SCIENTIFIC REPORT

The Relationship Between pH and Concentrations

of Antioxidants and Vasoconstrictors in Local
Anesthetic Solutions
Steven 0. Hondrum, DDS, MS, and John H. Ezell, BS
US Army Dental Research Detachment, Walter Reed Army Institute of Research, Fort George G. Meade, MD 20755-5305

pH affects the efficacy of local anesthetics by determining the percentage of the

lipid-soluble base form of the anesthetic available for diffusion and penetration of
the nerve sheath. The purpose of this study was to determine the relationship be-
tween pH and the concentrations of antioxidant and vasoconstrictor in dental local
anesthetic solutions over real-time and after accelerated aging. Several batches of
lidocaine and mepivacaine with vasoconstrictors were tested. Results showed that,
immediately upon receipt from the manufacturers, three batches were below the
USP pH limit (pH 3.3), and two batches contained less than the minimum limit of
vasoconstrictors (90%). Real-time tests on batches that were within normal limits
revealed that solutions were stable past 4 yr. Accelerated aging tests revealed a
strong correlation between a decrease in pH and loss of antioxidants and vasocon-
strictors. In conclusion, a quality batch of local anesthetic should remain efficacious
long past the manufacturer's stated shelf life; a batch that is less than optimal, or
one that is exposed to environmental stresses, will degrade rapidly, and efficacy may
be affected by decreases in pH and loss of vasoconstrictor. pH may be an inexpen-
sive, readily available screening test for efficacy of local anesthetics.
Key Words: Pharmaceutical efficacy; Shelf life.

Approximately five anesthetic failures occur each
week in general dental practices.1 The reasons for
local anesthetic failure involve not only patient and pro-
vider factors, -6but also pharmaceutical factors directly
relating to the drugs injected. Pharmaceutical factors in-
clude the nature of the drug product (dosage form, con-
centration, pH, absorption), the manufacturing process,
and the container-closure system.7-10
Pharmaceutical efficacy may also be affected by deg-
radation of the drug components over time or upon ex-
posure to environmental stresses. Fifty-six percent of
military dentists report problems with local anesthetics
that they attribute to the poor storage stability of these
drugs,'1 and recent manufacturer recalls of local anes-
thetics have emphasized the fragile stability of local an-
esthetic solutions.12
Because commonly used local anesthetics, such as
Address correspondence to Dr. Steven O. Hondrum, Commander,
USA Area Dental Laboratory, Bldg. 322 (MCDS-RG), Attn: Dental
Materials/COL Hondrum, Ft. Gordon, GA 30905-5661.
Anesth Prog 43:85-91 1996
© 1996 by the American Dental Society of Anesthesiology
85
mepivacaine and lidocaine, are highly resistant to deg-
radation,13 the continued efficacy of dental local anes-
thetic solutions over time is thought to depend largely
upon the stability of the vasoconstrictor constituent.9
Vasoconstrictors degrade primarily by oxidation, accel-
erated by the presence of molecular oxygen, elevated
temperature, light, heavy metals, and an increase in
pH.9°10'4-'8 However, degradation of vasoconstrictors
may not entirely account for the loss of pharmaceutical
efficacy upon aging or exposure. Since a 1: 200,000
solution of epinephrine may be as efficacious as a
1: 100,000 solution,7'920 the higher concentration
must diminish to more than 50% of its original strength
for loss of clinical efficacy to be appreciated. Moreover,
studies show that epinephrine solutions (including local
anesthetic solutions containing epinephrine) found to be
below the United States Pharmacopeia (USP) accept-
able limit (90%)21 have degraded to only an average of
80% of label claim, and most of these batches are past
expiration date.2223 Besides oxidation of vasoconstric-
ISSN 0003-3006/96/$9.50
SSDI 0003-3006(96)
86 pH of Local Anesthetics Anesth Prog 43:85-91 1996

Table 1. Drugs Testeda

Drug Code Concentrations/ml Manufacturers
Lidocaine LES 20 mg (2%) Astra Pharmaceutical,
Epinephrine 0.01 mg (1: 100,000) Westborough, MA
Sodium metabisulfite/bisulfite 0.5-0.55 mg Novocol Pharmaceutical,
Cambridge, Ontario, Canada
Mepivacaine MLA 20 mg (2%) Sterling Drug,
Levonordefrin 0.05 mg (1: 20,000) New York, NY
Acetone sodium bisulfite '2.0 mg Novocol Pharmaceutical,
Cambridge, Ontario, Canada
a Batch numbers are available upon request.

tor, then, there may be some other drug-degradation
factor that contributes to loss of efficacy over time.
The USP requires pH to be within 3.3 to 5.5 for
dental local anesthetic preparations containing vasocon-
strictors.21 Epinephrine becomes more unstable as pH
increases18'24: at pH 4.5, epinephrine concentrations
dip below minimal USP levels in less than 12 mo25;
above pH 6, epinephrine begins to deteriorate within
several hours.26 To stabilize sympathomimetic amines,
manufacturers acidify their local anesthetic prepara-
tions, usually with hydrochloric acid, and include a buff-
er.10 However, there must be a compromise between
the optimum pH for stability and that for pharmacolog-
ical activity. The necessity for the presence of an acidic
pH affects potency by exponentially decreasing the
available percentage of the lipid-soluble base form of the
anesthetic that is necessary for diffusion and penetration
of the nerve sheath. Since pKa is a constant, the relative
proportions of the local anesthetic that exist in solution
as uncharged molecules and positively charged cations
will depend upon the pH of the solution according to
the Henderson-Hasselbalck equation.27 The clinical sig-
nificance of this is that as pH decreases the chemical
equilibrium shifts more toward the charged cationic
form of the drug, proportionately more cation will be
present than free base, and, consequently, more anes-
thetic must be adjacent to the nerve membrane to effect
the same biologic result. Studies have shown that local
anesthetics that are pH-adjusted just prior to injection,
to maximize the percentage of base form, have short-
ened onset times, improved adequacy of the block, and
longer duration than more acidic preparations.2-30
The antioxidant constituent of dental local anesthetics
also affects the pH of these solutions. Antioxidants, usu-
ally sulfite salts such as sodium bisulfite, delay the oxi-
dation of vasoconstrictors by acting as sacrificial com-
pounds-they possess lower oxidation potentials than
vasoconstrictors and, therefore, react with catalysts, ox-
idation promoters, and oxygen at a higher rate than the
vasoconstrictor itself.9,10 As antioxidants oxidize from
sulfite to sulfate, there is an emission of protons, result-
ing in a decrease in pH.31 The buffer demand of epi-
nephrine and an added antioxidant is increased largely
due to the antioxidant.7'3233 Previous research has
shown that the pH of local anesthetic formulations may
decrease over time and upon exposure to environmental
stresses.34
The purpose of this study was to examine the rela-
tionship between pH and the concentrations of antiox-
idants and vasoconstrictors during real-time and accel-
erated degradation of dental local anesthetic solutions.
METHODS
Fourteen batches of lidocaine with epinephrine and so-
dium metabisulfite or bisulfite (LES) and nine batches of
mepivacaine with levonordefrin and acetone sodium bi-
sulfite (MLA) were studied. Manufacturers and label
claim values are listed in Table 1.
Baseline pH testing (pH meter Model 130, Corning,
Inc., Corning, NY, with combination electrode Model
#13-620-83) of LES and MLA was accomplished upon
receipt of the drugs from the manufacturers. At least
five baseline pH measurements were made of each
batch to determine inter- and intra-batch variation. Sam-
ples were then exposed to the following conditions:
(a) Control groups. Testing was accomplished at in-
tervals while samples were stored in controlled condi-
tions-original packaging intact, room temperature (69
± 2°F), and humidity (40 ± 10% RH).
(b) Experimental groups. Samples were shipped to
various overseas locations in the US military supply sys-
tem and returned at intervals for testing.
(c) Accelerated aging groups. Preliminary studies re-
vealed that, for LES, a critical factor in degradation was
exposure to light; for MLA, the critical factor was the
container-closure seal.32 For the accelerated aging
groups, then, LES samples were tested at intervals while
cartridges were continually exposed to fluorescent room
light; MLA samples were tested at intervals after the
vacuum can was opened.
Anesth Prog 43:85-91 1996 Hondrum and Ezell 87

5.5
AX

pH MLA
-

4.5

4.5

pH. LES

3.5

32

2.5
I
I as
Iv 2n
zu ,x
du 4u
ax
An 50
r, n 50
.
70
Time (Months) ~~~~~~~~~Time ([Xly*)
I -

Figure 1. A. Mean pH of LES and MLA (all groups) over 60 mo; n > 12 (at least one sample of each batch) at each interval
after baseline; B. Mean pH of accelerated aged LES (light exposed) and MLA (vacuum can open) over 350 days; n > 8 (at least
one sample of each batch) at each interval after baseline.

In addition to pH measurements on all groups at all
intervals, selected samples of each group were analyzed
quantitatively. Once variability had been determined at
baseline, three to four random cartridges of each group
were pulled for quantitative analysis at each test interval.
Preliminary assays of lidocaine and mepivacaine re-
vealed that, as expected, there was no loss of these
components of the solutions over real-time or upon ac-
celerated aging.33 Therefore, further analysis involved
only vasoconstrictors and antioxidants. The high-pres-
sure chromatographic system (HPLC) used for vasocon-
strictor determination was a Waters modular LC system
consisting of an M6000A HPLC column, a WISP 710B
autosampler, and a Waters 990 Photodiode Array de-
tector; the column was a Waters u-Bondapack C18 (Wa-
ters Chromatography, Milford, MA). Chromatograms
were obtained at 280 nm UV. The ion chromatograph
(IC) used for antioxidant determination consisted of a
Waters Model 590 HPLC pump, a Waters U60K man-
ual injector, and a Waters model 430 conductivity de-
tector; the column was an Alltech Anion R (Alltech-Ap-
plied Science Labs, State College, PA). Detection was
performed using suppressed conductivity. Single point
calibration was used to determine the concentrations of
vasoconstrictors and antioxidants.
Regression analysis was calculated to establish corre-
lation between pH, antioxidant, and vasoconstrictor.
RESULTS
The pH of two batches of LES and one batch of MLA
was found to be below minimum USP specifications (pH
3.3) upon receipt from the manufacturers: pH LES-
2.86 and 3.14; pH MLA-3.05. Quantitative analysis
(IC) of two of these batches revealed complete exhaus-
tion of the antioxidants. Vasoconstrictor levels were be-
low the USP minimum value of 90%: for epinephrine,
76% of label claim, and for levonordefrin, 68% of label
claim. The second LES batch was analyzed and vaso-

Table 2. Means (SD) of pH and Concentrations of Vasoconstrictors and Antioxidants in Control and Experimental Groups of
LES and MLA over 60 mo Real-timea
Months
<10 24 36 48 60
LES
pH 4.20 (0.13) 4.00 (0.14) 3.95 (0.22) 3.79 (0.14) 3.80 (0.12)
Epinephrine (,g/ml) 10.98 (0.44) 10.24 (0.08) 9.83 (0.44) 9.37 (0.20) 8.60 (0.80)
Sodium bi/metabisulfite (mg/ml) 0.38 (0.07) 0.31 (0.06) 0.26 (0.03) 0.13 (0.12) 0.04 (0.03)
MLA
pH 4.43 (0.19) 4.51 (0.18) 4.77 (0.18) 5.05 (0.18) 5.31 (0.09)
Levonordefrin (p,g/ml) 48.00 (0.54) 47.79 (0.37) 48.73 (2.62) 47.90 (0.88) 47.35 (1.90)
Acetone sodium bisulfite (mg/ml) 1.60 (0.22) 1.37 (0.25) 1.13 (0.31) 1.45 (0.32) 1.24 (0.17)
a A minimum of three samples was analyzed quantitatively at each interval past baseline.
 -. w -
88 pH of Local Anesthetics Anesth Prog 43:85-91 1996

S E
E
a
co
m a
I I
2c

pH Epinephrlne (ug/ml)

Figure 2. A. Raw data accelerated aging correlation between decrease in pH and loss of sodium metabisulfite antioxidant in LES;
B. Concomitant loss of epinephrine vasoconstrictor.

constrictor was also below USP limits, but this batch was
beyond expiration date at the time analysis was done.
These three batches were excluded from the study.
As there were no statistical differences in pH between
control and experimental groups (P > 0.50 at each in-
terval), all real-time results were combined and pH
means were plotted vs age in months (Figure 1A). The
pH of LES samples decreased only slightly (approxi-
mately pH 0.3) over 60 mo of storage (42 mo past
manufacturer's stated shelf life). The pH of MLA in-
creased almost one pH unit over 60 mo (36 mo past
expiration date) regardless of storage conditions, as long
as the vacuum cans remained closed. Quantitative anal-
ysis of LES revealed that this relatively small decrease
in pH corresponded to a slow but steady decrease of
antioxidant to virtually zero at 60 mo; the vasoconstric-
ZI
tor also decreased steadily, but did not pass USP mini-
mum limits (90%) until after 4 yr (Table 2). Quantitative
analysis of MLA revealed that the antioxidant remained
relatively constant from baseline to 60 mo; vasoconstric-
tor decreased only slightly, and did not pass USP min-
imum limits even after 60 mo, as long as the vacuum
remained intact (Table 2).
In the accelerated aging groups, LES continually ex-
posed to fluorescent room light showed a progressive
decrease in pH from baseline level to below pH 3.3
(USP minimal limit) after approximately 45 days, even-
tually leveling off at pH 2.8 after 100 days, indicating
exhaustion of the antioxidant (Figure 1B). MLA, tested
at intervals after the vacuum can was opened, showed
a decrease in pH from baseline level to below 3.3 within
150 days (Figure 1B). Chemical analysis of LES and
2c I.......
· I

A B
1.75 1.75
x

1.5 1.5
r2=O.64 x x

1.25 K x E 1.25
E
t
m
1 K xX
x/ / K Transformed r 2 =0.80
X xx
/x I
.75
.7 /x
I .2
co
x/
E .5
.5

.25 /X X
.25- x /x

v~ lx 0. 1 3-

2.5 .
3 X
3.5 4 4.5 5
I
I
5.5 5 10 15 20 25 30 35 40 45 50 55
pH Levonordetrln (ug/ml)

Figure 3. A. Raw data accelerated aging correlation between decrease in pH and loss of acetone sodium bisulfite antioxidant in
MLA; B. Concomitant loss of levonordefrin vasoconstrictor.
Anesth Prog 43:85-91 1996

-o

(0
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.r!.

C),.
0

"O

0
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LO
A
o~ c:0
o560000.
,-'~

00
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0000
,~ c

vo
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C,~ 00 C-

oy Lfn o)
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Hondrum and Ezell 89

MLA revealed that the decrease in pH to 3.3 corre-

sponded to a linear loss of antioxidant to approximately
one-third of label claim; raw data is depicted in Figures
2A and 3A, and means and standard deviations in Table
3. A concomitant exponential decrease of vasoconstric-
tor to approximately 70 to 80% of label claim is de-
picted in Figures 2B and 3B (raw data), and Table 3
(means and standard deviations). Note the correlation
coefficients in the graphs; in Figures 2B and 3B, vaso-
constrictor values were transformed (x3) to allow linear
correlation.

DISCUSSION
Batches that were outside USP pH specifications upon
receipt from the manufacturer (three out of 23 tested)
infer a quality control problem at the manufacturing lev-
el. This portends the need for not only better quality
assurance standards, but stricter USP specifications, and
perhaps greater buffer capacity in the solution. In ad-
dition, the local anesthetics assayed contained only 60
to 80% of the labeled concentration of antioxidant at
baseline. This implies that the antioxidant may lose al-
CLO CD
.°o c L -4 most half of its labeled concentration before there is a
(0
c5
CY c5c5i
-0¢ CO C; r_
01) significant change in pH (perhaps because of the buffer
.c '-4

vt °. X- CL capacity of the solution) and before the vasoconstrictor

a
X begins to oxidize. It may also indicate that batches are
UY)
C C>
m O stored for some significant length of time by manufac-
o O cq 0) turers before being shipped to distributors or user facil-
COLe-4 ities. For batches that are suspected to be less than op-
._
Q)
oo
000000
ON timal quality, pH may be an inexpensive and readily
LO o
r- N -i-
O Cy
co LO N
0
O 0) tv
CO oo *=0) available screening test.
C0 )00
U,)
As shown in the real-time data, the pH of MLA may
actually increase markedly over time, as long as the vac-
C,)
eo qC ege uum cans are kept closed. The rise in pH for MLA, as
C,)
z well as the pH stability of real-time LES tests even while
00) -0
U) the antioxidant degrades over real-time, is probably due
o0) S to slow extraction of alkali from rubber stoppers coun-
C;.,
1.. 7
C.)
(3 C; teracting the acidity from degradation of the antioxi-
0
^

.E dant.9'31 In addition, the measured decreases in pH once

O 0 vacuum cans of MLA were opened, and the slow de-
cy cr 10I.>t
-o
r- C) N crease in LES antioxidant over time, indicate that
C C;C
Ooo
*= X rubber-stoppered anesthetic cartridges are not a her-
cQO o1 sCy metically sealed system.31,35
)., ,: c)
*
us-
X
The decrease in pH over time and exposure in the
z accelerated aging groups is probably due to oxidation of
the sulfite; as each sulfite molecule oxidizes to sulfate,
UY)
a; two protons are generated. In addition, as antioxidant
(0
degradation approaches 40% of label claim, the vaso-
constrictor concentration falls outside USP minimum
limits. While most anesthetic failures in clinical practice
are undoubtably due to patient/provider factors, this
concomitant decrease in vasoconstrictor and pH may
90 pH of Local Anesthetics
contribute to clinical problems achieving local anesthe-
sia, as more anesthetic must be adjacent to the nerve
membrane to effect the same biologic result.
Real-time data from this study indicate that quality so-
lutions of local anesthetic remain stable long past man-
ufacturer's shelf life, even when exposed to stressful
transportation and storage conditions. Longer shelf lives
for local anesthetic solutions may be justified, assuming
adequate quality control and storage, as it would seem
that the loss of efficacy over time may be more of a
quality control problem than an inherent stability prob-
lem with the drugs themselves. Stricter quality control
and longer shelf lives would be particularly beneficial in
cases of military deployments to foreign lands, and in
care delivery in third-world countries distant from man-
ufacturers. Guidelines to prolong the efficacy of local
anesthetics have been published.36
CONCLUSION
A quality batch of local anesthetic should remain effi-
cacious long past the manufacturer's stated shelf life. A
batch that is less than optimal, or one that is exposed
to environmental stresses, will degrade rapidly, and clin-
ical efficacy may be affected by a decrease in pH and
loss of vasoconstrictor.
For batches of local anesthetic that are suspected to
be less than optimal in quality, the determination of pH
of the anesthetic may provide an inexpensive, easily
performed screening test to prognosticate efficacy.
ACKNOWLEDGMENT
The views of the authors do not purport to reflect the
views of the Department of the Army or the Depart-
ment of Defense (Para. 4-3, AR 360-5).
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