Syllabus:

Introduction to Biopharmaceutics.
Absorption: Mechanisms of drug absorption through GIT, factors influencing drug absorption though GIT, absorption of drug from Non per oral extra-vascular routes,
Distribution: Tissue permeability of drugs, binding of drugs, apparent, volume of drug distribution, plasma and tissue protein binding of drugs, factors affecting protein-drug binding. Kinetics of protein binding, Clinical significance of protein binding of drugs.

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Introduction to Biopharmaceutics:

• Biopharmaceutics is a combination of two words i.e., Bio and Pharmaceutics.
  Bio– Living organism/ living thing/ Living being.
  Pharmaceutics– is the branch of pharmaceutical science that deals with the formulation, preparation, manufacture, and dispensing of drugs into suitable dosage forms. Means it deals with drug, dose, dosage form and dosage regimen.
• Pharmacokinetics is a combination of two words i.e., Pharmacon and Kinetics.
  Pharmacon– Drug
  Kinetics– Movement/ Motion
• Drugs, whether obtained from plant, animal or mineral sources or synthesized chemically, are rarely administered in their pure 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.
• Earlier, it was believed that the therapeutic response by the body to a drug is an characteristic of its intrinsic pharmacological activity of the drug. But today, it is very much understood that the dose-response relationship obtained after drug administration by different routes- for example, oral and parenteral, are not the same.
• Variations are also observed when the same drug is administered as different dosage forms or similar dosage forms produced by different manufacturers, which in turn depend upon the physicochemical properties of the drug, the excipients present in the dosage form, the method of formulation and the manner of administration (dosage form). A new and separate discipline called biopharmaceutics has therefore been developed to account for all such factors that influence the therapeutic effectiveness of a drug.
• Biopharmaceutics is defined as the study of factors influencing the rate and amount of drug that reaches the systemic circulation and the use of this information to optimize the therapeutic efficacy of the drug products.
• Drug absorption is defined as the process of movement of unchanged drug from the site of administration to systemic circulation.
• Hence, Biopharmaceutics can also be defined as the study of factors influencing the rate and amount of drug absorption.
• Bioavailability is defined as the rate and extent (amount) of drug absorption.
• Any alteration in the drug’s bioavailability is reflected in its pharmacological effects.
• With bioavailability, there are other processes that also play a role in the therapeutic activity of a drug, they are distribution, elimination (metabolism and excretion).
• Drug Distribution is the movement of drug between one compartment and the other (generally blood and the extravascular tissues).
• Elimination is defined as the process that tends to remove the drug from the body and terminate its action.
• Elimination occurs by two processes—biotransformation (metabolism),which usually inactivates the drug, and excretion which is responsible for the exit of drug/metabolites from the body.
• In order to administer drugs optimally, knowledge is needed not only of the mechanisms of drug absorption, distribution, metabolism and excretion (ADME) but also of the rate (kinetics) at which they occur i.e. 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 as clinical pharmacokinetics.
• Below Figure is a schematic representation of processes comprising the pharmacokinetics of a drug.

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Drug administration and therapy can now be conveniently divided into four phases or processes:

1. The Pharmaceutical Phase: It is concerned with–
   (a) Physicochemical properties of the drug, and
   (b) Design and manufacture of an effective drug product for administration by a suitable route.
2. The Pharmacokinetic Phase: 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. In short, it is the sum of all the processes inflicted by the body on the drug.
3. The Pharmacodynamic Phase: It is concerned with the biochemical and physiological effects of the drug and its mechanism of action.
   Thus, in comparison –
   Pharmacokinetics is a study of what the body does to the drug, whereas,
   Pharmacodynamics is a study of what the drug does to the body.
   Pharmacokinetics relates changes in concentration of drug within the body with time after its administration, whereas
   Pharmacodynamics relates response to concentration of drug in the body.
4. The Therapeutic Phase: It is concerned with the translation of pharmacological effect into clinical benefit.

• 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. Knowledge of the factors affecting the bioavailability of drug helps in designing such an optimum formulation and saves many drugs that may be discarded as useless. On the other hand, 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 (the manner in which the drug should be taken).
• 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.

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Absorption of Drugs:

• A drug injected intravascularly (intravenously and/or intra-arterially) directly enters the systemic circulation and exerts its pharmacological effects.
• However, majority of drugs are administered extra-vascularly, generally orally. If intended to act systemically, such drugs can exert their pharmacological actions only when they come into blood circulation from their site of application, and for this, absorption is an important prerequisite step.
• Drug absorption is defined as the process of movement of unchanged drug from the site of administration to systemic circulation.
• Followingabsorption, the effectiveness of a drug can only be assessed by its concentration at the site of action. But, it is difficult to measure the drug concentration at such a site. Instead, the concentration can be measured more accurately in plasma. There always exist a correlation between the plasma concentration of a drug and the therapeutic response and thus, absorption can also be defined as the process of movement of unchanged drug from the site of administration to the site of measurement i.e. plasma. This definition takesinto account the loss of drug that occurs after oral administration due to pre-systemic metabolism or first-pass effect.
• Not only the magnitude of drug that comes into the systemic circulation but also the rate at which it is absorbed is important. This is clear from Below Fig.
• A drug that is completely but slowly absorbed may fail to show therapeutic response as the plasma concentration for desired effect is never achieved. On the contrary, a rapidly absorbed drug attains the therapeutic level easily to elicit pharmacological effect.

• Thus, both the rate and the extent of drug absorption are important. Such an absorption pattern has several advantages:
  1. Lesser susceptibility of the drug for degradation or interaction due to rapid absorption.
  2. Higher blood levels and rapid onset of action.
  3. More uniform, greater and reproducible therapeutic response.
• Drugs that have to enter the systemic circulation to exert their effect can be administered by three major routes:
  1. 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.
  2. 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.
  3. The Topical Route: includes skin, eyes or other specific membranes. The intranasal, inhalation, intravaginal and transdermal routes may be considered enteral or topical according to different definitions.

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Mechanisms of drug absorption through GIT:

Gastrointestinal Absorption of Drugs

• The oral route of drug administration is the most common for systemically acting drugs and therefore, more importance will be given to gastrointestinal (GI) absorption of drugs.
• Among all dosage forms, about 80% are oral dosage forms (70% tablets and 10% other orals) and remaining 20% are other dosage forms.
• Moreover, it covers all the aspects (or factors) of variability observed in drug absorption. Before proceeding to discuss absorption aspects, a brief description of cell membrane structure and physiology is necessary.

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 asdrug transport.
• The basic structure of cell membrane is shown in below Fig.

• 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 and inner 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 combined within the membrane structure. In short, the membrane is a mayonnaise sandwich where a bimolecular layer of lipids is contained between two parallel monomolecular layers of proteins.
• The hydrophobic core of the membrane is responsible for the relative protection of polar molecules.
• 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. In general, the bio-membrane acts like a semipermeable barrier permitting rapid and limited passage of some compounds while restricting that of others.
• 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.

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Mechanisms of Drug Absorption:

The three broad categories of drug transport mechanisms involved in absorption are –
A. Transcellular/intracellular transport
B. Paracellular/intercellular transport
C. Vesicular transport

A. Transcellular/Intracellular Transport

Transcellular/Intracellular Transport –is defined as the passage of drugs across the GI epithelium. It is the most common pathway for drug transport.
The various transcellular transport processes involved in drug absorption are –

1. Passive Transport Processes –These transport processes do not require energy other than that of molecular motion (Brownian motion) to pass through the lipid bilayer. Passive transport processes can be further classified into following types –
   a. Passive diffusion.
   b. Pore transport.
   c. Ion-pair transport.
   d. Facilitated- or mediated-diffusion.
2. Active Transport Processes –This transport process requires energy from ATP to move drug molecules from extracellular (outside the cell) to intracellular milieu (inside the cell membrane). These are of two types –
   a. Primary active transport.
   b. Secondary active transport – this process is further subdivided into two –
   i. Symport (co-transport).
   ii. Antiport (counter-transport).

B. Paracellular/Intercellular Transport

Paracellular/Intercellular Transport –is defined as the transport of drugs through the junctions between the GI epithelial cells. This pathway is of minor importance in drug absorption.
The two paracellular transport mechanisms involved in drug absorption are –

1. Permeation through tight junctions of epithelial cells –this process basically occurs through openings which are little bigger than the aqueous pores. Compounds such as insulin and cardiac glycosides are taken up this mechanism.
2. Persorption –is permeation of drug through temporary openings formed by shedding of two neighboring epithelial cells into the lumen.

C. Vesicular or Corpuscular Transport (Endocytosis)

Vesicular or Corpuscular Transport (Endocytosis): Vesicular transport is the active process by which cells move large molecules or bulk materials using small, membrane-bound sacs called vesicles. Since the mechanism involves transport across the cell membrane, the process can also be classified as transcellular.
Vesicular transport of drugs can be classed into two categories –

1. Pinocytosis.
2. Phagocytosis

Mechanisms of Drug Absorption Explanation

Passive Diffusion:

• Also called non-ionic diffusion, it is the major process for absorption of more than 90% of the drugs.
• The driving force for this process 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 ofthe kinetic energy of molecules.
• Since no energy source is required, the process is called as passive diffusion.
• During passive diffusion, the drug present in the aqueous solution at the absorption site (GIT) partitions and dissolves in the lipid material of the cell membrane and finally leaves it by dissolving again in an aqueous medium, this time at the inside of the membrane.
• Passive diffusion is best expressed by Fick’s first 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 following equation:

Where,
dQ/dt = rate of drug diffusion (amount/time). It also represents the rate of appearance of drug in blood
D = diffusion coefficient of the drug through the membrane (area/time)
A = surface area of the absorbing membrane for drug diffusion (area)
K_m/w = partition coefficient of the drug between the lipoidal membrane and the aqueous GI fluids (no units)
(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 (length)

• Based on the above equation, certain characteristics of passive diffusion can be generalized-
  1. The drug moves down the concentration gradient, indicating downhill transport.
  2. The process is energy-independent and non-saturable.
  3. The rate of drug transfer is directly proportional to the concentration gradient between GI fluids and the blood compartment.
  4. Greater the area and lesser the thickness of the membrane, faster the diffusion; thus, more rapid is the rate of drug absorption from the intestine than from the stomach.
  5. The process is rapid over short distances and slower over long distances.
  6. Equilibrium is attained when the concentration on either side of the membrane becomes equal.
  7. Drugs which can exist in both ionized and unionized forms, the equilibrium achieved primarily by the transfer of the unionized species; because, the rate of transfer of unionized species is 3 to 4 times more than the rate for ionized drugs.
  8. Greater the membrane/water partition coefficient of drug, faster the absorption; since the membrane is lipoidal in nature, a lipophilic drug diffuses at a faster rate by solubilizing in the lipid layer of the membrane.
  9. The drug diffuses rapidly when the volume of GI fluid is low; conversely, dilution of GI fluids decreases the drug concentration in these fluids (C_GIT) and lower the concentration gradient (C_GIT – C). This phenomenon is, however, made use of in treating cases of oral overdose or poisoning.
  10. The process is dependent, to a lesser extent,– drugs having molecular weights between 100 to 400 Daltons are effectively absorbed passively. The diffusion generally decreases with increase in the molecular weight of the compound. However, there are exceptions—for example, cyclosporin A, a peptide of molecular weight 1200, is absorbed orally much better than any other peptide.
• Initially, when the drug is ingested, C_GIT >> C and a large concentration gradient exists thereby acting as the driving force for absorption. As equilibrium approaches, the drug diffusion should stop and consequently a large fraction of drug may remain unabsorbed. But this is not the case; once the passively absorbed drug enters blood, it is rapidly swept away and distributed into a much larger volume of body fluids and hence, the concentration of drug at the absorption site, C_GIT, is maintained greater than the concentration of drug in plasma. Such a condition is called as sink condition for drug absorption.
• Since under usual conditions of absorption, D, A, Km/w and h are constants, the term DAKm/w/h can be replaced by a combined constant P called as permeability coefficient. Permeability refers to the ease with which a drug can penetrate or diffuse through a membrane. Moreover, due to sink conditions, the concentration of drug in plasma C is very small in comparison to CGIT. As a result, Fick’s first law of diffusion equation may be simplified to:

• Above Equation is an expression for a first-order process. Thus, passive diffusion follows first-order kinetics. Since a large concentration gradient always exists at the absorption site for passive diffusion, the rate of drug absorption is usually more rapid than the rate of elimination. Besides, dilution and distribution of the absorbed drug into a large pool of body fluids and its subsequent binding to various tissues are other reasons for elimination being slower than absorption.
• Below Figure illustrates the relative permeability of different molecules to lipid bilayer.

Pore Transport:

• It is also called convective transport (Momentum within fluid), bulk flow or filtration. This mechanism is responsible for transport of molecules into the cell through the protein channels present in the cell membrane.

• Following are the characteristics of pore transport –
  1. The driving force is constituted by the hydrostatic pressure or the osmotic differences across the membrane due to which bulk flow of water along with small solid molecules occurs through such aqueous channels. Water flux that promotes such a transport is called as solvent drag.
  2. 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 drugs like urea and sugars. flow through narrow, aqueous-filled channels or pores in the membrane structure.
  3. Chain-like or linear compounds of molecular weight up to 400 Daltons can be absorbed by filtration.
• Drug permeation through water-filled channels is of particular importance in renal excretion, removal of drug from the cerebrospinal fluid and entry of drugs into the liver.

Ion-Pair Transport:

• Yet another mechanism that explains the absorption of drugs like quaternary ammonium compounds(+) and sulphonic acids(-), which ionize under all pH conditions, is ion-pair transport.
• The charged drug molecules penetrate the membrane by forming reversible neutral complexes with endogenous ions (Within the body) of the GIT like mucin.
• Such neutral complexes have both the required lipophilicity as well as aqueous solubility for passive diffusion. Such a phenomenon is called as ion-pair transport (Fig. 2.5).
• Propranolol, a basic drug that forms an ion pair with oleic acid, is absorbed by this mechanism. Anti-cancer drugs and fat-soluble vitamins (A,D,E,K) sometimes absorb through this mechanism.

Carrier-Mediated Transport:

• Some polar drugs (partial positive and negative charges) cross the membrane more readily than can be predicted from their concentration gradient and partition coefficient values.
• This suggests presence of specialized transport mechanisms without which many essential water-soluble nutrients like monosaccharides, amino acids and vitamins will be poorly absorbed.
• The mechanism involves a component of the membrane called as the carrier that binds reversibly or non-covalently with the solute molecules to be transported. This carrier-solute complex traverses across the membrane to the other side where it dissociates and discharges the solute molecule. The carrier then returns to its original site to complete the cycle by accepting a fresh molecule of solute.
• Carriers in membranes are proteins (transport proteins) and may be an enzyme or some other component of the membrane. They are numerous in all biological membranes and are found dissolved in the lipid bilayer of the membrane.
• Important characteristics of carrier-mediated transport are:
  1. A carrier protein always has an uncharged (non-polar) outer surface which allows it to be soluble within the lipid of the membrane.
  2. The carriers have no directionality; they work with same efficiency in both directions.
  3. The transport process is structure-specific i.e. the carriers have special affinity for and transfer a drug of specific chemical structure only (i.e. lock and key arrangement); generally, the carriers have special affinity for essential nutrients.
  4. As the number of carriers is limited, the transport system is subject to competition between agents having similar structure.
  5. Since the number of carriers is limited, the system is capacity-limited i.e. at higher drug concentration; the system becomes saturated and approaches an asymptote. It is important to note that for a drug absorbed by passive diffusion, the rate of absorption increases linearly with the concentration but in case of carrier-mediated processes, the drug absorption increases linearly with concentration until the carriers become saturated after which it becomes curvilinear and approach a constant value at higher doses (see Fig. 2.6). Such a capacity-limited process can be adequately described by mixed order kinetics, also called as Michaelis-Menten, saturation or non-linear kinetics. The process is called mixed-order because it is first-order at sub-saturation drug concentrations and apparently zero-order at and above saturation levels. Moreover, the capacity-limited characteristics of such a system suggest that the bioavailability of a drug absorbed by such a system decrease with increasing dose—for example, vitamins like B1, B2 and B12. Hence, administration of a large single oral dose of such vitamins is irrational.
  6. Specialized absorption or carrier-mediated absorption generally occurs from specific sites of the intestinal tract which are rich in number of carriers. Such an area in which the carrier system is most dense is called as absorption window. Drugs absorbed through such absorption windows are poor candidates for controlled release formulations.
• Comparison of rate of absorption versus drug concentration plots for passive and carrier-mediated transport processes.

Facilitated Diffusion:

• It is a carrier-mediated transport system that operates down the concentration gradient (downhill transport) but at a much a faster rate than can be accounted by simple passive diffusion.
• The driving force is concentration gradient (hence a passive process). 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. 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.
• Facilitated diffusion of drug is illustrated in the below figure.

Active Transport:

• This transport mechanism requires energy in the form of ATP.
• Active transport is responsible fortransporting small foreign molecules (like drugs and toxins) especially out of cells which make them clinically important.
• Active transport is a more important process than facilitated diffusion in the absorption of nutrients and drugs and differs from it in several respects:
  1. The drug is transported from a region of lower concentration to higher concentration i.e. against the concentration gradient (in the case of ions, against an electrochemical gradient) or uphill transport, without any regard for equilibrium.
  2. The process is faster than passive diffusion.
  3. Since the process is uphill, energy is required in the work done by the carrier.
  4. As the process requires expenditure of energy, it can be inhibited by metabolic poisons that interfere with energy production like fluorides, cyanide and dinitrophenol and lack of oxygen, etc. Endogenous substances that are transported actively include sodium, potassium, calcium, iron, glucose, certain amino acids and vitamins like niacin, pyridoxin and ascorbic acid.
  5. Drugs having structural similarity to such agents are absorbed actively, particularly the agents useful in cancer chemotherapy. Examples include absorption of 5-fluorouracil and 5-bromouracil via the pyrimidine transport system, absorption of methyldopa and levodopa via an L-amino acid transport system and absorption of ACE inhibitor enalapril via the small peptide carrier system.
  6. Active transport is also important in renal and biliary excretion of many drugs and their metabolites and secretion of certain acids out of the CNS.
• Active transport of a drug is illustrated in the below figure.

• Below Figure- compares active and passive transport

Endocytosis:

• It is a minor transport mechanism which involves engulfing extracellular materials within a segment of the cell membrane to form a saccule or a vesicle (hence also called as corpuscular or vesicular transport) which is then pinched-off intracellularly (see below Fig.). This is the only transport mechanism whereby a drug or compound does not have to be in an aqueous solution in order to be absorbed.

• This phenomenon is responsible for the cellular uptake of macromolecular nutrients like fats and starch, oil soluble vitamins like A, D, E and K, water soluble vitamin like B12 and drugs such as insulin.
• Another significance of such a process is that the drug is absorbed into the lymphatic circulation thereby bypassing first-pass hepatic metabolism.
• Endocytosis includes two types of processes:
  1. Pinocytosis (cell drinking): uptake of fluid solute, and
  2. Phagocytosis (cell eating): adsorptive uptake of solid particulates.

Combined Absorption Mechanisms:

• A drug might be absorbed by more than just one mechanism—for example, cardiac glycosides are absorbed both passively as well as by active transport. Vitamin B12 is absorbed by passive diffusion, facilitated diffusion as well as endocytosis. The transport mechanism also depends upon the site of drug administration.
• Absorption of drugs by various mechanisms is summarized in below Fig.

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FACTORS INFLUENCING DRUG ABSORPTION AND BIOAVAILABILITY:

Biopharmaceutic Considerations in Dosage Form Design

• To achieve the desired therapeutic objective, the drug product must deliver the active drug at an optimal rate and amount.
• By proper biopharmaceutic design, the rate and extent of drug absorption can be varied from rapid and complete absorption to slow and sustained absorption depending upon the desired therapeutic objective. The chain of events that occur following administration of a solid dosage form such as a tablet or a capsule until its absorption into systemic circulation are depicted in below Fig.

Fig. Sequence of events in the absorption of drugs from orally administered solid dosage forms

• The process consists of four steps:
  1. Disintegration of the drug product.
  2. Deaggregation and subsequent release of the drug.
  3. Dissolution of the drug in the aqueous fluids at the absorption site.
  4. Absorption i.e. movement of the dissolved drug through the GI membrane into the systemic circulation and away from the absorption site.
• As illustrated in above Fig., the drug may also dissolve before disintegration or deaggregation of the dosage form, and before or after reaching the absorption site. Unless the drug goes into solution, it cannot be absorbed into the systemic circulation.
• In a series of kinetic or rate processes, the rate at which the drug reaches the systemic circulation is determined by the slowest of the various steps involved in the sequence. Such a step is called as therate-determining orrate-limiting step (RDS). The rate and extent of drug absorption from itsdosage form can be influenced by a number of factors in all these steps. The various factors that influence drug absorption (also called as biopharmaceutic factors in the dosage form design) can be classified asshown below.

Factors influencing GI Absorption of a Drug from its Dosage Form:

A. PHARMACEUTICAL FACTORS:

Include factors relating to the physicochemical properties of the drug, and dosage form characteristics and pharmaceutical ingredients

I. Physicochemical Properties of Drug Substances (API):

1. Drug solubility and dissolution rate
2. Particle size and effective surface area
3. Polymorphism and amorphism
4. Pseudopolymorphism (hydrates/solvates)
5. Salt form of the drug
6. Lipophilicity of the drug
7. pKa of the drug and gastrointestinal pH
8. Drug stability

II. Dosage Form Characteristics and Pharmaceutical Ingredients (Pharmaco-technical Factors)

1. Disintegration time (tablets/capsules)
2. Dissolution time
3. Manufacturing variables
4. Pharmaceutical ingredients (excipients/adjuvants)
5. Nature and type of dosage form
6. Product age and storage conditions

B. PATIENT RELATED FACTORS: 

Include factors relating to the anatomical, physiological and pathological characteristics of the patient

1. Age
2. Gastric emptying time
3. Intestinal transit time
4. Gastrointestinal pH
5. Disease states
6. Blood flow through the GIT
7. Gastrointestinal contents:
   • Other drugs
   • Food
   • Fluids
   • Other normal GI contents
8. Presystemic metabolism by:
   • Luminal enzymes
   • Gut wall enzymes
   • Hepatic enzymes
   • Hepatic enzymes

Factors Explanation:

PHYSICOCHEMICAL FACTORS AFFECTING DRUG ABSORPTION:

1. Drug solubility & dissolution rate 
2. Particle Size and Effective Surface Area of the Drug 
3. Polymorphism and Amorphism 
4. Hydrates/Solvates (Pseudopolymorphism) 
5. Salt form of the drug
6. Drug pKa and Lipophilicity and GI pH—pH Partition Hypothesis 
7. Drug stability

1. Drug Solubility and Dissolution Rate:

• An important prerequisite for the absorption of a drug by all mechanisms except endocytosis is that it must be present in aqueous solution. This in turn depends on the drug’s aqueous solubility and its dissolution rate. 
• Absolute or intrinsic solubility is defined as the maximum amount of solute dissolved in a given solvent under standard conditions of temperature, pressure and pH. Itis a static property. 
• Dissolution rate is defined as the amount of solid substance that goes into solution per unit time under standard conditions of temperature, pH and solvent composition and constant solid surface area. Itis a dynamic process.
• Except in case of controlled-release formulations, disintegration and deaggregation occur rapidly if it is a well-formulated dosage form. Thus, the two critical slower rate-determining processes in the absorption of orally administered drugs are:
  1. Rate of dissolution, and
  2. Rate of drug permeation through the bio-membrane.
• Dissolution is the RDS for hydrophobic, poorly aqueous soluble drugs like griseofulvin and spironolactone; absorption of such drugs is often said to be dissolution rate-limited.
• If the drug is hydrophilic with high aqueoussolubility—for example, cromolyn sodium or neomycin, then dissolution is rapid and RDS in the absorption of such drugs is rate of permeation through the bio-membrane. In other words, absorption of such drugs is said to be permeation rate-limited or transmembrane rate-limited.

Fig. The two rate-determining steps in the absorption of drugs from orally administered formulations.

• Based on the intestinal permeability and solubility of drugs, Amidon et al developed Biopharmaceutics Classification System (BCS) which classifies the drugs into one of the 4 groups as shown in the below table.

Class I drugs (high solubility/high permeability)are well absorbed orally since they have neither solubility nor permeability limitation.
Class II drugs (low solubility/high permeability)show variable absorption owing to solubility limitation.
Class III drugs (high solubility/low permeability)also show variable absorption owing to permeability limitation.
Class IV drugs (low solubility/low permeability)are poorly absorbed orally owing to both solubility and permeability limitations.

• Theories of Drug Dissolution
  1. Diffusion layer model/Film theory,
  2. Danckwert’s model/Penetration or Surface renewal theory, and
  3. Interfacial barrier model/Double-barrier or Limited solvation theory.

2. Particle Size and Effective Surface Area of the Drug:

• Particle size and surface area of a solid drug are inversely related to each other.
• Smaller the drug particle, greater the surface area. Two types of surface area of interest can be defined:
  1. Absolute surface area which is the total area of solid surface of any particle, and
  2. Effective surface area which is the area of solid surface exposed to the dissolution medium.
• Noyes-Whitney equation,

where,
D = diffusion coefficient (diffusivity) of the drug
A= surface area of the dissolving solid
Kw/o = water/oil partition coefficient of the drug considering the fact that dissolution body fluids are aqueous.
Since the rapidity with which a drug dissolves depends on the Kw/o, it is also called as the intrinsic dissolution rate constant. It is a characteristic of drugs.
V = volume of dissolution medium.
h= thickness of the stagnant layer.
(Cs – Cb) = concentration gradient for diffusion of drug.

• From the Noyes-Whitney equation, it is clear that larger the surface area, higher the dissolution rate. Since the surface area increases with decreasing particle size, a decrease in particle size, which can be accomplished by micronisation, will result in higher dissolution rates.
• However, it is important to note that it is not the absolute surface area but the effective surface area that is proportional to the dissolution rate.
• Greater the effective surface area, more intimate the contact between the solid surface and the aqueous solvent and faster the dissolution.
• But it is only when micronisation reduces the size of particles below 0.1 microns that there is an increase in the intrinsic solubility and dissolution rate of the drug. The surface of such small particles has energy higher than the bulk of the solid resulting in an increased interaction with the solvent. This is particularly true in case of drugs which are non-hydrophobic.
• Micronisation has in fact enabled the formulator to decrease the dose of certain drugs because of increased absorption efficiency—for example, the griseofulvin dose was reduced to half and that of spironolactone was decreased 20 times following micronisation.
• However, in case of hydrophobic drugs like aspirin, phenacetin and phenobarbital, micronisation actually results in a decrease in the effective surface area of such powders and thus, a fall in the dissolution rate. Three reasons have been suggested for such an outcome —
  • The hydrophobic surface of the drug adsorbs air onto their surface which inhibit their wettability.
  • The particles re-aggregate to form larger particles due to their high surface free energy, which either float on the surface or settle at the bottom of the dissolution medium.
  • Electrically induced agglomeration owing to surface charges prevents intimate contact of the drug with the dissolution medium.
• The net result of these effects is that there is a decrease in the effective surface area available to the dissolution medium and therefore a fall in the dissolution rate.
• The absolute surface area of hydrophobic drugs can be converted to their effective surface area by:
  1. Use of surfactant as a wetting agent that –
     1. Decreases the interfacial tension, and
     • Displaces the adsorbed air with the solvent.
       
  2. For example, polysorbate 80 increases the bioavailability of phenacetin by promoting its wettability.Adding hydrophilic diluents such as PEG, PVP, dextrose, etc. which coat the surface of hydrophobic drugparticles and render them hydrophilic.