Propylene glycol parenteral preparations

A water-soluble phosphine derivative of diazepam allows for more convenient parenteral tranquilizer therapy and avoids some complications due to blood pressure lowering caused by the propylene glycol medium otherwise required for administration. Fosazepam (82) is prepared from benzodiazepine by sodium hydride-mediated alkylation with chioromethyldimethyl phosphine... 

The use of cosolvents in small-volume parenteral preparations is often critical due to the limited volume of solution that can be administered by a single injection. Thus, the required dose of drug must often be incorporated in 1 or 2mL of solution. Table 6 lists parenteral products containing cosolvents. The cosolvents most often used include ethanol, propylene glycol, glycerin, PEG 400, and, sometimes, dimethylacetamide. Other cosolvents, such as DMSO, have been used as solvents for parenteral formulations of experimental anticancer agents however, their use is restricted due to toxicity and potential incompatibilities with plastic administration devices. ... 

In topical preparations, propylene glycol is regarded as minimally irritant, although it is more irritant than glycerin. Some local irritation is produced upon application to mucous membranes or when it is used under occlusive conditions. Parenteral administration may cause pain or irritation when used in high concentration. 

The most important requirement is that the salt possesses sufficient solubility at physiologically compatible pH values to permit incorporation into the dosage form. Buffering the solution to an appropriate pH can often enhance solubility. Salts may also be prepared in situ in the formulation. This is particularly useful when the main route of administration utilizes the parent drug form. Where the aqueous solubility of the salt is not sufficiently high, co-solvents may need to be added to enhance solubility (e.g. propylene glycol is used as the vehicle in phe-nobarbitone sodium injection). Parenteral solutions based on co-solvent vehicles normally cannot be directly injected intravenously because there is the risk of precipitation at the injection site. Therefore, such products are diluted with isotonic saline or 5%w/v dextrose solution to produce a lower concentration that remains soluble and can be safely administered by infusion. Alternative delivery routes are by subcutaneous or intramuscular administration by which, in... 

I. Mechanism of toxicity. Toxicity may be caused by the phenytoin itself or by the propylene glycol diluent used in parenteral preparations. To make it available for intravenous use, phenytoin must be dissolved in 40% propylene glycol and 10% ethanol at pH 12. 

B. The propylene glycol diluent in parenteral preparations may cause myocardial depression and cardiac arrest when infused rapidly (> 40-50 mg/min [0.5-1 mg/kg/min]). The mechanism is not known. The injectable form of phenytoin also is highly alkaline and can cause tissue necrosis if it infiltrates. Fosphenytoin, a water-soluble prodmg, does not contain the propylene glycol diluent and does not cause these toxic effects. 

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