GB2457455A - Polymorphic form I of the adamantylamino-platinum (IV) complex LA-12 - Google Patents
Polymorphic form I of the adamantylamino-platinum (IV) complex LA-12 Download PDFInfo
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- GB2457455A GB2457455A GB0802595A GB0802595A GB2457455A GB 2457455 A GB2457455 A GB 2457455A GB 0802595 A GB0802595 A GB 0802595A GB 0802595 A GB0802595 A GB 0802595A GB 2457455 A GB2457455 A GB 2457455A
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title description 7
- 229910052697 platinum Inorganic materials 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 75
- 238000000034 method Methods 0.000 claims abstract description 34
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 201000010099 disease Diseases 0.000 claims abstract description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 7
- 230000000771 oncological effect Effects 0.000 claims abstract description 7
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 33
- 238000002329 infrared spectrum Methods 0.000 claims description 17
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 9
- 229910052802 copper Inorganic materials 0.000 claims description 9
- 239000010949 copper Substances 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 8
- 238000001228 spectrum Methods 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- MHZGKXUYDGKKIU-UHFFFAOYSA-N Decylamine Chemical compound CCCCCCCCCCN MHZGKXUYDGKKIU-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 239000002552 dosage form Substances 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- 238000001757 thermogravimetry curve Methods 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000002244 precipitate Substances 0.000 claims description 2
- 125000000075 primary alcohol group Chemical group 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 150000003333 secondary alcohols Chemical class 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims 2
- 239000003814 drug Substances 0.000 claims 1
- 239000012047 saturated solution Substances 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 7
- 238000002955 isolation Methods 0.000 abstract description 2
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 abstract 1
- NDBYXKQCPYUOMI-UHFFFAOYSA-N platinum(4+) Chemical compound [Pt+4] NDBYXKQCPYUOMI-UHFFFAOYSA-N 0.000 description 7
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 4
- 238000012512 characterization method Methods 0.000 description 4
- 230000004927 fusion Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 238000002411 thermogravimetry Methods 0.000 description 3
- 238000004566 IR spectroscopy Methods 0.000 description 2
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 2
- 229920003118 cationic copolymer Polymers 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000000824 cytostatic agent Substances 0.000 description 2
- 230000001085 cytostatic effect Effects 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229910052759 nickel Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- JKNCOURZONDCGV-UHFFFAOYSA-N 2-(dimethylamino)ethyl 2-methylprop-2-enoate Chemical compound CN(C)CCOC(=O)C(C)=C JKNCOURZONDCGV-UHFFFAOYSA-N 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 238000001237 Raman spectrum Methods 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 190000008236 carboplatin Chemical compound 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 150000004682 monohydrates Chemical group 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 229920001490 poly(butyl methacrylate) polymer Polymers 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 238000000371 solid-state nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000002834 transmittance Methods 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/28—Compounds containing heavy metals
- A61K31/282—Platinum compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C211/34—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton
- C07C211/38—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton containing condensed ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/65—Metal complexes of amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
- C07C2603/74—Adamantanes
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Polymorphic form I of the compound (OC-6-43)- bis(acetato)(1-tricyclo[3,3,1,13,7]decylamine)amminedichloroplatinum(IV), an adamantylaminoplatinum (IV) complex, also called LA-12, having the structural formula (I). Methods of preparation, isolation and identification thereof, pharmaceutical compositions containing the same, use of such polymorph and compositions in the treatment of oncological diseases.
Description
POLYMORPHIC FORM (I) OF PLATINUM(IV) COMPLEX
FIELD OF THE INVENTION
The present invention relates to a novel polymorphic form of the compound (OC-6-43)- bis(acetato)( 1 -tricyclo[3, 3,1,1 37)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 difficult solubility. 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(lV) complexes intended for oral administration have been described in EP 0 328 274, EP 0423 707 and WO 99/61451.
One such platinum(IV) complex is represented by the structural formula: OCOCH3 H3N
H V
OCOCH3 and is described in WO 99/61451. The complex is prepared from (OC-6-43)(1-tricyclo[3,3, 1,1 37]decylamine)amminedichlorodihydroxoplatinum (IV), by reaction with excess of acetic anhydride to yield a solid which begins to decompose at 180 °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
The present invention provides a polymorph of the compound (OC-6-43)-bis(acetato)(1-tncyclo[3,3, 1,1 3'7]decylamine)amminedichloroplatinum(IV) designated "Form I" and having the following structural formula: OCOCH3 H3N..J Cl H2NflCI COG 113 Formula (I) Form I decomposes at the temperature of 175 °C � 5 °C.
As a first aspect, the present invention provides crystalline compound of formula (I) characterized by substantially the same differential scanning calorimetry (DSC) thermograms as Figure 1 wherein the DSC was performed at a scan rate 10 K/mm.
As a further aspect, the present invention provides 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 Ka-radiation according to the procedures described herein.
As a further aspect, the present invention provides crystalline compound of formula (I) characterized by an XRPD pattern expressed in terms of 2 theta angles and obtained with a diffractometer using copper Ka-radiation, according to the procedures described herein 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-spading.
As a further aspect, the present invention provides crystalline compound of Formula (I) characterized by substantially the same infrared (IR) spectrum as Figures 3 and 4, wherein the IR spectrum is obtained using a Nicolet-Magna 760 with DTGS KBr detector with a resolution of 0.5 cm1.
As a further aspect, the present invention provides crystalline compound of formula (I) characterized by an IR spectrum comprising peaks at five or more positions selected from the group consisting of 2909 �2cm1; 1665 �2cm1; 1596 �2cm1: 1366 �2cm1; 1339 �2cm1; 1278 �2cm'; 1081 �2cm1; 697 �2cm1.
As a further aspect, a crystalline compound of formula (I) may be prepared by precipitation from a solution of (OC-6-43)-bis(acetato)(1-tricyclo[3,3, 1,1 3'7jdecylamine)amminedichloroplatinumQV) in a suitable organic solvent.
As a further aspect, the present invention provides a pharmaceutical composition comprising crystalline compound of formula (I) according to the present invention. The pharmaceutical composition may further comprise one or more pharmaceutically acceptable carriers or diluents.
As a further aspect, the present invention provides a pharmaceutical composition comprising crystalline compound of formula (I) according to the present invention intended for oral administration. The pharmaceutical composition may further comprise one or more pharmaceutically acceptable carriers or diluents.
In a further aspect, the present invention provides a crystalline compound of formula (I) according to the present invention for use in therapy, particularly in the treatment of oncological diseases.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1. The differential scanning calorimetjy (DSC) thermogram for Form I of compound of formula (I) according to the present invention. DSC was performed on Netzsch DSC 204 Fl at scan rate of 10 KJmin, 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 Ka-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 cm1 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 cm1, 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 (lR) spectra, Raman spectra, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and solid state NMR.
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/mm 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 Ka-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 cm1.
Differential Scanning Calonmetry (DSC) was performed on on Netzsch DSC 204 Fl at scan rate 0110 K/mm.
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. 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 °C for the peak maximum and �20 JIg 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 600 2-theta, step size 0.01°, using the following acquisition parameters: 35 mA, 40kV, 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 Kczl 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 Ad-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 Int. (Rel.) Int. (Abs.) d value [A] 2 Theta value 8.01 85.41 223 11.7� 0.1 7.6� 0.1 21.15 225.5267 9.4� 0.1 9.5� 0.1 1066.32 5.9� 0.1 15.1�0.1 3.7 39.45384 5.7� 0.1 15.7� 0.1 13.99 149.1782 5.0�0.1 17.8�0.1 3.44 36.68141 4.7� 0.1 18.9� 0.1 1.15 12.26268 4.0�0.1 22.0� 0.1 1.65 17.59428 3.9�0.1 22.7�0.1 2.19 23.35241 3.7�0.1 24.2�0.1 3.14 33.48245 3.6� 0.1 24.6� 0.1 2.09 22.28609 2.9� 0.1 30.3� 0.1 3.99 42.54617 2.8�0.1 31.8�0.1 2.05 21.85956 2.7�0.1 32.3�0.1 1.53 16.3147 2.5� 0.1 36.0�0.1 3.13 33.37582 2.4� 0.1 38.1� 0.1 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 cm1. The wave number in cm' (x axis) is plotted against percentage transmittance (y axis). Representative peaks observed in the JR spectrum of Form I of compound of formula (I) are as follows: 2909 �2cm1; 1665 �2cm 1; 1596 �2cm1; 1366 �2cm'; 1339 �2cm1; 1278 �2cm'; 1081 �2cm1; 697 �2cm1.
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 �2cm1; 1665 �2cm1; 1596 �2cm1; 1366 �2cm'; 1339 �2cm1; 1278 �2cm1; 1081 �2cm1; 697 �2cm'. More particularly, at least peaks at 1339 �2cm' 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 cm1.
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 JR spectrum of Form I of compound of formula (I). If the lR spectrum is substantially the same as Figure 3 and 4, the previously unknown form can be readily and accurately identified as From 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).
The present invention includes Form I of compound of formula (I) 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 W0041087126, W006/026935, or W006/029579; 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.
Crystalline Form I of compound of formula (I) may be prepared by precipitation from a solution of crude platinum(IV) complex in an organic solvent by adding water with continuous stirring wherein the organic solvent: water ratio is between 1:1 and 1:90.
Preferred organic solvent is acetone. Suitably, the temperature is in the range 0.5 °C and °C.
Alternatively, the solution of crude platinum(IV) complex is a solution in a primary or secondary alcohol having I -8 carbon atoms under the conditions described above.
Alternatively, the solution of crude platinum(IV) complex is a solution in one or more solvents selected from acetone, methanol, ethanol, propanol, 2-propanol, butanol or acetic acid with water in the ratio of 1:1 to 99:1. The saturated platinum(IV) complex solution is heated under reflux for 10 minutes. Crystallization is performed by means of cooling the solution to a temperature between 30 °C and -50 C. Suitably the platinum(lV) complex is (OC-6-43)-bis(acetato)(1-tricyclo[3, 3,1,1 37Jdecyla mine)amminedichloroplatinum(IV).
Suitably the dosage form may be for oral use or for parenteral use, and comprises the crystalline Form I in admixture with at least one pharmaceutically acceptable excipient.
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 I
1 g of LA-I 2, 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 °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°C and 100 °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 Fl at scan rate of 10 K/mm equipped with a refrigerated cooling system.
The DSC thermogram of Form I of compound of formula (I) displays a broad peak at 120 DC. The enthalpy of fusion determined by integrating this peak was 81 JIg.
The margin of error is approximately �10 °C for the peak maximum and �15 JIg for the heat of fusion.
X-ray powder diffraction (XRPD) The diffraction pattern of Figure 2 was obtained using copper Kcz 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, 40kV, 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 cm1. 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 �2cm1, 1665 �2cm1; 1596 �2cm1; 1366 �2cm'; 1339 �2cm'; 1275 �2cm1; 1081 �2cm'; 697 �2cm1.
The margin of error in the foregoing peak assignments is approximately �2cm1.
Claims (17)
- CLAIMS1. A crystalline compound of formula (I) characterized by substantially the same differential scanning calorimetry (DSC) thermograms as Figure 1 wherein the DSC was performed at 10 K/mm.
- 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 Ka-radiation.
- 3. A crystalline compound of formula (I) characterized by an XRPD pattern expressed in terms of 2 theta angles and obtained with a diffractometer copper using Ka-radiation, according to the procedures described herein comprising 2 theta angles at 7.5�0.1, 9.4�0.1, 15.1�0.1, 17.6�0.1 degrees or 11.7�0.2, 9.4�0.2, 5.9�0.2, 5.0i0,2A d-spacing.
- 4. 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 a Nicolet-Magna 760 with DTGS KBr detector with a resolution of 0.5 cm1.
- 5. A crystalline compound of fomiula (I) characterized by an IR spectrum obtained using a Nicolet-Magna 760 with DTGS KBr detector with a resolution of 0.5 cm1according to the procedures described herein comprising peaks at five or more positions selected from the group consisting of 2909 �2cm1; 1665 �2cm1; 1596 �2cm1; 1366 �2cm1; 1339 �2cm1; 1278 �2crri1; 1081 �2cm1; 697 �2cm'.
- 6. A crystalline compound of formula (I) characterized by an IR spectrum obtained obtained using a Nicolet-Magna 760 with DIGS KBr detector with a resolution of 0.5 cm 1according to the procedures described herein comprising peaks at 1339 �2cm1.
- 7. A procedure for the preparation of crystalline Form I of the compound of Formula (I) as claimed in any preceding claim, comprising precipitation from a solution of (OC-6- 43)-bis(acetato)(1 -tricyclo[3,3, 1,1 37]decylamine)amminedichloroplatinum(lV) in an organic solvent by adding water, wherein the ratio of organic solvent: water is between 1: 1 and 1:90 and the temperature is in the range 0.5°C to 30°C.
- 8. A procedure as claimed in claim 7, wherein the organic solvent is acetone.
- 9. A procedure as claimed in claim 7, wherein the organic solvent is a primary or secondary alcohol having 1 -8 carbon atoms.
- 10. A procedure for the preparation of crystalline Form I of the compound of Formula (I) as claimed in any of claims 1 to 6, comprising heating (OC-6-43)-bis(acetato)(1-tricyclo[3,3, 1,1 3'7jdecylamine)amminedichloroplatinum(IV) in one or more solvents selected from acetone, methanol, ethanol, propanol, 2-propanol, butanol or acetic acid with water in the ratio of 1:1 to 99:1 under reflux to form a saturated solution, followed by cooling the solution to a temperature in the range 30°C to -50°C and collecting the precipitate formed.
- 11. A dosage form for oral use comprising the crystalline Form I of (OC-6-43)-bis(acetato)(1 -tricyclo[3,3, 1,1 37]decylamine)amminedich?oroplatinum(IV), as claimed in any of claims 1 to 6, in admixture with at least one pharmaceutically acceptable excipient.
- 12. A dosage form for parenteral use comprising the crystalline Form I of (OC-6-43)-bis(acetato)(1 -tricyclo[3,3, 1,1 31]decylamine)amminedichloroplatinum(IV)1 as claimed in any of claims 1 to 6, in admixture with at least one pharmaceutically acceptable excipient.
- 13. A pharmaceutical composition comprising Form I of compound of formula (I), as claimed in any of claims I to 6, in conjunction with at least one pharmaceutically acceptable diluent or carrier therefor.
- 14 Form I of compound of formula (I), as claimed in any of claims 1 to 6, for use in therapy.
- 15. Form I of compound of formula (I), as claimed in claim 14, in which the therapy is the treatment of oncological disease.
- 16. A method of treatment of an oncological disease comprising administration of an effective amount of Form I of compound of formula (I), as claimed in any of claims I to 6, to a patient in need thereof.
- 17. Use of Form I of compound of formula (I), as claimed in any of claims 1 to 6. in the preparation of a medicament for the treatment of oncological disease.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0802595A GB2457455B (en) | 2008-02-12 | 2008-02-12 | Polymorphic crystalline form (I) of (OC-6-43)-Bis(Acetato)-1-(Tricyclo[3,3,1,1 (3,7)]Decylamine)Amminedichloroplatinum(IV) |
| PCT/CZ2009/000011 WO2009100688A1 (en) | 2008-02-12 | 2009-02-12 | Polymorphic form ( i ) of the adamantylamino-platinum (iv) complex la-12 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0802595A GB2457455B (en) | 2008-02-12 | 2008-02-12 | Polymorphic crystalline form (I) of (OC-6-43)-Bis(Acetato)-1-(Tricyclo[3,3,1,1 (3,7)]Decylamine)Amminedichloroplatinum(IV) |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB0802595D0 GB0802595D0 (en) | 2008-03-19 |
| GB2457455A true GB2457455A (en) | 2009-08-19 |
| GB2457455B GB2457455B (en) | 2010-04-21 |
Family
ID=39247531
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB0802595A Expired - Fee Related GB2457455B (en) | 2008-02-12 | 2008-02-12 | Polymorphic crystalline form (I) of (OC-6-43)-Bis(Acetato)-1-(Tricyclo[3,3,1,1 (3,7)]Decylamine)Amminedichloroplatinum(IV) |
Country Status (2)
| Country | Link |
|---|---|
| GB (1) | GB2457455B (en) |
| WO (1) | WO2009100688A1 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999061451A1 (en) * | 1998-05-27 | 1999-12-02 | Pliva-Lachema A.S. | Platinum complex, its preparation and therapeutic application |
-
2008
- 2008-02-12 GB GB0802595A patent/GB2457455B/en not_active Expired - Fee Related
-
2009
- 2009-02-12 WO PCT/CZ2009/000011 patent/WO2009100688A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999061451A1 (en) * | 1998-05-27 | 1999-12-02 | Pliva-Lachema A.S. | Platinum complex, its preparation and therapeutic application |
Non-Patent Citations (1)
| Title |
|---|
| J. Med. Chem. Vol. 47, No. 3, 2004, Frantisek Zak et al, "Platinum (IV) Complex with Adamantylamine as Nonleaving Amine Group: Synthesis, Characterization, and in Vitro Antitumor Activity against a Panel of Cisplatin-Resistant Cancer Cell Lines", * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2009100688A1 (en) | 2009-08-20 |
| GB2457455B (en) | 2010-04-21 |
| GB0802595D0 (en) | 2008-03-19 |
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