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)
