6,132,758

34
unidentified impurities occur regularly and have been col- Lory infections), and analgesics, such as aspirin,
lectively denoted as "Group A"; these materials number acetaminophen, ibuprofen, naproxen or ketoprofen (for
about 5 to 7 and elute together in an HPLC analysis, at relief of pain and, except in the case of acetaminophen, for
retention times which indicate a higher polarity than that of reducing inflammation). Antitussives, such as codeine,
loratadine. The severity of the degradation may be at least 5 hydrocodone or dextromethorphan, for relief from
approximately related to the volume in a product bottle coughing, and expectorants such as guaifenesin, for increaswhich is not filled with syrup, i.e., the "headspace." As it is ing cough productivity, also are included in combination
not practical to nil each bottle completely to the top, a test products. Any of these additional ingredients, including salts
has been conducted where the headspace was filled with thereof and other drugs from the same therapeutic classes,
nitrogen gas; results were inconclusive, possibly due to the 1o are suitable for inclusion in the syrups of the present
unavoidable oxygen permeability of the polymeric bottle invention.
closure'
The
invention
will
be
further
described
by
means
of
the
Another test was conducted, wherein common antioxidant following examples, which are not intended to limit the
additives were incorporated into the syrup. Ideally, the scope of the invention as denned by the appended claims.
antioxidant will be soluble in the syrup and is safe for use in 15 Where the term "percent" is used herein, it is intended to
foods and pharmaceutical preparations. Among the water- represent percent by weight, unless the context clearly
soluble materials, ascorbic acid at 0.1 and 1 mg/mL was evidences otherwise.
found
to
somewhat
reduce
degradation,
but
also
caused
an
unacceptable strong color change in the product, while EXAMPLE 1
sodium bisulHte imparted a pungent, disagreeable odor to 20 A syrup was formulated to contain the following
the syrup. The oil-soluble antioxidants butylated hydroxy- ingredients, wherein amounts of all except water are
toluene and tocopherol were not soluble in the syrup, so also expressed in milligrams.
were not found acceptable.
It has been found that the addition of small amounts of an

,
,
,.
.,
,
,
.f
,,
.
,
amlnopolycarooxyuc aclu, me term speclncauy Incluulng 25
salts of the acids, can stabilize the syrups against degradaIngredlent Amount
Lion.
Useful
aminopolycarboxylic
acids
and
salts
thereof
are
Loratadinc,
those which are safe for ingestion and have sufficient solu- Citric acid 8.78
bility in the syrup formulations to make a stable single phase lavoring agent ] O
composition. Commercially available compounds which 30 cye glycol O
could
be
used
include
iminodiacetic
acid,
methyliminodiSodium
acetic acid, nitrilotriacetic acid, ethylenediaminetetraacetic Disodium EDTA 0.25
acid
("EDTA"
diethvlenetriaminenentaacetic
acid
1
2^- .-~

AA A ," A-AAJ AW AA- `A A-A-r -AA-FF- - `A- F-A-' '

,.

micronized

benzoate

Sucrose

600

Water to make 1.0 mL

dlamlnocyclohexane-tetraacetlc acld,__
N-hydroxyethylenediaminetriacetic

acid

and

related

com-

35

pounds. Mixtures of two or more of the foregoing are This syrup is prepared using the following procedure: (a)
suitable for use. From the aspects of ready availability, about 80 percent of the water is placed in a vessel, heated to
safety, efficacy and cost, the alkali metal salts of EDTA are 75-85o C., charged with the sugar and stirred to form a
presently preferred, and the remainder of this description solution; (b) the citric acid is charged to the solution and
will focus on those materials. 40 stirring is continued to form a solution, then the sodium
An aminopolycarboxylic acid or salt will typically be benzoate is added and dissolved; (c) the solution is cooled to
present in a syrup at about 0.05 mg/mL to about 5 mg/mL. 3035o C., with continued stirring, and the disodium EDTA
More preferably, the level of aminopolycarboxylic acid will is added and dissolved; (d) the glycerin is added and stirring
be about 0.1 mg/mL to about 1 mg/mL. As with any additive continued while the solution cools to 25-30o C.; (e) in a
component in a formulation intended for ingestion, it is 45 separate vessel, the propylene glycol and loratadine are
desirable to incorporate the minimum level which will yield combined and stirred to form a solution (note that the use of
the desired result. This level can be readily determined by micronized loratadine particles decreases the time required
means of an accelerated storage stability test, in which to accomplish dissolution), then the flavoring agent is added
packages of the final product are stored at elevated tempera- and stirred to achieve homogeneity; (f) the product of step
lures above the usual storage temperatures to which the 50 e is combined with the product of step d, with stirring to
product is expected to be exposed; the present inventors ensure homogeneity, and sufficient water is added to provide
have used temperatures up to 550 C. for this purpose, the proper formulation weight; and (g) the resulting syrup is
although such temperatures tend to cause a minor discol- passed through clarifying niters. The syrup is a clear,
oration (darkening) of the syrups, probably due to some colorless liquid (which could readily be colored as desired,
carmelization of the contained sucrose. It is expected that 55 such as by adding a suitable pharmaceutically acceptable
most drug degradation reactions will be accelerated by the water-soluble dye to the sugar solution of step a) and is
elevated temperature. At predetermined intervals, some of denoted Sample A.
the packages are opened and analyzed to determine the Another syrup is similarly formulated, except that it
amount of active ingredients and impurities present in the further contains 1 mg/mL of the disodium salt of EDTA.
formulation. 60 This is denoted Sample B.
Antihistaminic syrup formulations frequently also contain Twenty five mL portions of the two syrups are placed into
other drugs, for obtaining more than one therapeutic result 50 mL Hint glass vials, then sealed with rubber stoppers and
from a single dose. Typical drug substances included with aluminum caps. The sealed vials are stored at 550 C. until
t he a n t ihi st a m ine a r e s y mp a t horn ime t ic a m ine their removal and analysis by high performance liquid
decongestants, such as pseudoephedrine or phenylpropano- 65 chromatography. Results of the analyses are as follows,

lamine (for relief of the upper airway congestion often where "NQ" indicates a result below the limit of quantifiaccompanying disorders such as rhinitis and upper respira- cation (0.1%) but above the limit of detection (0.02%):