Pharmaceutical Technology 1 Mixing

15-Nov-21 Pharmaceutical Technology 1 15-Nov-21 1  Theoretical definition: an operation in which two or more components in separate or roughly mixed conditions are treated, so that each particle lies as nearly as possible in contact with a particle of the other ingredients >>> if this is achieved, it produces a theoretical “ideal” situation, i.e. a perfect or ideal mix. This situation is not normally practical. 15-Nov-21 2 1 15-Nov-21 • The statistical probability of achieving such a perfect mix is so minute that the best attainable mix, regardless of the method of mixing or time of mixing, is a random mix (Fig1c). • A random mix may be defined as one where the probability of sampling a particular type of particles is proportional to the number of such particles in the total mix. Example: In a large number of trials where single particles were withdrawn there would be around the same number of each type (for our 1:1 example) drawn from the random mix. Figure 1.Different states of powder mixing. (a) Complete segregation (unmixed). (b) An ideal or “perfect” mix. (c) A random mix. 15-Nov-21 3 • Objective of mixing: To obtain a mixture that when divided into subunits, each subunit will contain the same quantity of a given component and the same ratio of components in the entire mixture. • Ideal (perfect) mixing is in accordance with the previous theoretical definition of mixing while random mixing is not. • However, random mixing can achieve the objective of mixing depending on the final unit dose size. • In contrast to the ideal mixing, random mixing can be achieved practically. 15-Nov-21 4 2 15-Nov-21 1. Unit weight (unit dose size)  Often a mixing process produces a large 'bulk' of mixture that is subsequently subdivided into individual dose units (e.g. a tablet, a capsule) and it is important that each dosage unit contains the correct amount/concentration of active component(s).  e.g. Suppose you need to prepare 2 g of A and B (1 g each) and the mixture is to be filled into single 2 g unit. Here, just adding the two components to each other would be enough, despite that the drug is not homogeneously distributed in the mix. But if we decided to make 4 units (0.5 g each), then adding the two components is not enough and we should have mixing to achieve the same content for all units.  In conclusion: As the unit weight is increased, achievement of the objective of the mixing process will be easier. e.g. it is easier to achieve more homogenous mixing for 1000 mg tablets, than for 100 mg tablets (both containing the same mixture). 15-Nov-21 5 2. % of the active ingredient As the percentage is decreased the mixing process becomes more difficult. Potent drugs with percentage less than 1% present mixing problems. To improve mixing for potent drugs: ✓ Particle size reduction. ✓ Geometric (serial) dilution. 15-Nov-21 6 3 15-Nov-21 3. Particle size  Reduction of particle size will increase the number of particles per unit weight and lead to improvement in achieving the mixing objectives.  However, size reduction increases surface area and hence would increase cohesiveness between particles leading probably to reduced powder flow.  Moreover, too much size reduction would create surface charge leading to agglomerates and retarding powder flow as a result of strong electrostatic forces and inter-particulate friction and cohesion. 15-Nov-21 7 4. Particle size distribution: A. B. PSD affects packing characteristics and bulk density of the powder. The smaller particles occupy interstices between the larger particles, creating a more densely packed powder. Densely packed powder usually flows with difficulty. Accordingly, the narrower the particle size distribution the better the flow and the easier the mixing. Wide particle size distribution can lead to segregation during or after mixing. ✓ Narrow particle size distribution ✓ Less densely packed powder ✓ Good flow ✓ Easy mixing ✓ Broad particle size distribution ✓ More densely packed powder ✓ Bad flow ✓ Difficult mixing 15-Nov-21 8 4 15-Nov-21 5. Particle shape:  Particle shape affects powder inter-particulate friction and consequently the flow properties of the powder.  The optimum particle shape for optimum flow and mixing is spherical shape.  Particles with round edges flow readily than those of sharper edges or those with two-dimensional flat, flake like particles.  Poor powder flow is usually encountered with particles having an interlocking shape (irregular) or fibrous configuration or needle like. This is why size reduction of these shapes to change the shape to more rounded one is helpful. 15-Nov-21 9 5. Particle shape: Effect of particle shape on powder flow. 15-Nov-21 10 5 15-Nov-21 5. Particle shape…… cont.:  However, the opposite can be said about the effect of particle shape on segregation, as segregation is encouraged by good powder flow.  Accordingly, spherical shape leads to higher segregation than irregular shape, this of course if we rule out the effect of size distribution by comparing two powders of similar size distribution, but of different particle shape. 15-Nov-21 11 6. Mixing time  Non-segregating mixes will improve with continued increases in mixing time up to a certain point.  This may not, however, occur for segregating mixes, where there is often an optimum mixing time. ✓ This is because the factors causing segregation generally require longer to take effect than the time needed to produce a reasonable degree of mixing. It is therefore disadvantageous to prolong the mixing time beyond an optimum point. 15-Nov-21 12 6 15-Nov-21  Segregation is the opposite effect to mixing, i.e. components tend to separate out.  Segregation happens during or after mixing (due to handling or pouring).  The main factors promoting segregation are: Differences in particle size Differences in particle shape Differences in particle density ✓ ✓ ✓ These differences mean that particles will tend to behave differently when forced to move and hence, tend to separate.  15-Nov-21 13 ❖ Percolation segregation  The movement of particles through the voids in the powder bed.  It will occur in a static bed if the percolating particles are so small that they can fall into the void spaces between the larger particles and so move to the bottom of the mass. 15-Nov-21 14 7 15-Nov-21 Pouring of powders would also lead to segregation either by rolling or dusting. Segregation by rolling: during pouring, a powder pile is formed and gradually built up. During this pile formation, the larger particles, because of their mass, have tendency to roll down outside the powder pile. On the other hand, fine particles have tendency to stick to the top and concentrate in the middle of the pile. ❖ 15-Nov-21 15 Segregation by dusting: In this case the fine particles become air-borne and separate from the bulk of the powder. ❖ 15-Nov-21 16 8 15-Nov-21 There are three main mechanisms by which powder mixing occurs: A. Diffusion (micro-mixing):  When a powder bed is forced to move or flow it will 'dilate', i.e. the volume occupied by the bed will increase. This is because the powder particles will become less tightly packed and there is an increase in the air spaces or voids between them. Under these circumstances there is the potential for the particles to fall under gravity, through the voids created.  The redistribution of individual particles by the random movement of particles relative to each other is referred to as diffusive mixing. 15-Nov-21 17 B. Convection (macro-mixing): The movement of group of adjacent particles from one place to another within the mixture, as might occur when a mixer blade or paddle moves through the mix, for example. 15-Nov-21 18 9 15-Nov-21 C. Shear:  The change in the configuration of ingredients through the formation of slip planes in the mixture.  This might be due to the removal of a mass by convective mixing creating an unstable shear/slip plane, which causes the powder bed to collapse.  Shear mixing will occur as a velocity gradient is produced, the top layer moving with the greatest velocity and the velocity decreasing as the distance from the surface increases. 15-Nov-21 19  Since diffusive mixing involves individual particles, it can in time produce a truly random mix.  Shear and convective mixing can quickly produce a rough mix but local groups of particles may remain unseparated unless subjected to diffusive mixing. 15-Nov-21 20 10 15-Nov-21 1. Rotational (tumbling) mixers: • Rotational mixers are composed of rotating vessels of various shapes so that the charge flows with the vessel. Mixing containers are generally mounted so that they can be rotated about an axis. • Rotational mixers can be with or without agitator mixing bar (or blade) (e.g. the Vmixer with agitator bar or blade). 21 1. Rotational (tumbling) mixers: Mechanism of mixing • When operated at the correct speed, the tumbling action indicated in Figure below is achieved. Shear mixing will occur as a velocity gradient is produced, the top layer moving with the greatest velocity and the velocity decreasing as the distance from the surface increases. When the bed tumbles it dilates, allowing particles to move downwards under gravitational force, and so diffusive mixing occurs. • Too high a rotation speed will cause the material to be held on the mixer walls by centrifugal force and too low a speed will generate insufficient bed expansion and little shear mixing. • Addition of baffles or rotating bars will also cause convective mixing. 22 11 15-Nov-21 1. Rotational (tumbling) mixers: 1.1 With no agitator mixing blade:  They create particle movement by rotation of the entire mixer shell or body.  The shape of the shell is varied but the V-shaped and double cone mixers are the mostly used ones. V-shape blenders(to left) and Double cone (to right) 15-Nov-21 23 1. Rotational mixers: 1.1 With no agitator mixing blade:  The shear forces generated in tumbling mixers are insufficient to break up agglomerates and to induce sufficient flow.  Therefore, they are good for free flowing powders/granules but not efficient for poor/cohesive powders.  They are used only for solid-solid mixing, such as blending of dry granulation with lubricant, and disintegrant prior to tablet compression.  They mix powders with minimal energy imparted to powder bed; they cause minimal size reduction and maintain particle size during mixing.  Serial dilution (geometric mixing) is required for the addition of low dose active ingredients. 15-Nov-21 24 12 15-Nov-21 1. Rotational mixers: 1.1 With no agitator mixing blade: Factors that affect mixing A. Loading volume: Affect powder bed dilation. Should be approximately 50-60% of the blender volume. B. Blender speed: The slower the blender speed the lower the shear force. However, high blending speed may result in dusting or segregation of fine particles. 15-Nov-21 25 1. Rotational mixers: 1.2 With agitator or mixing blade:     Agitator blade gives versatility to the tumbling blenders by virtue of high shear for both wet and dry mixing which allows for both solid-solid and liquid-solid mixing. The agitator gives wide range of shearing which allows for intimate mixing of poor flow powder. Serial dilution is not needed when incorporating low dose active ingredients. However possible attrition of the particle may happen for friable granules or particles as a result of the high speed agitator. 15-Nov-21 26 13 15-Nov-21 15-Nov-21 27 2. Stationary shell or body with rotating mixing blades: Mixing force is transferred to the powder bed by moving blades, while the shell is fixed, and hence the main mixing mechanism is convection. 2.1 Ribbon mixer:      Ribbon (spiral) shaped blade that is attached to motor driven shaft and traverse the entire length of trough like shell with a semicircular bottom. The ribbon mixer is top-loading, with bottom discharge port. It can be used for both liquid-solid and solid-solid mixing. It has a major disadvantage: the possibility of dead spots (areas that remain unmixed) at the ends and in the corners of the mixer. It provides low shear compared to sigma blade. 15-Nov-21 28 14 15-Nov-21 2. Stationary shell or body with rotating mixing blades: 2.2 Conical screw mixer:  It has conical vessel and screw shaft.  The screw shaft rotates around the periphery of the cone and spins around its axis during this rotation.  It has minimal dead spots as the screw visits each part of the interior 15-Nov-21 29 2. Stationary shell or body with rotating mixing blades: 2.2 Conical screw mixer:  As the screw turns, the material is carried from the bottom of the mixer to the top and then falls as cascade back to the bottom.  The mixer thus combines diffusive, shear and convective mixing.  Still, the shear force is limited and therefore the mixer is used mainly for solid-solid blending. 15-Nov-21 30 15 15-Nov-21 2. Stationary shell or body with rotating mixing blades: 2.3 Sigma blade mixer:  It has two S shaped blades that are motor driven and rotates in opposite direction causing interlocking of the material and thus kneading.  It is top loading and emptied by tilting the whole shell. 15-Nov-21 31 2. Stationary shell or body with rotating mixing blades: 2.3 Sigma blade mixer:  It provides higher shear compared ribbon and conical screw mixers.  It is good choice for granulation where wetted powder requires kneading for good liquid-solid distribution.  It is used mainly for liquid-solid blending although it can be used for solid-solid blending.  The clearance between the blades and walls of the shell is kept small due to the shape of blade, and the blade covers the edges and corners. Accordingly, the blender has the advantage of minimal dead spots. 15-Nov-21 32 16 15-Nov-21  When mixing formulations in which there is a relatively low proportion of active ingredient(s), a more even distribution may be obtained by sequentially building up the amount of material in the mixer.  Care must be taken to ensure that the volume of powder in the mixer is appropriate, as both over- and underfilling may significantly reduce mixing efficiency.  Although theory suggests that fine powders should form better mixes by increasing the number of particles in a given sample weight there is a complication caused by the increase in cohesion as the particle size decreases. Vigorous convection and shear mixing are required to break up aggregates and disperse the particles into the bulk.  The mixer used should produce the mixing mechanisms appropriate for the formulation. For example, diffusive mixing is generally preferable if potent drugs are to be mixed, and high shear is needed to break up aggregates of cohered material and ensure mixing at a particulate level. The impact or attrition forces generated if too-high shear forces are used may, however, damage fragile material and thus produce fines.  In order to determine the appropriate mixing time, the process should be checked by removing and analysing representative samples after different mixing intervals. 15-Nov-21 33  Testing blend homogeneity is important to determine the optimum mixing time or to validate that a specified mixing time will provide the objectives of the mixing process.  This is usually done when one is developing a new formula and procedure for a product and during scale up.  This is particularly true in case of expecting mixing problems such as potent drugs. Three issues must be considered 15-Nov-21 34 17 15-Nov-21 Three issues must be considered: A. Sample size: try to make you sample size equal to unit size. For example if you testing a formula to be compressed to tablets of 800 mg, then sample size of approximately 800 mg is a good choice  It is the weight of the dosage unit that dictates how closely the mix must be examined to ensure it contains the correct dose/concentration. This weight is known as the scale of scrutiny and is the amount of material within which the quality of mixing is important. For example, if the unit weight of a tablet is 200 mg then a 200 mg sample from the mix needs to be analysed to see if mixing is adequate; the scale of scrutiny is therefore 200 mg. If a larger sample size than the scale of scrutiny is analysed this might mask important micro-nonuniformity. >>>This may lead to the acceptance of an inadequate mix. 15-Nov-21 35  Three issues must be considered: B. Number of samples: the larger the number of samples taken from different locations, the more representative is the sampling. One way to take samples is to view the powder bed as three layers (top, middle and bottom) and each layer is divided to three locations: right, center and left. Taking samples from the 9 locations is a reasonable way. C. Sampling devices: There are two common sampling devices 15-Nov-21 36 18 15-Nov-21 There are two common sampling devices: A. Scoop: It has drawbacks. Scooping can not remove a sample from the middle or bottom of a blender without considerable disturbance of the mixture. Scooping from the top of powder may produce samples that were segregated on standing. B. Thief sampler: This is the most common device, which permits you to take samples deep within the mixture without considerable disturbance. It consists of outer and inner tubes. 15-Nov-21 37 B. Thief sampler……cont.  The outer tube is pointed with openings at the bottom, middle and top. The inner tube has dies or sample containers at the same location of openings of the outer tube. It also has a handle to rotate inside the inner tube.  Before the insertion into the powder bed for sampling, the inner tube is aligned so that the openings and dies do not match; thus upon insertion no powder will be filled into the dies. After insertion, the inner tube is rotated so the openings and dies match and the product flows in and fills the dies. The openings and dies are reunmatched and the whole device is removed from the mix. 15-Nov-21 38 19 15-Nov-21 15-Nov-21 39 20