Martin Nicklasson

Investigation of the film formation of magnesium stearate by applying a flow‐through dissolution technique

The film formation of magnesium stearate on the surface of acetylsalicylic acid was investigated by applying a flow‐through dissolution technique. The effect of mixing time, lubricant surface area, and the addition of colloidal silica was studied. The film formation increased by increasing mixing time. The final level reached was independent of the specific surface area of the lubricants, but granular magnesium stearate gave a lower surface coverage than the powdered lubricants. The lubricating effect was independent of the mixing time and specific surface area of the lubricants. Colloidal silica was found to interact primarily with the free fraction of magnesium stearate.

A collaborative in vitro dissolution study: comparing the flow-through method with the USP paddle method using USP prednisone calibrator tablets

Abstract A collaborative in vitro dissolution study has been performed in 5 laboratories using the flow-through method with different cell types and at various hydrodynamic conditions. The USP disintegrating prednisone calibrator tablets have been used as a test formulation. The results obtained by the flow-through method were compared with data generated using the USP XXI paddle method. The flow-through method was found to produce reproducible and corresponding dissolution data both within and between the different laboratories. It was found that the linear flow rate in the flow-through cells is a fundamental parameter for the dissolution rate of the formulation. There was a conformity in dissolution rate between cells with different diameters when applying the same linear flow rate of the dissolution medium using the flow-through method. At low flow rates the flow-through method was found be a sensible instrument to establish differences in the disintegration properties between the various prednisone tablets examined.

Studies of some characteristics of molecular dissolution kinetics from rotating discs

Abstract The maximum mass transfer from solid to liquid phase i.e. the intrinsic rate of dissolution has been shown to be experimentally accessible with good precision using a generalized rotating disc method in combination with extrapolation to infinite speed of revolution and/or infinite distance from the disc to the center of rotation. The method has with very good result been applied to the determination of dissolution rates from non-disintegrating discs of sulfamethizole and alaproclate hydrochloride in water. In the present paper assumptions for the theory of such experiments are reviewed and compared with numerical values for a number of characteristic kinetic parameters applying simple mathematical models. This comparison supports the assumptions made. The modified rotating disc method described in this paper could therefore be recommended as part of a preformulation program for new solid drug compounds.

The relationship between intrinsic dissolution rates and solubilities in the water—ethanol binary solvent system

Abstract Solubilities and intrinsic dissolution rates for alaproclate hydrochloride, oxazepam and dextropropoxyphene napsylate have been determined in binary mixtures of water and ethanol. On a log-log scale, a linear relationship between the solubilities and the corresponding intrinsic dissolution rates with a slope of 1.0 was found. A solubility range of four log-units was covered. However, dextropropoxyphene napsylate in pure ethanol appeared to diverge from this relationship. This was explained by a change in crystalline form as indicated by differential scanning calorimetry. By calculating the solubility in ethanol before the crystal form changed, a better fit for the solubility-intrinsic dissolution rate relationship was obtained.

A collaborative in vitro dissolution study using the flow-through method

Abstract A collaborative in vitro dissolution study has been performed in 4 laboratories using the flow-through method at various hydrodynamic conditions. The USP XXI salicylic acid calibrator tablet was used as test formulation. The results obtained by the flow-through method were compared with data generated using the compendial USP XXI paddle method. The flow-through method was found to produce reproducible and corresponding dissolution data both within and among the different laboratories. It can be concluded that the flow-through method does not produce larger variations, expressed in terms of ranges of amount dissolved at various times, compared to the paddle method. In fact, at some flow conditions, smaller variations were obtained with the flow-through method compared to the paddle method. This was confirmed by the coefficients of variation for the time to dissolve 20, 50, and 80% of the salicylic acid. The coefficient of variation was also found to decrease with increasing hydrodynamic intensity for both dissolution methods. The use of deaerated dissolution medium was found to be a critical experimental factor and the need for a proper pretreatment of the medium must be emphasized.

A collaborative study of the in vitro dissolution of phenacetin crystals comparing the flow through method with the USP Paddle method

Abstract A collaborative in vitro dissolution study has been performed comparing the flow through cell apparatus with the USP Paddle method. The objective was to compare the two methods regarding their suitability for measuring the in vitro dissolution of a drug substance per se. Phenacetin, a sparingly soluble compound was used as the test material. The results indicate that the flow through cell method shows less variation both within and among the laboratories compared with the USP Paddle method. The flow through cell method was also found to generate faster in vitro dissolution rates for phenacetin than those found with the USP Paddle method, probably caused by steeper concentration gradients at the vicinity of the crystals as well as better ability to uniformly wet the phenacetin crystals. Also, the flow through cell method was found to be less dependent on the hydrodynamics and the amount of substance tested in each run, which generated a better overall reproducibility of the in vitro dissolution data. The USP Basket method was tested in one of the laboratories but it was found to give substantially slower dissolution rates than the other two methods showing a high variability between each vessel.

Program for evaluating drug dissolution kinetics in preformulation.

The in vitro dissolution kinetics of various drugs were studied at different experimental conditions using both a centrically rotating disc method and a modified excentrically rotating disc method. The combination of these two methods provides a preformulation program that includes many important pharmaceutical and biopharmaceutical parameters related to drug dissolution. The influence of the hydrodynamic conditions on the dissolution rate was demonstrated and the intrinsic dissolution tendency was obtained. Further, the acid dissociation constant, diffusion coefficient and enthalpy of dissolution can be calculated from data obtained from the rotating disc experiments. The relationship between dissolution rate and aqueous solubility of each drug tested is also considered.

Assessment of in vivo drug dissolution by means of numerical deconvolution considering gastrointestinal availability

Abstract Numerical deconvolution has been applied for calculating the in vivo dissolution process. Due to intraindividual variations in drug absorption on different occasions of administration, a misleading picture of the actual amount dissolved in vivo can be obtained. A modified method for calculating the amount of drug dissolved in vivo is presented which considers both the reference formulation (weighting function) and the test formulation (response function) as equally available to the gastrointestinal tract, i.e. the place where the dissolution process actually occurs. The potential antipsychotic compound, remoxipride, administered as controlled release microcapsules, is used as a model system. It is demonstrated that if the deconvolution data are compensated for the amount of remoxipride absorbed from each formulation (test and reference), very good quantitative in vitro/in vivo dissolution correlations are obtained for each subject. The impact of considering both the conventional deconvolution curve and the modified one will be discussed.

A preformulation study on the kinetics of HI-6 in concentrated solution

Abstract The degradation kinetics of HI-6 have been investigated at various temperatures and at different pHs at a concentration of 200 mg/ml. Both aqueous and other hydrophilic solvents (glycols and glycerol-water mixtures) have been used. The degradation of HI-6 follows pseudo-first-order kinetics with respect to HI-6. The observed rate seems to depend on a hydroxyl ion-catalyzed reaction ( k OH ) and an un/water catalyzed reaction ( k 0 ) which show influence at pH below 3. The pH profile shows a positive slope less than one, which seems to depend on an error in the determination of the rate constants at higher pH. k OH was determined to be 1 · 10 9 and k 0 to be 0 · 011 h −1 at 60° C. The observed rate seems to be independent of the dielectric constant of the solvent. The activation energy k 0 has been determined to be 82.0 kJ mol −1 . Based upon these data the predicted shelf life ( t 90% ) at pH 0 will not be long than 13 days at 25 ° C and 9 months at 0°C. Thus, the systems studied seem to be unsuitable to formulate a stable intramuscular formulation of HI-6.

Correlations between in vitro dissolution rate and bioavailability of alaproclate tablets.

In two different absorption studies, quantitative correlations between the in vitro dissolution rate and the bioavailability have been shown after single administration of various tablet compositions of alaproclate hydrochloride to healthy subjects. Both statistical moment analysis and the use of empirical single value parameters were tested. For conventional tablets a linear relationship was obtained between mean dissolution time in vitro and in vivo. A similar relationship was obtained between the mean dissolution time in vitro and the mean residence time for controlled release tablets of the matrix type. It was also possible to establish an in vitro-in vivo correlation for these latter tablets by using the single point estimate of maximum plasma concentration as in vivo parameter. When comparing the mean dissolution time in vitro to the total area under the plasma drug concentration-time curve attained after different types of tablets, it is obvious that the extent of bioavailability of alaproclate will not fall below 80% of the value found for an aqueous solution until the mean dissolution time in vitro exceeds approximately 3 hr. Statistical moment analysis seems to have a broader applicability than the use of empirical point estimates, and it seems to be useful both for conventionally dissolving tablets and controlled release tablets.