Correlations between surface composition and aerosolization of jet-milled dry powder inhaler formulations with pharmaceutical lubricants.

Co-jet-milling drugs and lubricants may enable simultaneous particle size reduction and surface coating to achieve satisfactory aerosolization performance. This study aims to establish the relationship between surface lubricant coverage and aerosolization behavior of a model drug (ciprofloxacin HCl) co-jet-milled with lubricants [magnesium stearate (MgSt) or l-leucine]. The co-jet-milled formulations were characterized for particle size, morphology, cohesion, Carr's index, and aerosolization performance. The surface lubricant coating was assessed by probing surface chemical composition using X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary-ion mass spectrometry (ToF-SIMS). The effects of co-jet-milling on the surface energy and in vitro dissolution of ciprofloxacin were also evaluated. Our results indicated that, in general, the ciprofloxacin co-jet-milled with l-leucine at >0.5% w/w showed a significant higher fine particle fraction (FPF) compared with the ciprofloxacin jet-milled alone. The FPF values plateau at or above 5% w/w for both MgSt and l-leucine. We have established the quantitative correlations between surface lubricant coverage and aerosolization in the tested range for each of the lubricants. More importantly, our results suggest different mechanisms to improve aerosolization for MgSt-coating and l-leucine-coating, respectively: MgSt-coating reduces inter-particulate interactions through the formation of low surface energy coating films, while l-leucine-coating not only reduces the surface energy but also creates rough particle surfaces that reduce inter-particulate contact area. Furthermore, surface coatings with 5% w/w MgSt (which is hydrophobic) did not lead to substantial changes in in vitro dissolution. Our findings have shown that the coating structure/quality and their effects could be highly dependent on the process and the coating material. The findings from this mechanistic study provide fundamental understanding of the critical effects of MgSt and l-leucine surface coverages on aerosolization and powder flow properties of inhalation particles.

Simultaneous Particle Size Reduction and Homogeneous Mixing to Produce Combinational Powder Formulations for Inhalation by the Single-Step Co-Jet Milling.

Homogeneous mixing of 2 cohesive jet-milled drug powders is a challenge for pharmaceutical manufacturing on account of their cohesive nature resulting in the formation of strong and random agglomerates. In this study, colistin and ciprofloxacin were co-jet milled to develop combinational antibiotic dry powder formulations for inhalation. The properties of particle size, morphology, content uniformity, and in vitro aerosolization were evaluated. The distribution of 2 drugs in the co-jet milled powders was assessed using time-of-flight-secondary ion mass spectrometry. The co-jet milled powders demonstrated an acceptable content uniformity indicating homogeneity. In general, time-of-flight-secondary ion mass spectrometry images showed relatively homogeneous distributions of ciprofloxacin and colistin in the co-milled formulations. Importantly, the 2 drugs generally had the similar fine particle fraction and deposition behavior in each combinational formulation supporting that the particle mixtures were relatively homogenous and could maximize the antimicrobial synergy. In conclusion, co-jet milling could be a viable technique to produce the combination powders for inhalation.

Effects of the antibiotic component on in-vitro bacterial killing, physico-chemical properties, aerosolization and dissolution of a ternary-combinational inhalation powder formulation of antibiotics for pan-drug resistant Gram-negative lung infections.

Combinational antibiotic formulations have emerged as an important strategy to combat antibiotic resistance. The main objective of this study was to examine effects of individual components on the antimicrobial activity, physico-chemical properties, aerosolization and dissolution of powder aerosol formulations when three synergistic drugs were co-spray dried. A ternary dry powder formulation consisting of meropenem (75.5 %w/w), colistin (15.1 %w/w) and rifampicin (9.4 %w/w) at the selected ratio was produced by spray drying. The ternary formulation was characterized for in-vitro antibacterial activity, physico-chemical properties, surface composition, aerosol performance and dissolution. All of the formulations demonstrated excellent aerosolization behavior achieving a fine particle fraction of >70%, which was substantially higher than those for the Meropenem-SD and Colistin-Meropenem formulations. The results indicated that rifampicin controlled the surface morphology of the ternary and binary combination formulations resulting in the formation of highly corrugated particles. Advanced characterization of surface composition by XPS supported the hypothesis that rifampicin was enriched on the surface of the combination powder formulations. All spray-dried formulations were amorphous and absorbed substantial amount of water at the elevated humidity. Storage at the elevated humidity caused a substantial decline in aerosolization performance for the Meropenem-SD and Colistin-Meropenem, which was attributed to increased inter-particulate capillary forces or particle fusion. In contrast, the ternary combination and binary Meropenem-Rifampicin formulations showed no change in aerosol performance at the elevated storage humidity conditions; attributable to the enriched hydrophobicity of rifampicin on the particle surface that acted as a barrier against moisture condensation and particle fusion. Interestingly, in the ternary formulation rifampicin enrichment on the surface did not interfere with the dissolution of other two components (i.e. meropenem and colistin). Our study provides an insight on the impact of each component on the performance of co-spray dried combinational formulations.

Understanding the Impacts of Surface Compositions on the In-Vitro Dissolution and Aerosolization of Co-Spray-Dried Composite Powder Formulations for Inhalation.

PURPOSE: Dissolution behavior of dry powder inhaler (DPI) antibiotic formulations in the airways may affect their efficacy especially for poorly-soluble antibiotics such as azithromycin. The main objective of this study was to understand the effects of surface composition on the dissolution of spray dried azithromycin powders by itself and in combination with colistin. METHODS: Composite formulations of azithromycin (a poorly water-soluble molecule) and colistin (a water-soluble molecule) were produced by spray drying. The resultant formulations were characterized for particle size, morphology, surface composition, solid-state properties, solubility and dissolution. RESULTS: The results demonstrate that surfaces composition has critical impacts on the dissolution of composite formulations. Colistin was shown to increase the solubility of azithromycin. For composite formulations with no surface colistin, azithromycin released at a similar dissolution rate as the spray-dried azithromycin alone. An increase in surface colistin concentration was shown to accelerate the dissolution of azithromycin. The dissolution of colistin from the composite formulations was significantly slower than the spray-dried pure colistin. In addition, FTIR spectrum showed intermolecular interactions between azithromycin and colistin in the composite formulations, which could contribute to the enhanced solubility and dissolution of azithromycin. CONCLUSIONS: Our study provides fundamental understanding of the effects of surface concentration of colistin on azithromycin dissolution of co-spray-dried composite powder formulations.

Composite particle formulations of colistin and meropenem with improved in-vitro bacterial killing and aerosolization for inhalation.

Antibiotic combination therapy is promising for the treatment of lower respiratory tract infections caused by multi-drug resistant Gram-negative pathogens. Inhaled antibiotic therapy offers the advantage of direct delivery of the drugs to the site of infection, as compared to the parenteral administrations. In this study, we developed composite particle formulations of colistin and meropenem. The formulations were characterized for particle size, morphology, specific surface area, surface chemical composition, in-vitro aerosolization performance and in-vitro antibacterial activity. The combinations demonstrated enhanced antibacterial activity against clinical isolates of Acinetobacter baumannii N16870 and Pseudomonas aeruginosa 19147, when compared with antibiotic monotherapy. Spray-dried meropenem alone showed a poor aerosolization performance as indicated by a low fine particle fraction (FPF) of 32.5 ±â€¯3.3%. Co-spraying with colistin improved the aerosolization of meropenem with up to a two-fold increase in the FPF. Such improvements in aerosolization can be attributed to the enrichment of colistin on the surface of composite particles as indicated by X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS), and the increases in particle porosity. Intermolecular interactions between colistin and meropenem were observed for the combination formulations as measured by FT-IR. In conclusion, our results show that co-spray drying with colistin improves the antibacterial activity and aerosol performance of meropenem and produces a formulation with synergistic bacterial killing.

Improved Physical Stability and Aerosolization of Inhalable Amorphous Ciprofloxacin Powder Formulations by Incorporating Synergistic Colistin.

This study aimed to develop dry powder inhaler (DPI) combination formulations of ciprofloxacin and colistin for use in respiratory infections. Effects of colistin on physical stability and aerosolization of spray-dried ciprofloxacin were examined. The combination DPI formulations were produced by co-spray drying colistin and ciprofloxacin in mass ratios of 1:1, 1:3, and 1:9. Colistin and ciprofloxacin were also co-sprayed with l-leucine in the mass ratio of 1:1:1. The physical and aerosolization stability of the selected co-sprayed formulations stored at 20, 55, and 75% relative humidity (RH) were examined. Formulation characterizations were carried out using powder X-ray diffraction (PXRD) for crystallinity, scanning electron microscopy for morphology and particle size distribution, and dynamic vapor sorption for moisture sorption. Particle surface analysis was performed using X-ray photoelectron spectroscopy, energy dispersive X-ray spectrometry, and nano-time-of-flight secondary ion mass spectrometry. Potential intermolecular interactions were studied using Fourier-transform infrared spectroscopy (FTIR). Aerosol performance was evaluated using a multistage liquid impinger with a RS01 monodose inhaler device. PXRD diffractograms showed that the co-spray-dried colistin-ciprofloxacin formulation in the mass ratio (1:1) was amorphous at 55% RH for up to 60 days; whereas the co-spray-dried colistin-ciprofloxacin (1:3) and colistin-ciprofloxacin (1:9) crystallized after storage for 3 days at 55% RH. However, the extent of crystallization for the combination formulations was less as compared to the spray-dried ciprofloxacin alone formulation. Surface morphology of the co-spray-dried formulations at different concentrations did not change even after storage at 55% RH for 60 days, unlike the spray-dried ciprofloxacin alone powder which became rougher after 3 days of storage at 55% RH. Surface analysis data indicated surface enrichment of colistin in the co-spray-dried formulations. Increasing colistin concentration on the composite particles surfaces improved aerosol performance of ciprofloxacin. FTIR data demonstrated intermolecular interactions between colistin and ciprofloxacin, thereby delaying and/or preventing crystallization of ciprofloxacin when co-spray-dried. Co-spray drying ciprofloxacin with colistin in the mass ratio (1:1) completely prevented crystallization of ciprofloxacin at 55% RH for up to 60 days. However, the colistin-ciprofloxacin formulation (1:1) began to fuse when stored at 75% RH due to moisture absorption resulting in a compromised aerosol performance. In contrast, the colistin-ciprofloxacin-leucine (1:1:1) formulation demonstrated no particle fusion, enabling a stable aerosol performance at 75% RH for 7 days. This study demonstrated that incorporation of colistin in the spray-dried formulations can improve physical stability and aerosolization of amorphous ciprofloxacin at 55% RH. At 75% RH, further addition of l-leucine in the formulation prevented particle fusion and deterioration in aerosol performance, attributed to the enrichment of nonhygroscopic l-leucine on the particle surface.

Qualitative and Quantitative Characterization of Composition Heterogeneity on the Surface of Spray Dried Amorphous Solid Dispersion Particles by an Advanced Surface Analysis Platform with High Surface Sensitivity and Superior Spatial Resolution.

Surface composition critically impacts stability (e.g., crystallization) and performance (e.g., dissolution) of spray dried amorphous solid dispersion (ASD) formulations; however, traditional characterization techniques such as Raman and infrared spectroscopies may not provide useful information on surface composition on the spray dried ASD particles due to low spatial resolution, high probing depth, and lack of quantitative information. This study presents an advanced surface characterization platform consisting of two complementary techniques: X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS). Such a platform enables qualitative and quantitative measurements of surface composition for the fine spray dried ASD particles with ultrasurface-sensitivity (less than 10 nm from the surface) and superior spatial resolution (approximately 250 nm for ToF-SIMS). Both XPS and ToF-SIMS demonstrated that the polymer (PVPVA) was dominantly enriched on the surface of our spray dried naproxen-PVPVA ASD particles. Of a particular note was that XPS could differentiate two batches of spray dried ASD particles with a subtle difference in surface composition produced by varying feed solution solvents. This advanced surface characterization platform will provide essential surface information to understand the mechanisms underlying the impact of surface composition on stability (e.g., crystallization) and functionality (e.g., dissolution) in future studies.

Influence of excipients on physical and aerosolization stability of spray dried high-dose powder formulations for inhalation.

The aim of this study is to investigate the influence of excipients on physical and aerosolization stability of spray dried Ciprofloxacin dry powder inhaler formulations. The model drug, Ciprofloxacin hydrochloride, was co-spray dried with excipients such as disaccharides (sucrose, lactose, trehalose), mannitol and l-leucine. The spray dried samples were stored at two different relative humidity (RH) conditions of: (1) 20% and (2) 55% RH at 20 °C. Ciprofloxacin co-spray dried with disaccharides and l-leucine in the mass ratio of 1:1 demonstrated an increase in fine particle fraction (FPF) as compared with the spray dried Ciprofloxacin alone when stored at 20% RH. However, deterioration in FPF of Ciprofloxacin co-spray dried with disaccharide and mannitol was observed upon storage at 55% RH as compared to the corresponding formulations stored at 20% RH due to particle agglomeration. Whereas, 10% and 50% w/w l-leucine in the formulation showed no change in aerosol performance (FPF of 71.1 ±â€¯3.5% and 79.5 ±â€¯3.1%, respectively) when stored at 55% RH for 10 days as compared to 20% RH (FPF of 68.1 ±â€¯0.3% and 73.6 ±â€¯7.1%, respectively). l-Leucine demonstrated aerosolization stability by alleviating crystallization of Ciprofloxacin to some extent and preventing significant change in particle morphology. l-Leucine is well-recognized as aerosolization enhancer; our study has shown l-leucine is also a physical and aerosolization stabilizer for spray dried Ciprofloxacin DPI formulations. Such stability enhancing activities were attributed to the enrichment of l-leucine on the particle surface as confirmed by XPS data, and intermolecular interactions between l-leucine and Ciprofloxacin as measured by FT-IR.

Correction to: Effects of Moisture-Induced Crystallization on the Aerosol Performance of Spray Dried Amorphous Ciprofloxacin Powder Formulations.

Page 4, right column, under section heading "In-Vitro Aerosol Performance", line 11.

Physico-Chemical Properties, Aerosolization and Dissolution of Co-Spray Dried Azithromycin Particles with L-Leucine for Inhalation.

PURPOSE: Inhalation therapy is popular to treat lower respiratory tract infections. Azithromycin is effective against some bacteria that cause respiratory tract infections; but it has poor water solubility that may limit its efficacy when administrated as inhalation therapy. In this study, dry powder inhaler formulations were developed by co-spray drying azithromycin with L-leucine with a purpose to improve dissolution. METHODS: The produced powder formulations were characterized regarding particle size, morphology, surface composition and in-vitro aerosolization performance. Effects of L-leucine on the solubility and in-vitro dissolution of azithromycin were also evaluated. RESULTS: The spray dried azithromycin alone formulation exhibited a satisfactory aerosol performance with a fine particle fraction (FPF) of 62.5 ± 4.1%. Addition of L-leucine in the formulation resulted in no significant change in particle morphology and FPF, which can be attributed to enrichment of azithromycin on the surfaces of composite particles. Importantly, compared with the spray-dried amorphous azithromycin alone powder, the co-spray dried powder formulations of azithromycin and L-leucine demonstrated a substantially enhanced in-vitro dissolution rate. Such enhanced dissolution of azithromycin could be attributed to the formation of composite system and the acidic microenvironment around azithromycin molecules created by the dissolution of acidic L-leucine in the co-spray dried powder. Fourier transform infrared spectroscopic data showed intermolecular interactions between azithromycin and L-leucine in the co-spray dried formulations. CONCLUSIONS: We developed the dry powder formulations with satisfactory aerosol performance and enhanced dissolution for a poorly water soluble weak base, azithromycin, by co-spray drying with an amino acid, L-leucine.

Effects of Moisture-Induced Crystallization on the Aerosol Performance of Spray Dried Amorphous Ciprofloxacin Powder Formulations.

PURPOSE: This study aims to investigate the influence of different storage humidity conditions on crystallization and aerosol performance of inhalable spray dried amorphous powder formulations (Ciprofloxacin hydrochloride as the model drug). METHODS: The spray dried samples were stored at 20%, 55% and 75% relative humidity (RH). Crystallinity was monitored by Powder X-ray diffraction (PXRD), and particle morphology was measured by scanning electron microscopy (SEM) and atomic force microscopy (AFM). Aerosol performance was evaluated using a multi-stage liquid impinger (MSLI). RESULTS: PXRD diffractograms showed the spray dried Ciprofloxacin stored at 20% RH for three weeks were amorphous; whereas those stored at 55% RH and 75% RH started crystallizing after one hour. Fine particle fraction (FPF) of the particles was improved from 28% to 42% after storage at 55% RH for three days. Such improvement was attributed to the crystallization of amorphous powders, which led to increased particle roughness and reduced particulate contact area, as visualized by SEM and quantified by AFM. A linear relationship was observed between degree of crystallinity/crystallite size and FPF (R2 = 0.94 and R2 = 0.96, respectively). However, deterioration in aerosol performance was observed after storage at 75% RH due to formation of inter-particulate liquid/solid bridges, as confirmed by SEM. CONCLUSIONS: This study provides a fundamental understanding in moisture-induced physical and aerosol instability of the spray dried powder formulations.

Effects of Coating Materials and Processing Conditions on Flow Enhancement of Cohesive Acetaminophen Powders by High-Shear Processing With Pharmaceutical Lubricants.

This study has investigated the surface coating efficiency and powder flow improvement of a model cohesive acetaminophen powder by high-shear processing with pharmaceutical lubricants through 2 common equipment, conical comil and high-shear mixer. Effects of coating materials and processing parameters on powder flow and surface coating coverage were evaluated. Both Carr's index and shear cell data indicated that processing with the lubricants using comil or high-shear mixer substantially improved the flow of the cohesive acetaminophen powder. Flow improvement was most pronounced for those processed with 1% wt/wt magnesium stearate, from "cohesive" for the V-blended sample to "easy flowing" for the optimally coated sample. Qualitative and quantitative characterizations demonstrated a greater degree of surface coverage for high-shear mixing compared with comilling; nevertheless, flow properties of the samples at the corresponding optimized conditions were comparable between 2 techniques. Scanning electron microscopy images demonstrated different coating mechanisms with magnesium stearate or l-leucine (magnesium stearate forms a coating layer and leucine coating increases surface roughness). Furthermore, surface coating with hydrophobic magnesium stearate did not retard the dissolution kinetics of acetaminophen. Future studies are warranted to evaluate tableting behavior of such dry-coated pharmaceutical powders.

Pulmonary delivery of nanoparticle chemotherapy for the treatment of lung cancers: challenges and opportunities.

Lung cancer is the second most prevalent and the deadliest among all cancer types. Chemotherapy is recommended for lung cancers to control tumor growth and to prolong patient survival. Systemic chemotherapy typically has very limited efficacy as well as severe systemic adverse effects, which are often attributed to the distribution of anticancer drugs to non-targeted sites. In contrast, inhalation routes permit the delivery of drugs directly to the lungs providing high local concentrations that may enhance the anti-tumor effect while alleviating systemic adverse effects. Preliminary studies in animals and humans have suggested that most inhaled chemotherapies are tolerable with manageable pulmonary adverse effects, including cough and bronchospasm. Promoting the deposition of anticancer drugs in tumorous cells and minimizing access to healthy lung cells can further augment the efficacy and reduce the risk of local toxicities caused by inhaled chemotherapy. Sustained release and tumor localization characteristics make nanoparticle formulations a promising candidate for the inhaled delivery of chemotherapeutic agents against lung cancers. However, the physiology of respiratory tracts and lung clearance mechanisms present key barriers for the effective deposition and retention of inhaled nanoparticle formulations in the lungs. Recent research has focused on the development of novel formulations to maximize lung deposition and to minimize pulmonary clearance of inhaled nanoparticles. This article systematically reviews the challenges and opportunities for the pulmonary delivery of nanoparticle formulations for the treatment of lung cancers.

Applying surface energy derived cohesive-adhesive balance model in predicting the mixing, flow and compaction behaviour of interactive mixtures.

OBJECTIVE: In this study, we investigated the applicability of cohesive-adhesive balance (CAB) model to predict the interactive mixing behaviour of small excipient particles. Further, we also investigated the application of this CAB model to predict the flow and compactibility of resultant blends. METHODS: Excipients created by co-spraying polyvinylpyrrolidone (PVP, a model pharmaceutical binder) with various l-leucine concentrations were used for this study. Paracetamol was used as model active pharmaceutical ingredient (API). The surface energy was used to derive the work of cohesion (wco) and work of adhesion (wad) to predict the interactive mixing behaviour of the excipients with paracetamol. The blends were visualised under a scanning electron microscopy microscope to assess the interactive mixing behaviour. In addition, the flow performance and tabletting behaviour of various blends were characterised. RESULTS: The surface-energy derived work of adhesion (wad) between excipient and paracetamol particles increased, while the corresponding work of cohesion (wco) between excipient particles decreased, with increasing l-leucine concentrations. In blends for which the work of cohesion was higher than the work of adhesion (wco>wad), small excipient particles were apparent as agglomerates. For excipients with 5% and higher l-leucine concentrations, the work of adhesion between excipient and paracetamol particles was higher than or equivalent to the work of cohesion between excipient particles (wad⩾wco) and agglomerates were less apparent. This is an indicator of formation of homogeneous interactive mixtures. At 5% (w/w) excipient proportions, blends for which wad⩾wco demonstrated higher compactibility than other blends. Furthermore, at 10% (w/w) and higher excipient proportions, these blends also demonstrated better flow performance than other blends. CONCLUSION: In conclusion, this is the first study to demonstrate that surface-energy derived CAB data effectively predict the interactive mixing behaviour of small excipient particles. Furthermore, at certain proportions of small excipient particles the CAB model also predicts the flow and compaction behaviour of the API/excipient blends.

Effect of the deformability of guest particles on the tensile strength of tablets from interactive mixtures.

In this study, we investigated the influence of deformability of specifically-engineered guest particles on the tensile strength of tablets of interactive mixtures. The binder polyvinylpyrrolidone (PVP) of different molecular weights were spray dried with l-leucine to create guest particle formulations. The guest particle formulations were characterized by their particle size, surface l-leucine concentration and glass transition temperature (Tg). These spray-dried particles were then blended with paracetamol to form interactive mixtures, which were compacted into tablets and tablet tensile strength and elastic recovery were determined. The guest particles had particle diameters in the range of 1-10µm, and surfaces that were l-leucine enriched. The Tg of guest particle formulations increased with increasing molecular weight of the PVP. All the guest particle formulations formed an observed homogeneous interactive mixture with paracetamol. The tensile strength of the tablets of interactive mixtures increased with decreasing Tg of the guest particles. In these interactive mixtures, higher tensile strength was also associated with lower tablet elastic recovery. The elastic recovery of the tablets showed a correlation with the elastic recovery of the tablets of guest particles. Thus, our results indicated that the deformability of guest particles dictates the tensile strength of the tablets of these interactive mixtures.

Relationship between the cohesion of guest particles on the flow behaviour of interactive mixtures.

In this study, we aimed to investigate the effects cohesion of small surface-engineered guest binder particles on the flow behaviour of interactive mixtures. Polyvinylpyrrolidone (PVP) - a model pharmaceutical binder - was spray-dried with varying l-leucine feed concentrations to create small surface-engineered binder particles with varying cohesion. These spray-dried formulations were characterised by their particle size distribution, morphology and cohesion. Interactive mixtures were produced by blending these spray-dried formulations with paracetamol. The resultant blends were visualised under scanning electron microscope to confirm formation of interactive mixtures. Surface coverage of paracetamol by guest particles as well as the flow behaviour of these mixtures were examined. The flow performance of interactive mixtures was evaluated using measurements of conditioned bulk density, basic flowability energy, aeration energy and compressibility. With higher feed l-leucine concentrations, the surface roughness of small binder particles increased, while their cohesion decreased. Visual inspection of the SEM images of the blends indicated that the guest particles adhered to the surface of paracetamol resulting in effective formation of interactive mixtures. These images also showed that the low-cohesion guest particles were better de-agglomerated that consequently formed a more homogeneous interactive mixture with paracetamol compared with high-cohesion formulations. The flow performance of interactive mixtures changed as a function of the cohesion of the guest particles. Interactive mixtures with low-cohesion guest binder particles showed notably improved bulk flow performance compared with those containing high-cohesion guest binder particles. Thus, our study suggests that the cohesion of guest particles dictates the flow performance of interactive mixtures.

Capsaicin-loaded vesicular systems designed for enhancing localized delivery for psoriasis therapy.

The aim of the current investigation is to evaluate the potential of capsaicin (CAP)-containing liposomes, niosomes and emulsomes in providing localized and controlled delivery, to improve the topical delivery of drug. CAP-bearing systems were prepared by the film hydration method and compared through various in vitro and in vivo parameters. The TEM photographs suggested that the carrier systems were spherical in shape and nanometric in size range. Skin retention studies of CAP from in vitro and in vivo experiments revealed significantly higher accumulation of drug in the case of the emul-gel formulation. Based on the results, we concluded that the emul-gel may be a potential approach for the topical delivery of CAP, for an effective therapy for psoriasis.

Particle Engineering of Excipients for Direct Compression: Understanding the Role of Material Properties.

Tablets represent the preferred and most commonly dispensed pharmaceutical dosage form for administering active pharmaceutical ingredients (APIs). Minimizing the cost of goods and improving manufacturing output efficiency has motivated companies to use direct compression as a preferred method of tablet manufacturing. Excipients dictate the success of direct compression, notably by optimizing powder formulation compactability and flow, thus there has been a surge in creating excipients specifically designed to meet these needs for direct compression. Greater scientific understanding of tablet manufacturing coupled with effective application of the principles of material science and particle engineering has resulted in a number of improved direct compression excipients. Despite this, significant practical disadvantages of direct compression remain relative to granulation, and this is partly due to the limitations of direct compression excipients. For instance, in formulating high-dose APIs, a much higher level of excipient is required relative to wet or dry granulation and so tablets are much bigger. Creating excipients to enable direct compression of high-dose APIs requires the knowledge of the relationship between fundamental material properties and excipient functionalities. In this paper, we review the current understanding of the relationship between fundamental material properties and excipient functionality for direct compression.

Relationship between surface concentration of L-leucine and bulk powder properties in spray dried formulations.

The amino acid L-leucine has been demonstrated to act as a lubricant and improve the dispersibility of otherwise cohesive fine particles. It was hypothesized that optimum surface L-leucine concentration is necessary to achieve optimal surface and bulk powder properties. Polyvinylpyrrolidone was spray dried with different concentration of L-leucine and the change in surface composition of the formulations was determined using X-ray photoelectron spectroscopy (XPS) and time of flight-secondary ion mass spectrometry (ToF-SIMS). The formulations were also subjected to powder X-ray diffraction analysis in order to understand the relationship between surface concentration and solid-state properties of L-leucine. In addition, the morphology, surface energy and bulk cohesion of spray dried formulations were also assessed to understand the relation between surface L-leucine concentration and surface and bulk properties. The surface concentration of L-leucine increased with higher feed concentrations and plateaued at about 10% L-leucine. Higher surface L-leucine concentration also resulted in the formation of larger L-leucine crystals and not much change in crystal size was noted above 10% L-leucine. A change in surface morphology of particles from spherical to increasingly corrugated was also observed with increasing surface l-leucine concentration. Specific collapsed/folded over particles were only seen in formulations with 10% or higher l-leucine feed concentration suggesting a change in particle surface formation process. In addition, bulk cohesion also reduced and approached a minimum with 10% L-leucine concentration. Thus, the surface concentration of L-leucine governs particle formation and optimum surface L-leucine concentration results in optimum surface and bulk powder properties.

The role of physico-chemical and bulk characteristics of co-spray dried L-leucine and polyvinylpyrrolidone on glidant and binder properties in interactive mixtures.

In this study, polyvinylpyrrolidone (PVP) was spray dried with l-leucine (PVP-Leu) to create a prototype multifunctional interactive excipient. The physico-chemical and bulk properties such as particle size, surface composition, surface energy and bulk cohesion of PVP-Leu was measured and compared against pure spray dried PVP (PVP-SD). The mixing behaviour of these excipients and their effect on flow and binder activity of paracetamol was assessed. The mean particle sizes of PVP-Leu PVP-SD and PVP were 2.5, 2.1 and 21.9µm, respectively. Surface composition characterization indicated that l-leucine achieved higher concentrations on the surface compared to the bulk of the PVP-Leu particles. The surface energy of PVP-Leu was significantly lower compared to PVP-SD. In addition, PVP-Leu exhibited a significantly lower bulk cohesion compared PVP-SD. The excipients were blended with paracetamol and qualitative characterization indicated that PVP-Leu blended more homogeneously with paracetamol compared to PVP-SD. Both PVP-Leu and PVP-SD then exhibited a significantly improved binder activity compared to PVP. The flow of the paracetamol was markedly improved with PVP-Leu while PVP-SD and PVP had negligible effect on its flow. This study reveals how physico-chemical and bulk properties of such prototype interactive excipients can play a key role in determining multi-factorial excipient performance.