Pharmaceutical Sciences: Drug Performance Factors
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Questions and Answers

Why is particle size significant for drugs with low solubility in biological fluids?

Particle size enhances the surface area exposed to dissolution media, which increases the dissolution rate of the drug.

What does the Noyes-Whitney equation represent in terms of drug dissolution?

The Noyes-Whitney equation describes the dissolution rate as proportional to the difference between the solubility of the drug and its concentration in solution.

What is the critical solubility limit listed by the U.S. FDA for bioavailability?

The U.S. FDA regulation lists 0.5 percent as the critical solubility limit for bioavailability.

Name two drugs that demonstrate therapeutic differences based on particle size.

<p>Aspirin and digoxin are two examples of drugs with therapeutic differences related to their particle size.</p> Signup and view all the answers

What happens to a drug's dissolution rate when its particle size is reduced?

<p>When particle size is reduced, the dissolution rate becomes more rapid due to increased surface area.</p> Signup and view all the answers

What is the smallest particle size typically used in pharmaceutical manufacture?

<p>The smallest particle sizes used in pharmaceutical manufacture are in the range of 1-10 µm.</p> Signup and view all the answers

Why might particle size reduction not be suitable for all drugs, even those with low solubility?

<p>Particle size reduction may not be suitable if dissolution rate is not the absorption rate-limiting step or if the drug decomposes faster than absorption time.</p> Signup and view all the answers

What role does the constant $k_a$ in the Noyes-Whitney equation play?

<p>$k_a$ is a constant that depends on factors like agitation intensity, temperature, solid surface structure, and diffusion coefficient.</p> Signup and view all the answers

What is the primary effect of adding an electrolyte to a solution of an organic nonelectrolyte?

<p>The electrolyte ionizes, consuming water for hydration and thereby reducing the available water for the nonelectrolyte, leading to its precipitation.</p> Signup and view all the answers

How does salting-in differ from salting-out in the context of organic nonelectrolytes?

<p>Salting-in enhances solubility due to the increase in hydrophilicity from salts, while salting-out leads to the precipitation of the nonelectrolyte.</p> Signup and view all the answers

What are clathrates and how are they formed in relation to drug dissolution?

<p>Clathrates are structured cages formed by certain substances that encapsulate drug molecules, facilitating their dispersion in a solvent when the clathrate-forming material dissolves.</p> Signup and view all the answers

List two substances that are capable of forming clathrates and mention a drug that utilizes this formation.

<p>Gallic acid and urea can form clathrates, while vitamin A is an example of a drug that utilizes this formation.</p> Signup and view all the answers

What happens to clathrates when exposed to water, and how does this affect drug release?

<p>Upon exposure to water, the clathrate-forming material rapidly dissolves, releasing the drug in a monomolecular form into the solution.</p> Signup and view all the answers

What is a solid-in-solid solution and how is it formed?

<p>A solid-in-solid solution is formed when a drug is dissolved in a melt of substances like mannitol and then solidified, resulting in a monomolecular dispersion of the drug.</p> Signup and view all the answers

What advantage do salts of electrolytes provide over free acids or bases?

<p>Salts of electrolytes generally have higher solubility and a faster dissolution rate than their corresponding free acids or bases.</p> Signup and view all the answers

Explain the role of the anions and cations in salting-in processes.

<p>In salting-in, the solubilizing effect is associated with the anion in salts of organic acids and with the cation in organic-substituted ammonium salts.</p> Signup and view all the answers

Why are co-solutes particularly important for low solubility drugs?

<p>Co-solutes help improve the solubility of poorly soluble drugs by altering the properties of the solvent system.</p> Signup and view all the answers

Explain the role of pH in the dissolution rate of acidic drugs.

<p>The dissolution rate of an acidic drug increases with increasing pH, but it does not increase as rapidly as solubility does with the same pH changes.</p> Signup and view all the answers

Define the process referred to as 'salting-out' in pharmaceutical terms.

<p>Salting-out is the process where the addition of electrolytes leads to the precipitation of organic nonelectrolytes due to reduced solvation availability.</p> Signup and view all the answers

How do esters of chloramphenicol behave in the gastrointestinal tract?

<p>Chloramphenicol esters are unstable in acidic gastric fluid but dissolve at higher pH levels in the small intestine, where they are hydrolyzed by enzymes.</p> Signup and view all the answers

What is the difference in solubility and dissolution rate between amorphous and crystalline solid particles?

<p>Amorphous solid particles are generally more soluble and have a higher dissolution rate compared to crystalline particles.</p> Signup and view all the answers

Why are chemical variations of drugs important in pharmacology?

<p>Chemical variations are important to enhance pharmacologic response or to change solubility through the formation of salts, esters, ethers, or complexes.</p> Signup and view all the answers

What impact does milling have on solid-in-solid solutions?

<p>Milling of solid-in-solid solutions can enhance drug dispersion and potentially improve its bioavailability and solubility.</p> Signup and view all the answers

How does the formation of complexes influence drug solubility?

<p>The formation of complexes can significantly alter a drug's solubility, facilitating better absorption and therapeutic effectiveness.</p> Signup and view all the answers

What is the equation that relates concentration to surface area, volume, and frequency at time A/f?

<p>The equation is $C'=(k.SA/2V.f)$.</p> Signup and view all the answers

Under what conditions does the dissolution profile first appear as a parabola before becoming linear?

<p>The dissolution profile appears as a parabola under sink conditions at low time points.</p> Signup and view all the answers

What does the parameter $t₁$ represent in relation to drug release?

<p>$t₁$ represents the time at which the solid drug is fully wetted in the dissolution process.</p> Signup and view all the answers

How do pharmacotechnical factors influence the biological performance of drugs?

<p>Pharmacotechnical factors can alter the rate and extent of drug release from dosage forms.</p> Signup and view all the answers

What is a prerequisite for drug absorption according to the provided content?

<p>A prerequisite for drug absorption is that the drug must be in aqueous solution.</p> Signup and view all the answers

Explain the relationship between drug release characteristics and blood level curves.

<p>Different drug release characteristics result in different blood level curves in vivo.</p> Signup and view all the answers

What mainly causes 'apparent' absorption rates in different dosage forms of the same drug?

<p>'Apparent' absorption rates are caused by differences in the rate of drug release, not the actual absorption rates.</p> Signup and view all the answers

What factors contribute to absorption difficulties in drug delivery?

<p>Absorption difficulties arise with drugs of low solubility or those released extremely slowly from their dosage forms.</p> Signup and view all the answers

What are the main differences in energy requirements for drug release between crystalline and amorphous forms?

<p>Crystalline forms require a higher amount of energy to free a drug molecule compared to amorphous forms.</p> Signup and view all the answers

Why is Penicillin G in amorphous form not suitable for oral use?

<p>Amorphous Penicillin G is more rapidly dissolved and inactivated in stomach fluid compared to its crystalline form.</p> Signup and view all the answers

Define hydrates and solvates in the context of drug formulation.

<p>Hydrates are drug-water addition compounds, while solvates are drug-organic solvent addition compounds.</p> Signup and view all the answers

How does the anhydrous form of ampicillin behave upon exposure to water?

<p>It dissolves rapidly, releasing the drug in a monomolecular state.</p> Signup and view all the answers

What effect does increased compression force have on tablet disintegration and dissolution time?

<p>Increased compression force leads to harder tablets, which prolongs disintegration and dissolution time.</p> Signup and view all the answers

How do binders affect the properties of granules and tablets during drug manufacturing?

<p>Increasing binder amounts raises tablet hardness, thereby prolonging disintegration and dissolution time.</p> Signup and view all the answers

What are the consequences of using high amounts of lubricants in tablet formulation?

<p>High lubricant amounts decrease hydrophilicity and wetting, leading to prolonged disintegration and dissolution time.</p> Signup and view all the answers

What issues can arise from temperature increases during tablet compression?

<p>High compression speeds and forces can raise tablet temperatures, potentially causing drugs to sinter and aggregate.</p> Signup and view all the answers

What factors contribute to the delayed intramuscular absorption of drugs in neonates?

<p>The factors include relatively low muscular blood flow, inefficient muscular contractions, and a higher percentage of water per unit of muscle mass.</p> Signup and view all the answers

How does the body composition of neonates differ from adults in terms of total body water and fat?

<p>Neonates have higher total body water percentages and a significant proportion of their body fat can contain as much as 57% water and 35% lipids.</p> Signup and view all the answers

What is the impact of decreased plasma protein binding in neonates on drug distribution?

<p>The free fraction of drugs that are highly protein-bound is increased, leading to a higher potential for systemic effects from medications.</p> Signup and view all the answers

Explain how skin permeability affects drug absorption in infants compared to older children.

<p>Neonates have a higher skin permeability, which can lead to systemic toxicity from percutaneous applications of certain drugs.</p> Signup and view all the answers

What developmental changes occur in body fat composition between ages 10 and 20 in males and females?

<p>In males, body fat decreases by approximately 50%, while in females it decreases from about 28% to 25%.</p> Signup and view all the answers

Why might the intramuscular route be less efficient for drug administration in neonates?

<p>This route is less efficient due to lower muscular blood flow and poor muscular contractions, leading to variability in drug absorption.</p> Signup and view all the answers

Discuss the importance of biliary function and microbial colonization in drug metabolism for neonates.

<p>Biliary function and microbial colonization are crucial as they influence the drug metabolism and absorption processes during early development.</p> Signup and view all the answers

How can the physicochemical properties of a drug influence its absorption in neonates?

<p>The physicochemical properties, such as solubility and molecular size, can affect the rate and extent of drug absorption through variable neonatal physiology.</p> Signup and view all the answers

Flashcards

Particle Size Effect on Drug Performance

Particle size affects the dissolution rate of poorly water-soluble drugs, leading to changes in bioavailability.

Dissolution Rate Equation

The Noyes-Whitney equation describes how fast a drug dissolves. It depends on surface area, solubility, and agitation.

Surface Area and Dissolution

Decreasing particle size increases the exposed surface area of a drug, which speeds up its dissolution.

Solubility and Particle Size

Reducing particle size (micronization) doesn't significantly change the actual solubility of a drug, just the dissolution rate.

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Dissolution Rate Limiting Step

When the rate at which a drug dissolves is slower than the rate at which it's absorbed, changes in particle size might not improve absorption.

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Low Solubility Drug Examples

Certain drugs, like Amphotericin and Aspirin, demonstrate variations in performance based on particle size.

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Micronization Limits

Particle size reduction is practically limited to a range of 1-10 µm for drug delivery.

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Micronization Not Universal

Modifying particle size isn't a solution for improving absorption of all poorly soluble drugs, as sometimes other factors limit absorption.

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Co-solutes importance

Co-solutes are crucial for drugs that have low solubility in water.

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Salting-out

Adding a solid electrolyte reduces the water available for a nonelectrolyte, causing it to precipitate.

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Salting-in

Adding certain salts increases the solubility of a nonelectrolyte by increasing the hydrophilicity of the solution.

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Hydrophilicity

The tendency of a substance to interact with water.

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Clathrate Formation

A substance forms channels (cages) that encapsulate another substance, forming a clathrate complex.

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Clathrate-forming substances

Certain substances (e.g., gallic acid, urea) that can form clathrates.

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Clathrate Stability

Clathrates are stable in dry form but prone to drug release when exposed to water.

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Drugs in clathrates

Certain drugs like vitamin A, sulfathiazole, and chloramphenicol can be incorporated in clathrates.

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Solid-in-Solid Solution Complex

A method where a drug is dissolved in a melt of mannitol or other carbohydrates, then solidified, resulting in a uniform dispersion of the drug within the solid matrix. This technique is used for improving the solubility and bioavailability of poorly soluble drugs.

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Spray-Congealing

A process where a liquid melt of a drug and carrier (like mannitol) is sprayed into a cool air stream, causing rapid solidification and the formation of beads or particles.

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Chemical Variation for Solubility

Altering the chemical structure of a drug to improve its solubility, often by forming salts, esters, ethers, or complexes.

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Salts and Solubility

Salts of electrolytes generally have better solubility and faster dissolution rates than the free acid or base form of a drug.

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pH and Dissolution Rate (Acidic Drugs)

The dissolution rate of acidic drugs increases with higher pH, but not as much as the increase in solubility.

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Salt Dissolution Rate and pH

The dissolution rate of a salt is relatively unaffected by the pH of the surrounding medium.

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Chloramphenicol Esters

Esters of chloramphenicol are designed to be stable in the stomach but dissolve and release the active drug in the small intestine.

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Amorphous vs. Crystalline

Amorphous forms of drugs have a higher solubility and dissolution rate than crystalline forms. This is because amorphous particles have a more disordered structure, allowing them to dissolve more easily.

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Amorphous vs. Crystalline Form Impact

The crystalline form of a drug often requires more energy to dissolve, making the amorphous form more biologically active. Example: amorphous novobiocin is active while its crystalline form is inactive.

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Penicillin G and Form Stability

Penicillin G is unstable in its amorphous form when taken orally (PO), as it dissolves too quickly and is inactivated in the stomach. The crystalline form is more stable.

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What are Hydrates?

Hydrates are drug compounds combined with water molecules. They have different physical properties than the anhydrous form, like solubility.

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What are Solvates?

Solvates are drug compounds combined with organic solvent molecules. These compounds also have different physical properties than the anhydrous form, like solubility.

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Anhydrous Form Behavior

The anhydrous (water-free) form of a drug can quickly dissolve when exposed to water, releasing the drug in a single-molecule state.

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Solid-in-Solid Solutions

These are mixtures where a drug is dissolved within a solid macromolecular carrier. Examples include griseofulvin in urea melts.

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Tablet Manufacturing Impact

High compression force during tablet production can increase tablet hardness, making it harder for the drug to disintegrate and dissolve.

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Heat and Drug Stability

Heat used in manufacturing, like for suppositories and ointments, can cause drugs to dissolve in the base. Upon cooling, the drug may form large crystals, slowing down its release.

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Neonatal Skin Permeability

The skin of newborns is more permeable to drugs, leading to increased systemic absorption and potential toxicity, especially during the first year of life.

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Intramuscular Absorption in Neonates

Drug absorption after intramuscular injection in newborns is slower and less predictable compared to older infants and children due to factors like low muscle blood flow and inefficient muscle contractions.

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Neonatal Drug Distribution: Water vs. Fat

The distribution of drugs in newborns is affected by their high water content and lower fat content compared to adults, leading to different drug concentrations in tissues.

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Plasma Protein Binding in Neonates

Newborns have lower levels of drug-binding proteins in their plasma, resulting in a higher proportion of free (active) drug available in the body.

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Factors Affecting Plasma Protein Binding

Factors like reduced binding affinity, acidic plasma pH, and competing substances (e.g., bilirubin) can further decrease drug binding in newborns.

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Why is Neonatal Pharmacokinetics Unique?

The unique physiological characteristics of newborns, such as high water content, low plasma protein binding, and altered drug absorption, lead to distinct patterns of drug distribution, elimination, and overall pharmacokinetics.

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How does Body Composition Change with Age?

Total body water, extracellular water, and body fat percentages change significantly during development, particularly in the first year of life, impacting drug distribution.

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Neonatal Adipose Tissue Composition

The adipose tissue (fat) of newborns has a higher water content and lower lipid content compared to adults, affecting drug distribution and metabolism.

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Sink Conditions

A situation during dissolution where the drug concentration in the surrounding medium (e.g., water) is much lower than its solubility, allowing for a continuous dissolution process.

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Dissolution Rate Equation (Sink Conditions)

C' = (k.SA/2V.f) - This equation describes the dissolution rate under sink conditions. 'C' is the concentration, 'k' is the dissolution rate constant, 'SA' is the surface area, 'V' is the volume, and 'f' is the flow rate.

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Parabola to Straight Line

The concentration profile during drug dissolution under sink conditions initially follows a parabola curve. Once all the solid drug is wetted, it transitions to a straight line.

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Time for Complete Wetting (t₁)

t₁ = (A-(1/2V))·(1/f) - This equation calculates the time it takes for the entire solid drug to become wetted during dissolution.

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Drug Release: Liberation

The process of bringing a drug into solution at the site of absorption. It's crucial for drug absorption, as the drug must be dissolved to be absorbed.

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Dissolution Rate Test

A laboratory method used to measure how fast a drug dissolves from a dosage form. It's important for evaluating drug performance.

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Apparent Absorption Rate

The rate at which a drug appears to be absorbed. However, it may actually be influenced by the rate of drug release from the dosage form.

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Dissolution as the Limiting Step

When a drug's dissolution rate is slower than its absorption rate, the dissolution becomes the rate-limiting step for overall drug absorption. This affects bioavailability.

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Study Notes

Physicochemical Factors Altering Biological Performance of Drugs

  • Particle size is important for drugs with low solubility in fluids like stomach or intestinal fluids.
  • If the solubility is less than 0.3% (or 0.5% according to FDA guidelines), particle size significantly impacts the dissolution rate.
  • Smaller particle size increases surface area exposed to dissolution media, increasing dissolution rate.
  • However, particle size reduction does not significantly alter actual drug solubility within the typical pharmaceutical manufacturing range (1-10 µm).

Co-Solutes and Complex Formation

  • Co-solutes are only important for drugs with low solubility.
  • Salting-out occurs when adding electrolytes to solutions of organic nonelectrolytes, causing precipitation of the nonelectrolyte.
  • Salting-in is when salts of organic acids/organic-substituted ammonium salts are added to nonelectrolyte solutions, improving solubility.
  • Clathrates form when a substance forms channels/cages to incorporate another substance, enhancing the substance's hydrophilicity.
  • Examples of clathrate-forming substances are gallic acid, urea, thiourea, amylose, and zeolite.
  • Drugs used in clathrates include vitamin A, sulfathiazole, chloramphenicol, and reserpine.

Chemical Variations

  • Chemical modifications are used to change the structure of the drug to improve its pharmacologic response or maintain its basic structure while altering its solubility.
  • Salts, esters, ethers, or complexes can be formed.

Solid Dispersion

  • Solid dispersion solutions involve dissolving a drug in a carrier material, such as mannitol or succinic acid.
  • If a carrier dissolves readily in water, the drug becomes readily accessible.

Polymorphism

  • Polymorphism refers to the ability of a drug to exist in different crystalline forms (polymorphs).
  • Stable forms have high stability but low dissolution rates; metastable forms have high dissolution rates but low stability.
  • An example is chloramphenicol palmitate which exists in 3 polymorphs, only one of which is biologically active.

Viscosity

  • Increasing viscosity prolongs the time taken for solvent molecules to reach the surface of solids.
  • Increasing viscosity of gastrointestinal contents slows dissolution and absorption of certain drugs (e.g., ethanol, salicylic acid).

Solubilizing Agents

  • Solubilizing agents (surfactants) are amphiphilic compounds enhancing solubility of drugs with low solubility.
  • Drug solubilization occurs via micelle formation (aggregates of 50-150 molecules).
  • Examples of drugs with improved bioavailability using solubilizing agents are vitamin A, cephaloridine, heparin, riboflavin, salicylamide, spironolactone, and sulfisoxazole

Manufacturing Factors

  • Manufacturing operations like increased compression force, addition of binders, or increasing amount of lubricants can increase tablet hardness and decrease disintegration/dissolution time.
  • High temperatures during compression can cause drug aggregation.

Dissolution

  • The dissolution rate of a drug in a medium follows a cube root law; exponential decay of mass dissolved versus time applies in nonsink conditions.
  • A lag time (t₁) is often present due to interfacial phenomena (wetting of solid surfaces).
  • The dissolution rate is particularly affected by the wetting property of the drug.

Pediatric Pharmacokinetics

  • Physiological development influences drug disposition (e.g., absorption, distribution, metabolism, excretion).
  • Age-dependent differences exist in GI function (e.g., gastric pH, motility, intestinal surface area), protein binding, and drug metabolism.

Renal Drug Excretion

  • The kidney is anatomically and functionally immature at birth, affecting drug excretion.
  • Glomerular filtration rate (GFR) increases postnatally, particularly within the first two weeks post-birth.

Drug Monitoring and Dose Adjustment

  • Therapeutic drug monitoring (TDM) monitors blood drug levels to adjust dosage regimes and maintain desired drug concentrations.
  • Adjusting for drugs with saturation kinetics involves calculations considering Michaelis-Menten kinetics parameters: rate constant, Michaelis-Menten constant, and maximum rate of metabolism.

Correlation of Clinical Response with Drug Disposition

  • Models to correlate the pharmacological/clinical response with drug disposition have been developed.
  • Models are categorized into Fixed-Effect, Linear, Log-Linear, and Nonlinear models; and the Pharmacodynamic-Pharmacokinetic models (Central Compartment or Tissue Compartment models).
  • Various methods for calculating or predicting the relationship between drug concentration and responses have also been described.

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Explore the physicochemical factors that influence the biological performance of drugs, including the significance of particle size and the role of co-solutes. This quiz covers how these factors affect drug solubility and dissolution rates, essential in pharmaceutical manufacturing.

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