Interaction of Methylparaben Preservative with Selected Sugars and Sugar Alcohols MINHUI MA,2 TONY LEE,1 ELIZABETH KWONG1 1
Pharmaceutical Research & Development, Merck Frosst Canada & Co., 16711 Trans Canada Highway, Kirkland, Quebec, Canada H9H 3L1 2
Analytical Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320
Received 25 January 2002; revised 7 March 2002; accepted 8 March 2002
ABSTRACT: The interaction of methylparaben preservative with selected sugars (glucose, fructose, sucrose, lactose, maltose, cellobiose) and sugar alcohols (lactitol, maltitol) were demonstrated in this study. It was observed that the formation of transesterification reaction products between methylparaben and the selected sugars occurred only under mild reaction conditions (e.g., pH 7.4 at 508C ), which were confirmed by HPLC-UV studies and mass spectrometry. On the other hand, under alkaline conditions and high temperature, degradation of the sugars predominated. Because sugars could easily undergo many possible degradation reactions and isomerization including on-column anomerization, the chromatograms of the reaction products were more complicated than those obtained from sugar alcohols. Sucrose, a nonreducing sugar, was much more stable than other selected sugars. The chromatogram of the transesterification reaction products of methylparaben with sucrose clearly showed eight peaks, which were likely to correspond to the same number of hydroxyl groups of sucrose. To compare the rate of the transesterification reaction of methylparaben with sucrose to that with sorbitol, kinetic studies were carried out. Similar rate constants were observed: 5.4 107 L mol1 s1 and 4.9 107 L mol1 s1 for sucrose and sorbitol, respectively. ß 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:1715–1723, 2002
Keywords: methylparaben; sugar; sugar alcohol; interaction; transesterification reaction; sucrose; sorbitol
INTRODUCTION Parabens, a group of alkyl esters of p-hydroxybenzoic acid, are the most-used antimicrobial preservatives in pharmaceuticals, food, and cosmetics.1 Their use as antimicrobial agents can be traced back to the 1920s.2 Their popularity is largely due to their high levels of safety and broad spectrum of preservative activity.2,3 Compared with other well-known preservatives such as
Correspondence to: Elizabeth Kwong (Telephone: 514-4283113; Fax: 514-428-2677; E-mail:
[email protected]) Journal of Pharmaceutical Sciences, Vol. 91, 1715–1723 (2002) ß 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association
sorbic acid and benzoic acid, the activity of parabens are less pH dependent. They are effective in a pH range between 4.0 and 8.0.2 The parabens increases in activity but decrease in aqueous solubility with increasing alkyl chain length. A combination of short and long chain esters is frequently used to provide effective preservation.4 Due to the formation of the phenolate anion (pKa ¼ 8.4), the antimicrobial activity of the parabens decreases at pH > 8.0.4 The parabens also undergo hydrolysis in weak alkaline and strong acidic solutions5–8 and the hydrolysis product, p-hydroxybenzoic acid, has practically no antimicrobial activity.4 Within a pH range of 3–6, however, parabens are stable enough to withstand a normal heat sterilization procedure.8
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Although hydrolysis is the most frequent degradation reaction in aqueous pharmaceutical formulations, other factors may also decrease the antimicrobial activity of the parabens such as sorption onto solid9–11 and plastic container,12– 14 solubilization by nonionic surfactants,15–17 partitioning into flavoring oils,18 and perhaps more importantly interaction/reaction with excipients. A wide range of excipients have been reported to interact/react with parabens, which include cellulose derivatives,19 ethanol,20 ethanolamine,21 b-cyclodextrin,22 and sugar alcohols (or polyols).23–26 In this article, we report the interaction of methylparaben with selected sugars through transesterification reaction, which to our best knowledge has not been reported in the literature. The sugars selected for this study are sucrose, maltose, lactose, cellobiose, glucose, and fructose. Related sugar alcohols, maltitol, lactitol, and sorbitol, are also used for comparison. The molecular structures of the selected sugars and sugar alcohols are shown in Figure 1. The interaction/reaction products were separated by HPLC and identified by LC-MS. The kinetics of the reaction between methylparaben and sucrose were studied and compared with that between methylparaben and sorbitol.
EXPERIMENTAL Materials The following materials were used as supplied: D-sorbitol (99%), D-fructose (99þ%), p-hydroxyl benzoic acid (99%) from Aldrich Chemicals Co. (Milwakee, WI); D-(þ)-glucose (99.5%), sucrose (> 99.5%), maltose (99%), maltitol (98%), a-lactose (monohydrate SigmaUltra), lactitol (99%), methyl paraben (99%), D-(þ)-cellobiose (98%) from Sigma (St. Louis, MO); sodium methyl paraben from Merck Research Laboratories (West Point, PA); tetrahydrofuran (THF) (99%) from Anachemia; trifluoroacetic acid (TFA) from Pierce; and acetonitrile (HPLC grade) from EM Science. Deionized water used for solution preparation was from a milli-Q water system. Transesterification Reactions of Methylparaben with Selected Sugars and Sugar Alcohols Individual sugar or sugar alcohol (D-glucose, maltose, lactose, D-fructose, cellobiose, lactitol, maltitol, sucrose, and D-sorbitol) solution at 0.20 M was prepared by dissolving the compound in 0.10 M phosphate buffer (pH 7.4) in a tightly capped vial. An aliquot of 750 mg of sodium methylparaben was added to each 50 mL of the sugar or sugar alcohol solutions, which was then placed in a 508C oven for up to16 h. The sample solution was then cooled to room temperature and approximately 1.5 mL of the solution was filtered through a 0.45-mm PTFE syringe filter and the last 1 mL was collected in an HPLC vial. The samples were analyzed by HPLC and LC-MS to confirm the formation of transesterification products. The mol ratios of the sugars to sodium methylparaben in the sample solutions were approximately 2:1. Kinetic Study of the Transesterification Reactions of Methylparaben with Sucrose and Sorbitol
Figure 1. Molecular structures of the selected sugars and sugar alcohols. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 7, JULY 2002
Sucrose and sorbitol solutions containing 0, 0.3, 0.6, 0.9, 1.2, and 1.5 M were prepared in 0.10 M phosphate buffer (pH 8.0). An amount of sodium methylparaben (69.64 0.02 mg) was weighed into six clean and dry 100-mL volumetric flasks. Each sodium methylparaben sample was then made up to volume with one of the above-mentioned six sucrose or sorbitol solutions. After the sample solution was thoroughly mixed, a 5-mL aliquot was pipetted into a 10-mL glass ampule
METHYLPARABEN PRESERVATIVE WITH SELECTED SUGARS
that was then sealed using a propane torch. Ten to 15 ampules were prepared for each of the sample solutions. An aliquot of each of the six sample solutions remaining in the flask was analyzed immediately by HPLC as initial. When all of the ampules were sealed, they were placed in a 608C oven. Ampules were withdrawn from the oven one at a time for each sample solution at predetermined time intervals. Samples withdrawn from the oven were cooled to room temperature before analysis. An aliquot (20 mL) of the sample solution was injected onto the HPLC to determine the concentration of the total transesterification reaction products. Another 200-mL aliquot of the sample solution was diluted to 1.0 mL with water and then injected immediately onto the HPLC to determine the concentration of methylparaben and p-hydroxybenzoic acid using a different HPLC method. Standard solutions of methylparaben and phydroxybenzoic acid were prepared in water at the concentrations ranging from 4.0 105 M to 8 .0 104 M. Because no standard was available for the transesterification reaction products, they were quantified using the same p-hydroxybenzoic acid standard solutions because they have the same UV spectra. Standard calibrations were performed daily. Liquid Chromatography The HPLC system used in this study was a HP 1090 liquid chromatograph (Hewlett-Packard, Palo Alto, CA) equipped with a chemstation, an autosampler, and a diode array detector. Chromatograms were acquired at 255 nm with a bandwidth of 4 nm. The injection volume was 20 mL. To improve the separation of the transesterification reaction products (positional isomers), two Hewlett Packard Zorbax SB-CN (3.5 mm) columns were coupled in series (75 4.6 mm and 150 4.6 mm). Column temperature was kept at 408C. For HPLC separation of the transesterification reaction products of methylparaben with selected sugars and sugar alcohols, the following gradient (I) was used: [the mobile phase A was 0.1% (v/v) TFA in water and B was 85:15 (v/v) THF/acetonitrile] 0–14 min at 4% B, 16–36 min at 20% B, 38–40 min at 30% B, 42–51 min at 4% B. For the quantitation of the transesterification reaction products in the kinetic study, the following gradient (II) was employed: 0–23 min 10% B, 27–29 min at 70% B, 31–40 min at 10% B. The flow rate for both gradients was 0.6 mL/min.
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For the quantitation of methylparaben and phydroxybenzoic acid in the kinetic study, one Zorbax SB-CN (3.5 mm) column (150 4.6 mm) using isocratic elution at 20% B was used. The flow rate was set at 0.8 mL/min, with a run time of 17 min. LC-MS Analyses The mass spectra of the transesterification reaction products of methylparaben with selected sugars and sugar alcohols were acquired using a Finnigan LCQ Deca ion-trap mass spectrometer (San Jose, CA) with an ESI source operated in negative ion mode. An HP 1100 HPLC system with two Zorbax SB-CN (3.5 mm) columns coupled in series (75 4.6 mm and 150 4.6 mm) were used. The HPLC conditions were the same as those described in the LC section using gradient (I). The following modifications were made: 0.1% TFA was replaced by 0.1% formic acid in mobile phase A to reduce the suppression of ionization, and postcolumn flow splitting was used to reduce flow rate from 0.6 mL/min to approximately 50 mL/ min for the ESI source. The operating parameters of the ESI source were as follows: sheath gas flow rate: 60, auxiliary gas flow rate: 5, spray voltage: 4.5 kV, capillary temperature: 3508C , capillary voltage: 41 V, and tube lens offset: 25 V. Mass spectra were acquired in full-scan MS mode with a mass scan range of 50 amu. The actual mass ranges were chosen such that the molecular ions of the transesterification reaction products would fall approximately in the center of the 50 amu mass scan range.
RESULTS AND DISCUSSION Transesterification Reactions of Methylparaben with Selected Sugars and Sugar Alcohols In a recent study on the transesterification reactions of methylparaben with 12 three- to sixcarbon sugar alcohols, we demonstrated that each of the hydroxyl groups of a sugar alcohol molecule could react with methylparaben to form transesterification reaction products.26 These reaction products were positional isomers with the same m/z ratio as determined by LC-MS. The number of reaction products that were separated by HPLC was exactly the same as that expected based on the number of distinct hydroxyl groups of the molecule. As a consequence, other common sugar JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 7, JULY 2002
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excipients in pharmaceuticals were also investigated. In theory, transesterification reaction could occur between parabens and any molecules containing hydroxyl groups. However, no such study on the reaction with sugars has been reported in the literature except one unsuccessful attempt, in which no reaction products between methylparaben and aldoses, for example, ribose, xylose, or cellobiose, were observed.24 The failure to observe any reaction products was most likely due to the harsh reaction conditions that were used in their experiments (908C for 3 h at unspecified pH).24 It is well known that sugars are much less stable than sugar alcohols. At high temperature and under alkaline conditions, sugars could undergo many possible degradation reactions such as caramelization, enolization, followed by fragmentation and additional secondary reactions.27,28 In a preliminary experiment of the present study, the reaction conditions employed for the 12 three- to sixcarbon sugar alcohols (pH 12 and 908C for 2 h) were utilized for the reactions of methylparaben with the selected sugars. Under these conditions, it was observed that sample solutions turned brown very quickly upon heating and that the HPLC chromatograms of the sample solutions showed no well-defined peaks but several broad bands of many small overlapping peaks in the retention region (4–18 min) of the transesterification products. Because of the serious degradation problem, the reactions between methylparaben and the selected sugars were carried out under much milder conditions: in phosphate buffer (pH 7.4) at 508C for up to 16 h. Even under these reaction conditions, the sugar solutions turned yellow after 16 h of heating and some unidentified broad peaks, most likely due to sugar degradation, were observed in the HPLC chromatograms. The chromatograms of the transesterification reaction products of methylparaben with the selected sugars and sugar alcohols are shown in Figure 2. Among the selected sugars, sucrose seemed to be more stable than other sugars, as indicated by the well-defined peaks of the reaction products between sucrose and methylparaben in the chromatogram (Figure 2c). This is probably due to the fact that sucrose is a nonreducing sugar. One common feature of other selected sugars was the presence of on-column reaction as characterized by the plateaus between peaks.29 In aqueous solution, a phenomenon common for sugars is mutarotation, which involves the equilibration of the JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 7, JULY 2002
a- and b-anomers. Anomerization between the a- and b-anomers was most likely responsible for the on-column reactions observed in Figure 2. Similar on-column anomerization has been reported in the literature for the HPLC separation of acyl glucuronides.30 Under the same reaction conditions, the selected sugar alcohols, maltitol and lactitol, were very stable. The sample solutions of maltitol and lactitol remained colorless after 16 h of heating and no extra peaks due to degradation were observed in the chromatograms of the reaction products (Figure 2g and h). Maltitol and lactitol both have three primary and six secondary hydroxyl groups. The chromatogram of the reaction products of methylparaben with maltitol showed exactly three major and six secondary peaks. In the case of lactitol, three major and only five secondary peaks were observed. The missing secondary peak for lactitol was most likely due to coelution with the other peak because the HPLC method shown in Figure 2 was developed using the transesterification products of maltitol and was not optimized for the reaction products of lactitol. There was no simple correlation between the number of peaks and the number of hydroxyl groups for the selected sugars except for sucrose. Sucrose has three primary hydroxyl groups—one on the glucose unit, and two on the fructose unit— and five secondary hydroxyl groups. Interestingly, five small peaks, two medium size peaks, and one major peak were observed in the chromatogram (Figure 2c). Glucose and fructose are monosaccharide with five hydroxyl groups, which, in theory, would generate five transesterification products (or positional isomers). However, after 7 h of heating at 508C, six peaks (three pairs of peaks due to on-column reactions) were observed in the chromatogram of the glucose/methylparaben mixture while only two peaks were observed in the case of fructose (chromatograms not shown). After 16 h, several additional peaks/shoulders were observed (see arrows in Figure 2a and b), which may be attributed to the isomerization reaction occuring for glucose and fructose. Due to enolization, glucose, fructose, and mannose are in equilibrium through the common 1,2-enediol. Glucose and fructose are the major components at equilibrium.28,31 This may explain why additional peaks (see arrows) with the same retention times as those major peaks found in Figure 2b were observed in Figure 2a and vice versa. Other selected sugars (cellobiose, maltose, and lactose)
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Figure 2. Chromatograms of the transesterification reaction products of methylparaben with (a) glucose, (b) fructose, (c) sucrose, (d) cellobiose, (e) maltose, (f ) lactose, (g) maltitol, and (h) lactitol at pH 7.4 and 508C for 16 h. Arrows in (a) and (b) indicating enolization reaction products of glucose and fructose, respectively.
are disaccharides that have eight hydroxyl groups including two primary ones. As can be seen from Figure 2d, e, and f it is not easy to count the number of well-defined peaks in the chromatograms due to the complication caused by oncolumn reaction and sugar degradation. However, it is important to note that the goal of the present study was not to achieve ideal separation but to demonstrate the presence of transesterification reaction between selected sugars and methylparaben. For this purpose, both the UV and the mass spectra of the peaks were used to identify the reaction products. Some of the small peaks that were likely caused by the reactions of methylparaben with sugar degradates were not the focus
of this study, and no attempts were made to identify those small peaks. The UV spectra of all the peaks shown in Figure 2 were acquired using a diode array detector. All the peaks showed UV spectra similar to those of methylparaben or p-hydroxybenzoic acid with a maximum absorption at 255 nm. Because all the peaks elute before p-hydroxybenzoic acid (22.5 min, peak not shown in Figure 2), these peaks are most likely the transesterification reaction products of methylparaben with the selected sugars. This was confirmed by the LC-MS experiments. Figure 3 shows some typical total ion chromatograms (a and c) and mass spectra (b and d) of the JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 7, JULY 2002
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Figure 3. Total ion chromatograms of the transesterification reaction products of methylparaben with (a) glucose and (c) sucrose. Typical mass spectra of the transesterification products peaks are shown in b (retention time ¼ 9.25 min, glucose) and d (retention time ¼ 10.40 min, sucrose), respectively.
transesterification reaction products of methylparaben with glucose and sucrose. Because the mass scan range was limited to the expected molecular ions of the reaction products, p-hydroxybenzoic acid and methylparaben were not detected, and therefore excluded from the total ion chromatograms. All the peaks shown on the total ion chromatograms were expected to be the reaction products. It can be seen that the total ion chromatograms in Figure 3a and c correspond well with the UV chromatograms in Figure 2a and c, respectively. It was found that all the peaks on the same total ion chromatograms had identical mass spectra with the same m/z ratio for their molecular ions. The m/z ratio matched what was expected based on the molecular weight of sugar monoesters of p-hydroxybenzoic acid. For example, the mass spectra of the five peaks shown in Figure 3a gave the same m/z ratio of 299 [(M-H)] as shown in Figure 3b, and the molecular weight of glucose monoesters of p-hydroxybenzoic acid is 300. The LC-MS data confirmed that all the peaks separated or partially separated in Figure 2 were indeed the transesterification reaction products of methylparaben with sugars. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 7, JULY 2002
Kinetic Study of the Transesterification Reactions of Methylparaben with Sucrose and Sorbitol The kinetics of the reaction between methylparaben and selected sugar alcohols has been reported,23 where the transesterification reaction was treated as a simple second-order reaction. In fact, transesterification reaction between methylparaben and sugar alcohols or sugars involves n parallel second-order reversible reactions because of the presence of n hydroxyl groups in the molecule. The possible interconversion between the transesterification reaction products (positional isomers) as demonstrated in a previous study26 could further complicate the situation. For such a complex system, it would be extremely difficult if not impossible to derive the rate equations for all involved reactions. The purpose of this kinetic study was to determine the overall transesterification rate of sucrose with methylparaben, and to compare to that of sorbitol. For this purpose, the simplified approach by Runesson and Gustavii23 as shown in Figure 4 is sufficient. The only modification needed is to call k1 the overall rate constant of the n transester-
METHYLPARABEN PRESERVATIVE WITH SELECTED SUGARS
Figure 4. The transesterification reaction and hydrolysis pathways.
ification reactions instead of the second-order rate constant for the transesterification. In theory, transesterification reaction is reversible. Because a large excess of sucrose and sorbitol (at least 85 times higher concentration than methylparaben) was used in this study, the reaction could be treated mathematically as an irreversible reaction. By following the derivation of Runesson and Gustavii,23 the rate of degradation of methylparaben can be expressed by dCmp =dt ¼ k1 Cs Cmp þ k2 Cmp
ð1Þ
where Cmp and Cs are the concentrations of methylparaben and sucrose or sorbitol, respectively, k2 is the pseudofirst-order rate constant for the hydrolysis of methylparaben. Because Cs >> Cmp, k1Cs & constant, eq. (1) can be rewritten as dCmp =dt ¼ kobs Cmp
ð2Þ
where the observed rate constant kobs ¼ k1 Cs þ k2
ð3Þ
Equation (2) can be integrated to give log Cmp;t ¼ log Cmp;0 kobs t=2:303
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xybenzoic acid agreed well (within 5%) in the concentration range used, which indicated that the effect of esterification on the UV absorptivity of p-hydroxybenzoic acid seemed to be minimal. Therefore, the standard of p-hydroxybenzoic acid was used to quantify the transesterification reaction products. The plots of log Cmp,t versus time t are shown in Figures 5 and 6, respectively, for the degradation (i.e., transesterification and hydrolysis) of methylparaben in sucrose and sorbitol solutions. According to eq. (4), the plots should be linear with a slope of kobs/2.303. This was indeed the case up to certain time points as shown in the figures. For the reactions in sucrose especially for those with higher sucrose concentrations, the slopes started to decrease after 300 h of reactions. Much less deviation from linearity was found for the reactions in sorbitol. For those solutions without sucrose and sorbitol, almost no deviation from linearity was found. These observations suggested that the deviation was most likely caused by the degradation of sucrose and sorbitol after a long time of heating at 608C in the pH 8.0 phosphate buffer. According to eq. (3), any decrease in sucrose or sorbitol concentration would decrease the observed rate constant, kobs, or the slope of the plots. Sorbitol is more stable than sucrose, so less deviation was expected. Because of the significant deviation, time points after 300 h were not included in the linear fitting. The observed rate constants, kobs, as a function of the concentrations of sucrose and sorbitol are plotted in Figure 7.
ð4Þ
where Cmp,0 and Cmp,t are the concentrations of methylparaben at initial and time t. According to eq. (4), a plot of log Cmp,t versus t should give a straight line with a slope of kobs/2.303. The values of k1 and k2 can be evaluated by plotting kobs versus Cs. According to eq. (3), it should give a straight line with a slope of k1 and an intercept of k2. In this study, the reaction of methylparaben with sucrose and sorbitol were carried out at pH 8.0 and 608C. The concentrations of the total transesterification reaction products, methylparaben and p-hydroxybenzoic acid in the sample solutions at different time points were analyzed by HPLC. Methylparaben and p-hydroxybenzoic acid were quantified using calibration curves of their standards. It was found that the two calibration curves of methylparaben and p-hydro-
Figure 5. Plots of log Cmp versus time for the hydrolysis and transesterification of methylparaben in (a) 0 M, (b) 0.3 M, (c) 0.6 M, (d) 0.9 M, and (e) 1.2 M of sucrose in 0.1 M phosphate buffer (pH 8.0) and at 608C. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 7, JULY 2002
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CONCLUSIONS
Figure 6. Plots of log Cmp versus time for the hydrolysis and transesterification of methylparaben in (a) 0 M, (b) 0.3 M, (c) 0.6 M, (d) 0.9 M, (e) 1.2 M, (f) 1.5 M of sorbitol in 0.1 M phosphate buffer (pH 8.0) and at 608C.
According to eq. (3), the overall rate constants for the transesterification reactions, k1, and the rate constants for the hydrolysis of methylparaben, k2, were obtained from the slopes and the intercepts of the plot: k1 ¼ 5.4 ( 0.3) 107 Lmol1s1 and k2 ¼ 8.7 ( 0.2) 107 s1 for sucrose and k1 ¼ 4.9 ( 0.5) 107 Lmol1s1 and k2 ¼ 8.5 ( 0.4) 107 s1 for sorbitol. The results showed that the rate of the transesterification reaction of methylparaben with sucrose was very similar to that with sorbitol, although sucrose has two more hydroxyl groups. Additionally, the results also showed that the hydrolysis of methylparaben is independent of the sugar or sugar alcohol molecules because the k2 values for both sucrose and sorbitol were very similar.
Figure 7. The observed rate constants for the degradation of methylparaben at varying concentrations of (*) sucrose and (&) sorbitol in phosphate buffer (pH 8.0) and at 608C. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 7, JULY 2002
The current study has clearly demonstrated that under suitable conditions not only sugar alcohols but sugars can also react with methylparaben to form transesterification reaction products. Because sugars are much less stable than sugar alcohols under alkaline conditions and at high temperatures (e.g., at pH 12 and 908C), sugar degradation predominates and no significant amount of transesterification reaction products can be observed in the HPLC chromatograms. Under milder reaction conditions used in this study, the chromatograms clearly show the formation of transesterification reaction products between methylparaben and the selected sugars, which is confirmed by LC-MS. However, the chromatograms obtained are not as clean as those obtained with sugar alcohols because of the occurrence of sugar degradation. Isomerization and on-column reaction (most likely anomerization) further complicated the chromatograms of the transesterification reaction products. Sucrose seems to be an exception, which gives well-defined chromatogram of the transesterification reaction products with eight peaks. The kinetic study indicates that the rates of the transesterification reactions of methylparaben with sucrose and sorbitol are very similar and that the rate of hydrolysis of the methylparaben is not affected by the sugar or sugar alcohol molecule.
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