Preservatives liquid dosage forms

Liquid Dosage Forms. Simple aqueous solutions, symps, elixirs, and tinctures are prepared by dissolution of solutes in the appropriate solvent systems. Adjunct formulation ingredients include certified dyes, flavors, sweeteners, and antimicrobial preservatives. These solutions are filtered under pressure, often using selected filtering aid materials. The products are stored in large tanks, ready for filling into containers. QuaUty control analysis is then performed. 

Liquid dosage forms which are disperse systems (colloidal, i.e., microspheres, nanoparticles, and micelles suspensions and emulsions) often contain preservatives which are methyl, ethyl, propyl, and butyl esters of para-hydroxybenzoic acid in various combinations. A typical example is the antacid suspensions which have high pH values which make the esters of the preservatives susceptible to hydrolysis. One way to circumvent this problem is to use several preservatives in combination with the hope that some quantities of the preservatives will remain to prevent the suspension from microbial attack. A report showing the assay of the four esters and the parent acid (one of the decomposition products) in drug products in which all the preservatives were used has been given [13]. 

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

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). 

Product Specifications The most important specifications or established limits for liquid dosage forms are microbial limits and test methods, medium pH, dissolution of components, viscosity, as well as particle size uniformity of suspended components and emulsified droplets. Effectiveness of the preservative system depends on the dissolution of preservative components and may be affected by the medium pH and viscosity. In addition, dissolved oxygen levels are important for components sensitive to oxygen and/or light [6],... 

Non-phenothiazines, such as haloperidol and loxitane, cause fewer urticarial reactions. As with any other class of drug, patients may be allergic to excipients in various tablet or capsule forms, or to preservatives, for example methylparabens in liquid dosage forms (522). 

Liquid dosage forms. The liquid products are prepared by dissolving the ingredients in the appropriate solvent systems. Dyes, flavors, sweeteners, and antimicrobial preservatives are added to mask unpleasant taste or appearance, and to prevent mold and bacterial growth. The final products are stored in large tanks before final packaging. If the liquid is used for injection or ophthalmic use, the liquid must be sterilized. Solutions for external or oral use do not require sterilization but generally contain antimicrobial preservatives [16, 17]. 

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

Sulfobutylether P-cyclodextrin can form noncovalent complexes with many types of compounds including small organic molecules, peptides, and proteins. It can also enhance their solubility and stability in water. The first application of sulfobutylether P-cyclodextrin was in injectable preparations it can also be used in oral solid and liquid dosage forms, and ophthalmic, inhalation, and intranasal formulations. Sulfobutylether P-cyclodextrin can function as an osmotic agent and/or a solubilizer for controlled-release delivery, and has antimicrobial preservative properties when present at sufficient concentrations. 

For a liquid or semi-solid pharmaceutical dosage form, it is crucial to include a preservative in the formulation. Commonly used preservatives in these systems include sodium benzoate, EDTA, sorbic acid, and parabens. A generic HPLC method is also recommended for the preservatives used in liquid formulations for routine monitoring to ensure the stability of the preservative itself and it must be validated specific to its use with the dosage form. (See chapters on Sample Preparation and Method Development.)... 

Dosage form Rituxan is a sterile, preservative-free liquid concentrate for injection. It is supplied at a concentration of lOmg/ml in either 100 mg (10 ml) or 500 mg (50 ml) single-use vials. 

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. 

Preservatives such as sodium benzoate, sorbic acid, and methyl and propyl parabens have been used in liquid and semisolid dosage forms. There have been reports that the parabens have been inactivated when used in the presence of various surfactants. This loss of activity was thought to be due to the formation of complexes between the preservative and the surfactant. The interaction between polysorbate (Tween) 80 and the parabens has been demonstrated by a dialysis technique (Ravin and Radebaugh, 1990). It has also been shown that molecular complexes form when the parabens are mixed with polyethylene glycol (PEG) and methylcellulose. The degree of binding was less than that observed with Tween 80. Sorbic acid also interacts with Tweens but does not interact with PEGs. The quaternary ammonium compounds are also bound by Tween 80, which reduces their preservative activity. 

The average number of recalls per annum for microbial contamination of non-sterile pharmaceutical and OTC drug products is six (Table 4). The emphasis on waterborne Gram-negative bacteria of the species Bulkholderia (Pseudomonas) cepacia (nine recalls), P. putida (three recalls), P. aeruginosa (three recalls). Pseudomonas spp. (two recalls), and Ralstonia (P.) pickettii (one recall) is notable and reflects the concern for bacteria capable of growth in liquid oral dosage forms that overwhelm the preservative system. 

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