PharDose Lec [Monthly Exam] 32-page booklet, 84 internal and 16 external drugs and

Introduction to Drugs and Pharmacy preaparations

Drug Lyman Spalding
Agent intended for use in the diagnosis, mitigation, Father of USP
treatment, cure or prevention of disease in humans or Proposed for a convention in 4 geographic districts
animals (FDCA, 1938) United States Pharmacopeial Convention
Pharmacology Revise USP every 10 years
Nature and mechanism of action of the drug on the 1940 meeting: revise the USP every 5 years
biologic system 1830 and 1840: pharmacists were invited
[The Heritage of Pharmacy] 1850: full membership of pharmacists
Practice of drug therapy was from experience USP
Early people believed illnesses were caused by demons or First published on December 15, 1820 in English and Latin
evil spirits in the body 217 drugs
People performed incantations, the application of noisome American Pharmaceutical Association (APhA)
materials and the administration of specific herbs or plant 1852
materials National Formulary of Unofficial Preparations
The First Apothecary Formulary containing many f the popular drugs and
Pharmakon (Gk.): charm or drug that can be used for formulas denied administration to the USP
good or for evil Changed to National Formulary on June 30, 1906 when
Knowledge of drug and their application to disease has President Theodore Roosevelt signed into law
always meant power USP XX and NF XV
Early Drugs USP: volume; NF: sections
Ebers Papyrus USP 23-NF 18
60 ft. long, a foot wide o Became official in 1995
16th century BC USP Pharmacists Pharmacopeia
Founded by Georg Ebers To address the needs of pharmacist practioners
800 formulas, 700 drugs Products
Introduction of the Scientific Viewpoint Manufactured drugs
Hippocrates Preparations
Introduction of scientific pharmacy and medicine Compounded drugs
Rationalized medicine, systemized medical knowledge, and USP and NF Monographs
put the practice of medicine on a high ethical plane Adopt standards for drug substances, pharmaceutical
Hippocratic oath of ethical behavior ingredients and dosage forms reflecting the best in the
Pharmakon beame for good only current practices of medicine and pharmacy
Father of Medicine Official parts of a monograph
Dioscorides o Official title (generic or nonproprietary name)
First to deal with Botany o Graphic or structural formula
De Materia Medica o Empirical formula
Claudius Galen o Molecular weight
Galenic pharmacy o Established chemical names
Galens Cerate, cold cream o Chemical Abstracts Service (CAS) registry number
Emperor Fredrick II USP Drug Research and Testing Laboratory
Had a decree, which separated pharmacy from medicine o Provides direct laboratory assistance to the USP
in 1240 AD and NF
Aureolus Theophrastus Bombastus von Hohenheim o Main functions: evaluation of USP reference
Aka Paracelsus standards and evaluation and development of
Transformation of pharmacy from a profession based analytical methods
primarily on botanical science to one based on chemical Other Pharmacopeias
science Homeopathic Pharmacopeia of the United States (HPUS)
Early Research Used by law enforcement agencies that must ensure the
Karl Wilhelm Scheele quality of homeopathic drugs
Discovered lactic acid, citric acid, ocalic acid, tartaric Homeopathy
acid, arsenic acid and oxygen o Coined by Samuel Hahnemann
Identified glycerin o Homoios = similar
Invented new methods of preparing calomel and benzoic o Pathos = disease
acid o Law of similars, like cures like
Friedrich Sertuner International Pharmacopeia (IP)
Isolation of morphine from opium Published by WHO
Joseph Caventou and Joseph Pelletier Intended as a recommendation to a national
Isolated quinine and cinchonine from chinchona pharmacopeial revision committees to modify their
Isolated strychnine and brucine from nux vomica pharmacopeias
Joseph Pelletier and Pierre Robiquet International Organization for Standardization
Isolated caffeine International consortium of representative bodies
Pierre Robiquet constituted to develop and promote uniform or harmonized
Separated codeine from opium international standards
[Drug Standards] Quality assurance (QA), quality control (QC), detectin of
The United States Pharmacopeia and the National Formulary defective products, quality management (WM)
Pharmacopeia [Drug Regulation Control]
Pharmakon: drug Food and Drug Act of 1906
Poiein: make First federal law in the US designed to regulate drug
Any recipe or formula or other standars required to make or products
prepare drug Required drugs marketed interstate to comply with their
Lititz Pharmacopeia caimed standards
First American pharmacopeia [The Federal Food, Drug and Cosmetic Act of 1938]
Published in 1778 at Lititz, Pennsylvania 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 New Drug Development and Approval Process
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
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 Lead Compound
labeling or formulation change Prototype chemical compound that has a fundamental
desired biologic or pharmacologic activity
Abbreviated New Drug Application (ANDA) Finasteride
Used to gain approval to market a duplicate of a product Prodrugs
Biologics Licensing Application (BLA) A compound that requires metabolic biotransformation
Biologic products (human blood products and vaccines) after administration to produce the desired
Investigational New Animal Drug Application (INADA) pharmacologically active compound
New Animal Drug Application (NADA) Conversion of an inactive prodrug to an active compound
Supplemental New Animal Drug Application (SNADA) occurs through enzymatic biological cleavage
[Drug Discovery and Drug Design] May be designed for solubility, absorption, biostability and
Alexander Fleming prolonged release
Penicillin o Absorption: a drug may be made more water or
International Conference on Harmonization lipid soluble
Fosters multinational drug approvals o Biostability: could result in site-specific action
Sources of New Drugs (dopamine&levodopa)
Serendipity o Prolonged release: may extend therapeutic
By accident activity
Reserpine FDAs Definition of a New Drug
Tranquilizer and hypotensive agent Any drug that is not recognized as being safe and effective
Rauwolfia serpentine in the conditions recommended for its use
Periwinkle Combination of 2 or more drugs or a change in the usual
Vinca rosea proportions of drugs
Treatment of diabetes mellitus A proposed new use, new dosage schedule, new route of
Antitumor capabilities administration or new dosage form
Paclitaxel Drug Nomenclature
Ovarian cancer C16H19N3O5Sx3H2O (amox)
Semisynthetic drugs Name must reveal every part of the compounds molecular
New structures from modified plant constituents structure
Recombinant DNA Non-proprietary/Generic name: shortened name
Most fundamental [Biologic Characterization]
Genetic materials can be transplanted from higher species Cell cultures
into a lowly bacterium (gene-splicing) Used to screen toxicity before progressing to whole-animal
Manipulation of proteins within the cells of lower animals testing
Human insulin, human growth hormone, hep B vaccine, Computer models
epoetinalpha and interferon Help predict the properties of substances and their
Recombinant DNA probable actions in living systems
Manipulation of proteins within the cells of higher animals Pharmacology
Used in home pregnancy testing products pharmaco = drugs
Human Gene Therapy Science concerned with drugs, their sources, appearance,
Used to prevent, treat, cure, diagnose or mitigate human chemistry, action and uses
diseases caused by genetic disorders Pharmacodynamics: study of biochemical and physiologic
AT CG effects of drugs and their mechanism of action
Gene Therapy Pharmacokinetics: deals with the absorption, distribution,
Medical intervention base on the modification of the metabolism/biotransformation and excretion (ADME) of
genetic material of living cells drugs
Ex vivo: outside the body Clinical pharmacology: the study of the effects and actions
In vivo: within in the body of drugs in humans
Goal Drug Whole-animal studies are used to evaluate the
Would produce the specifically desired effect, be pharmacologic effects of the agent on specific organ
administered by the most desired dosage route systems
Methods of Drug Discovery Primary objective of animal studies: to obtain basic
Random/Untargeted Screening information on the drugs effects that may be used to
Testing of large number of synthetic organic compounds or predict safe and effective use in humans
substances of natural origin Drug Metabolism
Used initially to detect an unknown activity of the test Bodys means of transforming nonpolar drug molecules into
compound or substance polar compounds
Non-random/Targeted Screens First-pass effect: rapid drug metabolism
Determine the specific activity or a compound/substance ADME studies: performed through the timely collection and
Biostaysis analysis of urine, blood and fecal samples and through a
Used to differenciate the effect and potency of the test careful examination of animal tissues and organs through
agent autopsy
High-throughput Screening Toxicology
Capable of examining 15,000 chemical compounds a Deals with the adverse or undesired effects of drugs
week Acute or short-term toxicity studies
Molecular Modification Designed to determine the toxic effects if a test compound
Chemical alteration of a known and previously when administered in a single dose or in multiple doses over
characterized organic compound for the purpose of a short period, usually a single day
enhancing its usefulness as a drug Doses are ranged to find the largest single dose that will not
Mechanism-based drug design produce a toxic effect
Molecular modification to design a drug that interferes 30-day post period
specifically with the known or suspected biochemical Subacute or subchronic studies
pathway or mechanism of a disease process Minimum of 2 weeks of daily drug administration at three or
Enalaprilat (enalapril), ranitidine, sertraline (for depression) more dosage levels to two animal species
Molecular graphics Initial human dose is usually one tenth of the highest non
Use of computer graphics to represent or manipulate the toxic dose
structure of the drug molecule 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 Dosage Form Design: Pharmaceutical Formulation
Subpart (D), Equipment Considerations
States that equipment used must be of appropriate design, Pharmaceutical ingredients
adequate size, and suitably located to facilitate operation Nonmedicinal agents
for its intended use [The Need for Dosage Forms]
Subpart (E), Control of Components and Drug Product Containers To protect the drug substance from the destructive
and Closures influences of atmospheric oxygen or humidity (coated
Describes the packaging requirements for compounded tablets, sealed ampules)
products. To protect the drug substance from the destructive
Subpart (F), Drug Compounding Controls influence of gastric acid after oral administration (enteric-
Discusses the written procedures to ensure that the finished coated tablets)
products are of the proper identity, strength, quality, and To conceal the bitter, salty, or offensive taste or odor of a
purity, as labeled. drug substance (capsules, coated tablets, flavored syrups)
Subpart (G), Labeling Control of Excess Products and Records and To provide liquid preparations of substances that are either
Reports insoluble or unstable in the desired vehicle (suspensions)
Describes the various records and reports that are required To provide clear liquid dosage forms of substances (syrups,
under these guidelines. solutions)
[Packaging, Labeling and Storage of Pharmaceuticals] To provide rate-controlled drug action (various controlled-
Containers release tablets, capsules, and suspensions)
That which hold the article and is or may be in direct To provide optimal drug action from topical administration
contact with the article at all rimes sites (ointments, creams, transdermal patches, and
Well-closed container ophthalmic, ear, and nasal preparations)
Minimally acceptable container To provide for insertion of a drug into one of the bodys
Protects the contents from extraneous solids and from loss of orifices (rectal or vaginal suppositories)
the article To provide for placement of drugs directly in the
Tight container bloodstream or body tissues (injections)
Protects the contents from contamination by extraneous To provide for optimal drug action through inhalation
liquids, solids or vapors, efflorescence, deliquescence or therapy (inhalants and inhalation aerosols)
evaporation [General Considerations in Dosage Form Design]
Capable of tight re-closure Master formula
Hermetic container Formulation that best meets the goals for the product
Impervious to air or any gas Systemic use: oral administration
Sterile hermetic container Preformulation Studies
Hold preparations intended for injection Provides the framework for the drugs combination with
Single-dose container pharmaceutical ingredients in the fabrication of a dosage
Cannot be resealed form
Fusion-sealed ampules, prefilled syringes and cartridges Physical Description
Glass Particle size, crystalline structure, melting point and solubility
Type I: highly resistant borosilicate glass Microscopic Examination
Type II: treated soda lime Gives an indication of particle size and size range of the raw
Type III: soda lime material along with the crystal structure
NP: general purpose soda lime Heat of Vaporization
Polyvinyl chloride (PVS) The amount of heat absorbed when 1g of a liquid vaporizes
Rigid and has good clarity Measured in calories
Blister packaging Melting Point Depression
Unsuitable for gamma sterilization Characteristic of a pure substance
Polyethylene terephthalate (PET), Amorphous polyethylene Temperature at which the pure liquid and solid exist in
terephthalate glycol (APET), polyethylene terephthalate glycol equilibrium
(PETG) The Phase Rule
Permeability Two-component (binary) or three-component
Process of solution and diffusion representations
Glass are less permeable than plastic Represent the melting point as a function of composition of
Humidity two or three systems
Test for a minimum of 12 months at 25 degrees C Particle Size
Desiccants Polymorphism
Oxidation Exhibit different physiochemical properties
Greater degree in plastic than in glass Solubility
Leaching Determined by the equilibrium solubility method
Movement of components of a container into the contents Solubility and pH
Soft-walled plastic containers of PVC: IV solutions for blood Dissolution
transfusion Time it takes for the drug to dissolve
Sorption May be increased by decreasing the drugs particle size
Binding of molecules to polymer materials Constant surface method
Child-resistant and Adult-Senior Use Packaging o Uses a compressed disc of known area
Potson Prevention Act o Eliminate surface are and surface electrical
Reduce accidental poisoning through ingestion of drugs charges as dissolution variables
Child-resistant containers (5 years and below) o Intrinsic dissolution rate
Align the arrows, press down and turn, squeeze and turn, o Mg dissolved per minute per cm squared
latch top Membrane Permeability
Storage Early assessment of passage of drug molecules across
Cold biologic membranes
8 degrees C Partition Coefficient
Cool Measure of a molecules lipophilic character
8-15 degrees C pKa/Dissociation Constants
Warm Drug and Drug Product Stability
30-40 degrees C 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, 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\