WO2009053697A1

WO2009053697A1 - Polymorphic forms of ( s ) -rotigotine hydrochloride

Info

Publication number: WO2009053697A1
Application number: PCT/GB2008/003590
Authority: WO
Inventors: Ivica Grebenar; Marina Markovic; Dubravka Pavlicic; Zvonimir Siljkovic
Original assignee: Pliva Hrvatska D.O.O.; Bucks, Teresa Anne
Priority date: 2007-10-26
Filing date: 2008-10-23
Publication date: 2009-04-30

Abstract

The present invention is concerned with new polymorphic forms of rotigotine hydrochloride, processes of preparing the new polymorphic forms, pharmaceutical compositions containing the same, therapeutic uses thereof and methods of treatment employing the same.

Description

POLYMORPHIC FORMS OF ( S ) -ROTIGOTINE HYDROCHLORIDE

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] The present application is related to U.S.S.N 60/984,964, filed November 2, 2007, the contents of which is herein incorporated by reference in its entirety.

FIELD OF INVENTION

[0002] The present invention relates to new polymorphic forms of rotigotine hydrochloride, processes of preparing the new polymorphic forms, pharmaceutical compositions containing the same, therapeutic uses thereof and methods of treatment employing the same.

BACKGROUND

[0003] The following description is provided to assist the understanding of the reader.

None of the information provided or references cited is admitted to be prior art to the present invention.

[0004] Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. Polymorphic forms of a given solid can differ from each other with respect to physical properties as well as structural properties. A single molecule can give rise to a variety of physical forms having distinct crystal structures and thermodynamic, spectroscopic, kinetic, mechanical, surface and packing properties such as melting point, X-ray diffraction pattern, infrared absorption fingerprint, solid state NMR spectrum, solubility, dissolution rate, and stability.

[0005] Polymorphic forms as referred to herein can include crystalline and amorphous forms as well as solvate and hydrate forms, which can be further characterized as follows: (i) crystalline forms have different arrangements and/or conformations of the molecules in the crystal lattice; (ii) amorphous forms consist of disordered arrangements of molecules that do not possess a distinguishable crystal lattice; (iii) solvates are crystal forms containing either stoichiometric or non-stoichiometric amounts of a solvent; and (iv) if the incorporated solvent is water, the solvate is commonly known as a hydrate. When a pharmaceutical substance exists in such polymorphic forms, it is said to exhibit polymorphism.

[0006] There are a number of methods that can be used to characterize polymorphs of a pharmaceutical substance. Demonstration of a non-equivalent structure by single crystal X-ray diffraction is currently regarded as definitive evidence of polymorphism. X-ray powder diffraction ("XRPD") can also be used to support the existence of polymorphs. Other methods, including microscopy, dynamic vapor sorption (DVS), thermal analysis, and spectroscopy {e.g., infrared [IR], Raman, solid-state nuclear magnetic resonance [ssNMR]) are also helpful to further characterize polymorphic forms. Thermal properties and behavior of polymorphs can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis ("TGA"), hot-stage microscopy (HSM) and differential scanning calorimetry ("DSC"), and can be used to distinguish polymorphic forms.

[0007] Polymorphic forms of pharmaceutical substances can exhibit different chemical, physical and mechanical properties, including aqueous solubility and dissolution rate, hygroscopicity, particle shape, density, flowability, and compactibility, which in turn can affect processing of the pharmaceutical substance and/or manufacturing of the pharmaceutical product. Polymorphs can also exhibit different stabilities. The most stable polymorphic form of a pharmaceutical substance is often chosen during pharmaceutical development based on the minimal potential for conversion to another polymorphic form and on its greater chemical stability. However, a meta-stable form can alternatively be chosen for various reasons, including bioavailability enhancement.

[0008] Another important aspect of solid systems, besides polymorphic form, is morphology. Crystal morphology is dependent upon the manner (i.e., rate and direction) in which the crystal grows. There are numerous examples in the chemical and pharmaceutical industries where crystal shape can affect important properties of chemical or drug substance such as solubility, dissolution rate, stability, particle size, water absorption, compactability and biological availability of pharmaceuticals which in turn affect the manufacture, packaging, shipping, storage and use of products. [0009] Crystal morphology also causes preferred orientation of particles in polycrystalline specimens and can introduce problems such as preferred orientation effects which can impact intensity measurements in routine crystallographic analysis, such as X-ray powder diffraction, which has to be taken into consideration with the interpretation of results. Quantitative analysis depend on intensity ratios which are generally distorted by preferred orientation.

[0010] These variations in pharmaceutical substance physical characteristics exhibited by different polymorphic forms and its impact on various process and analytical aspects calls for further identification and development of stable, non-hygroscopic, well-characterized and reproducible crystalline forms of drug substances and new methods for their preparation.

[0011] Rotigotine is the international non-proprietary name given for the compound (-)-

(6S)-6-[propyl[2-(thiophen-2-yl)ethyl]amino]-5,6,7₅8-tetrahydronaphtalen-l-ol (WHO Drug Information, Vol. 15, No. 1, 2001). It has the structure of Formula I:

Formula I

[0012] Rotigotine is a dopamine D2 receptor agonist and an antiparkinsonian agent. It is, therefore, employed in the treatment of Parkinson's disease. It is also being tested for use in the treatment of other diseases for which an increase of the dopamine level is beneficial such as the restless leg syndrome (RLS).

[0013] U.S. Pat. No. 4,743,618 describes optically active or racemic compounds of following general formula

and generically discloses rotigotine.

[0014] European Pat. No. EP 1232152B1 provides a process for preparing optically active and racemic nitrogen-substituted 2-aminotetralins of Formula (I), which generically incorporates rotigotine. The reference disclose a synthetic process which comprises alkylating the corresponding unsubstituted 2-aminotetralin of Formula (II) with a reactant of the Formula (III). The reaction scheme of the process can be represented as follows:

(III) base

[0015] A method of use of rotigotine for reducing the intraocular pressure in mammals is disclosed in U.S. Pat. No. 4,657,925.

[0016] U.S. Pat. No. 6,884,434 describes a pharmaceutical formulation of rotigotine in the form of a transdermal therapeutic system (transdermal patch) comprising an adhesive matrix layer containing rotigotine in an amount effective for the treatment of the symptoms of Parkinson's disease.

[0017] International application No. WO 2005/063236 relates to an intranasal pharmaceutical formulation containing a pharmaceutically acceptable salt of rotigotine.

SUMMARY

[0018] In one aspect, the present invention provides new polymorphic forms of rotigotine hydrochloride, including form I, form II, form III, form IV and form V. The polymorphic forms of rotigotine hydrochloride are particularly suitable for use in the preparation of pharmaceutical products. In particular we have found that form II is non-hygroscopic and is particularly stable. In another aspect, the invention provides pharmaceutical formulations that comprise the new polymorphic forms of rotigotine hydrochloride described herein and methods of using such forms in the preparation of pharmaceutical formulations. In yet another aspect the invention discloses methods for making and using the polymorphic forms of rotigotine hydrochloride.

BRIEF DESCRIPTION OF THE DRAWINGS

[0019] FIG. 1 depicts an X-ray powder diffraction pattern of rotigotine hydrochloride

Form I.

[0020] FIG. 2 depicts an X-ray powder diffraction pattern of rotigotine hydrochloride

Form II.

[0021] FIG. 3 depicts an IR spectrum of rotigotine hydrochloride Form II.

[0022] FIG. 4 depicts an X-ray powder diffraction pattern of rotigotine hydrochloride

Form III.

[0023] FIG. 5 depicts an X-ray powder diffraction pattern of rotigotine hydrochloride

Form IV. [0024] FIG. 6 depicts an X-ray powder diffraction pattern of rotigotine hydrochloride

Form V.

[0025] FIG. 7 depicts an IR spectrum of rotigotine hydrochloride form III (example 59).

[0026] FIG. 8 depicts an IR spectrum of rotigotine hydrochloride form IV (example 60).

[0027] FIG. 9 depicts a TGA thermogram of rotigotine hydrochloride form IV (example

60).

[0028] FIG. 10 depicts a IR spectrum of rotigotine hydrochloride form V (example 63).

[0029] FIG. 11 depicts a DSC thermogram of rotigotine hydrochloride form II (example

33) wherein the heating rate was 10 °C/min and the thermogram displays a thermal event at 186.09 ⁰C.

[0030] FIG. 12. depicts a TGA thermogram of rotigotine hydrochloride form II (example

46)

[0031] FIG. 13 depicts a DVS plot of rotigotine hydrochloride form II (example 46).

DETAILED DESCRIPTION OF THE INVENTION

[0032] The present invention is, in one aspect, directed to new polymorphic forms of rotigotine hydrochloride. In other aspects, the present invention provides pharmaceutical formulations of rotigotine hydrochloride and methods of using the formulations; and processes to prepare the stable polymorphic forms of rotigotine hydrochloride.

[0033] Polymorphic form I of rotigotine hydrochloride may exhibit an X-ray powder diffraction pattern comprising one or more characteristic X-ray powder diffraction peaks at about: 8.4°, 9.8°, 13.3°, 14.5° and 25.1° 2Θ. For example, the form I polymorph of rotigotine hydrochloride may exhibit two or more, three or more, four or more, or five, characteristic X-ray powder diffraction peaks at about 8.4°, 9.8°, 13.3°, 14.5° and 25.1° 2Θ. Form I of rotigotine hydrochloride can exhibit an X-ray powder diffraction pattern substantially as shown in FIG. 1. [0034] Polymorphic form II of rotigotine hydrochloride may exhibit an X-ray powder diffraction pattern comprising one or more of the following characteristic X-ray powder diffraction peaks at about: 7.9°, 10.6°, 12.1°, 14.1° and 15.9° 20. For example, the form II polymorph of rotigotine hydrochloride may exhibit two or more, three or more, four or more, or five, characteristic X-ray powder diffraction peaks at about 7.9°, 10.6°, 12.1°, 14.1° and 15.9° 2Θ. Polymorphic form II of rotigotine hydrochloride can exhibit an X-ray powder diffraction pattern substantially as shown in FIG. 2.

[0035] Polymorphic form II of rotigotine hydrochloride may also be characterized as having an IR spectrum comprising at least three or more of the following absorbance peaks at about: 3145.3, 2940.0, 2605.3, 2550.9, 1592.2, 1464.5, 1438.2, 1277.9, 1024.9, 950.9, 786.9 and 716.8 cm^"1. For example, polymorphic form II of rotigotine hydrochloride can exhibit four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, or twelve absorbance peaks at about: 3145.3, 2940.0, 2605.3, 2550.9, 1592.2, 1464.5, 1438.2, 1277.9, 1024.9, 950.9, 786.9 and 716.8 cm^"1. Polymorphic form II of rotigotine hydrochloride can exhibit an IR spectrum substantially as shown in FIG. 3.

[0036] The form II polymorph of rotigotine hydrochloride may also be characterized thermally. For example, the form II polymorph of rotigotine hydrochloride exhibits a thermal event as measured by DSC at about 186 °C. More particularly, the form II polymorph of rotigotine hydrochloride can exhibit a thermal curve as measured by DSC substantially as shown in FIG. 11. The form II polymorph of rotigotine hydrochloride may also exhibit a thermal curve as measured by TGA substantially as shown in FIG. 12.

[0037] Polymorphic form III of rotigotine hydrochloride may exhibit an X-ray powder diffraction pattern comprising one or more characteristic X-ray powder diffraction peaks selected from the following at about: 7.1°, 8.2°, 11.5°, 13.8° and 14.3° 2Θ. For example, the form III polymorph of rotigotine hydrochloride may exhibit two or more, three or more, four or more, or five, characteristic X-ray powder diffraction peaks at about 7.1°, 8.2°, 11.5°, 13.8° and 14.3° 2Θ. Polymorphic form III of rotigotine hydrochloride can exhibit an X-ray powder diffraction pattern substantially as shown in FIG. 4. [0038] Polymorphic form IV of rotigotine hydrochloride may exhibit an X-ray powder diffraction pattern comprising one or more (including but not limited to two or more, three or more, four or more or five) characteristic X-ray powder diffraction peaks selected from the following at about: 7.1°, 9.6°, 12.1°, 14.8° and 18.0° 2Θ. Polymorphic form IV of rotigotine hydrochloride may exhibit an X-ray powder diffraction pattern further comprising one or more (including but not limited to two or more, three or more, four or more or five) additional characteristic X-ray powder diffraction peaks selected from the following at about: 9.7°, 13.2°, 19.8°, 21.4° and 22.9° 2Θ. Polymorphic form IV of rotigotine hydrochloride may exhibit an X- ray powder diffraction pattern substantially as shown in FIG. 5.

[0039] Polymorphic form V of rotigotine hydrochloride may exhibit an X-ray powder diffraction pattern comprising one or more (including but not limited to two or more, three or more, four or more or five) characteristic X-ray powder diffraction peaks selected from the following at about: 6.8°, 9.2°, 14.8°, 18.4° and 20.8° 2Θ. Polymorphic form V of rotigotine hydrochloride may exhibit an X-ray powder diffraction pattern further comprising one or more (including but not limited to two or more, three or more, four or more or five) additional characteristic X-ray powder diffraction peaks selected from the following at about: 13.3°, 15.0°, 19.2°, 22.2° and 24.2° 2Θ. Polymorphic form V of rotigotine hydrochloride can exhibit an X-ray powder diffraction pattern substantially as shown in FIG. 6.

[0040] As is understood in the art, the values of analytical data disclosed herein may vary due to, e.g., random and systematic error in the methods used to measure the values. Thus, each peak, absorption band, or temperature may exhibit a range of values that will be recognized as being equivalent. For example, the values of characteristic X-ray powder diffraction peaks may vary by ±0.4°, ±0.3°, or ±0.2° 2Θ. The values of IR absorbance peaks may vary, e.g., by ±8, ±6, ±5, or ±4 cm^"1. The values of temperatures such as DSC and TGA temperatures may vary, e.g., by ±4°, ±3^o, ±2°, or ±rC.

[0041] In one aspect, the present invention provides methods of making polymorphic forms of rotigotine hydrochloride that include crystallizing rotigotine hydrochloride from various solvents. Suitable solvents used in the preparation of polymorphic forms of present invention comprise of both organic and aqueous solvents and include but are not limited to ketones, esters, alcohols, alkanes, chlorinated alkanes, ethers, benzene derivatives, cycloalkanes, nitriles, organophosphates, water and combinations of any two or more thereof.

[0042] In some embodiments, the organic solvents employed in the preparation of polymorphs of present invention include ketones such as acetone, methyl ethyl ketone, cyclohexanone, 3-pentanone, etc; esters such as n-propyl acetate, n-butyl acetate, methyl benzoate, ethyl acetoacetate, 1,2-propylene carbonate, etc; alcohols such as methanol, ethanol, 1- propanol, 2-propanol, 2-butanol, tert-butanol, 3-methyl-l-butanol, 1-pentanol, i-pentanol, or 1- octanol, etc; alkanes such as heptane, hexane, nitromethane; etc; chlorinated alkanes such as 1,2— dichloroethane, chloroform, etc; ethers such as diethyl ether, dibutyl ether, methyl-tert-butyl ether, 1,4-dioxane, etc; benzene derivatives such as benzonitrile, chlorobenzene, nitrobenzene, etc; cycloalkanes such as cyclohexane, etc; organophosphates such as tri-n-butyl phosphate, etc and nitriles such as, acetonitrile, etc; water; or combinations of any two or more thereof.

[0043] Certain classes of solvents provide predominantly a single polymorphic form of rotigotine hydrochloride. For example, rotigotine hydrochloride may be crystallized from ketones to provide polymorphic form I. However, polymorphic form III may be crystallized from cyclohexanone. In addition, form I may be crystallized from chlorinated alkanes, esters and benzenes. In contrast, polymorphic form II of rotigotine hydrochloride may be crystallized from water, alcohols, and polar ethers such as 1,4-dioxane. In addition, polymorphic form II rotigotine hydrochloride may be crystallized from 1,2-propylene carbonate and tri-n-butyl phosphate. Rotigotine hydrochloride may also be crystallized from acetonitrile to give the form IV polymorph.

[0044] In some embodiments, the present invention provides another process of preparing polymorphic forms of rotigotine hydrochloride. The process includes crystallizing rotigotine hydrochloride from various solvent/antisolvent mixtures. The process comprises the steps of dissolving or suspending rotigotine hydrochloride in a suitable solvent, optionally by heating the solution; adding an antisolvent drop wise to the solution; and cooling and maintaining the resulting suspension at room temperature to crystallize out the preferred polymorphic form. In some embodiments, the solution is stirred during cooling to provide a different polymorph (compare, e.g., Examples 26 and 64). Treatment with antisolvent can also be carried out by layering or vapor diffusion techniques. Suitable antisolvents include organic solvents, as well as water, that are generally miscible with the crystallizing solvent, yet are relatively poor solvents for the subject compound at the temperature of the crystallization. For example, rotigotine hydrochloride may be insoluble or sparingly soluble (< 10 mg/mL) in antisolvents used in the present methods.

[0045] In some embodiments, solvent/antisolvent mixtures comprise combinations such as ester/alcohol; alcohol/ether, alcohol/hydrocarbon, alcohol/ketone, chlorinated hydrocarbon/polar solvent or benzene derivatives/alcohols. Specific examples of solvent/antisolvent combinations which can be employed in the present invention include but are not limited to chlorobenzene/ethanol, butyl acetate/ethanol, methanol/methyl-tert-butyl-ether, ethanol/n-butyl acetate, ethanol/cyclohexane, tetrachloroethylene/acetonitrile, ethanol/methyl-tert- butyl ether, ethylacetate/ethanol, amyl acetate/ethanol, diethyl malonate/ethanol, 1- propanol/dibutyl ether, 1-propanol/n-butyl acetate, 2-propanol/ cyclohexane, and ethanol/heptane. In some embodiments, rotigotine hydrochloride was crystallized from alcohol/ether and alcohol/hydrocarbon combinations such as MeOHZEt₂O, MeOH/methyl t-butyl ether, and EtOH/methyl t-butyl ether.

[0046] In another aspect, the current invention provides a process for polymorphic transformation between various forms of rotigotine hydrochloride which can be affected by drying or exposing to humidity, a polymorphic form described herein. Thus in one embodiment of the present invention, one novel polymorphic form of rotigotine hydrochloride is converted to another form by drying a rotigotine hydrochloride polymorph at temperatures from about 30 ⁰C to about 100 ⁰C, or from about 50 ⁰C to about 90 ⁰C, optionally under reduced pressure, for a time period ranging from 1 hour to 1 month, more typically for a time period ranging from 24 hours to 14 days. By reduced pressure is meant a pressure below 1 atmosphere, such as, e.g., from about 0.01 mm Hg to about 500 mm Hg. In another embodiment, one novel polymorphic form of rotigotine hydrochloride is converted to another form by exposing a rotigotine polymorph to an atmosphere having a defined relative humidity of 50% to 100%. In other embodiments, the atmosphere has a relative humidity of 80% to 100% at a temperature of about 0 °C to about 50 °C, or at room temperature for a time period ranging from 1 hour to 1 month, more typically for a time period ranging from 24 hours to 14 days.

[0047] In some embodiments of the present invention, rotigotine hydrochloride form II is prepared by drying under reduced pressure one of rotigotine hydrochloride form I, form III, form IV or form V at a temperature selected from about 30 ⁰C to about 100 ⁰C, or from about 50 ⁰C to about 90 °C for a period of time ranging from 1 hour to 1 month, more typically for a period ranging from 24 hours to 14 days.

[0048] hi yet another embodiment of the present invention, rotigotine hydrochloride form

II is prepared by exposing one of rotigotine hydrochloride form I, form III, form IV, or form V to an atmosphere having a defined relative humidity of 50% to 100%, or 80% to 100% at a temperature selected from about 0 °C to about 50 °C, or at about room temperature, for a period ranging from 1 hour to 1 month, for example, a period ranging from 24 hours to 14 days.

[0049] In yet another embodiment, rotigotine hydrochloride form IV is prepared by exposing rotigotine hydrochloride form I to an atmosphere having a defined relative humidity of 50% to 100%, or about 80% at room temperature for a period of 24 hours.

[0050] In a further embodiment, the present invention is directed to a pharmaceutical formulation comprising: (a) a therapeutically effective amount of rotigotine hydrochloride form I, form II, form III, form IV, form V, or a mixture of any two or more thereof, as described herein, and (b) a pharmaceutically acceptable excipient. Herein, a "pharmaceutical formulation" refers to a medium useful for administering rotigotine hydrochloride, as described herein, to a subject in need thereof. In addition to rotigotine hydrochloride, such formulations can contain one or more pharmaceutically acceptable excipients. "Pharmaceutically acceptable" refers to those compounds, materials, and/or compositions which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other possible complications commensurate with a reasonable benefit/risk ratio. It is known in the art that a wide variety of pharmaceutically acceptable excipients can be used with rotigotine hydrochloride as described herein, including those listed in the Handbook of Pharmaceutical Excipients, Pharmaceutical Press 4th Ed. (2003), and Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st ed. (2005), which are incorporated herein by reference in their entirety. In some embodiments, at least one pharmaceutically acceptable excipient for use within the formulation is a bulking agent. As a preferred feature of the pharmaceutical formulation a pharmaceutically acceptable base is added. The base is preferably sodium hydroxide or potassium hydroxide.

[0051] As used herein, the term "therapeutically effective amount" refers to an amount of one or more of the polymorphic forms of rotigotine hydrochloride described herein, which prevent, ameliorate and/or eliminate a disease state which may be treated by administration of dopamine D2 receptor agonist or an antiparkinsonian agent.

[0052] hi the pharmaceutical formulations of the present invention for oral, sublingual, parenteral (subcutaneous, intramuscular, intravenous), topical, intratracheal, intranasal, transdermal or rectal administration, rotigotine hydrochloride form I, form II, form III, form IV, form V, or a mixture of any two or more thereof, as described herein, are administered to animals and humans in unit forms of administration, mixed with conventional pharmaceutical excipients, for the prophylaxis or treatment of Parkinson's disease and Restless Leg Syndrome (RLS). In some embodiments the form of administration includes tablets, gelatin capsules, powders, granules and solutions or suspensions to be taken orally, forms for sublingual, buccal, intratracheal or intranasal administration, forms for subcutaneous, intramuscular or intravenous administration and forms for rectal administration. In further embodiments the formulation is in the form applicable for parenteral (subcutaneous, intramuscular, intravenous) administration. Parenteral administration is effected using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersants and/or wetting agents, for example propylene glycol or butylene glycol. In further embodiments the pharmaceutical formulation is powder for injections or infusions.

[0053] In yet another aspect, the invention provides pharmaceutical formulations comprising a therapeutically effective amount of rotigotine hydrochloride form I, form II, form III, form IV, form V, or a mixture of any two or more thereof, optionally in the form of a transdermal patch. Methods of preparation or construction of formulation, including with suitable excipients, are known in the art, e.g., see US 6,884,434 or International Application No. WO 94/07468, each of which is incorporated by reference herein. Examples of transdermal formulations of rotigotine are provided in US20050079206 Al (Transdermal delivery system for the administration of rotigotine). The use of the chloride salt of rotigotine in transdermal formulations may benefit from the addition of a pharmaceutically-acceptable base in the preparation of the transdermal patch to aide the formation of the free base of rotigotine in situ. In the preparation of a transdermal patch rotigotine can be added as rotigotine hydrochloride, preferably in the forms as described above, or as rotigotine free base. If rotigotine free base is desired then either the free base of rotigotine is added directly, being formed from the rotigotine hydrochloride forms just prior to addition to the formulation, or rotigotine hydrochloride, in the forms described above, can be converted to the free base in-situ during the preparation of the transdermal patch by adding a pharmaceutically acceptable base, such as potassium hydroxide or sodium hydroxide, such as described in US 6,884,434.

[0054] In some embodiments the present invention is directed to methods of treating a disease prevented, ameliorated or eliminated by the administration of an dopamine D2 receptor agonist or an anti-Parkinsonian agent, in a subject in need thereof, the methods comprising administering to the subject a pharmaceutical formulation as described herein. In further embodiments the present invention is directed to methods of treating Parkinson's disease or RLS in a subject in need thereof, the methods comprising administering to the subject a pharmaceutical formulation as described herein.

[0055] Furthermore, there are provided methods of treating a disease state prevented, ameliorated or eliminated by the administration of dopamine D2 receptor agonist or an antiparkinsonian agent, in a subject in need of such treatment, which methods comprise administering to the subject a therapeutically effective amount of rotigotine form I, form II, form III, form IV, form V, or mixtures of any two or more thereof. More specifically, there are provided methods of treating Parkinson's disease in a subject in need of such treatment, which methods comprise administering to the subject a therapeutically effective amount of rotigotine form I, form II, form III, form IV, form V, or mixtures of any two or more thereof. [0056] In some embodiments the present invention also provides rotigotine hydrochloride of form I, form II, form III, form IV, form V, or a mixture of any two or more thereof, as described herein, for use in therapy.

[0057] In some embodiments the present invention also provides rotigotine hydrochloride of form I, form II, form III, form IV, form V, or a mixture of any two or more thereof, as described herein, for use as a medicament, preferably for use in treatment of a disease state prevented, ameliorated or eliminated by the administration of an dopamine D2 receptor agonist or an anti-Parkinsonian agent. In some embodiments the present invention also provides rotigotine hydrochloride of form I, form II, form III, form IV, form V, or a mixture of any two or more thereof, for use in the treatment Parkinson's disease or RLS.

[0058] In yet another aspect, the present invention provides rotigotine hydrochloride form

I, form II, form III, form IV, form V, or mixtures of any two or more thereof, for use in the manufacture of a medicament for the treatment of a disease state prevented, ameliorated or eliminated by the administration of a dopamine D2 receptor agonist or an anti-Parkinsonian agent. More specifically, these provide rotigotine hydrochloride form I, form II, form III, form IV, form V, or mixtures of any two or more thereof for use in the manufacture of a medicament for the treatment of Parkinson's disease or RLS.

[0059] The present invention is further illustrated by the Figures and non-limiting examples.

EXAMPLES

Example 1: Preparation of Rotigotine Hydrochloride

[0060] Step 1: (-)-5-Hydroxy-N-n-propyl-2-aminotetralin (3.02 g, 14.7 mmol) and 2-(2- thienyl)ethanol toluenesulfonate (8.30 g, 29.4 mmol) were suspended in isobutylacetate (30 mL) under an inert atmosphere. The reaction mixture was heated at 110 ⁰C for 10 hours and then filtered while hot to give 2.62 g (6.96 mmol) of (-)-5-hydroxy-N-n-propyl-2-aminotetralin toluenesulfonate and filtrate. The filtrate was evaporated to dryness, dissolved in a mixture of acetone-isopropanol when 1.91 g (5.30 mmol) of 1,5-naphthalenedisulfonic acid was added, and the resulting mixture was stirred at room temperature. The product was filtered, washed with 2-PrOH (30 mL) and dried under reduced pressure to yield 2.92 g (6.36 mmol, 43.2% yield based on starting 2-aminotetralin) of (S)-6-(propyl(2- thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-l-ol heminaphthalene-l,5-disulfonate.

[0061] Step 2: 2.62 g (6.96 mmol) of (-)-5-hydroxy-N-n-propyl-2-aminotetralin toluenesulfonate was suspended in a mixture of 10% NaOH (30 mL) and dichloromethane (30). The mixture was stirred for 30 minutes; the organic layer was separated, and the aqueous layer was washed again with dichloromethane (30 mL). The combined organic layers were dried with Na₂SO₄, filtered and evaporated to yield 1.41 g (6.87 mmol) of (-)-5-hydroxy-N-n-propyl-2-aminotetralin.

[0062] Step 3: (-)-5-Hydroxy-N-n-propyl-2-aminotetralin (1.41 g, 6.87 mmol) and 2-(2- thienyl)ethanol toluenesulfonate (3.88 g, 13.74 mmol) were suspended in isobutylacetate (15 mL) under an inert atmosphere. The reaction mixture was heated at 110⁰C for 10 hours and then filtered while hot to give 1.09 g (2.88 mmol) of (-)-5-hydroxy-N-n-propyl-2-aminotetralin toluenesulfonate and filtrate. The filtrate was evaporated to dryness, dissolved in a mixture of acetone-isopropanol when 0.87 g (2.40 mmol) of 1,5-naphthalenedisulfonic was added, and the resulting mixture was stirred at room temperature. The product was filtered, washed with 2-PrOH (15 mL) and dried under reduced pressure to yield 1.26 g (2.74 mmol, 39.9% yield based on starting 2-aminotetralin) of (S)-6- (propyl(2-thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-l-ol heminaphthalene-l,5- disulfonate.

[0063] Step 4: 1.09 g (2.88 mmol) of (-)-5-hydroxy-N-n-propyl-2-aminotetralin toluenesulfonate was transformed to 0.56 g (2.75 mmol) of (-)-5-hydroxy-N-n-propyl-2-aminotetralin in the same manner as described in Step 2.

[0064] Step 5: (-)-5-Hydroxy-N-n-propyl-2-aminotetralin (0.56 g, 2.75 mmol) and 2-(2- thienyl)ethanol toluensulfonate (1.55 mg, 5.50 mmol) were suspended in isobutylacetate (7 mL) under an inert atmosphere. The reaction mixture was heated at 110⁰C for 10 hours and then filtered while hot to give 0.41 g (1.10 mmol) of (-)-5-hydroxy-N-n-propyl-2-aminotetralin toluenesulfonate and filtrate. The filtrate was evaporated to dryness, dissolved in a mixture of acetone-isopropanol when 0.35 g (0.96 mmol) of 1,5-naphtalenedisulfonic acid was added and the resulting mixture was stirred at room temperature.. The product was filtered, washed with 2-PrOH (8 mL) and dried under reduced pressure to yield 0.48 g (1.04 mmol, 37.8% yield based on starting 2-aminotetralin) of (S)-6-(propyl(2- thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-l-ol heminaphthalene-l,5-disulfonate.

[0065] Step 6: (S)-6-(Propyl(2-thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-l -ol heminaphthalene-l,5-disulfonate from a), c) and e) was collected to give 4.66 g (10.1 mmol, 68.7% yield based on starting 2-aminotetralin) and suspended in dichloromethane (60 mL). The suspension was adjusted with 10% NaOH to pH 11.0, the organic layer separated, and the water layer was washed again with dichloromethane (30 mL). The organic layers were dried with Na₂SO₄ and evaporated to give (S)-6-(propyl(2-thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-l-ol which was converted in the usual manner to its hydrochloride salt form, with yield of 3.15 g (8.96 mmol, 60.9%). HPLC analysis on Chiralcel OD-H column, hexane/EtOH/DEA= 100/4/0.2 revealed more than 99.5 % ee.

Example 2: Preparation of Rotigotine Hydrochloride Form I

[0066] 22 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 5 ml of acetone by heating. The prepared solution was left at room conditions to evaporate and crystallize. Crystals of rotigotine hydrochloride form I were obtained.

Example 3: Preparation of Rotigotine Hydrochloride Form I

[0067] 13 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 3 ml of methyl ethyl ketone by heating. The prepared solution was left at room conditions to evaporate and crystallize. Crystals of rotigotine hydrochloride form I were obtained.

Example 4: Preparation of Rotigotine Hydrochloride Form I

[0068] 22 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 4 ml of 3-pentanone by heating. The prepared solution was left at room conditions to evaporate and crystallize. Crystals of rotigotine hydrochloride form I were obtained. Example 5: Preparation of Rotigotine Hydrochloride Form I

[0069] 17 mg of rotigotine hydrochloride, prepared as described in Example 1, partly dissolved in 8 ml of n-propyl acetate by heating. Suspension was filtered and the solution was left to cool down to room temperature. Crystals of rotigotine hydrochloride form I were filtered off.

Example 6: Preparation of Rotigotine Hydrochloride Form I

[0070] 20 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 5 ml of 1,2-dichloroethane by heating. The prepared solution was left at room conditions to evaporate and crystallize. Crystals of rotigotine hydrochloride form I were obtained.

Example 7: Preparation of Rotigotine Hydrochloride Form I

[0071] 18 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 1 ml of chloroform by heating. The prepared solution was left at room conditions to evaporate and crystallize. Crystals of rotigotine hydrochloride form I were obtained.

Example 8: Preparation of Rotigotine Hydrochloride Form I

[0072] 20 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 2 ml of bezonitrile by heating. The prepared solution was left at room conditions to evaporate and crystallize. Crystals of rotigotine hydrochloride form I were obtained.

Example 9: Preparation of Rotigotine Hydrochloride Form I

[0073] 15 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 4 ml of methyl benzoate by heating. The prepared solution was left at room conditions to evaporate and crystallize. Crystals of rotigotine hydrochloride form I were obtained. Example 10: Preparation of Rotigotine Hydrochloride Form I

[0074] 15 mg of Rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 3 ml of nitrobenzene by heating. The prepared solution was left at room conditions to cool down and crystallize. Crystals of Rotigotine hydrochloride form I were obtained.

Example 11: Preparation of Rotigotine Hydrochloride Form I

[0075] 16 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 1 ml of nitromethane by heating. The prepared solution was left at room conditions to evaporate and crystallize. Crystals of rotigotine hydrochloride form I were obtained.

Example 12: Preparation of Rotigotine Hydrochloride Form I

[0076] 19 mg of rotigotine hydrochloride was suspended in 5 ml of chlorobenzene. 1 ml of ethanol was added and obtained solution was left at room conditions to evaporate and crystallize. Crystals of rotigotine hydrochloride form I were obtained.

Example 13: Preparation of Rotigotine Hydrochloride Form I

[0077] 17 mg of rotigotine hydrochloride was suspended in 5 ml of toluene. 0,5 ml of ethanol was added and obtained solution was left at room conditions to evaporate and crystallize. Crystals of rotigotine hydrochloride form I were obtained.

Example 14: Preparation of Rotigotine Hydrochloride Form I

[0078] 15 mg of rotigotine hydrochloride was suspended in 7 ml of tetrachloroethylene. 5 ml of acetonitrile was added. Suspension was filtered and obtained filtrate was left at room conditions to evaporate and crystallize. Crystals of rotigotine hydrochloride form I were obtained.

Example 15: Preparation of Rotigotine Hydrochloride Form I

[0079] 205 mg of rotigotine hydrochloride, prepared as described in Example 1, were suspended in 3 ml of ethyl acetate. Suspension was heated to 70 ⁰C. Ethanol was added drop wise until the rotigotine hydrochloride was dissolved (1.8 ml of ethanol was added). The prepared solution was cooled to room temperature and stirred for another 90 minutes. Crystals of rotigotine hydrochloride form I were obtained.

Example 16: Preparation of Rotigotine Hydrochloride Form I

[0080] 18 mg of rotigotine hydrochloride was suspended in 5 ml of amyl acetate. 1 ml of ethanol was added. The prepared solution was left at room conditions to evaporate and crystallize. Crystals of rotigotine hydrochloride form I were obtained.

Example 17: Preparation of Rotigotine Hydrochloride Form I

[0081] 18 mg of rotigotine hydrochloride was suspended in 5 ml of butyl acetate. 1 ml of ethanol was added. The prepared solution was left at room conditions to evaporate and crystallize. Crystals of rotigotine hydrochloride form I were obtained.

Example 18: Preparation of Rotigotine Hydrochloride Form I

[0082] 19 mg of rotigotine hydrochloride was suspended in 6 ml of diethyl malonate. 1 ml of ethanol was added. The prepared solution was left at room conditions to evaporate and crystallize. Crystals of rotigotine hydrochloride form I were obtained.

Example 19: Preparation of Rotigotine Hydrochloride Form II

[0083] 100 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 2 ml of 2-butanol by heating. The prepared solution was left at room conditions to evaporate and crystallize. Crystals of rotigotine hydrochloride form II were obtained.

Example 20: Preparation of Rotigotine Hydrochloride Form II

[0084] 21 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 4 ml of tert-butanol by heating. The prepared solution was left at room conditions to evaporate and crystallize. Crystals of rotigotine hydrochloride form II were obtained. Example 21: Preparation of Rotigotine Hydrochloride Form II

[0085] 18 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 1 ml of i-pentanol by heating. The prepared solution was left at room conditions to evaporate and crystallize. Crystals of rotigotine hydrochloride form II were obtained.

Example 22: Preparation of Rotigotine Hydrochloride Form II

[0086] 20 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 4 ml of 2-propanol at room temperature. The prepared solution was left at room conditions to evaporate and crystallize. Crystals of rotigotine hydrochloride form II were obtained.

Example 23: Preparation of Rotigotine Hydrochloride Form II

[0087] 16 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 1 ml of 3 -methyl- 1-butanol by heating. The prepared solution was left at room conditions to evaporate and crystallize. Crystals of rotigotine hydrochloride form II were obtained.

Example 24: Preparation of Rotigotine Hydrochloride Form II

[0088] 15 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 3 ml of water by heating. The prepared solution was left at room conditions to evaporate and crystallize. Crystals of rotigotine hydrochloride form II were obtained.

Example 25: Preparation of Rotigotine Hydrochloride Form II

[0089] 19 mg of rotigotine hydrochloride, prepared as described in Example 1, were suspended in 5 ml of diethyl ether. 2,0 ml of ethanol was added to the suspension. The prepared solution was left at room conditions to evaporate and crystallize. Crystals of rotigotine hydrochloride form II were obtained. Example 26: Preparation of Rotigotine Hydrochloride Form II

[0090] 15 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 2 ml of ethanol at room temperature. 3.0 ml of heptane was added to the solution. The prepared solution was left at room conditions to evaporate and crystallize. Crystals of rotigotine hydrochloride form II were obtained.

Example 27: Preparation of Rotigotine Hydrochloride Form II

[0091] 30 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 1 ml of 1-Butanol by heating. The prepared solution was left at room conditions to evaporate and crystallize. Crystals of rotigotine hydrochloride form II were obtained.

Example 28: Preparation of Rotigotine Hydrochloride Form II

[0092] 30 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 1 ml of i-Butanol by heating. The prepared solution was left at room conditions to evaporate and crystallize. Crystals of rotigotine hydrochloride form II were obtained.

Example 29: Preparation of Rotigotine Hydrochloride Form II

[0093] 14 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 2 ml of 1,4-dioxane by heating. The prepared solution was left at room conditions to evaporate and crystallize. Crystals of rotigotine hydrochloride form II were obtained.

Example 30: Preparation of Rotigotine Hydrochloride Form II

[0094] 100 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 2 ml of ethanol by heating. The prepared solution was left at room conditions to evaporate and crystallize. Crystals of rotigotine hydrochloride form II were obtained. Example 31: Preparation of Rotigotine Hydrochloride Form II

[0095] 105 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 2 ml of ethanol by heating. The prepared solution was left stirring at room conditions for 20 hours. Crystals of rotigotine hydrochloride form II were obtained.

Example 32: Preparation of Rotigotine Hydrochloride Form II

[0096] 13 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 2 ml of ethylacetoacetate by heating. The prepared solution was left at room conditions to evaporate and crystallize. Crystals of rotigotine hydrochloride form II were obtained.

Example 33: Preparation of Rotigotine Hydrochloride Form II

[0097] 10 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 1 ml of 1-octanol by heating. The prepared solution was left at room conditions to crystallize. Crystals of rotigotine hydrochloride form II were obtained. DSC thermogram of obtained crystals is shown on FIG. 11.

Example 34: Preparation of Rotigotine Hydrochloride Form II

[0098] 20 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 1 ml of 1-pentanol by heating. The prepared solution was left at room conditions to evaporate and crystallize. Crystals of rotigotine hydrochloride form II were obtained.

Example 35: Preparation of Rotigotine Hydrochloride Form II

[0099] 20 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 1 ml of 1-propanol by heating. The prepared solution was left at room conditions to evaporate and crystallize. Crystals of rotigotine hydrochloride form II were obtained. Example 36: Preparation of Rotigotine Hydrochloride Form II

[00100] 29 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 1 ml of 1,2-propylene carbonate by heating. The prepared solution was left at room conditions to evaporate and crystallize. Crystals of rotigotine hydrochloride form II were obtained.

Example 37: Preparation of Rotigotine Hydrochloride Form II

[00101] 19 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 1 ml of tri-n-butylphosphate by heating. The prepared solution was left at room conditions to evaporate and crystallize. Crystals of rotigotine hydrochloride form II were obtained.

Example 38: Preparation of Rotigotine Hydrochloride Form II

[00102] 34 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 1 ml of methanol. The prepared solution was left at room conditions in diethylether atmosphere. Crystals of rotigotine hydrochloride form II were obtained.

Example 39: Preparation of Rotigotine Hydrochloride Form II

[00103] 200 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 2 ml of methanol by heating. 6 ml of methyl-tert-butyl ether was added dropwise to the solution. Stirred solution was left at room conditions to crystallize. Crystals of rotigotine hydrochloride form II were obtained.

Example 40: Preparation of Rotigotine Hydrochloride Form II

[00104] 27 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 1 ml of ethanol. 3 ml of n-butyl acetate was added to the solution. The prepared solution was left at room conditions to crystallize. Crystals of rotigotine hydrochloride form II were obtained. Example 41: Preparation of Rotigotine Hydrochloride Form II

[00105] 100 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 2 ml of ethanol by heating. 4 ml of cyclohexane was added dropwise to the solution. Stirred solution was left at room conditions to cool down and crystallize. Crystals of rotigotine hydrochloride form II were obtained.

Example 42: Preparation of Rotigotine Hydrochloride Form II

[00106] 100 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 2 ml of ethanol by heating. 6 ml of methyl-tert-butyl ether was added dropwise to the solution. Stirred solution was left at room conditions to cool down and crystallize. Crystals of rotigotine hydrochloride form II were obtained.

Example 43: Preparation of Rotigotine Hydrochloride Form II

[00107] 29 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 1 ml of ethanol. The prepared solution was left at room conditions in hexane atmosphere. Crystals of rotigotine hydrochloride form II were obtained.

Example 44: Preparation of Rotigotine Hydrochloride Form II

[00108] 16 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 1 ml of 1-propanol. 3 ml of dibutylether was added to the solution. The prepared solution was left at room conditions to crystallize. Crystals of rotigotine hydrochloride form II were obtained.

Example 45: Preparation of Rotigotine Hydrochloride Form II

[00109] 17 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 1 ml of 1-propanol. 4 ml of n-butyl acetate was added to the solution. The prepared solution was left at room conditions to crystallize. Crystals of rotigotine hydrochloride form II were obtained. Example 46: Preparation of Rotigotine Hydrochloride Form II

[00110] 200 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 15 ml of 2-propanol by heating. 15 ml of cyclohexane was added dropwise to the solution. Stirred solution was left at room conditions to cool down and crystallize. Crystals of rotigotine hydrochloride form II were obtained. TGA thermogram of obtained crystals is shown on FIG. 12. DVS plot of obtained crystals is shown in FIG. 13.

Example 47: Preparation of Rotigotine Hydrochloride Form II

[00111] Crystals of rotigotine hydrochloride form I were placed in a vacuum dryer at 50

⁰C. After 14 days crystals of rotigotine hydrochloride form II were obtained.

Example 48: Preparation of Rotigotine Hydrochloride Form II

[00112] Crystals of rotigotine hydrochloride form IV were placed in a vacuum dryer at 50

⁰C. After 14 days crystals of rotigotine hydrochloride form II were obtained.

Example 49: Preparation of Rotigotine Hydrochloride Form II

[00113] Crystals of rotigotine hydrochloride form I were placed in a vacuum dryer on 90

°C. After 24 hours crystals of rotigotine hydrochloride form II were obtained.

Example 50: Preparation of Rotigotine Hydrochloride Form II

[00114] Crystals of rotigotine hydrochloride form IV were placed in a vacuum dryer on 90

⁰C. After 24 hours crystals of rotigotine hydrochloride form II were obtained.

Example 51: Preparation of Rotigotine Hydrochloride Form II

[00115] Crystals of rotigotine hydrochloride form V were placed in a vacuum dryer on 90

°C. After 4 days crystals of rotigotine hydrochloride form II were obtained. Example 52: Preparation of Rotigotine Hydrochloride Form II

[00116] Crystals of rotigotine hydrochloride form I were exposed to 80 % relative humidity. After 14 days crystals of rotigotine hydrochloride form II were obtained.

Example 53: Preparation of Rotigotine Hydrochloride Form II

[00117] Crystals of rotigotine hydrochloride form IV were exposed to 80 % relative humidity. After 14 days crystals of rotigotine hydrochloride form II were obtained.

Example 54: Preparation of Rotigotine Hydrochloride Form II

[00118] Crystals of rotigotine hydrochloride form I were exposed to 95-100 % relative humidity. After 24 hours crystals of rotigotine hydrochloride form II were obtained.

Example 55: Preparation of Rotigotine Hydrochloride Form II

[00119] Crystals of rotigotine hydrochloride form III were exposed to 95-100 % relative humidity. After 4 days crystals of rotigotine hydrochloride form II were obtained.

Example 56: Preparation of Rotigotine Hydrochloride Form II

[00120] Crystals of rotigotine hydrochloride form IV were exposed to 95-100 % relative humidity. After 24 hours crystals of rotigotine hydrochloride form II were obtained.

Example 57: Preparation of Rotigotine Hydrochloride Form II

[00121] Crystals of rotigotine hydrochloride form V were exposed to 95-100 % relative humidity. After 4 days crystals of rotigotine hydrochloride form II were obtained.

Example 58: Preparation of Rotigotine Hydrochloride Form III

[00122] 105 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 2 ml of cyclohexanone by heating. The prepared solution was cooled down to room temperature and left to crystallize. Crystals of rotigotine hydrochloride form III were obtained. Example 59: Preparation of Rotigotine Hydrochloride Form III

[00123] 250 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 15 ml of cyclohexanone by heating. The prepared solution was filtered and left to cool down and stir at room conditions overnight. Crystals of rotigotine hydrochloride form III were obtained. The IR spectrum of the obtained crystals is shown in FIG. 7.

Example 60: Preparation of Rotigotine Hydrochloride Form IV

[00124] 500 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 50 ml of acetonitrile by heating. The prepared solution was filtered and stirred solution was left overnight to cool down and crystallize. Crystals of rotigotine hydrochloride form IV were obtained. The IR spectrum of the obtained crystals is shown on FIG. 8. A TGA thermogram of the obtained crystals is shown on FIG. 9.

Example 61: Preparation of Rotigotine Hydrochloride Form IV

[00125] 17 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 2 ml of acetonitrile by heating. The prepared solution was left at room conditions to crystallize. Crystals of rotigotine hydrochloride form IV were obtained.

Example 62: Preparation of Rotigotine Hydrochloride Form IV

[00126] Crystals of rotigotine hydrochloride form I were exposed to 80 % relative humidity. After 24 hours crystals of rotigotine hydrochloride form IV were obtained.

Example 63: Preparation of Rotigotine Hydrochloride Form V

[00127] 202 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 2 ml of ethanol by heating. 2 ml of cyclohexane was added dropwise to the solution. Stirred solution was left to cool down to room temperature and crystallize. Crystals of rotigotine hydrochloride form V were obtained. The IR spectrum of the obtained crystals is shown on FIG. 10. Example 64: Preparation of Rotigotine Hydrochloride Form V

[00128] 295 mg of rotigotine hydrochloride, prepared as described in Example 1, were dissolved in 5 ml of ethanol by heating. 10 ml of heptane was added dropwise to the solution. Stirred solution was left to cool down to room temperature and crystallize. Crystals of rotigotine hydrochloride form V were obtained. Stirring and cooling the solution resulted in the formation of form V rotigotine HCl.

Example 65: X-Ray Powder Diffraction

[00129] X-ray powder diffraction analyses on the rotigotine hydrochloride polymorphs prepared as described above were carried out on a Philips X'Pert PRO diffractometer using CuKαl radiation under the conditions detailed in Table 1 below. The standard error for peak positions obtained on this system is ±0.2°θ. Results for Forms I, II, III, IV, and V of rotigotine hydrochloride are shown in FIG. S 1, 2, and 4-6, respectively.

Table 1: X-ra owder diffraction ex erimental conditions

Temperature 293±2K

Example 66: IR Analyses

[00130] The IR spectra of polymorphic forms of rotigotine hydrochloride were obtained by using a KBr pellet and a Spectrum GX manufactured by Perkin-Elmer. The standard error for absorption band maximums is ±4 cm^"1. IR spectra obtained for forms II, III, and V are shown in FIGS. 3, 7, 8, and 10, respectively.

Example 67: DSC Analyses

[00131] DSC analyses were performed on the disclosed polymorphic forms of rotigotine hydrochloride and were carried out under the experimental conditions detailed in Table 2.

Table 2, Differential scannin calorimetry ex erimental conditions

TGA Analyses

[00132] TGA analyses were performed on the disclosed polymorphic forms of rotigotine hydrochloride and were carried out under the experimental conditions detailed in Table 3.

Table 3. Thermo ravimetric anal sis ex erimental conditions

DVS analysis

The hygroscopicity was characterized by dynamic vapour sorption at 25 ⁰C, ( a Surface Measurement Systems instrument), Relative humidity was in range from 0 % up to 90 %, with two cycles (sorbtion-desorbtion) recorded.

[00133] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as "up to," "at least," "greater than," "less than," "about" and the like include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 atoms refers to groups having 1, 2, or 3 atoms. Similarly, a group having 1-5 atoms refers to groups having 1, 2, 3, 4, or 5 atoms, and so forth.

[00134] All publications, patent applications, issued patents, and other documents referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.

[00135] While certain embodiments have been illustrated and described, it should be understood that changes and modifications can be made therein in accordance with ordinary skill in the art without departing from the invention in its broader aspects as defined in the following claims.

Claims

WHAT IS CLAIMED IS:

1. A polymorphic form I of rotigotine hydrochloride which exhibits an X-ray powder diffraction pattern comprising one or more characteristic X-ray powder diffraction peaks at about: 8.4°, 9.8°, 13.3°, 14.5° and 25.1° 2Θ.

2. The polymorphic form I of rotigotine hydrochloride, of claim 1, which exhibits an X-ray powder diffraction pattern substantially the same as that shown in FIG. 1.

3. A polymorphic form II of rotigotine hydrochloride which exhibits an X-ray powder diffraction pattern comprising one or more characteristic X-ray powder diffraction peaks at about: 7.9°, 10.6°, 12. 1°, 14. 1° and 15. 9° 2Θ.

4. A the polymorphic form II of rotigotine hydrochloride, of claim 3, which exhibits an X-ray powder diffraction pattern substantially the same as that shown in FIG. 2.

5. A polymorphic form II of rotigotine hydrochloride, of claims 3 and 4 which exhibits IR spectrum substantially the same as that shown in FIG. 3.

6. A polymorphic form II of rotigotine hydrochloride, of claim 5, characterized by three or more of characteristic bands observed in the IR spectrum at about the following values (cm^"1): 3141.8; 2939.5; 2604.8; 2551.1; 1592.4; 1464.3; 1438.2; 1277.9; 1025.2; 951. 7; 787.0, 729.6 and 716.0.

7. A polymorphic form III of rotigotine hydrochloride which exhibits an X-ray powder diffraction pattern comprising one or more characteristic X-ray powder diffraction peaks at about: 7.1°, 8.2°, 11.5°, 13.8° and 14.3° 2Θ.

8. The polymorphic form III of rotigotine hydrochloride of claim 7, exhibiting an X-ray powder diffraction pattern substantially the same as that shown in FIG. 4.

9. A polymorphic form IV of rotigotine hydrochloride which exhibits an X-ray powder diffraction pattern comprising one or more characteristic X-ray powder diffraction peaks at about: 7.1°, 9.6°, 12.1°, 14.8° and 18.0° 2Θ.

10. A polymorphic form IV of rotigotine hydrochloride which exhibits an X-ray powder diffraction pattern comprising one or more characteristic X-ray powder diffraction peaks at about: 9.7°, 13.2°, 19.8°, 21.4° and 22.9° 2Θ.

11. The polymorphic form IV of rotigotine hydrochloride of claims 9 and 10, which exhibits an X-ray powder diffraction pattern substantially the same as that shown in FIG. 5.

12. A polymorphic form V of rotigotine hydrochloride which exhibits an X-ray powder diffraction pattern comprising one or more characteristic X-ray powder diffraction peaks at about: 6.8°, 9.2°, 14.8°, 18.4° and 20.8° 2Θ.

13. A polymorphic form V of rotigotine hydrochloride which exhibits an X-ray powder diffraction pattern comprising one or more characteristic X-ray powder diffraction peaks at about: 13.3°, 15.0°, 19.2°, 22.2° and 24.2° 2Θ.

14. The polymorphic form V of rotigotine hydrochloride of claims 12 and 13 which exhibits an X-ray powder diffraction pattern substantially the same as that shown in FIG. 6.

15. A process of preparing polymorphic forms of rotigotine hydrochloride comprising crystallizing rotigotine hydrochloride from a solvent selected from the group consisting of ketones, esters, alcohols, alkanes, chlorinated alkanes, ethers, benzene derivatives, cycloalkanes, nitriles, organophosphates, water and combinations of any two or more thereof.

16. The process of claim 15 wherein the ketones are selected from one or more of acetone, methyl ethyl ketone, cyclohexanone or 3-pentanone.

17. The process of claim 15 wherein the esters are selected from one or more of n-propyl acetate, n-butyl acetate, methyl benzoate, ethylacetoacetate or 1,2-propylene carbonate.

18. The process of claim 15 wherein the alcohols are selected from one or more of methanol, ethanol, 1-propanol, 2-propanol, 2-butanol, tert-butanol, 3-methyl-l-butanol, 1-pentanol, i- pentanol, or 1-octanol.

19. The process of claim 15 wherein the alkane is heptane, hexane or nitromethane.

20. The process of claim 15 wherein the chlorinated alkanes are one ore both of following; 1,2— dichloroethane or chloroform.

21. The process of claim 15 wherein the ether is diethyl ether, dibutyl ether, methyl-tert-butyl ether, or 1,4-dioxane.

22. The process of claim 15 wherein the benzenes derivatives are selected from one or more of benzonitrile, chlorobenzene, or nitrobenzene.

23. The process of claim 15 wherein the solvent is one or more of cyclohexane, tri-n-butyl phosphate, acetonitrile, or water.

24. A process of preparing polymorphic forms of rotigotine hydrochloride, comprising crystallizing rotigotine hydrochloride from a solvent/antisolvent mixture.

25. The process of claim 24 wherein the solvent/antisolvent mixture is selected from the group comprising of ester/alcohol; alcohol/ether, alcohol/hydrocarbon, chlorinated hydrocarbon/polar solvent or benzene derivatives/alcohols.

26. The process of claim 24 wherein the solvent/antisolvent mixture is selected from chlorobenzene/ethanol, butyl acetate/ethanol, methanol/methyl-tert-butyl-ether ethanol/n- butyl acetate, ethanol/cyclohexane, tetrachloroethylene/acetonitrile, ethanol/methyl-tert-butyl ether, ethylacetate/ethanol, amyl acetate/ethanol, diethyl malonate/ethanol, 1-propanol/dibutyl ether, 1-propanol/ n-butyl acetate, 2-propanol/cyclohexane, and ethanol/heptane.

27. A process of converting one polymorphic form of rotigotine hydrochloride to another which comprises drying under reduced pressure a rotigotine polymorph at a high temperature.

28. A process of converting one polymorphic form of rotigotine hydrochloride to another which comprises exposing a rotigotine polymorph to an atmosphere having a defined relative humidity.

29. The process of claim 27, drying temperature selected from the range of about 30 ⁰C to about 100 ⁰C.

30. The process of claim 29, wherein the drying temperature is selected from the range of about 50 °C to about 90 ⁰C.

31. The process of claim 27, wherein the drying under reduced pressure is conducted for a period of time ranging between 1 hour to 1 month.

32. The process of claim 31, wherein the drying under reduced pressure is conducted for a period of time ranging between 24 hours to 14 days.

33. The process according to claim 28 wherein the relative humidity is 50 to 100%.

34. The process according to claim 28 wherein the relative humidity is 80 to 100%.

35. The process of claim 28, wherein the rotigotine hydrochloride polymorph is exposed to an atmosphere having a defined relative humidity for a period of time ranging between 1 hour to 1 month.

36. The process of claim 35, wherein the rotigotine hydrochloride polymorph is exposed to an atmosphere having a defined relative humidity for a period of time ranging between 24 hours to 14 days.

37. The process of claim 27 wherein one of rotigotine hydrochloride form I, form IV, or form V is converted to rotigotine hydrochloride form II.

38. The process of claim 28 wherein one of rotigotine hydrochloride form I, form III, form IV, or form V is converted to rotigotine hydrochloride form II.

39. The process of claim 28 wherein rotigotine hydrochloride form I is converted to rotigotine hydrochloride form IV.

40. A pharmaceutical formulation comprising (a) a therapeutically effective amount of rotigotine hydrochloride form I, form II, form III, form IV, form V, or a mixture of any two or more thereof, as described herein, and (b) a pharmaceutically acceptable excipient.

41. The pharmaceutical formulation of claim 40, contained in a transdermal patch.

42. A method of treating a disease prevented, ameliorated or eliminated by the administration of a dopamine D2 receptor agonist or an anti-parkinsonian agent, in a subject in need thereof, the method comprising administering to the subject the formulation of claim 40.

43. The method of claim 42 wherein the disease is parkinsonism or restless leg syndrome.