Process for the preparation of purified crystalline iohexol

Abstract: Hydrophobic contaminants and residual organic solvents are removed from iohexol by the use of a fluid such as ethanol in which the iohexol is insoluble. In one procedure, ethanol is added to an aqueous solution of iohexol. In another procedure, the iohexol is suspended in ethanol and then allowed to crystallise. Crystalline iohexol having a residual solvent content below 100 ppm can be made in this way.

Description: This invention relates to a process for preparing purified crystalline iohexol. It is known that non-ionic X-ray contrast media, such as iohexol, present advantages in relation to prior art ionic compounds. All of these products depend on the presence of large quantities of iodine in the molecule to provide an opaque background, allowing their use to visualise internal organs. However, the quantities needed for this purpose are extremely high, being many times higher than those normally needed for compounds used as medicines. For example, it is normal to inject as much as 200 g of contrast media agent into a patient. For this reason, the substances should have extremely low toxicity and minimal interference with the normal functions of the organism. Additionally, the high dosing regime requires the residual solvent content to be as low as possible. Therefore, there is an increasing need to develop manufacturing processes for the production of contrast media of the highest purity. There exist several methods which can be used to produce high purity bulk pharmaceutical products. Possibly, the most efficient method for the production of high purity product is a chromatographic process. However, in the present instance, such a method is difficult to implement given the extremely large quantities of product that are necessary. Chromatographic methods are usually associated with a low volume and high value product. Chemical methods, such as crystallisation or washing of a suspension, are the most suitable but they do not always allow the successful removal of impurities with molecular structures that are very similar to that of the primary product. In the case of iohexol, the most difficult impurities are O-alkylated derivatives. In terms of the molecular configuration in the crystal, the properties of these substances are very similar to those of iohexol, being easily introduced in the crystalline structure, with the consequent difficulty in their removal. Another general consideration is the fact that the molecules used as X-ray contrast media are extremely soluble, especially in aqueous media, and hence can be difficult to crystallise. It is believed that this is due to the high degree of freedom associated with the hydrophilic side chains containing alcohol functions. The prior art describes various solvent systems considered adequate for the crystallisation of iohexol. The first of these systems comprises the use of butanol, as described in US patent no. 4,250,113. In this case, the so-obtained product requires subsequent dissolution in water, followed by evaporation to dryness under vacuum, in order to remove the residual butanol from the crystallised product. US patent no. 5,191,119 describes the purification of iohexol using a chromatographic procedure. The product is obtained from a 10% methanol/water eluent mixture by an undisclosed process. Spanish patent no. 532,390 describes the crystallisation of iohexol using a mixture of aqueous methanol and isopropanol. US patent no. 5,204,086 states that the most effective method of purification of iohexol is crystallisation from boiling isopropanol, but it was found that only 25-30% of the O-alkylated products could be removed in a single crystallisation. Also, further crystallisations significantly increase the cost of the process. In addition to the insufficient removal of the O-alkylated products, we have found that the process contains a relatively large amount of isopropanol, eg. approximately 1000 ppm. The drying step, even though prolonged, does enable the isopropanol content to be reduced below several hundred parts per million. It is to be noted that the iohexol monograph published in the 3rd Edition of the European Pharmacopeia limits the presence of isopropanol to 100 ppm. The same monograph limits methanol and methoxyethanol contents to 50 and 100 ppm, respectively. The United States Pharmacopeia limits the content of the O-alkylated products to 0.6%. Similarly, crystallisations from methanol or butanol yield a product which, even after prolonged drying, still contains several hundred parts per million of the crystallisation solvents. In order to overcome the problem of high residual solvent content, the procedure which is currently recognised as the most suitable is to dissolve the iohexol in water, followed by freeze-drying or spray-drying, by which the product is obtained as an amorphous solid. An obvious disadvantage of this procedure is the requirement to carry out beforehand purification processes for the removal of impurities, such as the O-alkylated products, followed by the use of extremely expensive equipment and processing. There is thus a need for a simple chemical process by which the O-alkylated products can be removed, while at the same time a product is obtained that does not have any residual solvent above 100 ppm. We have now found a way of accomplishing both of these objectives, with the additional advantage that the final product is crystalline. Crystalline compounds are always preferred by the pharmaceutical industry as they are more stable. In one aspect, the present invention provides a process for the preparation of crystalline iohexol, with a residual solvent content below 100 ppm, characterised by the fact that ethanol and water are used in the crystallisation. In one procedure according to the invention, an aqueous solution of iohexol is concentrated followed by the addition of ethanol, to yield crystalline iohexol, provided that the mixture is heated to an adequate temperature (eg above 30°C, preferably to the reflux temperature) and the amount of water is less than that required to cause complete dissolution. Preferably the water content of the reaction mixture is reduced by azeotropic distillation. The crystallisation is preferably promoted by the addition of some iohexol crystals. After filtration and drying in a conventional drier, the iohexol thus obtained has an increased purity in relation to that of the starting solution and, unexpectedly, contains an ethanol content below 100 ppm. In another procedure, crystalline iohexol, optionally containing residual solvents above 100 ppm, is suspended in ethanol and water, the suspension is heated, filtered and the solids dried to form crystalline iohexol with a residual organic solvent level below 100 ppm and with an increased purity. The preferred procedure is to suspend crystalline iohexol, obtained for example from any of the known processes and containing a residual-solvent content above 100 ppm, in absolute ethanol and water. The suspension is then heated, preferably to reflux, after which it is cooled and the solid filtered. The solid obtained is then dried in a conventional drier. The iohexol so obtained contains less than 100 ppm of organic solvent. The content of O-alkylated products decreases by at least 25%, and typically by about 4%. Additionally, the iohexol is crystalline in contrast to the prior art product having residual solvents below 100 ppm, which is not crystalline but amorphous. Amorphous iohexol has a non-characteristic melting point: the United States Pharmaceopeial Reference Substance starts to melt at 190°C and the melting is complete at 240°C, whilst the crystalline iohexol melts at 262°C-263°C. The processes of the invention are highly suited for operation on an industrial scale. The following Examples are to illustrate the present invention EXAMPLE 1 An aqueous solution, weighing 1668.6 g and containing 295.5 g of iohexol with 1.3% of O-alkylated products, was concentrated to a weight of 325.1g. 1.182 It of absolute ethanol were added, followed by some iohexol crystals. After reflux, crystallisation occurred. The water content of the reaction mixture was corrected by azeotropic distillation and restoration of the distilled volume with absolute ethanol. After cooling, the product was filtered and dried at 70°C in a static bed drier. The yield of crystalline iohexol was 246.8 g, which contained 0.55% of O-alkylated products and an ethanol content below 40 ppm. Melting point: 262° - 263°C. EXAMPLE 2 200 g of iohexol containing 0.9% of O-alkylated products and 891 ppm of isopropanol were refluxed in absolute ethanol (1.6 lt) and water (20 ml). After cooling, the product was filtered and dried at 80°C, at an atmospheric pressure, in a static bed drier. The yield of crystalline iohexol was 157 g, which contained 0.5% of O-alkylated products, 71 ppm of isopropanol and 14 ppm of ethanol. Melting point: 257° - 263°C. EXAMPLE 3 20 g of iohexol, containing 1.12% of O-alkylated products and 2776 ppm of isopropanol, were refluxed in absolute ethanol (120 ml) and water (2 ml). After cooling, the product was filtered and dried at 70°C in a static bed drier. The yield of crystalline iohexol was 17.2 g which contained 0.56% of O-alkylated products, 60 ppm of isopropanol and 67 ppm of ethanol. Melting point: 253° - 254°C.

Claims: A process for the preparation of crystalline iohexol, with a residual solvent content below 100 ppm, characterised by the fact that ethanol and water are used in the crystallisation. A process for the purification and/or removal of residual solvents from iohexol, wherein crystalline iohexol, optionally containing residual solvents above 100 ppm, is suspended in ethanol and water, the suspension is heated, filtered and the solids dried to form crystalline iohexol with a residual organic solvent level below 100 ppm and with an increased purity. A process according to claim 2, wherein the starting crystalline iohexol has been obtained by crystallisation from isopropyl alcohol or isopropyl ether. A process according to claim 1, which comprises the steps of concentrating an aqueous solution of iohexol by adding ethanol, heating, and recovering crystalline iohexol. A process according to claim 4, wherein said heating is effected to a temperature above 30°C, preferably to the reflux temperature. A process according to claim 1, wherein iohexol is crystallised from an ethanol and water solution by reduction of the water content. A process according to claim 6, wherein said reduction of water content is effected by azeotropic distillation.

Inventors: ALVAREZ PEREZ CARLOS MANUEL, DU BOULAY VILLAX GUIDO, GANCHAS DE CARVALHO ALEXANDRE, ALVAREZ PEREZ, CARLOS MANUEL, DU BOULAY VILLAX, GUIDO, GANCHAS DE CARVALHO, ALEXANDRE JOSE, Ganchas de Carvalho, Alexandre José 
Applicants: HOVIONE INT LTD, HOVIONE INTER LTD.
Application year: 1997
Main classification: C07C231
IPC codes: A61K49, C07C231, C07B63, C07C237