GB2457454A - Polymorphic form II of the adamantylamino-platinum (IV) complex LA-12 - Google Patents
Polymorphic form II of the adamantylamino-platinum (IV) complex LA-12 Download PDFInfo
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- GB2457454A GB2457454A GB0802592A GB0802592A GB2457454A GB 2457454 A GB2457454 A GB 2457454A GB 0802592 A GB0802592 A GB 0802592A GB 0802592 A GB0802592 A GB 0802592A GB 2457454 A GB2457454 A GB 2457454A
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title description 9
- 229910052697 platinum Inorganic materials 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 74
- 238000000034 method Methods 0.000 claims abstract description 29
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 230000000771 oncological effect Effects 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- MHZGKXUYDGKKIU-UHFFFAOYSA-N Decylamine Chemical compound CCCCCCCCCCN MHZGKXUYDGKKIU-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 5
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 14
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 9
- 238000000862 absorption spectrum Methods 0.000 claims description 9
- 229910052802 copper Inorganic materials 0.000 claims description 9
- 239000010949 copper Substances 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 239000000243 solution Substances 0.000 claims description 4
- 238000001757 thermogravimetry curve Methods 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 239000012047 saturated solution Substances 0.000 claims description 3
- 239000002244 precipitate Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims 1
- 238000002955 isolation Methods 0.000 abstract description 2
- 238000002329 infrared spectrum Methods 0.000 description 11
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- 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
- 239000000203 mixture Substances 0.000 description 4
- 230000005855 radiation Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 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
- 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
- NDBYXKQCPYUOMI-UHFFFAOYSA-N platinum(4+) Chemical class [Pt+4] NDBYXKQCPYUOMI-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000002904 solvent 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
- 238000004566 IR spectroscopy Methods 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
- 238000011109 contamination Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000013480 data collection Methods 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
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003960 organic solvent Substances 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
- 230000004614 tumor growth Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- 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
-
- 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
- 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
-
- 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 II of the compound (0C-6-43)-bis(acetato)(1-tricyclo -[3,3,1,13 Ò 7] decylamine)amminedichloroplatinum(IV), also called LA-12, having the structure shown in formula (I), methods of preparation, isolation and identification thereof, pharmaceutical compositions containing the same, use of such a polymorph in therapy and in the treatment of oncological deseases.
Description
I
POLYMORPHIC FORM (U) OF PLATINUM(lV) COMPLEX
FIELD OF THE INVENTION
The present invention relates to a novel polymorphic form of the compound (OC-6-43)- bis(acetato)( I -tricyclo[3,3, 1,1 3'7Jdecylamine)amminedichloroplatiflum(,J) (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(lV) complexes, whose bioavaifability 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 0423 707 and WO 99161451.
One such ptatinum(lV) complex is represented by the structural formula: OCOCH3 H3N,Cl
H NICI
OCOCH3 and is described in WO 99161451.
The complex is prepared from (OC-6-43)(1-tricyclo[3,3, 1,1 3'7Jdecylamine)amminedIchlorodjhydroxop,atjflum(I) 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-tricyclo[3,3, 1,1 37jdecylamine)amminedichloroptatinum(lV) designated "Form II" and having the following structural formula: OCOCH3 H3N..J Cl H N' OCOCH3 Formula (I) Form II decomposes at the temperature of 170 °C �3.
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 Kcz-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 84�0.1, 15.4�0.1, 15.7�0.1 degrees or 10.5�01, 5.7�0.1, 5.6�0.1 A d-spacing.
As a further aspect, the present invention provides crystalline compound of formula (I) characterized by substantially the same infrared (IR) absorption spectrum as Figures 3 and 4, wherein the IR absorption 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 absorption spectrum comprising peaks at five or more positions selected from the group consisting of 2909 �2cm', 1662 �2cm', 1629 �2cm, 1593 �2cm', 1373 �2cm', 1268 �2cm, 1087 �2cm and 704 �2cm 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 3'7]decylamine)amminedichloroplatirium(lV) 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 calorimetry (DSC) thermogram for Form II of compound of formula (I) according to the present invention. DSC was performed at a scan rate 10 K/mm.
Figure 2. The XRPD pattern of Form II 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 II of compound of formula (I) according to the present invention. The x-axis is wavenumber in cm1 and the y-axis is percent absorbance.
The IR spectrum is obtained using Nicolet-Magna 760 with DIGS 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 (IR) spectra, Raman spectra, differential scanning calorimetry (DSC), therrnogravimetric analysis (TGA) and solid state NMR.
"Form II 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 at a scan rate of 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, according to the procedures described herein.
3) a crystalline compound of formula (I) characterized by substantially the same infrared (lR) absorption spectrum as Figure 3 and 4, wherein the IR absorption spectrum is obtained using Nicolet-Magna 760 with DIGS KBr detector with a resolution of 0.5 cm1.
Differential Scanning Calorimetry (DSC) was performed on DSC was performed on Netzsch DSC 204 Fl at scan rate of 10 K/mm.
The DSC thermogram plots the differential rate of heating in miliwatts per miligram against temperature. The DSC thermogram of Form II of compound of formula (I) displays endotherm peak at 150 °C �1. The enthalpy of fusion determined by integrating this peak is -77 J/g �5.
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 � 1.5 °C for the peak maximum and �10 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 II 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 II, the previously unknown form can be readily and accurately identified as Form II.
The X-ray powder diffraction pattern of Form II 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 (Philips, Holland) attached to PC for data collection. Radiations generated from CuK a source, radiation (0,15419 nm). Exciting voltage: 40kV, anode current: 35mA. The instrument was operated over the 2-theta range of 30 60°, step size: 0,01°. Sample: surface plain, in nickel sample holder, measured and stored at room temperature.
A lightly pressed powder disk sample of Form II 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 Kal 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 II compound of formula (I) certain characteristic 2 theta angle peaks occur at 8.4�0.1, 15.4�0.1, 15.7�0.1 degrees or 10.5�0.1, 5.7�0.1, 5.6�0.1 A d-spacing.
Although one skilled in the art can identify Form II 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 II compound of formula (I) according to Table 1.
Table 1 -XRPD characteristics of crystalline Form II ID Int. Rd. Int. Abs d value [A] 2Th value 1223 100 1952.72 10.5�0.1 8.4�0 1 1224 10.85 211.8701 9.5�0.1 9.3�0.1 1225 7.65 149.3831 8.0�0.1 11.1�0.1 1226 2.68 52.3329 7.2�0.1 12.2�0.1 1228 2.04 39.83549 6.3�0.1 14.1�0.1 1230 15.58 304.2338 5.7�0.1 15.4�0.1 1231 20.98 409.6806 5.6�0.1 15.7�0.1 1233 8.69 169.6914 5.3�0.1 16.9�0.1 1234 6.66 130.0511 5.2�0,1 17.0�0.1 ID mt. Rel. mt. Abs d value (A] 2Th value 1235 14.2 277.2862 5.0�0.1 17 7�0.1 1236 7.37 143.9155 4.7�0.1 18.9�0.1 1237 2.44 47.64637 4.4�0.1 20.2�0.1 1238 2.08 40.61657 4.3�0.1 20.5�0.1 1239 5.25 102.5178 4.0�0.1 22.4�0.1 1240 2.37 46.27946 3.8�0.1 23.1�0.1 1241 6.64 129.6606 3.6�0.1 24.9�0.1 1242 4.31 84.16223 3.5�0.1 25.4�0.1 1243 4.42 8631023 3.4�0.1 25.8�0.1 1245 1.29 25.19009 3.2�0.1 27.8�0.1 1246 4.25 82.9906 3.0�0.1 30.0�0.1 1248 2.93 57.21469 2.9�0.1 31.0�0.1 1250 3.02 58.97214 2.8�0.1 32.0�0.1 1251 3.17 61.90123 2.7�0.1 32.7�0.1 In one aspect at least 3, particularly 6 and more particularly all of the above are employed to identify Form II compound of formula (I).
Based upon the foregoing characteristic features of the XRPD pattern of Form II of compound of formula (I), one skilled in the art can readily identify Form II. It will be appreciated by those skilled in the art that the XRPD pattern of a sample of Form II 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 II 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 II.
The IR spectrum of the crystalline form of compound of formula (I) according to the present invention (i.e., Form II) 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 absorbance (y axis). Representative peaks observed in the IR spectrum of Form II of compound of formula (I) are as follows: 2909 �2cm, 1662 �2cm1, 1629 �2cm1, 1593 �2cm1, 1373 �2cm, 1268 �2cm1, 1087 �2cm1 and 704 �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 II compound of formula (I). Form II of compound of formula (I) can be identified by the presence of peaks at 5 or more positions selected form the group consisting of 1662 �2cm1, 1629 �2cm1, 1593 �2cm-1, 1373 �2cm1, 1268 �2cm More particularly, at least peaks at 1373 �2cm1 and 1268 �2cm1 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'.
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 lR 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 lR spectrum of Form II 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 From II 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 II 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 therrnogravimetric 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 II from other forms of compound of formula (I).
The present invention includes Form II of compound of formula (I) both in substantially pure form and in admixture with other forms of compound of formula (I). By usubstantially pure' is meant that the composition comprises at least 90 percent Form II 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 II and in one embodiment, at least 97 percent Form II compound of formula (I).
While it is possible that, for use in therapy, Form II 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 II 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.
Handling with the crude LA-12 is very complicated due to charging. It also causes a contamination of working environment. Compared to the crude LA-i 2 the crystalline form II has better properties for handling -it is not electrostaticaly charged during mixing.
Suitable pharmaceutical compositions of Form II polymorph (either alone or in admixture with other forms of the compound of formula (I) include those described in W0041087126, W006/026935, or W006F029579; 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 II of compound of formula (I) may be prepared by precipitation from a saturated solution of crude platinum(lV) complex in methanol or ethanol comprising heating under reflux to form a saturated solution, followed by cooling the solution to the temperature between 30 °C and -50°C.
In one aspect alcohol is methanol.
Suitably the platinum(IV) complex is (OC-6-43)-bis(acetato)(1-tricyclo(3,3, 1,1 37]decylamine)amminedichloroplatinum(lV).
Suitably the dosage form may be for oral use or for parenteral use, and comprises the crystalline Form Il in admixture with at least one pharmaceutically acceptable excipient.
The method of how to prepare the crystalline Form II 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-12 was dissolved in 30 mL of methanol under reflux for 20 mm. The resulting solution was slowly cooled to the temperature of 22 °C. Several hours later, the precipitate formed was filtered. 0.80 g of the substance was obtained.
XRPD, DSC and lR spectra were obtained by the procedures described herein, and the substance was designated crystalline Form II.
Differential Scanning Calorimetry (DSC) DSC was performed on a Netzsch DSC 204 Fl at scan rate of 10 K/mm equipped with a refrigerated cooling system.
The DSC thermogram of Form II of compound of formula (I) displays peak at 150 °C. The enthalpy of fusion determined by integrating this peak was -77 JIg.
The margin of error is approximately �1.5 °C for the peak maximum and �10 J/9 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 0,010, using the following acquisition parameters: 35 mA, 40kV, 0.01° 2-theta step.
A powder sample of Form Il of compound of formula (I) was used to produce the XRPD pattern of Figure 2.
Form II of compound of formula (I) can be identified by certain characteristic 2 theta angle peaks at 8.4�0.1, 15.4�0.1, 15.7�0.1 degrees or 10.5�0.1, 5.7�0.1, 5.6�0.1 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) Spectrpscopy IR analysis was performed on Nicolet-Magna 760 with DTGS KBr detector with a resolution of 0.5 cm1.
Representative peaks observed in the IR spectrum of Form II of compound of formula (I) were as follows: 2909 �2cm1, 1662 �2cm1, 1629 �2cm1, 1593 �2cm1, 1373 �2cm1, 1268 �2cm1, 1087 �2cm1 and 704 �2cm1 cm1.
The margin of error in the foregoing peak assignments is approximately �2 cm1.
Claims (15)
- 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 Ku-radiation, according to the procedures described herein comprising 2 theta angles at 8.4�0.1, 15.4�0.1, 15.7�0.1 degrees or 10.5�0.1, 5.7�0.1, 5.6�0.1 A d-spacing.
- 4. A crystalline compound of formula (I) characterized by substantially the same infrared (lR) absorption spectrum as Figure 3 and 4, wherein the lR absorption spectrum is obtained using a Nicolet-Magna 760 with DTGS KBr detector with a resolution of 0.5 cm1.
- 5. A crystalline compound of formula (I) characterized by an IR absorption spectrum obtained using a Nicolet-Magna 760 spectrometer 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 �2cm', 1662 �2cm1, 1629 �2cm1, 1593 �2cm1, 1373 �2cm1, 1268 �2cm1, 1087 �2cm1 and 704 �2cm'
- 6. A crystalline compound of formula (I) characterized by an IR absorption spectrum obtained obtained using a Nicolet-Magna 760 spectrometer with DTGS KBr detector with a resolution of 0.5 cm1 according to the procedures described herein comprising peaks at 1373 �2cm and 1268 �2cm1
- 7. A procedure for the preparation of crystalline Form II of the compound of Formula (I) as claimed in any preceding claim, comprising heating (OC-6-43)-bis(acetato)(1- 1 37]decylamine)amminedichloroplatinum(lV) in methanol or ethanol 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.
- 8. A procedure as claimed in claim 7, wherein the alcohol is methanol.
- 9. A dosage form for oral use comprising the crystalline Form II of (OC-6-43)-bis(acetato)(1 -tricyclo[3,3, 1,1 37]decylamine)amminedichloroplatinum(lV), as claimed in any of claims 1 to 6, in admixture with at least one pharmaceutically acceptable excipient.
- 10. A dosage form for parenteral use comprising the crystalline Form Il of (OC-6-43)-bis(acetato)(1 -tricyclo[3,3, 1,1 37jdecylamine)amminedichloroplatinum(lV), as claimed in any of claims 1 to 6, in admixture with at least one pharmaceutically acceptable excipient.
- 11. A pharmaceutical composition comprising Form II of compound of formula (I), as claimed in any of claims 1 to 6, in conjunction with at least one pharmaceutically acceptable diluent or carrier therefor.
- 12. Form II of compound of formula (I), as claimed in any of claims 1 to 6, for use in therapy.
- 13. Form II of compound of formula (I), as claimed in claim 14, in which the therapy is the treatment of oncological disease.
- 14. A method of treatment of an oncological disease comprising administration of an effective amount of Form II of compound of formula (I), as claimed in any of claims I to 6, to a patient in need thereof.
- 15. Use of Form II 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 |
|---|---|---|---|
| GB0802592A GB2457454B (en) | 2008-02-12 | 2008-02-12 | Polymorphic crystalline form II of (OC-6-43)-bis(acetate)(1-tricyclo[3,3,1,13,7]decylamine) ammine dichloroplatinum (IV) |
| PCT/CZ2009/000012 WO2009100689A1 (en) | 2008-02-12 | 2009-02-12 | Polymorphic form ( ii ) of adamantylamino- platinum ( iv) complex la-12 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0802592A GB2457454B (en) | 2008-02-12 | 2008-02-12 | Polymorphic crystalline form II of (OC-6-43)-bis(acetate)(1-tricyclo[3,3,1,13,7]decylamine) ammine dichloroplatinum (IV) |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB0802592D0 GB0802592D0 (en) | 2008-03-19 |
| GB2457454A true GB2457454A (en) | 2009-08-19 |
| GB2457454B GB2457454B (en) | 2010-05-12 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB0802592A Expired - Fee Related GB2457454B (en) | 2008-02-12 | 2008-02-12 | Polymorphic crystalline form II of (OC-6-43)-bis(acetate)(1-tricyclo[3,3,1,13,7]decylamine) ammine dichloroplatinum (IV) |
Country Status (2)
| Country | Link |
|---|---|
| GB (1) | GB2457454B (en) |
| WO (1) | WO2009100689A1 (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 GB0802592A patent/GB2457454B/en not_active Expired - Fee Related
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2009
- 2009-02-12 WO PCT/CZ2009/000012 patent/WO2009100689A1/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 |
|---|
| "Platinum (IV) complex with adamantylamine as nonleaving amine group: Synthesis, characterization and in vitro antitumour activity against a panel of cisplatin-resistant cancer cell lines" * |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2457454B (en) | 2010-05-12 |
| WO2009100689A1 (en) | 2009-08-20 |
| GB0802592D0 (en) | 2008-03-19 |
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