Preformulation Studies

What are preformulation studies? (1)

Laboratory studies to determine the characteristics of active substance and excipients that may influence - formulation design, formulation performance. PK and F, construction of formulation/product

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What are preformulation studies? (2)

Method of manufacture (ensure product is not destroyed), API, formulation. Product stability and packaging/during transport (learning before doing)

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What are preformulation studies? (3)

Need to be able to convert candidate molecule into a range of formulations under specific conditions (e.g. humidity). Data used to optimise parameters for formulation production

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Outline the drug discovery and development process (1)

Disease targets and molecular selection. Biological activity, cell systems. Biological activity, animal models (parameters e.g. doses). Regulatory approval. Clinical trials (healthy volunteers, patients). Regulatory approval. Prescription medicine

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Outline the drug discovery and development process (2)

Duration of time ~ 10 years (discovering and developing new medicines is a long, complex and expensive process). Very few ideas make it to market (numbers reduced with each step)

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Outline the drug discovery and development process (3)

Molecules synthesised/screened, studied in cellular models, animal studies, clinical trials, new medicine

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Outline the drug development and post marketing support (1)

Preformulation. Formulation. Product and process support. Formulation needs to remain consistent from nature to clinical trials

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Outline the drug development and post marketing support (2)

Patent application, acute toxicity, pharmacology, chronic toxicity, phase I clinical trials, phase II, phase III, registration and transparency, price, reimbursement, pharmacovigilance to SPC

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What are the direct benefits of preformulation studies? (1)

Helps in adjustment in PK and biopharmaceutical properties. Gives directions for development of formulation in choice of dosage form, excipients, composition, physical structure. Support for process development of formulation (e.g. drying conditions)

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What are the direct benefits of preformulation studies? (2)

Support for process development of drug substance (yield, filtration). Support for subsequent Process Analytical Technology (determination of critical process parameters)

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Outline how preformulation studies is involved in the steps of the drug discovery process (1)

Lead optimisation (choose preferred compound from a formulation/manufacturing perspective). Pre-clinical (determine best formulation for animal studies). Volunteer studies (determine best formulation for volunteer study). Phase II (best formulation)

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Outline how preformulation studies is involved in the steps of the drug discovery process (2)

Phase III (preformulation studies for final formulation and manufacture)

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What are the physical, chemical and technological features of a compound which need to be determined? (1)

Solubility, permeability, partition (aqueous, pKa, log P, log D) and dissolution (BCS). Hygroscopicity. Crystal properties (polymorph, habit, surface characteristics). Drug stability evaluation (physical, chemical, solution phase, solid phase)

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What are the physical, chemical and technological features of a compound which need to be determined? (2)

Compatibility analysis (drug substance, excipient, packaging materials). Technological characterisation (solids, particle size, size distribution, morphology, flowability, compactibility

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State features of solubility (1)

Absolute/intrinsic solubility. Can have different solubilities at different pH values (aqueous). Solubility in various solvents (e.g. ethanol, for chemical/pharmaceutical manufacture)

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State features of solubility (2)

Solubility rate (dissolution, determine rate at which product enters solution)

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State features of the partition coefficient, log P

Oil : Water. Octanol : Water at pH 7 (hydrophilicity/polar : hydrophobicity/non-polar). Used to determine log P of drugs (measured in octanol: water)

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What does permeability depend on? (1)

Solubility, partition (aqueous: lipids), diffusion coefficient (passive diffusion across model membranes, passive/active diffusion across biological membranes). Nature of membrane (chemical/biological composition, thickness)

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What does permeability depend on? (2)

Rate depends on other physicochemical properties of solutions (e.g. temperature, viscosity, density). Rate at which drug passes through membrane, varies in different locations in the body e.g. gut

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Describe features of the Noyes-Whitney equation (1)

dM = DS (Cs - Cb)/h. The rate of dissolution is dependent on the diffusion coefficient (from saturated liquid layer adjacent to crystal surface), SA exposed, concentration in saturated liquid layer directly adjacent to crystalline solid surface

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Describe features of the Noyes-Whitney equation (2)

Concentration in bulk solution further out from crystal (concentration gradient), thickness of liquid saturated layer

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Combining knowledge of which factors allows an initial estimate of what?

Combining a knowledge of solubility with a knowledge of permeability allows an initial estimate of bioavailability

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Outline the BCS (1)

Increasing permeability against increasing solubility. Class I (high solubility, high permeability). Class II (low solubility, high permeability). Class III (high solubility, low permeability). Class IV (low solubility, low permeability)

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Outline the BCS (2)

Decreasing bioavailability down the classes

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What is the definition of a highly soluble compound?

Highest dose fully soluble in <250 mL over the pH range of 1-7.5

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What is the definition of a highly permeable compound?

>90% absorbed in humans

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What is the definition of a rapidly dissolving compound?

>85% dissolved in 30 mins (dissolution rate limited leads to solubility rate being limited)

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Give examples of drugs in class I of the BCS

Paracetamol, propanolol, metoprolol, valproic acid

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Give examples of drugs in class II of the BCS

Carbamazepine, cyclosporin, ketoconazole, tacrolimus

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Give examples of drugs in class III of the BCS

Acyclovir (treatment for herpes), cimetidine, ranitidine

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Give examples of drugs in class IV of the BCS

Chlorothiazide, furosemide, methotrexate. Just because some medicines don’t fit into class I/II of BSC, doesn’t mean the medicine is not effective (prefer medicines to be categories I and II)

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What is the route of elimination for class I and II drugs in the BCS?

Metabolism (medicines with different permeabilities/solubilities have different routes of elimination)

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What is the route of elimination for class III and IV drugs in the BCS?

Renal and biliary elimination fo unchanged drug (majority of drugs on the market go straight through the body – excreted straight away)

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Which transporters are used for the classes of drugs in the BCS? (1)

Class I (transporter effects minimal in gut and liver, no need for transporter due a highly soluble/permeable drug). Class II (efflux transporter effects predominate in gut, uptake/efflux, affects liver)

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Which transporters are used for the classes of drugs in the BCS? (2)

Class III (absorptive transporter effects predominate but can be modulated by efflux transporters). Class IV (absorptive and efflux transporter effects important)

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What is hygroscopicity? (1)

Measures the amount of water taken up by the drug/excipient at different relative humidities and temperatures (graph). Non-hygroscopic (low water uptake).

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What is hygroscopicity? (2)

Cupboards at different humidities - measure weight of samples under different conditions, measure water uptake

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What are is sorption hypothesis?

E.g. starch. Dry state (absorption of water, high moisture uptake), wet state (desorption, lose water content). Disintegrate – if starch is already wet, lack of room for uptake of moisture (pre-formulation, use starch at a pre-dried level)

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Describe features of polymorphism (1)

Drugs/excipients can exist in crystalline/amorphous states depending on chemical composition and method of isolation/crystallisation. Examine morphology/physicochemical properties (m.p, hygroscopicity, solubility, stability) of different polymorphs

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Describe features of polymorphism (2)

Polymorphism depends on how it is crystallised (different shapes, depending on conditions)

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Outline the process for a bioavailability study

E.g. graph. Comparison of mean blood serum levels after administration of chloramphenicol palmitate suspensions using varying ratios of stable and metastable polymorphs (determine if delayed or instant release preferred)

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State features of solid-state stability polymorphism (1)

In early preformulation studies. Determine what polymorphic forms may exist and how these may be affected by temperature/crystallisation conditions. Techniques used

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State features of solid-state stability polymorphism (2)

Differential scanning calorimetry (polymorph heated, measure energy required to melt polymorph). Thermogravimetric analysis (heat polymorph, measure change in weight). Powder x-ray diffraction (crystals in cell, x-ray beam passes used, diffraction)

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What is the information obtained from stability studies used for? (1)

Provide feedback to the research team for modification of labile groups to improve stability. Help development for scientists to determine developability of compounds. Provide guidelines on compound/product handling and storage

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What is the information obtained from stability studies used for? (2)

Provide information to guide stabilisation strategies

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Which guidelines are used in stability testing? (1)

International Conference on Harmonisation of Regulatory Requirements Guidelines. Drug stability test guideline Q1A (R2)

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Which guidelines are used in stability testing? (2)

Requires that drug substance be tested under different stress conditions that are indicative of environmental challenges to which the drug will be exposed. Suggested that stress testing includes effect of pH

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Which guidelines are used in stability testing? (3)

Factors - temperature, humidity, light, oxidising agent

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Compounds can degrade through which processes?

Hydrolysis, oxidation, isomerisation (chiral carbons), polymerisation, photolytic decomposition. Different kinetics (rates of degradation 1/2/3 order). Order of reaction may vary with temperature

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State features of solid-state stability

Solid-state reactions that occur in drug substances include - solid-state phase transformation, dehydration/desolvation, degradation e.g. oxidation, cyclisation, hydrolysis

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Describe features of chemical degradation (1)

Hydrolytic degradation (in acidic/alkaline conditions - reflux with acid/alkali over 8-12 hrs, no reaction - stable, if reaction - determine which conditions to avoid). Stability in solvents in formulation/manufacture. Solid-state

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Describe features of chemical degradation (2)

Effect of humidity and temperature. Effect of solid state form e.g. amorphous vs crystalline

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In solid-state stability, the drug substance in evaluated under which conditions? (1)

Various temperatures and humidity conditions. Pre-weight samples stored in stability cabinets at 40/60/25 degrees Celsius, some with 85% RH, 40 degrees Celsius with 75% RH , open vials to observe degradation, for 2/4/8 weeks

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In solid-state stability, the drug substance in evaluated under which conditions? (2)

At pre-determined time intervals, samples are removed, dissolved in appropriate solvent, analysed by HPLC

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State features of chemical stability (1)

Requires robust, stability indicating assay (reverse phase HPLC, allows direct injection of stability samples). Assay show allow detection of degradation peaks equivalent to 0.1% of parent peak (not always practical at discovery stage)

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State features of chemical stability (2)

Techniques that perform and analyse multiple degradation experiments on drug substances under various stress conditions, some are amenable to high-throughput measurements in a 96- well format

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State features of chemical stability (3)

Important that drug doesn’t change its characteristics during manufacturing. Ensure that drug doesn’t degrade more than a certain quantity

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State features of chemical stability (4)

Ensure stability e.g. store in fridge. Need to know information about product throughout life cycle. Oily drugs degrade at different temperatures

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State features of photostability (1)

Solid photostability (store samples at high intensity light, UV conditions at 25 degrees Celsius in a photostability chamber. ICH guidelines (1.2 million lux h exposure to visible light and 200 W h/m2 to UV)

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State features of photostability (2)

Solution stability (store at different concentrations in various solvents, ICH conditions). Both solid and solution photostability (samples protected from light are stored under the same condition and used as controls). Spectrum of light wavelengths.

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State features of photostability (3)

Photostability cabinets, light beams with particular light frequency

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State features of pH-dependent stability in solution (1)

To understand its possible characteristics under physiological conditions and to develop solution dosage forms. Test at 37 degrees Celsius, pH 1/4/7/9 for 1 day up to 1 month. Studies should be initiated at a reasonable concentration

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State features of pH-dependent stability in solution (2)

To detect even minor decomposition products in the range of detection (empty stomach - pH of 1, full stomach pH of 6/entering gut, experience different pH environments, affects solubility)

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Describe features of oxidative stability (1)

Free radical chain processes (unsaturated compounds/oils), involves initiation/propagation/termination steps, catalysed heat/light/metals/free radicals

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Describe features of oxidative stability (2)

Degradation route may be temperature dependent so high temperature challenges may not reflect what happens at ambient temperatures

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Describe features of oxidative stability (3)

Oxygen electron-transfer reactions - solid state, oxidation occurs where molecular oxygen diffuses through crystal lattice to labile sites

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Describe features of oxidative stability (4)

Test in solution in presence of 100-200 ppm hydrogen peroxide or other free radical initiators such as 2,2-azobis (2-amidinopropane) dihyrochloride

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State features of stability and compatibility

Stability (of drug substance itself). Compatibility (drug substance in presence of other excipients e.g. lactose, sucrose, dextrose, Mg stearate etc, that might be used in formulations

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Describe features of solid state properties (1)

Fundamental (inherent physicochemical properties of compound e.g. m.p, solubility, stability, taste, absolute density, hardness etc.)

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Describe features of solid state properties (2)

Derived (those characteristics which are dependent upon the physical state of the solid (e.g. particle size/size distribution, packing properties, flowability, compression characteristics)

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What are the technical characteristics of solids?

Particle size, size distribution, SA, specific surface, particle shape, bulk and tapped density, cohesiveness, dispersibility, flowability, compactibility, material strength, stress relaxation, stress density, strength: pressure, force displacement

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Preformulation Studies

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