Parabens, example

This publication provides several examples of the use of solid-phase extractions for separating analytes from their matrices. Some of the examples included are caffeine from coffee, polyaromatic hydrocarbons from water, parabens from cosmetics, chlorinated pesticides from water, and steroids from hydrocortisone creams. Extracted analytes maybe determined quantitatively by gas (GC) or liquid chromatography (LG). 

Eigure 13.57 discusses in some detail the use of mobile-phase modifiers to prevent adsorption on PDVB resins. These concepts are very valuable in developing methods. Eor example, note how the observed column efficiencies improve for paraben analysis in the order of methanol < acetonitrile < 50/50 methanol/acetonitrile < THE. Eurthermore, when THE is used the chromato-... 

Some simple foods can be preservatives in their own right. Honey, salt, sugar, lactic acid, and vinegar are all examples of foods that inhibit microbial action. Some health professionals recommend consuming phytoestrogens from foods such as soybeans to achieve various health benefits. The phytoestrogens in the paraben family, found in blueberries, kill molds and fungi and are often added to food as preservatives. 

Before releasing a process column for chromatography, it is advisable to perform some test to measure efficiency, such as calculating height equivalent theoretical plates (HETP), both to forestall any problems in the column bed and to provide a benchmark by which to measure column reproducibility and predict degradation of the bed or material. Examples of compounds that are relatively innocuous for use in pharmaceutical applications are 1% NaCl (for gel filtration), concentrated buffer solutions (for ion exchange), and benzyl alcohol and parabens for reverse phase LC.10... 

The raw materials used in a particular product may present some challenges to the formulation chemist when selecting the most appropriate preservative. Problem ingredients may act as microbial nutrients, preservative inactivators or preservative adsorbers and careful testing and assessment of the preservative system is necessary in these cases. One notable example of this is the inactivation of parabens esters by certain non-ionic surfactants. 

There is a wide range of technical benefits to be gained by both the formulator and the consumer by using a preservative combination. A clear example of this is detailed in the following table. This demonstrates the well-known inactivation of parabens by non-ionics... 

LOD is defined as the lowest concentration of an analyte that produces a signal above the background signal. LOQ is defined as the minimum amount of analyte that can be reported through quantitation. For these evaluations, a 3 x signal-to-noise ratio (S/N) value was employed for the LOD and a 10 x S/N was used to evaluate LOQ. The %RSD for the LOD had to be less than 20% and for LOQ had to be less than 10%. Table 6.2 lists the parameters for the LOD and LOQ for methyl paraben and rhodamine 110 chloride under the conditions employed. It is important to note that the LOD and LOQ values were dependent upon the physicochemical properties of the analytes (molar absorptivity, quantum yield, etc.), methods employed (wavelengths employed for detection, mobile phases, etc.), and instrumental parameters. For example, the molar absorptivity of methyl paraben at 254 nm was determined to be approximately 9000 mol/L/cm and a similar result could be expected for analytes with similar molar absorptivity values when the exact methods and instrumental parameters were used. In the case of fluorescence detection, for most applications in which the analytes of interest have been tagged with tetramethylrhodamine (TAMRA), the LOD is usually about 1 nM. 

The calibration sensitivity of the analytical method employed is simply determined as the slope of the calibration curve. For example, in the case of methyl paraben, the value of calibration sensitivity obtained was 1.6 mAl I/min///M (Figure 6.22). Analytical sensitivity is defined as the ratio between calibration sensitivity and the value of the standard deviation obtained at each concentration.10 The value of the standard deviation encountered for a concentration of 0.6 //M was 0.1, resulting in an analytical sensitivity for methyl paraben at 0.6 //M of 16 m. II/min///M. As indicated for LOD and LOQ, the values obtained for linearity and sensitivity depend on the analytes employed and the corresponding method and instrumental parameters. For example, Liu et al.9 evaluated the LOD and LOQ for Drug A (released from OROS) for a particular analytical method employing //Pl.C to be 0.5 //g/ml. and 2.0 //g/mL, respectively. 

In addition, the solubility of many preservatives in a mostly aqueous system may not be high enough for effective antimicrobial activity. For example, the para-bens often require heating in order to be solubilized. Additionally, it is essential to understand that bacteriostatic agents can partition between organic and aqueous phases in such a way that their activity is significantly reduced. Methyl paraben... 

Preservative agents are added to injectable preparations when multiple dosing is expected out of the same unit. Examples of preservatives used in injectable preparations include phenol, benzyl alcohol, methyl and ethyl parabens, and benzalkonium... 

The modiLed solubility parameter in Equation 3.7 is different from the Hildebrand solubility parameters but is similarto the sum of the dispersion solubility pararfl tend the polarsolubility parameter, of the Hansen partial solubility parameters (Hansen, 1967). Values of the modiLed solubility parameters can be determined from the solubility of the solute in a nonpolar solvent. For example, pentane has been used as a solvent to determitsfeotlhieiethyl paraben (Ruelle et al., 1991). 

Example 1. Calculate the solubility of methyl paraben in water af(25The melting point of methyl paraben is 13C (VWndholz and Budavari, 1983). The chemical structure of methyl paraben is... 

As another example, desonide and parabens in cream and ointment formulations were cleaned up by SPE by first testing mixtures of hexane-chloroform with silica, diol, and aminopropyl sorbents [36]. The solvent combination of 20% chloroform in hexane was found to be the optimum for dissolving the ointment base and yielding high recoveries of the analytes. The silica and aminopropyl sorbents were found to give nearly identical quantitative results, whereas the diol sorbent gave lower recoveries. Table 2.4 outlines the solvent considerations needed to elute retained compounds on silica and C,8 sorbents. 

Additional interactions between silica and neutral and acidic analytes have been observed [3,317,321]. One example is the resolution of methyl-paraben from propylparaben, benzoic acid, and famotidine [3]. Retention mechanism studies appear to show that interactions with the siloxane bridges are important [322]. 

Certain substances have been reported to affect eczematous skin, but not normal skin. One example is parabens, a popular preservative that may sensitize eczematous skin, but rarely causes... 

One example that illustrates this is the GPC separation of aspirin and propyl paraben. These two compounds have identical molecular weights (MW = 180) but can be separated using GPC (e.g., on a 100-A jiStyragel columns). From the structures (Fig. 11-3) it can be hypothesized that propyl paraben acts as a larger molecule in solution than does aspirin. Since the side chain on propyl paraben would give the molecules a larger end-to-end size than the more compact aspirin molecule, propyl paraben should elute before aspirin. 

Some compounds are employed in only one of these areas, for example, the parabens (esters of 4-hydroxybenzoic acid) are used as preservatives in some types of cosmetic and pharmaceutical products, whereas chlorhexi-dine salts are utilized in all three areas. The collective term biocide (bios, life cido, to kill) is used widely nowadays to denote a compound used in one or more of these fields [2],... 

The principal advantages in the use of superheated water are that it is relatively easy to attain and the back-pressures required on the column are small. Thus even a modest length of narrow bore tubing can be employed to provide sufficient resistance to prevent boiling in the column and at these pressures many conventional spectroscopic flow cells can be used. Because of the high temperatures, there have been concerns about the thermal stability of the analytes, but of the numerous examples, there have been few reports of instability or a tendency for accelerated hydrolysis or oxidation, of the reported examples, only aspirin has hydrolyzed. Compounds which might be expected to be labile to oxidation or hydrolysis, such as the paraben antioxidants, have chromatographed without problems even up to 200°C [59]. 

A typical formulation might include up to 2%i polax-amer 188, up to 0.5% polysorbate 80, up to 0.1% sodium cholate, and up to 1% lecithin, or 3-10%i phospholipids or lecithin. Typically, lipids are more easily processed by homogenization than by bead milling. Nanosuspensions can be preserved with, for example, benzyl alcohol, or methyl paraben and propyl paraben. ... 

Patients allergic to additives, such as parabens in sodium iopodate, can react to them, for example with rash (218). 

The activity of the parabens increases with increasing chain length of the alkyl moiety, but solubility decreases. Activity may be improved by using combinations of parabens since synergistic effects occur. Ethylparaben is commonly used with methylparaben and propylparaben in oral and topical formulations (such mixtures are commercially available for example, Nipasept (Nipa Laboratories Inc.). Activity has also been reported to be improved by the addition of other excipients see Methylparaben for further information. 

Whilst the Maillard reaction between lactose and primary amines is well known, the same reaction between the secondary amine fluoxetine hydrochloride (Prozac ) and lactose has recently been reported (Wirth et al. 1998). In the solid-state water content, lubricant concentration and temperature were also found to influence the degradation. In addition to the chemical reactions noted above, the drug may also interact to form a molecular compound. For example, solid-state interactions between trimethoprim and antimicrobial paraben esters to form a 1 1 molecular compound has been reported (Pedersen et al. 1994). 

Surfactants may be included in an ophthalmic suspension to disperse the drug effectively during manufacture and in the product during use. Non-ionic surfactants are generally preferred because they tend to be less toxic. The level of surfactant included in the formulation should be carefully evaluated, as excessive amounts can lead to irritation in the eye, foaming during manufacture and upon shaking the product, or interactions with other excipients. The most likely interaction is with the preservative. For example, polysorbate 80 interacts with chlorobutanol, benzyl alcohol, parabens and phenyl ethanol and may result in a reduced preservative effectiveness in the product. 

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