powders- lec 1 Flashcards
1
Q
what is the importance of particle size
A
- The size of drug particles influence their biological activity- particle size influences drug dissolution
- The size of powder particles influences the manufacture of medicines- powder flow, packing to tablets and capsules
- Therefore particle size is the most important solid-state property routinely measured
2
Q
factors affected by particle size
A
- Drug dissolution rate and bioavailability- smaller the particle the greater the SA, the better the dissolution hence better bioavalibility
- Content uniformity
- Taste & texture- smaller particles more taste, larger SA= more dissolved in saliva: large particles= gritty
- Colour- Particles that arent uniform size cant get patchy when put with added colourant (mottling)
- Flow- large particles flow better than smaller: Poor flowability can lead to content uniformity/dose uniformity
- Compressibility- smaller particles, more SA
- Stability-
3
Q
Reasons to reduce particle size
A
- To increase drug surface area and therefore facilitate dissolution
-The products may require it: aerosol products (mean size 3 microns
+To improve suspension stability
-To produce a more homogenous mix: very important with low-dose products-dose uniformity
-To improve powder flow solid dosage form production
4
Q
Particle size drug absorption
A
-The oral absorption profile of many drugs are dependent on particle size: griseofulvin; nitrofurantoin; Spironolactone; several steroids
5
Q
How do we achieve size reduction
A
- milling: cutter mill; hammer mill; ball mill; air jet mill
- reprecipitation
- spray drying
6
Q
The cutter mill
A
- Feeder- where material is added
- consists of a series of knives attached to a horizontal rotor (rotating knives)
- these act against a set of stationary knives
- during milling, the particles fracture between the two sets of knives
- one small enough particles for through a screen ( the screen effects the size of the particles that can be filtered through so size of material)
- SEE blackboard for picture
7
Q
Advantages of cutting mill
A
- the high shear rates are useful in reducing the size of:
- of dried granulation before tabletting
- fibrous crude drugs- roots, before drug extraction
8
Q
The air jet mill
A
- Basically, the system provides a fast stream of particles which are rubbed against each other in a turbulent fluid (air) stream
- The size reduction is related to the pressure of fluid- Increase grinding pressure= decreased particle size
9
Q
advantages of air jet milling
A
- Well established technique
- Accepted by regulatory bodies
- Ease to achieve micronisation with many drug substances (Inhalation)
- Repeat passes may be used to closely control particle size
10
Q
disadvantages of air jet milling
A
- Some particles may not micronise by this technique: particle is too elastic; force imposed by being inefficient to fracture particle
- May promote phase changes in the product
- Possibility of contamination: mill materials; impurities of the air
- The material may have poor flow properties after processing
11
Q
Bead or ball milling
A
- The most common and versatile grinding unit
- A suspension of drug particles is passed through a chamber containing balls or beads of harder material
- The balls are rotated using a paddle
- Rotation speed is very important- at low speeds= incomplete size reduction; if at too high speed= all the beads settle around the circumFrance; correct speed= max time of bead drug contact
- Total number of beads: more beads= more size reduction as the beads are in contact with material more
- Fill the chamber with balls of different sizes and different types (ceramic or steel)
- Screen size= product size
- See BB for picture
12
Q
Factors influencing size reduction- ball milling
A
- Suspension feed rate: decreased feed rate = increase size reduction
- The paddle or rotation speed: increased speed = increased size reduction
- The size and loading of the beads: decreased bead loading= decrease in size reduction
- The suspension concentration: increased conc= decreased size reduction
- The number of passes through the mill: increased number of passes= increase in size reduction
13
Q
Advantages of ball milling
A
- Low initial cost, economical operational and maintenance cost
- Can be used for wet or dry milling
- Can achieve good particle size control
- In an aq. suspension may be possible to prevent temperature changes and limit polymorphic changes
- Can use very hard beads to mill difficult materials
14
Q
Disadvantages of ball milling
A
- Possibility of particulate contamination by milling materials (e.g. stainless stell= very sturdy) but ceramic beads can chip and cause contamination
- Not well-known system for regulatory authorities
15
Q
Hammer mill
A
- The powder/particles are fed into the mil via a hopper
- Rotating hammers impact the powder
- When the product is an appropriate size it passes through a screen
- Size is effected by the length of the hammers in relation to the drum and mesh size of the screen
16
Q
Material properties
A
- Size reduction often relies on stress being put on particles causing bonds within the particles to rupture and thus break the particle
- The ease at which the particles reduce in size will depend on their brittleness or plasticity- wont work v well
17
Q
size ranges for the different mills
A
- Fluid energy mill: 1-10,000 microns
- Cutting mill: 100- 100,000 microns
- Hammermill: 10-10,000 microns
- Ball mills: 1-100 microns
18
Q
reprecipitation
A
- Drug substance is dissolved in a suitable solvent (soluble)
- Anti-solvent is a solvent that is misible with the solvent that is used to solublaise the drug but will not solubalize the drug
- This is then mixed with an anti-solvent (solvent which the compound is less soluble in)
- This induces precipitation
- Rate of addition of anti-solvent and speed of mixing influences size distribution
19
Q
Advantages and disadvantages of reprecipitation
A
+ve: the product may be very pure
+ve: no contaminants may be introduced
-ve: could get a solvate- during the process, the solvent molecules can get trapped in the crystals- the resultant crystal is a solvate
-ve: product size distribution is difficult to control
-ve: may be difficult to scale up
20
Q
Spray drying
A
- Solution of drug is sprayed through a fine nozzle to create droplets
- Particles then fall through a counter current of drying air (hot air)- create a cyclone
- Each droplet dries to a solid particle
21
Q
Factors influencing particle size- spray drying
A
- The size of the droplet, by adjusting the size of the nozle: increased droplet size= increased particle size
- The concentration of the solution: increased concentration = increased particle size
22
Q
Advantages of spray drying
A
- Can create spherical particles (good flow properties)
- Can spray dry with other excipients to protect the product
- Creates uniform and controllable particle size
23
Q
Disadvantages of spray drying
A
- May produce the wrong polymorph
- Bulky equipment
- Cannot use heat sensitived materials= degradation
- Yeild from the process can be as low as 30-40%
24
Q
Selection of particle size reduction method
A
-Different processes give different products form the same starting materials
-Factors to consider: size reduction required; brittleness of particles; cost
-
25
Particle flow
- A large particle will flow better than a small one
- This is because of lower SA therefore the contact and interparticle forces are lower allowing better flow
- Anything less than 30-40 micrometers presents significant flowability issues due to cohesion
- 100-250 micrometers provide good flowability
- In inhalers particles need to be 2-5 micrometers- this is so the particles can reach the lungs (to small and the particles are exhaled out and too big the particles the drug wont reach the lungs)
- The particles are placed with a carrier to improve flowability when formulated, the the aerosol is initiated the drug will dislodge from the carrier (carrier is swallowed) and drug enters the lungs
26
3 general parts that mills are made of
- FEEDER
- CHAMBER
- COLLECTER
