Development of a novel self-emulsifying drug delivery system to enhance oral bioavailability

EFFECT OF LIPID ON SOLUBILITY OF ATORVASTATIN BY PASTILLATION TECHNOLOGYJSPMS Rajarshi Shahu College of Pharmacy and Research, Tathawade, Pune-331

Research Scholar:Mr.Tushar ChavanM. Pharm (2nd yr)

Research Supervisor:Dr. (Mrs) Ashlesha PanditM. Pharm PhDProject Presentation1CONTENTS2 Introduction Literature review Need and Objective Plan of work Materials and method Result & Discussion Conclusion References

2SOLUBILITY3Solubility is the property of a solid, liquid, or gaseous chemical substance called solute to dissolve in a solid, liquid, or gaseous solvent to form a homogeneous solution at definite temperature & pH.

DefinitionParts of solvent required for one part of solute Very soluble < 1 Freely soluble 1 - 10 Soluble 10 - 30 Sparingly soluble 30 - 100 Slightly soluble 100 - 1000 Very slightly soluble 1000 - 10,000 Insoluble > 10,00034 There are variety of new drugs & their derivatives available. Around 50% of drug molecules that reaches market have bioavailability issues due to poor aqueous solubility.

The lipophilic drug that reaches market requires a high dose to attain proper pharmacological action.

The basic aim is to make the drug available at proper site of action within optimum dose.

NEED OF SOLUBILITY ENHANCEMENT45Chemical, petrochemical and agrochemical industries for the solidification of dusty hazardous powders of chemicals into pastilles. Drops of chemical substances in molten statecooled stainless steelsurfacepastilles

PASTILLATION TECHNIQUE 6LITERATURE REVIEWDali Shukla et.al. 2011 developed a novel technique, Pastillation to fabricate lipid based oral multiparticulate controlled release dosage forms. Using laboratory scale device was designed to generate pastilles of doxofylline loaded stearic acid characterized for drug content uniformity, drug release profile, morphology and contact-angle. The optimized conditions for pastillation were 1.00 cm dropping height, 20 G needle orifice and 4 C plate temperature which produced good pastilles of uniform size (2.5 3.0 mm) with contact angle above 90. This multiparticulate system has very good flow property and is very uniform in size, weight and drug content. The biggest advantage of this technology is that the large-scale equipment for pastillation is well-established in chemical industries.

Peter Kleinebudde et.al. 2011 studied that the influence of different types of release modifiers on the dissolution from solid lipid extrudates was investigated. Diprophylline was extruded together with 45% tristearin and 5% (w/w) of a release modifier to suitable extrudates. Three groups of release modifiers were defined: Hydrocolloids, disintegrants and pore formers. They observed that, extrudates containing polyethylene glycol (PEG) exhibited a much higher release rate compared with extrudates containing sodium chloride or mannitol. 7Maikewind bergs et.al. 2009 studied that the chemical composition of glycerides used for the manufacturing of solid lipid extrudates was found to have a large influence on the solid-state behaviour and dissolution profiles. Due to its surfactant properties the partial glyceride exhibits a faster release of the drug compared to the triglyceride. In different mixtures of both lipids the partial glyceride led to increased incidence of the unstable -form of the triglyceride leading to recrystallization of the stable -form over time which causes fractal structures on the extrudate surface deteriorating the dissolution properties. Storage experiments under accelerated and ambient conditions revealed a strong influence of temperature on the recrystallization kinetics.V. Jannin et.al. 2007 reported approaches for the development of solid and semi-solidlipid-based formulations. In this review, mentioned the recent approaches in selecting the most appropriate lipid system; methods for characterization of their behavior in vitro and in vivo; and the current formulation and processing techniques to obtain various solid dosage forms.8 Pellets /pastilles disperse freely in the gastrointestinal (GI) tract. maximize drug absorption, reduce peak plasma fluctuation. Avoid high local drug concentration. Low inter and intra subject variability. Reduce dose dumping. Less systemic toxicity.

To fabricate an apparatus for preparation of lipid based pastilles.

To develop and evaluate oral lipid based formulation and enhance solubility of atorvastatin using pastillation technology.

NEED OBJECTIVES9Selection of drug and excipientsPreformulation studyPreparation of pastilles by pastillation technique

Characterization and stability study of optimized batchPLAN OF WORKExperimental design 10 Drug- Atorvastatin Category- HMG-CoA reductase inhibitor Rationale- poorly water soluble drug, oral bioavailibilty-12%

Solid lipid- Glycerol monostearate (GMS) Pore former-Poloxamer-407

SELECTION OF DRUG CANDIDATE SELECTION OF POLYMER AND PORE FORMER11DRUG PROFILE Drug AtorvastastinIUPAC name- (3R,5R)-7-[2-(4-fluorophenyl)-3-phennyl-4-(phenylcarbamoyl)- 5-propane-2-ylpyrrol-1yl]-3,5-dihydroxyheptanoic acidMolecular weight: 558.64 gm/molStructure:

CategoryHMG-CoA reductase inhibitorDose20-80mgHalf-life14 hrsBCS classIISolubilityMethanol, Chloroform, Melting point160C

12 Glycerol Monostearate (GMS)Synonym : Capmul GMS-50, Cutina GMS, Geleol, Myvaplex 600P, Protachem GMS-450. Molecular weight: 358.6 gm/mol.Melting point: 56-58 0C.

Solubility: Soluble in hot ethanol, ether, chloroform, hot acetone, mineral oil, and fixed oils.Practically insoluble in water, but may be dispersed in water with the aid of a small amount of soap or other surfactant.POLYMER PROFILE

13PREFORMULATION STUDYConfirmation of drug

Melting Point Determination Atorvastatin-156-160 0C.

Infra-red spectrum

Infrared spectrum of Atorvastatin14 UV spectroscopy

Standard calibration curve of Atorvastatin in HCL(0.1N)15Drug excipients interaction study

FT-IR spectra of Atorvastatin

FT-IR spectra of Glycerol Monostearate1.FTIR Study-16

FT-IR spectra of physical mixture of Atorvastatin and glycerol monostearateDrug-polymer interaction studies through IR spectroscopyDrug peak (cm-1)Polymer peak (cm-1)Drug + Polymer peaks (cm-1)Interactions 3661.19, 2962.13, 3067.58, 1602.2, 1312.321742.37, 2852.2, 2364.3 3661.19, 2933.2, 1742.37, 2357.3, 1312.32No interaction 17DSC Study-

DSC thermogram of Atorvastatin

DSC thermogram of Glycerol Monostearate18DSC thermogram of physical mixture (1:1)19FORMULATION AND DEVLOPMENTMethod- Pastillation MethodDrug- Atorvastatin Solid lipid- Glycerol monostearate (GMS)Pore former- Poloxamer-40720

FORMULATION AND DEVLOPMENTFigure. Schematic representation of in house developed pastillation devise 21

FORMULATION AND DEVLOPMENTFigure. In house developed pastillation devise Result & Discussion22 Physical appearance Prepared pastilles were white-yellow in colour of size 3.4 0.2mm to 4.0 0.15 mm of needle size 14G having smooth surface and hemispherical in shape. Drug Content Formulation codeDrug content (%)F194.280.03F294.830.014F399.110.06F496.630.2F597.050.018F696.960.020F7 99.330.09F899.300.05F999.970.0223 In Vitro Drug Release Study

Dissolution profile of drug (ATR), and F1-F9 Batches24Saturation Solubility StudiesSr.noSample% Solubility(mg/ml)1Drug0.2020.112F12.200.183F22.520.194F33.450.095F42.870.066F53.720.207F64.320.058F73.900.089F84.520.1310F95.070.04 Solubility studies of atorvastatin (Mean Standard Deviation) from pastills in comparison with plain drug25Powder X-Ray Diffraction

X-Ray diffraction graph of AtorvastatinX-Ray diffraction graph of Glycerol monosterate

26X-Ray diffraction graph optimized batch27Scanning Electron Microscopy

SEM Photograph of atorvastatin (A) and its formulation(pastills) (B)28 CONCLUSION Pastillation technology was successfully used to the solubility enhancement of pastilles of poorly water soluble drug using lipids as a carrier and release rate modifier.

This technology is very simple for producing lipid-based Pastillation system, as compared to the other available techniques (spray cooling, solid lipid extrusion, extrusion spheronization, supercritical fluid based methods melt-extrusion and freeze-pelletization).

This technology requires a single piece of equipment for the entire process (melting of lipid, mixing of drug and required excipients, followed by solidification).

In pastillation, energy cost is reduced owing to the absence of associated processes of grinding, crushing or other breaking processes. Pastilles of small dimensions can easily be filled into capsules, whereas the larger ones can either be strip-packed or filled directly into sachets 29REFERENCES Shukla, D., Chakraborty, S., Singh, S., Mishra, B., 2011. Pastillation: A novel technology for development of oral lipid based multiparticulate controlled release formulation. Powder Technology. 209, 6572.

R. Witzleba, A. Mullertzb, V.R. Kanikantic, H.J. Hamannc, P. Kleinebudde, Dissolution of solid lipid extrudates in biorelevant media, International Journal of Pharmaceutics(2012)116-124.

Sejal Shah,Sindhuri Maddineni,Jiannan Lu,Michael A. Repka, Melt extrusion with poorly soluble drugs, International Journal of Pharmaceutics(2012)324-332.

30 Kapil Kalra1, Shiva Sharma1and D.A.Jain, Internationaal Journal of pharmacy & life science, [Kalra et al., 3(3): Mar, 2012.

Windbergs, M., Strachan, C., Kleinebudde, P., 2009. Influence of the composition of glycerides on the solid-state behaviour and the dissolution profiles of solid lipid extrudates , Int. J. Pharm. 381, 184191.

Shukla, D., Chakraborty, S., Mishra, B., 2012. Evaluation of in vivo behavior of controlled and pulsatile release pastilles using pharmacokinetic and -scintigraphic techniques, Expert Opin drug deliv, 9(1):9-18.

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