VOLUME 40 : NUMBER 1 : FEBRUARY 2017

ARTICLE

Extemporaneously compounded medicines

James R Falconer
SUMMARY Lecturer
Kathryn J Steadman
Extemporaneously compounded medicines may be useful when a required dose or dose form is Associate professor
unavailable commercially, or for individualised dosing. Pharmacy Australia Centre
of Excellence
There are numerous established compounding formulae available, and new formulae may be University of Queensland
developed with the help of formulation guidelines and professional advice. Brisbane
Unlike registered medicines, compounded preparations have not generally been assessed
for safety and efficacy. Their use is off label and is based on extrapolation from the Keywords
component ingredients. dispensing medication,
drug compounding, drug
Short-term expiry dates are provided for compounded products unless their stability has control, off-label prescribing
been assessed.
Aust Prescr 2017;40:5–8
Introduction creams, eye drops, nasal sprays, oral dosage forms http://dx.doi.org/10.18773/
Extemporaneous compounding is the preparation or intravenous infusions. In Australia, products may austprescr.2017.001
be classified into simple or complex compounding
of a therapeutic product for an individual patient in
(Table 1). Simple compounding can be performed
response to an identified need.1 It is a practical way
by any pharmacist and is a core competency of
to have medicines supplied when there is no other
pharmacy training. Complex compounding requires
option. For example, compounding may be useful for
additional training and evidence, as described
patients with dysphagia who are unable to swallow
by the Pharmacy Board of Australia’s guidelines
solid medications whole, when an appropriate dose
on compounding.1
or dosage form is not commercially available, when
patients require an individualised dose, or when Regulation
medicines must be delivered via nasogastric or
The final medicine produced by compounding is
gastrostomy tubes.2
regulated according to the component’s schedule
Active pharmaceutical ingredients can be in the Poisons Standard (the SUSMP).3 For example
incorporated into a wide array of products including a topical progesterone (S4) cream requires a

Table 1 Classification of simple versus complex compounding

Compounding type Explanation Examples

All pharmacists have training during their undergraduate Topical creams, ointments, lotions, gels, e.g. steroids,
degree to prepare these products. hormones, coal tar, cholestyramine
Involves well-established preparations published in reputable Oral liquids (solutions, suspensions, emulsions, mixtures,
Simple
literature, e.g. the Australian Pharmaceutical Formulary and elixirs), tinctures, e.g. omeprazole suspension
Handbook, or formulae for which some data are available Capsules, tablets, powders, e.g. ethinylestradiol capsules
regarding quality, stability, safety, efficacy and rational design.
Suppositories, pessaries, e.g. paracetamol, clotrimazole

Pharmacists require further postgraduate training in Parenterals, e.g. morphine, clonidine

association with self-assessment of relevant competencies and Ingredients with a safety hazard, e.g. cytotoxics, hormones
documentation of the specific competencies in a continuing
Single unit micro-dose (<25 mg of drug or no more than
professional development plan.
25% w/v of a dosage form), e.g. naltrexone
Complex Specialised facilities (sterile room with positive pressure) and
Modified-release dosage forms, e.g. levothyroxine (T4),
equipment (laminar flow isolator, dry heat sterilisation oven)
progesterone capsules
are also required.
Ophthalmic preparations, e.g. phenylephrine, tropicamide,
ciprofloxacin

Source: Reference 1

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 VOLUME 40 : NUMBER 1 : FEBRUARY 2017

ARTICLE Extemporaneously compounded medicines

prescription whereas dithranol (S3) ointment can

Box Commercially available and
be supplied without instructions from a medical
compounded medicines in
practitioner. In contrast, a pharmacist must have been Australia
instructed by a veterinary surgeon to compound
medicines for an animal irrespective of the scheduling Commercially available medicines
of the active ingredient. All components of a
These products must be listed (AUST L) or registered
compounded product, that is the active ingredient (AUST R) on the ARTG. Listed medicines are evaluated for
and the excipients, are subject to quality standards quality and safety by the TGA and include vitamins and
set out in the Therapeutic Goods Act 1989, and are mineral supplements and herbal medicines. Registered
sourced from compounding supply companies that medicines are evaluated for quality, safety and efficacy
by the TGA and include all prescription medicines, most
undertake rigorous quality-assurance testing.
over-the-counter medicines (e.g. analgesics) and some
The Therapeutic Goods Administration (TGA) complementary medicines (e.g. high-dose calcium
specifies that all medicinal products must meet the supplements).
PIC/S* Guide to Good Manufacturing Practice for
Extemporaneously compounded medicines
Medicinal Products, which is an international
These products are prepared according to PIC/S Guide
standard.4 However, it is important to be aware that to Good Manufacturing Practice for Medicinal Products.
the final medicine produced by extemporaneous However, they are not listed or registered on the ARTG
compounding is exempt from assessment by the TGA. and assessment of the quality, stability and efficacy of the
final product is not required.
Commercially available medicines must be
listed or registered in the Australian Register for
Therapeutic Goods (ARTG) (see Box), unless exempt ARTG Australian Register of Therapeutic Goods
TGA Therapeutic Goods Administration
by the Therapeutic Goods Regulations. They are
PIC/S Pharmaceutical Inspection Convention and
manufactured by TGA-licensed manufacturers Pharmaceutical Inspection Co-operation Scheme
and undergo extensive testing to ensure an
accurate dose of active drug will be delivered in
a reasonably reproducible manner. Commercially
available medicines are also tested for stability so How is compounding performed?
an expiry date can be provided. Extemporaneously The active ingredient may be derived from
compounded medicines are not listed or registered, commercially available medications or the pure
and no assessment of the final medicinal product in chemical. Sometimes compounding is as simple as
terms of quality, stability or efficacy is required. mixing a crushed tablet or the contents of a capsule
in water to form a solution or suspension. However,
Where are compounded this may not be suitable and depends on the solubility
products made?
of the active ingredient. For example, insoluble tablet
Extemporaneous compounding takes place in excipients can lead to blockages in enteral feeding
community and hospital pharmacies. There are tubes.5 In the majority of compounded products,
usually specialist compounding pharmacies in additional non-active components (excipients) are
major towns and cities, but any pharmacy may included to ensure the active ingredient dissolves
undertake compounding as long as they have or remains suspended, or to adjust palatability
appropriate facilities according to state-based or viscosity.6
legislation (e.g. allocated clean bench, specific
A range of proprietary bases and excipient mixes
compounding equipment).
are available commercially through compounding
Complex compounding is performed in a pressurised suppliers to create preparations such as capsules,
clean room using a laminar flow cabinet, cytotoxic rapidly dispersing tablets, creams, gels, ointments, oral
drug safety cabinet or an isolator.1 Many public and liquids, lozenges, troches and suppositories. This can
private hospitals maintain large aseptic compounding simplify the preparation protocol and provide some
facilities to provide individualised dosing or background research, development and quality control
commercially unavailable formulations. for the base. All pharmacies are required to document
the compounding protocol used and maintain records
of all compounded products dispensed.

Compounding formulae
It is preferable to use standardised formulae,
* Pharmaceutical Inspection Convention and especially when some stability information is
Pharmaceutical Inspection Co-operation Scheme available. Formulae and associated preparation

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protocols are available for some of the more as testosterone and dopamine, undergo oxidative
commonly compounded products, for example the decomposition. A 10°C increase in temperature can
current edition of the Australian Pharmaceutical result in a 2–5-fold faster rate of degradation.
Formulary and Handbook 7 describes approximately It is essential that the active ingredient does not
130 formulae. Over 1000 other formulae may be interact with any excipients originating from the
found in older editions.8 Formulae may also be dosage form being crushed for reformulation
found through specialist journals and websites. (e.g. tablet lubricants and fillers), or from additives
Pharmacies that regularly compound, particularly in the new formulation (antioxidants, preservatives,
hospital and compounding pharmacies, often have suspending agents, colourants, emulsifiers).
their own compendium of formulae for products Interactions with other ingredients can result
that they dispense on a regular basis. The formulae in physical instability of the product, such as
are documented in the form of a batch sheet that precipitation of the active drug or phase separation
precisely describes the compounding method and (‘cracking’) of a cream, affecting drug solubility,
allows for documentation of the ingredients used. absorption and bioavailability.
Advice is available from experienced pharmacists that To minimise the risk of a compounded medicine
work for the companies that supply the raw materials degrading, short-term expiry dates are used
in Australia, such as the Professional Compounding (e.g. 28 days for oral and topical products, or 24 hours
Centers of America (membership required), for parenteral formulations), unless stability studies
Medisca and Bella Corporation (no membership have been conducted and indicate otherwise.
required). They can help to develop formulae
that will theoretically optimise drug delivery and Sterility of products
minimise instability. Microorganisms may grow if the water content is high
enough so exposure to an aqueous environment can
Stability of products cause medicines to ‘spoil’. Contamination can cause
In most instances, the actual stability of the drug in instability of the formulation or drug degradation,
the final compounded medicine is not known. Larger or both.
compounding companies or hospitals may undertake Microorganisms could potentially be introduced
or outsource stability testing for a particular product, during reformulation of non-sterile products.
and will reference published stability information when For example, if Candida albicans is inadvertently
preparing their batch sheets. Information regarding the introduced into freshly prepared multi-dose citric
chemical stability of the active ingredients can inform acid solutions that are to be used orally for cough
product design and expiry date. Active ingredients reflex testing, immunocompromised individuals could
may degrade when exposed to oxygen and water, become infected.11 Including a preservative is the
with reactions being initiated and accelerated by most common approach for non-sterile water-based
light, heat or certain trace metals (see Table 2).9,10 compounded products, especially when storage for
For example, active ingredients containing an ester more than a few days is required. Many factors affect
functional group, such as aspirin and penicillins, the choice of preservative, such as dosage form and
are susceptible to breakdown by hydrolysis, while pH of the product. Refrigerated storage can help
those containing aldehyde or hydroxyl groups, such delay deterioration.

Table 2 Common degradation pathways of active drugs in compounded products

Pathway Factors determining Susceptible functional groups Examples9,10

degradation rate

Oxidation Aldehydes, alcohols, phenols, alkaloids, Paracetamol, progesterone, testosterone, quinine, oils
(O2 dependent) unsaturated alkyl chains, carboxylic acids (unsaturated fats) such as soybean and corn oil, essential
Concentration of drug, fats, atorvastatin, atenolol
temperature, catalysts,
Hydrolysis solvents, light and Esters, amides, lactones, ethers, lactams, Aspirin, vigabatrin, norfloxacin, omeprazole, simvastatin
(H2O dependent) excipients imines, acetals, anhydrates, sulfonamides (statins), baclofen, diphenoxylate, methylphenidate,
lignocaine, sildenafil, penicillins, cephalosporins,
diazepam, digoxin, heparin, captopril, hydrocortisone

Note: drug molecules with more than one functional group can be more easily degraded. In fact, many drugs contain more than one functional group,
being susceptible to both oxidation and hydrolysis, e.g. atenolol (contains amide and alcohol groups).

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ARTICLE Extemporaneously compounded medicines

Parenteral products are compounded by ARTG because they are prepared for an individual
appropriately trained staff using aseptic techniques. patient. The quality of the components are
Multiple-use products will contain a suitable assured by purchase from reputable suppliers, and
preservative, while single-use syringes or infusions quantities used and the formulation method are
rely on good aseptic practice. Regular monitoring thoroughly documented within the pharmacy. The
of the environment, equipment and procedures is preparation of compounded medicines is subject
essential to ensure quality and sterility is maintained. to strict international standards, but they are
The consequences of failure can be catastrophic, generally dispensed without any testing for content,
for example methylprednisolone injections from a consistency, stability and sterility.
single compounding pharmacy in the USA resulted There is published information regarding chemical
in 137 cases of Aspergillus fumigatus meningitis and degradation of the active drug and for many
12 deaths.12 compounding formulae. However, usually there are
no data to inform the pharmacist or patient about
a specific product’s quality or stability. Products
Conclusion
are typically freshly prepared with a relatively
short-term expiry date based on guidelines in the
Medicines are commonly prepared by
Australian Pharmaceutical Formulary and Handbook 7
extemporaneous compounding in Australia and
to limit the risk of degradation or contamination
around the world when commercial preparations
by microorganisms.
are unavailable or individualised dosing is required.
They do not have to be listed or registered on the Conflict of interest: none declared

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(BAPEN) and British Pharmaceutical Nutrition Group. et al. An investigation into the stability and sterility of citric
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FURTHER READING
Glass BD, Haywood A. Stability considerations in liquid dosage Marriott JF, Wilson KA, Langley CA, Belcher D. Pharmaceutical
forms extemporaneously prepared from commercially available compounding and dispensing. 2nd ed. London: Pharmaceutical
products. J Pharm Pharm Sci 2006;9:398-426. Press; 2016.

8 Full text free online at nps.org.au/australianprescriber