Biopharmaceutics

Dr Suryaprakash Reddy C

Professor of Pharmaceutics

Annamacharya College of Pharmacy, Rajampet, AP, India

suryaprakashreddyc@gmail.com

Disclaimer

This presentation is prepared and delivered for educational purpose

only and not involved any commercial interests. The contents in this

presentation are compiled from various resources. Thus, presenter

shall not claim any copyright for this presentation and not responsible

for any copyright issues if arise.

Introduction

Biopharmaceutics

• It is the study of the relation of the physical and chemicalproperties of a drug to its bioavailability, pharmacokinetics, andpharmacodynamics and toxicological effects

1. A drug product is the finished dosage form (eg., tablet, capsule,suspension etc.) that contains the API in addition with nondrugingredients (excipients) that make up vehicle or formulationmatrix.

2. The Drug delivery system includes the formulation and thedynamic interactions among the drug, its formulation matrix, itscontainer and the patient

3. Bioavailability is a measurement of the rate and extent (amount)of systemic absorption of the therapeutically active drug.

Pharmacokinetics

• It is the study of the time course of drug movement in the bodyduring absorption, distribution and elimination (excretion andbiotransformation)

Pharmacodynamics

• It is the study of the relation of the drug concentration oramount at the site of action (receptor) and its pharmacologicresponse as a function of time.

Drug transport and Absorption

Drug transport and Absorption

• When drug molecules pass through the GIT, they encounterdifferent environments with respect to the pH, enzymes,electrolytes, surface characteristics, and viscosity of thegastrointestinal fluids

Features of the gastrointestinal tract

• Abundant blood supply

• Lined with mucous membrane through which drugs may bereadily transferred into the general circulation.

• The interior surface of the stomach is relatively smooth

• The small intestine presents numerous folds and projections

• 8–10 L per day of fluids are produced or secreted into thegastrointestinal tract and an additional 1–2 L of fluid is obtainedvia food and fluid intake

• Highly perfused by a capillary network

Important features of the stomach

• Contents are in the pH range 1–3.5, with a pH of 1–2.5

• The squeezing action of the stomach produces a mild butthorough agitation of the gastric contents

• A dosage form (tablet, capsule, etc.) may remain in the stomachfor approximately 0.5–2 h prior to moving to the pylorus and tothe duodenum(rapid on the fasting stomach or very slow if takenwith heavy high-fat meal)

Important features of the duodenum

• Drugs are subjected to a drastic change of pH (pH range 5–7)

• Drugs will encounter additional enzymes that were not presentearlier (in the stomach)

• The duodenum, jejunum, and upper region of the ileum providethe most efficient areas in the gastrointestinal tract for drugabsorption

• The occurrence of villi presents a large surface area for thetransport of drug molecules into the systemic circulation(absorption)

• The capillary network in the villi and microvilli is the primarypathway by which most drugs reach the circulation.

General principles

• A cell membrane is a semipermeable structure composedprimarily of lipids and proteins

• Drugs may be transported by passive diffusion, partitioning,carrier-mediated transport, Para cellular transport, or vesiculartransport

• Usually, proteins, drugs bound to proteins, and macromolecules donot easily cross cell membranes

• Nonpolar lipid-soluble drugs traverse cell membranes more easilythan do ionic or polar water-soluble drugs

• Low-molecular-weight drugs diffuse across a cell membrane moreeasily than do high molecular-weight drugs

Passive diffusion and partitioning

• Within the cytoplasm or in interstitial fluid, most drugs undergo

transport by simple diffusion

• It involves the transfer of drugs from an area of highconcentration (C1) to an area of lower concentration (C2)according to Fick’s law of diffusion:

• Passive drug transport across cell membranes involves thesuccessive partitioning of a solute between aqueous and lipidphases as well as diffusion within the respective phases

• Modified Fick’s law (including partition):

• Ionization of a weak electrolyte is affected by the pH of themedium in which the drug is dissolved as well as by the pKa of thedrug. The non ionized species is more lipid soluble than the ionizedspecies, and it partitions more readily across cell membranes

Carrier-mediated transport

Active transport

• It is the passage of the drug across a membrane by carrier-mediated process

1. The drug moves against a concentration gradient

2. The process requires energy

3. The carrier may be selective for certain types of drugs thatresemble natural substrates or metabolites that are normallyactively transported

4. The carrier system may be saturated at a high drug concentration

5. The process may be competitive (i.e., drugs with similarstructures may compete for the same carrier)

Facilitated diffusion

• It is also a carrier-mediated transport system. However,facilitated diffusion occurs with (i.e., in the direction of) aconcentration gradient and does not require energy

Paracellular transport

• Drug transport across tight (narrow) junctions between cells ortrans endothelial channels of cells is known as paracellulartransport

• It involves both diffusion and the convective (bulk) flow of waterand accompanying water-soluble drug molecules through theparacellular channels

Vesicular transport

• It is the process of engulfing particles or dissolved materials by acell

• Vesicular transport is the only transport mechanism that does notrequire a drug to be in an aqueous solution to be absorbed

• Endocytosis and exocytosis are the movement of macromoleculesinto and out of the cell, respectively

a. Pinocytosis is the engulfment of small solute or fluid volumes

b. Phagocytosis is the engulfment of larger particles, ormacromolecules, generally by macrophages

Other transport mechanisms

Transporter proteins

• Various transporter proteins (e.g.,P-glycoprotein) are embedded inthe lipid bilayer of cell membranes

• These proteins are ATP (energy) dependent “pumps,” which canfacilitate the efflux of drug molecules from the cell and are foundin conjunction with metabolizing enzymes such as cytochromeP450 3A4

• Their net effect is to reduce intracellular drug concentrations

• Thus they determine, the pharmacokinetic disposition andcirculating plasma concentrations of drugs (e.g., cyclosporine,nifedipine, digoxin) that are substrates for these proteins.

Time for recap

1. Which statement best describes bioavailability?

A. Relation between the physical and the chemical properties of adrug and its systemic absorption

B. Measurement of the rate and amount of therapeutically activedrug that reaches the systemic circulation

C. Movement of the drug into body tissues over time

D. Dissolution of the drug in the gastrointestinal tract

E. Amount of drug destroyed by the liver before systemic absorptionfrom the gastrointestinal tract occurs

ANS is B

2. After per oral administration, drugs generally are absorbed bestfrom the

A. Stomach

B. Duodenum

C. Ileum

D. Rectum

Ans is B

3. The passage of drug molecules from a region of high drugconcentration to a region of low drug concentration is known as

A. Active transport

B. Bioavailability

C. Biopharmaceutics

D. Simple diffusion

E. Pinocytosis

Ans is D

4. The characteristics of an active transport process include all ofthe following except for which one?

A. Active transport moves drug molecules against a concentrationgradient

B. Active transport follows Fick’s law of diffusion

C. Active transport is a carrier-mediated transport system

D. Active transport requires energy

E. Active transport of drug molecules may be saturated at high drugconcentrations

Ans is B

5. The route of drug administration that provides complete (100%)bioavailability is

A. Intramuscular injection

B. Intravenous injection

C. Intradermal injection

D. Per oral administration

E. Subcutaneous injection

Ans is B

6. The in vivo sink condition according to fick’s first law of diffusionis

A. Concentration at the absorbing membrane Cb >> concentration atthe serosal site Cs

B. Cs > Cb

C. Cs < Cb

D. None of the above

Ans is A

7. If C is the concentration of dissolved drug and Cs is thesaturation concentration. In which case, the sink conditions aresaid to be maintained?

A. C < 20% of Cs

B. C > 20% of Cs

C. C < 10% of Cs

D. C >10% of Cs

Ans is C

Factors affecting Drug Absorption

Physicochemical properties

Drug dissolution

• For most drugs with limited water solubility, the rate at whichthe solid drug enters into solution (i.e., the rate of dissolution) isthe rate-limiting step in bioavailability. (Dissolution rate limited)

• The Noyes–Whitney equation describes the diffusion-controlledrate of drug dissolution

• It is the mass transfer from surface of the solid to bulk solution

• Various models/theories which explain dissolution:

1. Diffusion layer model/Film theory

2. Dankwert’s Model (Penetration or Surface renewal theory)

3. Interfacial barrier model (Double Barrier Mechanism OR LimitedSolvation Theory)

Types of Models of Mechanism of Drug Release

• Zero order

• First order

• Higuchi model

• Korsemeyer-Peppas Model

• Hixon-Crowel plot

Interpretation of Dissolution Profile Comparison

• Moore and Flanner proposed a model independent mathematicalapproach to compare the dissolution profiles

1. Similarity factor (f2)

• The value ranges from 0 to 100

• ≥50 considered similar

• 100 – the profiles are Identical

2. Difference factor (f1)

• The value ranges from 0 to 15

• ≤15 indicates similarity

• =15 Profiles are identical

Official dissolution Apparatus

According to IP

1. Paddle Apparatus

2. Basket apparatus

According to BP

1. Basket Apparatus

2. Paddle apparatus

3. Flow Through Cell Apparatus

According to USP

1. Basket apparatus (IR,DR,ER)

2. Paddle apparatus (IR,DR,ER)

3. Reciprocating Cylinder (IR, ER)

4. Flow through cell apparatus (ER, poorly soluble API)

5. Paddle over disk apparatus (transdermal)

6. Cylinder apparatus (transdermal)

7. Reciprocating holder apparatus (ER)

Biopharmaceutical Classification System (BCS)

Amidon et al

• Class I - High soluble and High Permeable

• Class II – Low soluble and High permeable

• Class III – High soluble and Low permeable

• Class IV – Low soluble Low permeable

Class Boundaries of BCS

• Highly soluble when the highest dose strength is soluble in < 250 ml

water over a pH range of 1 to 7.5

• Highly permeable when the extent of absorption in humans isdetermined to be > 90% of an administered dose

• IR drug product is considered rapidly dissolving when no less than85% of the labeled amount of the drug substance dissolves within 30minutes, using U.S. Pharmacopeias (USP) Apparatus I at 100 rpm (orApparatus II at 50 rpm) in a volume of 900 ml or less in each of thefollowing media

i. 0.1 N HCl or Simulated Gastric Fluid USP without enzymes

ii. A pH 4.5 buffer

iii. a pH 6.8 buffer or Simulated Intestinal Fluid USP without enzymes

Drug solubility

• The concentration of drug in a saturated solution

• It is a static (equilibrium) property

• Whereas the dissolution rate of a drug is a dynamic propertyrelated to the rate of absorption

Particle size and surface area

• These are inversely related in a given mass of the substance

• As solid drug particle size decreases, particle surface areaincreases in given equal mass of both

• According to Noyes–Whitney equation the dissolution rate isdirectly proportional to the surface area

• With certain hydrophobic drugs, excessive particle size reductiondoes not always increase the dissolution rate instead it decreasesdissolution rate (reaggregation, air entrapment, chargegeneration)

• To prevent the formation of aggregates, small drug particles aremolecularly dispersed in polyethylene glycol (PEG),polyvinylpyrrolidone (PVP; povidone), dextrose, or other agents

Partition coefficient and extent of ionization

Partition coefficient

• It is the ratio of the solubility of the drug, at equilibrium, in a

non aqueous solvent (e.g., n-octanol) to that in an aqueous

solvent (e.g., water; pH 7.4 buffer solution)

• This value dictates the nature of drug, Hydrophilic or lipophilic

• More the value more lipophilic, less the value more hydrophilic

• Balance between hydrophilicity and lipophilicity essential forbetter Absorption (HLB)

• Hydrophilic drugs with higher water solubility have a fasterdissolution rate than do hydrophobic or lipophilic drugs

Extent of ionization

• The drugs (acidic/basic) exist in both ionized from and unionizedform in solution

• The extent of ionization/unionization depends on:

i. pKa of the drug or electrolyte

ii. pH of the environment/solution

• The ionized form is more polar, and therefore more water soluble,than the nonionized form

• The Henderson–Hasselbalch equation describes the relationbetween the ionized and the nonionized forms of a drug as afunction of pH and pKa

For weak acids

For weak bases

𝐩𝐇 = 𝐩𝐊𝐚 + log (𝐢𝐨𝐧𝐢𝐳𝐞𝐝)

(𝐮𝐧𝐢𝐨𝐧𝐢𝐳𝐞𝐝)

𝐩𝐇 = 𝐩𝐊𝐚 + log (𝐮𝐧𝐢𝐨𝐧𝐢𝐳𝐞𝐝)

(𝐢𝐨𝐧𝐢𝐳𝐞𝐝)

Salt formation

• While considering the salt form of drug, pH of the diffusion layeris important not the pH of the bulk of the solution

• Salt of weak acid - It increases the pH of the diffusion layer,which promotes the solubility and dissolution of a weak acid andabsorption is bound to be rapid

• A solid dosage form containing buffering agents may beformulated with the free acid form of the drug (e.g., bufferedaspirin)

a. The buffering agent forms an alkaline medium in thegastrointestinal tract, and the drug dissolves in situ

b. The dissolved salt form of the drug diff uses into the bulk fluid ofthe gastrointestinal tract, forms a fi ne precipitate thatredissolves rapidly, and becomes available for absorption

Time to Recap1. Which one of the following physicochemical properties is moreimportant for passive diffusion of drugs from the gastrointestinaltract?

A. Dissolution constant

B. Lipid solubility

C. Partition coefficient

D. pH of the gastrointestinal fluids

Ans is C

2. If the pKa of phenobarbitone is 7.4, what fraction of drug wouldbe ionized at pH 8.4?

A. 0.01

B. 0.5

C. 0.9

D. 0.1

..\Henderson.jpeg

Ans is C

3. The applicability of Noyes-Whitney equation is to describe the

A. First-order kinetics

B. Zero-order kinetics

C. Mixed-order kinetics

D. Dissolution rate

Ans is D

4. Which equation describes the rate of drug dissolution from atablet?

A. Henderson–Hasselbalch equation

B. Law of mass action

C. Michaelis–Menten equation

D. Noyes–Whitney equation

Ans is D

5. Which condition usually increases the rate of drug dissolutionfrom a tablet?

A. increase in the particle size of the drug

B. decrease in the surface area of the drug

C. use of the free acid or free base form of the drug

D. use of the ionized, or salt, form of the drug

Ans is D

6. The extent of ionization of a weak electrolyte drug depends onthe

A. pH of the media and pKa of the drug

B. oil to water partition coefficient of the drug

C. particle size and surface area of the drug

D. Noyes–Whitney equation for the drug

Ans is A

7. The rate-limiting step in the bioavailability of a lipid soluble drugformulated as an immediate-release compressed tablet is the rateof

A. disintegration of the tablet and release of the drug

B. dissolution of the drug

C. transport of the drug molecules across the intestinal mucosal cells

D. blood flow to the gastrointestinal tract

Ans is B

8. The relation between rate of diffusion and concentrationgradient across the barrier is

A. Inversely proportional

B. Directly proportional

C. log linear

D. Exponential

Ans is B

9. How many dissolution apparatus are official in USP

A. 3

B. 5

C. 7

D. 6

Ans is C

10. According to BCS Classification, drug with low permeability &high solubility are classified as

A. class 1

B. class 2

C. class 3

D. class 4

Ans is C

11. A drug whose solubility is 1 g/L in water, when given orally at adose of 500 mg is absorbed upto 95% of the administered dose.The drug belongs to which class according to the BCSclassification?

A. Class I

B. Class II

C. Class III

D. Class IV

Ans is B