INTRODUCTION:

Therapeutic effectiveness of a drug depends upon the bioavailability which is dependent on the solubility of a drug molecules. Solubility is important parameter to achieve desired concentration of drug in systemic circulation for pharmacological response to be shown.^[1] The poorly soluble drugs generally exhibit slow dissolution rates and incomplete bioavailability due to poor wettability in the gastro intestinal tract (GIT).^[2]Various techniques are reported to improve the dissolution of poorly soluble drugs, including solid dispersions, crystal engineering, ballmilling, complexation, self-emulsifying drug delivery systems and the use of mesoporous silica carriers. Recently, the liquisolid technique has shown promise for improved dissolution.^[3]

The concept of Liquisolid tablet is one of the most promising techniques to achieve enhanced solubility of poorly soluble drugs.

This approach is suitable for immediate or sustained release formulations and this depends upon the solubility of the drug in the non-volatile solvents.^[4]The liquisolid technique as described by Spireas is a novel concept, where a liquid may be transformed into a free flowing, readily compressible and apparently dry powder by simple physical blending with selected carrier and coating material.^[5]Once the carrier is saturated with liquid, a liquid layer is formed on the particle surface which is instantly adsorbed by the fine coating particles. Thus, an apparently dry, free flowing, and compressible powder is obtained. Usually, microcrystalline cellulose is used as carrier material and amorphous silicon dioxide as coating material.^[6]

Theory of Liquisolid Systems:

In order to address the flowability and compressibility of liquisolid compacts, simultaneously, the ‘‘new formulation mathematical model of liquisolid systems” was employed as follows to calculate the appropriate quantities of excipients required for producing liquisolid systems of acceptable flowability and compressibility.

This mathematical model was based on new fundamental powders properties (constants for each powder material with the liquid vehicle) called the flowable liquid retention potential (Φ-value) and compressible liquid retention potential ψ-number) of the constituent powders (carrier and coating materials)

According to the new theories, the carrier and coating powder materials can retain only certain amounts of liquid while maintaining acceptable flow and compression properties. Depending on the excipients ratio (R) or the carrier: coating ratio of the powder system used, where

R=Q/q ... (1)

As R represents the ratio between the weights of carrier (Q) and coating (q) materials present in the formulation. An acceptably flowing and compressible liquisolid system can be prepared only if a maximum liquid on the carrier material is not exceeded; such a characteristic amount of liquid is termed the liquid load factor (Lf) and defined as the ratio of the weight of liquid medication (W) over the weight of the carrier powder (Q) in the system, which should be possessed by an acceptably flowing and compressible liquisolid system. i.e.:

Lf=W/Q ... (2)

Spireas et al. [4] used the Flowable liquid retention potentials (Φ -values) of powder excipients used to calculate the required ingredient quantities, hence, the powder excipients ratios R and liquid load factors Lf of the formulations are related as follows:

Lf = Φ + Φ (1/R) ... (3)

Where, Φ and Φ are flowable liquid retention potential of carrier and coating material respectively. So in order to calculate the required weights of the excipients used, first, from Eq. (3), Φ and Φ are constants, therefore, according to the ratio of the carrier/ coat materials (R), Lf was calculated from the linear relationship of Lf versus 1/R. next, according to the used liquid vehicle concentration, different weights of the liquid drug solution (W) will be used.

So, by knowing both Lf and W, the appropriate quantities of carrier (Qo) and coating (qo) powder materials required to convert a given amount of liquid medication (W) into an acceptably flowing and compressible liquisolid system could be calculated from equation (1) and (2).^[7,8,9,10]

CLASSIFICATION:

A. Based on the type of liquid medication contained therein, liquisolid systems may be classified into three subgroups:

1 Powdered drug solutions

2 Powdered drug suspensions

3 Powdered liquid drugs

The first two may be produced from the conversion of drug solutions or (e.g. prednisolone solution in propylene glycol) or drug suspensions (e.g. gemfibrozil suspension in Polysorbate 80), and the latter from the formulation of liquid drugs into liquisolid systems.

B. Based on the formulation technique used, liquisolid systems may be classifies into two categories, namely,

1 Liquisolid compacts

2 Liquisolid Microsystems

Liquisolid compacts are prepared using the previously outlined method to produce tablets or capsules, whereas the liquisolid micro systems are based on a new concept which to produce an acceptably flowing admixture for encapsulations.^{[11, 12]}

Preformulation study:

1. Determination of drug solubility in different non-volatile solvents

2. Determination of angle of slide

3. Carrier-Coating material ratio (R)

4. Determination of flowable liquid retention potential (Ø value)

5. Calculation of liquid load factor (Lf)

6. Liquid solid compressibility test (LSC)^[13]

Solubility studies:

Solubility studies are carried out by preparing saturated solutions of drug in non volatile solvent and analyzing them spectrophotometrically. Saturated solutions are prepared by adding excess of drug to non volatile solvent and shaking them on shaker for specific time period under constant vibration. After this, the solutions are filtered and analyzed spectrophotometrically.^[14]

Formulation of Liquisolid Compact:

The formulation part of liquisolid compact mainly includes Pre-formulation studies and Formulation of liquisolid compact system.

Components:

Liquisolid compact mainly includes

1 Non volatile solvent

2 Disintegrant

3 Drug candidate

4 Carrier material

5 Coating material^[15]

Non volatile Solvent:

Non volatile Solvent should be Inert, high boiling point, preferably water-miscible and not highly viscous organic solvent systems and compatible with having ability to solubilise the drug. The non volatile solvent acts as a binding agent in the liquisolid formulation.

Examples of various non-volatile solvents used for the formulation of liquisolid systems include Polyethylene glycol 200 and 400, glycerin, polysorbate 80 and propylene glycol.^[16]

Disintegrant:

Superdisintigrants increases the rate of drug release, water solubility and wettability of liquisolid granules. Mostly superdisintigrants like sodium starch glycolate and crosspovidone are used.^[16]

Drug candidates:

This technique was successfully applied form low dose BCS class II and class IV drugs which are poorly water soluble and have slow dissolution rate.^[17]

Carrier Materials:

Carrier material should be porous material possessing sufficient absorption properties which contributes in liquid absorption. The carrier and coating materials can retain only certain amounts of liquid and at the same time maintain acceptable flow and compression properties hence, increasing moisture content of carrier’s results in decreased powder flowability. Some example include grades of microcrystalline cellulose such as avicel PH 102 and avicel PH 200, lactose, eudragit Rl.^[17]

Coating Materials:

Coating material should be a material possessing fine and highly adsorptive particles which contributes in covering the wet carrier particles and displaying a dry-looking powder by adsorbing any excess liquid. Coating material is required to cover the surface and so maintain the powder flowability. Coating material includes silica, Aerosil 200.^[18]

Preparation of liquisolid tablets:

Calculated quantities of drug and non-volatile solvent is accurately weighed in 20ml glass beaker and then heated to dissolve the drug in that solvent. The resulting hot medication is incorporated into calculated quantities of carrier and coating materials. Mixing process is carried out in three steps as described by Spireas et.al. During the first step, the system is blended at an approximate mixing rate of one rotation per second for approximately one minute in order to evenly distribute liquid medication in the powder. In the second stage, the liquid or powder admixture is evenly spread as a uniform layer on the surfaces of a mortar and left standing for approximately 5min. to allow drug solution to be absorbed in the interior powder particles. In the third stage, the powder is crapped on the mortar surface by means of aluminum spatula and then blended with sodium starch glycolate another 30sec. this gives final liquisolid formulation to be compressed.^[19]

Pre-compression Evaluation:

Fourier-transform infrared spectroscopy (FTIR):

FTIR spectra of pure drug and one formulation which showed highest dissolution rate were recorded as compatibility study.^[20]

Flow properties of the liquisolid system:

The flow properties of the liquisolid systems were estimated by determining the angle of repose, Carr’s index, and Hausner’s ratio. The angle of repose was measured by the fixed funnel and free standing cone method. The bulk density and tap densities were determined for the calculation of Hausner’s ratio and Carr’s Index.^[21]

Differential scanning calorimetry (DSC):

DSC is performed in order to assses the thermotropic properties and the thermal behaviors of the drug, excipients used in the formulation, as well as liquisolid system prepared. The drug is molecularly disappear within the liquisolid matrix.^[22]

X-RAY powder diffractometry (XRPD):

For characterization of crystalline state, the X-ray powder diffraction patterns are determined for drug. Excipients used in the formulation, physical mixture of the drug and excipients, finally for prepared liquisolid system.^[23]

Scanning electron microscopy (SEM):

Morphological evaluation of the pure drug and liquisolid compact which shows the highest dissolution rate was carried out by scanning electron microscope.^[24]

Post-compression Evaluation:

Weight variation test:

The weight variation test was carried out as per USP 30. 20 tablets were weighed accurately and average weight was calculated. ^[25]

Hardness and friability:

The hardness of the liquisolid compacts prepared was evaluated using Monsanto hardness tester. It is expressed in kg/cm². The mean hardness of each formulation was determined. The friability of the prepared liquisolid tablets were measured in a Roche type apparatus and the percentage loss in weight was calculated and used as a measure of friability.^[26]

Disintegration test:

The disintegration test was carried out using disintegration test apparatus as specified in the USP 30. ^[27]

Drug content uniformity:

Accurately weigh a tablet. Tablet was then crushed and powder transferred to 100ml volumetric flask containing 40ml methanol. The flask was shaken to dissolve the drug and adjusted to the volume with methanol to obtain stock solution. Further suitable dilution were done.The absorbance was recorded using UV/visible spectrophotometer.^[28]

In vitro release studies:

The in vitro release studies were performed by using the dissolution apparatus and compared the formulated liquisolid tablets with direct compression tablets. The percentage drug release was estimated.^[29]

Advantages:

· Method improves the solubility and bioavailability of orally administered water insoluble or poorly soluble drugs.

· Liquisolid systems are low cost formulations than soft gelatin capsules.

· Drug release can be modified using suitable formulation ingredients

· Drug can be molecularly dispersed in the formulation.

· Enhanced bioavailability can be obtained as compared to conventional tablets.

· Better availability of an orally administered water insoluble drug.^[30]

Applications:

1. It gives rapid release and sustained release of drugs are obtained in liquisolid formulations.

2. Sustained release of drugs which are water soluble drugs such as propranolol hydrochloride has been obtained by the use of this technique.

3. Solubility and dissolution enhancement.

4. Designing of controlled release tablets.

5. Application in probiotics.^[6]

CONCLUSION:

Various methods are known to improve water solubility and drug release, among which the liquisolid technology is one of the most promising approaches. The enhanced rate of drug dissolution from liquisolid tablet is probably due to increase in wetting properties and surface area of drug particle available for dissolution. They show improved disintegration rates, release rates and hence greater bioavailability.

REFERENCES:

1. Kulkarni AS, Aloorkar NH, Mane MS, Gaja JB. Liquisolid system: A Review. IJPSN.2010; 3(1):795-802.

2. Manogar PG, BN Vedha Hari, D Ramya Devi. Emerging Liquisolid Compact Technology for Solubility Enhancement of BCS Class-II Drug. J Pharm. Sci. and Res. 2011;3(12):1604-1611.

3. Chella Naveen, Shastri N, Tadikonda RR. Use of the liquisolid compact technique for improvement of the dissolution rate of valsartan. Acta Pharmaceutica Sinica B. 2012;2(5): 502-508.

4. Patel HM, Shah CN. A Review-Recent Research on Liquisolid Compact for Solubility and Dissolution Enhancement. J Pharm Sci Bioscientific Res. 2016; 6(5):628-634 .

5. Pavani E, Noman S, Syed IA. Liquisolid Technique Based Sustained Release tablet of Trimetazidine Dihydachloride. Drug Invention Today.2013;5: 302-310.

6. Patil SP, Gujrathi NA, Rane BR. Liquisolid Compact A Review. Pharma Science Monitor. 2014; 5(2):59-68.

7. Al-sarraf MA, Hussein AA, Jabbar AA. Dissolution Enhancement of Telmisartan by Liquisolid Compacts. Int J Pharm Pharm Sci.2014; 6(2):743-749.

8. Ahmed s. Abdul jabbar, Ahmed a. Hussein. Formulation and Evaluation of Piroxicam Liquisolid Compacts. Int J Pharm Pharm Sci.2013; 5(1):132-141.

9. Khan A, Iqbal Z, ShahY, Ahmad L, Ismail, Zia Ullah, Aman Ullah. Enhancement of dissolution rate of class II drugs (Hydrochlorothiazide); a comparative study of the two novel approaches; solid dispersion and liqui-solid techniques. Saudi Pharmaceutical Journal. 2015; 23: 650-657.

10. Kala NP, Shaikh MT, Shastri DH, Shelat PK. A Review on Liquisolid Systems. JDDT. 2014; 4(3): 25-31

11. Gavhane KS, Dr.Sayyad FJ. Liquisolid Compact A Review. IJPBR. 2013; 4 (2) :26-31.

12. Shinkar DM, Khatik AS, Saudagar RB. Liquisolid Technology:A Review. AJPSci .2016; 6(3):161-166.

13. Kumar P, Venugopalaiah P, Kumar P, Gnanaprakash K, Gobinath M. Liquisolid Systems - An Emerging Strategy For Solubilization and Dissolution Rate Enhancement of Bcs Class-II Drugs. IJPSRR. 2013; 3 (2):56-66.

14. Javadzadeh Y, Musaalrezaei L, Nokhodchi A. Liquisolid technique as a New Approach to Sustain Propranolol Hydrochloride Release Form Tablet Matrices. Int J Pharm. 2008; 362: 102-108.

15. Gavali SM, Pacharane SS, Sankpal SV, Jadhav KR, Kadam VJ. Liquisolid Compact: A New Technique for Enhancement of Drug Dissolution. IJRPC.2011; 1(3): 705-713.

16. Yadav VB, Yadav AV. Improvement of Solubility and Dissolution of Indomethacin by Liquisolid and Compaction Granulation Technique. J Pharm Sci. 2009; 1(2):44-51.

17. Yadav VB. Enhancement of Solubility and Dissolution Rate of BCS class II Pharmaceuticals by Nonaquious Granulation Technique. Int J Phar Res. 2010; 12(1).

18. Fahmy RH, Kassem MA. Enhancement of famotidine dissolution rate through liquisolid tablets formulation: In vitro and In vivo evaluation. Eur J Pharm Biopham. 2008; 69: 993-1003

19. Sayyad FJ, Tulsankar SL, Kolap UB. Design and development of liquisolid compact of candesartan cilexetil to enhance dissolution. Journal of Pharmacy Research. 2013; 7: 381-388.

20. Walunj D, Sharma Y, Rawat S, Bhise K. Formulation Development and Evaluation of Tamoxifen Citrate Liquisolid System. Int J Pharm Bio Sci. 2012; 3(4):591-603.

21. Rajesh K, Rajalakshmi R, Umamaheswari J, Ashok Kumar CK. Liquisolid Technique A Novel Approach to Enhance Solubility and Bioavailability. IJB. 2011; 2(1): 8-13.

22. Chella N, Narra N, Tadikonda RR. Preparation and Characterization of Liquisolid Compacts for Improved Dissolution of Telmisartan. Journal of Drug Delivery. 2014; 1-10.

23. Pardhi DM, Shivhare UD, Mathur VB, Bhusari KP. Liquisolid Technique for Enhancement of Dissolution Properties of Carvedilol. Der Pharmacia Lettre. 2010; 2(5):412-427.

24. Yala P, Srinivasan, Mahalingan, Alladi S, Zalaki S. Solubility enhancement of a model etoricoxib drug using Liquisolid compacts. IJBPR. 2012; 3(4): 577-585

25. Shinkar DM, Aher SB, Saudagar RB. Design and Development of Liquisolid Compact of Carvedilol. Res. J. Pharm. Dosage Form and Tech. 2015; 7(4): 243-255.

26. Prajapati ST, Bulchandani HH, Patel DM, Dumaniya SK, Pate CN. Formulation and Evaluation of Liquisolid Compacts for Olmesartan Medoxomil. Journal of Drug Delivery. 2013;1-9.

27. Ramesh J, Kumar BV, Reddy YN. Formulation and Evaluation of Olanzapine Liquisolid Compact Tablets. IJPT. 2016; 8(2): 11780-11789.

28. Baladaniya MK, Karkar AP, Kambodi JR. Enhancement of Dissolution Properties of Glibenclamide by using Liquisolid Compact Technique. Res. J. Pharm. Dosage Form. and Tech. 2015; 7(3): 199-211.

29. Burra S, Yamsani M, Vobalaboina V. The Liquisolid technique: an overview. BJPS. 2011; 47(3):475-482.

30. Deshmukh AS, Mahale VG, Mahajan VR. Liquisolid Compact Techniques: A Review. Res. J. Pharm. Dosage Form and Tech. 2014; 6(3): 161-166.

Received on 22.02.2018 Modified on 18.04.2018

Res. J. Pharma. Dosage Forms and Tech.2018; 10(3):188-192.

DOI: 10.5958/0975-4377.2018.00029.0