The Pharmacy The Pharmacy Technician 4ETechnician 4E

Chapter 9Chapter 9CompoundingCompounding

Chapter OutlineChapter Outline

CompoundingCompounding Compounding RegulationsCompounding Regulations Compounding ConsiderationsCompounding Considerations Stability and Beyond-Use DatesStability and Beyond-Use Dates EquipmentEquipment Using a BalanceUsing a Balance Volumetric EquipmentVolumetric Equipment Mixing Solids and SemisolidsMixing Solids and Semisolids Select Dosage FormsSelect Dosage Forms

CompoundingCompounding

Extemporaneous compounding Extemporaneous compounding On-demand preparation of a drug product.On-demand preparation of a drug product. According to a physician’s prescription.According to a physician’s prescription. Meets the unique needs of an individual patient.Meets the unique needs of an individual patient.

ManufacturingManufacturing The production or processing of a drug in a LARGE The production or processing of a drug in a LARGE

quantity by various mechanisms.quantity by various mechanisms.

Why Compound?Why Compound?

Pediatric patients Pediatric patients requiring diluted adult strengths of drugs.requiring diluted adult strengths of drugs. Patients Patients needing an oral solution needing an oral solution or suspension of a product or suspension of a product

that is only available in another form.that is only available in another form. Patients with Patients with sensitivity to dyessensitivity to dyes, preservatives, or flavoring , preservatives, or flavoring

agents found in commercial formulations.agents found in commercial formulations. Dermatological formulations Dermatological formulations with fortified (strengthened) or with fortified (strengthened) or

diluted concentrations of commercially available products.diluted concentrations of commercially available products. Specialized dosages for therapeutic drug monitoring.Specialized dosages for therapeutic drug monitoring. Care for Care for hospice patients hospice patients in pain management.in pain management. Compounding forCompounding for animals. animals.

The U.S. Pharmacopeia (USP)The U.S. Pharmacopeia (USP)

Established in the 1906 Pure Food and Drugs Act. Established in the 1906 Pure Food and Drugs Act. Has the federal authority to set standards Has the federal authority to set standards

pertaining to pharmacy compounding. pertaining to pharmacy compounding. Develops Develops STANDARDS STANDARDS where various topics are where various topics are

grouped into grouped into “CHAPTERS.” “CHAPTERS.” Publishes its standards in the resource book called Publishes its standards in the resource book called

the the USP/NF. USP/NF.

The U.S. Pharmacopeia (USP) Cont.The U.S. Pharmacopeia (USP) Cont.

Chapters are assigned numbers.Chapters are assigned numbers. Chapters numbered below Chapters numbered below 1000 are legally 1000 are legally

enforceable by the FDA.enforceable by the FDA. The USP/NF has over 60 chapters.The USP/NF has over 60 chapters. The USP also publishes The USP also publishes MONOGRAPHS MONOGRAPHS of the most of the most

commonly compounded preparations used in commonly compounded preparations used in practice.practice.

ChaptersChapters Chapters <795> Chapters <795> - called - called Pharmaceutical Compounding Pharmaceutical Compounding

- Nonsterile Preparations- Nonsterile Preparations Published in 2000Published in 2000 EnforceableEnforceable

Chapter <797> Chapter <797> - called - called Pharmaceutical Compounding - Pharmaceutical Compounding - Sterile Preparations, Sterile Preparations, Became official in 2004. Became official in 2004.

Other ChaptersOther Chapters Containers <661>Containers <661> Good Compounding Practices <1075>Good Compounding Practices <1075> Pharmaceutical Stability <1150> Pharmaceutical Stability <1150> Pharmaceutical Dosage Forms <1151>Pharmaceutical Dosage Forms <1151>

Compounding Regulations AppliesCompounding Regulations Applies

PersonnelPersonnel Facilities and EquipmentFacilities and Equipment Ingredient StandardsIngredient Standards Quality Assurance and Quality ControlQuality Assurance and Quality Control Packaging and StoragePackaging and Storage Documentation and Record KeepingDocumentation and Record Keeping

Ingredient StandardsIngredient Standards USP/NFUSP/NF

Meets standards set by the USP/NF.Meets standards set by the USP/NF. ACS reagent ACS reagent

High purityHigh purity Meets specifications of the Reagent Chemicals Meets specifications of the Reagent Chemicals

Committee of the American Chemical Society.Committee of the American Chemical Society. AR (analytical reagent) AR (analytical reagent)

Very high purity.Very high purity. HPLC HPLC

Very high purity.Very high purity. Used in high pressure chromatography.Used in high pressure chromatography.

Record KeepingRecord Keeping

Formulation Record Formulation Record Formulas and procedures (i.e., recipes) for what Formulas and procedures (i.e., recipes) for what

should happen when a formulation is compounded.should happen when a formulation is compounded. Compounding Record Compounding Record

A record of what actually happened when the A record of what actually happened when the formulation was compounded.formulation was compounded.

Standard Operating Procedures (SOPs) Standard Operating Procedures (SOPs) Equipment maintenance, equipment calibration, Equipment maintenance, equipment calibration,

handling and disposal of supplies, etc.handling and disposal of supplies, etc. Material Safety Data Sheets MSDSsMaterial Safety Data Sheets MSDSs

Ingredients records with certificates of purity.Ingredients records with certificates of purity.

Storage Temperature DefinitionsStorage Temperature Definitions

Freezer =Freezer = Protect from Freezing =Protect from Freezing = Cold =Cold =

Refrigerator =Refrigerator = Cool =Cool = Room Temperature =Room Temperature = Controlled Room Temperature =Controlled Room Temperature =

Warm =Warm = Excessive Heat =Excessive Heat =

-20°C to -10°C-20°C to -10°C Store above 0°CStore above 0°C Any temperature not exceeding Any temperature not exceeding

8°C8°C Between 2°C and 8°CBetween 2°C and 8°C Between 8°C and 15°CBetween 8°C and 15°C Temperature in the work areaTemperature in the work area Thermostatically controlled at Thermostatically controlled at

20°C to 25VC20°C to 25VC Between 30° and 40°CBetween 30° and 40°C Any temperature above 40°Any temperature above 40°

StabilityStability StabilityStability

The extent to which a dosage form retains the same The extent to which a dosage form retains the same properties and characteristics that it possessed at the time properties and characteristics that it possessed at the time of its manufacture.of its manufacture.

Expiration date Expiration date The date until which the manufacturer can guarantee of The date until which the manufacturer can guarantee of

the safety and full potency of a drug- usually determined the safety and full potency of a drug- usually determined after extensive study of the product’s stability. after extensive study of the product’s stability.

Beyond-use dates Beyond-use dates Used for compounded preparations only and are generally Used for compounded preparations only and are generally

in the order of “days” or “months.”in the order of “days” or “months.” Shelf life Shelf life

Length of time a packaged drug will last without Length of time a packaged drug will last without deteriorating deteriorating

Assigning a Beyond-Use DateAssigning a Beyond-Use Date Nonaqueous liquids and solid formulationsNonaqueous liquids and solid formulations

If the source of the active drug is a manufactured drug If the source of the active drug is a manufactured drug product, the beyond-use date is not later than 25% of the time product, the beyond-use date is not later than 25% of the time remaining until the drug product’s expiration date, or 6 remaining until the drug product’s expiration date, or 6 months, whichever is earlier.months, whichever is earlier.

If the source of the active drug is a USP or NF substance, the If the source of the active drug is a USP or NF substance, the beyond-use date is not later than 6 months.beyond-use date is not later than 6 months.

Water containing formulationsWater containing formulations When prepared from ingredients in solid form, the beyond-When prepared from ingredients in solid form, the beyond-

use date should be not later than 14 days when stored at cold use date should be not later than 14 days when stored at cold temperature.temperature.

For all other formulationsFor all other formulations The beyond-use date is not later than the intended duration The beyond-use date is not later than the intended duration

of therapy or 30 days, whichever is earlier.of therapy or 30 days, whichever is earlier.

Types of EquipmentTypes of Equipment

MeasuringMeasuring Balance, weights, Balance, weights,

weighing containers, weighing containers, volumetric glassware volumetric glassware (graduates, pipets, flasks, (graduates, pipets, flasks, syringes).syringes).

Mixing Mixing Beakers, Erlenmeyer Beakers, Erlenmeyer

flasks, spatulas, funnels, flasks, spatulas, funnels, sieves, mortar and pestle.sieves, mortar and pestle.

Molding Molding Hot plates, suppository Hot plates, suppository

molds, capsule shells, molds, capsule shells, ointment slabs.ointment slabs.

Packaging Packaging Prescription bottles, Prescription bottles,

capsule vials, suppository capsule vials, suppository boxes, ointment jars.boxes, ointment jars.

Class “A” Balance ScaleClass “A” Balance Scale A A two pan torsion two pan torsion that uses both internal and external weights. that uses both internal and external weights. Weights go on the right pan and powder on the left pan. Weights go on the right pan and powder on the left pan. SensitivitySensitivity: up to 6mg: up to 6mg Capacity:Capacity: 120mg to 60gms120mg to 60gms Degree of error:Degree of error: 5%5% Weights:Weights: 1gm to 50gms 1gm to 50gms

fraction weights 10mg to 500mgfraction weights 10mg to 500mg Electronic or Analytical BalanceElectronic or Analytical Balance

Using a BalanceUsing a Balance

1.1. Place on a level surface in a draft free area.Place on a level surface in a draft free area.2.2. Use clean weighting papers or boats.Use clean weighting papers or boats.3.3. Must be readjusted after a new paper or boat has Must be readjusted after a new paper or boat has

been placed on the pan.been placed on the pan.4.4. Arrest the balance before adding or removing Arrest the balance before adding or removing

weight.weight.5.5. Use a spatula.Use a spatula.6.6. Clean the balance.Clean the balance.

Using an Electronic BalanceUsing an Electronic Balance

1.1. Keep balance where it will Keep balance where it will not be moved.not be moved.

2.2. Turn the leveling feet.Turn the leveling feet.

3.3. Turn on the Turn on the balancebalance..4.4. First use of the day, check First use of the day, check

internal weight calibration.internal weight calibration.5.5. Removed top ring of the Removed top ring of the

draft shield. Place weighing draft shield. Place weighing boat in the center.boat in the center.

6.6. Add ingredientsAdd ingredients7.7. Clean spills with a lint-free Clean spills with a lint-free

towelette.towelette.8.8. Turn off balance at the end Turn off balance at the end

of the day.of the day.

Using a Prescription BalanceUsing a Prescription Balance

1. Lock the Balance by turning 1. Lock the Balance by turning the the arrest knobarrest knob..

2. Set the internal weights to 2. Set the internal weights to zero.zero.

Using a Prescription BalanceUsing a Prescription Balance

3. Unlock the balance and 3. Unlock the balance and level it level it leftleft to to rightright..

4. Lock the balance. Place a 4. Lock the balance. Place a weighing boat or paper.weighing boat or paper.

5. Unlock the balance by 5. Unlock the balance by releasing the arrest knob.releasing the arrest knob.

Using a Prescription BalanceUsing a Prescription Balance

6. Lock the balance and place 6. Lock the balance and place the required weights in the required weights in the boat.the boat.

7. Unlock the balance and 7. Unlock the balance and note the shift of the note the shift of the pointer.pointer.After an accurate After an accurate measurement is made, measurement is made, check your work.check your work.

Reason for Accurate WeighingReason for Accurate Weighing• Weighing of the product is one of the most essential

parts of the compounding process. • Weighing the exact amount prescribed is essential in

compounds for several reasons: • The product cannot be “checked” for content once

mixed.• The quantities weighed out are often very small,

and a slight overage could mean a serious overdose for the patient.

SpatulasSpatulas

• Spatulas • Used to transfer solid ingredients or prepare

ointments and creams or loosening material from the surfaces of a mortar and pestle.

• Types• Stainless steel • Hard rubber• Plastic

• Forceps should be used when picking up weights so that moisture and oils are not transferred to the weights.

SpatulationSpatulation

Mixes powders using a spatula.Mixes powders using a spatula.

Mixing can be done in a mortar, Mixing can be done in a mortar, on an ointment slab, or in a on an ointment slab, or in a plastic bag.plastic bag.

Mortar and PestleMortar and PestleMortar and PestleMortar and Pestle

• The coarser the surface of the mortar and pestle, The coarser the surface of the mortar and pestle, the finer the triturating, or grinding, that can be the finer the triturating, or grinding, that can be done.done.

Types Types • GlassGlass• WedgwoodWedgwood• PorcelainPorcelain

TriturationTrituration• The process of grinding powders to reduce the The process of grinding powders to reduce the

particle size.particle size.

Compounding SlabCompounding Slab

This is an ideal surface for mixing compounds because of its This is an ideal surface for mixing compounds because of its nonabsorbent surface.nonabsorbent surface.

Levigation Levigation Technique used to reduce the particle size of a powder Technique used to reduce the particle size of a powder

drug by triturating it with a solvent in which the drug is drug by triturating it with a solvent in which the drug is insoluble.insoluble.

Volumetric EquipmentVolumetric Equipment

GraduatesGraduates FlasksFlasks PipetsPipets SyringesSyringes

DroppersDroppers GraduatesGraduates PipettesPipettes SyringesSyringes Oral syringesOral syringes

Volumetric EquipmentVolumetric EquipmentGraduated CylindersGraduated Cylinders

Cylindrical and cone shaped.Cylindrical and cone shaped. Used for measuring and transferring liquids. Used for measuring and transferring liquids. Available in sizes ranging from 5 ml to 4,000 ml. Available in sizes ranging from 5 ml to 4,000 ml. Selecting a graduated cylinder.Selecting a graduated cylinder.

Choose the smallest one capable of containing the volume Choose the smallest one capable of containing the volume to be measured. to be measured.

Rule: Avoid measurements of volumes that are below 20 Rule: Avoid measurements of volumes that are below 20 percent of the capacity of the graduated cylinder.percent of the capacity of the graduated cylinder.

Example, a 100 ml graduated cylinder cannot Example, a 100 ml graduated cylinder cannot accurately measure volumes below 20 ml. accurately measure volumes below 20 ml.

When measuring small volumes, such as 20 ml and less, use a When measuring small volumes, such as 20 ml and less, use a syringe or pipet.syringe or pipet.

GraduatesGraduates

conical graduate cylindrical graduate

correct level

incorrect level

reading a graduate

meniscus

Small Volumetric EquipmentSmall Volumetric Equipment

Calibrated pipette

Single volume pipettes

Measure volume to edge of stopper.

Syringe

Volumetric EquipmentVolumetric Equipment SyringesSyringes

Range Range from 0.5 ml to 60 ml and in a variety of from 0.5 ml to 60 ml and in a variety of materials and styles. materials and styles.

Contain Contain graduation marks graduation marks on the barrel for on the barrel for measuring partial volumes.measuring partial volumes.

A A disposable hypodermic syringe disposable hypodermic syringe or an oral syringe or an oral syringe made of plastic is used for most compounding tasks made of plastic is used for most compounding tasks involving small volumes.involving small volumes.

Always Always choose the smallest syringechoose the smallest syringe capable of capable of containing the volume to be measured.containing the volume to be measured.

Liquid MeasurementLiquid MeasurementDroppersDroppers

Used to deliver small doses of liquid Used to deliver small doses of liquid medication. medication.

Medicine dropper must first be calibrated Medicine dropper must first be calibrated becausebecause The drop size will vary from dropper The drop size will vary from dropper

to dropper.to dropper. Personal factors can also contribute to Personal factors can also contribute to

the inaccuracy of droppers.the inaccuracy of droppers.

Measuring Liquid VolumesMeasuring Liquid Volumes

•Pour the liquid to be measured slowly into the graduate, watching the level of the liquid in the graduate as you do so.

•If the liquid is viscous, or thick, then you should attempt to pour it toward the center of the graduate to avoid having some of the liquid cling to the sides.

Liquid MeasurementLiquid MeasurementOral SyringesOral Syringes

Available for accurately administering liquid medication to the Available for accurately administering liquid medication to the patient. patient.

Have tips that are larger than tips on hypodermic syringes so Have tips that are larger than tips on hypodermic syringes so needles cannot be placed on these syringes. needles cannot be placed on these syringes.

After the dose is drawn into the syringe, a cap is placed on the After the dose is drawn into the syringe, a cap is placed on the tip to prevent leakage and prevent contamination.tip to prevent leakage and prevent contamination.

Oral syringes can be used with a device called an Oral syringes can be used with a device called an Adapt-a-Cap®Adapt-a-Cap® An example of an oral syringe cap the screws onto the bottle An example of an oral syringe cap the screws onto the bottle

containing the liquid, and the oral syringe is fitted into the containing the liquid, and the oral syringe is fitted into the other side of the cap.other side of the cap.

Mixing Powders - Geometric Mixing Powders - Geometric DilutionDilution

When mixing powders of unequal size, the smaller amount is mixed (triturated) with an equal amount of the other. That mixture is then mixed with an equal amount of the larger amount powder. This process is repeated until the mixture is completed.

SolutionsSolutions

The most commonly compounded The most commonly compounded products.products.

CClearlear (but not necessarily (but not necessarily colorless) colorless) liquids liquids in which the drug in which the drug is completely dissolved.is completely dissolved.

TheThe solubilitysolubility of the drug must be of the drug must be known before attempting to known before attempting to dissolve it in a solution. If a drug is dissolve it in a solution. If a drug is not soluble in a vehicle, then no not soluble in a vehicle, then no amount of mixing will help.amount of mixing will help.

Some solids need to be Some solids need to be triturated triturated before mixing in a solution.before mixing in a solution.

SuspensionSuspension A two phase system consisting of a A two phase system consisting of a

finely divided solid dispersed in a liquid.finely divided solid dispersed in a liquid. Flocculating AgentFlocculating Agent

Electrolytes used in the preparation Electrolytes used in the preparation of suspensions to form particles that of suspensions to form particles that can be easily redispersed.can be easily redispersed.

Thickening Agent Thickening Agent Ingredient used in the preparation of Ingredient used in the preparation of

suspensions to increase the viscosity suspensions to increase the viscosity of the liquid.of the liquid.

AdditivesAdditives FlavoringFlavoring

The human tongue contains about 10,000 taste buds The human tongue contains about 10,000 taste buds which distinguish salty, bitter, sour, and sweet tastes.which distinguish salty, bitter, sour, and sweet tastes.

SweetenersSweeteners Colorless, odorless, solubility in water at the Colorless, odorless, solubility in water at the

concentrations needed for sweetening, pleasant tasting concentrations needed for sweetening, pleasant tasting with no “after-taste,” and stable over a wide pH range.with no “after-taste,” and stable over a wide pH range.

ColoringColoring Not required in every formulation.Not required in every formulation. Contraindicated in all sterile solutions. Contraindicated in all sterile solutions. Dark colors, such as dark purple, navy, black, and brown Dark colors, such as dark purple, navy, black, and brown

may also be rejected because they are often associated may also be rejected because they are often associated with poisons.with poisons.

EmulsionsEmulsions Unstable system consisting of at least two Unstable system consisting of at least two

immiscible liquidsimmiscible liquids.. One is dispersed in the form of small One is dispersed in the form of small

droplets throughout the other. droplets throughout the other. The other is a stabilizing agent.The other is a stabilizing agent.

TypesTypes Oil-in-water (o/w) emulsion Oil-in-water (o/w) emulsion Water-in-oil (w/o) emulsionWater-in-oil (w/o) emulsion

EmulsionsEmulsions Emulsifier - Emulsifier - a stabilizing agent in emulsions.a stabilizing agent in emulsions.

commonly used emulsifying agents include commonly used emulsifying agents include tragacanth, sodium lauryl sulfate, sodium dioctyl tragacanth, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, and polymers known as the Spans® sulfosuccinate, and polymers known as the Spans® and Tweens®.and Tweens®.

Primary emulsion Primary emulsion the initial emulsion to which the initial emulsion to which ingredients are added to create the final product.ingredients are added to create the final product.

MucilageMucilage a wet, slimy liquid formed as an initial step in a wet, slimy liquid formed as an initial step in the wet gum method.the wet gum method.

OintmentsOintments

Used for many different purposes, e.g., as protect Used for many different purposes, e.g., as protect ants, antiseptics, emollients, antipruritics, ants, antiseptics, emollients, antipruritics, kerotolytics, and astrigents.kerotolytics, and astrigents.

Ointments are generally compoundedon an ointment slab.

Transferring ointment into anointment jar.

SuppositoriesSuppositoriesThree types of bases:

Oleaginous: primarily synthetic triglycerides.

Water soluble: containing glycerinated gelatin or polethylene glycols (PEGs).

Hydrophyllic: mixtures of oleaginous and water soluble bases.

Mold

Suppository box

SuppositoriesSuppositories Cocoa butter (Theobroma Oil) USPCocoa butter (Theobroma Oil) USP

A well-known oleaginous base.A well-known oleaginous base. At room temperature, cocoa butter is a solid. At room temperature, cocoa butter is a solid. At body temperature, it melts to a bland, non-irritating oil. At body temperature, it melts to a bland, non-irritating oil. No longer the base of choice because preparing No longer the base of choice because preparing

suppositories with it is difficult, and the suppositories suppositories with it is difficult, and the suppositories require refrigeration. require refrigeration.

Synthetic triglycerides can be used that do not have the Synthetic triglycerides can be used that do not have the formulation difficulties of cocoa butter, but they are more formulation difficulties of cocoa butter, but they are more expensive. expensive.

There are newer bases composed of mixtures of fatty acids There are newer bases composed of mixtures of fatty acids that do not have the formulation problems or the expense that do not have the formulation problems or the expense (e.g., FattiBase®, Witepsol®).(e.g., FattiBase®, Witepsol®).

Water Soluble or Miscible BasesWater Soluble or Miscible Bases Glycerinated gelatin or polyethylene glycol (PEG) Glycerinated gelatin or polyethylene glycol (PEG)

polymerspolymers. . Useful for vaginal suppositories. Useful for vaginal suppositories. Dissolve slowly to provide prolonged release of Dissolve slowly to provide prolonged release of

active ingredients. active ingredients. Can be formulated by molding or compression in a Can be formulated by molding or compression in a

wide range of hardness and melting points. wide range of hardness and melting points. Do not melt at body temperature, but dissolve Do not melt at body temperature, but dissolve

slowly to provide a prolonged release of drugs.slowly to provide a prolonged release of drugs. Available in Available in various molecular weight ranges.various molecular weight ranges.

200, 400, or 600 molecular weight are liquids. 200, 400, or 600 molecular weight are liquids. Molecular weights over 1,000 are solids.Molecular weights over 1,000 are solids.

CapsulesCapsules

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

Hard gelatin capsules consist of a Hard gelatin capsules consist of a body body and a and a cap cap which which fits firmly over the body of the capsule. fits firmly over the body of the capsule.

For human use, For human use, eight sizes eight sizes of capsules are available.of capsules are available.

Punch MethodPunch Method Used when filling a small number of capsules.Used when filling a small number of capsules.

Labeling, Record Keeping, and Labeling, Record Keeping, and Cleanup Cleanup

• After compounding• The product must be labeled with a prescription

label, and a careful record of the compounding operation should be kept.

• Once the compounding operation is finished• The equipment and area should be cleaned.• Everything should be returned to their proper places

in storage.• Compounding should never be rushed.

Labeling, Record Keeping, & Clean-upLabeling, Record Keeping, & Clean-up

Regardless of their apparent stability, all Regardless of their apparent stability, all suspensionssuspensions Should be dispensed with an auxiliary label reading Should be dispensed with an auxiliary label reading “Shake “Shake

Well.”Well.” TheThe qs qs abbreviation means to add abbreviation means to add “as much as necessary” “as much as necessary” to the to the

specified amount. specified amount. JCAHO recommends using text words rather than JCAHO recommends using text words rather than

abbreviations to minimize a medication error.abbreviations to minimize a medication error. Refer to a standard reference work on the subject.Refer to a standard reference work on the subject.

Example: Example: Remington: The Science and Practice of PharmacyRemington: The Science and Practice of Pharmacy

Terms to RememberTerms to Remember

1. Aliquot1. Aliquot2. Arrest knob2. Arrest knob3. Beyond-use date3. Beyond-use date4. Calibrate4. Calibrate5. Chapter <795>5. Chapter <795>6. Chapter <797>6. Chapter <797>7. Compounding record7. Compounding record

8. Compression molding8. Compression molding9. Emulsifier9. Emulsifier10. Finger cots10. Finger cots11. Flocculating agent11. Flocculating agent12. Formulation record 12. Formulation record 13. Fusion molding13. Fusion molding

Terms to RememberTerms to RememberTerms to RememberTerms to Remember