MXPA97010141A - Process for the preparation of iohexol cristalinoy exient de solve - Google Patents

Abstract

The object of the present invention is an industrial process for the purification and removal of residual solvents from iohexol, based on the suspension of crystalline iohexol, possibly containing residual solvents above 100 ppm, in a fluid where it has a low solubility, followed by heating, filtering and drying. The process allows the formation of crystalline iohexol without residual organic solvent above 100 ppm, and with a higher level of pure

Description

PROCESS FOR THE PREPARATION OF CRYSTALLINE IOHEXOL AND SOLVENT EXEMPT It is known that the non-ionic X-ray contrast medium, such as iohexol, has advantages over the ionic compounds of the prior art. All these products depend on the presence of large amounts of iodine in the molecule to provide an opaque background, allowing its use to visualize internal organs. However, the quantities necessary for this purpose are extremely high, being many times higher than those necessary for the compounds used as medicines. It is normal to inject as much as 200 grams of contrast agent to a patient. For this reason, the aforementioned substances must have an extremely low toxicity and minimal interference with the normal functions of the organism. Additionally, the high dosage regimen requires that the residual solvent content be as low as possible. Accordingly, there is a growing need to develop manufacturing processes for the production of contrast media of the highest purity. There are several methods that can be used to produce high purity bulk pharmaceuticals. Possibly, the most efficient method for the production of the high purity product is a chromatographic process. However, in the present case, this method is difficult to implement, given the extremely large quantities of product that are needed. Chromatographic methods are usually associated with a low volume and high value product. Chemical methods, such as crystallization or washing 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 those of the primary product. In the case of iohexol, the most problematic impurities are 0-alkylated derivatives. In terms of the molecular configuration of the crystal, the properties of these substances are very similar to those of iohexol, easily entering 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 consequently, their difficult crystallization. It is believed that this is due to the high degree of freedom associated with hydrophilic side chains containing alcohol functions. The prior art cites different1 solvent systems that are considered suitable for the crystallization of iohexol. The first of these systems comprises the use of butanol, as described in U.S. Patent No. 4,250,113. In this case, the product thus obtained required a subsequent dissolution in water, followed by evaporation until dried in vacuum, in order to remove the residual butanol from the crystallized product. U.S. Patent No. 5,191,119 describes the purification of iohexol using a chromatographic procedure. The product is obtained from an eluent mixture at 10 percent methanol / water by an unknown process. Spanish Patent No. 532,390 describes the crystallization of iohexol using a mixture of aqueous methanol and isopropanol. U.S. Patent No. 5,204,086 states that the most effective method for the purification of iohexol is crystallization from boiling isopropanol, but it was found that only 25 to 30 percent of the O-products could be removed. rented in a single crystallization. Also, other crystallizations significantly increase the cost of the process. In addition to the insufficient removal of the O-alkylated products, the inventors of the present invention have verified that the product of the latter process contains approximately 1., 000 ppm isopropanol. The drying step, even when prolonged, does not reduce the isopropanol content to less than several hundred parts per million. It should be noted that the iohexol monograph published in the Third Edition of the European Pharmacopoeia limits the presence of isopropanol of up to 100 ppm. The same monograph limits the methanol and ethoxyethanol contents to 50 and 100 ppm, respectively. The United States Pharmacopoeia limits the content of O-alkylated products to 0.6 percent. In the same way, crystallizations from methanol or butanol give a product which, after prolonged drying, contains several hundred parts per million of the crystallization solvents. In order to overcome the problem of the high content of residual solvent, the procedure currently recognized as the most appropriate is to dissolve the iohexol in water, followed by freeze drying or spray drying, where the product is obtained as a amorphous solid. An obvious drawback of this procedure is the requirement to perform purification processes in advance to remove impurities, such as O-alkylated products, followed by the use of extremely expensive equipment and processing.

Accordingly, there is a need for a simple chemical process that has the following advantages: to act as a purification process to remove the O-alkylated products; while at the same time, give a product that does not have residual solvent above 100 ppm. The present invention accomhes both objectives, with the additional advantage that the final product is crystalline. Crystalline compounds are always preferred by the pharmaceutical industry, since they are more stable. The inventors have discovered that the concentration in an aqueous solution of iohexol, followed by the addition of ethanol, produces crystalline iohexol, provided that the temperature is adequate and the amount of water is less than that required to cause complete dissolution. Crystallization is promoted by the addition of some iohexol crystals. After filtration and drying in a conventional dryer, the iohexol thus obtained has a higher purity relative to that of the starting solution, and unexpectedly contains an ethanol content of less than 100 ppm. The inventors have also discovered that, when iohexol is fluidized, that it contains a residual solvent content greater than the required limit, at a suitable temperature, in a medium containing another solvent, there is an exchange of these solvents. For the intended use, the obvious substitution solvent is water. The fl uidizing agent may optionally be a gas, preferably air or an inert gas, in which case, in spite of the reduction in the residual solvents, there will be no reduction in the other impurities. The use of a solvent or a mixture of solvents as fluidizing agent, allows to achieve the most general purpose. The exchange agent may eventually be the same as the fluidizing agent. The choice of the fluidizing agent and its proportion in relation to the exchange agent and the iohexol must be carried out carefully, in order that the iohexol solution is minimal, and there is an adequate dissolution of the impurities that are to be removed. A suitable fluidizing agent is ethanol, due to its low toxicity in relation to other organic solvents. The preferred exchange agent is water, and its amount must be less than that required to cause a complete dissolution of the iohexol. The procedure of choice is to suspend the crystalline iohexol, obtained from any of the known processes, and containing a residual solvent content greater than 100 ppm, in absolute ethanol and water. Then the suspension is heated, preferably to reflux, after which it is cooled, and the solid is filtered. The solid obtained is then dried in a conventional dryer.

The iohexol thus obtained contains less than 100 ppm of organic solvent. The content of O-alkylated products decreases by at least 25 percent, typically by 40 percent. Additionally, the iohexol is crystalline, with the inherent advantages added to this fact, and that distinguish it from the currently available product with a residual solvent content of less than 100 ppm, which is amorphous. Amorphous iohexol has a non-characteristic melting point: the United States Pharmacopeial Reference Substance begins to melt at 190 ° C, and the fusion is completed at 240 ° C, while the Crystalline iohexol melts at 262 ° C-263 ° C. Following the general concept of this invention, any person skilled in the art, with a reduced number of experiments, can optimize the conditions indicated therein, or find other solvents suitable for the intended purpose. The following examples serve to illustrate the present invention, and in no way should be considered as a limitation thereof.

EXAMPLE 1 An aqueous solution, weighing 1668.6 grams, and containing 295.5 grams of iohexol with 1.3 percent O-alkylated products, concentrated to a weight of 325.1 grams. 1,182 liters of absolute ethanol were added, followed by some iohexol crystals. After reflux, crystallization occurred. The water content of the reaction mixture was corrected by azeotrapsic distillation and restoration of the volume distilled with absolute ethanol. After cooling, the product was filtered and dried at 70 ° C in a static bed dryer. The yield of crystalline iohexol was 246.8 grams, which contained 0.55 percent of O-alkylated products, and an ethanol content of less than 40 ppm. Melting point: 262 ° C- 263 ° C.

EXAMPLE 2 200 grams of iohexol containing 0.9 percent of O-alkylated products, and 891 ppm of isopropanol were refluxed in absolute ethanol (1.6 liters) and water (20 milliliters). After cooling, the product was filtered and dried at 80 ° C, at atmospheric pressure, in a static bed dryer. The yield of crystalline iohexol was 157 grams, which contained 0.5 percent O-alkylated products, 71 ppm isopropanol, and 14 ppm ethanol. Melting point: 257 ° C-263 ° C.

EXAMPLE 3 20 grams of iohexol, containing 1.12 percent of O-alkylated products, and 2.776 ppm of isopropanol, were refluxed in absolute ethanol (120 milliliters) and water (2 milliliters). After cooling, the product was filtered and dried at 70 ° C in a static bed dryer. The yield of crystalline iohexol was 17.2 grams, which contained 0.56 percent of 0-alkylated products, 60 ppm of isopropanol and 67 ppm of ethanol. Melting point: 253 ° C-254 ° C.

Claims (13)

1. NOVELTY OF THE INVENTION
2. Having described the foregoing invention, it is considered as a novelty and, therefore, the content of the following is claimed as property:
3. CLAIMS 1. An industrial process for the preparation of crystalline iohexol, with a residual solvent content of less than 100 ppm, characterized by the fact that ethanol is used in crystallization. 2. An industrial process for the purification and removal of residual solvents from iohexol, characterized by the fact that crystalline iohexol is suspended, eventually containing residual solvents above 100 ppm, in a fluid where it has a low solubility, followed by heating, filtration and drying, thus allowing the formation of crystalline iohexol without residual organic solvent above 100 ppm, and with a higher level of purity. 3. An industrial process, according to claim 2, for the purification and removal of residual solvents from iohexol, characterized in that crystalline iohexol is suspended, eventually containing residual solvents above 100 ppm, in an organic solvent in which it has a low solubility, followed by heating, filtration and drying, thus allowing the formation of crystalline iohexol without residual organic solvent above 100 ppm, and with a higher level of purity.
4. 4. A process according to claim 2, characterized in that an amount of water less than that required for the complete dissolution of iohexol is added to the fluid in suspension.
5. 5. A process according to claim 3, characterized in that an amount of water less than that required for the complete dissolution of the iohexol is added to the organic solvent of the suspension.
6. 6. A process according to claim 2, characterized in that the fluid is ethanol.
7. 7. A process according to claim 3, characterized in that the organic solvent is ethanol.
8. 8. A process according to claim 2, characterized in that the starting crystalline iohexol is obtained by crystallization from isopropyl alcohol, and the fluid in suspension is ethanol.
9. 9. A process according to claim 3, characterized in that the crystalline starting iohexol is obtained by crystallization from isopropyl ether, and the organic solvent of the suspension is ethanol.
10. 10. A process according to claim 1, characterized in that an aqueous solution of iohexol is concentrated, followed by the addition of ethanol, and heating to a suitable temperature, in order to crystallize the iohexol.
11. 11. A process according to claim 10, characterized in that the temperature is greater than 30 ° C, preferably the reflux temperature.
12. 12. A process according to claim 1, characterized in that iohexol is crystallized from a solution of ethanol and water, by reducing the water content.
13. 13. Crystalline Iohexol, characterized in that it does not present residual solvent above 100 ppm.