WO2011099942A1 - New addition salts of raloxifene, process for the preparation thereof and use thereof in therapy - Google Patents
New addition salts of raloxifene, process for the preparation thereof and use thereof in therapy Download PDFInfo
- Publication number
- WO2011099942A1 WO2011099942A1 PCT/SI2010/000054 SI2010000054W WO2011099942A1 WO 2011099942 A1 WO2011099942 A1 WO 2011099942A1 SI 2010000054 W SI2010000054 W SI 2010000054W WO 2011099942 A1 WO2011099942 A1 WO 2011099942A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- raloxifene
- sulfamate
- preparation
- amorphous
- water
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D333/56—Radicals substituted by oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- raloxifene is [6-hydroxy-2-(4-hydroxy-phenyl)-benzothiophene-3-yl]-[4- [2-(l-piperidyl)ethoxy]phenyl]-methanone. It is a selective estrogen receptor modulator (SERM) and has an estrogen action on the bones and an anti-estrogen action on the uterus and the breast in women. It is as effective as tamoxifen for the prevention and treatment of breast cancer in postmenopausal women, yet in lower doses and with a lower risk of thromboembolism (V. Vogel, J. Constantino et al, JAMA, 295 (23), 2727-2741 and E. B. Connor et al, New England J. of Med., 355, 125-137, 2006).
- SERM selective estrogen receptor modulator
- raloxifene hydrochloride which is obtained according to the processes described in the patents EP 62503, US 5,629,425; in the patent application US 2007/0100147 Al and in the publications: J. Dominguez C. Leon, IUPAC.ORG/publications/cd/medicinal chemistry, Dec. 2006 and J. Med. Chem., 27, 1057-1066,(1986).
- Patent EP 0062504 discloses the use of raloxifene hydrochloride as a contraceptive agent.
- Patent EP 584 952 describes the use of acid addition salts of raloxifene such as hydrochloride, sulfate, lactate, succinate and malonate for the preparation of pharmaceutical formulations for inhibiting bone degradation and treating or preventing osteoporosis.
- Patent EP 910 369 describes raloxifene hydrochloride in crystal form with the crystals being smaller than 25 ⁇ , and patent EP 826 682 describes the amorphous form.
- Patent US 5,447,941 states a method for inhibiting pulmonary hypertensive diseases by the use of raloxifene and related benzothiophenes in the form of a broad palette of stated addition salts with organic and inorganic acids and bases. We have found that this is only a theoretical list of possible salts, which is not supported by experimental examples. Furthermore, many of these salts are not even theoretically possible, either due to steric hindrance in the molecules or due to too low ionic strength.
- Patent EP 0062504 discloses raloxifene hydrochloride and its use as an antiandrogen and antiestrogen agent. This patent has already expired.
- European patent EP 0839532 discloses a process for the prophylaxis of breast cancer and uses a similarly broad palette of raloxifene addition salts, which is not supported by experimental examples either.
- Patent EP 0670162 describes a pharmaceutical formulation containing raloxifene in the form of addition salts in combination with surfactants and a hydrophilic carrier.
- the use of only one salt, raloxifene hydrochloride, is supported by an example.
- Patent application US 20090069381 discloses deuterated raloxifene and the preparation thereof and also itemizes the possible salts of this compound, among others also sulfamate. Due to the different chemical formula and molecular weight, however, this compound cannot be deemed identical to raloxifene. In addition, none of the enumerated salts is supported by examples and the existence of these salts is not demonstrated by the statement of the synthesis and chemical properties nor is it not supported by chemical analyses and spectral data.
- Fig. 1 FTIR spectrum of amorphous raloxifene sulfamate
- the first object of the invention thus relates to raloxifene sulfamate in crystal and amorphous form and hydrates thereof, represented by the above general formula I.
- composition and structure of the compounds was demonstrated by elemental analysis, FTIR and ⁇ -NMR spectra.
- the melting points were determined according to Kofler method and corrected by the use of standards.
- the crystal structure was determined by means of X-ray powder diffraction on X'Pert
- FTIR spectra were recorded by Perkin Elmer 727B IR spectrometer.
- 1H-NMR spectra were recorded by Bruker Advance DPX NMR spectrometer at 300 MHz in tetradeutero methanol. Elemental analyses were performed on Perkin Elmer type 240 apparatus.
- Raloxifene sulfamate has, in comparison to raloxifene hydrochloride, a significantly improved solubility in water.
- Raloxifene salts are usually used orally, therefore the solubility in gastric juice, whose main constituent is diluted hydrochloric acid, is particularly important. Namely, due to the low pH value and the presence of chloride ions, the solubility of any salt used decreases close to the solubility level of raloxifene hydrochloride.
- raloxifene hydrochloride significantly decreases in the presence of chloride ions.
- solubility of raloxifene sulfamate is significantly better. This can be explained in that the present amino group from the sulfamate ion binds a portion of the chloride ions and thus their concentration in the solution decreases. In such a way the negative influence of chloride ions on solubility is reduced.
- raloxifene sulfamate has a surprisingly better solubility in diluted hydrochloric acid, which enables higher bioavailability in comparison with hitherto known addition salts of raloxifene.
- Raloxifene sulfamate in crystal or amorphous form or in any hydrate form is therefore very suitable for the preparation of pharmaceutical formulations for oral use.
- the second object of the present invention is a process for the preparation of raloxifene sulfamate in crystal and amorphous form and hydrates thereof of formula I:
- the obtained salt is isolated in solid form by crystallization, lyophilisation, drying, evaporation of the solvent or precipitation by means of another solvent; or
- a solution of any raloxifene salt is, by means of ion exchange, converted to sulfamate and isolated by concentration and crystallization.
- Raloxifene sulfamate can be prepared by the reaction of raloxifene base with sulfamic acid or from any other salt of raloxifene by means of ion exchange.
- Raloxifene sulfamate is very easily obtained directly by the reaction of 1 mol of raloxifene base with 1 mol of sulfamic acid in a suitable solvent, water, lower aliphatic alcohol having 1 to 4 carbon atoms, acetone, acetonitrile, dioxane, tetrahydrofuran, N-methylpyrrolidone, 1 ,3-dioxolane or a mixture of these solvents and water at a temperature of 30-80 °C, preferably 60-80 °C. After completed reaction and cooling, raloxifene sulfamate in a very pure form and in a high yield is obtained.
- Raloxifene sulfamate in amorphous form is obtained by suspending raloxifene base in a lower alcohol having 1 to 4 carbon atoms, acetone, acetonitrile, dioxane, methyl acetate, ethyl acetate, tetrahydrofuran, 1,3-dioxolane, dimethoxyethane or in a mixture of these solvents, which is followed by the addition of 1 mol of sulfamic acid dissolved in a small amount of water per 1 mol of raloxifene base.
- Another way of preparing raloxifene sulfamate comprises passing a solution of raloxifene hydrochloride or of any other raloxifene salt through a layer of an ion exchanger previously charged with ions of sulfamic acid, whereby an exchange of ions occurs so that raloxifene sulfamate is obtained quantitatively in the eluate.
- the solvent a mixture of a lower alcohol having 1 to 4 carbon atoms, acetone or acetonitrile with water is used.
- the eluate is concentrated by the evaporation of a portion of the solvent in a vacuum so that by further cooling raloxifene sulfamate in crystal form is precipitated. If necessary seeding with crystal nuclei can be done.
- a strong basic anion exchanger e.g. one with trimethyl- or triethylamine groups such as Dowex ® 1X2 or any other equivalent ion exchanger in the form of a granulate, semipermeable membrane, or in liquid form, preferably in the form of a granulate previously charged with sulfamic acid. It is only important to provide a good contact between the exchanger and the raloxifene salt solution.
- Raloxifene sulfamate obtained by ion exchange has the same properties as the sulfamate obtained by direct reaction of raloxifene base with sulfamic acid.
- Raloxifene base Chemical sfhifts for C atoms
- Raloxifene sulfamate obtained by direct neutralisation or by ion exchange can be used for the preparation of a pharmaceutical form for oral use such as tablets with an immediate or extended release of active substance, effervescent or dispersive tablets, coated tablets, capsules or other solid forms, by mixing it with conventional pharmaceutical excipients such as lactose, microcrystalline cellulose, mannitol, starch, silica, talc; with glidant additives at tabletting such as magnesium or calcium stearate and stearic acid, and with additives for a more rapid release such as croscarmellose and similar.
- a pharmaceutical form for oral use such as tablets with an immediate or extended release of active substance, effervescent or dispersive tablets, coated tablets, capsules or other solid forms, by mixing it with conventional pharmaceutical excipients such as lactose, microcrystalline cellulose, mannitol, starch, silica, talc; with glidant additives at tabletting such as magnesium or calcium
- the granulate for tabletting according to the invention can also be prepared by spraying a solution of raloxifene sulfamate in an appropriate solvent onto a mixture of excipients and fillers under simultaneous drying in a counterstream of warm air having a temperature between 30 °C and 50 °C.
- Tablets or capsules contain from 50 mg to 150 mg of raloxifene sulfamate.
- Raloxifene sulfamate of the present invention can also be used for the preparation of parenteral pharmaceutical forms such as injections or patches for topical use.
- This phenomenon is used in the preparation of granulate by means of the previously described method of spraying and drying and for the preparation of stable dry injections, particularly for intravenous use.
- An aqueous solution of an amorphous raloxifene sulfamate with the addition of mannitol is stabilized, sterile-filtered through a 0.22 ⁇ filter and subsequently an exactly defined amount is filled into ampoules, frozen and lyophilized. In such a way a preparation in the form of dry injections is obtained. Before the final use, the content of the ampoule is dissolved in pure water (for injections) and then injected.
- the solution is stable for more than 5 hours at room temperature.
- the transdermal system comprises a backing layer, which is impermeable for the active substance, a pressure-sensitive polymer layer serving as a reservoir for the active substance, a protective foil, which is perforated in several places to enable the penetrating of active substance therethrough, and a mechanical protective foil, which is removed immediately before use.
- the preparations are intended for preventing and treating osteoporosis, breast cancer in postmenopausal women and for the inhibition of bone degradation.
- a glass column having a diameter of 3.4 cm was loaded with Dowex ® 1X2, 100-200 mesh ion exchanger (70 mL). It was activated first by the passing through of a sodium hydroxide solution (5 %, 120 mL), washing with water to pH 6-7, charging by passing through of a sulfamic acid solution (4 % by weight, 150 mL), washing with water to pH 6 and then with ethanol (80 %, 70 mL).
- Raloxifene hydrochloride (2.0 g, 3.92 mmol) was dissolved in ethanol (80 %, 100 mL) and this solution was slowly passed through a column loaded with previously activated ion exchanger. Then the column was additionally washed with ethanol (80 %, 70 mL). The combined eluates were concentrated to about 20 mL by evaporation of the solvent in a vacuum at 50 °C. Gradually, water (16 mL) was added and it was left to crystallize overnight at 0 °C. The crystals were filtered off and dried in a vacuum.
- Elemental analysis corresponded to the formula C 28 H 30 N 2 O 7 S 2 -2H O.
- X-ray powder diffractogram only shows reflexes stronger than 10 rel. %: No. Position [2 ⁇ 9/°] Spacing [d/A] Relative intensity [%]
- Raloxifene base (2.0 g, 4.2 mmol) was suspended in acetonitrile (15 mL) and thereto sulfamic acid (0.41 g, 4.5 mmol) in water (1.5 mL) was added. It was stirred at 80 °C to clarify the soultion and then it was filtered through a fine filter (5 ⁇ ). The filtrate was rapidly poured into diethylether (220 mL) under vigorous stirring. The suspension was immediately filtered, the solid substance on the filter was thoroughly washed with diethyl ether and the cake was dried in a vacuum at 50 °C.
- the X-ray powder diffractogram did not show any reflexes - the substance was amorphous.
- Raloxifene base (2.0 g, 4.2 mmol) was suspended in ethanol (15 mL) and water (0.5 mL), thereto sulfamic acid (0.405 g, 4.2 mmol) was added and it was heated to 70-80 °C and stirred until everything dissolved. Then the solution was cooled to 30 °C, filtered through a fine filter (5 ⁇ ) and the filtrate was slowly added drop by drop into methyl tert-butyl ether (220 mL) under vigorous stirring. The suspension was filtered and the solid substance on the filter was thoroughly washed with methyl tert-butyl ether. Then it was dried in a vacuum at 50 °C. 2.34 g of a yellowish substance (98.07 %) with the melting point at 144-148 °C were obtained.
- the compound was well soluble in water: 10 g/ 100 mL of water; at longer standing or particularly at stirring recrystallization may occur.
- Amorphous raloxifene sulfamate (0.72 g) obtained in Example 3 was dissolved in water (7 mL) to give an entirely clear solution. The solution was stirred with a magnetic stirrer for 1 hour until it became opaque and started to crystallize, then it was left to stand overnight at 0 °C. The crystals were filtered, washed with ice water and dried in a vacuum at 50 °C. 0.67 g (93 %) of crystal raloxifene sulfamate with the melting point at 141-145 °C were obtained.
- Raloxifene base (20 g, 42 mmol) and sulfamic acid (4.1 g, 45 mmol) were dissolved under stirring at 60 °C in a mixture of 1 ,3-dioxolane (50 mL) and water (20 mL). Then water (totally 120 mL) was added gradually and under moderate stirring. It was left to stand first at room temperature for 6 hours and then at +5 °C overnight. The crystals were filtered off, thoroughly washed with cold water and dried at 70 °C in a vacuum. 18.9 g of yellow crystals (78.4 %) were obtained.
- Raloxifene base (2.0 g, 4.2 mmol) was suspended in ethanol (10 mL) and water (1 mL) and sulfamic acid (0.41 g, 4.5 mmol) was added thereto, it was heated to 70-80 °C and stirred until everything dissolved. Then, under stirring and stepweise cooling, water (totally 16 mL) was slowly (in 1 mL portions) added. The crystal suspension was left to stand overnight at 0 °C, then filtered and the crystals were washed with ice water and dried in a vacuum at 50 °C. 2.1 1 g of yellowish crystals (88.4 %) with the melting point at 138-142 °C were obtained.
- FTIR spectrum (cm -1 ): 3500, 3380, 2772, 2362, 1601, 1532, 1503, 1464, 1357, 1252, 1 173, 1050, 953, 903, 829, 620, 560.
- Raloxifene base (2.0 g, 4.2 mmol) was suspended in acetone (10 mL), a solution of sulfamic acid (0.41 g, 4.5 mmol) in water (1.5 mL) was added thereto and it was stirred at 65 °C until everything dissolved. Then water (15 mL) was added and it was concentrated to 15 mL in a vacuum. It was left to crystallize at 0 °C overnight, then the solid substance was filtered off and dried in a vacuum.
- Raloxifene base (2.0 g, 4.2 mmol) was suspended in acetonitrile (10 mL) and water (1 mL) and solid sulfamic acid (0.41 g, 4.5 mmol) was added thereto. It was stirred at 80 °C until everything dissolved. Then it was gradually cooled and water (totally 25 mL) was added in portions. It was crystallized at 0 °C overnight, then the crystal mass was filtered and dried in a vacuum. 2.10 g (83.2 %) of a salt with the melting point at 140- 143 °C, which was identical to the substance of Example 3, were obtained.
- Raloxifene base (2.0 g, 4.2 mmol) was suspended in isopropanol (17 mL) and water (3 mL). Sulfamic acid (0.41 g, 4.5 mmol) was added thereto and it was stirred at 80 °C until everything dissolved. Then water (totally 18 mL) was added gradually (in 1 mL portions) under cooling. It was left to crystallize at 0 °C overnight. Then the crystals were filtered off, washed with ice water and dried at 50 °C in a vacuum.
- FTIR (cm "1 ): 3495, 3354, 3016, 2957, 2889, 2770, 2703, 2602, 2363, 1900, 1601, 1531, 1501, 1464, 1358, 1250, 1174, 1123, 1047, 952, 905, 822, 772, 648, 619, 557, 525, 469.
- the DSC/DTG diagram represented in Fig. 7 demonstrates that the compound contained 3 molecules of water in 1 molecule of salt and was evidently a trihydrate.
- the X-ray powder diffractogram shows only reflexes stronger than 5 rel. %:
- XRD X-ray powder diffractogram
- the raloxifene salts - sulfamate as hemihydrate and dihydrate and comparatively hydrochloride - were incubated at 50 °C and 65 % relative humidity for 30 days.
- the content at the beginning and after 30 days was detennined by HPLC chromatography in the following system:
- raloxifene sulfamate The stability of raloxifene sulfamate is very good and comparable with the stability of hydrochloride, with hemihydrate being slightly better than dihydrate.
- test substance 200 mg was suspended in a water (200 mL) or hydrochloric acid (0.1 molar, 200 mL) and stirred at 18 °C for 6 hours. The insoluble portion was filtered off and the filtrate (100 mL) was frozen and then lyophilized in a weighed flask. The dry residue was precisely weighed and the solubility expressed in g/100 mL of water or hydrochloric acid was calculated.
- EXAMPLE 15 Preparation of granulate for tabletting - 20 000 tablets
- Raloxifene sulfamate (1000 g) and mannitol (1000 g) were dissolved in ethanol (40 %, 30 L), fine filtered, immediatly supplied to a dryer and sprayed onto a previously prepared mixture of fillers: lactose (2440 g) and microcrystalline cellulose (474 g).
- the velocity of the liquid supply was regulated so as to provide a constant uniform drying of the mixture.
- the solid mixture was dried by means of warm air to a 2-5 % humidity.
- croscarmellose sodium (40 g), silica (6.0 g) and magnesium stearate (40 g) were admixed in the final phase. Thereafter, this granulate was pressed into tablets having the weight of 250 mg and containing 50 mg of raloxifene sulfamate.
- Amorphous raloxifene sulfamate (2.0 g) and mannitol (2.5 g) were dissolved in water (40 mL, without Cl ⁇ ion! and sterile filtered through a fine filter (0.22 ⁇ ). Aliquot portions of the solution were sterile filled into ampoules, frozen and lyophilized. The obtained lyophilizate was easily soluble in water and the solution remained clear for at least 5 hours.
- Amorphous raloxifene sulfamate (1.0 g) and mannitol (1.0 g) were dissolved in water (20 mL), frozen and lyophilized.
- the dry substance i.e. raloxifene sulfamate in a stable and water-soluble form was dissolved in a mixture of dimethylsulfoxide (2 mL) and water (3 mL) and mixed with polyethylene glycol-400-monolaurate (0.3 g).
- the solution was added to a polymer solution (20 g, Monsanto, GELVA.RTM.737 ® ) and stirred for 30 minutes.
- a carrier polymer layer e.g. 3M.Scotchpack 1006 ®
- the application was twice repeated and dried with warm air each time.
- the dried layer was covered with a semiporous release foil.
- the foil was cut to appropriate size (e.g. 1 cm x 1 cm) and hermetically packed in patch envelopes.
- the resinuous sticky substance was then spread in a thickness of 0.35 mm on a siliconized polyethylene foil and the solvent was removed by drying at 55 °C.
- the adhesive film was then covered with a thin polyester foil of a thickness of 0.15 mm, which was perforated in defined places by a special tool, and then protected by an overlay foil.
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Physical Education & Sports Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention describes new raloxifene salts, namely raloxifene sulfamate in amorphous and crystal forms and hydrates thereof as well as processes for the preparation thereof. The compounds have a better solubility in water and in 0.1 molar hydrochloric acid than the hitherto used salt raloxifene hydrochloride, therefore they are very suitable for the preparation of pharmaceutical preparations for preventing and treating osteoporosis, bone degradation and breast cancer in postmenopausal women. The present invention also enables the preparation of a new pharmaceutical form suitable for exterior transdermal use. The present invention also relates to a process for improving the stability of amorphous raloxifene sulfamate by adding sugars, preferably mannitol, which also enables the manufacture of dry injections and solid forms of the preparations with increased stability.
Description
New Addition Salts of Raloxifene, Process for the Preparation Thereof
and Use Thereof in Therapy
Technical Field
The present invention belongs to the field of pharmaceutical chemistry and relates to new stable and well soluble addition salts of raloxifene - raloxifene sulfamate and its hydrates of the general formula I:
.HO3S-NH2 . x H2O wherein x means 0 to 3,
a process for the preparation thereof and the use thereof for the preparation of a pharmaceutical form for preventing and treating osteoporosis and breast cancer in postmenopausal women.
Technical Problem
The main problem of preparations containing raloxifene, particularly those with raloxifene hydrochloride, is a great hydrophobicity and extremely low solubility of the compounds in water and the consequent very low bioavailability (approx. 2 %). Therefore, in order to achieve a good therapeutical effect, it is necessary to use a high dose of the active compound, which is unfortunately connected with heavier side effects.
Thus, there exists a need for new addition salts with improved solubility, which would enable a better resorption and a higher bioavailability.
Prior Art
Chemically, raloxifene is [6-hydroxy-2-(4-hydroxy-phenyl)-benzothiophene-3-yl]-[4- [2-(l-piperidyl)ethoxy]phenyl]-methanone. It is a selective estrogen receptor modulator (SERM) and has an estrogen action on the bones and an anti-estrogen action on the uterus and the breast in women. It is as effective as tamoxifen for the prevention and treatment of breast cancer in postmenopausal women, yet in lower doses and with a lower risk of thromboembolism (V. Vogel, J. Constantino et al, JAMA, 295 (23), 2727-2741 and E. B. Connor et al, New England J. of Med., 355, 125-137, 2006).
The most common form of the active substance is raloxifene hydrochloride, which is obtained according to the processes described in the patents EP 62503, US 5,629,425; in the patent application US 2007/0100147 Al and in the publications: J. Dominguez C. Leon, IUPAC.ORG/publications/cd/medicinal chemistry, Dec. 2006 and J. Med. Chem., 27, 1057-1066,(1986).
Patent EP 0062504 discloses the use of raloxifene hydrochloride as a contraceptive agent.
International patent application WO 2004/029046 A2 also describes new raloxifene salts: L-lactate, DL-lactate, succinate and malonate and hydrates thereof. Yet these salts are not significantly better than raloxifene hydrochloride.
Patent EP 584 952 describes the use of acid addition salts of raloxifene such as hydrochloride, sulfate, lactate, succinate and malonate for the preparation of pharmaceutical formulations for inhibiting bone degradation and treating or preventing osteoporosis.
International patent application WO 09609045 describes raloxifene hydrochloride in crystal form and in the form of solvate.
Patent EP 910 369 describes raloxifene hydrochloride in crystal form with the crystals being smaller than 25 μπι, and patent EP 826 682 describes the amorphous form.
Patent US 5,447,941 states a method for inhibiting pulmonary hypertensive diseases by the use of raloxifene and related benzothiophenes in the form of a broad palette of stated addition salts with organic and inorganic acids and bases. We have found that this is only a theoretical list of possible salts, which is not supported by experimental examples. Furthermore, many of these salts are not even theoretically possible, either due to steric hindrance in the molecules or due to too low ionic strength.
Patent EP 0062504 discloses raloxifene hydrochloride and its use as an antiandrogen and antiestrogen agent. This patent has already expired.
European patent EP 0839532 discloses a process for the prophylaxis of breast cancer and uses a similarly broad palette of raloxifene addition salts, which is not supported by experimental examples either.
Patent EP 0670162 describes a pharmaceutical formulation containing raloxifene in the form of addition salts in combination with surfactants and a hydrophilic carrier. The use of only one salt, raloxifene hydrochloride, is supported by an example.
Patent application US 20090069381 discloses deuterated raloxifene and the preparation thereof and also itemizes the possible salts of this compound, among others also sulfamate. Due to the different chemical formula and molecular weight, however, this compound cannot be deemed identical to raloxifene. In addition, none of the enumerated salts is supported by examples and the existence of these salts is not demonstrated by the statement of the synthesis and chemical properties nor is it not supported by chemical analyses and spectral data.
Brief Description of the Figures
Fig. 1 FTIR spectrum of amorphous raloxifene sulfamate
Fig. 2 FTIR spectrum of raloxifene sulfamate hemihydrate
Fig. 3 FTIR spectrum of raloxifene sulfamate dihydrate
Fig. 4 XRD diffractogram of raloxifene sulfamate hemihydrate
Fig. 5 XRD diffractogram of raloxifene sulfamate dihydrate
Fig. 6 XRD diffractogram of amorphous raloxifene sulfamate
Fig. 7 DSC/DTG diagram of raloxifene sulfamate in the form of trihydrate
Fig. 8 XRD diffractogram of raloxifene sulfamate trihydrate
The Technical Solution
The problem of high hydrophobicity and poor solubility and of the consequent low bioavailability is solved by the introduction of a sulfamic acid ion into the raloxifene molecule. This significantly improves the solubility of the compound, and with the amorphous form a solubility of about 10 g/ 100 mL of water at 18 °C is reached, while the solubility of a common salt - raloxifene hydrochloride - is significantly less than 0.1 g/100 mL. Such an improved solubility represents an essential technical progress.
From the hitherto known patent and other literature it is evident that until now raloxifene sulfamate has not been synthesized and thus it represents a new compound.
The first object of the invention thus relates to raloxifene sulfamate in crystal and amorphous form and hydrates thereof, represented by the above general formula I.
The composition and structure of the compounds was demonstrated by elemental analysis, FTIR and Ή-NMR spectra.
The melting points were determined according to Kofler method and corrected by the use of standards.
The crystal structure was determined by means of X-ray powder diffraction on X'Pert
o
PRO X-ray diffractometer with alpha configuration, CuKa radiation, in a range 3-35 2 theta.
FTIR spectra were recorded by Perkin Elmer 727B IR spectrometer. 1H-NMR spectra were recorded by Bruker Advance DPX NMR spectrometer at 300 MHz in tetradeutero methanol.
Elemental analyses were performed on Perkin Elmer type 240 apparatus.
Raloxifene sulfamate has, in comparison to raloxifene hydrochloride, a significantly improved solubility in water.
The solubility of raloxifene salts in water at 18 °C, expressed in g of salt dissolved in
100 mL of water:
raloxifene sulfamate, dihydrate
raloxifene sulfamate, trihydrate
raloxifene sulfamate, amorphous
raloxifene hydrochloride
Raloxifene salts are usually used orally, therefore the solubility in gastric juice, whose main constituent is diluted hydrochloric acid, is particularly important. Namely, due to the low pH value and the presence of chloride ions, the solubility of any salt used decreases close to the solubility level of raloxifene hydrochloride.
Solubility of raloxifene salts in 0.1 mol/L HC1 at 18 °C (g/100 mL):
raloxifene sulfamate, dihydrate 0.03
raloxifene sulfamate, trihydrate 0.03
raloxifene sulfamate, amorphous 0.04
raloxifene hydrochloride 0.009
The method of solubility determination is separately described in Example 14.
The solubility of raloxifene hydrochloride significantly decreases in the presence of chloride ions. Surprisingly, the solubility of raloxifene sulfamate is significantly better. This can be explained in that the present amino group from the sulfamate ion binds a portion of the chloride ions and thus their concentration in the solution decreases. In such a way the negative influence of chloride ions on solubility is reduced.
According to the invention, raloxifene sulfamate has a surprisingly better solubility in diluted hydrochloric acid, which enables higher bioavailability in comparison with hitherto known addition salts of raloxifene.
Raloxifene sulfamate in crystal or amorphous form or in any hydrate form is therefore very suitable for the preparation of pharmaceutical formulations for oral use.
The second object of the present invention is a process for the preparation of raloxifene sulfamate in crystal and amorphous form and hydrates thereof of formula I:
.HO3S-NH2 . X H2O wherein x means 0 to 3,
wherein,
a) a solution of raloxifene base of formula II:
b) a solution of any raloxifene salt is, by means of ion exchange, converted to sulfamate and isolated by concentration and crystallization.
Raloxifene sulfamate can be prepared by the reaction of raloxifene base with sulfamic acid or from any other salt of raloxifene by means of ion exchange.
Raloxifene sulfamate is very easily obtained directly by the reaction of 1 mol of raloxifene base with 1 mol of sulfamic acid in a suitable solvent, water, lower aliphatic alcohol having 1 to 4 carbon atoms, acetone, acetonitrile, dioxane, tetrahydrofuran, N-methylpyrrolidone, 1 ,3-dioxolane or a mixture of these solvents and water at a temperature of 30-80 °C, preferably 60-80 °C. After completed reaction and cooling, raloxifene sulfamate in a very pure form and in a high yield is obtained.
By crystallization from water-containing media also hydrates containing up to 3 molecules of water can be obtained.
Raloxifene sulfamate in amorphous form is obtained by suspending raloxifene base in a lower alcohol having 1 to 4 carbon atoms, acetone, acetonitrile, dioxane, methyl acetate, ethyl acetate, tetrahydrofuran, 1,3-dioxolane, dimethoxyethane or in a mixture of these solvents, which is followed by the addition of 1 mol of sulfamic acid dissolved in a small amount of water per 1 mol of raloxifene base. It is stirred until the reaction is completed, filtered and then, by pouring it into an aliphatic ether such as diethyl ether, methyl tert-butyl ether, diisopropyl ether or cyclohexane, an amorphous salt is precipitated.
In order to accelerate crystallization or to carry out precipitation, another solvent such as water, 1,2-dimethoxyethane, cyclohexane, or aliphatic ethers such as diethyl ether, diisopropyl ether and methyl tert-butyl ether, in which sulfamic salt of formula I is less soluble, is added.
Another way of preparing raloxifene sulfamate comprises passing a solution of raloxifene hydrochloride or of any other raloxifene salt through a layer of an ion
exchanger previously charged with ions of sulfamic acid, whereby an exchange of ions occurs so that raloxifene sulfamate is obtained quantitatively in the eluate. As the solvent a mixture of a lower alcohol having 1 to 4 carbon atoms, acetone or acetonitrile with water is used. After leaving the column, the eluate is concentrated by the evaporation of a portion of the solvent in a vacuum so that by further cooling raloxifene sulfamate in crystal form is precipitated. If necessary seeding with crystal nuclei can be done.
For the ion exchange a strong basic anion exchanger is used, e.g. one with trimethyl- or triethylamine groups such as Dowex® 1X2 or any other equivalent ion exchanger in the form of a granulate, semipermeable membrane, or in liquid form, preferably in the form of a granulate previously charged with sulfamic acid. It is only important to provide a good contact between the exchanger and the raloxifene salt solution.
Raloxifene sulfamate obtained by ion exchange has the same properties as the sulfamate obtained by direct reaction of raloxifene base with sulfamic acid.
Research by the use of nuclear magnetic resonance, both H-NMR and ,JC-NMR, demonstrates that the salt was formed on piperidine nitrogen and not by substitution on phenolic groups.
1 H-NMR spectrum recorded in DMSO on Bruker apparatus demonstrates the presence of the two intact phenolic OH groups as a broad singlet at 9.79 ppm. In the comparative spectrum of raloxifene hydrochloride these are two singlets at 9.893 ppm and 9.867 ppm and, in addition, also the proton on piperidine nitrogen at 10.685 ppm is visible, which reveals the ionic nature of the salt in the case of raloxifene hydrochloride. This proton is not visible at raloxifene sulfamate since it is an addition salt.
C-NMR spectrum of raloxifene sulfamate in comparison with raloxifene hydrochloride and raloxifen base unambiguously shows an interaction with piperidine nitrogen but not on phenolic OH groups.
Table of chemical shifts (in ppm) in C-NMR spectra:
Raloxifene base: Chemical sfhifts for C atoms
*
Raloxifene hydrochloride:
Raloxifene sulfamate:
Raloxifene sulfamate obtained by direct neutralisation or by ion exchange can be used for the preparation of a pharmaceutical form for oral use such as tablets with an immediate or extended release of active substance, effervescent or dispersive tablets, coated tablets, capsules or other solid forms, by mixing it with conventional pharmaceutical excipients such as lactose, microcrystalline cellulose, mannitol, starch, silica, talc; with glidant additives at tabletting such as magnesium or calcium stearate and stearic acid, and with additives for a more rapid release such as croscarmellose and similar.
The granulate for tabletting according to the invention can also be prepared by spraying a solution of raloxifene sulfamate in an appropriate solvent onto a mixture of excipients and fillers under simultaneous drying in a counterstream of warm air having a temperature between 30 °C and 50 °C.
Tablets or capsules contain from 50 mg to 150 mg of raloxifene sulfamate.
Raloxifene sulfamate of the present invention can also be used for the preparation of parenteral pharmaceutical forms such as injections or patches for topical use.
We have also noted that the addition of mannitol to the solution of an amorphous raloxifene sulfamate surprisingly strongly increases the stability of this solution. For example, a 2 % solution of an amorphous raloxifene sulfamate becomes opaque at standing at 20 °C already after 30 minutes due to progressive recrystallization, whereas the same solution with the addition of 2.5 % of mannitol remains clear after this time.
In a similar, but a little less pronounced manner also other sugars act, such as glucose, lactose, sorbitol, trehalose, sucrose, fructose, mannose, maltose as well as glycerol and erythritol.
This phenomenon is used in the preparation of granulate by means of the previously described method of spraying and drying and for the preparation of stable dry injections, particularly for intravenous use.
An aqueous solution of an amorphous raloxifene sulfamate with the addition of mannitol is stabilized, sterile-filtered through a 0.22 μιη filter and subsequently an exactly defined amount is filled into ampoules, frozen and lyophilized. In such a way a preparation in the form of dry injections is obtained. Before the final use, the content of the ampoule is dissolved in pure water (for injections) and then injected.
The solution is stable for more than 5 hours at room temperature.
Due to the hydrophobicity of the active substance, the manufacture of preparations in the form of patches for topical, transdermal use is reasonable as well. This enables the action over a prolonged period of time and, due to the minor loading of organism, also fewer side effects.
The transdermal system comprises a backing layer, which is impermeable for the active substance, a pressure-sensitive polymer layer serving as a reservoir for the active substance, a protective foil, which is perforated in several places to enable the penetrating of active substance therethrough, and a mechanical protective foil, which is removed immediately before use.
The preparations are intended for preventing and treating osteoporosis, breast cancer in postmenopausal women and for the inhibition of bone degradation.
The invention is illustrated, but not limited, by the following Examples intended for the explanation of the processes.
EXAMPLE 1. Raloxifene sulfamate a) Preparation of the column with an ion exchanger
A glass column having a diameter of 3.4 cm was loaded with Dowex® 1X2, 100-200 mesh ion exchanger (70 mL). It was activated first by the passing through of a sodium hydroxide solution (5 %, 120 mL), washing with water to pH 6-7, charging by passing through of a sulfamic acid solution (4 % by weight, 150 mL), washing with water to pH 6 and then with ethanol (80 %, 70 mL). b) Ion exchange
Raloxifene hydrochloride (2.0 g, 3.92 mmol) was dissolved in ethanol (80 %, 100 mL) and this solution was slowly passed through a column loaded with previously activated ion exchanger. Then the column was additionally washed with ethanol (80 %, 70 mL). The combined eluates were concentrated to about 20 mL by evaporation of the solvent in a vacuum at 50 °C. Gradually, water (16 mL) was added and it was left to crystallize overnight at 0 °C. The crystals were filtered off and dried in a vacuum.
2.08 g (87.1 %) of yellow crystals having the melting point at 140-142 °C (corrected) were obtained.
Elemental analysis corresponded to the formula C28H30N2O7S2-2H O.
1H-NMR spectrum recorded in DMSO (ppm): 1.5 (s, broad, 2H); 1.7 (t, J = 5.04 Hz, 2H); 2.5 (t, J = 4.63 Hz, CH2); 3.1 (s, broad, 4H); 3.35 (t, J = 4.63 Hz, 2H); 3.5^.5 (s, broad, 3H, sulfamic acid); 4.35 (t, J = 4.65 Hz, 2H); 6.7 (d, J = 8.64 Hz, CH2); 6.87 (dd, J, - 8.75 Hz, J2 = 2.21 Hz, CH); 6.97 (d, J = 8.91 Hz, CH2); 7.18 (d, J - 8.64 Hz, CH2); 7.26 (d, J = 8.75 Hz, CH); 7.35 (d, J - 2.14 Hz, CH); 7.7 (d, J = 8.85 Hz, CH2; 9.8 (s, 2 x OH).
X-ray powder diffractogram only shows reflexes stronger than 10 rel. %:
No. Position [2 <9/°] Spacing [d/A] Relative intensity [%]
1 8.2216 10.74556 13.73
2 12.1265 7.29268 14.98
7 17.8051 4.96512 55.11
9 19.0463 4.65590 13.80
10 19.6850 4.50623 12.99
11 20.4394 4.34159 100.00
15 23.2557 3.82181 10.21
16 23.4651 3.78816 13.75
18 24.4429 3.63880 12.11
19 24.6732 3.60536 16.62
20 25.1821 3.53363 12.04
30 31.0829 2.87494 15.41
EXAMPLE 2. Amorphous raloxifene sulfamate
Raloxifene base (2.0 g, 4.2 mmol) was suspended in acetonitrile (15 mL) and thereto sulfamic acid (0.41 g, 4.5 mmol) in water (1.5 mL) was added. It was stirred at 80 °C to clarify the soultion and then it was filtered through a fine filter (5 μπι). The filtrate was rapidly poured into diethylether (220 mL) under vigorous stirring. The suspension was immediately filtered, the solid substance on the filter was thoroughly washed with diethyl ether and the cake was dried in a vacuum at 50 °C. 2.30 g of a yellow amorphous substance (96.4 %) with the melting point at 144-149 °C (corrected) were obtained. The compound is very easily soluble in water (approx. 10 %), but at standing and particularly at stirring with a magnetic stirrer recrystallization occurred. The elemental analysis corresponded to the composition C28H3oN2O7S2.
The X-ray powder diffractogram did not show any reflexes - the substance was amorphous.
EXAMPLE 3. Amorphous raloxifene sulfamate
Raloxifene base (2.0 g, 4.2 mmol) was suspended in ethanol (15 mL) and water (0.5 mL), thereto sulfamic acid (0.405 g, 4.2 mmol) was added and it was heated to 70-80
°C and stirred until everything dissolved. Then the solution was cooled to 30 °C, filtered through a fine filter (5 μηι) and the filtrate was slowly added drop by drop into methyl tert-butyl ether (220 mL) under vigorous stirring. The suspension was filtered and the solid substance on the filter was thoroughly washed with methyl tert-butyl ether. Then it was dried in a vacuum at 50 °C. 2.34 g of a yellowish substance (98.07 %) with the melting point at 144-148 °C were obtained.
The compound was well soluble in water: 10 g/ 100 mL of water; at longer standing or particularly at stirring recrystallization may occur.
Elemental analysis for C28H30N2O7S2:
Calculated: C: 58.93 % H: 5.30 % N: 4.91 %
Found: C: 58.92 % H: 5.78 % N: 4.60 %
FTIR (cm-1): 2953, 1599, 1539, 1503, 1469, 1423, 1360, 1252, 1170, 1045, 908, 839, 807.
XRD diffractogram: no reflexes, amorphous substance. EXAMPLE 4. Raloxifene sulfamate— crystals from water
Amorphous raloxifene sulfamate (0.72 g) obtained in Example 3 was dissolved in water (7 mL) to give an entirely clear solution. The solution was stirred with a magnetic stirrer for 1 hour until it became opaque and started to crystallize, then it was left to stand overnight at 0 °C. The crystals were filtered, washed with ice water and dried in a vacuum at 50 °C. 0.67 g (93 %) of crystal raloxifene sulfamate with the melting point at 141-145 °C were obtained.
An analysis of the composition as well as FTIR, XRD and NMR spectra confirmed the formula C28H3oN2O7S2-2H2O.
EXAMPLE 5. Raloxifene sulfamate - crystallization from N-methylpyrrolidone
Raloxifene base (2.0 g, 4.2 mmol) and sulfamic acid (0.41 g, 4.5 mmol) were dissolved under stirring at 60 °C in a mixture of N-methylpyrrolidone (5 mL) and
water (3 mL). Then water (totally 30 mL) was added gradually and under moderate stirring. It was left to stand first at room temperature for 4 hours and then at +5 °C overnight. The crystals were filtered off, thoroughly washed with cold water and dried at 70 °C in a vacuum. 1.81 g of yellow crystals (75.1 %) were obtained.
EXAMPLE 6. Raloxifene sulfamate— crystallization from tetrahydrof ran
Raloxifene base (2.0 g, 4.2 mmol) and sulfamic acid (0.41 g, 4.5 mmol) were dissolved under stirring at 60 °C in a mixture of tetrahydrofuran (7 mL) and water (2 mL). Then water (totally 23 mL) was added gradually and under moderate stirring. It was left to stand first at room temperature for 4 hours and then at +5 °C overnight. The crystals were filtered off, thoroughly washed with cold water and dried at 70 °C in a vacuum. 1.92 g of yellow crystals (79.7 %) were obtained.
EXAMPLE 7. Raloxifene sulfamate - crystallization from 1 ,3-dioxolane
Raloxifene base (20 g, 42 mmol) and sulfamic acid (4.1 g, 45 mmol) were dissolved under stirring at 60 °C in a mixture of 1 ,3-dioxolane (50 mL) and water (20 mL). Then water (totally 120 mL) was added gradually and under moderate stirring. It was left to stand first at room temperature for 6 hours and then at +5 °C overnight. The crystals were filtered off, thoroughly washed with cold water and dried at 70 °C in a vacuum. 18.9 g of yellow crystals (78.4 %) were obtained.
EXAMPLE 8. Raloxifene sulfamate dihydrate
Raloxifene base (2.0 g, 4.2 mmol) was suspended in ethanol (10 mL) and water (1 mL) and sulfamic acid (0.41 g, 4.5 mmol) was added thereto, it was heated to 70-80 °C and stirred until everything dissolved. Then, under stirring and stepweise cooling, water (totally 16 mL) was slowly (in 1 mL portions) added. The crystal suspension was left to stand overnight at 0 °C, then filtered and the crystals were washed with ice
water and dried in a vacuum at 50 °C. 2.1 1 g of yellowish crystals (88.4 %) with the melting point at 138-142 °C were obtained.
Elemental analysis for C28H30N2O7S2-2H2O:
Calculated: C: 55.43 % H: 5.39 % N: 4.62 %
Found: C: 55.46 % H: 5.68 % N: 4.52 %
FTIR spectrum (cm-1): 3500, 3380, 2772, 2362, 1601, 1532, 1503, 1464, 1357, 1252, 1 173, 1050, 953, 903, 829, 620, 560.
1 H-NMR spectrum: 1.65 (s, broad), 1.85 (t, J = 5.2 Hz), 3.3 (p, J = 1.6 Hz), 3.52 (t, J = 4.9 Hz), 4.36 (t, J = 4.75 Hz), 6.61 (dt, J = 4.7 Hz, J2 = 2.87 Hz), 6.85 (d, J = 2,27 Hz), 6.9 (d, J = 9.07 Hz), 7.16 (dt, Jx = 8.68 Hz, J2 = 2.83 Hz), 7.28 (d, J = 2.1 1 Hz), 7.42 (d, J = 8.78 Hz), 7.71 (dt, J = 8.91Hz).
XRD diffractogram:
No. Position [2 >/°] Spa .ting [d/A] Relative intensity [%]
1 8.2819 10 .66747 13.21
2 12.1877 7 .25623 13.87
4 13.3750 5 .73606 10.63
7 17.9145 4 .94740 54.91
9 19.1015 4 .64256 19.14
10 19.7490 4 .49178 19.24
1 1 20.5060 4 .32764 100.00
14 22.6202 3 .92771 12.09
15 23.3294 3 .80989 13.60
16 23.5078 3 .78138 10.33
18 24.51 12 3 .62880 15.48
19 24.7390 3 .59590 13.92
20 25.2472 3 .52466 14.10
23 26.5239 3 .35784 10.09
25 27.851 1 3 .20076 13.12
27 28.8281 3 .09448 10.68
28 29.8260 2 .99317 13.23
30 31.1460 2 .86927 18.90
32 32.2302 2 .77518 10.86
35 35.5084 2 .52612 12.93
EXAMPLE 9. Raloxifene sulfamate dihydrate
Raloxifene base (2.0 g, 4.2 mmol) was suspended in acetone (10 mL), a solution of sulfamic acid (0.41 g, 4.5 mmol) in water (1.5 mL) was added thereto and it was stirred at 65 °C until everything dissolved. Then water (15 mL) was added and it was concentrated to 15 mL in a vacuum. It was left to crystallize at 0 °C overnight, then the solid substance was filtered off and dried in a vacuum.
1.65 g (65.4 %) of raloxifene sulfamate dihydrate of the formula C28H30N2O7S2-2H2O with the melting point at 141-143 °C (corrected) were obtained. The XRD diffractogram corresponded to the crystal structure stated in Example 1.
EXAMPLE 10. Raloxifene sulfamate dihydrate
Raloxifene base (2.0 g, 4.2 mmol) was suspended in acetonitrile (10 mL) and water (1 mL) and solid sulfamic acid (0.41 g, 4.5 mmol) was added thereto. It was stirred at 80 °C until everything dissolved. Then it was gradually cooled and water (totally 25 mL) was added in portions. It was crystallized at 0 °C overnight, then the crystal mass was filtered and dried in a vacuum. 2.10 g (83.2 %) of a salt with the melting point at 140- 143 °C, which was identical to the substance of Example 3, were obtained.
EXAMPLE 11. Raloxifene sulfamate hemihydrate
Raloxifene base (2.0 g, 4.2 mmol) was suspended in isopropanol (17 mL) and water (3 mL). Sulfamic acid (0.41 g, 4.5 mmol) was added thereto and it was stirred at 80 °C until everything dissolved. Then water (totally 18 mL) was added gradually (in 1 mL portions) under cooling. It was left to crystallize at 0 °C overnight. Then the crystals were filtered off, washed with ice water and dried at 50 °C in a vacuum.
1.85 g (77.5 %) of raloxifene sulfamate hemihydrate with the melting point at 144- 148 °C were obtained.
Elemental analysis for C28H30N2O7S2 0.5H2O:
Calculated: C: 58.01 % H: 5.39 % N: 4.83 %
Found: C: 57.94 % H: 5.72 % N: 4.76 %
FTIR (cm"1): 3495, 3354, 3016, 2957, 2889, 2770, 2703, 2602, 2363, 1900, 1601, 1531, 1501, 1464, 1358, 1250, 1174, 1123, 1047, 952, 905, 822, 772, 648, 619, 557, 525, 469.
XRD diffractogram:
No. Position [26>/°] Spacing [d/A] Relative intensity [%]
2 8.2714 10.68090 27.54
4 12.1449 7.28167 13.66
5 13.3750 6.61462 13.26
6 15.4069 5.74654 11.28
9 17.9096 4.94876 58.48
13 20.4605 4.33716 100
14 21.4783 4.13387 15.04
16 22.6094 3.92956 24.29
17 23.2979 3.81498 25.80
18 24.4824 3.63301 12.63
19 24.7140 3.59949 35.08
20 25.2247 3.52777 43.33
22 26.4808 3.36321 17.30
27 29.8173 2.99402 10.59
29 31.1186 2.87172 11.59
Example 12. Raloxifene sulfamate trihydrate
Crude raloxifene sulfamate (15.82 g) was dissolved in ethanol (90 %, 50 mL) at 60- 70 °C under moderate stirring and water (20 mL) was additionally added to the solution. Then active charcoal (2 g) was added and it was stirred for 15 minutes. A still warm solution was filtered through a filter prepared with a layer of Celite, and the filter layer was washed with ethanol (90 %, 10 mL) and water (20 mL). All these solutions were combined and water (106 mL) was added thereto. It was crystallized for 4 hours at room temperature and then at +5 °C overnight. The crystal mass was
filtered and dried at 40 °C in a vacuum to a constant weight. 14.14 g of yellow crystals with the melting point at 152-156 °C were obtained.
Elemental analysis corresponds to C28H30N2O7S2-3H2O:
Calculated: C: 53.83 % H: 5.81 % N: 4.48 %
Found: C: 53.97 % H: 5.73 % N: 4.44 %
The DSC/DTG diagram represented in Fig. 7 demonstrates that the compound contained 3 molecules of water in 1 molecule of salt and was evidently a trihydrate.
The X-ray powder diffractogram shows only reflexes stronger than 5 rel. %:
No. Position [26>/°] Spacing [d/A] Relative intensity
1 8.2179 10.75041 12.10
2 12.1212 7.29584 14.65
3 13.3407 6.63153 5.11
4 15.3668 5.76142 6.75
5 17.5438 5.05111 6.10
6 17.8463 4.96616 38.88
7 18.1531 4.88291 10.45
8 19.6789 4.50763 12.11
9 20.4282 4.34394 100.00
10 21.8575 4.06301 5.99
11 22.5598 3.93809 5.89
12 23.2544 3.82201 7.90
13 24.4290 3.64083 8.83
14 24.6722 3.60549 12.17
15 25.1851 3.53321 12.73
16 26.4507 3.36696 6.01
17 27.0692 3.29142 6.79
18 27.7624 3.21079 5.50
19 27.9747 3.18690 6.87
20 28.7728 3.10029 5.69
21 29.7620 2.99946 9.49
22 31.0789 2.87531 15.11
The X-ray powder diffractogram (XRD) is represented in Fig. 8.
EXAMPLE 13. Determination of stability
The raloxifene salts - sulfamate as hemihydrate and dihydrate and comparatively hydrochloride - were incubated at 50 °C and 65 % relative humidity for 30 days. The content at the beginning and after 30 days was detennined by HPLC chromatography in the following system:
Column: Kromasil 100 5 μ, C18, 250 * 4.6 mm (or equivalent column); mobile phase A: buffer pH 2/acetonitrile = 80/20; mobile phase B: buffer pH 2/acetonitrile = 10/90; buffer composition: 0.92 g sodium heptanesulfonate/1 mL triethylamine in 1000 mL of water, and pH = 2 adjusted with HClO4; gradient: from 83 % phase A to 20 % phase A in 30 min, flow: 1 rnL/min, detection: UV at 210 nm.
Decrease of salt content at incubation: beginning: after 30 days:
Raloxifene sulfamate hemihydrate 99.2 % 98.9 %
Raloxifene sulfamate dihydrate 98.5 % 97.3 %
Raloxifene hydrochloride 99.0 % 98.7 %
The stability of raloxifene sulfamate is very good and comparable with the stability of hydrochloride, with hemihydrate being slightly better than dihydrate.
EXAMPLE 14. Determination of solubility of raloxifene sulfamate
The test substance (200 mg) was suspended in a water (200 mL) or hydrochloric acid (0.1 molar, 200 mL) and stirred at 18 °C for 6 hours. The insoluble portion was filtered off and the filtrate (100 mL) was frozen and then lyophilized in a weighed flask. The dry residue was precisely weighed and the solubility expressed in g/100 mL of water or hydrochloric acid was calculated.
EXAMPLE 15. Preparation of granulate for tabletting - 20 000 tablets
Raloxifene sulfamate (1000 g) and mannitol (1000 g) were dissolved in ethanol (40 %, 30 L), fine filtered, immediatly supplied to a dryer and sprayed onto a previously prepared mixture of fillers: lactose (2440 g) and microcrystalline cellulose (474 g). Under vigorous stirring by means of warm air (50 °C), the velocity of the liquid supply was regulated so as to provide a constant uniform drying of the mixture. After the completion of the solution supply, the solid mixture was dried by means of warm air to a 2-5 % humidity. To the granulate thus obtained, croscarmellose sodium (40 g), silica (6.0 g) and magnesium stearate (40 g) were admixed in the final phase. Thereafter, this granulate was pressed into tablets having the weight of 250 mg and containing 50 mg of raloxifene sulfamate.
EXAMPLE 16. Tablets
Ingredient: mg:
Raloxifene sulfamate 60.00
Lactose monohydrate 162.00
Cellulose Avicel 120 23.70
Croscarmellose - sodium salt 2.00
Colloidal silica 0.30
Magnesium stearate 2.00
250.00
EXAMPLE 17. Dry injections with amorphous raloxifene sulfamate
Amorphous raloxifene sulfamate (2.0 g) and mannitol (2.5 g) were dissolved in water (40 mL, without Cl~ ion!) and sterile filtered through a fine filter (0.22 μιη). Aliquot portions of the solution were sterile filled into ampoules, frozen and lyophilized. The
obtained lyophilizate was easily soluble in water and the solution remained clear for at least 5 hours.
EXAMPLE 18. Patch for transdermal use
Amorphous raloxifene sulfamate (1.0 g) and mannitol (1.0 g) were dissolved in water (20 mL), frozen and lyophilized. The dry substance i.e. raloxifene sulfamate in a stable and water-soluble form was dissolved in a mixture of dimethylsulfoxide (2 mL) and water (3 mL) and mixed with polyethylene glycol-400-monolaurate (0.3 g). The solution was added to a polymer solution (20 g, Monsanto, GELVA.RTM.737®) and stirred for 30 minutes. It was left for 30 minutes to settle down in order to eliminate air bubbles and then the solution was applied in a thin layer onto a carrier polymer layer (e.g. 3M.Scotchpack 1006®) and dried at 45-50 °C. The application was twice repeated and dried with warm air each time. The dried layer was covered with a semiporous release foil. The foil was cut to appropriate size (e.g. 1 cm x 1 cm) and hermetically packed in patch envelopes.
EXAMPLE 19. Preparation of a patch for transdermal use
In a solvent consisting of isopropanol (5 g), ethanol (5 g), butanone (2.5 g) and 1- dodecanole (7 g), amorphous raloxifene sulfamate (2.5 g) was dissolved.
Separately, crosslinked acrylate polymer (66 g) consisting of 2-ethyl-hexylacrylate, vinyl acetate and acrylic acid in a solvent mixture ethyl acetate/n- hexane/isopropanol/acetyl acetone/toluene = 40/25/25/1/4 (parts by volume) was prepared and this solution was added to the previously prepared solution of raloxifene sulfamate under vigorous stirring. It was thoroughly stirred, aluminium acetylacetonate (0.7 g) was added and it was stirred at 20 °C for another 4 hours to polymerize the mixture. The resinuous sticky substance was then spread in a thickness of 0.35 mm on a siliconized polyethylene foil and the solvent was removed by drying at 55 °C. The adhesive film was then covered with a thin polyester foil of a thickness
of 0.15 mm, which was perforated in defined places by a special tool, and then protected by an overlay foil.
Claims
1. Raloxifene sulfamate of general formula I:
.HO3S-NH2 . X H2O wherein x means 0 to 3.
2. Raloxifene sulfamate according to claim 1 in amorphous form.
3. Raloxifene sulfamate according to claim 1 in crystal form
4. Raloxifene sulfamate dihydrate according to claim 1 in crystal form with the following X-ray powder diffractogram (XRD):
No. Position [2 <9/°] Spacing [d/A] Relative intensity [%]
1 8.2819 10.66747 13.21
2 12.1877 7.25623 13.87
4 13.3750 5.73606 10.63
7 17.9145 4.94740 54.91
9 19.1015 4.64256 19.14
10 19.7490 4.49178 19.24
11 20.5060 4.32764 100.00
14 22.6202 3.92771 12.09
15 23.3294 3.80989 13.60
16 23.5078 3.78138 10.33
18 24.5112 3.62880 15.48
19 24.7390 3.59590 13.92
20 25.2472 3.52466 14.10
23 26.5239 3.35784 10.09
25 27.851 1 3.20076 13.12
27 28.8281 3.09448 10.68
28 29.8260 2.99317 13.23
30 31.1460 2.86927 18.90
32 32.2302 2.77518 10.86
35 35.5084 2.52612 12.93
5. Raloxifene sulfamate hemihydrate according to claim 1 in crystal form with the following X-ray powder diffractogram (XRD):
No. Position [2<9/°] Spacing [d/A] Relative intensity
2 8.2714 10.68090 27.54
4 12.1449 7.28167 13.66
5 13.3750 6.61462 13.26
6 15.4069 5.74654 1 1.28
9 17.9096 4.94876 58.48
13 20.4605 4.33716 100
14 21.4783 4.13387 15.04
16 22.6094 3.92956 24.29
17 23.2979 3.81498 25.80
18 24.4824 3.63301 12.63
19 24.7140 3.59949 35.08
20 25.2247 3.52777 43.33
22 26.4808 3.36321 17.30
27 29.8173 2.99402 10.59
29 31.1186 2.87172 1 1.59
6. Raloxifene sulfamate trihydrate according to claim 1 in crystal form with the following X-ray powder diffractogram (XRD):
Position [2< /°] Spacing [d/λ] Relative intensity [%]
1 8.2179 10.75041 12.10
2 12.1212 7.29584 14.65
3 13.3407 6.63153 5.11
4 15.3668 5.76142 6.75
5 17.5438 5.05111 6.10
6 17.8463 4.96616 38.88
7 18.1531 4.88291 10.45
8 19.6789 4.50763 12.11
9 20.4282 4.34394 100.00
10 21.8575 4.06301 5.99
11 22.5598 3.93809 5.89
12 23.2544 3.82201 7.90
13 24.4290 3.64083 8.83
14 24.6722 3.60549 12.17
15 25.1851 3.53321 12.73
16 26.4507 3.36696 6.01
17 27.0692 3.29142 6.79
18 27.7624 3.21079 5.50
19 27.9747 3.18690 6.87
20 28.7728 3.10029 5.69
21 29.7620 2.99946 9.49
22 31.0789 2.87531 15.11
7. Process for the preparation of raloxifene sulfamate in crystal and amorphous forms and hydrates thereof of general formula I:
.HO3S-NH2 . X H 2O wherein x means 0 to 3,
characterized in that
a) a solution of raloxifene base of formula II:
b) a solution of any raloxifene salt is converted to sulfamate by means of ion exchange and isolated by concentration and crystallization.
8. Process according to claim 7, characterized in that as the solvent a lower aliphatic alcohol having 1 to 4 carbon atoms, acetonitrile, acetone, dioxane, tetrahydrofuran, 1,3-dioxolane, N-methylpyrrolidone or a mixture of these solvents with water is used.
9. Process according to claims 7 and 8, characterized in that for the acceleration of crystallization or for precipitation another solvent, in which the sulfamic salt of formula I is less soluble, is added, such as water, 1,2-dimetoxyethane, cyclohexane or aliphatic ethers such as diethyl ether, diisopropyl ether and methyl tert-butyl ether.
10. Process according to claim 7, characterized in that for the ion exchange in b) an anion exchanger in the form of a granulate, semipermeable membrane or in liquid form is used, preferably in the form of a granulate previously charged with sulfamic acid.
11. Process according to claims 7 to 10 for the preparation of amorphous raloxifene sulfamate, characterized in that to an aqueous or aqueous/alcohol solution of amorphous raloxifene sulfamate a substance for enhancing stability is added, which is selected from the group of sugars such as lactose, sucrose, fructose, glucose, trehalose, maltose, mannitol, mannose, sorbitol as well as erythritol and glycerol, but preferably mannitol.
12. Process for the preparation of dry injections of amorphous raloxifene sulfamate characterized in that an aqueous or aqueous/alcohol solution of this salt is stabilized according to the process defined in claim 11, sterile filtered, filled into ampoules, frozen and lyophilized.
13. Process for the preparation of a granulate for tabletting and incapsulating containing stabilized amorphous raloxifene sulfamate, characterized in that an aqueous or aqueous/alcohol solution of amorphous raloxifene sulfamate with the addition of a stabilizer is sprayed onto other inert components and fillers for granulate preparation with simultaneous drying in a counterstream of warm air with a temperature between 30 °C and 50 °C.
14. Pharmaceutical preparations for preventing or treating osteoporosis and breast cancer in women, characterized in that they contain a therapeutically effective amount of amorphous or crystal raloxifene sulfamate together with pharmaceutically acceptable carriers and excipients.
15. Pharmaceutical preparations according to claim 14, characterized in that they are in the form of tablets for immediate or extended release of the active ingredient, in the form of effervescent or dispersive tablets, in the form of capsules or in parenteral forms, for example in the form of injections or patches for topical use.
16. Use of raloxifene sulfamate or hydrates thereof according to claims 1 to 6 for the preparation of a pharmaceutical form enabling an easy release in gastric juice.
17. Use of raloxifene sulfamate or hydrates thereof according to claims 1 to 6 for the preparation of a pharmaceutical form enabling oral use.
18. Use of raloxifene sulfamate or hydrates thereof according to claims 1 to 6 for the preparation of a pharmaceutical form enabling transdermal use.
19. Use of raloxifene sulfamate in amorphous form according to claim 2 for the preparation of a pharmaceutical form enabling intravenous use.
20. Method for determining the content and purity of raloxifene sulfamate, characterised in that Kromasil 100 5 μ, C18, 250 χ 4.6 mm column or an equivalent column having the following parameters is used: mobile phase A: buffer pH 2/acetonitrile = 80/20; mobile phase B: buffer pH 2/acetonitrile - 10/90; buffer composition: 0.92 g sodium heptanesulfonate/1 mL triethylamine in 1000 mL of water, and pH = 2 adjusted with HClO4; gradient: from 83 % phase A to 20 % phase A in 30 min, flow: 1 mL/min, detection: UV at 210 nm.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SIP-201000048 | 2010-02-09 | ||
| SI201000048A SI23291A (en) | 2010-02-09 | 2010-02-09 | New addition salts of raloxifen, procedure for their preparation and their use in therapy |
| SI201000137 | 2010-05-04 | ||
| SIP-201000137 | 2010-05-04 | ||
| SI201000164A SI23391A (en) | 2010-06-01 | 2010-06-01 | Procedure for preparation of new addition salts of raloxifene and their use in therapy |
| SIP-201000164 | 2010-06-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2011099942A1 true WO2011099942A1 (en) | 2011-08-18 |
Family
ID=43437258
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/SI2010/000054 WO2011099942A1 (en) | 2010-02-09 | 2010-09-23 | New addition salts of raloxifene, process for the preparation thereof and use thereof in therapy |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2011099942A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014135834A1 (en) | 2013-03-05 | 2014-09-12 | Cipla House | Oxalic acid addition salts and/or solvates of a selective estrogen receptor modulator |
Citations (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0062504A1 (en) | 1981-04-03 | 1982-10-13 | Eli Lilly And Company | Process for preparing 3-(4-aminoethoxybenzoyl)benzo(b)thiophenes |
| EP0062503A1 (en) | 1981-04-03 | 1982-10-13 | Eli Lilly And Company | Benzothiophene compounds and process for preparing them |
| EP0584952A1 (en) | 1992-07-28 | 1994-03-02 | Eli Lilly And Company | Improvements in or relating to benzothiophenes |
| US5447941A (en) | 1993-12-21 | 1995-09-05 | Eli Lilly And Company | Methods of inhibiting pulmonary hypertensive diseases with raloxifene and related benzothiophenes |
| EP0670162A1 (en) | 1994-03-02 | 1995-09-06 | Eli Lilly And Company | Pharmaceutical formulations containing raloxifere, a surfactant and a watersoluble diluent |
| WO1996009045A1 (en) | 1994-09-19 | 1996-03-28 | Eli Lilly And Company | Antiestrogenic benzothiophenyl compounds |
| US5629425A (en) | 1994-09-19 | 1997-05-13 | Eli Lilly And Company | Haloalkyl hemisolvates of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-piperidinoethoxy)-benzoyl]benzo[b]thiophene |
| EP0826682A1 (en) | 1996-08-28 | 1998-03-04 | Eli Lilly And Company | Amorphous benzothiophenes, methods of preparation, and methods of use |
| EP0839532A1 (en) | 1996-10-30 | 1998-05-06 | Eli Lilly And Company | Improvements in or relating to the prophylaxis of breast cancer by the administration of raloxifene |
| EP0910369A1 (en) | 1996-03-26 | 1999-04-28 | Eli Lilly And Company | Benzothiophenes, formulations containing same, and methods |
| WO2004029046A2 (en) | 2002-09-30 | 2004-04-08 | A/S Gea Farmaceutisk Fabrik | Novel raloxifene acid addition salts and/or solvates thereof, improved method for purification of said raloxifene acid addition salts and/or solvates thereof and pharmaceutical compositions comprising these |
| US20070100147A1 (en) | 2003-06-30 | 2007-05-03 | Massimo Ferrari | Process for preparing raloxifene hydrochloride |
| WO2008047105A1 (en) * | 2006-10-17 | 2008-04-24 | Cipla Limited | Crystalline form of benzothiophene compound and process for preparation thereof |
| US20090069381A1 (en) | 2007-09-12 | 2009-03-12 | Protia, Llc | Deuterium-enriched raloxifene |
-
2010
- 2010-09-23 WO PCT/SI2010/000054 patent/WO2011099942A1/en active Application Filing
Patent Citations (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0062504A1 (en) | 1981-04-03 | 1982-10-13 | Eli Lilly And Company | Process for preparing 3-(4-aminoethoxybenzoyl)benzo(b)thiophenes |
| EP0062503A1 (en) | 1981-04-03 | 1982-10-13 | Eli Lilly And Company | Benzothiophene compounds and process for preparing them |
| EP0584952A1 (en) | 1992-07-28 | 1994-03-02 | Eli Lilly And Company | Improvements in or relating to benzothiophenes |
| US5447941A (en) | 1993-12-21 | 1995-09-05 | Eli Lilly And Company | Methods of inhibiting pulmonary hypertensive diseases with raloxifene and related benzothiophenes |
| EP0670162A1 (en) | 1994-03-02 | 1995-09-06 | Eli Lilly And Company | Pharmaceutical formulations containing raloxifere, a surfactant and a watersoluble diluent |
| US5629425A (en) | 1994-09-19 | 1997-05-13 | Eli Lilly And Company | Haloalkyl hemisolvates of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-piperidinoethoxy)-benzoyl]benzo[b]thiophene |
| WO1996009045A1 (en) | 1994-09-19 | 1996-03-28 | Eli Lilly And Company | Antiestrogenic benzothiophenyl compounds |
| EP0910369A1 (en) | 1996-03-26 | 1999-04-28 | Eli Lilly And Company | Benzothiophenes, formulations containing same, and methods |
| EP0826682A1 (en) | 1996-08-28 | 1998-03-04 | Eli Lilly And Company | Amorphous benzothiophenes, methods of preparation, and methods of use |
| EP0839532A1 (en) | 1996-10-30 | 1998-05-06 | Eli Lilly And Company | Improvements in or relating to the prophylaxis of breast cancer by the administration of raloxifene |
| WO2004029046A2 (en) | 2002-09-30 | 2004-04-08 | A/S Gea Farmaceutisk Fabrik | Novel raloxifene acid addition salts and/or solvates thereof, improved method for purification of said raloxifene acid addition salts and/or solvates thereof and pharmaceutical compositions comprising these |
| US20070100147A1 (en) | 2003-06-30 | 2007-05-03 | Massimo Ferrari | Process for preparing raloxifene hydrochloride |
| WO2008047105A1 (en) * | 2006-10-17 | 2008-04-24 | Cipla Limited | Crystalline form of benzothiophene compound and process for preparation thereof |
| US20090069381A1 (en) | 2007-09-12 | 2009-03-12 | Protia, Llc | Deuterium-enriched raloxifene |
Non-Patent Citations (4)
| Title |
|---|
| E. B. CONNOR ET AL., J. OF MED., vol. 355, 2006, pages 125 - 137 |
| J. DOMINGUEZ; C. LEON, IUPAC, December 2006 (2006-12-01) |
| J. MED. CHEM., vol. 27, 1986, pages 1057 - 1066 |
| V. VOGEL; J. CONSTANTINO ET AL., JAMA, vol. 295, no. 23, pages 2727 - 2741 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014135834A1 (en) | 2013-03-05 | 2014-09-12 | Cipla House | Oxalic acid addition salts and/or solvates of a selective estrogen receptor modulator |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2011095059A1 (en) | Polymorphs of dasatinib, preparation methods and pharmaceutical compositions thereof | |
| SK8872002A3 (en) | Novel sertraline hydrochloride polymorphs, processes for preparing them, compositions containing them and methods of using them | |
| US7897613B2 (en) | Crystalline polymorphs of clopidogrel | |
| EP1844017A1 (en) | An amorphous and three crystalline forms of rimonabant hydrochloride | |
| WO2009017813A1 (en) | O-desmethyl venlafaxine saccharinate | |
| WO2003082806A1 (en) | Venlafaxine base | |
| US7964734B2 (en) | Raloxifene acid addition salts and/or solvates thereof, improved method for purification of said raloxifene acid addition salts and/or solvates thereof and pharmaceutical compositions comprising these | |
| WO2014135834A1 (en) | Oxalic acid addition salts and/or solvates of a selective estrogen receptor modulator | |
| WO2011099942A1 (en) | New addition salts of raloxifene, process for the preparation thereof and use thereof in therapy | |
| CN113979875B (en) | Dezocine derivative crystal form A and preparation method and application thereof | |
| JP7139116B2 (en) | Polymorphs of phenylaminopyrimidine compounds or salts thereof | |
| KR102663976B1 (en) | Monohydrate potassium salt of thienopyridone derivative and method for producing the same | |
| CA2434829C (en) | New benzoylguanidine salt | |
| WO2008156748A2 (en) | Crystal forms of o-desmethylvenlafaxine succinate | |
| WO2007005863A1 (en) | Crystalline forms of (2r-trans)-6-chloro-5[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-1-piperazinyl]carbonyl]-n,n, 1-trimethyl-alpha-oxo-1h-indole-3-acetamide monohydrochloride | |
| TWI659041B (en) | Polymorphic forms of a steroid-like compound and methods for the preparation and use thereof | |
| SI23391A (en) | Procedure for preparation of new addition salts of raloxifene and their use in therapy | |
| US11014890B2 (en) | Forms of (R)-N-(4-chlorophenyl)-2-(cis-4-(6-fluoroquinolin-4- yl)cyclohexyl)propanamide | |
| EP1674468A1 (en) | Polymorphs of clopidogrel hydrobromide | |
| AU2022412842A1 (en) | Novel acid addition salt and crystalline form of (2r,3s)-2-(3-(4,5-dichloro-1h-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol | |
| AU710334B2 (en) | Crystalline (-)-3R,4R-trans-7-methoxy-2,2-dimethyl -3-phenyl-4-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)chromane, hydrogen fumarate | |
| SI23291A (en) | New addition salts of raloxifen, procedure for their preparation and their use in therapy | |
| WO1998056782A1 (en) | Cristalline ( - ) - 3r,4r -trans-7-methoxy -2,2-dimethyl-3-phenyl-4- {4-[2-(pyrrolidin-1-yl)ethoxy] phenyl}chromane, hydrogen maleate | |
| MXPA98009293A (en) | Hydrogen smoke of (-) - 3r, 4r-trans-7-metoxy-2,2-dimethyl-3-fenil-4. { 4- [2- (pirrolidin-1-il) etoxy] fenil} crystal crystal | |
| CZ20004924A3 (en) | Paroxetine methane sulfonate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 10776842 Country of ref document: EP Kind code of ref document: A1 |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 10776842 Country of ref document: EP Kind code of ref document: A1 |