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
GELATINE CAPSULE SUMMARY
Variety of colours, sizes
Simpler formulations
Acceptable to patients and easy to use
Can modify release
Hard gelatin capsules
* Common dosage form
* Simpler manufacturing process
* Look out for defects
Soft gelatin capsules
* Used extensively for poorly soluble drugs and oils/lipids
* Specialised manufacturing equipment – longer processing times
Tablet coating
Sugar coating
Historically first coating process
Not used as much today
Relatively thick coat; >25% tablet weight
Film coating
Most common process
Thin coat; ca. 2% tablet weight
Film Coating Materials
Polymer
Cellulose ethers (HPMC, HPC, MC)
PVP
PEGs (high mol weight)
Plasticiser
PEGs, glycerine, triethyl citrate
Glycerol, mineral and vegetable oils
Colour
Soluble dyes, pigments (Al lakes, TiO2, iron oxides)
Natural dyes (riboflavine, carotenoids)
Solvent
Water, ethanol, methanol, acetone
(Methylene chloride)
Plus?
Wetting agents
Flavours
Note: Film coating solutions are a source of microbial growth. They should be freshly prepared (and typically used for up to a maximum of 24 hours as proven by verification/monitoring).
Common Coating Faults
Colour Variation or Mottling
Uneven colour
Caused by…
Too little coating applied
Inadequate mixing of tablets
Pan speed too low
Wrong baffle position
Poor opacity of solution
Too few spray guns
Too many tablets in pan
Roughness or ‘Orange Peel’
Non‐gloss or dimpled appearance
Caused by…
Poor atomisation of solution
Solution viscosity too high
Solution solids content too high
Drying temperature too high
Over‐wetting of tablets
Too high spray rate
Bridging
Logo or text debossed on core unreadable
Caused by…
Design of debossing
Surface characteristics of tablet
Lack of porosity
Hydrophobic ingredients
Coating solution
Applied too quickly
Air in solution
Viscosity too low
Blistering, Cracking, Splitting and Peeling
Local detachment of coat
Cracking caused by…
Expansion of core due to overheating
Lack of relaxation time following compression
Poor solution formulation
Inadequate plasticiser
Mineral fillers
Core has different thermal expansion properties to coating solution
Peeling caused by…
Poor adhesion of coat to tablet core
Too high spray rate
Over heating of tablet cores
Typically above 65°C
Low mechanical strength of coating
Picking
Film broken because of adherence to another tablet
Sticking
Tablets stuck together
Picking and sticking caused by…
Solution spray rate too high
Pan speed too low
Low bed temperature
Atomisation air pressure too low, leading to poor distribution of coating solution
Coating of baffles and walls, leading to flaking
Twinning
Tablets stuck together along edge
Caused by…
Tablet shape
Particularly ‘capsule’ shaped tablets
Edge Chipping or Splitting
Edges chipped, or film broken at tablet edges
Caused by…
Soft tablet cores
High friability
Sharp edges on tablets
Use punches with deeper concave
Worn tablet punches
Pan speed too high
Spray rate too low
Coating solution solids content too low
Core Erosion
Tablet core partially dissolved or eroded
Caused by…
Soft cores
High friability
Core sensitive to moisture
Pan speed too high
Spray rate too low
Try pre‐heating cores
Start with low rate and then increase
COATING PROCESS END POINT
Set quantity of film coating solution/suspension used
Overall tablet weight gain (%)
Appearance of film coated tablets
Oral solid does finished product testing
Uniformity of Dosage Units
Uniformity of Content (Assay)
Uniformity of Mass (weight)
Disintegration
Dissolution
Hardness
Friability
Uniformity of dosage
Two Methods
* Content Uniformity
* Calculate Acceptance Value for each from individual assay result
* Mass Variation
* Calculate Acceptance Value from Individual weights using single assay value from the assay test on a composite representative sample
Uniformity of content
Ph. Eur, USP<905> and JP mostly harmonised
* Applies if content less than 25mg or 25% of tablet weight
* USP also specifies Mass Variation may be used if assay validation has RSD <2%
Assay individually 10 tablets
Limits 85 – 115% on 10 tablets but retesting possible if values obtained between 75 – 125%
Uniformity of dose
Weight of individual 20 tablets
NMT 2 deviate from average weight by 5, 7.5 or 10% depending on tablet weight
None deviate by twice percentage
Disintegration parameters
Crude measure of ‘availability’ of drug
* Raise and lower in water at 37°
* Normally 15 minutes for uncoated tablets
Dissolution test
May give better link to bioavailability
* Controls batch variability?
* Required in all USP monographs
* Limited in Ph. Eur.
* Enteric coated tablets
* But expected in registration dossiers
Amount dissolved (Q) in time (T) using specified apparatus and conditions
Calibration and control important
* Physical parameters
* Temperature and composition of media
* Degassing!
* Speed, position, wobble etc. of basket or paddle
* Performance verification
* Mechanical tests
* USP calibrator tablets
* Prednisone, Salicylic Acid
Test carried out on at least 6 tablets
* USP → multi stage acceptable criteria up to 24 tablets
* Ph. Eur. → Q = 75%, T = 45 min. Retest possible if 1 tablet fails
* For enteric coated tablets → 2 stage test
* Acid resistance (0.1M HCL)
* Higher pH buffer
Hardness
Balance required to give robustness and disintegration
Electromechanical test equipment
Calibrate directly or by ‘mechanical tablets’
Multiple designs of tester
* Schleuniger
* Erweka
* CI
Non destructive by NIR
Combination instrument
* Hardness
* Thickness
* Diameter
Breaking strength or hardness refers to the force necessary to cause failure of the tablet under load
Thickness
Important in packaging
* But beware if you register a specification!
Friability
This is a measure of resistance to abrasion
* Measure of robustness during coating, packaging and use
* Performed on uncoated tablets
For uncoated tablets
* 10 – 20 tablets
* 25±1 rpm for 4 minutes
* NGT 1% mass loss
Measures resistance to abrasion. Perhaps the most important parameter to consider for
forward processing.
Tablets with friabilities approaching 0.5% will be very difficult to coat.
Liquid formulations
Solution
* Single phase liquid system
* Solvent and solute(s)
Suspension
* Liquid continuous phase, second suspended solid phase
Emulsion
* Liquid continuous phase, second emulsified liquid phase
Solution
Solvent
* Aqueous/Non aqueous
Solute
* Solubility enhancement
Excipients
* Taste masking
Solvent
Aqueous (water)
* Most common
* Correct quality grade employed
* Purified water
* Chemical and microbiological quality
Non-aqueous
* Alcohol, glycols,
* Unusual
* Quality important e.g. potable alcohol (ethanol)
Solute
Anything dissolved in solvent
Solubility enhancement
* pH adjustment
* Co-solvent
* Surfactant solubilisation
* Complexation
Other excipients
* Buffers
* Tonicity
* Viscosity
Sweeteners
Sucrose
* Oldest, best, simplest
* Additional benefits
* Antimicrobial
* Disadvantages
* Calorific (diabetics), cariogenic
Other Sugars
* Lower sweetening potential
Artificial Agents
* Saccharin, aspartame, acesulfame, cyclamate
* Low concentrations required
* Distinctive taste – mask low sucrose concentrations
Flavours
Enhance taste masking effect of sweetening agents
Smell and taste e.g. peppermint
Concentrated alcoholic solutions requiring dilution for manufacturing
Natural or synthetic
* Synthetic
* Cheaper, consistent, stable
* Natural
* Microbiological quality
Traditional tastes
* Antacids – minty
Colour
Final portion of organoleptic disguise
Match product colour to flavour
* e.g. red for strawberry flavour
Requires additives
* Not consumer friendly
Suspension
Three components
* Solvent(s)
* Continuous liquid phase
* Solute(s)
* Dissolved in solvent to modify behaviour
* Solid phase
* Non-dissolved material, discrete particles
Ideal suspension
Sediment – easily resuspended
Re-suspension – stable
* Dose withdrawal
Particle size – uniform
* Non-gritty (< 5 μm)
Emulsion
Three components
* Solvent(s)
* Continuous liquid phase
* Solute(s)
* Dissolved in solvent to modify behaviour
* Disperse phase
* Non-dissolved liquid, discrete particles
Disperse phase - common in Topical creams
Oil in water
* Oil – disperse phase (not more than 60% v/v)
* Active ingredient – cod liver oil
* Water – continuous phase
* Usual system
Water in Oil
* Water – disperse phase
* Oil – continuous phase
* Difficult to process oil into the water phase
Emulsifying agent
* Surfactant
* Polymeric agents
Viscosity enhancers
Density modifiers
Antioxidants
Masking fragrance
Liquid manufacture
Product ingredients
* Risk – water, excipients, containers
Manufacturing
* Equipment
* Closed vessels, distribution, cleaning, filling
Distribution
* Storage
* Validated hold times
* Ref Annex 9 EudraLex Vol. 4
* Consider Contamination Control Strategy
Preservative
* To deal with “in use” contamination
* Not manufacture based contamination
Preservation
* Complex area
* Product
* Suspension/emulsion
* Container interaction
Inhalation products - Inhalation products – DPI and MDI DPI Dry powder inhalers Breath actuated
Delivers drug as powder into lungs
May need to ‘load’ the drug
Reservoir or single dose
Need to consider moisture protection
Formulation Ingredients
Drug and diluent
Micronisation of API
Particle size of API and excipients
Interactions between drug and diluent
Mixing and segregation
Potential for moisture uptake
Actuation Device
Use of capsules, blister strips or chamber system
Mechanical disruption of powder
Moisture risk
Patient use impacts
Inhalation production - MDI Metered dose inhalers/aerosol pMDI – pressurised metered dose inhaler
Used inverted (valve down)
Meters a dose, rather than sprays continuously
Drug and propellants inhaled into the lungs
Formulation Ingredients
Particle size of API
Micronisation of API
Solubility characteristics of API – may need adjuvants
Surfactants aid suspension of drug substance
Surfactants aid valve lubrication
Propellants – CFC and HFA
Inhalation formulation issues
Crystals
Creaming and sedimentation
Agglomeration – fused aggregates that have broken away from their surface of origin to become entrained in the formulation with risk of occluding small atomisation orifices
* Causing increased variability and/or OOS results in medication delivery data
* Causing changes in the aerodynamic profile of the emitted dose
How can we eliminate agglomerates or minimise their effect?
Avoiding creaming formulations
Use a bulking agent to minimise the risk of dose variability impact of agglomerates by co-aggregating with the active
Reduce exposure to moisture that helps to fuse the particles in agglomerates – e.g. pouching and / or use of nylon as a desiccant can have a positive impact
Valve
Metal or plastic components
Elastomer components
Passivation of metal components
Cleaning
Design process e.g. tail off
Canister
Coating
Actuators/Spacers/BAIs/Dose Counters
Press and breathe actuators
Spacers – pros and cons
Breath Actuated Inhaler (BAIs) – design and complexity
Dose counters – FDA perspective
Active Drug Substance
Particle size – Micronisation
Impurities and Degradation Products
Surfactants
Concentrate manufacture
Propellants and Adjuvants
Filtration and refrigeration
Valve
Pressure filling/cold filling
Crimping process
Valve function testing
Canister
‘O’ ring
Canister marking and cleaning
Filtration of all fluids to 0.2 micron – Annex 10
Cold filling
Pressure filling – single and two-stage
100% check weighing (Annex 10)
Optimisation/scale-up/validation – matrixing
Inhalation manufacture controls
Facilities
Air classification – minimum Grade D at point of exposure of product or clean components (Annex 10)
Moisture control
Water bath or Heat tunnel
Actuator
Stem location
Critical dimension control in moulding
BAI Function testing
Documentation
Complex process
Well designed documentation
Many similarities to MDIs
Active Drug Substance
Moisture control
Freeze drying
Diluent
Particle size
Powder flow characteristics
Many similarities to MDIs
Active Drug Substance
Moisture control
Freeze drying
Diluent
Particle size
Powder flow characteristics
Inhalation release testing
Identification – drug, propellants, adjuvants
Fill weight/number of doses
Moisture content
Drug content
Adjuvant content
Leakage
Suspension particle size – Malvern and Microscopy
Release Testing
Valve delivery
Dose delivered – ex valve or ex actuator (through life)
Respirable dose – Andersen or New Generation Impactor
Impurity and Degradation Products
Foreign particulates
Microbial
