Preservatives oral liquids

Some compounded preparations are naturally preserved, as in the case of certain syrups and elixirs others require the addition of a preservative. Preservatives are commonly added to products to minimize microbial growth, as in the case of oral liquids, topicals, and multi-dose parenterals. A preservative is selected based upon its characteristics, including concentration, pH, taste, odor, and solubility. 

Oral liquid and semisolid formulations containing water as part of the vehicle may be prone to microbial spoilage in the absence of a preservative. In the case of pharmaceutical creams, these are usually oil-in-water emulsions stabilized using a surfactant. Phenolic preservatives, e.g., parabens esters, are inactivated in the presence of nonionic surfactants, and this detrimental interaction can have serious consequences for preservation of the product (20). 

Choosing an acceptable preservative when developing an oral liquid formulation is primarily limited by the number of approved excipients. As Table 10 demonstrates, there are many preservatives listed in the FDA inactive ingredient guide for dosage forms other than oral liquids however not many have been commonly used in oral solutions or suspensions. 

Table 10 Typical Preservatives Used in Oral Liquid Dosage Forms...

PG, similar to glycerin, is a multifunctional excipient that can be an effective preservative when used at concentrations of 15% to 30% in oral solutions. However, formulations containing 35% PG can cause hemolysis in humans. PG exhibits nonlinear pharmacokinetics and when elimination pathways are saturated, serum levels dramatically increase. Pyruvic and lactic acid are produced from the metabolic degradation of PG and can lead to acidosis. Neonates have a longer PG half-life (16.9 hours) compared with adults (5 hours) and seizures, and respiratory depression has occurred in children who have ingested oral liquid medications containing PG (9). Therefore, special consideration should be placed on the amount of PG in formulations that are intended for infants and children. 

It is essential to understand how and when the polymorphs of drug substance in oral liquid dosage forms and suspensions can be controlled. One approach to study this phenomenon is to seed the formulation with a small amount of a known polymorphic crystal (other than what is used for the product), which is a common practice to rapidly determine what effect this may have on long-term storage. From these types of studies, the appropriate excipients can be used to preserve the specific polymorphic form desired. However, even when the drug in its crystalline form is studied extensively, there are cases when a previously unknown polymorph may be formed in solution and lead to precipitation (14). 

Simoes SS, Ajenjo AC, Franco JM, Vieira DN, Dias MJ (2009) Liquid chromatography/tan-dem mass spectrometry for the qualitative and quantitative analysis of illicit drugs and medicines in preserved oral fluid. Rapid Commun Mass Spectrom 23(10) 1451-1460. doi 10.1002/ rcm.4020... 

De Boeck G, Samyn N (2005) Quantitative analysis of multiple illicit drugs in preserved oral fluid by solid-phase extraction and liquid chromatography-tandem mass spectrometry. Forensic Sci Int 150(2-3) 227-238. doi S0379-0738(05)00131-3 [pii] 10.1016/j. 

The other three classes of preservatives have been widely used in ophthalmic, nasal, and parenteral products, but not frequently in oral liquid preparations. The neutral preservatives are volatile alcohols their volatility introduces problems of odor and loss of preservative on aging in multidose preparations. The mercurials and quaternary ammonium compounds are excellent preservatives but are subject to incompatibilities.Mercurials are readily reduced to free mercury, and the quaternary compounds are inactivated by anionic substances. 

Microbiological protection of multiple-dose presentations such as liquid inhalations, nasal sprays, oral liquids, creams, and lotions is more complex. Once opened they are susceptible to microbiological contamination. If they are aqueous-based, they are in principle susceptible to proliferation of these new contaminants. To avoid this, they are formulated with antimicrobial agents or preservatives and are expected to be able to comply with preservative efficacy standards specified in the pharmacopeias. Preservative efficacy tests (not harmonized) are described in Section 51 of the USP and Section VIII. 14 of the PhEur (Fig. 3). 

Chemburkar PB, Joslin RS. Effect of flavoring oils on preservative concentrations in oral liquid dosage forms. ] Pharm Sci 1975 64 414-417. 

Van-Doorne H, Leijen JB. Preservation of some oral liquid preparations replacement of chloroform by other preservatives. Fharm World Sci 1994 16(Feb 18) 18-21. 

Compared to tablets and capsules, oral liquids have some disadvantages as well. Their extemporaneous formulation and preparation is not so easy. They may have an tmpleasant taste, the use of solvents and preservatives is restricted due to their toxicity (especially for children), and the safe use of suspensions requires proper shaking. 

If the oral liquid has been prepared from an oral sohd using potable water, it has to be added immediately after preparation, thereby causing no larger microbiological load than that of potable water. Oral liquids made fi om raw materials are preserved in most cases and thus have a low bioburden. 

Usually purified water (Aqua purificata) is used. Because of the chemical and microbiological quality it is preferred over potable water (see Sect. 20.3.1) although the taste of potable water may be better due to presence of ions. Water is a good growth medium for micro-organisms, so aqueous oral liquids generally have to be preserved, see Sect. 5.4.9. 

The pH of an oral liquid is important for the flavour, solubility and stability of the active substance and for preservation. The preferred pH for an oral solution is between 5.5 and 7.5. A pH < 5.5 often tastes better, but may degrade the tooth enamel although the total amount of free acid plays a role as well [30]. A pH above 8 often gives an unpleasant taste. 

Water supports the growth of micro-organisms, therefore oral aqueous solutions, suspensions, emulsions and solubilisates in multidose containers should be preserved. Preservatives may be used for that purpose as well as excipients with preservative properties, such as propylene glycol. See Sect. 23.8 for extensive information on preservatives. Table 5.18 summarises preservatives with properties especially relevant for oral liquids. 

The choice of the preservative is determined by the pH, the presence of antimicrobial co-solvents, the presence of a lipid phase and whether, because of the adverse effects, the liquid is intended for adults or neonates or children. It is shown that oral liquids with a pH > 8 are difficult to preserve, apart from giving taste problems. 

Ethanol preserves in concentrations above 15 % v/v. If sufficient ethanol is present in oral preparations, no other preservatives are needed. See Table 5.19 however for the restrictions for oral liquids for children. 

In many oral liquids the preservative methylparaben is used. Its dissolution rate can be increased by heating or by using concentrated solutions in organic solvents such as propylene glycol (see also Sect. 23.8.5). 

The pH is important for the preservative effect of sorbic acid and parahydroxybenzoic acid esters. These substances are most effective at pH <5. Since sorbic acid decomposes faster at low pH, pH 5 is used as a compromise (see Sect. 23.8.6). At a pH above 5.5-6.0, sorbic acid is not effective at all. At pH 7-8.5, the effectiveness of the parahydroxybenzoic acid esters is strongly reduced, in part due to their chemical instability. This implies that for dermatological preparations with a pH > 7, or in case of hypersensitivity for parahydroxybenzoic acid esters already > 5, the pharmacist has to resort to propylene glycol or probably phenoxyethanol. In case of an oral liquid with such a pH,... 

For the preservation of oral liquids and dermatological preparations at pH <5, sorbic acid or methyl parahydroxybenzoate is used, at pH 5-7 methyl parahydroxybenzoate, and at pH >7-8.5 methyl parahydroxybenzoate, even though its preservative effect is weak. It is therefore advised to reduce the pH or pay extra attention to the prevention of contamination. 

Syrups are a very commonly used form of sugars. They contain approximately 45-65 % of sugar, water and a preservative. Sometimes a flavouring is added. The preservative is most often methyl parahydroxybenzoate 0.1-0.15 %. Syrups can be very useful for improving the taste of oral liquid preparations and sometimes they can be used to stabilise a solubilisate of oil and polysorbate, e.g. in a vitamin A micellar solution (Table 23.12). 

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