ITRM950831A1 - PROCESS FOR THE CRYSTALLIZATION FROM WATER OF S-N,N'-BIS (2-HYDROXY -1-(HYDROXYMETHYL)ETHYL)-5-((2-HYDROXY-1-OXOPROPYL)AMINO).2,4,6- - Google Patents
PROCESS FOR THE CRYSTALLIZATION FROM WATER OF S-N,N'-BIS (2-HYDROXY -1-(HYDROXYMETHYL)ETHYL)-5-((2-HYDROXY-1-OXOPROPYL)AMINO).2,4,6- Download PDFInfo
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- ITRM950831A1 ITRM950831A1 IT95RM000831A ITRM950831A ITRM950831A1 IT RM950831 A1 ITRM950831 A1 IT RM950831A1 IT 95RM000831 A IT95RM000831 A IT 95RM000831A IT RM950831 A ITRM950831 A IT RM950831A IT RM950831 A1 ITRM950831 A1 IT RM950831A1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 title claims abstract description 21
- 238000002425 crystallisation Methods 0.000 title claims abstract description 15
- 230000008025 crystallization Effects 0.000 title claims abstract description 15
- XQZXYNRDCRIARQ-LURJTMIESA-N iopamidol Chemical compound C[C@H](O)C(=O)NC1=C(I)C(C(=O)NC(CO)CO)=C(I)C(C(=O)NC(CO)CO)=C1I XQZXYNRDCRIARQ-LURJTMIESA-N 0.000 claims abstract description 29
- 229960004647 iopamidol Drugs 0.000 claims abstract description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 239000000243 solution Substances 0.000 claims description 8
- 235000019441 ethanol Nutrition 0.000 claims description 7
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 244000052616 bacterial pathogen Species 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 3
- 239000013557 residual solvent Substances 0.000 claims description 3
- 239000002872 contrast media Substances 0.000 claims description 2
- 238000004042 decolorization Methods 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 230000000977 initiatory effect Effects 0.000 claims description 2
- 230000007928 solubilization Effects 0.000 claims description 2
- 238000005063 solubilization Methods 0.000 claims description 2
- 238000005406 washing Methods 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- -1 2-HYDROXY-1-OXOPROPYL Chemical class 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229940039231 contrast media Drugs 0.000 description 1
- 239000012297 crystallization seed Substances 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000004686 pentahydrates Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
- 231100000583 toxicological profile Toxicity 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Abstract
Si descrive un processo per la cristallizzazione dello Iopamidolo in forma cristallina anidra che impiega acqua.A process for the crystallization of Iopamidol in an anhydrous crystalline form which uses water is described.
Description
Descrizione dell’invenzione industriale avente per titolo: 'PROCESSO PER LA CRISTALLIZZAZIONE DA ACQUA DELLA S-N,N'-BIS-[2-IDROSSI-l-(IDROSSIMETIL)ETIL]-5- [(2-IDROSSI-l-OSSOPROPIL)-AMMINO]-2,4,6-TRIIODO-l,3-BENZENDICARBOSSAMMIDE' Description of the industrial invention entitled: 'PROCESS FOR THE CRYSTALLIZATION OF S-N, N'-BIS- [2-HYDROXY-1- (HYDROXIMETHYL) ETHYL] -5- [(2-HYDROXY-1-OXOPROPYL) FROM WATER AMINO] -2,4,6-TRIIODE-1,3-BENZENDICARBOXAMIDE '
La presente invenzione riguarda un processo per la cristallizzazione da acqua della S-N,N'-bis[2-idrossi-l-(idrossimetil)etil]-5-[(2-idrossi-lossopropil)ammino ]-2,4,6-triiodo-l,3-benzendicarbossammide, più noto con il nome d'uso Iopamidolo, che costituisce uno dei mezzi di contrasto radiografici di tipo non-ionico più venduti nel mondo. The present invention relates to a process for the crystallization from water of S-N, N'-bis [2-hydroxy-1- (hydroxymethyl) ethyl] -5 - [(2-hydroxy-loxopropyl) amino] -2,4,6- triiode-1,3-benzendicarboxamide, better known by the name of use Iopamidol, which is one of the best-selling non-ionic radiographic contrast media in the world.
Le sintesi dello lopamidolo in letteratura, per esempio quella descritta nel brevetto GB 1472050, prevedono una purificazione a fine reazione mediante il passaggio su resine scambiatrici di ioni e successiva ricristallizzazione da EtOH. Inoltre viene citata la sua buona solubilità in acqua (2.3 g di prodotto cristallizzano da una soluzione di 10 g in 10 mL di acqua posti per alcuni giorni in frigorifero a 4°C). Detta buona solubilità viene ribadita in articoli apparsi in letteratura posteriormente, come in Felder E. et al, Boll. Chim. Farm., 1981, 120, 639, oppure Felder E., Invest. Radiol., 1984, 19, S164 e nella monografia dedicata allo lopamidolo in Analytical Profiles of Drug Substances, vol. The syntheses of lopamidol in the literature, for example that described in the patent GB 1472050, provide for a purification at the end of the reaction by passing over ion exchange resins and subsequent recrystallization from EtOH. Furthermore, its good solubility in water is mentioned (2.3 g of product crystallize from a solution of 10 g in 10 mL of water placed for a few days in a refrigerator at 4 ° C). Said good solubility is reaffirmed in articles which appeared in the literature afterwards, as in Felder E. et al, Boll. Chim. Farm., 1981, 120, 639, or Felder E., Invest. Radiol., 1984, 19, S164 and in the monograph dedicated to lopamidol in Analytical Profiles of Drug Substances, vol.
17, 115, insieme alla scarsa solubilità in MeOH e all' insolubilità in Et20, benzene, cloroformio e EtOH. 17, 115, together with poor solubility in MeOH and insolubility in Et20, benzene, chloroform and EtOH.
Nei detti articoli vengono anche riportate le diverse forme cristalline dello lopamidolo, cioè l'anidra, la monoidrata e la pentaidrata, ciascuna caratterizzata da un distinto spettro IR, diffrazione su polveri ai raggi X e da distinti termogrammi entalpimetrici e gravimetrici. Tali cristalli sono stati ottenuti con una cinetica molto lenta da soluzioni acquose. Recentemente è apparsa una domanda di brevetto WO-A-9504031, in cui vengono indicati diversi solventi (n-BuOH, i-BuOH e/o t-BuOH) da cui cristallizzare convenientemente Iopamidolo. Nella stessa domanda di brevetto viene anche sperimentata la cristallizzazione da acqua di Iopamidolo, con l'intento di ottenere un prodotto conforme alle prescrizioni della farmacopea, ad esempio quella americana (US Pharmacopeia XXII, 712), ma con scarsi risultati, vista la bassa resa e la necessità di allontanare l'acqua di cristallizzazione per riscaldamento prolungato a temperature superiori ai 100*C. In said articles the different crystalline forms of lopamidol are also reported, i.e. the anhydrous, the monohydrate and the pentahydrate, each characterized by a distinct IR spectrum, X-ray diffraction on powders and by distinct enthalpimetric and gravimetric thermograms. These crystals were obtained with very slow kinetics from aqueous solutions. A patent application WO-A-9504031 has recently appeared, in which various solvents (n-BuOH, i-BuOH and / or t-BuOH) are indicated from which Iopamidol is conveniently crystallized. In the same patent application the crystallization of Iopamidol from water is also tested, with the aim of obtaining a product that complies with the prescriptions of the pharmacopoeia, for example the American one (US Pharmacopeia XXII, 712), but with poor results, given the low yield and the need to remove the water of crystallization by prolonged heating at temperatures above 100 ° C.
Abbiamo ora sorprendentemente trovato e costituisce oggetto della presente invenzione, che lo Iopamidolo può essere facilmente cristallizzato da acqua fornendo con rese industrialmente accettabili un prodotto avente caratteristiche idonee ai requisiti della farmacopea. Infatti, operando secondo il processo oggetto della presente invenzione è possibile ottenere Iopamidolo nella sua forma cristallina anidra che risulta idonea ai requisiti della farmacopea. We have now surprisingly found, and it is the object of the present invention, that Iopamidol can be easily crystallized from water, providing with industrially acceptable yields a product having characteristics suitable for the requirements of the pharmacopoeia. In fact, by operating according to the process object of the present invention it is possible to obtain Iopamidol in its anhydrous crystalline form which is suitable for the requirements of the pharmacopoeia.
Inoltre il processo oggetto della presente invenzione utilizzando l'acqua come solvente in cui attuare la purificazione per cristallizzazione dello Iopamidolo risulta particolarmente importante dal punto di vista della problematica ambientale evitando l'uso di solventi organici. Furthermore, the process object of the present invention using water as a solvent in which to carry out the purification by crystallization of the Iopamidol is particularly important from the point of view of the environmental problem, avoiding the use of organic solvents.
Il processo, oggetto della presente invenzione, prevede i seguenti passaggi : The process, object of the present invention, involves the following steps:
solubilizzazione di Iopamidolo a caldo in acqua deionizzata; hot solubilization of Iopamidol in deionized water;
- decolorazione della soluzione con carbone attivo; - decolorization of the solution with activated carbon;
- concentrazione sotto vuoto della soluzione acquosa a 60°C; - vacuum concentration of the aqueous solution at 60 ° C;
innesco della cristallizzazione mediante l'aggiunta di germi cristallini della forma anidra dello Iopamidolo; cristallizzazione alla temperatura costante di 60°C; initiation of crystallization by adding crystalline germs of the anhydrous form of Iopamidol; crystallization at a constant temperature of 60 ° C;
filtrazione del prodotto umido ottenuto; filtration of the wet product obtained;
essicaroento sotto vuoto del prodotto umido. vacuum drying of the wet product.
Particolarmente preferite sono le condizioni di cristallizzazione in cui la concentrazione di Iopamidolo in acqua è maggiore del 78,6% (g/mL di soluzione), condizioni in cui la soluzione è satura, in presenza di quantità variabili di opportuni germi di cristallizzazione {1%—5%—10%). Lo Iopamidolo ottenuto secondo il processo, oggetto della presente invenzione non assorbe umidità, mentre il prodotto amorfo, ottenuto per concentrazione a secchezza di soluzioni acquose dello Iopamidolo, assorbe immediatamente acqua sciogliendosi nella stessa. Particularly preferred are the crystallization conditions in which the concentration of Iopamidol in water is greater than 78.6% (g / mL of solution), conditions in which the solution is saturated, in the presence of variable quantities of suitable crystallization seeds {1 % —5% —10%). The Iopamidol obtained according to the process, object of the present invention does not absorb humidity, while the amorphous product, obtained by dry concentration of aqueous solutions of Iopamidol, immediately absorbs water and dissolves in it.
E' stato sorprendentemente trovato che, ed è anch'esso oggetto della presente invenzione, qualora il prodotto ottenuto mediante il processo della presente invenzione denunciasse all'analisi un contenuto di solvente residuo proveniente dai precedenti passaggi sintetici, un semplice lavaggio del solido cristallino filtrato con la quantità opportuna di un alcol C1-C4, lineare o ramificato, riduce i contenuti del solvente residuo a quantità inferiori alle 10 ppm. It has been surprisingly found that, and it is also an object of the present invention, if the product obtained by the process of the present invention reveals to the analysis a residual solvent content coming from the previous synthetic steps, a simple washing of the filtered crystalline solid with the appropriate quantity of a linear or branched C1-C4 alcohol reduces the contents of the residual solvent to quantities lower than 10 ppm.
Il lavaggio si è rivelato particolarmente utile per l'eliminazione della dimetilacetammide, solvente usato nel passaggio sintetico precedente secondo la procedura di sintesi dello Iopamidolo descritta nel brevetto GB 1472050. The washing proved to be particularly useful for the elimination of dimethylacetamide, a solvent used in the previous synthetic step according to the Iopamidol synthesis procedure described in the GB 1472050 patent.
Particolarmente preferito risulta a questo scopo l'uso dell'alcol etilico assoluto, vista la sua conveniente reperibilità, il suo ben noto profilo tossicologico e il facile smaltimento industriale. For this purpose, the use of absolute ethyl alcohol is particularly preferred, given its convenient availability, its well-known toxicological profile and easy industrial disposal.
I seguenti esempi hanno lo scopo di illustrare le migliori condizioni sperimentali per attuare il processo, oggetto dell'invenzione. The following examples are intended to illustrate the best experimental conditions for carrying out the process, object of the invention.
Parte Sperimentale Experimental Part
ESEMPIO 1 EXAMPLE 1
Cristallizzazione da acqua dello Iopamidolo Crystallization of Iopamidol from water
Una soluzione di 500 kg di Iopamidolo in 600 kg di acqua deionizzata viene decolorata utilizzando 5 kg di Carbopuron. Si filtra la sospensione e si lava con 100 kg di acqua. Si concentra la soluzione a ~60°C e a 150 mm Hg fino ad un volume di 370 L (625 kg) e si germina con un 1 kg di germi della forma cristallina anidra. Si lascia cristallizzare per 8 ore avendo cura che la temperatura si mantenga esattamente a 60°C. Si filtra a 60°C senza lavare e si raccolgono le acque madri (210 kg). Si ottengono, dopo essicamento sotto vuoto (5-30 mmHg) a 60°C, 350 kg del prodotto desiderato. A solution of 500 kg of Iopamidol in 600 kg of deionized water is decoloured using 5 kg of Carbopuron. The suspension is filtered and washed with 100 kg of water. The solution is concentrated at ~ 60 ° C and at 150 mm Hg up to a volume of 370 L (625 kg) and germinated with 1 kg of germs of the anhydrous crystalline form. It is left to crystallize for 8 hours, taking care that the temperature is kept exactly at 60 ° C. It is filtered at 60 ° C without washing and the mother liquors (210 kg) are collected. After drying under vacuum (5-30 mmHg) at 60 ° C, 350 kg of the desired product are obtained.
Resa: 69,9% Yield: 69.9%
Il prodotto presenta le caratteristiche chimico-fisiche conformi a quelle prescritte dalla farmacopea. The product has the chemical-physical characteristics that comply with those prescribed by the pharmacopoeia.
ESEMPIO 2 EXAMPLE 2
Recupero di Iopamidolo dalle acque madri ottenute secondo l'ESEMPIO 1 Recovery of Iopamidol from mother liquors obtained according to EXAMPLE 1
Si riuniscono in caldaia le acque madri relative a tre lavorazioni e si diluiscono con 285 L di acqua deionizzata. Si porta a 80°C, si decolora con 5 kg di Carbopuron e si filtra, lavando poi il filtro con 100 kg di acqua. Si concentra sotto vuoto a 60°C e 150 mm Hg fino ad avere un residuo pari a 333 L e si germina con 1 kg di prodotto proveniente da una preparazione precedente. Si lascia cristallizzare per 8 ore e a 60°C esatti. Si filtra senza lavare, si scaricano 355 kg di prodotto umido che si essicano sotto vuoto a 60°C, ottenendo 316 kg di lopamidolo. The mother liquors relating to three processes are combined in the boiler and diluted with 285 L of deionized water. The mixture is brought to 80 ° C, decoloured with 5 kg of Carbopuron and filtered, then washing the filter with 100 kg of water. It is concentrated under vacuum at 60 ° C and 150 mm Hg until it has a residue equal to 333 L and germinates with 1 kg of product coming from a previous preparation. It is left to crystallize for 8 hours and at exactly 60 ° C. It is filtered without washing, 355 kg of wet product are discharged and dried under vacuum at 60 ° C, obtaining 316 kg of lopamidol.
Resa (sul prodotto essicato): 63% Yield (on the dried product): 63%
Resa di cristallizzazione complessiva a partire dall' ESEMPIO 1: 90,9% Il prodotto presenta le caratteristiche chimico-fisiche conformi a quelle prescritte dalla farmacopea. Total crystallization yield starting from EXAMPLE 1: 90.9% The product has the chemical-physical characteristics conforming to those prescribed by the pharmacopoeia.
ESEMPIO 3 EXAMPLE 3
Purificazione di cristalli ottenuti come da ESEMPIO 1, quando sia presente un contenuto residuo di dimetilacetamznide Purification of crystals obtained as per EXAMPLE 1, when a residual content of dimethylacetamine is present
Il solido cristallino ottenuto dopo filtrazione secondo la procedura descritta nell'ESEMPIO 1, avente un contenuto di dimetilacetammide pari a 50 ppm viene lavato 5 volte con alcol etilico assoluto (rapporto pari a 12,5% peso di EtOH per peso di Iopamidolo di partenza) e si essica il solido ottenuto a 50°C sotto vuoto. The crystalline solid obtained after filtration according to the procedure described in EXAMPLE 1, having a dimethylacetamide content equal to 50 ppm, is washed 5 times with absolute ethyl alcohol (ratio equal to 12.5% weight of EtOH per weight of starting Iopamidol) and the solid obtained is dried at 50 ° C under vacuum.
L'analisi del prodotto cosi ottenuto mostra un contenuto di dimetilacetammide pari a 16 ppm. The analysis of the product thus obtained shows a dimethylacetamide content equal to 16 ppm.
Claims (13)
Priority Applications (19)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT95RM000831 IT1277950B1 (en) | 1995-12-19 | 1995-12-19 | Prepn. of crystalline, anhydrous Iopamidol - by crystallisation from deionised water, useful as X=ray contrast agent |
| ES96928403T ES2140887T3 (en) | 1995-09-08 | 1996-08-02 | PROCEDURE FOR CRYSTALLIZING IN WATER (S) -N-N'-BIS (2-HIDROXI-1- (HIDROXIMETIL) ETIL) -5 - ((2-HIDROXI-1-OXOPROPIL) AMINO) -2,4,6-TRIYODO -1,3-BENZENODICARBOXAMIDE. |
| JP50604597A JP4070235B2 (en) | 1995-09-08 | 1996-08-02 | (S) -N, N′-bis [2-hydroxy-1- (hydroxymethyl) ethyl] -5-[(2-hydroxy-1-oxopropyl) amino] -2,4,6-triiodo-1, Method for crystallizing 3-benzenedicarboxamide from water |
| EP96928403A EP0790979B1 (en) | 1995-09-08 | 1996-08-02 | Process for the crystallization from water of (s)-n,n'-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzendicarboxamide |
| HU9801837A HU220965B1 (en) | 1995-09-08 | 1996-08-02 | Process for the crystallization from water of (s)-n,n'-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzendicarboxamide |
| AU67888/96A AU708195B2 (en) | 1995-09-08 | 1996-08-02 | Process for the crystallization from water of (S)-N,N'-bis{2-hydroxy-1-(hydroxymethyl)ethyl}-5-{(2-hydroxy -1-oxopropyl)amino}-2,4,6-triiodo-1,3-benzendicarboxamide |
| CZ19971385A CZ288645B6 (en) | 1995-09-08 | 1996-08-02 | Crystallization process of Iopamidol |
| PL96320027A PL184937B1 (en) | 1995-09-08 | 1996-08-02 | Method of crystallising s)-n,n'-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[2-hydroxy-1-oxypropyl)amino]2,4,6-triiodine-1,3-benzenodicarboxyamide from aquepus solution |
| CA002204734A CA2204734C (en) | 1995-09-08 | 1996-08-02 | Process for the crystallization from water of (s)-n,n'-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzendicarboxamide |
| CN96191028A CN1070843C (en) | 1995-09-08 | 1996-08-02 | Process for crystallization from water of (S)-N,N'-bis[2-hydroxy-1-(hydroxymethyl) ethyl]-5-[(2-hydroxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzendicarboxamide |
| BR9606624A BR9606624A (en) | 1995-09-08 | 1996-08-02 | Process for the crystallization of (s) -n, n'-bisÚ2-hydroxy-1- (hydroxymethyl) ethyl¾-5-Ú (2-hydroxy-1-oxopropyl) amino¾-2,4,6-triiodo-1,3 -benzonodicar-boxamide from water |
| PCT/EP1996/003399 WO1997009300A1 (en) | 1995-09-08 | 1996-08-02 | Process for the crystallization from water of (s)-n,n'-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzendicarboxamide |
| DE69605528T DE69605528T2 (en) | 1995-09-08 | 1996-08-02 | METHOD FOR CRYSTALLIZING FROM WATER OF (S) -N, N'-BIS [2-HYDROXY-1- (HYDROXYMETHIEL) ETHYL] -5 - [(2-HYDROXY-1-OXOPROPYL) AMINO] -2,4,6- TRIIODO-1,3-BENZOLDICARBOXAMIDE |
| KR1019970702994A KR100270411B1 (en) | 1995-09-08 | 1996-08-02 | Process for the Crystallization from Water of (S)-N,N'-Bis[2-Hydroxy-1-(Hydroxymethyl)Ethyl]-5-[(2-Hydroxy-1-Oxopropyl)Amino]-2,4,6-Triiodo-1,3-Benzendicarboxamide |
| AT96928403T ATE187437T1 (en) | 1995-09-08 | 1996-08-02 | METHOD FOR CRYSTALLIZATION FROM WATER OF (S)-N,N'-BIS(2-HYDROXY-1-(HYDROXYMETHIEL)ETHYL>5-((2-HYDROXY-1-OXOPROPYL)AMINO>-2,4,6-TRIIODO - ,3- BENZOLDICARBOXAMIDE |
| US08/708,668 US5689002A (en) | 1995-09-08 | 1996-09-05 | Process for the crystallization from water of (S)-N,N'-bis 2-hydroxy-1-(hydroxymethyl)ethyl!-5- 2-hydroxy-1-oxopropyl)amino!-2,4,6-triiodo-1,3-benzendicarboxamide |
| NO971863A NO308841B1 (en) | 1995-09-08 | 1997-04-23 | Process for the crystallization of (S) -N, N'-bis [2-hydroxy-1- (hydroxymethyl) ethyl] -5 [(2-hydroxy-1-oxopropyl) amino] -2,4,6-triiodo-1 , 3-benzenedicarboxamide from water, and uses of (C1-C4 alcohols) |
| MXPA/A/1997/003341A MXPA97003341A (en) | 1995-09-08 | 1997-05-07 | Process for the crystallization of (s) -n, n'-bis [2-hydroxy-1- (hydroxymethyl) ethyl] -5 - [(2-hydroxy-1-oxopropyl) amino] -2,4,6-triyodo -1,3-bencendicarboxamide from a |
| HK98100990A HK1001861A1 (en) | 1995-09-08 | 1998-02-10 | Process for the crystallization from water of (s)-n,n'-bis(2-hydroxy-1-(hydroxymethyl)ethyl)-5-((2-hydroxy-1-oxopropyl)amino)-2,4,6-triiodo-1,3-benzendicarboxamide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT95RM000831 IT1277950B1 (en) | 1995-12-19 | 1995-12-19 | Prepn. of crystalline, anhydrous Iopamidol - by crystallisation from deionised water, useful as X=ray contrast agent |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| ITRM950831A0 ITRM950831A0 (en) | 1995-12-19 |
| ITRM950831A1 true ITRM950831A1 (en) | 1997-06-19 |
| IT1277950B1 IT1277950B1 (en) | 1997-11-12 |
Family
ID=11403721
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IT95RM000831 IT1277950B1 (en) | 1995-09-08 | 1995-12-19 | Prepn. of crystalline, anhydrous Iopamidol - by crystallisation from deionised water, useful as X=ray contrast agent |
Country Status (1)
| Country | Link |
|---|---|
| IT (1) | IT1277950B1 (en) |
-
1995
- 1995-12-19 IT IT95RM000831 patent/IT1277950B1/en active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| ITRM950831A0 (en) | 1995-12-19 |
| IT1277950B1 (en) | 1997-11-12 |
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