INTRODUCTION:

With the recent advent of high throughput, screening and combinatorial chemistry, properties of many chemical entities shifted towards high molecular weight and increasing lipophilicity which results in decreasing aqueous solubility; and which in turn results in number of poorly soluble drug molecules and the formulation of these poorly soluble drug moieties for oral route, presents a great challenge for formulation and development^[1]. According to the new formulation method of liquisolid compacts, liquid medications such as solutions or suspensions of water insoluble drugs in suitable non-volatile liquid vehicles can be converted into acceptably flowing and compressible powders by blending with selected powder excipients. It has been speculated that such systems exhibit enhanced release profiles. In this case, even though the drug is in a solid dosage form, it is held within the powder substrate in solution or, in a solubilized, almost molecularly dispersed state, which contributes to the enhanced drug dissolution properties. Therapeutic effectiveness of a drug depends upon the bioavailability which is dependent on the solubility of drug molecules.

Solubility is one of the important parameter to achieve desired concentration of drug in systemic circulation for pharmacological response^[2].Nowadays, the synthesis of poorly soluble drugs increasing steadily. Therapeutic effectiveness of a drug depends upon the bioavailability which is dependent on the solubility and dissolution rate of drug molecules. Solubility is one of the important parameter to achieve desired concentration of drug in systemic circulation for pharmacological response to be shown. The drugs which are poorly water soluble will be inherently released at a slow rate owing to their limited solubility within the GI contents. The dissolution rate is often the rate determining step in the drug absorption. The challenge for these drugs is to enhance the rate of dissolution or solubility. This in turn subsequently improves absorption and bioavailability. Formulation methods targeted at dissolution enhancement of poorly soluble substances are continuously introduced^[3]. Liquisolid system refers to formulations formed by conversion of liquid drugs, drug suspension or drug solution in non-volatile solvents in to non-adherant, free flowing and compressible powder mixtures by blending the solution or suspension with selected carriers and coating materials. As large proportions of new drug candidates have poor aqueous solubility, various formulation strategies were reported to overcome such a problem. Among these techniques is complexation with cyclodextrins, micronization, solid dispersion, co-precipitation and recently, the technique of ‘liquisolid compacts’. Several studies have shown that the liquisolid technique is a promising method for promoting dissolution rate of poorly water soluble drugs^[4]. The concept of ‘‘liquisolid tablets” was evolved from ‘‘powdered solution technology” that can be used to formulate ‘‘liquid medication”. The term ‘‘liquid medication” refers to solid drugs dispersed in suitable non-volatile liquid vehicles. By simple mixing of such ‘‘liquid medication” with selected carriers and coating materials, dry-looking, non-adherent, free-flowing and readily compactible powder admixtures can be produced. Spireas and Bolton suggested that particles possess porous surface with high absorption properties may be used as the carrier material such as cellulose, starch and lactose. Increasing moisture content of carriers results in decreased powder flowability. Coating material is required to cover the surface and so maintain the powder flowability. Accordingly, coating material should be a very fine and highly adsorptive silica powders^[5]. Liquisolid compacts are acceptably flowing and compressible powdered forms of liquid medications. The term liquid medication implies oily, liquid drugs and solutions or suspensions of water-insoluble solid drugs carried in suitable nonvolatile solvent systems termed the liquid vehicles. Using this new formulation technique, a liquid medication may be converted into a dry-looking, non-adherent, free-flowing, and readily compressible powder by a simple blending with selected powder excipients referred to as the carrier and coating materials Various grades of cellulose, starch, lactose, and so on, may be used as the carriers, whereas very fine-particle-size silica powders may be used as the coating [or covering] materials. In liquisolid compacts, even though the drug is in a tabletted or encapsulated dosage form, it is held in a solubilized liquid state, which consequently contributes to increased drug wetting properties, thereby enhancing drug dissolution. Another advantage of liquisolid systems is that their production cost is lower than that of soft gelatin capsules because the production of liquisolid systems is similar to that of conventional tablets^[6].

Historical development:

Historically, liquisolid compacts are descendants of ‘powdered solutions’, an older technique which was based on the conversion of a solution of a drug in a nonvolatile solvent into a dry-looking, nonadherent powder by mainly adsorbing the liquid onto silicas of large specific surfaces. Such preparations, however, have been investigated for their dissolution profiles while being in a powder dispersion form and not as compressed entities, simply because they could not be compressed into tablets. In later studies on powdered solutions, compression enhancers such as microcrystalline cellulose were added in such dispersions in order to increase the compressibility of the systems. In these studies, however, large quantities of silicas were still being used, and the flow and compression properties of the products were never validated and standardized to industrial specifications and requirements. Specifically, when such modified powdered solutions were compressed into tablets, they presented significant ‘liquid squeezing out’ phenomena and unacceptably soft tablets, thereby hampering the industrial application of such systems. Liquisolid compacts, on the other hand, are acceptably flowing and compressible powdered forms of liquid medications, and have industrial application. In addition, the term ‘liquid medication’ does not only imply drug solutions, as in powdered solutions, but also drug suspensions, emulsions, or liquid oily drugs. Therefore, in contrast to ‘powdered solutions’, the term ‘liquisolid compacts’ is more general and it may encompass four different formulation systems namely,

1. Powdered drug solutions

2. Powdered drug suspensions

3. Powdered drug emulsions

4. Powdered liquid drugs

Furthermore, the earlier term ‘powdered solutions’ seems to be inadequate even in describing the original systems, since it has not been proven that the drug remains in solution in the liquid vehicle after its deposition on the extremely large powder surfaces of silicas used. The new ‘liquisolid’ technique may be applied to formulate liquid medications [i.e., oily liquid drugs and solutions, suspensions or emulsions of water-insoluble solid drugs carried in nonvolatile liquid vehicles] into powders suitable for tableting or encapsulation. Simple blending of such liquid medications with calculated quantities of a powder substrate consisting of certain excipients referred to as the carrier and coating powder materials, can yield dry-looking, non-adherent, free flowing, and readily compressible powders^[2]. Spireas and Sadu, [1998] concluded that, the new technique of liquisolid compacts appears to be a promising alternative for the formulation of water insoluble drugs such as prednisolone, into rapid release tablets which may present improved oral bioavailability. As compared to conventional directly compressed tablets, the liquisolid compacts of prednisolone display significantly enhanced in-vitro release properties^[7].

Concept:

When the drug dissolved in the liquid vehicle is incorporated into a carrier material which has a porous surface and closely matted fibers in its interior as cellulose, both absorption and adsorption take place; i.e., the liquid initially absorbed in the interior of the particles is captured by its internal structure, and after the saturation of this process, adsorption of the liquid onto the internal and external surfaces of the porous carrier particles occur. Then, the coating material having high adsorptive properties and large specific surface area gives the liquisolid system the desirable flow characteristics^[8]. In liquisolid systems the drug is already in solution in liquid vehicle, while at the same time, it is carried by the powder particles [microcrystalline cellulose and silica]. Thus, due to significantly increased wetting properties and surface area of drug available for dissolution, liquisolid compacts of water-insoluble substances may be expected to display enhanced drug release characteristics and consequently, improved oral bioavailability. Since dissolution of a non-polar drug is often the rate limiting step in gastrointestinal absorption, better bioavailability of an orally administered water-insoluble drug is achieved when the drug is already in solution, thereby displaying enhanced dissolution rates. That is why soft gelatin elastic capsules containing solutions of such medications demonstrate higher bioavailability when compared to conventional oral solid dosage forms. A similar principle underlies the mechanism of drug delivery from liquisolid compacts and is chiefly responsible for the improved dissolution profiles exhibited by these preparations. The wettability of the compacts by the dissolution media is one of the proposed mechanisms for explaining the enhanced dissolution rate from the liquisolid compacts. Nonvolatile solvent present in the liquisolid system facilitates wetting of drug particles by decreasing interfacial tension between dissolution medium and tablet surface^{[9, 10]}. Figure 1 shows lower contact angle of liquisolid compacts than the conventional tablets and thus improved wettability.

Fig. 1: Comparison of wettability between conventional tablet and liquisolid compacts.

Mechanisms of enhanced drug release from liquisolid systems:

Several mechanisms of enhanced drug release have been postulated for liquisolid systems. The three main suggested mechanisms include an increased surface area of drug available for release, an increased aqueous solubility of the drug, and an improved wettability of the drug particles. Formation of a complex between the drug and excipients or any changes in crystallinity of the drug could be ruled out using DSC and XRPD measurements.

a) Increased drug surface area If the drug within the liquisolid system is completely dissolved in the liquid vehicle it is located in the powder substrate still in a solubilized, molecularly dispersed state. Therefore, the surface area of drug available for release is much greater than that of drug particles within directly compressed tablets^[11].

b) Increased aqueous solubility of the drug In addition to the first mechanism of drug release enhancement it is expected that Cs, the solubility of the drug, might be increased with liquisolid systems. In fact, the relatively small amount of liquid vehicle in a liquisolid compact is not sufficient to increase the overall solubility of the drug in the aqueous dissolution medium. However, at the solid/liquid interface between an individual liquisolid primary particle and the release medium it is possible that in this microenvironment the amount of liquid vehicle diffusing out of a single liquisolid particle together with the drug molecules might be sufficient to increase the aqueous solubility of the drug if the liquid vehicle acts as a cosolvent^[12].

c) Improved wetting properties Due to the fact that the liquid vehicle can either act as surface active agent or has a low surface tension, wetting of the liquisolid primary particles is improved [fig 1]. Wettability of these systems has been demonstrated by measurement of contact angles and water rising times^[12].

Components:

The major formulation components of liquisolid compacts are:

Carrier material

These are compression-enhancing, relatively large, preferably porous particles possessing a sufficient absorption property which contributes in liquid absorption. E.g. various grades of cellulose, starch^[9], lactose^[9], sorbitol^[10] etc.

Coating material

These are flow-enhancing, very fine [10 nm to 5,000 nm in diameter], highly adsorptive coating particles [e.g., silica of various grades like Cab-O-Sil M5, Aerosil 200, Syloid

244FP etc.] contributes in covering the wet carrier particles and displaying a dry-looking powder by adsorbing any excess liquid^[13-15].

Non-volatile solvents

Inert, high boiling point, preferably water-miscible and not highly viscous organic solvent systems e.g., propylene glycol, liquid polyethylene glycols, polysorbates, glycerin, N, N-dimethylacetamide, fixed oils, etc. are most suitable as vehicles.

Disintegrants

Most commonly used disintegrant is sodium starch glycolate [Explotab13, Pumogel, etc.]

Classification of liquisolid systems:

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 [e.g. clofibrate, liquid vitamins, etc.], into liquisolid systems. Since non-volatile solvents are used to prepare the drug solution or suspension, the liquid vehicle does not evaporate and thus, the drug is carried within the liquid system which in turn is dispersed throughout the final product.

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

1. Liquisolid compacts

2. Liquisolid microsystems.

Liquisolid compacts are prepared using the previously outlined method to produce tablets or capsules, whereas the liquisolid microsystems are based on a new concept which employs similar methodology combined with the inclusion of an additive, e.g., Polyvinylpyrrolidone [PVP], in the liquid medication which is incorporated into the carrier and coating materials to produce an acceptably flowing admixture for encapsulation. The advantage stemming from this new technique is that the resulting unit size of liquisolid microsystems may be as much as five times less than that of liquisolid compacts^[2,13-15].

General method of preparation:

As shown in figure 2, a liquid lipophilic drug [e.g., chlorpheniramine, clofibrate, etc.] can be converted into a liquisolid system without being further modified. On the other hand, if a solid water-insoluble drug [e.g., hydrochlorothiazide, prednisone, etc.] is formulated, it should be initially dissolved or suspended in a suitable non-volatile solvent system to produce a drug solution or drug suspension of desired concentration. Next, a certain amount of the prepared drug solution or suspension, or the liquid drug itself, is incorporated into a specific quantity of carrier material which should be preferably of a porous nature and possessing sufficient absorption properties, such as powder and granular grades of microcrystalline and amorphous cellulose are most preferred as carriers. The resulting wet mixture is then converted into a dry-looking, non adherent, free-flowing and readily compressible powder by the simple addition and mixing of a calculated amount of coating material. Excipients possessing fine and highly adsorptive particles, such as various types of amorphous silicon dioxide [silica], are most suitable for this step. Before compression or encapsulation, various adjuvants such as lubricants and disintegrants [immediate] or binders [sustained-release] may be mixed with the finished liquisolid systems to produce liquisolid compacts i.e. tablets or capsules^[2].

Determination of solubility:

Saturated solutions were prepared by adding excess drug to the polyethylene glycol and shaking on a shaker for 48 h at 25°C with constant vibration. The solutions were filtered through a 0.45 micron filter, diluted with water, and analyzed with a UV-Vis spectrophotometer at wavelength relates to that of the drug used with respect to a blank sample [the blank sample was a solution containing the same concentration used without the drug]. Determination was carried out in triplicate for each sample to calculate the solubility of drug.

Preparation of liquisolid compacts:

Calculated quantities of drug and polyethylene glycol were accurately weighed in a 20-mL glass beaker and then mixed well. The resulting medication was incorporated into calculated quantities of carrier and coating materials. The mixing process was carried out in three steps. In the first, the system was 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, the liquid/powder admixture was evenly spread as a uniform layer on the surface of a mortar and left standing for approximately 5 min to allow the drug solution to be absorbed inside powder particles. In the third, the powder was scraped off the mortar surface using an aluminum spatula. Then Carrier: Coating material [20:1] was added to this mixture and blended in a mortar. This provided the final formulation that was compressed into tablets using a 12mm single punch tablet compression machine after addition of disintegrating agent^[16].

Advantages and limitations

Advantages:

1) Several slightly and very slightly water-soluble and practically water-insoluble liquid and solid drugs, can be formulated into liquisolid systems.

2) Even though the drug is in a tablet or capsule form, it is held in a solubilised liquid state, which contributes to increased drug wetting properties, thereby enhancing drug dissolution.

3) Production cost is lower than soft gelatin capsules.

4) Rapid release liquisolid tablets or capsules of water insoluble drugs exhibit enhanced in-vitro and in-vivo drug release when compared to their commercial counter parts, including soft gelatin capsules preparation.

5) Sustained release liquisolid tablets or capsules of water insoluble drugs exhibit constant dissolution rates [zero-order release] comparable only to expensive commercial preparations that combine osmotic pump technology and laser-drilled tablets.

6) Can be applied to formulate liquid medications such as oily liquid drugs.

7) Simplicity.

8) Better availability of an orally administered water insoluble drug.

9) Lower production cost than that of soft gelatin capsules.

10) Production of liquisolid systems is similar to that of conventional tablets.

11) Viability of industrial production^[2,17-18].

Limitations:

1) Not applicable for formulation of high dose insoluble drugs.

2) If more amount of carrier is added to produce free-flowing powder, the tablet weight increases to more than one gram which is difficult to swallow.

3) Acceptable compression properties may not be achieved since during compression liquid drug may be squeezed out of the liquisolid tablet resulting in tablets of unsatisfactory hardness.

4) Introduction of this method on industrial scale and to overcome the problems of mixing small quantities of viscous liquid solutions onto large amounts of carrier material may not be feasible^[17].

Evaluation

Evaluation of liquisolid granules:

Flow behavior

The flowability of a powder is of critical importance in the production of pharmaceutical dosage forms in order to reduce high dose variations^[19]. Angle of repose, Carr’s index and Hausner’s ratio were used in order to ensure the flow properties of the liquisolid systems.

Angle of Repose^[20]

This is the maximum angle possible between the surface of a pile of powder and the horizontal plane.10 gm of powder was allowed to flow by funnel from 4 cm of height from the base. The height of pile and diameter of base was measured and calculate the angle of repose by following formula

tan θ = h/r

θ = tan^-1 h/r

Where, = angle of repose,

h = Height of the heap,

r = Radius of the heap.

Bulk Density^[20]

An accurately weighed quantity of powder, which was previously passed through sieve # 40 [USP] and carefully poured into graduated cylinder. Then after pouring the powder into the graduated cylinder the powder bed was made uniform without disturbing. Then the volume was measured directly from the graduation marks on the cylinder as ml. The volume measured was called as the bulk volume and the bulk density is calculated by following formula;

Bulk density = Weight of powder / Bulk volume

Tapped Density^[20]

After measuring the bulk volume the same measuring cylinder was set into tap density apparatus. The tap density apparatus was set to 300 taps drop per minute and operated for 500 taps. Volume was noted as [Va] and again tapped for 750 times and volume was noted as [Vb]. If the difference between Va and Vb not greater than 2% then Vb is consider as final tapped volume. The tapped density is calculated by the following formula

Tapped density = Weight of powder / Tapped Volume.

Carr’s Index [Compressibility Index]^[21]

It is one of the most important parameter to characteristic the nature of powders and granules. It can be calculated from the following equation-

Carr’s index = Tapped density - Bulk density / Tapped density X 100

Hausner’s Ratio^[22]

Hausner’s ratio is an important character to determine the flow property of powder and granules. This can be calculated by the following formula-

Hausner’s ratio = Tapped density / Bulk density

Evaluation of Liquisolid Tablets:^{[4, 22]}

Weight variation

Weight variation was measured by weighing 20 Tablets and average weight was found and percentage weight variation of the individual tablet should fall within specified limits in terms of percentage deviation from the mean.

Thickness

Thickness of tablet was measured by vernier caliper.

Hardness

It is a measure of the mechanical strength of a tablet using hardness tester [Monsanto hardness tester]. The mechanical strength of a tablet is associated with the resistance of a tablet to fracture or attrition.

Friability

It was determined using Roche friabilator, the percentage loss in tablet weight before and after 100 revolutions of 3 tablets were calculated and taken as a measure for friability.

Disintegration time

The time necessary to disintegrate 3 tablets of each tablet formulation was determined using disintegration tester.

In vitro dissolution studies

It is carried out as given in particular monograph of the drugs tablet formulation.

REFERENCES:

1) Mahajan HS, Dhamne MR, Gattani SG, Rasal AD, Shaikh HT. Enhanced dissolution rate of Glipezide by a liquisolid technique. International Journal of Pharmaceutical Sciences and Nanotechnology.3; 2011: 1205-1213.

2) Kulkarni AS, Aloorkar NH, Mane MS, Gaja JB. Liquisolid Systems: A Review. International Journal of Pharmaceutical Sciences and Nanotechnology.3; 2010: 795-802.

3) Nagabandi VK, Ramarao T, Jayaveera KN. LIQUISOLID Compacts: A Novel Approach to Enhance Bioavailability of Poorly Soluble Drugs. International Journal of Pharmacy and Biological Sciences.1; 2011: 89-102.

4) Chuahan PV, Patel HK, Patel BA, Patel KN, Patel PA. Liquisolid Technique for Enhancement of Dissolution Rate of Ibuprofen. International Journal for Pharmaceutical Research Scholars.1; 2012: 268-280.

5) Ngiik T, Elkordy A. Effects of liquisolid formulations on dissolution of naproxen. European Journal of Pharmaceutics and Biopharmaceutics. European Journal of Pharmaceutics and Biopharmaceutics.73; 2009: 373–384.

6) Kulkarni AS Gaja JB. Formulation and Evaluation of Liquisolid Compacts of Diclofenac Sodium. PDA Journal of Pharmaceutical Science and Technology. 64; 2010: 222-232.

7) El-Say KM, Samy AM, Fetouh MI. Formulation and Evaluation of Rofecoxib Liquisolid Tablets. International Journal of Pharmaceutical Sciences Review and Research. 3; 2010: 135-142.

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

9) Javadzadeh Y, Navimipour B, Nokhodchi A. Liquisolid technique for dissolution rate enhancement of a high dose water insoluble drug [carbamazepine], Int. J. Pharm.341; 2007: 26-34.

10) Javadzadeh Y, Siahi MR, Asnaashri S, et al., An investigation of physicochemical properties of piroxicam liquisolid compacts, Pharm. Dev. Tech.12; 2007: 337-34.

11) Spireas S, Sadu S. Enhancement of prednisolone dissolution properties using liquisolid compacts.Int. J. Pharm.166; 1998: 177-188.

12) Yadav, V.B., Nighute, A.B., Yadav, A.V., Bhise, S.B. Aceclofenac size enlargement by non aqueous granulation with improved solubility and dissolution. Arch. Pharm. Sci. & Res.12009: 115-122.

13) Spiras S. Liquisolid systems and methods for preparing same, United States patent.6;2002:423,339 B1.

14) Spiras S, Bolton SM. Liquisolid systems and methods for preparing same, United States patent. 6; 2000:096,337.

15) Spiras S, Wang T, Grover R. Effect of powder substrate on dissolution properties of methylclothiazide Liquisolid compacts, Drug. Dev. Ind. Pharm. 25; 1999: 63-168.

16) Gavali SM, Pacharane SS, Sankpal SV, Jadhav KR, Kadam VJ. Liquisolid Compact: A New Technique for Enhancement of Drug Dissolution. International Journal Of Research In Pharmacy And Chemistry. 1; 2011: 705-713.

17) Sambasiva RA, Naga AT. Liquisolid Technology: An Overview. International Journal of Research in Pharmaceutical and Biomedical Sciences. 2; 2011: 401-409.

18) Aulton ME. Pharmaceutics, The science of Dosage form Design. 2nd ed. Churchill Livingstone, New York; 2002.

19) Staniforth J., Powder flow, In: M. Aulton, Pharmaceutics: the Science of Dosage Form Design, Edinburgh, 2002, p. 197–210.

20) Subhramanyam CVS., Textbook of Physical Pharmaceutics; 2nd edition; Vallabh Prakashan. New Delhi; 2001.

21) Vajir S. Enhancement of dissolution rate of poorly water Soluble diclofenac sodium by liquisolid technique. International journal of pharmaceutical and chemical sciences. 1;2012: 989-1000.

22) Patric JS. Martin’s Physical Pharmacy and Pharmaceutical Sciencs. 5^th ed. Lippincott Williams and Wilkins; 2003.

Received on 10.04.2014 Modified on 12.05.2014

Res. J. Pharm. Dosage Form. and Tech. 6(3):July- Sept. 2014; Page 161-166