Drying

Introduction
Drying The removal of all or most of the liquid associated with
a wet pharmaceutical product.

Equally important in both

Primary Pharmaceutical Manufacturing
Secondary Pharmaceutical Manufacturing
To decrease the residual moisture present in the pharmaceutical
product.

Though most pharmaceutical materials are not completely free f

rom moisture.
Wet solid Exposure to moving, relatively dry air.

Solution and suspension Use of Spray dryer that is capable of

producing a dry product from solution or suspension in one ope
ration.

Evaporation and sublimation

Must provide latent heat for these processes without significant

temperature rise.
In most cases the liquid used is usually water but, volatile organi
c solvents may also need to be removed in a drying process.

Take note:
The toxicity and flammability of organic solvents pose additional
safety and process considerations.
Drying of wet solids
Fundamental properties a
nd interrelationships
Total moisture Content
Moisture content is the kilogram of moisture associated with 1 k
ilogram of the moisture-free (bone-dry) solid

Ex. 0.4 MC means that 0.4kg of water present per kg of the bon
e-dry solid.

Total moisture content is the total amount of liquid associated w

ith a wet solid.
Total moisture Content
There are two types of liquid found:

1.Unbound water
2.Bound water
Equilibrium moisture content
Evaporative drying processes will not remove all the possible mo
isture present in a wet product.

Moisture content of a solid under steady-state ambient conditio

ns.

Value changes with temperature and humidity of the air, and nat
ure of the solid.
Moisture content of air
Expressed as the kilogram of water per kilogram of bone-dry dr
y air.
The moisture content of air is not altered only by changing its te
mperature, but by changing the amount of moisture taken up by
the air.
Relative humidity of air
*Ambient air a simple solution of water in a mixture of gases a
nd as such follows the rules of most solutions.
Rules:
1.Increased water solubility increasing temperature.
2.Maximum solubility at a certain temperature.
3.Precipitation of the solute on cooling.

At a given temperature air is capable of taking up water vapour

until it is saturated.
Lower relative humidities
Percentage relative humidity
This is approximately equal to the percentage saturation.

The two differ slightly in practice and because water vapour doe
s not behave exactly like an ideal gas.

Relative humidity of air is dependent not only on the amount of

moisture in the air but also on its temperature.
The amount of water required to saturate air is itself dependent
on temperature.
Additional complication:
During the drying process, both temperature and moisture cont
ent of the drying air could change significantly.
Uptake into the drying air of evaporated water vapour from the
drying solid.
Evaporative cooling.
Loss of water from wet solids
Loss of water from wet solids
Silica Gel (3) (Fig. 2)

Phosphorus pentoxide (4) (Fig. 2)

*Unnecessary to overdry a product (Fig. 1)

TYPES OF DRYING METHOD
Considerations for choosing a drying method to be used:
heat sensitivity
physical characteristics
nature of the liquid
scale of the operation
necessity for asepsis
available sources of heat

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GENERAL PRINCIPLES FOR EFFICIENT DR
YING
large surface area
efficient heat transfer per unit area
efficient mass transfer of evaporated water through any surrou
nding boundary layers
efficient vapour removal

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 TYPES OF PHARMACEUTICAL DRYERS

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1. CONVECTIVE DRYING OF WET SOLI
DS
fluidized-bed dryer
- excellent method of obtaining good contact between warm d
rying air and wet particles
- developed to improve the efficiency of heat transfer and vap
our removal

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ADVANTAGES OF FLUIDIZED-BED DRYING
efficient heat and mass transfer give high drying rates
drying occurs at a constant rate
temperature of the fluidized bed is uniform
produces more spherical free-flowing product
free movement of individual particles
granules separate during drying
fluidization containers can be mobile
short drying times
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DISADVANTAGES OF FLUIDIZED-BED DRY
ING
turbulence of the fluidized state may cause too much attrition
fine particles may become entrained in the fluidizing air
vigorous movement of particles in hot air can lead to the gener
ation of charges of static electricity
danger is increased if the fluidized material contains a volatile
solvent

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 2. CONDUCTIVE DRYING
Vacuum oven
Parts:
1.Vessel jacketed, can withs
tand a vacuum within the o
ven and steam pressure
2.Condenser
3.Liquid receiver
4.Pump

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2. CONDUCTIVE DRYING
Vacuum oven
- operating pressure: 0.03 0/06 bar, water boils at 25-350C
- main advantage:
Drying takes place at a low temperature
Minimum risk of oxidation
For drying of thermolabile or oxygen-sensitive materials
For drying of development samples where heat stability of
the drug or formulation is uncertain

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3. RADIATION DRYING
Use of microwave radiation
- wavelength of 10mm-1m has been found to be an efficient hea
ting and drying method
GENERATION AND ACTION OF MICROWAVES
Magnetron produces the microwaves
Microwave energy reflected down a rectangular duct (wavegu
ide) or beamed through a transparent propylene window into t
he drying chamber.
Permitted to operate only at 960 2450 MHz
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GENERATION AND ACTION OF MICROWA
VES
When microwaves fall on substances with suitable electronic st
ructure, the electrons in the molecule resonate resulting in mol
ecular friction, which results in the generation of heat.
Large molecules of the solids do not resonate well
Loss factor ratio of microwave energy absorbed by molecules
to the microwave energy provided.
The higher the loss factor, the greater the absorption of e
nergy

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MICROWAVE DRYER FOR
GRANULATES
Operates under a slight vacuum to f
acilitate the airflow through the cha
mber
Radiation is generated by multiple
magnetrons each producing 0.75 k
W at 2450 MHz
Radiation passes through the propyl
ene window into the drying chambe
r
Radiation field intensity will rise onc
e drying is nearly complete
This rice is detected and magnetron
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progressively turns down automati
Advantages of microwave drying
Provides rapid drying at low temperatures
Thermal efficiency is high
The bed is stationary, avoiding problems of dust and attritions
Solute migration is reduced and there is uniform heating of the
wet mass
Equipment is highly efficient and refined
Granulation endpoint is possible by measuring residual micro
wave energy

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Disadvantages of microwave drying
The batch size is smaller
Care must be taken to shield the operators from the radiation

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Dryers for solutions and s
uspensions
Spray dryer
 Spray dryer

http://www.gea.com/en/binaries/26113/index.html
 Atomizer

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 Atomizer

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 Rotary Atomizer
ADVANTAGES DISADVANTAGES

The liquid feed system can operate at Produce large quantities of fine particles, so
relatively low pressure pollution control problems

Able to handle applications where clogging High capital cost & very expensive to maintain
would be a problem for nozzles

Particle size can be changed by changing the Difficult to use with highly viscous materials
wheel speed

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5/7/17
Advantages of the Spray drying process
Evaporation is rapid due to large surface area for heat and
mass transfer
Droplets do not attain a high temperature due to rapid evap
oration
High bulk density
Rapid dissolution
Uniform and controllable particle size of powders
Free flowing product, has excellent flow and compaction pro
perties
Increase the dissolution rate and bioavailability of poorly wa
Disadvantages of the Spray drying proce
ss
Bulky and expensive equipment
Low overall thermal efficiency
Uses of the Spray-drying process
Used for drying almost any substance, in solution or in su
spension
Useful for thermolabile materials and in large quantities
Capable of producing spherical particles in the respirable
range of 1-7 micrometers
It is possible to operate spray dryers aseptically using he
ated filtered air to dry products (e.g. serum hydrolysate)
Some spray dryers operate in a closed circuit mode with i
nert gas minimizing the oxidation of the product
Volatile solvents can be recovered from such systems
Fluidized Spray Dryer
Freeze drying
Freeze drying
Used to dry extremely heat sensitive materials
Allow the drying of proteins, blood products and micro
organisms
Frozen Liquid Solution/Suspension reduce pressure
Water removed (sublimation) Vapor
Three states of matter is involved in the process
Phase diagram for water

o Vapor, liquid and solid phase

o Two phases can coexist along a
line under the conditions of te
mperature and pressure.
Phase diagram for water

Point B (TRIPLE POINT)

The point where the three p
hases can coexist
o 610 Pa and 0.0075C
Phase diagram for water
o The boiling point of water decre
ases as the pressure lowers (CB)
o Relationship between the meltin
g point of ice and reduction of e
xternal pressure (DB)
o Reduction of the vapor pressure
exerted by the ice as the temper
ature is reduced (AB)
Phase diagram for water
Application of the phase diagram of water to freeze
drying:
1. Freezing the solution
2. Reducing the vapor pressure to below the triple point
of the substance
3. Adding a heat to the system to raise the temperature
to the sublimation curve to provide the latent heat of
sublimation
Stages of freeze-drying proce
ss Stage
1. Freezing
2. Vacuum application stage
3. Sublimation Stage
4. Secondary Drying
5. Packaging
Freezing stage
The temperature applied must be lower than the freezi
ng temperature of pure water to completely freeze the
material
Freezing stage
Methods of freezing:
Shell freezing
Centrifugal evaporative freezing
Freezing stage
Shell freezing
Fairly large volumes (blood products)
The bottles are rotated slowly in a refrigerated bath
Liquid freezes in a thin shell around the inner circu
mference of the bottle
Disadvantages: slow freezing and formation of large
ice crystals
Freezing stage
Centrifugal evaporative freezing
Solution is spun in a small container within a centrif
uge
The inside of the machine used in this method of fre
ezing is a vacuum
Around 20% of water is removed in this process prio
r to freeze drying
Vacuum application stage
The containers with the frozen material must be conne
cted to a source of vacuum sufficient to drop the temp
erature below the triple point.
Sublimation stage
Heat of sublimation must be applied
Slow process and surface area dependent
Sublimation stage
Primary Drying
Heat Transfer
Vapor Removal
Rate of Drying
Secondary Drying
Primary Drying
The latent heat of sublimation must be provided and t
he vapor removed

Heat transfer
Vapor removal
Rate of drying
Heat Transfer
Critical
Insufficient heat prolongs the process; excess heat will
cause melting
From the centrifuge, the containers are placed in a hea
ted cylinder or are connected to a manifold when heat
can be taken from the surrounding environment that
must be replaced by some form of input heat
Vapour Removal
Prevent the pressure within the container to rise above
the triple point pressure and thus preventing sublimati
on
Vacuum pumps Reduce pressure efficiently
Small Scale Two stage rotary pumps
Large Scale Ejector pumps
Vapour Removal
Small Scale
oDesiccant
oSmall Condenser
Large Scale
oMechanically refrigerated condensers
Rate of Drying
Very Slow (1mm thickness/hour)
Computer control monitor drying
cycle
Optimum vapour pressure at m
aximum sublimation rate
Heat Input

Continuous freeze drying

Secondary Drying
Removal of final amounts of residual moisture
50 or 60
PackagiNG
Protection from moisture
Controlled atmospheric conditions

Ampoules sealed on the manifold while still under v

acuum
Freeze Drying
Advantages Disadvantages
1.Inhibited enzyme action 1.Very hygroscopic
and minimized chemical nature of product
decomposition (e.g.
2.Uses very
hydrolysis)
expensive
2.Light and porous product complicated plant
3.Ready solubility of the and is a very slow
freeze-dried product process
4.No concentration of the
solution prior to drying
5.Oxidation is minimized
USES
Product cannot be dried by other heat method
Biological Products
Antibiotics, Blood Products, Vaccines, Enzyme Pre
parations, Microbiological Cultures
 SOLUTE MIGRATION
It is a phenomenon that occur during drying from which
movement of solution within the wet system.
Drugs and binding agent are soluble in granulating fluid.
Can lead to localized variability of concentration of solute
drugs and excipients
 Types of solute migration
1. Intergranular migration
Solutes move from granule to granule
Occur during the drying of static beds of granules
May have deficiency or an excess of the drug

2. Intragranular migration
Solute move towards periphery of each granule
 Consequences of Solute Migration
LOSS OF ACTIVE DRUG
-Periphery of each granule-enriched
-Interior of granule-depletion
-Fluidized bed-drying
 MOTTLING OF COLOURED TABLETS
-by adding soluble colour during wet granulation
-Intragranular migration of colour-highly coloured outer zone and
colorless interior
-Reduced by using insoluble aluminium lake of colouring material
-Small granules-do not fracture readily
 MIGRATION OF SOLUBLE BINDERS
-Soluble binder at the periphery
-Hoop stress resistance
-Aid bonding process
Influence of formulation factors on solut
e migration
NATURE OF THE SUBSTRATE
-Principles are similar to those of thin layer chromatography
-Common tablets possess affinity
-Absorbent material- minimize tablet solute migration
-Water insoluble aluminium lakes> water soluble dyes
 VISCOSITY OF GRANULATING FLUID
-Solutions of polymers are greater viscosity than water
-Viscosity impedes the movement of the moisture
-PVP solution
-Methylcellulose solution
Influence of process factors on solute mi
gration
DRYING METHOD
-Temperature gradient
-Slow convective drying- max. conc. Of migrated solute will occ
ur in the surface of drying bed
-Drying by microwave radiation-uniform heating
-Granules in motion abolish intergranular migration
 INITIAL MOISTURE CONTENT
-greater moisture content- greater moisture movement before pe
ndular state
SOME PRACTICAL MEANS OF MINIMIZIN
G SOLUTE MIGRATION
Use the minimum quantity of granulating fluid and ensure that
is well distributed
Prepare smallest granules that will flow easily
Avoid tray drying
If tray drying is unavoidable, dry granules should be remixed b
efore compression
If intragranular migration is troublesome, consider vacuum or
microwave drying