Pharmaceutical Dissolution Testing
The importance of dissolution rate on the clinical performance of drugs and drug delivery systems has long been recognized. It is the overwhelmingly important property of dosage forms that contributes to the rate and extent of drug availa ability to the body and, as such, is deserving of the effort that has been put forth to develop dissolution systems that provide fundamental information on the dissolution process of many drugs and chemicals as well as meaningful in vitro dissolution system models that can be correlated with some index of in vivo performance.
Notwithstanding the considerable efforts expended in trying to understand the fundamentals and application of dissolution, great deficiencies in our database still exist. Indeed, in the applied area of attempting to model in vivo with in vitro systems, it is not yet possible to routinely correlate in vitro dissolution rate data with the biological performance of sustained-release systems, i.e., in vivo data. The reason for this is simply that we do not yet understand the many bio logical variables that can influence the dissolution rate of dosage forms and, as such, all in vitro models are unable to realistically duplicate biological conditions.
An appreciation of the historic development of oral in vitro dissolution apparatus dramatizes our general lack of the biological variables involved in dis solution. Thus, when the Stohl-Gershberg disintegration apparatus was first introduced it was run in 500 mL of fluid because it was believed that was the volume of the resting stomach. The 32 cycles per minute of tube movement were to simulate the peristaltic motion of the stomach, and no allowance was made
for any form of mixing conditions. The resting stomach has closer to 30-50 mL of fluid in the fasted state and the motility pattern is divided into three separate phases of differing activity. The role of various biological solutes, in conjunction with the now-known mixing characteristics and motility pattern of the stomach, has not been fully explored. Indeed, the present official dissolution apparatus bear no relationship to physiological conditions, and hence it is not possible to completely examine the dissolution of drugs and drug delivery systems under simulated biological conditions nor to explore the influence of physio logical conditions, e.g., pH, bile salts, enzymes, and glycoproteins, on the dis solution process.
Despite the importance of dissolution, the various publications in scientific journals and review articles, and the numerous committees formed within the Academy of Pharmaceutical Sciences and AAPS, there are surprisingly few comprehensive texts in the field and none that. delineate problems in the area. The present text is badly needed and fills a void in the field. Dr. Banakar has provided a valuable service in the preparation of this text.
More than 100 years ago, Bernard S. Proctor recognized that "pill" dissolution was a necessary prerequisite for drug absorption. Nevertheless, it was not until 1930 that pharmaceutical scientists attempted to relate in vitro testing to in vivo availability. Parrot et al. have stated: "The release of a drug from the pri mary particle and its subsequent availability to the body is governed by the dissolution rate of the particle." There is little doubt that the determination of dissolution rates is an important tool in the design, fabrication, evaluation, and quality control of solid dosage forms.
Dissolution analysis of pharmaceutical solid dosage forms has emerged as the single most important test that, when carried out appropriately, will ensure the quality of the product. Interest in dissolution standards and their significance has been mounting steadily during the past decade. Knowledge of critical operating variables for a dissolution device is important to the pharmaceutical scientist interested in product development, quality control, and research applications. Since the recognition of the fact that the dissolution rate of a drug from its dosage form can often become the rate-limiting process in the physiological availability, interest has been focused on the development of a reliable in vitro dissolution test method that can positively characterize the in vivo dissolution rate-controlled absorption of drugs.
Dissolution tests are critical and they are difficult to carry out properly. There are a variety of critical factors that influence the dissolution behavior and subsequent bioavailability characteristics of a drug and drug product(s).
With the steady accumulation of data in this discipline over the past two decades, pharmaceutical dissolution technology has become an important area of study in pharmacy schools and a vital item in the armamentarium of techni cal know-how of a pharmaceutical scientist. Since dissolution is extremely important in pharmaceutical systems, particularly solid dosage forms, each chapter is devoted to a specific area in dissolution technology. Each area is discussed in sufficient depth with regard to historical background and development, theoretical and practical aspects, and current status. A wide variety of examples, citing references, along with rational guidelines for potential appli cations in practice are provided. It is the intention of this book to present a consolidated update of and comprehensive information on dissolution technology that is not otherwise currently available as a single source and to promote better understanding and fuller appreciation of the phenomenon.
It is hoped that Pharmaceutical Dissolution Testing will serve as an invaluable guide to aid the pharmacy professional, in both academia and practice (industry or otherwise), in selecting and utilizing the available means in over coming problems in design and development of better dosage forms. It is anti created that the collective knowledge gained hereby will result in the acquisition of expertise in the field of dissolution technology.
I wish to extend my gratitude and sincere appreciation to Ms. Barbara Lori more for her excellent technical expertise in preparing the manuscript. I also wish to acknowledge Ms. Kathleen Gardon, editorial assistant, for meticulous proofing. I appreciate the contributions by the authors of Chapters 4, 6, 10, and 11. Special appreciation is extended to Sandra Beberman and Carol Mayhew of Marcel Dekker, Inc., for their expert assistance. I owe special thanks to Dr. Joseph R. Robinson for writing the foreword to this text and for his encouragement in bringing this project to fruition. Last but not the least, I am indebted to my wife, Suneeta, and to my parents for their unending love and support.
Introduction, Historical Highlights, and the Need for Dissolution Testing
Dissolution is defined as the process by which a solid substance enters in the solvent to yield a solution. Stated simply, dissolution is the process by which a solid substance dissolves. Fundamentally, it is controlled by the affinity be tween the solid substance and the solvent. Pharmaceutical solid dosage forms and solid-liquid dispersed dosage forms on administration undergo dissolution in biological media, followed by absorp tion of the drug entity into systemic circulation. In determining the dissolution rate of drugs from solid dosage forms under standardized conditions, one has to consider several physicochemical processes in addition to the processes involved in the dissolution of pure chemical substances. The physical charac teristics of the dosage form, the wettability of the dosage unit, the penetration ability of the dissolution medium, the swelling process, the disintegration and deaggregation of the dosage form are a few of the factors that influence the dissolution characteristics of drugs. Wagner proposed the scheme depicted in Fig. 1.1 for the processes involved in the dissolution of solid dosage forms (1). This scheme was later modified to incorporate other factors that precede the dissolution process of solid dosage forms. Carstensen proposed a scheme incorporating the following sequence (2):
Theories of Dissolution
Over the last couple of decades, knowledge in the area of dissolution meth odology, in both theory and practice, has grown enormously. Numerous diversified attempts have been made to explain various intricacies associated with the process of dissolution and their implications in rational design of drug-dosage form. In most cases, these attempts have resulted in establishment of new and/or modified theories of dissolution, commonly referred to as models in the literature. In this chapter we review various pioneering ap proaches (theories) put forth by various investigators in the field of dissolution testing to explain the process of dissolution. In most cases, attention is given to situations in which physical models have been applied, in contrast to those where empirical or arbitrary mathematical kinetic models have been employed.
Dissolution Testing Devices
Approximately two decades ago, problems in biological availability of drugs were brought to the attention of regulatory agencies and compendia! standards groups. The problems centered around routine investigation of identical com petitive products by a pharmaceutical manufacturer. Substantial differences in bioavailability were observed during testing of the in vivo performance of the two items, which were otherwise pharmaceutically identical according to all then-existing tests for physical properties.
This triggered a study of various dissolution test methods. At that time, the major concern was over lifesaving drugs, particularly those with a narrow therapeutic index. The perfect example would be digoxin, since it is necessary for the physician to establish effective but nontoxic dosage levels for each patient in a titered dosage. Should the patient switch brands of this medication, it is imperative that the second brand closely approximate the first in its ability to sustain blood levels. It was then suggested, following investigations, that such ability could, to some degree, be correlated with dissolution-rate charac teristics.
Coordination of the studies was assigned to the then director of the Drug Standards Laboratories in Washington, which operated alongside the compen dial groups. Extensive and exhaustive evaluation of various methods was con ducted and followed by the selection of a new and official test procedure affecting all major disciplines in pharmacy, including pharmaceutical and medical professions, regulatory agencies, and drug manufacturers. Each device was tested for its ability to discriminate between subtle variations in dissolu tion characteristics, reproducibility from test to test, and its adaptability as completely as possible to existing apparatus. Dissolution research continued for over 10 years, during which time the variables affecting consistent and repeatable results were studied.
The first dissolution test procedure was published in NF XIII in 1970 (1). Dissolution test methods were made a part of the specification for five drugs: indomethacin capsules, and acetohexamide, methandrostenalone, methylpred nisone, and sulfamethoxyzole tablets. Method 3 was introduced for indometha cin capsules, due to a preestablished data base. This method used a modification of the existing disintegration equipment and has not been extended to other drugs.
The very first dissolution test device included a rotating basket, with the same dimensions as used now. Additionally, the device featured a 0.25-in. shaft, a water bath maintained at 37°C, and a standard 1-L resin flask with a flat or concave indentation at the apex of the bottom. A stirring device capable of maintaining a speed of 100 ±4% rpm could be employed, although other speeds were permitted.
With the establishment of an official dissolution test procedure, a series of collaborative tests were conducted by different laboratories for a variety of drugs. The resulting relative standard deviation and coefficient of variation between laboratories turned out to be wider than had been expected. This ini tiated the need for the development of dissolution testing standards.
Interlaboratory variability, as well as deviation from regulatory agency reports, can give rise to serious problems. In such situations, where two laboratories are within ± 5 percentage points but are above or below the lim its, precise definition and control of all equipment and analytical variables is necessary. Accordingly, during the 1970s, a vast amount of research was per formed to determine the effect of outside variables. The literature is full of reports and summaries on these investigations (2-4).
The results of these studies provided a foundation for defining and control ling input variables in the current dissolution protocol (5). Additionally, these results stimulated more extensive research into dissolution technique and instrumentation. The compendia! and regulatory authorities added restrictions on factors such as vibration, dissolved gas, statistical evaluation of test results, and so on, that influence the dissolution performance of dosage forms. The phenomenon of dissolution of dosage forms is still far from being understood completely. Although we have made significant progress in evaluation tech niques, as well as in understanding dissolution, more changes will be imple mented in the future to assist in a fuller and more complete understanding of in vitro dissolution behavior.
Automation in Dissolution Testing by William A. Hanson and Albertha M. Paul
A dissolution test consists of more than one procedure. The entire test is a series of procedures any one of which may be manual or automatic. An impor tant concept in planning automation is to survey the test as a whole system and decide which of the discrete operations should be automated (1). Illustrations on automation in dissolution testing
Factors That Influence Dissolution Testing
It has long been recognized that the availability of a drug for gastrointestinal absorption from solid dosage forms is often reflected by in vitro dissolution rates. It is also recognized that the rate-determining step in the absorption of drugs is generally the dissolution rate of drugs in the gastrointestinal fluids rather than the rapidity of their -diffusion across the gut wall. These observa tions have stimulated research in dissolution-rate studies. Consequently, with the passing of years , dissolution testing has emerged to the single most impor tant test that is employed not only as a quality control tool but also in the development of dosage form(s), solid dosage forms in particular.
The dissolution-rate data can be meaningful only if the results of successive tests on the same dosage form are consistent within reason. The dissolution test should yield reproducible results even when it is performed in different laboratories or with different personnel. To achieve high reproducibility, all variables that influence the test should be clearly understood and possibly con trolled.
Dissolution rate is influenced by many factors. The variety of factors that can affect the dissolution rate in vitro is considerable, and a large part of the literature is concerned with identifying and evaluating the extent to which
these factors are involved. Hanson (1) has listed more than a dozen common random input variables that influence the dissolution rate of a drug from a dosage form (refer Table 5.1). Wagner (2), on the other hand, suggests that the factors affecting dissolution rate of drugs from capsules and tablets in vitro and in vivo are similar to those that affect disintegration time of tablets and capsules (see Table 5.2).
The various factors affecting the dissolution rate of a drug from a dosage form fall in six main classes:
1. Factors related to the physicochemical properties of the drug
2. Factors related to drug product formulation
3. Factors related to dosage form
4. Factors related to dissolution testing device
5. Factors related to dissolution test parameters
6. Miscellaneous factors
It must be stated at the outset that this classification is oversimplified for the purpose of understanding their influence on the dissolution process. Addition ally, in most cases more than one factor is concomitantly in operation. Conse quently, it is rather difficult to get a true appreciation while evaluating the influence of any one of these factors on the overall dissolution-rate process. In this chapter we elucidate the various factors that influence the dissolution pro cess by presenting data illustrating the degree of effect. It is hoped that this approach will result in gaining a better and fuller appreciation for the relative magnanimity of the role that these factors play in dissolution testing of dosage forms.
Interpretation of Dissolution Rate Data and Techniques of In Vivo Dissolution by Umesh V. Banakar, Chetan D. Lathia, and John H. Wood
The rate at which a drug substance dissolves in a medium is commonly referred to as its rate of dissolution or dissolution rate. It is now well accepted that dissolution-rate data, when considered together with data on drug's solu bility and other important parameters, such as partition characteristics and dis solution constant, can provide crucial information as to the drug's absorption potential following administration.
There is an abundance of literature on the theory of dissolution rate. Gen erally, dissolution rate studies have one of two purposes:
Dissolution of Dosage Forms
Dissolution testing of dosage forms (wherever applicable) is considered one of the most important quality control tools while assessing the efficacy of a prod uct in vitro. The process of dissolution of an active ingredient from solid phar maceutical dosage forms involves several intermediate physicochemical steps, such as wetting, swelling, capillarity, solubility, and diffusion. Among the most significant factors that control the process of dissolution are the type and nature of the dosage form within which the active ingredient is contained. Consequently, it is crucial for a pharmaceutical scientist to understand and appreciate the various intricacies associated with the dissolution of dosage forms, solid pharmaceuticals in particular. The various theories of dissolution discussed in Chapter 2 address primarily the process of dissolution employing ideal, uninterrupted conditions as well as mechanistic approaches. However, the real-life situation is often much more complicated. Additionally, these situations represent a collective picture of a multitude of factors operating con comitantly. These situations often call for a realistic approach that can satisfac torily explain the dissolution process of a solid dosage form. It is the intention in this chapter to present simplistic theories that satisfactorily explain the dis solution performance of dosage forms. To do so, we address the process(es) of dissolution of such dosage forms and identify the critical factors that not only influence, but also control, the dissolution process of the dosage form in ques tion. In this chapter we will focus on the dissolution of conventional solid dosage forms. However, in Chapter 8 we will address the various aspects of noncon ventional solid dosage forms, particularly modified-release dosage forms, including sustained-, prolonged-, and controlled-release dosage units. Addi tionally, it must be noted that to avoid duplication, only aspects such as disso lution testing devices, commonly observed variables that influence the dissolution process, and so on, not covered elsewhere in the book and deemed most pertinent to the dissolution process of the dosage form in question are dis cussed. Readers are urged to review pertinent earlier chapters for a fuller coverage.
Dissolution of Modified-Release Dosage Forms
The recognition of the fact that the absorption rate of drugs into the body can be decreased by reduction of the rate of release of the drug from the dosage form is one of the more interesting results of pharmaceutical research. Accord ingly, some dosage forms are designed to release their medication to the body for absorption rapidly and completely, whereas other products are designed to release the drug slowly for more prolonged drug release and sustained drug action. Products formulated for the latter purpose have been described as sus tained action, sustained release, prolonged action, depot, repository, delayed action, retarded release, and timed release.
The term controlled release or rate-controlled release and similar terms indicate that the release of the drug from the dosage form occurs in a planned, predictable, and slower than normal manner. Controlled-release dosage forms release the drug (in vitro) as predicted by physicochemical mechanisms believed to be operating in physiological in vitro test conditions. Apparently, the rate and extent of absorption of the drug occur in humans as predicted from the rate and extent of drug release.
Pharmaceutical preparations with controlled-release characteristics have been a part of the pharmacists' armamentarium since the 1950s, with the pur pose of optimizing the bioavailability through the modulation of the time
Dissolution and Bioavailability
It has now been recognized with certainty that the knowledge of dissolution behavior and of the factors affecting such performance are of paramount importance in the design, evaluation, control, and therapeutic efficacy of solid dosage forms. Furthermore, it has been accepted that the biological activity of a given drug can be related to the rate at which the drug becomes available to the biological system postadministration. As early as 1955, Parrott and co workers (1) stressed that the release of a drug from the primary particle and its subsequent availability to the body is governed by the dissolution rate of the particle. In 1969, Poole (2) added that the properties of the dosage form that modify the dissolution rate must of necessity influence the blood levels of the drug, and thus may function as the controlling factor in determining the mag nitude of the pharmacological response elicited-and sometimes even of deter mining whether or not such a response is exhibited at all.
The pharmaceutical and medical literature is replete with reports showing variability in clinical response among orally administered drug products that contain chemically equivalent amounts of a drug (3). Those drugs are usually of limited aqueous solubility and the variation has generally been attributed to differences in their rate of dissolution. Additionally, it has often been asked, whether bioequivalence data per se ensure both product equivalence and appropriateness for substitution. In answer to that, one must say that even though the bioavailability data provided may appear to be adequate, the phar-
macist must be aware of the limitations of such infonnation. Bioavailability determinations often involve a single study perfonned on just one batch of a product. Thus unless the data obtained are correlated with in vitro quality con trol procedures that are employed to monitor all subsequent batches of the pro duct, such data alone cannot ensure batch-to-batch bioequivalence (4).
There is adequate evidence to conclude that the rate at which a drug dis solves (dissolution rate) from its intact or fragmented dosage fonns in the human gastrointestinal tract or in a parenteral injection site, often partially or completely controls the rate at which the drug appears in blood (absorption rate). Additionally, adequate evidence alludes to the fact that in many instances in vitro dissolution rate test results can be employed to "explain" observed differences in results obtained in animals and humans. Also, seemingly trivial changes in drug product fonnulations, manufacturing processes, or inadvertent variations in materials or manufacture can i fluence bioavailability signifi cantly. It is thus apparent that correlation between in vitro dissolution perfonn ance of a drug and its bioavailability must be demonstrated convincingly to guarantee reproducible biological response from batch to batch of a given drug product.
It is recognized that bioavailability testing of drug products in humans can
provide the most reliable means for evaluating in vitro dissolution. However, it is impractical to perform the extensive (in both time and personnel involve ment) and expensive human testing that might be routinely required. Further more, if such studies are conducted, a large number of human subjects would be placed at risk. The position of the FDA is that bioavailability testing in which humans are used as test subjects be minimized by the development and implementation of in vitro dissolution standards that reflect in vivo drug per fonnance (5).
To date, in vitro dissolution tests seem to be the most sensitive and reliable predictors of in vivo availability. Until recently, attempts to estimate physio logical availability of a drug from a solid dosage fonn by in vitro methods have been confined to the measurement of the rates of disintegration and ulti mate dissolution. Although official tests have great practical value, the fact that there is still a need for a test more directly related to bioavailability has been pointed out repeatedly. Since dissolution of a dosage form in vivo is often the rate-limiting factor determining the physiologic availability of a drug, meas urement of the in vitro dissolution rate or a related parameter is more likely to offer a meaningful indication of physiologic availability (4). If a correlation of "good," "definite," "likely," or "poor" exists between this parameter and some parameter of bioavailability, the relatively simple procedure of monitor ing the dissolution profile should permit the prediction of in vivo availability.
Dissolution Testing and the Assessment of Bioavailability/Bioequivalence
Dissolution testing has been recognized as a relatively fast and inexpensive in vitro technique that can be utilized in the assessment of the release characteris tics of dosage forms under investigation. Over the past 10 to 15 years it has been established that dissolution testing is probably the most important in vitro test that can be used to assess and control variables associated with formula tion excipients, design, and manufacturing, which may alter the release charac teristics of the active moiety from the formulation. Currently dissolution test ing is therefore implemented in the assessment and evaluation of the release rates and bioavailability of a variety of conventional tablet and capsule dosage forms. Further, the advent of controlled-release dosage forms has also resulted in the utilization of dissolution testing in evaluation of the release characteris tics of novel controlled-release oral and transdermal dosage forms during dosage form development for screening formulations with the desired release rate profiles and during the postdevelopment and marketing stages for assurance of batch-to-batch uniformity.
Recognition of the importance of dissolution testing has resulted in dissolu tion testing requirements being incorporated into official compendia and into regulatory criteria for drug and/or dosage form approval. This is evident in the substantial number of USP monographs that include dissolution testing (1). Further, "in instances where the dissolution test results have been correlated with in vivo performance of the product, in vitro dissolution test criteria are used as part of bioequivalence requirements by the Food and Drug Adminis tration" (2). In these particular cases, satisfying the dissolution requirements often ensures that batch-to-batch variability of in vivo bioavailability is mini mized.
A test product is deemed bioequivalent to a reference product when the rate and extent of absorption of the active moiety from the two products do not show a significant difference when administered in a similar fashion and under similar experimental conditions (3). For an in vivo assessment of bioe quivalence, traditionally, comparisons of AUC, Cmax and Tmax are conducted between the dosage forms. Comparisons of AUC serve as indicators of the relative bioavailability, and comparisons of Cmax and Tmax as indicators of the relative rate of release of the active species from the investigational dosage form. Therefore, attempts to assess bioequivalence of dosage forms using dis solution techniques would necessarily involve correlations of dissolution parameters to in vivo bioequivalence parameters (i.e., AUC, Cmax• and Tmax). Hence the role of dissolution testing in bioequivalence determinations rests largely on the reliability and predictive value of the foregoing correlations.
The primary aim of this chapter is to elucidate the importance of dissolution testing in the assessment of bioavailability/bioequivalence determinations of dosage forms. The fine line of demarcation between the role of dissolution tests in predicting bioavailability of dosage forms alone (i.e., in vitro-in vivo correlations) and in predicting bioequivalence determinations can sometimes be ignored. This is particularly true for the numerous methods employed to correlate in vitro dissolution data and in vivo parameters for a given product. Consequently, there will be some overlap of information, particularly in the methodology segment, that is inevitable. However, only information that is germane to the objectives of this chapter is presented. The information presented in this chapter is to be viewed in context with the assessment of the bioequivalence and bioavailability of dosage forms.
Dissolution Rediscovered by John H. Wood
It is difficult to say whether the in vitro dissolution of a tablet actually predicts the in vivo dissolution; however, we believe that if a tablet does not dissolve properly in our in vitro tests, it certainly won't do so in in vivo tests for dissolution; it will have a much greater chance of clinical success than its less well formulated coun terparts. Furthermore, any given active ingredient cannot be expected to produce the same therapeutic effects when administered in different formulations of the same dosage form
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