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What is a preformulation study?
- Laboratory studies to determine the characteristics of active substances and excipients that may influence formulation design and performance
What can a preformulation study help to determine?
- formulation design and performance
o This includes the construction of the product/formulation
o Method of manufacture
o Pharmacokinetics and bioavailability
o Product stability and packaging
What are the benefits of conducting a preformulation study?
o Provides directions of what you can and can’t do when developing a formulation eg form, excipients, composition, physical structure
o Allows for the adjustment of pharmacokinetic and biopharmaceutical properties
o Can adjust processes for yield, filtration etc
o Can adjust for development of formulation eg drying
When do preformulation studies begin?
Lewd optimisation stage
More occur during clinical trials too
What are the different types of preformulation studies?
o Pre-clinical studies – prefromulation studies determine the best formulation in animal studies
o Volunteer studies – preformulation studies determine the best formulation for volunteer studies
o Phase II clinical studies – Preformulation studies to determine the best clinical trial formulation
o Phase III clinical studies – preformulation to make the best final formulation and for manufacture
What are the different characteristics measured in preformulation studies?
Solubility
Permeability
Partition co-efficient
Dissolution
Hygroscopicity
Crystal properties
Drug stability evaluation
Compatibility analyses
Technical characteristics
Why is solubility studied?
o The drug will encounter different pH values at different parts of the body eg stomach and ileum etc
o So, the drug needs to be readily soluble in all of these places
o So the absolute or intrinsic solubility needs to be measured as well as the solubility in different pH values
o The solubility in different solvents also needs to be measured
Why is permeability studied?
o Dependent on solubility, diffusion co-efficient, partition, nature of the membrane, thickness of the membrane
o The rate of diffusion is dependent on other physiochemical properties such as temperature, viscosity and density
o In preformulation studies, the rate of diffusion across different membranes would need to be measured
o This would be measured using the Noyes Whitney equation
Why is log P measured?
o This provides an insight and initial estimate for bioavailability
o This shows how much drug will be absorbed by fatty tissue than just aqueous
Why is hygroscopicity measured?
o Measure the amount of water taken up by the drug and excipients in different relative humidities
Measure the weight of the formulation over time to see If water is taken up
Why are the crystal properties studied?
o Drugs and excipients exist in different crystal structures
o This is dependent on their chemical composition and method of ionisation and crystallisation
o These would have different physiochemical properties so it is important to measure these and ensure when manufacturing, there are no polymorphs
o It is important to investigate the different polymorphs and see how those affect the physiochemical properties
How are the crystal properties determined and assessed?
differential scanning calorimetery (DSC)
Thermogravimetric analysis (TGA)
Powder x ray diffraction
What is differential scanning calorimetry?
§ you heat the sample and assess how it absorbs heat
What is thermogrsvimetric analysis?
§ place the sample on a very fine and sensitive balance and heat it and see how the weight of the sample changes
What is powder x ray diffraction?
look at the sample through an x-ray and see if the structure remains the same
Why is drug stability studied?
o Provides information for modification of labile groups to improve stability
o This also helps the developmental scientists determine the developability of the compound
o Provides guidelines on the handling and storage of the drug
o Provides information on how to guide stabilisation strategies
The ICH guidelines requires that drug substances are to be tested under different stress conditions, which are indicative of the environmental challenges to which the drug will be exposed
What are the different environmental challenges a drug can be exposed to?
§ Temperature
§ Humidity – can cause mould growth
§ Light – exposure to a range of wavelengths can cause an unstable product
§ Oxidising agents
What are the mechanisms by which a drug degrades!
§ Hydrolysis
§ Oxidation
§ Isomerisation
§ Polymerisation
Photolytic decomposition
What factor does the order of reaction vary by?
Temperature
What are solid state stability reactions?
§ Solid-state phase transformation
§ Dehydration/desolvation
Degradation eg oxidation, cyclization, hydrolysis
How can chemical degradation occur and how is this relevant to medicines?
§ Hydrolytic degradation – in acidic and alkaline conditions
§ Stability in solvents used in formulation/manufacture
§ This could affect the humidity and temperature, affect the excipients and the form of the solid state (amorphous vs crystalline)
How can the solid state stability be measured?
o pre-weighed samples are stored in stability cabinets at different set temperatures and different relative humidities
§ At predetermined time intervals, samples are removed and dissolved in appropriate solvent and analysed using HPLC (40°C, 60°C, 25°C 85% RH open vials, 40°C 75% RH open vials
§ All of these would be for 2, 4 and 8 weeks
At what percentage should an assay for chemical degradation detect the degradation peak?
o assays should allow for detection of degradation peaks that are equivalent to 0.1% of the parent peak
How should photostability be studied?
§ Solid photostability - Store samples at high-intensity light and UV at 25°C in a photostability chamber
· ICH guidelines state 1.2million lux hour exposure to visible light and 200W hour/m2 to UV
§ Solution photostability – store at different concentrations in various solvents and use ICH conditions
§ For both methods, protect samples from light so they can be used as controls
How should pH dependent stability be measured?
§ Test at 37°C at pH 1,4,7,9 between 1 day and a 1 month
· These studies should be conducted at a reasonable concentration to detect even minor decomposition in the products
How does oxidation affect stability?
§ Free radical chain processes for unsaturated compounds/oils – involves initiation, propagation and termination steps and is catalysed by heat, light, metals or free radicals
· The degradation route may be dependent on temperature so a high temperature stress may not reflect what happens at ambient temperatures
§ Oxygen electron transfer reactions – molecular oxygen diffuses through the crystal lattice to the labile sites
How should oxidative stability be measured?
Test in solution in the presence of 100-200rpm hydrogen peroxide or other free radical initiatiors such as 2-aminidnopropane
What are the technical characteristics?
particle size, morphology etc but this is dependent on the formulation
What is compatibility analyses?
Analysis of the affect of substance, excipient, packaging, materials on each other
Wha are fundamental properties?
o melting point, solubility, stability, taste, density, hardness
What are the derived properties?
o characteristics which are dependent on the physical state of the solid eg packing properties, flowability, compression characteristics