LIQUISOLID COMPACT A REVIEW
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1 LIQUISOLID COMPACT A REVIEW KISHOR S. GAVHANE*, Dr.F.J.SAYYAD Govt. college of pharmacy, Vidyanagar, Karad , Satara, Maharashtra India. Shivaji University, Kolhapur, Maharashtra, India. Ph : Id: kishor.gavhane99@gmail.com ABSTRACT Liquisolid compact were used to formulate water insoluble drugs in non-volatile solvent and convert into acceptably flowing and compressible powders. the main of this method is enhance the dissolution rate and bioavailability of BCS II drugs. About 40-50% of drugs available in market are water insoluble in nature. In recent generations the limited solubility of drugs, which are challenging issue for industry during development of the ideal solid dosage unit. To overcome this consequence, liquisolid technique is a novel and promising approach. The technique is based upon the admixture of drug loaded solutions (or) liquid drug with appropriate carrier(microcrystalline cellulose,starch, lactose) and coating material(silica gel)it also contain disintegration agent used. Addition of the additives improves the technique. The selection of non-toxic hydrophilic solvent, carrier, coating excipients and its ratios are independent of the individual chemical entities. Indirectly it leads to enhance the bioavailability. However, poorly soluble drugs with low dose chemical entities are more ideal to formulate to this technique KEY WORDS: solvent poorly soluble drugs,liquisolid compact,carrier,coating,non-volatile. INTRODUCTION Therapeutic effectiveness of a drug depends upon the bioavailability which i dependent on the solubility and dissolution rate of drug molecules.solubility is one of the important parameter to achieve desired concentration of drug in system circulation for pharmacological response to be shown. Poorly water soluble drugs will be inherently released at a slow rate owing to their limited solubility within the GI contents. The dissolution rate is often the rate determining step in the drug absorption. The challenge for poorly water soluble drugs is to enhance the rate of dissolution. This in turn subsequently improves absorption and bioavailability Formulation methods targeted a dissolution enhancement of poorly soluble substances are continuously introduced1.as large proportions of new drug candidates have poor aqueous solubility,various formulation strategies were reported to overcome such a problem. Among these techniques is complexation with cyclodextrins, micronization, solid candidates have poor aqueous solubility, various formulation strategies were reported to overcome such a problem. Among these techniques is complexation with cyclodextrins, micronization, solid dispersion, co-precipitation and recently, the technique of liquisolid compacts. Several studies have shown that the liquisolid technique is a promising method for promoting dissolution rate of poorly water soluble drugs2-8. In liquisolid compact, a liquid medication is converted into acceptably flowing and compactible powder forms. The term liquid medication implies liquid lipophilic (oily) drug and solution or suspension of poorly water soluble drugs carried in suitable water miscible non-volatile liquid systems termed the liquid vehicle. By simple blending with suitable excipients carrier and coating materials, the liquid medication may be converted into a dry looking, non-adherent, free flowing and readily compactible powder9. Since drug dissolution is often the rate limiting step in gastrointestinal absorption, the significant increase in wetting properties and surface area of drug particles available for dissolution from liquisolid compacts may be expected to display enhanced drug release characteristics and,consequently, improved oral bioavailability. Components of Liquisolid Compact Formulation 10,16 1. Non volatile solvent 2. Disintegrant 3. Carrier material 4. Coating material 1. Non volatile Solvent Non volatile Solvent should be Inert, high boiling point, preferably water-miscible and not highly viscous organic solvent systems and compatible with having ability to solubilise the drug. The non volatile solvent acts as a binding agent in the liquisolid formulation Various non-volatile solvents sed for the formulation of liquisolid systems include Polyethylene glycol 200 and 400, glycerin, polysorbate 80 and propylene glycol. 2. Disintegrant ISSN : X Vol 4 Issue 2 Apr-May
2 Super disintegrate increases the rate of drug release, water solubility and wet ability of liquisolid granules. Mostly super disintegrates like sodium starch glycolate and crosspovidone. 3. Carrier Materials Carrier material should be porous material possessing sufficient absorption properties which contributes in liquid absorption.the carrier and coating materials can retain only certain amounts of liquid and at the same time maintain acceptable flow and compression properties hence, increasing moisture content of carrier s results in decreased powder flow ability These include grades of microcrystalline cellulose such as avicel PH 102 and avicel PH 200, Coating Materials Coating material should be a material possessing fine and highly adsorptive particles which contributes in covering the wet carrier particles and displaying a drylooking powder by adsorbing any excess liquid.coating material is required to cover the surface and maintain the powder flowability.coating material includes silica (Cab-O-Sil) M520,35,Aerosil 2003,syloid. CLASSIFICATION 16 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 classifies 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 micro systems are based on a new concept which to produce an acceptably flowing admixture for encapsulations. 2 ADVANTAGES OF LIQUISOLID COMPACT 1. A great number of slightly and very slightly water-soluble and practically water-insoluble liquid and solid drugs can be formulated into liquisolid systems using the new formulation mathematical mode. 2. This technique is successfully Applied for low dose water insoluble drug. 3. The absolute bioavability of the drug from the liquisolid tablet is 15% higher than that commercial one. 4. There production cost is lower than that of soft gelatin capsules because the production of liquisolid systems is similar to that of conventional tablets. 5. Drug dissolution from liquisolid compact is independent to the volume of dissolution media. 6. Most of liquid or solid water insoluble drug may be formulated into immediate release or sustained release Liquisolid compact or Liquisolid microsystem. 3 LIMITATIONS 1. This techniques is not applicable for high dose insoluble drug. 2. Mathematical calculation require4 ADVANTAGES OF LIQUISOLID COMPACT 1. A great number of slightly and very slightly water-soluble and practically water-insoluble liquid and solid drugscan be formulated into liquisolid systems using the new formulation-mathematical mode. 2. This technique is successfully applied for low dose water insoluble drug. 3. The absolute bioavability of the drug from the liquisolid tablet is 15% higher than that commercial one. 4. There production cost is lower than that of soft gelatin capsules because the production of liquisolid systems is similar to that of conventional tablets. 5. Drug dissolution from liquisolid compact is independent to the volume of dissolution media. ISSN : X Vol 4 Issue 2 Apr-May
3 6. Most of liquid or solid water insoluble drug may be formulated into immediate release or sustained release Liquisolid compact or Liquisolid microsystem.3 Limitations 2,5 Not applicable for formulation of high dose insoluble drugs. 1. 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. 2. 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. 3. 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 Theory of Liquisolid Systems A powder can retain only limited amounts of liquid while maintaining acceptable flow and compression properties. To calculate the required amounts of powder excipients(carrier and coating materials) a mathematical approach for the formulation of liquisolid systems has been developed by Spire as 12,13. This approach is based on the flow able (Ф-value) and compressible (Ψ-number) liquid retention potential introducing constants for each powder/liquid combination. The Ф-value of a powder represents the maximum amount of a given non-volatile liquid that can be retained inside its bulk [w/w] while maintaining an acceptable flow ability. The flow ability may be determined from the powder flow or by measurement of the angle of repose.the Ψ-number of a powder is defined asthe maximum amount of liquid the powder can retain inside its bulk [w/w] while maintaining acceptable compatibility resulting in compacts of sufficient hardness with no liquid leaking out during compression 14. The comp actability may be determined by the so-called plasticity which describes the maximum (plateau) crushing strength of a one-gram tablet compacted at sufficiently high compression forces. The terms acceptable flow and compression properties imply the desired and thus As soon as the optimum liquid load factoris determined, the appropriate quantities of carrier (Qo) and coating (qo) material properties which must be met by the final liquisolid formulation.depending on the excipient ratio (R) of the powder substrate an acceptably flowing and compressible liquisolid system can be obtained only if a maximum liquid load on the carrier defined as the weight ratio of the liquid formulation (W) and the carrier material (Q) in the system: Lf = W/Q (1) R represents the ratio between the weights of the carrier (Q) and the coating(q) material present in the formulation: R =Q/q (2) The liquid load factor that ensures acceptable flowability (Lf ) can be determined by: Lf =Φ+ φ. (1/R) (3) Where Φ and φ are the Ф-values of the carrier and coating material, respectively. Similarly, the liquid load factor for production of liquisolid systems with acceptable compact ability (ΨLf) can be determined by: ΨLf = Ψ+ψ *(1/R) (4) Where Ψ and ψ are the Ψ-numbers of the carrier and coating material, respectively. In liquisolid formulation parameters of various powder excipients with commonly used liquid vehicles are listed. Therefore, the optimum liquid load factor(lo) required to obtain acceptably flowing and compressible liquisolid systems are equal to either ΦLf or ΨLf, which ever represents the lower value. required to convert a given amount of liquid formulation (W) into an acceptably flowing and compressible liquisolid system may be calculated as follows: Q0 = W/Lo-----(5) And q0 = Q0/R (6) The validity and applicability of the above mentioned principles have been tested and verified by producing liquisolid compacts possessing acceptable flow and compaction properties Determination of solubility: Saturated solutions were prepared by adding excess drug to the polyethylene glycol and shaking on a shaker for 48 h at 25 C with constant vibration. The solutions were filtered through a 0.45 micron filter, diluted with water, and analyzed with a Shimadzu1700 UV-Vis spectrophotometer at specific wavelength with respect to a blank sample (the blank sample was a solution containing the same concentration used without the drug). Determination was carried out in triplicate for each sample to calculate th solubility. Preparation of liquisolid tablets ISSN : X Vol 4 Issue 2 Apr-May
4 Calculated quantities of drug and no volatile solvent is accurately weighed in 20ml glass beaker and then heated to dissolve the drug in that solvent. The resulting hot medication is incorporated into calculated quantities of carrier and coating materials. Mixing process is carried out in three steps as described by Spire as et al. During the first stage, the system is blended at an approximate mixing rate of one rotation per second for approximately one minute in order to evenly distribute liquid medication in the powder. In the second stage, the liquid/powder admixture is evenly spread a sa uniform layer on the surfaces of a mortar and left standing for approximately 5 min to allow drug solution to be absorbed in the interior of powder particles. In the third stage, the powder is scraped off the mortar surfaces by means of aluminium spatula and then blended with sodium starch glycolate for another 30 seconds in a similar way to the first stage. This gives final liquisolid formulation to be compressed. Precompression studies 1 Flow properties: Flow properties of liquisolid formulation were studied by angle of repose, Carr's index, and Hausner's ratio 13. Each analysis was carried out in triplicate. Bulk density measurements were carried by placing a fixed weight of powder in a graduated cylinder, and the volume occupied was Pre-formulation Studies Pre-formulation Studies includes 1. Determination solubility of drug in different non-volatile solvents 2. Determination of angle of slide 3.Determination of flow able liquid retention potential (Φ value) 4. Calculation of liquid load factor (Lf) 5. Liquisolid compressibility test (LSC )8 Pre Compression Evaluations The flow ability of a powder is of critical importance in the production of pharmaceutical dosage forms in order to ge ta uniform feed as well as reproducible filling of tablet dies, otherwise, high dose variations will occur. In order to ensure the flow properties of the liquisolid systems that will be selected to be compressed into tablets and further evaluated, angle of repose measurements, Carr s index and Hausner s ratios were adopted. Post compression Evaluations a) Content of uniformity b) Hardness c) Weight variation d) Friability e) Disintegration f) In - vitro dissolution studies These are should be in the official limits prescribed by official pharmacopoeia. 10 Evaluation of Liquisolid Systems Flow behavior Flow properties are the important concern inthe formulation and industrial production oftablet dosage form. Angle of repose is characteristic to the flow rate of powder. In general, values of angle of repose 40ºindicate powders with poor flow ability. Differential Scanning Calorimetry (DSC) It is necessary to determine any possible interaction between excipients used in the formulation. This will also indicate success of stability studies41. If the characteristic peak for the drug is absent in the DSC thermo gram, there is an indication that the drug is in the form of solution in liquisolid formulation and hence it is molecularly dispersed within thesystem X-ray diffraction (XRD) Generally, disappearance of characteristic peaks of drug in the liquisolid formulation and retaining peaks of carrier material is observed. This indicates that drug gets converted to amorphous form or in solubilized form in the liquisolid formulation.scanning Electron Microscopy (SEM) After SEM study, complete disappearance of crystals of drug which confirms that drug is totally solubilized in liquisolid system and this ensures the complete solubility. Fourier Transform Infrared spectroscopy ISSN : X Vol 4 Issue 2 Apr-May
5 (FTIR) FTIR studies are performed to determine the chemical interaction between the drug and excipients used in the formulation. Th presence of drug peaks in the formulation and absence of extra peaks indicates ther is no chemical interaction. 11 Estimation of drug content: 16 The liquisolid compacts are powdered well and powder equivalent to 10 mg of the drug is accurately weighed and suitably diluted using methanolic sulphuric acid. The drug content is calculated by at wavelength using UV-Visible spectrophotometer. In-vitro drug release study: 16 The in-vitro dissolution study is carried out for a period of 1 hour using USP XXIV type-ii (paddle) method with 900 ml of 0.1 N HCl and distilled water as the dissolution media at required rpm and 37oC+0.5oC. 10 ml of the sample is withdrawn and filtered at periodic time intervals in minutes. 10ml of fresh dissolution fluid is replaced to the baskets to maintain the constant volume (sink condition). The filtered samples are analyzed at wavelength by UV/Visible spectrophotometer. The mean of n=3 determination sis used to calculate the percentage drug release from each formulation.p.gowree Manogar et al /J. Pharm. Sci. & Res. Vol.3(12), 2011, Applications3,9 1. It gives rapid release and sustained release of drugs are obtained in liquisolid formulations. 2. Sustained release of drugs which are water soluble drugs such as propranolol hydrochloride has been obtained by the use of this technique. 3. Solubility and dissolution enhancement. 4. Designing of controlled release tablets. 5. Application in probiotics. CONCLUSION In conclusion, liquisolid compact refers to formulations formed by conversion of solid state to liquid state, 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 agents. The formed liquisolid tablets dosage form showed significantly greater extent of absorption due to their solubility and dissolution improvement. The technique is also used to design sustained release systems by using hydrophobic carriers instead of hydrophilic carries in liquisolid systems. Therefore, this formulation of the drug has the potential to be considered for human study in order to be manufactured on large scale. REFERENCE [1] Fahmy RH, Kassem MA. Enhancement of famotidine dissolution rate through liquisolid tablets for mulation: In vitro and in vivo evaluation. Eur J Pharm Biopharm. 2008; 69: [2] K. Kavitha, Kotha N. S. Lova Raju, N.S Ganesh, B. Ramesh. Effect Of Dissolution Rate By Liquisolid Compact Approach: An Overview. Scholar Research Library. 2011;3(1):71-8 [3] Elkordy AA and Ngiik T. Effects of Liquisolid formulations on dissolution of Naproxen. Eur J Pharm Biopharm [4] Neelam Seedher and Sonu Bhatia. 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