mixing contributes to macroscopic mixing of powder mixtures. Thus, mixing does not occur within group of particles moving together as a unit, unless much long time is allowed Convection mixing reduces the possibility of de-mixing 36 Shear mixing Shear mixing occurs when a layer of material flows over another layer during the mixing process, resulting in mixing at the layer interface. Tumbling mixers use the shear mixing principle Shear mixing contributes to semi- microscopic mixing or semi-micromixing There is a high chance of de-mixing 37 Diffusion mixing Diffusion mixing provides good random mixtures Diffusion mixing contributes to microscopic mixing or micromixing Diffusion mixing is the main mechanism for: Fluidised bed mixers: used for drying, mixing, granules preparation.. Fluidised bed mixer, Reproduced from Pilotech® 38 Demixing (segregation) Segregation is the opposite effect to mixing: components tend to separate out Segregation of powders in random mix converts it to non-random mix Powder mixtures are neutral mixtures, which require energy to de-mix Handling (processing) of powders can provide sufficient energy to allow de-mixing Segregation negatively affect the uniformity of content 39 Demixing (segregation) Segregation arises because powder mixes encountered in practice are not composed of mono-sized spherical particles but contain particles that differ in size, shape, density and surface properties These variations mean particles will behave differently when forced to move Particles with similar properties tend to congregate together, which creates un-even distribution within the blend The possibility, and extent, of segregation increases with vibration, and when particles have greater flowability 40 Size-based segregation Differences in the particle sizes of components of a formulation are the main cause of segregation in powder mixes in practice Size-based separation: Percolation, Trajectory, and Elutriation segragation In Percolation: smaller particles fall through the gaps between larger particles Percolation effect is more pronounced when powder bed is disturbed Percolation is likely to occur during solid dosage forms preparation Differences in densities may enhance Percolation effect 41 Size-based segregation Trajectory is a Size-based separation mechanism Trajectory separation occurs when pouring a powder mix from a container Large particles with more kinetic energies move to greater distances than smaller particles Differences in densities may enhance Trajectory effect 42 Size-based segregation Elutriation segregation (sometimes called Fluidisation segregation or dusting out) is a Size-based separation mechanism Elutriation segregation occurs as a result of having very small particles within the powder blend This portion of particles creates “dust” when discharging form a container “dust” will be blown upwards by turbulent air currents as the mass tumbles, and remain suspended in the air After discharging, “dust” will sediment and form a layer on top of larger particles 43 Density-based segregation When particles are of different densities, the denser particles will move downwards even if particle sizes are similar Differences in densities enhances the effect of Percolation and Trajectory segregation Differences in densities have a bigger impact than differences in sizes on Fluidised bed mixers Density-based segregation is not common as most materials used in pharmaceutical formulations have similar densities 44 Shape-based segregation Differences is shapes can be a serious risk of segregation Spherical particles have good flowability, and are easy to mix, and to segregate Non-spherical particles decrease the tendency to segregate Non-spherical particles have more cohesive forces Particles shape can change during processing (i.e., due to attrition, aggregation, etc) which change the possibility of segregation 45 Segregation prevention Careful selection of formulation components according to their properties Select particles with similar densities, and shapes Select particles with similar sizes to narrow-down the size distribution Use size separation methods such as sieving When having large particles: use size reduction methods When having small particles: use granulation Reduce handling/processing Use multitasking equipment to reduce transferring powder bed Use ordered mixing principle… 46 Ordered mixing Occurs between very small particles (