GB2457452A - Amorphous form of the adamantylamino-platinum (IV) complex LA-12 - Google Patents
Amorphous form of the adamantylamino-platinum (IV) complex LA-12 Download PDFInfo
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- GB2457452A GB2457452A GB0802590A GB0802590A GB2457452A GB 2457452 A GB2457452 A GB 2457452A GB 0802590 A GB0802590 A GB 0802590A GB 0802590 A GB0802590 A GB 0802590A GB 2457452 A GB2457452 A GB 2457452A
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- amorphous form
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- acetato
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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 61
- 238000000034 method Methods 0.000 claims abstract description 27
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- 230000000771 oncological effect Effects 0.000 claims abstract description 7
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 5
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 16
- MHZGKXUYDGKKIU-UHFFFAOYSA-N Decylamine Chemical compound CCCCCCCCCCN MHZGKXUYDGKKIU-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 238000001228 spectrum Methods 0.000 claims description 7
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 239000002552 dosage form Substances 0.000 claims description 4
- 238000001757 thermogravimetry curve Methods 0.000 claims description 4
- 150000001298 alcohols Chemical class 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 239000012047 saturated solution Substances 0.000 claims description 3
- 238000000411 transmission spectrum Methods 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims 1
- 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
- 238000002329 infrared spectrum Methods 0.000 description 15
- 238000000634 powder X-ray diffraction Methods 0.000 description 13
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 8
- 239000000843 powder Substances 0.000 description 6
- 230000005855 radiation Effects 0.000 description 6
- 239000007787 solid Substances 0.000 description 5
- 238000012512 characterization method Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 229910052759 nickel Inorganic materials 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- 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
- 238000004458 analytical method Methods 0.000 description 2
- 229920003118 cationic copolymer Polymers 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 239000000824 cytostatic agent Substances 0.000 description 2
- 230000001085 cytostatic effect Effects 0.000 description 2
- 238000013480 data collection Methods 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
- 150000003057 platinum Chemical class 0.000 description 2
- NDBYXKQCPYUOMI-UHFFFAOYSA-N platinum(4+) Chemical compound [Pt+4] NDBYXKQCPYUOMI-UHFFFAOYSA-N 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
- 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
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000004615 ingredient 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
- 229920001490 poly(butyl methacrylate) polymer Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 239000000243 solution Substances 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
- 238000002411 thermogravimetry Methods 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
- 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)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The amorphous form of the compound (OC-6-43)- bis(acetato)(1-tricyclo[3,3,1,13,7] decylamine)amminedichloroplatinum(IV), also called LA- 12, having the structure shown in formula (I), of methods of preparation, isolation and identification thereof, pharmaceutical compositions containing the same, and its use in therapy and the treatment of oncological deseases.
Description
AMORPHOUS FORM OF PLATINUM(IV) COMPLEX
FIELD OF THE INVENTION
The present invention relates to an amorphous form of the compound (OC-6-43)- bis(acetato)( 1 -tricyclo[3, 3,1,1 37]decylam ine)amminedichloroplatinum(IV) (also called LA- 12), methods of preparation, isolation and identification thereof, pharmaceutical compositions containing the same, and the use of such amorphous form 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 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(lV) complex, also known as LA-i 2, is represented by the structural formula: OCOCH3 H3NJ,Cl
H NICI COCH3
Formula (I) and is described in WO 99/61451. The complex is prepared from (OC-6-43)(1-tncyclo[3, 3,1,1 3'7]decylamine)amminedichlorodihydroxoplatinum( IV) by reaction with acetic anhydride to yield a solid which begins to decompose at 180 °C.
An amorphous solid is a solid in which there is no long-range order of the positions of the atoms. Solids in which there is long-range atomic order are called crystalline or morphous solids. Amorphous forms may exhibit distinct physical properties compared to crystalline species of the same molecule, 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 The Amorphous form of a compound of Formula (I) may be distinguished from other forms of the compound by x-ray diffraction spectroscopy and other methods including infra-red spectrometry and differential scanning calorimetry.
SUMMARY OF THE INVENTION
The present invention provides an amorphous form of the compound (OC-6-43)-bis(acetato)(1 -tricyclo(3,3, 1,1 3hldecylamine)ammiflediChlOrOPlatinUm(lV) having the following structural formula: OCOCH3 H3N.J,CI H NICl OCOCH3 Formula (I) Amorphous form decompose at the temperature of 175 °C � 5 °C.
As a first aspect, the present invention provides the amorphous form of the 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.
An X-ray powder diffraction (XRPD) pattern as shown in Figure 2 can be used to distinguish the amorphous form from other crystalline forms of the compound of formula (I).
As a further aspect, the present invention provides the amorphous form of the 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 the amorphous form of the compound of formula (I) characterized by an IR spectrum comprising peaks at five or more positions selected from the group consisting of 2909 �2cm1: 1655 �2cm1; 1635 �2cm1; 1361 �2cm'; 1288 �2cm1; 1080 �2crn1; 701 �2cm1.
As a further aspect, the present invention provides the amorphous form of the compound of formula (I) having a solubility from 0.31-0.33mg/mL, compared to 0.26 -0.27 mglmL for LA-12 prepared by the method described in WO 99161451. The solubility was determined at temperature of 22 �1°C during 18 hours.
As a further aspect, the amorphous form of the compound of formula (I) may be prepared by drying (OC-6-43)-bis(acetatO)(1 -tricyclo[3, 3,1,1 37]decylamine)amminediChloro platinum(IV) in a vacuum at a temperature between 20 and 120°C.
As a further aspect, the amorphous form of the compound of formula (I) may be prepared by cooling to 10 to -70°C of a at boiling point saturated solution of (OC-6-43)-bis(acetato)(1 -tricyclol3,3, 1,1 3h1decylamine)amminediChlOrOPtatiflumO'o) in a suitable organic solvent such as acetone, diethylketone, methyletyketofle, alcohols, dimethylformamide.
As a further aspect, the present invention provides a pharmaceutical composition comprising the amorphous form of the 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 the amorphous form of the 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 the amorphous form of the 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 the amorphous form of the compound of formula (I) according to the present invention. DSC was performed on Netzsch DSC 204 Fl at scan rate of 10 K/mm according to the procedures described herein.
Figure 2. The XRPD pattern of amorphous form of the compound of formula (I) according to the present invention. The XRPD pattern is obtained with powder diffractOmeter 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 3°-60°, step size: 0,010. Sample: surface plain, in nickel sample holder, measured and stored at room temperature.SamPtes were presented as lightly pressed powder disk.
FIgure 3 and 4. The IR spectrum of amorphous form of the compound of formula (I) according to the present invention. The x-axis is wavenumber in cm and the y-axis is percent transmitaflce. The lR 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 an amorphous form of the compound of formula (I) exhibiting one or more advantageous pharmaceutical properties or other advantages over the known crude LA-I 2. The amorphous form of the present invention is stable at ambient temperatures.
The amorphous form of the compound of formula (I) may be characterized and differentiated using a number of conventional analytical techniques1 including but not limited to x-ray powder diffraction (XRPD), infrared (IR) spectrum and differential scanning calorimetry (DSC).
"The amorphous form of the compound of formula (I)" as used herein refers to any of: 1) the amorphous form 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 Klmin on Netzsch DSC 204 Fl according to the procedures described herein.
2) the amorphous form of formula (I) characterized by substantially the same infrared (IR) transmittance spectrum as Figure 3 and 4, wherein the IR transmittance spectrum is obtained using Nicolet-Magna 760 with DTGS KBr detector with a resolution of 0.5 cm1.
Differential Scanning Calorimetry (DSC) was performed on Netzsch DSC 204 Fl at scan rate of 10 K/mm according to the procedures described herein.
The DSC thermogram plots the differential rate of heating in miliwatts per miligram against temperature. The DSC thermogram of the amorphous form of compound of formula (I) displays no peaks.
The X-ray powder diffraction pattern of the amorphous form 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 Kct 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 0.010, using the following acquisition parameters: mA, 40kV, 0.01° 2-theta step.
A lightly pressed powder disk sample of amorphous form of formula (I) was used to produce the XRPD pattern of Figure 2.
The lack of identifiable peaks in Figure 2 is indicative of an amorphous form.
The IR spectrum of the amorphous form of the compound of formula (I) according to the present invention 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'. The wave number in cm1 (x axis) is plotted against percentage transmittance (y axis). Representative peaks observed in the IR spectrum of the amorphous form of the compound of formula (I) are as follows: 2909 �2cm1; 1655 �2cm1; 1635 �2cm'; 1361 �2cm'; 1286 �2cm1; 1080 �2cm; 701 �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 the amorphous form of the compound of formula (I). The amorphous form of the compound of formula (I) can be identified by the presence of peaks at 5 or more positions selected form the group consisting of 2909 �2crW1; 1655 �2crmi1; 1635 �2cm1; 1361 �2cm1; 1288 �2cm1; 1080 �2cm1; 701 �2cm1.
More particularly, at least peaks at 1655 �2cm1 and 1635 �2cm1are 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 the compound of formula (I), obtained using the methods described herein, over Figure 1 and, using expertise and knowledge in the art, readily determine whether the lR spectrum of the unknown sample is substantially the same as the IR spectrum of amorphous form of the 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 the amorphous form of the compound of 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 and characterize the amorphous form of the compound of formula (I). Examples of suitable techniques which are known to those skilled in the art to be useful for the physical characterization and identification of the amorphous form 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 the amorphous form from other forms of compound of formula (I).
The present invention includes the amorphous form of the compound of formula (I) both in substantially pure form and in admixture with other forms of compound of formula (1).
By usubstantially pure" is meant that the composition comprises at least 90 percent amorphous form of the compound of formula (I) as compared to the other forms of the compound of formula (I) in the composition, more particularly at least 95 percent amorphous form and in one embodiment, at least 97 percent amorphous form of the compound of formula (I).
While it is possible that, for use in therapy, amorphous form of the 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 the amorphous form of the compound of 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 amorphous form of the compound of formula (I) as mentioned above is suitable for the preparation of dosage forms.
Suitable pharmaceutical compositions of the amorphous form (either alone or in admixture with other forms of the compound of formula (I)) include those described in W0041087126, W0061026935, or W006/029579: or a solid dispersion of the amorphous form 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 utreatment of oncological diseases1' 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 amorphous form of the compound of formula (I) may be prepared by drying (OC-6- 43)-bis(acetato)( I -tricyclo[3,3, 1,1 37]decylamine)amminediChlOrOPlatiflum(IV) in a vacuum under pressure in the range 10 -450 mBar at a temperature in the range 20 and 120°C for 10-72 hours.
Alternatively, preparation of the amorphous form of the compound of formula (I) comprises cooling to 10 to -70°C of a at boiling point saturated solution of (OC-6-43)-bis(acetato)(1 -tricyclo[3,3, 1,1 37]decylamine)ammiflediChlOroPlatiflUm(lV) in a suitable organic solvent such as acetone, diethylketone, methyletyketone, alcohols, dimethylformamide.
Suitably the platinum(lV) complex is (OC-6-43)-bis(acetatO)(1 -tricyclo[3,3,1,13'7]decylamine)ammiflediChtOrOPlatiflUm(l'I).
Suitably the dosage form may be for oral use or for parenteral use, and comprises the amorphous form of the compound of formula (I) in admixture with at least one pharmaceutically acceptable excipient.
The method of how to prepare the amorphous form of the compound of formula (I) according to the present invention is illustrated using the following examples of the preferred embodiment, without any limitation of the scope of the invention.
Example I
I g of LA-12 complex, synthesised according to the procedure described in WO 99161451, was dissolved in 4 mL of acetone at the temperature of 50°C. The resulting solution was cooled in a deep-freezer to the temperature of -30°C. The resulting precipitate was filtered and dried in a vacuum drier at the temperature of 45°C for 8 hours. The yield was 0.68 g. XRPD, DSC and IR spectra were obtained by the procedures described herein, and the substance was designated as the amorphous form.
Example 2
1 mass part of LA-12 complex, synthesised according to the procedure described in WO 99161451 was dried in the vacuum drier at the temperature of 115 °C and the pressure of 250-200 mBar for 35 hours. The yield was 0.96 mass parts. XRPD, DSC and IR spectra were obtained by the procedures described herein, and the substance was designated as the amorphous form.
DIfferential Scanning Calorimetry (DSC] DSC was performed on Netzsch DSC 204 Fl at scan rate of 10 K/mm according to the procedures described herein.
The DSC thermogram of the amorphous form of the compound of formula (I) displays no peak.
X-ray powder diffraction (XRPD) The diffraction pattern of Figure 2 was obtained using copper Ka radiation on a Philips 1730/10 diffractometer equipped with a powder diffractometer 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 3°-60°, step size: 0,01°. Sample: surface plain, in nickel sample holder, measured and stored at room temperature.Samples were presented as lightly pressed powder disk. The sample was packed in nickel holder, mesured 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 powder sample of the amorphous form of the compound of formula (I) was used to produce the XRPD pattern of Figure 2.
Infrared (IR) Spectroscopy lR analysis was performed on Nicolet-Magna 760 with DTGS KBr detector with a resolution of 0.5 cm1. Approximetely 2 mg of the sample is homogenised with 300 mg of KBr. This sample is pressed by pressure of I GPa.
Representative peaks observed in the IR spectrum of the amorphous form of the compound of formula (I) were as follows: 2909 �2cm1; 1655 �2crn1; 1635 �2cm1; 1361 �2cm1; 1288 �2cm'; 1080 �2cm1; 701 �2cm1.
The margin of error in the foregoing peak assignments is approximately �2cm1.
Claims (13)
- CLAIMS1. The amorphous form of the 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 on Netzsch DSC 204 Fl.
- 2. The amorphous form of the compound of formula (I) characterized by substantially the same infrared (lR) spectrum as Figure 3 and 4, wherein the lR transmittance spectrum is obtained using a Nicolet-Magna 760 with DTGS KBr detector with a resolution of 0.5 cm1.
- 3. The amorphous form of the compound of formula (I) characterized by an lR spectrum obtained using a Nicolet-Magna 760 spectrometer with DTGS KBr detector at resolution of 0.5 cm1 according to the procedures described herein comprising peaks at five or more positions selected from the group consisting of 2909 �2cm1; 1655 �2cm1; 1635 �2cm1; 1361 �2cm1; 1288 �2cm1; 1080 �2cm1; 701 �2cm1.
- 4. The amorphous form of the compound of formula (I) characterized by an lR spectrum obtained obtained using a Nicolet-Magna 760 spectrometer with DTGS KBr detector at resolution of 0.5 cm1 according to the procedures described herein comprising peaks ati 655 �2cm1 and 1635 �2cm1
- 5. A procedure for the preparation of the amorphous form of the compound of formula (I) as claimed in any preceding claim, comprising drying (OC-6-43)-bis(acetato)(1 -tricyclo[3,3, 1,1 3'7]decylamine)amminedichlOrOPlatiflUmOV) in a vacuum under pressure in the range 10 -450 mBar at a temperature in the range 20 and 120°C for 10-72 hours.
- 6. A procedure for the preparation of the amorphous form of the compound of formula (I) as claimed in any of claims I to 4, comprising cooling to 10 to -70°C of a at boiling point saturated solution of (OC-6-43)-bis(acetato)(1-tncyclo[3,3, 1,1 37]decylamine)amminedichloroplatiflUm(lV) in a suitable organic solvent such as acetone, diethylketone, methyletyketone, alcohols, dimethylformamide.
- 7. A dosage form for oral use comprising the amorphous form of (OC-6-43)-bis(acetato)(1 -tricyclo[3,3, 1,1 37]decylamine)amminedichloroplatinurn(IV), as claimed in any of claims 1 to 4, in admixture with at least one pharmaceutically acceptable excipient.
- 8. A dosage form for parenteral use comprising the amorphous form of (OC-6-43)-bis(acetato)(1 -tricyclo[3,3, 1,1 37]decylamine)amminedichloroplatinum(IV), as claimed in any of claims 1 to 4, in admixture with at feast one pharmaceutically acceptable excipient.
- 9. A pharmaceutical composition comprising the amorphous form of the compound of formula (I), as claimed in any of claims I to 4, in conjunction with at least one pharmaceutically acceptable diluent or carrier therefor.
- 10. The amorphous form of the compound of formula (I), as claimed in any of claims 1 to 4, for use in therapy.
- 11. The amorphous form of the compound of formula (I), as claimed in claim 10, in which the therapy is the treatment of oncological disease.
- 12. A method of treatment of an oncological disease comprising administration of an effective amount of the amorphous form of the compound of formula (I), as claimed in any of claims 1 to 4, to a patient in need thereof.
- 13. Use of the amorphous form of compound of formula (I), as claimed in any of claims I to 4, in the preparation of a medicament for the treatment of oncological disease.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0802590A GB2457452B (en) | 2008-02-12 | 2008-02-12 | Amorphous form of (OC-6-43)-bis(acetate)(1-tricyclo[3,3,1,13,7]decylamine) amminedichloroplatinum (IV) |
| PCT/CZ2009/000013 WO2009100690A1 (en) | 2008-02-12 | 2009-02-12 | Amourphous form of the adamantylamino-platinum ( iv) complexla-12 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0802590A GB2457452B (en) | 2008-02-12 | 2008-02-12 | Amorphous form of (OC-6-43)-bis(acetate)(1-tricyclo[3,3,1,13,7]decylamine) amminedichloroplatinum (IV) |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB0802590D0 GB0802590D0 (en) | 2008-03-19 |
| GB2457452A true GB2457452A (en) | 2009-08-19 |
| GB2457452B GB2457452B (en) | 2010-05-12 |
Family
ID=39247528
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB0802590A Expired - Fee Related GB2457452B (en) | 2008-02-12 | 2008-02-12 | Amorphous form of (OC-6-43)-bis(acetate)(1-tricyclo[3,3,1,13,7]decylamine) amminedichloroplatinum (IV) |
Country Status (2)
| Country | Link |
|---|---|
| GB (1) | GB2457452B (en) |
| WO (1) | WO2009100690A1 (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 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK1641438T3 (en) * | 2004-06-01 | 2010-06-07 | Teva Gyogyszergyar Zartkoeruen | Process for preparing the amorphous form of a drug |
-
2008
- 2008-02-12 GB GB0802590A patent/GB2457452B/en not_active Expired - Fee Related
-
2009
- 2009-02-12 WO PCT/CZ2009/000013 patent/WO2009100690A1/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 a 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 |
|---|---|
| GB2457452B (en) | 2010-05-12 |
| WO2009100690A1 (en) | 2009-08-20 |
| GB0802590D0 (en) | 2008-03-19 |
| WO2009100690A8 (en) | 2009-12-17 |
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| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 20150212 |