Simple Criterion for Stability of Aqueous Suspensions of Ultrafine

Article pubs.acs.org/Langmuir

Simple Criterion for Stability of Aqueous Suspensions of Ultrafine Particles of a Poorly Water Soluble Drug Alpana A. Thorat,† Manishkumar D. Yadav,† and Sameer V. Dalvi* Chemical Engineering, Indian Institute of Technology Gandhinagar, Chandkheda, Ahmedabad 382424, Gujarat, India. ABSTRACT: In this work, a simple criterion is proposed for prediction of a long-term stability of aqueous suspensions of ultrafine particles of a poorly water soluble drug, curcumin. A new “stability parameter” (γ0ε/γε0) has been defined, which is a ratio of nondimensional mechanical (mainly ultrasonic) energy (ε/ε0) to nondimensional solid−liquid interfacial energy (γ/γ0). The stability of aqueous suspensions of curcumin particles over a period of 1 year and 9 months has been correlated with this parameter. In order to calculate this parameter, solid−liquid interfacial energies were first estimated, from nucleation rates, which in turn were calculated from size distributions of curcumin particles precipitated using water as antisolvent. The mechanical energy was then estimated from the intensity of ultrasound and mechanical agitation used during precipitation. It was found that precipitations carried out with higher values of γ0ε/γε0 (more than 100) result in aqueous suspensions with particle size less than 1 μm. It was further observed that these suspensions remain stable (i.e., no or negligible change in average particle size) for a period of 1 year and 9 months. On the other hand, the suspensions of particles precipitated at lower values of γ0ε/γε0 (less than 10) were found to be highly unstable (i.e., the average particle size changes drastically). These results suggest that γ0ε/γε0 can be used as a parameter to engineer stable aqueous suspensions of curcumin particles. Further, it was found that the use of the Mersmann equation to estimate solid−liquid interfacial surface tensions can help in making this criterion predictive.

1. INTRODUCTION Low water solubility and dissolution rates limit the bioavailability of poorly water soluble drugs.1,2 The dissolution rate of such solid active pharmaceutical ingredients (APIs) can be increased by precipitating these APIs as nanoparticles or microparticles.3 Decrease in size due to formation of ultrafine particles increases the surface area and hence results in an increase in dissolution rates in aqueous media of body fluid.4 However, an increase in surface area also increases the surface energy of particles and results in enhanced interparticle interactions such as van der Waals interaction, electrostatic interaction, and hydrophobic interaction. This further leads to particle coagulation and agglomeration. Moreover, if these ultrafine particles are kept in a loose powder form, particle agglomeration and coagulation result in poor powder flow conditions and difficulties with downstream processing of such particles into different formulations. On the other hand, it is convenient to handle these ultrafine particles in liquid suspensions, i.e., colloidal dispersions of solid drug nanoparticles in a liquid phase. Use of aqueous suspensions enables easier control over crystal growth and particle agglomeration or aggregation and, hence, can result in suspensions with stable particle size and size distribution. Such stable aqueous suspensions of ultrafine particles can be used in preparation of various drug delivery forms such as liquid formulations, capsules containing liquid suspensions, and strip films for oral administrations as well as for making skin patches for transdermal drug delivery. © 2014 American Chemical Society

In order to produce ultrafine particles of APIs, several techniques are available and are being used in practice. However, control of particle size and size distribution, and the process scalability in comparison to liquid-antisolvent (LAS) precipitation is difficult for many of these techniques.5,6 Therefore, in this work, LAS precipitation technique is used to prepare aqueous suspensions of ultrafine particles of a poorly water soluble drug, curcumin. Curcumin is an ingredient found in traditional Indian spice, “turmeric” (Curcumin longa), and has potential antioxidant,7 anti-HIV,8 anti-inflammatory,7 antitumor,9 and antimicrobial properties.10 The LAS precipitation of curcumin particles was carried out in the presence of ultrasound, to improve micromixing and induce rapid nucleation,11,12 and stabilizers, to inhibit particle growth and increase nucleation rates.6,13 The stability of the precipitated particles in colloidal solutions, however, depends on agglomeration or flocculation which is driven by hydrophobic effects, electrostatic interaction, and weak van der Waals forces. There are a lot of studies reported in literature where attempts have been made to prepare stable aqueous suspensions of nanoparticles. However, most of these studies have reported contrasting observations which makes it difficult to follow a particular methodology reported.6 The objective of this study, therefore, was to develop a criterion which can be used as a guide to prepare stable aqueous Received: September 11, 2013 Published: April 4, 2014 4576

dx.doi.org/10.1021/la500825j | Langmuir 2014, 30, 4576−4592

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solid structure to an ordered lattice structure which results in enhanced stability of the precipitated particles against phenomena such as Ostwald ripening and growth. Thus, the ultrasonic energy added during the precipitation is not only consumed during nucleation but also for the arrangement/packing of solute molecules/layers on the growing nuclei surface. The ultrasound helps in compaction of solute layers into a particle. Also, ultrasound facilitates enhanced adsorption of stabilizer molecules on the crystal surface, thus restricting the growth of particles and improving the stability further.15 In order to take into account the effects of ultrasound and stabilizers on nucleation and growth behavior and the stability of particle suspensions, a new empirical parameter has been devised which is a ratio of a nondimensional mechanical (mainly ultrasound) energy (ε/ε0) to a nondimensional solid− liquid interfacial energy (γ/γ0). This ratio is termed as a “stability parameter” and is given as γε stability parameter = 0 γε0 (5)

suspensions of ultrafine particles of poorly water soluble drugs with sizes less than 1 μm. In order to do so, the stability of aqueous suspensions of ultrafine particles of curcumin has been studied over a period of almost 2 years in this work. Efforts have then been made to identify kinetic and thermodynamic process parameters that affect the nucleation rates and hence, the particle sizes and stability of aqueous suspensions of curcumin particles.

2. DEVELOPMENT OF A STABILITY CRITERION The process of precipitation consists of two simultaneous steps, nucleation and growth. Formation of nuclei from a supersaturated solution occurs through aggregation of molecules into tiny clusters. The reduction in the Gibbs free energy of the system due to the formation of a nucleus of radius r is given as14 ΔG = ΔGS + ΔG V

(1)

where ΔGS is the change in free energy due to the formation of a new surface and ΔGV is the change in free energy due to phase transformation (creation of a new volume). While creation of new volume releases energy, the generation of a new surface consumes energy. Since the two processes are simultaneous, the energy released, due to formation of a new volume, is used for creation of a new surface. If the energy released due to formation of a volume is not enough to create a new surface, the process of nucleation is slowed or does not proceed. The addition of external energy in such a situation, therefore, can enhance the rate of nucleation. The energy needs to be added until the size of the nuclei reaches a critical size which is characterized by the maximum total free energy (ΔG). The total change in free energy during formation of nuclei is the sum of two energy terms described in eq 1. ΔGS can be written as a product of surface area of a developing nucleus and interfacial tension (γ) between the surface of the nucleus and the supersaturated medium surrounding it, and ΔGV is given as a product of the volume of the nucleus formed and free energy per unit volume. ΔG = 4πr 2γ +

4πr 3 ΔGv 3

where γ is the solid−liquid interfacial energy when stabilizer is used during precipitation (N/m), γ0 is the solid−liquid interfacial energy when stabilizer was not used (N/m), ε is the total mechanical energy added when ultrasound is used (J/kg), and ε0 is the total mechanical energy added when ultrasound is not used (J/kg). The stability parameter defined in this work signifies the excess of mechanical energy available for compaction/annealing of the crystal surface and enhanced adsorption of stabilizer molecules on the crystal surface after consumption of a part of the added mechanical energy for enhancement of nucleation events.

3. EXPERIMENTAL SECTION 3.1. Materials. Curcumin, sodium dodecyl sulfate (SDS; 99+ % ACS reagent), hydroxypropyl methyl cellulose (HPMC; 80−120 cPs, FCC), Tween-80, hydroxyethyl cellulose ethoxylate, quaternized (polymer JR 400 (POL Jr)), bovine serum albumin (BSA), sodium alginate (Na-Alg), and pluronic F-68 (PF68), were purchased from Sigma-Aldrich Inc. Acetone (99% pure) and dimethyl sulfoxide (DMSO) were purchased from Sisco Research Laboratories (SRL). Ethanol (99.8% pure) was purchased from Chinachangshu Yangyuan Chemicals Pvt Ltd. All of these chemicals were used without further purification. Deionized Millipore water was used as an antisolvent. 3.2. Precipitation and Characterization of Curcumin Particles. Organic solutions of curcumin in different solvents (5−30 mg/mL) were introduced in water (100 mL) containing surfactants and polymers, maintained at a constant temperature (1 °C) quickly. The ultrasound horn was immersed in antisolvent at an immersion depth (below the antisolvent level) of 1.5 in. The tip (1 in. i.d.) of an ultrasound horn (Sonics) is directed over a surface of solvent− antisolvent mixture solution such that the solution can be dispersed instantaneously by vibrations (three different ultrasound amplitudes corresponding to 13,56, and 105 W for 10 min). Aqueous suspensions of curcumin particles were analyzed for particle size and distribution by laser scattering (Beckman Coulter LS 13320) at 0 h, 24 h, and other long-term periods such as 1 month, 3 months, and 1 year and 9 months. For each sample, three readings were recorded, and the particle size has been reported as an average of three readings. Particle morphology of curcumin was examined by scanning electron microscopy (SEM). One to two drops of curcumin suspensions freshly prepared or stored for different periods of time were put on a silicon wafer mounted on an aluminum stub with the help of a double sided adhesive carbon tape. These samples were kept in a vacuum desiccator for drying. The samples were then coated with platinum before being analyzed using SEM mode on a field emission SEM (JSM 7600F, JEOL). For the characterization of the particles by powder X-ray diffraction

(2)

For small numbers of molecules aggregating, the resulting clusters are unstable and they dissolve. As the cluster size increases, it reaches a point where Gibbs free energy reaches a maximum. This size of a critical nucleus is called the critical size of nuclei (rc). Expression for the critical size of such a cluster can be derived by equating the derivative dΔG/dr to zero. This yields the size (γ*) of a critical cluster given by the following equation

r* =

−2γ ΔGν

(3)

The value of a critical Gibbs free energy (ΔG*) can then be obtained from eq 2 as ΔG* =

4πγ(r *)2 16πγ 3 = 3 3(ΔGν)2

(4)

Equation 4 shows that the critical Gibbs free energy (ΔG*) is directly proportional to the solid−liquid interfacial tension (γ) and hence energy needed to be supplied during nucleation should be directly proportional to the solid−liquid surface tension at the growing solid surface. In addition to enhancing the nucleation rates, the energy added can convert a thermodynamically unstable matter into a more stable form by single or repeated application of energy.15,16 This addition of energy results in a conversion of a less ordered 4577


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(PXRD) and thermogravimetric analysis−differential scanning calorimetry (TGA-DSC), curcumin nanoparticles suspensions were freezedried using a Martin Christ (ALPHA 2-4 LD plus) freeze-dryer. The suspensions were dried at 0.042 mbar pressure and −80 °C as ice condenser temperature for 12−15 h. After drying, the lyophilized curcumin powder was used for XRD and TGA analysis. Powder diffraction analysis was carried out in the range of 5−50° for 2θ using an X-ray diffraction system (XRD; D8 Discover, Bruker AXS GmbH). TGA analysis was carried out using NETZSCH STA 449F3 Jupiter simultaneous TGA-DSCin the temperature range of 30−1000 °C, with heating rate of 10 deg/min. 3.3. Measurement of Particle Size by Light Scattering and Its Correlation with SEM Imaging. The particle size measured by laser scattering (Beckman Coulter LS 13320) is the hydrodynamic particle size of a spherical particle with the volume equal to the volume of a particle that is being measured. Therefore, there will always be a difference in the size measured by the light scattering technique and the size of the particles observed through image analysis of SEM micrographs in the case of nonspherical particle morphology. The curcumin particles precipitated by liquid antisolvent precipitation show needle shaped/rodlike morphology. A very good correlation can be established between the particle size measured by the light scattering and the particle size obtained by image analysis of SEM images through a simple analysis presented as follows. The mean size of the spherical particles in the nanosuspensions can be calculated using the Stokes−Einstein equation, which is given as16 Do =

onward are hydrodynamic particle sizes measured by light scattering only and not by the image analysis of SEM micrographs. 3.4. Estimation of Equilibrium Solubility of Curcumin in Aqueous Medium. Solubility of curcumin in aqueous organic solutions at 1 °C in the presence of stabilizers was estimated experimentally using a UV−vis spectrophotometer. An excess of curcumin was added in deionized water and organic solvent mixture containing 0.02 wt % stabilizers and was stirred overnight at 1 °C. The known amount of sample was pipetted out, filtered through a 0.22 μm syringe filter, and analyzed by UV−vis spectrophotometer using an absorption wavelength of 430 nm. 3.5. Estimation of Viscosity of Aqueous Nanosuspensions. Viscosities of curcumin nanosuspensions prepared by sonication for 10 min were estimated using Brookfield viscometer DV II+ Pro. Viscosity was measured at various RPM ranging from 0.5 to 100. It was found that the viscosity of most of the solutions remains constant from 20 RPM onward. Such constant values were then taken as the viscosities of suspensions and were then used for further calculations. Table 2 reports the viscosity values of various sonicated suspensions. It should be noted that the suspensions with stabilizer follow a non-

Table 2. Effect of Stabilizer on Viscosity (cP) of Solution Containing 10 mL of Organic (Ethanol, Acetone, DMSO) Solvent in 100 mL of Water Containing Stabilizers (20 mg/ mL)a μ (cP)

kT 6πηR

(6)

where Do is the translational diffusion coefficient, η is the viscosity of the medium of suspensions, T is the absolute temperature, k is the Boltzmann constant, and R is the radius of the sphere. Similarly, for diluted dispersions of rodlike particles, the diffusion coefficient of rodlike particles can be written as Do =

kT 2πηL

(7)

where L is the length of the rodlike particles. Equating eqs 6 and 7, one can obtain

a

Equation 8 can be used to correlate the hydrodynamic radius obtained by light scattering (R) and the length of the particles obtained through image analysis of an SEM micrograph (L). Table 1 presents a comparison between the particle sizes of curcumin suspensions measured by light scattering and the curcumin particle size obtained by image analysis of SEM micrographs. It can be seen that eq 8 works very well to correlate particle size measured by light scattering technique with the size obtained by image analysis of SEM micrographs. It should however be noted that the particle sizes reported from section 3.4

a

acetone + water

DMSO + water

1.42 1.22 1.27 1.31 1.00 1.29 1.2 1.1

1.45 1.25 1.31 1.36 1.01 1.31 1.25 1.19

1.1 1.00 1.06 1.04 1.01 1.06 1.07 1.02

The solutions were sonicated for 10 min using 105 W ultrasound.

Newtonian behavior and exhibit shear thinning phenomena under the influence of applied shear/ultrasound. This is quite apparent from Table 2 which shows that the viscosity of water−ethanol mixture (without any stabilizer) at 1 °C is higher than the viscosity of any suspension with a stabilizer at 1 °C. However, the difference in viscosity values of suspensions with stabilizers and without stabilizers is not much because the concentration of stabilizers used in suspensions in this work was very low at 0.02 wt % of the total solution. 3.6. Estimation of Diffusivity of Curcumin in Aqueous Organic Solutions in the Presence of Ultrasound and Stabilizers. Curcumin tablets were prepared with a compression weight of 3 tons. These curcumin tablets were kept suspended in a mixture of organic solvent and water solution (with the ratio of organic solvent and water to be 1:10, the same as the one used in the precipitation experiment), and the solution was irradiated at different ultrasonic power inputs such as 13, 56, and 105 W. A known quantity of irradiated solution was pipetted out at different times, and the concentration of curcumin in the pipetted sample was measured (after filtering the sample through a 0.22 μm syringe filter) using UV spectrophotometer at an absorption wavelength of 430 nm. The experimental data for variation in concentration of curcumin dissolved in solution with time was then fitted to the following equation:

Table 1. Comparison between the Length of Curcumin Particles Estimated by Image J Processing of SEM Images and Average Hydrodynamic Particle Diameter for the Curcumin Suspensions Obtained by Laser Scattering Using Beckman Coulter LS 13320

no Stabilizer Tween 80 Pluronic F68 SDS BSA HPMC

ethanol + water

(8)

L = 3R

stabilizer

stabilizer no stabilizer SDS PF-68 HPMC sodium alginate Tween-80 POL-Jr BSA

meana diam (μm)

mean radius (μm)

length = 3Rb

length (μm) (image J data)

0.650

0.325

0.975

1.02

0.471 0.488

0.236 0.244

0.708 0.732

1.15 1.19

0.747 0.913 1.00

0.374 0.457 0.500

1.12 1.37 1.50

1.95 1.79 1.72

CA = mt + n

(9)

The rate of dissolution of the tablet in the surrounding aqueous organic medium could be given as − dnA = kL(CA* − CA)A dt

b

Estimated by LS Coulter 13320. Calculated by eq 8. 4578

(10)


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Table 3. Effect of ultrasound and stabilizers on diffusivity of curcumin in ethanol-water mixture (volume ratio of ethanol/acetone/ DMSO to water was maintained at 1:10) at 1 °C viscosity at 1°C (cP)

DAB (× 109 m2/s)

enhancement

no stabilizer

1.39

SDS

1.45 1.10 1.17

PF-68

1.25 1.00 1.22

HPMC

1.31 1.06 1.28

sodium alginate

1.36 1.04 0.99

Tween-80

1.01 1.02 1.22

POL-Jr

1.31 1.06 1.23

BSA

1.25 1.07 1.03

0.37 5 20.3 117 117 117 0.44 5.9 23.9 138 135.7 128.7 0.42 5.42 22 127 129.5 121.4 0.4 5.42 22 127 124.7 123.7 0.52 7.02 28.5 164 167.9 127.4 0.42 5.69 23.1 133 129.5 121.4 0.42 5.65 22.9 132 135.7 120.2 0.5 6.74 27.4 157 142.5 126.1

− 13.51 54.86 316.22 316.22 316.22 1.19 13.41 54.32 313.64 308.41 292.50 1.14 12.90 52.38 302.38 308.33 289.05 1.08 13.55 55.00 317.50 311.75 309.25 1.41 13.50 54.81 315.38 322.88 245.00 1.14 13.55 55.00 316.67 308.33 289.05 1.14 13.45 54.52 314.29 323.10 286.19 1.35 13.48 54.80 314.00 285.00 252.20

ultrasound (W)

solvent

stabilizer

0 13 56 105 105 105 0 13 56 105 105 105 0 13 56 105 105 105 0 13 56 105 105 105 0 13 56 105 105 105 0 13 56 105 105 105 0 13 56 105 105 105 0 13 56 105 105 105

ethanol ethanol ethanol ethanol acetone DMSO ethanol ethanol ethanol ethanol acetone DMSO ethanol ethanol ethanol ethanol acetone DMSO ethanol ethanol ethanol ethanol acetone DMSO ethanol ethanol ethanol ethanol acetone DMSO ethanol ethanol ethanol ethanol acetone DMSO ethanol ethanol ethanol ethanol acetone DMSO ethanol ethanol ethanol ethanol acetone DMSO

1.19 1.02

equilibrium solubility of curcumin in solvent and water solution; CA is the concentration of curcumin in the solvent and water solution. A liquid-side mass transfer coefficient kL was obtained using eqs 9−11. Using film theory, kLcan be correlated to diffusivity as

The preceding equation was solved with a condition of nA = nA0 (initial number of moles of curcumin in a tablet) at t = 0 and using eq 9, to obtain an expression for mass transfer coefficient as kL =

2⎡

nA 0 − nA

2πr ⎣⎢(CA* − n)t −

mt 2 ⎤ ⎥ 2 ⎦

kL =

(11)

DAB δ

(12)

where δ is the liquid film thickness around a curcumin tablet. In order to estimate the effect of ultrasound on diffusivity, first the diffusivity of curcumin in aqueous organic solution in the absence of ultrasound (0 W) and stabilizer was estimated using the Stokes−Einstein equation.

where m and n are constants; t is the time; nA and nA0 are moles of curcumin after and before dissolution, respectively; r is the radius of curcumin tablet; A is the surface area of the curcumin tablet; CA* is the 4579


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This value of diffusivity was then used to find out the film thickness (δ) knowing the value of mass transfer coefficient kL at 0 W using eq 12. The values of DAB at 13, 56, and 105 W ultrasound levels were then estimated assuming δ does not change with the application of ultrasound and eq 12 remains valid. The effect of stabilizers on the diffusivity was taken into account by estimating the effect of stabilizers on the viscosity of solution. Diffusivity according to the Stokes−Einstein equation is inversely proportional to the viscosity, and hence, diffusivity of curcumin in the presence of ultrasound and stabilizer was estimated as follows. DAB(stabilizer) DAB(without stabilizer)

=

interfacial energy when stabilizer is not used) were estimated from experimental nucleation rates estimated from particle size distribution data as explained as follows. Assuming the nucleation events follow the mechanism of homogeneous nucleation, J is given as ⎛ B ⎞ ⎟ J = Ahom S exp⎜ − hom ⎝ ln 2 S ⎠

where Ahom is a kinetic parameter and Bhom is a thermodynamic parameter. Ahom depends on the mechanisms of attachment,19 such as interface transfer control and volume diffusion control. It is assumed in this work that, for a nucleation step, the main mechanism of attachment is the interface transfer controlled. The use of ultrasound during precipitation results in excellent mixing conditions and hence in a very low resistance to diffusion. Therefore, in this case, the controlling step could be the resistance for the integration of a molecule in the particle matrix. Ahom for interface transfer control is given as19

η(without stabilizer) η(stabilizer)

(13)

Table 3 presents calculated values of diffusivity of curcumin in aqueous organic solutions in the presence of stabilizers and ultrasound. 3.7. Estimation of Quantity of Stabilizers Occluded in Precipitated Curcumin Particles Using Thermogravimetric Analysis. The amount of stabilizer occluded in curcumin particles when precipitated with or without ultrasound was estimated using TGA. For this purpose, NETZSCH STA 449F3 Jupitersimultaneous TGADSCwas used in a temperature range of 30−1000 °C, with a heating rate of 10 deg/min. The difference in the weight loss of curcumin particles precipitated in the presence of ultrasound and stabilizers and curcumin particles precipitated with stabilizer and in absence of ultrasound was directly attributed to the increased occlusion of stabilizer in the curcumin particles precipitated in the presence of ultrasound.

Ahom =

B hom =

DAB =

(15)

(19)

kT 6πr0η

(20)

5. RESULTS AND DISCUSSION 5.1. Precipitation of Curcumin Particles from Organic Solutions in the Presence of Ultrasound and Stabilizers. Table 4 presents particle sizes and size distributions of curcumin particles (at 0 and 24 h) precipitated from its organic solutions in the presence and absence of stabilizer and ultrasound. As can be observed from Table 4, the size of the curcumin particles precipitated at 0 h was found to be 0.67 μm when precipitated without ultrasound and without stabilizer. However, the size of these particles was found to quickly increase to 6.62 μm after 24 h. Among the precipitation experiments conducted in the presence of ultrasound but in the absence of stabilizers, the highest increase in particle size was observed for the suspensions prepared at 13 W where particle size increased from 1.39 μm at 0 h to 6.37 μm at 24 h, whereas the least change in particle size was obtained for the suspensions prepared at 105 W where particle

L

∫L i+1 ni(Li) dLi i

tsample

16πω 2γ 3 3(kT )3

where r0 is the radius of the molecule, η is the dynamic viscosity of the solution, ω is the molecular volume, C* is the equilibrium solid solubility in the aqueous solution, S is the degree of supersaturation, γ is the surface tension at the solid−liquid interface, k is the Boltzmann constant, NA is the Avogadro number, and T is the solution temperature. In order to estimate γ, the following procedure was followed: (i) J were estimated using eqs 15 and 16. (ii) The degree of supersaturation (ln S) was calculated from experimentally estimated solubility of curcumin in aqueous organic solution as explained in sections 3.4 and 4.1. (iii) DAB in the presence of ultrasound and stabilizers was estimated as explained in section 3.6. (iv) γ was then calculated using eqs 17−19.

where ni is the population density of particles with average size, (Li). Δ(wt%) and ΔLi are the differential weight percent and the width of the size range i, respectively. kv is the volume shape factor for the spherical particles. MT and ρc are final suspension density and the particle density, respectively. The nucleation rates (J) were then estimated as18

J=

(18)

DAB, the diffusion coefficient, is given by the Stokes−Einstein equation:

Δ(wt%)M T k vρc Li 3ΔLi

⎛ 4π ⎞1/3⎛ γ ⎞1/2 ⎜ ⎟ ⎜ ⎟ DABC*NA ⎝ 3ω ⎠ ⎝ kT ⎠

and Bhom is defined as follows:

4. DATA TREATMENT 4.1. Estimation of Supersaturation. The supersaturation generated after mixing of antisolvent and solution is defined as C S= (14) C* where C is the actual concentration of API in solution (mg/mL) and C* is the equilibrium solubility (mg/mL) of API in a mixture of organic solvent and water, which was estimated experimentally as explained in section 3.4. 4.2. Nucleation Rate Estimation. To estimate nucleation rates, the particle number distribution data obtained from light scattering were converted to a cumulative mass percent distribution and then the values of population densities were calculated using the following equation.17 ni =

(17)

(16)

where tsample is the residence time of curcumin particles in the precipitation vessel. 4.3. Calculation of the Stability Parameter. In order to calculate the stability parameter, γ0ε/γε0, for all of the precipitation experiments, ε (the mechanical energy added when ultrasound was used) and ε0 (the mechanical energy added when ultrasound was not used) were calculated by knowing the level of ultrasound and mechanical agitation used. γ (solid−liquid interfacial energy when stabilizer is used) and γ0 (solid−liquid 4580


ethanol

solvent

5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 10 10 10 10 10 10 10 10 20 20 20 30 30

concn (mg/ mL)

0 13 56 105 0 0 0 0 0 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 0 0

ultrasound (W) no stabilizer no stabilizer no stabilizer no stabilizer Tween-80 SDS PF-68 BSA POL-Jr Tween-80 Tween-80 SDS SDS PF-68 PF-69 HPMC HPMC HPMC + Tween80 HPMC + SDS HPMC + PF68 HPMC + BSA HPMC + POL-JR HPMC + sodium alginate BSA POL-Jr sodium alginate no stabilizer Tween-80 SDS PF-68 HPMC BSA POL-Jr sodium alginate no stabilizer Tween-80 HPMC no stabilizer Tween-80

stabilizer (−) (−) (−) (−) antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent solvent antisolvent solvent antisolvent solvent antisolvent solvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent (−) antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent (−) antisolvent antisolvent (−) antisolvent

location of stabilizer 0.67 1.39 0.76 0.54 1.04 0.36 0.73 3.92 0.96 0.46 0.31 0.73 0.53 0.46 0.54 0.98 0.45 0.61 0.63 0.43 0.91 0.8 0.71 0.71 0.68 0.72 0.71 0.09 0.56 0.51 0.79 0.7 0.7 0.51 0.77 0.76 0.8 0.55 1.37

6.62 6.37 0.79 0.65 13.18 18.91 0.82 22.9 14.48 0.47 0.38 0.77 0.62 0.48 0.57 1.6 0.55 0.66 0.65 0.46 0.98 1.06 1.24 0.91 0.71 0.73 0.72 0.48 0.65 0.52 0.87 0.74 0.91 0.52 0.89 0.8 1.81 19.86 12.8

at 0 h at 24 h

particle size (μm)

5.65 5.65 5.65 5.65 3.35 6.22 4.17 3.55 6.12 3.35 3.35 6.22 6.22 4.17 4.17 6.34 6.34 2.48 5.39 3.49 3.26 5.14 3.76 3.55 6.12 4.81 6.34 4.04 6.92 4.87 7.04 4.25 6.81 5.5 7.04 4.73 7.73 7.44 5.14

ln S 0.02018 0.02082 0.02078 0.02035 0.01408 0.0204 0.01686 0.02008 0.02148 0.0146 0.01446 0.02254 0.02168 0.01657 0.01961 0.02299 0.02196 0.01881 0.02002 0.02113 0.02098 0.01929 0.02148 0.02162 0.02217 0.01897 0.02294 0.01602 0.02354 0.01863 0.0244 0.0234 0.02374 0.0202 0.02475 0.01873 0.02586 0.02485 0.01487

1018 1017 1018 1020 1018 1020 1019 1019 1017 1019 1019 1018 1020 1020 1020 1018 1020 1018 1019 1019 1018 1019 1019 1018 1018 1018 1018 1021 1020 1020 1018 1018 1019 1020 1018 1019 1019 1020 1020

× × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × 1.29 5.79 2.94 1.65 3.58 2.54 4.69 3.03 5.69 2.57 7.37 3.10 2.37 2.46 1.93 1.14 2.03 4.66 3.79 1.77 1.75 6.11 9.21 3.96 5.17 3.60 2.73 1.71 1.33 1.08 7.65 4.65 1.53 1.57 2.52 1.28 2.46 7.16 1.51

γb (J/m2)

J (no./m3 s) 0.0275 0.0275 0.0275 0.0275 0.02273 0.02869 0.02444 0.02316 0.02848 0.02273 0.02273 0.02869 0.02869 0.02444 0.02444 0.02894 0.02894 0.0257 0.02698 0.02779 0.02731 0.02644 0.02837 0.02316 0.02848 0.02577 0.0275 0.02273 0.02869 0.02444 0.02894 0.02316 0.02848 0.02577 0.0275 0.02273 0.02894 0.0275 0.01839

γc (J/m2) 36.2860 32.0966 32.3509 35.1475 61.4216 40.6604 45.0186 15.3583 32.5717 55.6945 57.2236 27.3340 32.3862 47.5216 24.6524 25.8536 31.7555 36.6401 34.7597 31.5310 30.1868 37.0947 32.0731 7.1554 28.4225 35.8292 19.8779 41.8938 21.8977 31.2095 18.6015 1.0187 19.9511 27.5391 11.1111 21.3635 11.9055 10.6640 23.6718

ARDd of γ (%) 1728.7 70909.1 305454.5 572727.3 1728.7 1728.7 1728.7 1728.7 1728.7 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 1728.7 1728.7

ε (J/kg) 11.64 1.82 0.87 0.64 11.64 11.64 11.64 11.64 11.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 11.64 11.64

mixing time (ms)

1 41.02 176.70 331.30 1.433 0.99 1.19 1.00 0.94 461.78 466.26 299.12 310.98 406.88 343.80 293.26 307.02 358.43 336.77 319.08 321.36 349.51 313.88 311.84 304.10 362.91 331.35 474.48 322.90 408.00 311.52 324.83 320.18 333.77 331.30 437.79 317.08 1.04 1.40

γoε/γε0

Table 4. Effect of Ultrasound and Stabilizers on Particle Size, Nucleation Rates and Solid-Liquid Interfacial Energy (Estimated Using Nucleation Rateb and Mersmann Equationc)a

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DMSO

acetone

solvent

ultrasound (W)

0 0 0 0 0 0 105 105 105 105 105 105 105 105 105 105 105 105 0 0 0 0 0 0 0 0 105 105 105 105 105 105 105 105 105 105 105 105 0 0

concn (mg/ mL)

30 30 30 30 30 30 30 30 30 30 5 5 5 5 5 5 5 5 30 30 30 30 30 30 30 30 30 30 30 30 5 5 5 5 5 5 5 5 30 30

Table 4. continued

SDS PF-68 HPMC BSA POL-Jr sodium alginate no stabilizer Tween-80 PF-68 HPMC no stabilizer Tween-80 SDS PF-68 HPMC BSA POL-Jr sodium alginate no stabilizer Tween-80 SDS PF-68 HPMC BSA POL-Jr sodium alginate no stabilizer Tween-80 PF-68 HPMC no stabilizer Tween-80 SDS PF-68 HPMC BSA POL-Jr sodium alginate no stabilizer Tween-80

stabilizer antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent (−) antisolvent antisolvent antisolvent (−) antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent (−) antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent (−) antisolvent antisolvent antisolvent (−) antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent (−) antisolvent

location of stabilizer 1.22 0.71 1.02 1.04 1.07 0.65 1.25 0.6 0.89 1.07 0.45 0.69 0.62 0.66 1.05 1.03 0.61 0.58 0.16 0.23 0.88 0.52 1.21 0.47 0.65 0.28 0.81 0.79 0.99 1.45 0.69 0.45 0.66 0.54 0.55 2.06 1.11 0.75 0.24 0.49

14.47 10.58 14.53 11.84 13.21 12.26 1.36 0.61 0.93 1.3 0.48 0.74 0.66 0.79 1.1 1.08 0.68 0.67 14.26 29.92 19.78 31.87 26.39 22.57 22.54 32.22 1.11 0.85 1.06 1.66 0.72 0.46 0.71 0.58 19.21 2.13 1.18 0.83 15.26 23.54

at 0 h at 24 h

particle size (μm)

8.01 5.97 8.13 5.34 7.91 6.6 7.44 5.14 5.97 8.13 3.55 2.93 4.49 4.05 3.27 3.67 3.69 4.66 5.35 4.72 6.28 5.84 5.06 5.46 5.47 6.45 5.35 4.72 5.84 5.06 3.49 2.34 5.48 4.78 5.65 5.05 5.13 6.12 5.29 4.18

ln S 0.02581 0.02131 0.02598 0.01881 0.02454 0.02271 0.02572 0.01986 0.02197 0.02756 0.01529 0.01338 0.01804 0.01692 0.0147 0.016051 0.01565 0.01848 0.01854 0.01704 0.02243 0.01942 0.01868 0.01928 0.01961 0.02113 0.02053 0.01875 0.02186 0.01999 0.01526 0.01559 0.02023 0.01809 0.02019 0.020168 0.019805 0.02161 0.01832 0.02057

10 18 1018 1018 1020 1020 1018 1018 1019 1019 1018 1019 1019 1019 1018 1018 1017 1019 1018 1020 1020 1017 1021 1019 1020 1020 1020 1018 1018 1018 1018 1018 1020 1019 1018 1021 1017 1018 1018 1021 1017

× × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × × 2.64 1.28 3.24 2.60 1.63 2.58 3.39 1.42 1.21 1.05 1.13 1.02 1.04 2.68 1.96 5.35 1.90 6.81 7.16 9.29 2.04 2.79 1.24 3.42 1.92 6.89 5.84 8.50 4.18 1.70 3.81 2.53 1.97 3.49 4.38 3.41 2.43 3.26 1.01 6.67

γb (J/m2)

J (no./m3 s) 0.02869 0.02444 0.02894 0.02316 0.02848 0.02577 0.0275 0.02273 0.02444 0.02894 0.02316 0.0218655 0.02510 0.0241937 0.0225815 0.0233977 0.0234338 0.025454 0.02316 0.0218655 0.02510 0.0241937 0.0225815 0.0233977 0.0234338 0.025454 0.02316 0.0218655 0.0241937 0.0225815 0.02304 0.0207416 0.02715 0.0257102 0.0275025 0.0262702 0.0264183 0.0284764 0.02304 0.0207416

γc (J/m2) 11.1585 14.6879 11.39338 18.7824 16.0554 13.4742 6.9207 14.4582 11.2623 5.0028 51.4716 63.4193 39.13799 42.9888 53.6159 45.7712 49.7366 37.7383 24.9191 28.3186 11.9059 24.5814 20.88617 17.5989 19.4991 20.4640 13.0693 16.6160 10.6757 12.9642 50.9830 33.0440 34.22217 42.1237 36.2185 30.2571 33.3921 31.7742 25.7642 0.8340

ARDd of γ (%) 1728.7 1728.7 1728.7 1728.7 1728.7 1728.7 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 1728.7 1728.7 1728.7 1728.7 1728.7 1728.7 1728.7 1728.7 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 572727.3 1728.7 1728.7

ε (J/kg) 11.64 11.64 11.64 11.64 11.64 11.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 11.64 11.64 11.64 11.64 11.64 11.64 11.64 11.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 0.64 11.64 11.64

mixing time (ms)

1.0 1.21 1.0 1.37 1.05 1.13 331.31 429.06 387.85 309.19 331.30 402.18 236.54 283.14 302.53 338.11 348.07 292.28 1.10 1.20 0.92 1.06 1.10 1.08 1.05 0.97 331.31 360.66 310.99 340.09 331.31 422.78 326.23 345.35 326.71 330.31 332.98 304.69 1.12 1.0

γoε/γε0

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Langmuir Curcumin particles were precipitated from 5 mg/mL ethanol solution (10 mL) of curcumin by addition of 100 mL of water maintained (at 1 °C with 20 mg of stabilizer) with sonication through a 1 in. probe at 13, 56, and 105 W for 10 min and without sonication using an overhead stirrer at 1200 rpm speed for 10 min. bγ estimated using nucleation rate. cγ estimated using Mersmann equation. dAbsolute relative deviation (%) in prediction of γ using Mersmann equation. Mixing time is calculated using τm = km(ν/ε)1/2 where km is the constant (the value of which is 17.24)29, ν is the kinematic viscosity (m2/ s), and ε is the energy dissipated (W/kg).

size increased to only 0.65 μm at 24 h from 0.54 μm at 0 h. These observations clearly indicate that the particle size of curcumin suspensions at 0 h exhibits a maximum with an increase in ultrasound power (in the absence of stabilizers). On the other hand, the particle size at 24 h decreases continuously with an increase in ultrasound. Ultrasound is known to cause agglomeration of particles due to enhanced motion of particles in the ultrasonic field.6,7 An increase in particle size at 0 h with an increase in ultrasound energy could be attributed to the agglomeration of particles due to interparticle collisions in the presence of ultrasound. The interparticle collisions increase as a result of higher velocities imparted to particles by cavitation events caused in the solution by ultrasound.6−9 While an increase in ultrasound power increases the agglomeration rate, it also increases the nucleation rates by increasing the diffusivity of the curcumin.13 (The nucleation rates calculated in the presence of ultrasound and the absence of stabilizers are reported in Table 4.) At lower ultrasonic energy levels, increase in particle size due to agglomeration results in an increase in particle size whereas at the higher ultrasonic levels an increase in nucleation rates (and hence low growth rates) results in lower particles sizes. Thus, the particle size of curcumin nanosuspensions at 0 h is the result of two opposing effects influencing particle size, namely, an increase in agglomeration due to ultrasound and an increase in nucleation rate due to ultrasound. However, the use of ultrasound results in stable particle suspensions at 24 h mainly due to compaction of layers of solute molecules in the particle and annealing of the particle surface. Table 4 also presents changes in particle size and size distribution of curcumin particles at 0 and 24 h, when precipitated with different stabilizers, with and without ultrasound. It can be observed that curcumin particles precipitated using SDS, sodium alginate, polymer JR 400, Tween-80, PF-68, and BSA along with 105 W ultrasound have sizes less than 1 μm at 0 as well as 24 h. However, when compared with curcumin particles precipitated without ultrasound and only with stabilizer, only two stabilizers, viz., SDS and PF-68, result in a comparatively lower average particle size at 0 h. Moreover, such particles precipitated without ultrasound and with stabilizer are highly unstable and result in particle sizes greater than 10 μm at 24 h (as can be observed from Table 4). The morphology of curcumin particles precipitated with stabilizers and ultrasound was studied through SEM. Figure 1 presents SEM micrographs of curcumin particles precipitated without using any stabilizer (Figure 1A) and with stabilizers such as PF-68, SDS, Tween-80, HPMC, and BSA (Figure 1B−F). A rice-seed-like or long rodlike morphology is observed for most of the precipitated particles except for the particles precipitated in the presence of BSA and 105 W ultrasound. A rice-seed-like morphology of precipitated curcumin particles can be attributed to the orthorhombic form of curcumin particles precipitated in the presence of ultrasound. Figure 2 presents PXRD patterns of curcumin particles precipitated from its organic solutions in ethanol and in presence of ultrasound, and with and without stabilizers. It can be observed that the precipitated particles are present in orthorhombic form20 of curcumin. Figure 3 presents a snapshot of a typical orthorhombic unit cell for curcumin with highlighted (001) plane. It is evident that the phenolic hydroxyl and phenolic methyl groups protrude out of (001) plane. These groups interact through hydrogen bonds with the phenolic methyl groups and phenolic hydroxyl groups of other curcumin molecules respectively. Such interactions result into a growth along the c axis and hence the elongated particle morphology in

a

0.89 0.96 0.86 0.93 0.93 0.86 331.31 394.23 286.42 262.87 11.64 11.64 11.64 11.64 11.64 11.64 0.64 0.64 0.64 0.64 1728.7 1728.7 1728.7 1728.7 1728.7 1728.7 572727.3 572727.3 572727.3 572727.3 17.7209 19.6379 15.07331 16.0647 19.5940 18.6023 12.1714 1.2777 8.2990 4.2157 0.02715 0.0257102 0.0275025 0.0262702 0.0264183 0.0284764 0.02304 0.0207416 0.0257102 0.0275025 0.02306 0.02149 0.02390 0.02205 0.02209 0.02401 0.02054 0.02101 0.02374 0.02639 × × × × × × × × × × 0 0 0 0 0 0 105 105 105 105 30 30 30 30 30 30 30 30 30 30

SDS PF-68 HPMC BSA POL-Jr sodium alginate no stabilizer Tween-80 PF-68 HPMC

antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent (−) antisolvent antisolvent antisolvent

0.27 0.68 0.93 0.38 0.73 0.99 1.64 0.98 2.66 9.99

19.99 30.27 23.59 25.47 21.64 30.57 5.02 2.01 3.46 17.39

7.21 6.57 7.44 6.84 6.91 7.64 5.29 4.18 6.58 7.44

1.81 3.86 2.03 5.05 6.02 1.92 1.99 1.64 2.45 1.47

1020 1020 1020 1020 1020 1020 1018 1019 1018 1018

γb (J/m2) at 0 h at 24 h ultrasound (W) concn (mg/ mL) solvent

Table 4. continued

stabilizer

location of stabilizer

particle size (μm)

ln S

J (no./m3 s)

γc (J/m2)

ARDd of γ (%)

ε (J/kg)

mixing time (ms)

γoε/γε0

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Figure 1. SEM micrographs of curcumin particles precipitated (A) without stabilizer and with (B) PF68 (C) SDS (D) Tween-80 (E) HPMC, and (F) BSA as a stabilizer.

Figure 2. Overlay of X-ray diffraction patterns of curcumin particles precipitated by addition of antisolvent to organic solutions of curcumin (A) in ethanol and in the presence of ultrasound but without surfactant, (B) in ethanol and in the presence of ultrasound and with SDS as surfactant, (C) in ethanol and in the presence of ultrasound and with Tween-80 as surfactant, (D) in ethanol and in the presence of ultrasound and with BSA as surfactant, and (E) in ethanol and in the presence of ultrasound and with HPMC as surfactant, and (F) calculated XRD pattern of orthorhombic form of curcumin.20 4584


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Figure 3. Arrangement of curcumin molecules in an orthorhombic unit cell and molecular groups present on (001) crystal plane visualized using Mercury software version 3.1.

Figure 4. Overlay of X-ray diffraction patterns of curcumin particles precipitated by addition of antisolvent to organic solutions of curcumin (A) in ethanol and in the absence of ultrasound but without surfactant, (B) in acetone and in the absence of ultrasound but without surfactant, and (C) in DMSO and in the absence of ultrasound but without surfactant, (E) in ethanol and in the presence of ultrasound but without surfactant, (F) in acetone and in the presence of ultrasound but without surfactant, and (G) in DMSO and in the presence of ultrasound but without surfactant, and calculated XRD patterns (D) of the monoclinic form20 and (H) of the orthorhombic form of curcumin20

results in a rodlike morphology. A similar growth controlling mechanism can be expected in the case of particles precipitated in the presence of ultrasound and surfactants of PF68 and SDS. In the case of particles precipitated in the presence of BSA and ultrasound, the spherical morphology indicates a quick arrest of particle growth in all directions and hence the spherical particle morphology.

that direction. The variation in particle morphology can be attributed to the interaction of stabilizers with curcumin. The rodlike morphology in the presence of Tween-80 is a result of the particle growth arrest in the 001 direction. Tween-80 interacts well with curcumin molecule through hydrogen bonding at the exposed functional groups at the 001 face and effectively decreases the curcumin particle growth in the 001 direction. This 4585


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Table 5. Variation in Average Particle Size of Curcumin Particles in Aqueous Suspensions with Nondimensional Stability Parameter, γ0ε/γε0a 0h

long termb

24 h

γ0ε/γε0

particle size (μm)

% < 1 μm

particle size (μm)

% < 1 μm

particle size (μm)

% < 1 μm

466.42 461.68 445.43 443.07 422.83 419.64 408.00 407.66 406.83 402.09 376.22 362.98 354.74 345.90 345.30 343.76 340.14 337.38 333.33 331.35 326.80 326.26 324.78 320.72 320.10 318.07 316.76 315.76 313.28 311.92 306.94 304.69 304.04 302.48 299.22 293.17 292.31 290.19 286.37 283.13 270.12 258.00 236.52 220.41 177.81 176.71 171.64 165.32 163.40 114.63 60.28 50.56 45.99 43.18 41.46 41.02 40.60 38.87

0.09 0.47 0.76 0.6 0.43 1.03 0.51 0.49 0.55 0.69 0.52 0.72 0.62 0.86 0.54 0.5 0.62 2.06 0.63 0.54 0.55 0.66 0.7 0.72 0.7 0.93 0.79 0.45 0.76 0.71 0.05 0.75 0.69 1 0.53 0.98 0.58 0.7 0.57 0.71 0.77 0.34 0.62 0.46 0.85 0.76 1.25 0.75 0.91 0.8 0.97 1.13 0.71 1.11 0.57 1.39 0.77 1.2

100 100 82.7 81 100 46.8 100 99.9 97.2 91.5 95 88.5 92.7 72.3 100 100 75.1 19.7 81.5 97.2 100 83.1 87.6 89.8 80.5 76.4 71.1 100 69.1 73.3 96.2 87.1 87.4 59.8 88.8 81.1 96.5 90.1 93.7 92.4 85.1 100 93.8 100 63 87 57.6 87.9 74.4 67.7 71.4 59.5 82.4 46.7 99.8 44.9 84.2 25.9

0.48 0.47 0.8 0.62 0.47 1.08 0.53 0.49 0.49 0.75 0.52 0.74 0.66 1.06 0.58 0.58 0.68 2.13 0.65 0.65 19.21 0.72 0.75 0.73 0.91 0.98 0.88 0.46 1.24 0.91 0.56 0.83 0.71 1.1 0.62 1.6 0.68 0.73 0.65 0.8 0.9 0.47 0.67 0.57 0.92 0.79 1.3 0.8 0.97 1.82 0.98 1.16 0.73 1.18 4.48 6.37 3.39 3.96

100 99 100 100 99.2 45.5 98.4 99.8 94.6 87.2 98.3 85.2 90.1 67.6 98.8 99.4 68.1 18.5 80.8 92.4 5.4 87 74.3 88 73.4 69.7 66.9 100 65 68.2 96.8 82.2 86.6 60.3 85.5 41.5 89.3 88 87.4 91.2 83.3 97.6 91.2 98.8 63.9 85.2 58.6 85 61.4 25.2 74.3 37.6 80.7 45.8 22.4 24.9 27 22.8

0.82* 0.57* 0.90*

81.8* 83.5* 74.9*

0.51* 0.91*

77.0* 72.1*

0.50*

93.3*

0.88*

71.3*

5.97

32

0.97 0.54 0.89* 0.99 0.67* 7.06

88.7 82.2 55.6* 60 81.2* 8.14

0.82* 0.98 0.78 1.64*

75.4* 65.2 71.1 39.9*

0.95 0.9 1.49

63.6 60.2 41.4

0.98

59.1

0.82 4.26

63.3 18.7

2.21

31.2

0.91* 0.47

81.0* 93.5

1.52 0.89 0.85 0.89 20 1.67* 0.98 5.37 2.01 0.88 5.19 16.02 4.261 9.64

39.7 65.1 67.7 65.7 9.9 14.4* 55.7 10.1 1 67.8 13.5 4.1 19 7.2

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Table 5. continued 0h γ0ε/γε0 1.43 1.20 1.01 1.00 0.99 0.94

long termb

24 h

particle size (μm)

% < 1 μm

particle size (μm)

% < 1 μm

particle size (μm)

% < 1 μm

1.04 0.73 3.92 0.67 0.36 0.96

74.8 62.8 31.1 99.9 86.7 63.5

13.18 0.82 22.9 6.62 18.91 14.48

1.9 8.5 3.64 16.2 7.9 7

20.42 7.89 22.26 16.25 22.17 15.83

0.9 11.2 1.9 3.4 3 3

a Particle sizes were measured at 0 h and 24 h and long term (90 days and 1 year and 9 months) after precipitation. bAsterisks (*) ndicate the average particle size measured after 90 days, and the data with no asterisk are the average particle sizes measured after 1 year and 9 months.

presence of ultrasound (as presented in Table 3) were then used to estimate γ the in absence of stabilizers following the procedure given in section 4.3. Table 4 presents the values of γ (in the absence of stabilizers) which seem to have not been affected significantly by ultrasound. Therefore, it can be concluded that the increase in nucleation rates in the presence of ultrasound (and the absence of stabilizers) can be attributed to an increase in the diffusivity due to ultrasound and not to the decrease in interfacial energy in the presence of ultrasound. Table 4 presents also nucleation rates estimated from particle size distributions of curcumin particles precipitated by LAS in the presence of stabilizers and ultrasound. The data presented in Table 4 suggest that the use of stabilizers in addition to ultrasound tremendously increases the nucleation rates and hence decreases the particle size. In order to analyze the effect of stabilizer on nucleation rates, C*, S, DAB, and solid−liquid γ were estimated as explained in sections 3.4, 4.1, 3.6, and 4.3, respectively, and are reported in Table 4. 5.3. Stability of Curcumin Nanosuspensions and Its Correlation with Stability Parameter. Table 4 presents the average sizes of curcumin particles in aqueous suspensions at 0 h as well as 24 h. It can be observed that a few suspensions are stable at 24 h (i.e., no or negligible change in particle size) whereas a few are highly unstable (i.e., a large change in particle size over the period of 24 h). Also, the percentage of particles less that 1 μm remains high (90−100%) for a few suspensions at the end of 24 h and decreases drastically to a very low value for those which are unstable. The average size of particles in these suspensions was further tracked over a period of 1 year and 9 months. Table 5 and Figure 5 present the variation in average sizes of curcumin particles in these aqueous suspensions (measured after 24 h, 90 days, and 1 year and 9 months) with the calculated values of γ0ε/γε0. It can be seen that curcumin particles precipitated with γ0ε/γε0 more than 100 have average sizes less than 1 μm even after a period of 24 h, 90 days, or 1 year 9 months, whereas the suspensions with the stability parameter lower than 10 are not stable even for 24 h. Thus, it can be observed that the higher the value of the stability parameter, the more stable is the aqueous suspension of ultrafine particles. This is mainly because a higher value of stability parameter indicates the availability of excess mechanical energy (the energy that remains available after consumption of energy for nucleation) for compaction/annealing of the crystal surface and enhanced and uniform adsorption of stabilizer molecules on the growing particle surface. In order to examine the enhanced adsorption of stabilizer on the particles precipitated in presence of ultrasound, TGA studies were performed on the particles precipitated in presence of ultrasound and a few selected stabilizers to estimate the percentage increase in stabilizer inclusion in the presence of ultrasound. The results obtained from TGA studies are presented

No significant influence of the nature of organic solvent could be found on the particle size, size distribution, and stability of curcumin particles when precipitated from organic solutions of curcumin in different solvents such as acetone, ethanol, and DMSO (as can be observed from Table 4). Figure 4 presents PXRD patterns of curcumin particles precipitated from their organic solutions in three different solvents, namely, acetone, ethanol, and DMSO, and in the absence and presence of ultrasound and without stabilizers. It can be observed that the particles precipitated from all three organic solutions and in the absence/presence of ultrasound are in crystalline form rather than being in amorphous form. However, there is a change in the crystal form upon application of ultrasound; from the monoclinic form in the absence of ultrasound to the orthorhombic form in the presence of ultrasound. Such polymorphic conversions in the presence of ultrasound have been reported for sonocrystallization of several APIs by many researchers.20−25 This issue is currently being investigated further in our research group to understand the basic mechanism of polymorphic transformation of curcumin upon application of ultrasound. 5.2. Effect of Ultrasound and Stabilizers on Interfacial Energy. It can be observed from Table 4 that the use of ultrasound increases the nucleation rates and hence decreases the particle size. Nucleation rates mainly depend on supersaturation (S), diffusivity (DAB), and interfacial energy (γ). Therefore, an increase in nucleation rates with the use of ultrasound could be explained through the effect of ultrasound on these variables. It is expected that ultrasound may affect interfacial energy and diffusivity but it does not alter the supersaturation as the equilibrium solubility is not affected by ultrasound. In order to verify the effect of ultrasound on interfacial energy, first the variation in diffusivity due to ultrasound was investigated as explained in section 3.6. The effect of ultrasound on diffusivity (in absence of stabilizer) of curcumin is presented in Table 3. It can be observed that the diffusivity increases manifolds due to ultrasound. The DAB in the presence of 105 W ultrasound increases by 316 times as compared to DAB when no ultrasound was used. Similar observation was made by Guo et al.,30 where it was found that the use of ultrasound for LAS precipitation of roxithromycin increases DAB of roxithromycin in aqueous solution. It should be noted that the enhancement in the diffusivity in the presence of ultrasound is not very sensitive to the use of a different stabilizer along with ultrasound (Table 3). The concentration of the stabilizer used is very low (only 0.02 wt % stabilizer was used in the aqueous suspensions), and hence it does not significantly affect the viscosity of the solutions (as can be observed from Table 2). Since the viscosities of the suspensions are not significantly affected, no effect of the type of a stabilizer is observed on the enhancement in the DAB (as per eq 13). The values of DAB of curcumin in aqueous solutions in the 4587


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eq 21, which describes the growth of particles by Ostwald ripening:27 D − Do = kt 1/ n

where t is time, k is a temperature-dependent material constant, and Do is the average particle diameter at t = 0. The value of exponent n depends upon the step which controls the process of Ostwald ripening. While n = 4 indicates the growth is controlled by dissolution kinetics at the solid−liquid interface of the dissolving particle, n = 3 indicates that the growth is diffusion limited and n = 2 indicates that the growth is interface transfer controlled. In order to investigate if the curcumin nanosuspensions undergo Ostwald ripening, particle sizes of curcumin nanosuspensions were tracked over a period of 24 h. The data for variation of particle size with time were then treated to regress the constants k and n in eq 21 and are reported in Table 7. It can be observed from Table 7 that the value of n is much higher for a majority of stabilizer cases except for BSA (n = 3). Hence, it can be concluded that except for these two cases, there is no Ostwald ripening occurring in the curcumin suspensions. Further to this, the long-term stability (3 months or 1 year 9 months) data presented in Table 5 also indicate that there is no significant growth of curcumin particle size over the period of even 3 months or 1 year 9 months. 5.5. Use of Mersmann Equation to Device a Predictive Criterion. To estimate the value of the stability parameter for the purpose of prediction of stability of aqueous suspensions of curcumin particles, the values of solid−liquid interfacial energies (γ andγ0) and the mechanical energy (ε and ε0) to be used should be known. ε and ε0 can be calculated easily knowing the level of ultrasound and mechanical agitation to be used. However, the estimation of γ andγ0, prior to precipitation experiments, is difficult as it primarily needs experimental particle size distribution, and hence the use of a stability parameter for the purpose of prediction of stability of particle suspensions is not possible unless these values are known. Therefore, to make the proposed criterion predictive, the equation proposed by Mersmann28 and given by eq 22 was evaluated for the purpose of prediction of γ and γ0 at the given operating conditions.

Figure 5. Variation of average particle sizes of curcumin particles in aqueous supensions measured at (◊) 24 h, (▲) 90 days, and (□) 1 year 9 months with stability parameter (γ0ε/γε0), where γ and γ0 are solid− liquid interfacial energies in the presence and absence of stabilizers, respectively, ε and ε0 are energy inputs per kilogram in the presence and absence of ultrasound. Curcumin particles precipitated by addition of curcumin solution in ethanol (5 mg/mL) in 100 mL of water maintained at 1 °C in the presence of stabilizers with sonication through a 1 in. probe at 13, 56, and 105 W for 10 min and without sonication using overhead stirrer at 1200 rpm. Dashed lines are a guide to the reader’s eyes.

in Table 6. It can be observed from Table 6 that the use of ultrasound enhances the percentage of stabilizer inclusion which Table 6. Occlusion of Stabilizers on Curcumin Nanosuspensions in the Presence and Absence of Ultrasound precipitation conditions of curcumin with SDS and without ultrasound with SDS and with 105 W ultrasound with Tween-80 and without ultrasound with Tween-80 and with 105 W ultrasound with HPMC and without ultrasound with HPMC and with 105 W ultrasound with BSA and without ultrasound with BSA and with 105 W ultrasound with sodium alginateand without ultrasound with sodium alginate and with 105 W ultrasound with POL-JR and without ultrasound with POL-JR and with 105 W ultrasound

% weight loss

% increased due to ultrasound

63.33 67.40 63.40 70.80

4.07

71.91 79.97 58.48 65.62 60.75

8.06

7.40

7.14 4.31

⎛N ⎞ ⎛ 1 ⎞ γ = 0.414kT ⎜ A ⎟ ln⎜ ⎟ ⎝ ν ⎠ ⎝ νCA* ⎠

65.06 66.50 73.70

(21)

7.20

(22)

where ν = MW/ρ, MW is the molecular weight of the solid solute, and ρ is the density of the solid. It was found that the percent average absolute relative deviation (% AARD) of the values of γ estimated using the Mersmann equation from the values of γ calculated from experimentally evaluated nucleation rates ranges from 18 to 42% (Table 4). However, as can be seen from Figure 6, which presents the variation in γ0ε/γε0 with particle sizes of curcumin particles in aqueous suspensions measured after a period of 24 h, 90 days, and 1 year 9 months, no significant deviation can be observed between the values of the stability parameter estimated using γ calculated by the Mersmann equation and γ calculated from experimentally evaluated nucleation rates. This further affirms that the Mersmann equation can be used to calculate the parameter γ0ε/γε0 without any precipitation experiments and predict the stability of aqueous suspensions of curcumin nanoparticles.

in turn enhances the stability of the curcumin particles in the suspensions. The correlation of the amount of stabilizer included with the type of stabilizer or physicochemical properties of stabilizers however was not investigated in this work as it will need more detailed analysis and will be a subject of further research. 5.4. Investigations on Ostwald Ripening of Curcumin Nanosuspensions. The stability of nanoparticles dispersions can be greatly affected by Ostwald ripening, where particles with sizes lower than the critical size of the particles population dissolve and particles larger than the critical size would grow.26 In order to evaluate the extent of Ostwald ripening in the curcumin suspensions, the variation in particle size with time was fitted to 4588


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Table 7. Estimation of Kinetic Constants Obtained by Application of Equation 21 to Long-Term Stability Data of Curcumin Suspensionsa particle size (μm) concn (mg/ mL)

solvent

5 30 30 30 5 5 5 10 20 30 5 30 5 30 5 30 30 30 5 5 5 5 10 20 30 5 30 5 30 5 30 30 30 5 5 5 10 5 5 5 30 30 30 5 5 5 5 10 5 5 30 30 30 5 5 5

ethanol ethanol acetone DMSO ethanol ethanol ethanol ethanol ethanol ethanol acetone acetone DMSO DMSO ethanol ethanol acetone DMSO ethanol ethanol ethanol ethanol ethanol ethanol ethanol acetone acetone DMSO DMSO ethanol ethanol acetone DMSO ethanol ethanol ethanol ethanol acetone DMSO ethanol ethanol acetone DMSO ethanol ethanol ethanol ethanol ethanol acetone DMSO ethanol acetone DMSO ethanol ethanol ethanol

stabilizer no stabilizer no stabilizer no stabilizer no stabilizer no stabilizer no stabilizer no stabilizer no stabilizer no stabilizer no stabilizer no stabilizer no stabilizer no stabilizer no stabilizer Tween-80 Tween-80 Tween-80 Tween-80 Tween-80 Tween-80 Tween-80 Tween-80 Tween-80 Tween-80 Tween-80 Tween-80 Tween-80 Tween-80 Tween-80 BSA BSA BSA BSA BSA BSA BSA BSA BSA BSA SDS SDS SDS SDS SDS SDS SDS SDS SDS SDS SDS HPMC HPMC HPMC HPMC HPMC HPMC

data collecn duration (days)


ultrasound (W)

K

n

R

(−) (−) (−) (−) (−) (−) (−) (−) (−) (−) (−) (−) (−) (−) antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent solvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent solvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent solvent

0 0 0 0 13 56 105 105 105 105 105 105 105 105 0 0 0 0 13 56 105 105 105 105 105 105 105 105 105 0 0 0 0 13 56 105 105 105 105 0 0 0 0 13 56 105 105 105 105 105 0 0 0 56 105 105

55519 0.0178 12.9834 0.0023 203.43 0.0369 0.004 0.0837 0.002 0.018 12.1789 0.0072 0.3812 0.5512 5.8513 1.1786 2.2578 0.0023 0.2471 0.0031 0.000002 0.5489 0.0075 0.0201 0.018 0.1278 0.0072 0.0467 0.0455 13150 11.789 10.289 0.0023 44.262 1.2817 0.046 0.0013 0.1297 45267 0.00004 0.0017 1.1789 229.78 3477 0.0282 4 × 10−7 0.0013 0.0013 0.00003 0.00004 0.0178 1.1789 2.569 2.6598 1.641 1 × 10−7

6 6 11 9 5 9 7 9 12 11 6 7 8 2 14 18 6 13 12 10 37 26 10 6 11 6 7 9 1 5 3 19 12 8 12 6 20 13 21 9 10 12 17 10 7 46 7 12 21 23 12 20 17 18 8 12

0.9284 0.9267 0.9325 0.9578 0.9284 0.9514 0.9831 0.9814 0.9382 0.9544 0.9539 0.9668 0.9432 0.9699 0.9408 0.9356 0.9512 0.9167 0.9593 0.9234 0.944 0.9673 0.9811 0.9891 0.9544 0.9822 0.9892 0.9634 0.9359 0.9334 0.9267 0.9267 0.9519 0.9397 0.9933 0.972 0.9755 0.9872 0.9731 0.9236 0.9723 0.9199 0.9725 0.957 0.9817 0.979 0.9736 0.9521 0.982 0.9799 0.9288 0.9915 0.9816 0.9727 0.98 0.969

4589

2

1 1 1 1 1 1 30 30 30 30 1 1 1 1 1 1 1 1 1 1 30 30 30 30 30 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

at 0 h at 24 h 0.67 0.55 0.16 0.24 1.39 0.76 0.54 0.72 0.77 1.25 0.49 0.81 0.7 1.64 1.04 1.37 0.23 0.49 0.97 0.34 0.46 0.33 0.09 0.76 0.6 0.69 0.79 0.43 0.98 3.92 1.04 0.47 0.38 0.77 0.85 0.71 0.7 1.03 2.06 0.36 1.22 0.88 0.27 1.2 0.75 0.53 0.74 0.57 0.62 0.66 1.02 1.21 0.93 0.91 0.98 0.05

6.62 19.86 14.26 15.26 6.37 0.79 0.65 0.72 0.89 1.36 0.51 1.11 0.72 5.02 13.18 12.8 29.92 23.54 0.97 0.46 0.47 0.47 0.48 0.8 0.61 0.74 0.85 0.46 2.01 22.9 11.84 22.57 25.47 3.39 0.92 0.91 0.74 1.08 2.13 18.91 14.47 19.78 19.99 3.96 0.8 0.62 0.77 0.65 0.66 0.71 14.53 26.39 23.59 0.97 1.6 0.55

γ0ε/γε0 1 1.03501 1.10649 1.12172 41.018742 176.69607 331.3052 331.34853 331.3052 331.3052 331.3052 331.3052 331.3052 331.3052 1.4332386 1.39856 1.20421 0.99901 60.268893 258.0285 461.78499 466.25594 474.47785 437.78984 429.06192 402.17656 360.65691 422.78024 394.22825 1.0049801 1.36735 1.07716 0.93197 40.60914 177.8085 311.8437 324.83484 338.10861 330.31029 0.9892157 0.996512 0.914846 0.8911534 38.871653 165.31948 299.11539 310.98067 322.90294 236.54355 326.22835 0.98999 1.098501 0.859832 163.40657 293.26058 307.01552


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Table 7. continued particle size (μm) concn (mg/ mL)

solvent

10 20 30 5 30 5 30 5 5 5 5 5 5 5 30 30 30 5 5 5 10 5 5 30 30 30 5 5 10 5 5 5 30 30 30 5 5 5 5 10 30 5 30 5 30

ethanol ethanol ethanol acetone acetone DMSO DMSO ethanol ethanol ethanol ethanol ethanol ethanol ethanol ethanol acetone DMSO ethanol ethanol ethanol ethanol acetone DMSO ethanol acetone DMSO ethanol ethanol ethanol acetone DMSO ethanol ethanol acetone DMSO ethanol ethanol ethanol ethanol ethanol ethanol acetone acetone DMSO DMSO

data collecn duration (days)

stabilizer


ultrasound (W)

K

n

R

HPMC HPMC HPMC HPMC HPMC HPMC HPMC HPMC + POL JR HPMC + SDS HPMC + Tween-80 HPMC + BSA HPMC + sodium alginate HPMC + PF68 POL JR POL JR POL JR POL JR POL JR POL JR POL JR POL JR POL JR POL JR sodium alginate sodium alginate sodium alginate sodium alginate sodium alginate sodium alginate sodium alginate sodium alginate PF68 PF68 PF68 PF68 PF68 PF68 PF68 PF68 PF68 PF68 PF68 PF68 PF68 PF68

antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent solvent antisolvent antisolvent antisolvent antisolvent antisolvent antisolvent

105 105 105 105 105 105 105 105 105 105 105 105 105 0 0 0 0 13 56 105 105 105 105 0 0 0 13 105 105 105 105 0 0 0 0 13 56 105 105 105 105 105 105 105 105

0.029 0.0837 0.05623 1.9924 213.56 3000000 8.0074 0.3744 0.0013 0.0068 0.0375 59902 0.9366 20000000 0.00027 0.19027 2.9762 42678 3.1109 0.0005 3 × 10−7 0.00002 0.2342 5000 0.1782 0.0016 10000 0.0015 4 × 10−7 0.00004 4 × 10−7 1000000 0.9927 0.9912 0.0023 28.229 55.667 0.411 0.0025 0.9823 0.00523 0.00023 0.5211 0.0021 0.0455

1 1 2 7 5 6 2 15 11 12 19 25 24 20 23 19 15 30 25 32 40 20 5 12 22 9 25 16 42 20 50 7 12 9 15 8 12 50 20 23 14 7 15 10 1

0.9601 0.9301 0.9662 0.9872 0.9512 0.9653 0.9539 0.9481 0.973 0.9464 0.9857 0.9638 0.9336 0.961 0.9367 0.9178 0.9967 0.9728 0.9901 0.932 0.9205 0.9752 0.971 0.9278 0.9978 0.9267 0.9694 0.9501 0.975 0.9531 0.9761 0.9493 0.9378 0.9278 0.9926 0.9881 0.9675 0.9909 0.9325 0.9652 0.9723 0.9731 0.9345 0.9678 0.9359

2

30 30 30 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

at 0 h at 24 h 0.79 0.8 1.07 1 1.45 0.55 9.99 0.86 0.63 0.62 0.93 0.76 0.45 0.96 1.07 0.65 0.73 0.57 1.25 0.69 0.7 0.62 1.11 0.65 0.28 0.99 0.71 0.72 0.52 0.58 0.75 0.73 0.71 0.52 0.68 1.13 0.46 0.55 0.5 0.51 0.89 0.71 0.99 0.54 2.66

0.87 1.81 1.3 1.1 1.66 19.21 17.39 1.06 0.65 0.66 0.98 1.24 0.46 14.48 13.21 22.54 21.64 4.48 1.3 0.71 0.91 0.68 1.18 12.26 32.22 30.57 0.73 0.73 0.51 0.67 0.83 0.82 10.58 31.87 30.27 1.15 0.56 0.48 0.57 0.52 0.93 0.79 1.06 0.58 3.46

γ0ε/γε0 311.52193 317.08444 309.18613 302.52813 340.08918 326.71285 262.86957 349.51067 336.76628 358.4296 321.35657 313.8762 319.07529 0.9394786 1.04808 1.0464 0.930285 41.456807 171.65705 304.10739 320.18261 348.07209 332.97677 1.13254 0.971131 0.85482 45.988703 362.91629 333.76539 292.2757 304.69066 1.1969158 1.20694 1.05664 0.95625 50.563068 220.39289 406.88357 343.80728 408.00511 387.85479 283.13733 310.99646 345.34796 286.42498

Curcumin suspensions were prepared by addition of 100 mL of water (maintained at 1 °C with 20 mg of stabilizer) to 5 mg/mL ethanol solution (10 mL) of curcumin in the presence of sonication through a 1in. probe at 13, 56, and 105 W for 10 min and without sonication using an overhead stirrer at 1200 rpm speed for 10 min. a

6. CONCLUSION Precipitation of curcumin particles was carried out using LAS in the presence of ultrasound and various stabilizers. The stability of aqueous suspensions of curcumin particles thus produced was correlated with the mechanical energy used during precipitation by defining a new parameter γ0ε/γε0, which is a ratio of nondimensional solid−liquid interfacial energy (γ/γ0) to nondimensional mechanical energy (ε/ε0). It was observed that the

sizes of curcumin particles remain stable even after 1 year and 9 months if γ0ε/γε0 is more than 100. The higher the value of this parameter, the more stable is the aqueous suspensions of curcumin particles. This is mainly because a higher value of stability parameter indicates the availability of excess mechanical energy for compaction/annealing of the crystal surface after consumption of energy for nucleation. It was also found that the parameter γ0ε/γε0 can be used as a criterion for prediction of the 4590


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r0: radius of the molecule (cm) S: supersaturation ratio T: temperature (K) Δ(wt%): differential weight percent Greek Letters

γ: solid−liquid interfacial tension (J/m2) ε: energy input per unit mass (J/kg) η: dynamic viscosity (cP) ρc: particle density (g/cm3) ω: molecular volume (cm3/molecule) Abbrevations Figure 6. Variation in average particle size of curcumin nanosuspensions measured after 24 h, 90 days, and 1 year and 9 months with stability parameter (γ0ε/γε0) where γ and γ0 are solid−liquid interfacial energies in the presence and absence of stabilizers, respectively, ε and ε0 are energy input per kilogram in the presence and absence of ultrasound. Curcumin particles precipitated by addition of curcumin solution in ethanol (5 mg/mL) in 100 mL of water maintained at 1 °C in the presence of stabilizers with sonication through a 1 in. probe at 13, 56, and 105 W for 10 min and without sonication using an overhead stirrer at 1200 rpm. Experimental data points are for γ calculated by classical nucleation theory (○) and γ calculated by the Mersmann equation (●); the dashed line is a guide to the reader’s eyes.

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REFERENCES

(1) Amidon, G. L.; Lennernäs, H.; Shah, V. P.; Crison, J. R. A theoretical basis for a biopharmaceutic drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 1995, 12, 413−420. (2) Lipinski, C. A. Poor Aqueous Solubility-an Industry Wide Problem in ADME Screening. Am. Pharm. Rev. 2002, 5, 82−85. (3) Noyes, A. A.; Whitney, W. R. The rate of solution of solid substances in their own solutions. J. Am. Chem. Soc. 1897, 19, 930−934. (4) Liversidge, G. G.; Cundy, K. C. Particle size reduction for improvement of oral bioavailability of hydrophobic drugs: I. Absolute oral bioavailability of nanocrystalline danazol in beagle dogs. Int. J. Pharm. 1995, 125, 91−97. (5) Chen, J.-F.; Zhang, J.-Y.; Shen, Z.-G.; Zhong, J.; Yun, J. Preparation and Characterization of Amorphous Cefuroxime Axetil Drug Nanoparticles with Novel Technology: High-Gravity Antisolvent Precipitation. Ind. Eng. Chem. Res. 2006, 45, 8723−8727. (6) Thorat, A. A.; Dalvi, S. V. Liquid antisolvent precipitation and stabilization of nanoparticles of poorly water soluble drugs in aqueous suspensions: Recent developments and future perspective. Chem. Eng. J. 2012, 181−182, 1−34. (7) Sugiyama, Y.; Kawakishi, S.; Osawa, T. Involvement of the ßdiketone moiety in the antioxidative mechanism of tetrahydrocurcumin. Biochem. Pharmacol. 1996, 52, 519−525. (8) Jordan, W. C.; Drew, C. R. CurcuminA natural herb with antiHIV activity. J. Natl. Med. Assoc. 1996, 88, 333. (9) Lee, Y. K.; Lee, W. S.; Hwang, J. T.; Kwon, D. Y.; Surh, Y. J.; Park, O. J. Curcumin exerts anti differentiation effect through AMPK a-PPARγ in 3T3-L1 adipocytes and anti proliferatory effect through AMPKaCOX-2 in cancer cells. J. Agric. Food Chem. 2008, 57, 305−310. (10) De, R.; Kundu, P.; Swarnakar, S.; Ramamurthy, T.; Chowdhury, A.; Nair, G. B.; Mukhopadhyay, A. K. Antimicrobial activity of curcumin against Helicobacter pylori isolates from India and during infections in mice. Antimicrob. Agents Chemother. 2009, 53, 1592−1597. (11) Doktycz, S. J.; Suslick, K. S. Interparticle collisions driven by ultrasound. Science 1990, 247, 1067−1069. (12) Prozorov, T.; Prozorov, R.; Suslick, K. S. High velocity interparticle collisions driven by ultrasound. J. Am. Chem. Soc. 2004, 126, 13890−13891. (13) Dalvi, S. V.; Dave, R. N. Analysis of nucleation kinetics of poorly water-soluble drugs in presence of ultrasound and hydroxypropyl methyl cellulose during antisolvent precipitation. Int. J. Pharm. 2010, 387, 172−179. (14) Myerson, A. S. Handbook of Industrial Crystallization, 2nd ed.; Butterworth-Heinemann: Woburn, MA, USA, 2002. (15) Xia, D.; Quan, P.; Piao, H.; Piao, H.; Sun, S.; Yin, Y.; Cui, F. Preparation of stable nitrendipine nanosuspensions using the precipitation−ultrasonication method for enhancement of dissolution and oral bioavailability. Eur. J. Pharm. Sci. 2010, 40, 325−334.

stability of curcumin particles in aqueous suspensions if the Mersmann equation is used for estimation of γ. Although this criterion has been developed for curcumin, it can very well be extended to predict/analyze the stability of aqueous suspensions of ultrafine particles of several other poorly water soluble APIs.

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HPMC: hydroxypropyl methyl cellulose LAS: liquid antisolvent polymer JR400: hydroxyethylcellulose ethoxylate, quaternized PSD: particle size distribution

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone: 091-79-3241-9529. Fax: 091-79-2397 2622. Author Contributions †

A.A.T. and M.D.Y. have contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge the financial support from the Department of Science and Technology (DST), Ministry of Human Resources and Development (MHRD), Government of India and Indian Institute of Technology Gandhinagar (IITGN) to carry out this work.

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NOTATIONS Ahom: kinetic parameter in nucleation rate Bhom: thermodynamic parameter in nucleation rate C: concentration of API in the solution (mg/mL) C*: equilibrium solid solubility in the aqueous solution (mg/ mL) DAB: diffusion coefficient (m2/s) J: nucleation rate (nuclei/m3/s) k: Boltzmann constant kv: volume shape factor for the spherical particles Li: average size (μm) ΔLi: differential width of the size range i (μm) MT: final suspension density (g/cm3) ni: population density of particles (number/cm3/μm). NA: Avogadro’s number 4591


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(16) Rossi, L.; ten Hoorn, J. W. M. S.; Melnikov, S. M.; Velikov, K. P. Colloidal phytosterols: Synthesis, characterization and bioaccessibility. Soft Matter 2010, 6, 928−936. (17) Jarmer, D. J.; Lengsfeld, C. S.; Randolph, T. W. Nucleation and Growth Rates of Poly(L-lactic acid) Microparticles during Precipitation with a Compressed-Fluid Antisolvent. Langmuir 2004, 20, 7254−7264. (18) Zarkadas, D. M.; Sirkar, K. K. Antisolvent crystallization in porous hollow fiber devices. Chem. Eng. Sci. 2006, 61, 5030−5048. (19) Lindenberg, C.; Mazzotti, M. Effect of temperature on the nucleation kinetics of a l-glutamic acid. J. Cryst. Growth 2009, 311, 1178−1184. (20) Sanphui, P.; Goud, N. R.; Khandavilli, U. B. R.; Bhanoth, S.; Nangia, A. New polymorphs of curcumin. Chem. Commun. (Cambridge, U. K.) 2011, 47, 5013−5015. (21) Sander, J. R. G.; Zeiger, B. W.; Suslick, K. S. Sonocrystallization and Sonofragmentation. Ultrason. Sonochem. 2014, http://dx.doi.org/ 10.1016/j.ultsonch.2014.02.005. (22) Gracin, S.; Uusi-Penttilä, M.; Rasmuson, Å. C. Influence of ultrasound on the nucleation of polymorphs of p-aminobenzoic acid. Cryst. Growth Des. 2005, 5, 1787−1794. (23) Louhi-Kultanen, M.; Karjalainen, M.; Rantanen, J.; Huhtanen, M.; Kallas, J. Crystallization of glycine with ultrasound. Int. J. Pharm. 2006, 320, 23−29. (24) Kurotani, M.; Hirasawa, I. Polymorph control of sulfamerazine by ultrasonic irradiation. J. Cryst. Growth 2008, 310, 4576−4580. (25) Hatakka, H.; Alatalo, H.; Louhi-Kultanen, M.; Lassila, I.; Hæggströ m, E. Closed-Loop Control of Reactive Crystallization PART II: Polymorphism Control of L-Glutamic Acid by Sonocrystallization and Seeding. Chem. Eng. Technol. 2010, 33, 751−756. (26) De Smet, Y.; Danino, D.; Deriemaeker, L.; Talmon, Y.; Finsy, R. Ostwald ripening in the transient regime: A cryo-TEM study. Langmuir 2000, 16, 961−967. (27) Huang, F.; Zhang, H.; Banfield, J. F. Two-stage crystal-growth kinetics observed during hydrothermal coarsening of nanocrystalline ZnS. Nano Lett. 2003, 3, 373−378. (28) Mersmann, A. Crystallization and precipitation. Chem. Eng. Process. 1999, 38, 345−353. (29) Dalvi, S. V.; Dave, R. N. Controlling particle size of a poorly watersoluble drug using ultrasound and stabilizers in antisolvent precipitation. Ind. Eng. Chem. Res. 2009, 48, 7581−7593. (30) Guo, Z.; Zhang, M.; Li, H.; Wang, J.; Kougoulos, E. Effect of ultrasound on anti-solvent crystallization process. J. Cryst. Growth 2005, 273, 555−563.

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