Control Of The Major Degradation Product Of Phenylephrine HCl In The Compound Tablet

Common cold is one of the most common diseases of mankind, and cold drug is one of the most frequently used drugs with relatively large consumption quantity. The most frequently used westen cold drugs are often a combination drug which consists of analgesic, antitussive, decongestion and anti-histamin compositions, among the most frequently used nasal decongestion agent is Pseudoephedrine hydrochloride (PSE). However due to the fact that PSE is easily be processed to be narcotic drugs, in recent years, most of the major countries in the world stimulated strict regulations on the PSE containing drugs and China is no exception. To ensure drug safety and the convenience for people to access common cold drugs, some major domestic and foreign pharmaceutical companies are enthusiastic in the effort to develop a new generation compound cold drug based on Phenylephrine hydrochloride (PE) instead of PSE.’An Ben Mei Min’ tablet is a new generation non-PSE compound cold drug, with each tablet contains 4 active ingredients namely Acetaminophen,Phenylephrine HCl, Dextromethorphan HBr and Chlorphenamine maleate. Study shows that PE in this compound tablet is prone to significant degradation which leads to serious efficacy and safety concerns. In order to study and develop an effective method for control of PE degradation, an analytical method based on HPLC technology was developed in this paper which is capable to assay the potential degradation impurities of PE and PE content smultanousely and was validated according to Chinese pharmacopeia requirement. By Comparing the HPLC retention time and the mass chromatogram of the main degradation product of PE with that’s of the available reference standard, the main degradation product of PE was identified as the aduct of PE and maleic acid (PHE-MAL).This paper revealed that Magnesium stearate as the most commonly used lubricant which is presented as an excipient in tablets could significantly accelerates the formation of PHE-MAL in the’An Ben Mei Min’tablet, the mechanism behind is discussed in this paper in details, assumption was made that inside a tablet which is a heterogenous system, Magnesium stearate reacts first with PE to form the base form of PE on the granule surface where Magnesium stearate and PE contacting to each other, then the base form of PE which contains the active secondary amino group will reacts with malic acid to form the PHE-MAL aduct through Michael addition reaction. Further experiments were done and the results shown that other micro-environment pH modifier like acidic excipients could inhibit this reaction while basic excipients do the opposite, the experiment results also shown that the presence of metal chelating agent has no inhibition impact to the formation of PHE-MAL adduct.In order to find a suitable control method that is practical and feasible for the manufacturing process of An Ben Mei Min’ tablets, trials were done trying to segregate PE and Manesium Stearate, control of residue moisture content, substitute Magnesium Stearate with other lubricants etc., but none of them succeeds. Based on the understanding of PHE-MAL formation mechanism, this paper proposed PHE-MAL inhibition method by adding micro environment pH modifier without further change of original formula. Further trials were carried out to optimize the selection, incorporation method as well as the concentration of the proposed addition of acidic excipient. Compared to add the acidic excipients in dry form, results shown that to add the acidic excipient through liquid spray is much more effective. However, negative impacts were observed as the quantity of acidic excipient increases, such negative impact including the color change on the tablets surface and significantly slow down of the disintegration and disslotion rate which are highly unexpected, the mechanism behind them were discussed and the best concentration was proposed.Finally, according to the above optimized formula and process, both the accelerated and long term stability testing shown that the degradation of Phenylephrine HCL of’An Ben Mei Min’ tablet manufactured was well controlled within the limit, so as to enssure the efficacy and safety of the product throughout its shelf-life.In conclusion, this paper developed a quantitative analytical method for assay of Phenylephrine HCL and its degradants in the compound tablet product which contains Acetaminophen, Phenylephrine HCL, Dextromethorphan HBr and Chlorphenamine maleate, the mechanism of the formation of the major degradant was investigated and finally the detail controlling method was proposed and validated.