PharDose Lec [Monthly Exam] [Drug Standards]

The United States Pharmacopeia and the National Formulary

Pharmacopeia
Chapter 1: Introduction to Drugs and Pharmacy
Pharmakon: drug
Poiein: make
Drug
Agent intended for use in the diagnosis, mitigation, Any recipe or formula or other standars required to
treatment, cure or prevention of disease in humans make or prepare drug
or animals (FDCA, 1938) Lititz Pharmacopeia
Pharmacology First American pharmacopeia
Nature and mechanism of action of the drug on the Published in 1778 at Lititz, Pennsylvania
biologic system 32-page booklet, 84 internal and 16 external drugs
[The Heritage of Pharmacy] and preaparations
Practice of drug therapy was from experience Lyman Spalding
Early people believed illnesses were caused by Father of USP
demons or evil spirits in the body Proposed for a convention in 4 geographic districts
People performed incantations, the application of United States Pharmacopeial Convention
noisome materials and the administration of specific Revise USP every 10 years
herbs or plant materials 1940 meeting: revise the USP every 5 years
The First Apothecary 1830 and 1840: pharmacists were invited
Pharmakon (Gk.): charm or drug that can be used 1850: full membership of pharmacists
for good or for evil USP
Knowledge of drug and their application to disease First published on December 15, 1820 in English and
has always meant power Latin
Early Drugs 217 drugs
Ebers Papyrus American Pharmaceutical Association (APhA)
60 ft. long, a foot wide 1852
16th century BC National Formulary of Unofficial Preparations
Founded by Georg Ebers Formulary containing many f the popular drugs and
800 formulas, 700 drugs formulas denied administration to the USP
Introduction of the Scientific Viewpoint Changed to National Formulary on June 30, 1906
Hippocrates when President Theodore Roosevelt signed into law
Introduction of scientific pharmacy and medicine USP XX and NF XV
Rationalized medicine, systemized medical USP: volume; NF: sections
knowledge, and put the practice of medicine on a USP 23-NF 18
high ethical plane o Became official in 1995
Hippocratic oath of ethical behavior USP Pharmacists Pharmacopeia
Pharmakon beame for good only To address the needs of pharmacist practioners
Father of Medicine Products
Dioscorides Manufactured drugs
First to deal with Botany Preparations
De Materia Medica Compounded drugs
Father of Botany USP and NF Monographs
Claudius Galen Adopt standards for drug substances, pharmaceutical
Galenic pharmacy ingredients and dosage forms reflecting the best in
Galens Cerate, cold cream the current practices of medicine and pharmacy
Emperor Fredrick II Official parts of a monograph
Had a decree, which separated pharmacy from o Official title (generic or nonproprietary
medicine in 1240 AD name)
Aureolus Theophrastus Bombastus von Hohenheim o Graphic or structural formula
Aka Paracelsus o Empirical formula
Transformation of pharmacy from a profession based o Molecular weight
primarily on botanical science to one based on o Established chemical names
chemical science o Chemical Abstracts Service (CAS) registry
Father of Toxicology number
Early Research USP Drug Research and Testing Laboratory
Karl Wilhelm Scheele o Provides direct laboratory assistance to the
Discovered lactic acid, citric acid, ocalic acid, tartaric USP and NF
acid, arsenic acid and oxygen o Main functions: evaluation of USP reference
Identified glycerin standards and evaluation and development
Invented new methods of preparing calomel and of analytical methods
Other Pharmacopeias
benzoic acid
Homeopathic Pharmacopeia of the United States (HPUS)
Friedrich Sertuner
Used by law enforcement agencies that must ensure
Isolation of morphine from opium
the quality of homeopathic drugs
Joseph Caventou and Joseph Pelletier
Homeopathy
Isolated quinine and cinchonine from chinchona
o Coined by Samuel Hahnemann
Isolated strychnine and brucine from nux vomica
o Homoios = similar
Joseph Pelletier and Pierre Robiquet
o Pathos = disease
Isolated caffeine
o Law of similars, like cures like
Pierre Robiquet
International Pharmacopeia (IP)
Separated codeine from opium
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
Chapter 2: 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 [Early Formulation Studies]
usual proportions of drugs
A proposed new use, new dosage schedule, new Drug solubility
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
Preformulation Studies
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
Chapter 3: 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
Chapter 4: 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 Area of study that elucidates the time course of drug
Antioxidants concentration in the blood and tissues (ADME)
o Aqueous: sodium sulfite, sodium bisulfite, Metabolism
sodium metabisulfite, hypophosphorous Major process by which foreign substances are
acid, ascorbic acid eliminated from the body
o Oleaginous preparations: alpha-tocopherol, Principles of Drug Absorption
butyl hydroxyl anisole, ascorbyl palmitate Passive Diffusion
Trace metals Passage of drug molecules through a membrane that
Polymerization (two or more identical molecules that does not actively participate in the process
form a new and generally larger molecule), chemical High to low concentration
decarboxylation and deamination Ficks Law: the rate of diffusion or transport across a
Stability Testing membrane is proportional to the difference in drug
Accelerated stability testing concentration on both sides of the membrane
o Use of exaggerated conditions of First-order kinetics
temperature, humidity, light and others pK: pH at which a drug is 50% ionized
Specialized Transport Mechanisms
Active: lower to higher concentration
[Pharmaceutical Ingredients and Excipients] [Dissolution and Drug Absorption]
Definitions and Types Diffusion layer: layer of solution
Solvents Dissolution rate of a drug may be increased by
Used to dissolve the drug substance increasing the surface area (reducing particle size)
Flavors and sweeteners Crystal or Amorphous Drug Form
Used to make the product more palatable Amorphous form of a chemical is usually more
Colorants soluble than the crystalline form
Enhance appeal Novoviocin and chloramphenicol palminatate are
Preservatives inactive when administered in crystalline form but is
Prevent microbial growth active in amorphous form
Diluents or fillers Penicillin: crystalline form > amorphous form
For tablets Salt Forms
Increase bulk of formation Addition of ethylenediamine to theophylline
Binders increases the water solubility of theophylline fivefold
Cause adhesion of the powdered drug and [Bioavailability and Bioequivalence]
pharmaceutical substances Bioavailability
Antiadherents/lubricants Rate and extent to which an active drug ingredient or
Smooth tablet formation therapeutic moiety is absorbed from a drug product
Disintegrating agents and becomes available at the site of action
Promote tablet breakup Depends on the drugs absorption or entry in the
Handbook of Pharmaceutical Excipients and Food and systemic circulation
Chemicals Codex Bioequivalence
Handbook of Pharmaceutical Excipients Comparison or bio availabilities of different
More than 250 excipients formulations, drug products or batches of the same
Appearance and Palatability drug product
Flavoring Pharmaceuticals Used to determine the amount or proportion of drug
Increase in the number of hydroxyl groups seems to absorbed, the rate at which the drug was absorbed.
increase the sweetness Duration of the drugs presence in the biologic fluid
Sweetening Pharmaceuticals or tissue correlated with the patients response,
Aspartame, saccharin and cyclamate relationship between drug blood levels and clinical
Delaney Clause: no new food additive may be used if efficacy and toxicity
animal feeding studies or tests showed that it caused [Routes of Drug Administration]
cancer Local effects: direct contact of the drug to the site of
Saccharin Study and Labeling Act action
Coloring Pharmaceuticals Systemic effect: entrance of the drug into the
Sulfur (yellow), riboflavin (yellow), cupric sulfate circulatory system and transport to the cellular site
(blue), ferrous sulfate (bluish green), cyanocobalamin of its action
(red), red mercuric iodide (vivid red) Bioavailability is lowest for drugs that undergo a
Coal tar: black significant first-pass effect
Preservatives Oral Route
Sterilization and Preservation Systemic drug effects
15% V/V alcohol will prevent microbial growth in acid Most natural, uncomplicated, convenient and safe
media, 18% in alkaline media means of administering drugs
Preservative Selection Disadvantages: slow drug response, destruction of
Cellulose derivatives: polyethylene glycols, natural certain drugs by the acid reaction of the stomach
gums: tragacanth Dosage forms applicable
Tablets
Chapter 5: Dosage Form Design: o Prepared by compression or molding that
Biopharmaceutical and Pharmacokinetic contains medicinal substances
Considerations o Diluents are fillers used to prepare tablets
o Disintegrants are used for the breakup or
Biopharmaceutics separation
o Enteric coatings: safe passage through the
Relationship between the physical, chemical and
acid environment
biologic sciences as they apply to drugs, dosage
forms and drug action Capsules
Pharmacokinetics o Enclosed in either a hard or soft shell,
 generally composed of gelatin Forearm, upper arm, thigh or buttocks
Suspension Intramuscular Injections
o Finely divided drugs in a suitable fluid Aqueous or oleaginous solutions or suspensions
vehicle Intravenous Injections
o Drug particles must be suspended in an Injected directly into the vein
insoluble vehicle Intradermal Injections
o Useful means to administer large amounts Administered into the corium of the skin (0.1mL)
of solid drugs Epicutaneous Route
Solution Topically
Elixir Nitroglycerin (antianginal), nicotine (smoking
o Solutions in a sweetened hydroalcoholic cessation), estradiol (estrogenic hormone), clonidine
vehicle (antihypertensive), and scopolamine (antinausea,
Syrups antimotion sickness)
o Use sucrose solution Local action
Absorption Ointments
Sublingual: with nitroglycerin and certain steroid sex o Simple mixtures of drug substances in an
hormones ointment base
Tetracycline drugs must not be taken with milk Creams
Rectal Route o Semisolid emulsions les viscid and lighter
Suppositories than ointments
o Promotion of laxation, soothing of inflamed Pastes
tissues, promotion of systemic effcts o Stiffer and less penetrating
Parenteral Route o Employed for its protective action
Para = beside Medicinal powder
Enteron = intestine o Relieves diaper rash, chafing, and athletes
Dosage Forms Applicable foot
Slow absorption = prolonged drug action; Lotions
subcutaneous or IM: depot or repository injection o Emulsions or suspensions generally in an
Subcutaneous (Hypodermic) Injections aqueous vehicle
Injection through the skin into the loose o Nongreasy
subcutaneous tissue Ocular, Oral, Otic and Nasal Routes
Insulin Local effects\
More capillaries = more surface are for absorption =
faster rate of absorption