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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