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80 Cards in this Set
- Front
- Back
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Discuss the importance of the physical form of a drug to pharmaceutical formulation |
Affects bioavailability of drugs – absorption through the G.I. tract Alters the stability of dosage forms Influences the way in which dosage forms are processed (Flow, compression and watersorption properties) Important for regulatory control of drugs (patents on polymorphs) |
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Describe crystal structure |
Crystals contain highly ordered array of molecules and atoms held together by noncovalent interactions Main common drug crystals unit cell (Internal) structures are orthorhombic, monoclinic and triclinic unit cell is the basic repeating units which constitutes a 3-D crystal lattice |
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Explain polymorphism formation |
Polymorphism is the existence of more than one unit cell for the same drug molecule |
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Crystalline system Definition |
Highly ordered array of molecules held together by non-covalent bonds |
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Define amorphous system |
A system with no internal long range order Essentially highly viscous liquid’s Formed by rapid cooling from melt – cooling too rapid to allow crystallization/ Alignments of molecules in the correct way Also formed by precipitation from certain solvent systems |
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Define particle |
One particle contains millions of molecules |
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Define particle |
Distinct entity containing a number of atoms |
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Define powder |
Visible mass of particles |
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Particle size and drug doses |
Typical doses 1–100 mg, many are in the microgram range Typical tablet weight is around 200 mg Usual particle size range from 10 to 100 µm Difficult to get the right amounts of drug in every tablets and for the tablet to be the right size to pick up and swallow |
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Bioavailability - Importance of solid-state characteristics |
Must be in solution to cross G.I. tract wall Rate limiting step to absorption is the dissolution rate Solid —(k1, dissolution )— solution —k2, permeation— absorption Can Be affected by excipients |
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Explain crystal formation |
First. supersaturation of the solution - At a given temperature and pressure the solute has a maximum concentration dissolved in the solution Supersaturation has more solute present thing can be dissolved and so solid particles in equilibrium form With a saturated solution. Can be achieved by removing the liquid by evaporation, cooling to reduce solubility, add an anti-solvent liquid to reduce solubility Secondly formation of the Crystal nuclei Formation of a small mass answer which a crystal can grow – homogenous, heterogenous Crystal growth around the nuclei - Is the addition of more solute molecules onto the nucleation site |
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Describe Crystal habits |
Habit describes the external shape of the crystal
If the environment in which the crystals form and grow is changed the crystal habit can change even if the unit cell is the same . Includes acicular [Needle like] , Isometric, Tabular, lamellar, collumnar For example• Increase in the degree of supersaturation tends to lead to moreneedle-like (acicular) crystals • Variation in the rate of obtaining supersaturation, e.g. naphthalene inethanol forms thin plate-like (lamellar) crystals on rapid cooling but formsmore prismatic (columnar) crystals on slow evaporation |
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Crystal habit |
Is the environments in which the crystals form and grow is changed For example Increase in the degree of supersaturation tends to a acicular crystals Lamella crystals form on rapid cooling Columnar crystals on slow evaporation |
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Polymorphs can have different chemical and physical properties. Give examples |
Melting points Chemical reactivity Apparent solubility Dissolution rate Vapor pressure and density Unstable polymorphs (metastable) will convert to the stable form over time Stability’s Lattice energies Crystal habits and processing properties Patent |
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Progesterone Polymorphs |
Alpha form is the stable Farm with high levels of hydrogen bonding in lattice and low solubility Beta form Is the meta stable form with only one hydrogen bonding site and higher solubility Metastable form will have Hi solubility and low melting point |
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How to detect polymorphism |
X-ray diffraction Thermal microscopy Differential scanning calorimetry – melting point measurement |
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solvate definition/ Pseudo polymorph |
Crystal which contains one or more molecules of the solvent as part of the lattice |
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Hydrates definition |
A material where water is incorporated into the crystal lattice For many drugs to hydrate form is the stable one compared to that and hydrate Hydrates have very Different physical properties compared to the anhydrate especially lower solubility With slower dissolution Can be monohydrate, dihydrate, hemihydrate |
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Why do hydrate have lower water solubilities And some have higher |
Mainly lower because one solid Dissolves Need to break solid – solid bronze – endothermic Interacts with the solvent – exothermic Delta G equals delta HYST Delta S, thus greater delta H is more likelihood of solution And hydrates the interaction with water has already taken place so less enthalpic (H) contribution to the dissolution process And a minority of cases solubilities greater due to water molecules disrupt the crystal lattice e.g. erythromycin Implications for bio availability |
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Glass transition temperature TG |
Temperature in which the material changes from brittle to rubbery due to a sudden increase of molecular mobility. Which allows rapid conversion to the crystalline form if temperature is below tG it is a brittle/glassy Above = rubbery Glass transition temperature can be lowered by adding a plasticiser which fits between the glassy molecules giving them greater mobility |
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Importance of particles/powder |
Most pharmaceutical products are based on powders e.g tablet, suspension, ointment Manufacture of products: mixing important of even distribution of drug and excipients - content uniformity different flow and packing properties - Compression behavior and segregation potential Dissolution profile of the drug particle |
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Noyes Whitney equation |
Rate of the dissolution (dC/dt) is proportional to the difference between instantaneous concentration and the saturation solubility |
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BP definition of powders |
• Coarse powder: median size (x50) > 355 µm • Moderately fine powder: x50 180-355 µm • Fine powder: x50 125-180 µm • Very fine powder: x50 ≤ 125 µm • Micronized powder: x50 < 10 µm (majority < 5 µm) |
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Polycrystalline systems vs mono crystalline |
Monocrystalline systems have well-defined habits – cubic, plates, needles Polycrystalline systems are composed of aggregates of ‘microcrystals’ usually less than 1µm |
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Particle size dispersion |
Ideal powders are monodispersed that is, the particle population consists of spheres of the same diameter/size Real powders, in fact, are polydispersed, Particles have a variety of sizes and thus multiple values of size are required to describe the powder |
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Representation of particle size and size distribution |
Poly disperse systems have an average and the range and interquartile range Normal distribution, skewed distribution or bi modal Cumulative frequency diagram overlap with oversize and undersized. The point where the two curves intersect is the sieve size median (D50) |
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Particle shape / Surface roughness |
Shapes Ideal particles are monosized and spherical Often have non-spherical shape eg needles Aspect ratio quantifies circularity. = length of particle/breath of particle Surface roughness affects cohesion and adhesion |
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Methods of characterizing powder flow Angle of repose and Hausner ratio / Carr's compressibility index |
• Pour a powder through a funnel and measure the angle it makes to a horizontal surface smaller particles tend to show more cohesion andmay aggregateCohesive powders do not flow well Low angles less than 20° a good flow High angle above 40° show poor flow Multiple angles show an uneven flow, collapse Coefficient of internal for action equals tan° • Varia+on between "bulk (loose poured)" and "tapped" density of the powder bed • Pour the powder into a measuring cylinder • Measure the volume • Tap a defined number of +mes • Re-measure the volume • Works because cohesive powders trap air (bridging) and the tapping knocks the air out • ↑ cohesive ⇒ ↑ air trapped ⇒↑ difference in volume • Hausner ra+o = Density (final) = Volume (ini+al) Density (ini+al) Volume (final) • Low values (< 1.20) ⇒ good flow • High values (>1.40) ⇒ poor flow • Carr's compressibility index = 100 x Tapped density - Bulk density Tapped density • Low values (5 to 15) ⇒ good flow • High values (> 25) ⇒ poor flow |
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Importance of powder flow |
• Each tablet / capsule must be identical in performance • Weight, content of drug, drug release profile Dependent on the initial mixing process
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Basic powder properties |
Adhesion between particles of different materials Cohesion between particles of the same material yet – VDW, surface tension forces, electrostatic charging Small particles tend to show more cohesion and aggreggate. Cohesive powders do not flow well |
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Importance of powder flow |
Uniform flow from bulk storage containers into the feed mechanisms (of tableting or capsule filling) equipment, allows uniform powder packing and the constant volume to mass ratio in order to maintain tablet weight uniformity Pharmaceutical products are made in large batches Powder flow properties govern the reproducibility a product. To improve weight uniformity and allow tablets to be produced with consistent physical and chemical properties Uneven powder flow can results in excess air within powders which may promote capping or lamination Can cause lubrication problems, and increased dust contamination risks During powder transfer |
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Powder size analysis methods |
Sieve analysis- dry or wet sieving stacks and vibrates for 10 mins. Largest sieve size on top Microscopy - light microscopy, or SEM Laser diffraction & dynamic light scattering - angle of diffraction inversely proportional to size Sedimentation - suspension of particles in a non- solvent liquid - determine sedimentation velocity Conductivity measurements - electrical steam sensing zone measurements- particles enter orifice Aerodynamic measurement |
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Hausners ratio/ Carr’s Compressibility index |
Variation between bulk and tapped density in the powder bed Pour the powder into a measuring cylinder and measure the volume Tap a defined number of times and remeasure the volume Works because cohesive powders trapper and the tapping knocks that out, leading into a big difference in volume Hausner ratio equals density final/density initial values of less than 1.2 indicate good flow, >1.4 are poor flow Carr’s compressibility index equals 100 times tapped density — bulk density/ Tapped density Low values of 5 to 15 equal good flow, More than 25 equals poor flow |
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Define Powder mixing, ideal vs real and importance of mixing |
Mixing is defined as an operation that treats two or more components initially unmixed so that each unit of the components light is nearly as possible in contact with the unit of each of the other components An ideal situation is a perfect mix, Random mix is where the probability of finding a type of particles proportion to the number of them in the overall mix Mixing is important in dispersions, granulation, drying and coating and uniform dosing |
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What is scale of scrutiny |
Scale of scrutiny is the weight/volume of the dosage unit which dictates how closely the mix must be analyzed to ensure it contains the correct dose of concentration If a larger sample size is used it may mask important micro – nonuniformities such as agglomerates and may lead to the acceptance of an in adequate mix. conversely analyzing two small sample size may lead to the rejection of an acceptable mix |
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How to ensure good distribution during mixing |
Use the appropriate mixing Process and equipment to maximize the even distribution of drug Avoid segregation during mixing Micronise the drug but beware of aggregation Particle shape – mixed morphology = poor mix vs spherical |
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Mechanisms of mixing |
Convective mixing– Move a large portion of the powder from one area to another Shear mixing one layer of powder flows over another lead generating shear plane Diffusive mixing - lift and drop the whole powder bed particles and tumble over each other and mix |
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Mixer types |
Tumble/roller mixers e.g. Turbula - for shear and diffusive mixing I’m good for free-flowing powders, direct compression mixtures and lubrication Not good for: very low drug loading, wet granulation, mixing odd shaped particles Agitated mixer for shear and convicting mixing Good for more cohesive powders, odd shaped particles, what granulation, a very low drug loading |
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Experimental considerations for mixing |
End point detection Sampling protocol- top, middle bottom Powder quantities Particle morphology Mixing time Mixing speeds Blade configuration |
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Segregation mechanism and cause |
Because of Particle movement, mixing process to long, conveying between operations, because in a hopper during processing further (tabletting) , leads to uneven products Mechanism: percolation, trajectory differences due to particles having different kinetic energies |
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Compressing the powder mix relation to powders |
Even though sink Flow of powder into equipment Drug dissolving from solid to dosage form so size must be important Tableting will involve a compression stage so deformation must be appropriate Compression effect: brittle fracture versus plastic deformation |
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What is granulation |
Granulation is a process of size enlargement and which particles of varying shapes and sizes are gathered into a larger, uniform and permanent aggregates in which the original particles can still be identified |
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Why granulate |
To improve flow properties of material To prevent segregationAnd maintain content uniformity To increase bulk density To reduce dust production To improve compression characteristics, dissolution rate For control of moisture content |
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What is a good granulation |
Have a narrow particle size distribution and spherical shape Easily fluidized and flow well Easily compressible stable when compressed Be produced by a robust and reproducible process Have a clear end point |
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Granulation processes |
Wet granulation produces Good granules. Use binder, disintegrant And diluent Dry granulation necessary when ingredients sensitive to heat and moisture |
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Binder |
Binder is cohesive, inert, easily blended and non-hygroscopic Can be either add it to the drugs and diluent dry And then add a granulation solvent versus preformed wet binder solution [faster] |
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Binder |
Binder is cohesive, inert, easily blended and non-hygroscopic Can be either add it to the drugs and diluent dry And then add a granulation solvent versus preformed wet binder solution [faster] Examples include sucrose which produces very hard granules Starch, PVP, Cellulose, Gelatin |
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Wet granulation |
Involves the massing of a mix of dry primary powder particles using the granulating fluid The granulating fluid contains a Solvent that is volatile, non-toxic And removed on drying The granulation liquid may be used alone or as a solvent containing dissolved adhesive/binder which is used to ensure particle adhesion once the granule is dry The dried granules have a porous structure, greater porosity gives faster dissolution but weaker granules Granules held Together by immobile liquid bridges (decrease inter-particulate distance ) or mobile liquid bridges |
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What holds the granules together |
Solid bridges – hardening of liquid binders: recrystallization: spot melting Noncovalent intermolecular Vandewal’s forces Surface tension forces from residual moisture Mechanical into looking |
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Target size of granules |
Small tablets 200 mg or less should be 75 to 100 µm Large tablet 600 mg or more should be larger granules |
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When granulation goes bad |
To little granulation fluid leads to an undergranulated granule: friable, Disintegrates - too soft And over wetted Granule: from a slurry and dissolution of granules ingredients |
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How to monitor granulation |
Manual determination Dash squeeze Pressure detection Light reflecting Humidity measurements Mass temperature Conductivity probe’s Power consumption Acoustic admission Torque measurement- newton meter |
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Wet granulators |
Low Shear granulators- high fluid, long process High shear mixers Fluid bed granulators- Dependent on droplet size and evaporation rate |
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Wet mixing pros and cons |
Advantages: Increases granule strength Can be use for a wide range of active concentrations Range of color intensity Uniform distribution and Prevents component segregation Resultant tablets a hot, non-friable and easy to coat Disadvantages: Many stages, long process time, large capital investment Potentially hazardous dust, heat is required to remove the solvent, requires solvent |
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Dry granulation |
Mix drug and excipients then compress to form a big lump Grind to produce Dry granules By roller compaction Old-fashioned |
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Pros and cons of dry granulation |
Pros: Less equipment so lower cost No expense of drying process No binder solution No heat or water - good for Sensitive drugs Cons: Mixing can be problematic and powder flow poor Week and non-porous granules Poor colour distribution Dust production Final tablets are softer and harder to coat |
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Which type of granulation to use |
For hygroscopic heat sensitive and moisture sensitive powder use dry granulation For non-wettable insoluble powder use wet granulation |
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Advantages and disadvantages of tablets |
Convenient and accurate dose Increased DrugStability Simple and easy administration Altered drug release rates Mass production Disadvantage: Some drugs may cause local irritant effects or harm the G.I. tract, Poor bioavailability of drugs due to solubility and absorption |
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Types of tablets |
Immediate release- drug release immediately after administration or dissolved into liquids- e.g effervescent, chewable, sublingual Controlled release- modified release- prolonged release/ delayed release -swallow whole Targeted release- release in a certain area of GI TRACT |
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Describe the properties of bi-layer tablets, Chewable tablets, mini tabs, Gastro resistant tablets |
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Explain with the diagrams the functioning of a single press tabletting machine |
Back (Definition) |
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Explain with the diagrams the functioning of a single press tabletting machine |
Back (Definition) |
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Diagram of a multi station tablet press |
Back (Definition) |
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Give three properties which the powder mixture must have for successful tablet formation. |
The powder must:• Flow well – to give a consistent tablet weight; • Not segregate – to give a consistent dosage per tablet; • Be compressible – to form robust tablets; • Be lubricated – to avoid sticking in the tableting machine. • Distintegrate – i.e. break up to release the drug; • Release the drug – determined by dissolution testing; • Be fit for purpose – tablets that the patient can handle! |
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What is an excipient? Why do we use them? |
An excipient is an inert substance added to an API during formulation. They are used to improvethe properties of the API, for instance increasing storage stability, enhancing the ease of tableting,etc.
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What is a compression aid |
We add a compression aid – a bulking agent with good flow andcompression properties;• Examples of compression aids include:– Microcrystalline cellulose (Avicel®);– Dicalcium phosphate (Emcompress®);– Spray dried lactose. If the drug is of low dosage and will flow well; |
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Direct compression pros and cons |
Advantages:• Two step process– Blend and compress• Improved stability– No heat– No waterDisadvantages• Require specialist (spray-dried) excipients• Poor flow/compression properties, particularly with high drug loading– Use of flow aid• Segregation (uniformity of dosage form), esp. with low drug loading– Size and density of API and excipients |
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What is a diluent |
• These are ‘inert’ substances added to increase bulk and make thetablet a practical size for compression; • Diluents used in direct compression need to have similar particle sizeto the drug, and good compressibility;• With insoluble drugs, need to add hydrophilic diluents;• The diluents must have good compatibility with the drug. Examples: Lactose monohydrate;• Microcrystalline cellulose; |
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What is a disintegrant |
DisintegrantsTo facilitate the break up of tablets into individual granules/particlesupon contact with water Mechanism of action• Wicking - capillary forces promoting rapid water uptake;• Swelling;• Release of gases upon contact with water;• Melting at body temperature;• Enzymatic destruction of binder. Example: General– Starches (corn, pre-gelatinised);– Alginates.• Super disintegrants– Cross-linked carboxymethylcellulose 2-6% (Ac-di-sol) ;– Sodium starch glycolate 2-8% (Explotab);– Crospovidone 2 - 6% (Kollidon CL or Polyplasdone); |
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Lubricants |
Lubricants• Reduce friction between powder and tableting tools (0.2 - 2%)• • Prevent powder from sticking to the tableting equipment;• Use low shear mixing, min amount of lubricant, and min lubricationtime;• Over-lubrication soft tablets / dissolution issues;• Under-lubrication sticking and picking (see later) E.g.:– Mg stearate / Ca stearate;– Polyethylene glycol;– Talc. |
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Glidant |
Glidants • To improve powder flowability • E.g.: – Colloidal silicon dioxide; – Talc; |
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Direct compression mix |
Typically:Drug 5 to 20 %Disintegrant 5 to 15 %Compression aid 10 to 30 %Lubricant 0.5 to 2 %Diluent to 100 % All excipients exceptthe lubricant should bespray dried to ensurethey are spherical, andmix and flow well |
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whats in a wet granulated formulation |
What’s in a wet-granulated formulation?• A typical formulation is made of:Drug 0.01 to 20 %(Super)disintegrant (2 to 5 %) 5 to 15 %Compression aid 10 to 30 %Lubricant 0.5 to 2 %Binder 2 to 10 %Colour / flavour qsDiluent to 100 %Granulation fluid (20 to 40 %v/w)We granulate first, then compress |
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defects which can arise in tablets, and suggest how these problems can be resolved. |
Capping/lamination – vary moisture content; adjust excipients to reduce elastic recovery; Chipping, cracking – reduce particle size, adjust excipients to reduce elastic recovery, reducehumidity of process; Poor weight control – increase particle size, regularise particle shape;Sticking, picking – reduce moisture content, regularise particle shape. |
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Tabletting facts |
• Typical compaction pressures are 1 to 10 MPa;• Greater compaction pressure leads to:– Greater tablet hardness (to a point);– Reduced tablet thickness.• Hardness, thickness and weight are all inter-correlated with thecompaction pressure;• The temperature can rise to around 60 °C in tableting (take care withheat sensitive drugs!). • There are two key routes to tablet formation:– Direct compression;– Wet/dry granulation. • Tablets are prepared using a press (various types of press exist);• Tablets contain excipients in addition to the API to improve theirproperties (diluents; disintegrants; lubricants; compression aids);• A range of defects may arise in tablets, and we use stringent qualitycontrol tests to identify/eliminate these. |
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10. When formulating high-dose tablets of a crystalline drug, why should we use a substantialamount of a lubricant? |
Crystalline materials can be very abrasive, so we add lots of lubricant to minimise abrasion on thetableting apparatus, |
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11. Why do we employ a filler with low-dose tablets? |
To increase bulk and make the tablet a practical size for compression |
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9. Give two examples of each of the following: compression aids; diluents; disintegrants;lubricants; glidants. |
Compression aids: microcrystalline cellulose, spray dried lactose, dicalcium phosphate. Diluents: lactose, microcrystalline cellulose, dicalcium phosphate, calcium sulphate. Distintegrants: starches, alginates, sodium starch glycolate (super-disintegrant) Lubricants: Mg stearate, Ca stearate, talc Glidants: colloidal Si dioxide, talc |
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2. Describe the properties of: bi-layer tablets; chewable tablets; minitabs; gastro-resistanttablets. |
Bi-layer tablets have two layers – these may contain the same or different APIs. Can use to controlthe delivery rate of one/two APIs, etc.Chewable tablets – formulated to effect slow release and local action of API, or for absorption ofAPI in mouth for subsequent systemic action.Minitabs (mini tablets) – small tablets with diameter ≤ 3 mm. Usually filled into a capsule orcompressed into larger tablets. Can put many different types of minitab into a capsule, e.g. withdifferent minitabs releasing drug at different times after administration.Gastro-resistant tablets – outer layer of tablet does not dissolve at low pH, and so the API cannotbe released in the stomach. Ensures API release lower down GI tract. |
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3. Explain, with diagrams, the functioning of a single-press tableting machine. |
First, the die is filled with the powder mixture. The tablet weight is then set, and a low-pressurepre-compress applied to the powder to achieve dense packing. This is followed by a higher-pressuremain compress, which compresses the powder mix into a tablet. The tablet is then ejected, and theprocess repeated as often as required to produce the desired number of tablets |
