WO2011030330A2

WO2011030330A2 - Process for the purification of ropinirole hydrochloride

Info

Publication number: WO2011030330A2
Application number: PCT/IL2010/000721
Authority: WO
Inventors: Hillel Pizem; Hannan Peleg; Rosa Cyjon
Original assignee: Taro Pharmaceutical Industries Ltd.
Priority date: 2009-09-09
Filing date: 2010-09-02
Publication date: 2011-03-17
Also published as: WO2011030330A3

Abstract

This invention is directed to a process for the preparation of pure ropinirole hydrochloride with purity of equal to or greater than 99.8% and less than 0.1% isatine impurity. In the process of the present invention, the isatine is removed during the reaction steps and no further cleaning steps are required.

Description

PROCESS FOR THE PURIFICATION OF ROPINIROLE HYDROCHLORIDE

FIELD OF THE INVENTION

[001] This invention is directed to a process for the preparation of pure ropinirole hydrochloride with purity of equal to or greater than 99.8% and less than 0.1% isatine impurity. In the process of this invention, the isatine is removed during the reaction steps and no further operations are required for isatine removal.

BACKGROUND OF THE INVENTION

[002] Ropinirole hydrochloride is a non-ergoline dopamine agonist. Its chemical name is 4-[2- (dipropylamino)ethyl]-l ,3-dihydro-2H-indol-2-one monohydrochloride. The structural formula of ropinirole hydrochloride is represented by formula (1):

[003] Ropinirole is indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease which is a debilitating disease characterized by disturbance of voluntary movements. The condition is believed to be caused by the degeneration of dopaminergic neurons in the nigral-striatal system of the brain, leading to inadequate release of the neurotransmitter dopamine. Administration of conventional anti-parkinsonian drugs like L-DOPA and ergot alkaloids relieves certain symptoms of the disease, but is associated with several undesirable side- effects like dyskinesia, psychiatric problems, nausea, vomiting, and abdominal distension. Ropinirole, an indolone derivative, alleviates this deficiency, and has particularly minimum liability to cause dyskinesia. Furthermore, it has additional beneficial effects on the central nervous system.

[004] There are various known procedures of synthesis of ropinirole and its pharmaceutically acceptable salts, including hydrochloride such as the procedures disclosed in US Patent No. 4,997,954, WO2005/080333, WO2008/075169, WO2005/105741, WO2007/110879 and US2007/0254941. However, the literature processes also have limitations due to the reaction sequence and the by-products/ impurities associated with them. The separation and quantification of these impurities require complex and expensive analytical methods.

[005] One of the most significant impurity produced during the synthesis of ropinirole is 4-(2- (dipropyl amino)ethyl) isatine hydrochloride which is the oxidized form of ropinirole, the structural formula of which is represented by formula (2):

[006] The isatine impurity produced during the synthesis of ropinirole cannot be removed by ordinary purification methods such as crystallization or extraction and special purification methods are required. It is therefore essential to develop an improved process for the preparation of pure ropinirole hydrochloride which removes the deficits of prior art processes. SUMMARY OF THE INVENTION

[007] The present invention is directed to an improved process for the production of highly pure ropinirole hydrochloride. The improved process is simple and industrial suitable for the purification of pure ropinirole hydrochloride where isatine is removed in a single step during the reaction work-up. No further special cleaning step is required to remove the isatine. [008] The improved process for the purification of pure ropinirole hydrochloride comprising the steps of:

(a) reacting crude ropinirole base with one or more hydride donors in acetonitrile-water mixture;

(b) adding dichloromethane to the solution of step (a) wherein ropinirole base substantially free of isatine is extracted into the dichloromethane phase;

(c) gradual cooling of the dichloromethane phase of step (b) and adding hydrochloric acid solution to yield crude ropinirole hydrochloride precipitation;

(d) isolating the precipitated crude ropinirole hydrochloride by filtration; and

(e) dissolving the crude ropinirole hydrochloride of step (d) in alcohol followed by crystallization to obtain pure ropinirole hydrochloride having HPLC purity equal to or greater than 99.8% and less than 0.1% isatine impurity.

[009] The present invention is also directed to a process for the preparation of pure ropinirole hydrochloride comprising the steps of:

(a) reacting dipropylamine and 4-(2-Bromo-ethyl)-l ,3-dihydro-indol-2-one in toluene and water under reflux to yield crude ropinirole base;

(b) reacting the crude ropinirole base of step (a) with one or more hydride donors in acetonitrile-water mixture;

(c) adding dichloromethane to the solution of step (b) to yield ropinirole base substantially free of isatine extracted into the dichloromethane phase; (d) gradual cooling of the dichloromethane phase of step (c) and adding hydrochloric acid solution to yield crude ropinirole hydrochloride precipitation;

(e) isolating the precipitated crude ropinirole hydrochloride by filtration; and

(f) dissolving the crude ropinirole hydrochloride of step (e) in alcohol followed by crystallization to obtain pure ropinirole hydrochloride having HPLC purity equal to or greater than 99.8% and less than 0.1 % isatine impurity.

[0010] The pure ropinirole hydrochloride obtained following crystallization in alcohol exhibits specific particle size distribution. In one embodiment, the d(0.9) value of the pure ropinirole hydrochloride is between about 200-400 μη . In another embodiment, the d(0.5) value of the pure ropinirole hydrochloride is between about 50-150 μηι. In another embodiment, the d(0.1) value of the pure ropinirole hydrochloride is between about 10-50 μη .

[001 1 ] In another embodiment, the present invention is directed to a pharmaceutical composition comprising pure ropinirole hydrochloride as obtained by the process of this invention comprising one or more pharmaceutically acceptable diluent, carrier or excipient. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Fig. 1 depicts a HPLC spectra of ropinirole hydrochloride, obtained following the process of the present invention.

[0013] It will be appreciated that for simplicity and clarity of illustration, elements shown in the figures have not necessarily been drawn to scale. For example, the dimensions of some of the elements may. be exaggerated relative to other elements for clarity. Further, where considered appropriate, reference numerals may be repeated among the figures to indicate corresponding or analogous elements.

DETAILED DESCRIPTION OF THE PRESENT INVENTION [0014] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the present invention.

[0015] The term "substantially free of isatine" refers to less than 0.1% isatine impurity, preferably less than 0.05% isatine impurity, more preferably, less than 0.02% isatine impurity.

[0016] The terms "d(0.9)'\ "d(0.5)" or "d(0.1)" refer to particle size distribution of the pure ropinirole hydrochloride following crystallization. D(0.9) value is defined as the size value where 90% of the particles have a size of this value or less. Likewise, d(0.1) value refers to 10% of the particles having a size equal or less than this value. D(0.5) refers to 50 % of the particles having a size equal or less than this value. Methods for determining d(0.1), d(0.5) and d(0.9) include laser diffraction, such as using equipment sold by Malvern Instruments Ltd., Malvern, Worcestershire, United Kingdom.

[0017] In one embodiment, the present invention is directed to a simple and industrial suitable process for the purification of pure ropinirole hydrochloride where isatine is removed in a single step during the reaction work-up. No further special cleaning step is required to remove the isatine.

[0018] The starting crude ropinirole base material of this invention may be prepared according to the process available in the prior art. In one embodiment, crude ropinirole base is obtained by reacting dipropylamine and 4-(2-Bromo-ethyl)-l,3-dihydro-indol-2-one in toluene and water under reflux. A portion of unreacted amine, toluene and water may be distilled out from the reaction mixture before proceeding with the purification process. [0019] Step (a) in the purification process of the present invention comprises dissolving crude ropinirole base with one or more hydride donors in acetonitrile- water mixture. Examples of hydride donors useful in the present invention include: sodium borohydride, lithium borohydride, calcium borohydride, potassium borohydride.

[0020] In a preferred embodiment, the hydride donor is sodium borohydride.

[0021] An organic solvent selected from dichloromethane is then added to the solution of step (a) to yield ropinirole base substantially free of isatine extracted into the dichloromethane phase. Without being bound by theory, it has now been found that the sodium borohydride converts the isatine impurity to its alcohol derivative which stays in the aqueous phase during the extraction step while the ropinirole base is extracted into the dichloromethane phase to obtain a ropinirole base substantially free of isatine. The extraction step of this invention is an irreversible step which prevents the formation of isatine and is stable in all pH ranges.

[0022] In the next step of purification, the dichloromethane phase obtained following the extraction step is gradually cooled to temperature of below 10°C and hydrochloric acid solution is added to the dichloromethane phase while stirring to yield crude ropinirole hydrochloride precipitation without the need of evaporation or distillation of the dichloromethane from the solution. In one embodiment, the hydrochloric acid solution is added to the dichloromethane phase at temperature of between about 2 - 7°C. In another embodiment, the hydrochloric acid solution is added to the dichloromethane phase at temperature of between about 3 - 6°C. In a preferred embodiment, the hydrochloric acid solution is added to the dichloromethane phase at temperature of about 5°C. Upon addition of hydrochloric acid solution to the cooled dichloromethane phase, crude ropinirole hydrochloride is precipitated from the solution. The crude ropinirole hydrochloride precipitated from the solution is preferably isolated by filtration. [0023] The filtrated crude ropinirole hydrochloride is then dissolved in alcohol under reflux until full dissolution. A portion of the alcohol is preferably distilled out under atmospheric pressure, followed by gradual cooling of the solution to form crystalline pure ropinirole hydrochloride. Preferably between about 20-50% of the alcohol is distilled out under atmospheric pressure, more preferably about 30-40% of the alcohol is distilled out under atmospheric pressure. In various embodiments, the alcohol may be ethanol, methanol, isopropanol, n-propanol, t-butanol, n-butanol, or any combination thereof. In a preferred embodiment, the solvent is absolute ethanol.

[0024] In one preferred embodiment, the dissolution of crude ropinirole hydrochloride in ethanol followed by gradual cooling of the solution to form crystalline pure ropinirole hydrochloride comprises the following steps: (i) dissolving the filtrated crude ropinirole hydrochloride in ethanol under reflux to full dissolution; (ii) distilling out about 30-40% of the ethanol under atmospheric pressure (iii) cooling said solution of (ii) to about 50-60°C and keeping said solution for about 1-2 hr; (iv) cooling said solution of (iii) to room temperature, wherein crystalline pure ropinirole hydrochloride is obtained.

[0025] The pure ropinirole hydrochloride obtained following the crystallization has HPLC purity equal to or greater than 99.8% and less than 0.1% isatine impurity. In a preferred embodiment, the purity of the ropinirole hydrochloride is above 99.9% and the level of isatine impurity is less than 0.02%.

[0026] The pure ropinirole hydrochloride obtained following crystallization in ethanol exhibits specific particle size distribution. In one embodiment, the d(0.9) value of the pure ropinirole hydrochloride is between about 200-400 μπι. In another embodiment, the d(0.5) value of the pure ropinirole hydrochloride is between about 50-150 μπι. In another embodiment, the d(0.1) value of the pure ropinirole hydrochloride is between about 10-50 μπι. [0027] This particle size distribution reflects relatively large particle size which is advantageous in case of ropinirole since it reduces the particle surface area and thus minimizes the oxidation of ropinirole, and also simplifies the process of dry mix tabletation. Furthermore, the large particle size does not affect the dissolution rate of ropinirole since ropinirole is highly soluble in water.

[0028] The present invention further provides for a pharmaceutical composition comprising purified ropinirole or it's salt as prepared according to the processes of the present invention.

[0029] In a preferred embodiment, the pharmaceutical compositions of the present invention comprise ropinirole hydrochloride containing less than 0.02 % of isatine and having a purity of ropinirole hydrochloride above 99.9% in combination with a pharmaceutically acceptable diluent, carrier or excipient.

[0030] As used herein, "pharmaceutical composition" means a "therapeutically effective amount" of the active ingredient, i.e. ropinirole hydrochloride as prepared herein, together with a pharmaceutically acceptable carrier, excipient or diluent.

[0031] Pharmaceutical compositions containing ropinirole and/or. it's salt can be administered to a subject by any method known to a person skilled in the art, such as orally, parenterally, intravascular ly, paracancerally, transmucosally, transdermally, intramuscularly, intranasally, intravenously, intradermally, subcutaneously, sublingually, intraperitoneally, intraventricularly, intracranially, intravaginally, by inhalation, rectally or intratumorally. Another method of administration is via aspiration or aerosol formulation.

[0032] The pharmaceutical compositions of the present invention are preferably administered orally, and thus may be formulated in a form suitable for oral administration, i.e. as a solid or a liquid preparation. Suitable solid oral formulations include, for example, tablets, capsules, pills, granules, pellets, powders, and the like. Suitable liquid oral formulations include, for example, solutions, suspensions, dispersions, emulsions, oils and the like. [0033] In one embodiment, this invention provides a method of treating Parkinson's disease or Restless Legs Syndrome wherein the method comprising administering to a patient an effective amount of a product-by-process composition of matter comprising ropinirole or its salt wherein the said ropinirole or its salt manufactured by the process of this invention.

EXAMPLES

EXAMPLE 1: Process for the preparation of pure ropinirole hydrochloride

Step 1. Preparation of Ropinirole HCl crude:

[0034] Under nitrogen, a flask was charged with 150 ml of water, 45 ml of toluene, 75 ml of dipropylamine and 15 gr of 4-(2-Bromoethyl)-3-Chloro-l,3-Dihydro-2H-Indoloe-2-One. The mixture was heated to reflux until reaction completion. The lower aqueous layer was separated and discarded and fresh water was added. Unreacted amine, toluene and some water were then distilled out. 75 ml of acetonitrile were added followed by addition of 0.75 gr of NaBH₄. The product was extracted into 150 ml of dichloromethane. 6 ml of concentrated HCl was added into the dichloromethane solution and the organic solution was cooled to about 5°C. The solution was stirred at this temperature for one hour. The product was collected by filtration. The cake was washed with dichloromethane and was used wet in the next step.

Step 2. Preparation of crystalline Ropinirole HCl pure

[0035] Wet ropinirole HCl crude was dissolved in 30 parts (w/v) ethanol absolute under reflux. The solution was stirred till full dissolution. 10 parts (w/v) of ethanol were distilled out under atmospheric pressure and the solution was cooled to 60°C. The solution was kept at 60°C for an hour and then cooled to room temperature. Pure ropinirole HCl was collected by filtration. The cake was washed with ethanol absolute then dried under vacuum conditions at 80°C. In this procedure ropinirole was obtained with an overall yield of about 48% and with purity of above 99.9% and isatine impurity of less than 0.02%.

EXAMPLE 2: Particle size distribution of pure ropinirole hydrochloride obtained following crystallization

[0036] The pure ropinirole hydrochloride obtained following crystallization in ethanol exhibits specific particle size distribution. Table 1 below lists the d(0.9), d(0.5) and d(0.1) values of the pure ropinirole hydrochloride obtained following crystallization in three different batches.

Table 1 :

Batch 1 Batch 2 Batch 3 Batch 4 d(0.1), μιη 41.8 23.7 17.0 16.1

d(0.5), μπι 132.1 102.2 71.6 69.7

d(0.9), μπι 365.8 327.8 244.0 236.2

EXAMPLE 3: HPLC spectra of ropinirole hydrochloride

[0037] Figure 1 depicts a HPLC spectra of ropinirole hydrochloride, obtained following the process of the present invention. As revealed from Figure 1, the peak of Isatine disappeared from the HPLC spectra following the reaction of crude Ropinirole base with NaBH₄ in acetonitrile-water mixture.

[0038] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.

Claims

What is claimed is:

1. A process for the purification of ropinirole hydrochloride comprising the steps of:

(c) gradual cooling of the dichloromethane phase of step (b) and adding of hydrochloric acid solution to yield crude ropinirole hydrochloride precipitation;

2. The process of claim 1 , wherein the one or more hydride donors is selected from sodium borohydride, lithium borohydride, calcium borohydride and potassium borohydride.

3. The process of claim 1 , wherein the alcohol is ethanol, methanol, isopropanol, n-propanol, t-butanol, n-butanol, or any combination thereof.

4. The process of claim 3, wherein the alcohol is absolute ethanol.

5. The process of claim 1, wherein the solution of step (c) is cooled to below about 10°C and between about 30-36% hydrochloric acid solution is added while stirring.

6. The process of claim 1 , whereiri step (e) comprises (i) dissolving the filtrated crude ropinirole hydrochloride in absolute ethanol under reflux to full dissolution; (ii) distilling out about 30-40% of the ethanol under atmospheric pressure (iii) cooling said solution of (ii) to about 50-60°C and keeping said solution for about 1-2 hr; (iv) cooling said solution of (iii) to room temperature, wherein crystalline pure ropinirole hydrochloride is obtained.

7. The process of claim 6, wherein the d(0.9) value of the pure ropinirole hydrochloride is between about 200-400 μπι, the d(0.5) value of the pure ropinirole hydrochloride is between about 50-150 μιη, and the d(0.1) value of the pure ropinirole hydrochloride is between about 10-50 μιη.

8. The process of claim 1, wherein said purified ropinirole hydrochloride as obtained in step (e) comprises ropinirole hydrochloride purity of above 99.9% and isatine impurity of less than 0.02%.

9. A pharmaceutical composition comprising pure ropinirole hydrochloride as obtained by the process of claim 1 , comprising one or more pharmaceutically acceptable diluent, carrier or excipient.

10. A process for the preparation of pure ropinirole hydrochloride comprising the steps of:

(b) dissolving the crude ropinirole base of step (a) with one or more hydride donors in acetonitrile- water mixture;

(c) adding dichloromethane to the solution of step (b) to yield ropinirole base substantially free of isatine extracted into the dichloromethane phase;

(d) gradual cooling of the dichloromethane phase of step (c) and adding hydrochloric acid solution to yield crude ropinirole hydrochloride precipitation;

(f) purifying the crude ropinirole hydrochloride filtrate of step (e) by dissolving in alcohol and crystallization to obtain pure ropinirole hydrochloride having HPLC purity equal to or greater than 99.8% and less than 0.1% isatine impurity.

1 1. The process of claim 10, wherein a portion of dipropylamine, toluene and water is distilled out prior to step (b).

12. The process of claim 10, wherein the one or more hydride donors is selected from sodium borohydride, lithium borohydride, calcium borohydride and potassium borohydride.

13. The process of claim 10, wherein the alcohol is ethanol, methanol, isopropanol, n- propanol, t-butanol, n-butanol, or any combination thereof.

14. The process of claim 13, wherein the alcohol is absolute ethanol.

15. The process of claim 10, wherein the solution of step (d) is cooled to below about 10°C and between about 30-36% hydrochloric acid solution is added while stirring.

16. The process of claim 10, wherein step (f) comprises (i) dissolving the filtrated crude ropinirole hydrochloride in absolute ethanol under reflux to full dissolution; (ii) distilling out about 30-40% of the ethanol under atmospheric pressure (iii) cooling said solution of (ii) to about 50-60°C and keeping said solution for about 1 -2 hr; (iv) cooling said solution of (iii) to room temperature, wherein crystalline pure ropinirole hydrochloride is obtained.

17. The process of claim 16, wherein the d(0.9) value of the pure ropinirole hydrochloride is between about 200-400 μηι, the d(0.5) value of the pure ropinirole hydrochloride is between about 50-150 μπι, and the d(0.1) value of the pure ropinirole hydrochloride is between about 10-50 μπι.

18. The process of claim 10, wherein said purified ropinirole hydrochloride as obtained in step (f) comprises ropinirole hydrochloride purity of above 99.9% and isatine impurity of less than 0.02%.