With the recent advent of high throughput, screening and combinatorial chemistry, properties of new chemical entities shifted towards higher molecular weight and increasing lipophilicity that result in decreasing aqueous solubility^5,6, which in turn result in number of poorly water soluble drug candidates and the formulation of poorly water soluble drug moiety for oral delivery. A great number of new and, possibly, beneficial chemical entities do not reach the public merely because of their poor oral bioavailability due to inadequate dissolution. Low water solubility result in poor absorption and low bioavailability, especially on oral administratio⁷.

More than 41% of the failures in new drug development have been attributed to poor biopharmaceutical properties, including water insolubility (Lipper, 1999; Prentis et al., 1988)⁸. To counter this problem, pharmaceutical companies are implementing the strategies to measure, predict and improve solubility of promising new drug candidates during preclinical phases of drug development. The Biopharmaceutical Classification System (BCS) class II drugs, which are poorly water soluble and highly permeable, make the best candidates for invention by formulation. Similarly generic drug manufacturers will need to employ economically efficient methods of delivery as more low solubility drugs go off patent, in order to maintain a competitive edge and sufficiently compete as profit margins shrink in this price sensitive industry⁹. Consideration of the modified Noyes-Whitney equation provides some hints as to how the dissolution rate of even poorly soluble compounds might be improved to minimize the limitation to oral bioavailability:

Where, D_R = Rate of dissolution

A = Surface area available for dissolution

D = Diffusion coefficient of the compound

Cs = Solubility of the compound in dissolution medium

C = Concentration of drug in the medium at time t

h = Thickness of the diffusion boundary layer adjacent to the surface of the dissolving compound.

From above, it is clear that the drug dissolution rate is directly proportional not only to the concentration gradient of drug in stagnant layer but also to the surface area available for dissolution. The main possibilities for improving dissolution according to this analysis are to increase surface area available for dissolution by decreasing the particle size of the solid compound and or by optimizing the wetting characteristics of the compound surface, to decrease the boundary layer thickness, to insure sink conditions for dissolution and last but definitely not least, to improve the apparent solubility of the drug under physiologically relevant conditions.⁷

Biopharmaceutical Classification System:

The BCS is a scientific framework for classifying drug substances based on its aqueous solubility and intestinal permeability. When combined with the in vitro dissolution characteristics of the drug product, the BCS takes into account three major factors: solubility, intestinal permeability and dissolution rate all of which govern the rate and extent of oral drug absorption from immediate release solid oral-dosage forms.¹⁰ It classifies the drugs into four classes (Fig. 1)

Fig. 1: A typical representation of the biopharmaceutical classification system¹¹

According to the BCS approach, the rate of drug absorption is determined by the dissolution rate (kd) and the permeability rate (kp). The rate of dissolution is a function of drug solubility and formulation characteristics, while the permeability rate is largely a function of a drug compound’s chemical structure (polarity, functional groups, salt form, etc.)¹².

Development of dosage forms with poorly water soluble drugs:

The increased emergence of poorly water soluble active compounds presents specific obstacles for the development of both immediate release and modified release dosage forms. Poorly water soluble drugs will be inherently released at a slow rate owing to their limited solubility within the GI contents. The challenge for poorly water soluble drugs is to enhance the rate of dissolution. This in turn subsequently improves absorption and bioavailability⁴. Formulation methods targeted at dissolution enhancement of poorly water soluble substances are continuously introduced^13,14.

There are several methods for enhancing dissolution rate of poorly water soluble drug including: (A) physical modification such as (a) reduction in particle size to increase surface area, thus increase the dissolution rate of drug, e.g. particle size reduction via micronization; (b) formulation by nanosuspension or nanoparticles (c) use of polymorphs or pesudopolymorph (d) complexation and solubilization by use of surfactant, microemulsion and self-emulsifying system. (B) chemical modification such as (a) drug derivatization such as strong electrolyte salt forms that usually have higher dissolution rate; (b) use of soluble prodrugs.

Among them, liquisolid compacts is one of the most promising and new techniques which promotes dissolution rate of water insoluble drug¹⁵.

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^16-20.

Historical development of liquisolid compact:

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 non-volatile solvent into a dry-looking, nonadharent powder by mainly adsorbing the liquid onto silica 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^21,22. In later studies on powdered solution, compression enhancers such as microcrystalline cellulose were added in such dispersions in order to increase the compressibility of the systems²³.

In these studies, however, large quantities of silica 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 systems²⁴.

Liquisolid compacts, on the other hand, are acceptably flowing and compressible powdered forms of liquid medications, and have industrial applications. In addition, the term ‘liquid medication’ does not only imply drug solutions, as in powdered solutions, but also drug suspensions, emulsion, or liquid oily drugs. Therefore, in contrast to ‘powdered solution’, 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 older term of ‘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 silica used²⁰.

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 characteristics²⁰.

In liquisolid systems the drug is already in solution in PG, 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.

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 properties²⁵.

Components:

Essentially, there are two major formulation components of liquisolid compacts: the powder substrate and the liquid medication. The powder substrate mainly consists of

(a) Compression-enhancing, relatively large, preferably porous carrier particles (e.g. Cellulose) and

(b) Flow-enhancing, very fine, highly adsorptive coating particles (e.g., silica).

Presumably, according to the new theories of liquisolid formation, the liquid medication is initially absorbed into the carrier powder particles, which are in turn covered by the fine coating particles to yield an overall acceptably flowing and compressible liquid/powder system²⁶.

The term ‘coating material’ refers to a material possessing fine and highly adsorptive particles, such as various types of amorphous silicon dioxide (silica), which contributes in covering the wet carrier particles and displaying a dry-looking powder by adsorbing any excess liquid. These adsorptive particles have a particle size range of about 10 nm to 5,000 nm in diameter^16-20.

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 (e.g. clofibrate, valproic acid, liquid vitamins, etc.), into liquisolid systems.

Regarding powdered drug solutions, it must be emphasized that their preparation is not a solvent deposition technique since it does not involve drying or evaporation. 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, namely,

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.^16-20

Definition:

The term “liquisolid systems” refers to powdered forms of liquid medications, formulated by converting drug solution of water-insoluble solid drug in suitable non-volatile solvent systems, into “dry” nonadherent, free flowing and readily compressible powder admixtures.

The term “liquisolid compact” refers to immediate or sustained release tablet or capsule that are prepared using the technique “liquisolid system”, combined with the inclusion of suitable excipients required for tableting or encapsulation such as disintegrant for immediate release, binder for sustained release action.

The term “carrier material” refers to the porous material possessing sufficient absorption properties for non-volatile liquids, such as micro-crystalline cellulose, lactose, starch etc.

The term “coating material” refers to the material possessing very fine and highly adsorbed particles, which covers the wet carrier particles and shows dry-looking powder by absorbing any excess liquid, such as silicon dioxide (silica).

The term “flowable liquid-retension potential” (φ value) of powder material displays its ability to retain specific amount of liquid while maintaining good flow properties. The φ value defined as the maximum weight of liquid that can be retained per unit weight of the powder material in order to produce an acceptably flowing liquid/powder admixture.

The term “compressible liquid-retention potential” (ψ value) of a powder material describes its ability to retain amount of liquid while maintaining good compression properties. The ψ – number is defined as the maximum weight of liquid that can be retained per unit weight of the powder material in order to produce an acceptably compressible liquid/powder admixture.i.e.being able to produce tablet of sufficient hardness without possessing any liquid squeezing out phenomenon during compaction.

The term “plasticity”, (Ω) of liqisolid system is the maximum hardness possessed by the liquisolid compact.

The term “liquid medication” incorporates liquid lipophilic drugs, and drug suspension, solution of poorly soluble drugs in suitable non-volatile solvent systems.

Preparation of Liqisolid Formulation:

The liquisolid systems are acceptably flowing and compressible powder form of liquid medication. The first step in the formulation of liquisolid system is formulation of liquid medication. The poorly soluble drugs were dispersed in liquid vehicle. Here the liquid vehicle is the non-volatile solvent such as propylene glycol,^20,27,28,29 Tween 80,^20,27,28,29 PEG 200, ^30,31,32PEG 400 ^{20,27,28,29,30} etc. Different drug concentration in W/W of drug and liquid vehicle can be prepared. R.H. Fafmy et al. uses different drug and solvent ratio as 10% W/W, 20% W/W, 30%W/W to optimise the effective liquisolid formulation³³.The drug and liquid vehicle mixture may be heated to sufficient temperature with constant stirring for proper mixture of both. R.H. Fafmy et.al heated liquid medication of famotidine and propylene glycol to 80-90⁰C with constant stirring and thereafter, the solution were sonicated for 15 minute to obtained homogeneous drug solution or liquid medication.³³Then next step is to add binary mixture of carrier and coating material. It is also possible to add carrier material first and then resulting wet mixture is converted into dry-looking, nonadherent, free flowing and readily compressible powder by the simple addition and mixing of a calculated amount of coating material. The carrier material incorporated are microcrystalline cellulose, lactose, starch, sorbitol etc. which has porous surface and closely matted fibers in their interior, which aids for absorbing property to wet itself by the liquid medication. Mainly coarse granular grade of MCC were used which are better for direct compression process such as Avicel PH 102, Avicel PH 200. Silicon dioxide (Silica) powder is used as coating material which has sufficient adsorption properties to dry the wet particles of carrier material and make them readily flowable and compressible. Different grade of silica can be used in liquisolid formulation such as Aerosil 200, Cab-O-Sil M5, Syloid 244 FP. Finally a disintegrant or binder is added in the mixture depending on the type of formulation to be prepared. i.e. for immediate release, disintegrant such as sodium starch glycolate (explotab), cross-carmellose etc. can be used.Y. Javadzadeh et al., 2008, in their literature used3% solution of HPMC K4M as a binder using wet granulation technique to prepare sustain release formulation. They also incorporated Eudragit RS and RL instead of MCC as a carrier material to formulate the sustain release formulation.³² Generally 5% W/W of disintegrant were used in many literatures, Y. Javadzadeh et al., 2005; Ali Nokhodchi et al., 2005. In short the liquisolid system are prepare by incorporating poorly soluble drug in liquid vehicle to prepare liquid medication. Then binary mixture of carrier and coating material were added. And finally a disintegrant or binder were added and all mixture were thoroughly mixed in suitable mixture. Liquisolid powdered mixture then compressed into tablet or encapsulated with desired unit weight quantity. A systematic representation of step involved in preparation of liquisolid system is given in figure.¹⁷

Fig. 2: Steps involved in the preparation of liquisolid system

The industrial application of this technique has been hampered by poor and erratic flowability and compressibility of the produced liquisolid formulation, if adequate and sufficient amount of excipients are not present in the liquisolid formulation. Therefore, there is need to have particular and accurate amount of excipients and amount of non-volatile solvent incorporated in liquisolid formulation. S. Spireas and M. Bolton, 1999, in their invention developed a new mathematical model for calculating required amount of excipients. Based on this, proposed new fundamental mathematical model, formulation of liquisolid system having acceptable flowability and compressibility has been addressed with the development of new fundamental powder properties termed “flowable (Φ value) and compressible (ψ number) liquid retention potential” of the constituent powders. According to proposed theories, the carrier and coating materials can retain only certain amount of liquid while maintaining the acceptable flow and compression properties. Also there must be a particular ratio (R) of excipients, i.e. ratio of carrier (Q) and coating material (q) present in the formulation. Depending on this excipients ratio (R=Q/q) and its ability to retain certain amount of liquid, there is characteristic maximum liquid load on the carrier material, termed “liquid load factor” (L_f) and s defined as ratio of amount of liquid medication (W) over the quantity of carrier material (Q) in the system (L_f=W/Q), which would be possessed by an acceptably flowing and compressible liquisolid system. According to fundamental model of liquisolid systems, there exists a linear relationship between the liquid load factors L_f and the reciprocal powder excipients ratios 1/R required to produce acceptably flowing and or readily compressible liquid-powder admixture.²⁶

The two key properties of liquisolid power excipients, called, φ- value and ψ-number, are determined by the method developed by S. Spires and M. Bolton, termed “ liquisolid flowability test (LSF) and liquisolid compressibility test (LSC).” In the LSF test, recording of powder flowmetry is used to assess and clarify powder flow characteristics such as flow rate and consistency, whereas in LSC test, a powder compaction properties termed “pactisity” and derived linear “pactisity equation” are used to classify compression characteristics of prepared liquisolid systems. The φ value can be determined by the LSF test and ψ- number can be determined by LSC test. Both properties are then used to calculate amount of excipients present in the liquisolid system.

Steps in formulation of liquisolid compacts:

1) If solid water-insoluble drug is to be formulated, the drug is first dissolved or suspended or dispersed in a non-volatile solvent to produce a drug solution or suspension of certain composition (% W/W). Different compositions of drug solution or suspension are prepared to optimise the desired liquisolid system, (e.g. 5% W/W, 7.5% W/W, 10% W/W). The amount of liquid vehicle incorporated must be optimised from LSF test.

2) The weight (W in grams) of drug solution or suspension or liquid drug required to be included in single liquisolid compact unit possessing a desired strength of active ingredient is selected. E.g. suppose dose of drug is 10 mg and weight composition selected is 10% W/W, then Weight of drug solution must be 0.1 gm.

3) The carrier material (e.g. Avicel PH 102) and coating material (e.g. Cab-O-Sil M5) which are to be included in liquisolid formulation are selected.

4) The characteristics excipients or carrier-coating ratio Rmin (W/W) and the flowable liquid retention potentials (φ - values, W/W) of carrier (φ) and coating (φ) materials are determined using the “Liquisolid flowability test” (LSF test).

5) The compressible liquid-retention potentials (ψ-numbers, W/W) of carrier (ψ) and coating (ψ) materials are determined using the “Liquisolid compressibility test” (LSC test).

6) The desired excipients or carrier-coating ratio R, where R> Rmin of the carrier-coating combination to be included in the liquisolid system is selected. If minimum unit dose (U_min) is desired, the excipients ratio of the formulation must be selected is to be equal to R_min which is the characteristic minimum excipients raio of carrier-coating system used.

7) The optimum load factor L0 (W/W) required to yield an acceptably flowing and compressible liquisolid system is assessed using equations 1 to 4.

L0 = ^φLf When ^φLf < ^ψLf...................equation 1

L0 = ^ψLf When ^φLf > ^ψLf..................equation 2

Where, ^φLf = φ + φ (1/R)..................equation 3,

and

^ψLf = ψ + ψ (1/R)...............................equation 4.

If a powder system (carrier-coating) mixed at its minimum excipients ratio (R_min) has been selected, the required maximum load factor L_maxmay be determine using equation 5 to 8.

L_max = ^φL_max when ^φL_max< ^ψL_max ..........equation 5

L_max₌^ψL_maxwhen ^φL_max> ^ψL_max............ equation 6

Where, ^φL_max₌^φ Lf = φ + φ (1/R_min).... equation 7

^ψLf = ψ + ψ (1/R_min)..............................equation 8

8) Finally, the optimum quantities (in grams) of carrier (Q0) and coating (qo) materials required to be mixed with the desired amount W of liquid vehicle in order to produce an acceptably flowing and compressible liquisolid compact are obtained by using equation 9 and 10, respectively.

Q0 = W/ L0........................................equation 9

qo = Q0/R..........................................equation 10

If the minimum carrier quantity (Q_min) and maximum coating quantity (q_max) required to produce an acceptably flowing and compressible liquisolid compact unit possessing minimum weight (U_min) and containing an amount W of liquid, then it may be assessed using equation 11 and 12 respectively.

Qmin = W/ Lmax.................................equation 11

qmax = Qmin/Rmin............................. equation 12

The unit dose weight Uw of liquisolid formulation can be calculated by using equation 13. The minimum possible unit dose weight Umin which can be produced by the carrier-coating system may be also predicted, having selected the weight W of the liquid medication (per unit dose) and having determined the minimum excipients ratio Rmin of the powder system and its corresponding maximum liquid load factor Lmax required to produce a flowable and compressible liquisolid system.

The unit dose weight Uw of liquisolid formulation can be calculated by using equation 13.

Uw = W + W(1/R) (1L0).......................equation 13

The above equation from 1 to 7 are used to predict the required and desired amount of excipients, to formulate the liquisolid systems. In short the design of liquisolid formulation must be depend upon the dose of the drug incorporate in the formulation. Depending on dose and selected drug-solvent % W/W composition, the weight of liquid medication predicted. Then from LSF and LSC tests, the liquid load factor (Lf) obtained for that liquid medication. Thus from equation Lf = W/Q , the required quantity of carrier material (Q) can be obtained and from the selected excipients ratio R, quantity of coating material (q) required must be specified. For efficient and better results, required quantities of excipients must be optimised with the help of test specified i.e LSF and LSC test.¹⁷

LSF Test:

This test method, named “liquisolid flowability (LSF) test” was developed and employed to predict the flowable liquid-retention potential (φ value) of powder excipients which are likely to included in liquisolid systems. This test is like titration procedure in which 25 to 30 gm of mixture of powder were investigated for flow properties. Several liquid-excipients mixtures (i.e. liquid/solid weight compositions), prepared with increasing amount of a non-volatile solvent using a standard mixing procedure which ensures uniformity, consistency. Their flow rate are assessed by using a recording powder flowmeter (RPF).¹⁷ Other methods for determining powder flow properties are also used, like hopper flow rate and angle of repose. In hopper flow rate technique, 100 cm³of powder placed in funnel of flowmeter. A simple shutter is then removed and the time taken for powder to discharge completely is recorded. By dividing this discharged powder volume by this time, a flow rate is obtained which can be used for quantitative comparison of different powders. The flow rate above 10 cm³/s was considered as acceptable flow rate for tabletting purpose³¹. Flow properties of powders were also evaluated by measuring angle of repose. Static angle of repose were measured according to fixed funnel and freestanding cone method. In another method, angle of slide were taken as a measure for the flow characteristics of powder. The angle of slide is defined as that angle to which a polished metal plate must be tilted in order for 10 gm of powder material to start sliding down the plate. The angle of slide has been preferred over the other method of determination (e.g. angle of repose) of flow properties for the powders which having particle size less than 150 µm.³⁰ Since in liquisolid formulation all excipients used, has particle size less than 150 µm (e.g . MCC used therein has particle size of less than 75 µm, when retain on air jet sieve). The angle of slide can be calculated with the help of metal plate which has polished surface, so the powders can flow on it smoothly. In this method, 10 gm of powder weighed accurately and placed at one end of metal plate. This end is then raised up gradually untill powder start flowing from upward end to downward end. The angle made by the metal plate to the horizontal surface, at which the powder starts flowing, is taken as angle of slide. An angle of slide corresponding to 33⁰ were taken for optimum flow properties or considered as the limit of acceptable flowability.¹⁷The powder which flows at angle of slide of 33⁰is taken for obtaining φ - value as φ - value = weight of liquid / weight of solid. Similarly by any method of characterising flowability, we can obtained flowable liquid retention potential (φ - value), by simple assessing a desired and preselected limit of acceptable flowabilty for powder which is under investigation. Non-volatile solvent used for this test must be that which were also employed in liquisolid formulation.

The LSF test consists of following steps:

1) First preparing several powder systems which contains carrier and coating material each, and selecting for each carrier- coating ratio R1...X , where 1....x correspond to powder system prepared

R1...X = Q1....X / q1....x

Where, Q1....X = the weight of carrier material, and

q1....x = the weight of coating material,

Similarly, R2...X = Q2....X / q2....x ; R3...X = Q3....X / q3....x.............Rx = Qx / qx

2) Next adding liquid vehicle in increasing amount to the prepared powder systems.

Now each prepared powder systems has unique liquid / solid weight composition

(Cw). Liquid vehicle added must be one which were utilised in liquisolid formulation.

3) Now assessing flow rate and consistency to the prepared liquid /solid admixtures by one of the methods specified such as angle of slide, angle, recording powder flowmetry, etc. Thus obtaining φ value and flowable liquid load factor (^φLf) for each powder admixture.

4) Plotting the flowable liquid load factor ^φLf thus obtained against the corresponding reciprocal carrier- coating ratios 1/ R of the powder system, thereby obtaining a linear plo having a Y- intercept equal to the flowable liquid retention potential φ value of the carrier material and a slope equal to the flowable liquid-retention potential φ value of the coating material.

LSC Test:

A test method, called “liquisolid compressibility test (LSC test)”, were developed and employed to determined the compressible liquid-retention potential (ψ- number), of several powder excipients which are likely to be included in formulation, as carrier or coating materials, in liquisolid compacts. The method were based on the calculating hardness of the prepared liquisolid compacts and pactisity (Ω) by which ψ- number and ^ψLf value can be obtained.

The LSC consist of following steps:

1) First preparing several powder systems which contains carrier and coating material each, and selecting for each carrier- coating ratio R1...X , where 1....x correspond to powder system prepared

R1...X = Q1....X / q1....x

Where Q1....X = the weight of carrier material, and

q1....x = the weight of coating material,

Similarly, R2...X = Q2....X / q2....x ; R3...X = Q3....X / q3....x.............Rx = Qx / qx

2) Next adding liquid vehicle in increasing amount to the prepared powder systems. Now each prepared powder systems has unique liquid / solid weight composition (Cw). Liquid vehicle added must be one which were utilised in liquisolid formulation.

3) The next step is compressing each liquid /powder admixture thus obtained into tablets of certain weight using plateau compression force to achieve maximum tablet crushing strength or hardness.

4) Assessing the average tablet crushing strength Sc, of the tablets produced and calculating their pactisity (Ω) , where { Ω = Sc / Wt } and Wt = the average tablet weight in grams.

5) Determining the average liquid content of the crushed tablet and calculating the net liquid solid weight composition (Cw) of the crushed liquid/powder admixture.

6) Determining the characteristics intrinsic pactisity, Ωo, and sponge index σi, of the powder system by plotting the data obtained as log Ω versus Cw, where

{ log Ω = log Ωo – σi. Cw }

7) Determining the ψmix, which is the compressible liquid-retention potential (ψ- number) of the powder system, where { ψmix = (log Ωo – log 20)/ σi }.

8) Determining the compressible liquid-load factor (^ψLf ) of the powder system,

Where { ^ψLf = ψmix ( 1 + 1/R ) }

9) Plotting the compressible liquid-load factors (^ψLf ) thus obtained against the reciprocal of carrier-coating ratios (1/R) of the powder systems, thereby obtaining a linear plot having a y- intercept equal to the compressible liquid- retention potential (ψ- number) of carrier material (ψ) and slope equal to compressible liquid-retention potential (ψ- number) of coating material (ψ).

Therefore, the ψ-number of a powder represents a certain liquid/solid content (W/W) Cw that when compressed at plateau pressures, termed standard pacticity conditions, and will yield a compact possessing a pacticity Ω equal to kg/gm.

Hence from both tests i.e. LSF and LSC tests, the physical properties of powder excipients, i.e., φ - values, ψ- number, liquid-load factor (Lf) and Rmin can be obtained, which are essential for formulating flowable and compressible liquisolid compacts.

Advantages of Liquisolid Systems:

A great number of slightly and very slightly water-soluble and practically water-insoluble liquid and solid drugs or poorly soluble drugs, (e.g. hydrocortisone,²⁰ indomethacin,¹⁶ Piroxicam^28,29 etc.) can be formulated into liquisolid system using the new formulation mathematical model. i.e. almost all drugs of BCS class II (low solubility and high permeability) and class IV (low solubility, low permeability). It is well established that for better bioavailability of an orally administered poorly soluble drugs, the bioavailability can be achieved when the drug is present already in solution form, thereby displaying enhanced dissolution rates. That is why the soft gelatine capsules containing drug in solubilised state shows higher bioavailability compared to conventional oral solid dosage forms³⁴. Similar principle can be applied to the liquidsolid formulation and powder drug solutions, and same one governs the mechanism of drug delivery from these formulations which is chiefly responsible for improved dissolution profile. Hence even though drug is in tabletted or encapsulated form, it is held in solubilised liquid state, which consequently contributes to increased drug wetting properties, thereby enhanced drug dissolution. As non-volatile, non-toxic solvents are used in these formulations, these methods do not involve drying and evaporation steps, hence there is no salt precipitation, aggregation. Hence there is no toxicity or any other compatability issue involved in these formulations.

Another advantages of liquisolid systems over the soft gelatin capsules is that, during dissolution of liquisolid, the drug solution or liquid drug is dispersed throughout the volume of dissolution medium; such a phenomenon does not exhibited by soft gelatin preparations. Hence more drug surface is exposed to the dissolving medium and exhibits enhance drug release. Also the production cost is much lower than that of the soft gelatin capsules, because the production of liquisolid system is similar to that of conventional tablet¹⁷. Also there is no issue of patient compliances as these formulations are administered in the same manner as conventional oral solid dosage forms. Many literatures show that there is no significant effect of aging on these liquisolid formulations.Yousef. Javadzadeh et al. Mentioned the effect of aging on hardness and dissolution rate of liquisolid compacts which are stored at 25°C and at 75% relative humidity for 9 months²⁹.

This technique was successfully applied for low dose poorly water soluble drugs e.g. indomethacin dose 25 mg;¹⁶ piroxicam dose 10 mg^28,29 etc. However formulation of the high dose water-insoluble drugs as a liquisolid tablets, results in very high tablet weight, more than 1 gm. In order to have acceptable flowability and compatibility for liquisolid powder formulation, loading factor has to be more than 0.25, which is not convenient as a high level of carrier and coating materials should be added and that in turn will increase the weight of each tablet above 1 gm which is very difficult to swallow. Therefore, in practice it is impossible with conventional method to convert high dose drugs to liquisolid tablet with the tablet weight less than 1 gm. In fact, when the therapeutic dose of drug is more than 50 mg, dissolution enhancement in the presence of low levels of hydrophilic carrier and coating material is not significant. By adding some materials such as polyvinyl pyrrolidone (PVP); HPMC into liquid medication i.e preparing Microsystems¹⁷ it is possible to produce dry powder formulations containing liquid with high concentration of drug. By adding such a materials to the liquid medication , low amount of carrier is required to obtained dry powder with free flowablility and good compatibility.

CONCLUSION:

The in vivo evaluation studies of liquisolid formulations of hydrochlorothiazide was carried out on male beagle dogs by Khaled et.al 2001, the hydrochlorothiazide liquisolid tablets showed greater extent of absorption than commercial tablets. Also protection of male albino mice against the convulsion, induced by electroshock, was carried out by Saadia A. Tayel et.al 2008. In vivo evaluation of famotidine liquisolid formulation in human was done by R.H. Fahmy et.al 2008, the bioavailability study indicated that the prepared optimal liquisolid formula did not differ significantly from marketed famotidine tablets. Morever, it was previously established that the higher dissolution rates displayed by liquisolid compact, in comparison with conventional tablets, can imply enhance oral bioavailability due to increased wetting properties and surface of drug available for dissolution. Therefore the liquisolid formulations can be a promising alternative for formulation of water-insoluble drugs, and it has potential to be considered for human study in order to be manufactured on large scale.

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Received on 22.06.2010

Accepted on 02.08.2010

Research Journal of Pharmaceutical Dosage Forms and Technology. 2(5): Sept.-Oct. 2010, 314-322