US20070238738A1

US20070238738A1 - Crystalline ziprasidone HCI and processes for preparation thereof

Info

Publication number: US20070238738A1
Application number: US11/804,301
Authority: US
Inventors: Anna Balanov; Judith Aronhime; Boaz Gome; Tamas Koltai; Natalia Shenkar; Marioara Mendelovici; Ehud Amir
Original assignee: Teva Pharmaceutical Industries Ltd; Entire Interest
Current assignee: Teva Pharmaceutical Industries Ltd; Entire Interest
Priority date: 2003-06-03
Filing date: 2007-05-16
Publication date: 2007-10-11
Also published as: WO2005035531A1; IL172004A0; CA2528192A1; WO2005016325A3; KR100880279B1; CA2528100A1; US20080090835A1; EP1546146A1; KR20060015750A; KR20060024788A; KR20080093164A; US20080091020A1; EP1530570A2; US20050059680A1; KR20080022595A; IL172005A0; US7678799B2; US20050043324A1; WO2005016325A2

Abstract

Provided is crystalline ziprasidone HCl and processes for preparation thereof.

Description

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No. 10/860,864, filed Jun. 3, 2004 and claims the benefit of U.S. provisional application Ser. No. 60/475,806, filed Jun. 3, 2003; U.S. provisional application Ser. No. 60/487,913, filed Jul. 16, 2003; U.S. provisional application Ser. No. 60/494,970, filed Aug. 13, 2003; U.S. provisional application Ser. No. 60/528,346, filed Dec. 9, 2003, and U.S. provisional application Ser. No. 60/571,997, filed May 17, 2004, the contents of all of which are incorporated herein.

FIELD OF THE INVENTION

The present invention relates to the solid state chemistry of ziprasidone HCl.

BACKGROUND OF THE INVENTION

Ziprasidone is an antipsychotic agent that is chemically unrelated to phenothiazine or butyrophenone antipsychotic agents. Ziprasidone has the following structure:
The preparation of ziprasidone base is disclosed in U.S. Pat. No. 4,831,031 (example 16). Preparation of ziprasidone base is also disclosed in U.S. Pat. No. 5,312,925. A process for preparation of ziprasidone HCl monohydrate having a mean particle size equal to or less than about 85 microns is also disclosed in U.S. Pat. No. 6,150,366 and EP 0 965 343 A2.
Ziprasidone has been marketed under the name GEODON as an oral capsule and as an injectable drug. GEODON capsules contain the monohydrate hydrochloride salt of ziprasidone, and come in 20, 40, 60 and 80 mg dosage forms. GEODON for injection contains a lyophilized form of ziprasidone mesylate trihydrate, and contains 20 mg base equivalent of ziprasidone. The mesylate salts of ziprasidone, including monohydrate and trihydrate, are disclosed in U.S. Pat. Nos. 6,110,918 and 5,245,765.
The present invention relates to the solid state physical properties of ziprasidone HCl. These properties can be influenced by controlling the conditions under which ziprasidone HCl is obtained in solid form. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability.
Ziprasidone HCl has very low solubility in water (0.08 mg/ml). Increase in specific surface area (SSA) of low aqueous solubility materials may improve therapeutic activity (J. Phys. D: Appl. Phys. 26 (14 Aug. 1993) B181-B187). The surface area of a solid material provides information about the void spaces on the surfaces of individual particles or aggregates of particles (EL Parrott, in Pharmaceutical Technology: Fundamental Pharmaceutics, Burgess, Minneapolis, Minn., 1970, pp 1-36). Factors such as chemical activity, adsorption, dissolution, and bioavailability of the drug may depend on the surface of the solid (EL Parrott, in Pharmaceutical Technology: Fundamental Pharmaceutics, Burgess, Minneapolis, Minn., 1970, pp 1-36, EL Parrott, Pharm. Manuf., 2, 30-37 (1985)). The adsorption of inert gases onto solid materials represents the most widely used method for the determination of SSA, although other methods are available (S L Lowell and J E Shields, Powder Surface Area and Porosity, Chapman and Hall New York, 1984). The BET method (S. Brunauer, P H Emmett and E Teller, J. Am. Chem. Soc., 60, 309 (1938)) is generally used for gas adsorption surface area measurement.
These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a substance. These conformational and orientational factors in turn result in particular intramolecular interactions and intermolecular interactions with adjacent molecules that influence the macroscopic properties of the bulk compound. A particular polymorphic form may give rise to distinct spectroscopic properties that may be detectable by powder X-ray diffraction, solid state ¹³C NMR spectrometry and infrared spectrometry. The polymorphic form may also give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and can be used to distinguish some polymorphic forms from others.
Ziprasidone HCl hemihydrate is disclosed in U.S. Pat. No. 4,831,031, Example 16 (column 13, line 13). A crystalline form of ziprasidone HCl (herein designated Form M) is disclosed in U.S. Pat. No. 5,312,925 and EP 0 586 181 A1. Form M is characterized by XRD, IR and water content. It is reported that the water content of Form M ranges from 3.8 to 4.5% by weight, and that it is a monohydrate. Ziprasidone HCl Form M is prepared from ziprasidone base anhydrous.
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 additional polymorphic forms of ziprasidone HCl.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides for crystalline ziprasidone HCl, denominated Form A, characterized by data selected from the group consisting of a powder XRD pattern with peaks at 10.9, 17.4 and 19.1±0.2 degrees 2 theta and an FTIR spectrum with peaks at about 3400, 3344, 3172, 2949, 970, 940, 872 and 843 cm⁻¹.
In another aspect, the present invention also provides crystalline ziprasidone HCl form A, which consists of less than about 5% Form M.
In another aspect, the present invention also provides crystalline ziprasidone HCl form A, which does not transform to Form M by more than 5% upon heating.
In another aspect, the present invention also provides crystalline ziprasidone HCl form A, which does not transform to Form M by more than 5% upon storage at 0% humidity for 20 days or more.
In another aspect, the present invention also provides crystalline ziprasidone HCl form A, which does not transform to Form M by more than 5% upon storage at a temperature of between about 25° and 55° C. for at least 3 months.
In another aspect, the present invention also provides crystalline ziprasidone HCl form A, which has a specific surface area higher than about 4 m²/g.
In another aspect, the present invention also provides crystalline ziprasidone HCl form A, which has high crystallinity.
In another aspect, the present invention provides a process for preparing crystalline ziprasidone HCl form A comprising:

- a) providing a slurry of ziprasidone base, aqueous HCl and a solvent selected from the group consisting of toluene, monochlorobenzene, methanol, ethanol, diethyl-carbonate, water, isopropyl alcohol and mixtures thereof;
- b) maintaining the slurry to obtain crystalline ziprasidone HCl; and
- c) recovering the crystalline ziprasidone HCl.

In another aspect, the present invention also provides a process for preparing crystalline ziprasidone HCl form A comprising:

- a) dissolving, while stirring, ziprasidone base in a mixture of C_1-4alcohol and an organic acid;
- b) adding water and aqueous HCl to the solution;
- c) recovering the crystalline ziprasidone HCl.

In another aspect, the present invention also provides a process for preparing crystalline ziprasidone HCl form A, comprising:

- a) providing a slurry of ziprasidone HCl characterized by a powder XRD pattern of 7.4, 13.0, 20.7, 23.4, 25.9±0.2 degrees 2 theta in THF or ethanol;
- b) maintaining the slurry to obtain the crystalline ziprasidone HCl; and
- c) recovering the crystalline ziprasidone HCl.

In another aspect, the present invention provides a process for preparing crystalline ziprasidone HCl form A comprising exposing ziprasidone HCl characterized by a powder XRD pattern of 7.4, 13.0, 20.7, 23.4, 25.9±0.2 degrees 2 theta to a relative humidity of about 20% to about 60%;
In another aspect, the present invention provides a process for preparing crystalline ziprasidone HCl form A substantially free of ziprasidone HCl Form M comprising:

- a) preparing a slurry of ziprasidone HCl in water, optionally in the presence of an organic solvent, at a temperature of about OEC to about 40EC;
- b) maintaining the slurry to obtain the crystalline ziprasidone HCl; and
- c) recovering the ziprasidone HCl.

wherein the slurry is prepared by combining aqueous HCl in less than about 30 minutes with ziprasidone base in water.
In another aspect, the present invention provides a process for preparing ziprasidone HCl Form M comprising heating a slurry of the crystalline ziprasidone HCl Form A in ethanol.
In another aspect, the present invention provides a solid crystalline ziprasidone HCl having a water content of about 4.6% to about 6.6% by weight.
In another aspect, the present invention provides a process for preparing a solid crystalline ziprasidone HCl having a water content of about 4.6% to about 6.6% by weight comprising maintaining a slurry of ziprasidone HCl Form E in THF at a temperature below about 40° C.
In another aspect, the present invention provides a process for preparing a solid crystalline ziprasidone HCl having a water content of about 4.6% to about 6.6% by weight comprising maintaining a slurry of ziprasidone HCl Form E in THF at a temperature below about 40° C., drying solid obtained from the slurry at elevated temperature, contacting the solid with humid air to obtain the desired water content.
In another aspect, the present invention provides a solid crystalline ziprasidone HCl having a water content of about 4.6% to about 6.6% by weight which does not transform to Form M by more than 5% upon storage at 0% humidity for 20 days or more.
In another aspect, the present invention provides a solid crystalline ziprasidone HCl having a water content of about 4.6% to about 6.6% by weight which does not transform to Form M by more than 5% upon storage at a temperature of between about 25° and 55° C. for at least 3 months.
In another aspect, the present invention provides for solid crystalline ziprasidone HCl having specific surface area higher than about 4 m²/g.
Also provided are pharmaceutical compositions and a method of treating a patient suffering from schizophrenia.

FIGURES

FIG. 1 is an X-Ray powder diffractogram of crystalline ziprasidone HCl Form A
FIG. 2 is an X-Ray powder diffractogram of high crystallinity ziprasidone HCl Form A, containing about 5% Form M.
FIG. 3 is an X-Ray powder diffractogram of high crystallinity ziprasidone HCl Form A.
FIG. 4 is an IR spectra of crystalline ziprasidone HCl Form A.
FIG. 5 is an IR spectra of crystalline ziprasidone HCl Forms A and M.
FIG. 6 is an IR spectra of crystalline ziprasidone HCl Forms A and M.
FIG. 7 is an X-Ray powder diffractograms of crystalline ziprasidone HCl Form A before and after heating.
FIG. 8 is an X-Ray powder diffractograms of crystalline ziprasidone HCl Form M before and after heating.
FIG. 9 is an X-Ray powder diffractograms of crystalline ziprasidone HCl Form A before and after storage at 0% relative humidity.
FIG. 10 is an X-Ray powder diffractograms of crystalline ziprasidone HCl Form M before and after storage at 0% relative humidity.
FIG. 11 is a comparison of XRD patterns of crystalline Ziprasidone HCl Form A and Ziprasidone HCl Form M.
FIG. 12 is a DSC thermogram of ziprasidone HCl form A.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term slurry refers to a heterogeneous mixture.
As used herein, the term reduced pressure refers to a pressure below about 1 atm, more preferably below about 100 mmHg.
In one aspect, the present invention provides for crystalline ziprasidone HCl, denominated Form A, characterized by data selected from the group consisting of an X-Ray diffraction pattern having peaks at about 10.9, 17.4 and 19.1±0.2 degrees 2 theta, substantially as depicted in FIG. 1, and an FTIR spectrum with characteristic absorption bands at about 3400, 3344, 3172, 2949, 970, 940, 872 and 843 cm⁻¹, substantially as depicted in FIGS. 4 and 5. Crystalline ziprasidone HCl Form A of the present invention may be further characterized by XRD peaks at 25.0 and 26.0±0.2 degrees two-theta, and may be further characterized by XRD peaks at 13.9, 20.6, 21.3, 21.8 and 23.0±0.2 degrees two-theta. The crystalline ziprasidone HCl Form A provided in the present invention has a water content of about 0.5% to about 6.6% by weight, and may have high crystallinity, substantially as depicted in FIGS. 2 and 3.
The DSC thermogram of ziprasidone HCl Form A (FIG. 12) shows an endothermic peak of about 80 J/g at a temperature of about 85° C., which corresponds to dehydration of the ziprasidone HCl Form A. According to the thermogram, at about 270° C., ziprasidone HCl Form A starts to melt and decompose. The water content of ziprasidone HCl form A is in the range of about 4.6% to about 5.4% by weight, more preferably of about 4.7% to about 5.1% by weight. The level of about 5.0% water content corresponds to a 1 and ⅓ hydrate of ziprasidone HCl. It is possible to obtain a water content lower than about 4.6% by drying. However, equilibrium is reached easily in the range of about 4.6% to about 5.4%.
Ziprasidone HCl form A is stable in terms of crystal structure during heating and also during exposure to various ranges of relative humidity (0%-100% relative humidity). Ziprasidone HCl Form M, however, converts to the anhydrous form under various conditions, such as heating or exposure to 0% relative humidity.

TABLE NO 1

Water uptake (%) and crystal form of ziprasidone HCl Form A and

monohydrate equilibrated at different relative humidities

Form A Form M

(equilibration time: 22 days) (equilibration time: 7 days)

Water Water

RH (%) content (%) Crystal form content (%) Crystal form

0 4.7 A 0.7 Anhydrous

20 4.8 A 4.2 Monohydrate

40 4.6 A 4.4 Monohydrate

60 4.8 A 4.3 Monohydrate

80 5.1 A 4.3 Monohydrate

100 5.3 A 4.3 Monohydrate
Ziprasidone HCl form A may be heated to a temperature of up to about 140° C. without a change in the crystal structure (the water content after heating drops to less than about 2%, but the crystalline structure absorbs water again). Ziprasidone HCl Form A is stable by slurry in water. However, in ethanol slurry, 95% of ziprasidone Form A transforms to Form M. Ziprasidone HCl Form A is stable toward transformation to other crystalline forms of ziprasidone HCl despite exposure at high humidity for prolonged periods (such as 3 weeks, see table 1) or storage under accelerated aging conditions (such as 40° C., 75% RH) for at least about 3 months. As used herein, the term “stable” refers to a transformation of no more than about 5% to other crystalline forms.
The present invention provides processes for obtaining ziprasidone HCl Form A substantially free from other crystalline forms, i.e. no more than about 5% of other crystalline forms. A suitable technique for monitoring the crystalline content is X-Ray powder diffraction. Ziprasidone HCl novel form A may be prepared by combining ziprasidone base with aqueous HCl, in the presence or absence of an organic solvent such as toluene, monochlorobenzene/methanol, diethyl-carbonate, isopropyl alcohol or mixtures thereof to obtain a slurry, and allowing the slurry to last for a sufficient time to obtain Form A. The combining/reacting is preferably carried out at a temperature of at least about 40° C., more preferably from about 50° C. to about 70° C., and most preferably at about 60° C. The slurrying after the combining is preferably carried out at a temperature of from about 20° C. to about 30° C., more preferably at about room temperature.
The FTIR spectra of Forms A and M are similar, however differences can be seen in the ranges of 3600-2800 and 1000-750 cm⁻¹, substantially as depicted in FIGS. 4 and 5.
Ziprasidone HCl Form A may exist with crystallinity level. Crystalline ziprasidone HCl Form A and high crystallinity ziprasidone HCl Form A have the same characteristic peaks in XRD. However the peak width at half height for high crystalline ziprasidone is smaller than for crystalline ziprasidone HCl Form A; the peaks for high crystalline ziprasidone are sharper and well defined, while in the crystalline ziprasidone the peaks are wider and less resolved.

The peak width at half height for the peak at 10.9° 2Θ is 0.21° for high crystalline ziprasidone, and 0.30 for crystalline ziprasidone. For the peak at 17.4° 2Θ, 0.25° for high crystalline ziprasidone and 0.48 for crystalline ziprasidone. For the peak at 19.1° 2Θ, 0.20° for high crystalline ziprasidone and 0.30 for crystalline ziprasidone. For the peak at 23.0° 2Θ, 0.37° for high crystalline ziprasidone and 0.54° for crystalline ziprasidone. Preferably, the crystalline form has peaks with a higher than about the average width as illustrated (average of the two widths provided), more preferably higher than about 75% of the range of the two widths provided.

TABLE NO 2


Some Peak width at half height for Crystalline ziprasidone
HCl Form A and high crystallinity ziprasidone HCl Form A

	Peak width at half height	Peak width at half height
	for Crystalline ziprasidone	for high crystallinity
Peaks ±0.2	HCl Form A	ziprasidone HCl Form A
degrees 2 theta	(degrees 2 theta)	(degrees 2 theta)

10.9	0.30	0.21
17.4	0.48	0.25
19.1	0.30	0.20
23.0	0.54	0.37

The crystalline ziprasidone HCl Form A of the present invention may be substantially free from other crystalline forms, i.e. no more than about 5% of other crystalline forms, preferably Form M. A suitable technique for monitoring the crystalline content is X-Ray powder diffraction. In addition, no more than 5% of Form A transforms into Form M during heating and also during exposure to 0% relative humidity.
The crystalline ziprasidone HCl Form A of the present invention may be heated to a temperature of up to about 140° C. without a change in the crystal structure (see table 3 and FIG. 7).

TABLE NO 3

Crystalline ziprasidone HCl forms heated at 80-105° C. overnight

Crystal form after heating

Original crystal form at 80-105° C. overnight

Form A Form A

Form M (monohydrate) Anhydrous
The present invention provides a crystalline ziprasidone HCl Form A, of which no more than about 5% is transformed into Form M upon exposure at 0% humidity for prolonged periods (such as 3 weeks, see table 8 and FIG. 9), or storage under accelerated aging conditions (such as 40° C., 75% RH, see tables 4 and 5) for at least about 6 months. Ziprasidone HCl Form M, however, converts to the anhydrous form under heating (see table 3 and FIG. 8) or exposure to 0% relative humidity (see table 8 and FIG. 10).

TABLE NO 4

Stability results

Results

Time Interval 25° C. 40° C. 55° C.

t = 0 A

1 M A A

2 M A A

3 M A A A

6 M A A A

TABLE NO 5


Stability results

Time

Results

Interval	25° C.	40° C.	55° C.

t = 0	A + less than 5% M
1 M		A + less than 5% M
2 M		A + less than 5% M	A + less than 5% M
3 M	A + less than 5% M	A + less than 5% M	A + less than 5% M
6 M	A + less than 5% M	A + less than 5% M	A + less than 5% M

When slurried in water, no more than 5% Form A is transformed into Form M. However, in ethanol slurry, 95% of the crystalline ziprasidone transforms to Form M.

The crystalline ziprasidone HCl Form A provided in the present invention has a specific surface area (SSA) higher than about 4 m²/g, more preferably higher than about 8, most preferably higher than about 11 such as about 14 as measured by BET. Preferably, the SSA is about 5 to about 20 m²/g. The high SSA of the crystalline ziprasidone HCl is achieved by the rapid addition of HCl to the solution of ziprasidone base, and precipitation at a low temperature. The results are summarized in Table 6:

TABLE NO 6


Specific surface area results

	Specific
	surface	Crystal
Sample	area [m²/g]	form

** Repetition of U.S. Pat. No. 6,150,366	2.135	M
Example10
** Repetition of U.S. Pat. No. 6,150,366	3.908	M
procedure (comparative example 15)
** Repetition of U.S. Pat. No. 5,312,925	3.909	M
Example 2
** Sample prepared according to example 16	5.461	A
** Sample prepared according to example 19	11.335	A
* Sample prepared according to example 17	14.646	A
* Sample prepared according to example 18	18.831	A

* cell volume = 12 cm³
** cell volume = 9 cm³

The crystalline ziprasidone HCl Form A provided in the present invention has a significantly higher specific surface area than Form M prepared by repeating the procedure disclosed in U.S. Pat. No. 5,312,925 and Example 10 in U.S. Pat. No. 6,150,366.
Crystalline ziprasidone HCl Form A may be prepared by providing a slurry of ziprasidone base, aqueous HCl and a solvent selected from the group consisting of toluene, monochlorobenzene, methanol, ethanol, diethyl-carbonate, water, isopropyl alcohol or mixtures thereof, and allowing the slurry to last for a sufficient time (maintaining) to obtain crystalline ziprasidone HCl Form A. When the solvent is a non-polar solvent or water, the combining/reacting is preferably carried out at a temperature of at least about 40° C., more preferably from about 50° C. to about 70° C., and most preferably at about 60° C. The combining with HCl is preferably carried out rapidly. The slurrying after the combining is preferably carried out at a temperature of about 20° C. to about 30° C., more preferably at about room temperature. Form A obtained by this process may have high crystallinity.
Crystalline ziprasidone HCl Form A can also be prepared by stirring a solution of ziprasidone base, a C_1-4alcohol and an organic acid (such as a C₁to C₇carboxylic acid) at room temperature, then adding water and aqueous HCl to obtain crystalline ziprasidone HCl Form A. Preferably, the C_1-4alcohol is either ethanol or methanol. Preferably, the organic acid is a C_1-4carboxylic acid, more preferably the organic acid is acetic acid and formic acid.
The water content of crystalline ziprasidone HCl Form A can be increased by humidification.
Crystalline ziprasidone HCl Form A may also be prepared by slurrying another form of ziprasidone HCl in a suitable solvent such as tetrahydrofuran or ethanol. Preferred starting material is ziprasidone HCl Form E. The slurry is allowed to last for a sufficient time to obtain crystalline ziprasidone HCl, which may be recovered by techniques well known in the art such as filtration. The slurry temperature is preferably at least about 40° C. when using THF. Ziprasidone HCl Form E transforms to Form A when exposed to a relative humidity of about 20% to about 60% for about 22 days.
Ziprasidone HCl having a water content of about 4.6% to about 6.6% may be prepared by slurry of ziprasidone HCl Form E in THF. The temperature of the slurry is preferably less than about 40° C., more preferably about room temperature. The slurry is maintained preferably of about 12 hours to about 3 days. The wet solid may then be dried, for example at a temperature of about 40° C. to about 70° C., followed optionally by additional drying up to a temperature of preferably about 120° C., as illustrated in examples 20 and 21. The solid, if dehydrated, may then be put in a humid atmosphere, preferably more than about 50% humidity, more preferably more than about 80% humidity and most preferably about 100% humidity to obtain a hydrated crystal having a water content of about 4.6% to about 6.6% by weight.
In another embodiment, rather than starting with ziprasidone base, another polymorphic form of ziprasidone HCl is used for the slurry process. Preferred combination of solvents and starting forms include ziprasidone HCl Form F and THF and ziprasidone HCl Form E and n-butanol, preferably in mixtures with water. Preferably, the slurry is heated for a sufficient amount of time, more preferably to at least about 40° C.
Preparation of ziprasidone Form M and Form A may be similar in some instances in that both may be obtained from the same solvent such as water. However, a few parameters differentiate the preparation of the two forms: Form M substantially pure is obtained by slow crystallization, while Form A substantially pure is obtained by fast crystallization. Form M pure may be obtained by precipitation from the solution of base at ˜60° C., while Form A pure may be prepared by precipitation from the slurry of ziprasidone base at lower temperature.
If the crystallization parameters mentioned above are hot carefully controlled, mixtures of form A and From M may be obtained. As used herein, Form A or Form M substantially pure from the other crystal forms refers to NMT 5% by weight of the other crystal form. The term rapid crystallization means fast HCl addition and/or crystallization at low temperature; slow crystallization means HCl addition rate to induce the nucleation and crystallization at relatively higher temperature.
Ziprasidone HCl Form E when exposed to a high relative humidity, such as for about 22 days, transforms to the monohydrate form. Ziprasidone HCl form E transforms to amorphous form when exposed to about 10% to about 0%, more preferably about 0% relative humidity, for such as 22 days, or after heating at elevated temperature, preferably at about 80° C. overnight. Ziprasidone HCl Form E transforms to Form A when exposed to a relative humidity of about 20% to about 60% for about 22 days (see table 3 and 4).
Ziprasidone HCl novel form E may be prepared by combining ziprasidone base with aqueous HCl in acetonitrile or ethyl acetate to obtain a slurry, and allowing the slurry to last for a sufficient time to obtain Form E. The slurry process is preferably carried out overnight. The combining of HCl with ziprasidone base is preferably carried out at a temperature of from about 40° C. to about 60° C., with about 50° C. being preferred. The slurrying after the combining is preferably carried out at a temperature of from about 20° C. to about 30° C., more preferably at about room temperature. Ziprasidone Form E may also be obtained as a mixture with Form A with a slurry process that uses tetrahydrofuran as a solvent. Slurrying at room temperature results in the mixture, while slurrying at higher temperatures, such as above about 50° C. results substantially in Form A.
Ziprasidone HCl anhydrous may be prepared by drying ziprasidone HCl monohydrate, for example by exposing the material to low relative humidity, preferably about 0% relative humidity, for a sufficient period, preferably for about 1-3 weeks, more preferably for about 3 weeks.
Ziprasidone HCl Form M may be prepared by slurrying Form A in a C₁to C₄alcohol or acetic acid, preferably ethanol (preferably 95%), more preferably at a temperature of about reflux temperature and 20EC below the reflux temperature, even more preferably about 10EC below the reflux temperature to about reflux, and most preferably at about reflux temperature. About three hours at reflux temperature is sufficient to obtain a transformation.
The present invention also provides for preparing crystalline ziprasidone HCl Form A by exposing ziprasidone Form E to a relative humidity of about 20% to about 60% for about 22 days (see table 7).

TABLE NO 7

Water uptake (%) and crystal form of ziprasidone HCl form E

equilibrated at different relative humidities for 22 days

TGA weight loss

RH (%) (%) Crystal form

0 5.3 Amorphous

20 7.2 A

40 4.8 A

60 5.0 A

80 9.2 M + A

100 51.3 M + A + amorphous
The present invention also provides for preparation of substantially pure crystalline ziprasidone HCl Form A. In this embodiment, crystalline ziprasidone HCl is prepared by fast crystallization through addition of HCl to a slurry or solution of ziprasidone base in a solvent such as water, a C₁to C₄linear or branched alcohol, or mixtures thereof. An IPA/water ratio of about 2:1 to about 0:20 (v/v) is an appropriate solvent for preparation of substantially pure crystalline ziprasidone HCl Form A. Suitable temperature for the reaction is from about 0° C. to about 40° C. A suitable HCl quantity is from about 2 to about 8 equivalents. Preferably, the HCl is added at a fast rate. The addition rate is temperature related: at room temperature, the rate is preferably about 5 to about 30 minutes, more preferably about 5 to about 20 minutes, most preferably about 5 to about 10 minutes; at a lower temperature, the addition rate is preferably about 5 to about 60 minutes, more preferably about 5 to about 30 minutes. The addition may also be carried out in reverse, i.e., addition of ziprasidone base slurry/solution to HCl.
One of skill in the art would appreciate that as the slurry is allowed to last for a sufficient time to obtain a particular polymorphic form, the slurry may dry up due to for example evaporation of the solvents. As the examples illustrate, additional amounts of a solvent may be added (same or different solvent), preferably followed by stirring, to obtain a slurry.
A slurry is most effective when the solids of the heterogeneous mixture are in substantial contact with the solvent. When the solids settle down, the efficiency of the slurry process often decreases due to a decrease in contact. Thus, one of skill in the art would appreciate that if during the slurry process the solids settle down, a force such as stirring or agitating may be applied to disperse the solid. Even when the solids have not settled down, bringing of movement in the solvent may even further increase the efficiency of the slurry process.
Crystalline ziprasidone HCl Form A may be recovered from the slurry by conventional techniques in the art such as decanting, filtration and centrifugation.

The present invention also provides solid crystalline ziprasidone HCl having a water content of about 4.6% to about 6.6% by weight. This crystalline form may be sesquihydrate. No more than 5% of the solid crystalline ziprasidone HCl of the present invention transforms into Form M during exposure to 0% relative humidity (see table 8). The present invention further provides a solid crystalline ziprasidone HCl, of which no more than 5% transforms into Form M upon storage at 25, 40 and 55° C. for at least 3 months, preferably for at least 6 months (see table 9). This solid crystalline ziprasidone HCl has a specific surface area (SSA) higher than 4 m²/g, and preferably between 5 and 20 m²/g.

TABLE NO 8


Water uptake (%) and crystal form of crystalline ziprasidone
HCl forms equilibrated at 0% relative humidity

	Crystal form upon storage at
Original crystal form	0% relative humidity

Form A	Form A
Crystalline ziprasidone HCl having	Crystalline ziprasidone HCl having
a water content of 4.6-6.6%	a water content of 4.6-6.6%
Form M	Anhydrous

TABLE NO 9


Stability results

Time

Results

Interval	25° C.	40° C.	55° C.

t = 0	Cryst. ZPR HCl
	(4.6-6.5% water)
1 M		Cryst. ZPR HCl	Cryst. ZPR HCl
		(4.6-6.5% water)	(4.6-6.5% water)
2 M		Cryst. ZPR HCl	Cryst. ZPR HCl
		(4.6-6.5% water)	(4.6-6.5% water)
3 M	Cryst. ZPR HCl	Cryst. ZPR HCl	Cryst. ZPR HCl
	(4.6-6.5% water)	(4.6-6.5% water)	(4.6-6.5% water)
6 M	Cryst. ZPR HCl	Cryst. ZPR HCl	Cryst. ZPR HCl
	(4.6-6.5% water)	(4.6-6.5% water)	(4.6-6.5% water)

Pharmaceutical formulations of the present invention contain crystalline ziprasidone HCl, such as one of those disclosed herein, or ziprasidone HCl amorphous, optionally in mixture with other form(s) of ziprasidone. In addition to the active ingredient(s), the pharmaceutical formulations of the present invention may contain one or more excipients. Excipients are added to the formulation for a variety of purposes.
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, pregelatinized 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, sorbitol and talc.
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, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate and starch.
The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab®) and starch.
Glidants can be added to improve the flowability 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.
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 dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, 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 dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, 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 may be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol and tartaric acid.
Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
In liquid pharmaceutical compositions of the present invention, ziprasidone and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
Liquid pharmaceutical compositions may contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that may be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetyl alcohol.
Liquid pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum.
Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar may be added to improve the taste.
Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability.
According to the present invention, a liquid composition 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 used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
The solid compositions of the present invention include powders, granulates, aggregates and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, 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.
Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and losenges, as well as liquid syrups, suspensions and elixirs.
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.
The active ingredient and excipients may be formulated into compositions and dosage forms according to methods known in the art.
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 further 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 tableted, or other excipients may be added prior to tableting, such as a glidant and/or a lubricant.
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.
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 in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
A capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting, however, they are not subjected to a final tableting step.
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 route in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral. The dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
The dosage of GEODON may be used as guidance. The oral dosage form of the present invention is preferably in the form of an oral capsule having a dosage of about 10 mg to about 160 mg, more preferably from about 20 mg to about 80 mg, and most preferably capsules of 20, 40, 60 and 80 mg.
Instrumentation:
X-Ray powder diffraction data were obtained using by method known in the art using a SCINTAG powder X-Ray diffractometer model X′TRA equipped with a solid state detector. Copper radiation of 1.5418 Å was used. A round aluminum sample holder with round zero background quartz plate, with cavity of 25 (diameter)*0.5 (dept) mm. Detection limit: 5%.
TGA analysis was done using a Mettler M3 meter. The weight of the samples was about 10 mg; the samples were scanned at a rate of 10° C./min from 25° C. to 200° C. The oven was constantly purged with nitrogen gas at a flow rate of 40 ml/min. Standard 70 μl alumina crucibles covered by lids with 1 hole were used.
IR analysis was done using a Perkin Elmer SPECTRUM ONE FT-IR spectrometer in DRIFTT mode. The samples in the 4000-400 cm⁻¹interval were scanned 16 times with 4.0 cm⁻¹resolution.
The water content of ziprasidone HCl was measured by the methods known in the art like Karl Fisher or thermogravimetric analysis (TGA). The TGA of the crystalline ziprasidone HCl matched with the Karl Fisher analysis. Water content is measured as percent w/w.
Specific surface area measurement:
Instrument: Coulter SA3100
Degassing: without
Sensitivity: high
Calculation: BET
Type: multipoint
Points: 10
Sample cell: 9 and 12 cm³
Ziprasidone free base used for preparations of the crystal forms of ziprasidone HCl may be, but is not limited to Form B. Ziprasidone base Form B is characterized by X-Ray peaks at 12.1, 15.2, 16.3, 18.4, 25.0 degrees 2 theta and is further characterized by XRD peaks at 5.2, 10.4, 11.3, 13.1, 21.1, 22.1. The ziprasidone free base has a DSC thermogram in which 17 and 120 J/g endothermic peaks can be seen at 92 and 220° C. The first corresponds to dehydration, the second to melting of the ziprasidone free base. The water content of the sample of the base is about 1.2% by weight. The Loss on Drying by TGA is about 2.1% by weight. One of skill in the art would appreciate that the processes of the present invention may use other forms of ziprasidone base as starting material.

EXAMPLES

Example 1

Preparation of Ziprasidone Base

Ziprasidone base for the experiments below was prepared according to the procedure “EXPERIMENT” in U.S. Pat. No. 5,312,925, column 4. The water content of the base was 1.2% (Karl Fisher).

Example 2

Preparation of Ziprasidone Base Form B

Ziprasidone base (50 g) and toluene (250 ml) were charged into a 0.5 L three necked flask. The obtained slurry was heated at 85° C. for 2 hours. The hot slurry was filtrated and the solid washed with methanol. The solid was dried in air-circulated oven at 50° C. to afford the dried Ziprasidone base form B (by XRD) (45.39 g).

Example 3

Preparation of Crystalline Ziprasidone HCl Form a in Toluene from Ziprasidone Base Form B and Aqueous HCl

Ziprasidone base Form B (10 g) and toluene (200 ml) were heated to reflux, and the slurry was cooled to ˜65° C. At 65° C., aqueous HCl 37% (10 ml) was added and the slurry was stirred at room temperature over night. The solid was a sticky material; to which water was added (100 ml). The solid was then filtered and washed with toluene. The wet solid was crystalline ziprasidone HCl as confirmed by XRD. The product was dried in an oven at 50° C. The dried solid was crystalline ziprasidone HCl Form A, (10.64 g) as confirmed by XRD. (The water content was 4.7% by K.F.).

Example 4

Preparation of Crystalline Ziprasidone HCl Form a in Monochlorobenzene/Methanol from Ziprasidone Base Form B and Aqueous HCl

To a slurry of ziprasidone base Form B (log) in monochlorobenzene (100 ml) was added aqueous HCl (37%) (10 ml) at room temperature and the stirring was continued at room temperature over night. A sticky solid was formed, to which methanol (50 ml) was added, followed by stirring for an additional 4 hours. The solid was filtered and washed with methanol. The wet product was crystalline ziprasidone HCl as confirmed by XRD. After drying at 50° C. for about 16 hours, crystalline ziprasidone HCl Form A was obtained (10.37 g) as confirmed by XRD (The water content was 4.17% by K.F.).

Example 5

Preparation of Crystalline Ziprasidone HCl Form a in Water from Ziprasidone Base Form B and Aqueous HCl 3M

Ziprasidone base Form B (10 g) was added to a 3M solution of HCl (50 ml HCl (37%) in 150 ml HPLC grade water) and the slurry was heated at 60° C. The reaction mixture was then stirred at 60° C. for 18 hours. After cooling to room temperature, a solid was filtered and washed with water. The material was dried in an oven at 50° C. for 16 hours. The wet solid and the dried solid were crystalline ziprasidone HCl Form A (the water content of the dried solid is 4.88% by K.F.), as confirmed by XRD.

Example 6

Preparation of Crystalline Ziprasidone HCl Form a in Isopropyl Alcohol from Ziprasidone Base Form B and Aqueous HCl

Hydrochloric acid (37%) (10 ml) was added to a slurry of ziprasidone base Form B in iso-propyl alcohol (IPA) (100 ml). The slurry was stirred at room temperature over night. A solid was filtered, washed with IPA and dried at 50° C. for 16 hours. The dried solid was crystalline ziprasidone HCl Form A (The water content of the dried solid is 4.01% by K.F.), as confirmed by XRD.

Example 7

Preparation of Ziprasidone HCl Form E from Ziprasidone Base Form B in Acetonitrile and Aqueous HCl

Aqueous HCl (37%) (10 ml) was added to a slurry of ziprasidone base Form B (10 g) in acetonitrile (200 ml) at reflux. After the addition, the slurry was heated over night. A solid was filtered and washed with acetonitrile. After drying at 50° C. for ˜16 hours, ziprasidone HCl Form E was obtained (12.71 g) (The water content was 9.25% by K.F. and the loss on drying by TGA is 18.8%), as confirmed by XRD.

Example 8

Preparation of Ziprasidone HCl Monohydrate (M) from Ziprasidone HCl Form A

Crystalline ziprasidone HCl Form A (10 g) was heated in ethanol 95% (200 ml) at reflux for 3 hours. The hot slurry was filtered to obtain a solid. The solid washed with hot ethanol (10 ml×4). Part of the wet solid was dried at 50° C. for 16 hours and the other part at 45° C. under vacuum. The wet and dried solids were ziprasidone HCl Form M (the monohydrate) (The water content of the dried solids was 4.25 and 4.24% (by K.F) and the loss on drying by TGA are 4.6%.), as confirmed by XRD.
In all the above examples, drying was carried out in an air-circulated oven.

Example 9

Preparation of a Mixture of Monohydrate and Form a by Slurry of Ziprasidone HCl form E

Ziprasidone HCl Form E was stirred in tetrahydrofuran (20 ml) at room temperature for 23 hours. A solid was filtrated, washed with THF and dried at 50° C. in an air-circulated oven. The dried solid was a mixture of ziprasidone HCl monohydrate and Form A. When the slurry was at 60° C., Form A was the major component of the mixture (K.F. 4.57%).

Example 10

Preparation of Crystalline Ziprasidone HCl Form a BY Slurry of Ziprasidone HCl Form E

1) Ziprasidone HCl Form E (2 g) in ethanol 95% (20 ml) was stirred at room temperature for 24 hours. A solid was filtrated, washed with ethanol (95%) and dried at 50° C. in an air-circulated oven. The dried solid was crystalline ziprasidone HCl Form A (K.F. 5.16).
- The same result as was obtained when the temperature during the slurry was 50° C. (K.F. 5.06%).
2) Crystalline ziprasidone HCl Form A was obtained by slurry of Form E in ethanol with various water contents (from 5% to 30%) (K.F. 5.16%) at room temperature or at 50° C. (K.F. 5.06% and 4.99%) or by slurry of Form E in THF containing water at a temperature between room temperature and 50° C. For example, the slurry of E in THF containing 40% water at 50° C. gave crystalline ziprasidone HCl Form A (K.F. 4.76%).

Example 11

Preparation of Crystalline Ziprasidone HCl Form a with High Crystallinity from Ziprasidone Base in Diethyl-Carbonate/ag. HCl

To the slurry of ziprasidone base (log) (Form B) in diethyl-carbonate (250 ml) at 60° C. was added concentrated aqueous HCl (10 ml); then the slurry was stirred at room temperature for about 16 hours. Water (50 ml) was added and the stirring was continued for an additional three hours. A solid was filtrated, washed with water (2×20 ml) and dried in an air-circulated oven for 16 hours. The wet and the dried solid was crystalline ziprasidone HCl (K.F. 4.16%). The dried solid was Crystalline ziprasidone HCl Form A with high crytsallinity.

Example 12

Preparation of Substantially Pure Crystalline Ziprasidone HCl Form a

1) Preparation of Crystalline Ziprasidone HCl from Isopropyl-Alcohol: Water

In a 250 ml reactor were charged ziprasidone base (10 g) and a 1:1 mixture of isopropylalcohol-water (100 ml), and the mixture was cooled to 10° C. To the above slurry, aqueous HCl (32%) was added during 5 minutes, while maintaining the temperature less than 15° C. The obtained slurry was than stirred at 10-15° C. for 15 hours, and a solid was isolated by filtration, washed with IPA-water and dried at 50° C. under vacuum. The XRD of the dried material (10.79 g), which lacked the peak at 18.1, characteristic of Form M, indicates that the product was crystalline ziprasidone HCl Form A substantially free of Form M (water content by K.F. is 4.85%).

2) Preparation of Crystalline Ziprasidone HCl Form A from Water

To the slurry of ziprasidone base (10 g) in water (100 ml) at room temperature, aqueous HCl (10 ml) (32%) was added over 10 minutes. The slurry was then stirred at room temperature for 5 hours. The solid was filtrated, washed with water and dried on table, followed by drying at 50° C. The XRD of the solid, which lacked the peak at 18.1, characteristic of Form M, showed the product was crystalline ziprasidone HCl Form A substantially free of Form M (water content by K.F. 5.04).

3) Preparation of Crystalline Ziprasidone HCl Form A from IPA-water by Reverse Addition

A slurry of ZPR base (5 g), 25 ml IPA and 25 ml water was prepared in a 250 ml reactor. This slurry was dropped into a flask containing (32%) aqueous HCl (10 ml) at room temperature. During the addition, the temperature rose to ˜35° C. The slurry was than stirred at room temperature 24 hours. The solid was filtrated, washed with mixture water—IPA and dried at 50° C. The XRD of the dried solid (7.2 g), which lacked the peak at 18.1, showed the material was crystalline ziprasidone HCl Form A substantially free of Form M (water content by K.F. 4.89).

Example 13

Preparation of Form M from Crystalline Ziprasidone HCl Form A

The slurry of crystalline ziprasidone HCl Form A (30 g) and acetic acid (510 ml) was heated at 6.0° C. for 2 h. The mixture was than cooled to room temperature and the solid was filtrated and washed with acetic acid (2×30 ml). After drying at 50° C. ziprasidone HCl Form M was obtained (28.37 g). (Water content by K.F. 3.95%).

Example 14

Preparation of Ziprasidone HCl Form a in Humid Air Fluidized Bed

1) Precipitation from Solution
60 gr of Ziprasidone-base Cryst, 480 ml of Ethanol 95% and 300 ml of Acetic Acid were fed into a 1 liter stirred glass beaker at 25° C. The stirrer was turned on, and the mixture was stirred for 20 min until the Ziprasidone-base dissolved completely. 6 gr of “Eno” type Active Carbon were fed into the beaker, and the solution was Carbon treated for 30 min at 25° C. The used Carbon was removed by filtering the treated solution under reduced pressure through a No. 1 Whattman filtration paper.
The used carbon washed with 120 ml 95% Ethanol, and the wash filtrate was added to the filtered solution, both were fed into a 1 liter stirred glass reactor. 300 ml of treated Water were added into the reactor, and the solution was cooled to 0° C. 120 ml 10% w/w aqueous Hydrochloric acid solution was added drop wise into the reactor during 10 min. During the acid addition, Ziprasidone-hydrochloride precipitated. After the acid addition was completed, the slurry was stirred at 0° C. for additional 30 min.
The crystals were isolated by filtering the slurry under reduced pressure through a No. 1 Whattman filtration paper. After drainage of the mother liquor, The wet cake washed with 120 ml aqueous mixture consisting of 50% Ethanol 95%.
After the wash liquor was completely drained, the wet cake washed with 300 ml of water. The wet filter cake washed four additional times, each time with 300 ml (total 1500 ml) until pH-5 was obtained (the same pH as the pH of the fresh Water).
120 gr of wet Ziprasidone-HCl crystals were obtained.
The wet crystals Were tested by XRD and found to be ziprasidone HCl Form A.
The wet crystals were dried at 50° C. for 60 hrs, until the water content was 0.75%.
2) Humidification
20 gr of the dried product were humidified in a humid air fluidized bed drier (“Mini-Glatt”). The dry air inlet temperature was 50° C. After the water spray, the air temperature was 16° C.
After 30 min, the water content in the product was 5.77%
The humid product was discharged.

Example 15

Preparation of High Crystallinity Ziprasidone HCl Form a from Ziprasidone Base in IPA/water/HCl

Into a 250 ml flask were charged ZPR base (10 g), water (50 ml) and IPA (50 ml). To the obtained slurry HCl 32% (20 ml) was added during 0.5 h. The temperature rose from room temperature to about 30° C. The stirring was continued for 20 h at room temperature; after this the solid was filtrated, washed twice with a mixture IPA-water 1:1 (10 ml) and dried in vacuum oven at 50° C. The dried solid was high crystallinity ziprasidone HCl Form A (by XRD). (The water content is 4.89 by K.F.)

Example 16

Comparative Example: Preparation of Ziprasidone HCl Form M from THF: H₂O (from U.S. Pat. No. 6,150,366)

Into a 250 ml reactor, Ziprasidone base (3 g), THF (90 ml) and H₂O (9 ml) were charged. As the reactor was heated to reflux (64° C.), Ziprasidone dissolved, forming a clear, dark solution. The temperature was lowered to 60° C. and stirring to 103 rpm. HCl 11% was added until turbidity was observed. This turbid solution was left under stirring at 60° C. for 50 min., and the rest of 9 g HCl 11% was added dropwise during 30 min. The slurry was cooled to 13° C., kept at this temperature for 1 h 40 min., filtrated, and washed with two portions of 3 ml THF. The solid was dried at 23° C. overnight. The dried solid was crystalline ziprasidone HCl Form M (by XRD). Specific surface area 3.908 m2/g.

Example 17

Preparation of Ziprasidone HCl Form a from Etoh:H₂O

A 150 ml reactor equipped with mechanic stirring was charged with Ziprasidone base (3 g), EtOH abs. (15 ml) and H₂O (15 ml), cooled to 15° C., and a slurry was obtained. slurry. HCl 21% (4.55 ml) were added dropwise during 10 min. After the addition the slurry is left at the same temperature overnight. The slurry was then filtered, washed with EtOH:H₂O (10 ml), and dried at 65° C. under vacuum. The dried solid was crystalline ziprasidone HCl Form A (by XRD). Specific surface area: 5.461 m²/g.

Example 18

Preparation of Ziprasidone HCl Form A from IPA: H₂O at Room Temperature

A 50 ml flask equipped with mechanic stirring was charged with Ziprasidone (3.5 g), IPA (17.5 ml) and H₂O (17.5 ml), and a slurry was obtained.
HCl 32% (3.33 ml) was added dropwise during 2 min, and the temperature was raised from ˜25 to 29° C. After addition, the slurry was left overnight, while stirring. The slurry was then filtrated, washed with IPA: H₂O 1:1 (7 ml) and dried at 65° C. under vacuum. The dried solid was crystalline ziprasidone HCl Form A (by XRD). Specific surface area: 14.646 m²/g.

Example 19

Preparation of Ziprasidone HCl Form A from IPA: H₂O at 9° C.

A flask was charged with Ziprasidone (4.9 g), IPA (12.5 g) and H₂O (12.5 g), and was cooled in ice bath. When the temperature reached 9° C., HCl 21% (7.7 ml) was added dropwise during less than 5 minutes. The temperature was raised to 13° C., and the slurry was left, while stirring, at room temperature overnight. The slurry was then filtered, washed with EPA and dried at 50° C. under vacuum. The dried solid was crystalline ziprasidone HCl Form A (by XRD). Specific surface area: 18.831 m²/g.

Example 20

Preparation of Ziprasidone HCl Form a from Acetic Acid/Ethanol

Ziprasidone base (11.2 g) was dissolved in EtOH (112 ml) and Acetic acid (78.2 ml). The solution was treated with active charcoal at 0° C. for color improvement during 30 min and filtrated. The solution was cooled back to 0° C., and HCl 32% (10 ml) was added. 30 min after the addition, the slurry was filtered and the solid dried at 50° C. under vacuum. The dried solid was crystalline ziprasidone HCl Form A (by XRD). Specific surface area: 11.335 m2/g.

Example 21

Preparation of Crystalline Ziprasidone HCl Having a Water Content of 4.6-6.6% by Slurry of Ziprasidone HCl Form E

Ziprasidone HCl Form E was stirred in tetrahydrofuran (20 ml) at room temperature for 23 hours. A solid was filtrated, washed with THF and dried at 60° C. in an air-circulated oven. The dried solid was crystalline ziprasidone HCl (K.F. 4.57%).

Example 22

Preparation of Ziprasidone HCl having a Water Content of 4.6-6.6% from Acetic Acid/Ethanol

Crystalline ziprasidone HCl was prepared according to ex. 20. The wet solid was dried at 50° C. for about 16 hrs in vacuum oven, followed by an additional drying operation in vacuum-oven at 105° C. for 48 hrs. After drying, the solid contained 1.3% water (by Karl-Fischer).
The above dried material was kept in a chamber with RH 100% at 40° C. for 7 days. After this period of time the water content was 6.6% (by Karl-Ficher).

Example 23

Preparation of Ziprasidone HCl Form a from Acetic Acid/Ethanol

Ziprasidone base (15 g) was dissolved in a mixture of ethanol (150 ml) and acetic acid (75 ml). The solution was treated with basic alumina (1.5 g) for half hour. The discolored solution was filtrated and cooled to ˜10° C. Aqueous HCl (10%, 30 ml) was added during 3 min. at the chilled solution (10° C.). The stirring was continued for additional 10 min. at 10° C. The obtained solid was filtrated, washed with water to pH 4 and dried in vacuum-oven at 50° C. for about 4 days. The obtained dried solid contained 0.53% water (by K.F.).

Example 24

Preparation of Ziprasidone HCl Form a from AcOH/MeOh/Water

Ziprasidone base (5 g) was dissolved in a mixture of acetic acid (25 ml), methanol (47.5 ml) and water (2.5 ml); the obtained solution was treated with active carbon (10% w/w) and tonsil (10% w/w). The solution was filtrated, diluted with water (25 ml) and cooled to 10° C. While the temperature reached 10° C. 10% HCl was added (10 ml) over 5 minutes. The stirring was continued for 40 min., then the solid was filtrated and washed with water and then with a mixture of MeOH/water. The solid obtained after drying was crystalline ziprasidone HCl form A.

Other similar procedures are shown in the following table:



		Ratio
Example	Solvents	solvents	Ziprasidone form

24	AcOH:EtOH:water	3:6:3	A
25	AcOH:EtOH	5:10	A
26	AcOH:EtOH	3:20	A
27	AcOH:EtOH	5:10	A
28	AcOH:water	5:15	A
29	HCOOH:MeOH	3:17	A
30	HCOOH:MeOH	3:10	A
31	HCOOH:MeOH:water	3:3:6	A
32	HCOOH:MeOH:water	6:6:12	A
33	HCOOH:MeOH:water	1.7:1.7:3	A
34	HCOOH:MeOH:water	3:6:3	A
35	HCOOH:MeOH:water		A

AcOH = Acetic acid

Example 25

Preparation of Anhydrous Ziprasidone

In a three necked flask was charged toluene (100 ml) and Ziprasidone base (5 g). HCl(g) was bubbled to the above slurry at room temperature until the pH is 1.5. After this, the solvent has been removed by distillation under vacuum at 60° C. A sample was collected and was analyzed by XRD.
The remained solid was left over night with stirring at 60° C. under dried nitrogen. The dried solid after the distillation and after the final drying is ziprasidone HCl Form K. (water content by K.F. ˜1%).

Example 26

Processes for ZPR.HCl form A

1) New Process for Preparation of A from Solution:
This process includes the dissolution of ZPR base in acetic acid or formic acid diluted by ethanol or methanol or other alkanols, active carbon treatment for color improvement, cooling the solution, optionally dilution with water, and fast addition of aqueous HCl and isolation of the product ZPR.HCl form A.
We disclose:

- solvent mixtures (AcOH:EtOH:water, AcOH:MeOH:water, AcOH:EtOH, AcOH:water, HCOOH:MeOH:water, HCOOH:EtOH: water), the ratio of the solvents (about 1:1:1-1:3:3)
- the process of A preparation from solution
- the process for color improvement by making the operation in a cold solution (about −5-15° C.) by treating the solution with active carbon, tonsil, alumina (basic neutral, acid), silica gel, cellite.
- the process for preparation of pure and color-improved material ZPR.HCl form A.

a) Procedure for Color Improvement in ZPR.HCl form A.
Ziprasidone base (3 g) was dissolved in a mixture of acetic acid (15 ml) and ethanol (30 ml) while flow of nitrogen is purged in the system. The solution was cooled to ˜0° C. and treated with active carbon (10% w/w) and tonsil (10% w/w). After 30 minutes the carbon was filtrated and to the solution was rapidly added (over 2 min.) diluted HCl 10% (6 ml). The solid was filtrated, washed and dried at 50° C. in a vacuum-oven. The obtained solid is ZPR.HCl form A having an improved color (almost white).
2) Process for Drying and Water-Uptake of ZPR.HCl form A.
Usually the solid obtained from a mixture containing an alkanol contains up to 0.5-2% residual solvent (ethanol, IPA, n-butanol). Drying of the product at 60-100° C. and under vacuum (20-0.1 mmHg) gives a solid with a low content in residual solvents. (500-2000 ppm).
A low-residual solid (form A) uptakes water (5-6%) when exposed under water vapors (40-100% RH) at a temperature from room temperature to 60° C. An alternative procedure is the granulation of the dried material in a granulator.
We disclose:

- the drying process for a low-residual alkanols ZPR.HCl form A
- a low-residual solvents ZPR.HCl form A.
- the temperature (about 50-110° C., preferably about 50-85, more preferably about 60-80° C.).
- The drying under the above temp. and under vacuum (about 20-0.1 mmHg)
- The process for the preparation of A containing water about 5-6% by exposing the dried material under water vapors (about 40-100% RH) or by wet granulation and humid air fluidized bed drier in an industrial scale.
- The process for the preparation of A containing about 5-6% water by drying the solid prior to the water-uptake operation.
- ZPR.HCl form A with about 5-6% water (by K.F.)
- A stable ZPR.HCl form A containing about 5-6% water and a low residual solvents level.
- An industrial batch of ZPR.HCl form A with about 5-6% water.
- The process for preparation of A with about 10-12% water by wet granulation.
- ZPR.HCl form A containing about 10-12% water (by K.F.)
- The process for preparation of A with about 18-20% water by wet granulation.

ZPR.HCl form A containing about 18-20% water (by K.F.)
a) Experimental Conditions for ZPR.HCl form A having a Reduced Level of Residual Solvents
ZPR.HCl form A wet obtained according to one of the exp. Procedure was carried out by drying for 16 hours in a vacuum-oven. Total residual solvents was 0.5-0.6%.
This material was than dried in an oven under vacuum. The preferred drying conditions are as follows:

- temperature in the range of about 40-110° C., preferably about 50-85° C.
- vacuum: about 20-0.1 mmHg
- time: about 16 h-48 h.

b) Process for the Production of Ziprasidone-HCl Form A in Humid Air Fluidized Bed Drier
Step No. 1: Precipitation from Solution
Ziprasidone-base Cryst was dissolved in a mixture consisting of 8 Vol Ethanol 95%, and 5 Vol Acetic acid 100%. The mixture was stirred for about 30 min, until complete dissolution was obtained.
The clear solution was carbon treated by adding 10% w/w Active Carbon, and stirring the slurry for about 30 min.
The carbon was filtered under reduced pressure, and the used Carbon washed with 2 Vol Ethanol 95%.
Vol of treated water were added to filtered solution, afterwards it was cooled to about 0° C.
About 2.2 eq of hydrochloric Acid, as 10% w/w aqueous solution were added dropwise into the cold ZPR-base solution. During acid addition, the Ziprasidone-HCl precipitates. After the completion of the acid addition, the slurry was stirred for additional time. The crystals were isolated by filtering under reduced pressure. The wet filter cake was washed with 2 Vol of a mixture which consists of 1 Vol Ethanol 95%, and 1 Vol water. Subsequently, the crystals are washed with water, until the pH of the filtrate is equal to the pH of the fresh water. After the wash was completed the wet filter cake was discharged, and dried under reduced pressure at 50° C.
Step No. 2: Humidification
The dry Product was fluidized in a fluidized bed drier, equipped with water spraying system, at an inlet temperature at least 50° C. The spraying of water into the incoming air stream, results in increase in the air relative humidity and decrease in the air temperature. The product actually fluidizes in a humidified air.

Example 27

Process for Preparation of ZPR.HCl Hemihydrate

1) Preparation of ZPR HCl Hemihydrate from Solution
This process includes a full dissolution of crystallized ZPR base in an organic solvent (THF, DMA) and the addition of diluted HCl, the product is hemihydrate (by XRD).
We disclose:

- The process by dissolution of the base in an appropriate solvent.
- the temperature of the HCl addition is preferably about 40-80° C., more preferably about 55-65° C.
- The water amount.

a) experimental Procedure
To a solution of ZPR base cryst (15 g) in EtOH absolute (180 mL) at 60° C., a solution of HCl 10% (20 mL), was added. The mixture (slurry) was stirred at the same temperature for 1 h, then second amount of HCl 10% (13 mL) was added dropwise (30′). The slurry was stirred at 55EC for 3 h, then cooled to r.t., filtered and washed with methanol (2×25 mL). The resulting solid was dried in oven at 50° C., to obtain 13.7 g.
2) Preparation of ZPR HCl Hemihydrate from Slurry
The process consists in addition of HCl solution with a controlled water content to the slurry of crystallized ZPR base in an organic solvent (usually low alcohol).The product duct is hemihydrate (by XRD).
We disclose:

- the solvent is a C1 to C4 alcohol (as IPA, ethanol abs)
- the temperature is about 40-80° C., more preferably about 55-65° C.
- the quantity of water at the overall volume is preferably about (1.5-2.5% v/v).

a) Exp. Procedure:
To a mixture of ZPR base cryst (10 g) in EtOH absolute (300 mL) at 60° C., a solution of HCl in EtOH (EtOH abs—90 mL, HCl 32%—6 mL, water—4 mL) was added dropwise (1.5 h). The mixture was stirred at the same temperature for 2 h, than was filtered. The resulting solid was dried in oven at 60° C., to obtain 9.72 g. (The water content is 1.9% by K.F.)
The same process, when the slurry is in methanol lead to anhydrous in the wet solid, drying in an air-over yields the hemihydrate.

Example 28

Process for Preparation of ZPR.HCl Anhydrous

This process includes an addition of HCl gas to a slurry of crystallized ZPR base in ethanol absolute, the product is anhydrous (by XRD and KF).
We disclose:

- the solvent is ethanol absolute
- the temperature is about 40-80° C., more preferably about 55-65° C.
- in general: anhydrous conditions with use of HCl gas

a) Experimental Procedure
To a mixture of ZPR base cryst (5 g) in EtOH absolute (150 mL) at 60° C., a solution of HCl gas (2 g) in EtOH abs (10 mL) was added dropwise (1.5 h). The mixture was stirred at the same temperature for 2 h and then filtered. The resulting solid was dried in vacuum oven at 50° C., to obtain 4.96 g. (The water content is 0.2-0.4% by K.F.)
Having thus described the invention with reference to particular preferred embodiments and illustrative examples, those in the art can appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The Examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in numerous publications. Polymorphism in Pharmaceutical Solids, Drugs and the Pharmaceutical Sciences, Volume 95 may be used for guidance. All references mentioned herein are incorporated in their entirety.

Claims

1. A process for preparing color-improved crystalline ziprasidone HCl form A, comprising:

a) combining ziprasidone base with a mixture of acetic acid or formic acid in ethanol, methanol, water or mixtures thereof to obtain a solution;

b) cooling the solution to about −5° C. to about 15° C.;

c) adding active carbon, tonsil, alumina, silica gel, cellite, or mixtures thereof to the solution;

d) adding aqueous HCl to the solution to precipitate ziprasidone HCl form A; and

e) recovering the ziprasidone HCl form A.

2. A process for reducing the level of residual solvents in ziprasidone HCl form A, comprising drying the ziprasidone HCl at a temperature of about 50° C. to about 110° C. at a pressure of about 0.1 mmHg to about 20 mmHg to obtain ziprasidone HCl having 500 ppm to 2000 ppm of residual solvents.

3. The process of claim 2, wherein the drying takes place at a temperature of 60° C. to 100° C.

4. A process for increasing the water content of ziprasidone HCl form A, comprising exposing the dried ziprasidone HCl under water vapor at a relative humidity of about 40% to about 100% at a temperature of about 20° C. to 60° C., to obtain ziprasidone HCl having a water content of about 5% to about 6%.

5. A process for increasing the water content of ziprasidone HCl form A, comprising humidifying the dried ziprasidone HCl in a humid air fluidized bed drier equipped with a water spraying system, wherein the temperature of the inlet water is at least 50° C., to obtain ziprasidone HCl having a water content of about 5% to about 6%.

6. A process for increasing the water content of ziprasidone HCl form A, comprising increasing the water content of the dried ziprasidone HCl by wet granulation to obtain ziprasidone HCl having a water content of about 5% to about 6% or about 10% to about 12% or about 18% to about 20%.

7. A process for preparing ziprasidone HCl hemihydrate, comprising:

a) dissolving crystalline ziprasidone base in an organic solvent to form a solution;

b) adding aqueous HCl to the solution at a temperature of about 40° C. to about 80° C.; and

c) recovering ziprasidone HCl hemihydrate.

8. The process of claim 7, wherein the organic solvent is tetrahydrofuran.

9. The process of claim 7, wherein the organic solvent is dimethylacetamide.

10. The process of claim 7, wherein the organic solvent is ethanol.

11. A process for preparing ziprasidone HCl hemihydrate, comprising:

a) adding crystalline ziprasidone base to an organic solvent to form a slurry;

b) adding an HCl solution to the slurry at a temperature of about 40° C. to about 80° C.; and

c) recovering ziprasidone HCl hemihydrate.

12. The process of claim 11, wherein the organic solvent is a C₂to C₄alcohol.

13. The process of claim 11, wherein the organic solvent is methanol and the recovery step comprises drying the ziprasidone HCl in an air-over.

14. A process for preparing ziprasidone HCl anhydrous, comprising:

a) adding crystalline ziprasidone base to methanol to form a slurry;

c) recovering ziprasidone HCl anhydrous.

15. A process for preparing ziprasidone HCl anhydrous, comprising:

a) adding crystalline ziprasidone base to ethanol to form a slurry;

b) adding HCl gas to the slurry at a temperature of about 40° C. to about 80° C.; and

c) recovering ziprasidone HCl anhydrous.

16. A process for reducing color impurities in crystalline ziprasidone HCl form A with 500 ppm to 2000 ppm of residual solvents and about 5% to about 6% water content, comprising:

a) dissolving ziprasidone base in a mixture of acetic acid or formic acid in ethanol, methanol, other alkanols, water or mixtures thereof;

b) cooling the solution to about −5° C. to about 15° C.;

c) adding active carbon, tonsil, alumina, silica gel, or cellite, or mixtures thereof to the solution;

d) adding aqueous HCl to the solution; and

e) recovering ziprasidone HCl form A.

f) drying the ziprasidone HCl at a temperature of about 50° C. to about 110° C. at a pressure of about 0.1 mmHg to about 20 mmHg; and

g) exposing the dried ziprasidone HCl under water vapor at a relative humidity of about 40% to about 100% at a temperature of about 20° C. to 60° C.

17. The ziprasidone HCl prepared by the process of claim 1.

18. Crystalline ziprasidone HCl form A having 500 ppm to 2000 ppm residual solvents.

19. Crystalline ziprasidone HCl form A having a water content of about 5% to about 6%.

20. Crystalline ziprasidone HCl form A having a water content of about 10% to about 12%.

21. Crystalline ziprasidone HCl form A having a water content of about 18% to about 20%.