Tonicity adjusters

Ophthalmic Dosage Forms. Ophthalmic preparations can be solutions, eg, eye drops, eyewashes, ointments, or aqueous suspensions (30). They must be sterile and any suspended dmg particles must be of a very fine particle size. Solutions must be particle free and isotonic with tears. Thus, the osmotic pressure must equal that of normal saline (0.9% sodium chloride) solution. Hypotonic solutions are adjusted to be isotonic by addition of calculated amounts of tonicity adjusters, eg, sodium chloride, boric acid, or sodium nitrate. 

For parenteral products specific consideration needs to be included for tonicity adjustment, emulsion globule size, ease of resuspension and sedimentation rate, particle size and particle size distribution, viscosity and syringeability, and crystal form changes. Full consideration should be included of the proposed instructions for dilution or reconstitution of products and of compatibility with the proposed solvents or diluents. This should include a demonstration that the proposed storage temperature and extremes of concentration are suitable. 

Tonicity agents are added to injectable preparations to prevent osmotic shock at the site of injection upon administration, and thereby reduce local irritation. Typical excipients used for tonicity adjustment include saline, glycerin, mannitol, dextrose, and trehalose. Tonicity is a colligative property that depends primarily on the number of dissolved particles in solution. Hence, the amount of tonicity agent to be added depends on the specific formulation. Typically, osmolality of 280 to 320mOsm is considered iso-osmotic. 

The implications of the addition of tonicity adjusters must also be considered, particularly with respect to ionic strength and common ion effects. Some additives may affect the solubility or form insoluble salts with the actives, resulting in formulation failure. 

Table 8 Bulking agents, protectants, and tonicity adjusters...

Maltose serves as a tonicity adjuster and stabilizer in immune globulin formulation (Gamimune N ). 

The user enters all known data on the solubility (aqueous and non-aqueous), stability in specified solutions, compatibility, pAia, and molecular properties of the active ingredient (molecular weight, log/, etc.). As with the system for tablet formulation, the data may be numerical or symbolic. All relevant properties of additives used in parenteral formulation (e.g., buffers, antioxidants, chelating agents, antimicrobials, and tonicity adjusters) are present in the knowledge base. 

The system then selects additives, depending on the specification required (e.g., an antimicrobial will only be added if a multidose container is specified or a tonicity adjuster will only be added if the solution is hypotonic). The selection strategy is generally on the basis of ranking with some specific rules. 

Among the polymers used in lens comfort solutions are polyvinyl alcohol, polyvinylpyrrolidone, dextran, and various cellulose derivatives such as hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Surfactants include certain poloxamer and poloxamine compounds. Other normal components comprise appropriate preservative(s) as well as buffering and tonicity-adjusting agents. 

Finally, it may be necessary to ensure compatibility with the different tonicity adjusters used in formulations and infusion fluids. Where precipitation is likely to occur with a hydrochloride salt, selection of another drag salt or use of an alternative tonicity adjuster (e.g. glucose) must be considered. 

The use of Cremophore EL in the microemulsions is avoided nowadays due to several adverse effects such as anaphylactic shocks and histamine release [20 ]. The other important consideration is the concentration of surfactants and co-surfactants which should be minimal and preferably not exceed 20%. Furthermore, it is necessary to ensure that the microemulsion structure is preserved in the presence of the tonicity adjusting solutions such as 0.9% saline solution and preservatives. The parenteral microemulsions should also be able to withstand tests such as freeze-thaw cycling which ensure their physical stability. It has been shown that the colloidal carriers based on Solutol HS 15 can withstand freeze-thaw cycling very efficiently whereas lecithins can offer stability to autoclaving [ 112 ]. Cosurfactants such as benzyl alcohol cannot be used for intravenous applications but can be used for the small volume parenteral products up to the concentration of 1% w/v. Ethanol at concentrations above 10% usually results in the pain on injection. Co-surfactants such as glycofurol are reported to acceptable for parenteral products but there are no products based on glycofurol available for the human use. The pyrrolidone derivatives are reported to be acceptable for veterinary applications. 

Another important consideration is the physical stability of microemulsions in the presence of tonicity adjusting agents, preservatives and electrolytes. It is also necessary to... 

Tonicity Adjusters, Preservatives, Bulking Agents, Protectants. 318... 

Other additives such as antimicrobial agents, antioxidants, buffers and tonicity-adjusting agents can be included in injection formulations and it is the responsibility of the pharmacist to check that all excipients and adjuvants are suitable (benzyl alcohol, ethanol, sulfites, sodium content, etc.). Nevertheless, one is left with a difficult choice over excipients, either those for which toxicity is known and therefore predictable, or those with safety profiles that have not been established in children (see under Critical excipients, page 55). The pH and osmo-larity of the preparation must also be checked before administration by another route. 

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