Professional Documents
Culture Documents
Patrick Crowley
is a Vice President in
Pharmaceutical Development
E xcipients are included in dosage forms to aid
manufacture, administration or absorption.
Other reasons for inclusion concern product differ-
irritation of the skin or mucosal surfaces, sensitization
reactions or adversely affect appearance or
organoleptic properties. However, such effects are
at GlaxoSmithKline, 1250 South entiation, appearance enhancement or retention of not usually a consequence of drug–excipient interac-
Collegeville Road, Collegeville, quality.1 They rarely, if ever, possess pharmacological tion per se, so are not considered in this review.
PA 19426, USA. activity and are accordingly loosely categorized as
‘inert.’ However, excipients can initiate, propagate or Modes of drug decomposition
Dr Luigi G Martini participate in chemical or physical interactions with Medicinal agents invariably have structural features
Manager, Stategic Technologies. an active, possibly leading to compromised quality or that interact with receptors or facilitate metabolic
Pharmaceutical Development, performance of the medication. Chemical interaction handling. These inevitably confer some degree of
GlaxoSmithKline can lead to degradation of the active ingredient, lability, making them vulnerable to degradation (and
Pharmaceuticals, Harlow, Essex, thereby reducing the amount available for thera- interaction with other materials). Common modes of
CM19 5AW, UK. peutic effect; reaction products may compromise degradation are described below.
safety or tolerance. Physical interactions can affect Hydrolysis. Drugs with functional groups such as
rate of dissolution, uniformity of dose or ease of esters, amides, lactones or lactams may be suscep-
administration. Understanding the chemical and tible to hydrolytic degradation. It is probably the
physical nature of excipients, the impurities or most commonly encountered mode of drug and
residues associated with them and how they may product degradation because of the prevalence of
interact with other materials, or with each other, such groups in medicinal agents and the ubiquitous
forewarns the pharmaceutical technologist of possi- nature of water. Water can also act as a vehicle for
bilities for undesirable developments. interactions or can facilitate microbial growth.
Oxidation. Oxidative degradation is probably second
General considerations only to hydrolysis as a mode of decomposition. In
Excipients may have functional groups that interact contrast to hydrolysis, oxidative mechanisms are
directly with active pharmaceutical ingredients. complex, involving removal of an electropositive
Alternatively, they may contain impurities or atom, radical or electron or, conversely, addition of
residues, or form degradation products that in turn an electronegative moiety. Oxidation reactions can
cause decomposition of the drug substance. be catalysed by oxygen, heavy metal ions and light,
Excipients can be a source of microbial contami- leading to free radical formation (induction). Free
nation. They can also cause unwanted effects such as radicals react with oxygen to form peroxy radicals,
which in turn interact with the Direct interactions between reactions.4–7
oxidizable compound to generate actives and excipients Direct drug–excipient interactions
additional free radicals to fuel Excipients may be inorganic or seem to be most prevalent when the
further reactions (propagation). organic in composition, synthetic interacting species are water soluble
Aldehydes, alcohols, phenols, alka- or semi-synthetic, or derived from and in liquid systems. This is hardly
loids and unsaturated fats and oils biological or natural sources. Many surprising — interactions in solution
are all susceptible to oxidation. possess functional groups that can are more facile than in the solid state
Isomerization. Isomerization interact with other materials. It where there is less opportunity for
involves conversion of a chemical may be possible on occasion to collision between functional groups
into its optical or geometric isomer. exploit such attributes to stabilize or other reaction-enhancing events.
Isomers may have different unstable materials,3 but more usually This is why compatibility studies
pharmacological or toxicological interactions lead to loss of quality. involving solutions give many ‘false
properties. For example, the activity Charge interactions. Soluble and ion- positives.’ However, adsorbed mois-
of the laevo (L) form of adrenaline is izable excipients can generate ture may promote greater molecular
15–20 times greater than for the counter ions that interact with ioniz- flexibility and consequent facilitation
dextro (D) form. able drug substances leading to the of interactions in solid state systems.
Photolysis. Reactions such as oxida- formation of insoluble drug–excip- Solution interaction studies may
tion–reduction, ring alteration and ient products. Suspending agents such have some predictive capability
polymerization can be catalysed or as sodium alginate or sodium because of such possibilities.
accelerated by exposure to sunlight carboxymethylcellulose dissolve in Reactions with lactose. Lactose can
or artificial light. Energy absorption water to provide large negatively participate in complex reactions with
is greater at lower wavelengths and, charged anions. Co-formulation in compounds containing primary or
as many drugs absorb ultraviolet aqueous systems with drugs such as secondary amines. These can lead to
light, degradation by low-wavelength neomycin and polymyxin, the active assorted low molecular weight
radiation is common. Exposure to moieties of which are positively products and high molecular weight,
light almost invariably leads to dis- charged and of high molecular coloured entities. This ‘Maillard reac-
colouration even when chemical weight, results in precipitation. tion’ has been reported for the anti-
transformation is modest, or even Bentonite (negatively charged) and depressant fluoxetine (a secondary
undetectable. attapulgite (positive) are examples of amine) when formulated with lac-
Polymerization. Intermolecular materials of mineral origin that carry tose. Starch-based formulations did
reactions can lead to dimeric and electrical charges leading to interac- not yield such degradation products.8
higher molecular weight species. tion with drugs of opposite charge. The reactivity of lactose in the solid
Concentrated solutions of ampicillin, Such interactions are usually rapid state is reportedly related to the
an amino-penicillin, progressively and readily apparent in liquid sys- proportion of amorphous material
form dimer, trimer and ultimately tems. It is doubtful whether dosage present, as this lacks the stability
polymeric degradation products.2 forms containing such incompatible provided by the crystal lattice.
Table I lists examples of medicinal ingredients would progress to clinical Amorphous lactose is also more
agents susceptible to such modes of or pharmaceutical evaluation. It can hygroscopic, thereby increasing
degradation. Degradation may also be argued that such interactions possibilities for moisture-assisted
reflect vulnerability to environ- only concern liquid dosage forms. interactions.9
mental stresses such as heat, However, the possibility cannot be Reactions with silicon dioxide.
humidity, light or drug–drug ruled out that they could occur in Silicon dioxide can act as a Lewis
interactions. Degradation may also vivo with solid dosage forms, fol- acid (a substance that can accept an
be facilitated or promoted by excipi- lowing ingestion and hydration in the electron pair) under anhydrous con-
ents possessing the requisite func- gastrointestinal tract. ditions and promote reactions as
tional groups for interaction, or Hydrogen-donating interactions. diverse as dehydration, hydrolysis,
containing residues that catalyse/par- Polyvinylpyrrolidone (PVP or povi- epimerization, cyclization and trans-
ticipate in degradation processes. If done) can interact with compounds esterification. Unwelcome reactions
excipients are also susceptible to containing hydrogen-donating func- between this excipient and diethyl-
change, this provides additional tional groups. Incompatibilities of stilbestrol have been reported.10
possibilities for the generation of PVP with lansoprazole, famotidine Figure 1 shows the silicon dioxide-
species that participate in break- and atenolol all indicate that its car- catalysed oxidation of diethylstilbestrol
down processes. bonyl group is pivotal to degradation to the peroxide and conjugated
quinone degradation products.
Air auto-oxidation of methyl
Table I Modes of degradation of medicinal agents. linoleate to peroxides with subse-
Hydrolysis Oxidation Isomerization Photolysis Polymerization quent decomposition to aldehydes
has been shown to be accelerated in
Methyl dopa Calcitonin Tetracycline Riboflavin Ceftazidime the presence of colloidal silicon
Procaine Ascorbic acid Vitamin A Folic acid Ampicillin dioxide.11 Interaction between
chloramphenicol stearate and
Penicillins Isoprenaline Adrenaline Nifedipine
colloidal silica during grinding leads
to polymorphic transformation of drugs and excipients when consid- molecular weight or acts as a cata-
the chloramphenicol, demonstrating ering possibilities for interaction, it lyst. This is particularly true where
that unwanted effects of excipients must be stated that reactions ‘on an interaction product may pose
are not restricted to chemical trans- paper’ may not always occur in prac- safety questions and needs to be
formations.12 tice, particularly in solid state. Many ‘qualified’ by toxicology studies.
heterocyclic drugs contain amino Such complications often arise after
Physical interactions groups. In accordance with the con- mainstream safety studies have com-
Some excipients are capable of siderations above, lactose should be menced, and can result in delayed or
adsorbing active ingredients to their avoided as a formulation aid, but it is complicated programmes.
surfaces and this has been used to widely and successfully used in tablet Table II illustrates how reactive
enhance the surface area of drugs and capsule dosage forms. Solution chemical entities are commonplace in
and optimize dissolution rate. chemistry does not always translate widely used excipients. The list is not
However, if forces of attraction are to reactions in the solid state, partic- comprehensive, perhaps reflecting
high, desorption may be retarded ularly in terms of rate of reaction, the absence of such information in
and absorption compromised. In a which may be the all-important con- most pharmacopoeial monographs, as
similar context, adsorption of a novel sideration in a dosage form. well as the reluctance of excipient
K-opoid agonist by microcrystalline Stereochemistry, local environment, providers to be forthcoming about
cellulose led to incomplete drug degree of crystallinity or indeed modes of manufacture and types of
release from capsules.13 Adsorption drug–excipient ratio can mean that residues in their products.
of finely divided excipients on to some potential interactions are more Lactose. Lactose is one of the most
active ingredients can also occur and, a problem in concept than reality. widely used excipients in tablets.
if such excipients are hydrophobic, Purification during isolation may
dissolution rate and bioavailability Excipient residues involve treatment with sulphur
may be retarded. Excipients (like drug substances) are dioxide,15 but no complications
Adsorption may also initiate not exquisitely pure. In common with caused by residues of this powerful
chemical breakdown. Colloidal silica virtually all materials of mineral, syn- oxidizing agent have been reported
was shown to catalyse nitrazepam thetic, semi-synthetic or natural nor are limits stipulated for residues
degradation in tablet dosage forms, origin, manufacture involves using in the pharmacopoeial monographs.
possibly by adsorptive interactions starting materials, reagents and sol- Perhaps the volatility of sulphur
altering the electron density in the vents. Residues invariably remain dioxide results in very effective
vicinity of the labile azo group and after isolation. Low levels of residue removal during isolation and drying.
thus facilitating attack by hydro- can have a greater impact than might Lactose is a disaccharide of glu-
lysing entities.14 be expected, however — particularly cose and galactose (see Figure 2).
Although it is prudent to be aware where the ratio of excipient to drug These reducing sugars have been
of functional groups associated with is high, or where the residue has low found in spray-dried lactose,16 as has
the hexose degradation product,
5-hydroxymethylfurfural, probably
Table II Impurities found in common excipients. generated by heat encountered
Excipient Residue during spray-drying.17 As an alde-
hyde, 5-hydroxymethylfurfural can
Povidone, crospovidone, polysorbates Peroxides participate in addition reactions with
Magnesium stearate, fixed oils, lipids Antioxidants primary amino groups, resulting in
Lactose Aldehydes, reducing sugars Schiff base formation and colour
development.18
Benzyl alcohol Benzaldehyde
Dextrose is widely used in par-
Polyethylene glycol Aldehydes, peroxides, organic acids enteral nutrition solutions or as a
Microcrystalline cellulose Lignin, hemicelluloses, water tonicity modifier in parenterals.
Starch Formaldehyde Sterilization by autoclaving has been
Talc Heavy metals
Dibasic calcium phosphate dihydrate Alkaline residues
Figure 1 Degradation pathways of diethylstilbestrol.
Stearate lubricants Alkaline residues
Hydroxypropylmethyl/ethyl celluloses Glyoxal HO
20 Absorption
Desorption Effect of processing. A number of impurities. Peroxide residues in
food industry publications provide povidone (binder) and crospovidone
15 useful insights into how processing (disintegrant) were shown to be
can lead to impurity formation in responsible for the enhanced forma-
10 food additives that are also pharma- tion of the N-oxide degradation
ceutical excipients. High tempera- product of the oestrogen receptor
tures and low moisture contents can modulator, raloxifene. Correlation
5
induce caramelization of sugars and between residual peroxide levels and
oxidation of fatty acids to aldehydes, N-oxide formation enabled a limit to
0 lactones, ketones, alcohols and be set for peroxide content of the
1 20 40 60 80 100 esters.20,21 Such degradation prod- excipients.29
Relative humidity (%) ucts may also be present in the same Microcrystalline cellulose may
materials used in pharmaceutical contain low levels of non-saccharide
dosage forms. Unfortunately, organic residues. These emanate
pharmacopoeial monographs rarely from lignin, a cross-linked
Figure 4 Relationship between nitrazepam decomposition list such organic contaminants. biopolymer made up primarily of the
rate constant and nitrogen adsorption energies of various Microcrystalline cellulose. This com- three allylic alcohols/phenols in the
excipients. (Reprinted with permission from reference 12.) pound is a partially depolymerized wood chip starting material (see
cellulose that is part crystalline and Figure 5).30 It is possible that degra-
Decomposition rate constant/day 103