Formulation and Evaluation of Acetazolamide Tablet by Liquisolid Technique

Introduction

A Liquisolid tablet containing partially soluble drugs is considered as one of the novel pharmaceutical formulation techniques to improve the dissolution rate. This study was intended to improve rate of dissolution of Acetazolamide by preparing liquisolid tablets. Therapeutic efficiency of a drug stands upon the solubility and bioavailability of active moiety. Solubility is the chief framework to attain expected concentration of drug in systemic circulation. Partially soluble drugs will be intrinsically released at slow rate owing to their limited solubility within the GI content. Numerous approaches have been employed to describe improved dissolution and in turn, the absorption capacity of water insoluble drug. There are many methods like solid dispersion, inclusion complexes; micronization of all these method which can get better of this complication is by liquisolid technique the most worthy solid dosage form; in almost fine dispersed state, which gives to the improved drug dissolution effciencies.^{1, 2}

Various suitable approaches to increase the solubility of partially water soluble drugs have been developed - like sublimation technique³, natural polymers⁴, Co-Crystals⁵, Microcrystals⁶. To avoid the solubility problem of micronized hydrophobic drugs makes it less effective due to aggregation of particles, when the drug is converted to tablets or encapsulations⁷. Ever since active research in the improvement of drug dissolution by solid dispersion has gained popularity, only a less products, such as Kaletra® and Gris-PEG® have become available in market. The reason lies in knowing the stability problem during storage and difficulty in understanding the solid structure ⁸.

Different costlier and subtle approaches like soft gelatin are widely used ⁹. Other approaches, such as inclusion complexation, ¹⁰ microencapsulation¹¹, and preparation of nano-suspensions¹², self-nanoemulsions¹³ and solid lipid nanoparticles¹⁴ are some approaches to improve solubility of class II drugs. But these access lead to enhanced commercial cost by using novel techniques and/or sophisticated machinery.

To reduce these leading obstacles, liquisolid technique is the only novel development and advanced method for dissolution enhancement,¹⁵. The first to introduce this method is by Spireas et al. to take in water insoluble drugs for fast release solid dosage forms. The other percept of liquisolid system in powder form is by delivering the drug as that of soft gels. Liquisolid concept refers to altering liquid form of drug into distinctly dry, non-adherent, compressible and free flowing powder mixtures containing liquid medications with suitable excipients, which are referred to carrier and coatingmaterials¹⁶. The liquid form of drug is first absorbed in to the interior substructure. As the interior of the carrier is logged with liquid drug, a liquid layer gets adsorbed on carrier particles. Solely this forms fare flowable and compressible powder mixture. Usually, miscible in oral acceptable universal solvent like propylene and polyethylene glycols, are used as the fluidmedia. Porous materials with maximum interior surface boundary with high liquid absorption magnitude are carrier material to absorb liquid drug¹³. Various grades of cellulose, starch and any disaccharide can be taken as carriers. However, only excipients with finesses and highly adsorptive property can be used as covering matter.¹⁷

Materials and Methods

Materials

Acetazolamide was obtained from (Yarrow chemicals Mumbai- India), Poly Ethylene Glycol 400 (Yarrow chem),HPMC K4M (Yarrow chem), Tween 80, Propylene glycol and HCl ( Himedia), , Aerosil ( Yarrow chem), Poly Ethylene Glycol 400(Yarrow chem), Magnesium Stearate and Talc(Yarrow chem), Sodium Starch Glycolate ( Yarrow chem), Avicel PH102(Yarrow chem).

Components of liquisolid system The main constituents of liquisolid tablets are^18,19

1. Carrier Material: The material surface chosen should not only be porous but be fibers too in the interior there by improves the effective surface area, compression and by means of sorption mechanism of liquid increases dissolution. Examples are various grades of cellulose, lactose, starch, sorbitol etc.

2. Coating Material: Aggregation of particles and reduction of inter particulate traction can be observed as thin film of coating material. Coating material finesses of (0.1mm to 5mm)e.g. colloidal silica; the prodigy gives liquisolid material a dry appearance thereby absorbing excess liquid by giving it a cover it improves the flow property

3. Non-Volatile Solvent: This should be inert, soluble in water and possess adequate amount of drug solubility with less boiling point e.g. PG, PEG 100, polysorbates, glycerin, N, N-dimethylacetamide; edible oils etc.

4. Disintegrant: Based on the concepts of the investigator need; use of the type and quantity of disintegrant apply. For solubility enhancement studies, incorporation of super-disintegrant is assured. Most consistently used disintegrant is (Explotab13, Pumogel etc.). While for matrix type of systems intended for sustained release, disintegration is not required.

Solubility Studies

Surplus quantity ofdrug in non-volatile solvent like PEG 400, Polysorbate 80 and propylene glycol were carried out to get saturated solutions in controlled temperature shaker for 2 days at 25^O C±1^o C. The solution was filtered through membrane filter, diluted with HCl and analyzed by double beam UV-Visible spectrophotometer (Jascouvc V-630) at a wavelength of 266nm against blank²⁰.

Arithmetic representation of liquisolid system

In this study, PG, PEG, Tween 80 was used as liquid vehicle; carrier and coating materials as granular form of micro crystalline cellulose, HPMC K4M and colloidal silicon dioxide were used. For reproducible flow and compressible nature of liquisolid material, new arithmetic representation of liquisolid system was accepted to calculate the appropriate quantity of additives to produce liquisolid systems. (Table2). This Arithmetic representation was based on powders properties called liquid retention potential (φ-value) and compressible liquid withholding capacity (ψ-number) of the ingredients (carrier and coating materials) as previously discussed by Spireas et al. Stating that, it retains specific amount of liquid on the carrier and coating powder materials by allowing sustainable flow and compression properties.

R=Q/q

where R is proportion of carrier to coating material. The maximum acceptable liquid shows appropriate flow and compressible property; this amount of liquid attributes factor of liquid load (Lf) that is Lf=W/Q where W= weight of liquid medication over Q= carrier powder.^{21, 22.}

Formulation of liquisolid tablet

Weighed amount of Acetazolamide and non-volatile solvent PEG 400, Tween 80, Propylene glycol were mixed using mortar and pestle. The formed mixture was incorporated into calculated quantities of carrier and coating material as shown in the Table 2.

Procedure to follow in three steps

1. Powder was mixed for about a minute making the liquid medication equally distribute in the powder.

2. Evenly spread the mixture as uniform layer for about 5min for appropriate absorption of liquid in interior of powder.

3. By means of spatula powder was scrapped off the mortar surfaces and then blended with disintegrates, lubricants, and glidants.

Pre-compression study

It includes plotting standard graph of acetazolamide, FTIR studies of drug and excipients,(Table 1, Fig 1, Fig2), flow ability and compressibility behaviour. The following are the micromeritics pre-compression studies on liquisolid mixture ²³. 

Angle of Repose

In this study the angle of repose of the given sample will be determined by fixed funnel method. A funnel was fixed in a way that the top of the funnel was at a height of 2cm from the surface. The weighed quantity of powders was passed from the funnel so that they form a pile. The height (h) and the radius(r) of the heap were measured and angle of repose was calculated using the equation.

Ө= Tan-1 (h/r)

where Ө= repose angle, h= height of the heap (cm), r=radius of the heap (cm).

Bulk-Density

Required quantities of powder mixture were taken in a 10 ml graduated cylinder. Then the initial volume was noted. The graduated cylinder was tapped for 100 times and the final volume was measured using following formula:

Bulk density = W/VB

Tapped density = W/Vt where, W=Weight of the formulation, VB = Bulk volume, Vt = Tapped volume²⁴.

Compressibility Index (Carr’s Index CI)

The formula for Carr’s Index is as below:

Ci = Tapped density- Bulk density ×100 / Tapped density

Post-Compression Parameters:²⁵

Following quality control tests are:

Weight variation: Individual weightsand average weight of randomly selected 20 tablets were used to check weight variation.

Hardness: Tablet hardness was done using digital hardness tester

Friability: Fifteen tablets (W initial) were placed in Roche Friabilatorand were operated for 100 revolutions and the tablets were again weighed (W final). The percentage loss was measured

F= (W initial)-(W final)/(W initial) × 100

Uniformity of drug content

The 20 tablets of each formulation were weighed and powdered. The quantity of powder equivalent to 50mg of Acetazolamide was transferred into a 100ml volumetric flask and the volume was adjusted to 10ml with 0.1N HCl. The sample was filtered to remove the insoluble excipients. Further, 1ml of the above solution(Filtrate) was diluted to 100ml with 0.1N HCl and checked at its absorption maxima.

Disintegration test

The disintegration time was determined at 37^o C ± 2^o C. By placing each tablet in each six tubes of the apparatus and checked for no trace of material left was accessed.

In-Vitro Dissolution Study

Each tablet was placed in 900ml of 0.1M HCl (pH 1.2)previously equilibrated to the temperature of 37±0.5°C. in the dissolution vessel, the apparatus was operated at 50 rpm. At definite time intervals, 10 ml of the fluid was withdrawn; filtered and replaced with 10ml of the fresh dissolution fluid. Suitable dilutions were done with the dissolution fluid and analyzed spectrophotometrically at absorption maximum.(Figure 3).

Stability Study

The stability of optimized formulation (F1) was monitored up to 3 months at accelerated stability conditions of temperature and relative humidity (25°C±2°C, RH 65%±5% and 40°C±2°C, RH 75%±5%). Samples were withdrawn after each month and characterized for assay, tablet characteristics and dissolution profile.

Results and Discussion

Solubility studies were performed to select the solvent for liquisolid system. Table 3 explains the results of solubility studies. Acetazolamide showed maximum solubility in PEG 400.

The pre-compressional results were within the standard limits (Table 4). Formulations with PEG 400 showed better results (angle of repose and Carr’s index) when compared to formulations containing PG and Tween 80.

Physical properties like weight variation, friability, hardness, and content uniformity were complied with pharmacopoeial limits. The tablets should contain adequate hardness and at the same time on swallowing it should disintegrate.

The weight variation test showed that all the formulations were found to be within the pharmacopoeial limits i.e., not more than 5% of the average weight (Indian Pharmacopoeia,1996). These results showed that all the tablet formulations were found uniform in hardness, friability and drug content uniformity.(Table 5).

Release studies

Formulation F1 was considered as the best formulation to produce fast release of the Acetazolamide when compared to other formulations (Fig 3). The enhancement in dissolution rate of the liquisolid tablets is probably due to the drug presenting in a solubilised state, which contributes to increased wetting properties, there by improving the dissolution rate.

The samples were tested for any changes in physical appearance, drug content, in-vitro drug release studies at monthly intervals. The results of stability did not show any significant change in physical appearance, drug content, and in-vitro dissolution studies of above three formulations.  

Conclusion:

The objective of the study to get flow ability and compressibility behaviour of Acetazolamide liquisolid system for better dissolution rate was realized. The preformulation results obliged for better drug solubility. The solubility of Acetazolamide in PEG 400 was found to be 86.4µg/ml. PEG 400 showed solvent of choice for liquisolid systems. Sodium starch glycolate as super-disintegrant. FTIR studies confirmed better compatibility between drug and excipients. Finally, it can be concluded that, liquisolid formulation containing Acetazolamide with Avicel as carrier and Aerosil as coating material is efficient to improve rate of dissolution with promising flow and compression characters. Thus, liquisolid approach has potential utilities in improving dissolution rate of Acetazolamide.

Acknowledgement

The authors are thankful to Vision Group of Science and Technology Govt. of Karnataka, RGUHS Bangalore and Srinivas college of Pharmacy Mangalore for providing necessary equipment’sand chemicals under different grant schemes.