Formulation and Evaluation of Orodispersible Liquisolid compacts of Ni

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The aim of the present study was to enhance the dissolution of a practically insoluble Nifedipine by liquisolid compact technique and to enhance the onset of action by Orodispersible tablet technique.


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INTRODUCTION 1 Liquisolid technique is a new and promising method that can change the dissolution rate of drugs. It has been used to enhance dissolution rate of poorly water-soluble drugs. ODT as “a solid dosage form containing medicinal substances, which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue”. ADVANTAGES Drug release can be modified using suitable formulation ingredients. Enhanced bioavailability can be obtained as compared to conventional tablets. Production of liquisolid systems is similar to that of conventional tablets. Improvement of drug photostability. Rapid drug therapy. Better patient compliance Good mouth feel

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THEORETICAL ASPECTS OF LIQUISOLID SYSTEMS Flowable liquid retention potential determination weight of liquid Φ= weight of solid Liquid load factor W Lf = Q W= weight of liquid medication; Q= weight of carrier material It is used to calculate the amount of carrier and coating material in each formulation. 3

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Excipient ratio Q R= q Q = weight of carrier; q = coating material The liquid load factor that ensures acceptable flowability (Lf) can be determined by: Lf = Ф CA + Ф CO (1/R) By calculating Lf and W, we can calculate the amount of Q and required for the liquisolid system 4

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MECHANISMS OF ENHANCEMENT OF DRUG RELEASE Increased Effective Surface Area: since drug particles is present in a solubilized and molecularly dispersed state. Increased Aqueous Solubility: The solubility of the drug might be increased with liquisolid systems. Improved Wetting Properties: Due to the fact that the liquid vehicle can either act as surfactant 5

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CHALLENGES AND LIMITATIONS FOR ODTs Drugs with relatively larger doses are difficult to formulate into ODTs Should have suitable mechanical strength Palatability Bitter taste can be masked with enough sweetener and flavours. Size of tablet - 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 should be able to permeate oral mucosal tissue (logP > 1, or preferably > 2) requires special packaging . hygroscopic in nature 6

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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 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. 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 were prepared. 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 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 7

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Mohanchandran P.S (2010) In this study, fast dissolving tablets of amlodipine besylate using different superdisintegrants were prepared by direct compression method. 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. 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. 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 crosscarmellose 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 8

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Mustafa et al (2016) developed liquisolid 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 9

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NIFEDIPINE Empirical formula: C 17 H 18 N 2 O 6 Molecular weight: 346.3346 g/mole Melting point: 173°C or 342 to 345° F  Solubility: Insoluble in cold water, hot water. Soluble in ethanol, dimethyl sulfoxide Absorption: Rapidly and fully absorbed following oral administration. Metabolism: Predominantly metabolized by CYP3A4. Storage: Sensitive to light . Store in light- resistant containers. DRUG PROFILE 10

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Pharmacokinetic parameter Values Protein binding 92-98% Half life 2 hours Log P 2.2 pKa 4.3 Elimination half life 2-5 hours PHARMACOKINETIC PARAMETERS 11 MECHANISM OF ACTION

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EXCIPIENTS PROFILE Description: clear, slightly yellow-colored, viscous liquids. slight but characteristic odour and a bitter. Functional uses: solvent POLYETHYLENE GLYCOL-400 12 MICROCRYSTALLINE CELLULOSE PH 102 Description: white free flowing powder Functional uses: Act as a carrier material . AEROSIL 200 Description: White powder Functional uses: Coating agent, Flow-promoting agent, CROSSPOVIDONE Description: white to creamy-white, finely divided, free flowing powder Applications: It rapidly exhibits high capillary activity

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Description: odourless, grayishwhite powder. Applications: super-disintegrants CROSCARMELLOSE SODIUM 13 MANNITOL Description: White, odourless, crystalline powder Applications: diluent chewable tablet formulations because of its negative heat of solution, sweetness, and ‘mouth feel’. MAGNESIUM STEARATE Description: It is a very fine powder. Functional category: Tablet and capsule lubricant. TALC Description: Very fine, crystalline powder. Functional Category: Anti caking agent, Glidant.

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The aim of present study is to formulate orodispersible liquisolid compacts of Nifedipine using Co-processed superdisintegrants in different ratio, Avicel PH 102, Aerosil 200 as a carrier and coating material respectively. AIM & OBJECTIVES: To increase solubility of Nifedipine To increase dissolution of Nifedipine by liquisolid technique. to formulate orodispersible tablets of Nifedipine, for rapid disintegration of tablet in mouth STUDY DESIGN 14

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MATERIALS USED CATEGORY Nifedipine Active Pharmaceutical Ingredient Polyethyleneglycol-400 Solvent Avicel pH-102 Carrier Aerosil 200 Coating material Mannitol Diluent Co-processed CP & CCS Superdisintegrants Magnesium stearate Luricant Talc Glidant Mango flavour Flavour LIST OF MATERIALS LIST OF EQUIPMENTS 15 EQUIPMENTS SUPPLIERS Electronic Weighing Balance AUW220D, Shimazdu, Japan Tablet compression machine Clit single rotary- 16 station punching machine. UV Visible spectrophotometer Systronic 1800 UV/Vis double beam spectrophotometer, Japan Digital tablet dissolution test apparatus Lab India Disso Apparatus 2000, India. Friability test apparatus Roche Friabilator Camp-bell Electronics, Mumbai, India Tablet hardness tester Monsanto Hardness tester, Ketan scientific Industries, model-1101 , Mumbai, India Digital Vernier caliper Linker, Mumbai. Disintegration test apparatus Rolex, India. Fourier transform infrared spectroscopy Shimadzu, Japan. Power X-ray diffractometer Philips Analytical XRD Scanning electron microscopy Hitachi X650, Tokyo, Japan. Mechanical shaker Secor ,India Stability Chamber InlabsEquipments (P) Ltd. Madras.

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1.Preparation of standard calibration curve of Nifedipine 4. Calculation of liquid load factor (Lf) 2.Determination solubility of drug in different non-volatile solvents 5. Fourier Transform Infrared Spectroscopy 3. Determination of flowable liquid retention potential (Φ value) 1.Bulk density 4.Hausner’s ratio 2.Tapped density 5.Angle of repose 3.Compressibility index 1. Thickness & Hardness 7. Uniformity of dispersion 2. Weight variation test 8. In-vitro disintegration test 3. Friability 9. In-vitro drug release study 4. In-vitro dispersion time 10. Powder x-ray diffraction 5. Wetting time 11. Scanning Electron Microscopy 6. Wetting absorption ratio 1.Preparation of co-processed superdisintegrants 2.Preparation of orodispersible liquisolid tablets PRE-FORMULATION STUDIES PRE-COMPRESSION EVALUATION OF POWDER BLEND FORMULATION OF ORODISPERSIBLE LIQUISOLID COMPACT OF NIFEDIPINE POST COMPRESSION STUDIES OF ORODISPERSIBLE LIQUISOLID COMPACTS 16

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17 DRUG PEG- 400 Ca Co SD MANNITOL MS TALC FLAVOUR WEIGHT 1:1 1:2 1:3 F1 10 mg 10 mg 50mg 5mg 10 - - 110.5mg 2mg 2mg 0.5mg 200mg F2 10 mg 10 mg 50mg 5mg - 10 - 110.5mg 2mg 2mg 0.5mg 200mg F3 10 mg 10 mg 50mg 5mg - - 10 110.5mg 2mg 2mg 0.5mg 200mg F4 10 mg 10 mg 72mg 4.8mg 10 - - 88.7mg 2mg 2mg 0.5mg 200mg F5 10 mg 10 mg 72mg 4.8mg - 10 - 88.7mg 2mg 2mg 0.5mg 200mg F6 10 mg 10 mg 72mg 4.8mg - - 10 88.7mg 2mg 2mg 0.5mg 200mg Ca = AVICEL PH 102 (CARRIER); Co = AEROSIL 200 (COATING MATERIAL); SD = CO-PROCESSED SUPERDISINTEGRANTS MS = MAGNESIUM STEARATE

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Drug-Excipients compatibility studies by FT-IR RESULTS AND DISCUSSIONS 19 Assignment Peak report(cm -1 ) Peak observed(cm -1 ) N-H stretch 3400-3250 3332.12 C-H (alkane stretching) 2960-2862 2917.29 O-H (carboxylic acid) 3800-2500 2917.29 C=O stretch (ester) 1730-1630 1688.68 N-O stretch (nitro compound) 1550-1475 1530.59

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2. Calibration curve of Nifedipine The λmax of Nifedipine was 237 nm. The absorbance of the solution (2-10μg/ml) was measured in UV-spectrophotometer at 237 nm. The linear correlation coefficient was γ = 0.999. 20 Concentration (μg/ml) Absorbance 2 0.0690 4 0.1856 6 0.1309 8 0.2540 10 0.3156

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3. Vehicle selection The solubility of the drug contributes to molecular dispersion in a non-volatile solvent which will improve the dissolution rate. Based on the solubility data, PEG 400 was selected as the vehicle for Nifedipine. 21 Solvent Solubility (mg/ml) (mean± S.D.) * PEG 400 3.30±0.035 Propylene glycol 2.88±0.01 Glycerin 0.16±0.005 Polysorbate 80 0.18±0.026

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4. Determination of flowable liquid retention potential (φ-value) [Spireas, 2002] The Φ-value for Avicel PH 102 and Aerosil 200 is reported in the table below. 22 Non-volatile solvents Φ-value for carrier material (Avicel PH102) Φ-value for coating material (Aerosil 200) 1.Propylene glycol 0.16 3.31 2.PEG 400 0.005 3.26 3.Tween 80 0.003 3.95 4.Cremophor EL 0.18 0.80 5.capryol 90 0.16 0.40

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The results of angle of repose, Carr’s index, and Hausner’s ratio indicated good flow ability of powders and reported in Table and the powders were free flowing , tablets produced were of uniformity weight with acceptable weight variation due to uniform filling in the die . PRE COMPRESSION PARAMETERS OF POWDER BLEND 23 Formulation Code Angle of repose  ± SD* Bulk density (g/ml) ± SD* Tapped density (g/ml) ± SD* Carr’s Index (%)± SD* Hausner’s ratio ± SD * F1 33.37±1.54 0.802 ±0.05 0.877 ± 0.01 12.16 ± 0.84 1.096 ± 0.05 F2 32.98±1.83 0.806 ±0.02 0.896 ± 0.02 12.00 ± 1.55 1.112 ± 0.05 F3 32.96±1.73 0.820 ±0.01 0.935 ± 0.02 11.94 ± 1.77 1.146 ± 0.04 F4 34.16±1.83 0.832 ±0.01 0.937 ± 0.02 12.34 ± 0.81 1.074 ± 0.01 F5 31.69±0.67 0.841 ±0.01 0.926 ± 0.02 12.3 ± 0.72 1.099 ± 0.03 F6 33.15±1.12 0.834 ±0.00 0.912 ± 0.00 11.26 ± 0.94 1.017 ± 0.02

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POST-COMPRESSION PARAMETERS OF OD-LIQUISOLID COMPACTS 24 Tablet mean thickness was almost uniform in all the formulations. The prepared tablets in all the formulations possessed good mechanical strength with sufficient hardness. All the formulated tablets of orodispersible liquisolid compacts Nifedipine were shown the % friability within the official limits ( i.e., not more than 1%). The weight variation test was found to be within (±7.5) the prescribed official limits. Formulation *Hardness Kg/cm 2 Friability % *Thickness mm *weight Variation F1 3.41±0.20 0.490 4.01±0.022 Passes F2 3.33±0.25 0.620 4.01±0.012 Passes F3 3.58±0.37 0.450 4.01±0.014 Passes F4 3.50±0.44 0.510 4.02±0.010 Passes F5 3.58±0.09 0.480 4.01±0.005 Passes F6 3.56±0.20 0.590 4.00±0.015 Passes

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25 The formulation F3 showed lesser in-vitro dispersion time (45.33 sec) and shown in Figure. At 0 sec At 45.33 sec The disintegration time for all tablets was less than 2 min, which fulfil the pharmacopoeial requirement. The formulation F1 contains Co-processed superdisintegrants in the ratio of 1:1 showed 89.00±2.00 sec and in the ratio of 1:3 for formulation F3 showed lesser disintegration time of 49.33±1.52 sec. This is due to the rapid uptake of water from the medium, swelling and burst effect. The wetting time of tablets complies with the official specifications. The water absorption ratio was found to be in the range 68.15±0.89 –73.56±1.70 % and data are given in Table.

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26 Formulation * In-vitro dispersion time (sec) * Disintegration Time (sec) * Wetting time (min) * Water absorption Ratio (%) Uniformity of Dispersion F1 86.16±1.52 89.00±2.00 2.48±0.23 68.15±0.89 Passes F2 69.00±1.00 72.33±2.51 2.53±0.58 66.31±0.91 Passes F3 45.33±1.15 49.33±1.52 1.56±0.45 73.56±1.70 Passes F4 66.16±1.52 65.00±1.00 2.58±0.38 65.59±0.86 Passes F5 58.22±1.23 52.20±1.20 2.14±0.16 69.33±1.20 Passes F6 47.20±1.30 51.30±1.22 1.56±0.32 73.20±1.08 Passes Results of In-vitro dispersion time, wetting time and water absorption ratio of orodispersible Nifedipine tablet

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27 Estimation of % drug content The % drug content of F1 to F6 of Nifedipine liquisolid compact was shown in Table S. No Formulation Code Drug content (%) ± SD* 1 F1 96.12 ± 0.00 2 F2 96.30 ± 0.42 3 F3 99.15 ± 0.57 4 F4 96.15 ± 0.98 5 F5 98.53 ± 0.52 6 F6 96.20 ± 0.81

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28 IN-VITRO RELEASE STUDIES Dissolution studies Among the six formulations, F3 contains the co-processed superdisintegrants in the ratio of 1:3 and excipient ratio of R=10 achieved more than 50% of drug within 10 mins and 100% release within 35 min % Cumulative Drug Release Time F1 F2 F3 F4 F5 F6 0 min 0 0 0 0 0 0 5 min 25.81 25.72 35.32 34.3 32.04 29.71 10 min 39.54 39.9 52.33 42.03 41.39 41.42 15 min 48.23 62.8 73.06 60.34 51.66 53.84 25 min 71.08 71.43 81.06 65.7 69.51 67.85 35 min 89.27 81.12 100 92.6 85 85 45 min 101.67 101.02 100.3 97.63 96.69

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29 DRUG RELEASE KINETIC MODEL The release kinetic profile of selected formulation F3 follows Korsemeyer-Peppas release model. Slope value 0.963 (0.45 < n <0.89) suggest that the release of drug from tablets followed diffusion and non-Fickian transport and the drug releases in one dimensional way. Order R2 (F3) Zero order 0.886 First order 0.803 Higuchi model 0.949 Korsemeyer- peppas model 0.963 Hixson crowell Plot 0.916

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30 CHARACTERIZATION OF LIQUISOLID COMPACTS Scanning Electron Microscopy (A) needle like crystal shapes (B) dis appearance of needle like crystalline shape This indicate that the drug was solubilized in the liquid system

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31 X-ray powder diffraction analysis (A) sharp peaks at 15º,18º, 19º, 24º, and 26º (B) low intensity peaks This indicates that Nifedipine is entirely converted into amorphous or solubilized form.

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COMPARISON OF SELECTED FORMULATION WITH PURE DRUG (NIFEDIPINE) AND CONVENTIONAL TABLET The formulation F3 showed higher drug release than the pure drug and conventional tablets. The results were shown in Table and Figure. % Cumulative Drug Release TIME PURE DRUG CONVENTIONAL TABLET F3 FORMULATION 0 min 0 0 0 5 min 4.13 20.32 35.32 10 min 8.63 28.13 52.33 15 min 11.66 32.16 73.06 25 min 15.42 45.35 81.06 35 min 19.39 51.03 100 45 min 22.00 58.13

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STABILITY STUDIES No significant difference (𝑃 value 0.969 > 0.05) was found. The results are shown in Table. Tablets have not shown any significant changes during storage. S. No Storage condition Evaluation Parameters Duration in months 0 3 1 40±2 ° C and 75%±5% RH Hardness 3.58±0.37 3.58±0.34 In-vitro dispersion time 45.33±1.15 45.03±1.10 Drug content (%) 99.15 ± 0.57 99.00±0.41 % of drug release 100 99.93 33

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CONCLUSION The combined effect of liquisolid compact technique and inclusion of different ratio of co-processed superdisintegrants is useful in enhancement of dissolution rate of Nifedipine. It can be said that liquisolid technique with co-processed superdisintegrants is a promising strategy in improving dissolution of insoluble drugs and formulating immediate release solid dosage forms. 34

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1.Gohel MC. [2007]. Preparation and Assessment of Novel Co-processed Superdisintegrants Consisting ofCrospovidone and Sodium Starch Glycolate: A Technical Note. American Association of Pharmaceutical Scientists. PharmSciTech 8(1): 1-7. 2.Javadzadeh Y, Nokhodchi A. [2008]. Liquisolid technique for dissolution rate enhancement of a high dose water-insoluble drug (carbamazepine). International Journal of Pharmaceutics (341):26-34 3.Karmarkar AB, Gonjari ID, Hosmani AH, Dhabale PN, Bhise SB. [2009]. Dissolution rate enhancement of fenofibrate using liquisolid tablet technique. Part II: Evaluation of in-vitro dissolution profile comparison methods. Latin American Journal of Pharmacy 28(4): 538-543. 4.Spireas S.[2002].Liquisolid Systems and Methods of Preparing Same; U.S. Patent 6423339 B1. 5.Dobetti M. [2011]. Fast‐ Melting Tablets:  Developments and Technologies. Pharmaceutical Technology and Drug Delivery.44‐50. 6.Nayak AK, Kaushik M. [2011]. Current developments in orally disintegrating tablet technology. Pharmaceutical Education Research 2(1): 21 –34 7. Indian Pharmacopoeia. [1996]. 4th Ed. Vol. I: 511-13: Controller of Publications, Ministry of Health & Family Welfare, Govt. of India, Delhi. 8. Lachman L, Lieberman H and Kanig J. [1987]. The theory and practice of industrial pharmacy, 3rd Edn. Varghese Publishing House, Mumbai. REFERENCE 35

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36 S. No TITLE JOURNAL ISSUE 1 Orodispersible Liquisolid Compact: A Novel Approach to Enhance Solubility and Bioavailability Pharma Tutor Volume: 6 Issue: 6 Year: 2018 2 Formulation and Evaluation of Orodispersible Liquisolid Compacts of Nifedipine using Co-processed superdisintegrants Asian Journal of Pharmacy and Pharmacology Volume: 4 Issue: 4 Year: 2018 List of Articles published

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