DSpace at VNU: Modulation of particle size and molecular interactions by sonoprecipitation method for enhancing dissolution rate of poorly water-soluble drug

Modulation of particle size and molecular interactionsby sonoprecipitation method for enhancing dissolution rate of poorly water-soluble drug Pharmaceutical Engineering Laboratory, Biome

Modulation of particle size and molecular interactions

by sonoprecipitation method for enhancing dissolution

rate of poorly water-soluble drug

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 9 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 nano-particles 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

1 Introduction

Currently, one of the major current challenges of the

pharma-ceutical industry is related to strategies that improve the water

solubility of drugs because over 40% of new drug candidates are

associated with rate-limiting dissolution, slow absorption and

so far to overcome the troubles of poorly water-soluble drugs,

but on the whole there are only some general rules as follows:

par-ticle 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

cefur-oxime axetil[11], griseofulvin[12,13], ibuprofen[12], itraconazole

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

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 enhance-ment of curcumin (CUR) which is extremely poor water solubility

Zheng et al has studied on sonication–assisted synthesis of

CUR release was almost done after 20 h and may be only suitable for sustained release dosage forms More recently, the precipita-tion–ultrasonication method has been applied for preparation of stable CUR nanocrystal without reports of drug release profiles

http://dx.doi.org/10.1016/j.ultsonch.2014.11.020

1350-4177/Ó 2014 Elsevier B.V All rights reserved.

⇑ Corresponding authors Tel.: +84 (8) 37244270x3328; fax: +84 (8) 37244271.

E-mail addresses: ttdthao@hcmiu.edu.vn (T.T.-D Tran), thlphuong@hcmiu.edu.

vn (P.H.-L Tran).

Ultrasonics Sonochemistry

j o u r n a l h o m e p a g e : w w w e l s e v i e r c o m / l o c a t e / u l t s o n

researches This research would provide not only useful

informa-tion about the preparainforma-tion 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 Materials and methods

2.1 Materials

(NaOH) were purchased from Guangdong Guanghua Sci-Tech

from Wako Pure Chemical Industries (Japan) Hydrochloric acid,

Xilong Chemical Industry Incorporated Company (China)

Hydroxy-propyl methylcellulose 6 (HPMC 6), hydroxyHydroxy-propyl 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

for physicochemical analyses The detailed formulations including

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), 1 ml of medium was withdrawn for determination of

drug release An equivalent amount of fresh medium was replaced

to maintain a constant dissolution volume

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

(150  4.6 mm) was maintained at 25 °C ± 0.5 °C The UV–Vis

HPLC system for analysis

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)

2.2.5 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,

The samples were scanned in increments of 0.02° from 5° to 60° (diffraction angle 2h) at 1 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 nanopar-ticle powders The wavelength was scanned from 500 to

by gently mixing 1 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)

3 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 6 In the preliminary experiments, the dissolution of physical mixture (drug and poly-mer at the ratio 1:6) demonstrated insignificant effect on CUR release Percent of drug release from three polymers after 2 h in dissolution medium were under 40% For an investigation of ultra-sonication, drug and polymer ratio was also fixed at the ratio 1:6 and ultrasonication conditions were fixed at ultrasonic power

15 W in 20 min All of the polymeric nanoparticles showed a potential dissolution enhancement of CUR significantly at both

HPMC 6 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 min

as compared to HPMC 6 However, CUR was immediately precipi-tated after 10 min 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 6 could form a nano size of particles to enhance the dissolution (Table 2, FN3) In contrast, HPMC 4000 or PEO still showed a micro

Table 1

Formulation compositions and precipitation–ultrasonication conditions for

prepara-tion of polymeric nanoparticles CUR and polymer were dissolved in acetone and

water with concentration 30 mg/ml and 1 mg/ml, respectively.

Codes CUR

(mg)

PEO

(mg)

HPMC4000 (mg)

HPMC6 (mg)

Power (W) Time (min)

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Time (min)

0

20

40

60

80

100

120

FN1 FN3 pure curcumin

Time (min)

0 20 40 60 80 100 120

FN1 FN2 FN3 pure curcumin

Time(min)

0

20

40

60

80

100

FN4 FN5 FN3

Time(min)

0 20 40 60 80 100

FN4 FN5 FN3

Time(min)

0

20

40

60

80

100

FN6 FN7

Time(min)

0 20 40 60 80 100

FN6 FN7

Time(min)

0

20

40

60

80

100

FN8 FN9 FN3

Time(min)

0 20 40 60 80 100

FN8 FN3

Fig 1 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).

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

6 To obtain all of the particles at nano size, a higher level of

ultra-sonic power or longer time of ultraultra-sonication would be conducted

For further investigation of effects of ultrasonication conditions

on dissolution rate of CUR, polymeric nanoparticles were prepared

with HPMC 6 under various ultrasonication time and ultrasonic

power Three formulations with different ultrasonication times

(20 min, 10 min, 5 min corresponding to FN3, FN4, FN5,

respec-tively) were compared to evaluate the effect of ultrasonication

that the dissolution rate of CUR was significantly increased with

correlative time, i.e the longer ultrasonication time, the higher

for ultrasonication resulted in micro scale of particles Specifically,

when the ultrasonication time reduced from 20 min to 5 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

Similar to the effect of ultrasonication time, three formulations

(FN3, FN6, and FN7) were used to investigate the effect of

ultra-sonic power on the dissolution rate of CUR These formulations

were set at ultrasonic power 9 W, 12 W and 15 W in 20 min

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 min The dissolution rate was reduced with lower

level of ultrasonic power Especially, the ultrasonic power 9 W

showed the slowest release of drug at the first 20 min and started

to increase up to 100% at 30 min 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

aver-age size of this sample was 2560.1 nm with a part of particles was

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

precipita-tion 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 6 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 6 significantly reduced particles size

The increased amount of polymer could provide the steric

stabilization and arrested the particle growths which were attrib-uted 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

under the power of 15 W in 20 min For FN6 (power of 9 W,

was 2 °C in the case of FN5 (power of 15 W, 5 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

compared with FN3 while higher as compared with FN8 Similar phenomenon was observed in the case of particle size where FN3

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 6 showed a spherical shape with the encapsulation

of CUR and a narrow distribution (Figs.2C, F, G and3) 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

inFig 4A–C The PXRD diffractogram of pure CUR was highly crys-talline 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 dif-fraction 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 6 These results indicated that the crystalline structure of CUR was changed into amorphous form, leading to

3.3 Molecular interactions

In addition to crystalline structure, FTIR spectra were investi-gated to further figure out any molecular interaction among

of polymers and CUR, polymeric nanoparticles Spectra of all phys-ical mixtures are a combination of CUR peaks and polymer peaks, indicating no interaction between CUR and polymers in the phys-ical mixture This result seemed to be reasonable with the above PXRD patterns where crystalline peaks of CUR were still presented

of CUR in the physical mixture with PEO were at 3570, 3400, 1628,

mixture with HPMC 4000 and HPMC 6 were also at 3507, 3400,

Table 2

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)

4000

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Fig 2 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 3 TEM images of HPMC 6 nanoparticles containing CUR (FN3).

1628, 1607 cm 1 inFig 5B and C The peaks at 3570 cm 1 and

2 Theta

Physical mixture of PEO and CUR

FN1

Pure curcumin

2 Theta

Pure curcumin FN2 Physical mixture of HPMC 4000 and CUR

2 theta

Physical mixture of HPMC 6 and CUR

FN3

FN9

FN 8

FN5

FN6

Pure curcumin

Fig 4 (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 6 and CUR; and polymeric nanoparticles (FN3, FN5, FN6, FN8, and FN9).

Wavelength(cm -1

)

1000 2000

3000

4000

Pure curcumin

FN1

Physical mixutre of PEO and CUR

1000 2000

3000 4000

Pure curcumin Physical mixture of HPMC 4000 and CUR FN2

Wavelength (cm -1

)

1000 2000

3000 4000

Pure curcumin

FN6 FN5 FN8 FN9 FN3 Physical mixture of HPMC 6 and CUR

Wavelength(cm -1

)

(a)

(b)

(c)

Fig 5 (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 6 and CUR; and polymeric nanoparticles (FN3, FN5, FN6, FN8, and FN9).

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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 investigate an interaction between polymers and the drug

chan-ged However, the right shift was observed throughout all the

elucidated the role of polymer in an interaction with CUR HPMC

6 was a favorable polymer in this role to enhancing drug

dissolu-tion 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 6 amount could induce the peak more shifted to the right

respec-tively Regarding ultrasonication conditions, the reduction of

ultra-sonication time (FN5) or ultrasonic power (FN6) could also cause

of FN3 The FTIR spectra indicated that the intermolecular

interac-tion of FN3 was stronger than that of other formulainterac-tions In other

words, stronger interactions were observed at higher

concentra-tion of polymer, stronger ultrasonic power and longer

ultrasonica-tion time, and hence leading to the higher drug dissoluultrasonica-tion rate

peak of the sample FN3 (from HPMC 6 polymeric nanoparticles)

FN1 or FN2 (from PEO or HPMC 4000 polymeric nanoparticles,

respectively) did not cause any changes and hence, resulting in

lar-ger particle size Similarly, the reduction of ultrasonic power or

ultrasonication time (FN5 or FN6) only caused the right shift

the FN3 The change of polymer–drug ratios also affected the

shifted distance and particle size The distances were 0, 40,

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

4 Conclusions

The preparation of polymeric nanoparticles by precipitation–

ultrasonication method with PEO, HPMC 4000, HPMC 6 produced

amorphous form of CUR for significantly improving dissolution

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 interaction between them and hence, leading to the difference in drug dissolution rate

Acknowledgements

We would like to thank International University for their continued generous and invaluable support to our studies that greatly boost the efficiency of our research activities

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