3,099,524 United States Patent 0 Patented July 30, 1963

1 2 aluminium and with a mixture of sodium 3,099,524 hydroxide and sodium canbonate in appropriate amounts. ANTAClD CGMPOSITIONS The aluminium and magnesium salts are preferably the Frederick Grossmith, Pinner, England, assignor to chlorides. Beecham Research Laboratories Limited, Breutford, A further method for preparing the compounds of the Middlesex, England present invention is to suspend a magnesium hydroxo Filed June 28, 1960, Ser. No. 39,245 Claims priority, application Great Britain July 2, 1959 aluminate of the type disclosed in by said co?pending 6 Claims. (Cl. 23—l4) application Serial No. 842,042, ?led September 24, 1959, in a liquor containing ions. A suitable This invention relates to improvements in antacid 10 liquor is a dilute solution of magnesium bicarbonate. compositions and is particularly concerned with new A still further method for preparing the magnesium chemical compounds which have been found to have bicarbonate hydroxoaluminates, which method minimises desirable antacid properties being eminently suitable for the formation of a basic impurity, medicinal use for the treatment of gastric hyperacidity. is to react a solution containing aluminium and mag In my co-pending application Serial No. 842,042, ?led 15 nesium salts in appropriate amounts with sodium hy September 24, 1959, now abandoned, I have disclosed droxide at a suitable rate of delivery. An addition of certain novel compounds which are formed by reacting ‘ is made at an appropriate stage and aluminium and magnesium salts with caustic allcalis, in a ?nal addition of mixed sodium hydroxide and sodium which the magnesium content, expressed as Mg(OI-I)2, bicarbonate is made to precipitate all the magnesium lies between the approximate limits 2.5% to 75% by 20 without allowing the pH to rise too high. weight of the substantially dry product and in which Yet a further method of preparing the magnesium bi the aluminium content, expressed as Al(OI-I)3, lies be carbonate hydroxoaluminates is to react a solution con tween the approximate limits 75% to 25%. These com taining aluminium and magnesium salts in appropriate pounds, which we have termed magnesium hydroxo amounts with a solution of sodium carbonate. The car aluminates, have exceptionally desirable properties as 25 Ibon dioxide evolved from the reaction of sodium car antacids. bonate with the aluminium salt gives rise to bicarbonate We have now found that in magnesium hydroxoalumi ions and prevents the pH from rising high enough for nates the complex hydroxoaluminate ion is readily pene the direct precipitation of basic magnesium carbonate. trated by bicarbonate ions which replace the hydroxo A proportion of the double compound groups and that novel compounds are formed having a 30 constant ratio of two atoms of aluminium to one bicar NaMgH(CO3) 2.4H2O bonate ion. Accordingly, the present invention provides new com pounds Which are magnesium carbonate hydroxoalumi may be formed. As with the magnesium hydroxoalumin 35 ates, an inclusion of ammonium chloride limits the pre nates having the general formula cipitation of magnesium carbonate and thereby restricts double compound formation. A suitable a?ter treatment, for example, boiling the slurry, breaks down the residual double compound and completes the reaction to form 40 magnesium carbonato hydroxoaluminates. where n is an integer from 1 to 5. Yet another method of preparing the magnesium car The complete series of novel compounds is as follows: bonato hydroxoaluminates is to react a slurry prepared from basic magnesium carbonate, preferably Light Mag nesium Carbonate B.P., and a solution of sodium car bonate with a solution of aluminium chloride. The re Molec action may be initiated in the cold and aiiter diluting to ular Mg A1 Mg(OH)2 Al(OH)a 002 a suspension containing approximately 5% solids w./v. Weight by boling for a period. The following examples illustrate the invention: Mg[A.lz(OH)7.HCO3]._ 258.35 9.42 20.58 22.58 60.38 17.04 Mg2lAl2(OH)a.HCOa]._ 316.69 15.36 17.04 36.84 49.26 13.90 50 Mg3[Al2(OH)11.HCOa]. 375.03 19.46 14.39 46.67 41.59 11.74 Mg4[Al2(OH)1a.HCO3L 433.36 22.45 12.46 53.83 36.01 10.16 Example 1 MEslAlAOHhs-ECOaL 491.70 24.72 10.98 59.29 31.76 8.95 A solution of sodium aluminate, Na3[Al(OH)6] was 55 prepared from 48.27 g. of AlCl3.6H2O and 64.00‘ g. of The lower members of the series of the new com NaOH by adding slowly a solution of the aluminium pounds may be prepared by reacting a cold solution of chloride in 500 mls. of water to a solution of the so magnesium bicarbonate or a cold solution of a mag dium hydroxide in 500 mls. of water at room temperature. nesium salt and sodium bicarbonate, with a cold solu The clear solution produced was added to 1,760 mls. tion of an alkali aluminate, e.g. sodium aluminate. The 60 of a 2.5% solution of magnesium bicarbonate contain higher members of the series cannot be prepared by this ing free and in which the pH was ad method as the magnesium is partially precipitated as basic justed to 9 by the addition of sodium hydroxide. At this carbonate. point of addition of sodium hydroxide the solution was Alternatively, the compounds may be prepared by re just beginning to appear opIalescent. The addition of acting a solution of the appropriate amount of salts of 65 sodium al-uminate solution to magnesium bicarbonate solu 3,099,524 a . 4 tion was made at room temperature with constant stirring. added to a 5 litre beaker. The sodium hydroxide solu Finally, the precipitate was washed on a basket type tion was transferred to a dropping funnel and this solu centrifuge and was dried at 52° C. tion was introduced dropwise into the mixed chloride solution, which was agitated using a twin blade propeller Example 2 type stirrer, the mixing being carried out at room tem perature. During the addition of the sodium hydroxide The following solutions were prepared: a periodic check of pH was made and when the pH was approximately 7.0 the sodium bicarbonate solution added MgCl2.6H2O, 61 g. ______. In water to give 500 to the mixture. A1Cl3.6H2O, 24.15 g. ______.__ { mls. of solution. 10 At the completion of the addition of the sodium hy NaOH, 32 g. ______- In water to give 500 droxide (after approximately 1 hour), 500 mls. of the Na2CO3, 10.6 g. ______{ mls. of solution. sodium sesquicarbonate solution were added, when it was found that magnesium ion in the supernatant liquor The solutions were heated to 70° C. and then mixed was reduced to 100 ppm. The precipitate was then by pouring simultaneously into a 2 litre beaker. While washed with distilled water on a basket type centrifuge continuing to stir with a twin blade propeller type stir and was dried at 52° C. rer the slurrry was heated to 90° C. and incubated at this temperature for 20 minutes. The material was then Example 6 washed on a basket type centrifuge and dried at 52° C. 20 This material contained as impurity magnesium hydrate The following solutions were prepared: and/or basic magnesium carbonate which impurity was removed by digestion with a solution of ammonium chlo ride to give magnesium carbonato hydroxoaluminate. MgCl2.6HzO, 51.25 g ______. In distilled water to Formula I 11:5 (2a). give 150 mls. of solution. Example 3 AlCl3.6H2O, 21.38 g. ______- Do. NaOH, 26.96 g. ______. In distilled water to The ‘following solutions were prepared: give 200 mls. of solution. MgCl2Q6H2O, 68.37 g. ______[In water to give 500 NaHCO3, 141.4 g ______In distilled water to AlCl3.6H'2O, 59.73 g. ______}_ mls. of solution. give 2 litres of so NaOI-I, 113.98 g ______. lIIl water to give 500 lution. mls. of solution. 35 The solution of aluminium chloride was added slowly The solutions were heated to 90° C. then mixed by to the solution of sodium hydroxide, with vigorous stir adding the NaOH solution to the mixed chloride solution, ring. The sodium aluminate solution so prepared was over a period of 2 minutes. The mixture was incubated added to the mixed magnesium chloride solution and at 90° C. for 10 minutes. sodium bicarbonate solution, the mixing being carried The precipitate was Washed by decantation in a 5 40 out at room temperature, with constant stirring employ litre beaker, using as wash liquor 50 litres of approxi ing a twin blade propeller type stirrer. The precipitate mately 0.04% w./v. solution of magnesium bicarbonate was washed, employing a basket type centrifuge and was in distilled water. It was then ?ltered and washed on then dried at 52° C. the ?lter with distilled water, ?nally being dried at 52° C. A portion of approximately 6 g. of the precipitate was 45 suspended in 300 mls. of an approximately 2 volume Example 4 solution of carbon dioxide in water for 8 hours. After suspension in the carbonated water, the precipitate was The same quantities of reactants as those shown in Ex again washed and dried at 52° C. The molar ratio ample 3 were employed and the procedure followed was Mg:Al of the precipitate before suspending in carbonated similar, except that washing by decantation wasrcarried water was 1.7:1 and a pH peak of 7.4 was ‘found on the out using mains water containing 268 mg. per litre of activity test of Gore, Martin and Taylor, J. Pharm. and carbonate hardness. Again, the precipitate was dried at 52° C. Pharmacol, 5, 686-691, 1953. After suspension the molar ratio MgzAl was 1.01:1, and the pH peak on the Example 5 55 activity test was 5.2.

The following solutions were prepared: Example 7

MgCl2.6H2O, 31.35 g. ______The ‘following solutions were prepared: in distilled water to 60 give 1 litre of so lution. MgOl2;6I-I2O, 68.1 g_____ In distilled water to give 1 litre AlCl3.6H2O, 74.4 g. ______Do. of solution. NaOH, 43.2 g. ______In distilled water to ____ ._.. DO. give 11/2 litres of 65 solution. NaOH, 40.2 g ______. In distilled water to give 11/2 NaHCO3, 12.9 g ______. \In distilled water to litres of solution. give 250 mls. of NaHCO3, 14.08 g ______. In distilled Water to give 250 solution. mls. of solution. Sodium‘sesquicarbonate solution—prepared as in Exam A solution of sodium sesquicarbonate was prepared to 70 ple 5. contain 190 ‘g. in distilled water to give 11/2 litres of solution. The procedure followed was identical with that 'de scribed in Example 5, but 1,200‘ mls. of sodium‘ sesqui The aluminium and magnesium chloride solutions were carbonate was employed. 3,099,524. 5 6 Example 8 mixed and the mixed solutions and the sodium carbonate solution both heated to 95° C. were then reacted with The following solutions were prepared: stirring and the slurry centrifuged o?. The centrifuge MgCl2.6H2O, 94.2 ‘g_____ In distilled water to give 1 litre cake was then made up to 11/2 % slurry ‘dilution with tap of solution. water, and allowed to stand overnight, the supernatant AlCl3.6H2O, 31.75 g_____ Do. solution being siphoned off. Further tap water was then NaOH, 500g ______In distilled water to give 11/2 added to produce 11/z% slurry concentration and this litres of solution. was boiled for 30 minutes, then cooled to 80° C., cen NaHCO3, 5.53 g ______In distilled water to ‘give 100 trifuged and the ?lter cake dried at 50—55° C. mls. of solution. 10 A sample of the material was withdrawn prior to the Sodium sesquicarbonate solution—prepared as in Exam boiling procedure, and this example was examined sepa ple 5. rately, being referred to ‘as “pre-boil material.” The procedure followed was identical with that de Example 11 scribed in Example 5, but 1,700 mls. of sodium sesqui The ‘following solutions were prepared: carbonate solution‘ were employed. At this stage, the 15 supernatant solution contained not more than 250 ppm. MgCl2, 5,930 g ______. As 13.76 litres of 43.10% w./v. of magnesium ion. solution. Example 9 AlCl3, 3,330g ______As 9.45 litres of 35.26% w./v. solution. The following solutions were prepared: 20 Na2CO3, 11,140 g ______As 48.90 litres of 23.2% w./v. MgOl2.6H2O, 61.0 g_____ In distilled water to give 11/2 solution. litres of solution. Nl-I4Cl, 542 g ______. Dissolved in 2 litres of water. AlCl3.6H2O, 24.15 lg_____ Do. H01, 505 mls. of 36% w./v. solution diluted to 21/2 litres. NaOH, 36.0 g ______Do. 25 The magnesium, aluminum and ammonium chlorides The sodium hydroxide solution was added to the mixed were mixed and heated to 80° C. and then reacted with chloride solution as :a drip feed. About 1 hour was taken the sodium carbonate solution to 80° C. The reaction to complete the addition and throughout the mixing mixture was stirred for 5 minutes and then cold water period the suspension was stirred with a propeller type added to produce a 11/2% slurry concentration. The stirrer. At the end of the ‘addition a further 15 minutes 30 slurry Was heated to 100° C. and the hydrochloric acid stirring was ‘given and the precipitate was washed with solution added over a period of 30 minutes, the boiling distilled ‘water on a basket type centrifuge. The precipi continuing for a further 30 minutes. The precipitate tate was then ‘dried at 52° C. was Washed by decantation, centrifuged off and dried at The precipitate was suspended in a 5% solution of 50—55° C. 35 sodium bicarbonate in distilled water at the rate of 100 Example 12 mls. of solution for each 4 g. of precipitate. The suspen sion was allowed to stand overnight and was then ?ltered The following reactants were taken: and washed. This precipitate contained magnesium hy Light magnesium carbonate B.P., 58 kgms. drate and/or basic magnesium carbonate as impurity. 40 Na2CO3, 40.5 kgms ______153 litres of 26% w./v. solu The precipitate was digested with ya 2 M solution of tion. ammonium chloride for 4 hours, the precipitate again A1013, 34.4 kgms ______102 litres of 33.8% w./v. solu being washed and ‘dried at 52° C. After digestion with tion. the ammonium chloride the material 9(a) corresponded to the Mg, carbonate hydroxoalumin-ate. The magnesium carbonate and the solution of sodium carbonate were mixed with additional water to form a Example 10 slurry and the aluminum chloride solution was added Thegfollowing solutions were prepared: slowly over a period of half an hour with stirring. The slurry was diluted with main water to give approximately MgCl2, 5,940-g ______. As 13.4 litres of 45.2% w./v. 1268 litres of mixture and was then boiled for three hours. solution. 50 The slurry was then washed and concentrated on a hydro A1013, 3,330 g ______As 9.52 litres of 35.0% w./v. extractor, ?ltered and dried at a temperature of 100° C. solution. Magnesium and aluminum losses in the e?luents during Na2CO3, 15,850 g ______As 72.0 litres of 22.0% solu processing were negligible. tion‘. Some of the properties of the precipitates are shown The magnesium. and aluminium. . chloride. solutions. were 55 In- the followlng- tables._ Examples Properties 1 2 2(a) 3 4

Appearance of dried material. ___ Off white White O? white Apparent density, g./cc ______0. 94 . 0. 45 0. 4 Moisture over P105, percent . 10. 5 . 4. 55 1. 40 pH of slurry ______9. 5 . 8. 8 8.0 Antacid activity (dry bas mls. N. H01 ______. 24. 8 29. 7 ______29. 6 28.0 Highest pH on activity curve__._ 5. 6 7. 2 4. 8 5.1 5. 3 Percent: Aluminum as A1203" 17.95 ' 16. 40 Magnesium as MgO . _ _ _ _ ._ 36. 36 32. 80 Loss on ignition _ . . _ _ . _ _ . ._ 45. 80 43. 40 100.11 2 99. 87 Carbon dioxide, percent ______8.75 14.00 Sodium content, percent ______._ 3 100 3 560

1 Method of Gore, Martin and Taylor. 2 Including 7.27% calcium as (3:10. 3 P.p.m. 3,099,524

Exampies Properties 5 6 7 8 9 9(2),)

Appearance of dried materia1____ White White White White White White Apparent density, g/cc ______0.95 0 92 0 80 0.95 . 1 ______Moisture over P205, percent..- _ 11. 4 14. 6 8.0 8.8 5. 5 ______pH of slurry ______9. 4 8.0 7 9 7. 3 5 6.8 Antacid activity (dry basis),1 mls. N.H 1 ______24.0 32. 8 23 4 27.2 28 0 ______Highest pH on activity curve--- 4. 8 5. 2 4 9 5. 9 6 6 4. 8 Percent: Aluminum as A1203_-_ Magnesium as MgO_ Loss on ignition ______-I 91.49. 069o 92.6349: 70 98.48. e011 10253. 5940 101.47: 2100 ______._

Carbon dioxide, percent ______15. 1 12.08 8. 4 7. 91 7. 7 5. 7 Sodium content, percent ______3 300 3 170 0.12 ______._

Examples Properties 10 10 11 12 (pre-boil) (after-boil)

Appearance of dried material ______._ White White White Apparent density, g./cc ______0.32 O. 42 0.55 Moisture over P205, percent_____ 8.0 2. 8 6.3 pH of slurry ______9. 1 8. 8 8. O Antacid activity (dry basis), mls . H01 ______26.0 29.0 28. 8 Highest pH on activity curve ______8. 3 4. 8 4. 85 Percent: Aluminium as A1203 ______18.14 17. 95 16.97 Magnesium as MgO 33. 16 33. 33 33. 18 Loss on ignition ______50. 5 44. 7 45 8 101.80 95. 98 95. 95 Carbon dioxide, percent ______12.7 8. 8 6.95 Sodium content, percent ______1. 33 0. 35 ______

The ‘activity \curve is shown in the accompanying drawing. The material of Examples 1 to 11 correspond to the Example 6 f°11°Wmg c0111110511911“ Mg2[A12(OH)9.1-ICO3].2H2O ______85.4 Example 1: Water ______14.6 Percent — Mg[A12(.OH)n.HCO‘3].2H2O ______89.5 45 100.0 Water ______‘10.5 2 _ Example 7 100.0 _.._ M.g4[Al2(OH)13.HCO3]31-120 ______92-0 Example 2 50 Water ———————————————————————————————————— -- 3-0

Mg,(OH)2.Mg5[A12(OH)15.HCO3].4H2O ______92.5 100.0' ' Water ______7.5 __ 100.0 55 Example 8

Example 3 : Water ______._ 8.8

Mg[A12'(OH)15;HCO3].H2O ______95.45 —-— Water ______4.55 100-0 60 100.00 Example 9

Example 4 Mg(OH)2.Mg5[A12(OH)15.HCO3.].3H2O ______94.5 Mg5[A12(OH)15.HCO3].2H2O ______85.62 Water ------5-5 CaCO3 ______12.98 65 —— Water ______1.40‘ 100-0 100'00 Example 10.—Pre-B0il Material

_ 70 MgNaH(CO s ) 2 .2H 2 0 ______12 Emmplg 5 Mg5[A12(OH)15.HCO‘3] ______24 Mg[Al2(OH)q.-HCO‘3].2H2O ______88.6 M-gi[A12(OH)13.HCO3] ______56 Water ______11.4 Water ______._ 8

100.0 75 100