DE102005059191B4 - Process for the recovery of pharmaceutically acceptable iopromide from mother liquors - Google Patents

Abstract

method for recovery from for pharmaceutical Suitable iopromide by thermal treatment of the second or subsequent crystals of the mother liquor dissolved in a solvent in a Strömumgsrohrreaktor and subsequently Crystallization.

Description

The The invention relates to a process for the recovery of pharmaceutical Purpose of suitable Iopromide by thermal treatment of the mother liquors or the solved one Second crystals in a reactor and subsequent crystallization.

Iopromid Iopromide, 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid - [(2,3-dihydroxy-N-methyl-propyl) - (2,3-dihydroxypropyl)] - diamide, ( DE 196 41 178 C2 and EP 0 015 867 B1 ) is an iodine-containing X-ray contrast medium having the following chemical structure:

iopromid

The bulky iodine atoms impede the free rotation of the structural formula with 1 labeled bond between the aromatic ring and the amide group with the dihydroxypropyl-methylamino group by the presence of the N-methyl group significantly, leaving two thermally quite stable atropisomers occur. Such atropisomers are u. a. described in "Recent Advances in Atropisomerism "by M. Oki in journal "Topics in Stereochemistry ", 1983, Vol. 14, pp. 1-81 and Tetrahedron Letters no. 38, pages 4593-4598, 1966. One of the atropisomers contains the substituted nitrogen atom above the ring plane, the other isomer below the ring plane. The two atropisomeric compounds (isomer 1 and isomer 2) differ in their physical properties, especially in their solubilities in water and organic solvents. Only Iopromide of a particular composition with respect to these atropisomers is as an X-ray contrast agent allowed (40-51% isomer 1 and 49-60% isomer 2).

Cleansing methods for iodinated X-ray contrast agents, such as iopamidol, are known in the art, see EP 1 025 067 B1 and GB 2 280 436 A , It describes crystallizations at elevated temperatures. In Scripture WO 2004 031 110 A2 discloses the isomerization of chiral compounds by thermal treatment. However, these methods do not involve the treatment of iopromide mother liquors.

iopromid for pharmaceutical Purpose is obtained by crystallization from ethanol. in this connection falls regularly Mixture consisting of about 48% isomer 1 and about 52% isomer 2. In the mother liquor, isomer 1 is about 60% and isomer 2 only about 40% included. For this reason, from the mother liquor only a secondary crystals of the wrong composition with respect to Atropisomeren won (contains too much isomer 1).

at the production of iopromide, pure becomes a final crystallization made from alcohol. This leaves a proportion of about 10% of the Iopromids in dissolved form in the mother liquor, which is noticeable as loss of yield.

Earlier attempts from the resulting mother liquors by second crystallization further Iopromide crystallize out and thereby increase the yield hit fails, since the recovered from the mother liquors Iopromid K2 terms of the atropisomeric ratio is not compliant with specification. This behavior is due to the fact that in the mother liquor certain atropisomers preferentially accumulate.

Object of the invention:

The known in the prior art manufacturing process for Iopromid, pure have the disadvantage that a high yield loss must be taken into account and no technical process exists, which allows to recover from the mother liquors Iopromid, that in terms of atropisome ren-ratio is conform to specification and thus can be used for pharmaceutical purposes.

solution the invention:

The Surprisingly, the above-described disadvantages could be achieved solved be that from the iopromide, pure mother liquor first K2 is obtained by a suitable second crystallization, which subsequently by a suitable thermal treatment in a continuous Tubular reactor isomerized in accordance with specifications, without being significant Decomposition of the substance comes. The invention thus includes a process for recovery from for suitable for pharmaceutical purposes Iopromide and Iopromide mother liquors or solutions of the secondary and subsequent crystals by thermal treatment of Solution, preferably in a flow tube reactor at 100-300 ° C, with advantage at 200-220 ° C, and subsequent fast cooling to room temperature and crystallization. The thermal treatment in a flow reactor takes place with advantage in aqueous solution at hydrodynamic residence times of 1 to 60 minutes. The special ones embodiments are in the claims listed. By this method according to the invention the total yield of iopromide can be increased significantly, so that the profitability increases. In addition, less halogen-containing drops Waste.

Description of the method in detail:

Out The Iopromide, pure mother liquor is first a secondary crystals applied by the ethanolic mother liquors by a factor of 2-16 concentrated and dissolved in an alcohol at elevated temperature. examples for suitable alcohols are alkanols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol. Preference is given to ethanol, 1-propanol and 2-propanol used, more preferably 1-propanol, since this solvent the crystallization particularly quickly and completely and thus cost-saving happens. For triggering The crystallization can be inoculated with Iopromide, pure. The K2 crystals are subsequently added isolated by known methods, washed and dried.

Example 1:

Preparation of the K2 crystallizate

12000 g of iopromide, pure mother liquor (solids content about 6.2%) are concentrated in vacuo to a viscous oil of 892 g. 877 g of this residue are added in a suitable reaction vessel at a bath temperature of 65 ° C with 439 ml of 1-propanol with stirring. After inoculation with 0.73 g of iopromide, pure is stirred at a bath temperature of 65 ° C for a further 48 h. The crystal suspension is then cooled to 20 ° C, stirred for 1 h at this temperature and suction filtered through a suction filter. After washing with 4 portions of 110 ml of ethanol, the secondary crystals are dried at 40 ° C in a vacuum oven.
Yield: 363.8 g (about 52% v. E.)

The recovered from the mother liquor secondary crystals has the following atropisomer ratio: HPLC specification Result Isomer 1 40.0 to 51.0% 62.2% Isomer 2 49.0 to 60.0% 37.8%

The discharged secondary crystals are then brought into solution, i. H. in water solved and in a pressure-resistant, suitably designed continuously operated Tubular reactor thermally isomerized. Here are hydrodynamic Residence times of 1 to 60 minutes, preferably 1-30 minutes, especially preferably 1 to 10 minutes at temperatures between 100 to 300 ° C, preferably 150 ° C to 250 ° C, preferably 180 ° C to 230 ° C, especially preferably 200 ° C up to 220 ° C set. In a downstream heat exchanger is the term treated iopromide K2 solution subsequently briskly up Room temperature cooled.

Example 2:

Thermal isomerization of the iopromide secondary crystals

280 g of Iopromid-K2 from Example 1 are dissolved in 520 g of water. The solution is then at a flow rate of 3 ml / min. pumped through a provided with a pressure relief valve of 20 bar flow tube at 208-209 ° C. The flow tube used has an inner diameter of 1.7526 mm and a heated length of 5.5 m (s. 1 ).

A solution of the isomerized iopromide secondary crystals is then purified on ion exchange columns and crystallized from ethanol.

The Yield of the crystallized from ethanol Iopromids, based on the used in the isomerization of secondary crystals, at 80% of the E.

The crystals show a content by HPLC (standard method) of greater than 97.5% compared to external standard and has the following atropisomer ratio: HPLC specification Result Isomer 1 40.0 to 51.0% 49.4% Isomer 2 49.0 to 60.0% 50.6%

Claims (7)

Process for the recovery of pharmaceutical Suitable iopromide by thermal treatment of the second or subsequent crystals of the mother liquor dissolved in a solvent in a Strömumgsrohrreaktor and subsequently Crystallization. The method of claim 1, wherein the in the mother liquor or secondary or Folgekristallisates containing Iopromid a for pharmaceutical Purpose inappropriate isomer ratio and by thermal treatment in a flow tube reactor, then cooling down to room temperature and crystallization. A method according to claim 1 or 2, wherein the thermal Treatment in a flow tube reactor at 100-300 ° C he follows. Method according to at least one of claims 1-2, wherein the crystallization is from an alcohol. Method according to at least one of the methods 1-4, the specification-compliant, suitable for pharmaceutical purposes Iopromide amounts by heat treatment in a solvent dissolved Atropisomers are obtained. Method according to at least one of claims 1-5, wherein the hydrodynamic residence times of in a solvent dissolved Atropisomers in the flow tube reactor 1 to 60 minutes. Process according to claim 6, wherein as solvent Water is used.