Tabletting and associated technologies Flashcards
What % of drugs are oral?
77%
What % of drugs are topical?
3%
What % of drugs are nasal/pulmonary?
1%
Pill manufacture patent?
1843 – first patent for manufacturing tablets using hand operated devices was granted (William Brockendon)
Patent was for shaping pills, lozenges and black lead by pressure
Adv of tablets?
- Improves patient compliance
- Convenient and safe way of administration
- Easy to carry multiple doses
- Accurate and reproducible doses
- Aesthetically pleasing
- Easy to store and dispense
- Solid dosage forms have better chemical and physical stability
- Ease of low cost mass production
- Possible to modify release and performance characteristics
- Possible to mask unpleasant taste and appearance
- Different tablet forms available
Disadv of tablets?
- Manufacture requires a series of unit processes + product loss at each stage
- Drug absorption dependent on gastric emptying rate = inter-patient variation
- Compression difficulties due to powder physical properties
- Administration of tablets to certain patients may be a problem e.g. Children, geriatrics, comatose, patients who have a psychological block
Excipient definition?
“An inert substance that is used as a diluent or vehicle for preparing a drug product”
What makes a tablet low dose?
Low dose tablets – active < 5% tablet weight
What makes a tablet high dose?
High dose tablets – active > 50% tablet weight
Tablet size should be proportional to the amount of drug in the formulation. True or false?
True
What is the minimum and maximum tablet weight?
< 800 mg max
50mg min
What is the max number of tablets for patient compliance?
For patient compliance ≤ 2 tablets
At what does does a tablet require a filler?
Low dose < 5 mg - purely for ease of manufacture and handling.
Concentration range for disintergrants?
Concentration range 1% – 10% w/w
e.g. starch, calcium carbonate
Binder definiton?
Binder (= adhesive) added to ensure that tablets can be formed with the required mechanical strength
Binder can be added as:
- Dry powder (for wet or dry mixing)
- Solution
Concentration range for binder:
2% to 10% w/w
What is a glidant?
to improve flowability of the powder
Either for direct compaction or for granulation
Examples of glidants and their conc range?
Talc (1 – 2% w/w), colloidal silica (0.2% w/w), magnesium stearate (1 – 5% w/w)
What is a lubricant used for?
Role: to ensure that tablet formation and ejection can occur with low friction between the tablet and the die
Concentration range for lubricant:
Concentration range 0.25 – 1% w/w
What is an anti adherent and what is its concentration range?
- Role: to reduce the adhesion between the powder and the punches
- Could lead to uneven tablet surface
- Concentration ~ 0.5% w/w
Examples:
Magnesium stearate, talc, starch
Unit process steps in manufacturing?
- Weighing
- Mixing
- Granulation
- Tabletting
- QA check
- Dissolution
- Coating
- QC check
How is a tablet formed?
The Tablet press- basic process
1) Fill the stationary hopper
2) Die filling
3) Tablet compression
4) Tablet ejection
What does weighing involve?
- Required amount of excipients
- Weight of each ingredient dependent on final weight of the tablet
Mixing process in manufacturing process:
Critical step
Homogeneity
-Uneven API content
-Uneven properties
-Affects tablet shape and size
Y-Cone blender
- Dry blending
- Wet granulation
Tablet quality assurance check involves tests to ensure quality. These include–>
- Uniformity of content
- Tablet weight
- Disintegration
- Dissolution
- Mechanical Strength
- ->Friability
- -> Fracture resistance
- Tablet appearance
Importance of powder flow?
Determination of flow properties is critical
- Affects the way the powder flows
- From hopper to die cavity
- Bulk storage containers into feed mechanisms
Uneven powder flow
- Results in air trapped in the powder
- Capping and lamination
- Excess fine powder
- Dust contamination risk to handlers
Particle interactions affecting powder flow?
Particles can stick to themselves or to surfaces
Adhesive force –>
- Between particles and container surface
- Adhesive Force α 1/particle size
- Particle size > 250 μm – free flowing.
Cohesive force –>
- Between particles
- Cohesive force α particle surface area
- Particle size < 100 μm will experience greater cohesion. Need a glidant OR to use granulation to increase particle size
Reasons for Cohesion and Adhesion? (bulk solid parameters)
Bulk Solid Parameters:
- Particle size, shape, texture and distribution
- Particle hardness and Surface characteristics
- Moisture content
- Particle density/bulk density
- Temperature
Reasons for Cohesion and Adhesion? (container parameters)
- Wall surface roughness
- Chemical composition
- Temperature, pressure and humidity
- Environmental parameters – vibrations
Measurement of Adhesive/Cohesive Properties ?
Tensile Strength
- Characteristic of internal friction or cohesion of particles
- Measurement based on splitting of the powder
- Determined by Tilting Table Method
- Dual Plates: one fixed and the other free
- Correlates with Angle of repose
Angle of Repose
- Powder slides when the angle of inclination > frictional force
- Powder stops sliding when the angle of inclination < frictional force
- Can determine effect off added glidants etc. on flow
Effect of particle properties on bulk flow?
The following particle properties all affect bulk powder properties, including flow:
- Particle size
- Particle shape
- Particle density (true density)
- Packing geometry
Bulk density= density of the the bulk powder
Bulk density measurement?
- Measure a volume of powder
- Determine the weight -
- Subject to a pre-determined no. of taps
- Determine volume after tapping
What does bulk density allow you to calculate?
Hausners ratio
Carr’s/compressibility
Why is bulk density important?
- Affects packing geometry
- Die filling
- Particle size and distribution/ uniformity
- Packaging, handling and processing conditions
- Stability
How to improve powder flow?
- Change of particle size (size increase techniques aka granulation)
- Alter surface forces (controlled temp, humidity, storage)
- Formulation additives (glidants, lubricants and anti adherents)
- Change process conditions (vibration assisted hoppers, force feeders)
What is granulation?
Granulation is the process in which primary powder particles are made to adhere to form larger multi-particle entities called granules.
Why use granulation?
- Granules flow better than powder
- Prevent segregation of the ingredients
- Improve compaction
- Granule –> drying adhesive-adhesive interaction
- Ease of compaction –> stronger tablet
- Reduce fines i.e Toxic API, reduced dust
- Hygroscopic particles –> reduce caking –> improve flowability
- Granules less dense –> occupy less volume/unit weight –> ease of storage/transport
Mechanism of granulation:
1) Nucleation
- Particle-particle contact
- Formation of liquid bridges
2) Transition (Nuclei growth)
- Single particles swell in size
- Adhesion of multiple particles
3) Granule Growth
- Coalescence
- Breakage
- Layering
Procedure for wet granulation:
Step 1: Weighing and Blending – API, filler, disintegration agents.
Step 2: Add liquid binder/adhesive e.g. MC, CMC, acacia, corn starch.
Step 3: Sieve the damp mass into pellets or granules.
Step 4: Drying the granules.
Step 5: Sieving dried granules for selected mesh size.
Step 6: Add a dry lubricant if required.
Step 7: Add liquid binder if required e.g. PVP
What is slugging?
Used in dry granulation: Produce large tablets in tablet press
What is roller compaction?
Dry granulation:
- Roll the mixture between two rollers
- Produces a sheet of material
- Milling technique to produce desired particle size
Equipment required for dry granulation?
- Powder compressor
- Tablet press or roller compactor
- AND mill to obtain granules
What is dry granulation useful for?
Temperature and moisture sensitive material.
Advantages of Dry Granulation:
- Economical – less energy costs
- Versatile – can use a wide range of materials
- Low equipment costs
- Easy to scale-up
- Uniform mechanical strength of flakes
- Roller Compaction is “gentler” - tablet compaction is not affected
Uniformity of content test?
Number of tablets to be tested ≥ 5 tablets
Accepted limits 90 – 110% for the active ingredient
Follow specific BP monograph if available.
What does variation in uniformity of content suggest?
- Non-homogenous powder/granules
- Segregation of powders
- Problems associated with compression
Tablet weight testing method?
Critical for low dose tablets (API<5% total tablet weight)
Excipients»_space;> API
Direct correlation between Uniformity of Content and tablet weight
Method:
- Weigh 20 tabs at random from each container
- Not more than 2 should be > 10%
- None should be > 20%
- Could be specified in the individual monographs
Disintegration testing–>
- 6 Tablets usually tested (3 for large tablets)
- Separate tests for tablets (and capsules) of normal size as well as enteric coated tablets.(Also used for suppositories and pessaries)
- Performed in an aqueous medium.
Disintegration testing method:
- Drop one tab in to each tube
- Agitate in medium
- Monitor time taken for disintegration
- Disintegration time taken for the tab to break up [i.e. No residue remains on the screen; if soft mass it should not contain any solid; If only fragments of coating (tablets) or shell (capsules) remain]
- If 2 tabs fail repeat for a second full batch
Definition of dissolution?
The transfer of molecules or ions from the solid state into solution is termed dissolution.
Defined by the Noyes Whitney equation
Two methods of dissolution testing?
Stirred vessel AND continuous flow method
What is the stirred vessel method?
Solid dosage form dropped into dissolution medium (e.g. 0.1N HCl) and stirred – sample taken at “t”
Apparatus used?
- Basket methods
- Paddle method
What is the continuous flow method?
Solid dosage form held in a cell and dissolution medium pumped at a controlled rate
What is mechanical strength?
Resistance to:
- -> Attrition
- -> Fracture
Reason for determining mechanical strength:
Assess importance of formulation and production variables for the resistance of a tablet to fracture and attrition during design, development and production.
Method for testing friability:
Mimics forces that are present in:
- Production
- Storage
- Administration
Reduction in tablet weight (breakage)
Uneven dosage administered
20 tabs in revolving cycle
≤1% weight loss
Resistance to crushing method?
- Determine the force required to fracture along its diameter
- All values determined in Newtons (N)
For a tablet:
Crush = Fail
Split in two = Pass
Repeat determinations on 10 tabs
Tablet appearance monitoring?
Chipping
- Breakage on edges
- Ejection from machine
- Transfer into storage
Indicator of:
- Friability failure
- Machine related issues
- E.g. High compaction pressure
Powder compaction problems
Unusual formulations?
Gastro retentive tablets-
- For drugs which are primarily absorbed in the upper intestine e.g. ciprofloxacin for once daily administration
Muco adhesive tabs
Coating is used to:
- Improve specific physical attributes – strengthening
- Controlled release of drug
- Improve its taste
- Standardise colour
- Make more easy to handle, identify and package
- Protect from physical elements e.g. Light, Moisture etc.
- Improve patient compliance – easy of swallowing, appearance
What are the three types of coating process?
1) Film coating
Popular
Tablets, granules, capsules
2) Sugar coating
Traditional method
Confectionary
E.g. Chewable Vitamin tablets
3) Compression coating
Less common
Modified release dosage forms
Method of coating?
- Pan coating
- Fluidised bed coating (used for granule coating, film coating, modified or controlled release)
What are some of the film coating compounds?
Polymers e.g. HPMC, MC, HPC, PVP, PVA
–> For modified release e.g. EC, cellulose acetate, methylmethacrylate copolymer, phthalate esters of HPMC and PVP
Plasticizers
E.g. PEG, PG, diethyl phthalate, triethyl citrate, fractionated coconut oil
Colourants
E.g. Iron oxide pigments, titanium dioxide
Solvated
E.g. Organic polymer solutions, aqueous polymer dispersions
Film coating polymer ideal characteristics:
Correct Solubility =
Dictates bioavailability of drug from the formulation
Viscosity =
Low – ideal for spraying
Permeability =
Important for taste, drug stability, bioavailability
Mechanical properties =
- Film strength (critical during coating process)
- Film flexibility (reduce film cracking)
- Film adhesion (from production consumption)
Film coating process?
Quantity of the coat –> want short and fast coating
Distribution of the coat –> need even and quick distribution of the coat
Drying –> want quick drying of the solvent from the solid dosage form
- Short repeated doses rather than prolonged wet coats
Problems associated with coating?
- Erosion, peeling and breakage –> Due to soft or poor friability
- Porous tablet/ Uneven coat
- Poor mechanical strength –> leading to tablet breakage
- Tablet peeling –> Excess moisture in tablet
Sugar coating equipment needed and characteristics?
Involves successive applications of sucrose solution
Equipment = Pan coating
Characteristics:
- Immediate release of the drug
- Main reason – to mask the taste
- Possible to use it in combination with film coating to alter drug release profiles
Characteristics of sugar coated tablets?
Appearance =
- Smooth Rounded contour
- Even colour distribution
- Glossy finish
Weight increase =
- 30-50%
Logo =
- Not possible
Process stage =
- Multiple stages
Coating time = > 8 hours
Can be a functional coat, if in combination with film coating
Process of sugar coating?
Sealing =
-of porous tablet core – using shellac, PVAP, CAP
Sub-coating (wt increase – 50%+) =
- Using bulking agents, anti-adherants, binders
Smoothing =
- Additional coat to subcoat (titanium dioxide + sucrose)
Colouring (to obtain an elegant product) =
-Water soluble and water in-soluble dyes used
Polishing (to obtain a high gloss finish) =
- Using waxes (carnauba, beeswax etc) in solvent
Printing (optional) =
-Using edible inks
Compression coating:
- Novel drug delivery and development process
- Dry process
- Specialist equipment
1st compression – makes core
- Transfer core to larger die
- Fill
2nd compression – makes coating
What was granted in 1834 to Mothes and Dublanc?
Apatent for a method to produce a single-piece gelatin capsule.
All modern soft-gel encapsulation uses variations of a process (rotary die encapsulation process) developed in 1933
Both of these classes of capsules are made from aqueous solutions of gelling agents:
- Animal proteins (mainly gelatin)
- Plant polysaccharides or their derivatives, like carrageenans and modified forms of starch and cellulose.
Manufacture of soft gel capsules:
Manufacturing process of soft gelatin capsules:
- Gelatin Preparation
- Material (Fill) Preparation
- Encapsulation
- Drying
- Inspection
- Polishing
- Packaging
Two-piece or Hard capsule encapsulation process:
1) Capsules oriented in to die and then separated using vacuum.
2) Recheck capsules are open.
3) Eject unopened capsules.
4) Filling point (pellet) – depends on device fitted to the machine.
5) Filling point (granule) – depends on device fitted to the machine.
6) Filling point for powder injection –depends on device fitted to the machine.
7) Recovery point for any unused powder.
8) Capsules joined together by closing upper and lower pins.
9) Ejection point for the filled capsules.
10) Clean any residue left behind by capsules and then repeat cycle
