ITMI20132115A1 - A CRYSTAL SHAPE OF POSACONAZOLO - Google Patents
A CRYSTAL SHAPE OF POSACONAZOLOInfo
- Publication number
- ITMI20132115A1 ITMI20132115A1 IT002115A ITMI20132115A ITMI20132115A1 IT MI20132115 A1 ITMI20132115 A1 IT MI20132115A1 IT 002115 A IT002115 A IT 002115A IT MI20132115 A ITMI20132115 A IT MI20132115A IT MI20132115 A1 ITMI20132115 A1 IT MI20132115A1
- Authority
- IT
- Italy
- Prior art keywords
- posaconazole
- crystalline form
- analysis
- days
- propanol
- Prior art date
Links
- RAGOYPUPXAKGKH-XAKZXMRKSA-N posaconazole Chemical compound O=C1N([C@H]([C@H](C)O)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3C[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 RAGOYPUPXAKGKH-XAKZXMRKSA-N 0.000 claims description 36
- 229960001589 posaconazole Drugs 0.000 claims description 31
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 239000002244 precipitate Substances 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 238000002844 melting Methods 0.000 claims description 3
- 230000008018 melting Effects 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 238000000634 powder X-ray diffraction Methods 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000004458 analytical method Methods 0.000 description 6
- 238000000113 differential scanning calorimetry Methods 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000002411 thermogravimetry Methods 0.000 description 5
- 230000004580 weight loss Effects 0.000 description 5
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000001757 thermogravimetry curve Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 2
- 238000004566 IR spectroscopy Methods 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 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
- 238000001816 cooling Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 description 1
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 1
- 206010017533 Fungal infection Diseases 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
- 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
- 208000031888 Mycoses Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process 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
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 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
- 238000009472 formulation Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 238000004868 gas analysis Methods 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
- 239000008101 lactose Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 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
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 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
- 238000002076 thermal analysis method Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Description
Titolo: “Una forma cristallina di Posaconazolo” Descrizione Title: “A crystalline form of Posaconazole” Description
E’ oggetto della presente invenzione una nuova forma cristallina di Posaconazolo, denominata Forma C avente nuove e distintive caratteristiche chimicofisiche qui descritte, oltre che una composizione farmaceutica che lo comprende. Forma ulteriore oggetto della presente invenzione un processo per la preparazione di detto Posaconazolo, Forma C. The subject of the present invention is a new crystalline form of Posaconazole, called Form C having new and distinctive chemical-physical characteristics described herein, as well as a pharmaceutical composition that includes it. A further object of the present invention is a process for the preparation of said Posaconazole, Form C.
Stato dell’arte State of the art
Posaconazolo (CAS Registry Number 171228-49-2), rappresentato dalla formula (I) che segue, è noto come agente antifungino. Posaconazole (CAS Registry Number 171228-49-2), represented by the formula (I) below, is known as an antifungal agent.
Nome chimico del Posaconazolo di formula (I) è 2,5-anidro-1,3,4-trideossi-2-C-(2,4-difluorofenil)-4-[[4-[4-[4-[1-[(1S,2S)-1-etil-2-idrossipropil]-1,5-diidro-5-osso-4H-1,2,4-triazol-4-yl]fenil]-1-piperazinil]fenossi]metil]-1-(1H-1,2,4-triazol-1-yl)-D-treo-pentitolo. Chemical name of Posaconazole of formula (I) is 2,5-anhydrous-1,3,4-trideoxy-2-C- (2,4-difluorophenyl) -4 - [[4- [4- [4- [1 - [(1S, 2S) -1-ethyl-2-hydroxypropyl] -1,5-dihydro-5-oxo-4H-1,2,4-triazol-4-yl] phenyl] -1-piperazinyl] phenoxy] methyl] -1- (1H-1,2,4-triazol-1-yl) -D-threo-pentitol.
WO95/17407 e WO 96/38443 descrivono un composto di formula (I) e il suo uso nel trattamento di infezioni fungine. WO95 / 17407 and WO 96/38443 describe a compound of formula (I) and its use in the treatment of fungal infections.
Tre forme polimorfiche di Posaconazolo, Forma I, II e III sono descritte e caratterizzate in WO 99/18097 Vi è la necessità di forme alternative di Posaconazolo che siano più stabili quando usate in composizioni farmaceutiche e/o che abbiano proprietà vantaggiose per la loro preparazione e stoccaggio. Three polymorphic forms of Posaconazole, Form I, II and III are described and characterized in WO 99/18097 There is a need for alternative forms of Posaconazole which are more stable when used in pharmaceutical compositions and / or which have advantageous properties for their preparation and storage.
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 è 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 è misurato in laboratorio con tecniche quali il punto di fusione capillare, l’analisi termo gravimetrica (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 dissolution rate of the active ingredient in a patient's stomach 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. The thermal behavior is measured in the laboratory with techniques such as the capillary melting point, thermo gravimetric 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 Posaconazolo fornisce una nuova opportunità per migliorare il processo di sintesi del principio attivo farmaceutico (API), portando ad una forma di Posaconazolo 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 Posaconazole provides a new opportunity to improve the synthesis process of the active pharmaceutical ingredient (API), leading to a form of Posaconazole with improved characteristics, for example in terms of fluidity and solubility, which are noticeable. in the state of the art.
Qui è per la prima volta preparata, descritta e caratterizzata una nuova forma cristallina di Posaconazolo, avente caratteristiche chimico-fisiche distintive e vantaggiose. Here a new crystalline form of Posaconazole, having distinctive and advantageous chemical-physical characteristics, is prepared, described and characterized for the first time.
Descrizione dell’invenzione Description of the invention
Scopo della presente invenzione è mettere a disposizione una nuova forma cristallina di Posaconazolo. The purpose of the present invention is to make available a new crystalline form of Posaconazole.
Una comprensione più completa della presente invenzione può essere ottenuta riferendosi alle tabelle riassuntive di alcune caratteristiche chimico fisiche di Posaconazolo in seguito riportate. A more complete understanding of the present invention can be obtained by referring to the summary tables of some chemical and physical characteristics of Posaconazole reported below.
Vengono riportati i picchi principali di diffrazione ai raggi X, le bande principali e caratteristiche dello spettro FT-IR, l’analisi termica a scansione differenziale (DSC), l’analisi termo gravimetrica, analisi dei gas evoluti (EGA). The main peaks of X-ray diffraction, the main bands and characteristics of the FT-IR spectrum, differential scanning thermal analysis (DSC), thermo-gravimetric analysis, evolved gas analysis (EGA) are reported.
Il diffrattogramma della polvere ai raggi X (XRPD) è stato ottenuto usando lo strumento X'Pert PRO PANalytical equipaggiato con rivelatore X'Celerator e tubo a raggi X (Cu LFF PW3373/00 DK312503) con intensità di corrente 40mA e tensione 40kV. Il campione viene posto su un supporto e analizzato utilizzando i seguenti parametri: The X-ray powder diffractogram (XRPD) was obtained using the X'Pert PRO PANalytical instrument equipped with X'Celerator detector and X-ray tube (Cu LFF PW3373 / 00 DK312503) with 40mA current intensity and 40kV voltage. The sample is placed on a support and analyzed using the following parameters:
- Campo di scansione (°): 3,0010-39,9997 - Scanning range (°): 3.0010-39.9997
- Step size (°): 0,0167 - Step size (°): 0.0167
- Modalità di scansione: continua - Scan mode: continuous
- Tempo di conteggio (s): 12,700 - Counting time (s): 12,700
- Fessura Soller (rad): 0.04 - Soller slot (rad): 0.04
- Fessura divergente: 1/4 - Diverging slot: 1/4
- Fessura Antiscatter: 1/2 - Antiscatter slot: 1/2
Lo spettro FT-IR (spettroscopia IR a trasformata di Fourier) è stato registrato usando l’apparato Nicolet FT-IR 6700 (ThermoFischer) equipaggiato con uno splitter KBr e un detector DTGS KBr. Lo spettro è stato acquisito in 16 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 16 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 350°C ad una . velocità di riscaldamento di 10K/min. The DSC analyzes were obtained by using a DSC 200 F3 Maia® differential scanning calorimeter. The samples were loaded on aluminum crucibles and heated to 350 ° C at one. heating rate of 10K / min.
Sensore: sistema di flusso di calore. Sensor: heat flow system.
Range di misura da 0 mW a ± 600 mW. Measurement range from 0 mW to ± 600 mW.
Accuratezza della temperatura: 0,1 K Temperature accuracy: 0.1K
Accuratezza dell’entalpia: generalmente <1% Enthalpy accuracy: generally <1%
Opzioni di raffreddamento: ad aria forzata (fino a temperatura ambiente), azoto liquido (fino a -170 ° C) Portata del gas di lavaggio: 60 ml/min Cooling options: forced air (down to room temperature), liquid nitrogen (down to -170 ° C) Purge gas flow: 60ml / min
I termogrammi sono stati ottenuti mediante l’utilizzo di una termobilancia Mettler Toledo Stare System. I campioni sono stati caricati su crogioli in alluminio e scaldati a 460°C ad una velocità di riscaldamento di 10 K/min. The thermograms were obtained using a Mettler Toledo Stare System thermobalance. The samples were loaded on aluminum crucibles and heated to 460 ° C at a heating rate of 10 K / min.
Accuratezza della temperatura ± 1 K. Temperature accuracy ± 1 K.
Precisione della temperatura ± 0,4 K. Temperature accuracy ± 0.4 K.
Tempo di raffreddamento 20 min (da 1100 a 100 º C). Cooling time 20 min (1100 to 100 º C).
Volume del campione ≤ 100 l. Sample volume ≤ 100 l.
Descrizione delle figure Description of the figures
Figura 1: spettro XRPD di Posaconazolo, Forma C. Figure 1: XRPD spectrum of Posaconazole, Form C.
Figura 2: spettro FT-IR di Posaconazolo, Forma C. Figure 2: FT-IR spectrum of Posaconazole, Form C.
Figura 3: analisi DSC di Posaconazolo, Forma C. Figure 3: DSC analysis of Posaconazole, Form C.
Figura 4: analisi TGA di Posaconazolo, Forma C. Figure 4: TGA analysis of Posaconazole, Form C.
Figura 5: analisi EGA di Posaconazolo, Forma C. Figure 5: EGA analysis of Posaconazole, Form C.
Figura 6: confronto tra il profilo di assorbimento del gas che si libera a circa 100°C da Posaconazolo, Forma C e il profilo del 2-propanolo così come disponibile in banca dati. Figure 6: comparison between the absorption profile of the gas released at about 100 ° C by Posaconazole, Form C and the profile of 2-propanol as available in the database.
Figura 7: spettri XRPD di Posaconazolo, Forma C e della polvere risultante dopo 30 giorni in agitazione in 2-propanolo a temperatura ambiente di Posaconazolo, Forma I. Figure 7: XRPD spectra of Posaconazole, Form C and of the resulting powder after 30 days stirring in 2-propanol at room temperature of Posaconazole, Form I.
Descrizione dettagliata dell’invenzione: Detailed description of the invention:
Posaconazolo Forma C nella presente invenzione è caratterizzato dai parametri chimico-fisici che seguono. Posaconazole Form C in the present invention is characterized by the following physico-chemical parameters.
L’analisi XRPD porta all’ottenimento del caratteristico spettro riportato in Figura 1. I picchi principali a 2teta /- 0,3 gradi sono: 7,0, 14,5, 15,8, 17,8, 20,4, 23,1. La tabella 1 che segue riporta i picchi significativi dello spettro. The XRPD analysis leads to obtaining the characteristic spectrum shown in Figure 1. The main peaks at 2theta / - 0.3 degrees are: 7.0, 14.5, 15.8, 17.8, 20.4, 23 , 1. 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 è 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 a circa 97°C, associato ad una perdita di solvente. A questo, segue un secondo picco endotermico a circa 133°C, associato ad una transizione solido-solido. Si osserva infine un terzo picco endotermico a circa 167°C associato alla fusione. The DSC analysis, shown in Figure 3, shows an endothermic peak at about 97 ° C, associated with a loss of solvent. This is followed by a second endothermic peak at about 133 ° C, associated with a solid-solid transition. Finally, a third endothermic peak is observed at about 167 ° C associated with the fusion.
Il termogramma riportato in Figura 4 riporta una perdita di peso di circa il 3,6% a circa 90°C associata alla perdita di 2-propanololo, come confermato dall’analisi EGA descritta oltre. Si assiste inoltre ad una continua perdita di peso passando da circa 400°C a circa 450°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 eventi a circa 90°C, perdita di 2-propanolo, a circa 170°C, fusione, e a circa 410°C, associato alla degradazione del campione in seguito al riscaldamento. The thermogram shown in Figure 4 shows a weight loss of about 3.6% at about 90 ° C associated with the loss of 2-propanolol, as confirmed by the EGA analysis described below. There is also a continuous weight loss passing from about 400 ° C to about 450 ° 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 events at about 90 ° C, loss of 2-propanol, at about 170 ° C, melting, and at about 410 ° C, associated with the degradation of the sample following heating.
Per meglio caratterizzare gli eventi osservati con l’analisi termo gravimetrica, è stata condotta un’analisi dei gas evoluti (EGA) i cui risultati sono riportati in Figura 5. Andando a confrontare l’assorbanza del gas emesso dall’analisi EGA in corrispondenza della perdita di peso osservata a circa 90°C con il profilo di assorbanza di 2-propanolo così come disponibile in banca dati, vedi Figura 6, si conferma che la perdita di peso osservata a circa 90°C per Posaconazolo, Forma C è da attribuirsi alla perdita di 2-propanolo. To better characterize the events observed with the thermo-gravimetric analysis, an analysis of evolved gases (EGA) was carried out, the results of which are shown in Figure 5. Comparing the absorbance of the gas emitted by the EGA analysis at the weight loss observed at about 90 ° C with the absorbance profile of 2-propanol as available in the database, see Figure 6, it is confirmed that the weight loss observed at about 90 ° C for Posaconazole, Form C is to be attributed to the loss of 2-propanol.
Detta forma cristallina che qui si rivendica viene ottenuta a partire da Posaconazolo Forma I, così come descritto in WO9918097A1. Said crystalline form claimed herein is obtained starting from Posaconazole Form I, as described in WO9918097A1.
Forma ulteriore oggetto della presente invenzione il processo per la preparazione di detta Forma C di Posaconazolo. Detto processo comprende una precipitazione mediata da aggiunta di solvente a temperatura ambiente. In particolare, detto processo comprende: A further object of the present invention is the process for the preparation of said Form C of Posaconazole. Said process comprises a precipitation mediated by the addition of solvent at room temperature. In particular, this process includes:
i) risospendere Posaconazolo Forma I in un solvente adatto; i) resuspend Posaconazole Form I in a suitable solvent;
ii) mantenere in agitazione a temperatura ambiente per un tempo opportuno; ii) keep stirring at room temperature for a suitable time;
iii)filtrare la miscela ottenuta in ii) così da isolare il precipitato; iii) filtering the mixture obtained in ii) so as to isolate the precipitate;
iv) essiccare il precipitato ad una temperatura adatta. iv) drying the precipitate at a suitable temperature.
In una forma di realizzazione preferita, detta fase i) utilizza 2-propanolo come solvente e detta fase ii) si protrae per 7 giorni, oppure per 30 giorni. In a preferred embodiment, said step i) uses 2-propanol as solvent and said step ii) lasts for 7 days, or for 30 days.
La figura 7 mostra come, dopo 30 giorni di agitazione a temperatura ambiente in 2-propanolo di Posaconazolo Forma I si ottenga il profilo XRPD atteso per Posaconazolo, Forma C. Figure 7 shows how, after 30 days of stirring at room temperature in Posaconazole Form I 2-propanol, the expected XRPD profile for Posaconazole, Form C is obtained.
Il prodotto ottenuto è Posaconazolo, Forma C rivendicato nella presente invenzione. The product obtained is Posaconazole, Form C claimed in the present invention.
Detta forma cristallina di Posaconazolo, Forma C 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 Posaconazole, Form C can find application in pharmaceutical compositions. The pharmaceutical composition that includes said crystalline form may contain additives such as sweeteners, flavors, coating substances, inert diluents such as lactose and talc, binders such as starch, hydroxyethylcellulose, hydroxypropylcellulose and similar. Any conventional technique can be used for the preparation of pharmaceutical formulations according to the present invention.
ESEMPI EXAMPLES
Esempio 1: Preparazione di Posaconazolo, Forma C. Example 1: Preparation of Posaconazole, Form C.
50 mg di Posaconazolo, Forma I sono stati sospesi in 2 ml di 2-propanolo e mantenuti sotto agitazione a temperatura ambiente per 30 giorni. La sospensione è stata quindi filtrata e il solido analizzato mediante XRPD. L’analisi ha portato al pattern di diffrazione della Forma C (figura 7, linea tratteggiata). 50 mg of Posaconazole, Form I was suspended in 2 ml of 2-propanol and stirred at room temperature for 30 days. The suspension was then filtered and the solid analyzed by XRPD. The analysis led to the diffraction pattern of Form C (Figure 7, dotted line).
Claims (5)
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| Application Number | Priority Date | Filing Date | Title |
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| IT002115A ITMI20132115A1 (en) | 2013-12-18 | 2013-12-18 | A CRYSTAL SHAPE OF POSACONAZOLO |
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| IT002115A ITMI20132115A1 (en) | 2013-12-18 | 2013-12-18 | A CRYSTAL SHAPE OF POSACONAZOLO |
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| IT002115A ITMI20132115A1 (en) | 2013-12-18 | 2013-12-18 | A CRYSTAL SHAPE OF POSACONAZOLO |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999018097A1 (en) * | 1997-10-07 | 1999-04-15 | Schering Corporation | Crystalline antifungal polymorph |
| WO2009147075A2 (en) * | 2008-06-02 | 2009-12-10 | Sandoz Ag | Pharmaceutical compositions containing a crystalline form of posaconazole |
| EP2141159A1 (en) * | 2008-07-03 | 2010-01-06 | Sandoz AG | A Crystalline form of posaconazole |
| WO2011003992A1 (en) * | 2009-07-09 | 2011-01-13 | Sandoz Ag | A crystalline form of posaconazole |
| WO2011158248A2 (en) * | 2010-05-12 | 2011-12-22 | Glenmark Generics Limited | Process for preparation of posaconazole and crystalline polymorphic form v of posaconazole |
| WO2013042138A2 (en) * | 2011-09-19 | 2013-03-28 | Msn Laboratories Limited | Process for the preparation of triazole antifungal drug, its intermediates and polymorphs thereof |
-
2013
- 2013-12-18 IT IT002115A patent/ITMI20132115A1/en unknown
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999018097A1 (en) * | 1997-10-07 | 1999-04-15 | Schering Corporation | Crystalline antifungal polymorph |
| WO2009147075A2 (en) * | 2008-06-02 | 2009-12-10 | Sandoz Ag | Pharmaceutical compositions containing a crystalline form of posaconazole |
| EP2141159A1 (en) * | 2008-07-03 | 2010-01-06 | Sandoz AG | A Crystalline form of posaconazole |
| WO2011003992A1 (en) * | 2009-07-09 | 2011-01-13 | Sandoz Ag | A crystalline form of posaconazole |
| WO2011158248A2 (en) * | 2010-05-12 | 2011-12-22 | Glenmark Generics Limited | Process for preparation of posaconazole and crystalline polymorphic form v of posaconazole |
| WO2013042138A2 (en) * | 2011-09-19 | 2013-03-28 | Msn Laboratories Limited | Process for the preparation of triazole antifungal drug, its intermediates and polymorphs thereof |
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