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Biopharmaceutics is a major branch in pharmaceutical sciences which relates between the Pharmacokinetics refers to the study of the time course of a drug within the body (extent and .. pharmacology-spring/lecture-notes/ ln34hmspdf Brahmankar DM, Jaiswal SB, 76–90, Vallabh Prakashan, New Delhi. Biopharmaceutics And Pharmacokinetics By Brahmankar. Biopharmaceutics & Pharmacokinetics A Treatise by Dm Brahmankar,Sunil B Jaiswal, free pdf, click. Biopharmaceutics & Pharmacokinetics A Treatise by Dm Brahmankar,Sunil B Jaiswal, free pdf, click on link.
It is for this reason that P-gp is called as multi-drug resistance MDR protein. ABC transporters present in brain capillaries pump a wide range of drugs out of brain. Secondary active transport In these processes, there is no direct requirement of ATP i. The energy required in transporting an ion aids transport of another ion or molecule co-transport or coupled transport either in the same direction or in the opposite direction.
Accordingly this process is further subdivided into i. Symport co-transport involves movement of both molecules in the same direction e. Antiport counter-transport involves movement of molecules in the opposite direction e. Active absorption of a drug Fig. Types of active transport Active transport is a more important process than facilitated diffusion in the absorption of nutrients and drugs and differs from it in several respects: 1. The drug is transported from a region of lower to one of higher concentration i.
The process is faster than passive diffusion. Since the process is uphill, energy is required in the work done by the carrier. As the process requires expenditure of energy, it can be inhibited by metabolic poisons that interfere with energy production like fluorides, cyanide and dinitrophenol and lack of oxygen, etc.
Endogenous substances that are transported actively include sodium, potassium, calcium, iron, glucose, certain amino acids and vitamins like niacin, pyridoxin and ascorbic acid. Drugs having structural similarity to such agents are absorbed actively, particularly the agents useful in cancer chemotherapy. Examples include absorption of 5-fluorouracil and 5bromouracil via the pyrimidine transport system, absorption of methyldopa and levodopa via an L-amino acid transport system and absorption of ACE inhibitor enalapril via the small peptide carrier system.
A good example of competitive inhibition of drug absorption via active transport is the impaired absorption of levodopa when ingested with meals rich in proteins. Active transport is also important in renal and biliary excretion of many drugs and their metabolites and secretion of certain acids out of the CNS.
Comparison between active and passive transport Endocytosis It is a minor transport mechanism which involves engulfing extracellular materials within a segment of the cell membrane to form a saccule or a vesicle hence also called as corpuscular or vesicular transport which is then pinched-off intracellularly Fig.
This is the only transport mechanism whereby a drug or compound does not have to be in an aqueous solution in order to be absorbed. Endocytic uptake of macromolecules. This phenomenon is responsible for the cellular uptake of macromolecular nutrients like fats and starch, oil soluble vitamins like A, D, E and K, water soluble vitamin like B12 and drugs such as insulin. Another significance of such a process is that the drug is absorbed into the lymphatic circulation thereby bypassing first-pass hepatic metabolism.
Endocytosis includes two types of processes: 1. Phagocytosis cell eating : adsorptive uptake of solid particulates, and 2. Pinocytosis cell drinking : uptake of fluid solute.
Orally administered Sabin polio vaccine, large protein molecules and the botulism toxin that causes food poisoning are thought to be absorbed by pinocytosis. Sometimes, an endocytic vesicle is transferred from one extracellular compartment to another. Such a phenomenon is called as transcytosis. Combined Absorption Mechanisms A drug might be absorbed by more than just one mechanismfor example, cardiac glycosides are absorbed both passively as well as by active transport.
Vitamin B12 is absorbed by passive diffusion, facilitated diffusion as well as endocytosis. The transport mechanism also depends upon the site of drug administration see Table 2. Absorption of drugs by various mechanisms is summarized in Fig. Pre-uptake phase the two important pre-uptake processes are a Dissolution of drug in the GI fluids. Uptake phase is three processes involved in drug uptake are a Delivery of drug to the absorption site in the GIT.
Post-uptake phase - the three important post-uptake processes are a Metabolism of drug by the liver, en route to the systemic circulation first-pass hepatic metabolism. Routes of Drug Transfer from the Absorption Site in GIT into the Systemic Circulation A drug is transferred from the absorption site into systemic circulation by one of the two routes 1. Splanchnic circulation which is the network of blood vessels that supply the GIT.
It is the major route for absorption of drug into the systemic circulation. A drug that enters splanchnic circulation goes to the liver first where it may undergo presystemic metabolism before finally arriving into the systemic circulation.
A drug whose uptake is through stomach, small intestine or large intestine goes into the systemic circulation via splanchnic circulation. Rectally administered drugs have direct access to systemic circulation and thus circumvent firs-pass effect. Lymphatic circulation is a path of minor importance in drug absorption into systemic circulation for two reasons a The lymph vessels are less accessible than the capillaries b The lymph flow is exceptionally slow.
However, fats, fat-soluble vitamins and highly lipophilic drugs are absorbed through lymphatic circulation. There are three advantages of lymphatic absorption of drugs a Avoidance of first-pass effect. By proper biopharmaceutic design, the rate and extent of drug absorption also called as bioavailability or the systemic delivery of drug to the body can be varied from rapid and complete absorption to slow and sustained absorption depending upon the desired therapeutic objective.
The chain of events that occur following administration of a solid dosage form such as a tablet or a capsule until its absorption into systemic circulation are depicted in Fig. Sequence of events in the absorption of drugs from orally administered solid dosage forms The process consists of four steps: 1. Disintegration of the drug product. Deaggregation and subsequent release of the drug. Dissolution of the drug in the aqueous fluids at the absorption site. Absorption i. Unless the drug goes into solution, it cannot be absorbed into the systemic circulation.
In a series of kinetic or rate processes, the rate at which the drug reaches the systemic circulation is determined by the slowest of the various steps involved in the sequence.
Such a step is called as the rate-determining or rate-limiting step RDS. The rate and extent of drug absorption from its dosage form can be influenced by a number of factors in all these steps. The various factors that influence drug absorption also called as biopharmaceutic factors in the dosage form design can be classified as shown in Table 2. TABLE 2. Dissolution time 3. Manufacturing variables 4. Nature and type of dosage form 6. Product age and storage conditions B. Age 2.
Gastric emptying time 3. Intestinal transit time 4. Gastrointestinal pH 5. Disease states 6.
Blood flow through the GIT 7. Gastrointestinal contents: a. Other drugs b. Food c. Fluids d. Other normal GI contents 8. Presystemic metabolism by: a. Luminal enzymes b. Gut wall enzymes c. Bacterial enzymes d.
Physicochemical properties of the drug, and 2. Type of formulation e. Nature of excipients in the formulation. Except in case of controlled-release formulations, disintegration and deaggregation occur rapidly if it is a well-formulated dosage form. Thus, the two critical slower rate-determining processes in the absorption of orally administered drugs are: 1.
Rate of dissolution, and 2. Rate of drug permeation through the biomembrane. Dissolution is the RDS for hydrophobic, poorly aqueous soluble drugs like griseofulvin and spironolactone; absorption of such drugs is often said to be dissolution rate-limited. If the drug is hydrophilic with high aqueous solubilityfor example, cromolyn sodium or neomycin, then dissolution is rapid and RDS in the absorption of such drugs is rate of permeation through the biomembrane.
In other words, absorption of such drugs is said to be permeation rate-limited or transmembrane rate-limited Fig. The two rate-determining steps in the absorption of drugs from orally administered formulations Based on the intestinal permeability and solubility of drugs, Amidon et al developed Biopharmaceutics Classification System BCS which classifies the drugs into one of the 4 groups as shown in the table 2.
An important prerequisite for the absorption of a drug by all mechanisms except endocytosis is that it must be present in aqueous solution. This in turn depends on the drugs aqueous solubility and its dissolution rate.
Absolute or intrinsic solubility is defined as the maximum amount of solute dissolved in a given solvent under standard conditions of temperature, pressure and pH. It is a static property. Dissolution rate is defined as the amount of solid substance that goes into solution per unit time under standard conditions of temperature, pH and solvent composition and constant solid surface area.
It is a dynamic process. Several drugs have poor aqueous solubility to have a bearing on dissolution rate. However, there are well known examples of drugs such as cisapride which despite their low aqueous solubility have sufficient oral bioavailability. Two reasons can be attributed to thisone, the rapid rate of dissolution despite low intrinsic solubility and two, the therapeutic dose of drug may be so small that the GI transit time is sufficient for adequate dissolution and absorption to occur.
Thus, in contrast to absolute solubility, the dynamic process of drug dissolution is better related to drug absorption and bioavailability. Theories of Drug Dissolution Dissolution is a process in which a solid substance solubilises in a given solvent i.
Several theories to explain drug dissolution have been proposed. Some of the important ones are: 1. Here, the process of dissolution of solid particles in a liquid, in the absence of reactive or chemical forces, consists of two consecutive steps: 1. Diffusion of the soluble solute from the stagnant layer to the bulk of the solution; this step is slower and is therefore the rate-determining step in drug dissolution. The model is depicted in Fig.
Diffusion layer model for drug dissolution The earliest equation to explain the rate of dissolution when the process is diffusion controlled and involves no chemical reaction was given by Noyes and Whitney: dC dt k Cs - C b 2. Equation 2. It is a characteristic of drugs. The influence of various parameters in equation 2. 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 effect on the dissolution rate of the drug i. 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: 1. 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 intranasal, inhalation, intravaginal and transdermal routes may be considered enteral or topical according to different definitions. Moreover, it covers all the aspects o f variability observed in drug absorption. Before proceeding-to discuss absorption aspects, a brief description o f cell membrane structure and physiology is necessary. Cell Membrane: Structure and Physiology For a drug to be absorbed and distributed into organs and tissues and eliminated from the body, it must pass through one or more biological.
Such a movement o f drug across the membrane is called as d ru g transport. The basic structure of cell membrane is shown in Fig.
W ater-filled polar pore. Globular protein molecules are associated on either side of these hydrophilic boundaries and also interspersed within the membrane structure. In short, the membrane is a mayonnaise sandwich where a bimolecular layer of lipids is contained between two parallel monomolecular layers of proteins.
The hydrophobic core o f the membrane is responsible for the relative impermeability o f polar molecules.
Aqueous filled pcres or perforations of 4 to 10 A in diameter are also present in the membrane structure through which inorganic ions and small organic wa ter-soluble molecules like urea can pass. Thus, for a drug to get absorbed after oral administration, it must first pass through this biological barrier.
Facilitated diffusion Active transport Ionic or electrochemical diffusion Ion-pair transport Endocytosis. The driving force for this process is the concentration or electrochem ical gradient. It is defined as the differ ence in the drug concentration on either side o f the membrane. Drug movement is a result o f the kinetic energy o f molecules. Since no energy source is required, the process is called as passive diffusion.
During passive diffusion, the drug present in the aqueous solution at the absorp tion site partitions and dissolves in the lipid material o f the membrane and finally leaves it by dissolving again in an aqueous medium, this time at the inside o f the membrane. Passive diffusion is best expressed by Ficks first law o f diffusion, which states that the drug molecules diffuse from a region o f higher. It can be mathematically expressed by the.
Based on the above equation, certain characteristics o f passive diffu sion can be generalized: The drug moves down the concentration gradient indicating down. The rate o f drug transfer is directly proportional to the concentra tion gradient between GI fluids and the blood compartment. Greater the area and lesser the thickness o f the membrane, faster fie diffusion; thus, more rapid is the rate o f drug absorption from the intestine than from the stomach 4.
Equilibrium is attained when the concentration on either side o f the membrane becomes equal 5. Drugs which can exist in both ionized and unionized forms ap proach equilibrium primarily by the transfer o f the unionized species; the rate o f transfer o f unionized species is 3 to 4 times the rate for ionized drugs 6.
The drug diffuses rapidly when the volume o f GI fluid is low; conversely, dilution o f GI fluids decreases the drug concentration in these fluids C qit and lower the concentration gradient C q u - C. This phenomena is, however, made use o f in treating cases o f oral overdose or poisoning. Passive diffusion process is energy independent and nonsaturable but dependent, to a lesser extent, on the square root o f the molecular size o f the drug.
The molecular weights o f most drugs lie between to daltons which can be effectively absorbed passively. The diffusion gener ally decreases with increase in the molecular weight o f the compound.
However, there are exceptions for example, cyclosporin A, a peptide o f molecular weight , is absorbed orally much better than any other peptide. As equilibrium approaches, the drug diffusion should stop and consequently a large fraction o f drug may remain unabsorbed. Permeability refers to the ease with which a drug can penetrate or diffuse through a membrane. Moreover, due to sink conditions, the concentration o f drug in plasma C is very small in comparison to C g jj.
As a result, equation 2. Thus, passive diffusion follows first-order kinetics. Since a large concentration gradient always exist at the absorption site for passive diffusion, the rate o f drug absorption is usually more rapid than the rate o f elimination. Besides, dilution and distribution o f the absorbed drug into a large pool of body fluids and its subsequent binding to various tissues are other reasons for elimination being slower than absorption.
Pore Transport It is also called as convective transport, bulk flow or filtration. The process is important in the absorption of low molecular weight less than K 0 , low molecular size smaller than the diameter o f the pore and generally water-soluble drugs through narrow, aqueous-filled channels or pores in the membrane structure for example, urea, water and sugars.
Chain-like or linear compounds o f molecular weight upto daltons can be absorbed by: The driving force is constituted by the hydro static pressure or the osmotic differences across the membrane due to which bulk flow o f water alongwith small solid molecules occurs through such aqueous channels. Water flux that promotes such a transport is called as solvent drag. Drug permeation through water-filled channels is o f particular impor tance in renal excretion, removal o f drug from the cerebrospinal fluid and entry o f drugs into the liver.
Carrier-M ediated Transport Some polar drugs cross the membrane more readily than can be predicted from their concentration gradient and partition coefficient val ues. This suggests presence o f specialized transport mechanisms without which many essential water-soluble nutrients like monosaccharides, amino acids and vitamins will be poorly absorbed. The mechanism is thought to. This carrier-solute complex traverses across the membrane to the other side where it dissociates and discharges the solute molecule.
The carrier then returns to its original site to complete the cycle by accepting a fresh molecule o f solute. The carrier may be an enzyme or some other compo nent o f the membrane.
Important characteristics o f carrier-mediated transport are: Since the system is structure-specific, drugs having structure simi lar to essential nutrients, called as false nutrients, are absorbed by the same carrier system. This mechanism is o f particular impor tance in the absorption o f several antineoplastic agents like 5-fluorouracil and 5-bromouracil which serve as false nutrients. As the number of carriers are limited, the transport system is subject to competition between agents having similar structure.
Since the number o f carriers is limited, the system is capacitylimited i. It is important to note that for a drug absorbed by passive diffusion, the rate o f absorp tion increases linearly with the concentration but in case of carrier-mediated processes, the drug absorption increases linearly with concentration until the carriers become saturated after which'. Such a capacity-limited process can be adequately described by mixed order kinetics, also called as Michaelis-Menten, satura tion or non-linear kinetics.
The process is called mixed order because it is first-order at subsaturation drug concentrations and apparent zero-order at and above saturation levels. Moreover, the capacity-limited characteristics o f such a system suggest that the bioavailability o f a drug absorbed by such a system decrease with increasing dose for example, vitamins like Bj, B2 and B Hence, administration o f a large single oral dose o f such vitamins is irrational.
Specialized absorption or carrier-mediated absorption generally occurs from specific sites o f the intestinal tract which are rich in number o f carriers. Such an area in which the carrier system is most dense is called as absorption window. Drugs absorbed through such absorption windows are poor candidates for con trolled release formulations. Two types o f carrier-mediated transport systems have been identified.
They are facilitated diffusion and active transport. The driving force is concentration gradient hence a passive process. Since no energy expen diture is involved, the process is not inhibited by metabolic poisons that Intestinal Lumen. Facilitated diffusion is o f limited impor tance in the absorption o f drugs. Examples o f such a transport system include entry o f glucose into RBCs and intestinal absorption of vitamins Bi and B2.
A classic example o f passive facilitated diffusion is the GI absorption o f vitamin B An intrinsic factor IF , a glycoprotein pro duced by the gastric parietal cells, forms a complex with vitamin B 12 which is then transported across the intestinal membrane by a carrier system Fig.
Active Transport Active transport is a more important process than facilitated diffusion in the absorption o f nutrients and drugs and differs from it in several respects: The drug is transported from a region o f lower to one o f higher concentration i. Since the process is uphill, energy is required in the work done by the carrier 3. As the process requires expenditure o f energy, it can be inhibited by metabolic poisons that interfere with energy production like fluorides, cyanide and dinitrophenol and lack of oxygen, etc.
Endogenous substances that are transported actively include sodium, potassium, calcium, iron, glucose, certain amino acids and vitamins like niacin, pyridoxin and ascorbic acid. Drugs having structural similarity to. Examples include absorption of 5-fluorouracil and 5bromouracil via the pyrimidine transport system, absorption o f methyldopa and levodopa via an L-amino acid transport system and absorption of ACE inhibitor enalapril via the small peptide carrier system.
A good example o f competitive inhibition o f drug absorption via active transport is the impaired absorption of levodopa when ingested with meals rich in proteins. Active transport is also important in renal and biliary excretion o f many drugs and their metabolites and secretion of certain acids out of the CNS Fig. Ionic or Electrochemical Diffusion The charge on the membrane influences the permeation of drugs.
Molecular forms of solutes are unaffected by the membrane charge and permeate faster than ionic forms. O f the ionic forms, the anionic solute permeates faster than the cationic f o r m. The permeation of ionized drugs, particularly the cationic drugs, de pend on the potential difference or electrical gradient as the driving force across the membrane.
A cationic drug is repelled due to positive charge on the outside of the membrane. As a result, only those cations with a high kinetic energy penetrate the ionnc barrier. However, once inside the membrane, thfe cations are attracted to negatively charged intracellular membrane thereby creating an electrical gradient.
Such a drug is then said to be moving downhill with electrical gradient. If the same drug moves from a higher to lower concentration, it is said to be moving down the electrical gradient and the phenomena is called as electrochemical diffusion.
Like passive diffusion, the process continues until equilibrium is reached. Ion-Pair Transport Yet another mechanism that explains the absorption of drugs like quaternary ammonium compounds and sulfonic acids, which ionize under all pH conditions, is ion-pair transport.
Such neutral complexes have both the required lipophilicity as well as aqueous solubility for passive diffusion. Such a phenomena is called as ion-pair transport Fig. Endocytosis ii is a minor transport mechanism which involves engulfing extracellu lar materials within a segment of the cell membrane to form a saccule or a vesicle hence also called as corpuscular or vesicular transport which is then pinched-off intracellularly Fig. Outside Cell. This phenomena is responsible for the cellular uptake o f macromolecular nutrients like fats and starch, oil soluble vitamins like A, D, E and K and drugs such as insulin.
Another significance of such a process is that the drug is absorbed into the lymphatic circulation thereby bypassing firstpass hepatic metabolism. Endocytosis includes two types of processes: Phagocytosis cell eating: Pinocytosis cell drinking: Orally administered Sabin polio vaccine and large protein molecules are thought to be absorbed by pinocytosis. Sometimes, an endocytic. Such a phenomenon is called as transcytosis. A drug might be absorbed by more than just one mechanism for example, cardiac glycosides are absorbed both passively as well as by active transport.
The transport mechanism also depends upon the site o f drug administration see Table 2. Absorption o f drugs by various mechanisms is summarized in Fig. Most drugs having high lipophilicity and molecular weight in the range Structure-specific drugs with affinity for carriers transported from specific sites.
Drugs that ionize at all pH conditions absorbed after complexing with oppositely charged ions. By proper.
The chain of events that occur following administration o f a solid dosage form such as a tablet or a capsule until its absorption into systemic circulation are depicted in Fig. The process consists of four steps: Disintegration o f the drug product 2. Deaggregation and subsequent release o f the drug 3. Dissolution o f the drug in the aqueous fluids at the absorption site 4. Movement o f the dissolved drug through the GI membrane into the systemic circulation and away from the absorption site As illustrated in Fig.
Unless the drug goes into solution, it cannot be absorbed into the systemic circulation. In a series o f kinetic or rate processes, the rate at yvhich the drug. Such a step is called as the rate-determining or rate-limiting step RDS. The rate and extent of drug absorption from its dosage form can be influenced by a number o f factors in all these steps.
The various factors that influence drug absorp tion also called as biopharmaceutic factors in the dosage form design can be classified as shown in Table 2. Salt form of the drug 6. Lipophilicity of the drug 7. Drug stability N. Product age and storage conditions B. Other drugs b. Food c. Fluids d. Other normal GI contents 8. Ptesystemic metabolism by: Lumenal enzymes b.
Gut wall enzymes c. Bacterial enzymes d. Hepatic enzymes. Except in case o f controlled release formulations, disintegration and deaggregation occur rapidly if it is a well formulated dosage form. Thus, the two critical slower rate-determining processes in the absorption of orally administered drugs are: Rate o f dissolution, and 2. Rate o f drug permeation through the biomembrane.
Dissolution is the RDS for hydrophobic, poorly aqueous soluble drugs like griseofulvin and spironolactone; absorption o f such drugs is often said to be dissolution rate-limited. If the drug is hydrophilic with high aqueous solubility for example, cromolyn sodium or neomycin, then dissolution is rapid and the RDS in the absorption o f such drugs is rate o f permeation through the biomembrane.
In other words, absorption o f such drugs is said to be permeation rate limited or transmembrane ratelimited Fig. This in turn depends on the drugs aqueous solubility and its dissolution rate. Absolute or intrinsic solubility is defined as the maximum amount. It is a static property.
Dissolution rate is defined as the amount o f solid substance that goes into solution per unit time under standard conditions o f temperature, pH and solvent composi tion and constant solid surface area. It is a dynamic process. Several drugs have poor aqueous solubility to have a bearing on dissolution rate.
Two reasons can be attributed to this one,. Thus, in contrast to absolute solubility, the dynamic process o f drug dissolution is better related to drug absorption and bioavailability.
Theories of Drug Dissolution Dissolution is a process in which a solid substance solubilizes in a. Several theories to explain drug dissolution have been proposed. Some o f the important ones are: Here, the process o f dissolution o f solid particles in a liquid, in the absence o f reactive or chemical forces, consists o f two consecutive steps: Stagnant layer of thickness h and concentration Cs' Solid Drug Particle.
The model is depicted in. The earliest equation to explain the rate o f dissolution when the pro cess is diffusion controlled and involves no chemical reaction was given by Noyes and Whitney: Equation 2. Brunner incorporated Ficks first law of diffusion and modified the Noyes-Whitneys equation to: It is a characteristic o f drugs.
The influence of various parameters in equation 2. TABLE 2. Greater the value, faster the dissolution. Diffusion decreases as the viscosity of dissolution medium increases.
Greater the surface area, faster the dissolution; can be increased by micronization of drug. Influence on drug dissolution Higher the value, more the hydrophilicity and faster the dissolution in aqueous fluids. Greater the concentration gradient, faster the diffusion and drug dissolu tion; can be increased by increasing drug solubility and the volume of dissolution medium. More the thickness, lesser the diffusion and drug dissolution; can be decreased by increasing agitation.
Under such a situation, dissolution is said to be under nonsink conditions. This is true in case o f in vitro dissolution in a limited dissolution medium.
Dissolu tion in such a situation slows down after sometime due to build-up in the concentration o f drug in the bulk o f 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 o f the solution and hence no retarding effect on the dissolution rate o f the drug i. Cs and sink conditions are maintained. Under sink conditions, if the volume and surface area o f solid are kept constant, then equation 2. 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 by: Bathing the dissolving solid in fresh solvent from time to time 2.
Removing the dissolved drug by partitioning it from the aqueous phase o f the dissolution fluid into an organic phase placed either above or below the dissolution fluid for 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 o f the dissolving solid remains constant during dissolution, which is practically not possible for dissolving particles.
Hence, dissolution methods that involves use o f constant surface area discs are employed to determine the rate of dissolution. To account for the particle size decrease and change in surface area accompanying dissolution, Hixson and Crowells cubic root law of dis solution is used: Such solute containing packets are continuously. Since the solvent packets are exposed to new solid i 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. When considering the dissolu tion o f a crystal, each face o f the crystal will have a different interfacial barrier. Such a concept is given by the following equation:. In this theory, the diffrsivity D may not be independent o f saturation concentration Cs. The interfacial barrier model can be extended to both diffusion layer model and the Danckwerts model for in vitro drug.
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: The various physicochemical properties o f drug that affect drug disso lution and its rate are solubility, particle size, polymorphism, salt form, pseudopolymorphism, complexation, wettability, etc.
Dosage form factors include several formulation factors and excipients incorporated in the dosage form. Each o f these factors will be discussed in detail in the latter part o f this chapter. O f the various factors listed above, the factor o f prime importance is drug solubility. Almost every factor that affects dissolution rate, influ ences 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 o f a drug from its solubility is: Particle Size and Effective Surface Area of the Drug Particle size and surface area o f a solid drug are inversely related to each other.
Smaller the drug particle, greater the surface area. Two types o f surface area o f interest can be defined: Absolute surface area which is the total area o f solid surface o f any particle, and.
From the modified Noyes-Whitney equation 2. Since the surface area increases with decreasing particle size, a decrease in particle size, which. 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 micronization reduces the size o f particles below 0. The surface o f such small particles have energy higher than the bulk o f the solid resulting in an increased interaction with the solvent. This is particularly true in case of drugs which are nonhydrophobic, for example, micronization of poorly aqueous soluble drugs like griseofulvin, chloramphenicol and several salts of tetracycline results in superior disso lution rates in comparison to the simple milled form o f these drugs.
Micronization has in fact enabled the formulator to decrease the dose o f certain drugs because o f increased absorption efficiency for example, the griseofulvin dose was reduced to half and that o f spironolactone was decreased 20 times following micronization.
However, in case o f hydrophobic drugs like aspirin, phenacetin and phenobarbital, micronization actually results in a decrease in the effective surface area o f such powders and thus, a fall in the dissolution rate. Three reasons have been suggested for such an outcome 1. The hydrophobic surface of the drugs adsorb air onto their surface which inhibit their wettability; such powders float on the dissolu tion medium.
The particles reaggregate to form larger particles due to their high surface free energy, which either float on the surface or settle at the bottom o f the dissolution medium.
Extreme particle size reduction may impart surface charges that may prevent wetting; moreover electrically induced agglomeration may prevent intimate contact of the drug with the dissolution medium.
The net result o f 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 o f hydrophobic drugs can be converted to their effective surface area by: Particle size reduction and subsequent increase in the surface area and dissolution rate is not always advisable especially when the drugs are unstable and degrade in solution form penicillin G and erythromycin , produce undesirable effects gastric irritation caused by nitrofurantoin or when a sustained effect is desired.
In addition to increasing the dissolution rate, the second mechanism by which a reduction in particle size improves drug dissolution is through an increase in its solubility.
However, such an effect can only be achieved by reducing the particle size to a submicron level which is possible by use o f one o f the following specialized techniques such as formation of: 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. Polymorphs are of two types:. 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 com pression characteristics.
They can be prepared by crystallizing the drug from different solvents under diverse conditions. The existence o f the polymorphs can be determined by using techniques such as optical crys tallography, X-ray diffraction, differential scanning calorimetry, etc.
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 o f 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 formulations for ex ample, o f 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 water-soluble than the form I.
However, because o f their poor thermo dynamic stability, aging o f dosage forms containing such metastable forms usually result in formation o f less soluble, stable polymorph for ex ample, the more soluble crystalline form II of cortisone acetate converts to the less soluble form V in an aqueous suspension resulting in caking o f solid.
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 sulfapyridine can. 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 solubil ity than the crystalline forms because the energy required to transfer a molecule from crystal lattice is greater than that required for noncrystalline amorphous solid -fo r example, the amorphous form o f novobiocin is 10 times more soluble than the crystalline form.
Chloramphenicol palmitate, cortisone acetate and phenobarbital are other examples where the amor phous forms exhibit higher water solubility. The stoichiometric type o f adducts where the solvent. 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 o f drugs. Generally, the anhydrous form o f 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 compari son to the anhydrates thermodynamically higher energy state for further interaction with water.
The anhydrous form o f 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 nonsolvates for example, the n-pentanol solvate o f fludrocortisone and succinylsulfathiazole and the chloroform solvate of griseofulvin are more water-soluble than their nonsolvated forms.
Like polymorphs, the solvates too differ from each other in terms of their physical properties. 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 approach to enhance the solubility and dissolution rate o f such drugs is to convert them into their salt forms.
Generally, with weakly acidic drugs, a strong base salt is prepared such as the sodium and potassium salts of barbiturates and sulfonamides. In case o f weakly basic drugs, a strong. The influence o f salt formation on the drug solubility, rate o f dissolution and absorption can be explained by considering the pH o f the diffusion layer and not the pH o f the bulk o f the solution refer diffusion layer theory o f drug dissolution.
Consider the case of a salt of a weak acid. At any given pH of the bulk o f the solution, the pH o f the diffusion layer saturation solubility o f the drug of the salt form of a weak acid will be higher than that observable with the free acid form o f the drug can be practically observed in the laboratory. Owing to the increased pH o f the diffusion layer, the solubility and dissolution rate o f a weak acid in this layer is promoted, since it is a known fact that higher pH favors the dissolution o f weak acids.
Thus, if dissolution is faster, absorption is bound to be rapid. In case o f salts o f weak bases, the pH of the diffusion layer will be lower in comparison to that found with the free base form o f the drug. Consequently, the solubility o f a basic drug at this lower pH is enhanced. Thus, if: The increase and decrease in pH o f 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.
Bulk of the solution, relatively lower pH soluble form of the drug diffusion of soluble drug particles. Yet another convincing reason for enhanced solubility o f salts o f weak acids is the precipitation o f the drug as very fine particles. When the soluble ionic form o f the drug diffuses from the stagnant diffusion layer.
Consequently, this free acidic form of the drug is precipi tated in the form o f fine particles. The resultant increase in the surface area is then responsible for the rapid dissolution and absorption in com parison to the drug administered in just the acidic form Fig. The principle of in situ salt formation has been utilized to enhance the dissolution and absorption rate o f certain drugs like aspirin and penicillin from buffered alkaline tablets.
The approach is to increase the pH o f the microenvironment o f the drug by incorporating buffer agents and promote dissolution rate. Apart from the enhanced bioavailability, buffered aspirin tablets have two more advantages: The selection o f appropriate salt form for better dissolution rate is also important.
It has been shown that the choline and the isopropanolamine salts o f theophylline dissolve 3 to 4 times more rapidly than the ethylenediamine salt and show better bioavailability. A factor that influences the solubility o f salt forms of the drug is the size o f the counter ion. Generally speaking, smaller the size of the counter ion, greater the solubility o f salt for 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 o f 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. An identical result was obtained with hydrochloride salts o f several tetracycline analogs and papaverine; better dissolution and bioavailability was observed with the free bases. The reason for poor solubility and dissolution rate was the suppression action o f the common ion effect. The pH partition theory Brodie et al.
The theory states that for drug compounds o f mo. The dissociation constant pKa o f the drug. The pH at the absorption site. Since most drugs are weak electrolytes weak acids or weak bases , their degree o f ionization depends upon the pH o f the biological fluid. If the pH on either side on the membrane is different, then the compartment whose pH favors greater ionization o f the drug will contain greater amount o f drug, and only the unionized or undissociated fraction o f drug, if sufficiently lipid soluble, can permeate the membrane passively until the concentration o f unionized drug on either side o f the membrane becomes equal i.
The above statement o f the hypothesis was based on the assumptions that: The GIT is a simple lipoidal barrier to the transport o f drug. Larger the fraction o f unionized drug, faster the absorption. Drug pKa and Gastrointestinal pH The amount o f drug that exists in unionized form is a function of dissociation constant p K J o f the drug and pH o f the fluid at the absorp tion site.
It is customary to express the dissociation constants of both acidic and basic drugs by pKa values. The lower the pKa o f an acidic drug, stronger the acid i. The higher the pKa o f a basic drug, the stronger the base. When the concentration of ionized and unionized drug becomes equal, the second term of equations 2. The pKa is a characteristic o f the drug. 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 o f the intestine where they largely exist in unionized form. A summary o f above discussion is given in Table 2.
Unionized in gastric pH and ionized in intestinal pH; better absorbed from stomach. Ionized at gastric pH, relatively unionized at intestinal pH; better absorbed from intestine.
By using equations from 2. An example o f this is illustrated in Fig. Influence of pH on ionization of drug. As mentioned earlier, it is the pKa o f a drug that determines the degree o f ionization at a particular pH and that only the unionized drug, if sufficiently lipid soluble, is absorbed into the systemic circulation.
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