API Exam 1|236 Questions with Verified Answers,100% CORRECT

API Exam 1|236 Questions with Verified Answers Timeline for Nanomedicines rugs? - CORRECT ANSWER 1965 --> liposomes (lipid based vehicles drug inside membrane OR inside core) 1976 --> polymeric systems 1978 --> Dendrimers 1980 --> PEGylated liposomes (liposomes with PEG polymer on surface, which keeps the drug in circulation longer) 1995 --> doxil (PEGylated liposomes, one of the first drugs approved) 2013 --> Kadcyla (antibody drug) It's not necessarily that efficacy improves, but rather that toxicity DECREASES Liposomal Amphotericin B - Purpose, Mechanism of Action, and Toxicity - CORRECT ANSWER Broad-spectrum polyene antifungal agent - but very POOR solubility Mechanism of Action: 1. Bind to ergosterol in fungal cell membranes 2. Create transmembrane channels and lead to cellular component leakage (how it kills fungal cells) 3. Bind to cholesterol in mammalian membranes, which forms pores in host membrane --> TOXICITY On top of Infusion-related reaction: nausea, vomiting, rigors, fever, hypertension, hypotension, hypoxia Significant Nephrotoxicity - direct damage of distal tubular membranes leading to wasting of Na+, K+, and Mg+ - Tubular-glomerular feedback: further constriction of arterioles - constriction of the afferent arterioles leading to decreased glomerular filtration Amphotericin B Injection (Fungizone) vs Ambisome vs Abelcet - CORRECT ANSWER Amphotericin B Injection Sodium Deoxycholate --> amphiphilic molecule that forms micelle Most Toxic to Least Toxic: 1. Fungizone 2. Abelcet 3. Ambisome Abelcet - DMPG is negative, and has interaction with positive amphotericin B Ambisome - HSPC = positive - DSPG = negative - cholesterol for stability **this is the SAFEST* BUT no generic here in the US - but many abroad (some less efficacious and some more toxic) *Lambin (generic of ambisome) (sun pharmaceuticals) was withdrawn due to toxicity issues Amphotericin B Injection (Fungizone) - CORRECT ANSWER Colloidal Dispersion Composition - Amphotericin B - Sodium deoxycholate (solubilizer) Micellar structure - EASY for AmpB to dissociate after administration Abelcet - CORRECT ANSWER Composition - Amphotericin B - DMPC/DMPG Ribbon like structure Ambisome - CORRECT ANSWER Composition - Amphotericin B - HSPC, DSPG, Cholesterol, tocopherol - stays STABLE in phospholipid bilayer of liposomes - Amphotericin B interacts with DSPG to form ionic complex How is AmBisome Manufactured - CORRECT ANSWER HIGH temperature due to high transition temperature of AmBisome. Even small changes can alter the drug's toxicity. PK of Ambisome vs Fungizone - CORRECT ANSWER AmBisome has: - higher AUC - reduced nephrotoxicity - MUCH higher cost ($82/vial vs $3.88/vial) When compared to Fungizone. How are Tumors Targeting Via EPR0basec nanomedicine therapy? - CORRECT ANSWER EPR = enhanced permeability and retention effect Nanodrugs prevent accumulation of chemotherapy in healthy tissues, and promote accumulation at pathological sites Paclitaxel - CORRECT ANSWER Originally formulated as TAXOL, which was 50% by volume alcohol Cremophor is a solvent that often has toxicity Abraxane - CORRECT ANSWER Nanoparticle albumin-bound (gab) Nanotech-based drug delivery platform *NO surfactants/solvents* Nab Pacitaxel (Abraxane) is slightly safer than Cremo-paclitaxel (TAXOL) + allows for greater doses of this chemotherapy Mechanism of Action of Paclitaxel formulations - CORRECT ANSWER Designed based on Paclitaxel's innate tendency to bind to albumin DOXIL - CORRECT ANSWER Stealth Liposomes DOXIL: - anthracycline antibiotic - has a well-established position in the treatment of human malignancies - cardiotoxicity is a MAJOR clinical handicap limiting its cumulative dosage DOXIL manufacturing - CORRECT ANSWER Suspension Definition - CORRECT ANSWER A coarse dispersion in which internal phase (therapeutically active ingredient) is dispersed uniformly throughout the external phase. Molecular Dispersion Colloidal Dispersion Coarse Dispersion - CORRECT ANSWER Dispersed systems consist of particulate matter known as dispersed phase, dispersed throughout a continuous or dispersion medium. Classified according to particle size (picture) Why are suspensions used for oral administration? - CORRECT ANSWER - Insoluble drug or poorly soluble drug - children, elderly, and pts with trouble swallowing - to overcome instability of drugs in aqueous solution (insoluble derivative formulated as suspension - to mask TASTE - Some materials are needed to be present in the GI tract in a finely divided form, to increase the surface area For example: - Mg carbonate and Mg trisilicate are used to adsorb some toxins (thus need large SA) Classification of Suspension - CORRECT ANSWER - Route of Admin (oral, externally applied, parenteral) - Size of Solid Particles (colloidal <1 micron vs coarse >1 micron) - Based on Proportion of Solid Particles (dilute 2-10% w/v OR concentrated suspension 50% w/v) - Based on Electro-kinetic Nature of Solid Particles What is the Order of Bioavailability - CORRECT ANSWER Solution > Suspension > Capsule > Compressed Tablet Theory of Suspension: Sedimentation is expressed by which law? - CORRECT ANSWER Stokes Law What are the two primary ways settling and aggregation occurs in suspensions? Which is worse? - CORRECT ANSWER 1. Suspension shall form loose networks of flocks that settle rapidly, do not form cakes, and are easily resuspended 2. Setting and aggregation may result in the formation of cakes that is difficult to resuspend. What factors related to the API are important for suspensions? - CORRECT ANSWER - Size of particles - Size distribution of the powder - Ease of wetting - Surface electric charge of the particles in the suspension - Chemical stability of the drug, and possible interactions and incompatibilities with other suspension constituents How are surface free energy, total surface area, and interfacial tension related? - CORRECT ANSWER What are common suspending mediums or vehicles? - CORRECT ANSWER 1. Water 2. Water - Organic solvent Mixture (alcohol, glycerol) 3. Non-aqueous vehicles (topical use) Purpose of Wetting Agents (Surfactants) - CORRECT ANSWER 1. Difficult to disperse solid particles in a liquid vehicle due to layer of adsorbed air on the surface --> this causes particles (even w/ high density) to float on the surface of the liquid until the layer of air is displaced completely --> Use of wetting agent allows to remove this air from surface _ easily penetrate the vehicle into pores 2. Powders, which are NOT easily wetted by water (and accordingly show a large contact angle) such as sulfur, charcoal, and magnesium stearate are called hydrophobic 3. Powders which are readily wetted by water are called hydrophilic (zinc oxide, talc) 4. The "wettability" of a powder may be ascertained easily by observing the contact angle and spreading coefficient. What is a good contact angle for wetting of powders? - CORRECT ANSWER Poor Wetting: angle > 90 Good Wetting: 90 > angle > 0 Complete Wetting: angle --> 0 Spreading Coefficient - CORRECT ANSWER For convenient wetting, the value of spreading coefficient (Sc) should be positive This could be achieved by modification of the values of surface tension of several surfaces involved until + value of spreading coefficient is reached. Surfactants - CORRECT ANSWER Reduce the interfacial tension between the solid particles and a vehicle. As a result of the lowered interfacial tension the Sc will be positive and the contact angle is lowered, air is displaced from the surface of particles, and wetting is promoted. --> disadvantage is surfactants have foraming tendencies Three categories of wetting agents? - CORRECT ANSWER 1. Surfactants 2. Glycerin and Similar Hydroscopic Substances 3. Hydrophilic Colloids Glycerin and Similar Hydroscopic Substances - CORRECT ANSWER Hydrophilic Colloids - CORRECT ANSWER How do we control Stability and Sedimentation? - CORRECT ANSWER What are common suspending agents and co-solvents? - CORRECT ANSWER Flocculating Agents - CORRECT ANSWER Electrolytes as Flocculating Agents - CORRECT ANSWER Zeta potential is the potential difference between the ions in the tightly bound layer and the electroneutral region. Zeta potential governs the degree of repulsion between adjacent, similar charged, solid dispersed particles. Nernst vs Zeta Potential - CORRECT ANSWER Nernst layer is defined by the concentration of negative particles Flocculating Agents: Surfactants - CORRECT ANSWER Flocculating Agents: Polymers - CORRECT ANSWER Sedimentation Volume - CORRECT ANSWER Suspensions are evaluated by determining their physical stability. 1. Sedimentation volume: (F), sedimentation volume of a suspension is expressed by the ratio of the equilibrium volume of the sediment, Vu, to the total volume, Vo of the suspension. F = Vu/Vo The value of F provides a qualitative knowledge about the physical stability of the suspension. F= 1 No sedimentation, no clear supernatant F =0.5 50% of the total volume is occupied by sediment F > 1 Sediment volume is greater than the original volume due to formation of floccules which are fluffy and loose Degree of flocculation - CORRECT ANSWER Re-Dispersibility - evaluation of suspension - CORRECT ANSWER This is determined by the number of upside down inversions of the suspension contained in a measure. The smaller the number, the easier it would be to re-disperse the sediment. A number greater than 15 inversions indicates caking. Rheological Characteristics of Suspension - CORRECT ANSWER What is important when considering matching drug/dosage form? - CORRECT ANSWER 1. Physical properties (solubility, MP) 2. Chemical properties (stability) 3. Route of admin 4. Drug delivery profile (instantaneous, immediate, delayed, controlled) 5. Biological barriers to overcome (absorption) 6.Manufacturability Why are dosage forms needed? - CORRECT ANSWER 1. Achieve rapid onset of action 2. Mask undesirable taste 3. Protect drug following oral administration (capsule, coated tablet) 4. Stabilize the drug under specified storage conditions (powders for reconstitution) 5. Provide useful dosage forms for poorly water-soluble or insoluble drugs (suspension) 6. Prolong the therapeutic effect (modified release tablets, capsules, and suspensions.) Blister Packaging - CORRECT ANSWER Primary Component: Cavity or Pocket Usually made from thermoformed plastic and backing membrane or using aluminum foil Polyvinyl Chloride (PVC) is used for forming cavity or pocket. Strip packaging - CORRECT ANSWER An alternative form of packaging for unit dose Made from regenerated cellulose, paper, plastic, foil, or combo of these The use of high barrier material like aluminum foil or saran-coated film. Bottle with Dropper Assembly - CORRECT ANSWER Collapsible Tubes - CORRECT ANSWER Metals: aluminum, tin, and lead Plastics: low density polyethylene Cap: high density polyethylene, polypropylene, and PVC Aerosol Spray - CORRECT ANSWER Container: to withstand pressure 140-180 psig 1. Tin Plate Container: 2. Aluminum Container: 3. Stainless Steel Container 4. Glass Container: Valve: 1. Mounting cup/ferrule - tin plate steel, aluminum, brass 2. Valve body/housing - nylon or delrin Pre-filled syringe - CORRECT ANSWER Used for small volume parenteral preparation Reduction of medication errors like drug overfill Give increased assurance of sterility Irrigation Solution Container - CORRECT ANSWER Made of LDPE, polyolefin, polypropylenes AVOID hanging breakage glass Lightweight, transparent, impermeable to water What types of medications MUST be administered in a clinic? - CORRECT ANSWER Chemo (IV) - Route: IV infusion - Hospital or infusion center Vaccination - SQ, IM, or intradermal - doctors office or pharmacist Pregnancy Injections: - Medications for preventing pregnancy, preterm labor, or autoimmune rxns - injection or infusion - doctor's office or hospital Osteoporosis IV medications What is another word for lozenge? - CORRECT ANSWER Troches are small lozenges that dissolve between the cheek and gum over a period of about 30 minutes can he hard or SOFT GUMMY as long as location + takes time to dissolve What is Intravitreal injection? - CORRECT ANSWER Intravitreal Injection: - substance is delivered into the vitreous humor of the eye via injection What are the various parenteral dosage forms? - CORRECT ANSWER - Solutions - Suspensions - Emulsions - Reconstituted Lyophilized Powders What are the ~general~ requirements for parenteral dosage forms? - CORRECT ANSWER - sterility - pyrogen free - no particulate matter - stability - clarity - isotonicity ALSO - vehicles/cosolvents must meet special purity standards - restrictions on buffers, stabilizers, and preservatives - Must be prepared under aseptic conditions - Specific packaging Advantages of parenteral drug products? - CORRECT ANSWER Disadvantages of parenteral drug products? - CORRECT ANSWER What classes of vehicles and co-solvents are common as parenteral excipients? - CORRECT ANSWER 1. Aqueous vehicles - Water for Injection (WFI) 2. Water miscible vehicles - Ethanol, PEG, Glycerine, Propylene Glycol 3. Non aqueous solvents - fixed oils (vegetable origin, liquid, and rancid resistance, unsaturated) What are Aqueous vehicles examples (for parenteral administration) - CORRECT ANSWER Aqueous vehicles - Water for Injection (WFI) only ?? pH of 5-7 WFI may be prepared by either distillation or reverse osmosis When are water miscible vehicles used? What are challenges with these agents? (parenterally) - CORRECT ANSWER Water miscible vehicles - Ethanol, PEG, Glycerine, Propylene Glycol Used when: - drug is water insoluble - drug is susceptible to hydrolysis Challenges: - tissue irritability/pain at injection site - hemolysis - toxicity - drug precipitation (don't use water to dilute) Propylene Glycol considerations (parenterally) - CORRECT ANSWER Challenges with Propylene Glycol - Metabolizes to lactic acid (causes lactic acidosis) - Causes cardiotoxicity - should be infused SLOWLY *In Phenytoin Infusion, Diazepam and Lorazepam* Propylene Glycol Cardiotoxicity (parenterally) - CORRECT ANSWER Propylene Glycol metabolizes to lactic acid, leading to elevated lactic acid levels Can result in: - anion gap metabolic acidosis - osmolar gap - hypernatremia (high sodium) When are non-aqueous solvents used (parenterally). - CORRECT ANSWER Non aqueous solvents Used When: - Drug is unstable in aqueous system - When some oil-soluble IM preparations are not properly soluble in water (testosterone) Includes: - fixed oils (vegetable origin, liquid, and rancid resistance, unsaturated) - NOTE: mineral oils can NOT be used as they are not absorbed by body tissues Buffering agents parenterally - CORRECT ANSWER - Adjust and maintain pH - Increase stability, solubility, and adsorption of API **humira citrate-free causes less pain causing injection** Examples: - acetates - citrates - glutamate - phosphate - tartrate Antioxidants (parentally) as excipients - CORRECT ANSWER Functions: 1. prevent or inhibit oxidation of drug 2. protect components of dosage form 3. should be effective at low concentrations 4. should not alter solubility of API Reducing Agents: - Ascorbic acid - Sodium Bisulfite - Sodium metabisulphite - Thiourea Blocking Agents: - Tocopherol (Vit E) - BHA (butylated hydroxyanisole) - BHT (butylated hydroxytoluene) Preservatives in parenteral solutions - CORRECT ANSWER Function: - added to protect drug from microbial contamination - mostly used in MULTIPLE dose containers Examples: - phenol, benzyl alcohol, methyl and ethyl parabens, benzalkonium chloride Challenges: - may cause drug instability (proteins, peptides) - toxicities What are the challenges with Benzyl Alcohol as a preservative in parenteral solutions? - CORRECT ANSWER Safe up to 5% in adults, but can cause DEATH in infants What are some examples of tonicity-adjusting agents in parenteral dosage forms? - CORRECT ANSWER Function: - make formulation isotonic - prevent osmotic shock at site of injection ***buffers may act as tonicity contributor*** Examples: - saline - glycerin - mannitol - dextrose - trehalose What does a solubilizing agent do in a parenteral form? - CORRECT ANSWER Function: - increase solubility of poorly water-soluble drugs - used where pH and salt formation are NOT adequate Examples: - Cremophor - Glycerin - DMA - PEG 300, 400 - Polysorbate 80 - Propylene glycol *Cyclodextrin is also KEY solubilizing agent* Cyclodextrins. What drugs USE cyclodextrins? - CORRECT ANSWER Structure: Sugars connected together in circle Use: Forms complex with API to increase solubility Challenges: 1. IV use causes build up in patients with decreased renal clearance --> nephrotoxicity 2. Because of formation of complex with cyclodextrins there is lower free concentration of drug. This affects PK/Pd of API Examples of drugs using cyclodextrins: Voriconazole, Televancin, Alprostadil, Mitomycin, Prostaglandin E1 Niemann-Pick C Disease - CORRECT ANSWER Rare inherited genetic mutation (progressive disorder) Lysosomal Storage Disease: - Characterized by an inability of the body to transport cholesterol and lipids INSIDE of cells This causes cholesterol and other fats to accumulate in liver, spleen, lungs, and brain. NPC2 or NPC1 are nonfunctional Niemann-Pick Type C Disease Treatment - CORRECT ANSWER Administration of cyclodextrin (CYCLO) rapidly overcomes the C transport defect seen in NPC1 and NPC2 disease and allows the sterol to move to the cytosolic compartment of cells, to be transported to the liver, and ultimately to be excreted from the body as bile acid. Renal toxicity of Cyclodextrin when used in Voriconazole - CORRECT ANSWER Voriconazole --> broad spectrum antifungal agent limited aqueous solubility In HEALTHY subjects --> eliminated with half life = 1.6 h In renally impaired ---> mean Cmax and AUC increased by 50% and 4-fold respectively Cremophor is used as what? - CORRECT ANSWER Cremophor Use: increase solubility of poorly water-soluble drugs (example: Taxol chemotherapeutic ) Challenges: 1. P-glycoprotein inhibition: cremophor can module PGP activity changing overall kinetics of drug product 2. Hypersensitivity: 3-5% of patients have reactions (low BP, hives, difficulty breathing, anaphylaxis) due to reactivity to cremophor Chelating Agents Use + Controversy - CORRECT ANSWER - Form a complex w/ metallic ions - Prevent the oxidation process enhanced by metal ions - Also used alone in treating lead poisoning Example: EDTA, Disodium edetate, tetrasodium edetate Controversially and fatally used as a 'treatment' for autism to remove heavy metals due to vaccines. What excipients are commonly in Lyophilized Products? - CORRECT ANSWER 1. Bulking agents: - often used in low dose formulations (solid < 2%) and as stabilizers, tonicity agents, and help in cake formation 2. Collapse Temperature Modifiers - higher collapse Temp is preferred 3.Lyo/CryoProtectants - Amino acids, sugars, polyols, sucrose, trehalose, glycine, arginine, sorbitol, mannitol - protect from freezing and drying stresses What is angle of injection for IM vs SQ vs IV vs ID? - CORRECT ANSWER IM: 90 deg SQ: 45 deg IV: 25 deg ID: 10 deg What ionic reactants when mixed pose a significant threat of forming insoluble substances? - CORRECT ANSWER Mixing solutions containing divalent Ca2+ or Mg2+ has SUBSTANTIAL risk of forming insoluble calcium or magnesium salt IM Injection Volumes + Placement - CORRECT ANSWER Volume 2 mL --> deltoid Volume up to 6 mL --> glutes Infants --> thigh IV administration considerations + infusion pump - CORRECT ANSWER Air or particulate matter injected directly into bloodstream may cause embolism, blockage in a vessel, or severe painful reaction at the injection site Braun Pump: IV infusion in which a programmable infusion pump is used Intraspinal injection (injection into Cerebrospinal Fluid) - CORRECT ANSWER - Inserting a needle into the lower back to reach into the spinal cord's subarachnoid space - Mainly for diagnostic purpose - administer drugs, such as local anesthetics, spinal analgesics, anti-inflammatory corticosteroids, and chemotherapeutics. Sterility - CORRECT ANSWER MOST important safety specification Should be prepared in aseptic surrounding and free from any kind of microorganisms Raw materials used to prepare should have low bioburden Packaging materials have to be pre-washed Aseptic Technique - CORRECT ANSWER Aseptic technique guideline for manual operation in a biological safety cabinet, under laminar flow hood or in a clean bench The underlying principle of laminar flow hood is that a constant flow of HEPA filtered air at a rate of approximately 90 linear feet per minute physically sweeps the work area and prevents the entry of contaminated air Heat Sterilization (Steam vs Dry Heat) - CORRECT ANSWER Most widely used and reliable method, involving destruction of enzymes and other essential cell constituents. Only applied to the THERMO STABLE PRODUCTS (121 °C), but it can be used for MOISTURE-SENSITIVE MATERIALS. Steam Sterilization: bacteria is destroyed at LOWER temperature when MOISTURE is present! Greater pressure = higher temp = less time required Dry heat sterilization is generally used for substances NOT effectively sterilized by moist heat (oils, glycerin, petroleum products) ALSO used for glassware and surgical instruments Sterilization by Filtration - CORRECT ANSWER Does NOT destroys but removes the microorganisms by a sieving mechanism Commercially available filters are produced with a variety of pore size specifications. Drugs administered in low doses might have chances of being absorbed by the filter membrane. - MUST be careful not to filter out the drug!! What happened with preservative-free methylprednisolone acetate? - CORRECT ANSWER WHO - 753 patients across 20 states diagnosed with fungal infections after epidural injections - 64 deaths CAUSES - Improper sterilization - Improper testing to verify sterility - Concealing mistakes and shipping untested vials - Dirty facility! - Expired ingredients RESULTS •18 different types of fungi in vials •Spinal/paraspinal infections and/or meningitis, peripheral-joint infections, strokes Endotoxins and the Pyrogenic Response - CORRECT ANSWER Pyrogens come from Gram-NEGATIVE bacteria NOTE: medical equipment that has been sterilized may still contain endotoxins Particulate Matter: USP acceptable limits - CORRECT ANSWER These are SUB visible particles Particulate Contamination: Extrinsic vs Intrinsic vs Inherent - CORRECT ANSWER Extrinsic - Environmental Contaminants (insect parts, hair, ribers, paint, rust) Intrinsic (within the process) - processing equipment, primary package (stainless steel, glass, rubber, silicone oil) Inherent (part of formulation) - Protein agglomerates How can glass contamination occur? - CORRECT ANSWER Pharmacopeias describe the glass to be used for pharmaceutical containers as its composition is varied. "It is either borosilicate glass or soda-lime-silica glass" Borosilicate glass - high hydrolytic resistance and high thermal shock resistance Soda-lime-silica glass - moderate hydrolytic resistance Isotonicity - CORRECT ANSWER In the range of osmotic pressure 250-350 mOsm/kg Deviation of the isotonicity of the formulation from the respective body fluid may cause some adverse effects What is a Small volume parenteral (SVP) - CORRECT ANSWER A solution volume of 100 mL (as defined by USP) or less that is intended for intermittent intravenous administration (usually defined as an infusion time not lasting longer than 6-8 hours) Mostly given as multiple doses. Different packaging: - ampules, vials, dry powders, prefilled syringes What is a large volume parenteral (LVP) - CORRECT ANSWER LVP are supplied for single dose having more than 100 ml They are designed to provide fluid, calories (dextrose solution) and electrolytes. Packaging: typically bags or bottles containing large volume of IV solutions. Difference between SVP & LVP - CORRECT ANSWER Components of Parenteral Nutrition - CORRECT ANSWER - Carbohydrates - Parenteral Lipid Emulsion - Single Dose Amino Acid Solution - Trace Elements - Vitamins & Minerals Types of Parenteral Nutrition - CORRECT ANSWER IVFE: intravenous fat emulsions 2-in-1: dextrose and amino acids with electrolytes, vitamins, minerals, and trace elements for IV infusion (sugars + protein, but no lipids) TNA or 3-in-1: Total Nutrition Admixture - Combo of all macronutrients (dextrose, amino acids, IVFE) with electrolytes, vitamins, minerals, trace elements all in 1 IV solution (sugars, proteins, lipids) Safety considerations with parenteral nutrition - CORRECT ANSWER All components must be aseptically compounded by pharmacy Bacterial growth over long infusion times Stability and compatibility IVFE Stability - CORRECT ANSWER IVFE is most stable at its manufactured pH ~8, surface pot. -35 mV Factors affecting stability - pH, temperature, lipid globule, light exposure, container size, storage - Dextrose addition --> decrease in pH and affects IVFE stability - Medication incompatibility Results - "cracking" or coalescence of lipid globules- destruction of lipid emulsion and Precipitation Stages: creaming --> oiling --> cracking "Creaming" of IVFE is usually reversible What are the challenges with mixing and co-infusions of parenteral drugs and nutrition? - CORRECT ANSWER Amount of electrolytes Trivalent (iron) > divalent (calcium, magnesium) > monovalent (sodium, potassium) cations may all cause a decrease in the surface potential of the lipid droplets leading to aggregation and coalescence Calcium or phosphate precipitation •Due to higher pH of IVFE Co-infusion compatibility - Consider Precipitation Solution- 1.2um filter to reduce risks of precipitate issues What drug interactions can occur with plastics? - CORRECT ANSWER What kind of plastic should diazepam NOT be put through? Why? - CORRECT ANSWER PVC shows high sorption of Diazepam What are things to consider when deciding if you should mix two products? - CORRECT ANSWER Insoluble drugs formulated in propylene glycol/ethanol precipitate when mixed with aqueous solutions (Diazepam, digoxin, clonazepam, phenytoin, amiodarone) Precipitation upon pH shift with dilution. Weak organic acids (benzylpenicillin sodium) are formulated at high pH to increase solubility. Lowering pH reduces solubility. The salts of monovalent cations (Na and K) are more soluble than those of divalent cations (Ca and Mg). --> Mixing solutions containing calcium or magnesium ions has a substantial risk of forming an insoluble calcium or magnesium salt. Needle Length by Type of Injection - CORRECT ANSWER Needle Gauge by Type of Injection - CORRECT ANSWER Vial with Stopper for Parenteral Solutions - CORRECT ANSWER Mainly used for multiple dose parenteral preparations Provided with closure followed by aluminum seal to ensure the perfect air tight packing Closure: - made from butyl rubber, nitrile rubbers, neoprene, silicone rubbers Has compression recovery, coring resistance, solvent resistance, heat resistance, radiation resistance with very low water absorption and permeability properties What is a Polymer? - CORRECT ANSWER Simply a material composed of many repeating molecular units called monomers that link together into chains or branches. Copolymer - CORRECT ANSWER Formed from two or more different monomers Homopolymer - CORRECT ANSWER Formed from identical monomers What are the THREE types of polymer chains? - CORRECT ANSWER Linear polymers - the smallest repeating unit arrange in straight line path. Example: polyvinyl chloride (PVC) Branched polymers - contain linear chains having some branches. Cross-linked polymers - formed from bi-functional and trifunctional monomers and contain strong covalent bonds. What are the pharmaceutical applications of polymers? - CORRECT ANSWER 1. Modify drug release 2. Stabilize amorphous drugs 3. Binders (particles in tablets) 4. Disintegrants 5. Coating materials 6. Suspending agents 7. Emulsifying agents How can we modify drug release using polymers? - CORRECT ANSWER Reservoir (coated in polymer) vs Matrix (crug dispersed as solid in polymer --> solid dispersion) vs Monolithic (drug dissolved in polymer --> solid solution) AND/OR Use of Porous Systems NOTE: a combination of mechanisms can be used to achieve desired drug release Reservoir Dissolution Systems - CORRECT ANSWER Reservoir (encapsulated): drug release is controlled by: - thickness AND - dissolution rate of the polymer membrane surrounding the drug core. *Once the polymer membrane dissolves, the entire drug is available for dissolution* Spansule System (Smith-Kline) has what kind of polymer drug system? - CORRECT ANSWER Each capsule contains hundreds of tiny beads where drug is coated with water soluble polymers EACH bead is coated with a reservoir dissolution system! Matrix Type Diffusion-Controlled Drug Release Systems - CORRECT ANSWER Drug is dispersed in a polymer matrix and the rate of release is controlled by molecular diffusion through pores or between polymer chains Pores are created by polymer swelling in the interior of the matrix Smaller drugs can escape through voids at rate controlled by molecular diffusion Examples: polyethylene, polyvinyl acetate Reservoir Type Diffusion-Controlled Drug Release Systems - CORRECT ANSWER Drug is surrounded by a polymer membrane (contained in a core). Classified according to membrane porosity. Nonporous reservoir systems: drug molecules diffuse through polymer membrane Microporous Reservoir Systems: drug release depends on the diffusion through micropores that fill with water. Microporous membranes can be prepared by making hydrophobic polymer membranes in the presence of water-soluble materials such as poly(ethylene glycol) What does DIFFUSION depend on in diffusion-controlled dosage forms? - CORRECT ANSWER - Drug molecules diffuse through the polymer membrane or polymer matrix to be released. - Drug diffusion through polymer membrane or polymer matrix depends on the size of drug molecules and space available between polymer chains. - Mobility and continuous movement of polymer chains allow for drug diffusion EVEN WHEN the space between polymer chains is SMALLER than the drug molecule. Osmotic Pressure Role in Drug Release - CORRECT ANSWER Osmosis is the natural movement of water into a solution through a semi-permeable membrane (only water molecules diffuse through, not solutes). Drug release through the small orifice in the membrane is a result of the osmotic pressure inside the device. --> osmotic pressure PUSHES drug out *polymer membrane is a semi-permeable membrane* Cellulose Acetate is frequently used polymer Water Vapor Transmission Value (WVTV) - CORRECT ANSWER Used to select appropriate polymer film for drug release The higher the WVTV, the higher the permeability! Degradation of Polymers (Surface Erosion vs Bulk Degradation) - CORRECT ANSWER Surface Erosion: - sample is eroded from the SURFACE - Mass loss is FASTER than the INGRESS of water in the bulk - occurs with poly(ortho)esters and polyanhydrides Bulk Degradation: - degradation takes place throughout the whole sample - INGRESS of water is FASTER than the rate of degradation - occurs in polylactic acid. (PLA), polyglycolic acid (PGA), poly lactic-co-glycolic acid (PLGA), and polycaprolactone (PCL) Biodegradable polymers - CORRECT ANSWER Used in drug delivery systems that are injected or implanted into the body. Polymers that breakdown into monomer units in the body. The most commonly used are: poly(lactic acid), poly(glycolic acid), and poly(lactic-co-glycolic acid) Full List of Modified Release Dosage Forms - CORRECT ANSWER Sustained Release Formulation - CORRECT ANSWER Sustained release over an extended time period - reduce dosing frequency - uses water insoluble polymers including ethyl cellulose (EC), polymethacrylates, polyvinyl acetate (PVA) - Hydrophobic polymer may be blended with hydrophilic materials to adjust film permeability. Useful for water insoluble drugs Enteric Coated Formulation - CORRECT ANSWER Delayed release - dosage form dissolves in intestine, NOT stomach - pH sensitive, gastro resistant - protect drugs from stomach acid - prevent gastric irritation - local action on intestine - uses polymers with pH-dependent solubility - soluble at intestinal pH - insoluble at gastric pH - polymer examples include: shellac and cellulose esters What are common polymers used as binders, disintegrants, coating materials, and enteric coating materials? What is used to make capsules? - CORRECT ANSWER Binders: HE, HPMC, PVP, PVA Disintegrating agents: starch, sodium carboxymethyl cellulose (NaCMC) Coating materials: HPMC, PVP (water soluble, used for immediate release coating) Enteric coating materials: methacrylic acid and phthalate esters. Capsules --> gelatin is a natural polymer for manufacturing of capsules What polymers are commonly used in suspensions? - CORRECT ANSWER Polymers like Acacia, Tragacanth, Cellulose derivative, Xanthan gum, are ALL used as suspending agents What polymers are commonly used in emulsions? - CORRECT ANSWER Polymers like Teens (polysorbates) are used as emulsifying agents These prevent coalescence of droplets in emulsions Where might some implantable polymeric drug delivery devices go? - CORRECT ANSWER 1. intracraneal (brain) 2. intraocular (eye) 3. SQ implant (arm) 4. Intrauterine implant (uterus) Crystalline vs Amorphous vs Semi-Crystalline Polymers (Solid-State) - CORRECT ANSWER These describe the solid-state arrangement of molecular chains Crystalline Polymer: When the macromolecular chains of a polymer sample are arranged in an orderly fashion (repeats periodically in 3 dimensions to infinite extent) Amorphous Polymer (Glass): When the chains are not arranged in ordered crystals and are disordered, even in solid state - Does NOT have long-range order (periodicity) Semi-Crystalline Polymers: In most cases, no fully crystalline polymer exists, which explain why polymers have Tg and Melting Point What are the TWO states amorphous solids can exist in? - CORRECT ANSWER 1. Super-Cooled Liquid (rubbery state): a viscous equilibrium liquid form of the material, soft 2. Glass: a solid non-equilibrium form of the same material; harder Glass Transition Temperature (Tg) - CORRECT ANSWER The temperature at which the polymers undergo transition form glassy to rubbery state Glass = solid Rubbery = liquid SO., ABOVE Tg polymer is rubbery state, BELOW Tg polymer is glassy state What does the Value of Tg depend on? Why is identifying Tg important? - CORRECT ANSWER Value of Tg depends on the mobility of polymer chains Identifying Tg is used for quality control and development. Tg is an important parameter used to modify polymer properties Glass Transition Temperature vs Melting Temperature - CORRECT ANSWER Amorphous material ONLY exhibit glass transition temperature (Tg) Crystalline materials only exhibit a melting temperature (Tm) Partially amorphous/crystalline materials exhibit BOTH Tg and Tm What factors can affect Tg? - CORRECT ANSWER 1. Chemical Structure: - Molecular weight: Tg increases with MW in straight chain polymers - Molecular structure: insertion of bulky, inflexible groups INCREASES Tg due to decreased mobility - Cross-linking: increases Tg - Polar group: increases Tg 2. Plasticizers: get in between polymer chains and sets them apart from each other, increasing their mobility and decreasing Tg 3. Water or Moisture Content: Formation of H-bonds with polymer chains increases the distance between polymer chains, increases free volume, and decreases Tg What is the importance of the glass transition temperature (Tg)? - CORRECT ANSWER Measured vita thermal analytical methods (Differential Scan Calorimetry or DSC) The Tg of an amorphous material is one of its characteristic properties that can be used to assess its likely stability and suitability for use in pharmaceutical dosage forms Physical transformations (usually solid-state mediated crystallization) are often directly linked to molecular mobility and Tg Hot melt extrusion is usually carried out above Tg Plasticizer s - CORRECT ANSWER Enhance molecular mobility and flexibility of polymer - reduce Tg of polymer/plasticizer mixer Used to: - achieve desired film quality in film coating - reduce process temperature for melt granulation (carried out below Tm and above polymer Tg) Examples: - PEG - propylene glycol - glyceryl triacetate (triacetin) - water How can Tg be determined? Predicted? - CORRECT ANSWER Tg can be experimentally determined by DSC and predicted by the simplified Fox equation Where w= weight fraction Tg = glass transition temperature in kelvin Know the excipients of Propofol and what they are used for - CORRECT ANSWER Propofol 10mg/ml soybean oil --> oil component glycerol --> tonicity egg lecithin --> emulsifier disodium edetate (EDTA) --> antimicrobial/preservative (slows down antimicrobial growth) sodium hydroxide to adjust pH to 7~8.5 Emulsion USP Definition - CORRECT ANSWER Emulsions are two-phase systems in which one liquid is dispersed throughout another liquid in the form of small droplets What is the procedures to form an emulsion? - CORRECT ANSWER 1. The surfactant is dispersed in the aqueous phase along with any water-soluble components (like glycerol for tonicity), by stirring and heating as necessary until a homogeneous mixture is formed. 2. The OIL phase is then added with stirring or shaking to form a "premix" with large (>10micrometer) droplets, which is then subjected to high-energy mechanical homogenization. Why is droplet size important in parenteral emulsions? What size should parenteral emulsion droplets be? - CORRECT ANSWER Droplet size is important because it directly affects drug release Emulsions for parenteral use should have droplet size LESS than 1 micrometer (generally 100-1000nm) --> often called submicron emulsions Where is the drug in an emulsion? - CORRECT ANSWER Drugs are generally present in the dispersed phase (inside droplet) or at the interface (happens when drug doesn't have good solubility in oil OR water) How do we introduce a drug into emulsion if the drug is lipophilic? - CORRECT ANSWER If a drug is lipophilic, it can be dissolved in the oil phase before premix formation. Ex. Penclomedine When and how would we introduce a drug to a premade emulsion? - CORRECT ANSWER In some cases, an oil-soluble drug can be added to an already-prepared emulsion! The drug will preferentially partition into the oil phase (drugs that are liquid at room temperature will partition more quickly) Examples of Drugs: - halothane - propofol Examples of Emulsions: - Intralipid (soybean oil, egg phospholipids, and glycerin) Liposyn Series In what situation would we use a cosolvent to introduce a drug into an emulsion? - CORRECT ANSWER When a drug has little or no solubility in water OR oil, use of cosolvent (amphiphilic) in which drug is highly soluble is necessary. After dissolved in cosolvent, dissolve in oil phase first or add to pre-made emulsion. Examples of acceptable cosolvents: - ethanol - PEG - Acetylated monoglycerides - dimethylacetamide If a drug is soluble in a cosolvent, what is the advantage of formulating it into an emulsion anyways? - CORRECT ANSWER When in an emulsion, after dissipation of the cosolvent, lipids will remain to prevent drug precipitation and thus increase bioavailability. Excess cosolvents dissipate immediately upon dilution, and may cause precipitation of the drug Therefore [cosolvents] must be LIMITED. What do you do when a drug is not soluble in water or oil, and there is no cosolvent available (and you're formulating an emulsion)? - CORRECT ANSWER Use high-pressure homogenization!! Powdered or finely-milled drug suspensions added to emulsions by stirring, and then homogenized The emulsion formed needs to be examined carefully with microscope for presence of crystals ex. ketoconazole emulsion THIS IS NOT FOR PARENTERAL DRUGS - TOO BIG OF PARTICLES What are the challenges associated with sterilizing emulsions with autoclaving? What are some solutions? - CORRECT ANSWER Issues: - hydrolysis of lipids - liberation of free fatty acids - lowering of pH - temperature issues Solutions: - adjust pH to slightly alkaline (pH 8) before autoclaving - sterile filtration (passing thru 0.22 micron filter) What are the two ways we typically package oral emulsions? - CORRECT ANSWER 1. Capsules --> most convenient (made in gelatin and hydroxypropyl methyl cellulose (HPMC) capsules) caution: for formulations in gelatin capsule shells, certain cosolvents (propylene glycol) can migrate into shells and cause softening. 2. Liquid --> more acceptable to pediatric and geriatric patients Know these terms, and which are reversible in an emulsion system - Settling - Caking - Creaming - Phase separation - CORRECT ANSWER Settling and Creaming are reversible Caking and Phase Separation are irreversible Flocculation vs Coalescence - CORRECT ANSWER Flocculation: process of contact and adhesion wheeby particles of a dispersion form larger-size clusters. --> synonymous with aggregation and agglomeration --> reversible Coalescence: come together and FUSE, interface disrupted; continued coalescence leads to phase separation --> irreversible What happens in small and large droplets in emulsions with Ostwald Ripening? - CORRECT ANSWER Small droplets get smaller Large droplets get larger! (small crystals dissolve, then redeposit on large crystals, over and over) Summary of Phase Instability of Emulsions. When can phase inversion occur? - CORRECT ANSWER Phase inversion can occur due to sudden changes in temp above inversion temperature. For emulsion Dosage Forms, we want to limit the concentration of which phase? What is acceptable? Desirable? - CORRECT ANSWER We want to limit to concentration of the dispersed phase (droplet phase)! - Acceptable: <40% of total volume - Desirable: <20% of total volume What is the effect of storage temperature on emulsion droplet size? What temperature should emulsions be stored at? - CORRECT ANSWER Storage at HIGH temperatures will INCREASE the particle size of emulsions HOWEVER We also don't want to freeze an emulsion, and we want to avoid sudden changes in storage conditions! Store 20deg C below the inversion temperature What is the fate of an emulsion droplet upon entering biological enviornment? - CORRECT ANSWER Three Fates: 1. Taken up and destroyed by phagocytic cell 2. Cleared by the liver 3. Diffusion out of oil droplet and into the serum (what we WANT!) How does logP and Size of droplet relate to mechanism of parenteral drug release from emulsion formulations? - CORRECT ANSWER Drugs with a logP > 9 will be stably retained in the oil droplet regardless of the composition of the emulsions. BUT this logP has no indication on the kinetics Large emulsion droplets (>500nm) will be eliminated MORE rapidly by phagocytic cells than smaller ones NOTE: composition of emulsion will impact the binding of emulsion droplets by apolipoproteins, and thus difference in rate of clearance. apolipoproteins = proteins that bind lipids to form lipoproteins What is one way to target the liver with lipid emulsions? - CORRECT ANSWER Cell-Selective Targeting of Lipid Emulsions is big area!! Addition of Apo E to emulsion will increase liver accumulation by more than two-fold. (example Hepatitis B Virus) What is one way to keep emulsion droplets in sustained circulation? - CORRECT ANSWER Sustained-circulation lipid emulsions: - addition of sphingomyelin or PEG coating using PEG-modified lipids resulting in prolonged retention in the blood circulation and reduced phagocytosis. What are three general mechanisms of drug release of emulsions in oral applications? - CORRECT ANSWER 1. Simple partition (lipid-drug OR drug partition into intestinal lumen) 2. Lipolysis (breakdown of fats to release drug) 3. Solubilization by Bile (breakdown by bile to release drug) NOTE: Dispersion and intestinal processing is NOT understood in significant detail What are the general advantages associated with emulsion drug delivery systems? - CORRECT ANSWER - Drug solubilization, improved efficacy - compared with cosolvent approach, emulsion can potentially avoid precipitation upon dilution - drug targeting - prolonged activity Dry Emulsions as a Future Perspective in Emulsions - CORRECT ANSWER Novel Method!! Once emulsion is formed, water is removed by lyophilization. Resulting dry powder is put into capsules or compressed into tablets, alleviates chemical stability problems!! --> also lighter (and cheaper) to transport! Example: hydrochlorothiazide NOTE: the droplet size of emulsions is MUCH larger following reconstitution in water Advantage/disadvantage of emulsion dosage form. - CORRECT ANSWER Advantage: - offer higher doses for a typical water-insoluble drug - Drug solubilization, improved efficacy - Compared with cosolvent approach, emulsion can potentially avoid precipitation upon dilution - Drug targeting - Prolonged activity Disadvantage - emulsions not easy to sterilize (autoclaving) - potential for microbial contamination if not handled properly - harder to preserve What is a surfactant - CORRECT ANSWER An amphiphilic compound/agent that: - forms oriented monolayers at phase interfaces - exhibits higher equilibrium concentration at phase interfaces than that in the bulk - balance between the water and oil soluble groups (too hydrophilic dissolves in the aqueous phase, too lipophilic dissolves in the oil phase) HLB Scale - CORRECT ANSWER Surfactants with HLB values >8 are favorable for formation of oil/water emulsions Surfactants with LOWER HLB values (3-6) are more suitable for w/o emulsions What is the required HLB? - CORRECT ANSWER The HLB value of surfactants that provides the lowest interfacial tension between the oil and water phases for a given mixture is called the required HLB. Emulsion is MOST stable when a surfactant or combination of surfactants have a HLB value close to that of the required HLB value of the oil phase. Example Oils common in Emulsions - CORRECT ANSWER Soybean Oil Sesame Oil Critical Micellization Concentration (CMC). What factors affect the CMC? How is it related to interfacial tension? - CORRECT ANSWER The concentration of surfactants above which micelles form and all additional surfactants added to the system will form micelles. Interfacial Tension: the cohesive force causing each liquid to resist breaking up into smaller particles Surfactants self-associate in aqueous solution to minimize the area of contact between their hydrophobic tails and the aqueous solution. - the use of emulsifiers results in the lowering of interfacial tension of two immiscible liquids Factors affecting CMC - increase in hydrocarbon chain will result in decrease in CMC What are some natural polymers? - CORRECT ANSWER alginic acid gelatin chitosan polyglycolide acid What are some synthetic polymers? - CORRECT ANSWER polyvinvyl pyrroliodone polyethylene glycol polyvinyl alcohol What are some semi-synthetic polymers? - CORRECT ANSWER methyl cellulose hydroxymethyl cellulose What is true of a reservoir type drug release mechanism? - CORRECT ANSWER - rate limiting step is diffusion - drug is contained in core, and its release depends on diffusion rate through the polymer membrane and fluid surrounding the solid - ethyl cellulose is a polymer used for this type of release mechanisms What occurs at the lowest, middle, and highest temperature? - glass transition temperature - crystallization temperature - melting point - CORRECT ANSWER LOWEST TEMP - glass transition temperature MIDDLE - crystallization temperature HIGHEST - melting point What is true of amorphous soilds? - CORRECT ANSWER - have glass transition temperature - can exist in rubbery or classy states DO NOT have a MP What is true about glass transition temperature? - CORRECT ANSWER - Tg decreases with increasing moisture content - Tg is decreased by plasticizers - Tg increases with cross-linking Block copolymer vs Random copolymer vs Alternate copolymer vs Homopolymer - CORRECT ANSWER On a graph, identify the following transition events for an amorphous polymer in the figure below: - glassy state - rubbery state - glass transition - CORRECT ANSWER Temps below Tg - glassy state Temps above Tg - rubbery state What is true regarding enteric coated polymers? - CORRECT ANSWER - are acids with pKa values greater than 4 (need to not dissolve in acidic stomach) - are insoluble in gastric pH - are soluble in intestinal pH What caused the infections associated with contaminated methylprednisolone injections? - CORRECT ANSWER fungus!! - Improper sterilization - Improper testing to verify sterility - Concealing mistakes and shipping untested vials - Dirty facility! - Expired ingredients Contact Angle and Wetting - CORRECT ANSWER How are suspensions classified? - CORRECT ANSWER - Based on Route of Administration (oral, external, parenteral) - Based on Size of Solid Particles (colloidal, coarse, nano) - Based on Proportion of Solid Particles (dilute vs concentrated) - Based on Electro-kinetic Nature of Solid Particles (flocculated vs deflocculated suspension) Theory of Suspension: Sedimentation - CORRECT ANSWER What would increase velocity of sedimentation? - increased diameter of particle - smaller viscosity of the dispersion medium - greater density of the dispersed phase (particles) - smaller density of the dispersed medium Which dosage form has the LEAST physical stability? - CORRECT ANSWER Suspensions have the LEAST physical stability of ALL dosage forms due to sedimentation and cake formation Viscosity of suspension must be maintained within optimum range to yield stable (low settling velocity) and easily pourable suspensions. Why are flocculating agents added? - CORRECT ANSWER Enhance re-dispersibility Flocculation is the formation of light, fluffy groups of particles held together by weak van der waal's forces Flocculated suspensions can always be re-suspended with gentle agitation. Controlled flocculation is obtained by adding flocculating agents that are - electrolytes - surfactants - polymers - CORRECT ANSWER Electrolytes acts as flocculating agents by reducing the electrical barrier between the particles, thus, decrease the zeta potential, this leads to decrease in repulsion potential and makes the particle come together to form loosely arranged groups Dispersed solid particles in a suspension may have charge in relation to their surrounding vehicle, because of what? - CORRECT ANSWER Selective adsorption of a particular ionic species present in the vehicle. AND/OR Ionization of functional group of the particle. Potential-Determining Ions --> (ions that give the particle its charge) serve to repel the particles Counter Ions --> immediately adjacent to the surface of the particle is a layer of tightly bound solvent molecules, together with some ions oppositely charged to potential determining ions (called counter ions!!) Flocculating Agents --> Surfactants - CORRECT ANSWER Ionic and nonionic surfactants can be used to control flocculation The concentration of surfactants needed to achieve flocculation is critical since these compounds may also act as wetting agents to achieve dispersion. Optimum concentrations of surfactants bring down the surface free energy by reducing the surface tension between liquid medium and solid particles. Flocculating Agents: polymers - CORRECT ANSWER Starch, alginates, cellulose derivatives, carbomers, are all long chain (high MW) compounds containing active groups spaced along their length These agents act as flocculating agents because part of the chain is ADSORBED on the particle surface with remaining parting projecting out in the dispersion medium --> bridging these portions leads to the formation of floccules Polymers exhibit pseudo-plastic flow in promoting physical stability of suspension Spreading Coefficient - CORRECT ANSWER For convenient wetting, the value of spreading coefficient should be positive How is this done? - by adding wetting agent (surfactant with HLB value 7-9) - non ionic surfactant (polysorbate) What are some disadvantages of surfactants? - CORRECT ANSWER - foaming tendencies - most are bitter What are the three kinds of wetting agents? - CORRECT ANSWER - Surfactants - Glycerin (+ similar hygroscopic substances) - Hydrophilic colloids Sedimentation Volume (F) - CORRECT ANSWER F = (volume of sediment Vu)/(original volume Vo) --> provides a qualitative knowledge about the physical stability of the suspension F = 1 (no sedimentation, clear supernatant) F = 0.5 (50% of total volume is occupied by sediment) --> F less than 1 indicates SEDIMENTATION F > 1 (sediment volume is greater than the original volume due to formation of floccules which are fluffy and loose) Degree of Flocculation (B) - CORRECT ANSWER Ratio of the sedimentation volume of the flocculated suspension (F), to the sedimentation volume of the deflocculated suspension (F0) ß is a quantitative & more fundamental parameter than F as it relates the volume of flocculated sediment to that in a deflocculated system Amphotericin B (three products) - CORRECT ANSWER Fungizone = Amphotericin B --> LEAST SAFE Abelect Ambisome --> SAFEST *these bind to cholesterol in the mammalian membrane, which forms pores in the host membrane, causing toxicity* Tumor targeting via EPR (enhanced permeability and retention effect) - CORRECT ANSWER Tumor has leaky vasculature (and low pH), which allows molecules (liposomes and nanoparticles) to accumulate in tumor tissue much more than they do in normal tissue. Nanodrugs prevent chemotherapy accumulation in healthy tissues and promote accumulation at pathological sites Enteral vs Parenteral dosage forms - CORRECT ANSWER Enteral - Given orally (usually) - Pass through the GI tract to be absorbed in the bloodstream and metabolized by the liver - Includes: oral, naso-gastric, rectal routes Parenteral - Bypasses enteral route (do NOT pass through the liver before entering bloodstream) - Includes: injections **Note: topical and inhalation routes are in their own category What does API stand for? - CORRECT ANSWER Active Pharmaceutical Ingredients (aka: drugs) What are Inactive Pharmaceutical Ingredients? - CORRECT ANSWER AKA: Excipients Ex: diluents, thickeners, solvents, flavorants, preservatives, etc. 3 main sources of new drugs - CORRECT ANSWER Naturally-occurring - Materials in both plants and animals - Ex: Taxol, opium Synthesis of organic compounds - Closely related to naturally-occurring - Ex: morphine, cortisone, cocaine Pure synthesis - Not patterned after known and naturally occurring compound - Ex: antihistamines, barbiturates, diuretics, antiseptics About how many years does it take to develop an approved drug? Do compounded drugs go through this process? - CORRECT ANSWER 10-15 years - Discovery/pre-clinical - Clinical trials (Phases I-3) - FDA Review/Post approval (Phase 4) Compounded drugs do not go through this process Out of these options, which is NOT a reason for pharmacy compounding? - Limited dosage forms - Limited strengths - Special patient populations - Price - Veterinary compounding - CORRECT ANSWER Price What special populations can compounding be used for? - CORRECT ANSWER What does USP-NF stand for? - CORRECT ANSWER United States Pharmacopeia - National Formulary 503A vs 503B pharmacy - CORRECT ANSWER 503A (Traditional compounding) - Licensed pharmacist can compound reasonable drug quantities that are not commercially available - Rx must be unsolicited (can advertise that they compound, but not specify what products) - Can compound drugs in limited quantities prior to receiving Rx on basis of past history - Should not compound for other pharmacies or practitioners for resale - Non-sterile compounding 503B (Outsourcing facility) - Drugs must be compounded in compliance with cGMP (good manufacturing practices) - By or under the direct supervision of a licensed pharmacist - Sterile compounding Which USP-NF chapters are mandatory/enforceable? Which are considered to be informational and not binding? - CORRECT ANSWER Enforceable: chapters 999 and below Non-enforceable: chapters 1000+ What happened at the NECC and why was it important to compounding? - CORRECT ANSWER - 2012 - New England Compounding Center (NECC) - Outbreak of fungal meningitis traced back to medication used for steroid injections - Traced back to NECC - 14,000 patients were exposed - 64 deaths, 753 with persistent fungal infections - 2 people from NECC were charged with 2nd degree murder - New laws were created to regulate compounding pharmacies What are the 3 main measurement systems in pharmacy? - CORRECT ANSWER Metric - Preferred and most frequently used Apothecary - Written in Roman numerals (instead of Arabic) - Mostly used for fluid measure in pharmacy - Ex: fluid ounce, pint, quart, gallon, etc. Avoirdupois - System for measuring mass - Ex: pounds (16 oz.) **Note: the basic unit is the grain for both the Apothecary and the Avoirdupois systems What is the percent error allowed for most compounding? How is it calculated? - CORRECT ANSWER Most formulas allow for ± 5% percentage of error Conversions worth knowing: How many mLs? - 1 fl oz: - 1 cup (8 fl oz): - 1 pint (16 fl oz): - 1 quart (32 fl oz): - 1 gallon (128 fl oz): - 1 tsp = _____ mL - 1 tbsp = _____ mL 16 oz = _____ lbs 16 fl oz = _____ pint (pt) 1 grain = _____ mg 1 oz = _____ g 1 lb = _____ g (_____ kg) 1 kg = _____ lb 1 fl oz = _____ mL 1 kg = _____ g 1 g = _____ mg 1 mg = _____ mcg (μg) - CORRECT ANSWER How many mLs? - 1 fl oz: 30 mL - 1 cup (8 fl oz): 240 mL - 1 pint (16 fl oz): 480 mL - 1 quart (32 fl oz): 960 mL - 1 gallon (128 fl oz): 3800 mL - 1 tsp = 5 mL - 1 tbsp = 15 mL 16 oz = 1 lbs 16 fl oz = 1 pint (pt) 1 grain = 65 mg 1 oz = 28.35 g 1 lb = 453.6 g (0.4536 kg) 1 kg = 2.2 lb 1 fl oz = 30 mL 1 kg = 1000 g 1 g = 1000 mg 1 mg = 1000 mcg (μg) How do you calculate the possible percent error when the sensitivity of the balance is known? - CORRECT ANSWER How do you calculate the LWQ (least weighable quantity) when the sensitivity of the balance is known? - CORRECT ANSWER What does it mean to have a two-place balance? A three-place balance? - CORRECT ANSWER **The lowest amount that can be weighed on a two-place balance is 200mg, and on a three-place balance is 20mg When is the liquid aliquot method used? When is trituration used? - CORRECT ANSWER Which has higher accuracy: graduated cylinders or plastic syringes? - CORRECT ANSWER plastic syringes **picture is just FYI Is it more accurate to measure 50 mL in a 50 mL graduated cylinder or a 100 mL graduated cylinder? - CORRECT ANSWER 50 mL graduated cylinder Which kind of graduate is more accurate: conical or cylindrical? - CORRECT ANSWER graduated cylinder Is the final volume of a prescription always represented by the sum of the individual volumes of its ingredients? - CORRECT ANSWER No - especially with aqueous vs non-aqueous polar systems (ex: alcohol-water combinations) Which glassware are non-volumetric? What does this mean? - CORRECT ANSWER - Erlenmeyer flasks, beakers, prescription bottles - Graduation marks are only approximations of liquid capacity (unless you first calibrate them to a known volume) What is the purpose of geometric dilution? - CORRECT ANSWER To ensure equal distribution when making a suspension What important factor needs to be taken into account when measuring substances like the one shown? - CORRECT ANSWER **cover answer to view picture** answer: # of water molecules What is the purpose of using a salt form of a drug? After salts, what is the most important acid derivative used in pharmacy? Why? - CORRECT ANSWER The salt form enhances the solubility of the drug Most important after salts: esters - Esters can be used for solubility, stability, prodrugs, etc. What is the inherent issue with complex molecules and biotechnology products containing proteins? - CORRECT ANSWER Proteins are unstable molecules that can denature/degrade without special handling What is the definition of stability? What are the 5 general types of stability? - CORRECT ANSWER The extent to which a product retains specific properties throughout its period of storage and use 5 Types - Chemical - Physical - Microbiological - Therapeutic - Toxicological **the last two fall under the chemical category as well What factors can affect the stability of a drug and dosage form? - CORRECT ANSWER 5 different types of flavoring techniques - CORRECT ANSWER - Blending: mixing citrus flavor with acidic drug - Overshadowing: using a strong flavor to cover the drug's taste - Physical methods: making a suspension/emulsion to separate drug from taste buds - Chemical methods: putting drug into inclusion complex or adding adsorbent - Physiological methods: cooling effect to mask drug taste, using cinnamon for heat, or anesthetics like peppermint For each term, determine if it is an antioxidant, sweetening agent, or preservative: - CORRECT ANSWER Sweeteners - Aspartame - Fructose - Mannitol - Saccharin - Saccharin sodium - Sorbitol - Sorbitol solution - Sucralose sucrose - Sugar compressible - Sugar confectioner's - Syrup - Stevia Preservatives - Alcohol/ethanol - Benzalkonium chloride (BAK) - Benzethonium chloride (BZT) - Benzoic acid and salts - Sodium benzoate - Benzyl alcohol - Chlorobutanol - Parabens (methyl, propyl) What is preservation? What two main factors does the choice of preservative take into account? What other factors? What types of preparations are preservatives typically added to? - CORRECT ANSWER Preservation: The prevention/inhibition of microbial growth involving the addition of a substance to a product Two factors - Characteristics of the product - Acceptability to the patient Other factors - Nontoxic - Stable - Compatible - Inexpensive - Acceptable taste, odor, and color - Effective against variety of bacteria, fungi, and yeasts Why do syrups not need an added preservative? - CORRECT ANSWER Syrups are inherently preserved by their high concentration of sugar, which acts as an osmotic preservative What are the 5 basic methods of sterilization? - CORRECT ANSWER - Moist heat: uses an autoclave to produce a steam environment; objects must contain water or allow steam to penetrate - Dry heat: uses a high-temp oven (higher heat than autoclave) to sterilize hard-surface materials and dry powders - can also do some injectable oily solutions - Filtration: removes but does not destroy microorganisms (pyrogens) - Chemical - Radiation What are the 3 main dosage routes that require sterility? - CORREC