A combined modelling and experimental study of the surface energetics of alpha-lactose monohydrate.

The surface energy of alpha-lactose monohydrate measured by inverse gas chromatography (IGC) is reported along with a dynamic molecular modelling study of the interaction of the various molecular probes with different surfaces of alpha-lactose monohydrate. The IGC results show that alpha-lactose monohydrate is acidic in nature. Using quantitative calculations of the energy of adsorption, the acidic nature of the surface is confirmed and the calculated values agree closely with the experimentally measured values. Along with the acidic nature, dynamic molecular modelling also reveals that the presence of a channel and water molecules on a surface affects the surface energetics of that face. The presence of water on the surface can decrease or increase the surface energy by either blocking or attracting a probe molecule, respectively. This property of water depends on its position and association with other functional groups present on the surface. The effect of a channel or cavity on the surface energy is shown to depend on its size, which determines whether the functional groups in the channel are assessable by probe molecules or not. Overall molecular modelling explains, at the molecular level, the effect of different factors affecting the surface energy of individual faces of the crystal.

The application of molecular modelling to the interpretation of inverse gas chromatography data.

The use of molecular modelling in the interpretation of inverse gas chromatography data is discussed. Crystal faces can be visualised and likely cleavage planes calculated using the surface attachment energies. Assuming that the preferred cleavage plane is the crystal face with the smallest attachment energy then the predominant crystal faces of a crystalline particle can be predicted. Surface adsorption can be modelled using Van der Waals and electrostatic interactions to evaluate the interaction energies between individual atoms of the probe molecule and atoms of the test molecule orientated as in the surface. Using examples of pharmaceutical materials, modelling has been shown to be successful in the understanding of changes in the surface energetics.

The changes in surface energetics with relative humidity of carbamazepine and paracetamol as measured by inverse gas chromatography.

The surface energetic parameters of carbamazepine and paracetamol have been studied using inverse gas chromatography modified to produce dry and ambient conditions within the column. The values of the dispersive component of the surface free energy (gamma(S)D) do not change significantly at the increased relative humidity. In contrast the specific component of the free energy of adsorption (-DeltaG(A)SP) as measured by polar probes, can either remain constant or decrease by up to 10%, depending on the material and the probe. This indicates that an increase in the relative humidity causes a decrease in the surface energetics of the powder surface. It is proposed that where the water molecules are adsorbing to the same sites as the polar probes, the interaction of these probes with the surface is decreased. To identify these sites, the preferential interaction of each probe, including water, with the drug molecule has been modelled.

Interpretation of the differences in the surface energetics of two optical forms of mannitol by inverse gas chromatography and molecular modelling.

Inverse gas chromatography (IGC) has been successfully used to characterise the nature of the surface of two optical forms of mannitol, DL and betaD. This has shown that the surface energetics of the two forms are significantly different with the DL form having higher values for the interactions with the dispersive and basic probes. Molecular modelling was used to predict the slip planes by utilising attachment energy calculations and so the dominant faces exposed upon milling could be predicted. Imaging these faces showed that the orientation of the molecules at these surfaces differed between the two forms. A visual comparison of the faces indicated that the DL form had a higher density of acidic and dispersive sites exposed at the surfaces than the betaD form. The results from the modelling agreed with the trends seen in the changes in surface energetics as measured by IGC. This suggests that the components of the surface energetic terms reflect the density of exposed groups at the particle surfaces.

Applicability of a scale-up methodology for wet granulation processes in Collette Gral high shear mixer-granulators.

This study investigates the extension of a scale-up methodology based on dimensionless power relationships, to a series of vertical mixer-granulators in which the bowl is removable, i.e. both impeller and chopper blades are mounted on top-driven vertical shafts positioned through the lid. Granulation runs were carried out in several bowl sizes belonging to the series of Collette Gral mixer-granulators, ranging from 8 to 600 l capacities. It was shown that under certain conditions a common scale-up master curve could be drawn from the data gathered for each bowl, thus permitting the use of such a curve for the determination of mixer-granulator power consumption at a defined granulation end-point. The results also helped to clarify the concept of similitude, both geometrical and dynamic, which is implied in the methodology. The importance of wall slippage (as promoted by the insertion of a PTFE lining into the bowls) and batch size are illustrated.

Process control in a high shear mixer-granulator using wet mass consistency: the effect of formulation variables.

This work investigates the relationships between the wet mass consistency/viscosity of samples prepared in a mixer-granulator and physical properties of the dry granules produced from the wet mass; namely, size distribution, bulk density (Hausner ratio), friability, and flow avalanching behavior. The correlation between the consistency of the wet mass and the downstream dry granule properties confirms that consistency is the key parameter to control in wet granulation by mechanical agitation. Variations in the formulation affect the dimensionless power relationship of the mixer-granulator considered; that is, the equivalence between wet mass consistency and mixer net power consumption, which is actually the parameter used to monitor the wet granulation process. The same variations in formulation also affect the relationships between wet mass consistency and dry granule properties.

A methodology for the optimization of wet granulation in a model planetary mixer.

This paper investigates a methodology for the optimization of wet granulation processes in planetary mixers. A model formulation was granulated in a planetary mixer (two different bowl sizes). The wet masses were characterized by their bulk density and consistency (as measured by mixer torque rheometry), and the feasibility of scale-up from one mixer bowl to the other was studied using a dimensionless numbers approach for the estimation of the power consumption at the granulation end point. Both bowls gave the same dimensionless power relationships (a relationship between the power number, Reynolds number, Froude number, and bowl fill ratio), which could therefore be used for calculating the power consumption level when the wet mass achieves its target values of density and consistency, i.e., the point at which granulation should be stopped. It was also shown that batches granulated in different conditions (batch size, blade speed) in two planetary mixers, but presenting similar wet mass characteristics (bulk density and consistency) led to dry granules of similar properties: granule size distribution, density, friability, and flow. This work suggests that it is possible to characterize the wet mass by only two parameters which describe the quality of the downstream granules. The scale-up procedure based on the use of dimensionless numbers was found to be applicable to planetary mixers, provided they give one common dimensionless power relationship.