Dosage Compounding Exam 1 PDF

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Dosage Form Design and Compounding Exam 1 Lecture 1: Drug: substance that acts on the body to alter physiological process. Used for prevention, dx, and tx of disease Medicine: drug with definite form and dose therapeutically used for tx of diseases Dosage Forms: ● Enteral: goes through GI tract ○ Tabs, Caps, Caplets, Oral soln, suspension, syrups ○ Elixirs and tinctures contain EtOH ○ Rectal suppositories, enemas, emulsions, lozenge ● Parental: generally injected, bypasses GI tract ○ Injectable drugs: usually solution or powder mixed with sterile diluent to → injectable soln ○ Topical, sublingual ● Inhalation: Inhaled → respiratory system Drug product composition ● Active Pharmaceutical Ingredient (API) = drug ● Inactive pharmaceutical ingredients (Excipients) = anything that helps get drug to target ○ Ex: diluents, thickeners, solvents, flavorants, colorants, tablet coatings, etc Sources of new drugs ● Naturally occuring materials in plants/animals: Taxol, Opium ● Synthesis of organic compounds structurally sim to naturally occurring compounds: Morphine, Atropine ● Pure synthetic: not patterned after a known naturally occurring compound: antihistamines, barbiturates Drug Development ● 3 stages before market ● 20% of drugs are approved ● 4th stage is post market ● Very expensive process → very expensive drugs to recoup costs Compounded Drug Preparations ● Unapproved drug products, approved drug ingredients. ● Individualizing drug therapy ● Makes a drug product that isn’t commercially available ○ Dosage form, strength, etc. ○ Discontinued drugs: not removed from market or d/c d/t safety or efficacy ○ Drug shortages ○ Vet compounding ○ New therapeutic approaches ○ Special pt pops: peds, geriatrics, bioident HRT, pain management, dental pts Oversite/guidelines ● USP-NF ○ # below 1000: enforceable ○ Above 1000: good guideline ○ 797: sterile compounding Lecture 2 Legislation DQSA: Drug Quality and Security Act of 2013 -- Under FDA ● 503A - Traditional Compounding ○ Compound reasonable qty of drug preps that aren’t commercially available for an individual pt on the unsolicited receipt of a valid prescription ■ Can make pre-emptive product for specific script 1

○ Must be performed by licensed pharmacist or physician ○ Can’t compound for other pharmacies or practitioners ○ Can advertise that they offer prescription compounding services but not for specific compounds ● 503B - Outsourcing Facility ○ Good manufact processes under direct supervision of licensed pharmacist in registered facility. ○ Non pt specific compounding. (Can provide to hospitals or pharmacies) ○ Still not commercially available products ○ Ex: NECC - New England Compounding Center ■ Fungal meningitis in triamcinolone inj ■ Many people injured or killed from infection ■ → Revised act regarding 503B facilities Resources ● Compounding Today. Com (not free but great resource) ● Many many places both free and subscription Drug Quality and Security Act of 2013 ● Added 503B section ● Must comply with good manufacturing processes ● Inspected by FDA according to risk based schedule ● Must meet certain other conditions: report ADE and provide FDA with certain info about products compounded Measurement Systems: ● 2 most crucial steps in compounding ○ Accurate calculation ○ Measurement ● The metric system ○ Preferred and most frequently used in pharmacy ● Apothecary system ○ Fluid ounce, pint, quart, gallon

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○ Avoirdupois System ○ System of weights (mass) based on pound = 16 oz ○ Pound = 0.4536 kg ○ Grain - same as apothecary system ■ Armour thyroid and phenobarbital Conversions:

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○ Weighing ● Official compendia allow a tolerance of +/- 5% for most formulas ○ Critical, narrow therapeutic index, or toxic - more accuracy needed ● % error = Error in measurement/ Qty desired ○ (Expected - Actual)/Expected ● Sensitivity (potential error) ○ Can calculate percent possible error ○ % error = Sensitivity/ Qty desired ■ 2 place balance = 0.01 g or 10 mg ■ 3 place balance = 0.001 mg or 1 mg ○ Most prescription balances ■ Lowest amt weighed for 2 place- 200 mg ○ Least weighable Qty (LWQ) ■ Sensitivity / % error tolerated ■ 3 place balance = 0.001 g or 1 mg ■ Lowest amt weighed - 20 mg = 1 mg/0.05 Lecture 3 Weigh smaller than sensitivity allows: ● Aliquot method: liquids ○ Solution, suspension, or emulsion ● Trituration method: solids ○ Incorporate as a solid into powders, tabs, caps, or pastes ● Can add color to ensure homogenization: make sure to acct for wt of added substance Liquid Measurement: ● Syringes ○ Able to accept needle ■ Luer Slip or Luer Lock (can screw into tip) ■ Variety of sizes from 0.3 mL (0.1 mL increments) to 60 mL (2 mL increments) 3

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Oral: ■ Won’t accept needle d/t thicker tip ● Graduated cylinders ○ Used for measuring and transferring liquids less precise than pipet ○ General rule: measure vol >/= ½ of capacity ○ Conical: worse per Dr. Myers ○ Cylindrical: more accurate and preferred ○ Error: Read straight across at bottom of meniscus ○ Don’t dissolved solids in them: they can accumulate at the bottom ● Non-volumetric Glassware and Devices ○ Ex: Erlenmeyer Flasks, Beakers, Prescription Bottles ○ NOT used for measuring liquids; Graduation marks are approximations of liquid capacity ○ Calibrate first and can then use ● Teaspoon: ○ Regarded as 5 mL ○ House teaspoons range 3-7 mL ○ Minimize error by using mL Guidelines for selecting liquid measurement devices ● Use smallest device that will accomodate the desired vol of liquid ● Oily and viscous liquids are difficult to remove from graduates and pipets ○ Get density and measure by weight rather than volume ● When small or very accurate doses are required give pt some help Geometric Dilution ● Use when mixing a little of 1 component with a lot of another. ● Start with equal parts of each and mix (1:1) → 2 ● Then add equal parts of mixture with greater component (2:2) → 4 ● Then add equal parts of mixture with greater component (4:4) → 8 … etc. ● Hint: doesn’t need to be exact, just approximate Compound ingredient considerations ● Purity and form of all ingredients used in compounding esp API ● Where to get info on what form it is in (ex, salt, base, ester, hydrate, solvate, etc) ● Chem structure or empirical formula and certificates of analysis ● Certificate of analysis ● -- USP/NF: resource to find all this info Drug molecule forms (salts, hydrates, esters, etc) ● Dose on label can be molecule (morphine sulfate) or API (doxycycline) ● Read pkg insert or label to clarify Hydrates and Solvates ● More molecules of H2O in the molecule → greater amt of chemical that must be weighed to obtain actual active drug ● Hyclate = ½ H2O molecule per drug molecule ● Molecular weight of compound/ molecular weight of API = factor to adj measurement Organic Salts ● .Dose may be based on total salt form or just the base form of the drug ● Molecular weight of compound/molecular weight of API = factor to adj measurement Esters ● Most important acid derivative after salts ● May be prepared for # of reasons: solubility, stability, degradation resistance, and use in prodrugs 4

Lecture 4 8/27/2018 Potency-designated ingredients ● Some APIs, potency is based on activity and expressed in units of activity ○ mcg/mg ● Must be labeled with the actual potency, use that in calculations for dosing before compounding ● Calculations must be done, checked, and documented ○ Different lots of same API may have diff potencies ● Ex: ○ 500 mg neomycin sulfate ○ Label on API shows 650 mcg neomycin activity per mg of powder ○ How much powder to make 500 mg of neomycin sulfate? ○ 650 mcg/mg = 65% neomycin sulfate ○ 500 mg/ 0.65 = 769 mg powder Complex Organic Molecules ● Generally proteins or peptide like molecules ● Unstable molecules, degradation profiles can be quite complex: be gentle ● Special handling info in pkg insert ○ Stabilization, formulation, and delivery ot site of action Commercial products as source of active drugs ● Product is approved and has been assayed ● Exact quality is not known ○ Amt in product can be 90-110% of label ● FDA recommends commercial products ● Dr. Myers recommends using bulk powder med Good manufacturing practices ● GMPs ● cGMPs ● Standard Operating Procedures (SOPs) ○ All sig procedures performed laid out clearly ○ → consistency ● Records and record keeping ○ Must keep records for each formulation ○ Provide documentation of all ingredients of a preparation, facilitate a prep recall ○ Ensure consistency ○ Compounding record: ■ What is done: ● Contains: Name, strength, and dosage form ■ Includes formulation record ■ Quality control procedures ■ Qty of prep prepared ■ Sig of pharmacist or tech compounding the prep ■ Sig of pharmacist responsible for supervising the prep and conducting in process and final checks of compounded prep ■ Date of preparation and beyond-use date ○ Formulation record: recipe ■ Individual ingreds, lot numbers, and actual qty measured/weighed Stability of Compound Preparations ● Stability: extent to which a product retains specific properties throughout its period of storage and use 5

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USP/NF: defines 5 general types of stability ○ Chemical: Each active ingred retains chemical integrity and labeled potency within specified limits (90-110%) ○ Physical: Original physical properties are retained ■ Appearance, palatability, uniformity, dissolution, suspendability ○ Microbiological: Sterility or resistance to microbial growth is retained according to specified requirements ○ Therapeutic: therapeutic effect remains unchanged ○ Toxicological: no sig increase in toxicity occurs ● Factors that affect stability: ○ pH: oral, IV soln ■ Dependent on product about how pH will affect it ○ Temp: faster degradation at warmer temps ○ Solvent: some products can hydrolyze if in water ■ Ex. loss of EtOH from solvent can → precipitation ○ Light ■ Ex: Nifedipine breaks down in light very quickly ○ CO2: Soln can absorb → pH decrease ○ Moisture or humidity: esp with orals ○ Particle size: larger → less SA for rxn ○ O2 → oxidation (add antioxidant to protect product) ■ Antioxidant mech: preferentially oxidized instead of drug ● Tocopherol (Vit E) ● BHT ● Na bi, meta, thio sulfite ● Ascorbic acid (Vit C) Flavors, Sweeteners, and Colors ● Help with pt compliance -- especially important with kids ● Many drugs have bad tastes ○ Flavor + bad taste doesn’t necessarily make good taste ● Adults: can use more bitter flavors like chocolate, anise, spice ● Kids: sweet ● Long time period of med: milder flavor preferred ● Sweet (sucrose), sour (H+), salty (NaCl), bitter (caffeine) Flavoring techniques ● Challenge: no single correct method exists ● Opportunity: can make a prep that a pt is willing to take ● Goal: ○ Immediate flavor identity (at least that it is pleasant) ○ Rapid full flavor development ○ Acceptable mouth feel ○ Short aftertaste ○ No undesirable sensations ● Approaches to minimize bad taste ○ Blending: take the nature of the bad taste and add a complimentary flavor ■ Ex. acid + citrus flavor → blended tasty flavor ○ Overshadowing: additive overtakes bad taste ■ Ex. bad taste + strong peppermint (licorice, wintergreen) 6

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Physical Methods: physically separate drug from the taste bud ■ Put drug in a suspension ○ Chemical Methods: use another chemical formulation that doesn’t have the bad taste ■ Metronidazole benzoate- breaks down to flagyl, but tastes better ■ Inclusion complex, Ion exchange resin ○ Physiological Methods: Use flavor to our advantage ■ Ex. peppermint can act as an anesthetic on taste buds to help bad w/ flavors ■ Menthol, mannitol, spearmint, clove, or cinnamon can have same effect Lecture 5 8/29/2018 Flavors used to mask basic tastes: ● Sweet: Vanilla, fruit, grape, bubblegum, berry ● Sour: Lemon, lime, orange, cherry, grapefruit, raspberry, acacia ● Salty: nut, butter, butterscotch, spice, maple ● Bitter: licorice, coffee, chocolate, mint, grapefruit, cherry, peach, raspberry, orange, lemon, lime ● Oily: peppermint, anise, wintergreen ● Metallic: Berry, mint, grape, marshmallow Sweeteners: ● Examples: ○ Sucrose, dextrose, corn syrup, sorbitol, mannitol ○ Saccharin: sweeter, bitter aftertaste ○ Aspartame: sweeter, less aftertaste, stability profile: pH and temp dependent ○ Xylitol: can kill dogs ● Often used in high conc can → increase viscosity and slow drug dissolution rate Coloring agent ● Not always necessary, Use minimal qty of dye ● Generally match the flavor Sterile Compounding Preservation: ● Goal: prevent or inhibit microbial growth ○ Oral liquids, topicals: minimize growth ○ Sterile preps: inhibit growth ● Methods: ○ Addition of a substance ■ Doesn’t degrade or have incompatibility with product ■ Acceptability to pts (if pt can’t use paraben or sulfate, etc) ● Examples of preservatives: ○ EtOh ○ Benzalkonium chloride ○ Benzoic acid and salts ○ Sodium benzoate ○ Benzyl alcohol ○ Parabens ■ Methyl and Propyl ■ Added together → wide spectrum preservative effectiveness ● Selection factors ○ Concentration, pH, taste, odor, and solubility ○ Some preps are inherently preserved by high [sugar] ○ Nontoxic, stable, compatible, inexpensive, wide range of efficacy 7

Sterilization: ● Best method: start with sterile product and keep them that way ● Absence of all viable life forms ● Methods ○ Moist heat ■ Autoclave 121 degree C at 15 psi X 20 mins ■ Make sure steam can get to all surfaces ○ Dry heat ■ Takes longer than moist heat and Lower temp = more time ● 180 deg c - 45 to 60 mins ■ Have an indicator for validation ■ Can do some dry powders that are stable at high temp ■ Injectable oily soln can be dry heat sterilized if active is stable at high temp ○ Filtration ■ Recommended for most compounding situations ■ Removes but doesn’t destroy microorganisms ■ Filters pore size 0.22 micron or less ● Use Pharmaceutical grade not lab grade ■ Filter material for solvents, gasses, water or oil based ■ Check for integrity after use by a bubble point test ○ Chemical ○ Radiation ● Need to be validate sterilization method regularly ● Heat is a reliable method of sterilization: Dependent on temp, time, moisture, and pressure Lecture 6 8/31/2018 Preparation of prescription medications ● Review and interpretation of the prescription ● Calc of measurable qty of all components ● Accurate weight or measurement of all components ● Use of appropriate compounding tech to convert indiv components into a finished product ● Proper packaging and labeling of the product ● Delivery of the correct, complete product to the correct pt w adequate instructions for admin Prescription Product Labeling ● Prescription # and Date of initial dispensing ● Pt name ● Direction of use; Name and strength of drug product (API) ● Prescriber’s name and Name of dispensing pharmacist ● Expiration or beyond use date ○ Non-sterile prep ■ Non-aqueous formulations: not later than the time remaining until the earliest expiration date of any API or 6 mo (whichever is earlier) ■ H2O-containing oral forms: not later than 14 days when stored at controlled cold temp ■ H2O-containing topical/dermal, mucosal liquid & semisolid formulations: no > 30 days ○ Sterile prep ■ Low risk level ● 48 H at controlled room temp ● 14 days at cold temp ● 45 days in solid frozen state between -25 and -10 deg C 8

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Medium risk level ● 30 H at controlled room temp ● 9 days at cold temp ● 45 days in solid frozen state between -25 and -10 deg C ■ High risk level ● 24 H at controlled room temp ● 3 days at cold temp ● 45 days in solid frozen state between -25 and -10 deg C ● Controlled substances: ○ “Caution: Federal law prohibit the transfer of this drug to any person other than the pt for whom it was prescribed.” ● Label guidelines: ○ Indicate dosage form ie. tablet ○ Use words instead of numbers and Don’t use abbreviations ○ Express qty to be admin in units that are not ambiguous ie. mL vs teaspoon ○ Specify any action prior to admin ie. unwrap and insert, mix with … Auxiliary Labels ● Supplements info regarding proper and safe admin use or storage ● Ex: shake well before using, for the eye, refrigerate don’t freeze Liquid dosage forms ● Types: ○ Solutions ■ Homogeneous mixture: Liquid preps containing 1+ drug substances molecularly dispersed in a suitable solvent or a mixture of mutually miscible solvents ■ Oral liquids containing 1+ substances w/wo flavoring, sweetening, or coloring agents dissolved in water or co-solvent-water mixtures ■ Can be either formulated for direct oral admin to pt or dispensed in a concentrated form that requires dilution before dispensing or admin ○ Syrups ■ Concentrated aqueous prep of a sugar or sugar substitute w/wo flavoring agent and medicinal substances ■ Can act as pleasant tasking vehicle for active drug ■ Generally more acidic (pH 4 or less) ■ Commercially avail bases have preservatives in them generally ○ Elixirs ■ Clear, sweetened, hydroalcoholic soln; flavored & used for drugs insoluble in H2O alone ■ Less sweet and less viscous than syrups, generally less effective in masking taste ■ Co-solvent systems: glycerin, sorbitol, propylene glycol, water ■ Prep: ● Dissolving EtOH soluble components in EtOH and the H2O soluble in H2O ● Aqueous phase is generally added to EtOH soln to maintain highest [EtOH] ● Sucrose: not well dissolved, use artificial sweeteners PRN ■ EtOH: 5-40% ● Solubilization ○ Selection of a solvent depends on physicochemical char of solute and solvent ○ Process of dissolution involves ■ Breaking of interionic or intermolecular bonds in the solute ■ Separation of the molecules of the solvent to provide space in the solvent for the solute 9

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■ Interxn between solvent and solute molecule or ion ○ Like dissolves like: polar solutes/polar solvent Composition ○ Most drugs are more susceptible to degradation in an aqueous soln ○ Adding buffers to adj pH, preservatives, and antioxidants can help prevent degradation ○ Parenterals and ophthalmics should be isotonic pH ○ Drug stability: often directly depends on pH of environment ○ Low buffer capacity should be used: physiologic buffers will quickly 𝚫 pH to physiologic range ○ Slight adj can greatly affect solubility and stability of drug ○ pH should be controlled in prep ○ pH change can → precipitation ○ Acidifying agents: ■ Acids: acetic, citric, fumaric, HCL, lactic, malic, nitric, phosphoric, propionic, sulfuric, tartaric ■ Na phosphate monobasic ○ Alkalizing Agents: ■ Ammonia ■ Diethanolamine ■ Potassium hydroxide ■ Na bicarb, borate, carbonate, hydroxide, ■ Na phosphate dibasic Vehicles ○ Generally water ○ Purified water ○ Sterile water for injection: no antimicrobial agent ○ Bacteriostatic water for injection: contains 1+ antimicrobial agents (generally benzyl alcohol) ○ Sterile water for irrigation: not for injection but it is sterile with no antimicrobials Preparation: ○ Dissolving: most can dissolve with stirring but some need heat or increased agitation ○ Methylcellulose or parabens: add part amt of hot H2O, add rest of vol as ice H2O/ice → hydrate ○ Intermediate liquid (EtOH or glycerin) before H2O → displace air trapped in powder → water will wet powder more easily ○ Surfactant: aid in solubilizing Physicochemical considerations: ○ Small particles → ↑ dissolution rate ○ Stirring → ↑ dissolution rate ○ More soluble drugs → ↑ dissolution rate ○ Decrease viscosity → ↑ dissolution rate ○ Increase temp → ↑ solubility and dissolution rate ○ Add electrolyte can increase or decrease solubility of nonelectrolyte drug ○ Poorly soluble base may dissolve better in acidic media ○ Poorly soluble acid may dissolve better in basic media

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