1
Q
Wet granulation equipment- Oscillating granulator
A
- Blade in the granulator oscillates (Moves back and forth in rhythm)
- Pushs the damp granules through the screen
- Like when we did with the size
2
Q
Wet granulation equipment- Counter rotating roller
A
-2 rollers- First roller has a screen in it (wholes)
-2nd roller is solid and the solid roller pushes the granules through the wholes of the screen
NB-The particles are pushed together when going through wet granulation machines this shown by the fact that the sample seems to get wetter as we push sample through because the water is being pushed to the edge from the middle
3
Q
Wet granulation equipment- High speed mixer- KNOWN as feilder and diosner
A
- Large mixer blade and the bottom
- Chopper blade at the side
- Along with a outlet filter and discharge port
- Load all powders dry into mixer
- Impeller blade does the mixing of the powders
- Liquid is then added until the correct amount is present
- The chopper blade is then added- this adds so much energy to the system it is equivalent of pushing through a screen- produces granules
- Takes 30s- 2min to turn 250g batch into granules
- Granules are then discharged and placed into dryer
4
Q
Spray drying
A
- Particles of drug are suspended in binder solution
- This is then pumped into the column/chamber
- The air in warmed and pumped through the atomiser
- The solvent dries off and only the particles are left
- Get spherical particles
- Binder is at the surface of the particle with the drug in the middle- this means that the drug can form tablets better because the binder is very compressable
- This is used for drugs that are poorly compressable - paracetamol
- VERY EXPENSIVE
- VERY BIG - 30ft high
5
Q
Influence of binder on a tablet properties
A
- We used 3.5.7% binder with paracetamol tablets
- We also spray and wet granulated them
- Those that were spray dried where harder than wet granulation
- They will stand handling pressure then wet dranulation
- The down side if expensive interms of energy and equipment cost
6
Q
Effect of binder solution conc
A
- 3 and 4% binder gave far stronger tablets than 2%
- 3% gave far quickier dissolution rate than 4% (18 min compared to 30 min)
- The type of binder makes a difference
- Povidone gave far quickier dissolution compared to HPMC
7
Q
Dry granulation- Slugging
-e.g. METFORMIN
A
- Mix powders including some lubricant and some disintergrant
- Slug- make large rough compacts for further processing
- Mill the slugs- This turns them into granules
- Add further lubricant and disintergrant
- Compress into final tablet
- This prolongs the time your powders feel the force of the compression for tableting- done by doing in 2 stages
8
Q
Dry granulation by roller- Penicillin
A
-Similar process to slugging but with different equipment
-Instead of tablet machine use a roller compactor otherwise known as chilsonator
PROCESS
-Mix powders including some lubricant and some disintegrant
-Compact into ribbon (using a roller)
-Mill the ribbon (like hammer mill)- to give granules
-Add further lubricant
-Compress into final tablet
9
Q
Advantages of dry granulation
A
- Avoid heat- good for drugs that are heat sensitive
- Avoid solvent- good for water sensitive drugs- particularity for storage
10
Q
Disadvantage
A
-It is not good for drugs like paracetamol
+ It is poorly compressable so wont form good flake (rough compact) and so good granules
11
Q
Direct compression
A
- All you do is just mix and compress
12
Q
Advantages of direct compression
A
- Simple formulation
- Quicker processing times
- No exposure to heat or moisture
- Less energy use
- Less equipment use
13
Q
Disadvantages
A
- Limited range of suitable materials
- Capacity of excipient- It can only cope with 50% of drug any more we tend to struggle making tablets
- Risk of segregations or demixing- if the drug particles are very different size to the excipient, during the compression process this can cause segregation of the different sized particles- DOSE UNIFORMITY
- Excipient cost-
- Inflexible- it works or it doesn’t cant really change the formulation for it to work
14
Q
Physics of compression
A
-Bonding in solids
-Particle deformation
+Plastic
+Elastic
+Time dependant (Visco-elastic)
-Characterisation of compression process
-Research methods
15
Q
Interparticulate bonding
A
- ++Solid bridges
- Bonding by liquids- liquid capillary forces in wet granulation
- Binder bridges- these form in granules, so binder at the surfaces of different particles bond
- ++Intermolecular and electrostatic forces-
- Mechanical interlocking
- ++Both require close contact between clean (sugar coated gum wont bind together) surfaces caused by particle deformation
16
Q
Particle deformation
A
- Particle rearrangement -At low applied forces by moving the air and placing in the minimum area that you can
- Plastic-
- Elastic-
- Time dependant (Visco-elastic)-
17
Q
Stress-strain diagram for a hookean elastic (A spring) solid within elastic limit
A
- Elastic deformation is when the applied stress is equal to the strain
- You place a weight on it, it stretches and bounces back
- If you exceed the elastic limit- you will permanent deformation of the material
18
Q
Stress-strain diagram for a brittle elastic solid- glass
A
- If you take a brittle elastic solid and take it to its limit it will fracture
- However with glass it can bend only when kept in a sterile environment it becomes elastic
- When in a non-sterile environment, materials come into contact causing micro-scratches causing it to become brittle
- when you compress glass particles you shatter the particles this creates new clean surfaces
19
Q
Plastic v Elastic
A
- Particles deform under compressive force
- Compressive forces removed
1) Elastic deformation- particles return to their former shape and cohesion is lost
2) Plastic deformation- particles remain deformed but cohesion is retained- allow to form compressed tablet
20
Q
Quality attributes of tablets (specification)
A
- Drug content
- Uniformity of content
- Impurities
- Drug release rate- dissolution profile
- Thickness
- Weight
- Friability- assessment of the surface of the tablet (surface chipping) abrasion- this can lead to underdosing
- Crushing strength (hardness)- a measure of tablet integrity during shelf life
- Disintegration time= dissolution= bioavailability
21
Q
Drug content; uniformity of content; impurities
A
- All chemical tests requiring suitable assay methods
- Uniformity of content may be by uniformity of weight
22
Q
Mechnical properties
A
-Hardness \+The max force the tablet can withstand before fracture -Crushing strength -Tensile Strength -Resistance to crushing -The 'Brazillian test'
23
Q
Disintegration time test
A
-BP general standard for non-coated tablets is <15 minutes
-BP general standard for coated tablets is <60 minutes
+Why the difference: increase conc of disintegrant; compaction (lower compression force); reduce conc of binder; Larger particles of same materials
-Need not be carried out if dissolution test is required in the individual monograph
-Frequently used as in-process test during routine production
24
Q
Tablet dissolution
A
-One of the most important aspects of tablets quality to be considered during development of a new product
25
Dissolution testing
-Tablet (small amount of drug will enter into solution-k1) -->
-Disintegration of tablet into granules (quite alot of drug enters solution k2) -->
-Deaggregation of drug particles into stomach (the majority of the drug enters solution- k3)
-Once in solution the drug can pass through biological membranes and enter the systemic circulation-k4
NB- majority of the metabolism occurs in liver some can happen in stomach
26
Dissolution testing- Why do it
| -Look at BB slides to get graphs
DIGOXIN TABLETS-
- Digoxin, a cardiac glycoside widely used in 60s and 70s. LOW solubility approx 24mg/L
- Low dose (around 1mg), narrow therapeutic index, fatal overdose
- Large number of brands manufactured
- Original product was lanoxin made by burroughs Welcome
- 1972 there were 44 brands of digoxin in US market
- Increasing numbers of reports were being made of either toxicity or ineffectiveness
- Bioavailability study (involving fDA) found major differences between brands and between batches
- First pharmacopoeial dissolution test into USP in 1970
- Later in BP in 1975
27
Dissolution testing
- All tablets now need dissolution test as part of their release specification
- Generally accepted that a dissolution rate of about >80% in about 45 minutes in both SIF (stimulated interstial fluid) and SGF (stimulated gastric fluid) using a standard method is an acceptable value
28
Denvelopment of non-standard dissolution method
-Standard volume in 900ml
-Some drugs are not sufficiently soluble in 900 ml
-Need sink conditions- the volume of the liquid should be such that if the tablet was to disintegrate immediately and drug is released immediately, the solvent should be able solubalise all of the drug
-Under sink conditions there should be 0 order dissolution rate
-Under non-sink conditions will be unser 1st order
+There is not enough solvent the solubles all of the tablets, not all of the drug will be dissolved
+This therefore means there would be different dissolution profiles
29
Development of non-standard dissolution method
-Ibuprofen solubility at pH1 = 54mg in 900ml (not sink)
At pH 7= 3200mg in 900ml (SINK)
-Use of alternative methods- flow cell- infinite volume
-Must relate to some in vivo properties
-Use for routine quality control
+Minor reformulation
+Changes of manufacturing site
30
Tablet coating
- Sugar coating- rarely used for new products- Nurofen
- Film coating- most common coating
- Dry or press coating- double compression of dry granules
31
Reasons for coating
- A tablet is commonly a fully function dusage form so why coat
- Protection from light and moisture
- Taste masking- addition barrier
- Masking of mottling due to coloured drugs
- Reduce dust during packing
- Elegance (marketing)
- Functional coats: Enteric and controlled release coats
- Separation of reacting content
32
Dry and press coating
- Components that are in the dry states compressed together
- XEED dosage form
- 1st compression: iosoniazid core with special polymer coating for site specific release
- 2nd compression: API's (rifampicin, ethambutol, pyrazinamide) outer layer with outer coating to protect from moyster and light
33
Coating- sugar coated
- Rounded tablets
- No defined edges
- Highly polished
- 30-100% weight increase
- No break line possible- NEGATIVE
- Long multistage process (can be several days, usually 12 hours)
- Enteric coated possible
34
Coating- film coated
- Most shapes possible
- Clear edges
- Semi-matt finish
- 2-3% weight increase
- Break lines and other embossing possible
- Single stage rapid process (2hours)
- Different function coats possible- enteric coated
- Enteric coated used so that tablets can go through acidic stomach without breakdown, disintegration and dissolution occurs further down the GI tract in high pH and more alkaline conditions (5.5-6.5)
- Various polymers can be added to the coating of the tablet to give it unique release profile: e.g. when it comes into contact with GI fluid it begins to swell- not giving the tablet the opportunity disintegrate, as its encapsulated tablet inside, also controls rate at which GI fluid can enter tablet causing disintegration and fragment), also control drug release into GI tract
35
Sugar coating- method
- Spraying- droplets of coating cover particles
- Wetting/distribution- sugar coating wet onto the surface and coalesce
- Recrystalisation occurs as the layer build up
- We then get a sugar coated particle
- Different layers of sugar coated tablets: Polishing layer, finishing layer, coloring layer, smoothing layer, subcoating layer, core tablet
- Enteric coating can be added as wella s mult-vitamin layers
- Think children, elderly and diabetic
36
Film coating coating
-Developed in the 1960's
-Originally using mixed organic systems (methylene chlorid , methanol)
-Aqueous based systems now used almost exclusively
-Single most widely used films former is HPMC (used as a binding agent in granulation)- use about 2-3%
+NB- higher the MW of HPMC the more vicous the solution
37
Film coat formulation
-Polymer- film forming material
-Plastizer- Optimise mechanical properties of film. NOT always required (this occurs in packaging)- by modifying polymer composition it changes the mechanical properties e.g. PVC is normally ridgid can be made soft and flexible- this allows even distribution across tablet giving uniform coverage
Colourants- usually commercially available
-Solvent- water or mixed organic solvents e.g. methylene chloride/methanol
38
Side vented perforated pan (Accela cota)
- Hot and cold air input
- Nozzle that sprays film solution
- Place tablets in drum and spray with film coating
- The air will drug the solvent (mostly water)
- The air then leaves the drum through the perforations of the drum
39
Potential problems with coating
1) Edge and chipping/Erosion
- Low mechanical strength of coating
- Excessive pan speed
- Low solids content in coating liquid
- Low spray rate
- Sharp edges on tablets
- Worn tablet punches
- Low tablet hardness/ friability
2) Twinning
- Spray rate too high
- Pan speed to low
- Inappropriate tablet shape
- Tacky coating formulation
- Spray guns to close to tablet bed
3) Peeling
- Low mechanical strength of coating
- Poor adhesion of coating to tablet surface
- Excess lubricant usage in formulation
40
potential problems with coating
4) Picking/Sticking (bigger scale than twinning)
- Spray rate too high
- Inadequate drying conditions
- Pan speed to low
- Inadequate atomization of coating liquid
- Poor distribution of coating liquid
5) Core erosion
- Inherent softness or high friability of core
- Excessive pan speed in coating porcess
- Spray rate too low
- Low solid content of spray solution
- Premature swelling of hydrophilic super disintegrate in formulation
6) Cracking
- Low mechanical strength of coating, exacerbated by inadequate plasticization (not flexible enough) or excessive pigmentation
- Core has significantly different thermal expansion characteristics than coating
- Extended elastic recovery of core after compression
- Inadequate plasticization
41
Functional coats
- Controlled release coats
- Enteric coats- A coat using conventional film coating techniques that is resistant to dissolution in acid conditions (pH<4.5) but dissolves rapdily in the neutral pH of the intestines
42
Controlled release coating
- 'Oros'- oral omotic system
| - Developed by alza to give 0 order (constant rate) release over period of time up to about 24 horus
43
Oros system
-Semi-permeable flim coated
-Compressed tablet containing osmotic agent and drug
-Lazer drilled hole where solution of drug and osmotic excipients are released
_This can enhance compliance espcially in elderly population with polypharmacy- have to take less tablets per day
44
Film coating standard v Oros
1) Weight gain
- Standard= 2-5%
- Oros= 8-10%
2) Process time to achieve uniform colour
- Standard= 2 hrs
- Oros= 2 hrs
3) Process time to achieve uniform release rate
- Standard= n/A
- Oros= 10 hours
45
Reasons for enteric coating
- Drug irritant to gastric mucosa
| - Drug rapidly degraded in stomach acid
PH2503- formulations
flashcards
Decks in class (18)
# Cards
-
powders- lec 126
-
Pre-formulation Reformulation Of Powders36
-
Powders-Lec 215
-
Powders- Lec 3+435
-
tabletting56
-
RE-formulation7
-
Overview of the drug development process20
-
Solid state properties26
-
Fill weight calcollations4
-
Tableting 245
-
Kinetics31
-
Packaging19
-
Packaging 230
-
Assessment of pharma products- thermal analysis16
-
Clinical trials19
-
Regulatory affairs in the pharmaceutical industry19
-
Kinetics 26
-
Kinetic equations14
