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Excipients as stabilizers
Patrick J. Crowley
Excipients are better known as promoters of degradation than as sta- mass can possess functional groups that render
them susceptible, to some degree, to interactions
bilizers of drug substances. This is not surprising. Functional groups
that lead to quality being compromised.
or residues in excipients can have the propensity to interact with The long shelf-lives that are usually required
labile active ingredients, with attendant loss of molecular integrity for medicinal products reinforce the need for
quality retention as a key consideration during
or other changes in quality. Thus, the canon of work on excipients as formulation. In contrast to foodstuffs, soft drinks
stabilizers is not extensive. Nevertheless, possibilities exist to capital- and many other commodities, it is usual to expect
the quality of medicines to be retained for as long
ize on our knowledge of how a drug substance degrades, and of the
as 35 years. Such long use by periods are es-
properties and composition of excipients, to convert unstable drugs pecially important for remote and climatically
into viable products. This article discusses such approaches to prod- hostile regions, because of the complexities of sup-
ply and distribution. As there is no such thing as a
uct stabilization.
totally impervious pack, it will be apparent that the
protection afforded by the pack will be limited in
an environmentally hostile environment.
Drug substances can be fragile entities. It might be necessary, therefore, to consider
Patrick J. Crowley
Environmental stresses, as well as those associ- developing a formulation that compensates for
SmithKline Beecham
Pharmaceuticals ated with turning a drug into a medicine, all have any basic deficiencies in stability of the drug sub-
New Frontiers Science Park the potential to cause changes that compromise stance. In such cases, excipients must play a key
South quality. Such stresses can cause molecular com- role in turning an unstable drug into an accept-
Third Avenue position to change to some extent. This reduces able product.
Harlow
the amount of active ingredient in the medi-
UK CM19 5AW
tel: 144 1279 643509
cation and might generate novel molecular enti- General considerations
fax: 144 1279 643887 ties that could compromise safety. Physical The potential for excipients to prevent or retard
e-mail: patrick_j_crowley@ changes can lead to altered dissolution or other degradation will be determined by the factors
sbphrd.com delivery properties. Sedimentation in liquid that cause the molecular transformation of drug
products, consequent to altered solubility, could substances.These include:
present safety as well as efficacy problems.
Preformulation studies should identify environmental components, such as water
propensity for change on the part of the drug vapour and sunlight;
substance and clarify the strategy for develop- stresses during conversion to the dosage
ment of the dosage form. Drugexcipient form, such as size reduction, compaction or
compatibility studies might further constrain or sterilizing processes;
clarify the options for formulation. Packaging interactions between adjacent molecules of a
suitable to protect the product offers additional drug, or between functional groups on the
scope for providing a stable product. Such avoid- same molecule.
ance tactics might suffice for many dosage form
development programmes, but not in all cases. If excipients are to act as stabilizers they must
Drug substances that are elaborated by semisyn- obviate or attenuate such effects.
thetic means and those emanating from biotech-
nology-based programmes usually have proper- Moisture-related degradation
ties that can render them intrinsically unstable. Water can be associated with the drug or the
Even heterocyclic compounds of low molecular excipients. It can be incorporated during
1461-5347/99/$ see front matter 1999 Elsevier Science. All rights reserved. PII: S1461-5347(99)00158-3 237
reviews research focus PSTT Vol. 2, No. 6 June 1999
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PSTT Vol. 2, No. 6 June 1999 research focus reviews
E
in solid-state dispersions. 0.4
2
However, formulation additives have been effective stabili-
zers in vitamin preparations. Tocopherol, butylated hydroxy- 0.2
anisole, butylated hydroxytoluene and propylgallate have all 1
been used to stabilize vitamins A and D3 (Refs 811). Ascorbic 300 400 500
acid solutions have been stabilized by a combination of chelat- l [nm]
ing agent and antioxidant12. Ascorbic acid has also been stabi-
(b)
lized by magnesium, calcium or aluminium stearate13. It is not 8
clear, however, whether these materials effected stabilization per 7
6 2
se or whether it was produced by antioxidants that are usually
5
present in stearates and other fatty acids.
4
Content (mg 50 ml-1)
Photodegradation
Exposure to light can precipitate a plethora of degradation re-
actions. These can include addition reactions in unsaturated Spilgies used the spectral overlay approach to stabilize solu-
systems, substitution reactions, polymerization, isomerization tions of a photolabile b-lactam using acceptable food colorants
and photo-oxidation14. Suitable light-resistant packaging can, having UV spectra that went some way to providing spectral
in many cases, prevent or reduce degradation. However, degra- cover17 (Fig. 3).
dation during product use is also a possibility and it might be A similar approach was used by Sanderson et al. to stabilize a
necessary to stabilize the formulation itself. potential anti-psoriasis agent for application as an ointment18.
The concept of spectral overlay was pioneered by Thoma and Although stable in the formulated, packaged product, the active
Klimek15,16.This approach involves formulating with a material ingredient was photolabile. Isomerization and polymerization
whose UV absorption spectrum overlaps (or substantially over- reactions occurred when the ointment was exposed as a thin
laps) that of the compound requiring stabilization. The impact film to simulated sunlight. In-use degradation was therefore a
of damaging radiation will thus be attenuated as the excipient possibility and stabilization needed to be considered.
competes with the active compound for the photons from the Table 1 shows the effect of including benzophenones (agents
radiation source. Thoma showed that the photolabile calcium used in sunscreens) on photostability.The reduced degradation
antagonist nifedipine can be effectively stabilized by the natural can be ascribed to the partial spectral overlay provided by the
food colorant curcumin, or by riboflavine15. Neither of these benzophenones (Fig. 4).
additives provided complete spectral cover but stability en- Sanderson et al. also noted that stability could be enhanced by
hancement was significant (Fig. 2). the addition of a blocker such as titanium dioxide and by
239
reviews research focus PSTT Vol. 2, No. 6 June 1999
1
not augment the stabilizing effect of the grade of paraffin in
1.0 1 2 question. Thus the enhancement seen is more likely to be a
spectral overlay effect (Fig. 5). Some aromatic residue or other
additive in the paraffin might be responsible for the spectral
0.5
cover.These findings highlight the need to be aware of the basic
2 stabilization mechanism and the need for change control sys-
3
0 tems for excipients. Change of supplier of paraffin could lead to
250 300 350 400 450 500 550
a less-stable product in this case.
Wavelength (nm)
In a similar vein, the presence of the UV absorber oxybenzone
in the film coat was shown to stabilize sulphisomidine tablets18.
(b) Successful application of the spectral overlay approach re-
100
quires excipients with the appropriate absorption spectra. Obvi-
80 ously they must also be free from pharmacological activity and
Remaining content of
BRL42715B (%)
2.0
1
1.2
(samples exposed for one hour in a Sol-2 light cabinet)
0.8
Stabilizer Level (% w/w) Degradation %
2
0.4
None 49 3
Oxybenzone 0.25 35 0.0
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PSTT Vol. 2, No. 6 June 1999 research focus reviews
(a) (b)
-OOC
OH COO-
OH
200 220 240 260 280 300 320 340 360 380 400 420 440
OH OH
Wavelength (nm) OH
OH
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PSTT Vol. 2, No. 6 June 1999 research focus reviews
avoid the conclusion that some steric hindrance effect prevents claims, as evidenced by the number of patent claims referenced
degradation by rearrangement. in this article. Thus there are potential commercial advantages
for organizations with the will to make the effort and the skills
Overview to provide inventive approaches to stabilization.
Many products contain excipients that can be categorized as sta-
bilizers in a general sense. Using suspending agents to prevent References
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