Biopharmaceutical Considerations in Drug

Product Design and In Vitro

Drug Product Performance: Introduction,
biopharmaceutical factors affecting drug
bioavailability

Ameerunnisa
Second semester M Pharm
CPS, Pariyaram, Kannur

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Contents

• Introduction
• Biopharmaceutical factors affecting drug
bioavailability

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Introduction

• Biopharmaceutics is the study of the

physicochemical properties of the drug and the
drug product, in vitro, as it relates to the
bioavailability of the drug, in vivo, and its desired
therapeutic effect.
• Also links the physical and chemical properties of
the drug and the drug product to their clinical
performance, in vivo.
• Bioavailability refers to the measurement of the
rate and extent of active drug that becomes
available at the site of action

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• For the majority of orally administered drugs, the
site of action is within the systemic circulation and
the drug must be absorbed to achieve a
pharmacological response.
• Oral drug absorption involves at least three distinct
steps:
a) drug release or dissolution from the drug product
in the body’s fluids,
b) permeation of the drug across the gastrointestinal
(GI) linings into the systemic circulation, and
c) drug disposition during GI transit (Eg, GI stability,
motility, metabolism, etc.).

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• Additional drug disposition occur in the systemic
circulation leads to reduction in the concentration
of drug available to the target tissues.
• A drug product may also be designed to deliver the
drug directly to the site of action before reaching
the systemic circulation, which is often termed
locally acting drug.
• Some examples of products in this class include
ophthalmic, pulmonary, and nasal drug products.

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• Bioavailability strongly influenced by
physicochemical properties of the drug and drug
product, the rate and extent of drug release from
the drug product, and permeation at the target site
(Eg, skin physiology compared with that in the
cornea).
• Regardless of the intended site of drug action,
Biopharmaceutics aims to balance the amount and
extent of drug delivered from the drug product to
achieve optimal therapeutic efficacy and safety for
the patient.

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 BIOPHARMACEUTIC FACTORS AND
RATIONALE FOR DRUG PRODUCT DESIGN

• In broad terms, the factors affecting drug bioavailability

may be related to the formulation of the drug product or
the biological constraints of the patient.
• Drugs are not usually given as pure chemical drug
substances, but are formulated into finished dosage
forms (i.e., drug products). These drug products include
the active drug substance combined with selected
additional ingredients (excipients) that make up the
dosage form.
• Although excipients are considered inert with respect to
Pharmacodynamic activity, excipients are important in
the manufacture of the drug product and provide
functionality to the drug product with respect to drug
release and dissolution

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• Some common drug products include liquids,
tablets, capsules, injectable, suppositories,
transdermal systems, and topical creams and
ointments.
• These drug products are then given to patients to
achieve a specific therapeutic objective.
• The design of the dosage form, the formulation of
the drug product, and the manufacturing process
require a thorough understanding of the
Biopharmaceutics principles of drug delivery.

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• Considerations in the design of a drug product to
deliver the active drug with the desired
bioavailability characteristics and therapeutic
objectives include:
• (1) the physicochemical properties of the drug
molecule,
• (2) the finished dosage form (Eg, tablet, capsule,
etc.),
• (3) the nature of the excipients in the drug product,
(4) the method of manufacturing, and
• (5) the route of drug administration.

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• Biopharmaceutics allows for the rational design of drug
products and is based on:
• The physical and chemical properties of the drug
substance.
• The route of drug administration, including the
anatomic and physiologic nature of the application site
(Eg, oral, topical, injectable, implant, transdermal patch,
etc.)
• Desired Pharmacodynamic effect (Eg, immediate or
prolonged activity)
• Toxicological properties of the drug
• Safety of excipients
• Effect of excipients and dosage form on drug product
performance
• Manufacturing processes

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• Some drugs are intended for topical or local
therapeutic action at the site of administration.
• Drugs intended for local activity are designed to have
a direct Pharmacodynamic action without affecting
other body organs, and systemic drug absorption is
often undesirable.
• Locally acting drugs may be administered orally (Eg,
local GI effect) or applied topically to the skin, nose,
eye, mucous membranes, buccal cavity, throat, or
rectum
• May also be given intravaginal, into the urethral
tract, or intranasal; inhaled into the lungs; and
applied into the ear or on the eye.
• Examples: anti-infectives, antifungals, local
anaesthetics, antacids, astringents, vasoconstrictors,
antihistamines, bronchodilators, and corticosteroids
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• Each route of drug administration presents special
biopharmaceutical considerations in drug product
design.
• For example, An eye medication requires special
considerations for formulation pH, isotonicity,
sterility, the need to minimize local irritation to the
cornea, potential for drug loss from draining by
tears, and residual systemic drug absorption.

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• For a drug administered by an extravascular route
(Eg, intramuscular injection), local irritation, drug
dissolution at the application site, and drug
absorption from the intramuscular site are some of
the factors that must be considered.
• Systemic absorption after extravascular
administration is influenced by the anatomic and
physiologic properties of the site and the
physicochemical properties of the drug and the
drug product.
• On the other hand, if the drug is given by an
intravascular route (Eg, IV administration),
systemic drug absorption is considered complete or
100% bioavailable, because the drug is placed
directly into the general circulation.
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• A drug product may also be designed as a
combination drug/device product to allow the drug
formulation to be used in conjunction with a
specialized medical device or packaging component.
• For example, a drug solution or suspension may be
formulated to work with a nebulizer or metered-dose
inhaler for administration into the lungs.
• Both the physical characteristics of the nebulizer
and the formulation of the drug product can
influence the droplet particle size and its distribution,
the spray pattern, and plume geometry of the emitted
dose, which may affect its in vivo performance.

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• Drug-polymer coating may be applied to a cardiac
stent for local delivery of anti-proliferative drugs
directly to diseased tissue during percutaneous
coronary intervention to treat a blocked artery.
• By choosing the route of drug administration
carefully and properly designing the drug product,
the bioavailability of the active drug can be varied
from rapid and complete absorption to a slow,
sustained rate of absorption or even virtually no
absorption, depending on the therapeutic objective.
• Once the drug is systemically absorbed, normal
physiologic processes for drug distribution and
elimination occur.

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• These intrinsic factors may also be influenced by
the specific formulation of the drug (Eg,
encapsulated drug in liposome or microspheres
may change the drug distribution and systemic
clearance).
• The rate of drug release from the product and the
rate and extent of drug absorption are important in
determining the onset, intensity, and duration of
drug action.

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• Biopharmaceutical considerations often determine
the ultimate dose and dosage form of a drug
product.
• For example, the dosage form for a locally acting
drug such as a topical drug product (Eg, ointment)
is often expressed in concentration or as a
percentage of the active drug in the formulation
(Eg, 0.5% hydrocortisone ointment).
• The amount of drug applied is not specified
because the concentration of the drug at the active
site relates to the Pharmacodynamic action.

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• Biopharmaceutics studies must be performed to
ensure that the drug product does not irritate,
cause an allergic response, or allow significant
systemic drug absorption.
• In contrast, the dosage form for a systemically
acting drug is expressed in terms of mass, such as
milligrams or grams.
• In this case, the dose is based on the amount of
drug that is absorbed systemically and dissolved in
an apparent volume of distribution to produce a
desired drug concentration at the target site.

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• The therapeutic dose may also be adjusted based
on the weight or surface area of the patient, to
account for the differences in the apparent volume
of distribution, which is expressed as mass per
unit of body weight (mg/kg) or mass per unit of
body surface area (mg/m²).
• For many commercial drug products, the dose is
determined based on average body weight and may
be available in several dose strengths, such as 10-
mg, 5-mg, and 2.5-mg tablets, to accommodate
differences in body weight and possibly to titrate
the dose in the patient.

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 Biopharmaceutical factors affecting drug
bioavailability

• Includes factors relating to the physicochemical

properties of the drug, and dosage form characteristics
and Pharmaceutical ingredients.
 Physicochemical Properties Of Drug Substances
• Drug solubility and dissolution rate
• Particle size and effective surface area
• Polymorphism and amorphism
• Pseudo polymorphism (hydrates/solvates)
• Salt form of the drug
• Lipophilicity of the drug
• pKa of the drug and pH
• Drug stability

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 Dosage Form Characteristics and Pharmaceutical
Ingredients
• Disintegration time (tablets/capsules)
• Dissolution time
• Manufacturing variables
• Pharmaceutical ingredients (excipients/adjuvants)
• Nature and type of dosage form
• Product age and storage conditions

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REFERENCE

1. Leon Sharjel, Andrew B.C. Yu, Applied

Biopharmaceutics and Pharmacokinetics, 7th
Edition, page Number:415-418.
2. D.M. Brahmankar, Sunil B. Jaiswal,
Biopharmaceutics And Pharmacokinetics, A
Treatise, Vallabh Prakashan Publishers, 2005,
Page Number:18.

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