1. Biopharmaceutics & Pharmacokinetics
Course Instructor
Betty Philip

2. Chapter Content
Introduction to :
Biopharmaceutics
Bioavailability

3. Learning outcome
At the end of this chapter, the students shall be able to
Understand concepts of Biopharmaceutics and bioavailability

4. Biopharmaceutics
Biopharmaceutics is defined as the study of factors influencing the rate and the amount of drug that reaches the systemic circulation and the use of this information to optimize the therapeutic efficacy of the drug products.
Thus, Biopharmaceutics involves factors that influence the:
1) protection and stability of the drug within the product
2) the rate of drug release from the product
3) the rate of dissolution of the drug at the absorption site

5. Why study Biopharmaceutics
Drugs obtained from plant, animal or mineral sources or synthesized chemically, are rarely administered in their pure or chemical form.
Often they are combined with a number of inert substances (excipients/adjuvants) and transformed into a convenient dosage form that can be administered by a suitable route.
Variations are also observed when the same drug is administered as different dosage forms or similar dosage forms produced by different manufacturers,

6. the excipients present in the dosage form, the method of formulation and the manner of administration.
Therefore, Biopharmaceutics has been developed to account for all such factors that influence the therapeutic effectiveness of a drug

7. Common terms
Absorption: The process of movement of drug from its site of administration to the systemic circulation is called absorption.
Bioavailability: The amount of drug that reaches the systemic circulation
Distribution : The movement of drug between one compartment to the other (generally blood and extra vascular tissue) is referred to as drug distribution.
Elimination: It is defined as the process that tends to remove the drug from the body and terminate its action.

8. Common terms Together they are known as dug disposition
Elimination occurs by two processes-
Biotransformation : which occurs usually inactivates the drug
Excretion: which is responsible for the exit of drug/ metabolites from the body.

9. Common terms
Pharmacokinetics: Pharmacokinetics is defined as the study of time course of drug ADME and their relationship with its therapeutic and toxic effects of the drug.
The use of pharmacokinetic principles in optimizing the drug dosage to suit individual patient needs and achieving maximum therapeutic utility is called Clinical Pharmacokinetics.

10. Drug administration and therapy can be conveniently divided into 4 phases of processes:
The Pharmaceutic process: It is concerned with the formulation of an effective dosage form of the drug for administration by a suitable route.
The Pharmacokinetic process: It is concerned with the ADME of drugs as elicited by the plasma drug concentration- time profile and its relationship with the dose, dosage form and frequency and route of administration.

11. The Pharmacodynamic process: It is concerned with the biochemical and physiologic effects of the drug and its mechanism of action. Pharmacodynamics deals with what drug does to the body in contrast to pharmacokinetics which is a study of what the body does to the drug.
Therapeutic process: It is concerned with the translation of pharmacologic effect in to clinical benefit.

13. To achieve optimal therapy with a drug, the drug product must be designed to deliver the active principle at an optimal rate and amount, depending upon the patient’s needs.
The rational use of the drug or the therapeutic objective can only be achieved through a better understanding of pharmacokinetics (in addition to pharmacodynamics of the drug), which helps in designing a proper dosage regimen.

14. Thus the knowledge and concepts of biopharmaceutics and pharmacokinetics thus have an integral role in the design and development of new drugs and their dosage forms and improvement of therapeutic efficacy of existing drugs.

15. Chapter content Gastrointestinal drug absorption
Mechanism of absorption

16. Learning Outcome
At the end of this chapter, the students shall be able to
Apply the concepts of GI drug absorption
Discuss various mechanisms of drug absorption

17. ABSORPTION OF DRUGS
A drug injected intravascularly directly enters the systemic circulation and exerts its pharmacologic effects.
However, majority of the drugs are administered extravascularly, generally by oral route.
If intended to act systemically, such drugs can exert their pharmacologic actions only when they come into blood circulation from the site of application, and for this, absorption is an important prerequisite

18. Drug absorption is defined as the process of movement of unchanged drug from the site of administration to systemic circulation.
Drugs that have to enter the systemic circulation to exert their effect can be administered by three major routes:
The Enteral Route
Includes  peroral i.e. gastrointestinal, sublingual/buccal and rectal routes. The GI route is the most common for administration of majority of drugs.

19. The Parenteral Route
Includes all routes of administration through or under one or more layers of skin. While no absorption is required when the drug is administered i.v., it is necessary for extravascular  parenteral routes like the subcutaneous and the intramuscular routes.
The Topical Route
Includes skin, eyes or other specific membranes.

20. GASTROINTESTINAL ABSORPTION OF DRUGS
The oral route of drug administration is the most common for systemically acting drugs.
Cell Membrane: Structure and Physiology
For a drug to be absorbed and distributed into organs and tissues and eliminated from the body, it must pass through one or more biological membranes/barriers at various locations.
Such a movement of drug across the membrane is called as drug transport

22. The cellular membrane consists of a double layer of amphiphilic phospholipid molecules arranged in such a fashion that their hydrocarbon chains are oriented inwards to form the hydrophobic or lipophilic phase and their polar heads oriented to form the outer hydrophilic boundaries of the cellular membrane that face the surrounding aqueous environment.
Globular protein molecules are associated on either side of these hydrophilic boundaries and also interspersed within the membrane structure.
The hydrophobic core of the membrane is responsible for the relative impermeability of polar molecules.

23. Aqueous filled pores or perforations of 4 to 10 Å in diameter are also present in the membrane structure through which inorganic ions and small organic water-soluble molecules like urea can pass.
The GI lining constituting the absorption barrier allows most nutrients like glucose, amino acids, fatty acids, vitamins, etc. to pass rapidly through it into the systemic circulation but prevents the entry of certain toxins and medicaments.
Thus, for a drug to get absorbed after oral administration, it must first pass through this biological barrier.

24. Mechanisms of Drug Absorption
The principal mechanisms for transport of drug molecules across the cell membranes in order of their importance are
Passive diffusion
Pore transport
Facilitated diffusion
Active transport
Ionic or electrochemical diffusion
Ion-pair transport
Endocytosis.

25. Passive Diffusion Also called nonionic diffusion
Major process for absorption (more than 90% of the drugs)
Driving force is the concentration or electrochemical gradient.
It is defined as the difference in the drug concentration on either side of the membrane
Drug movement is a result of the kinetic energy of molecules. Since no energy is required, the process is called as passive diffusion.

26. dQ =DAKm/w (C GIT –C ) dt h
Passive diffusion is best expressed by Fick’s law of diffusion, which states that the drug molecules diffuse from a region of higher concentration to one of lower concentration until equilibrium is attained and that the rate of diffusion is directly proportional to the concentration gradient across the membrane. It can be mathematically expressed by the equation:
dQ =DAKm/w (C GIT –C )
dt h

27. Where dQ = rate of drug diffusion (amount/time)dt
D = Diffusion coefficient of the drug through the membrane (area/time)
A= surface area of the absorbing membrane for drug diffusion.
Km/w = Partition coefficient of the drug between the lipoidal membrane and the aqueous GI fluids
(C GIT –C )= difference in the concentration of drug in the GI fluids and the plasma, called as the concentration gradient (amount/volume)
h=thickness of the membrane

28. Pore Transport
It is also called as convective transport, bulk flow or filtration.
The process is important in the absorption of low molecular weight (less than 100)
Low molecular size (smaller than the diameter of the pore) and generally water soluble drags through narrow, aqueous- filled channels or pores in the membrane structure – for example, urea, water and sugars.

29. Carrier-Mediated Transport
Some polar drugs cross the membrane more readily than can be predicted from their concentration gradient and partition coefficient values.
This suggests presence of specializes transport mechanisms without which many essential water-soluble nutrients like monosaccharide, amino acids and vitamins will be poorly absorbed.
The mechanisms is thought to involve a component of the membrane called as the carrier that binds reversibly or non- covalently with the solute molecules to be transported.

30. Two types of carrier- mediated transport systems have been identified
Two types of carrier- mediated transport systems have been identified. They are
Facilitated Diffusion
and
Active Diffusion

31. Facilitated Diffusion
It is a carrier –mediated transport system that operates down the concentration gradient (downhill transport) but at a much faster rate than simple passive diffusion.
The driving force is concentration gradient (hence a passive process)

32. Since no energy expenditure is involved , the process is not inhibited by metabolic poisons that interfere with energy production.
Facilitated diffusion is of limited importance in the absorption of drugs.
Examples of such a transport system include entry of glucose into RBCs and intestinal absorption of vitamins B1 and B2.

33. A classic example of passive facilitated diffusion is the GI absorption of vitamin B12. An intrinsic factor (IF), a glycoprotein produced by the gastric parietal cells, forms a complex with vitamin B12 which is then transported across the intestinal membrane by a carrier system.

34. Active transport
Active transport is a more important process than facilitated diffusion in the absorption of nutrients and drugs.
The drug is transported from a region of lower concentration to a region of higher concentration; uphill transport.
Since the process is uphill, energy is required in the work done by the carrier.
Endogenous substances that are transported actively include sodium, potassium, calcium etc.

36. Ionic or electrochemical diffusion
The charge on the membrane influences the permeation of drugs.
Molecular forms of solutes are unaffected by the membrane charge and permeate faster than ionic forms.
Of the ionic forms the anionic solutes permeate faster than the cationic forms.
Thus, at a given pH, the rate of permeation is in the following order:
Unionized molecules> anions> cations.

37. Ion-pair Transport
Quaternary ammonium compounds and sulphonic, which ionize under all pH conditions, is transported by ion-pair transport.
Despite their low o/w partition coefficient values, such agents penetrate the membrane by forming reversible neutral complexes with endogenous ions of the GIT like mucin.
Such neutral complexes have both the required lipophilicity as well as aqueous solubility for passive for passive diffusion. Such a phenomena is called as ion-pair transport.

38. Endocytosis (corpuscular or vesicular transport)
It is a minor transport mechanism which involves engulfing extra cellular material within a segment of the cell membrane to form a saccule or a vesicle which is then pinched off intracellularly.
This phenomena is responsible for the cellular intake of macromolecules nutrients like fats and starch, oil soluble vitamins like A, D, E and K and drugs such as insulin.

39. Endocytosis includes two types of processes:
Phagocytosis (cell eating) : Adsorptive uptake of solid particulates.
Pinocytosis (cell drinking) : Uptake of fluid solute.
Orally administered Sabin polio vaccine and large protein molecules are thought to be absorbed by Pinocytosis.

40. Chapter Content Factors affecting absorption of drugs
Physico-chemical and biological
Pharmaceutic
Patient

41. Learning Outcome
At the end of this chapter, the students shall be able to
Identify the physico-chemical and biological factors affecting absorption of drugs.
Identify the pharmaceutic and patient related factors affecting drug absorption.

42. Factors influencing GI absorption of a drug from its dosage form.
Pharmaceutical Factors:
Includes factors relating to the physiochemical properties of the drug, and dosage form characteristics and pharmaceutic ingredients.
Patient Related Factors:
Includes factors relating to the anatomic, physiologic and pathologic characteristics.

43. Pharmaceutical Factors
Physicochemical properties of the drug substances
Drug solubility and dissolution rate
Particle size and effective surface area
Polymorphism and Amorphism
Pseudo-polymorphism (hydrates/solvates)
Salt form of the drug
Lipophilicity of the drug
pKa of the drug and pH
Drug Stability

44. Dosage form characteristics and Pharmaceutic ingredients
Disintegration Time
Dissolution Time
Manufacturing Variables
Pharmaceutic ingredients
Nature and type of Dosage forms
Product age and storage conditions.

45. Patient related factors
Age
Gastric emptying time
Intestinal transit time
Gastrointestinal pH
Disease states
Blood flow through the GIT
Gastrointestinal contents
Other drugs

46. Other normal GI contents Presystemic metabolism by:
Food
Fluids
Other normal GI contents
Presystemic metabolism by:
Lumenal enzymes
Gut wall enzymes
Bacterial enzymes
Hepatic enzymes

47. Physicochemical factors affecting the drug absorption
Drug solubility and dissolution rate
Aqueous solubility has been recognized as an important physicochemical property in pharmaceutical sciences. The two critical slower rate-determining processes in the absorption of orally administered drugs are:
Rate of Dissolution
Rate of drug permeation through biomembrane

48. Dissolution is the RDS for hydrophobic poorly aqueous soluble drugs like gresiofulvin and spiranolactone; absorption of such drugs is often said to be dissolution- rate limited.
If the drug is hydrophilic with high aqueous solubility- for example cromolyn sodium or neomycin, then dissolution is rapid and the RDS in the absorption of such drugs is rate of permeation through the biomembrane. In other words, absorption of such drugs is said to be permeation limited or transmembrane rate - limited.

49. RDS for hydrophilic drug RDS for lipophilic drug
Drug in the body
Drug in solution
at the
Absorption site
Solid dosage
form
Solid drug
particles
Permeation
across the
biomembrane
Disintegration
Dissolution
Deaggregation
RDS for hydrophilic drug
RDS for lipophilic drug
Important prerequisite for the absorption of a drug by all mechanisms
except endocytosis is that it must be in aqueous solution.

50. The dissolution of drugs can be described by the modified Noyes-Whitney equation:
dC = DAKw/o (Cs – Cb )
dt Vh
Where,
D= diffusion coefficient of drug.
A= surface area of dissolving solid.
Kw/o= water/oil partition coefficient of drug.
V= volume of dissolution medium.
h= thickness of stagnant layer.
(Cs – Cb )= conc. gradient for diffusion of drug.

51. The factors that affect the rate of dissolution according to Noyes Whitney equation are:
diffusion coefficient,
surface area of the solute particle,
concentration of the solute particles at the boundary layer and
height of the boundary layer.
Noyes Whitney equation states that the rate of dissolution is directly proportional to the surface area of the solute particle, diffusion coefficient and the concentration of solute particles present at the boundary layer.

52. The higher the value of the diffusion coefficient, the greater the surface area and the more concentrated the solute particles at the boundary layers are, the higher the rate of dissolution.
On the other hand, according to the equation the height of the boundary layer is indirectly proportional to the rate of dissolution, so the lower the height the faster the rate of dissolution.

53. Particle size and effective surface area
Particle size and surface area are inversely related to each other.
As the particle size decreases, surface area increases which in turn increases the solubility and dissolution.
Two types of surface area –
Absolute surface area which is the total surface area of any particle.
Effective surface area which is the area of solid surface exposed to the dissolution medium.

54. Polymorphism and amorphism
When a substance exists in more than one crystalline form, the different forms are designated as polymorphs and the phenomenon as Polymorphism.
Polymorphs are of two types:
Enantiotropic polymorph: is the one which can be reversibly changed into another form by altering the temperature or pressure e.g. sulfur.
Monotropic polymorph : is the one which is unstable at all temperatures and pressures e.g. glyceryl stearates.
Polymorphs differ from each other with respect to their physical properties.
Their existence can be determined by using x- ray diffraction, DSC, etc

55. Stable polymorphs has lower energy state, higher M. P
Stable polymorphs has lower energy state, higher M.P. and least aqueous solubility.
Metastable polymorphs has higher energy state, lower M.P. and higher aqueous solubility.
Since the metastable forms have greater aqueous solubility, they show better bioavailability and therefore preferred in formulations.
Eg: Of the three forms of chloramphenical palmitate A,B and C, the B form shows best availability and the A form is virtually inactive.

56. Amorphous form of drug which has no internal crystal structure represents higher energy state and greater aqueous solubility than crystalline forms.
E.g.- amorphous form of novobiocin is 10 times more soluble than the crystalline form.
Thus, the order for dissolution of different solid forms of drug is –
amorphous > metastable > stable

57. Hydrates/solvates
The stoichiometric type of adducts where the solvent molecules are incorporated in the crystal lattice of the solid are called as the solvates, and the trapped solvent as solvent of crystallization.
The solvates can exist in different crystalline forms called as pseudomorphs. The phenomenon is called pseudomorphism.
When the solvent in association with the drug is water, the solvate is known as hydrates.

58. The anhydrous form of a drug has greater aqueous solubility than hydrates. This because the hydrates are already in interaction with water and therefore have less have less energy for break-up in comparison to the anhydrates.
The anhydrous form of theophylline and ampicillin have greater aqueous solubilities.
The organic solvates also have greater aqueous solubility than the nonsolvates.
E.g. – chloroform solvates of griseofulvin is more water soluble than their nonsolvated forms

59. Salt form of the drug
Dissolution rate of weak acids and weak bases can be enhanced by converting them into their salt form.
With weakly acidic drugs, a strong base salt is prepared like sodium and potassium salts of barbiturates and sulfonamides.
With weakly basic drugs, a strong acid salt is prepared like the hydrochloride or sulfate salts of alkaloidal drugs.

60. pH - Partition Theory
According to the pH-partition hypothesis, the gastrointestinal epithelia acts as a lipid barrier towards drugs which are absorbed by passive diffusion, and those that are lipid soluble will pass across the barrier.
The theory states that for drug compounds of molecular weight greater than 100 , which are primarily transported across the bio membrane by passive diffusion, the process of absorption is governed by:
The dissociation constant (pKa) of the drug
The lipid solubility of the unionized drug
The pH at the absorption site.

61. Since most drugs are weak electrolytes their degree of ionization depends upon the pH of the biological fluid. If the pH on either side on the membrane is different , then the compartment whose pH favours greater ionization of the drug will contain greater amount of drug, and only unionized or undissociated fraction of drug if sufficiently lipid soluble can permeate the membrane passively until the concentration of unionized drug on either side of the membrane becomes equal i.e. until equilibrium is attained.

62. Henderson - Hasselbach Equation - Weak Bases
The extent to which a weakly acidic or basic drug ionizes in solution in the gastrointestinal fluid may be calculated using Henderson - Hasselbach equation.
Henderson - Hasselbach Equation - Weak Bases

63. Limitations of the pH-partition hypothesis:
Despite their high degree of ionization, weak acids
are highly absorbed from the small intestine and
this may be due to:
The large surface area that is available for
absorption in the small intestine.
A longer small intestine residence time.
A microclimate pH, that exists on the surface of
intestinal mucosa and is lower than that of the
luminal pH of the small intestine

64. Drug stability
A drug for oral use may destabilize either during its shelf-life or in the GIT. Two major stability problems resulting in poor bioavailability of an orally administered drug are:
Degradation of the drug into active form
Interaction with one or more different components either of the dosage form or those present in the GIT to form a complex that is poorly soluble or is unabsorbable.

65. Dosage form characteristics and Pharmaceutic ingredients
Disintegration Time (Tablets /Capsules)
In-vitro disintegration test is by no means a guarantee of drug’s bioavailability because if the disintegrated particles do not dissolve, absorption is not possible.
If a solid dosage form does not confirm to the DT, it portends bioavailability problems because the subsequent process of dissolution will be much slower and absorption may be insufficient.
Coated tablets, especially sugar coated ones have long DT.

66. Rapid disintegration is thus important in the therapeutic success of a solid dosage form.
DT is directly related to the amount of binder present and the compression force of a tablet.
A harder tablet with larger amount of binder has a long DT.
After disintegration of a solid dosage form into granules, the granules must deaggregate into fine particles as dissolution from such tiny particles is faster than that from granules

67. Manufacturing / Processing variables
Several manufacturing processes influence drug dissolution .
Method of granulation
Compression force
The wet granulation process is the most conventional technique in the manufacture of tablets.
The method of direct compression has been utilized to yield tablets that dissolve at a faster rate.
Agglomerative phase of communition (APOC) is another method that results in superior product.

68. Compression force
The compression force employed in tabletting process influence density, porosity, hardness, disintegration and dissolution of tablets.
Pharmaceutical excipients
Vehicle
Diluents
Lubricants
Binders
Surfactants
colorants

69. Nature and type of Dosage form
Apart from the selection of the drug, clinical support to a greater extend on the proper selection of dosage form of that drug.
For a given drug, a 2 to 5 fold or perhaps more difference could be observed in the oral bioavailability of a drug depending upon the nature and type of dosage form.
As a general rule, the bioavailability of a drug from various dosage forms decreases in the following order:
Solutions > Emulsions> Suspensions> Capsules> Tablets> Coated tablets> Enteric coated tablets > CR products.

70. Product Age and Storage Conditions
A number of changes, especially in the physicochemical properties of drug form, can result due to aging and alterations in the storage conditions which can adversely affect the bioavailability.
For eg: With solution dosage form, precipitation of drug due to altered solubility, especially due to conversion of metastable into poorly soluble, stable polymorph can occur during the shelf-life of the product

71. Patient related factors affecting drug absorption
Gastrointestinal tract:
The gastrointestinal tract (GIT) comprises of a number of components, their primary function being secretion, digestion and adsorption.
The mean length of the entire GIT is 450 cm.
The major functional components of the GIT are stomach, small intestine (deuodenum, jejunum and ileum) and the large intestine (colon) which grossly differ from each other in terms of anatomy, function, secretions and pH.
The entire length of the GI mucosa from the stomach to large intestine is lined by a thin layer of mucopolysaccharides (mucus/mucin) which normally acts as an impermeable barrier to the particulates such as bacteria, cells or food products.

72. Stomach
The stomach is a bag like structure having a smooth mucosa and thus small surface area.
Its acidic pH, due to secretion of HCl, favours absorption of acidic drugs if they are soluble in the gastric fluids since they are unionized to a large extend in such pH.

73. Small intestine
The major site for absorption of most drugs due to its large surface area.
The blood flow to the small intestine is 6-10 times that of stomach.
The peristaltic movement of intestine is slow, transit time is ling, and permeability is high.

74. Large intestine
The main role of large intestine is in the absorption of water and electrolytes.
However, because of long residence time, colonic transit may be important in the absorption of some poorly soluble drugs.

75. Some of the patient related factors that influence drug absorption are:
Age: In infants, the gastric pH is high and intestinal surface and blood flow to the GIT is low resulting in altered absorption pattern in comparison to adults.
Gastric emptying
Apart from dissolution of a drug an its permeation through the biomembrane, the passage from stomach to small intestine, called as gastric emptying, can also be a rate limiting step in drug absorption because the major site of drug absorption is intestine. Thus, rapid GE increases bioavailability of a drug.

76. Rapid GE is advisable where:
A rapid onset of action is desired e.g. sedatives
Dissolution of drugs occur in the intestine e.g. enteric coated dosage forms
The drugs are not stable in the gastric fluids e.g. penicillin G and erythromicin
The drug is best absorbed from distil part of the small intestine e.g. vitamin B12

77. Delayed GE is preferred in:
The food promotes the drug dissolution and absorption e.g. griseofulvin
The drugs dissolve slowly e.g. griseofulvin
The drugs irritate the gastric mucosa e.g. aspirin, phenylbutazone
The drugs are absorbed from the proximal part of the small intestine and prolonged drug-absorption site contact is desired e.g. vitamin B12 and vitamin C

78. Factors influencing Gastric Emptying
Volume of meal: The larger the starting volume, the greater the initial rate of emptying, after this initial period, the larger the original volume, the slower the rate of emptying.
Composition of meal: The rate of gastric emptying for various food materials is in the following order : carbohydrates > proteins > fats.
Physical state and viscosity of meal: Liquid meals take less than an hour to empty whereas solid meal may take as long as 6-7 hrs.
Temperature of the meal: High or low temperature of the ingested food reduce the gastric emptying rate.

79. GI pH: Gastric emptying is retarded at low stomach pH and promoted at higher at alkaline pH.
Electrolytes and osmotic pressure: Water, isotonic solutions, and solutions of low salt concentration empty the stomach rapidly whereas a higher electrolyte concentration decreases gastric emptying rate.
Body posture: Gastric emptying is favored while standing and by lying on the right side.
Emotional state: Stress and anxiety promote gastric motility whereas depression retards.

80. Exercise: Retards gastric emptying
Disease state: gastroenteritis, gastric ulcer, diabetis and hypothyroidism retard gastric emptying.
Drugs: Drugs that retard gastric emptying include poorly water soluble antacids, anticholenergics, narcotic analgesics and tricyclic anti depressents.

81. Presystemic Metabolism/ First- Pass Effects
For a drug administered orally, the 2 main reasons for its decreased bioavailability are:
Decreased absorption, and
First-pass/ presystemic metabolism
Before a drug reaches blood circulation, it has to pass for the first time through organs of elimination namely the GIT and the liver.

82. The loss of drug through biotransformation by such eliminating organs during its passage to systemic circulation is called as first- pass or presystemic metabolism.
The diminished drug concentration or rarely, complete absence of the drug in plasma after oral administration is indicative of first pass effects.

83. The 4 primary systems which affect presystemic metabolism of a drug are:
Lumenal enzymes
Gut wall enzymes/ mucosal enzymes
Bacterial enzymes
Hepatic enzymes

84. Routes of Drug Administration
The route of administration that is chosen may have a profound effect upon the speed and efficiency with which the drug acts
The possible routes of drug entry into the body may be divided into two classes:
Enteral
Parenteral
Topical

85. Sublingual/Buccal Advantages rapid absorption Disadvantages
Some drugs are taken as smaller tablets which are held in the mouth or under the tongue.
Advantages
rapid absorption
drug stability
avoid first-pass effect
Disadvantages
inconvenient
small doses
unpleasant taste of some drugs

86. Oral Advantages Disadvantages Sometimes inefficient First-pass effect.
Convenient - can be self- administered, pain free, easy to take
Absorption - takes place along the whole length of the GI tract
Cheap - compared to most other parenteral routes
Disadvantages
Sometimes inefficient
First-pass effect.
Irritation to gastric mucosa
destruction of drugs by gastric acid and digestive juices
effect too slow for emergencies
unpleasant taste of some drugs
unable to use in unconscious patient

87. Rectal 1. Can be given to unconscious patients and children
2. If patient is nauseous or vomiting
3. Easy to terminate exposure
4. Absorption may be variable
5. Good for drugs affecting the bowel such as laxatives

88. Parenteral Routes
Intravascular (IV, IA)- placing a drug directly into the blood stream
Intramuscular (IM) - drug injected into skeletal muscle
Subcutaneous - Absorption of drugs from the subcutaneous tissues
Inhalation - Absorption through the lungs

91. Topical
Mucosal membranes (eye drops, antiseptic, sunscreen, callous removal, nasal, etc.)
Skin
a. Dermal - rubbing in of oil or ointment (local action)
b. Transdermal - absorption of drug through skin (systemic action)
i. stable blood levels
ii. no first pass metabolism
iii. drug must be potent or patch becomes too large

92. Chapter Content Bioavailability and measurement and bioequivalency.
Plasma drug concentration time profile
Compartment modeling
Measurement of bioavailability
Drug dissolution rate and bioavailability
Invitro dissolution rate and bioavialabiltiy

93. Learning Outcome
At the end of this chapter, the students shall be able to
Apply & discuss the concepts of bioavailability.
Discuss about bioavailability measurements and its objectives.
Discuss bioequivalency

94. Pharmacokinetics
Pharmacokinetics provides a mathematical basis to assess the time course of drugs and their effects in the body. It enables the following processes to be quantified:
Absorption
Distribution
Metabolism
Excretion
These pharmacokinetic processes, often referred to as ADME, determine the drug concentration in the body when medicines are prescribed.

95. Drug in Drug at Drug interaction Response
Pharmacokinetics is defined as the kinetics of drug absorption, distribution, metabolism and excretion and their relationship with the pharmacologic, therapeutic or toxicologic response in man and animals.
Drug in Drug at Drug interaction Response
systemic circulation site of action with receptor
Pharmacokinetics Pharmacodynamics

96. A variety of techniques is available for representing the pharmacokinetics of a drug. The most usual is to view the body as consisting of compartments between which drug moves and from which elimination occurs. The transfer of drug between these compartments is represented by rate constants.
Rates of reaction
The rate of a reaction or process is defined as the velocity at which it proceeds.

97. Zero-order reaction
It can be defined as a reaction whose rate is independent of the concentration of drug undergoing reaction i.e. the rate of reaction cannot be increased further by increasing the concentration of reactants.

98. First-order reaction
The first order process is the one whose rate is directly proportional to the concentration of drug undergoing reaction i.e. greater the concentration, faster the reaction.

99. Pharmacokinetic models
Pharmacokinetic models are hypothetical structures that are used to describe the fate of a drug in a biological system following its administration.
One-compartment model
In single-compartment modelling, the drug is considered to be distributed instantaneously into a unique compartment in the body. This compartment is characterized by a distribution volume. The drug input into this volume depends on the dosage regimen. The drug output from this volume is characterized by an elimination constant rate.

101. Two-compartment model
The two-compartment model resolves the body into a central compartment and a peripheral compartment. Although these compartments have no physiological or anatomical meaning, it is assumed that the central compartment comprises tissues that are highly perfused such as heart, lungs, kidneys, liver and brain. The peripheral compartment comprises less well-perfused tissues such as muscle, fat and skin.
A two-compartment model assumes that, following drug administration into the central compartment, the drug distributes between that compartment and the peripheral compartment. However, the drug does not achieve instantaneous distribution, i.e. equilibration, between the two compartments.

103. More Definitions
Exposure: A measure for the amount of drug that an organism has really "seen"
Clearance: A measure of the elimination of a compound from the blood given as volume cleared/time
Volume of Distribution: A measure of the theoretical volume that a compound distributes to.
Half-Life: A measure of the time it takes for the organism to decrease the concentration of the drug by 50%

104. Bioavailability and bioequivalency
Bioavailability (BA) is defined as “the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action.
For drug products that are not intended to be absorbed into the bloodstream, BA may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.”

105. Bioequivalence (BE) is defined as “the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.”

106. Objectives of the Bioavailability studies
Primary stages of development of a suitable dosage form for a new drug entry
Determination of influence of excipients, patient related factors and interaction with other drugs on the efficiency of absorption
Development of new formulations of the existing drugs
Control of quality of a new drug product during the early stages of marketing in order to determine the influence of processing factors, storage and stability on drug absorption.

107. Considerations in Bioavailability study design Absolute vs Relative
The systemic availability of a drug administered orally is determined in comparison to its iv administration; it is called as Absolute bioavailability. It is denoted by symbol F.
I.V dose is selected as a standard because the drug is administered directly into the systemic circulation (100% bioavailability) and avoids absorption step.
Intramuscular dose can also be taken as reference standard if the drug is poorly soluble.

108. When the systemic availability of a drug after oral administration is compared with that of an oral standard of the same drug (such as an aqueous or non- aqueous solution or suspension) it is referred to as relative bioavailability.
It is denoted by Fr
In contrast to absolute bioavailability, it is used to characterize absorption of a drug from its formulation.
F and Fr are generally expressed in percentages

109. Measurement of bioavailability
The quantitative evaluation of bioavailability can be divided into 2 categories
Pharmacokinetic methods
Widely used and based on the assumption that the pharmacokinetic profile reflects the therapeutic effectiveness of a drug. Thus these are indirect methods.
The 2 Pharmacokinetic methods are:
Plasma level – time studies
Urinary excretion studies

110. Pharmacodynamic methods
Complementary to pharmacokinetic approaches, direct measurement of drug effect on a pathophysiologic process as a function of time.
The 2 Pharmacodynamic methods involve determination of bioavailability from:
Acute pharmacologic response
Therapeutic response

111. RRoute
BiBioavialability (%)
Characteristics IV
100
Most rapid onset IM
75 to < 100
Large volumes often feasible; may be painful SC
Smaller volumes than IM; may be painful
Oral
5 to < 100
Most convenient; first pass effects may be significant
Rectal
30 to < 100
Less first pass effects than oral
Inhalation
Often very rapid onset
Transdermal
80 to < 100
Usually very slow absorption; used for lack of first pass effect; prolonged duration of action.

112. Plasma level - Time studies
Unless determination of Plasma Drug Concentration is difficult or impossible, it is the most reliable method of choice.
The method is based on the assumption that two dosage forms that exhibit super – imposable plasma level- time profiles in a group of subjects should result in identical therapeutic activity.
Following the administration of a single dose of a medication, blood samples are drawn at specific time intervals and analyzed for drug content.

113. A profile is constructed showing the concentration of drug in blood at the specific times the samples were taken.
Bioavailability (the rate and extent of drug absorption) is generally assessed by the determination of following three parameters. They are.
Cmax(Peak plasma concentration)
tmax (time of peak)
AUC (Area under curve).

114. Plasma drug concentration time profile

115. The three important pharmacokinetic parameters that describe the plasma level-time curve and useful in assessing the bioavailability of a drug from its formulation are:
Peak plasma concentration (Cmax)
The point of maximum concentration of drug in plasma is called as the peak and the concentration of drug at peak is known as peak plasma concentration.
Time of Peak Concentration (tmax)
The time for drug to reach peak concentration in plasma is called as the time of peak concentration.
Area under the curve (AUC)
It represents the total integrated area under the plasma level-time profile and expresses the total amount of drug that comes into the systemic circulation after its administration.

116. F = [AUC]oral [D] iv
[AUC]iv [D]oral
Fr = [AUC]test [D] std
[AUC] std [D]test

117. Bioavailability data are used to determine:
the amount or proportion of drug absorbed from a formulation or dosage form,
the rate at which the drug was absorbed,
the duration of the drug’s presence in the biologic fluid or tissue,
the relationship between drug blood level and clinical efficacy and toxicity.

118. Single dose vs Multiple dose studies
The dose to be administered for a bioavailability study is determined from preliminary clinical experiments.

119. Single dose study Advantages More common Easy and less tedious
Offer less exposure to drugs
Disadvantages
Difficult to predict
the steady state concentration
inter- subject variability

120. Multiple dose study Advantages Accurate
Easy to predict the peak and valley characteristics
Few blood samples required
higher blood levels due to cumulative effect
Ethical
Small inter subject variability
Can detect non-linearity in pharmacokinetics
Better evaluation of controlled release formulations

121. Disadvantages
Poor subject compliance
Tedious and time consuming
More drug exposure

122. Urinary excretion studies
Based on the principle that the urinary excretion of unchanged drug is directly proportional to the plasma concentration of drug.
The study is particularly useful for drugs extensively excreted unchanged in the urine.
Even if a drug is excreted to some extent (at least 10-20%) in the urine, bioavailability can be determined.
For example, certain thiazide diuretics and sulfonamides and for drugs that have urine as site of action – for example, urinary antiseptics such as nitrofurantoin and hexamine.
This method is useful when there is lack of sufficiently sensitive analytical technique to measure drug concentration.
Its is non-invasive method, so better patient compliance.

123. F = [Xu∞] oral Div
[Xu∞]iv Doral
The 3 major parameters examined in urinary data obtained with a single dose study
(dX/dt)max: The maximum urinary excretion rate
(tu)max: The time for maximum excretion rate
Xu: The cumulative amount of drug excreted in the urine

124. Human Volunteers – healthy subjects Versus patients
The bioavailability studies should be carried out in patients because of the apparent advantages.
The patient will be benefited from the study
Reflects better therapeutic efficacy
Drug absorption pattern in disease states can be evaluated
Avoids the ethical quandary

125. Disadvantages
Disease states, other drugs may affect study
Stringent study conditions difficult to be followed by patients.

126. Healthy Volunteers
Young
Healthy
Body weight within narrow range
Restricted dietary and fixes activity conditions
Male (Female for OC pills).
Drug washout period for a minimum of ten biological half-lives must be allowed for between any two studies in the same subject.

127. Pharmacodynamic methods
Acute Pharmacologic Response Method:
When bioavailablity measurement by pharmacokinetic method is difficult, an acute pharmacologic effect such as effect on pupil diameter, EEG & ECG readings related to time course of drug can be done.
Bioavailability can then be determined by construction of pharmacological effect- time curve as well as dose response graphs.
Disadvantages:
It tends to be more variable.
Observed response may be due to an active metabolite whose concentration is not proportional to concentration of parent drug.

128. Therapeutic Response Method:
This method based on observing the clinical response to a drug formulation given to patient suffering from disease.
Drawbacks: The major drawbacks of this method is that quantitation of observed response is too improper to allow for reasonable assessment of relative bioavailability between two dosage forms of the same drug.
E.g. Anti-inflammatory drugs. Many patients receive more than one drug

129. Chapter Content Dissolution studies Need for dissolution
Factors affecting dissolution rate
Invitro dissolution testing
Introduction to Bioequivalence

130. Learning outcome
At the end of this chapter, the students should be able to
Comprehend the concepts of dissolution and bioequivalence

131. DRUG DISSOLUTION RATE & BIOAVAILABILITY

132. The physicochemical property of most dugs that has greatest influence on their absorption characteristics from the GIT is dissolution rate.
The best available tool which can at least quantitatively assure about the biologic availability of a drug from its formulation is its in vitro dissolution test.
For an in vitro test to be useful, it must predict the in vivo behavior to such an extent that in vivo bioavailability test need not be performed.

133. NEED FOR DISSOLUTION TESTING:
Evaluation of bioavailability.
Batch to batch drug release uniformity.
Development of more efficacious and therapeutically optical dosage forms.
Ensures quality and stability of the product.
Product development, quality control, research and application.

134. FACTORS AFFECTING DISSOLUTION RATE
1. Physicochemical Properties of Drug
2. Drug Product Formulation Factors
3. Processing Factors
4. Factors Relating Dissolution Apparatus
5. Factors Relating Dissolution Test Parameters

135. 1. PHYSICOCHEMICAL PROPERTIES OF DRUG
1) DRUG SOLUBILITY
Solubility of drug plays a prime role in controlling its dissolution from dosage form.
Aqueous solubility of drug is a major factor that determines its dissolution rate.
Minimum aqueous solubility of 1% is required to avoid potential solubility limited absorption problems.

136. 2) SALT FORMATION
It is one of the common approaches used to increase drug solubility and dissolution rate. It has always been assumed that sodium salts dissolve faster than their corresponding insoluble acids.
Eg. sodium and potassium salts of Peniciilin G, sulfa drugs, phenytoin, barbiturates etc

137. 3) PARTICLE SIZE
There is a direct relationship between surface area of drug and its dissolution rate. Since, surface area increases with decrease in particle size, higher dissolution rates may be achieved through reduction of particle size.
Micronization of sparingly soluble drug to reduce particle size is by no means a guarantee of better dissolution and bioavailability.

138. 4) SOLID STATE CHARACTERISTICS
Solid phase characteristics of drug, such as amorphicity, crystallinity, state of hydration and polymorphic structures have significant influence on dissolution rate.
Anhydrous forms dissolve faster than hydrated form bcz they are thermodynamically more active than hydrates. Eg. Ampicillin anhydrate faster dissolution rate than trihydrate.
Amorphous forms of drug tend to dissolve faster than crystalline materials. E.g. Novobiocin suspension, Griseofulvin.

139. 5) CO-PRECIPITATION
Dissolution rate of sulfathiazole could be significantly increased by co-precipitating the drug with povidone.

140. 2. DRUG PRODUCT FORMULATION FACTORS
Dissolution rate of pure drug can be altered significantly when mixed with various adjuncts during manufacturing process such as diluents, dyes, binders, granulating agents, disintegrants and lubricants

141. Diluents in capsule & tablet influence the dissolution rate of drug.
Studies of starch on dissolution rate of salicylic acid tablet by dry double compression process shows three times increase in dissolution rate when the starch content increase from the 5 – 20 %.

142. 2) DISINTEGRANTS
Disintegrating agent added before & after the granulation affects the dissolution rate.
Studies of various disintegrating agents on Phenobarbital tablet showed that when copagel (low viscosity grade of Na CMC) added before granulation, decreased dissolution rate but if added after did not had any effect on dissolution rate.

143. 3) BINDERS AND GRANULATING AGENTS
The hydrophilic binder increase dissolution rate of poorly wettable drug.
4) LUBRICANTS
Lubricants are hydrophobic in nature (metallic stearates) and prolong tablet disintegration time by forming water repellant coat around individual granules. This retarding effect is an important factor in influencing rate of dissolution of solid dosage forms.

144. 5) SURFACTANTS They enhance the dissolution rate of poorly soluble drug. This is due to lowering of interfacial tension, increasing effective surface area, which in turn results in faster dissolution rate. 6) WATER-SOLUBLE DYES Dissolution rate of single crystal of sulphathiazole was found to decrease significantly in presence of FD&C Blue No.1

145. 7) COATING POLYMERS-
Tablets with MC coating were found to exhibit lower dissolution profiles than those coated with HPMC at 370C

146. 3. PROCESSING FACTORS 1) METHOD OF GRANULATION-
Granulation process in general enhances dissolution rate of poorly soluble drug. Wet granulation is traditionally considered superior.
2) COMPRESSION FORCE
The compression process influence density, porosity, hardness, disintegration time & dissolution of tablet.

147. 3) DRUG EXCIPIENT INTERACTION These interactions occur during any unit operation such as mixing, milling, blending, drying, and/or granulating result inchange in dissolution. 4) STORAGE CONDITIONS Dissolution rate of Hydrochlorthiazide tablets granulated with acacia exhibited decrease in dissolution rate during 1 year of aging.

148. 4. FACTORS RELATING DISSOLUTION APPARATUS
AGITATION
Relationship between intensity of agitation and rate of dissolution varies considerably according to type of agitation used, the degree of laminar and turbulent flow in system, the shape and design of stirrer and physicochemical properties of solid.

149. 2) STIRRING ELEMENT ALIGNMENT
Studies indicant that significant increase in dissolution rate up to 13% occurs if shaft is offset 2-6 mm from the center axis of the flask

150. 3) SAMPLING PROBE POSITION & FILTER
Sampling probe can affect the hydrodynamic of the system & so that change in dissolution rate.

151. 5. FACTORS RELATING DISSOLUTION TEST PARAMETERS
1) TEMPERATURE
Drug solubility is temperature dependent, therefore careful temperature control during dissolution process is extremely important.

152. 2) DISSOLUTION MEDIUM
It is very imp factor affecting dissolution and is itself affected by number of factors such as:
A. Effect of pH
For weak acids, dissolution rate increases with increase in pH whereas for weak bases, there is increase with decrease in pH.
B. Volume of dissolution medium and sink conditions
If drug is poorly soluble, a relatively large amount of fluid should be used if complete dissolution is to be expected.

153. C. Deaeration of dissolution medium
Dissolved air in distilled water could significantly lower its pH and consequently affect the dissolution rate of drugs that are sensitive to pH changes.

154. Sink condition
A Sink conditions describe a dissolution system that is sufficiently dilute so that the dissolution process is not impeded by approach to saturation of the compound of interest.
Sink conditions affect the production of the sample but not the condition of the solution upon sampling.
In vivo condition, there is no concentration build up in the bulk of the solution and hence no retarding effect on the dissolution rate of the drug i.e. Cs>>Cb and sink condition maintain.

155. Rotating Basket apparatus
It is basically a closed compartment beaker type apparatus comprising of a cylindrical glass vessel with hemispherical bottom of one litre capacity.
The temperature of the media inside the vessel is kept constant by a water bath or heating jacket.
The cylindrical vessel is partially immersed in a water bath to maintain the temperature at 370C. The apparatus consists of a metallic drive shaft connected to the cylindrical basket. A basket is positioned inside a vessel made of glass or other inert, transparent material. The solution in the vessel is stirred smoothly by the rotating stirring element

156. The cylindrical basket is made of 22 mesh to hold the dosage form and is located centrally in the vessel at a distance of 2cm from the bottom and rotated by a variable speed motor through a shaft.
The basket should remain in motion during drawing of samples.

157. Rotating paddle apparatus
As same as the apparatus I except the rotating basket is replaced with a paddle which acts as a stirrer. The dosage form is allowed to sink to the bottom of the vessel.

159. Basket apparatus
Paddle apparatus

160. Bioequivalence studies
Equivalence: It is a relative term that compares drug products with respect to a specific characteristic or function or to a defined set of standards. There are several types of equivalence.
Chemical equivalence: It indicates 2 or more products that contain the same labelled chemical substances as an active ingredient in the same amount.
Pharmaceutic equivalence: It indicates that 2 or more products are identical in strength, quality, purity, content uniformity, and disintegration and dissolution characteristics; they may however differ in containing different excipients.

161. Bioequivalence: It is a relative term that denotes the drug substance in 2 or more identical dosage forms, that reaches the systemic circulation at the same relative rate and to the same relative extent. ie. Their plasma time-profiles will be identical without significant differences.
Therapeutic equivalence: It denotes that 2 or more drug products that contain the same therapeutically active ingredient, elicit identical pharmacological effects and can control the disease to the same extent.