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Home , Magnesium carbonate, Magnesium hydroxide

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 cellent, ideal . Teruhiko Kumura and Norio Imataki, Takamatsu-shi, Hydrotalcite is known as a 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 to a mixture of U.S. C. 23-315 4 Claims 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 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 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 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 , diar come apparent upon reading the following descriptions. rhea or alkalosis to the patient; and that its 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 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- 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, -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 , pepsin. Also many of the products of this type crystallize. , 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 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 of fail to satisfactorily overcome the decrease in the reactivity 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 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 , 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 . 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 , 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 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. 30 end of the slurry of the formed hydrotalcite. According to a preferred embodiment of the invention, In another embodiment of the invention wherein alumi the mixing is performed to make the pH of the entire num hydroxide is used as the aluminum component, an system composed of the aluminum component, magnesium aqueous slurry of aluminum hydroxide is added with neu component and aqueous medium at least 8, inter alia, tral magnesium carbonate, and the system is heated at above 9.5. With the pH of the entire system below 8, the 35 such temperature for such time as sufficient to cause dis object hydrotalcite is obtainable only at low yield. In appearance of the magnesium carbonate which order to maintain the pH of the entire System at the said can be confirmed by microscopic observation of the sam level during the reaction, alkaline substances such as ple taken desired hydrotalcite is formed. And, when neu alkali hydroxide and/or alkali carbonate may be suitably tral magnesium carbonate in the above process is re added to the aqueous medium, when water-soluble alumi 40 placed by basic magnesium carbonate, the heating to num salt and/or water-soluble magnesium salt is used. slightly elevated temperatures is sufficient, and without The required presence of carbonate ion in the reaction further positive heating during the reaction hydrotalcite system can be effected by blowing carbon dioxide gas into can be obtained by considerably prolonged drying of the the system or by addition of a carbonate. Obviously such product. In the foregoing two methods, the formed prod procedure may be omitted when an aluminum hydroxide ucts do not contain soluble impurities and therefore need alkali carbonate complex is used as the aluminum com not be washed with water. ponent or magnesium carbonate, as the magnesium com According to still another embodiment of the invention, ponent, since in those cases the reaction system will con hydrotalcite is formed by either addition of alkali car tain the sufficient amount of carbonate ion. Also when bonate (including alkali bicarbonate) or blowing-in of water-soluble aluminum salt and/or water-soluble mag carbon dioxide gas, to a slurry of aluminum hydroxide nesium salt is used, it is convenient to use the combination and magnesium oxide or magnesium hydroxide. In that of alkali carbonate and alkali hydroxide as the carbonate, case the mol ratio of alkali carbonate to aluminum hy because whereby control of pH of the reaction system droxide should preferably be no less than 1:1. If the con and the carbonate ion supply can be achieved by single centration of the suspension is smaller, it is necessary to operation. make the molar ratio of alkali carbonate larger. The pre The critical feature of the invention resides in that the ferred reaction temperature is above 45 C., it being the reaction of the aluminum component, magnesium com case the higher the temperature, the better for hydrota ponent and carbon dioxide is performed in water and cite formation. Also alkali bicarbonate is preferred over under basic condition. Because the reaction of the three neutral alkali carbonate. Basic aluminum carbonate can is performed in water according to the invention, it is 60 similarly be used in place of the said aluminum hydroxide. made possible to provide carbon dioxide in the form of In another embodiment of the invention, aluminum carbonate ion, and consequently mild reaction conditions hydroxide-alkali carbonate complex or aluminum amino with respect to pressure and temperature become feasible. acid Salts and magnesium oxide or hydroxide are mixed The temperature conditions for the reaction vary con as an aqueous slurry. Because aluminum hydroxide-alkali siderably depending on the types of the aluminum com carbonate complex and aluminum aminoacid salts are ponent and magnesium component employed, but nor highly stable compared with aluminum hydroxide, the mally the range of 0-150° C. is preferred. The reaction use of the complex is advantageous in that the selection time also to some extent is a dependent factor on Teaction of reaction conditions becomes easier. For instance, in temperature and specific types of the starting materials. the practice of passing carbon dioxide gas through a sus For instance, if a difficulty water-soluble substance is used pension containing aluminum hydroxide and magnesium as at least one of the starting materials, it is preferable to oxide or hydroxide, it is preferred to cause the absorption effect heating to a temperature above 40 C., and above of carbon dioxide gas at low temperatures and thereafter 50° C. to accelerate the reaction rate. The reaction time heating the system to 70° C. or above, in consideration is shorter as a higher heating temperature is used, but if of the fact that a part of aluminum hydroxide loses re starting materials having a good reactivity are chosen, hy 75 activity upon heating. When the carbon dioxide gas above 3,539,306 5 6 50° C., such care is desirable to employ an aluminum hy Thus, it should pe apparent that the hydrotalcite of this droxide which is particularly stable under high temper invention can provide an antacid which is excellent in its atures, or to shorten the duration of high temperature prompt but lasting neutralising action, and is never im treatment. In contrast thereto, when aluminum hydrox paired by a long time storage and that it can exhibit said ide-alkali carbonate complex or aluminum aminoacid excellent neutralising action as well as its acid consum salt are used, the reaction is performed with ease by pass 5 ing capacity even after it has been boiled, while the con ing carbon dioxide gas through a suspension containing ventional antacid such as magnesium carbonate aluminum the complex and magnesium hydroxide or oxide with hydroxide codried gel, loses almost its capacity after one heating at the temperatures ranging from 50° C. to that hour's boiling. Of course the antacid of the invention below the boiling point. O may suitably contain, besides the hydrotalcite, aluminum Besides the afore-described embodiments, it should be hydroxide, magnesium carbonate, , obvious to the experts that, as either of the aluminum or magnesium hydroxide, aluminum hydroxide-alkali car magnesium components, an aqueous solution of the water bonate complex, silicate and the like. Such antacid com soluble salt may be used. In any of the embodiments, prising hydrotalicite and the foregoing substances can be however, it is essential that the reaction among the alu 15 prepared by mixing the latter with hydrotalcite or minum component, magnesium component and carbon di coprecipitating hydrotalcite with the substance or sub oxide is performed in water at the pH of basic side. stances by reacting the starting materials for the hydro The so obtained hydrotalcite has a structure repre talcite in the presence of a suitable amount of the fore sented by the general formula below. going substances or of the starting materials for such 20 Substances. Al2O3: 6MgO, CO. 12H2O Furthermore, the hydrotalicite of the insibility when The characteristic values of the hydrotalcite of the in made into tablet, and the compressed hydrotalcite has vention and those of natural (ASTM card excellent hardness and compression strength. For these No. 14-191) as obtained from the results of X-ray diffrac reasons it is highly useful as an excipient for tablet in the tion analysis are given in Table 1 below, in which d means pharmaceutical field and in other chemical industries. the spacing of the . The relation between the hardness and compression TABLE 1. pressure in hydrotalcite of the present invention and Hydrotalcite according Product of the invention, known is shown in Table 3 below. to ASTM card, d. A.: d. A. 30 7.69 ------7.75 3.88 ------3.89 TABLE 3.-COMPRESSION PRESSURE-HARDNESS Compression Hardness (kg.fcm.2) 2.58 ------2.59 pressure 2.30 ------2.30 (kg.fcm.?) Hydrotalcite Aluminum Crystalline Microcrystal 1.96 ------1.96 hydroxide lactose line cellulose 1.53 ------1.53 dried gel 818------14.2------2.4------0 12.3. 1.50 ------1.50 636------Over 25----- 6.0---- 0 19.8. 955--- 0.9 Over 25. In spite of its high magnesium content, the hydrotalcite 1,274- 1, 8 Over 25. obtained in the invention gives a pH of 9.0-8.4 when 1 1,911- 2.8 Over 25. g. thereof is suspended in 50 ml. of water, and that of 40 2,548. 5.8 Over 25. 5-6 when 2 g. thereof is thrown into 100 ml. of N/10 hydrochloric acid. Also when 1. g. thereof is thrown into 150 ml. of artificial gastric juice (0.068 N hydrochloric It is clear from the above table that the hydrotalcite of acid) and stirred for 10 minutes, thereafter the artificial the present invention can give tablets sufficient hardness gastric juice is added to the system continuously at the at a lower pressure than the known excipients. rate of 2 ml./min., the pH of the system reaches 3.0 with The invention will now be described with reference to in 10–30 seconds. The maximum pH is about 4.1, and the the following Examples. duration of pH above 3.0 is about 2.5 hours. These data substantiate the appropriety of the product of the inven EXAMPLE 1. tion as an antacid. Again the above effects were not changed when pepsin was added to the artificial gastric 6.86 liters of an aqueous suspension containing alumi juice, or the hydrotalcite was heated for 3 hours in boil num hydroxide in the amount corresponding to 102 g. ing water. The results of testing the acid consuming capac of alumina, 350 g. of magnesium hydroxide and 420 g. ity of the hydrotalcite of the invention and of known of was heated to 85 C. with agita antacid in the artificial gastric juice in accordance with 55 tion, and maintained at the said temperature for 3 hours. the above method are given in Table 2 below. Thereafter the system was filtered to separate the mother TABLE 2 liquor, and the solid was washed with 21 liters of water Acid Maxi and dried at 70° C. to provide 650 g. of the product. The consuming l reaction formula, and the analysis value (MgO:Al2O3:CO2 capacity (Sec.) pH (min.)2 60 in terms of mol ratio) and the acid consuming capacity Hydrotalcite------278 12 4.15 139 of the product were as follows: Hydrotalcite (boiled for one hour)------28 3 4.10 138 Aluminum hydroxide dried gel------296 300 3.8 19 Calcium carbonate-- 195 9 5.8 78 Magnesium carbonat - 207 10 7.6 87 Sodiumdihydroxyaluminu bicarbonate--- In 119 3 6.2 23 aminoacetate------175 60 3.8 53 Magnesium carbonate aluminum hydroxide Molar ratio co-dried gel------286 36 3.8 120 Measured value Calculated value

Magnesium carbonate aluminum hydroxide 6.05 6.00 co-dried gel (boiled for 1.00 .00 one hour)------210 1,580 ------1.42 1.00 Magnesium trisilicate...----- 04 480 3.7 2 Acid consuming capacity, ml. 279 ------1 Time required for the gastric juice to reach a pH of 3.0 NOTE. The acid consuming capacity is expressed by number of ml. of 2 Time required for the gastric juice to reach a pH below 3.0. 5 0.1N hydrochloric acid required to neutralize 1.g. of the product. 3,539,306 7 8 EXAMPLE 2. liters, in an amount of 16.7 ml/min. and 25 ml. Wmin. To an aqueous suspension of aluminum hydroxide respectively. The pH of the reacted suspension was 10.4. complex containing 5 g. of aluminum After three hours' pouring at room temperature, the component as alumina (0.5 mol) and 75.5 g. of carbonate reacted suspension was collected, washed with 6 liters of ion source as sodium bicarbonate (0.9 mol), 122 g. (3 water, and dried at a temperature not higher than 150° C. mols) of magnesium oxide was added to make the total to give 210g, of a final product. of 3.5 liters of the suspension. The same was heated to The analytical values and acid consuming capacity are 85 C. with agitation for 2 hours and filtered. The solid as follows: was washed with water and dried to provide 330 g. of Molar ratio O MgO ------5.98 the product. The reaction formula and the analysis valve Al2O3 ------OO and acid consuming capacity of the product were as CO2 ------1.43 follows: Acid consuming capacity, 258 ml. Al(OH)-NaHCO3--6MgO--8HO EXAMPLE 6 se- MgAl(OH)16CO3 E 4HO--Na2CO 5 Basic aluminum carbonate containing 34 g. of AO Molar ratio and basic magnesium carbonate containing 13.4 g. of MgO ------6.00 MgO, and magnesium hydroxide containing 67.2 g of Al2O3 ------1.00 MgO were suspended into water to make 2 liters of a CO2 ------1.6 20 Suspension. The suspension was heated to 85 C. Im Acid consuming capacity, 269 ml. mediately, the reacted suspension was dehydrated and EXAMPLE 3 dried to give 213 g. of a final product. The analytical values and acid consuming capacity are Aluminum sulfate in the amount corresponding to 17 25 as follows: g. of alumina was used to make 1 liter of a solution, and Molar ratio 106 g. of sodium carbonate was also made into 1 liter MgO ------5.85 of a solution, which were then poured into a suspension Al2O3 ------OO formed of 60 g. of magnesium hydroxide suspended in Co2 ------1.05 0.4 liter of water at a constant flow rate with agitation. Acid consuming capacity, 275 ml. Thereafter the suspension was washed with water until 30 presence of sulfate radical became no more observable, EXAMPLE 7 and again suspended in water. After 3 hours of heating at 85 C., the system was dehydrated and dried to pro One hundred grams of dihydroxyaluminum aminoace vide 110 g. of the product. The reaction formula, and tate containing 35.0% of Al2O3 and 100 g. of magnesium the analysis value and acid consuming capacity of the 35 hydroxide containing 83 g. of MgO were suspended into product were as follows: Water to make 1.5 liters of suspension. It was put into an autoclave and heated while stirring. After having been maintained at a temperature of 120° C. for 20 minutes, 40 the suspension was washed with water, dehydrated, and dried to give 212 g. of a final product. Molar ratio The analytical values and acid consuming capacity are MgO ------6.00 as follows: Alsos ------OO Molar ratio CO2 ------1.7 MgO ------5.90 Acid consuming capacity, 272 ml. Alaos ------OO CO2 ------1.33 EXAMPLE 4 N ------percent.-- 0.0 To aluminum hydroxide in the amount corresponding Acid consuming capacity, 286 ml. to 25.5 g. of alumina, an aqueous solution containing 120 50 g. of caustic soda was added to make a total of 1 liter What is claimed is: of a solution with agitation. The same was mixed under 1. A process for the preparation of hydrotalcite con agitation with 3 liters of magnesium chloride solution sisting essentially of a product of the formula: of which solid content corresponding to 60.5 g. of mag nesia and whereby reacted while carbon dioxide gas was Al2O3.6MgO.CO2.12HO introduced into the system. After the reaction the precip which comprises mixing (A) an aluminum component itate was filtered, washed with water and dried to pro Selected from aluminum hydroxide, aluminum amino acid vide 160 g. of the product. The analysis value and the Salts, aluminum alcoholate, water-soluble aluminates, acid consuming capacity of the product were as follows: aluminum nitrate, and aluminum sulphate, (B) a magne 60 sium component selected from magnesium oxide, magne Molar ratio sium hydroxide, and water-soluble magnesium salts, and MgO ------5.85 (C) an alkali carbonate or an alkali bicarbonate, in an Alsos ------a sm and a or a 'as fact was era was 1.00 aqueous medium at a temperature of from 0 to 150° C. CO2 ------1.04 at a pH of at least 8, in a ratio in terms of AIO:MgO Acid consuming capacity, 280 ml. of substantially 1:6 and recovering the precipitated EXAMPLE5 product. 2. The process of claim 1, wherein the carbonate ion Aluminum Sulphate and magnesium chloride were dis is present in a ratio of at least 1:9 to each aluminum atom. solved into water to make a solution containing 10.2 g. 3. The process of claim , wherein the pH of the of AlaO3 and 24.2 g of MgO per liter. Separately, a aqueous medium is at least 9 at the completion of the solution containing 40 g. of caustic soda and 35 g. of reaction. sodium carbonate per liter was prepared. The former 4. A process for the preparation of hydrotalcite con solution and the latter solution were continuously poured, sisting essentially of a product of the formula: while stirring, into a reaction vessel which was adapted to overflow with the amount of liquid maintained at 1.2 AlO3.6MgO.CO2. 1 2HO 3,539,306 10 which comprises mixing an aluminum component selected References Cited from basic aluminum carbonate and aluminum hydroxide alkali metal carbonate complexes, with a magnesium UNITED STATES PATENTS component selected from magnesium oxide, magnesium 2,958,626 11/1960 Schenck et al. ------23-315 hydroxide, neutral and basic magnesium and water-soluble magnesium salts, in an aqueous medium 5 OSCAR R. VERTIZ, Primary Examiner at a temperature of from 0 to 150° C. at a pH of at least H. S. MILLER, Assistant Examiner 8, in a ratio in terms of Al2O3:MgO of substantially 1:6 and in terms of carbonate ion: aluminum of at least 1:9, U.S. C.X.R. and recovering the precipitated product. 424-154