Improving solubility of norfloxacin

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IMPROVING DRUG SOLUBILITY USING SOLID DISPERSIONS Presented By By MR. Abikesh Prasad Kumar Mahapatra B.Pharm. (Final Year) Regd. No.: 0403254002 Guided By Mr. Anjan Kumar mahapatra Lecturer(Pharmaceutics) Royal College of Pharmacy & Health Sciences, Berhampur 2008

AIM OF WORK : 

AIM OF WORK IMPROVING DRUG SOLUBILITY USING SOLID DISPERSIONS

Topics CovereD : 

Topics CovereD Introduction Need & Objective Plan Of Work Experimental Work Result & Discussion Summary & Conclusion Bibliography

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Solubility is defined as the ability of a substance to form a solution with another substance. Table 1: Terms of Solubility

IMPORTANCE OF SOLUBILITY : 

IMPORTANCE OF SOLUBILITY It helps for the identification of potential screening and bioavailability issues. It is important for he confirmation of bioavailability issues. It is important for the confirmation of bioavailability issues. During early trials of drugs it is used in the design of animal formulations as well as human formulation design. Solubility knowledge is needed for biopharmaceutical classification, biowaivers, and bio equivalence. It is also required for formulation optimization and salt selection. Solubility also affects the optimization of manufacturing process.

SOLID DISPERSION : 

SOLID DISPERSION Chio and Riegelman defined the term solid dispersion as “a dispersion of one or more active ingredients in an inert carrier or matrix of solid state prepared by melting (fusion), solvent or melting solvent method”. Melting of fusion method Solvent method Melt adsorption method Lyophilization Technique Melt agglomeration process Extruding method Spray drying Use of surfactant Electro spinning Super critical fluid technology

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CARRIERS

BIOPHARMACEUTICS SYSTEM OF CLASSIFICATION (BCS) : 

BIOPHARMACEUTICS SYSTEM OF CLASSIFICATION (BCS)

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NEED AND OBJECTIVEPoor solubility can hinder or even prevent drug development yet the volume and level of poorly soluble drugs is dramatically increasing leaving gaps in the development Pipelines. Currently only 8% of new drugs candidates have both high permeability. In the present study, we have taken Norfloxacin(poorly soluble drug) as the model drug . The main objective of present work was to prepare solid dispersion of poorly water soluble drug Norfloxacin to enhance its in-vitro dissolution rate and aqueous solubility of drug. In present study polyethylene glycol selected as carrier because of their chemical and pharmacological inertness. Polyethylene glycol by virtue of their water solubility leads high degree of solubilization of poorly soluble drug.

PLAN OF WORK: : 

PLAN OF WORK: In order to achieve the main objective of the study i.e. improvement of solubility of poorly water soluble drug solid dispersion, following was the plan of work. Preparation of calibration curve of Norfloxacin by spectrophotometric method. Preparation of solid dispersion of Norfloxacin with PEG. Phase or saturation solubility studies of Norfloxacin and solid dispersions of Norfloxacin. In-vitro dissolution studies of solid dispersions. Study of the effect of formulation variables/process variables on the in-vitro dissolution rate of Norfloxacin. Effect of different grades of PEG Effect of different concentration of PEG

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LIST OF EQUIPMENT USED:

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LIST OF CHEMICALS USED:

EXPERIMENTAL WORK : 

EXPERIMENTAL WORK DRUG PROFILE:   NORFLOXACIN Chemical Formula - C16H18FN3O3 Chemical Name - 1-ethyle-6-Fluro-1,4-dihydro-4-oxo-7-(1- piperazinyl)-3- quinolonecarboxylic acid. Category - Antibiotic Molecular Weight - 319.34 Description - White to almost white (crystalline powerder) Solubility _ Freely soluble in acetic acid, Sparingly soluble in Chloroform, slightly soluble in acetone & ethanol, Very slightly soluble in water, methanol, ethylacetate, insoluble in ether. Dose - 600mg to 1.6g daily Storage - Store in tightly closed light resistant container in a Cool and dry place.

POLYMER PROFILE: : 

POLYMER PROFILE: POLY ETHYLENE GLYCOL: Synonym - Carbowax Chemical name - ?-hydro-w-hydrowy-poly (oxy-1, 2-ethanediyl) Molecular Weight: PEG 4000- 2600-3800 PEG 6000 - 7000-9000 PEG 8000 - 7300-9300 Functional Category - Ointment base, plasticizer, solvent, suppository base Melting point - 45 – 510C Condition - Chemically stable in air and in solution. Do not support microbial growth, nor become rancid. should be stored in well closed containers in a and dry place. Safety - Non-toxic and non-cool irritant Pharmaceutical Application - Solid grades are generally employed in ointment bases,suppository bases

STEPS INVOLVED : 

STEPS INVOLVED Analytical Method development Preparation Of Solid Dispersion Analysis Of Drug In Solid Dispersion Phase solubility Study Dissolution Study

ANALYTICAL METHOD DEVELOPMENT: : 

ANALYTICAL METHOD DEVELOPMENT: Determination of ?max   The UV spectrophotometer was set to auto zero & the standard solution was scanned to obtain the max. Wavelength absorption against blank between wavelength of 200-400 nm. The standard solution was scanned for absorbance maxima against blank. The max. absorbance was found to be 278nm which was fixed as a wavelength for Drug analysis Procedure for calibration curve:  The aliquots of Norfloxacin solution was prepared & the absorbance was measured at ?max of 278nm against reagent blank. Similarly the calibration curve in different media was done in same manner.

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CALIBRATION CURVE IN 0.1N HCl CALIBRATION CURVE IN DISTILLED WATER

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CALIBRATION CURVE IN 0.5% SLS:

PREPARATION OF SOLID DISPERSIONS: : 

PREPARATION OF SOLID DISPERSIONS: PREPARATION OF SOID DISPERSION OF NORFLOXACIN – PEG 4000 BY MELTING METHOD:   Solid dispersion of Norfloxacin in PEG 4000 in different ratios (1:1,1:2,1:3) respectively well prepared by melting method as follows. Norfloxacin was added to the molten PEG 4000 at 720C with constant stirring & the resulting homogenous dispersion was rapidly cooled in an ice bath & stored in desiccators for 24hrs.Subsequently the dispersion was ground in a mortar. PREPARATION OF SOLID DISPERSION OF NORFLOXACIN-PEG 8000 BY MELTING METHOD;-   Solid dispersion of Norfloxacin in PEG 8000 in different grade weight ratios (1:1,1:2,1:3) respectively were prepared by melting method as follows . Norfloxacin was added to the molten PEG 8000 at 720C with constant stirring & the resulting homogenous dispersion was rapidly cooled in an ice bath & stored in desiccators for 24hrs.Subsequently the dispersion was ground in a mortar.

ANALYSIS OF DRUG IN SOLID DISPERSION- : 

ANALYSIS OF DRUG IN SOLID DISPERSION- The content of Norfloxacin in each solid dispersion (PEG 4000,PEG 8000) was determined using UV spectrophotometric method. Accurately weighed solid dispersion equivalent to 20mg of Norfloxacin was transferred to 10ml volumetric flask &diluted to 10ml with vehicle (0.1 N HCl)&kept on rotashaker for 24hrs for complete solubilization of drug. Solution was filtered with membrane filter paper 0.45?m. Then the solution absorbance was checked at 278nm.

PHASE SOLUBILITY STUDIES : : 

PHASE SOLUBILITY STUDIES : It was carried out on pure drug and with the carriers PEG 4000 & PEG 8000.Excess amount of drug was added to 10ml of distilled water containing various concentration of carrier. The suspension were shaken for 24hrs on a rotary shaker at 370C &filtered through Whatman no.1 filter paper. The filtrate so obtained was analyzed spectrophotometrically at 278 nm

FREE ENERGY: : 

FREE ENERGY: Besides Enthalpy ,internal energy & entropy the other two types of thermodynamic functions, which depend on the state of matter of the system   These are – (a)Helmtoltz free energy (b)Gibbs free energy Free energy is defined as the energy that is fred to do useful work in any reaction. As per the free energy concept a spontaneous process is accompanied by a loss of free energy at a constant temp.& pressure G=E+PV-TS G=G0+nRTlnP ?G=-2.303RT log s0/s Where, s0= Soluibility in presence of polymer, S= Soluibility with out polymer R = Universal Gas Constant, n = No. of moles, G = Free Energy.

DISSOLUTION STUDY : : 

DISSOLUTION STUDY : Following condition were followed to study the invitro dissolution of Norfloxacin.   USP Dissolution Apparatus Type- II(Paddle Method) Dissolution medium 0.1 N HCl Volume of Dissolution Fluid 900 ml Temperature 37±0.5°C Sample Size 20 mg

COMPARATIVE DISSOLUTION STUDY: PEG 4000 : 

COMPARATIVE DISSOLUTION STUDY: PEG 4000

COMPERATIVE DISSOLUTION STUDY (PEG 8000) : 

COMPERATIVE DISSOLUTION STUDY (PEG 8000)

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% Cumulative Norfloxacin release

RESULT AND DISCUSSION: : 

RESULT AND DISCUSSION: Phase solubility with PEG showed maximum solubility with PEG 8000 at 1:3 of Drug polymer ration. Solubility of the drug increased with increasing molecular weight of PEG. From the dissolution study of API, it was found that the solid dispersion with PEG 8000 in ratio 1: 3 give better drug release which may be because of the change in the structure of the drug from crystallinity to amorphous, reduction of particle size, increase in solubility of the drug owing to the presence of water solubility carrier.

SUMMARY AND CONCLUSION: : 

SUMMARY AND CONCLUSION: From the above discussion it can be concluded that with solid dispersion of the drug in PEG 8000 AT 1: 3, there has been significant improvement of dissolution that may be due to the combination of effects, the significant of which is reduction of particle size to an extent that can’t be readily achieved by conventional comminution approaches. . More over the increase in solubility and dissolution may be due to conversion of crystalline nature of drug particles to amorphous form with the preparation of solid dispersions. Hence from the study it can be concluded that solid dispersion technique is a good approach for enhancement of dissolution of poorly soluble drugs The work can be carried out with common laboratory facilities available, without requirement of any sophisticated equipments or instruments. The approach is economical and time saving. Hence, can be a good approach considering industrial/economical view point.

BIBLIOGRAPHY : 

BIBLIOGRAPHY Noyes, A.A. Whitny, W.R. (1897). The rate of solution of solid dispersion substances in their own solutions. J. Am. Chem. Soc. 19, 930-934. Leunier, C and Dressman, J. (2000). Improvement of solubility for oral delivery using solid dispersion. Euro. J. of Pharmaceutics and biopharmaceutics.50.47-60. Chiu, W.L. and Riegelman, S.(1971). Pharmaceutical application of solid dispersion. J. of Pharm. Sci. 60(9), 1281-1302. Yang Yu, B., Ruan, Fu. G. and Zhu, D. (2005) Improving the solubility of ampelopsin by solid dispersions inclusion complexs. J. Pharm. Bio. Ana. Article in press. Stane, S., N., Obreze, A., Bele, M. (2005). Physical properties and dissolution behaviour of nifedipine/ mannitol solid dispersions preparaed by hot melt method. Int. J. Pharm., 291, 51-58. Tashtoush, M.B., AL-Quasi, S.Z. and Najib, M.N. (2004). In-vitro and in vivo evaluation of glibenclamide in solid dispersion systems. Drug Dev. Ind. Pharm., 30(6), 601-607.

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Joshi, N. N., Tejwani, W. R., Davidovich, M., Sahasrabudhe, P. V., Jemal, M., Bathala, S. M., Varia, A.S., and Serajudin, M. T. Abu. (2004). Bioavailability enhancement of poorly water-soluble drug by solid dispersion in polyethylene glyco-polysorbate 80 mixture. Int. J. Pharm., 269(1) 251-258. S.Yang Yu, B., Ruan, L., Fu. G. and Zhu, D., (2005) Improving the solubility of ampelopsin by solid dispersions inclusion complexes. J. Pharm. Bio. Ana., Article in Press. Stane, S., Zajc, N., Obreza, A., Bele, M. (2005). Physical properties and dissolution behaviour of nifedipine/ mannitol solid dispersions prepared by hot melt method. Int. J. Pharm., 291, 51-58. Tashtoush, M. B., AL-Quasi, S. Z. and Najib, M. N. , (2004) In-vitro and in vivo evaluation of glibenclamide in solid dispersion systems. Drug. Dev. Ind. Pharm., 30(6), 601-607. Joshi, N. N., Tejwani, W. R., Davidovich, M., Sahasrabudhe, P. V., Jemal, M., Bathala, S. M., Varia, A. S. and Serajudin, M.T. Abu (2004). Bioavailibity enhancement of poorly water-soluble drug by solid dispersion in polyethylene glycol-polysorbate 80 mixture. Int. J. Pharm., 269(1) 251-258. Wang, X., Michoel, A. and Mooter, D. V. G., (2004). Study of the phase behaviour of polyethylene glycol 6000-itraconazole solid dispersion using DSC. Int. J. Pharm. 272(1-2), 181-187.

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Gohel, M.C. and Patel, L.D., (2003). Processing of nimesulide-PEG 400-PG-PVP solid dispersion: preparation, characterization and in-vitro dissolution. Drug. Dev. Ind. Pharm., 29(3), 299-310. Narang. S. A. and Srivastav, K.A. (2002). Evaluation of solid dispersions of clofazimine. Drug Dev. Ind. Pharm. 28(8), 1001-1013. Emara. S.A., Badr, R. M. and Abd Elbary, A. (2002). Improving the dissolution and bioavailability of nifedipine using solid dispersions and solubilizers. Drug. Dev. Ind. Pharm. 28(7), 795-807. Mehta, A. K., Kislalioglu, S. M., Phuapradit, W., Mallick, W.A. and Shah, H. N. (2002). Multi unit controlled release system of nifedipine and nifedipine:pluronic® F-68 solid dispersions : characterization of release mechanisms. Drug. Dev. Ind. Pharm. 28(5), 275-285. Iqbal, Z., Babar, A., and Ashraf, M. (2002). Controlled-realease naproxen using micronized ethyl cellulose by wet-granulation and solid dispersion method. Drug Dev. Ind. Pharm. 28(2), 129-134.

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Web Site: www.spingerlink.com www.elsevier.com www.pharmazenith.com www.sciencedirect.com www.aaps.com www.scienceindia.com

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