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Study of Complex Formation by Polyethylene Glycol and Dimethylurea with Some Pharmaceuticals*
Study of Complex Formation by Polyethylene Glycol and Dimethylurea with Some Pharmaceuticals* By J. L. LACH, K. RAVEL, and S. M. BLAUG The formation of molecular complexes in aqueous solution by the interaction of pharmaceuticals and some complexing agents has been reported. However, the complexing agents used in these studies were high molecular weight compounds such as polyethylene glycol, carboxymethylcellulose, polyvinylpyrrolidone, and the xanthines. Experimental evidence is offered to sup ort the existence of the formation of complexes in solution between sym-dimetiylurea, a highly soluble low molecular weight compound, and p-aminobenzoic acid, p-hydroxybenzoic acid, o-hydroxybenzoic acid, m-hydroxybenzoic acid, p-aminosalicylic acid, and acetylsalicylic acid. Phenobarbital did not undergo interaction with sym-dimethylurea. The interaction of polyethylene glycol and the parabens was also studied. The effect of such interaction on the antibacterial activity of the parabens is currently under investigation.
These molecular reactions may be of the type: Dimethylurea & c i d s D i m e t h y l u r e a -Acidn. No attempt was made to calculate the stability constants for these reactions, since an exact stoichiometrical relationship of amide-acid ratio concentration of the complex is required. The solubility method employed in these studies does not permit such a calculation. since the free acid concentration
of molecular complexes in Taqueous solution by the interaction of pharmaceuticals and some complexing agents has been reported (1-5). However, the complexing agents HE FORMATION
+
used in these studies were high molecular weight compounds such as PEG, carboxymethylcellulose, PVP, and the xanthines. sym-Dimethylurea, a highly soluble, low molecular weight compound, was investigated for purposes of comparison; since, on the basis of a previously proposed theory a carbonyl group of an amide, being a good electron donor, would be expected to show an attraction for the electron-accepting groups of compounds having acidic hydrogen. Additional information on the interaction of PEG and certain pharmaceuticals, such as the parabens and PABA, would be of value in studies being conducted in these laboratories on the effect of this reaction on the antibacterial activity of the compounds under investigation.
0 6 12 18 24 30 36 42 48 54 60 66 72 CONCN. OF DIMETHYLUREA I N MOLES/L. X
EXPERIMENTAL Interactions with sym-Dimethy1urea.-In this study the solubility method previously described (4) has been employed to determine the extent of the complexing tendency of polyethylene glycol 4000 and 6000 and dimethylurea with some pharmaceutical compounds. Data from these solubility studies are recorded in Fig. 1. The phase diagram shows the effect of varying concentrations of dimethylurea on the solubility in water a t 30' of the compounds investigated. I t is evident that these acidic compounds, with the exception of phenobarbital, do undergo molecular complex formation with dimethylurea as shown by their increase in solubility. The lack of interaction of phenobarbital is attributed in part to a greater competition of dimethylurea for the water molecules than for the phenobarbital molecules.
* Received January 7 , 1957, from the State University of Iowa, College of Pharmacy, Iowa City.
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Fig. 1.-Phase diagram showing the effect of varying concentrations of dimethylurea on the apparent solubility of several organic acids in water at 30'. in the system is an invariant. However, data presented here does offer a means of comparison of the extent of complex formation of the various pharmaceuticals under investigation. Interactions with Polyethylene GlycoL-The effect of the polyethylene glycol on the apparent solubility in water a t 30" of several compounds under study is represented in Figs. 2 and 3. I t is seen that p-aminobenzoic acid and methyl and propyl p-hydroxy benzoate do exhibit a definite reaction as would be expected on the basis of a previously proposed theory (1). Sorbic acid exhibited little tendency to complex, whereas boric acid did not interact with the polyethylene glycol. This negative interaction may probably be attributed to
615
616
JOURNAL OF THE
AMERICAN PHARMACEUTICAL A s s o c r A r r o N
the high hydropliilic nature of boric acid. As with the dimethylurea interactions, no attempt was made t o calculate stability constants for reasons already mentioned.
GENERAL DISCUSSION Data have been presented indicating complex formation between sym-dimethylurea and polyethylene glycol with a number of pharmaceutical compounds. Although the information presented here does not permit calculation of exact stability constants for these reactions, it does provide a qualitative means of comparison of the degree of interaction of the various complexing agents under study. It also indicates that reactions of this type are far more widespread than commonly realized. Consideration of such interactions in formulation of drug prepaxations should be recognized. It was for this reason that a study of the parabens and polyethylene glycol was undertaken. Evidence has been presented, Fig. 2, indicating that methyl
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concentrations of dimethylurea or polyethylene glycol. Fifty milliliters of distilled water was added to each, except for the hydroxybenzoic acids, to which was added 50 ml. of 0.005 N sulfuric acid solution in order t o suppress any ionization. The bottles were placed in a mechanical shaker in a constant-temperature bath and equilibrated for a period not less than ten hours a t 30' after which
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20
30
40
50
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L_--
CONC OF PEG 4000 IN EQUIV./L. X 10'
616
2 2 .4
Fig. 3.-Phase diagram showing the effect of varying concentrations of PEG 4000 on the apparent solubility of certain acids in water at 30".
1 T
10 20 30 40 50 60 70 CONCN. O F PEG IN EQUIV./L. X lo2
0
Fig. 2.-Tnfluence of PEG 4000 and 6000 on the solubility of the parabens in water at 30". and propyl p-hydroxy benzoate do undergo molecular formation with PEG. The effect of this interaction on the antibacterial activity of the parabens is being studied in our laboratory.
PROCEDURE Reagents.-Recrystallized p-aminobenzoic acid, p-hydroxybenzoic acid, o-hydroxybenzoic acid, mhydroxybenzoic acid, p-aminosalicylic acid, methyl p-hydroxybenzoate, propyl P-hydroxybenzoate, acetylsalicylic acid, boric acid, sorbic acid, and phenobarbital; 0.05 N barium hydroxide solution, 0.1 N alcoholic sodium hydroxide solution, bromothymol blue, and thymol blue as indicators; sym-dimethylurea and polyethylene glycol 4000 and 6000. Method of Amlysis.--Excess quantities of the compounds under investigation were placed in 125ml. glass-stoppered bottles together with varying
time aliquot portions of the supernatant liquid were removed and analyzed for acid content by titration. p-Aminobenzoic acid was titrated with barium hydroxide solution, using bromothymol blue as the indicator. The remaining acids, except boric acid in which the U. S P . XV method was used for analysis, were titrated with alcoholic sodium hydroxide solution, using thymol blue as the indicator. The quantity of the acids used were as follows: p aminobenzoic acid 0.5 Gm.. p-hydroxybenzoic acid 1.0 Gm., 0-hydroxybenzoic acid 0.4 Gm., m-hydroxybenzoic acid 1.0 Gm., p-aminosalicylic acid 0.2 Gm., phenobarbital 0.3 Gm., boric acid 5.0 Gm., and sorbic acid 1.0 Gm. Both methyl and propyl phydroxybenzoate were determined spectrophotometrically a t a wavelength of 256 mp, correction being made for the very small absorption due t o the polyethylene glycol. The quantity of methyl and propyl p-hydroxybenzoate used per 50 ml. distilled water was 0.4 and 0.2 Gm., respectively.
REFERENCES .. . (1). .
Higuchi, T.,and Lach. J. L., THISJOURNAL, 43, 465
These molecular reactions may be of the type: Dimethylurea & c i d s D i m e t h y l u r e a -Acidn. No attempt was made to calculate the stability constants for these reactions, since an exact stoichiometrical relationship of amide-acid ratio concentration of the complex is required. The solubility method employed in these studies does not permit such a calculation. since the free acid concentration
of molecular complexes in Taqueous solution by the interaction of pharmaceuticals and some complexing agents has been reported (1-5). However, the complexing agents HE FORMATION
+
used in these studies were high molecular weight compounds such as PEG, carboxymethylcellulose, PVP, and the xanthines. sym-Dimethylurea, a highly soluble, low molecular weight compound, was investigated for purposes of comparison; since, on the basis of a previously proposed theory a carbonyl group of an amide, being a good electron donor, would be expected to show an attraction for the electron-accepting groups of compounds having acidic hydrogen. Additional information on the interaction of PEG and certain pharmaceuticals, such as the parabens and PABA, would be of value in studies being conducted in these laboratories on the effect of this reaction on the antibacterial activity of the compounds under investigation.
0 6 12 18 24 30 36 42 48 54 60 66 72 CONCN. OF DIMETHYLUREA I N MOLES/L. X
EXPERIMENTAL Interactions with sym-Dimethy1urea.-In this study the solubility method previously described (4) has been employed to determine the extent of the complexing tendency of polyethylene glycol 4000 and 6000 and dimethylurea with some pharmaceutical compounds. Data from these solubility studies are recorded in Fig. 1. The phase diagram shows the effect of varying concentrations of dimethylurea on the solubility in water a t 30' of the compounds investigated. I t is evident that these acidic compounds, with the exception of phenobarbital, do undergo molecular complex formation with dimethylurea as shown by their increase in solubility. The lack of interaction of phenobarbital is attributed in part to a greater competition of dimethylurea for the water molecules than for the phenobarbital molecules.
* Received January 7 , 1957, from the State University of Iowa, College of Pharmacy, Iowa City.
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Fig. 1.-Phase diagram showing the effect of varying concentrations of dimethylurea on the apparent solubility of several organic acids in water at 30'. in the system is an invariant. However, data presented here does offer a means of comparison of the extent of complex formation of the various pharmaceuticals under investigation. Interactions with Polyethylene GlycoL-The effect of the polyethylene glycol on the apparent solubility in water a t 30" of several compounds under study is represented in Figs. 2 and 3. I t is seen that p-aminobenzoic acid and methyl and propyl p-hydroxy benzoate do exhibit a definite reaction as would be expected on the basis of a previously proposed theory (1). Sorbic acid exhibited little tendency to complex, whereas boric acid did not interact with the polyethylene glycol. This negative interaction may probably be attributed to
615
616
JOURNAL OF THE
AMERICAN PHARMACEUTICAL A s s o c r A r r o N
the high hydropliilic nature of boric acid. As with the dimethylurea interactions, no attempt was made t o calculate stability constants for reasons already mentioned.
GENERAL DISCUSSION Data have been presented indicating complex formation between sym-dimethylurea and polyethylene glycol with a number of pharmaceutical compounds. Although the information presented here does not permit calculation of exact stability constants for these reactions, it does provide a qualitative means of comparison of the degree of interaction of the various complexing agents under study. It also indicates that reactions of this type are far more widespread than commonly realized. Consideration of such interactions in formulation of drug prepaxations should be recognized. It was for this reason that a study of the parabens and polyethylene glycol was undertaken. Evidence has been presented, Fig. 2, indicating that methyl
VOl. );r,VT.
NO.
10
concentrations of dimethylurea or polyethylene glycol. Fifty milliliters of distilled water was added to each, except for the hydroxybenzoic acids, to which was added 50 ml. of 0.005 N sulfuric acid solution in order t o suppress any ionization. The bottles were placed in a mechanical shaker in a constant-temperature bath and equilibrated for a period not less than ten hours a t 30' after which
e
$31
42b *O".,C
.G,O
l D l l D 111,
$1
0
10
20
30
40
50
60
70
L_--
CONC OF PEG 4000 IN EQUIV./L. X 10'
616
2 2 .4
Fig. 3.-Phase diagram showing the effect of varying concentrations of PEG 4000 on the apparent solubility of certain acids in water at 30".
1 T
10 20 30 40 50 60 70 CONCN. O F PEG IN EQUIV./L. X lo2
0
Fig. 2.-Tnfluence of PEG 4000 and 6000 on the solubility of the parabens in water at 30". and propyl p-hydroxy benzoate do undergo molecular formation with PEG. The effect of this interaction on the antibacterial activity of the parabens is being studied in our laboratory.
PROCEDURE Reagents.-Recrystallized p-aminobenzoic acid, p-hydroxybenzoic acid, o-hydroxybenzoic acid, mhydroxybenzoic acid, p-aminosalicylic acid, methyl p-hydroxybenzoate, propyl P-hydroxybenzoate, acetylsalicylic acid, boric acid, sorbic acid, and phenobarbital; 0.05 N barium hydroxide solution, 0.1 N alcoholic sodium hydroxide solution, bromothymol blue, and thymol blue as indicators; sym-dimethylurea and polyethylene glycol 4000 and 6000. Method of Amlysis.--Excess quantities of the compounds under investigation were placed in 125ml. glass-stoppered bottles together with varying
time aliquot portions of the supernatant liquid were removed and analyzed for acid content by titration. p-Aminobenzoic acid was titrated with barium hydroxide solution, using bromothymol blue as the indicator. The remaining acids, except boric acid in which the U. S P . XV method was used for analysis, were titrated with alcoholic sodium hydroxide solution, using thymol blue as the indicator. The quantity of the acids used were as follows: p aminobenzoic acid 0.5 Gm.. p-hydroxybenzoic acid 1.0 Gm., 0-hydroxybenzoic acid 0.4 Gm., m-hydroxybenzoic acid 1.0 Gm., p-aminosalicylic acid 0.2 Gm., phenobarbital 0.3 Gm., boric acid 5.0 Gm., and sorbic acid 1.0 Gm. Both methyl and propyl phydroxybenzoate were determined spectrophotometrically a t a wavelength of 256 mp, correction being made for the very small absorption due t o the polyethylene glycol. The quantity of methyl and propyl p-hydroxybenzoate used per 50 ml. distilled water was 0.4 and 0.2 Gm., respectively.
REFERENCES .. . (1). .
Higuchi, T.,and Lach. J. L., THISJOURNAL, 43, 465