WO1997002235A1 - A process for preparing iopamidol by using a c1-c5 monoalkylether of a c2-c10 alkylen-glycol - Google Patents
A process for preparing iopamidol by using a c1-c5 monoalkylether of a c2-c10 alkylen-glycol Download PDFInfo
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- WO1997002235A1 WO1997002235A1 PCT/EP1996/002863 EP9602863W WO9702235A1 WO 1997002235 A1 WO1997002235 A1 WO 1997002235A1 EP 9602863 W EP9602863 W EP 9602863W WO 9702235 A1 WO9702235 A1 WO 9702235A1
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- Prior art keywords
- iopamidol
- alkylen
- glycol
- propandiol
- process according
- Prior art date
Links
- 229960004647 iopamidol Drugs 0.000 title claims abstract description 50
- 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 title claims abstract description 49
- 150000001346 alkyl aryl ethers Chemical class 0.000 title claims abstract description 23
- 238000004519 manufacturing process Methods 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 24
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 15
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 15
- 239000007864 aqueous solution Substances 0.000 claims description 10
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 9
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 8
- 229940093475 2-ethoxyethanol Drugs 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 238000010533 azeotropic distillation Methods 0.000 claims description 5
- RWNUSVWFHDHRCJ-UHFFFAOYSA-N 1-butoxypropan-2-ol Chemical compound CCCCOCC(C)O RWNUSVWFHDHRCJ-UHFFFAOYSA-N 0.000 claims description 4
- JOLQKTGDSGKSKJ-UHFFFAOYSA-N 1-ethoxypropan-2-ol Chemical compound CCOCC(C)O JOLQKTGDSGKSKJ-UHFFFAOYSA-N 0.000 claims description 4
- NTKBNCABAMQDIG-UHFFFAOYSA-N 3-butoxypropan-1-ol Chemical compound CCCCOCCCO NTKBNCABAMQDIG-UHFFFAOYSA-N 0.000 claims description 4
- XHMWPVBQGARKQM-UHFFFAOYSA-N 3-ethoxy-1-propanol Chemical compound CCOCCCO XHMWPVBQGARKQM-UHFFFAOYSA-N 0.000 claims description 4
- JDFDHBSESGTDAL-UHFFFAOYSA-N 3-methoxypropan-1-ol Chemical compound COCCCO JDFDHBSESGTDAL-UHFFFAOYSA-N 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- ARXJGSRGQADJSQ-UHFFFAOYSA-N 1-methoxypropan-2-ol Chemical compound COCC(C)O ARXJGSRGQADJSQ-UHFFFAOYSA-N 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- ZXKXJHAOUFHNAS-UHFFFAOYSA-N fenfluramine hydrochloride Chemical compound [Cl-].CC[NH2+]C(C)CC1=CC=CC(C(F)(F)F)=C1 ZXKXJHAOUFHNAS-UHFFFAOYSA-N 0.000 claims description 3
- 239000000243 solution Substances 0.000 claims description 3
- LHENQXAPVKABON-UHFFFAOYSA-N 1-methoxypropan-1-ol Chemical compound CCC(O)OC LHENQXAPVKABON-UHFFFAOYSA-N 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 239000013557 residual solvent Substances 0.000 claims description 2
- 230000003381 solubilizing effect Effects 0.000 claims description 2
- 239000000203 mixture Substances 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 238000002425 crystallisation Methods 0.000 description 12
- 230000008025 crystallization Effects 0.000 description 12
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- UEFGLENGHNNEBY-UHFFFAOYSA-N 1-methoxyethanol hydrate Chemical compound O.COC(C)O UEFGLENGHNNEBY-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- ALHZEIINTQJLOT-VKHMYHEASA-N [(2s)-1-chloro-1-oxopropan-2-yl] acetate Chemical compound ClC(=O)[C@H](C)OC(C)=O ALHZEIINTQJLOT-VKHMYHEASA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- FJQXCDYVZAHXNS-UHFFFAOYSA-N methadone hydrochloride Chemical compound Cl.C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 FJQXCDYVZAHXNS-UHFFFAOYSA-N 0.000 description 1
- 239000003690 nonionic contrast media Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000007487 urography Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
- C07C227/42—Crystallisation
Definitions
- the present invention relates to a process of purification of iopamidol. by crystallization with a solvent which is a C ⁇ -Cc monoalkylether of a alkylen- glycol.
- 5-lactamimido-isophtalimide commonly known as iopamidol
- iopamidol is a highly soluble non ionic contrast medium, widely utilized in radiology for diagnostic purposes.
- USP 4,001,323 describes the synthesis process, starting from 2,4,6- tri-iodo-5-amino-isophtalic acid chloride , which is successively treated with L-2 -acetoxy-propionyl chloride, and finally with 2- ami no- 1,3 propandiol.
- Iopamidol is a white solid, decomposing, without melting at about
- the product as such exhibits a low toxicity, (LD50 ranges from 19.4 in rabbit to 44,5 g/kg in mouse) [The Merck Index 11 th Ed. No. 943 Ed. -
- the product is isolated by evaporation of the aqueous solution thereof and the obtained raw product is crystallized from ethanol.
- iopamidol can be obtained in hydrated, mono- hydrated or pentahydrated form and in low yields also by slow crystallization from water.
- the drawback of these crystallization processes resides in that a significant quantity of solvent, which is not easily removable either by heating at elevated temperatures or under vacuum, always remains in the crystalline product. Also the remotion of residual traces of water from the crystalline product, coming from the above mentioned crystallization processes, requires prolonged heating at temperatures higher than 100°C.
- the most recent GB 2,280,436 describes a process for crystallizing iopamidol from butanol aqueous solution, allowing to obtain in high yield a crystalline product, having the above mentioned requirements established in US Pharmacopeia.
- the Applicant has now unexpectedly found that by using as the crystallization solvent a alkylen- glycol, it is possible to obtain crystalline iopamidol having a purity degree ranging from 99.5 to 99.9 starting from a iopamidol having a HPLC purity degree of 99.1%.
- the object of the present invention is a process for obtaining crystalline iopamidol in high yield and in an almost complete absence of residual solvents, comprising crystallizing iopamidol from a a C j _- Cc monoalkylether of a C2-C-J_Q. alkylen- glycol as the solvent , optionally in the presence of water.
- C ⁇ -Cc monoalkylether of a C 2 -C ⁇ Q alkylen- glycol belongs to one of the following classes represented respectively by the following general formulas ( I ) and ( II ) :
- a further object of the present invention is crystalline iopamidol having a purity degree higher than or equal to 99- •
- the preferred C ⁇ -Cc monoalkylether of a C 2 ⁇ C 1 Q alkylen- glycol used in the process according to the present invention are those of formula
- R is a C- ⁇ C/ j alkyl radical.
- the C ⁇ -Cc monoalkylether of a C 2 ⁇ C 1 Q alkylen- glycol is selected from the group consisting of: 1,2 propandiol-monomethylether, 1,2 propandiol-monoethylether, 1,2 propandiol-monobutylether, 1,3 propandiol-monomethylether, 1,3 propandiol-monoethylether, 1,3 propandiol-monobutylether, 2- ethoxyethanol, 2-methoxyethanol.
- the process according to the present invention can be carried out in the absence of water, by crystallization of iopamidol from a Ci-Ce monoalkylether of a C ⁇ -C- ⁇ Q alkylen- glycol. In this case for the dissolution of iopamidol in this solvent the amount of water still incorporated in iopamidol itself is used.
- the process is preferably carried out in the presence of water.
- the process when carried out in water it preferably comprises the following steps: a) dissolving iopamidol at a temperature ranging from 80 and 150 °C in a C ⁇ -Cc monoalkylether of a C 2 -C ⁇ Q alkylen- glycol and in the presence of the necessary amount of water for solubilizing iopamidol, partially or completely removing water by azeotropic distillation and optionally restoring the distilled solvent; b) cooling at a temperature comprised between 0 and 0 °C the solution coming from step (a) and recovering the crystallized product by filtration.
- the volume of the C- ⁇ -Cc monoalkylether of ⁇ C ⁇ Q alkylen- glycol used in step (a) is comprised between 1 and 10 times, preferably between 3 and 5 times the theoretical ponderal quantity of iopamidol to be purified.
- the following ratio volume of water / volume of solvent is generally comprised between 1/8 and 1/4.
- the presence of humidity residues in the crystallization mixture does not adversely affect the quality and the yield of the final product, which is in any case obtained in an almost anhydrous form.
- the crystallization directly from an aqueous solution of iopamidol, prepared for this specific purpose or an aqueous solution coming from the same synthesis process.
- the C ⁇ -Cc monoalkylether of a C 2 -C ⁇ Q alkylen- glycol is preferably added in the above mentioned ratios to the aqueous solution containing iopamidol.
- step (b) the mixture is then heated to carry out the azeotropic distillation of water, and this distillation is continued until the mixture reaches the boiling temperature of the pure solvent.
- a third solvent such as toluene, suitable to form a ternary azeotrope with water, may be added to the mixture of iopamidol water and said C ⁇ -Cc monoalkylether of a C -C- ⁇ Q alkylen- glycol in order to make easier the complete remotion of water.
- the cooling temperature of step (b) in the case the process is carried out in a solvent selected from the group consisting of: 2- ethoxyethanol, 2-methoxyethanol, is preferably comprised between 20 and 90 °C, in the case the process is carried out in the presence of a solvent selected from the group consisting of: 1,2 propandiol- monomethylether, 1,2 propandiol-monoethylether, 1,2 propandiol- monobutylether, 1,3 propandiol-monomethylether, 1,3 propandiol- monoethylether, 1,3 propandiol-monobutylether, ranges from 0 to 80° C. In both the above mentioned cases the cooling temperature is more preferably comprised between 50 and 70°C.
- step (b) the crystallization of the product occurs, and the product is maintained at the cooling temperature for a period comprised between 30 minutes and 3 hours, the desired product is recovered by filtration and dried under vacuum for 3-4 hours at a temperature of 60° C.
- the properties of the iopamidol thus obtained are determined by HPLC. For example for determining the HPLC degree of purity of iopamidol the standard operating conditions reported in Pharmeuropa 6, No. 4, page 343 , (1994) may be followed .
- the crystallization yields of the process according to the present invention are very high and in any case are comprised between 80 and 95%-
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A process for purifying iopamidol consisting of crystallizing this product from a C1-C5 monoalkylether of a C2-C10 alkylen-glycol. This process allows to obtain crystalline iopamidol in a high yield with optimum physical-chemical properties.
Description
A PROCESS FOR PREPARING IOPAMIDOL BY USING A C^-Cg MONOALKYLETHER OF A
C2-C10 ALKYLEN-GLYCOL.
FIELD OF THE J-NVENTION
The present invention relates to a process of purification of iopamidol. by crystallization with a solvent which is a C^-Cc monoalkylether of a
alkylen- glycol.
TECHNOLOGICAL BACKGROUND
( S ) -N , N ' -bis [ 2-hydr oxy- 1 - ( hydr oxy-methyl ) ethyl ] -2 , 4 , 6 - triiodo-
5-lactamimido-isophtalimide, commonly known as iopamidol, is a highly soluble non ionic contrast medium, widely utilized in radiology for diagnostic purposes.
USP 4,001,323 describes the synthesis process, starting from 2,4,6- tri-iodo-5-amino-isophtalic acid chloride , which is successively treated with L-2 -acetoxy-propionyl chloride, and finally with 2- ami no- 1,3 propandiol.
Iopamidol is a white solid, decomposing, without melting at about
300° C, being highly soluble in water, scarcely soluble in methanol and almost insoluble in chloroform and ethanol.
The product as such exhibits a low toxicity, (LD50 ranges from 19.4 in rabbit to 44,5 g/kg in mouse) [The Merck Index 11th Ed. No. 943 Ed. -
Rahway, N.J. USA 1989] however in order to be effective as a contrast medium, it must be administered in quite high dosages.
For example, in the case of i.v. urography, it is suggested administering from 40 to 80 ml of an aqueous solution containing from 61.2 to 75.5% iopamidol [Martindale 13 tn Ed., page 708. The
Pharmaceutical Press Ed., London England].
The above high quantities of iopamidol, especially if associated to the potentially critical intravenous administration, render necessary an extreme purification of this product, in order to minimize or avoid any side effect due to the presence of reaction by¬ products.
For this purpose in US Pharmacopeia it is established that the amount of impurities be not higher than 5000 ppm [US Pharmacopeia Ed. 23. page 828, (1995)]- Iopamidol syntheses described in literature generally contemplate a purification of the final product, starting from its aqueous solution.
For example according to the above mentioned US patent, the product is isolated by evaporation of the aqueous solution thereof and the obtained raw product is crystallized from ethanol.
A similar solution is also encompassed in the International Application W0 88/ 09328, wherein raw iopamidol obtained by evaporation of the aqueous solution is crystallized from anhydrous ethanol, using for the dissolution of iopamidol in this solvent the amount of water still incorporated in iopamidol itself.
These methods utilize the higher solubility in ethanol of the hydrated form than that of the anhydrous form of iopamidol.
In fact it is known that iopamidol can be obtained in hydrated, mono- hydrated or pentahydrated form and in low yields also by slow crystallization from water.
The drawback of these crystallization processes resides in that a significant quantity of solvent, which is not easily removable either by heating at elevated temperatures or under vacuum, always remains in the crystalline product. Also the remotion of residual traces of water from the crystalline product, coming from the above mentioned crystallization processes, requires prolonged heating at temperatures higher than 100°C. The most recent GB 2,280,436 describes a process for crystallizing iopamidol from butanol aqueous solution, allowing to obtain in high yield a crystalline product, having the above mentioned requirements established in US Pharmacopeia.
However this type of purification is practically effective, when the iopamidol to be purified has already a degree of purity very close to that required in Pharmacopeia. THE PRESENT INVENTION
The Applicant has now unexpectedly found that by using as the crystallization solvent a
alkylen- glycol, it is possible to obtain crystalline iopamidol having a purity degree ranging from 99.5 to 99.9 starting from a iopamidol having a HPLC purity degree of 99.1%.
The object of the present invention is a process for obtaining crystalline iopamidol in high yield and in an almost complete absence of residual solvents, comprising crystallizing iopamidol from a a Cj_- Cc monoalkylether of a C2-C-J_Q. alkylen- glycol as the solvent , optionally in the presence of water.
In particular the C^-Cc monoalkylether of a C2-C^Q alkylen- glycol
belongs to one of the following classes represented respectively by the following general formulas ( I ) and ( II ) :
CH2-A CH3- (CH2) W-CH- (CH2) g-CH- (CH2) tCH3
OR OR OH
(I ) (ID wherein A has one of the following meanings : i) - (CH2; 1-CH2-0H ,
ii) -CH- (CH2)m-CH3 , OH
iii) - (CH2)m-CH-CH3 OH wherein 1 is = 0 or an integer of from 1 to 8; m is s 0 or an integer of from 1 to 7, in formula (II) w, s and t equal or different from eachother are = 0 or integers of from 1 to 5. provided their sum is not higher than 6, R is a linear or branched alkyl radical of from 1 to 5 carbon atoms .
A further object of the present invention is crystalline iopamidol having a purity degree higher than or equal to 99- •
DETAILED DESCRIPTION OF THE PRESENT INVENTION
The preferred C^-Cc monoalkylether of a C2~C1Q alkylen- glycol used in the process according to the present invention are those of formula
(I) , wherein 1 or m is preferably = 0 or equal to an integer of from 1 to 3. R is a C-^C/j alkyl radical.
According to a particularly preferred embodiment of the process
according to the present invention the C^-Cc monoalkylether of a C2~ C1Q alkylen- glycol is selected from the group consisting of: 1,2 propandiol-monomethylether, 1,2 propandiol-monoethylether, 1,2 propandiol-monobutylether, 1,3 propandiol-monomethylether, 1,3 propandiol-monoethylether, 1,3 propandiol-monobutylether, 2- ethoxyethanol, 2-methoxyethanol.
The process according to the present invention can be carried out in the absence of water, by crystallization of iopamidol from a Ci-Ce monoalkylether of a C^-C-^Q alkylen- glycol. In this case for the dissolution of iopamidol in this solvent the amount of water still incorporated in iopamidol itself is used. The process is preferably carried out in the presence of water. When the process is carried out in water it preferably comprises the following steps: a) dissolving iopamidol at a temperature ranging from 80 and 150 °C in a C^-Cc monoalkylether of a C2-C^Q alkylen- glycol and in the presence of the necessary amount of water for solubilizing iopamidol, partially or completely removing water by azeotropic distillation and optionally restoring the distilled solvent; b) cooling at a temperature comprised between 0 and 0 °C the solution coming from step (a) and recovering the crystallized product by filtration.
The volume of the C-^-Cc monoalkylether of ~C^Q alkylen- glycol used in step (a) is comprised between 1 and 10 times, preferably between 3 and 5 times the theoretical ponderal quantity of iopamidol
to be purified.
In the same step (a) the following ratio volume of water / volume of solvent is generally comprised between 1/8 and 1/4. In any case the presence of humidity residues in the crystallization mixture does not adversely affect the quality and the yield of the final product, which is in any case obtained in an almost anhydrous form. Anyway with the process according to the present invention, it is also possible to obtain in high yield the crystallized product in one of the hydrated forms, if in step (a) the water is partially removed. From an industrial point of view it is preferable to carry out the crystallization directly from an aqueous solution of iopamidol, prepared for this specific purpose or an aqueous solution coming from the same synthesis process. In this case the C^-Cc monoalkylether of a C2-C^Q alkylen- glycol is preferably added in the above mentioned ratios to the aqueous solution containing iopamidol.
In step (b) the mixture is then heated to carry out the azeotropic distillation of water, and this distillation is continued until the mixture reaches the boiling temperature of the pure solvent. Small quantities of a third solvent, such as toluene, suitable to form a ternary azeotrope with water, may be added to the mixture of iopamidol water and said C^-Cc monoalkylether of a C -C-^Q alkylen- glycol in order to make easier the complete remotion of water. The cooling temperature of step (b) , in the case the process is carried out in a solvent selected from the group consisting of: 2- ethoxyethanol, 2-methoxyethanol, is preferably comprised between 20 and 90 °C, in the case the process is carried out in the presence of a
solvent selected from the group consisting of: 1,2 propandiol- monomethylether, 1,2 propandiol-monoethylether, 1,2 propandiol- monobutylether, 1,3 propandiol-monomethylether, 1,3 propandiol- monoethylether, 1,3 propandiol-monobutylether, ranges from 0 to 80° C. In both the above mentioned cases the cooling temperature is more preferably comprised between 50 and 70°C.
In step (b) the crystallization of the product occurs, and the product is maintained at the cooling temperature for a period comprised between 30 minutes and 3 hours, the desired product is recovered by filtration and dried under vacuum for 3-4 hours at a temperature of 60° C. The properties of the iopamidol thus obtained are determined by HPLC. For example for determining the HPLC degree of purity of iopamidol the standard operating conditions reported in Pharmeuropa 6, No. 4, page 343 ,(1994) may be followed . The crystallization yields of the process according to the present invention are very high and in any case are comprised between 80 and 95%-
For illustrative purposes in the following tables reported are the results obtained with the process according to the present invention encompassing in particular the use of a C-^-Cc monoalkylether of a C2-C-Q alkylen- glycol , selected from l-methoxy-2-ethanol, and l-methoxy-2-propanol in comparison with the corresponding results obtained with the crystallization prior art processes, contemplating the use as crystallization solvents of ethanol, and butanol.
-TABLE 1-
Solvent HPLC Starting purity Yield HPLC Final purity (%) (%) (%)
ethanol 99.1 95 99.2 n-butanol 99-1 97 99.3
1-methoxy-
-2-ethanol 99-1 88 99.7
1-methoxy-
-2-propanol 99-1 89 99.6
The following examples are reported of the process according to the present invention for illustrative, but not limitative purposes . EXAMPLE 1
10 g iopamidol (12,8 mmol) with HPLC purity degree 99.1% are suspended in 40 ml 2-methoxyethanol (Methyl-Cellosolve ) and 5 nil water are added to the suspension.
The mixture is then heated under reflux (104-105°C), until complete dissolution of the suspension. 45 ml solvent consisting of an azeotropic mixture of water and 2-methoxyethanol are then removed by distillation. The starting volume is restored by adding 2- methoxyethanol and the obtained mixture is cooled to 70°C. The precipitated solid is then recovered by filtration and dried under vacuum at 60° C. 8,8 g of iopamidol are obtained (yield 88%) with
HPLC purity degree 99,7%. EXAMPLE 2
10 g iopamidol (12,8 mmol) with HPLC purity degree 99.1% are treated with 40 ml 2-methoxyethanol and 5 ml water, by following the same operating conditions of Example 1. After azeotropic distillation and restoration of the starting volume of the solvent, the mixture is cooled to 25° C. A solid precipitates, which is recovered by filtration, then it is dried under vacuum at 60° C to give 9 E iopamidol (yield 90%) with HPLC purity degree 99-5%. EXAMPLE 3
10 g iopamidol (12,8 mmol) with HPLC purity degree 99.1% are suspended in 40 ml 2-ethoxyethanol (Cellosolve ) , and 5 ml water are added to the suspension thus obtained. The mixture is then heated under reflux (104-105° C), until complete dissolution of the suspension. 4 ml solvent consisting of an azeotropic mixture of water and 2-ethoxyethanol are then removed by distillation. The starting volume is restored by adding 2- ethoxyethanol and the obtained mixture is cooled to 70° C. The precipitated solid is then recovered by filtration and dried under vacuum at 60° C. 8,8 g of iopamidol are obtained (yield 88%) with HPLC purity degree 99.7%. EXAMPLE 4
10 g iopamidol (12,8 mmol) with HPLC purity degree 99-1% are suspended in 40 ml l-methoxy-2-propanol and 5 ml water are added to the suspension thus obtained. The mixture is heated to the reflux temperature of the solvent (110-115° C) , until complete dissolution of
the suspension. The azeotropic distillation is then carried out until the temperature of the vapours reaches 118° C. The starting volume of 1-methoxy-propanol is then restored, while maintaining the temperature of the mixture comprised between 110 and 115° C. The mixture is then cooled to 70° C and left at this temperature for 2 hours. The precipitated solid is filtered at 70°C and dried under vacuum at 6θ°C. 8.9 g iopamidol are obtained (yield 89%), having HPLC purity degree 99.6%.
Claims
CLAIMS 1. A process for obtaining crystalline iopamidol in a high yield in almost complete absence of residual solvents comprising crystallizing said product from a C-^-Cc monoalkylether of a C2-C^n alkylen-glycol, as the solvent. 2. The process according to claim 1, wherein said C^-Cc monoalkylether of a C2~C^Q alkylen-glycol belongs to one of the following classes represented respectively by the following general formulas (I) and (II):
CH2-A CH3-(CH2)W-CH-(CH2)g-CH-(CH2)tCH3
OR OR OH
(I) (ID
wherein A has one of the following meanings :
i) - (CH^-C^-OH ,
ii) -CH-(CH2)m-CH3, OH
iii) -(CH2)m-CH-CH3 OH wherein 1 is = 0 or an integer of from 1 to 8; m is = 0 or an integer of from 1 to 7. in formula (II) w, s and t equal or different from eachother are = 0 or integers of from 1 to 5. provided their sum is not higher than 6, R is a linear or branched alkyl radical of from 1 to 5 carbon atoms. 3- The process according to claim 2, wherein, a C-^-Cc monoalkylether
of a C -C-J_Q alkylen- glycol of formula (I) is used as the solvent, having 1 or m = 0 or equal to an integer of from 1 to 3, R is a <^l~<-'4 alkyl radical . 4. The process according to claim 3. wherein the C^Cc monoalkylether of a C2-C1Q alkylen- glycol is selected from the group consisting of: 1.2 propandiol-monomethylether, 1 ,2 propandiol-monoethylether, 1 ,2 propandiol-monobutylether, 1 , 3 propandiol-monomethylether , 1 , 3 propandiol-monoethylether , 1 , 3 propandiol-monobutylether , 2- ethoxyethanol , 2-methoxyethanol . 5 - The process according to claim 1 , wherein the iopamidol is crystallized from said C^-Cc monoalkylether of a C2-C^n alkylen- glycol in the absence of water. 6. The process according to claim 1 , wherein it is carried out in the presence of water and comprises the following steps: a) dissolving iopamidol at a temperature ranging froin 80 to 150 °C in a
alkylen-glycol and in the presence of the amount of the necessary water for solubilizing iopamidol , partially or completely removing water by azeotropic distillation and optionally restoring the distilled solvent; b) cooling at a temperature comprised between 0 and 90 °C the solution coming from step ( a) and recovering the crystallized product by filtration. 7 - The process according to claim 6 , wherein in step (a) said C-^-Cπ monoalkylether of a C2-C^Q alkylen-glycol is added to an aqueous solution containing iopamidol prepared for this purpose, or an aqueous
solution coming from the synthesis process of iopamidol itself. 8. The process according to claim 6 , wherein in step (a) the volume of said C-^-Cc monoalkylether of a C2-C10 alkylen-glycol is comprised between 1 and 10 times the theoretical ponderal amount of iopamidol to be purified, and the following ratio volume of water / volume of said Cj^-Cc monoalkylether of a C2-C10 alkylen-glycol is comprised between 1/8 and 1/4. 9- The process according to claim 8, wherein the volume of said Ci-Cc monoalkylether of a
alkylen-glycol is comprised between 3 and 5 times the theoretical ponderal amount of iopamidol to be purified. 10. The process according to claim 6, wherein, when in step (a) the water is partially removed, one of the hydrated forms is obtained of iopamidol. 11. The process according to claim 6, wherein in step (a) a third solvent is used, able to form a ternary azeotrope with water and said alkylen-glycol.
12. The process according to claim 6, wherein the cooling temperature of step (b) , when the process is carried out in a solvent selected from the group consisting of: 2-ethoxyethanol, 2-methoxyethanol is comprised between 20 and 90° C, when the process is carried out in the presence of a solvent selected from the group consisting of: 1,2 propandiol-monomethylether, 1,2 propandiol-monoethylether, 1,2 propandiol-monobutylether, 1,3 propandiol-monomethylether, 1,3 propandiol-monoethylether, 1,3 propandiol-monobutylether, it ranges from 0 to 80° C. 13- The process according to claim 12 wherein the cooling temperature
of step (b) is comprised between 50 and 70° C. 14. The process according to claim 6 , wherein in step (b) the product is maintained at the cooling temperature for a period comprised between 30 minutes and 3 hours, then the desired product is recovered by filtration and dried under vacuum for 3-4 hours at a temperature of 60° C.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP96924828A EP0842141A1 (en) | 1995-07-04 | 1996-07-01 | A process for preparing iopamidol by using a c1-c5 monoalkylether of a c2-c10 alkylen-glycol |
| AU65161/96A AU6516196A (en) | 1995-07-04 | 1996-07-01 | A process for preparing iopamidol by using a c1-c5 monoalkylether of a c2-c10 alkylene-glycol |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT95MI001429 IT1275473B (en) | 1995-07-04 | 1995-07-04 | Crystallising iopamidol from a mono:alkyl ether of an alkylene glycol - to obtain crystalline iopamidol in high yield with optimum physical- chemical properties |
| ITMI95A001429 | 1995-07-04 | ||
| IT95MI002572 IT1277049B1 (en) | 1995-12-06 | 1995-12-06 | Crystallising iopamidol from a mono:alkyl ether of an alkylene glycol - to obtain crystalline iopamidol in high yield with optimum physical- chemical properties |
| ITMI95A002572 | 1995-12-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1997002235A1 true WO1997002235A1 (en) | 1997-01-23 |
Family
ID=26331296
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1996/002863 WO1997002235A1 (en) | 1995-07-04 | 1996-07-01 | A process for preparing iopamidol by using a c1-c5 monoalkylether of a c2-c10 alkylen-glycol |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0842141A1 (en) |
| AU (1) | AU6516196A (en) |
| IN (1) | IN181340B (en) |
| WO (1) | WO1997002235A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998034908A1 (en) * | 1997-02-11 | 1998-08-13 | Bracco International B.V. | PROCESS FOR THE CRYSTALLIZATION FROM A LINEAR OR BRANCHED (C5-C6) ALCOHOL OR THEIR MIXTURES OF (S)-N,N'-bis[2-HYDROXY-1- (HYDROXYMETHYL)ETHYL]-5-[ (2-HYDROXY-1-OXOPROPYl)AMINO]-2,4,6- TRIIODO-1,3-BENZENDICARBOXAMIDE |
| EP0992245A1 (en) * | 1998-09-16 | 2000-04-12 | Goldham Bioglan Pharma GmbH | Radio-contrast agents |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1988009328A1 (en) * | 1987-05-22 | 1988-12-01 | Bracco Industria Chimica S.P.A. | Preparation of 5-acylamino-2,4,6-triiodo- or tribromo-benzoic acid derivatives |
| GB2280436A (en) * | 1993-07-30 | 1995-02-01 | Zambon Spa | Process for crystallization of iopamidol |
-
1996
- 1996-07-01 WO PCT/EP1996/002863 patent/WO1997002235A1/en not_active Application Discontinuation
- 1996-07-01 EP EP96924828A patent/EP0842141A1/en not_active Withdrawn
- 1996-07-01 AU AU65161/96A patent/AU6516196A/en not_active Abandoned
- 1996-07-03 IN IN1220CA1996 patent/IN181340B/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1988009328A1 (en) * | 1987-05-22 | 1988-12-01 | Bracco Industria Chimica S.P.A. | Preparation of 5-acylamino-2,4,6-triiodo- or tribromo-benzoic acid derivatives |
| GB2280436A (en) * | 1993-07-30 | 1995-02-01 | Zambon Spa | Process for crystallization of iopamidol |
Non-Patent Citations (1)
| Title |
|---|
| FELDER, ERNST ET AL: "Iopamidol", ANAL. PROFILES DRUG SUBST. (1988), 17, 115-54 CODEN: APDSB7;ISSN: 0099-5428, XP002012662 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998034908A1 (en) * | 1997-02-11 | 1998-08-13 | Bracco International B.V. | PROCESS FOR THE CRYSTALLIZATION FROM A LINEAR OR BRANCHED (C5-C6) ALCOHOL OR THEIR MIXTURES OF (S)-N,N'-bis[2-HYDROXY-1- (HYDROXYMETHYL)ETHYL]-5-[ (2-HYDROXY-1-OXOPROPYl)AMINO]-2,4,6- TRIIODO-1,3-BENZENDICARBOXAMIDE |
| CZ299420B6 (en) * | 1997-02-11 | 2008-07-23 | Bracco International B. V. | Crystallization process of iopamidol |
| EP0992245A1 (en) * | 1998-09-16 | 2000-04-12 | Goldham Bioglan Pharma GmbH | Radio-contrast agents |
| WO2000015266A3 (en) * | 1998-09-16 | 2000-05-25 | Goldham Bioglan Pharma Gmbh | Radio-contrast agents |
Also Published As
| Publication number | Publication date |
|---|---|
| IN181340B (en) | 1998-05-16 |
| AU6516196A (en) | 1997-02-05 |
| EP0842141A1 (en) | 1998-05-20 |
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