3: Factors Affecting Absorption Pt.2

Fundamental pharmaceutics rule stating that as a dosage form formulation becomes more complex, what happens to the potential for absorption problems?

The potential for absorption problems increases proportionally.

What three factors are involved in increasing complexity?

Adding more excipients (diluents, binders), Utilizing advanced processing techniques (e.g., nanotechnology), Exposing the formulation to high or low heat extremes

Each added excipient or processing step introduces potential physical/chemical barriers to drug release.

True.

Simple formulation consisting of water and sugar.

Oral Syrups.

Despite its simplicity, absorption issues in oral syrups can arise from which two factors?

Microbial contamination, Altered dissolution rates if sugar concentration is inadequate

Complex drug delivery systems require rigorous quality control to prevent what two failures?

Unintended bioequivalence, Absorption failures

The step-by-step physical process required for an oral solid dosage form to liberate its active ingredient for absorption into systemic circulation.

Process of Drug Release from Oral Dosage Form.

Active drug is liberated into an aqueous solution via what process followed by dissolution?

Disintegration.

The dissolved drug in aqueous solution moves across membranes primarily via which mechanisms? A. Convection and active transport B. Convection and passive diffusion C. Passive diffusion and endocytosis D. Active transport and facilitated diffusion E. Convection and exocytosis

B. Convection and passive diffusion

Oral dosage forms pass through the liver/GIT first-pass effect, ensuring that systemic bioavailability is never what percentage?

100%.

For conventional oral dosage forms, what is the slowest (rate-limiting) step in the series of drug release?

Dissolution.

Formulations designed to alter the timing or location of drug release, such as enteric-coated tablets that prevent drug degradation in acidic gastric environments.

Modified-Release (Delayed/Enteric-Coated) Systems.

Protects the drug from stomach acid, allowing it to pass intact into the small intestine where targeted release and absorption occur.

Enteric Coating.

Unlike conventional dosage forms, the rate-limiting step for modified-release or targeted-release formulations is dissolution.

False. The correct statement is: Unlike conventional dosage forms, the rate-limiting step for modified-release or targeted-release formulations is liberation (drug release).

Mathematical relationship governing the rate of drug diffusion and dissolution across a concentration gradient.

Fick’s Law of Diffusion and Dissolution Dynamics.

Which factors directly increase the rate of diffusion/dissolution?

Diffusion rate constant, Surface area, Drug concentration gradient

The thickness of the stagnant layer surrounding the drug particle is inversely proportional to the rate of dissolution.

True.

What are the primary formulation strategies to enhance drug dissolution?

Increasing particle surface area (e.g., micronization), Decreasing stagnant layer thickness

Liquid dosage forms containing completely dissolved drug particles, yielding rapid and complete gastrointestinal absorption.

Oral Solutions and Hydroalcoholic Systems.

Oral solutions bypass the need for what two processes?

Disintegration, Dissolution

Faster gastric emptying promotes quicker transit to the small intestine, where what structure vastly increases surface area for maximum absorption?

Microvilli.

Hydroalcoholic solutions offer good absorption in the stomach due to mild acidity, but carry a risk of what? A. Microbial contamination B. Separation of droplets C. Drug precipitation in gastric fluids D. Decreased surface area E. Complete and irreversible separation

C. Drug precipitation in gastric fluids

What interferes with dilution and mixing with GIT contents, slowing overall absorption?

Highly viscous solutions.

Two-phase liquid preparations composed of immiscible oil and water phases requiring stabilization.

Emulsions.

Merging of dispersed droplets into larger aggregates.

Coalescence.

Reversible separation of droplets based on density.

Creaming / Sedimentation.

Complete and irreversible separation of oil and water phases.

Cracking.

Physical instability directly destroys formulation uniformity, impairing what?

Predictable drug absorption.

Disperse systems containing insoluble solid particles distributed throughout a liquid vehicle.

Suspensions.

Suspended particles provide a large surface area for what process?

Rapid dissolution.

Added to suspensions to improve particle wetting and enhance dissolution/absorption.

Surface-Active Agents (Surfactants).

High formulation viscosity slows gastric emptying time and dissolution rate, resulting in what?

Decreased drug absorption.

Solid dosage forms consisting of two-part gelatin shells enclosing dry powder or granule fills.

Hard Shell Capsules.

Excessive compaction during filling causes what? A. Separation based on density B. Rapid dispersion C. Improved particle wetting D. Powder aggregation E. Faster gastric emptying

D. Powder aggregation

Powder aggregation due to excessive compaction reduces exposed surface area and hinders what two processes?

Drug dissolution, Release

Added to the powder blend to prevent particle aggregation, ensuring rapid dispersion, maximum surface area, and optimized dissolution upon shell rupture.

Dispersing Agents.

What parameters are critical to avoid delayed oral bioavailability in hard shell capsules?

Compaction force control, Surfactant/dispersing agent selection

Hermetically sealed, one-piece capsule formulations containing liquid, suspension, or semi-solid fills.

Soft Gel Capsules.

Manufacturing complexity is significantly lower than hard shell capsules, decreasing absorption variability.

False. The correct statement is: Manufacturing complexity is significantly higher than hard shell capsules, increasing absorption variability.

Formulating drugs in hydrophobic oil vehicles results in what? A. Faster gastric emptying B. Poorer absorption compared to standard compressed tablets C. Maximum surface area D. Predictable drug absorption E. Rapid dissolution

B. Poorer absorption compared to standard compressed tablets

Storage conditions and aging cause what effects within the capsule shell?

Structural degradation, Drug aggregation

Structural degradation or drug aggregation within the capsule shell negatively alters what?

Bioavailability.

Soft gel capsules require careful monitoring of what parameters to prevent physical deterioration and absorption failure?

Storage conditions, Vehicle polarity

Solid oral dosage forms produced by compressing granulations or powders into a dense unit dose.

Tablet.

Compression force directly determines what two parameters?

Tablet hardness, Disintegration profile

Excessive compression increases tablet hardness, which impedes what process?

Aqueous penetration.

Impeded aqueous penetration delays tablet disintegration and slows what?

Overall drug dissolution.

Hardness and compression parameters must be balanced during manufacturing to avoid what?

Bioavailability failures caused by delayed release.

Inactive additives formulated alongside the active pharmaceutical ingredient (API) to facilitate manufacturing, stability, and drug release.

Functional Classes of Tablet Excipients.

Each excipient possesses distinct physicochemical properties that directly influence what two processes?

Drug dissolution, Intestinal absorption

Provide necessary tablet volume and bulk.

Bulking Agents / Diluents / Fillers.

What are examples of Bulking Agents / Diluents / Fillers?

Lactose, Starch

Assist fluid penetration to aid in powder dissolution.

Wetting Agents.

Promote tablet breakdown into smaller fragments in the presence of GI fluids.

Disintegrants.

Improve powder flowability during compression.

Flow Activators / Glidants / Lubricants.

Which of the following is an example of Flow Activators / Glidants / Lubricants? A. Lactose B. Starch paste C. Magnesium stearate D. Water E. Sugar

C. Magnesium stearate

Impart cohesive qualities to powders, binding particles together into granules.

Granulating Agents / Binders.

Which of the following is an example of Granulating Agents / Binders? A. Magnesium stearate B. Lactose C. Starch paste D. Diluent E. Glidant

C. Starch paste

Chewable tablets require a disintegrant because mechanical mastication in the oral cavity performs physical disintegration.

False. The correct statement is: Chewable tablets do NOT require a disintegrant because mechanical mastication in the oral cavity performs physical disintegration.

Tablet cores enclosed in protective outer layers to alter release, improve stability, or enhance aesthetic appeal.

Coated Tablet.

Sugar coatings mask unpalatable taste and improve physical presentation to what?

Target patient populations.

Sugar-coated tablets are formulated specifically for what compliance?

Pediatric compliance, Geriatric compliance

Modified-release dosage forms coated with acid-resistant polymers designed to remain intact in the acidic stomach and disintegrate exclusively in the neutral-to-alkaline small intestine.

Enteric-Coated Tablets.

Prevents contact between the active drug and the gastric region, protecting what from degradation?

Acid-labile drugs.

Delays liberation until reaching the small intestine, increasing what?

Overall absorption capacity.

What are the primary advantages of enteric-coated tablets?

Minimizes gastric mucosal irritation, Prevents inactivation of acid-sensitive active ingredients, Maximizes absorption surface area in the small intestine

Increased manufacturing complexity and significantly higher cost compared to uncoated tablets.

Disadvantage of Enteric-Coated Tablets.

A scientific framework that classifies drug substances based on their aqueous solubility and intestinal permeability to predict in vivo pharmacokinetic performance from in vitro data.

Biopharmaceutical Classification System (BCS).

What categorization is High Solubility, High Permeability (Rapid dissolution and rapid absorption)?

Class 1.

Metoprolol is an example of what BCS Class?

Class 1.

What categorization is Low Solubility, High Permeability?

Class 2.

What categorization is High Solubility, Low Permeability?

Class 3.

What categorization is Low Solubility, Low Permeability?

Class 4.

Utilized in drug discovery, development, and regulatory approval to accomplish what?

Fast-track bioequivalence studies, Establish biowaivers

Standardized physiological numerical criteria defining whether an active drug substance is designated as highly soluble or highly permeable.

BCS Quantitative Class Boundaries.

The highest single dose strength dissolves completely in le 250 mL of aqueous media across a pH range of 1.0 to 7.5.

Highly Soluble.

Extent of intestinal absorption is determined to be ge 90% of the administered dose (compared to an intravenous reference dose).

Highly Permeable.

Pharmacological modification of gastrointestinal transit rate, which directly alters what?

The residence time of orally administered drugs at primary absorption sites.

Gastric Emptying Rate (GER) and Gastric Emptying Time (GET) share an inverse relationship.

True.

Accelerating GER delivers drugs faster to the small intestine, resulting in what?

Enhancing the rate of absorption.

Delaying GER retards drug delivery to the small intestine, slowing absorption rate and delaying what?

Clinical onset of action.

Speed up gastric emptying to treat nausea and vomiting (e.g., cancer chemotherapy-induced emesis).

Gastroprokinetics (Increase GER / Decrease GET).

Which of the following are examples of Gastroprokinetics? A. Loperamide, Diphenoxylate B. Metoclopramide, Domperidone C. Tricyclic Antidepressants (TCAs) D. Atropine, Metoprolol E. Magnesium stearate, Lactose

B. Metoclopramide, Domperidone

Slow down motility, leading to delayed drug absorption and onset.

Antimotility / Slowing Agents (Decrease GER / Increase GET).

Which of the following are examples of Antimotility / Slowing Agents?

Loperamide, Diphenoxylate, Tricyclic Antidepressants (TCAs)

Parenteral routes (Intravenous, Intra-arterial) bypass GI motility completely by delivering drugs directly into systemic circulation, achieving what?

Maximum bioavailability (100%).

Co-administered drugs altering drug absorption through receptor binding competition, adverse GI reactions, or suppression of GI secretions.

Competitive Drug Interactions and Secretory Inactivation.

Blockers binding to allosteric sites induce conformational changes in drug targets, impairing what?

Drug binding, Absorption profiles

Certain drugs induce laxative activity or hypermotility, leading to what?

Premature drug expulsion.

Inhibits parasympathetic stimulation, reducing stomach acid secretion and lowering gastric motility.

Anticholinergic Activity.

Which of the following is an anticholinergic agent causing reduced stomach acid and diminished GI motility, opposing cholinergic "DUMBBELSS" effects? A. Metoclopramide B. Loperamide C. Atropine D. Domperidone E. Metoprolol

C. Atropine

Systemic disease states that impair the physiological mechanisms governing drug delivery, systemic absorption, and tissue distribution.

Pathologic Factors Affecting Drug Disposition.

In Congestive Heart Failure (CHF), reduced cardiac output weakens myocardial contraction force, resulting in what?

Decreasing systemic blood perfusion.

In CHF, vascular congestion and ischemia create circulatory barriers (hypoxic tissue), preventing efficient distribution of drugs to what?

Absorption sites, Target organs

Altered transit times shorten or prolong the dissolution window, resulting in erratic or incomplete drug absorption.

Diarrhea / Constipation.

Pathological organ failure or neurodegenerative conditions altering systemic drug clearance, accumulation, and GI transit.

Neurological and Organ Impairment.

Neurodegenerative alterations in dopaminergic and cholinergic pathways disrupt GI motility patterns, altering drug absorption kinetics.

Parkinson’s Disease.

Liver damage decreases drug-metabolizing enzyme activity, impairing clearance and resulting in what?

Elevated systemic drug concentrations.

Kidney dysfunction reduces renal excretion, leading to what?

Drug accumulation, Potential toxicity

Parkinson's Disease leads to neurodegenerative alterations in what specific pathways?

Dopaminergic pathways, Cholinergic pathways