Principles of Dosage Forms Design

Dr.Saad.M.YACOUB

PharmaceuticaI industry(Lecture 1)

Principles of Dosage Forms Design

OIntroduction to pharmaceutics

ODevelopment of new drugs and dosage

forms

ODosage forms and why we need them

OFactors that influence dosage form design

.1Biopharmaceutical considerations

.2Drug factors

.3Therapeutic considerations

Pharmaceutics:

is the general area of study

concerned with the formulation,

manufacture, stability, and

effectiveness of pharmaceutical

dosage forms.

Introduction: Pharmaceutical Dosage Form development

Drug

discovery

Pre-

formulation

Formulation of

Pharmaceutical

dosage forms

Stage 1

Stage 2

Stage 3

Drug’s life stages from discovery to market launching

6.5 years 7 years 1.5 years

Preclinical studies Clinical trials

(Experiments on humans)

FDA

review

Post-

market

studies

Starts when a new

chemical entity NCE is

obtained from:

• Chemical synthesis

• Isolation from natural

sources

This stage include the

study of:

• Physicochemical

properties (pre-

formulation)

• Pharmacology and

toxicology studies,

performed on animals

Consists of three phases:

Phase I: test the drug candidate in a small

group of healthy human volunteers to

ensure it is safe

Phase II: test the drug candidate in a small

group of patients for evidence of efficacy

and determination

of dose, in parallel with longer term

nonclinical safety testing in animals.

Phase III: define the marketable dosage

form of the drug candidate or “drug product”

and test the potential drug product in a

large group of patients

for evidence of safety and efficacy.

Phase IV

III

IV

Pharmaceutical Dosage Form: Drug + ? Drugs are rarely

administered as pure

chemical substances

alone and are almost

always given as

formulated

preparations or

medicines through the

use of appropriate

additives or excipients

in the formulations

Excipients/additives

+

Final product

Formulation

Active Pharmaceutical

Ingredient (API)

The pharmaceutical ingredients (excipeints)

may:

Drug Substance

solubilize

thicken

dilute emulsify

stabilize

preserve color

flavor

The drug and pharmaceutical materials (excipients) must be compatible

with one another to produce a drug product that is stable, efficacious,

attractive, easy to administer, and safe.

Why do we need dosage forms?

Why do we need dosage forms?

Dosage forms are needed for the following reasons:

1. To provide a

mechanism for

safe and

convenient

delivery of

accurate

dosage,

especially for

potent drugs

(drugs with low

dosage;e.g.

Ethinyl

estradiol)

Why do we need dosage forms?

.2To protect the drug substance from the destructive

influences of atmospheric oxygen or humidity (coated

tablets, sealed ampules)

.3To protect the drug substance from the destructive

influence of gastric acid after oral administration (enteric-

coated tablets)

.4To conceal the bitter, salty, or offensive taste or odor of a

drug substance (capsules, coated tablets, flavored syrups)

.5To provide liquid preparations of substances that are

either insoluble or unstable in the desired vehicle

(suspensions)

.6To provide clear liquid dosage forms of substances

(syrups, solutions)

.7To provide rate-controlled drug action (various controlled-

release tablets, capsules, and suspensions)

.8To provide optimal drug action from topical

administration sites (ointments, creams, transdermal

patches, and ophthalmic, ear, and nasal preparations)

.9To provide for insertion of a drug into one of the body's

orifices (rectal or vaginal suppositories)

.10To provide for placement of drugs directly in the

bloodstream or body tissues (injections)

.11To provide for optimal drug action through inhalation

therapy (inhalants and inhalation aerosols)

Pharmaceutical dosage forms and their prevalence of use

Dosage Form %

Tablets 46

Oral liquids 16

Capsules 15

Injections 13

suppositories 3

Topical preparations 3

Ophthalmic preparations 2

Aerosols 1

others 1

Dosage forms available for routs of administration

Administration route Dosage forms

Oral Solutions, suspensions, emulsions, gels,

powders, granules, capsules, tablets

Rectal Suppositories, ointments, creams,

powders, solutions

Topical Ointments, creams, pastes, lotions, gels,

topical aerosols

Parenteral Injections Solution, suspension, emulsions, implants

Respiratory Aerosols inhalations, sprays, gases

Nasal Solutions, inhalations

Eye Solutions, ointments, creams

Ear Solutions, suspensions, ointments, creams

Routes of Administration TERM SITE

Oral Mouth

Peroral Gastrointestinal

tract via mouth

Sublingual Under the tongue

Parenteral Other than the

gastrointestinal

tract (by injection)

Intravenous Vein

Intraarterial Artery

Intracardiac Heart

Intraspinal or intrathecal

Spine

Intraosseous Bone

Intraarticular Joint

Intrasynovial Joint fluid area

TERM SITE

Intracutaneous, intradermal

Skin

Subcutaneous Beneath the skin

Intramuscular Muscle

Epicutaneous (topical)

Skin surface

Transdermal Skin surface

Conjunctival Conjunctiva

Intraocular Eye

Intranasal Nose

Aural Ear

Intrarespiratory Lung

Rectal Rectum

Vaginal Vagina

Design of the appropriate dosage form depends on

.1Biopharmaceutical considerations, including factors

affecting the absorption of the drug substance from

different administration routes.

.2Drug factors, such as the physical and chemical

properties of the drug substance.

.3Therapeutic considerations, including consideration of the

clinical indication to be treated and patient factors.

1- Biopharmaceutical aspects of the dosage form design

OBiopharmaceutics is: the study of the relationship between

the physical, chemical and biological sciences applied to

drugs, dosage forms and drug action.

OThe biologic response to a drug is the result of an interaction

between the drug substance and functionally important cell

receptors or enzyme systems. The response is due to an

alteration in the biologic processes that were present prior to

the drug's administration. The magnitude of the response is

related to the concentration of the drug achieved at the site of

its action.

OThis drug concentration depends on:

OThe dosage of the drug administered (libration).

OThe extent of its absorption and distribution to the site.

OThe rate and extent of its elimination from the body (metabolism

and excretion).

OBiopharmaceutics is very much connected

with pharmacokinetics, which is the study of

the kinetics of absorption, distribution,

metabolism, and excretion (ADME) of drugs

and their corresponding pharmacologic,

therapeutic, or toxic effects in animals and

man.

OBiopharmaceutics focuses on the study of

factors that influence drug absorption

including formulation, biological factors,

route of administration.

OOnce absorbed, the drug can exert a

therapeutic effect.

Bioavailability OBioavailability is a measurement of the rate and extent (amount) of

systemic absorption of the therapeutically active drug.

OGraphically, bioavailability of a drug is portrayed by a concentration

time curve of the administered drug in an appropriate tissue system,

for example plasma.

OFormulation factors can influence their therapeutic performance

(bioavailability).

Important Parameters:

AUC: Are under the curve

Cmax: Peak height concentration

Tmax: Time of peak concentration

ODuring the product development stages of a proposed drug

product, pharmaceutical manufacturers employ

bioavailability studies to compare different formulations of

the drug substance to ascertain which one allows the most

desirable absorption pattern.

OLater bioavailability studies may be used to compare the

availability of the drug substance in different production

batches.

OThey may also be used to compare the availability of the

drug substance in different dosage forms (e.g., tablets,

capsules, elixirs), or in the same dosage form produced by

different (competing) manufacturers.

Bioequivalence of drug products

OBioequivalent drug products are pharmaceutical

equivalents or pharmaceutical alternatives

whose rate and extent of absorption do not show

a significant difference when administered at

the same molar dose of the therapeutic material

under similar experimental conditions, either

single dose or multiple dose.

O The rate and extent to which a drug in a dosage

form becomes available for biologic absorption

or use depends in great measure on the

materials in the formulation and on the method

of manufacture. Thus, the same drug when

formulated in different dosage forms may be

found to possess different bioavailability

characteristics and hence exhibit different

clinical effectiveness.

OThere have also been variations in the

bioavailability of different batches of drug

products from the same manufacturer.

OComparing the blood levels of drug achieved after

oral administration of equal doses of formulations A

formulation A will in the following figure: and B

achieve the required blood levels of drug to produce

the desired pharmacologic effect, whereas

formulation B will not.

: minimum effective concentration

OThe following figure shows equal doses of

toxic effects the two formulations result in

desired but only produced by formulation A

. The objective in the effects by formulation B

individual dosing of a patient is to achieve

the MEC but not the MTC.

: minimum toxic concentration

: minimum effective concentration

Therapeutic range

OThe size of the dose influences the blood level

concentration and Cmax for that substance.

OThe following figure displays the influence of dose on the

blood level–time curve for a drug administered by the same

route and in the same dosage form.

Ois proportionately higher maxthe CAs the dose increases,

, is the same for maxand the AUC proportionately greater. T

each dose.

OWhen the drug is administered from dosage forms designed

to deliver via the buccal, respiratory, rectal, intramuscular or

subcutaneous routes, it passes directly into the blood-

stream from absorbing tissues.

OThe intravenous route is the most direct of all (no absorbing

site).

OWhen delivered by the oral route the onset of drug action

will be delayed because of the required transit time in the

gastrointestinal tract, and the absorption process.

Time of onset of action for dosage forms

example: tablets

absorption

Drug in blood

Disintegration

Granules

Drug in solution

Onset of action

Dissolution Dissolution

Time of onset of action for dosage forms

OAn individual drug substance may be

formulated into multiple dosage forms that

result in different drug absorption rates and

times of onset, peak, and duration of action.

OAn example is the drug nitroglycerin that is

formulated in various dosage forms. The

sublingual, intravenous, and buccal forms

present extremely rapid onsets of action,

whereas the oral (swallowed), topical

ointment, and topical patch present slower

onsets of action but greater durations of

action. The patch provides the longest

duration of action, up to 24 hours following

application of a single patch to the skin. The

transdermal nitroglycerin patch allows a

single daily dose, whereas the other forms

require multiple dosing to maintain drug

levels within the therapeutic window.

Blood level curves of nitroglycerin following

administration of dosage forms by various routes

Dosage and kinetics of nitroglycerin in various dosage forms

Nitro-glycerin,

Dosage Form

Usual Dose

(Mg)

Onset Of Action

(Min)

Peak Action

(Min) Duration

Sublingual 0.3-0.8 2-5 4-8 10-30 min

Buccal 1-3 2-5 4-10 30-300 min

Oral 6.5-19.5 20-45 45-120 2-6 hours

Ointment (2%) 0.5-2 inches 15-60 30-120 3-8 hours

Patches

(Discs) 5-10 30-60 60-180

Up to 24

hours

Time of onset of action for dosage forms

Time of onset of action

Dosage forms

Second i.v. injections

Minutes i.m. and s.c. injections, buccal

tablets, aerosols

Minutes to hours suspensions, powders, tablets,

modified-release

Several hours Enteric-coated formulation

Days Depot injections, implants

Varies Topical preparations

2- Drug Factors in dosage form design

OParticle size and surface area

OSolubility

ODissolution

OPartition coefficient and pKa

OCrystal properties: polymorphism

OThese factors will be covered under

solubility and dissolution

3- Therapeutic considerations in dosage

form design OThe principal objective of dosage form design is to

achieve a predictable therapeutic response to a

drug included in a formulation.

OFactors need to be considered:

.1The nature of the disease.

.2The need for systemic or local therapy.

.3The duration of action required.

.4Whether the drug will be used in emergency situations.

.5The age of the patient.

The nature of the disease

It is necessary to relate the drug substance to the clinical

indication being treated before the correct combination of drug

and dosage form can be made, as each disease or illness often

requires a specific type of drug therapy.

The need for systemic or local therapy

OOne of the fundamental considerations in dosage form design is

whether the drug is intended for local or systemic effects.

OLocal effects are achieved by direct application of the drug to the

desired site of action, such as the eye, nose, or skin.

OSystemic effects result from the entrance of the drug into the

circulatory system and transport to the cellular site of its action.

For systemic effects, a drug may be placed directly in the blood

stream via intravenous injection or absorbed into the venous

circulation following oral or other route of administration.

The age of the patient also plays an

important role:

OChildren can have difficulty in swallowing

solid dosage forms, and for this reason

many oral preparations are prepared as

pleasantly flavoured syrups or mixtures.

Therapeutic considerations in dosage form design OA single drug substance is usually prepared into a number of

dosage forms and for administration by alternative delivery

routes to maximize therapeutic response to satisfy both the

particular preferences of the patient or physician and the

specific needs of a certain clinical situation.

OE.g., many asthmatic patients use inhalations for rapid

emergency relief, and oral products for chronic therapy.

OE.g., nitroglycerin sublingual tablets are used for urgent relief

from angina pectoris, due to rapid drug absorption from the

buccal cavity.

Other considerations

OSome other features are required to ensure dosage form quality, include :

.1 chemical and physical stability

.2 suitable preservation against microbial contamination

.3 uniformity of dose of drug

.4 acceptability to users including both prescriber and patient

.5 suitable packaging and labelling