WEBVTT 00:00:00.000 --> 00:00:01.700 Have you ever really thought about what goes 00:00:01.700 --> 00:00:04.240 into that tiny pill you swung? I mean, it seems 00:00:04.240 --> 00:00:06.540 pretty simple, right? A solid little chunk of 00:00:06.540 --> 00:00:08.800 medicine. Well, yeah, you would think so. But 00:00:08.800 --> 00:00:12.419 there's a whole world of fascinating science 00:00:12.419 --> 00:00:15.599 happening at the molecular level. And it all 00:00:15.599 --> 00:00:17.620 starts with something called crystallization. 00:00:18.239 --> 00:00:20.219 That's right. And today, we're going to do a 00:00:20.219 --> 00:00:23.440 deep dive into crystallization and solid form 00:00:23.440 --> 00:00:25.879 selection. Exactly and to do this we're going 00:00:25.879 --> 00:00:28.859 to pull from all sorts of sources like the really 00:00:28.859 --> 00:00:30.899 in -depth stuff from pharmaceutical scientists 00:00:30.899 --> 00:00:34.439 You know the hardcore chemistry and then also 00:00:34.439 --> 00:00:36.960 some more general overviews of drug development 00:00:37.149 --> 00:00:40.229 Yeah, it's amazing how much goes into just choosing 00:00:40.229 --> 00:00:42.689 the right solid form of a drug. It's not just 00:00:42.689 --> 00:00:45.409 making a solid, it's like a fundamental decision. 00:00:45.549 --> 00:00:47.909 Fundamental decision, really? Oh yeah, it impacts 00:00:47.909 --> 00:00:50.329 everything. Like how easy is that drug to handle? 00:00:50.350 --> 00:00:52.329 How long it will last on the shelf? And most 00:00:52.329 --> 00:00:54.750 importantly, how well it actually works inside 00:00:54.750 --> 00:00:56.369 your body. So it's kind of like choosing the 00:00:56.369 --> 00:00:57.869 right building blocks for the medicine. Yeah, 00:00:57.869 --> 00:01:00.950 exactly. A good analogy, actually. So to kick 00:01:00.950 --> 00:01:03.609 things off, let's talk about why this whole crystallization 00:01:03.609 --> 00:01:05.849 thing is so important. OK, yeah, let's do that. 00:01:06.329 --> 00:01:08.989 What makes it so important that a drug needs 00:01:08.989 --> 00:01:12.129 to be in a specific solid state? Well, for a 00:01:12.129 --> 00:01:15.090 drug to do its job, it usually needs to be absorbed 00:01:15.090 --> 00:01:17.329 into your system, right? Right. And to reach 00:01:17.329 --> 00:01:19.989 its target and do its thing. Like we see in the 00:01:19.989 --> 00:01:21.909 process of new drug discovery and development, 00:01:22.390 --> 00:01:24.909 absorption is really tied to the drug's properties 00:01:24.909 --> 00:01:28.590 in its solid form, especially its ability to 00:01:28.590 --> 00:01:30.969 dissolve. OK. So it's not just about getting 00:01:30.969 --> 00:01:32.969 it into a solid form. It has to be the right 00:01:32.969 --> 00:01:35.189 kind of solid form. Precisely. Think of it like 00:01:35.189 --> 00:01:40.180 this. If a drug can't dissolve properly, it can't 00:01:40.180 --> 00:01:42.019 get where it needs to go and, you know, won't 00:01:42.019 --> 00:01:45.260 do much good. Even for injected drugs, they still 00:01:45.260 --> 00:01:48.079 need to stay in solution to avoid causing problems. 00:01:48.239 --> 00:01:50.280 So the drug has to dissolve properly at the right 00:01:50.280 --> 00:01:52.599 time and the right place in the body. Yeah, exactly. 00:01:52.799 --> 00:01:54.879 So even if a drug is injected, it still needs 00:01:54.879 --> 00:01:57.579 to remain in a dissolved state at that injection 00:01:57.579 --> 00:02:00.739 site. Gotcha. So then what about polymorphism? 00:02:00.879 --> 00:02:02.819 I've heard that term before. How does that play 00:02:02.819 --> 00:02:05.549 into all of this? Ah, polymorphism. Yeah. It's 00:02:05.549 --> 00:02:08.009 pretty fascinating. Basically, it's the ability 00:02:08.009 --> 00:02:10.930 of a drug to exist in more than one crystal form. 00:02:11.349 --> 00:02:13.610 Oh, okay. So it's not just one solid form. There 00:02:13.610 --> 00:02:15.930 could be multiple ones. Right. Think of it like 00:02:15.930 --> 00:02:18.250 carbon. You've got diamond super hard, and then 00:02:18.250 --> 00:02:19.729 you've got graphite. Like what's in your pencil? 00:02:19.849 --> 00:02:21.689 Totally different. Totally. But they're both 00:02:21.689 --> 00:02:24.090 made of carbon. Exactly. Same atoms, different 00:02:24.090 --> 00:02:25.750 arrangement. And that's the same with these drug 00:02:25.750 --> 00:02:27.830 crystals. Different arrangements mean different 00:02:27.830 --> 00:02:30.150 properties. OK. So for a drug, that means? Different 00:02:30.150 --> 00:02:32.310 properties mean different ways it behaves in 00:02:32.310 --> 00:02:35.050 the body, like how easily it dissolves or how 00:02:35.050 --> 00:02:37.349 stable it is on the shelf, all that jazz. So 00:02:37.349 --> 00:02:39.569 different polymorphs, which is what these different 00:02:39.569 --> 00:02:42.110 forms are called, can actually impact how well 00:02:42.110 --> 00:02:45.879 the drug works. Big time. Even the same polymorph 00:02:45.879 --> 00:02:49.060 can change over time. Like this research from 00:02:49.060 --> 00:02:52.819 back in 1990 by Cinco, Yi, and Amidon, it showed 00:02:52.819 --> 00:02:55.979 that a solid drug's ability to dissolve can actually 00:02:55.979 --> 00:02:58.699 change as it ages. Well, hold on. So even if 00:02:58.699 --> 00:03:00.780 you have the right form, it can still change 00:03:00.780 --> 00:03:03.360 and maybe not work as well. That's a bit scary. 00:03:03.659 --> 00:03:05.879 It is something to keep in mind. And it's discussed 00:03:05.879 --> 00:03:08.280 in early drug development, bringing a preclinical 00:03:08.280 --> 00:03:10.840 candidate to the clinic. And when you start with 00:03:10.840 --> 00:03:13.620 different polymorphs from the get go, Well, those 00:03:13.620 --> 00:03:15.580 differences in how fast they dissolve can be 00:03:15.580 --> 00:03:18.460 even more dramatic. This is super important for 00:03:18.460 --> 00:03:20.659 drugs taken orally because if it doesn't dissolve 00:03:20.659 --> 00:03:22.979 well in your stomach, it might not get absorbed 00:03:22.979 --> 00:03:25.860 properly. Exactly. It's like trying to make tea 00:03:25.860 --> 00:03:27.680 with a tea bag that doesn't open. You're not 00:03:27.680 --> 00:03:30.159 going to get a very strong brew. Uh -huh. I get 00:03:30.159 --> 00:03:33.120 it. There was a study done in 2002 by Angst and 00:03:33.120 --> 00:03:36.080 others. They looked at an antiretroviral drug. 00:03:36.740 --> 00:03:39.500 It highlighted how a drug's solubility is affected 00:03:39.500 --> 00:03:42.280 by its solid form and how that can interact with 00:03:42.280 --> 00:03:44.520 how it's formulated and even whether you've eaten 00:03:44.520 --> 00:03:47.509 or not. It's also talked about in early drug 00:03:47.509 --> 00:03:50.409 development, bringing a pre -clinical candidate 00:03:50.409 --> 00:03:52.830 to the clinic. Wow, so many factors to consider. 00:03:52.949 --> 00:03:54.689 So how do scientists make sure they get the right 00:03:54.689 --> 00:03:56.789 polymorph in the first place? Well, controlling 00:03:56.789 --> 00:03:59.490 the crystallization process is key. As we saw 00:03:59.490 --> 00:04:02.729 discussed in continuous manufacturing of pharmaceuticals, 00:04:02.930 --> 00:04:05.090 using techniques like continuous crystallization 00:04:05.090 --> 00:04:07.610 gives them much more control over which form 00:04:07.610 --> 00:04:10.960 is produced. Makes sense. More control, less 00:04:10.960 --> 00:04:12.840 chance of ending up with the wrong form. Now, 00:04:12.879 --> 00:04:15.539 what about stability? How long a drug lasts on 00:04:15.539 --> 00:04:17.399 the shelf matters too, right? Oh, absolutely. 00:04:17.579 --> 00:04:20.000 The stability of a drug substance, both physically 00:04:20.000 --> 00:04:22.620 and chemically, is a big deal. Okay, so we don't 00:04:22.620 --> 00:04:24.759 want the drug to break down or change over time. 00:04:25.120 --> 00:04:27.819 Right, because as... pre -clinical development 00:04:27.819 --> 00:04:30.620 handbook ADME and biopharmaceutical properties, 00:04:31.279 --> 00:04:33.699 explains if a drug degrades, it becomes less 00:04:33.699 --> 00:04:36.160 effective and potentially unsafe. So keeping 00:04:36.160 --> 00:04:38.879 that shelf life long is super important. But 00:04:38.879 --> 00:04:41.060 how does this all tie back to crystallization 00:04:41.060 --> 00:04:43.319 and the solid form? Well, the solid form you 00:04:43.319 --> 00:04:45.279 choose can directly impact stability. You can 00:04:45.279 --> 00:04:48.879 think of it like stacking boxes. A well -organized 00:04:48.879 --> 00:04:50.920 stack is going to be much more stable than a 00:04:50.920 --> 00:04:53.259 messy pile, right? Yeah, so a more ordered structure 00:04:53.259 --> 00:04:56.389 is more stable. Makes sense. Exactly. And the 00:04:56.389 --> 00:04:58.769 crystalline structure does just that. It creates 00:04:58.769 --> 00:05:01.550 a more ordered, stable environment for those 00:05:01.550 --> 00:05:04.430 drug molecules. And there are tons of examples 00:05:04.430 --> 00:05:06.589 in the scientific literature where researchers 00:05:06.589 --> 00:05:09.709 have found ways to make drugs more stable through 00:05:09.709 --> 00:05:12.069 crystallization. Oh, really? Like what? Well, 00:05:12.110 --> 00:05:13.949 imagine a scenario where they're working with 00:05:13.949 --> 00:05:16.430 a drug that's not very stable. They might find 00:05:16.430 --> 00:05:19.649 that a specific crystal form is way more resistant 00:05:19.649 --> 00:05:22.160 to breaking down, so then they focus on tweaking 00:05:22.160 --> 00:05:24.759 the crystallization process to produce that more 00:05:24.759 --> 00:05:26.899 stable form consistently. So they're kind of 00:05:26.899 --> 00:05:28.839 like fine -tuning the recipe to get the best 00:05:28.839 --> 00:05:31.379 results. That's a great way to put it. They might 00:05:31.379 --> 00:05:34.000 find that adjusting the acidity of the solution 00:05:34.000 --> 00:05:36.779 or using a specific blend of solvents does the 00:05:36.779 --> 00:05:39.279 trick. In some cases, they might even be able 00:05:39.279 --> 00:05:41.860 to remove impurities during recrystallization 00:05:41.860 --> 00:05:44.459 that could speed up degradation. And voila, a 00:05:44.459 --> 00:05:47.060 more stable drug. That's incredible. So it's 00:05:47.060 --> 00:05:49.560 clear that getting the right solid form is crucial, 00:05:49.800 --> 00:05:52.519 but how does it affect turning that solid into 00:05:52.519 --> 00:05:54.920 something we can actually take, like a pill or 00:05:54.920 --> 00:05:57.759 a capsule? How do they formulate it? Great question. 00:05:58.600 --> 00:06:01.839 The solid form of the drug basically dictates 00:06:01.839 --> 00:06:03.879 what's possible when it comes to formulation. 00:06:04.100 --> 00:06:07.259 Okay. As the process of new drug discovery and 00:06:07.259 --> 00:06:09.800 development points out, those who formulate the 00:06:09.800 --> 00:06:12.800 final medicine need to consider a lot of things, 00:06:13.100 --> 00:06:15.139 like the drug's physical and chemical properties 00:06:15.139 --> 00:06:16.699 and how it behaves in the body, you know, all 00:06:16.699 --> 00:06:20.160 those details. Yeah. So solubility and dissolution, 00:06:20.279 --> 00:06:22.600 which we've talked about and which are influenced 00:06:22.600 --> 00:06:24.879 by the crystal form, are super important for 00:06:24.879 --> 00:06:26.620 the formulator. Right, because they directly 00:06:26.620 --> 00:06:29.519 impact bioavailability. Right. Yeah. Like how 00:06:29.519 --> 00:06:31.500 much of the drug actually gets into our system. 00:06:31.660 --> 00:06:35.199 Exactly. If a drug doesn't dissolve well, formulators 00:06:35.199 --> 00:06:37.600 have to get creative. They might have to use 00:06:37.600 --> 00:06:40.240 techniques like making nanosuspensions. It's 00:06:40.240 --> 00:06:42.300 this cool thing where they create these teeny 00:06:42.300 --> 00:06:44.759 tiny drug particles to boost the surface area, 00:06:44.980 --> 00:06:47.180 which helps with dissolution. Wait, so they make 00:06:47.180 --> 00:06:49.220 the particles super small so they dissolve better? 00:06:49.600 --> 00:06:51.800 Yep, that's the idea. And there's some research 00:06:51.800 --> 00:06:55.019 from 2001 by Muller, Jacobs, and Kaiser on this. 00:06:55.279 --> 00:06:57.699 It's mentioned in early drug development, bringing 00:06:57.699 --> 00:07:00.620 a preclinical candidate to the clinic. It's kind 00:07:00.620 --> 00:07:02.680 of like grinding coffee beans the finer the grind 00:07:02.680 --> 00:07:05.399 the stronger the coffee I see the analogy So 00:07:05.399 --> 00:07:07.819 they're basically manipulating the physical properties 00:07:07.819 --> 00:07:10.959 of the drug to overcome limitations caused by 00:07:10.959 --> 00:07:13.740 the crystal form Precisely. And the scientific 00:07:13.740 --> 00:07:16.399 literature is full of real -world examples of 00:07:16.399 --> 00:07:19.160 this. Think about a situation where a drug keeps 00:07:19.160 --> 00:07:22.139 forming big, stubborn crystals that don't want 00:07:22.139 --> 00:07:24.939 to dissolve. They can tweak the crystallization 00:07:24.939 --> 00:07:27.620 process to produce smaller particles instead. 00:07:28.160 --> 00:07:30.100 You know, carefully controlling things like the 00:07:30.100 --> 00:07:31.980 solvent they use and the speed at which it's 00:07:31.980 --> 00:07:34.800 added. They might even use seed crystals to guide 00:07:34.800 --> 00:07:36.959 the process. Seed crystals. Yeah, it's like giving 00:07:36.959 --> 00:07:38.959 the crystal formation a blueprint to follow. 00:07:39.319 --> 00:07:41.560 But the goal here is to avoid uncon... controlled 00:07:41.560 --> 00:07:43.959 crystal formation, what's called secondary nucleation, 00:07:44.420 --> 00:07:46.860 you want a nice consistent batch of particles 00:07:46.860 --> 00:07:50.000 all roughly the same size. Got it. That makes 00:07:50.000 --> 00:07:52.000 the formulation more predictable and reliable. 00:07:52.899 --> 00:07:55.180 So we've talked a lot about the physical aspects, 00:07:55.240 --> 00:07:57.480 but what about the chemistry involved in all 00:07:57.480 --> 00:07:59.660 this? Ah, the chemistry. It's the foundation 00:07:59.660 --> 00:08:02.199 of everything, really. Understanding the chemical 00:08:02.199 --> 00:08:05.019 processes during crystallization is crucial for 00:08:05.019 --> 00:08:08.079 controlling the solid form we end up with, by 00:08:08.079 --> 00:08:11.240 manipulating things like temperature, solvents, 00:08:11.699 --> 00:08:14.660 mixing speed, all that good stuff. It's like 00:08:14.660 --> 00:08:17.120 they're conducting a microscopic orchestra, getting 00:08:17.120 --> 00:08:19.240 everything in sync to produce the perfect crystal. 00:08:19.389 --> 00:08:22.009 That's a great way to put it. And with techniques 00:08:22.009 --> 00:08:23.930 like continuous crystallization, they have a 00:08:23.930 --> 00:08:26.009 lot more control over these parameters. That 00:08:26.009 --> 00:08:28.449 means they can consistently get high quality 00:08:28.449 --> 00:08:31.149 crystals and effectively get rid of impurities. 00:08:31.430 --> 00:08:33.830 It sounds very precise. Oh, it is. They even 00:08:33.830 --> 00:08:35.889 use advanced techniques like seeding, which we 00:08:35.889 --> 00:08:38.250 talked about before, adding small crystals of 00:08:38.250 --> 00:08:40.830 the desired form to guide the growth. And they 00:08:40.830 --> 00:08:42.809 use sensors that monitor the crystallization 00:08:42.809 --> 00:08:45.879 in real time. This is called Process Analytical 00:08:45.879 --> 00:08:49.500 Technology, or PAT for short. And all of this 00:08:49.500 --> 00:08:52.139 helps them control what we call super saturation. 00:08:52.379 --> 00:08:54.779 Super saturation. That sounds important. Oh, 00:08:54.779 --> 00:08:57.759 it is. It's like the driving force behind crystallization. 00:08:58.179 --> 00:09:00.580 Think of it as how much of the drug is dissolved 00:09:00.580 --> 00:09:02.960 in the solution beyond its normal solubility 00:09:02.960 --> 00:09:06.019 limit. The higher the supersaturation, the stronger 00:09:06.019 --> 00:09:08.080 the push for the drug to come out of solution 00:09:08.080 --> 00:09:10.980 and form crystals. So by carefully controlling 00:09:10.980 --> 00:09:14.120 supersaturation, they can kind of steer the crystallization 00:09:14.120 --> 00:09:16.360 process in the right direction. Exactly. And 00:09:16.360 --> 00:09:18.779 you can find lots of examples in the literature 00:09:18.779 --> 00:09:21.240 where scientists have used their knowledge of 00:09:21.240 --> 00:09:24.159 chemistry to really fine tune this process. For 00:09:24.159 --> 00:09:25.919 instance, there's a case where they use what's 00:09:25.919 --> 00:09:28.500 called a two -phase system with a phase transfer 00:09:28.500 --> 00:09:31.240 catalyst. This allows them to carry out a chemical 00:09:31.240 --> 00:09:33.840 reaction in a more controlled manner, ultimately 00:09:33.840 --> 00:09:36.360 helping them get the right solid intermediate, 00:09:36.799 --> 00:09:39.320 which is a stepping stone to the final drug crystal. 00:09:39.519 --> 00:09:41.679 So even the steps before crystallization are 00:09:41.679 --> 00:09:43.840 influenced by this deep understanding of chemistry. 00:09:44.299 --> 00:09:47.200 Absolutely. Everything is connected. There was 00:09:47.200 --> 00:09:49.980 another case where they carefully control the 00:09:49.980 --> 00:09:52.960 amount of a solvent called methanol and the temperature 00:09:52.960 --> 00:09:55.519 during a reaction and then followed that with 00:09:55.519 --> 00:09:58.379 crystallization. And by doing this, they were 00:09:58.379 --> 00:10:01.960 able to produce a super pure and stable intermediate. 00:10:02.039 --> 00:10:04.340 It's all about tweaking those chemical parameters 00:10:04.340 --> 00:10:08.409 to get the best results. Fascinating. Even seemingly 00:10:08.409 --> 00:10:10.690 small changes can have a ripple effect throughout 00:10:10.690 --> 00:10:12.990 the whole process. For sure. And as we mentioned 00:10:12.990 --> 00:10:16.429 earlier, with continuous crystallization, controlling 00:10:16.429 --> 00:10:18.490 supersaturation isn't just about getting the 00:10:18.490 --> 00:10:20.730 right crystal form. It's also about preventing 00:10:20.730 --> 00:10:23.490 issues like agglomeration, which is when crystals 00:10:23.490 --> 00:10:26.029 clump together, and particle breakage. Those 00:10:26.029 --> 00:10:28.730 things can really mess with the final formulation. 00:10:29.070 --> 00:10:31.250 Wow. So much complexity in something that seems 00:10:31.250 --> 00:10:34.159 so simple. It's incredible how much science goes 00:10:34.159 --> 00:10:36.460 into creating something like a pill. Right. And 00:10:36.460 --> 00:10:38.840 it all starts with understanding crystallization 00:10:38.840 --> 00:10:40.820 and solid form selection. It seems like we've 00:10:40.820 --> 00:10:42.659 just scratched the surface here. Oh, definitely. 00:10:43.220 --> 00:10:45.720 But hopefully... This deep dive has given you 00:10:45.720 --> 00:10:48.259 a new appreciation for the hidden world of drug 00:10:48.259 --> 00:10:51.580 development. Absolutely. We've seen that crystallization 00:10:51.580 --> 00:10:54.299 is much more than just making a solid. It's a 00:10:54.299 --> 00:10:56.919 fundamental process that shapes a drug's properties, 00:10:57.419 --> 00:11:00.059 from its polymorphism and stability to how it 00:11:00.059 --> 00:11:02.360 can ultimately be formulated into an effective 00:11:02.360 --> 00:11:06.000 medicine. It really underscores the interconnectedness 00:11:06.000 --> 00:11:09.120 of chemistry, solid state science, and formulation. 00:11:09.620 --> 00:11:11.980 It's a beautiful dance of scientific disciplines 00:11:11.980 --> 00:11:15.000 all working together to ensure that the medicines 00:11:15.000 --> 00:11:18.679 we rely on actually work as intended. It's amazing 00:11:18.679 --> 00:11:20.779 to think that every time we take a pill or a 00:11:20.779 --> 00:11:23.039 capsule, we're benefiting from this intricate 00:11:23.039 --> 00:11:26.419 process. Scientists have carefully selected a 00:11:26.419 --> 00:11:29.039 specific crystal structure, often from numerous 00:11:29.039 --> 00:11:31.519 possibilities, to ensure it dissolves at the 00:11:31.519 --> 00:11:34.529 right time stays stable on the shelf, and ultimately 00:11:34.529 --> 00:11:37.149 delivers its therapeutic benefit. It makes you 00:11:37.149 --> 00:11:39.649 wonder what other hidden complexities are at 00:11:39.649 --> 00:11:41.830 play in the medicines that keep us healthy. It's 00:11:41.830 --> 00:11:43.970 something to ponder for sure. Well on that note, 00:11:44.110 --> 00:11:46.490 we'll wrap up this deep dive. Thank you for joining 00:11:46.490 --> 00:11:49.590 us as we explored the fascinating world of crystallization 00:11:49.590 --> 00:11:52.230 and solid form selection. It's been a pleasure. 00:11:52.409 --> 00:11:54.549 Always happy to talk shop. Until next time, stay 00:11:54.549 --> 00:11:54.889 curious.