Formulation and Evaluation of Orodispersible Liquisolid compacts

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Orodispersible liquisolid system is the combination of liquisolid technique and orodispersible system. The poor dissolution rate of water insoluble drug is a major drawback for the development of pharmaceutical dosage forms. The oral absorption of drug is most often controlled by dissolution in the gastrointestinal tract. Liquisolid system has been used to enhance dissolution rate of poorly water-soluble drugs. Orodispersible tablets are given in order to provide fast action by disperse in the mouth, without the need of water and make them compliance for paediatric and geriatric patients and to bypass the liver metabolism.

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DEPARTMENT OF PHARMACEUTICS,COLLEGE OF PHARMACY MOTHER THERESA POSTGRADUATE AND RESEARCH INSTITUTE OF HEALTH SCIENCES. (A GOVT. OF PUDUCHERRY INSTITUTION) INDIRANAGAR, GORIMEDU, PUDUCHERRY-605006 . FORMULATION AND EVALUATION OF ORODISPERSIBLE LIQUISOLID COMPACTS Presented By P.VINOTH KUMAR B.Pharm M.PHARM II-YEAR (Reg.No:16150154) Under the guidance of Dr. A.N.RAJALAKSHMI M.Pharm., Ph.D. Mr. P. STEPHEN M.Tech., M.Pharm HOD, Dept. Of Pharmaceutics MANAGER, FR & D. MTPG & RIHS, PUDUCHERRY-6. Sai Mirra Innopharm Pvt., Ltd. Chennai.

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INTRODUCTION Many newly developed drugs are poorly water soluble compounds, which lead to problems in the development of dosage forms with sufficient bioavailability. Solubility is the most important parameter to achieve the desired concentration of the drug in the systemic circulation for therapeutic response to be shown . The majority of the hydrophobic drugs are sparingly soluble, slightly soluble, very slightly soluble and practically insoluble drug. For each drug substances mentioned above, the dissolution is the rate- limiting step; so, the challenges for absorption of poorly water-soluble drugs are to improve the dissolution rate. This lead to enhancement of the absorption and bioavailability of these drugs. The term liquid-solid systems refer to the “powdered forms of liquid drugs formulated by changing liquid drugs, drug suspensions or solutions of water- insoluble solid drugs in suitable non-volatile vehicle systems into dry, non-adherent, freely flowing and readily compressible powder mixtures” by simple mixing with selected powder excipients known as the carrier and coating materials. Generally, micro-crystalline cellulose (Avicel®) is utilized as the carrier material and amorphous silicon dioxide (colloidal silica) as a coating material 1

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ODT’s Many patient groups like elderly, children and mentally retarded patients who are uncooperative, nauseated or on decreased liquid intake/diets have difficulties in swallowing the solid dosage forms. Those who are travelling or have little water access are evenly affected. To accomplish these medical needs, pharmaceutical technologists have developed a patient-friendly novel oral dosage form known as “Orally Disintegrating Tablets ” which disintegrate rapidly in saliva, usually within seconds, without need for water . Drug dissolution, absorption, the onset of therapeutic effect and drug bioavailability may be significantly better than those obtained from conventional dosage forms 2

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CONCEPT OF LIQUISOLID SYSTEM The liquid initially absorbed in the interior of the particles is captured by its internal structure After the saturation of this process, adsorption of the liquid onto the internal and external surfaces of the porous carrier particles occurs. The coating material having high adsorptive properties and large specific surface area provides the liquisolid system the desirable flow characteristics The wettability of the compacts in the dissolution media is one of the proposed mechanisms for explaining the enhanced dissolution rate from the liquisolid compacts. 3

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CLASSIFICATION OF LIQUISOLID SYSTEMS Liquisolid systems are classified based on two approaches. They are 1. Powdered drug solutions 2. Powdered drug suspensions 3. Powdered drug emulsions 4. Powdered liquid drugs The first three may be produced from the conversion of drug solutions or drug suspensions and emulsions, the later from the formulation of liquid drugs into liquisolid systems. A. Based on the Type of liquid Medication 1. Liquisolid compacts 2. Liquisolid microsystems The liquisolid microsystems are based on a new concept which employs similar methodology combined with the inclusion of an additive e.g. PVP B. Based on the Formulation Technique 4

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THEORETICAL ASPECTS OF LIQUISOLID SYSTEMS Flowable liquid retention potential determination: The flowable liquid retention potential (Φ-value) of a powder is defined as the maximum amount of a given non-volatile liquid that can be retained inside its bulk (w/w) while maintaining acceptable flowability . weight of liquid Φ= weight of solid Lf= Øca + Ø co(1 / R ) The Φ-values for carrier and coating material has been abbreviated as Ф CA and Φ CO respectively. The carrier and coating material with maximum liquid retention potential have been selected as optimum. 5 For getting good flow behavior and compressibility of liquisolid systems a mathematical model designed by Spireas is used as formulation design model for the liquisolid tablets. Prerequisites for this include suitable drug candidate, suitable non-volatile solvent, carrier and coating materials. The amounts of excipients (carrier and coating materials) used to prepare liquisolid compacts depend on the flowable liquid retention potential values (Ф-value) and the liquid loading factors (Lf).

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Liquid load factor The amount of carrier: coat admixture is used to convert into free flow powder and it is determined by using the following formula W Lf = Q W= weight of liquid Q= weight of carrier material It is used to calculate the amount of carrier and coating material in each formulation. Excipient ratio The excipients ratio R of powders is defined as ratio of weight of carrier and coating material present in the formulation. R is suitably selected for successful formulation. Q R= q Q = weight of carrier q = coating material 6

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Non-volatile solvents Φ-value for carrier material ( Avicel PH102) Φ-value for coating material ( Aerosil 200) Propylene glycol 0.16 3.31 PEG-400 0.005 3.26 Tween 80 0.003 3.95 Cremophor EL 0.18 0.80 capryol 90 0.16 0.40 The Φ-value for Avicel PH 102 and Aerosil 200 is reported in the table below 7

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COMPONENTS OF LIQUISOLID SYSTEMS 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. 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, polysorbates,glycerin , fixed oils, etc. DISINTEGRANT Superdisintegrants increases the rate of drug release,water solubility and wettability of liquisolid granules. Mostly Superdisintegrants like Croscarmellose sodium , Sodium starch glycolate , Crospovidone are used 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, Avicel PH 102 and 200 ,starch, lactose , sorbitol , Eudragit RL and RS, amorphous cellulose etc. 8

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METHOD OF PREPARATION OF LIQUISOLID SYSTEM If liquisolid system of a solid water-insoluble drug is to be formulated, it should be initially dissolved or suspended in a suitable non-volatile solvent system to produce a drug solution or drug suspension of desired concentration. Next, a certain amount of the prepared drug solution or a liquid drug itself is incorporated into a specific quantity of carrier material which should be preferably of a porous nature and possessing sufficient absorption properties. The resulting wet mixture is then converted into a dry-looking, non adherent, free-flowing and readily compressible powder by the simple addition and mixing of a calculated amount of coating material. Before compression or encapsulation,various adjuvant like lubricants and disintegrants (immediate release) or binders (sustained release) may be added to final liquisolid system to produce liquisolid compacts. 9

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MECHANISMS OF ENHANCEMENT OF DRUG RELEASE If the drug within the liquisolid system is completely dissolved in the liquid vehicle, it is located in the powder substrate still in a solubilized and molecularly dispersed state. The surface area of drug available for release is much greater than that of drug particles within directly compressed tablets. Increased Effective Surface Area In addition to the first mechanism of drug release enhancement, it is expected that the solubility of the drug might be increased with liquisolid systems. Increased Aqueous Solubility Due to the fact that the liquid vehicle can either act as surface active agent or has a low surface tension, wetting of the primary liquisolid particles is improved. Improved Wetting Properties 10

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Drug release can be modified using suitable formulation ingredients Several slightly and very slightly water- soluble and practically water-insoluble liquid and solid drugs can be formulated into liquisolid systems. Better availability of an orally administered water insoluble drug. Production of liquisolid systems is similar to that of conventional tablets. Can be used in controlled drug delivery. Rapid release liquisolid tablets or capsules of water insoluble drugs exhibit enhanced In-vitro and in-vivo drug release when compared to their commercial counter parts, including soft gelatin capsules preparation. ADVANTAGES Liquisolid compact technology is a powerful tool to improve bioavailability of water insoluble drugs. Rapid release rates are obtained in liquisolid formulations. Can be efficiently used for water insoluble solid drugs or liquid lipophilic drugs. Designing of Controlled Release Tablets Bioavailability Enhancement Application in probiotics . The possibility of using liquisolid technique as a promising alternative to conventional coating for the improvement of drug photostability APPLICATIONS 11

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ORODISPERSIBLE TABLETS The concept of orodispersible tablet emerged with an objective to improve patient’s compliance. These dosage forms rapidly disintegrate and/or dissolve to release the drug as soon as they come in contact with saliva, thus without the need for water during administration, an attempts that makes them highly attractive for pediatric and geriatric patients. 12

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SYNONYMS OF ORALLY DISINTEGRATING DOSAGE FORM S Melt-in-FAST tablets Repimelts Porous tablets Oro-dispersible Quick dissolving Rapid disintegrating tablets. 13

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CHALLENGES AND LIMITATIONS FOR ODTs Drugs with relatively larger doses are difficult to formulate into ODTs Mechanical strength - ODTs are made of porous or soft molded matrices in order to allow its disintegration in mouth. This makes tablet friable and handling becomes diffilcult Palatability - ODTs are intended to be dissolved in mouth. Most of the drugs have bitter taste. Bitter taste can be masked with enough sweetener and flavors . Size of tablet - 7 and 8 mm are easy to swallow while tablets of size 8mm are easy to handle. Hence, tablet sizes which are both easy to handle and swallow are difficult to achieve. Drug candidates should be stable both in water and in saliva, should not ionize at oral cavity pH and should be able to permeate oral mucosal tissue to diffuse and partition in upper GI epithelium ( logP > 1, or preferably > 2) ODT requires special packaging for proper stabilization and safety of stable product. Drugs in form of ODTs are hygroscopic in nature and hence need to be protected from humidity. 14

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APPROACHES FOR ORODISPERSIBLE TABLETS 15

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DRUG SELECTION CRITERIA  Able to saturate the oral mucosa.  At least moderately non-ionized at oral cavity pH.  Have the ability to diffuse and partition into the epithelium of upper GIT.  Small to moderate molecular weight  Low dose drugs mostly less than 50 mg.  Should have good stability in saliva and water.  Should have lower bio availability are good candidates for ODT. ADVANTAGES Administration to the patients who cannot swallow, such as the elderly, stroke victims, bedridden patients, patients affected by renal failure & patients who refuse to swallow such as pediatric , geriatric & psychiatric patients. Rapid drug therapy intervention. Achieve increased bioavailability/rapid absorption through pregastric absorption of drugs from mouth, pharynx & esophagus as saliva passes down. Good mouth feel property helps to change the perception of medication as bitter pill particularly in pediatric patients. The risk of chocking during oral administration of conventional formulations due to physical obstruction is avoided, thus providing improved safety. 16

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Spireas (2002) developed and patented a method of producing a free-flowing and compressible liquid/powder admixture of a liquid medication. The method involves conversion of the liquid medication into a liquisolid system using a carrier material and a coating material to be included in the liquisolid system. The patent describes the process of admixture of the liquid medication with optimum quantity of carrier material to make a wet mixture and blending it with the coating material to produce a non-adherent, free-flowing and compressible liquid/ powder admixture. The amounts of liquid medication,carrier material and coating material were calculated by a mathematical model to optimize flow and compressibility according to values predetermined by liquisolid flowability and liquisolid compressibility tests Arun Raj et al (2013) developed several formulations of liquisolid compacts having different drug concentration (15% to 40% w/w) and with varying ratios of carrier to coat (i.e., different R values,ranging from 15 to 20) were prepared. Avicel and aerosil were used as carrier and coat material,respectively,and poly ethylene glycol was used as a nonvolatile liquid to prepare liquid medication. The values of post-compression parameters were found to be within IP, BP limits. The liquisolid tablets of nifedipine were compared with directly compressed tablets of nifedipine and the results revealed that liquisolid tablets shows much higher dissolution rate than the directly compressed conventional tablets Jayashri Y Chaudri et al (2014) formulated different liquisolid tablets by suspending Nifedipine in PEG 400 with Avicel PH 102 as carrier, Aerosil 200 as coating material and Sodium starch glycolate as disintegrating agent The formulated liquisolid tablets were evaluated for post compression parameters such as weight variation, hardness, friability and drug content uniformity. The result showed that liquisolid formulation of Nifedipine exhibited higher percentage of drug release than directly compressed tablets which show significant benefit of liquisolid tablet in increasing wetting properties and surface area of drug available for dissolution. LITERATURE REVIEW FOR LSC 17

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Mohanchandran P.S et.al (2010) In this study, fast dissolving tablets of amlodipine besylate using different superdisintegrants were prepared by direct compression method. Effect of different superdisintegrants on disintegration behaviour of tablets was evaluated in phosphate buffer pH 7.2. All formulations were evaluated for pre‐compression and post‐ compression parameters.Wetting time of formulations containing croscarmellose sodium was least and tablets showed fastest disintegration. FT‐IR studies revealed that there was no physico ‐ chemical interaction between amlodipine besylate and other excipients . Of the twelve formulations studied, F10 showed short dispersion time with maximum drug release in 30 minutes Hemant D. Patil et al (2014) In the present research, mouth dissolving tablet of Nifedipine was made using various tabletiing aids. The prepared tablets were evaluated for weight, thickness, hardness, friability with disintegration time of less than 30 seconds and drug dissolution of about 75 % achieved within 30 minutes. The prepared tablets were stability tested at 40°C having 75 % Relative Humidity for 3 months and were found to be stable. Prepared mouth dissolving tablets of Nifedipine 10 mg was found to be bioequivalent under fasting and fed conditions with the marketed product. Omprakash G et al (2015) solid dispersions of Nifedipine were formulated with five different polymers as PVP k30, PEG 4000, PEG 6000, Urea and Mannitol.The solid dispersion giving the maximum solubility was formulated into fast dissolving tablets using various ratios of cross povidone and cross carmellose sodium ( ccs ) as superdisintegrants . Based on the in-vitro disintegration time, Promising formulations F5and F6, which facilitate the faster disintegration in the mouth. LITERATURE REVIEW FOR ODTs 18

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Mustafa et al (2016) developed l iquisolid ODTs of zolmitriptan were prepared from; microcrystalline cellulose (Avicel PH-102) as carrier, colloidal silicon dioxide ( Aerosil 200) as a coating material, croscarmellose sodium (CSS), sodium starch glycolate (SSG), and crospovidone (CP) as super disintegrants , and propylene glycol as liquid vehicle.The prepared liquid-solid system compacts were evaluated for their post-compression evaluation which includes: hardness, friability, wetting time,  in vitro disintegration time, drug content and  in vitro  drug release.Among the three super disintegrants , CP found to be the best in term of showing the fastest disintegration time. The optimized selected formula (F11) was prepared using 5% w/w crospovidone , by direct compression showed the shortest disintegration time (24 s), superior drug release profile Hamsanandhini J et al (2015) developed Orodispersible liquisolid compact of Meloxicam by direct compression method using PEG 600, MCC and silica gel as non-volatile solvent, carrier, coating material respectively and Banana powder as natural superdisintegrants in different concentration 2.5 mg, 5 mg, 7.5 mg, 10 mg respectively. The liquisolid compact were characterized by X-ray powder diffraction, DSC and FT-IR respectively. Orodispersible liquisolid compacts of Meloxicam tablets (F4) containing banana powder exhibit quick disintegration time and maximum drug release. LITERATURE REVIEW FOR OD-LSC 19

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A. BULK DENSITY Bulk density = Weight of the powder/Bulk volume of powder   B.TAPPED DENSITY Tapped density= Weight of powder taken/ Tapped Volume   C. COMPRESSIBILITY INDEX Compressibility index (%) = ρt – ρo * 100 / ρt . D.HAUSNER’S RATIO Hausner ratio= Tapped density/ Bulk density E.ANGLE OF REPOSE tan ϴ = h/ r PRE-COMPRESSION EVALUATION OF POWDER BLEND . 20

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POST COMPRESSION STUDIES OF ORODISPERSIBLE LIQUISOLID COMPACTS

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A.GENERAL APPEARANCE: The general appearance of a tablet, its visual identity and over all "elegance" is essential for consumer acceptance. Include in are tablet's size, shape, colour, presence or absence of an odour, surface texture, physical flaws and consistency and legibility of any identifying marking. B.SIZE AND SHAPE: The size and shape of the tablet can be dimensionally described, monitored and controlled C.THICKNESS: The thickness of tablets is measured by Vernier Caliper . It is expressed in mm. The thickness variation allowed are ± 5% of the size of the tablet. 21

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D.WEIGHT VARIATION TEST: Twenty tablets are randomly selected from each batch and individually weighed.It passes the test if less than two of the individual tablet weights deviate from the weight by quite than the allowed proportion deviation and none deviate by more than twice the proportion shown. It was calculated on an electronic weighing balance. E.HARDNESS (CRUSHING STRENGTH): Tablet hardness is measured with hardness testers like Monsanto. The hardness of ODTs is generally kept lower than conventional tablets as increased hardness delays the disintegration of the tablet. A good compromise between mechanical strength and disintegration time is achieved for a satisfactory mouth dissolving formulation. 22 Average weight of tablet Percentage deviation 80 mg or less ± 10 More than 80 mg but less than 250 mg ±7.5 250 mg or more ±5

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F.FRIABILITY: Friability is a measure of mechanical strength of the tablet. If a tablet has more friability it may not remain intact during packaging, transport or handling.The friability of the tablet can determined using Roche Friabilator . It is expressed percentage (%). 10 tablets weighed and transferred into the friabilator . The friabilator was operated at 25 rpm for 4 minutes.The tablets are weighed again. And the % friability is calculated as Friability=([ W o –W]/ Wo )100 Where,Wo =initial weight of tablet, W = after test weight of tablet. G. INVITRO DISPERSION TIME: The tablet is then carefully positioned in the centre of the Petri dish containing 6 ml of water and the time required for the tablet to completely disintegrate into fine particles is noted. Three tablets from each formulation are randomly selected and In-vitro dispersion time is measured. H.UNIFORMITY OF DISPERSION: Keep the Two tablets in 100ml water and stir gently for 2 minutes. The dispersion is passed through 22 meshes. The tablets will consider passing the test if no residue remained on the screen. 23

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I.MOISTURE UPTAKE STUDIES: It is an important study in the case of orodispersible tablets. This study is carried out in order to assess the stability of the tablets. 10 tablets are kept in the desiccators over calcium chloride at 37°C for 24 h. The tablets are then weighted and exposed to 75% relative humidity, at room temperature for 2 weeks.Required humidity is achieved by keeping saturated sodium chloride solution at the bottom of the desiccators for 3 days. One tablet as control (without super- disintegrant ) is kept to assess the moisture uptake due to other excipients . Tablets are weighed and the percentage increase in weight is recorded J.WETTING TIME: A piece of tissue paper is folded and placed twice and placed in small petri dish containing sufficient water. A tablet is kept on the paper and the time for complete wetting of tablet is measured. 24

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K.WETTING ABSORPTION RATIO: The weight of the tablet prior to placement in the petri dish is noted ( Wb ). The wetted tablet is removed and reweighed ( Wa ). Water absorption ratio R, is then determined by R = 100 × ( Wa - Wb )/ Wb Where Wb and Wa are tablet weights before and after water absorption, respectively L. IN-VITRO DISINTEGRATION TEST: To perform this,a modified DT apparatus is used. Here a wire basket of 3cm height and 2 cm diameter and mesh size of #10 is placed above a beaker containing 900 ml of simulated saliva. The basket is so positioned in the liquid that it contains only 6 ml of the liquid. The assembly is supported with a heater to maintain temperature at 37°C and a magnetic stirrer.DT is noted at 25 rpm. One of the simplest methods is to take 6ml of simulated saliva in a measuring cylinder and place the tablet in it. The liquid is neither shaken nor stirred and DT is noted. 25

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M.DISSOLUTION TEST: The dissolution method for oral disintegrating tablets is the same as that of conventional tablets. USP 2 paddle apparatus is most suitable and common choice for dissolution test of oral disintegrating tablets, where the paddle speed is 50 rpm is used. The USP 1 (basket) apparatus may have certain application for such tablets but is used less frequently due to specific physical properties of tablets. N.DIFFERENTIAL SCANNING COLORIMETRY: Differential Scanning Colorimetry (DSC) is performed in order to assess the thermo tropic 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 formulation of the drug solution in the liquisolid powder system, i.e., the drug is molecularly dispersed within the liquid matrix. 26

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O.POWDER X-RAY DIFFRACTION: The disappearance of characteristic peaks and holding of additional peaks of carriers within the liquisolid formulation is observed. It indicates that drug converted to amorphous form or to stabilized form. P.SCANNING ELECTRON MICROSCOPY: After SEM study, complete disappearance of crystals of the drug which confirms that the drug is totally solubilized in liquisolid system and this ensures the complete solubility. Q.DRUG CONTENT UNIFORMITY: Ten tablets is randomly selected and allow to equilibriate with Phosphate buffer pH 7.4 overnight and the solution is filtered after 24 hrs.Suitable concentrations can be made with the same to get the concentrations in Beer’s range. Absorbance of the solution is noted using Phosphate buffer pH 7.4 as a blank and drug content per tablet was calculated. 27

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The Liquisolid system is a technique for formulation of water insoluble drugs to enhance their aqueous solubility, absorption as well as dissolution rate which leading to enhancement of bioavailability of drugs as compared to conventional directly compressed tablets . Orodispersible tablets may give rapid onset of action by rapid absorption through pre-gastric absorption of drug from mouth, pharynx and oesophagus as saliva passes down and beneficial to reduce dose. By combining Liquisolid technique and Orodispersible DDS, may enhance solubility , dissolution rate by means of Liquisolid technique and can achieve rapid onset of action with lower dose of drug by using Orodispersible DDS and hence may increase patient compliance. CONCLUSION 28

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1.Spireas, S., Liquisolid systems and methods of preparing same. United State Patent 6423,339 B1. 2.Spireas, S., Sadu , S., Enhancement of prednisolon dissolution properties using liquisolid compacts. Int. J. Pharma, 1998: 166,177-188 3.Shashidher, B., Veera , R.,Formulation and evaluation of carvedilol liquisolid tablets. A. j. p. s. p, 2012:30-44. 4..Sambasiva AR and Naga TA. Liquisolid Technology: An Overview. Int J Res Pharma Biomed Sci , 2011; 2(2): 401-409 5.Javadzadeh Y and Nokhodchi A. Liquisolid technique for dissolution rate enhancement of a high dose water-insoluble drug ( carbamazepine ). Int J Pharm. 341:26-34 6.Dobetti  L. Fast‐  Melting  Tablets:Developments   and  Technologies: Pharmaceutical Technology. Drug Delivery  2001  (Supplement): 44‐50.   7. Mr. Hemant D. Patil . Formulation and Evaluation of Nifidepine Mouth Dissolving Tablet by Direct Compression Method: Imperial J. of Interdisciplinary Research Vol-2, Issue-11, 2016:105-109 8.Allen  LV, Wang  B, Davis  JD, et al. US patent NO.5, 807, 567, 1998  9.Rish  RK.  A  review  on  fast  dissolving  tablets  techniques.  The  Pharma  Review 2004; 2: 32.  10. Ayesha S, Venkateswara R, Santosh G. Asra J.A Novel Approach to Enhance Solubility of Olmesartan Medoxomil by Liquisolid Compact Technique, International Journal of Pharmaceutical and Chemical Sciences .2015; 4(2). REFERENCE 29

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