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
th
16 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 newdrug 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 dose-response
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 (enteric-coated 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 controlled-release
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 Prepared by compression or molding that contains medicinal
substances
o Diluents are fillers used to prepare tablets
o Disintegrants are used for the breakup or separation
o 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, antimotion 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\