METHOD FOR THE CRYSTALLIZATION OF IOPAMIDOL

Abstract: Disclosed is the crystallization of Iopamidol using a mixture of an alcohol and water as a crystallization solvent. The ratios of water:Iopamidol from 1:10 to 1:1 (v/w) and alcohol:Iopamidol from 1:1 to 1:10 (v/w) allow Iopamidol to be crystallized to an anhydrous pure form with industrially valuable yields without producing monohydrates and pentahydrates.

Description: METHOD FOR THE CRYSTALLIZATION OF IOPAMIDOL Technical Field The present invention relates to a novel method for crystallizing lopamidol to an anhydrous form, which is generally used as an X-ray contrast medium. More particularly, the present invention is concerned with a method for purifying lopamidol to pharmaceutically acceptable purity, by which anhydrous lopamidol can be produced at industrial yields. Background Art Crystalline forms of lopamidol exist as an anhydrous, monohydrated or pentahydrated state. Of them, anhydrous lopamidol is pharmaceutically acceptable and thus, is now produced industrially. Techniques with which industrially beneficial lopamidol can be obtained are found in U.S. Pat. Nos. 5,571,941 and 5,689,002. U.S. Pat. No. 5,571,941 discloses a method for purifying lopamidol, teaching that use of butanol, such as n-butanol, sec-butanol, isobutanol or t-butanol, as a crystallization solvent allows pharmaceutically pure lopamidol with industrially acceptable yields. On the other hand, U.S. Pat. No. 5,689,002 discloses a method for crystallizing lopamidol, in which water is used as a crystallization solvent to yield anhydrous pure lopamidol which meets the pharmacopeia standards. Disclosure of the Invention The intensive and thorough research on the crystallization of lopamidol, repeated by the present inventors, resulted in the surprising finding that a mixture of water and alcohol allows lopamidol to be crystallized into an anhydrous pure form without producing monohydrates and pentahydrates. As far as the present invention is concerned, lopamidol, whether it exists as a monohydrate or a pentahydrate, can be crystallized into highly pure, anhydrous forms with industrially available yields. Therefore, it is an object of the present invention to provide a method for the crystallization of lopamidol, by which anhydrous lopamidol with high purity can be industrially produced. It is another object of the present invention to provide a method for purifying lopamidol to pharmaceutically acceptable purity. These and other objects can be attained in a method for crystalizing lopamidol, comprising the steps of dissolving lopamidol in deionized water, distilling a part of the water off under a vacuum condition, adding alcohol to the aqueous solution, subjecting the solution to reflux for 3-4 hours to give white precipitates, filtering the precipitates, and drying the precipitates to yield pure anhydrous lopamidol. Particularly preferable is that the deionized water is used at an amount of water : lopamidol from 1 : 10 to 1 : 1 (v/w) and the alcohol is used at an amount of alcohol : lopamidol from 1 : 1 to 1 : 10 (v/w). Further preferable is that the alcohol is selected from the group consisting of ethanol and propanol. Best Modes for Carrying Out the Invention To be useful for injection, lopamidol, which is used as an X-ray contrast medium, must exist as an anhydrous white crystalline form, but not as monohydrates or pentahydrates, and exhibit a solubility of 80% (w/v) in water. In addition, for industrial application, anhydrous lopamidol must be produced with high purity at high yields while avoiding residual solvents which may cause an environmental problem. In accordance with the present invention, a mixture of alcohol and water is used as a crystallization solvent for lopamidol. The crystallization of the present invention starts by dissolving lopamidol, whether existing as a monohydrate or a pentahydrate, in deionized water. Under a vacuum condition, this aqueous suspension is concentrated to distill off a part of the deionized water. The concentrated mixture is added with alcohol and brought to reflux for a predetermined period of time. During the reflux, lopamidol begins to precipitate as white crystals. These precipitates are filtered off and dried. Useful in the present invention is ethanol or propanol. This alcohol is used at an amount of alcohol : lopamidol from 1 : 1 to 1 : 10 (v/w). As for water, it is used at an amount of water : lopamidol from 1 : 10 to 1 :1 (v/w). With reference to Fig. 1 , there is a graph showing the solubility of lopamidol plotted against reflux time when a ratio of lopamidol : water : ethanol 4:1 :8 (w/v/v) is used in accordance with the method of the present invention. As shown in this graph, the reflux for 4 hours or greater allows the crystallized lopamidol to have a solubility of 80% or greater. This indicates that, when the reflux continues to be performed for 4 hours, only pure anhydrous lopamidol exists. Because lopamidol monohydrates or pentahydrates are of about 50% solubility, the method of the present invention can convert lopamidol monohydrates or pentahydrates into lopamidol anhydrides. A better understanding of the present invention may be obtained in light of the following examples which are set forth to illustrate, but are not to be construed to limit the present invention. EXAMPLE I 10 kg of lopamidol was dissolved in 10 liters of deionized water, followed by vacuum distilling 8 liters of the water. After being added with 5 liters of ethanol, the suspension was subjected to reflux for 4 hours. During the reflux, lopamidol began to precipitate as white crystals which were, then, filtered off. After drying at 60 °C for 4 hours in vacuo, 7.5 kg of pure anhydrous lopamidol was obtained. Yield : 75%). EXAMPLE II 10 kg of lopamidol was dissolved in 10 liters of deionized water, followed by vacuum distilling 7.5 liters of the water. After being added with 20 liters of ethanol, the suspension was subjected to reflux for 4 hours. During the reflux, lopamidol began to precipitate as white crystals which were, then, filtered off. After drying at 60 °C for 4 hours in vacuo, 9.3 kg of pure anhydrous lopamidol was obtained. Yield : 93%). EXAMPLE III 10 kg of lopamidol was dissolved in 10 liters of deionized water, followed by vacuum distilling 8 liters of the water. After being added with 20 liters of propanol, the suspension was subjected to reflux for 4 hours. During the reflux, lopamidol began to precipitate as white crystals which were, then, filtered off. After drying at 60 °C for 4 hours in vacuo, 9.41 kg of pure anhydrous lopamidol was obtained. Yield : 94.1%. EXAMPLE IV 10 kg of lopamidol was dissolved in 10 liters of deionized water, followed by vacuum distilling 8 liters of the water. After being added with 30 liters of ethanol, the suspension was subjected to reflux for 4 hours. During the reflux, lopamidol began to precipitate as white crystals which were, then, filtered off. After drying at 60 °C for 4 hours in vacuo, 9.0 kg of pure anhydrous lopamidol was obtained. Yield : 90%>. EXAMPLE V 10 kg of lopamidol was dissolved in 10 liters of deionized water, followed by vacuum distilling 7.5 liters of the water. After being added with 20 liters of propanol, the suspension was subjected to reflux for 4 hours. During the reflux, lopamidol began to precipitate as white crystals which were, then, filtered off. After drying at 60 °C for 4 hours in vacuo, 9.4 kg of pure anhydrous lopamidol was obtained. Yield : 94%>. TEST EXAMPLE I In order to determine proper reflux time, the same procedures of the above examples were repeated, except that the reflux was performed for 1, 2, 3, 4 and 5 hours per procedure round. The solubility of the lopamidol obtained was measured by dissolving 80 g of the lopamidol in 100 ml of water. The results are given in Table 1 , below. TABLE 1 Solubility of lopamidol according to Reflux Times TEST EXAMPLE II The purity of the anhydrous lopamidol obtained in the above examples was measured using high performance liquid chromatography (HPLC). The results are given in Table 2, below. TABLE 2 Purity of lopamidol Brief Description of the Drawing Fig. 1 is a graph showing the solubility change of the lopamidol with reflux time. Industrial Applicability As described hereinbefore, the crystalizing method of lopamidol, according to the present invention, does not need active carbon for decolorization, in contrast to the conventional crystalizing technique from water, and nor causes harm to the human body owing to residual solvents which may be problematic in the conventional technique using butanol as a crystallization solvent. In addition, the method of the present invention allows anhydrous lopamidol 99.5% or higher purity, with a yield of 90%>, so that it can be industrially applied for the mass production of lopamidol. The present invention has been described in an illustrative manner, and it is to be understood the terminology used is intended to be in the nature of description rather than of limitation. Many modifications and variations of the present invention are possible in light of the above teachings. Therefore, it is to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described.

Claims: CLAIMS 1. A method for crystalizing lopamidol, comprising the steps of: dissolving lopamidol in deionized water; distilling a part of the water off under a vacuum condition; adding alcohol to the aqueous solution; subjecting the solution to reflux for 3-4 hours to give white precipitates; filtering the precipitates; and drying the precipitates to yield pure anhydrous lopamidol. 2. A method as set forth in claim 1 , wherein the deionized water is used at an amount of water : lopamidol from 1 : 10 to 1 : 1 (v/w) and the alcohol is used at an amount of alcohol : lopamidol from 1 :1 to 1 :10 (v/w). 3. A method as set forth in claim 1 or 2, wherein the alcohol is selected from the group consisting of ethanol and propanol.

Inventors: CHOI KYUNG SEOK, LEE DONG JUN, LEE DONG YUB, LEE IN KYU, PARK JIN KYU, SONG CHANG HUN, CHOI, KYUNG, SEOK, LEE, DONG, JUN, LEE, DONG, YUB, LEE, IN, KYU, PARK, JIN, KYU, SONG, CHANG, HUN
Applicants: CHOI KYUNG SEOK, DONG KOOK PHARM CO LTD, LEE DONG JUN, LEE DONG YUB, LEE IN KYU, PARK JIN KYU, SONG CHANG HUN, CHOI, KYUNG, SEOK, DONG KOOK PHARMACEUTICAL CO., LTD., LEE, DONG, JUN, LEE, DONG, YUB, LEE, IN, KYU, PARK, JIN, KYU, SONG, CHANG, HUN
Application year: 1999
Main classification: C07C237
IPC codes: B01D9, C07C231, C07C237