Dissolution Testing

What is the issue with delivery systems? (1)

Not all delivery systems administer all their drug load to a patient form a medicine e.g. BDP metered dose inhaler, dose deposited in mouth (side effect - oral thrush due to corticosteroids in mouth, need to rinse mouth after use)

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What is the issue with delivery systems? (2)

Solution - determine amount of drug delivered from each and every medicine

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Which test is used to measure the release of dosage forms?

Dissolution testing - (drug release - absorption)

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When is dissolution testing performed?

Not during clinical practice but during drug development and formulation manufacture. QC, formulation design, bioavailability/bioequivalence studies

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What influences drug release?

Solute, formulation, particle size, solubility/saturatior, methodology

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Describe features of the Noyes-Whitney equation

Dissolution rate = dissolution coefficient x SA of particle x (concentration at particle surface - concentration in bulk)

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Which factors are considered during dissolution experiments in a lab?

Solvent, agitation, volume, diameters of vessels, temperature

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What are the different types of dissolution apparatus used to test dissolution? (1)

Basket (rotation, large microparticles, floating dosage forms). Paddle (rotation, tablets/capsules, sinking dosage forms). Flow through (flow rate, tablets/capsules/particles, sinking/floating dosage forms)

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What are the different types of dissolution apparatus used to test dissolution? (2)

N = 6, fully automated, temperature controlled, computer run, time, agitation, sampling. Franz cell system - non-compendial, semi-solids, suspensions, membrane, identical principle (formulation sprayed on and dose measured in receiver fluid)

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Which test apparatus is used for the following: E/C ibuprofen tablets, paracetamol tablets, itraconazole microparticles, lemsip powder, subutex sublingual, betamethasone mousse?

Paddle, paddle, basket, flow through, basket, Franz cell system - dissolution apparatus depends on dosage form (lecture slide)

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Describe features of dissolution fluid

Try to mimic in vivo environment. Gastric vs intestinal vs colon vs lung vs nasal. Numerous models exist for each. Simple - complex. Often specified in products monograph. Composition, volume, pH, temperature

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Describe the dissolution fluid used to mimic the stomach

Water, 0.1 M HCl, simulated gastric fluid - 2 g NaCl, 3.2 g pepsin powder, 80 mL of 0.1 M HCl and dilute to 1 L with water

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Describe the dissolution fluid used to mimic the intestine

Water, simulated intestinal fluid, 6.8 g monobasic potassium phosphate in 250 mL water, 10 g pancreatin, adjust to pH 6.8 and dilute with water to 1000 mL

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Describe the dissolution fluid used to mimic the fasted state SIF

pH 6.5. Osmolality of 270 mOsmol/kg. Sodium taurocholate 3 mM. Egg phosphatidylcholine 0.75 mM. Sodium dihydrogen phosphate 28.66 mM, sodium chloride 106 mM. Sodium hydroxide 13.8 mM

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Describe the dissolution fluid used to mimic the fed state SIF

pH 5.0. Osmolality of 635 mOsmol/kg. Sodium taurocholate 15 mM. Egg phosphatidylcholine 3.75 mM. Acetic acid 144 mM, sodium chloride 173 mM. Sodium hydroxide 101 mM

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Why does the dissolution fluid in a fasted or fed state affect the dissolution of the drug?

Can affect the pKa of the drug and Log P (some cases where drugs are non-ionisable) - also effects of gastric/intestinal passage, varying pH and triggering system

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Describe features of the dissolution assay

Should be fit for purpose. Simple budders (UV analysis), calibration, interference minimal, SIFs - LC, calibration, matrix interference, polymers, must achieve mass balance

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Outline a dissolution method design

Drug properties - formulation (assay, apparatus, media)

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What are the stages of tablet dissolution?

Mechanical lag, wetting, penetration of fluid, disintegration, disaggregation, dissolution, occlusion

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How can the dissolution rate be measured?

Noyes-whitney equation (for small concentrations), Hixson and Crowell (change in SA), Wagner (conventional tablets/1st order). Higuchi (CR/SA remains constant)

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Describe features of IVIVC (1)

In vivo bioavailability (PK), in vitro dissolution (compendial apparatus). Consider cost/assumptions/type of drug when performing PK studies

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Describe features of IVIVC (2)

Dissolution originally for QC/reproducibility, bioequivalence only needs to be in vitro if referenced to bioequivalence standard (in vitro test proven IVIVC). Dissolution may have good IVIVC. IVIVC established (replaced PK standards), cost/ethics

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Describe features of IVIVC data

Simple point (single marker in vitro compared to single marker in vitro, misleading, used for simple systems). Intercept (Vaughan, 1s order, traditional dosage form), deconvolution method, (case studies)

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What causes poor IVIVC

Poor study design, polar drug, GE dependent, best IVIVC when dissolution is rate limiting step/never replace bioavailability. Still useful for QC, batch-batch variation, monograph

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Describe features of the BCS

Class 1 (high solubility, high permeability, propanolol). Class 2 (low solubility, high permeability, carbamazepine). Class 3 (high solubility, low permeability, atenolol). Class 4 (low solubility, low permeability, frusemide)

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Dissolution Testing

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