WO2010136522A2

WO2010136522A2 - A piperazine derivative free, or essentially free, of potential genotoxicity, and a process for preparing the same

Info

Publication number: WO2010136522A2
Application number: PCT/EP2010/057315
Authority: WO
Inventors: Iolanda CHAMORRO GUTIÉRREZ; Raquel Bou Bosch
Original assignee: Medichem S.A.
Priority date: 2009-05-27
Filing date: 2010-05-27
Publication date: 2010-12-02
Also published as: WO2010136522A3

Abstract

Disclosed is ranolazine, or a composition containing ranolazine, which is free, or substantially free, of potential genotoxicity wherein 2-(2-methoxyphenoxy)- methyloxirane is present in an amount equal to or less than 750 ppb (w/w) relative to ranolazine, and provides a process for preparing the same. Also disclosed is a method for determining the purity of ranolazine, wherein 2-(2-methoxyphenoxy)- methyloxirane is employed as a reference marker and/or standard.

Description

A PIPERAZINE DERIVATIVE FREE, OR ESSENTIALLY FREE, OF POTENTIAL GENOTOXICITY, AND A PROCESS FOR PREPARING THE SAME

This application claims the benefit of the U.S. Provisional Patent

Application Ser. No 61/181607 filed on May 27, 2009.

BACKGROUND OF THE INVENTION

Ranolazine (Compound I) is the international common accepted name for (±)- 1 -[3-(2-methoxyphenoxy)-2-hydroxypropyl]-4-[Λ/-(2,6-dimethylphenyl)- carbamoyl-methyljpiperazine, and has an empirical formula of C24H33N3O4 and a molecular weight of 427.54.

Ranolazine is an active pharmaceutical substance which has antianginal and anti-ischemic effects that do not depend upon reductions in heart rate or blood pressure. In the United States, ranolazine is marketed under the name RANEXA™, and is indicated for the treatment of chronic angina.

The preparation of ranolazine is disclosed in U.S. Patent No. 4,567,264. More precisely, U.S. Patent No. 4,567,264 describes the preparation of ranolazine base by using a guaiacol derivative (i.e. 2-(2-methoxyphenoxy)-methyloxirane, compound III) as an intermediate compound (See Scheme 1).

Scheme 1

Since compound (III) is used as an intermediate for the synthesis of ranolazine, it is likely to be present as an impurity not only in the active pharmaceutical ingredient, but also in the finished product. Further, given that compound (III) is not classified as a toxic substance, to date its presence in both the ranolazine active pharmaceutical ingredient and in the corresponding finished drug is controlled in order to fulfill the general acceptance of not more than 0.05% established for ranolazine impurities. BRIEF SUMMARY OF THE INVENTION

The invention provides a method of determining the presence or amount of potentially geno toxic impurities in (±)-l-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-4-

[Λ/-(2,6-dimethylphenyl)carbamoylmethyl]piperazine (i.e. ranolazine) or in a composition containing ranolazine, wherein 2-(2-methoxyphenoxy)-methyloxirane is employed as a reference marker or reference standard.

Additionally, the invention provides ranolazine free, or substantially free, of potential genotoxicity wherein compound (III) is present in an amount equal to or less than 750 ppb (w/w) relative to ranolazine, and provides a process for preparing the same. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a GC chromatogram of a reference standard solution of compound (III) in toluene [1.5 μg/mL; which corresponds to 750 ppb of compound (III) relative to ranolazine (w/w)].

Figure 2 is the GC chromatogram of the sample solution obtained from ranolazine of Example 1.

DETAILED DESCRIPTION OF THE INVENTION

The present inventors have found that 2-(2-methoxyphenoxy)- methyloxirane (compound III),

shows potential genotoxic properties when tested in the Ames bacterial mutagenicity test, which is an indication that the material may have mutagenic and carcinogenic potential.

In an embodiment, the invention provides a method of determining the presence of potentially genotoxic impurities in (±)-l-[3-(2-methoxyphenoxy)-2- hydroxypropyl]-4-[Λ/-(2,6-dimethylphenyl)carbamoylmethyl]piperazine (i.e. ranolazine) or in a composition containing ranolazine, wherein 2-(2- methoxyphenoxy)methyloxirane is employed as a reference marker. Thus, the invention refers to the use of compound (III) as a reference marker in the determination of potentially genotoxic impurities in a sample of a ranolazine batch.

The term "reference marker", as used herein, refers to a compound that is employed in qualitative analysis to identify components of a mixture based on their position in a chromatogram, e.g. in a HPLC or GC chromatogram, or on a Thin Layer Chromatography (TLC) plate. The term "composition containing ranolazine", as used herein, refers to a chemical or pharmaceutical mixture containing ranolazine intended for pharmaceutical use.

In another embodiment, the invention provides a method for determining the amount of potentially genotoxic impurities in (±)-l-[3-(2- methoxyphenoxy)-2-hydroxypropyl]-4-[Λ/-(2,6-dimethylphenyl)carbamoylmethyl]- piperazine (i.e. ranolazine) or in a composition containing ranolazine, wherein 2-(2- methoxyphenoxy)-methyloxirane is employed as a reference standard. Thus, the invention refers to the use of compound (III) as a reference standard in the determination of potentially genotoxic impurities in a sample of a ranolazine batch, and for example refers to its use in order to quantify the amount of compound (III) in said sample of a ranolazine batch.

The term "reference standard", as used herein, refers to a compound that may be used both for quantitative and qualitative analysis of ranolazine. For example, the HPLC retention time of the reference standard allows a relative retention time with respect to ranolazine to be determined, thus making qualitative analysis possible. Furthermore, the concentration of compound (III) in a solution injected into an HPLC or GC column allows the areas under the HPLC or GC peaks to be compared, thus making quantitative analysis possible. A reference marker is used only for qualitative analysis, while a reference standard may be used for quantitative or qualitative analysis, or both. Hence a reference marker is a subset of a reference standard, and is included within the definition of a reference standard.

In addition, the present inventors have found that the acceptable limit for compound (III) in both the ranolazine active substance and in the corresponding finished drug product needs to be significantly narrowed to a value much lower than the 0.05% general acceptance for impurities in ranolazine.

Namely, the applicants have found that the presence of compound (III) in ranolazine and in the corresponding finished drug product needs to be tightly controlled and restricted in order to fulfill the permitted daily dose for potential genotoxic impurities present in a pharmaceutical product. In this regard, a dose of 1.5 micrograms/day has been described as the acceptable level for genotoxic impurities in pharmaceuticals. Thus, the concentration of a potential genotoxic impurity considered acceptable in a pharmaceutical product can be calculated according to the following formula: maximum concentration of the potential genotoxic impurity (ppm) = 1.5 μg/active ingredient daily dose (in g). Since the maximum recommended dose of ranolazine is of Ig twice daily (i.e. 2 g/day), the present inventors have found that the compositions of ranolazine for use in pharmaceuticals require a maximum concentration of compound (III) of not more than 750 ppb (i.e. 0.750 ppm or 0.000075%) by weight. Thus, control of compound (III) at such low limits represents a significant challenge, particularly from an analytical point of view. In this regard, the present inventors have found that the standard HPLC methods for analyzing the chemical purity of ranolazine are not suitable methods for determining the presence of compound (III) at such low limits, and have provided an improved method, e.g., GC method, which is suitable for this purpose.

In another aspect, the invention provides a standard solution for the determination of potentially genotoxic impurities in samples of a ranolazine batch, wherein said standard solution comprises a solution of compound (III) in an organic solvent having a concentration between 0.60 - 2.00 μg/mL, and preferably having a concentration of 0.60 μg/mL, 0.80 μg/mL, 1.00 μg/mL, 1.20 μg/mL, 1.50 μg/mL, or 2.00 μg/mL [i.e. which correspond to 300 ppb, 400 ppb, 500 ppb, 600 ppb, 750 ppb, and 1.000 ppb, of compound (III), respectively]. The said standard solutions are suitable standard solutions for determining the concentration of compound (III) in ranolazine according to the limit concentration of 750 ppb (w/w) found by the inventors. In an aspect, the said standard solutions are used for preparing a linear calibration curve which is suitable for determining the concentration of compound (III) in ranolazine according to the limit concentration of 750 ppb (w/w) found by the inventors.

The organic solvent of the standard solution of the invention is preferably toluene. In an embodiment, the invention provides an analytical method for the determination of potentially genotoxic impurities in samples of a ranolazine batch, wherein said method can detect at least a concentration equal to or less than 750 ppb of compound (III) relative to ranolazine (w/w), said method comprising: (i) preparing a test sample by extracting the ranolazine from the sample of a ranolazine batch containing an unknown amount of compound (III), to obtain a solution in an organic solvent having an unknown amount of compound (III) and free, or substantially free, of ranolazine, preferably containing less than 0.5% of ranolazine, more preferably less than 0.1%, even more preferably less than 0.05%, and most preferably less than 0.01% of ranolazine,

(ii) measuring by a suitable GC apparatus the test sample of step (i) to obtain a GC chromatogram, wherein measuring comprises comparing the height and/or area of the peak corresponding to the impurity, and

(iii) determining the presence of compound (III) in the sample of the ranolazine.

Preferably, the preparing a test sample of step (i) comprises:

(i) (a) treating the sample of a ranolazine batch containing an unknown amount of compound (III) with a suitable amount of an acidic compound in the presence of water and a water non-miscible organic solvent, to obtain an aqueous / organic biphasic system comprising an aqueous phase containing the acid addition salt of ranolazine and an organic phase having an unknown amount of compound (III) and free, or essentially free, of ranolazine, preferably containing less than 0.5% of ranolazine, more preferably less than 0.1%, even more preferably less than 0.05%, and most preferably less than 0.01% of ranolazine, and (i) (b) removing the aqueous phase from the mixture, thereby obtaining a test sample solution in a water non-miscible organic solvent having an unknown amount of compound (III) and free, or essentially free, of ranolazine, preferably containing less than 0.5% of ranolazine, more preferably less than 0.1%, even more preferably less than 0.05%, and most preferably less than 0.01% of ranolazine. The determining the presence of compound (III) in the sample of the ranolazine of step (iii) of the analytical method above can be carried out by (iii) (a) comparing the height and/or area of the peak corresponding to the impurity in step (ii) to the height and/or area of the peak corresponding to the impurity in a standard solution preparation containing a known amount of compound (III) of between 0.60 - 2.00 μg/mL, and preferably containing a known amount of compound (III) of 0.60 μg/mL, 0.80 μg/mL, 1.00 μg/mL, 1.20 μg/mL, 1.50 μg/mL, or 2.00 μg/mL. Alternatively, the determining the presence of compound (III) in the sample of the ranolazine of step (iii) of the analytical method above can be carried out automatically by (iii) (b) using a linear calibration curve previously prepared from at least two standard solution preparations, preferably from at least five standard solution preparations, and more preferably from six standard solution preparations, of compound (III) having a concentration between 0.60 - 2.00 μg/mL, preferably having a concentration of 0.60 μg/mL, 0.80 μg/mL, 1.00 μg/mL, 1.20 μg/mL, 1.50 μg/mL, or 2.00 μg/mL [i.e. which correspond to 300 ppb, 400 ppb, 500 ppb, 600 ppb, 750 ppb, and 1.000 ppb, of compound (III), respectively], and more preferably by using a linear calibration curve previously prepared from six standard solution preparations of compound (III) having a concentration of 0.60 μg/mL, 0.80 μg/mL, 1.00 μg/mL, 1.20 μg/mL, 1.50 μg/mL, and 2.00 μg/mL, respectively. In keeping with the invention, the analytical method of the invention above can detect down to 132 ppb of compound (III) relative to ranolazine in a sample of a ranolazine batch. Further, the analytical method of the invention shows a linear calibration curve using standard solution preparations of compound (III) having a concentration of 0.60 μg/mL, 0.80 μg/mL, 1.00 μg/mL, 1.20 μg/mL, 1.50 μg/mL, and 2.00 μg/mL [i.e. which correspond to 300 ppb, 400 ppb, 500 ppb, 600 ppb, 750 ppb, and 1.000 ppb, of compound (III), respectively].

The organic solvent suitable for the analytical method above may be any suitable organic solvent which is immiscible in water. Preferably, the organic solvent is a hydrocarbon, e.g., toluene. A water non-miscible organic solvent is an organic solvent which shows a reduced solubility in water and therefore it separates as an upper or lower phase when the concentration of water is increased over its solubility limit. Preferred water non-miscible organic solvents are those having water solubility values (w/w) of less than 50%, more preferably less than 10%, even more preferably less than 1%, and even more preferably less than 0.1%. Non limiting examples of suitable water non-miscible organic solvents include pentyl acetate, anisole, benzaldehyde, benzene, bromobenzene, butyl acetate, butyl ether, chlorobenzene, chloroform, cyclohexane, cyclohexanone, cyclopentane, 1 ,2- dichlorobenzene, 1,2-dichloroethane, dichloromethane, diethoxymethane, diisobutyl ketone, dimethoxymethane, ethyl acetate, ethylbenzene, 1 ,2-diethoxyethane, ethyl ether, phosphoral, n-heptane, n-hexane, isobutyl acetate, isopropyl acetate, isopropyl ether, methyl acetate, methyl tert-butyl ether, methyl cyclohexane, methyl ethyl ketone, methyl formate, methyl isobutyl ketone, nitrobenzene, n-pentane, 3- pentanone, propyl acetate, propylene carbonate, l-methoxy-2-propanol acetate, propylene oxide, tetrachloroethylene, toluene, 1,1,1-trichloroethane, trichloroethylene, xylene, and mixtures thereof. Particularly preferred organic solvents for the analytic method above are ethyl acetate, isopropyl acetate, methyl tert-butyl ether, methyl ethyl ketone, methyl isobutyl ketone, toluene, xylene, and mixtures thereof, and more particularly the more preferred organic solvent for the analytic method above is toluene.

The acidic compound of the step (i) (a) of the analytical method above is preferably an organic or an inorganic acid compound, more preferably is an organic acid compound, and more preferably is tartaric acid.

The suitable GC apparatus of step (ii) preferably comprises a column having a polysiloxane as stationary phase, and preferably comprises column having 5% phenyl 95% dimethyl polysiloxane as stationary phase. For example, a suitable GC apparatus is preferably an Agilent 6890N apparatus, wherein a suitable column is preferably a TRB-5A column (composition: 5% phenyl 95% dimethyl polysiloxane, 30 m length, 0.32 mm internal diameter, 0.5 μm film thickness), and a suitable detector is preferably a flame ionization detector (FID). In yet another embodiment, the invention provides a process for preparing ranolazine which is free, or substantially free, of potential genotoxicity, said process comprising:

(i) providing ranolazine, (ii) determining the concentration of compound (III) in the ranolazine, and preferably by the chromatographic method of the invention, and

(iii) reducing the residual amount of compound (III) in the ranolazine if the concentration of compound (III) in the ranolazine is higher than 750 ppb (w/w).

The providing the ranolazine of step (i) of the process above, preferably comprises:

(i)(a) synthesizing ranolazine directly, or

(i)(b) isolating ranolazine from a pharmaceutical composition comprising ranolazine.

The reducing the residual amount of compound (III) in the ranolazine of step (iii) of the process above preferably comprises crystallizing or digesting the ranolazine, and more preferably comprises digesting the ranolazine in a non- hydroxylic organic solvent.

The digesting the ranolazine in a non-hydro xylic organic solvent preferably comprises: (iii) (a) suspending the ranolazine in a non-hydroxylic organic solvent,

(iii) (b) optionally, heating the suspension, and

(iii) (c) removing the solvent from the suspension, preferably by filtering the suspension.

The non-hydroxylic organic solvent of the process of the invention above is preferably a ketone solvent, and more preferably is methyl ethyl ketone.

In another aspect, the process of the invention above further comprises an additional step of (iv) admixing the ranolazine with at least one pharmaceutically acceptable carrier, thereby obtaining a pharmaceutical composition comprising ranolazine which is free, or essentially free, of potential genotoxicity.

The at least one pharmaceutically acceptable carrier is preferably methacylic acid-ethyl acrylate copolymer, microcrystalline cellulose, hypromellose, sodium hydroxide, magnesium stearate, titanium dioxide, polyethylene glycol, polysorbate 80, glycerol triacetate, lactose monohydrate, or mixtures thereof.

As said above, the amount of undesired compound (III) in ranolazine or in a composition containing ranolazine can be reduced by methods such as recrystallization or digestion. Recrystallization or digestion of samples containing ranolazine can be performed in any suitable solvent. For digestion methods, the preferred solvent is any suitable non-hydroxylic organic solvent. More preferably, methyl ethyl ketone is the suitable non-hydroxylic organic solvent for reducing the amount of compound (III) in compositions containing ranolazine by means of digestion methods. Also, the amount of undesired compound (III) in compositions containing ranolazine can be reduced by adjusting the stoichiometric amount of compound (III) used in the preparation of ranolazine.

In other embodiments, the present invention provides ranolazine which is free, or substantially free, of potential genotoxicity. More precisely, the said ranolazine which is free, or substantially free, of potential genotoxicity has a concentration of compound (III) of equal to or less than 750 ppb (w/w).

In another further aspect, the present invention relates to a pharmaceutical composition comprising ranolazine which is free, or essentially free, of potential genotoxicity, and wherein said pharmaceutical composition has a concentration of compound (III) of equal to or less than 750 ppb (w/w), relative to ranolazine.

The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope. Examples

General Experimental Conditions

GC Method:

The GC analysis was performed on an Agilent 6890N. The following parameters were used: Gas carrier: He; Column head pressure: 10 psi (constant pressure); Split ratio: 3:0, Injector Temp.: 250 ⁰C; Detector Temp. (FID): 300 ⁰C;

Column: TRB-5A (5% phenyl 95% dimethyl polysiloxane), 30 m length, 0.32 mm internal diameter, 0.5 μm film thickness.

The following temperature program was used: Initial Temp.: 170 ⁰C; Initial time: 10 min; Rate: 10 °C/min; Final Temp.: 280 ⁰C; Final time: 10 min. Injection volume: 4 μL (Agilent 7683 autosampler).

Standard solutions of compound (III): A stock solution of 100 μg/mL of compound (III) in toluene was prepared by weighing 10 mg of compound (III) in a

100 mL volumetric flask and dissolving with toluene. The stock solution of 100 μg/mL of compound (III) was diluted quantitatively with toluene to obtain solutions containing 0.6, 0.8, 1.0, 1.2, 1.5 and 2.0 μg/mL of compound (III).

Blank preparation: 2g of tartaric acid were dissolved with 10 mL of water. Then, 2 mL of toluene and Ig of sodium chloride were added. The mixture was stirred, the aqueous phase was removed, and the organic phase was injected into the GC apparatus.

Preparation of a reference standard solution preparation: 2g of tartaric acid were dissolved with 10 mL of water. Then, Ig of sodium chloride and 2 mL of a standard solution of compound (III) in toluene (i.e. solutions containing 0.60, 0.80, 1.0, 1.2, 1.5 and 2.0 μg/mL) were added. The mixture was stirred, the aqueous phase was removed, and the organic phase was injected into the GC apparatus. A linear calibration curve was determined using the six standard solution preparations [i.e. 0.6, 0.80, 1.0, 1.2, 1.5 and 2.0 μg/mL; which correspond to 300 ppb, 400 ppb, 500 ppb, 600 ppb, 750 ppb, and 1.000 ppb, of compound (III), respectively]. The obtained GC chromatogram for the preparation prepared using the standard solution containing 1.5 μg/mL of compound (III) is shown in Figure 1.

Test sample preparation: 2g of ranolazine were weighed with 2 g of tartaric acid and dissolved with 10 mL of water. Then, 2 mL of toluene and Ig of sodium chloride were added. The mixture was stirred, the aqueous phase was removed, and the organic phase was injected into the GC apparatus.

System suitability: a standard preparation prepared from a standard solution in toluene of compound (III) of 1.5 μg/mL was used as standard solution preparation for calculating the content of compound (III) in the samples of ranolazine. Alternatively, other standard preparations of compound (III) prepared from standard solutions having a concentration of (III) between 0.60 - 2.0 μg/mL can be used as standard solution preparation for calculating the content of compound (III) in the samples of ranolazine.

Approximate GC Retention Time for 2-(2-methoxyphenoxy)- methyloxirane (compound III): 7.2 minutes.

Calculation: The calculation of the content of compound (III) in the sample of ranolazine can be calculated using the equation below:

ri ^c _{s i nnn} ppb of compound of formula (III) = — x X lUUU rs w where: ri = Area peak response of compound (III) in the Test sample preparation. rs = Area peak response of compound (III) in the standard solution preparation. c_s = Concentration (μg/mL) of compound (III) in the standard solution of compound (III). w = Weight (g) of ranolazine in the Test sample preparation. 1000 = convention factor to convert the result to ppb. The limit of detection (LOD): 132 ppb of compound (III). Alternatively to the equation above, the content of compound (III) in the sample of ranolazine can be calculated automatically from the linear calibration curve determined above from the six standard solution preparations [i.e. 0.6, 0.80, 1.0,

1.2, 1.5 and 2.0 μg/mL; which correspond to 300 ppb, 400 ppb, 500 ppb, 600 ppb, 750 ppb, and 1.000 ppb, of compound (III), respectively].

HPLC Method:

The chromatographic separation was carried out in a Symmetry C 18, 5 μm, 250 x 4.6 mm LD column; at 37 ⁰C.

The mobile phase A was prepared by mixing 297.5 g of acetonitrile with 1620 g of pH= 4.4 buffer, which was prepared from 1.87 g of ammonium acetate in 1620 mL of water adjusting the pH to 4.4 with glacial acetic acid. This mobile phase was mixed and filtered through 0.22 μm nylon filter under vacuum.

The mobile phase B was acetonitrile.

The chromatograph was equipped with a 230 nm detector and the flow rate was 1.0 mL per minute.

The chromatograph was programmed as follows: Initial 0-2 min. isocratic 100% mobile phase A, 2-16 min. linear gradient to 93% mobile phase A, 16-

24 min. isocratic 93% mobile phase A, 24-45 min. linear gradient to 80% mobile phase A, 45-62 min. isocratic 80% mobile phase A, 62-82 min. linear gradient to 100% mobile phase A and 82-95 min. equilibration with 100% mobile phase A.

Test samples were prepared by dissolving the appropriate amount of sample to obtain 5 mg per mL in mobile phase, and 20 μL were injected.

Approximate HPLC Retention Times:

Example 1: Preparation of Ranolazine free of potential genotoxicity. 30.56 g of ranolazine [24.07 g of estimated dry mass; HPLC purity:

99.8%; Compound III (GC Method): higher than 900 ppb (i.e. about 2.5 ppm)] was suspended in 103 mL of methyl ethyl ketone and the suspension was heated to 80 ⁰C. The solution was cooled to 20-25 ⁰C and kept at that temperature for 1 hour. The suspension was filtered, washed with 8.05 g (10 mL) of methyl ethyl ketone and dried in a vacuum oven at 50-60 ⁰C till constant weight. 22.73 g of ranolazine was obtained [purification yield: 94.4%; HPLC purity: 99.91%; Compound III (GC method): 378 ppb (See Figure 2). Not detected by HPLC].

All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

Claims:

1. A process for preparing ranolazine, compound of formula I,

which is free, or essentially free, of potential genotoxicity, said process comprising:

(i) providing ranolazine,

(ii) determining the concentration of compound (III),

in the ranolazine, and (iii) if the concentration of compound (III) in the ranolazine is higher than

750 ppb, reducing the residual amount of compound (III) in the ranolazine.

2. A process according to claim 1, wherein the providing ranolazine of step (i) comprises: (i)(^a) synthesizing ranolazine directly, or

3. A process according to any of claims 1 and 2, wherein the reducing the residual amount of compound (III) in the ranolazine of step (iii) comprises crystallizing or digesting the ranolazine.

4. A process according to claim 3, wherein the reducing the residual amount of compound (III) in the ranolazine of step (iii) comprises digesting the ranolazine in a non-hydroxylic organic solvent.

5. A process according to claim 4, wherein the digesting the ranolazine in a non- hydroxylic organic solvent comprises:

(iii) (a) suspending the ranolazine in a non-hydroxylic organic solvent, (iii) (b) optionally, heating the suspension, and

6. A process according to any of claims 4 and 5, wherein the non-hydroxylic organic solvent is a ketone solvent, and preferably is methyl ethyl ketone.

7. A process according to any of claims 1 to 6, said process further comprising an additional step of (iv) admixing the ranolazine with at least one pharmaceutically acceptable carrier, thereby obtaining a pharmaceutical composition comprising ranolazine which is free, or essentially free, of potential genotoxicity.

8. A process according to claim 7, wherein the at least one pharmaceutically acceptable carrier is methacylic acid-ethyl acrylate copolymer, microcrystalline cellulose, hypromellose, sodium hydroxide, magnesium stearate, titanium dioxide, polyethylene glycol, polysorbate 80, glycerol triacetate, lactose monohydrate, or mixtures thereof.

9. Ranolazine which is free, or essentially free, of potential genotoxicity, and wherein said ranolazine has a concentration of compound (III) of equal to or less than 750 ppb (w/w).

10. A pharmaceutical composition comprising ranolazine which is free, or essentially free, of potential genotoxicity, and wherein said pharmaceutical composition has a concentration of compound (III) of equal to or less than 750 ppb (w/w), relative to ranolazine.

11. A standard solution for the determination of potentially genotoxic impurities in samples of a ranolazine batch, wherein said standard solution comprises a solution of compound (III) in an organic solvent having a concentration between 0.60 - 2.00 μg/mL, and preferably having a concentration of 0.60 μg/mL, 0.80 μg/mL, 1.00 μg/mL, 1.20 μg/mL, 1.50 μg/mL, or 2.00 μg/mL.

12. The standard solution of claim 11 , wherein the organic solvent is toluene.

13. Use of compound (III) as a reference standard and/or marker in the determination of potentially genotoxic impurities in a sample of a ranolazine batch.

14. An analytical method for the determination of potentially genotoxic impurities in samples of a ranolazine batch, characterized in that said method can detect at least a concentration equal to or less than 750 ppb of compound (III) relative to ranolazine (w/w), said method comprising: (i) preparing a test sample by extracting the ranolazine from the sample of a ranolazine batch containing an unknown amount of compound (III), to obtain a solution in an organic solvent having an unknown amount of compound (III) and free, or substantially free, of ranolazine, (ii) measuring by a suitable GC apparatus the test sample of step (i) to obtain a GC chromatogram, wherein measuring comprises comparing the height and/or area of the peak corresponding to the impurity, and

(iii) determining the concentration of compound (III) in the sample of the ranolazine batch.

15. An analytical method according to claim 14, wherein the preparing a test sample of step (i) further comprises:

(i) (a) treating the sample of a ranolazine batch containing an unknown amount of compound (III) with a suitable amount of an acidic compound in the presence of water and a water non-miscible organic solvent, to obtain an aqueous / organic biphasic system comprising an aqueous phase containing the acid addition salt of ranolazine and an organic phase having an unknown amount of compound (III) and free, or essentially free, of ranolazine, and (i) (b) removing the aqueous phase from the mixture, thereby obtaining a test sample solution in a water non-miscible organic solvent having an unknown amount of compound (III) and free, or essentially free, of ranolazine.

16. An analytical method according to claim 15, wherein the water non-miscible organic solvent is at least one of the group consisting of pentyl acetate, anisole, benzaldehyde, benzene, bromobenzene, butyl acetate, butyl ether, chlorobenzene, chloroform, cyclohexane, cyclohexanone, cyclopentane, 1 ,2-dichlorobenzene, 1,2- dichloroethane, dichloromethane, diethoxymethane, diisobutyl ketone, dimethoxymethane, ethyl acetate, ethylbenzene, 1 ,2-diethoxyethane, ethyl ether, phosphoral, n-heptane, n-hexane, isobutyl acetate, isopropyl acetate, isopropyl ether, methyl acetate, methyl tert-butyl ether, methyl cyclohexane, methyl ethyl ketone, methyl formate, methyl isobutyl ketone, nitrobenzene, n-pentane, 3-pentanone, propyl acetate, propylene carbonate, l-methoxy-2-propanol acetate, propylene oxide, tetrachloroethylene, toluene, 1,1,1-trichloroethane, trichloroethylene, xylene, and mixtures thereof, preferably is at least one of the group consisting of ethyl acetate, isopropyl acetate, methyl tert-butyl ether, methyl ethyl ketone, methyl isobutyl ketone, toluene, xylene, and mixtures thereof, and more preferably is toluene.

17. An analytical method according to any of claims 15 and 16, wherein the acidic compound is an organic or an inorganic acid compound, more preferably is an organic acid compound, and more preferably is tartaric acid.

18. An analytical method according to any of claims 14 to 17, wherein the suitable GC apparatus of step (ii) comprises a column having a polysiloxane as stationary phase, and preferably comprises column having 5% phenyl 95% dimethyl polysiloxane as stationary phase.

19. A process according to any of claims 1 to 8, wherein the determining the concentration of compound (III) in ranolazine of step (ii) comprises carrying out an analytical method as defined in any of claims 14 to 18.