BiopharmaceuticsDosage form factors influencing bioavailability

Lec:5

Ali Y Ali BSc Pharmacy

MSc Industrial Pharmaceutical Sciences

Dept. of Pharmaceutics School of Pharmacy

University of Sulaimani16/12/2019 1

Biopharmaceutics Physicochemical

properties

Dosage form Route of

Administration

Bioavailability(Rate & Extent)

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Overview

• Dosage form factors influencing bioavailability– Type of dosage form

– Aqueous solutions and suspensions– Capsules; liquid- and powder-filled– Tablets; uncoated, coated and enteric-coated

– Excipients– Diluents– Surfactants– Lubricants– Disintegrants– Viscosity-enhancing agents

– Biopharmaceutical classification scheme

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Introduction

• Bioavailability of drug in a dosage form can be affected by :– Formulation (the contents)– Production

• Dosage forms are designed and changed to influence of the release and absorption of drugs.

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Aqueoussolution

Aqueoussuspension

Immediaterelease

solid dosageform

Suspension offine particles

of drug inGI fluids

Aggregateor granules

Solution ofdrug in GI

fluids

Possible steps between administration andappearance of drug in SOLUTION in GI fluids

Disintegration

Deaggregation

Precipitation

Dissolution Absorption

Dissolution

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Aqueous Solution

• Drugs soluble and stable in the aqueous solution

• Formulation as solution eliminates the dissolution step in vivo in the absorption process.

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Aqueous Solution

• Poorly soluble drugs– Cosolvency – Complex formation

• Dilution by GI fluids might lead to precipitation

• Exposure of salt of acidic drug to the acidic environment of the stomach also precipitates the drug as it will be in the free from.

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• The fine nature of the precipitate allows fast redissolution of the drug particles compared to other dosage formsa) Aqueous suspension b) Hard gelatin capsule and tablet

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Formulation factors of Aqueous Solution affecting bioavailability

1. Chemical stability:– Dosage form and GIT

2. Complexation: drug-excipints – Increase aqueous solubility – Increase viscosity of the dosage form

3. Solubilisation– Incorporation into micelles in order to increase the

aqueous solubility 4. Viscosity of the dosage form

– Viscosity enhancing agents

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Aqueous Suspension

• Insoluble and poorly soluble drugs • Dissolution rate limited

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Particle size & effective surface area of dispersed drug

• If increase total surface area then increase dissolution rate

• For a given mass of drug, smaller particles have a higher effective surface area

• If absorption of drug is dissolution-rate limited, then increase absorption by decreasing particle size

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Aqueous suspensions: factors affecting bioavailability

1. Particle size and effective surface area of dispersed drug

2. Crystal form of drug• Amorphous vs. crystalline• Novobiocin – antibiotic no longer in BNF

– Rapidly dissolving amorphous form readily absorbed form an aqueous suspension. Crystalline is inactive

• Polymorph:– e.g. chloramphenicol palmitate suspension A is stable

polymorph, B is metastable. – more rapid dissolution of B the increased bioavailability– because Dissolution of A so slow effectively inactive 12

Aqueous suspensions: factors affecting bioavailability

4. Possible complexation with excipient– Complexation to reduce bioavailability – drug and

viscosity enhancing agent e.g. carboxymethylcellulose and amfetamine

5. Inclusion of surfactant as wetting, flocculating or deflocculating agent

6. Viscosity13

Viscosity-enhancing agents and drug absorption

• Liquid dosage forms improve1. Palatability 2. Ease of pouring 3. Rate of sedimentation of the dispersed particles

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Viscosity-enhancing agents and drug absorption

1. Complex formation1. Complexation to reduce bioavailability

• e.g. carboxymethylcellulose (CMC) and amphetamine

2. Increase viscosity of GI contents1. Decreased dissolution rate of solid particles2. Decreased rate of diffusion of drug molecules

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Liquid filled capsules

• Liquid can be filled into hard or soft gelatincapsules

• Advantages:1. Unit dosage form 2. Rapid absorption

• Dissolved • Suspended

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Liquid filled capsules

• Non-aqueous vehicles1. Water miscible (hydrophilic)

• Polyethylene glycols (PEGs)• Non-ionic surfactants (polysorbate-80)

2. Water immiscible (lipophilic)• Vegetable oils (digestible or non-digestible)

• Release of contents:– Dissolution and splitting of the shell

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Types of Vehicle of Liquid filled capsules

1. Water miscible vehicle: – Solution or suspension– disperses and/or dissolves in GIT, releasing the drug as

either suspension or solution, respectively.– Allows rapid absorption

2. Water Immiscible: – Solution or suspension– Release of the drug from the dosage form followed by

dispersion • Solution, emulsion, suspension

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Water Immiscible• Water immiscible (lipophilic):

a) Vehicle is digestible oil and drug is highly soluble in the vehicle:

• In GIT it is possible that the drug remain in solution in the dispersed oil phase and absorbed along with the oil droplet, by fat absorption mechanisms

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Water Immiscible

b) Drug is less soluble in the oily vehicle or the drug is dissolved in the non-digestible oil:

– The drug must partition from the oily phase or into the aqueous GI fluids

– Absorption depends on this partition– Increase interfacial (oil/aqueous) will increase

dissolution rate

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Suspension

• Suspension in oily phase :– Dissolution in the vehicle – Diffusion to the oil/aqueous interface – Partition across the interface

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Poorly soluble drugs with improved bioavailability

• Digoxin:– Formulated as soft gelatin showed faster absorption

compared to tablets

• Saquinavir– Antiviral – Peptidomimetic– Soft glatin (fortovase) showed improvement in

bioavailability compared to hard gelatin powder filled 22

Liquid-filled capsules: factors affecting bioavailability

1. Solubility of drug in vehicle (and GI fluids)

2. Particle size of drug (if suspended in vehicle)

3. Nature of vehicle (hydrophilic or lipohilic)

4. Inclusion of surfactant

5. Inclusion of suspending agent

6. Complexation23

Powder-filled Capsules• Dissolution of hard gelatin shell

• Penetration of GI fluids into encapsulated mass

• excipients and packing density important

• Dispersion of encapsulated mass in GI fluids

• Dissolution of dispersed drug particles24

Only hydrophobic drug particles Hydrophobic drug particlesHydrophilic diluent particles

Shell dissolves

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Powder-filled capsules: factors affecting bioavailability

1. Surface area and particle size of drug2. Use of salt form3. Crystal form of drug4. Chemical stability of drug5. Composition and properties of capsule shell

(including enteric capsules)6. Interactions between capsule shell and

contents7. Complexation 26

Phenytoin Capsules

• Occurred in Australia in the late 1960s

• A capsule was reformulated that contained phenytoin

• The diluent used was changed from calcium sulfate to lactose

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Phenytoin Capsules

• In the months following this change, there was reports of side-effects similar to overdosing of product

• It was demonstrated that the change had had a significant effect on the bioavailability of phenytoin

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Tablets

1. Uncoated 2. Coated ( enteric-coated)

• The most widely used dosage form

• Characterised by large reduction in the surface area owing to the production methods used – Granulation – Compaction

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Tablet

• Reduction in the surface area can be solved by formulation, this is by addition of excipientsthat serve to increase surface area upon administration

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?

Tablet Granules Fineparticles

Drug insolution

Stomach

Smallintestine

Tran

sit

ABSORPTION

Release and absorption of a drug from a tablet

?

?

?

Fine suspension 31

Uncoated tablets: factors affecting bioavailability of a poorly soluble drug

1. Physicochemical properties of liberated drug particles in GI fluids

2. Nature and quantity of excipients• Diluent, binder, disintegrant, lubricant, wetting agent

3. Drug-excipient interactions4. Manufacturing factors

• Granule size, compaction pressure and speed

5. Storage and age of tablet

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Coated tablets

• Coating presents physical barrier between tablet core and GI fluids

• Problems of uncoated tablets• PLUS• Problems of coating

• Coating must dissolve/disrupt

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Types of coating

1. Poorly water-soluble coating– Can delay and or reduce rate of drug release

• Shellac, cellulose acetate phthalate (CAP), ethylcellulose (EC)

2. Water-soluble coating– No significant effect on drug release

• Hydroxypropyl methylcellulose (HPMC)

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Enteric-coated tablets

• Resists low pH of gastric fluids• Dissolves at higher pH of duodenal fluids (pH

5)

• Coatings include:• Cellulose acetate phthalate CAP• Hydroxypropyl methylcellulose phthalate • Copolymers of methacrylic acid and their esters• Poly vinyl acetate phthalate PVAP

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Enteric-coated tablets

Enteric coating

• Delays drug release to improve bioavailability• Can protect stomach

• Types – EC tablet (monolith)

– Onset of action dependent on gastric emptying time

– EC granules or pellets (< 1 mm)– Gradual release from stomach with liquids

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Excipients

• Excipients are added to the formulation in order to facilitate the preparation, patient acceptability and functioning of the dosage form as a drug delivery system.

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Diluents

• Increased incidence of phenytoin intoxication in Australia from phenytoin ??

• Changing the diluent in the capsules from calcium sulphate dihydrate to lactose.

• This is because of forming non absorbable complex between Ca-phenytoin

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Surfactants

• Emulsifying agent• Solubilising agent • Suspension stabilisers • Wetting agent

• Inert? – Increase– Decrease – No effect

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Surfactants

• Inhibition of absorption :– drugs normally soluble in

the GIT fluids:presence of surfactants in micellar concentration decrease absorption by incorporation of the drug in the micelles

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Surfactants

• Increase absorption:– Poorly soluble drugs, increase dissolution by

solubilisation (Cs), this leads to rapid absorption – Disrupting biological membranes increases

membrane permeability

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Lubricants

• Added to reduce friction between solid particles and metal parts of machinery in the manufacturing of solid dosage forms

• Hydrophobic

• Mg stearate: retard penetration of GI fluids

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• How we solve it ?– Overcome

• Wetting agent • Hydrophilic diluent

– Decrease Mg stearate content

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• Mg sterate as lubricant

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Disintegrants

• Break up tablet capsules and granules into primary particles

• Disintegration failures – Incomplete absorption – Delay in onset

• Tolbutamide

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Biopharmaceutical Classification Scheme

Permeability

SolubilityClass I

High solubilityHigh permeability

Class IILow solubility

High permeability

Class IVLow solubility

Low permeability

Class IIIHigh solubility

Low permeability

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Biopharmaceutical Classification Scheme

• Considers aqueous solubility (Dose and Solubillity) and permeability via oral route of delivery (90%)

• Class I – high solubility, high permeability– rapid absorption, good bioavailability

• e.g. propanolol, metaprolol

• Class II – low solubility, high permeability– drug controls absorption; potential for particle size effects

on bioavailability• e.g. ketoprofen, carbamazepine

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Biopharmaceutical Classification Scheme

• Class III - high solubility, low permeability– drug dissolves rapidly but poorly absorbed– require rapid drug release to maximise absorption

• e.g. ranitidine, atenolol

• Class IV - low solubility, low permeability– challenging molecules, likely to exhibit low bioavailability

• e.g. hydrochlorothiazide, ``

• option to increase permeability - modify drugs as ‘prodrugs’

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Further Readings

• Shargel L, Yu AB, (Eds.), Applied Biopharmaceutics and Pharmacokinetics.

• Aulton's Pharmaceutics: The Design andManufacture of Medicines, M.E.Aulton, Churchill Livingstone, 2007.

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Thank You

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