A NOVEL POLYMORPH OF SERTRALINE HYDROCHLORIDE AND
COMPOSITIONS CONTAINING THEREOF, NOVEL METHODS FOR
PREPARATION OF SERTRALINE HYDROCHLORIDE POLYMORPHS AND
AMORPHOUS FORM
CROSS-REFERENCE TO RELATED APPLICATIONS
This application corresponds to U.S. patent application Serial No. 09/575,634, filed May 22, 2000, and Serial No. 09/586,842, filed June 5,2000. U.S. Serial No. 09/575,634, filed May 22, 2000 claims priority tcrKS. provisional application Serial No. 60/182,159,

filed February 14,2000. U.S. application Serial No. 09/586,842, filed June 5,2000 is a continuation-In-part of U.S. application Serial No. 09/448,985, filed November 24,1999, which claims the benefit of U.S. provisional application No. 60/147,888, filed August 9, 1999. The contents of each of these applications are incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to novel crystalline Form JI its pharmaceutical compositions, and reproducible methods for the preparation of sertraline hydrochloride. crystalline Forms JJ, HI and V through X, as well as the preparation of amorphous form of' sertraline hydrochloride.
BACKGROUND OF THE INVENTION
Sertraline hydrochloride, (1 S-cis) -(3,4 dichlorophenyl)-1,2,3,4-terrahydro-N-methyl-1 -maphrhalenamine hydrochloride, having the formula
(Formula Removed)is approved, under the trademark Zoloft®, by the U.S. Food and Drug Administration, for the treatment of depression, obsessive-compulsive disorder and panic disorder.
U.S. Patent No. 4,536,5 18 ("the '518patent") describes the preparation of sertraline hydrochloride with a melting point of 243-245°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.
According to U.S. Patent No. 5,248,699 ("the '699 patent"), the sertraline hydrochloride produced by the method of the '518 patent has a crystalline form
"Foun II." The '6yy patent discloses four other polymorphs I, HI, .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 n is produced by rapid crystallization of sertraline hydrochloride from an organic solvent, including isopropyl alcohol, ethyl acetate or hexane, and generally describes methods for making sertraline hydrochloride Forms I-V. According to this patent, the preferential' formation of Forms I, n or IV in an acidic solution consisting of isopfopy] alcohol, bexane, acetone, methyl isobutyl ketone, glacial acetic acid or, preferably, ethyl acetate, depends on - the rapidity of crystallisation. 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 °C to about the solvent reflux temperature, preferably from about 40° to 60 °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 is said to produce Form I. Form HI is described as being formed by heating Forms I, II or IV to temperatures above about 1 80° C. Granulating either of Forms H, HI or TV in any of the solvents listed above at a temperature from about 40 °C to 60 °C is said to cause 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 1 80-190°C. However, in our hands attempts to repeat this procedure to obtain Form V have been unsuccessful.
The experimental procedure for the preparation of sertraline hydrochloride described
in the '518 patent, was repeated in the laboratory. According to the '699 patent, the '518 procedure produces sertraline hydrochloride Form II. Four experiments were performed according to the description IB the '518 patent. By following the procedures described in the 1699 patent for preparation of sertraline hydrochloride Form II, we were unable to obtain sertraline hydrochloride Form II. Thus there remains a need for reproducible methods for the preparation of sertraline hydrochloride Form II.
SUMMARY OF THE INVENTION
Je present invention reJates to a process for making sertraline hydrochloride Form II comprising the steps of dissolving sertraline base or sertraline rnandelate in an organic solvent to form a solution; adding hydrogen chloride to the solution; heating the solution to a temperature between about room temperature, and about reflux for a time sufficient to induce the formation of sertraline nydrochloride Form II; and isolating sertraline hydrochloride Form n.
The present invention also relates to a process for making sertraline hydrochloride Form II comprising the steps of dissolving sertraline hydrochloride in dimethylformamide, cyclohexanol, acetone or a rnrxturethereof; heating the solution for a time sufficient to affect transformation to sertraline iydrochloride Form II; and isolating sertraline hydrochloride Form II.
The present invention further relates to a process for making sertraline hydrochloride Form H comprising the steps of granulating sertraline hydrochloride Form V in ethanol or methanol; and stirring the mixture of sertraline hydrochloride Form V and ethanol or methanol for a time sufficient to induce transformation to sertralihe hydrochloride Form II.
The present invention stilrfurfier relates to a process for making a mixture of : sertraline hydrochloride Form II and Form V comprising the steps of heating sertraline hydrochloride ethanolate Form VI at up to 3 atmosphere pressure; and isolating a mixture of sertraline hydrochloride Form n and Form V.
The present invention still further relates to a process for making sertraline faydrodhloride Form n •comprising tire steps of suspending a water or solvent adduct of sertraline bydrochloride in a sol vent selected from the group consisting of acetone, t-butyl-methyl ether, cyclohexane, n-butanol, and ethyl acetate such that a slurry is formed, for a
time sufficient to effect transformation to sertraline hydrochloride Form II; and filtering the slurry to isolate sertraline hydrochloride Form n.
The present invention still further relates to sertraline hydrochloride Form n, characterized by an x-ray powder diffraction pattern comprising peaks at about 5.5, 11.0, 12.5, 132,14.7,16.4,17.3,18.1,19.1, 20.5,21.9,22.8,23.8,245,25.9,27.5, and 28.0 degrees two theta; pharmaceutical compositions for the treatment of depression comprising sertraline hydrochloride Form II together with a pharmaceutically acceptable carrier, and a method for treating depression comprising the step of administering to a subject in need of
icrapcutically effect! ve aiuount of Lbe such a pharmaceutical composition.
The present invention also relates to a process for making sertraline hydrochloride Form V comprising the steps of: dissolving or suspending sertraline hydrochloride in a suitable solvent; removing the solvent; and drying to form sertraline hydrochloride Form V.
The present invention also relates to a process for making sertraline hydrochloride Form V comprising the steps of: dissolving or suspending sertraline base in a solvent; adding hydrogen chloride to the solvent to reduce the pH of the solution or suspension"; arid isolating sertraline hydrochloride Form V from the .solution or suspension.
The present invention also relates to a process for making sertraline bydrochloride Form V comprising the step of drying sertraline hydrochloride Form VII.
The present invention also relates to a process for making sertraline hydrochloride Form V comprising the steps of: dissolving or suspending sertraline hydrochloride in water; adding a sufficient amount of hydrochloric acid or hydrogen chloride to facilitate precipitation of sertraline hydrochloride; removing the water; and isolating sertraline hydrochloride Form V.
The present invention also relates to a process for making sertraline hydrochloride Form VI comprising the steps of: dissolving sertraline base in a solvent; adding hydrochloric acid to the solvent; and isolating sertraline hydrocMoride Form VI without further drying.
The present invention also relates to a process for making sertraline hydrochloride Form ~VT comprising the steps of: dissolving or suspending sertraline hydrochloride in
ethanol or methanol; stirring for a time sufficient to induce the transformation of sertraline hydrochloride to sertraline lydrochloride Form VI; and isolating sertraline hydrochloride Form VI.
The present invention also relates to a process for making sertraline hydrochloride Form VIII comprising the steps of: suspending sertraline base in water; adding hydrogen chloride to the water; and filtrating the precipitate so obtained without further drying.
The present invention also relates to a process for making sertraline hydrochloride Form "VTO comprising the steps of: suspending or dissolving sertraline hydrochloride of water and isopropyl alcohol; and isolating sertraline hydrochloride Form VIII'.
The present invention also relates to a process for making sertraline hydrochloride Form IH comprising the steps of: heating sertraline hydrochloride Form V or Form Vf to a temperature sufficient, and for a time sufficient, to induce the transformation of sertraline hydrochloride Form V or Form VI to sertraline hydrochloride Form III; and isolating .sertraline hydrochloride Form HI.
The present invention also relates to a process for making amorphous sertrallne
hydrochloride comprising the. steps-of: suspending or dissolving sertraline. base in a non-polar organic solvent; adding gaseous hydrochloric acid; and isolating amorphous sertraline hydrochloride.
BRIEF BESdaPITON OF THE DRAWINGS
Figure 1 is a characteristic x-ray powder diffraction spectrum of sertraline hydrochloride prepared by the methods of U.S. Patent No. 4,536,518.
Figure 2 is a characteristic x-ray powder diffraction spectrum of sertraline hydrochloride prepared by the methods of UiS. Patent No. 5,248,699.
Figure 3 is a characteristic x-ray powder diffraction spectrum of sertraline .hy.drochloride Form II prepared by the methods of the present invention.
Figure 4 is a characteristic x-ray powder diffraction spectrum of sertraline hydrochloride Form V.
Figure 5 is a characteristic x-ray powder diffraction spectrum of amorphous sertraline hydrochloride.
Figure 6 Is a characteristic differential scanning calorimetric (DSC) thermogram of sertraline hydrochloride Form V,
Figure 7 is a characteristic infrared (IR) absorption spectrum of sertraline hydrocbloride Form V.
Figure 8 is a characteristic x-ray powder diffraction spectrum of sertraline hydrochloride Form VI.
Figure 9 is a characteristic x-ray powder diffraction spectrum of sertraline hydrochloride Form VIL
hydrochloride Form VIIL
Figure 11 is a characteristic x-ray powder diffraction spectrum of sertraime hydrochloride Form IX.
Figure 12 is a characteristic differential scanning calorimetric (DSC) thermogram of sertraline hydrochloride Form VIII.
Figure 13 is a characteristic differential scanning calorimetric (DSC) thermogram of sertraline hydrochloride Form DC.
Figure 14 is a characteristic infrared (IR) absorption spectrum of sertraline hydrochloride Form VIII.
Figure 15 is a characteristic infrared (IR) absorption spectrum of s'ertraline hydrochloride Form IX.
Figure 16 is a characteristic differential scanning calorimetric (DSC) thermogram of sertraline hydroohloride Form VI.
Figure 17 is a characteristic x-ray powder diffraction spectrum of sertraline Ihydrochloride Form X.
Figure 18 is a characteristic infrared (IR) absorption spectrum of sertraline hydrochloride Form X.
Figure 19 is a characteristic differential scanning calorimetric i(DSC) thermpgram of sertraline hydrochloride Form X.
DETAILED DESCRIPTION OF THE INVENTION Forrnn
The present invention provides new processes for making sertraline hydrochloride
Form II from sertraline base or sertraline mandelate. Sertraline base may be made by
> methods known in the art, including the methods of the '518 patent. Sertraline base is
dissolved in a suitable solvent. Suitable solvents include ethyl acetate, acetone, t-methyl-butyl ether, isopropyl alcohol, n-butanol, t-butanol, iso-butanol, hexane, and cyclohexane, and mixtures thereof. ThepH of the sertraline base solution is lowered by the addition of hydrogen chloride, which may result in a temperature increase. As used herein, "hydrogen chloride" includes both gaseous hydrogen chloride and aqueous hydrogen chloride (i.e. hydrochloric acid). Hydrogen chloride also may be added as a solution with an organic solvent, such as a solution of isopropyl alcohol and hydrogen chloride, n-butanol and hydrogen chloride, acetone and hydrogen chloride, or the like. The solution of sertraline base or sertraline mandelate in'the solvent is heated to a temperature between about room, temperature and the reflux temperature of the solvent and maintained at that temperature for a period of time sufficient to effect the transformation to sertraline hydrochloride Form H." Preferably the soTtin'on Is"heated to a temperature between about 45°C and the reflux temperature of the solvent. Most preferably the solution is heated to at or about the reflux temperature of the solvent. Upon cooling of the mixture, for example to room temperature, sertraline hydrochloride Form II is isolated by filtration.
In a preferred variation of this method, the solution of sertraline base or sertraline mandelate m a solvent is heated to the reflux temperature of the solvent The mixture is refhcced fora time sufficient to effect the transformation to sertraline faydrochlqride Form n. Preferably the mixture is refluxed for about 1 to 4 hours.
Numerous experiments were performed in an attempt to repeat the procedure described in U.S. Patent No. 4,536,518 for preparing Form IT wherein sertraline base was dissolved in ethyl acetate, ether was added arid the solution was acidified with gaseous hydrogen cMoride. The material obtained after filtration and air drying was sertraline •hydrochlorade amorphous, not Form H as was expected. These experiments are set forth in Examples 13-16 below.
The x-ray powder diffraction graphs for the .products of each of these experiments are
equivalent, containing peaks at 11.0,12.0, 15.4,16.2,22.4,22.9 degree two-theta (See
Figure 1 for a representative example). Figure 1 does not contain the typical peaks of
sertralme hydrochloride Form EL, indicating an absence of sertraline hydrochloride Form n
in those samples. Thus, none of these experiments, which follow the procedure described
in the '518 patent for preparation of sertraline hydrochloride Form II, leads to sertraline
hydrochloride Form n.
The '699 patent provides experimental procedures for preparation of sertraline hydrochloride. The '699 patent does not provide experimental procedure for preparation of serlraliue hydrochloride Form II,~rJiit it is mentioned that sertraline hydrochloride Form II
may be prepared by "rapid crystallization" from the same solvents.
The procedure of the '699 patent was repeated in an attempt to prepare sertraline hydrochloride form n from ethyl acetate. In a trial of the methods according to the '699 patent: An aqueous solution of sodium hydroxide, 10.%, was added to a slurry of sertraline mandelate crystals (44.6 g) in ethyl acetate (290 mL), until complete dissolution. The organic phase was separated and the aqueous phase was extracted with.ethyl acetate (280 mL) and combined with the organic phase. The resulting organic solution was washed -with water-(S x 100 mL) then with brine (100TnL)3nd concentfared ori a fotavapor to a volume of 356 mL. The concentrated solution was cooled to 58°C and seeded with sertraline hydrochloride Form n. Concentrated hydrochloric acid (32 %, 8.1 mL) was • added to this solution. The solution was then rapidly cooled to 30°C over 5 minutes. A heavy gel was obtained and the stirring was continued overnight. The .solid was filtrated, washed with ethyl acetate and dried at 50°C. The dried solid, sertraline hydrochloride, was not sertraline hydrochloride Form II, as shown hy *he x-ray diffraction.pattern of Figure 2. By following the procedures described in the '699 patent for preparation of sertraline hydrochloride Form H, we did not obtain sertraline hydrochloride Form EL It is thus apparent that neither the '699 patent nor the '518 patent disclose a useful method for the preparation of sertraline hydrochloride Form EL
The present invention also provides new processes for making sertraline-hydrochJofide Form II from sertraline hydrochloride Form V by granulation. In the conversion of sertraline hydrochloride Form V to sertraline hydrochloride Form II, sertraline hydrochloride Form V is combined "with a small amount of ethanol or methanol.
The mixture of sertraline hydrochloride Form V and ethanol or methanol is stirred for at least a period of at least a few horns., up to several days, preferably about two days, to induce the transformation of Form V to Form n. Sertraline hydrochloride Form n is then, isolated by filtration.
The present invention also provides new processes for making sertraline hydrochloride Form n by recrystallization of sertraline hydrochloride under heating conditions. In the conversion of sertraline hydrochloride to sertraline hydrochloride Form IT, sertraline hydrochloride is dissolved in a suitable organic solvent. The solution is' heated for a time sufficient to effect transformation to sertraline hydrochloride Form II. Suitable solvents include dimethylforrnarnide, cyclohexanol and acetone. Dimethylformamide is preferred. The suspension may be heated to a temperature between about 70°C and 120°C. Sertraline hydrochloride Form II is then isolated by filtration.
The present invention provides new processes.for making sertraline bydrochloride Form II frofla sertraline hydrochloride Form VI, Form VII or Form VTQ by reslurry in organic solvents at temperatures between 25-80 °C, followed by drying. Sertraline hydrochloride Form VT may be made following the methods of Examples 2 and 3. SertralinehydroichlorideFdrrh VITis'a water adduot and may be made by the methods of Examples 19 and 20. Sertraline hydrochloride Forrxl VHI may be made by the methods of Examples 17 and 18. The methods provided in the present invention have advantages-over the rapid recrystallization method Of U.S. Patent 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 crystalMzatiim The presetitmethod utilizes less solvent than the method of the '699 patent, since the sertraline hydrochloride starting material need not be completely dissolved.
In the conversion of sertralirie hydrochloride Form VI, Form VH or Form VTJQ[ to
sertralme hydrochloride Form H, -according to the present invention, sertraline
hydrochloride Form "Vl, Form VH water adduct, or Form VTH is combined with an aprotic organic solvent to form a slurry. Suitable solvents include n-butanol, acetone, t-butyl-ethyl ether (MTBE), ethyl acetate and cyciohexane. The conversion may take place at room temperature, but preferably the sertraline hydrochloride Form VI, Form VU water
adduct, or Vm and solvent are heated to temperatures between 25 °C and 80 °C. About 1 to about 10 volumes of solvent are preferred, based on the weight of the sertraline hydrochloride starting material. See Examples 8 (3 volumes of solvent) and 9 (5 volumes of solvent) below. Smaller amounts of solvent will also effect the transformation., albeit in some instances more slowly. The reaction is carried out for a time sufficient to convert the. Form VI, Form VH or Form Vm to Form EL We have not'observed any further conversion of Form H upon treatment under these conditions for times longer than the minimum time necessary to effect the transformation.
me present invention also provides new processes for making a mixture of sertraline hydrochloride Form 13 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. Form V
The present invention provides newprocesses for: making sertralirie 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. Patent 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.
Where the present invention provides methods for the conversion of sertraline hydrochloride to sertraline hydrochloride Form V, in one embodiment sertraline hydrochloride is combined with a solvent Suitable solvents include methanol, ethanol, 1-methoxy-2-propanol, trichloroethane, water, and mixtures thereof. If a mixture of isopropyl alcohol and water is used, it is preferably an about ,6:1 mixture. ^Preferably the solvent is methanol, ethanol,: or mixtures thereof, and most preferably the Solvent is ethanol. Sertraline hydrochloride Form V is then isolated by allowing the solution to cool. One preferred method is to rapidly cool the solvent to 5°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.
Alternatively, Form V may be obtained by forming a solution or suspension of sertraline hydrochloride in a suitable solvent and spray drying the solution or suspension. Preferred solvents include water and water/alcohol mixtures.
The present invention also provides methods for the conversion of sertraline hydrochloride to sertraline hydrocUoride Form V wherein the solvate sertraline hydrochloride Form VI (described in more detail below) is an intermediate, hi this embodiment of the present invention, sertraHne hydrochloride is suspended or dissolved in
i or ethanol or mixtures thereof thereby forming sertraline hydrochloride Form VI. This intermediate sertraline hydrochloride Foiin VI is then dried, with or without a separate isolation step, to remove all solvent and sertraline nydrochloride Form V is isolated. Sertraline hydrochloride Form V can also be prepared by suspending or dissolving sertraKne hydroehloride solvate Form VI in water.
Sertraline hydrochloride Form V can also be prepared by drying Form VII (described in more detail below). In this embodiment of the present invention, sertraline hydrochloride Form V is dried at 80° C overnight thereby forming sertraline hydrochloride Fprm-V,
. The present invention also provides methods for the conversion of sertraline hydrochloride to sertraline hydrochloride Form V'wherein the sertralme hydrochlbride Form VEQ (described in-more-detail below) is an intermediate: In this embodiment of the present inventio% serfraline hydroehloride Form H is suspended or dissolved in water thereby forming sertraline hydrochloride Form VUL This intermediate sertraline hydrocflloride Form VEI is then dried, with or without a separate isolation step, to remove al} solvent and sertraline hydrocaloride Form V is isolated. Methods for the preparation of sertraline hydrochloride Form H are disclosed in U.S. applications serial nos. 09/448,985 filed November 24, !999 and 09/575,634 filed May 22,2000, the contents of which are here~by,inoorp©rated fey reference.
The present invention also provides methods for the conversion of sertraline base to sertraline hydrocMoride Form V. fa one such embodiment, sertraline base is added to at least one.solvent, and hydrogen chloride gas is bubbled through the solution. Suitable solvents include memanol, ethanol, water, ethyl acetate, isopropyl alcohol, ether, hexane,
and toluene, and mixtures thereof. Alternatively, an appropriate amount of hydrogen chloride gas dissolved in a suitable solvent and then combined with the sertraline base solution. As used herein, "hydrogen chloride" includes both gaseous hydrogen chloride and aqueous hydrogen chloride (i.e. hydrochloric acid). Sertraline hydrochloride Form V is isolated by allowing precipitation to occur from about 0°C to about 60°C followed by filtration and.drying. Preferred solvents include methanol, ethanol, hexane, isopropyl alcohol, or mixtures thereof. In a variation of this method, sertraline base is added to a suitable solvent and the resulting solution is added to a hydrochloric acid solution of pH 0 4; preferably the pH ol the solution is about 1.
Alternatively, sertraline base is added to a solvent. The solution is heated and concentrated hydrochloric acid is added. Water may also be added. The solvent may be partially removed by distillation. 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. Suitable solvents for use in this method include methanol, ethanol, water, hexane, isopropyl alcohol, and ethyl acetate, and mixtures thereof.
Alternatively, sertraline base maybe" combined with" a solvent "selected from lie 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.
Form V may also be obtained by forming'a,Suspension of sertraline base and hydrochloric acid in water or a water/ethanol mixture and spray drying the suspension. In this embodiment of-the present invention., the solution' or 'suspension of sertraline base and hydrochloric acid is sprayed into a heated chamber. The temperature of the chamber is such that the solvent is removed thus forming serrraline hydrochloride Form V.
Serrralme 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. Patent Nos. 4,536,518 and 5,248,699, the contents of which are incorporated herein by reference.
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°C to • about 80°C or is stored at room temperature for a period between a few hours and several days depending on the temperature.
The sertraline hydrochloride Form V that results from practicing the invention as ecfcuiplifiod herein can be charactenzed by its powder X-ray difiMcm pattern. Figure 4 is a representative pattern of sertraJine hydrochloride Form V. The principal peaks observed are at about 5.2° ±0.2,10.4° ±0.2, 1 1.0° ±0.2,14.3° ±0.2,16.5° ±0.2, 17.3° ±0.2, 18:4° ±0.2, 19.1°±0.2,19.7° ±0.2,20.9° ±0.2,22.0° ±0.2,23.2° ±0.2,23.6° ±0.2, 25.5° ±0.2,26.0 ±0.2, and 29.1° ±0.2 degrees 2 theta.
Three experiments -were performed in order to repeat the procedure described in U.S. Patent 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 17Q-19fl°C. A third-experiment-was performed^fsubliffiating a sample of Fonn " I under high vacuum (0^1 mm Hg) and temperature between 180-195DC.
The three samples of sertraline hyoxochlbride prepared by sublimation were analyzed by powder x-ray diffraction. In all cases, thelypical broad featureless pattern without, sharp peaks typical of amorphous materials was obtained: Figure 5 is one such pattern.'
in conclusion, sertraline hydrochloride could not be obtained by following the procedure set forth in US, Patent No. 5,248,699 for preparing Form V by sublimation of Form I.
The IR spectrum of sertraline hydrochloride Form V produced by the present process is characterized by the following bands: 773 cnV1, 822 cm-1,1012 cm'1,1032 cm'1,1054 cm'1,1133 .cm'1. Big cm', 1562 cm'1, and 1590 ranJ, as shown in Figure 7.
The sertealine hydrochloride-Form V of the present process is further characterized by the DSC thermpgram data, for example, as disclosed in Figure 6. The DSC thermogram is characterized by a small endotherm (-3 Joule per gram) at about 210*C, believed to be a solid-solid transformation (based upon observation under a'hot stage microscope) to Form
HI, and a melting peak 25l"C. Form VI
Sertraline hydrochloride Form VI is a solvated crystal form of sertraline hydrochloride. 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 methanqlatei 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.
To form the novel crystalline form sertraline hydrochloride Form VI, sertraline base is
added to the appropriate solvent. Which solvent is appropriate will depend on which
solvate is to be formed, e.g. ethanol (to form the ethanolate) and methanol (to form the
methanolate). 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 Ihermogram of Fonn VI crystallized from ethanoldisplays a
desolvation peak at 95°C.(see Fig. ,16).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.
The present invention also provides new processes for making sertraline hydrochloride solvate Form VI by reslurry of other sertraline hydrochloride crystalline forms. In the conversion of sertraline hydrochloride to sertraline hydrochloride ethanolate Form VI, sertraline hydroehloride is dissolved in the appropriate solvent and stirred for about 18-36 hours; 24 hours is preferred. Sertraline hydrochloride solvate Form VI is isolated by a.suitable method, such as filtration. Sertraline hydrochloride Forms I, n, HI, TV, V and X are suitable for use as starting materials in this process.
The sertraline hydrochloride Form VI so isolated is a solvate and exhibits the powder x-ray diffraction pattern of Figure 8, comprising peaks at 7.3°±0.2, 12.1 °±0-2, 12.7°±OJ2,

14.0°±0.2,15.6'±0.2, 17.6°±0.2,20.1-L0.2, 20.6°±0.2,21.9°±0.2,22.7°±0.2, 23.0°±0.2 23.8°:tG.2,24.3°±0.2, 25.4°±0.2, and 26.3°i0.2 degrees two-theta. Drying of the precipitated sertraline hydrochloride Form VI at 50-60°C overnight yields sertraline hydrochloride Form V. fermVH
It has also been discovered that a new crystalline form of sertraline bydrochloride, designated Form VH, may be obtained by suspending or dissolving Form V in water, and filtrating the suspension after one day without further drying.
In another embodiment oflie invention, sertraline hydrochloride Form VII is made fiomsertralme 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 between about 30°C and about 900C, preferably to about 80°C. - The pH is then lowered, preferably to about pH 1, and the mixture is allowed to cool to room temperature arid stirred until the reaction is complete. Preferably
the reaction is stirred for two hours at room temperature. Sertraline hydrochloride Form
VH is isolated by filtration and washing with water.
AssBown-in-Figure9,
unique strong x-ray powder diffraction peaks at 4.0°±0.2, and 20.0 degrees two-theta and
medium intensity peaks at 8.0° ±0.2,11;6°±0.2,12.0 ±0.2,13.S*±0.2,16.5°±0.2,
22^02,24.r±0.2,25.0U0.2,26v6°±G.2, 30.7°±0.2,34.7^0.2 2 two-theia. The TGA
curve shows a 1 oss on drying of about 45 %.
Forms VBI and Tlf
Additional new crystal^ forms of-sertralinfeaydrochloride, Forms VHI and IX, have alsobeen discovered.. Sertraline hydrochloride hydrate Form VHI may be produced by suspending sertraliae base in water and heating, followed by acidification and filtration. Form IX is obtained by drying of Form VHI. Preferably the sertraline base is suspended in -. water, the suspension heated to a temperature betweea about 30°C and about 80°C. Hydrogen chloride is added to reduce the pH, preferably to between about 1 to about 4, and me resulting solution is coaled to room temperature.
The present inventieHralso provides new processes for making sertraiine hydrochloride Form VHI &om sertraline hydrochloride etbanolate Form VI. In one
embodiment of the present invention., a slurry of sertraline hydrochloride ethanol ate Form VI in water or a mixture of water and isopropyl alcohol is stirred, preferably for about one hour. The slurry is then filtered and washed with water and sertraline hydrochloride hydrate Form VHIis isolated.
The present invention also provides processes of making sertraline hydrochloride Form VHI from sertraline hydrochloride Form n. In the conversion of sertraline hydrochloride Form II to sertraline hydrochloride Form VIII, sertraline hydrochloride Form II is suspended in water or a mixture of water and isopropyl alcohol and stirred, preferably
Sertraline hydrochloride Form VIII is characterized by x-ray powder diffraction peaks at4:7°±0.2, 11.80±0.23'l630±0.2, 17.8°±0.2, 19.60±0.2,23.2°±0.2,24.2°±0.2,25.r±0.2, and 26.0°±0.2 two-theta, as described in Figure 10.
The DSC thermogram for Form VIII is characterized.by a strong endotherm below
100°C, small endothermic and exothermic events at about 220°C and a melting peak at
247°C as described in Figure 12.
The TGA curve shows a loss on drying step of about 20% below 100°C.
The IR spectrunr of Forjm.VItt is-characterized by- the following bands: 740 cm"1, 779
cm'1, 822 cnf1, 887cnr',915 cm"1,1031 cm'1, 1053 cm'1,1110cm-', 1134cm-', 1153 cm'1,
1217 cm'1,1307 cm'1, and 1377 cmf1, as described in Figure 14. .
Sertraline hydrochloride Form IX is characterized by x-ray powder diffraction peaks at5.1°±0.2,14J2°±0.2,15.8°±0.2,16.8°±0.2,19.2°±Q.2, 19.7°±0.2,22i4°±0.2,23.2^0.2, 25.3P±0.2 and 26.1 °±0.2 two-theta, as described in Figure 11.
The UL spectrum of Form IX is .characterized by the followiag?bands:701 cm'1,715 cm'1,741 cm'1,758 cnrl,780 cm', 816 cm'1, 823 cm\ 1030 cm:', 1053 cm-', 1078'Cm1, 1110 cm'1,1204 cm'1; 1217 cm'1,1307 ran1, and 1350 cm'1, as .described inFigure 15. FormX
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, and heating to facilitate dissolution. The solution is cooled and the precipitate filtered, washed with benzyl alcohol and .dried, to yield sertraline hydrochloride Form X.
The Form X produced in this manner is characterized by a powder x-ray diffraction
pattern having its principal peaks at 15.0D±0.2, 16.0°±0.2, 16.5°±0.2, 17.0°±0.2,
18.1 °±0.2, 2 1 .0 °±0.2, 22.4 °±0.2, 24.9 °±0.2, 25.4 °±0.2, 26.2 °±0.2, 27. 1 °±0.2, 28.4 °±0.2,
and 29.0°±0.2 degrees two-theta as described in Figure 17.
The IR spectrum of Form X is characterized by the following bands: 742 cm"1, 776 cm'1, 806cm'1, 824 cm'1, 1002 cm'1, 1017 cm'1, 1028 cm'1, 1060 cm'1, 1079 cm'1, 1135 crrf *, 1218 cm"1, 1314 cm"1, 1336 cm"1, and 1560 cm"1 as described in Figure 18.
The DSC of Form X shows a small endotberm at about 1'90°C followed by a melting endotherm at about 250°C (see Figure 19). Form IHr
The present invention provides new processes for making sertraline hydrocbJoride Form M from sertraline hydrochloride Forms V and VI. In the conversion of sertraline hydrochloride Form V to sertraline hydrochloride Form HI, Form V is heated to a temperature between about 1 50°C and about 1 80°C for about 3 hours to about 2 days to induce the formation of sertraline hydrochloride Form HI. Heating for 24 hours is preferred. The reaction may be stirred. The method of the present invention has the advantage of using no solvent. Amorphous Sertrglip&Hydrochleride-
In an embodiment of the present invention, amorpnous sertraline is made by dissolving sertraline hydrochloride in water or a water/alcohol mixture and drying the • solution by the spray dryer technique. Amorphous sertraline hydrochloride may also be made by sublimation of sertraline hydrochloride,
„ , 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. Figure 5 is one such pattern.
Experimental
The powder X-ray diffraction patterns were obtained by methods known in the art using a Philips X-ray powder difiraetometer, Goniometer model 1050/70 at a scanning speed of 2° per minute, .with a Cu radiation of X = 1 .5418 A.
.The .differential scanning calorimeter thermograms were obtained by methods known in the art using a DSC Mettler 821 Star0. The weight of the samples was less man 5 mg. The temperature range of scans was 300C-30Q°C at a rate of 1 0°C/min. Samples were
purged with nitrogen gas at a flow rate of 40 mL/miri. Standard 40 j^l aluminum crucibles were used having lids with three small holes.
The infrared spectra were obtained by methods known in the art using a Perkin Elmer FT-ER Paragon 1000 spectrometer. Samples were analyzed in Nujol mulls. Spectra were obtained at 4 cm"1 resolution and 16 scans each. Pharmaceutical Compositions Containing Sertraline Hydrochloride Polymorphs
In accordance with the present invention, these new crystalline forms of sertraline hydrochloride and knovm forms of sertraline hydrochloride prepared by the new methods •disclosed hereiri 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.
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 etnulsion;-wfailer for rectal administration suitable forms for administration include suppositories with hydrophilic or hydrophobic vehicle. .For topical administration the invention provides suitable transderrnal delivery systems known in the art, and for nasal delivery there are provided suitable aerosol delivery systems known in the art.
PharrnaceutipaJl compositions of the present invention contain sertraline iyarochloride Forins n, El, and V to X, optionally in mixture with .other forms or amorphous sertraline. In addition to the active ingredient(s), the pharmaceutical compositions of the present invention may contain one or more excipients. Excipients are added to the composition for a variety of purposes.
Diluents increasethe bulk of a solid pharmaceutical composition andmay makea pharmaceutical dosage form containing the composition easier for the patient and care • giver to handle. Diluents for solid compositions include,, for example, microcrystalline cellulose (e.g. Avicel®), microfine cellulose, lactose, starch, pregelitinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphatedihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit®), potassium chloride, powdered cellulose., sodium chloride, sorbitol and talc.
Solid pharmaceutical compositions that are compacted into a dosage form like a tablet may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include-acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethy] cellulose, gelatin, guar gum, hydrogenated
hydroxypropyl methy] cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate and starch.
The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased -by the addition of a disintegrant to-the composition. : Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium- (e.g. Ac-Di-Sol®, Primellose®), colloidal silicon dioxide,
__crpscamiellose sodium^ crospovidone (e.g. KeHidoa^ PoJypfesdone1^, guargum,
magnesium aluminum silicate, methy] cellulose, macrocrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch . .g3ycoIate:(e.g.Explotab®) and starch.
Glidante,can be added to improve the flowability of non-compacted solid composition .and imjHwe-fte accuracy of-dosiing. Excipients that may function as gHdants include colloidal silicon?aixoide, magnesium trisilicate, powdered eelluldse, starch, talc and tribasic.calciujn phosphate.
"When a dosage form such as a tablet is made by compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active-ingredients have a tendency to adhere to foe surfaces of the punch and dye, which can cause the product to have pitting and other surfece irregularities. A lubricant can "be added to the; .composition to reduce adhesion and ease release of the product form the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl pahnitostearate, hydrogenated castor oil^ hydrogenated vegetable
oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of
the product and unit dosage level.
In liquid pharmaceutical compositions of the present invention., the sertraline Forms and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
Liquid pharmaceutical compositions may contain emulsifying agents to disperse uniformly throughout the. composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that may be .useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, 'tragacanuX chondrus,-peetin5 methyl ellulose,rearbomer,-cetostearyr alcohol "arid"cetyt alcohol.
Liquid pharmaceutical compositions of the present invention may also contain a . viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, cafboxymethylcelrulose calcium or sodium, cetostearyl alcohol, methyl cellulose,: ethylcellulpse, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gurn.
Sweetening agents such as sorbitolj saccharin, sodium saccharin, sucrose;, aspartarne, fiuctose, mannitol and invert sugar may be added to improve the taste.
Preservatives and .chelating agents such as alcohol, sodium benzoate, burylated hydroxy toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability.
A liquid composition according to the present invention may also contain a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate or sodium acetate.
Selection of excipients and the amounts to use may be readily determined by the
formulation scientist based upon experience and consideration of standard procedures and
reference works in the field.
The solid compositions of the present invention include powders, granulates, aggregates and compacted compositions. The dosages include dosages suitable for oral, "buccal, rectal, parenterai {including subcutaneous,.intramuscular, and intravenous), inhalant and ophthalmic administration. Although the most suitable route in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral. The dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and losenges as well as liquid syrups, suspensions and elixirs.
Achdosagerfbim'of tfae~present invention is a capsule containing the composition,
preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell. The shell maybe made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an'opacifying agent or colorant.
The active ingredient and excipients maybe formulated into compositions and dosage forms according to methods known in the art
A composition for tableting or capsule filing may be prepared by wet granulation. In wet granulation some or all of the active ingredients and excipients in powder form are blended and then fiirther mixed in the presence of a liquid, typically water, that causes the powders to clump up into granules. The granulate is screened and/or milled, dried and then screened and/or milled to the desired particle sfcze. The granulate may then be tableted or other excipients may be added prior to tableting such as'a glidant and or lubricant.
A tableting composition may be prepared conventionally by dry blending. For instance, the blended composition of the actives and excipients may be compacted into a
slug or a sheet and then comminuted into compacted granules. The compacted granules may be compressed subsequently into a tablet.
As an alternative to dry granulation, a blended composition may be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited to direct compression tahleting include microcrysta]]ine cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of • these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
A capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting, only they are not subjected to a final tableting step.
Capsules, tablets and lozenges and other unit dosage forms preferably contain a dosaee level of about 20,25, 50 or 100 mg of equivalent base.
, EXAMPLES
Thepresenriirvention will "flow be'fufth'eT'expTamedfri the'fbllowihg 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
Sertraline mandelate was prepared according to procedures in U.S. Patent No. 5,248,699. Sertraline mandelate (5 g) was stirred at room temperature with 50 mL ethyl acetate. Aqueous sodium hydroxide was added dropwise until the sertraline mandelate was completely neutralized. The phases were separated and the organic phase was dried over MgSQ4 and filtered. Hie solvent was removed under reduced pressure resulting in sertraline base as an oil (3.2 g).
Example 2 Preparation of Sertraline Hydrochloride Ethanolate Form VI by Reslurry of Form I
Sertraline hydrochloride Form I (1 g) and absolute ethanol (20 mL) were stirred at room temperature for 24 hours. Filtration of the mixture yielded Sertraline hydrochloride ethanolate Form VI.
Example 3 Preparation of Sertraline Hydrochloride Ethanolate Form VI by Reslurry of Form V
Sertraline hydrochloride Form V (1 g) and ethanol absolute (20 mL) were stirred at room temperature for 24 hrs. Filtration of the mixture yielded sertraline hydrochloride ethanolate Form VI.
Example 4 Preparation of Sertraline Hydrochloride Form II
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 ~2. The stirring was continued overnight at room temperature. The resulting solid was filtered, washed with acetone and dried to yield sertraline hydrpchjpride Form II (2.61.g, yield 77.6%).
Example 5 Preparation of Sertraline Hydrochloride Form II in n-Butanol
HC1 (g) was bubbled through a solution of sertraline base (33 g) in n-butanol (264 mL). The temperature rose to about 45°C- A gel-like solid was formed. The addition of HC1 (g) was continued until pH 0.5 was reached. Then "the stirring was continued at room temperature for 2.5 c. During the stirring the solid became a fine crystalline solid. The solid was filtered, washed with n-butanql (2x1-0 mL) and dried at 80°C for 24 h. The product is sertraline hydrochloride Form n. The x-ray powder diffraction spectrum obtained is Figure 3.
Example 6 Preparation of Sertraline Hydrochloride Form n
Sertraline hydrochloride Form V (10 g) was suspended in dimethylformamide (DMF) (30 mL). Heating was started and at about 70°C a dear solution is obtained. The solution was cooled to room temperature and the solid was filtered. After drying at 80°C for 24
hrs., sertraline hydrochloride Form II was obtained (6.6 g, yield 66%).
Example 7 Preparation of Sertraline Hydrochloride Form H by Granulation oif Form V
Sertraline hydrochloride Form V (2 g) and absolute ethanol (0.5 mL) were stirred in a rotavapor at room temperature for 2 days. At the end of two days, the material contained sertraline hydrochloride Form II.
Example 8 Preparation of Sertraline Hydrochloride Form II from Form VI—
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 arid filtered. The solid was washed with t-butyl-methyl ether (50 mL) and dried in a reactor under vacuum of 30 mm Hg with stirring. The dried solid so obtained is sertraline hydrochloride Form II (38.26 g: yield 86.7 %).
Example 9 Preparation of Sertraline Hydrochloride Form n from Form VI
Sertraline hydrochloride-Form VI .(25 g was stirred with" acetone (250 mLJaf 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 H (20:09 g: yield 98.6 %).
Example 10
. Preparation of Sertraline Hydrochloride Form n. and Sertraline Hydrochloride Form V by Drying Form VI
Sertraline hydrochloride ethanolate Form VI was dried at 105°C under vacuum " (< 10 mm Hg) over 24 hours. The resulting dried material was sertraline hydrochloride Form fl mixed with sertraline hydrochloride Form V.
Example 11
Preparation of Sertraline Hydrochloride Form 13 from Sertraline Mandelate in n-Butanol
Sertraline mandelate (20 g) and n-butanol were stirred at room temperature. The mixture was acidified with hydrogen chloride until pH 0 was reached. During the acidification the temperature of the reaction mixture rose to ~50°C. After the natural
cooling to room temperature, the mixture was stirred at room temperature for two hours. The solid was filtrated, washed with n-butanol and dried at 80°C to afford sertraline hydrochloride Form II (9.02 g).
Example 12
Preparation of Sertraline Hydrochloride Form II from Sertraline Hydrochloride Form VHI
Sertraline hydrochloride Form VIH (13 g) was heated in acetone (130 mL) at reflux for 1 hour. The slurry was than cooled to room temperature and the solid was filtrated and
washed with acetone (2x10 mL). After drying sertraline hydrochloride Form II was nhkined (7.9 g).
Example 13
An aqueous sodium hydroxide solution, 10 %, was added drop-wise to a slurry of sertraline mandelate crystals (10 g) in ethyl acetate (650 mL), until complete dissolution was obtained (25 rriL). After separation of the phases, the organic phase was washed with water (300 mL) and then dried with MgSO4. The organic solution was diluted with ether (690 mL) and gaseous hydrochloric acid was bubbled through the solution until pH 1.3 was reached;- The -addition of hydrogen chloride resulted in a temperature increase to about 30°C. The resulting slurry of sertraline was stirred at room temperature overnight. The solid was then isolated by filtration, washed twice with ether (2 x.20 mL) and air dried. The dried solid, sertraline hydrochloride, was not sertraline hydrochloride Form II, as shown in Figure 1.
Example 14
An aqueous sodium hydroxide solution, 10 %, was added drop-wise to a slurry of sertraline mandelate crystals (15 g) in ethyl acetate (810 mL), until complete dissolution was obtained (35 mL). The organic and aqueous phases were separated and, the organic phase was dried over MgSO4 The organic solution was then diluted with ether (820 mL) and gaseous hydrogen chloride {2.3.6 g, 2 eq.) was;bubbled through the solution until pH 1.5 was reached. The temperature was about 25°C. The slurry was stirred at room temperature overnight The solid was filtrated, washed with ether (2x15 mL) and air-dried. The dried solid, sertraline hydrochioride, was not sertraline hydrochloride Form II.
Example 15
An aqueous sodium hydroxide solution, 10 %, was added drop-wise to a slurry of sertraline mandelate crystals (15 g) in ethyl acetate (810 mL), until complete dissolution was obtained. The organic and aqueous phases were separated and the organic phase was dried over MgSO4 and diluted with an equal volume of ether (820 mL). Gaseous hydrochloric acid (4.82 g) was bubbled through the solution until pH 1 was reached. The slurry was stirred at room temperature overnight The solid was filtrated, washed with ether (2x15 mL) and air-dried. The dried solid, sertraline hydrochloride, was not
;>ci Lalinc ItyuiuulJonde Fouii it.
Example 16
An aqueous sodium hydroxide solution, 10%, was added drop-wise to a slurry of
sertraline mandelate crystals (15 g) in ethyl acetate (810 mL), until complete dissolution is
obtained. The phases were separated and the organic phase was dried over MgSO4 and
diluted with an equal volume of ether (820 mL). Gaseous hydrogen chloride was slowly
bubbled through the solution (over about 3 hours) until pH L5 was reached. The slurry
was stirred at room temperature over night The dried solid, sertraline hydroehloride, was
not sertraline hydrochloride Form n
Example 17 Preparation of Sertraline Hydrochloride Form VHI
Sertraline base (2.7 g) was suspended in 27 mL of water. This mixture was heated to 80eC and treated with hydrochloric acid until about pH 1 was reached. A clear solution was obtained which on cooling gave a precipitate. After 2 hours stirring at room temperature the solid was isolated by filtration. This solid was characterized by powder x-ray -diffraction and found to be sertraline hydrochloride Form VIII.
Example 18 Preparation of Sertraline Hydrochloride Form Vin
Sertraline hydrochloride ethariolate (Form VI) (40 g) was stirred with, water (80 mL) for 1 hour at room temperature. The slurry was filtrated and washbrf with water to yield sertraline hydrochloride hydrate Form "VTIL
Example 19 Preparation of Sertraline Hydrochloride Form VII
Sertraline hydrochloride Form V (1.003 g) was stirred for 24 hours at room
temperature in 20 mL water (HPLC grade). At the end of the stirring the mixture looked like-a jelly suspension. The suspension was filtrated and the compound obtained was kept at cold conditions (4°Q until analyzed by x-ray diffraction, which determined the compound to be sertraline hydrochloride Form VII.
Example 20 Preparation of Sertraline Hydrochloride Form VI and Form V
Sertraline base (25 g) was dissolved in methanol (125 mL) at room temperature. The solution was acidified with hydrogen chloride gas until pH 1.5 was reached. (Precipitation
—occurifcd dming acidification.) The temperature rose to approximately 4Q°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 21
Preparation of Sertraline Hydrochloride Form VI and Form V Sertraline base (3.2 g) was dissolved in absolute ethanol (32 mL) at room temperature and then hydrogen chloride>gas was bubbled in tintil pH 0.5 .was reached. The temperature rose to 40°C. The slurry was allowed, to cool to room temperature and stirred for about ] 6 hours. The solid was separated by filtration, and washed with ethanol (3x2 mL). Figure 5 sets forth the X-ray diffraction pattern of the product (sertraline hydrochloride etbanolate Form VI) so obtained. Drying overnight at 50-60°C of that product yielded 2.95 g (82%) of sertraline hydroehloride Form V.
Example 22 Preparation of Sertraline Hydrochloride Form V
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 drppwise to -reaeh- a-pH of~l 3. The resulting slurry was .stirred at room temperature overnight. The solid was separated by filtration and dried overnight at 50-60°C yielding 2.75 g (81. 8%) sertraline hydrochloride Form V.
Example 23 Preparation of Sertraline Hydrochloride Form V
Sertraline "base (3 g)~was dissolved in absolute ethanol (15.5 mL) at room temperature and then the solution was cooled to approximately 0°C. Hydrogen chloride gas was
bubbled until pH 0.5 was reached. The temperature rose to approximately 7°C. Precipitation occurred and the slurry was stirred at about 10 °C for 2 hours. The solid was isolated by filtration, washed with ethanol and dried at approximately 50°C. The dried material (2.87 g, yield 82.7%) was sertraline hydrochloride Form V.
Example 24 Preparation of Sertraline Hydrochloride Form V
Sertraline,base (3 g) was stirred with 35 mL water. The slurry was heated at ~70°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° C, yielding 3.23 g (96%) sertraline hydrochloride Form V.
Example 25 Preparation of Sertraline Hydrochloride Form V
Sertraline base (3 g) was dissolved in 10 mL absolute ethanol at 40°C. The solution was heated to 50°-60°C and concentrated hydrochloric acid 32% (1.2 mL) was added until pH-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°C, yielding 3.18 g (94.65%) sertraline hydrochloride Form V.
Example 26 Preparation of Sertraline HydrochlorJde'Form V
Sertraline base (3.7 g) was dissolved in 18.5 mL absolute ethanol and the solution Was heated to <50°C. Hydrogen chloride gas was bubbled through the ethanol solution until pH -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° C was sertraline hydrochloride Form V (3.16 g, yield 76%).
Example 27 Preparation of Sertraline Hydrochloride Form V
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 28 Preparation of Sertraline Hydrochloride Form V
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 (17.5 g) at 35°C with precipitation. After 2 hours, the solid was filtrated, washed with ethanol and dried at ~^ut 80° C to yield sertraline hydrochJoride Form V (12.9 g, yield 87%).
Example 29 Preparation of Sertraline Hydrochloride Form V
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°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°C yielding 1.71 g (85.5%) of sertraline hydrochloride Form V.
Example 30 Preparation of Sertraline HydrochJoride Form V
Sertraline hydrochloride ethanolate (Form VI) (40 g) in 400 mL water was heated to 80 °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°C for approximately 1-6 hours, yielding sertraline hydrochloride Form V.
Example 31 Preparation of Sertraline HydrocWoride Form V
Sertraline hydrochloride ethanolate (Form VI) (2 g) was mechanically stirred with
i^STriE^at room temperature ibr 4u hours. The resulting solid was sertraline hydrochloride Form V.
Table 1 sets forth a summary of additional experiments conducted generally following procedures described above.
TABLE 1(Table Removed)
Example 32 Preparation of Sertraline Hydrochloride Form VH
1.003 g Sertraline hydrochjoride 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 coinpound obtained was kept
at cold conditions (4°C) until analyzed by x-ray diffraction.
Example 33
Preparation of Sertraline Hydrochloride Form VH from Sertraline Hydrochloride Form VI
A solution of sertraline hydrochloride ethanolate (Form VT) (40 g) in water (400 mL). was heated at 80°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 VH.
Sertraline hydrochloride Form VII dried overnight at 80°C forms sertraline hydrochloride Form V.
Example 34
Preparation of Sertraline Hydrochloride Forms VTII and IX from Sertraline Base
Sertraline base (2.7 g) was suspended in 27 mL of water. This mixture was heated to 80°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 Figure 3, Form VIII). Drying for 24 hours at ~50°C yielded 2.32 g (76.8%) of sertraline' hydrochloride Form IK, characterized by powder x-ray diffraction, infra-red absorption., differentia] scanning calqrimetry, and thermal gravimetric analysis as set forth above and depicted in Figures 8,10, and 12.
Example 35
Preparation of Sertraline Hydrochloride Form Yin from Sertraline Hydrochloride Form II
Sertraline hydrochloride Form U (0.4 g) and water (8 mL) were stirred at room temperature over night The solid was filtrated to yield sertraline hydrochloride hydrate FormVUL .
Example 36 Preparation of,Sertraline Hydrochloride JForm X
In a 0.1 liter three-necked bottom round flask equipped with a mechanical stirrer^ a condenser and a thermometer, SJLinLfaerizylAalcobotJs-addedto-i^-firstiiUalijje hydrochloride. The suspension is heated to 100°C when a clear solution is obtained. The solution is cooled 2 hburs to 25°C and the precipitate is filtered and washed with benzyl alcohol; After drying under vacuum at 80°C for 24 hours, 6.2 g of sertraline .hydrochloride Form 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 Figure 14 and Figure 15.
Example 37 Preparation of Sertraline Hydrochloride Ethanolate Form VI by Reslurry of Form n
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 38 Preparation of Amorphous Sertraline Hydrochloride
temperature, ether (690 mL) was added to the sertraline ethyl acetate solution and the solution was acidified with HC1 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 g, yield 83.8%).
Example 39 Preparation of Sertraline Hydrochloride Form IH from'Form V
Sertraline hydrochloride Form V was heated at 150° C in a reactor under mechanical stirring for 24 hrs. The resulting material obtained was sertraline hydrochloride Form HI.
Example 40 Preparation of Sertraline Hydrochloride Form in from Form VI
Sertraline hydrochloride form VI was heated to 180° C for 24 hours. The dried material is sertraline hydrochloride Form HI.
Example 41 Preparation of Sertraline Hydrochloride Form HI from Form V
Sertraline hydrochloride'Form Vwas heated at a temperature s 180° C for 24 hours. The resulting material was sertraline hydrochloride Form HI.
Preparation of Amorphous Sertraline Hydrochloride
Sertraline Bydrochloride 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 Sertrah'ne hydrochloride amorphous.
Example 43 Preparation of Amorphous Sertraline Hydrochloride by Sublimation
, Sertraline hydrochloride Form I was sublimated at 190-200°C,, at a vacuum of 30-0.1 mm Hg, using a laboratory-type sublimator. The resulting material was amorphous sertraline hydrochloride.
A similar procedure starting from Form V also gave amorphous sertraline Hydrochloride,
Example 44
from Amorphous Sertraline Hydrochloride
Sertraline hydrochloride amorphous was heated to SO°C for 24 hours. The resulting product was sertraline hydrochloride Form V.
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 arid in a manner consistent with the scope and spirit of the invention.

WE CLAIM:
1. A process for making sertraline hydrochloride Form II comprising the steps of:
(a) Granulating sertraline hydrochloride Form V in methanol; and
(b) Stirring the mixture of sertraline hydrochloride Form V and
ethanol or methanol to induce transformation to sertraline
hydrochloride Form II.
2 A process for making sertraline hydrochloride Form II substantially as herein described with reference to the foregoing description.