BIOPHARMACEUTICAL CONSIDERATION IN DRUG PRODUCT DESIGN

BySarafadeen Adebayo, Ph.D.

DEVELOPING DRUG DELIVERY SYSTEM THAT HIT A DESIRED TARGET

PHARMACOKINETIC TARGET – BLOOD/PLASMA CONCENTRATION LYING BETWEEN MEC & MTC

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IN

AROUND

OUT

MouthLungsRectumSkinParenteral

AbsorptionDistribution

oRBC

oPLASMAPLASMA PROTEIN

WATER

MetabolismExcretion

oKidneysoLungsoSkinoOthers

Cp=Do/Vd

For many drugs of low aqueous solubility, dissolution is rate limiting in absorption

Absorption/Distribution/Elimination

Distribution/Elimination

Liberation

Elimination

The LADMETOX SchemeCp

Time

THERAPEUTIC WINDOW

TOxic

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Design and formulation of drug products

Require a thorough understanding of the biopharmaceutical principles of drug delivery.

Biopharmaceutics studies the in vitro impact of physicochemical properties of drugs and drug products on delivery to the body under normal or pathologic conditions.

Bioavailability is the assessment of the rate and extent at which the active drug becomes available at the site of action.

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Drug delivery to tissues Since it is the systemic circulation that delivers therapeutically active

drug to the tissues and sites of action, changes in bioavailability affects:

changes in the pharmacodynamics

toxicity of a drug.

Therefore, the aim of biopharmaceutics is to adjust the delivery of drug from drug products in such a manner as to provide: optimal therapeutic activity

safety for the patient.

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BIOPHAMACEUTICAL CONSIDERATIONSBiopharmaceutics enables the rational

design of drug products through the understanding of:

Physical & chemical properties of the drug substance

The rate of administration including the anatomic & physiologic nature of the site of application

BIOPHAMACEUTICAL CONSIDERATIONS ../2

Desired pharmacodynamic effects (immediate or prolonged activity)

Toxicologic properties of the drug

Safety & compatibility of excipients

Effect of excipients & dosage form on drug delivery

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BIOPHAMACEUTICAL CONSIDERATIONS …cont.

By choosing the route of administration carefully, and properly designing the drug product, the bioavailability of the active drug can be varied from

Rapid and complete absorption through

Slow sustained rate of absorption, to

No absorption at a site

depending on the therapeutic objective of the

formulation.

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BIOPHAMACEUTICAL CONSIDERATIONS …cont.

Following systemic absorption of a drug:

Normal physiologic processes of distribution and elimination occur and these are not normally influenced by the specific formulation of the drug.

However, the rate of drug release from the product and the rate and extent of drug absorption would determine

the distribution

Onset

intensity and

duration of action

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BIOPHAMACEUTICAL CONSIDERATIONS …cont.

Biopharmaceutics consideration usually determines

the ultimate dose and dosage form of a drug product.

o Dosage of a drug for local activity (topical ointment) is often expressed in concentration or % of API in the formulation

Dosage of a drug

Dosage of drug intended for systemic absorption is expressed on the basis of mass e.g. mg or g.

Dosage is based on the amount of drug absorbed systemically

and dissolved in an apparent volume of distribution to produce the desired concentration at the target site.

In this case, also, therapeutic dose may be based on the patient’s weight or Body Surface Area (BSA, m2) in order to account for difference in the Vdapp.

Hence, doses may be expressed as mass per unit body weight (mg/Kg) or mass per unit BSA (mg/ m2).

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BIOPHAMACEUTICAL CONSIDERATIONS …cont.

Doses for many commercial drug products are:

Determined on average body weight

May be available in several dose strengths as 10 mg, 5 mg, 2.5 mg tablets –

To accommodate differences in body weight

For possible titration of dose in the patient.

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Physico-chemical Nature of the Drug Physico-chemical nature of the drug and excipient would

affect

Dissolution kinetic of drug product,

Stability of product

Risk to manufacturing personnel in drug production.

Rate and extent of drug availability in the systemic circulation depends on a number of physicochemical (& physiologic) factors.

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Physico-chemical Nature of the DrugThese factors include the

ionization constant

partition coefficient,

solubility & dissolution rate,

crystal form,

surface area of drug substance and the dosage form (Verbeeck et al, 2005).

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Physiologic FactorsPhysiologic factors that could contribute

significantly to drug absorption include the gastro-intestinal environment and its effect on:

drug solubility,

drug permeability through g.i. membrane and

the pH profile of git,

presence of bile salts and other physiologic surfactants,

effect of food and disease conditions of the subjects.

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Contribution of solubility The contribution of solubility to the potential of a candidate’s suitability as

medicinal substance is very significant.

Drugs that were subjects of intense scientific and regulatory scrutiny in the 1970s & 1980s were those with poor aqueous solubility

Generally in the range of 20 – 100 μg/mL.

Nowadays, drug substances of solubility as low as 1 μg/mL are quite common.

Considerable attention has been paid to how to control drug substance solubility and permeability

Drug molecules have now been classified into different categories based on their physicochemical properties

Amidon et al. Pharm. Res. 12: 413 – 420, 1995.

19

Effect of Physicochemical properties on Oral AbsorptionPhysicochemical properties have provided

models/tools for predicting oral absorption during dosage form design and development. Most important physicochemical property-based

models include:pH-Partition theory, Absorption Potential (AP), Mass Balance, Compartmental Absorption &Transit (CAT) Models

(Goodacre & Murry, 1981. J. Clinical & Hospital Pharm. 6: 117 – 133; Dressman & Fleisher, 1986 – JPS 75: 109 – 116; Yu et al 1996 – IJP 140: 111 – 118.

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The Lipinski’s “Rule of Five”

The Lipinski’s “Rule of Five” provides experimental and computational approaches to the estimation of solubility and permeability in drug discovery and early developmental stage based on physicochemical properties of new drug molecules.

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Dissolution & solubility

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Solubility versus Absorption PotentialAs a rule, absorption of a drug substance is preceded by

dissolution and is a function of solubility.

Solubility of a compound together with its dose are important for the evaluation of its Absorption Potential.

Johnson & Swindell (1996 – Pharm. Res. 13: 1795 – 1798) proposed a simple approach for the estimation of Maximum Absorbable Dose (MAD) as:

SITTSIWVksMAD a

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Maximum Absorbable Dose ..cont.Where s = solubility (mg/mL) at pH 6.5;

ka = intestinal absorption rate constant (min-1) obtained from rat intestinal perfusion experiment (considered to be similar to human ka);

SIWV = small intestinal water volume (mL) ≈ 250 mL;

SITT is the residence time of drug in the small intestine (generally assumed to be 3 Hr.

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Dissolution & solubilitySolid drugs need to dissolve before

they can be available for absorption.

Noyes-Whitney equation gives a more comprehensive relationship between various factors controlling particle dissolution:

Where dC/dt is the rate of drug particle dissolution;

D is the diffusion coefficient of the drug in solution in the gastric fluid;

A is the effective surface area of drug particles in contact with the git fluid;

h is the thickness of the diffusion layer around each drug particle;

Cs is the saturation solubility of the drug in solution in the diffusion layer;

Cb is the concentration of drug in the git fluid.

h

CCDAdt

dC bS )(

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Noyes-Whitney equation

Although various factors limit the application of Noyes-Whitney equation, the equation serves to illustrate and explain how various physicochemical and physiologic factors can influence the rate of dissolution in the git fluid and suggests ways by which the difficulties may be overcome.

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Effect of physico-chemical parameters of a drug on factors modulating drug release

According to Dressman et al (1998): Effect of physico-chemical parameters of a drug on factors modulating

drug release from dosage form and subsequent appearance in systemic circulation include:

A: Particle size and wetability

Cs: Hydrophilicity, crystal structure & solubilization

C: Permeability

D: Molecular size, partition coefficient

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Drug Factors Affecting Dissolution Rate

Solubility – An understanding of the solubility of a drug can be regarded as the most important aspect of pre-formulation studies.

Drugs are generally less stable when in solution and, hence, it is often desirable to limit aqueous solubility in a liquid dosage form (Lund, 2004).

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Mechanisms of solvent action

Substances that are chemically similar are expected to show mutual solubility in line with the adage “Like dissolves like”.

According to Hartley (1956), liquids are mutually soluble to the extent depending on the difference between the forces of attraction between unlike molecules and the mean of those between the like pairs.

Generally, attraction between unlike molecules is less than the mean attraction between like molecules, so attractive forces are best separated by dissociation of the molecules, like with like, in separate phases.

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Mechanisms of solvent action .. Cont.

Crystalline solids have ordered arrangement of their units (atoms, ions, molecules) in fixed positions.

Insolubility of unionized solutes is explained by the stable crystalline arrangement and low inter-molecular forces between solvent and solute. Their melting point reflects the structure of the intramolecular

forces and the solute.

Hence, the higher the melting point, the less the tendency to dissolve in a liquid (for solutes of similar molecular structure e.g. hydroquinone (m.p. 170°C) < soluble than phenol (m.p. 41°C).

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Solubility of ElectrolytesElectrostatic forces of attraction/repulsion (most

important of which is dielectric constant) govern the solubility of electrolytes.

Water has high dielectric constant and is a polar solvent and a good solvent for other polar substances e.g. electrolytes.

When electrolytes dissolve in water, the cations are attracted to the negative ends of water dipoles and becomes associated with a strong shell of strongly attracted water molecules:

O δ-

δ+H Hδ+

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Polarity of organic substancesPolarity of organic substances containing groups

such as OH, COOH, NH2 is due to the unequal sharing of electrons of the covalent bond.

Attraction exists between the molecules containing these polar groups and water molecules and the molecules are consequently readily distributed between the H2O molecules.

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Polarity of organic substances …cont.

Ethanol is miscible with water in all proportions

Higher alcohols such as propyl-, butyl-, etc. become increasingly less soluble due to increasing non-polar part of the molecules.

Long chain alcohols e.g. cetyl alcohol (C15H31OH) are sparingly soluble in H2O and orientate themselves at an air-water interface with –OH group in water and hydrocarbon chain directed towards the air.

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Examples of properties of a compound that depends on structure differences

Solubility Hardness

Water uptake (deliquescence) Cleavage

Colour Density

Optical & electrical properties Chemical stability

Solid-state reactivity Thermoanalytical behaviour

Physical stability Can you think of any other??

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Models of solubility

Dissolution of solute (liquid or solid) in a solvent (liquid) does not increase its volume as much as the “additivity rule” would predict.

This suggests that the solute must be fitting into “cavities” within the liquid structure.

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Solubility ModelSolubility Process – can be divided into

three parts:

Removal of molecule from the solute

Preparation of cavity in the solvent

Positioning of the solute molecule in the cavity

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Solubility Model – Factors controlling solubility

On the basis of this model, solubility is related to solute-solute bonds – i.e. the lattice energy for crystals (which

is often assessed by melting point)

the solvent-solvent bond strength (ease of making a cavity,

which may be linked to boiling point)

the size of the solute molecule (larger molecules require larger cavities)

the interaction between the solute and the solvent.

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Solubility Model… cont.Expressing this model in terms of the work

involved, one can calculate the work (w) required to dissolve each molecule of the solid solute as:

(2)

Where wSS, wLL and wSL are the bond strengths between two solid (solute) molecules, two liquid molecules and a detached solute molecule and a liquid molecule respectively.

SLLLSS wwww 2

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Model prediction of solubility

On the basis of this model, solubility will depend upon the:

lattice energy of the solid (e.g. polymorphism, crystal defect, etc)

nature of the liquid (which can be adjusted with additives such as co-solvents)

interaction between the two.

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Solubility Model: Chemical properties of solute & solvent

The interaction between a solute and a solvent will depend on chemical and physical properties of the solute and solvent.

The chemical aspects determine the polarity of the molecule which can be considered on the generalization that “like dissolves like”.

Solubility Models: Physical properties of solute & solvent

ionization, the extent of which will be greatly influenced by interaction with a solvent.

Ionized species are much more soluble in water than unionized

Unionized species are more soluble in non-polar solvents.

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Ionization constant (pKa)

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Ionization constant (pKa)

Most drug molecules contain ionisable groups, existing as weak acids or weak bases.

Solubility of weak Acids – Most weak acids (e.g. Non-steroidal Antiinflammatory Drugs, NSAID) will dissociate in water:HA H+ + A- (3)

Solubility (S) of weak acids will relate to the solubility of the unionized (SHA) and ionized (SA-) forms according to the equation:

S SHA + SA-

From this equation, dissociation constant is given by:

HA

AHka

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Ionization and solubility

Substituting solubility parameters for concentration coefficients in above equation according to:

[A-] = SA = S-SHA

[HA] =SHA

Will yield:

HA

AHka

HA

HAa

S

SS

H

k

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Ionization and solubility .. Cont.

Taking logarithm:

Hence, if solubility is measured at a point when only the unionized form of the drug is present, S = SHA, the pKa of the drug can be calculated.

With the knowledge of pKa, it is now possible to calculate the solubility at any other pH using the same equation.

HA

HA

S

SSpKapH log

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Application

The equation enables the prediction of the range of pH over which a desired concentration of drug in solution could be achieved.

Conversely, the pH at which a drug in solution will precipitate can be determined.

SHA is otherwise known as the “intrinsic solubility” of the drug and is often given the symbol CO.

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Particle Size Rate of solution is proportional to the

surface area of the solid in contact with the solvent.

Hence, rate of solution can be increased by using finely divided solids with high surface area per unit weight.

The relationship between solubility (Sr) of a particle of radius r and the bulk solubility S∞ is given by:

Where: ρ is density

ɣ is surface free energy

r is particle size,

R is gas constant,

T is temperature, M is molecular weight.

RT

M

rS

S r

2ln Thus solubility increase of 8 %

demands a reduction in particle size from coarse crystal to about 0.1 μm.

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DissolutionNoyes-Whitney equation predicts dissolution rate as a

function of concentration gradient according to the equation:

Cs = concentration of saturated solutionC = concentration in the bulk solutionk = rate constantUnder sink condition, N-W predicts a first order

dissolution process according to the equation;

when concentration in the bulk medium is low.

)( CCkdt

dCS

SkCdt

dC

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Partition (Distribution) Coefficient

When a substance is distributed between two immiscible solvents A & B:

(10)

i.e.

For sparingly soluble substances,

This can be invalidated by deviation from ideal behaviour.

tCoefficienon Distributi BSolvent in ion Concentrat

A Solvent in ion Concentrat

KC

C

B

A

B

A

S

SK

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Deviation from Ideal:

If a solute exists as monomer in solvent A and as dimmer in solvent B, then K is given by:

If dissociation into ions occurs in aqueous layer (B), the degree of dissociation is consider and the applicable equation becomes:

where α is the degree of dissociation in the aqueous phase.

B

A

C

CK

)1(

B

A

C

CK

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Application of Distribution Coefficient in Extraction

Attempt an iterative extraction with bulk and instalment solvent quantities.

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Salt SelectionA good salt should possess the following

desirable characteristics:

Acceptable organoleptic properties

Easy to synthesize

Good flow and compaction properties

Minimal hydration

Salt Selection

Non-toxic

Reproducible particle size & size distribution

Stable

Suitable aqueous solubility & intrinsic dissolution characteristics

Suitable bulk density

Suitable & sharp melting point.

Non-irritating to veins

Non-hygroscopic

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Excipient SelectionDepends on intended

dosage form:

Tablets & capsules:Lubricants, binders,

disintegrants, diluents

Parenteral: Tonicic agents, antioxidants, buffers, preservatives

Rational stability studies –

Wide range of products with multinational market authorization

Evidence of bioequivalence

To generate meaningful results

Avoid stresses that can not be extrapolated to normal conditions of handling

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Xtal Properties

Polymorphism

Monotropic

Enantiotropic

Pseudopolymorphism

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Other Factors Affecting Solubility

Temperature

Common Ion Effect

Solubilization

Crystal Purity

Crystal Properties and Solubility

Polymorphism and Solubility

Pseudopolymorphism & Solubility

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THANK YOU FOR YOUR ATTENTION

BIOPHARMACEUTICAL CONSIDERATION IN DRUG PRODUCT DESIGN