WEBVTT 1 00:00:00.120 --> 00:00:03.720 Imagine just like holding a standard over the counter headache 2 00:00:03.720 --> 00:00:05.759 pill right in the palm of your hand. It weighs 3 00:00:05.799 --> 00:00:09.679 practically nothing, you know, it just looks like this completely inert, 4 00:00:09.839 --> 00:00:13.880 simple white speck of chalk. Yeah, totally unassuming exactly, and 5 00:00:13.919 --> 00:00:15.560 you swallow it with a gulp of water, and then 6 00:00:15.640 --> 00:00:19.079 thirty minutes later you're throbbing headache just vanishes. It feels 7 00:00:19.079 --> 00:00:24.519 like magic, but the reality is far stranger. That tiny 8 00:00:24.559 --> 00:00:29.679 white tablet is actually a masterpiece of extreme engineering. Absolutely, 9 00:00:29.920 --> 00:00:33.520 It's carefully designed to run this gauntlet of destructive physical 10 00:00:33.560 --> 00:00:35.439 and biological environments inside you. 11 00:00:35.799 --> 00:00:39.479 It really is the ultimate example of invisible complexity. I mean, 12 00:00:39.520 --> 00:00:43.280 to truly understand how that medication functions, we can't just 13 00:00:43.359 --> 00:00:45.880 look at human biology. We have to look at the 14 00:00:45.920 --> 00:00:49.719 severe physical chemistry of the raw materials, the mechanical violence 15 00:00:49.759 --> 00:00:53.600 of the manufacturing process, and even like the quantum physics 16 00:00:53.719 --> 00:00:54.840 used to prove its purity. 17 00:00:55.240 --> 00:01:00.000 Well, welcome to a special custom tailored deep dive designs 18 00:01:00.000 --> 00:01:03.479 specifically for you. Whether you're a pharmacy student gearing up 19 00:01:03.520 --> 00:01:07.159 for your exams, or maybe a young professional navigating the industry, 20 00:01:07.280 --> 00:01:11.239 or just an insanely curious self learner. Consider this your 21 00:01:11.319 --> 00:01:12.480 ultimate masterclass. 22 00:01:12.519 --> 00:01:14.760 We are going to be tracking the entire life cycle 23 00:01:14.799 --> 00:01:15.719 of a medicine today. 24 00:01:15.799 --> 00:01:20.519 Yes, we are drawing exclusively from the comprehensive guide GPAT 25 00:01:20.560 --> 00:01:24.799 and Gate Pharmacy. We're going from raw powder to mass manufacturing, 26 00:01:25.120 --> 00:01:28.280 into the bloodstream, and finally into the analytical lab. 27 00:01:28.400 --> 00:01:30.359 And we are skipping all the rope memorization. 28 00:01:30.480 --> 00:01:33.159 Oh yeah, definitely. We want to understand the mechanisms, right, 29 00:01:33.359 --> 00:01:36.280 the why and the how behind the science. Okay, let's 30 00:01:36.319 --> 00:01:39.200 unpact this. Before a drug can heal you, it actually 31 00:01:39.239 --> 00:01:41.840 has to be built, and that starts at this molecular 32 00:01:41.879 --> 00:01:43.599 stage known as preformulation. 33 00:01:44.200 --> 00:01:47.439 Yes, so when a pharmaceutical company develops a new active ingredient, 34 00:01:47.799 --> 00:01:49.000 they're essentially dealing with. 35 00:01:49.000 --> 00:01:51.319 Bulkpowder, just big vats of powder. 36 00:01:51.159 --> 00:01:54.079 Exactly, and you have to characterize that powder before you 37 00:01:54.079 --> 00:01:57.159 could even think about putting it into machines. A critical 38 00:01:57.159 --> 00:02:01.400 distinction here is separating a drug's habit from its crystal. Wait. 39 00:02:01.439 --> 00:02:03.159 I always thought this were kind of the same. 40 00:02:03.000 --> 00:02:04.159 Thing A lot of people do. 41 00:02:04.280 --> 00:02:09.400 Actually, but the habit is simply the outer external appearance 42 00:02:09.800 --> 00:02:12.919 of the powder grain. Okay, but the crystal that is 43 00:02:12.960 --> 00:02:17.199 the internal three dimensional arrangement of the actual molecules. 44 00:02:16.639 --> 00:02:18.199 Which brings us to polymorphism. 45 00:02:18.319 --> 00:02:18.479 Right. 46 00:02:18.560 --> 00:02:21.520 Yeah, This is when the exact same chemical substance can 47 00:02:21.560 --> 00:02:24.199 exist in like multiple different crystalline forms. 48 00:02:24.240 --> 00:02:27.439 Dicisely, the building blocks are identical, but they're just stacked differently. 49 00:02:27.520 --> 00:02:30.479 It reminds me of carbon you know, stack carbon atoms 50 00:02:30.520 --> 00:02:32.840 one way and you get the soft graphite and a pencil. 51 00:02:32.960 --> 00:02:34.159 Oh, that's a great analogy. 52 00:02:34.240 --> 00:02:36.560 Yeah, and then stack those exact same atoms in a 53 00:02:36.599 --> 00:02:39.840 different geometric lattice and boom, you get a diamond. It 54 00:02:39.879 --> 00:02:42.919 makes total sense that if a drug changes its internal 55 00:02:43.000 --> 00:02:46.120 physical architecture, its medical properties might change too. 56 00:02:46.240 --> 00:02:49.919 Right. What's fascinating here is that the internal crystalline structure 57 00:02:50.400 --> 00:02:55.120 dictates the thermodynamics of the drug, specifically how easily it 58 00:02:55.120 --> 00:02:58.960 breaks apart and dissolves in water. Right. In polymorphism, we 59 00:02:59.039 --> 00:03:02.439 basically categorize them into two main behaviors. First is an 60 00:03:02.479 --> 00:03:04.000 antiotropic polymorphism. 61 00:03:04.000 --> 00:03:05.319 In antiotropic okay. 62 00:03:05.199 --> 00:03:08.479 Yeah, where one crystal form can reversibly shift into another 63 00:03:08.520 --> 00:03:12.560 form just by changing the ambient temperature or pressure. Elemental 64 00:03:12.560 --> 00:03:14.120 sulfur actually does this naturally. 65 00:03:14.240 --> 00:03:17.240 Wow, So the manufacturer has to be incredibly careful about 66 00:03:17.280 --> 00:03:20.400 the temperature of the factory floor then, or the drug 67 00:03:20.479 --> 00:03:24.680 might literally transform into a different structural version of itself. 68 00:03:24.520 --> 00:03:28.800 Exactly, which could completely render it insoluble in the human body. 69 00:03:28.919 --> 00:03:30.159 That's terrifying, right. 70 00:03:30.199 --> 00:03:33.759 And the second type is monotropic polymorphism, and this one 71 00:03:33.879 --> 00:03:38.120 is irreversible. One form is inherently unstable at all temperatures 72 00:03:38.120 --> 00:03:40.840 and pressures, and it will eventually just degrade into the 73 00:03:40.840 --> 00:03:41.479 stable form. 74 00:03:41.599 --> 00:03:42.280 Ah okay. 75 00:03:42.360 --> 00:03:45.800 Glycerl steerrates are a classic example of this. But to 76 00:03:45.840 --> 00:03:50.039 predict exactly when these structural shifts happen, formulation scientists rely 77 00:03:50.120 --> 00:03:51.879 on something called a van hoffplot. 78 00:03:52.360 --> 00:03:54.240 Yes, I was looking at these plots in the text. 79 00:03:54.319 --> 00:03:58.120 Instead of just guessing, they graph the log moolar solubility 80 00:03:58.120 --> 00:04:01.479 of the drug against the temperature. By tracking the solubility 81 00:04:01.479 --> 00:04:04.280 lines of two different polym morphs on the graph, you 82 00:04:04.360 --> 00:04:08.479 find the exact intersection point that transition temperature is where 83 00:04:08.520 --> 00:04:11.599 both forms have identical free energies, which. 84 00:04:11.439 --> 00:04:14.039 Is crucial because it gives the engineers a strict thermal 85 00:04:14.080 --> 00:04:16.439 boundary they cannot cross during manufacturing. 86 00:04:16.519 --> 00:04:20.480 That is so precise, But along with temperature, surface area 87 00:04:20.600 --> 00:04:23.639 is like perhaps the most heavily scrutinized metric. 88 00:04:23.439 --> 00:04:23.800 Isn't it. 89 00:04:23.879 --> 00:04:24.000 Oh? 90 00:04:24.040 --> 00:04:24.600 Absolutely. 91 00:04:24.720 --> 00:04:27.160 I mean the more surface area drug particle has, the 92 00:04:27.199 --> 00:04:30.399 faster the surrounding stomach fluid can interact with it and dissolve. 93 00:04:30.399 --> 00:04:31.120 It makes sense. 94 00:04:31.560 --> 00:04:33.920 We measure the raw size of the particles using stream 95 00:04:33.959 --> 00:04:36.160 counting devices like a culter counter or. 96 00:04:36.160 --> 00:04:38.600 An hia hiac right. 97 00:04:38.519 --> 00:04:42.480 Which basically monitor electrical or light changes as the particles 98 00:04:42.480 --> 00:04:46.079 flow through a tiny aperture. But for true surface area 99 00:04:46.399 --> 00:04:48.199 they use bt adsorption. 100 00:04:48.519 --> 00:04:51.759 Oh, the Bruneauer emmet Teller method. This is brilliant because 101 00:04:52.199 --> 00:04:54.120 I mean, you can't just use a tiny ruler to 102 00:04:54.120 --> 00:04:56.839 measure a microscopic, jagged grain of powder. 103 00:04:56.959 --> 00:04:57.800 No, you really can. 104 00:04:58.120 --> 00:05:01.040 Instead, they cool the sample down with liquid nitrogen to 105 00:05:01.240 --> 00:05:04.160 negative one hundred and ninety six degrees celsius. It's an 106 00:05:04.199 --> 00:05:08.439 extreme environment, yeah, And at that extreme low temperature, nitrogen 107 00:05:08.519 --> 00:05:12.360 gas condenses and coats the entire surface of the drug 108 00:05:12.399 --> 00:05:15.319 particle in a layer exactly one molecule thick. 109 00:05:15.600 --> 00:05:15.839 Yep. 110 00:05:16.360 --> 00:05:20.000 And because we know one single nitrogen molecule occupies precisely 111 00:05:20.079 --> 00:05:23.800 sixteen ankstrum squared, the machine just counts how much nitrogen 112 00:05:23.879 --> 00:05:24.959 was absorbed. 113 00:05:24.519 --> 00:05:28.160 And calculates the total microscopic surface area from there. That 114 00:05:28.319 --> 00:05:29.079 is wild. 115 00:05:29.240 --> 00:05:33.360 It's an incredibly elegant solution for measuring the unmeasurable. And 116 00:05:34.759 --> 00:05:38.160 if the scientists need a visual conformation of the morphology, 117 00:05:38.199 --> 00:05:40.639 they use a scanning electron microscope or SAM. 118 00:05:41.399 --> 00:05:44.040 But wait, the tech said, organic drug powders are terrible 119 00:05:44.079 --> 00:05:45.600 conductors of electricity, right. 120 00:05:45.480 --> 00:05:45.959 Yeah, they are. 121 00:05:46.000 --> 00:05:48.160 If you blast them with a high energy electron beam, 122 00:05:48.240 --> 00:05:48.959 they just burn up. 123 00:05:49.160 --> 00:05:50.879 So how do they get the picture? 124 00:05:51.319 --> 00:05:53.639 To solve this, the sample is placed in a vacuum 125 00:05:53.720 --> 00:05:57.600 chamber and they literally coat it in a microscopic atom 126 00:05:57.639 --> 00:06:00.920 thick layer of pure gold. 127 00:06:00.199 --> 00:06:03.199 Gold plating the medication, just to take a picture of it. Yes, 128 00:06:03.279 --> 00:06:06.360 that is insane. Now, all this meticulous data about surface 129 00:06:06.399 --> 00:06:09.800 area and solubility feeds directly into a mathematical model called 130 00:06:09.839 --> 00:06:11.439 the Noise Whitney equation. 131 00:06:11.279 --> 00:06:13.079 Right, the classic dissolution formula. 132 00:06:13.360 --> 00:06:15.319 Yeah, when you look at the formula and the text, 133 00:06:15.360 --> 00:06:19.439 it's just this giant string of variables. But conceptually it's 134 00:06:19.480 --> 00:06:23.120 really just describing the speed limit of dissolution exactly. It 135 00:06:23.160 --> 00:06:26.199 tells us that the rate a drug dissolves depends entirely 136 00:06:26.279 --> 00:06:29.079 on its surface area. The thickness of the stagnant fluid 137 00:06:29.120 --> 00:06:32.000 layer surrounding it, and the concentration gradient. 138 00:06:31.720 --> 00:06:35.000 Which basically means how much drug is already dissolved in 139 00:06:35.040 --> 00:06:36.879 the fluid versus how much is still solid. 140 00:06:37.000 --> 00:06:40.839 Right, and the output of that equation dictates a drug's 141 00:06:40.879 --> 00:06:44.600 fate in the Biopharmaceutical classification System, the BCS. 142 00:06:44.680 --> 00:06:48.680 Yes, the BCS categorizes drugs into four classes based on 143 00:06:48.839 --> 00:06:51.360 solubility and intestinal permeability. 144 00:06:51.439 --> 00:06:53.720 Okay, so classie is the best class Eiye, drugs are 145 00:06:53.720 --> 00:06:54.399 the golden standard. 146 00:06:54.480 --> 00:06:58.319 Yeah, high solubility, high permeability. They dissolve easily, just slip 147 00:06:58.399 --> 00:07:01.560 right into the bloodstream. And the word Class four drugs 148 00:07:01.600 --> 00:07:06.199 are the nightmare scenario for a formulation scientist. Low solubility 149 00:07:06.240 --> 00:07:07.199 and low permeability. 150 00:07:07.519 --> 00:07:10.639 Man, good luck making that work. Okay, So we have 151 00:07:10.680 --> 00:07:15.160 a perfectly characterized powder. The surface area is maximized, the 152 00:07:15.199 --> 00:07:18.240 crystal structure is locked in. How do we take that 153 00:07:18.360 --> 00:07:21.240 raw material and physically forge it into a pill a 154 00:07:21.279 --> 00:07:22.680 patient can actually swallow. 155 00:07:22.839 --> 00:07:25.240 Well, you can't just compress pure active ingredient. It we 156 00:07:25.399 --> 00:07:26.360 just crumble into dust. 157 00:07:26.519 --> 00:07:27.720 Right, You need excipients. 158 00:07:27.920 --> 00:07:32.160 Eccipients are the unsung heroes of pharmaceutics. You need diluents 159 00:07:32.319 --> 00:07:34.839 to add physical bulk, otherwise the pole would be the 160 00:07:34.839 --> 00:07:36.959 size of a grain of sand. Good point. You need 161 00:07:36.959 --> 00:07:40.120 binders to act as a glue under pressure, and disintegrants, 162 00:07:40.319 --> 00:07:43.279 which are designed to rapidly swell and literally explode the 163 00:07:43.319 --> 00:07:45.480 tablet apart once it hits the stomach. 164 00:07:45.519 --> 00:07:45.800 Acid. 165 00:07:46.079 --> 00:07:50.439 The text highlighted microcrystalline cellulose, known commercially as avisol. 166 00:07:50.560 --> 00:07:53.920 Right, Yes, avesol is heavily utilized because it's a dual threat. 167 00:07:54.000 --> 00:07:57.360 It's a fantastic dry binder, but it also draws water 168 00:07:57.399 --> 00:08:01.079 into the tablet via capillary action, acting a powerful disintegrin 169 00:08:01.120 --> 00:08:01.879 at the same time. 170 00:08:02.120 --> 00:08:05.519 That's super efficient. But combining chemicals is always a risk. 171 00:08:05.720 --> 00:08:09.480 Like the sources highlight this specific danger. If your active 172 00:08:09.560 --> 00:08:13.959 drug contains acamine groups, which are nitrogen based compounds, you 173 00:08:14.040 --> 00:08:16.439 have to avoid using the common deluent lactose. 174 00:08:16.480 --> 00:08:19.360 Oh yes, you really have to avoid that combination. 175 00:08:19.000 --> 00:08:21.399 Right, because if you mix a chemines and lactose, you 176 00:08:21.439 --> 00:08:25.040 trigger a major type condensation reaction. 177 00:08:24.879 --> 00:08:28.120 Which is wild because the Maillard reaction is the exact 178 00:08:28.199 --> 00:08:32.000 same chemical process that occurs when you see a steak 179 00:08:32.039 --> 00:08:34.679 on a grill. Wait, really yeah, Or like when you 180 00:08:34.720 --> 00:08:37.639 bake bread until the crest turns brown. It is a 181 00:08:37.679 --> 00:08:40.840 reaction between amino acids and reducing sugars. 182 00:08:40.919 --> 00:08:43.399 Okay, So in a kitchen that's delicious, sure, But. 183 00:08:43.440 --> 00:08:46.320 In a pharmaceutical bottle it means your highly engineered medication 184 00:08:46.440 --> 00:08:50.960 is browning, degrading, and completely losing its medical efficacy before 185 00:08:51.000 --> 00:08:52.480 the patient even opens the cap. 186 00:08:52.679 --> 00:08:55.159 Yikes. So, even if the chemistry is perfectly stable, the 187 00:08:55.200 --> 00:08:58.360 mechanical violence of a tablet press can still just ruin 188 00:08:58.399 --> 00:08:59.720 the batch right absolutely. 189 00:08:59.799 --> 00:09:03.399 These machines use immense hydraulic pressure to smash powder between 190 00:09:03.399 --> 00:09:05.000 two metal punches, and. 191 00:09:04.960 --> 00:09:08.399 If the formulation traps air or if the powder doesn't 192 00:09:08.399 --> 00:09:11.679 bind correctly, you get physical defects like capping. 193 00:09:11.919 --> 00:09:12.080 Right. 194 00:09:12.159 --> 00:09:14.840 Capping is where the top or bottom crown of the 195 00:09:14.879 --> 00:09:18.240 tablet just cleanly snaps off. This often happens because they 196 00:09:18.360 --> 00:09:22.799 use deeply concave punches that unfortunately trap air during the compression. 197 00:09:23.200 --> 00:09:26.679 And then there's lamination, which sounds like flooring, but here 198 00:09:26.720 --> 00:09:30.200 it's where the entile tablet splits horizontally into a stack 199 00:09:30.240 --> 00:09:31.799 of thin layers like a pastry. 200 00:09:31.879 --> 00:09:32.600 Yeah. 201 00:09:32.960 --> 00:09:36.399 Manufacturers also have to battle picking and sticking, where the 202 00:09:36.440 --> 00:09:39.120 powder physically adheres to the punch tips or the. 203 00:09:39.120 --> 00:09:41.519 Dye walls, just gumming up the machine exactly. 204 00:09:41.960 --> 00:09:45.159 This is usually due to excessive moisture or maybe insufficient 205 00:09:45.240 --> 00:09:46.639 lubrication in the powder. 206 00:09:46.320 --> 00:09:48.360 Plant, So how do they fix it? 207 00:09:48.399 --> 00:09:51.879 To mitigate this physically? The steel tooling is often plated 208 00:09:51.919 --> 00:09:55.840 with hard chromium or colloidal silica to really reduce that friction. 209 00:09:55.960 --> 00:09:58.320 Okay, And of course there is modeling, which I read 210 00:09:58.480 --> 00:10:01.159 isn't a structural failure but a cosmetic. 211 00:10:00.799 --> 00:10:03.720 One, right, an unequal ugly distribution of die that just 212 00:10:03.759 --> 00:10:05.120 makes the tablet look spoiled. 213 00:10:05.440 --> 00:10:07.360 Nobody wants to take a weirdly spody pill. 214 00:10:07.440 --> 00:10:08.000 Definitely not. 215 00:10:08.360 --> 00:10:11.159 So let's assume the tablet survives the press and it 216 00:10:11.200 --> 00:10:16.200 looks perfect. The final hurdle in manufacturing is controlling its destruction, right. 217 00:10:16.559 --> 00:10:19.759 The disintegration time is strictly enforced. 218 00:10:19.519 --> 00:10:20.120 Very strictly. 219 00:10:20.159 --> 00:10:22.480 A dispersable tablet which is meant to dissolve in a 220 00:10:22.480 --> 00:10:26.039 glass of water, has a hard limit of three minutes. Okay, 221 00:10:26.399 --> 00:10:30.440 A standard uncoded tablet gets fifteen minutes, film coded gets 222 00:10:30.600 --> 00:10:33.519 thirty minutes, and sugar coated gets up to an hour. 223 00:10:33.759 --> 00:10:37.200 But ento coded tablets have a radically different mission entirely. 224 00:10:36.879 --> 00:10:39.799 Oh completely, Because the stomach is essentially a vat of 225 00:10:39.960 --> 00:10:44.519 highly corrosive hydrochloric acid, some drugs are instantly destroyed by 226 00:10:44.519 --> 00:10:47.960 that acid, or they severely irritate the stomach lining, So 227 00:10:48.240 --> 00:10:52.480 entero coatings are designed to be impenetrable in acidic environments. Impenetrable, yes, 228 00:10:52.759 --> 00:10:55.720 The regulatory standard dictates an enteroic tablet must sit in 229 00:10:55.799 --> 00:10:58.759 acid for a full two hours without showing any signs 230 00:10:58.759 --> 00:11:02.360 of breaking apart. But the moment it passes into the intestines, 231 00:11:02.440 --> 00:11:05.679 which have a basic alkaline pH, it must completely dissolve 232 00:11:05.759 --> 00:11:06.399 within one hour. 233 00:11:06.720 --> 00:11:10.200 To pull off that kind of time release magic, they 234 00:11:10.320 --> 00:11:15.559 use pH sensitive polymers, right, materials like cellulose acetate FELLT 235 00:11:15.679 --> 00:11:18.879 or cap and various udroget polymers. 236 00:11:19.159 --> 00:11:23.000 Exactly, they remain tightly coiled and solid at a low pH, 237 00:11:23.320 --> 00:11:26.440 but they ionize and just dissolve at a high pH. 238 00:11:26.799 --> 00:11:28.759 It's essentially a chemical trip wire. 239 00:11:29.200 --> 00:11:30.759 That's a perfect way to describe it. 240 00:11:30.799 --> 00:11:32.639 But what'll really caught my attention in the reading was 241 00:11:32.679 --> 00:11:36.480 the traditional sugar coating process. The outline describes a four 242 00:11:36.559 --> 00:11:40.000 step process that literally sounds more like making gourmet candy 243 00:11:40.080 --> 00:11:41.120 than making a medicine. 244 00:11:41.200 --> 00:11:43.799 Yeah, which is why sugarcoating is largely being replaced by 245 00:11:43.799 --> 00:11:44.799 modern film coating. 246 00:11:44.799 --> 00:11:44.960 Now. 247 00:11:44.960 --> 00:11:48.240 It's just so incredibly time consuming, a labor intensive. 248 00:11:47.879 --> 00:11:50.000 Tell me about it. Step one is the seal coating. 249 00:11:49.840 --> 00:11:50.360 Right, yep. 250 00:11:50.679 --> 00:11:53.240 You have to waterproof the core tablet, often using a 251 00:11:53.279 --> 00:11:57.039 corn protein called zine, so the subsequent liquid syrups don't 252 00:11:57.080 --> 00:11:58.320 soak in and ruin the drug. 253 00:11:58.440 --> 00:12:02.679 And then step two is subcoding. Here, heavy sticky binders 254 00:12:02.720 --> 00:12:05.600 like gelatin or acacia are applied along with a dusting 255 00:12:05.639 --> 00:12:08.679 powder to round off the sharp mechanical edges of the. 256 00:12:08.600 --> 00:12:11.759 Tablet, and that step alone can increase the tablet's weight 257 00:12:11.799 --> 00:12:12.919 by up to one hundred percent. 258 00:12:13.120 --> 00:12:15.840 Wait, so making a sugar coated pill is basically a 259 00:12:15.879 --> 00:12:17.480 four step culinary process. 260 00:12:17.600 --> 00:12:20.879 It really is, because then step three brings the actual 261 00:12:20.919 --> 00:12:23.840 sugar syrup and the color dye to make it smooth. 262 00:12:24.279 --> 00:12:27.360 And finally, step four is polishing the dry tablet with 263 00:12:27.440 --> 00:12:30.600 carnabo wax in a rotating canvas drum to give it 264 00:12:30.679 --> 00:12:32.919 that elegant, glossy finish. 265 00:12:33.200 --> 00:12:36.039 It's an ordeal. If a manufacturer wants to skip that 266 00:12:36.240 --> 00:12:39.639 entire headache, they just use a capsule much easier. Hard 267 00:12:39.720 --> 00:12:43.399 gelatin capsules are brilliant in their simplicity, but the gelatin 268 00:12:43.480 --> 00:12:47.039 itself must be rigorously tested for its bloom strength. Bloom 269 00:12:47.080 --> 00:12:49.600 strength yeah, which typically needs to fall between one hundred 270 00:12:49.600 --> 00:12:52.600 and fifty and two hundred and fifty grams. The bloom 271 00:12:52.679 --> 00:12:56.120 test uses a standardized plunger to press into a chilled 272 00:12:56.200 --> 00:13:00.000 gelatin gel to measure its cohesive cross linking strength. 273 00:13:00.080 --> 00:13:02.399 Basically testing how squishy or tough it is. 274 00:13:02.559 --> 00:13:05.399 Basically, if the bloom strength is too low, the capsule 275 00:13:05.480 --> 00:13:08.159 is brittle and will shatter during shipping. But if it's 276 00:13:08.200 --> 00:13:10.639 too high, the gelatin is too tough and might not 277 00:13:10.679 --> 00:13:12.879 dissolve properly in the gastrointestinal tract. 278 00:13:13.080 --> 00:13:16.519 And the size and convention for these capsules is famously counterintuitive. 279 00:13:16.840 --> 00:13:19.279 You might assume a higher number means a bigger capsule, 280 00:13:19.879 --> 00:13:22.720 but they range from size zero zero down to size five. 281 00:13:23.120 --> 00:13:26.960 Size zero zero is the absolute massive horsepill size, while 282 00:13:27.000 --> 00:13:29.159 size five is the tiniest shell available. 283 00:13:29.240 --> 00:13:30.879 Yeah, you have to memorize that backwards. 284 00:13:31.320 --> 00:13:36.879 So okay, we have successfully manufactured a stable, perfectly characterized 285 00:13:36.919 --> 00:13:37.679 dosage form. 286 00:13:37.799 --> 00:13:40.200 The patient places it on their tongue and swallows right. 287 00:13:40.240 --> 00:13:42.559 And this is where we cross the border from pharmaceutics, 288 00:13:42.679 --> 00:13:46.240 which is making the drug, into pharmacokinetics. 289 00:13:45.279 --> 00:13:47.879 Which is the study of what the human body does 290 00:13:47.919 --> 00:13:50.679 to the drug. Here's where it gets really interesting, it. 291 00:13:50.600 --> 00:13:55.360 Really does, because the first barrier is absorption. How does 292 00:13:55.399 --> 00:13:59.080 the drug physically cross from the stomach into the bloodstream. 293 00:13:59.159 --> 00:14:02.759 Well, this entire processes governed by the Henderson Hasselback equation right, 294 00:14:03.000 --> 00:14:05.679 which looks at the pH of the digestive tract and 295 00:14:05.720 --> 00:14:09.360 the PKI or acid dissociation constant of the drug itself. 296 00:14:09.639 --> 00:14:12.519 If you connect this to the bigger picture understanding pH 297 00:14:12.519 --> 00:14:16.399 and PKI actually allows pharmacologists to weaponize the body's natural 298 00:14:16.440 --> 00:14:20.679 absorption systems. Well. Cell membranes are made of lipids, basically fats. 299 00:14:21.440 --> 00:14:24.200 For a drug to easily slip through a fat based membrane, 300 00:14:24.240 --> 00:14:28.120 it needs to be uncharged or unionized AH like dissolves 301 00:14:28.200 --> 00:14:31.799 like precisely, let's look at aspirin, which is a weak 302 00:14:31.879 --> 00:14:34.360 acid with a low PK of about three point five. 303 00:14:35.519 --> 00:14:38.279 When you drop ansperin into the highly acidic stomach, which 304 00:14:38.279 --> 00:14:41.159 has a pH of around one point five, the aspirin 305 00:14:41.240 --> 00:14:45.080 remains largely unionized. It carries no electrical charge. 306 00:14:45.000 --> 00:14:47.720 And because it's uncharged, it is highly. 307 00:14:47.360 --> 00:14:50.360 Livid soluble and absorbs rapidly right through the stomach wall. 308 00:14:50.759 --> 00:14:54.120 Wow. Conversely, consider a basic drug like atropine with a 309 00:14:54.200 --> 00:14:58.720 high PK of ten in stomach acid. Atropine becomes heavily ionized, 310 00:14:59.080 --> 00:15:01.679 It gains a strong a lay electrical charge, and charged 311 00:15:01.720 --> 00:15:04.919 molecules repel lipid membranes exactly. 312 00:15:04.519 --> 00:15:06.879 So the atropine bounces off the stomach wall and simply 313 00:15:06.879 --> 00:15:10.480 travels downstream until it reaches the alkaline environment of the intestines, 314 00:15:10.480 --> 00:15:12.480 where it finally loses its charge and absorbs. 315 00:15:12.519 --> 00:15:15.000 You know, you can bypass all of that gastric math 316 00:15:15.080 --> 00:15:17.679 by just using different routes of administration right. 317 00:15:17.720 --> 00:15:23.080 Oh, sure, Intravenous or IV administration gives one hundred percent 318 00:15:23.279 --> 00:15:27.720 bioavailability because you are injecting the active ingredient directly into 319 00:15:27.759 --> 00:15:28.559 the blood plasma. 320 00:15:28.639 --> 00:15:31.720 But the sources also point out the rectal route, highlighting 321 00:15:31.759 --> 00:15:36.879 a specific acronym pedia Pedia. Yes, THATP stands for peraldehyde 322 00:15:37.159 --> 00:15:43.240 or gotamine, diazepam, indomethicin, and aminophyleine. But why give a 323 00:15:43.279 --> 00:15:46.559 drug like diazepam rectally instead of just swallowing a pill? 324 00:15:47.200 --> 00:15:50.480 Well, Diazepam is often used to stop severe seizures. A 325 00:15:50.519 --> 00:15:53.759 seizing patient physically cannot swallow a tablet, and trying to 326 00:15:53.799 --> 00:15:56.559 find a vein for an IV and a convulsing patient 327 00:15:56.759 --> 00:15:57.840 is incredibly difficult. 328 00:15:57.919 --> 00:15:58.840 That makes total sense. 329 00:15:58.919 --> 00:16:03.200 Plus u Kosa is highly vascularized, meaning the drug absorbs 330 00:16:03.279 --> 00:16:06.759 rapidly into the blood, and more importantly, the lower rectum 331 00:16:06.799 --> 00:16:09.840 actually bypasses the liver's first pass metabolism. 332 00:16:09.919 --> 00:16:12.679 Oh or the liver chemically filters and destroys a large 333 00:16:12.679 --> 00:16:15.000 portion of an oral drug before it ever reaches systemic 334 00:16:15.039 --> 00:16:16.000 circulation exactly. 335 00:16:16.039 --> 00:16:17.200 You skip the liver entirely. 336 00:16:17.240 --> 00:16:19.519 Okay, here's another thing from the text. Sometimes the drug 337 00:16:19.559 --> 00:16:21.320 use swallow isn't actually a drug at all. 338 00:16:21.519 --> 00:16:23.399 Pro drugs co drugs are fascinating. 339 00:16:23.559 --> 00:16:26.159 I love this concept. A pro drug is like a 340 00:16:26.159 --> 00:16:30.559 biological trojan horse. It is an inactive, totally harmless chemical 341 00:16:30.720 --> 00:16:33.720 that is specifically designed to slip past the body's early 342 00:16:33.759 --> 00:16:36.000 defenses and distribution barriers. 343 00:16:35.879 --> 00:16:39.320 And then once it reaches the target, the body's own 344 00:16:39.440 --> 00:16:43.120 metabolic enzymes metabolize it, breaking it open to release the 345 00:16:43.159 --> 00:16:44.440 active drug inside. 346 00:16:44.639 --> 00:16:46.480 Lev Doopa is a prime example of this. 347 00:16:46.600 --> 00:16:49.879 Isn't it It is dopamine cannot cross the blood brain 348 00:16:49.960 --> 00:16:53.320 barrier to treat Parkinson's disease. The brain security system just 349 00:16:53.399 --> 00:16:54.679 blocks it outright. 350 00:16:54.360 --> 00:16:56.720 So we administer leve dopa instead, which is a pro 351 00:16:56.799 --> 00:16:59.639 drug structure that the brain readily imports. 352 00:16:59.279 --> 00:17:03.639 Right inside the brain tissue enzymes converted into active dopamine. 353 00:17:03.840 --> 00:17:06.920 Another one is innenelapl which is totally inactive until the 354 00:17:06.920 --> 00:17:10.559 liver metabolizes it into enoloprolate, which is a really potent 355 00:17:10.599 --> 00:17:11.720 blood pressure medication. 356 00:17:11.960 --> 00:17:14.559 And then there is also this bizarre category called hit 357 00:17:14.599 --> 00:17:17.680 and run drugs. The outline gives us the acronym gone 358 00:17:17.759 --> 00:17:22.480 rome to remember them, gone rome, yep, quanefidine, resser pain, omeprazol, 359 00:17:22.559 --> 00:17:26.920 and MAO inhibitors. From what I understand, the drug enters 360 00:17:26.960 --> 00:17:30.920 the body, does its job and is completely excreted. The 361 00:17:31.000 --> 00:17:34.160 drug is completely gone from the blood, but its biological 362 00:17:34.200 --> 00:17:37.119 effect persists for days. How is that even possible? 363 00:17:37.519 --> 00:17:39.400 It comes down to the type of chemical bond that 364 00:17:39.480 --> 00:17:43.400 drug forms. Take Omeprazol the acid reflux medication, Okay, it 365 00:17:43.440 --> 00:17:46.039 doesn't just block the proton pumps in your stomach lining 366 00:17:46.440 --> 00:17:50.359 it forms a permanent, irreversible covalent bond with them. The 367 00:17:50.400 --> 00:17:54.519 pump is basically fundamentally broken. Wow, So inin a few hours, 368 00:17:54.559 --> 00:17:56.920 your kidneys have filtered all the omeprozol out of your system. 369 00:17:56.960 --> 00:17:59.559 The drug is run away, but your stomach acid remains 370 00:17:59.599 --> 00:18:02.799 low for days because your body has to literally synthesize 371 00:18:03.000 --> 00:18:06.720 entirely new proton pumps from scratch to replace the destroyed ones. 372 00:18:06.799 --> 00:18:10.319 That is wild, and to control those concentrations, doctors utilize 373 00:18:10.319 --> 00:18:13.960 two dosing strategies. A loading dose, which is a massive 374 00:18:14.000 --> 00:18:16.920 initial hit designed to rapidly fill the body's volume of 375 00:18:16.960 --> 00:18:20.160 distribution and get the drug concentration up to the therapeutic 376 00:18:20.200 --> 00:18:21.319 threshold immediately. 377 00:18:21.359 --> 00:18:23.640 And once you're there, you switch to a much smaller 378 00:18:23.640 --> 00:18:24.680 maintenance does. 379 00:18:24.480 --> 00:18:27.440 Which is carefully calculated to perfectly match the rate at 380 00:18:27.440 --> 00:18:29.640 which your liver and kidneys are clearing. 381 00:18:29.279 --> 00:18:32.640 The drug exactly so once the drug reaches its target tissue, 382 00:18:32.759 --> 00:18:35.920 we move into pharmacode dynamics. We know what the body 383 00:18:35.960 --> 00:18:38.359 does to the drug, now we examine what the drug 384 00:18:38.400 --> 00:18:41.880 does to the cells. Right, the body operates via receptors, 385 00:18:41.960 --> 00:18:44.720 which are protein structures on the surface of cells that 386 00:18:44.799 --> 00:18:47.079 basically act as biological. 387 00:18:46.400 --> 00:18:50.079 Locks, and the drug molecule is the key. But pharmacology 388 00:18:50.119 --> 00:18:53.640 breaks that key down into two specific properties, right, Yes, 389 00:18:53.799 --> 00:18:56.839 First is affinity, which is simply the drugs ability to 390 00:18:56.920 --> 00:18:59.599 find the lock and insert itself into the keyhole. And 391 00:18:59.640 --> 00:19:03.960 second is intrinsic activity or efficacy. This is the drug's 392 00:19:04.000 --> 00:19:06.839 ability to actually turn the lock, open the door and 393 00:19:06.880 --> 00:19:08.400 trigger a cellular response. 394 00:19:08.759 --> 00:19:09.240 Spot on. 395 00:19:09.599 --> 00:19:12.240 So if a drug has both affinity and efficacy, we 396 00:19:12.279 --> 00:19:15.599 call it an agonist. It binds and activates. Okay, But 397 00:19:15.759 --> 00:19:20.119 an antagonist is a drug that has affinity but zero efficacy. 398 00:19:20.480 --> 00:19:23.599 It jams itself into the lock perfectly, but it cannot turn. 399 00:19:24.039 --> 00:19:26.799 And furthermore, because it's stuck in the keyhole, it blocks 400 00:19:26.839 --> 00:19:30.240 the body's natural chemicals from binding. The text divides this 401 00:19:30.400 --> 00:19:35.200