Spherical Crystallization Technique Research Articles

Optimizing irbesartan spherical agglomerates through principal component analysis and experimental design

Background: This study explores the amalgamation of crystallization and agglomeration through spherical crystallization, aiming to develop the spherical crystals of Irbesartan with improved micromeritic properties. The main objective is to use spherical crystallization techniques to improve the micromeritic characteristics of Irbesartan, which has poor flow and compressibility because of its crystal habit. Methodology: A solvent change approach was utilized to synthesize spherical agglomerates of Irbesartan. Several system parameters, including the amount of bridging liquid, the rate of stirring, and the concentration of the polymer, were tuned to enhance the particle size distribution and mechanical qualities. SEM, GC, PXRD, DSC, and FTIR analyses characterised the spherical crystals. Result and Discussion: The study demonstrated that spherical crystallization significantly enhanced Irbesartan's micromeritic properties. The angle of repose of optimized agglomerates was reduced by around 52%, indicating improved considerably flowability of irbesartan. The sphericity of the crystals was validated by SEM examination (shape factor: 0.996), and the solvent levels were found to be within allowable bounds by GC analysis. PXRD data showed no polymorphism alterations, and DSC/FTIR analyses confirmed that the excipients and drug were compatible. Conclusion: This process provides a feasible alternative to classic granulation and agglomeration procedures, resulting in better flow, compressibility, and spherical crystals. It streamlines the Irbesartan formulation, improving efficiency and uniformity, reducing manufacturing costs, higher tablet consistency, and enhancing patient compliance.

Sustainable preparation of spherical particles of novel carbamazepine-hesperetin cocrystal via different crystallization strategies: From mechanism to application

Spherical crystallization is widely employed in pharmaceutical industry to produce spherical particles that exhibit improved micrometric performances of active pharmaceutical ingredients (APIs), including particle size, morphology, flowability, and compressibility. Especially for APIs with poor powder performance and low solubility, spherical co-crystallization offers the potential to enhance both dissolution properties and tablet manufacturability by combining the API and cocrystal coformer (CCF) into a spherical particle. In this study, we aimed to enhance the physicochemical properties of carbamazepine (CBZ) and hesperetin (HPE) by synthesizing a novel cocrystal with the stoichiometric ratio of 1:1. Crystal structure of the CBZ-HPE cocrystal was determined using single crystal X-ray diffraction (SCXRD). To further improve the poor powder performances such as low flowability and compressibility resulting from the needle morphology of the cocrystals, we designed three spherical crystallization strategies: common spherical agglomeration, oil-out-induced spherical agglomeration and spherulitic growth method. The spherical particles of CBZ-HPE cocrystals were characterized by powder X-ray diffraction (PXRD), polarized light microscopy (PLM), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), particle size instrumentation, and Fourier transform infrared spectroscopy (FTIR) to provide information about crystal structure, particle morphology, particle size and circularity distribution. The results revealed significant differences in particle morphology, flowability, particle size and dissolution rate among the various spherical crystallization strategies. Theoretical calculations elucidated three spherical crystallization mechanisms: spherical agglomeration (SA), oil-out-induced spherical agglomeration (OOSA) and spherulite growth (SG). This study offers both experimental and theoretical foundations for the application of different spherical crystallization techniques in the pharmaceutical industry.

Improved Spherical Particle Preparation of Ceftriaxone Sodium via Membrane-Assisted Spherical Crystallization

Spherical drug particles prepared by the spherical crystallization technique can simultaneously improve the mobility of particles, mechanical properties, drug solubility and bioavailability, etc. However, high-efficient mixing of a solution and the formation of uniform bridging liquid droplets were crucial for accurate control of spherical crystallization processes. Herein, a novel membrane-assisted spherical crystallization (MASC) technology was proposed to produce monodisperse spherical agglomerates of ceftriaxone sodium. The poor solvent permeation rate of MASC was stabilized by adjusting the liquid flow velocity in the shell side and tube side. Uniform bridging liquid droplets constructed by a polytetrafluoroethylene hollow fiber membrane were observed in real time. A stable flow field and crystallization microenvironment were provided on the hollow fiber membrane surface. The crystal size distribution and the coefficient of variation of ceftriaxone sodium products were improved compared with those of conventional spherical crystallization (CSC) under the same stirring rate. The impurities of CSC products did not meet the requirements due to the degradation after 14 days’ acceleration experiment, while the one of MASC products still met the pharmacopoeia requirements after 30 days. This study provides a potential membrane-based technology for the enhancement of spherical crystallization of related drugs.

Effect of polymers and process parameters in augmenting the compactability and dissolution behaviour of oxcarbazepine spherical agglomerates

The hypothesis for the present work is proposed to explore the spherical crystallization technique for improving the micromeritics, compactability, and solubility characteristics of oxcarbazepine (OXZ), an anticonvulsant drug. Agglomerates containing different polymers (PEG 6000 and PVP K30) and process parameters were investigated for the enhancement of overall physicochemical performance and dissolution. Water, dichloromethane, and chloroform were used as a poor solvent, good solvent, and bridging liquid, respectively. Pure OXZ and spherical agglomerates were characterized for several properties including Fourier transformation-infrared spectroscopy, Differential scanning calorimetry, Scanning electronic microscopy, X-ray powder diffraction analysis, micromeritics, solubility studies, and in-vitro drug release kinetics. From the results, a considerable improvement in drug solubility and micromeritics of agglomerates than pure OXZ was observed. Compressibility parameters assessed from the Heckel plot showed agglomerates with a polymer having a higher value of slope (k) and less MyP is accountable for plastic deformation in agglomerates. Prepared spherical agglomerates showed an enhancement in solubility and rate of dissolution, which might improve their bioavailability.

Preparation and Pharmacokinetics Evaluation of Solid Self-Microemulsifying Drug Delivery System (S-SMEDDS) of Osthole.

The study was performed aiming to enhance the solubility and oral bioavailability of poorly water-soluble drug osthole by formulating solid self-microemulsifying drug delivery system (S-SMEDDS) via spherical crystallization technique. Firstly, the liquid self-microemulsifying drug delivery system (L-SMEDDS) of osthole was formulated with castor oil, Cremophor RH40, and 1,2-propylene glycol after screening various lipids and emulsifiers. The type and amount of polymeric materials, good solvents, bridging agents, and poor solvents in S-SMEDDS formulations were further determined by single-factor study. The optimal formulation contained 1:2 of ethyl cellulose (EC) and Eudragit S100, which served as matrix forming and enteric coating polymers respectively. Anhydrous ethanol and dichloromethane with a ratio of 5:3 are required to perform as good solvent and bridging agent, respectively, with the addition of 0.08% SDS aqueous solution as poor solvent. The optimized osthole S-SMEDDS had a high yield (83.91 ± 3.31%) and encapsulation efficiency (78.39 ± 2.25%). Secondly, osthole L-SMEDDS was solidified to osthole S-SMEDDS with no significant changes in terms of morphology, particle size, and zeta potential. In vitro release study demonstrated a sustained release of the drug from osthole S-SMEDDS. Moreover, in vivo pharmacokinetic study showed that the Tmax and mean residence time (MRT(0-t)) of osthole were significantly prolonged and further confirmed that osthole S-SMEDDS exhibited sustained release effect in rabbits. Comparing with osthole aqueous suspension and L-SMEDDS, osthole S-SMEDDS increased bioavailability by 205 and 152%, respectively. The results suggested that S-SMEDDS was an effective oral solid dosage form, which can improve the solubility and oral bioavailability of poorly water-soluble drug osthole.

Spherical Crystallization: An Overview

Introduction: In 1986, Kawashima developed the spherical crystallization technique for size enlargement of drugs in the field of pharmacy. Spherical crystallization is defined as “An agglomeration process that transforms crystalline drug directly into compact spherical forms for improving the flowability, solubility and compactability”. Methods: General methods for preparing spherical crystallization are spherical agglomeration, emulsion solvent diffusion method, ammonia diffusion method and neutralization method. Factors controlling the process of agglomeration include solubility profile, mode and intensity of agitation, temperature of the system and residence time. Results: Spherical crystals can be characterized by Optical microscopy, X-ray powder diffraction, Electron scanning microscopy, Fourier Transform Infrared spectrometer (FTIR) and differential scanning calorimeter (DSC).Spherical crystallization has wide applications in pharmaceuticals like improvement of flowability and compressibility of poorly compressible drugs, masking bitter taste of drugs and improving the solubility and dissolution rate of poorly soluble drugs. Conclusion: Spherically agglomerated crystals can be directly converted into a tablet thus saving time and reducing cost.

Spherical crystallization: A technique use to reform solubility and flow property of active pharmaceutical ingredients.

Tablets have been choice of manufacturers over the years due to their comparatively low cost of manufacturing, packaging, shipping, and ease of administration; also have better stability and can be considered virtually tamper proof. A major challenge in formulation development of the tablets extends from lower solubility of the active agent to the elaborated manufacturing procedures for obtaining a compressible granular material. Moreover, the validation and documentation increases, as the numbers of steps increases for an industrially acceptable granulation process. Spherical crystallization (SC) is a promising technique, which encompass the crystallization, agglomeration, and spheronization phenomenon in a single step. Initially, two methods, spherical agglomeration, and emulsion solvent diffusion, were suggested to get a desired result. Later on, the introduction of modified methods such as crystallo-co-agglomeration, ammonia diffusion system, and neutralization techniques overcame the limitations of the older techniques. Under controlled conditions such as solvent composition, mixing rate and temperature, spherical dense agglomerates cluster from particles. Application of the SC technique includes production of compacted spherical particles of drug having improved uniformity in shape and size of particles, good bulk density, better flow properties as well as better solubility so SC when used on commercial scale will bring down the production costs of pharmaceutical tablet and will increase revenue for the pharmaceutical industries in the competitive market. This review summarizes the technologies available for SC and also suggests the parameters for evaluation of a viable product.

Solubility and Dissolution Enhancement of Albendazole by Spherical Crystallization

Spherical crystallization technique combines crystallization followed by agglomeration to generate spherical crystals with improved micromeretic properties, thus obviating need for further processing by agglomeration and granulation. The present study was focused on spherical crystallization of an antihelmentic drug Albendazole (ABZ) using spherical crystallization technique. Apart from being poorly water-soluble, ABZ 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, dichloromethane) and polymers (Carboxymethyl Celluose Sodium [Na CMC] and Hydroxyl propyl methyl cellulose [HPMC]), by employing different crystallization conditions such as variation of polymer type, polymer concentration, variation of bridging liquid, bridging liquid concentration, rate of stirring and stirring time. The final parameters were optimized to obtain crystals for the formulation of tablet through direct compression. The agglomerates exhibited better flow properties, higher bulk density and improved compressibility compared to pure powder drug. Spherical crystals generated in the presence of Sodium CMC and HPMC indicated better compressibility of spherical crystals than the spherical crystals prepared with organic solvents in the absence of Sodium CMC and HPMC.

Preparation and In Vitro/In Vivo Evaluation of Puerarin Solid Self-Microemulsifying Drug Delivery System by Spherical Crystallization Technique.

The aim of this work was to establish a method for preparing stable and controllable solid self-microemulsifying drug delivery system (S-SMEDDS) by spherical crystallization technique, which was explored for promoting the dissolution, oral bioavailability, and process efficiency. Solubility test, preparation of liquid self-microemulsifying drug delivery system (L-SMEDDS), and the obtained ternary phase diagrams test have been performed to screen and optimize the composition of LSMEDDS. The optimized formulation was used to prepare puerarin solid self-microemulsifying drug delivery system (Pue-SSMEDDS) by spherical crystallization technique. Droplet size and morphological analysis of the optimal Pue-SSMEDDS were determined to evaluate the final formulation. And the Pue-SSMEDDS was also assessed by flowability study, angle of repose, Carr's index, and flow velocity. Furthermore, the vitro dissolution and pharmacokinetic profile in vivo were analyzed. The study in vitro showed the Pue-SSMEDDS could disperse in the dispersion medium within 60s and was spherical with the particle size of 19.66nm and zeta potential of -28.3mV. It could keep stable at low temperature and seal condition for 3months. In vivo pharmacokinetic experiments of rats, the mean plasma concentration of self-microemulsion group was much higher than that of conventional tablets and could play a long-lasting efficacy, while there was no significant difference between the LSMEDDS and S-SMEDDS. The results suggested the potential of S-SMEDDS could improve the oral bioavailability of poorly water-soluble drug, such as puerarin.

Quasi emulsion spherical crystallization technique based environmentally responsive Tulsion® (pH dependent) microspheres for colon specific delivery

pH-dependent sustained-release Tulsion® microspheres bearing clarithromycin were prepared using quasi-emulsion solvent diffusion method with thermocoat L 30 D 55 as a release retardant. Both, clarithromycin and thermocoat L 30 D 55, were found to be non-hemolytic during in vitro toxicity assay against human red blood cells. Ratiometric optimization of different solvents using phase diagrams was performed on amount of good solvent, bridging liquid, dispersing liquid and poor solvent. The developed microspheres were evaluated for the recovery (67.27±3.3%), average particle size (52.0±0.46μm) and encapsulation efficiency (61.0±3.1%). Scanning electron microscopy and transmission electron microscopy revealed that the microspheres were smooth in surface and spherical in shape, respectively. The drug release study was conducted at different pH of GIT and it gave a pH dependent release for clarithromycin. The bioavailability study revealed increased AUC (2 fold) and half-life (1.2 fold) of microspheres as compared to plain drug. The manuscript reported the debut work on thermocoat L 30 D 55 based novel drug delivery system, the polymer is safe to be used, quasi emulsion spherical crystallization technique is a good technique to prepare microspheres, the prepared microspheres provides sustain release profile as well as targeting to colon.

Design and characterization of aceclofenac and paracetamol spherical crystals and their tableting properties

The objectives of the present research were to prepare directly compressible paracetamol (DCP) by nontypical spherical crystallization technique and spherical crystals of aceclofenac (SCA) by typical spherical crystallization technique. Both spherical crystals were combined and compressed into tablets by direct compression technique. FT-IR and DSC study exhibited no interaction between the drug and the excipients used in the formulation. The Kawakita analysis showed that spherical crystals were less cohesive due to dense nature of particles. Both DCP and SCA showed plastic deformation suggesting improved compressibility. Lower elastic recovery was observed with higher compaction pressure. The Leuenberger analysis showed that maximum crushing strength is reached faster at lower pressures of compression. In vitro dissolution study showed that more than 90% paracetamol and aceclofenac were released within 45 and 180min, respectively. Hence, the combined formulation of SCA and DCP can be used for preparing tablet by direct compression method.

Preparation, Evaluation and Need of Spherical Crystallization in Case of High Speed Direct Tabletting

In direct compression (DC), the significance of usual flow properties of powder from the hopper to the dies of the tablet machine cannot be overstressed. Ensuring the free flow of powder presents a number of challenges to the pharmaceutical formulator in case of high speed tabletting. This research work was conceived to obtain directly compressible agglomerates by spherical crystallization technique and were comparatively evaluated for physicochemical properties as well as tableting properties of agglomerates and unprocessed aceclofenac. Agglomerates of aceclofenac were developed via spherical crystallization method by a solvent arrangement containing dichloromethane (DCM) as a good solvent, water as a bad solvent and acetone as a bridging liquid. Hydroxypropyl cellulose (HPC) in variable quantity was implemented as hydrophilic polymer. The agglomerates were evaluated for yield, solubility, drug content, FTIR spectroscopy, porosity, particle size, micromeritic properties, differential scanning calorimetry (DSC), X-ray diffraction studies (XRD), scanning electron microscopy (SEM), and dissolution studies. The agglomerates expressed improved micromeritic and dissolution properties, in equivalence to pure drug. Formulation F3 (optimized agglomerates) exposed estimable rotundity, better drug release, and easily compression into tablets by high speed DC Technique. The tablets showed acceptable physicochemical properties and complied with the pharmacopoeial specifications. The dissolution rate of prepared tablets from agglomerates was better than the tablets of pure drug. The F3 agglomerates show splendid physicochemical and micromeritic properties. Agglomerated compression mix also showed good tableting properties as needed for high speed compression and enough stability under accelerated conditions at least for 1 month.

Spherical crystallization of ezetimibe for improvement in physicochemical and micromeritic properties

Spherical agglomerates of ezetimibe (EZT) were prepared with hydrophilic polymers; polyvinyl pyrrolidone K30 (PVP) and/or poloxamer 188 (poloxamer) at drug to polymer ratios of 1:1 (w/w) by spherical crystallization technique, in order to improve its physicochemical and micromeritic properties. Three different bridging liquids; chloroform, dichloromethane and/or ethyl acetate along with good solvent acetone and poor solvent water were used to form six batches of agglomerates. Initial characterization of all batches in terms of micromeritic and physicochemical properties resulted in optimization of (A3, EZT:PVP:ethyl acetate) and (B3, EZT:poloxamer:ethyl acetate) batches and hence further investigated for drug–polymer interaction, crystallinity and morphology using FTIR, XRPD, DSC and SEM techniques. The results indicated presence of hydrogen bonding, crystallinity and spherical shape in agglomerates. Therefore, the optimized agglomerates (B3) were directly compressed into tablet. Unfortunately, drug release from the tablet was not satisfactory, suggesting a need of disintegrant from dissolution point of view. Therefore, these agglomerates were recompressed incorporating certain excipients and evaluated as per pharmacopoeia. The dissolution rate of prepared tablet was similar to that of marketed tablet (p > 0.05). It could be concluded that spherical crystallization could be one of the effective and alternative approaches for improved performance of EZT and its tablet formulation.

Spherical Crystallization of Carbamazepine/Saccharin Co-Crystals: Selective Agglomeration and Purification through Surface Interactions

Spherical crystallization involves crystallization and simultaneous agglomeration of a crystalline particle using an immiscible phase, which has preferential affinity for the crystal surface. Here, we report application of a spherical crystallization technique to the field of co-crystallization. Carbamazepine/saccharin (CBZ/SAC) co-crystals were generated using reverse antisolvent addition and agglomerated using different bridging liquids. Two crystal forms of CBZ/SAC co-crystals were formed, depending on the levels of supersaturation achieved during processing. The selective agglomeration of co-crystal occurred during the agglomeration stage, depending on the relative interaction between bridging liquid and the crystal surfaces. The computational investigation of isosteric heats of adsorption of the bridging liquids at the prominent crystal surfaces proved to be a useful tool in understanding the surface interactions. The spherical crystallization technique shows opportunity to generate co-crystals and its purification through selective agglomeration.

Spherical Crystallization as Particle Engineering Technique to Improve Processability of Poor Flowing Furosemide

The pharmaceutical industry is focusing on developing simple and economical formulations to meet desired drug delivery challenges. Tablet continues to be the most popular dosage form. From the manufacturing point of view tablets can be produced at much higher rate than any other dosage forms. The formulation of tablet must be optimized to achieve desired goals. Poor flow of active pharmaceutical ingredient may raise issues like loss of tablet hardness and weight variation. This may restrict the formulator to use granulation techniques or higher levels of lubricants and glidants to impart the flow, which may adversely affect dissolution and compaction. Furosemide is a class IV drug from BCS classification and possesses poor flow properties. The main objective of study was to improve the flow properties of furosemide and thereby improve its solubility leading ultimately improvements in its bioavailability. We used two different techniques of spherical crystallization to improve the flow properties of furosemide. Our results reveal that the spherical crystallization by neutralization technique is better method than wet spherical crystallization to improve the flow properties of furosemide. Flow properties of excipients also affect the compression process. In conclusion, spherical crystallization technique could be used to enhance the flow properties of furosemide.

Preparation and evaluation of sodium CMC zaltoprofen spherical agglomerates for direct compression

Zaltoprofen spherical agglomerates were prepared by spherical crystallization technique using a three solvent system comprising a good solvent (acetone), a bad solvent (water) and a bridging liquid (dichloromethane) by using a hydrophilic polymer sodium CMC in different concentrations for enhancing micromeritic properties and dissolution rate. The prepared zaltoprofen spherical agglomerates were evaluated in terms of flow properties, particle size analysis, compression and dissolution behavior. Physical characters of the crystals were studied for the morphology of crystals using scanning electron microscope (SEM), identification of polymorphism done by X-ray powder diffraction (XPRD) and for thermo dynamic properties using differential scanning colorimetry (DSC). The prepared agglomerates were improved the micromeritic properties, packability, wettability, solubility and compaction behavior, as well as dissolution behavior in comparison to pure zaltoprofen drug.

How spherical crystallization improves direct tableting properties: a review.

Direct tableting has been renewed as a preferable process by simply mixing and compressing powder to save time and cost in comparison with granule tableting. Direct compression tableting as a technique has been successfully applied to numerous drugs on the industrial scale, although the success of any procedure, and resulting mechanical properties of tablets, is strongly affected by the quality of the crystals used. Good flowability, packability and compactability are prerequisite for drug to be prepared by direct tableting. When the mechanical properties of the drug particles are inadequate a primary granulation is necessary. The use of spherical crystallization as a technique appears to be an efficient alternative for obtaining suitable particles for direct tableting. Spherical crystallization is a particle design technique, by which crystallization and agglomeration can be carried out simultaneously in one step and which has been successfully utilized for improvement the micromeritic properties of crystalline drugs. In this review, we will discuss how the micromeritic properties of the particles such as flowability, packability and compactability can be improved by spherical crystallization technique.

Enhanced dissolution rate of simvastatin using spherical crystallization technique

Simvastatin is a hypocholestrolemic drug that is insoluble in water. Its low water solubility rate limits the pharmacological effects. The aim of this study was to improve the dissolution rate of simvastatin using spherical crystallization method. The drug was dissolved in boiling dichloromethane as the good solvent. This solution was added to 5°C water as the non-solvent. After sedimentation, isopropyl acetate was added as the bridging solvent. At the end the crystals were collected and dried for 12 h in a 50°C oven. The FTIR and DSC results showed no change in the drug after crystallization process. XRPD studies showed the sharp peaks are present in the diffractograms of spherical crystals with minor reduction in height of the peaks. The particle size of spherical aggregates was about 37 μm and the dissolution efficiency of simvastatin up to 60 min increased to about 2-fold in phosphate buffer solution containing 0.5% sodium dodecyl sulfate (pH 7) using the rotating paddle method. Spherical crystals showed enhanced solubility than untreated powder possibly due to partial conversion to amorphous form. Their dissolution rate at 60 min was still 4-fold of untreated powder when stored at 25°C and 84% relative humidity for one month.

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.

Preparation and evaluation of solid dispersions of piroxicam and Eudragit S100 by spherical crystallization technique

Objective: To improve the dissolution rate of piroxicam (PX), enteric-release microparticles having solid dispersion (SD) structure were prepared in one step. Methods: SD of PX and Eudragit S100 (Eu S100) with the aid of silicon dioxide (Aerosil® 200), as an antiadhesion agent, were prepared by spherical crystallization technique. The microparticles were characterized by differential scanning calorimetry, X-ray powder diffraction, and Fourier transform infrared spectroscopy and were evaluated for yield, encapsulation efficiency, flowability, packability, and drug release (at pH 1.2 and pH 7.4). The samples were stored at severe condition [40°C, 75% relative humidity (RH)] for 3 months to investigate their stability. The effects of the polymer–drug and polymer–Aerosil ratios on the characteristics of the microparticles were also investigated. Results: PX microparticles exhibited significantly improved micromeritic properties in comparison to the crystalline pure drug. The dissolution of drug from microparticles in phosphate buffer (pH 7.4) indicated a significant increase in dissolution of PX when dispersed in Eu S100. The results of X-ray powder diffraction and differential scanning calorimetry analysis indicated that in microparticles at 2:1 Eu S100:PX ratio the crystalline form of PX was disordered, suggesting that PX was highly dispersed in microparticles, as that in the amorphous state. Fourier transform infrared spectroscopy analysis demonstrated the presence of intermolecular hydrogen bonding between PX and Eu S100 in SD. In stability test, the release profiles of the microparticles were unchanged as compared with the freshly prepared SDs; amorphous PX in the SD particles did not crystallize under storing at 40°C, 75% RH for 3 months.