- In the 1990s, an HIV drug was part of a fascinating and baffling chemical mystery. Abbott Pharmaceuticals launched ritonavir in 1996. It was lifesaving.
75,000 people were on it. Magic Johnson was on it. It was a miracle drug, until June of 1998, when a batch of the drug failed its quality control tests.
If you cut a capsule open, you were supposed to get a gel, but instead, they were getting a white paste. So the scientists at Abbott put this paste under the microscope and saw these sharp, needle-like crystals that they had never seen before. They did a bunch of chemistry and realized that these crystals were, in fact, the drug.
This was ritonavir, but it was behaving completely differently than ever before. Now this is bad because solid crystals of ritonavir are completely useless. They cannot dissolve in water, so they don't get into your bloodstream, so even though the crystals are chemically identical to the ritonavir of the past, they were basically not the drug anymore.
And then things got much, much worse. After the first batch failed, that production facility could no longer make the original drug anymore. Every other batch also failed.
And then things got much, much worse. After analyzing the crystals in the lab, that lab couldn't produce the original drug anymore either. So the company sent some scientists over to Italy where they had another production facility, to see what the US folks were doing wrong, and that's when things got much, much worse.
A few weeks after that visit, the Italian facility couldn't make the original drug anymore either. It seemed almost as if there was some sort of failure virus attaching itself to company scientists and infecting whatever lab or facility they happened to visit. It turns out that what was happening was this.
(upbeat music) This is charcoal. It's mostly carbon, and it burns really well. You know it burns really well.
I'm not gonna light this on fire in my basement just to prove it to you. And recently Joe Hanson asked if I wanted to burn a different form of carbon, a diamond. Obviously, yes.
If you want to burn a bunch of diamonds, you can't just heat 'em up with a Bunsen burner. You also need to run a stream of pure oxygen over them while you heat them up. So both of these are carbon, but they have extremely different properties, because the carbon atoms in each of these substances are bonded to each other in completely different ways.
Molecules of a drug can do the same kind of thing. The exact same molecule can form multiple different crystal structures, and that can give you different properties, solubilities, melting points, even different colors. Chemists call different crystal structures of the same molecule polymorphs.
this is one polymorph of chocolate. This is another, or at least it was until it melted all over my hand. This one is better because it's shiny, it doesn't melt in my hand, and it has a satisfying snap to it.
(chocolate snapping) These crystals that the Abbott scientists saw under the microscope were a totally new, never before seen polymorph of ritonavir that the scientists called form two. Now, when you make a drug, you usually make it in solution, and when it is dissolved in a liquid, there's no form one, there's no form two, there's no polymorphs, none of that stuff. It is just the drug in solution.
But to purify the drug, you need to get it out of solution while leaving all the stuff you don't want behind in solution, and the classic way to do that is called crystallization. This is a sodium acetate solution. It's actually a supersaturated sodium acetate solution, which means there is more sodium acetate dissolved in this water than this water can dissolve.
That sounds impossible by definition, but actually it happens all the time. What I did to make this was I heated up the water, which increases the amount of sodium acetate that it can dissolve. Then I dissolved that larger amount of sodium acetate in the water, and then I let it cool to room temperature so that I can do this again.
Now, you've seen this before. What we're looking at here is crystallization. When you add a seed crystal, you are giving the molecules in solution a surface that is already in its crystal form that they can snap to, and as more and more of them snap to it, that surface grows and grows and grows until everything that can come out of solution has.
The seed crystal that you add is a specific polymorph, and molecules come out of solution by snapping to that specific polymorph, so in theory, you should get back whatever you add. Add a seed crystal of form one, you should get back crystals of form one. Add a seed crystal of form two, you should get back crystals of form two.
That is how it's supposed to work, and that's mostly how it does work in chemistry. But every time the Abbott scientists tried crystallizing form one, they always got at least some form two. Make ritonavir in solution and evaporate off the solvent?
They got Form two. Use a form one seed crystal to try and crystallize form one? They still got form two.
Use your lucky Erlenmeyer flask while wearing victory red underwear? Still form two! But where did form two come from in the first place?
This is a reference to the television show "The Office. " Amazingly, it probably resulted from something called heterogeneous nucleation. This is a supersaturated sodium acetate solution, and you already know what happens if I add a seed crystal of sodium acetate, but what if I instead add a seed crystal of sodium chloride, table salt?
Let's find out. (upbeat music) it worked! Oh my god, I can't believe that.
That was awesome. This is heterogeneous nucleation, when crystallization of chemical A is caused by a seed crystal of chemical B. Now let's try menthol.
(upbeat music) Oh, that time it really worked. That is incredible. The crystal sat on top and then it nucleated from there.
Sucrose. (upbeat music) Wow, look at that. Nothing.
This chemical is a degradation product of ritonavir, and when the Abbott scientists added it to a supersaturated solution of ritonavir, they got- (drumsticks tapping) Form two. That was a drum roll. So the first crystal of form two was seeded by this chemical, and then the Abbott scientists brought it back into their analysis lab.
What happened next? We are not exactly sure. Maybe they ground it up in a mortar and pestle.
Maybe they filtered it through a Buchner funnel. Maybe they did something else that would have aerosolized submicroscopic seed crystals, which might then have gotten sucked up by the HVAC system, spread throughout the entire building and attached themselves to people's clothes, hair, and skin, and then when those same people traveled to Italy, maybe those seed crystals fell off into the production lines, and that's what caused the Italy plant to fail. And at that point, Abbott was stuck with form two, because it turns out that form two is actually more stable than form one.
But if that's the case, why didn't form two come out of solution first? Why didn't the original synthesis of ritonavir produce the more stable form two? Well, a German chemist asked this very same question around the turn of the 20th century.
Wilhelm Ostwald noticed this weird trend that the least stable polymorph would crystallize out of solution first. Energy diagram. Ritonavir in solution.
Two different polymorphs, form one, form two. These little humps right here, this is the activation energy. It's the energy you need to spend to get from ritonavir in solution to either polymorph, and as you can see, the activation energy here is lower, so it's way more accessible to get to form one, and the reason for that is because form one is closer in energy to the ritonavir in solution.
That is Ostwald's Rule. Now here's the thing. The activation energy over here is way higher, so you could go months, years even, never getting to form two, even though it's more stable than form one, because the activation energy is so high, but a seed crystal (marker tapping) dramatically lowers the activation energy.
Now it's way lower than form one, so you're gonna go all the way down to here. Form two, it's the more stable form, and you are stuck with this. Once form two is there, it's there.
It's ready to seed any solution of ritonavir. This is not the first time that one polymorph has completely replaced another. It has happened before.
In one case, scientists prepared a polymorph of a compound called benzocaine picrate They then prepared a second polymorph by heating up the first one. After they'd prepared the second polymorph, they could no longer prepare the first one. So they cleaned the entire lab thoroughly, destroyed all samples of the second polymorph, waited about 10 days and then tried again, and it worked.
In another case, scientists were working with a polymorph of N-4-methylbenzylodine-4-methylaniline When it disappeared. They happened to be switching to a new lab a few miles away, so they hired a new student by phone, prohibited her from ever coming to their old lab or meeting anyone who had worked in their old lab, told her to buy all new glassware and try and make the old polymorph in the new lab. She successfully did.
In my favorite case, scientists actually sprinkled some powder of a new polymorph onto an old one, and then watched as the old one transformed into the new one Within minutes. Imagine sprinkling some diamond dust on some graphite and then the graphite slowly turns to diamonds. That is how crazy that is.
Now these were small, isolated incidents, but ritonavir was a big deal, especially to the 75,000 people who were on it. Could have easily been life or death for them. Now, luckily, Abbott had a liquid formulation, but that tasted terrible so after a lot of work, Abbott finally was able to make an amorphous version of ritonavir, which is still on the market today.
It's actually used as a booster for other antivirals. For example, it's in Paxlovid. Now, drug companies try and avoid this whole situation by doing extensive polymorph screening.
They try and find every possible polymorph of a compound before it goes to market, but there's never any guarantee that you find them all, so another ritonavir could happen at any time.
