The present invention relates to a process for the crystallization of lopamidol and, more particularly, it relates to a process for the crystallization of lopamidol which uses a butanol as solvent.

The term lopamidol is the International Non-proprietary Name (INN) of the compound L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthal- ic acid bis-(1 ,3-dihydroxyisopropylamide). This compound was described for the first time by the Swiss company

Savac A.G. for example in the British patent no. 1,472,050. lopamidol is used in diagnostics as non-ionic contrast medium.

Physically, it is a white high-melting solid.

The syntheses of lopamidol described in the literature foresee a final purification of the product in aqueous solution.

Thereafter, in order to obtain the product in solid form, it is necessary to crystallize it.

In the above cited British patent, it is reported that the product is isolated by evaporation of the aqueous solution which contains it and the crude is crystallized from ethanol.

Also in the International patent application no. W088/09328 in the name of Bracco Industrie Chimica S.p.A. , it is reported that the crude lopamidol obtained by evaporation of the aqueous solvent is crystallized from absolute ethanol. In the monograph on lopamidol published in "Analytical Profiles of

Drug Substances", vol. 17, pages 115-154, Academic Press, San Diego,

(1988), it is reported that lopamidol can be crystallized from water, with a very slow kinetics, yielding a onohydrate or pentahy- drate crystalline product. Thus, with the aim of preparing lopamidol with a crystalline form

having the characteristics corresponding to the requisites of phar¬ macopoeia, for example US Pharmacopoeia XXII, page 712, we have tried to crystallize lopamidol from ethanol or from water according ς to the literature.

The product crystallized from ethanol contains an amount of ethanol corresponding to 4000-8000 ppm which cannot be removed either by heating at high temperatures or under vacuum. Thus, the resultant product is not suitable because its ethanol content is too'high. In 0 fact, the USA Pharmacopoeia requires that no impurity exceeds 5000 ppm.

Similarly, lopamidol crystallized from water is not suitable because of the water of crystallization which needs a very long heating at temperatures higher than 100°C to be removed. 5 Furthermore, the yield of the crystallization from water is very poor and therefore the process is not suitable also from an industrial point of view.

The literature data about the solubility of lopamidol are rather conflicting each other and therefore they do not suggest other 0 practical solutions to solve the problem of the crystallization of the product.

In fact, for example, in the above cited British patent it is re¬ ported that lopamidol dissolves very easily in water, has a practi¬ cally unlimited solubility in methanol and that also in ethanol the 5 solubility is about 10% at room temperature.

However, one of the Inventors of that patent, in a subsequent paper published on Bull. Chim. Farm., 120. 639, (1981), reports that lopamidol is very soluble in water but is slightly soluble in metha¬ nol and practically insoluble in ethanol, diethylether, benzene and _Q chloroform.

We have now surprisingly found and it is an object of the present invention that lopamidol can be crystallized from n.butanol, sec.bu¬ tanol, isobutanol or t.butanol giving with high yields a product with suitable characteristics according to the requisites of pharma¬ copoeia.

We have further found that it is not necessary to start from a solid crude lopamidol but it is possible to obtain the desired product by directly treating an aqueous solution of the product with n.butanol, sec.butanol, isobutanol or t.butanol.

Therefore, a second object of the present invention is a process for obtaining crystalline lopamidol with high yields consisting in the treatment of an aqueous solution of lopamidol with n.butanol, sec.butanol, isobutanol or t.butanol. The terms n.butanol, sec.butanol, isobutanol and t.butanol are the common names used to indicate the four isomers of butanol having the formula C*Hι _O 0; more precisely, n.butanol is the common name for 1-hydroxybutane, sec.butanol is the common name for 2-hydroxybutane, isobutanol is the common name for 1-hydroxy-2-methylpropane and t.butanol is the common name for 1 ,1-dimethyl-1-hydroxyethane.

Hereinafter, for the sake of simplicity, we will use the term buta¬ nol to indicate indifferently n.butanol, sec.butanol, isobutanol or t.butanol, if not otherwise specified. In the process object of the present invention, preferably, a part of water is removed by distillation until lopamidol begins to crys¬ tallize.

An amount of residual water in the crystallization mixture, for example even an amount of water corresponding to the weight of lopamidol, is not critical for the quality and the yield of the product itself.

The amount of butanol to be used is from 3 to 20 times (volume/ weight) with respect to the amount of lopamidol which is present in the aqueous solution. ς

Preferably, the amount of butanol is from 3 to 12 times (volume/ weight) with respect to the amount of lopamidol.

Still more preferably, the amount of butanol is from 3 to 10 times

(volume/weight) with respect to the amount of lopamidol.

It is self-evident that when the azeotropic mixture, obtained by 0 distillation, separates in its components, the butanol can be re¬ covered and recycled. In this case lower amounts of butanol may be used.

Alternatively, it is also possible to add to the mixture water, lopamidol and butanol, a little amount of a third solvent, for 5 example toluene, able to form a ternary azeotrope with water.

From a practical point of view, the direct use of an aqueous solu¬ tion of lopamidol is preferred because it is practically and econom¬ ically more advantageous not to remove all the water and because the resultant product has better characteristics having a very low 0 content of residual solvent.

In a practical embodiment which is particularly advantageous from an industrial point of view, an aqueous solution of lopamidol is additioned with butanol in an amount from 3 to 20 times (volume/weight) with respect to that of lopamidol. The reaction 5 mixture is heated at the boiling temperature to azeotropically remove part of the water. The precipitation of lopamidol is obser¬ ved.

The distillation is continued until reducing the water to an amount by weight equal to or lower than that of lopamidol. Q Then, the heating is stopped and the temperature is brought to

10-30°C, preferably to about 25°C, and lopamidol is separated by filtration.

In another practical embodiment, the starting mixture water, Iopa i- dol and butanol is added with a third solvent able to form an azeo- trope with water, for example toluene.

Also in this case, during the distillation step a precipitate of lopamidol begins to form.

The characteristics of the product obtained with the process object of the invention fulfil the pharmacopoeia requirements since the amount of butanol remained in the product is decidedly lower than the limits required by pharmacopoeia and, when it is obtained di¬ rectly from the aqueous solution, the residual solvent is even equal to or lower than 200 ppm. The resultant product has a very high chromatographic purity, higher than that of the starting product in aqueous phase. Thus, the lopamidol obtained by the purification process of the invention is particularly suitable for the preparation of non-ionic contrast media according to usual techniques. Furthermore, the crystallization yields are very high, at least higher than 80% and in most cases also higher than 95%. As far as the instant process is concerned, mixtures of butanols appear to behave in substantially the same way as the single components and thus mixture of butanols do not depart from the spirit of this invention.

In order to better illustrate the present invention the following examples are now given.

The water content in the azeotrope and in the final product was determined by Karl-Fisher method, while the content of butanol in the final product was determined by gas-chromatographic route.

Example 1 Sec.butanol (1600 ml) was added under stirring and by keeping the temperature at 85°C to a solution of lopamidol (200 g; 0.257 moles) in water (200 ml).

The solution was heated to the reflux temperature, while distilling at ordinary pressure the mixture sec.butanol/water at the rate of 10 ml/minute. During the distillation lopamidol begins to precipitate. In all, 853 g of sec.butanol/water mixture (water=23.1%) were dis- tilled off.

The suspension was cooled to 25°C in 1 hour, kept at 25°C for one further hour and the precipitate was filtered off and washed with sec.butanol (2 x 100 ml). After drying under vacuum at 60°C until constant weight, lopamidol (192 g; 0.247 moles; 96% yield) was obtained; water content=0.15% and residual solvent sec.butanol 200 ppm.

Example 2 Sec.butanol (1800 ml) was added under stirring and by keeping the temperature at 80°C±2°C to a solution of lopamidol (200 g; 0.257 moles) in water (270 ml).

The solution was heated to the reflux temperature, while distilling at ordinary pressure the mixture sec.butanol/water at the rate of 10 ml/minute. During the distillation lopamidol begins to precipitate. In all, 700 g of sec.butanol/water mixture (water=22%) were distil- led off. About 116 g of water were still present.

The suspension was cooled to 25°C in 1 hour, kept at 25°C for one further hour and the precipitate was filtered off and washed with sec.butanol (2 x 100 ml). After drying under vacuum at 60°C until constant weight, lopamidol (190 g; 0.244 moles; 95% yield) was obtained; water content=0.2%,

residual solvent sec.butanol 180 ppm.

Example 3

Sec.butanol (150 ml) and toluene (20 ml) were added under stirring and by keeping the temperature at 80-85°C to a solution of lopamidol

(20 g; 0.0257 moles) in water (30 ml).

The mixture was brought to reflux and a part of water was azeotrop¬ ically removed. During the distillation lopamidol begins to precipi¬ tate. in all, 12 ml of water were distilled off.

The suspension was cooled in 1 hour to 25°C, kept at 25°C for one further hour and the precipitate was filtered off and washed with sec.butanol (2 x 10 ml). After drying under vacuum at 60°C until constant weight, lopamidol (1 .2 g; 0.0247 moles; 96% yield) was obtained; water content=0.2%, residual solvent sec.butanol 100 ppm and toluene 2 ppm.

Example 4 N.butanol (200 ml) was added under stirring and by keeping the tem¬ perature at 80°C±2°C to a solution of lopamidol (20 g; 0.0257 moles) in water (20 ml).

The solution was heated to the reflux temperature, while distilling water (8.5 g) with a florentine flask. During the distillation lopamidol begins to precipitate. The distillation was completed by further distilling 54 g of n.buta- no1/water mixture (water=21%).

The suspension was cooled to 25°C and the precipitate was filtered off and washed with n.butanol (2 x 10 ml).

After drying under vacuum at 60°C until constant weight, lopamidol (19.4 g; 0.025 moles; 97% yield) was obtained; water content=0.2%, residual solvent n.butanol 70 ppm.

Example 5 N.butanol (200 ml) was added under stirring and by keeping the tem¬ perature at 80°C±2°C to a solution of lopamidol (20 g; 0.0257 moles) in water (80 ml).

The solution was heated to boiling, while distilling water (72 g) with a florentine flask. During the distillation lopamidol begins to precipitate.

The distillation was completed by further distilling 50 g of n.buta- nol/water mixture (water=21%).

The suspension was cooled to 25°C and the precipitate was filtered off and washed with n.butanol (2 x 10 ml).

After drying under vacuum at 60°C until constant weight, lopamidol (19.3 g; 0.0248 moles; 96.5% yield) was obtained; water content=0.2%, residual solvent n.butanol 80 ppm.

Example 6 A solution of lopamidol (20 g; 0.0257 moles) in water (20 ml) was brought to residue under vacuum (70°C - 30 mmHg). Sec.butanol (150 ml) was added to the residue containing water (2.3%) and the heterogeneous mixture, kept under stirring, was brought to reflux and kept at the reflux temperature for 30 minutes. The suspension was cooled to 25°C and the precipitate was filtered off and washed with sec.butanol (2 x 10 ml).

After drying under vacuum at 70°C until constant weight, lopamidol (19.4 g; 0.025 moles; 97% yield ⁾ was obtained; water content=0.2%, residual solvent n.butanol 1300 ppm.

Example 7 A mixture of lopamidol (20 g; 0.0257 moles), water (20 ml) and isobutanol (150 ml) was heated to reflux while distilling water (9

^ml) -

During the distillation lopamidol begins to precipitate.

In all, 47 g of isobutanol/water mixture (water=18.3%) were distil¬ led off.

The suspension was cooled to 25°C and the precipitate was filtered off and washed with isobutanol (2 x 10 ml).

After drying under vacuum at 60°C until constant weight, lopamidol

(19.7 g; 0.0254 moles; 98.5% yield) was obtained; water con- tent=0.17%, residual solvent isobutanol 100 ppm. Example 8

T.butanol (150 ml) was added under stirring and by keeping the tem¬ perature at 70°C to a solution of lopamidol (20 g; 0.0257 moles) in water (20 ml).

The suspension was heated to the reflux temperature, while distil- ling at ordinary pressure 57 g of the mixture t.butanol/water (wa- ter=13.3%). During the distillation lopamidol begins to precipitate.

The suspension was cooled to 25°C and the precipitate was filtered off and washed with t.butanol (2 x 10 ml).

After drying under vacuum at 60°C until constant weight, lopamidol (16 g; 0.0206 moles; 80% yield) was obtained; water content=0.25%, residual solvent t.butanol 150 ppm.

Example 9

Charcoal (8 Kg) was added to an aqueous solution (2500 1) containing lopamidol (about 290 Kg). After stirring for 30 minutes and filtration of the charcoal, the resultant solution was concentrated under vacuum up to a final concentration of 70-75% (w/w).

The concentrated solution was heated to 85°C and, while keeping the temperature between 80°C and 85°C, sec.butanol (1300 Kg) was added. At the end of the addition, the resultant suspension was kept at

80-85°C for 30 minutes and then cooled to 25°C.

After stirring at 25°C for 2 hours and filtration, the solid residue was washed with sec.butanol (190 Kg) and dried at 50-55°C under vacuum.

Pure lopamidol (275 Kg) was obtained.