PHYSIO-CHEMICAL FACTORS AFFECTING DRUG ABSORPTION

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FACILITATE D BY
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Satish

Presented by Omkar.S.K Dept of pharmaceutics PESCP

ABSORPTION OF DRUGS
Drug Solubility and Dissolution Rate
the two critical slower rate-determining processes in the absorption of orally administered drugs are:

Click of edit Master subtitle style 1. Rate to dissolution, and 2. Rate of drug permeation through the biomembrane.

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etermining 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 solubilityfor example, cromolyn sodium or neomycin, then dissolution is rapid and the RDS in the absorption of such drugs is rate of permeation through thesubtitle style In other words, Click to edit Master biomembrane. absorption of such drugs is said to be permeation rate limited or transmembrane rate limited.

Soli d dosa ge form

Disintegration deggregation

Solid drug parti cles

dissolution Drug in solution permeation

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Dru at the g in absorption site the bod y RDS for RDS for lipophillic drug Hydrophilli

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.

Click to edit Master rate Dissolutionsubtitle style

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
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Theories of Drug Dissolution

Dissolution 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 Click to edit Master subtitle style dissolution. 1. Diffusion layer model/Film theory 2. Danckwert's model/Penetration or Surface renewal theory, 3. Interfacial barrier model/Double barrier or Limited solvation theory

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Dissolution and ph

Dissolution Increase with increase rate Weak acidMaster subtitle style Click to edit in pH Dissolution rate Increase with decrease in pH

Weak base

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Diffusion Layer Model/Film Theory

1.

2.

3.

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 Click to and Master subtitle Stagnant layer of thickness h style rapid, edit And concentration Cs Diffusion of the soluble solute from the stagnant layer to the bulk of the solution; this step is slower and is therefore the rate Solid determining step in drug dissolution. Drug It is given by Noyes and Whitney: partie Bulk of the solution with
concentration Cb

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Dissolving drug

GI lumen

GI barrrier Blood

Noyes and Whitney:

dC/dt= k ( C s-Cb ) Click to where.edit Master subtitle style dC/dt = dissolution rate of the drug, k = dissolution rate constant (first order), Cs = concentration of drug in the stagnant layer (also called 4/15/12 as the saturation or maximum

Modified Noyes-Whitney's equation

dC/dt = DAKw/p(Cs-Cb)/Vh
where D = diffusion coefficient (diffusivity) of the drug Click to edit Master subtitle style 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/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.
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Non-Sink condition
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 CONDITION as in case of in-vivo Zero-order dissolution there is less built of under sink conditions Click to edit Master subtitle style concentration in the bulk since the drug first-order dissolution is distributed under sink conditions immediately after the dissolution therefore Thus, under in vivo conditions, there is no concentration build-up in the bulk 4/15/12 time of the solution and

Concentration of the drug

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 Click to to eddy currents, absorb the fashion due edit Master subtitle style 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.

Dissolv ing solid

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Fresh packet of solvent approaching the packet of solvent inerface saturated with

Interfacial Barrier Model (Double Barrier or Limited Solvation Theory)

The diffusion layer model and the Danckwert's model were based on two assumptions: 1. The rate-determining step that controls Click to edit the mass transport. dissolution isMaster subtitle styleand the The diffusion layer model 2. Solid-solution equilibrium is achieved at the Danckwert's model were based on solid/liquid interface.

two assumptions: 1. The rate-determining step that controls dissolution is the mass transport. 2. Solid-solution equilibrium is achieved at the solid/liquid interface. 4/15/12

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 Click to function subtitle style and is aedit Masterof solubility rather than diffusion. When considering the dissolution of 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) Where 4/15/12 G-dissolution rate per unit area

Factors Affecting Drug Dissolution and Dissolution Rate

Factors of in vivo. importance that can affect dissolution and hence absorption can be categorized into 2 classes: 1. Physicochemical properties of Click to edit Master subtitle style the drug, and 2. Dosage form factors.

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Partition coefficien t pKa and pH profile

Physicochemi Click to edit Master subtitle style cal properties of the drug

Polymorp hism

Particle size 4/15/12

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: Click to edit Master subtitle style 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.

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Particle Size and Effective Surface Area of the Drug

Noyes whitney equation

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

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Biopharmaceutical importance of particle size

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Figure shows the effect of particle size of phenobarbital suspensions on the drugs 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.
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Particle size control of drugs

In the case of digoxin there is evidence that milling to reduce particle size can produce an amorphous modification of the drug with enhanced solubility and hence increased bioavailability. Click to edit Master subtitle style The possibility of changing the crystal structure during processing is therefore important: comminution, recrystallisation and drying can all affect crystal properties.

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Particle size control of drugs

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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 Click to edit Master subtitle higher micronization, will result instyle dissolution From the modified Noyesrates.

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 4/15/12 particle size, which can be

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 Click to edit Master subtitle style 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 4/15/12 charges that may prevent wetting; moreover electrically

Solutions
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 decreases the interfacial tension and displaces the adsorbed air Click to edit Master subtitle style with the solventfor example, tween 80 increases the bioavailability of phenacetin by promoting its wettability, and 2. Adding hydrophilic diluents such as PEG, PVP, dextrose, etc. which coat the surface of hydrophobic drug particles and render them hydrophilic.

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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 Click toreduction in particle sizestyle which a edit Master subtitle 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, or 2. Solid dispersion where such a drug is dispersed in a soluble carrier such as PVP, PEG, urea, etc.
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Polymorphism and Amorphism

Polymorphism 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 polymorphism 1. Enantiotropic polymorph is the one which can be

reversibly changed into another form by altering the Click to edit Master subtitle style temperature or pressure e.g. sulfur 2. Monotropic polymorph is the one which is unstable at all temperatures and pressures e.g. glyceryl stearates.

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Stable polymorph

Metastable polymorph

Click to edit Master subtitle style Lowest energy, Least solubility, Highest MP low bioavailability

high energy, high solubility, lowest MP better bioavailability No internal structure High energy High solubility

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Amorphous drugs

tructure
Crystals contain highly ordered arrays of molecules and atoms held together by noncovalent interactions. We can consider as a simple example the unit cell of an Click to salt, sodium chloride. inorganic edit Master subtitle style

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Crystal form

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crystal habits
The habit describes the overall shape of the crystal in rather general terms and includes, for example, acicular (needlelike), 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 Click state. to edit Master subtitle style 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.

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Polymorphism
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 Click to edit Master subtitle style 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.

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Polymorhpism
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.

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Spironolactone
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.

Click to edit Master subtitle style 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 0C.

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.
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paracetamol
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 Click to procedure that is both costly tableting, aedit Master subtitle style 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).

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

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The most important consequence of polymorphism is the possible difference in the bioavailability 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. Click to edit Master subtitle style

Consequences

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Of the three polymorphic forms of chloramphenicol palmitate Form A has 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 4/15/12 polymorphic tendencies of poorly soluble drugs.

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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 Master different crystalline forms called as Click to edit exist in subtitle style 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.

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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; for Click to edit Master subtitle hydrogen-bonded example, it may be part of a style 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 4/15/12 the crystal bonding and merely occupies

spironolactone
spironolactone which we considered earlier. As well as the two polymorphs, this compound also possesses four solvates, depending onClick to editcrystallized from style whether it is Master subtitle 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.

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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 have melting points and solubilities sufficiently different to affect their pharmaceutical behaviour. Click to edit Master subtitle style For example,

Pharmaceutical consequences of solvate formation

Drug Form Glutethimide anhydrous Glutethimide hydrated

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MP 83 68

Solubility .042% .026

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Hydrates/Solvates (Pseudopolymorphism)
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 Click to edit Master subtitle style nonsolvatesfor example, the n-pentanol solvate of Drug Solvate Form Hydrate Solubility fludrocortisone and succinylsulfathiazole and the form chloroform solvate of griseofulvin are more waterAmpicillin,theophylline Anhydrous Faster Ampicillin,theophylline Hydrates Mono or tri Low soluble than their nonsolvated forms. Like polymorphs, the solvates too differ from each other Exceptions stated below in terms of their physical properties.
1.

Flurocortisone Flurocortisone
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n-pentol -

Faster Low

Salt Form of the Drug

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 Click to edit Master subtitle style 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.

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Dissolution
Click to edit Master subtitle style Bulk of the Diffusion layer solution higher pH(5-6) relatively lower pH(1-3) Salt of weak acid
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Soluble form of the drug

Drug in solution Fine precipitate

Mechanism 1
Consider 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 Click to edit Master subtitle style 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 4/15/12 that found with the free base form of the drug.

Mechanism 2
Yet 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 Click to edit Master stagnant diffusion layer into the drug diffuses from thesubtitle style 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. 4/15/12

size of the counter ion.

Generally speaking, smaller the size of the counter ion, greater the solubilityof saltfor example, the bioavailability of novobiocin from its sodium salt, Click salt and free subtitle style calciumto edit Master acid form was found to be in the ratio50 : 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 itselffor 4/15/12 example, the pamoates,

Drug pKa and Lipophilicity and Gl pHpH Partition Hypothesis in solution that exists in the The fraction of drug
nonionised form is the function of both the dissociation constant of the drug and pH of the solution. Click to edit Master subtitle style for weak acids. PH = pKa+log

(ionized drug concentration/ unionized drug concentration)

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FACTORS AFFECTING ABSORPTION

1. The dissociation constant (pKa) of the drug. 2. The lipid solubility of the unionized drug. 3. The pH at the absorption site. Click to edit Master subtitle style Acidic drug
LOW pH

Unioniz ed form
ionized form

High pH
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Ionisation
Since 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 compartment whose pH favors greater ionization of the drug will contain greater amount Master subtitle styleunionized or Click to edit of drug, and only the 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 4/15/12

Imporatance of Ionization
The 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 these Click to completely subtitle style drugs are edit Master ionised and hence readily excreted. Conversely, the pH of the urine may be altered to prevent ionisation of a drug in cases where reabsorption is required for therapeutic reasons. Sulfonamide crystalluria may also be avoided by making the urine alkaline.
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Drug pKa and Gastrointestinal pH

The 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 Click to edit Master subtitle style

Henderson-Hasselbach equations: for weak acids. PH = pKa+log (ionized drug concentration/ unionized drug concentration) 4/15/12 % Drug Ionized = (10pH-pKa/1+10pH-

Dissociation of weakly acidic and basic drugs and their salts

According to the Lowry__Brnsted 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 Click to edit Master subtitle style weak acid, could be represented as follows In 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.

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Click to edit Master subtitle style

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Salts of weak acids or bases are essentially completely ionised in solution. For example, ephedrine hydrochloride (salt of Click to base ephedrine, and the the weakedit Master subtitle style 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, 4/15/12

of weakly acidic or basic drugs and their salts

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Calculate the percentage of cocaine existing as the free base in a solution of cocaine hydrochloride at subtitle style Click to edit Master pH 4.5, and at pH 8.0. The pKb of cocaine is 5.6.

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For weak acids

DRUG Acidic range pKa rangeIonization state Ph absorptio dependency n Independent Well absorbed Better absorbed in gastric pH Poorly absorbed

Phenytoin, Weakly pKa>8 Un-ionised Click to edit Ethosuxamide acidic Master subtitle style Aspirin Moderately 2.5-7.5 Acidic

Unionized dependent when(pH<pK a)

cromolyn sodium

Strongly acidic

Less than 2.5

Ionized

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For weak bases

DRUG Basic pKa range range Weakly <5.0 basic edit Master Modera 5-11 tely basic Ionization Ph absorpti state dependencyon Un-ionised Independent Well absorbed style Better absorbed in intestinal pH Poorly absorbed

Caffeine, theophylline Click to Morphine, chloroquine

subtitle

Ionized in pH acidic and dependent unionized in basic ph Ionized

Mecamylamin

Strong 11 base

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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 if it has poor lipid solubility (or low K<j/W). Ideally, for Click to edit Master subtitle style 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 into the systemic circulation. In other words, a perfect hydrophilic lipophilic balance (HLB) should be there in the structure of the drug for optimum bioavailability. 4/15/12 The lipid solubility of a drug is determined from its

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