Influence of Medium and Temperature on the Hydrolysis Kinetics of Propacetamol Hydrochloride: Determination Using Derivative Spectrophotometry

Abstract

Paracetamol (acetaminophen; PA) is a poorly water-soluble analgesic that is widely used in hospital and ambulatory practice for the relief of mild to moderate pain associated with headache, backache, arthritis pain, and postoperative pain.1-3) It has been used in the treatment of pain in combination with aspirin, caffeine, opiates and/or other agents. Paracetamol also has antipyretic effects that do not differ significantly from those of aspirin, although it has only weak antiinflammatory effects. 4,5) Paracetamol is a step 1 agent in the analgesic ladder of WHO.6) During the advanced stages of cancer, nearly 75% of the patients have pain that is moderate or severe, and according to the WHO analgesic ladder, the first step is used for the treatment of mild to moderate pain starting with either NSAIDs or PA.In recommended therapeutic dosage regimens, PA is usually well tolerated. The most common side effect is lightheadedness. Skin rash and other allergic reactions occur occasionally. Overdoses of PA may cause nausea, vomiting, sweating, and exhaustion. The most serious adverse effect of acute overdosage is a dose-dependent, potentially fatal hepatic necrosis. 7)Due to its poor water solubility that prevents parenteral administration in a soluble form, the clinical indications for PA are limited, especially in the postoperative setting. Contrary to the latter, propacetamol hydrochloride [N-N-diethyl, 4-acetylamino) phenyl ester monohydrochloride] (PRO) is a water-soluble prodrug of paracetamol, which can be parenterally administered as analgesic 8,9) for the treatment of postoperative pain, acute trauma, and gastric and/or intestinal disorders where oral administration is not possible. PRO has also shown efficacy in the symptomatic control of fever in the fields of oncology, infectious disease, and hematology. [10][11][12][13] In these circumstances, PRO can be administered in physiologic or glucose solutions since it is rapidly and quantitatively hydrolyzed into PA by plasma estearases within 7 min after intravenous injection.8) With the exception of absorption, PRO exhibits similar disposition kinetics when given by either the intravenous route as PA or by mouth as conventional tablets. 14)Screening of the literature revealed that PRO can be analytically determined by first-derivative spectrophotometry. 15)This technique has been utilized to investigate the kinetics of drug degradation processes since it is an analytic tool that offers a convenient solution to a number of problems, especially its potential for increasing the detection sensitivity of minor spectral features. [15][16][17] The first-derivative spectrophotometric technique has the advantages of the speed, low cost, and environmental protection. The derivative methods circumvent the problem of overlapping spectral bands, allowing for the simultaneous determination of PRO and PA without prior separation, and providing accurate, precise, rapid, reproducible results. Therefore this was the analytic technique chosen for the present study.Since PRO is fr...

First Multigram Preparation of SCP-123, A Novel Water-Soluble Analgesic

“…[8][9][10] As illustrated in Scheme 1, the two routes differ primarily in the sequence in which the saccharin moiety is added to the acetyl unit. In Route A, 9,10 the saccharin moiety is added in the last step to the 2-chloroacetamide intermediate 8 that has been previously generated from 4-aminophenol (6) and 2-chloroacetyl chloride (7). This yields 3 via a two-step process.…”

“…A water-soluble analogue of 1 is the prodrug propacetamol hydrochloride ( 2 ) 5,6. This form of acetaminophen is rapidly and completely hydrolyzed by plasma esterases to release 1 7. The pharmacological effects in clinical trials have shown that 2 possesses similar efficacy to 1 , but due to its greater water-solubility can be parenterally administered and thus can be employed when oral administration is not possible 5,6…”

“…5,6 This form of acetaminophen is rapidly and completely hydrolyzed by plasma esterases to release 1. 7 The pharmacological effects in clinical trials have shown that 2 possesses efficacy similar to that of 1; however, due to its greater water solubility it can be parenterally administered and thus be employed when oral administration is not possible. 5,6 The recent discovery that the analgesic properties of the saccharin derivative of acetaminophen, SCP-1 (3), possess a potency equal to that of the properties of acetaminophen, with significantly diminished hepatotoxicity, has prompted an extensive investigation into this class of compounds as a new generation of analgesic drugs.…”

Green approach for drug design and discovery of paracetamol analogues as potential analgesic and antipyretic agents

“…1 H NMR spectra were recorded in DMSO-d 6 using tetramethylsilane (TMS) as an internal standard with 400-MHz spectrometer. Mass spectra were recorded on an Agilent-liquid chromatography-mass spectrometry (LCMS) instrument under chemical ionization (CI) conditions and given by Q+1 values only.…”

“…A water-soluble analogue of 1 is the prodrug propacetamol hydrochloride 2 (5). This form of paracetamol is rapidly and completely hydrolysed to release 1 (6). The pharmacological effects in clinical trials have shown that 2 possesses efficacy similar to that of 1.…”