BHRAMANKAR - Biopharmaceutics - Free ebook download as PDF File .pdf), Text File .txt) or read book online for free. Bhramakar book. Pharmacokinetics A. Jrm. D. M. BRAHMANKAR raukhamatfrogal.ga, Ph.D. SC. SUNIL B. JAISWAL. raukhamatfrogal.ga, Pn -. Click to Download PDF. Biopharmaceutics and Pharmacokinetics-A Treatise. Image result for brahmankar biopharmaceutics. Textbook of Biopharmaceutics and Clinical Pharmacokinetics. BOOKS REVIEWS Textbook of Biopharmaceutics and Clinical Pharmacokinetics.. By S.. NIAZI.
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Labels: biopharmaceutics and pharmacokinetics pharmacokinetics free pdf brahmankar book pdf free pharmacy pdf books pharmacy study. Get this from a library! Biopharmaceutics and pharmacokinetics: a treatise. [D M Brahmankar; Sunil B Jaiswal]. Pharmainfo Biopharmaceutics and pharmacokinetics book by brahmankar pdf. Application of Pharmacokinetics in new drug By D. M. Brahmankar and Sunil.
Facilitated Diffusion It is a carrier-mediated transport system that operates down the concentration gradient downhill transport but at a much a faster rate than can be accounted by simple passive diffusion. The driving force is concentration gradient hence a passive process. Since no energy expenditure is involved, the process is not inhibited by metabolic poisons that interfere with energy production.
Facilitated diffusion is of limited importance in the absorption of drugs. Examples of such a transport system include entry of glucose into RBCs and intestinal absorption of vitamins B1 and B2.
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A classic example of passive facilitated diffusion is the GI absorption of vitamin B An intrinsic factor IF , a glycoprotein produced by the gastric parietal cells, forms a complex with vitamin B12 which is then transported across the intestinal membrane by a carrier system Fig. Active transport mechanisms are further subdivided into a. Primary active transport In this process, there is direct ATP requirement. Moreover, the process transfers only one ion or molecule and in only one direction, and hence called as uniporter e.
Carrier proteins involved in primary active transport are of two types i Ion transporters are responsible for transporting ions in or out of cells. A classic example of ATP-driven ion pump is proton pump which is implicated in acidification of intracellular compartments. Two types of ion transporters which play important role in the intestinal absorption of drugs have been identified a Organic anion transporter which aids absorption of drugs such as pravastatin and atorvastatin.
The latter is responsible for pumping hydrophobic drugs especially anticancer drugs out of cells. Presence of large quantity of this protein thus makes the cells resistant to a variety of drugs used in cancer chemotherapy, a phenomenon called as multi-drug resistance.
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.
Biopharmaceutics and pharmacokinetics: a treatise D.M. Brahmankar and Sunil B. Jaiswal
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. According to the interfacial barrier model. Since the surface area increases with decreasing particle size.
Almost every factor that affects dissolution rate. 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: Absolute surface area which is the total area o f solid surface o f any particle.
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. Dosage form factors include several formulation factors and excipients incorporated in the dosage form. 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. Dosage form factors. Effective surface area which is the area o f solid surface exposed to the dissolution medium.
Two types o f surface area o f interest can be defined: Smaller the drug particle. From the modified Noyes-Whitney equation 2. Physicochemical properties o f the drug.
An empirical relation which is useful to predict the dissolution rate o f a drug from its solubility is: From several equations pertaining to dissolution rate. Extreme particle size reduction may impart surface charges that may prevent wetting. This is particularly true in case of drugs which are nonhydrophobic. Greater the effective surface area. Micronization has in fact enabled the formulator to decrease the dose o f certain drugs because o f increased absorption efficiency— for example.
But it is only when micronization reduces the size o f particles below 0. The absolute surface area o f hydrophobic drugs can be converted to their effective surface area by: The particles reaggregate to form larger particles due to their high surface free energy.
The hydrophobic surface of the drugs adsorb air onto their surface which inhibit their wettability. 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.
Three reasons have been suggested for such an outcome— 1. When a substance exists in more than one crystalline form. In addition to increasing the dissolution rate. Polymorphs are of two types: Polymorphism and Amorphism Depending upon the internal structure. Adding hydrophilic diluents such as PEG. Solid dispersion where such a drug is dispersed in a soluble carrier such as PVP.
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.
X-ray diffraction. They can be prepared by crystallizing the drug from different solvents under diverse conditions. Monotropic polymorph is the one which is unstable at all temperatures and pressures e. Such a stable polymorph represents the lowest energy state.
III of riboflavin is 20 times more water-soluble than the form I. The remaining polymorphs are called as metastable forms which represent the higher energy state. Because o f their higher energy state. The polymorphic form. A metastable form cannot be called unstable because if it is kept dry. 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.
Since the metastable forms have greater aqueous solubility. B and C. The stoichiometric type o f adducts where the solvent molecules are incorporated in the crystal lattice o f the solid are called as the solvates. Hydrates are most common solvate forms o f drugs.. Such drugs represent the highest energy state and can be considered as supercooled liquids. When the solvent in association with the drug is water.
This phenomenon is called as pseudopolymorphism. Salt Form of the Drug Most drugs are either weak acids or weak bases. On the other hand. Some drugs can exist in amorphous form i. Chloramphenicol palmitate. One of the easiest approach to enhance the solubility and dissolution rate o f such drugs is to convert them into their salt forms.
BHRAMANKAR - Biopharmaceutics
The anhydrous form o f theophylline and ampicillin have higher aqueous solubilities. Like polymorphs. In case of organic solvates. In case o f weakly basic drugs. The solvates can exist in different crystalline forms called as pseudopolymorphs. When the soluble ionic form o f the drug diffuses from the stagnant diffusion layer. 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.
The influence o f salt formation on the drug solubility. Consider the case of a salt of a weak acid. Owing to the increased pH o f the diffusion layer. At any given pH of the bulk o f the solution. In case o f salts o f weak bases. At a given pH. One such study was the comparative dissolution of sodium phenobarbital and free phenobarbital from their tablets.
These forms are. A factor that influences the solubility o f salt forms of the drug is the size o f the counter ion. There are exceptions where the so called more soluble salt form of the drug showed poor bioavailability. 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. Apart from the enhanced bioavailability.
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. The approach is to increase the pH o f the microenvironment o f the drug by incorporating buffer agents and promote dissolution rate.
The selection o f appropriate salt form for better dissolution rate is also important. Generally speaking. 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 reason for poor solubility and dissolution rate was the suppression action o f the common ion effect. An identical result was obtained with hydrochloride salts o f several tetracycline analogs and papaverine. The GIT is a simple lipoidal barrier to the transport o f drug. Since most drugs are weak electrolytes weak acids or weak bases.
The above statement o f the hypothesis was based on the assumptions that: The lower the pKa o f an acidic drug. The higher the pKa o f a basic drug. The pH at the absorption site. If the pH on either side on the membrane is different. It is customary to express the dissociation constants of both acidic and basic drugs by pKa values.
Larger the fraction o f unionized drug. The dissociation constant pKa o f the drug. If there is a membrane barrier that separates the aqueous solutions of different pH such as the GIT and the plasma. Acids in the pKa range 2. The pKa is a characteristic o f the drug. Such drugs are better absorbed from the relatively alkaline conditions o f the intestine where they largely exist in unionized form.
Bases in the pKa range 5 to A summary o f above discussion is given in Table 2. An example o f this is illustrated in Fig. This value is a measure o f the degree of distribution o f drug between one of the several organic. Some o f the deviations from the theory are: Rate of dissolution can be increased by altering the physical properties such as particle size or crystalline structure but its permeability can only be promoted by modification of chemical structure see chapter 6 on prodrugs.
Limitations of pH-Partition Hypothesis The pH-partition hypothesis over-simplified the otherwise complicated process o f drug absorption and therefore has its own limitations. If such drugs have. Presence of Virtual Membrane pH: Absorption of Ionized Drugs: Dotted lines indicate curves predicted by pH-partition hypothesis and bold lines indicate the practical curves.
This virtual membrane pH actually determines the extent o f drug ionization and thus. 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. This is true to a large extent as ionized drugs have low lipid solubility and relatively poor permeability.
Absorption o f ionized drug 3. Influence of GI surface area and residence time of drug 4. An S-shaped curve. Presence of aqueous unstirred diffusion layer 1. Presence o f virtual membrane pH 2. Such a model is depicted in Fig. Other mechanisms are also involved in the absorption o f ionized drugs such as active transport.
With the incorporation o f unstirred aqueous diffusion layer. This could be true under conditions where the surface area o f stqjnach and intestine are same.
According to the pH-partition theory. In the original pH-partition theory. It could also mean that once an acidic drug reaches the intestine.
Presence of Aqueous Unstirred Diffusion Layer: The pH-shift in the absorption o f acidic and basic drugs. Despite its limitations. A harder tablet with large amount o f binder has a long DT. Two major stability problems resulting in poor bioavailability o f an orally administered drug are— degradation o f the drug into inactive form.
Coated tablets. Disintegration can be aided by incorporating disintegrants in suitable amounts during formulation. Destabilization o f a drug during its shelf-life and in the GIT will be discussed in detail under formulation factors and patient related factors respectively.
Rapid disintegration is thus important in the therapeutic success of a solid dosage form. This applies in particular to high molecular weight fatty acids and bile acids. After disintegration o f a solid dosage form into granules.
The process involves grinding o f drugs in a ball mill for time long enough to affect spontaneous agglomeration. Compression force. Processes o f such importance in the manufacture of tablets are: On the one hand. One o f the more recent methods that has resulted in superior product is agglomerative phase of communition APOC. The curve obtained by plotting compression force versus rate of dissolution can take one of the 4 possible shapes shown in Fig.
The processing factor of importance in the manufacture o f capsules that can influence its dissolution is the intensity o f packing o f capsule contents. The influence o f excipients such as binders. The method o f direct compression has been utilized to yield tablets that dissolve at a faster rate.
Manufacturing processes. The method also involves a large number o f steps each o f which can influence drug dissolution— method and duration of blending.
The limitations o f this method include— i formation o f crystal bridge by the presence o f liquid. Compression Force: The compression force employed in tableting process influence density. Method o f Granulation: The wet granulation process is the most conventional technique in the manufacture o f tablets and was once thought to yield tablets that dissolve faster than those made by other granulation methods.
Method o f granulation. The reason attributed to it was an increase in the internal surface area o f the granules prepared by APOC method. A combination o f both the curves A and B is also possible as shown in curves C and D. This results in an increase in the dissolution rate o f the tablet curve B o f Fig.
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. The more the number o f excipients in a dosage form. Intensity of Packing of Capsule Contents: Like the compression force for tablets. Commonly used excipients in. Almost always. Opposite is also possible. Excipients are added to ensure acceptability.
Diffusion o f GI fluids into the tightly filled capsules creates a high pressure within the capsule resulting in rapid bursting and dissolution o f contents.
Despite their inertness and utility in the dosage form. These hydrophilic powders are very useful in promoting the dissolution o f poorly water-soluble. Diffusion into the bulk o f GI fluids and thus absorption o f a drug from a viscous vehicle may be slower.
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.
A diluent may be organic or inorganic. Viscosity of the vehicles is another factor in the absorption of drugs.
Bioavailability o f a drug from vehicles depend to a large extent on its miscibility with biological fluids. In case o f water immiscible vehicles. The cause is formation of divalent calcium-tetracycline complex which is poorly soluble and thus. Diluents Fillers: Quite often.
The 3 categories o f vehicles in use are— aqueous vehicles water. Solubilizers such as tween 80 are sometimes used to promote solubility of a drug in aqueous vehicles. Vehicle or solvent system is the major component o f liquid orals and parenterals. One classic example o f drug-diluent interaction resulting in poor bioavailability is that o f tetracycline and DCP.
Among the inorganic diluents. Popular binders include polymeric materials natural. Sometimes dilution o f such vehicles with the body fluids results in precipitation o f drug as fine particles which. Among organic diluents. Others include gelatin and sugar solution.
MC and synthetic gums which primarily stabilize the solid drug particles by reducing their rate of settling through an increase in the viscosity of the medium. Microcrystalline cellulose is a very good disintegran and a binder too but at high compression forces. Adsorbing disintegrants like bentonite and veegum should be avoided with low dose drugs like digoxin.
The dissolution profile o f certain coating materials change on aging. These agents and some! The commonly used lubricants are hydrophobic in nature several metallic stearates and waxes and known to inhibit wettability.
Non-aqueous binders like ethyl cellulose also retard drug dissolution. This can. 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 o f soluble lubricants like SLS and carbowaxes which promote drug dissolution. Almost all the disintegrants are hydrophilic in nature.
These agents are added to tablet lormulations to aid flow o f granules. PEG was found to be a deleterious binder for phenobarbital as it forms a poorly soluble complex with the drug. A decrease in the amount o f disintegrant can significantly lower bioavailability.
Popular suspending agents are hydrophilic polymers like vegetable gums acacia. Their influence on drug absorption is very complex. Laxative action induced by a large surfactant concentration Buffers: Promotion o f wetting through increase in effective surface area and dissolution o f drugs e.
Better membrane contact o f the drug for absorption 3. They may enhance or retard drug absorption either by interacting with the drug or the membrane or both.
Decreased absorption of drug in the presence of surfactants has been suggested to be due to: They also retard the GI transit o f drugs. An increase in viscosity by these agents acts as a mechanical barrier to the diffusion o f drug from the dosage form into the bulk o f GI fluids and from GI fluids to the mucosal lining by forming a viscid layer on the GI mucosa.
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. Mechanisms involved in the increased absorption o f drug by use of surfactants include: Formation o f unabsorbable drug-micelle complex at surfactant concentrations above critical micelle concentration 2.
Such agents can influence drug absorption in several ways. Enhanced membrane permeability of the drug The beneficial effects of surfactants have beer observed at pre-critical micelle concentration levels.
Such an inhibitory effect of the various buffer cations on the drug transfer rate is in the following order: Surfactants are widely used in formulations as wetting agents. Even a very low concentration o f water-soluble dye can have an inhibitory effect on dissolution rate o f several crystalline drugs.
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Dyes have also been found to inhibit micellar solubilization effect of bile acids which may impair the absorption o f hydrophobic drugs like steroids. For a given drug.
Enhanced dissolution through formation o f a soluble complex e.. Crystal Growth Inhibitors: In addition to maintaining the initial physical properties of a drug in suspension.
Complex formation has been used to alter the physicochemical and biopharmaceutical properties of a drug. Apart from the proper selection o f drug. Cationic dyes are more reactive than the anionic ones due to their greater power for adsorption on primary particles. Enhanced membrane permeability e. Enhanced lipophilicity for better membrane permeability e. The dye molecules get adsorbed onto the crystal faces and inhibit drug dissolution— for example.
Several examples where complexation has been used to enhance drug bioavailability are: B asically. A complexed drug may have altered stability. Nature and Type of Dosage Form V. Complexation can be deleterious to drug absorption due to formation o f poorly soluble or poorly absorbable complex e. The more complex a 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 o f dosage form. Important factors in the bioavailability of a drug from suspensions include particle size.
Powders and granules are popularly administered in hard gelatin capsules whereas viscous fluids and oils in soft elastic shells. Emulsion dosage forms have been found to be superior to suspensions in administering poorly aqueous soluble lipophilic drugs. A hydrophobic drug with a fine particle size in capsule results in a decrease in porosity o f powder bed and thus. Scientists have claimed that a drug administered in oily vehicle emulsified and solubilized in the GIT by bile salts to form mixed micelles can direct the distribution o f drug directly into the lymphatic system thereby avoiding the hepatic portal vein and first-pass metabolism.
Hydrophilic diluents like lactose improve wettability. Major factors to be considered in the absorption o f a drug from powders are particle size.
Factors that limit the formulation o f a drug in solution form include stability. Emulsion dosage form present a large surface area o f oil to the GIT for absorption of a drug. Factors that influence bioavailability o f a drug from solution dosage form include— the nature o f solvent aqueous.
The major rate-limiting step in the absorption o f a drug from suspension dosage form is drug dissolution which is generally rapid due to the large surface area o f the particles. Though powders are superior to tablets and capsules. A drug in a solution syrups. It was observed with indoxole an NSAID that when it is dissolved in a vegetable oil and emulsified in water.
O f the two types of coatings. The bioavailability problems with tablets arise from the reduction in the effective surface area due to granulation and subsequent compression into a dosage form. The influence o f capsule processing factors on drug dissolution and bioavailability have already been discussed.
Other factors o f importance include possible interaction between the drug and the diluent e. Compressed tablets are the most widely used convenienct and cost effective dosage forms. This moisture migrates into the shell content and crystallization o f drug occurs during the drying stage resulting in altered drug dissolution characteristics. Such poorly soluble drugs can be dissolved in PEG or other suitable solvent with the aid o f surfactants and encapsulated without difficulty.
Coated Tablets: In addition to factors that influence drue release from compressed tablets. Since dissolution is most rapid from primary drug particles due to their large surface area. Softgels are thus o f particular use where the drug dose is low. The sealing coat which is generally ot shellac. The problem o f gastric emptying can. In one o f the studies.
Aging of the dosage form also affects drug release. Sustained Release Products: Drug release from such products is most unpredictable. The stomach is a bag like structure having. The mean length o f the entire GIT is cm. The gastric i. Gastrointestinal tract The gastrointestinal tract GIT comprises o f a number o f components.
Changes in particle size distribution have been observed with a number o f suspension dosage forms resulting in decreased rate o f drug dissolution and absorption. Its acidic pH. In case o f solid dosage forms. In one o f the studies conducted on prednisone tablets containing lactose as the filler. Changes that occur during the shelf-life of a dosage form are affected mainly by large variations in temperature and humidity.
An increase in these parameters o f tablets has been attributed to excipients that harden on storage e. 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. The folds in the intestinal mucosa. The surface o f these folds possess finger like projections called as villi which increase the surface area 30 times. Absorptive role Absorptive m echanism s endocytosis Small Intestine: It is the major site for absorption o f most drugs due to its large surface area.
Gastric Emptying Apart from dissolution of a drug and its permeation through the biomembrane. Its contents are neutral or alkaline. Age In infants. Large Intestine: Some of the patient related factors that influence drug absorption are discussed below.
Dissolution o f drug occurs in the intestine e. The blood flow to 6 to 10 times that Gf stomach. Rapid gastric emptying is advisable where: A rapid onset of action is desired e. Since gastric emptying. The drugs are not stable in the gastric fluids e. In elderly persons. Disintegration and dissolution o f dosage form is promoted by gastric fluids 3. Several parameters are used to quantify gastric emptying: Since gastric emptying is a first-order process.
Delay in gastric emptying is recommended in particular where: The drugs dissolve slowly e. Volume of meal: Larger the bulk of the meals. The drugs irritate the gastric mucosa e. V Gastric emptying of a drug is delayed by co-administering food bej cause unless the gastric contents are fluid enough or the size of the solid particles is reduced below 2 mm.
The food promotes drug dissolution and absorption e. In vivo gastric emptying o f a drug so also the disintegration o f dosage form and drug release can be studied by using radio-opaque contrast materials like barium sulfate or tagging the drug with a radioisotope and scanning the stomach at regular intervals o f time.
Longer the gastric emptying time. Gastric emptying ty2 is the time taken for half the stomach contents to empty. Partial or total gastrectomy. Disease states: Diseases like gastroenteritis. Emotional state: Stress and anxiety promote gastric motility whereas depression retards it.
Chemicals that affect gastrointestinal pH also alter gastric emptying.
Body posture: Gastric emptying is favored while standing and by lying on the right side since the normal curvature of the stomach provides a downhill path whereas lying on the left side or in supine position retards it.
Vigorous physical training retards gastric emptying. Composition of meal: T em p eratu re of the meal: High or low temperature o f the ingested fluid in comparison to body temperature reduce the gastric emptying rate. Electrolytes and osmotic pressure: With alkaline solutions. Viscous materials empty at a slow rate in comparison to less viscous materials. Physical state and viscosity of meal: Liquid meals take less than an hour to empty whereas a solid meal may take as long as 6 to 7 hours.
G astrointestinal PH: Drugs that retard gastric emptying include poorly soluble antacids alum inium hydroxide. Fats promote secretion o f bile which too has an inhibitory effect on gastric emptying. Drugs absorbed from specific sites in the intestine several B vitamins Intestinal transit time is relatively short in comparison to the gastric emptying time and as the contents move down the intestine into the colon.
Delayed intestinal transit is desirable for: Drugs that dissolve or release slowly from their dosage form sustained release products I 2. The passage o f drug through the esophagus. In such cases. The mixing movement o f the intestine that occurs due to peristaltic contractions promote drug absorption. This can be overcome by preparing prodrugs o f such drugs that do not degrade or dissolve in acidic pH e. The GI pH generally increases gradually as one moves down the stomach to the colon and rectum see Fig.
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Your rating has been recorded. Write a review Rate this item: Preview this item Preview this item. Biopharmaceutics and pharmacokinetics: Print book: English View all editions and formats Rating: Subjects Biopharmaceutics. More like this Similar Items. Allow this favorite library to be seen by others Keep this favorite library private.In the latter case. Persorption is permeation of drug through temporary openings formed by shedding of two neighbouring epithelial cells into the lumen.
Passive diffusion is the major mechanism for absorption of most drugs. This can be overcome by preparing prodrugs o f such drugs that do not degrade or dissolve in acidic pH e. The process is dependent, to a lesser extent, on the square root of the molecular size of the drug drugs having molecular weights between to Daltons are effectively absorbed passively.
Polymorphs are of two types: 1. The process is faster than passive diffusion.