Amorphous ziprasidone hydrochloride (5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one hydrochloride) and processes to produce the same

This is a divisional application of U.S. patent application Ser. No. 10/884,991, filed on Jul. 7, 2004.

New amorphous ziprasidone hydrochloride (5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one hydrochloride) and processes to Produce the same.

Ziprasidone hydrochloride (5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one hydrochloride) is a potent neuroleptic agent useful in the treatment of various disorders including schizophrenia, anxiety and pain. It is currently marketed under the proprietary name of Geodon. Ziprasidone hydrochloride is known to exist in three crystalline forms; namely, the monohydrate, hemihydrate and anhydrous form as disclosed in U.S. Pat. Nos. 4,831,031 and 5,312,925, both of which are herein incorporated by reference. U.S. Pat. No. 5,312,925 states that ziprasidone hydrochloride monohydrate is hygroscopically stable, thus alleviating potential problems due to weight changes of the active pharmaceutical ingredient during the final formulation process. Nevertheless a very low aqueous solubility is observed for this crystalline form.

Canadian patent 2,252,898 attempts to overcome some of the deficiencies of the prior art, especially the poor aqueous solubility of ziprasidone hydrochloride monohydrate, by formation of various mesylate hydrate salts.

In U.S. Pat. No. 6,150,366 the poor aqueous solubility is purportedly increased by controlling, by various methods, the mean particle size of the crystalline ziprasidone free base or ziprasidone hydrochloride to a mean particle size equal to or less than about 85 μm.

U.S. Pat. No. 5,935,960 describes another attempt to overcome the poor aqueous solubility of ziprasidone hydrochloride by formation of a pro-drug of ziprasidone, specifically 1-[2-(6-chloro-2,3-dihydro-2-oxo-1H-indol-5-yl)ethyl]-4-[imino(2-mercaptophenyl)methyl]piperazine or one of its pharmaceutically acceptable salts, for instance the dihydrochloride.

Canadian patent 2,245,269 describes numerous compositions comprising of solid spray dried dispersions of sparingly water soluble drugs, including ziprasidone free base, and hydroxypropylmethylcellulose acetate succinate. Again, the form obtained purportedly provides increased aqueous solubility and/or bioavailability.

Therefore, a method which produces an improved form of ziprasidone hydrochloride in high yields and purity, and helps to overcome some of the deficiencies of the known forms is desired.

It is an object of the present invention to provide a method for the preparation of an improved form of ziprasidone hydrochloride in high yields and purity.

We have surprisingly found that using low-polarity organic solvents such as C 5 to C 12 substituted or unsubstituted cyclic and acyclic hydrocarbons such as hexanes, heptanes, or cyclohexanes; or C 1 to C 3 chlorinated hydrocarbons such as dichloromethane or chloroform and mixtures thereof to carry out the reaction between ziprasidone free base and anhydrous hydrogen chloride, unexpectedly a novel amorphous form of ziprasidone hydrochloride is obtained. (See FIGS. 1 , 2 and 3 to this specification)

Thus, in accordance to an aspect of the present invention there is provided a process for preparing the novel amorphous form of ziprasidone hydrochloride comprising the steps of:

(i) suspending ziprasidone free base in about 5 to 100 volumes of such low-polarity organic solvent or mixture of solvents at a temperature of from about −10 to about 40° C., (ii) one of the following steps:

a) bubbling hydrogen chloride gas for a period between 1 and 12 hours or, b) exposing the mixture to a suitable pressure of hydrogen chloride or, c) adding a solution of hydrogen chloride in a suitable organic solvent,

(iii) stirring the mixture at a temperature between about −10 and 40° C. until product is produced, (iv) filtering and washing the solid at ambient temperature, (v) if required, stirring the solid with a suitable organic solvent between about −10 and 60° C., (vi) if required, filtering and washing the solid, (vii) drying the solid.

Thus according to another aspect of the invention, there is provided a process for producing the novel amorphous form of ziprasidone hydrochloride comprising the steps of:

(i) suspending ziprasidone free base preferably in about 5 to 100 volumes of a low-polarity organic solvent or mixture of solvents at a temperature of from about −10 to about 40° C., (ii) adding hydrogen chloride to the suspension, (iii) recovering the amorphous ziprasidone hydrochloride.

Examples of low polarity organic solvents, which are useful in the reaction of the present invention include, but are not limited to a C 5 to C 12 substituted or unsubstituted cyclic and acyclic hydrocarbon solvent such as hexanes, heptanes, or cyclohexane; or a C 1 to C 3 chlorinated hydrocarbon solvent such as dichloromethane or chloroform, and their mixtures thereof. The most preferred solvent is heptanes or dichloromethane.

Examples of suitable organic solvents, which are useful for preparing solutions of anhydrous hydrogen chloride [step (iv)], include but are not limited to, isopropanol, ethanol and ethyl ether.

This novel amorphous form has advantageous properties relative to those of the prior art, for instance, better water solubility and potentially improved bioavailability. It also has the advantage of simplicity in that it avoids the necessity of having to resort to specialized preparation methods. For instance this more aqueous soluble amorphous form does not necessitate the use of a different salt form of ziprasidone as taught in Canadian patent 2,252,898 or a pro-drug of ziprasidone as taught in U.S. Pat. No. 5,935,960. Also it avoids the use of specialized spray dried dispersion compositions of ziprasidone free base as taught in Canadian patent 2,245,269 or specialized process equipment to ensure that the mean particle size produced is below 85 μm as taught in U.S. Pat. No. 6,150,366.

FIG. 1 is a typical example of a PXRD Diffractogram of a sample of Amorphous Ziprasidone Hydrochloride

FIG. 2 is a typical example of an IR (KBr) Spectrum of a sample of Amorphous Ziprasidone Hydrochloride. Some of the peaks occur at about 3407.24; 3171.16; 2952.60; 2546.88; 2442.20; 1708.39; 1628.54; 1590.81; 1561.86; 1484.65; 1445.99; 1422.64; 1383.13; 1293.54; 1246.90; 1206.81; 1179.90; 1117.82; 1072.78; 992.41; 971.81; 943.16; 865.55; 774.23; 738.96; 701.98; 693.89; 677.49; 652.15; 568.58; and 500.07.

FIG. 3 is a typical DSC Thermogram of a sample of Amorphous Ziprasidone Hydrochloride. Method: 20.0-360.0° C. @ 10.00° C./min Al Std 40 μl N. Section A: Integral 60.31 mJ; normalized 54.44 Jg −1 ; Onset 151.82° C.; Peak Height 0.43 Wg −1 ; Extrapol. Peak 163.77° C.; Peak Width 22.63° C. Section B: Integral 35.83 ml; normalized 32.34 Jg −1 ; Onset 201.79° C.; Peak Height 0.36 Wg −1 ; Extrapol. Peak 207.09° C.; Peak Width 16.69° C. Section C: Integral −56.49 mJ; normalized −50.99 Jg −1 ; Onset 293.12° C.; 1.30 Wg −1 ; Extrapol. Peak 302.04° C.; Peak Width 5.73° C.

The following examples illustrate the preparation of ziprasidone hydrochloride anhydrate and amorphous ziprasidone hydrochloride and are not to be construed as limiting the scope of the invention in any manner.