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ENHANCEMENT OF SOLUBILITY BY LIQUISOLID TECHNIQUE: A REVIEW

 

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About Authors:
Patel Chirag J1*, Satyanand Tyagi2, Patel Jaimin1, Chaudhari Bharat1, Tarun Parashar3, Soniya3
1Maharishi Arvind Institute of Pharmacy, Department of Pharmaceutics, Jaipur, Rajasthan.
2President, Tyagi Pharmacy Association & Scientific Writer (Pharmacy), Chattarpur, New Delhi, India.
3Department of Pharmaceutics, Himalayan Institute of Pharmacy and Research, Rajawala,
Dehradun, Uttarakhand, India. 
*Mr. Patel Chirag has published various books, research and review articles. His academic works include 16 Publications (2 books were published in Lambert Academic Publishing, Germany & 8 Research Articles and 6 Review Articles were published in standard and reputed National and International Pharmacy Journals).
chirag.bangalore@gmail.com

ABSTRACT
Solving solubility problems is a major challenge for the pharmaceutical industry with developments of new pharmaceutical products, since nearly half of the active substances being identified are either insoluble or poorly soluble in water soluble. Various techniques are used for the enhancement of the solubility of poorly soluble drugs which include Liquisolid technique, micronization, nanonization, sonocrystallization, supercritical fluid method, spray freezing into liquid and lyophilization, evaporative precipitation into aqueous solution, use of surfactant, use of co-solvent, hydrotropy method, use of salt forms, solvent deposition, solubilizing agents, modification of the crystal habit, co-crystallisation, complexation and drug dispersion in carriers.The “Liquisolid” technique is a novel and capable addition towards such an aims for solubility enhancement and dissolution improvement, thereby it increases the bioavailability.Liquisolid technique is based upon the admixture of drug loaded solutions with appropriate carrier and coating materials. The use of non-volatile solvent causes improved wettability and ensures molecular dispersion of drug in the formulation and leads to enhance solubility. By using hydrophobic carriers (non-volatile solvents) one can sustained the release of drugs by this technique. Liquisolid compacts demonstrated a considerably higher drug dissolution rates than those of conventionally made capsules and directly compressed tablets. This was due to the increased wetting properties and surface of drug available for dissolution. By using this technique, solubility and dissolution rate of water insoluble drugs can be improved. This review paper highlights the advantages, disadvantages, mechanism of enhanced drug release, classification, evaluation and application of liquisolid technique to enhance the solubility and dissolution of water insoluble drugs.

Reference Id: PHARMATUTOR-ART-1513

INTRODUCTION
The solubility is defined as a maximum quantity of solute that can dissolve in a certain quantity of solvent or quantity of solution at a specified temperature1. Almost More than 90% drugs are orally administered. Drug absorption, bioavailability, pharmacokinetic profile of orally administered drug substances is highly dependent on solubility of that compound in aqueous medium. More than 90% of drugs are approved since 1995 have poor solubility. It is estimated that 40% of active new chemical entities (NCEs) identified in combinatorial screening programs employed by many pharmaceutical companies are poorly water soluble2,3. Low aqueous solubility is the major problem encountered with formulation development of new chemical entities as well as for the generic development. The insufficient dissolution rate of the drug is the limiting factor in the oral bioavailability of poorly water soluble compounds4. These poorly water soluble drugs are allied with slow drug absorption leading to inadequate and variable bioavailability and gastrointestinal mucosal toxicity of drugs5. Poorly water soluble drugs belong to BCS class II and class IV6.

The technique of liquisolid preparation is used to formulate drug solution in solid dosage forms. Drug solution is generally, prepared by dissolving the drug in non-volatile water-miscible solvent. The prepared tablet of liquisolid formulation contains the drug held in solution. Accordingly, the dissolution step, a pre-requiste for drug absorption, may be bypassed and better bioavailability of poorly soluble drugs achieved. Liquisolid system refers to formulations formed by conversion of liquid drugs, drug suspensions or drug solution in non-volatile solvents into dry, nonadherent, free-flowing and compressible powder mixtures by blending the suspension or solution with selected carriers and coating materials7. The drugs which are water insoluble or lipophilic are dissolved in a suitable non-volatile solvent. This non-volatile solvent with drug dissolved may be existing in solution or else suspension nature known as ‘liquid medicament’. The liquid medicament is converted into free flowing, non-adhere, dry form and readily compressible powders with the help of different compressible carriers like (starch, cellulose and lactose etc.) and else coating materials like (collidol silica and talc). Because of drug present in the liquid medicament as solubilised or moleulary 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 and may also increase bioavailability8.

ADVANTAGES9,10

1.      Enhanced bioavailability can be obtained as compared to conventional tablets.
2.      Greater drug surface area is exposed to the dissolution medium.
3.      Production cost is low compared to soft gelatin capsules.
4.      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.
5.      These liquisolid systems formulate into immediate release or sustained or controlled release dosage forms.
6.      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.
7.      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.
8.      Capability of industrial production is also possible.
9.      Omit the process approaches like nanonisation, micronization techniques.

DISADVANTAGES9,10
1.      The liquisolid systems have low drug loading capacities and they require high solubility of drug in non-volatile liquid vehicles.
2.      To maintain acceptable flowability and compatibility for liquisolid powder formulation high levels of carrier and coating materials are require and that in turn will increases the weight of each tablet above 1 gm which is very difficult to swallow.
3.      It requires more efficient excipients which have higher adsorption capacities which provide faster drug release with a smaller tablet size to improve liquisolid formulations.

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MECHANISMS OF ENHANCED DRUG RELEASE FROM LIQUISOLID FORMULATIONS
The three recommended mechanisms include an increased surface area of drug available for release, an increased aqueous solubility of the drug, and an improved wettability of the drug particles.
1.      Increased drug surface area11,12
When the drug within the liquisolid system is absolutely dissolved in the liquid vehicle it is positioned in the powder substrate 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. Consequently, with increasing drug content beyond the solubility limit and thus, increasing fraction of undissolved drug in the liquid vehicle the release rate decreases. It has been pragmatic with various drugs that the release rates are directly proportional to the fraction of themolecularly dispersed drug (FM) in the liquid formulation. FMis defined by Spireas as the ratio between the drug's solubility (Sd) in the liquid vehicle and the actual drug concentration (Cd) in this vehicle carried by each system.

Therefore FM = Sd/Cd

Where FM =1 if Sd ≥ Cd

2.      Improved wetting properties13-14
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 confirmed by measurement of contact angles and water rising times.

3.      Increased aqueous solubility of the drug13,15
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 co solvent.

MATERIALS REQUIRED FOR FORMULATION10,16
1.     
Non volatile solvents: They may be hydrophilic or lipophilic in nature based on selection of type of formulation like immediate or control release. Some of them are propylene glycol, span 80, span 20, polyethylene glycol, liquid paraffin, tween 80, tween 20, cremophore L.
2.      Drugs:They are poorly soluble or insoluble in water.
3.      Carrier materials:They are preferred to be coarser granular for acceptable flow, Methyl cellulose, Avicel PH 102, Ethyl cellulose, Avivel PH 200, Ethocel and Starch 1500.
4.      Coating materials:Nano meter sized silica mostly preferred, like Aerosil, talc.

CLASSIFICATION OF LIQUISOLID SYSTEMS7,9
Liquisolid systems may be classified into two categories:
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 drug suspensions (e.g. gemfibrozil suspension in polysorbate 80, and the latter from the formulation of liquid drugs (e.g. clofibrate, liquid vitamins, etc.) into liquisolid systems.

B. Based on the formulation technique used, liquisolid systems may be classified into two categories
1. Liquisolid compacts
2. Liquisolid Microsystems

METHOD OF PREPARATION OF LIQUISOLID7,9,17
1.      A drug substance was initially dispersed in the nonvolatile solvent systems (Polysorbate 80, Polyethylene glycol-200) termed as liquid vehicles with different drug: vehicle ratio.
2.      Then a mixture of carrier or different polymers and excipients were added to the above liquid medication under continuous mixing in a mortar. These amounts of the carrier and excipients are enough to maintain acceptable flow and compression properties.
3.      To the above binary mixture disintegrant like sodium starch glycolate and other reaming additives were added according to their application and mixed for a period of 10 to 20 minutes in a mortar.
4.      The final mixture was compressed using the manual tableting machine to achieve tablet hardness.
5.      Characterize the final liquisolid granules for solubility, dissolution, flowability, compressibility and other physicochemical properties.

EVALUATION OF LIQUISOLID 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.

1.      Flow behavior18
The flowability 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 were used in order to ensure the flow properties of the liquisolid systems.

2.      Fourier Transform Infra Red Spectroscopy (FT-IR)19
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-1 against background interfereogram. Spectra are analyzed by software.

3.      X-ray diffraction (XRD)20
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.

4.      Differential scanning calorimetry21-23
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.

5.      Scanning electron microscopy (SEM)9,24
Scanning electron microscopy (SEM) is utilized to assess the morphological characteristics of the raw materials and the drug-carrier systems.

6.      Contact angle measurement9,23,24
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.

7.      In vivo evaluationof liquisolid systems14
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.

8.      In vitro dissolution studies25-27
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.

APPLICATION OF LIQUISOLID TECHNIQUES
1.     
Solubility and dissolution improvement7,9
In order to overcome the limited solubility of the pharmaceutical, pharmaceuticals were formulated as liquisolid tablets. The method of preparation of liquisolid tablets as well as the effect of various formulation and processing variables on the preparation and the release properties of the tablets were studied y number of scientists. This technique was successfully applied for low dose waterinsoluble drugs. However, formulation of the high dose insolubledrugs as liquisolid tablets is one of the limitations of the liquisolid technique. 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. But by adding some materials such as polyvinyl pyrrolidone (PVP) to liquid medication, it would be possible to produce dry powder formulations containing liquid with high concentration of drug. By adding such materials to the liquid medication, low amount of carrier is required to obtain dry powder with free flowability and good compatibility.

2.      Flowability and compressibility28,29
Liquisolid compacts possess acceptable flowability and compressibility properties. They are prepared by simple blending with selected powder excipients referred to as the carriers and the coating materials. Many grades of cellulose, starch, lactose, etc. can be used as carriers, whereas silicas of very fine particle size can be used as coating materials. In order to have acceptable flowability and compactability for liquisolid powder formulation, high levels 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 of less than 1 gm. In such systems, the drug existed in a molecular state of subdivision and systems were free flowing, on-adherent, dry looking powders. In further studies, compression enhancers were added to these powdered solutions like microcrystalline cellulose. However, the compression of these latter systems resulted in a significant ‘Liquid Squeezing Out’ phenomenon. In this system liquid medication is to be mixed with the excipients and then compressed to tablets. It was proved that the smaller the drug concentration in the liquid medication, the more rapid the release rates, since drugs in a high concentration tend to precipitate within the polymers pores. Polymers possessing large surface areas, and diluents like microcrystalline cellulose of fine particle size and granular grades produced good flow and compression properties, resulting in Acceptable tablets.

3.      Bioavailability improvement7,9
In the liquisolid and powdered solution systems the drug might be in a solid dosage form, it is held within the powder substrate in solution, or in a solubilized, almost molecularly dispersed state. Therefore, due to their significantly increased wetting properties and surface of drug available for dissolution, liquisolid compacts of water- insoluble substances may be expected to display enhanced drug release properties, and consequently, improved bioavailability.

4.      For designing of sustain release tablet29
Development of sustained release oral dosage forms is beneficial for optimal therapy in terms of efficacy, safety and patient compliance. Ideally, a controlled release dosage form will provide therapeutic concentration of the drug in the blood that is maintained throughout the dosing interval. There are several techniques for preparation of sustained release formulations, among which control of drug dissolution is one of the best and most successful methods due to its simplicity and low cost. To achieve this aim, several methods have been developed such as preparation of salt form of drug, coating with special materials and incorporation of drugs into hydrophobic carriers. Liquisolid technique is a new and promising method that can change the dissolution rate of drugs. It is claimed that if hydrophobic carriers such as Eudragit RL and RS are used instead of hydrophilic carries in liquisolid systems, sustained release systems can be obtained. Therefore, it is suggested that the method have the potential to be optimized for the reduction of drug dissolution rate and thereby production of sustained release systems.

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Table 1: Examples and Application of Liquisolid Technique

Sr.

No

Drug

Applications

Reference

1

Piroxicam

Bioavailability improvement

32

2

Methchrothiazide

Bioavailability improvement

33

3

Carbamazepine

Bioavailability improvement

34

4

Famotidine

Solubility and dissolution improvement

35

5

Naproxen

Solubility and dissolution improvement

36

6

Prednisolone

Solubility and dissolution improvement

37

7

Atorvastatin

Flowability and compressibility

38

8

Propranolol

For designing of sustain release tablet

39

CONCLUSSION
This novel Liquisolid technique is found to be efficient method for formulation of water insoluble solid drugs and liquid lipophilic drugs. Liquisolid technique gives a design to enhance the absorption as well as dissolution rate their by it may enhance the bioavailability of a poorly soluble, insoluble or lipophilic drug and to formulate them into immediate release or sustain or control release by selection of suitable solvent and carrier.Liquisolid formulations are designed to contain liquid medications in powdered form and hence possess drug delivery mechanisms similar to that of soft gelatin capsule preparations, containing liquids. Liquisolid formulations show better flowability, compressibility, improve solubility, dissolution and hence better absorption.The technique is also used to design sustained release systems by using hydrophobic carriers instead of hydrophilic carries in liquisolid systems.

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