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The Crystal That Could Destroy All Medicine — Transcript

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0:00- For two years, this drug was a miracle.
0:03It was introduced in 1996 to treat HIV.
0:06And by 1998, 75,000 patients across the country
0:10were taking up to 20 of them every day.
0:12It's called ritonavir,
0:14and it turned a certain death into a manageable condition.
0:19This particular pill is on its way
0:20to quality control to a dissolution tester.
0:23Here, analysts monitor each batch of capsules,
0:27checking that they do dissolve in around 30 minutes,
0:29which is quickly enough to be absorbed properly.
0:32It's a rigorous precaution for a drug
0:34that for two years and 240 consecutive lots
0:38has never failed. (grim music)
0:41But now an analyst sees something unusual.
0:44This capsule hasn't dissolved properly.
0:47So they follow protocol and trigger an emergency shutdown.
0:51(alarm blaring)
0:52They destroy the entire batch
0:54and deep clean the production line
0:56to eliminate any possible traces of contamination.
0:59But the next day, at quality control,
1:01the same thing happens.
1:03On the line the clear capsules are turning white and cloudy,
1:07technicians at the nearby research and development lab
1:10study the paste under a microscope
1:12and find they're filled with millions of tiny needles.
1:16They're crystals, but no one has seen them before.
1:19They need a control to compare the needles against,
1:23so they make some of their own ritonavir in the lab,
1:26but to their horror, it also comes out cloudy.
1:29So they try again, but all attempts yield the same result:
1:34a white paste every time. (subdued music)
1:37The researchers are stumped.
1:39They had been making ritonavir for two years.
1:42They knew its exact chemical composition
1:45and every part of the process used to make it,
1:48so they check all the input ingredients again,
1:51all the settings, every temperature setting and procedure.
1:54But all of it seems to be done correctly.
1:57Yet at the factory,
1:58the cloudy capsules are appearing more and more frequently.
2:02Within a week, every tablet produced
2:04by either the lab or the factory comes out cloudy.
2:08Abbott needs to halt all production
2:10of ritonavir immediately.
2:12But they can't just cut off the supply
2:14because people need these tablets.
2:17- [Narrator] "We called on as many resources as we could.
2:20We tried everything.
2:21We conducted countless experiments.
2:23We rebuilt facilities and new lines.
2:25We looked at alternative sites
2:27to see if we could start clean in a new environment."
2:32(gentle music)
2:32- And they found an alternative site, a factory in Italy.
2:36They start ritonavir production there,
2:37and to their relief,
2:39all the pills passed the dissolution test.
2:41This is great news.
2:43But it also means
2:44that Chicago must have been making a mistake.
2:47So a team of scientists flies over
2:49to look at what the Italians are doing differently.
2:52They check everything, the pressure, temperature, humidity,
2:56the exact weight of all the chemicals,
2:58but it all matches perfectly
2:59with what they're doing in Chicago.
3:02None of it makes any sense.
3:04But at least Italy can keep making the medicine.
3:08(phone ringing) (soft brooding music)
3:08But when the Chicago team returns home, they get a call.
3:12It's from Italy.
3:13Within days after their visit,
3:15one of the tablets fails the dissolution test.
3:19- [Narrator] "There was no gradual trend.
3:21There was no early warning.
3:22In a matter of weeks, maybe five or six weeks,
3:25every place the product was
3:27became contaminated with the crystals.
3:29We did not know how to detect it.
3:31We did not know how to test for it.
3:32We did not know what caused it.
3:34We did not know how to prevent it.
3:36We did not know how to get rid of it.
3:38And we kept asking the question, 'Why now?'"
3:43- They were witnessing a rare disaster.
3:47It had happened before, and in theory could happen again
3:50to just about any drug or chemical compound.
3:53It spreads like a disease,
3:55but the thing that's getting infected is the medicine.
3:58One day you can make it, the next it's gone forever.
4:02- [Narrator] "It is frightening that this could happen
4:04to any drug that we've taken on, which we're dependent."
4:06- And the scariest part
4:08is you can't predict if it will happen, when it will happen,
4:12or to which medicine or compound.
4:15Overnight, drugs we all rely on might just disappear.
4:20So what was happening inside those ritonavir capsules?
4:23What were those crystals inside?
4:25They appeared to be an entirely new compound,
4:28but when they tested them,
4:30everything indicated they were ritonavir.
4:33It sounds impossible,
4:34but something similar had actually been the center
4:37of a heated debate 170 years earlier.
4:41(mellow music)
4:41- [Casper] In his Paris laboratory,
4:43chemist Justus von Liebig was reading a paper.
4:47It was about a newly discovered compound,
4:49and what elements it was made of.
4:51This kind of work
4:52was at the cutting edge of chemical research.
4:55Research he knew better than almost anyone
4:57because he had personally pioneered most of it.
5:00This had made him highly respected in his field,
5:03but he also had a reputation
5:04for being difficult to work with.
5:06He was arrogant, hot-tempered, and didn't suffer fools.
5:10And the more he read this paper,
5:12the more incensed he got, because to him,
5:14it was clearly written by a fool, Friedrich Wöhler.
5:20So we headed over to the lab at Imperial
5:22to recreate what Wöhler claimed to have discovered.
5:25- So I've got it here wrapped in foil
5:27because it is a bit photo-sensitive.
5:29- [Casper] It's a bit like, like, little rocks in there.
5:31- Yeah.
5:32- Beige powder, okay.
5:34Made of one silver, one nitrogen, one oxygen,
5:37and one carbon. - Exactly.
5:38- (laughs) You wanna light it up?
5:40- Yeah, sure, let's do it.
5:42You seem quite excited.
5:43- I am quite excited.
5:47Yeah. Not much is happening.
5:50Oh, it's melting a little, or it's, like,
5:53it is getting a little discolored.
5:55- [Dr. Kafizas] Yes, it is.
5:56- I guess the issue was he said,
5:59"Okay, I found this beige powder
6:01and I know exactly what it's made of,
6:02one silver, one carbon, one nitrogen, and one oxygen."
6:05He publishes this. (curious music)
6:07The paper reaches Liebig, and he is like,
6:10"There's no way, because I've just discovered that compound.
6:13And when I tried to put a flame to it,
6:15it behaves completely differently."
6:18And we've got some of that right here too.
6:21(serious music)
6:21Should we try to burn this one?
6:22- Yeah. I made some fresh this morning.
6:24Let's just see how a small amount behaves.
6:26So we're gonna go with, I don't know,
6:28maybe a few milligrams.
6:30I've left it a bit moist.
6:33When it's in its moist- (compound snaps)
6:36Oh! - Oh, my God.
6:36I didn't expect that. - Yeah!
6:38- It's so loud. (Dr. Kafizas laughs)
6:40- It's very sensitive.
6:42I'm sorry about that. - That is crazy.
6:44- [Dr. Kafizas] And that was just a small amount.
6:45- Oh my God, my ears.
6:47What? I was not ready for that.
6:48- I wasn't ready for that either.
6:50I made it moist so that it's less likely
6:52to self-detonate, but clearly I was wrong.
6:56- Clearly Wöhler had made a mistake.
6:59These can't possibly be made of exactly the same elements.
7:02So Liebig wrote a paper slamming Wöhler's work,
7:05calling him a "hopeless analyst"
7:07and saying he should go back, check his work,
7:10and publish again when he's found his mistake.
7:13And Wöhler does exactly that.
7:15He checks his work but finds no mistakes.
7:18So now he's even more sure that he's correct.
7:21So he writes up his results in a second paper,
7:24but Liebig wasn't having any of this
7:26and replies with another paper saying he must be wrong.
7:29So this public back-and-forth continues for two years,
7:33with each side becoming more and more convinced
7:35that the other is out of their mind,
7:37until finally they agreed
7:39to meet on neutral ground in Frankfurt
7:41to put this whole thing to bed once and for all.
7:44They would replicate each other's work
7:45and let the results speak for themselves.
7:48But when they did, they were stunned.
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9:35And now back to what was happening with Liebig and Wöhler.
9:43(soft music)
9:43- They were both right? - Yeah.
9:44- Like, they both had a compound
9:46that was made of exactly one carbon, one nitrogen,
9:48one oxygen, and one silver atom.
9:50And one could be boring as hell (laughs)
9:53and the other one can, well, blow up your face.
9:59(compound snaps) - Oh!
9:59(compound bangs)
9:59- Whoa! (laughs)
10:01- This was surprising because at the time
10:04a compound was thought to be just the atoms
10:06that made it up and nothing more.
10:08But now this whole conception had to change.
10:12Von Liebig and Wöhler had discovered
10:14that the way those atoms are arranged also matters.
10:18At the time, they had no way to work out that ordering,
10:21but today we can.
10:23(inquisitive music)
10:23When you shine light on a molecule,
10:25its electric field tugs on the electrons and nuclei.
10:29They get pulled back and forth
10:30as the field changes direction.
10:33This can stretch, squeeze,
10:34and bend the bonds in the molecule
10:36as the atoms oscillate back and forth.
10:39But each bond responds differently to the light
10:41depending on how strong it is
10:43and the mass of the atoms it connects.
10:45It's like each bond is a boat on the ocean.
10:48If the waves are small and rapid,
10:51they won't rock it very much.
10:53And if the waves are very slow,
10:54like the tides coming in and out,
10:56that also won't rock the boat very much.
10:59The boat just gets lifted up and down.
11:02It's only when the waves are just the right size
11:04that the boat gets tossed around.
11:06And because of this, each bond will react strongest
11:10to a specific frequency of light, which we can measure.
11:13By hitting the molecule
11:14with a range of infrared frequencies,
11:16we get a spectrum like this
11:18with peaks that tell us when bonds are reacting.
11:21This acts like a fingerprint for the molecule
11:24and tells us which bonds are there.
11:28Wöhler's compound has a broad peak,
11:30which corresponds to bending
11:31an N double-bonded to C double-bonded to O group.
11:35Liebig's compound, on the other hand,
11:37has a spectrum that looks like this,
11:39with these two prominent peaks,
11:41one at high frequency and one at low frequency.
11:44These correspond to stretching a double bond
11:46between a carbon and a nitrogen
11:47and a single bond between a nitrogen and an oxygen.
11:51We now know that Wöhler's compound was silver cyanate,
11:54and it looks like this.
11:56The carbon, nitrogen, and oxygen
11:58are joined with those two strong double bonds,
12:01which is why it's so stable.
12:02In contrast, Liebig's compound, silver fulminate,
12:06looks like this.
12:07The silver is bonded to the carbon instead,
12:10so the other elements are arranged this way.
12:13The bond between the carbon and nitrogen is a triple bond,
12:16but the oxygen and nitrogen are very weakly connected.
12:20And this single bond is very easy to break,
12:23and once it does,
12:24the atoms can rearrange into much more stable gases,
12:27which is why it's so explosive.
12:30They had discovered isomers.
12:32That it's not just the atoms in a molecule
12:34that dictate how it behaves, but its bonds as well.
12:38So naturally the scientists at Abbott
12:41suspected something similar might be happening to ritonavir.
12:44They knew that the spectrum of ritonavir
12:46should look like this.
12:48So they put a sample of white paste into a spectrometer,
12:52expecting to see something completely different.
12:54But instead they saw this, the same peaks.
12:59The paste had all the same bonds as ritonavir,
13:02so it must be ritonavir.
13:05But they also noticed it wasn't exactly the same.
13:08There were these small deviations between the two.
13:11The arrangement of the atoms was the same,
13:13but something about the bonds had changed slightly.
13:17- Well, it turns out there's another way
13:19to change the properties, and I can show you how
13:22with probably the most delicious demo I'll ever do,
13:25because this, of course, is a piece of chocolate.
13:28It's nice, it's shiny, it's durable,
13:31and it has that nice snap when you crack it.
13:34But you'll notice
13:34that if you've ever let your chocolate melt,
13:37then it never returns to being quite the same.
13:40Suddenly it melts in your hand when you pick it up,
13:43you know, it's dull, it's bendy,
13:44and it doesn't quite taste the same.
13:46You're not imagining this.
13:48There really is a subtle difference,
13:49and I can explain what's happening
13:51with a little help from my friend Chris over here.
13:53- Hey. - Hello.
13:54So Chris runs his own YouTube channel, Chris Young Cooks,
13:58and this is way overkill for what we need here probably,
14:00because he was the head development chef
14:02at a three-Michelin star restaurant.
14:04- Yes.
14:05(subdued music)
14:06- We've got some nice shiny chocolate here.
14:08But look what happens when we turn up the heat.
14:17(heat gun whirs)
14:17Oh yeah, that goes quite quick.
14:23Oh, that is surprisingly satisfying.
14:27- We obviously melted some of the chocolate, no surprise.
14:30But this is what happens, right?
14:31You leave it somewhere warm,
14:32the chocolate gets above body temperature,
14:34it starts to melt, and then as it cools back down,
14:36it's gonna harden again.
14:37- So you've got the chocolate.
14:39- [Chris] That looks like heat-damaged chocolate, right?
14:41- [Casper] I know.
14:42- Like, you've seen this, you've opened a chocolate bar,
14:44maybe it was left in your car sitting in a sunny window.
14:46Touch the edge, like, you can feel,
14:49feel how that's just soft- - Yeah.
14:51- and kind of sticky.
14:52- Immediately.
14:53- Compare it to a nicely tempered piece of chocolate.
14:56Like, you can pick that up with your bare hands,
14:58it will eventually melt in your hand, but much more slowly.
15:01- Now if this ever accidentally happens to you,
15:04we'll show you how to get it back
15:06to the nice and shiny form.
15:08But what's interesting here
15:09is that we didn't change any of the ingredients
15:12and yet the properties changed completely.
15:15Chocolate is made of three main ingredients.
15:17There are other minor ones as well,
15:19but three main ones to focus on.
15:21It's got cocoa solids, that's what gives it its color,
15:24there are sugar, of course, for sweetness,
15:26and then there is cocoa butter.
15:28That's what gives it its texture.
15:31(gentle music)
15:31And this cocoa butter is the culprit.
15:33It's a fat made from three long carbon chains
15:35bonded together in the middle to make this sort of Y shape.
15:39And that Y shape can form together to form solids.
15:42But there are multiple ways they can stack together.
15:45There are many forms the crystal can take,
15:48each with different properties.
15:49And so we call these polymorphs.
15:52Chocolate actually has six polymorphs.
15:55The dull chocolate is mostly Form IV,
15:57and that has a melting point of around 27 degrees Celsius.
16:01While the shiny chocolate, which is the one we want,
16:04is mostly Form V, and that has a higher melting point
16:07of around 34 degrees Celsius.
16:09- So the challenge and the art of chocolate making
16:12is managing these polymorphs
16:14to get the right form of crystal
16:16by managing both temperature and, importantly, time.
16:19The nice thing about chocolate is you can start over.
16:21You just need to heat it back up to 45 to 50 Celsius
16:24to wipe the memory- - Okay.
16:25- of the wrong crystals.
16:26That's hot enough to melt out all of the crystals,
16:29but not too hot to start changing
16:31the flavor of the chocolate,
16:32evaporating a lot of the volatile aromatics.
16:35- [Casper] After around 10 minutes
16:36at roughly 50 degrees Celsius,
16:38all the crystals should have fully melted.
16:40- So at this point, we're trying to cool it back down
16:43to the temperature where crystals start to form again.
16:46And that's gonna start at about 34 Celsius.
16:48You'll start getting Form V crystals forming at 34,
16:51as we cool even lower,
16:52we start to get Form IV and Form III.
16:55Those can all form at these temperatures.
16:57And that's okay. We want all of these crystals initially.
17:00We want- - Oh, really?
17:00- Yeah, we want to have
17:02sort of a shotgun of nucleation going on
17:05because we wanna make sure we get lots of everything.
17:08- That's surprising.
17:09- It does seem surprising.
17:10- Because we just want Form V, right?
17:13- We do just want Form V.
17:14The trick is, if we just come down to the temperature
17:17where Form V forms,
17:19so if we just went to like 32 degrees, 33 degrees,
17:22and just waited there, you'd be waiting a very long time
17:24and you'd get a very random process
17:26of when does that crystal form,
17:28and maybe only a few crystals would form.
17:30And so they would get very large.
17:32- Ah. - By bringing the temperature
17:33all the way down to 27,
17:34we get lots of nucleation really fast.
17:36The downside, of course,
17:37is we get the crystals we don't want as well,
17:40but we get lots of Form V,
17:41and we get lots of small Form V.
17:43- Yeah.
17:43- So once we have that starting to form,
17:46we can select for the ones we want
17:48just by raising the temperature back up.
17:50And melting the Form III and Form IV,
17:52leaving us with only Form V, but, importantly,
17:55lots of Form V. - Right.
17:57After holding the chocolate
17:58at around 32 degrees Celsius for 5 to 10 minutes,
18:02we can pour it into the mold.
18:03- Okay, I think we're gonna be okay here, so.
18:07- Oh.
18:10I don't know what I was expecting,
18:11but I was not expecting it to go like this.
18:13It really comes out as a sort of sheet.
18:16- One of the things here
18:18is I do have some trapped air bubbles.
18:20- Yep.
18:26- Oh, yeah.
18:28- It's like a liquefaction. - Yeah, yeah.
18:32- [Chris] So at this point,
18:35seems like we're done, right? - Yeah.
18:36- But actually now we need to lock in
18:38that crystal pattern that we've created, right?
18:41- Yep. - Like, as it cools down,
18:42there's liquid oil in there
18:43and we're gonna drop back down through the temperature
18:45where Form IV and Form III can form.
18:47- Yep. - So what we need to do
18:48is we need to come down
18:49through that temperature relatively quickly
18:51so that we get mostly Form V growing
18:54and lock them in by getting rid of most of the liquid oil.
18:57So we really need to get this down to about 12 C.
19:00- [Casper] So we put it in the fridge
19:02and waited for around 20 to 30 minutes.
19:04- Get the door closed. - Great.
19:08If we did this correctly, it should be mostly Form V,
19:12which means all the molecules
19:13should have stacked tightly together,
19:15resulting in a shiny and snappy bar.
19:18(tray cracking) Ah! Ooh!
19:20That was satisfying.
19:21- They're just barely hanging on.
19:23- Wow!
19:24- And you can see they're nice.
19:26- Perfect. - Shiny.
19:28- This is all Form V?
19:29- This is all Form V, and we've got a nice shiny surface.
19:35Got a couple spots where maybe the molds
19:36could have been polished a little bit more,
19:38but give it a snap, just see how that is.
19:40(chocolate snaps) - Ooh. It's a very good snap.
19:42- [Chris] Yeah, that's a nice.
19:43- It's very sturdy.
19:44- That's a good chocolate bar.
19:48- Delicious. - That
19:48is how you temper a chocolate bar.
19:49- Amazing. (curious music)
19:51- But the stacking of the molecules in the crystals
19:53also changes something else.
19:55Since each molecule is surrounded by other molecules,
19:58it changes how the bonds inside can move.
20:01This is what the scientists at Abbott
20:03had seen in the spectrum.
20:04The needles they had seen under the microscope
20:06were a new polymorph of ritonavir,
20:09and a more stable one at that.
20:11Form I crystals looked like this instead.
20:15Now at first this might seem like good news.
20:17It was still ritonavir, even if it looked a bit different.
20:21It's just like how dull chocolate,
20:23even if it's not quite as nice, is still chocolate.
20:26But the problem was this new polymorph was far too stable.
20:30- Ritonavir Form II
20:33is substantially more stable than Form I.
20:37And the way we know it's more stable
20:39is because it's less soluble.
20:41But if that crystal structure
20:43happens to be much more stable,
20:46then it won't dissolve properly.
20:49And then it's a bit like you haven't taken the drug at all.
20:53- But with chocolate, we can change which polymorph we have.
20:57We just had to heat it up to switch it from shiny to dull,
21:00and then by cooling it down again in a specific way,
21:03we could get back to shiny.
21:05So you might expect that Abbott
21:07could just do something similar with ritonavir.
21:09And they tried, but the problem was
21:12that no amount of heating or cooling
21:15could turn Form II back into Form I.
21:18They were stuck.
21:19We can see what's happening by taking a look at this here.
21:24See, each polymorph has different energy levels.
21:27And in the case of chocolate that looks something like this,
21:30where Form IV has a higher energy level
21:33and Form V a lower one,
21:34and they're separated with this sort of hill in between.
21:38Now, after heating up the chocolate bar,
21:40we were mostly left with Form IV.
21:42So let's drop this little ball in there,
21:45and then you'll see it will slowly settle down
21:49into that valley.
21:51But not to the more stable Form V.
21:53And that's because there's this little hill in between.
21:56But now imagine adding some heat to this.
21:59It's like giving the ball a little bit of a kick.
22:02And you can see that the ball
22:03will suddenly start to move around.
22:05And if I give it enough of a kick,
22:08whoop, it will roll down into Form V.
22:11And now it is stuck there.
22:13Now you could keep adding more heat
22:15and you could get it back over the hill back to Form IV,
22:19but then you would just end up with a mess of both forms,
22:23because whenever you start cooling it down again,
22:25you know, the ball could just randomly settle
22:27in one of the two valleys.
22:28So that's what happened
22:29when we melted the chocolate uncontrollably.
22:31We just got a mixture of these two forms.
22:34But with ritonavir, the situation is a little different.
22:38The hill between the two forms is now much taller,
22:41but the Form II valley is also much deeper.
22:44So once the ball does get down there,
22:46it's basically impossible to get it back out of there,
22:49which is why no matter what the scientists at Abbott tried,
22:52they couldn't get back to Form I.
22:55- But this still doesn't explain why Form II
22:59was suddenly everywhere.
23:01Nothing had changed in their procedures.
23:03The barrier between the two forms should still be there.
23:07So it shouldn't have been possible
23:08to make this much Form II at all.
23:11And yet, 300 years earlier,
23:13legends of such a transformation
23:15spread across northern Europe.
23:18(gothic music)
23:18- It was a bitter winter morning,
23:20and it had been like this for months.
23:22The organist was on his way to a cathedral.
23:25The cold had been messing with the organ pipes.
23:27It's gone out of tune again.
23:29But that wasn't what the congregation thought.
23:32There were stories of other organs
23:34getting sick with warts or leprosy eating away at the pipes.
23:39Some thought it was the devil attacking the organ
23:42to punish an unfaithful flock.
23:45It was even said that when it was very quiet,
23:48you could hear these organs screaming
23:50and groaning in pain from the lesions.
23:54Nonsense, of course,
23:56it was just the metal contracting and expanding.
23:59(subdued music)
23:59Except these pipes weren't just contracting,
24:03they were cracked.
24:04And others are indeed covered
24:06in what looks like these lesions,
24:08black growths all over the organ.
24:17(dark music)
24:17Now, originally when this happened,
24:18people thought that this was the work of Satan.
24:21Of course, that's not what was going on,
24:23and we can explain what was actually happening.
24:25So we've got some normal tin right here,
24:28which is what those organ pipes were made out of.
24:30It kind of looks silver, it feels pretty strong,
24:34and it's sort of the form we're used to.
24:36- Exactly.
24:37- But here we have a slightly different form of tin.
24:40You can look at it, it's a bit more gray,
24:43it's a bit more crumbly.
24:45And at room temperature,
24:46normally the silvery tin is sort of more stable.
24:50But if you cool tin down
24:53to something like below 13 degrees Celsius,
24:55and ideally way colder,
24:57then it can transform into this new kind of gray tin.
24:59And we're gonna see what happens
25:01when we put it on top of the silver tin.
25:04- [Dr. Kafizas] We want to try and get it
25:05to around minus 30 degrees Celsius.
25:07- [Casper] Yep.
25:07- And what better to get us to those temperatures
25:09is dry ice. - Okay.
25:11- So dry ice is frozen carbon dioxide.
25:14And that is around minus 78 degrees Celsius.
25:17- [Casper] Yep.
25:18Now we've taken a thermo flask
25:20and filled it up with dry ice,
25:21and then put a platform on top on which we'll put our tin.
25:25This should cool it down to around minus 30 degrees Celsius.
25:29Now we left this here for around 14 hours,
25:32and what you'll see is that initially
25:34there's a very tiny speck of tin
25:36that suddenly transformed into gray tin,
25:39and then it spreads from there
25:40almost like an infectious disease,
25:43which is why this is also known as tin pest.
25:47And because gray tin is less dense, the tin expands.
25:50And so if you look closely,
25:52you can see it start to tear apart the metal.
25:56Now, normally it takes a lot of energy
25:59to transform some silver tin into gray tin,
26:02but once you get a tiny bit of gray tin,
26:05something strange happens,
26:06because now it acts as a nucleation site
26:08that other tin can attach to,
26:10and it effectively brings that hill way down.
26:13It lowers the activation energy.
26:15And so now it becomes very easy
26:16to switch from silver tin to gray tin.
26:18And so it starts to spread, it starts to take over.
26:23And the same thing was happening to those organ pipes.
26:25Once you got a lesion on one of those pipes,
26:28well then it would grow and spread everywhere.
26:30Little flakes would come off the pipes
26:32and seed all the others, and it would spread.
26:36And that's also exactly what happened with ritonavir.
26:40Once a tiny bit of Form II appeared,
26:42it acted as a nucleation site,
26:44lowering that massive activation energy
26:47and causing all the Form I to crystallize into Form II.
26:51Tiny seed crystals then broke off,
26:54could become airborne, and spread,
26:56attaching themselves to people's clothes
26:59and making it to other parts of the production line,
27:02effectively seeding them
27:04so that when new ritonavir was synthesized,
27:07it contained these seed crystals
27:09and turned the entire capsules into Form II.
27:12And because everyone likely had
27:14these seed crystals on their clothes,
27:16when the Chicago team flew over to Italy,
27:19they seeded that factory too.
27:22And in this way,
27:23soon not a single place was able to manufacture Form I.
27:27- [Derek] Ritonavir is arguably the most dramatic case
27:31of what we now call a disappearing polymorph.
27:34The YouTube channel Reactions made a great video about this
27:37that involves lots of physical demos,
27:39so I highly recommend you check it out.
27:42- [Narrator] "When this happened to us,
27:43we conducted an extremely thorough investigation
27:45to see if there was something
27:46that we did which would have caused this.
27:49While we've speculated
27:50on the cause of this chemical transformation,
27:52we do not have conclusive proof of what happened."
27:55- It might be that a mistake on the production line
27:59caused some chemicals to dry out.
28:01This might have created a new crystal
28:03similar in shape to Form II ritonavir,
28:06which acted like a seed.
28:08Or it might have just been bad luck
28:10that a seed crystal formed on its own purely by chance.
28:13- Even if you have a seed crystal,
28:16if there are some dust particles
28:18or some scratches in the recipient
28:23where actually crystals can start to nucleate,
28:28that can induce, then, different crystal structures.
28:30So it happens that in some pharmaceutical companies
28:34where they produced the same polymorph for years and years,
28:39that suddenly there is, I would say,
28:41a hair or some other particle that,
28:44kind of, gets into the process
28:46and will change the entire crystallization of the compound,
28:51and is then very difficult to control.
28:54- And once a more stable form has appeared,
28:56it can spread and quickly seed the entire planet.
29:00- It might be that you
29:01will never, ever get the initial polymorph again.
29:04- After five months of research, Abbott's researchers
29:07held a press conference to share their findings.
29:10(intense music)
29:10- [Narrator] "Good afternoon.
29:11My colleagues and I are here today
29:13to explain what has happened, why it has happened,
29:16how we've responded to the problem,
29:18and what we're going to do to correct the problem.
29:21Sometime during this summer,
29:22the semi-solid formulation of ritonavir
29:25began to change into a crystal form,
29:28a transformation that we believed
29:29was a scientific and chemical impossibility.
29:39- [Narrator] "You are a large multinational company.
29:41Your scientists are obviously smart.
29:44How could this happen?"
29:45- [Narrator] "A company's size and the collective IQs
29:48of their scientists have no relationship to this problem.
29:52This phenomenon is, I believe, unpredictable.
29:54We are, in some sense, the victim of bad luck.
29:58There are many mysteries of nature that we've not solved.
30:01Hurricanes, for example,
30:02continue to occur and often cause massive devastation.
30:05There is nothing that we can do today
30:07to prevent a hurricane from striking any community
30:09or polymorphism from striking any drug.
30:13Science cannot provide a solution to all our problems."
30:20(curious music)
30:20- Now, here's a good question.
30:21Is everything polymorphic?
30:24So nobody had discovered a polymorph of aspirin, right?
30:28So it had been around, it's one of the earliest drugs.
30:31It had been crystallized in industry
30:33for what, 130, 140 years?
30:38And so can you say,
30:39"Because nobody had discovered
30:41a polymorph of aspirin, therefore..."
30:43No. Right?
30:44The only problem is
30:47I discovered Form II of aspirin. (laughs)
30:50By accident. Right?
30:51- It turns out over half of all compounds
30:54are known to be polymorphic, and there could be more.
30:57- The number of polymorphs
30:58is proportional to the amount of time
31:00and money you spend researching that compound.
31:03- In fact, nowadays we know
31:04there are not two forms of ritonavir, but at least five.
31:08So are new cases of disappearing polymorphs
31:11something to worry about?
31:12- It's quite, quite rare.
31:14We certainly know a lot more
31:17than we did when ritonavir occurred,
31:21but I wouldn't be surprised to see it happen again.
31:25- If there's a 1% chance the world's gonna end,
31:28you're gonna do something about it, right?
31:30If there's a 1% chance a plane is gonna crash,
31:33you're not gonna fly, right?
31:36So, so yeah.
31:37So we're at that situation where it might only be
31:42in that order of 1%, but if it happens,
31:45it's gonna cost you a hell of a lot more
31:47than a few weeks of research on polymorphs.
31:50Ritonavir was one of the red flags
31:55that caused a lot of regulatory activity
31:58and a lot of scientific activity around polymorphs.
32:01- Nowadays, pharmaceutical companies
32:03can spend hundreds of thousands
32:05to millions of dollars screening for polymorphs.
32:08In the end, there was no way
32:10of getting Form I ritonavir back successfully.
32:12There were attempts, but all were incredibly costly,
32:16and they risked being infected again.
32:19So instead, Abbott went back
32:20to an older liquid formulation of the drug
32:23and abandoned Form I entirely.
32:26- [Narrator] "Our initial activities were directed
32:28towards eliminating Form II from our environment.
32:30We finally accepted that we could not.
32:33Our subsequent activities were directed
32:35towards figuring out how to live in a Form II world.
32:39Nature would appear to favor it."
32:43(curious music)
32:43- The liquid formulation was not ideal.
32:46It had worse side effects,
32:47and not all patients could tolerate it well, but it worked.
32:51- [Narrator] "It is frightening that this could happen
32:53to any drug that we've taken and on which we're dependent,
32:55even though it is not that common.
32:57This time, it has happened to Abbott
32:59and to the tens of thousands of people
33:01taking the semi-solid capsule.
33:03Thankfully, we had the liquid formulation as a safety net.
33:06Next time it may happen to another drug
33:08that may not have the safety net."
33:13(curious music continues)

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