INTRODUCTION:

Dissolution is the critical parameter of pharmaceutical dosage form and used to ensure batch to batch quality control, for the assessment of bioequivalence and sometimes to correlate in-vitro with in-vivo drug release characteristics.[1] The liquisolid technique as described by Spireas [1] is a novel concept, where a liquid may be transformed into a free flowing, readily compressible and apparently dry powder by simple physical blending with selected carrier and coating material.[2-3] The liquisolid compacts are acceptably flowing and compressible powdered forms of liquid medications. The term ‘liquid medication’ refers to liquid lipophilic (oily) drugs or water-insoluble solid drugs dissolved in suitable water-miscible non-volatile solvent systems termed as the liquid vehicle.[4]

The use of poorly soluble drugs has a number of drawbacks such as increasing the dosage, administration frequency and the resultant occurrence of side effects. Furthermore, the rate-limiting step in the absorption process for poorly water-soluble drugs is the dissolution rate of such drugs in the gastro intestinal fluids rather than the rapidity of their diffusion across the gut wall; it is however, important to improve the oral bioavailability of poorly water soluble drugs by improving their dissolution rate and solubility. The dissolution rate is the rate limiting factor in drug absorption for class II (low solubility and high permeability) and class IV (low solubility and low permeability) drugs as defined in the Biopharmaceutics Classification System.5-7. The Liquisolid compacts have two major formulation components namely, powder substrate and liquid medication. The powder substrate mainly consists of: a) compression enhancing, large preferably porous carrier particles; b) flow enhancing, very fine, highly adsorptive coating material particles. Liquisolid preparations may be hampered by their poor and erratic flow and compaction properties. Inherently, the acceptable flow and compaction characteristics of the finished powder / liquid admixtures are secured. The quantities of various excipients required for powder solution formulations are determined in accordance with a new mathematical model expression. [8] The absorbate molecules diffuse inside the absorbent and are eventually captured by the powder particles within their bulk, and thus absorption of the liquid occurs. Adsorption is the phenomenon in which liquid is not truly absorbed and instead of being dispersed throughout the interior of the solid, the molecules only cling to its available surface, internal and external. However, depending on the sorbent properties, both of these processes can occur simultaneously, and is termed sorption. Initially the liquid is absorbed in the interior of the particles captured by its internal structure and after saturation of this process adsorption of the liquid onto the internal and external surfaces of the porous carrier particles occurs. [9]

DEFINITIONS:

Liquid medication:

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

Solubility:

Water insoluble drugs include those drugs that are “sparingly water soluble” (one part solute into 30-100 parts of water), slightly water- insoluble (one part solute into 1000 -10,000 parts of water) and practically “water-insoluble” or insoluble (one part solute into 10,000 or more parts of water).

The liquisolid technique systems refers to powdered forms of liquid medications formulated by changing to liquid lipophilic drugs or drug suspensions or solutions of water insoluble solid drugs in suitable non-volatile solvent systems into dry-looking, non-adherent, free moderately flowing.

Liquisolid systems based on the type of liquid medication can be classified into three sub groups:

(i)“Powdered drug solutions”

(ii)“Powdered drug suspensions”

(iii)“Powdered liquid drug ”

The first two groups may exist or be produced by changing drug solutions and drug suspensions while the third is produced from the formulation of liquid drugs into liquisolid systems.

“Liquisolid compacts”: refers to immediate sustained-release tablets or capsules that are described under “liquisolid systems”.

“Liquisolid Microsystems”:

Refers to capsules prepared by “liquisolid systems” plus the inclusion of an additive resulting in a unit size that may be as much as five times less than that of a liquisolid compact.

Liquid load factor (L_f):

Defined as the ratio of the amount of liquid medication (W) over the quantity of carrier material (Q) in the system.

Lf = ––WQ

Carrier: Coating Material Ratio (R): Ratio between the quantities of carrier (Q) and coating materials (q) present in the formulation.

QR= –– q

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,[10] lactose[11] ,sorbitol[12] , Avicel PH 102 and 200 , Eudragit RL and RS, amorphous cellulose etc.[13]

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.[9,14,15]

Non-volatile solvents

Inert, high boiling point, preferably water-miscible and not highly viscous organic solvent systems. Various non-volatile solvents used for the formulation of liquisolid systems include Polyethylene glycol 200 and 400, glycerin, polysorbate 80 and propylene glycol, propylene glycol, liquid polyethylene glycols, polysorbates, glycerin, N, N-dimethylacetamide, fixed oils, etc.[13]

Drug candidates

This technique is successfully applied for low dose BCS class II and class IV drugs which are poorly water soluble and have slow dissolution rate[18]

Components of Liquisolid Compact1,2

Liquisolid compact mainly includes

1. Non volatile solvent

2. Disintegrant

3. Drug candidate

4. Carrier material

5. Coating material

TABLE

Release Drug	Non-volatile vehicle	Carrier and coating material
Aceclofenac	Propylene glycol, PEG 400 and Tween 80	MCC19
Aceclofenac	PEG 400	MCC and colloidal silica 20
Atorvastatin calcium	Propylene glycol, Polyethylene glycol 400	MCC and colloidal silica21
Bromhexine HCL	Propylene glycol	MCC and colloidal silica22
Carvedilol	PEG 400	MCC and colloidal silica23
Carbamazepine	PEG 200	MCC and colloidal silica24
Clofibrate (liquid)	---------	MCC and colloidal silica25
Diclofenac sodium	Propylene glycol	MCC and colloidal silica26
Etoricoxib	PEG 400	MCC and colloidal silica27
Famotidine	Propylene glycol	MCC and colloidal silica28
Fenofibrate	Propylene glycol	MCC and colloidal silica29
Fenofibrate	PEG 400	MCC and colloidal silica30
Furosemide	Synperonic® PE/L 81, Caprol® PGE-860 and PEG 400	MCC and colloidal silica31
Glibenclamide	PEG 400	MCC and colloidal silica32
Griseofulvin	PEG 400	MCC and colloidal silica33
Glipizide	PEG 400	MCC and colloidal silica34
Hydrochlorothiazide	PEG 200	MCC and colloidal silica35
Hydrocortisone	PEG 400	MCC and colloidal silica36
Ibuprofen	PEG 400	MCC and silica gel37
Indomethacin	PEG 200, Glycerine	MCC and colloidal silica38
Indomethacin	Propylene glycol	MCC and colloidal silica39
Indomethacin	PEG 400	MCC and HPMC40
Ketoprofen	Propylene glycol and Tween80	Dicalcium phosphate and silica gel41
Ketoprofen	PEG 400	MCC, starch, dicalcium phosphate, lactose and silica gel42
Lamotrigine	PEG 400	MCC and colloidal silica43
Methyclothiazide	PEG 400	MCC and colloidal silica44
Naproxen	Cremophor EL, Synperonic PE/L61 and PEG400	MCC and colloidal silica45
Nifedipne	PEG 400	MCC and colloidal silica with HPMC 46
Piroxicam	Tween 80	MCC and colloidal silica 47
Polythiazide	PEG 400	MCC and colloidal silica48
Prednisolone	Tween 80, PEG 400, propylene glycol, Glycerine	MCC and colloidal silica49
Prednisolone	N,N dimethylacetamide /PEG400 (7:3v/v)	Various silicas50
Prednisone	Propylene glycol	MCC and colloidal silica51
Propanolol HCL	Tween 80	Eudragit RS or RL and colloidal silica with HPMC52
Repaglinide	Tween 80	MCC and calcium silicate53
Rofecoxib	PEG 600	MCC and colloidal silica54
Simvastatin	PEG 400	MCC and colloidal silica55
Theophylline	Tween 80	Eudragit RS or RL and colloidal silica with HPMC56
Tramadol HCL	Propylene glycol	MCC and colloidal silica with HPMC57
Valsartan	Propylene glycol	MCC and colloidal silica58

Disintegrants:

Most commonly used disintegrant is sodium starch glycolate (Explotab13, Pumogel, etc.)

Liquid medication includes liquid lipophilic drugs and drug suspensions or solutions of solid water insoluble drugs in suitable non-volatile solvent systems.[16]

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.[16]

ADVANTAGES:

1) Huge number of Bio-Pharmaceutical classification class II drugs with high permeability, slightly or very slightly water soluble and practically insoluble liquids and solid drugs can be formulated into liquisolid systems.

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

3) This principle governs or administers the mechanism of drug delivery from liquisolid systems of powdered drug solutions and it is mainly responsible for the improved dissolution profiles exhibited by this preparations.

4) In this technique, production cost is low compared to soft gelatin capsules.

5) 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.

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

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

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

9) Optimized sustained release, liquisolid tablets or capsules of water insoluble drugs demonstrate

constant dissolution rates (zero order release).

10) It is used in controlled drug delivery systems.

11) Drug can be molecularly dispersed in the formulation.

12) Drug release can be modified using suitable formulation ingredients.

13) Capability of industrial production is also possible.

14) Enhanced bioavailability can be obtained as compared to conventional tablets.

15) Differentiate the dosage form by admixture of colour into liquid vehicle.

16) To minimize excipients in formulation compare with other formulations like solid dispersions.

17) Omit the process approaches like nanonisation, micronization techniques.

APPLICATIONS:

1. Liquisolid compact technology is a powerful tool to improve bioavailability of water

2. Insoluble drugs. Several water insoluble drugs on dissolving in different non-volatile solvents, have been formulated into liquisolid compacts.

3. Literature cites different drugs successfully incorporated into liquisolid compacts.

4. Rapid release rates are obtained in liquisolid formulations.

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

6. Sustained Release of drugs which are water soluble drugs such as propranolol

7. Hydrochloride has been obtained by the use of this techni

8. Solubility and dissolution improvement

9. Flowability and compressibility

10. Designing of Controlled Release Tablets

11. Bioavailability Enhancement

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.

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 to produce an acceptably flowing admixture for encapsulations.[17]

Basic theoretical aspect to formulate:

Liquisolid Compact:

These studies are related to the flow and compression of formulation. The mathematical model of 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 (Q)and coating powder(q) materials can retainonly 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 the formulation, 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 ‘acceptablycompressible’ 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 fundamental properties of powders and are referred to as their flowable and compressible liquid retention potentials. 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 characterised by the ratio between (W) and (Q), as shown in Eqs. 1 and 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.

A schematic outline of steps involved in the preparation of liquisolid systems is given.

Fig.2 steps involved in the preparation Liquisolid[19]

Methodology:

Spireas et al proposed the new mathematical model in accordance to retain good flow behavior and compressibility to design the formulation for Liquisolid technique.8, 9Mandatory requirements for this technique are suitable drug candidate, suitable non-volatile solvent, carrier and coating materials. The basic properties of powder are proposed according to Spireas et al is “Flowable liquid retention potential” (value) and compressible liquid retention potential”(ψ value). Flowable liquid retentional potential: defined as maximum weight of liquid (solvent) that can be retained per unit weight of powder (excipient) material to produce good flow.

Compressible liquid retention potential: defined as the compression force applied to produce tablets with acceptable strength withoutsqueezing out any liquid during compression.

Evaluation of liquisolid systems:

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. ^[22]Angle of repose, Carr’s index and Hausner’s ratio were used in order to ensure the flow properties of the liquisolid systems. ^[23]

Pre compression studies of the prepared liquisolid:

Powder systems: In order to ensure the suitability of the selected excipients, Fourier Transform Infra Red Spectroscopy, Differential scanning Calorimetry, X-ray Diffraction and Scanning Electron Microscope studies are to be performed. In addition, flowability studies are also to be carried out to select the optimal formulae for compression, prior to the compression of the powders the dosage forms such as into tablets and capsules.

Fourier Transform Infra Red Spectroscopy (FT-IR):

FT-IR spectra of prepared melt granules are recorded on FTIR-8400 spectrophotometer. Potassium bromide (KBr) pellet method is employed and background spectrum is collected under identical situation. Each spectrum is derived from single average scans collected in the region 400 4000cm^-1at spectral resolution of 2cm^-2and ratio against background interfereogram. Spectra are analyzed by software. ^[26]

Differential scanning calorimetry (DSC):

Differential scanning calorimetry (DSC) is performed in order to assess the thermotropic properties and the thermal behaviors of the drug, excipients used in the formulation of the liquisolid system. 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. ^[25,26,27]

X-ray diffraction (XRD):

For the characterization of crystalline state, X-ray diffraction (XRD) patterns are determined for physical mixture of drug and excipients used in formulation and for the prepared liquisolid compacts. Absence of constructive specific peaks of the drug in the liquisolid compacts in X-ray diffractogram specify that drug has almost entirely converted from crystalline to amorphous or solubilized form. Such lack of crystallinity in the liquisolid system was understood to be as a result of drug solubilization in 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 compacts it may contribute to the consequent improvement in the apparent solubility and enhancement of dissolution rate of the drug. ^[21]

Scanning electron microscopy (SEM):

Scanning electron microscopy (SEM) is utilized to assess the morphological characteristics of the raw materials and the drug-carrier systems.

Contact angle measurement:

For assessment of wettability, contact angle of liquisolid tablets is measured according to the imaging method. The commonly used method is to measure contact angle directly for a drop of liquid resting on a plane surface of the solid, the so-called imaging method. A saturated solution of the drug in dissolution media is prepared and a drop of this solution is put on the surface of tablets. The contact angles are calculated by measuring the height and diameter of sphere drop on the tablet.

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 hydrocortisone, Prednisolone Carbamazepine Piroxicam. Also several water insoluble drugs nifedipine, gemfibrozil, and ibuprofen, have shown higher bioavailability in rats as compared to their commercial counterparts.

In vivo evaluation of liquisolid systems:

This liquisolid technology is a promising tool for the enhancement of drug release of poorly soluble drugs. The absorption characteristics of Hydroclorothiazide liquisolid compacts in comparison with commercial tablets were studied in beagle dogs. Significant differences in the area under the plasma concentration-time curve, the peak plasma concentration and the absolute bioavailability of the liquisolid and the commercial tablets were observed. However, for the mean residence time, the mean absorption time, and the rate of absorption no significant differences were found. The absolute bioavailability of the drug from liquisolid compacts was 15% higher than that from the commercial formulation. ^[20].

Optimization of Liquisolid Formulations with Enhanced Drug Release:

The liquisolid technology has been successfully applied to low dose, poorly water soluble drugs. The formulation of a high dose, poorly soluble drug is one of the limitations of the liquisolid technology. As the release rates are directly proportional to the fraction of molecularly dispersed drug (FM) in the liquid formulation a higher drug dose requires higher liquid amounts for a desired release profile. Moreover, to obtain liquisolid systems with acceptable flowability and compactability high levels of carrier and coating materials are needed. However, this results in an increase in tablet weight ultimately leading to tablet sizes which are difficult to swallow^28-29. Therefore, to overcome this and various other problems of the liquisolid technology several formulation parameters may be optimized which are available in the literature.

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29. Nokhodchi A, Javadzadeh Y, Siahi- Shadbad MR, Barzegar-Jalali M. The effect of type and concentration of vehicles on the dissolution rate of a poorly Soluble drug (Indomethacin) from Liquisolid Compacts. J Pharm Sci 2005; 8: 18-25.

Received on 25.04.2016 Accepted on 04.06.2016

Asian J. Res. Pharm. Sci. 2016; 6(3): 161-166.

DOI: 10.5958/2231-5659.2016.00022.9

ABSTRACT: