Martin J. Snowden

Depletion flocculation in colloidal dispersions

Abstract The destabilisation of colloidal dispersions by free, non-adsorbing polymer molecules in solution is reviewed from both a theoretical and experimental perspective. Consideration is given to the behaviour of polymers in solution in relation to the theories proposed by Flory, de Gennes, and Scheutjens and Fleer. Similarly, the theories describing the behaviour of polymers at or near an interface are also examined together with an outline of their relevance to the depletion interaction. The depletion interaction itself is also comprehensively reviewed, taking into account the different segment density profile theories currently in the scientific literature. Experimental reports of the depletion phenomena are described, covering both hard sphere and soft sphere systems, with both the direct and indirect evidence of the depletion interaction being considered.

Colloidal copolymer microgels of N-isopropylacrylamide and acrylic acid: pH, ionic strength and temperature effects

Aqueous colloidal microgels have been prepared, based on poly(N-isopropylacrylamide)[poly(NIPAM)], cross-linked with bisacrylamide, containing 5% w/w acrylic acid (AAc) as a comonomer. Transmission electron micrographs of the microgels show that the copolymer microgels are monodisperse spheres. The size of the microgel particles containing 5% AAc has been studied, using dynamic light scattering, as a function of pH (3–10), ionic strength (10–4–10–1M NaCl) and temperature (20–75 °C). The hydrodynamic diameter of the copolymer microgels decrease both with increasing ionic strength (at pH 6 and 25 °C) and reversibly with increasing temperature at pH values of 2.6, 3.4 and 6.5. However, under isothermal conditions in 10–3M NaCl at 25 °C, the hydrodynamic diameter increases in going from pH 3.3–9.4. In addition, the temperature-induced conformational changes in the polymer chains have been followed using high-sensitivity differential scanning calorimetry (HSDSC). A comparison is made with the behaviour of poly(NIPAM) microgel particles, not containing AAc. Explanations are offered to account for the pronounced difference in the physico-chemical properties observed.

Heteroaggregation in colloidal dispersions

Abstract The theory of heteroaggregation is an important concept for the understanding of many natural and industrial processes. It relates to any process where particles differ. It is based on an expansion of the DLVO theory, and now involves highly mathematical computation. Heteroaggregation has been continually developed to extend the use of a formula to encapsulate all particle type variations. McCormack et al. [29] have reported such an equation, and it is necessary for these complex equations to be related to experimental conditions. Many of the early forms of the theory of heteroaggregation were based on the use of assumptions such as constant surface potential, constant surface charge conditions and that surfaces are smooth. This is now known to cause anomalies in the theoretical predictions when compared to the experimental situation, as the situation of a discrete surface charge is more applicable for colloidal particles due to the heterogeneous nature of the surface [41]. Furthermore, particle surfaces are rarely smooth. Another problem highlighted is that the theoretical predictions are influenced by particle size, and yet when assessed experimentally no such dependence was recognised [58]. This inconsistency is attributed to the inability of the DLVO theory to consider the dynamics of particle-particle interactions. This review has focused on aqueous systems, although work has been reported in non-aqueous environments, for example toluene, in which the heteroflocculation of non-aqueous silica dispersions were investigated by Skuse et al. [85]. In this example, adsorption was controlled by strong Lewis acid-base interactions. Deflocculation was achieved by the addition of strong acid or base, which is in contrast to aqueous systems where high concentrations of electrolytes are used to induce desorption. This review also defines both Brownian and shear coagulation mechanisms, although most of the theories stated relate to Brownian coagulation. Shear coagulation introduces new mathematical equations and system parameters. Wang [2] and Adler [73] have reported in-depth studies in this field. Heteroaggregation in colloidal particles is therefore, an important concept for both a fundamental and for an applied understanding in colloidal science which, from a theoretical point of view, is still in its infancy when considering the sophistication and accuracy of the models developed to describe experimentally observed behaviour. A challenge, therefore, exists to advance this field in an attempt to gain a clearer picture of the often complex interactions which exist between unlike particles.

A Review of Hot-Melt Extrusion: Process Technology to Pharmaceutical Products

Over the last three decades industrial adaptability has allowed hot-melt extrusion (HME) to gain wide acceptance and has already established its place in the broad spectrum of manufacturing operations and pharmaceutical research developments. HME has already been demonstrated as a robust, novel technique to make solid dispersions in order to provide time controlled, modified, extended, and targeted drug delivery resulting in improved bioavailability as well as taste masking of bitter active pharmaceutical ingredients (APIs). This paper reviews the innumerable benefits of HME, based on a holistic perspective of the equipment, processing technologies to the materials, novel formulation design and developments, and its varied applications in oral drug delivery systems.

Drug–polymer intermolecular interactions in hot-melt extruded solid dispersions

The purpose of the study was to investigate and identify the interactions within solid dispersions of cationic drugs and anionic polymers processed by hot-melt extrusion (HME) technique. Propranolol HCl (PRP) and diphenhydramine HCl (DPD) were used as model cationic active substances while pH sensitive anionic methacrylic acid based methyl methacrylate copolymers Eudragit L100 (L100) and ethyl acrylate copolymer Eudragit L100-55 (Acryl EZE) (L100-55) were used as polymeric carriers. The extrudates were further characterised using various physicochemical characterisation techniques to determine the morphology, the drug state within the polymer matrices and the type of drug-polymer interactions. Molecular modelling predicted the existence of two possible H-bonding types while the X-ray photon spectroscopy (XPS) advanced surface analysis of the extrudates revealed intermolecular ionic interactions between the API amino functional groups and the polymer carboxylic groups through the formation of hydrogen bonding. The magnitude of the intermolecular interactions varied according to the drug-polymer miscibility.

The use of microemulsion electrokinetic chromatography in pharmaceutical analysis

The use of a single set of microemulsion electrokinetic chromatography (MEEKC) separation conditions has been assessed for its applicability in the analysis of a range of pharmaceutical compounds. Particular emphasis was placed on neutral or very hydrophobic compounds, which can be difficult to analyse by conventional capillary electrophoresis. The microemulsion employed for the majority of separations consisted of 0.81% w/w octane, 6.61% w/w 1-butanol, 3.31% w/w sodium dodecyl sulphate and 89.27% w/w 10 mM sodium tetraborate buffer. Good separations of methyl, ethyl, butyl and propyl hydroxybenzoates, and a range of ionic and neutral water soluble and insoluble compounds was achieved using a single set of separation conditions. A number of novel applications of MEEKC were developed included the simultaneous determination of the active components and preservatives in liquid formulation and determination of drug related impurities. Improved performance was obtained through use of internal standards and preparation of the samples dissolved in the microemulsion solution. Validation aspects such as linearity, repeatability, accuracy, injection precision and sensitivity were successfully assessed.

Characterisation of the aggregation behaviour in a salmeterol and fluticasone propionate inhalation aerosol system.

The nature of the drug-drug aggregation phenomena between salmeterol xinafoate and fluticasone propionate used in a metered-dose inhaler system has been examined. Interactions between the drugs in the solvents 1,1,2-trichlorotrifloroethane (CFC-113) and 1,1,1,2-tetrafluoroethane (HFA-134a) have been characterised using a focused beam reflectance measurement probe by measuring the average floc size of the drug particles individually and in combination as a function of stirrer rate. The floc composition in the CFC-113 system, where the drug particles cream, was determined by high-performance liquid chromatography analysis. The aggregation behaviour of the individual drugs was shown to depend on the physical and chemical properties of both the drug substance and the media. Larger flocs were observed for salmeterol xinafoate compared with fluticasone propionate, while both drugs formed larger aggregates in HFA-134a compared with in CFC-113. The floc composition studies demonstrated that, in the combined formulation in CFC-113, salmeterol xinafoate and fluticasone propionate aggregate together to form hetero-flocs. The interaction between the two drugs was such that they did not separate on creaming, despite having different densities. The average floc size of the combined drug suspension was also found to depend on the dispersion medium.

A review on the taste masking of bitter APIs: hot-melt extrusion (HME) evaluation.

Abstract The majority of active pharmaceutical ingredients (APIs) found in oral dosage forms have a bitter taste. Masking the unpleasant taste of bitter, APIs is a major challenge in the development of such oral dosage forms. Taste assessment is an important quality-control parameter for evaluating taste-masked formulations of any new molecular entity. Hot-melt extrusion (HME) techniques, have very recently, been accepted from an industrial compliance viewpoint in relation to both manufacturing operations and development of pharmaceuticals. HME achieves taste masking of bitter APIs via various mechanisms such as the formation of solid dispersions and inter-molecular interactions and this has led to its wide-spread use in pharmaceutical formulation research. In this article, the uses of various taste evaluation methods and HME as continuous processing techniques for taste masking of bitter APIs used for the oral delivery of drugs are reviewed.

The effect of pH and concentration upon aggregation transitions in aqueous solutions of poloxamine T701

Thermally induced aggregation transitions have been investigated for aqueous solutions of the poloxamine block copolymer T701-(OE(4)OP(13))(2)NCH(2)CH(2)N(OP(13)OE(4))(2)-using differential scanning calorimetry. The calorimetric signals obtained were fitted to a mass action model description of aggregation using a previously reported analytical procedure (Patterson et al., Langmuir 13 (1997) 2219). The presence of a central ethylene diamine moiety in the molecular structure renders the T701 molecule basic; this was confirmed and measured by acid/base titration. Basicity is shown to have an important impact upon aggregation. At low pH (2.5), the poloxamine exists in its protonated form and the bulk solution proton concentration is sufficient to suppress de-protonation, aggregation-as a consequence-is shifted to a higher temperature range. Any increase in pH reduces the temperature range over which aggregation occurs. The derived experimental calorimetric parameters, obtained from model fitting procedures, can be used to compute the fraction of poloxamine existing in an aggregated form, at any particular temperature. The data sets obtained were interpolated to show that at human body temperature (310.6 K) the fraction of poloxamine found in its aggregated form is zero at a pH of 2.5. However at a pH of 6.8, the percentage aggregation increases to about 85%. These aggregation characteristics of T701 have important implications for the design of drug delivery systems, which incorporate poloxamines.

Continuous cocrystallisation of carbamazepine and trans-cinnamic acid via melt extrusion processing

A solvent free process for the formation of carbamazepine (CBZ)–trans-cinnamic acid (TCA) cocrystals, in stoichiometric ratios, was developed using continuous hot melt extrusion processing. Physicochemical characterization of the CBZ–TCA extrudates included scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and hot stage microscopy to evaluate the shape, morphology, purity and crystallinity of the freshly made cocrystals. The obtained cocrystals were of high quality compared to the prototype produced by a solvent crystallization technique. Furthermore, an in-line NIR probe was used to investigate the gradual formation of cocrystals during extrusion processing. The quality of the CBZ–TCA cocrystals was found to depend on the processing parameters such as temperature and the screw type. The extruded cocrystals showed faster dissolution rates compared to bulk CBZ and the prototype cocrystals.