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There are these everyday things that one should know as a scientist and especially as a chemist, but which never come to light in an academic curriculum — at least not in mine.

One such thing is the purpose of imperative non-disruption of the cold chain. It is clear that there are plenty of reasons why it is crucial to transport food and also pharmaceuticals in a refrigerated condition. On the one hand, it reduces the risk of bacteria proliferating significantly, but it also prevents labile substances from decomposing or reacting with other ingredients. So far, so good. But why shouldn't you cool down products again once the cold chain has been interrupted?

I have read, for example, in the package insert of a pharmaceutical product that the drug should always be stored below 25 °C. In pharmacies, the product is kept in the refrigerator, and I, as the consumer, should continue storage in the refrigerator if possible. If this is not feasible for me, e.g., due to lack of space, the storage temperature should not exceed 25 °C. It is also pointed out that I should not keep the drug in the refrigerator after storage at room temperature. This reminded me of the wise words of my grandmother, who said that fish, for example, should only be frozen once because otherwise, it will go bad. With many other foods, similar claims are made. Since these indications can be found across countries and cultures, I assume that there are known scientific reasons for this, but I am not aware of them. I can't figure out why it should be bad to refreeze a defrosted piece of meat or why I shouldn't put my medicine in the refrigerator on hot days anymore after storing it at room temperature for a while.

Maybe a few food chemists and/or pharmacists can shed some light on this.


Edit: Poutnik and Julian, I wish I could accept both of your answers. I find it difficult to decide which answer is "the best", as they both address a different aspect of my question which they explain in a very understandable way. I have decided to mark Julian's answer as accepted since he — despite his long membership — has a much lower reputation than Poutnik.

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    $\begingroup$ In general, pharma companies can and will only guarantee that a product will behave properly when treated within certain bounds which they are legally expected to test and have tested. If you handle the product outside these bounds then you cannot expect legal compensation if the product does not behave as advertised (including causing harm). For specific food and pharmaceuticals the reasons are bound to be more specific. $\endgroup$ – Buck Thorn Sep 29 at 10:28
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    $\begingroup$ @Sam Julian is the good choice. $\endgroup$ – Poutnik Oct 1 at 9:04
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Answer here from a quality manager in the pharmaceutical field in Europe.

Pharmaceutical companies are obliged to perform stability tests for their products according to the relevant pharmaceutical (GMP) agency in your market (FDA/EMA/etc) and the international agreed guidelines like ICH Q1A-F and the WHO).

These tests are carried out in stability chambers with specific temperature and humidity according to your market. A product intended to be stored at room temperature in Europe and the US will need a study for minimum 12 month up to 5 years at 25 °C and 60% relative humidity (RH) as well as an intermediate study at 30 °C and 65% RH for 6 month to 5 years and a an accelerated test at 40 °C and 75% RH for at least 6 month. Cool stored products will have the long time storage at 5 °C and the accelerated test at 25 °C and 60% RH and there is a whole lot of other stability studies you can (or can be forced to) test. Based on a risk assessment and your stability protocol you will analyze your drug after defined times (like 1, 3, 6, 9, 12, 18, 24, … month).

For each pharmaceutical product there must be a defined specification. This might includes the assay, impurities like degradation products, metal residues, solvent residues, color, taste, microbiological contamination etc.

Now, after each time point you test your defined specification if everything is still within the specification. The scope is based again (as nowadays everything in the pharmaceutical environment) by a risk assessment.

Using this information you can define your storage conditions and shelf life of your drug. If you find out you fulfill the specification at 25 °C for the whole duration but not at 30 °C, you will define the storage condition to be below 25 °C to be on the safe/legal side. Same with the storage at 5 °C. If the tests at 25 °C fail after 2 month, you can e.g. define a storage of max 2 weeks at room temperature to be on the safe side.

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  • $\begingroup$ I remember doing such stability tests by quantitative TLC by CAMAG scanning device. $\endgroup$ – Poutnik Sep 30 at 4:44
  • $\begingroup$ @Julian Specifically about tablets, because of the formulation of the active ingredient into a matrix (including @Poutnik's comment) one may read this like as to probe if the chemicals did not undergo unwanted chemical reactions during storage where covalent bonds altered. The complementary question, do these tests include checks of the phase purity, i.e. as a probe for crystallographic phase transitions which may differ e.g., by solubilisation rates as the original API (and may be under a different patent than the intended API)? $\endgroup$ – Buttonwood Sep 30 at 10:44
  • $\begingroup$ @Buttonwood If this is in the specification, sure. Usually if there are phase requirements, these are in the specification for the product and should be analyzed. I just never had such a product for testing. $\endgroup$ – Julian Sep 30 at 11:01
  • $\begingroup$ @buttonwood This is IMHO controlled indirectly, as there are performed simulated dissolutions at standardized conditions. So matrix or phase alternation effects would affect the content of active or controlled compounds in the resulting solution. $\endgroup$ – Poutnik Sep 30 at 12:52
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    $\begingroup$ @Buttonwood It was not suggestion, it is done routinely anyway within stability studies. $\endgroup$ – Poutnik Sep 30 at 13:27
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Avoiding cooling again after keeping it ( for non critical products ) at room temperature is mainly to prevent forgetting it was not cold all the time and that it may will not last as long as expected.

Taking food from the fridge, you may not remember after a week or two that it was outside longer than it should be. It can violate the safety by growth of microbes, which does not fully stop when it gets cold back.

For drugs or similar critical products, it violates stability and guarantee of usability, as thoroughly described by @Julian answer. I did related analysis within drug stability studies in past as well.

Food freezing is another case. Industrial freezing of food is done by a shock freezing by liquid nitrogen. This leads to quick forming of small ice crystals that do not puncture the cell walls, so after melting melting food before usage, it is OK.

But when refrozen back e.g in a freezer, freezing is slow, leading to growing big ice crystals puncturing the plant/animal cells. After another melting, cell liquids goes out , cell loose their tonus and the stuff gets unpleasant mechanical and sensory state, affecting the final taste. Additionally, what was told above about the fridge applies here as well.

Presence of free ice along with frozen vegetable is a sign the content got refrozen.

Slow melting of previously fast frozen stuff leads to growth of bigger crystals, similarly as recrystallization happens, as bigger crystals are thermodynamically preferred due lower surface energy. So some cell wall tearing and subsequent deterioration of the content happens even during melting and continues until content is frozen again. Also, fast freezing is still some stress, even lower than slow freezing.

So the final effect of

  • fast freeze -> slow melting -> slow freeze -> melting

can be much worse then just

  • slow freeze -> melting

as the former has more time and opportunity to cause damage.

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  • $\begingroup$ Also intact cell walls inhibit microbial growth rather effectively. Fresh apples or pumpkins stay good on a cool shelve for months, even tomatoes, but not if there is the smallest dent in their skin. When thawed a second time, food should be used immediately, because all their cells are broken. +1 $\endgroup$ – Karl Sep 29 at 17:44
  • $\begingroup$ Thanks for your answer! The growth of differently sized ice crystals is very interesting. Why is that? $\endgroup$ – Sam Sep 29 at 18:06
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    $\begingroup$ Also, the answer explains why deep-frozen products should not be re-frozen. But often we also freeze leftover food, or freeze the meat after visiting the butcher. So far I have never had problems with the meat tasting odd, even though it was frozen slowly and therefore these larger ice crystals must have formed. $\endgroup$ – Sam Sep 29 at 18:06
  • $\begingroup$ @Sam below the freezing point, the solid phase is more energetically favorable than the liquid phase, but the solid/liquid boundary is still unfavorable. Small ice crystals have very high surface area / volume, so they are unstable. Close to the freezing point, freezing will mostly proceed by increasing the size of the few crystals that manage to grow large enough to be stable. So average size of crystals is large. At temperatures well below the freezing point, the energetic preference for the solid phase is greater, so far more crystals survive, and the average size is smaller. $\endgroup$ – timeskull Sep 29 at 19:08

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