78
Chemical Stability and Shelf-Life
Determination
8.1 Introduction
Since all pharmaceuticals are chemicals in nature, it is
expected that once the preparation is made, chemical deg-
radation of the active pharmaceutical ingredient (API) (and
other ingredients) begins to occur. These degradation reac-
tions reduce the concentration of the API in the product
over time and replace it with its by-products, which may
be toxic. According to the general rule, the product main-
tains its shelf-life status as long as it contains a minimum
of 90% of the labeled API amount (or concentration).
A more exact definition for the shelf life is the time required
for a product to lose a quantity of the API beyond that spe-
cified by the United States Pharmacopeia (U.S.P.).
From the point of view of chemical stability, APIs may
undergo hydrolysis (e.g. esters and β-lactams), oxidation
(e.g. aldehydes and nitrite derivatives), decarboxylation
(e.g. loss of CO2 from the carboxyl group with heat), dehy-
dration (e.g. tetracycline), epimerization (e.g. tetracycline
drugs), or photochemical reactions (e.g. phenothiazines
and nifedipine) (Allen 2011). Most of the chemical reac-
tions occurring on drug products are either hydrolysis or
oxidation. Oxidative reactions can be promoted in solution
by the presence of residual trace metals, oxygen, and expo-
sure to light (about one-third of all drugs are of concern
with respect to photostability) (Templeton and Klein
2007). These reactions can be prevented by using opaque
or amber-colored containers and the inclusion of chelating
agents in the formulation to trap trace metals. Hydrolysis
reactions are common due to the ubiquitous use of water
as a solvent in formulations. Reduction or total replace-
ment of water by other solvents can either eliminate or sig-
nificantly reduce the hydrolysis reactions. Moreover, the
choice of an optimal pH of the preparation can also play
a role in reducing both the rate of hydrolysis and oxidation
to a significant extent (Shabir and Arain 2004). Although
stability issues can also be physical, they will be discussed
in more detail under each specific dosage form, such as
pharmaceutical suspensions and emulsions.
Integrated Pharmaceutics: Applied Preformulation, Product Design, and Regulatory Science, Second Edition.
Antoine Al-Achi, Mali Ram Gupta, and William Craig Stagner.
© 2023 John Wiley & Sons, Inc. Published 2023 by John Wiley & Sons, Inc.
Companion website: www.wiley.com/go/Al-Achi/IntegratedPharmaceutics
Stability issues are not necessarily confined to aqueous
pharmaceutical preparations. They can occur in any formu-
lation, including solid products or oily liquids. In the latter
case, the oils in these formulations undergo lipid peroxida-
tion reactions. This may be controlled in several ways,
including trace metal chelation, protection from light expo-
sure, the inclusion of antioxidants in the formulation, and
preventing hydrolysis reactions for lipids with fatty acid
esters (Cannon 2008).
Traditional stability studies on drug products include
forced degradation, accelerated stability testing, and long-
term stability determination. Studies have shown that six-
month accelerated stability studies are often sufficient to
assign a shelf life of 18–24 months to a drug product,
although certain regulatory agencies (e.g. the International
Conference on Harmonization) may require longer dura-
tions for stability studies (e.g. 12 months) (Beaman 2010).
Drug stabilization examples are discussed in
Section 3.2.2. Stabilization by cosolvents, surfactants,
micelles, oils, emulsions, liposomes, and complexation
are discussed. Stabilization to oxidation reactions are dis-
cussed in Sections 17.2.2.3 Antioxidants, 17.2.2.3.2 Selection
of Antioxidants, and 17.2.2.4 Metal Sequestrants.
The U.S.P. provides general guidelines for products com-
pounded in a pharmacy operation where no other informa-
tion is available concerning their stability. According to
these guidelines, the beyond-use date (BUD) for a com-
pounded solid or nonaqueous prescription is 25% of that
listed on the commercial products (when a commercial
product is used in its preparation), or six months,
whichever is earlier. If the product is prepared from
U.S.P. chemicals, the BUD is no more than six months.
For water-containing preparations, the BUD is 14 days or
the duration of therapy, whichever is earlier, and the prod-
uct has to be stored under refrigeration. For all other non-
sterile preparations, the BUD is 30 days or the duration of
therapy, whichever comes first. The U.S.P. guidelines for
establishing BUD for sterile products are more restrictive,
and for non-preserved preparations, the guidelines allow

a 28-hour BUD under refrigeration. The BUD for multidose
preparations containing a preservative can be up to 30 days
(the range is between 1 and 30), depending on many
factors, such as the conditions under which the product
is being stored and the number of times a patient uses
the product. (Readers interested in learning more
about this topic are encouraged to refer to the current
U.S.P. chapters <795> and <797> as new require-
ments and guidelines may vary with the latest revi-
sions of the U.S.P.)
8.2 Shelf-Life Determination
8.2.1 Extraction Concepts
In determining the shelf life of a drug in a dosage form, the
drug concentration (or amount) is measured over a period
of time under accelerated stress conditions of temperature
and relative humidity. The dosage form is usually stored
under stress conditions, and periodically a sample is
removed for analysis. An extraction process is usually
needed to separate the drug from its dosage form to get it
ready for chemical analysis. This process of extracting the
drug depends on its partition coefficient value between
the phases used in the extraction process. Typically, the
drug is dissolved in an aqueous solution if it is present in
solid dosage form or is extracted directly from its liquid
aqueous preparation (such as syrups or elixirs). Once the
drug is transferred to an aqueous vehicle, it is extracted
with an organic solvent such as chloroform or ether.
A multiple extraction procedure is customarily done to
assure almost complete transfer of the drug from the aque-
ous solution into the organic phase. Then the organic phase
is entirely removed by evaporation (typically, under a vac-
uum), leaving behind a solid residue of the drug. The drug
residue is subsequently dissolved in an aqueous vehicle
before chemical analysis. The following equations govern
the extraction of the drug from its aqueous vehicle by an
organic solvent (Martin et al. 1983):
PQ
x= 81
PQ + 1
−1
z = PQ + 1 82
x+z=1 83
n n
Fraction remaining = x or z 84
Total fraction extracted = 1 − x n or 1 − zn 85
where P is the partition coefficient of the drug, Q is a vol-
ume ratio (upper/lower), x and z are the fraction of the drug
in the upper and lower phases at equilibrium, respectively,
and n is the number of extractions. For example, assume
8.2 Shelf-Life Determination 79
that a drug with a partition coefficient value of 0.125 in a
water–chloroform system was extracted three times (chlo-
roform was the extractant). What percentage of the drug
is extracted from a 25 mL aqueous portion into chloroform
(25 mL each)? Since chloroform is heavier than water, it
will occupy the lower phase. Calculate for x and z:
0 125
x= = 11 1
1 125
z = 100 − 11 1 = 88 9
3
Fraction remaining = zn = 0 111 = 0 00137
Total fraction extracted in three extractions
= 1 − zn = 1 − 0 00137 = 99 9
Practically speaking, a drug that is 99.9% extracted is
considered to be complete. Once the drug is analyzed for
its content of the active principle, the results reflect its
actual concentration in the product (Martin et al. 1983).
8.2.2 Factors Affecting the Stability
Although the factors that can affect the chemical stability of
the ingredients in the product are numerous, the most nota-
ble are the storage temperature and the pH of the product.
(Other factors can be the presence of additives in the formu-
lation, agitation, or the dosage-form type.)
8.2.2.1 Effect of Temperature
Temperature affects the stability of the product by supply-
ing more “free energy” at a higher temperature, allowing
the reactions to proceed at a much faster rate (Shabir and
Arain 2004). According to the Arrhenius model, proposed
in the 1870s, the rate constant for degradation can be esti-
mated by the following first-order rate expression (Shabir
and Arain 2004):
k = Se − ΔH a RT
86
where k is the degradation rate constant, S the frequency
factor (the number of collisions occurring between the
reacting molecules per unit time), ΔHa the molar heat of
activation (the amount of heat needed to drive the reaction
forward; for most drugs, this value is about 20 kcal/mol,
with a normal range between 15 and 60 kcal/mol), R is
the gas constant, and T is the temperature of the reaction
in kelvin. Equation (8.6) may be linearized by taking the
natural logarithm of both sides of the equation:
ΔH a 1
ln k = ln S − 87
R T
A plot of ln k vs. 1/T yields a straight line with a slope
of −(ΔHa/R) and a y-intercept of ln S. The plot affords an
80 8 Chemical Stability and Shelf-Life Determination

estimation of the degradation rate constant k at storage reactions. The linear expressions for zero-, first-, and sec-
temperatures (25 or 4 C) after estimating Eq. (8.7) at ele- ond-order reactions are:
vated temperatures (i.e. accelerated studies). The value of
A = A0 − k 0 t zero-order 8 11a
k at storage temperatures allows estimation of the shelf life
of a product (usually, it is t90, the time needed for 10% of the lin A = lin A0 − k 1 t first-order 8 11b
drug to degrade) (Shabir and Arain 2004). 1 1
= + k2 t second order 8 11c
Equation 8.7 can be rearranged so that a rate constant at A A0
any temperature can be determined if ΔHa is known (see
A second-order reaction can also be of the type
Eq. 8.7a). In the case of estimating a shelf life, one usually
is interested in determining the extrapolated rate constant dA
− =kA B 8 12
at 25 C. This rate constant is then used in the shelf-life dt
equations discussed below to determine the drug’s
where B is another substance reacting with component
estimated shelf life at 25 C.
A (Shabir and Arain 2004).
ln k 2 k 1 = ΔH a R T 2 – T 1 T2T1 8 7a The degradation of cefazolin sodium in sterile ophthal-
mic solutions stored in sterile glass dropper bottles was
This equation is used to calculate an unknown rate con- evaluated under various temperatures (7, 17, 25, and 40 C)
stant, k2, when k1, T1, and ΔHa are known and T2 is the (Kommanaboyina et al. 2000). Cefazolin sodium undergoes
given temperature for determining k2. a hydrolysis reaction in solution and thus is susceptible to
Of interest is how much of the drug remains in the for- pH changes. The degradation reaction followed first-order
mulation after a specific time of storage. Assume that the kinetics (or perhaps pseudo-first-order kinetics) (at 7 C the
drug [A] reacts with water molecules [W]. Intuitively, reaction was too slow to reach a definite conclusion as to
the rate by which [A] and [W] react together depends the reaction order). The energy of activation obtained from
on the number of collisions the molecules undergo dur- an Arrhenius plot averaged 95.7 kJ/mol, with an average
ing the reaction. Experimentally, it was determined that frequency factor of 5.6 × 1012 collisions/hour.
this rate is a factor of the molar concentration of the When the actual chemical degradation of a drug follows
reactants: first-order kinetics in solution, it is expected that the same
drug behaves as if it follows a zero-order degradation reac-
Reaction rate Ad Ww 88
tion (i.e. an apparent zero-order reaction) in a suspension
The exponents d and w refer to the number of molecules dosage form (Qasem et al. 2003):
of each reactant needed to react. Equation (8.8) can be writ-
k0 = k1 A 8 13
ten with the specific reaction rate constant, k, a constant
that varies with the factors such as temperature, solvent where k0 is the zero-order rate constant, k1 the first-order
dielectric strength, and ionic strength. rate constant, and [A] the solubility of the API in the sol-
vent system. The shelf life of the product can be estimated
Reaction rate = k A d W w 89 from
1 dA 1 dW
Reaction rate = − = − =kAd Ww 0 1 A0
d dt w dt t 90 = 8 14
k0
8 10
with t90 being the time for 10% of the drug to degrade, [A0]
Thus, the degradation rate constant that is calculated
the initial concentration of the drug in the formulation, and
from Eq. (8.7) belongs to a rate of reaction of the type
k0 the zero-order rate constant for degradation. Equa-
dA tion (8.14) may be used to calculate the beyond-use date
− =kAr 8 11 for drugs undergoing a zero-order or apparent zero-order
dt
reaction. To estimate the shelf life of products that experi-
where −(dA/dt) is the rate of degradation (the negative sign ence first- or second-order reactions, the following equa-
implies that the drug concentration is decreasing over tions may be used:
time), [A] the concentration of the drug at time t, and r
the order of the reaction. The symbol [ ] signifies a molar 0 105
t 90 = 8 15
concentration. If r = 0, the reaction follows a zero-order k1
kinetics; if r = 1, the reaction is first order; when r = 2,
the reaction is second order; and so on. Most pharma- 0 11
t 90 = 8 16
ceutical APIs follow either zero-, first-, or second-order A0 k 2
 8.2 Shelf-Life Determination 81

where Eq. (8.15) is for the first-order reaction and Eq. (8.16)
is for the second-order reaction.
Propylthiouracil is an antithyroid agent used in the treat-
ment of hyperthyroidism. This drug was shown to undergo
an apparent zero-order kinetics for its stability in aqueous
suspensions with a characteristic energy of activation of
21 kJ/mol and a frequency factor of 12.61 × 103 collisions/
hour (Alexander 2005). The estimated reaction rate con-
stant at room and refrigerator temperatures was 0.078
and 0.04%, respectively. From the rate constants for degra-
dation obtained from the Arrhenius model at various tem-
peratures (4, 30, 50, 60, and 70 C), the calculated shelf life
of propylthiouracil in suspensions was 127 and 248 days at
25 and 4 C, respectively (Alexander 2005). Table 8.1 pre-
sents various examples of compounded drug products
and their estimated beyond-use dates. Gupta (2007)
reported the degradation of desonide (a corticosteroid used
for ear inflammation) in an eardrop formulation to follow
first-order kinetics at room temperature:
ln concentration = 4 6087 − 0 0005 time days
From the slope of the line, the first-order rate constant is
0.0005 day−1. The shelf life of the drug is calculated as
0 105 0 105
t 90 = = = 210 days
k1 0 0005
However, the actual reading of the decomposition was
91.8% of the original label claim at day 180. Thus, the
author recommended the latter figure for the beyond-use
date for desonide at room temperature in the eardrop for-
mulation [50 mg desonide, 2 mL glacial acetic acid, 50 mL
glycerin, and q.s. (a sufficient quantity) to 100 mL with pro-
pylene glycol] (Gupta 2007).
Reaction rate prediction can be problematic when it
comes to preparations stored under their glass transition
temperature (Tg), defined as the temperature above which
the material converts from a glass state into a less viscous
(more mobile) state, characterized by an increase in flow
rate and heat capacity. The kinetics presentation described
by the Arrhenius model does not apply in this situation,
and to predict the rate constant of reaction, the empirical
Williams–Landell–Ferry (WLF) model is employed instead
(Martin and Mo 2007):
− C1 T − T g
ln k = 8 17
C2 + T − T g
where C1 and C2 are model constants and T is the storage
temperature. The WLF model is suitable for systems that
exhibit high viscosity with a rubbery consistency upon stor-
age. It was shown that the kinetics in these systems is an
order of magnitude higher than that obtained from an
Arrhenius liquid. Thus, systems stored at temperatures
approaching their Tg value experience a significant increase
in reaction rate (Martin and Mo 2007).
8.2.2.2 Effect of pH
Most APIs are either weak acids or weak bases. In solutions,
the pH is normally adjusted so that the API is soluble in the
preparation. However, the same pH that helps achieve

Table 8.1 Sucrose octaacetate chemical kinetic observed first-order regression equations at the designated temperature and pH.

pH

2.00 4.00 5.20 6.00 8.00

35 ya = 0.505e−0.0225t N/A N/A N/A y = 0.471e−0.0235t

R2 = 0.9999b N/A N/A N/A R2 = 0.9963
−0.0464t
45 y = 0.510e N/A N/A N/A y = 0.468e−0.0420t
R2 = 0.9999 N/A N/A N/A R2 = 0.9961
−0.0933t
55 y = 0.515e N/A N/A N/A y = 0.464e−0.0740t
R2 = 0.9999 N/A N/A N/A R2 = 0.9957
−0.00249t −0.00206t −0.00997t
60 N/A y = 0.515e y = 0.497e y = 0.479e N/A
2 2 2
N/A R = 0.9998 R = 0.9972 R = 0.9955 N/A
70 N/A y = 0.514e−0.00468t y = 0.485e−0.00532t y = 0.467e−0.0267t N/A
N/A R2 = 0.9998 R2 = 0.9991 R2 = 0.9942 N/A
−0.00908t −0.0140t
80 N/A y = 0.522e y = 0.484e y = 0.464e−0.0731t N/A
N/A R2 = 0.9984 R2 = 0.9997 R2 = 0.9953 N/A
a
y is the sucrose octaacetate concentration in mg/mL at a given time, e is Euler’s number, t is time in hours.
b
Coefficient of determination for the regression equation for three independent kinetic studies.
Source: Gaddam and Stagner 2017, Table II. Reproduced with permission from Springer.
82 8 Chemical Stability and Shelf-Life Determination
solubility can be detrimental to an API’s stability. To
achieve an optimum pH for product stability, the degrada-
tion rate constant of the API is first obtained under varying
pH values. A plot of the logarithm of k vs. pH yields a graph
with a nadir at the inflection point. The corresponding pH
to that point represents the pH of optimum stability (Shabir
and Arain 2004). For most applications, it appears that an
acidic pH is most favorable for both weak acid and weak
base pharmaceuticals, and this acidic pH is also optimal
to protect the API from both hydrolysis and oxidation reac-
tions (Shabir and Arain 2004). In some instances, a slight
change in the pH of the formulation can produce a signif-
icant effect on a drug’s stability. For example, the stability of
perphenazine (for the control of severe nausea and vomit-
ing; for schizophrenia) in two commercially available syrup
vehicles was found to deteriorate rapidly if the pH of the
vehicle was reduced from 4.5 to 4.2 (Gupta 2008b).
8.2.2.3 Oxidative Degradation
Oxidative degradation can be initiated by molecular oxy-
gen, heat, light, transition metals, and base. Autoxidation
occurs when molecular oxygen oxidizes a drug in the
absence of a catalysis. Oxidative chain reactions occur
through three concurrent reactions: initiation, propaga-
tion, and termination. Free radicals are predominately
involved with oxidative chain processes. Oxidative degrada-
tion is discussed in much more detail in Chapter 17,
Section 17.2.2.3 Antioxidants.
8.2.3 Case Study: Estimation of Sucrose
Octaacetate Shelf Life at 4 and 25 C
Below are the general steps to estimate a drug shelf life.
1) Determine at least three (3) rate constants at three tem-
peratures by plotting the best fit of the concentration
versus time using the zero-order, first-order, and sec-
ond-order equations (Eqs. 8.11a–8.11c).
a) The rate constants should be determined in triplicate
to provide a greater degree of confidence in the cal-
culated values.
b) At one temperature, study the effect of concentration
on the rate constant. If the rate constants are concen-
tration independent, the reaction is zero order (see
Eqs. 8.11, 8.11b, and 8.15).
1) Find the ΔHa, by plotting ln k versus 1/T using
the Arrhenius relationship (use Eq. 8.7).
2) For each pH, determine k for the shelf-life tem-
perature of interest by substituting the ΔHa deter-
mined in Step 2 into Eq. (8.7a). This rate constant
is referred to as the extrapolated rate constant,
kextrapolated.
3) For each pH and temperature, substitute the
kextrapolated, determined in Step 3, into the appro-
priate shelf-life expression (see Eq. 8.14, 8.15, or
8.16). Calculate the estimated shelf-life for each
studied pH and temperature.
To determine the shelf-life at the drug’s optimally sta-
ble pH and temperature, a pH-rate profile needs to be
constructed for each shelf-life temperature using the
above data.
4) A pH-rate profile is constructed by plotting the ln
kextrapolated against their respective pH values for a
specific temperature.
5) For a specific temperature, the optimum drug sta-
bility pH is located at the minimum of the pH-rate
profile.
6) For a specific temperature, the rate constant value
at the minimum of the pH-rate profile is then
used as the rate constant to determine the drug’s
shelf-life at its most stable pH.
The goal of the sucrose octaacetate (SOA) chemical
kinetic study was to determine its shelf life at 4 and 25 C
at its optimum pH (Gaddam and Stagner 2017). The steps
discussed above were used to accomplish this goal. Prelim-
inary studies showed that SOA was susceptible to acidic
and basic media degradation. Figure 8.1 is a plot of SOA
concentration remaining versus time at pH 2.00 and 8.00
at 35, 45, and 55 C.
Figure 8.2 shows the SOA degradation at pH 4.00, 5.20,
and 6.0 at 60, 70, and 80 C. A first-order rate expression,
A = A0e−kt where A is the SOA concentration, fit all the data
the best. Table 8.1 gives the equation for the best-fit line
with its accompanying R2 value at a given temperature
and pH. The calculated observed rate constant is given in
the exponent.
ln k obs = ln A – ΔH a RT 8 18
where ln is the natural logarithm, kobs is the observed rate
constant in h−1 shown in Table 8.1 as the “exponent,” S is
the Arrhenius number or frequency factor whose units
are the same as the rate constant (h−1), ΔHa is the activa-
tion energy in kcal/mol, R the universal gas constant
(1.987E-3 kcal/K/mol), and T is the absolute temperature
in kelvin (K). A plot of ln kobs versus 1/T (Figure 8.3) gives
a slope of −ΔHa/R. The activation energy can be calculated
from the slope. Table 8.2 lists the ΔHa values for pH 2.00,
4.00, 5.20, 6.00, and 8.00.
In this report, Eq. (8.19) was used to calculate the extra-
polated rate constants for temperatures not studied.
ln k 2 k extrapolated = Ea R T 2 – T extrapolated T 2 T extrapolated
8 19
 8.2 Shelf-Life Determination 83

0.6

a
0.5
SOA concentration remaining (mg/mL)

b
f c
e d
2x
0.4

0.3

0.2

0.1
a
f d b
e c
0
0 20 40 60 80 100 120 140
Time (min)
[a] pH 2.00, 35°C [c] pH 2.00, 45°C [e] pH 2.00, 55°C
[b] pH 8.00, 35°C [d] pH 8.00, 45°C [f] pH 8.00, 55°C

Figure 8.1 Sucrose octaacetate (SOA) concentration remaining versus time for samples stored at pH 2.00 and 8.00 and 35, 45, and 55 C.
Bars represent standard deviation of three independent kinetic studies. Source: Gaddam and Stagner 2017, Figure 2. Reproduced with
permission from Springer.

0.6
2x

b
0.5 g h
f e d a
SOA concentration remaining (mg/mL)

i c

0.4

0.3

0.2

0.1
b
a
f c e
i h g d
0
0 100 200 300 400 500 600 700 800 900 1000
Time (min)
[a] pH 4.00, 60°C [d] pH 4.00, 70°C [g] pH 4.00, 80°C
[b] pH 5.20, 60°C [e] pH 5.20, 70°C [h] pH 5.20, 80°C
[c] pH 6.00, 60°C [f] pH 6.00, 70°C [i] pH 6.00, 80°C

Figure 8.2 Sucrose octaacetate (SOA) concentration remaining versus time for samples stored at pH 4.00, 5.20, and 6.00 and 60.0, 70.0,
and 80.0 C. Bars represent standard deviation of three independent kinetic studies. Source: Gaddam and Stagner 2017, Figure 3.
Reproduced with permission from Springer.

where k2 is the observed rate constant at T2 in kelvin, Table 8.2, the estimated SOA shelf lives at pH 2.00 and 8.00 at
kextrapolated is the extrapolated rate constant at the extrapo- 25 C are less than a day! The SOA estimated shelf life at pH
lated temperature in kelvin, Textrapolated, at a given pH. The 5.2 and 4 C is over five years! This highlights the significant
extrapolated temperatures chosen in this study were the effect that temperature and pH have on SOA’s stability.
shelf lives of interest, which was 4 and 25 C. The extrapo- To find SOA’s optimum stability pH, a pH-rate profile
lated rate constants at these temperatures and pH 2.00, was constructed by plotting log kextrapolated versus pH
4.00, 5.20, 6.00, and 8.00 are provided in Table 8.2. Also from (Figure 8.4) at 4 and 25 C. SOA’s most stable pH was
84 8 Chemical Stability and Shelf-Life Determination

–2.00

–2.50 pH 2.00

–3.00 pH 8.00

–3.50
ln [k] observed

–4.00
pH 6.00

–4.50

–5.00

–5.50
pH 4.00

–6.00 pH 5.20

–6.50
0.00280 0.00285 0.00290 0.00295 0.00300 0.00305 0.00310 0.00315 0.00320 0.00325 0.00330
1/Temperature (1/K)

Figure 8.3 Arrhenius plots for the natural logarithm values of kobs as a function of reciprocal temperature in kelvin (K) at pH 2.00, 4.00,
5.20, 6.00, and 8.00. Bars represent relative error from 3 independent kinetic studies. Source: Gaddam and Stagner 2017, Figure 4.
Reproduced with permission from Springer.

Table 8.2 Sucrose octaacetate activation energy, extrapolated degradation rate constants at 4 and 25 C, and estimated shelf life at
4 and 25 C.

Shelf life, 4 oC Shelf life, 25 oC

1
pH Ea, kcal mol−1 k4 oC, h−1
3 4
k25 oC, h−1 Years Days

2.00 14.3 ± 0.02 1.65E-3 ± 1E-5 1.03E-2 ± 1E-5 7.24E-3 ± 4E-4 4.25E-1 ± 8E-2
4.00 15.1 ± 0.3 2.51E-5 ± 2E-7 1.73E-4 ± 2E-6 4.78E-1 ± 4E-3 2.53E1 ± 3E-2
5.20 22.4 ± 0.7 2.28E-6 ± 3E-8 3.84E-5 ± 2E-6 5.26E0 ± 8E-2 1.14E2 ± 6E0
6.00 23.3 ± 0.3 8.14E-6 ± 9E-8 1.60E-4 ± 2E-6 1.47E0 ± 1E-2 2.74E1 ± 4E-1
8.00 11.5 ± 0.1 2.87E-3 ± 2E-5 1.25E-2 ± 6E-5 4.17E-3 ± 2E-5 3.49E-1 ± 5E-2

located at the pH-rate profile’s minimum. The optimum pH
at 4 C was 5.40 and its corresponding extrapolated
rate constant was 1.41E-6 h−1. At 25 C, SOA had an
optimum pH 5.10 and its extrapolated rate constant
was 2.00E-5 h−1. These respective extrapolated rate con-
stants were substituted into Eq. (8.15) to calculate the shelf
life at the optimum pH. SOA’s shelf life at 4 C and pH 5.40
was estimated to be 8.5 years. Its estimated shelf life at 25 C
and pH 5.10 was 219 days.
8.3 Stability of Biotechnology
Products
Biotechnology products are increasingly becoming a
major component of the pharmaceutical industry, the esti-
mate for marketed products being nearly $50 billion a year
(Matejtschuk et al. 2009). Because of their fragile nature,
biotechnology products must be stabilized to accommo-
date handling requirements during processing and by
patients. One method for improving the stability of these
products is lyophilization (freeze-drying). During the
process of lyophilization, the material is subjected first
to a freezing cycle, followed by a low-pressure cycle to
induce sublimation for initial drying, and a final drying
cycle (Blue and Yoder 2009; Matejtschuk et al. 2009). Opti-
mum conditions (Matejtschuk et al. 2009) for this opera-
tion were determined to include an initial rapid-freezing
step accompanied by periods of slow cooling, allowing lar-
ger ice crystals to materialize. (Larger ice crystals require
less time for the sublimation step.) During the sublimation
phase, it is desirable to keep the product below its glass
transition temperature (Tg) (i.e. the temperature at which
noncrystalline components of the product become immo-
bilized). Maintaining the material below Tg was found to
be associated with better product stability. Additives in the

–1
–2 25 °C
log [k] extrapolated
4 °C
–3
–4
–5
–6
0 1 2 3
Specific hydrogen ion catalysis
Figure 8.4 Sucrose octaacetate pH-rate profiles of logarithm values of kextrapolated versus pH. The plotted lines were constructed assuming
specific hydrogen ion catalysis occurred at pH 2 and 4 and hydroxide-ion-specific catalysis existed at pH 6 and 8. Source: Gaddam and
Stagner 2017, Figure 5. Reproduced with permission from Springer.
formulation also play a major role from the point of view
of stability. Trehalose, a sugar, was found in many cases to
provide a good final stability profile for a product. The
final stage of the lyophilization process is a secondary dry-
ing step to reduce the content of water “bound” to the API.
This is normally achieved by adjusting the temperature to
ambient ranges or higher (Blue and Yoder 2009). The
amount of moisture content in the final product can range
from below 1% to up to 5% by weight (Blue and Yoder
2009; Matejtschuk et al. 2009). The closer the moisture
content to the Tg value, the poorer is the stability of the
preparation (Blue and Yoder 2009). Ideally, the moisture
content should be well below the Tg value and should
never exceed it (Blue and Yoder 2009). Desiccating the
product to reduce its moisture content may be necessary
as a final step for certain biotechnology materials. Accel-
erated stability studies are done at relatively high tempera-
tures applying Arrhenius kinetics principles (Matejtschuk
et al. 2009).
Therapeutic proteins have made significant inroads as
drug therapies used to treat human conditions that were
not treatable with noncomplex molecules such as growth
hormone replacement and multiple sclerosis. These mole-
cules have special physicochemical characteristics that
need to be considered carefully during formulation devel-
opment. In addition to the effect of pH and temperature
on deamidation, dimerization, oxidation, proteolysis,
disulfide exchange, β-elimination, Maillard reactions,
and racemization reactions, therapeutic proteins require
additional attention to maintaining their three-dimensional,
native, folded, active state. Physical changes such as unfold-
ing or denaturation, aggregation, and precipitation can occur
8.3 Stability of Biotechnology Products 85
4 5 6 7 8 9
pH
Specific hydroxide ion catalysis
due to shear or shaking, adsorption, heating, freezing, dehy-
dration, and pH changes. Peptides and proteins are surface
active and therefore migrate to the air–vehicle and container
closure plastic or glass interface with the solution vehicle.
Adsorption may lead to protein unfolding, aggregation,
and precipitation. Also, as surface-active materials, peptides
and proteins tend to self-associate or aggregate and lose
activity. The level of aggregation increases with increased
peptide or protein concentration. Aggregation can lead to
significant drug loss. There is also a growing association
between the presence of aggregates and the stimulation of
immunogenic responses to the aggregates.
Table 8.3 lists the typical peptide and protein degradation
reactions. These reactions are more likely to occur if the
reactive amino acid is on the surface of the protein or acces-
sible to the aqueous environment and not buried in the
interior or the more lipophilic folded structure.
Preformulation studies should identify the most critical
physical and chemical stability issues that are specific to
a particular therapeutic protein. A protein-specific stabili-
zation strategy can then be developed. The following dis-
cussion presents an array of stabilizing excipients and
methods that can be used to increase the shelf life of a ther-
apeutic protein. Human serum albumin is a well-known
stabilizer that has a molecular mass of approximately
65,000 Da, 584 amino acids, and 17 disulfide bonds. It is
well known as a binding molecule for noncomplex drugs
that circulate in the plasma. Albumin has some interesting
physicochemical properties that make it well suited as a sta-
bilizing excipient. Even though it is a protein, it is reason-
ably stable to changes in temperature and pH. Albumin is
stable to pasteurization conditions of 60 C for 10 hours. At
86 8 Chemical Stability and Shelf-Life Determination

Table 8.3 Typical peptide or protein degradation reactions.

Type of
chemical pH of most reactivity Generalized optimal
reaction Affected amino acid (Generalized) stable pH

β-Elimination Cysteine, serine, and threonine >7 3–6

Deamidation Asparagine, glutamine <3 and >7.5 3–5
Dimerization Reaction between the N- and C-terminal ends. Other
(covalent reactions between amino acids, such as disulfide
bond) formation and amide formation
Oxidation Methionine, cysteine, histidine, tryptophan, tyrosine, ~5–7 and greater 2–4 (in general, oxidation
phenylalanine, and proline reactions increase with
increasing pH)
Proteolysis All amide linkages, and aspartic acid–proline linkages, Hydrolysis (<3 and >8), Hydrolysis 4–6,
are more susceptible diketopiperazine (5–8 diketopiperazine 3–4
and greater)
Maillard Lysine (primary and secondary amines react with Acid catalyzed 4–6
reaction aldehydes, and more specifically, reducing sugars: the
Maillard reaction)
Disulfide Cysteine ~5–7 and greater 3–4
exchange

a pH of 1–2, albumin elongates but returns reversibly to its
native state as the pH is increased to its isoelectric point of
4.8. Unlike many proteins, albumin is soluble at its isoelec-
tric point. It is also soluble in dilute base. Albumin has been
used as a stabilizer for a number of commercial proteins
Wang and Hanson 1988). At 0.003% w/v, albumin decreased
the adsorption of erythropoietin to glass and plastic surfaces.
At 0.003% w/v, albumin decreased the dissociation of alcohol
dehydrogenase subunits. It has been used at concentrations
ranging from 0.1 to 15% w/v as a cryoprotectant, an agent
that protects a protein from denaturing during the freezing
step of freeze-drying (Wang and Hanson 1988). Albumin
may be a carrier or solubilizer for peptides and proteins in
the same way that it is a carrier for bilirubin.
Amino acids such as aspartic acid and glutamic acid have
been shown to inhibit protein adsorption to silicone-treated
glass. Glycine and alanine have been shown to stabilize pro-
teins undergoing heat treatment. Glycine has been used as
a stabilizer for anti-Rh, a-interferon, and antithymocyte
globulin at concentrations in the range 0.015, 2, and
2.25% w/v, respectively. Phospholipids and surfactants such
as polysorbate 80 (Tween 80), polysorbate 20 (Tween 20),
and poloxamer (Pluronic) have been shown to be stabilizers
(Wang and Hanson 1988). They may preferentially adsorb
to surfaces and compete for interfaces with the proteins.
They may also decrease the surface tension at the interface
and make proteins less likely to unfold during shaking or
other forms of shear.
Polyols such as polyhydric alcohols (glycerin, erythritol,
xylitol, and sorbitol), nonreducing disaccharides (sucrose,
trehalose, raffinose, and maltose), poly(ethylene glycol),
and hydroxymethyl cellulose have been used to decrease
aggregation by affecting water structure. Polymers such
as poly(vinylpyrrolidone), gelatin, poly(ethylene glycol),
and hydroxymethyl cellulose may act as protective
colloids that prevent the proteins from interacting to self-
associate.
Peptides have been shown to be stable for several years in
solution at room temperature. Oxytocin has a five-year
shelf life when stored at room temperature. Most solution
therapeutic proteins require refrigerated storage. For exam-
ple; humanized growth hormone, insulin, and natalizumab
have shelf lives of 18 months, 18–24 months, and 4 years,
respectively, when stored at 2–8 C. These products require
a cold storage distribution chain from manufacturing,
to the distribution warehouse or wholesaler, to the
pharmacy, to the patient, and in the home as is the case
of insulin. Many product labels also warn against shaking
the product, which may result in loss of potency. For more
extensive discussions concerning protein formulation
development, see Wang and Hanson (1988), Pearlman
and Wang (1996), and McNally and Hastedt (2013).
8.4 Compounded Products and Their
Beyond-Use Dates
Table 8.4 presents various examples of compounded drug
products and their estimated beyond-use dates (BUD).
Recall that BUD is a term used with compounded prepara-
tions, whereas expiration dates are for manufactured
products.
Table 8.4 Beyond-use date for compounded preparations: selected examples.

BUD under
Drug name Therapeutic action Formulation type BUD room temperature refrigeration Comments Reference

Acyclovir sodium For herpes virus Sterile solution in 0.9% 30 d Physical instability Stored in polypropylene syringes (Becton, Ling and Gupta
infection sodium chloride injection (precipitations within Dickinson Co., NJ) (2001a)
(10 mg/mL) 5 d)
Alatrofloxacin mesylate Antibacterial Intravenous injection in 5% At least 9 d — Sterile preparation in poly(vinyl chloride) Gupta and Bailey
dextrose injection (1.88 mg/ plastic containers (2000)
mL)
Antibacterial Intravenous injection in At least 9 d — Sterile preparation in poly(vinyl chloride) Gupta and Bailey
0.45% sodium chloride plastic containers (2000)
injection (1.88 mg/mL)
Albuterol Bronchodilator/ A sterile solution (in 0.9% — At least 7 d Sterile solutions of drug were prepared in Lardinois et al.
exercise induced sodium chloride; 0.060 mg/ 0.9% sodium chloride and stored in (2019b)
asthma mL) polypropylene syringes protected from
light
Albuterol sulfate Bronchodilator/ Nebulizer solution: sterile At least 7 d At least 7 d Storage containers: poly(vinyl chloride), Hunter et al.
exercise-induced solution in 0.9% sodium polyolefin, polypropylene syringes, (1998)
asthma chloride injection (0.2 mg of borosilicate glass, and polypropylene
albuterol/mL) microcentrifuge tubes
Allopurinol For hyperuricemia/ Suspension (20 mg/mL) 8.3 yr — Suspension was prepared from tablets and Alexander et al.
gout stored in amber-colored glass bottles (1997a)
Alprostadil Vasodilator Sterile alcoholic solutions in — 10 d Alcoholic solutions of drug were diluted McCluskey et al.
0.9% sodium chloride in 0.9% sodium chloride solution. 2017
Solutions were kept in polyvinyl chloride
containers
Aminocaproic acid Fibrinolysis Sterile solutions in 0.9% At least 7 d At least 7 d Stored in poly(vinyl chloride) bags Zhang and Trissel
inhibitor/for life- sodium chloride injection (10 (1997)
threatening and 100 mg/mL)
hemorrhaging
Amiodarone Antiarrhythmic Suspension (20 mg/mL) 193.4 d 677.3 d — Alexander and
hydrochloride Thyagarajapuram
(2003)
Antiarrhythmic Solution of amiodarone — 28 d Solutions stored in polypropylene Lardinois et al.
hydrochloride (25 mg/mL) in syringes and protected from light (2019c)
syringes of dextrose 5%
Antiarrhythmic Oral suspensions At least 90 d At least 90 d Suspensions were prepared in SyrSpend Geiger et al. (2015)
SF PH4 and packaged in low-actinic
plastic bottles
Amitriptyline For the treatment of Topical 90 d — Prepared in Lipoderm Base and PLO Gel Shakshuki and
neuropathic pain Mediflo 30 (MEDISCA, USA) Agu (2019)
For the treatment of Oral suspension (20 mg/mL) 91 d 91 d Suspensions were prepared in Nahata (2016b)
neuropathic pain commercial vehicles [OraPlus:OraSweet

(Continued)
Table 8.4 (Continued)

BUD under
Drug name Therapeutic action Formulation type BUD room temperature refrigeration Comments Reference

(1 : 1)] and stored in plastic prescription

bottles
For the treatment of Oral suspension (20 mg/mL) 28 d 42 d Suspensions were prepared in 1% Nahata (2016b)
neuropathic pain methylcellulose:simple syrup (1 : 10) and
stored in plastic prescription bottles
Amlodipine besylate Calcium channel Oral suspensions (various 7d 90 d Suspensions were prepared in SuspendIt Graves et al.
blocker/for angina concentrations) base (PCCA, TX) (2019)
prevention
Amphotericin B Antifungal Eyedrop sterile solution 16 d 120 d Protected from light exposure Peyron et al.
in 5% dextrose solution (1999)
(5 mg/mL)
Ampicillin Antibiotic Sterile solutions in 0.9% NaCl 24 h 48 h Solutions were prepared with 10 mM Maher et al. (2016)
(12 g/L) sodium phosphate for injection
Atenolol Antihypertensive/for Liquid preparations in 14 d — Liquid preparations in vehicles of simple Patel et al. (1997)
angina pectoris and simple syrup or Ora-Sweet syrup and Ora-Sweet (Paddock
myocardial infarction (2 mg/mL) Laboratories, MN)
Antihypertensive/for Liquid preparations in At least 28 d — Liquid preparations in vehicles of Ora- Patel et al. (1997)
angina pectoris and methylcellulose or Ora- Sweet SF (Paddock Laboratories, MN)
myocardial infarction Sweet SF (2 mg/mL) and methylcellulose
Atropine sulfate Decrease salivation/ Sterile solution in 0.9% 364 d 364 d Solution was prepared from atropine Donnelly and
bronchial secretions sodium chloride solution sulfate powder dissolved in isotonic saline Corman (2008)
prior to surgery (2 mg/mL) solution, filtered through 0.2-μm pore
filters, and packaged in polypropylene
For bradycardia syringes (Becton, Dickinson Co., NJ)

An antidote for
mushroom
poisoning and
cholinergic drugs
Azathioprine Immunosuppressive Oral solutions (50 mg/mL) 14 d 14 d Suspension was prepared from drug Polonini et al.
agent powder in SyrSpend® SF From Fagron (2020)
(St. Paul, MN)
Bethanechol chloride For urinary retention Oral liquid (concentration 40 d — Making the solution from commercially Gupta and
(postoperatively) unknown) available tablets was not stable; solutions Maswoswe
were made from commercial injections of (1997b)
the drug
Bevacizumab Eye diseases Sterile solutions — 3d Solutions were repackaged in plastic Pereboom et al.
syringes (2015)
Cancer
Brompheniramine Antihistamine Oral liquid (0.4 mg/mL) At least 202 d — Stored in amber-colored glass bottles Gupta and Gupta
(2011)
Brompheniramine Antihistamine Oral liquid (0.4 mg/mL) 202 d — Stored in amber-colored glass bottles Gupta and Gupta
maleate (2011)
Captopril Angiotensin- Oral suspensions — 14 d Suspensions were prepared in SyrSpend Geiger et al.
converting enzyme (0.8 mg/mL) SF and stored in low-actinic plastic bottles (2013a)
inhibitor and protected from light
Cefazolin sodium Antibacterial Ophthalmic sterile solution 6d 14 d Stored in sterile ophthalmic dropper Kommanaboyina
in 0.9% sodium chloride bottles et al. (2000)
injection (3.5 mg/mL)
Antibacterial/for Sterile solutions in 0.9% 7d 22 d Stored in polypropylene syringes (Becton, Gupta (2003a)
urinary tract sodium chloride (50 mg/mL) Dickinson Co., NJ)
infections/lower
respiratory tract
infections
Cefepime Antibacterial/urinary Sterile solutions in 5% 2d 23 d Solutions stored in plastic bags (Baxter Gupta et al. (1997)
hydrochloride tract infections dextrose injection (0.05 mg/ Healthcare Corp., IL)
mL)
Antibacterial/urinary Sterile solutions in 5% 2d 23 d Solutions stored in plastic bags (Baxter Gupta et al. (1997)
tract infections dextrose injection (0.05 mg/ Healthcare Corp., IL)
mL)
Antibacterial/for Sterile solution in 0.9% At least 2 d At least 21 d Stored in polypropylene syringes (Becton, Ling and Gupta
urinary tract sodium chloride injection Dickinson Co., NJ) (2001b)
infections/ (20 mg/mL)
pneumonia/skin
infections
Cefmetazole sodium Antibiotic/urinary Sterile solution in 5% 2d 28 d Stored in 50-mL plastic bags (Baxter Gupta and
tract infections dextrose injection (0.2 g/mL) Healthcare Corp., IL) Maswoswe
(1997e)
Antibiotic/urinary Sterile solution in 0.9% 2d 28 d Stored in 50-mL plastic bags (Baxter Gupta and
tract infections sodium chloride injection Healthcare Corp., IL) Maswoswe
(0.2 g/mL) (1997e)
Cefotaxime sodium Antibiotic/urinary Sterile solution in 0.9% 1d 18 d Stored in polypropylene syringes Gupta (2002b)
tract infections/lower sodium chloride injection
respiratory tract (50 mg/mL)
infections
Cefuroxime sodium Antibacterial/for Sterile solution in 0.9% 2d 21 d Packaged in polypropylene syringes Gupta (2003b)
urinary tract sodium chloride injection (Becton, Dickinson Co., NJ)
infections/lower (50 mg/mL)
respiratory tract
infections
Clindamycin Antibiotics Oral suspension 182 d 182 d Suspensions were prepared in SuspendIt Pramar et al.
hydrochloride (PCCA, Texas) (2016)
Clindamycin phosphate Antibiotics Sterile solutions in 0.9% 7d 30 d Packaged in AutoDose Infusion System Xu and Trissel
sodium chloride (6 and 12 Bags (Tandem Medical, Inc., CA) (2003)
mg/mL)
Clonazepam For epilepsy Suspension in Hospital for — At least 60 d HSC contains simple syrup and Roy and Besner
Sick Children (HSC) vehicle methylcellulose; suspensions were stored (1997)

(Continued)
Table 8.4 (Continued)

BUD under
Drug name Therapeutic action Formulation type BUD room temperature refrigeration Comments Reference

in poly(vinyl chloride) amber-colored

plastic bottles
Clonidine Antihypertensive Oral suspension (0.1 mg/mL) 90 d 90 d Suspension was prepared from drug Polonini et al.
hydrochloride agent powder in SyrSpend® SF From Fagron (2020)
(St. Paul, MN)
Clopidogrel bisulfate Inhibits platelet Oral suspension (5 mg/mL) 90 d 30 d Suspension was prepared from crushed Polonini et al.
aggregation tablets in SyrSpend® SF From Fagron (St. (2020)
Paul, MN)
For cardiovascular
illnesses (e.g.
myocardial
infarction)
Cocaine hydrochloride Anesthetic Sterile solutions (50 mg/mL) 48 h 15 d Solutions were stored in in glass bottles Dewulf et al.
(2015)
Dalteparin Anticoagulant Sterile solution (1000 units/ — At least 30 d Solutions were prepared and stored in Kirkham et al.
mL) in 0.9% sodium chloride 1-mL polypropylene syringes (2017)
for injection
Dehydroepiandrosterone Hormonal precursor Rapid-dissolving tablets Over 6 mo — Tablets were packaged in amber blister Rush et al. (2017)
(10 mg/Tab) packs
Desonide Corticosteroid/for ear Ear drops (0.5 mg/mL) 180 d — Stored in amber-colored glass bottles Gupta (2007)
inflammation (Owens-Illinois Prescription Products,
OH)
Dexamethasone Adrenocortical Sterile solutions in 0.9% 22 d — Stored in polypropylene syringes (Becton, Gupta (2002a)
sodium phosphate steroid sodium chloride injection Dickinson Co., NJ)
(0.1 and 1 mg/mL)
Diclofenac sodium Anti-inflammatory Sterile solution (25 mg/mL) 23 d Drug precipitates Packaged in clear-glass vials and stored in Gupta (2006a)
out from solution the dark
Diphenhydramine Antiemetic Sterile solutions of Over 48 h — Sterile solution were stored in Anderson et al.
hydrochloride, diphenhydramine polypropylene syringes (2015)
lorazepam, and hydrochloride (4 mg/mL),
dexamethasone lorazepam (0.16 mg/mL),
sodium phosphate and dexamethasone sodium
phosphate (0.27 mg/mL)
Dobutamine For congestive heart Intravenous injection in 5% 30 d 30 d Sterile preparation Webster et al.
hydrochloride failure dextrose injection (4 mg/mL) (1999)
Doxycycline Antibiotic Oral suspensions (5 mg/mL) 2 wk 2 wk Suspensions stored in plastic prescription Nahata (2015)
bottles
Droperidol Neuroleptic Sterile solution in 0.9% 180 d — Stored in polypropylene syringes; McCluskey and
sodium chloride injection solutions were stored, protected from Lovely (2011)
(0.625 mg/mL) light
Ephedrine sulfate A pressor agent Sterile solutions in 0.9% 60 d 60 d Solutions were packaged in Storms et al.
during spinal sodium chloride injection polypropylene syringes (Becton, (2001)
anesthesia (5 mg/mL) Dickinson Co., NJ)
Eslicarbazepine Anticonvulsant Oral suspensions (40 mg/ Up to 2 mo Up to 2 mo Suspensions were prepared in 50 : 50 v/v Zhao et al. (2018)
acetate mL) Ora-Sweet:Ora-Plus or Ora-Sweet SF:
Ora-Plus vehicles
Esomeprazole A proton-pump Sterile solutions (0.4 and — 20 d (for 0.4 mg/mL) Solutions prepared in 5% dextrose Hecq et al. (2015)
inhibitor; for GERD 0.8 mg/mL) 29 d (for 0.8 mg/mL) polyolefin bags. Subjected to freeze-thaw
cycle using microwave
Ethacrynate sodium Diuretic Sterile solution in 0.9% At least 14 d At least 22 d Stored in polypropylene syringes (Becton, Ling and Gupta
sodium chloride injection Dickinson Co., NJ) (2001c)
(1 mg/mL)
Ethacrynic acid Diuretic Oral aqueous liquid (2.5 mg/ 3 d 24 d The dosage form contained 0.05 M Ling and Gupta
mL) phosphate buffer and 10% mannitol (2001d)
Ethambutol For the treatment of Oral aqueous suspension 90 d 90 d Suspension was prepared from drug Polonini et al.
hydrochloride tuberculosis (50 mg/mL or 100 mg/mL) powder in SyrSpend® SF From Fagron (2020)
(powder) (St. Paul, MN)
For the treatment of Oral suspension (50 mg/mL) 90 d 90 d Suspension was prepared from crushed Polonini et al.
tuberculosis tablets in SyrSpend® SF From Fagron (St. (2020)
Paul, MN)
Fentanyl Opiate analgesic Sterile solution (0.05 mg/mL) 28 d 28 d (protected Stored in polypropylene syringes or Donnelly (2005)
(exposed to light) from light) poly(vinyl chloride) bags
Opiate analgesic Sterile solutions (10 μg/mL; 93 d 93 d Solutions prepared and stored in in Donnelly (2015)
50 μg/mL) in sodium polyvinyl chloride bags. Solutions kept at
chloride 0.9% room temperature were exposed to light;
those placed under refrigeration were
protected from light
5-Fluorouracil Antineoplastic agent/ Ophthalmic sterile solution 7d 7d Stored in 1-mL tuberculin syringes Fuhrman et al.
for glaucoma/ in 0.9% sodium chloride (Becton, Dickinson Co., NJ) solutions (2000)
pterygium/retinal injection (10 mg/mL) stored in the freezer (−10 C) also had a
detachment/ beyond-use date of 7 d
premalignant eye
lesions
Fluoxetine For depression and Organogels (50 mg/mL) 180 d — Drug was dissolved in Pluronic lecithin Peacock and
obsessive-compulsive organogels and stored, protected from Sauvageot (2014a)
disorder light

For controlling urine

spraying in felines
(veterinarian)
Furosemide Diuretic Sterile solutions in 0.9% 84 d 84 d Solutions were protected from light and Donnelly (2002)
sodium chloride injection stored in polypropylene syringes
(1.2, 2.4, and 3.2 mg/mL)
Diuretic Oral suspensions (2 mg/mL) 30 d 30 d Suspensions prepared by crushing tablets Svirskis et al.
and suspended in commercial vehicles (2020)
(Ora-Blend, Ora-Blend SF, or SyrSpend-
SF Alka, Perrigo, Allegan, MI)

(Continued)
Table 8.4 (Continued)

BUD under
Drug name Therapeutic action Formulation type BUD room temperature refrigeration Comments Reference

Diuretic Oral suspensions — At least 14 d Suspensions were prepared in SyrSpend Geiger et al. (2015)
SF Alka and stored in low-actinic plastic
bottles
Glycopyrrolate Preoperative Oral liquids prepared from 25 d — Solutions were stored in amber-colored Gupta (2001b)
antimuscarinic/for tablets (0.5 mg/mL) in water bottles (Owens-Illinois Prescription
salivary, Products, OH)
tracheobronchial,
and pharyngeal
secretion reduction
Preoperative Oral liquid (0.5 mg/mL) At least 129 d — Stored in amber-colored bottles Gupta (2003c)
antimuscarinic/for
salivary,
tracheobronchial,
and pharyngeal
secretion reduction
Preoperative Sterile solution (0.2 mg/mL) 90 d 90 d Stored in polypropylene syringes (Becton, Storms et al.
antimuscarinic/for Dickinson Co., NJ) (2003)
salivary,
tracheobronchial,
and pharyngeal
secretion reduction
Preoperative Oral suspensions (0.2 mg/ 14 d 14 d Suspensions were prepared in 1% Nahata (2016b)
antimuscarinic/for mL) methylcellulose:simple syrup (1 : 10) or
salivary, commercial vehicles [OraPlus:OraSweet
tracheobronchial, (1 : 1)] and stored in plastic prescription
and pharyngeal bottles
secretion reduction
Griseofulvin Antifungal Oral suspension (25 mg/mL) 90 d 90 d Suspensions prepared by drug powder Polonini et al.
suspended in commercial vehicles (Ora- (2020)
Blend, Ora-Blend SF, or SyrSpend-SF
Alka, Perrigo, Allegan, MI)
Heparin sodium Anticoagulant Sterile solutions (1000 and 30 d — Polypropylene syringes (CADD-Micro Stiles et al. (1997)
40,000 units/mL) Medication Reservoir, 10 mL, Sims
Deltec, Inc.)
Hydralazine For hypertension Sterile solution in 0.9% 2d — Packaged in poly(vinyl chloride) bags Gupta (2005a)
hydrochloride sodium chloride injection
(0.2 mg/mL)
For hypertension Sterile solution in 5% 1h — Packaged in poly(vinyl chloride) bags Gupta (2005a)
dextrose injection (0.2 mg/
mL)
Antihypertensive Oral solutions (1 and 10 mg/ — Up to 30 d Stored in glass and plastic bottles; Okeke et al. (2003)
mL) formulations were either flavored or
unflavored
 Antihypertensive Oral suspension (4 mg/mL) 30 d 30 d Suspensions were prepared from crushed Polonini et al.
tablets suspended in commercial vehicles (2020)
(Ora-Blend, Ora-Blend SF, or SyrSpend-
SF Alka, Perrigo, Allegan, MI)
Hydroxychloroquine Antirheumatic Oral suspensions (25 mg/ At least 90 d At least 90 d Suspensions were prepared in MADISCA McHenry et al.
sulfate mL) vehicles (Oral Mix and Oral Mix SF). (2017)
Antimalarial Suspensions were stored in amber 50-mL
polyethylene terephthalate bottles or
amber 3-mL syringes
Hydrocortisone Various applications Oral suspension (2 mg/mL) 90 d 90 d Suspensions were prepared from Manchanda et al.
pulverized tablets in Oral Mix (Medisca, (2018)
USA). Following preparation,
suspensions were stored in amber, plastic
prescription bottles, and oral syringes
Various applications Oral suspension (2-mg/mL) Up to 42 d Up to 42 d Suspensions were prepared in InOrpha Bourget et al.
(INRESA, France) (2014)
Various applications Oral suspensions (2 mg/mL) 2 wk 2 wk Suspensions stored in plastic prescription Nahata (2015)
bottles
Hydrocortisone Various applications Oral suspensions At least 60 d At least 60 d Suspensions were prepared in SyrSpend Geiger et al. (2015)
hemisuccinate and SF PH4 and packaged in low-actinic
sodium phosphate plastic bottles
Hydrocortisone sodium Various diseases Sterile solution in 0.9% 7d 21 d Stored in polypropylene syringes (Becton, Gupta and Ling
succinate sodium chloride injection Dickinson Co., NJ) (2000)
(10 mg/mL)
Hydromorphone Analgesic Sterile solutions in 0.9% At least 60 d At least 60 d Packaged in polypropylene syringes Trissel et al.
hydrochloride sodium chloride injection (Becton, Dickinson Co., NJ) (2002b)
(1.5 and 80 mg/mL)
Hydroxycarbamide For sickle-cell disease Oral suspensions (100 mg/ 120 d 120 d Crushed tablets were dispersed in Ora- Kabiche et al.
mL) Plus in combination with either Ora- (2017)
Sweet or Ora-Sweet SF, Ora-Blend, or
Ora-Blend SF. Suspensions were
packaged in 60-mL amber glass bottles
Indomethacin sodium Anti-inflammatory/ Sterile solution in 0.9% At least 10 d — Sterile preparations in plastic bags Gupta and
trihydrate analgesic sodium chloride injection Maswoswe (1998)
(0.1 mg of indomethacin/
mL)
Isoniazid For tuberculosis Oral aqueous liquid (10 mg/ At least 42 d — Stored in amber-colored glass bottles Gupta and Sood
mL) (2005)
Isosorbide dinitrate To prevent angina A solution (0.6 mg/mL; in — 28 d Solutions stored in polypropylene Lardinois et al.
0.9% sodium chloride syringes (2020)
injection)
Ketamine hydrochloride Anesthetic Sterile solution in water for At least 30 d — Stored in polypropylene syringes Gupta (2002c)
injection (10 mg/mL)
Ketoprofen Nonsteroidal anti- Organogel 6 mo — Drug was dissolved in Pluronic lecithin Peacock et al.
inflammatory drug organogel and stored, protected from light (2014c)
(NSAID)

(Continued)
Table 8.4 (Continued)

BUD under
Drug name Therapeutic action Formulation type BUD room temperature refrigeration Comments Reference

Ketorolac tromethamine Nonsteroidal anti- Sterile solution in 5% 7d At least 50 d Stored in 50-mL plastic bags (Baxter Gupta and
inflammatory dextrose injection (0.6 mg/ Healthcare Corp., IL) Maswoswe
mL) (1997c)
Nonsteroidal anti- Sterile solution in 0.9% 7d At least 50 d Stored in 50-mL plastic bags (Baxter Gupta and
inflammatory sodium chloride injection Healthcare Corp., IL) Maswoswe
(0.6 mg/mL) (1997c)
Levothyroxine Thyroid hormonal Oral suspensions (25 mcg/ 1 wk 2 wk Suspensions stored in plastic prescription Nahata (2015)
therapy mL) bottles
Levothyroxine sodium Thyroid hormonal Syrup (sorbitol 70%; 0.04 mg/ 15 d 47 d — Alexander et al.
therapy mL) (1997b)
For reduced or absent Sterile solution in 0.9% — At least 7 d Stored in polypropylene syringes Gupta (2000b)
thyroid function sodium chloride injection (Monoject, MO)
(0.1 mg/mL)
Lidocaine hydrochloride Antiarrhythmic/local Sterile solution (20 mg/mL) 90 d 90 d Stored in polypropylene syringes (Becton, Storms et al.
anesthetic Dickinson Co., NJ) (2002)
Lisinopril Angiotensin- Syrup (2 mg/mL) At least 30 d At least 30 d Compounded from tablets (Zestril, Rose et al. (2000)
converting enzyme Zeneca Pharmaceuticals, DE); syrup was
inhibitor/for stored in amber-colored prescription
hypertension bottles
Magnesium sulfate Tocolytic agent; Sterile solution in 0.9% 3 mo — Stored in glass bottles (type I) or Sarver et al. (1998)
anticonvulsant sodium chloride injection poly(vinyl chloride) bags
(37 g/mL)
Tocolytic agent; Sterile solution in lactated 3 mo — Stored in glass bottles (type I) or Sarver et al. (1998)
anticonvulsant Ringer’s injection (37 g/mL) poly(vinyl chloride) bags
Mechlorethamine Anticancer/for Ointment (topical; 0.01%) 7d — Ointment was packaged in screw-cap Zhang et al. (1998)
hydrochloride mycosis fungoides ointment jars
Mercaptopurine Anticancer Oral suspensions 90 d — Suspensions were prepared from Peacock et al.
(leukemia) pulverized tablets in a commercially (2016)
available vehicle [Ora-Sweet and Ora-
Plus (1 : 1)]. Suspensions were packaged
in glass and plastic containers
Memantine For Alzheimer’s Oral liquid (0.166 mg/mL) 7d 28 d Stored in glass bottles Yamreudeewong
disease et al. (2006)
Meperidine Analgesic – pain Sterile solutions in 5% At least 28 d At least 28 d Sterile preparations in polypropylene Donnelly and
hydrochloride management dextrose solution (0.25, 1, 10, syringes/preservative-free Bushfield (1998)
20, and 30 mg/mL)
 Analgesic – pain Sterile solutions in 0.9% At least 28 d At least 28 d Sterile preparations in polypropylene Donnelly and
management sodium chloride solution syringes/preservative-free Bushfield (1998)
(0.25, 1, 10, 20, and 30 mg/
mL)
Methadone For heroin addiction/ Oral solutions of methadone 21 d (chemically stable after 91 d; 91 d — Donnelly (2004)
analgesic powder or concentrate in however, bacterial growth observed
orange-flavored Tang drink after 21 d)
(5 mg/mL)
Methylprednisolone Adrenocorticosteroid Sterile solution in 0.9% 4d At least 21 d Stored in polypropylene syringes (Becton, Gupta (2001a)
sodium succinate hormone/for various sodium chloride injection Dickinson Co., NJ, and Monoject, MO)
diseases (10 mg/mL)
Metoclopramide For stimulating the Sterile solution in 0.9% At least 21 d — Packaged in polypropylene syringes Gupta (2005b)
hydrochloride motility of the upper sodium chloride injection (Becton, Dickinson Co., NJ)
gastrointestinal tract (0.5 mg/mL)
Metoprolol tartrate Beta-adrenergic Aqueous solutions (5 mg/ 16 d — Solutions were prepared from tablets and Gupta and
blocking agent/for mL) stored in amber-colored glass bottles Maswoswe
high blood pressure, (1997a)
heart failure, and
angina
Methylcobalamin Vitamin B12 Injection 181 d — Stored in amber serum vials (protected Ip et al. (2019)
(therapeutically from light)
active form)
Metronidazole Antibiotic/ Suspension (15 mg/mL) 90 d — Suspensions were prepared from 500-mg Alexander et al.
antiparasitic tablets; actual shelf life was estimated to (1997d)
be 73 yr; However, for practical
considerations, a 90-day shelf life was
proposed
Antibiotic/ Oral suspensions (50 mg/ 90 d 90 d Suspensions were made in Oral Mix and Jarouche et al.
antiparasitic mL) Oral Mix Sugar-Free. USP drug powder or (2020)
drug powder obtained from tablets were
used. Suspensions were stored in 50-mL
amber polyethyleneterephthalate bottles
or 3-mL amber plastic syringes
Antibiotic/ Oral suspensions (50 mg/ 93 d 93 d Suspensions prepared in simple syrup or Donnelly and
antiparasitic mL) Ora-Blend and stored in amber polyvinyl Ying (2015)
chloride bottles
Midazolam For status epilepticus Intranasal sterile solution 30 d 30 d Packaged in clear glass vials, placed, in Lester Elder et al.
(in dogs) (50 mg/mL) turn, in light-resistant containers (2011)
For status epilepticus Intranasal sterile solution 30 d 30 d Stored in clear glass vials Lester Elder et al.
(in dogs) (50 mg/mL) (2011)
Central nervous Oral suspensions (1 mg/mL) At least 58 d At least 58 d Suspensions were prepared in SyrSpend Geiger et al.
system depressant SF or SyrSpend SF and stored in low- (2013b)
actinic plastic bottles protected from light
Milrinone lactates For congestive heart Sterile solutions in 0.9% 14 d 14 d Sterile preparations in poly(vinyl Nguyen et al.
failure and sodium chloride injection chloride) bags (1998)
myocardial infarction (0.4, 0.6, and 0.8 mg/mL)

(Continued)
Table 8.4 (Continued)

BUD under
Drug name Therapeutic action Formulation type BUD room temperature refrigeration Comments Reference

For congestive heart Sterile solutions in 5% 14 d 14 d Sterile preparations in poly(vinyl Nguyen et al.
failure and dextrose injection (0.4, 0.6, chloride) bags (1998)
myocardial infarction and 0.8 mg/mL)
For congestive heart Sterile solution in 0.9% 14 d 14 d Sterile preparations in poly(vinyl Wong and Gill
failure and sodium chloride injection chloride) bags (1998)
myocardial infarction (0.2 mg/mL)
For congestive heart Sterile solutions in 5% 14 d 14 d Sterile preparations in poly(vinyl Wong and Gill
failure and dextrose injection (0.2 mg/ chloride) bags (1998)
myocardial infarction mL)
Minoxidil Stimulates hair Topical foam (50-mg/ml At least 90 d — Solutions were prepared and stored in Geiger et al.
growth solution) plastic foam-activating bottles (Fagron; St. (2013c)
Paul, MN)
Mitomycin Antibiotic Sterile solutions (0.5 mg/mL) 7 d 28 d Stored in 1-mL tuberculin syringes Gupta and
(Monoject, MO) Maswoswe
(1997d)
Morphine sulfate Analgesic Sterile solution (1 mg/mL) 3 yr — Terminally sterilized at 120 C for 20 min Nguyen-Xuan
and stored in polypropylene bags et al. (2006)
(Polimoon Langeskov, (Norway)
Analgesic Sterile solutions in 0.9% At least 60 d At least 60 d (with Packaged in polypropylene syringes Trissel et al.
sodium chloride injection precipitation (Becton, Dickinson Co., NJ) (2002a)
(5 and 50 mg/mL) developed within
2–4 d)
Analgesic Sterile solutions in sterile At least 60 d At least 60 d (with Packaged in polypropylene syringes Trissel et al.
water for injection (5 and precipitation (Becton, Dickinson Co., NJ) (2002a)
50 mg/mL) developed within
2–4 d)
Analgesic Aqueous solutions (0.2 mg/ At least 60 d — Solutions were prepared by aqueous Nahata (2016b)
mL) dilution of drug elixir (2 mg/mL) and
packaged in amber plastic syringes
Morphine hydrochloride Narcotic analgesic Sterile solutions in 0.9% NaCl — 58 d Solutions were stored in polyolefin bags or Hecq et al. (2014)
infusion (1 mg/mL) polypropylene syringes. Solutions in
polyolefin bags were frozen and
microwave thawed
Nafcillin sodium Antibacterial Sterile solution in 0.9% At least 7 d At least 44 d Stored in polypropylene syringes (Becton, Ling and Gupta
sodium chloride injection Dickinson Co., NJ) (2000)
(10 mg/mL)
Naltrexone For opiate addiction Sterile solution (1.4 mg/mL) At least 42 d — Stored in clear-glass vials Gupta (2008a)
hydrochloride
For opiate addiction Oral suspensions (0.5 and 180 d 180 d Suspensions were prepared in SuspendIt Pramar et al.
5.0 mg/mL) (PCCA, TX) (2019b)
Naratriptan For migraines Suspension in Syrpalta 7d 90 d Packaged in amber-colored, plastic, Zhang et al. (2000)
hydrochloride vehicle (Humco, TX; 0.5 mg/ screw-cap prescription bottles
mL)
 For migraines Suspensions made from At least 7 d At least 90 d Vehicles used Ora-Plus:Ora-Sweet (1 : 1) Zhang et al. (2000)
tablets (0.5 mg/mL) or Ora-Plus:Ora-Sweet SF (1 : 1; Paddock
Laboratories, MN)
Nifedipine Antihypertensive Oral suspensions At least 90 d At least 90 d Suspensions were prepared in SyrSpend Geiger et al. (2015)
(calcium-channel SF PH4 and packaged in low-actinic
blocker) plastic bottles
Nitrofurantoin Antibiotic Oral suspension (10 mg/mL) 90 d 90 d Suspensions prepared from drug powder Polonini et al.
suspended in commercial vehicles (Ora- (2020)
Blend, Ora-Blend SF, or SyrSpend-SF
Alka, Perrigo, Allegan, MI)
Nitroglyercin For angina Sterile solutions (100 mcg/ — 24 d Solutions were prepared in 5% dextrose McCluskey et al.
mL) injection and packaged in Terumo (2013)
polypropylene syringes (protected from
light)
Noradrenaline bitartrate To treat life- Sterile solution in 0.9% NaCl — 30 d Solutions prepared in a 0.9% sodium Lardinois et al.
threatening vehicle (0.240 mg/mL) chloride vehicle and stored in (2018)
hypotension polypropylene syringes
Omeprazole Proton-pump Oral liquid (suspension; 2 4 wk — Content of capsules (20 mg) was emptied Garg et al. (2009)
inhibitor mg/mL) and mixed for 3 min and suspended in
8.4% sodium bicarbonate solution
Proton-pump Oral liquid (suspension; 2 1 wk — Content of capsules (20 mg) was emptied Garg et al. (2009)
inhibitor mg/mL) and turned into a fine powder using a
glass mortar; the resulting powder was
mixed and suspended in 8.4% sodium
bicarbonate solution
Proton-pump Oral suspension (2 mg/mL) — 20 d Suspensions prepared from capsules, Meissner et al.
inhibitor tablets, and powder, in 8.4% w/v sodium (2020)
bicarbonate solution
Pentobarbital sodium Sedative/hypnotic/ Sterile injections in 0.9% At least 31 d — Solutions were packaged in glass or Gupta (2001c)
anticonvulsant sodium chloride injection polypropylene syringes (Becton,
(10 mg/mL) Dickinson Co., NJ)
Pentoxifylline For peripheral Topical cream (5% w/w) in 62 d — Stored in plastic white opaque ointment Gupta (2012)
vascular diseases Dermabase cream jars
Pergolide mesylate For equine Cushing’s Oral liquid (suspension; 0.2 45 d — — Shank and Ofner
syndrome mg/mL) III (2009)
Perphenazine For schizophrenia/ Oral liquid in Ora-Sweet 114 d — Final pH = 4.2 Gupta (2008b)
severe nausea and syrup (Paddock Laboratories,
vomiting MN; 0.5 mg/mL)
For schizophrenia/ Oral liquid in Humco’s syrup 183 d — Final pH = 4.5 Gupta (2008b)
severe nausea and (Humco, TX; 0.5 mg/mL)
vomiting
Antiemetic Oral liquid (0.5 mg/mL) 30 d — Vehicle used was Ora-Sweet (Paddock Gupta (2005c)
Laboratories, MN)

(Continued)
Table 8.4 (Continued)

BUD under
Drug name Therapeutic action Formulation type BUD room temperature refrigeration Comments Reference

Phenobarbital For seizures Oral suspensions At least 154 d — Suspensions were prepared in SyrSpend Geiger et al. (2015)
SF PH4 and packaged in low-actinic
plastic bottles
Phenytoin sodium Antiseizure/topically Suspensions in 0.9% sodium 14 d — Nonsterile suspensions prepared from Rhodes et al.
for open-wound chloride solution (20 mg/mL) capsules added to 0.9% sodium chloride (2006)
healing solution
Piperacillin sodium Antibacterial/for Sterile solution in 0.9% 5d 28 d Sterile solutions in polypropylene Gupta and Ling
urinary tract sodium chloride injection syringes (Becton, Dickinson and Co., NJ) (2001)
infections/respiratory (40 mg/mL)
tract infections
Pravastatin Cholesterol-lowering Oral suspensions (10 mg/ 1 wk 1 wk Suspensions stored in plastic prescription Nahata (2015)
drug mL) bottles
Prednisolone sodium Various conditions Oral suspensions At least 30 d At least 30 d Suspensions were prepared in SyrSpend Geiger et al. (2015)
phosphate (e.g. arthritis and SF PH4 and packaged in low-actinic
breathing plastic bottles
difficulties)/
immunosuppressant
Prednisone Anti-inflammatory/ Oral suspensions (5 mg/mL) At least 90 d At least 90 d Suspensions were prepared in in Oral Mix Friciu et al. (2015)
Immunosuppressant vehicle and stored in amber glass bottles
or polypropylene syringes (PreciseDose
Dispenser Medisca Pharmaceutique, Inc.)
Propylthiouracil Antithyroid/for Suspension (5 mg/mL) 127 d 248 d Stored in amber-colored glass bottles Alexander (2005)
hyperthyroidism
Progesterone A steroid hormone Rapid-dissolving tablets 6 mo (60 C and 75% relative — Stored under accelerated conditions of Sayre et al. (2019)
humidity) 60 C and 75% relative humidity
Promethazine Antiemetic Organogel 60 d — Drug was dissolved in Pluronic lecithin Peacock and
hydrochloride organogel Sauvageot (2014b)
Pyridoxine B-complex vitamin Sterile solution (100 mg/mL) 180 d — Packaged in polypropylene syringes Gupta (2006b)
hydrochloride (Becton, Dickinson Co., NJ)
Ranitidine For the treatment of Oral suspensions At least 30 d At least 58 d Suspensions were prepared in SyrSpend Geiger et al. (2015)
hydrochloride duodenal and gastric SF PH4 and packaged in low-actinic
ulcers plastic bottles
Revefenacin and For chronic Inhalation solution Up to 25 h — — Ngim and Patel
formoterol fumarate obstructive admixture (2020)
pulmonary disease
Ribavirin Antiviral Suspension (40 mg/mL) At least 28 d At least 28 d Suspension was prepared from oral Chan et al. (2004)
capsules
Antiviral Sterile solutions for At least 45 d At least 45 d (units Solutions were packaged in syringes or Larson et al.
inhalation in Sterile Water that were frozen and glass vials (2016)
for Injection (67 mg/mL) thawed with
microwave also had
beyond-use-date of at
least 45 d)
Rifampin Antibiotic Oral suspensions (25 mg/ At least 60 d At least 60 d Suspensions were prepared in SyrSpend Sorenson and
mL) SF (Fagron, Inc., St. Paul, MN) Whaley (2013)
Sildenafil For erectile Suspensions (2.5 mg/mL) 91 d 91 d Suspensions were prepared from crushed Nahata (2016a)
dysfunction tablets and suspended in 1%
treatment methylcellulose:simple syrup (1 : 7) or in
commercial vehicles [OraPlus:OraSweet
(1 : 1)]. Suspensions were packaged in
plastic prescription bottles
Simvastatin Cholesterol-lowering Oral suspensions — At least 90 d Suspensions were prepared in SyrSpend Geiger et al. (2015)
agent SF PH4 and packaged in low-actinic
plastic bottles
Sodium benzoate Preservative Oral solutions (250 mg/mL) 90 d 90 d Solutions were made by dissolving sodium Atkins et al. (2018)
benzoate in either cherry syrup or Ora-
Sweet. Solutions were stored in 4-oz amber
plastic bottles in dimmed light
Sodium nitroprusside Severe hypertension Sterile solutions (1 mg/mL) — At least 9 d Solutions were packaged in Anderson et al.
(acute) polypropylene syringes and stored, (2016)
protected from light
Sotalol hydrochloride For cardiac rhythm Suspensions in various At least 12 wk At least 12 wk Vehicles used: Ora-Plus:Ora-Sweet (1 : 1)l Sidhom et al.
disorders vehicles (5 mg/mL) Ora-Plus: Ora-Sweet SF (1 : 1; Paddock (2005)
Laboratories, MN); or simple syrup:
methylcellulose (1 : 2.4)
Spironolactone Diuretic Suspension (5 mg/mL) 90 d 90 d Suspensions were prepared from 25-mg Alexander et al.
tablets (1997c)
Diuretic Oral suspensions 180 d 180 d Suspensions were prepared in SuspendIt Graves et al.
vehicle (PCCA, TX) (2017b)
Diuretic Oral suspensions At least 90 d — Suspensions were prepared in SyrSpend Geiger et al. (2015)
SF PH4 and packaged in low-actinic
plastic bottles
Succinylcholine chloride Skeletal muscle Sterile solution (20 mg/mL) 45 d 90 d Stored in polypropylene syringes (Becton, Storms et al.
relaxant Dickinson Co., NJ) (2003)
Skeletal muscle Sterile solution (20 mg/mL) 6 mo — — Roy et al. (2008)
relaxant
Sufentanil citrate Opioid analgesic Sterile solution in 0.9% Stable for 24 h in polypropylene — Simulated epidural administration for Jappinen et al.
sodium chloride injection syringes connected to epidural 24 h: a polypropylene syringe connected (1998)
(0.002 mg of sufentanil/mL) catheters and in entire infusion to polyethylene or poly(vinyl chloride)
system using polyethylene tubing; tubing and filter to an epidural catheter
not stable if PVC tubing is present in
the system
Sufentanil–ropivacaine– Intrathecal analgesia Mixtures (different — At least 7 d Drugs were mixed together and stored Sorrieul et al.
baclofen mixture concentrations) with light protection at 5 C ± 3 C in (2020)
polypropylene syringes
Teicoplanin Antibiotic Sterile solution in 5% — 6d Solutions were stored in poly(vinyl Galanti et al.
dextrose injection (0.004 mg/ chloride) bags (Baxter, Belgium) (2001)
mL)

(Continued)
Table 8.4 (Continued)

BUD under
Drug name Therapeutic action Formulation type BUD room temperature refrigeration Comments Reference

Temozolomide For refractory Suspension in Ora-Plus and 7d — Packaged in amber-colored plastic Trissel et al. (2006)
anaplastic Ora-Sweet (1 : 1; Paddock prescription bottles
astrocytoma Laboratories, MN; 10 mg/
mL)
For refractory Suspension in Ora-Plus and 14 d — Packaged in amber-colored plastic Trissel et al. (2006)
anaplastic Ora-Sweet SF (1 : 1; Paddock prescription bottles
astrocytoma Laboratories, MN; 10 mg/
mL)
Terbutaline sulfate For bronchospasm/ Sterile solution in 0.9% 23 d — Stored in poly(vinyl chloride) bags Gupta (2004)
chronic obstructive sodium chloride injection
lung disease (0.1 mg/mL)
Testosterone Hormonal Sterile solution in 0.9% 1h 9h Sterile preparation in plastic bags White and
sodium chloride solution Quercia (1999)
(0.001 mg/mL)
Tetracaine Local anesthetic Topical solution 1% 60 d — Solutions were prepared in propylene McPherson et al.
glycol. Solutions were stored in (2013)
polypropylene droptainer bottles
Local anesthetic Topical solution 1% 90 d — Solutions were prepared in PEG 400. McPherson et al.
Solutions were stored in polypropylene (2013)
droptainer bottles
Tetracaine and Local anesthetic and Topical solutions (tetracaine 60 d — Solutions were prepared in propylene McPherson et al.
clotrimazole fungal otitis externa 1% and clotrimazole 1%) glycol. Solutions were stored in (2013)
combination polypropylene droptainer bottles
Local anesthetic and Topical solutions (tetracaine 90 d — Solutions were prepared in PEG 400. McPherson et al.
fungal otitis externa 1% and clotrimazole 1%) Solutions were stored in polypropylene (2013)
droptainer bottles
Thioguanine (powder) Anticancer/ Oral suspension (2.5 mg/mL) 90 d 90 d Suspensions prepared from drug powder Polonini et al.
antimetabolite suspended in commercial vehicles (Ora- (2020)
Blend, Ora-Blend SF, or SyrSpend-SF
Alka, Perrigo, Allegan, MI)
Tranexamic acid Antifibrinolytic Mouth rinse 31 d 31 d Stored, protected from light, in Donnelly (2018)
polyethylene terephthalate bottles
Antifibrinolytic Solutions (1.54%; 2%) in 0.9% 180 d — Solutions prepared and stored in clear McCluskey et al.
NaCl Type 1 borosilicate glass vials (2014)
Antifibrinolytic Solutions (1.54%; 2%) in 0.9% 90 d 90 d Solutions prepared and stored in McCluskey et al.
NaCl ethylene/propylene copolymer plastic (2014)
containers
Trastuzumab Anticancer Sterile solutions in 0.9% 28 d — Stored in polypropylene bags; solutions Kaiser and
sodium chloride injection were kept at room temperature without Krämer (2011)
(0.4 and 4 mg/mL) protection from light
Treprostinil sodium For pulmonary Sterile solutions (1, 2.5, 5, At least 60 d At least 60 d Packaged in plastic syringe reservoirs Xu et al. (2004)
arterial hypertension and 10 mg/mL) (Medtronic MiniMed, CA)
Trimethoprim and Antibacterial Oral suspensions 182 d 182 d Suspensions were prepared in SuspendIt Graves et al.
sulfadiazine mixture (trimethoprim 20 mg/mL/ vehicle (PCCA, TX) (2017a)
sulfadiazine 200 mg/mL)
Trovafloxacin mesylate Antibiotic Oral liquid (10 mg/mL) 14 d — Stored in amber-colored glass bottles Gupta (2000a)
Tubocurarine chloride Neuromuscular Sterile solution (3 mg/mL) 45 d 90 d Stored in polypropylene syringes Stewart et al.
blocking agent (2002)
Urapidil For hypertension Solutions in 0.9% NaCl (1.6 10 d (7 d when given as home — Drug solution was placed in elastomeric Tomasello et al.
mg/mL and 3.3 mg/mL) infusion therapy) pumps (2016)
Ursodeoxycholic acid Cholagogue and Oral solutions 181 d 181 d Solutions were prepared in SuspendIt Pramar et al.
choleretic base (PCCA, TX). Solutions were stored in (2019a)
plastic amber bottles
Valproate sodium To prevent migraine Sterile solution (20 mg/mL; — At least 30 d Solutions prepared and stored in Lardinois et al.
headaches in 0.9% sodium chloride) polypropylene syringes (2019a)

For seizures

For bipolar disorders

Valsartan Antihypertensive Oral suspensions (80 mg/5 30 d — Suspensions were prepared from crushed Zaid et al. (2014)
mL) tablets (80 mg/Tab.)
Vancomycin Antibiotic Oral solution (50 mg/mL) Up to 30 d Up to 30 d Stored in plastic-capped oral syringes and Brown and Lewis
hydrochloride heat-sealed dosing cups (2020)
Antibiotic Sterile infusion (1 g/dL) in — 57 d Sterile solutions were packaged in Huvelle et al.
5% glucose polyolefin bags (2016)
Venlafaxine Antidepressant Extended-release suspension 28 d 28 d Stored in amber-colored plastic bottles Donnelly et al.
in Ora-Plus/Ora- Sweet (2011)
(Paddock Laboratories, MN;
15 mg/mL)
Antidepressant Extended-release suspension 28 d 28 d Stored in amber-colored plastic bottles Donnelly et al.
in simple syrup (15 mg/mL) (2011)
Vinorelbine tartrate Anticancer Sterile solution in 5% 120 h — Sterile preparations in poly(vinyl Lieu and Gill
dextrose injection chloride) minibags; exposure to constant (1999)
(0.5 mg/mL) fluorescent lighting
Anticancer Sterile solution in 0.9% 120 h — Sterile preparations in poly(vinyl Lieu and Gill
sodium chloride injection chloride) minibags; exposure to constant (1999)
(2 mg/mL) fluorescent lighting
Vitamin K1 For normal blood Oral solutions in Sterile — 105 d Solutions were prepared and stored in a Huffman et al.
clotting Water for Injection refrigerated amber glass bottle (2018)
Oral solutions in Sterile — 14 d Solutions prepared and stored in amber Huffman et al.
Water for Injection plastic syringes (2018)
Zonisamide For seizures Oral suspension (10 mg/mL) 91 d 91 d Suspensions were prepared in 1% Nahata (2016b)
methylcellulose:simple syrup (1 : 10) or
commercial vehicles [OraPlus:OraSweet
(1 : 1)] and stored in plastic prescription
bottles
102 8 Chemical Stability and Shelf-Life Determination
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