IL44189A - Aluminium salts of 2-(3-phenoxyphenyl) propionic acid and pharmaceutical suspensions prepared therefrom - Google Patents

Description

44189/2 ALUMINUM SALTS OF 2- (3-PHENOXYPHENYL)PROPIONIC ACID AND PHARMACEUTICAL SUSPENSIONS PREPARED THEREFROM D'Q'mni n'Ji'ana( '3D'Dj j3-3)-2 nxnin ϊν DIJ'DI^K 'n n /J>IP6 This invention relates to mono- and di-basic aluminum salts of 2- (3-phenoxyphenyl ^propionic acid^ and a suspension thereof in an aqueous medium, to a process for preparing the aluminum salts and to a process for preparing the suspension.

The invention provides mono- and di-basic aluminum salts of 2- (3-phenoxyphenyl) propionic acid in substantially water-insoluble form.

The invention further provides for a suspension consisting of water and the substantially water-insoluble aluminum salts. The salts are suspended in an amount providing from 20 to 200 rag. of aluminum salts per ml. of suspension .

The aluminum salts are prepared by reacting 2- ( 3-phenoxyphenyl) propionic acid or its sodium salt with a water oolublc aluminum compound to form a substantially water-insoluble aluminum salt of 2- (3-phenoxy-phenyl) ropionic acid.

The suspension is prepared by grinding the desired aluminum salt to a powder having a mesh size below 200 (U.S. screen) and adding the resulting finely divided powder to a vehicle adjusted to an appropriate specific gravity and viscosity with commonly utilized pharmaceutical suspension adjuvants.

Physiologically active substituted phenylalkanoic acids are taught and claimed in United States Patent No. 3,600,437. The substituted phenylalkanoic acids there-taught are particularly active as antiinflammatory agents.

Antiinflammatory agents are almost uniformly prescribed in most clinical cases of arthritis. And, generally, arthritis is an affliction of the older segment of the population. In those persons 70 and older, almost every one has an active case of clinically diagnosed arthritis. Solid pharmaceutical dosage forms for oral administration, such as capsules, granules, pills, powders, and tablets can be readily prepared directly from the more soluble salts of substituted phenylalkanoic acids. However, many older persons prefer liquid medical preparations to the solid forms, because such are easier to swallow.

Most salts of substituted phenylalkanoic acids having antiinflammatory activity are difficult to formulate into pharmaceutically acceptable liquid dosage form because of a small amount of water solubility which makes the taste hard to mask .

It has now been discovered that the mono- and dibasic aluminum salts of 2 - ( 3-phenoxyphenyl) propionic acid of the following formula: (R) n-Λ1-(0Ι1) j-n Formula I wherein R is 2-- (3-phenoxyphenyl) propionyloxy radical and n is 1 or 2 , the salts having antiinflammatory activity, are practically water insoluble, tasteless, unreactive towards commonly employed pharmaceutical suspension adjuvants, chemically stable at a pll of from about 6.0 to 9.0, and .adapted for formulating into exceptionally elegant pharmaceutical suspensions. Such salts are prepared by reacting 2- (3-phenoxyphenyl) propionic acid or its sodium salt with a water soluble aluminum compound such as aluminum chloride hexahydrate or aluminum nitra e monohydrate, in water-soluble sodium salt, the concentration ol: the presence of sodium A/hich can be adjusted to produce either the mono- or di-basic salt or by directly reacting 2- ( 3-phenoxy- or a sodium salt thereof phenyl) propionic acid/with a dispersion of aluminum hydroxide gel in water.

The term "monobasic" refers to the aluminum salt which has one hydroxyl (OH) substituent bonded to the aluminum. The term "dibasic" refers to the aluminum salt which has two hydroxyl (OH) substituents bonded to the aluminum. 2- (3-Phenoxyphenyl ) propionic acid is an excellent anti-inflammatory agent. United States Patent No. 3,600,437 describes the useful anti-inflammatory activity of a class of alkanoic acid compounds. Methods for the preparation of representative members of this class of compounds are exemplified in the aforementioned patent.

The aluminum salts described herein have antiinflammatory activity similar to the anti-inflammatory activity of the alkanoic acids of the U.S. patent but the mono- and di-basic aluminum salts of 2- (3-phenoxyphenyl) -propionic acid have the surprising additional useful property of tastelessness .

This useful property of tastelessness, coupled with the almost total lack of solubility-in-water associated with the aluminum salts of the physiologically active 2- ( 3-phenoxyphenyl) propionic acid, provide compounds which can be incorporated into suspensions possessing outstanding pharmaceutical elegance. And, upon ingestion into the acid environment of the stomach of a mammal, including humans, the acid, moiety is disaeeociated from the salt and reverts to the 2- (3-phenoxyphenyl) propionic acid compound. As such, it is assimilated from the gastro-intestinal tract and becomes biologically available to effect an antiinflammatory activity.

The aluminum salts of 2- ( 3-phenoxyphenyl) propionic acid are prepared by (1) reacting in an aqueous medium n equivalents of a compound of the formula Formula II wherein R' is hydrogen or sodium and n is 1 or 2, with one equivalent of a water or aluminum hydroxide gel soluble aluminum compound in the presence of 3 oquivalcnto of a water oolublo oodium salt when R'—io hydrogen and 3-n equivalents of a water ooluble oodium oalt when R '—io sodium and (2) recovering a substantially water insoluble mono or di-basic aluminum salt of 2- ( 3-phenoxyphenyl) propionic acid.

Specifically the aluminum salts of 2- ( 3-phenoxyphenyl) propionic acid can be prepared by a number of different procedures. One procedure involves reacting the sodium salt of 2- ( 3-phenoxyphenyl) propionic acid with a water soluble aluminum salt; e.g., aluminum nitrate, or aluminum chloride. Sodium carbonate or bicarbonate is added to provide sodium ion and to buffer the suspension to a pH from 5.0 to 9.0.

The preparation is carried out in an aqueous medium with vigorous agitation.

A second method involves reacting 2- ( 3-phenoxy- or a sodium salt thereof phenyl ) propionic acid/with aluminum hydroxide in ιΐι^ pi-miriw^ *}£ d Wa-ter se-Jrttfei'e so iwn salt in a well-stirred hot aqueous medium.

Still another method, which is a variation of the first, calls for the controlled addition of two solutions into a well-stirred vessel. One solution contains the aluminum ion and the other solution contains the sodium salt of 2- (3-phenoxyphenyl) propionic acid plus an excess of sodium hydroxide to neutralize the remaining anions of the reaction. The two solutions are brought together at equivalent rates in an aqueous reaction medium held at a temperature of about 50°C. The pH is maintained in the preferred range of 6.0-8.0.

It is not necessary to heat the reaction medium for the reaction to proceed. Slight heating merely facilitates filtration of the product.

In any of the above instances either the mono-or di-basic aluminum salt of 2- (3-phenoxyphenyl) propionic acid can be prepared. Which salt is prepared is dependent upon the molecular equivalents of the 2- (3-phenoxyphenyl) -propionic acid in proportion to the aluminum which is present. When the 2- (3-phenoxyphenyl) propionic acid is present in a ratio of 2:1, the mono-basic aluminum salt is formed. When the ratio of 2- (3-phenoxyphenyl) propionic acid to aluminum is 1:1, the di-basic aluminum salt is formed . In both instances it is -necessary that three equivalents of sodium be proocnt,—cither in the form of a water soluble sodium salt or as the sodium -propionic acid salt ■ For instance,—in Example 1 bolow,—there aro two sodium ion equivalonto—(0.2 M)—rocont ao tho water oolublo 44189/2 Example 1 Preparation of 2-{3-Phenoxyphenyl)propionyloxy Aluminum Dihydroxide To 100 ml. of deionized water in a suitable vessel were added 2ft.16 g. (0.1 mole) of 2-(3-phenoxyphenyl) propionic acid. The acid was dissolved by the addition of 20 ml. of 5N NaOH to form sodium 2- (3-phenoxyphenyl)pro- pionate. The pH was about 9.4.

In a separate vessel, 37.5 g. (0.1 mole) of Al (N03)3' 9H2P were dissolved in 250 ml. of deionized water.

The pH was about 1.6, In a third vessel, a three necked round bottom flask equipped with a stirrer, 16,8. g (0.2 mole) of aHCOj were dissolved in 200 ml. of deionized water.

The reaction forming the 2-(3-phenoxyphenyl)pro-pionylj^xy pionoocy- aluminum dihydroxide was carried out in the third vessel by slowly adding continuously equivolumetric quantities of each of the solutions of the sodium 2- (3*- phenoxyphenyl)propionate and of the alumintkm nitrate to the sodium bicarbonate solution with continuous stirring. About 30 minutes were required to complete the addition of the two solutions to the reaction vessel as the rate of addition was controlled to minimize foaming. Stirring was continued for another 30 minutes and the resulting precipitate was filtered°^and washed. The filter cake was dried for 48 hours at 50 °C. Twenty-eight and four- tenths grams of reaction product (94% yield) were obtained propionyloxy which analyzed 98.2% 2- ( 3-phenoxyphenyl )-prep^nexy- aluminum dihydroxide.

Example 2 Preparation of -D-t-{2- (3-Phenoxyphenyl) prop-ionox-y}-- propionyloxy Aluminum Hydroxide In a suitable vessel, 3.28 g. of anhydrous sodium carbonate were dissolved in 100 ml. of deionized water.

To this solution were added 10 g. of 2- (3-phenoxyphenyl) - propionic acid. The reaction mixture was agitated vigorously until all of the acid was in solution and reacted to form sodium 2- (3-phenoxyphenyl) propionate.

In a separate vessel, 4.98 g. of A1C13"6H20 were dissolved in 200 ml. of deionized water. The aluminum chloride solution was diluted to ml. total volume and placed in an addition^ funnel.

The reaction forming - [ 2- (3-phenoxyphenyl ) pro-p|¾¾i8^] aluminum hydroxide was carried out by continuously, slowly adding the aluminum chloride solution to the propionate solution with stirring. The rate of addition was controlled to minimize foaming and required about 15 minutes. When the addition of the aluminum chloride solution was complete, the reaction mixture was slowly heated to 70°C. with stirring and then gradually cooled to off 50°C. The precipitate which formed was filtered/ using a sintered glass filter, and the filter cake was washed with methanol. The resulting reaction product was dried at 50 °C. overnight. The reaction product obtained weighed 10.7 g. (98.52% yield). Analysis showed 89.7% 2- ( 3-phenoxy-phenyl) propionic acid and 11.74% aluminum oxide.

The mono- and di-basic aluminum salts of 2- (3-phenoxyphenyl) propionic acid are formulated into pharmaceutical suspensions having exceptional palatability and stability. And when such a suspension is ingested into the acid environment of the stomach, the physiologically 2-3(-phenoxy » active moiety -the/ pheny^propionic acid- is disaesociated from the aluminum salt and is assimilated into the blood stream of the ingester who then receives the benefit of the antiflammatory activity of the propionic acid.

The mono- and di-basic aluminum salts of 2- (3-phenoxyphenyl) propionic acid are essentially tasteless and practically insoluble in water at a pH from near neutral to slightly alkaline; e.g., from 6.0 to 9.0. Furthermore, these salts are pharmaceutically compatible with a wide range of suspension adjuvants commonly employed in formulating pharmaceutical suspensions.

It is desirable that physiologically active agents formulated into pharmaceutical suspensions should have a particle size below 150 mesh (U.S. screen) , preferably from 200 to 325 mesh. The particle size should be small enough to impart good feel to the mouth when the suspension is taken orally. The absence of grittiness is desired. But at the same time, the particle size should not be a great deal smaller than needed, because ultra small particles tend to thicken a suspension and as a consequence reduce the practical quantity of material which can be effectively formulated into a suspension.

The aluminum salts described herein can be readily ground to a powder suitable for incorporation in a pharmaceutical suspension. It was found that a powder of these compounds which passes 200 mesh (U.S. screen) is particularly suitable for formulation into a suspension.

Pharmaceutical suspensions are usually prepared by employing a specific gravity adjusting agent, such as one of the edible sugars, e.g., fructose, dextrose, mannose, lactose, sucrose, and the like, an edible polyol such as glycerin, propylene glycol, amnnitol, and the like. The specific gravity adjusting agent is dissolved in water to provide a vehicle having a specific gravity just a little bit below the specific density of the physiologically active agent suspended therein. About 40 percent by weight of sucrose in water provides a suitable vehicle for suspending the aluminum salts therein.

A viscosity adjusting substance is generally utilized in a pharmaceutical suspension to retard the rate of settling of the physiologically active agent. Among such substances are methyl cellulose, polyvinylpyrolidone , hydroxypropyl-cellulose, sodium carboxymethylcellulose , microcrystalline cellulose, finely ground bentonite, gelatin, naturally occurring gums such as guar, and the like. A particularly well adapted viscosity adjusting substance for use in preparing a suspension of the aluminum salts is a combination of about 89 percent microcrystalline cellulose and 11 percent sodium carboxymethylcellulose. The combination is employed in an amount of about 2.5 percent weight/volume of the finished suspension.

A preservative, such as one of the parabens, is generally added to the suspension. Methylparaben is an amount of about 0.08 percent weight/volume of the finished suspension serves as an effective preservative of a pharmaceutical suspension of the aluminum salts. l¾a¾maceutical elegance is provided by employing suitable flavoring agents and colorants. Generally the color is selected to provide harmony with the flavors employed.

Typical pharmaceutical suspensions of both the mono-and di-basic aluminum salts of 2- (3-phenoxyphenyl) propionic acids are exemplified in Examples 3 and 4, below. The concentration of 300 mg. of propionic acid equivalent per 5 ml. of suspension was designed to provide one recommended dose in 5 ml. Other concentrations can be easily prepared by simply adjusting the amount of the aluminum salt of the propionic acid that is added to the vehicle. Suspensions containing as much as 1000 mg. per 5 ml. can be readily formulated. The 5 ml. quantity of suspension was exemplified as this is the amount generally measured by one teaspoon.

Other amounts can be just as easily employed to contain the desired quantity of the physiologically active agent.

Example 3 Typical Pharmaceutical Suspension Containing 300 mg. of 2- (3-Phenoxyphenyl) propionic Acid Equivalent as 2- (3-Phenoxyphenyl ) pr-opienpxy Aluminum Dihydroxide per 5 ml. of Suspension fcu uii Lux* 1 To make 1 liter of suspension employ the formula and method of preparation that follows: Place in suitable container calibrated to 1 liter-Water Purified 400.00 ml, Methylparaben . . . . 0.80 g Heat to 60 °C. Dissolve, add- Microcrystalline Cellulose 89 percent with Sodium- Carboxymethylcellulose 11 percent 25.00 g.

Mix well, maintain 60 °C. while mixing.

Mix for 30 minutes.

Let stand overnight at room temperature.

Mix well, add- Sucrose Granulated Cane . . . 400.00 g.

Dissolve, add- Water, Purified 100.00 ml Mix well, add slowly- propionyloxy 2- ( 3-phenoxyphenyl)p apionaxy aluminum dihydroxide, 200 mesh powder 75.00 g.

Mix until uniform, add- (Imit. Pineapple Flavor RF1698 (Rhodia) 0.10 ml (Orange Flavor Imit. 59.107/A(Firmenich) 0.10 ml (alcohol 95%) 1.80 ml Mix well, add- (F D and C Yellow No. 5 0.40 g.

(F D and C Yellow No. 6 0.02 g.

(Water Purified) 5.00 ml Mix well, add- Water Purified q.s. to 1000.00 ml Mix well, run through mill, mix well.

Example 4 Typical Pharmaceutical Suspension Containing 300 mg. of 2- ( 3 -Phenoxyphenyl) propionic AcTd Equivalent as -Pi- [2-~f3-Phenoxyphenyl) r^ionoxy] Aluminum Hydroxide per 5 ml. of™ Suspension propionyioxy - — Proceed as outlined in Example 3 except for 2- (3- , 75.0 g., substitute d-i- [2- (3-phenoxyphenyl )-p-j?epionoxy-j aluminum hydroxide, 65.22 g.

In addition to the suspension exemplified in Examples 3 and 4, a pharmaceutically elegant suspension bis propionyloxy containing -ai- [2- ( 3-phenoxyphenyl )pr-opi©*xxy] aluminum hydroxide as the compound containing the physiologically active moiety, 2- (3-phenoxyphenyl) propionic acid was prepared by reacting the phenylalkanoic acid with aluminum hydroxide iri situ . The preparation of this pharmaceutical suspension comprises the steps of: A- In a suitable vessel, 1) dissolving a preservative in water, and 2) dispersing a viscosity adjusting agent in the solution from 1) ; B- In a separate vessel, 1) mixing aluminum hydroxide powder with water, 2) heating the mixture from 1) to 65°C, and 3) adding a sodium 2- (3-phenoxyphenyl) propionate solution slowly to the heated mixture from 2) ; and C- 1) adding the reaction mixture from (B) to the dispersion from (A) , and 2) adding a specific gravity adjusting agent thereto.

The same preservatives, viscosity adjusting substances and specific gravity adjusting agents as are illustrated above can be employed in preparing the aforementioned in situ suspension.

As was discussed before, the utilization of flavoring agents and colorants adds to the pharmaceutical elegance of the suspension. However, such are not essential to the preparation of a suspension that is chemically and physically stable. bis- [2- (3-phenoxyphenyl) - The in situ preparation of a/di (propionic acid) aluminum hydroxide suspension is exemplified in Example 5.

Example 5 Preparation of a Pharmaceutical In Situ Suspension Contain- ing^ 00* ng" "o¾ 2- f3-PhenoxypTenyLpropionic Acid Equivalent To make 2 liters of suspension employ the formula and process of preparation that follows : (A) - Place in suitable container calibrated to 2 liters- Water purified . 400 ml 2- (3 -Phenoxyphenyl) propionic acid 40 g.

Sodium carbonate, anhydrous 13.2 Mix well to dissolve (B) - Place in suitable container- Water purified 400 ml Aluminum chloride, hexahydrate 20 g.

Mix well to dissolve.

(C) - Add solution from (B) slowly over 1 hour period to solution from (A) .

Add sodium lauryl sulfate 1 g, Dissolve. Add- 30% silicone emulsion 1 g.

Mix well.

(D) - In separate suitable container place- Water purified 550 ml.

Methylparaben 1.6 g.

Mix well. Heat to 60 °C. to dissolve. Add- Microcrystalline cellulose 89% with sodium carboxymethylcellulose 11% 40 g.

Mix well at 60 °C. for 30 minutes, let stand overnight.

(E) - Mix reaction mixture from (D) well and add to (C) .

Add- Sucrose, granulated 800 g.

Xanthate gum 4 g.

Mix well. Add- F D and C Yellow No. 5 0.006 g.

F D and C Red No. 40 0.06 g.

Mixed fruit imitation flavor blend 0.6 ml.

Mix well. Add water purified q.s. to 2000 ml.

Put mixture through homogenizer at 1500 PSI , mix well.

The suspension prepared in Example 5 above, is a very fine suspension requiring no grinding for the particles to pass 200 mesh. Further, the suspension has improved bio-availibility because it dissolves easily in the stomach of the subject. The suspension is compatible with other pharmaceutical preparations placed in the suspension because the aluminum is highly insoluble and as such is inert to other potential reactants.

Claims (16)

1. A compound of the formula : (R) -Al-(OH) Formula I n J-n wherein R is 2- (3-phenoxyphenyl) propionyloxy radical and n I or 2.

2. A pharmaceutical suspension comprising the aluminum salt of Claim 1 in finely divided form suspended in water in the presence of a preservative, a specific gravity adjusting agent and a viscosity adjusting agent.

3. A suspension according to Claim 2 wherein the aluminum in finely divided form has a particle size below 200 mesh (U.S. screen).

4. A suspension according to Claim 2 or 3 wherein the preservative is methylparaben , the specific gravity adjusting agent is sucrose and the viscosity adjusting agent is a blend of 89% microcrystalline cellulo and 11% sodium carboxymethylcellulose .

5. A suspension according to any of Claims 2,3, or 4 wherein the suspension is comprised of 6 percent by weight of the acid moiety of a compound of claim 1, 0.08 I percent by weight of methylparaben, 2.5 percent of the combination of 89 percent microcrystalline cellulose and II percent sodium carboxymethylcellulose, 40 percent 49. 92 sucrose and 5i percent water.

6. A process for preparing a compound of the formula : (R) Formula I wherein R is 2- (3-phenoxyphenyl ) propionyloxy radical and n is 1 or 2, which comprises (1) reacting in an aqueous medium n equivalents of a compound of the formula Formula II wherein R* is hydrogen or sodium and n is as defined above, with one equivalent of a water soluble aluminum compound in the presence of a water soluble sodium , 'salt ' .and ·; '. ' ■.·..:■,·.■ . , ■ (2) recovering a substantially water insoluble mono or di-basic aluminum salt of 2-(3-phenoxyphenyl)propionic acid.

7. he process of claim 6 herein the alumindm compound is aluminum nitrate, aluminum chloride.

8. The process cf claim 7 or 6 wherein the 2- (3-phenoxy-phenyl)propionic acid to aluminum ion molar ratio is 2:1 and the aluminum salt obtained is the mono basic salt.

9. The process of claim 7 or 6 wherein the 2- (3-phenoxy-phenyl)propionic acid to aluminum ion molar ratio is 1:1 and the aluminum salt obtained is the di-basic salt.

10. A process for preparing a pharmaceutical suspension containing as the active ingredient the aluminum salt of claim 1 which comprises: (A) 1) dissolving a preservative in water in a suitable vessel, and 2) dispersing a viscosity adjusting substance in the solution from 1) ; (B) 1) mixing aluminum hydroxide powder with water in a suitable separate vessel, 2) heating the mixture from 1) to about 65°C. and 3) adding slowly the sodium salt of 2- (3-· phenoxyphenyl ) propionic acid to the heated mixture from 2) ; and (C) 1) adding the reaction mixture from (B) to the dispersion from (A) , and 2) adding a specific gravity adjusting agent to the combination from 1) .

11. A process for preparing a pharmaceutical suspension containing as the active ingredient the aluminum salt of claim 1, which comprises: (A) dissolving 2- (3-phenoxyphenyl) propionic acid and sodium carbonate in water; (B) dissolving aluminum chloride hexahydrate in water; (C) slowly adding over a 1 hour period the solution of (B) to the solution of (A) thereby obtaining a suspension; and (D) adding a preservative, a viscosity adjusting agent to the suspension obtained in (C) .

12. A mono- or di-basic aluminum salt of 2- (3-phenoxyphenyl) propionic acid substantially as hereinbefore described with particular reference to Examples 1 and 2.

13. A process for preparing a mono- or di-basic aluminum salt of 2- ( 3-phenoxyphenyl) propionic acid substantially as hereinbefore described with particular reference to Examples 1, 2, 5 and 6.

14. A pharmaceutical suspension substantially as hereinbefore described with particular reference to Examples 3, 4, 5 and 6.

15. IS 4 A process for the preparation of a pharmaceutical suspension substantially as hereinbefore described with particular reference to Examples 3, 4, 5 and 6,

16. A process for preparing a compound of the formula: (R) -A1-(0H)_. Formula I . 9 3-n wherein R is 2-(3-phenoxyphenyl)propionyloxy radical and n is 1 or 2, which comprises (1) Reactifig;',in an aqueous medium n equivalents of a compound of the formula Formula I wherein R1 is hydrogen or sodium and n is as defined above, with one equivalent of aluminum hydroxide gel; and (2) recovering a substantially water insoluble mono or di-basic aluminum salt of 2- (3-phenoxyphenyl)-propionic acid.