U.S. patent application number 13/617907 was filed with the patent office on 2013-01-10 for trazodone and trazodone hydrochloride in purified form.
This patent application is currently assigned to AZIENDE CHIM. RIUN. ANG. FRANC. A.C.R.A.F. S.p.A.. Invention is credited to Giuseppe Biondi, Giovanni Battista Ciottoli, Tommaso Iacoangeli, Marcello Marchetti.
Application Number | 20130012520 13/617907 |
Document ID | / |
Family ID | 39064326 |
Filed Date | 2013-01-10 |
United States Patent
Application |
20130012520 |
Kind Code |
A1 |
Marchetti; Marcello ; et
al. |
January 10, 2013 |
TRAZODONE AND TRAZODONE HYDROCHLORIDE IN PURIFIED FORM
Abstract
A process of production of trazodone or trazodone hydrochloride
that comprises: (a) preparing an organic phase comprising trazodone
in at least one organic solvent; (b) preparing an aqueous phase
comprising at least one basic compound; (c) mixing said aqueous
phase with said organic phase; (d) heating at a temperature of at
least 40.degree. C. for at least 30 minutes; (e) recovering said
trazodone; and, optionally, (f) treating said trazodone with
hydrochloric acid to obtain trazodone hydrochloride. Trazodone or
trazodone hydrochloride comprising less than 15 ppm of alkylating
substances, and a pharmaceutical composition comprising said
trazodone hydrochloride.
Inventors: |
Marchetti; Marcello; (Rome,
IT) ; Iacoangeli; Tommaso; (Rome, IT) ;
Ciottoli; Giovanni Battista; (Rome, IT) ; Biondi;
Giuseppe; (Castel Gandolfo (Rome), IT) |
Assignee: |
AZIENDE CHIM. RIUN. ANG. FRANC.
A.C.R.A.F. S.p.A.
Rome
IT
|
Family ID: |
39064326 |
Appl. No.: |
13/617907 |
Filed: |
September 14, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13370735 |
Feb 10, 2012 |
8314236 |
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13617907 |
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12513048 |
Sep 21, 2009 |
8133893 |
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PCT/EP08/59640 |
Jul 23, 2008 |
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13370735 |
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60976535 |
Oct 1, 2007 |
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Current U.S.
Class: |
514/253.04 |
Current CPC
Class: |
A61P 25/22 20180101;
A61K 47/10 20130101; A61K 47/36 20130101; A61P 43/00 20180101; A61K
47/26 20130101; A61P 25/24 20180101; A61K 47/44 20130101; A61P
25/14 20180101; A61P 25/36 20180101; A61P 25/32 20180101; A61K
47/06 20130101; A61K 31/496 20130101; A61P 29/02 20180101; A61P
25/20 20180101; A61K 9/08 20130101; A61K 47/14 20130101; A61K 47/18
20130101; A61P 25/30 20180101; A61P 25/04 20180101; C07D 249/18
20130101; A61K 47/38 20130101; A61K 47/22 20130101; A61K 9/0053
20130101; A61P 25/00 20180101; A61P 29/00 20180101 |
Class at
Publication: |
514/253.04 |
International
Class: |
A61K 31/496 20060101
A61K031/496; A61P 25/14 20060101 A61P025/14; A61P 25/20 20060101
A61P025/20; A61P 25/04 20060101 A61P025/04; A61P 25/24 20060101
A61P025/24; A61P 25/22 20060101 A61P025/22 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 3, 2007 |
IT |
MI2007A 001603 |
Claims
1-28. (canceled)
29. A pharmaceutical composition, comprising trazodone
hydrochloride and at least one pharmaceutically acceptable
excipient, wherein said trazodone hydrochloride comprises less than
15 ppm of alkylating substances.
30. A pharmaceutical composition according to claim 29, wherein
said trazodone hydrochloride comprises less than 10 ppm of
alkylating substances.
31. A pharmaceutical composition according to claim 29, wherein
said trazodone hydrochloride comprises less than 2.5 ppm of
alkylating substances.
32. A pharmaceutical composition according to claim 29, wherein
said at least one pharmaceutically acceptable excipient is selected
from the group consisting of antiadherents, binders, disintegrants,
fillers, diluents, flavouring agents, colorants, fluidizers,
lubricants, preservatives, moistening agents, absorbents, and
sweeteners.
33. A pharmaceutical composition according to claim 29, wherein
said at least one pharmaceutically acceptable excipient is a
sugar.
34. A pharmaceutical composition according to claim 33, wherein
said sugar is selected from the group consisting of lactose,
glucose and sucrose.
35. A pharmaceutical composition according to claim 29, wherein
said at least one pharmaceutically acceptable excipient is a
starch.
36. A pharmaceutical composition according to claim 35, wherein
said starch is selected from the group consisting of maize starch
and potato starch.
37. A pharmaceutical composition according to claim 29, wherein
said at least one pharmaceutically acceptable excipient is
cellulose or a derivative thereof.
38. A pharmaceutical composition according to claim 37, wherein
said cellulose or a derivative thereof is selected from the group
consisting of sodium carboxymethylcellulose, ethylcellulose and
cellulose acetate.
39. A pharmaceutical composition according to claim 29, wherein
said at least one pharmaceutically acceptable excipient is a glycol
or a polyol.
40. A pharmaceutical composition according to claim 39, wherein
said glycol or polyol is selected from the group consisting of
propylene glycols, glycerol, sorbitol, mannitol, and polyethylene
glycol.
41. A pharmaceutical composition according to claim 29, wherein
said at least one pharmaceutically acceptable excipient is an
ester.
42. A pharmaceutical 1 composition according to claim 41, wherein
said ester is selected from the group consisting of ethyl oleate
and ethyl laurate.
43. A pharmaceutical composition according to claim 29, wherein
said at least one pharmaceutically acceptable excipient is an
oil.
44. A pharmaceutical composition according to claim 43, wherein
said oil is selected from the group consisting of peanut oil,
cottonseed oil, safflower oil, sesame oil, olive oil, maize oil,
and soya oil.
45. A pharmaceutical composition according to claim 29, wherein
said at least one pharmaceutically acceptable excipient is selected
from the group consisting of gum tragacanth, malt, gelatin, talc,
cocoa butter, waxes, agar-agar, magnesium hydroxide, aluminium
hydroxide, alginic acid, water, isotonic solutions, ethanol, buffer
solutions, polyesters, polycarbonates, and polyanhydrides.
46. A pharmaceutical composition according to claim 29, wherein
said composition is for oral or parenteral administration.
47. A pharmaceutical composition according to claim 46, wherein
said composition for oral or parenteral administration is in the
form of tablets, lozenges, capsules, solutions, suspensions,
dispersions, and syrups.
48. A pharmaceutical composition according to claim 29, wherein
said alkylating substances are selected from the group consisting
of 2,2-dichloroethylamine, 1-bromo-3-chloro-propane,
N-(3-chlorophenyl)-N'-(3-chloropropyl)-piperazine,
2-(3-chloropropyl)-s-triazolo-[4,3-a]-pyridin-3-one,
3-chloro-N,N'-dichloro-ethyl-aniline,
2-{3-[bis-(2-chloroethyl)-amino]-propyl}-2H-[1,2,4]triaz-olo[4,3-a]pyridi-
n-3-one, 2,2-dibromoethylamine, and 1,3-dichloro-propane.
49. A pharmaceutical composition according to claim 29, wherein
said trazodone hydrochloride comprises less than 1 ppm of each of
said alkylating substances.
50. A pharmaceutical composition according to claim 49, wherein
said alkylating substances are selected from the group consisting
of 2,2-dichloroethylamine, 1-bromo-3-chloropropane,
N-(3-chlorophenyl)-N'-(3-chloropropyl)-piperazine,
2-(3-chloropropyl)-s-triazolo-[4,3-a]-pyridin-3-one,
3-chloro-N,N'-dichloroethylaniline,
2-{3-[bis-(2-chloroethyl)-amino]-propyl}-2H-[1,2,4]triazolo[4,3-a]pyridin-
-3-one, 2,2-dibromoethylamine, and 1,3-dichloropropane.
51. A pharmaceutical composition according to claim 49, wherein
said alkylating substances are selected from the group consisting
of 2,2-dichloroethylamine, 1-bromo-3-chloro-propane, and
N-(3-chlorophenyl)-N'-(3-chloropropyl)-piperazine.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a purified form of
trazodone and trazodone hydrochloride, and the process for
preparation thereof.
[0002] In particular the invention relates to a purified form of
trazodone and trazodone hydrochloride comprising less than 15 ppm
of alkylating substances of proven or suspected genotoxicity.
PRIOR ART
[0003] Trazodone, or
2-[3-[4-(3-chlorophenyl)-1-piperazinylpropyl]-1,2,4-triazolo[4,3-a]pyridi-
n-3(2H)-one, is an antidepressant which, though having a
significant effect on the serotonin receptors, is neither a
psychostimulant, nor a MAO inhibitor, nor a tricyclic
antidepressant. Furthermore, trazodone possesses analgesic
properties.
[0004] Trazodone alleviates the characteristic symptoms of
depression, in particular anxiety, somatization, psychomotor
retardation, hypochondria, mood swings, irritability, insomnia,
apathy, feeling of fatigue and lack of energy, depressed mood.
[0005] Trazodone has also proved effective in controlling
pronounced essential tremor, probably on account of its
serotoninergic activity.
[0006] Moreover, the antidepressant and anxiolytic properties of
trazodone have proved useful in the treatment of symptoms of
withdrawal from cocaine, benzodiazepines and alcohol. Besides the
above-mentioned activities, its sleep-inducing activity is also
very interesting.
[0007] Trazodone is preferably used medically in the form of a
pharmaceutically acceptable salt of acid addition. The preferred
form is the hydrochloride form obtained by treatment of the free
base with hydrochloric acid.
[0008] Trazodone hydrochloride is represented by the following
structural formula:
##STR00001##
[0009] Some economically advantageous methods of preparation of
trazodone hydrochloride are described in U.S. Pat. No. 3,381,009
and EP 1,108,722.
[0010] A first method comprises reacting
s-triazolo-[4,3-a]-pyridin-3-one of formula I with
N-(3-chlorophenyl)-N'-(3-chloropropyl)-piperazine of formula
II:
##STR00002##
[0011] A second method comprises reacting
2-(3-chloropropyl)-s-triazolo-[4,3-a]-pyridin-3-one of formula III
with N-(3-chlorophenyl)-piperazine of formula IV:
##STR00003##
[0012] A third method comprises reacting
2-(.gamma.-morpholino-propyl)-s-triazolo-[4,3-a]-pyridin-3-one of
formula V with 3-chloroaniline of formula VI
##STR00004##
[0013] A fourth method comprises reacting
2-(3-aminopropyl)-s-triazolo[4,3-a]-pyridin-3-one of formula VII
with 3-chloro-N,N'-dichloroethylaniline of formula VIII:
##STR00005##
[0014] A fifth method comprises reacting
2-{3-[bis-(2-chloroethyl)-amino]-propyl}2H-[1,2,4]triazolo[4,3-a]pyridin--
3-one of formula IX with 3-chloroaniline of formula VI.
##STR00006##
[0015] Once trazodone has been obtained, trazodone hydrochloride is
easily obtained by reaction with hydrochloric acid, for example by
treating an organic solution of trazodone with an aqueous solution
of hydrochloric acid, as described for example in patent EP
1,108,722.
[0016] Preparation of the aforementioned intermediates from I to IX
requires the use of alkylating substances of proven genotoxicity,
such as 2,2-dichloroethylamine, used for obtaining compound IV by
reaction with compound VI; 1-bromo-3-chloropropane, used for
obtaining compound II by reaction with compound IV.
[0017] Compounds II, III, VIII and IX are also alkylating
substances and therefore potentially genotoxic. Apart from the
aforementioned alkylating substances, in alternative processes for
production of trazodone it may be possible to use similar
alkylating substances, for example 2,2-dibromoethylamine or
1,3-dichloropropane.
[0018] The content of said alkylating substances in the final
product, represented by trazodone and trazodone hydrochloride,
should be reduced to the least possible amount. In particular, the
toxicological threshold for ingestion of these alkylating
substances has been determined as 1.5 .mu.g per day.
[0019] Therefore, assuming a daily dose of 100 mg of trazodone
hydrochloride, the quantity of alkylating substances present as
impurities in the product should be less than 15 ppm. If, however,
we consider the maximum daily dose of 600 mg of trazodone
hydrochloride, the quantity of alkylating substances present as
impurities in the product should even be less than 2.5 ppm.
[0020] Unfortunately, the processes of preparation described in the
aforementioned patents U.S. Pat. No. 3,381,009 and EP 1,108,722 do
not allow the content of these alkylating substances to be reduced
to below 15 ppm, let alone below 2.5 ppm.
[0021] Therefore, the applicant tackled the problem of devising a
process for production of trazodone and trazodone hydrochloride
that makes it possible to lower the content of these alkylating
substances in the final product to below 15 ppm. Moreover, said
production process must be economically advantageous and must give
high yields of final product.
DEFINITIONS
[0022] In the present description and in the claims given later,
the expression "trazodone" means trazodone in the form of free
base, whereas the expression "trazodone hydrochloride" means the
salt formed by the addition of hydrochloric acid to trazodone.
[0023] Moreover, in the present description and in the claims given
later, the expression "alkylating substances" is used to indicate
substances that are capable of introducing an alkyl group in a
compound used in the synthesis of trazodone or of an intermediate
thereof.
DESCRIPTION OF THE INVENTION
[0024] Surprisingly, the applicant found that addition of an
aqueous solution comprising a basic compound to a solution of
trazodone in an organic solvent reduces the amount of alkylating
substances in the final product to below 15 ppm.
[0025] Therefore, the present invention relates to a production
process of trazodone or of trazodone hydrochloride that comprises
the steps of:
[0026] (a) preparing an organic phase comprising trazodone in at
least one organic solvent;
[0027] (b) preparing an aqueous phase comprising at least one basic
compound;
[0028] (c) mixing said aqueous phase with said organic phase;
[0029] (d) heating at a temperature of at least 40.degree. C. for
at least 30 minutes;
[0030] (e) recovering said trazodone; and, optionally
[0031] (f) treating said trazodone with hydrochloric acid to obtain
trazodone hydrochloride.
[0032] The production process of the present invention makes it
possible to reduce the amount of alkylating substances in the final
product, represented by trazodone or by trazodone hydrochloride, to
below 15 ppm, preferably below 10 ppm, and more preferably below
2.5 ppm.
[0033] Advantageously, according to a preferred aspect of the
present invention, the production process of the present invention
makes it possible to reduce the amount of alkylating substances in
the final product to below 1 ppm.
[0034] The process of the present invention has been shown to be
economically advantageous, keeping the yield of the final product
above 85%, and preferably above 90%.
[0035] Preferably said organic phase is represented by a solution
of trazodone in said organic solvent.
[0036] Advantageously, said organic solvent can be selected from
any organic solvents that are inert with respect to trazodone and
that are able to dissolve trazodone.
[0037] Preferably, said organic solvent is selected from the group
comprising alcohols, for example, ethyl alcohol, propyl alcohol,
isobutyl alcohol, hexyl alcohol, and benzyl alcohol; ethers, for
example ethyl ether, propyl ether; hydrocarbons, for example
toluene, benzene, xylene; ketones, for example acetone, methyl
ethyl ketone, methyl isobutyl ketone; esters, for example ethyl
acetate. The preferred organic solvent for preparation of the
organic phase is isobutyl alcohol.
[0038] Preferably, said organic phase comprises an amount of
trazodone in the range from 10 g to 50 g per 100 grams of organic
phase, more preferably from 20 g to 35 g per 100 grams of organic
phase, and even more preferably from 25 g to 30 g per 100 grams of
organic phase.
[0039] Preferably said aqueous phase is represented by a solution
of a basic compound in water.
[0040] Advantageously, said aqueous phase comprises at least one
basic compound selected from the group comprising at least one
inorganic base, at least one organic base, or mixtures thereof.
[0041] Useful examples of inorganic bases are sodium hydroxide,
potassium hydroxide, sodium carbonate, potassium carbonate, sodium
bicarbonate, potassium bicarbonate, sodium phosphate, potassium
phosphate, ammonium hydroxide, magnesium oxide, hydrazine, and
hydroxylamine.
[0042] Useful examples of organic bases are aliphatic or aromatic
amines, for example methylamine, ethylamine, propylamine,
butylamine, diethylamine, trimethylamine, triethylamine,
ethanolamine, diethanolamine, triethanolamine,
N,N-dimethylethanolamine, N-methylethanolamine, ethylenediamine,
piperidine, quinoline, imidazole, benzimidazole, histidine,
pyridine, picoline, lutidine, collidine, morpholine,
N-methylmorpholine, benzylamine, and cyclohexylamine.
[0043] Preferably, said basic compound is added in an amount in the
range from 0.05 to 1 mol per mol of trazodone, more preferably from
0.2 to 0.8 mol per mol of trazodone, and even more preferably from
0.4 to 0.6 mol per mol of trazodone.
[0044] Advantageously, said aqueous phase is added in an amount in
the range from 30 g to 100 g per 100 grams of organic phase, more
preferably from 40 g to 90 g per 100 grams of organic phase, and
even more preferably from 50 g to 80 g per 100 grams of organic
phase.
[0045] Preferably, said aqueous phase comprises a phase transfer
catalyst.
[0046] Advantageously, said phase transfer catalyst is selected
from the group comprising quaternary ammonium salts and quaternary
phosphonium salts.
[0047] Preferably, said quaternary ammonium salts are selected from
the group comprising benzyl tributyl ammonium bromide, benzyl
tributyl ammonium chloride, benzyl triethyl ammonium bromide,
benzyl triethyl ammonium chloride, benzyl trimethyl ammonium
chloride, cetyl pyridinium bromide, cetyl pyridinium chloride,
cetyl trimethyl ammonium bromide, didecyl dimethyl ammonium
chloride, dodecyl trimethyl ammonium bromide, dodecyl trimethyl
ammonium chloride, methyl tributyl ammonium chloride, methyl
tributyl ammonium hydrogen sulphate, methyl tricaprilyl ammonium
chloride, methyl trioctyl ammonium chloride, phenyl trimethyl
ammonium chloride, tetrabutyl ammonium borohydride, tetrabutyl
ammonium bromide, tetrabutyl ammonium chloride, tetrabutyl ammonium
fluoride, tetrabutyl ammonium hydrogen sulphate, tetrabutyl
ammonium hydroxide, tetrabutyl ammonium iodide, tetrabutyl ammonium
perchlorate, tetraethyl ammonium bromide, tetraethyl ammonium
chloride, tetraethyl ammonium hydroxide, tetrahexyl ammonium
bromide, tetrahexyl ammonium iodide, tetramethyl ammonium bromide,
tetramethyl ammonium chloride, tetramethyl ammonium fluoride,
tetramethyl ammonium hydroxide, tetramethyl ammonium iodide,
tetraoctyl ammonium bromide, tetrapropyl ammonium bromide,
tetrapropyl ammonium chloride, tetrapropyl ammonium hydroxide,
tributyl methyl ammonium chloride, triethyl benzyl ammonium
chloride.
[0048] Advantageously, said quaternary ammonium salts are selected
from the group comprising tetrabutyl ammonium bromide, tetrabutyl
ammonium chloride, benzyl triethyl ammonium bromide, benzyl
triethyl ammonium chloride, benzyl trimethyl ammonium chloride,
benzyl trimethyl ammonium bromide, benzyl tributyl ammonium
bromide, and benzyl tributyl ammonium chloride.
[0049] The series of phase transfer catalysts Aliquat.RTM. produced
and marketed by the company Cognis Corp., Tucson, Ariz. can be used
advantageously in the production process of the present invention.
Preferred examples are Aliquat.RTM. 100, Aliquat.RTM. 134,
Aliquat.RTM. 175, and Aliquat.RTM. 336.
[0050] Preferably, said quaternary phosphonium salts are selected
from the group comprising benzyl triphenyl phosphonium bromide,
benzyl triphenyl phosphonium chloride, butyl triphenyl phosphonium
bromide, butyl triphenyl phosphonium chloride, ethyl triphenyl
phosphonium acetate, ethyl triphenyl phosphonium bromide, ethyl
triphenyl phosphonium iodide, hexadecyl tributyl phosphonium
bromide, methyl triphenyl phosphonium bromide, tetrabutyl
phosphonium bromide, and tetraphenyl phosphonium bromide.
[0051] Preferably, said aqueous phase comprises an amount of phase
transfer catalyst in the range from 0.05 g to 0.5 g per 100 grams
of aqueous phase, more preferably from 0.1 g to 0.3 g per 100 grams
of aqueous phase, and even more preferably from 0.15 g to 0.2 g per
100 grams of aqueous phase.
[0052] Preferably, said heating step (d) is carried out at a
temperature between 40.degree. and the boiling point of the mixture
of organic phase and aqueous phase, for a period of time between 30
minutes and 300 minutes, preferably between 60 and 240 minutes,
more preferably between 90 and 180 minutes.
[0053] Preferably, the recovery step (e) is carried out by
separating the aqueous phase from the organic phase comprising the
trazodone, and cooling the latter to a temperature below 30.degree.
C., preferably below 20.degree. C., and even more preferably below
10.degree. C., to promote the crystallization and precipitation of
trazodone, which is finally separated, for example by
filtration.
[0054] Advantageously, in the final treatment step (f), the
trazodone is preferably dissolved in a suitable organic solvent,
selected, for example, from those stated previously for the
preparation of the organic phase. The solvent preferred in this
step is acetone. The solution thus obtained is treated with an
aqueous solution of hydrochloric acid as described in patent EP
1,108,722. The precipitate of trazodone hydrochloride is then
filtered, washed, and dried according to the conventional
techniques known by a person skilled in the art.
[0055] The trazodone and the trazodone hydrochloride obtained by
the process of the present invention are characterized by a content
of alkylating substances, of proven or suspected genotoxicity,
below 15 ppm.
[0056] Depending on the production process selected for the
production of trazodone and of trazodone hydrochloride, the
alkylating substances present as impurities are, for example,
2,2-dichloroethylamine, 1-bromo-3-chloro-propane,
N-(3-chlorophenyl)-N'-(3-chloropropyl)-piperazine (formula II),
2-(3-chloropropyl)-s-triazolo-[4,3-a]-pyridin-3-one (formula III),
3-chloro-N,N'-dichloroethyl-aniline (formula VIII),
2-{3-[bis-(2-chloroethyl)-amino]-propyl}-2H-[1,2,4]triazolo[4,3-a]pyridin-
-3-one (formula IX), 2,2-dibromoethylamine, and
1,3-dichloropropane.
[0057] In particular, the alkylating substances encountered most
frequently are represented by 2,2-dichloroethylamine,
1-bromo-3-chloro-propane, and
N-(3-chlorophenyl)-N'-(3-chloropropyl)-piperazine.
[0058] 2,2-Dichloroethylamine (CAS No. 334-22-5) and
1-bromo-3-chloro-propane (CAS No. 109-70-6) are known genotoxic
substances as reported in TOXNET, a database published by the
National Library of Medicine, US on the website
http://toxnet.nlm.nih.gov/.
[0059] The genotoxic activity of
N-(3-chlorophenyl)-N'-(3-chloropropyl)-piperazine has been assessed
on histidine-dependent auxotrophic mutants of Salmonella
typhimurium strains TA1535, TA1537, TA 98 and TA100, and on
tryptophan-dependent mutants of Escherichia coli strain WP2 uvrA
(pKM101), exposed to a solution of
N-(3-chlorophenyl)-N'-(3-chloropropyl)-piperazine in
dimethylsulphoxide (DMSO) and using DMSO as negative control. Two
independent mutation tests were performed, both in the presence and
absence of a liver microsomal fraction (S9 mix) of rat treated with
phenobarbital and 5,6-benzoflavone. Tests were standard plate
incorporation assays and performed according to the current
regulatory guidelines. A substantial increase in reversion to
prototrophy was obtained on strain TA1535 in the presence of S9
mix. In the two assays the increase was concentration related and
reached, following exposure to 1500 .mu.g per plate of
N-(3-chlorophenyl)-N'-(3-chloropropyl)-piperazine, 6.4 and 5.1
times the control value. It was therefore concluded that
N-(3-chlorophenyl)-N'-(3-chloropropyl)-piperazine exhibited
genotoxic activity in said bacterial system following metabolic
activation.
[0060] Surprisingly, the total content of said alkylating
substances in the trazodone or in the trazodone hydrochloride
obtained using the process of the present invention was below 15
ppm, preferably less than 10 ppm, and even more preferably less
than 2.5 ppm. In the preferred embodiment, the content of each of
said alkylating substances in the trazodone or in the trazodone
hydrochloride obtained using the process of the present invention
was below 1 ppm.
[0061] Therefore, the present invention also relates to trazodone
or trazodone hydrochloride comprising less than 15 ppm of
alkylating substances, preferably less than 10 ppm, and even more
preferably less than 2.5 ppm.
[0062] In a preferred embodiment, the present invention also
relates to trazodone or trazodone hydrochloride comprising less
than 1 ppm, and preferably less than 0.5 ppm, of each alkylating
substance.
[0063] Preferably said alkylating substances are selected from the
group comprising 2,2-dichloroethylamine, 1-bromo-3-chloro-propane;
and [0064] N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine
(formula II), 2-(3-chloropropyl)-s-triazolo-[4,3-a]-pyridin-3-one
(formula III), 3-chloro-N,N'-dichloroethyl-aniline (formula VIII),
2-{3-[bis-(2-chloroethyl)-amino]-propyl}-2H-[1,2,4]triazolo[4,3-a]pyridin-
-3-one (formula IX), 2,2-dibromoethylamine, and
1,3-dichloro-propane.
[0065] Even more preferably said alkylating substances are selected
from the group comprising 2,2-dichloroethylamine,
1-bromo-3-chloropropane, and
N-(3-chlorophenyl)-N'-(3-chloropropyl)-piperazine.
[0066] The trazodone hydrochloride of the present invention can be
used advantageously in the preparation of pharmaceutical
compositions mixed with at least one pharmaceutically acceptable
excipient.
[0067] Thus, the present invention also relates to a pharmaceutical
composition comprising the trazodone hydrochloride of the present
invention as described previously together with at least one
pharmaceutically acceptable excipient.
[0068] The term "pharmaceutically acceptable excipient" means,
without particular limitations, any material suitable for the
preparation of a pharmaceutical composition that is to be
administered to a living being. Such materials, known by a person
skilled in the art, are for example antiadherents, binders,
disintegrants, fillers, diluents, flavouring agents, colorants,
fluidizers, lubricants, preservatives, moistening agents,
absorbents, and sweeteners.
[0069] Useful examples of pharmaceutically acceptable excipients
are sugars, such as lactose, glucose or sucrose, starches, such as
maize starch, and potato starch, cellulose and derivatives thereof,
such as sodium carboxymethylcellulose, ethylcellulose, and
cellulose acetate, gum tragacanth, malt, gelatin, talc, cocoa
butter, waxes, oils, such as peanut oil, cottonseed oil, safflower
oil, sesame oil, olive oil, maize oil, and soya oil, glycols such
as propylene glycols, polyols, such as glycerol, sorbitol,
mannitol, and polyethylene glycol, esters, such as ethyl oleate,
and ethyl laurate, agar-agar, buffers, such as magnesium hydroxide,
and aluminium hydroxide, alginic acid, water, isotonic solutions,
ethanol, buffer solutions, polyesters, polycarbonates,
polyanhydrides, and so on.
[0070] The pharmaceutical composition of the present invention can
be represented by any composition that can be used for
administration of the trazodone hydrochloride of the present
invention, preferably compositions for oral or parenteral
administration, for example tablets, lozenges, capsules, solutions,
suspensions, dispersions, and syrups.
[0071] The invention is illustrated by the following examples,
though without limiting it.
Example 1
Preparation in the Presence of a Strong Base (NaOH) 37.1 g of
trazodone (equal to about 0.100 mol) obtained according to example
1 of U.S. Pat. No. 3,381,009 was put in a 500-ml flask together
with 140 ml of isobutyl alcohol. Then 100 ml of an aqueous solution
of NaOH at 2% was added, and the resultant mixture was heated to
about 80.degree. C. and held at this temperature, with stirring,
for about 3 hours.
[0072] Then the organic phase was separated from the aqueous phase
and then washed with water. The residual water present in the
organic phase was removed by azeotropic distillation. The resultant
solution was cooled to 5.degree. C. to precipitate the crystals of
trazodone base, which were separated by filtration.
[0073] The wet product (about 40 g) was dissolved in about 270 ml
of acetone, heated until dissolution occurred, and then 12N HCl
aqueous solution was added to the solution up to pH between 3 and 4
to salify the trazodone base and obtain the corresponding
hydrochloride.
[0074] The resultant solution was cooled to 5.degree. C. to
precipitate the crystals of trazodone hydrochloride. The trazodone
hydrochloride thus obtained was filtered, washed with acetone and
dried at reduced pressure. At the end of drying, 35.5 g of
trazodone hydrochloride was obtained (equal to about 0.087 mol), at
a product yield equal to about 87%.
TABLE-US-00001 TABLE 1 Alkylating substances N-(3- 1-bromo-3-
chlorophenyl)-N'- 2,2- chloro- (3-chloropropyl)- dichloroethylamine
propane piperazine Initial content 10 15 50 (ppm) Final content
<0.46 <0.2 <0.04 (ppm)
Example 2
Preparation in the Presence of Weak Base (Na.sub.2CO.sub.3)
[0075] 37.1 g of trazodone (equal to about 0.100 mol) obtained
according to example 1 of U.S. Pat. No. 3,381,009 was put in a
500-ml flask together with 140 ml of isobutyl alcohol. Then 100 ml
of an aqueous solution containing 5.3 g of Na.sub.2CO.sub.3 was
added, and the resultant mixture was heated to about 80.degree. C.
and left at this temperature, with stirring, for about 4 hours.
[0076] Then the organic phase was separated from the aqueous phase
and then washed with water. The residual water present in the
organic phase was removed by azeotropic distillation. The resultant
solution was cooled to 5.degree. C. to precipitate the crystals of
trazodone base, which were separated by filtration.
[0077] The wet product (about 42 g) was dissolved in about 270 ml
of acetone, heated until dissolution occurred, and then a 12N HCl
aqueous solution was added to the solution until the pH was between
3 and 4 to salify the trazodone base and obtain the corresponding
hydrochloride.
[0078] The resultant solution was cooled to 5.degree. C. to
precipitate the crystals of trazodone hydrochloride. The trazodone
hydrochloride thus obtained was filtered, washed with acetone and
dried at reduced pressure. At the end of drying, 37.0 g of
trazodone hydrochloride was obtained (equal to about 0.091 mol), at
a product yield equal to about 91%.
TABLE-US-00002 TABLE 2 Alkylating substances N-(3- 1-bromo-3-
chlorophenyl)-N'- 2,2- chloro- (3-chloropropyl)- dichloroethylamine
propane piperazine Initial content 5 20 35 (ppm) Final content
<0.46 <0.2 <0.4 (ppm)
Example 3
Preparation in the Presence of Weak Base (Na.sub.2CO.sub.3) and
Phase Transfer Catalyst (Benzyltriethylammonium Chloride)
[0079] 37.1 g of trazodone (equal to about 0.100 mol) obtained
according to example 1 of U.S. Pat. No. 3,381,009 was put in a
500-ml flask together with 140 ml of isobutyl alcohol. Then 100 ml
of an aqueous solution containing 5.3 g of Na.sub.2CO.sub.3 and 150
mg of benzyltriethylammonium chloride was added, and the resultant
mixture was heated to about 80.degree. C. and left at this
temperature, with stirring, for about 2 hours.
[0080] Then the organic phase was separated from the aqueous phase
and then washed with water. The residual water present in the
organic phase was removed by azeotropic distillation. The resultant
solution was cooled to 5.degree. C. to precipitate the crystals of
trazodone base, which were separated by filtration.
[0081] The wet product (about 38.5 g) was dissolved in about 270 ml
of acetone, heated until dissolution occurred, and then a 12N HCl
aqueous solution was added to the solution until the pH was between
3 and 4 to salify the trazodone base and obtain the corresponding
hydrochloride.
[0082] The resultant solution was cooled to 5.degree. C. to
precipitate the crystals of trazodone hydrochloride. The trazodone
hydrochloride thus obtained was filtered, washed with acetone and
dried at reduced pressure. At the end of drying, 36.7 g of
trazodone hydrochloride was obtained (equal to about 0.090 mol), at
a product yield equal to about 90%.
TABLE-US-00003 TABLE 3 Alkylating substances N-(3- 1-bromo-3-
chlorophenyl)-N'- 2,2- chloro- (3-chloropropyl)- dichloroethylamine
propane piperazine Initial content 5 20 35 (ppm) Final content
<0.46 <0.2 <0.04 (ppm)
Example 4
Preparation in the Presence of Strong Base (KOH)
[0083] 37.1 g of trazodone (equal to about 0.100 mol) obtained
according to example 1 of U.S. Pat. No. 3,381,009 was put in a
500-ml flask together with 140 ml of methylisobutyl ketone. Then
100 ml of an aqueous solution containing 2.8 g of KOH was added,
and the resultant mixture was heated to about 80.degree. C. and
left at this temperature, with stirring, for about 3 hours.
[0084] Then the organic phase was separated from the aqueous phase
and then washed with water. The residual water present in the
organic phase was removed by azeotropic distillation. The resultant
solution was cooled to 5.degree. C. to precipitate the crystals of
trazodone base, which were separated by filtration.
[0085] The wet product (about 38 g) was dissolved in about 270 ml
of acetone, heated until dissolution occurred, and then a 12N HCl
aqueous solution was added to the solution until the pH was between
3 and 4 to salify the trazodone base and obtain the corresponding
hydrochloride.
[0086] The resultant solution was cooled to 5.degree. C. to
precipitate the crystals of trazodone hydrochloride. The trazodone
hydrochloride thus obtained was filtered, washed with acetone and
dried at reduced pressure. At the end of drying, 35.5 g of
trazodone hydrochloride was obtained (equal to about 0.087 mol), at
a product yield equal to about 87%.
TABLE-US-00004 TABLE 4 Alkylating substances N-(3- 1-bromo-3-
chlorophenyl)-N'- 2,2- chloro- (3-chloropropyl)- dichloroethylamine
propane piperazine Initial content 7 10 50 (ppm) Final content
<0.46 <0.2 <0.4 (ppm)
[0087] The initial and final content of the alkylating substances
shown in the above Tables 1 to 4 was determined according to the
following procedures.
[0088] Assay for the Determination of 2,2-dichloroethylamine in
Trazodone Hydrochloride by UV/Vis Spectrophotometry
[0089] The assay is based on the reaction of 2,2-dichloroethylamine
with 4-(4-nitrobenzyl)-pyridine according to a modified
Friedman-Boger procedure as described in Anal. Chem. 33, 906-910,
1961, "Colorimetric estimation of nitrogen mustards in aqueous
media".
[0090] Briefly, a solution of 4-(4-nitrobenzyl)pyridine in acetone
was added to an aqueous solution of trazodone hydrochloride (0.25
g/ml). The resultant mixture was heated to 100.degree. C. for 20
minutes, and then quickly cooled on an ice bath. 1 ml of acetone
and 3 ml of 1N sodium hydroxide were added to the solution. The
coloured derivative was then extracted in chloroform (3 ml). The
absorbance value at 544 nm was recorded against a blank sample, and
the second derivative (.delta.) was calculated from the value
obtained. The content, in ppm, of 2,2-dichloroethylamine in the
trazodone hydrochloride was found by using the external standard
method.
[0091] The reaction was specific for 2,2-dichloroethylamine as no
coloured derivative was obtained in the conditions described for
other alkylating agents such as 1-bromo-3-chloropropane and
N-(3-chlorophenyl)-N'-(3-chloropropyl)-piperazine.
[0092] Linearity was verified from 1 to 10 ppm of
2,2-dichloroethylamine. The accuracy of the calibrators was always
between 85 and 115% of the theoretical value.
[0093] The lower limit of quantification (LLOQ) was set at 1 ppm
based on the values of precision (measured as standard deviation,
.sigma.) of the blank, as follows:
.delta..sub.LLOQ=.delta..sub.blank+10*.sigma.=0.00048+10*0.00024=0.00288
corresponding to 1.1 ppm.
[0094] The limit of detection (LOD) was set at 0.46 ppm, based on
the values of precision (measured as standard deviation, .sigma.)
of the blank, as follows:
.delta..sub.LLOQ=.delta..sub.blank+3*.sigma.=0.00048+10*0.00024=0.00288
corresponding to 0.46 ppm.
[0095] The precision was evaluated by calculating the coefficient
of variation (CV %) of six determinations. The CV % at 5 ppm was
equal to 12.2% and at 10 ppm it was equal to 11.2%.
[0096] Assay for the Determination of 1-bromo-3-chloropropane in
Trazodone Hydrochloride by the Headspace Technique
[0097] The trazodone hydrochloride was dissolved in a
water/methanol solution. After complete dissolution, the solution
was put in a headspace autosampler and the content of
1-bromo-3-chloropropane was determined by gas chromatography using
a capillary column of medium polarity. The column effluent was
monitored using a flame ionization detector. The content of
1-bromo-3-chloropropane was determined as assay limit relative to a
standard sample with known content (2 ppm).
Chromatography Conditions
TABLE-US-00005 [0098] Gas chromatograph Trace Ultra Analytical
column Capillary column, L = 30 m, inside diameter 0.53 mm, 3 .mu.m
(RTX 1301 or equivalent) Stationary phase 6% cyanopropylphenyl, 94%
dimethyl polysiloxane Oven temperature 90.degree. C. per 2 min then
increased to 130.degree. C. at 10.degree. C./min and maintained at
130.degree. C. for 1 min Mobile phase (pressure) Nitrogen (100 kPa)
Detector FID (air 350 kPa, hydrogen 35 kPa) Retention time Approx.
3.5 min for 1-bromo-3- chloropropane Run time 7 min Injector
temperature 250.degree. C. Detector temperature 250.degree. C.
Hydrogen pressure 35 kPa Air pressure 350 kPa
Conditions for the Autosampler
TABLE-US-00006 [0099] Headspace autosampler Perkin Elmer
TurboMatrix 40 Operating mode continuous Diameter of transfer tube
.sup. 0.25 mm Sample temperature 90.degree. C. Needle temperature
150.degree. C. Temperature of transfer tube 170.degree. C. Time for
thermostatic control .sup. 15 minutes Pressurization time .sup. 1
minute
[0100] 100 mg of trazodone hydrochloride was accurately weighed in
a 22-ml test tube, then an aqueous solution of methanol at 0.025%
(v/v) was added. The test tube was sealed with an aluminium crimp
cap and PTFE coated butyl rubber septum and was then put in the
headspace autosampler.
[0101] Linearity was verified from 0.2 to 9.3 ppm of
1-bromo-3-chloropropane, obtaining a correlation coefficient equal
to 0.992 (by least squares regression analysis).
[0102] The limits of detection (LOD) and the lower limit of
quantification (LLOQ) were obtained from the signal/noise ratio
(S/N) as follows:
LOD=3.times.S/N=0.2 ppm
LLOQ=10.times.S/N=0.5 ppm
[0103] The precision, determined on the basis of six repeat
determinations, was found to be equal to 3.6% (CV) at 0.5 ppm. The
accuracy was determined as recovery %. Within the range of
linearity it was always 100% with reference to the theoretical
concentration.
[0104] Assay for the Determination of
1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine (CCP) in Trazodone
Hydrochloride by High-Performance Liquid Chromatography Coupled to
Tandem Mass Spectrometry (HPLC/MS/MS).
[0105] The trazodone hydrochloride was dissolved in water and
injected into the analyser. Chromatographic separation was obtained
using a reversed-phase analytical column of the alkyl amide
type.
[0106] The eluate from the column was monitored by positive-ion
mass spectrometry using the "Multiple Reaction Monitoring" (MRM)
technique.
Chromatography Conditions
TABLE-US-00007 [0107] HPLC system Agilent series 1200 (or
equivalent) Analytical column ABZ Plus, 75 .times. 4.6 mm, 3 .mu.m
(Supelco) Oven temperature 40.degree. C. Solvent A Methanol Solvent
B ammonium acetate 5 mM + 0.1% (v/v) formic acid Operational flow
rate 2 ml/min, a split was used to reduce the flow at the ion
source to 0.3 ml/min Elution Isocratic Solvent A/B = 12/88 (v/v) 3
min Purge Isocratic Solvent A/B = 80/20 (v/v) 5 min Injection
volume 5 .mu.l Retention time Approx. 2.5 min for CCP Run time 10.0
min
Mass Spectrometry Conditions
TABLE-US-00008 [0108] Mass spectrometer Sciex API3000 LC/MS/MS
Source Turbo Ion Spray .RTM. Mode Positive-ion Detection Multiple
Reaction Monitoring (MRM) Resolution Q1 low resolution (mass =
273.1 amu), Q3 unit resolution (mass = 154.1 amu).
[0109] Linearity was verified from 0.4 to 8 ppm of
1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine, obtaining a
correlation coefficient equal to 0.9987 (by least squares
regression analysis).
[0110] The accuracy was always between 85% and 115% of the
theoretical value.
[0111] The lower limit of quantification (LLOQ) was set at 0.4 ppm
based on the values of accuracy (85%) and precision (CV=6.7%)
obtained from six determinations.
[0112] The limit of detection (LOD) was set at 0.04 ppm based on
the value of the signal/noise ratio (S/N): LOD=3.times.S/N=0.04
ppm.
* * * * *
References