Chapter 5

Dosage Form Design:

Biopharmaceutical and
Pharmacokinetic
Considerations
 Biopharmaceutic Considerations

Biopharmaceutics is the area of the study embracing the

relationship between physical, chemical and biological sciences
as they apply to drug and to drug action
ADME

Bioavailability - describe the rate and extent to which an

active drug ingredient or therapeutic moiety is absorbed from a
drug product and becomes available at the site of the
drug action.
Bioequivalence - refers to the comparison of bioavailabilities of
different formulations, drug products, or batches of the
same drug product.
Bioavailability Data are used to
determine:
1. The amount or proportion of drug absorbed
from a formulation or dosage form
2. The rate at which the drug was absorbed
3. The duration of the drugs presence in the
biologic fluid or tissue; and, when correlated
with patient response
4. The relationship between drug blood levels
and clinical efficacy and toxicity
Terms Used To define The Type or Level Of
Equivalency Between Drug Products

Pharmaceutical Equivalents -are drug products that contain

identical amounts of the identical active ingredient. Example:
the same salt or ester of the same therapeutic moiety

Pharmaceutical Alternatives - are drug products that contain

the identical therapeutic moiety, or its precursor, but not
necessarily in the same amount or dosage form or as the same salt or
ester.

Bioequivalent 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 moiety under similar
experimental conditions, either single dose or multiple dose.
Therapeutic Equivalent - has been used to indicate
pharmaceutical equivalent which, when administered
to the same individuals in the same dosage
regimens, will provide essentially the same
therapeutic effect.
The most common experimental plan to compare
the bioavailability of two drug products is the simple
crossover design study.
(12 to 14 individuals, males between 18 to 40
years, same height and weight)
How A Drug Passes Through The Body
1. Absorption = The site at which a drug enters
the body affects its rates of absorption
a. Skin c. Digestive Tract
b. Lungs d. Bloodstream
2. Distribution = Most drugs enter the
bloodstream; many are then distributed to
cells of various organs
a. Bone e. Glands
b. Nerves f. Heart
c. Muscles g. Cells
d. Brain h. Other organs
3. Metabolism = A drug is partially broken
down, usually in the liver, before or after
distribution
a. Liver
4. Elimination = Finally, a drug is eliminated,
mainly via kidneys, but also in stools
and tears or through breathing
a. Breast milk c. Tears
b. Saliva d. Sweat
APPROVAL REQUIREMENTS FOR GENERIC DRUG
PRODUCTS

1. Contain the same active ingredients as the pioneer

drug (inert ingredient may vary)
2. Be identical in strength, dosage form, and route of
administration
3. Have the same indications and precautions for use and
other labeling instructions
4. Be bioequivalent
5. Meet the same batch to batch requirements for
identity, strength, purity, and quality
6. Be manufactured under the same strict standards of
FDAs CGMP regulations as required for pioneer
products.
Some Factors Which Can influence The
Bioavailability Of Orally Administered
Drugs

I. Drug Substance Physiochemical

Properties
II. Pharmaceutical Ingredients and
Dosage Form Characteristics
III. Physiologic Factors and Patient
Characteristics
Some Factors Which Can influence The
Bioavailability Of Orally Administered Drugs

I. Drug Substance Physiochemical

Properties
A. Particle Size
B. Crystalline or Amorphous Form
C. Salt Form
D. Hydration
E. Lipid/Water Solubility
F. pH and pKa
Some Factors Which Can influence The
Bioavailability Of Orally Administered
Drugs

II. Pharmaceutic Ingredients and Dosage Form

Characteristics
A. Pharmaceutical Ingredients
1. Fillers 7. Surface Active Agents
2. Binders 8. Flavoring Agents
3. Coatings 9. Coloring Agents
4. Disintegrating Agents 10. Preservative Agents
5. Lubricants 11. Stabilizing Agents
6. Suspending Agents
Some Factors Which Can influence The Bioavailability Of Orally
Administered Drugs
B. Disintegration Rate (Tablets)
C. Dissolution Time of Drug in Dosage Form
D. Product Age and storage Conditions
III. Physiologic Factors and Patient Characteristics
A. Gastric Emptying Time
B. Intestinal Transit Time
C. Gastrointestinal Abnormality or Pathologic Condition
D. Gastric Contents
1. Food
2. Other Drugs
3. Fluid
E. Gastrointestinal pH
F. Drug Metabolism (gut and during first passage through liver)
Examples Of Drugs That Undergo Significant Liver Metabolism and
Exhibit Low Bioavailability when Administered by First-pass Routes

Drug Class Examples

Analgesics Aspirin, meperidine, Pentazocine
Propoxyphene
Antianginal Nitroglycerin
Antiarrhythmics Lidocaine
Beta-adrenergic Labetolol, Metoprolol, Propranolol
blockers
Calcium channel Verapamil
blockers
Sympathomimetic Isoproterenol
amines
Tricyclic Desipramine, Imipramine,
antidepressants Nortriptyline
Several Examples of Biotransformations
occurring within the body are as follows:

1. Acetaminophen Conjugation Acetaminophen glucuronide

(active) (inactive)
2. Amoxapine Oxidation 8-hydroxy-amoxaphine
(active) (inactive)
3. Procainamide Hydrolysis p-Aminobenzoic acid
(active) (inactive)
4. Nitroglycerin reduction 1-2 and 1-3 dinitroglycerol
(active) (inactive)
Some compound under full, partial no
biotransformation
1. Lisinopril (zestril) - does not go metabolism,
excreted unchanged
2. Verapamil (Calan) - 12 metanolites, the
most prevalent is norverapamil
3. Diltiazem (Cardizem) - partially metabolized
to desacetyldiltiazem
4. Indomethacin (Indocin) - metabolized in part
to desmethyl, desbenzoyl, and
desmethylbenzoyl
5. Propoxypehene napsylate (Darvon N) -
metabolized to norpropoxyphene
 Routes Of Drug Administration
TERM SITE
oral mouth
peroral (per os, p.o.) gastrointestinal tract via mouth
sublingual under the tongue
parenteral other than GIT (by injection)
intravenous vein
intraarterial artery
intracardiac heart
intraspinal/intrathecal spine
intraosseous bone
intraarticular joint
intrasynovial joint-fluid area
intracutaneous/intradermal skin
subcutaneous beneath the skin
intramuscular muscle
 Routes Of Drug Administration

TERM SITE

epicutaneous (topical) skin surface

transdermal skin surface
conjunctival conjunctiva
intraocular eye
intranasal nose
aural ear
intrarespiratory lung
rectal rectum
vaginal vagina
urethral urethra
 DOSAGE FORM/DRUG DELIVERY SYSTEM APPLICATION

Route Of Administration Primary Dosage Forms

oral tablets, capsules, solutions, syrups

elixirs, suspensions,magmas, gels
and powders
sublingual tablets, troches or lozenges
parenteral solutions, suspensions
epicutaneous/transdermal ointments, creams, infusion pumps
pastes, plasters, powders, aerosols
lotions, transdermal patches, discs
conjunctival contact lens inserts, ointments
intraocular/intraaural solutions, suspensions
intranasal solutions, sprays, inhalants, oint.
Intrarespiratory aerosols
 DOSAGE FORM/DRUG DELIVERY SYSTEM APPLICATION

Route Of Administration Primary Dosage Forms

rectal solutions, ointments, suppositories

vaginal solutions, ointments, emulsion foams,
tablets, inserts, suppositories, sponge
urethral solutions, suppositories
Factors That Determine A Dosage Regimen
Activity, Toxicity Pharmacoknetics
Minimum therapeutic dose Absorption
Toxic Dose Distribution
Therapeutic index Metabolism
Side effects Dosage Excretion
Regimen
Dose-response relationship

Clinical Factors Other Factors

Clinical State of patient Management of Therapy
Age, weight, urine pH Multiple drug therapy Tolerance-dependence
Condition being treated Convenience of regimen Pharmacogenetics-
idiosyncrasy
Existence of other disease states Compliance of patient Drug interactions