complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the
same molecular formula yet having distinct advantageous physical properties compared to
other crystalline forms of the same compound or complex.
[0008] One of the most important physical properties of pharmaceutical
compounds is their solubility in aqueous solution, particularly their solubility in the
gastric juices of a patient. For example, where absorption through the gastrointestinal
tract is slow, it is often desirable for a drug that is unstable to conditions in die patient's
stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious
environment. Different crystalline forms or polymorphs of the same pharmaceutical
compounds can and reportedly do have different aqueous solubilities.
[0009] The discovery of new polymorphic forms of a pharmaceutically useful
compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. There is a need in the art for polymorphic forms of duloxetine HCI.
iSUMMARY OP THE INVENTION
[00010] In one embodiment, the present invention provides crystalline duloxetine
HCI, herein defined as Form B, characterized by X-ray powder diffraction peaks at about
11.1,12.1,14.9,21.6 and 24.2 degrees two-meta± 0.2 degrees two-roeta.
[00011] In another embodiment, the present invention provides a method of
preparing duloxetine HCI crystal Form B, comprising providing a solution of duloxetine
HCI in water and a solvent selected from the group consisting of CM alcohols, and
removing the solvent to obtain duloxetine HCI crystal Form B.
[00012] In another embodiment, the present invention provides a process of
preparing purely amorphous form of duloxetine HCI, comprising spray drying a solution of duloxetine HCI in a solvent selected from the group consisting of CM alcohols, where the inlet temperature is ambient, and the outlet temperature is less than the inlet temperature.
[00013] m another embodiment, the present invention provides pharmaceutical
compositions comprising duloxetine HCI crystal Form B.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 illustrates the powder X-ray diffraction pattern for duloxetine HC1 Form A. Figure 2 illustrates the powder X-ray diffraction pattern for duloxetine HC1 Form B. Figure 3 illustrates the IR spectrum for duloxetine HC1 Form A from 4000 to 400 cm"1. Figure 4 illustrates the IR spectrum for duloxetine HC1 Form A from 4000 to 2000 cm"1. Figure 5 illustrates the IR spectrum for duloxetine HC1 Form A from 2000 to 1000 cm"1. Figure 6 illustrates the IR spectrum for duloxetine HC1 Form A from 1000 to 400 cm"1. Figure 7 illustrates the IR spectrum for duloxetine HC1 Form B from 4000 to 400 cm"1. Figure 8 illustrates the IR spectrum for duloxetine HC1 Form B from 4000 to 2000 cm"1. Figure 9 illustrates the IR spectrum for duloxetine HC1 Form B from 2000 to 1000 cm"1. Figure 10 illustrates the IR spectrum for duloxetine HC1 Form B from 1000 to 400 cm"1. Figure 11 illustrates the Raman spectrum for duloxetine HC1 Form A from about 3500 to about 50 cm-1.
Figure 12 illustrates the Raman spectrum for duloxetine HC1 Form A from about 3500 to 1500cm-1.
Figure 13 illustrates the Raman spectrum for duloxetine HC1 Form A from 1500 to 750 cm-1.
Figure 14 illustrates the Raman spectrum for duloxetine HC1 Form A from 750 to 50 cm-1.
Figure 15 illustrates the Raman spectrum for duloxetine HC1 Form B from about 3500 to about 50 cm-1.
Figure 16 illustrates the Raman spectrum for duloxetine HC1 Form B from about 3500 to 1500cm-1.
Figure 17 illustrates the Raman spectrum for duloxetine HC1 Form B from 1500 to 750cm-1.
Figure 18 illustrates the Raman spectrum for duloxetine HC1 Form B from 750 to 50 cm"1. Figure 19 illustrates the powder X-ray diffraction pattern for the purely amorphous form of duloxetine HC1.
IWMiFD DESCRIPTION OF THE INVENTIQN
[00014] As used herein the term "anhydrous" refers to duloxetine HCI containing not more than 1% water/solvent by weight.
[00015] As used herein, the term "purely amorphous" in reference to duloxetine
hydrochloride, refers to non-crystalline duloxetine HCL Preferably, the purely amorphous
duloxetine hydrochloride contains less than about 5 percent crystalline forms, more
preferably, less than about 3 percent, and, most preferably, less than about 1 percent, as
measured as area percentage of peaks present in the XRD diffractogram.
[00016] As discussed above, preparation of duloxetine HC1 using prior art
processes provides an anhydrous crystalline form of duloxetine HC1 in a form referred to
herein as Form A. Crystals of Form A duloxetine HC1 were analyzed using an X-ray
diffraction (XRD) diffractometer, a Fourier Transform Infrared (FTIR) spectrometer, and
a Fourier Transform Raman (FTRaman) spectrometer. The XRD pattern of Form A
obtained in the XRD analysis is illustrated hi Fig. 1, the FTIR spectrum of Form A is
illustrated in Figs. 3 to 6, and the FTRaman spectrum of Form A is illustrated in Figs. 11
to 14.
[00017] in one embodiment, the present invention provides crystalline duloxetine
HC1, herein defined as Form B. Form B of duloxetine HC1 is characteristically different
from Form A, as demonstrated by its XRD pattern, illustrated in Fig. 2, its FTIR
spectrum, illustrated in Figs. 7 to 10, and its FTRaman spectrum, illustrated in Figs. 15 to
18.
[00018] Duloxetine HC1 crystal Form B in accordance with the invention is
characterized by X ray powder diffraction peaks at about 11.1,12.1,14.9,21.6 and 24.2
degrees two-theta ± 02 degrees two-theta. The crystalline form may be further
characterized by a X-ray powder diffraction pattern with peaks at about 16.3 and 27.1 ±
0.2 degrees two-theta
[00019] Duloxetine HC1 crystal Form B in accordance with the invention can also
be characterized by a weight loss measured by thermal gravimetric analysis (TGA) of
about 0.3 percent by weight
[00020] Duloxetine HC1 crystal Form B in accordance with the invention can also
be characterized by an FTIR spectrum with characteristic peaks at about 1093,1024,797,
and 778 cm"1'
[00021 ] Duloxetine HC1 crystal Form B in accordance with the invention can also
be characterized by an FT Raman spectrum with characteristic peaks at about 2931,1379,
512, and 469 cm-1.
[00022] Duloxetine HCL crystal Form B in accordance with the invention is an
anhydrous form.
[00023] In a further embodiment, the invention is directed to polymorphically pure
duloxetine HC1 Form B. As used herein, the term "polymorphically pure" means that the
Form B duloxetine HC1 crystalline contains impurities in an amount of less than about 5
percent by weight, based on the total weight of duloxetine HC1. The term "impurities" is
defined to include other polymorphic forms of duloxetine HC1, including, but not limited
to, Form A.
j 00024] Preferably, the Form B of duloxetine HC1 polymorph has an average
particle size of no more than about 500 /mi, more preferably, no more than about 300 pxn,
more preferably, no more than about 200 p.m, and, most preferably, no more than about
100 (mi. A particularly preferred Form B duloxetine HC1 polymorph has an average
particle size of no more than about 50 fjan.
100025] As used herein, the term "average particle size" refers to the average
particle diameter, which may be measured by any method commonly known in the art,
including, but not limited to, sieves, sedimentation, electrozone sensing (coulter counter),
microscopy, or Low Angle Laser Light Scattering (LALLS).
100026] In another embodiment, the present invention provides a method of
preparing duloxetine HC1 crystal Form B, comprising providing a solution of duloxetine
MCI in water and a solvent selected from the group consisting of CM alcohols, and
removing the solvent to obtain duloxetine HC1 crystal Form B.
[00027] Preferably, the solvent is selected from a group consisting of methanol and
ethanol. Most preferably, the solvent is methanol.
[00028] Preferably, before removing the solvent, the solution is maintained while
stirring. More preferably, the solution is maintained while stirring at about room
temperature for about 15 minutes.
100029] Preferably, the solvent is removed by evaporation. More preferably, the
solvent is evaporated to dryness at a temperature of from about 35° to about 45°C.
[00030] Duloxetine HC1 crystal Form B may be recovered by any method known
in the art, such as drying the particles, preferably at a temperature of from about 40°C to
about 53°C under reduced pressure.
[00031] In another embodiment, the present invention provides a process of
preparing purely amorphous form of duloxetine HCL The broad powder X-ray
diffraction pattern of the purely amorphous form of duloxetine HC1 is illustrated in Fig.
19. This process comprises spray drying a solution of duloxetine HC1 in a solvent
selected from the group consisting of CM alcohols, where the inlet temperature is
ambient, and the outlet temperature is less than the inlet temperature.
[00032] Preferably, the solvent is selected from a group consisting of methanol and
ethanol. Most preferably, the solvent is methanol.
[00033] The spray drying may preferably be conducted with an outlet temperature
of below about 20°C, and more preferably about 18°C.
[00034] Spray drying broadly refers to processes involving breaking up liquid
mixtures into small droplets (atomization), and rapidly removing solvent from the
mixture. In a typical spray drying apparatus, there is a strong driving force for
evaporation of solvent from the droplets, which may be provided by providing a drying
gas. Spray drying processes and equipment are described in Perry's Chemical Engineer's
Handbook, pp. 20-54 to 20-57 (6th ed. 1984) and Remington: The Science and Practice of
Pharmacy, 19th ed., vol. fl, pg. 1627, which are herein incorporated by reference.
[00035] By way of non-limiting example only, the typical spray drying apparatus
comprises a drying chamber, atomizing means for atomizing a solvent-containing feed
into the drying chamber, a source of drying gas that flows into the drying chamber to
remove solvent from the atomized-solvent-containing feed; an outlet for the products of
drying, and product collection means located downstream of the drying chamber.
Examples of such apparatuses include Niro Models PSD-1, PSD-2 and PSD-4 (Niro A/S,
Soefaorg, Denmark). Typically, the product collection means includes a cyclone
connected to the drying apparatus. In the cyclone, the particles produced during spray
drying are separated from the drying gas and evaporated solvent, allowing the particles to
be collected. A filter may also be used to separate and collect the particles produced by
spray drying.
[00036] The drying gas used in the process of the present invention may be any
suitable gas, although inert gases such as nitrogen, nitrogen-enriched air, and argon are
preferred.
[00037] fhe duloxetine HC1 product produced by spray drying may be recovered
by techniques commonly used in the art, such as using a cyclone or a filter.
[0003 8] In another embodiment, the present invention provides pharmaceutical
compositions comprising duloxetine HC1 crystal Form B.
[00039] Pharmaceutical compositions may be prepared as medicaments to be administered orally, parenterally, rectally, transdermally, bucally, or nasally. Suitable forms for oral administration include tablets, compressed or coated pills, dragees, sachets, hard or gelatin capsules, sub-lingual tablets, syrups, and suspensions. Suitable forms of parenteral administration include an aqueous or non-aqueous solution or emulsion, while for rectal administration, suitable forms for administration include suppositories with hydrophilic or hydrophobia vehicle. For topical administration, the invention provides suitable transdermal delivery systems known in the art, and, for nasal delivery, there are provided suitable aerosol delivery systems known in the art.
[00040] In addition to the active ingredients), the pharmaceutical compositions of the present invention may contain one or more excipients or adjuvants. 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.
[00041 ] 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 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 phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragjt*), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc. [00042] Solid pharmaceutical compositions that are compacted into a dosage form, such as 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 vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel*), hydroxypropyl methyl cellulose (e.g. Methocel*), liquid glucose, magnesium aluminum silicate, maltodextrin, memylcellulose, polymethacrylates, povidone (e.g. Kollidon*, Plasdone"5*), pregelatimzed starch, sodium alginate, and starch. [00043] The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a tfa'sintegrant to the
composition. Disintegrants include alginic acid, carboxymethyicelrolose calcium, carboxyrnethylcelhilose sodium (e.g. Ac-Di-Sol®, Primellc-se®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum, magnesium alummum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Bxplotab®), and starch,
[00044] Glidants can be added to improve the flowabifity of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
[00045] When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and die. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and die, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the die. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl pahnitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauiyl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate. [00046] 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, fumade acid, ethyl maltol, and tartaric acid,
[00047] Solid and liquid compositions may also be died using any
pharmaceuticaUy acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
[00048] In liquid pharmaceutical compositions of the present invention, the active
ingredient and any other solid excipients are suspended in a liquid carrier, such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin. [00049] 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, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl
alcohol, and cetyl alcohol.
[00050] 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, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl
cellulose, emylcellulose., gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl
cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone,
propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch grycolate,
starch tragacanth, and xanthan gum.
[00051 ] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose,
aspartame, fructose, mannitol, and invert sugar may be added to improve the taste.
[00052] Preservatives and chelating agents such as alcohol, sodium benzoate,
butyiated hydroxy toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic
acid may be added at levels safe for ingestion to improve storage stability.
[00053] According to the present invention, a liquid composition may also contain
a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate,
sodium lactate, sodium citrate, or sodium acetate.
[00054] Selection of excipients and the amounts used may be readily determined
by the formulation scientist based upon experience and consideration of standard
procedures and reference works in the field.
[00055] The solid compositions of the present invention include powders,
granulates, aggregates, and compacted compositions. The dosages include dosages
suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and
intravenous), inhalant, and ophthalmic administration. Although the most suitable
administration 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.
[00056] Dosage forms include solid dosage forms like tablets, powders, capsules,
suppositories, sachets, troches, and losenges, as well as Liquid syrups, suspensions, and
elixirs.

[00057] The dosage form of the present invention may be a capsule containing the
composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell. The shell may be made from gelatin, and, optionally, contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant [00058] The active ingredient and excipients may be formulated into compositions and dosage forms according to methods known in the art.
[00059] A composition for tableting or capsule filling 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 former mixed in the presence of a liquid, typically water, that causes the powders to clump into granules. The granulate is screened and/or milled, dried, and then screened and/or milled to the desired particle size. The granulate may then be tabletod or other excipients may be added prior to tableting, such as a glidant and/or a lubricant.
[00060] A tableting composition may be prepared conventionally by dry blending.
For example, 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 subsequently be compressed into a tablet
[00061 ] 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 for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients hi direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
[00062] A capsule filling of the present invention may comprise any of the
aforementioned blends and granulates that were described with reference to tableting, however, they are not subjected to a final tableting step.
[00063] While it is apparent that the invention disclosed herein is well calculated to
fulfill the objects stated above, it will be appreciated that numerous modifications and embodiments may be devised by those skilled in the art. Therefore, it is intended that the appended claims cover all such modifications and embodiments as falling within the true spirit and scope of the present invention.
EXAMPLES
[00064] While the present invention is described with respect to particular examples and preferred embodiments, it is understood that the present invention is not limited to these examples and embodiments. The present invention, therefore, includes variations front the particular examples and preferred embodiments described herein, as will be apparent to one of skill in foe art
[00065] i he X-ray difEraction diffractometer used to analyze and identify the
crystalline forms of duloxetine HC1 was a Scintag X-ray powder diffractometer model X'TRA, Cu-tube solid state detector. The sample holder was a standard round aluminum sample holder with a rough zero background quartz plate, having a cavity diameter of 25 mm and a depth of 0.5 mm. The scanning parameters were:
range. 2 to 40° 20; scan mode: continuous scan; step size: 0.05 deg.; and rate: 3 degiteinwte,
[00066] The FUR spectrometer used to analyze and identify the crystalline forms of duloxetine HC1 was a Perkin-Elmer Spectrum One Spectrometer, incorporating the Diffuse Reflectance Accessory. Samples were finely ground with potassium bromide, and spectra were recorded using a diffuse reflectance technique and a potassium bromide background in the Diffused Reflectance Accessory. The scanning parameters were:
Wavelength range; 4000 to 400 cm-1; Scans: 16 scans; and Resolution: 4.0 cm-1.
[00067] The FTRaman spectrometer used to analyze and identify the crystalline forms of duloxetine HC1 was a Bruker RFS-100/S Raman spectrometer. The scanning parameters were:
Range: 3500 to 50 cm-1,
Aperture Setting: 10.0mm;
Low Pass Filter 16: 1kHz;
Source Setting Laser. 9394.0 cm'1,1600 mW;
Raman Laser Power 500 mW;
Scanner Velocity 5.0 at 4 kHz;
Sample Scans: 100; and
Resolution: 4.0cm-1.
[00068] Typically, for a determination of weight loss (LOD) by Thermal Gravimetric Analysis (TGA), a sample was heated from about 25°C to about 200°C at a heating rate of about 10°C per minute, while purging with nitrogen gas at a flow rate of 40 ml/minute.
Example 1
[00069] Fifty milliliters of water were added to a solution of 2 g of duloxetine hydrochloride in 25 ml methanol. The solution was stirred at room temperature for fifteen minutes, and the solvent evaporated at 4S°C under vacuum to give the wet solid, which was analyzed by XRD, to be duloxetine HCL Form B. The XRD data is provided in Fig. 2,
Example 2
[00070] Fifty milliliters of water were added to a solution of 2 g of duloxetine hydrochloride in 25 ml of methanol. The solution was stirred at room temperature for fifteen minutes, evaporated to dryness at 4S°C under vacuum, and dried in a vacuum oven at 40 °C for 15 hours. The resulting solid was analyzed by XRD, to be duloxetine HCL Form B. The XRD data is provided in Fig. 2.
Example 3
[00071] Ten grams of duloxetine hydrochloride was dissolved in 250 ml of metbanol, and the resulting solution was sprayed at a rate of 72ml/hour into a chamber with ambient nitrogen at a co-current flow of 38ras/hour and a temperature of 42°C. The atomizing flow of nitrogen at 6601/hour produced droplets, leading to a high evaporation rate. The temperature of the outlet solids was fixed at 32°C. The resulting powder was analyzed using XRD, and found to be the purely amorphous form.
Example 4
[00072] Ten grams of duloxetine hydrochloride was dissolved in 250 ml of methanol, and the resulting solution was sprayed at 145ml/nour into a chamber with ambient nitrogen at a co-current flow of 38m3/hour and a temperature of 27°C. The atomizing flow of nitrogen at 4401/hour produced droplets, leading to a high evaporation
rate. The temperature of the outlet solids was fixed at 18°C. The resulting powder was analyzed by XRD, and found to be the purely amorphous form.

What is claimed:
1. A crystalline form of duloxetine hydrochloride, characterized by at least one of:
an X-ray powder diffraction pattern having peaks at about 11.1,12.1,14.9,163,21.6,
24.2,27-1, and 30.0 degrees two-theta ± 0.2 degrees two-theta;
an IR spectrum having peaks at about 1093,1024, 797, and 778 ran"1; and
a Raman spectrum having peaks at about 2931,1379,512, and 469 on"1.
2. The crystalline form of claim 1, characterized by X-ray powder diffraction pattern
havingpeaks at about 11.1,12.1,14.9,21.6 and 24.2 degrees two-thetadb 0.2 degrees
two-theta.
3. The crystalline form of claim 2, further characterized by X-ray powder diffraction
pattern having peaks at about f 6,2, and27.1 degrees two-theta ± 0.2 degrees two-
theta.
4. The crystalline form of claim 3, characterized by an XRD pattern substantially
identified by Figure 2.
5. The crystalline form of claim 1, characterized by IR spectrum having peaks at about
1093,1024,797, and 778 cm'1.
6. The crystalline form of claim 5, characterized by an IR spectrum substantially
identified by Figures 7-10.
7. The crystalline form of claim I, characterized by a Raman spectrum having peaks at
about 2931,1379, 512, and 469 cm'1.
8. The crystalline form of claim 7, characterized by a Raman spectrum substantially
identified by Figures 15-18.
9. The crystalline form of chum 1, comprising less than about 5 percent by weight of
other polymorphic forms of dujoxetine hydrochloride.
10. A method of preparing the crystalline form of claim 1 comprising:
a. providing a solution of duloxetine HC1 in water and a solvent selected from the
group consisting of CM alcohols; and
b. remo vtag the solvent, to obtain the crystalline form of claim 1.
11. The method of claim 10, wherein the solvent is selected from a group consisting of
methanol and ethanol,
12. The method of claim 11, wherein the solvent is methanol.
13. The method of claim 10, wherein the solvent is removed by evaporation.
14. The method of claim 13, wherein the solvent is evaporated to dryneas at a temperature
of from about 35° to about 45°C.
15. A process of preparing purely amorphous form of duloxetine HC1 comprising spray
drying a solution of duloxetine HC1 in a solvent selected from the group consisting of
CM alcohols, wherein the spray has an ambient inlet temperature and an outlet
temperature less than die inlet temperature.
16. The process of claim 15, wherein the solvent is selected from the group consisting of
methanol and ethanoi,
17. The process of claim 16, wherein the solvent is methanol.
18. The process of claim 15, wherein the outlet temperature is below about 20°C.
19. The process of claim 18 wherein the outlet temperature is 18°C.
20. A pharmaceutical composition, comprising the crystalline form of claim 1.