pharmaceutics exam 1 Flashcards
what is pharmacy
the science, art, and practice of preparing, preserving, compounding, and dispensing medicinal drugs and of giving instructions for their use”
pharmacy as a
place
profession
business
A Place: Licensed pharmacists receive prescriptions to dispense medicines
- A Profession:
– Study and training,
– Associations (many pharmacy organizations) - A Business: Pharmacists can own their own pharmacy – business people
– practitioners
Pharmacy Heritage
instinct
awareness of drug effects on the person
What shaped early pharmacy/medicine
Our instinct to survive served an important purpose in early pharmacy
* There was evidence of drug use long before the formal documentation of use, they found that…
* Cool water alleviated pain
* Leaves from plants were used to treat infected skin areas
* Mud was used to close and heal wounds etc…
- What shaped early pharmacy/medicine was the trial and error approach = Drug therapy
According to early history, why did people become sick?
what was their view on the mood of God?
what made someone healthy
The cause of disease was usually not biologically-based, due to environmental exposure or hereditary links.
The main reason was believed to be due to Evil Spirits.
* “In the land of the blind the one eye man is king”
– The man or woman with the most knowledge of how plants could be used to make remedies was usually consulted
- Drugs alone were not sufficient to treat sickness
- Compassion of a god
- Observance of ceremonies
- Absence of evil spirits (drive it out of your body) (made someone healthy)
- Healing intent of the dispenser
The Tribal Apothecaries (person who prepared and sold meds.)
failures
successes
Failures:
-Inactive agents
-Underdosing
-Overdosing
-Poisoning
Successes
-Coincidence
-Inconsequential effect of drug
-Placebo effect (psychologic- non-therapeutic effect)
Early Research on plants for drugs
Their scientific knowledge increased over
time, and so did the application to the pharmacy
* Scientists began conducting research
* Karl Wilhelm Scheele (1742-1786)
-isolated morphine from opium
Friedrich Serturner (1783-1841)
* Joseph Caventou- (1795-1877)
* Joseph Pelletier- (1788-1842)
* Combined their talents
what was made to ensure drug Standards and Quality
what is USP/NF?
was it written vaguely?
what did books like USP and NF adopt, reflect, provide and demonstrate
Need for uniform standards to ensure quality
* Therefore, Pharmacopeia’s or Formularies were created. These are organized sets of monographs or books of standards.
- Written with a high degree of clarity and specificity
- USP* and NF – First one in 1820*
– Adopt standards for drugs, pharmaceutical ingredients, and dosage forms
– Reflect on the best current practices of medicine
– Provides information on tests and assay procedures for - Demonstrating compliance with these standards – For individual components, not combinations
Drug Regulation & Control
the Food and Drug Act of 1906 was the first federal law to do what
the manufacturer’s claims of therapeutic benefit in 1912 said what about false claims and declared what about products
Food and Drug Act of 1906:
Was the very first Federal Law in the U.S. that required that “drugs marketed interstate comply with claimed standards for strength, purity and quality”.
- Manufacturer’s claims of therapeutic benefit in 1912.
- In this case, the Sherley Amendment said,
» No More False Claims
» Declared Products Misbranded
The Federal Food, Drug, and Cosmetic Act of 1938
what tragedy preceded this act
Why did 105 people lose their lives?
what was the excipient that was used?
what is the excipient used for today?
how did the FDA remove this drug from the market
There is a need for safe administration of drugs after a tragedy caused by Sulfanilamide a “wonder drug”.
- toxicity: diethylene glycol
- The drug was manufactured as an elixer, and diethylene glycol was used as the solvent to prepare the elixir
- What is this drug used for today???- antifreeze for car
because they weren’t able to ban unsafe drugs at the time, the FDA removed/banned it based on a technecality that elixirs need to be prepared with alcohol and it did not have alcohol so it was banned
The FDCA of 1938 required all new drugs to be tested by whom for what
where did these tests have to be submitted and via what
what did this act mandate for drugs to be labeled with
what did this act authorize the FDA to do
– Required that all new drugs be tested by their manufacturers for safety.
- Required that those tests be submitted to the government for marketing approval via the NDA (newdrug application)
- Mandated that drugs be labeled with adequate directions
– Authorized FDA to conduct unannounced inspection
Federal Food, Drug, and Cosmetic Act of 1938
- before a drug was distributed what needed to be filed and who needed to be approved
-did the FDA require drugs to be effective
- No new drug could be distributed without the prior filing of a new drug application (NDA), and approval of the FDA.
- The FDA now dealt with safe use of drug substances, but did not require that the drugs be (efficacious) effective in the treatment of disease
The FDA was given the job to
grant or deny products entering the market
based on
P
M
S
P
P
T
C
did they require drugs to effective?
– Product’s ingredients
– Methods used to evaluate products
– Standards used to evaluate formulations
– Preclinical studies
Pharmacology
Toxicology
– Clinical trials
Still, the FDA did not require drugs to be efficacious
Thalidomide Tragedy
who was thalidomide prescribed to
what did thalidomide cause
– Introduced on to the market October 1,1957 in West Germany
– Prescribed to pregnant women with morning sickness
– “Thalidomide” babies resulted all around the world
- caused Phocomelia
What was the conclusion of the thalidomide tragedy/what did we need to strengthen
Thalidomide could have passsed our current drug laws
There is no question that we need to strengthen our food and drug regulations to include routine testing of new compounds pregnant animals
What medical condition did thalidomide cause
Phocomelia
What was the Kefauver-Harris amendments of 1962
- The thalidomide tragedy was the main reason behind the development of this act
- This amendment required manufacturers to prove a drug to be both safe and productive before granting FDA approval for marketing.
-Exempted from both safety and efficacy requirements were drugs that happened to enter the market between 1906 and 1938 aka ~ grandfather clause. Why? Drugs were never subjected to NDAs.
Drug classification on the basis of drug type
How are agents that are approved by the FDA categorized?
how is an agent that is safe to use without a provider categorized/classified
how is an agent that cannot be safely used without a provider categorized/classified
what is put on an agent that is not safe to use without a provider categorized/classified
- Agents approved for marketing by the FDA are categorized according to the way that they may be obtained legally
- For example,
– If the drug is safe enough for a layman in treatment the agent is classified as “over the counter” (OTC)
– If the drug may be used only after expert diagnosis drug packaging must bear the symbol, “Rx-only” or bear the caution label
- “Caution: Federal law prohibits dispensing without prescription”
*Durham-Humphrey Amendment of 1952
No refills (dispensing of drugs) without a valid prescription
- This clarified the dispensing obligations of pharmacists
- Defined drugs that cannot be used safely without proper medical supervision
- Determined what drugs are OTC and what drugs are not
- Refilling is necessary only if authorized in the prescription
- Further supported by the Comprehensive Drug Abuse Prevention and control Act of 1970.
Comprehensive Drug Abuse Prevention and Control Act of 1970
what were drugs of abuse put under
what did this act establish
Drugs of abuse were put under a comprehensive regulatory framework
- The act established 5 “schedules” for classification and control of drug substances, particularly those that were more likely to be abused
Schedule I, II, III, IV & V
The schedules provide decreasing levels of control from schedule I to schedule V.
- Schedule I & II are high potential: ex.Heroin for schedule I
- Schedule III is moderate potential: ex. Codein
- Schedule IV&V is low potential: ex. Diazepam for schedule IV
FDA Pregnancy Categories
what are the 5 categories
what is the first category
what is the last category
1979- US FDA introduced the classification of fetal risks due to pharmaceutical agent use
- What is the Risk vs. Benefit Ratio?
– Category A: Studies failed to demonstrate a risk to the fetus (1st trimester- no evidence of risk in a later trimester)
– Category B
– Category C
– Category D
– Category X: Animal studies or humans demonstrated fetal abnormalities. Women outweigh potential benefits
“Black Box” Warnings
what is the FDA’s strongest labeling requirement used for
what does the FDA’s strongest labeling requirement emphasize when using the medication?
when is the FDA’s strongest labeling requirement used concerning adverse rxn and benefits?
when the FDA approves the drug does it still use FDA’s strongest labeling requirement? if so when
can local/state laws weaken FDA laws
FDA’s absolute strongest labeling requirements are used for the highest-risk medications.
– It emphasizes the importance of close patient monitoring when using the medications.
– Used when an adverse reaction is so serious in proportion to the potential benefit
– FDA approves the drug but restrictions to/when prescribing and distributing to ensure safety
– Local and State Laws may only strengthen FDA laws, never weaken them.
Drug Listing Act of 1972
what must each firm that manufactures or repackages drugs do with the FDA and submit for listing
what is an NDC & what does it stand for
how long is an NDC
“Each firm that manufactures or repackages drugs for the ultimate sale or distribution to patients or consumers must register with the FDA and submit appropriate information for listing”
- National Drug Code (NDC) permanent registration code to identify manufacturer or distributor.
- The code is 10 (or 11) digits long
National Drug Code (NDC)
– Example of NDC: NDC 00081-5421-12
what are the first 4 digits?
what are the next 3-4 digits?
what are the last 2 digits?
what is the correct format for NDC numbers
“Labeler code” “Product code” “Package code”
– How is one different from the other?
– Labeler code: Manufacturer/ distributor (1st 4 digits)
– Product code: Used to identify drug formulation (3-4)
– Package Code: Used to identify package size & type (3-2)
5-4-2 format!
what do
NDC 0081-5421-12 Represent
NDC 0057-346-421Represent
NDC 0081-5421-12
* Represents 4-2 digit product-code-package-
code configuration
NDC 0057-346-421
* Represents 3-3 digit product-code-package-code- code configuration
Abbreviated New Drug Application (ANDA)
The Drug Price Competition and Patent Terms Restoration Act of 1984 said that..
“Any originally approved new drug can be filed through an ANDA and bypass animal and human study testing.”
This reduced the time and money to market the generic version of a drug compound.
Prescription Drug Marketing Act of 1987
- prohibited what for drugs (RSTP)
-What did this decrease entering the legitimate market
Revisited and updated
Prescription Drug User Fee Act of 1992.
- what did it allow the FDA to do concerning drug and biological companies in addition to reviewing new drug and biologic applications within time frames
1987 Law- Prohibited the reimportation of drugs, and prohibits sales, trading, and purchasing of drugs. It decreased the risk of misbranded, repackaged, or mislabeled drugs entering the legitimate market
1992 Law- Prescription Drug User Fee Act of 1992. Allowed the FDA to accept user fees from drug and biologic companies in return for committing to review new drug and biological applications within certain time frames.
Dietary Supplement Health & Education of 1994
Dietary supplement and nonprescription drug consumer protection Act of 2006
- Due to growing interest in using dietary supplements*, Congress expressed the need to regulate all labeling claims.
- Manufacturers had to state the following:
– “This product is not intended to diagnose, treat, cure, or prevent any disease” - Influences on body structure and function okay
- Ex; increasing blood circulation; lowering cholesterol
- Statements must be “truthful and not misleading”
- vitamins, minerals, amino acids, and botanicals
Dietary Supplement and Nonprescription Drug Consumer Protection Act of 2006
Enabled FDA to implement a policy of GMPs for dietary supplements similar to those in place for pharmaceutical products.
- Dietary supplements are now manufactured according to quality standards.
FDA Modernization Act of 1997
Revisited and updated
FDA Amendment Act of 2007
Streamlined FDA policies
* To codify many of the agency’s new regulations
* Monitors for regulatory compliance
* Establishes product labeling requirements
* Directs product recalls
* Expanded patient access to investigational treatment for serious life-threatening diseases
* Accelerated approval of new drugs
* Pediatric use of investigational drugs made possible
Drug Product recall
what are the 3 classes of recall
[FDA or manufacturer reveals that product presents a threat to the public]
- Class I: Exposure will cause serious adverse health consequences or even death
- Class II: Exposure will cause temporary or medically reversible adverse health consequences
- Class III: Exposure is not likely to result in adverse health consequences
Code of Ethics
Conduct work in a professional manner- high principles are essential
- No scientific misconduct tolerated
- Recognize and respect differences in opinion in the interpretation of scientific data
- Disclose sources of external conflicts
- Report results honestly and accurately
- Respect ownership rights of others and seek prior written approval from owner before disclosure
- Do not discriminate on the basis of race, gender, creed or national origin
Brief History of Drug Discovery & Development
Plant poisons
Where did morphine, quinine, digitalis and belladonna come from originally
1800 to 1820: Organic plant acids were extracted from plants by pharmacists in Germany, France, and Sweden
1883: Synthesis of antipyrine.
Important because done in a test tube and this changed the way drugs were discovered from this point forward
1925 to 1945: Rapid advances in pharmacy research.
Alexander Flemming discovered Penicillin
James-Watson Crick solved the structure of DNA
Morphine: from opium poppy
Quinine: from cinchona bark
Digitalis: from foxglove
Belladonna: from deadly night shade
The alkaloids are not present in plants to supply us with medicines but are probably present to discourage predators
Problem is with purity and producing enough for our needs
Not all plants of same species are grown under same conditions so potency will vary
what was the issue with getting our meds from plants
Problem is with purity and producing enough for our needs
Not all plants of same species are grown under same conditions so potency will vary
The alkaloids are not present in plants to supply us with medicines but are probably present to discourage predators
what drugs came from vinca rosea
Vinblastine and Vincristine
what did Vinblastine and Vincristine treat
Vinblastine- treat Hodgkin’s disease (a form of lymphoid cancer)
Vincristine-used clinically in the treatment of children’s leukaemia
and breast cancer (not sure actually)
what drugs came from Pacific yew (taxus brevifolia)
taxol
which is used today to treat breast cancer patients
the tree we get it from is about 100 yrs old and its content could treat 3 out of the 4 rounds of chemo
is it worth cutting all the Pacific yew (taxus brevifolia) trees down for medicinal use? so what did we do
No! so we made the synthetic form of the chemical in lab and also made isomers of it too
this even increases purity!
what is the propose of Drug Discovery
who is involved in this
To find active ingredients and/or modify the chemical structures of existing active ingredients of drugs to form the basis of a new agent.
Chemists
Pharmacologists
Toxicologists
Formulation developers (i.e. pharmaceutics
state what each one does
Chemists
Pharmacologists
Toxicologists
Formulation developers (i.e. pharmaceutics
Chemists: an expert in chemistry; a person engaged in chemical research or experiment
Pharmacologists: medical scientists working to develop new drugs. They may work in a lab, testing medications by studying tissue and cell samples. They may work in clinical trials, conducting research on voluntary patients.
Toxicologists: a scientist who has a strong understanding of many scientific disciplines, such as biology and chemistry, and typically works with chemicals and other substances to determine if they are toxic or harmful to humans and other living organisms or the environment.
Formulation developers (i.e. pharmaceutics) scientists must determine the most appropriate route to achieving effective drug delivery based on patient need, then optimize the formulation’s characteristics based on a knowledge of the drug product’s bioavailability and processing requirements.
what Is the purpose of drug development and what does it require and do they work
To provide superior dosage forms and a way of delivering effective drugs throughout the body
Mostly done by scientists usually with a PhD
At a pharmaceutical company
At a school of Pharmacy
Early Formulation Studies addresses what question
are early formulation studies completed before or after preclinical studies
What properties related to pharmaceutics are studied?
EARLY FORMULATION STUDIES ARE COMPLETED BEFORE PRECLINICAL STUDIES INVOLVING ANIMAL EXPERIMENTATION
what does each letter mean in the Early Formulation Studies/ What properties related to pharmaceutics are studied?
DPDPS
Drug solubility:
Less than 10 mg/ml is considered poorly soluble
Partition coefficient:
Preference for one phase (i.e., lipid) verses a second phase (aqueous).
Dissolution Rate:
Speed at which a drug substance dissolves in a medium
Physical Form:
Crystal verses amorphous verses powder etc.. Will alter the rate and extent of absorption
Stability:
Retention of drug substances within dosage forms
Temperature and relative humidity (RH) effects
What is The “Goal Drug”
Ideally this group seeks to develop a compound with the following characteristics
Can produce a desired effect
Can be administered at the most desirable route (orally)
Can be administered at a minimal dosage and frequency
After exerting a necessary effect should be eliminated from the body efficiently without side effects
A “Lead Compound”
This compound is the closest agent to the “goal drug”, possessing the fundamental desired biologic or pharmacologic activity
It may NOT contain all of the properties of the desired compound, and so medicinal chemists often modify the lead compound
what does a Drug Researcher have to know
Pharmacology
Drug Metabolism
Toxicology
explain Pharmacology, Drug Metabolism, toxicology
that a drug researcher has to know
What is the purpose of CDER?
How does the CDER balance the benefit vs. known risks ?
Pharmacology: Determines biologic activity and mechanism of drug action in vitro & In vivo
Drug Metabolism: Determines the absorption, distribution, metabolism and elimination (ADME)
What is the extent of drug absorption and distribution in the body?
What is the mechanism of the drug metabolized by the body?
Toxicology: Deals with adverse and undesirable effects of the drug. Consider: What is the maximum tolerated dose? What is the lethal dose?
purpose of CDER - Assess benefit to risk relationship
- Is a particular drug safe and effective enough?
Other examples of issues addressed by researchers in vivo
Make sure that the appropriate dosage form is being used to deliver therapeutics to the intended site of drug action
Non-specific delivery to intended targets is the main reason for drug-related side-effects
ex: used a mouse to see the angiogenesis of a tumor
what does the CDER do
Other examples of issues addressed by researchers in vivo
Assess benefit to risk relationship:
- Is a particular drug safe and effective enough?
- AZT (azidothymidine) toxic but highly effective
Make drugs available to the public sooner
Provide clear standards for drug evaluation
High priority drugs– These are defined as drugs that offer a significant medical advantage over current therapies
Cancer drugs–Division of Oncology
Contraceptive drug & urologic drug products–Division of reproductive & Urologic drug products
Generic drugs– Division of Generic drugs
Make sure that the appropriate dosage form is being used to deliver therapeutics to the intended site of drug action
Non-specific delivery to intended targets is the main reason for drug-related side-effects
Investigational New Drug (IND) Application
Once a drug has been developed, before it can be tested in humans, it must be filed with the FDA. This is an IND Application.
Application protects the rights & safety of subjects and makes certain that the research objectives stated in the investigational plan can be achieved.
What is the main purpose of the IND application?
what happens after IND application
to provide the FDA with sufficient information to make a meaningful evaluation of a new drug
IND is next assigned to a CDER official,
- Officials can place hold on trial due to inadequate information, inadequate qualifications of investigators or potential harmful risk to patients
IND Application
What Is the goal of phase I clinical trials
Preclinical studies demonstrate adequate safety. This is to be determined by Phase I clinical trials.
Phase I Clinical Trials
Drug should show promise as a useful drug
- Phase I: What is the safe dose in 20 to100 patients)?
- Usually brief study (less than 1 year).
- Purpose is to determine toxicology, metabolism, and pharmacologic actions
Application contains:
- The plan for the study
- Chemical Structure
- Animal testing results
- Manufacturing information
phase I clinical trial
has how many people
for how long
what question does it want to answer
how is drug used
where is it done
Phase I: What is the safe dose in 20 to100 patients)?
Usually brief study (less than 1 year).
Purpose is to determine toxicology, metabolism, and pharmacologic actions
Application contains:
The plan for the study
Chemical Structure
Animal testing results
Manufacturing information
What about clinical trial material (CTM) for Phase I studies?
Biopharmaceutical properties –> clinical study
Practical considerations
–Actual supply of bulk
–Time allowed for preparing bulk stock
Advantages of extemporaneous formulations
–Short development time
–Minimal drug substance requirements (few hundred grams)
–Minimal formulation development
–Minimal analytical work
Disadvantages of extemporaneous formulations
–Unpleasant taste
–Patient compliance issue
–Dosing inconvenience for
–multiple dose studies
Phase II clinical trials
has how many people
for how long
what question does it want to answer
how is drug used
where is it done purpose
To determine compound’s effectiveness
Drug is tested in hundreds of patients (~100 to 300 people).
Patients have the disease that the drug is intended to treat
Extensive pharmacologic, toxicological and pharmacological testing
Many clinical agents do not make it to this point cause they prove to be unsafe
What about clinical trial material (CTM) for Phase II studies?
“powder in a bottle”- not very good approach
Capsules or tablets are typically necessary
Generally, same dosage form as phase I can be used here.
Except, When required dosage strength is not supported & When medium-to-large scale is not feasible
Alternatively, a new formulation closer to desired commercial dosage form can be introduced during Phase II
What about (CTM) for Phase II studies?-Continued-
Other Critical factors:
- Phase II covers a large dose range so # of dose strengths may be large
- This is determined by,
Team of scientists (pharmaceutical scientists, pharmacokineticists, & clinical study and clinical supply coordinators)
Limitations with high dose strengths:
–Dissolution and processability
Limitations with low dose strengths:
–Content uniformity and stability issues
Phase III clinical trials purpose
To demonstrate long-term safety & efficacy of drug product; to discover drug’s efficacy standards
phase III clinical trials
has how many people
for how long
what question does it want to answer
how is drug used
where is it done
Several thousands of patients in many centers (~1000-3000 people)
Carried out over several years
How good is the drug in treating the disease or condition?
What are the short-term side effects and risks associated with drug use in patients whose health is impaired?
Investigational drug will be used in several randomized, controlled studies in various clinical research facilities including,
Clinical research facilities
Veterans administration
University teaching hospitals
What about clinical trial material (CTM) for Phase III studies?
Data from stability should be performed on at least 3 primary batches of drug products
Stability testing must cover minimum period of12 months typically at 25 ºC
Changes in dosage strengths and manufacturability of CTM may be necessary to achieve specific goals of Phase III
However, the same formulation, processing and packaging procedures as with commercial product is recommended
in phase I, II, III, what is the % of drugs that are successfully tested
phase I: 70%
phase II: 33%
phase III: 25%-30%
Usual adult dose
Starting dose for a patient
Usual dosage range
Safety dose range for administering drug product
Dosage Regimen
Schedule of dosage
Maintenance doses
Maintain clinically relevant drug levels in blood
Prophylactic dose
Administered to prevent patients from contracting the disease
Therapeutic dose
Administered once disease has been contracted
Minimum effective concentration (MEC):
The minimum dose required to get a desired effect
Minimum toxic concentration (MTC):
Administering drugs above this level will produce dose related toxicities
Median effective dose (MED):
This dose will produce a desired intensity of a drug effect in 50% of the individuals tested
Time-blood level curve
Ideally, the drug serum levels should be maintained above the MEC and below the MTC.
Concentrations above the MTC will cause toxic side effects
Age
Neonatal, Pediatric & Geriatric Patients
Body Weight
Milligrams (of drug)/ per kilogram of body weight
Body Surface Area
1 mg/M2 BSA- NOMOGRAM
found using a nomogram
Sex
Men and Women have different responses to certain drugs due to biochemical & Physiologic factors
Pathologic State
Disease State
Times of administration
: Before or after meals
Tolerance
Ability to endure influence of a drug
BSA is used to determine drug dose in humans
Due to the correlation that exists between physiological processes and body surface area (BSA), some drug doses are determined based on this relationship
An adult measuring 67 inches in height and weighing 132 pounds would have a BSA of approximately how many square meters?
1.7
Batch
a specific quantity of a drug of uniform specified quality produced according to a single manufacturing order during the same cycle of manufacture
Batch wise control
the use of validated in-process sampling and testing methods in such a way that results prove that the process has done what it purports to do for the specific batch
Certification
documented testimony by qualified authorities that a system qualifications, calibration, validation or revalidation has been performed appropriately and that the results are acceptable
Compliance
determination through inspection of the extent to which a manufacturer is acting in accordance with prescribed regulations, standards, and practices
Component
any ingredient used in the manufacture of a drug product, including those that may be present in the finished product
Drug Product
a finished form that contains an active drug and active ingredients. the term may also include a form that does not contain an active ingredient
Active Ingredient or active pharmaceutical ingredient (API)
any component that is intended to furnish pharmacologic activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or function of the body of man or other animals.
Inactive ingredient
Any component other than the active ingredients in a drug product.
Lot
: A batch or any portion of a batch having uniform specified quality and a distinctive identifying lot number.
Lot number, control number, or batch number:
Any distinctive combination of letters, numbers, or symbols from which the complete history of the manufacture, processing, packaging, holding, and distribution of a batch or lot of a drug product may be determined.
Master record
Record containing the formulation, specifications, manufacturing procedures, quality assurance requirements, and labeling of a finished product.
Quality assurance
Provision to all concerned the evidence needed to establish confidence that the activities relating to quality are being performed adequately.
Quality audit
A documented activity performed in accordance with established procedures on a planned and periodic basis to verify compliance with the procedures to ensure quality.
Quality control
The regulatory process through which industry measures actual quality performance, compares it with standards, and acts on the difference.
Quality control unit
An organizational element designated by a firm to be responsible for the duties relating to quality control.
Quarantine
An area that is marked, desig- nated, or set aside for the holding of incoming components prior to acceptance testing and qualification for use.
Representative sample
A sample that accurately portrays the whole.
Reprocessing
The activity whereby the finished product or any of its components is recycled through all or part of the manufacturing process.
Strength
The concentration of the drug substance per unit dose or volume.
Verified
Signed by a second individual or recorded by automated equipment.
Validation
Documented evidence that a system (e.g., equipment, software, controls) does what it purports to do.
who establishes regulations under the standards for good cGMPS
what is the purpose of establishing regulations/what do they have to do with quality?
what act inspired the first set of GMP
Who is the established requirements for, and does it apply to domestic or foreign suppliers who sell most of their product in the U.S., What can the people who established this do concerning inspections
is there a distinction in the way that the regulations are applied
Regulations are established by the FDA
Purpose: to set minimum standards for product quality
Kefauver-Harris Act inspired the first set of GMP regulations
Established requirements for all aspects of pharmaceutical manufacture
Applied to domestic and foreign suppliers with bulk components and finished products sold in the US.
Unannounced FDA inspections applied here as well
No distinction in how regulations are applied to domestic and foreign suppliers and manufacturers
what should you know about cGMP for Finished Pharmaceuticals?
O P
B F
E
L C
R R
you should know the P, L, S&T of pharmaceuticals
Organization and personnel
Buildings and Facilities
Equipment
Laboratory Controls
Records and Reports
Packaging, Labeling, Storage, and Transportation of Pharmaceuticals
The regulatory process through which the industry measures quality performance, and compares with standards and acts on the difference?
Quality assurance
Quality audit
Quality control
Quality control unit
Quality control
what are the organization and personnel responsible for
what is this division responsible for in terms of education and training, product components, product specifications, finished product standards for packaging and labeling
what should any supervisor have to oversee the task?
Quality control, employees, consultants
Responsibilities are:
Adequate education and training
Assess product components and reject if necessary
Assess product specifications, finished products, standards of packaging and labeling
Any supervisory personnel must have adequate training and qualifications to oversee the task
buildings and facilities
what do they deal with in terms of design, features, and functional aspects
They ensure that their design enables thorough what and effective use of what
what physical things do they deal with
W
S
L
M
W M
S A
F S A
S A Q P & H A F R C
Afterward, who must be logged in, inspected, and signed off on
Deals with design, features, and functional aspects of buildings and facilities
Must be designed to enable thorough cleaning, inspection, safe & effective use for performance operations and evaluations
Water quality standards
Security
Lighting
Materials used for floors, walls, ceilings
Weighing and measuring rooms
Sterile areas
Flammable storage areas
Storage areas for quarantine purposes, and holding areas for rejected components
Everything must be logged in, inspected by a supervisor, and signed off
equipment
what is it exactly to
this goes for the equipment’s
T
L
R C
P O E must not interfere with the D O D P
F M M N M with I D P. This must be prevented
Exact to the specifications
Type
location
Routine calibration
Parts of equipment must not interfere with the development of drug products
Filter materials must not mix with injectable drug products. This must be prevented.
for Control of components, containers, and closures
Written procedures must be _____ and ______
Bulk chemical ingredients ______ must meet __________ at time _________
When ingredients are received ________
what must be logged in for ingredients that just came
logged in for ingredients:
Purchase ______
D of R
Suppliers______: stays with _________________________________
Q R
What happens to raw materials
what happens to materials not meeting specifications
Written procedures must be developed and followed
Bulk chemical ingredients of drug products must meet all specifications at the time of ordering
When ingredients are received they must be officially logged in.
When ingredients are received they must be officially logged in
logged in for ingredients:
Purchase order number
Date of receipt
Suppliers Stock or Control number: stays with the product and follows it all the way through development
Quantity received
Raw materials are quarantined, and quality verified.
Materials not meeting specifications are rejected
Production and process controls
Written documentation is required to make sure that each drug product has the correct: I, S, Q & P
All automated equipment is what
what is done to batches on a regular interval to check for what—who performs this
Written documentation is required to make sure that each drug product has the
Correct Identity
Correct Strength
Correct Quality
Correct Purity
All automated equipment is evaluated
Batches are evaluated at regular intervals to check on batch-batch consistency
Production personnel
Quality control laboratory
Packaging and Labeling Control
Written documentation is required for R, S, H, S, and T of products
what happens to outdated labels
what happens when drugs need further investigation by quality control
what happens when drug products are approved by quality control operations and what does it prevent
Written documentation is required for
Receipt, storage, handling, sampling and testing of products
All outdated labels must be destroyed, it must be destroyed
When drug products need further investigation by the quality control unit the problems must be identified and resolved
When drug products are approved by quality control operations, visual and/or electronic inspection is performed–This prevents mislabeling of products
Check for expiration date, product batch, or lot #
Tamper-evident packaging required
Records and Reports
Production information must be ______ for at least ______ following______ batch
Control records must include the list below, and must be made available to the FDA officials at the time of inspection.
N S of product dosage form
C & D units
Control ________
E used
_______controls
R of _______
C of instruments
Production information must be maintained on file for at least 1 year following expiration date of batch
Control records must include the list below, and must be made available to the FDA officials at the time of inspection.
Name and Strength of product dosage form
Components and dosage units
Control procedures
Equipment used
In-process controls
Results of analysis
Calibration of instruments
Returned and Salvaged Drug Products
must be identified by _____ and _____ quality
What do you do when products come back from the marketplace? may be ______ or ______
if the product was not stored under appropriate conditions, can it be on the marketplace again
what must be documented and dated
Must be identified by lot# and product quality
What do you do when products come back from the marketplace?
—If the products happen to meet all product specifications they may be used again. The product may be “Salvaged or Reprocessed.”
If the products have not been stored under appropriate conditions the products should never see the marketplace again
The exact reason for product return must be documented and dated.
Additional cGMP Regulatory Requirements
Pharmaceutical excipients must be ______ to _______ specifications.
is there an FDA approval system for pharm. excipients
Pharmaceutical excipients must be produced according to cGMP specifications.
NO FDA APPROVAL SYSTEM FOR PHARMACEUTICAL EXCIPIENTS
Clinical Trial Materials
CTM in ________ investigations must be ________ to _____________ regulations
Pharmaceutical __________ are ____________ and optimized for human_______ from phase ___ to ________.
All regulatory requirements must be __________ and reported to ____________
For example, the production of 100,000 capsules
Placebos and/or comparator products must be prepared by this stage
CTM in clinical investigations must be produced according to cGMP regulations
Pharmaceutical products are continuously characterized and optimized for human treatment from phase I to phase II.
All regulatory requirements must be met by phase III and reported to the FDA
For i.e., production of 100,000 capsules
Placebos and/or comparator products must be prepared by this stage
Current Good Compounding Practices
Patient-specific medications, why?
Dosages are not_____ ____
_____ _______forms are not available
Patients are _______ to certain _______ or cannot take due to ___________
Children have __________
Some medicines _________ dispensing
____________ not yet available by the manufacturer
Physicians have _____________
Veterinary products not always ________
Home health care __________ :__________
Hospice care: _________ to pain management
Dosages are not commercially available
Certain dosage forms are not available
Patients are allergic to certain excipients or cannot take due to religious reasons
Children have different needs
Some medicines require frequent dispensing
Some medicines not yet available by manufacturer
Physicians have different needs
Veterinary products not always available
Home health care pharmacies: Sterile preparations
Hospice care: new approaches to pain management
Packaging, Labeling, and Storage of Pharmaceuticals
Containers:
Must meet what
Specifications vary according to container type, I.e.,
Parenterals and non-parenteral
_________
________, _________ and metal
Containers:
Must meet specifications for clinical trials
Specifications vary according to container type,
I.e:
Parenterals and non-parenterals
Pressurized
Glass, plastic and metal
Plastic vs. Glass containers
how do plastic containers have that glass do not
L
R to I
G F
P S B
U D D
Autoclavable Plastic:
PVC is produced when
Plastic containers have an advantage over glass containers:
Lightness in terms of weight
Resistance to impact
Greater flexibility in terms of design and appearance
Plastic squeeze bottles (for ophthalmics, nasal sprays, lotions)
Unit-dose dispensing (ie., in healthcare institutions)
autoclavable plastic:
Polyvinyl chloride (PVC) is produced if a chloride atom is added to every other carbon atom in a polyethylene polymer.
PVC is a strong and rigid material useful for packaging capsules and tablets, but can not be sterilized by gamma radiation.
Newer plastics such as polyethylene terephthalate (PET) which can be sterilized by gamma radiation?
What are the problems with plastic containers over glass?
Permeability of ________
—-Atmospheric _____________
_________ of constituents of container to _________ contents
—-Such as ________ additives
Absorption of _________ from contents to ________
Transmission of ________ through container
Change in ________ material _________
Permeability of containers
——-Atmospheric oxygen, moisture vapors
Leaching of constituents of container to internal contents
——-Such as polymer additives
Absorption of drug from contents to container
Transmission of light through container
Change in container material over time
what is the purpose of Child-resistant and Adult-senior-use packaging?
what makes a container child-resistant/what age is the threshold for child resistance
what designs are used to prevent children from opening containers:
_______arrows,
press _______ and _______
________ and turn
Latch _______
why are some drugs exempt from this
To prevent accidental poisoning
The child-resistant container is one that is difficult to open for children under 5 years of age
Designs used to prevent children from opening containers are:
Align arrows
press down and turn
Squeeze and turn
Latch top
Certain drugs are exempt due to practical considerations, sublingual tablets, and cardiac drugs due to immediate access.
what makes up Compliance Packaging
__________
Prescription ________
_________ Labeling
________
Labeling
Prescription Label
OTC Labeling
Storage
what must the label meet?
what does labeling include: ________ container, packaging, ______ , company ________ , brochures, and any ________-
where must the benefit to risk factors be indicated?
what is put on prescription labels to reduce medication errors and what does it assure pharmacists that the prescribed drug is appropriate
Must meet the Code of Federal Regulations
Labeling includes immediate containers, packaging, inserts, company literature, brochures, and any mailings
The benefit to risk factors must be indicated in the packaging inserts…..
To reduce medication errors, there is thought to include “indication” on prescription labels to help pharmacists ensure that the prescribed drug is appropriate
what must a pharmacist include on the dispensed medication
Name and _______ of ________
______ number of the ________
Date of ________ (or date of its filling/refilling)
________ of the _______
Name of __________
Directions for ________ (including any precautions as indicated on the prescription)
Name and address of pharmacy
Serial number of the prescription
Date of prescription (or date of its filling/refilling)
Name of the prescriber
Name of patient
Directions for use (including any precautions as indicated on the prescription)
OTC Labeling in 1997
why did the FDA require it
what did the FDA say the label had to be organized into
what must it contain?
Due to inconsistent practices, the FDA developed a standard procedure for labeling OTC drug products
FDA called for simple headings and subheadings for easy understanding
OTC package labeling must contain warning statements if misuse can lead to serious complications
OTC labeling: What is required on the label?
________ name
Net _______ of _______
–This includes all ingredients
Must indicate the _______ category
_______ and warnings to protect _______
_______ content (for oral products) when necessary if
5 mg or more per single ______
140 mg or more in ________ dose
Storage _________
—Must include storage in a safe place out of the reach of _______
—-_______ number and expiration ________
Product name
Net quantity of contents
This includes all ingredients
Must indicate the pharmacologic category
Cautions and warnings to protect consumer
Sodium content (for oral products) when necessary if
5 mg or more per single dose
140 mg or more in the maximum dose
Storage conditions
Must include storage in a safe place out of the reach of children
Lot number and expiration date
what may OTC lead to
ex: what may a laxative cause
as a result, what does the warning label say
Medication may lead to serious complications
Ex: Laxatives may cause additional pain during appendicitis. For this reason,
“Warning: Do no use when abdominal pain, nausea, or vomiting is present. Frequent or prolonged use of this preparation may result in dependence on laxatives”
what can medications mask requiring medical attention?
ex: how serious is a cough
what does the warning label say
Medications can mask serious conditions requiring medical attention
Ex: how serious is a cough?
“Warning: A persistent cough may be a sign of a serious condition. If cough persists for more than 1 week, tends to recur, or is accompanied by a fever, rash, or persistent headache, consult a doctor ”
Dietary Supplement Labeling
Claims must be _________ and __________
No disease claims _______
For ex, those that infer “drug can be used to prevent, treat __________ a disease.”
Claims must be accurate and truthful
No disease claims allowed
For ex, those that infer “drug can be used to prevent, treat cure,
mitigate, or diagnose a disease.”
Storage conditions and special considerations
what is the purpose of having storage conditions?
Freezer: ___ and _____
Cold: Does not exceed ____ (46 ºF)
Cool: Between ______ and ______
Room Temp: _____ to _____
Warm: Between ____ and ______
Excessive Heat: Above ______
To ensure the stability of pharmaceutical preparation
The following are conditions defined by USP
Freezer: -25 and -10 ºC
Cold: Does not exceed 8 ºC (46 ºF)
Cool: Between 8 ºC and 15 ºC
Room Temp: 20 ºC to 25 ºC
Warm: Between 30 ºC and 40 ºC
Excessive Heat: Above 40 ºC
Protection from Freezing
Protection from Light
You must maintain appropriate
conditions of temperature and
humidity during shipment.
Special consideration
may be needed
Characteristics of the ideal dosage form
what should the final dosage form be
B
D & D form should be _______
F should be: S, E admin., S admin, Efficacious
Biocompatible
Drug and dosage forms should be compatible
Formulation should be
Stable
Easily administered
Safely administered
Efficacious
Other reasons why we need dosage forms?
To ______protection from destructive _____ influences (atmospheric oxygen, humidity…)
To provide _______ from ______ pH
To address _________ taste or ________
To provide ________ preparations
To control the _______ of drug release
To _______ drug _____
To provide for ________ into body’s ______
To provide protection from destructive chemical influences (atmospheric oxygen, humidity…)
To provide protection from gastric pH
To address offensive taste or odors
To provide liquid preparations
To control the rate of drug release
To improve drug action
To provide for insertion into the body’s orifices
General considerations
Match ______ form to the _______illness
Select dosage forms to ________ patient-_______needs
For children less than________ the ______dosage forms for oral route of administration are best
To assist the ______ with self-_______ procedures
Match dosage form to the appropriate illness
Select dosage forms to address patient-specific needs
For children less than 5 years of age the liquid dosage forms for oral route of administration is best
To assist the elderly with self-medication procedures
Preformulation considerations
Physical ______
Microscopic ______
Melting ______depression
The ______rule
Particle ______
Polymorphism
______
Amorphous
_______
Solubility and ______size
Solubility and _____
Dissolution
Membrane _________
Diffusion
_______Law
Partition _______
Pharmaceutical _______ & Excipients
Reaction _____
Zero ______ reactions
First order _____
Physical Description
Microscopic examination
Melting point depression
The phase rule
Particle size
Polymorphism
Crystal
Amorphous
Solubility
Solubility and Particle size
Solubility and pH
Dissolution
Membrane Permeability
Diffusion
Ficks Law
Partition Coefficient
Pharmaceutical Ingredients & Excipients
Reaction rates
Zero-order reactions
First order reactions
Physical Description
The majority of drugs are in _____form:
Crystalline or ______ constitution
Chemical properties:
Structure, _____ , and _______
Physical Properties:
Particle size, _______ structure, melting _______and solubility
Biologic Properties:
Ability to get to ______ of drug ______ and elicit a _______response
The majority of drugs are in solid form
Crystalline or amorphous constitution
Chemical properties:
Structure, form, and reactivity
Physical Properties:
Particle size, crystalline structure, melting point and solubility
Biologic Properties:
Ability to get to the site of drug action and elicit a biologic response
Microscopic Examination
Is the appropriate site of
____ ______ targeted?
Gives indication of
particle _____ for finished
_______
Some ideas of _____
of ______ form
Is the appropriate site of
drug action targeted?
Gives indication of
particle size for finished
Pharmaceuticals
Some ideas of stability
of dosage form
Particles are sized directly and
individually, rather than grouped statistically
Melting Point Depression
Low____ _____ drugs soften during a ______ step where _____ is generated
The melting point can be used to determine ______
DSC = Differential Scanning Calorimetry
Measures thermal phase ____, which can be used to determine the _____ of a given drug substance. How??
Low melting point drugs soften during a processing step where heat is generated
The melting point can be used to determine purity
DSC = Differential Scanning Calorimetry
Measures thermal phase behavior, which can be used to determine purity of a given drug substance. How??
Mp Pure A = 124 ºC
Mp Contaminated A (5% B) = 95-115 ºC
Used for determining:
Determination of purity
Solid drug + Solid pharmaceutics ingredients
what is melting point depression used for
Determination of purity
Solid drug + Solid pharmaceutics ingredients
Thermogram
what is a sample chamber
what is an experimental chamber
A plot of the energy absorbed as the temperature of the system is raised.
For e.g., the peak is caused by the absorption of energy required to melt the lipid bilayer
This is a thermogram for the melting of lipids used to prepare dosage forms.
Sample chamber:
Contains dosage form without the drug
Experimental chamber: Contains dosage form with drug
Phase diagrams
what do they reveal about melting point
what are the phases
what happens is a substance is added to either one of these phases
what is the minimum melting point
A phase diagram (aka~ temperature-composition diagram) “reveals the melting point as a function of composition of two or
three component systems”
The phases are non-solid and solid
When a substance is added to either one of these phases (that is Pure A or Pure B), the melting temperature of the pure component(s) decrease.
Minimum melting point = EUTECTIC POINT
Each phase I, II, III, & IV is a
different part of the system
separated by boundaries
Particle Size
what does particle size distribution effect
what are the types of Physical and chemical properties of drug substances
Physical and chemical properties of drug substances
Drug dissolution rate
Bioavailability
Content uniformity
Sedimentation
Textures
Polymorphism
how much of it does it represent for all organic drug compounds
what are the Physicochemical properties of drug compounds
is more more energy required for a molecule to escape from a crystal or from a amorphous powder–what can we conclude
PolymorphismRepresents 1/3 rd of all organic drug compounds
Physicochemical properties of drug compounds
Non crystalline (or amorphous forms)
Crystalline (crystal structure)
“The energy required for a molecule of drug to escape from a crystal is much greater than the energy required to escape from an amorphous powder”
therefore
Amorphous form of drug is more soluble than the crystal form
Polymorphism: examples’
which is more soluble, crystal form or amorphous form
amorphous form
are antibiotic substances like novobiocin and chloramphenicol more soluble in crystal or amorphous form and what does that allow for GI tract absorption
which can be more active crystal or amorphous forms of drugs like penicillin G and thus what is made better
they are more soluble in amorphous form –Absorption from GI tract is rapid
in amorphous form
crystal form can be more active than amorphous form and thus Its crystal form results in a better therapeutic response
what must a drug possess to be considered effect, can increase solubility
what determines solubility
what can you do to Make an excess amount of a drug dissolve and what can be determined from it
“Drug must possess some aqueous solubility to be considered effective”–insoluble compounds can lead to incomplete absorption. Solubility can be increased by chemical modification (ie., salt or ester form of a drug is a favorable chemical modification)
Solubility is determined by an ‘equilibrium solubility’ method.
Excess of drug is placed in a solvent and shaken at a constant temperature until an equilibrium is obtained.
This is done to determine the degree of solubility
Solubility and pH
what is pH
what can be adjusted to enhance solubility
can all drugs benefit from the answer above
what can be used instead of the above option
The pH can be adjusted to enhance solubility.
Not all drugs can benefit from adjustments to pH. Why not?
“For example weak acids or basic drugs require significant changes in pH that are outside the physiological limits.
When manipulation of pH is not an option due to physiological issues the following can be used:
Co-solvents:
Micronization:
Dispersion:
Emulsion:
Which of the following is used to improve flow properties of powder mixtures?
colloidal silica
acacia
bentonite
colloidal silica for tablet gliding!
acacia for emulsifying
bentonite for clarifying agent and suspending agent
what is dissolution (drug, fluids, absorption site)
what is the rate limiting step in the absorption process
_____ goes up when _____ goes down
____ goes up when _____ goes up
what can dissolution time effect
is the time it takes for a drug to dissolve in fluids at the absorption site.
Dissolution is the rate limiting step in the absorption process
absorption rate will rise when particle size goes down
dissolution goes up when solubility goes up
dissolution time can influence duration of therapeutic effect
what makes up a dissolution apparatus
motor
paddle
compact
solvent (could be HCl)
Diffusion
what do most drugs under go and usually in what part of the cell
what is fick’s law of diffusion
Most drugs undergo transport by simple diffusion, whether in the cytoplasm or interstitial fluid environment
fick’s law of diffusion is simple passive diffusion from high concentration of solute to a low concentration of solute
Membrane Permeability
what must a drug cross to get a biological response
do lipid-soluble drugs have a hard time passing cell membranes?
do lipid insoluble drugs have a hard time passing cell membranes?
Drugs must cross biological membranes to exert a biologic response
Lipid soluble drugs have little problem
Lipid insoluble drugs require additional assistance
what is “Everted intestinal sac” used for
how does everted intestinal sac work
Used to evaluate absorption characteristics of drug substances
–A piece of intestine is removed from an intact animal, everted
–filled with drug to be tested and degree
–rate of passage of drug through membrane is determined
what is partition coefficient (water and lipid)
what is octanol
what is water
P =
optimal balance between water and lipid solubility
octanol: (hydrophobic environment)
water: (Aqueous environment)
P = (conc. of drug un octanol)/(conc. of drug in water)
when is the partition coefficient useful
antibiotics & fermentation broths
extracting drugs & therapeutic monitoring
absorption & dosage forms
flavoring oils. & oil/water emulsions
When recovering antibiotics from fermentation broth
When extracting drugs from biologic fluids for therapeutic monitoring
Absorption of drugs from dosage forms (ointments, suppositories etc..)
Study of distribution of flavoring oils between oil and water phases of emulsions
How is the partition coefficient measured?
flask
phosphate buffer
HPLC
Shake a known amount of drug in a flask containing a measured amount of water and octanol.
Phosphate buffer (pH 7.4) is used to mimic physiological pH. This also corrects for the ratio of [conjugated base]/[acid] found in vivo.
The amount of drug in one or both of the phases is determined by HPLC (or by some other quantitative analytical approach).
For octanol/water partition coefficients
what does it mean that it is lower than 1
what does it mean that it is higher than 1
lower than 1: hydrophilic
higher than 1: hydrophobic/lipophilic
Pharmaceutics Ingredients and Excipients
One or more inactive agents are used to prepare final dosage forms
Flavors, and sweeteners:
Colorants:
Preservatives:
Stabilizers:
Diluents or fillers:
Binders:
Anti-adherents/ or lubricants:
Disintegrating agents:
Flavors, and sweeteners: improve taste
Colorants: enhances appearance
Preservatives: prevent microbial growth
Stabilizers: prevent decomposition
Diluents or fillers: to increase bulk
Binders: improves adhesive properties
Anti-adherents/ or lubricants: smooth coating
Disintegrating agents: promotes tablet breakup
Reaction rates
what are the most common degradation processes, do we want them to happen
what is important for development of drug products and drug behavior
what is rate of reaction
what is the outcome of a drug
hydrolysis, oxidation—do not want to happen
Since drug therapy is a dynamic process, the time it takes for a reaction to occur is important for development of drug products, and drug behavior.
rate of rxn: Actual speed of velocity at which the dynamic process occurs
drug: Some Product, or Some Outcome
- Drug decomposition
- Drug dissolving in H20 to give solution
- Drug absorption
- Drug metabolism
Chemically, drug substances are prone to hydrolysis or oxidation
what drug substances are prone to hydrolysis and what to oxidation
Prone to hydrolysis
Esters:
Amides
Lactones
Lactams
prone to oxidation
-Aldehydes
-Alcohols
-Phenols
-Sugars
-Alkaloids
-Unsaturated fats, oils
Zero order reactions
what is the rate and does it change over time
what is ko
what eon will give you the amount of drug removed over any given period of time
In this reaction rate, the rate is a constant, and thus does not change with time.
The term ko is the zero order reaction rate
The amount of drug removed over any given period of time is a constant
= -kot + Co
used to calculate zero order rxn
First-Order Reactions
what does it depend on
what happens to the rate when concentration (C) is large
what happens has C decreases
the higher the concentration, the water the what
what do most rxn with pharmaceutical products deal with
what eon is used to calculate first order rxn
The amount of drug removed each year decreases with time, but percentage or
the_____________________________
This reaction rate depends on the concentration of only one reactant.
Rate of reaction is initially fast when the concentration (C) is large; as C decreases the reaction slows as the reaction proceeds
The higher the concentration of drug the faster the rate process
Most reactions dealing with pharmaceutical products follow this process
lnc = -kt + lnCo
The amount of drug removed each year decreases with time, but percentage or
the fraction removed over this period of time remains constant
A drug suspension (125 mg/ml) decays with zero order kinetics with a reaction rate constant of 0.5 mg/ml/hr. What is the concentration of intact drug remaining after 3 days (72 hrs)?
89 mg/ml/hr
A drug suspension (125 mg/ml) decays with zero order kinetics with a reaction rate constant of 0.5 mg/ml/hr. How long will it take the suspension to reach 90% of its original concentration?
T = 25 hours
A drug suspension (125 mg/ml) decays with zero order kinetics with a reaction rate constant of 0.5 mg/ml/hr. What its half-life (t1/2 )?
125 hrs
What is the ingredient used in liquid and semi solid preparations to prevent the growth of microorganisms?
AntimicroBial preservative
B for:
Benzalkonium chloride
The Pediatrician has clearly communicated to the compounding pharmacist that his patient is allergic to preservatives. Therefore, which of the following must NOT be used to prepare the Nasal Spray?
A) Butylparaben
B) Ethylparaben
C) Benzalkonium chloride
D) A and B only
E) A, B and C
the answer is E!
Butylparaben and ethylparaben are both anti fungal PRESERVATIVES and benzalkonium chloride is an anti microbial preservative
where should the drug be in terms of MEC & MTC
what will happen if it was above the MTC
Ideally, the drug serum levels should be maintained above the MEC and below the MTC
.
* Concentrations above the MTC will cause toxic side effects
What is the process from discovery/development of new chemical to postmarketing
*where is most of the time spent in the cascade
what happens to a lead drug
new chemical entity
–organic synthesis
–molecule modification
–isolating from plants
preclinical studies
–chemistry
–physical properties
–biological: pharmacology, ADME, toxicology
–preformulation
preclinical trials
–long term animal toxicity
–product formulation
–manufacturing and controls
–package and label design
clinical trials
–phase I
–phase II
–phase IIII
new drug application (NDA)
–submission
–FDA review
–preapproval plant inspection
–FDA action
postmarketing
–phase IV clinical studies
–clinical pharmacology/toxicology
–additional indications
–adverse rxn reporting
–product defect reporting
–product line extension
most time spent in clinical trials
Lead drug; preclinical testing; phase I,II,III, and then NDA submission
Timeline for development of a new drug
preclinical research and development: ___ years
clinical–research and development: average ____ years
NDA review: average ____ years
average ___ years from initial synthesis to approval of NDA
preclinical research and development: 6 1/2 years
clinical–research and development: average 7 years
NDA review: average 1 1/2 years
average 15 years from initial synthesis to approval of NDA
post marketing surveillance
percentage of drugs successfully tested
phase 1: 70%
phase 2: 33
phase 3: 25-30%
Powder- a drug substance composed of what
what can it refer to - physical form or pharm. what
can it be used externally and internally?
how do many of the active and nonactive agents occur
A drug substance composed of finely divided particles
Term powder can refer to,
– Its physical form, or
– Type of pharmaceutical preparation
A type of pharmaceutical preparation, a medicated powder intended for internal (I.e., oral) or external (i.e., topical) use
Many of the active and non-active pharmaceutical agents occur in the solid state as amorphous powders or as crystal
powders as a dosage form
powders are mixtures of what – are they wet, are they fine, are they drugs, are they for internal or external use?
what do powders consist of- in terms of particle sizes (very fine to very coarse)
what are the sizes of powders used to describe vegetable and animal drugs?
As a dosage form, powders are thorough mixtures of dry, finely divided drugs and excipients intended for internal or external use.
Powders consist of particles ranging in the size from 1 μm (very fine) to approximately 10 mm (very coarse).
– Very coarse
– Coarse,
– Moderately coarse
– Fine,
– Very fine
how should the particle size be
how big should In the micron unit range
– Opthalmic suspension
– Oral suspensions
– Parenteral suspension
– Aerosols for lung
– Tablets and capsules-immediate release
– Topical aerosols
– Topical emulsions
– Topical suspensions
be
Particle sizes should be uniform
In the micron unit range
– Opthalmic suspension (≤10 )
– Oral suspensions (10-50)
– Parenteral suspension (0.5 to 25)
– Aerosols for lung (1 to 5)
– Tablets and capsules-immediate release (≤50) – Topical aerosols (50 to 100)
– Topical emulsions (≤50)
– Topical suspensions (10 to 50)
what do the terms very coarse, coarse, moderately coarse, fine and very fine relate to
how is the passing powder particles through sieves accomplished and what is used
The terms very coarse, coarse, moderately coarse, fine, and very fine are related to the proportion of powder that can pass through standardized sieves of varying dimensions.
The passing of powder through standardized sieves is done over a specified time period under shaking, and generally with a mechanical sieve shaker
Opening of Standard Sieves
what number is
very coarse
coarse
moderately coarse
fine
very fine
numbers go up, what happens to size
very coarse - No. 8 - 2.36 mm
coarse - No. 20 - 850 um
moderately coarse - No. 40 - 425 um
fine - No. 60 - 250 um
very fine - No. 80 - 180 um
numbers go up, size goes down
As the sieve number
Increases the size of the sieve
opening decreases
As the sieve number _____ the size of the sieve opening _____
As the sieve number Increases the size of the sieve opening decreases
Very coarse: No 8
All particles pass through a No.8 sieve and not more than 20% through a No. 60 sieve
Coarse: No 20
All particles pass through a No.20 sieve and not more than 40% through a No. 60 sieve
sieve sizes
- Moderately Coarse: No.40
All particles pass througha No.40 sieve and not more than 40% through a No. 80 sieve
Fine:No.60
All particles pass through a No.60 sieve and not more than 40% through a No.100 sieve
Very Fine:No.80
All particles pass through a No.80 sieve and there is no limit as to greater fineness
Bulk powders for external use
are they dry, free-flowing?
what are examples of them?
what are the advantages?- easy what, absorb what, dry what
what are the disadvantages?- may block what, get inhaled by who, not suitable for what
Usually dry, free-flowing preparations
– Finely powdered substances
– Ex: Chlorhexidine and Tinaderm
dusting powders
- Advantages: easy application, absorb moisture, has dry
cooling effect - Disadvantages: may block pores, get inhaled by infants, and not suitable for all skin-related medical problems
Bulk powders for internal (oral) use
what does it resemble
advantages- stability, is it easily administered, does it absorb into the GI tract
disadvantages- is the accuracy of the dose guaranteed, it easy to carry, is it easy to mask unpleasant taste
Resemble dusting powders except given orally
– Preparations are formulated on the basis of dose-
weights [5 ml spoon = 5 grams ????].
Advantages: stability, easily administered (i.e.,
Indigestion powders), absorption by GI tract is rapid
Disadvantages:
– accuracy of dose not guaranteed, – large dose containers
– difficult to carry, and
– difficult to mask unpleasant tastes
The particle size of a powder can influence…
dissolution
Suspendability
uniform distribution in what
penetrability of what
lack of grittiness of solid particles in what
Dissolution rate of particles
- Suspendability of particles
- Uniform distribution of a drug substance in powder mixture
- Penetrability of particles
- Lack of grittiness of solid particles in dermal ointments and creams
Particle size of powders influence
the dissolution rate of particles- what can increase the rate of drug dissolution and its bioavailability
suspendability – particles are supposed to remain undissolved but what dispersed in a liquid vehicle
The dissolution rate of particles:
– micronization of particles can increase the rate of drug dissolution and its bioavailability
- Suspendability:
– Particles intended to remain undissolved but uniformly dispersed in a liquid vehicle
Uniform distribution of a drug in a mixture or solid dosage form ensures what about dose
what does penetrability intend to do concerning the respiratory tract?
nongrittiness (smoothness) is found in what type of substances
Uniform distribution of a drug substance in a powder mixture or solid dosage form to ensure dose- to-dose content uniformity
- Penetrability of particles intended to be inhaled for deposition deep in the respiratory tract (1-5 microns).
- Nongrittiness of solid particles in dermal ointments, creams, and ophthalmic preparation (50 to 100 microns)
what are the Methods used for determining particle size
S
S
L
L
M
C
sieving
sedimentation rate
light scattering
laser holography
microscopy
cascade impaction
A single method may be sufficient to determine the size for some powders but a combination is preferred.
In general a single method is usually sufficient
Sieving
size range
Particles pass through a series of sieves of known successively smaller sizes
Size range:
* 40–9,500μm(micron)
microscopy– grid used to do what
size range
A calibrated grid background is used to measure particle size
- Size range:
- 0.2-100μm
Sedimentation rate:
– The velocity of particles through a liquid medium in a gravitational or centrifugal environment
- Size range:
- 0.8–300μm
Light scattering:
– Reduction in the amount of light reaching the sensor as the particle dispersed in liquid or gas passes through the sensing zone range
- Size range:
- 0.02–2,000μm
Laser Holography:
laser
aerosolized particle spray
photograph with camera
– A pulsed laser is fired through an aerosolized particle spray and photographed in three dimensions with a camera
- Size range:
- 1.4-100 μm
Cascade impaction:
a particle is driven by what impacts what
particles are separated into various what by doing what
is there a specific size range for this? what makes this method special?
– A particle, driven by an airstream impacts on a surface in its path.
– Particles are then separated into various size ranges by successively increasing velocity of the airstream.
- No specific size range
Comminution of drugs
Grinding a drug in mortar to reduce its particle size
- A mortar with rough surface (as opposed to a glass mortar) is used.
Trituration
* Levigation
* Levigating agent
Trituration
The process of rubbing, crushing, grinding or pounding materials.
– May be employed to both comminute and mix powders
Levigation
The process of reducing the particle size and grittiness
Levigating agent
A small amount of some liquid added to the powder to form a paste
Blending Powders
Generally when two or more powdered substances are to be combined to form a uniform mixture
S
S
T
T
what is the difference between levigating and tritulation
Spatulation
* Sifting
* Trituration
– Geometric dilution - add inert color to see if the mixture is uniformly distributed
* Tumbling
levigating - reducing particle size using a liquid and mortar
tritulation - reducing particle size using a mortar
Spatulation
what is speculation used for
what is it not recommended for
what substances can form eutectic mixtures: MPCAT & similar chemicals
– What to add to avoid the formation of an eutectic mixture
A spatula moves through powders on a sheet of paper or ointment tile.
– Not recommended for large quantities
– used to mix solid substances that form eutectic mixtures, because little compression or compacting of powder with spatulation
– Substances that can form eutectic mixtures are: phenol, camphor, menthol, thymol, aspirin and similar chemicals
– What to add to avoid formation of eutectic mixture
- – Magnesium oxide
– Magnesium carbonate
Trituration
what is it used for
how is it used
why is an inert color added
Trituration may be employed to comminute and mix powders
* Glass mortar is preferred if no need for
comminution
Why? Read section on pg 177
* During geometric dilution an inert color is added to ensure uniform distribution
Sifting
how are powders mixed?
should you sift fluffy products?
In this method, powders are mixed by passing them through sifters
Sifting Fluffy products- no because it will get everywhere
- Not acceptable for incorporation of potent drugs into a diluent powder
Tumbling
what causes tumbling motion
where is it most widely used?
Tumbling powder enclosed in a rotating container
- Special blenders mix/ blend powders by tumbling motion
- Most widely used in the pharmaceutical industry
Medicated Powders
what are aerosol powders good for
what are medicated powders?
how are most taken after mixing with what
what if you want to use it externally?
-Aerosol powders deliver medication deep within the lungs
-Inert propellants and diluents to increase flow properties and protect against humidity
Aerosol powders
- Most taken orally after mixing with water
- If intended for external use the label should
read
– EXTERNAL USE ONLY - Some intended to be inhaled into the lungs for local and systemic effects
Aerosol powders deliver medication
deep within the lungs
-Inert propellants and diluents to increase
flow properties and protect against humidity
Quality control considerations
bulk powders
- what should pharmacists compare the final weight of the product to
- what should the powder be examined for – uniformity of what, particle what, flow, freedom from what
divided powders
- what should pharmacists compare the final weight of the divided powders product to
- what should the packets be checked for
Bulk Powders:
– Pharmacist should compare the final weight of the product to the theoretical weight.
– The powder should be examined for uniformity of color, particle size, flowability, and freedom from caking
- Divided Powders:
– Pharmacists should individually weigh the divided powders and
then compare that weight to the theoretical weight.
– The packets should be checked to see that they are uniform.
Granules
are they regularly shaped, can they be forced into certain shapes
- How are they prepared– screen, air, oven, mass formed
Prepared aggregates of smaller particles of powder
- They are irregularly shaped, may be forced into certain shapes mechanically
- First passed through a screen, then dried in air, then put in
the oven and a pasty mass is formed
How are they prepared?
- First passed through a screen, then dried in air, then put in the oven and a pasty mass is formed
Granules
- how does the flow and size compare to powders
- are they more easily or harder wetted by liquids
- what are they prepared to contain
Characteristics
– Flow well when compared to powders
– Have a smaller surface area compared to powders of a comparable volume
– More easily wetted by liquids
– Prepared to contain colorants, flavorants and other pharmaceutical ingredients
Effervescent Granules
these are granules that contain what in a dry mixture
what are these granules exposed to? make sure you know what they are exposed to for the exam!
how are the Effervescent granules produced?
- Why important? what can the carbonated soln now mask
These are granules (coarse to very coarse powders) containing a medicinal agent in a dry mixture composed of sodium bicarbonate, citric acid, and tartaric acid
- When water is added carbon dioxide is liberated and sparkles (and bubbles) are produced
add water, releases CO2, sparkles are produced - Why important?
– Because the carbonated solution produced can now mask undesirable tastes associated with drug
