GB1596660A

GB1596660A - Prepaation of aluminium hydroxide gel

Info

Publication number: GB1596660A
Application number: GB46572/77A
Authority: GB
Original assignee: Purdue Research Foundation
Current assignee: Purdue Research Foundation
Priority date: 1977-11-09
Filing date: 1977-11-09
Publication date: 1981-08-26

Description

(54) THE PREPARATION OF ALUMINIUM HYDROXIDE GEL (71) We, PURDUE RESEARCH FOUNDATION, a corporation organized and existing under the laws of the State of Indiana, United States of America, of Lafayette, Indiana, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement: Aluminium hydroxide gels are widely used as antacids. They possess many of the properties of an ideal antacid, such as acid-consuming capacity and nonabsorbability. Many effective antacid fluid dosage forms currently marketed use an aluminium hydroxide gel. However, when an aqueous aluminium hydroxide gel is used to produce a dried gel which can be formulated into solid dosage forms, its total antacid reactivity, as well as acid reaction rate, is decreased. Of even greater potential significance, the aging of a dried aluminium hydroxide gel at ambient or elevated temperature results in significant losses in antacid reactivity. An antacid preparation which is initially active can become inactive over a relatively short period of time. However, the convenience of a solid antacid dosage form over a fluid dosage form is readily appreciated and makes highly desirable the development of an initially acid-reactive dried aluminium hydroxide gel which maintains its acid reactivity for an extended period of time.

According to the present invention, an amorphous antacid aluminium hydroxide powder has a minimum surface area of 150 m2/g and a pH stat t50 value of from 6 to 20 minutes, and which contains from 40 to 63% by weight aluminium oxide. Such a product can be obtained by contacting an amorphous aqueous aluminium hydroxide gel with an inert organic solvent of sufficient solubility in water to maintain a single phase when contacted in 1:1 volume ratio with the aqueous gel, to replace water in the gel; removing the inert organic solvent; and drying the amorphous aluminium hydroxide gel.

A pharmaceutical composition according to the invention comprises a powder of the invention in association with a solid pharmaceutical carrier, e.g. in unit dosage form.

The aqueous amorphous aluminium hydroxide gel which is dried is a standard acid reactive aqueous gel which can be obtained from various manufacturers such as Chattem Chemical Company, Reheis, Barcroft, and J.T. Baker. An amorphous aqueous aluminium hydroxide gel which meets the United States Pharmacopeia 19th Revision specification is preferably employed. If it is desirable to initially prepare an aqueous amorphous aluminium hydroxide gel rather than purchasing a commercially prepared gel, known methods for preparing an acid reactive gel can be employed. For example, antacid active amorphous aqueous gels are prepared through the reaction of a watersoluble aluminium salt such as aluminium chloride or aluminium sulfate, and a basic aqueous solution such as an alkali metal carbonate or bicarbonate solution.

Although the reason is not clearly understood, gels of higher antacid activity are prepared from carbonate or bicarbonatecontaining bases.

Once the aqueous gel is obtained, it is contacted with an inert organic solvent of sufficient water solubility to replace water in the gel. The term "inert" as used herein refers to the lack of chemical reactivity of the organic solvent with the gel. Examples of organic solvents which can be employed in this invention are those solvents which are miscible with water, for example, methanol, ethanol, propanol, isopropanol, acetone, acetaldehyde, dimethylformamide, formamide, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane and pyridine. Inert organic solvents which are not miscible in water but which can be employed are higher alcohols such as butanols and pentanols, esters such as ethyl acetate, and higher homologues thereof having one to three carbon atoms attached to the acyl moiety; and ketones having four to six carbon atoms. For convenience and ease of handling the gel, the inert organic solvent should be added to the aqueous gel in such quantities that a single liquid phase is present. By definition, a water-miscible solvent will only form a single phase with water. For practical reasons, the single phase should exist for other organic solvents not miscible in water when the solvent is added in quantities up to a 1:1 ratio with respect to the volume of aqueous gel. It should be noted that organic solvents may be used in mixtures for replacement of the water in the gel. For example, a 1:1 ratio, ethanol (50%), benzene (50%):aqueous gel volume, still maintains a single phase with the aqueous gel even though benzene, if added alone to the aqueous gel, would create two phases.

The organic solvent may be added to the gel in various proportions and the addition of solvent repeated after removal as well.

For preparing a dried gel with high acid reactivity as measured by the pH-stat t50 value, as well as the Rossett-Rice test, ethanol should be added to the aqueous gel at a volume of 3:1. The water and ethanol are removed by decantation, vacuum filtration, or preferably centrifugation, and the entire treatment step should be repeated twice. As a balance between cost, handling and acid reactivity, ethanol should be added to the gel at a volume ratio of 2:1, water and ethanol removed and then followed by a 1:1 addition of ethanol. The secondary treatment volumes of organic solvent are measured on the basis of the original gel volume.

At each treatment step, the aluminium hydroxide gel is maintained as a moist cake.

Following the final solvent treatment, the gel is dried using standard means such as spray drying, vacuum drying, forced air drying or drum drying.

The dried amorphous aluminium hydroxide gel prepared by this process has high antacid reactivity as measured by the Ros sett-Rice time and the pH stat 4() time.

Rossett-Rice time is the length of time a quantity of the dried gel equivalent to 300 mgs. of aluminium oxide dispersed in 70 milliliters of 0.1N hydrochloric acid and 30 milliliters of water at 37"C. remains at a pH between 3 to 5 as 0.1N hydrochloric acid is added to the mixture at a rate of 4 milliliters per minute. The pH stat test is a more sensitive test of acid reactivity. This test measures the volume of acid required to maintain pH at a preset value as a function of time. The t50 is the time required for one-half of the antacid to be consumed. The rate of loss of antacid activity as measured by Rossett-Rice time of gels prepared after drying from water is substantially greater than for gels prepared after drying from an inert organic solvent. The rate constant for loss of reactivity for gels dried from water is about 0.48/month at 400C. in contrast to about 0.071/month at 400C. for gels dried from the organic solvent. This is a significant difference which is reflected in a much greater retention of acid reactivity at room temperature by the gels of the invention.

This difference illustrates the stability of the product prepared by this process over an extended period of time. The term "extended period of time" as used in this specification indicates a period of time over which the dried gel is capable of neutralizing acid at such a rate and at such a pH that a pharmaceutical composition comprising that gel would have a useful shelf life. A period of at least two years is contemplated. It is this extended antacid activity which distinguishes the amorphous gel prepared by the process of this invention from the gels of the art dried from water and allows the preparation of a potent antacid for therapeutic purposes.

This extended antacid activity is manifested by the composition characteristics of an increased surface area over gels prepared by drying from water in combination with certain pH-stat tso values. The products of the invention have a minimum surface area of 150 m2/gm, as measured by nitrogen adsorption. A minimum surface area above 170 m2/gm. is preferred. The composition has a pH-stat t50 time of six to twenty minutes. A pH-stat 4() of six to fifteen minutes is preferred. The aluminium oxide content of the gel, as measured by the United States Pharmacopeia 18th Revision assay system can vary from 40 to 63%' by weight and still provide gels which are antacid active for an extended period of time. A preferred range of aluminium oxide is 45 to 59%. The 18th Revision of the United States Pharmacopeia discloses a range of 50-57.5%. Dried gels within this range are active and stable. The percentage aluminium oxide is dependent upon the drying time and does not appear to be intrinsically associated with extended antacid activity. However. amorphous gels dried from water seem to be required to fall within the 50-57.5% range of the U.S.P. to be active for even a short period of time, The dried amorphous aluminium hydroxide gel of this invention may be compounded into oral solid dosage pharmaceutical compositions for administration to individuals requiring antacid therapy. These oral, solid dosage forms are chewable or swallowable, the latter being preferred because of the chalky nature of the conventional chewable dosage form. The swallowable dosage form can be either a tablet or a capsule. When formulated into tablet form, the usual excipients can be employed, however, a strong disintegrant such as Starex is preferred for appropriate antacid action.

The following Example illustrates the invention.

Example In a five litre beaker, an 11.4% aqueous solution containing 0.755 moles of aluminium chloride hexahydrate is added to an aqueous solution containing 2.8% sodium carbonate (0.57 moles) and 4.5% sodium bicarbonate (1.336 moles). The mixture is stirred for a few minutes at room temperature and the aluminium hydroxide gel which is formed is washed several times with deionized water to remove the residual salts.

The gel is then treated three times with a volume of ethanol equal to the volume of aluminium hydroxide gel (about 500 ml.) by thoroughly dispersing the gel in the alcohol and filtering through a Buchner funnel using No. 1 filter paper, being careful to maintain the aluminium hydroxide as a moist cake.

The final product is dried at an elevated temperature to obtain a powder having an aluminium oxide content of from 40 to 63% by weight.

The Rossett-Rice time, lag time, acid consuming capacity, and pH-stat t50 on aging of the above dried amorphous aluminium hydroxide gel indicate a substantially more potent product than similarly prepared gels dried from water. The Rossett Rice time and pH-stat t50 tests were previously defined. The lag time is the length of time required for the pH to reach 3.0 after starting the addition of the hydrochloric acid in the Rossett-Rice time determination.

Acid consuming capacity is the method used in U.S.P. 19th Revision.

The pH-stat t50 values in this specification are obtained under the following conditions.

A sample of dried aluminium hydroxide gel containing 38 mg. of aluminium hydroxide, as measured by the assay procedure of the United States Pharmacopeia, 19th Revision, is dispersed in twenty-two (22) ml. of distilled water in a fifty (50) ml. beaker. The pH-stat t50 value for a pH of 3 is then obtained for this sample using a typical pH-stat tritrator assembly with a stirrer operating at 900 rpm. The particular pH-stat titrator assembly is not unduly significant.

Such assemblies are available from Mettler, Beckman and Radiometer A/S (Copenhagen, Denmark). The specific assembly components used were obtained from Radiometer and are: pH meter PlIM 26 Titrator TIT II Autoburet ABU12 (2.5 ml.) Titration Assembly TTA3 Recorder SBR 2 WHAT WE CLAIM IS: 1. An amorphous antacid aluminium hydroxide powder having a minimum surface area of 150 m2/g and a pH stat t50 value of from 6 to 20 minutes, and which contains from 40 to 63% by weight of aluminium oxide.

2. A powder according to claim 1 which contains from 45 to 59goo by weight aluminium oxide.

3. A process for preparing a powder according to either preceding claim, which comprises contacting an amorphous aqueous aluminium hydroxide gel with an inert organic solvent of sufficient solubility in water to maintain a single phase when contacted in a 1:1 volume ratio with the aqueous gel, to replace water in the gel; removing the inert organic solvent; and drying the amorphous aluminium hydroxide gel.

4. A process according to claim 3 wherein the organic solvent is methanol, ethanol, propanol, isopropanol, acetone, acetaldehyde, dimethylformamide, formamide, tetrahydrofuran, 1,3-dioxane, 1 ,4-dioxane or pyridine.

5. A process according to claim 4 wherein the solvent is methanol, ethanol, propanol, isopropanol or acetone.

6. A process according to claim 5 wherein the solvent is methanol or ethanol.

7. A process according to any of claims 3 to 6 wherein the organic solvent comprises a mixture of compounds.

8. A process according to claim 3 substantially as described in the Example.

9. A powder prepared by a process according to any of claims 3 to 8.

10. A pharmaceutical composition which comprises a powder according to any of claims 1, 2 and 9 in association with a solid pharmaceutical carrier.

11. A composition according to claim 10 which is in an orally acceptable form.

12. A composition according to claim 10 or claim 11 in unit dosage form.

13. A composition according to claim 12 in tablet form.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. oral, solid dosage forms are chewable or swallowable, the latter being preferred because of the chalky nature of the conventional chewable dosage form. The swallowable dosage form can be either a tablet or a capsule. When formulated into tablet form, the usual excipients can be employed, however, a strong disintegrant such as Starex is preferred for appropriate antacid action. The following Example illustrates the invention. Example In a five litre beaker, an 11.4% aqueous solution containing 0.755 moles of aluminium chloride hexahydrate is added to an aqueous solution containing 2.8% sodium carbonate (0.57 moles) and 4.5% sodium bicarbonate (1.336 moles). The mixture is stirred for a few minutes at room temperature and the aluminium hydroxide gel which is formed is washed several times with deionized water to remove the residual salts. The gel is then treated three times with a volume of ethanol equal to the volume of aluminium hydroxide gel (about 500 ml.) by thoroughly dispersing the gel in the alcohol and filtering through a Buchner funnel using No. 1 filter paper, being careful to maintain the aluminium hydroxide as a moist cake. The final product is dried at an elevated temperature to obtain a powder having an aluminium oxide content of from 40 to 63% by weight. The Rossett-Rice time, lag time, acid consuming capacity, and pH-stat t50 on aging of the above dried amorphous aluminium hydroxide gel indicate a substantially more potent product than similarly prepared gels dried from water. The Rossett Rice time and pH-stat t50 tests were previously defined. The lag time is the length of time required for the pH to reach 3.0 after starting the addition of the hydrochloric acid in the Rossett-Rice time determination. Acid consuming capacity is the method used in U.S.P. 19th Revision. The pH-stat t50 values in this specification are obtained under the following conditions. A sample of dried aluminium hydroxide gel containing 38 mg. of aluminium hydroxide, as measured by the assay procedure of the United States Pharmacopeia, 19th Revision, is dispersed in twenty-two (22) ml. of distilled water in a fifty (50) ml. beaker. The pH-stat t50 value for a pH of 3 is then obtained for this sample using a typical pH-stat tritrator assembly with a stirrer operating at 900 rpm. The particular pH-stat titrator assembly is not unduly significant. Such assemblies are available from Mettler, Beckman and Radiometer A/S (Copenhagen, Denmark). The specific assembly components used were obtained from Radiometer and are: pH meter PlIM 26 Titrator TIT II Autoburet ABU12 (2.5 ml.) Titration Assembly TTA3 Recorder SBR 2 WHAT WE CLAIM IS: