MXPA00005858A - Thermodynamically stable form of (r)-3-[ [(4-fluorophenyl) sulphonyl]amino]-1,2,3,4- tetrahydro -9h-carbazole -9-propanoic acid (ramatroban) - Google Patents
Thermodynamically stable form of (r)-3-[ [(4-fluorophenyl) sulphonyl]amino]-1,2,3,4- tetrahydro -9h-carbazole -9-propanoic acid (ramatroban)Info
- Publication number
- MXPA00005858A MXPA00005858A MXPA/A/2000/005858A MXPA00005858A MXPA00005858A MX PA00005858 A MXPA00005858 A MX PA00005858A MX PA00005858 A MXPA00005858 A MX PA00005858A MX PA00005858 A MXPA00005858 A MX PA00005858A
- Authority
- MX
- Mexico
- Prior art keywords
- ramatroban
- thermodynamically stable
- modification
- thermodynamically
- active compound
- Prior art date
Links
- LDXDSHIEDAPSSA-OAHLLOKOSA-N 3-[(3R)-3-[(4-fluorophenyl)sulfonylamino]-1,2,3,4-tetrahydrocarbazol-9-yl]propanoic acid Chemical compound N([C@@H]1CCC=2N(C3=CC=CC=C3C=2C1)CCC(=O)O)S(=O)(=O)C1=CC=C(F)C=C1 LDXDSHIEDAPSSA-OAHLLOKOSA-N 0.000 title claims abstract description 38
- 229950004496 ramatroban Drugs 0.000 title claims abstract description 37
- 230000004048 modification Effects 0.000 claims abstract description 32
- 238000006011 modification reaction Methods 0.000 claims abstract description 32
- 150000001875 compounds Chemical class 0.000 claims abstract description 11
- 238000002844 melting Methods 0.000 claims abstract description 6
- 238000010899 nucleation Methods 0.000 claims abstract description 5
- 208000006673 Asthma Diseases 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- 238000001228 spectrum Methods 0.000 claims description 7
- -1 4-FLUOROPHENYL Chemical class 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 238000001237 Raman spectrum Methods 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 238000001816 cooling Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 239000003960 organic solvent Substances 0.000 claims 1
- 238000001953 recrystallisation Methods 0.000 abstract 1
- 239000000725 suspension Substances 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-M caproate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 229920003114 HPC-L Polymers 0.000 description 2
- 238000001069 Raman spectroscopy Methods 0.000 description 2
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 238000001757 thermogravimetry curve Methods 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- 238000004922 13C solid-state nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 230000036912 Bioavailability Effects 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- RZWIIPASKMUIAC-VQTJNVASSA-N Thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000003042 antagnostic Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000035514 bioavailability Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 238000007707 calorimetry Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000001413 far-infrared spectroscopy Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229920003117 medium viscosity grade hydroxypropyl cellulose Polymers 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000009331 sowing Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000001238 wet grinding Methods 0.000 description 1
Abstract
The present invention relates to a thermodynamically stable modification of the active compound ramatroban of formula (I). The thermodynamically stable form is prepared either by melting of the metastable form and subsequent recrystallization or by seeding a solution of the metastable active compound with a seed crystal of the thermodynamically stable form. The thermodynamically stable active compound can be employed as an asthma agent.
Description
THERMODYNAMICALLY STABLE FORM OF THE ACID (R) - 3- [[(4-FLUOROPHENYL) SULFONYL] AMINO] -1, 2, 3, -TE RAHIDRO -9H-CARBAZOL-9-PROPANOIC (RAMATROBAN)
Field of the Invention The invention relates to a new form of ramatroban that is thermodynamically stable at room temperature, to a process for its preparation, to pharmaceutical products comprising this form, and to its use in the control of diseases.
Background of the Invention The preparation and use of ramatroban as an A2 antagonist of thromboxane have already been described in European Patent 242 518.
Description of the Invention In the form described there, ramatroban is obtained in the form of a crystal modification that is designated in the following text .co or modification II. Mod. II has a melting point of 137 ° C and a fusion enthalpy of 80 J / g (CED, Heating Rate 2 K min-1) and an X-ray diffractogram, IR spectrum, 13C-NMR spectrum in
ref: 120478 solid state, "FIR spectrum, characteristic Ra spectrum (Figs 1-6). It has now been found that Mod. II is metastable and therefore not suitable for use in pharmaceutical formulations, such as, for example, solid and semi-solid preparations Surprisingly, a second modification of ramatroban has now been found to be thermodynamically stable and is also stable in storage after processing by means of suspensions and, therefore, is especially suitable for use in pharmaceutical formulations , such as, for example, suspensions or creams, but also in other preparations that are prepared by means of suspended active compound, such as, for example, in aqueous granulation or wet milling. This new modification is designated in the following text as modification I. The present invention also relates to pharmaceutical formulations containing ramatroban in the modified I ion as an active substance. The formulation may contain one or more pharmaceutically acceptable auxiliaries, such as, for example, binders, solvents, fillers, etc.
J. Halbelian,. McCro ne, J. Pharm. Sci. 58 (1969) 911 and J. 0. Henck et al., Pharm. Ind. 59 (1997) 165-169 disclose that when a thermodynamically metastable polymorphic form is used in solid and semi-solid formulations, such as, for example, tablets, suspensions and ointments, the stable form may result. As a concomitant phenomenon here, unwanted crystal growth, changes in bioavailability, agglomeration, etc. are observed. The two modifications of ramatroban crystals differ in their solubility at room temperature by 60%. By using the stable modification I according to the invention, it is ensured that no change in solubility can result as a result of the conversion. This increases the safety of ramatroban preparations and the risk to patients is thereby reduced. Compared to Mod. II, Mod. I has a CED thermogram, X ray diffractogram, solid state 13 C-NMR spectrum, FIR spectrum and clearly distinguishable Raman spectrum (Figs 1-6). The melting point of Mod. I is 151 ° C and the enthalpy of fusion is 87 J / g.
The CED and TGA thermograms were obtained using a DSC 7 and TGA 7 from Perkin-Elmer. X-ray diffractograms were recorded on a Stoe transmission diffractometer. The IR, FIR and Raman spectra were recorded using Bruker's IFS 66 (IR), IFS 66v (FIR) and IFS 88 (Raman) IR Fourier IR spectrometers. The 13 C solid state NMR spectra were recorded using a Bruker MSL 300. Modification of ramatroban crystals is employed in high purity in pharmaceutical formulations. For reasons of stability, Mod. I should not contain relatively large proportions of Mod. II. A degree of active compound with less than 10% Mod. II, very particularly preferably with less than 5%, it is preferred. Mod. I is prepared by suspending modification ramatroban II in water or inert substances, for example, in lower alcohols, ketones or alkanes, seeding with crystals, Modification I and stirring until the desired degree of conversion is achieved, particularly preferably until the conversion quantitative to Mod. I. As a rule, this conversion occurs at 20-50 ° C, preferably at 40 ° C. The crystals of Mod. I obtained are separated and, to remove the solvent present, they are dried to constant weight at temperature In order to prepare the necessary seed crystals, the active compound is completely melted and then rapidly cooled to room temperature.The amorphous form of the active compound thus obtained is suspended in an inert solvent at room temperature and stirred until which becomes completely modified by thermodynamically stable crystals, the residue is filtered and dried until more a constant vacuum.
EXAMPLES Example 1 Preparation of crystals for seeding the molten material Approximately 300 mg of ramatroban from Mod. II are completely melted and rapidly cooled to room temperature. The amorphous substance is suspended in 5 ml of ethanol / water (1: 1) and the suspension is stirred at room temperature for 24 h. After completion in stirring time, the suspension is filtered and the residue is dried under vacuum at room temperature.
Example 2 Sowing Process 130 g of ramatroban (Modification II) are dissolved in 650 g of n-butyl acetate and 15 g of water at about 40 ° C. 175 g of the solvent are separated by vacuum distillation at 40-45 ° C.
Then, the solution is seeded with 1 g of ramatroban
(Modification I) and another 300 g of solvent are separated by vacuum distillation at 40 to 45 ° C.
The obtained crystal suspension is cooled to room temperature and stirred for a few hours. It is filtered off with suction, washed with n-butyl acetate and methyl tert-butyl ether and dried under vacuum at 50 ° C. Approximately 100 g of ramatroban are obtained (Modification I).
EXAMPLE 3 Precipitation Method 75 g of ramatroban (Modification II) are dissolved in 135 g of ethyl acetate with heating. 85 g of petroleum ether (35/60) are added dropwise at about 40 ° C and the batch is seeded with 1 g of ramatroban (Modification I). The mixture is stirred at 40 ° C for about 2 - 3 hours and then cooled to room temperature. Another 130 g of petroleum ether (35/60) are added to the suspension and further stirred at room temperature for about 5 hours. It is filtered off with suction, washed with 100 g of petroleum ether (35/60) and it is dried at 50 ° C under vacuum. Approximately 65 g of ramatroban are obtained (Modification I).
Example 4 Conversion in suspension 1 50 g of ramatroban are suspended
(Modification I) in 75 g of n-butyl acetate and mixed with 0.5 g of ramatroban (Modification I). The mixture is stirred at room temperature for about 100 hours. Then, it is filtered off with suction, washed with methyl tert-butyl ether and dried at 50 ° C under vacuum. Approximately 40 g of ramatroban are obtained (Modification I).
Example 5 Conversion in suspension 2 Approximately 0.5 g of Mod. I and II (mixing ratio about 1: 1) are suspended in 8 ml of n-heptane and refluxed at about 80 ° C. After one week, the suspension is filtered and the residue is dried under vacuum at room temperature for one day.
EXAMPLE 6 Production of Tablets 4590 g of microfine ramatroban of Mod. I are dispersed in a homogenizer with 9180 g of aqueous HPC-L (367 g) and then filtered through a screen ha a mesh width of 355 μm. The granulation liquid is reacted in a granulator with 13,500 g of a premixed and pre-heated aqueous solution, which consists of 3162 9 of lactose, 4860 g of HPC-L and 540 g of HPC-M, to form granules. The resulting granules are dried at 65 ° C. Then, the pressing is carried out on a rotary press to give tablets ha a diameter of 9.0 mm.
Table 1 Differential Exploration Calorimetry
Table 2 X-ray diffractometry
Table 2 (continued)
Table 2 (continued)
Table 2 (continued)
Table 3 IR spectroscopy
Table 3 (continued)
Table 3 (continued)
Table 4 C NMR spectroscopy in the solid state Table 4 (continued)
Table 5 FIR spectroscopy Table 6 Raman spectroscopy Table 6 (continued)
Table 6 (continued)
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Ha described the invention as above, the content of the following is claimed as property.
Claims (11)
1. Thermodynamically stable modification of ramatroban.
2. Thermodynamically stable modification I of ramatroban according to claim 1, characterized in that the substance has a melting point of 151 ° C (CED, 2 K min "1)
3. Thermodynamically stable modification of ramatroban according to the - claim 1, characterized in that its X-ray diffractogram has reflections at 10.1, 12, 0 and 19.8 (2 theta)
4. Thermodynamically stable modification I of ramatroban according to claim 1, characterized in that its spectrum of IR has maximum peaks at 3338 c "1, 1708 cm-1 and 1431 cm-1.
5. Thermodynamically stable modification of ramatroban according to claim 1, characterized in that its spectrum of 13 C NMR in solid state has maximum peaks at 107.9; 118.2 and 135.0 ppm.
6. Thermodynamically stable modification I of ramatroban according to claim 1, characterized in that its FIR spectrum has a maximum peak at 264 cm-1 and at 207 cm-1.
7. Thermodynamically stable modification I of ramatroban according to claim 1, characterized in that its Raman spectrum has maximum peaks at 3080 cm-1, 1580 cm-1 and 122 cm'1.
8. Process for the preparation of seed crystals of the thermodynamically stable ramatroban modification I according to claims 1 to 7, characterized in that the active compound is converted to the amorphous form by melting and rapid cooling and then this becomes the I modify stable by stirring in inert solvents.
9. Process for the preparation of a thermodynamically stable form of ramatroban according to claims 1 to 7, characterized in that a modification of thermodynamically metastable ramatroban in water or inert organic solvents is suspended, it is sown with stable modification I and the conversion is carried out until the desired degree of conversion is achieved.
10. Medicament characterized in that it comprises a thermodynamically stable form of ramatroban according to claims 1 to 7.
11. Use of a modification of thermodynamically stable ramatroban according to claims 1 to 7 in the control of diseases. AMMADELY STABLE THERMODY FORM OF ACID (R) - 3- [[(4-FLUOROPHENYL) SULFONYL] AMINO] -1, 2, 3, 4 -TETRAHYDRO -9H-CARBAZOL-9-PROPANOIC (RAMATROBAN) SUMMARY OF THE INVENTION The present invention relates to a thermodynamically stable modification of the ramatroban active compound of formula (I). The thermodynamically stable form is prepared by melting the metastable form and subsequently recrystallizing or seeding a solution of the metastable active compound with a crystal for seeding in the thermodynamically stable manner. The thermodynamically stable active compound can be used as an agent for asthma.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19757983.3 | 1997-12-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA00005858A true MXPA00005858A (en) | 2002-03-05 |
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