EP1313745A1 - Monohydrate d'amifostine et son procede de production - Google Patents
Monohydrate d'amifostine et son procede de productionInfo
- Publication number
- EP1313745A1 EP1313745A1 EP01969659A EP01969659A EP1313745A1 EP 1313745 A1 EP1313745 A1 EP 1313745A1 EP 01969659 A EP01969659 A EP 01969659A EP 01969659 A EP01969659 A EP 01969659A EP 1313745 A1 EP1313745 A1 EP 1313745A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- monohydrate
- amifostine
- trihydrate
- water
- methanol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 23
- CWHOHHKTRJUFTR-UHFFFAOYSA-N 2-(3-aminopropylamino)ethylsulfanylphosphonic acid;hydrate Chemical compound O.NCCCNCCSP(O)(O)=O CWHOHHKTRJUFTR-UHFFFAOYSA-N 0.000 title claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 title claims description 12
- 229960001097 amifostine Drugs 0.000 claims abstract description 68
- JKOQGQFVAUAYPM-UHFFFAOYSA-N amifostine Chemical compound NCCCNCCSP(O)(O)=O JKOQGQFVAUAYPM-UHFFFAOYSA-N 0.000 claims abstract description 62
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 39
- 239000000126 substance Substances 0.000 claims abstract description 17
- 239000007864 aqueous solution Substances 0.000 claims abstract description 13
- 239000002552 dosage form Substances 0.000 claims abstract 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 37
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- 238000002844 melting Methods 0.000 claims description 21
- 230000008018 melting Effects 0.000 claims description 21
- 238000010438 heat treatment Methods 0.000 claims description 19
- 238000000354 decomposition reaction Methods 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 5
- 239000000725 suspension Substances 0.000 claims description 5
- 239000002244 precipitate Substances 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 2
- 238000007605 air drying Methods 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 238000007911 parenteral administration Methods 0.000 claims 1
- 238000005406 washing Methods 0.000 claims 1
- 150000004682 monohydrates Chemical class 0.000 description 69
- 150000004684 trihydrates Chemical class 0.000 description 63
- 239000002775 capsule Substances 0.000 description 17
- -1 AF monohydrate Chemical class 0.000 description 15
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 14
- 239000013078 crystal Substances 0.000 description 12
- 238000003795 desorption Methods 0.000 description 12
- 238000001179 sorption measurement Methods 0.000 description 12
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 238000001035 drying Methods 0.000 description 10
- 238000012360 testing method Methods 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 238000011835 investigation Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 229940098617 ethyol Drugs 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000003860 storage Methods 0.000 description 5
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 239000003125 aqueous solvent Substances 0.000 description 4
- 239000003086 colorant Substances 0.000 description 4
- 230000018044 dehydration Effects 0.000 description 4
- 238000006297 dehydration reaction Methods 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- 238000002411 thermogravimetry Methods 0.000 description 4
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000010926 purge Methods 0.000 description 3
- 230000005855 radiation Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000004611 spectroscopical analysis Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 2
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 238000001069 Raman spectroscopy Methods 0.000 description 2
- 229910000831 Steel Inorganic materials 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 238000007707 calorimetry Methods 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000001120 cytoprotective effect Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 230000010287 polarization Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000010959 steel Substances 0.000 description 2
- 238000002076 thermal analysis method Methods 0.000 description 2
- 238000001757 thermogravimetry curve Methods 0.000 description 2
- 230000036962 time dependent Effects 0.000 description 2
- PAWQVTBBRAZDMG-UHFFFAOYSA-N 2-(3-bromo-2-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(Br)=C1F PAWQVTBBRAZDMG-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 241001507939 Cormus domestica Species 0.000 description 1
- 238000005079 FT-Raman Methods 0.000 description 1
- 206010016936 Folliculitis Diseases 0.000 description 1
- 238000000305 Fourier transform infrared microscopy Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- 238000001237 Raman spectrum Methods 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 238000012443 analytical study Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 238000004590 computer program Methods 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000010192 crystallographic characterization Methods 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 230000004223 radioprotective effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000002336 sorption--desorption measurement Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000003396 thiol group Chemical class [H]S* 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
Classifications
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/16—Esters of thiophosphoric acids or thiophosphorous acids
- C07F9/165—Esters of thiophosphoric acids
- C07F9/1651—Esters of thiophosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
Definitions
- the invention relates to the production of a trihydrate, a monohydrate and the amorphous form of amifostine (AF), in particular the reproducible production of the monohydrate of AF.
- AF amifostine
- Amifostin is S- [2- (3-aminopropylamino) ethyl] dihydrogen phosphorothioate (anhydrate: CAS No. 20537-88-6, C5H15N203PS, No. 214.22). It is used as a cytoprotective agent in tumor therapy. AF (prodrug) is dephosphorylated to free thiol (active form) by the alkaline phosphatase. AF therefore selectively protects non-tumor-infested cells from radiation and cystostatics, because the concentration of alkaline phosphatase in healthy cells is much higher than in tumor cells. The usual dose is 0.910 g / m 2 body surface area in adults (15-minute infusion) (Hunnius Pharmaceutical Dictionary; 8th edition, A. Burger and H. Wamba; Berlin, New York: de Gruyter, 1998).
- AF is first synthesized by Piper J.R. et al. in the Journal of Med. Chem. 12, 236-243 (1969) in the search for potential protective agents against radioactive radiation.
- the synthesis proceeds over several stages, the final step being a precipitation of an aqueous solution of AF by adding methanol. There is no information about the concentration of the aqueous solution and a precise description of the addition.
- AF monohydrate (probably based on elemental analysis) with a melting point of 160 to 161 ° C (Kofler heating bench) is mentioned as the product of the synthesis.
- the analytical investigations are carried out by Piper et al. not detailed. No thermoanalytical, morphological or crystallographic characterization of the monohydrate was carried out (except for the determination of the melting point).
- Freeze-drying amorphous AF is described by Zadeii, J.M. et al. in Pharm. Res. 8, 172 (1991) contrasted crystalline AF without, however, addressing the water content of AF.
- AF trihydrate is mentioned as a synthesis product, which is formed by adding ethanol to an aqueous solution of AF.
- the trihydrate of amifostine (melting point 85-88 ° C. with decomposition; DSC, 5 K / min) is generally obtained by crystallization from aqueous solvents or by stirring the suspension of any form of AF in aqueous solvents.
- the object of the invention is to provide the monohydrate of amifostine and a reproduced process for its production.
- a trihydrate, a monohydrate and the amorphous form of amifostine (AF) are produced quantitatively and reproducibly.
- AF trihydrate (melting point 85-88 ° C with decomposition; DSC, 5 K min), which precipitates out by crystallization from aqueous solvents or by stirring the suspension of any form of AF in aqueous solvents, is between 13 and 43 at 25 ° C % relative humidity (RF) stable in the investigation period of 13 days.
- RF relative humidity
- Amorphous AF can be easily produced by storing the trihydrate over phosphorus pentoxide.
- the monohydrate of AF (melting point approx. 134 to 136 ° C. with decomposition; DSC, 5 K min "1 ) is achieved by continuously adding an aqueous solution of AF (with respect to anhydrous substance) to a 2-20-fold excess of methanol within 2-20 minutes, the solution is preferably concentrated to 10-30%, the excess of methanol is 2-10 times and the addition is preferably carried out within 10-20
- the quantity ratio water / methanol as well as the type of implementation play a decisive role for a quantitative and reproducible recovery AF monohydrate is stable at 25 ° C between 13 and 62% relative humidity in the investigation period of 9 days.
- the three solid shapes produced were characterized and identified using thermal analysis, X-ray diffractometry and vibration spectroscopy.
- the DSC method and X-ray diffractometry should be given preference, since it is the easiest way to recognize admixtures of other forms.
- the water is completely removed by storing the monohydrate over phosphorus pentoxide at 25 ° C. for several days. When subsequently stored at 13% relative humidity, the monohydrate forms again within 1 hour.
- the amorphous form is formed within less than 2 days.
- An anhydrous, crystalline form is not yet known. In particular, no direct conversion from trihydrate to monohydrate was observed. A conversion from monohydrate to trihydrate was only found at relative humidities from 75%. The behavior of monohydrate and trihydrate after complete water removal is interesting. After subsequent exposure to low relative humidity (13%), the dried monohydrate immediately absorbs water again with the formation of a monohydrate. In contrast, an amorphous phase can be found in the trihydrate after water removal, the sorption properties of which differ depending on the original trihydrate product.
- the present invention shows that trihydrate, monohydrate and amorphous form of amifostine can be obtained quantitatively and reproducibly.
- the reproducible AF crystal form according to the invention is distinguished by a particular stability compared to known compositions and does not require an additional stabilizer, such as e.g. Mannitol.
- the chemically and physically very stable monohydrate is advantageous over the trihydrate when amifostine is processed into sterile products for reconstitution.
- the latter must be stored under refrigerator conditions, since it is already converted into the amorphous form at temperatures above 35 ° C.
- the production of the trihydrate requires considerable validation effort in order to arrive at a reproducible product.
- Fig. 3 DSC curve of AF monohydrate (S1), perforated capsule, heating rate 5 K min "1 .
- Fig. 5 DSC curve of AF monohydrate (S1), high pressure capsule, heating rate 5 K min "1 .
- Fig. 6 DSC curves of AF trihydrate (E), comparison of different sample capsules,
- Fig. 8 TGA curves of monohydrate (S1) and trihydrate (recrystallized from 20% ethanol and inoculated with E), heating rate 5 K min "1 .
- M monohydrate (S1), a: amorphous form.
- Fig. 12 Water vapor sorption (mass change Wt based on dry matter) of the amorphous form, obtained from trihydrate E, between 13 and 84% RH at 25 ° C.
- Fig. 14 Water vapor desorption and sorption of the monohydrate (S1) (mass change Wf based on the hydrated substance) at 0 and 13% relative humidity (25 ° C).
- Fig. 15 Water vapor desorption (mass change Wf based on the hydrated substance) of the trihydrate (E and SN 40.1) and the monohydrate (S1) over phosphorus pentoxide (0% RH) at 25 ° C.
- Fig. 16 Water vapor desorption (mass change Wf based on the hydrated substance) of the trihydrate SN 40.1 at 25 ° C and relative humidity of 13 to 43%; for comparison also the desorption curve at 0% RH.
- Thermomicroscopy with Kofler heating table (Reichert, Vienna), mounted on an Olympus microscope BH-2 equipped with a video system or with a Kofler heating table microscope Thermovar® (Reichert, Vienna); both microscopes with polarization device.
- Siemens X-ray diffractometer D-5000 Diffrac / AT with ⁇ / ⁇ geniometer (Siemens AG, Düsseldorf, Germany), CuK ⁇ radiation (acceleration voltage 40 kV, tube current 40 mA), nickel filter for monochromatization, Göbel mirror, scintillation counter, angular range 2 ° to 40 ° (2 ⁇ ), step size 0.01 ° (2 ⁇ ), measuring time 2 s. Calibration of the d values (CuK ⁇ ⁇ ) with silicon NBS standard.
- Air-conditioned sample chamber consisting of low-temperature chamber, TTK (Anton Paar KG, A-Graz), in conjunction with the SYCOS-H humidification system (asynco, D-Karlsruhe). Determination of drying loss
- the sorption measurements were carried out at 25 ° C and 13, 31, 43, 62, 75 and 84% relative air humidity, the desorption measurements at 25 ° C and 0% and at 35 ° C and 13% relative humidity.
- the release or absorption of water by the test substance was determined gravimetrically depending on the time (from 2 hours to 16 days).
- special semi-micro hygrostats UJ Griesser and A. Burger, Int. J. Pharm. 120, 83-93 (1995)
- the sample weights for Ethyol® were approx. 40 to 50 mg and approx. 180 mg for amifostine trihydrate (SN 35.6 and SN 40.1) and were carried out to an accuracy of ⁇ 0.02 mg.
- the relative humidity (RF) in the thermostatted semi-micro hygrostats was adjusted with phosphorus pentoxide (RF 0%) and saturated Saline solutions of lithium chloride (RF 13%), calcium chloride (RF 31%) and potassium carbonate (RF 43%), ammonium nitrate (RF 62%), sodium chloride (RF 75%) and potassium chloride (RF 84%).
- RF relative humidity
- the moisture measurements were measured or checked with an air humidity measuring device Lufft GTL (G. Lufft Mess- und Regeltechnik GmbH, D-Stuttgart). This air humidity measuring device was calibrated with saturated solutions of lithium chloride and magnesium chloride.
- the thermostats of the hygrostats were thermostatted in an incubator thermostatted at 25 or 35 ° C, which is located in the cooling room thermostatted at 15 ° C. The temperature of these locations of the hygrostats was checked over time with a registering thermometer. It was constant at +0.5 K.
- Ethyol® (Ch. 98D16-17), AF trihydrate (SN 35.6 and SN 40.1), AF amorphous (SN 35.6 UK after drying tests) and Amifostin S1 (SN 35/3 UK) were added to the sample vessel of the semi-micro hygrostat weighed in and immediately afterwards placed in the conditioned hygrostat.
- the trihydrate can e.g. by suspending any mixture of trihydrate, monohydrate and amorphous form in water or methanol, and by recrystallization from ethanol / water (for example 20% v / v) or tert-butyl alcohol / water (for example 20% v / v), subsequent filtration using a water jet vacuum (approx. 10 mbar, approx. 10 min) and drying at room temperature.
- ethanol / water for example 20% v / v
- tert-butyl alcohol / water for example 20% v / v
- the use of seed crystals can be beneficial in this procedure.
- Precipitation with ethanol (96%) or with tert-butyl alcohol from an aqueous solution at room temperature is particularly useful.
- the appropriate precipitant should not be dropped too quickly into the aqueous solution up to a maximum content of 20%.
- a white precipitate forms.
- the monohydrate can be produced reproducibly in the following way: For example, 200 mg of trihydrate (for example SN 40.1, see Table 1) are dissolved in 0.5 ml of water by heating to 40 ° C. for about 1 minute. 4 ml of methanol are introduced into a 50 ml round bottom flask and stirred with a magnetic stirring at room temperature (about 300 U min "1). The aqueous solution is slowly added dropwise with a Pasteur pipette, forming a white precipitate. The suspension is min. 10 min stirred and then filtered with a microglass filter (G4) over a water jet vacuum, washed with 4 ml of ethanol (96%) and air-dried on a filter paper.
- a microglass filter G4
- the amorphous form (anhydrous) is obtained by storing the trihydrate over phosphorus pentoxide to constant weight, which is associated with approx. 20% mass loss. The time required for this depends on the production of the trihydrate and the temperature. The process takes a few hours at approx. 50 ° C, and one to a few days at 25 ° C.
- the trihydrate (E) obtained by lyophilization is in the form of white rods and small irregular platelets, as well as grains.
- the sample shows practically no interference colors in polarized light.
- the crystals are already removed approx. 50 ° C darker due to dehydration. From 70 ° C the crystals are much darker. The remaining crystals show no pronounced onset of melting, but flow into one another at approx. 110 ° C. The melting end is approx. 130 ° C.
- the sample melts with decomposition.
- Silgel a suitable silicone oil for thermomicroscopic examination
- the majority of the rods and stems also show low interference colors, only a few larger plates show higher interference colors.
- a change in the interference colors due to dehydration can be observed from 73 ° C.
- glass bubbles form at this temperature, which increases sharply above 80 ° C.
- the crystals flow between 138 and 155 ° C with decomposition.
- the white crystals of the monohydrate (S1) have a small-grained habit and melt (melt) when heated on a thermal microscope from 145 ° C with decomposition.
- DSC Differential calorimetry
- Fig. 1 shows the DSC curve of E (trihydrate produced by lyophilization).
- Fig. 2 shows the DSC curve of a trihydrate, which was produced by recrystallization from ethanol 20% (V / V).
- the melting point of the monohydrate (S1) determined by DSC is between 134 and 136 ° C (Fig. 3).
- the very broad melting peak of the monohydrate is in accordance with the thermomicroscopic examinations and can be attributed to the fragility of the sample. This is also the explanation for the fact that when the melting point is determined with the Kofler heating bench (determination of the instant melting point), as is customary with decomposable substances, a much higher value (160 to 161 ° C) is found. If the heating-up speed is reduced from 5 K / min to 0.5 K / min in the DSC examinations, the melting is already carried out at 120 ° C.
- Fig. 6 shows the DSC curves of E recorded using different DSC sample capsules.
- the melting point of the trihydrate (E) determined using a tightly closed aluminum sample capsule is 87 ° C.
- Fig. 7 presents an overview of the DSC curves of the 3 crystal forms of AF recorded with perforated aluminum sample capsules.
- the mass losses are between 16.6 and 19%.
- Fig. 8 shows the TGA curves of monohydrate and trihydrate recorded under the same conditions.
- the greater thermal load capacity of the monohydrate can be clearly seen, in which a significant loss of mass only begins at around 100 ° C, but in the case of the trihydrate at around 60 ° C.
- the FTIR spectra of E, S1 and the amorphous form of AF obtained using the KBr pressing technique show considerable differences and can therefore be used for identification (Fig. 9).
- the comparison of the 3 IR spectra shows particularly significant band shifts between 3300 and 3500 cm and between 1750 and 1300 cm.
- the 3 crystal forms of AF can also be characterized by means of FT Raman spectroscopy (Fig. 10).
- the areas 2800 to 3100 cm “1 , 1350 to 1500 cm “ 1 and 900 to 1100 cm “1 are particularly suitable for identification.
- the powder X-ray diffractograms (Fig. 11) of the two hydrates of amifostine show marked differences in the interplanar spacing and reflection intensities.
- the amorphous shape shows a corresponding absorption ridge.
- the powder X-ray diffractogram calculated using the atomic coordination published in the literature (Kraus, W. and Nolze, G., Powder Cell. (1, 8), computer program, Federal Institute for Materials Research and Testing, Berlin (1995)) of the trihydrate corresponds to the experimentally determined diffractogram of the trihydrate investigated.
- the X-ray diffractograms recorded as a function of the temperature show the presence of pure monohydrate at 100 ° C when small amounts of trihydrate (E and SN 40.1) are used. The monohydrate is no longer available quantitatively in the corresponding recordings of larger quantities (Tab. 3).
- Fig. 12 shows the percentage of water absorption of the amorphous form obtained from the trihydrate after drying, measured as a function of time and storage conditions, at 25 ° C at various relative air humidities (RF).
- Fig. 13 shows the sorption of S1 (monohydrate) at 25 ° C and different relative humidity.
- Fig. 14 shows the water vapor desorption and sorption of the monohydrate (S1) at 0 and 13% relative humidity. In contrast to trihydrate, dehydration lasts over 2 weeks. On the other hand, the re-formation of the monohydrate is complete after 1 hour at 13% relative humidity. However, the repeated storage of the monohydrate at 0% RH shows that it only takes about 1 week to dehydrate.
- Fig. 15 shows a comparison of the desorption behavior of the trihydrate (E and SN 40.1) and the monohydrate (S1) over phosphorus pentoxide (0% RH).
- the desorption of the trihydrate takes less than 2 days to form the amorphous form.
- the two trihydrate crystals E and SN 40.1 practically do not differ in the recorded dehydration process.
- the mass loss determined here is approximately 20% in each case.
- the calculated mass loss for a trihydrate is 20.13% (based on the water-containing substance) when the anhydrate is formed.
- the desorption of the monohydrate (theoretical mass loss 7.75%) is significantly slower and is only completed after 10 days.
- the mass loss measured is 7.5%.
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Abstract
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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DE2000143170 DE10043170C2 (de) | 2000-09-01 | 2000-09-01 | Amifostin-Monohydrat und Verfahren zu seiner Herstellung |
DE10043170 | 2000-09-01 | ||
PCT/EP2001/009902 WO2002018396A1 (fr) | 2000-09-01 | 2001-08-28 | Monohydrate d'amifostine et son procede de production |
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EP1313745A1 true EP1313745A1 (fr) | 2003-05-28 |
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EP01969659A Withdrawn EP1313745A1 (fr) | 2000-09-01 | 2001-08-28 | Monohydrate d'amifostine et son procede de production |
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EP (1) | EP1313745A1 (fr) |
AU (1) | AU2001289844A1 (fr) |
DE (1) | DE10043170C2 (fr) |
WO (1) | WO2002018396A1 (fr) |
Families Citing this family (6)
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EP1945604A1 (fr) * | 2005-11-03 | 2008-07-23 | Albermarle Corporation | Procede de fabrication d'halogenures de (omega-aminoalkylamino)alkyle et conversion en amifostine |
WO2007096901A1 (fr) * | 2006-02-24 | 2007-08-30 | Natco Pharma Limited | Nouvelle forme dihydrate d'amifostine et son procédé de préparation |
US8815833B2 (en) | 2006-11-09 | 2014-08-26 | Seidose, LLC | Stable amifostine liquid concentrate |
CN102286020A (zh) * | 2011-07-11 | 2011-12-21 | 大连美罗大药厂 | 一水合3-氨基丙基胺乙基硫代磷酸的制备方法 |
CN103509049B (zh) * | 2013-10-15 | 2016-05-25 | 美罗药业股份有限公司 | 一种制备药用氨磷汀的方法 |
EP3824880A1 (fr) * | 2019-11-25 | 2021-05-26 | Clevexel Pharma | Poudre lyophilisée contenant du 2-[(3-aminopropyl)amino]éthanethiol et son utilisation pour la préparation d'un thermogel |
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US3892824A (en) * | 1968-12-16 | 1975-07-01 | Southern Res Inst | S-{107 -({107 -aminoalkylamino)alkyl dihydrogen phosphorothioates |
DD289448A7 (de) * | 1982-07-29 | 1991-05-02 | Amt Fuer Atomsicherheit Und Strahlenschutz,De | Verfahren zur herstellung von s-[2-(3-amino-propylamino)ethyl]-dihydrogenthiophosphat |
DD289449A7 (de) * | 1983-07-29 | 1991-05-02 | Amt Fuer Atomsicherheit Und Strahlenschutz,De | Verfahren zur herstellung von s-[2-(3-amino-propylamino)ethyl]-dihydrogenthiophosphat |
US5424471A (en) * | 1992-07-31 | 1995-06-13 | U.S. Bioscience, Inc. | Crystalline amifostine compositions and methods of the preparation and use of same |
SG47101A1 (en) * | 1992-07-31 | 1998-03-20 | Us Bioscience | Crystalline amifostine compositions and methods for the preparation and use of same |
US6407278B2 (en) * | 1998-11-16 | 2002-06-18 | Medimmune Oncology, Inc. | Stable amorphous amifostine compositions and methods for the preparation and use of the same |
-
2000
- 2000-09-01 DE DE2000143170 patent/DE10043170C2/de not_active Expired - Fee Related
-
2001
- 2001-08-28 AU AU2001289844A patent/AU2001289844A1/en not_active Abandoned
- 2001-08-28 EP EP01969659A patent/EP1313745A1/fr not_active Withdrawn
- 2001-08-28 WO PCT/EP2001/009902 patent/WO2002018396A1/fr not_active Application Discontinuation
Non-Patent Citations (1)
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See references of WO0218396A1 * |
Also Published As
Publication number | Publication date |
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DE10043170C2 (de) | 2002-10-24 |
WO2002018396A1 (fr) | 2002-03-07 |
DE10043170A1 (de) | 2002-03-28 |
AU2001289844A1 (en) | 2002-03-13 |
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