ITMI20090190A1 - CRYSTAL FORM OF BROMIDRATED BUPROPION - Google Patents
CRYSTAL FORM OF BROMIDRATED BUPROPION Download PDFInfo
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- ITMI20090190A1 ITMI20090190A1 IT000190A ITMI20090190A ITMI20090190A1 IT MI20090190 A1 ITMI20090190 A1 IT MI20090190A1 IT 000190 A IT000190 A IT 000190A IT MI20090190 A ITMI20090190 A IT MI20090190A IT MI20090190 A1 ITMI20090190 A1 IT MI20090190A1
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- Prior art keywords
- ppm
- ethanol
- bupropion hydrobromide
- crystalline form
- solvent
- Prior art date
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- SNPPWIUOZRMYNY-UHFFFAOYSA-N bupropion Chemical compound CC(C)(C)NC(C)C(=O)C1=CC=CC(Cl)=C1 SNPPWIUOZRMYNY-UHFFFAOYSA-N 0.000 title description 4
- 229960001058 bupropion Drugs 0.000 title description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 37
- WSTCENNATOVXKQ-UHFFFAOYSA-N 2-(tert-butylamino)-1-(3-chlorophenyl)propan-1-one;hydrobromide Chemical compound Br.CC(C)(C)NC(C)C(=O)C1=CC=CC(Cl)=C1 WSTCENNATOVXKQ-UHFFFAOYSA-N 0.000 claims description 34
- 229960002302 bupropion hydrobromide Drugs 0.000 claims description 24
- 239000006185 dispersion Substances 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 14
- 239000007787 solid Substances 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 13
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 10
- 238000004090 dissolution Methods 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 6
- 239000013078 crystal Substances 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 239000003495 polar organic solvent Substances 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 2
- 238000011084 recovery Methods 0.000 claims description 2
- 238000010583 slow cooling Methods 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 238000000113 differential scanning calorimetry Methods 0.000 description 7
- 238000001914 filtration Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000003586 protic polar solvent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- 241000220304 Prunus dulcis Species 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
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 229940022682 acetone Drugs 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 235000020224 almond Nutrition 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 238000002356 laser light scattering Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 1
- 229940032007 methylethyl ketone Drugs 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000005979 thermal decomposition reaction Methods 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
Description
Descrizione del brevetto per invenzione industriale avente per titolo: Description of the patent for industrial invention entitled:
“FORMA CRISTALLINA DI BUPROPIONE BROMIDRATO” "CRYSTALLINE FORM OF BUPROPIO BROMIDRATE"
CAMPO DELL’INVENZIONE FIELD OF THE INVENTION
La presente invenzione riguarda una nuova forma cristallina di 1-(3-clorofenil)-2-[(1,1-dimetiletil)amino]-1-propanone bromidrato (Bupropione bromidrato). The present invention relates to a new crystalline form of 1- (3-chlorophenyl) -2 - [(1,1-dimethylethyl) amino] -1-propanone hydrobromide (Bupropion hydrobromide).
STATO DELLA TECNICA STATE OF THE TECHNIQUE
Bupropione, ovvero 1-(3-clorofenil)-2-[(1,1-dimetiletil)amino]-1-propanone, è un antidepressivo noto da US 3,819,706. WO 2007/002597 rivendica tre forme cristalline di Bupropione bromidrato, definite Forma I, Forma II e Forma III. Bupropion, namely 1- (3-chlorophenyl) -2 - [(1,1-dimethylethyl) amino] -1-propanone, is a known antidepressant from US 3,819,706. WO 2007/002597 claims three crystalline forms of Bupropion hydrobromide, termed Form I, Form II and Form III.
Come noto, forme diverse di composti biologicamente attivi, quali in particolare le forme polimorfe, possono essere utili in terapia, grazie alle diverse biodisponibilità, tempi di rilascio e solubilità. Questo comporta un grande vantaggio per i pazienti, in quanto può permettere, ad esempio, sia una riduzione del dosaggio del farmaco sia un allungamento dell’intervallo tra le somministrazioni. Inoltre le diverse caratteristiche fisiche, che spesso accompagnano la diversa forma fisica del farmaco, possono essere vantaggiosamente utilizzate nell’allestimento di diverse formulazioni farmaceutiche. Esiste quindi la necessità di disporre di nuove forme cristalline di Bupropione bromidrato, che possano offrire proprietà vantaggiose. As known, different forms of biologically active compounds, such as in particular the polymorphic forms, can be useful in therapy, thanks to the different bioavailability, release times and solubility. This has a great advantage for patients, as it can allow, for example, both a reduction in the dosage of the drug and an extension of the interval between administrations. In addition, the different physical characteristics, which often accompany the different physical form of the drug, can be advantageously used in the preparation of different pharmaceutical formulations. There is therefore a need for new crystalline forms of Bupropion hydrobromide, which can offer advantageous properties.
SOMMARIO DELL’INVENZIONE SUMMARY OF THE INVENTION
Si è sorprendentemente trovato che Bupropione bromidrato può esistere in una nuova forma cristallina solvata con etanolo, sostanzialmente anidra, qui denominata Forma α. It has surprisingly been found that Bupropion hydrobromide can exist in a new crystalline form solved with ethanol, substantially anhydrous, here called Form α.
BREVE DESCRIZIONE DELLE FIGURE E METODI ANALITICI BRIEF DESCRIPTION OF THE FIGURES AND ANALYTICAL METHODS
Bupropione bromidrato Forma α è stato caratterizzato tramite diffrazione da raggi X da polveri (XRPD) (X-ray powder diffraction), mediante spettrometro di risonanza magnetica nucleare<1>H-NMR e mediante calorimetria differenziale a scansione (DSC). Il contenuto d’acqua nei campioni è stato determinato mediante titolazione con la tecnica di Karl Fisher. Gli spettri di diffrazione di raggi X (XRPD) sono stati raccolti con il diffrattometro automatico per polveri e liquidi APD-2000 della ditta Ital-Structures nelle seguenti condizioni operative: radiazione CuKα (λ = 1.5418 Å), scansione con intervallo angolare 3-40° in 2θ, con passo angolare di 0,03° per un tempo 1 sec. Gli spettri<1>H-NMR sono stati acquisiti con lo spettrometro Varian Mercury 300, impiegando DMSO-d6 come solvente. I tracciati DSC sono stati acquisiti con il calorimetro differenziale a scansione Mettler-Toledo DSC 822e, nelle seguenti condizioni operative: capsula di alluminio aperta, intervallo 25-300°C con velocità di 10°C/min, con azoto come gas di spurgo (80 ml/min). Bupropion hydrobromide Form α was characterized by X-ray powder diffraction (X-ray powder diffraction), by <1> H-NMR nuclear magnetic resonance spectrometer and by differential scanning calorimetry (DSC). The water content in the samples was determined by titration with the Karl Fisher technique. The X-ray diffraction spectra (XRPD) were collected with the automatic diffractometer for powders and liquids APD-2000 of the company Ital-Structures under the following operating conditions: CuKα radiation (λ = 1.5418 Å), scanning with angular interval 3-40 ° in 2θ, with an angular step of 0.03 ° for a time of 1 sec. The <1> H-NMR spectra were acquired with the Varian Mercury 300 spectrometer, using DMSO-d6 as the solvent. The DSC tracings were acquired with the Mettler-Toledo DSC 822e differential scanning calorimeter, under the following operating conditions: open aluminum capsule, range 25-300 ° C at a rate of 10 ° C / min, with nitrogen as purge gas ( 80 ml / min).
Figura 1: Spettro XRPD di Bupropione bromidrato Forma α. Figure 1: XRPD Spectrum of Bupropion Hydrobromide Form α.
Figura 2: Tracciato DSC di Bupropione bromidrato Forma α. Figure 2: DSC trace of Bupropion hydrobromide Form α.
Le dimensioni delle particelle ed il D50sono determinati con la nota tecnica di laser light scattering impiegando uno strumento Malvern Mastersizer MS1 nelle seguenti condizioni operative: Particle size and D50 are determined with the known laser light scattering 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; • 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. • 500 mg sample dispersed in 10 ml of hexane (ACS reagent) with 1% of SPAN 85 <®>, without presonication, and with a stirring speed of 2500 rpm.
DESCRIZIONE DETTAGLIATA DELL’INVENZIONE DETAILED DESCRIPTION OF THE INVENTION
La presente invenzione fornisce una nuova forma cristallina di Bupropione bromidrato solvata con etanolo e sostanzialmente anidra, qui definita come Forma α, contenente circa da 2,5% p/p a 4,5% p/p di etanolo, preferibilmente 3,5% p/p di etanolo corrispondente a circa 0,25 moli di etanolo per mole di Bupropione bromidrato; avente un XRPD come sostanzialmente illustrato in Figura 1, dove i picchi più intensi si riscontrano a 7.9, 12.0, 15.1, 15.5, 15.7, 17.8, 19.4, 23.1, 23.9, 24.9, 25.2, 28.6 e 29.4 ± 0,2° in 2θ; ed un tracciato DSC come sostanzialmente riportato in Figura 2, dove le principali endotermie si riscontrano a circa 80°C (perdita del solvente di cristallizzazione) e a circa 235-240°C (fusione e decomposizione termica). The present invention provides a novel crystalline form of ethanol-solved and substantially anhydrous Bupropion hydrobromide, herein defined as Form α, containing about 2.5% w / w to 4.5% w / w ethanol, preferably 3.5% w / w of ethanol corresponding to about 0.25 moles of ethanol per mol of Bupropion hydrobromide; having an XRPD as substantially illustrated in Figure 1, where the most intense peaks are found at 7.9, 12.0, 15.1, 15.5, 15.7, 17.8, 19.4, 23.1, 23.9, 24.9, 25.2, 28.6 and 29.4 ± 0.2 ° in 2θ ; and a DSC trace as substantially reported in Figure 2, where the main endotherms are found at about 80 ° C (loss of the crystallization solvent) and at about 235-240 ° C (melting and thermal decomposition).
Tale Forma cristallina α ha un contenuto d’acqua di bagnatura compreso tra 0 e 1%, tipicamente tra 0,01 e 0,5%, tale da poter essere definita sostanzialmente anidra. This crystalline form α has a wetting water content between 0 and 1%, typically between 0.01 and 0.5%, such that it can be defined as substantially anhydrous.
Bupropione bromidrato Forma cristallina α, come prima definito, può essere preparato mediante un procedimento comprendente: Bupropion hydrobromide Crystalline form α, as defined above, can be prepared by a process comprising:
• Dispersione di Bupropione bromidrato in etanolo o una sua miscela con un altro solvente, e sua dissoluzione; • Dispersion of Bupropion hydrobromide in ethanol or a mixture thereof with another solvent, and its dissolution;
• Lento raffreddamento della soluzione; e • Slow cooling of the solution; And
• Recupero del solido formato. • Recovery of the solid format.
Una sua miscela di etanolo con un altro solvente può essere una miscela con uno o più solventi, preferibilmente 1 o 2, scelti indipendentemente tra un solvente organico apolare, un solvente organico polare aprotico ed un solvente polare protico. A mixture thereof of ethanol with another solvent can be a mixture with one or more solvents, preferably 1 or 2, independently selected from an apolar organic solvent, an aprotic polar organic solvent and a protic polar solvent.
Un solvente organico apolare può essere ad esempio un idrocarburo alifatico o aromatico, preferibilmente esano, eptano o toluene; un C1-C4alchil esteri di un acido carbossilico, preferibilmente acetato di etile o acetato di isopropile; un etere, preferibilmente THF. An apolar organic solvent can be for example an aliphatic or aromatic hydrocarbon, preferably hexane, heptane or toluene; a C1-C4alkyl esters of a carboxylic acid, preferably ethyl acetate or isopropyl acetate; an ether, preferably THF.
Un solvente organico polare aprotico può essere ad esempio un C3-C7chetone, preferibilmente acetone, metil-etil chetone o metil-isobutil chetone. An aprotic polar organic solvent can be for example a C3-C7ketone, preferably acetone, methyl-ethyl ketone or methyl-isobutyl ketone.
Un solvente polare protico può essere ad esempio acqua o un C1-C4alcanolo, preferibilmente metanolo, etanolo o isopropanolo, più preferibilmente etanolo come unico solvente. A polar protic solvent can be for example water or a C1-C4alkanol, preferably methanol, ethanol or isopropanol, more preferably ethanol as the only solvent.
La concentrazione di Bupropione bromidrato nella dispersione di partenza può essere compresa tra circa 2 e 60% p/p, preferibilmente tra circa 10 e 30%. The concentration of Bupropion hydrobromide in the starting dispersion can be comprised between about 2 and 60% w / w, preferably between about 10 and 30%.
Per facilitare la dissoluzione di Bupropione bromidrato nella dispersione, questa può essere riscaldata ad esempio fino a riflusso. To facilitate the dissolution of Bupropion hydrobromide in the dispersion, the dispersion can be heated, for example, to reflux.
Il raffreddamento è preferibilmente effettuato a una velocità non superiore ai 6-7°C/min., più preferibilmente ad una velocità compresa tra circa 0,5 e 5°C/min., fino a portare la temperatura della miscela di reazione ad una temperatura compresa tra la temperatura ambiente e circa 0°C. The cooling is preferably carried out at a rate not exceeding 6-7 ° C / min., More preferably at a rate comprised between about 0.5 and 5 ° C / min., Until the temperature of the reaction mixture is brought to a temperature between room temperature and about 0 ° C.
La cristallizzazione e precipitazione di Bupropione bromidrato in Forma cristallina α può essere favorita per aggiunta di cristalli della Forma α, precedentemente ottenuti. The crystallization and precipitation of Bupropion hydrobromide in crystalline Form α can be favored by adding crystals of Form α, previously obtained.
Bupropione bromidrato in Forma cristallina α può essere recuperato dalla dispersione finale con una delle tecniche note, come filtrazione o centrifugazione, preferibilmente per filtrazione. Bupropion hydrobromide in crystalline form α can be recovered from the final dispersion with one of the known techniques, such as filtration or centrifugation, preferably by filtration.
La dimensione dei cristalli di Bupropione bromidrato Forma α ottenuti in accordo al presente procedimento è caratterizzata da un valore di D50compreso tra 25 e 250 µm. Se desiderato, tale valore può essere ridotto mediante micronizzazione o fine molitura. The size of the crystals of Bupropion hydrobromide Form α obtained according to the present process is characterized by a value of D50 comprised between 25 and 250 µm. If desired, this value can be reduced by micronization or fine milling.
Bupropione bromidrato Forma cristallina α, come ottenibile dal procedimento dell’invenzione, ha un grado di purezza uguale o maggiore del 99,9%, cioè di qualità idonea a soddisfare le normative regolatorie per i prodotti di uso terapeutico. Bupropion hydrobromide Crystalline form α, as obtainable from the process of the invention, has a degree of purity equal to or greater than 99.9%, that is, of a quality suitable to meet the regulatory standards for products for therapeutic use.
Bupropione bromidrato Forma cristallina α, similmente a Bupropione bromidrato in forme note, è utile nel trattamento delle stesse patologie. Oggetto dell’invenzione è anche una composizione farmaceutica comprendente un diluente e/o veicolante e, come principio attivo, Bupropione bromidrato Forma cristallina α. Tale composizione, se desiderato, può contenere in aggiunta, come principio attivo, almeno una delle forme note di Bupropione o un suo sale, ad esempio quelle prima citate. Bupropion hydrobromide Crystalline form α, similar to Bupropion hydrobromide in known forms, is useful in the treatment of the same pathologies. The subject of the invention is also a pharmaceutical composition comprising a diluent and / or carrier and, as an active ingredient, Bupropion hydrobromide. Crystalline form α. This composition, if desired, can additionally contain, as an active principle, at least one of the known forms of Bupropion or one of its salt, for example those mentioned above.
La scelta del rapporto tra la quantità della nuova Forma α e quelle note dipende dalle loro proprietà fisiche e biologiche ed è lasciata alla discrezione degli esperti del settore. The choice of the ratio between the quantity of the new Form α and the known ones depends on their physical and biological properties and is left to the discretion of the experts in the field.
Le composizioni farmaceutiche dell’invenzione possono essere formulate in una varietà di forme farmaceutiche per la somministrazione nell’uomo o negli animali, in accordo a tecniche note. Queste possono essere ad esempio sotto forma di capsule, compresse, confetti od altre forme note. I seguenti esempi illustrano l’invenzione. The pharmaceutical compositions of the invention can be formulated in a variety of pharmaceutical forms for administration in humans or animals, according to known techniques. These can be for example in the form of capsules, tablets, sugared almonds or other known forms. The following examples illustrate the invention.
Esempio 1. Preparazione di Bupropione HBr Forma α Example 1. Preparation of Bupropion HBr Form α
2,5 g di Bupropione bromidrato vengono sospesi in 12 ml di etanolo. La dispersione viene scaldata a riflusso fino a dissoluzione completa del solido. La dispersione viene poi lentamente riportata a temperatura ambiente, precipita un solido. Si recupera il solido per filtrazione su Bückner. 2.5 g of Bupropion hydrobromide are suspended in 12 ml of ethanol. The dispersion is heated under reflux until complete dissolution of the solid. The dispersion is then slowly brought back to room temperature, a solid precipitates. The solid is recovered by filtration on Bückner.
XRPD: Picchi principali a 7.9, 12.0, 15.1, 15.5, 15.7, 17.8, 19.4, 23.1, 23.9, 24.9, 25.2, 28.6 e 29.4 ± 0,2° in 2θ. XRPD: Main peaks at 7.9, 12.0, 15.1, 15.5, 15.7, 17.8, 19.4, 23.1, 23.9, 24.9, 25.2, 28.6 and 29.4 ± 0.2 ° in 2θ.
H<1>-NMR (in DMSO): m (1H) 9.0 ppm; m (1H) 8.6 ppm; d (1H) 8.25 ppm; d (1H) 8.15-17 ppm; dd (1H) 7.8 ppm; t (1H) 7.6 ppm; m (1H) 5.3 ppm; q (0.5H) 3.4 ppm; d (3H) 1.5 ppm; s (9H) 1.3 ppm; t (0.75H) 1.0 ppm. H <1> -NMR (in DMSO): m (1H) 9.0 ppm; m (1H) 8.6 ppm; d (1H) 8.25 ppm; d (1H) 8.15-17 ppm; dd (1H) 7.8 ppm; t (1H) 7.6 ppm; m (1H) 5.3 ppm; q (0.5H) 3.4 ppm; d (3H) 1.5 ppm; s (9H) 1.3 ppm; t (0.75H) 1.0 ppm.
DSC: Principali endotermie a circa 80°C (perdita del solvente di cristallizzazione) e a circa 235-240°C. Purezza 99,8%. DSC: Main endotherms at about 80 ° C (loss of crystallization solvent) and at about 235-240 ° C. Purity 99.8%.
Esempio 2. Preparazione di Bupropione HBr Forma α Example 2. Preparation of Bupropion HBr Form α
2,0 g di Bupropione bromidrato vengono sospesi in 10 ml di etanolo e la dispersione viene scaldata a riflusso fino a dissoluzione completa del solido. La dispersione viene poi riportata a temperatura ambiente, precipita un solido. Si raffredda in bagno di acqua e ghiaccio e si recupera il solido per filtrazione su Bückner. 2.0 g of Bupropion hydrobromide are suspended in 10 ml of ethanol and the dispersion is heated under reflux until complete dissolution of the solid. The dispersion is then brought back to room temperature, a solid precipitates. It is cooled in an ice and water bath and the solid is recovered by filtration on Bückner.
XRPD: Picchi principali a 7.9, 12.0, 15.1, 15.5, 15.7, 17.8, 19.4, 23.1, 23.9, 24.9, 25.2, 28.6 e 29.4± 0,2° in 2θ. XRPD: Main peaks at 7.9, 12.0, 15.1, 15.5, 15.7, 17.8, 19.4, 23.1, 23.9, 24.9, 25.2, 28.6 and 29.4 ± 0.2 ° in 2θ.
H<1>-NMR (in DMSO): m (1H) 9.0 ppm; m (1H) 8.6 ppm; d (1H) 8.25 ppm; d (1H) 8.15-17 ppm; dd (1H) 7.8 ppm; t (1H) 7.6 ppm; m (1H) 5.3 ppm; q (0.5H) 3.4 ppm; d (3H) 1.5 ppm; s (9H) 1.3 ppm; t (0.75H) 1.0 ppm. H <1> -NMR (in DMSO): m (1H) 9.0 ppm; m (1H) 8.6 ppm; d (1H) 8.25 ppm; d (1H) 8.15-17 ppm; dd (1H) 7.8 ppm; t (1H) 7.6 ppm; m (1H) 5.3 ppm; q (0.5H) 3.4 ppm; d (3H) 1.5 ppm; s (9H) 1.3 ppm; t (0.75H) 1.0 ppm.
Esempio 3. Preparazione di Bupropione HBr Forma α 5,0 g di Bupropione bromidrato vengono sospesi in 25 ml di etanolo e la dispersione viene scaldata a riflusso fino a dissoluzione completa del solido. La dispersione viene poi raffreddata a 0°C. Si recupera il solido per filtrazione su Bückner. Si recuperano 2,8 g di Bupropione bromidrato Forma α. Example 3. Preparation of Bupropion HBr Form α 5.0 g of Bupropion hydrobromide are suspended in 25 ml of ethanol and the dispersion is heated under reflux until complete dissolution of the solid. The dispersion is then cooled to 0 ° C. The solid is recovered by filtration on Bückner. 2.8 g of Bupropion hydrobromide Form α are recovered.
XRPD: Picchi principali a 7.9, 12.0, 15.1, 15.5, 15.7, 17.8, 19.4, 23.1, 23.9, 24.9, 25.2, 28.6 e 29.4 ± 0,2° in 2θ. XRPD: Main peaks at 7.9, 12.0, 15.1, 15.5, 15.7, 17.8, 19.4, 23.1, 23.9, 24.9, 25.2, 28.6 and 29.4 ± 0.2 ° in 2θ.
H<1>-NMR (in DMSO): m (1H) 9.0 ppm; m (1H) 8.6 ppm; d (1H) 8.25 ppm; d (1H) 8.15-17 ppm; dd (1H) 7.8 ppm; t (1H) 7.6 ppm; m (1H) 5.3 ppm; q (0.5H) 3.4 ppm; d (3H) 1.5 ppm; s (9H) 1.3 ppm; t (0.75H) 1.0 ppm. H <1> -NMR (in DMSO): m (1H) 9.0 ppm; m (1H) 8.6 ppm; d (1H) 8.25 ppm; d (1H) 8.15-17 ppm; dd (1H) 7.8 ppm; t (1H) 7.6 ppm; m (1H) 5.3 ppm; q (0.5H) 3.4 ppm; d (3H) 1.5 ppm; s (9H) 1.3 ppm; t (0.75H) 1.0 ppm.
DSC: Principali endotermie a circa 80°C (perdita del solvente di cristallizzazione) e a circa 235-240°C. DSC: Main endotherms at about 80 ° C (loss of crystallization solvent) and at about 235-240 ° C.
Contenuto d’acqua: 0,02%. Contenuto di etanolo: 3,5%. Purezza: 99,9%. Water content: 0.02%. Ethanol content: 3.5%. Purity: 99.9%.
Esempio 4. Preparazione di Bupropione HBr Forma α Example 4. Preparation of Bupropion HBr Form α
3,0 g di Bupropione bromidrato vengono sospesi in 14 ml di etanolo e la dispersione viene scaldata a riflusso fino a dissoluzione completa del solido. La dispersione viene poi lentamente riportata a temperatura ambiente, precipita un solido. Si recupera il solido per filtrazione su Bückner e si lava con acetonitrile. 3.0 g of Bupropion hydrobromide are suspended in 14 ml of ethanol and the dispersion is heated under reflux until complete dissolution of the solid. The dispersion is then slowly brought back to room temperature, a solid precipitates. The solid is recovered by filtration on Bückner and washed with acetonitrile.
XRPD: Picchi principali a 7.9, 12.0, 15.1, 15.5, 15.7, 17.8, 19.4, 23.1, 23.9, 24.9, 25.2, 28.6 e 29.4 ± 0,2° in 2θ. XRPD: Main peaks at 7.9, 12.0, 15.1, 15.5, 15.7, 17.8, 19.4, 23.1, 23.9, 24.9, 25.2, 28.6 and 29.4 ± 0.2 ° in 2θ.
H<1>-NMR (in DMSO): m (1H) 9.0 ppm; m (1H) 8.6 ppm; d (1H) 8.25 ppm; d (1H) 8.15-17 ppm; dd (1H) 7.8 ppm; t (1H) 7.6 ppm; m (1H) 5.3 ppm; q (0.5H) 3.4 ppm; d (3H) 1.5 ppm; s (9H) 1.3 ppm; t (0.75H) 1.0 ppm. H <1> -NMR (in DMSO): m (1H) 9.0 ppm; m (1H) 8.6 ppm; d (1H) 8.25 ppm; d (1H) 8.15-17 ppm; dd (1H) 7.8 ppm; t (1H) 7.6 ppm; m (1H) 5.3 ppm; q (0.5H) 3.4 ppm; d (3H) 1.5 ppm; s (9H) 1.3 ppm; t (0.75H) 1.0 ppm.
DSC: Principali endotermie a circa 80°C (perdita del solvente di cristallizzazione) e a circa 235-240°C. Purezza: 99,9%. DSC: Main endotherms at about 80 ° C (loss of crystallization solvent) and at about 235-240 ° C. Purity: 99.9%.
Claims (10)
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