New Approach to Pesticide Delivery Using Nanosuspensions

May 3, 2011 - Chia-Tai Enterprise Co., Ltd., Taoyuan 32464, Taiwan ... bioavailability problems caused by weak solubility, limited chemical stability ...
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New Approach to Pesticide Delivery Using Nanosuspensions: Research and Applications Chih-Ping Chin,†,‡ Ho-Shing Wu,*,† and Shaw S. Wang† † ‡

Department of Chemical Engineering and Materials Science, Yuan Ze University, Chungli, Taoyuan 32003, Taiwan Chia-Tai Enterprise Co., Ltd., Taoyuan 32464, Taiwan ABSTRACT: In pharmacology, development of a formulated nanosuspension, a potential drug delivery system for poorly soluble drugs, has been investigated to overcome the bioavailability problems caused by weak solubility, limited chemical stability following administration (i.e., a short half-life), poor bioavailability, and potentially strong side effects requiring drug enrichment at the site of action. For first time use in a pesticide delivery system, a two-step milling process for preparing a nanosuspension in a system of active compound/surfactant/water is described in this paper. First, all the components were mixed at a certain composition to prepare a microsuspension by the general milling process. Then, the microsuspension was taken into a nanomilling process with zirconium oxide beads, having a diameter range of 0.10.2 mm, as the milling media to generate the nanosuspension. Therefore, a nanosuspension concentrate was formed. To demonstrate the potential applications of this novel system, it was used to make a formulation with a poorly soluble crystalline insecticide, carbofuran. In a comparative study, two kinds of carbofuran formulations, a microsuspension (commercial) and a nanosuspension, were administered to a diamondback moth (DBM) to test their efficacy and stability as a pesticide. The results indicate that carbofuran has the same efficacy at a lower dose for the nanosuspension compared to the microsuspension. The nanosuspension system was also physically and chemically stable over a period of 2 years, as indicated by the unchanged particle size and specification tests.

1. INTRODUCTION Challenges in developing new pest control strategies not only include identifying novel active compounds, but also improving the delivery of a pesticide at the biological level. The development of a new drug delivery strategy is important. A significant number of pesticide active compounds on the market are poorly soluble in water, and it is expected they will be even less soluble in the future. Therefore, formulation of poorly water-soluble active compounds is an important challenge to be faced. Nanonization technology has frequently been applied in liquid formulations for medical drug delivery system for many years. In general, poorly soluble compounds can be formulated as organic solutions by solubilizing in organic solvents or using emulsions. With the exception of organic solutions and emulsions, significant amounts of additives and organic solvents are often needed to increase the solubility required for those formulations, which may induce unwanted side effects. It would be more desirable to have a universal formulation approach to process any poorly soluble drug. In pharmaceutical science, a newer drug delivery system for poorly water-soluble compounds has come out in the last several years. In this novel system, poorly water-soluble compounds are formulated by nanosizing the drug particle. A number of previous studies with different poorly soluble drugs have demonstrated that particle size reduction can increase the bioavailability of the compounds, including AZ68,1 buparvaquone,2,3 danazol,4 glucocorticoids,5 naproxen,6 and tarazepide.7 The increase in bioavailability is caused by an increase in the surface area and dissolution of drug particles. Liversidge and Conzentino also proved that particle size reduction in naproxen, which is a nonsteroidal anti-inflammatory drug (NSAID), could effectively eliminate any local irritant effect r 2011 American Chemical Society

induced by a high local drug concentration effect. Therefore, the particle size of a poorly soluble compound can markedly affect the bioavailability. For amorphous active compounds, an interesting alternative is amorphous nanosuspensions with typical particle sizes less than 100 nm. To obtain an amorphous nanosuspension, the drug and additives are first dissolved in an organic solvent and the resulting solution is then rapidly mixed with water. The mechanism of particle formation as suspended droplets following the solvent quench process has been studied in two recent papers.8,9 For crystalline active compounds, which are poorly soluble in water and perhaps also in organic solvents, a second approach may be needed. A classical formulation approach for such poorly soluble drugs is to use micronization to form a suspension concentrate (SC), where a coarse drug powder is milled with water and additives to an ultrafine powder with a mean particle size typically in the range of 13 μm. Nowadays, many of the new pesticides display exceedingly low solubility and micronization does not lead to a sufficiently high bioavailability. Consequently, the next step taken to move from micrometer- to nanometer-sized particles involves producing nanocrystals (typically between 200 and 500 nm) of these drugs. There are two basic disintegration technologies for drug nanocrystals: bead/ball milling10,11 and high-pressure homogenization12,13 with different homogenizer types/homogenization principles. Only the first technique is used in the present Received: January 16, 2011 Accepted: May 3, 2011 Revised: May 3, 2011 Published: May 03, 2011 7637

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Figure 1. Structure of carbofuran.

industry; it is less costly in equipment installation and is easy to be operated. In the milling approach, the drug microsuspension is filled into a milling container. Milling beads from, e.g., glass, zirconium oxide, or special polymers such as hard polystyrene derivatives, are then added to the vessel. Using a ball/ground mill, the contents are rotated at high speed and the drug is ground to nanocrystals between the beads. Nanosizing a drug/carrageenan complex is used to increase both the solubility and the dissolution rate of a poorly water-soluble compound during the wet-milling process.14 As the total surface area of the resulting nanosuspension is typically orders of magnitude larger compared to a coarse suspension, large quantities of additives may be necessary to ensure adequate stabilization.15 These stability issues of formulation may include the physical (e.g., Ostwald ripening16 and agglomeration in particle size) and chemical (e.g., degradation in active compounds) properties. In the present study, a comparison was made between two formulations, a crystalline microsuspension and a crystalline nanosuspension of carbofuran, administered to the larvae of the diamondback moth (DBM) for the efficacy test.17,18 The purpose of the study was to find if the carbofuran nanosuspension formulation was comparable and safe to administer. Carbofuran is a biochemistry cholinesterase inhibitor intended for controlling soil-dwelling and foliar-feeding insects in a wide variety of field crops, including potatoes, corn, flowers, fruits, and soybeans. It is a systemic insecticide with chiefly contact and stomach action. It is marketed under the trade name of Furadan, by FMC Corp., USA.19 The compound has high stability and poor solubility in water, thus fulfilling the criteria for a suspension concentrate formulation.

2. MATERIALS AND METHODS 2.1. The Test Active Compound. Carbofuran (2,3-dihydro2,2-dimethyl-7-benzofuranyl methylcarbamate, CAS Registry No. 1563-66-2) as shown in Figure 1 has a molecular mass of 221.3 g/mol. The substance is a colorless crystalline compound with a melting point of about 153 °C. The value of Kow log P (Kow is the octanolwater partition coefficient) is 1.52 at 20 °C. The solubility is 320 mg/L in water at 20 °C and 200 g/L in dichloromethane at 20 °C. It is stable in acidic and neutral media but unstable in alkaline media. It has been formulated as flowable concentrate for seed treatment (FS), granules (GR), suspension concentrates (SC), and wettable powders (WP). Since carbofuran is a typical compound having good stability but low solubility in water, it is an attractive candidate for particle size reduction before administration. 2.2. Chemicals. Atlox 4913 is a poly(methyl methacrylate) poly(ethylene glycol) graft copolymer and was bought from Croda Chemicals Ltd., U.K. Polyvinylpyrrolidone (PVP) K30 is a nonionic polymer and was purchased from Fluka Ltd., Japan.

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Atlox 4913 and PVP K30 (a surfactant and a polymer) are both stabilizers and are expected to cover the surface of the active compound when dispersed in water. In a recent report,15 Eerdenbrugh et al. reported that linear synthetic polymers such as PVP K30 and PVP K90 displayed a better stabilizing potential when applied in high concentrations. The stability was also affected by the molecular weight of the polymer, and polymers with lower molecular weight showed better stability. Miglyol 812 was purchased from Union Chemical Ind. Co., Taiwan. It is used here as an Ostwald ripening inhibitor and is a 60/40 (w/w) mixture of C8 and C10 triglycerides. Ostwald ripening is a process where the differences in solubility, as a function of the particle sizes, lead to a transport of material from small to larger particles, with an accompanying increase in the mean particle size over time. Propylene glycol (PG) was bought from Mitsui Chemicals Polyurethanes Inc., Japan, and was used as an antifreezing agent. The antifoaming agent AT-120 is a polydimethylsiloxane (PDMS) emulsion and was bought from Tai County Silicones Ltd., Taiwan. 2.3. Preparation of Suspension Concentrate. In Taiwan, the active compound of carbofuran is generally formulated and registered as 3% (w/w) GR and either 40.6% (w/w) or 44% (w/w) SC. In this study, only the 40.6% (w/w) SC was formulated with different particle sizes (micro and nano) for finding the differences between these two suspensions. Carbofuran, additives, and pure water were prepared by mixing to make a 40.64% (w/w) carbofuran SC. In the formulations, there are the technical active 97% carbofuran (to 40.64%), PVP K30 (13%), Altox 4913 (47%), and Miglyol 812 (13%) for stabilization and distribution, ethylene glycol (15%) as an antifreeze, AT-120 (15%) as a defoamer, and water (to 100%). The 40.64% (w/w) crude suspension was mixed in a homogenizer (HD-0025, Sun-Great Technology Ltd., Taiwan) and treated with ultrasound (T490DH, Sunway Scientific Co., Taiwan) for 10 min to form a well -dispersed slurry. A 500 mL sample of the slurry was pumped in a circular motion to a milling vessel (50 mL) which had milling beads (0.60.8 mm) of zirconium oxide inside. The vessel was sealed and the slurry was milled at 3000 rpm for 120 min with intermediate sampling at each 15 min, using a high-energy-intensive ball mill (Microfer Netzsch Co., Germany.). The milled microsuspension was collected, and the milling beads were rinsed with pure water. The milled microsuspension was divided into two samples with equal volumes of 200 mL. One of the samples was milled by the same ball mill having milling beads (0.10.2 mm) of zirconium oxide inside, and the other remained as a microsuspension. Then, the nanosuspension sample was prepared under the same operating conditions for a second milling. The averaged particle size (diameter) of the crystalline suspensions was measured using laser diffraction to ensure there was no fraction of the material that had not been properly reduced in size in the milling process. The suspension was diluted to 5 mM with or without 5% mannitol. In this case, a 5% (w/w) mannitol solution was used. Further measurements in the stability studies of the average particle size of the crystalline suspensions were carried out using dynamic light scattering (DLS; N4 Submicrometer, Beckman Coulter Ltd., USA). A field emission scanning electron microscope (SUPRA 40, Carl Zeiss SMT Inc., USA) was also used, and comparable results were obtained. 2.4. Formulation Analysis. An official CIPAC HPLC gradient method (Carbofuran 276, CIPAC Handbook Volume D)20 7638

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Figure 2. Particle size distribution of carbofuran 40.64% SC microsuspension.

was used for the purity determinations of the technical active compound and the content of the formulations. This method uses a reverse phase C18 column and a water/methanol mobile phase with phosphoric acid (35 drops/L). The LC system was comprised of an LC-10ATVP high-performance liquid chromatography (HPLC) pump (Shimadzu, Kyoto, Japan), a Model SPD-10AVP fluorimetric detector (Shimadzu, Kyoto, Japan), a Model 9725 valve injector with a 20-μL loop (Rheodyne, Cotati, CA, USA), a Luna 5u C18 column (250  4.6 mm i.d.; Phenomenex Inc.), and SISC-32 data processing software (SISC, Taipei, Taiwan). In formulation characterization studies, including suspensibility (MT15, CIPAC Handbook Volume F), stability at 0 °C (MT39, CIPAC Handbook Volume F), accelerated storage procedure (MT46, CIPAC Handbook Volume F), persistent foaming (MT47, CIPAC Handbook Volume F), and spontaneity of dispersion (MT160, CIPAC Handbook Volume F), all test methods follow the official CIPAC standard method outlined in CIPAC Handbook Volume F.21 2.5. Efficacy of Formulation. The diamondback moth (DBM), Plutella xylostella L. (Lepidoptera: Yponomeutidae), is a cosmopolitan species of considerable importance as a pest of cruciferous plants. The larvae of the DBM were collected from a biolaboratory in Fwusow Industry Co., Taiwan, and reared on an artificial diet. The insects were maintained at 30 ( 2 °C with 70 ( 5% relative humidity (RH) and a 12L:12D (i.e, 12 h of light and 12 h of darkness) photoperiod. All tested insects were second, third, or fourth, 12 cm long instar larvae after rearing for three generations. Pieces of cabbage leaf (4 cm  4 cm) were dipped into aqueous solutions of microsuspension and nanosuspension for 1 min. The aqueous solutions used for all tests contained five concentrations (5, 10, 20, 50, and 100 mg/L) for microsuspension and nanosuspension, and each concentration was tested three replications. After drying, the treated leaf pieces were fed to the insects. The mortality of larvae, prepupae, and pupae were recorded 5 days after treatment irrespective of the stage at which the insects had been treated. The death of each prepupa and pupa was confirmed by the nature of pupation or the absence of emergence from the pupae. The median lethal dose (LD50) and fiducial limit (95% confidence interval, FL0.95) were also calculated from data analysis.

Figure 3. FESEM images of carbofuran 40.64% SC microsuspension particle: (a) low magnification (20000) and (b) high magnification (35000).

3. RESULTS AND DISCUSSION 3.1. Particle Size of Formulations. The particle size of a freshly prepared microsuspension was measured using DLS (volume weighted mean 1483 nm, d(0.9) = 1503 nm) to be around 1500 nm as shown in Figure 2. The particle size of freshly prepared microsuspension was also confirmed by the field emission scanning electron microscope (FESEM). As shown in Figure 3, the particle’s size is around 16001900 nm. The result of FESEM images agreed with the result of DLS measurement quite well. The particle sizes of the freshly prepared nanosuspension particles were around 30 nm, as measured by DLS (volume weighted mean 29 nm, d(0.9) = 30 nm) and shown in Figure 4. The particle size of a freshly prepared nanosuspension was also confirmed by field emission scanning electron microscopy (FESEM), as shown in Figure 5. The particle size was around 5960 nm. In the nanonization milling process for nanosuspension preparation, we sampled the slurry for measuring the variation in particle size using DLS at selected intervals of 30 min. The variations in particle size distribution and particle size (d(0.9)) during the nanonization milling process are shown in Figures 6 and 7. We found the particle size dramatically 7639

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Figure 4. Particle size distribution of carbofuran 40.64% SC nanosuspension.

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Figure 6. Variation in particle size distribution of carbofuran 40.64% SC nanosuspension with various milling times: (b) 1 h; (O) 2 h; (1) 3 h.

Figure 7. Plot of particle size (d(0.9)) of carbofuran 40.64% SC nanosuspension versus milling time.

Figure 5. FESEM images of carbofuran 40.64% SC nanosuspension particle: (a) low magnification (35000) and (b) high magnification (200000).

decreased with a concentrated distribution and the optimum milling time was 120 min since the degree of particle size

reduction would not go any further after that. During the nanonization milling process, we also found viscosity increased as the milling process continued. This was probably due to the increase in dispersion. Stability tests were performed with DLS measurements using two methods. One used the accelerated storage test (maintained at a temperature of 54 °C in the heating oven for 2 weeks), and the other remained at room temperature for 2 years. The experimental results showed the particle size remained under 100 nm, the same as the freshly prepared nanosuspension without any reaggregation in size. The sample is still well dispersed without caking in the formulation. In the storage test at room temperature, the particle size was measured at intervals of 6 months. A slight reaggregation occurred after 2 years of storage, but the mean particle size of nanosuspension was still maintained in the nanoscale. The variation in particle sizes of the accelerated storage test and normal storage test are shown in Figures 8 and 9. The experimental results showed the particle size distribution was stable in the nanosuspension. 3.2. Formulation Analysis. In the development of pesticide dosage forms, one of the persistent challenges is ensuring acceptable stability, i.e., the storage time allowed before the 7640

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Table 1. Performance Index of Carbofuran 40.64% SC with Microsuspension and Nanosuspension Formulations test item

microsuspension

nanosuspension

appearance

yellow white

bright white

content (%, w/w) decomposed ratio after

39.3278 0.8

39.9267 3.2

accelerated storage test (%) stability at 0 °C

no caking

no caking

suspensibility (%)

85.0

100.0

spontaneity of dispersion (%)

98.9

100.0

persistent foaming (mL)

39

48

viscosity (cP)

200

850

pH value

6.4

6.8

Table 2. Efficacy Test of Carbofuran 40% SC with Different Formulations to Larvae of DBM in the Laboratory Figure 8. Variation in particle size distribution of carbofuran 40.64% SC nanosuspension with accelerated storage test (54 ( 2 °C, 14 days) and different storage times. (b) Accelerated storage test; (O) 6 months; (1) 12 months; (4) 18 months; (9) 24 months.

Figure 9. Plot of particle size (d(0.9)) of carbofuran 40.64% SC nanosuspension versus storage time.

potency is too low or the product degrades in the dosage form to a sufficiently high level that it poses a threat to the target species. The contents of carbofuran in the microsuspension and the nanosuspension are 39.33 and 39.93%, which are in the acceptable range of specification. In the determination of activity, we also found no degradation of the nanosuspension after the milling process. The experimental results of performance studies were processed for both microsuspension and nanosuspension formulations, as shown in Table 1, and two formulations appeared to be stable in storage. In the low temperature storage test, two formulations were kept in a freezer (0 ( 2 °C) for 7 days, and no caking was observed in either the microsuspension or the nanosuspension. During the accelerated storage test, after being kept in the oven (54 ( 2 °C) for 14 days, about 0.8% of the compound was decomposed in the microsuspension and 3.2% of the compound was degraded in the nanosuspension. The decomposed ratios of microsuspension and nanosuspension were

toxicity regression treatment

equation

LD50

FL0.95

R2

(mg/L)

(mg/L)

microsuspension

Y = 4.50X þ 1.9

0.9723

10.69

7.7114.82

nanosuspension

Y = 4.55X þ 7.16

0.9159

9.42

7.0912.50

in the acceptable range of specification (e5%). Therefore, the nanosuspension appeared to be as chemically stable as the microsuspension. The formulation of the nanosuspension was as stable as the microsuspension. In addition to stability, the nanosuspension showed better suspensibility and dispersion than the microsuspension, due to the smaller particle size. 3.3. Efficacy against Larvae. The use of particle size reduction to increase the surface area for dispersion and thereby increase the bioavailability of poorly water-soluble molecules has recently been an attractive alternative for medical formulation scientists. In the present article, two different formulations were given to the larvae of DBM, through feeding and contacting. In the laboratory efficacy trials, the applied dosages for two formulations were five concentrations (5, 10, 20, 50, and 100 mg/L). In the study, there were no adverse indications that the larvae could tolerate the formulations. The experimental results for the formulations are listed in Table 2, and the toxicities of each formulation calculated as toxicity regression equations, LD50, and FL0.95 are also provided. Table 2 shows that a lower LD50 (9.42 mg/L) to DBM larvae for the nanosuspension has a similar efficacy compared to the microsuspension with a higher LD50 (10.69 mg/L). According to the experimental results, the efficacy of carbofuran was increased 13.5% as the suspension particle size decreased to the nanoscale. This is due to the latter’s reduced rate of absorption of the active compound. This result indicates that the nanosuspension concentrate can be administered in a lower dose, which is safer to administer and to crop plants. In a toxicology study, we completed a brief test in which we orally administered to mice (three females and three males; the females were nulliparous and nonpregnant) two formulations at three different concentration levels (1, 4, and 6 mg/kg). We found no significant difference between these two formulations. Therefore, the nanosuspensions were as safe as the commercial formulation in terms of toxicity to the mammals. 3.4. Phytotoxicity Test of Formulations. The target plant used in this study was cabbage strain 222, which was grown in 7641

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Table 3. Phytotoxicity of Carbofuran 40.64% SC Microsuspension and Nanosuspension Formulations with Different Concentrations observation period (day) concentration formulation nano-SC

micro-SC

(mg/L)

1

4

7

10

508

no adverse effect was observed

1016

no adverse effect was observed

1625.6

no adverse effect was observed

508 1016

no adverse effect was observed no adverse effect was observed

1625.6

no adverse effect was observed

14

pots by using commercial potting soil at pH 5. The environmental conditions were maintained under good horticultural practices in greenhouses at temperature 2532 °C, humidity 6080%, and sufficient light to ensure good plant growth. The pots were large enough to allow normal growth. All pots were irrigated with 500 mL of water at 8:00 a.m. every day during the experiment period. There were four pots for each application concentration. The test carbofuran 40.6% SC formulations were sprayed onto the surfaces of target plants at various concentrations (1626, 1016, and 508 mg/L) which were prepared according to the application diluted ratio (250, 400, and 800) announced by the Taiwanese government. The emerging plants are also maintained under same environment conditions. The phytotoxicity tests were performed with 3 replications. The observation frequency was executed every day after the target plants have emerged and lasted for 14 days. The plants are observed frequently (at least weekly) for visual phytotoxicity and mortality. The experimental results are shown in Table 3. There was no adverse effect on the plants observed in the treatment with two formulations of various concentrations. Therefore, the carbofuran 40.64% SC nanosuspension is as safe as the commercial formulation to plants because it causes no damage to the target plant and is friendly to the environment.

4. CONCLUSION Challenges in developing new crop protection strategies include not only identifying novel active compounds, but also improving the delivery of the drug at the biological level. The development of a new drug delivery strategy is important for preventing pests and diseases in plants. Further consideration of the agro-product is often required for food security, environmental issues, and administration convenience reasons. The present work is the first evidence demonstrating a novel drug delivery system in crop protection, and the results from the present work are encouraging. The experimental results of the formulation analysis showed no significant difference between the two formulations with different particle sizes. Note that the results show very little variation between individuals. Thus, for a poorly soluble compound, the nanosuspensions were as effective as the commercial formulation and could be used for administration. They appear to be an attractive alternative for formulating sparingly soluble pesticides. In contrast to microsuspensions, there is also a possibility that the administration of nanosuspensions would allow reduction in the doses of pesticides, which is

important from the viewpoint of reducing costs and adverse effects. Moreover, nanosuspensions may give added value, be environmentally friendly, increase food safety, and allow a reduction in either the dose or its frequency of administration. Therefore, nanosizing is a practical technology to deliver new active compounds and refurbish marketed products for improving their performance and value.

’ AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Tel.: þ8863-4638800, ext 2564. Fax: þ886-3-4559373.

’ ACKNOWLEDGMENT This work was supported entirely by Chia-Tai Enterprise Co., Ltd., Taiwan. ’ REFERENCES (1) Sigfridsson, K.; Forssen, S.; Holl€ander, P.; Skantze, U.; Verdier, J. D. A formulation comparison, using a solution and different nanosuspensions of a poorly soluble compound. Eur. J. Pharm. Biopharm. 2007, 67, 540–547. (2) Kayser, O. A new approach for targeting to Cryptosporidium parvum using mucoadhesive nanosuspensions: research and applications. Int. J. Pharm. 2001, 214, 83–85. (3) M€uller, R. H.; Jacobs, C. Buparvaquone mucoadhesive nanosuspension: preparation, optimization and long-term stability. Int. J. Pharm. 2002, 237, 151–161. (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) Kassem, M. A.; Abdel Rahman, A. A.; Ghorab, M. M.; Ahmed, M. B.; Khalil, R. M. Nanosuspensions as an ophthalmic delivery system for certain glucocorticoid drugs. Int. J. Pharm. 2007, 340, 126–133. (6) Liversidge, G. G.; Conzentino, P. Drug particle size reduction for decreasing gastric irritancy and enhancing absorption of naproxen in rats. Int. J. Pharm. 1995, 125, 309–313. (7) Jacobs, C.; Kayser, O.; M€uller, R. H. Nanosuspensions as a new approach for the formulation for the poorly soluble drug tarazepide. Int. J. Pharm. 2000, 196, 161–164. (8) Lindfors, L.; Forssen, S.; Skantze, P.; Skantze, U.; Zackrisson, A.; Olsson, U. Amorphous drug nanosuspensions. 2. Experimental determination of bulk monomer concentrations. Langmuir 2006, 22, 911–916. (9) Lindfors, L.; Skantze, P.; Skantze, U.; Westergren, J.; Olsson, U. Amorphous Drug Nanosuspensions. 3. Particle Dissolution and Crystal Growth. Langmuir 2007, 23, 9866–9874. (10) Liversidge, G. G.; Cundy, K. C.; Bishop, J. F.; Czekai, D. A. Surface Modified Drug Nanoparticles. U.S. Patent 5,145,684, 1992. (11) Merisko-Liversidge, E.; Liversidge, G. G.; Cooper, E. R. Nanosizing: a formulation approach for poorly-water-soluble compounds. Eur. J. Pharm. Sci. Rev. 2003, 18, 113–120. (12) M€uller, R. H.; Jacobs, C.; Kayser, O. Nanosuspensions as particulate drug formulations in therapy rationale for development and what we can expect for the future. Adv. Drug Delivery Rev. 2001, 47, 3–19. (13) M€uller, R. H.; Katrin, P. Nanosuspensions for the formulation of poorly soluble drugs I. Preparation by a size-reduction technique. Int. J. Pharm. 1998, 160, 229–237. (14) Dai, W. G.; Dong, L. C.; Song, Y. Q. Nanosizing of a drug/ carrageenan complex to increase solubility and dissolution rate. Int. J. Pharm. 2007, 342, 201–217. 7642

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