Controlled and Novel Drug Delivery Edited by : NUK. Jain Prot, Dept. of Pharmaceutical Scie Dr. H.S. Gour Vishwavidyal aya yal Sagar (MP) 470003 cBS CBS PUBLISHERS & DISTRIBUTORS 11, Darya Ganj, New Delhi — 110 002 (India)3N:81-239-0517-3 st Edition : 1997 print : 2002 print : 2004 >rint : 2005 Author & Publisher is book or parts thereof may not be reproduced or utilised in any ‘m or by any means, electronic or mechanical, including photo- ying, recording or otherwise without prior written permission of author and publishers blished by Satish Kumar Jain for CBS Publishers & Distributors, Worl-A, 1 Daryaganj, New Dethi - 110 002 (India. ser typeset at erman Graphics, Delhi-95 need at ia Printograph ola Nath Nagar, Shahdara, Delhi - 110 032Foreword Ve Lar Controlled and Novel Drug Delivery, which was only a dream or at best a possibility, is now a reality: <2 SES During the last decade and half, pharmaceutical and other scientists have carried out extensive and intensive investigations in this field of drug research. ‘The use of drugs began with local application and oral ingestion followed by parenteral administration. In the course of development, traditional bases fér locally applied medication underwent tremendous modification and the oral dosage forms too were reformed to render them aesthetically and therapeutically superior, sustained or designed to make the medication site specific. Introduction of pressurised systems added a note worthy dimension to targetting drugs to the affected organs. Administration of medication by the parenteral route received great impetus ever since a variety of methods for sterilization were developed. However, for ambulatory patients the topical and oral routes of drug administration will continue to be popular and acceptable. During the last 3 decades, scientific concepts e.g. bio-availability, bio-equivalence, pharmacokinetics and pharmacodynamics ete. became important in the understanding and application of drug delivery, availablity, absorption, distribution, metabolism and elimination of drugs from the biological system. This led to optimization of bio-availability and reducing toxicity. ‘Numerous techniques and devices have been experimented with to approach the problem of developing rational and therapevcally superior systems in which drug delivery is based upon novel and non-traditional methods hitherto not exploited commercially. Further, if the drug delivery can be designed to control bio-availability in a desired manner, and to the desired extent, the benefits will be immense. Coating of particles, developments of polymers and penetration enhancers, liposomes, niosomes, iontophoresis etc. have greatly contributed to this up coming mode of drug delivery. However, many horizons will have to be crossed to develop ideal drug delivery systems. Professor N.K. Jain of the Department of Pharmaceutical Sciences of Dr. Hari Singh Gour Vishwavidyalaya, Sagar, the Editor in-chief of the project of writing this text is a Pharmaceutical Scientists who has contributed considerably in the area of controlled and novel drug delivery research. He and the distinguished scientists who have associated themselves in this endeavour deserve praise and congratu- lations on this excellent presentation - a piece of literature which will be extremely helpful to the scientists engaged in Pharmaceutical research in this field. May the spirit of search in discovering bettem remedies and optimizing drug action emerge to provide superior medication to the suffering humai rast Lg o S.N, Sharma Professor Emeritus, Hamdard University, ‘New Delhi & Honorary Advisor, Dr. KIN. Modi Institute of Education & Research, Modi NagarPreface The "magic bullet" concept of Paul Ehrlich though realized very late, offers a logical solution to the ageold problem of unrelated and unwanted effects of therapeutic agents and optimizing the drug therapy in its true sense. Although "controlled" drug delivery can be considered as the progenitor of magic bullet concept in practice, the term “controlled” has been used with the widest possible meaning. Drugs were there, are there and will be there till there is life on this planet. However over the years we-have leamt that optimization of drug therapy is of paramount importance and in the process; patient safety, convenience, compliance, economic and industrial feasibility are not to be overlooked. From the crude drugs to supramolecules, from drug extracts to drug loaded erythrocytes, liposomes and other carriers vis a vis the growing emphasis on site specific and receptor specific drug delivery systems; there has been a complete shift in the approach the ingenious pharmacist is adopting, Most of the diseases are related to sietabolic disorders. We have yet to devise meaningful metabolic parameters which would monitor the healthy state to disease condition. Paul Ehrlich's magic bullet is yet another step in this direction. In future a health conditioning kit may be developed which would monitor metabolic disorders and daily, w kly or monthly screening through a computerized health check up should be possible. In future it should be possible to design individualized drug delivery systems taking care of the exact requirement of the drug at a specifi¢ site for a definite time interval for an individual patient. Many of my colleagues in Indian universities have been feeling that some attempt should be made to focus our contribution in the field of research in novel drug delivery and I being the author of some of the most popular text books in pharmacy and also being actively involved in research, the choice rested upon me. I took up the challenge and took nearly three years in turning out a dream into reality. One more consideration in our mind had been our post-graduate students who always complain about the paucity of really useful books on novel drug delivery. Similarly my friends in R & D laboratories in industry have, over the years, been encouraging me to take up such an activity. This book is an humble attempt to present an overview of the advances in novel drug delivery systems based on the contributions from the scientists working in Indian universities and research laboratories. The coverage of the topics is obviously wide though not exhaustive. Therefore there may be few repetitions in some chapters but this should be acceptable if contributors’ perception of the depth of the topic is to be honoured. The untiring efforts of all the learned contributors are gratefully acknowledged. They have been very considerate in acceeding to my repeated requests to revise, amend and sometimes rewrite the respective manuscripts. I am also thankful to my research students Mr. Ajay J. Khopade and Mr. Sanjay Jain for their most active cooperation in the preparation of this book. The Publisher, M/s. CBS Publishers & Distributors, Delhi, took keen interest in the publication of this book and I am personally thankful to them.vill Preface 1 am obliged to Dr. $.N. Sharma, Emeritus Professor, Hamdard University, New Delhi, my teacher and mentor who has been kind enough to accede to my request to write a foreword for this book. Lastly I must acknowledge the moral support and understanding from my wife, Dr. Asha, and sons, Master Parijat and Kshitj This is a modest beginning and with the encouragement and support of our readers and contributors t should be possible for me to continue my mission. The present volume should be useful to graduate nd post graduate students and teachers, pharmaceutical industries and R’& D personnel. Suggestions from any comer for improving this volume and for the preparation of subsequent volumes vould be appreciated and personally acknowledged. Prof. N.K. Jain (Editor) agar, 1997nt 12. 13. a. 1s. 16. 17. Contents Foreword Preface . Biopharmaceutical and pharmacokinetic considerations N.S. Parmar and Shivprakash Biodegradable polymers RS.R. Murthy Oral transmucosal drug delivery Padma V. Devarajan and Manisha Heman Adani Ocular drug delivery S.A. Mengi and S.G. Deshpande Transdermal drug delivery AN. Misra Targeted devices for periodontal diseases JK. Pandit Controlled delivery of vaccines S. Ganga, Manish Diwan, Rajeev S., Raghuvanshi, Amit Misra and G.P. Talwar . Novel approach to male contraception Sujoy K. Guha Lymphatics : Drug targeting and transportati S-P. Vyas lontophoretic drug delivery RK. Khar and A. Nanda Sonophoresis : Biophysical basis of transdermal drug delivery Sneh Anand and Sanju Nanda Biodegradable polymeric miscrospheres as drug carriers A. Jayakrishnan and M.S. Latha Resealed erythrocytes as drug carriers Sanjay Jain and N.K. Jain Niosomes as drug carriers NN. Udupa Liposomes as drug carriers Sanjay K. Jain and N.K. Jain Mucoadhesive drug delivery Roop K. Khar, Alka Ahuja and Javed Ali ‘Supramolecular drug delivery Shelly, A. J. Khopade and N.K. Jain Index 27 32 82 100 130 147 165 169 191 208 236 256 292 304 353 381 405Biopharmaceutical and Pharmacokinetic Considerations in the Development of Controlled Release Drug Products N.S, Parmar’ and Shivprakash’ * MPharm..M.Se.(Med),Ph.D.,F.1.C., Principal & Professor of Pharmacology, K.B. Institute of Pharmaceutical Education & Research, Gandhinagar-382023. India “* MPharm., Ph.D., Chief, Dept. of Pharmacology (R&D), Cadila Health Care Pvt. Ltd., 244, Ghodasar, Amedabad-380050. India |. INTRODUCTION Controlled release dosage forms cover a wide range of prolonged action formulations which provide continuous release of their active ingredients at a predetermined rate and for a predetermined time, The majority of these formulations are designed for oral administration; however, recently such devices have also been introduced for parenteral administration, ocular insertion and for transdermal application. The most important objective for the development of these systems is to furnish an extended duration of action and thus assure greater patient compliance (Abdou, 1989). The advantages of controlled release preparations have been summarized in Table 1.1. (Malinowski, 1983) Table 1.1. Advantages of Controlled Release Preparations Decreased incidence and/or intensity of adverse effects and toxicity. Better drug utilization, Controlled rate and site of release. More uniform blood concentrations. Improved patient compliance. Reduced dosing frequency. More consistant and prolonged therapeutic effect. A greater selectivity of pharmacological activity Ideally , the optimization of therapeutic efficacy and safety may be attained as a result of providing a nearly constant pharmacologic response, thereby avoiding the normal peak and valley pattern associated with multiple dosing of conventional drug products. Therefore in order to evaluate ‘controlled release dosage form, blood levels of a drug must be correlated well with the claimed therapeutic response to the particular delivery system under study.Controlled and Novel Drug Delivery Adverse side effects == =Toxic level 8 Therapeutic = range Minimum effective concentration No therapeutic effects Drug concentration 1 2 3 4 Frequencies of dosing Fig. 1.1. Hypothetical drug concentration profies in the systemic circulation resulting from the consecutive ‘administration of multiple dosage of an immediate release delivery sysyem (At. A2...). a compared to the ideal drug concentration profile 8 for a medication. In other instances controlled release products may have no significant advantages or they may actually less effective and/or more hazardous than conventional dosage forms of the same drug. In some cases, trolled release products may be therapeutically advantageous primarily for certain sub-population of ients. Table 1.2 outlines certain disadvantages of controlled release preparations. Ordinarily, oral trolled drug release dosage forms should not be developed unless the recommended dosage interval the controlled release dosage form is longer than that for immediate release dosage form or unless aificant clinical advantages for the controlled release dosage form can be justified like the decreased 2 effects resulting from a lower Crag. with the controlled release form as compared to the immediate vase or conventional dosage form Table 1.2. Disdvantages of Controlled Release Preparations Tnereased variability among dosage units. Stability problems, Toxicity due to dose dumping, Increased cost. More rapid development of tolerance, ‘Need for additional patient education and counselling Guidelines for the evaluation of controlled release dosage forms may provide assistance to those igning, conducting, and evaluating studies. However, it is important to recognize that each drug may sess inherent properties that require considerations specific to that drug and its dosage forms which / override the generalities of these guidelines. Thus considerations of first pass metabolism, dose ping, food effects, gastric emptying, intestinal motility, diumal variation and occupancy time. in tion to controlled release drug product warrant special attention (Skelly, 1986) st pass metabolism fraction of drug metabolized during first pass hepatic metabolism can be significantly altered by age forms which change the rate at which the drug is presented to the enzyme system. If the enzyme ems are saturable, then a slower rate of presentation may result in a greater fraction of drugBiopharmaceutical and Pharmacokinetic Considerations 3 metabolized. Phenytoin is an example of this type. Steady state plasma levels of phenytoin absorbed with equal doses of an extended release product are less, than with a prompt release product, The difference in plasma level does not appear to be due to decreased absorption, but rather increased metabolism as the amount of total drug in the urine is the same for both the formulations Phenytoin is an example of a drug with a significant first pass effect which leads to only slight blood level differences, but because of its narrow margin of safety, non-linear kinetics and different clinical uses as anticonvulsant and antiarrhythmic drug, the USP recognizes two dosage forms; prompt- for immediate-release and extended- for controlled release. Similarly, the steady-state plasma levels of proprénolol observed with equal doses of the controlled release Inderal-LA are about 60% of that obtained fer the prompt release product. In this case too, the difference in the plasma level is not due to decreased absorption, but to increased metabolism. Because of its wide therapeutic ratio, the clinical effect of the controlled release dosage form appears to be the same as that of its prompt release form Inderal Dose dumping Dose dumping takes place when more than the planned amount of the drug specified for the product is released per unit time and it is one of the major concerns with the use of controlled release dosage forms since they may contain two to four times the usual dose of a drug. Any event that results in more than the usual fraction being released can cause dose dumping and lead to toxicity Food effects Presence and type of food can have a significant effect on the pharmacokinetics of controlled release dosage forms. Dose dumping has been most notably associated with food. A meal with high fat content has been shown to increase the rate and extent of bioavailability of the controlled release preparations of theophylline. In one study (Petersen & Moeller-Petersen, 1982), it has been shown that the rate of absorption of theophylline was significantly delayed when a controlled release preparation was administered with food. The FDA of U.S.A. requires a single dose food/fasting study for all prescription ‘New Drug Application (NDA) controlled release drug products submitted for approval as well as multiple dose steady state studies. Every controlled release dosage form should be studied in a single dose, three way crossover study with treatments being (i) the controlled release, dosage form administered uinder fasting conditions, (ii), a rapidly available dosage form administered under fasting conditions; and (iii) controlled release dosage form administered immediately following the ingestion of a meal or an alternative meal which has the potential of affecting the bioavailability of drugs. The purpose of such studies is two fold : first to determine whether there is any need for labelling specifications of special conditions for administration with, respect to meals; and secondly, to provide information concerning the pattern of absorption of the controlled release dosage form compared to the rapidly available or conventional dosage form. Gastric emptying and intestinal motility Gastric emptying is subject to both neuronal and hormonal regulation apart from being influenced by factors like the degree of distension, composition and viscosity of stomach contents as well as pH and temperature. Due to multiple causes, both the intra- and inter-individual variations are large. Unaffected by extemal influence gastric emptying may take place at intervals of 0.5-10 hr. In addition drug action may also come into play. Thus gastric emptying is inhibited by anticholinergics and narcotic analgesics while enhanced by metoclopramide. The large variability of gastric emptying may have a deleterious influence on the reproducibility of therapeutic effect of drug as seen in the case of levodopa and digitoxin. In many cases not only the rate but also the extent of bioavailability are affected, particularly when the formulation requires complete gastric emptying for its pyloric passing, i.e. when the drug can be present either in the stomach or in the small intestine exclusively. This is exactly the case of controlled-release4 Controlled and Novel Drug Delivery single unit dose which, having considerable dimensions (10-16mm in diameter), is unable to reach the small intestine independently of gastric emptying. Accordingly, the emptying of undisintegrated tablets from the stomach shows variations ranging from less than 0.5 to more than 7 hr. As many drugs show optimum absorption in the upper small intestine, a lasting detention of the dose in stomach might imply 1 severely delayed absorption. An additional delay may occur if the amount of drug released in the stomach s diluted by becoming intimately mixed with, and possibly absorbed to the bulk of food. If the drug ‘elease from the depot is pH dependent, e.g. low in an acid environment, the release process will only yet properly started when the depot is emptied into the intestine. In this case also the bioavailability rate will depend closely on gastric emptying and the reproducibility of the effect is rendered questionable. 4 particular disadvantage connected with the inclination of single-unit depots to be trapped in narrow assage, is constituted by the risk of local irritation or erosion when the released agent concentrates at he site of the trap. This risk attracted special notice in the case of potassium chloride and it now provides 1 adequate reason for refraining from formulating local irritants as single unit depot preparations Stanislaus & Huber, 1987). Application of the multiple-units dose principle essentially eliminates the lependence of the drug effect on gastric emptying, the mini-depots being sufficiently small (125 mL.min“! e.g. probenecid, para-aminohippuric acid and salicylates. ii) Similarly, reabsorption will result in a renal clearance of <125 mL.min"! e.g. glucose and vitamins. Linear one-compartment open model (a) intravendus administration In this case the body is represented as a single uniform compartment in which the dose administered intravenously equilibrates instantaneously in the volume (Scheme 1) c veo Scheme | The drug loss or disappearance is considered to follow a first order process and the rate constant is represented by K,, and C is the concentration at any given time t. The differential equation describing the behavior of C over time is described as £ = -Kyc a integrating equation 1, we obtain CHC, okelt @ where C, is the drug concentration at zero time and will depend upon the amount adi Transforming equation (2) in a straight line, we obtain nC = In C,-Ky.t @ ‘Phe slope of the straight line obtained from equation (3) can be computed with the formula inc, r (4)The volume of distribution is gi D * Vea 6 © and theoretical area under the time versus plasma concentrations curve is auc= {,cydt= Cy. eX 6 (0) Extravascular administration According to this model, the dose administered is not instantaneously distributed in the compartment which represents the body. Only a factor F.D., between 0 and J, reaches the systemic circulation with 4 peak at time t. The absorption follows first-order kinetics (Scheme TD D_K, vi Ky cm) Scheme Il In this modél, drug elimination too is assumed to follow a first-order rate process. In other words, during the first phase, plasma levels increase according to the first order rate process. This is followed by a more or less short phase in which the absorption and elimination rates are similar and then by a third phase in which plasma level delay follows a first order rate process. The model can be described by the equations: $= Kc, - KC (7) dc, RUSS (7) where C is plasma drug concentration at time t, C, is drug concentration in the compartment from which absorption takes piace, K, is rate constant of absorption, K,, is rate constant of elimination, FD is fraction of dose absorbed and Vis apparent volume of distribution Integrating the equation (7b), one obtains the formula FD ekat err) @) and then by integrating the equation (7a), equation 9 isobtained : BDK, (ekett _ ekay c= TPP cokes. eke . 0 Multipte dosing To ensure the therapeutic success of a dosage regimen it is essential that the plasma concentration of the drug be maintained within its prescribed therapeutic window. This therapeutic objective is met by giving an initial loading dose to achieve the plasma concentration desired and then maintaining this concentration by replacing the amount of drug lost with time, with a maintenance dose, When the amount of drug administered within a dosing interval equals the amount of drug eliminated, a characteristic plateau is achieved, defined as the steady state. The size of the maintenance dose and the frequency of administration are governed by two factors, (i) the width of the therapeutic window, and (ii) the speed of drug elimination (Welling & Tse, 1988).10. Controlled and Novel Drug Delivery Non-linear kinetics 3y definition linearity describes the rate or extent of drug/biological interaction as being directly yroportional to the drug concentration, In a linear system, the pharmacokinetic parameters t), V4 and 2, are characteristic and constant for a drug, unaltered by the rate or amount of dose administered, and he AUC is directly proportional to the amount of the dose. These relationships do not hold true in a von-linear system. ‘The primary reason that drugs behave non-linearly is the upper limit in the concentration of enzyme, srotein or receptor available for interaction in metabolising, transporting or binding the drug. This sroduces the condition of capacity-limitation, as the amount of the biological material becomes the imiting factor in the velocity or extent of the rate or binding process. The classical equation for describing phenomenon is the Michaelis-Menten equation : Za (10) K, +S vhere V = Rate of the reaction Vinax = The maximal rate of the reaction The substrate (drug) concentration = The Michaelis-Menten constant (Value of S at the point where V = /4V, max) At low substrate concentrations, the rate of the reaction approaches first order, and at high substrate concentrations, it approaches zero order. In a zero order reaction, the rate of the reaction is constant and ndependent of the substrate (drug) concentration (Rowland & Tozer, 1970; Curry, 1980). The existence of non-linearity or saturation or capacity-limited kinetics is discerned by the following sbservations : (@) An AUC which is disproportionate to dose. (b) Changes in t,,. and fraction of drug metabolised or excreted by different pathways, with different doses. (©) The drug input rate alters the AUC and other parameters derived from AUC. (@) The semilogarithmic plot of amount of drug in the body versus time is curvilinear. V. OPTIMUM INFORMATION TO CHARACTERIZE THE DRUG ENTITY *hysicochemical Characteristics 1. Diffusion lost drugs are transported across membranes by passive diffusion. It may be assumed that more than 15% of all drugs follow this pathway of transport. The transport stream Q depends on the diffusion constant if drug in lipid material D, the surface area of the membrane A, the partition coefficient K, the membrane hickness h, and the concentration C, and C, on both sides of the membrane : _ DAKG-G) oe Under sink conditions, such as in unrestricted absorption, where the drug is immediately carried away wy the blood after crossing the membrane and is diluted within the volume of distribution, one can use ick’s first law of diffusion, the amount dq of substance diffusing in time dt across a place of area A s directly proportional to the change of concentrations de with distance travelled dx. de dt ox an aq ro)Biopharmaceutical and Pharmacokinetic Considerations 11 The flux of diffusion constant D decreases with increasing molecular weight. Usually the lower the molecular weight, the faster and more complete is the transport. 2. pKa A large number of drugs belong to the group of weak electrolytes. The non-ionized moiety is usually lipid soluble, hence may dissolve in the lipid material of a membrane and may be transported by passive diffusion, whereas the ionized moiety usually is not lipid soluble enough to permit permeation. The percent of ionization can be calculated from the Henderson equation Oe 1 + antilog (pKa - pH) 100 1+ antilog (pH - pKa) % ionized (for acidic compounds) = (13) % ionized (for basic compounds) = 4) Considerable change in degree of ionization can be expected with change of pH for acidic drugs having a pKa between 3 and 7.5, and for basic drugs having a pKa between 7 and 11 In drug delivery design it is important to calculate the degree of ionization and the percentage of drug non-ionized to obtain an indication of whether absorption from a particular site or transport can be assumed to be unrestricted in case of passive diffusion. To cross or to reach membranes or regions by passive diffusion within the body, the percentage of drug non-ionized at that site should be between at Teast 0.1 and 5%, 3. Solubility ‘The drug should be in the form of the solution at the site of absorption. During the preformulation phase it is necessary to determine a u'vg’s solubility not only in water but also at various pH values, depending upon the anticipated route of administration. Usually the pH dependent solubility will cover the pH values 1.5-3 (stomach), 4.5 (acid mantle of skin, sweat), 5.5 (acidic urine), 6.5 (duodenum, bile, jejunum, saliva), 74 (plasma, ileum, cerebrospinal fluid) and 7.8 (colon, rectum). ‘The aqueous and pH dependent solubility is of importance for drug release. When considering controlled release dosage forms by diffusion by the drug when present in the liquid ‘compartment, one would select the limit of solubility in order to utilize the concentration gradient as the driving force for drug release. Solubility is a prerequisite for a drug to be absorbed and transported in the body. For weak electrolytes, solubility is a function of pH. 4. Apparent Partition Coefficient (APC) ‘The lipid/water coefficient APC denotes the ratio of the concentrations of drug in two immiscible phases. Whereas the “true” partition coefficient applies only to completely immiscible, non-associating or dissociating species in either fluid, at low concentration and slight solubility in either phase. In biopharmaceutics the apparent partition coefficient is used, since mostly non-ideal conditions are found. Usually APC is determined between n-octanol and a buffer solution in certain pH at 37°C according to equation : oo C,-C,) Vv, apc = 20.7)! (as) ¥ 2 M2 o 1 where C, is the drug concentration in the aqueous phase before | equilibration, C, is the drug concentration in the aqueous phase after equilibration, V, is the volume of aqueous phase, and V, is the volume of the lipid phase.Controlled and Novel Drug Delivery Drugs being absorbed by passive diffusion must have a certain minimal APC. With increasing APC drug will increasingly enter the brain tissue (CNS drugs) due to the high lipid content of the myelin ath surrounding the nerve fibres in the grey matter. Also, with increasing APC the volume of iribution may increase due to paxitioning into fat tissue. Rate and extent of absorption of drugs usually rease with increasing APC. armacokinetic characterization practically all controlled release dosage forms, a basic pharmacokinetic understanding of a given a's disposition in the human (or animal) body is essential. Most controlled release dosage forms are intended just to release the drug at a delayed or prolonged rate, but are expected to reach and maintain ertain target concentration in blood, in plasma, or at specific sites or organs. These dosage forms are Itiple-dose products designed to result in steady state concentrations, C,.. The magnitude of C,, depends the dose rate R° (amount of drug/unit of time) and the total clearance CL (loss of drug from the ume of distribution/point of time) of the drug. To understand the design and evaluation of controlted rase dosage forms, some basic principles are discussed here. Elimination or terminal half-life (t,.) 2 ty is the time required to reduce the concentration in blood, plasma, or serum to one-half, after ilibrium is reached. The t,,. can be determined from the slope of the terminal line of a semilogarthmic t of serum concentrations’ versus time plot by regression analysis. The ty is an important parameter the selection of drug to be incorporated into controlled delivery system. The shorter the t,, the greater I be the amount of drug to be incorporated into the delivery system. Only drugs whose t,,. can be related with the pharmacological response are candidates for controlled delivery system. Area under the concentration-time curve (AUC) > AUC is a measure of the quantity of drug in the body. If curve fitting is done, which assumes a cific model, the AUC can be determined from the coefficients and constants. However, most iveniently the AUC is determined by a compartment model-independent apparoaches, using the linear rezoidal rule. The AUC is a very important parameter, permitting the estimation of total clearance, | consequently the apparent volume of distribution. The ratio of the AUC’s between extravascular and avascular administration is the absolute bioavailability, and the ratio of the AUCS between a test and idard product given by the same route of administration is the relative bioavailability Total clearance (C,) 2 C, is that hypothetical volume of distribution of unmetabolized drag that is cleared per unit of time any pathway of drug removal. The value of C,, can be determined from the dose adminstered D, and olute bioavailability, and AUC : DF AUC 1) In addition, C,, Vg, and typ are interrelated, whereas C, and V, are the independent variables and is the dependent variable: 0.693 V, q- ae an ha Upon multiple dosing, once steady state is reached, C, is : D "Re D wD 2re AUC (n+l) is the AUC during any dosing interval.