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Ultrasonics Sonochemistry xxx (2014) xxx–xxx Contents lists available at ScienceDirect Ultrasonics Sonochemistry journal homepage: www.elsevier.com/locate/ultson Modulation of particle size and molecular interactions by sonoprecipitation method for enhancing dissolution rate of poorly water-soluble drug Thao Truong-Dinh Tran ⇑, Kiet Anh Tran, Phuong Ha-Lien Tran ⇑ Pharmaceutical Engineering Laboratory, Biomedical Engineering Department, International University, Vietnam National University – Ho Chi Minh City, Viet Nam a r t i c l e i n f o Article history: Received October 2014 Received in revised form 29 November 2014 Accepted 29 November 2014 Available online xxxx Keywords: Curcumin Polymeric nanoparticles Molecular interactions Crystallinity Ultrasonication a b s t r a c t Aim of present work was to originally elucidate the roles of ultrasonication method for modulating the size and molecular interactions in controlling release of poorly water-soluble drug Curcumin was chosen as a model drug Three types of polymers were investigated as carriers for preparation of polymeric nanoparticles under various ultrasonication conditions and polymer–drug ratios Changes in drug crystallinity, particle size, and molecular interactions which would be factors enhancing drug dissolution rate were evaluated Amorphous form of curcumin, size reduction of nanoparticles and interaction between drug and polymer in formulations were attributed to improved drug dissolution rate Particle size was strongly affected by polymer type, polymer–drug ratio and ultrasonication conditions Interestingly, control of those factors caused differences in molecular interactions of the hydroxyl groups and then, highly affected particle size of the nanoparticles It was obvious that there was a reciprocal influence between the drug–polymer interactions and particle size of the nanoparticles This relation could be modulated by polymers and ultrasonication processes for enhancing drug dissolution rate Ó 2014 Elsevier B.V All rights reserved Introduction Currently, one of the major current challenges of the pharmaceutical industry is related to strategies that improve the water solubility of drugs because over 40% of new drug candidates are water-insoluble agents [1–3] These drugs have problems associated with rate-limiting dissolution, slow absorption and low bioavailability [4,5] Many techniques have been investigated so far to overcome the troubles of poorly water-soluble drugs, but on the whole there are only some general rules as follows: particle size reduction, salt formation, complexation, solid dispersion, addition of solvent or surface active agents A reduction of particle size and changes of physicochemical properties of a formulation are efficient strategies to improve dissolution rate of these drugs, resulting in a substantial increase in oral bioavailability [6–9] The precipitation process has been widely investigated for production of nanoparticles in the last few decades However, it has been reported that the sonoprecipitation method has been rarely used in this process to prepare polymeric nanoparticles [10] The technique has been employed for few drugs such as cefur⇑ Corresponding authors Tel.: +84 (8) 37244270x3328; fax: +84 (8) 37244271 E-mail addresses: ttdthao@hcmiu.edu.vn (T.T.-D Tran), thlphuong@hcmiu.edu (P.H.-L Tran) oxime axetil [11], griseofulvin [12,13], ibuprofen [12], itraconazole [12], sulfamethoxazole [12], nitrendipine [14], isradipine [15] Regarding physicochemical properties of formulations of poorly water-soluble drugs, changes of drug crystallinity and molecular interactions are aspects to be concerned to investigate mechanism of enhanced drug dissolution While an alternative structure of drug from crystalline to amorphous state may occur to improve the dissolution, an interaction among agents is another factor to contribute to the enhanced drug dissolution Although molecular interaction between drug and polymer has been known as an important factor for improving dissolution rate [3,7,16–18], there have been no studies through sonoprecipitation method indicating modulation of molecular interactions and its interesting effects on particle size for the control of drug dissolution rate in details Moreover, there have been no reports on dissolution enhancement of curcumin (CUR) which is extremely poor water solubility (11 ng/ml) [19] by precipitation–ultrasonication method In 2010, Zheng et al has studied on sonication–assisted synthesis of polyelectrolyte-coated CUR nanoparticles [20] Nevertheless, the CUR release was almost done after 20 h and may be only suitable for sustained release dosage forms More recently, the precipitation–ultrasonication method has been applied for preparation of stable CUR nanocrystal without reports of drug release profiles [21] Also, mechanisms of CUR release were not mentioned in those http://dx.doi.org/10.1016/j.ultsonch.2014.11.020 1350-4177/Ó 2014 Elsevier B.V All rights reserved Please cite this article in press as: T.-T.D Tran et al., Modulation of particle size and molecular interactions by sonoprecipitation method for enhancing dissolution rate of poorly water-soluble drug, Ultrason Sonochem (2014), http://dx.doi.org/10.1016/j.ultsonch.2014.11.020 T.T.-D Tran et al / Ultrasonics Sonochemistry xxx (2014) xxx–xxx researches This research would provide not only useful information about the preparation of CUR polymeric nanoparticles by the precipitation–ultrasonication method but also an interesting aspect about the modulation of molecular interaction on particle size and drug dissolution rate The crystallinity of CUR in polymeric nanoparticles was also investigated The report may suggest a solution for further studies in the effort of enhancing dissolution rate of poorly water-soluble drugs 2.2.3 HPLC analysis The quantification of CUR was performed by HPLC system (Dionex, USA) The mixture of methanol and acetic acid solution (2%) was used as the mobile phase with ratio 8:2 The flow rate was maintained at 1.2 mL/min Luna l C18 analytical column (150 Â 4.6 mm) was maintained at 25 °C ± 0.5 °C The UV–Vis detector was set at 425 nm 20 lL of sample were injected into HPLC system for analysis Materials and methods 2.2.4 Particle size analysis After treating by ultrasonication, the nanosuspension sample was immediately analyzed particle size by the Particle Size Distribution Analyzer (LA-920, HORIBA, Japan) 2.1 Materials Curcumin (CUR), acetic acid (CH3COOH), sodium hydroxide (NaOH) were purchased from Guangdong Guanghua Sci-Tech company (China) Monopotassium phosphate (KH2PO4) was purchased from Wako Pure Chemical Industries (Japan) Hydrochloric acid, acetone (CH3COCH3), Sodium chloride (NaCl) were purchased from Xilong Chemical Industry Incorporated Company (China) Hydroxypropyl methylcellulose (HPMC 6), hydroxypropyl methylcellulose 4000 (HPMC 4000), and polyethylene oxide N-60K (PEO) were provided by Dow Chemical Company (USA) Methanol–HPLC grade was purchased from Thermo Fisher Scientific Inc 2.2 Methods 2.2.1 Preparation of polymeric nanoparticles Polymeric nanoparticles were prepared in the following steps CUR used in all of the formulations was firstly dissolved in acetone PEO (or HPMC 4000 or HPMC 6) was dissolved in distilled water The CUR solution was quickly introduced into the polymer solution under stirring The precipitated sample in 1000 mL-glass beaker was continuously treated with tip of ultrasonicator (QSONICA, USA) at a controlled room temperature (25 °C) The temperature of each sample was measured before and after ultrasonication Acetone was completely evaporated under stirring The nanosuspension was then lyophilized at À50 °C until powder was obtained for physicochemical analyses The detailed formulations including ultrasonic powers (W) are described in Table 2.2.2 Dissolution studies Dissolution rate of CUR was tested in enzyme-free simulated gastric fluid (pH 1.2) and enzyme-free simulated intestinal fluid (pH 6.8) by dissolution tester (DT 70 Pharma Test, Germany) The samples equivalent to 30 mg CUR were exposed to 900 mL of dissolution medium at 37 ± 0.5 °C and the paddle was set at 50 rpm At regular time intervals (10, 20, 30, 60, 90 and 120 min), ml of medium was withdrawn for determination of drug release An equivalent amount of fresh medium was replaced to maintain a constant dissolution volume Table Formulation compositions and precipitation–ultrasonication conditions for preparation of polymeric nanoparticles CUR and polymer were dissolved in acetone and water with concentration 30 mg/ml and mg/ml, respectively Codes CUR (mg) PEO (mg) HPMC4000 (mg) HPMC6 (mg) Power (W) Time (min) FN1 FN2 FN3 FN4 FN5 FN6 FN7 FN8 FN9 30 30 30 30 30 30 30 30 30 180 – – – – – – – – – 180 – – – – – – – – – 180 180 180 180 180 60 120 15 15 15 15 15 12 15 15 20 20 20 10 20 20 20 20 2.2.5 Powder X-ray diffraction (PXRD) CUR, physical mixtures of drug and polymer (HPMC 6, HPMC 4000 and PEO), polymeric nanoparticle powders were analyzed the crystallinity by X-ray Diffractometer (Bruker D8 Advance, Germany) using Cu-Ka radiation at a voltage of 40 kV, 50 mA The samples were scanned in increments of 0.02° from 5° to 60° (diffraction angle 2h) at s/step, using a zero background sample holder 2.2.6 Fourier transform infrared spectroscopy (FTIR) A FTIR spectrophotometer (Bruker Vertex 70, Germany) was used to investigate the spectra of CUR, physical mixtures of drug and polymer (HPMC 6, HPMC 4000 and PEO), polymeric nanoparticle powders The wavelength was scanned from 500 to 4000 cmÀ1 with a resolution of cmÀ1 KBr pellets were prepared by gently mixing mg of the sample with 200 mg KBr 2.2.7 Transmission electron microscopy Transmission electron microscopy (TEM) was used to observe the encapsulation of CUR in polymeric nanoparticles, as well as size and shape of the nanoparticles The samples were examined using JEM-1400 Transmission Electron Microscope (Jeol, Japan) Results and discussion 3.1 Dissolution enhancement of polymeric nanoparticles: the role of particle size formation Dissolution enhancement of CUR was firstly investigated with three polymers: PEO, HPMC 4000 and HPMC In the preliminary experiments, the dissolution of physical mixture (drug and polymer at the ratio 1:6) demonstrated insignificant effect on CUR release Percent of drug release from three polymers after h in dissolution medium were under 40% For an investigation of ultrasonication, drug and polymer ratio was also fixed at the ratio 1:6 and ultrasonication conditions were fixed at ultrasonic power 15 W in 20 All of the polymeric nanoparticles showed a potential dissolution enhancement of CUR significantly at both pH 1.2 and pH 6.8 (Fig 1A and B) However, among polymers, HPMC showed the best ability to increase the dissolution rate of CUR Meanwhile, drug release from the nanoparticles of PEO or HPMC 4000 was lower Specially, the same amount of drug was released from HPMC 4000 nanoparticles at the first 10 as compared to HPMC However, CUR was immediately precipitated after 10 and then had the same release profile as that of PEO nanoparticles at both pH 1.2 and pH 6.8 These results indicated that polymer type played a critical role on formation of nanoparticles which directly affected dissolution of CUR HPMC could form a nano size of particles to enhance the dissolution (Table 2, FN3) In contrast, HPMC 4000 or PEO still showed a micro scale of particles (Table 2, FN1 and FN2) Different size of the Please cite this article in press as: T.-T.D Tran et al., Modulation of particle size and molecular interactions by sonoprecipitation method for enhancing dissolution rate of poorly water-soluble drug, Ultrason Sonochem (2014), http://dx.doi.org/10.1016/j.ultsonch.2014.11.020 120 120 100 100 80 80 % drug release % drug release T.T.-D Tran et al / Ultrasonics Sonochemistry xxx (2014) xxx–xxx 60 FN1 FN2 FN3 pure curcumin 40 20 60 FN1 FN2 FN3 pure curcumin 40 20 0 20 40 60 80 100 120 20 40 60 100 100 80 80 60 FN4 FN5 FN3 40 %drug release %drug release 80 100 120 Time (min) Time (min) 20 60 FN4 FN5 FN3 40 20 0 20 40 60 80 100 120 20 40 Time(min) 60 80 100 120 Time(min) 100 100 80 %drug release %drug release 80 FN6 FN7 FN3 60 40 20 FN6 FN7 FN3 60 40 20 0 20 40 60 80 100 120 20 40 100 80 100 120 100 80 80 FN8 FN9 FN3 60 40 20 %drug release %drug release 60 Time(min) Time(min) FN8 FN9 FN3 60 40 20 0 20 40 60 Time(min) 80 100 120 20 40 60 80 100 120 Time(min) Fig Dissolution profiles of CUR from polymeric nanoparticles at pH 1.2 (left) and pH 6.8 (right) Effect of polymer types: (A) and (B) Effect of ultrasonication time: (C) and (D) Effect of ultrasonic power: (E) and (F) Effect of polymer ratio: (G) and (H) Please cite this article in press as: T.-T.D Tran et al., Modulation of particle size and molecular interactions by sonoprecipitation method for enhancing dissolution rate of poorly water-soluble drug, Ultrason Sonochem (2014), http://dx.doi.org/10.1016/j.ultsonch.2014.11.020 T.T.-D Tran et al / Ultrasonics Sonochemistry xxx (2014) xxx–xxx Table Average particle size of polymeric nanoparticles containing CUR under various changed temperatures and ultrasonic power application Formulation Polymer Ratio Power (W) Times (min) Diameter (nm) Increased temperature (°C) FN1 FN2 PEO HPMC 4000 HPMC HPMC HPMC HPMC HPMC 1:6 1:6 15 15 20 20 2407.3 3778 4 1:6 1:6 1:6 1:2 1:4 15 15 15 15 20 20 20 20 265 2290.4 2560.1 1006.5 283.5 3.5 4 FN3 FN5 FN6 FN8 FN9 6 6 particles may be explained by the difference of molecular weight of polymers In other words, larger molecular weight of HPMC 4000 or PEO could produce larger particle size as compared to HPMC To obtain all of the particles at nano size, a higher level of ultrasonic power or longer time of ultrasonication would be conducted For further investigation of effects of ultrasonication conditions on dissolution rate of CUR, polymeric nanoparticles were prepared with HPMC under various ultrasonication time and ultrasonic power Three formulations with different ultrasonication times (20 min, 10 min, corresponding to FN3, FN4, FN5, respectively) were compared to evaluate the effect of ultrasonication time on the dissolution rate of CUR (Fig 1C and D) It was noted that the dissolution rate of CUR was significantly increased with correlative time, i.e the longer ultrasonication time, the higher dissolution rate, and vice versa Table shows that time reduction for ultrasonication resulted in micro scale of particles Specifically, when the ultrasonication time reduced from 20 to min, the particle size could be increased from 265 nm to 2290.4 nm These results demonstrated that the longer time length of ultrasonication completely comminuted particles, leading to smaller size of the particles to promote the dissolution enhancement However, continuous and longer time of ultrasonication might not provide more reduced size of the particles when the particles reached the bounds of nano-size as in a previous report [6] Similar to the effect of ultrasonication time, three formulations (FN3, FN6, and FN7) were used to investigate the effect of ultrasonic power on the dissolution rate of CUR These formulations were set at ultrasonic power W, 12 W and 15 W in 20 Fig 1E and F indicate that the higher power in ultrasonication could provide more energy to enhance the dissolution rate of drug Drug release could increase up to 100% with the ultrasonic power 15 W during 20 The dissolution rate was reduced with lower level of ultrasonic power Especially, the ultrasonic power W showed the slowest release of drug at the first 20 and started to increase up to 100% at 30 Nevertheless, the precipitation was observed with CUR thereafter The fluctuation of CUR release might be attributed to the large size and broad distribution of the particles which had been caused by ultrasonic power The average size of this sample was 2560.1 nm with a part of particles was under 1000 nm and others were from 1000 nm to 6000 nm (Fig 2) The gradual increase of dissolution rate might be caused by dissolving particles gradually However, the long retention of large particles might cause the aggregation and produced the precipitation of CUR The role of polymer amount was investigated to determine the effect on dissolution rate and particle size which was produced by the same method The ratio of CUR–HPMC was set at 1:2 (FN8); 1:4 (FN9) and 1:6 (FN3) In general, when using the same method, the increase amount of HPMC significantly reduced particles size and improved the drug dissolution rate (Table and Fig 1G and H) The increased amount of polymer could provide the steric stabilization and arrested the particle growths which were attributed to the reduction of particles size [22] Lastly, the elevated liquid temperature which was caused by ultrasonication may result in a significant effect on dissolution rate or particle size of formulations For this reason, the temperature of samples before and after preparation was measured to determine increased temperature – DT (Table 2) Overall, the DT was °C under the power of 15 W in 20 For FN6 (power of W, 20 min), slight smaller DT (3.5 °C) was observed In contrast, DT was °C in the case of FN5 (power of 15 W, min) These results demonstrated that the range of power in this study (9–15 W) insignificantly effected on temperature However, ultrasonication time increased the temperature The elevated temperatures of samples seemed not to affect the dissolution rate of CUR or particle size Dissolution profiles of FN3 (DT = °C), FN5 (DT = °C) and FN8 (DT = °C) were compared FN5 showed a slower release as compared with FN3 while higher as compared with FN8 Similar phenomenon was observed in the case of particle size where FN3 (DT = °C), FN5 (DT = °C) and FN6 (DT = 3.5 °C) showed 265 nm, 2290.4 nm and 2560.1 nm, respectively These results demonstrated that the range of temperature used in this research was safely controlled for preparation of samples Generally, the ultrasonication conditions as well as polymer types highly affected the dissolution rate of CUR through changing the size of particles Also, polymer types affected the distribution of particles HPMC showed a spherical shape with the encapsulation of CUR and a narrow distribution (Figs 2C, F, G and 3) in defiance of polymer ratio Oppositely, HPMC 4000 and PEO which are larger molecular weight showed a broad distribution and large particle size These samples may need more energy to produce smaller and homogeneous particles Therefore, the use of low molecular weight polymers benefits in cost and time reductions 3.2 Crystallinity studies The powder X-ray diffractograms of pure CUR, physical mixtures of polymer and CUR, polymeric nanoparticles are shown in Fig 4A–C The PXRD diffractogram of pure CUR was highly crystalline with many characteristic peaks in the range between 8° and around 30° Most of these CUR peaks, for example, peaks at 8.88°, 12.18°, 14.58°, 17.193°, 19.21°, 23.71°, 26.104°, 26.84° were appeared in the physical mixture The encapsulation of CUR in the polymeric nanoparticles induced the disappearance of these peaks, regardless of polymer types or polymer–drug ratios In the case of PEO polymeric nanoparticles, the diffractogram exposed only two peaks which were attributed to peaks of PEO at the diffraction angles of 2h at 19.21° and 23.71° Similar phenomenon was also observed in the cases of polymeric nanoparticles of HPMC 4000 and HPMC These results indicated that the crystalline structure of CUR was changed into amorphous form, leading to the improved dissolution rate [23–25] 3.3 Molecular interactions In addition to crystalline structure, FTIR spectra were investigated to further figure out any molecular interaction among functional groups Fig shows spectra of pure CUR, physical mixtures of polymers and CUR, polymeric nanoparticles Spectra of all physical mixtures are a combination of CUR peaks and polymer peaks, indicating no interaction between CUR and polymers in the physical mixture This result seemed to be reasonable with the above PXRD patterns where crystalline peaks of CUR were still presented in the samples of physical mixtures In Fig 5A, characteristic peaks of CUR in the physical mixture with PEO were at 3570, 3400, 1628, 1607 cmÀ1 Similarly, characteristic peaks of CUR in the physical mixture with HPMC 4000 and HPMC were also at 3507, 3400, Please cite this article in press as: T.-T.D Tran et al., Modulation of particle size and molecular interactions by sonoprecipitation method for enhancing dissolution rate of poorly water-soluble drug, Ultrason Sonochem (2014), http://dx.doi.org/10.1016/j.ultsonch.2014.11.020 T.T.-D Tran et al / Ultrasonics Sonochemistry xxx (2014) xxx–xxx Fig Particle size distribution of polymeric nanoparticles from various type of polymers, ratio of drug–polymer and ultrasonication conditions (A): FN1; (B): FN2; (C): FN3; (D): FN5; (E): FN6; (F): FN8 and (G): FN9 Fig TEM images of HPMC nanoparticles containing CUR (FN3) Please cite this article in press as: T.-T.D Tran et al., Modulation of particle size and molecular interactions by sonoprecipitation method for enhancing dissolution rate of poorly water-soluble drug, Ultrason Sonochem (2014), http://dx.doi.org/10.1016/j.ultsonch.2014.11.020 T.T.-D Tran et al / Ultrasonics Sonochemistry xxx (2014) xxx–xxx (a) (b) (c) Physical mixture of HPMC and CUR Physical mixture of HPMC 4000 and CUR FN3 FN5 Physical mixture of PEO and CUR FN6 FN2 FN1 FN Pure curcumin FN9 Pure curcumin Pure curcumin 10 20 30 40 50 10 60 20 30 Theta 40 50 10 60 20 30 Theta 40 50 60 theta Fig (A) PXRD patterns of CUR, physical mixture of PEO and CUR and its polymeric nanoparticles (FN1) (B) PXRD patterns of CUR; physical mixture of HPMC 4000 and CUR; and polymeric nanoparticles (FN2) (C) PXRD patterns of CUR; physical mixture of HPMC and CUR; and polymeric nanoparticles (FN3, FN5, FN6, FN8, and FN9) (c) Physical mixture of HPMC and CUR FN3 FN9 (b) FN2 FN8 (a) FN5 FN1 FN6 Physical mixture of HPMC 4000 and CUR Physical mixutre of PEO and CUR Pure curcumin Pure curcumin Pure curcumin 4000 3000 2000 1000 -1 Wavelength(cm ) 4000 3000 2000 1000 -1 Wavelength(cm ) 4000 3000 2000 1000 -1 Wavelength (cm ) Fig (A) FTIR spectra of CUR, physical mixture of PEO and CUR and its polymeric nanoparticles (FN1) (B) FTIR spectra of CUR; physical mixture of HPMC 4000 and CUR; and polymeric nanoparticles (FN2) (C) FTIR spectra of CUR; physical mixture of HPMC and CUR; and polymeric nanoparticles (FN3, FN5, FN6, FN8, and FN9) 1628, 1607 cmÀ1 in Fig 5B and C The peaks at 3570 cmÀ1 and 3400 cmÀ1 were attributed to AOH stretching [26] Meanwhile, the peaks at 1628 cmÀ1 and 1607 cmÀ1 were attributed to C@O and C@C of CUR, respectively [27] In all formulations of polymeric nanoparticles, peak of the phenol group, intra-molecular hydrogen bond at 3570 cmÀ1 [28] was disappeared These results Please cite this article in press as: T.-T.D Tran et al., Modulation of particle size and molecular interactions by sonoprecipitation method for enhancing dissolution rate of poorly water-soluble drug, Ultrason Sonochem (2014), http://dx.doi.org/10.1016/j.ultsonch.2014.11.020 T.T.-D Tran et al / Ultrasonics Sonochemistry xxx (2014) xxx–xxx Table Relationships between particle sizes of polymeric nanoparticles containing CUR and shift distance in FTIR spectrum of OH stretching at 3400 cmÀ1 Formulation Diameter (nm) Shifted distance in FTIR spectra (cmÀ1) FN1 FN2 FN3 FN5 FN6 FN8 FN9 2407.3 3778 265 2290.4 2560.1 1006.5 283.5 0 66 40 40 40 demonstrated that there was an interaction like an intermolecular hydrogen bonding between CUR and the polymer (PEO or HPMC 4000, or HPMC 6), causing the change of crystalline form of CUR to amorphous structure [29] Another OH stretching at 3400 cmÀ1 of CUR was also observed to investigate an interaction between polymers and the drug According to Fig 5A and B, this position was insignificantly changed However, the right shift was observed throughout all the formulations of HPMC (Fig 5C) These FTIR spectra clearly elucidated the role of polymer in an interaction with CUR HPMC was a favorable polymer in this role to enhancing drug dissolution rate significantly Interestingly, the shifted distances of OH stretching were different depending on HPMC concentrations as well as ultrasonication conditions Regarding the ratio of drug– polymer at 1:2 (FN8), 1:4 (FN9) and 1:6 (FN3), the increase of HPMC amount could induce the peak more shifted to the right This peak was kept at 3400 cmÀ1 at the ratio 1:2, but was shifted to 3440 cmÀ1 and to 3466 cmÀ1 at the ratio 1:4 and 1:6, respectively Regarding ultrasonication conditions, the reduction of ultrasonication time (FN5) or ultrasonic power (FN6) could also cause the right shift at 3440 cmÀ1 which was shorter than the right shift of FN3 The FTIR spectra indicated that the intermolecular interaction of FN3 was stronger than that of other formulations In other words, stronger interactions were observed at higher concentration of polymer, stronger ultrasonic power and longer ultrasonication time, and hence leading to the higher drug dissolution rate Moreover, the right shift of AOH peak was related to the size of particles (Table 3) According to the change of polymer types, this peak of the sample FN3 (from HPMC polymeric nanoparticles) could be shifted to the right 66 cmÀ1; meanwhile, the sample FN1 or FN2 (from PEO or HPMC 4000 polymeric nanoparticles, respectively) did not cause any changes and hence, resulting in larger particle size Similarly, the reduction of ultrasonic power or ultrasonication time (FN5 or FN6) only caused the right shift 40 cmÀ1 which leaded to the larger particle size as compared to the FN3 The change of polymer–drug ratios also affected the shifted distance and particle size The distances were 0, 40, 66 cmÀ1 for the drug–polymer ratio of 1:2, 1:4, 1:6, respectively These results suggested that the changes of formulation compositions or any ultrasonication process could cause different interactions between drug and polymer and then, had influence on the size of particles, leading to the differences in dissolution rate Conclusions The preparation of polymeric nanoparticles by precipitation– ultrasonication method with PEO, HPMC 4000, HPMC produced amorphous form of CUR for significantly improving dissolution rate of CUR Specially, the modulation of particle size and molecular interactions by ultrasonication process could provide a promising approach and improve the efficiency for dissolution enhancement of a poorly water-soluble drug Among the formulations, FN3 showed a potential condition for improving CUR dissolution The differences of drug dissolution among formulations were clearly elucidated through size–distribution of particles and molecular interactions based on ultrasonication process Also, the changes in drug–polymer ratio affected the 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Modulation of particle size and molecular interactions by sonoprecipitation method for enhancing dissolution rate of poorly water-soluble drug, Ultrason Sonochem (2014),... press as: T.-T.D Tran et al., Modulation of particle size and molecular interactions by sonoprecipitation method for enhancing dissolution rate of poorly water-soluble drug, Ultrason Sonochem (2014),