Impact of carrier particle surface properties on drug nanoparticle attachment.

HYPOTHESIS: The stabilization and isolation to dryness of drug nanoparticles has always been a challenge for nano-medicine production. In the past, the use of montmorillonite (MMT) clay carrier particles to adsorb drug nanoparticles and maintain their high surface area to volume ratio after isolation to dryness has proven to be effective. We hypothesise that the distribution of hydrophilic and hydrophobic patches on the clay's surface as well as its porosity/roughness, hinder the agglomeration of the drug nanoparticles to the extent that they retain their high surface area to volume ratio and display fast dissolution profiles. EXPERIMENTS: In this work, the distribution of hydrophobicity and hydrophilicity, and the porosity/roughness, of the surface of selected silica carrier particles were varied and the impact of these variations on drug nanoparticle attachment to the carrier particle and subsequent dissolution profiles was studied. FINDINGS: The fastest dissolution profiles at the highest drug nanoparticle loadings were obtained with a periodic mesoporous organosilane carrier particle which had a homogeneous distribution of hydrophobic and hydrophilic surface properties. Carrier particles with rough/porous surfaces and a combination of hydrophobic and hydrophilic patches resulted in nanocomposite powders with faster dissolution behaviour than carrier particles with predominantly either a hydrophobic or hydrophilic surface, or with non-porous/smoother surfaces.

Preparation, stabilisation, isolation and tableting of valsartan nanoparticles using a semi-continuous carrier particle mediated process.

This work investigated the technical feasibility of preparing, stabilizing and isolating poorly water-soluble drug nanoparticles via a small-scale antisolvent precipitation process operating in semi-continuous mode. Specifically, a novel semi-continuous process was demonstrated for the carrier particle mediated production, stabilization and isolation of valsartan nanoparticles into a solid form using montmorillonite clay particles as the carrier. The semi-continuous process operated robustly for the full duration of the experiment (~16 min) and steady-state conditions were reached after ~5 min. Nanoparticles of valsartan (51 ± 1 nm) were successfully prepared, stabilized and isolated with the help of montmorillonite (MMT) or protamine functionalized montmorillonite (PA-MMT) into the dried form by this semi-continuous route. The dissolution profile of the isolated valsartan nanocomposite solids was similar to that of valsartan nanocomposite solids produced via the corresponding laboratory scale batch mode process, indicating that the product quality (principally the nanoscale particle size and solid-state form) is retained during the semi-continuous processing of the nanoparticles. Furthermore, tablets produced via direct compression of the isolated valsartan nanocomposite solids displayed a dissolution profile comparable with that of the powdered nanocomposite material. PXRD, DSC, SSNMR and dissolution studies indicate that the valsartan nanoparticles produced via this semi-continuous process were amorphous and exhibited shelf-life stability equivalent to > 10 months.

Modification of the zeta potential of montmorillonite to achieve high active pharmaceutical ingredient nanoparticle loading and stabilization with optimum dissolution properties.

Nanoparticles (NPs) of three poorly water-soluble BCS class II active pharmaceutical ingredients (APIs) (clozapine (CLO), curcumin (CUR) and carbamazepine (CBMZ) with zeta potentials -28.5 ±â€¯2.5, -33 ±â€¯1.5 and -13 ±â€¯1.5 mV respectively) were produced, stabilized and isolated into the solid state with the help of Montmorillonite (MMT) clay carrier particles. The nanoparticles of clozapine (27 nm), curcumin (170 nm) and carbamazepine (30 nm) were produced and stabilized in suspension using a reverse antisolvent precipitation technique in the presence of 'as received' MMT carrier particles (∼30 µm) and/or MMT carrier particles whose surface had been slightly modified with a cationic protein, protamine sulphate salt (PA). The resulting nanoparticle carrier composites were isolated directly from suspension into a solid state form by simple filtration followed by air-drying. The API dissolution rates from these dried NP-carrier composites were comparable with those of the respective stabilized API nanoparticles in suspension up to maximum CLO, CUR and CBMZ loadings of 23%, 21.8% and 33.3% (w/w) respectively, although surface modification of the MMT carrier particles with PA was needed for the CLO and CUR NP-carrier composites in order to preserve the fast API nanosuspension-like dissolution rates at higher API loadings. For both of these APIs, the optimal loading of PA on MMT was around 4 mg/g, which likely helped to limit aggregation of the API nanoparticles at the higher API loadings. Interestingly, no MMT surface modification was needed to preserve fast API dissolution rates at higher API loadings in the case of the CBMZ NP-carrier composites. This discrimination among the three APIs for carrier particle surface modification was previously observed in reported studies by our group for three other APIs, namely valsartan, fenofibrate and dalcetrapib. When examined together, the data for all six APIs suggest a general trend whereby API nanoparticles with zeta potentials more positive than around -25 mV do not require carrier particle surface modification with PA in order to preserve their fast dissolution rates from NP-carrier composites at higher API loadings. Thus, this study offers a potentially effective means of transforming poorly water soluble BCS Class II APIs into fast dissolving solid dosage NP-carrier composites, whereby the surface properties of the carrier particle can be tuned with prior knowledge of the zeta potential of the API nanoparticles.

Carrier particle mediated stabilization and isolation of valsartan nanoparticles.

Drug nanoparticles are a promising solution to the challenging issues of low dissolution rates and erratic bioavailability due to their greater surface/volume ratio. The central purpose of this study is to prepare, stabilize and isolate nanoparticles of poorly water-soluble active pharmaceutical ingredients (APIs) into a dried form with the help of clay carrier particles. Isolation of nanoparticles from suspension into the dried state is crucial to avoid the problems of aggregation and Ostwald ripening. In this study nanoparticles of the API valsartan were generated via a reverse antisolvent process at high supersaturations. Montmorillonite (MMT) and protamine functionalized montmorillonite (PA-MMT) were employed for stabilization and isolation of the valsartan (Val) nanoparticles (ca. 50 nm) into a dried form. A high dissolution rate of the resultant solid formulation at high drug loadings (up to 33.3% w/w) was achieved. The dissolution rates of the isolated valsartan nanoparticle carrier composites (dried Val-MMT nanocomposites and dried Val-PA-MMT nanocomposites) were similar to that of freshly prepared suspended valsartan nanoparticles, confirming that the high surface area of the nanoparticles is retained during the adsorption and drying processes. Differential scanning calorimetry and PXRD studies indicated that the valsartan nanoparticles were amorphous when adsorbed onto the carrier particles. The dissolution rates of the Val-MMT and Val-PA-MMT nanocomposites were maintained after 10 months' storage which indicates that no aggregation or solid state transformation of the carrier-stabilized Val nanoparticles had occurred.

The extent and influence of Asbestos Safety Awareness training among managers who had previously commissioned an asbestos survey in their workplace buildings.

A telephone survey was conducted among a sample of managers (n=30) in Ireland who had previously commissioned an asbestos survey in their workplace buildings. The aims of the telephone survey were to examine the extent to which managers had completed Asbestos Safety Awareness (ASA) training, and to assess how such training might influence (i) their instinctive thoughts on asbestos, and (ii) their approach to aspects of asbestos management within their buildings. Managers' motivations for commissioning the asbestos survey were also identified. The study found that ASA-trained managers (n=11) were not significantly more likely to work in larger organisations or in organisations which operated an accredited management system. Though ASA-trained managers' instinctive thoughts on asbestos were of a slightly poorer technical quality compared with those of non-ASA-trained managers, they were still significantly more cognisant of their responsibilities towards those of their employees at specific risk of asbestos exposure. Most managers (n=28) commissioned the asbestos survey to satisfy a pre-requisite of external contractors for commencing refurbishment/demolition work in their buildings. Given its potential to positively influence the occupational management of asbestos, the authors recommend the general promotion of suitably tailored ASA-training programmes among building managers and external contractors alike.