Drying 1 and Drying 2

Question 1

What is drying and how is it achieved?

Answer 1

Drying is the removal of all or most of the liquid from a material (solid) by the application of heat

• Achieved by transfer of the liquid from surface of the material into an unsaturated vapour phase

Question 2

What is the reason for drying or removal of water

Clue: 3 reasons

Answer 2

1. To increase drug stability
2. To minimise the growth of micro-organisms
3. To achieve free-flowing properties of the solid particles

Question 3

Define moisture content, absolute humidity, saturated humidity

Answer 3

Moisture content: kg of moisture associated with one kg of ‘moisture free’ (bone-dry) solid

• 10% = 10g of water in 100g bone-dry solid

Absolute humidity: moisture content of the air expressed as mass(kg) of water per unit mass (kg) of bone-dry air

• not altered by change of temp unless further moisture is taken up by the air

Saturated humidity: humidity at which the air is completely saturated with water and it can not absorb any more moisture from drying material at a given temperature. Saturated humidity = 100% relative humidity

Question 4

What is relative humidity and what is the relative humidity (%RH) equation

Answer 4

• Relative humidity is the amount of moisture in the air compared to what the air can “hold” at that temperature.
• A reading of 100 percent relative humidity means that the air is totally saturated with water vapor and cannot hold any more

Vapour pressure of water vapour in the air / vapour pressure of water vapour in saturated air at the same temp

= (Qty of vapour present per kg of dry air / Qty required to saturate the air the same temp) * 100

Question 5

What is the wet bulb and dry bulb temperature? Also why does wet bulb have a lower temperature?

Answer 5

Wet bulb temp: temperature of a thermometer which has been immerse in water in water then lift up in the air

Dry bulb temp: temperature of thermometer that stays in the air

• Wet bulb has a lower temperature due to evaporation of water
• During drying, temperature of the material may go up leading to overheating when the unbound water is removed (dry bulb).
• Over drying and overheating can cause degradation or burn of the material

Question 6

What is the EMC (equilibrium moisture content)?

Answer 6

Moisture content present in solids under a particular ambient condition, at which no more water can be removed from the solid without altering the drying condition

Question 7

What are the two conditions neccesary to dry a material?

Answer 7

1. Latent heat of vaporisation must be provided
2. Liberated vapour must be removed, eg by a moving air stream

Latent heat of vaporisation: The heat, which generates the steam without any increase in temperature. Latent heat is utilised to change liquid water into vapour at constant temprature

> Two types of water in solids: free water and bound water

> Bound water: water contained in cells or in the capillaries or internal pores of a solid

• Bound water does not develop full vapour pressure

Question 8

Draw the graph for the drying process

Answer 8

Question 9

Draw and describe the drying curve, provide the formula for rate of drying

Answer 9

Rate of drying = AK(Ps-Pa)

A: surface area
K: mass transfer constant (flow of air stream)

Ps: vapour pressure at the surface of solid

Pa: vapour pressure of air stream

Question 10

Draw the EMC line graph and define the four stages

What influences EMC (equilibrium moisture content)

Answer 10

The value of the EMC depends on the material and the relative humidity and temperature of the air with which it is in contact.

Question 11

Describe the Hot Air Oven, also discuss its advantages and disadvantages

Answer 11

Two factors: A (surface area) and Tempeature

Advantages: cheaper and simple

Disadvantages:

1. Long drying time
2. Can not be used for removal of organic solvent
3. Non-uniform temperature in trays
4. Final product tends to form a cake
5. Cannot be used for dusting solids

Rate of Drying = AK (Ps-Pa)

Question 12

Describe the Vacuum drier + Tumbling Vacuum drier, also discuss its advantages and disadvantages

Answer 12

Vacuum drier

Ps-Pa increased –> rate of drying increases

Disadvantages

1. Drying time is relatively long
2. Sucking of fine particles
3. Requiring drying agent

Tumbling vacuum drier

• A is larger (surface area), K is bigger, Ps-Pa is increased
• A more efficient process –> drying time is short

Disadvantages

• Producing fine powders

Question 13

Describe the Fluidised Bed Drier, also discuss its advantages and disadvantages

Answer 13

Capacity: 5-20 kg, Average drying time 20-40 mins

Advantages

• Minimum heating time for thermolabile materials (destroyed by heat)
• Process is economic, high output
• Most of drying is constant rate and falling rate period is very short minimising the possibility of overheating
• Temp of fluidised bed can be controlled precisely and uniformly
• Producing a free flowing product
• Eliminates the risks of soluble materals migrating (intragranular)
• It can be made into continuous process eg use of conveyor belt, reducing the handling of an labour cost

Disadvantages

• It may break down product and product fine particles
• Fine particles must be collected, avoid segregation and loss of fines
• Possibility of generation of charges of static electricity (due to movement of particles in hot air). Suitable precaution must be taken.

Use an inert gas instead of air when the product contains a volatile solvent such as isopropanol

Question 14

In what ways does the solute migrate during drying?

Clue: 2 ways

Answer 14

Intergranular migration: solutes move towards the surface of the bed and is deposited there when the fluid evaporates

> Occurs in convective drying

Intragranular migration: solute move towards the periphery of each granule, occurs with fluidised bed drying and tumbling drying. It may cuase:

• Loss of active ingredient when enriched outer layer is abraded
• Mottling (spots) of compressed colour tablets

Question 15

How to minimize solute migration

Answer 15

• Minimise amount of granulating fluid and ensure its well distributed
• Prepare small granules
• Avoid tray drying
• Mixing granules before compression if using tray drying

Question 16

Difference between bound water from unbound water??

Question 17

What is freeze drying (lyophilization) and what is it used for?

Answer 17

Process which removes water in a product by sublimation –> producing a dried solid product

• Utilises the sublimation curve in phase diagram of water, using low pressure (kept below the triple point pressure) and low temp to turn ice directly into vapour without going through the liquid stage

> Final product’s solute is relatively undisturbed from that originally in solution and is finely divided with a large SA

>Use for preparation and preservation of;

• Pharmaceutical products, food, biological samples, plants

Question 18

What are some of the advantages of freeze drying?

Answer 18

1. Removing water fron materials which are heat sensitive, water sensitive and oxidation sensitive
2. Formulating a drug product in a dried powder form which can provide prolonged stability under storage and is readily redispersed when water and buffer is added prior to use
3. Be able to remove and water from any type of sample, wet or semi-dried solids

Question 19

What are three steps of freeze drying?

Answer 19

3 steps: Freezing, primary drying (sublimation) and secondary drying (controlled heating)

1. Freezing (< - 40 ⁰ c)

• Freezing temp has to be below lowest temp for eutectic (Te) (crystalline system) as well as the collapse Temp (Tc) (amorphous system) –> KEY POINT
• Glass transition temp (Tg) is the temp above which softening of the material occurs and material exhibits viscous flow and eventual matrix solubilization or collapse
• temperatures below Tg, product is stil an amoprhous glass but remains rigid and will be suitable for primary drying
• TO SUMMARISE –> Tc < Tg (collapse temp)

Two basic methods for freezing

- Fast cooling: achieved by immersion method using liquid N2, dry ice or solid C02 + acetone/alcohol

> Biological specimens are normally treated using fast cooling methods to avoid osmotoic and PH damages during slow feezing. Cyroprotectants such as sugars or glycerol are added to protect against harmful freeing effects

- Slow coooling: conventional shelf freezing or refreezing in a freezer (<0.20 C/min)

In both methods, one should generate a thin film of frozen materials on the walls of the vial to increase the SA to reduce the thickness of frozen solution

2. Primary drying (sublimation, 0.1 mmHg or less)

The unbound water of the product (70-95 %) is removed by sublimation. Temp is very much below the eutectic temp (Te) or glass transition temp (Tg) and reduced pressure is used

• Latent heat of sublimation is provided
• Vacuum pump is used to continuously remove the vapour. The vapour is often cooled on a condenser which has a lower temp
• Constant rate often accounts for upto 95% of H20 removed
• Falling rates account for 5% removed water, 20% of drying time
• EMC can get to as low as 0.5 %

3) Secondary drying

• Removes bound water eg water of hydration, ion-dipole, hydrogen bonded; water associated with amorphous glassy masses
• Temp is raised gradually to +20⁰ C for bio products and 50⁰ C for many drugs; vaccum level increased (pressure decreased) to boil off the remaining water

Question 20

What are some of the conditions that freezing drying has to have?

Answer 20

1. Ps > Pa (high vacuum ensures it)
2. Latent heat of sublimation is provided
3. Evolved vapour must be removed
4. Temp and pressure must be controlled below the triple point

Question 21

What are some of the excipients required for freeze drying, describe their common functions

Answer 21

1. Bulking agents eg mannitol, lactose, glycine, sucrose and dextran
2. pH and osmotic adjustment agents eg buffers and salts (potential dehydrating agents for protein) should be kept minimum
3. Cyroprotectants eg Povidone, polyethylene glycol and dextran, sucrose, lactose, glycine and human serum albumin

Bulking agents: provide mass to hold the product thereby avoiding potency loss due to processing conditions(blow-out prevention). They may modify Te, Tg, providing freeze/thaw protection

Cyroprotectants offer stabilisation against harmful salt concentration and pH shifts during freezing by closely associating with the active moiety, providing protection of the physical structure of the bio-products

Question 22

What is a blowout and what are some of the possible functions of cryoprotectants?

Answer 22

Blowout: loss of materials which are taken away by the water vapour leaving the vial

Possible function of cyroprotectants

• Replace water as a stabilising agent
• Increase the glass transition temp (Tg) of the frozen system
• Absorb moisture from the stopeprs
• Slow down secondary drying process and minimise overdrying

Question 23

Design a basic freeze dry formulation

Answer 23

Monoclonal antibody

Bulking agent such as mannitol or lactose: 4% w/v

pH adjustment agent, such as phosphates, acetates 1% w/v

Cyroprotectants, such as polyethylene glycol, glycine 0.75% w/v

Process;

1. Product freezing (-30 degrees)
2. Primary drying (-20 degrees for 10 hours)
3. Secondary drying (25 degrees for 4.5 hours)
4. Residual moisture 2-4 % w/w

Question 24

What does a freeze drier contain and what are its advantages/ disadvantages

Answer 24

1. Sample chamber for vacuum drying
2. A vacuum source (pump)
3. Heat source for latent heat (conductive or radient)
4. Vapour removal system (condenser and pump)

Advantages

1. Product is light and porous no case-hardening
2. Porous form of the product gives easy reconstitution
3. Minimises degradation caused by heat, oxidation and micro-organism action
4. Stability of product can be obtained and maintained

Disadvantages

1. May yield a very hygroscopic product (absorb moisture from air) due to the porosity and solubility
2. Process is slow, requires complicated equipment and is expensive
3. Difficult to adapt the drying method for solutions containing non-aqueous solvents

Question 25

What is spray drying>

Answer 25

Production of highly dispersed powders from a fluid feed by evaporating the solvent

• Achieved by atomizing (spraying) a solution or suspension/emulsion into a vessel which contrains heated gas
• Upon mixing with the hot gas, the high surface-to-mass ratio droplets produced will cause rapid evaporation of the solvent to form spherical particles (hollow if feed is solution or non-hollow or solid if suspension) in seconds due to high SA contact with the drying gas

Question 26

What are the steps of spray drying?

Answer 26

• Preparation of feed liquid: solution, suspension or emulsion –> not too viscous
• Set up drying conditions –> inlet and oulet air temp, feeding rate
• Atomise the solution/suspension/emulsion via atomizer into the drying chamber
• Formation of the uniform sized small droplets with high surface-to-mass ratio; rapid evaporation of solvent to form solid particles (hollow spheres if feed is a solution, solid spheres for suspension) in seconds
• Particle size can be in nano or micron range
• Collect samples from drying chamber

Question 27

What are some distinct features of spray drying

Answer 27

Atomizer controls the formation of the droplet (doubled walled, simple, multi-core, irregular, particulate, matrix)

Rotary atomizer: effective for both solution and suspension; gives uniform spray and is not easily blocked

Distinct features of spray died products:

• Uniform in appearance
• Hollow spherical particles with good flow properties
• Retain the properties of original solution eg emulsion o/w

Question 28

What are some applications for spray drying and what are its advantages/disadvantages?

Answer 28

Applications

• Can be used in solution, suspension or emulsion
• Sustained release microspheres for proteins
• Microencapsulation: Vitamins A D in gelatin; masking taste
• Uniform reduction of particle size + increasing solubility of product (micronization)
• Change solid structure from crystalline form to amorphous form
• Used in food processing industry, instant coffee, milk powder
• inert gas can be used to minimise oxidation of product and dissacharide (sucrose) to stabilise the proteins

Advantages

• Very rapid drying time (a few seconds for a droplet). A + K are very large. Ps-Pa is big
• Most of heat have been used as latent heat of vaporization and droplets do not attain a high temperature
• Labour costs are low
• Particles are formed readily soluble when reconstituted
• More economical than freeze drying, better control in particle size and shape of final product, organic solvent can be readily removed by the process

Disadvantages

• Equipment is bulky and expensive
• Thermal efficacy is rather low. Air must be kept hot enough when it leaves the drier to avoid condensation of moisture
• Sterile filtration of very large volume of air
• Need for precise control of drying conditions to prevent overheating
• Yield is low for the small scale production