COMPOUNDING CHAPTER 8

CHAPTER OUTLINE Compounding Regulations Stability & Beyond-Use Dates Compounding considerations Equipment Using a Balance Volumetric Equipment Measuring Liquids Mixing Solids and Semisolids Compounding Select Dosage Forms Aqueous Solutions Syrups Nonaqueous Solutions Suspensions Flavoring Sweeteners Coloring Emulsions & Emulsifiers Ointments Suppositories Capsules Tablets Review

COMPOUNDING Chapter Outline Compounding Regulations Stability and Beyond-Use Dates Compounding Considerations Equipment Using a Balance Volumetric Equipment Measuring Liquids Mixing Solids and Semisolids Compounding Select Dosage Forms

WHY COMPOUND? Pediatric patients requiring diluted adult strengths of drugs Patients needing an oral solution or suspension of a product that is only available in another form Patients with sensitivity to dyes, preservatives, or flavoring agents found in commercial formulations Dermatological formulations with fortified (strengthened) or diluted concentrations of commercially available products Specialized dosages for therapeutic drug monitoring Care for hospice patients in pain management Compounding for animals

COMPOUNDING Compounding Manufacturing On-demand preparation of a drug product According to a physician’s prescription Meets the unique needs of an individual patient Manufacturing Production or processing of a drug or device Packaging or labeling for re-sale to pharmacies or practitioners

REGULATION OF COMPOUNDING Compounding is regulated by the individual states’ boards of pharmacy. USP-NF has federal authority to set standards pertaining to pharmacy compounding and manufacturing. Some states accept the USP-NF standards as their standards. Some states do not.

REGULATION OF COMPOUNDING USP-NF is a resource published yearly. USP-NF Chapters are assigned numbers Chapters numbered below 1,000 are legally enforceable by the FDA. Chapters numbered above 1,000 are informational chapters. Enforcement of USP-NF chapters by the FDA - not always clear-cut (jurisdiction resides with the states) Case-by-case basis

REGULATION OF COMPOUNDING The USP-NF also publishes monographs of commonly compounded preparations Stability information Beyond-use dates

REGULATION OF COMPOUNDING USP-NF standards cover Personnel Facilities and Equipment Ingredient Standards Quality Assurance and Quality Control Packaging and Storage Documentation and Record Keeping Many more…

DOCUMENTATION AND RECORD KEEPING Formulation record what should happen when the formula is compounded Compounding Record what actually happened when the formulation was compounded Standard Operating Procedures equipment maintenance and calibration, handling and disposal of supplies, etc Ingredients Record certificates of purity from commercial vendors Material Safety Data Sheets (MSDS)

STABILITY AND BEYOND-USE-DATES The extent to which a dosage form retains the same properties and characteristics it possessed at the time it was made Expiration date The date until which the manufacturer can guarantee the safety and full potency of a drug determined after extensive study of the product’s stability Beyond-use dates Used for compounded preparations only and are generally in the order of “days” or “months”

USP-NF RECOMMENDED BEYOND-USE DATES* Topical, dermal, mucosal liquid or semisolid formulations containing water not later than 30 days Oral formulations containing water not later than 14 days stored at a controlled cold temperature Nonaqueous formulations the earliest expiration date of any active principle ingredient (API) or 6 months, whichever is earlier *default dates if no other information is available

CONSIDERATIONS IN COMPOUNDING Whether to compound Is there a commercial product? Before beginning Are there appropriate personnel and equipment? Prepare a formulation record. During compounding Compound according to formulation record. Complete a compounding record. After compounding Recheck all work. Perform required equipment maintenance.

TYPES OF EQUIPMENT Measuring Mixing Molding Packaging balance, weights, weigh boats, volumetric glassware (graduates, pipets, flasks, syringes) Mixing beakers, Erlenmeyer flasks, spatulas, funnels, sieves, mortar and pestle Molding hot plates, suppository molds, capsule shells, ointment slabs, tablet molds Packaging prescription bottles, capsule vials, suppository boxes, ointment jars

BALANCES Types Reasons to accurately weigh Class A torsion balance Electronic balance Reasons to accurately weigh One of the most essential parts of the compounding process The product cannot be “checked” for content once dispensed to the patient. The quantities weighed are often very small, and a error could mean an incorrect dosing of the patient.

CLASS A TORSION BALANCE A two pan balance that uses both internal and external weights Weights go on the right pan Weighted material on the left pan Sensitivity: 6 mg or less Capacity: 60 g or 120g Weights brass weights: 1 g to 50 g fractional weights: 10mg to 500mg Image copyright Perspective Press and Morton Publishing Company. May not be copied, re-used, reproduced, or re-transmitted without express written permission from the publisher.

Using a Class A Torsion Balance Place on a level surface in a draft free area. Level front-to-back and left-to-right. Use clean weigh papers or boats with each new material. Arrest the balance before adding or removing weight or material. Use a spatula; do not pour from a bottle. Clean balance after use.

USING AN ELECTRONIC BALANCE Place on a level surface in a draft free area. Level front-to-back and left-to-right. Turn on the balance; if first use of the day, check internal weight calibration. Use clean weigh papers or boats with each new material Use a spatula: it may be necessary to remove the draft shield to introduce or remove material. Clean balance after use. Turn off balance at end of day.

VOLUMETRIC EQUIPMENT Non-volumetric Glassware Volumetric Glassware Erlenmeyer flasks beakers prescription bottles Volumetric Glassware graduated cylinders volumetric flasks pipets syringes burets Image copyright Perspective Press and Morton Publishing Company. May not be copied, re-used, reproduced, or re-transmitted without express written permission from the publisher.

MEASURING LIQUIDS Selecting a liquid measuring device Choose the smallest one capable of containing the volume to be measured. Avoid measurements of volumes that are below 20 percent of the capacity of the device. Example: a 100 ml graduated cylinder cannot accurately measure volumes below 20 ml. When measuring small volumes, use a syringe or pipet. Liquids have a meniscus. Image copyright Perspective Press and Morton Publishing Company. May not be copied, re-used, reproduced, or re-transmitted without express written permission from the publisher.

LIQUID MEASURING DEVICES Droppers Graduated cylinders Single volume pipets Calibrated pipets Syringes Oral syringes

MEASURING LIQUIDS Graduated cylinders Cylindrical graduates are more accurate than conical graduates. Pour liquids into the center of the graduate. Allow 15 seconds for aqueous and hydroalcoholic liquids to drain from graduate. Allow 60 seconds for syrups, glycerin, other viscous liquids. Image copyright Perspective Press and Morton Publishing Company. May not be copied, re-used, reproduced, or re-transmitted without express written permission from the publisher.

MEASURING LIQUIDS Droppers Used to deliver small doses of liquid medication Medicine dropper must first be calibrated The drop size will vary from dropper to dropper. Personal factors will contribute to dropper inaccuracy. Image copyright Perspective Press and Morton Publishing Company. May not be copied, re-used, reproduced, or re-transmitted without express written permission from the publisher.

MEASURING LIQUIDS Calibrated Pipet Single Volume Pipets Images copyright Perspective Press and Morton Publishing Company. May not be copied, re-used, reproduced, or re-transmitted without express written permission from the publisher.

MEASURING LIQUIDS Syringes Hypodermic or oral Range from 0.5 ml to 60 ml Always choose smallest size capable of containing the volume to be measured. Oral syringes can be used with an Adapt-a-Cap®. Image copyright Perspective Press and Morton Publishing Company. May not be copied, re-used, reproduced, or re-transmitted without express written permission from the publisher.

MIXING SOLIDS AND SEMISOLIDS Mortar and Pestle Glass – mixing liquids and semisolids Wedgwood Porcelain Trituration The process of grinding powders to reduce the particle size. for triturating crystals and large particles Image copyright Perspective Press and Morton Publishing Company. May not be copied, re-used, reproduced, or re-transmitted without express written permission from the publisher.

MIXING SOLIDS AND SEMISOLIDS Mixing powders/geometric dilution Spatulation Ointment slabs Levigation Electronic mortar and pestle Ointment mill

MIXING POWDERS – GEOMETRIC DILUTION When mixing powders of unequal size, the smaller amount powder is triturated with an equal amount of the larger amount powder. That mixture is then mixed with an equal amount of the larger amount powder. The process is repeated until the mixture is completed. Images copyright Perspective Press and Morton Publishing Company. May not be copied, re-used, reproduced, or re-transmitted without express written permission from the publisher.

OINTMENT SLAB An ideal surface for mixing compounds because of its nonabsorbent surface. Image copyright Perspective Press and Morton Publishing Company. May not be copied, re-used, reproduced, or re-transmitted without express written permission from the publisher.

SPATULAS Spatulas Types used to transfer solid ingredients, prepare ointments and creams, or loosening material from the surfaces of a mortar and pestle Types stainless steel hard rubber plastic Image copyright Perspective Press and Morton Publishing Company. May not be copied, re-used, reproduced, or re-transmitted without express written permission from the publisher.

SPATULATION Mixing powders using a spatula Can be done in a mortar, on an ointment slab, or in a plastic bag. Images copyright Perspective Press and Morton Publishing Company. May not be copied, re-used, reproduced, or re-transmitted without express written permission from the publisher.

LEVIGATION Reduces particle size of a powder drug by triturating it with a solvent in which the drug is insoluble Images copyright Perspective Press and Morton Publishing Company. May not be copied, re-used, reproduced, or re-transmitted without express written permission from the publisher.

MIXING LARGE QUANTITIES Electronic mortar and pestle blade assembly inside a plastic mixing jar length of time and speed of mixing can be varied Ointment mill achieves very uniform particle size in formulations gives smoothness and elegance

SOLUTIONS Clear (but not necessarily colorless) liquids in which the drug is completely dissolved The solubility of the drug must be known before attempting to dissolve it in a solution. Some solids need to be triturated before mixing into a solution. Image copyright Perspective Press and Morton Publishing Company. May not be copied, re-used, reproduced, or re-transmitted without express written permission from the publisher.

SOLUTIONS Syrups – concentrated sucrose solution in water Nonaqueous solutions Dissolve alcohol soluble ingredients in alcohol, and water soluble ingredients in water. Add water solution to the alcohol solution. Elixir Glycerates Tincture Collodions Spirit Liniment Fluid extract Oleaginous solutions

SUSPENSIONS A two phase system consisting of a finely divided solid dispersed in a liquid Flocculating agent electrolytes used in the preparation of suspensions to form particles that can be easily redispersed Thickening agent ingredient used in the preparation of suspensions to increase the viscosity of the liquid

ADDITIVES Flavoring The human tongue can distinguish salty, bitter, sour, and sweet tastes. Sweeteners Colorless, odorless, solubility in water at the concentrations needed for sweetening, pleasant tasting with no “after-taste,” and stable over a wide pH range Coloring Not required in every formulation Contraindicated in all sterile solutions Dark colors may be rejected because they are often associated with poisons

EMULSIONS Unstable system consisting of an oil and water One is dispersed in the form of small droplets throughout the other. Oil-in-water (o/w) emulsion Water-in-oil (w/o) emulsion Emulsifier tragacanth, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, and polymers known as the Spans® and Tweens® Images copyright Perspective Press and Morton Publishing Company. May not be copied, re-used, reproduced, or re-transmitted without express written permission from the publisher.

EMULSIONS Methods of preparation – requires energy input Dry Gum method – primary emulsion 4:2:1 – gum + oil then water Wet Gum method – mucilage 4:2:1 – gum + water then oil Beaker method water soluble and oil soluble ingredients heated in different beakers add internal phase to external phase

OINTMENTS Used for many different purposes protectants antiseptics emollients antipruritics Methods to compound ointments incorporate drug into ointment base create the ointment base as part of compounding

SUPPOSITORIES Oleaginous primarily synthetic triglycerides e.g., FattiBase®, Witepsol® Water soluble glycerinated gelatin dissolve slowly to provide prolonged release of active ingredients polyethylene glycols (PEGs) 200, 400, or 600 molecular weight are liquids over 1,000 molecular weight are solids Hydrophilic mixtures of oleaginous and water soluble bases Image copyright Perspective Press and Morton Publishing Company. May not be copied, re-used, reproduced, or re-transmitted without express written permission from the publisher.

SUPPOSITORIES Ways to compound suppositories compression molding fusion molding Suppository molds metal (steel, aluminum) plastic rubber Image copyright Perspective Press and Morton Publishing Company. May not be copied, re-used, reproduced, or re-transmitted without express written permission from the publisher.

CAPULES Hard gelatin capsules consist of a body and a cap which fits firmly over the body of the capsule. 8 sizes available for human use Sizes Volume (ml) 000 1.37 00 0.95 0 0.68 1 0.50 2 0.37 3 0.30 4 0.20 5 0.13 Image copyright Perspective Press and Morton Publishing Company. May not be copied, re-used, reproduced, or re-transmitted without express written permission from the publisher.

PUNCH METHOD* *used when filling a small number of capsules Images copyright Perspective Press and Morton Publishing Company. May not be copied, re-used, reproduced, or re-transmitted without express written permission from the publisher.

CAPSULES – ADDITIONAL COMPOUNDING TIPS To avoid finger prints on the capsules, use a cap as a holder, or use finger cots. Liquids that do not dissolve gelatin can be dispensed in capsules. fixed oils Tablets and smaller capsules can be placed inside of a capsule. reduces the number of single dosage forms

MOLDED TABLETS Tablet base is a combination of lactose, dextrose, sucrose, or mannitol Ingredients in base are slightly dissolved with a wetting solution (alcohol: water) Pressed into a tablet triturate mold must be calibrated Image copyright Perspective Press and Morton Publishing Company. May not be copied, re-used, reproduced, or re-transmitted without express written permission from the publisher.

TABLETS – OTHER COMPOUNDED TABLETS Single punch tablet machine chewable, effervescent, compressed tablets Rapid dissolve tablets (RDT) disintegrate or dissolve within minutes on tongue ingredients are very water soluble Image copyright Perspective Press and Morton Publishing Company. May not be copied, re-used, reproduced, or re-transmitted without express written permission from the publisher.