CS261477B1 - A method of cleaning theophylline - Google Patents

Abstract

The solution ae concerns the field of production of pharmaceutical substances used in human medicine. It effectively solves the possibility of processing theophylline of poor quality into a drug of a more complex structure, which would otherwise be difficult to obtain from this theophylline. The essence of the purification procedure is the easy degradability of ballast substances in theophylline, causing emission radiation in the ultraviolet region, by the oxidative action of an aqueous solution of potassium permanganate on theophylline. The method can also be used to obtain separate, purified theophylline, or its other derivatives used for common and pharmaceutical purposes

Description

The invention relates to a process for purifying theophylline used for pharmaceutical purposes or as an intermediate in organic pharmaceutical synthesis.

Theophylline is itself a physiologically active substance and is used in medical practice for its bronchodilator, vasodilator, cardiostimulatory and diuretic effect. In addition, it is a substance used in organic synthesis for the preparation of more complex drugs, eg it is an essential raw material for the synthesis of the drug nicotinate xanthinolia, which is industrially produced by alkylating the sodium salt of theophylline 1- (N-methyl-N-2-hydroxyethyl) amino-3-chloro -2-propanol and converting the resulting intermediate to the nicotinate salt.

Synthetically produced theophylline substance often contains impurities that cause emission in the ultraviolet region with intense fluorescence and can be easily identified. This type of impurities is not affected by the valid analytical pharmacopoeial criteria and therefore does not interfere with the use of theophylline in medical practice. However, it has been found that theophylline containing these impurities also causes the fluorescence of the nicotinate xanthinolium in the synthesis of which it was used. This defect cannot be remedied by repeated conventional refining procedures and the xanthinolium nicotinate thus obtained (containing fluorescing impurities in the ultraviolet region) is not compliant with SsL 3 and cannot be used in medical practice.

Surprisingly, it has been found that the action of oxidizing agents, preferably potassium permanganate, on an aqueous solution or aqueous suspension of theophylline results in the destruction of fluorescent impurities and subsequent removal of theophylline. Thus purified theophylline / used in the synthesis of nicotinate xanthinolia, provides a product meeting all the purity requirements of

SsL 3o

261 477

The theophylline purification process is preferably carried out by dropwise addition of an aqueous solution of potassium permanganate to an aqueous solution of theophylline at 95-100 ° C in a neutral environment, filtering the reaction mixture with activated carbon and after cooling and precipitating theophylline by separating it. The cleaning process is also effective in both acidic and alkaline environments. an aqueous suspension of theophylline.

This cleaning process is very effective and environmentally friendly as it does not use organic solvents. It has been found that the amount of potassium permanganate to perform the purification operation is optimal in the range of 0.05 to 1.00 g per 100.0 g of theophylline. The exact amount of potassium permanganate depends on the degree of theophylline contamination.

Examples

Example 1

800.0 ml of water are introduced into the flask and 100.0 g of theophylline containing ultraviolet fluorescing impurities are added. The contents of the flask are heated to 95.0 to 100.0 ° C and 0.17 g of potassium permanganate dissolved in 17.0 ml of water is added dropwise. After stirring for five minutes, the reaction mixture is filtered with 3.0 g of activated carbon, reheated to 95.0 to 100.0 ° C and a solution of 0.21 g of sodium dithionite in 4.0 ml of water is added and allowed to stir. 5 minutes. It is then cooled to 15.0 ° C, the precipitated suspension is stirred for 1 hour at 10.0 to 20.0 ° C, filtered off with suction and washed with 2 x 50.0 ml of water and the wet product is dried at 100.0 ° C. 94.1 g of white theophylline of m.p. 275.0-276.0 ° C, which does not show fluorescence in the ultraviolet range.

Example 2

The flask was charged with 800.0 mL of water and 100.0 g of theophylline containing ultraviolet fluorescent impurities was added. The contents of the flask are heated to> 60.0 to 65.0 ° C, with part of the theophylline being dissolved. 0.20 g of potassium permanganate in 20.0 ml of water is added dropwise. After stirring for 15 minutes, the reaction mixture is heated to 95.0 ° C and filtered with 3.0 g of activated carbon, reheated to 95.0 ° C and added to it.

261 477 solution of 0.2 g of sodium dithionite in 4.0 ml of water and allowed to stir for 5 minutes. Thus cooled to 20.0 ° C and at this temperature the precipitated suspension was stirred for 1 hour, filtered off with suction and washed with 2 x 50.0 ml. ml of water, and the wet product is dried at 100.0 ° C. _e 93.0 g of white theophylline of mp 274.5 to 276.0 ° C are obtained which does not show fluorescence in the ultraviolet region.

Claims (1)

SUBJECT OF THE INVENTION Method for purifying theophylline by destroying ballasts causing fluorescence emission in the ultraviolet region, characterized in that the destruction is carried out by treatment with potassium permanganate in an amount of 0.05 g to 1.00 g per 100.0 g of theophylline in aqueous medium at a temperature 60-100 ° C ₀ Printed by Moravian printing works, center. 11 100, cl. People's Miles 3, Olomouc Price: 2,40 Kčs