Topic 3

Question 1

Define equilibrium moisture content

Answer 1

The portion of water in a wet solid that cannot be removed by inlet air because of the humidity of the inlet air.

Question 2

Define free water

Answer 2

The difference between total water content of the solid and emc

Question 3

Define bound moisture

Answer 3

• exerts and equilibbrium vapour pressure less than that of free water at the same temperature
• how this moisture is retained depends on nature of solid, it may be retained in fine capillaries, adsorbed onto surfaces or within a cell or fibre walls, or in physical/chemical combination with the solid

Question 4

Define unbound moisture

Answer 4

exerts an equilibrium vapour pressure equal to water at same temperature. This water is retained in the voids of solids

Question 5

Why don’t we dry beyond emc?

Answer 5

Solid cannot be dried past emc as materials exposed to humid conditions will regain moisture, the solid will regain moisture from the inlet air. there is no advantage in drying to moisture content lower than that which material will have under conditions of use

Question 6

2 mechanisms of moisture movement + dedscribe?

Answer 6

1. Diffusion theory - rate of movement of water to the air interface is governed by rate transfer
2. Capillary theory - the forces controlling the movemt of water are capillary arising from the minute pore spaces between the individual particles

Question 7

Describe rate of drying w/ ref to graph (in slides)

Answer 7

AB: constant drying rate
- drying takes place by evaporation of moisture from a saturated surface
- involves diffusion of water vapour through a ‘stationary’ air film and into bulk of the air

BC: 1st falling rate period
- Point B - critical moisture content
- at this point, surface of the solid is no longer saturated and ‘dry spots’ appear
- the outside wet area may reduce progressively and rate of drying falls off
- Point C - original surface film has evaporated completely
- Beyond this point, rate of drying is controlled by rate of moisture movement through the solid

CD: second falling rate period
- drying rate largely independent of conditions outside solid
- for example, if moisture transfer from within solid to surface is by vapour diffusion, the forces which control this diffusion determine drying rate
- Point D - end of drying where moisture content of solid is at it’s emc

Question 8

Types of drying methods?

Answer 8

Convective drying
- tray dryers
- fluid bed dryers

Conductive drying
- vacuumn oven
- vacuum tumble dryers

Radiation drying
- microwave dryers

Dryers for dilute solutions and suspensions
- drum dryers
- spray dryers

Freeze drying - lyophilization

Question 9

Key considerations for drying?

Answer 9

• heat sensitivity of powder
• powder physical characteristics like particle size, distribution
• nature of liquid to be removed
• scale of opoeration
• necessity for aseptic operation
• heat sources (steal, electrical)

Question 10

General principles for efficient drying?

Answer 10

• large surface area for heat transfer
• efficient heat transfer per unit area
• efficient mass transfer of evaporated water through any surrounding boundary layers i.e. sufficient turbulence to minimize boundary layer thickness
• efficient vapour removal i.e. low relative humidity air at adequate velocity

Question 11

Describe tray dryers + considerations

Answer 11

Convective dryer

1. consists of a cabinet containing trays connected to hot air or nitrogen source. powder to be dried is placed on these trays
2. air temperature controlled by thermostat usually between 60-8-degc
3. air enters bottom of chamber below trays and rises through the trays of powder being dried, then exits from an opeoning at top of chamber
4. trays designed to force air to follow a longer zigzag route which increases air/powder contact time -> allowing efficient drying

Considerations:
- provide large surface area to drying powder for effction moisture removal by convection
- relative humidity of drying air must be much below its saturation point
- maintain turbulent airflow over powder surface
- constant air temperature
- suitable for friable material

Question 12

Describe Fluid bed dryer +

Question 13

Describe spray dryers + adv and disadv

Answer 13

Dryer for dilute solutions and suspensions

• large surface area for heat and mass trasnfer by atomizing the liquid or slurry to small droplets
• droplets sprayed into stream of hot air so each droplet dries to an individual solid particle
• particle size controlled by type of Atomiizer hence choice is critical
• jet atomizers easy blocked by rapid evaporation and deposition of solid particles on nozzle and droplet size likey to vary, hence rotary type atomizers overcome this problem
• air enters chamber tangentially and rotates drying powder droplets to increase their residence time. Dust carried over in air outlet stream recovered by cyclone separator or filter bag

Adv:
- suitable for heat sensitive products (can be spray dried easily at relatively high temps), temperature at droplet kept low due to evaporative cooling
- fast drying due to millions of small droplets -> large surface area for heat/mass transfer
- high bulk density product achieved -> hence rapid dissolutino
- free flowing product with spherical particles achieved
- uniform size due to atomization
- minimize product handling (dry powder from dilute suspension achieved -> filtration NOT REQUIRED)
- can be operated aseptically by using sterile air filtered by HEPA

Disadv:
- bulky equipment with anciallry equipment (requires more space)
- high equipment cost
- low thermal efficiency as hot exaust air required to prevent condensation of moisture
- high maintenance cost on bag filters/atomizers/sterile filters/HEPA

Question 14

Need for milling and size control?

Answer 14

• particle size of ingredients in a formulation, especially API greatly impacts bioperformance and process capability
• produce consistent results in vivo and can be manufactureed reporducibly
• milling increases surface area of solids -> increase dissolution rate -> affects bioavailability of drug
• dissolution rate directly proportional to particle size
• mean size and particle size distribution of API relative to excipients to be mixed with can influence tendency of API to segregate/not mix uniformly with other ingredients

Question 15

What is segregation

Answer 15

the tendency of particles to separate according to their physical properties
- occurs due to difference in particle size, shape, density etc
- particle size plays the most important role in segregation

Question 16

Formulation requiements for:
a. dry power/metered dosed inhalers?
b. suspensions or controlled release formulations?

Answer 16

a. API size < 5 to 6um to reach deep lunch and not be exhaled
b. tight requirements on mean and top (largest) size in API particle size distribution

Question 17

Problems with milling

Answer 17

Milling API can achieve propotionaltely tight particle size distribition (tall narrow distribution curve)

Problems:
- can result in high proportion of fines that increase cohesive behaviour (stick tgt) and not flow well, causing process problems downstream
- energy for breaking particles can convert crystal forms to amorphous forms
- both affects production and reproducibility and formulation efficiency

Question 18

Crystalline vs Amorphous

Answer 18

Crystalline;
- long range order
- sharp melting point
- breaks at definite planes

Amorphous:
- short range order
- no sharp melting point
- irregular breakage

Question 19

Problems with amorphous state? (3)

Answer 19

• lower physical and chemical stability than crystalline state
• high hygroscopicity
• variability

Question 20

Characterization of solids - particle size

Answer 20

Equidimentionsal particles - use diameter (e.g. sphere)

Non-equidimentsional particles (irregularly shaped)
- use 2nd longest dimension (e.g. needles, take thickness)
- use equivalent spherical diameters (definees size of an irregular particle by equating a property of that particle to a sphere, equivalent surface area) -> diameter of particle is diameter of circle (refer to slides), measurements made with microscope

Units:
Coarse - in or mm
Fine - screen size
Very fine - um or nm
(fine/very fine most common)

Question 21

Characterization of solids - size distribution

Answer 21

Described by measure of variation in size: (using screen shaker)
- weight (most relevant)
- surface
- number (quantity)

Question 22

Describe screen shaker

Answer 22

Used for mixed particle size and size analysis

Tyler Mesh number: number of openings per inch
e.g. 10 mesh, Dp = 1/10 = 0.1 inch -> opening of mesh is 0.1 in (refer to slides if dont get)

Analysis with standard screen:
1. screens arranged serially in a stack
2. finest mesh at bottom and coarsest at top
3. materials loaded at top then vibrated for a period of time (15-20min)
4. particles on each screen removed and weighed and converted to mass fraction for each mesh number
5. avg particle diameter calculated in each increment

Question 22

Characterization of solids - particle shape

Answer 22

Affects powder flowability and powder bulk density

Higher powder bulk density -> particles closer to eo -> greater cohesion -> less free flowing (affects uniformity)

• shape of particle expressed by sphericity
• sphericity is the ratio of surface area of a sphere with equal volume as particle and surface area of particle
• sphericity = 1 for spherical particle with diameter Dp
• high sphericity particles have good flowability
• sphericity 0.8-1 is good

Question 22

Characterization of solids -densities

Answer 22

True particle density = mass of particle/vol of particle

Bulk density = mass of powder sample/vol occupied by powder sample ,, density of powder in loose state after pouring freely/density of a batch or sample

Tapped density
- volume measured after tapping powder (vol should decrease, density increase)

Due to voids between solid particles,
bulk < tapped < true

Question 22

1. Rittinger's law? 2. Kick's law? 3. Compare. 4. When to use which?

Answer 22

1. Energy consumed in size reduction of solids is proportional to new surface produced 2. deformation energy, the energy required by material just before rupture called strain energy is proportional to volume. Unit volume of particles at stage of rupture contains same deformation energy independent of particle size. Hence, same amount of energy is present at each stage of grinding in size reduction process 3. Kick's law considers deformation energy requirement up to just before rupture, while Rittinger's law considers energy required for actual fracture of particle once it has reached deformation. 4. Rittinger's - perfrectly brittle materials. Kick's - elastic materials

Question 23

a. Energy requirements for size reduction? b. actual energy requirement for particle size reduction?

Answer 23

a. 1. create new surfaces 2. particle-particle and particle-machine friction 3. wasteful movement of particles within mill 4. elastic and plastic deformation of solikds 5. production of heat, nonise and vibrations 6. losses due to inefficient power transmission b. 1. input and output particle sizes 2. hardness 3. strength 4. other mechanical properties of solids

Question 24

Mechanism of Size reduction

Answer 24

Rapidly applied force normal to particle surface and directed towarsds centre - mass fracture or breakage into a few large fragments Force applied slowly - compression is main cause of particle breakage Force applied parallel to surface of solid - particle can break into may fine particles over time (attrition)

Question 25

Criteria for size reduction equipment

Answer 25

1. large capacity 2. require small power input per unit of product 3. yeild a product of the single size distribution desired

Question 26

Closed and open milling circuiut?

Answer 26

Closed: - good size control - operated batch wise if batch is small (<10kg) or narrow PSD required - sizing or classifier may be integral to equipment Open: - continuous/batch wise - control of how narrow PSD is may not be as good

Question 27

Milling equipment mechanisms?

Answer 27

Impact - involves contact of material with a fast moving part which imparts its kinetic energy to material - causes internal stresses in particle -> breaking it Compression - involves gripping material between 2 surfaces and force imposed on it by one or both surfaces Cutting - involves application of force over a very narrow area of material using a sharp edge of a cutter Attrition - involves collision between 2 particles havinghigh kinetic energy, high velocity particle with stationary surface

Question 28

Describe Hammer mills

Answer 28

- Materials broken by impact - used to mill crystalline organic powders - 5-20kg capacity - produces typical particle size 20-60um How it works: 1. comprises hammers attached to high speed rotor 2. materials enter at top and thrown to outside of milling chamber where it is broken up by impact 3. materials exit the mill when it is fine enough to pass through the screen 4. speed of rotor and size and shape of screen apertures control particle size (rotor speed increase, force applied increase) 5. entrained dust separated by bag filter or cyclone separator 6. can be equipped with cooling jacket to prevent temp increase and dusing or decomposing of susceptible drugs

Question 29

Describe Pin mills

Answer 29

- suitable for grining soft, non-abrasive powders - produces typical particle size15-30um - size reduction by impact and attrition How it works: 1. comprises of 2 disks with intermeshing rows of pins 2. one disk rotates with high speed up to 120m/s, the other static 3. material fed throuogh centre of stationary upper disk on to lower revolving disc 4. as powder moves through pins, size reduction occurs by impact and attrition 5. fineness of milled powder can be varied with disks of different designs 6. if both disks rotate, particle size of 5um can be obtained

Question 30

Describe jet mills spiral jet

Answer 30

- capable of milling hard, fine grained material - produces typical particle size of 2-10um - size reduction by impact and attrition - aka microniser or fluid energy mill 3 types: SPIRAL JET MILL, loop jet mill, fluidized bed jet mill How SPIRAL JET MILL works: 1. micronisation accomplished through particle- particle collisions caused by high velocity gas streams 2. feed material suspended in high velocity air (N2) stream and fed into mill using venturi tube injection system 3. feed tube set at 45degree angle to radius of mill so feed is thrown towards outside of mill into the path of large particles already in the mill 4. main feed gas at 80-100psi enters chamber through jet nozzle, expands and energy releases, imparting a high rotation velocity to the material 5. as air moves at high speed in circular or elliptical path, it carries the fine particles to the centre of the mill where they are discharged 6. the exhaust air passes out through an air relief bag that acts as a filter to collect overground material 7. large particles remain in the mill and are carried outside to be exposed to further collisions until they are of suitable size to be discharged 8. gases cool on expansion, so operating temp is low (can use for heat labile API)