The preparation of agglomerates containing solid dispersions of diazepam by melt agglomeration in a high shear mixer

The aim of this study was to prepare by melt agglomeration agglomerates containing solid dispersions of diazepam as poorly water-soluble model drug in order to evaluate the possibility of improving the dissolution rate. Lactose monohydrate was melt agglomerated with polyethylene glycol (PEG) 3000 or Gelucire 50/13 (mixture of glycerides and PEG esters of fatty acids) as meltable binders in a high shear mixer. The binders were added either as a mixture of melted binder and diazepam by a pump-on procedure or by a melt-in procedure of solid binder particles. Different drug concentrations, maximum manufacturing temperatures, and cooling rates were investigated. It was found to be possible to increase the dissolution rate of diazepam by melt agglomeration. A higher dissolution rate was obtained with a lower drug concentration. Admixing the binders by the melt-in procedure resulted in similar dissolution rates as the pump-on procedure. The different maximum manufacturing temperatures and cooling rates were found to have complex effects on the dissolution rate for formulations containing PEG 3000, whereas only minor effects of the cooling procedure were found with Gelucire 50/13. Gelucire 50/13 resulted in faster dissolution rates compared to PEG 3000.     

Characterization of agglomerated carvedilol by hot-melt processes in a fluid bed and high shear granulator

The purpose of this study was to prepare and characterize granulated carvedilol by melt-in and spray-on melt granulation in a fluid bed and a high shear granulator. Granulates having comparable particle size distribution and good flow properties were obtained with proper adjustment of process parameters for each binder (poloxamer 188, polyethylene glycol 4000, and gliceryl monosterate), procedure (spray-on and melt-in) and equipment (fluid bed and high shear granulator). In-line probes for particle size measurements proved to be a useful tool for determining the end point of melt granulation. The product temperature during melt granulation was found to be the critical process parameter for achieving appropriate granulate particle size distribution. The results showed that melt granulation using hydrophilic binders is an effective method to improve the dissolution rate of carvedilol. The method of binder addition to the powders (melt-in or spray-on procedure) was found to strongly influence the dissolution rate of carvedilol. The highest dissolution rates were obtained when the spray-on procedure is used, independently from the type of granulator used. The results also suggest that the most probable explanation for the increase in the dissolution rate of granulated carvedilol is improvement of the wettability through intimate contact between hydrophilic binder and hydrophobic drug.     

Effects of binder rheology on melt agglomeration in a high shear mixer

Lactose monohydrate was melt agglomerated in an 8-l high shear mixer using Gelucire 50/13, Stearate 6000 WL 1644, or polyethylene glycol (PEG) 3000 as meltable binder. The impeller speed was varied at two levels, and massing time was varied at six levels. In order to obtain a similar agglomerate growth, a larger binder volume had to be used with Gelucire 50/13 than with Stearate 6000 WL 1644 and PEG 3000. The lower viscosity of Gelucire 50/13 gave rise to agglomerates of a wider size distribution and a higher porosity as well as more adhesion of mass to the bowl. A lower binder viscosity resulted in more spherical agglomerates at the low impeller speed.     

Effects of droplet size and type of binder on the agglomerate growth mechanisms by melt agglomeration in a fluidised bed.

This study was performed in order to evaluate the effects of binder droplet size and type of binder on the agglomerate growth mechanisms by melt agglomeration in a fluidised bed granulator. Lactose monohydrate was agglomerated with melted polyethylene glycol (PEG) 3000 or Gelucire 50/13 (esters of polyethylene glycol and glycerol), which was atomised at different nozzle air flow rates giving rise to median droplet sizes of 40, 60, and 80 microm. Different product temperatures were investigated, below the melting range, in the middle of the melting range, and above the melting range for each binder. The agglomerates were found to be formed by initial nucleation of lactose particles immersed in the melted binder droplets. Agglomerate growth occurred by coalescence between nuclei followed by coalescence between agglomerates. Complex effects of binder droplet size and type of binder were seen at low product temperatures. Low product temperatures resulted in smaller agglomerate sizes, because the agglomerate growth was counteracted by very high binder viscosity or solidification of the binder. At higher product temperatures, neither the binder droplet size nor the type of binder had a clear effect on the final agglomerate size.     

Effects of physical properties of powder particles on binder liquid requirement and agglomerate growth mechanisms in a high shear mixer.

A study was performed in order to elucidate the effects of the physical properties of small powder particles on binder liquid requirement and agglomerate growth mechanisms. Three grades of calcium carbonate having different particle size distribution, surface area, and particle shape but approximately the same median particle size (4-5 microm), were melt agglomerated with polyethylene glycol (PEG) 3000 or 20,000 in an 8-l high shear mixer at three impeller speeds. The binder liquid requirement was found to be very dependent on the packing properties of the powder, a denser packing resulting in a lower binder liquid requirement. The densification of the agglomerates in the high shear mixer could be approximately predicted by compressing a powder sample in a compaction simulator. With the PEG having the highest viscosity (PEG 20,000), the agglomerate formation and growth occurred primarily by the immersion mechanism, whereas PEG 3000 gave rise to agglomerate growth by coalescence. Powder particles with a rounded shape and a narrow size distribution resulted in breakage of agglomerates with PEG 3000, whereas no breakage was seen with PEG 20,000. Powder particles having an irregular shape and surface structure could be agglomerated with PEG 20,000, whereas agglomerate growth became uncontrollable with PEG 3000. When PEG 20,000 was added as a powder instead of flakes, the resultant agglomerates became rounder and the size distribution narrower.     

Hydration of an amphiphilic excipient, Gelucire 44/14

The incorporation of drugs into Gelucires has been reported to increase the dissolution rate of poorly soluble drugs, often leading to improved drug bioavailability. In pharmaceutical applications, it is important to know how the excipient interacts with the drug, and how the mixture behaves during manufacturing, storage as well as during administration. The uptake of water by an amphiphilic excipient, Gelucire 44/14, has been investigated in two ways: storage in humid air and addition of liquid water. During exposure to humid air, the uptake goes in stages that correspond to the dissolution of the components of the excipient, starting with the most hydrophilic ones: glycerol, then polyethylene glycol (PEG), PEG esters (PEG monolaurate and PEG dilaurate), and finally glycerides (trilaurin). At each stage, the remaining crystals are in equilibrium with an interstitial solution made of water and the dissolved components. In this range of hydrations, the total uptake is close to the sum of the equilibrium hydrations of the components. In the pharmaceutical formulation, the active ingredient could dissolve in the liquid phase. At larger hydrations, obtained through addition of liquid water, the state of Gelucire 44/14 differs from those of its components. Gelucire 44/14 forms a lamellar phase and this phase melts at 30 degrees C whereas the pure PEG esters form hexagonal and cubic mesophases. The cubic mesophases do not melt until the temperature exceeds 40 degrees C. At body temperature, all crystals in Gelucire 44/14 melt to an isotropic fluid as soon as the total water content exceeds 5%. Therefore the formulation of amphiphilic excipients can be optimized to avoid the formation of mesophases that impede dissolution of the excipient at body temperature.     

Effect of the melt granulation technique on the dissolution characteristics of griseofulvin

This work describes a melt granulation technique to improve the dissolution characteristics of a poorly water-soluble drug, griseofulvin. Melt granulation technique is a process by which pharmaceutical powders are efficiently agglomerated by a meltable binder. The advantage of this technique compared to a conventional granulation is that no water or organic solvents is needed. Because there is no drying step, the process is less time consuming and uses less energy than wet granulation. Granules were prepared in a lab scale high shear mixer, using a jacket temperature of 60 degrees C and an impeller speed of approximately 20,000 rpm. The effect of drug loading (2.5/5%), binder (PEG 3350/Gelucire 44/14), filler (starch/lactose), and HPMC on the dissolution of griseofulvin was investigated using a half two level-four factor factorial design. The granules were characterized using powder XRD, DSC and SEM techniques. A significant enhancement in the in vitro dissolution profiles of the granules was observed compared to the pure drug and drug excipient physical mixtures. The factorial design results indicated that higher drug loading and the presence of HPMC reduced the extent of dissolution of the drug, whereas, the presence of starch enhanced the dissolution rate. XRD data confirmed crystalline drug in formulation matrices. DSC results indicated monotectic mixtures of griseofulvin with PEG in the granulated formulations. In conclusion, the results of this work suggest that melt granulation is a useful technique to enhance the dissolution rate of poorly water-soluble drugs, such as, griseofulvin.     

壬二酸固体分散体的制备及其表征

目的:制备壬二酸固体分散体,改善壬二酸的溶出度,从而提高其生物利用度。方法:分别以聚乙二醇6000(PEG)、泊洛沙姆188为载体并选取药物与其不同比例(1:3、1:6、1:9),采用熔融法、溶剂-熔融法制备壬二酸固体分散体,并对其进行体外溶出度的考察及比较;采用差示扫描量热法、X射线粉末衍射法鉴别壬二酸在固体分散体中的存在状态。结果:以PEG为载体的固体分散体的药物溶出优于以泊洛沙姆188为载体的固体分散体(90min内溶出分别为100%和80%);且当药物与PEG的比例为1:9时,药物的溶出效果最好,与原料药比较药物溶出50%所需的时间大大缩短(12.65、45.65min)。壬二酸-PEG固体分散体中药物部分呈分子状态分散,部分呈微晶状态分散。结论:壬二酸与PEG(1:9)的固体分散体能显著提高药物的溶出度。     

The effect of droplet size and powder particle size on the mechanisms of nucleation and growth in fluid bed melt agglomeration

This study was performed in order to evaluate the effects of binder droplet size and powder particle size on agglomerate formation and growth in fluid bed spray agglomeration using a meltable binder. Three different lactose grades, 100, 125 or 350 mesh, were agglomerated using polyethylene glycol (PEG) 3000 at two different concentrations, 11.5 or 22% (volume/mass), and three spray droplet sizes, 30, 60 or 90 microm were applied. The ratio of droplet size/particle size was found to determine whether the mechanism of nucleation was distribution or immersion. Distribution was promoted by a low ratio, whereas immersion was promoted by a high ratio. Distribution as nucleation mechanism led to a more open agglomerate structure and immersion to a denser structure. When the nucleation phase was terminated, coalescence between rewetted nuclei or agglomerates was the growth mechanism with both preceding mechanisms of nucleation. A larger particle size of the lactose led to larger agglomerates. The difference in the effect on growth between the 30 and 60 microm droplets was generally low. The 90 microm droplets at 22% binder concentration offered a potential for uncontrollable growth giving rise to markedly larger agglomerates and a lower reproducibility than 30 and 60 microm droplets.     

Evaluation of melt granulation and ultrasonic spray congealing as techniques to enhance the dissolution of praziquantel

Praziquantel (PZQ), an anthelminthic drug widely used in developing countries, is classified in Class II in the Biopharmaceutics Classification Systems; this means that PZQ has very low water solubility and high permeability, thus the dissolution is the absorption rate-limiting factor. The aim of this work was to evaluate the suitability of melt granulation and ultrasonic spray congealing as techniques for enhancing the dissolution rate of PZQ. Granules in high shear mixer were prepared by melt granulation, using polyethylene glycol 4000 or poloxamer 188 as meltable binders and alpha-lactose monohydrate as a filler. Quite regularly shaped granules having main size fraction in the range 200-500 microm were obtained using both formulations; however, only poloxamer 188 granules demonstrated a significant (P=0.05) increase of the PZQ dissolution rate compared to pure drug. To evaluate the potential of ultrasonic spray congealing, Gelucire 50/13 microparticles having different drug to carrier ratios (5, 10, 20 and 30%, w/w) were then prepared. The results showed that all the microparticles had a significant higher dissolution rate (P=0.05) respect to pure PZQ. The increase of the PZQ content considerably decreased the dissolution rate of the drug: 5 and 10% PZQ loaded systems evidenced dissolution significantly enhanced compared to 20 and 30% PZQ microparticles. The microparticle's characterisation, performed by Differential Scanning Calorimetry, Hot Stage Microscopy, X-ray powder diffraction and FT-Infrared analysis, evidenced the absence of both modifications of the solid state of PZQ and of significant interactions between the drug and the carrier. In conclusion, melt granulation and ultrasonic spray congealing could be proposed as solvent free, rapid and low expensive manufacturing methods to increase the in vitro dissolution rate of PZQ.     

Preparation and characterisation of ibuprofen-poloxamer 188 granules obtained by melt granulation.

The aim of this study was to prepare, by melt granulation, granules containing ibuprofen as a poorly water soluble model drug in order to improve its dissolution rate and its availability; lactose as a diluent and poloxamer 188 (Lutrol F68), as a new meltable hydrophilic binder, were used. The granules were prepared in a laboratory-scale high-shear mixer, using a jacket temperature of 50 degrees C and an impeller speed of 500 rpm. The particle size analysis shows that the main fraction was between 200 and 500 microm, while the determination of drug content indicated that ibuprofen was quite uniformly distributed in all the fractions. Scanning Electron Microscopy (SEM), image and fractal analysis revealed that the granules did not have a perfect spherical shape and a rugged surface (D(s)=2.6475). The in vitro dissolution tests showed an increase in the dissolution rate of granules compared to pure drug and physical mixture. The characterisation of the samples, performed by Differential Scanning Calorimetry (DSC) and X-ray powder diffraction (XRD), suggests that the improvement of dissolution rate could be correlated to the formation of a eutectic mixture between the drug and the binder. Stability studies indicated that the granule properties do not change, at least after 1 year of storage at 25 degrees C. In conclusion, the results of this work suggest that the melt granulation technique is an easy and fast method to improve the dissolution rate of ibuprofen, using poloxamer 188 as a new hydrophilic meltable binder.     

Melt agglomeration with polyethylene glycol beads at a low impeller speed in a high shear mixer.

This study was performed in order to evaluate the possibility of obtaining spherical agglomerates with a high content of meltable binder by a melt agglomeration process in a high shear mixer. Lactose monohydrate was melt agglomerated with polyethylene glycol (PEG) 1500 or 6000 in a 10-l high shear mixer at an impeller speed of 400 rpm. The PEG 1500 was used as a size fraction of beads, and the PEG 6000 as a fine powder, a powder, unfractionated beads, and size fractions of beads. It was found to be possible to incorporate a high amount of PEG (28% m/m of the amount of lactose), because the rather low impeller speed applied in the present experiments caused less densification of the agglomerates. The fine powder of the PEG 6000 caused a complete adhesion of the mass to the bowl shortly after melting. A rapid agglomerate growth by coalescence was found to be the dominant growth mechanism when agglomeration was performed with the PEG 6000 powder. The PEG beads resulted in a slow and more controllable agglomerate growth, because the growth occurred primarily by an immersion of the lactose particles in the surface of the molten binder droplets. The initial shape of the agglomerates produced with the PEG beads was similar to the spherical shape of the beads. This shape could not be maintained during the process due to a breakage of the agglomerates caused by a hollow structure of the PEG beads.     

Stabilization and Improved <Emphasis Type="BoldItalic">in Vivo</Emphasis> Performance of Amorphous Etoricoxib using Gelucire 50/13

Purpose Amorphous drugs have gained importance because of their advantageous biopharmaceutical properties; however, their stabilization remains a challenge. The purpose of this work was to stabilize the amorphous form of etoricoxib (ET) by using a low excipient/drug ratio to improve drug dissolution and thus bioavailability. Methods The effect of Gelucire and polyvinylpyrrolidone (PVP) on stabilization and bioavailability of amorphous etoricoxib (AET) was studied. X-ray powder diffractometry, differential scanning calorimetry, and scanning electron microscopy were used to study the physical state of the drug. Dissolution studies were performed for melt granules of AET with Gelucire 50/13 (MG-AET) and solid dispersion with PVP (SDP) to differentiate dissolution performance. A stability study on samples was conducted for 3 months to evaluate the physical state of the drug and its dissolution in the formulation. The in vivo performance of the optimized and stable formulation of ET was evaluated in rat. Results Dissolution of MG-AET was significantly improved as compared to AET and SDP. Both factors, amorphization of drug and melt granulation with lipid, seemed to be important for improving dissolution. Stability data revealed that MG-AET was significantly advantageous for AET stabilization, whereas PVP was not. The amount of Gelucire required for the stabilization of one part of AET was 0.5 part (by weight), whereas even 1.5 part (by weight) of PVP failed to elicit the same result. The superior in vivo performance of MG-AET has been attributed to the altered physiochemical properties of AET and the presence of lipid in the system. Conclusion Gelucire can stabilize AET and improve its biopharmaceutical performance at a low excipient/drug ratio and may provide a better alternative to conventional stabilizers such as PVP.     

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.     

盐酸小檗碱泊洛沙姆188固体分散体的制备

目的:制备盐酸小檗碱泊洛沙姆188固体分散体。方法:采用熔融法制备固体分散体,考察药物和载体的比例、熔融温度、冷却温度对溶出率的影响,比较固体分散体和物理混合物的溶出率的区别。结果:药物和载体比例达到1∶1时,载体的量足够使药物分散均匀;熔融温度对溶出率影响不大;冷却温度对溶出率影响较大,0℃时溶出率最快。与物理混合物相比,固体分散体将盐酸小檗碱的溶出率提高了近1倍。结论:盐酸小檗碱泊洛沙姆188固体分散体提高了盐酸小檗碱的体外溶出率。     

Improved solubility and dissolution rate of piroxicam using gelucire 44/14 and labrasol

Piroxicam is a nonsteroidal anti-inflammatory drug that is characterized by low solubility-high permeability. The present study was designed to improve the dissolution rate of piroxicam at the physiological pH's through its increased solubility by preparing semi-solid dispersions of drug using Gelucires and Labrasol. These excipients are essentially characterized by their melting points and HLB (hydrophilic-lipophilic balance) values. The dissolution tests of the preparations were performed in the media with different pH's. Differential scanning calorimetry (DSC), were used to examine the interaction between piroxicam and excipients. Gelucire 44/14 and Labrasol at the concentration of 15% w/v in water provided 20- and 50-fold increase in the solubility of piroxicam, respectively. The semi-solid dispersion containing 1/20 of drug/excipient mixture (20% Gelucire 44/14 and 80% Labrasol in w/w) produced the dissolution not less than 85% of piroxicam within 30 min in each dissolution media (simulated gastric fluid (SGF), pH 1.2; phosphate buffers, pH 4.5 and 6.8; and water). DSC analysis of this semi-solid dispersion indicated that there was no chemical reaction between the drug and excipients, and that a solid-state solution of piroxicam with excipient formed.     

Physicochemical characterization of solid dispersions of the antiviral agent UC-781 with polyethylene glycol 6000 and Gelucire 44/14

The purpose of this study was to prepare and characterize solid dispersions of the antiviral thiocarboxanilide UC-781 with PEG 6000 and Gelucire 44/14 with the intention of improving its dissolution properties. The solid dispersions were prepared by the fusion method. Evaluation of the properties of the dispersions was performed using dissolution studies, differential scanning calorimetry, Fourier-transform infrared spectroscopy and X-ray powder diffraction. To investigate the possible formation of solid solutions of the drug in the carriers, the lattice spacings [d] of PEG 6000 and Gelucire 44/14 were determined in different concentrations of UC-781. The results obtained showed that the rate of dissolution of UC-781 was considerably improved when formulated in solid dispersions with PEG 6000 and Gelucire 44/14 as compared to pure UC-781. From the phase diagrams of PEG 6000 and Gelucire 44/14 it could be noted that up to approximately 25% w/w of the drug was dissolved in the liquid phase in the case of PEG 6000 and Gelucire 44/14. The data from the X-ray diffraction showed that the drug was still detectable in the solid state below a concentration of 5% w/w in the presence of PEG 6000 and Gelucire 44/14, while no significant changes in the lattice spacings of PEG 6000 or Gelucire 44/14 were observed. Therefore, the possibility of UC-781 to form solid solutions with the carriers under investigation was ruled out. The results from infrared spectroscopy together with those from X-ray diffraction and differential scanning calorimetry showed the absence of well-defined drug–polymer interactions.     

Melt pelletization with polyethylene glycol in a rotary processor

The purpose of this study was to investigate the effect of the airflow, the binder concentration, the massing time, the friction plate rotation speed, and the surface structure of the friction plate on melt pelletization in a laboratory scale rotary processor. Lactose monohydrate was melt agglomerated with polyethylene glycol (PEG) 3000 as meltable binder. The study was performed as a full factorial design. An increase in agglomerate size was found when the binder concentration, the massing time, or the friction plate rotation speed was increased. The agglomerate size was also increased when increasing the shearing forces by using a friction plate with a different surface structure. The size distribution of the agglomerates was significantly narrowed when the binder concentration or the shearing forces caused by the friction plate were increased. An increase in the adhesion of material to the friction plate was found when the shearing forces of the friction plate were increased either by the rotation speed or by the surface structure. Generally, the rotary processor was found to be a suitable alternative to melt pelletization in a high shear mixer.     

Solubility enhancement of desloratadine by solid dispersion in poloxamers

The present study investigates the possibility of using poloxamers as solubility and dissolution rate enhancing agents of the poorly water soluble drug substance desloratadine that can be used for the preparation of immediate release tablet formulation. Two commercially available poloxamer grades (poloxamer P 188 and poloxamer P 407) were selected, and solid dispersions (SDs) containing different weight ratio of poloxamers and desloratadine were prepared by a low temperature melting method. All SDs were subjected to basic physicochemical characterization by thermal and vibrational spectroscopy methods in order to evaluate the efficiency of poloxamers as solubility enhancers. Immediate release tablets were prepared by direct compression of powdered solid dispersions according to a General Factorial Design, in order to evaluate the statistical significance of two formulation (X(1) - type of poloxamer in SD and X(2) - poloxamer ratio in SD) and one process variable (X(3) - compression force) on the drug dissolution rate. It was found that desloratadine in SDs existed in the amorphous state, and that can be largely responsible for the enhanced intrinsic solubility, which was more pronounced in SDs containing poloxamer 188. Statistical analysis of the factorial design revealed that both investigated formulation variables exert a significant effect on the drug dissolution rate. Increased poloxamer ratio in SDs resulted in increased drug dissolution rate, with poloxamer 188 contributing to a faster dissolution rate than poloxamer 407, in accordance with the results of intrinsic dissolution tests. Moreover, there is a significant interaction between poloxamer ratio in SD and compression force. Higher poloxamer ratio in SDs and higher compression force results in a significant decrease of the drug dissolution rate, which can be attributed to the lower porosity of the tablets and more pronounced bonding between poloxamer particles.     

Single-step preparation and deagglomeration of itraconazole microflakes by supercritical antisolvent method for dissolution enhancement

Itraconazole (ITZ) microflakes were produced by supercritical antisolvent (SAS) method and simultaneously mixed with pharmaceutical excipients in a single step to prevent drug agglomeration. Simultaneous ITZ particle formation and mixing with fast-flo lactose (FFL) was performed in a high-pressure stirred vessel at 116 bar and 40 °C by the SAS-drug excipient mixing (SAS-DEM) method. The effects of stabilizers, such as sodium dodecyl sulfate and poloxamer 407 (PLX), on particle formation and drug dissolution were studied. Drug-excipient formulations were characterized for surface morphology, crystallinity, drug-excipient interactions, drug content uniformity, and drug dissolution rate. Mixture of drug microflakes and FFL formed by the SAS-DEM process shows that the process was successful in overcoming drug-drug agglomeration. PLX produced crystalline drug flakes in loose agglomerates with superior dissolution and flow properties even at higher drug loadings. Characterization studies confirmed the crystallinity of the drug and absence of chemical interactions during the SAS process. The dissolution of ITZ was substantially higher due to SAS and SAS-DEM processes; this improvement can be attributed to the microflake particle structures, effective deagglomeration, and wetting of the drug flakes with the excipients.