Rob Price 286 Lectures Flashcards
Drug companies need a “pipeline” of NCEs, what does this mean?
Pipeline of new chemical entities
I.e some drugs going into phase 1 some going into phase 2 some at drug dis discovery stage
Should always be looking for a pipeline that shows 10% growth, so that you don’t lose money
If you don’t have one, go to other companies to help you do it.
Drug company must frequently bring new discoveries to market to be successful
What is the difference between pharmaceutical research and development, and product development?
Pharmaceutical research and development is to do with converting a synthesised chemical compound into candidate drugs for development.
Product development involves converting candidate drugs into dosage forms for registration and sale
Are clinical trials done in healthy or unhealthy humans? I.e do they have the disease?
In HEALTHY humans
Don’t want to make the person worse
What is a generic drug?
A drug which is BIOEQUIVALENT to a leading brand name
I.e it pharmacodynamic and pharmacokinetic properties are the same!
Same crystalline form
Same dose, route of administration,
Same safety and efficacy as innovator brand
Do bioequivalent drugs cost a lot to make?
No! Lower than innovators
No investing in R&D needed
Testing and manufacturing costs low, just need small group of people to test on
When can Generic businesses kick in?
When a leading brand loses it’s Patent
Makes leading brands profits lower
Pharma R&D have introduced life cycle management to increase their patent protection, where they try to squeeze out every last penny by making the drug in several diff formulations
What is the Hatch Waxmans litigation (legal) act?
This is where Generic drugs are granted a 180-day period of exclusivity to the market, this increases the economic incentive for generic companies to be “FIRST to FILE” when a big companies Patent runs out and be first to get to market.
I.e NO other generic companies can enter the market during the 180 day period
It provides incentive for generic companies to challenge a patent validity and ‘design around’ patents to find an alternative
How should the 180-day exclusivity work?
Generic company launches generic drug
They are first to file, so have a 180-day period of exclusivity
During this period the company earns a return on investment
The company COULD invalidate the PATENT of the company that has the new drug on the market (the BRAND), and therefore come to Market a few years EARLY (before 10 year patent ends)
After the 180 day exclusivity period other generic company’s jump in, decrease the sales of the first filer.
What is a “war chest”?
Kind of like PROFIT a GENERIC company makes during it’s 180 day “first to file” exclusive period of sales.
GENERIC Drug company needs this war chest for future development, just like big companies do when they release a blockbuster
The search for a blockbuster being the Heart of R&D drug companies strategy needs to change. WHY?
Due to advances in pharmacoGENOMICs and PERSONALISED medicines
So they don’t have as bigger market as shaping drugs design to specific people, focussing on specific ailments/ therapies
Future blockbuster drugs aren’t forthcoming
How can a drug company extend their patent by 6 months?
By testing their product in children between 10-17 years old.
Eg. Pfizer did this, extended their patent for Lipitor by releasing paediatric data and launching chewable version of the tablets for children by the end of their patent: so extended it for 6 months.
What is the innovation cycle?
Each drug product has it’s own life cycle
It’s to do with sales;
Introduction, development (large increase), maturity (peaks, becomes worthless here, if you’re going to sell company sell it here!), decline OR revitalisation(could get another 5 years sales if you tweak a few things!)
What is consolidation?
Where drug companies merge together to succeed
Eg; Astra Zeneca (Astra AB/ Zeneca PLC)
Those nominated as candidate drugs, 1 in 5- 1 in 10 reach registration and sale,
For drugs marketed, only 3 in 10 are likely to achieve a fair return on investment.
How can we help to ensure product success?
Early phase candidate drug selection and product design is critical.
Aim: to ensure the compound has desired safety, selectivity, efficacy (potency/duration),
and properties of solubility, stability ( we want shelf life to last for at least 2 years) and bioavailability
Medicinal chemistry and drug discovery: Investigates pharmacological properties: Potency Selectivity Duration of action (everything we've been doing in 244) Safety and toxicology
Formulation science and product development: Pharmaceutical properties: Solubiltiy Thermal stability Crystalline nature Hygroscopicity (ability to absorb water)
What is a BLOCKBUSTER?
A drug that makes OVER 1 BILLION dollars A year!!
Pre 1990’s, what kind of methods could we get Lead compounds from?
Serendipity- coming across drugs by mistake
Rational design- building on structures of known compounds
Natural products- base drug on these e.g Taxol, cyclosporin
Herbal remedies
Post 1990s, how could we get lead compounds ?
Hight throughput screening Combinatorial chemistry Lots of drug companies use these method Obtain leads efficiently Relatively easy to achieve invitro potency (in a tube)
In these modern methods, introducing oral activity is unpredictable
Molecular weights are Increasing
Lipophilicity is increasing
Solubility is increasing
All making oral bioavailability worse
What is done with automated High Throughput screening?
It assays Small samples (1 microliter)
Can analyse thousands of samples a day using WELL micro plates
Used to measure pharmacological activity, binding in the wells emits a colour from a Fluorophore
But can also be used to assess metabolism, other pharmacokinetics and toxicity
Automated high throughput screening speeds up drug discovery through finding a ‘hit and a lead’ what does this mean?
where small molecule hits from a high throughput screen (HTS) are evaluated and undergo limited optimization to identify promising lead compounds.
A chemical lead from HTS then is used to generate specific compounds with the OPTIMAL desired characteristics. How?
By testing a range of selected compounds in vitro and in vivo (tests for pharmacology effect and toxicity)
Then go on to preformulation and biopharmaceutical studies. This highlights the most relevant physiochemical and biopharmaceutical properties of potential candidate drugs. Tells us which candidate drugs to select to carry forward
HTS uses a black box approach, what does this mean?
Black-box testing is a method of software testing that examines the functionality of an application (e.g. what the software does) without peering into its internal structures or workings. This is a problem as pharma companies tend to leave something’s in the dark.
For e.g for fluticasone you have to wait a whole year before you can formulate it, it just sits in storage, drug companies don’t know why you do this, they just do it (Novartis wait 2 years)
If the company looked into WHY they have to wait this long, then They could probably find a solution and speed things up (this is a limitation of HTS)
Why is causal understanding of functionality required?
Need to understand mechanisms and categories of circumstances which influence functionality
It will increase out predictive understanding, it will generate success
Technologies can subsequently flourish and be optimised and streamlined to save time!
What is preformulation?
It is the PHYSICOCHEMICAL characterisation of the properties of compounds
Takes place before the candidate to be explored is nominated
It is very important as whatever you do at preformulation stage may effect success of your product
When does the preformulation stage occur?
Preformulation testing is the FIRST step in rational development of dosage forms of a drug substance
(Remember rational means based on logic/ reasoning)
The objective: to generate information useful to the person formulating the drug about its stability and bioavailable dosage forms
It’s all about ensuring the right formulation is made
What is the ultimate aim of preformulation?
To produce a mathematical model for drug behaviour when it’s been formulated
Also to provide an initial working model of behaviour of dosage forms in vitro and in vivo
In order to optimise the dosage form, what do we need a clear understanding of?
Stability and solubility of the API
How to inhibit decomposition and increase shelf life of the product
Shelf life should be at least 2 years
What is the very critical decision to make just before formulating the drug(part of preformulation)?
As you won’t have made much of the compound At this this stage, there is limited arount of compound available to carry forward.
CRITICAL decision:
WHICH compound, the SALT or POLYMORPHIC is going to proceed into development?!
If this decision is wrong, and at a later stage it’s decided the other was needed, it will really slow down the time to market :(
Therefore in order to get the decision right, upon candidate selection a more detailed preformulation study is undertaken
Can you name a few PHYSICOCHEMICAL tests that need to be carried out as part of preformulation studies?
Spectroscopy (NMR, IR, Mass) HPLC pKa Log P Initial Solution solubility/ solution stability Crystallinity investigations Initial Solid stability Hygroscopicity if a drug takes up water an increases it volume you could cause death :(
Compounds with an aqueous solubility greater than ___% (__mg/ml) solution over pH range ___ at ____ oC are NOT expected to have any dissolution related absorption problems, and can dissolve fine in GI fluids prior to absorption
Compounds with an aqueous solubility greater than 1% (10 mg/ml) solution over pH range 1- 7 at 37 oC are NOT expected to have any dissolution related absorption problems, and can dissolve fine in GI fluids prior to absorption
What does a solubility LESS than 1mg/ml indicate?
The need for the SALT form (rather than the polymorphic) particularly if the dosage form is a TABLET or CAPSULE
What does polymorph mean?
the ability of a solid material to exist in more than one form or crystal structure.
It’s all about crystal structure
Should it be in salt or crystal formation
What are the four choices you have to make when undergoing salt selection?
Do we choose salt, polymorph, Solvate OR hydrate?
What are the various tests when undergoing salt selection?
Solubility
Initial polymorphism studies
Thermal analysis (melting temp)
X ray powder diffraction
Crystal habit
Solid stability (at what temp, humidity?)
Spectroscopy (what’s in the finger print region?)
Amorphous Vs Crystaline
What does this mean?
Amorphous is a non crystalline solid
E.g hailstones- never undergo crystallisation, they just get cooler and cooler until the snap solid, but not like a snow flake does as molecules don’t get aligned in a certain way like they do in a crystal
Crystalline:
Eg snow crystals, undergo controlled nuclear ion and crystal growth during slowly varying temperature changes
Shape and size of the crystal is dependent on the rate of change in temperature.
When you make a crystal all the molecules arrange in a certain way. With polymorphics this happens eg with granite and diamond
Solubilities of crystalline and amorphous substances?
Crystalline:
Low solubility
Amorphous:
High solubility
Freely soluble in boiling water and rapidly dissolved!
What properties of a given compound are determined primarily by the nature of the crystal structure:
Solubility and dissolution rates
Crystal hardness (how easily can it be compressed into tablets?)
Chemical stability (eg Hygroscopicity, melting, sublimation temperatures)
Others include:
colour and refractive index (how light goes through the crystal)
Heat capacity
Conductivity
Volume
Density
What is the HABIT?
The external shape of a crystal
What is the habit associated with?
The crystal habit is associated with the way solute molecules orientate themselves when growing- therefore the external shape (habit) is determined by the way the molecules grow
What is the GENERAL (not external) shape of a crystal related to?
General shape is related to the growth of individual crystal faces
The slowest growing face dominates
Solvent molecules can adsorb onto crystal faces which can create different shaped crystals, will these crystals still belong to the same system?
Yes
different shape crystals can be formed whilst still belonging to the same system
What does crystal habit influence?
Influences flow, compaction, stability, and solubility of the drug
A company can PATENT the habit (ie patent the external shape of your drug so other companies can’t copy, as this will influence many important factors)
Effects of habit: INJECTABLES?
Plate shaped crystals will pass through the needle of the injection better than long needle-like crystals
Effect of habit: forming Tablets?
Plate- like Tolbutamol crystals do not flow and have poor compressibility- not good for making tablets
habit effect: dry powder inhaler formulations?
Needle-like crystals usually have better fine particle fraction (fraction of dose that will deposit in the lung is greater= good)
What happens to the crystal form if we modify the crystal habit?
Nothing
No alteration To the internal molecular order (crystal form) of the compound
Each crystal face has a designated index plane
These are known as ______ indicies
Miller indicies
Miller index provides information about the molecular ordering of the surface of a crystal face
Every different face will have a different miller index, due to a different molecule arrangement
If you slice the molecule each different face you expose will have a different miller index depending on how you slice it
What is a unit cell?
The crystal structure of a material (the arrangement of atoms within a given type of crystal) can be described in terms of its unit cell.
The unit cell is a small box containing one or more atoms arranged in 3-dimensions.
The unit cells stacked in three-dimensional space describe the bulk arrangement of atoms of the crystal. See notes for more
What are the 7 types of crystal structures? (Unit cell shapes)
Cubic Tetragonal Orthorhombic Rhombohedral Monclinic Triclinic Hexagonal
Unit cells: What are BCC’s?
Body centered cubic unit cells where there is an atom in the centre of a cube shaped unit cell
Unit cells: what are FCCs?
Face centred cubic
Atom is placed in centre of each face of the cube
How many possible Bravais lattices are there in 3D space?
14
There are 14 different types of bravais lattices in a crystal
What does crystal form mean?
Ordering of atoms and molecules to form crystal structure
It does NOT mean outer appearance- this is habit
Polymorphism definition?
When the same chemical compound exists in different crystal forms
Examples: diamond and graphite: diamond is just carbon (graphite) grown under a very high pressure (can’t make diamonds artificially due to needing this v high pressure- get them from mining!)
What are pseudopolumorphs?
Special cases of polymorphs
Example:
SOLVATES
HYDRATES
Pseudopolymorps: Solvate, hydrate. what is a Solvate? What is a hydrate?
Solvate: Solvent molecules in a crystal lattice
Hydrate: water molecules in a crystal lattice
What is enantiomorphism?
When chiral molecules Crystallise into two different crystal forms that are mirror images of each other
A mixture of D (dextro) and L (levo) crystal forms (enantiomorphs) are known as a: Racemic mixture
What’s an example of where a marketed Racemic mixture has gone wrong??
Thalidomide
L enantiomer was Tetragenic
D enantiomer was an effective sedative
If only the D form had been administered, this disaster wouldn’t have happened!!
Both enanatiomers are formed in the body due to the body’s pH
What is a Racemic switch?
It is the development of a single enantiomer form of a drug that was first approved as a racemate.
You can get specific Racemic switch company’s that patent single enanatiomers
Eg L salbutamol (avoids some side effects of the D form)
What is a salt and a Co-crystal then?
A Salt when counter ions exist within a crystal lattice
A co crystal is when solid exipients exist within a crystal lattice
Can you think of any properties that may be influenced by crystal forms?
Solubility and dissolution
Compaction behaviour: how easily can the drug be compacted, crystals can influence this property
Flow properties (related to shape and friction, related to surface energy)
Melting point and solid state stability
Different polymorphs can have different rates of uptake in the body. This will lead to higher or lower biological activity than desired.
Different enanatiomers may be tetragenic (cause malformations in an embryo)
Why is it essential during the preformulation stage that the most thermodynamically stable polymorph is formed?
A more favourable form may be obtained upon scale up.
You don’t want to make a polymorphic form that then has thermodynamic reason to become a different polymorph
The Manufacturer needs to indicate the characterisation of the various forms of the drug I.e if there are different polymorphs that can be present these need to be indicated
Patents can be done for as many polymorphic forms as possible
It is CRUCIAL a drug company finds out about different polymorphic forms before anything goes out to patients
What’s the example case study where polymorphs being discovered at a later stage has been a problem?
Ritonavir
HIV drug
Wrong crystalline form of the drug was formed :(
Crystal Forms I and form II can have different bioavailability. want only pure crystal I, but what happens if form II gets in the lab?
You can’t get it out again!!
Rival drug companies will send in packets of seeds with crystal form II in them, so that when the lab opens it it will contaminate the lab so they can no longer make pure form I. Have to make a mixture of form I and form II!
How many polymorphic forms does chloramphenicol-3-palmitate have? (CAPP)
CAPP can crystallise in at least THREE polymorphic forms
What is Aripiprazole an example of?
When humidity can effect a drug!
Aripiprazole is formulated as the anhydrate
However when exposed to humidity, a monohydrate is formed
This can change the BIOAVAILABILITY!
It is packaged in blister packs to prevent exposure to humidity, must not be opened until use so water doesn’t enter
It therefore can’t be packaged into calendar packs (Dosette boxes)
What does the crystalline form need to be for a drug to be bioequivalent to the branded drug?
Needs to have the SAME crystalline form!
Sulphathiazole has four different polymorphic forms: Form I, II, III, IV.
It’s also been recently discovered that there’s a form 5 and 6
Form __ has the highest aqueous ___ at all temperatures
Form __ is the easiest to compress into ______.
Form I has the highest aqueous SOLUBILITY at all temperatures
Form I is easiest to compress into TABLETS (has the lowest yield stress)
Got to watch out: it’s possible to grow all of these polymorphs during an industrial crystallisation process (we don’t want this)
Crystal Form I of Sulphathiazole is Othorhombic.
What does this mean?
Orthorhombic is one of the seven lattic point groups in crystal systems.
It is a rectangular prism unit cell shape.
Molecules of Sulphathiazole randomly scattered in the unit cell
Form III of Sulphathiazole is monoclinic. What does this mean?
Monoclinic is again one of the 7 lattice point groups. They form a rectangular prism (like orthorhombic) but instead with a parallelogram as its base.
Molecules of Sulphathiazole appear to be more equally aligned in this unit cell type
Vibrational spectroscopy is a piece of analytical equipment. What physical property is it used to look at ?
Qualitative identification of polymorphs, I.e what kind of crystals they are
What analytical methods can be used for the quantitive detection of polymorphs and crystallinity, and for looking at CRYSTAL STRUCTURE?
X- ray diffraction
Powder X-ray diffraction
Remember x rays: you can see structure of crystals and the numbers of polymorphs
What physical property can Differential Scanning Calorimetry (DSC) and Thermal analysis look at?
MELTING behavior
also Quantitative detection of crystal forms (I.e are there Hydrates, solvates, the different types of polymorphs..)
What analytical method is used for looking at moisture induced thermodynamic processes and recrystallisation of amorphous forms?
Isothermal microcalorimetry
Why would we want to change a drug from its free base or acid to a particular salt form?
To modify chemical and biological properties without modifying drugs structure
To improve certain PK properties like solubility, absorption, and PHYSICOCHEMICAL properties like stability, Hygroscopicity, stability etc
In terms of solubility, for any new compound what are the 2 fundamental properties?
Intrinsic solubility (So) This will dictate ease for formulation
Dissociation constant pKa
Allows us to see how pH affects solubility and to choose salts wisely.
These help is determine if we need the SALT form of our drug
Salts of a drug are chosen by considering certain factors, such as?
Structure of our drug substance
PKa of the drug
Stability of the drug
How easily the salt can be prepared on a large scale
What’s the most common salt used for basic drugs?
Hydrochloride sale (43% usage)
Sulphate next choice (7.5% usage)
These are anions
What’s a common choice for a possible salt for an acid drug?
Sodium salt (62% usage)
Could also use calcium, potassium…
Some cations and anions can cause toxic effects and contribute to the toxicity of the salt form. Can you think of an example of a cation and an anion, and think what they cause?
Lithium cations
Can cause irreversible kidney damage in large doses
Tartrate anions
Poorly absorbed in the GI tract, Can cause renal damage
Typically, a salt form which is rapidly/slowly? absorbed from the GI tract is LESS toxic
SLOWLY absorbed is less toxic
Changing the salt of a drug can reduce its toxic effects
The stability of a SALT of a drug can be affected by their Hygroscopicity.
Why can this be affected?
Salts of mineral acids such as hydrochloride and sulphates are highly polar
Ionised polar groups on crystal surface create a Hydrophillic surface
This leads to water coming in
Can reduce stability if drug is susceptible to hydrolysis degradation
If the surface of a crystal is hygroscopic and water can affect the stability, how can this problem be overcome?
Stability can be enhanced by introducing a hydrophobic salt-forming acid
Eg introducing the hydrophobic Aryl sulphonic acid to Xilobam tablets
Drugs with very ____ and very ____ doses can be difficult to formulate
Very low doses - e.g ethinyl estradiol has 0.05mg aspirin in it
And Very high doses - if the drug has poor flow or compressibility it can be hard to make a tablet out of it as it will just be way too big!!
What does starch act as as an excipient?
A disintegrant:
an agent used in pharmaceutical preparation of tablets, which causes them to disintegrate and release their medicinal substances on contact with moisture.
What is a lubricant?
prevents ingredients from clumping together and from sticking to the tablet punches or capsule filling machine.
Lubricants also ensure the smooth (low friction) ejection of the tablet from the die. (The kind of case that the tablet is compressed into shape in by puncher)
Then put a film of low shear strength at the interface between the tablet and die wall and the punch face. (See notes for what this means)
What is sodium bicarbonate in Panadol Actifast?
A Super disintegrant
What is the job of a filler/ diluent ?
Good in helping the compression to form a tablet
Bulks it out, helps to make a reasonable sized tablet
An example is: microcrystalline cellulose
Why is a whitening agent sometimes used?
Because people don’t like non white agents; they think they are off!!
How many years should you be aiming for shelf life?
Wherever possible, commercial pharmaceutical products should have a shelf life of 5 years
ARound 2 years- 2 and a half years usually
Companies will invest in packaging which will increase shelf life by 2-3 months
What are exipients? Should they be reactive?
All the other components but the active itself
They should be chemically and physically inert (unreactive)
Should be evaluated for safety
Some people object to certain excipients eg Gelatin
How can excipients influence life cycle management?
Companies can make as many different formulations as possible before their patent runs out eg chewable or melt in your mouth, or dispersible. So there’s not that many options when the patent runs out
What are excipients used for?
Aid the processing of the system during manufacture
Protect/ enhance stability , bioavailability and acceptability (accepted by patient)
Enhance safety and effectiveness of drug during storage and use
Why can lubricants, eg Magnesium stearate, be troublesome?
Can introduce hydrophobicity to a formulation
This inhibits drug dissolution
Should therefore try to minimise the % lubricant
Examples of common Diluents?
Lactose: has a pleasant taste, rapidly dissolves in water, it is not hygroscopic
Dicalcium phosphate: particularly used in wet granulation (insoluble in water, less hygroscopic)
Starches also used as Diluents and binding agents, very hygroscopic, over 14% moisture uptake.
Tell me about microcrystalline cellulose:
It has really good compressibility Has some Disintegration properties Poor flow Sensitive to lubricant - lubricant will hinder strong bonds forming between layers :( Moisture sensitive (5% moisture uptake)
We can get microcrystalline cellulose in various grades, what are these?
Different particle sizes (90, 200 and 15 micrometer)
Can get a low moisture grade of 1.5%
Can get it in higher bulk density grade- helps with blending
Low bulk density grade- increases tablet strength
Cheaper grades
What are the most effective punch lubricants? (I.e the lubricants that coat the punch face that pushes down on the tablet with force to compress it)?
Talc and
Magnesium stearate
Which is more effective as a die lubricant? (Ie lines the kind of case that’s used to hold tablet powder in when it’s about to be compressed)?
Stearic acid
What is the most popular choice of lubricant in tabletting?
Magnesium stearate
It’s incorporated with dry granules of your drug/excipients just before compression takes place
Only a very thin layer needed (just as effective as a thick layer)
What are some disadvantages of magnesium stearate specifically?
Can cause tablets to become soft if it’s at high concentrations due to decreased disintegration times and weakens binding forces (only want it to do this once it’s inside the Gut, not outside the body!)
Hydrophobic nature
Incompatible with many drugs eg aspirin
Ethical problems: primarily derived from cows fat
What are glidants/ flow agents? How do they work?
Materials added to tablets to improve flow properties of the granules
They work by reducing inter- particle friction by reducing contact area between particles, they’re little puff ball shapes needed to significantly reduce van der waals forces existing between particles
The difference between the particle surface and the puff balls should be less than 1 micro meter (um)
What is the most commonly used glidant/ flow agent?
Fumed silica
Formed from colloidal silica (at very high temperatures)
Aerosil: nano particles, very sticky but they work.
Addition of a very low amount (<0.1% w/w) can dramatically improve flow ability of granules
Tell me about the flow agent that is a combination of two?
Silicified MCC (micro crystalline cellulose)
Combo of MCC and silicon dioxide
This dramatically increases particle flow
No need for as many lubricants and flow agents in the formulation,
Better blending,
Only downside: there’s only one supplier so it’s VERY expensive!!!
What’s the best choice of exipient to function as an anti-adherent and anti glidant?
Talc
What’s the best exipient to use as a lubricant and anti adherent?
Magnesium (metallic) stearate!
Punch weight is the weight of tablet powder left on the puncher after it’s punched down and compressed the tablet. What do you think happens to the punch weight with and without lubricant present?
Without lubricant: punch weight increases the more and more times it punches the tablet powders in the dies. This is because the powder sticks and collects on the puncher.
With lubricant: punch weight remains low through the whole process as the lubricant stops the tablet powder sticking to the puncher.
What do you think Happens to the surface roughness of the tablet with and without an anti-adherent present?
Without lubricant: surface roughness is more
With a 1% w/w anti adherent- surface roughness is less
Lubricants smooth out the surface as the punchers rougher surface doesn’t come into contact with the tablets surface as much!!
What are disintegrants added to tablets for?
Promote breakup of tablets in the body
They aid the first stage in dissolution of drugs,
Especially important in dissolution of insoluble drugs
Rapidly disintegrates the tablets and increase the surface area of the formed deaggregates so they can be attacked by water even more.
Think they help both disintegration and deaggregation
Are disintegration and deaggregation the same thing?
No
Tablet firstly disintegrates to form granules that have a moderate rate of drug dissolution
They them deaggregate to form primary drug particles that have a rapid rate of drug dissolution!
O——–> o o o o ——-> :.:.::.::
Tablet. Granules. Primary drug particles
What are BINDERs? (Adhesives)
These bind powders together in the wet granulation process or granules during direct compression
Binders can be added in 2 ways, what are these?
As a powder IN the formulation, as in slugging.
As a solution to the mixed powders in wet granulation, but liquid additives must be removed before Compression stage.
Binders can effect dissolution rate
Name 2 typical binding agents?
Important binder: PVP (this is soluble in water and alcohol, releases the drug rapidly. Typically at concs 2-10% (w/v)
Starch mucilage
Gelatin
What are adorbents?
Substances which are capable of holding quantities of fluids in an apparently dry state
For example, Liquid flavourings or oils can be mixed with adsorbents and then granulated and compressed into a tablet!!
Examples of adsorbents?
Fumed silica,
Microcrystalline cellulose
Kaolin
Magnesium carbonate
Sodium bicarbonate is an effervescence exipient.
What is this?
Used in effervescence tablets and powders.
Means that you dissolve it in water and drink it like a solution.
It produces carbon dioxide
Tablets are designed to break up in water so people can drink the solution of the tablet
What can be added to a drug to increase permeability? I.e take from class III BCS to class I
Mucoadhesion, Absorption enhancing excipients
Efflux inhibitors
How could we take something from class IV BCS to class I?
Use liquid filled capsules (so once capsules break open there’s not worry about dissolution)
Absorption enhancing excipients, to increase permeability
How could we take a drug from class II to class I? (I.e from poor solubility to high solubility)?
Use nanoparticles
Select a more soluble salt
Use Liquid filled capsules
Solid dispersions (effervescence tablets)
Addition of surfactant to a solid dosage formation (SLS is a surfactant you can use to try and deaggregate your drug)
What are sink conditions?
If dissolution is said to occur under sink conditions, the solute is removed from the dissolution medium (due to good permeability through gut wall) at a faster rate than solute passes into solution (GI fluid) from the dissolving drug.
Like someone is running water but the plug is let out
In dissolution process, what is the boundary layer?
A concentrated saturated layer around dissolving drug particles, surrounded by a very dilute layer (rest of solution).
Molecules diffuse through it
The diffusion of a dissolved solute across the boundary layer is described by the ___________ equation
Noyes Whitney equation
What is the Noyes Whitney equation?
dm/dt = kA (Cs -Ct)
Where: m= mass of solute passed into solution in time t dm/ dt= rate of dissolution A= surface area of undissolved solid Cs= saturation concentration of solute C= concentration at time t K= intrinsic dissolution rate constant
Experience suggests that compounds with intrinsic dissolution rates greater than ______ are not likely to present dissolution rate limited absorption problems. Those with rates below ______ are likely to present these problems and those in between require further information.
Intrinsic dissolution rates Greater than 1mg/min.cm2
Below 0.1mg/min.cm2 are likely to have absorption problems
The ideal immediate release profile will go through Five main stages. What are these?
Disintegration Deaggregation Release Occultation (start to saturate the solution) Occlusion (saturated solution)
What do controlled release tablets control?
Controlled disintegration and deaggregation of the formulation.
What are organoleptic properties?
Many drug substances don’t taste or look nice.
Therefore sweetners and flavourings are added
Usually for liquid oral forms and chewable dosage forms (ones the patient will have to taste)
Very unpleasant drugs will be prepared as coated tablets to avoid taste buds of the tongue eg ibuprofen
2 common sweetners?
Sucrose Sodium saccharine (sweeter than sucrose)
Sweetner used for diabetics?
Sorbitol
Why are red tablets no longer used?
The dye was found to be toxic!
It’s becoming increasingly hard to colour medicines due to banning or colours
It’s regards to drug stability, within the shelf life what percentage should potency not fall under?
Should not fall below 90-95% under the recommended storage conditions
And the product should still look and perform as it did when it was first manufactured
(After ten years potency should not be below 90%)
What are the four main drug degredation processes ?
Hydrolysis (due to H20, OH-, pH)
Oxidation (due to 02)
Photolysis (due to UV and visible light)
Trace metal ion catalysis (fe2+, Cu2+)
The most common pathways of degredation are oxidation and hydrolysis
What could we use to protect against hydrolysis degredation? (Eg by H20)
Reduce moisture content eg use a dry desiccant
Reduce water activity eg by adding a solvent or a solute
Packaging should protect from water
Use solid dosage form if possible
Reduce Hygroscopicity eg by using salt
How could you avoid photolysis degredation of eg injection vials?
Use AMBER vials!!
If dissolution is said to occur under sink conditions, I.e the solute is removed from the dissolution medium (permeability through gut wall) at a faster rate than solute passes into solution from the dissolving drug
How does the Noyes Whitney equation change??
Becomes just dm/ dt = kACs (we remove the term Ct)
For what 5 types of tablets must EXCIPIENTS be soluble??
Effervescent Soluble Chewable Sublingual Lozenges
Patients dislike the “grittiness feel” otherwise
What are the two types of tabletting machines out there?!
Single puncher machines
Have a slow rate of production
Mainly used in R & D labs for producing just a few tablets.
Rotary tablet machines
Fast rate of production
Loads of tablets filled, punched and ejected at the same time!
What actually happens in compression into a tablet? How does it actually work?
Particles DEFORM under compressive forces (turn more flattened and rectangular) OOOO—>
Sometimes the particles can spring back into their original shape. This is called elastic deformation. We don’t want this! Cohesion is lost between particles :(
If they remain in their flattened shape this is known as plastic deformation ( this is good ) cohesion is retained.
What are moulded tablets?
Small tablets that are made by moulding a soft mass with a suitable SOLVENT
The soft mass is usually active drug and diluent
Moulded tablets are good because they rapidly disintegrate in the presence of moisture and water
How do we prepare moulded tablets? I.e what’s the recipe
Drug + diluent (such as lactose or sucrose)
Moisten with alcohol so it can be shaped and moulded (like dough!)
Mix into a wet mass
Put into a mold, fill holes in top portion of the mold
Press the top portion of the mold over Lower and press to place the moulded tablets on top of pegs
Compressed tablets can be divided into two different methods:
Dry methods
Wet methods
What are these?
Dry methods mean direct compression of the mixture of ingredients (No moisture is involved here)
Also use the dry granulation methods:
Slugging
Roller compaction
Wet methods:
Wet granulation
Tell me about direct compression of tablets?
Basically firstly particle sizes are reduced
Then all the ingredients are mixed together (drug, filler, disintegrant, lubricant, glidant) by dry mixing, add a compressible vehicle such as MCC or lactose
Then this is just directly compressed together into a tablet- simples!!
Why do we need to mix the ingredients (by dry mixing), before putting them into a tablet?
Ensures good drug content uniformity
Ensures all ingredients are free from lumps
Raw materials should be screened through sieves, makes mixing more reliable
Can you make a blender available for mixing?
Ribbon blender
Bin blender
V cone blender
Double cone blender
What is granulation?
The process by which primary powder particles adhere to form large multi-particulate entities called granules
(Basically forming grains to make a tablet with)
In granulation, how are bonds formed?
Bonds formed Either by compression or by a binding agent
Note: powdered material is harder to compress into a tablet than granulated material
Do companies prefer wet or dry granulation?
Most use wet granulation Methods include: Wet massing Spray granulation High shear granulation
Why do we granulate ?
Produces uniform, normalised particles, particles have: Good flow properties Increased compressibility Segregation resistance Reduced dusting
The granulation process produces large agglomerates
Add plasticizers and binders to increase compressibility
What is agglomeration?
The act of things coming together to form a mass
What is segregation?
The tendency of particles to Seperate out by size or shape
Particles that have been granulated are less susceptible to segregation because of the relatively high interparticulates forces that resist interparticulate motion.
