United States Patent Office Patented Nov
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3,539,306 United States Patent Office Patented Nov. 10, 1970 2 properties of quick activity, durable effect and storage 3,539,306 PROCESS FOR THE PREPARATION Stability, and that, therefore, the same can provide an ex OF HYDROTALCITE cellent, ideal antacid. Teruhiko Kumura and Norio Imataki, Takamatsu-shi, Hydrotalcite is known as a mineral having a chemical Katuyuki Hasui, Kagawa-ken, and Takeo Inoue and 5 Structure of the formula Kimiaki Yasutomi, Nagao-machi, Kagawa-ken, Japan, assignors to Kyowa Chemical Industry Co., Ltd., Tokyo, MgAl(OH) 16CO3 4HO O Al2O3 6MgO CO2: 12H2O Japan, a corporation of Japan No Drawing. Filed July 21, 1967, Ser. No. 654,977 which has been naturally produced in only very limited Claims priority, application Japan, July 25, 1966, areas as Norway and Ural. Also a process for the syn 41/48,349; July 17, 1967, 42/45,658 O thesis of hydrotalcite was disclosed, which comprises add Int. C. COf 5/00, 7/00, A61k 27/06 ing Dry Ice or ammonium carbonate to a mixture of U.S. C. 23-315 4 Claims magnesium oxide and y-alumina or the thermal decom position product from of magnesium nitrate and aluminum nitrate, and thereafter maintaining the system at tempera ABSTRACT OF THE DISCLOSURE, tures below 325 C. and under elevated pressures of total A process for the preparation of hydrotalcite which 2,000-20,000 p.s.i. (Roy et al.: American Journal of comprises mixing an alumium component such as alumi Science 251, 350-353 (1953)). However this process is num Salt With a magnesium component such as magnesium obviously unpractical for industrial scale production of Salt in an aqueous medium in the presence of carbonate hydrotalcite, because the reaction system must be main ion at a pH of at least 8 and thereafter recovering the 20 tained under considerably high pressures. Whereas, we resultant product. An antacid or an excipient comprising now found a process by which hydrotalcite can be syn hydrotalcite of the general formula thesized with industrial ease without requiring such high pressures. Al2O3: 6MgO CO. 12HO Accordingly, the object of the present invention is to 25 provide a novel process by which synthetic hydrotalcite This invention relates to a novel method of synthesis can be industrially produced from readily available start of hydrotalcite, and to the gastric anacid and excipient ing material without especially complicated operations. containing the said hydrotalcite. An another object of the invention is to provide a novel The ideal gastric antacid is required to meet the follow 30 gastric antacid containing hydrotalcite, which has excel ing conditions: that it should show the maximum neutralis lently quick activity, durable effect and storage stability. ing effect in the possible shortest time to such an extent Still another object of the invention is to provide a that it raises the pH of gastric juice to around 3 within novel excipient for pharmaceutical and other chemical one minute after administration; it should neutralise an industrial use containing hydrotalcite, which is excellent adequate amount of gastric hydrochloric by maintaining 35 in such properties as compressibility as well as hardness the pH of gastric juice to 3-5 during the normal period of and compression strength after the shaping. gastric digestion; any excess, however great, should not Further objects and advantages of the invention will be cause alkalisation of gastric juice nor constipation, diar come apparent upon reading the following descriptions. rhea or alkalosis to the patient; and that its acid con According to the invention, there is provided a process Sunning capacity should not be impaired by pepsin nor 40 for the preparation of hydrotalcite which comprises mix affected by moisture or temperature. ing an aluminum component with a magnesium compo Heretofore the researches for such antacid meeting the nent in an aqueous medium in the presence of carbonate above requirements have been centered on aluminum hy ion at a pH of at least 8 and thereafter, recovering the droxide. However, while aluminum hydroxide gel im resultant precipitate, the said aluminum component being mediately after its preparation is amorphous under X-ray selected from a group consisting of aluminum hydroxide, examination and highly reactive with acid and further basic aluminum carbonate, aluminum hydroxide-alkali more its acid consuming capacity is little damaged by carbonate, complex, aluminum aminoacid salt, aluminum pepsin, with the time lapse or when it is made into dry alcoholate, water-soluble aluminum salt, and water-soluble product its reactivity with acid falls and its acid con aluminate, and the said magnesium component being Suming capacity tends to be more appreciably damaged by 50 Selected from a group consisting of magnesium oxide, pepsin. Also many of the products of this type crystallize. magnesium hydroxide, magnesium carbonate and water With the purpose to prevent or control such phenomena, it soluble magnesium salt. has been proposed to add to the aluminum hydroxide gel The aluminum component to be employed in the in Such matter as organic acid, amino acid, protein, sac vention may be any member of the group consisting of charide and the like, or to co-precipitate with the aluminum aluminum hydroxide, basic aluminum carbonate, alumi hydroxide gel calcium carbonate, magnesium carbonate, num hydroxide-alkali carbonate complex, aluminum silicic acid and the like. These methods however are ob aminoacid salt, aluminum alcholate, water-soluble alumi jectionable in that since the substances having no acid num salt and water-soluble aluminate. As examples of consuming capacity or those which impair acid consuming aluminum hydroxide-alkali carbonate complex, those pre capacity are whereby added, the products have lowered 60 pared in accordance with the processes disclosed in U.S. acid consuming capacity per gram and furthermore be Pats. Nos. 2,783,124, 2,783,127 and 2,783,179 may be come more expensive. Also in most cases those methods used. As water-Soluble aluminum salt, aluminum salts of fail to satisfactorily overcome the decrease in the reactivity acids Such as aluminum Sulphate, aluminum chloride, with acid of aluminum hydroxide gel with the time lapse. aluminum nitrate and aluminum acetate, and their com For these reasons, an antacid having quick-appearing 65 plex salt such as alum can be used, and as the water and Sustaining effect as well as excellent storability has soluble aluminate, there can be used an alkali aluminate been strongly demanded. Such as Sodium aluminate. Obviously, in accordance with Whereas, we found that hydrotalcite which itself is a the invention it is permissible to form aluminum hydrox stable, crystalline substance possesses desired combined ide, aluminum hydroxide-alkali carbonate complex, basic 3,539,306 3. 4. aluminum carbonate or aluminum aminoacid, salt in situ, drotalcite is formed within 10 minutes even if the temper preceding the described reaction. ature is around 50° C. When water-soluble materials alone As the magnesium component which is the other react are used, reaction takes place instantaneously at a tem ant, any member of the group consisting of magnesium perature ranging from 0 to 150° C. oxide, magnesium hydroxide, magnesium carbonate and According to the invention, as the hydrotalcite formed water-soluble magnesium salt may be used. As the water 5 is obtained in the form of precipitate, the product is fil soluble magnesium salt, there can be mentioned mineral tered, washed with water if desired and thereafter the acid salts of magnesium such as magnesium chloride, solid is separated by known solid-liquid separation means magnesium nitrate, magnesium sulphate, magnesium di such as centrifuge, followed by drying to serve as the dry carbonate and bittern. O product. According to this invention, the said aluminum com In a preferred embodiment of the invention, a water ponent is mixed with the magnesium component in a soluble aluminim salt and a water-soluble magnesium salt basic aqueous medium in the presence of carbonic acid are mxed to form a homogeneous aqueous solution, and ion. To increase the yield of the hydrotalcite at this time, the system was added with alkali hydroxide and carbon it is preferable to mix the aluminum component with the ate ion by means of addition of alkali carbonate solution magnesium component so that the atomic ratio of Al to or blowing-in of carbon dioxide gas. Thereafter the system Mg may be 1:2/3-8, and to cause the carbonic ion to be was mixed, and the resultant precipitate was filtered, present in a ratio of at least 1/9 to each aluminum atom. washed with water and dried to provide the desired prod Of course, it is most preferable to react the coponents in uct. If the ratio of Al to Mg deviates from 1:3 at this stoichiometrical amounts. In that occasion, the difficulty time, it is possible to produce hydrotalcite having less im water-soluble aluminum component such as aluminum hy purities, because excessive reactant remain in the solution. droxide, basic aluminum carbonate, aluminum aminoacid In accordance with the above embodiment, because the salt and aluminum hydroxide-alkali carbonate complex, reaction progresses in a homogeneous system the reaction or the difficulty water-soluble magnesium component such conditions can be controlled with ease, and furthermore as magnesium oxide, magnesium hydroxide and magnes there is another advantage in that the entire procedure ium carbonate can be added to the aqueous medium as can be practiced continuously by supplying continuously they are, or as liquid suspension. On the other hand, when from one end the aluminum componet, magnesium com water soluble aluminum salt and/or water-soluble mag ponent, basic component and carbonate component and nesium salt are used, it is preferred to add those salts to concurrently withdrawing continuously from the other the aqueous medium in the form of aqueous solution.