Biopharmaceutics: Physicochemical Factors

• Biopharmaceutics studies the relationship between a drug's physicochemical properties and its effects on the body.

Factors Affecting Oral Drug Absorption

• Oral drug absorption is affected by physicochemical, physiological, and pharmaceutical factors.

Physicochemical Factors Affecting Oral Drug Absorption

• Physicochemical factors affecting oral drug absorption are drug related

pKa of the drug

• pKa is the ionic strength (acidic or basic) and ability of a drug to ionize.
• Drugs can be strongly acidic, weakly acidic, weakly basic, or strongly basic, based on pKa value.
• High ionization results in less absorption, while low ionization results in more absorption.
• pKa value affects a drug's ionization and thus its absorption.

Water lipid solubility

• Sufficient water solubility is needed for effective disintegration and dissolution of a drug.
• Lipid solubility is required for absorption through the lipid membrane of the gastrointestinal tract.
• Ideally, good absorption requires both water and lipid solubility.

Particle size and surface area

• Particle size and surface area influence dissolution, disintegration, and ultimately absorption.
• A smaller particle size results in greater total surface area and more absorption.
• A larger particle size results in smaller surface area and less absorption.

Disintegration and dissolution rate

• A greater disintegration and dissolution rate leads to higher absorption.
• A lower disintegration and dissolution rate leads to lesser absorption.

Salt form of drug

• The salt form of a drug can increase its solubility, disintegration, dissolution, and absorption.
• For example, valproate sodium, a salt form, has greater absorption than valproic acid.

Physical form of drug

• Drugs can exist in crystalline or amorphous forms.
• Crystalline forms have organized crystal lattices and dissolve/disintegrate slowly.
• Amorphous forms lack a crystal lattice and dissolve readily.
• Amorphous forms have greater disintegration and dissolution rates than crystalline forms.

Polarity of drug

• Polarity favors dissolution and disintegration, but too high polarity can decrease absorption through the lipid cell membrane.

Stability of drug molecule

• Factors affecting the stability of a drug molecule include excessive ionization and interaction with gastrointestinal contents.

Chemical chelation/complex formation

• Drug molecules can interact with ions (Mg++, Al++++) to produce large, charged complexes.
• These complexes are often poorly absorbed from the gastrointestinal tract.

Molecular size of drug

• Smaller molecular sizes generally lead to better absorption.

Physiological Factors Affecting Oral Drug Absorption

• Physiological factors affecting oral drug absorption are patient related

pH of gastrointestinal fluids

• pH of stomach, intestine, and fluids plays a significant role.
• Strongly acidic drugs become ionized in the small intestine, resulting in poor absorption.
• Strongly basic drugs become ionized in the stomach, resulting in poor absorption.
• Weakly acidic and weakly basic drugs remain unionized in the stomach and small intestine and are well absorbed.

Gastric emptying

• Gastric emptying is the transfer of drug from the stomach to the small intestine.
• Drug absorption through the small intestine requires gastric emptying.
• Faster gastric emptying leads to rapid absorption, and slower gastric emptying leads to slower absorption.

GIT wall motility

• GIT wall motility affects the drug absorption rate.
• Greater gut motility results in less contact time with the absorption site and less absorption.
• Slower gut motility results in saturation of the absorption site, leading to more absorption.
• Optimal gut motility provides good absorption.

Absorption surface area

• Greater the surface area, larger will be absorption.
• The small intestine offers greater surface area due to the presence of villi and microvilli.

Blood flow

• Good absorption requires higher blood flow to the absorption site.
• Both the stomach and small intestine have effective blood flow, but the small intestine offers better absorption due to villi.

Villi and microvilli

• Presence of villi and microvilli offers greater surface area in the small intestine and hence more absorption.

GIT Juices

Gastric juice and intestinal juices affect the drug absorption through two mechanisms;

• Solubilizes/disintegrates and absorbs the oral drug.
• Ionization of drug (due to change in pH).

Presence of absence of food

Food affects the drug absorption by following ways:

• Secretion of gastric and intestinal juice
• Formation of chemical chelates due to presence of ions (Mg++, Ca++).

Gastrointestinal microbial flora

• Normal microbial flora in the gastrointestinal tract can metabolize drugs, reducing their absorption, e.g., Digoxin.

Enterohepatic circulation

• Some drugs, like oral contraceptives, undergo enterohepatic circulation and are reabsorbed, so their dose should be designed carefully.

Diseased Conditions Affecting Drug Absorption

Gastrointestinal disorders

• Diarrhea increases the GIT wall motility and decreases the contact time of drug with absorption resulting in decreased absorption of the drug.
• Constipation decreases the GIT wall motility and causes the saturation of absorption site, therefore decreases the drug absorption.

Cardiovascular diseases

• Congestive heart failure results in decreased blood flow to small intestine and that results in decreased drug absorption.

Hepatic diseases

• Liver cirrhosis disturbs drug absorption through changes in portal blood circulation and bile flow.

Pharmaceutical Factors Affecting Oral Drug Absorption

• Pharmaceutical factors affecting oral drug absorption are drug related

Manufacturing variables

• Granulation methods: Wet granulation, Dry granulation, and direct compression
• Granulation method may change the crystal lattice of final dosage forms and hence the dissolution of tablets.
• Compression force: large compression force can increase tablet hardness and decrease dissolution rate. Small compression force can make space in the tablet and increases the dissolution rate.
• Capsule filling pressure: Tightly filled capsules may undergo slow dissolution and slow absorption. Loosely filled capsules may dissolve and absorb readily.

Type of oral dosage form

• Different dosage forms affect the absorption by affecting dissolution and disintegration.
• Liquid dosage forms are absorbed faster because they don't require dissolution or disintegration.
• Solid dosage forms undergo disintegration and dissolution before absorption, resulting in them being absorbed slowly.

Pharmaceutical excipients

• The number of excipients in a formulation may complicate its integrity and impair disintegration, dissolution, and absorption.
• The amount of excipient can change the dissolution and absorption. A high amount of binding agent can decrease the rate of absorption.

Product age and storage variables

• Storage conditions, like temperature, moisture, or light, can change the stability of the dosage form.
• Increased product age increases the exposure of the product to changing storage conditions, affecting dissolution and absorption.

Disintegration time

• Disintegration time is dependent on the binder and disintegrating agent quantities in the drug product.
• Higher binder amounts increase disintegration time and reduce absorption.
• Higher disintegrating agent amounts decrease disintegration time, which increases absorption.
• Tablets generally have longer disintegration times than elixirs.

Mechanisms of Drug Absorption

Transcellular passive diffusion

• It involves simple diffusion of drug molecules from high concentration to lower concentration across the cell membrane.
• The process doesn't require energy or a transporter.
• It typically involves non-ionic transport.
• More than 90% of the drug molecules follow this absorption mechanism.
• Fick's Law of Diffusion states that drug molecules diffuse from an area of higher concentration to the area of lower concentration until equilibrium is achieved.

Convective transport

• It is also called as pore transport/bulk flow/filtration
• Drug molecules pass through water permeable channels present in cell membrane.
• The drugs having low molecular size and high water solubility follow this type of mechanism, e.g., urea and water.
• Rate of absorption depends on the number of pores in cell membrane.

Ion pair transport

• Responsible for the absorption of ionized drugs, e.g., quaternary ammonium groups containing drugs.
• Ionized drugs form reversible neutral complexes with endogenous ions of GIT with both i.e., water and lipid solubility.

Electrochemical and Ionic diffusion

• Ionized drugs find charge on the cell membrane at some points.
• On another side of cell membrane, drugs become neutral by binding to the opposite charged molecules.
• This neutralisation creates concentration gradient and facilitates diffusion.

Facilitated diffusion

• It uses a transporter for movement across the cell membrane.
• It doesn't require energy expenditure.
• Its driving force is a concentration gradient.
• The absorption rate through this mechanism depends on two parameters; concentration gradient and number of transporters.

Active transport

• This mechanism uses a transporter.
• This mechanism uses energy in the form of ATP.
• It is of 2 types: -Primary active transport: Only one drug molecule is transported in one direction across the cell membrane. ATP is directly used. -Secondary active transport: More than one type of molecules transported across cell membrane.
• ATP is used to pump one molecule (electrolyte/glucose) for another molecule (drug).

Endocytosis

• It is the mechanism that cell absorbs the drug molecules by engulfing it.

Transcytosis

• In this mechanism, the drug molecules are transferred across the whole cell in form of vesicles.

Explore the impact of physicochemical properties on drug absorption. Learn how factors like pKa and water-lipid solubility influence a drug's effectiveness within the body. Understand the relationship between ionization and absorption.