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EFFECT OF LIPID ON SOLUBILITY OF

ATORVASTATIN BY PASTILLATION
TECHNOLOGY
JSPMS Rajarshi Shahu College of Pharmacy
and Research, Tathawade, Pune-33
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Research Scholar:
Mr.Tushar Chavan
M. Pharm (2
nd
yr)

Research Supervisor:
Dr. (Mrs) Ashlesha Pandit
M. Pharm PhD
Project Presentation
CONTENTS
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Introduction
Literature review
Need and Objective
Plan of work
Materials and method
Result & Discussion
Conclusion
References


SOLUBILITY
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Solubility 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.

Definition
Parts 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 > 10,000
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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 ENHANCEMENT
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Chemical, petrochemical and agrochemical industries
for the solidification of dusty hazardous powders of
chemicals into pastilles.

Drops of chemical substances
in molten state
cooled stainless steel
surface
pastilles
PASTILLATION TECHNIQUE
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LITERATURE REVIEW
Dali 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.

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Maikewind 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.

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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
OBJECTIVES
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Selection of drug and excipients
Preformulation study

Preparation of pastilles by
pastillation technique

Characterization and stability study
of optimized batch
PLAN OF WORK
Experimental design
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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 FORMER
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DRUG PROFILE
Drug Atorvastastin
IUPAC name- (3R,5R)-7-[2-(4-fluorophenyl)-3-phennyl-4-(phenylcarbamoyl)-
5-propane-2-ylpyrrol-1yl]-3,5-dihydroxyheptanoic acid
Molecular weight: 558.64 gm/mol
Structure:


Category HMG-CoA
reductase
inhibitor
Dose 20-80mg
Half-life 14 hrs
BCS class II
Solubility Methanol,
Chloroform,
Melting point 160C
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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
0
C.



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
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PREFORMULATION STUDY
Confirmation of drug

Melting Point Determination
Atorvastatin-156-160
0
C.





Infra-red spectrum




Infrared spectrum of Atorvastatin
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UV spectroscopy
Standard calibration curve of
Atorvastatin in HCL(0.1N)
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Drug excipients interaction study
FT-IR spectra of Atorvastatin
FT-IR spectra of Glycerol Monostearate
1.FTIR Study-
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FT-IR spectra of physical mixture of Atorvastatin and glycerol
monostearate
Drug-polymer interaction studies through IR
spectroscopy
Drug peak (cm
-1
)
Polymer peak
(cm
-1
)
Drug + Polymer
peaks (cm
-1
)
Interactions
3661.19, 2962.13,
3067.58, 1602.2,
1312.32
1742.37, 2852.2,
2364.3
3661.19, 2933.2,
1742.37, 2357.3,
1312.32
No interaction
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DSC Study-
DSC thermogram of Atorvastatin
DSC thermogram of Glycerol Monostearate
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DSC thermogram of physical mixture
(1:1)
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FORMULATION AND DEVLOPMENT
Method- Pastillation Method
Drug- Atorvastatin
Solid lipid- Glycerol monostearate (GMS)
Pore former- Poloxamer-407
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FORMULATION AND DEVLOPMENT
Figure. Schematic representation of in house developed
pastillation devise
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FORMULATION AND DEVLOPMENT
Figure. In house developed pastillation devise
Result & Discussion
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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 code Drug content (%)
F1 94.280.03
F2 94.830.014
F3 99.110.06
F4 96.630.2
F5 97.050.018
F6 96.960.020
F7 99.330.09
F8 99.300.05
F9 99.970.02
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In Vitro Drug Release Study
Dissolution profile of drug (ATR), and F1-F9 Batches
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Saturation Solubility Studies
Sr.no Sample % Solubility(mg/ml)
1
Drug 0.2020.11
2
F1 2.200.18
3
F2 2.520.19
4
F3 3.450.09
5
F4 2.870.06
6
F5 3.720.20
7
F6 4.320.05
8
F7 3.900.08
9
F8 4.520.13
10 F9 5.070.04
Solubility studies of atorvastatin (Mean Standard Deviation)
from pastills in comparison with plain drug
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Powder X-Ray Diffraction
X-Ray diffraction graph of Atorvastatin
X-Ray diffraction graph of Glycerol monosterate
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X-Ray diffraction graph optimized
batch
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Scanning Electron Microscopy
SEM Photograph of atorvastatin (A) and its
formulation(pastills) (B)
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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
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REFERENCES
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.

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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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THANK YOU