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Chelakara et al1 incorporated polymer HPMC during agglomeration, which significantly enhanced the dissolution rate of mefenamic acid while incorporation of solubilizing agent lecithin improved the solubility of nabumetone.
Nocent et al2 described how the spherical crystallization process by QESD method can be applied to a water-soluble drug, salbutamol sulfate. The type of solvent, anti solvent, and emulsifier and the concentration of emulsifier to be used for the production of spherical particles with a size range 80-500 m were determined. Furthermore, the solvent/anti solvent ratio and the temperature difference between them (T) were studied. It was observed that, in the case of salbutamol sulfate, the T value has no influence on the formation of spherical particles. A very large metastable zone of salbutamol sulfate in water could explain this phenomenon. Finally, the influence of emulsifier concentration and of maturation time on the size of spherical particles was studied. The results showed that these two parameters must be fixed to control the size of the recovered particles
Aly et al3 observed the poor flow and compaction characteristics owing to its needle-like (acicular) crystalline structure and visco elastic properties of ibuprofen. A crystal change of ibuprofen's fine cohesive crystals into more spherical particles that possess better compressibility generally improves its processing into tablet and capsule forms. Hence developed spherical agglomerates of ibuprofen with optimized properties suitable for processing in solid dosage forms.
Puechagut et al4 Prepared agglomerated crystals of norfloxacin by a spherical crystallization technique using the ammonia diffusion system (ADS), Which made it possible to agglomerate amphoteric drugs like norfloxacin, which cannot be agglomerated by conventional procedures. The ammonia-water solution plays a role both as a good solvent for norfloxacin and as a bridging liquid, allowing the crystals' collection to take place in one step. It has been proven that the agglomeration mechanism follows three steps: first acetone enters into the droplets of ammonia-water (this emulsion is formed because of the system characteristics); dissolved norfloxacin is consequently precipitated while the droplets collect the crystals; simultaneously, a part of the ammonia contained in the agglomerates diffuses to the outer organic solvent phase, thereby forming the norfloxacin spherical agglomerates. The correct selection of solvents has enabled us to obtain a suitable stable crystalline shape.
Penttilia and Rasmuson5 studied agglomeration behaviour of paracetamol in acetone-toluene-water systems. The aim was to experimentally determine how the solvent composition influences the agglomeration tendency of paracetamol. They found that for the chosen solvent system there is one main region where paracetamol agglomerates: the region with large amounts of acetone (>65 wt %) and very small amounts of water (<4 wt %). The same behaviour can be observed both within the one-phase region and within the two-phase region. The experimental agglomeration results were compared with molecular simulations from literature. Both methods indicate that it is more likely for paracetamol crystals to agglomerate in organic systems than in aqueous systems.
Wagner and Gerhard6 prepared purified and crystallized riboflavin by a process that includes dissolving needle-shaped riboflavin of the stable modification. A form in an aqueous mineral acid solution at a temperature not exceeding about 30 oC with intensive intermixing. Active charcoal was then added to the resulting solution. After adsorption of the dissolved impurities from the solution onto the active charcoal, the solution containing the active charcoal was subjected to counter-current filtration over a ceramic membrane having a pore size of about 20 to about 200 nm. The resulting filtrate was treated with a five-to ten-fold amount of water (vol. /vol.) at a temperature not exceeding about 30oC The resulting precipitated, spherical crystals of riboflavin were then separated by centrifugation or filtration. If desired, the spherical crystals of riboflavin may be washed with water and subsequently dried. The purified and crystallized riboflavin formed by this process is suitable for pharmaceutical and foodstuff applications.
Subero-Couroyer et al7 prepared agglomerates from the suspension of salicylic acid fine particles. Agglomeration in suspension is a size enlargement method which facilitates the operations of solid processing such as filtration, transport and galenic while preserving the solubilisation properties of fine particles. With optimized quantity of binder injected and optimized injection mode, spherical and dense agglomerates can be obtained. They analyzed the first step of the agglomeration process, i.e. the wetting period, which corresponds to the injection of the binder liquid and its dispersion within the particle suspension. They studied the agglomeration of salicylic acid microparticles using chloroform as binder. They developed visualization cell in order to observe under optical microscope the interactions between a liquid binder droplet and the particles to be agglomerated. Clearly, an immersion mechanism was observed. Experiments were also carried out in a stirred vessel to visualize the wetting phase within the reactor using an image acquisition probe. The effect of the injection mode and quantity of binder on the agglomerate size was analyzed. A fast binder injection under high stirring and an optimum quantity of binder favor the formation of small agglomerates.
Daniel and Biscans8 proposed and validated a method for selecting the best wetting agent allowing obtaining spherical agglomerates during crystallization. This method was based on the so-called Washburn's test (capillary rise of liquids in a granular medium). Crystallization tests carried out at different conditions showed that the best results were obtained in the presence of n-hexane that was effectively found to be a better wetting liquid of the lobenzarit crystals than the other solvents.
Ikegami et al9 prepared spherical agglomerates of steroid KSR-592, consisting of fine primary drug crystals suitable for dry powder inhalation (DPI), by the spherical agglomeration method in liquid with a bridging liquid. They found that the particle size of primary crystals increased until the dispersing medium was saturated with the bridging liquid introduced to the system, whereas the spherical agglomeration of primary crystals continued even after the saturation. The growth rates of primary crystals and agglomerates increased with an increase in the temperature and/or a reduction in the agitation speed of the system. The growth of primary crystals in the spherical agglomerates was explained by a crystallization and fusion mechanism proposed by them. The primary crystals were mechanically stronger than their agglomerates so that the agglomerates were disintegrated easily into the primary crystals, which retained their original size, under the shear force generated on being mixed with carrier particles for DPI.
Martino et al10 prepared spherical propyphenazone crystals by an agglomeration technique using a three solvents system. After selecting the best propyphenazone solvent (ethyl alcohol), non-solvent (dematerialized water) and bridging liquid (isopropyl acetate), several of their ratios were tested by a Sheffé ternary diagram. Micromeritic properties of agglomerates such as flowability were improved and their compression behavior was investigated and compared to that of raw crystals. By compression and densification studies, along with tablet SEM analysis, that have been able to explain the compression mechanism of propyphenazone spherical crystals and have shown that their better tablet/ability can be due to the small size of individual particles in the agglomerates.
Kachrimanis et al11 prepared spherical crystal agglomerates of ibuprofen in the presence of EudragitÂ® S100 using the solvent-change (ethanol-water) method and applying different crystallisation conditions such as initial supersaturation under both increasing and constant drug: polymer ratios and different rates of stirring and cooling. The temperature in the crystallisation liquid and water consumption were recorded to determine the effects of polymer presence on crystallisation parameters (drug loading efficiency, crystal yield and mean 'apparent crystal growth' rate) and to correlate them with the physico mechanical properties of the agglomerates. They found that crystal yield and drug loading efficiency are not affected by the crystallisation conditions, while the mean 'apparent crystal growth' rate increases with initial supersaturation ratio and stirring rate; however, the cooling effect is stirring dependent, probably due to changes in the nucleation mechanism. The particle size of agglomerates decreases, while sphericity, surface roughness and intraparticle porosity increase with polymer presence. Also, particle size and sphericity decrease, while intraparticle porosity increases with initial supersaturation. The effects of EudragitÂ® addition on the fundamental particle properties were attributed to the habit and growth rate changes of ibuprofen microcrystals, as well as to their coating before binding into spherical agglomerates. The stirring rate effect on particle size is enhanced by slow cooling, and sphericity becomes maximal at slow cooling and fast stirring. The size and sphericity changes due to stirring and cooling are attributed to the polymer binding ability and to detachment of small fragments from the agglomerate surface. Flow or packing behaviour and densification of agglomerates at low compression were determined by the sphericity changes and their yield pressure by the brittleness due to the incorporated polymer.
Espitalier et al12 applied spherical crystallization process by the quasi-emulsion mechanism 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 was 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 them 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.
Kawashima et al13 investigated the parameters determining the agglomeration behaviour and micromeritic properties of spherically agglomerated crystals of acebutolol hydrochloride prepared by the spherical crystallization technique with a two- or three-miscible-solvent system (i.e., bridging liquid, good solvent, poor solvent). With decreasing amount of water (= bridging liquid) in the three-solvent system, the median diameter of agglomerated crystals increased, having a wider size distribution. When the composition of the system approached that of phase separation (= saturation with water), smaller sized agglomerates with a narrower size distribution were produced. The median diameter of agglomerates decreased with increasing content of ethanol (= good solvent) in the formulation. Spherically agglomerated crystals were produced evenly with the two-solvent system, i.e., water and isopropyl acetate (= poor solvent), in which the water played both the roles of bridging liquid and good solvent. The median diameter of agglomerates decreased with increasing agitation speed of the system.
Morishima et al14 investigated tabletting properties of bucillamine agglomerates prepared by two spherical crystallization techniques, i.e., a spherically agglomeration method and an emulsion solvent diffusion method. The flow and packing properties of agglomerates, represented in terms of the angle of repose and change in tapping density, were much improved by this technique compared with those of conventional crystals due to the spherical shape and smooth surface. Furthermore, spherical agglomerates possessed superior strength characteristics to conventional crystals; in particular, agglomerates obtained by the emulsion solvent diffusion method were compressed into compacts having considerable hardness without capping at high compaction pressure. The excellent compactibility of agglomerates was attributed to the fragmentation property and a greater degree of plastic deformation under compression.
Morishima et al15 modified the physical properties of bucillamine by the application of two spherical crystallization techniques - the spherical agglomeration and the emulsion solvent diffusion methods. The mechanisms of spherical agglomeration and crystallization were investigated. In the spherical agglomeration method, the microcrystalline drug precipitates were aggregated via liquid bridges of dichloromethane liberated from the crystallization solvent system. The growth rates were mainly determined by the amount of dichloromethane formulated. In the emulsion solvent diffusion method, the drug was precipitated within finely dispersed ethanol drops and these quasi-emulsion droplets were transformed into rigid spherical agglomerates. The mechanism determining the structure of the resultant agglomerates was clarified by measuring their mechanical strength. The crystal binding points within agglomerates produced by the spherical agglomeration method were distributed uniformly through the entire cross-section, whereas in the agglomerates prepared by the emulsion solvent diffusion method, they were localized in the agglomerate surface crust.
Kawashima et al16 produced direct agglomeration of sodium theophylline monohydrate crystals by salting out in a liquid in a stirred vessel. Addition of aqueous ethylene diamine 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.
Pawar et al17 obtained directly compressible agglomerates of ibuprofen-paracetamol containing a desired ratio of drugs using a Crystallo-co-agglomeration technique. Crystallo-co-agglomeration is an extension of the spherical crystallization technique, which enables simultaneous crystallization and agglomeration of 2 or more drugs or crystallization of a drug and its simultaneous agglomeration with another drug or excipient. Dichloromethane (DCM)-water system containing polyethylene glycol (PEG) 6000, polyvinyl pyrrolidone, and ethyl cellulose was used as the crystallization system. DCM acted as a good solvent for ibuprofen and bridging liquid for agglomeration. The process was performed at pH 5, considering the low solubility of ibuprofen and the stability of paracetamol. Loss of paracetamol was reduced by maintaining a low process temperature and by the addition of dextrose as a solubility suppressant. The agglomerates were characterized by differential scanning calorimetry, powder x-ray diffraction (PXRD), and scanning electron microscopy and were evaluated for tableting properties. The spherical agglomerates contained an ibuprofen-paracetamol ratio in the range of 1.23 to 1.36. Micromeritic, mechanical, and compressional properties of the agglomerates were affected by incorporated polymer. The PXRD data showed reduction in intensities owing to dilution and reduced crystallinity. Thermal data showed interaction between components at higher temperature. Ethyl cellulose imparted mechanical strength to the agglomerates as well as compacts. The agglomerates containing PEG have better compressibility but drug release in the initial stages was affected owing to asperity melting, yielding harder compacts. The agglomeration and properties of agglomerates were influenced by the nature of polymer.
Rasenack and Muller18 prepared and characterized different crystal forms of the analgesic drug ibuprofen. Various conditions were used for the crystallization: crystallization was carried out using the solvent change method, the temperature change method, and the solvent evaporation method. Crystals were grown from different solvents. Different crystal forms with different properties were observed: cubic, needle-shaped, and plate-shaped crystals were obtained. Spherical agglomeration occurs when crystallization is carried out in acetonitrile or methanol. Flowability of these spherical crystals is increased. All crystals were determined as isomorphic by differential scanning calorimetry and x-ray analysis--which queries doubtful results of recent publications. Properties like dissolution behavior and properties influencing the manufacturing of dosage forms--like flowability--differ. Thus the choice of the optimal preparation method influencing the crystal habit is important in manufacturing the drug ibuprofen.
Kachrimanis et al19 examined the effects of Eudragit(R) nature on the formation and spherical agglomeration of ibuprofen microcrystals when solvent change (ethanol-water) technique is applied. Four methacrylic polymers (Eudragit(R) S100, L100, RS, and RL), with different solubility and solubilizing ability, were used. The extrapolated points of maximum temperature deviation rate in crystallization liquid that reflect the maximum crystallization rate and the corresponding water addition were determined, as well as crystal yielding and incorporation of drug and polymer in the agglomerates. The physicomechanical properties of the agglomerates, such as size, sphericity, surface roughness and porosity, as well as flow and packing or compression behavior during tableting, were evaluated for different drug/polymer ratios. They found that crystal yield is greatly reduced in the presence of water-insoluble polymers and that formation of the microcrystals and incorporation of drug and polymer are affected by the polymer nature. Crystal formation changes are attributed to alterations in the metastable zone, whereas the changes in drug and polymer incorporation and crystal yield are caused by changes in the polymers' solubility and micellization. The size of agglomerates depends on the polymer nature and its interactions with the ibuprofen microcrystals formed. Sphericity, surface roughness, and intraparticle porosity of agglomerates increase, in general, with the presence of polymer owing to changes in habit and growth rate of the microcrystals and to their coating before binding into spherical agglomerates. The particle density or intraparticle porosity and size changes determine flow or packing behavior and densification of agglomerates at low compression.
Niwa et al20 modified adhesive and cohesive properties of chlorpromazine hydrochloride (CP) crystals to improve their powder processing, e.g., direct tabletting and microencapsulation, by agglomeration. Moreover, sustained-released gelling microcapsules of CP were devised to prolong the pharmacological effect. The spherical crystallization technique was applied to prepare agglomerates for direct tabletting and microencapsulation to use them as core materials. The ethanolic solution dissolving CP was poured into a stirred cyclohexane, yielding spherically agglomerated crystals. The resultant agglomerates were free-flowing and easily packable spheres with average diameters of 200 to 1000 microns. The agglomerates reserved the high compressibility of the original powder having a small particle size (14 microns). The compression behavior represented by Heckel's equation suggested that the agglomerates were disintegrated to individual primary crystals at low compression pressures, and then they were closely repacked and plastically deformed at higher pressures. After agglomeration, microencapsulation was continuously performed in the same batch by a phase separation method. Coacervate droplets produced by pouring cyclohexane into a dichloromethane solution, dissolving polyvinyl acetate as a coating polymer, were added to the crystallization system under stirring, to prepare the microcapsules. By filling the microcapsules in gelatin hard capsules or tabletting them, their drug release rates became retarded compared with the physical mixture treated in the same way, having the same formulation as the microcapsules. This phenomenon was due to the gelation of polyvinyl acetate of the microcapsules in the dissolution medium, whose glass transition temperature is very low. This novel sustained-release dosage form is termed "gelled microcapsules."
Lasagabaster et al21 found suitable proportions of the solvent mixture benzene: methanol: aqueous hydrochloric acid to yield the spherically agglomerated crystals of cyanin. The physicochemical properties and dissolution rate of the agglomerates, in comparison with the crystals obtained by a conventional method, have been analyzed. 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 color 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 Hygroscopicity with subsequent technological and stability advantages.
Teipel et al22 prepared spherical ammonium dinitramide (ADN) particles of different sizes with a narrow particle size distribution. The crystallization process consists of two stages. In the first stage, molten ADN is dispersed in a continuous phase in which ADN is insoluble. The droplet size produced can be controlled by varying the amount of mechanical energy supplied to the two-phase system. In addition to discussing the influence of the different process parameters, such as dispersion rate, dispersion power, emulsification time etc. this paper also reports the influence of emulsifying agents and the rheological behavior of the continuous phase. In the second stage of the process, crystallization of the emulsified ADN droplets to spherical, solid particles is obtained by reducing the temperature of the system. The process described enables production of spherical ammonium dinitramide particles with mean sizes from 10 Âµm to 600 Âµm. The product quality of the crystallized ADN, which is also discussed in this paper, was determined using various analysis techniques, including differential scanning calorimetry (DSC), IR spectroscopy, and ion chromatography and laser light diffraction spectrometry.