Material characterisation and parameter effects on bulk solid dissolution rate of paracetamol in a stirred tank vessel using an in situ UV-ATR probe
Abstract
The progress from batch to continuous manufacture of pharmaceuticals has highlighted the requirement for dosing solid feed material directly, efficiently and accurately into continuous flow systems. Solids are currently dissolved in batch vessels before feeding into a flow system. This study focuses on gaining scientific understanding on rate kinetics of solid dissolution and parameters affecting solid dosing in current batch systems as a starting point; the knowledge gained will inform future continuous solid dosing work. Paracetamol was the model compound and the mixtures of water/ IPA the solvent systems. An in situ UV spectrometer was used to quantify the concentration of solute in solution during dissolution. In this paper, we present the dissolution kinetics results from a parametric study of effects of temperature, solvents, mixing and particle sizes on dissolution characteristics in a stirred tank vessel. The dissolution profiles from our system are similar to that of published work, with the fastest kinetics for the micronised particles, albeit problematic when dosing as a single shot. Dissolution rate is increased with increasing temperature, solvent content (solubility), mixing intensity and decreasing particle size.
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Introduction
Traditionally batch manufacture is used to produce pharmaceutical products from synthesis and work up to reaction and from isolation to tableting. Although the introduction of continuous manufacture and crystallisation into the pharmaceutical industry has been gathering momentum (1, 2), work up technology and inventory in pharmaceutical manufacture still remain batch operation (3); ―charging solids into a tank of solvent and leaving it stirred for hours‖ has been the norm in industrial work up operation (4-6) that are too large to use and too inflexible to change for continuous crystallisation (7, 8). As a result, there has generally been a lack of scientific understanding in terms of solid dissolution, dosing and associated operations in batch processes (9, 10). This is also reflected by the very limited publications in this area, as academic researchers largely regard the work up being a technical problem. With the realization of benefits of consistent crystal properties that continuous crystallisation has brought about (11-13), investigations on continuous work up have been identified as an unmet need, this work is one of the earliest research in this area. The ultimate purpose is to be able to feed solute solid particles and the selected solvent concurrently, accurately and continuously into a plug flow system for unit operations; this would require knowledge and understanding of dissolution kinetics, mechanisms and parameters affecting these. The current work addresses this very subject.
Dissolution research began in 1897 when Noyes and Whitney (14) conducted the first dissolution experiments of two sparingly soluble compounds, benzoic acid and lead chloride; noticed that the rate of dissolution was proportional to the difference between the instantaneous concentration, C at time t, and the saturation solubility Cs. The authors attributed the mechanism of dissolution to a thin diffusion layer which was formed around the solid surface and through which the molecules diffused to the bulk aqueous phase.
Higuchi (15) reviewed the diffusion layer model that considered interfacial transport was the limiting step due to a high activation energy level. Danckwerts (16) proposed an alternative mechanism by constantly renewing macroscopic packets of solvent to reach the solid surface and absorb molecules of solute, delivering them to the solution. In the 1950s the pharmaceutical sciences used the concept of in vitro dissolution when it became clear that the dissolution rate was the limiting step.
Conclusion
Some critical factors impacting the dissolution rate in a batch system are realised through this initial study. For the same type of particles, solvent composition (solubility) is the major parameter when dissolving bulk solids in a batch system, temperature is the 2nd contributing factor, while mixing has less effect on dissolution rates. For the same solvent and temperature, the smallest particle size has the fastest dissolution rate. The mechanism for dissolution of paracetamol in the stirred tank vessel could be the combination of both surface and transport processes. Although micronised solids increased the dissolution rate, the flowability of such material would have a negative impact in a continuous flow system, potentially leading to bridging, blockages for instance. The learning from this work is being applied to the investigation of solid dissolution in a continuous flow system using a twin screw mixer. We shall report these in a separate communication.