Formulation Flashcards
REASONS FOR CHOOSING A DELAYED RELEASE FORMULATION
Drug release in stomach undesirable:
* Drug insoluble or unstable at low pH
* Stomach lining damaged by prolonged contact with drug
* Concentrated drug release needed lower in GI tract
Achieved by application of an ‘enteric’ coat
ENTERIC COATING FOR DELAYED DRUG RELEASE
Pharmacopoeial requirements:
Dosage form must remain intact in pH 1.2 simulated gastric fluid in the disintegration apparatus for 30 minutes at 37C (United States Pharmacopoeia)
Dosage form must remain intact in 0.1M HCl in the disintegration apparatus for 2 hours at 37C (British Pharmacopoeia)
Dosage form must disintegrate within 1 hour in BP mixed phosphate buffer at pH 6.8
Diluents (fillers) – increase the volume of the material to accommodate easier processing of the drug and to make suitable size for patient
* Lactose
* Sucrose
* Calcium phosphate
Binders – cement the active and inert components of tablets together to maintain cohesive and discrete portions
* Polyvinyl pyrollidone (PVP)
* Hydroxypropylmethylcellulose (HPMC)
* Starch paste
Disintegrant – assist tablets to break up in the GI tract (they swell when wet)
* Starch and derivatives e.g. sodium starch glycollate
* Crosspovidone
* Microcrystalline cellulose
NB: Microcrystalline cellulose can act as filler, binder and disintegrant
Glidants (flow enhancers) – added to powdered materials used in tablet/pill production to aid their movement through tabletting machinery
* Silicon dioxide
Lubricants – ease the release of compressed tablets from their dies, improving the efficiency of manufacturing
* Metal stearates (e.g. magnesium stearate)
* Fatty acids and alcohols
* Talcum powder
Added (by blending) as a last step just prior to compressing. Can cause problems with dissolution. If granules get coated with too much they become insoluble Film formers/coatings – used to protect against premature physical break‐up and to prevent unwanted environmental interactions. They can mask bad taste and allow pills to be swallowed easily:
* Polymers and plasticizer
* Shellac
* Sugars
Printing inks – biologically safe dyes used for printing information or company logos on the surface of tablets or capsules
WET GRANULATION END POINT CONTROL
High Shear mixers
* Rapid and reproducible moment to switch off
* Viscosity of the mixture is proportional to mixing blade force. Similarly torque on paddle blade or shaft or property of granule
Controls:
* Time
* Mechanical monitors (torque, rotation, speed)
* Electrical monitors (current, power)
* Sound, conductance, reflectance
FLUID BED DRYING
At pre-set intervals the drying is stopped and the bag filters are shaken to release product stuck to the fabric
End Point is by product ΔT (Differential Temp.) on the granule or by exhaust temperature
* PAT using NIR
Common Compression Problems
- Weight control
- Tablet strength
- Disintegration time
Weight Control
- Bulk density of granulation
➢ Review granulation history - Poor flowing
➢ Review sizing history
➢ Confirm environmental conditions are appropriate
➢ Check moisture content - Machine issues
➢ Appropriate fill cam
➢ Proper feed frame set up and operation - Erratic weights
➢ Check for uniform discharge from feed hopper
➢ Evaluate for possible flooding of feed frame
➢ Confirm tooling has met specifications and is clean
➢ Confirm weight control features on press are working properly
N.B. Always establish acceptable weight control throughout the batch, especially at Run Out.
Tablet Strength
- Adjust compression force
➢ Remember – tablets with low breaking strength may have been over‐compressed.
Strength may with compression force - Study how the tablet fractures during hardness testing
➢ If the tablet laminates, suspect low moisture, over‐compression, over‐blending, excessive lubricant, etc - Is tablet strength being compromised during ejection?
➢ Check for ‘rub marks’ on tablet side band
➢ Tablet lamination may reflect tooling issues
➢ Damaged (hooked) punch tips
Disintegration
Check compression force. Normally too much but sometimes the opposite
* Check lubricant mix times
* Check lubricant quantities
* Double check particle size distribution of granulation
WEIGHT CONTROL – ‘CAN’T GET WEIGHT?’
Bulk density of granulation
* Review granulation history
Poor flowing
* Review sizing history
* Confirm environmental conditions are appropriate
* Check moisture content
Machine issues
* Appropriate fill cam
* Proper feed frame set up and operation
Erratic weights
- Check for uniform discharge from feed hopper
- Evaluate for possible flooding of feed frame
- Confirm tooling has met specifications and is clean
- Confirm weight control features on press are working properly
TABLET STRENGTH/HARDNESS – ‘TOO MUCH OR TOO LITTLE?’
Adjust compression force
* Remember: Tablets with low breaking strength may have been over-compressed. Strength may with compression force
Study how the tablet fractures during hardness testing
* If the tablet laminates, suspect low moisture, over compression, over-blending, excessive lubricant etc.
Is tablet strength being compromised during ejection?
* Check for ‘rub marks’ on tablet side band
Tablet lamination may reflect tooling issues:
* Damaged (hooked) punch tips
DISINTEGRATION – ‘TIMES ARE TOO LONG?’
Check compression force. Normally too much but sometimes the opposite
Check lubricant mix times
Check lubricant quantities
Double check particle size distribution of granulation
Common compression defects
Chipping
Lamination
Capping
Cracking
Sticking/picking
Mottled/discoloured
Facility controls:
Warehouse
Access control
* Warehouse personnel
* Other company personnel
* Wagon drivers
Goods receipt and dispatch areas
Storage locations
* Groupings by material type
* Returns and rejects
Pest control
Production facility controls
Materials
* Clear flow – IN/OUT
* Use of airlocks
People
* Changing rooms
* Gowning
* Access control
* Handwash
Cross contamination risk
Cross-contamination should be prevented by appropriate design and operation of manufacturing facilities
The measures should be commensurate with the risks
Use Quality Risk Management principles to assess and control the risks
It may be necessary to dedicate premises and equipment for manufacturing and/or packaging operations
Dedicated facilities
Dedicated facilities are required for manufacturing when a medicinal product presents a risk because:
The risk cannot be adequately controlled by operational and/or technical measures
Scientific data from the toxicological evaluation does not support a controllable risk
Relevant residue limits, derived from the toxicological evaluation, cannot be satisfactorily determined by a
validated analytical method
High risk categories
Other antibiotics
Cytotoxics; particularly low dose materials
Hormones and certain steroids
Radio isotopes; health and safety requirements for staff usually mean completely separate facilities
Narcotics; subject to strict control, e.g. by Home Office in UK
Other potent or sensitising materials
