ITMI20111291A1 - ALISKIREN EMIFUMARATE ETYL ACETATE SOLVATE - Google Patents
ALISKIREN EMIFUMARATE ETYL ACETATE SOLVATE Download PDFInfo
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- ITMI20111291A1 ITMI20111291A1 IT001291A ITMI20111291A ITMI20111291A1 IT MI20111291 A1 ITMI20111291 A1 IT MI20111291A1 IT 001291 A IT001291 A IT 001291A IT MI20111291 A ITMI20111291 A IT MI20111291A IT MI20111291 A1 ITMI20111291 A1 IT MI20111291A1
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- IT
- Italy
- Prior art keywords
- aliskiren
- crystalline form
- ethyl acetate
- acetate solvate
- aliskiren hemifumarate
- Prior art date
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 title claims description 50
- 239000012453 solvate Substances 0.000 title claims description 20
- UXOWGYHJODZGMF-QORCZRPOSA-N Aliskiren Chemical compound COCCCOC1=CC(C[C@@H](C[C@H](N)[C@@H](O)C[C@@H](C(C)C)C(=O)NCC(C)(C)C(N)=O)C(C)C)=CC=C1OC UXOWGYHJODZGMF-QORCZRPOSA-N 0.000 title claims description 16
- 229960004601 aliskiren Drugs 0.000 title claims description 16
- KLRSDBSKUSSCGU-KRQUFFFQSA-N aliskiren fumarate Chemical compound OC(=O)\C=C\C(O)=O.COCCCOC1=CC(C[C@@H](C[C@H](N)[C@@H](O)C[C@@H](C(C)C)C(=O)NCC(C)(C)C(N)=O)C(C)C)=CC=C1OC.COCCCOC1=CC(C[C@@H](C[C@H](N)[C@@H](O)C[C@@H](C(C)C)C(=O)NCC(C)(C)C(N)=O)C(C)C)=CC=C1OC KLRSDBSKUSSCGU-KRQUFFFQSA-N 0.000 claims description 24
- 229960004863 aliskiren hemifumarate Drugs 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 9
- 239000002244 precipitate Substances 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 4
- 238000002844 melting Methods 0.000 claims description 4
- 230000008018 melting Effects 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000000634 powder X-ray diffraction Methods 0.000 claims 2
- 238000000113 differential scanning calorimetry Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 4
- -1 hemifumarate ethyl acetate Chemical compound 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000002411 thermogravimetry Methods 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 3
- 238000001757 thermogravimetry curve Methods 0.000 description 3
- 230000004580 weight loss Effects 0.000 description 3
- 102100030988 Angiotensin-converting enzyme Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 2
- 238000004566 IR spectroscopy Methods 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 1
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 1
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 1
- 101800000734 Angiotensin-1 Proteins 0.000 description 1
- 102400000344 Angiotensin-1 Human genes 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- 102400000345 Angiotensin-2 Human genes 0.000 description 1
- 102000004881 Angiotensinogen Human genes 0.000 description 1
- 108090001067 Angiotensinogen Proteins 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000407429 Maja Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 1
- 102100028255 Renin Human genes 0.000 description 1
- 108090000783 Renin Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229960002478 aldosterone Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 210000002439 juxtaglomerular apparatus Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000002461 renin inhibitor Substances 0.000 description 1
- 230000036454 renin-angiotensin system Effects 0.000 description 1
- 229940086526 renin-inhibitors Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000003639 vasoconstrictive effect Effects 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Fats And Perfumes (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Titolo: “Aliskiren emifumarato etil acetato solvato†Descrizione Title: â € œAliskiren hemifumarate ethyl acetate solvatedâ € Description
E’ oggetto della presente invenzione una nuova forma cristallina di Aliskiren emifumarato, Aliskiren etil acetato solvato, avente nuove e distintive caratteristiche chimico-fisiche. Forma ulteriore oggetto della presente invenzione un processo per la preparazione di detta forma cristallina di Aliskiren emifumarato etil acetato solvato. The object of the present invention is a new crystalline form of Aliskiren hemifumarate, Aliskiren ethyl acetate solvate, having new and distinctive chemical-physical characteristics. A further object of the present invention is a process for the preparation of said crystalline form of Aliskiren hemifumarate ethyl acetate solvate.
Stato dell’arte State of the art
Aliskiren à ̈ un antiipertensivo che agisce sul sistema renina-angiotensina-aldosterone inibendolo. In particolare, Aliskiren à ̈ un inibitore diretto della renina. La renina à ̈ un enzima che, secreto dall'apparato iuxtaglomerulare renale in seguito a stimolazione simpatica provocata da un abbassamento della pressione arteriosa, converte l'angiotensinogeno (proteina inattiva prodotta dal fegato e normalmente circolante) in Angiotensina 1, la quale viene poi convertita dall'enzima ACE (Angiotensin Converting Enzyme) in Angiotensina 2, proteina attiva dalle capacità vasocostrittrici e stimolante la produzione di aldosterone. Aliskiren is an antihypertensive that acts on the renin-angiotensin-aldosterone system by inhibiting it. Specifically, Aliskiren is a direct renin inhibitor. Renin is an enzyme which, secreted by the renal juxtaglomerular apparatus following sympathetic stimulation caused by a lowering of blood pressure, converts angiotensinogen (inactive protein produced by the liver and normally circulating) into Angiotensin 1, which is then converted from the ACE enzyme (Angiotensin Converting Enzyme) into Angiotensin 2, an active protein with vasoconstrictive properties and stimulating the production of aldosterone.
Nome chimico dell’Aliskiren di formula (A) à ̈ (2S,4S,5S,7S)-5-ammino-N-(3-ammino-2,2-dimetil-3-ossopropil)-4-idrossi-7-[[4-metossi-3-(3-metossipropossi)fenil]metil]-8-metil-2-propan-2 Chemical name of Aliskiren of formula (A) à ̈ (2S, 4S, 5S, 7S) -5-amino-N- (3-amino-2,2-dimethyl-3-oxopropyl) -4-hydroxy-7 - [[4-methoxy-3- (3-methoxy propoxy) phenyl] methyl] -8-methyl-2-propan-2
ilnonanammide. ilnonanamide.
A TO
Sono note difficoltà legate alla formulazione di Aliskiren. Queste sono principalmente attribuibili all’alta igroscopicità di Aliskiren e alla sua relativamente bassa stabilità . Difficulties associated with the formulation of Aliskiren are known. These are mainly attributable to the high hygroscopicity of Aliskiren and its relatively low stability.
Il sale emifumarato dell’Aliskiren à ̈ noto ed à ̈ usato in terapia. The hemifumarate salt of Aliskiren is well known and used in therapy.
WO2009/064479 descrive forme amorfe e polimorfe di Aliskiren emifumarato e processi per la loro preparazione. Forme cristalline di Aliskiren emifumarato sono descritte in WO2008/061622. WO2009/143423 descrive invece Aliskiren monofumarato e processi preparativi per lo stesso. La base libera dell’Aliskiren à ̈ descritta in WO2009/149344. WO2009 / 064479 discloses amorphous and polymorphic forms of Aliskiren hemifumarate and processes for their preparation. Crystal forms of Aliskiren hemifumarate are described in WO2008 / 061622. WO2009 / 143423 instead describes Aliskiren monofumarate and preparatory processes for the same. The free base of Aliskiren is described in WO2009 / 149344.
Le proprietà fisiche di un principio attivo allo stato solido sono fondamentali per la gestione del materiale durante la trasformazione in un prodotto farmaceutico. Si evidenziano in particolare le proprietà di scorrimento, oltre al tasso di dissoluzione in un liquido acquoso. Quest’ultimo influenzerà la velocità di dissoluzione del principio attivo nello stomaco di un paziente con evidenti conseguenze terapeutiche. Il tasso di dissoluzione à ̈ da tenere in forte considerazione anche nella formulazione di sciroppi, elisir e di altri medicamenti liquidi. Queste ed altre caratteristiche fisiche sono influenzate dalla conformazione e dall'orientamento delle molecole nella cella unitaria, che definisce una particolare forma polimorfica di una sostanza. La forma polimorfica può dar luogo a un comportamento termico diverso da quello del materiale amorfo o un'altra forma polimorfica. Il comportamento termico à ̈ misurato in laboratorio con tecniche quali il punto di fusione capillare, l’analisi termogravimetrica (TGA) e la calorimetria differenziale a scansione (DSC) e può essere utilizzato per distinguere alcune forme polimorfe da altre. Una particolare forma polimorfica può anche dar luogo a distinte proprietà spettroscopiche, rilevabili con cristallografia a raggi X, spettrometria NMR e spettrometria a infrarossi. The physical properties of an active substance in the solid state are fundamental for the management of the material during transformation into a pharmaceutical product. The flow properties are highlighted in particular, as well as the dissolution rate in an aqueous liquid. The latter will affect the speed of dissolution of the active ingredient in the stomach of a patient with obvious therapeutic consequences. The dissolution rate is also to be taken into consideration in the formulation of syrups, elixirs and other liquid medicaments. These and other physical characteristics are influenced by the conformation and orientation of the molecules in the unit cell, which defines a particular polymorphic form of a substance. The polymorphic form can give rise to a different thermal behavior from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory with techniques such as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and can be used to distinguish some polymorphic forms from others. A particular polymorphic form can also give rise to distinct spectroscopic properties, detectable with X-ray crystallography, NMR spectrometry and infrared spectrometry.
La scoperta di nuove forme di Aliskiren emifumarato fornisce una nuova opportunità per migliorare il processo di sintesi del principio attivo farmaceutico (API), portando ad una forma di Aliskiren emifumarato con caratteristiche migliorate, ad esempio in termini di fluidità e solubilità , di cui si avverte la mancanza nello stato dell’arte. The discovery of new forms of Aliskiren hemifumarate provides a new opportunity to improve the synthesis process of the pharmaceutical active ingredient (API), leading to a form of Aliskiren hemifumarate with improved characteristics, for example in terms of fluidity and solubility, of which it is felt the lack in the state of the art.
Qui à ̈ per la prima volta preparata, descritta e caratterizzata una nuova forma cristallina di Aliskiren emifumarato, Aliskiren etil acetato solvato. Here a new crystalline form of Aliskiren hemifumarate, Aliskiren ethyl acetate solvate, is prepared, described and characterized for the first time.
Descrizione dell’invenzione Description of the invention
Scopo della presente invenzione à ̈ mettere a disposizione una nuova forma cristallina di Aliskiren emifumarato, Aliskiren etil acetato solvato. The purpose of the present invention is to make available a new crystalline form of Aliskiren hemifumarate, Aliskiren ethyl acetate solvate.
Una comprensione più completa della presente invenzione può essere ottenuta riferendosi alle tabelle riassuntive di alcune caratteristiche chimico fisiche di Aliskiren emifumarato etil acetato solvato in seguito riportate. A more complete understanding of the present invention can be obtained by referring to the summary tables of some physico-chemical characteristics of Aliskiren hemifumarate ethyl acetate solvate reported below.
Vengono riportati i picchi principali di diffrazione ai raggi X, le bande principali e caratteristiche dello spettro FT-IR, l’analisi termogravimetrica. The main X-ray diffraction peaks, the main bands and characteristics of the FT-IR spectrum, the thermogravimetric analysis are reported.
Il diffrattogramma della polvere ai raggi X (XRPD) à ̈ stato ottenuto usando lo strumento X'Pert PRO PANalytical con una singola scansione, utilizzando una radiazione Kα1. Il diffrattogramma à ̈ misurato in modalità riflessione nell’intervallo 3-40°2Î ̧. The X-ray powder diffractogram (XRPD) was obtained using the X'Pert PRO PANalytical instrument with a single scan, using a KÎ ± 1 radiation. The diffractogram is measured in reflection mode in the range 3-40 ° 2Î ̧.
Lo spettro FT-IR (spettroscopia IR a trasformata di Fourier) à ̈ stato registrato usando l’apparato Nicolet FT-IR 6700 (ThermoFischer) equipaggiato con uno splitter KBr e un detector DTGS KBr. Lo spettro à ̈ stato acquisito in 32 scansioni a una risoluzione di 4 cm<-1>. The FT-IR spectrum (Fourier transform IR spectroscopy) was recorded using the Nicolet FT-IR 6700 (ThermoFischer) apparatus equipped with a KBr splitter and a DTGS KBr detector. The spectrum was acquired in 32 scans at a resolution of 4 cm <-1>.
Le analisi DSC sono state ottenute mediante l’utilizzo di un calorimetro differenziale a scansione DSC 200 F3 Maia®. I campioni sono stati caricati su crogioli in alluminio e scaldati a 5°C/min nel range di temperatura da 30 a 350°C. The DSC analyzes were obtained by using a DSC 200 F3 Maia® differential scanning calorimeter. The samples were loaded on aluminum crucibles and heated at 5 ° C / min in the temperature range from 30 to 350 ° C.
I termogrammi sono stati ottenuti mediante l’utilizzo di una termobilancia STA 409 PC Luxx® Netzsch. I campioni sono stati caricati su crogioli in alluminio e scaldati a 10°C/min nel range di temperatura da 25 a 490°C. The thermograms were obtained using a STA 409 PC Luxx® Netzsch thermobalance. The samples were loaded on aluminum crucibles and heated at 10 ° C / min in the temperature range from 25 to 490 ° C.
Descrizione delle figure Description of the figures
Figura 1: spettro XRPD di Aliskiren emifumarato etil acetato solvato. Figure 1: XRPD spectrum of Aliskiren hemifumarate ethyl acetate solvate.
Figura 2: spettro FT-IR di Aliskiren emifumarato etil acetato solvato. Figure 2: FT-IR spectrum of Aliskiren hemifumarate ethyl acetate solvate.
Figura 3: analisi DSC di Aliskiren emifumarato etil acetato solvato. Figure 3: DSC analysis of Aliskiren hemifumarate ethyl acetate solvate.
Figura 4: analisi TGA di Aliskiren emifumarato etil acetato solvato. Figure 4: TGA analysis of Aliskiren hemifumarate ethyl acetate solvate.
Descrizione dettagliata dell’invenzione: Detailed description of the invention:
Aliskiren emifumarato etil acetato solvato rivendicato nella presente invenzione à ̈ un solido cristallino caratterizzato dai parametri chimico-fisici che seguono. Aliskiren hemifumarate ethyl acetate solvate claimed in the present invention is a crystalline solid characterized by the following chemical-physical parameters.
L’analisi XRPD porta all’ottenimento del caratteristico spettro riportato in Figura 1. I picchi principali a 2teta /- 0,3 gradi sono: 5,1, 6,6, 7,7, 18,4, 18,6, 20,4, 23,4. La tabella 1 che segue riporta i picchi significativi dello spettro. The XRPD analysis leads to the obtainment of the characteristic spectrum shown in Figure 1. The main peaks at 2theta / - 0.3 degrees are: 5.1, 6.6, 7.7, 18.4, 18.6 , 20.4, 23.4. Table 1 below shows the significant peaks of the spectrum.
Tabella 1: Table 1:
L’analisi FT-IR dà lo spettro che si riporta in Figura 2. Detto spettro FT-IR à ̈ caratterizzato dai picchi riportati nella tabella 2 che segue. FT-IR analysis gives the spectrum shown in Figure 2. Said FT-IR spectrum is characterized by the peaks shown in table 2 below.
Tabella 2: Table 2:
L’analisi DSC, riportata in Figura 3, evidenzia un picco endotermico corrispondente al punto di fusione a circa 100,8°C, tra i 93 e i 103°C. Si osserva inoltre un secondo picco, di minore intensità , a circa 58°C, tra i 39 e gli 80°C che corrisponde alla perdita di solvente. The DSC analysis, shown in Figure 3, shows an endothermic peak corresponding to the melting point at about 100.8 ° C, between 93 and 103 ° C. A second peak, of lower intensity, is also observed at about 58 ° C, between 39 and 80 ° C, which corresponds to the loss of solvent.
Il termogramma riportato in Figura 4 riporta una continua perdita di peso passando da circa 25 a circa 490°C. Gli eventi caratteristici della perdita di peso misurata sono meglio osservabili sulla curva DTG, riportata sullo stesso grafico. La curva DTG rappresenta la derivata del termogramma e permette di osservare un evento significativo con perdita in peso di circa il 3.58% tra i 40°C e i 110°C che corrisponde alla perdita di solvente seguita dalla fusione del campione. Gli altri eventi osservati dopo i 150°C sono associati alla degradazione del campione in seguito al riscaldamento. The thermogram shown in Figure 4 shows a continuous weight loss passing from about 25 to about 490 ° C. The characteristic events of the measured weight loss are best observed on the DTG curve, shown on the same graph. The DTG curve represents the derivative of the thermogram and allows to observe a significant event with a weight loss of about 3.58% between 40 ° C and 110 ° C which corresponds to the loss of solvent followed by the melting of the sample. Other events observed after 150 ° C are associated with sample degradation upon heating.
Forma ulteriore oggetto della presente invenzione il processo per la preparazione di detta forma cristallina di Aliskiren emifumarato etil acetato solvato. A further object of the present invention is the process for the preparation of said crystalline form of Aliskiren hemifumarate ethyl acetate solvate.
In particolare, detto processo comprende: In particular, this process includes:
i) disciogliere Aliskiren emifurato in etil acetato, riscaldando a una temperatura compresa tra i 50 e gli 80°C, preferibilmente a circa 65°C; i) dissolving Aliskiren hemifurate in ethyl acetate, heating to a temperature between 50 and 80 ° C, preferably at about 65 ° C;
ii) raffreddare ad una temperatura e per un tempo adatti la soluzione ottenuta in i), ottenendo un precipitato; ii) cooling the solution obtained in i) to a suitable temperature and time, obtaining a precipitate;
iii)filtrare il precipitato ottenuto in ii); iii) filtering the precipitate obtained in ii);
iv) essiccare il precipitato ottenuto in iii) a una temperatura compresa tra i 25 e i 40°C, preferibilmente a circa 30°C, per un tempo compreso tra 1 e 4 ore, preferibilmente per circa 2 ore. iv) drying the precipitate obtained in iii) at a temperature ranging from 25 to 40 ° C, preferably at about 30 ° C, for a time ranging from 1 to 4 hours, preferably for about 2 hours.
Il prodotto ottenuto à ̈ la forma cristallina di Aliskiren emifurato etil acetato solvato rivendicata nella presente invenzione. The obtained product is the crystalline form of Aliskiren hemifurate ethyl acetate solvate claimed in the present invention.
In detta fase i), detta soluzione di Aliskiren emifurato in etil acetato à ̈ preferibilmente sovrasatura ed à ̈ una soluzione limpida. In detta fase ii) detto raffreddamento avviene preferibilmente a circa 0,5 – 5 °C/min., fino al raggiungimento di temperatura ambiente. In said phase i), said solution of hemifurate Aliskiren in ethyl acetate is preferably supersaturated and is a clear solution. In said step ii) said cooling preferably takes place at about 0.5 - 5 ° C / min., Until room temperature is reached.
Detta forma cristallina di Aliskiren emifumarato etil acetato solvato può trovare applicazione in composizioni farmaceutiche. La composizione farmaceutica che comprende detta forma cristallina può contenere additivi quali dolcificanti, aromi, sostanze di rivestimento, diluenti inerti quali lattosio e talco, leganti quali l’amido, l’idrossietilcellulosa, l’idrossipropilcellulosa e analoghi. Qualsiasi tecnica convenzionale può essere usata per la preparazione di formulazioni farmaceutiche in accordo con la presente invenzione. Said crystalline form of Aliskiren hemifumarate ethyl acetate solvate can find application in pharmaceutical compositions. The pharmaceutical composition which includes said crystalline form may contain additives such as sweeteners, flavors, coating substances, inert diluents such as lactose and talc, binders such as starch, hydroxyethyl cellulose, hydroxypropyl cellulose and analogues. Any conventional technique can be used for the preparation of pharmaceutical formulations according to the present invention.
Esempio 1: Processo per la preparazione di Aliskiren emifumarato etil acetato solvato, forma cristallina. Example 1: Process for the preparation of Aliskiren hemifumarate ethyl acetate solvate, crystalline form.
0.5 g di Aliskiren emifumarato sono stati disciolti in 6 ml di etil acetato a 65°C così da ottenere una soluzione sovra satura. La soluzione limpida à ̈ stata poi raffreddata lentamente fino alla temperature di 25°C e si à ̈ ottenuto un precipitato. Questo precipitato à ̈ stato filtrato, essiccato a 30°C per 2 ore e analizzato mediante XRPD. Il precipitato ottenuto à ̈ la forma cristallina di Aliskiren emifumarato etilacetato solvato. 0.5 g of Aliskiren hemifumarate were dissolved in 6 ml of ethyl acetate at 65 ° C to obtain an over saturated solution. The clear solution was then slowly cooled down to a temperature of 25 ° C and a precipitate was obtained. This precipitate was filtered, dried at 30 ° C for 2 hours and analyzed by XRPD. The precipitate obtained is the crystalline form of Aliskiren hemifumarate ethyl acetate solvate.
Claims (8)
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| IT001291A ITMI20111291A1 (en) | 2011-07-11 | 2011-07-11 | ALISKIREN EMIFUMARATE ETYL ACETATE SOLVATE |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008061622A1 (en) * | 2006-11-07 | 2008-05-29 | Novartis Ag | Crystalline forms of aliskiren hemifumarate |
| WO2009064479A1 (en) * | 2007-11-13 | 2009-05-22 | Teva Pharmaceutical Industries Ltd. | Polymorphic forms of aliskiren hemifumarate and process for preparation thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008061622A1 (en) * | 2006-11-07 | 2008-05-29 | Novartis Ag | Crystalline forms of aliskiren hemifumarate |
| WO2009064479A1 (en) * | 2007-11-13 | 2009-05-22 | Teva Pharmaceutical Industries Ltd. | Polymorphic forms of aliskiren hemifumarate and process for preparation thereof |
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