Transcript
0:00Dissolution and solubility
Lesson 2.1 of our absorption module: dissolution and solubility. A drug in a tablet or capsule must dissolve in the gut fluid before it can pass through the gut wall. Dissolution is the process in which molecules leave the solid drug and enter the fluid. The dissolution rate is the mass of drug that dissolves in a unit of time. Solubility is the concentration of dissolved drug when the fluid is in equilibrium with the solid drug.
0:37The BCS
The Biopharmaceutics Classification System, or BCS, sorts drugs into four classes. It uses two properties that limit oral absorption: solubility, and permeability through the gut wall. A drug is highly soluble when its highest single dose is completely soluble in 250 milliliters or less of water-based fluid. This must be true at every pH from 1.2 to 6.8. By this solubility criterion, about 40 percent of marketed drugs are poorly soluble. Among drugs in development, the share is about 90 percent. A dosage form passes through the small intestine in about 3 hours. Drug that is still undissolved after this time cannot be absorbed there. Poorly soluble drugs therefore often have a low and variable oral bioavailability. Oral bioavailability is the fraction of the dose that reaches the systemic circulation unchanged, after the drug passes through the gut wall and the liver.
1:54The Noyes-Whitney equation
The Noyes-Whitney equation describes the dissolution rate. The rate rises with three terms: the diffusion coefficient, the surface area of the solid, and the solubility minus the drug concentration in the fluid. The diffusion coefficient tells how fast dissolved molecules move through the fluid. The equation divides by h, the thickness of the diffusion layer, a thin layer of still fluid around the particle. At the particle surface, the concentration equals the solubility, and molecules diffuse across this layer into the surrounding fluid. A larger surface area or a higher solubility therefore gives a faster rate. Three factors that change these terms are the particle size, the pH of the gut fluid and the salt form of the drug.
2:53Particle size
The first is particle size, which sets the surface area. When a manufacturer mills a drug to smaller particles, the same mass has a larger total surface area. Very small particles also have a thinner diffusion layer. Because the equation divides by h, a thinner layer gives a faster rate.
3:18pH
The second is pH. Many drugs are weak acids or weak bases. The fraction of molecules that carry a charge depends on the pH of the fluid and on the pKa of the drug. The pKa is the pH at which half of the molecules carry a charge. When the pH is below the pKa, most molecules of a weak base take up a proton and become cations, positively charged ions. The charged form is more soluble in water than the neutral form. When the pH is above the pKa, most molecules of a weak acid give up a proton and become anions, negatively charged ions. A weak acid is therefore more soluble at higher pH, and a weak base at lower pH. In the fasted stomach, the median pH is 1.7. In the duodenum, the first part of the small intestine, the median pH is 6.1. Some weak bases are therefore highly soluble in the stomach and poorly soluble in the small intestine, where the pH is above 6. Weak acids show the opposite pattern. When a dissolved weak base moves from the stomach into the small intestine, part of it can precipitate, that is, form a solid again.
4:53The salt form
The third is the salt form. A salt is the charged drug paired with a counter-ion, an ion of opposite charge. An example is chloride in the hydrochloride salt of a weak base. Compared with the neutral drug, a salt usually has a higher solubility and a faster dissolution rate.
5:18Ketoconazole and stomach acid
Ketoconazole shows a large effect of pH on dissolution. It is an antifungal drug and a weak base. In a laboratory test, a ketoconazole tablet dissolved completely in simulated gastric fluid within 30 minutes. In a fluid that simulates the fasted small intestine, only 6 percent dissolved in 2 hours. A clinical study tested the effect of gastric pH on ketoconazole absorption in people. Nine healthy volunteers took three treatments in random order, one week apart. In the control treatment, they took a 200 milligram ketoconazole tablet with water. In the other two treatments, they first took omeprazole, a drug that reduces gastric acid secretion, and their gastric pH rose above 6. The study measured the AUC, the area under the serum concentration-time curve. In the control treatment, the mean ketoconazole AUC was 17.9 milligram hours per liter. After omeprazole with water, the mean AUC was 3.5, about one fifth of the control value. When they took ketoconazole with an acidic cola drink at pH 2.5 after omeprazole, absorption rose to about 65 percent of the control mean.
6:56Summary
In summary, a drug in a tablet or capsule must dissolve before it can pass through the gut wall. Particle size, pH and the salt form change the dissolution rate, and pH and the salt form also change the solubility. For some weak bases, absorption depends on gastric acid. When omeprazole raised the gastric pH, the ketoconazole AUC fell to about one fifth of control. This concludes lesson 2.1 on dissolution and solubility.
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Illustrations adapted from Servier Medical Art (smart.servier.com), CC BY 4.0. Structures drawn with RDKit.
