John Sjögren

Force-displacement measurements in tableting

The influence of particle interaction, i.e. friction and bonding, on the net work (NETW) during compaction and on Heckel plots was tested by varying the particle size, the lubrication or the moisture content. The NETW was found to be significantly affected by particle interaction. The yield pressure, calculated from Heckel plots, was far less dependent on particle interaction and appears to be more useful for the evaluation of the deformation properties of materials. The NETW may be useful as a test of inter‐lot variations in compaction behaviour of materials, due to its high sensitivity to both inter‐ and intraparticle properties, good reproducibility and low dependence upon die wall conditions. However, it appears to be a poor measure of the plastic properties of the substance.

Studies on direct compression of tablets II. The influence of the particle size of a dry binder on the mechanical strength of tablets

Abstract Tablets of free-flowing lactose, paracetamol, ascorbic acid and sodium chloride were compressed in an instrumented single-punch press. Five size fractions of methyl cellulose powder were added as binder. Increasing amounts of methyl cellulose increased the tablet strength of all materials. Small additions of coarse binder reduced the strength of sodium chloride tablets, however. The particle size of the binder was very important for the effect and fine fractions were considerably more effective. The effect of the particle size was smallest in lactose tablets, possibly due to the pronounced fragmentation of this material during compaction. Sodium chloride which did not fragment during tabletting was most affected by particle size variation of the binder. For paracetamol and ascorbic acid the tablet strength was directly related to the degree of surface coating obtained by the binder.

In vitro and in vivo erosion of two different hydrophilic gel matrix tablets

The aim of the present work was to establish in vivo predictive in vitro tests for the tablet erosion of two different compositions (A and B) of hydrophilic matrix tablets based on hydroxypropyl methylcellulose. The tablet erosion was studied in a modified USP II apparatus at different agitation intensities and ionic strengths according to 2(2) factorial design. The in vivo tablet erosion was studied in 8 healthy human volunteers by gamma scintigraphy after administration of the tablets together with breakfast. In vitro agitation intensity increased the erosion rate for both tablets whereas increased ionic strength caused a slower rate for tablet A and a faster rate for tablet B. The choice of in vitro testing conditions proved to be critical for the attainment of in vivo predictive results. The best in vitro/in vivo correlation for the two formulations was obtained at a paddle stirring rate of 140 rpm and a ionic strength of 0.14 obtained by addition of sodium chloride.

The influence of mixing time and colloidal silica on the lubricating properties of magnesium stearate

Abstract The influence of mixing time and colloidal silica on the lubricating properties of magnesium stearate was studied using an instrumented single-punch machine. The lubricant was mixed with sodium chloride, anhydrous lactose, calcium citrate granulate and sodium chloride-colloidal silica-mixtures. Short mixing time decreased the negative effects of magnesium stearate on tablet strength and disintegration without reducing the lubricating efficiency. Addition of colloidal silica had a positive effect on the strength of lubricated sodium chloride tablets but increased the friction and did not improve the disintegration.

Development of A New Controlled Release Metoprolol Product

AbstractA new controlled-release preparation intended for once-daily dosage has been developed for the β-selective adrenoreceptor antagonist metoprolol. The scope of this presentation is to discuss biopharmaceutical and technical considerations in the development of the product.Metoprolol is well absorbed from the entire gastro-intestinal tract. In-vitro/in-vivo correlation studies showed that a pH-independent and constant (zero-order) release during about 20 hours was suitable for the final preparation. A “multiple-unit” tablet consisting of several hundred coated metoprolol pellets was developed. Desired release properties were obtained by choosing a suitable salt (succinate), preparing compact pellets without soluble additives and coating the pellets with a pH-independent polymeric layer. The final preparation has shown good manufacturing reproducibility and produces uniform plasma concentration-time curves in vivo.

Investigation of prandial effects on hydrophilic matrix tablets.

The prolonged release of drug from hydrophilic matrix tablets can be greatly affected by administration in connection with the intake of food. Changes of the tablet erosion are one of the main components of this effect. The aim of the present study was to identify the postprandial factors responsible for changes in tablet erosion and to develop predictive in vitro tests. Two formulations, one sensitive and the other robust to prandial effects in vivo, were investigated in vitro (a) in a complex physiological media simulating fasting and fed conditions; (b) according to a factorial experimental design that included agitation and pH concentrations of salt, surface-active agent, and nonionic solute as factors; and (c) at varying agitation intensities in three different sets of dissolution apparatus. Of the studied factors, only increased agitation enhanced the erosion of tablets in accordance with the in vivo effects of a meal. The other factors retarded erosion or had only minor effects. The hydrodynamic mechanical stress was thus considered to be the main factor responsible for postprandial effects on tablet erosion. The influence of changes in agitation and the opportunity to discriminate between sensitive and robust formulations differed among the three sets of dissolution apparatus. The modified USP II apparatus, operated at speeds of 50 and 100 rpm, is proposed as a discriminatory test.

In vitro release characteristics of a membrane-coated pellet formulation — influence of drug solubility and particle size

Abstract The impact of drug solubility and particle size on the in vitro release characteristics of membrane-coated pellets has been investigated for the metoprolol salts, sorbate, benzoate, succinate and fumarate. Three well-defined size fractions of small spherical pellets were prepared for each salt and coated with a membrane of ethylcellulose and hydroxypropyl methylcellulose (proportion 3:1). The particle diameter, surface area, volume and apparent density were determined for each fraction of coated pellets and their drug release properties were characterized by an initial lag-time, a constant release rate phase and a final declining release rate phase. Both the particle size and drug solubility were shown to be important for the release properties of the pellets. Thus, the constant release rate was approximately proportional to the surface area of the pellets over the entire solubility range (~ 20–500 mg/ml). All three phases of the drug release curve were strongly influenced by the drug solubility. This was explained on the basis of the different concentration gradients over the membrane as well as by osmotic effects. Although the release rate was shown to be markedly affected by the osmotic pressure, evaluation of the release kinetics did not reveal osmotic pumping to be the major mechanism for the release. Also, diffusion appears to be important for the drug release from the investigated formulations.

Work of friction and net work during compaction.

Series of tablets were compressed in a reciprocating tablet machine with a gradually increasing die wall friction. The force needed on the upper punch to maintain the tablet dimensions constant increased with the die wall friction while the lower punch force decreased. The change in punch forces due to differences in die wall friction had no effect on the tablet strength. The net work of compaction should be constant under these circumstances. The net work calculated by subtracting the work of friction and the expansion work from the gross work input was constant when the frictional work was calculated according to one of the two equations proposed in the literature (Järvinen & Juslin 1974) while the other appears to give an overestimation of the work of friction.

Evaluation of sodium stearyl fumarate as a tablet lubricant

Abstract The ability of sodium stearyl fumarate to reduce friction and adhesion to the punches was investigated as well as its influence on the tablet strength and the disintegration time. The effect of lubricant concentration, particle size and the mixing time was investigated using lactose and sodium chloride as tablet materials. A direct comparison with magnesium stearate in 6 tablet formulations was also made. The friction during compression and ejection of the tablets was measured in an instrumented tablet machine. Sodium stearyl fumarate reduced the friction and the adhesion to about the same degree as magnesium stearate and had also about the same influence on tablet strength and disintegration. The particle size of sodium stearyl fumarate was of great importance and all effects correlated better to the surface area than to the weight fraction. Prolonged mixing improved its lubricating effect and had no effect on the disintegration but reduced the strength of sodium chloride tablets. Sodium stearyl fumarate appears to be a good alternative to magnesium stearate.

Comparison of Methods for Evaluation of Friction During Tableting

AbstractThe friction between a tablet and the die wall can be evaluated by comparison of the forces on the upper and lower punches, i.e. force ratio (R-value) or force difference (FD, or by measuring the forces on the lower punch immediately before ejection (REF) or during ejection (EJF). These parameters were compared for different materials using an instrumented single-punch press. The compaction load and the dimensions of the compact had an obvious influence on all parameters studied. By correcting for differences in contact area between tablet and the die wall it appears possible to eliminate the influence on FD, REF and EJF from variation in tablet height. Several compaction loads within the range of interest have to be studied to get a complete picture of the behaviour of a tablet granulate. The different parameters did not always give correlating results and EJF appears to give the best prediction of adhesion problems.