DRYING

- last stage of manufacturing before packaging

- residual moisture is low enough to prevent product deterioration
- wet crystallized product may be freed from its residual moisture by
initial treatment in a dewatering centrifuge
- removal of all or most of the liquid by supplying latent heat to cause
thermal vaporization

DRYING OF WET SOLIDS
MOISTURE CONTENT OF WET SOLIDS
- kilograms of moisture associated with 1kg of the moisture-free or
bone dry solid

Total moisture content
- total amount of liquid associated with a wet solid
- free moisture content- easily removable water
- equilibrium moisture content- moisture which is more difficult to
remove
- unbound water- easily removable water
- exists as a liquid and exerts its full vapour pressure
- removed readily by evaporation
- air dry- water is easily lost but the resulting solid is not
completely free from water

Equilibrium moisture content
- moisture content present in a solid under steady-state ambient
conditions
- not all possible moisture present in a wet product will be removed
because the solid equilibrates with the moisture in air
- bound water- more difficult to remove than unbound
- adsorbed on the surfaces of solid as individual water
molecules which may form a mono- or bi- layer on the solid
surface
- absorbed water- liquid trapped in capillaries within the solid
by surface tension

RELATIVE HUMIDITY (RH) OF AIR
- increased solubility with increase in temperature
- maximum solubility at a particular temperature (saturation)
- precipitation of the solute on cooling (condensation)
- temperature raised, take up more moisture, RH falls
- RH may rise during the process where warm air is passed over the
wet solid surface
a. Uptake of evaporated water vapour from the wet solid
b. Cooling of the supply air as it transfers heat to the wet solid
(evaporative cooling)
- dew point- liquid water will condense and be deposited

Wet-bulb and dry-bulb temperature
- evaporative cooling- latent heat of evaporation is taken from the
sensible heat of the water surrounding the bulb
- keeping the bulb moist by a wet cotton wick immersed in a water
reservoir; thermometer will register a lower temperature

Moisture content of air
- kg of water per kg of bone dry air

RELATIONSHIP BETWEEN EQUILIBRIUM MOISTURE CONTENT AND
RELATIVE HUMIDITY
- equilibrium moisture content varies with the RH
- ordinary atmospheric conditions are of the order of 20C and 70-
75% RH
- mineral 1% moisture
- starch-based product 30% or more
- matl exposed to humid conditions will regain moisture

LOSS OF WATER FROM WET SOLIDS
- reduce moisture content by reducing the RH of the air
- small scale, desiccators (eg. Silica gel) --- does not take water from
solid but removes water from air
- phosphorus pentoxide has greater affinity for the water in storage
air
- moisture may be regained very quickly from the atmosphere

TYPES OF DRYING METHOD
- convective, conductive or radiant

CONVECTIVE DRYING OF WET SOLIDS
1. Fixed (or static) bed convective drying
- Tray, shelf or compartment is the drier

Tray drier
- Directed circulation
- Air is periodically reheated after it has cooled by passage over the
wet material on one shelf before it passes over the next
- Heat transfer from air is relatively inefficient
- Slow, can take up to 24 hours to dry
- Periodic reheating of the air is the temperature falls so that it can
pick up further moisture
- Outgoing (wetter) air contacts with the wettest material

Rate of drying in fixed beds
- Constant-rate period- linear relationship; drying rate is uniform
- Evaporation occurs at the surface and it remains wet since the
liquid from below replaces those vaporized at the top
- First falling-rate period- solvent level decreases and has to further
travel to the point of evaporation
- as drying rate decreases, less heat is used as heat of
vaporization, heat input should be reduced
- Critical moisture content- end of the constant rate period
- Falling-rate period (second falling-rate period)- rate of loss of
moisture decreases; decrease in rate of drying until equilibrium
moisture content is reached
- Danger of overheating is highest
- Drying rate depends on the movement of the vapour
through the pores of the bed to the surface (molecular
diffusion)
- Thermal conductivity of solid decreases as it becomes dry
- Thermostable- safe to allow temperature gradient to
increase to maintain heat transfer
- Thermolabile- heating must be decreased

2. Dynamic convective driers
Fluidized-bed drier
- matter is contained in a vessel, the base is perforated enabling a fluid
to pass through the bed of solids
- when air velocity is low, flow takes place between the particles
without causing disturbance
- as velocity is increased, fractional drag on the particle is equal to the
force of gravity on that particle
- rearrangement of the particle occurs to offer least resistance
- particles are suspended in air and can move
- because of great porosity, pressure drop decreases slightly
- further increase in the air velocity causes particles to separate and
move freely- bed is fully fluidized
- any additional increase in velocity separates the particles further, the
bed expands w/o appreciable change in the pressure drop
- velocity is sufficient to entrain the solid particles and transport them
out of the top of the bed
- boiling bed- air flowing through the bubbles
- produces conditions of great turbulence
- if hot air is used, the turbulent conditions lead to high heat and mass
transfer rates
- offers rapid drying

Advantages:
i. Short drying time
ii. Drying occurs from the surface of all individual particles
iii. Temperature is uniform
iv. Turbulence causes attrition--- producing more spherical free-
flowing products
v. Free movement of particles--- eliminates risk of migration
vi. Mobile containers
vii. High output due to short drying times
Disadvantages:
a) Turbulence may cause excessive attrition--- production of too
much dust, damage to granules
b) Fine particles entrained in fluidizing air
c) Movement of particles my generate static electricity (if lactose
is present, ignition by static charges and explosion can occur.
Increased danger if volatile solvent- isopropanol is present)

CONDUCTIVE DRYING OF WET SOLIDS
- Wet solid is in thermal contact with a hot surface

Vacuum oven
- Airtight seal
- 0.03-0.06 bar, water boils at 25-35C
Advantages:
a) Drying takes place at a low temperature
b) Minimum risk of oxidation since little air is present

Vacuum tumbling drier
- Heat transfer rates are higher than in convectional vacuum oven

RADIATION DRYING OF WET SOLIDS
1. Radiant heat transmission
- no transfer medium needs to be present

Use of infrared radiation
Disadvantages:
a) absorbed very quickly and does not penetrate far into the wet
mass
b) surface layers dry quickly and the absorption of further energy
raises the temperature of the product, which is detrimental

2. Use of microwave radiation
- wavelength range 10mm to 1m penetrates better that IR radiation
- longer wavelength

Generation and action of microwaves
- Microwaves are produced by magnetrons
- Frequency of 960- 2450MHz to avoid interference with radio & TV
- Molecular friction results in the generation of heat
- Loss factor is a measure of the ratio of the microwave energy
absorbed by individual molecules; the higher the number, the
greater the absorption of microwave energy

Microwave drier for granules
- Air flow allows the continuous removal of evaporated solvent
- Heat generated in the mass drives off the moisture and the evolved
vapour is drawn away in the air flows as it is formed
- When drying is nearly complete, radiation field intensity will rise
- Rise is detected and the magnetrons are turned off automatically to
give an accurate control of the final moisture content and minimize
the danger of overheating

Advantages:
a) Rapid drying at low temperatures
b) Thermal efficiency is high
c) Bed is stationary- avoid dust and attrition problems
d) Solute migration is reduced- uniform heating
e) Highly efficient and refined equipment
f) Granulation end-point is possible
Disadvantages:
a) Batch size is smaller
b) Can cause damage (in organs such as eyes and testes) to
operators--- put failsafe devices

DRIERS FOR DILUTE SOLUTIONS AND SUSPENSIONS
- Objective is to spread the liquid to a large surface area for heat and
mass transfer and to provide an effective means of collecting the
drying solid
- spread the liquid to a thin film on a drum
- Second, disperse the liquid to a spray of small droplets
Drum drier
- liquid is applied to the surface of the drum and spread to a film
- simplest method is where the drum dips into a feed pan
- rate is controlled by the speed of rotation of the drum and temp
- drum can be heated by steam or warm water
- product is scraped by the means of a doctor knife
- for starch products, ferrous salts, suspensions of kaolin, zinc oxide
Advantages:
a) Rapid drying
b) Equipment is compact
c) Heating time is short (few seconds)
d) Drum in a vacuum jacket (temp is reduced)
e) Product is in flake form
Disadvantages:
a) Operating conditions are critical
b) Impose careful control on feed rate, film thickness, speed of
drum rotation and drum temperature

Spray drier
- large surface area for heat and mass transfer
- atomizing the liquid to small droplets
- drying chamber resembles a cyclone- good air circulation, facilitates
heat, encourages separation of dried particles from air
- jet atomizers easily blocked by rapid evaporation and deposition of
solid on the nozzle and droplet size is likely to vary
- rotary atomizer has the advantage of being equally effective with
solutions or suspensions of solid and can operate efficiently at various
feed rates
- rotates the drying droplets around the chamber to increase
residence time and drying time
- filter the air and to heat it indirectly by heat exchanger
- uniform in appearance, easily recognizable
- particle shape is hollow sphere sometimes with a small hole
- any substance in solution or in suspension
- most useful for thermolabile materials
- for citric acid, sodium phosphate gelatine, starch, barium sulfate,
calcium phosphate, powdered antibiotic formulations for
reconstitution to syrup, dry powder inhalers
Advantages:
a) Millions of small droplets= large surface area for heat and mass
transfer= very rapid evaporation (overall, few seconds)
b) Droplets do not attain high temp. Particles kept cool by
evaporative cooling
c) High bulk density= rapid dissolution (large surface area)
d) Uniform and controllable particle size
e) Excellent flow and compaction prop for tablet manufacture
f) Low labour costs

Disadvantages:
a) Equipment is very bulky and expensive
b) Overall thermal efficiency is low (air must be hot when it leaves
the drier to avoid condensation)

FREEZE DRYING/ LYOPHILIZATION
- dry extremely heat-sensitive materials
- allows drying w/o excessive damage of proteins, blood products and
microorganisms
- initial liquid is frozen, pressure above frozen state reduced (pressure
below triple point), water removed by sublimation (liquid-solid-
vapour; all under 0 C)
- triple point- all three phases coexist (610 Pa, 0.0075 C)
- for biological productsantibiotics, blood, vaccines, enzyme
preparations, microbiological cultures

Problems:
a) Must be within -10 to -30C
b) Sublimation only occurs at frozen surface and slow process
c) At low pressure, large volumes of water vapour are produced
which must be rapidly removed to prevent the pressure rising
above the triple point pressure
d) Dry material often needs to be sterile
Advantages:
a) Drying at very low temperatures- enzyme action inhibited,
chemical decomposition by hydrolysis is minimized
b) Product is light and porous
c) Porous form is soluble
d) No concentration of the solution prior to drying
e) Oxidation is minimized
Disadvantages:
a) Porosity, ready solubility and complete dryness= hygroscopic
product
b) Very slow process, expensive

Stages of freeze drying process:
Freezing stage
- frozen before application of vacuum to avoid frothing
i) Shell freezing- fairly large volumes (blood products)
- horizontally
-slow and large crystals form= damage blood cells and
reduce viability of microbial cultures
- vertical spin freezing
- solution supercools and freezes rapidly, formation of
small ice crystals
ii) Centrifugal evaporative freezing (ampoules) - prevents foaming

Vacuum application stage
- drop the pressure below the triple point and remove the large
volumes of low pressure vapour formed

Sublimation stage
i) Primary drying- reduce moisture content of a freeze-dried solid to
0.5%
ii) Heat transfer- insufficient, longer process; excess heat- melting
- added heat but no significant increase in temperature
- prefrozen bottles- blood, shelf- frozen materialsshelf,
ampoulescentrifuge head
iii) Vapour removal- to avoid pressure rise that stops sublimation
- use efficient vacuum pumps (small scaletwo-stage rotary
pumps; large scaleejector pumps)
- absorb vapour (small scaledesiccant like phosphoruus
pentoxide, cooled with solid carbon dioxide; large scale
mechanically refrigerated condensers)
iv) Rate of drying very slow

Secondary drying
- removal or residual moisture at the end of primary drying
- raising the temperature to 50-60 C

Packaging
- ensure protection from moisture

SOLUTE MIGRATION DURING DRYING
- movement of a solution within a wet system
- solvent moves towards the surface of a solid
Intergranular migration- solutes move from granule to granule
- result in gross maldistribution of the active drug
- during drying of static beds (tray drying)
Intragranular migration- solutes move towards the periphery of each
granule

Consequences of Solute Migration
Loss of active drug
- occurs in fluidized-bed drying
- interior has a depletion of active drug

Mottling of coloured tablets
- reduced by insoluble aluminium lake of colouring materials
- small granules which do not fracture readily

Migration of soluble binders
- hoop stress resistance= granules harder, more resistant to abrasion

Influence of Formulation Factors on Solute Migration
Nature of substrate
- presence of absorbent materials (starch and microcrystalline
cellulose)minimize tablet solute migration
- granule substrate has affinity for the soluteimpede migration
- water-insoluble lakesreduces mottling

Viscosity of granulating fluid
- impedes movement of moisture by increasing fluid friction
- increase concentration= increase viscosity of PVP solutionslows
down migration of drugs in fixed beds of wet granules

Influence of Process Factors on Solute Migration
Drying method
- intergranular migration- whenever temperature gradient is present
(convective drying)
- microwave radiationminimizes solute migration
- methods that keep granules in motionabolish intergranular
migration (intragranular may still occur; fluidized bed)
- vacuum tumblingreduce migration

Initial moisture content
- greater moisture content= greater moisture movement

Practical Means of Minimizing Solute Migration
a) Minimum quantity of granulating fluid and ensure it is well
distributed
b) Smallest granules that will flow easily (= large surface area) for
mottling
c) Avoid tray drying
d) Tray drying, remix before compression
e) Vacuum or microwave drying as alternative to fluidized- bed
drying --- for intragranular migration





PACKS AND PACKAGING
- economical means of providing presentation, protection,
identification/information, containment, convenience and compliance
for a product during storage, carriage, display and use until such time
as the product is used or administered.
- reel-fed materials for blisters and strips

The role of the pack
- emphasis as the shelf-life of all pharmaceutical products
- economical and contribute to overall profitability
- provide protection against climatic, biological, physical, chemical
hazards; provide acceptable presentation, maintain adequate
identification & information, contribute to convenience & compliance
- consider total (shelf) life of the product, periods of storage (static),
carriage (motion), display and use of administration
- compliment product confidence, provide clear and concise product
ID, adequate information, route of administration, storage conditions,
batch number, expiry date, manufacturers name, address and
product license number, assist in patient complicate, aesthetically
acceptable design
- primary pact- packaging components that form the part of the pack
directly containing the product (bottle, cap, cap liner, label)
- functions- contain and restrict any chemical, climatic, biological
or mechanical hazards that may lead to product deterioration
- secondary packaging- provides the additional physical protection to
ensure the safe warehousing and delivery of the product to the point
where bulk quantities are broken down into individual or specific units

THE PACK AS A PROTECTION
- protection is most critical factor since it controls the total shelf-life

Mechanical hazards
i) Compression
- top pressure or loading
- crushing of a carton- product unsealable even though no damage
occurs to the contents
- occur during stacking, vibration adds to further hazard
ii) Vibration
- two variables- frequency and amplitude
- components of product may separate, screw caps may loosen,
labels or decoration may abrade
iii) Abrasion
- visual appearance of the product or pack can be affected
iv) Puncture or piercing
- penetration from sharp objects e.g. poor control of forklift trucks
- adequate cushioning and/or resistance to penetration

Climatic or environmental hazards
- ever-present hazards
i) Moisture
- moisture loss or moisture gain
- cause physical changes (e.g. dulling, softening, hardening)
- cause chemical change (hydrolysis, effervescence)
- carrier for other contaminants
- plastics are permeable to moisture
- passage depends on sealing medium, torque, evenness and shape
of sealing surface, aperture size, circumferential area of the
container
ii) Temperature
- higher temperatures generally represent an acceleration effect
- deterioration may increase at lower temperatures
- high temp together with high RH will produce a shower effect if
the temp is lowered to reach dew point
- encourage mould and bacterial growth
iii) Pressure
- air-pressure differentials
iv) Light
- printed or decorated packaging materials may suffer from
discolorationimplying a change in product efficacy or strength
- exclude light by tin plate or foil
- reduce penetration or filter out selected wavelengths by opacity
or color
- additional use of UV absorbers in plasticsrestrict light rays
v) Atmospheric gases
- oxygen, carbon dioxide, nitrogen
- oxygenoxidation
- carbon dioxidecause pH shift (unbuffered solution in plastic
LDPE bottles); most permeable
- ratio of 1:4:20 (N, O
2
, CO
2
)
vi) Solid airborne contamination (particulates)
- plastic contamination may be increased by electrostatic
attraction under dry conditions
- particulates increase microbiological contamination risk

Biological hazards
i) Microbiological
- sterile products, pack & closure must maintain 100% effective seal
- ingress of yeasts is critical with sugar-based products
- mould will grow on cellulose-based materials
ii) Other forms of infestation
- attack by insects, termites, vermin, rodents or any bird or animal-
containing source
iii) Pilferage and adulteration risks
- need for tamper-resistant packs
- security seals- means of increasing and maintaining user
confidence in the product and pack

Chemical hazards
- interaction or incompatibility between product and pack
- interaction or contamination, covering migration, absorption,
adsorption, extraction, corrosion, erosion
- changes may be organoleptic, increase in toxicity/ irritancy,
degradation, loss or gain of microbial effectiveness, precipitation,
haze, turbidity, color change, pH shift

Chemical reactions:
1) adsorption of chemical entities on to component surfaces, losses of
EDTA & preservatives (benzalkonium chloride, thiomersal, mercurials)
2) more volatile preservatives (chlorobutol, phenol, 2-phenylethanol)
show rapid loss through low-density polythene by absorption and
surface evaporation
- fix by external overwrap
3) surface-active ingredients (antistatic, slip, antislip, mould release
agents, antiblock agents, lubricants) may enter the product by
dissolution, surface abrasion
4) detachment of glass spicules in alkaline solutions (citrates, tartrates,
chlorides and salicylates)
- occur when treated or neutral glass is autoclaved in alkaline salts
- fix by storing in soda glass
5) organoleptic changes by permeation of volatile or odorous
substance through plastic materials

Stages in the Development of a Pack-Product Combination
- no pharmaceutical excipient, drug entity, intermediate or finished
product can exist without a pack
- packs should not be exposed to more than 45C, max of 6 months,
not exceed 12 months

Preformulation
- understand limitations associated with any packaging contact matl
used to contain or retain the material

Product formulation
- necessary to make certain that all packaging contact materials are
defined and that all pack parameters are identified, controlled and
documented

Consideration of container materials
- basic knowledge of all packaging matl, properties, characteristics
and processes by which they are fabricated, decorated as packaging
container and how these and other processes may affect their prop
- eg. Sterilization by ethylene oxideethylene oxide and ethylene
glycol residues
- gamma irradiation of low-density polyethylenereduces material
flexibility due to molecular cross-linkage, give rise to formic acid and
formaldehyde residues

Pack feasibility tests
- product is tested in a range of possible packs under conditions from
-20 to 45C and cycling conditions (temperature-humidity range)
- extractive tests- mandatory for plastics used for injectable and
ophthalmic products
- feasibility tests- 1-12 months (3-6 mos. minimum before proceeding)
- accelerate conditions does not necessarily mean a pack will fall under
more realistic climatic conditions

Formal stability tests
- three large-scale batches
i) 25C and 60% RH (long-term stability)
ii) 40C 75% RH (accelerated stability)
- sampled over period of 5 years at examination intervals of 0 initial),
3, 6, 9, 12, 18, 24, 30, 36, 48 and 60 months

Ongoing stability
- repeated stability on random batchesconfirm that the shelf-life
does not change

Complaints
- final means of monitoring the success of the product and pack
- final aim is having a successful product which is effective, safe and
profitable

Pack Selection
Factors influencing choice of pack
i) Product
- chemical and physical characteristics of drug entity, ecxcipients
and formulation
ii) Market
- eventual channels of sale (where, how, by whom, etc)
- where product may be used, for home trade or export, quantity
per pack, predicted sales for initial launch and follow-up sales
iii) Distribution system
- conventional wholesale/ retail outlets or direct to selected outlets
- where less sophisticated transport systems
- where climatic conditions may be more severe
iv) Manufacturing facilities

Packaging Materials
i) Glass and glass containers
ii) Metal and metal containers
iii) Plastic and plastic containers
iv) Paper and board
v) Films, foils and laminates
vi) Rubber-based components