1
Q
What is the definition of a tablet
A
- Tablets are solid preparations consisting of one or more active ingredients and other necessary excipients obtained by compressing uniform volumes of particles. into various shapes and sizes.
- Usually intended for oral administration
- Mainly systemic but some local: -Swallowed whole; after chewing; dissolved in water; retained in mouth (buccal mucosa; slow release prep;)
2
Q
Compressed tablets
A
- First patent awarded to William Brockeden 1843
- Used to compress graphite powder into pencil leads and were known as tabloids
3
Q
Types of tablets
A
- Tablet triturates (moulded tablets)
- Compressed tablets
- Disintegrating
- Chewable
- Effervescent
- Lozenges
- Sublingual and buccal
- Freeze dried tablets (Zydis)
4
Q
Advantages of tablets (capsules): production aspect
A
- Large-scale production at low cost
- Easiest and cheapest to package and ship
- High stability (chemical, mechanical and biological)
- Lightest and most compact formulation
5
Q
Advantages of tablets (capsules): formulation aspect
A
- Greatest dose precision with least content variability
- Lend to give special release profile products- enteric coated or MR products
- Product identification is cheap- embossing or monogrammed punch face
6
Q
Advantages of tablets (capsules): patient aspect
A
- Ease of handling
- Coating can mask unpleasant taste and improve patient acceptability
- Easy to identify
7
Q
Disadvantages of tablets
A
- Some wet drugs resist compression into dense compacts (paracetamol); USE WET GRANULATION
- Drugs with poor wetting, slow dissolution or high dose may be difficult to formulate into a tablet or capsule with the desirable properties: add surfactant, micronize, give as 2 tablets
- Unpleasant taste or sensitivity to oxygen or moisture may add complexity: use coating, film or sugar (ibuprofen), protect using appropriate packaging
8
Q
Tablet machine or press
A
- Single punch is known as eccentric
- Rotary- many different manufacturers and capacities
- See BB for pictures
9
Q
Single punch machine
A
1) upper punch is raised and lower punch dropped
2) hopper shoe has moved forward over the die and granules fall in
3) Hopper shoe has moved back. Upper punch has come down compressing granules into tablet- volumetric filling
4) Upper punch has moved upwards. Lower pinch has moved upwards to eject tablet and the cycle is repeated
10
Q
Terms used to describe tablet manufacturing
A
- Wet granulation
- Dry granulation- slugging roller compaction
- Direct compression- whatever process is used, the first step is mixing
11
Q
Types of mixing- fill in this slide when you have audio file
A
- Random mix- no order
- Perfect mix- structured mix exactly in order where we know exactly how it is mixed
- Ordered mix- when particles are adsorbed onto the surface of another molecule
12
Q
Mixing SD
A
-The larger the sample size (scale of scrutiny), the smaller the variable
BUT
-Scale of scrutiny (around 500mg-5g) is determined by what you want the data for
the optimum random mix of spherical particles of equal size and density SD=Square root of p(1-p)/n
P= proportion of the component in the mix. n= total number of particles in mix
NB- as proportion of active decreases, SD decreases. Less active, easier mix
13
Q
Mixing CV
A
Use Coefficient of variation
-CV is the content standard deviation expressed as a % of the mean content
%CV= SD/mean
14
Q
Mixing
A
- The lower the proportion of active, the more difficult it is to mix
- The more particles in a sample, the smaller the deviation
- Small particle size MAY improve mixing; BUT aggregation, dust etc
15
Q
In addition to mixing powder, flow is also important
A
- Both tablets dies and capsule shells are filled by volume
- If powder flow is poor and inconsistent, the weight of powder in the same volume will vary
- This leads to tablet or capsule weight variation and dose variation
16
Q
Measurement of flow
A
- Angle of repose
- Pour powder through a hole and we get a cone
- We measure the angle of the cone the smaller the angle the greater the flow
- Dynamic angle of repose- spinning drum and we measure the angle of the powder as it spins
17
Q
Factors affecting flow
A
- Particle size
- Size distribution
- Particle density
- Particle shape
- Moisture content
- Electrostatic charge
18
Q
Flow: effect of particle shape
A
19
Q
Hausner ratio
A
V1= initial volume of powder in cylinder
V2= Final volume after n taps
Hauner ratio= V2/V1
-Large drop= poor flow due to large gaps between the particles
-Small drop= good flow beacause the powder has flowed well into cylinder so tapping has very little effect
20
Q
Improving powder flow
A
- Control particle size
- Change particle shape or texture
- Control moisture
- Reduce electrostatic charge and earth equipment
- Add glidants- induce flow in poorly flowing powders
- Use force feeder (agitation or vibraiton)
21
Q
Formulation of tablets: frequently used
EXCIPIENTS
A
- Wet binders (make granules)- gelatin or starch; HPMC
- Lubricants (reduce friction at die wall)- Mg stearate
- Disintegrant (break up tablet when in aqueous environment): starch
- Diluents- lactose
- Coats
22
Q
Formulations of tablet excipients: sometimes used
A
- Anti-adherent
- Colours
- Glidants- help powder flow into the die- gives consitent fill volume and so tablet size
23
Q
Flow- All the powder flow measurements are empirical therefore the best measure of powder flow in relation to tableting properties-
A
- Weight variablility of the tablets/capsules gives the best indications of flow
- IF the flow is poor then the weight variability of the tablet will be high
- If the flow is good then the weight variability of the tablet is low
24
Q
Formulation of tablets excipients: rarely used
A
- Wetting agent- help wet the drug
- Flavours
- pH modifiers- if the drug is unstable in acid or alkali conditions
25
Formulation of tablets: examples of drug % in tablets
- Active drug can be between 0.02% and 95%- usuallt 20%
- Paracetamol 500mg drug is 550mg tablet
- Thyroxine 20 mcg drug in 100 mg tablet
26
Excipients
- All non-drug components of a formula are termed excipients
- Diluents (fillers): diluents are fillers used to increase the bulk volume of a tablet. By combining the AI and diluent the tablet is an adequate size and weight and size to assist production and handling (use to give the perfect size)
27
Ideal fillers should fulfil a series of requirements such as
- Inert so as not to cause pharmacological or chemical activity of its own
- Biocompatible with the drug substance and other excipients used in the formulation
- Non-hygroscopic (doesn't absorb water from air)
- Compatible and of similar particle size to the active ingredient and should have good dilution capacity
- Non- conductive to microbiological development
- Non-toxic, cheap, commercially available in acceptable grades, colour-compatible, have no deleterious effect on bioavailability of the drugs (lactose with 1ary and 2ndry amines)
- If drug product is classified as food (vitamins), excipients must be approved direct food additives
- PPI are very unstable in acidici conditions- cant use enteric coat because the coat itself is acidic so much cover drug in inert layer
28
Lactose
- Relatively non-reactive in anhydrous and hydrous form
- Hydrous form undergoes Maillard reaction leading to browning and discolouration of certain drugs- tertiary amines, hence anhydrous form is preferred
- But anhydrous form picks up moisture when exposed to humidity
- In wet granulation, hydrous lactose of 2 varieties are used coarse (60-80 mesh) and regular (80-100 mesh)
- Low-cost diluent
- But may discolour in presence of amine drug bases or salts of alkaline compound
29
Spray dried lactose
- Mixture of large alpha monohydrate crystals and spherical aggregates of smaller crystals
- Good flowability but less compressibility
- Poor dilution potential
30
Microcrystalline cellulose (Avicel)
- The most important tablet excipient developed in modern times
- Derived from special grade of purified alpha wood cellulose by severe acid hydrolysis to remove the amorphous cellulose portions, yielding particles consisting of bundles of needle-like microcrystals
- PH101, PH102 are 2 grades available. PH102 is more agglomerated, larger particle size, better fluidity but not significant decrease in compressibility
- Both grades are most compressible
31
Microcrystalline cellulose (avicel) continued
- A strong compact is formed due to the extremely large number of clean surfaces brought in contact with the plastic deformation and the strength of hydrogen bonds formed
- Not used as the only filler because of its cost and density
32
Microcrystalline cellulose (avicel) continued
- A strong compact is formed due to the extremely large number of clean surfaces brought in contact with the plastic deformation and the strength of hydrogen bonds formed
- Not used as the only filler because of its cost and density
- Usually use in conc of 10-25% as a filler-binder-disintegrant, rapid passage of water into the compact and the instantaneous rupture of hydrogen bonds
- At high concentration, disintegrant effect is lost
33
Other diluents
- Starch
- Starch 1500- partially hydrolysed
- Dextrose
- Mannitol
- Sorbitol- sugar-free mints, cooling effect in the mouth
- Maltodextrin
- Sucrose
- Dicalcium and tricalcium phosphate- used quite alot
34
Binders and adhesives
- Wet binders: used in wet granulation
- Dry binders: used in dry granulation and direct compression; often function as the only or partial diluent- DUAL FUNCTION
35
Wet binders (HPMC; Cant use normal starch= disintergrant but can use pre-gelatinized starch (heat treated) the ruptured starch molecules act as a wet binder; PVP- povidone)
- Used in tablet formulation to make powders more compressible and to produce tablets that are more resistant to breakage during handling
- Are hydrophilic and can help wet hydrophobic drugs
- Allow the fine powders to form agglomerates (collect in a mass), improving flow and preventing segregation
- Added in solution or as a dry powder which is then activated by the added solvent
- Preferable to use aq. solutions but organic solvent such as ethanol can be used
36
Examples of wet binders: commonly used
- HPMC
- HPC
- Pre-gelatinised starch
- PVP
37
Examples of wet binders rarely used
- Acacia
| - Pectin
38
Lubricants
-Added to reduce friction at the die wall during compression and ejection
-Other functions: prevent adhesion to punch face
-Reduce interparticle friction
-Small improvements in flow
-Lubricants have glidant properties
N.B: most are hydrophobic, can effect dissolution. Use in the lowest quantity possible
-V.small particles outside the granules, they smear and form a flim on the die wall
OTHER FUNCTION
-Prevent adhesion to punch face
-Reduce interparticile friction (Improve flow = glidant)
39
Examples of lubricants
- Mg stearate (Normally 1%)- alkaline conditions can't use
- Stearic acid
- PEG
- Hydrogenated vegetable oils
- Used at 0.05 to 5% depending on friction and material
- We use the minimum amount of lubricant because most are hydrophobic materials and therefore negatively impact disintegration and dissolution
- Added extragranularly (no internal lubrication)
40
Glidants
- Added to improve flow of powders and granules: Talc 1-2% (similar to Mg stearate)
- Colloidal silica "aerosil" 0.2%
- Small particle size- they work like ball bearings reducing friction by
- NO FLOW
41
Anti-adherent
- These are used to prevent the powders or granules from sticking to the punch face
- If the punch faces are slightly rough, we can get particles starting to stick and film will form
42
Disintegrants
- A tablet needs to be robust enough to withstand handling and transport, but disintegrate rapidly in an aq. environment
- Disintegrants added intragranularly and/or extragranularly
43
Disintegrant 2
- Disintegrant, an important excipient of the tablet formulation, are always added to tablets to induce breakup or disintegration when it comes into contact with GI fluid and this process of desegregation of constituent particles before the drug dissolution occurs, is known as disintegration process and excipient which induce this process are known as disintegrants
- Disintegrates may function by drawing water into the tablet, swelling and causing the tablet to burst apart
- Rapid disintegration is a critical step in oral bioavailability
- Disintegration is a necessary but not sufficient pre-requisite for bioavailability
44
Examples of disintegrants
- Starch: 5-10%
- Modified starch(Na carboxymethyl starch and Na starch glycollate): 1-5%
- Cross-linked PVP: 1-5%
- Microcrystalline cellulose: 5-15% - above 15% it acts as a compression aid
45
Preformulation
-Determining those chemical and physical properties of the drug substance that are important to the dosage form required
46
Preformulation for tablets
- Particle size
- pH solubility profile
- pH stability profile
- Compressibility
- Solid state stability dry and at high humidity
- Hygroscopicity
- Solution stability
- Organoleptic properties
- Excipient compatibility
47
Excipient compatibility
- Excipients must not react with drug or cause drug to degrade to the extent that the degradation products exceed that given in the specification and which can be justified by toxicology studies
- Real-time stability takes 2-5 years so we must be confident that we have selected the correct excipients
48
Excipient compatibility 2
- Mix drug with excipient and subject to high temperature and humidity
- Select 2 or 3 of each class of excipient
- Assay for drug and degradation products
- Use TLC, HPLC, DSC and appearance
49
Excipient compatibility
- 50:50 drug excipient ratio?- this will maximise any reaction rate
- Ratio as found in the tablet?
- Powder mix?
- Granulated mix?
- Compressed?
50
How can we use these data to help formulate
- Drug ver unstable in an acid solution - half life 3 min at pH 2, 60 min at pH 7 and 600 min at pH9. reacts with enteric coating polymers
- Drug moderately unstable at pH above 5. Half life, say 1 week at pH 5 but 3 months at pH3. evidence of hydrolysis when stored as solid exposed to high humidity
- Drug shows evidence of incompatibility with Mg stearate
51
Why is disintegration so important
- The drug goes into solution dependant on its SA
- A whole tablet has a small SA
- When broken up into granules which causes increased drug absorption
- But deaggregation also occurs which causes even greater drug dissolution- MAX SA
52
How we choose excipients
READ ALTON- see bb lec 6 for the chapter
53
Wet granulation
- The most populate method employed for the production of compressed tablets (70%)
- Wet granulation is a process of using solution binder to the powder mixture.
- The amount of liquid can be properly managed; over wetting will cause the granules to be to hard and underwetting will cuase the granules to be too soft and friable
- Aqueous solutions have the advantage of being safer to deal with than other solvents
- Originally developed to overcome raw material variability
- Coats hydrophobic drug surface with hydrophilic material
54
Rationale for granulating powders (drug and filler mixture) prior to tableting
- To prevent segregation of the constituents of the powder blend
- To improve flowability of the powder mixture
- To improve the compaction characteristics of the powder mixture due to better distribution of the binder within the granules
- To improve homogeneity and thus ensure content uniformity of powder blend
55
Wet granulation mechanisms
- Adhesion and cohesion in immobile liquid films between primary particles
- Interfacial forces in mobile liquid in granules
- Solid bridge formation after drying
- Interparticulate attractive forces
- Mechanical interlocking
56
For solvents with no dissolved binder and in which none of the solids are soluble
- Droplet --> capillary --> funicular
- Finally it enters the pendular forms which is when there is a layer of solvent (water)- there is then interfacial and capillary forces holeing the particles together- these are known as liquid bridges
- This is the dry walkthrough, if you go the other way this is what happens in granulation
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
