MIXED HYDROTROPY TECHNIQUE USED FOR SOLUBILITY ENHANCEMENT OF ALBENDAZOLE

MIXED HYDROTROPY TECHNIQUE USED FOR SOLUBILITY ENHANCEMENT OF ALBENDAZOLE

Akanksha Hatwal *, Rita Saini and Shivanand Patil

Department of Pharmacy, Shree Dev Bhoomi Institute of Education Science & Technology, Dehradun, Uttarakhand, India.

ABSTRACT: Purpose: Albendazole (ABZ) is a drug that shows anthelmintic activities, also used for treating neurocysticercosis, also known as pork tapeworm infection caused by contact with infected human stool, infected food, and water. But the serious challenge is the hydrophobicity of albendazole, which slow down the dissolution rate and bioavailability, so it can be given in high concentration, which can cause residual toxicity, so the purpose of this research article is to enhance the solubility of albendazole by mixed hydrotropic technique. Hydrophobic drug shows the difficulty in absorption when reaching the aqueous area, leading to failure in formulation development. Method: Solid dispersion was prepared by using a blend of citric acid and piperazine by mixing them with ABZ with the help of ethanol as solvent, carried out the content in a china dish on a magnetic stirrer until solvent evaporated completely, use of FTIR for functional group determination, determination of melting point by capillary method, determination of thermal behaviour by DSC, XRD studies were done, Further evaluation of solid dispersion were done for determination of drug content, Percentage yield, solubility studies, and In-vitro evaluation. Results: In the present observation, an attempt was made to enhance the solubility of hydrophobic drug albendazole by using a blend of hydrotropes such as Citric acid and piperazine as hydrotropes and ethanol as a solvent which enhanced the solubility of ABZ up to 5 times. Conclusion: Based on research work, it was concluded that mixed hydrotropy enhanced the solubility of ABZ by using piperazine and citric acid as hydrotropes which also reduces the chances of residual toxicity.

Keywords: Solubility, Solvent, Albendazole (ABZ) mixed hydrotropy, Citric acid, Tannic acid, Piperazine, Caffeine as hydrotropes

INTRODUCTION: Solubility has the maximum amount of solute dissolved in a specific amount of solvent at a specific temperature, pH, and pressure. Drug solubility is directly proportional to bioavailability.

According to their aqueous solubility and intestinal permeability, all drugs are categorized into four biopharmaceutical classification systems (BCS) ¹.

Most of the drug is given through the oral route, and their solubility plays a crucial role in their absorption, so various techniques have been used to improve the solubility of hydrophobic drug ². Highly soluble drugs show greater solubility in 250 ml of aqueous phase at pH of 1.0- 7.5 and highly permeable drugs show 90% permeability in intestinal membrane ³. Albendazole (ABZ) is a hydrophobic drug that comes under II class of biopharmaceutical classification system. It shows anthelmintic activities ⁴, used to inhibit or kill helminths species such as Ascaris Lumbricoides, A. suum, and Necator americanus ⁵. Enhancing the effectiveness of ABZ can be possible by improving its dissolution ⁶. To enhance the solubility of ABZ, the most desirable technique for solubility enhancement is mixed hydrotropy ⁷. The mixed hydrotropy technique has been used to enhance the hydrophobic drug's solubility by using hydrotropic blends of desirable hydrotropes, or we can say that a large concentration of secondary hydrophilic solute is added with a drug that enhances the aqueous solubility of the hydrophobic drug. Hydrotropes are those compounds that have been used to enhance in solubility of hydrophobic drugs ⁸.

Advantages of Hydrotropes: Hydrotropy is the most important tool for the other solubilization methods, such as micellar solubilization, spray drying, salting, and miscibility, because of the independent character of the solvent. Chemical modification is not required in the hydrotropic method. It is efficient and simple for various pharmaceutical industries as organic transformations. They are easily available, having low cost. It reduces the chances of residual toxicity. Hydrotropes do not need any specific temperature when dissolved in water ⁹.

MATERIALS AND METHODS:

Materials: Lasa super generics ltd provided the drug ABZ to conduct this study. Ideal suppliers gave the remaining materials such as ethanol, citric acid and piperazine.

Pre-Formulation Study:

Fourier Transform Infrared Spectroscopy: FTIR was used to determine the functional group. The sample containing the group was combined with Potassium bromide, which was compressed to the discs, and hydraulic pressure was implemented to 5 tons ¹⁰.

Melting Point: The drug was filled in a sealed capillary, put inside the melting point apparatus, and observed the value at which the drug melted ¹¹.

Selection of Pro-eminent Hydrotropes: Four hydrotropes were used for solubility enhancement, such as Piperazine, Citric acid, Tannic acid and Caffeine. The hydrotropes that showed high solubility were selected using the solubility determination technique.

The drug ABZ showed different solubility with each hydrotropes, and the procedure for solubility determination is as follows first, take 4 beakers in which an appropriate quantity of distilled water was taken, added each hydrotropes individually; after that, an excessive amount of ABZ was also added.

Kept the solution on a magnetic stirrer for 24 hrs. When the equilibrium state was reached, then filtration of the solution takes place; the filtrate was collected, diluted, and observed through UV spectrophotometry at 308 nm¹².

Solubility Studies: Solubility was performed in triplicate according to Higuchi and Connors’s method to evaluate the increment in the solubility of ABZ (solid dispersion). An Excess amount of ABZ (approximately 50mg) was added to the container containing hydrotropes. The container was then placed in a magnetic stirrer for 24 hrs.

After that, the solution was filtered, diluted and analyzed using UV spectroscopy at λmax in the range of 308nm. The observed solubility was compared with pure drug solubility, and the obtained data from solubility studies were used to determine the solubility enhancement ratio formula given below ¹³.

Solubility Enhancement = Solubility of a drug in hydrotropic solution / Solubility of a drug in distilled water × 100

Preparation of Solid Dispersion by Solvent Evaporation Method: For the preparation of solid dispersion, first mix ABZ with the blend of citric acid and piperazine in an appropriate ratio such as (1:2, 1:4, 1:6, 2:1,2:4)  with the help of ethanol to form homogenous mixtures which were stirred by stirring rod until it dissolved completely and put it inside the China dish placed on a magnetic stirrer.

When solvent evaporated completely, scratched out the sample through a spatula, put in butter paper, and placed inside the oven, temperature should be maintained at 55±2°C and passed through sieve no. 40 and then the prepared solid dispersion (SD1- SD5) were stored in the desiccators for further evaluation ^13,14_.

Characterization of Formulated Batches (SD1- SD5):

FTIR Studies: Fourier transform infrared spectroscopy is used to detect the impurity of the drug. The sample was prepared as KBr pellet method. The range of wavelength was selected from 400 -2000. Selected IR peak was obtained for solid dispersion of ABZ, and the best optimized solid dispersion was selected according to drug release and the solubility of the solid dispersion of drug ^{10, 17}.

DSC Studies: DSC studies help understand the hydrotropic blend's thermal behavior ¹⁵.

XRD Studies: The XRD of solid dispersion were determined using the X-ray, and diffract meter, respectively to investigate change in the crystalline of ABZ and the scanning speed of the instrument was 4°C  per minute over a range of 5°C ¹³.

Drug Content: Solid dispersion, equivalent to 50 mg of ABZ was dissolved in a suitable solvent such as ethanol; after that, the solution was filtered using whatman filter paper. The final sample was analyzed by UV spectrophotometry at 308nm, and the concentration of ABZ was determined by using the formula below ^{13, 15}.

Drug content (%) =Practical amount of solid dispersion / Theoretical amount of solid dispersion × 100

Percentage Yield: The percentage yield was used to determine the amount of loss ingredient during the preparation of solid dispersion. It was calculated by using the formula given below ¹⁴.

Percentage Yield (%) = Practical amount of solid dispersion / Theoretical amount of solid dispersion × 100

In-vitro Dissolution Studies: Dissolution studies are the study of drug release when it reaches inside the human body. It solubilizes at a definite time interval. The apparatus used to determine drug release was “USP Basket Type 1 apparatus” and maintained the biological condition such as pH temperature similar to the human body.

Rotation was set to 100 rpm, and drug release was observed for up to 60 minutes and compared the dissolution rate of pure drug with the formulation having a maximum dissolution rate ¹³.

RESULT:

Pre-formulation Studies:

Fourier Transform Infrared Spectroscopy: The presence of different bands was observed, which showed the presence of the functional group in Fig. 1 and the various functional groups with different peaks shown in Table 1, and the spectrum of ABZ is shown in Fig. 1.

FIG. 1: SPECTRUM OF ABZ

TABLE 1: FTIR PEAK NAME WITH FUNCTIONAL GROUP

Melting Point: The melting point of albendazole was found to be 208.1℃

Solid dispersion of ABZ: By solvent evaporation method, solid dispersion was prepared with the help of a hydrotropic blend of piperazine and citric acid and ethanol as solvent. And the ratio of drug with hydrotropic blend is shown in Table 2, and photos of different solid dispersion are shown in Fig. 2.

TABLE 2: RATIO OF SOLID DISPERSION (DRUG: HYDROTROPIC BLEND)

FIG. 2: DIFFERENT FORMULATION IMAGES OF PREPARED SOLID DISPERSION

Evaluation Parameters:

FTIR: The range of wavelength was selected from 400 -2000. Selected IR peak was obtained for solid dispersion of ABZ and the best optimized solid dispersion was selected according to drug release and the solubility of the solid dispersion of the drug. And the FTIR peak with a functional group is shown in Table 4.

FIG. 3 FTIR OF SOLID DISPERSION

TABLE 3: FTIR PEAK NAME WITH FUNCTIONAL GROUP IN SOLID DISPERSION

DSC: The differential scanning calorimetry shows a sharp endothermic peak near 200, corresponding to the melting point of ABZ. And DSC of SD5 is shown in Fig. 4.

FIG. 4: DSC OF SOLID DISPERSION (SD5)

XRD: Solid albendazole dispersion was prepared using the solvent evaporation method .and diffractograms of five formulations (SD1-SD5) were observed in an X-ray diffractometer. The conditions for measuring were followed as voltage should be 40 Kv, 300 mA. The SD5 formulation showed a peak in Fig. 5.

FIG. 5: XRD OF SOLID DISPERSION (SD5)

Percentage Yield and Drug Content: The percentage yields and drug content were determined by the formula mentioned in the previous procedure and the result is given below in Table 4.

TABLE 4: PERCENTAGE YIELD AND DRUG CONTENT OF VARIOUS FORMULATIONS

Saturation Solubility: Saturation solubility of various solid dispersions was measured. And saturation solubility of the different formulations is mentioned in Table 5. Based on the solubility of hydrotropes, two hydrotropes, piperazine, and citric acid, show high solubility, which was mentioned in Table 6 with their solubility enhancement ratio.

TABLE 5: SATURATION SOLUBILITY OF VARIOUS FORMULATIONS

TABLE 6: SOLUBILITY OF ABZ IN DIFFERENT HYDROTROPES AND THEIR SOLUBILITY ENHANCEMENT RATIO

Dissolution Studies: Table 7 shows the dissolution of ABZ in different solid dispersion along with per, which increases with increment in hydrotropic blend ratio. All Solid dispersion samples showed an improved dissolution rate of ABZ as compared to pure ABZ. The in-vitro drug dissolution profile of pure drug and SD5 are mentioned in Fig. 6.

TABLE 7: DISSOLUTION STUDY OF PURE DRUG WITH VARIOUS FORMULATIONS

FIG. 6: DISSOLUTION PROFILE OF PURE DRUG WITH SD5 FORMULATION

DISCUSSION: ABZ is a drug that comes under the BCS II class, with low solubility and high permeability and is categorized as anthelmintic. SO solubility studies were conducted, and the mixed hydrotropy method was used to enhance the solubility of ABZ by adding a blend of piperazine and citric acid because they both showed high solubility of ABZ, so they were chosen for further work. Solid dispersion was prepared using different ratios of the drug, solvent and hydrotropic blend. Five formulations were prepared from which SD5 was selected, which improved the solubility of ABZ drastically and was then used for further evaluation, such as FTIR, XRD and DSC.

CONCLUSION: In this present research work, the aim was to enhance the solubility of albendazole by using the mixed hydrotropy technique by preparing a hydrotropic blend of piperazine and citric acid. Piperazine and citric acid show high improvement in solubility of hydrophobic drug albendazole. Mixed hydrotropic can be a safe and simple process for increasing the dissolution rate of albendazole as they reduce the residual toxicity by combining two hydrotropes. The drug release of pure drug of albendazole was observed at 19.20 in 60 minutes, and after using hydrotropic blend, the dissolution rate was observed as 72.98 in 60 minutes. The solubility was increased up to 5 times.

ACKNOWLEDGEMENTS: All author wishes to acknowledge the support provided by Shree Dev Bhoomi Institute of technology for their help.

CONFLICTS OF INTEREST: The authors declare there is no conflict of interest.

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    How to cite this article:

    Hatwal A, Saini R and Patil S: Mixed hydrotropytechnique used for solubility enhancement of albendazole. Int J Pharm Sci & Res 2023; 14(2): 898-03. doi: 10.13040/IJPSR.0975-8232.14(2).898-03.

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