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258 Cards in this Set
- Front
- Back
2 general requirements for FDA approval to market a drug product?
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1. demonstrated safety & efficacy
2. demonstrated process control & validation |
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what are the 2 main stages of research and development
|
pre-clinical and clinical
|
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T/F: the pre-clinical stage of research and development has the substages of drug discovery, biological characterization, preformulation, & initial formulations
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True
|
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what is the method of drug discovery?
|
most today result from carefully designed rational research programs
|
|
put the following steps of drug discovery in order?
lead, target, candidate, hit |
target-----hit-----lead----candidate
|
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this step of drug discovery is the identification and screening
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hit
|
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_________is the preclinical and then clinical drug development of drug discovery
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candidate
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identification and validation is which step in drug discovery
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target
|
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T/F: Lead is the identification and validation step of drug discovery
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False Lead is the identification and optimization step of drug discovery
|
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In which stage of research and development do you spend the most money?
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clinical
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the biological characterization of drug is its potential for use as a therapeutic agent and is charcterized by examinations of its
a. pharmacology b. toxicology c. disposition (what happens when u take it) d. pharmacokinetics (how fast does it work) e. all of the above |
E all of the above
|
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preformulation consists of what?
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physiocochemical properties
analytical method development |
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In essence ________ ________ is the proess of turning an active compound into a form and strength sutiable for human use.
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dosage formulation
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once the physicochemical properties are understood, initial dosage forms aredeveloped for use in clinical trials; this is what stage of pre-clinical?
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initial formulations
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a comprehensive application delineating all aspects of the pre-clinical studies and the plan for clinical studies
|
investigational new drug application
|
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the main purposes of investigational new drug (IND) application
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1. to protect the rights & safety of the human subjects
2. to ensure that teh investigational plan is sound |
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FDA Review of IND
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1. 30 day safety review
2. review by experts |
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what happens when IND is reviewed by experts?
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the application is forwarded to a specific division within the FDA, where it is reviewed by experts within the field
|
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what is the automatic time period during which teh drug cannot be administered to humans?
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30 day safety review
|
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For FDA drug classification system, drugs are classified by what 2 things?
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1. chemical type
2. therapeutic potential |
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What are 3 phases of clinical research & development
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phases 1,2,& 3
|
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what is the purpose of phase 1?
Phase 2/? phase 3? |
phase 1: mainly safety
phase 2: mainly effectiveness, but also short term safety phase 3: safety, effectiveness, & dosage |
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patients in this phase of testing are usually healthy volunteers?
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phase 1
|
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in which phase or phases are patients tested are those that are suffering from the indicated condition
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phases 2 & 3
|
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Number of patients used for each phase of teh clinical part of research and development?
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phase 1: 20-100
phase 2: up to several hundred phase 3: several hundred to several thousand |
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what is the length of testing for each phase of the clinical trials?
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phase 1: several month
phase 2: several months to 2 years phase 3: 1 to 4 years |
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what is the % of drugs completing each phase of the clinical trials?
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phase 1 :67%
phase 2: 45% phase 3: 5-10% |
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during _______ ________, the final formulation is completed as well as the packaging and labeling.
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clinical studies
|
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The new drug application has what kind of data?
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pre-clinical & clinical data
|
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what summaries are found in the new drug application?
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1.summaries of human pharmakinetics
2. bioavailability 3. microbiology (if it's an antibiotic) |
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what are 4 points addressed in the new drug application?
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1. a presentation of pre-clinical & clinical data
2. summaries of human pharmacokinetics, bioavailability, microbiology 3. discussion of the benefits and risks of the drug's usage 4. complete proposed product labeling (including dosage) |
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Describe new drug application
|
integrates all data
typically 100K pages or more and takes on average a year to rvu. |
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New Drug application is comprised of what 3 things?
|
1. the application
2. the inspection 3. the decision |
|
The inspection for the new drug must comply with what?
|
1. The quality standards contained in the application
2. The quality standards specified in the FDA's Current Good Manufacturing Practice Standards |
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The decision for the new drug application consists of the complete response letter. What will the letter contain?
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It will either contain an approval stating that the application is approved or it will outline deficiencies and may recommend actions needed to be taken for approval.
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What is the phase of clinical studies that has post marketing?
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phase 4
|
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What happens in phase 4?
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following approval, the drug product is continually monitored in clinical investigations which adds to the understanding of the drug's effects.
|
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The 3 steps in post marketing?
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1. phase 4 clinical studies
2. adverse reaction reporting 3. comprehensive annual reports are required. |
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what happens in adverse rxn reporting?
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The drug's sponsor is required to rvu and report to the FDA all adverse effects reported to them by all sources such as MDs, postmarketing studies, pharmacists, etc.
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In adverse rxn reporting, who reports to who?
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The drug's sponsor reports to the FDA
|
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what are orphan dz?
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rare dzs or conditions that affects fewer than 200,000 people in USA
|
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what is the problem with drugs and orphan dz?
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there is no reasonable expectation that costs of research and development for the dz indicated can be recovered by sales of the product.
|
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What is the purpose of developing IND for orphan drugs?
|
the purpose is to provide incentives to develop drugs where there is an insufficient market incentive by:
1. giving financial support for clinical trials 2. 7 years of exclusive marketing rights |
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What 4 variations are there in the drug development process?
|
1. IND for orphan drugs
2. Treatment IND 3. Abbreviated new drug application 4. Supplemental new drug application |
|
This variation of the drug development process omits nonclinical laboratory studies and clinical studies except those pertaining to bioavailability
|
abbreviated new drug application which is used for generic drugs
|
|
Define supplemental new drug application?
|
required for certain types of changes like in method of synthesis, formulation, analytical standards, container, manufaturing facilities...etc
|
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Define bioavalibality?
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fraction of an administered dose that reaches the systemic circulation
|
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Treatment IND is given for what reason?
|
for patients with life threatening or severely debilitation illnesses, where no satisfactory alternative exists.
|
|
Give examples of orphan dzs?
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cystic fibrosis and chronic lymphocytic leukemia
|
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Give examples of life threatening or severely debilitating illnesses that go thru treatment IND
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advanced AIDS
Alzheimer's dz Advanced Parkinson's dz |
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what is the purpose of treatment IND?
|
to facilitate getting the drugs to these patients while in clincial trials.
|
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Give an example of treatment IND & explain?
|
"treatment protocol" where the IND is filed during phase 1 or 2 to allow treatment for the ill patients
|
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The stage of drug development during which the physical & chemical properties of a drug substance are evaluated towards the formulation of a stable, safe, and effective dosage form.
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Preformulation
|
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what part of the drug is evaluated during preformulation?
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the physical and chemical properties
|
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what is the purpose of preformulation?
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to form a stable, safe, and effective dosage form
|
|
the manner in which a drug is formulated is crucial for what?
|
its bioavailability and acceptability by the patient
|
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solution, suspension, tablet, capsule, suppository represents what part of the drug?
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dosage form
|
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during preformulation, 4 points are considered by the physical pharmacist?
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1. drug is suitable for dosage formulation, for teh desired route of administration
2. drug has sufficient water solubility 3. drug has sufficient lipid solubility 4. drug is sufficiently stable |
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Name the four drug properties that we are interested in?
|
1. physical properties
2. dissolution 3. partitioning 4. stability |
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most drugs are in what state?
|
solid state
|
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Most solid drugs are what shape?
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crystalline
|
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Describe the arrangement of the crystalline form of the solid drug?
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has a repeating or periodic arrangement of the individual moleucles that creates teh crystal lattice
|
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T/F: Different molecular arrangements are possible within a solid. A particular arrangement defines the extrnal structure
|
False: a particular arrangement defines the INTERNAL structure
|
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The internal structure determines what?
|
the crystal habit
|
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Define habit in a crystal solid drug?
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It's the description of the outer appearance of a crystal
|
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How do you get different habits of crystalline form?
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Different habits can result from minor changes in the synthetic conditions
|
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Which solid form, crystalline or amorphous will dissolve faster?
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amorphous
|
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This type of solid form is without distince crystalline structure?
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amorphous form
|
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What is the arrangement of the amorphous form?
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has no repeating or periodic arrangement
|
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This form has random molecules with no crystal lattice, looser arrangement and in slight motion
|
Amorphous form
|
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5 things that are affected by the form of the solid drug?
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1. Flow properties
2. mechanical properties 3. bioavailability 4. melting point 5. solid state stability |
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Give an example of solid state stability
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Hygroscopicity which is water uptake unto a solid or liquid and which can change the stability of the drug
|
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Define polymorphism?
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capacity for appearing in many forms
|
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Depending on crystallization conditions, some drug solids may have at least ________ different molecular arrangements, each giving distinct ___________ species, or polymorphs
|
two
crystalline |
|
The different properties of polymorphs?
|
1. intermolecular interactions
2. solubility |
|
define matastable?
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being in an unstable & transient but relatively long lived state of a chemical or physical system
|
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Give an example of a molecule with weak molecular interactions
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amorphous solids b/c they're metastable
|
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Which polymorph would be more soluble?
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metastable polymorphs more soluble than their more stable counterparts b/c of weaker interactions
|
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A drug that may crystallize as a combo of pure drug and the solvent of crytallization is called what?
Give ex? |
solvate
hydrate where water is part of the crystal |
|
changes in hydrate form can affect what?
|
solubility
|
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How do hydrates affect solubility? explain
|
hydrates are generally less soluble thatn their anhydrous counterparts.
This is because of the energetics of dissolution (the water and drug are holding on to each other more tightly) |
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how do hydrates affect bioavailability?
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since there is less dissolution of the drug from the water, there is less bioavilability of the drug
|
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Particle size of a solid drug can affect what 3 things?
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1. dissolution rate
2. particle settling in suspensions 3. particle flow |
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The smaller the particle the ________ the dissolution
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faster
|
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The smaller the particle the _________ the surface area
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greater
|
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How did dissolution rate affect griseofulvin as a drug
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micronization reduced the dose needed by 50% b/c the faster the dissolution the great the bioavailability
|
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How did dissolution rate affect nitofurantoin?
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crystals of the drug were too small and dissolution was too fast. The result was was nausea.
|
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what are some factors that determine particle flow as a solid drug property?
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1. particle cohesiveness
2. particle density 3. particle shape 4. particle size |
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What are 3 variables affected by particle flow?
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1. mixing & pouring
2. speed of processing during manufacture 3. settling and stratification during handling, mixing, and storage |
|
Define stratification?
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process of arranging in layers
|
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Particle cohesivenss of particle flow is affected by what 2 things?
how does each work in affecting particle cohesiveness? |
electrostatic charge
adsorbed moisture Electrostatic charge can affect particle interactions Adsorbed moisture can make the powder sticky |
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A drug must be in _________ to be absorbed and to cause an _________.
|
solution
effect |
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a homeogenous mixture of 2 or more substances
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solution
|
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define a solute
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the molecular, atomic, or ionic component of a sol'n that is dissolved by the solvent
|
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the component of a sol'n that dissolves the solute
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solvent
|
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what are the 4 sol'ns that we need to know & give an example of each
|
1. gas/liquid carbonated h2o, holothane
2. liquid/liquid miscible liquids (eg alcohol in H2O) 3. solid/solid drug in polymer 4. solid/liquid drug in water |
|
define miscible liquids
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liquids that completely dissolve in each other in all proportions
|
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this process involves the relocation of a solute molecule from an environment where it is surrounded by identical molecules into a cavity in a liquid where it becomes surrounded by non-identical molecules, with which it may interact to varying degrees
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process of dissolution
|
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each step of the dissolution process involves what?
|
energy
|
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T/F: the overall dissolution process can be endothermic or exothermic
|
True
|
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tell the difference btwn endothermic & exothermic
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endo: heat is absorbed
exo: heat is given off or evolved |
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what are the steps in the dissolution of a crystalline solute
|
1.removal of solute molecule
2. creation of a hole in the SOLVENT 3. placement of SOLUTE in the hole ***** See picture in notes under drug dissolution****** |
|
the concentration of a solute in a saturated solution at a certain temperature
|
solubility
|
|
How is solubility expressed?
|
the # of mL of solvent needed to dissolve 1gm of solute
|
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Relate the solubility of a sol'n to how much solvent is needed for 1 gm of solute
|
the more mL of solvent needed for each gm of solute, the less soluble the sol'n will be.
ex: <1ml of solvent for 1gm of solute means the sol'n is very soluble whereas >10,000mL of solvent for 1gm of solute means the sol'n is very insoluble |
|
besides # of mL solvent/gm of solute, how else is solubility expressed?
|
molality
molarity percentage |
|
4 factors governing the solubility of a solid in a water
|
1. nature of the solid
2. nature of the solute 3. nature of the solvent 4. Temperature |
|
T/F: metastable polymorph is more soluble than its more stable counterpart
|
True
|
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the 2 natures of the solid in sol'n w/ water
|
polymorph
pseudoopolymorph |
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define pseudopolymorph
|
anhydrous crystals are generally more soluble than hydrates & therefore have better bioavailibility
|
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give an example of a pseudopolymorph drug
|
ampicillin
|
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2 things must be considered for a solute's solubility in water
|
1. molecular structure of the solute
2. ionization state of the solute |
|
what defines the molecular structure of the solute's solubility?
|
size, shape, and substituent groups can all be important for solubility
|
|
what happens in a molecular structure of a solute that has hydrophilic substituents?
|
most can form H+ bonds with H2O.
|
|
the effect of hydrophilic substituents on water solubility can be dramactic. give an ex of this
|
phenol is 100x more soluble than benzene b/c that alcohol group in phenol increases its solubility dramatically
|
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Again with regard with molecular structure of a solute, how does size and shape compare with the substituent grp in affecting the solubility?
Give ex? |
the bulk of a molecule can be more important than the substituent.
ex of this is estradiol where the corticosteroid ring structure & 2 hydroxyl grps have a solubility of 5mcg/ml |
|
__________ __________is one of the most important physiocochemical properties determined during preformulation since it affects both water and lipid solubility
|
the ionization state of the solute
|
|
the ionization state of the solute affects what 4 things?
|
1. dosage formulation
2. absorption 3. distribution 4. excretion |
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T/F: most drugs have ionizable groups where they are either weak bases, weak acids, or amphoteric
|
True
|
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which part of the drug is generally the most water soluble form?
|
the ionized form
|
|
The degree of ionization is a fxn of medium pH and can be measured by ______.
|
pKa or dissociation constant
|
|
define pKa?
|
it's the pH at which the drug is 50% ionized
|
|
be familiar with the henderson hasselbalch equation for acid & base
|
ACID: pH= pKa + log [A-]/[HA]
BASE: pH=pKa + log [B]/[BH+] |
|
99.9% of the drug will be ionized at 3 pH units below (for a ______) or above (for an ________) the drug's _______.
|
base
acid pKa |
|
relate ionization of a drug with its pH?
|
for a weak acid drug, it will be unionized in acidic pH. As the pH increases, it will become ionized & therefore its solubility will increase
|
|
be familiar with modified henderson hasselbalch equations for acid & base?J
|
ACID: pH=pKa + log [S-So]/[So]
BASE: pH = pKa + log [So]/ [S-So] |
|
what does S & So stand for?
|
S is the overall solubility of the drug
So is the solubility of the unionized form (S= So+[ ] of ionized form) |
|
3 things that pertain to the nature of the solvent in affecting solubility?
|
1. pH of the solvent
2. solvent polarity 3. presence of solubilizing agents |
|
how does the solvent pH affect the solubility
|
it affects the drug's ionization state
|
|
how does the solvent polarity affect the solubility?
|
changing the solvent's polarity to better match the drug's polarity is often used as a method to improve solubility (like dissolves like)
|
|
how is the polarity of a solvent measured?
|
it's measured by its dielectric constant, w/c is the ability of a solvent to separate oppositely charged ions.
|
|
name 5 types of solvents
|
1. H2O
2. glycerin 3. propylene glycol 4. ethanol 5. PEG 400 |
|
Some solvents can also be used as __________ to help solublize drugs
|
co-solvents
|
|
Chloroform is a type of solvent. why is it not a good co-solvent?
|
b/c it's not miscible in H2O
|
|
give a couple of examples of solubilizing agents?
|
surfactants, cyclodextrins
|
|
What is the fxn of co-solvents? what is the exception?
|
When you use co-solvents, you want to decrease the polarity of the solvent.
The exception would be in inhalers where you want to INCREASE polarity |
|
How does temperature affect solubility?
|
since dissolution is usually an endothermic process where energy is needed to break bonds in a solid, greater heat (higher temps) would generally increase the solubility of the solid
|
|
what are some common methods for altering the solubility? (4)
|
1. altering the solid
2. altering the solute 3. altering the solvent 4. adding solubilizing agents |
|
how can u alter the solubility of a solid
|
1. create the desired solid form
2. form a solid sol'n or despersion |
|
how can u improve the drug's solubility by altering the solid?
|
a drug can be dissolved or finely dispersed in a water soluble solid. This can be done by separating the drug where all the crystals are separated and then mixing them with something hydrophilic
|
|
what 2 approaches can alter the solute?
|
creating salts
creating prodrugs |
|
of all the ways of affecting solubility, what is a very common form?
|
salt formation where you alter the solute; 50% of drugs are done this way
|
|
which types of drugs can theoretially be transformed into a salt?
|
every drug that has acid or base properties
|
|
what is the general process of salt formation
|
an ionized drug forms an ionic interaction with a counterion in a solvent containing a strong acid or base
|
|
in salt formation, what happens to salt?
|
the salt gets crystalized from the solvent
|
|
how does salt formation affect solubility?
|
it can either decrease or increase drug's solubility
|
|
what are 2 reasons one would use salt formation to decrease drug solubility?
|
stability
taste |
|
how does stability of drug relate to a decrease in solubility when salt formation occurs?
why is this? |
a solid drug (ie in suspension) is more chemically stable than drug molecules in solution. this is b/c chemical breakdown generally occurs to drug molecules in sol'n
|
|
how does salt formation to decrease drug solubility affect taste?
why is this? |
a decrease in drug solubility can help mask a bad taste; this is b/c drugs must be in sol'n (therefore soluble) in order to interact w/ taste bud chemoR
|
|
give an ex of a drug salt that decreases drug solubility & increase stability
|
propoxyphene napsylate is less solube than prooxyphene hydrochloride & thus more stable under aqueous conditions of manufacture
|
|
give an ex of a drug salt that decreases drug solubility & mask taste?
|
same drug as the one for stability: proposyphene napsylate is less bitter than propoxyphene hydrochloride b/c its less soluble
|
|
2 features of why one would want salt formation of a drug to increase solubility
|
1. salt formation can improve drug's water solubility significantly
2. a very low intrinsic solubility (less than 1mg/ml) indicates the need for a salt form for the drug. |
|
how does salt formation of a drug increase solubility?
|
b/c of the greater degree of ionic dissociation of salt molecules, there is a greater degree of interaction with water molecules
|
|
give 2 ex of drugs where their salt formation is more soluble & in what form are they used?
|
1. phenytoin is very slightly soluble in water therefore used an oral suspension while phenytoin sodium is more soluble in water & therefore used for injection
2. ampicillin is slightly soluble in water & is used as an oral suspension while ampicillin sodium is very soluble in water & therefore used for injection |
|
T/F: the solubility of the ionized drug needs salt formation b/c it's less soluble than it's unionized form
|
False: the unionized drug needs a salt formation b/c it's less soluble than its ionized form
|
|
what are some examples of salts for basic drugs?
|
the following anions:
1. hydrochloride 2. sulfate 3. tartrate 4. maleate 5. citrate 6. mesylate 7. succinate |
|
what are the salts used for acidic drugs?
|
cationic
1. sodium 2. potassium 3. calcium |
|
give 4 drug names that use the hydrochloride salt to form a salt drug?
|
1. pseudoephedrine hydrochloride
2. diphenhydramine " 3. propoxyphene " 4. clindamycin " |
|
give a drug name that uses the sulfate salt to form a salt drug?
|
terbutaline sulfate
|
|
name a drug that uses the salt tartrate to form a salt drug?
|
metoprolol tartrate
|
|
maleate salt can form what drug?
|
chlorpheniramine maleate
|
|
citrate salt can form what 2 drugs?
|
tamoxifen citrate & fntanyl citrate
|
|
mesylate can form what drug?
|
doxazosin mesylate
|
|
succinate can form what drug?
|
metoprolol succinate
|
|
sodium can form what 2 drugs?
|
phenytoin sodium & ganciclovir sodium
|
|
potassium can form what drug?
|
clavulanate potassium
|
|
calcium can form what drug?
|
leucovorin calcium
|
|
what are 7 properties of pharmaceutical salts we need to look at?
|
1. pH of sol'ns of drug salts
2. taste (palatability) 3. toxicity 4. lower % of active drug 5. hygroscopicity 6. polymorphism 7. corrosiveness |
|
relate pH of salt to its formed sol'n?
|
--salts prepared from weak bases yield more acidic solutions
--salts prepared from weak acids yield more alkaline solutions |
|
give 2 ex of drug salts with their pH?
|
1. minocycline HCl IV sol'n has pH of 2-2.8
2. ganciclovir Na IV sol'n has pH of 11. |
|
give an ex of salt drug & taste effect?
|
potassium salt drugs tend to have a metallic taste
|
|
be familiar with drug salt toxicity and % activity of a drug?
|
--some salts are more toxic than others
-- sometimes more of a drug is needed when combined with a salt b/c less of the drug is active when it's combined with a salt |
|
a synthetic drivative of a drug that is transformed in vivo to liberate an active drug molecule
|
prodrug
|
|
a prodrug approach is used to do what?
|
alter the solute (remember a solute can be altered by adding a salt or by using a prodrug)
|
|
how are most prodrugs formed?
|
they are created with an ester linkage that is cleaved in vivo with the help of esterases
|
|
what are some pharmacolgical purposes for synthesizing a prodrug?
|
1. biostability/ prolonged action
2. targeting (targeting brain-- lipophilic to cross BBB) 3. solubility |
|
what are some pharmaceutical purposes for synthesizing a prodrug?
|
1. taste
2. stability 3. solubility |
|
give an example of how a drug decreases solubility?
|
becomes more lipophilic which could improve absorption, distribution and other drug properties
|
|
For erythromycin, its prodrug EES is given to decrease solubility, tell 3 reasons why?
|
1. better tasting- drug is in suspension
2. bypasses gastric degradation-- erythromycin degrades rapidly in acidic conditions 3. better absorption--more lipohilic |
|
1 A prodrug can also increase solubility, what would be a good reason for this?
2 How is it most commonly done? 3 give examples of drugs |
1. reason: to create a more water soluble prodrug for inje.ction
2. a phosphate group is added to create a phosphate ester derivative. in vivo phosphate ester linkages are cleaved by phophatases. 3. clindamycin phophate, fosphenytoin sodium, dexamethasone sodium phosphate |
|
T/F: a phosphate ester is the same as a phosphate salt
|
False: it is not the same.
|
|
Give an ex of a phosphate salt
|
disopyramide phosphate
|
|
For some of the more poorly water soluble drugs, the drug's __________ rate will be the most important determinant of its oral _____________.
|
dissolution
bioavailability |
|
What can be the rate limiting step for absorption for a poorly water soluble drug
|
it would be the drug's dissolution rate
|
|
The dissolution of a solid in a liquid basically occurs in 2 consecutive stages, what are they?
|
1. an interfacial rxn that liberates solute molecules from the solid phase
2. diffusion of the liberated molecules away from the solid into the bulk liquid |
|
what is the static boundary layer?
|
the area which is very highly [ ] w/ drugs & also known as the stagnant layer.
|
|
The overall rate of mass transport of the solute from the solid in a liquid will be what?
|
it will be determined by the slowest stage, which is usually diffusion through a static boundary layer
|
|
what are the factors affecting dissolution rates (Noyes-Whitney)
|
A: total surface area of the undissolved solid
Cs: drug solubility C: concentration of solute in the bulk liquid k: dissolution rate constant |
|
How does "A" or the total SA of the undissolved solid affect dissolution rate
|
--size of particles: as size decreases, SA increases
--dispersibility of teh powder in the dissolution medium: if the particles clump, they will inhibit H2O acces & therefore dissolution will be slower |
|
How does "C" or [ ] of solute in the bulk liquid affect dissolution?
|
volume of the dissolution medium: increase volume, decrease [ ] for ex, taking med w/ a glass of water
any process that removes dissolved solute from the dissolution medium; this is absorption of the drug |
|
how does "k" of dissolution rate constant affect dissolution?
|
thickness of the stagnant boundary layer w/c can be decreased by agitation or shaking
diffusion coefficient of solute in the dissolution medium which decreases by an increase in liquid viscosity so the more viscous the sol'n the lower the dissolution **** if you know something won't dissolve in syrup, dissolve it in H2O first then mix it w/ more viscous sol'n |
|
define partition:
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to move as a molecule from 1 phase to another
ex: between polar and nonpolar phases |
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what is the importance of partitioning btn polar & nonpolar phases?
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1. traversing the lipid bylayer
2. other relevant partitioning phenomena |
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drugs that traverse a partiular membrane by passive diffusion must __________ into it.
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partition
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The drug must have what properties to cross membrane?
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it should have both some aqueous and lipid solubility
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besides the lipid bylayer, name 5 other partitions that drugs could go through?
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1. into fat
2. into microorganisms 3. into plastic 4. btwn oil & water: seen in emulsions 5. btwn chromatographic phases: for drug analysis or separating drugs analytically |
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Fxn of partition coefficient?
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during preformulation, the ability of a drug to partition btwn 2 poorly miscible (polar & nonpolar) phases is determined by measuring the partition coefficient of the drug
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If a drug is more lipophilic, how would it affect P (partition coefficient)
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it would increase it
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what is the partition coefficient equation?
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P= [Co]/[Cw]
Co is the drug's [ ] in an organic (nonpolar) phase Cw: drug's [ ] in the aqueous (polar) phase. |
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What is one of the most important methods for determining a drug's lipophilicity?
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measuring a drug's partition coefficient
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what factors determine P?
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choice of organic phase
effect of ionization |
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which organic solvent best mimics membrane properties?
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octanol which is the most common organic solvent used
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what are the 3 oragnic solvents mentioned that determine P?
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octanol: best mimics membrane properties
butanol: mimics buccal membrane chloroform: mimics BBB |
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For ionizable drugs, what has the higher P? what does say about polarity of the drug?
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unionized has higher P which means the drug is less polar
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where is P generally studied?
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it's studied over a range of pHs similar to what is found in the GI tract, as a means of estimating where absorption of the drug might be greatest.
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where might be the absorption of the drug be the greatest?
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it's more likely absorbed in regions w/ pHs favoring the unionized form
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what are some factors to consider for GI absorption?
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1.ionized form of the drug can partition in some cases. an ex of this is very lipophilic corticosteroids
2. ionization is an equilbrium process: when unionized drug is absorbed, some remaining ionized drug becomes unionized to maintain the equilibrium 3. the SA of the absorption site is often more important. SA is greatest in SI-far greater than in the stomach therefore most drugs and nutrients get absorbed there. |
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the extent to which a drug product retains, within specified limits, and throughout its period of storage & use the same properties & characteristics that it possessed at the time of its manufacture
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drug stability
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what is the drug product
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finished dosage form that contains an active drug + inactive ingredient
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what is the shelf life?
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period btwn date of manufacture of a drug product & the exp date.
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what are the properties to be considered relevant to stability of a drug?
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1. chemical properties
2. physical properties 3. microbiolgical properties |
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what are the drug's chemical properties & what affect can changes in these properties do?
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it's the chemical integrity where the drug must stay intact.
if there is changes in these properties, therapeutics can be affected, toxicity, and organoleptic properties can also be affected |
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what are some examples where changes in the chemical property of the drug led to toxicity?
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1. tetracycline can epimeriz and dehydrate to potentially fatal nephrotoxic cpd
2. penicillins can decompose in acidic sol'ns to possibly allergenic cpds. |
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one of 2 moleucles that differ only in the spatial arrangement around a single carbon atom
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epimerize
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what causes fanconi's syndrome
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nephrotoxicity from tetracycline epimerization. rare syndrome
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what does organoleptic properties mean?
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susceptible to sensory impressions such as sight, sound, & taste which is a big one
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give 2 ex of organoleptic properties?
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1. epinepherine can oxidize to a therapeutically active, but intensely colored product
2. erythromycin can dehydrate to a therapeutically active, but worse tasting cpd. |
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how do physical properties affect stability of a drug?
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this is also critical b/c crystal structure changes & leads to polymorphism
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changes in physical structures can affect what?
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therapeutics & organoleptic properties
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ex of therapeutics that can be affected with physical properties changes
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blood levels can change from dissolution changes
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ex of organoleptic properties that can be affected with physical properties changes?
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dissolution in suspensions where drug in sol'n elicits taste
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what are the microbioligical properties that can affect stability
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microbial invasion of a drug product is consdiered a stability probelm which can be unappealing and even deadly
|
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what are the 6 mechanisms of chemical degradation?
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1. hydrolysis
2. oxidation 3. photolysis 4. dehydration 5. isomerization 6. polymerization |
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what is the most common mechanisms of chemical degradation?
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hydrolysis & also oxidation
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define hydrolysis
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cleavage of a molecule by reaction w/ H2O
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what are some ex of functional groups susceptible to hydrolytic cleavage?
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1. esters like in aspirin, procaine, cocaine, & physostigimine
2. amides like in dibucain & chloramphenicol 3. lactams like in penicillins, cephalosporins, chlordiazepoxide 4. lactones like in pilocarpine, spironolactone ****know general structure of each class see notes under chemical degradation mechanisms |
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define oxidation
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refers to the removal of electrons
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a type of oxidation that involves the uncatalyzed oxidation of a substrate by molecular O2
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autoxidation
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this type of oxidation is a slow process
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autoxidation b/c O2 is not very reactive
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molecular oxygen is a ________ __________ & has 2 unpaired electrons with parallel spins
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triplet diradical
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what are some other oxygen species that might be more reactive than molecular oxygen
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superoxide O2-
hydrogen peroxide H2O2 hyroxyl radical OH |
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which reactive O2 is formed with the aid of a metal catalyst
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Hyroxyl radical which is very reactive
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free radical mechanism of oxidation involves what 3 things?
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1. initiation
2 propagation 3. termination |
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This formation of substrate free radicals necessary for the propagation of the chain?
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initiation
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what is the formula for initiation?
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RH + In -----> R + InH
|
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the 3 features of initiation
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1. involves hydrogen abstraction
2. can occur through autooxidation by molecular O2 or w/ other chain initiating radical 3. chain initiating radicals are generated by the action of light, heat transition metals (iron & copper) or reactive cpds (peroxides) |
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what happens in propagation & what is the rxn
|
free radicals grow in #
R + O-O ------> R-O-O R-O-O + RH -------> R-O-O-H + R |
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free radicals combine to form chemically inert products
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termination of free radicals
|
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what are the rxns for termination?
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2R-O-O ------> inert products
R + R-O-O -----> inert products 2R -----> inert products |
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what are some functional groups that are susceptible to oxidation & drug ex of each
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1. phenols -----> morphine
2. catechols ------> epinephrine 3. thols 4. polyunsaturated hydrocarbons |
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this type of chemical degradation is due to chemicl breakdown caused by lite usually by complex mechanisms
|
photolysis
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what is the most common photolytic mechanism
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photoxidation
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define potoxidation
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include certain hydrolysis + dehydration rxns
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Give example of a drug that can undrgo photolysis
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sodium nitroprusside in aqueous sol'n which is used in IV infusions. Shelf life in the dark is 1 yr. Once exposed to light, its shelf life becomes 4 hours!
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a chemical degradation where a water molecule is eliminated from the chemical structure?
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dehydration
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give an ex of dehydration?
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erythromycin where deydration occurs under acidic conditions to yield a less active product
|
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what happens in a physical dehydration degradation?
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removal of water from a crystal hydrate (this is a type of polymorphism). This process can cause a change in solubility
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give an ex of some drugs that can undergo physical dehydration degradation?
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theophyllin hydrate & ampicillin trihydrate
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conversion of a drug to its optical or geometric isomer
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isomerization
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define optical
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isomerism about an asymmetric carbon atom
|
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synonym for cis-trans isomerism
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geometric isomer
|
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give an example of a drug that undergoes isomerization?
|
amphotercin B
|
|
what is the significance of isomerization?
|
1. 50-60% of drugs are chiral cpds
2. enantiomers can have different bilogical properties w/ ex of albuterol vs levlbuterol 3. drugs marketed as pure enantiomer may racemize w/ ex of thalidomide which undergoes base catalyzed raceization in aqueous media |
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1 of a pair of molecular entities which are mirror images of each other & non super impossable
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enantiomers
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the partial conversion of 1 enantiomer into another
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racemize
|
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geometric isomers can differ in their physiochemical properties, what are they?
|
solubility
stability compatibility w/ other cpds |
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this type of chemical degradation has 2 or more drug molecules that combine to form a complex molecule
|
polymerization
|
|
give an ex of polymerization? side effect
|
concentrated solutions of aminopenicillins
ampicillin & amoxicillin can form dimers, w/c are thought to be allergenic |