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Posted on: March 6 2013

A loco Actifed syrup with a peculiar problem

Composition: Codeine phosphate 400mg, pseudoephedrine HCl 1200mg, Triprolidine 80mg, after citrate 300mg aqua purif 20 ml, guaifenesin 4g, ethanol 94 ° 25g, Vanillinne 200mg, ethanol 94 °; 5ml, Sirupus sorbitoli 70% NF6 ad 200cc < br/> What is the problem now? After some time this syrup discolours pink and the color increases with time in intensity: My first idea was that it had to go for an oxidation reaction and therefore added 1 g of ascrobinic acid to the preparation. The syrup discolored no more pink but yellow! Also the color of the dammed with the time. The syrup was also prepared with citric acid instead of with sodium citrate. This gave a remarkable result: the syrup remained clear for a month and only started to show a very slight yellowing after a full month. The discoloration also increased in intensity but never as dark as this from above. The combination of citric acid with the ascorbic acid as an anti-oxidant gave a bright yellowing.
We had a second formula in which no sorbitol syrup was used but hydroxyethylcellulose (500 mg), glycerol (100 g) and Aqua Conservans AD 200 cc. A bottle with and é é n without ascorbic acid was also prepared: again Intense pink and intense yellow discoloration respectively. The discoloration occurred faster compared to the actifed based on sorbitol syrup.
what could be the cause of this discoloration and how can we best remedy this problem?

Answer

There are in the composition several components, which can dissolve and give rise to discoloration: Tripolidine, Guaifenesin and vanillin. Let us start with the first.

Stability of triprolidine hydrochloride in liquid dosage form Many factors was found to affect the stability of triprolidine HCl in liquid dosage form like temperature, water, pH, UV light, and some excipients. Triprolidine HCl was found to be unstable in water and followed first order kinetics. UV light was found to affect aggressively the stability of Triprolidine HCl, but its degradation at pH 2 is much of than that at pH 8. The PH-rate profile for the degradation of Triprolidine HCl was found to exhibit a bell shape with base by portion above PH 7.0 but this portion was not found in the presence of 60% sucrose which lowered the degradation rate at ph above 8.0, but increased it at ph 5 , 6, and 7 aggressively. Maximum stability of Triprolidine HCl was found to occur at acidic medium of pH less than 3.0. Some Fonterra Excipients studied was found to enable Triprolidine HCl solution, like sorbitol, mannitol, glycerin, and aspartame due to water structure enhancement, others was found to have no effect on the stability of triprolidine HCl like sodium saccharin and Propyleneglycol, while others like glucose and to a higher extent Polyethyleneglycol 400 were found to increase the degradation rate of triprolidine HCl. Sucrose at low concentration, below 5% was found to enable Triprolidine HCl in water, while at concentration higher than 10%, it was found to increase the degradation rate. The rate of degradation of triprolidine HCl in commercial grade sucrose was much higher than that in analytical grade sucrose due to the presence of some impurities. Gene rally any substance that may enhance water structure will improve the stability of triprolidine HCl in water. In addition Triprolidine HCl has two nitrogen atoms that are subjected to be ionized or unionized, at pH conditions where these two atoms were found in the ionized form maximum stability of Triprolidine HCl was achieved.

Guaifenesin or Glyceryl guaiacolate (3-(2-methoxyphenoxy)-1.2-Propaaandiol) can also hydrolyze and then a phenol function is released which is oxidizable. Both the hydrolysis and the oxidation will be slower in light acid center. We must ensure that the middle is slightly acidic.

There are a few essential differences between your composition and these given up for Actifed syrup, old formula. The commercial product contains no Nacitraat and also no ethanol. The latter is probably not bostrous and can take over the role of Methylhydroxybenzoate present in the brand product. Nacitraat must be deleted from the formula. Optionally, you can add a small amount of citric acid. I would never add more than 100mg! Also the added water can be deleted and although the brand product contains sucrose However, I would use sorbitol 70%, taking into account the text above.

Based on your experiences it strikes me that Actifed syrup is colored with orange yellow S. This allows to camouflage a minimal dissolution and discoloration of the specimen. I do not mean that Actifed syrup does not have the announced stability. But a minimum dissolution (< 1%) Can cause a slight discoloration, which alerts the user useless.