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International Journal of Green Nanotechnology: Biomedicine

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Development and Dissolution Velocity Studies of an Oral Albendazole Nanocrystal Solid Formulation
R. Ravichandran
a a

Regional Institute of Education (NCERT), Bhopal, India Published online: 10 Dec 2010.

To cite this article: R. Ravichandran (2010): Development and Dissolution Velocity Studies of an Oral Albendazole Nanocrystal Solid Formulation, International Journal of Green Nanotechnology: Biomedicine, 2:2, B55-B66 To link to this article: http://dx.doi.org/10.1080/1943085x.2010.532066

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International Journal of Green Nanotechnology: Biomedicine, 2:B55B66, 2010 Copyright c Taylor & Francis Group, LLC ISSN: 1943-085x print / 1943-0906 online DOI: 10.1080/1943085x.2010.532066

Development and Dissolution Velocity Studies of an Oral Albendazole Nanocrystal Solid Formulation
R. Ravichandran

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ABSTRACT. During the last 10 years, the formulation of drugs as nanocrystals has rapidly evolved into a mature drug delivery strategy, with currently ve products on the market. The major characteristic of these systems is the rapid dissolution velocity, enabling bioavailability enhancement after oral administration. This study describes the preparation of a solid dosage tablet form of spray-dried albendazole nanocrystal and compares its dissolution behavior with a market tablet in different media. The aim was to obtain a stable nanocrystal loaded drug tablet with an increased drug saturation solubility and dissolution velocity. Solubility and dissolution experiments were performed to verify the obvious improvement of the dissolution behavior compared with the commercial product. Improved dissolution behavior in drug nanocrystal-loaded solid dosage forms should lead to better bioavailability of poorly soluble drugs in the body. KEYWORDS. albendazole, nanocrystal, tablet, dissolution evaluation

INTRODUCTION
Albendazole (ABZ), methyl [5-(propylthio)1 H-benzimidazol-2yl] carbamate (Figure 1) is an effective broad-spectrum anthelmintic used in the treatment of intestinal helminth infections.[1] Systemic absorption of ABZ is warranted for the treatment of inoperable or disseminated cases of hydatidosis, other systemic helminthiases, AIDS-related microspordia, and giardiasis.[27] It is the drug of choice in the; treatment of echinococcosis.[1] Albendazole therapy is especially important in systemic cestode infections, particularly in neurocysticercosis.[8] Though albendazole is effective for treatment of these diseases, the therapeutic response is unpredictable

due to its low and erratic bioavailability as a result of its low aqueous solubility.[911] ABZ belongs to biopharmaceutical classication system type II (low aqueous solubility with high permeability), thus showing dissolution ratelimited absorption.[12,13] Thus, it has poor solubility and poor oral bioavailability.[10] Improvement of oral bioavailability is of clinical importance in the treatment of systemic helminthiasis such as echinococcosis because it is an alternative to surgery.[11] Researchers followed different approaches in an attempt to improve oral bioavailability. For example, albendazole solution was formulated by use of surfactants such as polysorbates and bile salts or cosolvents like transcutol.[14] Some of these excipients may also

Received 9 July 2010; accepted 8 October 2010. Facilities were obtained from Torrent Research Center, Ahmedabad, High Security Animal Disease Laboratory, Bhopal and Central Food Technological Research Institute, Mysore. R. Ravichandran is afliated with the Regional Institute of Education (NCERT), Bhopal, India. Address correspondence to R. Ravichandran, Regional Institute of Education (NCERT), Bhopal 462 013, India. E-mail: ravincert@gmail.com
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FIGURE 1. Chemical structure of albendazole: methyl [5-(propylthio)-1 H-benzimidazol-2yl] carbamate; formula C12 H15 N3 O2 S; mol. mass 265.333 g/mol. (Figure provided in color online.)

have some absorption-enhancing effects, which can be useful for increasing the oral bioavailability of ABZ formulations. Unfortunately, many of these agents can be irritants to digestive system linings, so their use must be restricted whenever possible. Alternatively, the ABZ solubility can be improved by elaboration of solid dispersions with polyvinylpyrrolidone,[15] although use of organic cosolvents and the high quantity of the complexing agent in complexation techniques are the limiting factors for these products. Another possible way of overcoming this problem is to improve wetting and increase the surface area of the drug by formulating as drug nanoparticles. This may result in improved solubility and dissolution rate, thereby enhancing oral bioavailability.[16,17] In the last decade the area of oral nanoparticulate drug delivery systems has received considerable attention.[18,19] Nanoparticulate systems studied include polymeric, solid lipid, liposomes, niosomes, micelles, microemulsions, submicron emulsions, and drug nanoparticles. Nanonization is gaining commercial importance, with more products seen in the market.[2024] Sirolimus (Rapamune, Wyeth) and fenobrate (Emend, Merck) are commercially available on the market with the drug as nanocrystals. Many other products are in the pipeline at different phases of clinical trials.[25] Drug nanoparticles or drug nanosuspensions consist of drug particles between 200 and 500 nm stabilized with/without additives.[25] Nanonization helps in signicant improvement of pharmacokinetic parameters of poorly bioavailable drugs.[2628] Unlike other nanosystems, this dosage form contains surfactants at very low concentrations. Albendazole has dissolution ratelimited bioavailability and therefore formulating as a nanosuspension might improve its dissolution rate, thereby enhanc-

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ing oral bioavailability.[29,30] The ultimate goal of our research was to produce a greater improvement in the dissolution and bioavailability of ABZ through nanoparticulate formulations. Recently we have prepared albendazole nanosuspensions by high-pressure homogenization and characterized them for their physicochemical properties.[31] A solid oral formulation was tested for improved bioavailability in vivo in rats by pharmacokinetic studies.[32] In this article we report the preparation and formulation of an oral solid dosage form of albendazole nanocrystals in the form of a tablet along with its dissolution characteristics compared to commercial tablets.

MATERIALS AND METHODS Materials

Albendazole was gift sample from Juggat Pharma, Bangalore, India. Albendazole nanosuspensions were stabilized by the block copolymer Poloxamer 188 (Sigma-Aldrich) and sodium dodecyl sulfate (Fluka, Switzerland). Milli-Q Plus water, double-distilled water (Millipore), was used as dispersion medium. The other chemicals were of analytical reagent grade (SRL, Mumbai, India).

Preparation of Albendazole Nanosuspensions

The albendazole nanosuspension (ABZ-NS) was produced via high-pressure homogenization (HPH) in pure water using a Micron Lab 40 (APV Homogenizer, Germany) at room temperature, applying 20 homogenization cycles at 1500 bar (equal to 150,000 kPa and 21,756 psi).

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Spray Drying
Spray drying was employed to obtain freely owable albendazole nanocrystal powder. Albendazole nanosuspensions, having a drug concentration of 10% (w/w), were dried with a Mini Spray-dryer B-190 (Buchi Lab, Switzerland). The Mini Spray-dryer B-190 was set with regard to temperature inlet (110100 C), outlet (7476 C), and air volume (600 L/h). The spray-dried albendazole nanocrystals were directly collected after the process.

TABLE 1. Composition of albendazole tablet formulations

Excipients (mg) Formulation A B C Market NC (mg) 200 200 MC (mg) 200 200 AV 594 594 594

AC 35 35

Ex Mg 35

T 7 7 7

14 14 14

NC = albendazole nanocrystal (ABZNC-E); MC = albendazole microcrystal; AV = Avicel PH 101; AC = AcDiSol; Ex = Explotab; Mg = Mg stearate; T = talc; Market = marketed tablet; * not known.

Particle Size Analyses

Photon correlation spectroscopy (PCS; Zetasizer Nano ZS, Malvern Instruments, UK) and laser diffraction (LD; Coulter LS230, BeckmanCoulter, Germany) were employed to determine the particle size. PCS measurements were performed at 20 C and each sample was analyzed three times. PCS yields the intensity weighted mean diameter of the bulk population (z-average, measuring range: 3 nm3 m) and the polydispersity index (PI) as measures for the width of the size distribution. The PI ranges from zero (monodisperse particles) to 0.500 (broad distribution); values above 0.5 do not allow allocation of a logarithmic normal distribution to the PI. LD was repeated three times and the results were calculated as volume size distribution using Mie theory with the optical parameters 1.593 for the real refractive index and 0.01 for the imaginary refractive index. As characterization parameters the diameters 10%, 50%, 90%, and 99% were used. For example, diameter 99% means that 99% of the particles are below the given size value. have the same content of albendazole (200 mg) and a total mass equal to the marketed tablet (850 mg). The tablet mass was prepared for 200 tablets by adding the spray-dried albendazole nanocrystals (ABZNC-E) to the tablet excipients (Table 1) in a tumbler (Turbula, Switzerland). The tablets were prepared using direct compression by a single punch tablet machine (Korsch Pressen, Germany). The dissolution tests were performed using a USP XXIII rotating paddle apparatus with a Pharmatest PTW SIII (Pharma Test, Germany) at 37 C and a rotating speed of 100 rpm. Tablets were placed in the dissolution chamber containing the dissolution media (900 mL). At certain times, samples were drawn from each dissolution chamber. The samples were ltered through Sartorius R 0.1 m lters (Sartorius, Germany). From each vial an aliquot was withdrawn with a 1-mL glass syringe (Poulten & Graf, Germany) and assayed by high-performance liquid chromatography (HPLC) to evaluate the amount of albendazole dissolved. Any dilution of the samples was intentionally avoided, to prevent any possible interference with the chemical equilibrium, particularly by considering the presence of colloidal particles.

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Preparation of the Tablets and Drug Release

Albendazole is a white to off-white powder. It is soluble in dimethylsulfoxide, strong acids, and strong bases. It is slightly soluble in methanol, chloroform, ethyl acetate, and acetonitrile. Albendazole is practically insoluble in water. Each white to off-white, lm-coated tablet contains 200 mg of albendazole. The formulations of the albendazole tablets are shown in Table 1. The mass of each tablet prepared was calculated to

HPLC Analysis of Albendazole

A sensitive and selective HPLC chromatography method using ultraviolet (UV) detection was developed for the determination of albendazole with oxibendazole as the internal standard. The HPLC system consisted of a Shimadzu LC 6A HPLC instrument equipped with a solvent

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FIGURE 2. (A) PCS and (B) LD particles size distribution of albendazole formulations. (Figure provided in color online.)
1200 1000

100

PCS (nm)

LD (m)

800 600 400 200 0 Raw ABZNS-E After 1 Year Spray dried Formulation

10

< d10% m < d50% m < d90% m

< d99% m

0.1 Raw ABZNS-E After 1 Year Spray dried Formulation

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delivery pump, a Rheodyne injector valve, and a variable-wavelength UV detector. The column used was C18 Gemini RS (Phenomenex) analytical column (5 m particle size; 25 cm 4.6 mm ID) with mobile phase of methanol water (60:40). The ow rate was maintained at 0.8 mL/min. The eluate was monitored at 308 nm. Retention time for ABZ and internal standard are 18.8 and 8.2 min, respectively. The data were recorded and calculated using Winchrome software.

RESULTS AND DISCUSSION

The albendazole nanosuspension on a lab scale is typically produced by premilling followed by HPH in pure water using a continuous Micron Lab 40 at room temperature, applying 20 homogenization cycles at 1500 bar. The formulation of albendazole nanosuspension was prepared using albendazole 10%, Poloxamer 188 1%, sodium dodecyl sulfate (SDS) 0.2%, and water 88%. Figure 2 shows the particle size distribution of albendazole formulations by PCS and LD. The ABZNS had LD particle size distribution of 0.1 (<d10%), 0.2 (<d50%), 0.8 (<d90%), and 2 m (<d99%). PCS size was 289 nm, with zeta potential (mV) of 30.4 in water and 21.6 in original medium. Visual examination of crystals in nanosuspensions from images of the nanosuspensions from light microscopy and scanning electron microscopy showed ne, stable homogeneous distribution. It showed very good physical and chemical stability over a oneyear period. A spray-drying process was employed to obtain dried albendazole nanocrystals having good redispersability, saturation solubil-

ity, and dissolution velocity. LD values were 0.33 (<d10%), 0.15 (<d50%), 1.12 (<d90%), and 2.38 m (<d99%). PCS size was 312 nm with a PI of 0.37. In general, the saturation solubility of the nanocrystals was distinctly vefold higher than for microparticles. The result also showed the superiority of albendazole nanocrystals in dissolution behavior and was in agreement with the Noyes-Whitney equation. According to these results, albendazole nanocrystals are suitable for incorporation into solid dosage form, such as tablets, capsules, pellets, etc. The nal product of a solid dosage form containing albendazole nanocrystals is evaluated in this work with respect to dissolution testing and compared to marketed dosage forms.

Preparation of Solid Dosage Forms

Nanosizing refers to the reduction of drug particle size down to the submicron range. Though reduction of particle size has been employed in the pharmaceutical industry for several decades, recent advances in milling technology and our understanding of such colloidal systems have enabled the production of drug particles of 50 to 200 nm size in a reproducible manner. The submicron particles are stabilized with surfactants or polymers in nanosuspensions, which can be further processed into standard dosage forms suitable for oral administration. These nanosuspensions offer increased dissolution rates for drug compounds and complement other technologies used to enhance the bioavailability of insoluble compounds (BCS classes II and IV), such as solubility enhancers (i.e., surfactants), liquid-lled capsules, or solid dispersions of drugs in their amorphous state. Based on the Noyes-Whitney principle, reduction in particle

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FIGURE 3. Albendazole nanocrystal-loaded tablets (a) and marketed tablets (b). (Figure provided in color online.)

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size will increase the dissolution rate due to increased effective particle surface area. This size dependency comes only into effect for particles of a size below approximately 1 m (submicron particulate), a phenomenon observed in tableting that leads to an increase of the dissolution rate of such ne drug particles.[21]

Formulation
On the market, no oral albendazole tablet is found in single dose form. Albendazole is normally not combined with any other drugs. R R ZENTEL and Albenza tablets contain 200 mg albendazole. The complete albendazole tablet formulations are presented in Table 1. Microcrystal cellulose (Avicel PH 101) was used as tablet ller due to good compressibility properties. AcDiSol and Explotab were used as dry disintegrants. Magnesium stearate and talc were incorporated as lubricant, glidant, and antiadherent. Dried albendazole nanocrystals were admixed gently to the other tablet excipients. A tumbler was used to mix albendazole nanocrystals with the excipients. The tablet mass was nally compressed using a single punch tablet machine. Albendazole nanocrystal-loaded tablets were produced using direct compression.

during longer processing by granulation. This method is evidently more effective in avoiding particle agglomerates and aggregates in tableting. Avicel PH 101, AcDiSol, and Explotab are good excipients for direct compression tablets. They offer suitable properties such as good owability and compressibility for the direct compression method. AcDiSol and Explotab are superdisintegrants designed to improve dissolution behavior and are normally used for the direct compression method.[33] To ensure successful tablet production using direct compression, spray-dried albendazole nanocrystals were selected because spray-dried albendazole nanocrystals offer better properties for the direct compression compared to lyophilized nanocrystals. Albendazole nanocrystals were admixed to other tablet excipients (Table 1) in a tumbler. The process continued with compressing in a single punch tablet machine. Finally, the albendazole nanocrystal-loaded tablets were produced in simple form. Albendazole microcrystal tablets were also produced using the same method. The same procedure was employed, with albendazole nanocrystals substituted for albendazole microcrystals in the tablets. The nal product of the albendazole nanocrystal-loaded tablets can be seen in Figure 3.

Direct Compression of the Tablet

The direct compression method was employed to produce albendazole nanocrystalloaded tablets. Direct compression was chosen to minimize agglomeration of the nanocrystals

Dissolution Study of Solid Dosage Forms

A dissolution test of drug tablets was performed using a USP XXIV rotating paddle apparatus. This method is known as method 2 in

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FIGURE 4. Percentage dissolved albendazole in water from nanocrystal formulations A and B versus microcrystal formulation C. (Figure provided in color online.)
30

% dissolved drug

25 20 15 10 5 0 0 5 10 15 Time (min) 20 25 30 Formulation A Formulation B Formulation C

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United States Pharmacopoeia.[34] Given the drug contents in the tablets, the dissolution test was not performed in sink conditions (drug amount in tablets above 30% of saturation solubility). Therefore, at a certain time the percentage of dissolved drugs will be constant or change little because the saturation solubility in the dissolution media is going to be approached.

In Buffer at pH 1.2
Albendazole dissolution from albendazole tablets was evaluated in buffer solution having a pH of 1.2. Albendazole was dissolved faster from nanocrystal tablets compared to microcrystal tablets, resembling the dissolution behavior in water. Within 5 min, the nanocrystal tablets (formulation A) could dissolve almost 36% of the drug. By comparison, only 9% of the albendazole in the microcrystal tablets (formulation C) dissolved in the same time. Dissolution of albendazole from nanocrystal tablets distinctly increased over time. In a period of 30 min, almost 43% to 52% of albendazole was dissolved from the nanocrystal tablets. This was more than twice as fast as the dissolution of albendazole from microcrystal tablets (Figure 5). It was also noticed that in acidic medium the drug dissolution was considerably greater than in water.

In Water
Three formulations of albendazole tablets were prepared successfully. The dissolution behavior of these tablets was evaluated and compared with each other. The dissolution proles of the three albendazole tablets in water medium are presented in Figure 4. In water medium, formulation A could release albendazole faster than the other formulations. Formulation A contained albendazole nanocrystals with AcDiSol used as dry disintegrant. Compared to the microcrystal tablets (formulation C), the nanocrystal tablet showed superior dissolution velocity. Within 30 min, nanocrystal tablets of formulation A dissolved 24% of their albendazole content. In contrast, microcrystal tablets let to the dissolution of only 11% of albendazole over the same time. The rate of dissolution was very high in the rst 15 min with almost 22% dissolution and further increase was only an additional 2% with a stagnation effect. This shows the superiority of albendazole nanocrystal-loaded tablets (formulations A and B), which were fastest in dissolution of albendazole.

In Buffer at pH 6.8
Nanocrystal tablets were again superior in dissolving albendazole in buffer at pH 6.8. In this media, 22% of albendazole was dissolved from the nanocrystal tablet (formulation A) within 10 min. In contrast, microcrystal tablets dissolved only 7% of the drug under the same conditions. This means that nanocrystal tablets could dissolve drugs at triple the rate of the microcrystal tablets over a 10-min period (Figure 6).

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FIGURE 5. Percentage dissolved albendazole in buffer at pH 1.2 from nanocrystal formulations A and B versus microcrystal formulation C. (Figure provided in color online.)
60

% dissolved drug

50 40 30 20 10 0 0 5 10 15 Time (min) 20 25 30 Formulation A Formulation B Formulation C

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FIGURE 6. Percentage dissolved albendazole in buffer at pH 6.8 from nanocrystal formulations A and B versus microcrystal formulation C. (Figure provided in color online.)
30

% dissolved drug

25 20 15 10 5 0 0 5 10 15 Time (min) 20 25 30 Formulation A Formulation B Formulation C

FIGURE 7. Percentage of dissolved albendazole from nanocrystal tablets A and B versus marketed tablet in water. (Figure provided in color online.)
30

% dissolved drug

25 20 15 10 5 0 0 5 10 15 Time (min) 20 25 30 Formulation A Formulation B Market Tablet

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FIGURE 8. Percentage dissolved albendazole from nanocrystal tablets A and B versus marketed tablet in buffer having a pH of 1.2. (Figure provided in color online.)
60

% dissolved drug

50 40 30 20 10 0 0 5 10 15 Time (min) 20 25 30 Formulation A Formulation B Market Tablet

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Comparison of Nanocrystal-Loaded Tablets and Marketed Tablets

Albendazole nanocrystal-loaded tablets (formulations A and B) were also compared to the marketed albendazole tablets. Figures 7, 8, and 9 show dissolved albendazole from formulations A and B and the marketed tablets. The nanocrystal tablets were distinctly superior in all dissolution media. In water, the nanocrystal tablets (formulation A) dissolved about 22% of the drug within 15 min. Within the same time, the marketed tablets dissolved only 1.4% of their alben-

dazole. The nanocrystal tablets (formulation A) thus dissolved albendazole 16 times faster than marketed tablets in the rst 15 min. In other media, the dissolution behavior was also distinctly improved. After 5 and 10 min, the nanocrystal tablets (formulation A) dissolved 36% and 22% of the drugs in buffer having a pH of 1.2 and 6.8. Meanwhile in the same time, only 3% and 1.8% of albendazole was dissolved from the marketed tablets in buffer having a pH of 1.2 and 6.8. This suggests that albendazole nanocrystalloaded tablets have a high potential for oral administration and can improve the bioavailability

FIGURE 9. Percentage of dissolved albendazole from nanocrystal tablets A and B versus marketed tablet in buffer having a pH of 6.8. (Figure provided in color online.)
30

% dissolved drug

25 20 15 10 5 0 0 5 10 15 Time (min) 20 25 30 Formulation A Formulation B Market Tablet

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of drugs in cases in which dissolution performance restricts bioavailability of drugs in the body.

Dissolution Performance
Compared to microcrystal tablets and marketed tablets, the nanocrystal tablets denitively showed higher levels of percentage dissolved albendazole. In all three dissolution media, nanocrystal tablets dissolved albendazole at distinctly faster rates compared to microcrystals and marketed tablets. Therefore, nanocrystal tablets have superior characteristics to microcrystals and marketed tablets, indicating a major opportunity to enhance the bioavailability of drugs by nanosuspensions for oral administration, in cases when dissolution is a rate-limiting factor in bioavailability in the body like that of albendazole. It is easy to understand that a bio-relevant medium will need a similar surface activity as biouids and hence a study on in vivo pharmacokinetic evaluation of albendazole nanoformulation with improved bioavailability was also carried out and is found to yield a similar positive result.[32]

dissolution velocity in addition to the surface effect.[37] Figure 10 summarizes these effects. An increase in dissolution velocity and an increase in saturation solubility can also be achieved by changing the crystalline state of the material (e.g., from crystalline to amorphous or partially amorphous). Due to thermodynamic reasons, the preservation of the amorphous state is critical; therefore, the production of nanocrystals should lead to crystalline particles. The crystalline state of the albendazole nanocrystals investigated in our study remained unchanged (100% crystalline) upon both HPH and drying.

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Perspectives on Drug Nanocrystals for Oral Application

Recently, the particle size reduction effectiveness of drug substanceloaded tablets on oral bioavailability has been intensively investigated. It has been proven that particle size reduction leads to improved oral bioavailability in the body. Takano et al. have specied that particle size reduction leads to improved dissolution rate and bioavailability.[38] In addition, the rate-limiting steps of oral absorption were simulated. An increase in the dissolution rate and administered dose showed a shift from dissolution ratelimited to solubility-limited absorption. In the study in dogs, the particle size reduction of the drugs improved the oral absorption.[38] Such studies provide a powerful tool to predict dose linearity and will aid in the development of formulating poorly soluble drugs (Biopharmaceutical Classication System [BCS] class II [as well as IV] drugs). According to Hintz and Johnson,[39] a computer method has been developed to describe the theoretical dissolution rate of a polydisperse powder under non-sink conditions based on its weight percentage particle size distribution. It was shown that ner particles in the size distribution showed an improved dissolution behavior. Moreover, the particle size distributions were used to simulate their effect on the amount of drug absorbed orally.[39] Similarly, we suggest this promising albendazole tablet dosage form for oral administration. It leads to superior physicochemical properties and should overcome the in vivo absorption problem of the

Dissolution Velocity
An outstanding feature of nanocrystals is the increase in saturation solubility and consequently an increase in the dissolution velocity of the compound. Based on the Noyes-Whitney equation,[35] this increase in dissolution velocity takes place in addition to the increase caused by the enlargement of the surface area, for example, exploited in micronized products.[36] By decreasing the particle size (e.g., to the nanometer range), the surface area of the particulate is further increased. In addition, the Noyes-Whitney equation describes that the dissolution velocity dc/dt depends on the concentration gradient (cs cx )/ h(cs is the saturation solubility; cx is the equilibrium concentration in the bulk phase, and his the diffusional distance) and the Prandtl equation describes that the diffusional distance his reduced for small particles. Thus, the simultaneous increase in the saturation solubility cs and the decrease in hlead to an increased concentration gradient (cs cx )/ h, enhancing the

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FIGURE 10. Transfer of microcrystals to nanocrystals leads to an increase in surface area (upper). Increase in saturation solubility cs, decrease in diffusional distance h, and increase in the concentration gradient cs cx /h. All effects increase the dissolution velocity dc/dt. (Figure provided in color online.)

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FIGURE 11. Mechanism of action: nely dispersed nanocrystals versus aggregated nanocrystals (similar to micrometer crystals). (Figure provided in color online.)

marketed tablets. Dissolution velocity of drug nanocrystals from solid dosage forms was superior compared to microcrystal-loaded solid dosage forms and the marketed solid dosage forms (tablet). Improved dissolution behavior in drug nanocrystal-loaded solid dosage forms should lead to better bioavailability of poorly soluble drugs in the body.

REFERENCES
1. Cook, G. C. Use of benzimidazole chemotherapy in human helminthiases: Indications and efcacy. Parasitol. Today 1990, 6(4), 133136. 2. Wen, H.; New, R. R. C.; Craig, P. S. Diagnosis and treatment of human hydatidosis. Br. J. Clin. Pharmacol. 1993, 35, 565574. 3. WHO Informal Working Group on Echinococcosis. Guidelines for treatment of cystic alveolar echinococcosis in humans. Bull. World Health Organ. 1996, 74, 231242. 4. Misra, P. K.; Kumar, A.; Agarwal, U.; Jagota, S. C. A comparative clinical trial of albendazole vs. metronidazole in giardiasis. Indian Pediatr. 1995, 32, 291294. 5. Lecuit, N.; Oksenhendler, E.; Sarfati, C. The use of albendazole for disseminated microsporidian infection in patients with AIDS. Clin. Infect. Dis. 1994, 19, 332333. 6. Lopez-Garcia, M. L.; Torrado-Duran S.; TorradoDuran, J.; Martinez, A. R.; Bolas, F. Albendazole versus ricobendazole against enteral and parenteral stages of Trichinella spiralis in mice. Int. J. Parasitol. 1997, 27, 781 785. 7. Keramidas, D.; Mavridis, G.; Soutis, M.; Passalidis, A. Medical treatment of pulmonary hydatidosis: Complications and surgical management. Pediatr. Surg. Int. 2004, 19, 774776. 8. Del Brutto, O. H.; Sotelo, I.; Raman, G. C. Therapy for neurocysticercosis: A reappraisal. Clin. Infect. Dis. 1993, 17, 730733. 9. Gil Grande, L. A.; Rodriguez-Caabeiro, F.; Prieto, J. G.; S anchez-Ruano, J. J.; Brasa, C. Randomised controlled trial of efcacy of albendazole in intra-abdominal hydatid disease. Lancet 1993, 342, 12691272. 10. Van Nieuwkerk, K. M. J.; Veenstra, J.; Wassenaar, R. P.; Blaauwgeers, H. L.; Geraedts, A. A.; Kroes, H. Pancreatitis causes by rupture of liver hydatid cyst. Eur. J. Gastroenterol. Hepatol. 1993, 5, 563565. 11. Yasawy, M. I.; ALKarawi, M. A.; Are, M. Combination of praziquantel and albendazole in the treatment of hydatid disease. Trop. Med. Parasitol. 1993, 44, 192195. 12. Amidon, G. L.; Lennernas, H.; Shah, V. P.; Crison, J. R. A theoretical basis for a biopharmaceutic drug classication: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 1995, 12, 413 420.

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poorly soluble albendazole as class II BCS drug. Figure 11 summarizes the effects on bioavailability enhancement in the gut. It is important that the nanocrystals are released from the tablet or capsule as ne nanocrystals. It could be shown that a slight aggregation does not yet impair the dissolution velocity,[40] but pronounced aggregation will decrease the dissolution velocity strongly.[41]

CONCLUSION
Nanosuspensions were formulated by highpressure homogenization to overcome problems caused by poor aqueous solubility. Increase in surface area enhances the dissolution rate. Spray-dried albendazole nanocrystals prepared by a high-pressure homogenization technique can be employed to produce solid dosage forms of the drug like tablets. Dried drug nanocrystals offer superior physicochemical properties. Albendazole nanocrystal-loaded tablets can be produced using direct compression. From the Noyes-Whitney equation, the increased surface area and saturation solubility due to the decreased radius result in increased dissolution velocity. This phenomenon was clearly demonstrated by the albendazole nanocrystals. The dissolution velocity of nanocrystal-loaded solid dosage forms was evaluated. Drug nanocrystals were released from the nanocrystal tablets at a faster rate compared to microcrystal tablets or

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