Several methods such as salt formation, solubilization, co solvency, complexation, solid dispersion and particle size reduction have been introduced to increase dissolution rate and thereby oral absorption and bioavailability of such drugs. There are some practical limitations of the above mentioned techniques. To overcome some of the problems of above mentioned techniques a new technique called “Liquisolid Technique” has been introduced which consist of dissolving of water insoluble drug in non volatile solvent prior to compression which is well converted in free flowing powder by using suitable coating and carrier material which is free flowing, non adhering, dry and readily compressible powder which can be readily compressed with the help of different compressible carriers like (Starch, cellulose and lactose etc.) and else coating materials like (Colloidal silica and Talc etc.).

Because of drug present in the liquid medicament as solubilized or molecularly dispersed state, as the dissolution is enhanced due to increased surface area as well as wetting area. Their by the Liquisolid technique is applied for water insoluble drugs to enhance dissolution rate may also increase bioavailability.

The structure of the plaque biofilm might restrict the penetration of antimicrobial agents, while bacteria growing on a surface grow slowly and display a novel phenotype, one consequence of which is a reduced sensitivity to inhibitors^{[8,
12, 14]}. Plaque is natural and contributes (like the resident microflora of all other sites in the body) to the normal development of the physiology and defenses of the host ^{[9, 10, 11]}.

LIQUISOLID TECHNOLOGY^[^{3, 4]}

The concept of powdered solutions enables one to convert a liquid drug or poorly water-soluble solid drug dissolved in a suitable non-volatile solvent into a dry, non-adherent, freeflowing and readily compressible powder by its simple admixture with selected carrier and coating materials. Inspite of formulating the drug in a tableted or a encapsulated dosage form, it is held in solution thus enhancing its release.

Definitions:

Liquid medication includes liquid lipophilic drugs and drug suspensions or solutions of solid water insoluble drugs in suitable non-volatile solvent systems.

Liquisolid systems refers to powdered forms of liquid medications formulated by converting liquid lipophilic drugs, or drug suspensions or solutions of water insoluble solid drugs in suitable nonvolatile solvent systems, into dry, non-adherent, free-flowing and readily compressible powder admixtures by blending with selected carrier and coating materials.

Carrier material refers to a preferably porous material possessing sufficient absorption properties, such as microcrystalline and amorphous cellulose, which contributes in liquid absorption.

Coating material refers to a material possessing fine and highly adsorptive particles, such as various types of silica, which contributes in covering the wet carrier particles and displaying a dry looking powder by adsorbing any excess liquid.

MATERIALS REQUIRED FOR FORMULATION^{[9, 10]}

Drugs: Which are poorly soluble or else insoluble drugs in water. Non volatile solvent: They may be hydrophilic or lipophilic in nature based on selection of type of Formulation like immediate or control release.

Some of them are

· Polyethylene glycol,

· Propylene glycol,

· Tween 80, 20,

· Span 80, 20,

· Liquid Paraffin,

· Cremophore L etc.,

Carrier material: They are preferred to be coarser granular for acceptable flow, Methyl cellulose, Ethyl cellulose, Starch etc (Avicel PH 102, Avivel PH 200, Starch 1500, Ethocel)

Coating material: Nano meter sized silica mostly preferred, like Aerosil, talc.

Disintegrants: Mostly Super Disintegrates like Sodium starch glycolate and crosspovidone. Etc.,

PREPARATION OF LIQUISOLID COMPACTS^[1,3,4]

The technology involved in preparation of liquisolid compacts is simple but novel. Drug is dissolved in non-volatile solvent to form a solution or a suspension. Inert, preferably water-miscible organic solvent systems with high boiling point such as propylene glycol, liquid polyethylene glycols, or glycerine are best suitable as liquid vehicles. The wet particles so formed are converted into dry particles by the addition of coating material. With the liquisolid technology, a liquid may be transformed into a free flowing, readily compressible and apparently dry powder by simple physical blending with selected excipients named the carrier and coating material. The liquid portion, which can be a liquid drug, a drug suspension or a drug solution in suitable non-volatile liquid vehicles, is incorporated into the porous carrier material. The liquisolid systems are made into compacts by the addition of other tablet excipients like disintegrants as shown in Fig 1.

Theoretical considerations in powdered solution formulations:

Determination of optimum amount of carrier and coating material to ensure proper flowabillity and other formulation properties is a daunting task. Mathematical expressions for the calculation of amount of excipients needed for powdered solution formulation was proposed by Liao. The various terms used in deriving various mathematical expressions are as described as in Table 1.

Table 1. Mathematical expressions and their terms.

SYMBOL	DEFINITIONS
W_Liquid	Weight of liquid medication
W_Solid	Weight of carrier and coating material
Q	Weight of carrier powder material
R	Powder excipients ratio
L_f	Liquid loading factor
Φ	Flowable liquid retention potential of the carrier powder
V	Total volume of liquid
V_Φ	Total volume of liquid absorbed into carrier material
Ρ	Density of liquid
V φ	Total volume of liquid adsorbed into coating material

Flowable liquid-retention potential (Φ value) of a powder:

Absorption of a liquid by a powder material occurs when the absorbate molecules diffuse inside the absorbent and are eventually captured and held by the powder particles within their bulk. In some cases, the liquid is not truly absorbed, and instead of being dispersed throughout the interior of the solid, the liquid molecules only cling to its available surface i.e., internal and external. This process is known as adsorption. Sometimes, however, depending on the sorbent properties, both of these processes may occur simultaneously. The combined process is termed sorption. For instance, if a liquid is incorporated into a material which has a porous surface and closely matted fibers in its interior, e.g., cellulose, both absorption and adsorption takes place. The liquid is initially absorbed in the interior of the particles captured by its internal structure. After the saturation of this process, adsorption of the liquid onto the internal and external surfaces of the porous carrier particles occurs. This liquid retention capacity of the powder material can be generally referred to as the total liquid-retention potential or “holding capacity” of the sorbent. The flowable liquid-retention potential (Φ value) of a powder material describes its ability to retain a specific amount of liquid while maintaining good flow properties. The Φ value is defined as the maximum weight of liquid, (W _liquid) that can be retained per unit weight of the sorbent, (W _solid), yielding a mixture with acceptable flowabillity.

W _liquid

W _solid

As the flowable liquid-retention potential of the carrier material is approached, the liquid is held entirely in the interior of the particles. This maintains the surface of carrier material relatively dry, thus yielding powders with acceptable flow properties. When the Φ value is exceeded, the interior of particles become saturated, resulting in the formation of a liquid layer on the available surface of carrier particles.

Mechanism of powdered solutions:

Suppose a liquid drug or drug solution having a total volume V is incorporated into a carrier powder material. Depending on the holding capacity of the material, a part of the liquid, say,

VΦ is absorbed and retained in the interior of the carrier particles. This volume is dependent on the flowable liquid retention potential (Φ) of the carrier material. The remaining liquid, VL, is uniformly distributed and adsorbed onto the internal and external surfaces of the particles.

When a coating material, having a very small particle size, large specific surface, and high flowable liquid retention potential, like silica, is added to such a mixture, its fine particles will cover the wet carrier material retaining the excess liquid. This helps in maintaining acceptable flow properties. The resultant product is a dry, nonadherent, and free flowing powder mixture. T If only a specific volume (VΦ) of liquid is incorporated into the carrier material, the liquid would be absorbed in the interior of the particles without significantly wetting their surface, and consequently, the powder would be dry and free flowing. This portion of the liquid is represented by VC. It depends on the flowable liquid retention potential, Φ, and the quantity, Q, of the carrier material used. Since W_solid = Q and W_liquid = V_Φρ, where ρ is the density of the liquid incorporated into the carrier material, Eq (1) can be expressed as

Principle of sufficient coating:

For the coating to be sufficient to convert the wet surface of the carrier particles to dry surface, the volume VL of the adsorbed liquid must be retained by the coating particles while maintaining their free-flowing texture. The volume VL must be equal to a volume VΦ, of the liquid which is a quantity, q, of the coating particles can retain and yet maintain acceptable flowabillity, therefore

Eq.(1) can be rewritten as

Vφ, represents the same characteristics of the coating material as represented by VΦ, for the

carrier material in Eq.,(3). Thus it can be concluded that

Where φ is the flowable liquid retention potential of the coating material. Thus, Vφ is dependent on the flowable liquid retention potential, φ, and quantity, q, of the coating material. Substituting the values of VΦ (Eq., 3) and V φ (Eq., 5) in Eq., 4 we obtain

Above equation can be rearranged as

Excipient Ratio (R):

In some cases, however, the dosage formulation may require a specific ratio of carrier/ coating material in the final powder admixture. This ratio may be termed the excipient ratio, R, and

written

For such cases, Eqs.(6, 7, 8) can be modified to include the excipient ratio, R. Combining Eqs.(6, 9) , and considering a predetermined quantity, Q, of the carrier material, we obtain

Furthermore, solving for Q and considering a predetermined volume V of liquid, Eq.(1.10) will become

Accordingly, combining Eqs. (6, 9) and considering a predetermined quantity, q, of the coating material, one obtains

For a predetermined volume V of drug solution Eq(1.12) can be solved for q to give

Many authors were successful in applying the above developed mathematical expressions to calculate the optimum amounts of ingredients required to produce liquid/powder admixtures possessing, with acceptable flow characteristics.

Evaluation of liquisolid systems Flow behavior ^{(1-2, 12-19)}

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

Precompression studies of the prepared liquisolid powder systems

In order to ensure the suitability of the selected excipients, differential scanning calorimetry, X-ray diffraction, and scanning electron microscope studies are performed. In addition, flowabillity studies are also carried out to select the optimal formulae for compression. Prior to the compression of the formulations into tablets.

Differential scanning calorimetry (DSC)

This is prerequisite to know if any possible interaction present between the excipients and the drug used in the formulation. The characteristic peak in the DSC thermogram belongs to drug is absent that indicates that the drug is present in molecularly dispersed in this system.

X- Ray diffraction (XRD)

To get justification that the drug is in the solubilized state or converted into amorphous form because of disappearance of characteristic peaks belongs to drug and their by appearance of peaks which belongs to carrier is absorbed.

Scanning electron microscopy (SEM)

To study the morphological characteristics of the materials used and the drug–carrier systems; Scanning Electron Microscopy (SEM) is applied.

In vitro dissolution studies

Works of many researchers revealed that technique of liquisolid compacts could be a promising alternative for formulation of water-insoluble drugs. This technique of liquisolid compacts has been successfully employed to improve the in-vitro release of poorly water soluble drugs as the poorly soluble antiepileptic drug carbamazepine drug release was measured from liquisolid compacts and commercial tablets. It was observed that drug release from liquisolid compacts and that from commercial tablets is comparable. Hydrocortisone (Spireas S et al., 1998), prednisolone (Spireas S et al., 1998), Hydrochlorothiazide (Khaled et al., 2001), piroxicam (Javadzadeh Y et al., 2008; Javadzadeh Y et al., 2005; Rakshit P, 2007), Carbamazepine (Tayel et al., 2008). (Saharan et al) etc. Also several water insoluble drugs, namely, nifedipine, gemfibrozil, and ibuprofen, have exhibited higher bioavailability in rats as compared to their commercial counterparts.

In-Vitro release profiles of drug from the preferred tablets were studied using dissolution apparatus and compared with the formulated Liquisolid tablet. Drug release, % drug dissolved can be calculated of both the formulation results are estimated.

ADVANTAGES ^(1-4)

Number of water-insoluble solid drugs can be formulated into liquisolid systems.

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

· Better availability of an orally administered water insoluble drug.

· Lower production cost than that of soft gelatin capsules.

· Production of liquisolid systems is similar to that of conventional tablets.

· Can be used for formulation of liquid oily drugs.

· Exhibits enhanced in-vitro and in-vivo drug release as compared to commercial counterparts, including soft gelatin capsule preparations.

· Drug release can be modified using suitable formulation ingredients.

· Drug can be molecularly dispersed in the formulation.

· Capability of industrial production is also possible.

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

DISADVANTAGES ^(4,22)

· Not applicable for formulation of high dose insoluble drugs.

· If more amount of carrier is added to produce free-flowing powder, the tablet weight increases which is difficult to swallow.

· Acceptable compression properties may not be achieved since during compression liquid drug may be squeezed out of the liquisolid tablet.

· 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.

· Requirement of high solubility of drug in non-volatile liquid vehicles.

APPLICATIONS ^(1-4)

· These can be efficiently used for water insoluble solid drugs or liquid lipophilic drugs.

· Sustained release as well as rapid release of drugs which are water soluble drugs can be obtained by the use of this technique.

· Solubility and dissolution enhancement can be achieved.

· Designing of controlled release tablets can be done using various polymers.

REFERENCES:

1) S. Rao A, N. Arpana T, Liquisolid Technology: A Review, International Journal of Research in Pharmaceutical and Biomedical Sciences, 2(2), pp 401-409, 2011.

2) K. Santhosh Kumar, K. Suria Prabha, K. Sathish, K. Sathyanarayana , R. H. Kumar, Solubility Enhancement of A Drug By Liquisolid Technology, International Journal of Pharma and Bioscience, 1,(3), pp 01-05, 2010.

3) A. S. Kulkarni, N. H. Aloorkar, M. S. Mane, J. B. Gaja, Liquisolid Compacts: - Review, International Journal of Pharmaceutics and Biopharmaceutics, 3(1) pp 795-802, 2010.

4) V. K. Nagabandi, T. Ramarao, K. N .Jayaveera, Liquisolid Compacts: A Novel Approach to Enhance Bioavailability of Poorly Soluble Drugs, International Journal of Pharmacy and Biological Sciences,1(3), pp 89-102, 2011.

5) A. Modi, P. Tayade , Enhancement of Dissolution Profile by Solid Dispersion (Kneading) Technique. AAPS Pharm Sci Tech, 7(3): Article 68, 2006.

6) Bindu MB, Kusum B and David Banji; Novel Strategies for Poorly Water Soluble drugs, International Journal of Pharmaceutical Sciences Review and Research,4(3), pp 72-76 2010.

7) A. B. Karmarkar, I. D. Gonjari, A. H. Hosmani, P. N. Dhabale, S. B. Bhise, Liquisolid Tablets: A Novel Approach for Drug Delivery, 2, pp 45-50, 2009.

8) A. Sharma , C.P Jain, Techniques to enhance solubility of poorly soluble drugs: a review. Global Pharmaceutical Technology 2, pp 18-28 2010.

9) L. Lachman, H. A. Lieberman, J. B. Schwartz, Pharmaceutical Dosage Forms, Tablet 2, Marcel Dekker, pp 417-437.

10) D. M. Brahmankar, S. B. Jaiswal, Biopharmaceutics and Pharmacokinetics – A treatise, pp 19-20, 2002.

11) S . Spireas, C. I. Jarowski, C. I. Rohera, X Powdered Solution Technology: Principles and Mechanism. Pharm. Res., 9, pp 1351- 1358, 1992.

12) S. S. Spireas, Development of a New Theory for Powdered Solution Technology and Evaluation of Amorphous (E.G.C.) and Microcrystalline (M.C.C.) Celluloses as Carriers for Prednisolone Powdered Solutions. M.S. Thesis, St. John’s University, New York, 1988.

13) R. H. Fahmy, M. A. Kassem, Enhancement Of Famotidine Dissolution Rate Through Liquisolid Tablets Formulation: In Vitro And In Vivo Evaluation. European Journal of Pharmaceutics and Biopharmaceutics; 69, pp 993-1003. 2008.

14) K. A. Khaled, Y.A. Asiri, Y.M. El-Sayed, In vivo evaluation of hydrochlorothiazide liquisolid tablets in beagle dogs. International Journal of Pharmacy, pp 1-6, 2001.

15) P. Costa, J. M. S. Lobo. Modeling and comparison of dissolution profiles. European Journal of Pharmaceutical Sciences, 13, pp 123- 133, 2001.

16) V.A. Saharan, V. Kukkar, M. Kataria, M. Gera, M.Choudhury, Dissolution enhancement of drugs. Part I: technologies and effect of carriers. International Journal of Health and Research 2, 107-124, 2009.

17) V. A .Saharan, V. Kukkar, M. Kataria, M. Gera, P. K. Choudhury, Dissolution Enhancement of Drugs. Part II: effect of carriers. International Journal of Health and Research, 2, pp 207-223, 2009.

18) Y. Javadzadeh, M. R. Siahi, S. Asnaashri, Enhancement of dissolution rate of piroxicam using Liquisolid compacts, IL Farmaco. 60, pp 361-365, 2005.

19) S.A. Tayel, I. I. Soliman, D. Louis, Improvement of dissolution properties of carbamazepine through application of the liquisolid tablet technique. European Journal of Pharmacy and Biopharmaceutics 69, pp 342-347, 2008.

20) Y. Javadzadeh, M. R. Siahi, S. Asnaashri, An Investigation Of Physicochemical Properties of Piroxicam Liquisolid Compacts, Pharm. Dev. Tech. 12, pp 337-34, 2007.

21) Y. Javadzadeh , M. R. Siahi , M. Barzegar-Jalali, The effect of type and concentration of vehicles on the dissolution rate of a poorly soluble drug (indomethacin) from liquisolid compacts, Journal of Pharmacy and pharmaceutical Sciences, 8, pp 18- 25, 2005.

22) S. Spireas, C. I. Jarowski and B. D. Rohera, Powdered Solutionn Technology: Principles and Mechanism, Pharmaceutical Research, 9(10), pp 1351-1358,.1992.

Received on 01.04.2012

Modified on 06.05.2012

Accepted on 12.08.2012

Research Journal of Pharmaceutical Dosage Forms and Technology. 5(1): January- February, 2013, 01-06