POLYMORPHIC FORM ( I ) OF THE ADAMANTYLAMINO- PLATINUM ( IV) COMPLEX LA-12

FIELD OF THE INVENTION The present invention relates' tό a novel polymorphic form of the compound (OC-6-43)- -bis(acetato)(1-tricyclo[3,3,1 ,1 ³ⁱ⁷ ]decylamine)amminedichloroplatinum(IV), (also called LA- 12), methods of preparation, isolation and identification thereof, pharmaceutical compositions containing the same, use of such polymorph and compositions in the treatment of oncological deseases.

BACKGROUND OF THE INVENTION

Generally, platinum cytostatics cannot be administered orally due to their insufficient stability in gastro intestinal' track. This problem has been bridged over by using platinum(IV) complexes, whose bioavailability after oral administration is generally higher in comparison with routinely used platinum cytostatics such as e.g. cisplatin, carboplatin or oxaliplatin. Said platinum(IV) complexes intended for oral administration have been described in EP 0 328 274, EP o;423 707 and WQ 99/61451.

One such platinum(IV) complex is represented by the structural formula:

and is described in WO 99/β1451. The complex is prepared from (OC-6-43)(1- tricyclo[3,3,1,1 ³ ' ⁷ ]decylamine)arnminedichlorodihydroxoplatinum(IV), by reaction with excess of acetic anhydride to yield a solid which begins to decompose at 180 ⁰ C.

Polymorphism is defined as the ability of an element or compound to crystallise in more than one distinct crystalline species. Thus polymorphs are distinct solids sharing the same molecular formula, however since the properties of any solid depends on its structure, different polymorphs may exhibit distinct physical properties such as different solubility profiles, different melting points, different dissolution profiles, different thermal and/or photostability, different shelf life, different suspension properties and different

physiological absorption rate. Inclusion of a solvent in the crystalline solid leads to solvates, and in the case of water as a solvent, hydrates.

Polymorphic forms of a compound may be distinguished by x-ray diffraction spectroscopy and other methods including infra-red spectrometry.

SUMMARY OF THE INVENTION

As a first aspect, the invention provides a polymorphic crystalline form (I) of (OC-6-43)- bis(acetato)(1-tricyclo[3,3,1 ,1 ³ ' ⁷ ]decylamine)amminedichloroplatinum(IV), characterized by substantially the same differential scanning calorimetry (DSC) thermograms as Figure 1 wherein the DSC was performed at 10 K/min.

As a further aspect, the invention provides a polymorphic crystalline form (I) of (OC-6-43)- bis(acetato)(1-tricyclo[3,3,1 ,1 ³⁷ ]decylamine)amminedichloroplatinum(IV), characterized by substantially the same X-ray powder diffraction (XRPD) pattern as Figure 2, wherein the XRPD pattern is expressed in terms of 2 theta angles and obtained with a diffractometer using copper Kα-radiation according to the procedures described herein.

As a further aspect, the invention provides a polymorphic crystalline form (I) of (OC-6-43)- bis(acetato)(1-tricyclo[3,3,1 ,1 ^3|7 ]decylamine)amminedichloroplatinum(IV), characterized by an XRPD pattern expressed in terms of 2 theta angles obtained with a diffractometer copper using Kα-radiation according to the procedures described herein and comprising 2 theta angles at 7.5±0.1 , 9.4±0.1 , 15.1 ±0.1, 17.8±0.1 degrees or 11.7±0.2, 9.4±0.2, 5.9±0.2, 5.0±0.2 A d-spacing.

As a further aspect, the invention provides a polymorphic crystalline form (I) of (OC-6-43)- bis(acetato)(1-tricyclo[3,3,1 ,1 ³ⁱ⁷ ]decylamine)amminedichloroplatinum(IV), characterized by substantially the same infrared (IR) spectrum as Figure 3 and 4, wherein the IR spectrum is obtained using a Nicolet-Magna 760 with DTGS KBr detector with a resolution of 0.5 cm ^"1 according to the procedures described herein.

As a further aspect, the invention provides a polymorphic crystalline form (I) of (OC-6-43)- bis(acetato)(1-tricyclo[3,3,1 ,1 ³ ' ⁷ ]decylamine)amminedichloroplatinum(IV), characterized by

an IR spectrum obtained using a Nicolet-Magna 760 with DTGS KBr detector with a resolution of 0.5 cm ^"1 according to the procedures described herein and comprising peaks at five or more positions selected from the group consisting of 2909 ±2cm ^"1 ; 1665 ±2cm ^"1 ; 1596 ±2cm ^"1 ; 1366 +2cm ^"1 ; 1339 ±2cπV ¹ ; 1278 ±2cm ^"1 ; 1081 ±2crτϊ ¹ ; 697 ±2cm ^"1 .

As a further aspect, the invention provides a polymorphic crystalline form (I) of (OC-6-43)- bis(acetato)(1-tricyclo[3,3,1 ,1 ³ ' ⁷ ]decylamine)amminedichloroplatinum(IV), characterized by an IR spectrum obtained using a Nicolet-Magna 760 with DTGS KBr detector with a resolution of 0.5 cm ^"1 according to the procedures described herein and comprising peaks at 1339 ± 2cm ^"1 .

As a further aspect, the invention provides a procedure for the preparation of the polymorphic crystalline form (I) of (OC-6-43)-bis(acetato)(1-tricyclo[3,3,1 ,1 ³ ' ⁷ ]decyl- amine)amminedichloroplatinum(IV), as defined above, comprising the precipitation carried out at a temperature of from 0,5°C to 3O ⁰ C from a solution of (OC-6-43)-bis(acetato)(1- -tricyclo[3,3,1 ,1 ³ ' ⁷ ]decyl-amine)-amminedichloroplatinum(IV) in an organic solvent by adding water to reach a ratio organic solvent:water of from 1 : 1 to 1:90.

As a further aspect, the invention provides the procedure as defined above, wherein the organic solvent is acetone.

As a further aspect, the invention provides the procedure as defined, wherein the organic solvent is a primary or secondary alcohol having 1 - 8 carbon atoms.

As a further aspect, the invention provides a procedure for the preparation of the polymorphic crystalline form (I) of (OC-6~43)-bis(acetato)(1-tricyclo[3,3,1 ,1 ³ ' ⁷ ]decyl- amine)amminedichloroplatinum(IV), as defined above, comprising heating (OC-6-43)- -bis(acetato)(1-tricyclo-[3,3,1 ,1 ³ ' ⁷ ]decylamine)amminedichloroplatinum(IV) in a miixture of one or more solvents selected from acetone, methanol, ethanol, propanol, 2-propanol, butanol or acetic acid with water in a ratio solvent(s):water of from 1:1 to 99:1 under reflux to form a saturated solution, followed by cooling the solution to a temperature in the range of from 30 ⁰ C to -50 ⁰ C and collecting the precipitate formed.

As a further aspect, the invention provides a dosage form for oral use comprising the polymorphic crystalline form (I) of (OC-6-43)-bis(acetato)(1-tricyclo[3,3,1 ,1 ³ ' ⁷ ]decylamine)- amminedichloroplatinum(IV), as defined above, in admixture with at least one pharmaceutically acceptable excipient.

As a further aspect, the invention provides a dosage form for parenteral use comprising the polymorphic crystalline form (I) of (OC-6-43)-bis(acetato)(1-tricyclo- [3,3,1 ,1 ³ ' ⁷ ]decylamine)amminedichloroplatinum(IV), as defined above, in admixture with at least one pharmaceutically acceptable excipient.

As a further aspect, the invention provides a pharmaceutical composition comprising the polymorphic crystalline form (I) of (OC-6-43)-bis(acetato)(1-tricyclo- [3,3,1, 1 ³ ' ⁷ ]decylamine)amminedichloroplatinum(IV), as defined above, in conjunction with at least one pharmaceutically acceptable diluent or carrier therefor.

As a further aspect, the invention provides a polymorphic crystalline form (I) of (OC-6-43)- -bis(acetato)(1-tricyclo[3,3,1 ,1 ³⁷ ]decylamine)amminedichloroplatinum(IV), as defined above, for use in therapy.

As a further aspect, the invention provides a polymorphic crystalline form (I) of (OC-6-43)- -bis(acetato)(1-tricyclo[3,3,1 ,1 ³⁷ ]decylamine)amminedichloroplatinum(IV), as defined above, wherein the therapy is the treatment of oncological disease.

As a further aspect, the invention provides a method of treatment of an oncological disease comprising administration of an effective amount of the polymorphic crystalline form (I) of (OC-6-43)-bis(acetato)(1-tricyclo[3,3,1 ,1 ³ ' ⁷ ]decylamine)amminedichloro- platinum(IV), as defined above, to a patient in need thereof.

As a further aspect, the invention provides a use of the polymorphic crystalline form (I) of (OC-6-43)-bis(acetato)(1-tricyclo[3,3,1,1 ³ ' ⁷ ]decylamine)amminedichloroplatinum(IV), as defined above, in the preparation of a medicament for the treatment of an oncological disease.

It is evident from the foregoing that the present invention provides a crystaline polymorph of the compound (OC-6-43)-bis(acetato)(1-tricyclo[3, 3,1 ,1 ^3|7 ]decylamine)ammine- dichloro-platinum(IV) designated "form (I)" and having the following structural formula:

Formula (I)

This crystalline polymorphic form (I) decomposes at the temperature of 175 ⁰ C ± 5 ⁰ C.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1. The differential scanning calorimetry (DSC) thermogram for form I of compound of formula (I) according to the present invention. DSC was, performed on Netzsch DSC 204 F1 at scan rate of 10 K/min, according to the procedures described herein.

Figure 2. The XRPD pattern of form (I) of compound of formula (I) according to the present invention. The XRPD pattern is expressed in terms of 2 theta angles and obtained with a diffractometer using copper Kα-radiation, according to the procedures described herein.

Figure 3 and 4. The IR spectrum of form (I) of compound of formula (I) according to the present invention. The x-axis is wavenumber in cm ^"1 and the y-axis is percent transmitance. The IR spectrum is obtained using Nicolet-Magna 760 with DTGS KBr detector with a resolution of 0.5 cm ^"1 , according to the procedures described herein.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a novel crystalline form of compound of formula (I) exhibiting one or more advantageous pharmaceutical properties or other advantages over

the known crude LA-12. The crystalline form of the present invention is stable at ambient temperatures.

The various forms of compound of formula (I) may be characterized and differentiated using a number of conventional analytical techniques, including but not limited to X-ray powder diffraction (XRD) patterns, infrared (IR) spectra, Raman spectra, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and solid state NMR.

"Form I of compound of formula (I)" as used herein refers to any of:

1) a crystalline compound of formula (I) characterized by substantially the same differential scanning calorimetry (DSC) thermograms as Figure 1 wherein the DSC was performed on Netzsch DSC 204 Flat a scan rate of 10 K/min according to the procedures described herein

2) a crystalline compound of formula (I) characterized by substantially the same X-ray powder diffraction (XRPD) pattern as Figure 2, wherein the XRPD pattern is expressed in terms of 2 theta angles and obtained with a diffractometer using copper Kα-radiation, according to the procedures described herein.

3) a crystalline compound of formula (I) characterized by substantially the same infrared (IR) spectrum as Figure 3 and 4, wherein the IR spectrum is obtained using Nicolet- Magna 760 with DTGS KBr detector with a resolution of 0.5 cm ^"1 .

Differential Scanning Calorimetry (DSC) was performed on on Netzsch DSC 204 F1 at scan rate of 10 K/min.

The DSC thermogram plots the differential rate of heating in milliwatts per miligram against temperature. The DSC thermogram of form (I) of compound of formula (I) displays a endotherm peak at 120°C±5 ^c C. The enthalpy of fusion determined by integrating this peak is -90 J/g±10.

Slight variations in the observed peak is expected based on the specific instrument and pan configuration employed, the analyst's sample preparation technique, and the sample

size. Some margin of error is present in the peak assignment reported above. The margin of error is approximately ±10 ⁰ C for the peak maximum and ±20 J/g for the heat of fusion.

One skilled in the art can determine whether the DSC thermogram of an unknown sample is substantially the same as the DSC thermogram of form (I) of the compound of formula (I). If the DSC thermogram is substantially the same as Figure 1 and the peak position is substantially the same as those for form (I), the previously unknown form can be readily and accurately identified as form (I).

The X-ray powder diffraction pattern of form (I) compound of formula (I) can be determined using conventional techniques and equipment known to those skilled in the art of analytical chemistry and physical characterization. The diffraction pattern of Figure 2 was obtained using copper Ka radiation on a Philips 1730/10 diffractometer. The sample was packed in a nickel holder, measured and stored at room temperature, scanned from 3 to 60° 2-theta, step size 0.01°, using the following acquisition parameters: 35 mA, 4OkV, 0.01° 2-theta step.

A lightly pressed powder disk sample of form (I) of compound of formula (I) was used to produce the XRPD pattern of Figure 2. 2 Theta angles in degrees (x-axis) is plotted against peak intensity in terms of the count rate per seconds (y-axis). The XRPD pattern for each crystalline form is unique, exhibiting a unique set of diffraction peaks which can be expressed in 2 theta angles (°), d-spacings (A) and/or relative peak intensities.

2 Theta diffraction angles and corresponding d-spacing values account for positions of various peaks in the XRPD pattern. D-spacing values are calculated with observed 2 theta angles and copper Ka 1 wavelength using the Bragg equation. Slight variations in observed 2 theta angles and d-spacings are expected based on the specific diffractometer employed and the analyst's sample preparation technique. More variation is expected for the relative peak intensities. Large variations of relative peak intensities may be observed due to preferred orientation resulting from differences in crystal morphology. Identification of the exact crystal form of a compound should be based primarily on observed 2 theta angles or d-spacings with lesser importance place on relative peak intensities. To identify form (I) compound of formula (I) certain characteristic 2 theta angle peaks occur at

7.5±0.1 , 9.4±0.1, 15.1 ±0.1, 17.8±0.1 degrees or 11.7±0.2, 9.4±0.2, 5.9±0.2, 5.0±0.2 A d- spacing.

Although one skilled in the art can identify form (I) from these characteristic 2 theta angle peaks, in some circumstances it may be desirable to rely upon additional 2 theta angles or d-spacings for the identification of form (I) compound of formula (I) according to Table 1.

Table 1 - XRPD characteristics of crystalline form (I)

In one aspect at least 2, particularly 4 and more particularly all of the above are employed to identify form (I) compound of formula (I).

Based upon the foregoing characteristic features of the XRPD pattern of form (I) of compound of formula (I), one skilled in the art can readily identify form (I). It will be appreciated by those skilled in the art that the XRPD pattern of a sample of form (I) of compound of formula (I), obtained using the methods described herein, may exhibit additional peaks.

Some margin of error is present in each of the 2 theta angle assignments and d-spacings reported above. The error in determining d-spacings decreases with increasing diffraction scan angle or decreasing d-spacing. The margin of error in the foregoing 2 theta angles is approximately ±0.1 degrees for each of the foregoing peak assignments.

Since some margin of error is possible in the assignment of 2 theta angles and d- spacings, the preferred method of comparing XRPD patterns in order to identify the particular form of a sample of compound of formula (I) is to overlay the XRPD pattern of the unknown sample over the XRPD pattern of a known form. For example, one skilled in the art can overlay an XRPD pattern of an unknown sample of compound of formula (I), obtained using the method described herein, over Figure 2 and, using expertise and knowledge in the art, readily determine whether the XRPD pattern of the unknown sample is substantially the same as the XRPD pattern of form (I) of compound of formula (I). If the XRPD pattern is substantially the same as Figure 2, the previously unknown form can be readily and accurately identified as form (I).

The IR spectrum of the crystalline form of compound of formula (I) according to the present invention (i.e., form (I)) can be determined using conventional equipment and techniques known to those skilled in the art of analytical chemistry and physical characterization. The IR spectra of Figure 3 and 4 was obtained on a Nicolet-Magna 760 with DTGS KBr detector with a resolution of 0.5 cm ^"1 . The wave number in cm ^"1 (x axis) is plotted against percentage transmittance (y axis). Representative peaks observed in the IR spectrum of form (I) of compound of formula (I) are as follows: 2909 +2cm ^'1 ; 1665 ±2crτϊ ¹ ; 1596 ±2cm ^"1 ; 1366 ±2cm ^"1 ; 1339 ±2cm ¹ ; 1278 ±2cm ^"1 ; 1081 ±2cm ^"1 ; 697 ±2crτϊ ¹ .

As will be apparent to those skilled in the art, not all of these peaks are necessary to conclusively identify an analyzed sample as form (I) compound of formula (I). Form (I) of compound of formula (I) can be identified by the presence of peaks at 5 or more positions selected form the group consisting of 2909 ±2cm ^"1 ; 1665 ±2cm ^"1 ; 1596 ±2cm ^'1 ; 1366 ±2cm ^"1 ; 1339 ±2cm ^"1 ; 1278 ±2cm ^"1 ; 1081 ±2cm ^"1 ; 697 ±2cm ^"1 . More particularly, at least peaks at 1339 ±2cm ^"1 are present, in one embodiment 2, 3 or 4 further peaks are present and in a further embodiment, all of the foregoing peaks are present.

Slight variations in observed peaks are expected based on the specific spectrometer employed and the analyst's sample preparation technique. Some margin of error is present in each of the peak assignments reported above. The margin of error in the foregoing peak assignments is approximately ±2 cm ^'1 .

Since some margin of error is possible in the peak assignments, a useful method of comparing IR spectra in order to identify the particular form of a sample of compound of

formula (I) is to overlay the IR spectrum of the sample over the IR spectrum of each of the known forms. For example, one skilled in the art can overlay an IR spectrum of an unknown form of compound of formula (I), obtained using the methods described herein, over Figure 3 and 4 and, using expertise and knowledge in the art, readily determine whether the IR spectrum of the unknown sample is substantially the same as the IR spectrum of form (I) of compound of formula (I). If the IR spectrum is substantially the same as Figure 3 and 4, the previously unknown form can be readily and accurately identified as form (I) of compound or formula (I).

Any of the foregoing analytical techniques can be used alone or in combination to identify a particular form of compound of formula (I). In addition, other methods of physical characterization can also be employed to identify the characterize form (I) compound of formula (I). Examples of suitable techniques which are known to those skilled in the art to be useful for the physical characterization of identification of a crystalline form or solvate include but are not limited to melting point, and thermogravimetric analysis. These techniques may be employed alone or in combination with other techniques to characterize a sample of an unknown form and to distinguish form (I) from other forms of compound of formula (I).

Form (I) of compound of formula (I) can be both in substantially pure form and in admixture with other forms of compound of formula (I). By "substantially pure" is meant that the composition comprises at least 90 percent form (I) of compound of formula (I) as compared to the other forms of compound of formula (I) in the composition, more particularly at least 95 percent Form I and in one embodiment, at least 97 percent form (I) compound of formula (I).

While it is possible that, for use in therapy, form (I) of a compound of formula (I), according to the present invention, (either alone or in admixture with other forms of the compound of formula (I)), may be administered as the raw chemical, it is more suitable to present the active ingredient as a pharmaceutical composition. Accordingly, the invention further provide a pharmaceutical composition comprising form (I) compound of the formula (I) and one or more pharmaceutically acceptable carriers, diluents, or excipients. The carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

The crystalline form as mentioned above may be prepared by precipitation from systems containing water, see Example 1. It is a monohydrate and is suitable for the preparation of dosage forms. The crystalline form prepared in this way may be obtained reproducibly in high purity (>99.8 %).

Suitable pharmaceutical compositions of form (I) polymorph (either alone or in admixture with other forms of the compound of formula (I) include those described in WO04/087126, WO06/026935, or WO06/029579; or a solid dispersion of the polymorph with polymetacrylate, suitably with the cationic copolymer of poly butyl methacrylate with 2- dimethylaminoethyl methacrylate and methyl methacrylate in the ratio of 1 :2:1. Said cationic copolymer is commercially available under the name EUDRAGIT E.

The term "treatment of oncological diseases" means inhibition of characteristic signs and symptoms of a disease on biological objects carrying a tumor, namely an inhibition of a tumor growth and increase of survival time of the biological object.

The method of how to prepare the crystalline form (I) of compound of formula (I) according to the present invention is illustrated using the following example of the preferred embodiment, without any limitation of the scope of the invention.

Example 1

1 g of LA-12, synthesised according to the procedure described in WO 99/61451 , was dissolved in 17 mL of acetone. The mixture was filtered. 51 mL of distilled water were gradually added during 60 minutes to the filtrate while stirring continuously. The mixture was then stirred at the 22-24 ⁰ C for 60 minutes. The resulting precipitate was filtered, rinsed with 10 volume parts of distilled water and dried in a vacuum drier at the temperature between 65 ⁰ C and 100 ⁰ C. The yield was 0.9 of the mass parts. XRPD, DSC and IR spectra were obtained by the procedures described herein, and the substance was designated crystalline form (I).

Differential Scanning Calorimetry (DSC)

DSC was performed on on Netzsch DSC 204 F1 at scan rate of 10 K/min equipped with a refrigerated cooling system.

The DSC thermogram of form (I) of compound of formula (I) displays a broad peak at 120

°C. The enthalpy of fusion determined by integrating this peak was 81 J/g.

The margin of error is approximately ±10 ⁰ C for the peak maximum and ±15 J/g for the heat of fusion.

X-ray powder diffraction (XRPD)

The diffraction pattern of Figure 2 was obtained using copper Ka radiation on a Philips 1730/10 diffractometer. The sample was packed in nickel holder, mesured and stored at room temperature, scanned from 3 to 60° 2-theta, step size 0,01°, using the following acquisition parameters: 35 mA, 4OkV, 0.01° 2-theta step.

A powder sample of form (I) of compound of formula (I) was used to produce the XRPD pattern of Figure 2.

Form (I) of compound of formula (I) can be identified by certain characteristic 2 theta angle peaks at 7.5±0.1, 9.4±0.1 , 15.1 ±0.1, 17.8±0.1 degrees or 11.7±0.2, 9.4±0.2, 5.9±0.2, 5.0±0.2 A d-spacing.

The margin of error in the foregoing 2 theta angles is approximately ±0.1 degrees for each of the foregoing peak assignments.

Infrared (IR) Spectroscopy

IR analysis was performed on Nicolet-Magna 760 with DTGS KBr detector with a resolution of 0.5 cm ^"1 . Approximately 2 mg of the sample is homogenised with 300 mg of KBr. This sample is pressed by pressure of 1 GPa.

Representative peaks observed in the IR spectrum of form (I) of compound of formula (I) were as follows: 2909 ±2cm ^"1 ; 1665 ±2cm ^"1 ; 1596 ±2cm ^"1 ; 1366 ±2cm ^"1 ; 1339 ±2cm ^'1 ; 1278 ±2cm ^"1 ; 1081 ±2cm ^"1 ; 697 ±2crτϊ ¹ .

The margin of error in the foregoing peak assignments is approximately ±2cm ^~1 .