The Crystal That Could Destroy All Medicine

0:00 For two years, this drug was a miracle.

0:03 It was introduced in 1996 to treat HIV.

0:06 And by 1998, 75,000 patients across the country

0:10 were taking up to 20 of them every day.

0:12 It's called ritonavir,

0:14 and it turned a certain death into a manageable condition.

0:19 This particular pill is on its way to quality control to a dissolution tester.

0:23 Here, analysts monitor each batch of capsules,

0:27 checking that they do dissolve in around 30 minutes,

0:29 which is quickly enough to be absorbed properly.

0:32 It's a rigorous precaution for a drug that for two

0:36 years and 240 consecutive lots has never failed.

0:40 (grim music) But now an analyst sees something unusual.

0:44 This capsule hasn't dissolved properly.

0:47 So they follow protocol and trigger an emergency shutdown.

0:51 (alarm blaring) They destroy the entire batch and deep clean

0:55 the production line to eliminate any possible traces of contamination.

0:59 But the next day, at quality control, the same thing happens.

1:03 On the line the clear capsules are turning white and cloudy,

1:07 technicians at the nearby research and development lab study the paste

1:11 under a microscope and find they're filled with millions of tiny needles.

1:16 They're crystals, but no one has seen them before.

1:19 They need a control to compare the needles against,

1:23 so they make some of their own ritonavir in the lab,

1:26 but to their horror, it also comes out cloudy.

1:29 So they try again, but all attempts yield the same result:

1:34 a white paste every time.

1:36 (subdued music) The researchers are stumped.

1:39 They had been making ritonavir for two years.

1:42 They knew its exact chemical composition and every

1:45 part of the process used to make it,

1:48 so they check all the input ingredients again,

1:51 all the settings, every temperature setting and procedure.

1:54 But all of it seems to be done correctly.

1:57 Yet at the factory, the cloudy capsules are appearing more and more frequently.

2:02 Within a week, every tablet produced by either

2:05 the lab or the factory comes out cloudy.

2:08 Abbott needs to halt all production of ritonavir immediately.

2:12 But they can't just cut off the supply because people need these tablets.

2:17 [Narrator] "We called on as many resources as we could.

2:20 We tried everything.

2:21 We conducted countless experiments.

2:23 We rebuilt facilities and new lines.

2:25 We looked at alternative sites to see if we could start clean in a new

2:31 environment." (gentle music)- And they found

2:33 an alternative site, a factory in Italy.

2:36 They start ritonavir production there, and to their relief,

2:39 all the pills passed the dissolution test.

2:41 This is great news.

2:43 But it also means that Chicago must have been making a mistake.

2:47 So a team of scientists flies over

2:49 to look at what the Italians are doing differently.

2:52 They check everything, the pressure, temperature, humidity,

2:56 the exact weight of all the chemicals,

2:58 but it all matches perfectly with what they're doing in Chicago.

3:02 None of it makes any sense.

3:04 But at least Italy can keep making the medicine.

3:08 (phone ringing) (soft brooding music) But when

3:09 the Chicago team returns home, they get a call.

3:12 It's from Italy.

3:13 Within days after their visit, one of the tablets fails the dissolution test.

3:19 [Narrator] "There was no gradual trend.

3:21 There was no early warning.

3:22 In a matter of weeks, maybe five or six weeks,

3:25 every place the product was became contaminated with the crystals.

3:29 We did not know how to detect it.

3:31 We did not know how to test for it.

3:32 We did not know what caused it.

3:34 We did not know how to prevent it.

3:36 We did not know how to get rid of it.

3:38 And we kept asking the question,

3:42 'Why now?'"- They were witnessing a rare disaster.

3:47 It had happened before,

3:48 and in theory could happen again to just about any drug or chemical compound.

3:53 It spreads like a disease,

3:55 but the thing that's getting infected is the medicine.

3:58 One day you can make it, the next it's gone forever.

4:02 [Narrator] "It is frightening that this could

4:04 happen to any drug that we've taken

4:05 on, which we're dependent."- And the scariest part

4:08 is you can't predict if it will happen,

4:11 when it will happen, or to which medicine or compound.

4:15 Overnight, drugs we all rely on might just disappear.

4:20 So what was happening inside those ritonavir capsules?

4:23 What were those crystals inside?

4:25 They appeared to be an entirely new compound,

4:28 but when they tested them, everything indicated they were ritonavir.

4:33 It sounds impossible, but something similar had actually been the center

4:37 of a heated debate 170 years earlier.

4:41 (mellow music)- [Casper] In his Paris laboratory,

4:43 chemist Justus von Liebig was reading a paper.

4:47 It was about a newly discovered compound, and what elements it was made of.

4:51 This kind of work was at the cutting edge of chemical research.

4:55 Research he knew better than almost anyone

4:57 because he had personally pioneered most of it.

5:00 This had made him highly respected in his field,

5:03 but he also had a reputation for being difficult to work with.

5:06 He was arrogant, hot-tempered, and didn't suffer fools.

5:10 And the more he read this paper, the more incensed he got,

5:13 because to him, it was clearly written by a fool, Friedrich Wöhler.

5:20 So we headed over to the lab at Imperial

5:22 to recreate what Wöhler claimed to have discovered.

5:25 So I've got it here wrapped in foil because it is a bit photo-sensitive.

5:29 [Casper] It's a bit like, like, little rocks in there.

5:32 Yeah.

5:32 Beige powder, okay.

5:34 Made of one silver, one nitrogen, one oxygen, and one carbon.

5:38 Exactly.

5:39 (laughs) You wanna light it up?

5:40 Yeah, sure, let's do it.

5:42 You seem quite excited.

5:44 I am quite excited.

5:47 Yeah.

5:48 Not much is happening.

5:50 Oh, it's melting a little, or it's, like, it is getting a little discolored.

5:55 [Dr.

5:55 Kafizas] Yes, it is.

5:57 I guess the issue was he said, "Okay,

5:59 I found this beige powder and I know exactly what it's made of, one silver,

6:03 one carbon, one nitrogen, and one oxygen." He publishes this.

6:06 (curious music) The paper reaches Liebig, and he is like,

6:10 "There's no way, because I've just discovered that compound.

6:13 And when I tried to put a flame to it,

6:15 it behaves completely differently." And we've got some of that right here too.

6:21 (serious music) Should we try to burn this one?

6:22 Yeah.

6:23 I made some fresh this morning.

6:24 Let's just see how a small amount behaves.

6:26 So we're gonna go with, I don't know, maybe a few milligrams.

6:30 I've left it a bit moist.

6:33 When it's in its moist- (compound snaps) Oh!

6:36 Oh, my God.

6:36 I didn't expect that.

6:37 Yeah!

6:38 It's so loud.

6:39 (Dr.

6:39 Kafizas laughs)- It's very sensitive.

6:42 I'm sorry about that.

6:43 That is crazy.

6:44 [Dr.

6:44 Kafizas] And that was just a small amount.

6:45 Oh my God, my ears.

6:47 What?

6:47 I was not ready for that.

6:49 I wasn't ready for that either.

6:50 I made it moist so that it's less likely to self-detonate,

6:53 but clearly I was wrong.

6:57 Clearly Wöhler had made a mistake.

6:59 These can't possibly be made of exactly the same elements.

7:02 So Liebig wrote a paper slamming Wöhler's work,

7:05 calling him a "hopeless analyst" and saying he should go back,

7:09 check his work, and publish again when he's found his mistake.

7:13 And Wöhler does exactly that.

7:15 He checks his work but finds no mistakes.

7:18 So now he's even more sure that he's correct.

7:21 So he writes up his results in a second paper,

7:24 but Liebig wasn't having any of this and replies

7:27 with another paper saying he must be wrong.

7:29 So this public back-and-forth continues for two years,

7:33 with each side becoming more and more convinced

7:35 that the other is out of their mind,

7:37 until finally they agreed to meet on neutral ground in Frankfurt

7:41 to put this whole thing to bed once and for all.

7:44 They would replicate each other's work and let the results speak for themselves.

7:48 But when they did, they were stunned.

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9:35 And now back to what was happening with Liebig and Wöhler.

9:43 (soft music)- They were both right?

9:44 Yeah.

9:45 Like, they both had a compound that was made of exactly one carbon,

9:48 one nitrogen, one oxygen, and one silver atom.

9:50 And one could be boring as hell (laughs) and the other one can,

9:56 well, blow up your face.

9:59 (compound snaps)- Oh!

9:59 (compound bangs)- Whoa!

10:01 (laughs)- This was surprising because at the time a compound was thought

10:05 to be just the atoms that made it up and nothing more.

10:08 But now this whole conception had to change.

10:12 Von Liebig and Wöhler had discovered

10:14 that the way those atoms are arranged also matters.

10:18 At the time, they had no way to work out that ordering, but today we can.

10:23 (inquisitive music) When you shine light on a molecule,

10:25 its electric field tugs on the electrons and nuclei.

10:29 They get pulled back and forth as the field changes direction.

10:33 This can stretch, squeeze,

10:34 and bend the bonds in the molecule as the atoms oscillate back and forth.

10:39 But each bond responds differently to the light depending on how

10:42 strong it is and the mass of the atoms it connects.

10:45 It's like each bond is a boat on the ocean.

10:48 If the waves are small and rapid, they won't rock it very much.

10:53 And if the waves are very slow, like the tides coming in and out,

10:56 that also won't rock the boat very much.

10:59 The boat just gets lifted up and down.

11:02 It's only when the waves are just

11:04 the right size that the boat gets tossed around.

11:06 And because of this, each bond will

11:09 react strongest to a specific frequency of light, which we can measure.

11:13 By hitting the molecule with a range of infrared frequencies,

11:16 we get a spectrum like this with peaks that tell us when bonds are reacting.

11:21 This acts like a fingerprint for the molecule

11:24 and tells us which bonds are there.

11:28 Wöhler's compound has a broad peak,

11:30 which corresponds to bending an N double-bonded to C double-bonded to O group.

11:35 Liebig's compound, on the other hand,

11:37 has a spectrum that looks like this, with these two prominent peaks,

11:41 one at high frequency and one at low frequency.

11:44 These correspond to stretching a double bond between a carbon

11:47 and a nitrogen and a single bond between a nitrogen and an oxygen.

11:51 We now know that Wöhler's compound was silver cyanate, and it looks like this.

11:56 The carbon, nitrogen, and oxygen are joined with those two strong double bonds,

12:01 which is why it's so stable.

12:02 In contrast, Liebig's compound, silver fulminate, looks like this.

12:07 The silver is bonded to the carbon instead,

12:10 so the other elements are arranged this way.

12:13 The bond between the carbon and nitrogen is a triple bond,

12:16 but the oxygen and nitrogen are very weakly connected.

12:20 And this single bond is very easy to break, and once it does,

12:24 the atoms can rearrange into much more stable gases,

12:27 which is why it's so explosive.

12:30 They had discovered isomers.

12:32 That it's not just the atoms in a molecule that dictate how it behaves,

12:36 but its bonds as well.

12:38 So naturally the scientists at Abbott suspected

12:41 something similar might be happening to ritonavir.

12:44 They knew that the spectrum of ritonavir should look like this.

12:48 So they put a sample of white paste into a spectrometer,

12:52 expecting to see something completely different.

12:54 But instead they saw this, the same peaks.

12:59 The paste had all the same bonds as ritonavir, so it must be ritonavir.

13:05 But they also noticed it wasn't exactly the same.

13:08 There were these small deviations between the two.

13:11 The arrangement of the atoms was the same,

13:13 but something about the bonds had changed slightly.

13:17 Well, it turns out there's another way to change the properties,

13:20 and I can show you how with probably the most delicious demo I'll ever do,

13:25 because this, of course, is a piece of chocolate.

13:28 It's nice, it's shiny, it's durable,

13:31 and it has that nice snap when you crack it.

13:34 But you'll notice that if you've ever let your chocolate melt,

13:37 then it never returns to being quite the same.

13:40 Suddenly it melts in your hand when you pick it up,

13:43 you know, it's dull, it's bendy, and it doesn't quite taste the same.

13:46 You're not imagining this.

13:48 There really is a subtle difference,

13:49 and I can explain what's happening with a little

13:52 help from my friend Chris over here.

13:54 Hey.

13:54 Hello.

13:54 So Chris runs his own YouTube channel, Chris Young Cooks,

13:58 and this is way overkill for what we need here probably,

14:00 because he was the head development chef at a three-Michelin star restaurant.

14:05 Yes.

14:05 (subdued music)- We've got some nice shiny chocolate here.

14:08 But look what happens when we turn up the heat.

14:17 (heat gun whirs) Oh yeah, that goes quite quick.

14:23 Oh, that is surprisingly satisfying.

14:27 We obviously melted some of the chocolate, no surprise.

14:30 But this is what happens, right?

14:31 You leave it somewhere warm, the chocolate gets above body temperature,

14:34 it starts to melt, and then as it cools back down, it'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,

14:44 maybe it was left in your car sitting in a sunny window.

14:46 Touch the edge, like, you can feel, feel how that's just soft-- Yeah.

14:51 and kind of sticky.

14:53 Immediately.

14:54 Compare it to a nicely tempered piece of chocolate.

14:56 Like, you can pick that up with your bare hands,

14:58 it will eventually melt in your hand, but much more slowly.

15:02 Now if this ever accidentally happens to you,

15:04 we'll show you how to get it back to the nice and shiny form.

15:08 But what's interesting here is that we didn't change

15:10 any of the ingredients and yet the properties changed completely.

15:15 Chocolate is made of three main ingredients.

15:17 There are other minor ones as well, but three main ones to focus on.

15:21 It's got cocoa solids, that's what gives it its color,

15:24 there are sugar, of course, for sweetness, and then there is cocoa butter.

15:28 That's what gives it its texture.

15:31 (gentle music) And this cocoa butter is the culprit.

15:33 It's a fat made from three long carbon chains bonded

15:36 together in the middle to make this sort of Y shape.

15:39 And that Y shape can form together to form solids.

15:42 But there are multiple ways they can stack together.

15:45 There are many forms the crystal can take, each with different properties.

15:49 And so we call these polymorphs.

15:52 Chocolate actually has six polymorphs.

15:55 The dull chocolate is mostly Form IV,

15:57 and that has a melting point of around 27 degrees Celsius.

16:01 While the shiny chocolate, which is the one we want, is mostly Form V,

16:05 and that has a higher melting point of around 34 degrees Celsius.

16:10 So the challenge and the art of chocolate making is managing these polymorphs

16:14 to get the right form of crystal

16:16 by managing both temperature and, importantly, time.

16:19 The nice thing about chocolate is you can start over.

16:21 You just need to heat it back up to 45 to 50 Celsius to wipe the memory-- Okay.

16:25 of the wrong crystals.

16:26 That's hot enough to melt out all of the crystals,

16:29 but not too hot to start changing the flavor of the chocolate,

16:32 evaporating a lot of the volatile aromatics.

16:35 [Casper] After around 10 minutes at roughly 50 degrees Celsius,

16:38 all the crystals should have fully melted.

16:40 So at this point, we're trying to cool it back

16:43 down to the temperature where crystals start to form again.

16:46 And that's gonna start at about 34 Celsius.

16:48 You'll start getting Form V crystals forming at 34,

16:51 as we cool even lower, we start to get Form IV and Form III.

16:55 Those can all form at these temperatures.

16:57 And that's okay.

16:58 We want all of these crystals initially.

17:00 We want-- Oh, really?

17:00 Yeah, we want to have sort of a shotgun of nucleation

17:04 going on because we wanna make sure we get lots of everything.

17:08 That's surprising.

17:09 It does seem surprising.

17:11 Because we just want Form V, right?

17:13 We do just want Form V.

17:14 The trick is, if we just come down to the temperature where Form V forms,

17:19 so if we just went to like 32 degrees, 33 degrees, and just waited there,

17:23 you'd be waiting a very long time and you'd get

17:25 a very random process of when does that crystal form,

17:28 and maybe only a few crystals would form.

17:30 And so they would get very large.

17:32 Ah.

17:32 By bringing the temperature all the way down to 27,

17:34 we get lots of nucleation really fast.

17:36 The downside, of course, is we get the crystals we don't want as well,

17:40 but we get lots of Form V, and we get lots of small Form V.

17:43 Yeah.

17:43 So once we have that starting to form,

17:46 we can select for the ones we want just by raising the temperature back up.

17:50 And melting the Form III and Form IV,

17:52 leaving us with only Form V, but, importantly, lots of Form V.

17:57 Right.

17:57 After holding the chocolate at around 32 degrees Celsius for 5 to 10 minutes,

18:02 we can pour it into the mold.

18:04 Okay, I think we're gonna be okay here, so.

18:09 Oh.

18:10 I don't know what I was expecting, but I was not expecting it to go like this.

18:13 It really comes out as a sort of sheet.

18:16 One of the things here is I do have some trapped air bubbles.

18:23 Yep.

18:26 Oh, yeah.

18:29 It's like a liquefaction.

18:31 Yeah, yeah.

18:33 [Chris] So at this point, seems like we're done, right?

18:36 Yeah.

18:37 But actually now we need to lock

18:38 in that crystal pattern that we've created, right?

18:41 Yep.

18:41 Like, as it cools down,

18:42 there's liquid oil in there and we're gonna drop back down

18:44 through the temperature where Form IV and Form III can form.

18:47 Yep.

18:47 So what we need to do is we need

18:48 to come down through that temperature relatively quickly so

18:51 that we get mostly Form V growing and lock them

18:54 in by getting rid of most of the liquid oil.

18:57 So we really need to get this down to about 12 C.

19:00 [Casper] So we put it in the fridge and waited for around 20 to 30 minutes.

19:05 Get the door closed.

19:08 Great.

19:08 If we did this correctly, it should be mostly Form V,

19:12 which means all the molecules should have stacked tightly together,

19:15 resulting in a shiny and snappy bar.

19:18 (tray cracking) Ah!

19:20 Ooh!

19:20 That was satisfying.

19:22 They're just barely hanging on.

19:24 Wow!

19:24 And you can see they're nice.

19:27 Perfect.

19:27 Shiny.

19:28 This is all Form V?

19:30 This is all Form V, and we've got a nice shiny surface.

19:35 Got a couple spots where maybe the molds

19:36 could have been polished a little bit more,

19:38 but give it a snap, just see how that is.

19:40 (chocolate snaps)- Ooh.

19:41 It's a very good snap.

19:42 [Chris] Yeah, that's a nice.

19:43 It's very sturdy.

19:45 That's a good chocolate bar.

19:48 Delicious.

19:48 That is how you temper a chocolate bar.

19:50 Amazing.

19:50 (curious music)- But the stacking of the molecules

19:52 in the crystals also changes something else.

19:55 Since each molecule is surrounded by other molecules,

19:58 it changes how the bonds inside can move.

20:01 This is what the scientists at Abbott had seen in the spectrum.

20:04 The needles they had seen under

20:06 the microscope were a new polymorph of ritonavir, and a more stable one at that.

20:11 Form I crystals looked like this instead.

20:15 Now at first this might seem like good news.

20:17 It was still ritonavir, even if it looked a bit different.

20:21 It's just like how dull chocolate,

20:23 even if it's not quite as nice, is still chocolate.

20:26 But the problem was this new polymorph was far too stable.

20:31 Ritonavir Form II is substantially more stable than Form I.

20:37 And the way we know it's more stable is because it's less soluble.

20:41 But if that crystal structure happens to be much more stable,

20:46 then it won't dissolve properly.

20:49 And 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.

20:57 We just had to heat it up to switch it from shiny to dull,

21:00 and then by cooling it down again in a specific way, we could get back to shiny.

21:05 So you might expect that Abbott could just do something similar with ritonavir.

21:09 And they tried, but the problem was that no amount

21:13 of heating or cooling could turn Form II back into Form I.

21:18 They were stuck.

21:19 We can see what's happening by taking a look at this here.

21:24 See, each polymorph has different energy levels.

21:27 And in the case of chocolate that looks something like this, where

21:30 Form IV has a higher energy level and Form V a lower one,

21:34 and they're separated with this sort of hill in between.

21:38 Now, after heating up the chocolate bar, we were mostly left with Form IV.

21:42 So let's drop this little ball in there,

21:45 and then you'll see it will slowly settle down into that valley.

21:51 But not to the more stable Form V.

21:53 And that's because there's this little hill in between.

21:56 But now imagine adding some heat to this.

21:59 It's like giving the ball a little bit of a kick.

22:02 And you can see that the ball will suddenly start to move around.

22:05 And if I give it enough of a kick, whoop, it will roll down into Form V.

22:11 And now it is stuck there.

22:13 Now you could keep adding more heat and you could

22:16 get it back over the hill back to Form IV,

22:19 but then you would just end up with a mess of both forms,

22:23 because whenever you start cooling it down again, you know,

22:26 the ball could just randomly settle in one of the two valleys.

22:28 So that's what happened when we melted the chocolate uncontrollably.

22:31 We just got a mixture of these two forms.

22:34 But with ritonavir, the situation is a little different.

22:38 The hill between the two forms is now much taller,

22:41 but the Form II valley is also much deeper.

22:44 So once the ball does get down there,

22:46 it's basically impossible to get it back out of there,

22:49 which is why no matter what the scientists at Abbott tried,

22:52 they couldn't get back to Form I.

22:56 But this still doesn't explain why Form II was suddenly everywhere.

23:01 Nothing had changed in their procedures.

23:03 The barrier between the two forms should still be there.

23:07 So it shouldn't have been possible to make this much Form II at all.

23:11 And yet, 300 years earlier,

23:13 legends of such a transformation spread across northern Europe.

23:18 (gothic music)- It was a bitter winter morning,

23:20 and it had been like this for months.

23:22 The organist was on his way to a cathedral.

23:25 The cold had been messing with the organ pipes.

23:27 It's gone out of tune again.

23:29 But that wasn't what the congregation thought.

23:32 There were stories of other organs getting sick

23:35 with warts or leprosy eating away at the pipes.

23:39 Some thought it was the devil attacking the organ to punish an unfaithful flock.

23:45 It was even said that when it was very quiet,

23:48 you could hear these organs screaming and groaning in pain from the lesions.

23:54 Nonsense, of course, it was just the metal contracting and expanding.

23:59 (subdued music) Except these pipes weren't just contracting, they were cracked.

24:04 And others are indeed covered in what looks like these lesions,

24:08 black growths all over the organ.

24:17 (dark music) Now, originally when this happened,

24:18 people thought that this was the work of Satan.

24:21 Of course, that's not what was going

24:23 on, and we can explain what was actually happening.

24:25 So we've got some normal tin right here,

24:28 which is what those organ pipes were made out of.

24:30 It kind of looks silver, it feels pretty strong,

24:34 and 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.

24:40 You can look at it, it's a bit more gray, it's a bit more crumbly.

24:45 And at room temperature, normally the silvery tin is sort of more stable.

24:50 But if you cool tin down to something like below 13 degrees Celsius,

24:55 and ideally way colder, then it can transform into this new kind of gray tin.

24:59 And we're gonna see what happens when we put it on top of the silver tin.

25:04 [Dr.

25:04 Kafizas] We want to try and get it to around minus 30 degrees Celsius.

25:07 [Casper] Yep.

25:07 And what better to get us to those temperatures is dry ice.

25:10 Okay.

25:11 So dry ice is frozen carbon dioxide.

25:14 And that is around minus 78 degrees Celsius.

25:17 [Casper] Yep.

25:18 Now we've taken a thermo flask and filled it up with dry ice,

25:21 and then put a platform on top on which we'll put our tin.

25:25 This should cool it down to around minus 30 degrees Celsius.

25:29 Now we left this here for around 14 hours,

25:32 and what you'll see is that initially there's a very

25:35 tiny speck of tin that suddenly transformed into gray tin,

25:39 and then it spreads from there almost like an infectious disease,

25:43 which is why this is also known as tin pest.

25:47 And because gray tin is less dense, the tin expands.

25:50 And so if you look closely, you can see it start to tear apart the metal.

25:56 Now, normally it takes a lot of energy

25:59 to transform some silver tin into gray tin,

26:02 but once you get a tiny bit of gray tin, something strange happens,

26:06 because now it acts as a nucleation site that other tin

26:09 can attach to, and it effectively brings that hill way down.

26:13 It lowers the activation energy.

26:15 And so now it becomes very easy to switch from silver tin to gray tin.

26:18 And so it starts to spread, it starts to take over.

26:23 And the same thing was happening to those organ pipes.

26:25 Once you got a lesion on one of those pipes,

26:28 well then it would grow and spread everywhere.

26:30 Little flakes would come off the pipes and seed all the others,

26:35 and it would spread.

26:36 And that's also exactly what happened with ritonavir.

26:40 Once a tiny bit of Form II appeared, it acted as a nucleation site,

26:44 lowering that massive activation energy and causing all

26:48 the Form I to crystallize into Form II.

26:51 Tiny seed crystals then broke off, could become airborne, and spread,

26:56 attaching themselves to people's clothes and making

26:59 it to other parts of the production line,

27:02 effectively seeding them so that when new ritonavir was synthesized,

27:07 it contained these seed crystals and turned the entire capsules into Form II.

27:12 And because everyone likely had these seed crystals on their clothes,

27:16 when the Chicago team flew over to Italy, they seeded that factory too.

27:22 And in this way, soon not a single place was able to manufacture Form I.

27:28 [Derek] Ritonavir is arguably the most dramatic case

27:31 of what we now call a disappearing polymorph.

27:34 The YouTube channel Reactions made a great video

27:37 about this that involves lots of physical demos,

27:39 so I highly recommend you check it out.

27:42 [Narrator] "When this happened to us,

27:43 we conducted an extremely thorough investigation to see if there

27:46 was something that we did which would have caused this.

27:49 While we've speculated on the cause of this chemical transformation,

27:52 we do not have conclusive proof of what happened."- It might be

27:57 that a mistake on the production line caused some chemicals to dry out.

28:01 This might have created a new crystal similar in shape to Form II ritonavir,

28:06 which acted like a seed.

28:08 Or it might have just been bad luck

28:10 that a seed crystal formed on its own purely by chance.

28:14 Even if you have a seed crystal,

28:16 if there are some dust particles or some scratches

28:21 in the recipient where actually crystals can start to nucleate,

28:28 that can induce, then, different crystal structures.

28:30 So it happens that in some pharmaceutical companies where

28:35 they produced the same polymorph for years and years,

28:39 that suddenly there is, I would say,

28:41 a hair or some other particle that, kind of, gets

28:45 into the process and will change the entire crystallization of the compound,

28:51 and is then very difficult to control.

28:54 And once a more stable form has appeared,

28:56 it can spread and quickly seed the entire planet.

29:00 It might be that you will never, ever get the initial polymorph again.

29:04 After five months of research,

29:06 Abbott's researchers held a press conference to share their findings.

29:10 (intense music)- [Narrator] "Good afternoon.

29:11 My colleagues and I are here today to explain what has happened,

29:15 why it has happened, how we've responded to the problem,

29:18 and what we're going to do to correct the problem.

29:21 Sometime during this summer,

29:22 the semi-solid formulation of ritonavir began to change into a crystal form,

29:28 a transformation that we believed was a scientific and chemical impossibility.

29:39 [Narrator] "You are a large multinational company.

29:41 Your scientists are obviously smart.

29:44 How could this happen?"- [Narrator] "A company's size and the collective

29:48 IQs of their scientists have no relationship to this problem.

29:52 This phenomenon is, I believe, unpredictable.

29:54 We are, in some sense, the victim of bad luck.

29:58 There are many mysteries of nature that we've not solved.

30:01 Hurricanes, for example, continue to occur and often cause massive devastation.

30:05 There is nothing that we can do today to prevent

30:08 a hurricane from striking any community or polymorphism from striking any drug.

30:13 Science cannot provide a solution to all our problems." (curious music)- Now,

30:21 here's a good question.

30:21 Is everything polymorphic?

30:24 So nobody had discovered a polymorph of aspirin, right?

30:28 So it had been around, it's one of the earliest drugs.

30:31 It had been crystallized in industry for what, 130, 140 years?

30:38 And so can you say, "Because nobody

30:40 had discovered a polymorph of aspirin, therefore..." No.

30:44 Right?

30:44 The only problem is I discovered Form II of aspirin.

30:49 (laughs) By accident.

30:51 Right?

30:51 It turns out over half of all compounds are known to be polymorphic,

30:55 and there could be more.

30:57 The number of polymorphs is proportional to the amount

30:59 of time and money you spend researching that compound.

31:03 In fact, nowadays we know there are not

31:05 two forms of ritonavir, but at least five.

31:08 So are new cases of disappearing polymorphs something to worry about?

31:13 It's quite, quite rare.

31:14 We certainly know a lot more than we did when ritonavir occurred,

31:21 but I wouldn't be surprised to see it happen again.

31:25 If there's a 1% chance the world's gonna end,

31:28 you're gonna do something about it, right?

31:30 If there's a 1% chance a plane is gonna crash, you're not gonna fly, right?

31:36 So, so yeah.

31:37 So we're at that situation where it might only

31:42 be in that order of 1%, but if it happens, it's gonna cost you a hell of a lot

31:47 more than a few weeks of research on polymorphs.

31:50 Ritonavir was one of the red flags that caused a lot

31:56 of regulatory activity and a lot of scientific activity around polymorphs.

32:02 Nowadays, pharmaceutical companies can spend hundreds of thousands

32:05 to millions of dollars screening for polymorphs.

32:08 In the end, there was no way of getting Form I ritonavir back successfully.

32:12 There were attempts, but all were incredibly costly,

32:16 and they risked being infected again.

32:19 So instead, Abbott went back to an older liquid

32:22 formulation of the drug and abandoned Form I entirely.

32:26 [Narrator] "Our initial activities were directed

32:28 towards eliminating Form II from our environment.

32:30 We finally accepted that we could not.

32:33 Our subsequent activities were directed towards figuring out

32:36 how to live in a Form II world.

32:39 Nature would appear to favor it." (curious

32:43 music)- The liquid formulation was not ideal.

32:46 It had worse side effects,

32:47 and not all patients could tolerate it well, but it worked.

32:51 [Narrator] "It is frightening that this could happen to any

32:53 drug that we've taken and on which we're dependent,

32:55 even though it is not that common.

32:57 This time, it has happened to Abbott and to the tens

33:00 of thousands of people taking the semi-solid capsule.

33:03 Thankfully, we had the liquid formulation as a safety net.

33:06 Next time it may happen to another drug

33:08 that may not have the safety net." (curious music continues)