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.

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

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

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

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

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

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

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. Signup and view all the answers

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

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

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

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

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

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

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

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

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

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

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

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

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

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. Signup and view all the answers

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

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

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

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. Signup and view all the answers

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

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

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

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. Signup and view all the answers

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

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

How do esters of chloramphenicol behave in the gastrointestinal tract?

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

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

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

Why are chemical variations of drugs important in pharmacology?

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

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

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

How does the formation of complexes influence drug solubility?

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

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

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

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

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

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

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

How do pharmacotechnical factors influence the biological performance of drugs?

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

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

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

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

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

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

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

What factors contribute to absorption difficulties in drug delivery?

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

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

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

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

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

Define hydrates and solvates in the context of drug formulation.

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

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

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

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

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

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

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

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

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

What issues can arise from temperature increases during tablet compression?

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

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

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

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

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. Signup and view all the answers

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

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

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

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

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

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

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

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

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

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

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

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

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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Description

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.