Drying Flashcards
Drying
removal of some or all of a solvent from a system - usually water for pharmaceuticals
Drying importance for pharmaceuticals (4 factors)
- Chemical stability
- Processing and handling
- Toxicity
- Dosing
Applications of Pharmaceutical Drying
- Preservation of biologicals
- Inhalable formulations
- Transdermal delivery
What kind of heat is involved in drying?
Latent heat. Applied heat may cause degradation of the drug if it is biological
Moisture content
- expressed as % w/w
- 3% w/w means 3g of water removed from 100g wet material
Types of water in a solid sample
- Water of crystallisation (hydrates
- ‘Free’ water (water present as liquid)
- ‘Bound’ water (hydrogen bonded to substrate)
Equilibrium Moisture Content
- Equilibrium will be established between water content of material and moisture in atmosphere
- Value will depend on ambient conditions
What is the typical equilibrium moisture content for drugs in terms of % w/w?
0.2-2.5%
Relative Humidity
- Measure of water content in air
- At 100% RH, maximum solubility of water vapour in air has been reached
- Air can hold more water at higher temperatures
What is normal RH?
54%
Relative humidity after rain
75%
What types of sample have a greater Moisture uptake
- Organic material takes up much more water than inorganics
- Hygroscopic samples will take up water readily
- Non-hydroscopic samples take up less water
Example of organic material that takes up water?
Kaolin
Example of hygroscopic materials that take up water readily?
sucrose, lactose
Examples of non-hygroscopic materials that take up water less readily?
inorganics, metals, non-polar materials
Water loss profile
See lecture graph
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Constant Rate Period (A-B)
- Sample loses water from surface of bed and saturates air immediately above surface
- Water is replaced immediately
- Rate will be constant
- Controlled by rate at which water vapour can be removed
First Falling Rate Period (B-C)
(3)
- Rate of vaporisation not sufficient to saturate air above surface
- Drying rate determined by rate of transfer to surface
- As drying proceeds, this becomes increasingly difficult hence rate decreases
What is rate of transfer determined by?
- Diffusion
- Suction potential of porous material
- Capillary force
Second falling rate period (3)
- water loss is from within bed itself (no more free water)
- as solid becomes dryer, thermal conductivity decreases
- may need to increase bed temperature (problematic for thermolabile materials)
Methods of drying
- Convection drying
- Conduction drying
- Radiation drying
- Spray drying
- Freeze drying
Convection drying
- drying takes place via latent heat of evaporation provided via a hot air steam
Types of convection drying
Tray/Fixed bed drying, fluid bed drying
Fixed bed/tray drying
- Tray of wet material placed in oven with hot air circulated around material via fan or baffle system
- used in small scale experimentation, not efficient
What causes Caking
- Rapid water loss from inappropriate choice of drying conditions which leads to rapid water loss from surface of material to form a hard dry crust
Problem with caking
- caked material prevents further water loss from deeper in the bed while the now dry crust becomes hot
Types of solute migration
- intergranular migration
- intragranular migration
Intergranular migration
Drug and water soluble excipients dissolve in aqueous phase and be transported to top of the bed. Evaporation then leads to deposit of material on bed surface
Intragranular migration
Water soluble materials migrate to surface of specific granules and are then deposited
Effects of intragranular migration
- Intragranular migration of dyes may lead to higher concentration on granule surface
- On compression, granules fractures and colourless interior exposed, leading to mottled appearance
- This reduces patient confidence in the product
Fluidized bed drier
- hot air steam through powder bed gives buoyancy to particles
- particles form a fluidised suspension in air
- water loss takes place from individual particles
Advantages of fluid bed drying
- efficient process with short drying times
- negligible intergranular migration
- uniform and controllable temperature
- small size and simple equipment
- ensures stability of thermolabile drugs
disadvantages of fluid bed drying
- intragranular migration may take place
- may be some attrition of surface of particles, generates fines and may also lead to drug loss
- risk of explosion if not properly earthed (problem with organic solvents)
Conductive drying
- wet solid is on direct contact with a hot surface
- heat transfer occurs via conduction
- example is vacuum oven
advantages of conductive drying
- useful for low temperature drying of thermolabile materials
- less chance of oxidation during drying
disadvantages of conductive drying
- tends to be fairly slow
- small capacity
- expensive
- temperature must be controlled to avoid caking
where is conductive drying most used?
in research labs
Radiation drying
- molecule sensitive, polar solvents will resonate as their dipole moments vibrate at microwave frequencies. This movement causes friction which generates heat leading to evaporation
Key points for radiation drying
- dry solids do not resonate as much so do not heat to same extent
- good heat penetration leads to uniform drying throughout solid
- very effective when combined with vacuum
When is radiation drying useful?
- useful for granulation
- useful for drugs where containment is an ussue
- efficient since casing remains cool, since wet material absorbs most of the energy
- solvents are fully recoverable
disadvantages of radiation drying
- batch size small
- danger from radiation
Spray drying
- used to produce dried product from aqueous solutions or suspensions
- solution is atomised and sprayed into stream of hot air
- results in free-flowing powder sample
- spray dried products may be recognised by hollow spherical shape
- outer surface dried very rapidly
- particles may be intact or broken spheres
3 steps of spray drying
- formation of droplets after the liquid is atomised at the top of the drying chamber
- evaporation of water from droplets to form product in drying chamber
- collection of feedstock in collecting flask
advantages of spray drying
- products dried very rapidly, a whole batch can be dried in seconds
- rapid and efficient drying results in low temperatures, as heat input goes into evaporation rather than temperature increase
- product is uniform size and free flowing
- liquid is transformed into a powder in one step
When is spray drying useful?
- useful for tablet and capsule formulations
- examples include paracetamol
Spray Drying for Dry Powder Inhalers
- Considerable interest
- due to good flow properties and well controlled characteristics
Disadvantages of spray trying
- higher cost
- bulky equipment
- products are partially or completely amorphous
- means that material can recrystallize on storage
Freeze Drying / Lyophilisation
- used to produce dried product from aqueous solutions or suspensions in vials
- important because it involves use of low temperatures
- results in porous solid
- used for preparation of proteins
Freeze drying in general terms
- solution is frozen
- pressure is reduced
- ice then sublimes (solid directly into gas)
- heat is applied to remove remaining water
Initial freezing
- takes place via nucleation as temperature drops below 0
- water may undergo considerable supercooling
- removal of water as ice leads to concentration of remaining solutes
Further Cooling
Two things can occur:
1. Eutectic mixture is formed
2. Amorphous matrix (glass) formed
Eutectic mixture
Formed when two components both crystallize; system is now an intimate crystalline mixture of one component in the other
Amorphous Matrix
- more usually formed
- system forms a mix of a glass with ice crystals distributed throughout
- glassy matrix has characteristic glass transition value (Tg)
Tg
- materials are rigid below Tg and rubbery above Tg
- Presence of water lowers Tg of dry material considerably
Saquinavir as an example of water affecting Tg
Tg reduced from 120 degrees to 70 by presence of 5% w/w water
Primary Drying
- Pressure reduced to near-vacuum and heat applied to sublime ice
- Typical 1o drying temperature is around -35oC
Primary Drying Continued
- primary drying conducted at temperature close to Tg of glassy matrix
- if it takes place above Tg, matrix is in liquid state and product will collapse
- Removal of ice gives porous structure
Implications of primary drying
On basis that reduction of primary drying temperature of 1oC will increase drying time by 13%, cost implications of drying at too low a temperature are considerable
Secondary Drying
- drives off remaining water trapped in matrix
- maximum temperature 25-60
- left with dry porous product which can be easily reconstituted
- system is amorphous and will have its own Tg
- important to store below Tg to prevent collapse on storage
Freeze drying of proteins
- Large problem, as many proteinaceous drugs lose activity on freezing and drying
- Cryoprotectants and/or lyoprotectants are necessary
Cryoprotectant
Protects substrate during freezing
Lyoprotectant
Material which protects protein through whole freeze Drying process
Most commonly used cryoprotectants and lyoprotectants
Sucrose, trehalose, polymers, amino acids
Advantages of freeze drying
- low temperature is suitable for thermolabile materials
- high dissolution rate due to amorphous structure
Disadvantages of freeze drying
- expensive
- time consuming
- complicated process
- stability issues due to amorphous structure
