IL23427A - New,water-soluble,coccidiostatic preparations containing 3,5-dinitro-o-toluamide - Google Patents

Description

PATENTS AND DESIGNS ORDINANCE.

SPECIFICATION.

-"NEW, WATER-SOLUBLE .COCCIDIOSTATIC PREPARATIONS'" — CONTAINING 3,5 dinitro-e-tolu,amide" ~gQ»¾a noarfr ota&an Ο*ΒΤΉΠ ρϊτρκοονηο ρ Ο»Ί¾¾ΒΑ». 1 / WE » G»F, BOSHRINSER & SOBHKB Sm¾H, a company of the e ex«l.

Federal BepU¾lic of Ge many, do hereby declare the nature of this invention and in what manner the same is to be performed, to be particularly described and ascertained in and by the following statement : - » .The present invention is concerned with new, water-soluble preparations containing 3 ,5-dinitro-o- toluamide. 3 ,5-dinitro-o-toluamide is a coocidiostatic with a reliable action and a good compatibility which, in recent years, has achieved increasing importance under . the names "Zoalen" and "D.O.T," (c.f., for example, · Poultry. Science, 39, 739-74-5/1960; Res. in Vet. sci. , 1 , 363-370/1960) .

In order to administer a veterinary medicine of this type in as uniform a doaage as possible, jit can j be admixed either with the food or with the drinking water. However, since 3» 5-dinitro-o-toluamide is practically insoluble in water, hitherto only the first mentioned possibility could be realised. If it is desired to ensure a fine and uniform distribution of the active material in the food, then such a food mixture must be produced mechanically, i.e. on a large scale, before being supplied to the actual user. It would, of course, be much simpler and more rational if the final user or the veterinarian could be supplied with a suitable preparation of the active material which only had to be mixed with the animals' drinking water.

For the administration of 3 »5-dinitro-o-toluamide in animals' drinking water, there are, in principle, the following possibilities.*. a) production of a uniform, finely-di ided and stable suspension and . b) production of a solution with the help Of solubilisers.

However, the production of suspensions of 3»5- dinitro-o-toluamide meet3 with considerable, difficulties; in order to stabilise a suspension of this compound in water, it would be necessary to increase the viscosity to such an extent that the suspension obtained could no longer be regarded as drinking water. . ' » A solubiliser which is to be added to the drinking water of poultry must satisfy certain conditions; it should not so influence the taste of the water that the animals refuse to drink it;' the substance must be completely pharmacologically inert for the type of animals in question and must not cause toxicological harm; the compound must not make the water strongly acidic or strongly alkaline ; the naturally-occurring materials in the water, such as calcium and magnesium salts, carbonate-s and the like, must not be impaired by the solubiliser; and, finally, the amount of solubiliser needed must not be so great that, merely due to the high concentration of the solubiliser, the animals will be harmed or will refuse -to drink the water. A further important consideration in the case of the use of a solubiliser is that, in practice, it must permit a rapid production of the drinking water because it would clearly be impracticable to have. to stir the drinking water for several hours, or even to have to leave it to stand for several hours, until the substance has dissolved.

Our investigations have shewn that the conventional wetting agents, such as sodium lauryl sulphate, do not exert a solubilising effect on 3,5-dinitro-o-toluamide .

Furthermore, numerous known solubilisers , such as, for example, sym.-dimethyl-urea, urethane, salicylamide , ' salicylamide-o-acetic acid, dimethyl-pyrazolone , dimethyl-aminophenyl-dimethyl-pyrazoione , sodium phenyl-dimeth l-pyrazolone-methylaminomethane-sulphonate , polyvinylpyrrolidone, uric acid salts, ethylene-diamine-tetraacetic acid, sodium potassium tartrate, glycocoll, citric acid, tartaric acid, polyoxyethyl-castor oil (Cremophor EL) , hydrophilic fatty acid esters (Cremophor L 10), polyoxy-ethylene-sorbitan-monooleate (Tween 80) , have not proved to be satisfactory for one or other of the above-mentioned reasons.

We have now, surprisingly, found that water-soluble preparations of 3 ,5-dinitro-o-toluamide are obtained, which satisfy all of the above-mentioned retirements for a stable and readily compatible preparation, when the active material is finely ground, together with a water-soluble salicylate and/or urea.

As salicylate, it is preferred to use an alkali metal salt of salicylic acid, such as sodium salicylate.

For the production of the preparations according to the present invention, there can be used the conventional mills, such as ball mills, mortar mills, pin mills, hammer mills and the like.

In the case of a polynitro compound, it must always be borne in mind that such substances could possibly be explosive when subjected to intensive mechanical forces, even though no reports have hitherto been made in this regard concerning 3,5-dinitro-o-toluamide. Therefore , for the mixing and grinding of the preparations according to the present invention, it is advantageous to use a jet mill.

If desired, a wetting agent, such as sodium lauryl sulphate, can also be added to the new preparations. The more rapid wetting of the hydrophobic particles of 3»5-dinitro-o-toluaraide hereby achieved results in" a de inite acceleration of the dissolving process. In this manner, there are obtained preparations of 3,5-dinitro-o-toluamide which rapidly dissolve in water to give solutions with , the therapeutically necessary concentrations of up to mg.%. These solutions are stable over long periods of time and have an outstanding compatibility.

As can be seen from the following Examples, in the case of finely grinding 3>5-dinitro-o-toluamide there is obtained a non-wettable powder which does not form a suspension. By the admixture of a wetting agent, there is admittedly achieved a rapid wetting but also a rapid deposition of the powder (see Example 1). Good solubilising effects are only achieved by the use of urea or of the salicylate (see Examples 2 and 3)· However, a mixture of these two substances works substantially better than the two individual substances (see Example 4).

Example 1. 3,5-dinitro-o-toluamide is very finely ground in a jet mill (particle size less than 10 microns) and suspended in water. Initially the powder is not wetted at all, floats in lumps on the surface and finally, after a long time, sinks to the bottom.

By the admixture of 20% sodium lauryl sulphate, there is achieved a more rapid wetting but also a quicker deposition of the powder. A stable suspension cannot be obtained in this manner.

Example 2. 16 g. urea, 2 g. sodium lauryl sulphate and 2 g. 3 ,5-dinitro-o-toluamide are ground as finely as possible in a jet mill. 200 mg. of the mixture obtained slowly dissolve in 100 ml. water to give a relatively stable solution.

When the amount of urea used is increased to 18 g. and the same amounts of the other ingredients are used, then there is obtained a mixture, 220 mg. of which dissolve rapidly and completely in 100 ml. water.

Example 3» 16 g. sodium salicylate, 2 g. sodium lauryl sulphate and 2 g. 3,5-dinitro-o-toluamide are ground as finely as possible in a jet mill. 200 mg. of the mixture obtained dissolve rapidly in 100 ml. water to give a clear solution. The solution remains completely clear even after standing in a refrigerator for a long time.

Example 4« a) 14 g. sodium salicylate', 2 g. urea, 2 g. sodium lauryl sulphate and 2 g. 3,5-dinitro-o-toluamide are ground as finely as possible in a jet mill. 200 mg. of the mixture obtained give a clear solution in 100 ml. water which remains stable even after standing in the cold for a long time. b) 14 g. urea, 2 g. sodium salicylate, 2 g. sodium lauryl sulphate and 2 g. 3,5-dinitro-o-toluamide are ground as finely as possible in a je.t mill. 220 mg. of the mixture obtained dissolve rapidly in 100 ml. water- to give a relatively stable solution. c)' 1 g. Jj^-dinitro-o- oluamide, 0·1 g. sodium lauryl sulphate, 2.25 δ· sodium salicylate and 6,67 g» urea aire ground as finely as possible in a jet mill. 200 mg. of the mixture obtained dissolve very rapidly" in 100 ml. water. This mixture shews particularly good results with regard to storage properties, as well as speed of dissolV' ing and the extremely low use of solubiliser. '",■'·

Claims (1)

1. of n the is that is t j preparations containing 3 comprising a very finely ground mixture of with urea a Preparations according to claim wherein a wetting agent is also present in finel ground Preparations according to 1 or the wetting agent is sodium lauryl preparations according to any of the preceding wherein the salicylate is alkali metal salt of salicylic Preparations according to claim wherein the alkali metal salt of acid is sodium preparations according to any of the preceding which are hereinbefore specifically Process for the production of preparations containing wherein a mixture of with urea a salicylate is very finely Process according to claim wherein the mixture to be ground also contains a wetting Process according to claim or wherein the grinding is carried out in a jet Process to claim 7 or wherein the grinding is carried out in a ball a mortar a pin mill or a hammer Process according to claim 7 preparation of arations of substantially as hereinbefore described and insufficientOCRQuality