Rocuronium bromide

C2H3CIO 75-36-5) see Acebutolol Acetiamine Acetylcholine chloride L-Alanine Benfurodil hemisuccinate . Chlorprothixene Flumetasone Ibuprofen lotalamic acid loxitalamic acid Levodopa Methestrol dipropionate Midecamycin acetate Naproxen Nimesulide Paclitaxel Paramethasone Phensuximide Retinol Rocuronium bromide Rofecoxib Ropinirole Tazarotene Thiopropazate Tiracizine Vecuronium bromide... 

C2,H37N02 1193U2-I9-1) see Rocuronium bromide (5a,6a,liP)-S,6-cpoxy-ll,17,21-trihydroxypregnane-3,20-dione cyclic bis(l,2-ethanediyl acetal)... 

Rockwell hardness testing, 25 369 Rocuronium bromide, 4 360t Rod... 

Recently, Organon workers have discovered a derivative of y-cyclodextrin (Sugam-madex) that rapidly removes - by inclusion - rocuronium bromide (18) from the receptor sites, thus accelerating surgical after-care [32]. 

In addition to the medicines mentioned above, a number of opiate- and non-opiate-based analgesics, including COX-2 inhibitors, anaesthetics (e.g. propofol, desflurane, sevoflurane, ropivacaine, levobupivacaine and remifentanil), neuromuscular blockers (e.g. rocuronium bromid, zemuron, cisatracuiium, doxacurium. 

The molecular formula of rocuronium bromide is C32H53BrN204, and the substance is characterized by a molecular weight of 609.7 [1, 5-7]. 

Rocuronium bromide is freely soluble in either water or in anhydrous ethanol, and is characterized by a n-octanol /water partition coefficient of 0.5 at 20 °C [2, 8]. 

Rocuronium bromide has a specific optical rotation of +28.5° to +32°, when measured on an anhydrous and solvent-free basis at 20 °C. A 1% solution of the substance in water yields pH values ranging from 8.9 to 9.5 [5-7]. 

Compendial reviews state that rocuronium bromide had been identified as having eight different impurities, which are labeled as impurities A, B, C, D, E, F, G, and H. Impurity A (i.e., related compound A) is 3a-hydroxy-2/i (morpholin-4-yl)-16/ -(pyrrolidin-l-yl)-5a-androstan-17/ -yl acetate impurity B (i.e., related compound B) is l-[3a,17/i-bis(acetyloxy)-2/i-(morpholin-4-yl)-5a-androstan-16/i-yl]-l-(prop-2-enyl)pyrrolidinium impurity C (i.e., related compound C) is l-[3a,17/i-dihydroxy-2/i-(morpholin-4-yl)-5a-androstan-16/ -yl]-l-(prop-2-enyl)pyrrolidinium and impurity D (i.e., related compound D) is l-[3a-(acetoxy)-17/J-hydroxy-2/J-(morpholin-4-yl)-5x-androstan-16/j-yl]-l-(prop-2-enyl)pyrrolidinium impurity E (i.e., related compound E) is l-[17/ -(acetoxy)-3a-hydroxy-2/ -(pyrrolidin-l-yl)-5a-androstan-16/)-yl]-l-(prop-2-enyl)pyrrolidinium impurity F (i.e., related compound F) is l-[3a,17/ -bis(acetiloxy)-2/ -(pyrrolidin-l-yl)-5a-androstan-16/i-yl]-l-(prop-2-enyl)pyrrolidinium impurity G (i.e., related compound G) is 2/)-(morpholin-4-yl)-16/i-(pyrrolidin-l-yl)-5a-androstane-3a,17/i-diol and impurity H (i.e., related compound H) is l-[17/i-(acetyloxy)-2-(morpho-lin-4-yl)-3-oxo-57-androst-l-en-16/i-yl]-l-(prop-2-enyl)pyrrolidinium [5-7], The molecular structure of rocuronium bromide is shown in Fig. 6.1, while the structures of the known impurities are illustrated in Fig. 6.2. 

Identification methods of rocuronium bromide in compendias only specify an identification method for its bulk drug substance, and none of these mention identification of rocuronium bromide in any of its pharmaceutical dosage forms. 

European Pharmacopoeia (EP) 6.0 [6] and British Pharmacopoeia (BP) 2009 [7] use infrared absorption spectroscopy and a solution test for bromide ion to identify rocuronium bromide. For the infrared absorption... 

BP and EP recommend that for the bromide test, a sample solution has to be first acidified with dilute nitric acid, and silver nitrate solution is added to produce a curdled, pale yellow precipitate. This precipitate will dissolve with difficulty when suspended in a solution consisting of 2 ml of water and 1.5 ml of ammonia. Unlike BP and EP, USP employs a silver nitrate test for identification of bromide. In this test, addition of silver nitrate test solution to the solution of rocuronium bromide (1 part of rocuronium bromide in 100 parts of water) will produce a white precipitate which is insoluble in nitric acid and slightly soluble in 6N ammonium hydroxide. 

USP32 NF 27 [5] also adds a chromatographic method for identification purposes. Here, USP specifies that the retention time of the major peak obtained must be similar with the RS when the procedure is conducted as per the assay in Section 2.3. The liquid chromatographic method used for identification of rocuronium bromide is similar with the method used to quantify rocuronium bromide in bulk drug substance, as detailed in Section 2.3.1. 

All compendias [5-7] specify use of a liquid chromatographic method to determine the eight known rocuronium bromide impurities. The chromatographic method corresponds to the chromatographic method used to determine rocuronium in bulk drug substance, as detailed in Section 2.3.1. For the purpose of analyzing impurities, the RS used is the RS of rocuronium that is intended for peak identification, where the identification standard contains impurities of rocuronium bromide and rocuronium bromide itself. 

TABLE 6.1 Relative retention time of each impurity of rocuronium bromide, its requirement, and limitation... 

Calculation of the levels of each impurity is performed by multiplying the peak areas of impurities A, F, G, and H with the corresponding correction factor of those impurities, as provided in Table 6.1. In addition, the requirement that the peak area of each impurity in the test solution corresponds with the principal peak of rocuronium bromide obtained from the RS is also detailed in Table 6.1. In addition, all compendias [5-7] suggest that any peak eluted prior to the elution of impurity A should be ignored due to the blank and to bromide ion that elutes just before impurity A. Furthermore, any peak with an area less than 0.5 times of the principal peak of rocuronium bromide should be disregarded. 

A 400 MHz nuclear magnetic resonance (NMR) method for the identification of rocuronium bromide was reported by Fielding [10]. The aH spectra were referenced to an internal TMS standard, while the solvent signals at 77.0 ppm (CDCI3) or 39.6 ppm (DMSO-dg) were used as references for the 13C data. Based on the NMR spectra, it was concluded that... 

Another NMR method was utilized by Cameron et al. [11] to determine rocuronium bromide in its complexed form with y-cyclodextrin. In this method, the experiments were performed at 400 MHz on a Bruker DRX spectrometer at 303 K. The method entailed the use of aH NMR spectra of samples that had been dissolved in D20 at pH 7.5. However, in this report, the authors did not specifically discuss the aH NMR result for rocuronium bromide as single compound. 

Two LC methods have been reported for determining rocuronium bromide in pharmaceutical dosage forms [12,13]. The first method reported was used to examine the stability of a propofol-rocuronium mixture, a mixture employed for the rapid induction of anesthesia. In this method, a /iBondapak CN column (150 mm x 3.9 mm i.d.) was used as the stationary phase. A standard mixture of rocuronium bromide and propofol was prepared in acetonitrile, having 5 3 proportion of rocuronium bromide and propofol, respectively. The mobile phase consisted of 60 40 (v/v) acetonitrile/water, and the wavelength detection was set at 220 nm. It was found that in this mixture, rocuronium bromide was stable up to 48 h after mixing [13]. 

Blazewicz et al. [12] reported a liquid chromatographic method that used electrochemical detection to determine rocuronium bromide and its impurities, particularly impurities A and C. These latter impurities are also known to be two metabolites of rocuronium bromide, namely N-desallylrocuronium and 17-desacetylrocuronium (impurity A and impurity C, respectively). In this method, the mobile phase used was the same as mentioned in all compendias, and the column used was a Hypersil 100 Silica 5 /im (250 mm x 4.6 mm). Although the solvent and the composition of the mobile phase is the same as the compendial methods, and the flow rate was set up at a lower rate than the compendial methods (1.5 ml/min), the retention time of rocuronium bromide and its... 

By using this method, the limit of detection (LOD) and limit of quantitation (LOQ) achieved were 7 and 25 ng/ml, respectively, for impurities A and G. The highest LOD and LOQ were 225 and 750 ng/ml for impurity B. Recoveries of rocuronium bromide and impurity C ranged between 98.91% and 104.20%. Moreover, when stored at 6 2 °C, stock solutions of rocuronium and its impurities were stable in the solvent system for 2 weeks. After 2 months of storage, the content of impurity A in the mixture decreased while the levels of impurities C and G increased. 

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