ITMI20100188A1 - CRYSTAL FORM OF SMOKED FESOTERODINE AND PROCEDURE FOR ITS PREPARATION - Google Patents
CRYSTAL FORM OF SMOKED FESOTERODINE AND PROCEDURE FOR ITS PREPARATION Download PDFInfo
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- ITMI20100188A1 ITMI20100188A1 IT000188A ITMI20100188A ITMI20100188A1 IT MI20100188 A1 ITMI20100188 A1 IT MI20100188A1 IT 000188 A IT000188 A IT 000188A IT MI20100188 A ITMI20100188 A IT MI20100188A IT MI20100188 A1 ITMI20100188 A1 IT MI20100188A1
- Authority
- IT
- Italy
- Prior art keywords
- fesoterodine
- crystalline form
- fumarate
- fesoterodine fumarate
- organic solvent
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 21
- 238000002360 preparation method Methods 0.000 title claims description 15
- DCCSDBARQIPTGU-HSZRJFAPSA-N fesoterodine Chemical compound C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(CO)C=2)OC(=O)C(C)C)=CC=CC=C1 DCCSDBARQIPTGU-HSZRJFAPSA-N 0.000 title claims description 13
- 229960002978 fesoterodine Drugs 0.000 title claims description 10
- MWHXMIASLKXGBU-RNCYCKTQSA-N (e)-but-2-enedioic acid;[2-[(1r)-3-[di(propan-2-yl)amino]-1-phenylpropyl]-4-(hydroxymethyl)phenyl] 2-methylpropanoate Chemical compound OC(=O)\C=C\C(O)=O.C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(CO)C=2)OC(=O)C(C)C)=CC=CC=C1 MWHXMIASLKXGBU-RNCYCKTQSA-N 0.000 claims description 35
- 229960004524 fesoterodine fumarate Drugs 0.000 claims description 34
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 24
- 239000007787 solid Substances 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 9
- 238000009835 boiling Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 238000001228 spectrum Methods 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000002244 precipitate Substances 0.000 claims description 4
- 125000002015 acyclic group Chemical group 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 239000002798 polar solvent Substances 0.000 claims description 3
- 238000011084 recovery Methods 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 239000002585 base Substances 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 10
- -1 (R) -2- (3-diisopropylamino-1-phenylpropyl) -4- (hydroxymethyl) -phenol isobutyrate fumarate Chemical compound 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000000113 differential scanning calorimetry Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 206010020853 Hypertonic bladder Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 208000009722 Overactive Urinary Bladder Diseases 0.000 description 1
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 1
- 206010046543 Urinary incontinence Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001022 anti-muscarinic effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000001033 granulometry Methods 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 208000020629 overactive bladder Diseases 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000010079 rubber tapping Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C219/26—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C219/28—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton having amino groups bound to acyclic carbon atoms of the carbon skeleton
Description
Descrizione Description
“FORMA CRISTALLINA DI FESOTERODINA FUMARATO E PROCEDIMENTO PER LA SUA PREPARAZIONE†⠀ œCRYSTALLINE FORM OF SMOKED PHESOTERODINE AND PROCEDURE FOR ITS PREPARATIONâ €
CAMPO DELL’INVENZIONE FIELD OF INVENTION
La presente invenzione riguarda (R)-2-(3-diisopropilammino-1-fenilpropil)-4-(idrossimetil)-fenol isobutirrato fumarato (Fesoterodina fumarato) in forma cristallina e procedimento per la sua preparazione. The present invention relates to (R) -2- (3-diisopropylamino-1-phenylpropyl) -4- (hydroxymethyl) -phenol isobutyrate fumarate (Fesoterodine fumarate) in crystalline form and the process for its preparation.
STATO DELLA TECNICA STATE OF THE TECHNIQUE
La Fesoterodina o (R)-2-(3-diisopropilammino-1-fenilpropil)-4-(idrossimetil)-fenol isobutirrato di formula (I) Fesoterodine or (R) -2- (3-diisopropylamino-1-phenylpropyl) -4- (hydroxymethyl) -phenol isobutyrate of formula (I)
O OR
O OR
N No.
OH OH
(I) (THE)
à ̈ un noto composto ad attività antimuscarinica, impiegato in clinica sotto forma di sale fumarato nel trattamento della sindrome da vescica iperattiva ed in particolare dell’incontinenza urinaria. It is a well-known compound with antimuscarinic activity, used in the clinic in the form of fumarate salt in the treatment of overactive bladder syndrome and in particular of urinary incontinence.
US 6858650 ne descrive la preparazione e l’isolamento come sale fumarato. US 6858650 describes its preparation and isolation as a fumarate salt.
Fino ad ora, non à ̈ mai stata riportata la preparazione di una forma solida cristallina ben definita e caratterizzata dal punto di vista cristallografico della Fesoterodina fumarato. US 6858650 riporta infatti la preparazione di fesoterodina fumarato per cristallizzazione da una miscela di cicloesano e 2-butanone con un punto di fusione di 98,8°C che, dopo ricristallizzazione dalla stessa miscela solvente, porta ad un solido cristallino con punto di fusione di 103°C, non caratterizzato in alcun modo dal punto di vista cristallografico. Inoltre, gli inventori della presente invenzione hanno ripetuto più volte la procedura di US 6858650, incluse sue possibili comuni varianti, provando a ricristallizzare un campione solido di fesoterodina fumarato, senza essere mai riusciti ad ottenere la precipitazione di alcun solido. Molto ben caratterizzata à ̈ invece la forma amorfa di fesoterodina fumarato, descritta in IPCOM 000181861D e in WO 2009/044278. Until now, the preparation of a well defined crystalline solid form of Fesoterodine fumarate has never been reported. US 6858650 in fact reports the preparation of fesoterodine fumarate by crystallization from a mixture of cyclohexane and 2-butanone with a melting point of 98.8 ° C which, after recrystallization from the same solvent mixture, leads to a crystalline solid with a melting point of 103 ° C, not characterized in any way from the crystallographic point of view. Furthermore, the inventors of the present invention have repeated several times the procedure of US 6858650, including its possible common variants, trying to recrystallize a solid sample of fesoterodine fumarate, without ever having been able to obtain the precipitation of any solid. The amorphous form of fesoterodine fumarate, described in IPCOM 000181861D and in WO 2009/044278, is instead very well characterized.
Come noto, le proprietà fisiche di un farmaco sono di fondamentale importanza nell’allestimento di forme farmaceutiche. Un aspetto importante dei farmaci in forma solida, soprattutto nel caso di sali di addizione di acidi ad ammine à ̈ la loro scorrevolezza, granulometria, densità , volume al tapping, comprimibilità , parametri cruciali che condizionano la formulazione delle forme farmaceutiche solide, quali ad esempio compresse, capsule, granulati. Esiste quindi la necessità sia di disporre di più forme cristalline di fesoterodina fumarato, in modo da poter selezionare la forma cristallina con le caratteristiche migliori per la preparazione di una formulazione farmaceutica, specialmente in forma solida, sia di un metodo applicabile e soprattutto riproducibile anche industrialmente per ottenere fesoterodina fumarato in forma cristallina. As known, the physical properties of a drug are of fundamental importance in the preparation of pharmaceutical forms. An important aspect of drugs in solid form, especially in the case of addition salts of acids to amines, is their flowability, granulometry, density, volume at tapping, compressibility, crucial parameters that affect the formulation of solid pharmaceutical forms, such as for example tablets, capsules, granules. There is therefore the need both to have more crystalline forms of fesoterodine fumarate, in order to select the crystalline form with the best characteristics for the preparation of a pharmaceutical formulation, especially in solid form, and of an applicable and above all reproducible method also industrially. to obtain fesoterodine fumarate in crystalline form.
SOMMARIO DELL’INVENZIONE SUMMARY OF THE INVENTION
È stato qui trovato che (R)-2-(3-diisopropilammino-1-fenilpropil)-4(idrossimetil)-fenol isobutirrato fumarato può esistere in forma solida cristallina, in particolare in forma anidra, qui di seguito definita come forma cristallina Α, stabile a temperatura ambiente. It has been found here that (R) -2- (3-diisopropylamino-1-phenylpropyl) -4 (hydroxymethyl) -phenol isobutyrate fumarate can exist in crystalline solid form, in particular in anhydrous form, hereinafter defined as crystalline form Π', stable at room temperature.
L’invenzione fornisce pertanto (R)-2-(3-diisopropilammino-1-fenilpropil)-4-(idrossimetil)-fenol isobutirrato fumarato (Fesoterodina fumarato) in tale forma cristallina, un metodo per la sua preparazione ed una composizione farmaceutica contenente tale forma. The invention therefore provides (R) -2- (3-diisopropylamino-1-phenylpropyl) -4- (hydroxymethyl) -phenol isobutyrate fumarate (Fesoterodine fumarate) in this crystalline form, a method for its preparation and a pharmaceutical composition containing that form.
BREVE DESCRIZIONE DELLE FIGURE E METODI ANALITICI BRIEF DESCRIPTION OF THE FIGURES AND ANALYTICAL METHODS
La forma cristallina di (R)-2-(3-diisopropilammino-1-fenilpropil)-4-(idrossimetil)-fenol isobutirrato fumarato , Ã ̈ stata caratterizzata tramite diffrazione da raggi X da polveri cristalline (XRPD) (X-ray powder diffraction), mediante spettrometro di risonanza magnetica nucleare 1H-NMR e mediante calorimetria differenziale a scansione (DSC). The crystalline form of (R) -2- (3-diisopropylamino-1-phenylpropyl) -4- (hydroxymethyl) -phenol isobutyrate fumarate, was characterized by X-ray diffraction from crystalline powders (XRPD) (X-ray powder diffraction), by 1H-NMR nuclear magnetic resonance spectrometer and by differential scanning calorimetry (DSC).
Il contenuto d’acqua nel composto à ̈ stato determinato mediante titolazione con la tecnica di Karl Fisher. The water content in the compound was determined by titration with the Karl Fisher technique.
Lo spettro di diffrazione di raggi X (XRPD) à ̈ stato raccolto con il diffrattometro automatico Î ̧/Î ̧ per polveri e liquidi APD-2000 della ditta Ital-Structures nelle seguenti condizioni operative: radiazione CuKα (λ = 1.5418 Ã…), scansione con intervallo angolare 3-40° in 2Î ̧, con passo angolare di 0,03° per un tempo 1 sec. The X-ray diffraction spectrum (XRPD) was collected with the Î ̧ / Î ̧ automatic diffractometer Î ̧ / Î ̧ for powders and liquids APD-2000 from Ital-Structures in the following operating conditions: CuKÎ ± radiation (Î »= 1.5418 Ã… ), scanning with angular interval 3-40 ° in 2Î ̧, with an angular step of 0.03 ° for a time of 1 sec.
Il tracciato DSC à ̈ stato acquisito con il calorimetro differenziale a scansione Mettler-Toledo DSC 822e, nelle seguenti condizioni operative: capsule di alluminio, intervallo 30-400°C con velocità di 10°C/min, con azoto come gas di spurgo (80 ml/min). The DSC trace was acquired with the Mettler-Toledo DSC 822e differential scanning calorimeter, in the following operating conditions: aluminum capsules, range 30-400 ° C with a speed of 10 ° C / min, with nitrogen as purge gas ( 80 ml / min).
Le dimensioni delle particelle sono state determinate con la nota tecnica di “laser light scattering†impiegando uno strumento Malvern Mastersizer MS1 nelle seguenti condizioni operative: The particle size was determined with the known â € œlaser light scatteringâ € technique using a Malvern Mastersizer MS1 instrument under the following operating conditions:
• lente da 300RF mm con lunghezza del raggio laser di 2,4 mm; â € ¢ 300RF mm lens with 2.4 mm laser beam length;
• campione di 500 mg disperso in 10 ml di esano (reagente ACS) con l’1% di SPAN 85<®>, senza presonicazione, e con velocità di agitazione di 2500 rpm. â € ¢ 500 mg sample dispersed in 10 ml of hexane (ACS reagent) with 1% of SPAN 85 <®>, without presonication, and with stirring speed of 2500 rpm.
Figura 1: Spettro XRPD della Forma cristallina Α di Fesoterodina fumarato. Figure 1: XRPD spectrum of the crystalline form Π'of Fesoterodine fumarate.
Figura 2: Tracciato DSC della Forma cristallina Α di Fesoterodina fumarato. Figure 2: DSC trace of the crystalline form Π'of Fesoterodine fumarate.
DESCRIZIONE DETTAGLIATA DELL’INVENZIONE DETAILED DESCRIPTION OF THE INVENTION
Come primo oggetto, la presente invenzione fornisce (R)-2-(3-diisopropilammino-1-fenilpropil)-4-(idrossimetil)-fenol isobutirrato fumarato (Fesoterodina fumarato) in forma cristallina, anidra, qui di seguito definita come forma cristallina A. As a first object, the present invention provides (R) -2- (3-diisopropylamino-1-phenylpropyl) -4- (hydroxymethyl) -phenol isobutyrate fumarate (Fesoterodine fumarate) in crystalline, anhydrous form, hereinafter defined as crystalline form TO.
Detta forma cristallina A ha un contenuto in acqua compreso circa tra 0 e circa 0,2%, così da poter essere definita come sostanzialmente anidra. Said crystalline form A has a water content comprised between about 0 and about 0.2%, so that it can be defined as substantially anhydrous.
Tale forma cristallina A ha un tracciato DSC come sostanzialmente riportato in Figura 2, dove la principale endotermia si riscontra a circa 104°C; ed uno spettro XRPD come sostanzialmente illustrato in Figura 1, dove i picchi di diffrazione più intensi si riscontrano a 9,7; 10,4; 11,6; 12,9; 14,9; 17,5; 19,0; 19,4; 19,9; 20,8; 21,9; 22,9; 24,7; 25,9 e 28,0 ± 0,2° in 2Î ̧. This crystalline form A has a DSC pattern as substantially reported in Figure 2, where the main endothermia is found at about 104 ° C; and an XRPD spectrum as substantially illustrated in Figure 1, where the most intense diffraction peaks are found at 9.7; 10.4; 11.6; 12.9; 14.9; 17.5; 19.0; 19.4; 19.9; 20.8; 21.9; 22.9; 24.7; 25.9 and 28.0 ± 0.2 ° in 2Î ̧.
LA Fesoterodina fumarato forma cristallina A, come sopra definita, può essere preparata ad esempio mediante un procedimento comprendente: - la formazione di una soluzione di Fesoterodina fumarato in un solvente organico basso bollente; Fesoterodine fumarate crystalline form A, as defined above, can be prepared for example by means of a process comprising: - the formation of a solution of fesoterodine fumarate in a low boiling organic solvent;
- la concentrazione della soluzione fino ad ottenere un residuo gommoso; - the concentration of the solution until a rubbery residue is obtained;
- il trattamento del residuo gommoso con metil tert-butiletere ad ottenere un precipitato bianco cristallino; e - treating the gummy residue with methyl tert-butylether to obtain a white crystalline precipitate; And
- il recupero del solido cristallino. - the recovery of the crystalline solid.
La soluzione di Fesoterodina fumarato può essere preparata ad esempio secondo US 6858650. The Fesoterodine fumarate solution can be prepared for example according to US 6858650.
Un solvente organico basso bollente à ̈ un solvente organico con punto di ebollizione inferiore agli 85°C, tipicamente un solvente polare aprotico, ad esempio acetonitrile; un etere ciclico o aciclico, ad esempio, tetraidrofurano o metil tert-butiletere; un solvente clorurato, ad esempio, diclorometano o cloroformio; un estere, ad esempio acetato di etile o di metile; un C3-C12chetone, ad esempio acetone o metiletilchetone; oppure un C1-C4alcanolo lineare o ramificato, ad esempio metanolo o isopropanolo; oppure una miscela di due o più, preferibilmente di due o tre, di detti solventi. Preferibilmente esso à ̈ un C3-C12chetone, più preferibilmente acetone. A low boiling organic solvent is an organic solvent with a boiling point below 85 ° C, typically an aprotic polar solvent, for example acetonitrile; a cyclic or acyclic ether, for example, tetrahydrofuran or methyl tert-butylether; a chlorinated solvent, for example, dichloromethane or chloroform; an ester, for example ethyl or methyl acetate; a C3-C12 ketone, for example acetone or methylethyl ketone; or a linear or branched C1-C4alkanol, for example methanol or isopropanol; or a mixture of two or more, preferably two or three, of said solvents. Preferably it is a C3-C12 ketone, more preferably acetone.
La concentrazione di Fesoterodina fumarato nel solvente organico basso bollente, ad esempio in acetone, Ã ̈ normalmente compresa tra 0,1M e 10M, preferibilmente tra 0,2M e 2M. The concentration of Fesoterodine fumarate in the low boiling organic solvent, for example in acetone, is normally between 0.1M and 10M, preferably between 0.2M and 2M.
La soluzione di Fesoterodina fumarato può essere concentrata ad ottenere un residuo gommoso, per distillazione del solvente a pressione atmosferica o a pressione ridotta. La distillazione del solvente può essere effettuata in un intervallo di temperatura compreso tra circa 0°C e la temperatura di riflusso del solvente, preferibilmente la temperatura di evaporazione à ̈ compresa tra circa 25 e circa 40°C. The Fesoterodine fumarate solution can be concentrated to obtain a rubbery residue, by distillation of the solvent at atmospheric pressure or at reduced pressure. The distillation of the solvent can be carried out in a temperature range between about 0 ° C and the reflux temperature of the solvent, preferably the evaporation temperature is between about 25 and about 40 ° C.
Il residuo gommoso, ottenuto dopo evaporazione del solvente viene trattato con una quantità di metil tert-butiletere (MTBE) compresa tra circa 5 ml di MTBE /g di sale fumarato e circa 100 ml di MTBE/g di sale fumarato, preferibilmente intorno a circa 10 ml/g. Si ottiene una miscela eterogenea che viene mantenuta in agitazione per almeno 24 ore ad una temperatura compresa tra circa -10 ºC e circa 25°C, preferibilmente tra circa 0 ºC e circa 20°C, da cui si forma un precipitato cristallino. The gummy residue, obtained after evaporation of the solvent, is treated with a quantity of methyl tert-butylether (MTBE) comprised between about 5 ml of MTBE / g of fumarate salt and about 100 ml of MTBE / g of fumarate salt, preferably around about 10 ml / g. A heterogeneous mixture is obtained which is kept under stirring for at least 24 hours at a temperature between about -10 ºC and about 25 ° C, preferably between about 0 ºC and about 20 ° C, from which a crystalline precipitate is formed.
Il precipitato cristallino così ottenuto può essere recuperato secondo tecniche note, ad esempio per filtrazione o centrifugazione, opzionalmente seguite da essiccamento sotto vuoto. Preferibilmente il prodotto à ̈ recuperato per filtrazione, seguita da essiccamento sotto vuoto a temperatura ambiente. The crystalline precipitate thus obtained can be recovered according to known techniques, for example by filtration or centrifugation, optionally followed by drying under vacuum. Preferably the product is recovered by filtration, followed by drying under vacuum at room temperature.
La purezza chimica di Fesoterodina fumarato così ottenuta, valutata per HPLC, à ̈ uguale o superiore al 99%, preferibilmente uguale o superiore al 99,5%. La sua purezza enantiomerica calcolata per HPLC chirale, espressa in termini di rapporto enantiomerico, à ̈ tipicamente uguale o superiore a 99:1. The chemical purity of Fesoterodine fumarate thus obtained, evaluated by HPLC, is equal to or greater than 99%, preferably equal to or greater than 99.5%. Its enantiomeric purity calculated by chiral HPLC, expressed in terms of enantiomeric ratio, is typically equal to or greater than 99: 1.
Quando nella preparazione di Fesoterodina fumarato forma cristallina A, in accordo al procedimento sopra descritto, viene utilizzata come materia prima di preparazione Fesoterodina base con una purezza chimica valutata per HPLC uguale o inferiore al 99%, preferibilmente intorno al 98%, la Fesoterodina fumarato forma cristallina A ottenuta ha una purezza chimica, valutata per HPLC, uguale o superiore al 99,1%, preferibilmente uguale o superiore al 99,5%. When in the preparation of Fesoterodine fumarate crystalline form A, according to the procedure described above, Fesoterodine base with a chemical purity evaluated by HPLC equal to or less than 99%, preferably around 98%, is used as a raw material of preparation, Fesoterodine fumarate forms The obtained crystalline A has a chemical purity, evaluated by HPLC, equal to or greater than 99.1%, preferably equal to or greater than 99.5%.
La dimensione dei cristalli di Fesoterodina fumarato forma cristallina A, ottenuti secondo l’invenzione, à ̈ caratterizzata da un valore di D50compreso tra circa 25 e circa 250 µm, dove D50indica il diametro delle particelle tale che il 50% (in volume) del campione di particelle ha un diametro uguale o inferiore allo specifico valore. Tale valore, se desiderato, può essere ridotto mediante micronizzazione o fine molitura. The size of the crystals of Fesoterodine fumarate crystalline form A, obtained according to the invention, is characterized by a value of D50 between about 25 and about 250 µm, where D50 indicates the diameter of the particles such that 50% (by volume) of the particle sample has a diameter equal to or less than the specified value. This value, if desired, can be reduced by micronization or fine milling.
Un ulteriore oggetto dell’invenzione à ̈ un procedimento per la preparazione di Fesoterodina base, comprendente la conversione di Fesoterodina fumarato forma cristallina A in Fesoterodina base. A further object of the invention is a process for the preparation of Fesoterodine base, comprising the conversion of Fesoterodine fumarate crystalline form A into Fesoterodine base.
La conversione di Fesoterodina fumarato forma cristallina A in Fesoterodina base può essere effettuata ad esempio sciogliendo Fesoterodina fumarato forma cristallina A in acqua e per successiva aggiunta di una base. Una base può essere organica o inorganica tipicamente scelta ad esempio tra trietilammina, feniletilammina, un idrossido o un carbonato di un metallo alcalino, come ad esempio idrossido di sodio, di potassio, sodio o potassio carbonato. La soluzione viene mantenuta in agitazione per un tempo compreso tra circa 15 minuti e circa 5 ore e quindi estratta una o più volte con un solvente organico. Il recupero di Fesoterodina base può avvenire mediante metodiche note all’esperto del ramo. The conversion of Fesoterodine fumarate crystalline form A into Fesoterodine base can be carried out for example by dissolving Fesoterodine fumarate crystalline form A in water and by subsequent addition of a base. A base can be organic or inorganic typically selected for example from triethylamine, phenylethylamine, a hydroxide or a carbonate of an alkali metal, such as for example sodium hydroxide, potassium, sodium or potassium carbonate. The solution is kept under stirring for a time ranging from about 15 minutes to about 5 hours and then extracted once or more times with an organic solvent. The recovery of Fesoterodina base can take place using methods known to the expert in the art.
Il rapporto stechiometrico tra Fesoterodina fumarato forma cristallina A e base nella soluzione acquosa à ̈ almeno stechiometrico, preferibilmente uguale o superiore a 1:2. The stoichiometric ratio between Fesoterodine fumarate crystalline form A and base in the aqueous solution is at least stoichiometric, preferably equal to or greater than 1: 2.
Un solvente organico può essere tipicamente un solvente polare aprotico, ad esempio acetonitrile; un estere, ad esempio acetato di metile o etile; un etere ciclico o aciclico, ad esempio tetraidrofurano o dietiletere; un solvente etereo; un solvente clorurato, ad esempio cloroformio o diclorometano, preferibilmente acetato di etile. An organic solvent can typically be an aprotic polar solvent, for example acetonitrile; an ester, for example methyl acetate or ethyl; a cyclic or acyclic ether, for example tetrahydrofuran or diethyl ether; an ethereal solvent; a chlorinated solvent, for example chloroform or dichloromethane, preferably ethyl acetate.
L’evaporazione del solvente organico permette di ottenere Fesoterodina base avente una purezza valutata per HPLC uguale superiore al 99,1%, preferibilmente uguale o superiore al 99,5%. The evaporation of the organic solvent allows to obtain the esoterodine base having a purity evaluated by HPLC equal to greater than 99.1%, preferably equal to or greater than 99.5%.
Un ulteriore oggetto della presente invenzione à ̈ una composizione farmaceutica comprendente, come principio attivo, almeno Fesoterodina fumarato forma cristallina A, come qui definita, ed un opportuno veicolante e/o eccipiente farmaceuticamente accettabile. A further object of the present invention is a pharmaceutical composition comprising, as active principle, at least Fesoterodine fumarate crystalline form A, as defined herein, and a suitable pharmaceutically acceptable carrier and / or excipient.
I seguenti esempi illustrano l’invenzione. The following examples illustrate the invention.
Esempio 1. Preparazione di (R)-2-(3-diisopropilammino-1-fenilpropil)-4-(idrossimetil) fenol isobutirrato fumarato Forma cristallina A (Fesoterodina fumarato Forma cristallina A) Example 1. Preparation of (R) -2- (3-diisopropylamino-1-phenylpropyl) -4- (hydroxymethyl) phenol isobutyrate fumarate Crystalline form A (Fesoterodine fumarate Crystalline form A)
(R)-2-(3-diisopropilammino-1-fenilpropil)-4-(idrossimetil)-fenol isobutirrato (13,8 g; 33,6 mmoli) viene disciolto in acetone (70 ml) e la soluzione à ̈ addizionata ci acido fumarico (3,8 g; 33,6 mmoli). La soluzione à ̈ concentrata a pressione ridotta fino ad ottenere un residuo gommoso. Il residuo viene trattato con metil tert-butiletere (170 ml) e lasciato in agitazione per 48 ore. Il solido bianco cristallino ottenuto à ̈ filtrato ed essiccato sotto vuoto a 40°C. Si ottengono 13,6 g di fesoterodina fumarato in forma solida cristallina A, con una resa del 77% e una purezza del 99,9% calcolata per HPLC. (R) -2- (3-diisopropylamino-1-phenylpropyl) -4- (hydroxymethyl) -phenol isobutyrate (13.8 g; 33.6 mmol) is dissolved in acetone (70 ml) and the solution is added there fumaric acid (3.8 g; 33.6 mmol). The solution is concentrated under reduced pressure until a rubbery residue is obtained. The residue is treated with methyl tert-butylether (170 ml) and left under stirring for 48 hours. The white crystalline solid obtained is filtered and dried under vacuum at 40 ° C. 13.6 g of fesoterodine fumarate are obtained in crystalline solid form A, with a yield of 77% and a purity of 99.9% calculated by HPLC.
Il contenuto d’acqua nel composto determinato mediante titolazione secondo Karl Fisher risulta circa 0.1%. Lo stesso prodotto presenta un tracciato DSC come sostanzialmente riportato da Figura 2, ed uno spettro XRPD come sostanzialmente illustrato da Figura 1, dove i picchi di diffrazione più intensi si riscontrano a 9,7; 10,4; 11,6; 12,9; 14,9; 17,5; 19,0; 19,4; 19,9; 20,8; 21,9; 22,9; 24,7; 25,9 e 28,0 ± 0,2° in 2Î ̧. The water content in the compound determined by titration according to Karl Fisher is about 0.1%. The same product has a DSC trace as substantially reported in Figure 2, and an XRPD spectrum as substantially illustrated by Figure 1, where the most intense diffraction peaks are found at 9.7; 10.4; 11.6; 12.9; 14.9; 17.5; 19.0; 19.4; 19.9; 20.8; 21.9; 22.9; 24.7; 25.9 and 28.0 ± 0.2 ° in 2Î ̧.
Esempio 2. Preparazione di (R)-2-(3-diisopropilammino-1-fenilpropil)-4-(idrossimetil) fenol isobutirrato (Fesoterodina base) Example 2. Preparation of (R) -2- (3-diisopropylamino-1-phenylpropyl) -4- (hydroxymethyl) phenol isobutyrate (Fesoterodine base)
(R)-2-(3-diisopropilammino-1-fenilpropil)-4-(idrossimetil)-fenol isobutirrato fumarato Forma cristallina A (13,6 g; 25,9 mmoli) viene disciolta in acqua (60 ml) e la soluzione à ̈ addizionata di sodio idrossido (2,07 g; 51,7 mmoli). La soluzione viene mantenuta in agitazione per circa 1 ora e quindi estratta tre volte con acetato di etile (3 X 50 ml). Le fasi organiche vengono separate dalla fase acquosa e quindi riunite e anidrificate con sodio solfato (Na2SO4). La sospensione viene quindi filtrata su filtro BÃ1⁄4ckner e il residuo di sodio solfato viene lavato due volte con acetato di etile (2 X 10 ml). Le fasi organiche vengono quindi evaporate a pressione ridotta ad una temperatura di circa 40°C. Si ottengono 10,6 g di Fesoterodina base con una purezza calcolata per HPLC del 99,9%. (R) -2- (3-diisopropylamino-1-phenylpropyl) -4- (hydroxymethyl) -phenol isobutyrate fumarate Crystalline form A (13.6 g; 25.9 mmol) is dissolved in water (60 ml) and the solution Sodium hydroxide is added (2.07 g; 51.7 mmoles). The solution is kept under stirring for about 1 hour and then extracted three times with ethyl acetate (3 X 50 ml). The organic phases are separated from the aqueous phase and then combined and anhydrified with sodium sulphate (Na2SO4). The suspension is then filtered on a BÃ1⁄4ckner filter and the sodium sulphate residue is washed twice with ethyl acetate (2 X 10 ml). The organic phases are then evaporated under reduced pressure at a temperature of about 40 ° C. 10.6 g of Fesoterodine base are obtained with a purity calculated by HPLC of 99.9%.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6858650B1 (en) * | 1999-11-16 | 2005-02-22 | Schwarz Pharma Ag | Stable salts of novel derivatives of 3,3-diphenylpropylamines |
| WO2007140986A1 (en) * | 2006-06-09 | 2007-12-13 | Schwarz Pharma Ltd | Synthesis of phenolic esters of hydroxymethyl phenols |
| WO2009044278A1 (en) * | 2007-10-01 | 2009-04-09 | Actavis Group Ptc Ehf | Amorphous fesoterodine fumarate |
| WO2009122303A2 (en) * | 2008-04-04 | 2009-10-08 | Actavis Group Ptc Ehf | Novel mandelate salt of fesoterodine |
| WO2010010464A2 (en) * | 2008-07-21 | 2010-01-28 | Actavis Group Ptc Ehf | Fesoterodine substantially free of dehydroxy impurity |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6858650B1 (en) * | 1999-11-16 | 2005-02-22 | Schwarz Pharma Ag | Stable salts of novel derivatives of 3,3-diphenylpropylamines |
| WO2007140986A1 (en) * | 2006-06-09 | 2007-12-13 | Schwarz Pharma Ltd | Synthesis of phenolic esters of hydroxymethyl phenols |
| WO2009044278A1 (en) * | 2007-10-01 | 2009-04-09 | Actavis Group Ptc Ehf | Amorphous fesoterodine fumarate |
| WO2009122303A2 (en) * | 2008-04-04 | 2009-10-08 | Actavis Group Ptc Ehf | Novel mandelate salt of fesoterodine |
| WO2010010464A2 (en) * | 2008-07-21 | 2010-01-28 | Actavis Group Ptc Ehf | Fesoterodine substantially free of dehydroxy impurity |
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