HIGH-DENSITY ANTACID POWDERS

Abstract: High-density antacid powders are produced by precipitating magnesium and aluminum compounds simultaneously with an alkali metal hydroxide or amonium hydroxyde at a pH not exceeding 8.5, and making the precipitate into a powder.

Description: HIGH-DENSITY ANTACID POWDERS This invention relates to improved antacid compositions. More particularly, this invention relates to high-density antacid powders capable of being com- pounded into standard dosage forms, such as tablets and capsules, having increased amounts of active antacid per dose. Antacid compositions are designed for relieving hyperacidity and associated conditions caused by excess acid in the stomach. Such an antacid composition, inter alia, should neutralize an adequate amount of gastric hydrochloric acid and maintain its action during the period of gastric digestion; adequate and repeated doses should be palatable to the hyperacid patient; it should not have side effects such as gastric irritation; and it should maintain its antacid properties upon ageing so that the proper amount of active agent is ingested on extended use. Antacid compositions have been prepared in a variety of forms such as solutions, suspensions, emulsions, powders, capsules and tablets. The composition in each case includes an active antacid substance such as aluminum hydroxide-magnesium carbonate co-dried gel, dihydroxyaluminum sodium carbonate, magnesium trisilicate, aluminum hydroxide, aluminum basic carbonates, magnesium hydroxide and the like. The beneficial response of conditions and diseases treated with antacid compositions is in direct propor¬ tion to the amount of antacid ingested and its duration of action with the stomach. The tablet or capsule form of antacid compo¬ sition is more convenient than antacid liquid compositions to the patient. These may be carried in a small package and may be taken as needed without any need for extra equipment, such as a spoon, for the measuring of dosages. The convenience of these solid forms of the antacid makes them a popular kind of antacid composition. However, the solid antacid products of the prior art contain relatively small amounts of 10 active antacid inqredients per tablet or capsule. And since the size of the capsules or tablets may not be increased substantially without rendering them too large for human consumption, it is necessary to repeat doses and increase frequency of ingestion - * - • --' to achieve the desirable therapeutic results. However, a higher density antacid powder would allow a smaller capsule or tablet size. Another advantage for the use of high-density antacid powders is that they are more flowable and 20 directly compressible than lower density powders. Because of this property, the powders can be more easily processed into capsules and tablets, and they can be processed using a direct compression method. This is a less expensive method than the wet granulation method, typically used to process lower density powders. Accordingly, it is the object of the present invention to provide solid antacid compositions having high bulk or apparent densities. 30 35 1 It is another object of the present invention to provide a method for the preparation of antacid powders having high bulk or apparent densities. These and other objects of the present invention - 5 will be apparent from the description that follows. Broadly speaking, the highrdensity antacid powders of the present invention are produced by: preparing aqueous solutions of aluminum and magnesium compounds; precipitating the magnesium and aluminum 10 compounds simultaneously in a reactor with an alkali metal hydroxide or ammonium hydroxide at a pH not exceeding 8.5; optionally adjusting the pH to 9-10 with a basic solution in the post-precipitation stage; optionally adding an alkali or ammonium salt in the 15 post-precipitation stage; and making the precipitate into a powder. Various combinations of metal hydroxides are known in the prior art and are used for various purposes, among others, as therapeutic agents for treating 20 stomach hyperacidity. These and other types of antacid compounds can be produced in the form of powders which in turn can be formed into tablets and capusles of proper dosage. The antacid powders so produced normally have an apparent density in the range of 25 about 0.1 to 0.4 g/cc. Applicants have discovered a process by which antacid powders having an apparent density greater than 0.5 g/cc may be produced. The use of such high density powders advantageously provides for the delivery of higher 30 levels of active antacids in standard size tablets or capsules. 5 The powders so produced normally have a compo¬ sition in the range of: MgO = 25-40% w/w, A1 2 0 3 ** ■ * ■ 15-25% w/w, and A 6-20% w/w, where A represents an anionic species or a mixture of anionic species. In the practice of the present invention any water-soluble aluminum compounds may be used, such as an aluminum halide, alkali metal aluminate, aluminum nitrate, aluminum sulfate and the like. Similarly, any water-soluble magnesium compound can be used, such as a magnesium halide, magnesium nitrate, magnesium sulfate and the like. In another embodiment of the present invention, it is contemplated to include water- soluble calcium compounds to produce an antacid powder wherein all or part of the magnesium is replaced by calcium. The anionic species represented by A include 0H~, Cl~, HCO ~ , CO- j 1 -*, HS0 4 ~, SO^, HP0 4 ~, H20P4- and P0 4 =. In carrying out the process of the present invention, aqueous solutions of the reactants are mixed to precipitate the desired antacid complex, and the precipitate is formed into a powder as follows: Aqeuous solutions of an aluminum compound, a magnesium compound and sodium hydroxide are simul¬ taneously metered into a reactor at a rate to maintain ό the pH below 8.5 to precipitate the magnesium- aluminum antacid. For convenience, the aluminum and magnesium compound solutions can be mixed before metering into the reactor. The maintenance of the pH below 8.5 is critical in the precipitation process in order, to obtain the high-density antacid powder.. Normally, the reactants are added at a rate to maintain the pH between 7.5 and 8.5. This pH range was found optimal for obtaining antacid 10 powders having a density in the range of 0.5 to 1.1 g/cc. Above the pH of 8.5 powder densities decrease, while below 7.5 the washing time of the precipitate becomes excessive. A post-precipitation step to prevent the ■ "-5 loss of soluble magnesium may be included in the process. This post-precipitation step is carried out with the addition of a base, normally a sodium, potassium, or ammonium hydroxide solution, to raise the pH to 9-10, without any detriment to the powder 20 density. A solution of a salt such as Na~C0 , 2 3 NaHCO-, Na 2 S0 4 , NaHS0 4 , aH 2 P0 4 , Na 2 HP0 4 , Na 3 P0 4 and the like can be added with mixing to the magnesium-aluminum precipitate to substitute the anion carried by the precipitate with an anion from 5 the added salt. For example, if the starting magnesium or aluminum compounds are chlorides, bromides or fluorides, the chloride, bromide or fluoride ions will be substituted with anions such as carbonate, sulfate or phosphate. 0 δ The precipitate obtained, with or without the inclusion of the post-precipitation steps, is washed and formed into a cake having a thick gel-like consistency. The cake is then repulped and dried at a temperature not exceeding about 150°C. Drying is accomplished using methods and equipment used in the art of processing materials into a powder, such as oven drying, freeze drying or spray drying. Another important aspect to the process of the present invention is the use of an alkali metal hydroxide or ammonium hydroxide as the base in the constant-pH precipitation process, instead of sodium carbonate or sodium bicarbonate, although small amounts of carbonates or bicarbonates can be tolerated. It has been found that precipitation with an alkali metal hydroxide or ammonium hydroxide produces the desired high-density antacid powders, while precipitation with alkali carbonates or bicarbonates results in the production of antacid powders having densities less than 0.5g/cc. This and other aspects of the present invention will be further illustrated by the examples that follow. EXAMPLE 1 3000 Grams of 24° Baume A1C1., were mixed with 3630grams of a 50% MgCl 2 .6H 2 0 solution. 4.500 liters of water were added to a 20-liter reactor, and an overhead mixer was set up and turned on to ensure proper mixing. The mixed chloride solution and 6.300 liters of a 14.7% NaOH solution were simultaneously metered into the 20-liter reactor. The rates were adjusted to hold a constant pH of 8.0 with a total precipitation time of 46 minutes. The precipitation slurry was divided into parts A, B, C and D. Part A had no post-precipitation addition; parts B and C had additions of NaOH solution to raise the pH to 9.0 and 10.0, respectively. Part D had an addition of 0.5 liter of 16° Baume Na^CO^ solution with an end pH of 9.5. The slurries in each part were then washed, repulped and spray dried at an outlet temperature of 125°C. to a powder. The results obtained are shown in Table I. TABLE I Properties Formulas B C D % w/w A1 0 3 23.4 22.6 21.7 20.9 % w/w MgO 30.9 32.6 32.5 31.6 % w/w Na 0.13 0.13 0.24 0.20 % w/w Cl 8.58 8.85 9.30 1.44 % w/w C0 2 1.47 1.93 1.33 6.57 Apparent Density, 3/ 1.0 1.0 1.0 0.68 pH Stat* at 37°C, T 5() -min 2.8 2.8 2.3 3.2 T g0 - in 10.3 12.3 11.3 5.3 ACC**, ml 0.1N HCL/g 251 261 257 275 ACCD***, ml 0.1N HCl/cc 251 261 257 187 The pH stat* test here and hereinbelow is a measure of antacid rate of reactivity and total neutrali¬ zation capacity. ACC** means acid-consuming capacity as determined by the pH-stat titration. ACCD*** is the ACC multiplied by the apparent density. The pH-stat titration is performed as follows. A weight of sample containing exactly 500 mg total oxide (J k-* 2 < * ) _ + M 9°) i* 3 suspended in 300 ml of deionized water. The suspension is maintained at 37°C±1° and stirred at 300 rpm. The sample is titrated with 1.0N HC1 at such a rate as to maintain a constant pH of 3.0, while recording on a strip chart the volume of acid used versus time. The titration is continued until no more acid is consumed. The times, in minutes, when 50% ( 5Q ) and 90% (T gQ ) of the total antacid are consumed by the acid are determined. The ACC is calculated by dividing the total number of milli- • meters (times10) of 1.0N HC1 by the weight of the sample in grams. The apparent density is determined by transferring 15-20 grams of sample to a 250-ml, flat bottomed, graduated cylinder. The cylinder is given 60 taps (1 sec. lift, 1 sec. drop; 1 inch drop) , and the volume in cubic centimeters is read. The apparent density (g/cc) is equal to the weight of the sample (g) divided by the measured volume of the sample (cc) . In the following examples, the same procedures are followed to determine apparent density and pH-stat reactivity and total neutralization capacity. EXAMPLE 2 The precipitation process of Example 1 was repeated except that instead of sodium hydroxide a sodium carbonate solution was used as the base in the precipitation, and the precipitation slurry so obtained was divided into parts E and F. Part E of the precipitation slurry had no post-addition treatment, while part F had a post addition of NaOH solution to raise the pH to 9.0. The results are shown in Table II. ~ TABLE I I Properties Formula E F % w/w A1 0 3 40.7 23.8 % w/w MgO 10.12 24.5 % w/w Na 0.23 0.21 % w/w Cl 0.11 0.11 Apparent Density, g/cc 0.42 0.24 pH Stat* at 37°C, T 50 - minutes 0.75 0.35 T - minutes 90 2.33 1.66 ACC,** ml 0.1N HCl/g 309 281 ACCD,*** ml 0.1N HCl/cc 130 67 The results show that the powders produced, using Na ? CO, for precipitation, have densities less than 0.5g/cc, and also, powder E has a low concentration of MgO which is the result of soluble magnesium loss. EXAMPLE 3 3.7 Liters of a 34° Baume MgS0 4 solution was mixed with 2.5 liters of a 24° Baume AlCl- solution. 4.5 Liters of water was placed in a 20-liter reactor which was fitted with an overhead mechanical mixer. The acid mixture and 5.1 liters of a 14.7% naOH solution .were simultaneously metered into the reactor. The flow rate was adjusted to hold a constant pH of 7.4 and a precipitation time of 48 minutes. The slurry obtained was divided into parts G, H, I, and J. Part G had no post addition; parts H and I had additions of respectively 1.0 and 1.3 liters of 16° Baume Na 2 C0_ solutions; and part J had a post addition of NaOH solution to raise the pH to 9.0. The results are shown in Table III. TA BLE I T T Properties Formulas G II I J % w/w A1 2 0_ 24.9 ' 21.5 21.0 18.5 % w/w MgO 26.1 30.1 30.6 " 31.8 " % w/w Na 00..3366 00..11 00..0088 00..2299 % w/w Cl 0.51 0.19 0.21 0.42 % w/w S0 4 14.41 9.43 8.22 14.34 % w/w co 9 0.85 4.7 5.9 1.59 Apparent Density, g/cc 0.74 0.59 0.54 0.83 pH Stat* at 37°C, T 5Q -min. 1.4 0.3. 0.33 1.7 T 90 -min. 4.33 1.0 0.85 4.4 ' • ACC**, ml 0.1N HCl/g 247 259 259 239 ACCD***, ml 0.1N IICl/cc 183 153 140 198 The addition of Na 2 CO_, increased the amount of % CO,, in Formulas H and I while decreasing the amount of sulfate . a_ EXAMPLE 4 The precipitation process of Example 1 is repeated except that the rates were adjusted to hold a constant pH of 8.9. The precipitation slurry was divided into parts K, L, M, and N. Part K had. no post-precipitation addition; parts L, M, and N had additions of 0.25, 0.35, and 0.50 liter respectively of 16° Baume Na 2 C0_ solution. The final pH's were 9.5, 10.2 and 10.5, respectively. The results obtained are shown in Table IV. TΛELE IV Properties Formulas K M N % w/w A1 2 0 3 21.2 20.4 20.9 20.0 % w/w MgO 32.2 32.1 32.1 32.3 % w/w Ma 0.02 0.03 0.09 0.05 % w/w Cl 9.21 2.73 0.95 0.22 % w/w C0 2.60 6.50 8.33 8.64 Apparent Density, g/cc 0.38 0.28 0.30 0.30 pH Stat* at 37°C, T -min 3.6 1.3 1.6 1.3 • T 9Q -min 17 12.3 12.0 10.7 ACC**, ml 0.1N HCl/g 263 282 278 282 ACCD***, ml 0.1N HCl/cc 100 7 * 83 85 The results show that the powders produced at a precipitation pH above 8.5 have apparent densities less than 0.5g/cc and correspondingly low ACCD values. EXAMPLE 5 The precipitation process of Example 1 was repeated. The precipitation slurry was divided into parts 0, P, Q, and R. Part 0 had no post-precipitation addition; parts P and Q had additions respectively of 300 ml and 600 ml of a 14.5% a^O^ solution; part R had an addition of 0.5 liter of 16° Baume Na~CO, solution. The results are shown in Table V. U) ) ro H H Ul o UI o Ul O Ul TABLE V Properties Formulas 0 P Q R % w/w A1 2°3 22.3 21.2 20.3 20.3 % w/w MgO 32.5 35.1 32.1 32.8 % w/w Na 0.07 0.13 0.19 . 0.19 % w/w Cl 8.77 3.55 1.39 0.85 % w/w S0 4 0.27 9.10 13.65 0.47 % w/w co. 1.88 1.62 1.19 8.80 Apparent Density, g/cc 0.97 0.94 0.89 0.59 pH Stat* at 37°C, T 5Q -min. 1.55 1.0 0.7 1.0 T 9Q -min. 3.66 3.7 2.3 4.3 ACC**, ml 0.1N HCl/g 245 246 245 2.75 ACCD***, ml 0.1N HCl/cc 238 231 218 162 2 . 1 EXAMPLE 6 3000 Grams of 24° Baume A1C1_ 3 , 2928 grams of a 50% MgCl 2 6H 2 0 solution and 533 grams of a 50% CaCl 2 . 2H ? 0 solution were added to a 20 liter reactor and - 3 reacted with 14.7% NaOH solution as in Example 1. The precipitation slurry so obtained"was divided into parts S, T, U, and V. Part S had no post-precipitation addition, parts T, U, and V had additions of 0.25, 0.35, and 0.50 liter respectively of 16° Baume Na 2 CO- solution. The powder results are shown in Table VI. (Jk) U) (V) fu H H Ul o Ul o Ul O Ul Properties Formulas T U V % w/w Λ1 2 0 3 25.7 24.2 22.7 20.8 % w/w MgO 29.3 29.1 27.4 25.5 % w/w CaO 0.5 1.08 4.88 7.79 % w/w Na 0.044 0.041 0.083 0.097 % w/w Cl 7.43 1.49 1.33 1.03 r- Apparent Density, g/cc 1.09 0.88 0.71 0.68 pH Stat* at 37°C. , T 50 -min 4.2 2.5 1.8 1.8 T 9Q -min 13 6.5 6.0 3.3 ACC**, ml 0.1N HCl/g 249 285 284 ■ 276 ACCD***, ml 0.1N HCl/cc 271.4 250.8 201.6 187.7 . This example shows the incorporation of calcium into high-density aluminum magnesium antacid powders. 2*. •*** The high-density powders of the present inven¬ tion prepared as above described may be compressed into tablets or filled into capsules of desired form using standard tableting and capsuling procedures, -•* ■' including wet granulation and direct compression. While the invention has been set forth and demonstrated in terms of certain embodiments, it is to be understood that other embodiments may be utilized, and many changes and variations may be ° made within the spirit of the invention and within the scope of the appended claims. 5 0 5 0 5

Claims: WHAT IS CLAIMED IS: 1. An aluminum magnesium antacid powder having a bulk or apparent density greater than 0.5 gram/cc comprising on a percent by weight basis: about 25-40% MgO; about 15-25% Al 2 0 3 ; and about 6-20% A; wherein A represents an anionic species or a mixture of anionic species. 2. The aluminum magnesium antacid powder of Claim 1 wherein said anionic species is selected from the group consisting of OH , Cl , HC0 3 , C0 3 ~, HS0 4 " , S0 4 ~, H 2 P0 4 ~, HP0 4 = and P0 4 ~. 3. The antacid powder of Claim 1 wherein all or part of the magnesium is replaced by calcium. 4. A method for the preparation of an antacid powder having an apparent density greater than 0.5 gram/cc comprising the steps of: a) preparing an aqueous solution of an aluminum compound and a magnesium compound; b) precipitating the magnesium aluminum compounds simultaneously with a solution of a base selected from the group consisting of alkali metal hydroxides and ammonium hydroxide at a pH not exceed- ing 8.5; and c) making the precipitate into a powder having a density greater than 0.5 gram/cc. 5. The method of Claim 4 further comprising a post-precipitation step of adding a basic solution to the precipitate to raise the pH to 9-10 thereof, . to precipitate soluble magnesium. 6. The method of Claim 5 wherein said pre¬ cipitate is washed, repulped, and dried into a powder. 7. The method of Claim 4 further comprising a post-precipitation step of adding an alkali or ammonium 5 salt selected from the group consisting of HC0 3 , C0_~, HS0 4 ~, S0 4 ~, H 2 0 4 ~, HP0.~, and' P0 4 ~ to introduce the anion of the salt into the antacid precipitate. 8. The method of Claim 7 wherein said pre¬ cipitate is washed, repulped, and dried into a powder. ° 9. The method of Claim 4 wherein said magnesium compound is selected from the group consisting of magnesium halide, magnesium sulfate and mixtures thereof. 10. The method of Claim 4 wherein said -* *> aluminum compound is selected from the group consisting of aluminum halides, alkali metal aluminates, aluminum nitrate, aluminum sulfate and mixtures thereof. 11. The method of Claim 4 wherein said pH is between about 7.5-8.5. 0 12. The method of Claim 4 wherein " said base is sodium hydroxide, potassium hydroxide or ammonium hydroxide. 5 0 5

Inventors: ABBRUSCATO VICTOR J, NELSON ROGER E, ABBRUSCATO, VICTOR, J., NELSON, ROGER, E.
Applicants: ARMOUR PHARMA, ARMOUR PHARMACEUTICAL COMPANY
Application year: 1985
Main classification: A61K33
IPC codes: A61K33, A61P1