Buffers, Buffering Agents, and Ionic Equilibria

Harry G. Brittain
Center for Pharmaceutical Physics, Milford, New Jersey, U.S.A.

INTRODUCTION

expressed as the negative of their base10 logarithms.

The value of pKW would then be calculated as

It is well known that many drugs are unstable when

exposed to certain acidic or basic conditions, and such
information is routinely gathered during the preformulation stage of development. When such instabilities
are identified, one tool of the formulation sciences is
to include a buffering agent (or agents) in the dosage
form with the hope that such excipients will impart sufficient stability to enable the formulation. The properties that enable buffering agents to function as such is
derived from their qualities as weak acids or bases, and
have their roots in their respective ionic equilibria.

pKW
logKW

and would have a value equal to 13.997 at 25 C.

Defining pH as
pH
logH3 O 

and
pOH
logOH


then Eq. (3) can then be expressed as

AUTOIONIZATION OF WATER

H2 O H2 O $ H3 O OH

In Eq. (1), H3O is known as the hydronium ion,

and OH
is known as the hydroxide ion. This reaction
is reversible, and the reactants are known to proceed only
slightly on to the products. Approximating the activity of
the various species by their concentrations, one can write
the equilibrium constant for this reaction as
KC

H3 O OH

H2 O2

In aqueous solutions, the concentration of water is

effectively a constant (55.55 M), and so Eq. (2) simplifies to:

KW H3 O OH 

KW is known as the autoionization constant of

water, and is sometimes identified as the ion product
of water. The magnitude of KW is very small, being
equal to 1.007  10
14 at a temperature of 25 C.[1]
For the sake of convenience, Srensen proposed the
p scale, where numbers such as KW would be

The autoionization of water is an endothermic reaction, so KW increases as the temperature is increased.[1]

This temperature dependence is plotted in Fig. 1.

IONIC EQUILIBRIA OF ACIDIC

AND BASIC SUBSTANCES
Of the numerous definitions of acids and bases that
have been employed over the years, the 1923 definitions of J. N. Brnsted and T. M. Lowry have proven
to be the most useful for discussions of ionic equilibria
in aqueous systems. According to the BrnstedLowry
model, an acid is a substance capable of donating a
proton to another substance, such as water:
HA H2 O $ H3 O A

The acidic substance (HA) that originally donated

the proton becomes the conjugate base (A
) of that
substance, because the conjugate base could conceivably accept a proton from an even stronger acid than
the original substance. One can write the equilibrium
constant expression corresponding to Eq. (8) as
KC

Encyclopedia of Pharmaceutical Technology DOI: 10.1081/E-EPT-120011975

Copyright # 2007 by Informa Healthcare USA, Inc. All rights reserved.

H3 O A

HAH2 O

385

Bio-VBuffer

pKW pH pOH
Even the purest grade of water contains low concentrations of ions that can be detected by means of appropriate conductivity measurements. These ions arise
from the transfer of a proton from a water molecule
to another:

386

Buffers, Buffering Agents, and Ionic Equilibria

substance, because the conjugate acid could conceivably

donate a proton to an even stronger base than the
original substance. The equilibrium constant expression
corresponding to Eq. (12) is:
KC

BH OH

BH2 O

13

pKw

Because [H2O] is a constant, the constants are collected on the left-hand side of the equation to derive
the base ionization constant expression:
KB

BH OH

B

14

pKB is defined as
pKB
logKB

Temperature (C)
Fig. 1 Temperature dependence of the autoionization constant of water. (From Ref.[1].)

Bio-VBuffer

But because [H2O] is a constant, one can collect the

constants on the left-hand side of the equation to
derive the acid ionization constant expression:
KA

H3 O A

HA

10

And, of course, one can define pKA as

pKA
logKA

11

A strong acid is a substance that reacts completely

with water, so that the acid ionization constant defined
in Eq. (10) or (11) is effectively infinite. This situation
can only be achieved if the conjugate base of the strong
acid is very weak. A weak acid will be characterized by
an acid ionization constant that is considerably less
than unity, so that the position of equilibrium in the
reaction represented in Eq. (8) favors the existence of
unreacted free acid.
A discussion of the ionic equilibria associated with
basic substances parallels that just made for acidic substances. A base is a substance capable of accepting a
proton donated by another substance, such as water:
B H2 O $ BH OH

12

The basic substance (B) that originally accepted the

proton becomes the conjugate acid (BH) of that

15

A strong base is a substance that reacts completely

with water, so that the base ionization constant defined
in Eq. (14) or (15) is effectively infinite. This situation
can only be realized if the conjugate acid of the strong
base is very weak. A weak base will be characterized by
a base ionization constant that is considerably less
than unity, so that the position of equilibrium in the
reaction represented in Eq. (12) favors the existence
of unreacted free base.
IONIC EQUILIBRIA OF CONJUGATE
ACIDS AND BASES
Once formed, the conjugate base of an acidic substance
(i.e., the anion of that acid) is also capable of reacting
with water:
A
H2 O $ HA OH

16

Because aqueous solutions of anions are commonly

prepared by the dissolution of a salt containing that
anion, reactions of the type described by Eq. (16) are
often termed hydrolysis reactions. Eq. (16) is necessarily characterized by its base ionization constant
expression:
KB

HAOH

A


17

and a corresponding pKB defined in the usual manner,

but because
OH
 KW =H3 O 

18

it follows that
KB

HAKW
A
H3 O 

19

Buffers, Buffering Agents, and Ionic Equilibria

387

Eq. (19) contains the right-hand side expression of

Eq. (10), so one deduces that

of ionization constant expressions. For an acidic

substance, Eq. (10) can be rearranged as

KB KW =KA

H3 O 

20

KA A

HA

22

Taking the negative of the base 10 logarithms of the

various quantities yields the relation known as the
HendersonHasselbach equation:

or
KW KA KB

21
pH pKA logfA
=HAg

IONIC EQUILIBRIA OF BUFFER SYSTEMS

A buffer can be defined as a solution that maintains an
approximately equal pH value even if small amounts of
acidic or basic substances are added. To function in
this manner, a buffer solution will necessarily contain
either an acid and its conjugate base, or a base and
its conjugate acid.
The action of a buffer system can be understood
through the use of a practical example. Consider acetic
acid, for which KA 1.82  10
5 (pK 4.74). The
following pH values can be calculated (for solutions
having a total acetate content of 1.0 M) using its acid
ionization constant expression:
Acetate ion, [A
]

Calculated pH

0.4

0.6

4.92

0.5

0.5

4.74

0.6

0.4

4.56

Eq. (23) indicates that when the concentration of acid

and its conjugate base are equal (i.e., [HA] [A
]),
then the pH of the solution will equal the pKA value.
Therefore, a buffer system is chosen so that the target
pH is approximately equal to the pKA value.
Viewed in this light, a buffer system can be envisioned as a partially completed neutralization reaction
HA OH
$ A
H2 O

24

where comparable amounts of HA and A
are present

in the solution. The buffer region within a neutralization reaction is shown in Fig. 2, where the horizontal
region in the graph of anion concentration and

pH

Acetic acid, [HA]

23

Bio-VBuffer

The same relation between ionization constants of a

conjugate acidbase pair can be developed if one were
to begin with the conjugate acid of a basic substance,
so Eq. 21 is recognized as a general property of conjugate acidbase pairs.

When an acidic substance is added to a buffer system it would immediately react with the basic component, as a basic substance would react with the acidic
component. One therefore concludes from the table
that the addition of either 0.1 M acid or 0.1 M base
to a buffer system consisting of 0.5 M acetic acid and
0.5 M acetate ion would cause the pH to change by
only 0.18 pH units. This is to be contrasted with the
pH changes that would result from the addition of
0.1 M acid to water (i.e., 7.0 to 1.0, for a change of
6.0 pH units), or from the addition of 0.1 M base to
water (i.e., 13.0 to 1.0, also for a change of 6.0 pH
units).
A very useful expression for describing the properties of buffer system can be derived from consideration

[acetate]
Fig. 2 Neutralization curve obtained during the titration
of 1.0 M acetic acid, plotted as a function of the acetate ion
concentration.

388

Buffers, Buffering Agents, and Ionic Equilibria

observed pH reveals the buffer region of the system.

For practical purposes, the buffer region would extend
over [HA]/[A
] ratios of approximately 0.2 to 0.8.

SELECTION OF AN APPROPRIATE
BUFFER SYSTEM
The selection of a buffer system for use in a pharmaceutical dosage form is relatively straightforward. It
is evident from the preceding discussion that the most
important prerequisite for a buffer is the approximate
equality of the pKA value of the buffer with the
intended optimal pH value for the formulation.
Knowledge of the pH stability profile of a drug substance enables one to deduce the pH range for which
formulation is desirable, and the basis for the most
appropriate buffer system would be the weak acid or
base whose pKA or pKB value was numerically equal
to the midpoint of the pH range of stability.
There are, of course, other considerations that need
to be monitored, such as compatibility with the drug
substance. Boylan[2] has provided a summary of the
selection criteria for buffering agents:

Bio-VBuffer

1. The buffer must have adequate capacity in the

desired pH range.

2. The buffer must be biologically safe for the

intended use.
3. The buffer should have little or no deleterious
effect on the stability of the final product.
4. The buffer should permit acceptable flavoring
and coloring of the product.
A practical consequence of Eq. (23) is that as long as
the concentration of a buffer is not overcome by reaction demands, a buffer system will exhibit adequate
capacity within 1 pH unit with respect to its pKA or
pKB value.
The second criterion from the preceding list restricts
buffering agents to those deemed to be pharmaceutically acceptable. A list of appropriate buffer systems
is provided in Table 1, along with values for their
pKA or pKB values sourced from the compilations of
Martell and Smith.[36] The use of buffering agents is
most critical for parenteral formulations, and it has
been noted over the years that phosphate, citrate,
and acetate are most commonly used for such purposes.[7,8] Ethanolamine and diethanolamine are also
used to adjust pH and form their corresponding salts,
whereas lysine and glycine are often used to buffer protein and peptide formulations. Akers[9] has reviewed
the scope of drugexcipient interactions in parenteral
formulations and has provided an overview of the
effect of buffers on drug substance stability.

Table 1 Acids and bases suitable for use as buffer systems in pharmaceutical products
Martell and
Smith reference

pK2

pK3

4.56

[5], p. 3

Adipic acid

5.03

4.26

[5], p. 118

Arginine

9.01

2.05

[3], p. 43

Benzoic acid

4.00

[5], p. 16

Boric acid

8.97

[6], p. 25

Basis for buffering system

pK1

Acetic acid

Carbonic acid

10.00

6.16

Citric acid

5.69

4.35

2.87

Diethanolamine

8.90

[4], p. 80

Ethanolamine

9.52

[4], p. 15

Ethylenediamine

9.89

7.08

[4], p. 36

Glutamic acid

9.59

4.20

[3], p. 27

Glycine

9.57

2.36

[3], p. 1

Lactic acid

3.66

[5], p. 28

10.69

9.08

2.04

[3], p. 58

5.83

1.75

11.74

6.72

2.00

Tartaric acid

3.95

2.82

[5], p. 127

Triethanolamine

7.80

[4], p. 118

Tromethamine

8.09

[4], p. 20

Lysine
Maleic acid
Phosphoric acid

[6], p. 37
[5], p. 161

[5], p. 112
[6], p. 56

Buffers, Buffering Agents, and Ionic Equilibria

389

BUFFERS IN PHARMACEUTICAL SYSTEMS

Table 2 Some of the buffer systems used to stabilize various

parenteral products

It is well known that the stability of many active pharmaceutical substances can be strongly dependent on
the degree of acidity or basicity to which they are
exposed, and that a change in pH can cause significant
changes in the rate of degradation reactions. For such
compounds, formulators commonly include a buffer
system to ensure the stability of the drug substance
either during the shelf life of the product, or during
the period associated with its administration.
In addition, preformulation scientists routinely use
buffer systems to set the pH of a medium in which they
intend to perform experimentation. For instance, the
pH stability profile of a drug substance is routinely
obtained through the use of buffers, and the pH dependence of solubility is frequently measured using
buffered systems. However, the possibility that the buffer system itself may influence or alter the results must
be considered in these studies.

Basis for buffering system

Product trade name

Acetic acid

Miacalcin injection

Benzoic acid

Valium injection

Citric acid

Aldomet injection
Ceredase
Cerezyme
Duracillin A.S.

Diethanolamine

Bactrim IV

Glycine

Hep-B Gammagee

Lactic acid

Ergotrate maleate
Fentenyl citrate and
Droperidol

Maleic acid

Librium injection

Monoethanolamine

Terramycin solution

Phosphoric acid

Humegon
Zantac injection
Pregnyl
Prolastin
Synthroid

Stabilization of Drug Substances

in Formulations by Buffers

Tartaric acid

Compazine injection
Methergine injection
Priscoline injection

As mentioned previously, the stability of parenteral

formulations is often established through the use of
buffer systems, and Table 2 contains a partial listing
of such systems.[7,8]
The inclusion of a phosphate buffer in homatropine
hydrobromide ophthalmic solution enabled formulators to fix the solution pH at 6.8, enabling the product
to be lyophilized.[10] This lyophilized product could be
stored for extended periods without degradation. Tromethamine was found to effect a stabilizing effect on
N-nitrosoureas (such as lomustine, carmustine, and
tauromustine) in aqueous solutions.[11]
It has been reported that replacing succinate buffer
with glycolate buffer improved the stability of lyophilized g-interferon.[12] In this work, it was found that
the succinate buffer could crystallize in the frozen
state, which limited its ability to maintain the appropriate pH, and therefore led to degradation. On the
other hand, use of the glycolate buffer appeared to
minimize the freeze-induced pH shifting, and the
lyophilized product exhibited superior solid-state
stability.
However, the use of buffers in parenterals is not
always benign, and numerous instances have been
summarized where buffers or other excipients have
caused stability problems.[9] For instance, the complexation of Ca(II) and Al(III) with phosphate buffer
solutions has been studied at great length, as well as
the kinetic characteristics of the subsequent precipitation of calcium and aluminum phosphate salts.[1317]
The use of metal complexing excipients, such as citric

Tromethamine

Optiray

acid or ethylenediaminetetraacetic acid, was found to

be useful in delaying the onset of precipitation.
The use of buffering agents in solid dose forms is
not as widespread as the use in parenteral products.
Nevertheless, the current Handbook of Pharmaceutical Excipients lists calcium carbonate, monobasic
and dibasic sodium phosphate, sodium and potassium
citrates, and tribasic calcium phosphate as potential
buffering agents.[18]
In one study, the effect of 11 different compounds
representing various classes of buffering agents were
studied with respect to their effect on the dissolution
kinetics of aspirin from tablet formulations.[19] It
was found that buffering agents capable of reacting
with acidic substances to evolve carbon dioxide
(sodium bicarbonate, magnesium carbonate, or calcium carbonate) yielded the fastest dissolution rates,
and hence were deduced to be more useful as tablet
excipients. Less effective were water-soluble buffering
agents (such as sodium ascorbate or sodium citrate),
and least effective were water-insoluble buffering
agents (such as magnesium oxide, magnesium trisilicate, dihydroxyaluminum aminoacetate, or aluminum
hydroxide).
In another study, the kinetics of aspirin, salicylic
acid, and salicyluric acid were followed upon oral

Bio-VBuffer

From Refs.[7,8].

390

administration of aspirin as either an unbuffered tablet

or two buffered solutions.[20] Significant differences in
the absorption rates were observed, with the solution
having 16 mEq of buffer being the fastest, the solution
having 34 mEq of buffer being intermediate, and the
unbuffered tablet being the slowest. These studies
demonstrate that inclusion of a buffering agent in a
tablet formulation of an acid-sensitive compound will
lead to the generation of better dosage forms.

Use of Buffers to Study the pH Stability

Profile of Drug Substances

Bio-VBuffer

The evaluation of the pH stability profile of a drug

substance is an essential task within the scope of preformulation studies. Knowing the pH conditions under
which a given compound will be stable is of vital
importance to the chemists seeking to develop methods
of synthesis, to analytical scientists seeking to develop
methods for analysis, and to formulators seeking to
develop a stable drug product. Typically, the preformulation scientist will prepare solutions of the drug
substance in a variety of buffer systems, and will then
determine the amount of drug substance remaining
after a predefined storage period. However, for the
information to be useful, the investigator will also need
to verify that the buffer itself does not have an effect
on the observed reactions.
The hydrolysis kinetics of vidarabine-50 -phosphate
were studied at a variety of pH values that enabled
the compound to exist as its protonated, neutral, and
monoionized form.[21] It was found that the hydrolysis
reaction followed first-order kinetics at the five pH
conditions tested, and that the buffer system used did
not influence the reaction rates. The pHrate profile
suggested that even though the compound was most
stabile over pH 9.0 to 9.5, the stability at pH 7.4
(i.e., physiological pH) was more than adequate for
development of a parenteral formulation.
The degradation kinetics of phentolamine hydrochloride were studied over a pH range of 1.2 to 7.2
and in various glycol solutions.[22] The kinetics were
determined to be first order over all pH values studied,
and a consideration of the ionization constant of the
compound indicated that only the protonated form
of the compound had been studied. At relatively low
acidities, a pH-independent region (pH 3.14.9) was
noted for the hydrolysis, and the kinetics were not
affected by the concentration of buffer used. However,
the degradation reaction was found to proceed at a
much faster rate at a pH of 7.2, and a small dependence
of rate constant on the concentration of phosphate in
the buffer system was noted.
Other examples where buffers were successfully used
to study the pH stability of drug substances (and where

Buffers, Buffering Agents, and Ionic Equilibria

little or no effect could be ascribed to the buffer system

used) include the chemical stability of diisoxazolylnaphthoquinone[23] and metronidazole[24] in aqueous
solution. In another detailed study, the effect of pH,
buffer species, medium ionic strength, and temperature
on the stability of azetazolamide was studied.[25]
There are probably as many instances where buffer
catalysis exerts a strong influence on pH stability
studies as where no such effect exists. For instance,
the kinetics associated with the acid/base hydrolysis
of ciclosidomine were found to be strongly affected
by the concentration of buffer used to set the solution
pH for each study.[26] However, because a linear relationship was found between buffer concentration and
observed first-order rate constant, the effect of pH on
the degradation was assessed by extrapolating to zero
buffer concentration. This information was used to
deduce the buffer-independent pHrate profile.
In another study on solutions of spironolactone, the
concentration of buffer was found to exert a strong
influence on the degradation rate constants.[27] At the
same time, the ionic strength of the medium did not
appear to affect the rate constants. The decomposition
pathway for aqueous solutions of batanopride hydrochloride was found to depend on the pH of the medium used for the study, although the concentration of
buffer was found to exert catalytic effects.[28]
To those beginning work in this field, the study
reported by Zhou and Notari on the kinetics of
ceftazidime degradation in aqueous solutions may be
used as a study design template.[29] First-order rate
constants were determined for the hydrolysis of this
compound at several pH values and at several temperatures. The kinetics were separated into bufferindependent and buffer-dependent contributions, and
the temperature dependence in these was used to
calculate the activation energy of the degradation via
the Arrhenius equation. Ceftazidime hydrolysis rate
constants were calculated as a function of pH, temperature, and buffer by combining the pHrate expression
with the buffer contributions calculated from the buffer
catalytic constants and the temperature dependencies.
These equations and their parameter values were able
to calculate over 90% of the 104 experimentally determined rate constants with errors less than 10%.

Use of Buffers to Study the pH Dependence

of Drug Substance Solubility
An evaluation of the effect of pH on the aqueous solubility of a drug substance is an essential component
of preformulation research, and such work is usually
conducted along with determinations of ionization
constants, solubilization mechanisms, and dissolution
rates.[30] Methods for the determination of the solubility

Buffers, Buffering Agents, and Ionic Equilibria

CONCLUSIONS
Buffers and buffering agents have been widely used for
the stabilization of pharmaceutical formulations, and
this aspect has proven to be especially important for
parenteral products. Buffers and buffering agents have
also been found to play a vitally important role during
drug characterization studies, being vitally important
to the conduct of solubility and drug stability studies.
The range of pharmaceutically acceptable buffer systems spans all useful pH values, and it can be said that
there is a buffer available for every intended purpose.

REFERENCES
1. Dean, J.A. Langes Handbook of Chemistry, 12th Ed.;
McGraw-Hill: New York, 1979; 57.
2. Boylan, J.C. Liquids. In The Theory and Practice of Industrial Pharmacy; Lachman, L., Lieberman, H.A., Kanig, J.,
Eds.; Lea & Febiger: Philadelphia, 1986; 459460, Chapter
15.
3. Martell, A.E.; Smith, R.M. Critical Stability Constants;
Amino Acids; Plenum Press: New York, 1974; Vol. 1.
4. Smith, R.M.; Martell, A.E. Critical Stability Constants;
Amines; Plenum Press: New York, 1975; Vol. 2.
5. Martell, A.E.; Smith, R.M. Critical Stability Constants;
Other Organic Ligands; Plenum Press: New York, 1977;
Vol. 3.
6. Smith, R.M.; Martell, A.E. Critical Stability Constants;
Inorganic Complexes; Plenum Press: New York, 1976;
Vol. 4.
7. Wang, Y.-C.J.; Kowal, R.R. Review of excipients and pHs
for parenteral products used in the United States. J. Parenter. Drug Assoc. 1980, 34, 452462.
8. Nema, S.; Washkuhn, R.J.; Brendel, R.J. Excipients and
their use in injectable products. PDA J. Pharm. Sci. Technol. 1997, 51, 166171.
9. Akers, M.J. Excipientdrug interactions in parenteral formulations. J. Pharm. Sci. 2002, 91, 22832300.
10. Garrell, R.K.; King, R.E. Stabilization of homatropine
hydrobromide ophthalmic solution at pH 6.8 by lyophilization. J. Parenter. Drug Assoc. 1982, 36, 452462.
11. Loftsson, T.; Fridriksdottir, H. Stabilizing effect of tris(hydroxymethyl)aminomethane on N-nitrosoureas in aqueous
solutions. J. Pharm. Sci. 1992, 81, 197198.
12. Lam, X.M.; Contantino, H.R.; Overcashier, D.E.; Nguyen,
T.H.; Hsu, C.C. Replacing succinate with glycolate buffer
improves the stability of lyophilized interferon-g. Int. J.
Pharm. 1996, 142, 8595.
13. Hasegawa, K.; Hashi, K.; Okada, R. Physicochemical stability of pharmaceutical phosphate buffer solutions. I. complexation behavior of Ca(II) with additives in phosphate
buffer solutions. J. Parenter. Sci. Technol. 1982, 36, 128133.
14. Hasegawa, K.; Hashi, K.; Okada, R. Physicochemical stability
of pharmaceutical phosphate buffer solutions. II. complexation behavior of Al(III) with additives in phosphate buffer
solutions. J. Parenter. Sci. Technol. 1982, 36, 168173.
15. Hasegawa, K.; Hashi, K.; Okada, R. Physicochemical stability of pharmaceutical phosphate buffer solutions. III. Gel
filtration chromatography of Al(III) complex formed in
phosphate buffer solutions. J. Parenter. Sci. Technol.
1982, 36, 174178.
16. Hasegawa, K.; Hashi, K.; Okada, R. Physicochemical
stability of pharmaceutical phosphate buffer solutions. IV.
prevention of precipitation in parenteral phosphate solutions. J. Parenter. Sci. Technol. 1982, 36, 210215.

Bio-VBuffer

of pharmaceutical solids have been discussed at length,[31]

and a large number of pHsolubility profiles have been
published in the 30 volumes of the Analytical Profiles
series.[3234] A general treatment of the characteristics
of the pHsolubility profiles of weak acids and bases
is available.[35]
When the pH conditions used for a given solubility
determination are set through the use of buffers, the
possible solubilization of the buffering systems must
be established. For instance, no buffer effect was
reported during the determination of the solubilities
of trimethoprim and sulfamethoxazole at various pH
values.[36] On the other hand, correction for buffer
effects was made during studies of some isoxazolylnaphthoquinone derivatives.[37]
With the continuing development of compounds
exhibiting low degrees of intrinsic aqueous solubility,
the combination of pH control and complexing agents
in formulations has become important, and buffers
play an important role in many of these formulations.
A theoretical analysis of the synergistic effect observed
in the combined systems has been developed and used
to explain the solubilization noted for flavopiridol.[38]
In a subsequent work, the solubilization of this substance by pH control combined with cosolvents,
surfactants, or complexing agents was investigated.[39]
The combined effect of pH and surfactants on the
dissolution of piroxicam has been reported.[40] In this
system, the dissolution rate and solubility of the drug
substance could be well estimated by a simple additive
model for the effect of pH and surfactant, where the
total dissolved concentration equaled the summation
of the amount of dissolved non-ionized substance, the
amount of dissolved ionized substance, and the amount
of substance solubilized in the surfactant micelles. It was
suggested that the model developed in this work could
be useful in establishing an in vitroin vivo correlation
for piroxicam.
An equilibrium-based model was proposed to characterize the drugsurfactant interactions observed in
the system consisting of furbiprofen and polysorbate
80 in solutions of different pH.[41] The model reflected
both interactions and interdependence among all drugcontaining species, namely, non-ionized drug in water,
ionized drug in water, non-ionized drug in micelles,
and ionized drug in micelles. The mathematical treatment also enabled modeling of the drug solubilization
in the pHsurfactant solutions without requiring the
use of inappropriate approximations. It was found that
the solubility data estimated by the proposed model
were more reliable when the surfactant concentration
was high in the system. This finding confirmed that
that consideration of interrelations and interdependence
of all drug species in the various solutions was appropriate for this model.

391

392

Bio-VBuffer

17. Hasegawa, K.; Hashi, K.; Okada, R. Physicochemical

stability of pharmaceutical phosphate buffer solutions. V.
Precipitation behavior in phosphate buffer solutions. J. Parenter. Sci. Technol. 1983, 37, 3844.
18. Rowe, R.C.; Sheskey, P.J.; Weller, P.J. Handbook of
Pharmaceutical Excipients, 4th Ed.; Pharmaceutical Press:
London, 2003; 754.
19. Javaid, K.A.; Cadwallader, D.E. Dissolution of aspirin
from tablets containing various buffering agents. J. Pharm.
Sci. 1972, 61, 13701373.
20. Mason, W.J.; Winer, N. Kinetics of aspirin, salicylic acid,
and salicyluric acid following oral administration of aspirin
as either a tablet and two buffered solutions. J. Pharm. Sci.
1981, 70, 262265.
21. Hong, W.-H.; Szulczewski, D.H. Stability of vidarabine-50 phosphate in aqueous solutions. J. Parenter. Sci. Technol.
1984, 38, 6064.
22. Wang, D.-P.; Tu, Y.-H.; Allen, L.V. Degradation kinetics of
phentolamine hydrochloride in solution. J. Pharm. Sci.
1988, 77, 972975.
23. Longhi, M.R.; de Bertorello, M.M.; Brinon, M.C. Isoxazoles V: chemical stability of diisoxazolylnaphthoquinone
in aqueous solution. J. Pharm. Sci. 1989, 78, 408411.
24. Wang, D.-P.; Yeh, M.-K. Degradation kinetics of metronidazole in solution. J. Pharm. Sci. 1993, 82, 9598.
25. Parasrampuria, J.; Gupta, V.D. Preformulation studies of azetazolamide: effect of pH, two buffer species, ionic strength, and
temperature on its stability. J. Pharm. Sci. 1989, 78, 855857.
26. Carney, C.F. Solution stability of ciclosidomine. J. Pharm.
Sci. 1987, 76, 393397.
27. Pramar, Y.; Gupta, V.D. Preformulation studies of spironolactone: effect of pH, two buffer species, ionic strength,
and temperature on its stability. J. Pharm. Sci. 1991, 80,
551553.
28. Nassar, M.N.; House, C.A.; Agharkar, S.N. Stability of
batanopride hydrochloride in aqueous solutions. J. Pharm.
Sci. 1992, 81, 10881091.
29. Zhou, M.; Notari, R.E. Influence of pH, temperature,
and buffers on the kinetics of ceftazidime degradation in
aqueous solutions. J. Pharm. Sci. 1995, 84, 534538.

Buffers, Buffering Agents, and Ionic Equilibria

30. Fiese, E.F.; Hagen, T.A. Preformulation. In The Theory and

Practice of Industrial Pharmacy; Lachman, L., Lieberman,
H.A., Kanig, J., Eds.; Lea & Febiger: Philadelphia, 1986;
184189, Chapter 8.
31. Grant, D.J.W.; Brittain, H.G. Solubility of pharmaceutical
solids. In Physical Characterization of Pharmaceutical
Solids; Brittain, H.G., Ed.; Marcel Dekker: New York,
1995; 321386, Chapter 11.
32. Florey, K., Ed.; Analytical Profiles of Drug Substances;
Academic Press: San Diego, 19721991; Vols. 120.
33. Brittain, H.G., Ed.; Analytical Profiles of Drug Substances
and Excipients; Academic Press: San Diego, 19922002;
2129.
34. Brittain, H.G., Ed.; Profiles of Drug Substances, Excipients,
and Related Methodology; ElsevierAcademic Press:
Amsterdam, 2003; Vol. 30.
35. Streng, W.H.; His, S.K.; Helms, P.E.; Tan, H.G.H. General
treatment of pHsolubility profiles of weak acids and bases
and the effects of different acids on the solubility of a weak
base. J. Pharm. Sci. 1984, 73, 16791684.
36. McDonald, C.; Faridah, H. Solubilities of trimethoprim
and sulfamethoxazole at various pH values and crystallization of trimethoprim from infusion fluids. J. Parenter. Sci.
Technol. 1991, 45, 147151.
37. Granero, G.; de Bertorello, M.M.; Brinon, M.C. Solubility
profiles of some isoxazolyl-naphthoquinone derivatives. Int.
J. Pharm. 1991, 190, 4147.
38. Li, P.; Tabibi, S.E.; Yalkowsky, S.H. Combined effect of
complexation and pH on solubilization. J. Pharm. Sci.
1998, 87, 15351537.
39. Li, P.; Tabibi, S.E.; Yalkowsky, S.H. Solubilization of
flavopiridol by pH control combined with cosolvents,
surfactants, or complexants. J. Pharm. Sci. 1999, 88, 945
947.
40. Jinno, J.; Oh, D.-M.; Crison, J.R.; Amidon, G.L. Dissolution of ionizable water-insoluble drugs: the combined
effect of pH and surfactant. J. Pharm. Sci. 2000, 89, 268
274.
41. Li, P.; Zhao, L. Solubilization of flurbiprofen in pHsurfactant solutions. J. Pharm. Sci. 2003, 92, 951956.