Drying

Question 1

Drying process - main points

Answer 1

It is (generally) the last and more critical operation in manufacturing pharmaceutical ingredients:
Drying before packaging ensures quality performances in terms of material processing (intermediate materials, e.g. flowability) and product stability (final product)

During manufacturing drying is essential to guarantee process performances e.g. granulation, compaction

Question 2

Moisture content in air

Answer 2

Moisture content is defined as the amount of water contained in a material
%Moisture by volume (MV) is defined as the molecules of water per unit volume by the total number of molecules per unit volume
In case of air, it can be defined as kg of contained water per kg of dry air (water free)

Moisture content differs from the relative humidity

Question 3

Humidity

Answer 3

Humidity is referred as the amount of water vapour present in the air
Relative Humidity (RH), indicates the amount of moisture in the air as a percentage of the maximum amount of moisture that the air can hold (at a specified temperature)
The maximum water content in air depends on temperature, having higher content with increased temperature
Relative Humidity is temperature dependent

Question 4

relationship between temperature and moisture content in air
What does this mean in practice?

Answer 4

The higher the temperature, the higher is the amount of water vapour that can be hold
In practice
In practice:
water evaporation from a solid to the air (with increase in MV) is promoted by increasing the temperature
BUT if vapour is not removed, the drying efficiency will fall

Question 5

Dew point

Answer 5

The dew point is:
related to the quantity of moisture in the air
the temperature to which moisture condense and evaporate at the same rate (equivalent to 100%RH or saturated with water vapour)
When the dew point is reached, and the temperature further cooled, the water vapour will condense (RH cannot exceed 100%!)

Question 6

impact of dew point on manufacture

Answer 6

During the drying process of temperature sensitive material it might be necessary to cool down the supplied air

It is important to avoid to design a drying process with conditions close to the dew point

Question 7

what 2 things change during drying?

Answer 7

During drying, moisture content AND temperature can change:
Evaporation of water from the material to the drying air
It is possible to saturate the drying air, if air exchange is not applied (or the rate is not properly designed)
Cooling of drying air to reduce heat-exchange with the material
Reduction of water solubility in air and condensation of water should be considered

Question 8

Moisture content in materials
Moisture content analysis
Quality control
Hygroscopic substances

Answer 8

Moisture content is the quantity of water contained in a material
Moisture content analysis is important in defining the material quality (quality control applied in most production sites and laboratories)
Hygroscopic substances attract and hold water molecules from the surrounding environment (as function of temperature and relative humidity)

Question 9

Moisture content in paper

Answer 9

Paper is hygroscopic, hence absorbs and loses moisture accordingly to the ambient relative conditions
If less moisture in air- paper releases moisture
If more moisture in air - paper absorbs moisture

Question 10

Wet solids: total mixture

Answer 10

Total moisture is the total amount of water (or liquid phase) associated with a wet solid
TOTAL = FREE + EQUILIBRIUM

Question 11

Free moisture content

Answer 11

Free moisture content is the amount of water that can be easily removed e.g. evaporation
Also known as unbound water

Question 12

Equilibrium moisture content

Answer 12

Equilibrium moisture content is the portion of water that is more difficult to be removed
Also known as bound water

Question 13

Equilibrium moisture

Answer 13

Once unbound water is removed, the remaining moisture is in equilibrium with the moisture in the air
Only variation of the external conditions could influence the equilibrium moisture content
Example: reduction of %RH using silica gels or phosphorous pentoxide to remove water from the conditioned air.

Question 14

Describe solute migration

Answer 14

Movement of solution in a wet system during drying

The solute is transported towards the surface, being left where the solvent evaporates

Question 15

Inter-granular migration

Answer 15

Inter-granular migration: the solute moves between granules towards the surface
Differences in solute composition between granules

Question 16

Intra-granular migration

Answer 16

Intra-granular migration: granules are separated during the process
Even distribution of solute within a granule

Question 17

Inhomogeneity between granules impact what?

Answer 17

Quality aspects
Dose
Manufacturing
Appearance

So try to reduce solute migration

Question 18

How to reduce solute migration phenomena

Answer 18

Initial moisture content
Slow convective drying
Drying by microwave radiation
Dynamic drying methods (“granules in motion”)

Question 19

Factors to consider when choosing drying methods

Answer 19

Heat sensitivity of materials used

• Heat source AND transfer
• Heat transfer surface

Materials physical characteristics
Solvent/liquid to be removed e.g. boiling point
Efficient mass transfer of evaporated liquid
Efficient vapour removal from drying air
Amount of material to be processed e.g. scale-up considerations
Sterility

Question 20

How are drying methods for wet solids categorised?

Answer 20

Drying methods for wet solids are categorised as function of the heat transfer methods:
Convection - flames
Conduction - metal rod on a flame
Radiation - the sun

Question 21

For wet solids, how are the following mechanisms used in machines? i.e. what machines are used:

1) Convection
2) Conduction
3) Radiation

Answer 21

1) Fluidized-bed
2) Vacuum-oven
3) Microwave

Question 22

Fluidized bed drier - how it works
Capacity
Drying time

Answer 22

Optimised contact between warm drying air and wet powders/particles
Typical capacities (0.4-1.2 kg) with drying times of 20-40 min

Question 23

Fluidized bed drier - what will an increase in air velocity cause?

Answer 23

Increase in air velocity will induce a pressure drop with powders/particles suspended in the air
Frictional drag equal to gravitational force (Stokes’ Law)
Further increase will cause particle free move

Such turbulence induce:
Particle mixing with good contact with air
Maximised surface area of the powder bed
Efficient heat and mass transfer 
Reduced drying time
Good vapour removal

Question 24

Advantages of fluidized-bed dryer

Answer 24

Efficient heat transfer (minimising effects on thermosensitive materials)
Homogeneous process:
Movement of particles guarantees drying of all individual ones
Uniform temperature, as result of turbulence
Free movement of particles reduces:
-Migration process
-Separation/aggregation phenomena

Question 25

Fluidized bed dryer disadvantages

Answer 25

Turbulence might damage granules
Reduction of size
Production of dust
Small particles might need specific attention to be removed from the fluidizing air
Particle movement in turbulence and warm environment might cause charges of static electricity
Adequate electrical grounding is essential

Question 26

Vacuum open

Answer 26

Large area for heat conduction (direct contact between hot surface and material)
Airtight seal to control the drying air
Vacuum pump to bring operating pressure to 0.03-0.06 bar (low air content minimises risk of oxidation)
Temperature between 25-35°C are sufficient to boil water (convenient for thermo-sensitive materials)
Generally used for small-scale processes e.g. development laboratories

Question 27

Microwive drying - how it works
Better results with what kind of molecules?
What is loss factor?

Answer 27

• Microwave penetration in wet material generate uniform heat
• Better results are obtained with ‘small’ polar molecules
• Loss factor is defined as ratio of absorbed microwave energy to the provided energy: higher values return better performances for heat generation
• Different solvents have different loss factor, which is the result of their electronic molecular structure

Question 28

Microwave advantages

Answer 28

Rapid dry at controlled temperatures
Energy absorbed in the wet material, not in the air
Stationary conditions minimise small particles movement
Uniform heating reduces solute migration effect

Question 29

Microwave disadvantages

Answer 29

Small batch size

Shielding from radiation is essential

Question 30

Pharmaceutical driers for solutions and suspensions

Answer 30

• Spray dryer

- freeze drying

Question 31

Spray dryer

How it works

Answer 31

Generates large surface area to promote:
-Heat exchange
-Mass transfer
Particle formation and drying occur in one process
Small droplets provide a larger surface area: beneficial for heat exchange and mass transfer
Circulating air to dry each individual particle

Question 32

Spray dryer final particle size

Answer 32

Final particle size is determined by the initial droplet volume
Uniform and constant flow rate of the solution through the nozzle
Droplet formation faster than solvent evaporation

Question 33

Sprayer dryer optimisers

Answer 33

Several atomizers have been developed to optimise:
droplet size (1-500 μm),
jet stream (uniformity),
solution feed rate (up to 100 L/hour),

Question 34

Spray dryer atomizers

Answer 34

-Solid-stream jet atomizer
-solid-stream shaped orifice e.g. v-shaped orifice, flat jet
-Rotary atomizer (hollow cone jet)
-Two-fluid nozzle (gas flow promotes formation of smaller droplets)
-Ultrasonic nozzle: vibration used to reduce droplet size
Note: the higher the flow rate, the smaller the droplets

Question 35

Two-fluid nozzle atomizer

Answer 35

Generally combines interaction of high velocity gas and fluid stream: the design of the nozzle determine where the mix between air and liquid occur

Question 36

Spray dryer
impact of surface area
particle size of dry powder compared to generated droplets?

Answer 36

Large surface area: beneficial for heat exchange and mass transfer
Particle size of dry powder is smaller than generated droplets

Question 37

Spray dryer: drying chamber

Answer 37

Tangent air flow to increase droplets residence time and allowing a more effective drying process
Different size from laboratory batch products to scale-up systems
Products are relatively uniform in size

Question 38

Freeze drying
How it works
Obtained products have what characteristics?
High-vacuum conditions do what?

Answer 38

Low drying temperature making this process:
-Suitable for heat-sensitive materials
-Able to minimise chemical decomposition and enzymatic activity
Obtained products are porous, with faster solubility due to larger surface area
High-vacuum conditions minimise the contact with air, hence oxidation in reduced

Question 39

Freeze-drying basic principle

Answer 39

The triple point: solid to vapour transition

0. 01 degrees celcius
1. 006 pressure (atmospheres)

Question 40

Freeze-drying process steps

Presence of solutes does what?

Answer 40

Freezing: Freezing temperature are well below the normal freezing point of water
The presence of solute(s) shifts the phase diagram
Vacuum: Pressure is reduced below the triple point
Sublimation: Ice is tranformed to vapour at the frozen surface
Surface area and sublimation time should be evaluated to optimized the drying process
Primary drying: Porous dry product with about 0.5% moisture
(Secondary drying): happens at higher temperature (50-60°C)
Packaging: necessary step to protect the product from air moisture