Spherical Crystallization Technique Research Articles

Preparation of microparticles of naproxen with Eudragit RS and Talc by spherical crystallization technique

Microparticles of naproxen with Eudragit RS and talc were prepared by the spherical crystallization technique, i.e. quasi-emulsion solvent diffusion method. The obtained microparticles were evaluated by micromeritic properties, yield, encapsulation efficiency, drug physical state and dissolution rate of drug. The influence of formulation factors and preparation condition (drug: polymer ratio, talc: polymer ratio, SLS concentration, stirring speed) on the properties of the microparticles were also examined. The resultant microparticles were finely spherical and uniform with high incorporation efficiency and yield. Greater encapsulation efficiency was obtained by increasing the drug: polymer ratio and talc: polymer ratio and by reducing the SLS %. The dissolution rate of naproxen from microparticles was enhanced significantly with increasing the ratio of drug: polymer and stirring rate, and sustained by increasing SLS % in crystallization medium. The results of X-ray diffraction and differential scanning calorimeter analysis indicated that naproxen was highly dispersed in microparticles, so as amorphous state. Studies carried out to characterize the micromeritic properties of formulations, such as flowability and packability showed that microparticles were suitable for further pharmaceutical manipulation (e.g. capsule filling). Hence, the spherical crystallization technique can be successfully used for obtaining spherical microparticles, generating a heterogeneous matrix system and providing sustained drug release.

Preparation and, in vitro, preclinical and clinical studies of aceclofenac spherical agglomerates

Aceclofenac agglomerates were prepared by spherical crystallization technique using a three solvent system comprising acetone: dichloromethane (DCM): water (bridging liquid, good solvent and bad solvent, respectively). Hydroxypropyl methylcellulose-50 cps (HPMC) in different concentrations was used as hydrophilic polymer. The effect of speed of rotation and amount of bridging liquid on spherical agglomeration were studied. The agglomerates were subjected to various physicochemical evaluations such as practical yield, drug content, particle size, loss on drying, porosity, IR spectroscopy, differential scanning calorimetry, X-ray diffraction studies, relative crystallinity, scanning electron microscopy, micromeritic properties, solubility and dissolution studies. The agglomerates showed improved micromeritic properties as well as dissolution behaviour in comparison to conventional drug crystals. The optimized agglomerates (F-9) showed good sphericity as well as high drug release, and hence they were compressed into tablets by direct compression. The tablets were found within the limits with respect to various physicochemical parameters. The dissolution rate of prepared tablets was better than that of marketed tablet and pure drug. The optimized agglomerates and tablet formulations were found to be stable for 6 months under accelerated conditions. The in vivo studies (preclinical pharmacokinetics, pharmacodynamics and toxicity studies, and clinical pharmacokinetics) of optimized agglomerates were carried out. The results of preclinical studies revealed that the agglomerates provided improved pharmacodynamic and pharmacokinetic profiles of drug besides being nontoxic. The results of pharmacokinetic studies of optimized tablet in human subjects indicated improved pharmacokinetic parameters of drug in comparison with that of marketed tablet.

Preparation of Spherical Crystal Agglomerates of Naproxen Containing Disintegrant for Direct Tablet Making by Spherical Crystallization Technique

The purpose of this research was to obtain directly compressible agglomerates of naproxen containing disintegrant by spherical crystallization technique. Acetone-water containing hydroxypropyl celloluse (HPC) and disintegrant was used as the crystallization system. In this study croscarmellose sodium (Ac-Di-Sol) was employed as disintegrant. The agglomerates were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (XRPD), and scanning electron microscopy and were evaluated for flow, packing and tableting properties and drug release. The growth of particle size and the spherical form of the agglomerates resulted in formation of products with good flow and packing properties. The improved compaction properties of the agglomerated crystals were due to their fragmentation occurred during compression. DSC and XRPD studies showed that naproxen particles, crystallized in the presence of HPC and Ac-Di-Sol did not undergo structural modifications. The dissolution rate of naproxen from tablets made of naproxen-(Ac-Di-Sol) agglomerates was enhanced significantly because of including the disintegrant in to the particles. This was attributed to an increase in the surface area of the practically water insoluble drug is exposed to the dissolution medium. In conclusion the spherical crystallization technique developed in this study is suitable for obtaining agglomerates of drug with disintegrant.

Spherical Crystallization of Mebendazole to Improve Processability

Spherical crystallization technique combines crystallization and agglomeration directly to generate spherical crystals with improved micromeretic properties, thus obviating need for further processing by granulation and agglomeration. The present study was focused on spherical crystallization of an antihelmentic drug – Mebendazole (MBZ) – using spherical agglomeration technique. Apart from being poorly water-soluble, MBZ exhibits poor flow and compressibility owing to its needle shaped crystal habit and electrostatic charge. Spherical agglomeration was carried out in the presence of different bridging liquids (hexane, octanol, toluene, dichloromethane) and polymers (polyethylene glycol, cross-povidone, starch, cross carmellose sodium, hydroxyl propyl methyl cellulose (HPMC), hydroxyl propyl cellulose (HPC), ethyl cellulose (EC), Eudragit®S100, Eudragit®RLPO, Eudragit®RD100, Eudragit®E), by employing different crystallization conditions such as variation of polymer type, polymer concentration, and rate of stirring. The final parameters were optimized to obtain crystals with an aspect ratio in the range of 1–2 compared to a value of 12 for untreated MBZ. These agglomerates retained form C of MBZ, and exhibited good flow properties, high bulk density and improved compressibility. Lower elastic:plastic energy (EE/PE) ratio for spherical crystals generated in the presence of Eudragit®-S100 and Hydroxypropylcellulose (HPC) indicated better compressibilty of spherical crystals.

Preparation of agglomerated crystals for improving flowability and compactibility of poorly flowable and compactible drugs and excipients

Agglomerates of naproxen, carbamazepine and lactose were developed by two spherical crystallization techniques, i.e., a spherical agglomeration method for carbamazepine and an emulsion diffusion method for naproxen and lactose. 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 (XRPD) and for thermodynamic properties using differential scanning calorimetery (DSC). The results showed that the flow and packing properties of agglomerates, represented in terms of the angle of repose and changes in tapping density, were much improved by these techniques compared with those of conventional crystals. This may be due to the spherical shape of agglomerated particles, since the area of contact in the powder bed for spherical agglomerates was smaller than that for other crystal shapes. Under static compression the acceptable tablet with a sufficient strength was produced successfully without capping, although the capping occurred with the original unagglomerated crystals. The improved compactibility of agglomerates was attributed to their structural characteristics. Scanning electron microscope showed that the agglomerates were comprised of small crystals and this particular structure was responsible for large relative volumes change which occurred during the early stage of the compression process, as a consequence of fragmentation. XRPD and DSC results showed that during the agglomeration process, naproxen did not undergo any polymorphic changes. XRPD and DSC results for carbamazepine and lactose revealed that during the agglomeration process, carbamazepine Form III changed to Form I and some of α-lactose monohydrates were converted to anhydrous β-lactose.

Improved Compaction and Packing Properties of Naproxen Agglomerated Crystals Obtained by Spherical Crystallization Technique

Naproxen was crystallized from acetone-water in the presence of different concentrations of hydroxypropylcellulose (HPC). Naproxen particles recrystallized in the presence of HPC exhibited an obvious improvement in their packing, flow, and mechanical properties compared to naproxen recrystallized in the absence of the polymer (control particles). The results showed that the particle size distributions of the treated samples were broader than those obtained when HPC was absent. The agglomerates produced in the presence of 0.25% HPC displayed superior flow characteristics (displaying both a low angle of repose and Carr index) in comparison to samples produced in the presence of other concentrations of HPC. This was attributed to the spherical shape and smooth surface, since the area of contact in the powder bed for spherical agglomerates was smaller than that for other crystal shapes. However it was found that the tensile strength of tablets with the particles isolated in the presence of 1% HPC was increased to a greater extent than tablets produced using the spherical particles. Generally, the tensile strengths of the tablets increased with increasing concentrations of HPC present in the crystallization medium. Differential scanning calorimetry (DSC) and X-ray powder diffraction studies showed that naproxen particles, crystallized in the presence of HPC did not undergo structural modifications.

Effect of three types of additives in poor solvent on preparation of sustained-release nitrendipine microspheres by the quasi-emulsion solvent diffusion method

Sustained-release microspheres of nitrendipine with hydroxypropylmethylcellulose phthalate (HP-55) having a solid dispersion structure were prepared by using the quasi-emulsion solvent diffusion method of the spherical crystallization technique. To investigate the effect of the additives in poor solvent on the preparation of the nitrendipine microspheres, three types of additives, i.e. C 12 H 25 ,NaO 4 S (sodium dodecyl sulfate), NaOH, and KH 2 PO 4 NaOH mixture, were chosen. The resultant microspheres were evaluated with respect to their recoveries, micromeritic properties and release rates. The mechanisms involved in the effect of different poor solvents on formation of the microspheres are discussed. The sustained-release nitrendipine microspheres could not be prepared without using any additives added to the poor solvent. The additives dissolved in poor solvent could affect the micromeritic properties and the release profiles of the resultant microspheres. On increasing the amount of additives, the total recoveries of microspheres were increased and the average diameter of the microspheres was reduced. It was found that a dissociation of HP-55 in poor solvent contributed to the formation of sustained-release nitrendipine microspheres. The release rate of the microspheres prepared with sodium dodecyl sulfate aqueous solution was slower than that of the other two additives, due to the more dense structure formed. Since HP-55, a pH-dependent polymer, was formulated in the present microspheres, the pH value of dissolution medium was one of critical factors to determine the dissolution rate.

Crystallo-co-agglomeration: A novel technique to obtain ibuprofen-paracetamol agglomerates

The purpose of this research was to obtain 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 pyrollidone, and ethylcellulose 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. Ethylcellulose 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.

苦味マスキングを目的とした球形晶析法によるイブプロフェンマイクロスフェアの調製とその錠剤化

Bitter taste masked ibuprofen microsphere co-precipitated with enteric polymer was prepared by the spherical crystallization technique. Particle diameter of resultant microspheres could be controlled with agitation speed and feed rate of drug-polymer solution. Flowability and packability of microspheres were improved significantly compared to the original crystal. It was found that the microsphere reduced the drug releasing rate, causing the taste masking satisfactorily in vitro. Hardness of tablet of the microspheres was higher than that of the original crystal due to improved bonding of particles under compaction. Ibuprofen releasing rates from the tablets of microspheres and original crystals were very slow because no disintegration occurred during the dissolution test. By formulating a small amount of disintegrant into tablet, the microsphere tablet became disintegrable and capable of releasing the drug in a similar manner to the original microspheres, even though the original crystal tablet with disintegrant was not disintegrated.

Design of sustained-release nitrendipine microspheres having solid dispersion structure by quasi-emulsion solvent diffusion method

To improve the bioavailability of nitrendipine microspheres, a sustained-release microspheres having solid dispersion structure were prepared in one step. Two types of polymer, i.e. solid dispersing and sustained-release polymers, were employed to prepare the microspheres by the spherical crystallization technique, i.e. quasi-emulsion solvent diffusion method. The factors of effect on micromeritic properties and release profiles of the resultant microspheres were investigated. And the bioavailability of nitrendipine microspheres was evaluated in six healthy dogs. The results showed that the particle size of microspheres was determined mainly by the agitation speed. The dissolution rate of nitrendipine from microspheres was enhanced significantly with increasing the amount of dispersing agents, and sustained by adding retarding agents. The release rate of microspheres could be controlled as desired by adjusting the combination ratio of dispersing agents to retarding agents. The results of X-ray diffraction and differential scanning calorimetry analysis indicated that the crystalline form of nitrendipine was disordered, suggesting that nitrendipine was highly dispersed in microspheres, so as amorphous state. The release profiles and content of the microspheres stored at a temperature of 40°C and a relative humidity of 75% were unchanged during 3 months of accelerating condition of storage. And the relative bioavailability of the sustained-release microspheres compared with the Baypress™ tablets and the conventional tablets was 107.78% and 309.82%. In conclusion, the sustained-release microspheres with solid dispersion structure improved the bioavailability of the water insoluble drug and prolonged the T max value.

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.

Development of Agglomerated Crystals of Ascorbic Acid by the Spherical Crystallization Technique for Direct Tableting, and Evaluation of Their Compactibilities [Translated]<sup>†</sup>

Development of Agglomerated Crystals of Ascorbic Acid by the Spherical Crystallization Technique for Direct Tableting, and Evaluation of Their Compactibilities [Translated]<sup>†</sup>

Crystal growth of drug materials by spherical crystallization

One of the crystal growth processes is the production of crystal agglomerates by spherical crystallization. Agglomerates of drug materials were developed by means of non-typical (magnesium aspartate) and typical (acetylsalicylic acid) spherical crystallization techniques. The growth of particle size and the spherical form of the agglomerates resulted in formation of products with good bulk density, flow, compactibility and cohesivity properties. The crystal agglomerates were developed for direct capsule-filling and tablet-making.

球形晶析法による直接打錠用アスコルビン酸原末結晶の開発と圧縮成形性評価

Spherically agglomerated crystals of ascorbic acid for direct tableting were successfully prepared by the spherical crystallization technique. The micromeritic and compaction properties of the original ascorbic acid crystals were dramatically improved. The dominating mechanisms of improved compaction properties of the spherically agglomerated crystals depended on their fragmentation and plastic deformation during compaction. This mechanism was supported by higher stress relaxation and less elastic recovery of the compact of agglomerated crystals in comparison with the original crystals. The spherically agglomerated crystals were tableted directly without capping using a single punch machine under dynamic compaction, although the tensile strength of tablet with the spherically agglomerated crystals decreased with increasing compression speed.

Development of spherical crystal agglomerates of an aspartic acid salt for direct tablet making

Agglomerates of an aspartic acid salt were developed by means of a non-typical spherical crystallization technique. The aspartic acid salt was crystallized by a salting-out method combined with cooling. Traditional mechanical stirring crystallization (samples A and B) and the recirculation process (sample C) were used. The control material was commercial aspartic acid salt with very poor flowability and compressibility. The particle sizes of the samples were measured by sieve analysis. The morphology of the crystals and crystal agglomerates was controlled by SEM. The specific surfaces of the products were determined by the BET method and the micropore volumes were calculated via the BJH theory. The Carr index, rearrangement constant, plasticity and compressibility values were calculated. The samples were controlled by thermoanalytical investigations (TG, DTG and DSC). Both of the crystallization techniques used resulted in spherical agglomerates of the aspartic acid salt with very good flowability and compressibility parameters. Primarily sample B, with a closed “cauliflower-like” structure, can be suggested for tablet making involving a large mass (e.g., chewable tablets) by direct tablet pressing. Faster initial cooling rate and slower stirring rate were very favourable in the building-up of crystal agglomerates of sample B with a closed structure and a large particles. Sample B can be suggested further for capsule filling because of its high poured density, very good flowability and fast rearrangement.

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.

Preparation of Norfloxacin Spherical Agglomerates Using the Ammonia Diffusion System

□ Agglomerated crystals of norfloxacin were prepared by a spherical crystallization technique using the ammonia diffusion system (ADS). This technique makes it possible to agglomerate amphoteric drugs like norfloxacin, which cannot be agglomerated by conventional procedures. When an ammonia–water solution of norfloxacin is poured into an acetone dichloromethane mixture under agitation, a small amount of ammonia is liberated in the system. The ammonia– water solution plays a role both as a good solvent for norfloxacin and as a bridging liquid, allowing the crystalsʹ 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 emultion 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.

球形晶析法による低融点ビタミンＥの打錠用細粒の設計と錠剤化

Spherically microagglomerated crystals of waxy drug (tocopherol nicotinate) for direct tableting were successfully prepared by a spherical crystallization technique. The micromeritic properties of the original tocopherol nicotinate crystals, such as flowability, packability, and mixing characteristics with excipients were drastically improved for tableting. The surface-modified agglomerated crystals with deposition of colloidal silica reduced sticking (caking) properties under loading and exudation of drug from agglomerated crystals under compression. The agglomerated crystals provided acceptable tablets with easily disintegrating and releasing functions by compressing with a suitable additives.

Effect of Drug Properties on Physical and Release Characteristics of Eudragit Microspheres Prepared by Spherical Crystallization Technique

Ten compounds having different solubilities and molecular weights were evaluated for incorporation into Eudragit microspheres using the spherical crystallization technique, and the effects of drug-related factors on the properties of Eudragit microspheres were investigated. The entrapment of the active compound within the microspheres was highly dependent on the acidic or basic characteristics of the drug. Structural changes were also observed on the microsphere surface prepared at different pH values. Microspheres prepared with slightly and very slightly soluble drugs such as salicylic acid, naproxen, piroxicam, indomethacin, and methylpred-nisolone indicated controlled-release properties. Generally, drug release from microspheres followed the Fickian diffusion model.

Modification of ketoprofen bead structure produced by the spherical crystallization technique with a two-solvent system

Poorly-compressible crystals of ketoprofen were agglomerated by the spherical crystallization technique with a two-solvent system (acetone/demineralized water). In order to study a possible modification of particle texture, spherical crystals were formulated with low concentrations of additives. The results showed that the procedure was possible with ethylcellulose, cross-linked PVP and cross-linked CMC, all at a concentration of 1%. However, no spherical beads could be obtained with the water-soluble compounds tested (PVP and Eudragit L100-55®), Eudragit RS100® and colloidal silica. These formulation trials have indicated two main factors with their possible influences: the polymer solubility and viscosity in the solvent/non-solvent system leading to two kinds of nucleation and changes in mass transfer and drug/polymer interactions leading to the formation of reversible complexes or irreversible complexes and possibility of drug release modifications. Moreover, formulations with the methacrylic acid derivatives were found to be incompatible with the operating conditions, in terms of temperatures changes, stirring or residence time. Furthermore, an optimization of the formulation with ethylcellulose yielded a controlled release form with 1% of the polymer, whereas the addition of very low concentrations increased the drug release.