Crystal doping aided by rapid expansion of supercritical solutions

The purpose of this study was to test the utility of rapid expansion of supercritical solution (RESS) based cocrystallizations in inducing polymorph conversion and crystal disruption of chlorpropamide (CPD). CPD crystals were recrystallized by the RESS process utilizing supercritical carbon dioxide as the solvent. The supercritical region investigated for solute extraction ranged from 45 to 100°C and 2000 to 8000 psi. While pure solute recrystallization formed stage I of these studies, stage II involved recrystallization of CPD in the presence of urea (model impurity). The composition, morphology, and crystallinity of the particles thus produced were characterized utilizing techniques such as microscopy, thermal analysis, x-ray powder diffractometry, and high-performance liquid chromatography. Also, comparative evaluation between RESS and evaporative crystallization from liquid solvents was performed. RESS recrystallizations of commercially available CPD (form A) resulted in polymorph conversion to metastable forms C and V, depending on the temperature and pressure of the recrystallizing solvent. Cocrystallization studies revealed the formation of eutectic mixtures and solid solutions of CPD+urea. Formation of the solid solutions resulted in the crystal disruption of CPD and subsequent amorphous conversion at urea levels higher than 40% wt/wt. Consistent with these results were the reductions in melting point (up to 9°C) and in the ΔH_fvalues of CPD (up to 50%). Scanning electron microscopy revealed a particle size reduction of up to an order of magnitude upon RESS processing. Unlike RESS, recrystallizations from liquid organic solvents lacked the ability to affect polymorphic conversions. Also, the incorporation of urea into the lattice of CPD was found to be inadequate. In providing the ability to control both the particle and crystal morphologies of active pharmaceutical ingredients, RESS proved potentially advantageous to crystal engineering. Rapid crystallization kinetics were found vital in making RESS-based doping superior to conventional solvent-based cocrystallizations.     

Formulation of a dry powder influenza vaccine for nasal delivery

The purpose of this research was to prepare a dry powder vaccine formulation containing whole inactivated influenza virus (VIIV) and a mucoadhesive compound suitable for nasal delivery. Powders containing WIIV and either lactose or trehalose were produced by lyophilization. A micro-ball mill was used to reduce the lyophilized cake to sizes suitable for nasal delivery. Chitosan flakes were reduced in size using a cryo-milling technique. Milled powders were sieved between 45 and 125 μm aggregate sizes and characterized for particle size and distribution, morphology, and flow properties. Powders were blended in the micro-ball mill without the ball. Lyophilization followed by milling produced irregularly shaped, polydisperse particles with a median primary particle diameter of ≈21 μm and a yield of ≈37% of particles in the 45 to 125 μm particle size range. Flow properties of lactose and trehalose powders after lyophilization followed by milling and sieving were similar. Cryo-milling produced a small yield of particles in the desired size range (<10%). Lyophilization followed by milling and sieving produced particles suitable for nasal delivery with different physicochemical properties as a function of processing conditions and components of the formulation. Further optimization of particle size and morphology is required for these powders to be suitable for clinical evaluation. Published: March 10, 2006     

Experimental Technique for Studying Aerosols of Lyophilized Bacteria

An experimental technique is presented for studying aerosols generated from lyophilized bacteria by using Escherichia coli B, Bacillus subtilis var. niger, Enterobacter aerogenes, and Pasteurella tularensis. An aerosol generator capable of creating fine particle aerosols of small quantities (10 mg) of lyophilized powder under controlled conditions of exposure to the atmosphere is described. The physical properties of the aerosols are investigated as to the distribution of number of aerosol particles with particle size as well as to the distribution of number of bacteria with particle size. Biologically unstable vegetative cells were quantitated physically by using ¹⁴C and Europium chelate stain as tracers, whereas the stable heat-shocked B. subtilis spores were assayed biologically. The physical persistence of the lyophilized B. subtilis aerosol is investigated as a function of size of spore-containing particles. The experimental result that physical persistence of the aerosol in a closed aerosol chamber increases as particle size is decreased is satisfactorily explained on the bases of electrostatic, gravitational, inertial, and diffusion forces operating to remove particles from the particular aerosol system. The net effect of these various forces is to provide, after a short time interval in the system (about 2 min), an aerosol of fine particles with enhanced physical stability. The dependence of physical stability of the aerosol on the species of organism and the nature of the suspending medium for lyophilization is indicated. Also, limitations and general applicability of both the technique and results are discussed.     

Ultrasound-assisted powder-coating technique to improve content uniformity of low-dose solid dosage forms

An ultrasound-assisted powder-coating technique was used to produce a homogeneous powder formulation of a low-dose active pharmaceutical ingredient (API). The powdered particles of microcrystalline cellulose (MCC; Avicel^® PH-200) were coated with a 4% m/V aqueous solution of riboflavin sodium phosphate, producing a uniform drug layer on the particle surfaces. It was possible to regulate the amount of API in the treated powder. The thickness of the API layer on the surface of the MCC particles increased near linearly as the number of coating cycles increased, allowing a precise control of the drug content. The tablets (n = 950) prepared from the coated powder showed significantly improved weight and content uniformity in comparison with the reference tablets compressed from a physical binary powder mixture. This was due to the coated formulation remaining uniform during the entire tabletting process, whereas the physical mixture of the powders was subject to segregation. In conclusion, the ultrasound-assisted technique presented here is an effective tool for homogeneous drug coating of powders of irregular particle shape and broad particle size distribution, improving content uniformity of low-dose API in tablets, and consequently, ensuring the safe delivery of a potent active substance to patients.Key words: content uniformity, homogeneity, low-dose API, powder coating, ultrasound     

Electro-hydrodynamic atomization of drug solutions for inhalation purposes.

Monodisperse aerosols show therapeutic advantages, but they are difficult to generate. A new method (electrohydrodynamic atomization) is described. A high voltage is applied to a nozzle through which a solution, containing dissolved drug, is pumped. At the nozzle tip, a liquid cone is formed and a stream of monodisperse droplets is released. The droplet diameter is governed by the density, conductivity, and the flow rate of the fluid. The droplets are charged and need to be neutralized. Therefore, a corona discharge system is used. Methylparahydroxybenzoate was used as a model drug, and additional data were generated by using beclomethasone dipropionate (BDP). At a flow rate of 1 ml/h and 0.5% methylparahydroxybenzoate, 1.58-microm particles were produced with a geometric SD of 1.18. Increasing the flow rate to 3 ml/h and the concentration to 3% resulted in 4.55-microm particles with a geometric SD of 1.29. The experiments with BDP resulted in similar particle sizes. The mass of BDP was found to range between 1.42 and 6 microg/l air. Aqueous solutions cannot be sprayed by using this setup. This method can be used to deliver antiasthma drugs to patients.     

Spherical composite particles of rice starch and microcrystalline cellulose: A new coprocessed excipient for direct compression

Composite particles of rice starch (RS) and microcrystalline cellulose were fabricated by spray-drying technique to be used as a directly compressible excipient. Two size fractions of microcry stalline cellulose, sieved (MCS) and jet milled (MCJ), having volumetric mean diameter (D₅₀) of 13.61 and 40.51 μm, respectively, were used to form composite particles with RS in various mixing ratios. The composite particles produced were evaluated for their powder and compression properties. Although an increase in the microcrystalline cellulose proportion imparted greater compressibility of the composite particles, the shape of the particles was typically less spherical with rougher surface resulting in a decrease in the degree of flowability. Compressibility of composite particles made from different size fractions of microcrystalline cellulose was not different; however, using MCJ, which had a particle size range close to the size of RS (D₅₀=13.57 μm), provided more spherical particles than using MCS. Spherical composite particles between RS and MCJ in the ratio of 7∶3 (RS-MCJ-73) were then evaluated for powder properties and compressibility in comparison with some marketed directly compressible diluents. Compressibility of RS-MCJ-73 was greater than commercial spray-dried RS (Eratab), coprocessed lactose and microcrystalline cellulose (Cellactose), and agglomerated lactose (Tablettose), but, as expected, lower than microcrystalline cellulose (Vivapur 101). Flowability index of RS-MCJ-73 appeared to be slightly lower than Eratab but higher than Vivapur 101, Cellactose, and Tablettose. Tablets of RS-MCJ-73 exhibited low friability and good self-disintegrating property. It was concluded that these developed composite particles could be introduced as a new coprocessed direct compression excipient.     

Interactions between protein-gold complexes and cell surfaces: a method for precise quantitation

We have developed a rapid and precise electron microscope technique for the quantitation of gold particles in suspension using latex microspheres as a reference (EM latex technique). This technique allowed us to determine the specific absorption of colloidal gold at its absorption maximum (520 nm) and the average number of ligands ([125I]IgG) bound to one gold particle. On the basis of these values important binding characteristics of protein-gold complexes to cell surfaces were analyzed in a model system consisting of Staphylococcus aureus with protein A on the cell wall as a specific binding site for IgG-Au. Our observations showed that the number of binding sites represented by one IgG-gold complex depended primarily on the particle size, with one 20-nm IgG-Au corresponding to 15 and one 6-nm IgG-Au to 2.5 binding sites. Hence, the efficiency of binding of IgG-Au complexes increased with decreasing gold particle size. Saturation of binding sites, however, was not achieved. The technique also made possible the determination of the affinity between IgG-Au complexes and the cell surface; this affinity can either be regarded as a characteristic of the ligand IgG or of the gold particle. We observed that the affinity of IgG decreased with the size of the gold particles to which IgG was bound, whereas the affinity of the entire gold particle increased with particle size. The EM latex technique for quantitation of gold particles extends the general use of protein-gold complexes to the quantitative characterization of their interaction with cell surface constituents.     

Supercritical assisted atomization: A novel technology for microparticles preparation of an asthma-controlling drug

The objective of this study was to produce microparticles of a new asthma-controlling drug by supercritical assisted atomization (SAA), proposed as an alternative to conventional jet-milling process. SAA is based on the solubilization of supercritical carbon dioxide in a liquid solution containing the drug; the ternary mixture is then sprayed through a nozzle, and microparticles are formed as a consequence of the enhanced atomization. SAA process parameters studied were precipitator temperature, nozzle diameter, and drug concentration in the liquid solution. Their influence was evaluated on morphology and size of precipitated particles. Spherical particles with mean particle size ranging from 1 to 3 μm of the new anti-asthma drug were produced by SAA. The mass median aerodynamic diameter (MMAD) of the SAA micronized particles and of the conventional jet-milled drug was used to compare, the results obtainable using the 2 techniques. Particularly, MMADs from 1.6 to 4.0 μm were obtained by SAA at the optimum operating conditions and by varying the concentration of the solution injected. MMAD of 6.0 μm was calculated for the jet-milled drug. SAA samples also exhibited narrower particle size distribution (PSD). A good control of particle size and distribution together with no drug degradation was obtained by SAA process. Published: October 22, 2005     

Size control of silica nanoparticles and their surface treatment for fabrication of dental nanocomposites

Nearly monodispersed silica nanoparticles having a controlled size from 5 to 450 nm were synthesized via a sol-gel process, and then the optimum conditions for the surface treatment of the synthesized silica nanoparticles with a silane coupling agent (i.e., 3-methacryloxypropyltrimethoxysilane (gamma-MPS)) were explored to produce dental composites exhibiting enhanced adhesion and dispersion of silica nanoparticles in the resin matrix. The particle size was increased by increasing amounts of the catalyst (NH4OH) and silica precursor (tetraethylorthosilicate, TEOS) and by decreasing the amount of water in the reaction mixtures regardless of solvents used for the synthesis. The particle size prepared by using ethanol as a solvent was significantly larger than that prepared by using methanol as a solvent when the composition of the reaction mixture was fixed. The nanosized particles in the 5-25 nm range were aggregated. The amount of grafted gamma-MPS on the surface of the synthesized silica nanoparticles was dependent on the composition of the reaction mixture when an excess amount of gamma-MPS was used. When surface treatment was performed at optimum conditions found here, the amount of the grafted gamma-MPS per unit surface area of the silica nanoparticles was nearly the same regardless of the particle size. Dispersion of the silica particles in the resin matrix and interfacial adhesion between silica particles and resin matrix were enhanced when surface treated silica nanoparticles were used for preparing dental nanocomposites.     

Aerodynamic and Electrostatic Properties of Model Dry Powder Aerosols: a Comprehensive Study of Formulation Factors

The impact of formulation variables on aerodynamic and electrostatic properties of dry powder aerosol particles is of great importance to the development of efficient and reproducible inhaler products. Systematic evaluation requires a well-designed series of experiments using appropriate methods. A factorial experimental design was employed. In broad terms, the conditions considered were two drugs, albuterol and budesonide, in combination with different excipients, drug concentrations, delivered doses, and metering system (capsule composition) and sampled under different flow conditions using standard entrainment tubes. Samples were collected in an electrical low-pressure impactor, to evaluate distribution of electrostatic properties, and an Andersen eight-stage nonviable cascade impactor, to estimate aerodynamic particle size distribution, concurrently. The deposition studies allowed calculation of approximate per particle charge levels for drug. The results showed very high particle charge levels, often in the 1,000–10,000 of elementary charges per particle range, orders of magnitude higher than charge levels predicted by the Boltzmann charge distribution. The charge levels are considerably higher than had previously been estimated (200e per particle).KEY WORDS: aerodynamics, aerosol(s), electrostatics, experimental design, formulation factors     

Self-built Supercritical CO2 Anti-solvent Unit Design, Construction and Operation using Carbamazepine

The purpose of this study was to design and build a supercritical CO₂ anti-solvent (SAS) unit and use it to produce microparticles of the class II drug carbamazepine. The operation conditions of the constructed unit affected the carbamazepine yield. Optimal conditions were: organic solution flow rate of 0.15 mL/min, CO₂ flow rate of 7.5 mL/min, pressure of 4,200 psi, over 3,000 s and at 33°C. The drug solid-state characteristics, morphology and size distribution were examined before and after processing using X-ray powder diffraction and differential scanning calorimetry, scanning electron microscopy and laser diffraction particle size analysis, respectively. The in vitro dissolution of the treated particles was investigated and compared to that of untreated particles. Results revealed a change in the crystalline structure of carbamazepine with different polymorphs co-existing under various operation conditions. Scanning electron micrographs showed a change in the crystalline habit from the prismatic into bundled whiskers, fibers and filaments. The volume weighted diameter was reduced from 209 to 29 μm. Furthermore, the SAS CO₂ process yielded particles with significantly improved in vitro dissolution. Further research is needed to optimize the operation conditions of the self-built unit to maximize the production yield and produce a uniform polymorphic form of carbamazepine.     

Effective Modification of Particle Surface Properties Using Ultrasonic Water Mist

The goal of the present study was to design a new technique to modify particle surface properties and, through that, to improve flowability of poorly flowing drug thiamine hydrochloride and pharmaceutical sugar lactose monohydrate of two different grades. The powdered particles were supplied by a vibratory feeder and exposed to an instantaneous effect of water mist generated from an ultrasound nebulizer. The processed and original powders were evaluated with respect to morphology (scanning electron microscopy, atomic force microscopy, and spatial filtering technique), flow, and solid state properties. It was found that rapid exposition of pharmaceutical materials by water mist resulted in the improvement of powder technical properties. The evident changes in flowability of coarser lactose were obviously due to smoothing of particle surface and decreasing in the level of fines with very slight increment in particle size. The changes in thiamine powder flow were mainly due to narrowing in particle size distribution where the tendency for better flow of finer lactose was related to surface and size modifications. The aqueous mist application did not cause any alteration of the crystal structures of the studied materials. The proposed water mist treatment technique appears to be a robust, rapid, and promising tool for the improvement of the technological properties of pharmaceutical powders.     

Influence of formulation and process parameters on pellet production by powder layering technique

The goal of the present study was to evaluate the influence of the formulation and operating conditions on pellet preparation by pan technique. To this end, a new pelletization process, typified by the application of powdered drug on sugar-based cores using the GS coating system was studied. Inert cores were intermittently treated with micronized drug powder and adhesive solution. This treatment led to the formation of multiple layers of drug particles around an inert core resulting in the production of pellets that can further be coated by different polymers to obtain modified release formulations. Different procedures have been used to evaluate a series of important parameters such as initial core weight; speed of powder application; speed, type, and position of the atomizers; atomization degree: temperature; and air cap. Good yield of drug layering was obtained by adjusting the quantity of both the drug powder to apply and the binder solution. Pellets obtained following the optimal operating conditions (defined in a pre-formulation study) were film coated with the acrylic polymer Eudragit L30D in order to produce a model formulation consisting of enteric polymer-coated pellets containing ibuprofen. During its preparation, the formulation showed no degradation of the drug, moreover, a low percentage of residual humidity was obtained, indicating that this system is very efficient for the production of highly stable formulations. This study showed the good performance of the GS automated pan-coating system in obtaining enteric coated pellets prepared by powder layering technique using aqueous solutions.     

Evidence for particle-induced horizontal gene transfer and serial transduction between bacteria

Incubation of the amino acid-deficient strain Escherichia coli AB1157 with particles harvested from an oligotrophic environment revealed evidence of horizontal gene transfer (HGT) with restoration of all deficiencies in revertant cells with frequencies up to 1.94 × 10(-5). None of the markers were preferentially transferred, indicating that the DNA transfer is performed by generalized transduction. The highest gene transfer frequencies were obtained for single markers, with values up to 1.04 × 10(-2). All revertants were able to produce particles of comparable size, appearing at the beginning of the stationary phase. Examination of the revertants using electron microscopy showed bud-like structures with electron-dense bodies. The particles that display the structural features of membrane vesicles were again infectious to E. coli AB1157, producing new infectious particles able to transduce genetic information, a phenomenon termed serial transduction. Thus, the <0.2-μm particle fraction from seawater contains a particle size fraction with high potential for gene transfer. Biased sinusoidal field gel electrophoresis indicated a DNA content for the particles of 370 kbp, which was higher than that of known membrane vesicles. These findings provide evidence of a new method of HGT, in which mobilizable DNA is trafficked from donor to recipient cells via particles.     

Synthesis of ultrasmall superparamagnetic iron oxides using reduced polysaccharides

Investigation into the effect of the reducing sugar of dextran on formation and stability of dextran-coated ultrasmall superparamagnetic iron oxides (USPIO) has demonstrated that reduction of the terminal reducing sugar can have a significant effect on particle size, coating stability, and magnetic properties. Four aspects of polysaccharide-coated USPIO particle synthesis were investigated: (i) the effect reduction of the terminal polysaccharide sugar has upon polysaccharide usage, particle size, stability, and magnetic susceptibility; (ii) the effect an exogenous reducing sugar can have upon particle synthesis; (iii) the effect the molecular weight of the reduced polysaccharide has on particle synthesis; and (iv) the effectiveness of reduced and native dextrans in stabilizing a preformed magnetic sol. For low molecular weight dextrans (MW 20,000 x 10(-6) cgs). Similar results were obtained with a 12 kDa pullulan. The effect of polysaccharide molecular weight on particle size was studied, wherein higher molecular weight reduced dextrans produced larger particles. The effectiveness of the reduced and native dextrans in stabilizing a preformed magnetic sol was compared. Reduced dextrans were found to be superior for stabilizing the magnetic sol. The observed effects of reduction of the terminal sugar in dextran compared with the native dextran were modeled using the Langmuir adsorption isotherm. A good fit of experimental data with this model was found.     

Rapid expansion from supercritical to aqueous solution to produce submicron suspensions of water-insoluble drugs

Stable suspensions of submicron particles of cyclosporine, a water-insoluble drug, have been produced by rapid expansion from supercritical to aqueous solution (RESAS). To minimize growth of the cyclosporine particles, which would otherwise occur in the free jet expansion, the solution was sprayed into an aqueous Tween-80 (Polysorbate-80) solution. Steric stabilization by the surfactant impedes particle growth and agglomeration. The particles were an order of magnitude smaller than those produced by RESS into air without the surfactant solution. Concentrations as high as 38 mg/mL for 400-700 nm particles were achieved in a 5.0% (w/w) Tween-80 solution.     

An investigation of optimal gold particle size for immunohistological immunogold and immunogold-silver staining to be viewed by polarized incident light (EPI polarization) microscopy

We investigated the optimal gold particle size for use with polarized incident light (epi polarization) microscopy with immunogold immunohistological preparation in both immunogold indirect (IGS) and silver-enhanced immunogold-silver staining (IGSS) techniques. A range of gold particle sizes from 5 nm-40 nm was used along with tissue of known immunoreactivity with a well-characterized primary monoclonal antibody. Checkerboard titrations were carried out for each technique and for each particle size. The preparations were viewed using a standard polarized incident light microscope and assessed in a semi-quantitative manner. Adequate visualization of gold particles was achieved using the indirect staining method only with a particle size of 40 nm. With silver enhancement (IGSS), particles of all sizes were clearly seen. However, 5-nm particles were considered optimal for this method because of reduced background staining, high titration of antisera possible, and crisp localization of the visual signal.     

水溶性三七总皂苷制备与表征

为提高三七总皂苷的水溶性及其制剂在体内的稳定性和生物利用度,运用喷雾干燥法对三七总皂苷进行超细化,利用正交试验分析得到喷雾干燥制备三七总皂苷超细粉的最佳条件并对其各项指标进行检测。经分析所得最佳制备条件为：进口温度为140℃、三七总皂苷的浓度为65 g·L^-1、进料流速为30 L·h^-1和空气脉冲为4。对三七总皂苷原粉和喷雾干燥所得超细粉进行了理化性质检测,SEM扫描结果显示超细粉形貌规则,激光粒度仪测得粒径为70.5 nm;红外光谱检测所得结果证实超细粉化学性质较原粉无明显改变,不影响其药性;通过DSC、X-Ray检测所得结果显示超细粉与原粉相比晶体结晶度有所改变说明其水溶性增加。