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Aug 11, Biopharmaceutics and Pharmacokinetics-A Treatise. Image result for brahmankar biopharmaceutics. Click to Download PDF. Advertisements. Read Biopharmacuitics And Pharmacokinetics book reviews & author details and more at mtn-i.info by Brahmankar Jaiswal (Author) The twin disciplines of Biopharmaceutics and Pharmacokinetics have, therefore, been developed with. Get this from a library! Biopharmaceutics and pharmacokinetics: a treatise. [D M Brahmankar; Sunil B Jaiswal].
Diffusion coefficient decreases as the viscosity of dissolution medium increases. Surface area A Greater the surface area, faster the drug dissolution; can be of solid micronisation of drug. Concentration Cs Cb Greater the concentration gradient, faster the diffusion and drug gradient dissolution; can be increased by increasing drug solubility and the volume of dissolution medium.
Thickness of h More the thickness, lesser the diffusion layer and drug stagnant dissolution; can be decreased by increasing agitation. Under such a situation, dissolution is said to be under non-sink conditions. This is true in case of in vitro dissolution in a limited dissolution medium. Dissolution in such a situation slows down after sometime due to build-up in the concentration of drug in the bulk of the solution. The in vivo dissolution is always rapid than in vitro dissolution because the moment the drug dissolves; it is absorbed into the systemic circulation.
Thus, under in vivo conditions, there is no concentration build-up in the bulk of the solution and hence no retarding. Under sink conditions, if the volume and surface area of solid are kept constant, then equation 2. Dissolution rate under non-sink and sink conditions. To obtain good in vitro-in vivo dissolution rate correlation, the in vitro dissolution must always be carried under sink conditions. This can be achieved in one or more of the following ways: Bathing the dissolving solid in fresh solvent from time to time.
Increasing the volume of dissolution fluid. Removing the dissolved drug by partitioning it from the aqueous phase of the dissolution fluid into an organic phase placed either above or below the dissolution fluidfor example, hexane or chloroform. Adding a water miscible solvent such as alcohol to the dissolution fluid, or 5.
By adding selected adsorbents to remove the dissolved drug. The Noyes-Whitneys equation assumes that the surface area of the dissolving solid remains constant during dissolution, which is practically not possible for dissolving particles. Hence, dissolution methods that involve use. To account for the particle size decrease and change in surface area accompanying dissolution, Hixson and Crowells cubic root law of dissolution is used: Since the solvent packets are exposed to new solid surface each time, the theory is called as surface renewal theory.
The Danckwerts model is expressed by equation:. The rate-determining step that controls dissolution is the mass transport. 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 dissolution of a crystal, each face of the crystal will have a different interfacial barrier.
Such a concept is given by the following equation: In this theory, the diffusivity D may not be independent of saturation concentration Cs. The interfacial barrier model can be extended to both diffusion layer model and the Danckwerts model for in vitro drug dissolution models refer chapter 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: Dosage form factors.
The various physicochemical properties of drug that affect drug dissolution and its rate aresolubility, particle size, polymorphism, salt form, pseudopolymorphism, complexation, wettability, etc. Dosage form factors include several formulation factors and excipients incorporated in the dosage form. Each of these factors will be discussed in detail in the latter part of this chapter. Of the various factors listed above, the factor of prime importance is drug solubility. Almost every factor that affects dissolution rate, influences the drug solubility in one way or the other.
From several equations pertaining to dissolution rate, it is clear that it is directly related to drug solubility. An empirical relation which is useful to predict the dissolution rate of a drug from its solubility is:.
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: 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.
From the modified Noyes-Whitney equation 2. Since the surface area increases with decreasing particle size, a decrease in particle size, which can be accomplished by micronisation, will result in higher dissolution rates. However, it is important to note that it is not the absolute surface area but the effective surface area that is proportional to the dissolution rate. Greater the effective surface area, more intimate the contact between the solid surface and the aqueous solvent and faster the dissolution.
But it is only when micronisation reduces the size of particles below 0. The surface of such small particles has energy higher than the bulk of the solid resulting in an increased interaction with the solvent. This is particularly true in case of drugs which are non-hydrophobic, for example, micronisation of poorly aqueous soluble drugs like griseofulvin, chloramphenicol and several salts of tetracycline results in superior dissolution rates in comparison to the simple milled form of these drugs.
Micronisation has in fact enabled the formulator to decrease the dose of certain drugs because of increased absorption efficiencyfor example, the griseofulvin dose was reduced to half and that of spironolactone was decreased 20 times following micronisation.
However, in case of hydrophobic drugs like aspirin, phenacetin and phenobarbital, micronisation actually results in a decrease in the effective surface area of such powders and thus, a fall in the dissolution rate. Three reasons have been suggested for such an outcome 1. The hydrophobic surface of the drug adsorbs air onto their surface which inhibit their wettability. The particles re-aggregate to form larger particles due to their high surface free energy, which either float on the surface or settle at the bottom of the dissolution medium.
Electrically induced agglomeration owing to surface charges prevents intimate contact of the drug with the dissolution medium. The net result of these effects is that there is a decrease in the effective surface area available to the dissolution medium and therefore a fall in the dissolution rate. The absolute surface area of hydrophobic drugs can be converted to their effective surface area by: Use of surfactant as a wetting agent that Decreases the interfacial tension, and Displaces the adsorbed air with the solvent.
For example, polysorbate 80 increases the bioavailability of phenacetin by promoting its wettability. Particle size reduction and subsequent increase in the surface area and dissolution rate is not advisable under following circumstances When the drugs are unstable and degrade in solution form penicillin G and erythromycin , When drugs produce undesirable effects gastric irritation caused by nitrofurantoin 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: Refer chapter 11 for methods used in enhancing the bioavailability of drugs.
Polymorphism and Amorphism Depending upon the internal structure, a solid can exist either in a crystalline or amorphous form Fig. When a substance exists in more than one crystalline form, the different forms are designated as polymorphs and the phenomenon as polymorphism. Polymorphs are of two types:. Enantiotropic polymorph is the one which can be reversibly changed into another form by altering the temperature or pressure e.
Monotropic polymorph is the one which is unstable at all temperatures and pressures e. The polymorphs differ from each other with respect to their physical properties such as solubility, melting point, density, hardness and compression characteristics. They can be prepared by crystallizing the drug from different solvents under diverse conditions. The existence of the polymorphs can be determined by using techniques such as optical crystallography, X-ray diffraction, differential scanning calorimetry, etc.
Classification of internal structure of a compound Depending on their relative stability, one of the several polymorphic forms will be physically more stable than the others. Such a stable polymorph represents the lowest energy state, has highest melting point and least aqueous solubility. The remaining polymorphs are called as metastable forms which represent the higher energy state, have lower melting points and higher aqueous solubilities.
Because of their higher energy state, the metastable forms have a thermodynamic tendency to convert to the stable form. A metastable form cannot be called unstable because if it is kept dry, it will remain stable for years. Since the metastable forms have greater aqueous solubility, they show better bioavailability and are therefore preferred in formulationsfor example, of the three polymorphic forms of chloramphenicol palmitate -A, B and C, the B form shows best availability and the A form is virtually inactive biologically.
The polymorphic form III of riboflavin is 20 times more watersoluble than the form I. However, because of their poor thermodynamic stability, aging of dosage forms containing such metastable forms usually result in.
Such a transformation of metastable to stable form can be inhibited by dehydrating the molecule environment or by adding viscosity building macromolecules such as PVP, CMC, pectin or gelatin that prevent such a conversion by adsorbing onto the surface of the crystals.
Barbital, methyl paraben and sulphapyridine can exist in as many as 6 polymorphic forms and cortisone acetate in 8 forms. Some drugs can exist in amorphous form i. Such drugs represent the highest energy state and can be considered as supercooled liquids. They have greater aqueous solubility than the crystalline forms because the energy required to transfer a molecule from crystal lattice is greater than that required for non-crystalline amorphous solidfor example, the amorphous form of novobiocin is 10 times more soluble than the crystalline form.
Chloramphenicol palmitate, cortisone acetate and phenobarbital are other examples where the amorphous forms exhibit higher water solubility. 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 pseudopolymorphism. 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. Generally, the anhydrous form of a drug has greater aqueous solubility than the hydrates. This is because the hydrates are already in interaction with water and therefore have less energy for crystal break-up in comparison to the anhydrates thermodynamically higher energy state for further interaction with water.
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. On the other hand, the organic nonaqueous solvates have greater aqueous solubility than the non-solvatesfor example, the n-pentanol solvate of fludrocortisone and succinylsulphathiazole and the chloroform solvate of griseofulvin are more water-soluble than their non-solvated forms.
Like polymorphs, the. In case of organic solvates, if the solvent is toxic, they are not of therapeutic use. Salt Form of the Drug Most drugs are either weak acids or weak bases.
One of the easiest approaches 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 sulphonamides. In case of weakly basic drugs, a strong acid salt is prepared like the hydrochloride or sulphate salts of several alkaloidal drugs. The influence of salt formation on the drug solubility, rate of dissolution and absorption can be explained by considering the pH of the diffusion layer and not the pH of the bulk of the solution refer diffusion layer theory of drug dissolution.
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 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 favours 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. Thus, if: The increase and decrease in pH of the diffusion layer by the salts of weak acids and bases have been attributed to the buffering action of strong base cation and strong acid anion respectively.
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 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. Dissolution and absorption of an acidic drug administered in a salt form The principle of in situ salt formation has been utilized to enhance the dissolution and absorption rate of certain drugs like aspirin and penicillin from buffered alkaline tablets.
The approach is to increase the pH of the microenvironment of the drug by incorporating buffer agents and promote dissolution rate. Apart from the enhanced bioavailability, buffered aspirin tablets have two more advantages: The selection of appropriate salt form for better dissolution rate is also important. It has been shown that the choline and the isopropanolamine salts of theophylline dissolve 3 to 4 times more rapidly than the ethylenediamine salt and show better bioavailability.
A factor that influences the solubility of salt forms of the drug is the size of the counter ion. Generally speaking, smaller the size of the counter ion, greater the solubility of saltfor example, the bioavailability of novobiocin from its sodium salt, calcium salt and free acid form was found to be in the ratio These forms are, however, useful in several ways such as to prolong the duration of action steroidal salts , to overcome bad taste chloramphenicol palmitate , to enhance GI stability erythromycin estolate or to decrease the side effects, local or systemic.
There are exceptions where the so called more soluble salt form of the drug showed poor bioavailability. One such study was the comparative dissolution of sodium phenobarbital and free phenobarbital from their tablets. Slower dissolution with sodium salt was observed and the reason attributed to it was that its tablet swelled but did not disintegrate and thus dissolved slowly. The reason for poor solubility and dissolution rate was the suppression action of the common ion effect.
The theory states that for drug compounds of molecular weight greater than , which are primarily transported across the biomembrane by passive diffusion, the process of absorption is governed by: The dissociation constant pKa of the drug. The pH at the absorption site. Since most drugs are weak electrolytes weak acids or weak bases , their degree of ionisation depends upon the pH of the biological fluid.
If the pH on either side on the membrane is different, then the compartment whose pH favours greater ionisation of the drug will contain greater amount of drug, and only the unionised or undissociated fraction of drug, if sufficiently lipid soluble, can permeate the membrane passively until the concentration of unionised drug on either side of the membrane becomes equal i.
The above statement of the hypothesis was based on the assumptions that: The GIT is a simple lipoidal barrier to the transport of drug. Larger the fraction of unionised drug, faster the absorption. Drug pKa and Gastrointestinal pH The amount of drug that exists in unionised form is a function of dissociation constant pKa of the drug and pH of the fluid at the absorption site.
It is customary to express the dissociation constants of both acidic and basic drugs by pKa values. The lower the pKa of an acidic drug, stronger the acid i.
Higher the pKa of a basic drug, stronger the base. Thus, from the knowledge of pK a of drug and pH at the absorption site or biological fluid , the relative amount of ionised and unionised drug in solution at a particular pH and the percent of drug ionised at this pH can be determined by Henderson-Hasselbach equations: The pKa is a characteristic of the drug.
If there is a membrane barrier that separates the aqueous solutions of different pH such as the GIT and the plasma, then the theoretical ratio R of drug concentration on either side of the membrane can be given by equations derived by Shore et al: If one considers the pH range in the GIT from 1 to 8, that of the stomach from 1 to 3 and of the intestine from duodenum to colon 5 to 8, then certain generalisations regarding ionisation and absorption of drugs can be made, as predicted from the pH-partition hypothesis: For Weak Acids: Acids in the pKa range 2.
For Basic Drugs: Bases in the pKa range 5 to Such drugs are better absorbed from the relatively alkaline conditions of the intestine where they largely exist in unionised form. A summary of above discussion is given in Table 2. By using equations from 2. An example of this is illustrated in figure 2. Influence of pH on ionisation of drug.
It is defined as the sum of concentration of ionised drug in solution and concentration of unionised drug in solution. The solubility of unionised form of the drug is known as the intrinsic solubility of the drug. For weakly basic drugs, 1. Lipophilicity and Drug Absorption As mentioned earlier, it is the pKa of a drug that determines the degree of ionisation at a particular pH and that only the unionised drug, if sufficiently lipid soluble, is absorbed into the systemic circulation.
In other words, a. This value is a measure of the degree of distribution of drug between lipophilic solvents such as n-octanol and an aqueous phase water or a suitable buffer.
Schanker, J. Limitations of pH-Partition Hypothesis The pH-partition hypothesis over-simplified the otherwise complicated process of drug absorption and therefore has its own limitations.
Some of the deviations from the theory are:. Presence of virtual membrane pH Absorption of ionised drug Influence of GI surface area and residence time of drug Presence of aqueous unstirred diffusion layer. Presence of Virtual Membrane pH: The pH-partition hypothesis suggested that only the unionised drug at a given GI lumen pH is absorbed. An S-shaped curve, called as the pH-absorption curve denoting the dissociation of drug, is obtained when pH is plotted versus rate of drug absorption Fig.
Dotted lines indicate curves predicted by pH-partition hypothesis and bold lines indicate the practical curves. However, differences in the extent of absorption of salicylic acid has been observed at a given GI pH than that predicted by pH-partition hypothesis. The experimental pH-absorption curves are less steep and shift to the left lower pH values for a basic drug and to the right higher pH values for an acidic drug.
This led to the suggestion that a virtual pH, also called as the microclimate pH, different from the luminal pH exists at the membrane surface.
This virtual membrane pH actually determines the extent of drug ionisation and thus, drug absorption. Absorption of Ionised Drugs: An important assumption of the theory was that only unionised form of the drug is absorbed and permeation of the ionised drug is negligible since its rate of absorption is 3 to 4 times less than that of unionised drug.
This is called as principle of non-ionic diffusion. The principle is true to a large extent as ionised drugs have low lipid solubility and relatively poor permeability. However, the pH-absorption curve shift suggested that ionised forms of some drugs also get absorbed to a considerable extent. If such drugs have a large lipophilic group in their structure, despite their ionisation, they will be absorbed passivelyfor example, morphinan derivatives.
Other mechanisms are also involved in the absorption of ionised drugs such as active transport, ion-pair transport and convective flow. According to the pH-partition theory, acidic drugs are best absorbed from stomach acidic pH and basic drugs from intestine alkaline pH in which conditions they are unionised to a large extent. This could be true under conditions where the surface area of stomach and intestine are same.
It could also mean that once an acidic drug reaches the intestine, the remaining fraction will be poorly absorbed and that unless a basic drug reaches the intestine and gets absorbed considerably, it may not be able to attain its therapeutic level.
But, irrespective of the GI pH and the degree of ionisation, both acidic and basic drugs are more rapidly absorbed from the intestine, primarily because of its large surface area and secondly, because of long residence time of the drug in the intestine. Presence of Aqueous Unstirred Diffusion Layer: The pH-shift in the absorption of acidic and basic drugs, as discussed earlier, also accounts for the fact that the bulk of the luminal fluid is not in direct contact with the membrane but a barrier called as aqueous unstirred diffusion layer is interposed between them.
Such a model is depicted in Fig. Presence of aqueous unstirred diffusion layer on the membrane surface Such a layer has a real thickness and is a barrier to absorption of drugs. In the original pH-partition theory, the rate-limiting step in the absorption of drugs was the partitioning in the lipid barrier.
With the incorporation of unstirred aqueous diffusion layer, a drug must diffuse first through this aqueous barrier and then through the lipoidal barrier. Thus, drugs having large partition coefficient can rapidly penetrate the lipid membrane but diffusion through unstirred water layer is the rate-limiting step in their absorption. This applies in particular to high molecular weight fatty acids and bile acids. Despite its limitations, the pH-partition theory is still useful in the basic understanding of drug absorption and movement of drug between various body compartments.
Drug Permeability and Absorption. Most orally administered drugs enter the systemic circulation by passive diffusion and their absorption is expressed mathematically by equation 2.
Since it is difficult to alter or control surface area and residence time of drug, focus for promoting absorption depends on enhancing permeability of drug or drug concentration at absorption site see BCS classification of drugs, Table 2. The three major drug characteristics that determine the passive transport or permeability of drugs across intestinal epithelium are Lipophilicity of drug expressed as log P.
Polarity of drug which is measured by the number of H-bond acceptors and number of H-bond donors on the drug molecule. Molecular size. The net effect of the above three properties of drug on its permeability across intestinal epithelium is given as Rule of Five by Lipinski et al which is written as Molecular weight of drug Lipophilicity of drug, log P 5 Number of H-bond acceptors 10 Number of H-bond donors 5 For a given drug, if any two of these values is greater than that specified above, then oral absorption may be significant problem.
Two major stability problems resulting in poor bioavailability of an orally administered drug aredegradation of the drug into inactive form, and interaction with one or more different component s either of the dosage form or those present in the GIT to form a complex that is poorly soluble or is unabsorbable.
Destabilization of a drug during its shelf-life and in the GIT will be discussed in detail under formulation factors and patient related factors respectively. Stereochemical Nature of Drug. Majority of these are marketed as racemic mixtures.
Although it is well established that optical isomers differ in the potency of pharmacological effect, it is only recently that attention is being paid to influence of chirality on pharmacokinetic processes like absorption, distribution and elimination.
Enantiomers possess identical physical and chemical properties despite significant differences in spatial configuration. Thus, biological processes which are passive in nature and thereby depend only upon physical and chemical characteristics of the molecule do not display selectively for one isomer over another. However, biological processes such as protein binding which require interaction of a drug with a macromolecule may exhibit stereoselectivity. As majority of drugs are absorbed passively, they do not display stereoselectivity.
Conversely, demonstration of stereoselective absorption would be strong evidence that a drug is absorbed by a carrier-mediated process. In vitro disintegration test is by no means a guarantee of drugs bioavailability because if the disintegrated drug particles do not dissolve, absorption is not possible.
However, if a solid dosage form does not conform to the DT, it portends bioavailability problems because the subsequent process of dissolution will be much slower and absorption may be insufficient. Coated tablets, especially sugar coated ones have long DT.
Rapid disintegration is thus important in the therapeutic success of a solid dosage form. DT of a tablet is directly related to the amount of binder present and the compression force hardness of a tablet. A harder tablet with large amount of binder has a long DT.
Disintegration can be aided by incorporating disintegrants in suitable amounts during formulation. After disintegration of a solid dosage form into granules, the granules must deaggregate into fine particles, as dissolution from such tiny particles is faster than that from granules. The dosage form related factors that influence dissolution and hence absorption of a drug from such formulations are: Excipients formulation ingredients apart from the active principles , and.
Manufacturing processes. The influence of excipients such as binders, lubricants, disintegrants, etc. Several manufacturing processes influence drug dissolution from solid dosage forms. Processes of such importance in the manufacture of tablets are: Method of granulation, and 2. Compression force. The processing factor of importance in the manufacture of capsules that can influence its dissolution is the intensity of packing of capsule contents.
Method of Granulation: The wet granulation process is the most conventional technique in the manufacture of tablets and was once thought to yield tablets that dissolve faster than those made by other granulation methods.
The limitations of this method include i ii Formation of crystal bridge by the presence of liquid, The liquid may act as a medium for affecting chemical reactions such as hydrolysis, and.
Involvement of large number of steps each of which can influence drug dissolutionmethod and duration of blending, method, time and temperature of drying, etc. The method of direct compression has been utilized to yield tablets that dissolve at a faster rate. One of the more recent methods that have resulted in superior product is agglomerative phase of communition APOC.
The process involves grinding of drugs in a ball mill for time long enough to affect spontaneous agglomeration. The tablets so produced were stronger and showed rapid rate of dissolution in comparison to tablets made by other methods.
The reason attributed to it was an increase in the internal surface area of the granules prepared by APOC method. Compression Force: The compression force employed in tabletting process influence density, porosity, hardness, disintegration time and dissolution of tablets.
The curve obtained by plotting compression force versus rate of dissolution can take one of the 4 possible shapes shown in Fig. On the one hand, higher compression force increases the density and hardness of tablet, decreases porosity and hence penetrability of the solvent into the tablet, retards wettability by forming a firmer and more effective sealing layer by the lubricant, and in many cases, promotes tighter bonding between the particles, all of which result in slowing of the dissolution rate of tablets curve A of Fig.
On the other hand, higher compression forces cause deformation, crushing or fracture of drug particles into smaller ones or convert a spherical granule into a disc shaped particle with a large increase in the effective surface area. This results in an increase in the dissolution rate of the tablet curve B of Fig.
A combination of both the curves A and B is also possible as shown in curves C and D. In short, the influence of compression force on the dissolution rate is difficult to predict and a thorough study on each formulation should be made to ensure better dissolution and bioavailability. Intensity of Packing of Capsule Contents: Like the compression force for tablets, packing density in case of capsule dosage form can either inhibit or promote dissolution.
Diffusion of GI fluids into the tightly filled capsules creates a high pressure within the capsule resulting in rapid bursting and dissolution of contents.
Opposite is also possible. It has been shown that capsules with finer particles and intense packing have poor drug release and dissolution rate due to a decrease in pore size of the compact and poor penetrability by the GI fluids. Almost always, a convenient dosage form to be administered by a suitable route is prepared.
Such a formulation contains a number of excipients non-drug components of a formulation. Excipients are added to ensure acceptability, physicochemical stability during the shelf-life, uniformity of composition and dosage, and optimum bioavailability and functionality of the drug product.
Despite their inertness and utility in the dosage form, excipients can influence absorption of drugs. The more the number of excipients in a dosage form, the more complex it is and greater the potential for absorption and bioavailability problems. Commonly used excipients in various dosage forms are vehicles, diluents fillers , binders and granulating agents, disintegrants, lubricants, coatings, suspending agents, emulsifiers, surfactants, buffers, complexing agents, colorants, sweeteners, crystal growth inhibitors, etc.
Vehicle or solvent system is the major component of liquid orals and parenterals. The 3 categories of vehicles in use areaqueous vehicles water, syrup, etc. Bioavailability of a drug from vehicles depends to a large extent on its. Aqueous and water miscible vehicles are miscible with the body fluids and drugs from them are rapidly absorbed. Quite often, a drug is more soluble in water miscible vehicles like propylene glycol serving as a co-solvent and show better bioavailability.
Sometimes dilution of such vehicles with the body fluids results in precipitation of drug as fine particles which, however, dissolve rapidly. Solubilisers such as polysorbate 80 are sometimes used to promote solubility of a drug in aqueous vehicles. In case of water immiscible vehicles, the rate of drug absorption depends upon its partitioning from the oil phase to the aqueous body fluids, which could be a rate-limiting step.
Viscosity of the vehicles is another factor in the absorption of drugs. Diffusion into the bulk of GI fluids and thus absorption of a drug from a viscous vehicle may be slower. Diluents Fillers: Diluents are commonly added to tablet and capsule formulations if the required dose is inadequate to produce the necessary bulk. A diluent may be organic or inorganic. Among organic diluents, carbohydrates are very widely usedfor example, starch, lactose, microcrystalline cellulose, etc.
These hydrophilic powders are very useful in promoting the dissolution of poorly water-soluble, hydrophobic drugs like spironolactone and triamterene by forming a coat onto the hydrophobic surface of drug particles and rendering them hydrophilic. Among the inorganic diluents, dicalcium phosphate DCP is most common. One classic example of drug-diluent interaction resulting in poor bioavailability is that of tetracycline and DCP. The cause is formation of divalent calcium-tetracycline complex which is poorly soluble and thus, unabsorbable.
Binders and Granulating Agents: These materials are used to hold powders together to form granules or promote cohesive compacts for directly compressible materials and to ensure that the tablet remains intact after compression. Popular binders include polymeric materials natural, semisynthetic and synthetic like starch, cellulose derivatives, acacia, PVP, etc.
Others include gelatin and sugar solution. In general, like fillers, the hydrophilic aqueous binders show better dissolution profile with poorly wettable drugs like phenacetin by imparting hydrophilic properties to the granule surface.
However, the proportion of strong binders in the tablet formulation is very critical. PEG was found to be a deleterious binder for phenobarbital as it forms a poorly soluble complex with the drug.
Non-aqueous binders like ethyl cellulose also retard drug dissolution. These agents overcome the cohesive strength of tablet and break them up on contact with water which is an important prerequisite to tablet dissolution. Almost all the disintegrants are hydrophilic in nature. A decrease in the amount of disintegrant can significantly lower bioavailability. Adsorbing disintegrants like bentonite and veegum should be avoided with low dose drugs like digoxin, alkaloids and steroids since a large amount of dose is permanently adsorbed and only a fraction is available for absorption.
Microcrystalline cellulose is a very good disintegrant and a binder too but at high compression forces, it may retard drug dissolution. These agents are added to tablet formulations to aid flow of granules, to reduce interparticle friction and sticking or adhesion of particles to dies and punches. The commonly used lubricants are hydrophobic in nature several metallic stearates and waxes and known to inhibit wettability, penetration of water into tablet and their disintegration and dissolution.
This is because the disintegrant gets coated with the lubricant if blended simultaneously which however can be prevented by adding the lubricant in the final stage. The best alternative is use of soluble lubricants like SLS and carbowaxes which promote drug dissolution. In general, the deleterious effect of various coatings on drug dissolution from a tablet dosage form is in the following order: The dissolution profile of certain coating materials change on aging; e.
This can, however, be prevented by incorporating little PVP in the coating formulation. Popular suspending agents are hydrophilic polymers like vegetable gums acacia, tragacanth, etc. These agents and some sugars are also used as viscosity imparters to affect palatability and pourability of solution dosage forms. Such agents can influence drug absorption in several ways.
The macromolecular gums often form unabsorbable complexes with drugsfor example, sodium CMC forms a poorly soluble complex with amphetamine. An increase in viscosity by these agents acts as a mechanical barrier to the diffusion of drug from the dosage form into the bulk of GI fluids and from GI fluids to the mucosal lining by forming a viscid layer on the GI mucosa.
They also retard the GI transit of drugs. Surfactants are widely used in formulations as wetting agents, solubilisers, emulsifiers, etc. Their influence on drug absorption is very complex. They may enhance or retard drug absorption either by interacting with the drug or the membrane or both.
Mechanisms involved in the increased absorption of drug by use of surfactants include:. Promotion of wetting through increase in effective surface area and dissolution of drugs e. Better membrane contact of the drug for absorption.
Enhanced membrane permeability of the drug. The beneficial effects of surfactants have been observed at pre-critical micelle concentration levels. However, physiologic surfactants like the bile salts anionic and lysolecithin nonionic promote absorption of hydrophobic drugs like steroids, oil soluble vitamins and griseofulvin by their micellar solubilising property. Decreased absorption of drug in the presence of surfactants has been suggested to be due to: Formation of unabsorbable drug-micelle complex at surfactant concentrations above critical micelle concentration 2.
Laxative action induced by a large surfactant concentration Buffers: Buffers are sometimes useful in creating the right atmosphere for drug dissolution as was observed for buffered aspirin tablets. However, certain buffer systems containing potassium cations inhibit the drug absorption as seen with vitamin B2 and sulphanilamide. The reason attributed to it was the uptake of fluids by the intestinal epithelial cells due to which the effective drug concentration in the tissue is reduced and the absorption rate is decreased.
Such an inhibitory effect of the various buffer cations on the drug transfer rate is in the following order: Hence, the buffer system for a salt of a drug should contain the same cation as the drug salt and introduce no additional cations.
Complexing Agents: Complex formation has been used to alter the physicochemical and biopharmaceutical properties of a drug. A complexed drug may have altered stability, solubility, molecular size, partition coefficient and diffusion coefficient. Basically, such complexes are pharmacologically inert and must dissociate either at the absorption site or following absorption into the systemic circulation.
Several examples where complexation has been used to enhance drug bioavailability are: Enhanced dissolution through formation of a soluble complex e. Enhanced lipophilicity for better membrane permeability e. Enhanced membrane permeability e. Complexation can be deleterious to drug absorption due to formation of poorly soluble or poorly absorbable complex e.
Reasons for poor bioavailability of some complexes are 4. Failure to dissociate at the absorption site, and 5. Large molecular size of the complex that cannot diffuse through the cell membranefor example, drug-protein complex. Even a very low concentration of water-soluble dye can have an inhibitory effect on dissolution rate of several crystalline drugs. The dye molecules get adsorbed onto the crystal faces and inhibit drug dissolution for example, brilliant blue retards dissolution of sulphathiazole.
Dyes have also been found to inhibit micellar solubilisation effect of bile acids which may impair the absorption of hydrophobic drugs like steroids. Cationic dyes are more reactive than the anionic ones due to their greater power for adsorption on primary particles. When a significant increase in free drug concentration above saturation or equilibrium solubility occurs, it results in supersaturation which in turn lead to drug precipitation or crystallization.
Increasing the viscosity of vehicle. Prevent conversion of a high-energy metastable polymorph into stable, less soluble polymorph.
Adsorbing on the faces of crystal and reduce crystal growth. Nature and Type of Dosage Form Apart from the proper selection of drug, clinical success often depends to a great extent on the proper selection of dosage form of that drug.
For a given drug, a 2 to 5 fold or perhaps more difference could be observed in the oral bioavailability of a drug depending upon the nature and type of dosage form. Such a difference is due to the relative rate at which a particular dosage form releases the drug to the biological fluids and the membrane. The relative rate at which a drug from a dosage form is presented to the body depends upon the complexity of dosage form. The more complex a dosage form, greater the number of rate-limiting steps and greater the potential for bioavailability problems.
The rate at which a particular dosage form releases the drug following administration is given in Fig. Course of events that occur following oral administration of various dosage forms As a general rule, the bioavailability of a drug from various dosage forms decreases in the following order: Thus, absorption of a drug from solution is fastest with least potential for bioavailability problems whereas absorption from a sustained release product is slowest with greatest bioavailability risk.
Several factors, especially the excipients which influence bioavailability of a drug from its dosage form, have been discussed earlier.
A drug in a solution syrups, elixirs, etc. Factors that influence bioavailability of a drug from solution dosage form includethe nature of solvent aqueous, water miscible, etc. Quite often, dilution of a drug in solution with GI fluids results in precipitation of drug as fine particles which generally dissolve rapidly.
Factors that limit the formulation of a drug in solution form include stability, solubility, taste, cost of the product, etc. Emulsion dosage forms have been found to be superior to suspensions in administering poorly aqueous soluble lipophilic drugs. It was observed with indoxole an NSAID that when it is dissolved in a vegetable oil and emulsified in water, absorption increases 3 fold over its aqueous suspension. Emulsion dosage form presents a large surface area of oil to the GIT for absorption of a drug.
Scientists have claimed that a drug administered in oily vehicle emulsified and solubilised in the GIT by bile salts to form mixed micelles can direct the distribution of drug directly into the lymphatic system thereby avoiding the hepatic portal vein and first-pass metabolism.
The major rate-limiting step in the absorption of a drug from suspension dosage form is drug dissolution which is generally rapid due to the large surface area of the particles. Important factors in the bioavailability of a drug from suspensions include particle size, polymorphism, wetting agents, viscosity of the medium, suspending agents, etc.
Though powders are superior to tablets and capsules, they are not in use nowadays due to handling and palatability problems. Major factors to be considered in the absorption of a drug from powders are particle size, polymorphism, wettability, etc. Powders and granules are popularly administered in hard gelatin capsules whereas viscous fluids and oils in soft elastic shells. Factors of importance in case of hard gelatin capsules include drug particle size, density, polymorphism, intensity of packing and influence of diluents and excipients.
Hydrophilic diluents like lactose improve wettability, deaggregation and dispersion of poorly aqueous soluble drugs whereas inhibitory effect is observed with hydrophobic lubricants like magnesium stearate.
A hydrophobic drug with a fine particle size in capsule results in a decrease in porosity of powder bed and thus, decreased penetrability by the solvent with the result that clumping of particle occurs. Other factors of importance include possible interaction between the drug and the diluent e.
The influence of capsule processing factors on drug dissolution and bioavailability have already been discussed. Soft elastic capsules as such dissolve faster than hard gelatin capsules and tablets and show better drug availability from oily solutions, emulsions or suspensions of medicaments especially hydrophobic drugs. One of the best examples of this is the faster dissolution of indoxole equivalent to that of an emulsion dosage form when formulated as soft gelatin capsule in comparison to hard gelatin capsule and aqueous suspension.
Such poorly soluble drugs can be dissolved in PEG or other suitable solvent with the aid of surfactants. Soft gelatin capsules are thus of particular use where the drug dose is low, drug is lipophilic or when oily or lipid based medicaments are to be administered. This moisture migrates into the shell content and crystallization of drug occurs during the drying stage resulting in altered drug dissolution characteristics.
Compressed tablets are the most widely used convenience and cost effective dosage forms. A schematic representation of disintegration, deaggregation, dissolution and absorption of a drug from a tablet dosage form is shown in Fig. Sequence of events in the absorption of a drug from tablet dosage form The bioavailability problems with tablets arise from the reduction in the effective surface area due to granulation and subsequent compression into a dosage form.
Since dissolution is most rapid from primary drug particles due to their large surface area, disintegration of a tablet into granules and subsequent deaggregation of granules into fine particles is very important.
A number of formulation and processing factors influencing these steps and also the physicochemical properties of drug substance that influence bioavailability have already been discussed in the earlier sections of this chapter. Coated Tablets: In addition to factors that influence drug release from compressed tablets, the coating acts as yet another barrier which must first dissolve or disrupt to give way to disintegration and dissolution of tablet. Of the two types of coatings, the film coat, which is thin, dissolves rapidly and does not significantly affect drug absorption.
The sugar coat which though soluble, is generally tough and takes longer to dissolve. The sealing coat which is generally of shellac, is most deleterious. Press coated tablets may be superior to sugar coated tablets in such cases. Enteric-Coated Tablets: Enteric coated tablets have great potential in creating bioavailability problems because the coat dissolves only in the alkaline pH of the intestine and it may take as long as 2 to 4 hours for such a tablet to empty from the stomach into the intestine depending upon the meals and the GI motility.
Hence, the pharmacological response may eventually be delayed by as much as 6 to 8 hours. The problem of gastric emptying can, however, be overcome by enteric coating the granules or pellets and presenting them in a capsule or compressing into a tablet.
The thickness of enteric coat is yet another determinant factor in drug dissolution, increasing thickness being more problematic. Aging of the dosage form also affects drug release, especially with shellac. Sustained-Release Products: Drug release from such products is most unpredictable, the problems ranging from dose dumping to unsatisfactory or no drug release at all.
However, with the development of newer innovations and technologies, it is becoming increasingly reliable and the results reproducible with little inter-subject variations. Product Age and Storage Conditions A number of changes, especially in the physicochemical properties of a drug in dosage form, can result due to aging and alterations in storage conditions which can adversely affect bioavailability.
With solution dosage form, precipitation of drug due to altered solubility, especially due to conversion of metastable into poorly soluble, stable polymorph can occur during the shelflife of the product. Changes in particle size distribution have been observed with a number of suspension dosage forms resulting in decreased rate of drug dissolution and absorption.
In case of solid dosage forms, especially tablets, disintegration and dissolution rates are greatly affected due to aging and storage conditions. An increase in these parameters of tablets has been attributed to excipients that harden on storage e. PVP, acacia, etc. Changes that occur during the shelf-life of a dosage form are affected mainly by large variations in temperature and humidity.
In one of the studies conducted on prednisone tablets containing lactose as the filler, high temperature and high humidity resulted in harder tablets that disintegrated and dissolved slowly. Gastrointestinal tract The gastrointestinal tract GIT comprises of a number of components, their primary function being secretion, digestion and absorption.
The mean length of the entire GIT is cm. The major functional components of the GIT are stomach, small intestine duodenum, jejunum and ileum and large intestine colon which grossly differ from each other in terms of anatomy, function, secretions and pH Fig. The stomach is a bag like structure having a smooth mucosa and thus small surface area.
Its acidic pH, due to secretion of HCl, favours absorption of acidic drugs if they are soluble in the gastric fluids since they are unionised to a large extent in such a pH. The gastric pH aids dissolution of basic drugs due to salt formation and subsequent ionisation which are therefore absorbed to a lesser extent from stomach because of the same reason.
The stomach is not the principal region for drug absorption because 1. The total mucosal area is small.
The epithelium is dominated by mucus-secreting cells rather than absorptive cells. The gastric residence time is limited due to which there is limited opportunity for gastric uptake of drug. Small Intestine: It is the major site for absorption of most drugs due to its special characteristics 1. Large surface area the folds in the intestinal mucosa, called as the folds of Kerckring, result in 3 fold increase in the surface area.
The surface of these folds possess finger like projections called as villi. From the surface of villi protrude several microvilli about from each absorptive cell that lines the villi resulting in times increase in the surface area Fig. Great length of small intestine approximately cms result in more than square meters of surface which is several times that of stomach.
Greater blood flow - the blood flow to the small intestine is 6 to 10 times that of stomach. Favourable pH range the pH range of small intestine is 5 to 7. Slow peristaltic movement prolongs the residence time of drug in the intestine 6. High permeability the intestinal epithelium is dominated by absorptive cells. A contribution of all the above factors thus make intestine the best site for absorption of most drugs.
Representation of the components of intestinal epithelium that accounts for its large surface area Large Intestine: Its length and mucosal surface area is very small villi and microvilli are absent in comparison to small intestine and thus absorption of drugs from this region is insignificant.
Its contents are neutral or alkaline. The main role of large intestine is in the absorption of water and electrolytes. However, because of the long residence time 6 to 12 hours , colonic transit may be important in the absorption of some poorly soluble drugs and sustained release dosage forms.
In elderly persons, causes of impaired drug absorption include altered gastric. Gastric Emptying Apart from dissolution of a drug and its permeation through the biomembrane, the passage from stomach to the small intestine, called as gastric emptying, can also be a rate-limiting step in drug absorption because the major site of drug absorption is intestine.
Thus, generally speaking, rapid gastric emptying increases bioavailability of a drug. Rapid gastric emptying is advisable where: A rapid onset of action is desired e. Dissolution of drug occurs in the intestine e.
The drugs are not stable in the gastric fluids e. The drug is best absorbed from the distal part of the small intestine e. For better dissolution and absorption, the gastric emptying can be promoted by taking the drug on empty stomach. Since gastric emptying is altered by several factors due to which large intersubject variations are observed, all biopharmaceutic studies that require the drug to be taken orally are performed in volunteers on empty stomach.
Gastric emptying of a drug is delayed by co-administering food because unless the gastric contents are fluid enough or the size of the solid particles is reduced below 2 mm, its passage through the pylorus into the intestine is not possible.
Delay in gastric emptying is recommended in particular where: The food promotes drug dissolution and absorption e. Disintegration and dissolution of dosage form is promoted by gastric fluids. The drugs dissolve slowly e. The drugs irritate the gastric mucosa e. The drugs are absorbed from the proximal part of the small intestine and prolonged drug-absorption site contact is desired e. Several parameters are used to quantify gastric emptying: Gastric emptying rate is the speed at which the stomach contents empty into the intestine.
Gastric emptying time is the time required for the gastric contents to empty into the small intestine. Longer the gastric emptying time, lesser the gastric emptying rate. Gastric emptying t is the time taken for half the stomach contents to empty.
In vivo gastric emptying of a drug so also the disintegration of dosage form and drug release can be studied by using radio-opaque contrast materials like barium sulphate or tagging the drug with a radioisotope and scanning the stomach at regular intervals of time.
A large number of factors influence gastric emptying as discussed below. Volume of meal: Larger the bulk of the meals, longer the gastric emptying time. However, an initial rapid rate of emptying is observed with a large meal volume and an initial lag phase in emptying of a small volume meal. Please enter your User Name, email ID and a password to register. International Shipping at best shipping prices! Notify Me We will send an email as soon as we get it in stock.
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