Water soluble polyvinyl lactam-drug complexes

WATER SOLUBLE POLYVINYL LAL1AM-DRLIG COMPLEXES

The invention relates to water soluble complexes of normally water insoluble drugs such as chlorothiazide, aminobenzoic acid, furosemide and mixtures thereof wherein the complexing agent is a polyvinyl lactam such as polyvinylpyrrolidone, polyvinylpyrrolidone-halogen complex or mixtures thereof.

The invention also relates to the preparation of these complexes which involves dissolving the reactive components in an aqueous inert solvent combining the complexing agent and drug in a weight ratio of from about 1:1 to about 10:1 with agitation for a period of at least 5 minutes at a temperature above 3’C. and below the boiling point of the aqueous solvent solution under a pressure up to about 50 psig.

Chlorothiazide (6-chloro-7-sulfamyl-l,2,4-benzothiadiazine-1,1-dioxide) is a known antihypertensive and diuretic drug which is also used to treat congestive heart failure in animals. Furosemide (4-chloro-N-furfuryl-5sulfamoyl anthranilic acid) is also a well known diuretic. However, administration of these compounds in solution is complicated by their water-insolubility. The water solubility of chlorothiazide is only 0.5 g. per liter at pH 6 and although this drug is soluble in alkaline aqueous solutions, it decomposes rapidly on standing.

US Patent 3,673,163 refers to a novel pharmaceutical preparation af acronycine comprising an acronycine polyvinylpyrrolidone coprecipitate of increased solubility.

US Patent 3,923,974 refers to a composition which is suitable for direct tablet compression and which comprises a solid fine crystalline paracetamol polymer complex, said polymer selected from homopolymers and copolymers of vinyl acetate and vinyl pyrrolidone.

US Patent 3,985,540 refers to a complex formed by reacting 8hydroxyquinoline and a water-insoluble but water swellable cross-linked polymer selected from the group consisting of Nvinyllactam or N-alkyl-N-vinylamide monomers.

US Patent 4,344,934 refers to a pharmaceutical composition in dry solid form comprising a mixture of a therapeutically effective amount of a poorly water soluble drug and a nontoxic, pharmacologically acceptable, water-soluble polymer.

The meta- ortho- and para- amino benzoic acids are also well known water insoluble compounds and are used as dye intermediates, pharmaceuticals, vitamin adducts and nutritional substances for veterinary use.

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Because of their applications in pharmaceutical areas, it is important that no solvent having toxic or other deleterious side effects be employed for solubilization of these compounds in medicinal uses. Accordingly, it is an object of the present invention to provide a highly water soluble form of aminobenzoic acid, chlorothiazide and furosemide with no objectionable side effects. Another object is to provide a chlorothiazide in a water soluble form having fortified diuretic properties.

According to this invention there is provided mono- and multi- complexed water soluble products of the above drugs which are derived from the reaction between a polyvinyl lactam such as polyvinylpyrrolidone or a polyvinylpyrrolidone-halogen complex and the selected drug or mixture of drugs. These products are true complexs containing repeating units of the complexed drug and vinyl pyrrolidone moieties.

The complexed product of this invention may also contain non-complexed vinyl lactam moiety sites of the general formula:

ch₂

--------CH

<img file="IL82264A_D0001.tif" />

CH

<img file="IL82264A_D0002.tif" />

n

<img file="IL82264A_D0003.tif" />

^CH2>״

CH

<img file="IL82264A_D0004.tif" />

wherein n has a value of from 1 to 3.

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In the case of aminobenzoic acid complexed with a poly(N-vinyl-2-lactam)-halogen complex, preferably a poly(N-vinyl-2-pyrrolidone)-halogen complex, the product contains repeating units of the following structures involving hydrogen bonding.

<img file="IL82264A_D0005.tif" />

--CH

CH ch₂

CH0-\ ״

I ² I \ ^CHr^&lt;CH2⁾n x

<img file="IL82264A_D0006.tif" />

ha!03®

<img file="IL82264A_D0007.tif" />

wherein n is an integer having a value of from 1 to 3 and halo is iodine, chlorine or bromine, iodine being preferred.

However, it is to be understood that hydrogen bonding explains only one of the possible structures which can be attributed to the complex. For example, hydrophobic bonding, as well as bonding by various forms 15 of Van der Waals forces can be present to either a major or minor extent in the complex.

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Indeed, it is most probable that the bonding between the polymer and drugs such as chlorothiazide and furosemide takes place through hydrophobic bonding in which the aromatic moieties of the drug compounds and the hydrocarbon chain of the poly(vinyl pyrrolidone) are responsible for the complexing interaction. ׳The hydrophobic bonding force will bring the drug molecules and the polymer chain in close contact where short range dispersion forces become operative and contribute to the stabilization of the complex. While complexation through hydrogen bonding between the carbonyl group of the lactam ring and the proton present in the donors of the respective imino drugs cannot be entirely excluded, the probability of such effect is small, under the conditions of the reaction and the initial formation of a salt. However, once the salt is destroyed, hydrogen bonding becomes more possible.

The scope of this invention is not to be restricted by theoretical considerations with respect to the nature of the complex bonding since it will be recognized that the ability of the compound to be complexed and solubilized by a poly(vinyl lactam) depends to a great extent upon the chemical, physical and morphological characteristics of the compound, the hydrophilic-hydrophobic ratio of its structural elements, the nature and relative position of its substituents, the bulkiness of the molecule in general and the substituents in particular. Small differences in any of the above factors may significantly alter the solubilizing capability. While the complexability of the compound with a poly(vinyl lactam) such as poly(N-vinyl-2-pyrrolidone) may be predicted to some extent, on the chemical character of its substituents, its solubility cannot be predicted on structural similarities alone. Instead a combination of

1465747780 aforesaid factors interacting between the compound to be complexed and the polymer must be considered. Thus, each compound must be viewed and tested individually for a determination of its solubility. To illustrate the above discussion, a compound having solubility parameters similar to both chlorothiazide and furosemide, including good solubility in alkali hydroxides, is represented by chlorzoxazone, i.e.

<img file="IL82264A_D0008.tif" />

This compound has a phenolic-type hydroxyl substituent, which complexes readily with poly(vinyl pyrrolidone). Nevertheless, the coprecipitate of this compound with poly(vinyl pyrrolidone) was found to be insoluble in water, while the coprecipitates of chlorothiazide and furosemide showed good water solubility.

The complexed units in the polymer may occur in block, random or alternating distribution. In any case, the products of this invention contain at least 8 wt. % to about 30 wt. % preferably at least 12 wt. % complexed units, and usually at least 90% of the drug component can be complexed with the lactam. For the purposes of this invention, complexing is sufficient to retain properties associated with the drug.

As indicated above, a mixture of drugs can be incorporated in the present complexes. One such mixture involves chlorothiazide fortified with furosemide in a ratio of 1:99 to 99:1, preferably between about 45:55 and about 60:40. The complexed state of the present products has been established by experiment showing that at gradual dilution from 2% to 0.01% in water, no free drug precipitated from the aqueous solution. Had the drug

1465747780 not complexed, it would have precipitated out of solution in this range of dilution. A complex water solubility of at least 15% is desired and water solubility as high as 25% and more has been achieved. In the case of ο-, m- and p- aminobenzoic acid or mixtures thereof or chlorothiazide, a 50-fold increase in water solubility has been realized. That the material remains in solution at high dilution, significantly above the solubility limit of the uncomplexed drug, is indeed unexpected. For example, only 0.3% water solubility at room temperature for aminobenzoic acid and only 0.05% water solubility at room temperature for chlorothiazide is noted.

While the complexes of the invention are stable under normal conditions, they are subject to in vivo hydrolytic forces and other physical chemical effects which lead to slow dissociation. Therefore these complexes can function as slow release systems suitable for the sustained delivery of the drug portion of the complex in medical and veterinarial applications.

The preferred complexing agents of this invention are the poly(N-vinyl-2-pyrrolidone) and poly(N-vinyl-2-pyrrolidone)-halogen complex wherein the halogen most preferably is iodine or bromine. Accordingly the preferred products of this׳invention may contain halogen complexed and/or un-complexed N-vinyl-2pyrrolidone units derived from poly(N-vinyl-2-pyrrolidone) having a K value between 12 and 30; although polymers from an oligomer to K-90 may also be employed in certain cases. Polymers of K-100 or more, because of their high solution viscosity, may limit the amount of drug which they can bring into solution in complexed form.

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־

The poly(N-vinyl-2-pyrrolidone)-halogen complex reactant of this invention can be prepared according to the process disclosed in U.S. Patent No. 4,684,519, which ׳זר.’, entitled

METHOD OF PREPARING A POLYVINYLPYRROLIDONE-HALOGEN COMPLEX; although other convenient processes for the preparation of the poly(vinyl lactam)-halogen complexes are known and can be employed to provide the complexed polymeric reactant as complexing agent in the present invention. The mole ratio of halogen to poly(N-vinyl-2-pyrrolidone) in the complex is generally between about 1:3 and about 1:15, preferably 1:8-12 so that the polymer contains a significant number of non-complexed sites on which additional complexing with drug can occur. The poly(N-vinyl-2-pyrrolidone)-halogen complex reactant of this invention can have a number average molecular weight between about 5,000 and about 150,000; between 15,000 and 50,000 being preferred.

In general, the complexes of the present invention are prepared by a relatively simple and direct process which involves dissolving the selected drug or drugs and the selected complexing agent in an inert solvent such as an aqueous alcoholic or alkali metal hydroxide solution to produce a solution containing between about 5% and about 25% by weight, preferably between about 8% and about 15% by weight of each reactant. It is recommended that solutions of the drug and complexing agent be prepared separately and then combined in the desired weight ratio of lactam to drug. For example, a weight ratio of from about 1:1 to about 10:1 has been found suitable.

The resulting solution containing drug and complexing components are thoroughly mixed over a period of from about 5 minutes to about 3 hours at a temperature

1465747780 above 3°C. and below the boiling point of the solvent under atmospheric pressure up to a pressure of about 50 psig.

After reaction is completed to the degree of complexing desired, solvent is removed and the product is recovered.

More specifically, aminobenzoic complexes of this invention can be prepared by separately dissolving the aminobenzoic acid and the vinyl lactam complexing agent in a to Cg alcohol solution, preferably an ethanol solution. The vinyl lactam reactant can be defined by the formula

--a! ------- ch₂--

<img file="IL82264A_D0009.tif" />

--Wn Jm wherein n has a value of 1 to 3 and m has a value of from 5 to 3,500 or the halogen complex of this lactam, preferably the iodine or bromine complex of the lactam.

The solutions are then preferably combined in a weight ratio of complexing agent to acid of between about

4-7:1, and thoroughly mixed at a temperature preferably between about 4°C. and about 100°C., most preferably from 10’C. to about 40°C. The mixture is agitated under these conditions for a period of from about 10 and about 30 minutes.

After completion of the reaction the resulting mixture comprising a liquid alcohol phase and a solid multicomplexed product phase is treated to remove solvent by any conventional means, such as rotary evaporation or freeze drying. Evaporation is conducted in vacuo, e.g. under a pressure of from about 2 to about 40 mm Hg,

1465747780 preferably not more than 20 mm Hg. The remaining solids are recovered and dried at a temperature between about

45°C. and about 100°C., preferably between about 50°C. and about 65®C. for a period of 1 to 24 hours.

The dried product of the process is readily dissolved in water and the water solubility of the aminobenzoic acid in this multicomplexed form is increased from about 0.3% to at least 25% at room temperature.

The chlorothiazide complexes of this invention are similarly prepared by e.g. separately dissolving chlorothiazide or a chlorothiazide-furosemide 50/50 mixture and the complexing agent described above in an aqueous alkali metal hydroxide solution, e.g. a 1.8% to 5% sodium hydroxide or potassium hydroxide solution, to provide solutions preferably containing 8% to 15% by weight concentration of the respective reactants.

These solutions are then combined so as to provide a weight ratio of complexing agent to total drug reactant between about 4:1 and about 7:1. The resulting solution, at a pH of between about 7.5 and about 10, e.g. between 8 and 9, is thoroughly mixed at a temperature preferably between about 4’C. and about 100°C., most preferably between about 10^eC. and about 40’C. for a period of from about 10 to about 30 minutes to produce the alkali metal salt of the drug moiety or moieties when mixtures are employed as the drug component.

After completion of the reaction, or complexing to the degree desired, the resulting liquid mixture comprising the alkali metal salt moieties of the complex and aqueous alkali metal hydroxide solvent, is treated to remove solvent by any conventional means, such as rotary evaporation or freeze drying. Evaporation is conducted in vacuo, e.g. under a pressure of from about 2 to about 40 mm Hg, preferably not more than 25 mm Hg. The complexed salt liquid is recovered and dried at a

1465747780 temperature between about 45’C. and about 100°C., preferably between about 50’C. and about 65°C. in vacuo for a period of 1 to 24 hours to produce a solid salt complex.

The dried complex is then mixed with water and the pH is adjusted to between about 3.5 and about 7, preferably to between about 5 and about 6.3 with a mineral acid, preferably HC1 in a 1.8-5% aqueous solution, to convert the complexed alkali metal salt of the sulfamyl group to a sulfamyl radical and the metal carboxylate group to a carboxyl radical so as to produce the complexed product of the invention.

The resulting chlorothiazide or chlorothiazide and furosemide in this complexed form is stable and is found to have a water solubility increased from about 0.05% to at least 15% or more at room temperature.

Having thus generally described the present invention, reference is now had to the following examples which illustrate preferred embodiments but which are not to be construed as limiting to the scope of the invention as more broadly set forth hereinabove and in the appended claims.

EXAMPLE 1

Poly(N-vinyl-2-pyrrolidone), K-30 (12.5 grams) was dissolved in 112.5 grams of a 2% aqueous sodium hydroxide solution and poured into a dropping funnel. Chlorothiazide (1.25 grams) dissolved in 11.25 grams of 2% aqueous sodium hydroxide solution and 1.25 grams of furosemide in 11.25 grams of 2% aqueous hydroxide solution were poured into separate dropping funnels. The solutions from each dropping funnel were gradually added to a 500 ml glass flask over a period of 15 minutes during which

1465747780 period they were thoroughly mixed at room temperature at atmospheric conditions. The contents of the flask was then subjected to rotary evaporation under 21 mm Hg vacuum at 80״C. to remove the water. The dried material which is the sodium salt □f the complex was ground in a mortar to a particle fineness passing a 100 mesh screen.

In a screwcap jar, 2 grams of the above salt complex was agitated on a horizontal shaker at room temperature with 20 grams of distilled water, corresponding to a 1.6% solution of the chlorothiazide and furosemide. After about 0.5 hour a clear solution was obtained and the pH was adjusted to 5.5 with a small amount of concentrated hydrochloric acid solution. The complexed chlorothiazide and furosemide remained in solution at the acid pH.

An additional 2 grams of the salt complex was added to the clear liquid, thus raising the concentration of chlorothiazide and furosemide to 3.2%. The pH was again adjusted to 6 without the appearance of haze. The step of additional 2 gram additions with adjustment of the pH to the acid side was repeated 5 times until a total of 14 grams of the polymer-chlorothiazide-furosemide complex was reached, corresponding to 10.5% solution of chlorothiazide and furosemide in water. After adjusting the pH to 6.2, the solution remained clear and its clarity did not diminish on standing for 7 days

As a control, 1 gram of chlorothiazide in 90 grams of distilled water was introduced into a screwcap jar and the pH adjusted to 6 with a buffer solution. Water was added to bring concentration of chlorothiazide to 1% and the mixture was shaken at room temperature for 24 hours after which the solubility of chlorothiazide was found to be 0.05%.

The solubility test for chlorothiazide was repeated except that furosemide was substituted. The water solubility of furosemide was found to be 0.06%.

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EXAMPLE 2

Example 1 was repeated and 3.5 grams of the dry complexed product were dissolved in 5.0 grams of distilled water. The resulting solution was adjusted to a pH of 6.2 with concentrated hydrochloric acid. This aqueous solution, containing 10.5% of chlorothiazide and furosemide, remained clear and its clarity did not diminish after standing for 1 week.

Examples 1 and 2 are intended to set forth preferred embodiments of the present invention; however, many variations and modifications of the above experiment and complexed products will become apparent from the foregoing description and disclosure. For example, other alkali metal hydroxide solvents, as well as other higher or lower molecular weight poly(N-viny!pyrrolidones) or other mole ratios of polymer to drug species can be employed to provide the corresponding complexes wherein the water solubility of chlorothiazide and furosemide is markedly increased.

EXAMPLE 3

COMPARATIVE EXAMPLE

Poly(N-vinyl-2-pyrrolidone K-30 (12.5 grams) was dissolved in 112.5 grams of 0.2% aqueous sodium hydroxide solution. Chlorzoxazone (2.5 grams) was dissolved in 22.5 grams of 2% sodium hydroxide solution.

The solutions were mixed and coprecipitated using the procedure of Example 1. Two grams of the resulting solid were placed in a screwcap jar and 20 grams of distilled water were added. After shaking for 1 hour, the solution was acidified to pH 5.5 with concentrated hydrochloric acid. The solid precipitated out of the solution, and remained insoluble even when it was diluted further with the addition of another 20 grams of distilled water and shaken overnight.

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EXAMPLE 4

Chlorothiazide (5 grams) was dissolved in 45 a 2% aqueous solution of sodium hydroxide and the added to a dropping funnel. Poly(N-viny1-2K-30 (20 grams) was separately dissolved in

-------ium hydroxide solution and grams of the grams of solution pyrrolidone), 180 grams of an aqueous 2% sodi poured into a separate dropping funnel, chlorothiazide solution and 200 grans of the polyvinylpyrrolidone solution were charged dropwise over a period of 15 minutes to a 500 milli_liter ״ash and the result!״״ solution agitated for 15 minute־ at room temperature. The P of the reacting mixture _{was about and}formed with the sodium salt of poly(N-viny1-2pyrrolidone) and chlorothiazide.

The liquid reaction medium is then evaporated

- —Ivent and the similar vacuum at 60’C.

under about 20 mm Hg to remove the sol resulting solid was dried under overnight.

In complex was temperature with 20 grams of distilled wat corresponding to 2.2» of the complex. .־_ hour a clear solution was obtained and the to 5.5 with concentrated hydrochloric acid polymer-ohlorothiazide complex remained in acid pH.

An additional 2 grams of the salt added to the clear liquid, of chlorothiazide to 4.3%. about 6 without the appearance of ha “ ^acre״^oaP iar, 2 grams of the above salt agitated on a horizontal shaker at room er,

After about 1/2 pH was adjusted solution. The solution at the complex was thus raising the concentration The pH was again adjusted to -- 4ze. The step of additional 2 gran additions with adjustment of the pH to the acid side was repeated 8 times until a total of 20 grams of the polyner-chlorothiazide complex was reached corresponding to 16.2* solution of chlorothiazide in water.

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As a control, chlorothiazide (1 gram) was placed in a screwcap jar, where it is mixed with 90 grams of distilled water. The pH was adjusted with a buffer solution to 6 and distilled water was added to bring the solution to 1% concentration. The resulting mixture was agitated on a horizontal shaker at room temperature for 24 hours. After this period the water solubility of the chlorothiazide solid which remained in the aqueous solution was found to be 0.05%.

EXAMPLE 5

Chlorothiazide (5 grams) and poly(vinylpyrrolidone) K-15 (20 grams) respectively, were dissolved in 2% aqueous sodium hydroxide to form 10% solutions. These solutions were mixed and the mixture were dried as described in Example 1. The product was the sodium salt of the poly(vinylpyrrolidone)-chlorothiazide complex.

The complex sodium salt solid (20 grams) was placed in a screwcap jar wherein it was agitated on a horizontal shaker with 18.0 grams of distilled water for a period of 1/2 hour. The pH was then adjusted to 6.5 with a concentrated aqueous hydrochloric acid solution to convert the complexed salt to the complexed product of the process and agitation was continued for 2 hours. At the end of this period, a clear solution having a pH of 6.5 was obtained and the water solubility of the chlorothiazide in the complex was found to be 16.2%.

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EXAMPLE 6

Example 1 was repeated except that dimethyl formamide was substituted for the 2% sodium hydroxide solution. 1 gram of the resulting precipitate containing 0.2 grams of chlorothiazide was added to 99 grams of distilled water. After shaking for 24 hours at room temperature none of the chlorothiazide had dissolved in the water.

Examples 1-2 and 4-6 are intended to set forth a preferred embodiment of the present invention; however, many variations and modifications of the above experiments and complexed products will become apparent from the foregoing description and disclosure. For example, other alkali metal hydroxide solvents can be employed and other higher or lower molecular weight poly(N-vinylpyrrolidones) or poly(N-vinyl-caprolactams) or other mole ratios of polymer to chlorothiazide can be substituted to produce complexes wherein the chlorothiazide shows markedly increased water solubility.

EXAMPLE ^A. PREPARATION OF POLY(N-VINYL-2-PYRRQLIDONEIODINE COMPLEX

A 35% poly(N-vinyl-2-pyrrolidone) in aqueous solution was made up. A separate ethanol solution of iodine and hydriodic acid, in a mole ratio of 4:1 was separately prepared. Into a 5 liter, 4-necked flask equipped with a mechanical stirrer, a reflux condenser and a thermometer, was introduced 2214.0 grams of the aqueous polymer solution. The solution was heated to 85°C.

146 5747780 whereupon 789.0 grams of 20% iodine in ethanol and 68.6 grams of 56% hydriodic acid was added over a 2 minute period. The resulting mixture was stirred at 85°C. for 90 minutes to form the poly(N-vinyl-2-pyrrolidone)-iodine complex. The flask was then equipped with a Liebig condenser and distilled to remove the ethanol-water azeotrope at a temperature increasing from 85‘C. to 90°C. During distillation, distilled water was added so as to maintain the solid complexed product in the reaction mixture at about 24%.

After 90 minutes, the distilland was cooled below 40^־C. and the condenser was attached to a vacuum source through 3 aeetone-dry ice traps. Remaining azeotrope was then removed at 38-39’C. under 55 mm/Hg pressure. The remaining poly(N-vinyl-2-pyrr_olidone)-iodine complexed solution was cooled to room temperature and deionized water (1800 grams) was added. The solution was fed to a spray dryer from a graduated dropping funnel, said spray dryer operating at 5.4 Kg/cm² air pressure; inlet air temperature between 270 and 280״C.; outlet air temperature between 105 and 1250־. and feed rate of 15 mils per minute. The available iodine of the spray dryad complexed product was 11.89%.

^B. PREPARATION OF POLY(N-VINYL-2-PYRROLIDONE)lODINE-p-AMINOBENZOIC DOUBLE COMPLEX

100 grams of p-aminobenzoic acid were dissolved m 1,000 grams of ethanol and 100 grams of poly(N-vinyl-2pyrrolidone)-iodine complex from part A was separately dissolved in 1,000 grams of ethanol. These solutions were introduced into separate dropping funnels from which 100 grams of p-aminobenzoic acid solution and 400 grams of the iodine complex solution were introduced dropwise in a

1465747780 period of about 20 minutes into a 1,000 milliliter flask and mixed for a period of about 15 minutes at room temperature. The flask was then placed on a rotary evaporator and ethanol solvent was removed in vacuo (about 20 mm Hg). The remaining solid multicomplexed compound was then dried in a vacuum oven in vacuo at 60’C. for δ hours. The multicomplexed product contained 20 % by _wt. of p-aminobenzoic acid.

EXAMPLE

WATER SOLUBILITY OF THE DOUBLE COMPLEX grams of the poly(N-vinyl-2~pyrrolidone)iodine-p-aminobenzoic acid double complex was placed in a screwcap jar and agitated with 35 grams of distilled water in a horizontal shaker at room temperature for one hour after which a viscous solution was obtained. The solution was allowed to stand at room temperature for an additional 5 hours during which time bubbles entrained during the shaking operation disappeared, it was noted that all of the solids went into solution and that the solution contained 13 grams of p-aminobenzoic acid, corresponding to a 27.1% solubility of the para-aminobenzoic acid moiety.

As a control, the solubility of uncomplexed p-ammobenzoic acid in water was found to be 0.3%.

EXAMPLE

PREPARATION OF POLY(N-VINYL-2-PYRROLIDQNE)-lODINE o-AMINOBENZOIC ACID DOUBLE COMPLEX

The procedure in Example 7 parts A and B were repeated except that o-aminobenzoic acid was substituted for p-aminobenzoic acid.

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The double complexed product recovered after drying in the vacuum oven was subjected to the solubility test described in Example 7. The amount of o-aminobe״zoic acid dissolved in the form of the double complex was 13 grams corresponding to 27.1% solubility in water.

As a control, the solubility of the uncomplexed o-aminobenzoic acid in water was tested and found to be 0.5%.

As above, Examples 7-9 are intended to set forth preferred embodiments of the present invention; however, many variations and modifications of the above experiments and complexed products will become apparent from the foregoing description and disclosure. For example, other alcohol solvents can be employed for the reacting species as well as other poly(N-viny!pyrrolidone)-halogen complexes such as the bromine or chlorine complex to provide multicomplexes wherein the aminobenzoic acid shows markedly increased water solubility.

EXAMPLE

COMPARATIVE EXAMPLE

The procedure in Example 7 was repeated except that p-dimethylamino benzoic acid was substituted for p-amino-benzoic acid.

The adduct recovered after drying was subjected to the solubility test described in Example 8 by dissolving 2 grams of adduct in 20 grams of distilled water. However, the material failed to dissolve even after it was further diluted by the addition of another 20 grams of distilled water.

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EXAMPLE 11

Para-aminobenzoic acid and poly(N-vinyl-2pyrrolidone) K-30 were each separately dissolved in ethanol to provide 10% solutions. A 200 g. solution containing 20 g. of the aminobenzoic acid and 1000 grams of the poly(vinylpyrrolidone) solution were then charged dropwise into a 2000 milliliter glass flask over a period of 10 minutes. The mixture was stirred for an additional 10 minutes, after which the flask was placed on a rotary evaporator and ethanol was removed in vacuo. The remaining complexed product of solid p-aminobenzoic and/poly(N-vinyl-2-pyrrolidone) was recovered and dried in vacuo at 60°C. overnight.

Twenty grams of the dried complexed product were placed in a screwcap jar and 10 grams of distilled water were added thereto. The mixture was placed on a horizontal shaker and was agitated for 6 hours at room temperature. At the end of this period, the solid complex was completely dissolved and the water solubility of the aminobenzoic acid in the complex was found to be 25%.

EXAMPLE 12

The experiment of Example 11 was repeated, except that poly(N-vinyl-2-pyrrolidone) K-12 was substituted for K-30 and the mole ratio of poly(vinylpyrrolidone) to p-aminobenzoic acid was maintained at 4:1. The resulting dried solid complexed compound (21.6 grams) was placed in a screwcap jar with 9 grams of distilled water and agitated for 24 hours at room temperature to yield a clear viscous solution. The water solubility of the p-aminobenzoic acid in the p-aminobenzoic acid/polyvinylpyrrolidone complexed product of this experiment was found to be 32.5%.

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EXAMPLE 13

By way of comparison, p-aminobenzoic acid (1 gram) was placed in a screwcap jar with 99 grams of distilled water and the mixture was agitated for 24 hours at room temperature. After this extended mixing time, th« aqueous phase contained almost the original amount of solid aminobenzoic acid. The water solubility of the aminobenzoic acid was found to be 0.5%.

EXAMPLE 14

The experiment of Example 11 was repeated except that m-aminobenzoic acid was substituted for p-amino benzoic acid and K-15 poly(N-vinyi-2-pyrrolidone) was substituted for K-30 poly(_N-vi״_yl-2-pyrrolido״e). After repeating the solubility test described in Example 11, the water solubility of the m-aminobenzoic acid in the resulting m-aminobenzoic acid/poly(N-vinyl-2-pyrrolldone) complex was found to be 6.3%.

EXAMPLE 15

As a control £or Example 14, 1 gram of m-aminobenzoic acid was placed in a screwcap jar with 99 grams of distilled water and agitated for 24 hours at room temperature. At the end of this period, almost all the original solid m-aminobenzoic acid remained and the water solubility of this compound was found to be 0.5%.

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EXAMPLE 16

The experiment of Example 11 was repeated except that o-aminobenzoic acid was substituted for p-amino benzoic acid. Twenty grams of the resulting amorphous solid complex of o-aminobenzoic acid/poly(N-vinyl-2pyrrolidone) were then placed in a screwcap jar where it was mixed with 10 grams of distilled water at room temperature and agitated for 6 hours. At the end of this period, a clear solution was obtained and the water solubility of o-aminobenzoic acid in the complex was found to be 25.0%.

EXAMPLE 17

The complexing reaction reported in Example 16 was repeated except that poly(N-vinyl-2-pyrrolidone) K-12 was substituted for poly(N-vinyl-2-pyrrolidone) K-30 and the mole ratio of polymer to o-aminobenzoic acid was maintained at 4:1. The resulting o-aminobenzoic acid/poly(N-vinyl-2-pyrrolidone) complex product was recovered and after drying, 21.6 grams of the solid complex was placed in a screwcap jar where it was agitated with 9 grams of distilled water'at room temperature for 24 hours. After this period, a clear solution was obtained and the water solubility of the o-aminobenzoic acid in the complex was found to be 32.5%.

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EXAMPLE 18

By way of control for Examples 16 and 17, o-ammobenzoic acid (1 gram) was placed in a screwcap jar where it was agitated with 99 grams of distilled water at room temperature for 24 hours. After this period, almost all of the original o-aminobenzoic acid solids still remained and the water solubility of o-aminobenzoic acid was found to be 0.3%.

Examples 11, 12, 14, 16 and 17 are intended to set forth preferred embodiments of the present invention; however, many variations of the above experiments and complexed products will become apparent from the foregoing description and disclosure. For example, other alcohol solvents can be employed as well as other higher or lower molecular weight poly(N-vinylpyrrolidones) or poly(Nvinyl-caprolactams) can be substituted to produce complexes wherein the aminobenzoic acid shows markedly increased water solubility.

EXAMPLE 19

For comparison, 100 g. of a 10% ethanolic solution of p-dimethylamino benzoic acid, and 500 g. of ethanolic poly(vinylpyrrolidone), containing 50 g. polymer were charged dropwise into a 1000 milliliter flask over a period of 10 minutes. The mixture was stirred for an additional 10 minutes, then the solvent was removed in vacuo on a rotary evaporator, and the solid adduct was recovered and dried in vacuo at 60״C. overnight. Two grams of the adduct were placed in a screwcap jar, and 20 g. distilled water was added. The flask was placed on a horizontal shaker and was agitated for 24 hours at room temperature. After that period, the adduct remained undissolved, which indicates that a soluble complex was not formed.