U.S. patent application number 10/218863 was filed with the patent office on 2003-03-20 for sertraline hydrochloride polymorphs.
Invention is credited to Aronhime, Judith, Liberman, Anita, Mendelovici, Marioara, Nidam, Tamar, Schwartz, Eduard, Singer, Claude, Valdman, Evgeni.
Application Number | 20030055112 10/218863 |
Document ID | / |
Family ID | 23782424 |
Filed Date | 2003-03-20 |
United States Patent
Application |
20030055112 |
Kind Code |
A1 |
Schwartz, Eduard ; et
al. |
March 20, 2003 |
Sertraline hydrochloride polymorphs
Abstract
The present invention is directed to forms II, III, V, VI, VII,
VIII, IX and X of sertraline hydrochloride and novel methods for
their preparation. According to the present invention, sertraline
hydrochloride polymorph II may be produced by slurrying sertraline
hydrochloride polymorph VI in aprotic organic solvent. Sertraline
hydrochloride polymorphic form III may be produced by heating
sertraline hydrochloride polymorphs V and VI. Sertraline
hydrochloride forms V and VI may be produced from either sertraline
hydrochloride or sertraline base by crystallization. Sertraline
hydrochloride Form VII may be produced by suspending sertraline
chloride polymorph V in water, followed by filtration. Sertraline
hydrochloride Forms VIII and IX may be produced by suspending
sertraline base in water followed by acidification and filtration.
Sertraline hydrochloride Form X may be produced by suspending
sertraline hydrochloride in benzyl alcohol with heating, followed
by filtration.
Inventors: |
Schwartz, Eduard; (Rechovot,
IL) ; Nidam, Tamar; (Yehud, IL) ; Liberman,
Anita; (Tel-Aviv, IL) ; Mendelovici, Marioara;
(Rechovot, IL) ; Aronhime, Judith; (Rehovot,
IL) ; Singer, Claude; (Kfar Saba, IL) ;
Valdman, Evgeni; (Petah Tikva, IL) |
Correspondence
Address: |
Steven J. Lee
KENYON & KENYON
One Broadway
New York
NY
10004
US
|
Family ID: |
23782424 |
Appl. No.: |
10/218863 |
Filed: |
August 13, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10218863 |
Aug 13, 2002 |
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09448985 |
Nov 24, 1999 |
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60110113 |
Nov 27, 1998 |
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60125172 |
Mar 19, 1999 |
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60133117 |
May 7, 1999 |
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60147888 |
Aug 9, 1999 |
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Current U.S.
Class: |
514/657 ;
564/428 |
Current CPC
Class: |
A61P 25/24 20180101;
A61K 31/135 20130101; C07C 209/84 20130101; C07C 211/42 20130101;
C07C 2602/10 20170501; A61P 25/28 20180101; A61P 43/00
20180101 |
Class at
Publication: |
514/657 ;
564/428 |
International
Class: |
A61K 031/135; C07C
211/42 |
Claims
What is claimed is:
1. A process for making sertraline hydrochloride Form V comprising
the steps of: (a) dissolving sertraline hydrochloride in a suitable
solvent; (b) removing the solvent; and (c) drying to form
sertraline hydrochloride Form V.
2. The process of claim 1, wherein the solvent is selected from the
group consisting of methanol, ethanol, water, methoxypropanol, and,
isopropyl alcohol and mixtures thereof.
3. The process of claim 2 wherein the solvent is methanol.
4. The process of claim 2 wherein the solvent is ethanol.
5. The process of claim 2 wherein the solvent is a mixture of
isopropyl alcohol and water.
6. The process of claim 1, further comprising the steps of seeding
the solution with sertraline hydrochloride Form V.
7. The process of claim 1 wherein the sertraline hydrochloride of
step (a) is sertraline hydrochloride Form I.
8. The process of claim 1 wherein the sertraline hydrochloride of
step (a) is sertraline hydrochloride Form VI.
9. The process of claim 1 wherein the sertraline hydrochloride of
step (a) is sertraline hydrochloride Form VII.
10. The process of claim 1 wherein the sertraline hydrochloride of
step (a) is sertraline hydrochloride Form VIII.
11. The process of claim 1 wherein the sertraline hydrochloride of
step (a) is sertraline hydrochloride Form IX.
12. A process for making sertraline hydrochloride Form V comprising
the steps of: (a) dissolving or suspending sertraline base in a
solvent, (b) adding hydrogen chloride or hydrochloric acid to
reduce the pH of the solution or suspension; and (c) isolating
sertraline hydrochloride Form V.
13. The process of claim 12 wherein the pH of the solution or
suspension of sertraline base and hydrogen chloride of hydrochloric
acid is a solvent is about 0 to about 4.
14. The process of claim 12 wherein the solvent is selected from
the group consisting of methanol, ethanol, water, ethyl acetate,
isopropyl alcohol, hexane, and toluene and mixtures thereof.
15. The process of claim 14 wherein the solvent is methanol.
16. The process of claim 14 wherein the solvent is ethanol.
17. The process of claim 14 wherein the solvent is water.
18. The process of claim 14 wherein the solvent is a mixture of
hexane and isopropyl alcohol.
19. The process of claim 14 wherein the solvent is a mixture of
isopropyl alcohol and water.
20. The process of claim 14 wherein the solvent is a mixture of
ethanol and water.
21. The process of claim 14 wherein the solvent is ethyl
acetate.
22. The process of claim 14 wherein the solvent is a mixture of
ethanol and isopropyl alcohol.
23. The process of claim 14 wherein the solvent is a mixture of
methanol and isopropyl alcohol.
24. A pharmaceutical composition comprising a therapeutically
effective amount of sertraline hydrochloride Form V and a
pharmaceutically acceptable carrier.
25. A process for making sertraline hydrochloride Form V comprising
the step of drying sertraline hydrochloride ethanolate Form VI.
26. A process for making sertraline hydrochloride Form V comprising
the step of drying sertraline hydrochloride Form VII.
27. A process for making sertraline hydrochloride Form V comprising
the step of drying sertraline hydrochloride hydrate Form VIII.
28. A process for making sertraline hydrochloride Form V comprising
the steps of: (a) suspending or dissolving sertraline hydrochloride
in a solvent selected form the group consisting of ethanol,
methanol and water and mixtures thereof; and (b) isolating
sertraline hydrochloride Form V.
29. A process for making sertraline hydrochloride Form V comprising
the steps of: (a) dissolving sertraline hydrochloride Form VI in
water; (b) adding a sufficient amount of hydrochloric acid or
hydrogen chloride to facilitate precipitation of sertraline
hydrochloride Form V; (c) removing the water; and (d) isolating
sertraline hydrochloride Form V.
30. A process for making sertraline hydrochloride Form V comprising
the steps of: (a) heating amorphous sertraline hydrochloride for a
time sufficient to effect the transformation to sertraline
hydrochloride Form V; and (b) isolating sertraline hydrochloride
Form V.
31. The process of claim 30 wherein amorphous sertraline
hydrochloride is heated to a temperature up to about 80.degree.
C.
32. Sertraline hydrochloride Form VI.
33. Sertraline hydrochloride Form VI ethanolate.
34. Sertraline hydrochloride Form VI methanolate.
35. Sertraline hydrochloride Form VI, which is characterized by an
x-ray powder diffraction pattern comprising peaks at about
7.3.degree..+-.0.2, 12.1.degree..+-.0.2, 12.7.degree..+-.0.2,
22.0.degree..+-.0.2, 22.9.degree..+-.0.2, 23.2.degree..+-.0.2,
24.0.degree..+-.0.2, and 24.5.degree..+-.0.2 degrees two-theta.
36. A pharmaceutical composition comprising a therapeutically
effective amount of sertraline hydrochloride Form VI and a
pharmaceutically acceptable carrier.
37. A process for making sertraline hydrochloride Form VI
comprising the steps of: (a) dissolving sertraline base in a
solvent; (b) adding hydrogen chloride gas to the solution; and (c)
isolating sertraline hydrochloride Form VI without further
drying.
38. The process of claim 37 wherein the isolation step comprises
precipitation of sertraline hydrochloride Form VI followed by
filtration.
39. The process of claim 37 wherein the solvent is ethanol or
methanol.
40. The product of the process of claim 37.
41. A process for making sertraline hydrochloride Form VI
comprising the steps of: (a) dissolving sertraline hydrochloride in
ethanol or methanol; (b) stirring for a time sufficient to induce
the transformation of sertraline hydrochloride to sertraline
hydrochloride Form VI; and (c) isolating sertraline hydrochloride
Form VI.
42. The process of claim 41 wherein the sertraline hydrochloride of
step (a) is Form I.
43. The process of claim 41 wherein the sertraline hydrochloride of
step (a) is Form II.
44. The process of claim 41 wherein the sertraline hydrochloride of
step (a) is Form V.
45. Sertraline hydrochloride Form VII.
46. A pharmaceutical composition comprising a therapeutically
effective amount of sertraline hydrochloride Form VII, and a
pharmaceutically acceptable carrier.
47. A process for making sertraline hydrochloride Form VII
comprising the steps of: (a) suspending sertraline hydrochloride
Form V in water; and (b) filtering the suspension without
drying.
48. The product of the process of claim 47.
49. A process for making sertraline hydrochloride Form VII
comprising the steps of: (a) dissolving sertraline hydrochloride
ethanolate Form VI in water such that the sertraline hydrochloride
Form VI is converted to sertraline hydrochloride Form VII; (b)
filtering the sertraline hydrochloride Form VII; and (c) washing
the filtered sertraline hydrochloride Form VII with water.
50. A process for making sertraline hydrochloride Form VII
comprising the steps of: (a) dissolving sertraline hydrochloride
ethanolate Form VI in water; (b) heating the solution to facilitate
dissolution of sertraline hydrochloride Form VI; and (c) isolating
sertraline hydrochloride Form VII without drying.
51. The process of claim 50 comprising the additional step of
lowering the pH to facilitate precipitation of sertraline
hydrochloride Form V.
52. Sertraline hydrochloride Form VII, which is characterized by
the x-ray powder diffraction pattern substantially depicted in FIG.
6.
53. Sertraline hydrochloride hydrate Form VIII.
54. Sertraline hydrochloride Form VIII, which is characterized by
an x-ray powder diffraction pattern comprising peaks at about
4.7.degree..+-.0.2, 16.3.degree..+-.0.2, 17.8.degree..+-.0.2,
19.6.degree..+-.0.2, 23.2.degree..+-.0.2, 24.2.degree..+-.0.2,
25.1.degree..+-.0.2, and 26.0.degree..+-.0.2 two-theta.
55. A pharmaceutical composition comprising a therapeutically
effective amount of sertraline hydrochloride Form VIII, and a
pharmaceutically acceptable carrier.
56. A process for making sertraline hydrochloride Form VIII
comprising the steps of: (a) suspending sertraline base in water;
(b) adding hydrochloric acid; and (c) filtrating the precipitate so
obtained without further drying.
57. The product of the process of claim 58.
58. A process for making sertraline hydrochloride Form VIII
comprising the steps of: (a) dissolving sertraline hydrochloride
ethanolate Form VI in water; and (b) isolating sertraline
hydrochloride Form VIII.
59. A process for making sertraline hydrochloride Form VIII
comprising the steps of: (a) dissolving sertraline hydrochloride
Form II in water; and (b) isolating sertraline hydrochloride Form
VIII.
60. Sertraline hydrochloride Form IX which is characterized by the
x-ray diffraction pattern substantially as depicted in FIG. 8.
61. Sertraline hydrochloride Form IX, which is characterized by an
x-ray powder diffraction pattern comprising peaks at about
5.1.degree..+-.0.2, 14.2.degree..+-.0.2, 15.8.degree..+-.2.0,
16.8.degree..+-.0.2, 19.2.degree..+-.0.2, 19.7.degree..+-.2.0,
22.4.degree..+-.2.0, 23.2.degree..+-.0.2, 25.3.degree..+-.0.2 and
26.1.degree..+-.0.2 two-theta.
62. A pharmaceutical composition comprising a therapeutically
effective amount of sertraline hydrochloride Form IX, and a
pharmaceutically acceptable carrier.
63. A process for making sertraline hydrochloride Form IX
comprising the steps of: (a) suspending sertraline base in water;
(b) adding hydrochloric acid such that a precipitate is formed; (c)
filtrating the precipitate; and (d) drying the precipitate.
64. The product of the process of claim 63.
65. A process for making sertraline hydrochloride Form IX
comprising the step of drying sertraline hydrochloride Form VIII
and isolating sertraline hydrochloride Form IX.
66. A process for making sertraline hydrochloride Form X comprising
the steps of: (a) suspending sertraline hydrochloride in benzyl
alcohol; (b) heating the suspension to facilitate dissolution; (c)
cooling the solution such that a precipitate is formed; (d) heating
the solution to about 80.degree. C.; and (e) isolating sertraline
hydrochloride Form X.
67. The process of claim 66 wherein the sertraline hydrochloride
Form X is isolated by filtration and washing with benzyl alcohol
and heating.
68. The product of the process of claim 66.
69. Sertraline hydrochloride Form X.
70. Sertraline hydrochloride Form X which is characterized by an
x-ray powder diffraction pattern comprising peaks at about
15.0.degree..+-.0.2, 16.0.degree..+-.0.2, 16.5.degree..+-.0.2,
17.0.degree..+-.0.2, 18.1.degree..+-.0.2, 21.0.degree..+-.0.2,
22.4.degree..+-.0.2, 24.9.degree..+-.0.2, 25.4.degree..+-.0.2,
26.2.degree..+-.0.2, 27.1.degree..+-.0.2, 28.4.degree..+-.0.2, and
29.0.degree..+-.0.2 degrees two-theta.
71. A pharmaceutical composition comprising a therapeutically
effective amount of sertraline hydrochloride Form X, and a
pharmaceutically acceptable carrier.
72. A process for making sertraline hydrochloride Form II
comprising the steps of: (a) suspending sertraline hydrochloride
Form VI in an organic aprotic solvent for a time sufficient to
effect transformation to Form II; and (b) filtrating the
suspension.
73. The process of claim 72 wherein the process takes place at
temperature between about 25.degree. C. and about 80.degree. C.
74. The process of claim 72 in which the sertraline hydrochloride
form VI is suspended in about 1 to about 10 volumes of organic
aprotic solvent.
75. The process of claim 72 wherein the solvent is selected from
the group consisting of acetone, t-butyl-methyl-ether, cyclohexane,
and ethyl acetate.
76. The process of claim 77 wherein the solvent is
t-butyl-methyl-ether.
77. The process of claim 77 wherein the solvent is acetone.
78. A process for making sertraline hydrochloride Form II
comprising the steps of: (a) suspending sertraline hydrochloride
Form V in dimethylformamide or cyclohexanol; (b) heating the
solution for a time sufficient to effect transformation to
sertraline hydrochloride Form II; and (c) isolating sertraline
hydrochloride Form II.
79. A process for making sertraline hydrochloride Form II
comprising the steps of: (a) dissolving sertraline base in acetone;
(b) adding a hydrogen chloride solution to induce the formation of
sertraline hydrochloride Form II; and (c) isolating sertraline
hydrochloride Form II.
80. A process for making sertraline hydrochloride Form II
comprising the steps of: (a) granulating sertraline hydrochloride
Form V with ethanol; and (b) stirring the mixture for a time
sufficient to induce transformation to sertraline hydrochloride
Form II.
81. 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.
82. The process of claim 81 wherein the sertraline hydrochloride
Form VI is heated to about 80.degree. C. to about 105.degree.
C.
83. A process for making sertraline hydrochloride Form III
comprising the steps of: (a) heating sertraline hydrochloride Form
V for a time sufficient to induce the transformation of sertraline
hydrochloride Form II to sertraline hydrochloride Form V; and (b)
isolating sertraline hydrochloride Form III.
84. The process of claim 83 wherein sertraline hydrochloride Form V
is heated to about 150.degree. C. to about 180.degree. C.
85. A process for making sertraline hydrochloride Form III
comprising the steps of: (a) heating sertraline hydrochloride Form
VI for a time sufficient to induce the transformation of sertraline
hydrochloride Form V to sertraline hydrochloride Form III; and (b)
isolating sertraline hydrochloride Form III.
86. The process of claim 85 wherein sertraline hydrochloride is
heated to about 180.degree. C.
87. A process for making amorphous sertraline hydrochloride
comprising the steps of: (a) suspending or dissolving sertraline
base in a non-polar organic solvent; (b) adding gaseous
hydrochloric acid; and (c) and isolating amorphous sertraline
hydrochloride.
88. The process of claim 87 wherein the solvent is selected from
the group consisting of ether, toluene and t-butyl-methyl
ether.
89. A process for making amorphous sertraline hydrochloride
comprising the steps of: (a) lyophilization of sertraline
hydrochloride; and (b) isolating amorphous sertraline
hydrochloride.
90. Amorphous sertraline hydrochloride, which is characterized by
the x-ray diffraction pattern substantially as depicted in FIG. 2.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to novel crystalline forms of
sertraline hydrochloride,
(1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahy-
dro-N-methyl-1-naphthalenaminehydrochloride, denominated Forms VI
through X, an amorphous form and novel, reproducible methods for
preparing them and for preparing previously reported polymorphs II,
III and V.
BACKGROUND OF THE INVENTION
[0002] Sertraline hydrochloride, (1S-cis)-4-(3,4
dichlorophenyl)-1,2,3,4-t- etrahydro-N-methyl-1-naphthalenamine
hydrochloride, having the formula 1
[0003] 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.
[0004] U.S. Pat. No. 4,536,518 describes a synthesis of sertraline
hydrochloride. U.S. Pat. No. 5,248,699 describes five crystalline
forms of sertraline hydrochloride, designated Form I, Form II, Form
III, Form IV and Form V.
[0005] U.S. Pat. 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] 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 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, hexane, 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. Form I is
described as being made by crystallizing sertraline hydrochloride
in an acidic solution using an organic solvent such as those listed
above. The crystallization of Form I is carried out at a
temperature from about 20.degree. C. to about the solvent reflux
temperature, preferably from about 40.degree. to 60.degree. C. 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. Slow crystallization or
granulation of sertraline hydrochloride will produce Form I. Form
III is described as being formed by heating Forms I, II or IV to
temperatures above about 180.degree. C. Granulating either of Forms
II, III or IV in isopropyl alcohol, ethyl acetate, hexane or any of
the solvents listed above at a temperature from about 40.degree. to
60.degree. C. causes conversion to Form I. The only method
described in this patent for making Form V is by sublimation of
sertraline hydrochloride Form I at reduced pressure and at a
temperature from about 180-190.degree. C. onto a condenser.
However, in our hands attempts to repeat this procedure to obtain
Form V have been unsuccessful.
SUMMARY OF THE INVENTION
[0007] It has now been discovered that sertraline hydrochloride
Form V can be formed by crystallization from various solvents
rather than by sublimation. The existence of new crystal forms of
sertraline hydrochloride, denominated Forms VI, VII, VIII, IX and
X, and an amorphous of sertraline hydrochloride have been
discovered. Form VI is a useful intermediate in the formation of
previously reported sertraline hydrochloride Forms II, II and
V.
[0008] The present invention also relates to sertraline
hydrochloride ethanolate and processes for making sertraline
hydrochloride ethanolate.
[0009] The present invention also relates to sertraline
hydrochloride methanolate and processes for making sertraline
hydrochloride methanolate.
[0010] The present invention also relates to sertraline
hydrochloride solvate and processes for making sertraline
hydrochloride solvate.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1 is a characteristic x-ray powder diffraction spectrum
of sertraline hydrochloride Form V.
[0012] FIG. 2 is a characteristic x-ray powder diffraction spectrum
of amorphous sertraline hydrochloride Form V.
[0013] FIG. 3 is a characteristic differential scanning
calorimetric (DSC) thermogram of sertraline hydrochloride Form
V.
[0014] FIG. 4 is a characteristic infrared (IR) absorption spectrum
of sertraline hydrochloride Form V.
[0015] FIG. 5 is a characteristic x-ray powder diffraction spectrum
of sertraline hydrochloride Form VI.
[0016] FIG. 6 is a characteristic x-ray powder diffraction spectrum
of sertraline hydrochloride Form VII.
[0017] FIG. 7 is a characteristic x-ray powder diffraction spectrum
of sertraline hydrochloride Form VIII.
[0018] FIG. 8 is a characteristic x-ray powder diffraction spectrum
of sertraline hydrochloride Form IX.
[0019] FIG. 9 is a characteristic differential scanning
calorimetric (DSC) thermogram of sertraline hydrochloride Form
VIII.
[0020] FIG. 10 is a characteristic differential scanning
calorimetric (DSC) thermogram of sertraline hydrochloride Form
IX.
[0021] FIG. 11 is a characteristic infrared (IR) absorption
spectrum of sertraline hydrochloride Form VIII.
[0022] FIG. 12 is a characteristic infrared (IR) absorption
spectrum of sertraline hydrochloride Form IX.
[0023] FIG. 13 is a characteristic differential scanning
calorimetric (DSC) thermogram of sertraline hydrochloride Form
VI.
[0024] FIG. 14 is a characteristic x-ray powder diffraction
spectrum of sertraline hydrochloride Form X.
[0025] FIG. 15 is a characteristic infrared (IR) absorption
spectrum of sertraline hydrochloride Form X.
[0026] FIG. 16 is a characteristic differential scanning
calorimetric (DSC) thermogram of sertraline hydrochloride Form
X.
DETAILED DESCRIPTION OF THE INVENTION
[0027] Form V
[0028] The present invention provides new processes for making
sertraline hydrochloride Form V from sertraline hydrochloride,
sertraline base or amorphous sertraline hydrochloride. The methods
provided in the present invention are more commercially practicable
than the sublimation-condensation method of U.S. Pat. No.
5,248,699, which we have not been able to reproduce. It has also
surprisingly been found that, by the present method, Form V is
formed even at different crystallization rates.
[0029] Where the present invention provides methods for the
conversion of sertraline hydrochloride to sertraline hydrochloride
Form V, sertraline hydrochloride is combined with a solvent
selected from the group consisting of methanol, ethanol,
1-methoxy-2-propanol and a mixture of isopropyl alcohol and water.
If a mixture of isopropyl alcohol and water is used, it is
preferably an about 6:1 mixture. Preferably the solvent is methanol
or ethanol, and most preferably the solvent is ethanol. Sertraline
hydrochloride Form V is isolated by allowing the solution to cool.
One preferred method is to rapidly cool the solvent to 5.degree. C.
Another preferred method comprises seeding the solution with
sertraline hydrochloride Form V crystals, followed by slow cooling
to room temperature, followed by filtration and drying. Sertraline
hydrochloride Form V can also be prepared by recrystallizing
sertraline hydrochloride Form VI (described below) from water.
[0030] The present invention also provides methods for the
conversion of sertraline hydrochloride Form II or II to sertraline
hydrochloride Form V wherein the solvate sertraline hydrochloride
Form VI is an intermediate. In this embodiment of the present
invention, sertraline hydrochloride Form I and Form II is dissolved
in either methanol or ethanol thereby forming sertraline
hydrochloride Form VI. Where ethanol is the solvent, the sertraline
hydrochloride Form VI is the ethanolate solvate. Where methanol is
the solvent, the sertraline hydrochloride Form VI is the
methanolate solvate. This intermediate sertraline hydrochloride
Form VI is then dried, with or without a separate isolation step,
to remove all solvent and sertraline hydrochloride Form V is
isolated.
[0031] The present invention also provides methods for the
conversion of sertraline hydrochloride Form II to sertraline
hydrochloride Form V wherein the sertraline hydrochloride Form VIII
is an intermediate. In this embodiment of the present invention,
sertraline hydrochloride Form II is dissolved in water thereby
forming sertraline hydrochloride Form VIII This intermediate
sertraline hydrochloride Form VIII is then dried, with or without a
separate isolation step, to remove all solvent and sertraline
hydrochloride Form V is isolated.
[0032] The present invention also provides methods for the
conversion of sertraline base to sertraline hydrochloride Form V,
wherein sertraline base is added to at least one solvent, and
hydrogen chloride gas is bubbled through the solution. Preferred
solvents include methanol, ethanol, water, or mixtures of ethanol,
methanol, isopropyl alcohol, hexane, ethyl acetate with each other
or with water. Alternatively, an appropriate amount of hydrogen
chloride gas dissolved in methanol, ethanol, water, hexane,
isopropyl alcohol, ethyl acetate, or a mixture thereof is combined
with the sertraline base solution. Sertraline hydrochloride Form V
is isolated by allowing precipitation to occur from about 0.degree.
to about 60.degree. C. followed by filtration and drying.
Preferably the solvent is hexane, isopropyl alcohol or a mixture
thereof. In another method, sertraline base is added to a solvent
and the resulting solution is added to a hydrochloric acid solution
of pH 0-4; preferably the pH of the solution is about 1.
[0033] Alternatively, sertraline base is added to a solvent
selected from the group consisting of methanol, ethanol, water,
hexane, isopropyl alcohol, and ethyl acetate or a mixture thereof.
The solution is heated and concentrated hydrochloric acid is added.
Water may also be added. Sertraline hydrochloride Form V is
isolated by allowing the mixture to cool to room temperature and
remain at room temperature overnight, followed by filtration and
drying.
[0034] Alternatively, sertraline base may be combined with a
solvent selected from the group consisting of ethanol, ethanol and
water, ethyl acetate, and a mixture of ethyl acetate and water. The
solution is heated to about 50-60.degree. C. and water is added.
The solvent is partially removed by distillation. Sertraline
hydrochloride Form V is isolated by allowing the solution to cool
to room temperature, followed by filtration and drying at the
precipitate.
[0035] Alternatively, sertraline base may be combined with a
solvent selected from the group consisting of methanol, ethanol and
a mixture thereof. A saturated solution of hydrogen chloride gas in
isopropyl alcohol is added to induce formation of sertraline
hydrochloride Form V. Sertraline hydrochloride Form V is isolated
by allowing the solution to stand at room temperature overnight,
followed by filtration and drying of the precipitate.
[0036] Sertraline base for use in the processes of the present
invention may be produced by dissolving sertraline mandelate in
ethyl acetate followed by neutralization of the sertraline
mandelate with aqueous sodium hydroxide. The organic phase is
separated from the aqueous phase and dried using magnesium sulfate.
The solvent is removed under reduced pressure to produce sertraline
base as an oil. Methods for making sertraline base are set forth in
U.S. Pat. Nos. 4,536,518 and 5,248,699.
[0037] Where the present invention provides methods for the
conversion of amorphous sertraline hydrochloride to sertraline
hydrochloride Form V, amorphous sertraline hydrochloride is kept in
a closed container, such as a bag, and warmed to about 40.degree.
C. to about 80.degree. C. or is stored at room temperature for a
period between a few hours and several days depending on the
temperature.
[0038] The sertraline hydrochloride Form V that results from
practicing the invention as exemplified herein can be characterized
by its powder X-ray diffraction pattern. FIG. 1 is a representative
pattern of sertraline hydrochloride Form V. The principal peaks
observed are at about 5.2.degree..+-.0.2, 10.4.degree..+-.0.2,
11.0.degree..+-.0.2, 14.3.degree..+-.0.2, 16.5.degree..+-.0.2,
17.3.degree..+-.0.2, 18.4.degree..+-.0.2, 19.1.degree..+-.0.2,
19.7.degree..+-.0.2, 20.9.degree..+-.0.2, 22.0.degree..+-.0.2,
23.2.degree..+-.0.2, 23.6.degree..+-.0.2, 25.5.degree..+-.0.2,
26.0.degree..+-.0.2, and 29.1.degree..+-.0.2 degrees 2 theta.
[0039] Three experiments were performed in order to repeat the
procedure described in U.S. Pat. No. 5,248,699 for preparing Form V
by sublimation. Two experiments were performed by sublimating a
sample of Form I under 30 mm Hg vacuum and temperature between
170-190.degree. C. A third experiment was performed by sublimating
a sample of Form I under high vacuum (0.1 mm Hg) and temperature
between 180-195.degree. C.
[0040] The three samples of sertraline hydrochloride prepared by
sublimation were analyzed by powder x-ray diffraction. In all
cases, the typical broad featureless pattern without sharp peaks
typical of amorphous materials was obtained. FIG. 2 is one such
pattern.
[0041] In conclusion, sertraline hydrochloride could not be
obtained by following the procedure set forth in U.S. Pat. No.
5,248,699 for preparing Form V by sublimation of Form I.
[0042] The IR spectrum of sertraline hydrochloride Form V produced
by the present process is characterized by the following bands: 773
cm.sup.-1, 822 cm.sup.-1, cm.sup.-1, 1012 cm.sup.-1, 1032
cm.sup.-1, 1054 cm.sup.-1, 1133 cm.sup.-1, 1328 cm.sup.-1, 1562
cm.sup.-1, and 1590 cm.sup.-1, as shown in FIG. 4.
[0043] The sertraline hydrochloride Form V of the present process
is further characterized by the DSC thermogram data, for example,
as disclosed in FIG. 3. The DSC thermogram is characterized by a
small endotherm (.about.3 Joule per gram) at about 210.degree. C.,
believed to be a solid-solid transformation (based upon observation
under a hot stage microscope) to Form III, and a melting peak. Form
III at 251.degree. C.
[0044] Form VI
[0045] Sertraline hydrochloride Form VI is a solvated crystal form
of sertraline hydrochloride. In the present invention, sertraline
hydrochloride Form VI may be an ethanolate, wherein ethanol is
incorporated into the crystal structure of Form VI. Alternatively,
sertraline hydrochloride Form VI may be a methanolate, wherein
methanol is incorporated into the crystal structure of sertraline
hydrochloride Form VI. All sertraline hydrochloride Form VI
solvates have identical powder x-ray diffraction patterns.
Therefore, when referring to sertraline hydrochloride Form VI all
sertraline hydrochloride Form VI solvates such as, sertraline
hydrochloride Form VI ethanolate and sertraline hydrochloride Form
VI methanolate, are necessarily included.
[0046] To form the novel crystalline form sertraline hydrochloride
Form VI, sertraline base is added to absolute ethanol or methanol.
Hydrogen chloride gas is then bubbled through the solution.
Sertraline hydrochloride Form VI is isolated by allowing
precipitation to occur, followed by filtration. The DSC thermogram
of Form VI crystallized from ethanol displays a desolvation peak at
95.degree. C. (see FIG. 13) and loses 11.2% weight (by TGA); Form
VI crystallized from methanol loses 8.3% weight (by TGA) upon
desolvation; Form VI crystallized from ethanol is an ethanolate,
and more specifically is a monoethanolate. Form VI crystallized
from methanol is a methanolate, and more specifically is a
monomethanolate.
[0047] The present invention also provides new processes for making
sertraline hydrochloride ethanolate Form VI by reslurry of Forms I,
II and V. In the conversion of sertraline hydrochloride Form I, II,
V to sertraline hydrochloride ethanolate Form VI, sertraline
hydrochloride Form I, II or V is dissolved or suspended in ethanol
or in methanol and stirred for about 18-36 hours, 24 hours is
preferred. Sertraline hydrochloride ethanolate Form VI is isolated
by filtration.
[0048] The sertraline hydrochloride Form VI so isolated exhibits
the powder x-ray diffraction pattern of FIG. 5, comprising peaks at
7.3.degree..+-.0.2, 12.1.degree..+-.0.2, 12.7.degree..+-.0.2,
14.0.degree..+-.0.2, 15.6.degree..+-.0.2, 17.6.degree..+-.0.2,
20.1.degree..+-.0.2, 20.6.degree..+-.0.2, 21.9.degree..+-.0.2,
22.7.degree..+-.0.2, 23.0.degree..+-.0.2, 23.8.degree..+-.0.2,
24.3.degree..+-.0.2, 25.4.degree..+-.0.2, and 26.3.degree..+-.0.2
degrees two-theta. Sertraline hydrochloride Form VI so obtained is
a solvate. Drying of the precipitated sertraline hydrochloride Form
VI at 50-60.degree. C. overnight yields sertraline hydrochloride
Form V.
[0049] Form VII
[0050] It has also been discovered that a new crystalline form of
sertraline hydrochloride Form VII, may be obtained by suspending
Form V in water, and filtrating the suspension after one day
without further drying.
[0051] In another embodiment of the invention, sertraline
hydrochloride Form VII is made from sertraline hydrochloride Form
VI. Sertraline hydrochloride Form VI is dispersed in water and the
mixture is heated to facilitate the dissolution of sertraline
hydrochloride Form VI. The solution may be heated to about
30.degree. C. to 90.degree. C., preferably to about 80.degree. C.
The pH is then lowered, preferably to about pH 1 and the mixture is
allowed to cool to room temperature and stirred until the reaction
is complete. Preferably the reaction is stirred for two hours at
room temperature. Sertraline hydrochloride Form VII is isolated by
filtration and washing with water.
[0052] As shown in FIG. 6, sertraline hydrochloride Form VII is
characterized by two unique strong x-ray powder diffraction peaks
at 4.0.degree..+-.0.2, and 20.0 degrees two-theta and medium
intensity peaks at 8.0.degree..+-.0.2, 11.6.degree..+-.0.2,
12.0.degree..+-.0.2, 13.8.degree..+-.0.2, 16.5.degree..+-.0.2,
22.8.degree..+-.0.2, 24.1.degree..+-.0.2, 25.0.degree..+-.0.2,
26.6.degree..+-.0.2, 30.7.degree..+-.0.2, 34.7.degree..+-.0.2 2
two-theta. The TGA curve shows a loss on drying of about 45%.
[0053] Forms VIII and IX
[0054] Additional new crystalline forms of sertraline
hydrochloride, Forms VIII and IX, have also been discovered.
Sertraline hydrochloride hydrate Form VIII may be produced by
suspending sertraline base in water followed by acidification and
filtration. Form IX is obtained by drying of Form VIII. Preferably
the sertraline base is suspended in water, heated to approximately
80.degree. C., adding hydrochloric acid to reduce the pH to about
1, and cooling the resulting solution to room temperature.
[0055] The present invention also provides new processes for making
sertraline hydrochloride Form VIII from sertraline hydrochloride
ethanolate Form VI. In one embodiment of the present invention, a
slurry of sertraline hydrochloride ethanolate Form VI in water is
stirred, preferably for about one hour. The slurry is then filtered
and washed with water and sertraline hydrochloride hydrate Form
VIII is isolated.
[0056] The present invention also provides precesses of making
sertraline hydrochloride form VIII from sertraline hydrochloride
Form II. In the conversion of sertraline hydrochloride Form II to
sertraline hydrochloride Form VIII, sertraline hydrochloride Form
II is suspended in water and stirred, preferably stirred overnight
and sertraline hydrochloride hydrated Form VIII is isolated by
filtration.
[0057] Sertraline hydrochloride Form VIII is characterized by x-ray
powder diffraction peaks at 4.7.degree..+-.0.2,
11.8.degree..+-.0.2, 16.3.degree..+-.0.2, 17.8.degree..+-.0.2,
19.6.degree..+-.0.2, 23.2.degree..+-.0.2, 24.2.degree..+-.0.2,
25.1.degree..+-.0.2, and 26.0.degree..+-.0.2 two-theta, as
described in FIG. 7.
[0058] The DSC thermogram for Form VIII is characterized by a
strong endotherm below 100.degree. C., small endothermic and
exothermic events at about 220.degree. C. and a melting peak at
247.degree. C. as described in FIG. 9.
[0059] The TGA curve shows a loss on drying step of about 20% below
100.degree. C.
[0060] The IR spectrum of Form VIII is characterized by the
following bands: 740 cm.sup.-1, 779 cm.sup.-1, 822 cm.sup.-1, 887
cm.sup.-1, 915 cm.sup.-1, 1031 cm.sup.-1, 1053 cm.sup.-1, 1110
cm.sup.-1, 1134 cm.sup.-1, 1153 cm.sup.-1, 1217 cm.sup.-1, 1307
cm.sup.-1, and 1377 cm.sup.-1, as described in FIG. 11.
[0061] Sertraline hydrochloride Form IX is characterized by x-ray
powder diffraction peaks at 5.1.degree..+-.0.2,
14.2.degree..+-.0.2, 15.8.degree..+-.0.2, 16.8.degree..+-.0.2,
19.2.degree..+-.0.2, 19.7.degree..+-.0.2, 22.4.degree..+-.0.2,
23.2.degree..+-.0.2, 25.3.degree..+-.0.2 and 26.1.degree..+-.0.2
two-theta, as described in FIG. 8.
[0062] The IR spectrum of Form IX is characterized by the following
bands: 701 cm.sup.-1, 715 cm.sup.-1, 741 cm.sup.-1, 758 cm.sup.-1,
780 cm.sup.-1, 816 cm.sup.-1, 823 cm.sup.-1, 1030 cm.sup.-1, 1053
cm.sup.-1, 1078 cm.sup.-1, 1110 cm.sup.-1, 1204 cm.sup.-1, 1217
cm.sup.-1, 1307 cm.sup.-1, and 1350 cm.sup.-1, as described in FIG.
12.
[0063] Form X
[0064] It has further been discovered that another crystalline form
of sertraline hydrochloride, denominated Form X, may be obtained by
suspending sertraline hydrochloride in benzyl alcohol heating to
facilitate dissolution. The precipitate is then filtered, washed
with benzyl alcohol and dried, to yield sertraline hydrochloride
Form X.
[0065] The Form X produced in this manner is characterized by a
powder x-ray diffraction pattern having its principal peaks at
15.0.degree..+-.0.2, 16.0.degree..+-.0.2, 16.5.degree..+-.0.2,
17.0.degree..+-.0.2, 18.1.degree..+-.0.2, 21.0.degree..+-.0.2,
22.4.degree..+-.0.2, 24.9.degree..+-.0.2, 25.4.degree..+-.0.2,
26.2.degree..+-.0.2, 27.1.degree..+-.0.2, 28.4.degree..+-.0.2, and
29.0.degree..+-.0.2 degrees two-theta as described in FIG. 14.
[0066] The IR spectrum of Form X is characterized by the following
bands: 742 cm.sup.-1, 776 cm.sup.-1, 806 cm.sup.-1, 824 cm.sup.-1,
1002 cm.sup.-1, 1017 cm.sup.-1, 1028 cm.sup.-1, 1060 cm.sup.-1,
1079 cm.sup.-1, 1135 cm.sup.-1, 1218 cm.sup.-1, 1314 cm.sup.-1,
1336 cm.sup.-1, and 1560 cm.sup.-1 as described in FIG. 15.
[0067] The DSC of Form X shows a small endotherm at about
190.degree. C. followed by a melting endotherm at about 250.degree.
C., (see FIG. 16).
[0068] Form II
[0069] The present invention provides new processes for making
sertraline hydrochloride Form II from sertraline hydrochloride Form
VI by reslurry or granulation in organic solvents at temperatures
between 25-80.degree. C., followed by drying. 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.
[0070] In the conversion of sertraline hydrochloride Form VI to
sertraline hydrochloride Form II, sertraline hydrochloride Form VI
is combined with an aprotic organic solvent. Suitable solvents
include acetone, t-butyl-methyl ether (MTBE), ethyl acetate and
cyclohexane. One preferred method is to heat sertraline
hydrochloride Form VI and solvent, preferably MTBE, to reflux for
one hour. The slurry is cooled to room temperature and sertraline
hydrochloride Form II is isolated by filtration. Another preferred
method of making sertraline hydrochloride Form II comprises
stirring sertraline hydrochloride Form VI and suitable solvent,
preferably acetone, at room temperature for 2 hours, followed by
filtration. About 1 to about 10 volumes of solvent are preferred,
based on the weight of the sertraline hydrochloride starting
material. See Examples 9 (3 volumes of solvent) and 10 (5 volumes
of solvent) below. However, 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 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.
[0071] 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 ethanol. The sertraline
hydrochloride Form V ethanol mixture is stirred for at least a few
hours to several days, preferably about two days to induce the
formation of sertraline hydrochloride Form II.
[0072] Sertraline hydrochloride Form II may also be made by
recrystallization of sertraline hydrochloride from suitable
solvents such as dimethyl formamide or cyclohexanol. Sertraline
hydrochloride is dissolved by warming in the solvent followed by
cooling the solution at room temperature. Sertraline Form II is
isolated by filtration.
[0073] The present invention also provides a new process for making
sertraline hydrochloride Form II form sertraline base. Sertraline
base is dissolved in a suitable such as acetone and the pH of the
solution is lower by the addition of a hydrogen chloride solution,
such as isopropyl alcohol and hydrogen chloride. The hydrogen
chloride solution is added to induce the formation of sertraline
hydrochloride Form II. Upon cooling of the mixture, for example to
room temperature, sertraline hydrochloride Form II is isolated by
filtration.
[0074] An experiment was performed in order to repeat the procedure
described in U.S. Pat. No. 4,536,518 for preparing Form II.
Sertraline base was dissolved in ethyl acetate, ether was added and
the solution was acidified with hydrogen chloride gas. The material
obtained after filtration and air drying was sertraline
hydrochloride amorphous, not Form II as was expected.
[0075] 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.
[0076] Form III
[0077] The present invention provides new processes for making
sertraline hydrochloride Form III from sertraline hydrochloride
From V. In the conversion of sertraline hydrochloride Form V to
sertraline hydrochloride Form III, Form V is heated to a
temperature between about 150.degree. to about 180.degree. C. for
about 24 hours to induce the formation of sertraline hydrochloride
Form III. The reaction may be stirred. The method of the present
invention has the advantage of using no solvent.
[0078] The methods of the present invention also provides new
processes for making sertraline hydrochloride Form III from
sertraline hydrochloride ethanolate Form VI by heating sertraline
hydrochloride Form VI at about 150.degree. to about 180.degree. C.
for about 24 hours. The dried material is sertraline hydrochloride
Form III.
[0079] Amorphous Sertraline Hydrochloride
[0080] The present invention provides new processes for making
amorphous sertraline hydrochloride from sertraline hydrochloride by
sublimation or by precipitating, from a non-polar solvent such as
toluene, ether and t-butyl-methyl ether sertraline base.
[0081] In an embodiment of the present invention, amorphous
sertraline is made by dissolving hydrochloride Form V in water and
drying the solution by the spray dryer technique. Amorphous
sertraline hydrochloride may also be made by sublimation of
sertraline hydrochloride.
[0082] The amorphous sertraline hydrochloride produced by methods
of the present invention is characterized by a powder x-ray
diffraction pattern having the typical broad featureless pattern
without sharp peaks typical of amorphous materials. FIG. 2 is one
such pattern.
[0083] Pharmaceutical Compositions Containing Sertraline
Hydrochloride Polymorphs
[0084] In accordance with the present invention, these new
crystalline forms of sertraline hydrochloride and known forms of
sertraline hydrochloride prepared by the new methods disclosed
herein may be prepared as pharmaceutical compositions that are
particularly useful for the treatment of depression,
obsessive-compulsive disorder and panic disorder. Such compositions
comprise one of the new crystalline forms of sertraline
hydrochloride with pharmaceutically acceptable carriers and/or
excipients known to one of skill in the art.
[0085] 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.
[0086] Experimental
[0087] 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.
[0088] The differential scanning calorimeter thermograms were
obtained by methods known in the art using a DSC Mettler 821
Star.degree.. The weight of the samples was less than 5 mg. The
temperature range of scans was 30.degree. C-300.degree. C. at a
rate of 10.degree. C./min. Samples were purged with nitrogen gas at
a flow rate of 40 mL/min. Standard 40 .mu.l aluminum crucibles were
used having lids with three small holes.
[0089] The infrared spectra were obtained by methods known in the
art using a Perkin Elmer FT-IR Paragon 1000 spectrometer. Samples
were analyzed in Nujol mulls. Spectra were obtained at 4 cm.sup.-1
resolution and 16 scans each.
EXAMPLES
[0090] 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
[0091] 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 Form VI and Form V
[0092] Sertraline base (25 g) was dissolved in methanol (125 mL) at
room temperature. The solution was acidified with hydrogen chloride
until pH 1.5 was reached. (Precipitation occurred during
acidification.) The temperature rose to approximately 40.degree. C.
The slurry was allowed to cool to room temperature and stirred for
about 2 hours. The solid was separated by filtration to give
sertraline hydrochloride methanolate--Form VI. Drying the product
overnight gave sertraline hydrochloride Form V.
Example 3
Preparation of Sertraline Hydrochloride Form VI and Form V
[0093] Sertraline base (3.2 g) was dissolved in absolute ethanol
(32 mL) at room temperature and then hydrogen chloride gas was
bubbled in until pH 0.5 was reached. The temperature rose to
40.degree. C. The slurry was allowed to cool to room temperature
and stirred for about 16 hours. The solid was separated by
filtration, and washed with ethanol (3.times.2 mL). FIG. 5 sets
forth the X-ray diffraction pattern of the product (sertraline
hydrochloride Form VI) so obtained. Drying overnight at
50-60.degree. C. of that product yields 2.95 g (82%) of sertraline
hydrochloride Form V.
Example 4
Preparation of Sertraline Hydrochloride Form V
[0094] Sertraline base (3 g) was dissolved in absolute ethanol (15
mL) at room temperature. A saturated solution of hydrogen chloride
in isopropyl alcohol was added dropwise to reach a pH of 1.3. The
resulting slurry was stirred at room temperature overnight. The
solid was separated by filtration and dried overnight at
50-60.degree. C. yielding 2.75 g (81.8%) sertraline hydrochloride
Form V.
Example 5
Preparation of Sertraline Hydrochloride Form V
[0095] Sertraline base (3 g) was dissolved in absolute ethanol
(15.5 mL) at room temperature and then the solution was cooled to
approximately 0.degree. C. Hydrogen chloride gas was bubbled until
pH 0.5 was reached. The temperature rose to approximately 7.degree.
C. Precipitation occurred and the slurry was stirred at about
10.degree. C. for 2 hours. The solid was isolated by filtration,
washed with ethanol and dried at approximately 50.degree. C. The
dried material (2.87 g, yield 82.7%) was sertraline hydrochloride
Form V.
Example 6
Preparation of Sertraline Hydrochloride Form V
[0096] Sertraline base (3 g) was stirred with 35 mL water. The
slurry was heated at .about.70.degree. C. and, while maintaining
this temperature, concentrated hydrochloric acid was added until pH
1 was reached. During acidification, almost complete dissolution
was observed followed by precipitation. The mixture was cooled to
room temperature and stirred for 2 hours. The solid was isolated by
filtration, washed with water and dried overnight at 50-60.degree.
C., yielding 3.23 g (96%) sertraline hydrochloride Form V.
Example 7
Preparation of Sertraline Hydrochloride Form V
[0097] Sertraline base (3 g) was dissolved in 10 mL absolute
ethanol at 40.degree. C. The solution was heated to 50-60.degree.
C. and concentrated hydrochloric acid 32% (1.2 mL) was added until
pH .about.1.3 was reached. Water (12 mL) was added. The resulting
clear solution was concentrated to half its volume and was allowed
to cool naturally to room temperature. The solid was isolated by
filtration, washed with water and dried overnight at 50-60.degree.
C., yielding 3.18 g (94.65%) sertraline hydrochloride Form V.
Example 8
Preparation of Sertraline Hydrochloride Form V
[0098] Sertraline base (3.7 g) was dissolved in 18.5 mL absolute
ethanol and the solution was heated to 60.degree. C. Hydrogen
chloride gas was bubbled through the ethanol solution until pH
.about.0.5 was reached. The mixture was cooled to room temperature
and the stirring was continued for 2 hours. The solid obtained
after filtration, washing with ethanol and drying at 50.degree. C.
was sertraline hydrochloride Form V (3.16 g, yield 76%).
Example 9
Preparation of Sertraline Hydrochloride Form V
[0099] Sertraline free base was dissolved in ethanol absolute and
the solution was acidified with hydrogen chloride gas to about pH
3. Precipitation occurs and the slurry was stirred at room
temperature for 2 hours. The resulting solid was filtered, washed
with ethanol and dried to yield sertraline hydrochloride Form
V.
Example 10
Preparation of Sertraline Hydrochloride Form V
[0100] Sertraline free base (13.3 g) was dissolved in absolute
ethanol (60 mL) and was added dropwise over one hour to ethanol (20
mL) containing hydrogen chloride gas (17.5 g) at 35.degree. C.
After 2 hours, the solid was filtrated, washed with ethanol and
dried at about 80.degree. C. to yield sertraline hydrochloride Form
V(12.9 gr., yield 87%).
Example 11
Preparation of Sertraline Hydrochloride Form V
[0101] Anhydrous sertraline hydrochloride (2 g) was stirred with 14
mL absolute ethanol and heated to reflux to obtain a clear
solution. The solution was seeded with sertraline hydrochloride
Form V and cooled naturally to room temperature. Massive
precipitation was observed at about 50.degree. C. The slurry was
stirred at room temperature during 2 hours. The solid was filtered,
washed with ethanol (3 mL) and dried overnight at 50-60.degree. C.
yielding 1.71 g (85.5%) of sertraline hydrochloride Form V.
Example 12
Preparation of Sertraline Hydrochloride Form V
[0102] Sertraline hydrochloride ethanolate (Form VI) (40 g) in 400
mL water was heated to 80.degree. C. and complete dissolution was
obtained The pH was adjusted to approximately one with hydrochloric
acid and the solution was naturally cooled to room temperature and
stirred for 2 hours. The solid was filtered and dried at 50.degree.
C. for approximately 16 hours, yielding sertraline hydrochloride
Form V.
Example 13
Preparation of Sertraline Hydrochloride Form V
[0103] Sertraline hydrochloride ethanolate (Form VI) (2 g) was
mechanically stirred with ethanol (0.5 mL) at room temperature for
40 hours. The resulting solid was sertraline hydrochloride Form
V.
[0104] Table 1 sets forth a summary of additional experiments
conducted generally following procedures described above.
1TABLE 1 PREPARATION OF SERTRALINE HCL - FORM V Exp't Method of
Crystallization XRD Yield (%) SERTRALINE BASE AS STARTING MATERIAL
A Methanol/HCl gas V 78.7 B Methanol/HCl gas V 69 C Methanol/HCl
aqueous V 87.8 D Ethanol/HCl gas V 80.9 E Water/HCl aqueous V 96 F
Hexane/Isopropropyl alcohol/HCl gas V 89.9 G Methanol/HCl
aqueous/water V 89 H Isopropyl alcohol/HCl aqueous/water V 78 I
Ethanol/HCl aqueous/evaporation of ethanol V 96.1 J Ethyl
acetate/HCl aqueous/water/evaporation of V 96.1 ethyl acetate K
Ethanol/isopropyl alcohol/HCl gas V 81.8 L Methanol/isopropyl
alcohol/HCl gas V 82.4 SERTRALINE HCl AS STARTING MATERIAL M
Methanol (Form I and amorphous) V 60 N Ethanol (Form V) V 85.5 O
Isopropyl alcohol/water (Form V) V 28 PXRD = powder x-ray
diffraction.
Example 14
Preparation of Sertraline Hydrochloride Form VII
[0105] 1.003 g Sertraline hydrochloride Form V 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 15
Preparation of Sertraline Hydrochloride Form VII from Sertraline
Hydrochloride Form VI
[0106] 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.
Example 16
Preparation of Sertraline Hydrochloride Forms VIII and IX
[0107] 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 (see FIG.
7). Drying for 24 hours at .about.50.degree. C. yielded 2.32 g
(76.8%) of sertraline hydrochloride Form IX, characterized by
powder x-ray diffraction, infra-red absorption, differential
scanning calorimetry, and thermal gravimetric analysis as set forth
above and depicted in FIGS. 8, 10, and 12.
Example 17
Preparation of Sertraline Hydrochloride Form VIII
[0108] 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 18
Preparation of Sertraline Hydrochloride Form VIII from Sertraline
Hydrochloride Form II
[0109] Sertraline hydrochloride Form II (0.4 g) and water (8 mL)
were stirred at room temperature over night. The solid was
filtrated to yield sertraline hydrochloride hydrate Form VIII.
Example 19
Preparation of Sertraline Hydrochloride Form H from Form VI
[0110] 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 20
Preparation of Sertraline Hydrochloride Form II From Form VI
[0111] 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 21
Preparation of Polymorph H by Granulation of V
[0112] Sertraline hydrochloride Form V (2 g) and absolute ethanol
(0.5 mL) were stirred in rotavapor at room temperature for 2 days.
At the end of two days, the material contained sertraline
hydrochloride Form II.
Example 22
Preparation of of Polymorph H by Drying of the Sertraline
Hydrochloride Form VI
[0113] 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 23
Preparation of Sertraline Hydrochloride Form H
[0114] 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 over
night at room temperature. The resulting solid was filtrated,
washed with acetone and dried to yield sertraline hydrochloride
Form II (2.61 gr., yield 77.6%).
Example 24
Preparation of Sertraline Hydrochloride Form II
[0115] Sertraline hydrochloride Form V (10 gr.) was suspended in
dimethylformamide (DMF) (30 mL). The 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 gr., yield 66%).
Example 25
Preparation of Sertraline Hydrochloride Form X
[0116] In a 0.1 liter three-necked bottom round flask equipped with
a mechanical stirrer, a condenser and a thermometer, 30 mL benzyl
alcohol is added to 10 g sertraline hydrochloride. The suspension
is heated to 100.degree. C. when a clear solution is obtained. The
solution is cooled 2 hours to 25.degree. C. and the precipitate is
filtered and washed with benzyl alcohol. After drying under vacuum
at 80.degree. C. for 24 hours, 6.2 g of sertraline hydrochloride
polymorph X is obtained (yield 62%). The sertraline hydrochloride
Form X was characterized by powder x-ray diffraction and infrared
absorption analysis as set forth above and in FIG. 14 and FIG.
15.
Example 26
Preparation of Sertraline Hydrochloride Ethanolate Form VI by
Reslurry of Form I
[0117] 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 27
Preparation of Sertraline Hydrochloride Ethanolate Form VI--by
Reslurry of Form II
[0118] Sertraline hydrochloride Form II (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 28
Preparation of Sertraline Hydrochloride Ethanolate--Form VI--by
Reslurry of Form V
[0119] Sertraline hydrochloride Form V (1 gr.) and ethanol absolute
(20 mL.) were stirred at room temperature for 24 hrs. Filtration of
the mixture yielded sertraline hydrochloride ethanolate Form
VI.
Example 29
Preparation of Amorphous Sertraline Hydrochloride
[0120] Sertraline free base (10 g) was dissolved in ethyl acetate
(690 mL). At room temperature, ether (690 mL) was added to the
sertraline ethyl acetate solution and the solution was acidified
with HCl gas to about pH 0.5. The resulting gelatinous suspension
was stirred at room temperature over night. Filtration and air
drying of the suspension yielded amorphous sertraline hydrochloride
(9.39 gr., yield 83.8%).
Example 30
Preparation of Sertraline Hydrochloride Form III from Form V
[0121] Sertraline hydrochloride Form V was heated at 150.degree. C.
in a reactor under mechanical stirring for 24 hrs. The resulting
material obtained was sertraline hydrochloride Form III.
Example 31
Preparation of Sertraline Hydrochloride from III from Form VI
[0122] Sertraline hydrochloride form VI was heated to 180.degree.
C. for 24 hours. The dried material is Sertraline hydrochloride
Form III.
Example 32
Preparation of Sertraline Hydrochloride Form III from Form V
[0123] Sertraline hydrochloride Form V was heated at a temperature
.gtoreq.180.degree. C. for 24 hours. The resulting material was
Sertraline hydrochloride Form III.
Example 33
Preparation of Amorphous Sertraline Hydrochloride
[0124] Sertraline hydrochloride Form V (10 g) was dissolved in
water (2L) and this solution was dried by the spray dryer
technique. The material obtained in this way is Sertraline
hydrochloride amorphous.
Example 34
Preparation of Amorphous Sertraline Hydrochloride by
Sublimation
[0125] Sertraline hydrochloride Form I was sublimated at
190-200.degree. C., at a vacuum of 30-0.1 mm Hg, using a
laboratory-type sublimator. The resulting material was amorphous
sertraline hydrochloride.
[0126] A similar procedure starting from Form V also gave amorphous
sertraline hydrochloride.
Example 35
Preparation of Sertraline Hydrochloride Form V from Amorphous
Sertraline
[0127] Sertraline hydrochloride amorphous was heated to 80.degree.
C. for 24 hours. The resulting product was sertraline hydrochloride
Form V.
Example 36
Preparation of Sertraline Hydrochloride Amorphous by Precipitation
from Toluene
[0128] Sertraline base (5.8 gr.) was dissolved in toluene (200 mL).
HCl gas was bubbled ( about pH 1.5) through the solution. A gel is
formed. Filtration and drying at 50.degree. C. for 16 hours gives
amorphous sertraline hydrochloride (6.61 gr.).
[0129] It should be understood that some modification, alteration
and substitution is anticipated and expected from those skilled in
the art without departing from the teachings of the invention.
Accordingly, it is appropriate that the following claims be
construed broadly and in a manner consistent with the scope and
spirit of the invention.
* * * * *