Simple process for the preparation of cetyltrimethylammonium naproxenate (naprocet)

Article abstract of DOI:10.1021/op500175v

Specifications for cetyltrimethylammonium (CTA) naproxenate (naprocet), the active ingredient of pharmaceutical liquid preparations used as antiseptic-antinflammatory detergents, fix severe limits to the presence of residual inorganic counteranion deriving from the starting CTA salt. A new simple procedure, which avoids ionic exchange chromatography and utilizes CTAHSO₄ in place of CTABr and CTACl, exploits the quantitative precipitation of K₂SO₄ from methanol to yield naprocet in line with such specification requirements.

Full text of DOI:10.1021/op500175v

Technical Note
pubs.acs.org/OPRD
Simple Process for the Preparation of Cetyltrimethylammonium
Naproxenate (Naprocet)
Cristiano Bolchi, Ermanno Valoti, Laura Fumagalli, Paola Ruggeri, Valentina Straniero,
and Marco Pallavicini*
̀
Dipartimento di Scienze Farmaceutiche, Universita degli Studi di Milano, via Mangiagalli 25, I-20133, Milano, Italia
S
* Supporting Information
ABSTRACT: Specifications for cetyltrimethylammonium (CTA) naproxenate (naprocet), the active ingredient of
pharmaceutical liquid preparations used as antiseptic−antinflammatory detergents, fix severe limits to the presence of residual
inorganic counteranion deriving from the starting CTA salt. A new simple procedure, which avoids ionic exchange
chromatography and utilizes CTAHSO4 in place of CTABr and CTACl, exploits the quantitative precipitation of K2SO4 from
methanol to yield naprocet in line with such specification requirements.
specifications for residual chlorides and sulfates are obviously
less stringent than for bromide, if chloride or sulfate has to be
replaced with another counteranion. However, also in these
cases, lowering chloride or sulfate content below fixed limits is
not easy.
Recently, we had to solve the problem of eliminating or
minimizing residual CTA inorganic counteranion in the
preparation of CTA naproxenate (naprocet),19 an organic salt
of CTA topically administered in humans as a 0.2% aqueous
solution for its combined antiseptic and anti-inflammatory
properties due to CTA and naproxen, respectively.
Here, we report a simple method to prepare naprocet
satisfying prescribed residual inorganic CTA counteranion
specifications without using CTABr and ion exchange
chromatography techniques.
INTRODUCTION
■
Cetyltrimethylammonium (CTA), also known as cetrimonium,
is one of the most widely employed quaternary ammonium
compounds.1 The use of its inorganic and organic salts spreads
over different areas ranging from active ingredients in
pharmaceuticals, such as antiseptics,2 disinfectants,3 and
tumoricidal irrigants,4 to cosmetics,5 colloids,6 nanoparticles,7
chemical reactants,8 additives,9 surfactants,10 functional ex-
cipients,11 and selective growth media components,12 to name
just a few.
CTA bromide (CTABr) is the most familiar CTA salt
because it has been commercially available in high purity grade
for a long time and is less hygroscopic and easier to handle than
other CTA salts (Chart 1). However, its use as a starting
material is sometimes conditioned by the fact that bromide has
some degree of toxicity.13 This is the case of pharmaceutical
manufacturing. A few active pharmaceutical ingredients (APIs),
administered in low dose, are reported as bromides or
hydrobromides in pharmacopoeia, while only traces of bromide
are tolerated in some substances for pharmaceutical use, which
are not APIs and are not subjected to the same dose restrictions
as APIs. For instance, 100, 1000, and 500 ppm maximum
bromide contents are fixed in NaCl,14 KCl,15 or MgCl2·6H2O16
for pharmaceutical use, respectively, and consequently a <1
ppm content in liquid preparations such as isotonic
physiological solutions. Such a limit is consistent with WHO
recommended bromide concentrations in drinking water (≤0.5
ppm),17,18 which can be used, if compatible, without further
purification as a pharmaceutical ingredient according to USP.
CTA salts, such as CTABr, are active ingredients; nevertheless,
manufacturing specifications can require that bromide is absent
in antiseptic CTA containing solutions for human use,
especially when applied to mucosae, likely because of the
non-negligible CTA concentration in these preparations and of
the variability of the topically applied quantity. Therefore,
preparing a CTA antiseptic solution from CTABr can raise the
issue of eliminating bromide. Alternatively, CTACl and
CTAHSO4, two CTA inorganic salts more recently commer-
cially available in high purity grade, can be used. The
RESULTS AND DISCUSSION
■
The first reported attempts at preparing naprocet exempt from
the pre-existing inorganic counteranion of CTA consisted of
combining equimolar CTABr and potassium naproxenate in
anhydrous ethanol and removing precipitated KBr by
filtration.20 However, such a method does not ensure an
acceptable grade of product purity due to incomplete removal
of KBr. Alternatively, the use of CTA hydroxide (CTAOH) was
proposed.21 CTAOH has the advantage that it can be directly
combined with naproxen acid to give water as the only
byproduct, but it is significantly more costly than CTABr, from
which it is prepared, for instance, by chromatographic Br−/
OH− exchange. Furthermore, CTAOH is commercially
available as an approximately trihydrate solid or as a
concentrated aqueous solution with variable water content.
Therefore, what we wanted was to use an anhydrous crystalline
inorganic salt of CTA, which was cheaper than CTAOH, and to
develop a new procedure to efficiently remove the inorganic
counteranion by simple precipitation and not by chromatog-
raphy.
Received: May 30, 2014
© XXXX American Chemical Society
A
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Technical Note
Chart 1. Cetyltrimethylammonium Salts
Table 1. Solubility of Common Sodium, Potassium, and Calcium Inorganic Salts in Methanol (Grams/100 Grams Solvent) at
a
25 °C
fluoride
chloride
bromide
iodide
nitrate
carbonate
sulfate
sodium
0.0231
2.286
1.401
0.5335
23.26
16.09
2.080
55.83
62.51
17.07
67.37
2.936
0.3795
127.1
0.3109
6.165
0.0113
0.0005
0.0046
potasssium
calcium
0.0145
0.0012
a
Data taken from ref 22.
Scheme 1. Preparation of Naprocet from CTAHSO4 and Naproxen in Methanol by Using (a) Potassium Carbonate or (b)
Potassium t-Butoxide
Literature data indicate that, among the common sodium,
potassium, and calcium salts, the sulfates are the most insoluble
ones in methanol and, in particular, potassium sulfate is less
soluble than any other (Table 1).22 Compared to KCl and to
KBr, it is 1000- and 4000-fold less soluble in methanol. This
suggested to us the idea of using CTAHSO4 in methanol
instead of CTACl and CTABr and of precipitating potassium
sulfate before adding naproxen. CTAHSO4 was combined with
an equimolar suspension of potassium carbonate in methanol
or with double molar amount of potassium tert-butoxide
dissolved in methanol (Scheme 1). After stirring overnight at
room temperature and cooling to 0−5 °C, precipitated K2SO4
was filtered off and naproxen acid was added to the resultant
solution of CTAHCO3 or CTA alcoholate. Successive removal
of methanol and carbonic acid or of methanol and tert-butanol
under vacuum afforded naprocet as a waxy residue, which was
optionally converted into a white spongy solid by dissolution in
water and lyophilization. Both procedures, the one with
potassium carbonate and the other with potassium tert-
butoxide, were repeated several times and analytical ion
exchange chromatography proved that residual sulfate in pure
naprocet was always <500 ppm. Such a value ensures a < 125
ppm concentration of sulfate in the 25% aqueous solution of
naprocet, for which a 200 ppm limit is fixed by specifications,
and a < 1 ppm concentration in the final 0.2% naprocet
antiseptic solution, which is industrially prepared by using the
25% solution as a starting material. The procedure with
potassium carbonate was scaled up to 1 kg without
encountering major difficulties in precipitating and in filtering
off potassium sulfate.
The optimal amount of methanol was found to be quintuple
the amount of CTAHSO4 (40 g per 7.94 g). Experiments with
halved or doubled amount of methanol led to little higher
residual sulfate contents (1500−1600 ppm). Critical issues of
the procedure are (a) K+/HSO4− ratio, which has to be slightly
higher than two, (b) efficient separation of K2SO4 from mother
liquor by filtration without washings, and (c) K2SO4 filtration
below room temperature, preferably at 0−5 °C.
Comparison of KCl and NaCl solubility in methanol (0.5335
and 1.401 g/100 mL) with that of K2SO4 (0.0005 g/100 mL)
unequivocally indicated that the same goal, <200 ppm chloride
in the 25% aqueous solution of naprocet, could not be achieved
by the same procedure, that is, by using CTACl and
precipitating KCl or NaCl from methanol. Nevertheless,
literature data on the much lower solubility of NaCl in 1-
propanol and in 2-propanol (0.004 g/100 mL and 0.016 g/100
mL, respectively, at 0 °C; Table 2)23 induced us, however, to
attempt the removal of chloride by precipitation of NaCl from
Table 2. Solubility of NaCl in Alcohols (Grams/100 Grams
a
Solvent) at 25 °C and at 0 °C
methanol
ethanol
1-propanol
2-propanol
25 °C
0 °C
1.4
0.065
0.019
0.0124
0.004
0.03
0.972
0.016
a
Data taken from ref 23.
B
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these alcohols. Equimolar amounts of CTACl and NaOH were
combined in water, which was then azeotropically removed by
repeated additions of 1-propanol followed by vacuum
concentration. The resultant alcoholic suspension of NaCl
was filtered and naproxen acid was added to the filtrate.
Alternatively, equimolar amounts of CTACl, NaOH, and
naproxen acid were combined in water and then water was
gradually replaced by 2-propanol through repeated additions of
2-propanol and distillations. Finally, NaCl was removed by
filtration. In both cases, as expected, naprocet resulting from
evaporation of 1- and 2-propanol still contained a noticeable
amount of chloride: 0.47% and 1.94%, respectively. These
results confirmed that alternative precipitations to that of
K2SO4 from methanol are not easy to conceive, considering (a)
the few commercially available CTA inorganic salts, (b) the
obligatory choice of reagents and solvents currently used on
large scale production of pharmaceutical substances, and (c)
the stringent limits of inorganic anion content imposed by
industrial pharmaceutical specifications.
20.8 mmol) was dissolved into the filtrate, which was
concentrated under vacuum. The resultant waxy residue was
dissolved in water and lyophilized to give 10.36 g (96.9%) of
naprocet as a white spongy solid. 1H NMR δ ppm 0.85 (t, 3 H),
1.0−1.3 (m, 28 H), 1.48 (d, 2 H, J = 7 Hz), 2.76 (s, 9 H),
2.80−2.87 (m, 2 H), 3.67 (q, 1 H, J = 7 Hz), 3.85 (s, 3 H),
7.0−7.05 (m, 2 H), 7.52 (s, 2 H), 7.57 (d, 1 H, J = 8.8 Hz),
7.66 (s, 1 H). Sulfate: 458 ppm.
The procedure was evaluated at 1 kg scale. CTAHSO4 (700
g) was added to a suspension of potassium carbonate (255.7 g)
in methanol (3.5 kg) in a 6 L reactor. The suspension was
stirred overnight at room temperature and then filtered at 0−5
°C; the filtrate was combined with naproxen (422.4 g). After
the evolution of carbon dioxide had ceased, the solution was
concentrated to give naprocet (908.9 g) as a viscous oil, which
solidified as a wax upon standing. 1H NMR was identical to that
reported above. Sulfate: 424 ppm.
Preparation of Naprocet from CTAHSO4 and Potassium
tert-Butoxide in Methanol. CTAHSO4 (7.94 g, 20.8 mmol)
was dissolved in methanol (20 g) and dropped into a stirred
solution of 97% potassium tert-butoxide (4.91 g, 42.44 mmol)
in methanol (20 g). Immediately, a white precipitate was
formed. The methanolic suspension was stirred at room
temperature overnight and then at 0−5 °C for 3 h. The
cooled suspension was filtered to remove K2SO4, which was
strenuously squeezed on the filter to recover the maximum
amount of mother liquors, but not washed. Naproxen (4.79 g,
20.80 mmol) was dissolved into the methanolic filtrate, which
was concentrated under vacuum. The resultant waxy residue
was dissolved in water and lyophilized to give 10.50 (98.3%) of
naprocet as a white spongy solid, containing <50 ppm sulfate.
1H NMR spectrum identical to that of the product obtained by
using K2CO3.
CONCLUSIONS
■
Naprocet, the active ingredient of antiseptic liquid preparations
for pharmaceutical use, must be exempt from bromide and
contain less than 0.08% chloride and sulfate. Therefore, the use
of CTABr as a starting material implies total bromide removal,
which cannot be accomplished by precipitation of a bromide
from nonaqueous solvents, but requires the chromatographic
exchange with another counteranion, such as OH−. Lowering
residual chloride below 0.08% by precipitation procedures,
when CTACl is used, is also difficult due to the lack of common
alkali and alkaline earth chlorides that are insoluble enough in
nonaqueous solvent, such as alcohols. On the contrary, thanks
to the high insolubility of K2SO4 in methanol, sulfate can be
quantitatively precipitated from CTAHSO4 methanolic sol-
utions by treatment with potassium carbonate or a potassium
alcoholate, and naprocet with <0.05% residual sulfate can be
obtained by successively adding naproxen acid. Such a
procedure allowed us to obtain naprocet complying with
specifications for inorganic anion content by using common
solvents and reagents and no ion exchange chromatography.
The two procedures above were repeated more than once on
laboratory scale, always finding <500 ppm residual sulfate (461
ppm in the worst case).
Preparation of Naprocet from CTACl and NaOH in 1-
Propanol. A 25% w/w aqueous solution of CTACl (66.5 g,
51.9 mmol) and 1 N NaOH (51.9 mL) were mixed. 1-Propanol
was added to the resultant solution, which was concentrated. 1-
Propanol addition and concentration were repeated more than
once to eliminate water. Finally, a propanolic suspension (40 g)
of sodium chloride was obtained. After cooling to 3 °C
overnight, the suspension was filtered and naproxen (11.96 g,
51.9 mmol) was dissolved into the filtrate. The waxy residue,
resulting from concentration under vacuum and corresponding
to naprocet in quantitative yield, showed a chloride content of
4700 ppm.
Preparation of Naprocet from CTACl and NaOH in 2-
Propanol. A 25% w/w aqueous solution of CTACl (66.5 g,
51.9 mmol) was added to a solution of naproxen (11.96 g, 51.9
mmol) in 1 N NaOH (51.9 mL). Water was removed by
azeotropic distillation with isopropanol and the waxy residue
was treated with 2-propanol (140 mL) under reflux for 4 h. The
resultant suspension of white solid was filtered after holding
overnight at room temperature. The filtrate was concentrated
and the residue dissolved into water and lyophilized to give
24.85 g (93.1%) of naprocet as a white spongy solid, which
showed a chloride content of 19400 ppm.
EXPERIMENTAL SECTION
■
General. CTACl solution (25% in water) was obtained
from Fluka, while CTAHSO4 was obtained from Sikel Italia. 1H
NMR spectra were recorded on a Varian Gemini 300 operating
at 300 MHz and chemical shifts are reported in ppm relative to
residual solvent (CHCl3) as internal standard. Residual
inorganic anions, sulfate or chloride, were determined by
ionic chromatography on a Dionex DX 120 instrument by
using a Dionex IonPac AG9-HC 30 × 4.0 mm precolumn, a
Dionex IonPac AS9-HC 250 × 4.0 mm column, and an
electroconductivity detector Dionex DS4−1 at 35 °C and by
eluting with 9 mM Na2CO3 at 1.0 mL/min flow.
Preparation of Naprocet from CTAHSO4 and K2CO3 in
Methanol. CTAHSO4 (7.94 g, 20.8 mmol) was added to a
suspension of potassium carbonate (2.90 g, 20.98 mmol) in
methanol (40 g). The methanolic suspension was stirred at
room temperature overnight, then at 0−5 °C for 2 h and,
finally, filtered to remove K2SO4 (3.75 g), which was
strenuously squeezed on the filter to recover the maximum
amount of mother liquors, but not washed so as not to
redissolve minimum quantities of K2SO4. Naproxen (4.79 g,
C
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Technical Note
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR spectrum of naprocet. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: marco.pallavicini@unimi.it.
■
Notes
The authors declare no competing financial interest.
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