PHYSIO-CHEMICAL FACTORS AFFECTING DRUG ABSORPTION

FACILITATED BY

Satish.C.SProfessor Dept of pharmaceuticsPESCP 

Presented byOmkar.S.KDept of pharmaceuticsPESCP 

ABSORPTION OF DRUGS

Drug Solubility and Dissolution Rate

the two critical slower rate-determining processes in the absorption of orally administered drugs are:

1. Rate of dissolution, and2. Rate of drug permeation through the biomembrane.

Rate determining steps• 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 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 rate limited or transmembrane rate limited.

Solid dosage form

Solid drug particles

Drug in solution at the absorption site

Drug in the body

RDS for RDS forlipophillic drug Hydrophillic drug

Disintegration deggregation dissolution permeation

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. It is 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. it is a dynamic property

Theories of Drug DissolutionDissolution is the process by which a solid drug substance becomes dissolved in a solvent. Solubility is the mass of solute that dissolves in a specific mass or volume of solvent at a given temperature Several theories to explain drug dissolution.

1. Diffusion layer model/Film theory2. Danckwert's model/Penetration or Surface renewal theory, 3. Interfacial barrier model/Double barrier or Limited solvation theory

Dissolution and ph

Weak acid

Weak base

Increase with increase in pH

Increase with decrease in pH

Dissolution rate

Dissolution rate

Diffusion Layer Model/Film Theory1. Solution of the solid to form a thin film or layer at the solid/ liquid

interface called as the stagnant film or diffusion layer which is saturated with the drug; this step is usually rapid, and

2. Diffusion of the soluble solute from the stagnant layer to the bulk of the solution; this step is slower and is therefore the rate determining step in drug dissolution.

3. It is given by Noyes and Whitney:

SolidDrugpartie

Bulk of the solution with concentration Cb

Stagnant layer of thickness hAnd concentration Cs

Dissolving drug GI lumen GI barrrier Blood

Noyes and Whitney: 

dC/dt= k ( C s-Cb ) where.dC/dt = dissolution rate of the drug,k = dissolution rate constant (first order),Cs = concentration of drug in the stagnant layer (also called as the saturation or maximum drug solubility), andCb = concentration of drug in the bulk of the solution at time t.

Modified Noyes-Whitney's equation

dC/dt = DAKw/p(Cs-Cb)/Vh whereD = diffusion coefficient (diffusivity) of the drugA = surface area of the dissolving solidKw/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/0, 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.

Non-Sink condition

Con

cen

trati

on

of

the d

rug

time

Zero-order dissolutionunder sink conditions

first-order dissolutionunder sink conditions

In case of in-vitro dissolution which is done in a limited amount of solvent thus there is drug concentration built up in the bulk of the liquid

SINK CONDITIONas in case of in-vivo there is less built of concentration in the bulk since the drug is distributed immediately after the dissolution therefore Thus, under in vivo conditions, 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.

Danckwert's Model (Penetration or Surface Renewal Theory)

•Danckwert did not approve of the existence of a stagnant layer and suggested that turbulence in the dissolution medium exists at the solid/ liquid interface. •As a result, the agitated fluid consisting of macroscopic mass of eddies or packets reach the solid/liquid interface in a random fashion due to eddy currents, absorb the solute by diffusion and carry it to the bulk of the solution. •Such solute containing packets are continuously replaced with new packets of fresh solvent due to which the drug concentration at the solid/liquid interface never reaches Cs and has a lower limiting value of Ci. Fresh packet of

solvent approaching the inerface

packet of solvent saturated with drug leaving the interface

Dissolving solid

Interfacial Barrier Model (Double Barrier or Limited Solvation Theory)

The diffusion layer model and the Danckwert's model were based ontwo assumptions:1. The rate-determining step that controls dissolution is the mass transport.2. Solid-solution equilibrium is achieved at the solid/liquid interface.

The diffusion layer model and the Danckwert's model were based ontwo assumptions:1. The rate-determining step that controls dissolution is the mass transport.2. Solid-solution equilibrium is achieved at the solid/liquid interface.

Interfacial Barrier Model (Double Barrier or Limited Solvation Theory)

According to the interfacial barrier model, an intermediate concentration can exist at the interface as a result of solvation mechanism and is a function of solubility rather than diffusion. When considering the dissolutionof a crystal, each face of the crystal will have a different interfacial barrier. Such a concept is given by the following equation

G=Ki(Cs-Cb)WhereG-dissolution rate per unit areaKi=effective interfacial transport constant

Factors Affecting Drug Dissolution and Dissolution Rate

Factors of in vivo. importance that can affect dissolution and henceabsorption can be categorized into 2 classes:1. Physicochemical properties of the drug, and2. Dosage form factors.

pKa and pH profile

Particle size

Polymorphism

Partition coefficient

Physicochemical properties

of the drug

pH

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, and2. Effective surface area which is the area of solid surface exposed to the dissolution medium.

Particle Size and Effective Surface Area of the Drug

dC/dt =DAKw/p(Cs-Cb)/Vh

Noyes whitney equation

Biopharmaceutical importance ofparticle size

Figure shows the effect of particle size of phenobarbital suspensions onthe drug’s bioavailability after intramuscular injection, compared with a solution of the drug, which probably precipitates in fine crystal form at the site of injection. The rate of solution of the drug crystals controls the extent of absorption from the intramuscular site.

Particle size control of drugs

In the case of digoxin there is evidence thatmilling to reduce particle size can producean amorphous modification of the drug withenhanced solubility and hence increased bioavailability.The possibility of changing thecrystal structure during processing is thereforeimportant: comminution, recrystallisationand drying can all affect crystal properties.

Particle size control of drugs

Micronization From the modified 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 micronization, will result in higher dissolution rates.

From the modified 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 micronization, will result in higher dissolution rates.

Exceptions in Micronization 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.

However, in case of hydrophobic drugs like aspirin, phenacetin and phenobarbital, micronization 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—1. The hydrophobic surface of the drugs adsorb air onto their surface which inhibit their wettability; such powders float on the dissolution medium.2. The particles reaggregate 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.3. Extreme particle size reduction may impart surface charges that may prevent wetting; moreover electrically induced agglomeration may prevent intimate contact of the drug with the dissolution medium.

SolutionsThe absolute surface area of hydrophobic drugs can be converted to their effective surface area by: 1 Use of surfactant as a wetting agent that decreases the interfacial tension and displaces the adsorbed air with the solvent—for example, tween 80 increases the bioavailability of phenacetin by promoting its wettability, and2. Adding hydrophilic diluents such as PEG, PVP, dextrose, etc. which coat the surface of hydrophobic drug particles and render them hydrophilic.

Solutions Particle size reduction and subsequent increase in the surface area and dissolution rate is not always advisable especially when the drugs are unstable and degrade in solution form (penicillin G and erythromycin), produce undesirable effects (gastric irritation caused by nitrofurantoin) or when a sustained effect is desired. In addition to increasing the dissolution rate, the second mechanism by which a reduction in particle size improves drug dissolution is through an increase in its solubility. However, such an effect can only be achieved by reducing the particle size to a submicron level which is possible by use of one of the following specialized techniques such as formation of:1. Molecular dispersion/solid solution where the sparingly soluble drug is molecularly trapped in the lattice of a hydrophilic agent such as cyclodextrins, or2. Solid dispersion where such a drug is dispersed in a soluble carrier such as PVP, PEG, urea, etc.

Polymorphism and AmorphismPolymorphism refers to the arrangement of a drug substance in various crystal forms .Depending upon the internal structure, a solid can exist either in a crystalline or amorphous form. When a substance exists in more than one crystalline form, the different forms are designated as polymorphs and the phenomenon as polymorphism1. Enantiotropic polymorph is the one which can be reversibly changed into another form by altering the temperature or pressure e.g. sulfur2. Monotropic polymorph is the one which is unstable at all temperatures and pressures e.g. glyceryl stearates. 

Stable polymorph

Lowest energy,Least solubility,Highest MPlow bioavailability

Metastable polymorph

high energy,high solubility,lowest MPbetter bioavailability

Amorphous drugs

No internal structureHigh energyHigh solubilityBetter bioavailability

Crystals contain highly ordered arrays of molecules and atoms held together by noncovalentinteractions. We can consider as a simple example the unit cell of an inorganic salt, sodium chloride.

Crystal structure

Crystal form

The habit describes the overall shape of the crystal in rather general terms and includes, for example, acicular (needle-like), prismatic, pyramidal, tabular, equant, columnar and lamellar types.  The crystal habit can also influence the ease of compression of a tablet and the flow properties of the drug in the solid state.

The plate-like crystals of tolbutamide, for example, cause powder bridging in the hopper of the tablet machine and also capping problems during tableting. Neither of these problems occurs with tolbutamide in other crystal habits.

crystal habits

•As we have seen, compounds can crystallize out of solution in a variety of different habits depending on the conditions of crystallisation. •These crystal habits usually have the same internal structure and so have the same X-ray diffraction patterns. A more fundamental difference in properties may be found when the compounds crystallise as different polymorphs. •When polymorphism occurs, the molecules arrange themselves in two or more different ways in the crystal; either they may be packed differently in the crystal lattice or there may be differences in the orientation or conformation of the molecules at the lattice sites.

Polymorphism

These variations cause differences in the X-ray diffraction patterns of the polymorphs and this technique is one of the main methods of detecting the existence of polymorphs. The polymorphs have different physical and chemical properties; for example, they may have different melting points and solubilities and they also usually exist in different habits.

Polymorhpism

Spironolactone which is a diuretic steroidal aldosterone agonist, crystallizes as two polymorphic forms and also as four solvated crystalline forms depending on the solvents and methods used for crystallization. We will consider the occurrence of solvated forms at the moment we will concentrate on the two polymorphs only.

  Form 1 is produced when spironolactone powder is dissolved in acetone at a temperature very close to the boiling point and the solution is then cooled within a few hours down to 0°C.

Form 2 is produced when the powder is dissolved in acetone, dioxane or chloroform at room temperature and the solvent is allowed to spontaneously evaporate over a period of several weeks.

Spironolactone

•This drug is known to exist in two polymorphic forms, monoclinic (Form 1) and orthorhombic (Form 2), of which •Form 1 is the more thermo- dynamically stable at room temperature and is the commercially used form. •However, this form is not suitable for direct compression into tablets and has to be mixed with binding agents before tableting, a procedure that is both costly and time-consuming. •In contrast, Form 2 can readily undergo plastic deformation upon compaction and it has been suggested that this form may have distinct processing advantages over the monoclinic form. •Monoclinic paracetamol is readily produced by crystallization from aqueous solution and many other solvents; production of the orthorhombic form has proved more difficult but may be achieved, at least on a laboratory scale, by nucleating a supersaturated solution of paracetamol with seeds of Form 2 (from melt-crystallised paracetamol).

paracetamol

Eight crystal modifications of phenobarbital have been isolated but 11 have been identified with melting points ranging from 112 to 176°C. Of the barbiturates used medicinally, about 70% exhibit polymorphism. The steroids frequently possess polymorphic modifications, testosterone having four: these are cases of true polymorphism and not pseudopolymorphism.

The most important consequence of polymorphismis the possible difference in thebioavailability of different polymorphic forms of a drug; particularly when the drug is poorly soluble. The rate of absorption of such a drug is often dependent upon its rate of dissolution.

Consequences

Of the three polymorphic forms of chloramphenicol palmitate Form Ahas a low biological activity because it is so slowly hydrolysed in vivo to free chloramphenicol.We can see from Fig. 1.13 that the maximum blood levels attained with 100% Form B polymorph are about seven times greater than with 100% Form A polymorph, and that with mixtures of A and B the blood levels vary in proportion to the percentage of B in the suspension.During formulation development it is vital that sufficient care is taken to determine polymorphic tendencies of poorly soluble drugs.

chloramphenicol palmitate

Hydrates/Solvates (Pseudopolymorphism)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 pseudopolymorphs. This phenomenon is called as pscudopolymorphism. When the solvent in association with the drug is water. the solvate is known as a hydrate. Hydrates are most common solvate forms of drugs.Crystals that contain no water of crystallisation are termed anhydrates.

Crystal solvates exhibit a wide range of behaviour depending on the interaction between the solvent and the crystal structure. With some solvates the solvent plays a key role in holding the crystal together; forexample, it may be part of a hydrogen-bonded network within the crystal structure. These solvates are very stable and are difficult to desolvate. When these crystals lose their solvent they collapse and recrystallise in a new crystal form. We can think of these as polymorphic solvates. In other solvates, the solvent is not part of the crystal bonding and merely occupies voids in the crystal. These solvates lose their solvent more readily and desolvation does not destroy the crystal lattice. This type of solvate has been called a pseudopolymorphic solvate.

spironolactone which we considered earlier. As well as the two polymorphs, this compound also possesses four solvates, depending on whether it is crystallized from acetonitrile, ethanol, ethyl acetate or methanol. Each of these solvates is transformed to the polymorphic Form 2 on heating, indicating that the solvent is involved in the bonding of the crystal lattice.

spironolactone

Modification of the solvent of crystallization may result in different solvated forms. This is of particular relevance because the hydrated and anhydrous forms of a drug can havemelting points and solubilities sufficiently different to affect their pharmaceuticalbehaviour. For example,

Pharmaceutical consequences of solvate formation

Drug Form MP SolubilityGlutethimide

anhydrous 83 .042%

Glutethimide

hydrated 68 .026

Hydrates/Solvates (Pseudopolymorphism)1. The anhydrous form of theophylline and ampicillin have higher aqueous

solubilities, dissolve at a faster rate and show better bioavailability in comparison to their monohydrate and trihydrate forms respectively.

2. On the other hand, the organic (nonaqueous) solvates have greater aqueous solubility than the nonsolvates—for example, the n-pentanol solvate of fludrocortisone and succinylsulfathiazole and the chloroform solvate of griseofulvin are more water-soluble than their nonsolvated forms. Like polymorphs, the solvates too differ from each other in terms of their physical properties.

Drug Solvate Form

Hydrate form

Solubility

Ampicillin,theophylline

Anhydrous - Faster

Ampicillin,theophylline

Hydrates Mono or tri

Low

Exceptions stated belowFlurocortisone n-pentol FasterFlurocortisone - Low

Most drugs are either weak acids or weak bases. One of the easiest approach to enhance the solubility and dissolution rate of such drugs is to convert them into their salt forms. Generally, with weakly acidic drugs, a strong base salt is prepared such as the sodium and potassium salts of barbiturates and sulfonamides. In case of weakly basic drugs, a strong acid salt is prepared like the hydrochloride or sulfate salts of several alkaloidal drugs.

Salt Form of the Drug

Dissolution

Salt of weak acid

Diffusion layer higher pH(5-6)

Bulk of the solution relatively lower pH(1-3)

Soluble form of the drug

Drug in solution

Fine precipitate

Mechanism 1Consider the case of a salt of a weak acid. At any given pH of the bulk of the solution, the pH of the diffusion layer (saturation solubility of the drug) of the salt form of a weak acid will be higher than that observable with the free acid form of the drug (can be practically observed in the laboratory). Owing to the increased pH of the diffusion layer, the solubility and dissolution rate of a weak acid in this layer is promoted, since it is a known fact that higher pH favors the dissolution of weak acids. Thus, if dissolution is faster, absorption is bound to be rapid. In case of salts of weak bases, the pH of the diffusion layer will be lower in comparison to that found with the free base form of the drug. Consequently, the solubility of a basic drug at this lower pH is enhanced.

Mechanism 2Yet another convincing reason for enhanced solubility of salts of weak acids is the precipitation of the drug as very fine particles. When the soluble ionic form of the drug diffuses from the stagnant diffusion layer into the bulk of the solution whose pH is low, it is transformed into its free acid form having lesser aqueous solubility at the lower pH of the bulk solution. Consequently, this free acidic form of the drug is precipitated in the form of fine particles. The resultant increase in the surface area is then responsible for the rapid dissolution and absorption in comparison to the drug administered in just the acidic form. 

size of the counter ion.Generally speaking, smaller the size of the counter ion, greater the solubilityof salt—for example, the bioavailability of novobiocin from its sodium salt, calcium salt and free acid form was found to be in the ratio—50 : 25 : 1.Where the counter ion is very large in size and/or has poor ionic strength (as in the case of ester form of drugs), the solubility may be much lower than the free drug itself—for example, the pamoates, stearates and palmitates of weak bases have poor aqueous solubility.

Drug pKa and Lipophilicity and Gl pH—pH Partition HypothesisThe fraction of drug in solution that exists in the nonionised form is the function of both the dissociation constant of the drug and pH of the solution.

for weak acids.

PH = pKa+log (ionized drug concentration/ unionized drug

concentration) for weak bases

PH = pKa+log (unionized drug concentration/ ionized drug concentration )

FACTORS AFFECTING ABSORPTION1. The dissociation constant (pKa) of the drug.2. The lipid solubility of the unionized drug.3. The pH at the absorption site.

Acidic drug LOW pH

Unionized form

High pHionized form

IonisationSince most drugs are weak electrolytes (weak acids or weak bases), 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 compartmentwhose pH favors greater ionization of the drug will contain greater amount of drug, and only the unionized or undissociated fraction of drug

The hypothesis was based on the assumptions that:

1. The GIT is a simple lipoidal barrier to the transport of drug.2. Larger the fraction of unionized drug, faster the absorption.3. Greater the lipophilicity (K0/w) of the unionized drug, better the absorption

Imporatance of IonizationThe pH of urine may be adjusted (for example by administration of ammonium chloride or sodium bicarbonate) in cases of overdosing with amfetamines, barbiturates, narcotics and salicylates, to ensure that thesedrugs are completely ionised and hence readily excreted. Conversely, the pH of theurine may be altered to prevent ionisation of a drug in cases where reabsorption is requiredfor therapeutic reasons. Sulfonamide crystalluria may also be avoided by making the urinealkaline.

Drug pKa and Gastrointestinal pHThe amount of drug that exists in unionized form is a function of dissociation constant (pKa) of the drug and pH of the fluid at the absorption site.The relative amount of ionized and unionized drug in solution at a particular pH and the percent of drug ionized at this pH can be

determined by Henderson-Hasselbach equations:

for weak acids.PH = pKa+log (ionized drug concentration/ unionized drug concentration)% Drug Ionized = (10pH-pKa/1+10pH-pKa)*100 for weak basesPH = pKa+log (umonized drug concentration/ ionized drug concentration)% Drug Ionized = (10pKa-pH/1+10pKa-pH)*100

Dissociation of weakly acidic and basic drugs and their salts

According to the Lowry_–_Brønsted theory of w = acids and bases, an acid is a substance which will donate a proton and a base is a substance which will accept a proton. Thus the dissociation of acetylsalicylic acid, a weak acid, could be represented as followsIn this equilibrium, acetylsalicylic acid acts as an acid, because it donates a proton, and the acetylsalicylate ion acts as a base, because it accepts a proton to yield an acid. An acid and base represented by such an equilibrium is said to be a conjugate acid_–_base pair.

Salts of weak acids or bases are essentially completely ionised in solution. For example, ephedrine hydrochloride (salt of the weak base ephedrine, and the strong acid HCl) exists in aqueous solution in the form of the conjugate acid of the weak base, C6H5CH(OH)CH(CH3) N!H2CH3, together with its Cl- counterions.In a similar manner, when sodium salicylate (salt of the weak acid salicylic acid, and the strong base NaOH) is dissolved in water, it ionises almost entirely into the conjugate base of salicylic acid, HOC6H5COO0, and Na+ ions. The conjugate acids and bases formed.this way are, of course, subject to acid–base equilibria described by the general equations above.

The effect of pH on the ionisation ofweakly acidic or basic drugs and their salts

Calculate the percentage of cocaine existingas the free base in a solution of cocaine hydrochloride at pH 4.5, and at pH 8.0. ThepKb of cocaine is 5.6.

DRUG Acidic range

pKa range

Ionization state

Ph dependency

absorption

Phenytoin, Ethosuxamide

Weakly acidic

pKa>8 Un-ionised Independent Well absorbed

Aspirin Moderately Acidic

2.5-7.5 Unionized when(pH<pKa)

dependent Better absorbed in gastric pH

cromolyn sodium

Strongly acidic

Less than 2.5

Ionized Poorly absorbed

For weak acids

For weak basesDRUG Basic

range

pKa range

Ionization state

Ph dependency

absorption

Caffeine,theophylline

Weakly basic

<5.0 Un-ionised Independent

Well absorbed

Morphine,chloroquine

Moderately basic

5-11 Ionized in acidic and unionized in basic ph

pH dependent

Better absorbed in intestinal pH

Mecamylamin Strong base

11 Ionized Poorly absorbed

Lipophilicity and Drug Absorption

As mentioned earlier, it is the pKa of a drug that determines the degree of ionization at a particular pH Thus, even if the drug exists in the unionized form, it will be poorly absorbed ifit has poor lipid solubility (or low K<j/W). Ideally, for optimum absorption, a drug should have sufficient aqueous solubility to dissolve in the fluids at the absorption site and lipid solubility (K<,/w) high enough to facilitate the partitioning of the drug in the lipoidal biomembrane and intothe systemic circulation. In other words, a perfect hydrophilic –lipophilic balance (HLB) should be there in the structure of the drug for optimum bioavailability.The lipid solubility of a drug is determined from its oil/water partition coefficient (Ko/w) value. This value is a measure of the degree of distribution of drug between one of the several organic, water immiscible, lipophilic solvents.