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176 Cards in this Set
- Front
- Back
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Expert Division (Committees)
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Over 15 divisions including Arthritis Drugs
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IND
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Investigational New Drug Application
Must be filled with the FDA before human testing. |
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Clinical
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Studies in Humans
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Pre-Clinical
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Studies NOT performed in humans.
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FDA tests drugs for safety mainly b/c of.....
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thalidomide
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FDA tests drugs for efficacy mainly b/c of...
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ethylene glycol
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Hit
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molecule that interacts with the target
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Example of a "Target"
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enzyme, receptor...
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Lead
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the best hits that warrant further investigation.
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Candidate
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The lead most suitable for extensive investigation.
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Physiochemical properties
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pka, solubility, stability
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Phase 1 purpose & volunteers
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mainly study safety and dosage.
healthy volunteers |
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Phase 2 purpose & volunteers
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mainly study effectiveness but also examine short-term safety.
sick volunteers |
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Phase 3 purpose & volunteers
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Confirm Effectiveness of drug but also determine long-term safety.
sick volunteers. |
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NDA Application
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Integrates all data in a 100k pg long paper.
It takes approx a year to review. |
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cGMP Standards
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FDA's Current Good Manufacturing Standards. Part of inspection process that applies to all aspects of pharmaceutical manufacture.
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Approval Letter
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Indicates the application is approved.
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Complete Response Letter
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Application not ready for approval and it outlines your deficiencies. May recommend actions needed for approval.
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Phase 4
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Following approval, drug is continually monitored in clinical investigations to add understanding to the drug's effects.
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Adverse Reaction Reporting
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The drug's sponsor is required to review and report to the FDA all adverse effects reported to them by any internal or external sources: ex: physicians, post-marketing studies, & pharmacists.
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orphan disease
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a disease that affects fewer than 200k people in the United States for which there is no reasonable expectation that costs of research and development for the indication can be recovered by sales of product in the US.
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examples of orphan dieases
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cystic fibrosis; chronic lymphocytic leukemia
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Why is there a different IND for Orphan Drugs?
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to provide incentives to develop drugs where there is an insufficient market incentive.
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What are the Orphan Drug Incentives?
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1. Financial Support for Clinical Trials
2. Seven years of exclusive marketing rights. (more time to work on it) |
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Treatment IND & purpose?
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For patients with life-threatening or severely debilitating illnesses, where no satisfactory alternative exists.
purpose is to facilitate drugs faster to these patients. |
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Examples of Diseases with Treatment INDs
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advanced AIDS, Alzheimer's Disease, Advanced Parkinson's.
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Treatment Protocol for Treatment IND
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Filed during Phase 1 or 2 to allow treatment of the desperately ill.
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Abbreviated New Drug Application
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Omits nonclinical lab studies & clinical studies except those pertaining to bioavailability.
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bioavailability
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fraction of an administered dose that reaches the systemic circulation.
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Supplemental New Drug Application
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Required for certain types of changes:
Changes in method of synthesis, formulation, analytical standards, container, manufacturing facilities. |
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Preformulation
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The stage of drug development during which the physical and chemical properties of a drug substance are evaluated, towards the formulation of a stable, safe and effective dosage form.
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The manner in which a drug is formulated is often crucial to its _____ and acceptability to the patient.
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bioavailability
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Drug Molecules
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Most are small organic molecules. (new ones are proteins)
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Solid Drugs
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Most drugs begin as solid crystals
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Dosage Forms
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If not a solution, the drug must be "liberated" from its dosage form.
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Routes of Administration
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Can be direct (IV) but most are not.
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Barriers to reaching the blood stream
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Enzymes & Membranes
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Barriers to reaching tissue targets
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Enzymes & Membranes
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Sufficient Water Solubility
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To be in its molecular form in the body
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Sufficient Lipid Solubility
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To traverse lipid membranes.
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habit
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description of the outer appearance of the crystal.
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different habits
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can result from minor changes in synthetic conditions
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amorphous form
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has no periodic arrangement w/o distinct crystalline structure.
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5 Important Reasons for understanding the "solid" form
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1. Flow properties
2. Mechanical Properties 3. Bioavailability 4. Melting Point 5. Solid State Stability |
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Flow properties are important for..
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uniformity of the dosage.
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An example of a mechanical property of a solid form is...
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Compaction - how well they are compacted.
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What is the dosage that has 100% bioavailability?
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IV.
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______ depends on two factors its ability to dissolve as well as its solubility in the human body.
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Bioavailability
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Melting point is
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a function of strength of molecular interactions.
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Solid State Stability examples:
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hygroscopicity & polymorphism
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hygroscopicity
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water uptake from atmosphere
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polymorphism
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the capacity for appearing in many forms
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Two different properties of polymorphs
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Intermolecular Interactions
& Solubility |
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polymorphs with weaker molecular interactions are called...
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metastable
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metastable
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being in an unstable and transient but relatively long-lived state of a chemical or physical system.
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What is an example of a metastable solid?
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an amorphous solid
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metastable polymorphs are generally more ____ than their more stable counterparts.
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soluble
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In the example about Chloramphenicol, A and B were placed in suspension. There were higher levels of B in the blood. Which was the more metastable of the two polymorphs and why?
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B was more metastable because it was more soluble.
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An example of a solvate is...
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a hydrate
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In a Hydrate...
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water is a part of the crystal lattice.
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When dealing with solvates, changes in _____ form can affect the solubility
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hydrate
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Which is more soluble?
Anhydrous form of a drug or the Hydrate form? An example of this? |
Anhydrous. This is due to the energetics of solution.
Ex: Ampicillin This is not true for all drugs but is true for most of them. |
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In the Ampicillin example, the anhydrous form peaked at a higher point in the graph than the hydrate form showing that there was more anhydrate in the blood at that point. What does this prove?
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That the anhydrous form had a higher dissolution and therefore a greater bioavailability.
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Manufacturers use melting behavior to determine ____ because each of these have different interactions & therefore different behaviors.
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polymorphs
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Manufacturers test melting behavior because the drug may experience ___ temperatures during processing.
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high
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The smaller the particle the ____ the dissolution rate due to an increase in ____.
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faster; surface area
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When the drug _____ was micronized, that reduced the dose needed by 50% thereby increasing the _____.
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Griseofulvin; dissolution
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When is an example of a drug when micronization is NOT favorable?
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Nitrofurantoin
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In the drug _____, macrodantin was favorable because when the crystals would dissolve quickly, it would cause nausea in patients.
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Nitrofurantoin
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Which particles fall faster in a suspension? Large or small?
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Large
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stratification means...
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arranging in layers
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Particle flow affects 3 variables:
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1. mixing & pouring
2. speed of processing 3. settling & stratification (uniformity) |
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Stratification happens because...
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different particles in the mix may have different flow properties.
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4 Factors that determine particle flow:
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1. particle cohesiveness
2. particle density 3. particle shape 4. particle size |
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particle cohesiveness is affected 2 factors:
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1. electrostatic charge
2. absorbed moisture |
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___ ___ can affect particle cohesiveness by either repelling them or bringing them closer together.
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electrostatic charge
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___ ___ can affect particle cohesiveness by making particles sticky.
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absorbed moisture
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Solution Definition:
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a homogeneous mixture of two or more substances.
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A drug must be in ____ to be absorbed and cause an effect.
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solution
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Solute Definition:
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The molecular, atomic or ionic component of a solution that is dissolved by the solvent.
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Solvent Definition:
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The component of a solution that dissolves the solute
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Example of a Solute/Solvent relationship in the Gas/Liquid form:
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Carbonated Water
Halothane - a general anesthetic |
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Halothane
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general anesthetic that is a gas dissolved in a liquid solvent.
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Example of a Solute/Solvent relationship in the form of Liquid/Liquid:
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alcohol in water
Miscible |
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miscible liquids definition
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liquids that completely dissolve in each other in all proportions.
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Example of a Solute/Solvent relationship in the form of Solid/Solid:
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drug in polymer - in some controlled release products
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Example of a Solute/Solvent relationship in the form of Solid/Liquid
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Drug in water
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Dissolution involves the relocation of a solute molecule from an environment where it is surrounded by _____ molecules in to a cavity of ____ where it is surrounded by ______ molecules.
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identical; liquid; non-identical
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Solubility Definition:
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The concentration of a solute in a saturated solution at a certain temperature. Amount dissolved per volume.
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Solubility is expressed in the ___ as the number of mL of solvent needed to dissolve ___ gram of solute.
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USP; 1
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Most hydrophillic substituents can form ____ bonds with water thereby increasing the solubility in water.
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hydrogen
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Example of how hydrophillic substituents can increase water solubility dramatically:
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phenol is 100x more soluble than benzene.
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Sometimes substituents are insignificant to solubility due to the ___ of the molecule and example of this is ____.
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bulk; estradiol
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_____ state is one of the most important physiochemical properties determined during preformulation as it affects dosage formulation, absorption, distribution & excretion.
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Ionization
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Most drugs are ___ acids & bases or ______.
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weak; amphoteric
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pKa is defined as...
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the pH at which the drug is 50% ionized.
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99.9% of the drug will be ionized at 3 pH units below (for a ____) or above (for an ___) the drug's pKa.
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base; acid
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In the example of the solubility of indomethacin, chlorpromazine, and oxytetracycline as a function of pH, indomethacin is a weak acid and its solubility _____ with increased pH, chlorpromazine is a weak base and its solubility _____ with increased pH. Oxytetracycline has two pKas so it had two soluble forms and the least soluble one was the _______ ion state.
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increased; decreased; zwitterion
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The modified Henderson Hasselbach equation Mobley showed us in class could help us determine
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predication of the precipitation of the unionized form.
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In the modified Henderson Hasselbach equation S is defined as....
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The overall solubility of the drug.
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In the modified Henderson Hasselbach equation So is defined as....
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the solubility of the unionized form
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S = So +.......
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concentration of the ionized form
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What is the pH below which sulfadiazine (pKa = 6.48) will begin to precipitate in an infusion fluid, when the initial molar concentration of sulfadiazine sodium is 4 x 10^-2 M and the solubility of sulfadiazine is 3.07 x 10^ -4?
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sulfadiazine sodium is a weak acid.
pH = pKa + log(S - So) / So pH = 6.48 + log [(4 x 10^-2) - (3.07 x 10^-4)]/(3.07 x 10^-4) pH = 6.48 + 2.11 pH = 8.59 |
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How much of a weak base will be ionized @ 2 pH units below pKa?
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-2 = log [B]/[BH+]
[B]/[BH+] = .01/1.0 .01 + 1.0 = 1.01 0.01 / 1.01 = 0.99 99% |
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The solvent can affect solubility in 3 ways:
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1. solvent pH
2. solvent polarity 3. presence of solubilizing agents |
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Solvent pH is important to solubility because it can affect....
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affect the drug's ionization state
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Solvent polarity is important to solubility because _____ the drug's polarity to the solvent will increase solubility.
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matching; LIKE DISSOLVES LIKE
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polarity of a solvent can be measured by its _____constant: of a solvent
to separate oppositely charged ions. |
dielectric
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Examples of solubilizing agents:
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surfactants; cyclodextrins
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Dissolution is usually an ________ process because energy is needed to break bonds in the solid. Therefore, _____ temperatures lead to increased solubility.
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endothermic; higher
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When trying to alter the solubility of a solid in a liquid you can either alter the ____, alter the ____, or add _____ agents.
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solid; solvent; solubilizing
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When altering a solid to alter solubility, you can create the form you want by making the _____ or _____ whichever one is most convenient at the time.
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polymorph (metastability) or pseudopolymorph (hygroscopicity)
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When altering a solid to alter solubility you can create a solid solution or _______. Drug is dissolved or finely dispersed in a very water soluble ____ to improve drug solubility.
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dispersion; solid
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This drug is finely dispersed as ultrafine particles in polethylene glycol to form a dispersion.
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Griseofulvin
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Is the Griseofulvin/PEG approach to increased solubility common?
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No. Used to make suppositories.
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Two approaches to altering the solubility via altering the solute are formation of a drug _____ and creating _____.
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salt; prodrugs
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Salt formation is the _______ common method of altering a drug's properties. About what % of drugs are made this way?
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most; 50%
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How is salt formation achieved?
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An ionized drug forms an ionic interaction with a counterion in a solvent containing a strong
acid or base. Salt is then crystallized from solvent. |
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Examples of Salt Formation Drugs:
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terbutaline sulfate - freebase & H2SO4
oxymetazoline hydrochloride – freebase & HCl (weak base, strong acid) |
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Give 2 reasons why someone would use salt formation to decrease solubility?
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1. Stability - drugs in solution are more vulnerable to chemical breakdown and are therefore less stable.
2. Taste - |
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Erythromycin Stearate is more soluble than.... and therefore more stable in what organ?
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Erythromycin base; stomach
decrease solubility by putting fatty on erythromycin base. |
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Propoxyphene napsylate was made more stable than...... in order to reduce solubility during encounters with water in the _____ process.
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Propoxyphene hydrochloride; manufacturing
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Sometimes we decrease _____ to make a better tasting product. Why would decreasing this make it taste better? What is an example of this?
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solubility; drug can't dissolve on your taste buds; Propoxyphene napsylate
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Drug must be in solution in order to react with taste bud ______.
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chemoreceptors
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Salt formation can increase drug _____ because of greater ionic dissociation of drug molecules therefore there is a greater degree of interaction with ____ molecules.
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solubility; water
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phenytoin is _____ soluble in water so it is used for _____ suspension. Its counter part phenytoin sodium is ____ soluble in water and is used for injections.
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slightly; oral; very
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ampicillin is _____ soluble in water while ampicillin sodium is ____ soluble in water. Therefore ____ is used for oral suspension and ___ is used for injections.
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slightly; very; ampicillin; ampicillin sodium
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What indicates the need for the salt formation of a drug?
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a very low intrinsic solubility (less than 1mg/ml)
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Intrinsic Solubility
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Solubility of the unionized drug
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Salts prepared from weak ____ yield more acidic solutions.
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bases
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Salts prepared from weak ____ yield more alkaline solutions.
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acids
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Drug in Salt form that has a pH of 2 to 2.8 in IV solution
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Minocycline HCl
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Drug in Salt form that has a pH of 11 in IV solution
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Ganciclovir Na
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Some drug salts don't taste as good as others... for example ____ salts have a metallic taste
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potassium
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In drug salts there is a ____ percentage of the active drug because of the contribution of the counter ion. Therefore you need a greater amount of ____ for a given amount of drug.
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lower; powder
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a synthetic derivative of a drug that is transformed in vivo to liberate an active drug molecule
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prodrug
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Three pharmacological purposes for prodrugs:
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1. biostability (prolonged action)
2. targeting 3. solubility |
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Three pharmaceutical purposes for prodrugs:
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1. taste
2. solubility 3. stability |
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To create a more water soluble prodrug for injection a _______ group is normally added to create a _______ ______ derivative. In vivo, these linkages are cleaved by ______.
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phosphate; phosphate-ester; phosphatases
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The rate limiting step for very lipid-soluble (poorly water soluble) drugs is...
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the dissolution
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Explain how the dissolution of a solid in a liquid happens (2 stages).
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1. An interfacial reaction that liberates solute molecules from the solid phase.
2. Diffusion of the liberated molecules away from the solid into the bulk liquid. |
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The Noyes-Whitney Equation
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dm/dt = kA (Cs - C)
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dissolution rate constant
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k = D/h
D = diffusion coefficient of the solute in the medium h = thickness of the static boundary layer |
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Clumping of particles in solution causes _____ to be slower.
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dissolution
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T/F Increased Volume will improve dissolution.
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True
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T/F Absorption allows more drug to be dissolved.
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True
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k is in strong relation to the thickness of the _______ _______ layer. The layer can be thinned with _______.
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stagnant boundary; agitation (shaking)
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Dissolution speed is ________ proportional to the viscosity of the medium.
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indirectly
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Partition
Example? |
To move as a molecule from one phase to another
ex: between polar and nonpolar phases. |
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Partitioning is important because drugs need to pass through a ________ ________.
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lipid bilayer OR cell membrane
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Drugs that traverse a particular membrane by ______ diffusion must partition into it. These drugs have a balance of aqueous and _____ solubility.
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passive; lipid
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Drugs that accumulate in fat need to ____ into the fat.
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partition
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Antibiotics need to partition into ___________ to function.
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microorganisms.
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Drugs that absorb into IV bags and tubing partition into ________.
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plastic
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Drugs that partition in emulsions are actually partitioning between ____ and ____.
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oil; water
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Drugs that partition in chromatographic phases are used for...
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drug analysis.
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The partition coefficient describes by seeing the ability of a drug to partition between two poorly miscible phases in this equation:
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P = Co/Cw
Co = organic Cw = water |
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The most common organic solvent used in partitioning is... b/c it mimics _____ very well. Butanol best mimics the _____ membrane and chloroform mimics the _____.
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octanol; membranes; buccal; BBB
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The higher the P the more ________ the drug is.
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lipophillic
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Unionized drugs usually have a higher or lower partition coefficient?
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higher b/c they are less polar.
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partition coefficient is usually studied over a range of _____ of the GI tract. Will more likely be absorbed in regions where it is ______.
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pHs; unionized
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T/F The ionized form of the drug can partition.
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True. It can in some cases such as corticosteriods.
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Ionization is an ______ process such that when unionized drug is absorbed, some remaining ionized drug becomes unionized.
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equilibrium
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_____ _____ of the absorption site is often the most important factor. That is why the Small Intestine is better at absorption than the stomach.
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Surface Area
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In an example given in class regarding phenobarbitol, as the chloroform/water partition coefficient increased, so did the percentage absorbed. Therefore there was better ______ diffusion across the colon.
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passive
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In an example given in class regarding penecillins, as the partition coefficient increased, the neurotoxicity ______ in the BBB.
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increased.
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the extent to which a (drug) product retains, within specified limits, and throughout its period of storage and
use (i.e., its shelf-life), the same properties and characteristics that it possessed at the time of its manufacture |
Drug Stability
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Drug Stability
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the extent to which a (drug) product retains, within specified limits, and throughout its period of storage and
use (i.e., its shelf-life), the same properties and characteristics that it possessed at the time of its manufacture |
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shelf-life
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period between date of manufacture of a drug and the expiration date
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Chemical Integrity
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how well the drug stays intact
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tetracycline can ______ (one of two molecules that differ only in the spatial arrangement around a single carbon atom) and dehydrate to a potentially fatal nephrotoxic compound causing _____ syndrome
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epimerize; Fanconi's
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______ can decompose in acidic solutions to possibly allergenic compounds.
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Penicillins
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Pralidoxime can degrade under basic conditions yielding _____ as a byproduct
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cyanide
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organoleptic properties definition:
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susceptible to sensory impressions
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Microbial invasion of a drug product is considered a ______ problem
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stability
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Most common methods of degredation: ______ & _____.
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hydrolysis & oxidation
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