FACTORS INFLUENCING DRUG ABSORPTION THROUGH GIT / Physicochemical Factors / Drug Solubility:

  FACTORS INFLUENCING DRUG ABSORPTION THROUGH GIT                  

1.3.1. Introduction 

The desired therapeutic objective is achieved when the drug product delivers the active drug at an optimal rate and extent, a nd at the target site. If a proper biopharmaceutical design is adopted, the rate and extent of drug absorption (i.e., bioavailability) or the systemic delivery of drug to the body can be varied from rapid and complete absorption to slow and sustained absorption depending on the desired therapeutic activity.

 The following factors influence drug absorption: 

1) Physicochemical factors, and 

2) Pharmaceutical factors. 

1.3.2. Physicochemical Factors

 Drug absorption through GIT is influenced by the following physicochemical factors

1) Drug Solubility: 

Almost all the factors that influence dissolution rate, also affect the drug solubility either directly or indirectly. The dissolution rate is considered to be directly related to drug solubility. An empirical relation used for predicting the dissolution rate of a drug from its solubility is:

 R = dt / dc = 2.24 Cs Where R = Dissolution rate of the drug. 

Bioavailability problems can be avoided if the dr ug exhibits a minimum aqueous solubility of 1%. 

An orally administered drug undergoes degradation due to the acidic or alkaline nature of gastrointestinal content, and the presence of enzymes and bacteria. For example, antibiotics are relatively stable be tween pH 6 -8 but get rapidly destroyed at gastric pH (1.5 -3.5). Longer is the gastric emptying time, more the drug is at risk to get degraded by acidic pH of the stomach. This problem of degradation can be avoided by enteric coating, but it delays drug release and absorption. As an alter native, the drug is administered via other routes such as sublingual, transdermal, or rectal. 

Due to degradation of drug, the following consequences may occur:

 i) Little drug is absorbed, so reduced bioavailability. 

ii) Toxicity increases upon degradation, e.g., salicylic acid is more irritant than aspirin. 

iii) Degradation process is essential for pro -drugs, because they release the therapeutically active molecule after degradation in the GIT. 

 The compromise between solubility and s tability of drug in gastrointestinal content is a key factor to determine the bioavailability of the orally administered drug. For example, Progabide is a weak base with pK a value of 3.41; it is highly soluble below pH 3 and poorly soluble above pH 4; it undergoes hydrolysis at acidic pH to release GABA and benzophenone; it has maximum solubility and undergoes rapid absorption from small intestine at pH 6.3. In such cases, the dosage form design and bioavailability is decided by considering the following drug characteristics:

 i) Drug micronisation increases the drug solubility in small intestine (a better absorption site), but also increases the drug degradation rate in stomach due to increased surface area.

 ii) Enteric coating protects the drug from acidic enviro nment, but the insoluble drug reaches the small intestine. 

 iii) The rapid gastric emptying of micronised drug ensures faster drug dissolution and minimum drug degradation.

 2) Dissolution Rate:

 For the absorption of drug, it should be in solution state at the absorption site. Therefore, the factors influencing dissolution rate of the drug in gastrointestinal fluid also influence the drug bioavailability.

Dissolution rate is the amount of substance that goes into the solution per unit time under standard conditions of temperature, pressure, and solvent composition. Dissolution is a dynamic process and involves mass transfer. The following theories explain the process of drug dissolution:

 

i) Noyes-Whitney Theory or Stagnant Film Theory: 

Noyes-Whitney equation describes the process of dissolution, and states that the dissolution rate of drug (d C/dt) is directly proportional to the diffusion coefficient of the drug in solution state in gastrointestinal fluid (D), effective surface area of the drug particle ava ilable for drug dissolution (A), difference in the saturation solubility of the drug in the diffusion layer (Cs), and the concentration of drug in solution state in the bulk of gastrointestinal fluid (C); while the dissolution rate of drug is inversely proportional to the thickness of diffusion layer (x) (equation 2):

ii) Danckwert’s Model: 

This model of dissolution does not consider the formation of diffusion layer and the solid surface is constantly exposed to fresh solvent causing mass transfer. It is assumed that the dissolution medium and the solid surface are under turbulence. T he agitated dissolution medium comprises of a mass of eddies or pockets, which are continuously exposed to the solid surface, absorb the solute by diffusion, and carry it to the bulk of the solution. The contact of fresh pockets with the solid surface tran sfers the mass to the bulk, and does not allow the formation of diffusion layer.  

Since this dissolution process involves the contact of fresh pockets of solvent with new solid surface, it is termed as surface renewal process.

iii) Limited So lvation Theory:

 This theory states that an intermediate concentration less than saturation exist at the interface due to salvation mechanism, which is the function of solubility than that of the diffusion. In the dissolution of crystals, the different faces of a crystal have different interfacial barrier. Limited solvation theory is demonstrated by the following equation: 

G = Ki  (Cs – C) ….. (6) 

Were, G = Dissolution rate per unit area.

 Ki = Effective interfacial transport constant.

 3) Wetting:

 Good wettability results in particle size reduction. Aggregation of powder and air adsorption on powder surface is minimised by adding a wetting agent. Surfactants and hydrophilic polymers have been added in dosage forms for enhancing drug dissolution and bioavailability. 

When phenytoin is agglomerated by spherical crystallisation, the formed agglomerates containing PEG show higher Area Under the blood concentration-time Curve (AUC) and C max. A drug with poor wettability in water or in conventional dissolution media may have good wetting by gastrointestinal fluid. The native surfactants in GIT, such as bile salts, may also help in the wetting of drug. 

4) Chemical Forms: 

The desired effect can be achieved by selecting an appropriate chemical form of drug. Sometimes, chemical modifications are made in the structure of drugs to have better therapeutic response or effect than the parent drugs. These modified drugs exhibit the same therapeutic value as they breakdown in the body into active forms of the parent drugs. The ideal conditions for a chemical form to act as a drug are: 

i) It should have sufficient water solubility for dissolution. 

ii) It should have optimum o/w partition coefficient for diffusion through lipid layers. 

iii) Chemical modifications are made in the part of drug molecule that obstructs absorption.

 Better therapeutic response can be achieved by implementing the following chemical modifications in the chemical forms: 

i) Specific Chemical Modifications: 

These involve chemical modifications of drugs, e.g., sulphonamides to succinyl sulphonamide or phthalyl sulphonamide. These chemical modifications in sulphonamides can ionise in the gut. Therefore, their lipid/water partition coefficient decreases, thus reducing the absorption of these chemically modified drugs. The antibacterial activity begins when the amide links are broken down by hydrolysis.

ii) Chemical Modifications to Increase Lipid Solubility: 

In some drugs, chemical modifications are done to enhance their lipid solubility. For example, increase in lipid solubility of barbiturates is directly 

proportional to their absorption from colon; doxycycline is better absorbed than its parent drug tetracycline; erythromycin is better absorbed than its estolate form.

iii) Salt Formation for Increasing Absorption: 

Drugs are mostly weak acids or bases. The salts of such drugs have different solubility than their parent drugs. The solubilit y of such drugs can be easily enhanced by converting them into their salt forms. Some examples are:

a) The aluminium salt of aspirin undergoes very slow dissolution in the GIT due to the deposition of insoluble aluminium on the surface of solid particles. Due to this reason, the drug is only partially absorbed. 

b) Dissolution rate of phenobarbital tablets is better than that of the tablets of sodium salt of phenobarbital because the former undergoes rapid disintegration while the latter swell and dissolve slowly from the surface. 

c) Heptabarbital in tablet form attains the peak plasma level (C max) in 1.5-5 hours (t max). However, its sodium salt attains C max at 0.4 -2 hours (tmax). Bioavailability of heptabarbital is up to 17% more than that of its sodium salt due to the precipitation of sodium salt of the drug in crystalline form. 

5) Drug pKa and Lipophilicity and GI pH (pH Partition Theory):

 Brodie gave the pH partition theory to explain the absorption process of drug from GIT and its distribution across the biological membranes. This theory states that the absorption of drug compounds with molecular weight more than 100 Daltons involves transportation across the biomembrane by passive diffusion, and this process depends on 

i) The dissociation constant (pKa) of the drug, 

ii) The lipid solubility (Ko/w) of unionised drug, and

iii) The pH at absorption site. 

Drugs are mostly either weak acids or weak bases; thus, their ionisation degree is influenced by the pH of biological fluid. If the pH on either side of the membrane is different, the compartment whose pH favour s greater ionisation of drug will have greater amount of drug. Also, the unionised or un-dissociated fraction of the drug, if is sufficiently lipid -soluble, will permeate the membrane by passive diffusion until equilibrium is attained between the concentra tions of unionised drug on either side of the membrane. The pH partition theory lies on the following assumptions:

 i) GIT acts as a lipoidal barrier to the transport of drug. 

ii) The absorption rate of a drug is directly proportional to the fraction of unionised drug. 

iii) Higher the lipophilicity (K o/w) of the unionised drug, better is its absorption.

 Limitations of pH-Partition Theory 

i) The pH-partition theory is based on the assumption that equilibrium is achieved by the distribution between the ionised and unionise d forms of a drug. However, drug is continuously swept away due to blood circulation, thus maintaining sink condition. This theory therefore failed in calculating the absorption from equilibrium distribution. 

ii) This theory describes absorption of weak acids and weak bases more suitably. 

iii) Ionisation of drug in the lumen occur s similarly as in blood, but ion trapping may also occur. 

iv) Absorption from GIT depends on pH of all sites, drug solubility in lipid, gastric residence, absorption surface area, drug degradation, etc. 

v) Weak acidic drugs are better absorbed from small intestine, because:

 a) Poorly soluble weakly acidic drug has a high dissolution rate in an alkaline environment. This results in availability of higher surface area for absorption of the dissolved drug. 

b) The weakly acidic pH (pH 5.3) at surface of the intestinal mucosa is responsible for effective absorption of weakly acidic drug that exists in unionised state. Thus, this hypothesis raises questions regarding the absorption of weakly basic drug that ex ists in unionised state. These weak bases can interact with organic cations and are secreted from blood into the intestinal lumen.

 A poorly water-soluble, weakly basic drug,which dissociates and dissolves in stomach to a greater extent, also show s better absorption, when it reaches to small intestine. The delayed gastric emptying rate would permit a longer time for dissolution of weak ly basic drug in acidic fluid and in turn would increase its absorption when it reaches the small intestine. For example, absorption of nitrofurantoin is increased in the presence of food. 

vi) Solubility of unionised form of drugs is the rate determining step in the absorption of a drug, but presence of unionised drug is not the sole  

concept, e.g., derivatives of barbituric acid h ave almost same pK a, but have different lipid solubilities, which can be ranked as barbital < apobarbital < pentobarbital.

 vii) Few drugs show good solubility in all parts of GI T, despite of good ionisation, e.g., theophylline and tetracycline. 

6) Drug pKa and Gas trointestinal pH: The dissociation constant (pKa) of drug and the pH of body fluid at the absorption site influence the amount of unionised drug. The unionised form of drug is also most suitable for absorption in GIT. The relative amounts of ionised and un ionised drug in a solution at a particular pH can be obtained from the pKa value of drug and pH of body fluid at the absorption site, by using the Henderson and Hasselbalch equation: For Weak Acids pH = pKa + log Unionizeddrugconcentration Ionizeddrugconcentration

If the concentrations of ionised and unionised drug are equal, the second term of equations (8) and (11) becomes zero (  log 1 = 0), and therefore pKa = pH. Thus, pKa is the characteristic of the drug. If a membrane barrier separates the aqueous solution of different pH (such as the GIT and plasma), the theoretica l ratio of drug concentration (Ra or Rb) on either side of the membrane can be obtained by the equations developed by Shore et al

If the pH ranges from 1 to 8 in the GIT, from 1 to 3 in the stomach, and from 5 to 8 in the intestine (duodenum to colon), certain generalisations about ionisation and absorption of drugs can be made from the pH -partition hypothesis.

For Weak Acids

 i) Weakly acidic drugs with pKa > 8, e.g., phenytoin, ethosuximide , and several barbiturates, are unionised at all pH values and hence their absorption rate is rapid and independent of gastrointestinal pH. 

ii) Weakly acidic drugs with pKa ranging from 2.5 to 7.5, e.g., aspirin, ibuprofen, ph enylbutazone, and penicillin analogues, undergo pH - dependent absorption. At acidic conditions of stomach (pH > pKa), they exist in unionised form and undergo better absorption.

 iii) Strongly acidic drugs with pKa < 2.5, e.g., cromolyn sodium, are ionised in the entire pH range of GIT and hence are poorly absorbed. 

For Basic Drugs 

i) Weakly basic drugs with pKa < 5.0, e.g., caffeine, theophylline, diazepam, oxazepam, and nitrazepam, are ionised at all pH values and hence undergo rapid and pH-independent absorption. 

ii) Weakly basic drugs with pKa ranging from 5 to 11 , e.g., morphine analogues, chloroquine, imipramine, and amitriptyline, undergo pH - dependent absorption. At alkaline conditions of the intestine, they exist in unionised form and undergo better absorption. 

iii) Strongly basic drugs with pKa > 11, e.g., mecamylamine and guanethidine, remain ionised in the entire pH range of GIT and hence are poorly absorbed.

7) Lipophilicity and Drug Absorption: If a drug exists in unionised form, it will still undergo poor absorption , provided its lipid solubility is low, i.e., it has a low value of K o/w. Thus, for a drug to undergo optimum absorption, it should be sufficiently soluble in aqueous medium at the absorption site and also highly lipid-soluble to bring about partitioning of the drug in the lipoidal biomembrane and into systemic circulation. Thus, for optimum bioavailability a perfect hydrophilic -lipophilic balance should exist in the drug structure. The lipid solubility of a drug can be determined from its oil/water partit ion coefficient value (Ko/w).

 8) Particle Size and Effective Surface Area of the Drug: A solid drug’s particle size and surface area are inversely proportional. Smaller the drug particle, greater is its surface area. Two types of surface area are: i) Absolute Surface Area: Total area of solid surface of any particle, and ii) Effective Surface Area: Area of solid surface exposed to the dissolution medium. With micronisation, the dose of certain drugs can be decreased because of increased absorption efficiency, for example, griseofulvin dose was reduced to half and spironolactone dose was reduced 20 times by micronisation.