I am currently studying to find a coloration method limited to opium alkaloids that is even better than Froehde reagents. Subjects include morphine, codeine, dihydrocodeine, oxycodone, and diacetyl morphine, 6-acetyl morphine, acetyl codeine, desomorphine, methyldesomorphine, and the like. This can also help with drug investigations for home-grown drugs that are spreading more explosively in the area. This problem is not known when and where it begins, and it is more likely to occur in areas where there is a particular dependence on potential cough medicines and where smuggling is tighter.

Many of our non-target specimens, whether pharmaceutical or non-pharmaceutical, contain lactose as a diluent. In addition, various alkaloid test solutions have coloration of saccharides.

By the way, there is a problem that I care about now. That is the effect of coexisting lactose and sucrose on solvent extraction of alkaloids from samples. Here is a summary of the question.

As an example, I have previously shown how much codeine salt contained in 1% diluted codeine phosphate for medical use (diluent is lactose) contains trace amounts of morphine salts remaining in the purification process, and how each alkaloid contains A quantitative test was performed to determine the average of the rates.

The specimen was adjusted to pH 12.2 with an aqueous sodium hydroxide solution containing sodium chloride, extracted with chloroform four times by a conventional method, and the extracted chloroform was washed with a small amount of an aqueous sodium chloride solution. Shake twice to combine and quantify all chloroform. (Morphine was extracted at pH 9.2 of the remaining aqueous solution.)

In this extraction method, almost all codeine was extracted, and we believe that the yield should be appropriate for quantification. At least the quantitation of codeine should be fairly constant for the same formulation, with slight variations.

As expected, our codeine quantification results, as well as the results of multiple codeine quantification tests that were once sent from each pharmaceutical company for the purpose of another study, showed slight variability, but roughly the same quantification value was. (The extraction method is completely unified).

This variation is, of course, acceptable and is an event that usually occurs. In our products in Japan, codeine base accounts for about 69-70% of codeine phosphate, and the difference in that ratio causes errors.

However, I have a curious document. It is the following literature.

“Colorimetric Determination of Codeine”

〔Yakugaku zasshi journal of the Pharmaceutical Society of Japan 76 (5): 608-610. May, 1956.〕

There is the following description in it.

(Before solvent extraction of lactose-diluted codeine phosphate preparations )

“ ⋯When the codeine preparation is a diluent powder or syrup or the like, even if it is extracted with chloroform using alkali hydroxide, the extraction rate is 60-80%, and its value is unstable and not quantitative. It is believed that this is based on the adsorptive action of lactose or sucrose, which has been used as an excipient or sweetener. Therefore, before extraction, it was previously dissolved in 1N hydrochloric acid, heated on a boiling water bath for 1 hour to hydrolyze lactose or sucrose, reduce its adsorptive power, and then extracted with chloroform in caustic, and extracted with 96-98 % Extraction could be performed almost quantitatively. ”

As mentioned above, does lactose and sucrose have an adsorption effect?

Searching for any other literature, neither is this opinion affirmed nor denied.

I am skeptical, but if this were the case, there would still be a lot of codeine left in the water. This is a serious problem.

If this is the case, the following questions will appear.

Disaccharides have an adsorptive effect, and monosaccharides have almost no adsorptive effect, does that mean that glucosidic bonds have some kind of adsorptive effect?

Or, because lactose is weakly acidic, does it form a bond with lactose instead of being completely free base even when the pH is raised with alkali hydroxide? (Like a water-soluble morphinate).

The question is whether this adsorption is a phenomenon that occurs in alkaloids in general or that is limited to codeine.

There is no point in using a boric acid-ion exchange resin to separate sugars, as long as codeine does not separate from the sugars forever. Boronic acids are even stronger acids. Binding codeine and boronic acid does not solve the problem.

This may be a clear answer if you make a 1% codeine phosphate powder made from pre-measured codeine base, phosphoric acid, and lactose and perform an extraction experiment. I'm going to do this, but before that, if you were to know about the "adsorption of codeine on lactose", I'd like to ask a question and use that opinion as a reference.

We welcome your comments.

Takeaki Miyamoto.