PharDose Lec [Monthly Exam]

Introduction to Drugs and Pharmacy

Drug

Agent intended for use in the diagnosis, mitigation,

treatment, cure or prevention of disease in humans or
animals (FDCA, 1938)
Pharmacology

Nature and mechanism of action of the drug on the

biologic system
[The Heritage of Pharmacy]

Practice of drug therapy was from experience

Early people believed illnesses were caused by demons or

evil spirits in the body

People performed incantations, the application of noisome

materials and the administration of specific herbs or plant
materials
The First Apothecary

Pharmakon (Gk.): charm or drug that can be used for

good or for evil

Knowledge of drug and their application to disease has

always meant power
Early Drugs
Ebers Papyrus

60 ft. long, a foot wide

16th century BC

Founded by Georg Ebers

800 formulas, 700 drugs

Introduction of the Scientific Viewpoint
Hippocrates

Introduction of scientific pharmacy and medicine

Rationalized medicine, systemized medical knowledge, and

put the practice of medicine on a high ethical plane

Hippocratic oath of ethical behavior

Pharmakon beame for good only

Father of Medicine
Dioscorides

First to deal with Botany

De Materia Medica
Claudius Galen

Galenic pharmacy

Galens Cerate, cold cream

Emperor Fredrick II

Had a decree, which separated pharmacy from medicine

in 1240 AD
Aureolus Theophrastus Bombastus von Hohenheim

Aka Paracelsus

Transformation of pharmacy from a profession based

primarily on botanical science to one based on chemical
science
Early Research
Karl Wilhelm Scheele

Discovered lactic acid, citric acid, ocalic acid, tartaric

acid, arsenic acid and oxygen

Identified glycerin

Invented new methods of preparing calomel and benzoic

acid
Friedrich Sertuner

Isolation of morphine from opium

Joseph Caventou and Joseph Pelletier

Isolated quinine and cinchonine from chinchona

Isolated strychnine and brucine from nux vomica

Joseph Pelletier and Pierre Robiquet

Isolated caffeine
Pierre Robiquet

Separated codeine from opium

[Drug Standards]
The United States Pharmacopeia and the National Formulary
Pharmacopeia

Pharmakon: drug

Poiein: make

Any recipe or formula or other standars required to make or

prepare drug
Lititz Pharmacopeia

First American pharmacopeia

Published in 1778 at Lititz, Pennsylvania

32-page booklet, 84 internal and 16 external drugs and

preaparations
Lyman Spalding

Father of USP

Proposed for a convention in 4 geographic districts

United States Pharmacopeial Convention

Revise USP every 10 years

1940 meeting: revise the USP every 5 years

1830 and 1840: pharmacists were invited

1850: full membership of pharmacists

USP

First published on December 15, 1820 in English and Latin

217 drugs
American Pharmaceutical Association (APhA)

1852
National Formulary of Unofficial Preparations

Formulary containing many f the popular drugs and

formulas denied administration to the USP

Changed to National Formulary on June 30, 1906 when

President Theodore Roosevelt signed into law
USP XX and NF XV

USP: volume; NF: sections

USP 23-NF 18
o
Became official in 1995
USP Pharmacists Pharmacopeia

To address the needs of pharmacist practioners

Products

Manufactured drugs
Preparations

Compounded drugs
USP and NF Monographs

Adopt standards for drug substances, pharmaceutical

ingredients and dosage forms reflecting the best in the
current practices of medicine and pharmacy

Official parts of a monograph

o
Official title (generic or nonproprietary name)
o
Graphic or structural formula
o
Empirical formula
o
Molecular weight
o
Established chemical names
o
Chemical Abstracts Service (CAS) registry number

USP Drug Research and Testing Laboratory

o
Provides direct laboratory assistance to the USP
and NF
o
Main functions: evaluation of USP reference
standards and evaluation and development of
analytical methods
Other Pharmacopeias
Homeopathic Pharmacopeia of the United States (HPUS)

Used by law enforcement agencies that must ensure the

quality of homeopathic drugs

Homeopathy
o
Coined by Samuel Hahnemann
o
Homoios = similar
o
Pathos = disease
o
Law of similars, like cures like
International Pharmacopeia (IP)

Published by WHO

Intended as a recommendation to a national

pharmacopeial revision committees to modify their
pharmacopeias
International Organization for Standardization

International consortium of representative bodies

constituted to develop and promote uniform or harmonized
international standards

Quality assurance (QA), quality control (QC), detectin of

defective products, quality management (WM)
[Drug Regulation Control]
Food and Drug Act of 1906

First federal law in the US designed to regulate drug

products

Required drugs marketed interstate to comply with their

caimed standards
[The Federal Food, Drug and Cosmetic Act of 1938]

Prohibits the distribution and use of any new drug or drug

product without prior filing of a new drug application (NDA)
and approval of the FDA

Required drugs to be safe for human use but did not require
it to be efficacious
Durham-Humphrey Amendment of 1952

Prescriptions for legend drugs may not be refilled without

the consent of the prescriber

Refill status was further regulated with the passage of the

Drug Abuse Amendments of 1965 and Comprehensive Drug
Abuse Prevention and Control of 1970
Kefauver-Harris Amendments of 1962

To ensure a grater degree of safety for approved drugs and

manufacturers were now required to prove a drug to be
both safe and effective

Sponsor of a new drug is now required to file an

investigational new-drug application (IND) before it can be
tested on humans
Comprehensive Drug Abuse Prevention and Control Act of 1970

To consolidate and codify authority over drugs of abuse in

a single statue

Schedule I
o
Drugs with no accepted medical use
o
Substances with high potential of abuse
o
Heroin, LSD, mescaline, peyote, methaqualone,
marijuana

Schedule II
o
Drugs with accepted medical uses and a high
potential for abuse, may lead to severe
psychologic or physical dependence
o
Morphine, cocaine, methamphetamine,
amobarbital

Schedule III
o
If abused, it may lead to moderate psychologic or
physical dependence
o
Specified quantities of codeine, hydrocodone

Schedule IV
o
Low potential for abuse, may lead to low
psychologic or physical dependence
o
Specified quantities of diphenoxin, diazepam,
oxazepam

Schedule V
o
Specified quantities of dihydrocodeine,
diphenoxylate
FDA Pregnancy Categories
Category X

Strongest

May be implicated as a teratogen and the risk benefit ratio

does not support the use of the drug
Category A

No risk in to the fetus

Category B

No risk to animal reproduction studies

No adequate and well-controlled studies in pregnant

women
Category C

Animal reproduction studies have shown an adverse effect

on the fetus
Category D

There is positive evidence of human fetal risk

Black Box Warning

Strongest labeling requirements for high-risk medicines

All anti-depressant medications

Most serios warning

Ads are not allowed

Drug Listing Act of 1972

Enacted to provide the FDA with the legislative authority to

compile a list of marketed drugs to assist in the enforcement
of federal laws
Drug Price Competition and Patent Term Restoration Act of 1984

Changes to speed the FDA approval of generic drugs and

the extension of patient life for innovative new drugs
Prescription Drug Marketing Act of 1987

Established new safeguards on the integrity if the nations

supply of prescription drug

Dingell Bill or Drug Diversion Act

Intended to reduce the risks of adultered, misbranded,

repackaged or mislabeled drugs entering the legitimate
marketplace through secondary sources

Reimportation, Sales restrictions, Distribution of samples,

Wholesale distributors
Dietary Supplement Health and Education Act of 1994

Forbids manufacturers or distributors of products (vitamins,

supplements) to make any advertising or labeling clams
that the use of the product can prevent or cure a specific
disease
The FDA and the Food and Drug Administration Modernization Act of
1997

FDAs mission: to protect the public health against risks

associated with the production, distribution and sale of
food and food additives, human drugs and biologicals

Enacted to streamline FDA policies and to codify manu of

the agencys newer regulations

Center for the Evaluation and Research (CDER) and Center

for Biologics Evaluation and Research (CBER)
Federal Register (FR) and Code of Federal Regulations (CFR)

Provide the most definitive information on federal laws and

regulations pertaining to drugs
Drug Product Recall

A drug may be recalled if it presents a threat or potential

threat to consumer safety

Voluntary recall: manufacturer recalls the drug

Class I
o
Will cause serious adverse health consequences or
death

Class II
o
May cause temporary or medically reversible
adverse health consequences

Class III
o
Not likely to cause adverse health consequences
[The Pharmacists Contemporary Role]
The Mission of Pharmacy

to serve society as the profession responsible for the

appropriate use of medications, devices and services to
achieve optimal therapeutic outcomes

Pharmacy is the health profession that concerns itself with

the knowledge system that results in the discovery,
development and use of medication and medication
information in the care of patients.

Medications
o
Refers to legend and nonlegend agents used in
the diagnosis treatment, prevention and cure of
disease

Devices
o
Equipment, process, biotechnological entities,
diagnostic agents

Services
o
Patient, health professional and public education
services

Definition of Pharmaceutical Care

component of pharmacy practice which entails the

direct interaction of the pharmacist with the patient for the
purpose of caring for that patients drug-related needs

Patient-centered

Goal: to optimize the patients health-related quality of life

and achieve positive clinical outcomes

Pharmacists should be
o
A problem solver
o
Able to achieve health outcomes through
effective medication use
o
Able to collaborate with others
o
Life-long learner

The Omnibus Budget Reconciliation Act of 1990

Established a requirement for each state to develop and

mandate DUR programs to improve the quality of
pharmaceutical care

Required patient counseling

New Drug Development and Approval Process

Treatment IND

For orphan drugs

Targeted to patients who have rare diseases

Supplemental New Drug Application (SNDA)

For certain changes in a previously approved NDA, such as

labeling or formulation change

Abbreviated New Drug Application (ANDA)

Used to gain approval to market a duplicate of a product

Biologics Licensing Application (BLA)

Biologic products (human blood products and vaccines)

Investigational New Animal Drug Application (INADA)
New Animal Drug Application (NADA)
Supplemental New Animal Drug Application (SNADA)
[Drug Discovery and Drug Design]
Alexander Fleming

Penicillin
International Conference on Harmonization

Fosters multinational drug approvals

Sources of New Drugs
Serendipity

By accident
Reserpine

Tranquilizer and hypotensive agent

Rauwolfia serpentine
Periwinkle

Vinca rosea

Treatment of diabetes mellitus

Antitumor capabilities
Paclitaxel

Ovarian cancer
Semisynthetic drugs

New structures from modified plant constituents

Recombinant DNA

Most fundamental

Genetic materials can be transplanted from higher species

into a lowly bacterium (gene-splicing)

Manipulation of proteins within the cells of lower animals

Human insulin, human growth hormone, hep B vaccine,

epoetinalpha and interferon
Recombinant DNA

Manipulation of proteins within the cells of higher animals

Used in home pregnancy testing products

Human Gene Therapy

Used to prevent, treat, cure, diagnose or mitigate human

diseases caused by genetic disorders

AT CG
Gene Therapy

Medical intervention base on the modification of the

genetic material of living cells

Ex vivo: outside the body

In vivo: within in the body

Goal Drug

Would produce the specifically desired effect, be

administered by the most desired dosage route
Methods of Drug Discovery
Random/Untargeted Screening

Testing of large number of synthetic organic compounds or

substances of natural origin

Used initially to detect an unknown activity of the test

compound or substance
Non-random/Targeted Screens

Determine the specific activity or a compound/substance

Biostaysis

Used to differenciate the effect and potency of the test

agent
High-throughput Screening

Capable of examining 15,000 chemical compounds a

week
Molecular Modification

Chemical alteration of a known and previously

characterized organic compound for the purpose of
enhancing its usefulness as a drug
Mechanism-based drug design

Molecular modification to design a drug that interferes

specifically with the known or suspected biochemical
pathway or mechanism of a disease process

Enalaprilat (enalapril), ranitidine, sertraline (for depression)

Molecular graphics

Use of computer graphics to represent or manipulate the

structure of the drug molecule

Lead Compound

Prototype chemical compound that has a fundamental

desired biologic or pharmacologic activity

Finasteride
Prodrugs

A compound that requires metabolic biotransformation

after administration to produce the desired
pharmacologically active compound

Conversion of an inactive prodrug to an active compound

occurs through enzymatic biological cleavage

May be designed for solubility, absorption, biostability and

prolonged release
o
Absorption: a drug may be made more water or
lipid soluble
o
Biostability: could result in site-specific action
(dopamine&levodopa)
o
Prolonged release: may extend therapeutic
activity
FDAs Definition of a New Drug

Any drug that is not recognized as being safe and effective

in the conditions recommended for its use

Combination of 2 or more drugs or a change in the usual

proportions of drugs

A proposed new use, new dosage schedule, new route of

administration or new dosage form
Drug Nomenclature

C16H19N3O5Sx3H2O (amox)

Name must reveal every part of the compounds molecular

structure

Non-proprietary/Generic name: shortened name

[Biologic Characterization]
Cell cultures

Used to screen toxicity before progressing to whole-animal

testing
Computer models

Help predict the properties of substances and their

probable actions in living systems
Pharmacology

pharmaco = drugs

Science concerned with drugs, their sources, appearance,

chemistry, action and uses

Pharmacodynamics: study of biochemical and physiologic

effects of drugs and their mechanism of action

Pharmacokinetics: deals with the absorption, distribution,

metabolism/biotransformation and excretion (ADME) of
drugs

Clinical pharmacology: the study of the effects and actions

of drugs in humans

Whole-animal studies are used to evaluate the

pharmacologic effects of the agent on specific organ
systems

Primary objective of animal studies: to obtain basic

information on the drugs effects that may be used to
predict safe and effective use in humans
Drug Metabolism

Bodys means of transforming nonpolar drug molecules into

polar compounds

First-pass effect: rapid drug metabolism

ADME studies: performed through the timely collection and

analysis of urine, blood and fecal samples and through a
careful examination of animal tissues and organs through
autopsy
Toxicology

Deals with the adverse or undesired effects of drugs

Acute or short-term toxicity studies

Designed to determine the toxic effects if a test compound

when administered in a single dose or in multiple doses over
a short period, usually a single day

Doses are ranged to find the largest single dose that will not
produce a toxic effect

30-day post period

Subacute or subchronic studies

Minimum of 2 weeks of daily drug administration at three or

more dosage levels to two animal species

Initial human dose is usually one tenth of the highest non

toxic dose

Chronic toxicity studies: 90-180 days

Carcinogenic Studies

Undertaken when the compounds has shown sufficient

promise s a drug to enter human clinical trials

Long term (18-24 months)

Reproduction studies

To reveal any effect if an active ingredient on mammalian

reproduction

Rabbit is the preferred choice

Genotoxicity or mutagenicity studies

Performed to determine whether the test compound can

affect gene mutation of cause chromosome or DNA
damge

Salmonella typhimurium strains are used

[Early Formulation Studies]
Preformulation Studies
Drug solubility

Poor soluble compounds (less than 10 mg/mL aqueous

solubility)
Partition coefficient

Drug molecules must first cross a biologic membrane of

protein and lipid

Measure of its distribution in a lipophilic-hydrophilic phase

system and indicates its ability to penetrate biologic
multiphase systems
Dissolution rate

Speed at it which a drug substance dissolves in a medium

Physical form

Reducing particle size = absorption is increased

Stability

Durations and environments of light and air and packaging

is essential
Initial Product Formulation and Clinical Trial Materials

Initial product is formulated using the information gained

during the preformulation studies
Phase 1 studies

Capsules are employed containing the active ingredient

alone
Phase 2 studies

Final dosage form is selected

Clinical supplies or clinical materials

Comprise all dosage formulation used in the clinical

evaluation of a new drug
Blinded studies

Controlled studies

At last one of the parties does not know which product is

being administered
[The Investigational New Drug Application]

Sponsor of a new drug must file an IND before the drug may
be given to human subjects

Sponsor must delay the use of drug in human subject for not
less than 30 days

Clinical hold is issued when there is concern that human

subjects will be exposed to unreasonable and significant risk
of illness or injury
The Clinical Protocol

Purpose and objectives of the study

Estimate number of patients involved

Approval of the authorized IRB

1994: National Institue of Health (NIH) issued its policy that

women and minorities be included in all NIH-supported
research

Purpose of IRB: to protct the safety of human subjects by

assessing a proposed clinical protocol, evaluate the
benefits against risks, and ensuring that the plan includes all
needed measures for subject protection
Pre-IND Meetings

May include advice on the adequacy of data to support

an investigational plan, the design of a clinical trial
FDA Review of an IND Application

Objecttives
o
Protect the safety and rights of the human
subjects
o
Help ensure that the study allows the evaluation of
the drugs safety and effectiveness
o
Stamped then sent to the Center for Drug
Evaluation Research (CDER) or the Center for

Biologics Evaluation and Research (CBER) for

review
FDA Drug Classification

By chemical type of therapeutic potential

Phases of a Clinical Investigation
Phase 1

Initial introduction of the investigational drugs into humans

for the purpose of assessing safety

20 to 100 subjects

Initial dose is one tenth of the highest no-effect dose

Designed to determine the human pharmacology of the

drug, structure-activity relationships, side effects associated
with increasing doses and early evidences of effectiveness

Rate of absorption, concentration of drug in blood over

time, rate of mechanism
Phase 2

Controlled clinical studies to evaluate the effectiveness of a

drug in patients with the condition

Asses side effects and risks that may be revealed

Additional date on the drugs pharmacokinetics and doseresponse and dose ranging (Phase 2a studies)

Dose determination studies (Phase 2b)

Drug product is refined

Phase 3

Include several hundred to several thousand patients in

controlled and uncontrolled trials

Objective is to determine the usefulness of the drug in an

expanded patient base

Completed studies (Phase 3a)

Additional studies (Phase 3b)

Clinical Study Controls and Designs
Blinded studies

Identity of the investigational drug and the control are not

revealed
Single blind studies

Patient is unaware of the agent administered

Double blind studies

Neither the patient nor the clinician is aware or the agent

administered
Parallel designs

Applicable to most clinical trials

Crossover designs

Useful in comparing different treatments within individuals

Drug Dosage and Terminology
Minimum effective concentration (MEC)

An average blood serum concentration that can be

expected to produce the drug's desired effects
Minimum toxic concentration (MTC)

Second level of serum concentration

Median effective dose

Amount that will produce the desired intensity of effect in

50% of the individuals tested
Therapeutic index

Relationship between the desired and undesired effects of

the drug

Defined as the ratio between a drugs median toxic dose

and its median effective dose (TD50/ED50)
Age
Pharmacogenetics
Body weight
BSA
Sex
Pathologic state
Tolerance

Ability to endure the influence of a drug, particularly during

continued use
Concomitant drug therapy

Effects of a drug may be modified by the prior or

concurrent administration of another drug
Time and conditions of administration
Dosage form and route of administration
Treatment IND

Permits the use of an investigational drug in the treatment

of patients not enrolled in the clinical study but who have
serious or immediately life-threatening disease
[The New Drug Application]

Purpose: to gain permission to market the drug product in

the US
FDA Review and Action Letters

Review clock: 180-day period

Phase 4 Studies and Postmarketing Surveillance

Phase 4: continued clinical investigations

Postmarketing Reporting of Adverse Drug Experience

15 working days
[Supplemental, Abbreviated and other Applications]
ANDA

Nonclinical laboratory studies and clinical investigations

may be omitted, except those pertaining to the desired
bioavailability

Usually for duplicates

[International Conference on Harmonization of Technical
Requirements for Registration of Pharmaceuticals for Human Use]

Focused on quality, safety and efficacy

Current Good Manufacturing Practices and Current Good

Compounding Practices
[Standards for Current Good Manufacturing Practice]

Established by the FDA to ensure that minimum standards

are met for drug product quality
[cGMP for Finished Pharaceuticals]
Active ingredient or active pharmaceutical ingredient (API)

Any component that is intended to furnish pharmacologic

activity or other direct effect in the diagnosis, prevention
of diseases
Batch

A specific quantity of a drug of uniform specified quality

produced according to a single manufacturing order
during the same cycle of manufacture
Batchwise control

Use of validated in-process sampling and testing methods

Certification

Documented testimony
Compliance

Determination through inspection

Component

Any ingredient used in the manufacture of a drug product

Drug product

A finished form that contains an active drug and inactive

ingredients
Lot

A batch
Master record

Record containing the formulation, specifications,

manufacturing procedures
Quality assurance

Provision to all concerned the evidence needed to

establish confidence
Quality audit

Documented activity performed in accordance with

established procedures on a planned and periodic basis
Quality control unit

Organizational element designed by a firm

Representative sample

A sample that accurately portrays the whole

Reprocessing

Activity whereby the finished product or any of its

components are recycled
Strength

Concentration of the drug substance per unit dose or

volume
Process validation

Documented evidence that a process does what it purports

to do
Validation protocol

A prospective experimental plan to produce documented

evidence that a system has been validated
Expiration Dating

Determined by the appropriate stability testing

Tamper-Evident Packaging
Film wrapper

Sealed around product and/or product container; fi lm

must be cut or torn to remove product

Blister/strip pack

Individually sealed dose units; removal requires tearing or

breaking individual compartment
Bubble pack

Product and container sealed in plastic, usually mounted

on display card; plasticmust be cut or broken open to
remove product
Shrink seal, band

Band or wrapper shrunk by heat or drying to conform to

cap; must be torn to open package
Foil, paper, plastic pouch

Sealed individual packet; must be torn to reach product

Bottle seal

Paper or foil sealed to mouth of container under cap; must

be torn or broken to reach product
Tape seal

Paper or foil sealed over carton flap or bottle cap; must be

torn or broken to reach product
Breakable cap

Plastic or metal tearaway cap over container; must be

broken to remove
Sealed tube

Seal over mouth of tube; must be punctured to reach

product
Sealed carton

Carton flaps sealed; carton cannot be opened without

damage
Aerosol container

Tamper-resistant by design
Records and Reports

Production, control and distribution documents must be

kept for at least one year after expiration
[Current Good Compounding Practices]
US Pharmacopeia-National Formulary

First compounding monographs became official in 1998

(Beyond-use dates)
For non aqueous liquids and solid formulations

Where the manufactured drug product is the source of the

active ingredient, not later than 25% or 6 months

Where a USP or NF substance is the source, nlt 6 months

For water-containing formulations

Nlt 14 days when stored at cold temperatures

Low-risk preparations at room temp

Nmt 48 hours

(Refrigerated) nmt 14 days

Medium-risk at room temp

Nmt 30 hrs

(Refrigerated) nmt 9 days

High-risk preparations at room temp

Nmt 24 hours

(Refrigerated) nmt 3 days

Low, Medium, High-risk s (-25 - -10 degrees C)

45 days in solid state

Low-risk and medium-risk compounding

Involves sterile products an equipment

Food and Drug Modernization Act of 1997

To ensure patients access to individualized drug therapy

and prevent unnecessary FDA regulation of health
professional practice

A compounded product is exempt if the drug product is

compounded for an individual patient

Mtdland decision: compounded preparations are not new

drugs
National Association of Boards of Pharmacy
Subpart (A), General Provisions

Compounding means the preparation of Components

into a Drug

Manufacturing means the production, preparation,

propagation, conversion, or processing of a Drug or Devices
Subpart (B), Organization and Personnel

Discusses the responsibilities of pharmacists and other

personnel engaged in compounding.

Stresses that only personnel authorized by the responsible

pharmacist shall be in the immediate vicinity of the drug
compounding operation
Subpart (C), Drug Compounding Facilities

Describes the areas that should be set aside for

compounding, either sterile or not

Subpart (D), Equipment

States that equipment used must be of appropriate design,

adequate size, and suitably located to facilitate operation
for its intended use
Subpart (E), Control of Components and Drug Product Containers
and Closures

Describes the packaging requirements for compounded

products.
Subpart (F), Drug Compounding Controls

Discusses the written procedures to ensure that the finished

products are of the proper identity, strength, quality, and
purity, as labeled.
Subpart (G), Labeling Control of Excess Products and Records and
Reports

Describes the various records and reports that are required

under these guidelines.
[Packaging, Labeling and Storage of Pharmaceuticals]
Containers

That which hold the article and is or may be in direct

contact with the article at all rimes
Well-closed container

Minimally acceptable container

Protects the contents from extraneous solids and from loss of

the article
Tight container

Protects the contents from contamination by extraneous

liquids, solids or vapors, efflorescence, deliquescence or
evaporation

Capable of tight re-closure

Hermetic container

Impervious to air or any gas

Sterile hermetic container

Hold preparations intended for injection

Single-dose container

Cannot be resealed

Fusion-sealed ampules, prefilled syringes and cartridges

Glass

Type I: highly resistant borosilicate glass

Type II: treated soda lime

Type III: soda lime

NP: general purpose soda lime

Polyvinyl chloride (PVS)

Rigid and has good clarity

Blister packaging

Unsuitable for gamma sterilization

Polyethylene terephthalate (PET), Amorphous polyethylene
terephthalate glycol (APET), polyethylene terephthalate glycol
(PETG)
Permeability

Process of solution and diffusion

Glass are less permeable than plastic

Humidity

Test for a minimum of 12 months at 25 degrees C

Desiccants
Oxidation

Greater degree in plastic than in glass

Leaching

Movement of components of a container into the contents

Soft-walled plastic containers of PVC: IV solutions for blood

transfusion
Sorption

Binding of molecules to polymer materials

Child-resistant and Adult-Senior Use Packaging
Potson Prevention Act

Reduce accidental poisoning through ingestion of drugs

Child-resistant containers (5 years and below)

Align the arrows, press down and turn, squeeze and turn,
latch top
Storage
Cold

8 degrees C
Cool

8-15 degrees C
Warm

30-40 degrees C

Dosage Form Design: Pharmaceutical Formulation

Considerations
Pharmaceutical ingredients

Nonmedicinal agents
[The Need for Dosage Forms]

To protect the drug substance from the destructive

influences of atmospheric oxygen or humidity (coated
tablets, sealed ampules)

To protect the drug substance from the destructive

influence of gastric acid after oral administration (entericcoated tablets)

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

drug substance (capsules, coated tablets, flavored syrups)

To provide liquid preparations of substances that are either

insoluble or unstable in the desired vehicle (suspensions)

To provide clear liquid dosage forms of substances (syrups,

solutions)

To provide rate-controlled drug action (various controlledrelease tablets, capsules, and suspensions)

To provide optimal drug action from topical administration

sites (ointments, creams, transdermal patches, and
ophthalmic, ear, and nasal preparations)

To provide for insertion of a drug into one of the bodys

orifices (rectal or vaginal suppositories)

To provide for placement of drugs directly in the

bloodstream or body tissues (injections)

To provide for optimal drug action through inhalation

therapy (inhalants and inhalation aerosols)
[General Considerations in Dosage Form Design]
Master formula

Formulation that best meets the goals for the product

Systemic use: oral administration

Preformulation Studies

Provides the framework for the drugs combination with

pharmaceutical ingredients in the fabrication of a dosage
form
Physical Description

Particle size, crystalline structure, melting point and solubility

Microscopic Examination

Gives an indication of particle size and size range of the raw

material along with the crystal structure
Heat of Vaporization

The amount of heat absorbed when 1g of a liquid vaporizes

Measured in calories
Melting Point Depression

Characteristic of a pure substance

Temperature at which the pure liquid and solid exist in

equilibrium
The Phase Rule

Two-component (binary) or three-component

representations

Represent the melting point as a function of composition of

two or three systems
Particle Size
Polymorphism

Exhibit different physiochemical properties

Solubility

Determined by the equilibrium solubility method

Solubility and pH
Dissolution

Time it takes for the drug to dissolve

May be increased by decreasing the drugs particle size

Constant surface method

o
Uses a compressed disc of known area
o
Eliminate surface are and surface electrical
charges as dissolution variables
o
Intrinsic dissolution rate
o
Mg dissolved per minute per cm squared
Membrane Permeability

Early assessment of passage of drug molecules across

biologic membranes
Partition Coefficient

Measure of a molecules lipophilic character

pKa/Dissociation Constants
Drug and Drug Product Stability
Drug Stability Mechanisms of Degregation

Hydrolysis: solvolysts process in which drug molecules

interact with water molecules to yield breakdown products

Oxidation

Autoxidation: occur spontaneously under the initial

influence of atmospheric oxygen and proceed slowly at first
then more rapidly
Drug and Drug Product Stability: Kinetics and Shelf Life

Stability: extent to which a product retains within specified

limits and throughout its period of storage and use the same
properties and characteristics that it possessed at the time
of its manufacture

Chemical, physical, microbiologic, therapeutic, toxicologic

Reaction kinetics: study of the rate of chemical change

and the way this rate is influenced y concentration of
reactants
Rate Reactions

Description of the drug concentration with respect to time

Q10 Method of Shelf Life Estimation

Lets the pharmacist estimate shelf life

Enhancing Stability of Drug Products

Reduction or elimination of water

Anhydrous vegetable oils may be used to reduce the

chance of hydrolytic decomposition in injectable

Decomposition by hydrolysis may be prevented in other

liquid drugs by suspending them in a nonaqueous vehicle

Reconstitution

Antioxidants
o
Aqueous: sodium sulfite, sodium bisulfite, sodium
metabisulfite, hypophosphorous acid, ascorbic
acid
o
Oleaginous preparations: alpha-tocopherol, butyl
hydroxyl anisole, ascorbyl palmitate

Trace metals

Polymerization (two or more identical molecules that form a

new and generally larger molecule), chemical
decarboxylation and deamination
Stability Testing

Accelerated stability testing

o
Use of exaggerated conditions of temperature,
humidity, light and others
[Pharmaceutical Ingredients and Excipients]
Definitions and Types
Solvents

Used to dissolve the drug substance

Flavors and sweeteners

Used to make the product more palatable

Colorants

Enhance appeal
Preservatives

Prevent microbial growth

Diluents or fillers

For tablets

Increase bulk of formation

Binders

Cause adhesion of the powdered drug and

pharmaceutical substances
Antiadherents/lubricants

Smooth tablet formation

Disintegrating agents

Promote tablet breakup

Handbook of Pharmaceutical Excipients and Food and Chemicals
Codex
Handbook of Pharmaceutical Excipients

More than 250 excipients

Appearance and Palatability
Flavoring Pharmaceuticals

Increase in the number of hydroxyl groups seems to

increase the sweetness
Sweetening Pharmaceuticals

Aspartame, saccharin and cyclamate

Delaney Clause: no new food additive may be used if

animal feeding studies or tests showed that it caused
cancer

Saccharin Study and Labeling Act

Coloring Pharmaceuticals

Sulfur (yellow), riboflavin (yellow), cupric sulfate (blue),

ferrous sulfate (bluish green), cyanocobalamin (red), red

mercuric iodide (vivid red)

Coal tar: black

Preservatives
Sterilization and Preservation

15% V/V alcohol will prevent microbial growth in acid

media, 18% in alkaline media
Preservative Selection

Cellulose derivatives: polyethylene glycols, natural gums:

tragacanth

Dosage Form Design: Biopharmaceutical and

Pharmacokinetic Considerations
Biopharmaceutics

Relationship between the physical, chemical and biologic

sciences as they apply to drugs, dosage forms and drug
action
Pharmacokinetics

Area of study that elucidates the time course of drug

concentration in the blood and tissues (ADME)
Metabolism

Major process by which foreign substances are eliminated

from the body
Principles of Drug Absorption
Passive Diffusion

Passage of drug molecules through a membrane that does

not actively participate in the process

High to low concentration

Ficks Law: the rate of diffusion or transport across a

membrane is proportional to the difference in drug
concentration on both sides of the membrane

First-order kinetics

pK: pH at which a drug is 50% ionized

Specialized Transport Mechanisms

Active: lower to higher concentration

[Dissolution and Drug Absorption]

Diffusion layer: layer of solution

Dissolution rate of a drug may be increased by increasing

the surface area (reducing particle size)
Crystal or Amorphous Drug Form

Amorphous form of a chemical is usually more soluble than

the crystalline form

Novoviocin and chloramphenicol palminatate are inactive

when administered in crystalline form but is active in
amorphous form

Penicillin: crystalline form > amorphous form

Salt Forms

Addition of ethylenediamine to theophylline increases the

water solubility of theophylline fivefold
[Bioavailability and Bioequivalence]
Bioavailability

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 action

Depends on the drugs absorption or entry in the systemic

circulation
Bioequivalence

Comparison or bio availabilities of different formulations,

drug products or batches of the same drug product

Used to determine the amount or proportion of drug

absorbed, the rate at which the drug was absorbed.
Duration of the drugs presence in the biologic fluid or tissue
correlated with the patients response, relationship between
drug blood levels and clinical efficacy and toxicity
[Routes of Drug Administration]

Local effects: direct contact of the drug to the site of action

Systemic effect: entrance of the drug into the circulatory

system and transport to the cellular site of its action

Bioavailability is lowest for drugs that undergo a significant

first-pass effect
Oral Route

Systemic drug effects

Most natural, uncomplicated, convenient and safe means

of administering drugs

Disadvantages: slow drug response, destruction of certain

drugs by the acid reaction of the stomach
Dosage forms applicable

Tablets

o
o
o
o

Prepared by compression or molding that contains

medicinal substances
Diluents are fillers used to prepare tablets
Disintegrants are used for the breakup or
separation
Enteric coatings: safe passage through the acid
environment

Capsules
o
Enclosed in either a hard or soft shell, generally
composed of gelatin

Suspension
o
Finely divided drugs in a suitable fluid vehicle
o
Drug particles must be suspended in an insoluble
vehicle
o
Useful means to administer large amounts of solid
drugs

Solution

Elixir
o
Solutions in a sweetened hydroalcoholic vehicle

Syrups
o
Use sucrose solution
Absorption

Sublingual: with nitroglycerin and certain steroid sex

hormones

Tetracycline drugs must not be taken with milk

Rectal Route

Suppositories
o
Promotion of laxation, soothing of inflamed tissues,
promotion of systemic effcts
Parenteral Route

Para = beside

Enteron = intestine
Dosage Forms Applicable

Slow absorption = prolonged drug action; subcutaneous or

IM: depot or repository injection
Subcutaneous (Hypodermic) Injections

Injection through the skin into the loose subcutaneous tissue

Insulin

More capillaries = more surface are for absorption = faster

rate of absorption

Forearm, upper arm, thigh or buttocks

Intramuscular Injections

Aqueous or oleaginous solutions or suspensions

Intravenous Injections

Injected directly into the vein

Intradermal Injections

Administered into the corium of the skin (0.1mL)

Epicutaneous Route

Topically

Nitroglycerin (antianginal), nicotine (smoking cessation),

estradiol (estrogenic hormone), clonidine
(antihypertensive), and scopolamine (antinausea, anti
motion sickness)

Local action

Ointments
o
Simple mixtures of drug substances in an ointment
base

Creams
o
Semisolid emulsions les viscid and lighter than
ointments

Pastes
o
Stiffer and less penetrating
o
Employed for its protective action

Medicinal powder
o
Relieves diaper rash, chafing, and athletes foot

Lotions
o
Emulsions or suspensions generally in an aqueous
vehicle
o
Nongreasy
Ocular, Oral, Otic and Nasal Routes

Local effects\