Preformulation Flashcards
What is preformulation
The process of gathering the parameters that influence the choice of formulation for a drug
Most drugs are solid tablets/capsules but why must we consider making an IV injection?
For the early animal studies and toxicology (you can’t make a mouse swallow a pill easily )
What are the main properties should be included in a preformulation study
- solubility, the drug needs to be soluble otherwise the bioavailability will be poor
- dissociation constant pKa, tells us how the drug will react in certain pH levels (ionised or unionised), unionised forms pass through membranes more easily so can be absorbed easier
- melting point
- LogD = distribution coefficient, this accounts for the ionised AND unionised forms of the drug
What information needs to be provided before we can formulate a drug
(4 things)
1) Identity of drug (chemical structure)
2) purity
3) assay methods (how concentrated/pure it is)
4) description (colour, physical appearance, smell)
What does NCE and API stand for
NCE - new chemical entity
API - active pharmaceutical ingredient
What info about the identity of the drug do we need
Name
Chemical formula & structure
Batch no.
Method of crystallisation ( beware of polymorphs)
Pharmacological action
Dose
Form required (e.g. liquid for eye drops)
What are polymorphs and why do we need to be careful of them
Crystals that have the same chemical composition but different crystal structures. We need to be careful of these because although they have the same chemical composition they can have different solubility levels and different melting points so they will react differently- we need to identify which one we need and expel others which may not produce the same desired therapeutic effects
What do we need to know in terms of purity
1) The nature of the impurities e.g.
is it moisture, therefore does that mean the drug will absorb water
Does it contain inorganic, organic or heavy metals -> ( commonly used as catalysts e.g. zinc or platinum)
DSc
2) We need to know the toxicity of these impurities, will they minimise the therapeutic effect of the drug?
3) We need to know the effect of impurities on the stability of the drug e.g. water and moisture present can increase the rate of hydrolysis of the drug
What do we need the assay methods for
Specificity - just assaying the drug
Sensitivity
The assay should be applicable for both pure drug and in mixture of body fluids
Methods include : UV spectroscopy (can detect presence of chromophores = double bonds with electrons that will absorb UV energy, drugs like metformin don’t have this) , titration and h.p.l.c. ( most commonly used)
What do we need to know in terms of the description
Appearance
Colour
Smell
Taste - most NCEs have bitter taste so we formulate taste maskers to the desire of parents - something healthy like fruits
What do we need to consider in preformulation for the solubility of a drug and what does it mean
Solubility = maximum conc of a solute attainable in a given solvent under given conditions
We need to consider how this will change with
Temperature
pH
Model intestinal fluids
These may alter the chemical structure (salts and hydrates) and physical structure (polymorphs)
What’s the henderson-hasselbalch dissociation constant pKa for weak acids and weak bases
Weak acid : pH = pKa + log10( [A-]/[HA-])
Weak base pH = pKa + log10([B]/[BH+])
What do we need to consider in preformulation for the permeability of a drug and what does it mean
Permeability = drug’s ability to diffuse through the membrane
We need to consider:
- solubility
- diffusion coefficient
- partition (aq:lipids)
- nature of membrane (chemical, biological, thickness, etc…)
- size of the molecule
Using the biopharmaceutical classification system describe class 1-4
Class 1 - high permeability, high solubility | decreasing
Class 2 - high permeability, low solubility | Bioavailability
Class 3 - low permeability, high solubility V
Class 4 - low permeability, low solubility
What do we classify as highly soluble and highly permeable
High soluble = highest dose FULLY soluble in <250mL over pH 1-7.5
Highly permeable = >90% absorbed (in humans)
How can we measure melting point
Using capillary melting ( done in preformulation lab)
Using hot plate microscopy
Using differential scanning calorimetry DSC
What’s heat flux DSC and what’s the equation for heat flow
= a sample and reference pan are heated from the same source and the temperature differential between pans is measured
🔺Q = (Ts - Tr)/RT Ts = temp of spample Tr= temp of reference
🔺Q= heat flow measured in Watts, units are J/s
Why does the temp increase stagger in heat flux DSC
Because e.g. the temp only increases once all the ice has melted on then does the temp rise so there is no heat flow until it all melts as well because the reference and the sample have the same temp
Why does the temp increase stagger in heat flux DSC
Because e.g. the temp only increases once all the ice has melted on then does the temp rise so there is no heat flow until it all melts as well because the reference and the sample have the same temp
What are the ones made of in heat flux DSC
Aluminium most commonly because it is inert and won’t react with the drug BUT if the temp is really high then we us gold pans
What temp do we measure on a heat flux DSC graph
The onset temp .i.e. draw tangent on the curve as the temp rises and use this as the value, we don’t take the value at the peak
What’s carbamazepine and what process produces its polymorphs
BONUS: what bonds change in a polymorph and what does it cause
It’s a drug used to treat epilepsy
It is ball milled (grinder using a ball) and quench cooled ( cooled using water) which produces different polymorphs
The polymorphs have the same chemical structure but different crystal structures
BONUS: the non-covalent bonds change but the covalent bonds stay the same, this gives rise to diff melting points and diff solubilities
What’s XRPD and what does it show
X Ray Powder Diffraction
It produces different patterns depending on the crystal structure so it can be used to identify different polymorphs
What’s DSC graph used for
- Identify different forms of API
- can measure melting points to identify different polymorphs (molecules stored in different ways produce different polymorphs) I.e. molecule can melt and recrystallise into a more stable polymorph
What’s thermogravimetric analysis
Measures changes in weight as sample is heated/cooled, good for measuring hydrate forms
What’s hygroscopicity
Measures moisture levels (ability to absorb moisture). We need to measure this because we need to know if some drugs will absorb water e.g. metformin absorbs water in humid conditions - this is important because the rate of degradation of the drug can increase (e.g. 5% moisture levels can increase the rate of hydrolysis) effecting therapeutic effect
What physical properties do we need to be aware of
The particles mean size and size distribution
The particle density
The stability (drugs require a shelf life of up to 5 years with no loss of potency) intrinsic stability ( good stability) will aid formulation
In terms of stability what processes can effect stability and example of drugs that experience this
- hydrolysis e.g. aspirin becomes unstable in water
- oxidation e.g. paracetamol becomes unstable when exposed to air
- photolysis e.g. nefedipine becomes unstable when exposed to sunlight
- trace metal catalyst e.g. aspirin becomes unstable
What method is used for accelerated stability testing + equation
Arrhenius relationship,
Stability is tested as a function of time
High temperatures are used to speed up the rate of the reaction which is then plotted as a function of storage temperature
The plot is extrapolated back to normal temperatures
Equation : k = A x exp(-Ea/RT)
How would we identify the -Ea/RT (room temp) and A
The slope (gradient) is -Ea/RT and A is the y intercept
What 2 assumptions do we make with the Arrhenius plot
1) the mechanism stays the same at both the high and low temperatures
2) the errors in the analysis are low
How do we measure excipient compatability
BONUS: examples
We run that active and the excipient separately in DSC then we run them together in DSC any unexpected heat flow mean likely incompatability
BONUS: aspirin + lactose = compatible
Aspirin + magnesium Stearate = incompatible
Name some preformulation information we would need to gather (there’s lots but it will differ depending on that particular drug)
- solubility - excipient compatability
- pKa - hydrates/polymorphs
- dissolution - bulk density
- melting point -compression properties
- crystallinity - angle of repose
- purity - salts
-stability Etc….. - powder flow
Why might we need different formulations for the same API
Different parts of the drug development may require different formulations e.g. in animal testing/studies IV injection would be most convenient, in clinical trials tablets might be most suitable
How long can it take to find a suitable drug for preformulation
10 years+
