Agglomeration behavior of anhydrous L-ornithine-L-aspatate crystals during semi-batch drowning-out crystallization

Crystallization of L-ornithine-L-aspartate (LOLA) by drowning out was carried out to produce the anhydrous form of agglomerates. The primary crystal size in the agglomerate remained unchanged after completion of the crystallization. The LOLA aqueous solution introduced into the system was immediately dispersed and cluster coagulated on the surface of the crystals. On the surface of the crystals, a cluster reached critical nuclei size, nucleated and intergrowth to form agglomerates. It was proposed that a spherical agglomeration occurred during secondary nucleation by coagulation model and intergrowth. The agglomerates size and size distribution were varied with the process parameters. The agglomerate sizes of LOLA crystals appeared to be ruled not only by secondary nucleation rate but also by the mass of suspended agglomerates. Moreover, the agglomeration rates of fine particles were higher than the agglomeration rates of large agglomerates. Using these properties, the uniform agglomerates size distribution could be obtained.     

The physicochemical parameters determining the size of agglomerate prepared by the wet spherical agglomeration technique

Lactose samples of five different particle sizes from 31 to 261 μm dispersed in chloroform were agglomerated with a small amount of saturated aqueous lactose solution which acted as a bridging liquid to wet the particles preferentially. The effects of raw particle size and the amount of bridging liquid on the average size of resultant agglomerate were investigated.

The agglomerate size increased with decreasing size of lactose. This effect was enhanced by increasing the amount of bridging liquid for lactose less than 79 μm. A linear correlation on a log—log plot was observed between the agglomerate size and the saturation ratio of bridging liquid. The slope increased with decreasing particle size of lactose. The size distribution of agglomerates was also determined for the particle size of lactose and the amount of bridging liquid used. The physicochemical properties of the bridging liquid, i.e. contact angle and interfacial tension, were also taken into account for interpreting the agglomerate size. The correlation between the agglomerate size and the above parameters was represented quantitatively by eqn. (10) in the text. The parameter n, which varies directly with agglomerate size, increased with increasing saturation ratio, or with decreasing lactose particle size.     

Adhesion force measurement of a DPI size pharmaceutical particle by colloid probe atomic force microscopy

The method to determine the adhesion characteristics of fine drug particles for dry powder inhalation (DPI) was established using a colloid probe which mounted a 1-3 μm drug particle on a commercial atomic force microscope (AFM) cantilever. A new preparation system of colloid probes for fine particles smaller than 2.5 μm in diameter was developed with the aid of a micromanipulator and a video microscope. Using this colloid probe, adhesion force distribution between a spherical polycrystalline drug particle and a plate of lactose monohydrate representing for DPI carrier materials or stainless steel for device wall materials was measured. Atmospheric humidity as well as the material and surface roughness of a target plate affected the determined adhesion force. With increasing surface roughness of a lactose plate, the adhesion force between a drug particle and the plate distributed more widely and their mean value decreased. Adhesion force increased meaningfully with atmospheric humidity. Adhesion force for stainless steel was higher than that for lactose.     

An experimental study of the kinetics of the spherical crystallization of aylline sodium theophylline monohydrate

Direct agglomeration of sodium theophylline monohydrate crystals produced by salting out in a liquid was carried out in a stirred vessel. Addition of aqueous ethylenediamine solution of theophylline and sodium chloride solution to a mixture of chloroform and ethanol (mixing ratio of chloroform:ethanol = 0.1 to 0.505:1) with agitation yielded spherically agglomerated crystals of sodium theophylline monohydrate. The diameter of the spherical agglomerate decreased with increase in agitation speed of the chloroform fraction in the mixture. The spherical crystallization process was described by first-order kinetics. The rate constant was a function of the agitation speed of the system and the difference between the residual concentration of theophylline in the solvent in the initial and the equilibrium state.     

Is spherical crystallization without additives possible?

The quasi-emulsion solvent diffusion method of spherical crystallization consists in producing in one step crystallization and agglomeration of small crystals in droplets of an emulsion. Additives are generally used to stabilize the emulsion before crystallization. The aim of this study is to investigate the feasibility of spherical crystallization without surfactant. Experiments were performed in an automated batch laboratory scale crystallization process to study the influence of the process operating conditions on the structure of the particles obtained. The results clearly show that, for the experiments performed two types of particles are formed: primary spherical particles and secondary agglomerates. The pattern of the primary particles, observed under scanning electron microscopy, suggests that these particles results from a spherulitic crystal growth mechanism inside the droplet. The secondary agglomerates results of the agglomeration of the spherical particles. In addition, a set of experiments were performed with carefully selected solvents to study the influence of the crystallization solution/water interfacial tension, at constant hydrodynamic conditions and supersaturation level. The results of these experiments demonstrate that the interfacial tension is not a key parameter for designing such a process.     

Preparation of spherical wax matrices of sulfamethoxazole by wet spherical agglomeration technique using a CMSMPR agglomerator

Spherical wax matrices of sulfamethoxazole were prepared by a wet spherical agglomeration technique using a model continuous mixed suspension mixed product removal (CMSMPR) agglomerator to develop a practical continuous operation system. The average diameter of products increased at the initial stage of operation until reaching a maximum at 5 to 7 minutes elapsed after starting. This maximum point roughly corresponded to a half of average retention time. Thereafter the particle size decreased gradually and reached the equilibrium state. The average size of products obtained at steady state decreased on decreasing the feeding rate of bridging liquid, but increased on decreasing the agitation speed and the feeding rate of aqueous suspension. The rate of agglomeration was analysed using the concept of population balance proposed by Randolph and Sikdar. The agglomeration rate increased with increase of particle size for sizes above 200 – 300 μm. For sizes below 200 μm, the agglomeration rate was almost independent of particle size.     

Particle design for dry powder inhalation via binderless powder coating by pressure swing granulation

Novel formulation for dry powder inhalation (DPI) particularly appropriate for very dilute drug concentration was developed based on the pressure swing granulation (PSG) technology. PSG was applied to the granulation of excipient lactose particles and to the coating/dusting of lactose granules with fine model drug particles. Size distribution and granule strength as well as the dispersibility of the drug particles for DPI were found to be successful for practical use. The drug particles dispersed into the respirable aerodynamic size range of 1-7 μm from the E-haler® was 53.9% for 1% coating/dusting (i.e. 1% drug in product granules) and 46.3% for 2%. E-haler® was capable of emitting 89.8% and 83.2% of drug particles charged for cases for 1% and 2% coatings, respectively.     

Spherical agglomeration in a conical drum

The spherical agglomeration process is a means of size enlargement in which agitated particles, suspended in a liquid, are bonded together by a second liquid, which will wet the solid surfaces and be immiscible with the suspending medium. A process is described in which agglomeration takes place in a cone shaped vessel, rotating horizontally about its symmetric axis. The cone configuration of the agglomerator imparts a longitudinal impulse to the charge, which is most effective on the largest particles. This causes a size classification within the cone, with the largest agglomerates congregating at the base. The result is the continuous production of uniformly sized, highly spherical pellets. The factors affecting agglomerate growth and size are outlined and discussed.     

Determination of particle size distribution of salt crystals in aqueous slurries

A method for determining particle size distribution of water-soluble crystals in aqueous slurries is described. The salt slurries, containing sodium salts of predominantly nitrate, but also nitrite, sulfate, phosphate, aluminates, carbonate, and hydroxide, occur in radioactive, concentrated chemical waste from the reprocessing of nuclear fuel elements. The method involves separating the crystals from the aqueous phase, drying them, and then dispersing the crystals in a non-aqueous medium based on nitroethane. Ultrasonic treatment is important in dispersing the sample into its fundamental crystals. The dispersed crystals are sieved into appropriate size ranges for counting with a HIAC brand particle counter. A preponderance of very fine particles in a slurry was found to increase the difficulty of effecting complete dispersion of the crystals because of the tendency to retain traces of aqueous mother liquor. Traces of moisture produce agglomerates of crystals, the extent of agglomeration being dependent on the amount of moisture present. The procedure is applicable to particles within the 2 – 600 μm size range of the HIAC particle counter. The procedure provides an effective means for measuring particle size distribution of crystals in aqueous salt slurries even when most crystals are less than 10 μm in size.     

球形木素基正离子交换树脂的制备与性能

以木素磺酸钙为原料,在一种价廉无毒的分散介质中通过反相悬浮聚合制备了球形木素基正离子交换树脂。研究了分散介质和分散剂用量、聚合温度及搅拌速度等多种因素对聚合反应和成球效果的影响,并对交换树脂的形貌、粒径、含水量、密度、交换容量及吸附性能进行表征与测;定。结果表明,在实验室条件下,交换树脂对;Cr^3＋的饱和吸附量达到59．28mg／g（干树脂）。     

Particle design Part B: batch quasi-emulsion process and mechanism of grain formation of ketoprofen

This study deals with the spherical crystallization process by the quasi-emulsion mechanism, applied to a pharmaceutical. The objective is to produce spherical agglomerates made of a number of small crystals of the drug, having properties adequate for direct compression when manufacturing tablets. The aim of this work is to make the link between the process and these properties. The different steps occurring in the process are the formation of an emulsion whose droplets are made of the drug dissolved in a solvent, the creation of the supersaturation of the drug in the droplets by mass and heat transfer and the nucleation, growth and agglomeration of drug crystals inside the droplets. The process has been carried out in a batch laboratory scale device. The variation of the operating parameters on the one hand and of the relative proportions of the various components on the other have enabled us to determine the influence on the internal and external structures of the produced agglomerates which influence the ability to be compressed. The identification of the phenomena occurring has led to a proposed mechanism for the formation of the agglomerates.     

Preparation of spherically agglomerated crystals of the 3,5-diglucoside of cyanidin (cyanin)

Suitable proportions of the solvent mixture benzene:methanol:aqueous hydrochloric acid to yield the spherically agglomerated crystals of cyanin have been found. The physicochemical properties and dissolution rate of the agglomerates, in comparison with the crystals obtained by a conventional method, have been analysed. No change in the crystalline form of the basic crystals was found in acid conditions, after agglomeration. The dissolution rate of spherical agglomerates did not decrease as much as predicted from their low specific surface areas because of their improved wettability. The crystallization speed would not only avoid colour loss during the isolation and purification of anthocyanins from their natural sources, but also would increase production, save time and cost. On the other hand, a decrease in the specific surface areas will reduce powder hydroscopicity with subsequent technological and stability advantages.     

流化床液固共存区域团聚结构表观黏结特性

通过TEB雾化喷嘴制造流化床团聚结构,利用层叠筛分方法对原始颗粒、成核聚团、黏结聚团、糊状聚团4种结构加以尺度区分,成功地实现了不同团聚阶段的分区域辨识.实验选取团聚结构最为稳定的异质共存区域为研究对象,对其黏结过程的表观结构特性和组织特性进行了分析.研究结果表明:成核聚团是诱导黏结聚团产生及增长的基本元素,团聚结构的黏结增长导致结构孔隙度随之增加,随着注入液体对孔隙结构的不断填充,结构逐渐趋于饱和,共存区域内任何尺度的团聚结构黏结增长速率均相同;尽管在异质共存区域内的团聚结构处于同一流化条件下,成核聚团及黏结聚团两者的水分含量及固体体积分数却表现出了明显的差异.     

The influence of additives on the primary particle nucleation and agglomeration in poly(vinyl-chloride)

The formation and agglomeration of PVC primary particles were studied in bulk polymerization experiments. In the absence of additives, the primary particles started to agglomerate at low conversions. The agglomeration conversion, as well as the size of the agglomerated particles, decreased when the agitation speed increased. At the highest speed tested, the agglomeration started already at 0.05 percent conversion. The primary particle size was about 0.16-0.18 μm, and seemed to be constant in the conversion interval studied (up to 5 percent). This indicated that the nucleation rate of primary particles was almost constant and that the growth rate of agglomerated particles was very low. The addition of sorbitan monolaurate produced a decrease in primary particle size. Polymeric additives such as PMMA, EVA, and PVAc stabilized primary particles against agglomeration but had no marked effect on the primary particle size. The monomer-soluble fraction of poly(vnyl alcohol-b-vinyl acetate) with high content acetate groups did not affect either the particle size or the agglomeration process.     

Design of the spherical agglomerate size in crystallization by developing a two-step bridging mechanism and the model

Spherical agglomeration technology can produce high-performance spherical particles in a single crystallization unit, although it is still challenging to control the particle size and shape. To solve this issue, a two-step bridging (TSB) mechanism containing a preconditioning period, size period, and shape period is proposed. The dynamic balance among the forces of adhesion, dispersion, and capillary action in the multi-liquid phases plays a key role. This is fully considered to establish the TSB-based thermodynamic size model and particle design framework by weighting the force action regions in multi-liquid phases with dynamic composition. The spherical agglomerates of benzoic acid, celecoxib, and salicylic acid with narrow particle size distributions and tunable particle size ranges of 2000–5000, 800–3500, and 1500–4500 μm, respectively, were designed and prepared successfully, showing good correlation with the calculation, which is superior to the reported methods and indicates that the mechanism has certain universality and guiding significance.     

Influences of seed crystals on agglomeration phenomena and product purity of m-chloronitrobenzene crystals in batch crystallization

Changes in the fraction of agglomerates, agglomeration kinetics and product purity of m-chloronitrobenzene (CNB) crystals with the number and size of seed crystals were examined in batch crystallization experimentally, and influences of seed types (ground and well-defined) on agglomerate purities were discussed. From the fraction of agglomerates and agglomeration kinetics, it was found that agglomeration occurred more frequently when the number of seed crystals was larger and its size was smaller. The amount of purity decrease by agglomeration was smaller for the smaller number of seeds and for the larger ones. As the number of the elementary crystals constituting agglomerates was smaller, the purity of agglomerates was higher. With ground crystals, more frequent agglomeration occurred and the purity of agglomerates was lower than those for the well-defined crystals.     

Kinetics of fluidized bed spray agglomeration for compact and porous particles

The effect of the primary particle porosity during the formation of agglomerates in spray fluidized beds is presented in this study. The method is based on the single micro-interactions occurring within the fluidized bed such as inter-particle collisions, droplet spread on the particle surface, aging of the deposited droplets and particle coalescence. The porous character of the particles is expected to directly affect the aging process of the deposited binder layer by penetration into the pores of the substrate. The droplet penetration process is experimentally analyzed by single droplet deposition on spherical, porous alumina particles. The results indicate that the penetration process is mainly governed by the viscosity of the liquid and that at relatively low viscosities, droplet penetration is fast. For highly viscous liquids, the penetration velocity slows down and an additional mechanism, namely drying becomes important. A combined imbibition–drying model is developed and included into a comprehensive stochastic agglomeration model that allows the simulation of agglomerate formation in a batch process. Lab-scale agglomeration experiments with porous and non-porous particles are carried out in an attempt to validate the general tendencies predicted by the main agglomeration model. The results show that the agglomeration rate for porous particles is significantly reduced due to the losses of deposited droplets into the pores of the primary particles; this tendency is much more pronounced at low binder viscosities.     

Morphology of Hydrophobic Agglomerates of Molybdenite Fines in Aqueous Suspensions

In this work the morphology of agglomerates formed in the hydrophobic agglomeration of molybdenite fines in aqueous suspensions has been studied by measuring fractal dimension with image analysis method. The results have shown that the morphology closely correlated with the mechanical conditioning in the hydrophobic agglomeration. The higher the stirring speed and the longer the stirring, the more spherical and more compact the agglomerates. Also, kerosene addition could make the agglomerates to be more spherical and compact.     

Control of the agglomeration of crystals in the reactive crystallization of 5-(difluoromethoxy)-2-mercapto-1H-benzimidazole

5-(Difluoromethoxy)-2-mercapto-1H-benzimidazole (DMB) was precipitated by adding acetic acid to the DMB sodium salt solution. The spherical agglomeration of DMB during the reactive crystallization in a batch crystallizer was monitored by real-time Particle Video Microscope (PVM). We found that the low feeding rate of acetic acid, high crystallization temperature, low agitation rate or adding seed crystal can facilitate the formation of spherical agglomerates. By using a simple model, the mean crystal agglomerate size of DMB thus predicted is generally in agreement with the experimental data. In addition, the crystallization process of DMB was optimized by a new control strategy of supersaturation to avoid disadvantages brought by agglomeration.