Peculiarities of Determining Bacterial Endotoxins in Oil Solutions of Drugs
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Pharmaceutical Chemistry Journal, Vol. 54, No. 5, August, 2020 (Russian Original Vol. 54, No. 5, May, 2020)
DISCUSSION PECULIARITIES OF DETERMINING BACTERIAL ENDOTOXINS IN OIL SOLUTIONS OF DRUGS O. V. Shapovalova,1 N. P. Neugodova,1 and G. A. Sapozhnikova1 Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 54, No. 5, pp. 58 – 61, May, 2020.
Original article submitted April 26, 2019. Issues related to reliable quality assessment of oil solutions of medicines with respect to the Bacterial Endotoxins indicator are considered. The maximum isolation of bacterial endotoxins from fat-soluble drugs for subsequent determination is assisted by vigorous stirring of samples in water previously heated to 60°C followed by separation of the two phases using centrifugation at 2300 rpm for 10 min. Keywords: bacterial endotoxins, extraction, oil solutions, dispersing solvent.
Nonaqueous solvents in addition to water for injection are used to manufacture drugs for injection and allow solutions of water-insoluble or poorly soluble substances and time-release dosage forms to be prepared [1]. The nonaqueous solvents according to requirements of GPM.1.4.1.0007.15 “Dosage forms for parenteral administration” are fatty vegetable oils that are safe and pharmacologically inert [2, 3]. The list of oil solutions for injection comprises a rather broad array of preparations. These are primarily hormonal preparations and their analogs in addition to anabolic steroids. Injectable dosage forms in oil are widely used in psychiatry to produce long-acting preparations. Subcutaneous or i.m. administration of oil solutions of vitamins is often used in veterinary medicine [1]. Dosage forms for parenteral administration and the drug substances used to prepare them are subject to testing for bacterial endotoxins (BE) or pyrogens according to current pharmacopoeial requirements, e.g., GPM.1.4.1.0007.15 “Dosage forms for parenteral administration”; GPM1.2.4.0006.15 “Bacterial endotoxins”; or GPM.1.2.4.0005.15 “Pyrogenicity.” The presence of pyrogenic impurities in injectable oil solutions is difficult to evaluate. For example, preparations being tested for pyrogenicity in animals must be 1
injected i.m. and the body temperature measured for 5 h because oil solutions cannot be injected i.v. [1, 2, 4, 5]. Determination using the LAL (or TAL) test of BE contents in nonaqueous solutions is also fraught with serious complications because of peculiarities in the behavior of pyrogenic impurities in oil solutions upon mixing them with water. Therefore, special sample-preparation techniques are required [4]. The simplest method for preparing and analyzing samples of fat-soluble drugs (FSDs) is determination of BE in water for BE testing (BET) after mixing it with FSDs. The BE contents are evaluated in the aqueous medium after layering considering the standard “not greater than 0.25 EU/mL” according to requirements of PM.2.2.0019.18 “Water for injection” [2]. This approach meets requirements of the USP monograph “Medical devices – bacterial endotoxin and pyr
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