PHA619

– LEC THE HERITAGE OF PHARMACY

PHARMACEUTICAL DOSAGE FORMS, DRUG DELIVERY Disease
SYSTEMS, AND MEDICAL DEVICES - Believed to be cause by the entrance of demons
or evil spirits into the body
Chapter 1: - The primary method of removing spirits were:
Introduction to Drugs and Pharmacy o Use of spiritual incantations
o Application of noisome materials
DRUG o Administration of specific herbs or plant
- An agent intended for use in the diagnosis, materials
mitigation, treatment, cure, or prevention of
disease in humans or in other animals (Food, The First Apothecary
Drug, and Cosmetic Act, 1938) Wise man and woman of the tribe
- Diverse actions and effects on the body - Knowledge of the healing qualities of plants had
- Selective uses (stimulate, decrease, reduce been gathered through experience or handed
pain, combat disease, assist, treat, protect, down by word of mouth
diagnose, replenish, sustain etc.) - Called upon to attend to the sick or wounded
o Mydriatic drugs – dilate pupil of the eye - Prepare the remedy
o Miotics – constrict or diminish pupillary - Preparation of medicinal materials that the at of
size apothecary originated
o Emetic – induce vomiting
o Diuretic – increase flow of urine Priest-physician
o Expectorant – increase respiratory tract - Healer of the body as well as of the soul
fluid
o Cathartics/Laxatives – evacuate the Pharmakon (Gk.)
bowel - Word pharmacy was derived
- Plant or animal source - Connotes a charm or a drug that can be used for
- Process of discovery and development is good or for evil
complex
- Its difference with poison is the dose Placebo effect
- Physically and chemically compatible - Successful treatment due to psychlogic rather
- To be determined: than therapeutic effects
o Short and long term effects - Inert or inconsequential chemicals
o Adverse effects
o Effective routes (oral, rectal, parenteral, Ebers papyrus
topical) - 60 feet long and a foot wide
o Dosages (neonates, adult, elderly) - George Ebers
o Dosage forms - Dominated by drug formulas, with more than
o Pharmaceutical ingredients (fillers, 800 formulas or prescriptions being described
thickeners, solvents, flavors, colorants) and more than 700 drugs mentioned

Pharmacist Hippocrates
- Intimate knowledge of drug actions, - Introduction of scientific pharmacy and
pharmacotherapeutics, drug information medicine
sources - Rationalized medicine, systematized medicinal
- Entrusted with legal responsibility for the knowledge, and put the practice of medicine on
procurement, storage, control and distribution, a high ethical lane
compounding and prescription filling, and - His works included the description of hundreds
patient counselling of drugs
- Term pharmakon came to mean purifying
remedy for good only
- Father of Medicine

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Dioscorides Friedrich Sertuner
- Greek physician and botanist - Isolation of morphine from opium
- First to deal with botany as an applied science
of pharmacy Joseph Caventou and Joseph Pelletier
- De Materia Medica - Isolated:
o A milestone in the development of o Quinine and cinchonine from cinchona
pharmaceutical botany and in the study o Strychnine and brucine from nux
of naturally occurring medicinal vomica
materials
- Pharmacognosy Joseph Pelettier and Pierre Robiquet
o Natural products chemistry - Isolated caffeine
o “Pharmakon” – drug; “Gnosis” –
knowledge Pierre Robiquet
- Separated codeine from opium
Claudius Galen
- Aimed to create a perfect system of physiology, Drugs isolated from a natural source:
pathology, and treatments - Taxol (paclitaxel)
- He originated so many preparations of o Agent with antitumor activity
vegetable drugs by mixing or melting the o From Pacific yew tree (Taxus baccata)
individual ingredients that the field of pharmacy o Treatment of metastatic carcinoma of
once commonly referred to as “Galenic the ovary
pharmacy” - Vincaleukoblastine
- Cold cream – Galen’s Cerate o Antineoplastic drug
o From Vinca rosea
Emperor Fredrick II of Germany - Digoxin
- Officially separated pharmacy from medicine o Cardiac glycoside
for the first time in 1240 AD o Digitalis lanata

Aureolus Theophrastus Bombastus von Honhenheim 1821
- Swiss physician and chemist - Philadelphia College of Pharmacy
- Paracelsus o Nation’s 1st school of Pharmacy
- Influenced the transformation of pharmacy 1820
from a profession based primarily of botanical - First United States Pharmacopeia (USP) was
science to one based on chemical science published
- Believed it was possible to prepare a specific o Created to aid in establishing standards
medicinal agent to combat each specific disease for drugs in the United States
- Introduces a host of chemical substances to
internal therapy DRUG STANDARDS

Karl Wilhelm Scheele Pharmacopeias / Formularies
- Most famous of all pharmacists because of his - Organized sets of monographs and books of
scientific genius and dramatic discoveries standards to ensure quality of drugs
- Discoveries were the chemicals:
o Lactic acid Pharmacopeia
o Citric acid - Gk. Pharmakon – drug
o Oxalic acid - Poiein – make
o Tartaric acid - Any recipe or formula or other standards
o Arsenic acid required to make of prepare a drug
- Identified glycerin
- Invented new methods of preparing calomel 1580
(Mercurous chloride) and benzoic acid - Term pharmacopeia was first used in
- Discovered oxygen a year before Priestly connection with a local book of drug standards

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British Pharmacopoeia (BP) 1940
- 1864, officially replaced the three city - Revise the USP every 5 years while maintaining
pharmacopoeias the use of periodic supplements

Lititz Pharmacopeia 1830 and 1840
- First American pharmacopeia - Prominent pharmacists were invited to assist in
- Published in 1778 the revision
- Used by the Military Hospital for the United
States Army 1850
- 32 page booklet containing information on 84 - Full membership of Pharmacists in the
internal and 16 external drugs and preparations convention and have participated regularly ever
since.
1808
- Massachusetts Medical society published a 272- 1870
page pharmacopeia containing information or - The USP was so nearly in the hands of
monographs on 536 drugs and pharmaceutical pharmacists
preparations
- Indigenous drugs to America 1880
- Industrial manufacture of chemicals and
THE UNITED STATES PHARMACOPEIA AND THE pharmaceutical products had become well
NATIONAL FORMULARY established

Lyman Spalding 1910
- On January 6, 1817, submitted a plan to the - Arsphenamine, a specific agent against syphilis,
Medical society of the County of New York for was introduced to medicinal science
the creation of a national pharmacopeia - Start of an era of chemotherapy
- Father of the United States Pharmacopeia o Era which the diseases of humans
became curable through the use of
1580 specific chemical agents
- Term pharmacopeia was first used in
connection with a local book of drug standards Paul Ehrlich and Sahachiro Hata
- Discovered arsphenamine
First United States Pharmacopeial Convention
- January 1, 1820 1852
- Draft pharmacopeias were submitted from 4 - American Pharmaceutical Association (APhA)
geographic districts – northern, middle was organized
southern, and western. These were reviewed,
consolidated, and adopted by the convention National formulary of Unofficial Preparations
- Revision of USP every 10 years - 1888
- Composed exclusively of physicians - “Unofficial preparations”
o Reflected the protest mood of the
December 15, 1820 authors because of strict selectivity of
- First USP was published in English and Latin the early revisions of the USP
- Was changed to National Formulary
Massachusetts Pharmacopeia o June 30, 1906
- Considered by some to be the precursor to the o President Theodore Roosevelt signed
USP into law the first federal Pure Food nd
Drug Act, designation both USP and NF
1900 as establish in legal standards for
- The Pharmacopeial Convention granted medicinal and pharmaceutical
authority to issue supplements the USP substances
whenever necessary to maintain satisfactory - Before 1940, the NF, like the USP, was revised
standards every 10 years. After that date, new editions

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 appeared every 5 years, with supplements DRUG REGULATIONAND CONTROL
issued periodically as necessary Food and Drug Act of 1906
- Law required drugs marketed interstate to
1975 comply with their claimed standards for
- The United States Pharmacopeial Convention, strength, purity, and quality
Inc. purchased the NF, unifying the official
compedia and providing mechanism for a single Federal Food, Drug, and Cosmetic Act of 1938
national compendium - Prohibits the distribution and use of any new
drug or drug product without the prior filing of
2006 a New Drug application (NDA) and approval of
- Spanish edition of the USP-NF was introduces the FDA

Products Durham-Humphrey Amendment of 1951
- Manufactured drugs - Established a legal distinction between
prescription and over-the-counter (OTC) or non-
Preparations prescription drugs.
- Compounded drugs - Prescription drug–dispensed only upon a valid
prescription or institutional medication order
OTHER PHARMACOPEIAS o Must bear the symbol “Rx only” or
legend “Caution: Federal Law Prohibits
Homeopathic Pharmacopeia of the United States Dispensing Without Prescription”
(HPUS) o New drug substances are limited to
- Used by pharmacists and homoeopathists as prescription-only
well as by law enforcement agencies that must - Prescriptions for legend drugs (prescription
ensure the quality of homeopathic drugs drugs) may not be refilled (dispensing again
after the initial filling of the prescription)
Samuel Hahnemann without the express consent of the prescriber
- Coined the term homeopathy
- Gk. Homoios –similar Kefauver-Harris Amendments
- Pathos – disease - The sponsor of a new drug is required to file an
investigational new drug application (IND) with
Homeopathy the FDA before the drug may be clinically tested
- Law of similar, or that like cures like on human subjects
- Drug that produces symptoms of the illness in
healthy persons will also be capable of treating Comprehensive Drug Abuse Prevention and Control
those same symptoms and curing the disease Act of 1970
- Served to consolidate and codify control
authority over drugs of abuse into a single
Pharmacopeia Interatonalis or International statute
Pharmacopeia(IP) - Established five “schedules” for the
- Published by the world Health Organization classification and control of drug substances
(WHO) that are subject to abuse
- Recommendation to national pharmacopeial o Schedule I: drugs with no accepted
revision committees to modify their medical use, or other substances with a
pharmacopeias according to international high potential for abuse
standards § Heroin
§ Lysergic acid diethylamide (LSD)
§ Mescaline
§ Peyote (Hallucinogenic drug)
§ Methaqualone
§ Marijuana / Cannabis
§ Ecstasy (Methylenedioxy
methamphetamine)

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 o Schedule II: drugs with accepted FDA Pregnancy Categories
medical uses and a high potential for - Appropriate prescribing and use of medications
abuse that if abused may lead to severe requires a risk-versus-benefit assessment of the
psychologic or physical dependence medication for a specific patient
§ Morphine - Five categories that can be used to estimate the
§ Cocaine potential or a systematically absorbed drug for
§ Methamphetamine causing birth defects:
§ Amobarbital o Category A: Adequate and well-
§ Hydromorphone (Dilaudid) controlled studies have failed to
§ Methadone (Dolophine) demonstrate a risk to the fetus in the
§ Meperidine (Demerol) first trimester of pregnancy (and there
§ Oxycodone (Oxycontin) is no evidence of risk in later trimesters)
§ Fentanyl (Sublimaze, Duragesic) o Category B: Animal reproduction
o Schedule III: drugs with accepted studies have failed to demonstrate a
medical uses and a potential for abuse risk to the fetus, and there are no
less than those listed in schedule I and II adequate and well-controlled studies in
that if abused may lead to moderate pregnant women
psychologic or physical dependence o Category C:Animal reproduction studies
§ Codeine have shown an adverse effect on the
§ Hydrocodone fetus and there are no adequate and
§ Hydromorphone (Dilaudid) well-controlled studies in humans, but
§ Methadone (Dolophine) potential benefits may warrant use of
§ Meperidine (Demerol) the drug in pregnant women despite
§ Oxycodone (Oxycontin) potential risks
§ Fentanyl (Sublimaze, Duragesic) o Category D: There is positive evidence
o Schedule IV: drugs with accepted of human fetal risk based on adverse
medical uses and low potential for reaction data from investigational or
abuse relative to those in Schedule III marketing experience or studies in
that if abused may lead to limited humans, but potential benefits may
physical dependence or psychologic warrant use of the drug in pregnant
dependence relative to drugs in women despite potential risks
schedule III o Category X: Studies in animals or
§ Difenoxin humans have demonstrated fetal
§ Diazepam (Valium) abnormalities and/or there is positive
§ Oxazepam evidence of human fetal risk based on
§ Alprazolam (Xanax) adverse reaction data from
§ Carisoprodol (Soma) investigational or marketing experience,
§ Clonazepam (Klonopin) and the risks involved in use of the drug
§ Lorazepam (Ativan) in pregnant women clearly outweigh
§ Midazolam (Versed) potential benefits
§ Temazepam (Restoril)
§ Triazolam (Halcion) Medication Exposures During Pregnancy and Lactation
o Schedule V: drugs with accepted - Every woman in the general population has a
medical used and low potential for 3% to 5% risk of having a child with a birth
abuse relative to those in schedule IV defect or mental retardation.
that if abused may lead to limited - Two important factors to consider when
physical dependence or psychologic assessing the teratogenic potential of a
dependence relative to drugs in medication:
schedule IV o Stage of pregnancy
§ Dihydrocodeine o Amount of medication taken
§ Diphenoxylate - See page 19 for some known teratogens (ADR
for Fetus)

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 - Pregnant or breast-feeding patient who is Prescription Drug Marketing Act of 1987
currently, or considering taking, a medication, - Established new safeguards on the integrity of
the patient needs to be counselled about the nation’s supply of prescription drugs.
potential adverse effects the medication could - Intended to reduce the risks of adultered,
have on her fetus or infant misbranded, repackaged, or mislabelled drugs
entering the legitimate marketplace through
Black Box Warnings “secondary sources”
- Is used to call attention to one of the following 1. Reimportation – prohibits the reimportation of
situations: drug products manufactured in the United
o There is an adverse reaction so serious States except by the manufacturer of the
in proportion to the potential benefit product
that it be considered in assessing the 2. Sales restrictions – prohibits selling, trading,
risks and benefits of using the drug purchasing, or the offer to sell, trade, or
o The risk of a serious adverse reaction purchase a drug sample. It also prohibits resale
can be prevented or reduced in severity by health care institutions of pharmaceuticals
by careful use of the drug (e.g. patient purchased explicitly for the use of institution.
selection, special monitoring, certain Charitable institutions that receive drugs at
concomitant therapy) reduced prices or no cost cannot resell the
o The FDA has approved the drug with drugs.
restrictions to prescribing/distribution 3. Distribution of samples – Samples may be
to ensure its safe use distributed only to a:
a. Practitioners licensed to prescribe such
Drug Listing Act of 1972 drugs
- Enacted to provide the FDA with the legislative b. At written request of the practitioner,
authority to compile a list of marketed drugs to to pharmacies of hospitals or other
assist in the enforcement of federal laws health care institutions
requiring that drugs be safe and effective and 4. Wholesale distributors – manufacturers are
not adulterated or misbranded. required to maintain a list of their authorized
distributors
Orphan drug Act of 1983
- Drugs intended for the treatment of “rare Prescription Drug User Fee Act of 1992
diseases and conditions” may be designated - Allows the FDA to accept user fees from drug
orphan drugs to help promote research on rare and biologic companies in return for committing
diseases. to review new drug and biologic applications
- Rare diseases within certain time frames
o Diseases affecting fewer than 200,000 - More rapid application review process and the
people or diseases that affect more speedier approval of new drug products
than 200,000 people but where
circumstances are such that a company Dietary Supplement Health and Education Act of 1994
is unlikely o recover its research and - Use of various herbs and dietary supplements
development costs and addressed the need to regulate the
labelling claims made for these products
Drug Price Competition and Patent Term Restoration - Products, which include vitamins, minerals,
Act of 1984 amino acids, and botanicals, legally are not
- Changes to speed FDA approval of generic drugs considered drugs if they have not been
and the extension of patient life for innovative submitted for review on NDAs and thus have
new drugs not been evaluated for safety and efficacy by
- Reduces considerably the time and expense of the FDA
bringing a generic version of a drug to market - Forbids manufacturers or distributors of these
products to make any advertising or labelling
claims that indicate that the use of the product
can prevent or cure a specific disease

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 - A disclaimer must appear on the product: “This Drug Product Recall
product is not intended to diagnose, treat, cure, - A marketed product presents a threat or a
or prevent any disease” potential threat to consumer safety
- Permit claims of benefit as they may properly - Product may be recalled or sought for return to
relate to a nutrient deficiency disease or, based the manufacturer
on scientific evidence - Reported problems may include product
defects, product adulteration, container
Dietary supplement and Non-prescription Drug leakage, improper labelling, unexpected
Consumer Protection Act of 2006 adverse reactions, and others
- Enabled the FDA to implement a policy of GMPs - Initiated by the FDA or by the manufacturer
(Good Manufacturing Practice) for dietary
supplements similar to those in place for Voluntary recall
pharmaceutical products - A drug product recall is initiated by the
- Requires that dietary supplements are manufacturer
manufactured according to quality standards
Numerical classification, as follows, indicates the
FDA (Food and Drug Administration) degree of hazard associated with the product being
- Established in 1938 to administer and enforce recalled:
the Federal Food Drug and cosmetic Act - Class I: There is a reasonable probability that
- Mission: the use of or exposure to a violative product will
o To protect the public health against cause serious adverse health consequences or
risks associated with the production, death
distribution, and sale of food and food - Class II: The use of or exposure to a violative
additives, human drugs and biologicals, product may cause temporary or medically
radiologic and medical devices, animal reversible adverse health consequences or the
drugs and feeds, and cosmetics. probability of serious adverse health
consequences is remote
FDA Modernization Act of 1997 - Class III: The use of or exposure to a violative
- Enacted to streamline FDA policies and to codify product is not likely to cause adverse health
many of the agency’s newer regulations consequences
- The bill expanded patient access to
investigational treatments for AIDS, cancer, Depth of recall
Alzheimer disease, and other serious and life- - Level of market removal or correction
threatening illness - Depends on the nature of the product, the
- Provided for faster new drug approvals by using urgency of the situation, and depth to which the
drug sponsors’ fees to hire additional internal product has been distributed
reviewers, by the authorized use of external - Lot numbers of packaging control numbers on
changes in the requirements demonstrating a the containers or labels of the products help in
drug’s clinical effectiveness identifying the product to be recalled
- Provided incentives for investigations of drugs
for children The Pharmacist’s Contemporary Role
- Pharmacy graduates holding:
Globalization and the FDA o Bachelor of Science (BS) in Pharmacy
Federal Food and Drug Administration degree
- Protect the public health by assuring th safety o Doctor of Pharmacy
and efficacy of the drugs and other products - Practice in a variety of settings
- Established foreign operational offices in - Basic pharmaceutical sciences, clinical sciences,
receptive supplier and professional training and experience
- Coalitions with foreign counterpart agencies - Community pharmacies, patient care
and together, they are generating global data institutions, managed care, home health care,
information systems and mechanisms to military and government service, academic
identify and quickly address potential risks settings, professional associations,
irrespective of geographic location pharmaceutical research and manufacturing

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 industry, as well as in other positions requiring Patient Protection and Affordable Care Act of 2010
the pharmacist’s expertise - Enacted to decrease the number of medically
uninsured while improving the quality and
The Mission of Pharmacy
reducing the overall costs of health care in the
- House of Delegates of the APhA adopted the
following mission statement for pharmacy United States
practice:
o To serve the society as the profession
responsible for the appropriate use of
medications, devices, and services to
achieve optimal therapeutic outcomes

Pharmaceutical Care
- The care that a given patient requires and
receives which assures rational drug usage
- Component of pharmacy practice which entails
the direct interaction of the pharmacist with the
patient for the purpose of caring for that
patient’s drug-related needs
- A patient-centered, outcomes-oriented
pharmacy practice that requires pharmacist to
work in concert with the patient and the
patient’s other healthcare providers to promote
heath, to prevent disease, and to assess,
monitor, initiate, and modify medication use to
assure that drug therapy regimens are safe and
effective (APha, 1992)
- Goal: to optimize the patient’s health-related
quality of life and achieve positive clinical
outcomes, within realistic economic
expenditures.

Mission of the Pharmacist
- ASHP, a national organization that represents
pharmacists who practice in hospitals
o The mission of the pharmacist is to
provide pharmaceutical care.
Pharmaceutical care is the direct,
responsible provision of medication-
related care for the purpose of
achieving definite outcomes that
improve a patient’s quality of life.

The Omibus Budget Reconciliation Act of 1990
Established a requirement for each state to
develop and mandate DUR (drug utilization
reviews) programs to improve the
pharmaceutical care provided to patients
covered by the federal medical assistance
program

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Chapter 2: - Preformulation studies (physical and chemical
NEW DRUG DEVELOPMENT AND APPROVAL PROCESS properties of the agent).
- Formulation studies follows
ACRONYMS o Develop initial feature of proposed
pharmaceutical product/dosage form
Clinical Drug Materials (CTM)
- Dosage formulations used for clinical evaluation Drug Substance
of a new drug - Active ingredient/component that produces
Investigational New Drug (IND) pharmacologic activity
- Protects the right and safety of the subjects - Produced by:
- Ensures investigational plan is sound and o Chemical synthesis
designed to achieve the stated objectives o Enzymatic reaction
New Drug Application (NDA) o Recovery from a natural product
- Gains permission to market the drug product o Recombinant DNA technology
Supplemental New Drug Application (SNDA) o Fermentation
- Application by the sponsor of approved NDA to o Combination of these processes
make changes - Purification needed before use in a drug
Abbreviated New Drug Application (ANDA) product
- Nonclinical laboratory studies and clinical
investigations may be omitted, except those New Chemical Entity (NCE)
pertaining to the drug’s bioavailability - Drug substance with unknown clinical,
Biologics License Application (BLA) toxicologic, physical and chemical properties
- Manufacture of biologicals (blood products,
vaccines, and toxins) Drug Product
International Conference on Harmonization (ICH) - Finished dosage form (containing the drug
- Brings together regulatory requirements substances + other excipients/inert substances)
- Establishes (long range goal) a uniform set of
standard for drug registration within geographic SOURCE OF NEW DRUG
area A. Variety of natural sources
- Serendipity / result of tireless pursuit
FACTORS TRIGGERED RAPID DRUG DEVELOPMENT - Plant materials have served as a reservoir of
AND PRODUCTION IN THE US potential new drug
- Pharmaceutical industry’s discovery of new - Conversion of botanic folklore remedies into
drugs and development into commercial modern wonder drugs
products B. Synthesis in the laboratory
- Scientific and biomedical information generated
worldwide (research institutes, academic center VARIETY OF NATURAL SOURCES
and industry) Reserpine
- Combined efforts in drug discovery and - tranquilizer and hyposensitive agent
development (chemists, biologists, molecular - Medicinal chemical isolated by design from the
biologists, pharmacologists, toxicologists, folklore remedy Rauwolfia serpentine
statisticians, physicians, pharmacists and
pharmaceutical scientist, engineers, and etc.) Perwinkle or Vinca rosea
- Rapid growth of pharmaceutical industry during - For diabetes mellitus
WWII
- Development of other antibiotics Paclitaxel (taxol)
- Post-war drug discovery with development of - for ovarian cancer
many new agents - from an extract of the pacific yew tree

Federal Food, Drug and Cosmetic Act Other plant constituent
- New drug be approved by the Food and Drug - inactive or unimportant therapeutically
Administration (FDA) before legally introduced - chemically modified to yield important drug
in interstate commerce. with profound pharmacologic activity

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 - examples, species of Dioscorea (Mexican yams) - GENE SPLICING – genetic material transplanted
o rich in chemical steroids structure: from higher species (human) which induce the
cortisone and estrogens lower organism (bacterium) to make proteins
o semi synthetically produces o Human insulin
o Human growth hormone
Animals have served human in their search for drugs: o Hepatitis B vaccine
Cattle, sheep, and swine from the endocrine gland o Epoetin α
- hormonal substances: thyroid extract, insulin, o Interferon
and pituitary hormone (replacement therapy in
the human body) MoAB
- Conducted within cells of higher animals
Pregnant Mares (from urine) (including patient)
- rich source of estrogen - Exploits cell to produce an antibody to combat
the specific agent
Production of various biologic product - Used in home pregnancy testing products
- serums, antitoxins, and vaccines (life saving) - In medicine: to stage and localize malignant
- small pox vaccine – pioneering work of Edward cells of cancer
Jenner in England in 1796. - Future: combat disease (lupus erythematosus,
- Cultures of renal monkey – poliomyelitis juvenile onset diabetes and myasthenia gravis)
vaccines
- Fluids of chicks embryo – mumps and influenza 2. Human gene therapy (promising new
vaccines technology)
- Duck embryo – rubella (German measles) - Prevent, treat, cure, diagnose, or mitigate
vaccines human disease caused by genetic disorder
- Skin of bovine calves inoculated with vaccinia - 1st human gene therapy
virus – small pox vaccines o Treat Adenosine deaminase (ADA)
deficiency (condition resulting in
SYNTHESIS IN THE LABOTATORY / MOLECULAR abnormal functioning of the immune
MANIPULATION system)
- Change natural chemical to different chemical
structure Goal Drug
- Produce:
1. Development of pharmaceutical drug products o Desire effect
(result of genetic engineering) o Administered by the most desired route
- Submicroscopic manipulation of the double (orally) at minimal dosage and dosing
helix, the spiral DNA chain of life frequently
o Exhibit no side effects
Two basic technologies that drive the genetic field of o Eliminates from the body efficiently,
drug development: completely and without residual effect
- Recombinant DNA (rDNA)
- Monoclonal Anti-body products (moAB) Lead Compound
production - Prototype chemical compound
- Fundamental desired biologic or pharmacologic
SIMILARITIES of rDNA and MoAB activity
- Manipulate and produce proteins (building
blocks of living matter) Prodrug
- Production techniques influence cells in their - Metabolic biotransformation of compound after
ability to produce proteins administration to produce desired
pharmacologically active compound
DIFFERENCES - Inactive prodrug to active compound
rDNA (enzymatic biochemical cleavage)
- More fundamental - Ex. Enalapril (enalapril maleate, Vasotec)
- Produce any protein

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 o Bioactivated to enalaprilat (ACE § Mechanism-based drug design
Inhibitor, for hypertension)
- Used for the following reasons: Random / non-targeted screening
o Solubility - Testing of large numbers of systematic organic
o Biostability compound or substance of natural origin for
o Absorption biologic activity.
o Prolonged release - Detects unknown activity of test compounds /
identifies compromising compounds to be
New Drug studied to determine specific activity
- (according to FDA) Not recognized among - Ex. Bioassays
experts as safe and effective o Detects and evaluates biological activity
- Change in previously approved drug product’s o Differentiates the effects and potency
formulation/method of manufacture of test agent compared with controls of
- New combination of 2 or more old known action and effect
drugs/change in proportions of drugs
- Proposed new use, new dosage regimen, new Molecular modification
route of administration or new dosage form - Chemical alteration of an organic compound
(frequently a lead compound) to:
Orphan Drug o Enhance its usefulness as a drug
- Treatment IND are sought for to target small o Enhancing specificity for a body’s target
number of patient with rare conditions / site
diseases (orphan diseases) where there are no o Increasing potency
satisfactory alternative treatments o Improving rate and extent of absorption
o Modifying time course in the body
Orphan Disease o Reducing toxicity
- Rare disease / condition affecting fewer than o Change of physical / chemical
200,000 people: properties to provide desired
o Chronic lymphocytes pharmaceutical features
o Leukemia
o Gaucher’s disease Mechanism-based drug design
o Cystic fibrosis - Drug design that interferes with the known or
o AIDS suspected biochemical pathway of mechanism
of a disease process
Pharmacologic Profile - Intention: interaction of the drug with:
- In vitro cultures of cells & enzyme systems and o Specific cell receptors
in vivo animal models are used o Enzyme systems
- Objective: to obtain basic information on the o Metabolic processes of the pathogens /
drug’s effects that may be used to predict safe tumor cells
and effective use in humans - Resulting in:
o Blocking
Molecular Graphics o Disruption
- Use of computer graphics to present and o Reversal of the disease process
manipulate the structure of the drug model to
fit the stimulated molecular structure of the Non proprietary names
receptor site - For single agents
- Complementary tool in drug molecule design
METHODS OF DRUG DISCOVERY Proprietary / Trademark names
- Some drugs may be result of: - Associated with a single chemical entity or with
o Fortuitous discovery a mixture of chemicals constituting a specific
o Carefully designed research programs proprietary product
of:
§ Screening
§ Molecular modification

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Pharmacology Two drugs in a biologic system
- Enhances: - Compete for the same binding sites
o Physical and chemical properties - Drug with stronger bonding attraction for the
o Biochemical and physiological effects site prevails
o Mechanisms of action, absorption, - Bound molecules of the more weakly bound
distribution, biotransformation & drug
excretion, therapeutic & other uses of - May be replaced from the binding site
drugs - Left free in the circulation as unbound drug
- Concerned with drugs, their sources,
appearance, chemistry, action, and uses METABOLIC CHARACTERIZATION
- Comes from the Latin word pharmaco (drug)
and logos (study of) Drug metabolism (chemical process within living
organism to maintain life)
SUB AREA OF PHARMACOLOGY - Series of animal studies of a proposed drugs
1. Pharmacodynamics ADME are undertaken to determine:
- Study of the biochemical and physiological a. Extent and rate of drug absorption from various
effect of drugs and their mechanism of actions routes of administration, including human use
2. Pharmacokinetics b. Rate of distribution of drug through the body
- Deals with the absorption, distribution, and the site or sites and duration of the drug
metabolism or biotransformation, and excretion residence
(ADME) of the drug c. Rate, primary and secondary sites, and the
mechanism of the drugs metabolism in the
TODAY’S EMPHASIS IN DEVELOPMENT OF NEW DRUGS body and the chemistry and pharmacology of
- Identifying the cause and process of a disease any metabolism
- Designing drug molecules capable of interfering d. The proportion of administered dose
with that process eliminated from the body and its rate and route
- Precise cause of each disease – not yet known of elimination
- Known is most diseases arising from:
o Biochemical imbalance BIOLOGIC CHARACTERIZATION
o Abnormal proliferation of cells Specific and non-specific enzymes
o Endogenous (internal cause) deficiency - Participate in drug metabolism (livers, kidneys,
o Exogenous (external factor) chemical lungs, and gut)
toxin or Invasive pathogen (harmful
bacterium) Drug following oral administration that enters the
hepatic circulation after absorption from gut
QUANTITY OF DRUG WILL INFLUENCE ITS EFFECTIVITY - Exposed to rapid metabolism
- There is relationship of drugs for:
o Interaction and the capacity of the 1st pass effect
specific receptor site - Transit through the liver and exposure to the
- Following a dose of drug and its transit to the hepatic enzyme system
site of action - To be avoided, other routes of administration
o Cell receptors may or may not become (buccal, rectal) may be used to absorb drug into
fully saturated with interacting drug the systemic circulation through blood vessels
o Receptors fully saturated – effects of other that hepatic
the specific interaction is maximized
o Additional drug present and not ADME studies
participating in the interaction – serve - Performed through the collection and analysis
as a reservoir to replace drug molecules of urine, blood and feces samples, and careful
that become releases from the complex exam of animal tissue and organs upon autopsy

GRH – 1APH 12

DIFFERENT STUDIES IN TOXICOLOGICAL PROFILE DIFFERENT PROPERTIES OF DRUG SUBTANCES
a. Acute or short-term toxicity INCLUDED IN PRE-FORMULATION STUDIES
- Toxic effect of a test compound when 1. Drug Solubility
administered in single dose and/or multiple - Drug substance must possess some aqueous
doses over short period, usually a single day solubility for system absorption and therapeutic
- Test compound administered at various levels, response
with toxic signs observes - Poorly soluble compounds – incomplete erratic
- Doses are ranged to fin dose not to produce and/or slow absorption producing minimum
toxic effect, severe toxic effect and response at desired dosage
intermediate toxic effect
2. Partition Coefficient
b. Sub-acute or sub-chronic studies - Drug molecules must first cross a biologic
- Considered: The relationship to project human membrane of protein and lipid to produce a
clinical studies for safety pharmacologic response, which acts as a
- Animal toxicity studies (minimum of two weeks lipophilic barrier to many drugs
of daily drug administration at 3 or more dosage - Measure of its distribution in a lipophilic/
levels to two animal species) are required to hydrophilic phase system, and is indicative of its
support the initial administration of a single ability to penetrate biologic multiphase system
dose in human clinical testing
3. Dissolution Rate
c. Chronic toxicity studies - Speed, rate, at which a drug substance dissolves
- Drugs intended to be given to humans for a in a medium
week or more, animal studies of 90 to 180 days - Provide indication of drug’s absorption
in length must demonstrate safely potential:
- For chronic human illness, long-term animal o Drug solubility
studies of 1 year or longer year o Partition coefficient

d. Carcinogenicity studies 4. Physical Form and Particle Size
- For limited number of rat and mouse strains - Affect the drug’s:
o There is reasonable information on o Dissolution rate
spontaneous tumor incidence o Rate and extent of absorption
- Long-term studies (18-24 months) with
surviving animals killed and studied at defined 5. Stability
weeks during the test period - Tests: various temperatures, conditions or
- Component of chronic testing, undertaken relative humidity and environment of light, air,
when the compound has shown sufficient and packaging
promise as a drug to enter human clinical trials - Critical in preparing a successful pharmaceutical
product, alone and when combined with
e. Reproduction studies formulation components
- reveals any effect of an active ingredient on - Drugs susceptible to:
mammalian reproduction o Oxidative decomposition – add
- evaluated for anatomical abnormalities, growth antioxidant stabilizing agent
and development: maternal parent, fetus, o Hydrolysis – processing and packaging
neonates and weaning offspring required
- Fertility and mating behaviour, mutagenecity,
teratology INITIAL PRODUCT FORMULATION AND CLINICAL TRIAL
MATERIALS (CTM)
f. Genetoxicity or Mutagenecity studies - Products formulated (preformulaton studies as
- Determines whether test compound affects basis) for the clinical studies and for the new
gene mutation or cause chromosome or DNA drug with consideration of:
damage o Dose
- Used in assays to detect mutations: Strains of o Dosage form
Salmonella typhimurium o Route of administration

GRH – 1APH 13

 - Clinical supplies / clinical trial materials (CTM) - Includes:
o Includes: o Advice on the adequacy of data to
§ Proposed new drug support an investigational plan
§ Placebos (non-medicated forms o Design of a clinical trial / investigational
for controlled studies) procedures
§ Drug products compared to o Data to meet requirement of the next
new drugs (comparator drugs step
or drug product) o Filing NDA to gain approval for
marketing
Blinded Studies
- Controlled studies where 1 of the parties is not FDA REVIEW OF AN IND APPLICATION
knowledgeable of which product is being - The FDA’s objectives in reviewing IND
administered - Protect the safety and right of human subjects
- Single blind studies - Ensure evaluation of the drug’s safety and
o Patient unaware of the: effectiveness
§ Agent administered - Objections are best met by the accuracy and
(investigational drug) completeness of the IND submission
§ Placebo (comparator drug) - Design and conduct of the:
- Double blind studies: o Investigational plan
o Neither the patient nor the clinician is o Expertise
aware of the agent administered o Diligence of the investigators

Open Label FDA DRUG CLASSIFICATION SYSTEM
- All parties are aware of the products - Upon receipt and examination of IND / NDA
administered application
Parallel designs - FDA classifies the drug by:
- Applicable to most clinical trials o Chemical type
Crossover designs o Therapeutic potential
- For comparing different treatments within
individuals since following one treatment, a PHASES OF PRODUCT DEVELOPMENT OF DRUG
patient is “crossed over” to a different PRODUCTS CONTAINING NCEs (page 57)
treatment Preclinical Stage
- Animal pharmacology and toxicology are
THE CLINICAL PROTOCOL obtained
- Part of the IND application - Determines the safety and efficacy of the drug
- Submitted to ensure the appropriate design and - Submission of investigational new drug (IND)
conduct of investigation application for human testing to the FDA
- Includes (page 54):
o Purpose and objectives Phase I
o Investigational plan - Initial introduction (Clinical Testing)
o Number of patients - Subjects: Healthy volunteers (20-100)
o Dosing plan - Determines drug tolerance and toxicity
o Subject selection (assessing safety)
o Clinical procedures, laboratory tests
o Patients’ observations, measurements Phase II
and tests etc. - Controlled clinical studies to several hundred
patients with the disease/conditions are treated
PRE-IND MEETINGS - Safety measures – determines the therapeutic
- FDA advices a sponsor relating to the index (ratio of toxic dose to effective dose)
preparation and submission of IND on: - Final drug formulation developed bioequivalent
o Scientific (same rate and extent of drug absorption to the
o Technical brand drug product) to the dosage form
o Formatting concerns

GRH – 1APH 14

Phase III FACTORS IN DETERMINING DRUG’S DOSE
- Several hundred to several thousand of patients - Age
with the disease/condition treated for which - Body weight
the drug was developed (controlled and - Sex
uncontrolled trials) - Body surface area
- Large scale, multicenter studies performed – to - Tolerance
determine safety and efficacy - General health status
- Side effects are monitored - Pathologic condition(s)
- Concomitant drug therapy
Phase IIIa - Dosage form, time & route of administration
- Completed studies sufficient for the NDA
DRUG DOSAGE AND TERMINOLOGY
Phase IIIb
- Additional studies are used to gather: Usual adult dose and starting dose for the patient
o Supplemental information to support - Amount of drug that produces the desired
certain labelling requests effect in the majority of adult patient
o Information on patients’ quality of life
issues Dosage regimen / schedule of dosage
o Product advantages over already - Determined from:
marketed competing drugs o Clinical investigation
o Evidence in support of possible o Inherent duration of action
additional drug indications o Pharmacokinetics
o Other clues for prospective o Characteristics of the dosage form
postmarketing studies
Unity of Activity
Submission of a New Drug Application (NDA) - Derived from biological assay methods
- An NDA is submitted to the FDA for review and - Reflects drug’s potency
approval when clinical trials are completed - Necessary when drug’s (antibiotics and
endocrine products) suitable chemical assay
Phase IV methods are unavailable
- Continual clinical investigation
- Manufacturing scale-up activities Minimum effective concentration (MEC)
- Drug formulation modified slightly - Drug’s average blood serum concentration
- To gather supplemental information (labelling, - Determines minimum concentration expected
product advantages, additional indications, to produce the drug’s desired effects in a
prospective postmarketing studies) patient
- Product development continues after the FDA’s
market approval of drug product Minimum toxic concentration (MTC)
- Drug product may be improved due to - Second level of serum concentration of drug
equipment, regulatory, supply or market - Above the average blood serum concentration
demands level producing toxic effects
- Negates desirable effects of the drug
Post marketing reporting of adverse drug experiences compromising safety of the patient
- A drug sponsor is required to report to the FDA
each adverse drug experience that is both ED50 / Median Effective Dose
serious (life threatening or fatal) and - Produces the desired intensity of effect in 50%
unexpected (not contained in the approved of the individuals tested
drug product labelling) regardless of the source
of the information within 15 working days of Median Toxic Dose
receipt information - Produces a defined toxic effect in 50% of the
individuals testes

GRH – 1APH 15

Therapeutic Index Oral
- Relationship between drug’s desired and - Rarely or if fully absorbed into bloodstream due
undesired effects to various reasons:
- Ratio of drug’s median toxic dose and median o Physical, chemical, and biologic barriers
effective dose, TD50/EF50 to their absorption

Maintenance Dosage Rectal, Gastrointestinal tract, Sublingual, Dermal
- Regularly schedule subsequent administration (skin), and other sites
to keep the most desirable concentration of - Varying rates and degrees of absorption
drug in the blood
ROUTES OF ADMINISTRATION
Initial Priming / Loading Dose - Fundamental considerations in dosage form
- Required to attain desired concentration of the design:
drug in the blood of tissues
1. Local effects
Prophylactic Dose - Direct application of the drug to the desired site
- Protects the patient from contracting the illness of action (eye, nose, or skin)

Therapeutic Dose 2. Systemic effects
- Administered to the patient after exposure or - Entrance of drug into circulatory system and
contraction of the illness transport to cellular site of its action
- Direct placement into the bloodstream via IV
INTERACTION injection or absorbed into the venous
circulation following oral/ other routes of
Drug-Drug Interaction administration
- Effects of drugs are modified by prior/
concurrent administration of another drug 1. Oral route
- Chemical or physical interaction between the - Most taken for systemic effects after absorption
drug /alteration of the absorption, distribution, from various surfaces along gastrointestinal
metabolism /excretion patterns of one of the tract
drugs - Most natural, uncomplicated, convenient and
- Include “social agents” (tobacco and alcohol) safe means of administering drugs
affecting pharmacokinetics of a number of - Disadvantages:
drugs and alter drug’s usual dose o Slow drug response
Drug-Disease Interaction o Chance of irregular absorption of drugs
Drug-Food Interaction (constitutional make-up, amount/type
Drug-Social Agent Interaction of food present within GIT)
o Destruction of certain by acid reaction
TIME AND CONDITIONS OF ADMINISTRATION of stomach or git enzymes
Time drug is administered
- Influence dosage 2. Rectal route
- Suppositories, solutions/ointments
Absorption more rapid - For systemic action preferred of drugs:
- Stomach and upper portions of intestinal tract o Destroyed/inactivated by the stomach
are empty of food and intestine environments
o Patient is unconscious or incapable of
DOSAGE FORM AND ROUTE OF ADMINISTRATION swallowing
Intravenous / Parenteral (Injectable) - Bypass the liver
- Drugs enter blood stream directly and - Disadvantages:
completely o Inconvenient
- Required to achieve the same blood levels / o Absorption is irregular and difficult to
clinical effects predict

GRH – 1APH 16

 3. Parenteral route o Estradiol (estrogenic hormone)
- Injected into the body using a fine needle at o Clonidine (antihyoertensive)
various sites and depths o Scopolamine (antinausea)
- Routes:
o SubQ B. For local action
o IM - Prolonged local contact with minimal
o IV absorption
o Intracardiac - Antiseptics, antifungal agents, anti-
o Intraspinal inflammatory agent, local anaesthetic agents,
- Preferred for drugs: skin emollients and protectants
o Destroyed/inactivated in GIT - Reams, ointments, powders, aerosol sprays,
o Poorly absorbed to provide satisfactory lotions, solutions
response
o Rapid absorption is essential 5. Ocular, Oral, and Nasal Routes
- Advantages: - For eye, ear and mucous membranes of the
o Treating patients who are nose (not for systemic effect)
uncooperative, unconscious, unable to
accept oral medication A. Ophthalmic preparations
- Disadvantages: - Solutions, suspensions, and ointments
o Once drug is injected, there is no
retreat B. Nasal preparations
- Solutions /suspensions by drops as fine mist
SubQ (Hypodermic) Injection from a nasal spray container
- Injected through the layers of skin inti the loose
subQ tissue C. Otic or ear preparations
- Aqueous solution / suspension (2ml or less) - Viscid to soften ear wax, relieve earache or
- Example: Insulin combat ear infection

IM Injection 6. Other routes
- Injected into the skeletal muscles –
gluteal/lumbar muscles Lungs
- Aqueous/oleaginous solution/suspension - Administration of gases and aerosol sprays
- Drug injected: those irritating the subQ tissue - Should attain proper drug particle size and
- 2 – 5ml ensure uniformity for consistent penetration

Intradermal Injection Drugs inserted into the:
- Administered to the corium of the skin (arm and A. Vagina
back) - Tablets, suppositories, ointments, emulsion
- 10th of a ml in volume foams, gels, solutions
- Use: diagnostic measures
- Example: tuberculin and allergy testing B. Urethra
- Suppositories or solutions
4. Epicuraneous route
- Applied topically to the skin (for actions at site Treatment IND/Treatment Protocol
of application or systemic drug effects) - Use of an investigational drug in the life-treating
disease in lieu of no satisfactory alternative
A. Transdermal delivery systems (adhesive disc or therapy
patch) - Makes promising new drug available to
- Slowly releases medication for percutaneous desperately ill patient, early as possible in the
absorption drug development process
- Example:
o Nitroglycerin (antianginal)
o Nicotine (smoking cessation)

GRH – 1APH 17


Withdrawal or Termination of an IND International Conference on Harmonization (ICH)
- By the sponsor any time ending all clinical - Harmonizing/bringing together regulatory
investigation requirements with long-range goal of
- Stock of clinical supplies returned to the establishing a uniform set of standards for drug
sponsor/ otherwise destroyed registration within these geographic areas
- If withdrawn because of safety reasons, must - Focused on 3 general areas:
advice: FDA, IRB, and all investigators o Quality
- FDA may terminate an IND for: safety, o Safety
efficiency, or regulatory compliance issue o Efficacy

Drug Product Labelling Quality topics
- According to federal regulation, includes: - Stability, light stability, analytical validation,
o Label placed on an immediate container impurities and biotechnology
o Information on the packaging, in
package insert, and in company Safety topics
literature, advertising, and promotion - Carcinogenicity, genotoxicity, toxicokinetics,
materials reproduction toxicity, and single and repeat
- The package insert required to contain the dose toxicity
summary information
o Description of the product Efficacy topics
o Clinical pharmacology - Population exposure, managing clinical trials,
o Indication and usage clinical study reports, dose response, ethnic
o Contraindications factors, good clinical practices and geriatrics.
o Warning
o Precaution
o Adverse reaction
o Drug abuse and dependence
o Over dosage
o Dose and administration
o How supplies

Completed New Drug Application
- Reviewed by the FDA, decides:
o To allow the sponsor to market the drug
o To disallow marketing
o To require additional data before
rendering judgment
- FDA respond within 180 days (review clock) of
receipt of an application

FDA Review and “Action Letters”
- Approvable letter
o Specific additional data or other
requested material is submitted/
specific conditions are met
o Pertains to development or wording of
the final product labelling
- Approval letter
o Approval of the application permitting
marketing
- Non-Approvable Letter
o One or more deficiencies

GRH – 1APH 18


ROUTES OF DRUG ADMINISTRATION ROUTE OF ADMINISTRATION AND DELIVERY SYSTEM
TERM SITE OF PRIMARY DOSAGE FORMS
Oral Mouth Oral Tablets
Peroral (per os )
α Gastrointestinal tract via Capsules
mouth Solutions
Sublingual Under the tongue Syrups
Parenteral Other than the Elixirs
gastrointestinal tract (by Suspensions
injection) Magmas
Intravenous Vein Gels
Intra-arterial Artery Powders
Intracardiac Heart Sublingual Tablets
Intraspinal or
Spine Troches, lozenges
Intrathecal Drops (solutions)
Intraosseous Bone Parenteral Solutions
Intra-articular Joint Suspensions
Intrasynovial Joint fluid area Epicutaneous, Ointments, gels
Intracutaneous, Skin Transdermal Cream
Intradermal Infusion pumps
Subcutaneous Beneath the skin Pastes
Intramuscular Muscle Plasters
Epicutaneous Skin surface Powders
(topical) Aerosols
Transdermal Skin surface Lotions
Conjunctival Conjunctiva Transdermal patches,
Intraocular Eye disks, solutions
Intranasal Nose Intraocular, Intraaural Solutions
Aural Ear Suspensions
Intrarespiratory Lung Intranasal Solutions
Rectal Rectum Sprays
Vaginal Vagina Inhalants
Ointments
Intrarespiratory Aerosols

Rectal Solutions

Ointments

Suppositories

Gels
Vaginal Solutions
Ointments
Emulsion foams
Gels
Tablets
Inserts, suppositories,
sponge
Urethral Solutions
Suppositories

GRH – 1APH 19


Chapter 4: Syrups, Solutions
Dosage Dorm Design: Pharmaceutical and Formulation - To provide clear liquid dosage forms substances
Considerations Controlled-release tablets
- To provide rate-controlled drug action
Pharmaceutics Ointments, creams, transdermal patches
- Study on the: formulation, manufacture, - To provide optimal drug action from topical
stability, and effectiveness of pharmaceutical administration sites
dosage forms Suppositories
- To provide the insertion of a drug into one of
Pharmaceutical Ingredients or Excipients the body’s orifices
- Selective use of these non medicinal agents Injections
- Uses: - To provide placement of drugs directly in the
o Solubilize bloodstream or body tissues
o Thicken Inhalants, inhalation aerosols
o Stabilize - To provide for optimal drug action through
o Flavor inhalation therapy
o Suspend
o Dilute General Considerations in Dosage Form Design
o Preserve
o Efficacious - Determine desired product type – framework
for product development
Requirement of a proper design and formulation of - Develop and examine initial formulations of the
dosage form product:
o Desired features: drug release profile,
Consideration of drug substances: bioavailability, clinical effectiveness
Physical, Chemical, and Biological characteristics o Pilot plant studies and production scale-
- Compatible with one another – stable, up
efficacious, attractive, easy to administer and - Master formula – formulation that best meets
safe the goals of the product
- Manufactured under appropriate measures of - Factors to consider before formulation of a
quality control and packaged in containers to medicinal agent in one or more dosage forms
make product stable o Therapeutic matters (nature of the
- Labelled to promote correct use and stored illness)
under conditions to maximize shell life o Manner it is treated (locally or through
systemic action)
The Need for Dosage Forms o Age and anticipated condition of the
patient
Coated tablets, sealed ampoules
- To protect the drug substance from the PREFORMULATION STUDIES
destructive influences of atmospheric oxygen or - Drug be chemically and physically characterized
humidity - Define the nature of the drug substance
Enteric-coated tablets
- To protect the drug substance from the Three ways liquid drug be given in solid form
destructive influence of gastric acid after oral
administration Liquid substances
Capsules, Flavored syrups - Sealed in soft gelatin capsule
- To conceal the bitter, salty or offensive taste or - Developed into a solid ester or salt form
odor of a drug substance suitable for tablets or drug capsules
Suspension - Mixed with a solid or semisolid material
- To provide liquid preparations of substances o Melted mixture is poured into hard
that are either insoluble or unstable im desired gelatin capsules to harden and capsules
vehicle sealed

GRH – 1APH 20

 - Polymorphic forms – different physical –
Preformulation Studies chemical properties (including melting point
1. Physical Description and solubility)
- Physical description - Evaluation of:
o Particle size o Crystal structure (microscopy, IR
o Crystalline structure spectroscopy, thermal analysis, x-ray)
o Melting point
o Solubility Solubility
- Chemical properties - Determined by equilibrium solubility method
o Structure form reactivity o Excess amount of drug + solvent =
o Purity of the chemical substances for: shaken at constant temperature over a
§ Identification and for evaluation prolonged period of time until
of its chemical, physical, and equilibrium is obtained
biologic properties. - Drug possess aqueous solubility – for
therapeutic efficacy
2. Microscopic Examination - Insoluble compounds: incomplete/erratic
- Indication of: particle size and size range of the absorption
raw material along with the crystal structure - Solubility and particle size
- Information in formulation processing - Solubility and pH
attributable to changes in particle or crystal o Drug formulated to liquid product:
characteristics of the drug adjustment of pH of solvent where drug
is dissolved to adjust solubility
3. Melting Point Depression o Weak acidic or basic drugs – require
- Determines the: extremes in pH outside or accepted
o purity of the substance physiologic limits or that may cause
o Compatibility of various substance stability problems with formulation
before inclusion in the dosage form ingredients
- Pure substances: sharp melting point
- Impure substances: depressed melting point Dissolution Rate
- Time for the drug to dissolve in the fluids at the
4. Phase Rule absorption site (rate-limiting step in absorption)
- Phase diagrams constructed determines: - Dissolution rate of the drugs – increased by
o Existence and extent of the presence of decreasing the particle size
solid and liquid phases in binary, - For higher dissolution rate
ternary and other mixtures o Use a highly water soluble salt of the
- Particle Size – affects: physical – chemical parent
properties of drug substances:
o Dissolution rate 2 methods in determining dissolution rates of chemical
o Bioavailability compounds
o Content uniformity 1. Constant surface method
o Stability - Intrinsic dissolution rate of the agent
o Taste - Characteristic of compounds and solvent under
o Texture fixed experimental conditions
o Flow properties - mg dissolved / min / cm square
o Absorption
o Sedimentation rate 2. Particulate dissolution
- Weighed amount of powdered sample +
Preformulation Studies dissolution medium in constant agitation
Polymorphism system
- Substances can exist in more than one - To study the influence of particle size, surface
crystalline form area, and excipients upon the active agent

GRH – 1APH 21

Fick’s Law (law of diffusion) Stability
- Describes the: - Extent a product retains within specified limits
o Relationship of diffusion and dissolution and through its period of storage and use
of the active drug in the dosage form - Stability studies conducted in the
and when administered in the body preformulation phase:
- 1st law – relates to a steady state flow o Solid-state of the drug alone
- 2nd law –relates to a change in concentration of o Solution phase
drug with time, at any distance, or a nonsteady o With the expected excipients
state of flow
Drug and Drug Product Stability
Membrane Permeability - Evaluation of:
- Everted intestinal sac o Physical and chemical stability of pure
o Determines degree and rate of passage drug substances – important for
of drug through the membrane sac by preformulation
passive and active transport - Drug Stability: Mechanisms of Degradation
- Early assessment of passage of drug molecules - Chemically drugs substances with different
across biologic membranes susceptibilities toward chemical instability:
- To produce a biologic response – drug molecule o Alcohols
must first cross a biologic membrane o Phenols
- The biologic membrane (lipid barrier) – permits o Aldehydes
absorption of lipid soluble substance by passive o Ketones
diffusion o Esters
o Ethers
Basis of pH-partition Coefficient o Acids
- Interelationship at the absorption site and o Salts
absorption characteristics of various drugs: o Alkaloids
o Dissociation constant o Glycosides
o Lipid solubility o others
o pH
- Indication of absorption expectations: MOST FREQUENTLY ENCOUNTERED DESTRUCTIVE
o Data from basic physiochemical studies: PROCESS
§ pKa
§ Solubility Hydrolysis (solvolysis process)
§ Dissolution rate - (drug) molecules interact with water molecule
to yield breakdown product
Partition Coefficient - Susceptible to the hydrolytic process:
- Selection of appropriate extraction solvents, o Esters
drug stability, use of salting-out additives and o Substituted amides
environmental concerns o Lactones
o Lactams
pKa / Dissociation Constants
- Extent of ionization of drug – strong effect on
formulation and pharmacokinetic parameters of Oxidation
the drug - Loss of electron from an atom or molecule
- Determined by potentiometric titration - Involves free radicals (molecules or atoms
o For the pharmacist important: containing one or more unpaired electrons)
§ Predicting precipitation in - Destructive to:
admixtures o Aldehydes
§ Calculating solubility of drugs at o Alcohols
certain pH values o Phenols
o Sugars
o Alkaloids
o Unsaturated fats and oils

GRH – 1APH 22

DRUG AND DRUG PRODUCT STABILITY: o Storage under refrigeration
- pH – major determinant in stability
A. KINETICS AND SHELF LIFE o optimum stability: pH 5 and 6
Five types of stability
o buffering agents increases stability
1. Chemical
- active ingredient retains chemical integrity and - Oxygen sensitive drugs
labelled potency within the specified limits o Prepared in dry state
- important for selecting: o Packaged in sealed containers with air
o storage conditions (temperature, light, replaced by inert gas (Nitrogen, Carbon
humidity) dioxide)
o proper container for dispensing o Add antioxidants (for stability):
o anticipating interactions when mixing
§ In aqueous preparations:
drugs and dosage forms
- must know reaction order and rate • Na2SO3
• NaHSO3
2. Physical • H3PO2
- Original physical properties, appearance • Ascorbic acid
palatability, uniformity, dissolution and
§ In oleaginous/unctuous
susceptibility are retained
preparations:

3. Microbiologic • Alpha tocopherol
- Sterility/resistance to microbial growth • Butylhydroxyanisole
• Ascorbyl parmitate
4. Therapeutic - Trace metals in drug, solvent, container or
- therapeutic effect remains unchanged
stopper

5. Toxicology o Source of difficulty in preparing stable
- No significant increase in toxicity occurs solutions
o Eliminated by:
B. RATE REACTIONS § Purification of source of
- Description of the drug concentration with contaminant
respect to time § Complexing or binding metals
C. Q10 METHOD
by using specialized agents
- Estimate the shelf life of a product that has
been stored or to be stored under a different (chelating agents – Calcium
set of condition disodium edentate and EDTA)
- Light
ENHANCING STABILITY o Catalyst to oxidation reactions
- Drugs subjected to hydrolysis o Preparations packed in light resistant or
o Water reduced or eliminated from the opaque containers
system
o Water-liable drugs – waterproof In summary: Easily oxidizable drugs may stabilized in
protective coating applied in the tablet formulation by:
o In liquid formulation – water replaced
by substitute liquids Selective exclusion from the system of:
o Suspending them in non-aqueous - Oxygen
vehicle - Light
o For injectable products – anhydrous - Oxidizing agents
vegetable oils may be used as solvent - Heat
- For unstable antibiotics - Trace metals
o supplied in dry form for reconstitution - Other chemical catalysis
before suspending
- For unstable preparations

GRH – 1APH 23

Add to create and maintain a favourable pH: o To ensure protection against microbial
- Antioxidants contamination
- Chelating agents
- Buffering agents Drug instability detected
- Change in:
OTHER DESTRUCTIVE PROCESS IN PHARMACEUTICAL o Physical appearance, color, odor, taste,
PREPARATIONS or texture of the formulation

Polymerization Scientific data pertaining to the stability of a
- Reaction between two or more identical formulation
molecules with resultant formation of new and - Leads to:
generally larger molecule (formaldehyde) o Prediction of the expected shelf-life of
the proposed product
Process where one or more active chemical groups o Redesign of the drug (to more stable
removed: salt or ester form)
- Chemical decarboxylation o Reformulation of the dosage form
- Deamination
Accelerated stability testing
Decarboxylation - Use of exaggerated conditions of temperature,
- Decomposition of RCOOH and release of CO2 humidity, light and others
- Accelerated temperature
Deanimation o 6 months study at 40 °C with 75%
- Removal of nitrogen containing group from relative humidity
organic amine (ex. Insulin)
Short term accelerated studies
IMPORTANCE OF DRUG STABILITY - Determines most stable of the proposed
- In preclinical testing and in clinical (human) formulations for a drug product
trials - Lesser temperature and humidity
o For a true and accurate assessment of - 30°C and 60% humidity
the drug/drug product evaluated
- Marketed drug product Stress Testing
o For the safety and effectiveness when - Temperature elevations in 10° increments
distributed and during the entire course higher than used in accelerated studies
of its shelf-life and use - Employed until chemical and physical
degradation
Product stability assessed before marketing:
- Formulation Long term stability studies
- Influence of: - Product is subjected to different climatic zone
o Pharmaceutic ingredients present (temperature and humidity) nationally and
o Container and closure internationally
- Manufacturing and processing conditions - Predicted from the data generated from
- Packaging components and conditions of continuing stability studies
warehousing/storage - 12 months minimum and conducted at 25°C ±
- Conditions of shipping, temperature, light, and 2°C and at a relative humidity of 60% ± 5%
humidity
- Shelf life and patient utilization PACKAGING AND STORAGE OF PHARMACEUTICALS
(Unit 3 p. 88)
Stability testing considerations
- Product containers, closures, and other Labelling is essential for:
packaging features - Product stability
- Parenteral and other sterile products must - Efficacious use
meet sterility test standards

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Containers Hermetic container
- Standards for packaging of pharmaceuticals by - impervious/resistant to air or any other gas
manufacturers are contained in the CGMP under the ordinary or customary conditions of
handling, shipment, storage, and distribution
TESTING PERFORMED DEPENDING ON THE INTENDED - those sterile are generally used to hold
USE AND TYPE OF CONTAINER: preparations intended for injection or
- Physiochemical tests parenteral administration
- Light-transmission tests for glass or plastic
- Drug compatibility Single-dose container
- Leaching and/or migration tests - quantity of drug contained is intended as a
- Vapor-transmission test for plastics, moisture single dose and when opened cannot be
barrier tests, toxicity studies for plastics resealed with assurance that sterility has been
- Valve, actuator, metered-dose, partial size, maintained
spray characteristics, leaking testing for - includes fusion-sealed ampoules, pre-filled
aerosols syringes and cartridges
- Sterility and permeation tests for parenteral - hold a quantity of drug intended for
containers administration as a single dose promptly after
- Drug stability for all packaging the container is opened
- single-unit package is termed a unit-dose
According to USP (p. 8?) package when dispensed to a patient
Container - may be performed on a large scale by a
- holds the article and is/or may be in direct manufacturer or distributor or on a smaller
contact with the article scale by the pharmacy dispensing the
Immediate Container medication
- in direct contact with the article at all times
Closure Multiple-dose container
- part of the container - hermetic container that permits withdrawal of
Closure and Container successive portions of the contents without
- clean and dry prior to its being filled with the changing the strength or endangering the
drug quality or purity of the remaining portion
- referred as vials
CLASSIFICATION OF CONTAINERS BY THE USP - contain more than a single unit or dose of the
medication
According to their ability to protect their contents
from external conditions: Tablets, capsules and oral liquids
- packaged in single-unit (foil/blister) or multiple-
Well-closed container unit (bottles) containers
- protects the contents from extraneous solids
and from: Single-unit packages
o loss of article under conditions of - convenient and sanitary means of maintaining
handling, shipment, storage and and utilizing the medication
distribution - advantages:
o positive ID of each dosage unit and
Tight container reduction of medication errors
- protects the contents from contamination by o reduced contamination of the drug due
extraneous liquids, solids, vapors, from: to its protective wrapping
o loss of the articles, and from o reduced dispensing time
efflorescence, deliquescence, or o greater ease of inventory control in the
evaporations under the ordinary or pharmacy or nursing station
customary conditions of handling, o elimination of waste through better
shipment, storage and distribution and medication management
is capable of tight re-closure

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Packaging materials Properties of plastics may be altered
- may be combinations of paper, foil, plastics or - Addition of:
cellophane o Plasticizers
o Stabilizers
Packaging of solid dosage forms in: o Antioxidants
- clear plastic or aluminum blister wells o Antistatic agents
o most popular method of single-unit o Antimold agents
o Colorants and others
Oral liquids - Drug substances subjected to oxidative
- may be single-unit dispensed in: oxidation
o paper o May undergo a greater degree of
o plastic degradation when packaged in plastic
o foil cups as compared to glass
o pre-packaged and dispensed in glass
containers (with threaded caps or Leaching
crimped aluminium caps) - Movement of components of a container into
the contents
Light resistant containers - Compounds leached from the plastic
- required by many pharmaceutical products to containers: polymer additives as the
protect them from photochemical deterioration plasticizers, stabilizers or antioxidants
- amber glass or light resistant opaque plastic – - Occurs when liquid or semi-liquid dosage forms
will reduce light transmission sufficiently to are packaged in plastic
protect a light-sensitive pharmaceutical - Little leaching occurs for tablets or capsules
- UV absorbers may be added to plastic to packaged in plastic
decrease the transmission of short UV rays - Influenced by:
- Must meet the USP standards which define the o Temperature
acceptable limits of light transmission at any o Excessive agitation of the filled
wavelength of light between 290 and 450 nm container
o Solubilizing effect of liquid contents on
Classification of glass used in packaging one or more of the polymer additives
pharmaceuticals depending upon the chemical
constitution of the glass and its ability to resist Soft-walled plastic containers of PVC – polyvinyl CI
deterioration: - Used to package IV solutions and blood for
transfusion
Type I – highly resistant, borosilicate glass
Type II – treated soda-lime glass Sorption
Type III – soda-lime glass - Binding of molecules to polymer materials
Type Non-parenteral (NP) – general purpose soda-lime - Absorption and adsorption are considered
glass - Occurs through chemical or physical means due
to:
Type I, II, III – for parenteral products o Chemical structure of the solute
Type NP – for non-parenteral molecules
o Physical and chemical properties of the
Problems encountered in the use of plastics in polymer
packaging: - Occurs with active pharmacologic agents or
- Permeability of the containers to atmospheric with pharmaceutical excipients thus,
oxygen and to moisture vapor ingredients must be examined in the proposed
- Leaching of the constituents of the container of plastic packaging to determine its tendency
the internal contents
- Absorption of drugs from the contents to the Pharmacists should dispense medication to patients in:
container - Same type and quality of container used by the
- Transmission of light through the container manufacturer of the drug
- Alteration of the container upon storage

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Child-Resistant / Adult-Senior Use Packaging Protection from Freezing
Child-resistant container - Protects the product from:
- Defined as: o Freezing
o Significantly difficult for children under o Risk of breakage of the container
5 years of age to open or to obtain a o Loss of strength or potency
harmful amount of its contents within a o Destructive alteration of the dosage
reasonable time form
o Not difficult for “normal adults” to use
properly Stability Testing
Signs of degradation of the specific dosage forms must
Child-proof closures be observed and reported
- Initial regulations called for its use for: - Tablets: appearance ( racking, chipping,
o Aspirin products mottling), friability, hardness, color
o Certain household chemical products - Capsules: moisture tackiness, color appearance,
- Shown to have a significant potential for shape, brittleness and dissolution
causing accidental poisoning in youngsters - Oral Solutions and Suspensions: apppearance,
precipitation, pH color, odor, dispersibility
Drugs intended for oral use (suspension) and clarity (solution)
- Dispensed by the pharmacist to the patient in - Opthalmic and Nasal and Oral Inhalation
containers having child-resistant closures unless preparations: appearance, color consistency,
the prescriber or the patient specifically pH, clarity (solutions), particle size, and
requests otherwise, or unless the product is resuspendability (suspensions, ointments),
specifically exempt from the requirement strength and sterility
- Adults, particularly the elderly or those with - Small Volume Parenterals: appearance, color,
arthritis or weakened hand-strength (with clarity, particulate matter, pH volumes and
difficulty opening child-resistant packages) extractables (when plastic containers are used),
o The regulations were amended (1998) sterility, pyrogenicity and closure integrity
to require that child-resistant
containers be capable of being readily FDA guidelines in stability for extemporaneous
opened by senior adults compounding
- Nonaqueous liquids and solid formulations
Storage (source of active ingredients)
- Products must be stored under proper o Not later than 25% of the time
conditions remaining until the product’s expiration
o To ensure the stability of a date or 6 months, whichever is earlier
pharmaceutical preparation for the - Nonaqueous liquids and solid formulations in
period of its intended shelf life which USP or NF substance (source of
- Labelling of each product ingredient)
o Includes the desired conditions of o Beyond-use not later than 14 days in
storage storage at cold temperatures
- Other formulations
Terms employed for the desired conditions as defined o Beyond-use date of the intended
by the USP duration of therapy or 30 days
Cold 2° - 8°C (36° and 46°F) whichever is earlier
Cool 8° and 15°C (46° and 59°F)
Room Temp 20° to 25°C (68°F to 77°F); allows PHARMACIST:
temperature variations between 15° - Oral aqueous liquid preparations made from
and 30°C (59° and 86°F) experiences existing tablet or capsule formulation
in pharmacies, hospitals, and drug o Pharmacist should make up only at
warehouses most a 14 days supply and must be
Warm 30° and 40°C (86° and 104°F) stored in a refrigerator
Excessive Above 40°C (104°F)
heat

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 - Must dispense the medication in a container Binders
conductive to stability and use - To cause adhesion of the powdered drug and
o Advise the patient of the proper pharmaceutical substances
method of use and conditions of
storage of the medication Antiadherents or Lubricants
- When compounding on the basis of - To assist smooth tablet information
extrapolated or less than concrete information
o Should keep the formulation simple and Disintegrating agents
not to shortcut but use the necessary - Promote tablet break up after administration
pharmaceutical adjuvants to prepare and coatings to improve stability, color
the prescription disintegration or enhance appearance

Stability Testing See table: Examples of Pharmaceutical Ingredients
Manufactured products
- Shelf life of 2 or more years to ensure stability Sweetening Pharmaceuticals
at the time of consumption - Used in foods and pharmaceuticals:
Expiration date o Sucrose
- Limits the time during which the product may o Artificial sweetening agents
be dispensed by the pharmacist or used by the - Mask unwanted taste
patient - Commonly used – sucrose
- Delaney Clause
Pharmaceutic Ingredients o No new food additives may be used ibn
- Required in preparing the drug substance into a animal studies/appropriate tests
final dosage form showed that it caused cancer
- For each dosage form:
o Establish the primary features of the Sccharin and Cyclamate
product - Used in foods
o Contribute to the physical form, - “Generally recognized as safe” (before the
texture, stability, taste and over all amendment’s passage)
appearance - Use on rats: developed incidence of bladder
tumors (cancers)
Pharmaceutical Ingredients and Excipients - Continued availability but with warning labels
Definition of terms be used
- Cyclamates (banned) – possible carcinogenicity,
Solvents genetic damage, testicular atrophy
- Are used to dissolve the drug substance
Aspartame
Flavors and sweeteners - 1st artificial sweetener (1958 amendment) with
- Are used to make the product more palatable requirement for pre- marketing proof of safety
- Acesulfame potassium (nonnutritive sweetener)
Colorants o Structurally similar to saccharin (USP
- Are added to enhance appeal approved)
o 130 times as sweet as sucrose, excreted
Preservatives unchanged in the urine
- May be added to prevent microbial growth o More stable than aspartame
- Stevia (Stevia rebaudiana Bertoni)
Stabilizers (Antioxidants and Chelating) o New sweetening agent: natural,
- To prevent decomposition nontoxic, safe
o 30x sweeter than cane sugar/sucrose
Diluents or Fillers
- To increase the bulk of the formulation

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 Source Sugar Chemical Methyl ester Factors in selecting dyes
cane; synthesis; dioeptide of - Solubility of prospective dye
sugar phthalic phenylalamine - pH and pH stability of the preparation to be
beet anhydride and asoartuc colored
acid - Dyes must be photostable
Relative 1 300 180-200
sweetness Preservatives
Bitterness None Moderate None - Liquid and semisolid preparations
to strong o Must be preserved against microbial
After taste None Moderate None contamination
to strong
metallic to Sterilization and Preservation
bitter - Some types of pharmaceutical products
Calories 4/g 0 4/g - Ex. Ophthalmic and Injectable preparations
acid o Sterilized by physical methods:
stability § Autoclaving (20 mins at 15 lb.
Acid Good Excellent Fair press & 121°C, dry heat at
stability 180°C for 1 hr
§ Bacterial filtration
Coloring Pharmaceuticals - Preparations that provide excellent growth
- For aesthetics media for microbes
- Coal Tar (pix carbonis) o Aqueous preparations: syrups,
o Thick black viscid liquid emulsions, suspensions
o By product of destructive distillation of o Semi solid preparations particularly
coal creams
o Source of synthetic coloring agents in o Hydro-alcoholic and most alcoholic
pharmaceutical products in the middle preparations
of the 19th century § May not require addition of
- Dyes chemical
o Added to pharmaceutical preparations - Prevent microbial growth:
in the form of diluted solutions o 15% alcohol in acid media
- Lakes o 18% alcohol in alkaline media
o Commonly used in the form of fine - Alcohol-containing pharmaceuticals (elixirs,
dispersions or suspensions spirits, and tinctures) – self sterilizing and do
- 90% of the dyes used in the products – not require additional preservation
synthesized from derivative if benzene (aniline)
- FDA – regulates use color additives in foods, Preservative Selection
drugs, and cosmetics (Federal Food, Drug, and - Conditions in selecting preservative in
Cosmetic Act of 1938) pharmaceutical preparations:
o FD&C color additives 1. Prevents the growth of the type of
§ Foods, drugs, and cosmetics microorganisms (contaminants of the
o D&C color additives preparations)
§ Drugs, some in cosmetics and 2. Soluble enough in water to achieve adequate
medical devices concentrations in aqueous phase with two or
o External D&C color additives more phase systems
§ Restricted to external parts of 3. Proportion of preservative remaining
the body (not including the lips undissociated at the pH of preparation (can
and other parts that are penetrate the microorganism and destroy its
covered by mucous membrane) integrity)
4. Concentration of the preservative does not
affect the safety/comfort of the patient

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 5. With adequate stability and not reduced in ACTIVITY: IDENTIFY THE PREFORMULATION STUDIES:
concentration by chemical decomposition/
volatilization 1. Diagrams constructed determines existence and
6. Compatible with all other formulative extent of the presence of solid and liquid phase
ingredients and does not interfere with them
7. Does not adversely affect the preparation’s 2. Evaluates if drug possesses aqueous solubility, for
container therapeutic efficacy

Mode of action 3. Time for the drug to dissolve in the fluids at the
Mechanisms preservative interfere with microbial absorption site
growth, multiplications, and metabolism:
1. Modifications of cell membrane permeability 4. Determines the physical properties, structure and
and leakage of cell constituents (partial lysis) reactivity of drug substance
2. Lysis and cytoplasmic leakage 5. indication of particle size and size range of the raw
3. Irreversible coagulation of cytoplasmic material along with the crystal structure
constituents
4. Inhibition of cellular metabolism by interfering 6. Determines the purity of the substance and
with enzyme systems / inhibition of cell wall compatibility of various substance
synthesis
5. Oxidation of cellular constituents 7. Extent of ionization of drug, through
potentiometric titration
PRESERVATIVE UTILIZATION
Preservative 8. Assessment of passage of drug molecules across
- Suitable substances added to enhance its biologic membranes
permanency or usefulness
- Examples (commonly employed): 9. Selection of appropriate extraction solvents, drug
o Benzoic acid stability, use of salting-out additives and
o Sodium benzoate environmental concerns
o Phenol
o Alcohol ACTIVITY: IDENTIFY THE DRUG-DRUG PRODUCT
o Phenylmercuric nitrate and acetate STABILITY
o Benzalkonium chloride
10. Estimate the shelf life of a product that has been
- IV preparations in large volumes as blood stored
replenishers/nutrients
o No bacteriostatic additives 11. Reaction order and rate
- Injectable preparations in small volumes
12. Description of the drug concentration with respect
to time

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