Ian M. Grimsey

Quantitative Analysis Of Mannitol Polymorphs - X-Ray Powder Diffractometry. Exploring Preferred Orientation Effects.

Mannitol is a polymorphic parmaceutical excipient, which commonly exists in three forms: alpha, beta and delta. Each polymorph has a needle-like morphology, which can give preferred orientation effects when analysed by X-ray powder diffractometry (XRPD) thus providing difficulties for quantitative XRPD assessments. The occurrence of preferred orientation may be demonstrated by sample rotation and the consequent effects on X-ray data can be minimised by reducing the particle size. Using two particle size ranges (<125 and 125-500 microm), binary mixtures of beta and delta mannitol were prepared and the delta component was quantified. Samples were assayed in either a static or rotating sampling accessory. Rotation and reducing the particle size range to <125 microm halved the limits of detection and quantitation to 1 and 3.6%, respectively. Numerous potential sources of assay errors were investigated; sample packing and mixing errors contributed the greatest source of variation. However, the rotation of samples for both particle size ranges reduced the majority of assay errors examined. This study shows that coupling sample rotation with a particle size reduction minimises preferred orientation effects on assay accuracy, allowing discrimination of two very similar polymorphs at around the 1% level.

Quantitative analysis of mannitol polymorphs. FT-Raman spectroscopy.

Mannitol is a polymorphic excipient which is usually used in pharmaceutical products as the beta form, although other polymorphs (alpha and delta) are common contaminants. Binary mixtures containing beta and delta mannitol were prepared to quantify the concentration of the beta form using FT-Raman spectroscopy. Spectral regions characteristic of each form were selected and peak intensity ratios of beta peaks to delta peaks were calculated. Using these ratios, a correlation curve was established which was then validated by analysing further samples of known composition. The results indicate that levels down to 2% beta could be quantified using this novel, non-destructive approach. Potential errors associated with quantitative studies using FT-Raman spectroscopy were also researched. The principal source of variability arose from inhomogeneities on mixing of the samples; a significant reduction of these errors was observed by reducing and controlling the particle size range. The results show that FT-Raman spectroscopy can be used to rapidly and accurately quantitate polymorphic mixtures.

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.

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.

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.

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.

Effect of formulation parameters and drug–polymer interactions on drug release from starch acetate matrix tablets

The aim of this study was to determine, whether interactions between a drug and hydrophobic polymer matrix are present, and if so, how they affect the drug release. In addition, the most important formulation parameters, for example porosity or structure of the tablet, which have the greatest impact on drug release, were defined. Six different drug compounds, that is allopurinol, acyclovir, metronidazole, paracetamol, salicylamide and theophylline, were used in different formulations with hydrophobic starch acetate (DS 2.7) as a matrix forming polymer. Results indicate that the formulation parameters describing directly or indirectly the structure of the matrix, such as porosity, compaction force and the particle size fraction of the filler-binder, have the strongest impact on drug release. The contribution of drug property based variables is not as high as formulation parameters, but they cannot be overlooked. The contribution of water solubility and dissolution rate of the compound are obvious, but there are other significant parameters, which describe the hydrophobic and hydrophilic regions of the molecule, that also affect the drug release. This can be seen especially with the salicylamide: compound which appears to have a strong and sufficiently high hydrophobic region that interacts with starch acetate and impairs the drug release.

Mapping the solid-state properties of crystalline lysozyme during pharmaceutical unit-operations

Bulk crystallisation of protein therapeutic molecules towards their controlled drug delivery is of interest to the biopharmaceutical industry. The complexity of biotherapeutic molecules is likely to lead to complex material properties of crystals in the solid state and to complex transitions. This complexity is explored using batch crystallised lysozyme as a model. The effects of drying and milling on the solid-state transformations of lysozyme crystals were monitored using differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), FT-Raman, and enzymatic assay. XRPD was used to characterise crystallinity and these data supported those of crystalline lysozyme which gave a distinctive DSC thermogram. The apparent denaturation temperature (Tm) of the amorphous lysozyme was ∼201 °C, while the Tm of the crystalline form was ∼187 °C. Raman spectra supported a more α-helix rich structure of crystalline lysozyme. This structure is consistent with reduced cooperative unit sizes compared to the amorphous lysozyme and is consistent with a reduction in the Tm of the crystalline form. Evidence was obtained that milling also induced denaturation in the solid-state, with the denatured lysozyme showing no thermal transition. The denaturation of the crystalline lysozyme occurred mainly through its amorphous form. Interestingly, the mechanical denaturation of lysozyme did not affect its biological activity on dissolution. Lysozyme crystals on drying did not become amorphous, while milling-time played a crucial role in the crystalline-amorphous-denatured transformations of lysozyme crystals. DSC is shown to be a key tool to monitor quantitatively these transformations.

A combined modelling and experimental study of the surface energetics of α-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.