HUT75090A - Process for producing hateromorph cristal-modification of urea-hydrogen-peroxide and solide pharmaceutical compositions containing them - Google Patents

Abstract

Field of the Invention The present invention relates to a process without an environmental by-product, but not to fOO% sos. Extractable, uninterruptible, tabletable, novel, heteromorphic crystal modulated urea hydrogen peroxide with stability benefits, with the two bands above 1600 cm @ 1 on the infrared spectrum of the product being the most intense and their transmission ratio not exceeding 1.05 and, on the X-ray diffraction powder chart, there are two peaks of approximately the same high intensity in the range 380 385 and 345 349 pm, and a tablet, pellet or granule solid phase drug formulation from the heteromorphic crystalline product, such that one part by weight of urea is 1.0- Reaction with hydrogen peroxide solution at a stoichiometric ratio of 1.3 to 2 in 5 portions, after which the solid phase reaction mixture is dried at 30-45, preferably at 40 ° C, and 0.5-3.0% organic in the last solution portion. inorganic, preferably tartaric, or ci Tromsic acid or formic acid and / or boric acid, preferably 1.0% tartaric acid, is added as a stabilizer to the product, optionally 0.5-2.0% peppermint oil or a menthol alcohol solution is added and the final product or use as in the instructions for use is used for the treatment of laryngeal or oral, ear, vaginal, uterine cavities. - {Description Page 8 + Figure 1)

Description

The present invention relates to a process for the preparation of a heteromorphic crystalline modification of urea hydrogen peroxide, based on the batch reaction, and the preparation thereof in the form of tablets and granules for solid phase pharmaceutical preparations.

It is known that urea hydrogen peroxide in the form of water-soluble tablets has been marketed as an external disinfectant under various brand names for about 80 years. An aqueous solution of the tablet can be used to rinse the ears, mouth, throat, vagina, uterus, treat wound dressings, wound skin, disinfect devices (Issekutz B., Issekutz L .: Medicines Order (Medicina Könyvkiadó Budapest 1969) page 575 ).

The compound was first made by Tanator by crystallization from a solution of 1 mol of urea and 1.5 mol of hydrogen peroxide (Journal d. Russischen Physikalisch-chemische Gesellschaft 40 378 (1908)). The preparation of the compound has since been based on the principle of adding the hydrogen peroxide solution to the urea or its aqueous solution in a single step, with excess cooling, followed by filtration of the crystalline product, drying with starch or citric acid or acetylated oxyamino acid. etc tableted with a stabilizer (Hagers Handbuch (Springer Veríag Berlin 1938) pages 1499-1500).

One disadvantage of these known processes is that the aqueous filtrate produces significant amounts of environmental pollution of urea and hydrogen peroxide, and the yield is not sufficient. In addition, due to the morphological properties of the crystalline product, it is often unsuitable for direct tabletting and the stability of the formulation is not uniform.

To overcome these disadvantages, systematic development studies have been carried out to eliminate the contaminant by-product solution, to increase the yield to 100%, and to optimize the crystalline modification of the product for direct tabletting and formulation stability.

Surprisingly, the addition of a small amount of stoichiometric hydrogen peroxide solution to solid phase urea, vigorously stirring, drying, and repeatedly adding the stabilizer to the final portion of the addition results in an environmental ♦ 100% yield in 100% yield without the formation of a contaminant by-product solution, · ····························································· Thus, a new product with an optimal crystal modification is obtained.

According to a preferred embodiment of the invention, 1 1.3 parts by weight of 27-50%, preferably 30% hydrogen peroxide solution in 1 to 2 parts by weight, based on the stoichiometric weight ratio, in 2-5 parts, In the case of a 1% solution of hydrogen peroxide, it is added in 4 portions to the urea. After mixing each moiety, the wet material is dried at 40 ° C, then the next moiety is mixed and the wet material is dried again. Dissolve the final solution in portions of 0.05-3.0% tartaric acid, or tartaric acid, citric acid, or other acid stabilizer, mixing batchwise, homogenizing and drying the product. This product is compressed into tablets of any size, preferably in a setting of 1 g, which is dispensed into containers or filled into a powder container with a measuring standard.

The solid state structure of the product prepared by batch addition as described was examined by X-ray diffraction. For comparison purposes, a powder diagram of the crystalline urea hydrogen peroxide obtained from the solution and urea was also determined. Images were taken with a Philips PW 1840 powder diffractometer with Cu-K radiation at 30 kV and 30 mA.

Surprising data for the powder diagrams are shown in the following table, wherein (A) the starting urea (B) is crystallized (C) is batch reacted urea hydrogen peroxide

Note: The position of the peaks in the port graph is given in picimeters (pm), 100 times the relative intensities (I / I _o ).

(THE) (B) (C) d _h ki pm I / I _o dhu pm I / Io d _{! lk} i pm _1/10 453 0.3 651 72.5 601 17 404 100 472 6 473 6.5 365 4 453 5.5 458 2.7 311 2 400 18 402 32.3 308 3 380 100 382 100 284 7 363 5 363 3 254 7 348 55 345 100 244 2.2 323 66 323 27 237 0.3 306 30 306 22 230 0.3 298 94 293 84 224 1.5 283 74 282 51 219 1.7 275 13 275 13 267 1.5 258 4.5 259 4 251 17 253 13 242 10 251 22 236 6 242 5 229 25 236 5 213 7.5 097 X-2- / 42 213 6.7

When searching for the reasons for the very significant differences in the powder diagrams, we took into account that urea with a high affinity tends to form a favorable mesomeric structure from the energy point of view (Bruckner, Gy .: Organic Chemistry (Tankönyvkiadó Budapest, 1961), Vol. It is also known in the literature to be able to form an oxonium salt (anionic) in urea acid addition compounds (Wemer: Liebigs Annalen der Chemie 322 304) and to form complex cations (Sell: Jahresbericht über die Fortschritte der Chemie 1882 382; 322 302). However, it was not known that acid peroxide 11.62 hydrogen peroxide and urea 13.82 base exponent (Mázor L .: Analytical Pocket Book (Technical Publisher Budapest 1971) pp. 139 and 148) had different stable hydro ·· - »gene- bridging bonds can be formed in solid phase, depending on whether they are reacted with hydrogen peroxide in one step or batchwise in several steps. As a result, the following crystalline phases with different chemical structures appear together in the solid phase:

nh ₂ nh ₂ , nh ₂ JL ~ hnh 1 nh. ° HNH ^Z ° nh ₂ HNH (I) (II) HOOH HOOH ΐ ΐ nh ₂ nh ₂ 1 HNH ¹ HNH HNH ^ í ⁰ HNH ^ nh ₂ I c ^Z iJh ₂ I HOOH HOOH

HNH iJh ₂

HOC _x NH ₂ ^ nh ₂ (1H)

COCNHJHA (IV) (V)

Urea (I and II), Isocarbamide (III), Urea Hydrogen Peroxide "Acid Addition Compound" (IV), Urea Hydrogen Peroxide (1/1) (V) Containing Hydrogen Peroxide in Crystal Form (Hagers Handbuch (Springer Verlag Berlin 1938, p. 1499), as well as other associative crystalline compounds thereof containing ligation (hydrogen bridge) bonds, form the heteromorphic solid structure. Heteromorphism was, moreover, observed when the solid components were pressed (J. Pogány, A.D. David, M. Kenéz: Acta Pharm. Hung. 58, 49 (1988)), but it was not known that it also develops in response.

In addition to X-ray diffraction, infrared spectrophotometry of samples (A), (B) and (C) was also performed. The images were taken on a Nicolete 20DX FTIR instrument using potassium bromide pellet technology. The IR spectra of the samples are illustrated in FIG.

The spectra show that the 2800 cm ^-1 bands of sample (B) have different shapes and the peaks of the highest intensity bands in sample (B) 1628, 1675 in sample (C) 1625, 1678 and a peak (shoulder) appears at a wave number of 1600 cm ' ¹ . In addition, the pattern (B) 1412 and 753 cm ^-1 bands are absent from the sample (C). Similarly, the 721 cm ^-1 band of sample (C) did not appear in sample (B). Furthermore, a surprising fact that the (A) (B) (C) samples in the case of the ratio of the two bands 1600 cm-over ^one transmission values urea for 1.153, crystallized from the solution sample in the case of 1.076, and then heteromorf modification 1,030, suggesting that the possible chemical interactions with the hydrogen bridge bonds around the acid amide group in the heteromorphic form are most balanced. The advantageous properties of the novel modification are interpreted by this chemical characteristic.

It has been found that by preparing the urea hydrogen peroxide by methods known in the art by reacting the urea with a molar excess of hydrogen peroxide solution in one step under cooling and stirring, the wet mass is dried to varying degrees of moisture. product. Hydrates of urea-hydrogen peroxide-water with stoichiometric ratios of (40/1), (20/1), (10/1), ... (4/1), respectively, have a moisture content of 0.48, 0.95, 1, It ranges from 88 to 4.56. The X-ray powder diffraction patterns of the various hydrates also change significantly. In terms of tabletability, products of less than 2% moisture content and above 4% moisture content cannot be used to make tablets of appropriate quality. During storage, the tablets will become powdery or stick together.

In contrast, the optimum moisture content of the product according to the invention can be well controlled by drying at 30-45, preferably 40 ° C.

The exact moisture content was determined from the sum of the urea content of the product as measured by the Kjeldahl method and the percentage of hydrogen peroxide as determined by permanganometry.

Because urea hydrogen peroxide may contain a stabilizer according to the Pharmacopoeia standard (Hungarian Pharmacopoeia, VII, Volume II, p. 854), formic acid is preferred in the literature (Nyekrasov, BV: General Chemistry (Tankönyvkiadó Budapest 1951) Vol. I 139 p.), as well as citric acid and tartaric acid stabilizers were also investigated.

To this end, according to a further preferred embodiment of the invention, 1 molar solution of 33% hydrogen peroxide in 1 molar solution of urea was added in 3 portions, after mixing each portion, the reaction mixture was dried at 30 ° C in vacuo and 0.5% formic acid, 1% citric acid for the second production and 1% tartaric acid for the third production were added to the reaction mixture. The moisture content of the final product was uniformly set at 2.63.0%.

The samples thus prepared were heat treated in a closed vessel at 50 ° C for various periods of time and the degradation data reported are shown in the following table:

0.5% formic acid 1% citric acid 1% tartaric acid Initial H ₂ O ₂ % 33.2 33.4 33.7 50 ° C after 1 week 30.4 32.4 32.8 After 2 weeks 27.4 31.7 32.5 After 3 weeks 25.6 28.7 32.1 After 5 weeks 0 0 31.2

Several further stability studies have shown that tartaric acid, citric acid, boric acid and formic acid have a decreasing stabilizing effect, respectively. In terms of solid structure, heteromorphism and tabletability, the stabilized product is most preferred in the same order as the boric acid and less preferred with formic acid.

The heteromorphic urea hydrogen peroxide prepared according to a further preferred embodiment of the present invention retains its advantageous properties even when the final product is mixed with 0.5% to 2.0% alcoholic solution of menthol oil or menthol in an alcohol-free solution.

Further details of the process of the present invention are given in the Examples without limiting the scope of the formulation products.

Example 1

Preparation of Carbamidum Peroxydatum (Ph.Hg.VH.)

100 kg of pharma grade urea are reacted with 40 kg of 35% hydrogen peroxide at 0-5 ° C in a suitable aluminum or enamel mixer with constant stirring kneading. After stirring for 30 minutes, the reaction mixture was dried at 40 ° C in a tray dryer to a weight loss of 13 kg. Subsequently, the dried intermediate is reacted with another 40 kg of 35% hydrogen peroxide in the mixer for 30 minutes and then dried again until a mass of 13 kg is achieved. The dried crystalline intermediate is reacted with 40 kg of 35% hydrogen peroxide solution containing 1.5 kg of tartaric acid in dissolved form and dried again to a weight loss of 13 kg. The product thus prepared is converted into a pharmaceutical form in a manner known per se.

Example 2

Preparation of Carbamidum Peroxydatum Tablets

The product prepared according to Example 1 was set within a range of 0.2-0.6 mm particle size through a plastic fiber screen so that the fraction below 0.2 mm was 10-30%. This granulate is tableted in a manner known per se, with tools of any diameter, set at 1.0 g, packed in well sealed containers and labeled.

Example 3

Carbamidum Peroxydatum buccal pellet

The product of Example 1 (10 kg) was sprayed with a solution of 50 g of peppermint oil in 300 g of alcoholic solution and dried at 30 ° C. The crystalline material thus prepared is tabletted to a pellet shape using a plastic fiber screen set at less than 0.15 drops, with a 2 mm compression number at a 10 mg setting.

Example 4

Carbamidum Peroxydatum granulate

The granules of Examples 1 or 3 are packaged in a powder container with a scaled dosing spoon, preferably dissolved in 100 cm ^{3 of} water with instructions for external or oral rinsing.

Claims (4)

Claims 1) A heteromorphic crystalline compound of urea hydrogen peroxide. 2) Pharmaceutical composition, characterized in that the heteromorphic urea hydrogen peroxide is present in an amount of 0.5 to 3.0% by weight inorganic, optionally an organic acid stabilizer such as boric acid, tartaric acid, citric acid, formic acid, optionally 0.12.0% Contains peppermint oil, menthol. 3) The composition of claim 2, wherein the solid phase tablet, pellet, granule form and an aqueous solution thereof are formulated for external use for the treatment of body wounds and oral cavities. 4) A process for preparing a crystalline modification of a heteromorphic urea-hydrogen peroxide, comprising reacting the urea with hydrogen peroxide in a stoichiometric ratio of 1.0 to 1.2 with stirring in 2-5 portions, after reacting each portion of the hydrogen peroxide solution. 30-45 ° C, dried at ratios such that the product has a residual water content remains within 1.8 to 3.0% threshold while the infrared spectra of the two peaks of maximum absorption of 1600 ^cm-1 above the value 1.05 transzmisszióhányadosa does not exceed.