KAILAS D. THAKKER AND LEE T.

GRADY
1. Description
1.1 Nomenclature
1.11 Chemical Name
Aminophylline is chemically known as 1Hpurine-
2,6-dione, 3,7-dih dro-l,3-dimethyl-, compound wTth
1,2-ethanediamine (2:l). P
1.12 Adopted Names
Aminophylline was also known as theophylline
ethylenediamine and euphylline. 1
1.13 Trade Names
Aminophylline is known as carena;
inophylline; metaphylline; theophyldine; aminocardol;
ammophylline; cardiocilina; cardophyllin; phylcardin;
tefamin; cardiomin; grifomin; minaphil; peterphylline;
stenovasan; the drox; diophylline; genophylline; phyllindon
and theolamine. P
1.2 Formula, Molecular Weight, and Composition:

2.11 Infrared
The infrared spectrum of aminophylline in
mineral oil mull, obtained on a B ckman 4250 spectrophotometer,
is shown in Figure l.5 It is generally
consistent wi h the reported infrared spectrum of
theophylline. 5,4 The stretches for -NH2 in ethylenediamine
and -NH in theophylline appear as a broad band (combined
with the mineral oil signal) in the region of 3.0-4.0 PM.
Other signals are in the same vicinity as those for
theophylline. The fingerprint region beyond 8.5 IJM is
distinctive and can be used for identification.

2.13 Nuclear Magnetic Resonance

2.13.1 Proton NMR
An 80 MHz proton magnetic resonance
spectrum of aminoph lline in d6-dimethyl sulfoxide, obtained
on a Varian FT-80A,' containing tetramethylsilane as an
internal reference, is shown in Figure 3 .
the reported (60 MHz) proton NMR of theophylline. The
assignments, based on assignments of theophylline protons,
are shown in Table I.

Carbon-13 NMR
The 20 MHz proton-noise decoupled
spectrum of aminophylline in d6-dimethyl sulfoxide,
obtained on a Varian FT-80A is shown in Figure 4.6 The
assignments are shown in Table 11. These are based on
assignments of dimethyluracil and 1-methylhypoxanthine. 7

 Stability in Solution
Solutions of aminophylline become turbid on
standing due to absorption of carbon dioxide, with
subsequent precipitation of theophylline.' S 8
preparation of aminophylline injection, excess
ethylenediamine is necessary to keep aminophylline from
During the
decomposing. 12

4.2 Stabilitv in Solid State

Aminophylline crystals, in the presence of
moisture, can absorb carbon dioxide fr m air and decompose
into theophylline and ethylenediamine.8 This accounts for
its characteristic odor.
Mixtures containing aminophylline and ephedrine
hydrochloride were found to be discolored13 due to an
exchange reaction between the two drugs. The ethylenediamine
in aminophylline is presumed to liberate ephedrine
base which decomposes rapidly. The color change was
accelerated by temperature and humidity.

5.5 Chromatographic Methods

5.51 Thin-Layer Chromatography
In addition to systems developed for theo-
~hylline,s~ev eral TLC systems have been developed for
"Aminophylline and theophylline are indistinguishable at
biological pH's. Therefore assays of theophylline in
biological fluids are also included here due to their
obvious applicability.

5.4 Spectroscopic Methods

Aminophylline solutions obey the Beer-Lambert Law
for a zqncentration range of 0.5-1.2 mg%.5 Schack and
Waxler developed a potentiometric assay for aminophylline
in biological fluids using chloroform/2-propano1 extraction
to isolate theophylline, followed by W-absorbance
measurement at 275 nm. The method of Schack and Waxler was
used most extensively for analysis of aminophylline in early
pharmacokinetics research. a Several other
spectrophotometric methods have been developed for
aminophylline in mixtures of pharmaceuticals, each one using
an extraction t organic solvent to isolate
aminophylline. ''*kg In one case, graphical correction was
applied to the W absorbances of mixtures of aminophylline
and phen barbital, measured at two wavelengths of
maxima.58 In another application, extraction of serum
samples with a salt-solvent pair of ammonium sulfate and
back
( PH
ch1oroform:hexane (7:3 v/v) was carried out followed b
extraction of theophyllinea into aqueous borate buffer
9.0) an measurement of UV absorbance at 275 nm.
PlavsicgZ used charcoal extraction to isolate theophyl
from other interfering substances. Since theophylline
reversibly adsorbed on charcoal, elution with organic
solvent was followed by measurement of W absorbance.