Hydrocortisone acetate, hydrolysis

As in the case of hydrocortisone acetate, where hydrocortisone might be expeeted to occur as a result of hydrolysis of the acetate ester, tests for the presenee of known impurities are based on the known manufacturing sequence or on likely degradation pathways. For example, the tests carried out on clotrimazole are based on the last step in its manufacture as shown in Figure 13.8. Unreacted imidazole is an obvious impurity and chlorotritanol would be readily formed from unreacted chlorotrityl bromide by hydrolysis, which would occur when the clotrimazole is extracted from the reaction mixture. 

Many functional groups are stable to alkaline hydrogen peroxide. Acetate esters are usually hydrolyzed under the reaction conditions although methods have been developed to prevent hydrolysis.For the preparation of the 4,5-oxiranes of desoxycorticosterone, hydrocortisone, and cortisone, the alkali-sensitive ketol side chains must be protected with a base-resistant group, e.g., the tetrahydropyranyl ether or the ethylene ketal derivative. Sodium carbonate has been used successfully as a base with unprotected ketol side chains, but it should be noted that some ketols are sensitive to sodium carbonate in the absence of hydrogen peroxide. The spiroketal side chain of the sapogenins is stable to the basic reaction conditions. 

Tang et al. [58] reported the analysis of corticosteroids in eqnine urine after enzymatic hydrolysis, liquid-liquid extraction (LLE) with ethyl acetate, and LC-MS-MS in positive-ion APCl mode. Hydrocortisone, deoxycorticosterone, and 21 synthetic corticosteroids can be analysed at 5 pg/1 level in urine within 10 min. As an example, the confirmation of deoxycortone in a urine sample is demonstrated in Figure 13.8. 

Branching of the esterifying acid, such as in flumethasone pivalate (trimethyl acetate) may, because of steric hindrance, slow down the rate of hydrolysis, thereby increasing effectiveness. Fluocinolone acetonide (Table 14-1) incorporates all these desirable features. Its topical potency is exemplified by its 0.01% concentration in commercial products (compared with hydrocortisone, 1%). 

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