Spherical Crystallization Process Research Articles

Spherical agglomerates of lactose as potential carriers for inhalation

We report here on spherical lactose agglomerates as potential carriers for inhalation applications. Micromeritic properties of three spherical lactose agglomerates (SA-A, SA-B, SA-C) and a standard lactose inhalation grade carrier (Lactohale 100; LH100) were evaluated and compared. Ordered mixtures with micronized salbutamol sulfate as the model active pharmaceutical ingredient (API) and lactose carriers at two drug loadings (2 wt%, 5 wt%) were prepared, and in-vitro aerosolization performance was assessed. The spherical crystallization process led to particles with tailored micromeritic properties. These had larger specific surface area and greater fine fraction < 10 µm, compared to LH100, due to their coarse morphology. Their properties were reflected in the flowability parameters, where two types of spherical agglomerates of lactose showed more cohesive behavior compared to the other lactose grades. Blend uniformity showed improved homogeneous distribution of the API at higher drug load. In-vitro aerosolization tests showed that the spherical agglomerates of lactose enhanced the dose of API, compared to LH100. SA-B and SA-C showed significantly higher fine particle fractions at low drug load compared to the others, whereas overall, the largest fine particle fraction was for SA-B at high drug load. The carrier material attributes related to particle size, specific surface area, compressibility, flowability (cohesion, flow function), and air permeability were critical for aerosolization performance.

Design of Experiments for Optimization of the Lactose Spherical Crystallization Process

This study provides a comprehensive assessment of the parameters of the spherical crystallization process and their impact on the micromeritic properties of lactose spherical agglomerates. A recently introduced definitive screening design was used to study various process parameters, with particular focus on building predictive models. The parameters included were: lactose solution concentration; volume ratio between the antisolvent and the whole crystallization system; crystallization system temperature; velocity of the addition of the lactose water solution; agitation velocity; and agitation time after whole addition of the lactose solution. Their effects on process yield, particle size parameters D10, D50 and D90, particle size distribution, morphological properties (roundness, solidity) and Hausner ratio were studied. Active effects were identified for all of these responses, with quadratic and interaction effects included. Lactose concentration, volume ratio, crystallization system temperature, and agitation velocity were identified as critical process parameters. For every response, a statistical model was built, where those for Hausner ratio, yield and roundness provided the best predictive performances. Based on these models, D10 and yield were successfully optimized. Definitive screening design proved as useful especially in the screening phase; however, additional experiments are needed to build models with high predictive power for all of these responses.

Exploring the effect of PVP on the spherical agglomeration process and micromeritic properties of ascorbic acid

Spherical agglomerated crystals of ascorbic acid (AA) have been prepared with a trace of polyvinylpyrrolidone (PVP) by a spherical agglomeration method. The process of spherical crystallization has been monitored online with a particle vision and measurement (PVM) probe. The effect of PVP on the metastable zone width of ascorbic acid in aqueous solutions has been characterized by a laser method. Hydrogen bonding interactions between AA and PVP have been identified by Fourier-transform infrared spectroscopy and 1H nuclear magnetic resonance. Differential scanning calorimetry and powder X-ray diffraction measurements have shown that the prepared spherical crystals still exhibited a crystallin nature. The micromeritic properties, namely flowability, packability, and compressibility, were significantly improved compared to those of the pure drug crystals. In this study, we have explored the mechanism of the spherical crystallization process in the presence of the polymer, and the beneficial effect of the polymer on the micromeritic properties of crystals of ascorbic acid.

Spherical Crystallization and the Mechanism of Clopidogrel Hydrogen Sulfate

AbstractClopidogrel hydrogen sulfate is a famous antiplatelet agent for vascular disease. Forms I and II can be used as medicine. However, both forms exhibit low density and flowability. In addition, form I shows low polymorph stability. To solve these problems, spherical crystallization technologies were developed for the two forms. For form I, the mechanism was studied and turned out to be 2D nucleation and spherulitic crystal growth. In case of form II, the spherical crystallization process was based on agglomeration. The influence of temperature, acid, and crystal seed were investigated. The optimized spherical forms I and II showed much higher density and flowability as well as high polymorph stability.

A Review on Spherical Crystallization Mechanisms and Characterization

Spherical crystallization is a novel agglomeration technique that can transform crystals directly into a spherical form during the crystallization process itself. In the spherical crystallization process, crystal formation, growth and agglomeration occur simultaneously within the same system. In this method, a third solvent called the bridging liquid is added in a smaller amount to purposely induce and promote the formation of agglomerates. Spherical agglomerates can be manufactured by four techniques, namely, spherical agglomeration, quasi emulsion solvent diffusion, ammonia diffusion and neutralization method. Spherical crystallization is influenced by solvent system, solubility, feeding rate, agitation, residence time, temperature and initial size of the crystals formed. Characterization includes mainly particle size distribution, morphology, porosity and mechanical properties such as compressibility, tensile strength, mechanical strength and elasticity. The spherical agglomerates prepared using spherical agglomeration possesses good physico-mechanical properties like spherical shape, mechanical strength, compressibility and low elastic recovery.

PH-Switchable vitamin B9 gels for stoichiometry-controlled spherical co-crystallization.

Vitamin B9 gels were found to be pH-switchable by adding triethylamine or acetic acid. Such recyclable gels can be used as novel co-crystallization media, resulting in four stoichiometric vitamin C co-crystals. Under highly supersaturated conditions, uniform microspheres of (VC)·(NA) with different particle sizes were obtained through a spherical crystallization process.

Application of 22 level factorial design in formulation and evaluation of spherical agglomerates by solvent change method

Candesartan cilexetil is an antihypertensive drug, which exhibit poor water solubility, poor flowability and poor dissolution. The main aim of study was to improve the dissolution of Candesartan cilexetil. Spherical agglomerates containing Candesartan cilexetil were prepared by solvent change method. By using ternary phase diagram ratio of solvent addition was maintained. Drug was dissolved in solvent blend of methanol (good solvent), water (poor solvent), dichloromethane (bridging liquid). The formulated agglomerates were characterized by scanning electron microscopy (SEM), differential scanning calorimeter (DSC), x-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR) and In-vitro dissolution studies. It was found that the B2 batch has shown better results with respect to all the parameters. Spherical agglomeration and crystallization process can be used to enhance water solubility, flowability and thereby dissolution.

Effect of process variables on physicomechanical properties of the agglomerates obtained by spherical crystallization technique

This study deals with the spherical crystallization process by the spherical agglomeration mechanism to obtain agglomerates with improved physicomechanical properties. The effect of temperature and speed of agitation on the micromeritic, mechanical and dissolution behavior of the agglomerates were investigated in order to make the link between the variables and properties of the agglomerates. Primary properties of the agglomerates were also evaluated by powder X-ray diffraction (XRPD) and differential scanning calorimetry (DSC). The mean particle size, flowability, bulk density and drug release of the agglomerates were found to be affected by either of the two variables, but there is no significant influence found on the compactibility properties. Hence, both variables must be fixed to obtained dense and well-shaped agglomerates adequate for direct tableting. XRPD and DSC results showed that during the agglomeration process, carbamazepine Form III changed to Form I.

Evaluation of physico-mechanical properties of drug-excipients agglomerates obtained by crystallization

Spherical crystallization (SC) of carbamazepine (CBZ) was carried out for preparation of the agglomerates using the solvent change method. The potential of the intraagglomerate addition of sodium starch glycolate (SSG) as a disintegrant agent and povidone (PVP) as a hydrophilic polymer was also evaluated. The process of SC involved recrystallization of CBZ and its simultaneous agglomeration with additives. An ethanol:isopropyl acetate:water system was used where isopropyl acetate acted as a bridging liquid and ethanol and water as good and bad solvents, respectively. The agglomerates were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (XRPD), and Scanning electron microscopy and were evaluated for yield, flowability, disintegration time and drug release. CBZ agglomerates exhibited significantly improved micromeritic properties as well as dissolution behavior in comparison to conventional drug crystals. The dissolution rate of drug from agglomerates was enhanced by inclusion of SSG, while addition of PVP to CBZ/SSG agglomerates led to reduction in the release rate of CBZ even below that of the conventional drug crystals. SC process can be considered as a suitable alternative to conventional granulation process to obtain agglomerates of CBZ with excipients with improved micromeritic properties and modified dissolution rate.

Investigation on the Spherical Crystallization Process of Cefotaxime Sodium

In order to obtain satisfied spherical agglomerated product and overcome the incomplete removal of the impurity during the traditional spherical agglomerated process, a new strategy incorporating the spherical agglomeration technique and the drowning-out crystallization process, by which the impurities can be efficiently removed, was performed. A triangular phase diagram showing the phase equilibrium of ternary solvent mixtures used in the process of spherical crystallization was constructed and the real-time spherical crystallization process was investigated by means of particle vision measurement and microscopy. The operation conditions, including the chloroform content, temperature of the system, and agitation speed, were also investigated in order to optimize the spherical crystallization process. The results of HPLC and GC indicated that the purity and residual solvents of the experimental agglomerated product can meet the requirements for use. Simultaneously, their bulk density, flowability, and com...

AN IMPROVEMENT OF PHYSICOMECHANICAL PROPERTIES OF CARBAMAZEPINE CRYSTALS

In order to improve particle properties, new processes combining granulation and crystallization are being developed. This work deals with the spherical crystallization process by the quasi-emulsion mechanism applied to carbamazepine, a pharmaceutical drug. The aim of the present study was to produce of spherical grains made of mall crystals of a drug that have adequate properties for direct compression when manufacturing tablets. Crabamazepine was crystallized under different conditions and the obtained spherical crystals were examined in terms of flow properties, particle size analysis, compression and dissolution behaviors. Physical characteristics of the crystals were studied for the morphology of crystals using scanning electron microscope, for the identification of polymorphism by x-ray powder diffraction and for thermodynamic properties using differential scanning calorimetry. The results showed that the agglomerates produced at 5°C under stirring rate of 300 rpm had superior flow than other agglomerates. Further more the results suggest that agglomerates flow and pack smoothly from the hopper into the die and that tablets formed from agglomerates attain uniformity in weight due to spherical shape of the treated samples. The results showed that, generally, the treated carbamazepine samples (agglomerated forms) possessed superior mechanical and better dissolution rate characteristics to untreated crystals. The results of DSC and x-ray showed that untreated sample and agglomerates were form III and form I of carbamazepine respectively.

Improved flowability and compactibility of spherically agglomerated crystals of ascorbic acid for direct tableting designed by spherical crystallization process

Spherically agglomerated crystals of ascorbic acid with improved compactibility for direct tableting were successfully engineered by the spherical crystallization technique. In this process, ascorbic acid crystals were precipitated by a solvent change method, followed by their agglomerations with the emulsion solvent diffusion (ESD) or spherical agglomeration (SA) mechanism. The micromeritic properties, such as flowability and packability of the spherically agglomerated crystals were preferably improved for direct tableting. Under static compression, the acceptable compact (tablet) with a sufficient strength was produced successfully without capping, although the capping occurred with the original unagglomerated crystals. The improved compaction properties of the agglomerated crystals were due to their fragmentation and plastic deformation occurred significantly during compression. This mechanism was supported by higher stress relaxation and less elastic recovery of the compact of agglomerated crystals. It was also found that the spherically agglomerated crystals were tableted directly without capping using a single punch machine under dynamic compression, although the tensile strength of resultant tablet decreased in tolerable degree with increasing punch velocity.

Definition of a Solvent System for Spherical Crystallization of Salbutamol Sulfate by Quasi‐Emulsion Solvent Diffusion (QESD) Method

In this paper we describe how the spherical crystallization process by QESD method can be applied to a water-soluble drug, salbutamol sulfate. The type of solvent, antisolvent, and emulsifier and the concentration of emulsifier to be used for the production of spherical particles with a size range 80-500 microm are determined. Furthermore, the solvent/antisolvent ratio and the temperature difference between them (Delta T) are studied. It was observed that, in the case of salbutamol sulfate, the Delta 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 is studied. The results show that these two parameters must be fixed to control the size of the recovered particles.

Development of spherical crystals of acetylsalicylic acid for direct tablet-making.

The production of spherical crystals has recently gained great attention due to the fact that the crystal habit (form, surface, size, etc.) can be modified during the crystallization process. Spherical crystals of ASA were developed by non-typical and typical spherical crystallization techniques. The non-typical spherical crystallization process (conventional stirred tank method) resulted in few monocrystals and non-spherical crystal agglomerates. The typical spherical crystallization process was carried out by the three solvent-system (ethanol-water-carbon tetrachloride). The products were qualified by morphological study, NIR investigation, salicylic acid content, dissolution rate, studies on flowability, compactibility, cohesivity and tablettability. The results demonstrate that only typical spherical crystallization can be recommended for the production of spherical crystals of ASA. Only product made by this technique shows excellent flow properties and favourable compactibility, cohesiveness and tablettability values.

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.

Particle design Part A: Nucleation kinetics of ketoprofen

This work is part of a study of the spherical crystallization process by the quasi-emulsion method. The induction time of ketoprofen in acetone + ketoprofen solutions and in solutions of acetone + water + ketoprofen have been experimentally determined. Ketoprofen presents a large metastable zone in the case of primary nucleation and a very narrow metastable zone in the case of secondary nucleation. The rate of primary nucleation in pure acetone has been measured and is correlated by the equation 1.0 × 1036 exp (-2.68 × 106/T3 × ln2S) (in number m3 s−1). The physico-chemical properties—phase diagram of the system acetone + water + ketoprofen involved in the process-are given. An experiment to study crystallization into a droplet is presented.

Modelling of the Mechanism of Formation of Spherical Grains Obtained by the Quasi-Emulsion Crystallization Process

In order to improve particle properties, new processes combining granulation and crystallization are being developed. This present work deals with the spherical crystallization process by the quasi-emulsion mechanism applied to a pharmaceutical drug, ketoprofen. The different steps occurring in the process are first the formation of an O/W emulsion, then the creation of the super saturation of drug into the droplets by mass transfer and heat transfer, and finally the nucleation, growth and agglomeration of drug crystals inside the droplets. The mechanism of formation has been modelled in order to aid control of the size, shape and internal structure of grains as a function of the droplet size.

医薬品製剤への応用をめざした球形晶析法（Ｓｐｈｅｒｉｃａｌ Ｃｒｙｓｔａｌｌｉｚａｔｉｏｎ Ｐｒｏｃｅｓｓ）の開発

医薬品製剤への応用をめざした球形晶析法（Ｓｐｈｅｒｉｃａｌ Ｃｒｙｓｔａｌｌｉｚａｔｉｏｎ Ｐｒｏｃｅｓｓ）の開発

Development of spherical crystallization technique and its application to pharmaceutical systems

A novel agglomeration technique, termed “Spherical Crystallization Process”, which can transform directly the fine crystals produced in the crystallization or the reaction process into a spherical shape was developed. By this technique, needle like crystals such as salicylic acid were transformed into free flowing and directly compressible agglomerates. Spherically agglomerated aminophylline crystals were obtained directly from the reaction system, which could reduce the preparation processes, e.g. synthesis, crystallization and agglomeration, into only one step. Sodium theophylline monohydrate agglomerates were prepared by salting out, the rate process of which was described by a first order kinetics. Agglomerated crystals of ndw complex of indomethacin-mepirizole were prepare with this technique; an improved therapeutic effect of the resultant crystals was expected.

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.