Ground Mixture Research Articles

A new approach for hydrogen generation from sewage sludge

A new process to produce hydrogen efficiently from sewage sludge (SWS) was developed with co-grinding operation of the dried SWS with calcium and nickel hydroxides (Ca(OH)2 and Ni(OH)2) and subsequent heating of the ground mixture at relatively low temperature below 600°C. A set of analytical methods were used to characterize the ground samples before heating and the gaseous and solid products after heating. Thermo-mass spectroscopic (TG-MS) analysis showed hydrogen occurrence around 450°C. Hydrogen yield over 70g per kg SWS with concentration of 93.6% was obtained with the hydroxide additions of Ca to C from SWS at 1:1 and Ni to C at 1:6, respectively. X-ray diffraction (XRD) analysis of the solid residues after heating confirmed the existences of calcium carbonate and nickel metal. Based on the obtained results, possible reaction pathway was proposed.

Extraction of Lithium from Lepidolite Using Mixed Grinding with Sodium Sulfide Followed by Water Leaching

Mixed grinding with Na2S followed by water leaching was performed to extract Li from lepidolite. The leachability of Li increases dramatically in the ground mixture, regardless of the mixing ratio over the range of 1:1 to 3:1, while only 4.53% of Li was extracted in lepidolite ground without Na2S. The leachability increased with an increase of the grinding time, and ultimately, 93% of the Li was leached by water from the ground mixture with a weight ratio of 3:1 (Na2S:Lepidolite). In the process of the mixed grinding, the Li-contained lepidolite was destructured crystallographically, and it might have changed to different compounds. This process enables us to extract Li from lepidolite via a water leaching treatment.

Spectroscopic and thermal approaches to investigate the formation mechanism of piroxicam–saccharin co-crystal induced by liquid-assisted grinding or thermal stress

The use of co-crystal technology applied to pharmaceutical industry has recently attracted considerable interest. It is important to better understand the mechanism of co-crystal formation via specific intermolecular interactions. The objective of the present study was to evaluate a stepwise mechanism of a co-crystal formation between piroxicam (PIR) and saccharin (SAC) after different grinding and thermal treatments by using spectroscopic and thermal analyses. The physical and ground mixtures of PIR–SAC (molar ratio = 1:1) and their preheated mixtures were analyzed using FTIR, DSC and DSC-FTIR techniques. Typical PIR–SAC co-crystal was prepared by solvent evaporation method. Various PIR–SAC ground mixtures after neat grinding process showed the same FTIR spectra as their physical mixtures, but these ground mixtures might be changed to co-crystals after further thermal treatment. By adding two drops of chloroform into PIR–SAC physical mixture, however, the PIR–SAC co-crystal was gradually formed with the increase in grinding time (>57 min) via inter-/intramolecular N–H···O and C–H···O hydrogen bonding between PIR and SAC. By preheating the PIR–SAC physical mixture over 170 °C, it was also gradually transformed into a co-crystal with temperature. The PIR–SAC co-crystal formation might be possibly attributed to a mobile phase formed between PIR and SAC, leading to a co-crystal formation. This mobile phase could be formed by either solution through a lubricating liquid added during grinding process or eutectic melt via thermal stress. A simultaneous DSC-FTIR technique also directly evidenced the PIR–SAC co-crystal formation via a one-step process. The present study concludes that the chloroform-assisted grinding process or thermal stress easily enhanced a PIR–SAC co-crystal formation via gradual induction of inter-/intramolecular hydrogen bonding between PIR and SAC.

Examination of the physicochemical properties of caffeic acid complexed with γ-cyclodextrin

Caffeic acid (CA) is a hydrophobic polyphenol with a high antioxidant capacity and γ-cyclodextrin (γ-CD) is a cyclic polysaccharide. The current study prepared a coprecipitate (CP), a freeze-dried (FD) preparation, a ground mixture (GM), and a physical mixture (PM) of CA and γ-CD, and this study then assessed the physicochemical properties and antioxidant capacity of these preparations. PXRD patterns revealed that a PM and a GM prepared at a certain molar ratio (CA/γ-CD = 1/1) produced a diffraction peak due to CA crystals. Diffractions peaks characteristic of CA and γ-CD disappeared with the CP, but new peaks were noted. In addition, an FD with CA and γ-CD at a molar ratio of 1/1 produced a halo pattern. DSC measurements revealed that the PM produced an endothermic peak at 220 °C due to the melting of CA, but the endothermic peak due to CA disappeared with the CP, FD, and GM. IR spectra revealed that the absorption peak due to the carbonyl group (C=O) of CA shifted for both the CP and the FD. The absorption peak due to C=C in the aromatic ring of CA also shifted. These findings presumably indicate molecular interaction between CA and γ-CD when the 2 substances are present at a molar ratio of 1/1 (CA/γ-CD). In the GM, molecular interaction presumably occurred as a result of heat. The preparations were compared to CA alone in dissolution testing, which revealed that the CP and FD both had a high rate of dissolution. 1H-1H NMR (NOESY) spectra revealed cross peaks involving protons of the γ-CD cavity and protons of the aromatic ring of CA. Thus, the formation of CA and γ-CD inclusion complexes helped to improve the dissolution of CA and γ-CD at a molar ratio of 1/1. The CP and FD had a higher antioxidant capacity than did CA alone. This presumably indicates that the formation of CA and γ-CD inclusion complexes helped to increase the electron density of CA in the CD cavity.

Effect of γ-cyclodextrin derivative complexation on the physicochemical properties and antimicrobial activity of hinokitiol

The aim of this study was to evaluate the physicochemical properties of solid dispersion on mixtures of hinokitiol (HT) and γ-cyclodextrin (γ-CD) and of HT and (2-hydroxypropyl)-γ-cyclodextrin (HP-γ-CD). Differential scanning calorimetry revealed that coground HT/γ-CD at a molar ratio of 1:1 and HT and HP-γ-CD at molar ratios of 1:1 and 1:2 lacked an endothermic peak due to melting of HT crystals. Powder x-ray diffraction revealed that HT crystal showed a halo pattern respectively, by mixing and grinding of the CDs and HT. Thus, coground HT/γ-CD and HT/HP-γ-CD at a molar ratio of 1:1 had molecular interaction. Assessment of dissolution revealed that ground mixtures had improved dissolution of HT compared to HT crystals, ground HT alone, and physical mixtures containing HT. 1H-1H NOESY NMR suggested that the 7-membered ring and isopropyl group of HT were located within the cavity of γ-CD and HP-γ-CD. The antimicrobial tests indicated that ground mixtures exhibited a minimum inhibitory concentration (MIC) of 20 μg/mL against Bacillus subtilis, 40 μg/mL against Staphylococcus aureus, and 20 μg/mL against Escherichia coli. GMs were found to have 4 times more antimicrobial activity than HT crystals. Ground mixtures also exhibited MIC of 160 μg/mL against Pseudomonas aeruginosa and they were found to 2 times more antimicrobial activity than HT crystals. Improvement in antimicrobial activity with the formation of inclusion complexes is presumably due to increase the solubility of HT as a result of the formation of HT/CD inclusion complexes.

Influence of MgO precursors on mechanically activated forsterite synthesis

Brucite-fumed silica and hydromagnesite-fumed silica mixtures were used to investigate the influence of MgO precursors on mechanically activated forsterite synthesis. The changes in morphology, chemical bond and phase composition of the ground and calcined mixtures were examined with scanning electron microscopy (SEM), Si 2p X-ray photoelectron spectroscopy (XPS) and 29Si magic angle spinning nuclear magnetic resonance (MAS-NMR), and X-ray diffraction (XRD), respectively. The XPS and MAS-NMR analyses show that high-energy milling generates more Mg–O–Si chemical bonds in the brucite-fumed silica mixture than in the hydromagnesite-fumed silica sample. This is because brucite has a higher concentration of Mg–OH bonds than hydromagnesite. However, single-phase forsterite forms at a higher temperature of 1000°C in the milled brucite-fumed silica mixture than that of 800°C in the ground hydromagnesite-fumed silica sample after the same grinding. The different forsterite completion temperature is probably due to the longer Mg2+ and Si4+ diffusion distance of over 500nm in the former milled mixture than that of less than 300nm in the latter ground sample.

Mg-O-Si Chemical Bond Formation in Light Burned Magnesia and Fumed Silica Mixture During Mechanical Activation

Mg-O-Si chemical bond formation in a light burned magnesia (MgO) and fumed silica (SiO2) mixture during mechanical activation was investigated by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), magic angle spinning nuclear magnetic resonance (MAS-NMR), and X-ray photoelectron spectroscopy (XPS). Crystallinity and intrinsic structure changes of the starting mixture during high-energy milling were examined by XRD. The formation of new Mg-O-Si chemical bonds of the ground mixture was illustrated by the incorporation of Mg2+ in Si-O-Si linkages, the appearance of new resonance in the 29Si NMR spectrum and the decrease of the Si 2p binding energy. The formation of Mg-O-Si chemical bonds created during grinding partly contributed to the lowered temperature of complete forsterite formation from 1400 to 1100°C.

In situ molecular elucidation of drug supersaturation achieved by nano-sizing and amorphization of poorly water-soluble drug

Quantitative evaluation of drug supersaturation and nanoparticle formation was conducted using in situ evaluation techniques, including nuclear magnetic resonance (NMR) spectroscopy. We prepared a ternary complex of carbamazepine (CBZ) with hydroxypropyl methylcellulose (HPMC) and sodium dodecyl sulfate (SDS) to improve the drug concentration. Different preparation methods, including grinding and spray drying, were performed to prepare the ternary component products, ground mixture (GM) and spray-dried sample (SD), respectively. Although CBZ was completely amorphized in the ternary SD, CBZ was partially amorphized with the remaining CBZ crystals in the ternary GM. Aqueous dispersion of the ternary GM formed nanoparticles of around 150nm, originating from the CBZ crystals in the ternary GM. In contrast, the ternary SD formed transparent solutions without a precipitate. The molecular-level evaluation using NMR measurements revealed that approximately half a dose of CBZ in the ternary GM dispersion was present as nanoparticles; however, CBZ in the ternary SD was completely dissolved in the aqueous solution. The characteristic difference between the solid states, followed by different preparation methods, induced different solution characteristics in the ternary GM and SD. The permeation study, using a dialysis membrane, showed that the CBZ concentration dissolved in the bulk water phase rapidly reduced in the ternary SD dispersion compared to the ternary GM dispersion; this demonstrated the advantage of ternary GM dispersion in the maintenance of CBZ supersaturation. Long-term maintenance of a supersaturated state of CBZ observed in the ternary GM dispersion rather than in the ternary SD dispersion was achieved by the inhibition of CBZ crystallization owing to the existence of CBZ nanoparticles in the ternary GM dispersion. Nanoparticle formation, combined with drug amorphization, could be a promising approach to improve drug concentrations. The detailed elucidation of solution characteristics using in situ evaluation techniques will lead to the formation of useful solid dispersion and nanoparticle formulations, resulting in improved drug absorption.

Synthesis and growth mechanism of whisker‐like Mg 2 B 2 O 5 crystals by an easy and environmentally hospitable non‐aqueous ionic liquid method

An environmentally hospitable NaCl non-aqueous ionic liquid method has been employed to prepare single crystalline whisker-like Mg2B2O5 crystals, which were synthesised by annealing a ground mixture of H3BO3, MgCl2·6H2O, NaCl and surfactant nonylphenyl ether (9) at 850°C for 2 h. The systemically comparative experiments have been performed to understand the formation mechanism of whisker-like Mg2B2O5 crystals. The results demonstrated that both non-aqueous ionic liquid and nonylphenyl ether (9) played vital roles in the formation of whisker-like Mg2B2O5 crystals. Based on the experimental results and analysis, a reasonable growth mechanism of whisker-like Mg2B2O5 crystals is proposed. This reported work opens up a relative low-temperature strategy for the synthesis of single crystalline whisker-like Mg2B2O5 crystals.

Al-O-Si Bond Formation in Boehmite-Fumed Silica Mixtures during Mechanochemical Activation

Al-O-Si bond formation in boehmite-fumed silica mixtures during mechanochemical activation was investigated by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), magic angle spinning nuclear magnetic resonance (MAS-NMR) and X-ray photoelectron spectroscopy (XPS). The intrinsic structure deformation of the boehmite was examined with XRD. Formation of new Al-O-Si bonds was illustrated by the incorporation of Al3+ in Si-O-Si linkages, the change in the Al coordination number of boehmite, and the appearance of new resonance in the 29Si NMR spectrum of the ground mixture. The presence of Al-O units in silica frameworks was verified by the increase of Al 2p binding energy and the decrease of Si 2p binding energy.

Evaluation of actarit/γ-cyclodextrin complex prepared by different methods

This study used actarit (ACT), an antirheumatic drug, to examine the molecular interaction of ACT and γ-CD in a solid state as a result of cogrinding or freeze-drying and it assessed the dissolution of ACT. Differential scanning calorimetry revealed that coground ACT and γ-CD at molar ratios of 1:2 and 1:3 and freeze-dried ACT and γ-CD at molar ratios of 1:1 and 1:2 lacked an endothermic peak due to melting of ACT crystals. Thus, coground ACT and γ-CD at a molar ratio of 1:2 had molecular interaction, as did freeze-dried ACT and γ-CD at a molar ratio of 1:1. Powder x-ray diffraction revealed that coground and humidified ACT and γ-CD at a molar ratio of 1:2 produced a characteristic diffraction peak at 2θ = 15.2° and 16.5° due to the cage structure of γ-CD. In addition, freeze-dried ACT and γ-CD at a molar ratio of 1:1 that had been humidified produced a diffraction peak at 2θ = 6.0° and 15.9° characteristic of a hexagonal structure with head-to-head channels due to γ-CD. Assessment of dissolution revealed that ground mixtures (GMs) and freeze-dried mixtures had improved dissolution of ACT compared to ACT, ground ACT alone, and physical mixtures. The mechanism for this is presumably the result of molecular interaction in a solid state or molecular interaction in an aqueous solution. 1H–1H NOESY NMR spectra suggested that in a GM of ACT and γ-CD the benzene ring and methyl group of ACT partially enter the CD cavity. In addition, spectra for freeze-dried ACT and γ-CD suggested that protons of the methylene group of ACT and the benzene ring of ACT partially enter the CD cavity. These findings indicate that ACT and γ-CD inclusion complexes feature different forms of inclusion depending on how they are prepared, e.g., cogrinding or freeze-drying. Findings also indicated that selection of a method of preparation may play a major role in drug development.

Structural Determination of a Novel Polymorph of Sulfathiazole–Oxalic Acid Complex in Powder Form by Solid-State NMR Spectroscopy on the Basis of Crystallographic Structure of Another Polymorph

Two polymorphic forms of a sulfathiazole (STZ):oxalic acid (OXA) 1:1 complex were successfully prepared by different cogrinding methods and characterized by multiple analytical techniques. Rod-milled and ball-milled ground mixtures had different powder X-ray diffraction patterns, showing polymorph formation of the STZ-OXA complex (complex A and complex B). The heat of fusion from differential scanning calorimetry curves and terahertz time-domain spectra helped differentiating the polymorphs. According to infrared spectra, 13C NMR chemical shifts, and the relative intensities of 15N NMR peaks, both polymorphs were salts where the proton of a −COOH group in OXA was transferred to a −NH2 group in STZ. High-resolution 1H NMR and 1H–13C heteronuclear correlation NMR spectra indicated that complex B in powder form had a cocrystal type structure compared to complex A having a clathrate-type structure. Complex B structure suggested by solid-state NMR coincided well with the experimentally determined one, which wa...

An Investigation of Indomethacin–Nicotinamide Cocrystal Formation Induced by Thermal Stress in the Solid or Liquid State

The impact of thermal stress on indomethacin (IMC)-nicotinamide (NIC) cocrystal formation with or without neat cogrinding was investigated using differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) microspectroscopy, and simultaneous DSC-FTIR microspectroscopy in the solid or liquid state. Different evaporation methods for preparing IMC-NIC cocrystals were also compared. The results indicated that even after cogrinding for 40 min, the FTIR spectra for all IMC-NIC ground mixtures were superimposable on the FTIR spectra of IMC and NIC components, suggesting there was no cocrystal formation between IMC and NIC after cogrinding. However, these IMC-NIC ground mixtures appear to easily undergo cocrystal formation after the application of DSC determination. Under thermal stress induced by DSC, the amount of cocrystal formation increased with increasing cogrinding time. Moreover, simultaneous DSC-FTIR microspectroscopy was a useful one-step technique to induce and clarify the thermal-induced stepwise mechanism of IMC-NIC cocrystal formation from the ground mixture in real time. Different solvent evaporation rates induced by thermal stress significantly influenced IMC-NIC cocrystal formation in the liquid state. In particular, microwave heating may promote IMC-NIC cocrystal formation in a short time.

Real-time co-crystal screening and formation between indomethacin and saccharin via DSC analytical technique or DSC–FTIR microspectroscopy

A tool for quick screening co-crystal formation between indomethacin (IMC) and saccharin (SAC) was attempted using DSC analytical technique or DSC–FTIR microspectroscopy as an accelerated method. The solid-state characterizations of IMC, SAC, and their physical, 30-min ground, or solvent-evaporated mixture, were, respectively, investigated. The DSC data evidences that two endothermic peaks at 154 and 184 °C but one exothermic peak at 158 °C were observed in the DSC curve of the physical mixture of IMC–SAC. The former appeared at 154 °C might be due to the fusion of eutectic mixture, but the latter at 184 °C was corresponded to the melting point of IMC–SAC co-crystal following the exothermic peak at 158 °C. The exothermic peak at 158 °C was due to the induction of molecular interaction of IMC and SAC, leading to IMC–SAC co-crystal formation. This indicates that DSC analytical technique could directly detect the thermal changes of the physical mixture of IMC–SAC to form an IMC–SAC co-crystal. Once the temperature was beyond 154 °C after determination with DSC–FTIR microspectroscopy, several new IR absorption peaks at 3165, 1736, 1684, 1319, 1221, and 1176 cm−1 due to the IMC–SAC co-crystal formation via an intermolecular interaction were simultaneously observed from the thermal-dependent three-dimensional FTIR spectral contour. This one-step DSC–FTIR microspectroscopic system giving thermodynamic and spectroscopic information could easily and directly screen and detect the IMC–SAC co-crystal formation in real time.

Solid-state study of Captopril and Metoprolol Tartrate binary system

The structural and thermal characterization of Captopril (CA) and Metoprolol Tartrate (MT) pure compounds and binary system have been obtained. Solid–liquid equilibrium for binary mixture CA–MT was investigated using differential scanning calorimetry. Simple eutectic behavior for this system was observed. The experimental solid–liquid phase temperatures were compared with predictions obtained from available eutectic equilibrium models. The results indicate non-ideality in this mixture. The negative value of the mixing enthalpy indicates the presence of clusters with hydrogen bonds formation in the melt, as confirmed by FT-IR measurements. The preparation of ground mixtures demonstrated that the application of mechanical energy can result in the partial melting of the sample because of the eutectic behavior. Trans–cis iso-merization of CA was observed for the samples annealed at high temperature, anticipated due to the presence of MT in the system.

Spray-dried voriconazole–cyclodextrin complexes: Solubility, dissolution rate and chemical stability

The present work investigates the effect of complexation with hydroxypropyl-beta-cyclodextrin (HPBCD) and 2-O-methyl-beta-cyclodextrin (2-O-MBCD), on voriconazole solubility, dissolution rate and chemical stability. Drug–cyclodextrin complexes were prepared as aqueous solutions, which were spray-dried, and their properties were compared to wet ground samples and physical mixtures. DSC analysis revealed absence of crystalline voriconazole from spray-dried complexes. FTIR spectroscopy indicated changes in the H-bonding network of the hydroxyl groups of cyclodextrin following drug inclusion. Dissolution rate of voriconazole was significantly higher from spray-dried complexes with either cyclodextrin in comparison with free drug, physical mixtures, or wet ground mixtures. However, two degradation impurities were found in aged samples, with slightly higher impurity level with HPBCD. Performed solubility studies suggested that 2-O-MBCD is more efficient solubilizer. Molecular docking simulations showed a difference in the 1:1 binding affinities and sites, with HPBCD surprisingly forming complexes of much lower energy, thus suggesting a multiple rather than a 1:1 complexation.

Examination of intermolecular interaction as a result of cogrinding actarit and β-cyclodextrin

In this study, investigations were performed in regard to the possibility of complexation of actarit (ACT) with β-cyclodextrin (β-CD) for improving the solubility and dissolution rate. Complexes of β-CD and ACT (ACT/β-CD molar ratio = 1/1) were prepared using the cogrinding method. Formation of an ACT/β-CD inclusion complex by cogrinding was confirmed using powder X-ray diffraction measurement. The powder X-ray diffraction of the ground mixture (ACT/β-CD = 1/1) showed a halo pattern. The diffraction pattern of the ground mixture after storage at RH 82 %, 40 °C exhibited new diffraction peaks at 2θ = 11.6o and 17.8o, and differed from those of ACT and β-CD crystals. In vitro studies showed that the solubility and dissolution rate of ACT were significantly improved by complexation with β-CD with respect to the drug alone. In 1H-NMR measurement, changes in chemical shift (1H) suggested that the drug phenyl moiety was included in the cavities of β-CD mainly by hydrophobic interaction, and that the primary hydroxy side of β-CD was tightly associated with each drug. The results show clear evidence of intermolecular interaction between β-CD and ACT.

Theophylline–citric acid co-crystals easily induced by DSC–FTIR microspectroscopy or different storage conditions

A simultaneous differential scanning calorimetry–Fourier transform infrared (DSC–FTIR) microspectroscopy was used to quickly investigate the co-crystal formulation between anhydrous theophylline (TP) and anhydrous citric acid (CA) in a one-step procedure. The raw materials of TP and CA, as well as the intact TP–CA co-crystal prepared by slow solvent evaporation were also respectively examined by this approach. The result indicates that the TP–CA co-crystal formulation was easily induced using this DSC–FTIR technique. The thermal-dependent changes in three-dimensional FTIR spectral contour profiles were started from 165 °C to induce the co-crystal formation of TP–CA, which was prior to the endothermic peak at 173 °C found in the conventional DSC curve. Beyond 165 °C, several new IR absorption peaks at 3515, 3124, 1730, 1710, 1677, 1648, 1552 and 1265 cm−1 corresponding to unique IR spectral peaks of intact TP–CA co-crystal were observed. The DSC–FTIR microspectroscopic results also evidenced the dimer–monomer transition of CA, but there were no markedly changes for TP or intact TP–CA co-crystal before its fusion. This strongly implies that the DSC–FTIR technique giving spectroscopic and thermodynamic information could simultaneously induce and identify the TP–CA co-crystal formation and phase transition of samples. Different storage conditions affecting the stability of both physical mixture and ground mixture of TP–CA were also determined. The physical mixture of TP–CA after storing at 55 °C/75% RH condition for one day was fast transformed to TP–CA co-crystal, indicating that TP–CA co-crystal was easily induced under accelerated storage condition. While the co-crystal formed from TP–CA ground mixture was stable in both 25 °C/75% RH and 55 °C/75% RH conditions.

A portable fiber-optic Raman analyzer for fast real-time screening and identifying cocrystal formation of drug-coformer via grinding process

A portable Raman analyzer with a fiber-optic probe was first used to rapidly screen and identify the cocrystal formation between drug and coformer. Indomethacin (IMC) and anhydrous theophylline (TP) were selected as model drugs, but saccharin (SAC) and anhydrous citric acid (CA) were chosen as model coformers. The cocrystal formation that occurred in the solid-state IMC–SAC or TP–CA system via mechanical grinding process was investigated. Differential scanning calorimetry (DSC) was also used to investigate the possible cocrystal formation. The present study indicates that this new portable fiber-opticRaman spectroscopic technique was an easy and fast “real-time” method to screen and identify the progressive cocrystal formation in solid-state IMC–SAC or TP–CA system in the process of mechanical grinding by inserting the probe directly into the ground mixtures.

Dissolution rate enhancement of clarithromycin using ternary ground mixtures: nanocrystal formation.

Clarithromycin (CLA), a broad-spectrum macrolide, is a poorly soluble drug with dissolution rate limited absorption. The aim of this investigation was to prepare CLA nanoparticles from a ternary ground mixture in the presence of sodium lauryl sulfate (SLS) and polyvinyl pyrrolidone (PVP) as co-grinding water-soluble compounds, in order to improve the drug dissolution rate. Different weight ratios of CLA: SLS: PVP were ground in a dry process by planetary ball mill using different grinding ball size. Following the dissolution rate study, physical properties of the best dissolved co-ground formulation was studied. The accelerated stability studies were also conducted on the co-ground formulation. The results revealed that the dissolution rate of ternary ground mixtures was much higher than that of the intact drug (p < 0.001). Decreasing the grinding ball size and weight with the same rotation speed resulted in particles with decreased dissolution. On the other hand, increasing the PVP concentration in the formulations reduced the drug dissolution. Dissolution efficiencies (DE10 and DE30) for the best dissolved formulation, which consisted of the equal ratio of each co-ground component, were 8.7 and 5 folds higher than the untreated CLA, respectively. This formulation formed nanocrystals with enhanced solubility after dispersing in water. X-ray diffraction, differential scanning calorimetry and infrared spectrophotometry confirmed no chemical interaction and phase transition during the process. Accelerated stability studies confirmed that the co-ground mixture almost remained unchanged in terms of dissolution rate, drug assay and particle size after exposing in stability conditions for three months.