PHARML COMPOUNDING TIPS AND HINTS INTRODUCTION Extemporaneous Compounding Development of Novel DF Assists in drug admn to Pt who may

may be noncompliant (very young and elderly) GOAL: Preparation of SAFE and EFFFECTIVE products using the BEST AVAILABLE RESOURCES and TECHNIQUES in MINIMUM TIME DISPENSING TECHNIQUES Compounding Accuracy - Use of proper eqvts when converting one system to another - Using CORRECT measuring devices MEASURING DEVICES 1. Prescription Balances perform counterbalance Class A max capacity: 120g Basic Tests Assuring Accuracy & Precision a. Sensitivity Reciprocal - Max change in load cx a sp change & subdivided in the index plate in the position of a 6mg is added b. Arm Ratio Test - Equality of length of both arms c. Shift Test - Correct arm and lever component d. Rider & Granulation Beam Test - Correct wt beam graduation when compared to 2 test wts

2.

Preferred: GLASS, CYLINDRICAL rather than conical due to lesser variations Inc Surface Tension = upper meniscus Dec ST = lower meniscus Conical = PARALLAX EFFECT

DISPENSING TECHNIQUES 1. Mixing and Grinding a. Mortar and pestle USES i. Reduce PS ii. Mix powders and liq iii. Make emulsions CORRECT USE i. Select correct type ii. Adeq mixing is achieved in qs space iii. Pestle rotated in (R) and (L) for thorough mixing AVOID i. Overfilling ii. Undue pressure powder impaction CHOICE i. Texture of surface ii. Type of DF iii. If emulsion: use rough iv. Why? Oil to be dispersed readily and dec PS to improve viscosity METHODS i. Trituration powd ii. Geometric Dilution potent 2. Manipulative Techniques a. Mixing even distribution of ing i. Liquids 1. Simple stirring or 2. Shaking 3. Agitation 4. Degree of stirring and shaking will be dependent on the viscosities ii. Solids w/ Liq 1. Know soly of solid 2. Red PS Inc dissolution or improve uniform distn of solid throughout liq 3. Grp 1A (Alkali Metals) form ionic salts and readily overcome by H2O 4. Polarity like dissolves like OH, RCOOR, ROR, ROH,RCOOH, Sulfates

Classes of Balances w/ Weighing Capabilities Type Min Wt Normal Max Wt Class A 50mg 1g (most accurate, hence prescribed) Class B 100mg 50g Class C 1g 2kg LIQUID MEASURING DEVICES 1. Rxist: means are available for Pt to selfadminister Graduated cylinders Pipettes Droppers Measuring cups

5. Use of Heat iii. Sol w/ Sol 1. Use M&P 2. Geometric Dilution 3. Block and Divide iv. Semisolids (Ointments) 1. Mix by rubbing on ungt slab w/ spatula 2. OR M&P, homogenizer SELECTION OF INGREDIENTS 1. Extemporaneous pptns have several ingredients w/c increases potential for error 2. Consider: a. Variety of forms Eg. Theobroma whose B-polymorph does not melt at RT Crystalline vs Amorphous b. Synonyms 3. Highest QUALITY PROBLEM SOLVING 1. Pharml Calc 2. Expiry Date 3. Counting & Measuring ALIQUOT METHOD a. LIQUIDS 1. Desired Volume 2. Calibration 3. Factor: __ X Desired Vol 4. Diluent/Solvent: (3) + ___ = Dil 5. (4)/Factor b. SOLIDS

Develop Good Practice Takes TIME and requires ATTENTION to DETAIL. DEVELOP the HABIT OF WORKING INDEPENDENTLY, though ASSISTANCE may be sought if NECESSARY.
COMPOUNDING vs MANUFACTURING Compound Manufacture Scale Small Large Extemporaneous cGMP Place Pharmacy Mfg company Interaction Ptn-oriented Pdt-oriented Equipment M&P, GW Machines Presence of Present Absent Prescriber No. of Personnel Less More Procedures Simple Complex

SOLUTIONS 1. Save time and produce uniform pdts, use: a. Magnetic stirrers b. Blenders c. Electric mixers 2. Breaking a foam, use: a. Stirring rod laid across TOP of beaker b. ROH spray (EtOH: internal solns) c. Silicone defoaming agent 3. Filtration Clarity 4. Predict & Prevent pH incompatibilities, use: a. Inexpensive pH meter aids 5. Remove stir rods add qs 6. D/salts in min qH2O add viscous vehicle *Viscosity inversely proportional to soly 7. Incorporate insoluble matl a. Levigate powder w/ small amt of vehicle/liq miscible w/ vehicle *homogeneity 8. (+) High viscosity liq to Low w/ k stirring 9. Small qts of items USE DILUTION or ALIQUOT METHOD (use a solvent, not just liquid) 10. Hydrocolloids a. Hydrate slowly before incorporating (i.e. bentonite) 11. Selection of vehicle, consider: a. [Drug] b. Soly c. pKa (if same pKa soluble substances) d. taste e. stability f. pH g. flavor h. color i. sweetener j. preservative k. viscosity l. compatibility m. if indicated, susp and emulsifying agent 12. Elixirs a. D/ROH-sol in ROH and D/H2O-sol in H2O b. (+) aq ROH w/ stirring - Maintain ROH concn as high as possible 13. Talc a. Removes excess flavouring oils b. 1-2g talc per 100ml solution (ie Aromatic Waters) Filter c. During Filtration, 1st portions are returned to filter until clear soln is obtained

14. Cosolvent systems a. Mxrs of water, ROH, glycerin, PEG b. USE: i. Clarifying agent for hazy and cloudy solns due to insolubility in water 15. Ultrasonic bath a. PRINCIPLE: electronic sound vibrations inc. dissolution rate b. Immerse beaker 16. Inc Dissolution Rate a. Reduce PS b. Stirring c. Inc solubility d. Less viscosity e. Inc Temp (except Ca(OH)2 and methylcellulose) 17. Common Ion Effect Soly of none-yte may be inc or dec by (+) e-yte 18. Alkaloidal base or any Nitrogenous base a. HMW poorly soluble unless pH is dec (Salt) Eg. Atropine SO4 form 19. Inc Soly of POORLY ACIDIC inc pH of medium conversion to SALT 20. Preservatives effectiveness related to pH Parabens: 4-8 Chlorobutanol: <5 Sodium benzoate: =<4 21. Stir smoothly and DONT SHAKE THE PRODUCT to AVOID FOAMING of ENTRAPPED AIR 22. Stir k minimize incompatibilities due to [effects] 23. Awareness of pH and ROH concn 24. FILTERING awareness of residue

SUSPENSIONS 1. Before suspending, comminute powd to very fine state 2. Aqueous susp a. THOROUGHLY WET powd w/ hydrophilic liquid add vehicle 3. Surfactant wetting hydrophobic powd 4. Methylcellulose preparations a. Disperse in of the total V of hot H2O (wetting agent to expand the ing) b. Addition of ice water/ice (completely stop the rxn)

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POLYMERS a. Easy dispersion mix w/ HYDROPHILIC SOLVENT (eg. glycerin) add to aq vehicle b. Sprinkle onto rapidly agitating H2O PACKAGING a. Wide mouth prescription ovals easily poured

12. PlastibaseTM should not be heated Composition: Jelene is composed of 5%LMW polyethylene and 95% mineral oil It is soluble in mineral oil above 90degC Cooled below 90degC, polymer ppts gelation Gel can be heated to about 6odegC w/o substantial loss of consistency Eg. Zinc Oxide Ointment = ZnO + Petrolatum CREAMS 1. Cream bases w/o AI softened in microwave using: a. Low power setting b. Short time 2. Humectant (glycerin, PEG, sorbitol 70%, PEG 300 or 400) minimize evaporation due to inc staying power of cream 3. LOW HEAT minimize evapn of water 4. Volatile oils (+) after cooling 5. ROH solns of flavors cool the prepn below BP of ROH first 6. Whether an emulsion is o/w or w/o TESTS: a. Drop Test / Water Solubility Test i. Gtt of emulsion or cream onto water surface ii. Gtt spreads out o/w since EP is miscible w/ water iii. Gtt remains as a ball w/o b. Spot Test c. Grease Test spreadability d. Washability e. Conductivity i. w/ light: o/w since H2O conducts electricity f. Dye Solubility i. If dye is H2O continuous phase o/w 7. 0.5% - 5% Surfactant for good emulsion 8. 4:2:1 (o:w:g) PASTES 1. Heat improves workability 2. Levigate insoluble powd w/ a qty of melted base Eg. Zinc Oxide Paste contains salicylic acid vs ungt

EMULSIONS 1. D/oil-sol ing in oil phase; w/w 2. M&P a. Light-rapid trituration is better than heavy-slow 3. (+) water & oil phases SLOWLY w/ constant agitation a. If not attained CRACK emulsion 4. In heat, aq phase shld be few deg warmer than oil phase OINTMENTS 1. Powd reduced to impalpable form via comminution (dec PS) 2. Mixtures of two/more ungt plastic bag 3. Ungt from plastic bag placed into tubes by a. cutting one corner of plastic bag b. squeeze contents from bag to ungt tube/jar Simplifies CLEAN-UP 4. Large qts use KITCHEN MIXER 5. Geometric dilution speeds mixing of ungt 6. LIQUID EMULSIONS In mixing oil and aq phases, HEAT AQ PHASE A FEW DEG HIGHER THAN OIL Why? Aq phase cools faster than oil phase 7. Few gtts mineral oil a. Enhance work ability of drugs that build electrostatic forces 8. Ungt bases, heat from HIGHEST MP TO LOWEST MP 9. In pouring liquefied ungt into tubes/jars, COOL ungt just a few deg BEFORE SOLIDIFICATION to minimize layering of ungt in packaging

10. Do not use volatile solvents in levigating powd Why? Solvent will EVAPORATE and LEAVE CRYSTALS OF DRUG BEHIND 11. HEAT a. Soften ungt to make filling easier b. Done w/ CAUTION i. to prevent stratification of ing ii. not to melt ing/ungt

GELS 1. Premix gelling agents (alginic acid) w/ powd aids in dispersion process 2. ROH dec. viscosity and clarity 3. Keep the propeller device @ bottom of cntr minimize incorporation of air into pdt 4. D/agents in vehicle (+)gelling agent 5. Carbomer resins sprinkle slowly into vortex of rapidly-stirred liquid easy dispersion CARBOMER COMPOSITION It is synthetic HMW cross-linked polymer of acrylic acid; composed of 56-68% of COOH grps 6. Remove any entrapped air in Carbomer dispersions (+)thickening agent 7. Air bubble removal 24h in ultrasonic bath or silicone antifoam agent 8. pH det viscosity of Carbomer gels GEL COMPOSITION Phase A 48% water 2% gluconolactone 0.9% tetrasodium EDTA Phase B 48.2% water 0.9% Carbomer 940 9. Bentonite a. Glycerin pre-wet b. Sprinkling in still water c. Allow particles to hydrate d. Settle at bottom 10. Gelatin gels a. D/gelatin in H2O b. Cool or a. Mix gelatin powd w/ org liquid in w/c it will NOT SWELL (EtOH and PEG) b. Add hot water c. Cool gel 11. Tragacanth gels a. EtOH, glycerine, PEG Prewet b. Other powd mized w/ dry tragacanth c. Add powd to vigorously stirred water 12. Natural gums HYDRATE about 24h to form best homogenous gel and/or magma LOTIONS (Emulsion-type) 1. Forbes Bottle Method preparation Simplify cleanup 2. Mechanical propeller mixer (Barnix) Prepare elegant lotions 3. Hand homogenizers 4. Dec globule size, Inc Stability

POWDERS 1. Coffee grinder red PS Cleaned well w/ camels hair brush or Washed w/ soap and water 2. Powd (same PS and Density) mixed in plastic bag using spatula to MINIMIZE qty of powd floating around in compounding area 3. Use DUSTS MASKS for excessively light powd that escapes into work area 4. Too fluffy powd Compacted (+)few gtts ROH, water or mineral oil 5. Magnesium stearate (<1% of total wt of mix) enhance lubrication & flow cxs 6. Sodium lauryl sulfate (up to 1%) neutralize electrostatic forces for powd that tend to fly all over or hard to handle surfactant CAPSULES 1. Cap-filling devices 50, 100, 300 time savers for large qts Hand operated CFD: max of 30 caps 2. Fewer than capacity of cap COVER remaining holes using stiff cardboard (index cards) 3. Colored: (+)dye to powd before placing in clear cap distinguish strengths 4. Liquids in cap by a. mixing w/ PEG 6000, 8000 b. Mixture is poured into cap solidify c. Closed 5. Liquid dispensed in cap a. Use syringe to drop liq into cap bases b. The liq must not be a solvent for the gelatin (such as oils) or a. Oil is mixed w/ fat or FA, cocoa butter, Fattibase b. Slightly heated c. Mix d. Pour into cap 6. Sealing of cap a. Moist open, outer edge of cap base or inner edge of cap cap b. Heat cap w/ ROH c. Cool d. Slight twist will improve seal 7. Cleaning of cap a. Use soft cloth or towel or a. Place in a large container full salt, sugar or sodium bicarbonate b. Capsules are added to cntr, then rotate

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Separate cap from coarse granular matl a. Pour thru a sieve large enough to allow salt/sugar/sodium bicarbonate to pass thru but retain cap 9. Sodium lauryl sulfate (up to 1%) (+)powd to neutralize electrostatic forces 10. Two incompatible ing are separated a. Place one inside a very small cap larger Eg. veterinary capsules 11. Small tabs of potent drugs + other ing cap 12. Locking capsules a. Minimize loss of contents b. Work well with hand-operated capsule filling machines OPHTHALMICS 1. Inventory of sterile dropper bottles save time by eliminating the need to sterilize cntnrs 2. Small, disposable sterile filters prepare small volumes 3. Larger, funnel type sterilization filters large volumes (100-200mL) SUPPOPSITORIES 1g = Pedia 3g = Adults 1. k Temp dry bath w/ sand (hold more heat than water; dessication of heat to become k) @ 37degC will provide proper temp for softening and melting FA and cocoa butter bases in minimum time Powd in impalpable form (uniform PS; diff to feel) incorporate to base Supp molds clean, dry ease release of sup Lubricant a. prevent sticking b. reusable molds c. not a solvent for sup base d. glycerine veg oil/cocoa butter as base e. mineral oil or PAM veg spray PEG Hand molding a. Dust small quantity of talc onto hands & pill tile enhance workability of matl Melts be poured in molds equilibrated at RT. Pouring in cold molds a. incompletely filled cavities b. supp fracture easily Pouring supp, start at one end & pour continuously w/o stopping. Small excess should be piled up so the cavity becomes full when cooled and contracted

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Max qty of drug + excipients incorporated into supp is 30% of the total wt Eg. Dulcolax Bisacodyl 10mg Glycerin 2.1g Plastic disposable molds !!! Temp of Melt should be lower than that which will melt the mold Excess matl removed from molds is removed: a. Dipping stainless steel spatula in warm water b. Cut, trim excess c. Smooth the back of supp Urethral supp a. Straw/Thin glass tube as mold b. 1 ml tuberculin syringe as mold (lower portion of barrel is cut off) c. Supp is removed from syringe barrel by inserting plunger d. Force the supp out after slight warning e. Large diameter needle, attached to large syringe filled w/ supp melt aids in transfer of pdt into 1ml tuberculin syringe Elegantly packaged: disposable molds Veg extracts (moistened by levigation w/ small qty of base) readily distribute throughout base Pulverize finely hard, crystalline matls or dissolve it in small qty solvent + base Liq ing + powd (eg. starch) a. Less fluid b. Easier to incorporate into base Large qty of powd dampened w/ few gtts of bland oil (mineral oil, water miscible liq: glycerin) easy incorporation to some bases

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TROCHES/LOZENGES 1. (+)Flavoring oil immiscible in base (+)glycerine/intermediate solvent to oil Principle of Cosolvent System 2. Soft lozenges PEG base 3. Chewable glycerine gelatin base 4. Hard sucrose syrup base 5. Troche molds are unavailable a. Use plastic snap cap from a plastic vial as mold b. Apply veg spray to cap c. Pour prepn to cap d. Solidify e. Cap is peeled away from troche or

a. b. c.

Melt dropped to heavy sheet of Al foil placed on a bed of ice cubes Drops immediately solidify in circular form Check wts

SOLUTIONS - homogeneous mixture composed of only one phase. In such a mixture, a solute is a substance dissolved in another substance, known as a solvent SUSP - heterogeneous mixture in which solute-like particles settle out of a solvent-like phase EMULSION - two phase system in w/c one liquid is dispersed in the form of small globules throughout another liquid in w/c it is immiscible UNGT - semisolid DF intended for external administration in skin or MM which may be medicated or unmedicated CREAMS - semisolid DF w. one/more medicinal agents D/D in either w/o or o/w emulsion or in another type of waterwashable base PASTES - semisolid DF applied to skin and contain larger proportion of solid matl than ungts stiffer GELS - semisolid systems whose dispersions is made up of either small inorg prtcls or large org mol enclosing and interpenetrated by liq LOTIONS - thick, smooth liquid preparation applied to the skin for medicinal or cosmetic purposes POWDERS - Fine dry particles produced by the grinding, crushing, or disintegration of a substance CAPSULES - small, soluble case of gelatin containing a dose of medicine, swallowed whole OPHTHALMICS - sterile prepartions administered to eye and its parts SUPPOSITORIES - solid DF inserted to body orifices where they melt, soften or dissolve and exert local or systemic effects

FLAVORING/COLORING 1. Drugs w/ objectionable taste prepared as susp or incorporated to int phases of emulsions w/ flavouring tovehicle to inc palatability 2. COMPLEMENTARY AGREEMENT Color = Flavor = Smell Eg. red = cherry; brown = chocolate 3. Effervescence mask salty drugs MISCELLANEOUS 1. SAME qty of liquid = REPETING PIPETTOR 2. Micropipets: very small volumes 3. Computerized databases for formulas and compounding record enhance compounding process 4. Master Formulas w/ instructions promte consistency 5. Large qts refer samples to analytical lab 6. Electronic balances are better than torsion balances a. Speed up weighing b. Allow Rxist to check rapidly c. Printers attached hard copy recording 7. Beakers w/ handles make manipulations easier when heat is used in preparation 8. Hot plates w/ magnetic stirrers versatile & save time 9. Magnetic mixers mix 4 or more beakers of soln simultaneously 10. LIGHT BOX (conveyor placed agst light) a. Observe clarity of solns, b. Turbidity and uniformity susp, c. Fill levels of supp plastic molds SUMMARY Methods and techniques 1. Job easier 2. More efficient 3. Improve Pt care Phi Delta Chi motto - Each Needs the Help of the Other