DE1061776B - Process for the production of streptomycin sulfate from the streptomycin-calcium chloride complex compound - Google Patents

Description

GERMAN

REGISTRATION DAY 8 JUNE1956

NOTICE
THE REGISTRATION
AND ISSUE OF THE
EDITORIAL JULY 23, 1959

The invention relates to a simple and economical one Process for the production of streptomycin sulfate from the streptomycin-calcium chloride complex compound

In some uses of streptomyein becomes the use of the streptomycimn sulfate those of the calcium chloride complex compound preferred

There are already various methods of transfer the streptomycin calcium chloride complex compound has been applied to the sulfate, but the Procedures are cumbersome and require expensive tools and work with considerable losses, for example is so far the streptomycin calcium chloride Complex compound with the help of a metal sulfate m Streptomycm sulfate is converted to where it falls calcium sulfate, but other metal ions are in the solution of the streptomycm sulfate formed so the filtrate has to continue with complicated extraction after removing the calcium sulfate. and precipitation processes are treated to remove the interfering metalhones and chloride ions from the Solution Removal Such procedures involve a large number of steps and require expensive tools and work with great losses because ChIondionen the solubility of the streptomycm sulfate in Methanol as high as possible

The process according to the invention is also advantageous because it enables dihydrostreptomycm sulfate to be prepared in a simple manner from the streptomycm calcium chloride complex compound enables

For some purposes, dihydrostreptomycin sulfate is used desired To produce it, wild ζ B according to a known method the Streptomycin-calcium chloride complex compound too Dihydrostreptomycin hydrochloride hydrogenates the calcium chloride removed from the solution as calcium carbonate by adding silver carbonate and dihydrostreptomycmsulfate after filtering off the calcium carbonate in the filtrate by adding ammonium sulfate formed from the solution of dihydrostreptomycin sulfate and ammonium chloride then becomes the dihydrostreptomycin sulfate precipitated with methanol This process also consists of several stages, which requires expensive aids and can only be carried out with significant losses of dihydrostreptomycin because the ammonium chloride the solubility of the dihydrosti eptomycin sulfate increased in methanol

With the help of the method according to the invention can you can now first produce streptomycin sulfate in a simple manner and then this in the usual way For this purpose, the solution is hydrogenated, which the streptomycin-calcium chloride complex compound contains, in a column on an anion exchanger Method of manufacture

of streptomycm sulfate

from the streptomycin calcium chloride

Complex connection

Applicant:

Merck & Co., Inc.,

Rahway, N. J. (V. St. A.)

Representative E Maemecke, Berlm-Lichterfelde West,

and Dr W Kühl, Hamburg 36, Esplanade 36 a,

Patent attorneys

Claimed priority
V St ν America of June 14, 1955

Frederick Charles Boss, Harnsonburg, Va,
Earl H Pierson, North Plamneld, NJ,

Frank Verbanac, Elkton, Va,
and Edward L Foerster, Harnsonburg, Va

(V St A),
have been named as inventors

in the sulphate cycle under such flow conditions brought into contact that no noteworthy Amounts of calcium sulfate precipitate in the resin layer The streptomycin sulfate solution that runs off can then be mixed with a fresh portion of the streptomycin calcium chloride id complex compound to be mixed for the next run to make a larger one Share of calcium from the streptomycin-calcium chloride complex to precipitate as calcium sulphate before the solution enters the column of the ammonium exchanger The streptomycm sulfate is introduced rich portion of the draining fluid (referred to as rich cut) is either on dry Streptomycm sulfate of satisfactory purity processed or directly after filtration, without the streptomycm sulfate being extracted therefrom, hydneit in the usual way to dihydrostreptomycin sulfate

The first pass becomes an aqueous solution the streptomycin-calcium chloride complex compound in a closed column above the resin layer Introduced as a Haizschicht is preferably a organic, nitrogen-containing anion exchanger

f 909 578/452

Used, its exchangeability essentially originates from quaternary ammonium groups and which is generally considered to be a staik basic anion exchanger referred to as. In particular, a strongly basic known as "Amberhte IRA-400"

[(Streptomycm • 3HCl) ₂ CaCl ₂ ] + resin sulfate >

While the streptomycin-containing inflow solution runs down through the resin layer, the chlorine ions are replaced by sulfate ions, whereby a state of calcium sulfate supersaturation is caused in the resin layer The flow rate is not sufficient to remove the supersaturated calcium sulfate solution before the Crystallization takes place is due to crystallization and the associated fall of calcium sulphate reduces the flow rate to practically one unusable value and possibly clogged the column

So you have to make the method practically applicable by the fact that the flow rate of the output material through the column proportionately keeps constant at a value at which practically no precipitation of calcium sulfate in the Resin layer is done There are numerous ways to get the flow rate to the desired one To keep value With a large plant, the Flow rate easily adjusted by that one works under increased pressure The flow rate the liquid through the resin layer is kept constant with the help of a valve, that the air pressure above the liquid level above Resin Layer Allowed to Change In general, the air pressure at the top of the column is initially The flow rate increases as the cycle progresses The liquid through the resin layer can also be supplied by a pump, which dissolves the resin layer feeds, be sustained This is a Convenient procedure for a small system. The eluate can also be drawn off in a vacuum, with the The flow rate is regulated by adjusting the vacuum used

The preferred resin material (»Amberhte IRA-400«) in the sulphate cycle is the flow rate of the solution through the resin layer preferably in such a way that the surface contact time of the Solution m of the resin layer amounts to about 15 to 60 minutes, in particular 25 to 50 minutes. These figures result from the volume of the resin layer divided by the flow rate.

3 [(Streptomycin 3HCl) ₂ CaCl ₂ ] -f [(Streptomycin ^ · 3H ₂ SO ₄ ]? ► 3CaSO ₄ + [(Streptomycin 3HCl)] II

(partly in solution and partly fixed)

shear ammonium exchanger (polystyrene resin with quaternary Ammonium groups) are used

The one caused in the Harz column on the first pass Exchange can be represented by the following equation

[(Streptomycin ^ 3H ₂ SO ₁ ] + CaSO ₄ + Harzchlond I.

The given resin layer is therefore the surface contact time the longer, the slower the flow velocity is

When the flow rate of streptomycin containing solution drops by the preferred resin material to a value that of a surface contact time of more than 60 minutes, a precipitate of calcium sulfate forms Resin layer in such a significant amount that it prevents the solution from flowing further through the resin layer is severely disabled

If the above-mentioned values are observed, calcium sulfate precipitates in the resin layer not one, at most often kuiz after leaving the effluent solution from the column, however, this is not disadvantageous since the precipitate can then easily be removed by filtration

The first part of the eluate consists of water that has been displaced from the resin layer Part is discarded in the next part, which is sometimes is referred to as "lead", the streptomycm sulfate is relatively more dilute Solution This is temporarily in a suitable Vessel lifted

The third part is an eluate in which the Streptomycm sulfate is relatively enriched and also free of chlorine ions ("rich cut") you get a portion in which a mixture of chlorides and sulphates of streptomycin and calcium is present

According to the invention, the streptomycm sulfate enriched portions worked up to dry salt or ζ B to dihydrostreptomycin sulfate processed The first runnings and the mixed portions are used alone or mixed as solvents for further portions of fresh streptomycin calcium chloride complex compound used, at the same time the streptomyin sulfate contained in them with the Streptomycin - calcium chloride complex compound reacts and calcium sulfate precipitates

The reaction that took place in the preparation vessel for the inflow solution is played by the following Equation can be represented

th washing water is about 4.0 that from the preparation vessel emerging reaction mixture is filtered to remove the precipitated calcium sulfate, and then passed through the resin layer

During the second and each subsequent pass, there is an ion exchange in the resin column due to the ground the following equation takes place

Because an excess of streptomycin-calcium chloride complex compound When introduced into the preparation vessel, the streptomycin hydrochloride formed is located and calcium chloride in solution

The ion exchanger is regeneneit after the first passage by customary methods The resin is preferably washed after the regeneration with water sufficiently, so that the _pH value of the letz-

[Streptomycin 3HCl] + [(Streptomycin 3HCl) ₂ CaCl ₂ ] + resin sulfate

> [(Streptomycin ^ 3H ₂ SO ₄ ] + Harzchlond + CaSO ₄

(in supersaturated solution)

As stated earlier, it is important to ensure that it is kept constant The flow rate should be carefully observed, and 7 ° The process is conducted so that as much as possible

high concentration of streptomycin sulfate in the »rich Cut «is present The return of the forerun and the mixed proportions therefore not only serves to improve the overall performance of the process, by avoiding a loss of the amounts of streptomycin it contains, but rather also to this in order to easily already have a considerable Remove amount of unwanted calcium ions from the system before replacing the solution is brought into contact with the resin

The height of the resin layer is expediently essential Larger than its diameter This results in a high concentration of streptomycin sulfate in the Eluate In a preferred embodiment of the invention, the height of the resin layer is about 3.05 m

It has been found that this ion exchange process of the streptomycin-calcium chloride complex compound feasible with concentrated aqueous solutions is, the 390,000 units of streptomycin base each ecm in the first run and 420,000 units Streptomycin base per ecm in the following runs contain

In order to produce solid streptomycin sulfate from the "rich cut" of the column, this is still m der calcium sulfate dissolved in aqueous solution by addition precipitated from methanol. Then the solution is filtered and the filtrate is slowly added to methanol, whereupon the streptomycin sulfate precipitates. This solution is filtered or centrifuged The filter cake is after drying, pure streptomycin sulfate

If you want dihydrostreptomycin sulfate from the If you create a "rich section" of the column, the precipitated calcium sulfate is filtered off and the filtrate conventionally with hydrogen at about 1.36 atu in the presence of a suitable catalyst, such as platinum oxide, hydrogenated After filtering off the catalyst, the filtrate is then treated with methanol, the precipitated calcium sulfate was filtered off and methanol and some crystal nuclei were added to the filtrate The precipitated dihydrostreptomycin sulfate is then filtered off or centrifuged and dried

The following examples serve to explain the invention

example 1
a) Manufacture of the column

A glass tube 3 feet long and 3 inches in diameter was treated with 7 l of the anion exchanger »Amberhte IRA-400 «filled The height of the resin layer was 1.52 m

A 5% aqueous solution of sulfuric acid was passed in descending order over the resin until the solution flowing off the resin was essentially free of chlorine ions. until the solution flowing off the resin was essentially free of sulfate ions. The resin was then washed in descending order with 40 l of water and then with a 5% strength aqueous solution of sulfuric acid until the resin was practically completely in the form of the liquid. The flow rate was 450 ecm per minute the resin was then washed with descending Wassei, was until the _pH value of the effluent solution 2.7 and neither chloride nor sulfate ions contained the resin was then treated with water in ascending order, then allowed to settle and the water was at Drained layer height

b) First pass

6.581 of an aqueous solution of the streptomycin-calcium chloride complex compound at a concentration of about 217,500 units of streptomycin base each ecm were descending at a rate from about 130 to 140 ecm per minute over the Resin passed This corresponded to a surface contact time from 50 to 54 minutes. Subsequently, water became descending at the same rate passed through the resin and the process continued until the specific gravity of the effluent solution In addition to the water displaced from the column, there were also 17 parts of drainage solution of about 900 ecm each and a residual solution decreased from 7300 ecm

The water content and the first two 900 ccm parts did not contain streptomycin The next Both parts 3 and 4 contained streptomycin in a relatively dilute solution, namely m one Concentration of about 105,000 units per ecm im fourth stake The next four stakes were 5 through 9 "Rich cuts" that are practically free of chlorine ions were with an example concentration of about 215,000 units of streptomycin per ecm and an average concentration of about 197,000 units per ecm The proportions 10 to 14 already contained again chlorine ions. The streptomycm concentration proportion 14 was very low and was around 3600 units per ecm. The next proportions 15 to 18 had an even lower concentration of streptomycin

There were no run-through difficulties in this run on, this indicates that there is practically no calcium sulfate In all samples 4 to 12 calcium sulfate precipitated if the samples were left to stand

Portions 5 through 9 were on solid streptomycin sulfate processed in the manner previously described, producing an anhydrous product with an effectiveness of 744 units per mg was obtained

Second run

The one used for the first run of Example 1, b) Column was filled with a 7% aqueous solution washed by sodium sulfate in descending order at a flow rate of 460 ecm per minute, until the drainage solution no longer contained any chlorine ions Then she was descending with 460 ecm of water each Washed minute until the effluent solution also no longer contained sulfate ions. The resin then rose flowed through with water, allowed to settle and drained the water at layer level

The feed solution was in a suitable container produced by combining the shares 3, 4, 10, 11, 12, 13 and 14 of the first Duichlauf, with the Portions 3 and 4 contained little streptomycin sulfate and the remaining portions from a mixture Chlorides and sulfates of streptomycin and calcium were made to these combined proportions 2.05 kg streptomycin-calcium chloride complex compound and enough water added to make the solution to bring to a total volume of 7.0 l. Calcium sulfate then precipitated out. The precipitate was filtered off and the filtrate (6.5 liters) at a concentration of about 254,000 units of streptomycin base each ecm descending in the same way through the resin layer guided like the initial solution for the first Pass-through There were no pass-through difficulties on, which indicates that in the resin layer no meikhche Precipitation of calcium sulfate had occurred

A water content of 2000 ecm was taken off again, then six portions of 1500 ecm each and then two portions 7 and 8 of 2000 and 4000 ecm, respectively. The portions 3 to 5 contained the main amount Streptomycin and were practically free of chlorine ions The streptomycin sulfate concentration was then about 220,000 units of streptomycin base per ecm Parts 6 and 7 already contained chlorine ions again

Proportions 3 through 5 were as above solid streptomycin sulfate worked up The mixed Shares were saved for another run

Example 2

a) Manufacture of the column

A 3.05 m long glass tube with a diameter of 2.54 cm was 800 ecm of the ammonia exchanger »Amberhte IRA-410« (polystyrene resin with quaternary Ammonium groups). The resin was charged with a 7% strength aqueous sodium sulfate solution washed at a rate of 52 ecm per minute until the drainage solution showed no trace of chlorine ions (visual test with silver nitrate) The resin then became ascending washed with 52 ecm of water per minute until the The drainage solution no longer contained sulfate ions (visual test with barium chloride). Then that was left Resin settle, the water was drained off at the level of the layer. The height of the settled layer was about 1.52 m

b) First pass

940 ecm of an aqueous solution of the streptomycin-calcium chloride complex compound were used as the inflow solution used at a concentration of about 371,000 units of streptomycin base per ecm The tributary solution was descending with a Flow rate of 27 ecm per minute over the resin is conducted This corresponds to a surface contact time of 29.6 minutes

The first portion of 500 ecm was substantial displaced water The second portion of 300 ecm was practically chloronone-free streptomycin sulfate an effectiveness of 366,000 units per ecm. The third and fourth proportions of 800 and 300 ecm, respectively mixed

The second portion was worked up on streptomycin sulfate in the manner previously described solid streptomycin sulfate had a potency of 730 units per mg

Second run

A double column, made similar to that used in the first run of this example, was charged with two portions of a feed solution Passed descending over the resin at the same speed as in the first run. This was followed by portion 2, which consisted of 280 ecm of portion 4 from the first Duichlauf, to which 195 g of solid streptomycin-calcium chloride complex compound had been added, so that the concentration of the solution about 365 000 units per cc was Then the solution with calcium hydroxide bringing the p _H -Werl to 5.0, the solution filtered and the filtrate passed descending at the same speed as the first pass through the resin, the first amount of 450 cc was in essentially displaced water The second portion of 400 ecm contained streptomycin sulfate practically free of chlorine ions Solution with an effectiveness of about 238,000 units per cubic centimeter, and the third portion of 800 cubic centimeters was mixed and contained chlonones

There were no run-through difficulties, which is a sign that there is no calcium sulfate had settled in the resin layer

Example 3

a) Manufacture of the column

A glass tube 2.54 cm in diameter and about 6.1 m long was charged with 1550 ecm anion exchanger "Amberhte IRA-400". The layer height was 3.05 m. The resin was treated with 1.0 N sulfuric acid at a rate of 100 ecm treated low per minute until the effluent solution, no significant amounts of Chlononen could the resin was then washed descending with 140 cc of water per minute longer be nachgeao reported until the _pH value of the effluent solution was increased to 3.1, the film was whirled up, allowed to settle and the water drawn off at layer level

b) First pass

1300 cc was Zuflußlosung complex compound streptomycin calcium chloride prepared by dissolving 500 g in water and the _pH value with CAI ciumhydroxyd adjusted to 4.5 The solution was filtered 1200 ecm filtrate were each ECM with Einei concentration of about 369 500 units descending over the resin, a continuously running pump was used to achieve a flow rate of 45 ecm per minute corresponding to a surface contact time of 34.5 minutes. Then water was passed through the column

The first portion of 750 ecm was substantial displaced water The second portion of 250 ecm contained streptomycin sulfate in a relatively dilute form State (about 166,000 units per ecm) The third portion of 750 ecm contained practically chlorine ion-free Streptomycin sulfate in a concentration of about 339 000 units per ecm of the most and already contained a fifth portion of 500 or 250 ecm Chlononen and had a concentration of about 270,000 or 68,600 units per ecm

Second run

The acid used for the first run was made in a manner similar to that used for that run regenerated.

The Zuflußlosung was prepared in a suitable container, by the units 2, 4 and 5 combines the first pass and 500 g streptomycin solid calcium chloride Komplexverbmdung were added, the _pH value adjusted to 5.5 with calcium hydroxide, the mixture filtered and Sufficient water was added to the filtrate to produce a 1350 cc feed solution at a concentration of about 338,000 units per cubic centimeter. Of this, 1300 cubic centimeters were passed descending over the resin using a pump and maintaining the same flow rate as in the first run The water was then passed through the column

The first portion of 750 ecm was substantial diluted water The second portion of 250 ecm contained relatively dilute Stieptotnycin-

sulfate (about 170 400 units per ecm) The third part of 850 ecm contained practically chlorine free from ions Streptomycm sulfate m a concentration of about 295 500 units per ecm The fourth and fifth part of 500 and 250 ecm contained chlorine ions and had a streptomycin concentration of about 238,000 or 46,500 units per ecm

Third pass

The column used for the first and second run was regenerated in much the same way as the first run, except that it was washed longer with water to bring the P _{3 of} the effluent solution to about 3.15 after the effluent solution was left overnight had confessed her Ph value had fallen, the layer was further washed with water to the _pH value to bring the effluent solution to 3.0

The Zuflußlosung was prepared in a suitable vessel by the units 2, 4 and 5 combines the first pass and 570 g of solid Streptomycm calcium chloride Komplexverbmdung were added, the _pH value with calcium hydroxide to 5.5 and the mixture filtneit The filter cake was washed with water and the filtrate and washing water were combined. 1300 ecm of a solution with a concentration of about 415,000 units per ecm was obtained. The dry cake weighed 34.1 g

With the column 111 was similar to that of the previous Duichlaufen worked by using 1200 ecm inflow solution and then Wassei became

The first portion, 750 ecm, was essentially displaced Water The second portion of 250 ecm contained streptomycm sulfate with a concentration of about 215,000 units per ecm. The third part of 750 ecm contained streptomycm sulfate practically free of chlorine ions and had a concentration of about 385,000 units per ecm The fourth and fifth portions of 500 and 250 ecm both contained chlorine ions and had a concentration of about 272,000 and 56,300 units per ecm, respectively

Each streptomycin-containing portion of each run was _{adjusted to a p E} of 4.5 with calcium hydroxide

None of these runs found any noticeable Precipitation of calcium sulfate takes place in the resin layer

The method according to the invention is therefore a simple one and economical process for direct conversion of the streptomycin-calcium chloride composite compound m streptomycm sulfate, with high concentrations of complex compound without difficulty used and high concentrations of sulfate can be obtained without any noticeable Loss of Stieptomycin is observed Das Veifahien So the subsequent one is also very powerful Isolation of the streptomycin sulphate or any subsequent hydrogenation carried out the streptomycin sulphate solution and isolation of the dihydrostreptomycin sulphate are thereby facilitated, that no foreign ions are present in the initial solution, which would complicate the isolation or lead to considerable losses

Claims (4)

Claims 1 process for the production of streptomycin sulfate from the streptomycin-calcium chloride complex compound, characterized in that an aqueous solution of the streptomycin-calcium chloride complex compound in contact with a strongly basic anion exchanger in the sulphate cycle is brought, the contact time is measured so that significant amounts of Calcium sulfate is not precipitated in the resin layer, the calcium sulfate which is in supersaturation precipitated from the drainage solution after leaving the resin layer, the solution filtered and the filtrate is mixed with a fresh amount of starting substance 2 The method according to claim 1, characterized in that the contact time is about 15 to 60 minutes amounts to 3 The method according to claim 1, characterized in that the calcium sulfate by adding Methanol is precipitated to the effluent solution 4 The method according to claim 1, characterized in that the starting solution is an aqueous Solution of the streptomycin-calcium chloride complex compound a concentration of from about 100,000 to about 500,000 units of streptomycmbase each ecm used Documents considered
German patents nos. 916 904, 919 735, 445, British Patent No. 687 476,
USA Patent Nos. 2 528 022, 2 528 188, 2 541420, Chem Technik, Vol. 7, 1955, pp. 255 to 261,
Chimia, Vol 9, 1955, pp 49 to 65,
Chem Zentralblatt, 1955, p. 2956 © 909 578/452 7