A NOVEL TOHMORPH OF SERTRALINE BXDROCHLOWDE 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 22,2008 claims priority toB.S. provteiOTSl application Serial No. 60/182,159, filed February 14,2000- U.S. application Serial No. 09/586,842, filed June 5, 2000 is a contmuation-m-paitofU.S. application Serial No. 09/448,985, filed November 24, 1999, which claims the benefit ofU.S. provisional application No. 60/147,888, filed August 9, 1999, The contents of each ofthese applications are incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to novel crystalline Form H its pharmaceutical compositions, and reproducible methods for the preparation ofsertralinehydrochloride crystalline Forms n, IHand V through X, as well as the preparation of amorphous form of" sertraline hydrochloride.
BACKGROUND OFTHE INVENTION
Sertralinehydrociiloride, (1 S-cis)-4-(3,4dicmorophenyI)-l,2,3,4-tetrahydro-N-methyl-1-naphthalenaioine hydrochloride, having the formula NHCHIs approved, under the trademark ZoJoft®,by tie "U.S. Food and Drug Administration, for the treatment of depression, obsessive-compulsive disorder and panic disorder.
U.S. PatentNo. 4,536,518 ("the '51S patent") describes the preparation ofsertraline hydrochlonde with a melting point of243-245°C by treating an ethyl acetate/ether solution ofthe free base with gaseous hydrogen chloride. The solid state properties ofthe sertraline hydrochlonde so produced are not otherwise disclosed.
According to U.S. PatentNo. 5,248,699 ("the '699patent"), thesertraline hydrochlori.de produced by the method ofthe '51Spatentbas a crystalline form
Jt:uuiJiijjattal~uFonn HT" The *W9 patent discloses four other pojyrnorphs 1, HI, .IV, and V, and characterizes them by single crystai x-ray analysis, powder x-ray diffraction, infra-red spectroscopy, and differential scanning calorimerry. The '699 patent reports that Form II is produced by rapid crystallization ofsertraline hydrochlonde from an organic solvent, including isopropyl alcohol, ethyl acetate orhexane, and generally describes methods for making sertraline hydrochlonde Forms I-V. According to this patent, the preferential' formation of Forms I, II or IV in an acidic solution consisting ofisopropyl alcohol, hexane, acetone, methyl isobutyl ketone, glacial acetic acid or, preferably, ethyl acetate, depends on . the rapidity of crystallization. Form I is described as being made by crystallizing sertraline hydrochloride in an acidic solution using an organic solvent such as those listed above. The crystallization ofForm 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 of granulation ofsertraline hydrochloride is said to produce Form I. Form HI is described as being formed by heating Forms I, n or IV to temperatures above about ISO" C. Granulating either ofForms H, IH or IV in any ofthe solvents listed above at a temperature from about 40 "C to 60"Cis said to cause conversion to Form I. The only method described in this patent for making Form V is by sublimation ofsertraline hydrochloride Form I at reduced pressure and at atemperature from about 130~190°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 '51S procedure produces sertraline hydrochloride Form II. Four experiments were performed according to the description ia the'5)8 patent. By following the procedures described in the *699patent for preparation ofsertralinehydrochloride Form II, we were unable to obtain sertraline hydrocHoride Form II. Thus there remains a need for reproducible methods for the preparation of sertraline hydrochloric^ Form II.
SUMMARY OF THE INVENTION
"The present invention relates to a process for making sertraline hydrochloride Form u comprising the steps of dissolving sertraline base or sertraline anandelate in an organic solvent to form a solution; adding hydrogen chloride to the solution; heating the solution to a temperature between aboutroom temperature, and about reflux for a time sufficient to induce the formation ofsertratineiiydrociiloride Form II; and isolating sertraline hydrochloride Form EL
The present invention also relates to a process for making sertialine hydrochloride Form II comprising tie steps of dissolving sertialine hydrochloride in dimethylformamide, cyclofaexanol, acetone or a inixttetfiereof; heating the solution for a time sufficientto affect transformation to sertraline hydro-chloride FormH; and isolating sertialine hydpochloride Form II.
The present invention further relates to a process for making sertraline hydrochloride Form H comprising the steps ofgranulating sertraline tiydrochloride Form V in ethanol or meihaaol; and stirring the mixture of sertraline hydrochloride Form V and ethanol or methanol for a time sufficientto indoce transformation to sertraline hydrochloride Form n.
The present invention stilllralbeirelates to a process for making a mixture of : sertraline hydrochloride Form n anilForm V comprising trie steps ofheating sertraline hydrochloride ethanolate Form VI atup to I atmosphere pressure; and isolating a mixture ofsertialine hydrochloride Form Hand Form V.
The present invention still further relates to a process for making sertraline faydrochloride Form IT'comprising fee steps of suspending a water or solvent adduct of sertraline hydrochloride in a solveatBelected from the group consisting of acetone, t-butyl-m ethyl ether, cyclobexane, n-butand, and ethyl acetate such ibat a slurry is form ed, for a
time sufficient to effecttransfonrtation to seitraline hydrochloride Form II; and filtering the slurry to isolate sertraline hydrochloride Form II.
The present invention still further relates to sertraline hydrochloride Formll, characterized by an x-ray powder diffraction pattern comprising peaks at about 5.5, 11.0, 12.5,132., 14.7, 16.4,173,18.1,19.1,20.5,21.9,22.8, 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 _such treatment a feerapcntically effective amount of the 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 hydrochloride 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 uspending sertraline hydrochloride in water; adding a sufficient amount ofhydrochloric acid or hydrogen chloride to fecilitate precipitation of sertraline liydrochloride; 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 hydrochloride Form VI without further drying.
The present invention also relates to a process for making sertraline hydrochloride Form "VI- comprising the steps of dissolving or suspending sertraline hydrochloride in
efhanol or methanol; stirring for a time sufficient to induce the transformation of sertraline hydrochloride to sertraline hydrochloride Form VI; and isolating sertraline hydrochloride Form VI.
The present invention also relates to aprocess formaking 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 aprocess formaking sertraline hydrochloride Form VIII comprising the steps of suspending or dissolving sertraline hydrochloride -ethanolate Form VI 01 sei tiafore hydrocETdrTde Form II in water oramixture ofwater and isopropyl alcohol; and isolating sertraline hydrochloride Form VIII.
The present invention also relates to aprocess formaking sertraline hydrochloride Form IH comprising the steps of heating sertraline hydrochloride Form V or Form VI to a temperature sufficient, and for atime sufficient, to induce the transformation ofsertraljne hydrochloride Form V or Form VI to sertraline hydrochloride Form III; and isolating sertralmehydrochloride Form Iff.
The present invention also relates to aprocess formaking amorphous sertraline hydrpchlpride comprising the-steps-ef; suspending or dissolving sertraline base in a non-polar organic solvent; adding gaseous hydrochloric acid; and isolating amorphous sertraline hy drochl oride.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a characteristic x-ray powder diffraction spectrum of sertraline fcydrocnldride prepared by the methods ofU.S. PatentNo. 4,536,518.
Figure 2 is a characteristic x-ray powder diffraction spectrum of sertraline hydrochloride prepared by foe methods ofUS- PatentNo. 5,248,699.
Figure 3 is a characteristic x-raypowder diffraction spectrum ofsertraline 'iiydracbloride Form II prepared by the methods of the present invention.
Figure 4 is a characteristic x-raypowder diffraction spectrum ofsertraline hydrochloride Form V.
Figure 5 is a characteristic x-raypowder diffraction spectrum ofamorphous sertraline bydrochtoride.
Figure 6 is a characteristic differential scanning calorimetric (DSC) thennograrn of sertraline hydrochloride Form V.
Figure 7 is a characteristic infrared (IR.) absorption spectrum of sertraline hydrochloride 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 VH.
Figure HMg-acfenrnr-t^rip^'j-jt-i'Hj' j."_''W'-V-i JifTraclion spectrum 01 sertraiine ' hydrochloride Form VIII.
Figure 11 is a characteristic x-ray powder diffraction spectrum of sertraline hydrochloride Form DC.
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 IX.
Figure 14 is a characteristic infrared (IR) absorption spectrum of sertraline hydrochloride Form VHL
Figure 15 is a characteristic infrared (IR) absorption spectrum of sertraline hydrochloride Form DC.
Figure 16is a characteristic differential scanning calorimetrjc (DSC) thermogram of sertralioe hydrocbloride Fonn VI.
Figure l?is a characteristic x-ray powder diffraction spectrum of sertraline hydrochloride Form X.
Figure 18is a characteristic infrared (IR) absorption spectrum of sertraline ' hydrochloride Form X.
Figure 19 is a characteristic differential scanning calorimetric CDSC) thermogram of sertraline hydrochloride Form X.
DETAILED DESCRIPTION OF THE INVENTION form II
The present invention provides new processes for making sertraljne hydrochloride . Form II from sertraline base or sertraline mandelate. Sertraline base may be made by methods known in the art, including the methods ofthe '518 patent. Sertraline base is dissolved in a suitable solvent. Suitable solvents include ethyl acetate, acetone, t-methy]-butyl ether, isopropyl alcohol, n-butanol, t-butanol, iso-bxitanol, hexane, and cyclohexane, and mixtures thereof. The pH ofthe sertraline base solution is lowered by tbg 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 ofisopropyl 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 solventis heated to a temperature between about room _ temperature and the reflux temperature ofthe solvent and maintained at that temperature for a period of time sufficient to effect the transformation to sertialine hydrochloride Form H." Preferably the soTufionis heated to a temperature between about 45°C and the reflux temperature ofthe solvent. Most preferably the solution is heated to at or about the reflux
• temperature ofthe solvent. Upon cooling ofthe mixture, for example to room temperature, sertraline hydioohloride Form II is isolated by filtration.
. • In a preferred variation ofthis method, the solution of sertraline base or sertraline anandelite in a solvent is heated to the reflux temperature ofthe solvent The mixture is reflrocedfora time sufficient to effect fee transformation to sertraline hydrochloride Form H. Preferably the mixture is reSuxed 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 II wherein sertraline base was dissolvedin ethyl acetate, etherwas added and the solution was acidifiedwith gaseous hydrogen chloride. The material obtained after filtration and air drying was sertraline faydrochloride 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 ofthese experiments are
equivalent, containing peaks at 11.0,12.0, 35.4,16.2,22,4, 22.9 degree two-tbeta (See Figure 1 for a representative example). Figure 1 does not contain the typical peaks of sertraline hydrochloride Form n, indicating an absence of sertraline hydrochloride Form n in those samples. Thus, none ofthese experiments, which follow the procedure described in the '518 patent for preparation of sertraline hydrochloride Form II, leads to sertraline hydrochloride Formn.
The '699 patent provides experimental procedures for preparation of sertraline hydrochloride. The'699 patent does not provide experimental procedure for preparation of "SErtraKnehydrochloride Form II, but it is mentionedthat 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 ofthe methods according to the '699 patent: An aqueous solution of sodium hydroxide, 10.%, was addedto a slurry ofsertraline mandejate crystals (44.6 g) in ethyl acetate (290 mL), until complete dissolution. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (280 mL) and combined with the organic phase. The resulting organic solution was washed - with water-(5 x lOQmL) then with brine (100-roL)andcoTiCejitfatedon aiotavaporto a ' volume of 356 mL. The concentrated solution was cooled to 58°C and seeded with sertraline hydrochloride Formn. Concentrated hydrochloric acid (32 %, 8.1 mL) was -added to this solution. The solution was then rapidly cooled to 30°Cover5 minutes. A heayygel was obtained and the stirringwas continued overnight. The.solidwas filtrated, washed with eihyl acetate and dried at 50°C. The dried solid, serfralme hydrochloride, was not sertraline hydrochloride Form IF, as Shown by the x-ray difiractionpatiein ofFigure 2.
By following the procedures described in the '699 patent for preparation of sertraline hydrochloride Form IL, we did not obtain sertraline hydrochloride Form n It is thus apparent that neither the '699 patent nor the '518 patent.disclose a useful method for the preparation of sertraliueliydrochloride Form II,
The present invention also provides new processes for making serlraJroe-hydrochloride Form It from sertraline hydrochloride Form V by granulation In the conversion ofsertraline hydrochloride Form Vto sertraline hydrochloride Form II, sertraline hydrochloride Form Vis combined with a small amount of etbanol ormethanoL
The mixture of seriraliiie hydrochloride Form V and etbanol or methane! is stirred for at least a period of at least a few hours, up to several days, preferably about two days, to induce lie transformation ofForm V to Form H. Sertraiinehydrochloride Form n is tben. isolated by "filtration.
The present invention also provides new processes for making serfraline hydrochloride Form n by recrystallization ofsertraline hydrochloride under hearing conditions. In the conversion ofsertraline hydrochloride to sertraline hydrochloride Form II, sertraline hydrochloride is dissolved in a suitable organic solvent. The solution is then Beate3 for a tirae sufficient to effect transformation to sertraline hydrochloride Form II. Suitable solvents include dimetirylformaffiide, cyclonexanol and acetone. Dimethylformamideis preferred. The suspensiohmaybeheated to a temperature between about 70°C and i2Q°C. Sertraline hydrochloride Form His then isolated by filtration.
The present invention provides new processes .formaking sertraline hydrochloride Form II from sertraline hydrochloride Form VI, Form "VII or Form VIII by resluny in organic solvents at temperatures between 25-80 "C, followed by drying. Sertraline hydrochloride Form VI may be made following the methods ofExainples 2 and 3. SeitralinehydrochlorideFormYII is a water adduct and may be made by the methods of Examples 19 and 20. Sertraline hyrfroch'loride Form VXD may be made by the methods of Examples 17 and 18. The methods provided in the presentinventionhaveadvantages'over the rapid recrystallization method ofU.S. Patent No. 5,248,699. The method ofthe present invention does not require Complete'dissolution of sertraline hydrochloride, controlling the rate ofheating or cooling of a sertraline solution, or controlling the rate of crystallization. The preserit method utilizes less solvent man the method ofthe '699 patent, since the sertraline hydrochloride starting material need not be completely dissolved.
hi the conversion ofsertraline hydrochloride Form VI, Form VII or Form VIU to
sertrahne hydrochloride Form H, according to the present invention, sertraline '.
hydrochloride Form VI, Form VK water adduct, or Form VTS is combined with an aprotic organic solventto form a slurry. Suitable solvents includen-tmtanol, acetone, t-butyl-metfayl ether (MTBE), ethyl acetate and cydobexaae. The conversion may take place at room temperature, but preferably the serfraiine hydrochloride Form VI, Form VII water
adduct, or Vffl 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 S (3 volumes of solvent) and 9 (5 volumes of solvent) below. Smaller amounts of solvent will also effectthe 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 VHI to Form JL.We have not'observed any further conversion ofForm K upon treatment under these conditions for times longer than the minimum time necessary to effect the transformation.
The present invention also provides new processes for making a mixture of sertraline hydrochloride Form II and sertraline hydrochloride Form V. In this embodiment ofthe 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 n and sertraline hydrochloride Form V. In this embodiment ofthe present invention, the heating of sertraline hydrochloride Form VI may be done under reduced pressure or atmospheric pressure. gorm V
The present invention provides new processes" for making sertralinehydrochloride 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 ofU.S. Patent No. 5,248,699, which we have not been able to reproduce. It has also surprisingly been found (hat, 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. Sertrahne hydrochloride Form V is then isolated by allowing the .solution to cool. One preferred method is to rapidly cool the solvent to 5DC. Another preferred method comprises seeding the solution with sertraline hydrochloride Form V crystals, followed by
slow cooling to room temperature, followedby filtration and drying.
Alternatively, Form V may be obtained by forming a solution or suspension of sertratine hydrocHoride 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 sertraiine hydrochloride to sertraiine hydrochloride Form V wherein the solvate sertraiine hydrochloride Form VI (described in more detail below) is an intermediate, hi this embodiment ofthe present invention, sertraiine hydrochloride is suspended or dissolved in
~eithff ttieQiafiol or ethanol or mixtures thereof thereby forming sertraiine hydrochloride Form VI. This intermediate sertraiine hydrochloride Form VI is then dried, with or without a separate isolation step, to remove all solvent and sertraiine hydrochloride Form V is isolated. Sertraiine hydrochloride Form V can also be prepared by suspending or dissolving sertraiine hydrochloride solvate Form VI in water.
Sertraiine hydrochloride Form V can also be prepared by drying Form VII (described inmore detail "below). In this embodiment ofthe present invention, sertraiine hydrochloride Form V is dried at80"C overnight thereby forming sertraiine hydrochloride
. P.ormV. ..-..- -• • ""• '
.Thepresentinvention also provides methods for the conversion of sertraiine hydrochloride to sertraline hydrochloride Form V wherein the sertraime hydrochloride Form Ylfl (described in-more detail below) is an intermediate; hi this embodiment ofthe present invention^ sertraline hydrochloride Form H is suspended or dissolved in water thereby forming sertraiine hydrochloride Form VtC. This intermediate sertraiine hydrochloride Form "VEIis then dried, "With or without a separate isolation step, to remove all solvent and sertraline hydrochloride Form V is isolated. Methods for the1 preparation of sertraline hydrochloride Ponnff are disclosed in U.S. applications serial nos. 09/448,985 filed November 24, 1999 and 09/575,634 filed May 22,2000, the contents ofwhich are 'hereby,_incorporated fey reference.
The present invention also provides methods for the conversion of sertraline base to sertraline hydrochloride Form V. In one such embodiment, sertraline base is added to at least one .solvent, and hydrogen chloride gas is bubbled through the solution. Suitable solvents include methaxtol, ethanoi, water, ethyl acetate, isopropyl alcohol, ether, hexane,
and toluene, and mixtures thereof. Alternatively, an appropriate amount ofhydrogen 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, nexane, isopropyl alcohol, or mixtures thereof, hi a variation ofthis method, sertraline base is added to a suitable solvent and the resulting solution is added to a hydrochloric acid solution ofpH 0-"^ preferably the pM of the solution is about 1.
Alternatively, sertraline base is added to a solvent. The solution is heated and concentrated hydrochloric acid is added. Watermay also be added. The solvent may be partially removed by distillation. Sertraline bydrochloride Form V is isolated by allowing the mixture to cool to room temperature-andremain 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 tfiereof.
Alternatively, sertraline base may "be- combined "mth a solvent "selecfedfrom the group
consisting ofmethanol, ethanol and amixture thereof. A saturated solution ofhydrogen chloride gas in isopropyl alcohol is added to induce formation ofsertraline hydrochloride Form V. Sertraline hydrochloride Form V is isolated by allowing the solution to stand at room temperature overnight, followed by filtration and drying ofthe precipitate.
Form Vmay also be obtained by forming ^suspension of sertraline base and hydrochloric acid in water or a •water/etbanol mixture and spray drying the suspension. In this embodiment of-the present invention, the solution'or'suspension ofsertraline base and hydrochloric acid is sprayed into a heated chamber. The temperature ofthe chamber is such that the solvent is removed thus forming sertraline hydrochloride Form V.
Sertraline base foruse in the processes ofthe present invention may be produced by dissolving sertraline mandelate in ethyl acetate followed by neutralization ofthe 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 sa oil. Methods for making sertraline base are set
forth inXJ.S. Patent Nos. 4,536,518 and 5,248,699, the contents ofwhich are incorporated herein by reference.
Where the present invention provides methods for the conversion of amorphous sertralmehydrochlorideto sertralihe hydrochloride Form V, amorphous sertraline bydroc&oride 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
•- extaiiplifitsi herein can be characterizedby its powder X-ray diffractionpattern. Figure 4 is a representative pattern of sertraline hydrochloride Form V. The principal peaks observed are at about 5.2° ±0.2, 10.4" ±0.2, 11.0° ±0.2,14.3° ±0.2, 16.5° ±0.2, 17.3° ±0.2, 184° ±0.2,19.r±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, and29.1 ° ±0.2 degrees 2 theta.
Three experiments were performed in order to repeatthe procedure described in U. S. Patent No. 5,248,699 for preparing Form V by sublimation. Two experiments were performed by sublimating a sample ofFoiin I under 30 mm Hg vacuum and temperature between J70-19D°C. A third experiment-was performe 24.1°±0.2,25:0^0.2,26.6D±0.2,30.7^.2, 34.7°±0.2 2two-theta. The TGA
curve shows a loss on drying of about 45%. Forms VIII and IX
Additional new crystalline foiiosof sertraline' hydrochtoride, Forms Yfll and DC, have also been discovered.. Sertraline hydrochloride hydrate Form VIH may be produced by suspending sertraline base in water and heating, followed by acidification and filtration. Form IX is obtained by drying ofForm VUL Preferably the sertraline base is suspended in
. water, the suspension heated to a temperature between about 30°C and about 80°C. Hydrogen chloride is added t© reduce the pH, preferably to between about 1 to about 4, and the resulting solution is cooled to room temperature. .
The present invention also provides new processes formaking sertraline hydrochloride Form VHI from sertraline hydrochloride ethanolate Form VI. In one
embodiment ofthe present invention, a slurry ofsertralinehydrochloride ethanolate 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 hydFOchloiide hydrate Form VIII is isolated.
The present invention also provides precesses ofmaking sertraline hydrochloride
Form VH1 from sertraline hydrochloride Form EL In the conversion of sertraline
hydrochloride Form II to sertraline hydroohloride Form VHI, sertraline hydrochloride Form
II is suspended in water or a mixture ofwater and isopropyl alcohol and stirred, preferably
—overnight, and sertraline hydrochloride hydrate Form VIII is isolated by filtration.
Sertraline hydrochloride Form VIII is characterized by x-ray powder diffraction peaks at 4:'7°±0.2,11.81>±0,25"l6.30±0.2, 17.8°±0.2,19.6°±0.2, 23.2°±0.2, 24.2°±0.2,25.r±0-2J and 26.0°±0.2 two-theta, as described in Figure 10.
The DSC thermogram for Form YEH is characterized by a strong endotherm below ] 00°C, small endothermic and exothermic events atabout220°C and a melting peak at 247°C as described in Figure 12.
The TGA curve shows a loss on drying step ofabout 20% below 100°C. ._.. TheIRsp_ectrum_ofForm Ylllis-cliaracterieedbythe following "bands: 740 cm"'? 779 ~ cm~1,822criftr887cnri,915 cm'1,1031 cm'1, 1053 cm"1,1110 cm'1,1134 cm'1,1153cm'1, 1217cm'1,1307cm-', and 1377cm'1, as described in Figure 14.
S ertraline bydrochloride Form IX is characterized by x-ray powder diffraction peaks
at 5.1°±0.2,14-20±G.2( 15.8°±0.2,16.8°±0.2,19.2°±0.2,19.7°4:0.2,2Z4°±0.2,23.2^0.2,
25.3°±0,2and26-l0±0.2two-aieta,asdescribedinFigure 11.
The IE-spectrum ofFormlXis.characterizedtythe following.'bands:701 cm~',715
cm'1,741 cm'V758cm'>7-80cm:1)816cm'1>823 cm'1, 1030cm:1, 1053 cm"1, lQ78'tnf' HlOran'1,1204cm"1, 1217cm'1,1307 cm'1, and 1350 cm"1, as-described in Figure 15,
FormX .
It has fiirtberbeen ^seoveredliiat another crystalhne form of sertraline hydrochloride, denominated Form X, may be obtained by suspending BeitraKnehydrochloride 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 15.0°±0.2,16.0°±0^, I6.5°±0.2, 17.0"±0.2, 18.1 *±OJ1,21.0''±0^ 22.4 D±0a, 24,9°±0.2,25.4 '±0.2, 26.2°±0.2,27.r±0.2! 28.4°±0.2, and 29.0 "±0.2 degrees two-thcta as described in Figure 17-
The Hi spectrum of Form X is characterized by the following bands: 742 cm'1, 776 cm"1, 806 cm-1, 824 cm'1,1002era', 1017 cm'1,1028 cm'1, 3060cm'1, 1079 cm*', .1135 cm' ', 1218 era"1,1314 cm'1,1336cm-1, and 1560cm'1 as described in Figure 18.
The DSC of Form X shows a sroall endotherm at about 190°C followed by a melting
endotherm at about 250°C (see Figure 19).
-Form BH
The present invention provides new processes formaking sertraline hydrochloride
Form TIE from sertraline hydrochloride Forms V and VI. In the conversion ofsertraline
bydrochltffide Form V to sejlraline hydrochloride Form HI, Form V is heated to a
temperature between about 150"C and about 18G°C for about 3 hours to about 2 days to
induce the formation of sertraline bydrochloride Form ID. Heating for 24 hours is
preferred. The reaction may be stirred. The method ofthe present invention has the
advantage ofusing no solvent.
ArnorghousSertralineHydrochleride '
hi an embodiment ofthe present invention, amorphous 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 ofsertraline hydrochloride.'
,. . The amorphous sertraline hycbrocbloride produced by methods of the present invention
is characterized "by-apowder x-ray diffraction pattern having the typical broad featureless
pattern without sharp peaks'typieal of amorphous materials. Figure 5 is one sachpattern.
Experimental
The powder X-ray diffraction patterns were obtained by methods known in the art using a ^Philips X-ray powder diffiactometer,Goniometer model 105t)/70at a scanning speed of2° perminute, with a Cu radiation ofX= 1 ;5418 A.
The differential-scaiming calorimeter thermograms "were obtained by methods known intheartusing aDSC Mettler821 Star0. The weight ofthe samples was less than 5 Tng. The temperature range ofscans was 3Q°C-30QSC at arate of lG°C/min- Samples were
purged with nitrogen gas at a flow rate of 40 iruVmiri. Standard 40 aluminum crucibles were used having lids with three small holes.
The infrared spectra were obtained by methods known in the art using a Perldn Elmer FT-IRParagon 1000spectrometer. Samples were analyzedinNujoImulls. Spectra were obtained at 4 cm'1 resolution and 16 scans each. Pharmaceutical Compositions Containing Sertraline Hydrochloride Jpolymorphs
hi accordance with the present invention, these new crystalline forms of sertraline hydrochloride and known forms ofsertraline hydrochloride prepared by the newmethods
""disclosed herein may be prepared as pharmaceutical compositions that are particularly useful for the treatment of depression, obsessive-compulsive disorder and panic disorder. Such compositions comprise one ofthe new crystalline forms ofsertraline hydrochloride with pharmaceutically acceptable carriers and/or excipients known to one of skill in the art.
For example, these compositions maybe prepared as medicaments to be administered
orally, parenterally, rectally, transderrnally, bucally, or nasally. Suitable forms for oral
administration include tablets, compressed or coated pills, dragees, sachets, bard or gelatin
capsules, sub-lingual tablets, syrups and suspensions. Suitable forms ofparenteral
administration include an aqueous or.nan^aqueous solution or- emulsions-while-ibrrectal"administration suitable forms for administration include suppositories with hydropailic or
hydrophobic vehicle. .Fortopical administration the invention provides suitable
transdermal delivery systems known in the art, and for nasal delivery there are provided
suitable aerosol delivery systems known in the art.
Pharmaceutical compositions ofthe present invention contain sertraline hydrochloride •Forms It, EH, and V to X, optionally in mixture with other form s or amorphous sertralioe. la addition to the active ingredient(s), the pharmaceutical compositions ofthe present invention may contain one or more excipients. Excipients are added to the composition for a variety pfpinposes.
Diluents increase the bulk of a solid pharmaceutical composition and may make a pharmaceutical dosage form containing the composition easier for the patient and care-giYerto 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 phosphate
dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbito] and talc.
Solid pharmaceutical compositions that are compactedinto 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, ethyl cellulose, gelatin, guar gum, hydrogenated -vegetableG&-,hydroxyethyl cerMoserbydroXypTopylcellulose (e.g. KJucel4),^ hydroxypropyl methyl cellulose (e:g.Methocel&), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. KoUIdon®, Plasdone®), pregelatinized starch, sodium alginate and starch.
The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach maybe increased by the addition of a disintegrant to the composition, r Disintegrantsinclude alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol"., Primellose®), colloidal silicon dioxide, crpscarmellGse .sodium, crospovidoae (e.gt KeHidon®j Polyplasdone®), guar glflli; magnesium aluminum sihcate, methyl cellulose,microcrystallme cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch . . glycplat& (e.g. Explotab®) and starch.
Glidants-canbe added to. improve the flowabilityofnon-compacted solid composition
andimproTeibe accuracy of dosing. Excipients that may function as glidants include
,. coUoidal aliconrdixoide, magaesram trisilicate, powdered celhilo'se, starch, talc and
-tribasic calcium 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 arid dye. Some fixcipieBts and active ingredients have a tendency to adhere to the surfaces ofthe punch and dye, which can cause the productto have pittbg and other surface irregularities. A lubricant caa "be added to the; composition to reduce adhesion sad ease release ofthe product form the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl moaostearate, glyceryl palmitostearate, 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 maybe included in the composition ofthe 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 ofthe 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 excipientthat is not soluble in the liquid carrier. Emulsifying agents that may be useful in liquid compositions ofthe present invention include, for example, gelatin, egg yolk, casern, cholesterol, acacia, tragacanth, chondrus,-pectin methyl cellulose, carbomer,-cetostearyhalcohol"and"oetyl alcohol.
Liquid pharmaceutical compositions ofthe present invention may also contain a . viscosity enhancing agent to improve the mouth-feel ofthe product and/or coatthe lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcelrulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcelhdose, gelatin guargum, hydroxyethyl cellulose, hydroxypropyj cellulose nydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol algiimte, sodium alginate, sodium starch glycolate; starch tragacanth and xanthan gum.
Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspaitame, fiuctose, inannitol and invert sugar may be added to improve the taste.
Preservatives and chelatmg agents such as alcohol, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole and ethylenediarnine 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 ofstandard procedures and reference works in the field.
The solid compositions of the present invention include powders, granulates,
s and compacted compositions. The dosages include dosages suitable for oral,
"bnccal; rectal, pafenteral-(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 ofthe present invention is oral. The dosages may be conveniently presented in unit dosage form andpreparedby any oftbemethods 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.
is a capsule containing the composition,
preferably a powdered or granulated solid composition ofthe invention, within either a hard or soft shell. The shell may be made from gelatin and optionally contain aplasticizer such as glycerin and sorbitol, and an'Opacifying agent or colorant.
• The active ingredient and excipients may'be formulated into compositions and dosage forms according to methods known in the art
A composition fortableting orcapsulefyling may be prepared by wet granulation, hi wet granulation some or all ofthe active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump up into granules. The granulate is screened and/ormilled, dried and then screened anel/ormilled to the desired particle sisse. The granulatemaythenbe tableted or other excipients may fee added prior to tableting such as'glidantand or lubricant.
Atableting composition may be prepared conventionally by dryblending. For instance, the blended composition ofthe actives and excipients may be compacted into a
slug or a sheet and then comminuted into compacted granules. The compacted granules maybe compressed subsequently into atab]et.
As an alternative to dry granulation, a blended composition may be compressed directly into a compacted dosage form using direct compressi on techniques. Direct compression produces amore uniform tablet without granules. Excipients that are particularly well suited to direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrata 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 ofthe present invention may comprise any ofthe 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 dosage level of about 20,25, 50 or lOOmgofequivalentbase.
, EXAMPLES
-The ^presentrmvention will now be "further explained in the following examples. However, the present invention should not be construed as limited thereby. One of ordinary skill in the art will understand how to vary the exemplified preparations to obtain the desired results.
Example 1 . .
Preparation of Sertraline Base
Sertralinemandelate was prepared according to procedures in U.S. OPatentNo.
• 5,248,699. Sertralinemandelate (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
overMgS.Q4 and filtered. "He solvent was removed tinder reduced pressure resulting in
sertralinetase as an oil (3.2 g).
Example 2 Preparation of Sertraline HydrochlorideEthanolateFonn VI by Reslurry ofForm I
Sertraline hydrochloride Form I (1 g) and absolute ethanol (20 mL) were stirred at .room temperature for 24 hours. Filtration ofthe mixture yielded sertraline hydrochloride ethanolate Form VI.
Example 3 Preparation of Sertraline Hydrochloride Ethanolate Form VI by Reslurry of Form V
SertralinehydrocMoride Form V (1 g) and ethanol absolute (20 mL) were stirred at room temperature for 24 hrs. Filtration ofthe mixture yielded sertraline hydrochloride ethanolate Form VI.
Example 4 Preparation of Sertraline Hydrochloride Form II
Sertraline base (3 g) was dissolved in acetone (]OmL). 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 hydrpchlpride Form H (2.61 g, yjeld 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 TVas reached Then the stirring was continued at room temperature for 2.5 u. During the stirring the solid became a fine crystalline solid. The solid was filtered, washed withn-butanql (2 x l!QrnL):and dried at 80°C for 24 h. The product is sertraline hydrochloride Form EL 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 dimethylforrnarmde (DMF) (30mL). Heating was started and at about 70°C a clear solution is obtained. The solution was cooled to room temperature and the solid was filtered. After drying at 80°C for 24
ins., sertraline hydrochloride Form II was obtained (6.6 g, yield 66%).
Example 7 Preparation of Sertraline Hydrochloride Form II by Granulation of Form V
Sertraline hyydrochlorideFormV (2 g) and absolute ethanol (0.5 mL)were stirred in a rotavapor at room temperature for 2 days. At the end oftwo 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-methy] 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 II from Form VI
• SertraMne hydrochloride Form VI (25 g) Was sfnre'dwftK acetone (25Cf hiLyattbonf "
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 %). t
. . Preparation of Sertraline Hydrochloride Form H. and Sertraline Hydrochloride Form V by Drying Form VI
Sertraline hydrochloride ethanolate Form VI was dried at 105"Cunder vacuum " {< 10 mm Hg) over 24 hours. The resulting dried material was sertraline ibydrochJoride Foim JH mixed with sertraline hydrochloride Form V.
Example 11
Preparation of Sertraline Hydrochloride Form n from Sertraline Mandelate in n-Butanol

mixtur
Sertraline mandelate (20 g) and n-butanol were stirred at room temperature. The e was acidified with hydrogen cb3oride until pH 0 was reached. During the cidification the temperature ofthe reaction mixture rose to -50DC. After the natural
cooling to room temperature, the mixture was stirred at room temperature for two hours. The solid was filtrated, washed with o-bulanol and dried at 80°Cto afford sertraline hydrochloride Form H (9.02 g).
Example 12
Preparation of Sertraline Hydrochloride Form n from SertraiinfeHydrochloriaeForm Vm
Sertraline hydrochloride Form YIH (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 "wjtE acetone (2x10 mL). After drying sertraline hydrochloride Form II was obtained (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 mL). After separation ofthe 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 - - wag 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,
JSgampje 14
An aqueous sodium hydroxide solution, 10%, was added drop-wise to a slurry of sertraline raandelate 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 t&en diluted with ether (820 mL) and gaseous hydrogen "chloride %Z.36g, 2 eq.) was:bubbled through the solution until pH 1.5 wasreached Thetemperaturewasabout25c'C- The slurry was stirred at room temperature overnight. Thesolidwasfiltiated,washedwith ether (2 x 15mL)andair-dried The dried solid, sertraline hydrochloride, was not sertraline hydrochloride Form II.
Example 15
An aqueous sodium hydroxide solution, 30 %,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 ofether (820 inL). Gaseous hydrochloric acid (4.82 g) was bubbled through the solution until pH 1 was reached. The sluny was stirred at room temperature overnight. The solid was filtrated, washed with ether (2x15 rnL) and air-dried. The dried solid, sertraline hydrochloride, was not Form II:
Example 16
An aqueous sodium hydroxide solution, 10%>was added drop-wise to a slurry of sertralinemandelate crystals (15 g) in ethyl acetate (81 OmL), until complete dissolution is obtained. The phases were separated and the organic phase was dried overMgSO4 and diluted with an equal volume ofether (820 rnL). Gaseous hydrogen chloride was slowly bubbled through the solution (over about 3 hours) until pH I.5 was reached. The slurry "was stirred at room temperature over night. The dried solid, sertraline hydroebloride, was not sertraline hydrochloride Form IL_
Example 17 Preparation ofSertraline Hydrochloride Form VHI
Sertraline base (2.7 g) was suspended in 27 mL ofwater. 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 and found to "bs sertraline hydrochloride Form VIH.
Example 18 Preparation of Sertraline Hydrocbloride Form VEH
•Sertraline hydrochloride ethariolate (Form V3) (40 g) was stirred with water (80 mL) for 1 hour at room temperature. The slurry was filtrated andwashed with waterto yield sertraline hydrochloride hydrate Form VTO.
Preparation ofSertraline Hydrochloride Form VH Sertraline hydrochloride Form V (1.003 g) was stirred for 24 hours atroom
temperature in 20 mL water (HPLC grade). At the end of the stirring the mixture looked . like ajelly suspension. The suspension was filtrated and the compound obtained was kept at cold conditions (4°c until analyzed by x-ray diffraction, which determined the compound to be sertraline hydrochloride Form VII.
Exampie20 Preparation of Sertraline Hydrochloride Form VI and Form V
Sertraline base (25 g) was dissolved in methanol (125 rnL) at room temperature. The solution was acidified with hydrogen chloride gas until pH 1.5 was reached. (Precipitation -occurred(faring acidfication} the temperature rose to approximately 40°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.
Exam pie 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 until pH 0,5 .was reached. The temperature lose to 40°C. The slimy was allowed to cool to room temperature and stirred for about 16 hours. The solid was separated by filtration, and washed with ethanol (3 x 2 mL). Figure 5 sets forth the X-ray diffraction pattern ofthe product (sertraline hydrochloride ethaoolate Form VI) so obtained. Drying overnight, at 50-6~0°C of that product yielded 2.95 g (82%) of sertraline hydrochlbride Porm 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 ofhydrogen chloride in isopropyl alcohol was added dropwise to -reaefo-apH of 1.3. 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%) sertrahline iydrpcbloride Form V.
Example 23. Preparation of Sertraline Hydrochloride Form V
Sertrahne 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
Sertranne,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 stined for j. 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 at40"CJ The solution was heated to 50°-60°C and concentrated hydrochloric acid 32% (1.2 mL) was added until pH-13 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 Hydrpchlqride1 Form V
Sertraline base (3.7 g) was dissolved in 18.5 mL absolute ethanol and the solution was heated to 60°C. Hydrogen chloride gas was bubbled through the ethanol solution until pH ~Gv5 was reached. The mixture was 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 Torra 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.
Preparation of Sertraline Hydrocnloride Form V
Sertrahne free base (13.3 g) was dissolved in absolute ethanol (60 mL) and was addet dropwise over one hour to ethanol (20 mL) containing hydrogen chloride (1 7.5 g) at 35°C with precipitation. After 2 hours, the solid was filtrated, washed with ethanol and dried at about 80° C to yield sertraline hydrochloride Form V (12.9 g, yield 87%).
Example 29 Preparation of Sertraline Hydrochloride Form V _
Anhydrous sertraline hydrochloride (2 g) was stirred with 1 4mL 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 5Q°C, The slurry was stirred at room temperature during 2 hours. The solid was filtered, washed with ethanol (3 mL) and dried overnight at 50-6QDC yielding 1.71 g (85.5%) ofsertraline hydrochloride Form V.
Example 30
Preparation of Sertraline Hydrochloride Form V
Sertrahne bydrocHoride 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 50flC for approximately 16hours, yielding sertialine hydrochloride Form V.
Example 31 Preparation of Sertraline Hydrochloride Form V
Sertraline hydrochloride ethanolate (Form VI) (2 g) was mechanically stirred with
-etbanoi-(ft5 mL) at room temperature foF4"0~lToais. The resulting solid was sertraline hydrochloride Form V.
Table! sets forth a summary of additional experiments conducted generally following procedures described above.

TABLE 1 PREPARATION OF SERTRALINE HCL - FORM V
SERTRALINE BASE AS STARTING MATERIA
(Table Removed)
PXRD = powder x-ray diffraction.
Example 32 Preparation of Sertraline Hydrochloride Form V
1.003 g Sertraline hydrochloride Form V was stirred for 24 hours at room temperature in 20 mL water (HPLC grade). At the'end of the stirring the mixture looked like a jelly suspension. The suspension was filtrated and the compound obtained was kep
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 VI) (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 VH dried overnight at 80°C forms sertraline rochloride Form V.
Example 34
Preparation of Sertraline Hydrochloride Forms VIII and IX from Sertrajine Base
" Sertrahne base (2.1 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 DC, characterized by powder x-ray diffraction, infra-red absorption, differentia] scanning calorimetry, 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 H
Sertraline hydrochloride Form H (0.4 g) and water (8 mL) were stirred at room temperature over night The solid was filtrated to yield sertraline hydrochloride hydrate FormVUI. .
Example 36 Preparation of .Sertraline Hydrochloride Form X
In a 0.1 liter three-necked bottom round flask equipped with a mechanical stirrer, a condenser and a therinometerJS&jnlJieiizyl^lGohoMs-added^^
hydrochloride. The suspension is heated to 100°C when a clear solution is obtained. The solution is cooled 2 hours to 25°C and the precipitate is faltered and washed with ben2yl 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
Sertralinf- free base (1 0 g) was dissnlvprl in ethyl acetate (100 ml-). At room 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 fronrForm
Sertraliiie hydrochloride Form V was heated at 1 50° 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 HI from Form VI
Sertraline hydrochloride form VI was heated to 180° C for 24 hours. The dried material is sertraline hydroehloride Form HI.
Example 41 Preparation of Sertraline Hydrp,chloride Form HI from Form V
Sertraline hydrochloride 'Form V was heated at a temperature 2. 180° C for 24 hours. The resulting material was sertraline hydrochloride Form HI.
Preparation of Amorphous Sertraline Hydrochloride
Sertraline hydrochloride Form V (1 0 g) was dissolved in water (2L) and this solution was dried by the spray dryer technique. The material obtained in this way is Sertralme 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 Preparationof sertraline Hydrochlide Form V
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.frorn 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 V comprising
the steps of:
(a) dissolving or suspending sertraline base in ether
(b) adding hydrogen chloride to the solvent to reduce the pH of
the solution or suspension; and
(c) isolating sertraline hydrochloride Form V from the solution
or suspension.
2. The process as claimed in claim 1, wherein the pH of the solution
or suspension of sertraline base and hydrogen chloride is about 0
to about 4.
3 A process for making sertraline hydrochloride Form V substantially as herein described with reference to the foregoing description.