1. Pharmaceutical Technology I
Mixing
Pharmaceutical Technology I
4/24/2017
IP-HA

2. Definition
Mixing may be defined as a process where two or more components are treated so as to allow particles of one component to lie as near as possible in contact with a particle of other components.
The aim of the process is to produce one of the followings:
a blend of solid particles (powder mixing)
a suspension of an insoluble solid in a liquid
a mixture of miscible liquids
a dispersion of particles in a semisolid as in preparation of ointments or pastes.
4/24/2017
IP-HA

3. Theory of mixing
Miscible liquids, gases and vapors will, in time, completely mix spontaneously by diffusion and no energy need be used for this to occur (Positive Mixing).
Negative mixing on the other hand is exemplified by the dispersion of insoluble solid particles within a liquid where particles will separate out unless work is done by stirring to keep them dispersed.
A mixture of powdered constituents is an example of a neutral mixing. Work must be done to mix them initially but usually there is then no tendency for demixing to occur spontaneously; though demixing is possible under certain circumstances.
4/24/2017
IP-HA

4. The mixing process
To simplify discussion the principles of mixing, we will be considering a system consisting of equal quantities of two constituents A and B of the same size and shape.
Before mixing starts the system may be represented by the following figure which shows the particles in a completely segregated state.
4/24/2017
IP-HA

5. The mixing process
4/24/2017
IP-HA

6. The mixing process
The theoretical end point of mixing is the formation of a perfect mix where each particle lies adjacent to a particle of the other component.
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.
4/24/2017
IP-HA

7. The mixing process
4/24/2017
IP-HA

8. The mixing process
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 on the total mix.
In a large number of trials where single particles were withdrawn there would be around the same number of each type (for our 1:1 example) drawn from the random mix.
4/24/2017
IP-HA

9. The mixing process
4/24/2017
IP-HA

10. The mixing process
It should be stressed that there is always some variation in the composition of samples from a random mix.
The standard deviation in the composition of a large number of such samples can be determined if an accurate assay method is available.
A random mix will give samples with a lower standard deviation (S) than mixes of the same components which have not been mixed com to the random state.
4/24/2017
IP-HA

11. Mechanisms of mixing
If a spatula is inserted into a heap of powder on a tile then a small pile may be withdrawn on the blade and deposited elsewhere ‑ Convective mixing.
The movement of group of adjacent particles from one place to another within the mixture.
4/24/2017
IP-HA

12. Mechanisms of mixing
At the same time an unstable shear plane is created which then collapses and produces some further mixing in the heap - Shear mixing.
Shear mixing: The change in the configuration of ingredients through the formation of slip planes in the mixture.
4/24/2017
IP-HA

13. Mechanisms of mixing
Diffusive mixing (micromixing) occurs in drum mixer and other tumbling type mixers. In its simplest form this is a rotating cylinder in which the mix is lifted past its angle of repose so that the particles tumble over each other.
There is a difference in velocity with the fastest layers near to the surface and individual particles can migrate from layer to layer in a way similar to the diffusion of molecules in liquids.
Diffusive mixing: The redistribution of individual particles by the random movement of particles relative to each other.
4/24/2017
IP-HA

14. Mechanisms of mixing
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.
4/24/2017
IP-HA

15. Mechanisms of mixing
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.
4/24/2017
IP-HA

16. Segregation (Demixing)
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
4/24/2017
IP-HA

17. Types of segregation 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.
The percolation also takes place for a short distance on either side of shear planes formed during the mixing process and for this to occur there need be very little difference in particle diameters. This is because of dilatation along the planes which separate the particles sufficiently for smaller particles to move downwards.
4/24/2017
IP-HA

18. Types of segregation
Percolation segregation
4/24/2017
IP-HA

19. Types of segregation Trajectory segregation:
During mixing particles are set in motion and kinetic energy is imparted to them.
Larger particles have larger energies and tend to move a greater distance into the powder mass before they are brought to rest. This may result in preferential separation and it can occur in horizontal as well as vertical planes.
4/24/2017
IP-HA

20. Types of segregation Trajectory segregation:
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.
4/24/2017
IP-HA

21. Types of segregation Densification segregation:
Segregation due to density differences between particles may cause segregation if the mass is subject to vibration.
This can occur, for instance, in the hopper of a tablet machine and it is actively promoted in vibratory sieving so as to place smaller particles directly over the mesh.
4/24/2017
IP-HA

22. Types of segregation Dusting segregation:
Segregation may occur on discharge of a mixed powder for handling elsewhere. In recent years equipment which can perform both mixing and other operations in the same vessel has become popular. This avoids handling the mass between operations.
4/24/2017
IP-HA

23. Types of segregation
Dusting segregation:
4/24/2017
IP-HA

24. Segregation and mixing time
Non‑segregating mixes will continue to improve with an extended mixing time but the reverse may be true for segregating mixes.
The factors promoting segregation require a longer time to establish a segregating mix than is needed to produce a reasonable degree of mixing. It is therefore disadvantageous to prolong the mixing time beyond an optimum point.
4/24/2017
IP-HA

25. Ordered Mixing
If one of the constituents of a powder mix is added in a fine, often micronized form, then on mixing with the larger particles (termed carrier particles) some of these very small particles may adsorb on to active sites on their surface and these are held tenaciously.
Such mixtures are markedly stable towards segregation.
Such mixes are termed 'ordered' since in contrast to random mixes, the constituent particles are not independent of each other and sampling a host particle necessitates removing some of the adsorbed particles with it.
4/24/2017
IP-HA

26. Ordered Mixing
Segregation could occur in an ordered mixture under some circumstances:
Ordered unit segregation
Displacement segregation
Saturation segregation
4/24/2017
IP-HA

27. Ordered Mixing Ordered unit segregation:
This may occur if there are size differences between particles of the carrier constituent since the larger particles are usually associated with more adsorbed material than the smaller particles.
Segregation of the carrier particles can then result in drug‑rich areas in the mix resulting in ordered unit segregation.
4/24/2017
IP-HA

28. Ordered Mixing Displacement segregation:
The addition of another constituent to an ordered mix may result in competition for the available sites on the carrier particles and some adsorbed particles may be displaced.
Magnesium stearate is commonly added as a lubricant to granulates and it can displace adsorbed drugs under certain circumstances.
4/24/2017
IP-HA

29. Ordered Mixing Saturation segregation:
As there are only a certain number of sites on the carrier particles any excess material will rapidly segregate by percolation if too much is added.
There is some evidence that certain sites are stronger than others and particles held on the weaker sites may become dislodged if the mix is vibrated vigorously.
4/24/2017
IP-HA

30. Mixing process
When the particles are loaded into a mixer, they form a static bed.
When a powder bed is forced to move as a result of a mixing force which could be due to tumbling or shear blade, it will “dilate” or “expand”, i.e. the volume occupied by the bed will increase.
Accordingly, there must be room for it to expand; that is, there must be enough void space remaining in the mixer after it has been charged with the ingredients to be blended.
4/24/2017
IP-HA

31. Mixing process
Once particle movement is possible with the expansion of the powder bed, shear forces are necessary to produce movement between particles.
4/24/2017
IP-HA

32. Mixing process In solid-solid mixing four operations are involved:
Expansion of the beds of solids
Application of 3D shear forces to the powder bed
This should continue for enough time to allow randomization of particles
Maintain randomization
4/24/2017
IP-HA

33. Factors affecting mixing
Unit weight (unit dose size)
As the unit weight is increased while fixing other parameters, such as percentage of the active ingredient, achievement of the objective of the mixing process will be easier.
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.
4/24/2017
IP-HA

34. Factors affecting mixing
% 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:
Geometric (serial) dilution.
Particle size reduction.
4/24/2017
IP-HA

35. Factors affecting mixing
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, 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.
4/24/2017
IP-HA

36. Factors affecting mixing
Particle size distribution:
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.
4/24/2017
IP-HA

37. Factors affecting mixing
Particle size distribution:
4/24/2017
IP-HA

38. Factors affecting mixing
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 more readily than ones with sharper edges or 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.
4/24/2017
IP-HA

39. Factors affecting mixing
Particle shape:
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.
4/24/2017
IP-HA

40. Factors affecting mixing
Particle shape:
4/24/2017
IP-HA

41. Tumbling mixers
Are composed of rotating vessels of various shapes so that the charge flows with the vessel when the angle of repose is exceeded.
The shear forces generated in tumbling mixers are insufficient to break up agglomerates and to induce sufficient flow and so they are suitable for free‑flowing material.
4/24/2017
IP-HA

42. Tumbling mixers
When operated at the correct speed, the tumbling action 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.
4/24/2017
IP-HA

43. Tumbling mixers
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.
4/24/2017
IP-HA

44. Tumbling mixers
4/24/2017
IP-HA

45. Tumbling mixers
4/24/2017
IP-HA

46. Tumbling mixers Factors that affect mixing
Loading volume: Affect powder bed dilation. Should be approximately 50-60% of the blender volume.
Blender speed: Too high a rotation speed will cause the material to be held on the mixer walls by centrifugal force and can cause segregation of fine particles by dusting and too low a speed will generate insufficient bed expansion and little shear mixing.
4/24/2017
IP-HA

47. Tumbling mixers
On rotation the charge flows into the two top arms of the Y and then back into the third arm.
Mixing by shear and diffusion takes place when the streams mingle. The mixer is often used to blend in lubricant with tablet granules prior to compression when the gentle action is an advantage.
Time must be allowed for the mix to flow into the arms and there is an optimum speed of rotation. Other tumbling mixers have the mixer vessel in the shape of a cube or double cone.
4/24/2017
IP-HA

48. Tumbling mixers
Addition of baffles or rotating bars will also cause convective mixing (e.g. the V-mixer with agitator bar or 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.
4/24/2017
IP-HA

49. Tumbling mixers
Serial dilution is not needed when incorporating low dose active ingredients in the presence of an agitator.
However possible attrition of the particle may happen for friable granules or particles as a result of the high speed agitator.
4/24/2017
IP-HA

50. Tumbling mixers
4/24/2017
IP-HA

51. Agitator mixers
These mixers depend on the motion of a blade or paddle through the charge producing a high degree of convective mixing.
The ribbon mixer is a common type. The helical blades rotate in a hemispherical trough.
‘Dead spaces' are difficult to eliminate and the shearing action of the ribbon may be insufficient to break up aggregates.
4/24/2017
IP-HA

52. Agitator mixers
The ribbon mixer is top-loading, with bottom discharge port.
It can be used for both liquid-solid and solid-solid mixing.
It provides low shear compared to sigma blade.
4/24/2017
IP-HA

53. Agitator mixers
4/24/2017
IP-HA

54. Agitator mixers
4/24/2017
IP-HA

55. Agitator mixers
4/24/2017
IP-HA

56. Agitator mixers
Another type of agitator mixer is the conical screw mixer (Nautamixer).
It consists of a conical vessel fitted at the base with a rotating screw which is fastened to the end of a rotating arm at the upper end.
The screw conveys material to near the top where it cascades back into the mass. The mixer thus combines diffusive, shear and convective mixing with an avoidance of dead spots since the screw visits each part of the interior in each revolution as the arm rotates.
4/24/2017
IP-HA

57. Agitator mixers
4/24/2017
IP-HA

58. Agitator mixers 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.
4/24/2017
IP-HA

59. Agitator mixers
Sigma blade mixer:
4/24/2017
IP-HA

60. Agitator mixers Sigma blade mixer:
Higher shear compared to 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.
4/24/2017
IP-HA

61. High speed mixers Composite equipments for mixing and granulation.
The mixer (impeller) acts to fluidize the powder bed allowing for diffusive, convective and shear mixing at the same time.
4/24/2017
IP-HA

62. High speed mixers
4/24/2017
IP-HA

63. High speed mixers
4/24/2017
IP-HA

64. Testing for blend homogeneity
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
24-Apr-17

65. Testing for blend homogeneity
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.
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.
24-Apr-17

66. Testing for blend homogeneity
Sampling devices:
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.
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.
24-Apr-17

67. Testing for blend homogeneity
24-Apr-17

68. Testing for blend homogeneity
Design of sample thief:
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 re-unmatched and the whole device is removed from the mix.
24-Apr-17

69. Testing for blend homogeneity
Rotating the inner tube opens the slots, which fill with individual samples (left side of figure). The inner tube is then rotated to the closed position and the sample thief withdrawn.
24-Apr-17

70. Testing for blend homogeneity
24-Apr-17