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Author: Subject: Vendors delivering wrong molecules...for who knows how long
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[*] posted on 15-5-2012 at 08:12
Vendors delivering wrong molecules...for who knows how long

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[*] posted on 15-5-2012 at 12:11

It happens to get the wrong compound when ordering from Chinese producers. It also happened to me that I got something different when I ordered a sample of a building block. Luckily I always check by NMR and compare on HPLC with an authentic sample when I have it, so this was immediately spotted. At first I was unpleasantly surprised, but then several coworkers told me it happened to them also.
Now, imagine you have no authentic sample to compare with and use the building block for some target drug that is still early in the clinical trials. The NMR of the end product can easily be misinterpreted, even if it is published in the literature, especially if it is a mess of multiplets and you don't pay enough attention to the 13C NMR. Other characterisation data, if available at all, such as the mp, IR, and even MS, can also be misleading, especially for isomers. It's easy to blame it on the company that had this misfortune, but they probably had no authentic sample to compare the final product with. Often there is no such sample available until the originator puts the drug on the market. Yet, what they should have done is a full characterization of the Chinese building block as soon as they received a commercial sample. This way they would easily spot the difference between the two dichloroanisidins. Trusting a cursory and negligent analysis and working in good faith apparently is not enough (any more).

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[*] posted on 15-5-2012 at 13:20

It gets worse. The original Wyeth patents reported two different NMRs for what was supposedly the same synthesis. Nobody noticed that there were at least two different molecules being sold as bosutinib until some academic researchers published an X-ray structure of the compound in an enzyme. Then a major reseller of the compound went back into the compounds delivered by their suppliers and found that of ten suppliers, two supplied one compound and eight supplied another. All of them provided all of the appropriate data, apparently, but since all of the products were clean and the 1H NMRs of the two isomers are very similar, nobody noticed.

That reseller is now calling on Pfizer to submit the actual lot of material that they have in clinical trials for X-ray analysis so they can at least demonstrate the exact structure of the compound that is going into people. Nobody else is really sure which isomer is actually bosutinib. They are both active in the enzyme assay (one is about 4x more active than the other), but I would bet that only one has been through tox screening, and if the other is being used in biological studies, the story behind the biological activity of this compound is going to get very confusing.
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[*] posted on 15-5-2012 at 16:53

I've first hand experience of product substitution which has negatively impacted on research. Not sure if the product was of Chinese origin or not, but it was definitely an eye opener of an experience

A few years ago, while working for a genetics laboratory, we started having random problems clearing infection from cell cultures. Protocol hadn't changed and had been extremely successful in the past

Whittling down the problem took a long time- turns out one of our techies had been occasionally using the antibiotic from an older bottle we'd sourced from the parent company who owned the trademark.

The antibiotic was proprietary, but was also available labelled as the same compound from several reputable culture supply vendors, and the fact that is was easier and cheaper to obtain from them as a part of our usual, larger orders led to us taking the easy option. We thought they were re-sellers, but as it turned out they weren't legally allowed to distribute that compound

When compared against the proprietary product sourced directly from the trademark owner, the allegedly identical compound from both culture suppliers was completely ineffective. The generic product had the same activity against the infection as water- ie 0% clearance rates. The clearance rate for the trademark owners antibiotic was consistent with earlier experiments and confirmed the validity of our protocol

I mentioned this to one of the culture suppliers, who denied that this was an issue, unsurprising given that any admission of error on their part would have exposed them to significant legal action. About two months later the product was quietly pulled from their catalogue.

We switched suppliers. The substitution nearly cost us the project as we couldn't make up for lost time and the impression poor results gave our backers

I now suspect every new product that comes in, record batch numbers and supplier for all ingredients, and analyse where possible

And I wonder who else it happened to, and how often it occurs elsewhere

[Edited on 16-5-2012 by 3xp0nential]

[Edited on 16-5-2012 by 3xp0nential]
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[*] posted on 15-5-2012 at 23:29

Even with very simple inorganic chemicals things can go terribly wrong.

I ordered 500 grams of Pb(NO3)2 from a UK-based seller. I received a bottle, labeled as 99% Pb(NO3)2, complete with warnings which apply to this compound (poison, oxidizer). I then tried to dissolve it in water and this only worked with some difficulty. When I added some of the solid to 20% HCl, the solid started fizzling and dissolved and the liquid turned clear yellow and a strong smell of Cl2 was produced.

After some testing and experimenting with the compound I came to the conclusion that the solid must be KBrO3. Quite a difference from Pb(NO3)2. Probably the seller purchases larger amounts of chemicals and repackages in smaller 500 gram containers and mistakenly has labeled a KBrO3 bottle as Pb(NO3)2.

I let the seller know of this error, but he never wanted to confirm this and I have the impression that he did not really believe me. He did not want the parcel sent back to him and a few days later I was surprised with another parcel, containing 500 grams of Pb(NO3)2. Probably he wanted the issue to be resolved in silence and without any publicity around it. I am content with how he resolved the issue, I have the Pb(NO3)2 and the KBrO3 I have as a bonus. But of course, it is not good at all. This error could have lead to high costs.

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