Chapter 15: Biopharmaceutic Considerations In Drug Product Design and In Vitro Drug Product Performance

Which of the following represents the correct sequence of events for the absorption process of an immediate-release tablet from ingestion to appearance in plasma?

Disintegration → Dissolution → Absorption

For an immediate-release tablet, which step directly controls how fast the drug becomes available for absorption?

Dissolution

Which of the following is NOT exempt from USP disintegration testing?

Immediate-release tablets

When any residue, except fragments of insoluble coating, has no palpably firm core is the __________ test.

Disintegration

Which of the following are the two most common dissolution test apparatuses?

Apparatus 1 (Basket) and Apparatus 2 (Paddle)

According to the Biopharmaceutics Classification System (BCS), which class of drugs has high solubility and high permeability?

Class I

Which BCS class of drugs is characterized by low solubility but high permeability, and often requires formulation strategies to improve dissolution?

Class II

Which BCS class of drugs has high solubility but low permeability, meaning absorption is limited by the ability of the drug to cross biological membranes?

Class III

Which BCS class of drugs exhibits both low solubility and low permeability, making them the most difficult to formulate for effective oral absorption?

Class IV

BCS Class II drugs require strategies to enhance permeation because their permeability is low.

False

BCS Class I drugs are highly soluble and highly permeable, and therefore are expected to have excellent oral absorption.

True

BCS Class II drugs are limited by their rate of dissolution due to low solubility.

True

Which equation describes the rate of dissolution of an immediate-release tablet in a solvent?

Noyes-Whitney equation

According to the Noyes-Whitney equation, the rate of dissolution is directly proportional to which variable?

Surface area (A)

In the Noyes-Whitney equation, if the surface area of the drug particles increases, what happens to the rate of dissolution?

increases

In the Noyes-Whitney equation, the rate of dissolution is inversely proportional to which factor?

Thickness of the diffusion layer (h)

If the difference between the saturation concentration (Cs) and the bulk concentration (C) increases, what happens to the dissolution rate?

increases

The greater the solubility, the _______ dissolution rate.

Faster

Which type of transport is the Noyes-Whitney equation describing?

Passive diffusion

Which physicochemical property describes how well a drug dissolves in an aqueous medium such as intestinal fluid?

Drug solubility

Decreasing the particle size of a poorly soluble drug _______ the dissolution rate.

increases

Increasing the particle size of a poorly soluble drug _______ the dissolution rate.

decreases

Which BCS class would benefit from decreasing the particle size to increase the surface area?

Class II

Which form of a drug is not in a crystalline state?

Amorphous form

Which crystalline form of a drug has charges due to ionization?

Salt form

Which crystalline form of a drug can exist in multiple structural arrangements while remaining chemically identical?

Polymorph form

Total solubility for a weak acid increases with ________ pH.

Higher

Total solubility for a weak acid decreases with ________ pH.

Lower

Total solubility for a weak base increases with ________ pH.

Lower

Total solubility for a weak base decreases with ________ pH.

Higher

The soluble salt form of a weak acid dissolves _______ than the corresponding free acid (neutral form).

Faster

The soluble salt form of a weak base dissolves _______ than the corresponding free base (neutral form).

Faster

Increased solubility _______ dissolution rate.

Increases

Rate of dissolution of a weak acid increases with a _________ in pH and _______ in H⁺.

Increase in pH and decrease in H⁺

Rate of dissolution of a weak base increases with a _________ in pH and _______ in H⁺.

Decrease in pH and increase in H⁺

Ionized weak acid [A⁻] dissolves ______ than neutral [HA].

Faster

Ionized weak base [BH⁺] dissolves ______ than neutral [B].

Faster

Both solvates and hydrates involve the incorporation of solvent molecules into the crystalline lattice.

True

An amorphous solid has _______ free energy than its corresponding crystalline solid.

Higher

Because an amorphous solid has higher free energy than a crystalline solid, it also has _______ apparent solubility an dissolution rate.

Higher

Reduction in particle size _______ surface area.

Increases

Increase in surface area _______ dissolution rate.

Increases

Which of the following crystalline forms typically has the higher solubility?

Amorphous form

According to the Biopharmaceutics Classification System (BCS), a drug is considered highly soluble when the highest dose strength dissolves in _______ mL or less of aqueous media within a pH range of 1-6.8 at 37 ± 1 °C.

250 mL

A drug is considered highly permeable when the systemic bioavailability or extent of absorption in humans is _______ or more of the administered dose.

85%

A drug is considered highly permeable when its absorption in humans is less than 50% of the administered dose.

False

Instead of human studies, researchers can use in vitro permeability predictor models such as _______ cells to estimate drug permeability.

Caco-2

Which of the following is commonly used as a reference compound for high permeability in the Biopharmaceutics Classification System (BCS)?

Metoprolol

Which BCS class do we want to improve dissolution to enhance oral absorption?

Class II

Which BCS class requires no major challenges for oral absorption because it has both high solubility and high permeability?

Class I

Which BCS class often requires the use of prodrugs or permeation enhancers to improve absorption?

Class III

Which BCS class is typically not feasible for oral administration and is often given intravenously (IV)?

Class IV

Which of the following excipients is specifically used in immediate-release tablets to facilitate tablet breakup and drug release?

Disintegrant

Which of the following excipients is specifically used in extended-release tablets to modify or slow drug release?

Drug release-modifying agent

Which of the following is a common disintegrant used in immediate-release tablets?

Croscarmellose sodium

Which of the following is a common lubricant used to reduce friction during tablet manufacturing?

Magnesium stearate

Which of the following is a common drug release-modifying agent used in extended-release formulations?

Methocel K4MP

Which of the following is a common binder used to help powders form granules during tablet manufacturing?

Methocel E5 PLV

Which of the following are common fillers used to increase tablet volume or weight?

Fast Flo lactose and microcrystalline cellulose

Which of the following excipients increases Ka (absorption rate), decreases Tmax (occurs earlier), and increases AUC?

Disintegrant

Disintegrants _______ Ka (absorption rate), _______ Tmax, and _______ AUC.

Increase, decrease, increase

All other excipients besides disintegrants _______ Ka (absorption rate), _______ Tmax, and _______ AUC.

Decrease, increase, decrease

Which type of formulation experiences flip-flop kinetics, where Ka < K?

Extended-release formulation

Which formulation experiences delayed dissolution in the intestines where the pH is higher?

Enteric-coated formulation

Lubricants can _______ drug dissolution in solution.

Decrease

Enteric tablet coatings require _______ media to dissolve.

Basic

Diluents ________ dissolution and ____________ bioavailability.

Increase, increase

Magnesium stearate can coat particles and _______ dissolution when overmixed under high shear or temperature.

decrease

Over-lubrication with magnesium stearate can lead to _______ dissolution and _______ tablet strength.

Slow, decreased

Which type of formulation requires a basic medium to dissolve and is typically used to protect acid-sensitive active agents from gastric acidity?

Enteric-coated formulation

Which type of formulation can protect the stomach lining from direct contact with irritating active agents?

Enteric-coated formulation

Which equation explains dissolution for sustained drug release?

Higuchi equation

Which equation explains dissolution for immediate-release drugs?

Noyes-Whitney equation

Which equation uses the square root of time to describe dissolution?

Higuchi equation

Which equation uses the first order of time to describe dissolution?

Noyes-Whitney equation

In dissolution testing, Apparatus 1 (basket) is the most frequently used method.

False

In dissolution testing, Apparatus 2 (paddle) is the most frequently used method.

True

Apparatus 2 (paddle) is less commonly used than Apparatus 1 (basket) in dissolution testing.

False

Which calibrator tablet represents a rapidly disintegrating immediate-release formulation?

Prednisone

Which calibrator tablet represents a non-disintegrating sustained-release formulation?

Salicylic acid

Which of the following is FALSE about a dissolution test?

Dissolution tests should vary each day to account for environmental changes

If two dissolution profiles have an f₂ value between 50 and 100, they are considered _______.

Similar

If two dissolution profiles have an f₂ value between 0 and 50, they are considered _______.

Different

An f₂ value of 70 indicates that two dissolution profiles are considered similar.

True

Which model-independent method is used to determine whether two dissolution profiles are similar or different?

Similarity factor (f₂)

In vitro-in vivo correlation (IVIVC) links the drug's plasma concentration profile to its dissolution rate.

True

What establishes a relationship between the clinical relevancy of the drug (plasma level) and a physicochemical property of the drug product, such as dissolution rate?

In vitro-in vivo correlation (IVIVC)

Which pharmacokinetic (PK) parameters are most often used in IVIVC correlation with the in vitro dissolution profile?

Plasma concentration, AUC, and Cmax

Which of the following is FALSE about in vitro-in vivo correlation (IVIVC) in drug development?

IVIVC eliminates the need for all in vivo studies

Which category of in vitro-in vivo correlation (IVIVC) is a predictive mathematical model for the relationship between the entire in vitro release time course and the entire in vivo response time course?

Level A

Which category of in vitro-in vivo correlation (IVIVC) is a predictive mathematical model for the relationship between summary parameters that characterize the in vitro and in vivo time courses?

Level B

Which category of in vitro-in vivo correlation (IVIVC) matches this example: models that relate the mean in vitro dissolution time to the mean in vivo dissolution time?

Level B

Which formulation is the in vitro-in vivo correlation (IVIVC) typically used to compare?

Sustained-release formulations

What is the rate-limiting step in the drug absorption of a sustained-release tablet?

Dissolution

When the dissolution rate is the rate-limiting step, it is often possible to establish a correlation between the rate of dissolution and the rate of absorption.

True

Which formulation type is most likely to have a correlation between dissolution rate and absorption rate?

Sustained-release formulation

If absorption is faster than dissolution, the dissolution rate has little effect on plasma drug levels.

False

In sustained-release formulations, the rate of absorption is typically limited by the rate of dissolution or release of the drug.

True

Which of the following correctly states when the IVIVC method can be used?

When the dissolution is the rate-limiting step in drug absorption

In a Level A IVIVC, Step 1 involves calculating the fraction of drug absorbed in vivo over time.

True