Wai Kiong Ng

Nano spray drying: a novel method for preparing protein nanoparticles for protein therapy.

There has been an increasing interest in the development of protein nanotherapeutics for diseases such as cancer, diabetes and asthma. Spray drying with prior micro mixing is commonly used to obtain these powders. However, the separation and collection of protein nanoparticles with conventional spray dryer setups has been known to be extremely challenging due to its typical low collection efficiency for fine particles less than 2μm. To date, there has been no feasible approach to produce these protein nanoparticles in a single step and with high yield (>70%). In this study, we explored the feasibility of the novel Nano Spray Dryer B-90 (equipped with a vibrating mesh spray technology and an electrostatic particle collector) for the production of bovine serum albumin (BSA) nanoparticles. A statistical experimental design method (Taguchi method based on three levels, five variables L(18) orthogonal array robust design) was implemented to study the effect of and optimize the experimental conditions of: (1) spray mesh size, (2) BSA solution concentration, (3) surfactant concentration, (4) drying air flow rate and (5) inlet temperature on: (1) size and (2) morphology (axial ratio). Particle size and morphology were predominantly influenced by the spray mesh size and surfactant concentration, respectively. The drying air flow rate and inlet temperature had minimal impact. Optimized production of smooth spherical nanoparticles (median size: 460±10nm, axial ratio: 1.03±0.00, span 1.03±0.03, yield: 72±4%) was achieved using the 4μm spray mesh at BSA concentration of 0.1% (w/v), surfactant concentration of 0.05% (w/v), drying flow rate of 150L/min and inlet temperature of 120°C. The Nano Spray Dryer B-90 thus offers a new, simple and alternative approach for the production of protein nanoparticles suited for a variety of drug delivery applications.

Formulation design, preparation and physicochemical characterizations of solid lipid nanoparticles containing a hydrophobic drug: Effects of process variables

This study aimed to prepare solid lipid nanoparticles (SLNs) of a hydrophobic drug, tretinoin, by emulsification-ultrasonication method. Solubility of tretinoin in the solid lipids was examined. Effects of process variables were investigated on particle size, polydispersity index (PI), zeta potential (ZP), drug encapsulation efficiency (EE), and drug loading (L) of the SLNs. Shape and surface morphology of the SLNs were investigated by cryogenic field emission scanning electron microscopy (cryo-FESEM). Complete encapsulation of drug in the nanoparticles was checked by cross-polarized light microscopy and differential scanning calorimetry (DSC). Crystallinity of the formulation was analyzed by DSC and powder X-ray diffraction (PXRD). In addition, drug release and stability studies were also performed. The results indicated that 10mg tretinoin was soluble in 0.45±0.07 g Precirol® ATO5 and 0.36±0.06 g Compritol® 888ATO, respectively. Process variables exhibited significant influence in producing SLNs. SLNs with <120 nm size, <0.2 PI, >I30I mV ZP, >75% EE, and ∼0.8% L can be produced following the appropriate formulation conditions. Cryo-FESEM study showed spherical particles with smooth surface. Cross-polarized light microscopy study revealed that drug crystals in the external aqueous phase were absent when the SLNs were prepared at ≤0.05% drug concentration. DSC and PXRD studies indicated complete drug encapsulation within the nanoparticle matrix as amorphous form. The drug release study demonstrated sustained/prolonged drug release from the SLNs. Furthermore, tretinoin-loaded SLNs were stable for 3 months at 4°C. Hence, the developed SLNs can be used as drug carrier for sustained/prolonged drug release and/or to improve oral absorption/bioavailability.

Stabilized Amorphous State of Ibuprofen by Co-Spray Drying With Mesoporous SBA-15 to Enhance Dissolution Properties

A novel formulation process via co-spray drying ibuprofen (IBU) with mesoporous SBA-15 submicron particles exhibited excellence in production of stable amorphous IBU with significantly enhanced dissolution rate. With drug loading of IBU/SBA-15 ratio being 50:50 (w/w) or below, most drug molecules were entrapped inside the straight mesoporous channels via the co-spray drying and the morphology of SBA-15 submicron particles remained unchanged. IBU confined inside the mesoporous structure was in the amorphous state shown by PXRD and DSC measurements. The amorphous state of IBU in the solid dispersion showed remarkable stability when subject to stress test condition of 40 degrees C/75% RH in open pans for 12 months. The uniform pore walls were believed to prevent the re-crystallization of the homogeneously dispersed drug molecules inside the mesoporous channels with confined nanospace. The dissolution rate of IBU from the co-spray-dried solid dispersion was significantly enhanced to achieve a rapid release. Even after the accelerated stability test, the rapid drug release property was well preserved.

Preparation and characterization of spironolactone nanoparticles by antisolvent precipitation

Due to low aqueous solubility and slow dissolution rate, spironolactone, a synthetic steroid diuretic, has a low and variable oral bioavailability. Nanoparticles were thus prepared by antisolvent precipitation in this work for accelerating dissolution of this kind of poorly water-soluble drugs. Effects of surfactant type/concentration and feed drug concentration on the precipitated particle size were evaluated. It was found that introduction of spironolactone solution in N-methyl-2-pyrrolidone (NMP) to the antisolvent water can produce the particles in the submicron range with hydroxypropyl methylcellulose (HPMC) as the stabilizer. The particle size decreased with the increase of HPMC concentration from 0 to 0.125% (w/v), further increase of which did not affect the size significantly. Increasing feed drug concentration from 10 to 100 mg/ml resulted in the particle size decrease. In comparison with raw drug, the chemical structure of nanosized spironolactone was not changed but the crystallinity was reduced. Dissolution of spironolactone nanoparticles in 0.1M HCl was 2.59 times faster than raw drugs in 60 min.

Physical state and dissolution of ibuprofen formulated by co-spray drying with mesoporous silica: Effect of pore and particle size

A model poorly aqueous-soluble drug, ibuprofen (IBU), was co-spray dried with mesoporous silica materials having different pore sizes and particle sizes for dissolution enhancement. Drug molecules were entrapped inside the mesoporous channels at a high drug loading of 50:50 (w/w). The pore sizes were found to affect the physical state and particle size of IBU in mesoporous structures, which influenced the dissolution profiles. When IBU was co-spray dried with MCM-41 and SBA-15 with pore size smaller than 10 nm, amorphous state of IBU was obtained due to nano space confinement. In contrast, nanocrystals were obtained when ibuprofen was co-spray dried with large pore SBA-15-LP with pore size above 20 nm. The physical state of ibuprofen played a key role in affecting the dissolution of IBU from the solid dispersion. IBU in the amorphous state exhibited a higher dissolution rate than nanocrystalline IBU, even though the larger pore size could facilitate diffusion from the host matrix. The particle size of mesoporous silica showed a less pronounced effect on the dissolution of IBU. Thus, the amorphous/nanocrystalline state of ibuprofen was the most important influence on drug dissolution followed by the diffusion kinetics, particle size of IBU and path length from host matrix to dissolution medium.

A continuous and highly effective static mixing process for antisolvent precipitation of nanoparticles of poorly water-soluble drugs

Rapid and homogeneous mixing of the solvent and antisolvent is critical to achieve submicron drug particles by antisolvent precipitation technique. This work aims to develop a continuous and highly effective static mixing process for antisolvent precipitation of nanoparticles of poorly water-soluble drugs with spironolactone as a model drug. Continuous antisolvent production of drug nanoparticles was carried out with a SMV DN25 static mixer comprising 6-18 mixing elements. The total flow rate ranged from 1.0 to 3.0 L/min while the flow rate ratio of solvent to antisolvent was maintained at 1:9. It is found that only 6 mixing elements were sufficient to precipitate the particles in the submicron range. Increasing the number of elements would further reduce the precipitated particle size. Increasing flow rate from 1.0 to 3.0 L/min did not further reduce the particle size, while higher drug concentrations led to particle size increase. XRD and SEM results demonstrated that the freshly precipitated drug nanoparticles are in the amorphous state, which would, in presence of the mixture of solvent and antisolvent, change to crystalline form in short time. The lyophilized spironolactone nanoparticles with lactose as lyoprotectant possessed good redispersibility and showed 6.6 and 3.3 times faster dissolution rate than that of lyophilized raw drug formulation in 5 and 10 min, respectively. The developed static mixing process exhibits high potential for continuous and large-scale antisolvent precipitation of submicron drug particles.

The nano spray dryer B-90

Introduction: Spray drying is an extremely well-established technology for the production of micro-particulate powders suited for a variety of drug delivery applications. In recent years, the rise in nanomedicine has placed increased pressure on the existing systems to produce nanoparticles in good yield and with a narrow size distribution. However, the separation and collection of nanoparticles with conventional spray dryer set ups is extremely challenging due to their typical low collection efficiency for fine particles < 2 μm. Currently, nanoparticles have to be agglomerated into larger microparticles, via a two-step approach, in order to collect them in a sizeable amount. However, this method has to contend with the issue of adequate redispersibility of the primary particles to reap the full benefits of nanosizing. Areas covered: An overview on the advances in spray drying technology is provided in this review with particular emphasis on the novel Buchi Nano Spray Dryer B-90. Readers will appreciate the limitations of conventional spray drying technology, understand the mechanisms of the Buchi Nano Spray Dryer B-90, and also learn about the strengths and shortcomings of the system. Expert opinion: The Buchi Nano Spray Dryer B-90 offers a new, simple and alternative approach for the production of nanoparticles suited for a variety of drug delivery applications.

Detection of trace crystallinity in an amorphous system using Raman microscopy and chemometric analysis

A novel analytical method to detect and characterize active pharmaceutical ingredient (API) trace crystallinity in an amorphous system using Raman microscopy and chemometric methods, namely band-target entropy minimization (BTEM) and target transformation factor analysis (TTFA) is developed. The method starts with Raman mapping measurements performed on some random areas of the amorphous system. This is followed by chemometric data analysis. In the case of a system without any a priori information, the BTEM algorithm is used to recover a set of pure component Raman spectral estimates followed by component and/or crystal structure identification. In the case of a system with some a priori information, TTFA is used to predict the presence or existence of a suspected component and/or crystal structure in the observed system. Four different amorphous systems were used as models. It is demonstrated that combined Raman microscopy and chemometric methods (BTEM or TTFA) outperformed powder X-ray diffraction (PXRD) in detecting trace crystallinity in amorphous systems. The spatial distributions of drug and polymer can also be directly obtained in order to study the homogeneity of the APIs in the solid dispersions. The present methodology appears very general and applicable to many other types of systems.

Monitoring Granulation Rate Processes Using Three PAT Tools in a Pilot-Scale Fluidized Bed

The purpose of this research was to analyze and compare the responses of three Process Analytical Technology (PAT) techniques applied simultaneously to monitor a pilot-scale fluidized bed granulation process. Real-time measurements using focused beam reflectance measurement (Lasentec FBRM) and near-infra red spectroscopy (Bruker NIR) were taken by inserting in-line probes into the fluidized bed. Non-intrusive acoustic emission measurements (Physical Acoustic AE) were performed by attaching piezoelectric sensors on the external wall of the fluidized bed. Powder samples were collected at regular intervals during the granulation process and characterized offline using laser diffraction, scanning electron microscopy, stereo-optical microscopy and loss on drying method. PAT data comprising chord length distribution and chord count (from FBRM), absorption spectra (from NIR) and average signal levels and counts (from AE) were compared with the particle properties measured using offline samples. All three PAT techniques were able to detect the three granulation regimes or rate processes (wetting and nucleation, consolidation and growth, breakage) to varying degrees of sensitivity. Being dependent on optical signals, the sensitivities of the FBRM and NIR techniques were susceptible to fouling on probe windows. The AE technique was sensitive to background fluidizing air flows and external interferences. The sensitivity, strengths and weaknesses of the PAT techniques examined may facilitate the selection of suitable PAT tools for process development and scale-up studies.

Scalable ionic gelation synthesis of chitosan nanoparticles for drug delivery in static mixers.

The purpose of this study is to synthesize chitosan (CS) nanoparticles (NPs) by ionic gelation with tripolyphosphate (TPP) as crossslinker in static mixers. The proposed static mixing technique showed good control over the ionic gelation process and 152-376 nm CS NPs were achieved in a continuous and scalable mode. Increasing the flow rates of CS:TPP solution streams, decreasing the CS concentration or reducing the CS:TPP solution volume ratio led to the smaller particles. Sylicylic acid (SA) was used as a model drug and successfully loaded into the CS NPs during the fabrication process. Our work demonstrates that ionic gelation-static mixing is a robust platform for continuous and large scale production of CS NPs for drug delivery.