INTRODUCTION:

Liquisolid technique is a novel and promising method that can change the dissolution rate of drugs. It has been used to improve dissolution rate of poorly water-soluble drugs. For poorly soluble (Class II) drugs and class (Class IV) the rate of oral absorption is often controlled by the dissolution rate in the gastrointestinal tract. The novel ‘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. Since, the liquisolid tablets contain a solution of the drug in suitable solvent; the drug surface available for dissolution is extremely increased. ^[1]During the past few years many techniques have been developed such as drug micronization,Solid dispersions, co-precipitation, lyophilization, micro– encapsulation, use of pro-drug andDrug derivatization processes, and inclusion of drug solutions into soft gelatine capsules.^[2]Micronization is the most common method used to increase the surface area of the drug, but this becomes less effective when they are formulated as tablets or encapsulations.^[3,4,5] The concept of powdered solutions makes it possible to convert drug solutions or liquid medications into moderately flowing powders by an admixture with selected powder Excipient.

Some investigators have used a similar approach to increase release profiles of several water–insoluble drugs.^[6]To increase dissolution rates of drugs, salt formation, particle size reduction etc., have commonly been used but achieving desired bioavailability enhancement may not always be possible due to some practical limitationswith these techniques^[7]Solid dispersion systems have shown promising results in increasing bioavailability of poorly water-soluble drugs in which the drug is dispersed in solid water-soluble matrices either molecularly or as fine particles.^[8,9,10]Among them, liquisolid compacts is one of the most promising and new technique which promotes dissolution rate of water insoluble drugs.The term liquisolid compact refers to immediate release or sustained release tablets or capsules, combined with the inclusion of appropriate adjuvant required for tabletting or encapsulating.^[11]

CLASSIFICATION:

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

· Powdered drug solutions

· Powdered drug suspensions

· 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, valproic acid, liquid vitamins, etc.), into liquisolid systems.

Based on the formulation technique used, liquisolid systems may be classified into two categories, namely,

a) Liquisolid compacts

b) 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 to produce an acceptably flowing admixture for encapsulations. ^[12]

PRINCIPLE OF LIQUISOLID COMPACTS:

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 (Fig. 1).

Fig 1: Schematic representation of liquisolid systems [13]

ADVANTAGES [14]:

1) Improvement of bioavailability of an orally administered water insoluble drugs is achieved.

2) In this technique, production cost is low compared to soft gelatine capsules.

3) Drug is formulated in a tablet form or encapsulated dosage form and is held in solubilized liquid state, which confers developed or improved drug wetting properties thereby improving drug dissolution profiles.

4) Greater drug surface area is exposed to the dissolution medium.

5) This liquisolid system is specifically for powdered liquid medications.

6) These liquisolid systems formulate into immediate release or sustained release dosage forms.

LIMITATIONS:

· 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 to more than one gram 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 resulting in tablets of unsatisfactory hardness.[15]

· 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.

· Hydrotropy is suggested to be superior to other solubilization method, such as miscibility, micellarsolubilization, co solvency and salting in, because the solvent character is independent of pH, has high selectivity and does not require emulsification.

· It only requires mixing the drug with the hydrotrope in water.

· It does not require chemical modification of hydrophobic drugs, use of organic

· Solvents or preparation of emulsion system.

APPLICATION:

· Liquisolid compact technology is a powerful tool to improve bioavailability of water insoluble drugs. Several water insoluble drugs on dissolving in different non-volatile solvents have been formulated into liquisolid compacts.

· Literature cites different drugs successfully incorporated into liquisolid compacts.

· Rapid release rates are obtained in liquisolid formulations.

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

· Sustained Release of drugs which are water soluble drugs such as propranolol hydrochloride has been obtained by the use of this technique.[16]

Components of Liquisolid:

1) Drug

2) Non volatile solvent

3) Carrier materials

4) Coating materials

5) Disintegrants

6) Lubricants

Drug:

The drug must be poorly water soluble and having biopharmaceutical classification system II and IV.

Non volatile solvent:

· Inert

· High boiling point

· Preferably water-miscible

· Less viscous organic solvent systems

e.g., propylene glycol, liquid polyethylene glycols, polysorbates, glycerine, N,N-dimethyl acetamide, fixed oils, PEG 600 and 400, Tween80 and 20, Span80 and 20, Glycerin,[25]

Carrier material:

· Materials with porous surface

· Closely matted fibers in their interior

· Sufficient absorption properties

e.g. Microcrystalline and amorphous cellulose, Starch, Lactose, MCC (Avicel PH 102), DCP dibasic calcium phosphate, Eudragit RL and RS.

Coating materials:

Fine and highly adsorptive particles Contributes in covering the wet carrier particles and displaying a dry-looking powder Particle size range of about 10 nm to 5,000 nm in diameter. Amorphous silicon dioxide (silica 2), HPMC, silica (Cab-O-Sil M5), Syloid etc.

Disintegrants:

Sodium starch glycolate, cross carmelosesodium, cross povidine, explotab, Pregelatinized Starch etc.

Basic theoretical aspect to formulate Liquisolid Compact:

These studies are related to the flow and compression of formulation. The mathematical modelof liquisolid systems, which is based on the flowable (Ф – value) and compressible (Ψ– number) liquid retention potentials of the constituent powders. According to the theories, the carrier and coating powder materials can retain only certain amounts of liquid while maintaining acceptable flow and compression properties.

Depending on the Excipient ratio (R) of the powder substrate,

Where:

R = Q/q (1)

Which is the fraction of the weights of the carrier (Q) and coating (q) materials present in theFormulation, an acceptably flowing and compressible liquisolid system can be prepared only if a maximum liquid load on the carrier material is not exceeded. Such a characteristic amount of liquid is termed the liquid load factor (Lf) and defined as the weight ratio of the liquid medication (W) and carrier powder (Q) in the system, i.e. :

Lf = W/Q (2)

It should be emphasized that the terms ‘acceptably flowing’ and ‘acceptably compressible’ imply preselected and desirable levels of flow and compaction which must be possessed by the final liquid: powder admixtures. Essentially, the acceptable flow and compaction characteristics of liquisolid systems are ensured and, in a way, built in during their manufacturing process via the(Ф – value) and (Ψ – number) concepts, respectively. These are introduced for fundamentalproperties of powders and are referred to as their flowable and compressible liquid-retention potentials, respectively [17]. The Ψ number of powders may be determined using a new method termed the liquisolid compressibility (LSC) test or ‘pactisityis testing’, which employs the recently proposed ‘pactisity theories’ to evaluate the compaction properties of the liquid: powder admixtures. Accordingly, the pactisity (Ω) or maximum crushing strength of the liquisolid compacts consisting of certain liquid and powder is inversely proportional to the liquid: solid weight ratio (Cw) of the preparations. The desired compression properties of the finished liquisolid systems may be adjusted during pactisity testing according to the requirements of the individual target product and are, in essence, built in the magnitude of the determined numbers of the carrier (Ψ) and coating powders (Ψ).The maximum amount of liquid loads on the carrier material, termed ‘‘load factor” (Lf). The coating/carrier ratio (R) is important for determining the ‘‘optimum flowable load factor” (Lf) which gives acceptable flowing powders and is characterized by the ratio between (W) and (Q), as shown in Eqs.1and 2.

Lf = Ф CA + Ф CO (1/R) (3)

Where, Ф CA is the flowable liquid-retention potential of the carrier and Ф CO is the flowable liquid-retention potential of the coating material. The appropriate amounts of carrier and coating materials to produce acceptable flowing and compactible powders are calculated using Eqs. (1) And (3), based on the physical properties of powders termed ‘‘flowable liquid-retention potential” (Ф – value). The ratio (R) of the amount of carrier (Q) and coating (q) materials is closely related to the amount of liquid medication (W). ^[18]

LIQUISOLID FORMULATIONS FOR ENHANCED DRUG RELEASE:

Several mechanisms of improved drug release have been postulated for liquisolid systems. The three main suggested mechanisms include an increased surface area of drug available for release, an improved aqueous solubility of the drug, and an improved wettability of the drug particles. Formation of a complex between the drug and Excipient or any changes in crystallinity of the drug could be lined out using DSC and XRPD measurements. ^[19]

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. ^[20]

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. ^[20]

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. Wettability of these systems has been demonstrated by measurement of contact angles and water rising times. ^[21]

Fig. 2: Comparison of wettability between Conventional tablet and liquisolid compacts.[21]

These include solubility determination of drug in different non-volatile solvents, determination of angle of slide, determination of Ø-values, calculation of liquid load factor (Lf), etc.

Solubility studies:

These are carried by preparing saturated solutions of drug in non-volatile solvents and analyzing them spectophotometrically. Saturated solutions are prepared by adding excess of drug to vehicles and shaking them on shaker for specific time period under constant vibration. After this, the solutions are filtered and analyzed spectrophotometrically.

Determination of angle of slide:

Required amount of carrier is weighed and placed at one end of a metal plate with a polished surface. The end is gradually raised till the plate becomes angular to the horizontal at which powder is about to slide. This angle is known as angle of slide. It was used as a measure of the flow properties of powders. Angle of 33o is regarded as optimum.^[21]

Determination of flowable liquid retention potential (Ø- value) ^[22]

Increasing amounts of liquid paraffin is added to a powdered material and mixed well. The powder absorbs or adsorbs only the liquid paraffin giving a change in flow properties. At each concentration of the liquid paraffin added, the angle of slide is redetermined according to previously described procedure.

The Ø-values are calculated according to equation:

Ø- Value = weight of liquid / weight of solid (4)

Calculation of liquid load factor (Lf):

Different concentrations of non-volatile solvents are taken and the drug is dissolved. Such liquid medication is added to the carrier-coating material admixture and blended. Using equation (2), drug loading factors are determined and used for calculating the amounts of carrier and coating materials in each formulation.

PRECOMPRESSION SYUDIES:

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 freestanding cone method. The Bulk density and Tap densities were determined for the calculation of Hausner’s ratio and Carr’s Index. ^[23]

Infra red spectra analysis:

The infra red spectra of solid dispersions were recorded by the KBr method using a Fourier transform infrared spectrophotometer (FTIR-8400s). A base-line correction was made using dried potassium bromide and then the spectrum of the pure ATR, liquisolid system was obtained. ^[24]

X-ray powder diffraction:

X-ray diffractograms are obtained using a Philips Analytical XRD instrument .The scanning range is from 10–70˚ 2θ. The X-ray diffraction (XRD) patterns are determined for drug, Excipient used in formulation, physical mixture of drug and Excipient, finally for the prepared liquisolid system.^[24] Absence of constructive specific peaks of the drug in the liquisolid X-ray diffractogram indicate that drug has almost entirely converted from Crystalline to amorphous or solubilized form. Such lack of crystallinity in the liquisolidsystem was understood to be as a result of drug solubilizationin the liquid vehicle i.e., the drug has formed a solid solution within the carrier matrix. This amorphization or solubilization of drug in the liquisolid system may contribute to the consequent improvement in the apparent solubility and therefore the dissolution rate of the drug.^[25]

Differential scanning calorimetry (DSC):

Thermo tropic properties and thermal behaviour of the samples (API, Excipient, and liquisolidCompacts) were recorded on a DSC. Samples (3-5 mg) were placed in aluminium pans and lids at constant heating of 15°C/min spanning a temperature range up to 30-300°C. Nitrogen was used as a purge gas through the DSC cell. Complete disappearance of characteristic peaks of drug indicates the formation of drug solution in the liquisolid powdered system, i.e., the drug is molecularly dispersed within the liquisolid matrix.^[26]

Scanning Electron Microscopy (SEM):

SEM study show complete disappearance of crystals of drug and confirms that drug is totally Solubilized in liquisolid system.^[26]

POST COMPRESSION STUDIES OF LIQUI-SOLID COMPACTS[27]

Weight Variation:

Twenty tablets were randomly selected from each batch and individually weighed. The average weight and standard deviation three batches were calculated. It passes the test for weight variation test if not more than two of the individual tablet weights deviate from the average weight by more than the allowed percentage deviation and none deviate by more than twice the percentage shown. It was calculated on an electronic weighing balance.

Thickness:

The thickness of liquisolid tablets was determined by using Digital micrometer. Ten individual tablets from each batch were used and the results averaged.

Hardness:

The hardness of the tablets was determined by using Monsanto hardness tester. Five individual tablets from each batch were and results averaged.

Friability:

The friability values of the tablets were determined using a Roche-type friabilator. Accurately weighed six tablets were placed in Roche friabilator and rotated at 25 rpm for 4 min. Percentage friability was calculated using the following equation.

Friability = ([WO – W] /WO) 100

Where,

WO = Weight of the tablet at time zero before revolution.

W = Weight of the tablet after 100 revolutions.

Disintegration Test:

Six tablets were taken randomly from each batch and placed in USP disintegration apparatus baskets Apparatus was run for 10 minutes and the basket was lift from the fluid, observe whether all of the tablets have disintegrated.

In-vitro Release:

Drug release from liqui-solid tablets was determined by using dissolution test United States Pharmacopoeia (USP) 24 type II (paddle). 5ml aliquots of dissolution media were withdrawn each time at suitable time intervals (5, 10, 15, 20, 25, 30, 45 and 60 minutes.) and replaced with fresh medium. After withdrawing, samples were filtered and analyzed after appropriate dilution by appropriate analytical method. The concentration was calculated using standard calibration curve.

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Received on 13.04.2013 Modified on 30.04.2013

Research J. Pharm. and Tech. 6(8): August 2013; Page 819-824