Ch. 15 Non-Sterile Compounding

Stabinksy

intro to compounding

a traditional compounded drug is prepared for an individual patient based on a prescription

the dose or formulation cannot be commercially available

types of compounding

nonsterile or sterile

nonhazardous or hazardous

U.S Pharmacopeia

USP sets the standards for compounding

795 --> nonsterile

797 --> sterile

800 --> hazardous

the USP chapters are considered to be the minimum acceptable standards

nonsterile compounding

includes meds given -->

• orally

• via tube

• rectally

• vaginally

• topically

• nasally

• in the ear

nonsterile compounding is primarily used to:

• prepare a dose or formulation that is not commercially available

• avoid an excipient

• add a flavor

space requirements

• can be performed in room air but must be separated from the dispensing part of the pharmacy --> must be specifically designated

• all ingredients and equipment must be stored off the floor

• temperature should be monitored daily (or continuously)

• sink is required

• purified water is needed for rinsing equipment and utensils

compounding personnel

there must be a designated person responsible

training

• training demonstrating proficiency must be completed initially and every 12 months

• core competencies include hand hygiene and garbing

garbing

• must complete hand hygiene with soap and water

• gloves are required

equipment

• must be calibrated regularly to confirm accuracy

• metal spatulas should not be used with compounds containing metal ions

• all measurements should be made in the metric system

weighing equipment

balances

balances

• class III (class A) torsion balance --> has a sensitivity requirement; MWQ is measured based on SR and acceptable error rate

• top loading electronic balance (analytical balance or scale) --> has higher sensitivity; can "tare" the balance to ensure that only the ingredients are weighed

• with either balance, the material to be weighed should never be placed directly on the balance --> place on a weight boat or on a glassine weighing paper

measuring volume

• cylindrical and conical graduates

• syringes

• pipettes and droppers

cylindrical and conical graduates

measuring equipment with lines on glass that are used measure volume

a graduated cylinder has the same diameter from top to bottom --> provides more accurate measurements

** the wider the mouth, the lower the accuracy, but the easier to stir with a glass stirring rod

measuring volumes that are smaller than 20% of the graduate's capacity can cause a measuring error

to read the volume, read the height from eye level

the liquid can curve downward --> meniscus

the measurement is read at the bottom of the meniscus

syringes

• syringes are most accurate for measuring small volumes and viscous liquids

• safety measures must be in place to prevent oral meds from being given by the wrong route

• clearly label oral syringes by placing "for oral use only" over the syringe cap

pipettes and droppers

pipettes are thin plastic or glass tubes

a volumetric pipette draws up set volumes only

a mohr pipette is graduates

grinding, mixing, and transferring equipment

mortars and pestles

spatulas

ointment slabs

powder sieves

mortars and pestles

glass mortars are used for liquids and for mixing compounds that are oily or can stain

wedgwood mortars have a rough surface

porcelain mortars have a smooth surface and are preferred for blending powders and pulverizing gummy consistencies

spatulas

used to mix and transfer

the flat part can be used to flatten and grind ingredients

stainless steel and plastic spatulas are used commonly

a steel (metal) spatula should NOT be used if making a compound that contains metal ions

ointment slabs

work surface for other purposes --> can be used to form pills (pill tile)

disposable parchment ointment pads can be used

powder sieves

sifters --> used to ensure powders are a uniform particle size

electric mixing equipment

ointment mills

homogenizers

grinders

ointment mills

draws the ointment between rollers that grind and homogenize the ingredients --> makes it uniform

homogenizers

electric mortar and pestle

grinders

can grind hard tablets into a rough powder

heating devices

hot plates

microwave ovens

hot plates

a water bath is helpful when the temp needs to be carefully controlled --> ingredients that need to be melted will be in a container that is placed into a large container filled with water

hot plate with a magnetic stirrer --> stirrer has a rotating magnet, causing the stir bar to spin

molds

used to prepare tablets

disposable plastic molds and refrigeration help the product retain its shape

a tablet press can be used

capsules and capsule machine

soft gels or hard shells

shells are made of gelatin, which is pork-derived, or from hypromellose or a similar plant-derived product

ingredients

all meds include active pharmaceutical ingredients (APIs) and the excipients

should be listed in the USP national formulary (USP-NF)

missing expiration date

ingredients degrade, and expiration dates are important to ensure that the product retains potency and is non-toxic

if there is an ingredient without an expiration date, the pharmacist will assign a conservative date

surfactants

contraction of the words surface active agent

lower the surface tension between two ingredients (or phases) to make them more miscible (easier to mix together) --> also keeps the phases from quickly separating

are amphiphilic

types of surfactants

allows for a more consistent dose by keeping the drug dispersed for longer

surfactants are called by a variety of names

wetting agents/levigating agents

reduce the surface tension between a liquid and a solid

levigation makes the particles smaller

mineral oil is a common levigating agent for lipophilic (oil-soluble) compounds

glycerin and propylene glycol are used for aqueous (water-soluble) compounds

suspending agent

a suspension is a solid dispersed in a liquid

suspending agents are added to suspension to help keep the solid particles from settling

suspensions must be shaken to redisperse the solid prior to use

suspending agents can also be called dispersants (or dispersing agents)

commercially available suspending agents

ora-plus

ora-sweet

ora-blend --> combo of the two

** both available in sugar free options

ora-plus

keeps particles suspended and prevents settling

bland taste

ora-sweet

provides flavor to ora-plus

foaming agents

anti-foaming agents are more commonly used (simethicone)

glycols and gels

PEG and poloxamer are both delivery vehicles and surfactants

have both hydrophilic and hydrophobic parts

emulsifiers

an emulsion is a mixture of two or more liquids which are not able to be blended together (immiscible)

emulsifiers are added to help keep the liquid dispersed throughout the liquid vehicle

hydrophilic-lipophilic balance

a primary consideration in selecting the surfactant is whether the emulsion is a water-in-oil (w/o) or oil-in-water (o/w) emulsion

the hydrophilic-lipophilic balance (HLB) number determines the type of surfactant required to make an emulsion

the HLB number

the HLB scale range is 0-20

the midpoint is 10

surfactants with a low HLB number (<10) are more lipid-soluble and are used for w/o emulsions

surfactants with a high HLB number (>10) are more water-soluble and are used for o/w emulsions

examples of surfactants and their HLB values

glyceryl monostearate --> 3.8 --> w/o

PEG 400 --> 11.4 --> o/w

span 65 --> 2.1 --> w/o

tween 81 --> 10

tween 85 --> 11 --> o/w

binders

stick together and provide stability

ex --> starch paste

diluents and fillers

diluents make something more dilute

fillers are used to bulk up a small amount

tablet/capsule ex --> starches, lactose, calcium salts, cellulose

topical ex --> petrolatum

disintegrants

oral products have to be dissolved in order to be absorbed

alginates and cellulose absorb water

ex --> alginic acid, cellulose products, starches

flavorings and coloring agents

sweeteners:

non-caloric, artificial --> aspartame, sucralose

glycerin

dextrose

mannitol, sorbitol, xylitol

stevia

lubricants

prevent ingredients from sticking

improve powder flowability

ex --> magnesium stearate

preservatives

prevent microorganism growth

do not use in neonates

ex --> chlorhexidine (also used as an antiseptic in surgical scrubs), povidone iodine, sodium benzoate/benzoic acid, benzalkonium chloride, sorbic acid/potassium sorbate, methyl/ethyl/propyl parabens, EDTA, thimerosal, cetylpyridinium chloride

buffers

keep the pH within a certain range

ionized compounds are more polar, which makes them more water-soluble

pH can be calculated using the henderson-hasselbalch equation

adsorbents

magnesium oxide/carbonate

kaolin

anti-foaming agents

simethicone

coatings

shellac, gelatin, gluten

cellulose acetate phthalate

gelling (thickening) agents

gelatin, cellulose, and bentonite are used commonly

agar, alginates, various gums (guar, xanthan, acacia), gelatins, bentonite, cellulose, starches, poloxamer (pluronic) gels

humectants

glycerin or glycerol

propylene glycol

PEG

hydrophilic solvents

water

sterile water

alcohols

glycols

water

purified water has been treated to remove chemicals --> types of purification include distillation, deionization, reverse osmosis

distilled water is used for reconstitution to prepare oral suspensions

potable water is safe to drink and used for hand washing

sterile water

must be free of bacterial endotoxins (pyrogens) that inhabit water

alcohols

have high miscibility (mixes easily) with water and can be used to dissolve solutes that would be insoluble in water alone

benzyl alcohol --> used as a solvent, preservative, and fragrance

IPA 70% --> preferred disinfectant

glycols

PEG is used as a surfactant, solvent, and lubricant --> is water-soluble and water-miscible

when PEG is linked to a protein drug (pegylated), it increases their half-life

polybase is a PEG mixture used as a suppository base --> also a good emulsifier

hydrophobic solvents

oils and fats

mineral oil --> ingredient in baby oil

emollients

moisturizer that softens and soothes the skin

ointments are best for extremely dry skin and thick skin

creams are usually best for normal and dry skin

lotions have the most water, and are best for oily skin

occlusive ointments, including petrolatum jelly (white petrolatum), theobroma oik (cocoa butter), and other waxes form a protective barrier to prevent the loss of water

ointments

0-20% water

ex --> petrolatum, polybase, aquaphor, aquabase

ointments are separated into 4 groups -->

hydrocarbon bases --> "oleaginous" ointment (no water) --> petrolatum (vaseline)

absorption bases

water-removable bases

water-soluble bases

creams

20-50% water

w/o or o/w emulsions

lotions

contain the most water

a small amount of alcohol added to solubilize ingredients

gels

gelling agents are added

liquid when refrigerated, gel at room temperature

works well for transdermal drug delivery

ex --> poloxamer (pluronic) lecithin organogel (PLO) gel

poloxamers contain a hydrophobic chain with two hydrophilic chains

suppository bases

polybase

hydrogenated vegetable oils

PEG

gelatin

when to avoid alcohol

in children

use an alternative solvent

when to avoid aspartame

contains phenylalanine --> avoid in phenylketonuria (PKU)

select an alternative sweetener

when to avoid gelatin

in vegetarians and vegans or anyone who wishes to avoid animal products

alternative --> hypromellose capsule shells (made from cellulose and are vegan)

when to avoid gluten

celiac disease or anyone who wishes to avoid gluten

alternative --> starch from a non-gluten source

when to avoid lactose

lactose intolerance or lactose allergy

select an alternative depending on the purpsoe

when to avoid preservatives

neonates

use preservative-free formulations

when to avoid sorbitol

IBS --> sorbitol can cause GI distress

select an alternative sweetener

when to avoid sucrose

diabetes --> depending on the amount used, can increase blood glucose

select an alternative sweetener

when to avoid xylitol

dogs --> can cause xylitol toxicosis

humans that have GI upset with xylitol use

select an alternative sweetener

nonsterile compounding preparation

the initial steps will be similar for most formulations, such as calibrating equipment and weighing ingredients

the final steps will be similar and include packaging and performing quality control

always review the safety data sheets (SDS) for each bulk ingredient to determine safety procedures, including the recommended personal protective equipment (PPE)

compounding steps

make the product according to the master formulation record

completion steps

document all compounding steps, ingredients, and other details in the compounding record

preparing powders

glidant/lubricant to improve the flowability of the powder --> magnesium stearate

surfactant to neutralize the static charge and keep the powder from floating away --> sodium lauryl sulfate

reducing particle size

can be accomplished with comminution, which means to reduce particle size by grinding, crushing, milling, or vibrating

after the powder has been ground, it is placed into a sieve (sifter) --> ensures that particle size is uniform

three main methods of comminution

trituration --> means to mix thoroughly (or make the product homogenous); trituration by grinding tablets with a mortar and pestle or by shaking an emulsion

levigation and spatulation --> incorporating a small amount of liquid to help with the grinding process

pulverization by intervention --> used for crystalline powders that will not crush easily; the crystals are dissolved with an intervening solvent

geometric dilution

a small amount of drug is mixed into an equal amount of diluent --> repeated until all of the ingredients are mixed together

melting point order

melt the ingredient with the highest melting point before adding the ingredients with the lower melting points

eutectic mixtures

means that the combo of the ingredients will melt at a lower temperature than either of the individual component's melting temperatures

dosage forms

solutions --> a solute dissolved in a solvent; homogenous (uniform)

suspensions --> a solid dispersed in a liquid; 2 phase heterogenous (not uniform) --> a wetting agent/levigating agent is a type of surfactant used to incorporate an insoluble drug into a liquid

emulsions --> liquid dispersed into a liquid; 2 phase heterogenous; o/w or w/o --> an emulsifier is a type of surfactant that is used to reduce the surface tension between two liquids and prevent them from separating

precipitation/sedimentation

can happen with suspensions and emulsion

shake or gently roll to redisperse

types of solutions

syrups

elixirs

tinctures

spirits

how to prepare solutions

gather ingredients

reduce the particle size of the solid drug to a fine powder

dissolve the solute in the solvent

the dissolution rate can be used to determine the time it will take for the solute to dissolve (calculated using Fick's first law of diffusion)

a larger surface area, stirring the preparation and using heat will increase the dissolution rate

add any required excipients (buffer to resist changes in pH, a preservative, flavorings, sweeteners, or coloring agents)

package the solution and apply a BUD and appropriate auxiliary labels

how to prepare suspensions

gather ingredients

reduce the particle size of the solid drug to a fine powder

wet the powder, and levigate to form a paste

continue to add liquid in portions

add a surfactant to help keep the suspension dispersed

transfer the mixture into a conical graduate or the container in which it will be dispensed and add a quantity of water sufficient to make (QS) the final volume

add any required excipients

package the suspension and apply a BUD

will need to be redispersed (shaken) prior to use

how to prepare emulsions

emulsions can be made by either the continental or english gum method, mixing oil, water, and an emulsifier (gum) in a 4:2:1 ratio

conventional (dry gum) method

levigate the gum with oil

add the water all at once

triturate by shaking in a bottle or mixing in a mortar until a cracking sound is heard and mixture is creamy white

add other ingredients by dissolving them first in solution and QS with water up to the final volume

homogenize

english (wet gum) method

triturate the gum with water to form a mucilage (thick and sticky like mucus)

add oil slowly while shaking or mixing

add other ingredients as in the dry gum method

tablets

molded tablet is the most common type made in compounding

compressed tablet is the most common type made in manufacturing

tablets contain the active drug and excipients, including diluents, binders, disintegrants, lubricants

how to prepare molded tablets

triturate the dry ingredients and mix by geometric dilution

add alcohol and/or water to moisten the powder

the powder mixture should have a pasty consistency, which can be molded into tablets and allowed to dry

coloring and coating may be added

capsules

capsules are soluble shells of gelatin or hypromellose (a vegetable product)

glycerol and sorbitol are used as plasticizers

how to prepare capsules

triturate the dry ingredients and geometrically mix with the fillers/other excipients

the powder is put into the capsules by either hand filling (punch method) or by using a capsule-filling machine

hand filling --> the powder is placed on powder paper or an ointment slap. the pile of powder is smoothed with a spatula to a height about a third of the length of the capsule. the open end of the capsule is repeatedly punched into the pile of powder until the capsule is filled. when the base is filled, it is fitted with the cap

manual capsule-filling machine --> these are small devices that help the pharmacist quickly load 50,100, or 300 capsules. plates help sort the capsule bodies and hold them upright and in place. the powder is above the capsules on to a plastic sheet where a plastic spreader is used to move the powder into the capsules. a comb or tamper are used repeatedly until the powder is packed into the capsules. then, the caps are put over the capsule bodies

lozenges/troches

acts locally in the mouth

a lozenge contains the active ingredient in a base of -->

sucrose or syrup for hard

PEG for soft

glycerin or gelatin for chewable