Preformulation and bioavailability

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31 Terms

1
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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

2
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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

3
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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

4
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When do preformulation studies begin?

Lewd optimisation stage

More occur during clinical trials too

5
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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

6
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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

7
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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

8
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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

9
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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 

10
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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

11
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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

12
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How are the crystal properties determined and assessed?

differential scanning calorimetery (DSC)

Thermogravimetric analysis (TGA)

Powder x ray diffraction

13
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What is differential scanning calorimetry?

§  you heat the sample and assess how it absorbs heat

14
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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

15
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What is powder x ray diffraction?

look at the sample through an x-ray and see if the structure remains the same

16
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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

17
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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

18
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What are the mechanisms by which a drug degrades!

§  Hydrolysis

§  Oxidation

§  Isomerisation

§  Polymerisation

Photolytic decomposition

19
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What factor does the order of reaction vary by?

Temperature

20
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What are solid state stability reactions?

§  Solid-state phase transformation

§  Dehydration/desolvation

Degradation eg oxidation, cyclization, hydrolysis

21
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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)

22
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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

23
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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

24
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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

25
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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

26
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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

27
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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

28
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What are the technical characteristics?

particle size, morphology etc but this is dependent on the formulation

29
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What is compatibility analyses?

Analysis of the affect of substance, excipient, packaging, materials on each other

30
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Wha are fundamental properties?

o   melting point, solubility, stability, taste, density, hardness

31
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What are the derived properties?

o   characteristics which are dependent on the physical state of the solid eg packing properties, flowability, compression characteristics