SUMMARY Bioavailability is an important area of pharmaceutical research containing many questions which are not yet resolved. This paper specifies some of the medical and pharmacological questions which need to be clarified before a statistician can make his contribution to a bioavailability study. The statistical considerations for designing and analyzing bioavailability studies are stated and various statistical approaches are listed. Suggestions are given for research in statistical methodology as applied to bioavailability studies. References to the literature of bioavailability experiments are provided. A number of issues have converged in recent years to focus increasing attention on an area of medical therapeutics which has come to be known as "bioavailability." Some of these issues are: the rising cost of medical care; the increasing involvement of Federal, state, and local governments in the financing and therefore the control of medical treatment; the "consumerism" movement and its scrutiny of the profits of the drug industry as they relate to the cost of medications; the cost factors associated with the researching of new drugs; the increasing regulatory activities of government; and the role of the pharmacist in the delivery of medicine to the patient. Assessment of bioavailability itself is a scientific problem, and statistics can make a significant contribution to its resolution. This paper presents some statistical aspects of bioavailability.

Bioavailability--a problem in equivalence.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jps.2600630403

Mass transport Phenomena and Models: Theoretical Concepts

Gas antisolvent (GAS) expansion of dimethylsulfoxide (DMSO) and N,N-dimethylformamide (DMFA) solutions with supercritical carbon dioxide was used to produce biologically active powders of insulin. Powders with 90% of the particles smaller than 4 μm and 10% smaller than 1 μm were obtained under all conditions tested when the process was operated continuously, with small liquid droplets sprayed into a flowing supercritical continuum. Slow pressurization of the stagnant protein solution resulted in larger particles. In vivo tests on rats revealed no differences between the biological activity of processed and unprocessed insulin, GAS processing of organic solution appears to be a reliable and effective method for the production of dry, biologically active microparticulate powders of peptides and proteins. © 1993 John Wiley & Sons, Inc.

Formation of microparticulate protein powder using a supercritical fluid antisolvent

Although the liver is the major site for drug biotransformation, the effect of hepatic dysfunction on drug disposition has not been consistent or predictable. Most early studies of drug kinetics in liver disease measured only half-life. Only in the past few years has it been realised that liver diseases can affect drug absorption, hepatic metabolism, tissue distribution, and protein binding, which complicate interpretation of any change, or lack of change in drug half-life. Furthermore, it is now apparent that the efficiency with which a drug is metabolised by the liver, the extent of binding to blood constituents, and the aetiology and stage of the hepatic disorder are each important in determining whether significant alterations in drug disposition will occur. A pharmacokinetic perfusion model which takes into account many of the above factors has been proposed, and appears to be useful for predicting changes in the disposition of rapidly metabolised compounds. Nevertheless, the state of knowledge about those factors which limit the rate of metabolism of individual drugs or classes of drugs is inadequate, and no general model or guidelines which are useful clinically have been developed. Patients with hepatic disorders may show increases or decreases in sensitivity independent of alterations in drug disposition. The clinician caring for such patients must be cautious about the use of any drugs, and rely heavily on careful patient observation to determine efficacy or toxicity.

Protein Binding and Kinetics of Drugs in Liver Diseases

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jps.2600610603

Correlation and prediction of mass transport across membranes I: Influence of alkyl chain length on flux‐determining properties of barrier and diffusant

The relationship of the upper and lower punch forces and the ejection force during the process of tablet compression has been studied. Large differences may exist between the maximum force exerted by the upper punch and the maximum force obtained at the lower punch. When such differences exist, substantial forces are needed to eject tablets from the die. The magnitude of the difference between the maximum upper and lower punch force and the magnitude of the ejection force appear to be linearly dependent on the area of the tablet in contact with the die wall. The value of the ejection force and the difference between the upper and lower punch forces are both markedly affected b the presence of lubricants. With a well-lubricated granulation the force exerted by the upper punch is essentially the same as that transmitted to the lower punch and a negligible force is required to eject the tablets from the die. A quantitative method for evaluating lubricants on the basis of these observations is suggested.

The physics of tablet compression: IV. Relationship of ejection, and upper and lower punch forces during compressional process: Application of measurements to comparison of tablet lubricants

A study of lubricants during compression and in finished tablets has shown that, (1) lubricants are confined to the surface and intergranular regions of the finished tablets and do not mix intimately with the contents of the granules, (2) approximately 1 per cent lubricant appeared to give nearly o timum granulation lubricity when applied to the test granulations used in this stucfy, (3) fluid lubricants appeared to flow into tablet voids and unlike solid lubricants did not usually cause significant increase in punch forces when added in increasing amounts if the machine settings and weights of die fill were constant, (4) the addition of lubricants, e. g., ma nesium stearate, to granulations tended to roduce slightly softer tablets and at t8e same time significantly prolonged tablet $isintegration time in the usual concentrations.

The Physics of Tablet Compression IX: Fundamental Aspects of Tablet Lubrication

Results obtained from studies on the dependency on compressional force of various physical properties of compressed tablets are shown to be in good qualitative agreement with those found in an earlier investigation on sulfathiazole tablets. Such differences in behavior of several granulations as were found could be attributed mainly to the difference in relative hardness and cohesive properties of the substances employed.

The Physics of Tablet Compression: V. Studies on Aspirin, Lactose, Lactose-Aspirin, and Sulfadiazine Tablets

Energy expended in the tablet compression process was calculated by consideration of the magnitude and relation between the several compression variables. In the compression of about 0.4 Gm. of unlubricated sulfathiazole granulation to a maximum force of 1200 Kg, on the lower punch with flat‐faced 3/8‐inch punches, about 8.6 calories were expended. For about the same weight of lubricated granulation the corresponding value was about 2.0 calories. By considering that only energy expended in the process of eliminating void space to form the tablet caused a temperature rise in the tablet, the temperature rise expected in the lubricated or unlubricated tablets mentioned above would be about 5°. When the energies expended in the processes of tablet ejection, overcoming wall friction and removing the upper punch from the die, were summed for a single punch machine making these tablets at the rate of 100 per minute, it was found that 43 kilocalories would be expended in each hour of operation if the tablets were unlubricated. If lubricated granulation were used the value would be 3 kilocalories. The bulk of these expenditures would probably cause heating of the punches and die and if the granulation was either poorly lubricated or unlubricated the heating might be severe.

The physics of tablet compression. VII. Determination of energy expenditure in the tablet compression process

The design and performance of an instrumented tableting machine are resented. A Stokes Model A-3 single punch machine has been fitted with strain and displacement gauges to permit simultaneous recording of several variables including the force exerted by the upper punch, the force exerted on the lower punch, the movement of the upper punch, and the ejection force. Several fields of tablet research which can benefit by the use of this instrument are discussed.

L.W. Busse

Papers

The physics of tablet compression: IV. Relationship of ejection, and upper and lower punch forces during compressional process: Application of measurements to comparison of tablet lubricants

The Physics of Tablet Compression IX: Fundamental Aspects of Tablet Lubrication

The Physics of Tablet Compression: V. Studies on Aspirin, Lactose, Lactose-Aspirin, and Sulfadiazine Tablets

The physics of tablet compression. VII. Determination of energy expenditure in the tablet compression process

The physics of tablet compression. III. Design and construction of an instrumented tableting machine