Pharmacy USTC

Biopharmaceutics

Introduction

· Biopharmaceutics is a pharmaceutical science encompassing the study of the relationship between the nature and the intensity of biologic effects and the various formulation factors, such as the chemical nature of the drug, inert formulation additives , the pharmaceutical processes used to manufacture the dosage forms.

· The nature ,the intensity of the biologic effects are generally proportional to the total amount of drug made available to the body.

· For example figure 1 presents a situation in which one of the two is totally ineffective since it fails to provide the minimum effective concentration in the body.

· If the two formulations produced identical blood levels, they would be considered bioequivalent, or equally bioavailable.

· The differences in the bioavailability or the extent of the drug absorption from a dosage form, are the result of differences in formulation as well as of differences in the physiologic and pathologic states of the patients.

· Therefore, various correlates have been developed to estimate the bioavailability of drug products through in-vitro or in-vivo techniques.

Gastrointestinal absorption

Pathways of drug absorption

· Once a drug molecule is in solution it has the potential to be absorbed.

· If there are no interfering materials present to decrease the absorption, the drug molecule must come in contact with the absorbing membrane.

· To accomplish this, the drug molecules must diffuse from GI fluids to the membrane surface .

· The most appropriate definition of drug absorption is the penetration of the drug across the intestinal membrane and its appearance , unchanged in the blood draining the GIT.

· For drug molecule to be absorbed from GIT and gain access to the body (i.e systemic circulation) it must effectively penetrate all regions of the intestine just cited.

· There are primarily three factors governing this absorption process once a drug is in solution.

1- Biologic factors.

2- Physicochemical characteristics of the molecule.

3- The properties and components of GI fluids and the nature of the absorbing membrane.

1- Biologic considerations

Drugs are most commonly given orally and the GIT plays The major role in determining the rate and the extent of drug absorption.

Membrane physiology

The GI barrier that separates the lumen of the stomach and intestines from the systemic circulation and the sites of drug action is a complex structure composed of:

v The barrier has the characteristics of semi-permeable membrane, permitting the rapid passage of some chemicals while retarding or preventing the passage of others.

v Amino acids, sugars, fatty acids, and other nutrients required for life readily cross the barrier in healthy individuals.

v At the same time the barrier can be highly restrictive. For example there is virtually no leakage of plasma protein in GIT.

v Certain toxins , which produce lethal effects if present in the circulation in minute quantities, are harmless if ingested because their inability to traverse the barrier.

v Most drugs used in clinical practice are administered orally and must contained with this barrier before reaching the systemic circulation.

v Thus the nature and characteristics of GI barrier are of considerable importance in bio-pharmaceutics.

Lipid soluble molecules

· Including many drugs, as well as, hydrophilic small molecules and ions are readily absorbed from GIT in apparently passive manner.

· On the other hand, certain larger polar molecules with M.W. up to several hundred are also absorbed but in a manner suggesting the active participation of components of the membrane.

· According, the biologic membrane may be viewed as a dynamic lipoid ΔΔpores or channels, too small to be seen.

· Lipid soluble molecules penetrate the barrier directly through the barrier directly through the fat-like portion of the lipoprotein membrane .

· Aqueous pores render the epithelial membrane freely permeable to water, to monovalent ions and to hydrophilic solutes of small molecular size such as urea.

· Membrane transport of drugs and other chemicals directly through the lipid or aqueous channels is called passive diffusion or non-ionic diffusion.

· Carrier mediated transfers of polar molecules is called active transport.

Passive diffusion mechanism

ü This process describe the movement of molecules from a region of high relative concentration to a region of lower relative concentration.

ü It also include the movement of ions from a region of high ionic charge of one type to a region of lower charge of the same type or of opposite charge.

ü ΔXa/Δt=DA (Cgut-C)

ü Where Xa = amount of the drug at the absorption site

ü D = diffusion coefficient

ü A = area of absorption surface

ü Cgut = conc. Of drug in the GIT

ü C = conc. Of drug in plasma

ü Passive diffusion mechanism is also described by Fick's law, which states that the rate of diffusion across a membrane. (dc/dt) is proportional to the difference in drug conc. On each side of the membrane (ΔC).

ü -dc/dt=k ΔC = K(C1-C2)

ü C1,C2 the drug conc.on each side of the membrane and K is proportionally constant.

Active transport mechanism

§ Although most drugs re absorbed from the GIT by passive diffusion, certain compounds of therapeutic interest and many substance of nutritional concern are absorbed by an active transport is a specialized process which require energy. The various active transport processes found in the GIT are relatively structure – specific and serve primarily in the absorption of natural substances.

§ Such as monosaccharides, 1- amino acids, pyrimidines, bile salts, and certain vitamines.

§ Also ions and organic substance such as sodium, calcium, iron, glucose and intestinal absorption of drugs such as fluorouracil and 5- bromouracil.

§ Examples of active transport are renal and biliary secretion of many acids and bases.

§ Active transport is specific not only in terms of chemical structure but also with respect to direction, transporting molecules mainly from the mucosal side to the serosal side of the GIT.

§ The transport can also take place against the conc. Gradient i.e. from a region of lower conc. Or activity to region of higher activity.

§ Since active transport involves involves enzymes, these can be saturated at higher conc. Of the drug, and that particular drug can compete with, and thus depress, the transport of another drug if both are transported by the same process.

§ Since active transport process consume energy, they can be inhibited by various metabolic poisons, such as fluoride or dinitrophenol, as well as lack of oxygen.

Facilitated diffusion

v Some compounds move through biological membrane at a rate and to an extent greater than that which can accounted by simple diffusion.

v Carriers present within the membrane, which can be enzyme or some other components of GI epithelial cells, are assumed to form a complex with the drug resulting in an improved membrane permeability for complex over that of the drug alone.

v After the complex traverses the membrane, the complex is dissociated and the drug is liberated. Facilitated diffusion occurs with the conc. Gradient. Transport of vitamin B1 and B2 are examples of compounds that cross membranes by Facilitated diffusion mechanism.

Gasterointestinal blood flow

v The blood perfusing the GIT plays a critical role in drug absorption by continuously maintaining the conc.gradient across the epithelial membrane.

v Polar molecules that are slowely absorbed show no dependence on blood flow, the absorption of the lipid soluble molecules that are small enough to easily penetrate the aqueous pores is rapid and highly dependent on rate of blood flow.

v The absorption of most drugs shows an intermediate dependence on blood flow rate.

v In general, the rate of drug absorption will be unaffected by normal variability in mesenteric blood flow because blood flow is rarely the rate limiting step in absorption process.

v The entire blood flow supply draining most of the GIT retunes to systemic circulation by way of liver.

v Therefore, the entire dose of a drug that is given orally and completely absorbed

Gastrointestinal absorption

II- Physicochemical considerations

Drug absorption is influenced by many physiologi factors, but also depend on the solubility, particle size, chemical form, and other physicochemical characters of the drug itself.

Chemical form

· Appropriate selection of the chemical form of a drug is very important in achieving desired bioavailability.

· Chemical modification can involve changing chemical structure of a drug to a form which different from the active drug entity.

· Particle size:

· Increased absorption due to reduction of particle size is a result of increase dissolution, which increase surface exposed to GI fluids. But this is not true for hydrophobic drugs.

There are other physicochemical factors which affect on the absorption of drugs as:

a- Ionization constant

b- Polymorphism and amorphysim

c- Salvation

d- Complexation

e- Surface activity

PH partition theory

The dissociation constant and lipid solubility of a drug as well as pH at the absorption characteristics of a drug from solution.

The relationship between these parameters is known as Partition theory of drug absorption.

· This theory is based on that the GIT is a simple lipid barrier to the transport of drugs and chemicals.

· According the non-ionized form an acid or basic drug, if sufficiently lipid soluble, is absorbed but the ionized form not.

· The larger the fraction of drug in a non-ionized form at specific absorption site, the faster is the absorption.

· Acid and neutral drugs may be absorbed from the stomach but basic drugs are not.

· The rate of absorption is related to oil- water partition coefficient of a drug, the more lipophilic the compound, the faster its absorption.

Drug pKa and GI pH

· The fraction of drug in solution that exists in non- ionized form is a function of the drug and pH of the solution.

· The dissociation constant is often expressed for both acids and bases as pKa.

· The relation between pH and pKa, and the extent of ionization is given by the Henderson- Hasselbalch equation:

For an acid:

pKa – pH = log ( Fu / Fi)

for basic drug:

pKa – pH = log ( Fi/ Fu)

· where Fu and Fi are the fractions of the drug present in the un – ionized and ionized forms respectively.

· According to this equation an increase in the pH of the stomach should retard the absorption of weak acids, but promote the absorption of weak bases.

· The gastric absorption of aspirin is considerably reduced when the drug is given in buffered solution ( gastric pH5) compared to the results following administration of asirin in unbuffered solution (gastric pH = 2).

Lipid solubility

· Certain drugs may be poorly absorbed after oral administration even though they are largely un- ionized in the small intestine, this is due to lipid solubility of the uncharged molecules .

· Sometimes the structure of an existing drug can be modified to develop a similar compound with impaired absorption. A prodrug is chemical modification, is an ester of the drug that reverts back to the original compound by means of metabolism or chemical reaction in the body .

· Prodrugs are developed to overcome one or more of undesirable characters of the parent compound, such as bitter taste, poor solubility, pain on injection, poor distribution, or poor absorption.

· Poor drugs designed to improve the permeability and oral absorption, are more lipid soluble than the parent compound and should be converted to the parent compound during absorption in the gut wall or liver.

· Prodrug of ampicillin ( bacampicillin) it is ester of ampicillin, it rapidly and completely absorbed after oral administration even when take with food. It is completely hydrolyzed into ampicillin. Peak blood level of bacampicillin are reached more quickly and twice those found after oral administration of prodrug.

· Absorption of ions

· Although the pH – partition theory of drug absorption has been found to be useful, it must be viewed as an approximation because it does not adequately account for certain experimental observation, such as the pharmacologic activity after oral administration of quaternary ammonium compounds.

Unstirred water layers

· The pH – partition theory suggests that a pH – drug absorption profile should be described by dissociation curve of the drug.

· To the contrary there is much experimental evidence to show that the pH – absorption profile is shifted two or more pH units from the theoretic curve

· This discrepancy can be resolved by assuming that another barrier to a drug transports exists in parallel with intestinal membrane.

· There is evidence that this additional barrier is an unstirred or stagnant water layer, adjacent to the lumen surface of the intestinal membrane.

A model describing these barriers is shown in the following figure

Lumen unstirred layer mucosal cell

C1 C2 C3

Fig: intestinal membrane with additional barrier.

Under these condition, the flux of drug molecules across the unstirred layer:

Flux = (D/h) (C1 – C2)

Where D : Diffusion coefficient of the drug

H: thickness of unstirred layer

C1, C2 : are the conc. In the lumen and the layer immediately adjacent to cell membrane respectively

On the other hand, flux across the membrane equals :

Flux = P(C2-C3)

Where P: permeability coefficient for the drug

C3: drug conc. In the cell.

We usually assume that the flux from the cell to the blood stream is large, so that the drug conc. In the cell is effectively = zero

Then the equation become :

Flux = P C2

Thus the absorption rate of the drug from solution –(dC/ dt) is given by

– dC /dt = (D/h) (C1 – C2) = PC2

Two limiting cases exist:

1- The unstirred layer is the major barrier to absorption.

2- The cell membrane is the major barrier to absorption.

1- If P ≥ (D/h), then the diffusion across the unstirred layer is the rate limiting step and

-dc/dt = (D/h) C1

· In this case, absorption rate is a function of the diffusion coefficient of the drug or solute and thickness of the layer.

· One would expect the unstirred layer to be the rate – limiting step in the absorption of high M.W. lipid soluble compounds. Yhis is indeed the casefor the absorption of bile acids and fatty acid from miceller solution .

2- If (D/h) ≥ P, the permeability of the membrane is the rate limiting absorption rate is given by:

-dc/dt = P C2

· In this case the absorption rate is a function of lipid solubility and related factors including the extent of ionization.

· One would expect the intestinal membrane to be rate limiting for absorption of low M.W. solutes having low to moderate lipid solubility. This case applies well to the absorption of fatty acid monomers and many drugs.

Dissolution

When a drug is given orally in the form of a tablet ,capsule, or suspension, the rate of the absorption is often controlled by how fast the drug dissolved in the fluid at the absorption site. In other words, the dissolution rate is often rate limiting step in the sequence.

Solid
		drug in solution at absorption site

Drug in systemic circulation

when the dissolution is the controlling step in the overall process, absorption is said to be rate limiting step.

Absorption from solution proceeds more rapidly absorbed from solution than from solid dosage form, it is likely that absorption is rate limited by dissolution.

A general relationship describing the dissolution process was first observed by Noyes- whitney equation stats that:

dc /dt = Ks (Cs – C)

where :dc / dt: is the dissolution rate

K : is a constant

S: is the surface area of the dissolving solid

Cs: is the solubility of the drug in the solvent

C: is the concentration of the drug in the solvent at time t

The constant K has been shown to be equal to D / h , where D is the diffusion coefficient of the dissolving drug, and h is the thickness of the diffusion layer.

The diffusion layer, like the unstirred water in the intestine, is thin stationary film of the solution adjacent to the surface of the solid.

The layer is saturated with drug , drug concentration in the layer is equal to Cs.

The term (Cs –C) ,represents the concentration gradient between the diffusion layer and the bulk solution.

In dissolution rate limited absorption, C is negligible compared to Cs. Under this condition, the dissolution rate is equal:

dc /dt = DSCs / h

The above equation describes a diffusion – controlled dissolution process

The solubility ( Cs) of many drugs increases with increasing temperature. Therefore dissolution is temperature dependent,

On other hand, diffusion coefficient D is inversely related viscosity, dissolution rate decreases as the viscosity of the solvent increases.

The dgree of agitation or stirring of the solvent can affect the thickness of the diffusion layer (h). the greater the agitation ,the thinnerthe layer and the more rapid the dissolution.

Changes in the solvent,such as pH, that affect the solubility of the drug affect the dissolution rate. Similarly, the use of different salts, or other chemical or physical forms of a drug, which have a solubility or effective solubility different from that of the parent drug, usually affect dissolution rate.

Increasing surface area of drug exposed to the dissolution medium, by reducing the particle size or by attaining more effective wetting of the solid by the solvent frequently increases the dissolution rate.

Bulk Solubility and Solubility in the Diffusion Layer

The solubility of weak acid or base can change as a function of pH. Therefore, differences are expected in the dissolution rate of such drugs in different regions of the GIT.

The dissolution rate of weak acids increases with increasing pH, whereas the dissolution of weak bases decreases with increasing pH.

It is important for poorly soluble weakly basic drugs to dissolve rapidly in stomach, since the dissolution rate of undissolved drug in the small intestine may be too low to permit complete absorption.

Ketoconazole, a systemic antifungal agent, is a weak base that requires acidity for dissolution and absorption. Patients also being treated with antacids, anticholinergics, or H2-blockers which reduce gastric acidity, should take these drugs at least two hours after Ketoconazole.

The relatively poor dissolution of weak acids at the pH of gastric fluids diminishes further the importance of the stomach as a drug absorption site.

Although gastric absorption of weak acids from solubility may substantial, it is unlikely that much drug dissolves during the limited residence of a solid dosage form in the stomach.

Dissolution and GI absorption studies with a series of sulfonamides (weak acids) suggest that the importance of gastric absorption is a function of drug solubility at gastric pH.

Changes in gastric pH alter the solubility of certain drugs and may affect dissolution and absorption rate. Patients with achlorhydria have a distinctly higher gastric pH and absorb aspirin (pKa = 3.5) more rapidly than healthy subjects.

Salts

The dissolution rate of particular salt is different from that of the parent compound.

Sodium and Potassium salts of weak acids dissolve more rapidly than the free acids, regardless of the pH of the dissolution medium.

Many of the examples exist on the effect of soluble salts on drug absorption. The bioavailability of novobiocin after oral administration of the sodium salt is twice that of calcium salt and 50 times that of free acid.

The potassium salt of penicillin V yields higher peak concentration of antibiotic in plasma than does the free acid.

A Clear example of the difference in pharmacologic response that may result from administering 2 different chemical forms of the same drug is found with tolbutamide sodium in 0.1 N Hcl is about 5000 times greater than that of the free acid. At pH 7.2 the dissolution rate of the sodium salt is about 275 times greater than that of tolbutamide.

Oral administration of sodium salts results in rapid and pronounced reduction in blood glucose to about 65 to 70% of control levels. The response is complete to that observed after IV administration.

The more slowly dissolving free acid produces a gradual decrease in blood sugar to about 80% of control levels, which is observed about 5 hr after administration.

It has been suggested that sodium salt of tolbutamide would produce an undesirable degree of hypoglycemia and that of free acid is the more useful from of the drug for treatment of diabetes.

Many barbiturates are available in the form of sodium salts to achieve a rapid onset of sedation. The sodium salt not only produced a more rapid onset of sleep but its effects were also more predictable.

The nonsteroidal anti- inflammatory drug naproxen was originally marked as free acid for the treatment of rheumatoid arthritis. The sodium salt is absorbed faster and is more effective in postpartum pain than the free acid.

Soluble prodrugs

Most efforts with prodrug have been directed at lipid solubility to increase permeability and absorption after oral administration.

The development of prodrug may also offer an alternative for drugs that show incomplete absorption because of limited water solubility.

Soluble prodrugs

Most efforts with prodrug have been directed at lipid solubility to increase permeability and absorption after oral administration.

The development of prodrug may also offer an alternative for drugs that show incomplete absorption because of limited water solubility

Surface area and particle size

A drug dissolves rapidly when its surface area increased, which accomplished by reducing the particle size of the drug.

Many poorly soluble, slowly dissolving drugs are marketed in micronized or microcrystalline from. Particle size reduction usually results in more rapid and complete absorption.

The problems associated with low water solubility were not fully appreciated when certain drugs were first introduced. For example, since the original marketing of spironolactone, the therapeutic dose has been reduced twenty fold ( from 500mg to 25mg) by reformulation containing micronized grisofulvin ,requires a daily dose of 0.5g, which is one half that needed when the dose was originally marked.

Particle size may also be an important factor in bioavailability of digoxin-tablets. Digoxin was found to have a mean particle diameter of 20-30 µm. This material was slowly and completely absorbed, compared to a solution of digoxin. Reduction of digoxin particle size to mean diameter 3.7µm led to an increase the rate and extent of absorption of the drug.

The effective surface area of hydrophobic drug particles may be increased also by the addition of a wetting agent to the formulation. The wetting agent enhances the rate and extent of absorption of phenacetin, by increasing the wetting and solvent penetration of the particles and minimizing aggregation of the suspended particles.

Physiologic surface active agents, like bile salts and lysolecithin, probably facilitate the dissolution and absorption of poorly soluble drugs in the small intestine.

There are instances in which particle size reduction fails to increase the absorption rate of drug. One reason may lbe that dissolution is not the rate limiting step in the absorption process.

Micronization sometimes dramatically increases the tendency of drug powder to aggregate, which may lead to a decrease in effective surface area. This problem may overcome by adding a wetting agent or other excipient to the formulation

Certain drugs such as penicillin G and erythromycin are unstable in gastric fluids. Chemical degradation is minimized if the drug does not dissolve readily in the stomach. Particle size reduction and the attendant increase in dissolution rate may degradation of the drug. It has been shown that the addition of a wetting agent to a formulation of erythromycin propionate results in lower drug levels in the blood, owing to increased dissolution and degradation of antibiotic in gastric fluids.

Crystal form

Many drugs can exist in more than one crystalline form, a property known as polymorphism. The drug molecules exhibit different space lattice arrangements in the crystal form one polymorph to another.

Although the drug is chemically undistinguishable in each, polymorph may differ with respect to certain physical properties such as density, melting point, solubility, and dissolution rate. At any temperature and pressure only on crystal form will be stable. Any other polymorph found under these conditions is metastable form and will eventually convert to stable form, but conversion may be slow

The metastable form is higer energy form of the drug and usually has a lower melting point, greater solubility, and greater dissolution rate than the stable crystal form. Accordingly, the absorption rate and clinical efficacy of a drug may depend on which crystal is administered.

Some drugs also occur in an amorphous form which shows little crystallinity. The energy required for a drug molecule to transfere from the lattice of crystalline solid to a solvated state is much greater than that required from an amorphous solid. For this reason, the amorphous form of a drug is always more soluble than the corresponding crystalline forms.

Two polymorphs of novobiocin have been identified, one of which is crystalline and the other amorphous material is at least 10 times more soluble than the crystalline form. Chloramphenicol palmitate exists in four polymorphs: three crystalline forms (A, B, and C) and an amorphous one.

Many drugs can associate with solvents to produce crystalline forms called solvates. When the solvent is water, the crystal is termed hydrate. Consistent with theory, the anhydrous forms of caffeine, theophylline dissolve more rapidly in water than do the hydrous forms of these drugs.

the anhydrous forms of ampicillin is about 25% more soluble in water at 37ºC than trihydrate form. The same difference has been found with respect to the extent of absorption of ampicillin from two forms of the drug. The solvate forms of the drug with organic solvent may dissolve in water much faster than the nonsolvated form e.g. n- pentanol solvate of succinyl- sulfathiazle. Also grisofulvin its rate and extent of absorption were significantly increased after administration of the chloroform solvate compared to that observed after administration of the non-solvated form of the drug.

Drug Stability and Hydrolysis in the GIT

Acid and enzymatic hydrolysis of drugs in GIT is common. Poor bioavailability results if degradation is extensive. The hydrolysis and the inactivation of penicillin G in the stomach is one example.

The half-life of penicillin G is one min. at pH 1 and about 9 min. at pH 2. The degradation rate of penicillin G decreases sharply with increasing pH, the drug is stable in the small intestine.

Chemical inactivation in the stomach is partially responsible for the relatively low bioavailability of penicillin G after oral adminiseration.

When a drug is unstable in gastric fluids rapid dissolution may reduce bioavailability e.g. erythromycin esters, which are unstable in stomach. With such drugs it is desirable to have minimal dissolution in the stomach and rapid dissolution in the small intestine.

Certain drugs must be hydrolyzed to parent drug in GI fluids to produce clinical effects. Clorazepate is rapidly converted to nor- diazepam at low pH. The only site for effective conversion is gastric fluid.

Chloramphenicol is sometimes given as palmitate or stearate ester, particularly practice. The low water solubility of these esters minimizes the objectionable taste of the drug and facilitate its use in oral suspensions.

Failure to effectively convert a prodrug to parent drug in the GI fluids. Gut wall or liver during absorption results in the prodrug reaching in the systemic circulation in relatively large amounts.

Chemical or enzymatic conversion of the prodrug to parent drug in blood or tissues is often limited and prodrug may be metabolized to inactive compound or excreted unchanged. Since the prodrug has little or no clinical activity, the net result may be an effectively reduced and inadequate bioavailability with respect to active drug.

This problem is evident with prodrug of erythromycin. Erythromycin base is unstable in gastric fluid which leads to poor bioavailability when the drug is given as such.

Complexation

Complexation of a drug in GI fluids may alter the rate and the extent of absorption. The complexing agent may be a substance normal to the GIT, a diatery compound, or a component of the dosage form. Intestinal mucus which contain the polysaccharide mucin, can bind streptomycin and dihydrostreptomycin this binding lead to poor absorptionof these antibiotics.

Complexation occurs often in pharmaceutical dosage forms. Complex formation between drugs and gums , cellulose derivatives, polylos, or surfactants is common.

Such complexes have much higher molecular weight and are usually more polar than the drug itself. The physicochemical properties of these complexes suggest poor absorption characteristics.

Fortunately, most of these complexes are freely soluble in the fluids of the GIT and dissociated rapidly. Thus in most instances, little or no effect on absorption is noted.

There are some exceptions. Amphetamine interacts with carboxymethyl cellulose to form a poorly soluble complex that leads to reduced absorption of the drug.

Phenobarbital forms an insoluble complex with polyethylene glycol 4000. The dissolution and absorption rate of the drug from tablets containing this polyols markedly reduced.

Drug complexes usually differ from the free drug with respect to water solubility and lipid water partition coefficient. So certain polar drugs which are poorly absorbed, may be made more permeable by forming lipid soluble complexes.

Adsorption

Certain insoluble substances may adsorb co-administered drug. This often leads to poor absorption. Cholestyramine is insoluble anionic exchange resins used to lower the serum cholesterol level in patients with cholesterolemia. This agent bind cholesterol metabolites and bile salts in the intestinal lumen and prevent enterohepatic cycling.

Gastrointestinal absorption

Role of dosage form

The modern dosage form is a drug delivery system, its selection may be as important to the clinical outcome of a given course of therapy as is the selection of the drug. One can routinely produce a 2 to 5 fold difference in the rate and extent of GI absorption, depending on the dosage form or its formulation. A difference of more than 60 fold has been found in the absorption rate of spironolactone from the worst formulation to the best formulation.

One would expect the bioavailability of a drug to decrease in the following order: solution˃ suspension ˃capsule ˃ tablet ˃ coated tablet.

The absorption rate of pentobarbital after administration in various oral dosage forms decreased in the following order:

Aqueous solution ˃ aqueous suspension ˃ of the free acid ˃ capsule of sodium salt ˃ tablet of free acid.

Dosage forms

Solutions

The solution dosage form is widely used for cough and cold preprations and for many other drugs, particularly in pediatric and geriatric patients. With rare exception drugs are absorbed more rapidly when given as a solution than in other oral dosage form.

The rate limiting step in the absorption of a drug from a solution dosage form is likely to be gastric particularly when the drug is given after meal.

When an acidic drug is given in solution in the form of salt, there is a possibility of ppt. in gastric fluid, but this ppt. is usually in finely subdivided and easily re-dissolved. However with highly water insoluble drugs, like phenytoin or warfarin may find that the absorption rate and extent of absorption form a well formulated suspension of the free acid is greater than from a solution of sodium salt.

Many drugs unless converted to a water soluble salt, are poorly soluble. Solutions of these drugs can be prepared by adding co-solvents, like alcohol or propylene glycol, complexing agents that form water soluble complexes with the drug, or surfactant in sufficient quantity that exceed the CMC to affect solubilization.

After administration of such water miscible preparations, dilution with GI fluid may result in ppt. of the drug. Again in most cases rapid re-dissolution takes place.

Certain materials such as sorbitol or hydrophilic polymers are sometimes added to solution dosage forms, to improve pourability and platability. The higher the viscosity of the formulation the slower are gastric emptying and absorption. Such effects are unlikely to be clinically important.

Drugs dissolved in oil has a rapid and complete absorption in some instances, particularly if the oil is administered in emulsified form.

Certain nontoxic but unpalatable solvents may be used for solubilizing drugs if the solution can be encapsulated. This approach can, in some cases improve the absorption of water insoluble drugs.

Suspensions

As a drug delivery system, the well formulated aqueous suspension is second in efficiency only to the solution dosage form.

Usually the absorption rate of drug from a suspension is dissolution rate limited, however the dissolution from suspension is often rapid because of a large surface area is presented to the fluids at the site of absorption.

Drug contained in capsule may never achieve the state of dispersion in the GIT that attainable with a finely subdivided, well formulated suspension.

Among the more important factors to consider in formulating suspension dosage forms for maximum bioavailability are particle size, inclusion of wetting agents, formulation of insoluble complexes, crystal form and viscosity.

The higher the viscosity of a suspension, the slower is the dissolution rate of the drug.

The inclusion of methylcellulose in an aqueous suspension of nitrofurantoin has been found to impair its rate and extent of absorption.

Capsules

The capsule dosage form has the potential to be an efficient drug delivery system.

Drug particles in capsules are not subjected to high compression forces that tend to compact the powder and reduce the effective surface area.

On disruption of the shell, the encapsulated powder should disperse rapidly to expose a large surface area to the GI fluid

Thus although one might expect better bioavailability of a drug from a capsule than from the compressed tablet, this is not always so.

It is usually necessary to have suitable diluents in a capsule dosage form, particularly when the is hydrophobic. The diluents serve to disperse the drug particles, minimize aggregation, and maximize the effective surface area and dissolution rate.

the incorporation of wetting agent in the formulation may also be advantageous. Other attempts to modify the wetting of poorly water soluble drugs have included treating the drug with solution of hydrophilic polymer such as methyl cellulose.

Phenytoin was found to dissolve and be absorbed faster from capsules containing untreated drug.

The diluents of capsule dosage form should have a little tendency to adsorb or interact with the drug. The use of dicalcium phosphate as diluents in tetracycline capsules has been found to impair absorption, because a poorly soluble calcium tetracycline complex is formed in the powder mass or during dissolution.

Factors that influence drug absorption from capsule dosage forms include the particle size and crystal form of the drug, and the selection of diluents and fillers.

Attempts to improve the oral absorption by the use of soft gelatin capsules. The soft gelatin capsules has a gelatin shell somewhat thicker than that of hard gelatin capsules, but the shell is plasticized by the addition of glycerin, or sorbitol. Unlike the hard gelatin capsules, the soft elastic capsule may be used to contain non-aqueous solutions of adrug or drugs that are liquid e.g. antitussive drugs or semisolids e.g. certain vitamins.

Tablets

The compressed tablets are the most widely used dosage form. It is complex dosage form and biopharmaceutic problems are often appear in its use.

Most bioavailability problems with drugs in tablet form are related to large reduction in effective drug surface area that results from the manufacturing process and to the difficulty in regenerating well dispersed primary drug particles after administration. The usual technique in tablet manufacturing process is to mix the powdered drug with other constituents of the formulation and convert this mixture in free flowing granules which are then compressed. After ingestion, the tablet first breaks down to granules, and then to primary drug particles.

Tablet disintegration is unlikely to be a rate limiting step in the absorption of drug administered as conventional tablets.

In most cases , granules disintegration and drug dissolution occur at slower rate than tablet disintegration.

Many factors related to formulation or manufacture of tablets may affect drug dissolution and absorption. Most formulations require the incorporation of hydrophobic lubricants, like magnesium stearate, to produce an acceptable tablet.

In general, the larger the quantity of lubricant in formulation, the slower is the dissolution rate.

Compression force may be also an important factor in drug bioavailability from compressed tablets. The in-vitro disintegration time of tablets has been shown to be directly proportional to compression force and tablet hardness.

High compression force may also increase the strength of the internal structure of the granules and retard the dissolution of the drug from the granules and disintegration of the granules.

The effect of particle size reduction on the dissolution and the absorption may be reduced by compression. Studied in man showed that 3.8 fold increase in specific surface area of grisofulvin led to 2.3 fold increase in blood concentration after administration of a suspension dosage form, but only 1.5 fold increase after administration of tablet dosage form.

Another approach to enhance the availability of poorly water soluble drugs from tablets has been used in marketed grisofulvin product. A molecular dispersion of the drug in PEG 6000, a freely water soluble, waxy polymer that congeals at about 60ºC, is prepared and suitably modified for incorporation into a tablet dosage form. The absorption of grisofulvin from this product appears to be complete and about twice that observed from commercial tablets containing micronized drug.

Drug –excipient interactions

It is well known that the preparation of tablets involves the use of so- called inert ingredients. Excipient materials are added as binding agent, lubricants, disintegrants, diluents and are necessary for the preparation of a good quality drug product.

Since these ingredients often constitute a considerable portion of a tablet, the possibility exists for drug excipient interaction to influence drug stability, dissolution rate, and drug absorption.

But a physical and chemical interaction between the drug and the excioient may result in modification of the physical state, particle size and/or surface area of the drug available to the absorption site. Drug bound by physical forces to the excipient in the solid state generally separate rapidly from the excipient in the aqueous solution. However drug s bound via chemisorption are strongly attached to the excipient which may result in incomplete absorption through GI membrane.

Dicumarol administered with talc, veegum, aluminium hydroxide and starch resulted in lower plasma level of the drug when compared to the drug alone. Significantly higher plasma level ( up to 180% of control values ) were observed when dicumarol was administered with magnesium oxide or hydroxide. Thus due to the formation of magnesium chelate which was more bioavailable than was the dicumarol itself.

Coated tablets

The most common coated medication are, sugar coated, film coated, and press-coated tablets.

Not only these dosage forms have the problems of the compressed tablets discussed before but also they impose a physical barrier between the GI fluid and the tablet containing the drug.

The coat must disrupt or dissolve before tablet disintegration and drug dissolution can occur.

The disintegration of certain coated tablets appears to be the rate limited process in drug absorption, since correlation has been found between the bioavailability and the in-vitro disintegration time.

Coating are used to mask the unpleasant tastes and odor, to protect the tablet ingredients from decomposition during storage , or to improve the appearance of the tablets

The sugar coated tablets is still widely used today. The sugar coated formulation is invariably complex the coating process is time consuming and require skill.

The application of sealing coat and the development of relatively dense crystalline barrier around the tablet retard the release of drug in GIT.

In general, we must assume that sugar coating will affect the bioavailability of a drug relative to that observed with the uncoated. This dosage form should not be used when a prompt clinical response is desired.

This basic disadvantages of sugar coating have stimulated a search for alternatives. The alternatives include the film coated tablet. Film coated tablets are compressed tablets that are coated with a thin layer of film of a water soluble material.

Enteric coated tablets

An enteric coat is usually a special film coat designed to resist gastric fluids and disrupt or dissolve in the intestine. The enteric coat is used to protect a drug from degrading in the stomach (e.g. erythromycin) or to minimize gastric distress caused by some drugs (e.g. aspirin).

Enteric coated tablets must empty from the stomach before drug absorption can begin. The rate of appearance of drug in the blood after giving an enteric coated tablet is therefore, a function of gastric emptying.

Aspirin produce gastric intolerance and injury are commonly observed with the high doses of aspirin required for optional effects. To over come the gastric side effects, the drug formulated as an enteric coated tablets.

The delay in drug absorption found after administration of enteric coated tablets could result of prolonged gastric emptying or slow dissolution of coated tablets after reaches the small intestine.

Since gastric emptying of the enteric coated dosage unit plays an important role in the onset of drug absorption, it is to be expected that administration of this dosage form after meal with further delay absorption.

Injectable medication

An (IV) injection places a drug directly into the blood stream, by passing conventional physicochemical and physiological influences.

Eventual drug absorption into the blood stream is influenced by several physicochemical and physiological factors.

A) physicochemical factors affecting drug absorption by injection:

As stated, no absorption step is necessary when a drug is administered directly into blood stream, therefore, there are no physicochemical factors to affect absorption.

Drugs given by extra-vascular injection require an absorption step before they can enter the blood stream.

Even drugs that are administered by intra-spinal and intra-cardiac routes undergo local penetration and permeation and then penetrate local capillaries in order to reach the blood stream.

At other extravascular sites, such as intramascular, subcutaneous, and intradermal, the drug travels to the blood or lymphatic circulation by means of physical penetration and permeation processes which are associated with passive diffusion and portioning through the capillary membrane and into the blood.

Drug solubility

A major physicochemical criterion for absorption by passive diffusion and portioning is drug solubility.

Regardless of the dosage form administered, a drug must be in solution in an aqueous form to be absorbed into the blood stream. Only the fraction of drug in solution at the injection site are generally absorbed quickly and easily, all other influencing factors being constant.

A critical difference between the pH of the administered drug solution and physiological pH at the injection site can cause an unpredictable decrease in absorption due to ppt. of the drug at the injection site.

Phenytoin, a commercial brand of diphenylhydantoin , is very insoluble free acid and is formulated as sodium salt in a solution of 40% propylene glycol, 10% alcohol, and water for injection. The pH must be adjusted at pH 12 with sodium hydroxide to solubilize the drug. The propylene glcol helps to solubilize the free acid fraction available at this pH. When injected into muscle tissue the large difference in pH causes conversion of the sodium salt to the less soluble free acid which ppt. in tissue fluids at the injection site. Simultaneous dilution of propylene glycol with tissue fluid contributes to free acid ppt. most of the drug is therefore available only slowly, depending predominantly on the dissolution rate of diphenylhydantoin crystals. Thus complete absorption takes 4 to 5 days. Similar reduction in bioavailability due to drug ppt. caused by pH and solubility changes have been reported for diazepam injection, clordiazoepoxide injection and digoxin injection.

Passive diffusion

Passive diffusion involves the spontaneous movement of solute molecules in solution from an area of higher concentration on one side of semipermeable membrane to an area of lower concentration on the other side of membrane.

In biological system, a drug in solution passes from the extracellular to intracellular tissue fluid by passive diffusion.

The rate of passage of a drug through a biological membrane by passive diffusion is affected by several physicochemical factors, such as concentration gradient, partition coefficient, ionization, macromolecular binding, and osmolality, in addition to difference in physical form of medication.

Concentration gradient:

The rate at which a drug molecule crosses the semipermeable membrane by Passive diffusion is described by Fick's law, expressed by the following equation for the unidirectional case:

dq / dt = DA ( C1-C2) / L (1)

Where

dq / dt = flux or amount of transfer of substance per unit of time

D = diffusion constant

A = surface area available for diffusion

C1 = concentration of diffusing substance in extracellular fluid

C2 = concentration of diffusing in ntracellular fluid

L = thickness of the membrane

For particular membrane where A and L are constant, the diffusion rate controlled by:

D (C1- C2)

The magnitude of the diffusion constant D is influenced by the physicochemical properties of the drug molecule and the characteristics of the membrane.

For any given drug in a contained in vitro system, the rate of passive diffusion is controlled by the concentration gradient (C1 – C2) that exists between both sides of the membrane. The rate at which drug molecules move from side 1 to side 2will decrease as the magnitude of C2 decreases and approaches C1.

When C1 equals C2 the system is at equilibrium. This is described mathematically as follows:

dq / dt = D ( C1-C2) / L (2)

where C1 = C2

dq / dt = 0 (3)

However, the concentration gradient (C1-C2) does not become a rate limiting factor in-vivo because of unidirectional movement of the drug through the membrane.

In this case as the drug reaches the other side of the membrane it is removed by the blood, leading to distribution, metabolism, and/or excretion. Therefore, C1 remains considerably greater than C2 at all times until the transfer is complete. This is referred to as a sink condition and equation 2 reduces to

dq / dt = D C1/ L (4)

Partition coefficient

the distribution of the solute between two immiscible solvents such as water and oil. This type of distribution, called partitioning, plays an important role in passive diffusion. The equation that describes partitioning is:

Partition coefficient (PC) = K = Ca / Cb

Where, by convention,

Ca = concentration of solute in the oil or lipid phase

Cb = concentration of non-ionized solute in the aqueous phase at a defined pH

K = Partition coefficient

The influence of the partition coefficient on passive diffusion of a drug through a biological membrane can be illustrated by considering the relative transfer of drug with high and low partition coefficients.

A drug with high partition coefficient (lipid soluble) will pass readily from the aqueous phase into membrane, whereas one with a low partition coefficient (water soluble) will remain in the aqueous phase and not pass into membrane.

As stated earlier, in a biological system, diffusion takes place as unidirectional process, this is equally true for the process of partitioning . the drug with higher partition coefficient will exhibits a higher rate of diffusion, dq /dt.

Thus lipid – soluble drugs are absorbed and distributed more rapidly than are water soluble drugs

Ionization

Whereas partitioning of neutral molecules takes place in relation to their oil- water solubility, this is not true for ionized drugs. Ionization has a profound effect on drug absorption, distribution and excretion. The dgree of ionization of an acid or base is determined by ionization constant of the compound, pKa, in addition to the pH, temperature, and ionic strength of the solution .

Since in biological system temperature and ionic strength are essentially constant, their influences can be neglected.

The degree of ionization of weak acids and bases changes rapidly as the difference between pH and pKa becomes greater until the pH value of the solution is 2 units away from pKa, at which further changes in pH have little effect on the degree of ionization of the acid or base.

When dealing with ionized and non-ionized forms of a drug, the relationship to lipid solubility and partition coefficient becomes apparent. The neutral (non-ionized) fraction of the drug is more readily partitioned into the non-polar lipid membrane.

During portioning of the non-ionized molecule the fraction of the remaining ionized drug rapidly equilibrates so that non-ionized drug is again formed and available for partitioning.

This dynamic process takes place until the entire drug partition through the membrane.

When the pH of a medium causes most of the drug to be in the ionized form (e.g. medium pH = 7 for an acidic drug with pka = 5), slow absorption can be expected since the partitionable non-ionized form constitutes only small fraction of the total drug, less than 1% in the case above.

A rank order demonstration of the effect of medium pH and drug pKa on partitioning is shown by the following hypothetical example.

A beaker containing a buffer solution is separated equally into two compartments be a semipermeable lipid membrane that allows only the nonionized weak acid (pKa = 5) to pass through. A quantity of the weak acid drug is dissolved in a negligible volume of buffer solution; the solution is then quickly injected into the left compartment, resulting in a homogeneous solution in that compartment.

After each equilibrium partitioning step takes place (i.e. HA partitions through the membrane leaving A and H behind) the buffer solution on the right side of the membrane (side becoming enriched with HA) is replaced with fresh buffer. The species A on the left side re-equilibrates with H to form more HA and the process is repeated until eventually all the drug is partitioned as HA.

Referring to the Henderson- Hasselbach equation:

pH = pKa + log [A] /[HA]

consider the following two cases, which will demonstrate the effect of pH and pKa on partitioning:

Case 1 : buffer solution on both sides of the membrane at pH 5. In this case equation indicate that log [A] /[HA] = 1; thus [A] = [HA].

Thus 50% of the total weak acid is the neutral form HA, able to partition through the membrane. The remaining ionized portion, A, is the unable to partition into lipid.

Case 2: buffer solution in both compartment at pH7.

Equation now indicate that log [A] / [H] = 100.

Substituting these values into Henderson- Hasselbach equation yields:

7 = 5 + log 100/1

Therefore only 0.99 of the total drug, HA + A, is in the form HA, able to partitioned.

These examples are meant to show the relationship between formulation pH, drug pKa, and amounts of partitionable nonionized weak acid or weak base species available for absorption from an injectable dosage form.

Binding to macromolecules

Biological fluids contain macromolecules such as proteins which may have affinity for certain drugs. These macromolecules are generally too large to pass through biological membranes by filteration, nor do they have lipid solubility required for passive diffusion. Therefore they confined within their immediate boundaries.

When a drug becomes adsorbed or complexed on such molecules, the effective (free) concentration of diffusible form becomes lowered. The equation described this reaction is:

Drug + macromolecule ↔ drug- macromolecule complex

Where:

K1 = adsorption rate constant

K2 = desorption rate constant

The equilibrium constant is then expressed as:

[ drug- macromolecule]

K = --------------------------------------------

[drug] [macromolecule]

Where K, the association constant, provides a quantitative measure of the affinity of the drug for the particular macromolecule.

Significant binding of macromolecules such as serum protein reduces the concentration of the free drug in the tissue fluids and hence reduces the rate of passive diffusion by lowering the concentration gradient in accordance with fick's law .

Since binding is an equilibrium process and thus readily reversible, the drug can eventually be described. It is important to note that protein binding reduce the rate of passive diffusion but does not prevent it. Protein binding has significant effect on passive diffusion when the drug is bound by more than 90% because the desorption rate from the drug protein complex is usually slower than the diffusion rate of the drug through membranes.

Osmolality:

A solution is isoosmotic with tissue fluid when the total number of dissolved particles in the two systems are equal. In general, injectable products are formulated to be iso-osmotic to reduce possibility of irritation that can result if osmotic differences between tissue fluid or red blood cell contents and the injection product are great. The effect of large differences in solution osmolality on passive diffusion can described by considering the following condition:

1- hypo-osmotic

2- iso-osmotic

3- hyper-osmotic

when an injection solution is hypo-osmotic, it contains fewer solute particles than does the tissue fluids. Based on the law of osmosis, solvent passes from a region of lower concentration of solute to one of higher concentration to reduce the pressure differential caused by the dissolved solute particle imbalance.

Therefore the extravascular injection of grossly hypo-osmotic solution would cause the movement of fluid away cause the movement of the fluid away from the injection site. In this case the apparent concentration of drug would increase, resulting in an increase in the rate of passive diffusion. Conversely the extravascular injection of a grossly hyper-osmotic solution causes an influx of fluid to the injection site, resulting in dilution of drug concentration and an apparent decrease in rate of diffusion.

Increasing the osmolality of atropine solution by addition of either prolidoxine chloride or sodium chloride led to an apparent reducing in intramascular absorption determined by its effect on reduction of heart rate. When an iso-osmotic solution is injected, there is no fluid fluxeither to away from the injection site, hence no demonstrable effect on passive diffusion.

It is important to differentiate between the terms isotonic and isoosmotic. They are synonymous only when the dissolved solute cannot pass through membranes of red blood cells. However such passage does occur, as with aqueous solutions of urea, alcohol, or boric acid, the solution acts as if it were pure water and both solute and solvent pass through the membrane into the red blood cells, causing them to swell and brust (hemolysis) .

The solution is considered isotonic based on sodium chloride equivalent calculations or as determined by its freezing point depression, however it was actually hypotonic or hypoosmotic with respect to red blood cells. The term isotonic should be used only to describe solutions having equal osmotic pressure with respect to a particular membrane, therefore, it is important to examine the osmotic behavior of new drug substances toward red blood cells before deciding whether an adjustment is to be made.

In order to make an iso-osmotic aqueous solution of a non-osmotic contributing substance such as urea, an external agent such as sodium chloride, sorbitol or other osmotic producing substance must be added at its isotonic level, such as 0,9% sodium chloride.

Volume of injection:

From fick's law, for the sink condition (C2 = 0),it was shown by equation (4) that: dq/dt = KC1.

When the volume V1 of drug solution at the absorption site remaining nearly constant, the rate of passive diffusion will be equal to :

dq /dt = K (A1 / V1)

Where A1 is the amount of drug at the site at any time.

Thus the diffusion rate is inversely proportional to volume V1, and absorption rate should increase when volumes decrease.

Smaller injected volumes have been reported to enhance drug absorption. Another way of expressing this is to consider the ratio of tissue surface areato volume of injection. An increase in injection volume with a relatively confined area results in a lowering of the tissue surface area to volume ratio.

Since passive diffusion is directly proportional to surface area, an increase in injection volume should cause a lowering in the rate of passive diffusion.

A physiological reason to keep injection volumes small is to help minimize or reduce pain caused hydrostatic pressure on surrounding tissues.

Iftakhar Khandakar Shukhon

B'Pharm(Hons) 3rd Year

University Of Science & Technology ,Chittagong

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