Biopharmaceutics of Oral Solids

The study of how the physicochemical properties of a drug, the dosage form, and the route of administration affect the rate and extent of systemic drug absorption

Biopharmaceutics

Core goal is to understand and optimize bioavailability, which is the fraction of an administered dose that reaches the systemic circulation unchanged

Biopharmaceutics

Primarily a function of solubility and permeability

Bioavailability

The ability to dissolve in GI fluids

Solubility

The ability to cross biological membranes

Permeability

The drug must first dissolve. If it doesn’t dissolve, it is ________ in the feces

Excreted

The drug must be _____ in the highly acidic gastric pH or against digestive enzymes

Stable

To reach systemic absorption, the drug must cross the intestinal ___

Wall

Once absorbed, the drug enters the ______ ____ and goes straight to the liver

Portal vein

The liver is the primary site of _______; significant portions of the drug may be deactivated here before ever reaching the heart/systemic circulation

Metabolism

Drugs that are weak acids or bases change _______ based on pH

Solubility

Salt forms are often used to increase drug _________

Solubility

________ forms of drugs generally dissolve faster than highly organized crystalline structures

Amorphous

Decreasing particle size increases ______ ____, which directly increases the dissolution rate

Surface area

Measures how well a drug likes fat vs. water

Partition coefficient

A high partition coefficient means better _________ but often results in poor solubility in water

Permeability

Generally, high molecular weight correlates with ____ permeability because the molecules are too “bulky” to diffuse through cell membranes easily

Poor

A pharmacologically inactive compound that is converted into an active drug within the body

Prodrugs

Prodrugs are used to “mask” poor properties - like making a highly polar drug more ________ to improve its absorption

Lipophilic

The goal of pharmaceutical formulation is to reduce barriers to __________

Bioavailability

______ forms generally offer faster solubilization compared to solids

Liquid

Surfactants _______ solubility

Improve

Used to increase the permeability of the drug across membranes

Permeation enhancers

The _____ is responsible for pre-systemic metabolism; drugs absorbed in the GI tract enter the portal vein and are processed by the ____ before reaching systemic circulation, which can significantly reduce bioavailability

Liver

Some drugs are excreted via ____ back into the intestine

Bile

Food alters the ________ state of drugs by changing the GI pH

Ionization

_________ varies significantly between different individuals and even within the same individual due to diet, health, and genetics

Absorption

The solid dosage form breaks into aggregates

Disintegration

Aggregates break down into fine particles

Deaggregation

The drug transitions into a solution (this is often the rate-limiting step)

Dissolution

________ drugs pass through the lipid membrane much more easily than charged drugs

Uncharged

This equation describes thee rate of dissolution of a solid drug in a solvent; it is a fundamental concept for understanding how quickly a drug enters solution to be absorbed

Noyes-Whitney equation

Dissolution variable; affected by molecular weight of drug and viscosity of medium

Diffusion

Higher viscosity means _______ dissolution

Lower

Smaller particles have ________ dissolution

Faster

Higher solubility means faster _________

Dissolution

Lower concentration (sink conditions) means ________ dissolution

Faster

Faster ____ creates a thinner stagnant layer which means faster dissolution

Mixing

As particle size decreases, the effective surface area ________ significantly

Increases

Smaller particles reach much higher amounts dissolved in a _______ time compared to larger granules

Shorter

Generally decrease dissolution rate; coats drug particles and prevents “wetting” since they are hydrophobic, making it harder for water to reach the surface

Lubricants

Generally increase dissolution rate; these reduce surface tension, improving the wetting of the drug and potentially increasing the solubility

Surfactants

The drug must first exit its dosage form and _____ into the GI fluid before it can be absorbed

Dissolve

Extreme stomach acidity or digestive enzymes can ______ the drug before it reaches the absorption site

Destroy

Movement across the intestinal wall into the portal circulation

Absorption

Drugs absorbed from the GI tract via the portal vein go to the liver; here, enzymes can ________ the drug before it ever reaches the rest of the body

Metabolize

The FDA uses the _____ _____ ________ to predict drug absorption based on two key factors: solubility and permeability

Biopharmaceutics classification system

Biopharmaceutics Classification System two parameters

Solubility and Permeability

Means the highest dose strength is soluble in <250 mL of water over a pH range of 1 to 7.5

High solubility

Means the extent of absorption is >90% of the administered dose

High permeability

High solubility and high permeability

Class I

Ideal drug; rapid absorption

Class I

Low solubility and high permeability

Class II

Absorption limited by dissolution

Class II

High solubility and low permeability

Class III

Absorption limited by permeability

Class III

Low solubility and low permeability

Class IV

Not ideal; poor bioavailability

Class IV

Class ___ drugs benefit most from formulation efforts because their only major barrier is getting into solution

II

_____ intake can significantly alter the bioavailability of drugs, particularly Class II

Food

Drug class affected most by food intake

Class II

Food often ______ the absorption of Class II drugs

Increases

Delayed gastric emptying gives _____ soluble drugs more time to dissolve in the stomach

Poorly

Changed gastric pH from food can increase the ________ of certain weak bases

Solubility

When food is present, bile salts act as natural detergents, helping to ________ lipophilic drugs

Solubilize

Food can interact directly with drugs, inhibit/promote metabolic _____, or interfere with transporter proteins in the gut wall

Enzymes