Title: Polymorphic forms of sertraline hydrochloride
Abstract: A crystalline form of sertraline hydrochloride was found, referred to hereinafter as polymorphic form CSC2 having a dissolution rate which surprisingly will increase rate of absorption of a drug.Furthermore, different crystalline forms of sertraline hydrochloride alcohol solvates, crystalline forms of sertraline hydrochloride hydrates, referred to hereinafter as polymorphic form CSC1, a process for the preparation of the amorphous form of sertraline hydrochloride, and different processes for the preparation of polymorphic forms I, II, V, and T1 are disclosed.
Patent Number: 6,939,992 Issued on 09/06/2005 to Van Der Schaaf, et al.
| Inventors:
|
Van Der Schaaf; Paul Adriaan (Allschwil, CH);
Schwarzenbach; Franz (Frenkendorf, CH);
Kirner; Hans-Jörg (Pratteln, CH);
Szelagiewicz; Martin (Münchstein, CH);
Marcolli; Claudia (Zürich, CH);
Burkhard; Andreas (Basel, CH)
|
| Assignee:
|
Ciba Specialty Chemicals Corporation (Tarrytown, NY)
|
| Appl. No.:
|
736195 |
| Filed:
|
December 15, 2003 |
Foreign Application Priority Data
| Current U.S. Class: |
564/308; 564/428 |
| Intern'l Class: |
C07C 211/00 |
| Field of Search: |
564/308,428
|
References Cited [Referenced By]
U.S. Patent Documents
| 4536518 | Aug., 1985 | Welch, Jr. et al.
| |
| 5082970 | Jan., 1992 | Braish.
| |
| 5248699 | Sep., 1993 | Sysko et al.
| |
| 5463126 | Oct., 1995 | Williams.
| |
| 5734083 | Mar., 1998 | Wilson et al.
| |
| 6495721 | Dec., 2002 | Schwartz et al.
| |
| Foreign Patent Documents |
| 0928784 | Jul., 1999 | EP.
| |
| 2000-26378 | Jan., 2000 | JP.
| |
| 98/27050 | Jun., 1998 | WO.
| |
| 99/47486 | Sep., 1999 | WO.
| |
| 00/32551 | Jun., 2000 | WO.
| |
Other References
J. B. Conant et al., Organic Syntheses, CV 1, 345.
L. G. Wade, Organic Chemistry, 2nd Ed., pp. 998-1001, (1991).
|
Primary Examiner: Barts; Samuel
Attorney, Agent or Firm: Mansfield; Kevin T.
Parent Case Text
This is a continuation of application Ser. No. 10/111,947, filed on Apr. 26,
2002 now U.S. Pat. No. 6,872,853, which is a 371 of PCT/EP 00/10416 filed on Oct.
23, 2000.
Claims
1. A process for the preparation of sertraline hydrochloride polymorphic form
II, wherein a solution of sertraline free amine is seeded with some crystals of
polymorphic form II and hydrogen chloride is added.
2. A process according to claim 1 wherein the solution of sertraline free amine
is seeded with some crystals of polymorphic form II and subsequently hydrogen chloride
is added.
3. A process according to claim 1 wherein hydrogen chloride is added to the solution
of sertraline free amine and subsequently the solution is seeded with some crystals
of polymorphic form II.
4. A process according to claim 1 wherein hydrogen chloride is added as a solution.
5. A process according to claim 1, wherein a solution of sertraline free amine
in a ketone is used.
6. A process according to claim 5, wherein the ketone is of formula R
1—CO—R
2,
where R
1 and R
2 independently are C
1-C
4alkyl.
7. A process according to claim 1, wherein a solution of sertraline free amine
in acetone, methyl ethyl ketone or methyl isobutyl ketone is used.
8. A process according to claim 4, wherein hydrogen chloride is added as an aqueous solution.
9. A process according to claim 1, wherein the amount of seeding crystals used
is 0.1 to 10 mol-%, based on the molar amount of sertraline.
Description
The present invention relates to crystalline polymorphic forms and the amorphous
form of (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine
hydrochloride, i.e. sertraline hydrochloride, to methods for preparing them, and
methods for preparing known polymorphic forms of sertraline hydrochloride.
Sertraline hydrochloride is useful as an antidepressant and anorectic
agent, and is also useful in the treatment of chemical dependencies, anxiety-related
disorders and premature ejaculation, and is described in U.S. Pat. No. 4,536,518
(Pfizer Inc.).
Sertraline hydrochloride can exist in different crystalline forms, polymorphic
forms, which differ from each other in their stability, physical properties, spectral
data and methods of preparation.
Sertraline has the following structural chemical formula:
##STR1##
U.S. Pat. No. 4,536,518 (Pfizer Inc.) discloses the synthesis of sertraline
hydrochloride. The amine is dissolved in a mixture of diethyl ether and ethyl acetate
and reacted with hydrogen chloride gas. The reference states that the compounds
of this invention may exist in different polymorphic forms, i.e. different crystalline
forms. The reference does not refer to specific polymorphic crystalline forms of
sertraline hydrochloride.
U.S. Pat. No. 5,248,699 (Pfizer Inc.) discloses 5 polymorphic forms of sertraline
hydrochloride (I, II, III, IV, and V) as well as methods for preparing them. The
reference further discloses that 'the synthetic procedure described and exemplified
in U.S. Pat. No. 4,536,518 produces the sertraline hydrochloride polymorph designated
herein as Form II'.
U.S. Pat. No. 5,734,083 (Torcan Chemical Ltd.) discloses a further polymorphic
form of sertraline hydrochloride (=T1), together with the process of preparation.
Although it is disclosed in U.S. Pat. No. 5,248,699 (Pfizer Inc.) that polymorphic
form I exhibits the greatest stability of the crystalline forms of sertraline hydrochloride,
the solubility of this form may be insufficient for successful application. For
example, the rate of absorption of a drug is dependent upon the dissolution rate.
The dissolution rate and the rate of absorption will either increase or decrease
depending upon the polymorph present. The most stable polymorph will have the lowest
solubility and in many cases the slowest dissolution rate. Other less stable polymorphs
will usually have higher dissolution rates. [Stephen R. Byrn in "Solid-State Chemistry
of Drugs", Academic Press, New York, 1982].
A crystalline form of sertraline hydrochloride was found, referred to hereinafter
as poly-morphic form CSC2 having a high solubility in combination with a good thermal stability.
Furthermore, the present invention refers to different crystalline forms
of sertraline hydrochloride alcohol solvates, crystalline forms of sertraline hydrochloride
hydrates, referred to hereinafter as polymorphic form CSC1, a process for the preparation
of the amorphous form of sertraline hydrochloride, and different processes for
the preparation of polymorphic forms I, II, V, and T1.
General Definitions
Sertraline Hydrochloride Alcohol Solvates
Substances formed by combination of the compound sertraline hydrochloride
with an alcohol of the general formula R—OH, wherein R is an organic group.
These substances have the general formula (C
17H
17Cl
2N.HCl)(ROH)
x
wherein X is between 0.5 and 2.
Sertraline Hydrochloride Hydrates
Substances formed by combination of the compound sertraline hydrochloride
with water. These substances have the general formula (C
17H
17Cl
2N.HCl)(H
2O)
x
wherein X is between 0 and 4 (in which X=0 stands for the desolvated hydrate).
The crystalline polymorph CSC2 exhibits a characteristic X-ray powder diffraction
pattern with characteristic peaks at diffraction angles 2 θ in degrees of
12.2, 15.7, 17.2, 18.3, 22.8, 23.0, 24.4 and 30.7 as depicted in FIG.
19.
Here and in the following the spectra are measured with a diffractometer using
copper radiation.
A discussion of the theory of X-ray powder diffraction patterns can be found
in
"X-ray diffraction procedures" by H. P. Klug and L. E. Alexander, J. Wiley, New
York (1974).
The crystalline polymorph CSC2 upon heating is transformed into form V at temperatures
of about >120° C., whereupon a second transformation takes place into
form III at temperatures of about >160° C. (experiment performed in a
DSC apparatus with heating rate of 20° C./minute).
The crystalline polymorph CSC2 is further characterized by the Raman absorption
spectrum having the following characteristic absorption bands, expressed in wave
number (cm
-1): 3052 (s), 2976 (s), 2963 (s), 2943 (s), 2885 (m), 2862
(m), 1590 (s), 1049 (m), 744 (m), 676 (s), 490 (m), 477 (m), 364 (m), 349 (m),
237 (m), 203 (m), 181 (s); [(m)=medium intensity; (s)=strong intensity] as depicted
in FIG.
20.
The present invention also relates to crystalline forms of sertraline hydrochloride
hydrates, referred to hereinafter as form CSC1. The crystalline form of sertraline
hydrochloride hydrate changes with the amount of water present in the crystal as
hydrate. With an X-ray diffractometer in which the humidity (RH) of the atmosphere
can be controlled during the measurements at least 5 distinct different X-ray powder
diffraction patterns with characteristic peaks expressed in 2θ can be distinguished
(FIG.
13):
CSC1 90% RH (wet): 4.0; 12.0; 19.7; 20.0; 22.7; 24.0; 26.6; 30.7; 34.7
CSC1 90% RH: 4.0; 4.2; 16.2; 17.2; 19.9; 20.7; 21.2; 22.7; 24.1; 25.2; 27.3;
29.9; 30.7; 31.3; 31.8
CSC1 50% RH: 4.7; 9.3; 13.9; 15.1; 16.0; 16.4; 16.8; 17.5; 17.9; 19.3; 20.5;
21.1; 21.5; 22.2; 23.0; 23.7; 24.1; 24.8; 25.8; 31.2; 32.2; 33.5
CSC1 20% RH: 4.9; 9.7; 12.1; 14.1; 15.4; 16.5; 17.0; 18.1; 19.4; 21.9; 22.3;
24.8; 25.9; 31.7
CSC1 0% RH: 5.0; 14.0; 15.6; 16.5; 18.1; 19.5; 22.1; 22.9; 25.1; 25.9; 30.3; 33.5.
The present invention also refers to different crystalline forms of sertraline
hydrochloride alcohol solvates, for example sertraline hydrochloride ethanol solvate,
sertraline hydrochloride isopropanol solvate and sertraline hydrochloride methanol solvate.
The crystalline form of sertraline hydrochloride ethanol solvate exhibits a characteristic
X-ray powder diffraction pattern with characteristic peaks expressed in 2 θ
at 12.7, 15.1, 15.8, 16.0, 17.0, 17.7, 17.9, 20.1, 20.5, 20.7, 21.0, 21.3, 21.9,
22.8, 23.1, 23.9, 24.4, 25.0, 25.4, 26.0, 26.4, 27.0, 28.6, 29.1, 31.3, 31.7, 32.0
and 32.9 as depicted in FIG.
22.
The crystalline form of sertraline hydrochloride ethanol solvate is further characterized
by the Raman absorption spectrum having the following characteristic absorption
bands, expressed in wave number (cm
-1): 3060 (s), 2974 (s), 2945 (s),
2878 (s), 1590 (s), 1046 (s), 740 (s), 672 (s), 504 (m), 475 (m), 462 (m), 377
(m), 361 (m), 232 (s), 211 (s), 197 (s), 182 (s), 144 (s), 104 (s) [(m)=medium
intensity; (s)=strong intensity] as depicted in FIG.
23.
The crystalline form of sertraline hydrochloride isopropanol solvate exhibits
a characteristic X-ray powder diffraction pattern with characteristic peaks expressed
in 2 θ at 6.4, 10.7, 12.9, 14.2, 15.0, 15.2, 16.3, 17.9, 19.1, 19.9, 20.4,
22.4, 22.9, 23.9, 24.5, 25.3, 25.5, 25.9, 27.8, 28.8, 29.6, 30.2, 33.0 and 34.2
as depicted in FIG.
24.
The crystalline form of sertraline hydrochloride isopropanol solvate is further
characterized by the Raman absorption spectrum having the following characteristic
absorption bands, expressed in wave number (cm
-1): 3057 (s), 2975 (s),
2939 (s), 2883 (m), 2865 (m), 1591 (s), 1043 (s), 744 (m), 676 (s), 505 (m), 491
(m), 477 (m), 461 (m), 355 (m), 229 (m), 196 (s), 182 (s), 148 (s), 125 (s) [(m)=medium
intensity; (s)=strong intensity] as depicted in FIG.
25.
The crystalline form of sertraline hydrochloride methanol solvate exhibits a
characteristic X-ray powder diffraction pattern with characteristic peaks expressed
in 2 θ at 7.4, 9.7, 12.0, 12.4, 12.8, 14.3, 16.0, 16.2, 17.9, 20.3, 20.7,
21.0, 22.1, 23.1, 23.6, 24.2, 24.4, 24.9, 25.7, 26.6, 27.1, 29.5, 30.6, 31.4, 31.9,
32.5, 33.2, 34.1, 35.1, 36.5, 38.0 as depicted in FIG.
28.
The crystalline form of sertraline hydrochloride methanol solvate is further
characterized by the Raman absorption spectrum having the following characteristic
absorption bands, expressed in wave number (cm
-1): 3061 (s), 2975 (s),
2959 (s), 2941 (s), 2876 (s), 1591 (s), 1046 (s), 740 (s), 673 (s), 505 (m), 477
(m), 462 (m), 378 (m), 361 (m), 234 (m), 213 (s), 197 (s), 179 (s), 129 (s), [(m)=medium
intensity; (s)=strong intensity] as depicted in FIG.
21.
The present invention also refers to the amorphous form sertraline hydrochloride.
This amorphous form of sertraline hydrochloride gives an X-ray powder diffraction
pattern with a broad bump with a maximum in 2 θ between 25 and 30, and some
broad peaks at 16 and 23 as depicted in FIG.
26.
The amorphous form of sertraline hydrochloride is further characterized by the
Raman absorption spectrum having the following characteristic absorption bands,
expressed in wave number (cm
-1): 3054 (s), 2970 (s), 2933 (s), 2872
(s), 1590 (s), 1043 (s), 745 (m), 676 (s), 491 (m), 478 (m), 359 (m), 236 (m),
206 (s), 181 (s), 130 (s), [(m)=medium intensity; (s)=strong intensity], as depicted
in FIG.
27.
The sertraline hydrochloride polymorphic form CSC2 may be formed by the addition
of a solution of sertraline free amine in a solvent, preferably ethanol to a solution
of hydrogen chloride in water, or by addition of an excess of a solution of hydrogen
chloride in water to a solution of sertraline free amine. Preferably, the reaction
is performed at temperatures from about 5 to 35° C., most preferably at room temperature.
The process for the preparation of sertraline hydrochloride polymorphic form
CSC2 is a further object of the present invention.
The hydrochloride alcohol solvates may be formed by crystallization or recrystallization
of sertraline hydrochloride from the corresponding alcohol, preferably selected
from ethanol, isopropanol and methanol or by prolonged stirring of a suspension
of sertraline hydrochloride in the corresponding alcohol at temperatures from about
-20 to 40° C., most preferably at room temperature.
The process for the preparation of the hydrochloride alcohol solvates is a further
object of the present invention.
The sertraline hydrochloride polymorphic form CSC1 may be formed when the reaction
of sertraline free amine with hydrogen chloride is carried out in the presence
of water at temperatures of about 5 to 40° C., most preferably at room temperature,
or by the crystallization or recrystallization of sertraline hydrochloride from
water at temperatures between about 5 and 40° C.
The sertraline hydrochloride polymorph form CSC1 may also be formed by recrystallization
of any polymorphic form of sertraline hydrochloride from water.
The sertraline hydrochloride polymorph form CSC1 may also be formed upon stirring
a suspension of any polymorphic form of sertraline hydrochloride, except for polymorphic
form I in aqueous solutions of hydrogen chloride at a pH between 0 and 2, most
preferably at pH about 1, at temperatures between 5 and 40° C.
The process for the preparation of the sertraline hydrochloride polymorphic form
CSC1 is a further object of the present invention.
A still further object of the present invention is a process for the preparation
of amorphous sertraline hydrochloride. Amorphous sertraline hydrochloride may be
formed after addition of hydrogen chloride gas to sertraline free amine in a solvent
like diethyl ether at temperatures between about 0 and 30°, most preferably
at temperatures between 0 and 10° C.
A still further object of the present invention is a process for th preparation
of polymorphic form T1. Sertraline hydrochloride polymorphic form T1 may be formed
when the reaction of sertraline free amine with hydrogen chloride is carried out
in a mixture of diethyl ether and ethyl acetate, or in dibutyl ether at temperatures
between about 0 and 30° C.
A still further object of the present invention is a process for the preparation
of polymorphic form I.
Sertraline hydrochloride polymorphic form I may be formed from a non-alcoholic
suspension of amorphous sertraline hydrochloride, or polymorphic form CSC1, or
polymorphic form CSC2, or a sertraline hydrochloride alcohol solvate upon prolonged
agitation, or with faster reaction times after seeding with some crystals of sertraline
hydrochloride polymorphic form I.
A still further object of the present invention is a process for the preparation
of polymorphic form II.
Sertraline hydrochloride polymorphic form II may be formed from a solution
of sertraline free amine with some seeding crystals of form II before or after
the addition of hydrogen chloride, e.g. as a solution of hydrogen chloride; or
from a stirred suspension of sertraline hydrochloride polymorphic form V with some
seeding crystals of sertraline hydrochloride polymorphic form II; or by drying
a sertraline hydrochloride alcohol solvate at temperatures from about 0 to 30°
C. in high vacuum (<1 mbar); or from stirred suspensions of sertraline hydrochloride
polymorphic form CSC1, CSC2 or T1 with some seeding crystals of sertraline hydrochloride
polymorphic form II.
Furthermore, Sertraline hydrochloride polymorphic form II may be formed
according to a process, wherein a solution of sertraline free amine is seeded with
some crystals of polymorphic form II and hydrogen chloride is added.
Preferably a solution of sertraline free amine in a ketone is used. Preferred
are ketones of formula R
1—CO—R
2, wherein R
1
and R
2 are C
1-C
4alkyl. Examples for R
1 and
R
2 are methyl, ethyl, n- or i-propyl and n-, s-, i- or t-butyl. R
1
is preferably methyl. R
2 is preferably methyl, ethyl or i-butyl.
Examples of ketones are acetone, methyl ethyl ketone or methyl isobutyl ketone.
The hydrogen chloride used can be, for example, a solution in an organic solvent,
like a ketone as given above, or preferably an aqueous solution.
It is preferred to add the seeding crystals of polymorphic form II before addition
of the solution of hydrogen chloride. Typical amounts of seeding crystals are 0.1
to 10 mol-%, based on the molar amount of sertraline.
A still further object of the present invention is a process for the preparation
of polymorphic form V.
Sertraline hydrochloride polymorphic form V may be formed by drying a
sertraline hydrochloride alcohol solvate at temperatures of about 50° to about
100° C. in medium vacuum (>10 mbar) or by heating sertraline hydrochloride
polymorphic form CSC2 at temperatures from about 80° to about 150° C.
This invention also relates to a pharmaceutical composition comprising an amount
of a polymorphic form CSC2, CSC1, the amorphous form or alcohol solvates of sertraline
hydrochloride with any of the above characteristics effective in treating depressions,
anxiety-related disorders, obesity, chemical dependencies, or addictions or premature
ejaculations in a human, and a pharmaceutically acceptable carrier.
The polymorphic forms, hydrates, the amorphous form and alcohol solvates may
be used as single components or mixtures.
The following examples will illustrate, but do not limit the scope of the present invention.
EXAMPLE 1
Preparation of Polymorph Form CSC2
A solution of 21 g sertraline free amine in 75 g ethanol is added dropwise over
a period of 30 min to a stirred, aqueous solution of HCl (8 g 37% HCl/H
2O
in 200 ml water). At the end of the reaction the reaction mixture has a pH=3. Stirring
is stopped and the crystals are allowed to separate from the solution overnight.
The crystals are filtered of and washed with water (3×50 ml) and dried in
vacuum (100 mbar) at 25° C. for 24 h.
The product, a white crystalline solid, is obtained in 92% yield (see FIGS. 19
and 20).
EXAMPLE 2
Preparation of the Sertraline Hydrochloride Ethanol Solvate
0.5 g sertraline hydrochloride is dissolved in 5 ml ethanol of 85° C. The
resulting clear solution is placed in an ice/water bath and a white crystalline
product is formed. These crystals are filtered and washed with a small amount of
cold ethanol. The resulting product is dried at ambient temperature in air.
Sertraline hydrochloride ethanol solvate is obtained in 92% isolated yield
(see FIGS. 22 and 23).
The formation of this ethanol solvate is independent from the polymorphic form
of the starting material.
EXAMPLE 3
Preparation of the Sertraline Hydrochloride Isopropanol Solvate
0.5 g sertraline hydrochloride is dissolved in 10 ml isopropanol of 90°
C. The resulting clear solution is cooled to 0° C. with stirring and a white
crystalline product is formed. These crystals are filtered and washed with some
cold isopropanol. The product is dried at ambient temperature in air.
Sertraline hydrochloride isopropanol solvate is obtained in 90% yield
(see FIGS. 24 and 25).
The formation of this isopropanol solvate is independent from the polymorphic
form of the starting material.
EXAMPLE 4
Preparation of the Sertraline Hydrochloride Methanol Solvate
A suspension of 0.4 g sertraline hydrochloride in 3 ml methanol is stirred for
30 min at room temperature. The white precipitate is filtered and dried in air
at room temperature.
Sertraline hydrochloride methanol solvate is obtained in 89% yield (see
FIGS. 21 and 28).
The formation of this methanol solvate is independent from the polymorphic form
of the starting material.
EXAMPLE 5
Preparation of Polymorphic Form CSC1
0.5 ml of a 4 molar HCl solution in water is added dropwise to a suspension of
610 mg sertraline free amine in 7 ml water. The resulting white suspension is stirred
at room temperature for 3 h and the pH changes from ca. 1 to ca. 6. The product
is filtered and washed with water (2×3 ml) and subsequently dried in vacuum.
The product is obtained in 86% isolated yield. The X-ray and Raman spectra obtained
depend on the dryness of the compound and also depend on the relative air humidity
(RH) when recorded with conventional instruments (typical examples are depicted
in FIGS. 9 to 12 and 14 to 18). When a wet sample is placed
in a X-ray diffractometer in which the relative humidity of the atmosphere can
be controlled the change in the X-ray spectra can be recorded (see FIG. 13).
EXAMPLE 6
Preparation of Amorphous Sertraline Hydrochloride
A solution of 2.85 g sertraline free amine (obtained after treating a solution
of sertraline mandelate salt in ethyl acetate with a 2 molar solution of NaOH in
water, followed by a standard organic work-up procedure) in 300 ml diethyl ether
is cooled to 0° C. At this temperature, gaseous HCl is introduced in the reaction
mixture for 30 minutes. The reaction mixture, a white suspension, is warmed to
room temperature and stirred overnight under an argon atmosphere. The white suspension
is filtered and the white product washed with diethyl ether (3×50 ml). The
resulting white solid is dried at room temperature by blowing gently a stream of
air over the product.
An X-ray powder diffraction pattern shows no significant signals indicating the
amorphous form of the product.
Surprisingly, even a sample taken after 12 months shows only some broad
signals at 2θ=16 and 23° indicating the thermal stability of the amorphous
form of sertraline hydrochloride (see FIGS. 26 and 27).
EXAMPLE 7
Preparation of Polymorphic Form T1
5.4 g of a HCl solution in acetone (prepared by mixing 9.47 g of an aqueous HCl
solution (37 wt %) with 138 g acetone) is added dropwise to a solution of 1 g of
sertraline free amine in 16 ml acetone. The white precipitate is filtered after
stirring for 3 h and dried in vacuum (100 mbar) at ambient temperature.
The product is obtained in 82% yield.
Raman and X-ray powder diffraction studies show the product to be polymorphic
form T1 (see FIGS. 7 and 8).
EXAMPLE 8
Preparation of Polymorph Form I from Sertraline Hydrochloride Isopropanolate
Heating sertraline hydrochloride isopropanol solvate at 70° C. in high
vacuum (0.1 mbar) for 20 h results in the quantitative formation of sertraline
hydrochloride polymorphic form I.
Raman and X-ray powder diffraction studies show the product to be polymorphic
form I (see FIGS. 24 and 25).
EXAMPLE 9
Preparation of Polymorphic Form II
24 g sertraline free amine are dissolved in 280 ml acetone. To this solution
1.2
g sertraline hydrochloride polymorphic form II are added as seeding crystals. To
this mixture are added dropwise 53.7 g of a solution of HCl in acetone (5.33 wt
%) at room temperature. The resulting white suspension is stirred for an additional
2 h, filtered, and the resulting white product washed with acetone (2×20 ml).
The product is dried in vacuum (0.1 mbar) for 16 h.
The product is obtained in 91% isolated yield.
Raman and X-ray powder diffraction studies show the product to be polymorphic
form II (see FIGS. 3 and 4).
EXAMPLE 10
Preparation of Polymorphic Form II
50 g of sertraline free amine are dissolved in 500 ml acetone. This solution
is
clarified by filtration, and the clear solution is well stirred and heated to reflux
temperature. At this temperature 2.5 g (5 mol %) of sertraline hydrochloride Form
II are added after which directly the addition of the aqueous hydrogenchloride
solution (32%) is started until pH<5. The resulting white suspension is cooled
to -5° C. and sertraline hydrochloride is isolated by filtration and dried
in vacuum. The sertraline is obtained as Form II.
EXAMPLE 11
Preparation of Polymorphic Form II
10 g sertraline free amine are dissolved in 85 ml methyl ethyl ketone. This solution
is clarified by filtration, and the clear solution is well stirred and heated to
60° C. At this temperature 0.5 g (5 mol %) of sertraline hydrochloride Form
II are added after which directly the addition of the aqueous hydrogenchloride
solution (37%) is started until pH<5. The resulting white suspension is cooled
to -5° C. and sertraline hydrochloride is isolated by filtration and dried
in vacuum. The sertraline is obtained as Form II.
EXAMPLE 12
Preparation of Polymorphic Form II
40 g sertraline free amine are dissolved in 360 ml methyl isobutyl ketone. This
solution is clarified by filtration, and the clear solution is well stirred and
heated to 60° C. At this temperature 2 g (5 mol %) of sertraline hydrochloride
Form II are added after which directly the addition of the aqueous hydrogenchloride
solution (37%) is started until pH<5. The resulting white suspension is cooled
to 20° C. and sertraline hydrochloride is isolated by filtration and dried
in vacuum. The sertraline is obtained as Form II.
EXAMPLE 13
Preparation of Polymorphic Form V
1 g of sertraline hydrochloride ethanol solvate is dried in vacuum (ca. 100 mbar)
at 70° C. for 12 h.
Raman and X-ray powder diffraction studies show the product to be polymorphic
form V (see FIGS. 5 and 6).
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a characteristic X-ray powder diffraction pattern for polymorphic
form I
FIG. 2 is a characteristic Raman spectrum of polymorphic form I
FIG. 3 is a characteristic X-ray powder diffraction pattern for polymorphic
form II
FIG. 4 is a characteristic Raman spectrum of polymorphic form II
FIG. 5 is a characteristic X-ray powder diffraction pattern for polymorphic
form V
FIG. 6 is a characteristic Raman spectrum of polymorphic form V
FIG. 7 is a characteristic X-ray powder diffraction pattern for polymorphic
form T1
FIG. 8 is a characteristic Raman spectrum of polymorphic form T1
FIGS. 9, 10, 11, and 12 are characteristic X-ray powder
diffraction patterns for different hydrates with varying amounts of water bonded
in the crystal lattice, generally designated as polymorphic forms CSC1
FIG. 13 is a plot of X-ray powder diffraction patterns for the hydrates at different
levels of relative humidity
FIGS. 14, 15, 16, 17 and 18 are characteristic
Raman spectra for different hydrates with varying amounts of water bonded in the
crystal lattice, generally designated as polymorphic forms CSC1
FIG. 19 is a characteristic X-ray powder diffraction pattern for polymorphic
form CSC2
FIG. 20 is a characteristic Raman spectrum of polymorphic form CSC2
FIG. 21 is a characteristic Raman spectrum of the methanol solvate
FIG. 22 is a characteristic X-ray powder diffraction pattern for the ethanol solvate
FIG. 23 is a characteristic Raman spectrum of the ethanol solvate
FIG. 24 is a characteristic X-ray powder diffraction pattern for the isopropanol solvate
FIG. 25 is a characteristic Raman spectrum of the isopropanol solvate
FIG. 26 shows the X-ray powder diffraction pattern of a sample of the amorphous
form after 12 months
FIG. 27 shows the Raman spectrum of the amorphous form
FIG. 28 is a characteristic X-ray powder diffraction pattern of the methanol solvate
*
