Preservatives/preservation, ophthalmic chlorobutanol

This aromatic alcohol has been an effective preservative and still is used in several ophthalmic products. Over the years it has proved to be a relatively safe preservative for ophthalmic products [138] and has produced minimal effects in various tests [99,136,139]. In addition to its relatively slower rate of activity, it imposes a number of limitations on the formulation and packaging. It possesses adequate stability when stored at room temperature in an acidic solution, usually about pH 5 or below. If autoclaved for 20-30 minutes at a pH of 5, it will decompose about 30%. The hydrolytic decomposition of chlorobutanol produces hydrochloric acid (HC1), resulting in a decreasing pH as a function of time. As a result, the hydrolysis rate also decreases. Chlorobutanol is generally used at a concentration of 0.5%. Its maximum water solubility is only about 0.7% at room temperature, which may be lowered by active or excipients, and is slow to dissolve. Heat can be used to increase dissolution rate but will also cause some decomposition and loss from sublimation. Concentrations as low as 0.125% have shown antimicrobial activity under the proper conditions. 

Chlorobutanol is primarily used in ophthalmic or parenteral dosage forms as an antimicrobial preservative at concentrations up to 0.5% w/v see Section 10. It is commonly used as an antibacterial agent for epinephrine solutions, posterior pituitary extract solutions, and ophthalmic preparations intended for the treatment of miosis. It is especially useful as an antibacterial agent in nonaqueous formulations. Chlorobutanol is also used as a preservative in cosmetics [see Section 16) as a plasticizer for cellulose esters and ethers and has been used therapeutically as a mild sedative and local analgesic. 

Chlorhexidine is also cationic like BKC and exhibits similar incompatibilities. It is not as stable as BKC to autoclaving and may irritate the eyes. It tends to be more favoured in Europe than in the United States, and is particularly used in contact lens products. Chlorobutanol and phenylethyl aclohol are also widely used in ophthalmic products. However, chlorobutanol will hydrolyse in solution, and autoclaving is not usually possible without loss of preservative activity. It is also volatile and may be lost through the walls of plastic containers. 

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. 

All ophthalmic medications are potentially absorbed into the systemic circulation (Figure 63-3), so undesirable systemic side effects may occur, as well as potential local toxic effects due to hypersensitivity reactions or to direct toxic effects on the cornea, conjunctiva, periocular skin, and nasal mucosa. Eyedrops and contact lens solutions commonly contain preservatives such as ben-zalkonium chloride, chlorobutanol, and chelating agents for their antimicrobial effectiveness. In particular, benzalkonium chloride may cause a punctate keratopathy or toxic ulcerative keratopathy. 

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