Mixing 1st Sem 2022 PDF

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 a separate or roughly mixed condition are treated so that each particle lies as nearly as possible in contact with a particle of each of th...

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 a separate or roughly mixed condition are treated so that each particle lies as nearly as possible in contact with a particle of each of the other ingredients.  THE OBJECTIVES OF MIXING IS CLASSIFIED AS FOLLOWS:  1. SIMPLE PHYSICAL MIXTURE: This may be simply the production of a blend of two or more miscible liquids or two or more uniformly divided solids.  2. PHYSICAL CHANGE: Ex. Solution of a soluble substances-> low efficiency of mixing is enough  3- DISPERSION: This 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. Usually good mixing is required to ensure stability.. 4. PROMOTION OF REACTION: Mixing will usually encourage a chemical reaction, so ensuring uniform products. TYPES OF MIXTURES  Mixturesmay be divided into three types that differ in their behaviour: 1. POSITIVE MIXTURES: Positive mixtures are formed from materials such as gases or miscible liquids, where irreversible mixing would take place, by diffusion, without the excessive work or energy.  In general, such materials do not present any problems in mixing.  2. NEGATIVE MIXTURES: Suspensions of solids in liquids are examples of negative mixtures that require work for their formation, and the components of which will separate unless work is continually expended on them.  Negative mixtures are more difficult to form and a higher degree of mixing efficiency is required. -  3. Neutral mixtures: Are static in their behavior, in which the components having no tendency to mix spontaneously. Many pharmaceutical products are examples of this type as pastes, ointments and mixed powders. THE MIXING PROCESS  Perfect mix: Ideal situation where each particle lay adjacent to a particle of the other component  Fig (a): 2 powder materials  Fig (b): chance of occurring is very small (1 in 1060)  Fig (c): in practice this is what can be obtained  Random Mix: a mix where the probability of selecting a particular type of particle is the same at all positions in the mix SCALE OF SCRUTINY  It is the wt/vol of the dosage unite that dictates how closely must be analysed to ensure it contains the correct dose/conc.  Scale of scrutiny is the amount of material within which the quality of mixing is imp.  Eg. 200mg tablet 200mg sample analyzed to see if mixing is adequate. So SOS is 200mg.  SCALE OF SCRUTINY  The no of particles in the scale of scrutiny depends on sample wt, particle size, and particle density and will increase as sample wt increases and particle size and density decrease.  Another imp. Factor is the proportion of the active component in the d.f. THE PROBLEM: LOW STRENGTH POTENT DRUGS 1. The lower the proportion of active component present in the mixture the more difficult it is to achieve an acceptably low deviation in active content 2. The more particles there are present in a unite dose/scale of scrutiny the lower the deviation in content  SOLUTION: increase No of particles  One way: is to decrease particle size (milling)  but aggregation may occur due to surface charges MATHEMATICAL TT OF THE MIXING PROCESS  The aim during formulation is to minimize variation to acceptable levels by selecting an appropraiate SOS, particle size and mixing procedure (choice of mixer, rotation speed...etc)  1. SD = √p(1-p)/n  SD: standard deviation in the proportion of component in the sample, p is the proportion of the component in the total mix  n is the total no of particles in the sample  - as n increases SD decreases ie less variation in sample content  - However, as p decreases SD decreases => this may lead to the incorrect conclusion that it is beneficial to have a low proportion of the active component which is not correct  2. A more useful parameter is %CV (percentage coefficient of variation) which indicate the average deviation as a percentage of the mean amount of the active component in the sample.  %CV = [Content SD/mean content(p)]x100  Ex.  - if n = 100 000, p = 0.5  SD = 1.58x10-3 and V = 0.32% which considered low deviation and acceptable  - If n = 100 000 while p = 0.001  SD = 9.99x10-5 and %CV = 10% which is not acceptable  - If we increase sample size (but keeping dose fixed): P will decrease. - If p is relatively high initially increasing sample size will increase %CV. If p is small, increasing sample size will have little effect. EVALUATION OF DEGREE OF MIXING  Reasons why:  1. To indicate the degree/extent of mixing  2. To follow a mixing process  3. To indicate when sufficient mixing has occurred  4. To assess the efficiency of a mixer  5. To determine the mixing time required for a particular process.  Generation of Mixing Index which compares the content SD of samples taken from a mix under investigation (Sact) with that of samples from a fully random mix (SR)  Mixing Index M= SR/Sact  At the start of the mixing process the value of Sact will be high M will be low. As mixing proceeds Sact will tend to decrease as mix approach random mix at which M=1 IN ORDER TO EVALUATE A MIXING PROCESS 2 REQUIREMENTS:  1. A sufficient no of samples which are representative of the mix. At least 10 samples are taken by “sampling thief” from different depths of the mix.  2. A suitable valid analytical technique MECHANISMS OF MIXING AND DEMIXING 1. POWDERS  There are 3 main mechanisms:  1. Convective Mixing:  arises when there is the transfer of relatively large groups of particles from one part of the powder bed to another. This type of mixing contributes mainly to microscopic mixing of powder mixtures and tend to produce a large degree of mixing quickly.  -Disadvantage: Mixing does not occur within the group of particles move together as a unit, an so long mixing time is required. 2. SHEAR MIXING  Occurs when a layer of material moves/ flows over an other layer. 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.  It may also occur in high shear mixers or tumbling mixers where the action of the mixer induce velocity gradients within the powder bed and hence shearing of one layer over an other. 3. DIFFUSION MIXING  Dinurg which a true random mix occurs. Indivdual particles move one close to the other, due to the fact that when the powder bed is forced to move it dilate (i.e. Vol increased). So particles become less tightly packed and there is an increase in the air spaces or voids between them. So particles fall, under the gravity, through the voids created. .  Disadv.: low rate of mixing  NB. All 3 mechanisms could occur in a mixing operation depending on mixer type, mixing conditions (laod, speed..) and flowability of powder 2. LIQUIDS: 3 MECHANISMS  1. Bulk transport: analogous to convective,  -involves the movement of a relatively large amount of material from one position to another  - tends to produce large degree of mixing quickly  2. Turbulent Mixing: arises from haphazard movement of molecules when forced to move in a turbulent manner.  -. ’ Disadvantage: eddies may occur in which small groups of molecules moving together as a unit. These tend to leave small unmixed areas within the eddies and near the container surfaces 3- MOLECULAR DIFFUSION  Occur with miscible fluids wherever a concentration gradient exists and will eventually produce a well-mixed product, although considerable time may be required if this is the only mixing mechanism.  - In most mixers all 3 mechanisms will occur. POWDER SEGREGATION (DEMIXING)  Is the opposite effect to mixing i.e. Components tend to separate out. This may lead to non- random mix which results in content uniformity variation in tablets or wt variation in capsules.  Particle size, shape and density may affect the occurance of demixing:  1. PARTICLE SIZE: MAIN CAUSE, 3 TYPES  1. Percolation Segregation: Smaller particles tend to fall through the voids between larger ones and so move to the bottom of the mass.  May occur in static powder bed but occur to grate extent when the bed dilates on being disturbed. Ex. cereals .  2. Trajectory segregation: During mixing, larger particles tend to have greater kinetic energy owing to their larger mass and therefore move greater distances than smaller particles leading to separation of particles of different size: Ex. large particls on powder heap.  3. Elutriation segregation: (Dusting out). During mixing dust (v.small particles) may blown upward by air currents and settle down at the end as a layer on top of bed 2. PARTICLE DENSITY  Usually the more dense material will have a tendency to move downwards, even the size is smaller. Trajectory segregation may also occur.  Pharm.materials usually are of similar density so density is generally not too important. Exception is the use of fluidized bed. 3. PARTICLE SHAPE  Spherical particles exhibit the greater flowability and therefore more easily mixed, but may also segregate more easily. Irregular or needle shaped particle tend to interlocked reducing the tendency to segregate.  Non-spherical particles will also have greater specific SA which tend to decrease segregation by increasing cohesive effects (contact SA).  Non-segregating mixes will improve with increasing mixing time. With segregating mixes there should be an optimum mixing time. This is because during the initial stages the rate of mixing is greater than the rate of demexing, After a period of time demixing predominate until an equilibrium reached. Time of mixing is critical APPROACHES TO CORRECT SEGREGATION PROBLEM  1. Selection of particular size range  2. Milling of components  3. Controlled crystallization during the production of drug/excepients to give components of particular shape or size range  4. Selection of excipients having similar density to API.  5. Granulation of the powder mix (size enlargement) so that different particles are evenly distributed in each granule.  6. Reduce extent of vibration or movement after mixing  7. Using filling machine hoppers designed to decrease residance time  8. Use equipment where several operations can be carried out without transfer the mix eg. High speed mixer granulator  9. Production of an Ordered Mix ORDERED MIXING  Occurs when sufficiently small (micronized) powder get adsorbed on to the active sites on the surface of larger carrier particles where they exhibit greater resistance to be dislodged.  This has the effect of minimizing segregation and maintaining good flow properties.  Ordered Mixing: particles are not independent of each other and their is a degree of order in the mix. If carrier particle are removed adsorbed particles also removed.  Used in production of dry antibiotics where they in fine form are made adsorbed on to larger sucrose or sorbitol particles  Ordered Mixing occurs to a certain extent in every pharmaceutical powder mix, owing to interaction and cohesive forces between constituents.  Pharm. Mixes are likely to be partly ordered and partly random depending on the component properties.  Some Benefits of Ordered mixing:  1. is beneficial for potent drugs.  2. imp in direct compression formulations.  3. Used in powder inhalers to deliver drugs to lungs SEGREGATION IN ORDERED MIXING: SEGREGATION MAY OCCUR IN ORDERED MIXING IF:  1. The carrier particles vary in size: If carrier particles seperate, drug rich areas where the smaller particles aggregetae  ordered unit segregation  2. There is competition for the active sites on the carrier particles: displacement segregation.  3. There are insufficient carrier particles: excess small-sized particles lead to saturation segregation  MIXING OF POWDER  Practical Considerations:  1. Geometric mixing: particularly low proportion active ingredients  2. Volume of powder in the mixer: Overfilling no dilation no diffusion. Underfilling powder bed doesnot move as required  3. The Mixer used should produce the mixing mechanism appropriate for the formulation.  4. The mixer design should be such that it is dust-tight, easily cleaned and the product fully discharged  5. Mixing time: detd by removing and analysing representative samples at different intervals  6. static charges may produced during mixing which lead to clumping or adherance to mixer surfaces. To solve  1. Earthing should be done. 2. process under 40% RH POWDER MIXING EQUIPMENT 1. TUMBLING MIXERS/BLENDERS - Used for mixing/blending of granules and free-Flowing powders - Mixing containers are mounted So that can be rotated about an axis  Itis common to use Intermediate bulk containers (IBCs) as a mixer and either to feed the hopper or as a hopper per se.  When operated at the correct speed tumbling and shearing occur - When the bed tumbles it dilates allowing particles to move down so diffusive mixing occur - Too high speed  materials held on the mixer walls by centrifugal force - Too low speed insufficient bed expansion and little shear mixing - Addition of baffles will cause convective mixing - Available to mix 50g (lab-scale) to 100kg (production scale). - Typically material occupy ½ to 2/3 of mixer vol. - Good for free-flowing powders/granules but poor for cohesive/poorly flowing powders 2- HIGH-SPEED MIXER-GRANULATOR  Can mix and granulate concomitantly without the need to transfer product between places and hence decrease segregation opportunity.  The centrally mounted impeller blade at the bottom rotates at high speed throwing material to wall by centrifugal force come upward before dropping back to centre high shear and expansion 3. FLUIDIZED-BED MIXER  Mainly used for drying and coating  May be used to mix powders prior to granulation in the same bowl. 4. AGITATOR MIXER  Depends on the motion of a blade or paddle through the product convective  Ex. Planetary mixer: the term `planetary' is analogous to the movement of a planet round the sun while rotating on its own axis  Ribbon mixer: Mixing is achieved by the rotation of helical blades in a hemispherical trough.  Disadv.: 1. dead spots difficult to eliminate 2. shearing action by blades is insufficient to break drug aggregates  Adv.: can mix poorly flowing powders and less likely to cause segregation  Nautamixer: consist of a conical vessel fitted at the base with a rotating screw fastened to end of a rotating arm  Adv.: combine convective mixing with shear and diffusive mixing MIXING OF LIQUIDS  1. Propeller Mixers: has angled blades, which cause the fluid to circulate in both an axial and radial direction.  If mounted centrally vortex occurs due to centrifugal force imparted to the liquid by the blades causes it to back up around the sides of the vessel and create a depression at the shaft - As speed increased air may be sucked in to fluid by vortex cause frothing and possible oxidation  To supress vortex: off-centre mounting or fitting vertical baffles into vessel which divert rotation  The ratio of the diameter of propeller stirrer to that of vessel is 1:10-1:20 and operate at speed of 1-20 rps.  Not suitable for viscous fluids since its action depends on axial and radial flow pattern which do not occur in viscous liquids. a 2- TURBINE MIXERS  May be used for more viscous fluids  The impeller has 4 flat blades surrounded by perforated inner and outer diffuser rings  The rotating impeller draws the liquid in to the mixer head and forces it through the perforations with radial velocity sufficient to overcome the viscous drag of bulk of fluids. - Forcing liquid through small orifices produce high shear sufficient to generate droplets of the dispersed phase to get stable dispersion ( eg. w/o Or o/w emulsions) THE BLADES MAY HAVE A PITCH GIVING SOME AXIAL FLOW, BUT MOST TURBINE IMPELLERS HAVE FLAT BLADES WHICH HAVE VERY LITTLE AXIAL OR TANGENTIAL FLOW AND THE LIQUID MOVED RAPIDLY IN A RADIAL DIRECTION MIXING OF SEMISOLIDS  The problem here is that semisolid do not flow easily, materials in dead spots will remain their.  So suitable mixers must have rotating elements with narrow clearances with the vessel wall with a high degree of shearing force 1. PLANETARY MIXERS  Mixing blade is set off-centre and carried on a rotating arm travels around the circumference of mixing bowl while simultaneously rotate around its own axis  A small clearance between paddle and vessel wall gives shear.  Scraping manually is necessary since some materials are forced to the top of the bowl 2- SIGMA-BLADE MIXER  A robust mixer deals with stiff pastes and ointments and depends for its action on the close intermeshing of the two blades which resemble the Greek letter (sigma).  The clearance between the blades and the mixing trough is kept small