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Industrial pharmacy
8/22/20171
 Industrial pharmacy is a discipline which includes
manufacturing, development, marketing ...
The Fundamentals unit operations
8/22/20172
 In a pharmaceutical industry a unit operation is a
basic step in a process
...
Fluid flow
8/22/20173
 Fluids are a form of matter that cannot achieve
equilibrium under an applied shear stress but
defo...
Reynolds’ experiment
8/22/20174
 a long glass tube was connected to
a reservoir providing a constant
head of water, with ...
Cont…
8/22/20175
When the velocity is low, the thread of colored liquid remains
undisturbed in the center of the water st...
Cont…
8/22/20176
Reynolds found that flow conditions were affected by four factors
 Diameter of pipe
Velocity of fluid
...
Distribution of Velocities Across the Tube
8/22/20177
 When a fluid flows along a tube, not all parts
are moving at the s...
Boundary Lines
8/22/20178
 whether flow in the tube is laminar or turbulent, the
velocity reaches very low values near th...
1.2 Heat Transfer
8/22/20179
 Heat is a form of energy.
 It can only be transferred from a region of higher
temperature ...
Cont…
8/22/201710
 Convection: is the transfer of heat from one point to another
within a fluid (gas, liquid) by the mixi...
Cont…
8/22/201711
Heat transfer by conduction
8/22/201712
 Conduction is the most familiar and widely
understood mechanism of heat transfer...
8/22/201713
 k ,which is characteristic for any material, is known
as the coefficient of thermal conductivity
 Thermal c...
1.3 Mass transfer
8/22/201714
involves the movement of material from one
phase to another
Eg. in drying a wet solid, the...
Solid fluid mass transfer
8/22/201715
 Consider a crystal of a soluble material immersed in
a solvent in which it is diss...
Cont…
8/22/201716
 Eddy diffusion will not be considered further
since, in general, molecular diffusion is the
controllin...
Factors affecting Solid fluid mass transfer
8/22/201717
 Agitation, which reduces the thickness of the
boundary layers an...
Unit operations
8/22/201718
 Unit operations:- are different processes and
equipments required in the manufacturing of
ph...
Drying
8/22/201719
 Removal of water or other liquid from a solution,
suspension or solid –liquid mixture to form a dry
s...
Factors affecting drying
8/22/201720
The critical factor in drying operations is the
vapor - carrying capacity of the air...
Convective Driers for Wet Solid
8/22/201721
Tray Drier
 Air flows in the direction of
the arrows over each shelf
in turn...
Dynamic Convective Driers
8/22/201722
Fluidized Bed
Drier(FBD)
 There is an excellent
contact between the warm
drying ai...
Advantages of Fluidized Bed Drying
8/22/201723
 Efficient heat and mass transfer. This
attributes to
 Short drying time ...
Disadvantages of FBD
8/22/201724
 Turbulence – Excessive attrition
 Production of too much dust –> too fine –> flow
prob...
Conductive Drying of wet solids
8/22/201725
 The wet solid is in thermal contact with a hot surface
and heat transfer mai...
Radiation drying of wet solid
8/22/201726
Microwave (MW) Radiation
 Microwave radiation in the Wave length of 10nm-
1nm ...
Advantage of MW drying
8/22/201727
 Rapid drying at fairly low Temp.
 Thermal efficiency is high
 most of the MW is abs...
Disadvantages of MW drying
8/22/201728
 Smaller batches sizes are used as compared to FBD
 Safety issues.
Care should b...
Driers for Dilute solutions and suspensions
8/22/201729
 Objective
 To spread the liquid to a large surface area for hea...
Drum driers
8/22/201730
 consists of a drum 0.75-1.5m
in diameter and 2-4m in length
 It is heated internally by steam
...
Advantages of the drum drier
8/22/201731
 gives rapid drying =>rapid heat and mass transfer
 The equipment is compact le...
Disadvantages
8/22/201732
 Operation conditions are critical i.e. it is
necessary to impose careful control on
 Feed rat...
Spray Driers
8/22/201733
 Provides a larger surface area for heat and mass
transfer
Works by atomizing the liquid to sma...
Cont…
8/22/201734
Advantages of the spray Drying process
8/22/201735
Rapid drying (fraction of sec)
 Evaporation is rapid =>the droplets d...
Disadvantages
8/22/201736
 The equipment is very bulky
 Thermal efficiency is low as the air is still hot when it
leaves...
Freeze drying (lyophilization)
8/22/201737
 Many products of pharmaceutical lose their viability
in the liquid state and ...
Advantages
8/22/201738
1. Drying takes place at low Temp., so that enzymes
action is inhibited and chemical decomposition,...
Disadvantage
8/22/201739
1. Very hygroscopic substance.
 The products should be dried in their final
containers and seale...
Size Reduction
8/22/201740
 is the mechanical process of reducing the particle
size of a substance to smaller pieces, to ...
the most common reasons for reducing material sizes
8/22/201741
Create appropriate particle sizes for subsequent
processi...
Factors affecting size reduction
8/22/201742
Hardness
 Hard materials are difficult to comminute
Toughness
 It is ofte...
Cont…
8/22/201743
 Softening Temperature
 The heat during size reduction processes softens and
melts materials with a lo...
Methods for size reduction
8/22/201744
There are four main methods of effecting size
reduction
 Cutting:- the material i...
Cutting
8/22/201745
 The cutter mill consists of a series of knives attached on
a horizontal rotary which act against a s...
Cont…
8/22/201746
Compression
8/22/201747
 Size reduction range 10-100μm
 Direct-pressure milling occurs when a particle is
crushed or pin...
Alternative technique/Roller Mill/
8/22/201748
 Compression mill which uses two cylindrical rollers
mounted horizontally ...
Attrition milling (1-100μm)
8/22/201749
 Is used for the Size reduction of solids in
suspensions, pastes and ointments
Ro...
Impact milling (1-10000μm)
8/22/201750
A hammer mill
 A hammer mill consists of a four or more hammers
hinged on a centr...
8/22/201751
Cont…
8/22/201752
Cont …
8/22/201753
 Example-2 Alternative Technique (Vibration
Milling)
 Uses a drum where 80% of the content is filled ...
Combined impact and attrition Method
8/22/201754
Ball mill
 Both impact and attrition methods are used
 Consists of a h...
Cont…
8/22/201755
Advantages of ball mill
8/22/201756
 It is capable of grinding a wide variety of materials
 It can produce very fine pow...
Fluid Energy Mill
8/22/201757
 Utilizes particle impaction and attrition
 Consists of a hallow tube with a diameter of 2...
Advantages Fluid energy mill
8/22/201758
 The particle size of the product is smaller than that
produced by any other met...
SIZE SEPARATION
8/22/201759
 In pharmaceutical industry, the control of particle size
and size range has great importance...
Size separation by sieving
8/22/201760
 There are several techniques for encouraging particles
to separate into their app...
Cont …
8/22/201761
Centrifugal methods
This type of sieve used a vertical cylindrical sieve
with a high speed rotor insi...
Mixing
8/22/201762
 is a process in which two or more components in a
separate or roughly mixed condition are treated so ...
Types of Mixtures
8/22/201763
 There are three types of mixing based on their
behavior:-
 Positive mixtures
 These mixt...
Cont…
8/22/201764
 Neutral Mixtures
 Here mixing of pastes, ointments takes place.
 When two powders are mixed, then it...
Mechanisms of solid mixing
8/22/201765
 Convective mixing
 Arises when there is the transfer of relatively large group
o...
Cont..
8/22/201766
 Diffusion mixing
 When the powder bed is forced to move or flow
 This is because the powder particl...
Mechanisms of Mixing for Liquids
8/22/201767
 Bulk transport
 involves the movement of a relatively large amount
of mate...
Powder Segregation /demixing/
8/22/201768
 Segregation is the opposite effect to mixing i.e.
components tend to separate ...
Causes of powder segregation
8/22/201769
 Particle size effect
 It is the main cause of segregation
a. Percolation segre...
8/22/201770
C. Elutriation segregation/Dusting out/
 When a material is discharged from a container, very
small particles...
Approach to Rectify Segregation
8/22/201771
Selection of particle size fractions
 E.g. sieving to remove fins or lumps t...
Powder mixing equipment
8/22/201772
Tumbling mixer equipments
 Used for mixing /blending of granules of free flowing
pow...
Cont…
8/22/201773
8/22/201774
 High speed mixer granulator( Rapid mixer
granulators)(RMG)
 It both mixes and granulates
 Fluidized Bed mi...
Mixing of Miscible Liquids and Suspensions
8/22/201775
 Propeller mixer
 It has angled blade which cause the fluid to ci...
8/22/201776
Mixing of Semi solids
8/22/201777
 The problem with semi solids is that they are
not free flowing
 For this reason, mixe...
8/22/201778
Clarification (Filtration)
8/22/201779
Filtration is process that involves the removal or
separation of a solid from a fl...
Terminologies in Filtration
8/22/201780
 Filters: - the porous (permeable) material that
separates particles from the liq...
Principles of Filtration
8/22/201781
 It is more of an art than a science
 The flow of liquid through a filter follows t...
Factors Affecting Filtration rate
8/22/201782
The area available for filtration (A)
 The pressure difference across the ...
Mechanisms of Filtration
8/22/201783
 Straining (sieving)
 the pores are smaller than the particles to be filtered,
and ...
Filtration Equipment
8/22/201784
•Equipment selection
 Equipment should
 Allow a fast filtration rate
 Minimize product...
Industrial Filtration Equipments
8/22/201785
Gravity Filter
 Filter that relay solely on gravity generate low
operating ...
8/22/201786
Advantages
8/22/201787
1. It is automatic and continuous in operation
2. It has a large capacity
3. Varied speed of rotati...
Pressure filters
8/22/201788
 The product is fed to the filter at a high pressure
 Most commonly used for processing of ...
Cartridge filter
8/22/201789
 Commonly used in the
preparation of
pharmaceutical products
 It poses a very large
filtrat...
Air Filtration (High Efficiency Particulate Air (HEPA) filter)
8/22/201790
 HEPA is a type of highly efficient filtration...
8/22/201791
 In most industries HEPA filters work along with
Dehumidifiers or humidity controllers and also along
with st...
8/22/201792
Crystallization
8/22/201793
 Crystallization refers to the formation of solid crystals
from a homogeneous solution
 It i...
Cont…
8/22/201794
 Primary nucleation is the first step in crystallization.
 Simply defined, it's the growth of a new cr...
Figure 3: Solubility's of Several Solids
8/22/201795
Equipment Used in Crystallization
8/22/201796
 Tank Crystallizers
 the oldest and most basic method of crystallization
...
Forced Circulating Liquid Evaporator-Crystallizer
8/22/201797
 These crystallizers combine crystallization and
evaporatio...
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Industrial pharmacy

Industrial pharmacy is a discipline which includes manufacturing, development, marketing and distribution of drug products including quality assurance of these activities

The reasons for the increasing of large scale manufacturing

Economic – As the scale of manufacturing batches increases so, proportionally, does the cost of production decreases

Accuracy – The larger the quantities of materials involved so, proportionally, is the accuracy of measurements increased

Greater scope – The increasing complexity of modern therapy has made it virtually impossible to prepare many medicaments on a small scale

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Industrial pharmacy

  1. 1. Industrial pharmacy 8/22/20171  Industrial pharmacy is a discipline which includes manufacturing, development, marketing and distribution of drug products including quality assurance of these activities  The reasons for the increasing of large scale manufacturing  Economic – As the scale of manufacturing batches increases so, proportionally, does the cost of production decreases  Accuracy – The larger the quantities of materials involved so, proportionally, is the accuracy of measurements increased
  2. 2. The Fundamentals unit operations 8/22/20172  In a pharmaceutical industry a unit operation is a basic step in a process Eg. tablet processing: mixing, milling, drying and sifting  It is convenient to break down the processes for the manufacture of pharmaceutical products into unit operations those unit operations are not fundamental  All unit operations involve and are controlled, to a greater or lesser extent, by one or more of the following basic processes. Fluid flow
  3. 3. Fluid flow 8/22/20173  Fluids are a form of matter that cannot achieve equilibrium under an applied shear stress but deform continuously, or flow, as shear stress is applied.  Certain aspects of all the unit operations employ the movement of a fluid through pipes or between or around particles, etc Mechanism of Fluid Flow  When a fluid flows through a pipe , the character of the flow can vary according to the conditions
  4. 4. Reynolds’ experiment 8/22/20174  a long glass tube was connected to a reservoir providing a constant head of water, with the control valve at the outlet so that the rate of flow could be varied  In the inlet of the tube a jet was inserted which allowed a colored liquid to be injected into the center of the tube for the visualization of the flow behavior
  5. 5. Cont… 8/22/20175 When the velocity is low, the thread of colored liquid remains undisturbed in the center of the water stream and moves steadily along the tube, with out mixing, this condition is known as streamline or laminar flow (a)  At moderate velocities, a point is reached (the critical velocity) at which the thread begins to waver, although no mixing occurs. This is the phase of transitional flow. As the velocity is increased to high values eddies begin to occur in the flow, so that the colored liquid mixes with the bulk of the water immediately after leaving the jet. Since this is a state of complete turbulence, the condition is known as turbulent flow.
  6. 6. Cont… 8/22/20176 Reynolds found that flow conditions were affected by four factors  Diameter of pipe Velocity of fluid  Density of fluid  Viscosity of fluid Re = ρvd/μ  where Re = Reynolds Number ρ = density of fluid (kg/m3) v = velocity of fluid (m/s) d = diameter of pipe (m) μ = viscosity of fluid (kg/m. s)  Reynolds number is just a number and it has no
  7. 7. Distribution of Velocities Across the Tube 8/22/20177  When a fluid flows along a tube, not all parts are moving at the same velocity  The fluid in the center travels at the highest velocity and that at the walls at the lowest  In laminar flow; Fluid in the centre can move at highest velocity with frictional force causing a continual decrease in the velocity towards the walls
  8. 8. Boundary Lines 8/22/20178  whether flow in the tube is laminar or turbulent, the velocity reaches very low values near the walls ultimately, it becomes zero at the wall itself  Reynolds Number is proportional to the velocity  So similar decrease in the value of the local Re.  This means that there will be a change from turbulence, through a transitional region to a sluggish streamline region and finally, to a stationary film on wall.  that boundary layers can never be eliminated  Increasing the velocity of the fluid over the surface will reduce the thickness of the layer
  9. 9. 1.2 Heat Transfer 8/22/20179  Heat is a form of energy.  It can only be transferred from a region of higher temperature to a region of lower temperature  Many pharmaceutical unit operations like distillation, drying, evaporation, sterilization etc involve the application of heat Heat is transferred by three mechanisms  Conduction: is the transfer of heat through a static material by direct contact of particles of matter is greater in solids, where atoms are in constant contact is limited to solids and to fluids that are ‘bound’ in
  10. 10. Cont… 8/22/201710  Convection: is the transfer of heat from one point to another within a fluid (gas, liquid) by the mixing of one portion of the fluid with another  In convection, the heat flow results from mixing or turbulence, which can occur in fluids only  Radiation: is the transfer of heat energy through empty space  No medium is necessary for radiation to occur
  11. 11. Cont… 8/22/201711
  12. 12. Heat transfer by conduction 8/22/201712  Conduction is the most familiar and widely understood mechanism of heat transfer  When heat is flowing under steady-state conditions, the quantity of heat transferred is given by:
  13. 13. 8/22/201713  k ,which is characteristic for any material, is known as the coefficient of thermal conductivity  Thermal conductivities vary considerably, ranging from metals that have high values to gases that have the lowest values Material Thermal conductivity (J/sm°c) Copper 379 Aluminum 242 Steel 43 Glass 1 Water 0.6 Air 0.03
  14. 14. 1.3 Mass transfer 8/22/201714 involves the movement of material from one phase to another Eg. in drying a wet solid, the liquid is converted to vapor and carried away in that form when a drug is extracted with a solvent, soluble material passes from the solid phase into solution and is taken away in the liquid phase
  15. 15. Solid fluid mass transfer 8/22/201715  Consider a crystal of a soluble material immersed in a solvent in which it is dissolving  transport of the molecules of the dissolving solid will take place in two stages  First the molecules move through the boundary layer by molecular diffusion, with no mechanical mixing  Once material has passed through the boundary layer, mass transfer takes place by bulk movement of the solution, known as eddy diffusion,  the controlling factor in the rate of solution of the crystal will be the molecular diffusion through the boundary layer
  16. 16. Cont… 8/22/201716  Eddy diffusion will not be considered further since, in general, molecular diffusion is the controlling process  Equation for mass transfer by molecular diffusion
  17. 17. Factors affecting Solid fluid mass transfer 8/22/201717  Agitation, which reduces the thickness of the boundary layers and disperses any local concentrations of solution, so increasing the concentration gradient.  Elevated temperatures which increase the diffusion coefficient and decrease the viscosity of the liquid, so reducing boundary layer thickness.  Size reduction of the solid, which increases the area over which diffusion can occur.
  18. 18. Unit operations 8/22/201718  Unit operations:- are different processes and equipments required in the manufacturing of pharmaceuticals Size reduction Mixing Drying Filtration  Crystallization
  19. 19. Drying 8/22/201719  Removal of water or other liquid from a solution, suspension or solid –liquid mixture to form a dry solid  involves heat transfer and mass transfer  Drying and evaporation are distinguishable merely by the relative quantities of liquid removed from the solid Purpose of drying/Application of Drying  In the preparation of granules Stabilizes moisture sensitive materials :-Aspirin & penicillin
  20. 20. Factors affecting drying 8/22/201720 The critical factor in drying operations is the vapor - carrying capacity of the air, nitrogen, or other gas stream passing over the drying material  The vapor - carrying capacity determines both rate and extent of drying Heat sensitivity of the product Physical characteristics of the product Nature of solvent to be removed
  21. 21. Convective Driers for Wet Solid 8/22/201721 Tray Drier  Air flows in the direction of the arrows over each shelf in turn  The wet material is spread on shallow trays resting as the shelves  The required latent heat of evaporation is transferred convectively from the air  Slow heat transfer=> slow rate of drying
  22. 22. Dynamic Convective Driers 8/22/201722 Fluidized Bed Drier(FBD)  There is an excellent contact between the warm drying air and the wet particle  The material to be dried is contained in a vessel, the base of which is perforated enabling a fluid (air) to pass through the bed of the solid from the bottom
  23. 23. Advantages of Fluidized Bed Drying 8/22/201723  Efficient heat and mass transfer. This attributes to  Short drying time (20-30 min) Good for thermolibile materials  Drying occurs from the surface of the individual particles  No migration of soluble API & Expients  The temperature of the fluidizing bed is uniform throughout and can be controlled precisely  Turbulence cause attrition – More spherical free flowing particles  The container can be mobile, good for material
  24. 24. Disadvantages of FBD 8/22/201724  Turbulence – Excessive attrition  Production of too much dust –> too fine –> flow problem – >segregation  Generation of static electricity  Mixture of air with organic materials (starch and lactose) can cause explosion  The danger is increased if the fluidizing material contains volatile solvents such as isopropyl alcohol  Therefore, adequate electrical earthing is
  25. 25. Conductive Drying of wet solids 8/22/201725  The wet solid is in thermal contact with a hot surface and heat transfer mainly occurs by conduction  Vacuum Oven  Consists of a jacketed Vessels sufficiently strong in construction to with stand vacuum and steam pressure in the jacket  Operating pressure can be as low as 0.03-0.06 bar,H2O boils at25-350c [[[  Commonly used in pharma R & D`s  Advantages:  For thermolibile products  Minimum oxidation
  26. 26. Radiation drying of wet solid 8/22/201726 Microwave (MW) Radiation  Microwave radiation in the Wave length of 10nm- 1nm penetrates much better than IR  More application in pharma than IR dries does Microwaves are produced by an electronic devices known as magnetron  When MW falls on substances of suitable electronic structure (Polar molecules e.g. water), the electrons in molecules attempt to resonate in sympathy with the radiation and the resulting molecular friction which in turn causes generation of heat
  27. 27. Advantage of MW drying 8/22/201727  Rapid drying at fairly low Temp.  Thermal efficiency is high  most of the MW is absorbed by the liquid No heating of the air  The bed is stationary avoiding the problem of dust generation  Solute migration is reduced as there is uniform heating of the wet mass.  Equipment is highly efficient and refined All product and operators safety have been incorporated CGMP compliant  Drying end point detection is possible
  28. 28. Disadvantages of MW drying 8/22/201728  Smaller batches sizes are used as compared to FBD  Safety issues. Care should be taken to shield operators from the MW radiation  which can cause damage to the eyes and testes
  29. 29. Driers for Dilute solutions and suspensions 8/22/201729  Objective  To spread the liquid to a large surface area for heat and mass transfer and to provide an efficient means of collecting the dry solid  Two main types are used  Spreading the liquid to a thin film on a drum  Dispersing the liquid to a spray of small droplets
  30. 30. Drum driers 8/22/201730  consists of a drum 0.75-1.5m in diameter and 2-4m in length  It is heated internally by steam  The liquid is applied to the surface of the drum and spread to a film  This is usually performed by Deeping the drum in the feeding pan  Drying rate is controlled by  Manipulating the speed of the drum  Manipulating Temp.  The product is scraped from
  31. 31. Advantages of the drum drier 8/22/201731  gives rapid drying =>rapid heat and mass transfer  The equipment is compact less space than spray drier  Heating time is short (a few sec)  The drum can be enclosed in vacuum =>the drying Temp. can be reduced  The product is obtained in flake form which is convenient for many purposes
  32. 32. Disadvantages 8/22/201732  Operation conditions are critical i.e. it is necessary to impose careful control on  Feed rate Film thickness Speed of drum  Drum Temperature  Pharmaceutical applications Drying of starch products  Ferrous salt  Suspensions of Zn oxide
  33. 33. Spray Driers 8/22/201733  Provides a larger surface area for heat and mass transfer Works by atomizing the liquid to small droplets The liquid is sprayed into a stream of hot air  Each droplet dries to an individual solid particles Mechanism of drying  The air enters the chamber tangentially and rotates the drying droplets around the chamber to increase their residence time  The air is heated by heat exchangers  Dust carried over in the air is recovered by cyclone separator of filter  Physical characteristics of spray dried products
  34. 34. Cont… 8/22/201734
  35. 35. Advantages of the spray Drying process 8/22/201735 Rapid drying (fraction of sec)  Evaporation is rapid =>the droplets do not attain high Temp.  good for thermolibile products High bulk density=> rapid dissolution due to increased surface area Uniform and controlled particle size The product is free flowing as the particles are spherical in shape Low labor costs. No human handling
  36. 36. Disadvantages 8/22/201736  The equipment is very bulky  Thermal efficiency is low as the air is still hot when it leaves the drier  Pharmaceutical Application  Gelatin  Starch  Some powdered antibiotics for reconstitution into syrup  Particles in 1-7mm can be dried and used in DPI (dry powder inhalers)  Can be operated with inert gases for 02 sensitive
  37. 37. Freeze drying (lyophilization) 8/22/201737  Many products of pharmaceutical lose their viability in the liquid state and readily deteriorate if dried in air at normal atmospheric pressures  It works by freezing the material and then reducing the surrounding pressure and adding enough heat to allow the frozen water in the material to sublime directly from the solid phase to gas
  38. 38. Advantages 8/22/201738 1. Drying takes place at low Temp., so that enzymes action is inhibited and chemical decomposition, particularly hydrolysis, is minimized 2. The solution is frozen such that the final dry product occupy the same volume as the original solution 3. Fast solubility due to high porosity 4. The process takes place under high vacuum; there is little chance for oxidation
  39. 39. Disadvantage 8/22/201739 1. Very hygroscopic substance.  The products should be dried in their final containers and sealed in situ 2. The process is very slow and uses complicated plants and not universal method.  Uses For drying of Biological products Such as Antibiotics, blood products and vaccines, and enzyme preparations
  40. 40. Size Reduction 8/22/201740  is the mechanical process of reducing the particle size of a substance to smaller pieces, to coarse particles, or to powder  Various terms have been used synonymously with size reduction depending on the product, the equipment, and the process Crushing , Grinding, Milling, Pulverization and Dispersion  particle size affects a number of characteristics in the manufacturing process  controlling the particle size helps assure that the milled material will be consistent and repeatable
  41. 41. the most common reasons for reducing material sizes 8/22/201741 Create appropriate particle sizes for subsequent processing or end use  Color - uniform particles assure batch-to-batch colo consistency /less chance for mottling/ Improve material blending and prevent segregation by making different sized products with similar particle size distributions Increase the material’s surface area to improve a material’s solubility Examples:- decrease particle size of griseofulvin decreased oral dosage regimen half. To facilitate drying of wet masses  reduces the distance the moisture must travel to
  42. 42. Factors affecting size reduction 8/22/201742 Hardness  Hard materials are difficult to comminute Toughness  It is often more important than hardness, so that a soft but tough material may present more problems in size reduction than a hard but brittle substance. Ex. - Rubber - Fibrous drugs Rubber are capable of absorbing large amount of energy through elastic and plastic deformation  Such materials can be milled by cooling Stickiness  It may cause difficulty in size reduction, since a material acts as a lubricant & lowers efficiency of the grinding surfaces.  Example:- Grinding of gummy or resinous
  43. 43. Cont… 8/22/201743  Softening Temperature  The heat during size reduction processes softens and melts materials with a low melting point.  Ex. – Synthetic gums and resins - Heat-sensitive drugs may be degraded or even charred  Moisture content  An increase in moisture can decrease the rate of size reduction to a specified product size  The presence of more than 5% water hinder comminution and often produces a sticky mass upon milling  Only a small amount of energy put into a milling operation actually effect size reduction (2%)
  44. 44. Methods for size reduction 8/22/201744 There are four main methods of effecting size reduction  Cutting:- the material is cut by means of a sharp blade or blades  Compression:- the material is crushed by application of pressure  Impact:- material is hit by an object moving at a high speed or it strikes a stationary surface and the material is broken down into small places  Attrition:- the pressure is applied to the material as in the case of compression, but the surfaces are in motion relative to each other.
  45. 45. Cutting 8/22/201745  The cutter mill consists of a series of knives attached on a horizontal rotary which act against a series of stationary knives attached to the mill casing.  Size reduction occurs by fracture of particles between the two sets of knives which have a clearance of a few millimeters Application  To produce a coarse degree of size reduction of dried granulation prior to tableting  To mill fibrous crude drugs such as roots or barks prior to extraction
  46. 46. Cont… 8/22/201746
  47. 47. Compression 8/22/201747  Size reduction range 10-100μm  Direct-pressure milling occurs when a particle is crushed or pinched between two hardened surfaces  Two rotating bars or one rotating bar and a stationary plate generally produce this milling action  Used in small scale by using a mortar and pestle  In large scale there are:  End runner mill- a weighted pestle is turned by friction of material passing beneath it- a mortar rotates under the powder  Edge runner mill -a pestle rotates against a bed of powder
  48. 48. Alternative technique/Roller Mill/ 8/22/201748  Compression mill which uses two cylindrical rollers mounted horizontally and rotated about their long axes  In rollers, one of the rollers is rotating and the other one is rotated by friction.  This are not like ointment mills where both rolls are driven at different speed and size reduction occurs by attrition  The commonest method in the pharmaceutical industry  USE - used for crushing, such as cracking the seeds of fixed oils to aid solvent penetration in extraction
  49. 49. Attrition milling (1-100μm) 8/22/201749  Is used for the Size reduction of solids in suspensions, pastes and ointments Roller Mill  Two or more metal rolls are mounted horizontally with an adjustable gap which can be as small as 20 μm  The rollers rotate at different speeds so that the material is sheared as it pass though the gap  The material is transformed from the slower to the faster roll  The material (milled) is removed by scraper
  50. 50. Impact milling (1-10000μm) 8/22/201750 A hammer mill  A hammer mill consists of a four or more hammers hinged on a central shaft which is enclosed in a rigid metal case  During milling, the hammer swing out radially from the central shaft  As size reduction continues the inertia of particles hitting the hammer reduces and sequentially fracture is less probable  Hence, hammer mill tend to produce powders with narrow size distribution
  51. 51. 8/22/201751
  52. 52. Cont… 8/22/201752
  53. 53. Cont … 8/22/201753  Example-2 Alternative Technique (Vibration Milling)  Uses a drum where 80% of the content is filled with porcelain or steel balls  During milling, the whole body of the mill is vibrated and size reduction occurs by repeated impaction  Comminuted particles fall through a screen at the base of the mill  The efficiency of vibration milling is greater than that of the conventional ball mill
  54. 54. Combined impact and attrition Method 8/22/201754 Ball mill  Both impact and attrition methods are used  Consists of a hollow cylinder containing balls (30- 50%) of its space  The amount of material in a mill is considerable important  Speed of ball mill has a considerable effect on grinding At low speed – balls will slide or roll over each other
  55. 55. Cont… 8/22/201755
  56. 56. Advantages of ball mill 8/22/201756  It is capable of grinding a wide variety of materials  It can produce very fine powders  It is economical and simple to operate  It can be used for batch or continuous operation  It can be used in completely enclosed form, which makes it especially suitable for use with toxic materials  Disadvantages  Contamination may happen because of wearing of balls and partially from casing.  Soft materials may stick on the sizes of the mill.
  57. 57. Fluid Energy Mill 8/22/201757  Utilizes particle impaction and attrition  Consists of a hallow tube with a diameter of 20-200mm  A fluid (air) is injected as a high pressure jet through nozzles at the bottom of the loop  The high velocity of the air gives rise to zones of turbulence into which solid particles are fed  The high kinetic energy of air causes the particles to impact with each other  A particle size classifier is incorporated so that particles are retained in the tube until sufficiently milled
  58. 58. Advantages Fluid energy mill 8/22/201758  The particle size of the product is smaller than that produced by any other method of size reduction  Is used for thermolabile substances because the cooling effect counteracts the heat generated by milling  There is no abrasion of mill so virtually no contamination of the product  For very sensitive materials it is possible to use inert gases  Having a classifier as an integral part of the system permits close control of particle size and of particle size distribution  Use:- used for obtaining very fine powders, e.g.
  59. 59. SIZE SEPARATION 8/22/201759  In pharmaceutical industry, the control of particle size and size range has great importance  Standards for sieves  There are different standards of sieves for standardization of particles size of powders  Number of sieves:- this is the number of meshes in a length of 25.4 mm (1 inch), in each direction, parallel to the wires  thus a number 10 sieve has 10 meshes in 2.54cm in each direction  Nominal size of aperture:- this is the distance between the wires, so that it represents the length of the side of the square aperture
  60. 60. Size separation by sieving 8/22/201760  There are several techniques for encouraging particles to separate into their appropriate size fractions efficiently Agitation methods A. Oscillation:- The sieve is mounted in a frame that oscillated back and forth B. Vibration:- the mesh is vibrated at high speed, often by means of an electrical device  Brushing methods  A brush can be used to move the particles on the surface of the sieve and to keep the meshes clear.
  61. 61. Cont … 8/22/201761 Centrifugal methods This type of sieve used a vertical cylindrical sieve with a high speed rotor inside the cylinder, so the particles are thrown outwards by centrifugal force Wet sieving  Wet sieving is more efficient than the equivalent dry process, particles being suspended readily and passing easily through the sieve with less blinding of the meshes.
  62. 62. Mixing 8/22/201762  is a process 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  Purposes of pharmaceutical mixing To ensure even distribution of the API  To ensure even appearance To ensure the release of the drug at the correct site and at the desired rate
  63. 63. Types of Mixtures 8/22/201763  There are three types of mixing based on their behavior:-  Positive mixtures  These mixtures are formed when two or more miscible liquids are mixed together by diffusion process.  Irreversible mixing would take place.  Negative mixtures  Hence insoluble solids are mixed with the vehicle to form a suspension or two immiscible liquids are mixed to form emulsion.  require energy for their formation  The components of which will separate unless work is continually expanded on them.
  64. 64. Cont… 8/22/201764  Neutral Mixtures  Here mixing of pastes, ointments takes place.  When two powders are mixed, then it forms a neutral mixtures  Components of the mixture have no tendency to mix spontaneously, nor do they segregate when mixed  They are static in their behavior
  65. 65. Mechanisms of solid mixing 8/22/201765  Convective mixing  Arises when there is the transfer of relatively large group of particles from one part of the powder bed to another as might occur when a mixture blade or paddle moves through the mix  In order to achieve a random mix an extended mixing time is required  Shear mixings  When a layer of material moves / flow over another layer
  66. 66. Cont.. 8/22/201766  Diffusion mixing  When the powder bed is forced to move or flow  This is because the powder particles will become less tightly packed and there is an increase in the voids space between them  Under this circumstance, there is a potential for the particles to fall under gravity through the void created  results in low rate of mixing  N.B all three mixing mechanisms are likely to occur in a certain mixing operation
  67. 67. Mechanisms of Mixing for Liquids 8/22/201767  Bulk transport  involves the movement of a relatively large amount of materials from one position in the mix to another  It tends to produce a large degree of mixing fairly quickly  Turbulent mixing  Arises from the haphazard movement of molecules when forced to move in a turbulent manner  Molecular diffusion  Occurs with miscible fluid whenever a concentration gradient exists and will eventually produce a well mixed product
  68. 68. Powder Segregation /demixing/ 8/22/201768  Segregation is the opposite effect to mixing i.e. components tend to separate out  is very important in pharmaceutical preparations as it causes a non random mixing  Effects of segregation  Increased content variation  Un acceptable variation in weight  Processing difficulties  Non uniform drug release rate
  69. 69. Causes of powder segregation 8/22/201769  Particle size effect  It is the main cause of segregation a. Percolation segregation  Smaller particles tend to fall through the void between larger ones and moves to the bottom of the mass.  Example - during vibration, Stirring or poring b. Trajectory segregation  During mixing larger particles will tend to have greater kinetic energy imparted to them and therefore will tend to move greater distance than smaller particles before come to rest
  70. 70. 8/22/201770 C. Elutriation segregation/Dusting out/  When a material is discharged from a container, very small particles dust in a mix may tend to be blown upward by turbulent air current as the mass tumbles and remains suspended in the air  Particle –density effect  If component are of different density, the more dense materials will have a tendency to move downward even if the particles size are similar  Particle shape  Spherical particles exhibit the greatest flow ability and are therefore more easily mixed, but they also segregate more easily than non spherical particles
  71. 71. Approach to Rectify Segregation 8/22/201771 Selection of particle size fractions  E.g. sieving to remove fins or lumps to achieve drug and excipients within narrow particles size distribution range Milling of components followed by sieving To reduce particle size range Controlled crystallization  Selection of excipients which have densities similar to the API Avoid vibration /proper material handling/  Use of filling machine hopers designed so that
  72. 72. Powder mixing equipment 8/22/201772 Tumbling mixer equipments  Used for mixing /blending of granules of free flowing powders  There are many designs  Examples :Double cone mixers, Twin shells ,Cube mixers , y- cone mixers, Drum mixers  Too high mixer speed  Will cause the material to be held on the wall by the centrifugal force  Too low mixer speed Will generate insufficient bed expansion and little shear mixing
  73. 73. Cont… 8/22/201773
  74. 74. 8/22/201774  High speed mixer granulator( Rapid mixer granulators)(RMG)  It both mixes and granulates  Fluidized Bed mixers  Used for mixing of powders prior to granulation  Agitator mixers Eg -ribbon mixers
  75. 75. Mixing of Miscible Liquids and Suspensions 8/22/201775  Propeller mixer  It has angled blade which cause the fluid to circulate in both axial and radial directions  Turbine Mixer  Used for more viscous fluids  The impeller has four flat blades surrounded by perforated inner and outer diffuser rings
  76. 76. 8/22/201776
  77. 77. Mixing of Semi solids 8/22/201777  The problem with semi solids is that they are not free flowing  For this reason, mixers with rotating elements and narrow clearance between themselves and mixing vessels wall  they must produce a high degree of shear mixing  Sigma blade mixer /- mixer/
  78. 78. 8/22/201778
  79. 79. Clarification (Filtration) 8/22/201779 Filtration is process that involves the removal or separation of a solid from a fluid or a fluid from another fluid The preparation of pharmaceutical dosage forms frequently requires the separation of particles from a fluid Objectives  Sparkling liquid that is free of  Crystalline precipitates or amorphous Colloidal hazes  Insoluble liquid drops Removal of microbes or sterilization
  80. 80. Terminologies in Filtration 8/22/201780  Filters: - the porous (permeable) material that separates particles from the liquid passes through it  Residue: - solids retained in the filter  Effluent filtrate:-the classified liquid  Cake filtration:- The solid forms a cake on the medium and if the recovery of this cake is required the process is called cake filtration  Clarification: - When the solid to be filleted is not exceeding 1.0% and the filtrate is the primary product  Ultra filtration- separation of inter molecular liquid from solids by the use of pressure in on a semi permeable
  81. 81. Principles of Filtration 8/22/201781  It is more of an art than a science  The flow of liquid through a filter follows the basic rules that govern flow of any liquid through a medium offering resistance  The rate of flow may be expressed as  Rate = driving force Resistance  The rate is expressed as volume per unit time & the driving force as a pressure differential  Rate of filtration:- ( dv) (area of filter) x (pressure difference) ( dt) (Viscosity) x (resistance of
  82. 82. Factors Affecting Filtration rate 8/22/201782 The area available for filtration (A)  The pressure difference across the filter bed (filler medium and any cake formed) The viscosity of the fluid passing through the filter i.e. the filtrate( μ pas) increase viscosity =>greater resistance for movement The thickness of the filter medium and any deposited cake (L) Increased Cake = >decreased rate of filtration
  83. 83. Mechanisms of Filtration 8/22/201783  Straining (sieving)  the pores are smaller than the particles to be filtered, and this results the particles to be retained on the filter medium.  Example – Removal of bacteria and fibers from parental preparation Impingement -A liquid following pattern is disturbed eg. Used mainly for removal of materials from gases  Entanglement  If the filter medium consists of a cloth with a nap or is a porous , then particles become entangled in the mass of fibers
  84. 84. Filtration Equipment 8/22/201784 •Equipment selection  Equipment should  Allow a fast filtration rate  Minimize production cost Cheap to buy and to run  Be easily cleanable  Be resistant to corrosion Be capable of filtering large volumes
  85. 85. Industrial Filtration Equipments 8/22/201785 Gravity Filter  Filter that relay solely on gravity generate low operating pressure  They are very simple and cheap and used in laboratories Are common in water treatment Ex - Sand filter Vacuum Filters The rotary Vacuum Filter  is continuous in operation and has a system for removing the cake  up to 2m in diameter and 3.5m in length with a filtration area of 20m2  Used for continuous filtration of slurry containing 15-
  86. 86. 8/22/201786
  87. 87. Advantages 8/22/201787 1. It is automatic and continuous in operation 2. It has a large capacity 3. Varied speed of rotation enables the cake thickness to be controlled  Disadvantage 1. It is complex and expensive 2. Ancillary equipments like vacuum pump  Vacuum receivers Slurry pumps are required 3. Less satisfactory for solids that forms impermeable cake
  88. 88. Pressure filters 8/22/201788  The product is fed to the filter at a high pressure  Most commonly used for processing of pharmaceuticals I. The Meta filter  The filter operates by pumping in the slurry under pressure  Advantages 1. High strength and no fear of bursting 2. No filter medium (stainless steel). This makes it economical  Application  The small surface area restricts the amount of solid that can be collected.
  89. 89. Cartridge filter 8/22/201789  Commonly used in the preparation of pharmaceutical products  It poses a very large filtration surface area in a small unit and is easy and cheap to operate  The cartridge is then fitted in a metal supporting cylinder and the product is pumped under pressure into one end of the
  90. 90. Air Filtration (High Efficiency Particulate Air (HEPA) filter) 8/22/201790  HEPA is a type of highly efficient filtration media that removes microscopic particles from air which passes through the filter  The most efficient HEPA filter removes 99.7% of particles with a size of 0.3η that enter the filter.  Such particles include tobacco smoke, household dust, and pollen.  ULPA filters, or "Ultra-HEPA" filters, are designed to trap 99.999%  Usually Microban is used in HEPA filters which is used to treat the HEPA filter
  91. 91. 8/22/201791  In most industries HEPA filters work along with Dehumidifiers or humidity controllers and also along with steam line and chillers which controls the temperature in such cases the system is termed as Heating, Ventilation and Air conditioning system (HVAC system)
  92. 92. 8/22/201792
  93. 93. Crystallization 8/22/201793  Crystallization refers to the formation of solid crystals from a homogeneous solution  It is essentially a solid-liquid separation technique  The processes by which a crystal forms are called nucleation and growth.  Nucleation is the formation of a small mass on to which a crystal can grow.  Growth is the addition of more solute molecules to the nucleation site  In order for crystallization to take place a solution must be "supersaturated“  Supersaturation refers to a state in which the solvent contains more dissolved solute
  94. 94. Cont… 8/22/201794  Primary nucleation is the first step in crystallization.  Simply defined, it's the growth of a new crystal  The second chief mechanism in crystallization is called secondary nucleation requires "seeds" or existing crystals to achieve crystal growth  The four most common methods of reaching supersaturation in industrial processes are: Cooling (with some exceptions) Ce2(SO4)3 Solvent Evaporation  Drowning :addition of a nonsolvent to the solution which decreases the solubility of the solid Chemical Reaction: alter the dissolved solid to
  95. 95. Figure 3: Solubility's of Several Solids 8/22/201795
  96. 96. Equipment Used in Crystallization 8/22/201796  Tank Crystallizers  the oldest and most basic method of crystallization  saturated solutions are allowed to cool in open tanks  After crystallization, the mother liquor is drained and the crystals are collected  The crystallization is essentially just "allowed to happen“  Heat transfer coils and agitation can be used  high operating costs
  97. 97. Forced Circulating Liquid Evaporator-Crystallizer 8/22/201797  These crystallizers combine crystallization and evaporation  The circulating liquid is forced through the tube side of a steam heater  The heated liquid flows into the vapor space of the crystallization vessel  flash evaporation occurs, reducing the amount of solvent in the solution  The supersaturated liquor flows down through a tube, then up through a fluidized area of crystals and liquor where crystallization takes place via secondary nucleation.  Larger product crystals are withdrawn while the liquor is recycled, mixed with the feed, and reheated.

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