ITMI20092334A1 - POLYMORPHIC FORM OF PHENOFIBRIC ACID, PROCESS FOR ITS PREPARATION, ITS COMPOSITIONS AND ITS USE - Google Patents
POLYMORPHIC FORM OF PHENOFIBRIC ACID, PROCESS FOR ITS PREPARATION, ITS COMPOSITIONS AND ITS USE Download PDFInfo
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- 208000032928 Dyslipidaemia Diseases 0.000 claims description 9
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- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 description 9
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- 229960002297 fenofibrate Drugs 0.000 description 6
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- 230000004913 activation Effects 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
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- 208000017170 Lipid metabolism disease Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 102000023984 PPAR alpha Human genes 0.000 description 2
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- 238000002441 X-ray diffraction Methods 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
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- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
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- ILPUOPPYSQEBNJ-UHFFFAOYSA-N 2-methyl-2-phenoxypropanoic acid Chemical class OC(=O)C(C)(C)OC1=CC=CC=C1 ILPUOPPYSQEBNJ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Descrizione del brevetto per invenzione industriale avente per titolo: Description of the patent for industrial invention entitled:
“FORMA POLIMORFICA DI ACIDO FENOFIBRICO, PROCESSO PER LA SUA PREPARAZIONE, SUE COMPOSIZIONI E SUO USO” "POLYMORPHIC FORM OF PHENOPHIBRIC ACID, PROCESS FOR ITS PREPARATION, ITS COMPOSITIONS AND ITS USE"
Campo tecnico dell’invenzione Technical field of the invention
La presente invenzione riguarda una forma polimorfica dell’acido fenofibrico. The present invention relates to a polymorphic form of fenofibric acid.
La presente invenzione è inoltre relativa a un processo per la preparazione della forma polimorfica, a composizioni comprendenti tale forma polimorfica nonché all’uso della stessa per la prevenzione e/o il trattamento di dislipidemie. The present invention also relates to a process for the preparation of the polymorphic form, to compositions including this polymorphic form as well as to the use of the same for the prevention and / or treatment of dyslipidemia.
Stato della tecnica State of the art
Il fenofibrato (propan-2-il 2-{4-[(4-clorofenile)carbonil]fenossi}-2-metilpropanoato, Formula 1) è un derivato dell’acido fibrico ed è un farmaco appartenente alla classe dei fibrati. Fenofibrate (propan-2-yl 2- {4 - [(4-chlorophenyl) carbonyl] phenoxy} -2-methylpropanoate, Formula 1) is a derivative of fibric acid and is a drug belonging to the class of fibrates.
Formula 1 Formula 1
Come gli altri fibrati, il fenofibrato riduce i livelli sia delle lipoproteine a bassa densità (LDL) che delle lipoproteine a bassissima densità (VLDL), così come dei trigliceridi e inoltre aumenta i livelli delle lipoproteine ad alta densità (HDL). Like other fibrates, fenofibrate reduces the levels of both low-density lipoproteins (LDL) and very low-density lipoproteins (VLDL), as well as triglycerides, and also increases the levels of high-density lipoproteins (HDL).
Il fenofibrato è usato da solo o in associazione con le statine nel trattamento delle dislipidemie, in particolare iperlipidemie, ipercolesterolemie e ipertrigliceridemie. Fenofibrate is used alone or in combination with statins in the treatment of dyslipidaemia, in particular hyperlipidemia, hypercholesterolemia and hypertriglyceridemia.
Questo è usato principalmente per ridurre i livelli di colesterolo in pazienti a rischio di malattie cardiovascolari. This is mainly used to reduce cholesterol levels in patients at risk for cardiovascular disease.
Gli effetti del fenofibrato nella modificazione dei lipidi, riportati nell’uomo, sono mediati attraverso l’attivazione dei Recettori Attivati dai Proliferatori Perossisomiali di tipo alfa (PPARα). The effects of fenofibrate in the modification of lipids, reported in humans, are mediated through the activation of Receptors Activated by Peroxisomal Proliferators of the alpha type (PPARα).
Attraverso l’attivazione di PPARα, il fenofibrato aumenta la lipolisi e l’eliminazione dal plasma di particelle aterogeniche ricche di trigliceridi attraverso l’attivazione di lipoproteinlipasi e la riduzione della produzione di Apoproteina CIII. Through the activation of PPARα, fenofibrate increases lipolysis and the elimination from the plasma of atherogenic particles rich in triglycerides through the activation of lipoproteinlipases and the reduction of the production of Apoprotein CIII.
Il metabolita attivo del fenofibrato è l’Acido Fenofibrico (Formula 2). The active metabolite of fenofibrate is Fenofibric Acid (Formula 2).
Formula 2 Formula 2
Il polimorfismo rappresenta la possibilità che una stessa sostanza si presenti in forme cristalline diverse. Polymorphism represents the possibility that the same substance occurs in different crystalline forms.
Il polimorfismo è dovuto alla diversa disposizione spaziale degli atomi della sostanza nel reticolo cristallino, in particolare determinata dalla pressione e dalla temperatura. The polymorphism is due to the different spatial arrangement of the atoms of the substance in the crystal lattice, in particular determined by pressure and temperature.
Il passaggio da una forma cristallina ad un'altra avviene ad una temperatura ben determinata, detta temperatura di trasformazione, al di sopra della quale è stabile una delle forme, mentre al di sotto è stabile l'altra forma. Le diverse forme polimorfiche mostrano proprietà fisiche differenti (quali ad esempio solubilità, dissoluzione, sfaldatura, durezza, peso specifico, punto di fusione, proprietà ottiche). The transition from one crystalline form to another occurs at a well-determined temperature, called transformation temperature, above which one of the forms is stable, while the other form is stable below. The different polymorphic forms show different physical properties (such as solubility, dissolution, cleavage, hardness, specific weight, melting point, optical properties).
I diversi polimorfi possono presentare differenze nell’attività terapeutica dovute al loro diverso profilo di dissoluzione, che determina quindi una differente biodisponibilità di ciascuna forma polimorfica. The different polymorphs may present differences in therapeutic activity due to their different dissolution profile, which therefore determines a different bioavailability of each polymorphic form.
Differenti forme polimorfiche dell’acido fenofibrico sono note nella dal letteratura. Different polymorphic forms of fenofibric acid are known in the literature.
Ad esempio, la struttura molecolare e cristallina di acido fenofibrico, determinate attraverso la diffrazione di raggi X da un singolo cristallo, sono state pubblicate nel 2005 [Rath e al., Acta Cryst. C61, 81-84 (2005)]. For example, the molecular and crystalline structure of fenofibric acid, determined by X-ray diffraction from a single crystal, was published in 2005 [Rath et al., Acta Cryst. C61, 81-84 (2005)].
Nello stato dell’arte sono state descritte per l’acido fenofibrico diverse forme polimorfiche, in particolare la Forma A e la Forma B. In the state of the art, various polymorphic forms have been described for fenofibric acid, in particular Form A and Form B.
La domanda di brevetto internazionale WO 2009/091967 descrive metodi per la preparazione della forma A e della forma B dell’acido fenofibrico. International patent application WO 2009/091967 describes methods for the preparation of form A and form B of fenofibric acid.
Tuttora sussiste però la necessità di individuare nuove forme polimorfiche alternative dell’acido fenofibrico. However, there is still a need to identify new alternative polymorphic forms of fenofibric acid.
Sommario dell’invenzione Summary of the invention
La presente invenzione è relativa a una forma polimorfica di acido fenofibrico di formula (I): The present invention relates to a polymorphic form of fenofibric acid of formula (I):
avente un diffrattogramma XRPD comprendente i seguenti picchi: (2 theta, cps) 18.44, 1100; 19.44, 542; 20.2, 466; 21.4, 782; 21.96, 249; 22.16, 261; 22.56, 346; 23.08, 1572, 25.04, 365; 26.44, 367; 30.12, 394; oltre che ai suoi sali, esteri e solvati. having an XRPD diffractogram comprising the following peaks: (2 theta, cps) 18.44, 1100; 19.44, 542; 20.2, 466; 21.4, 782; 21.96, 249; 22.16, 261; 22.56, 346; 23.08, 1572, 25.04, 365; 26.44, 367; 30.12, 394; as well as its salts, esters and solvates.
Inoltre, l’invenzione si riferisce a una composizione farmaceutica comprendente la forma polimorfica dell’acido fenofibrico sopra-descritta ed almeno un opportuno eccipiente e/o veicolo farmaceuticamente accettabile. Furthermore, the invention refers to a pharmaceutical composition comprising the polymorphic form of the fenofibric acid described above and at least one suitable pharmaceutically acceptable excipient and / or vehicle.
Tale forma polimorfica di acido fenofibrico è anche utile per l’uso come medicamento, in particolare, per l’uso nella prevenzione e/o nel trattamento di dislipidemie. This polymorphic form of fenofibric acid is also useful for use as a medicament, in particular, for use in the prevention and / or treatment of dyslipidemia.
In particolare, tali dislipidemie possono essere iperlipidemie, ipercolesterolemie, ipertrigliceridemie. In particular, these dyslipidemias can be hyperlipidemias, hypercholesterolemias, hypertriglyceridemias.
L’invenzione riguarda inoltre un processo per la preparazione della forma polimorfica di acido fenofibrico comprendente le seguenti fasi: The invention also relates to a process for the preparation of the polymorphic form of fenofibric acid comprising the following steps:
- idrolisi di un estere di acido fenofibrico con una soluzione alcalina di alcali organici o inorganici in una miscela di solventi comprendente acqua ed un solvente miscibile in acqua; - hydrolysis of an ester of fenofibric acid with an alkaline solution of organic or inorganic alkali in a mixture of solvents comprising water and a water-miscible solvent;
- correzione del pH con acidi inorganici o con acidi organici; - pH correction with inorganic acids or with organic acids;
- precipitazione dell’acido fenofibrico. - precipitation of fenofibric acid.
Descrizione della figura Description of the figure
La figura mostra il diffrattogramma XRPD che identifica la forma polimorfica dell’acido fenofibrico. The figure shows the XRPD diffractogram that identifies the polymorphic form of fenofibric acid.
Descrizione dettagliata dell’invenzione Detailed description of the invention
Si è sorprendentemente trovato che l’acido fenofibrico può esistere anche in un’ulteriore forma polimorfica stabile a temperatura ambiente. It has surprisingly been found that fenofibric acid can also exist in a further polymorphic form stable at room temperature.
La caratterizzazione della forma cristallina dell’acido fenofibrico può essere effettuata tramite l’impiego di tecniche analitiche note nello stato dell’arte, che comprendono ad esempio la Diffrazione a Raggi-X (XRD), la Calorimetria Differenziale a Scansione (DSC), la Spettroscopia ad Infrarosso (IR), l’Analisi Termogravimetrica (TGA). The characterization of the crystalline form of fenofibric acid can be carried out through the use of analytical techniques known in the state of the art, which include for example X-ray Diffraction (XRD), Differential Scanning Calorimetry (DSC), Infrared Spectroscopy (IR), Thermogravimetric Analysis (TGA).
La presente invenzione è relativa a una forma polimorfica di acido fenofibrico di formula (I): The present invention relates to a polymorphic form of fenofibric acid of formula (I):
caratterizzata da un diffrattogramma XRPD (X-Ray Powder Difraction -Diffrazione di Raggi X di polveri) comprendente i seguenti picchi: (2 theta, cps) 18.44, 1100; 19.44, 542; 20.2, 466; 21.4, 782; 21.96, 249; 22.16, 261; 22.56, 346; 23.08, 1572, 25.04, 365; 26.44, 367; 30.12, 394. characterized by an XRPD diffraction (X-Ray Powder Difraction) comprising the following peaks: (2 theta, cps) 18.44, 1100; 19.44, 542; 20.2, 466; 21.4, 782; 21.96, 249; 22.16, 261; 22.56, 346; 23.08, 1572, 25.04, 365; 26.44, 367; 30.12, 394.
La Figura mostra il diffrattogramma XRPD del composto allo stato solido cristallino e identifica la forma polimorfica dell’acido fenofibrico dell’invenzione. The Figure shows the XRPD diffractogram of the compound in the crystalline solid state and identifies the polymorphic form of the fenofibric acid of the invention.
Secondo un aspetto dell’invenzione, tale forma polimorfica dell’acido fenofibrico di formula (I) può essere salificata. According to one aspect of the invention, this polymorphic form of fenofibric acid of formula (I) can be salified.
Secondo un aspetto preferito, tale forma polimorfica dell’acido fenofibrico può essere salificata ad esempio con ammine alifatiche variamente sostituite o con basi inorganiche di elementi alcalini e alcalino-terrosi. According to a preferred aspect, this polymorphic form of fenofibric acid can be salified for example with variously substituted aliphatic amines or with inorganic bases of alkaline and alkaline-earth elements.
Una forma di realizzazione dell’invenzione è rappresentata da una composizione farmaceutica comprendente la forma polimorfica sopra descritta ed almeno un opportuno eccipiente e/o veicolo farmaceuticamente accettabile. An embodiment of the invention is represented by a pharmaceutical composition comprising the polymorphic form described above and at least one suitable pharmaceutically acceptable excipient and / or vehicle.
Tale forma polimorfica dell’acido fenofibrico può essere somministrata da sola o in combinazione con altri principi attivi. This polymorphic form of fenofibric acid can be administered alone or in combination with other active ingredients.
Secondo un primo aspetto dell’invenzione, la forma polimorfica di acido fenofibrico può essere utilizzata come medicamento, inoltre tale forma è utile, ad esempio, nella prevenzione e/o nel trattamento di dislipidemie. According to a first aspect of the invention, the polymorphic form of fenofibric acid can be used as a medicament, furthermore this form is useful, for example, in the prevention and / or treatment of dyslipidemias.
Secondo un altro aspetto, la forma polimorfica è utile per la preparazione di un medicamento per la prevenzione e/o il trattamento di dislipidemie. According to another aspect, the polymorphic form is useful for the preparation of a medicament for the prevention and / or treatment of dyslipidemias.
In particolare, l’acido fenofibrico nella forma polimorfica secondo l’invenzione può essere utilizzato nella prevenzione e/o nel trattamento di iperlipidemie, ipercolesterolemie, ipertrigliceridemie. In particular, fenofibric acid in the polymorphic form according to the invention can be used in the prevention and / or treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia.
L’acido fenofibrico, nella forma polimorfica secondo l’invenzione, può essere preparato, per esempio, per idrolisi di un estere di acido fenofibrico (ovvero ad esempio metil-, etil-, isopropil- estere) utilizzando soluzioni alcaline di alcali organici o inorganici (cioè, per esempio, idrossido di sodio, idrossido di potassio, carbonato o idrogenocarbonato di sodio o di potassio, ammoniaca, trietilammina, diisopropiletilammina, piridina, ecc. ...) in una miscela di solventi che comprende acqua ed un solvente miscibile in acqua, come alcoli (ad esempio metanolo, etanolo, isopropanolo), chetoni (ad esempio acetone), amidi (cioè DMF, DMA), ecc.. Fenofibric acid, in the polymorphic form according to the invention, can be prepared, for example, by hydrolysis of an ester of fenofibric acid (i.e. for example methyl-, ethyl-, isopropyl-ester) using alkaline solutions of organic or inorganic alkalis (i.e., for example, sodium hydroxide, potassium hydroxide, sodium or potassium carbonate or hydrogen carbonate, ammonia, triethylamine, diisopropylethylamine, pyridine, etc. ...) in a mixture of solvents which includes water and a solvent miscible in water, such as alcohols (e.g. methanol, ethanol, isopropanol), ketones (e.g. acetone), starches (i.e. DMF, DMA), etc.
L’acido fenofibrico viene precipitato dopo la correzione del pH con acidi inorganici (ovvero per esempio acido cloridrico o bromidrico, acido solforico, acido fosforico, ecc.) o con acidi organici (come ad esempio acido acetico, acido metansolfonico). Fenofibric acid is precipitated after pH correction with inorganic acids (ie hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, etc.) or with organic acids (such as acetic acid, methanesulfonic acid).
Secondo un primo aspetto preferito dell’invenzione, le soluzioni alcaline preferite sono soluzioni di idrossido di sodio e di idrossido di potassio. According to a first preferred aspect of the invention, the preferred alkaline solutions are sodium hydroxide and potassium hydroxide solutions.
Secondo un ulteriore aspetto preferito dell’invenzione, i solventi preferiti sono alcoli (quali ad esempio metanolo, etanolo, isopropanolo). According to a further preferred aspect of the invention, the preferred solvents are alcohols (such as for example methanol, ethanol, isopropanol).
Inoltre, in una realizzazione preferita dell’invenzione l'acido preferito è l'acido cloridrico. Furthermore, in a preferred embodiment of the invention the preferred acid is hydrochloric acid.
L’esempio di seguito riportato illustra ulteriormente, ma non limitativamente, l’invenzione. The example below further illustrates, but is not limited to, the invention.
Esempio - Preparazione della forma polimorfica dell’acido fenofibrico Example - Preparation of the polymorphic form of fenofibric acid
Il fenofibrato (50 Kg) è trattato con isopropanolo (500 L) e una soluzione acquosa al 30% di idrossido di sodio a circa 60°C. Dopo 24-36 ore, il solvente è stato parzialmente distillato e il pH è stato corretto con una soluzione acquosa al 30% di acido cloridrico pari a circa 8.5-9.5. La miscela è filtrata, quindi il pH della soluzione è corretto a 2-3 con acido cloridrico acquoso al 30%, sotto agitazione a 15-20°C per 2-8 ore e centrifugata. Il solido è lavato con acqua e portato a secco a circa 60°C sotto vuoto a dare 42 Kg di acido fenofibrico. Fenofibrate (50 Kg) is treated with isopropanol (500 L) and a 30% aqueous solution of sodium hydroxide at about 60 ° C. After 24-36 hours, the solvent was partially distilled and the pH was corrected with a 30% aqueous solution of hydrochloric acid equal to about 8.5-9.5. The mixture is filtered, then the pH of the solution is corrected to 2-3 with 30% aqueous hydrochloric acid, under stirring at 15-20 ° C for 2-8 hours and centrifuged. The solid is washed with water and dried at about 60 ° C under vacuum to give 42 kg of fenofibric acid.
L’acido fenofibrico ottenuto in questo modo mostra una forma cristallina identificata dal seguente pattern XRPD (come riportato nella Figura): (2 theta, cps) 18.44, 1100; 19.44, 542; 20.2, 466; 21.4, 782; 21.96, 249; 22.16, 261; 22.56, 346; 23.08, 1572, 25.04, 365; 26.44, 367; 30.12, 394. The fenofibric acid obtained in this way shows a crystalline form identified by the following XRPD pattern (as shown in the Figure): (2 theta, cps) 18.44, 1100; 19.44, 542; 20.2, 466; 21.4, 782; 21.96, 249; 22.16, 261; 22.56, 346; 23.08, 1572, 25.04, 365; 26.44, 367; 30.12, 394.
Claims (12)
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050148594A1 (en) * | 2002-12-17 | 2005-07-07 | Cink Russell D. | Salts of fenofibric acid and pharmaceutical formulations thereof |
| WO2009091967A2 (en) * | 2008-01-18 | 2009-07-23 | Mutual Pharmaceutical Company | Fenofibric acid polymorphs; methods of making; and methods of use thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050148594A1 (en) * | 2002-12-17 | 2005-07-07 | Cink Russell D. | Salts of fenofibric acid and pharmaceutical formulations thereof |
| WO2009091967A2 (en) * | 2008-01-18 | 2009-07-23 | Mutual Pharmaceutical Company | Fenofibric acid polymorphs; methods of making; and methods of use thereof |
Non-Patent Citations (2)
| Title |
|---|
| COSA, GONZALO ET AL: "A Laser Flash Photolysis Study of Fenofibric Acid in Aqueous Buffered Media: Unexpected Triplet State Inversion in a Derivative of 4-Alkoxybenzophenone", PHOTOCHEMISTRY AND PHOTOBIOLOGY, vol. 75, no. 3, 2002, pages 193 - 200, XP002593038, ISSN: 0031-8655, DOI: 10.1562/0031-8655(2002)075<0193:ALFPSO>2.0.CO;2 * |
| RATH, NIGAM P. ET AL: "Fenofibric Acid", ACTA CRYSTALLOGRAPHICA SECTION C, vol. C61, 2005, pages O81 - O84, XP002593037, ISSN: 0108-2701, DOI: 10.1107/S0108270104032573 * |
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