U.S. patent application number 10/198546 was filed with the patent office on 2002-12-05 for sertraline hydrochloride form ii and methods for the preparation thereof.
Invention is credited to Aronhime, Jodith, liberman, Anita, Mendelovici, Marioara, Nidam, Tamar, Schwartz, Eduard.
Application Number | 20020183555 10/198546 |
Document ID | / |
Family ID | 27495785 |
Filed Date | 2002-12-05 |
United States Patent
Application |
20020183555 |
Kind Code |
A1 |
Schwartz, Eduard ; et
al. |
December 5, 2002 |
Sertraline hydrochloride form II and methods for the preparation
thereof
Abstract
The present invention is directed to Form II of sertraline
hydrochloride and novel methods for its preparation. According to
the present invention, sertraline hydrochloride Form II may be
produced directly form sertraline base or sertraline mandelate. It
may also be produced from sertraline hydrochloride solvate and
hydrate forms, and crystallized from new solvent systems.
Pharmaceutical compositions containing sertraline hydrochloride
Form II and methods of treatment using such pharmaceutical
compositions are also disclosed.
Inventors: |
Schwartz, Eduard; (Rechovot,
IL) ; Nidam, Tamar; (Yehud, IL) ; liberman,
Anita; (Tel-Aviv, IL) ; Mendelovici, Marioara;
(Rechovot, IL) ; Aronhime, Jodith; (Rehovot,
IL) |
Correspondence
Address: |
KENYON & KENYON
ONE BROADWAY
NEW YORK
NY
10004
US
|
Family ID: |
27495785 |
Appl. No.: |
10/198546 |
Filed: |
July 18, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10198546 |
Jul 18, 2002 |
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09575634 |
May 22, 2000 |
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10198546 |
Jul 18, 2002 |
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09448985 |
Nov 24, 1999 |
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60182159 |
Feb 14, 2000 |
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60147888 |
Aug 9, 1999 |
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Current U.S.
Class: |
564/428 |
Current CPC
Class: |
C07B 2200/13 20130101;
C07C 211/62 20130101; C07C 2602/28 20170501; C07C 209/68 20130101;
C07C 209/84 20130101; A61P 25/24 20180101; C07C 209/68 20130101;
C07C 2602/10 20170501; C07C 211/42 20130101 |
Class at
Publication: |
564/428 |
International
Class: |
C07C 211/60 |
Claims
What is claimed is:
1. A process for making sertraline hydrochloride Form II comprising
the steps of: (a) dissolving sertraline base or sertraline
mandelate in an organic solvent to form a solution; (b) adding
hydrogen chloride to the solution; (c) heating the solution to a
temperature between about room temperature and about reflux for a
time sufficient to induce the formation of sertraline hydrochloride
Form II; and (d) isolating sertraline hydrochloride Form II.
2. The process of claim 1 wherein the solvent is selected form the
group consisting of ethyl acetate, acetone, hexane, t-butyl-methyl
ether, isopropyl alcohol, n-butanol, t-butanol, iso-butanol, and
cyclohexane, and mixtures thereof.
3. The process of claim 2 wherein the preferred solvent is
t-butyl-methyl ether.
4. The process of claim 2 wherein the preferred solvent is
n-butanol.
5. The process of claim 1 wherein the hydrogen chloride is added as
gaseous hydrogen chloride.
6. The process of claim 1 wherein the hydrogen chloride is added as
a solution of hydrogen chloride.
7. The process of claim 6 wherein the solution of hydrogen chloride
is selected from the group consisting of isopropyl alcohol and
hydrogen chloride, acetone and hydrogen chloride, and n-butanol and
hydrogen chloride.
8. The process of claim 1 wherein the solution is heated to the
reflux temperature of the solvent.
9. Sertraline hydrochloride Form II made by the process of claim
1.
10. A process for making sertraline hydrochloride Form II
comprising the steps of: (a) dissolving sertraline hydrochloride in
a solvent selected from the group consisting of dimethylformamide,
cyclohexanol, acetone and mixtures thereof; (b) heating the
solution for a time sufficient to effect transformation to
sertraline hydrochloride Form II; and (c) isolating sertraline
hydrochloride Form II.
11. Sertraline hydrochloride Form II made by the process of claim
10.
12. A process for making sertraline hydrochloride Form II
comprising the steps of: (a) granulating sertraline hydrochloride
Form V in ethanol or methanol; and (b) stiffing the mixture of
sertraline hydrochloride Form V and ethanol or methanol for a time
sufficient to induce transformation to sertraline hydrochloride
Form II.
13. Sertraline hydrochloride Form II made by the process of claim
12.
14. A process for making a mixture of sertraline hydrochloride Form
II and Form V comprising the steps of: (a) heating sertraline
hydrochloride ethanolate Form VI at up to 1 atmosphere pressure;
and (b) isolating a mixture of sertraline hydrochloride Form II and
Form V.
15. A mixture of sertraline hydrochloride Form II and Form V made
by the process of claim 14.
16. A process for making sertraline hydrochloride Form II
comprising the steps of: (a) suspending a water or solvent adduct
of sertraline hydrochloride in a solvent selected from the group
consisting of acetone, t-butyl-methyl ether, cyclohexane,
n-butanol, and ethyl acetate, such that a slurry is formed, for a
time sufficient to effect transformation to sertraline
hydrochloride Form II; and (b) filtering the slurry to isolate
sertraline hydrochloride Form II.
17. The process of claim 16 wherein the process takes place at a
temperature between about 25.degree. C. and about 120.degree.
C.
18. The process of claim 16 wherein the process takes place under
reflux conditions.
19. The process of claim 16 in which the sertraline hydrochloride
is suspended in about 1 to about 10 volumes of organic solvent.
20. The process of claim 16 wherein the solvent is
t-butyl-methyl-ether.
21. The process of claim 16 wherein the solvent is acetone.
22. The process of claim 16 wherein the solvent is ethyl
acetate.
23. The process of claim 16 wherein the solvent is n-butanol.
24. The process of claim 16 wherein the sertraline hydrochloride
water or solvate adduct is sertraline hydrochloride Form VI.
25. The process of claim 16 wherein the sertraline hydrochloride
water or solvate adduct is sertraline hydrochloride Form VII.
26. The process of claim 16 wherein the sertraline hydrochloride
water or solvate adduct is sertraline hydrochloride Form VIII.
27. Sertraline hydrochloride Form II made by the process of claim
16.
28. Sertraline hydrochloride Form II.
29. Sertraline hydrochloride characterized by an x-ray powder
diffraction pattern comprising peaks at about 5.5, 11.0, 12.5,
13.2, 14.7, 16.4, 17.3, 18.1, 19.1, 20.5, 21.9, 22.8, 23.8, 24.5,
25.9, 27.5, and 28.0 degrees two theta.
30. A pharmaceutical composition for the treatment of depression
comprising of the sertraline hydrochloride of claim 29 together
with a pharmaceutically acceptable carrier.
31. A method for treating depression comprising the step of
administering to a subject in need of such treatment a
therapeutically effective amount of the pharmaceutical composition
of claim 30.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of provisional
application Serial No. 60/182,159, filed Feb. 14, 2000; and is a
continuation-in-part of application Ser. No. 09/448,985, filed Nov.
24, 1999, which claims the benefit of provisional application No.
60/147,888, filed Aug. 9, 1999. The contents of each of these
applications are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to a novel crystalline form of
sertraline hydrochloride, and reproducible methods for its
preparation.
BACKGROUND OF THE INVENTION
[0003] Sertraline hydrochloride, (1S-cis)-4-(3,4
dichlorophenyl)-1,2,3,4-t- etrahydro-N-methyl-1-naphthalenamine
hydrochloride, having the formula 1
[0004] is approved, under the trademark Zoloft.RTM., by the U.S.
Food and Drug Administration, for the treatment of depression,
obsessive-compulsive disorder and panic disorder.
[0005] U.S. Pat. No. 4,536,518 ("the '518 patent") describes the
preparation of sertraline hydrochloride with a melting point of
243-245.degree. C. by treating an ethyl acetate/ether solution of
the free base with gaseous hydrogen chloride. The solid state
properties of the sertraline hydrochloride so produced are not
otherwise disclosed.
[0006] U.S. Pat. No. 5,734,083 describes the preparation of a form
of sertraline hydrochloride denominated polymorph "T1."
[0007] According to U.S. Pat. No. 5,248,699 ("the '699 patent"),
the sertraline hydrochloride produced by the method of the '518
patent has a crystalline form denominated "Form II. " The '699
patent discloses four other polymorphs of sertraline hydrochloride
designated Forms I, III, IV, and V, and characterizes them by
single crystal x-ray analysis, powder x-ray diffraction, infra-red
spectroscopy, and differential scanning calorimetry. The '699
patent reports that Form II is produced by rapid crystallization of
sertraline hydrochloride from an organic solvent, including
isopropyl alcohol, ethyl acetate or hexane, and generally describes
methods for making sertraline hydrochloride Forms I-V. According to
this patent, the preferential formation of Forms I, II or IV in an
acidic solution consisting of isopropyl alcohol, hexane, acetone,
methyl isobutyl ketone, glacial acetic acid or, preferably, ethyl
acetate, depends on the rapidity of crystallization. The only
method described in this patent for making Forms II and IV is by
the rapid crystallization of sertraline hydrochloride from an
organic solvent such as those listed above.
[0008] The experimental procedure for the preparation of sertraline
hydrochloride described in the '518 patent, was repeated in the
laboratory. According to the '699 patent, the '518 procedure
produces sertraline hydrochloride Form II. Four experiments were
performed according to the description in the '518 patent. By
following the procedures described in the '699 patent for
preparation of sertraline hydrochloride Form II, we were unable to
obtain sertraline hydrochloride Form II. Thus there remains a need
for reproducible methods for the preparation of sertraline
hydrochloride Form II.
SUMMARY OF THE INVENTION
[0009] The present invention relates to a process for making
sertraline hydrochloride Form II comprising the steps of dissolving
sertraline base or sertraline mandelate in an organic solvent to
form a solution; adding hydrogen chloride to the solution; heating
the solution to a temperature between about room temperature and
about reflux for a time sufficient to induce the formation of
sertraline hydrochloride Form II; and isolating sertraline
hydrochloride Form II.
[0010] The present invention also relates to a process for making
sertraline hydrochloride Form II comprising the steps of dissolving
sertraline hydrochloride in dimethylformamide, cyclohexanol,
acetone or a mixture thereof; heating the solution for a time
sufficient to effect transformation to sertraline hydrochloride
Form II; and isolating sertraline hydrochloride Form II.
[0011] The present invention further relates to a process for
making sertraline hydrochloride Form II comprising the steps of
granulating sertraline hydrochloride Form V in ethanol or methanol;
and stirring the mixture of sertraline hydrochloride Form V and
ethanol or methanol for a time sufficient to induce transformation
to sertraline hydrochloride Form II.
[0012] The present invention still further relates to a process for
making a mixture of sertraline hydrochloride Form II and Form V
comprising the steps of heating sertraline hydrochloride ethanolate
Form VI at up to 1 atmosphere pressure; and isolating a mixture of
sertraline hydrochloride Form II and Form V.
[0013] The present invention still further relates to a process for
making sertraline hydrochloride Form II comprising the steps of
suspending a water or solvent adduct of sertraline hydrochloride in
a solvent selected from the group consisting of acetone,
t-butyl-methyl ether, cyclohexane, n-butanol, and ethyl acetate
such that a slurry is formed, for a time sufficient to effect
transformation to sertraline hydrochloride Form II; and filtering
the slurry to isolate sertraline hydrochloride Form II.
[0014] The present invention still further relates to sertraline
hydrochloride Form II, characterized by an x-ray powder diffraction
pattern comprising peaks at about 5.5, 11.0, 12.5, 13.2, 14.7,
16.4, 17.3, 18.1, 19.1, 20.5, 21.9, 22.8, 23.8, 24.5, 25.9, 27.5,
and 28.0 degrees two theta; pharmaceutical compositions for the
treatment of depression comprising sertraline hydrochloride Form II
together with a pharmaceutically acceptable carrier, and a method
for treating depression comprising the step of administering to a
subject in need of such treatment a therapeutically effective
amount of the such a pharmaceutical composition.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 is a characteristic x-ray powder diffraction spectrum
of sertraline hydrochloride prepared by the methods of U.S. Pat.
No. 4,536,518.
[0016] FIG. 2 is a characteristic x-ray powder diffraction spectrum
of sertraline hydrochloride prepared by the methods of U.S. Pat.
No. 5,248,699.
[0017] FIG. 3 is a characteristic x-ray powder diffraction spectrum
of sertraline hydrochloride Form II prepared by the methods of the
present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0018] Form II from Sertraline Base or Sertraline Mandelate
[0019] The present invention provides new processes for making
sertraline hydrochloride Form II from sertraline base or sertraline
mandelate. Sertraline base may be made by methods known in the art,
including the methods of the '518 patent. Sertraline base is
dissolved in a suitable solvent. Suitable solvents include ethyl
acetate, acetone, t-methyl-butyl ether, isopropyl alcohol,
n-butanol, t-butanol, iso-butanol, hexane, and cyclohexane, and
mixtures thereof. The pH of the sertraline base solution is lowered
by the addition of hydrogen chloride, which may result in a
temperature increase. As used herein, "hydrogen chloride" includes
both gaseous hydrogen chloride and aqueous hydrogen chloride (i.e.
hydrochloric acid). Hydrogen chloride also may be added as a
solution with an organic solvent, such as a solution of isopropyl
alcohol and hydrogen chloride, n-butanol and hydrogen chloride,
acetone and hydrogen chloride, or the like. The solution of
sertraline base or sertraline mandelate in the solvent is heated to
a temperature between about room temperature and the reflux
temperature of the solvent and maintained at that temperature for a
period of time sufficient to effect the transformation to
sertraline hydrochloride Form II. Preferably the solution is heated
to a temperature between about 45.degree. C. and the reflux
temperature of the solvent. Most preferably the solution is heated
to at or about the reflux temperature of the solvent. Upon cooling
of the mixture, for example to room temperature, sertraline
hydrochloride Form II is isolated by filtration.
[0020] In a preferred variation of this method, the solution of
sertraline base or sertraline mandelate in a solvent is heated to
the reflux temperature of the solvent. The mixture is refluxed for
a time sufficient to effect the transformation to sertraline
hydrochloride Form II. Preferably the mixture is refluxed for about
1 to 4 hours.
[0021] Numerous experiments were performed in an attempt to repeat
the procedure described in U.S. Pat. No. 4,536,518 for preparing
Form II wherein sertraline base was dissolved in ethyl acetate,
ether was added and the solution was acidified with gaseous
hydrogen chloride. The material obtained after filtration and air
drying was sertraline hydrochloride amorphous, not Form II as was
expected. These experiments are set forth in Examples 13-16
below.
[0022] The x-ray powder diffraction graphs for the products of each
of these experiments are equivalent, containing peaks at 11.0,
12.0, 15.4, 16.2, 22.4, 22.9 degree two-theta (See FIG. 1 for a
representative example). FIG. 1 does not contain the typical peaks
of sertraline hydrochloride Form II, indicating an absence of
sertraline hydrochloride Form II in those samples. Thus, none of
these experiments, which follow the procedure described in the '518
patent for preparation of sertraline hydrochloride Form II, leads
to sertraline hydrochloride Form II.
[0023] The '699 patent provides experimental procedures for
preparation of sertraline hydrochloride. The '699 patent does not
provide experimental procedure for preparation of sertraline
hydrochloride Form II, but it is mentioned that sertraline
hydrochloride Form II may be prepared by "rapid crystallization"
from the same solvents.
[0024] The procedure of the '699 patent was repeated in an attempt
to prepare sertraline hydrochloride form II from ethyl acetate. In
a trial of the methods according to the '699 patent: An aqueous
solution of sodium hydroxide, 10%, was added to a slurry of
sertraline mandelate crystals (44.6 g) in ethyl acetate (290 mL),
until complete dissolution. The organic phase was separated and the
aqueous phase was extracted with ethyl acetate (280 mL) and
combined with the organic phase. The resulting organic solution was
washed with water (5.times.100 mL) then with brine (100 mL) and
concentrated on a rotavapor to a volume of 356 mL. The concentrated
solution was cooled to 58.degree. C. and seeded with sertraline
hydrochloride Form II. Concentrated hydrochloric acid (32%, 8.1 mL)
was added to this solution. The solution was then rapidly cooled to
30.degree. C. over 5 minutes. A heavy gel was obtained and the
stirring was continued overnight. The solid was filtrated, washed
with ethyl acetate and dried at 50.degree. C. The dried solid,
sertraline hydrochloride, was not sertraline hydrochloride Form II,
as shown by the x-ray diffraction pattern of FIG. 2.
[0025] By following the procedures described in the '699 patent for
preparation of sertraline hydrochloride Form II, we did not obtain
sertraline hydrochloride Form II. It is thus apparent that neither
the '699 patent nor the '518 patent disclose a useful method for
the preparation of sertraline hydrochloride Form II.
[0026] Form II from Sertraline Hydrochloride
[0027] The present invention also provides new processes for making
sertraline hydrochloride Form II from sertraline hydrochloride Form
V by granulation. In the conversion of sertraline hydrochloride
Form V to sertraline hydrochloride Form II, sertraline
hydrochloride Form V is combined with a small amount of ethanol or
methanol. The mixture of sertraline hydrochloride Form V and
ethanol or methanol is stirred for at least a period of at least a
few hours, up to several days, preferably about two days, to induce
the transformation of Form V to Form II. Sertraline hydrochloride
Form II is then isolated by filtration.
[0028] The present invention also provides new processes for making
sertraline hydrochloride Form II by recrystallization of sertraline
hydrochloride under heating conditions. In the conversion of
sertraline hydrochloride to sertraline hydrochloride Form II,
sertraline hydrochloride is dissolved in a suitable organic
solvent. The solution is then heated for a time sufficient to
effect transformation to sertraline hydrochloride Form II. Suitable
solvents include dimethylformamide, cyclohexanol and acetone.
Dimethylformamide is preferred. The suspension may be heated to a
temperature between about 70.degree. C. and 120.degree. C.
Sertraline hydrochloride Form II is then isolated by
filtration.
[0029] The present invention provides new processes for making
sertraline hydrochloride Form II from sertraline hydrochloride Form
VI, Form VII or Form VIII by reslurry in organic solvents at
temperatures between 25-80.degree. C., followed by drying.
Sertraline hydrochloride Form VI may be made following the methods
of Examples 2 and 3. Sertraline hydrochloride Form VII is a water
adduct and may be made by the methods of Examples 19 and 20.
Sertraline hydrochloride Form VIII may be made by the methods of
Examples 17 and 18. The methods provided in the present invention
have advantages over the rapid recrystallization method of U.S.
Pat. No. 5,248,699. The method of the present invention does not
require complete dissolution of sertraline hydrochloride,
controlling the rate of heating or cooling of a sertraline
solution, or controlling the rate of crystallization. The present
method utilizes less solvent than the method of the '699 patent,
since the sertraline hydrochloride starting material need not be
completely dissolved.
[0030] In the conversion of sertraline hydrochloride Form VI, Form
VII or Form VIII to sertraline hydrochloride Form II, according to
the present invention, sertraline hydrochloride Form VI, Form VII
water adduct, or Form VIII is combined with an aprotic organic
solvent to form a slurry. Suitable solvents include n-butanol,
acetone, t-butyl-methyl ether (MTBE), ethyl acetate and
cyclohexane. The conversion may take place at room temperature, but
preferably the sertraline hydrochloride Form VI, Form VII water
adduct, or VIII and solvent are heated to temperatures between
25.degree. C. and 80.degree. C. About 1 to about 10 volumes of
solvent are preferred, based on the weight of the sertraline
hydrochloride starting material. See Examples 8 (3 volumes of
solvent) and 9 (5 volumes of solvent) below. Smaller amounts of
solvent will also effect the transformation, albeit in some
instances more slowly. The reaction is carried out for a time
sufficient to convert the Form VI, Form VII or Form VIII to Form
II. We have not observed any further conversion of Form II upon
treatment under these conditions for times longer than the minimum
time necessary to effect the transformation.
[0031] The present invention also provides new processes for making
a mixture of sertraline hydrochloride Form II and sertraline
hydrochloride Form V. In this embodiment of the present invention,
sertraline hydrochloride Form VI is heated to induce the
transformation of sertraline hydrochloride Form VI to a mixture of
both sertraline hydrochloride Form II and sertraline hydrochloride
Form V. In this embodiment of the present invention, the heating of
sertraline hydrochloride Form VI may be done under reduced pressure
or atmospheric pressure.
[0032] Pharmaceutical Compositions Containing Sertraline
Hydrochloride Polymorphs
[0033] In accordance with the present invention, sertraline
hydrochloride Form II as prepared by the new methods disclosed
herein may be used in pharmaceutical compositions that are
particularly useful for the treatment of depression, obesity,
chemical dependencies or addictions, premature ejaculation,
obsessive-compulsive disorder and panic disorder. Such compositions
comprise at least one of the new crystalline forms of sertraline
hydrochloride with pharmaceutically acceptable carriers and/or
excipients known to one of skill in the art.
[0034] For example, these compositions may be prepared as
medicaments to be administered orally, parenterally, rectally,
transdermally, bucally, or nasally. Suitable forms for oral
administration include tablets, compressed or coated pills,
dragees, sachets, hard or gelatin capsules, sub-lingual tablets,
syrups and suspensions. Suitable forms of parenteral administration
include an aqueous or non-aqueous solution or emulsion, while for
rectal administration suitable forms for administration include
suppositories with hydrophilic or hydrophobic vehicle. For topical
administration the invention provides suitable transdermal delivery
systems known in the art, and for nasal delivery there are provided
suitable aerosol delivery systems known in the art.
[0035] Suitable non-toxic pharmaceutically acceptable carriers
and/or excipients will be apparent to those skilled in the art of
pharmaceutical formulation, and are discussed in detail in the tet
entitled Remington's Pharmaceutical Science, 17.sup.th edition
(1985), the contents of which are incorporated herein by reference.
Obviously, the choice of suitable carriers will depend on the exact
nature of the particular dosage form, e.g. for a liquid dosage
form, whether the composition is to be formulated into a solution,
suspension, gel, etc, or for a solid dosage form, whether the
composition is to be formulated into a tablet, capsule, caplet or
other solid form, and whether the dosage form is to be an
immediate- or controlled-release product.
[0036] Experimental Details
[0037] The powder X-ray diffraction patterns were obtained by
methods known in the art using a Philips X-ray powder
diffractometer, Goniometer model 1050/70 at a scanning speed of
2.degree. per minute, with a Cu radiation of .lambda.=1.5418
.ANG..
EXAMPLES
[0038] The present invention will now be further explained in the
following examples. However, the present invention should not be
construed as limited thereby. One of ordinary skill in the art will
understand how to vary the exemplified preparations to obtain the
desired results.
Example 1
Preparation of Sertraline Base
[0039] Sertraline mandelate was prepared according to procedures in
U.S. Pat. No. 5,248,699. Sertraline mandelate (5 g) was stirred at
room temperature with 50 mL ethyl acetate. Aqueous sodium hydroxide
was added dropwise until the sertraline mandelate was completely
neutralized. The phases were separated and the organic phase was
dried over MgSO.sub.4 and filtered. The solvent was removed under
reduced pressure resulting sertraline base as an oil (3.2 g).
Example 2
Preparation of Sertraline Hydrochloride Ethanolate Form VI by
Reslurry of Form I
[0040] Sertraline hydrochloride Form I (1 g) and absolute ethanol
(20 mL) were stirred at room temperature for 24 hours. Filtration
of the mixture yielded sertraline hydrochloride ethanolate Form
VI.
Example 3
Preparation of Sertraline Hydrochloride Ethanolate Form VI by
Reslurry of Form V
[0041] Sertraline hydrochloride Form V (1 g) and ethanol absolute
(20 mL) were stirred at room temperature for 24 hrs. Filtration of
the mixture yielded sertraline hydrochloride ethanolate Form
VI.
Example 4
Preparation of Sertraline Hydrochloride Form II
[0042] Sertraline base (3 g) was dissolved in acetone (10 mL).
Isopropanol containing hydrogen chloride (20 mL) was added to the
solution until the pH is .about.2. The stirring was continued
overnight at room temperature. The resulting solid was filtered,
washed with acetone and dried to yield sertraline hydrochloride
Form II (2.61 g, yield 77.6%).
Example 5
Preparation of Sertraline Hydrochloride Form II in n-Butanol
[0043] HCl (g) was bubbled through a solution of sertraline base
(33 g) in n-butanol (264 mL). The temperature rose to about
45.degree. C. A gel-like solid was formed. The addition of HCl (g)
was continued until pH 0.5 was reached. Then the stirring was
continued at room temperature for 2.5 h. During the stirring the
solid became a fine crystalline solid. The solid was filtered,
washed with n-butanol (2.times.10 mL) and dried at 80.degree. C.
for 24 h. The product is sertraline hydrochloride Form II. The
x-ray powder diffraction spectrum obtained is FIG. 3.
Example 6
Preparation of Sertraline Hydrochloride Form II
[0044] Sertraline hydrochloride Form V (10 g) was suspended in
dimethylformamide (DMF) (30 mL). Heating was started and at about
70.degree. C. a clear solution is obtained. The solution was cooled
to room temperature and the solid was filtered. After drying at
80.degree. C. for 24 hrs., sertraline hydrochloride Form II was
obtained (6.6 g, yield 66%).
Example 7
Preparation of Sertraline Hydrochloride Form II by Granulation of
Form V
[0045] Sertraline hydrochloride Form V (2 g) and absolute ethanol
(0.5 mL) were stiffed in a rotavapor at room temperature for 2
days. At the end of two days, the material contained sertraline
hydrochloride Form II.
Example 8
Preparation of Sertraline Hydrochloride Form II from Form VI
[0046] A slurry of sertraline hydrochloride Form VI (50 g) and
t-butyl-methyl ether (150 mL) were heated to reflux and the reflux
was continued for 1 hour. The slurry was then allowed to cool to
room temperature and filtered. The solid was washed with
t-butyl-methyl ether (50 mL) and dried in a reactor under vacuum of
30 mm Hg with stirring. The dried solid so obtained is sertraline
hydrochloride Form II (38.26 g: yield 86.7%).
Example 9
Preparation of Sertraline Hydrochloride Form II from Form VI
[0047] Sertraline hydrochloride Form VI (25 g) was stirred with
acetone (250 mL) at room temperature for 2 hours. The solid
material was filtered and washed twice with acetone (25 mL). The
wet solid was dried in a vacuum agitated drier to afford sertraline
hydrochloride Form II (20.09 g: yield 98.6%).
Example 10
Preparation of Sertraline Hydrochloride Form II and Sertraline
Hydrochloride Form V by Drying Form VI
[0048] Sertraline hydrochloride ethanolate Form VI was dried at
105.degree. C. under vacuum (<10 mm Hg) over 24 hours. The
resulting dried material was sertraline hydrochloride Form II mixed
with sertraline hydrochloride Form V.
Example 11
Preparation of Sertraline Hydrochloride Form II from Sertraline
Mandelate in n-Butanol
[0049] Sertraline mandelate (20 g) and n-butanol were stirred at
room temperature. The mixture was acidified with hydrogen chloride
until pH 0 was reached. During the acidification the temperature of
the reaction mixture rose to .about.50.degree. C. After the natural
cooling to room temperature, the mixture was stirred at room
temperature for two hours. The solid was filtrated, washed with
n-butanol and dried at 80.degree. C. to afford sertraline
hydrochloride Form II (9.02 g).
Example 12
Preparation of Sertraline Hydrochloride Form II from Sertraline
Hydrochloride Form VIII
[0050] Sertraline hydrochloride Form VIII (13 g) was heated in
acetone (130 mL) at reflux for 1 hour. The slurry was than cooled
to room temperature and the solid was filtrated and washed with
acetone (2.times.10 mL). After drying sertraline hydrochloride Form
II was obtained (7.9 g).
Example 13
[0051] An aqueous sodium hydroxide solution, 10%, was added
drop-wise to a slurry of sertraline mandelate crystals (10 g) in
ethyl acetate (650 mL), until complete dissolution was obtained (25
mL). After separation of the phases, the organic phase was washed
with water (300 mL) and then dried with MgSO.sub.4. The organic
solution was diluted with ether (690 mL) and gaseous hydrochloric
acid was bubbled through the solution until pH 1.3 was reached. The
addition of hydrogen chloride resulted in a temperature increase to
about 30.degree. C. The resulting slurry of sertraline was stirred
at room temperature overnight. The solid was then isolated by
filtration, washed twice with ether (2.times.20 mL) and air dried.
The dried solid, sertraline hydrochloride, was not sertraline
hydrochloride Form II, as shown in FIG. 1.
Example 14
[0052] An aqueous sodium hydroxide solution, 10%, was added
drop-wise to a slurry of sertraline mandelate crystals (15 g) in
ethyl acetate (810 mL), until complete dissolution was obtained (35
mL). The organic and aqueous phases were separated and, the organic
phase was dried over MgSO.sub.4 The organic solution was then
diluted with ether (820 mL) and gaseous hydrogen chloride (2.36 g,
2 eq.) was bubbled through the solution until pH 1.5 was reached.
The temperature was about 25.degree. C. The slurry was stirred at
room temperature overnight. The solid was filtrated, washed with
ether (2.times.15 mL) and air-dried. The dried solid, sertraline
hydrochloride, was not sertraline hydrochloride Form II.
Example 15
[0053] An aqueous sodium hydroxide solution, 10%, was added
drop-wise to a slurry of sertraline mandelate crystals (15 g) in
ethyl acetate (810 mL), until complete dissolution was obtained.
The organic and aqueous phases were separated and the organic phase
was dried over MgSO.sub.4 and diluted with an equal volume of ether
(820 mL). Gaseous hydrochloric acid (4.82 g) was bubbled through
the solution until pH 1 was reached. The slurry was stirred at room
temperature overnight. The solid was filtrated, washed with ether
(2.times.15 mL) and air-dried. The dried solid, sertraline
hydrochloride, was not sertraline hydrochloride Form II.
Example 16
[0054] An aqueous sodium hydroxide solution, 10%, was added
drop-wise to a slurry of sertraline mandelate crystals (15 g) in
ethyl acetate (810 mL), until complete dissolution is obtained. The
phases were separated and the organic phase was dried over
MgSO.sub.4 and diluted with an equal volume of ether (820 mL).
Gaseous hydrogen chloride was slowly bubbled through the solution
(over about 3 hours) until pH 1.5 was reached. The slurry was
stirred at room temperature over night. The dried solid, sertraline
hydrochloride, was not sertraline hydrochloride Form II.
Example 17
Preparation of Sertraline Hydrochloride Form VIII
[0055] Sertraline base (2.7 g) was suspended in 27 mL of water.
This mixture was heated to 80.degree. C. and treated with
hydrochloric acid until about pH 1 was reached. A clear solution
was obtained which on cooling gave a precipitate. After 2 hours
stirring at room temperature the solid was isolated by filtration.
This solid was characterized by powder x-ray diffraction and found
to be sertraline hydrochloride Form VIII.
Example 18
Preparation of Sertraline Hydrochloride Form VIII
[0056] Sertraline hydrochloride ethanolate (Form VI) (40 g) was
stirred with water (80 mL) for 1 hour at room temperature. The
slurry was filtrated and washed with water to yield sertraline
hydrochloride hydrate Form VIII.
Example 19
Preparation of Sertraline Hydrochloride Form VII
[0057] Sertraline hydrochloride Form V (1.003 g) was stirred for 24
hours at room temperature in 20 mL water (HPLC grade). At the end
of the stirring the mixture looked like a jelly suspension. The
suspension was filtrated and the compound obtained was kept at cold
conditions (4.degree. C.) until analyzed by x-ray diffraction.
Example 20
Preparation of Sertraline hydrochloride Form VII from Form VI
[0058] A solution of sertraline hydrochloride ethanolate (Form VI)
(40 g) in water (400 mL) was heated at 80.degree. C and complete
dissolution of sertraline hydrochloride ethanolate (Form VI) was
obtained. The pH was adjusted to about 1 and the solution was
allowed to cool to room temperature and then stirred for 2
additional hours. The solid was isolated by filtration and washed
with water to yield sertraline hydrochloride Form VII.
[0059] Although certain presently preferred embodiments of the
invention have been described herein, it will be apparent to those
skilled in the art to which the invention pertains that variations
and modifications of the described embodiments may be made without
departing from the spirit and scope of the invention. Accordingly,
it is intended that the invention be limited only to the extent
required by the appended claims and the applicable rules of
law.
* * * * *