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Research Article

Economical Feasibility Evaluation of an


Ethanol Injection Liposome Production Plant
Over the past few decades liposomes, which are lipid vesicles useful for the con-
trolled release of numerous bioactive compounds, have attracted significant in-
dustrial interest. Several techniques have evolved for the manufacture of lipo-
somes on a small scale. However, production on a commercially feasible scale is
still somewhat limited. Therefore, this research intends to evaluate the scale-up
potential of a liposome production unit using the ethanol injection method,
through preliminary economical feasibility estimation, as an addendum to a pre-
existing bioactive compound manufacture plant, with the aim of increasing the
compound aggregate value. The ethanol injection technique is selected due to its
simplicity and low cost, characteristics that make it easily scalable. The prelimin-
ary economic evaluation involves the assessment of capital investment, estimation
of operating costs, and analysis of profitability. The results of the economic analy-
sis suggest that the process is economically feasible for a plant with a daily pro-
duction capacity of 288 L of liposomal suspension.
Keywords: Economic evaluation, Ethanol injection method, Lipid vesicles, Liposomes
Received: September 29, 2008; accepted: October 20, 2009
DOI: 10.1002/ceat.200800502
1 Introduction
Liposomes, or vesicles consisting of lipid bilayers organized
around an aqueous inner compartment, are a very promising
approach to several industrial applications. Due to their inner
aqueous core and the amphiphilic characteristics of the lipids
which form the liposomal membrane, these vesicles can incor-
porate different compound types into their structure, as shown
in Fig. 1.
The most important characteristics contributing to the in-
dustrial success of liposomes are a consequence of their ability
to decrease drug toxicity, increase drug circulation lifetime,
and accumulate at specific sites. However, not only the phar-
maceutical area benefits from liposomes, but also the food and
cosmetic industries. Consequently, many processes have been
developed for lipid vesicle production, which seek to meet the
demands for their different industrial applications. Several of
these processes require the use of high-energy steps such as ul-
trasonic treatments and high-pressure extrusion through poly-
carbonate membranes after lipid hydration. However, these
techniques are not suitable for the encapsulation of sensitive
substances because of their exposure to high mechanical stress
[1]. Other major drawbacks of these methods, and also of
spray-drying-based processes, include the oxidation and hy-
drolysis of phospholipids and fatty acids and the denaturation
or inactivation of some thermolabile substances [2].
The effective use of liposomes in the manufacture of indus-
trial products depends on several parameters. Therefore, the
vesicles should be obtained at relatively low cost, using simple
and reproducible methods involving fairly inert raw materials.
In addition, efficient encapsulation and stability of the desired
biologically active material should be attained [3].
Several different methodologies have been employed in lipo-
some synthesis on a laboratory scale, but the published litera-
ture regarding scale-up of liposome production plants is
scarce, probably due to the complexity of the processes in-
volved. The most relevant problems concerning the industrial
production of liposomes are the limited stability of the vesicles
and the need for sterilization processes when therapeutic ap-
plications are involved, as well as the technical and economical
feasibility of the integrated scaled-up process [4].
Among typical methods, the atomization of an organic solu-
tion containing the solubilized lipids and the direct introduc-
tion of the lipids (also solubilized in an organic phase) into an
aqueous solution, are the methodologies that show the largest
potential for scale-up. However, the limitations and advantages
of each procedure must always be verified and the choice of
Chem. Eng. Technol. 2010, 33, No. 1, 1520 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.cet-journal.com
Oselys Rodriguez Justo
1
ngela Maria Moraes
1
1
Department of
Biotechnological Processes,
State University of Campinas,
Campinas, Brazil.

Correspondence: Prof. . M. Moraes (ammoraes@feq.unicamp.br),


Department of Biotechnological Processes, School of Chemical En-
gineering, State University of Campinas, P.O. Box 6066, 13083-870
Campinas-SP, Brazil.
Ethanol injection method 15
technology to be employed in a production plant depends on
product demand as well as on the feedstock and its quality. In
addition, the scale of the operation will affect both construc-
tion and operation costs.
As mentioned previously, to obtain liposomes, the lipids solu-
bilized in water-soluble organic solvents such as ethanol and
propylene glycol can be dispersed in water. Alternatively, the lip-
ids can be dissolved in organic solvents not soluble in water
(such as ether and freon) and the mixture can be injected into
an aqueous phase. Following removal of the organic solvent
(and possible recycling) by evaporation, gel exclusion chroma-
tography, ultrafiltration, or dialysis can be performed. Neverthe-
less, depending on the type and the final concentration of the
organic solvent employed in the preparation, this removal stage
may not be required if the amount of solvent remaining in the
sample is not deleterious. In addition, it could prevent microbial
growth in cosmetic, nutritional, or pharmaceutical products.
The ethanol injection method proposed by Batzri and Korn
[5] can be included among the preparation methods involving
solvent dispersion in the category of organic solvent soluble in
aqueous phases. This technique offers several advantages, e.g.,
its simplicity, fast implementation, and reproducibility as well
as the fact that it does not cause lipid degradation or oxidative
alterations. Another important advantage of this method is the
suitability for the entrapment of many different substances
such as large hydrophilic proteins or small amphiphilic drugs
[6].
Liposome formulations prepared by techniques based on
the principles of the ethanol injection method have been em-
ployed for the encapsulation of proteins [4, 7, 8], drugs
[917], vitamins [18], plant-derived bioactive compounds
such as ursolic acid [19], breviscapine [20], oxymatrine [21],
and paclitaxel [22]. Other types of encapsulated bioactive
agents include photosensitizing agents [23, 24] and therapeutic
molecules such as antisense oligodeoxynucleotides [25]. In ad-
dition, liposomes are useful as gene delivery vectors [2630].
The successful application of liposomes in the entrapment
and delivery of bioactive agents will depend not only upon
demonstration of the superiority of the liposome carrier for
the intended purpose, but also upon the technical and eco-
nomical feasibility of the formulation [1]. Therefore, the ma-
jority of important decisions for capital expenditures and
product commercialization are based on results of preliminary
process design and cost analysis.
The aim of this paper is to estimate the investment and pro-
duction cost of a liposome production plant, using the ethanol
injection method as a model process. It is assumed that the li-
posome plant will be implanted as an addendum to a pre-ex-
isting bioactive compound production plant in order to in-
crease the global plant product portfolio and also to generate a
product with a higher aggregate value than that of the bare
bioactive compound itself. The economic evaluation is based
on assumptions regarding production volume, feedstock, and
a method established for liposome production to demonstrate
the features and economic benefits of the implementation of
this process on an industrial scale.
2 Process Description
During liposome production via the ethanol injection method,
lipids previously dissolved in ethanol are placed in contact
with the aqueous phase by rapid injection. When both phases
(aqueous and organic) are put in contact, ethanol dilution oc-
curs immediately. Consequently, changes in lipid solubility
take place, resulting in the formation of precipitated molecules
that form lipid bilayer fragments. Through energy dissipation
in the system (by stirring and/or ultrasonication), the frag-
ments of these lipid bilayers tend to decrease the exposure of
the hydrophobic parts of their molecules to the aqueous envi-
ronment, resulting in the curvature of these fragments which,
when closed, have an oval structure. The stirring and injection
forces are usually strong enough to guarantee the complete ho-
mogenization of the medium. The ellipsoidal structures are
transformed into spherical bodies over time. Thus, the curva-
ture energy is minimal and the retained aqueous volume is
maximal, probably occurring through the translocation (flip-
flop) of lipid molecules [31].
Appropriate mixing is extremely important in these systems,
and frequently, the uniformity of the particles is directly re-
lated to the energy spent homogenizing the system. In addi-
tion, the size and other physical properties of the lipid vesicles
are influenced by the mixing rate and by the lipid composition
and proportions.
General Liposomal Plant Design Assumptions
The liposome plant production costs were estimated assuming
a daily production of two batches of 144 L each of liposomal
suspension at 5 mmol/L, via the ethanol injection method. As-
www.cet-journal.com 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eng. Technol. 2010, 33, No. 1, 1520
Hydrophilic compound in the aqueous core
Hydrophilic compounds bound to the internal or external surface
Hydrophobic compound immersed in the lipid bilayer
Amphiphilic compounds partially immersed in the lipid bilayer
Figure 1. Incorporation of compounds with different characteris-
tics at different locations of the liposome structure.
16 O. Rodriguez Justo, . M. Moraes
suming an encapsulation efficiency of ca. 20 %, this amount of
lipid suspension would be enough, for instance, to incorporate
ca. 50 mmol/L of a bioactive agent. It was also assumed that
the plant would function for 300 days and that the process
would be operated in batch mode, since most bioprocesses,
especially those employed in the production of high-value,
low-volume products, operate in such mode [32]. Therefore
almost 87 000 L of liposome suspension would be produced
annually.
The detailed process proposed for this plant, assuming losses
in production of ca. 10 %, is presented in Fig. 2. Basically,
0.377 kg of hydrogenated soy phosphatidylcholine, 0.123 kg of
cholesterol and 8 L of ethanol are placed into the mixing tank,
T1, equipped with an impeller (turbine type with three axial
blades) and heated to 50 C until complete lipid dissolution
occurs. The storage tank, T2, equipped with a heating jacket
and a condenser, contains citrate buffer at 300 mmol/L, pH 4
and 5 C or any other buffer more appropriate for the desired
application. In tank T3, the lipid solution is then injected
through a 4 lm nozzle into the citrate buffer transferred from
tank T2 and heated at 50 C. The mixture is then homogenized
at the same temperature at high speed for 5 min.
The lipid vesicles obtained using this ethanol injection tech-
nique have a relatively narrow size distribution, consisting of
vesicles with diameters of ca. 150 nm [13, 15, 33]. The lipo-
some suspension originally produced at pH 4.0 is then cooled
to 25 C or to another appropriate temperature, and the exter-
nal media can be titrated to pH 7.4 with a 10 M NaOH aque-
ous solution (or to another desired pH value) in tank T4. The
final liposome suspension is then cooled to 5 C and stored in
tank T5.
The step of incorporation of the bioactive agent into the ves-
icles depends on the physico-chemical characteristics of the
compound itself. If the compound is hydrophobic or amphi-
philic, it can be added to the lipids dissolved in the ethanol in
tank T1 and incorporated into the liposomal membrane dur-
ing the step involving injection of the mixture into the citrate
buffer. If the compound is hydrophilic, the solution of lipids
in ethanol can be injected in the citrate buffer (or another
buffer) mixed with the bioactive compound in tank T3, and
thus, during formation, the vesicles would enclose part of the
active agent solution. Finally, if the compound is a lipophilic
amine, it can be successfully incorporated into the liposomes
by a remote (or active) loading procedure, which consists of
initially establishing a pH gradient between the internal and
external liposome aqueous media (achieved by titration of the
external citrate buffer to pH 7.4) and afterwards adding the
bioactive compound solubilized in the pH 7.4 medium in tank
T4. In this situation, when dissolved in the external medium at
pH 7.4, the bioactive compound will have neutral charge, and
therefore, will be capable of crossing the lipid bilayer. Once in
the liposomal aqueous core at pH 4.0, the bioactive compound
will become positively charged and unable to return to the ex-
ternal aqueous medium, and consequently, will accumulate in-
side the vesicles.
Liposomes with different lipid compositions can be pre-
pared by this process. However, the cost of the formulations
based on natural phospholipids, especially those derived from
egg yolk or soybean phosphatidylcholine (SPC), is normally
lower than that of the liposomes prepared with synthetic phos-
pholipids. These natural phospholipids can also be modified
by partial hydrogenation to produce liposomes that are more
resistant to peroxidation. For this reason, the SPC and choles-
terol (60:40 mol.-%) formulation is recommended in this
study. Cholesterol is included to improve lipid packing and
membrane permeability characteristics. In addition, the natu-
ral phospholipid SPC has high biocompatibility and stability,
which are important considerations in the pharmaceutical,
food and cosmetic industries.
Chem. Eng. Technol. 2010, 33, No. 1, 1520 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.cet-journal.com
Figure 2. Process flow diagram for liposome production by the ethanol injection technique. The plant was designed to operate two
batches per day, 300 working days per year, with 90 % production efficacy.
Ethanol injection method 17
The estimation of capital investment and manufacturing
costs was based on the results of material balance calculations
and equipment sizing. As already mentioned, the material bal-
ance was performed to obtain a liposome suspension with a fi-
nal lipid concentration of ca. 5 mmol/L using a starting lipid
solution of ca. 100 mmol/L in ethanol. The procedure requir-
ing the largest number of steps for incorporation of the bioac-
tive compound into the liposomes was selected (the remote
loading approach), since it involves the largest number of pro-
cess tanks and, therefore, the highest costs.
3 Results and Discussion
Cost Analysis
The objective of this part of the study is to present and dis-
cuss the results of the preliminary economic evaluation of li-
posome production by the ethanol injection technique based
on the process flow diagram shown in Fig 2. The preliminary
economic evaluation of a project usually involves the estima-
tion of capital investment, estimation of manufacture cost,
and analysis of profitability [32]. The total capital investment
is comprised of direct and indirect costs. The direct costs in-
clude equipment acquisition and installation, process piping,
instrumentation, insulation, electrical connections, buildings,
yard improvement, and auxiliary facilities. The indirect invest-
ment costs include engineering and construction factors. In
addition, contractor fees and contingency costs must also be
considered in estimating the fixed capital investment.
The production costs also consist of additional direct and
indirect costs. The direct costs (variable and semivariable
costs) include raw materials, operating and supervisory labor,
maintenance (labor, materials, and contract maintenance),
utilities (electricity, fuels, water, steam, compressed air, etc.),
laboratory charges, pollution control (air, water, and solid
waste), overhead expenses (plant and payroll), and royalties.
Indirect production costs (fixed costs) include depreciation,
taxes, insurance, administration, and finance charges [35]. The
variable costs vary depending on process annual operating
hours, while the semivariable expenses have an element of
fixed cost in them, as in the case of maintenance costs which
still occur when the process plant is shut down [34, 35]. The
fixed costs, on the other hand, are related to organization and
administration. The indirect costs do
not change with variations in the pro-
duction scale.
Since it was agreed that the liposome
plant could be implanted in an existing
facility, as a process added to others al-
ready in place, utilities such as steam,
electricity, process and cooling water,
refrigeration, compressed air, and solid
and wastewater treatment are seen to
be already available and functional.
For preliminary design purposes, the
various items of direct investment cost
can be estimated based on the total
equipment purchase cost. This was de-
termined as a function of capacity based on known equipment
price (B, as obtained from Harrison et al. [32] and Peters et al.
[34]) by using the sixth-tenth rule and updating the costs em-
ploying the Chemical Engineering Plant Cost Index (CEPCI)
[36] (from 395.6 in 2002 to 549.2, applicable for March, 2008)
in accordance with Eq. (1):
Cost equipment A Cost equipment B

updated cost index


reference cost index

capacity of A
capacity of B

0:6
1
For the design of the liposomal plant, the sizes and specifica-
tions of the equipment required for liposome production were
determined in terms of flow per unit time calculated through
the material balances. The estimated equipment cost is sum-
marized in Tab. 1, and the supplementary equipment men-
tioned includes mainly heat exchangers, condensers, and
NaOH solution storage tanks.
The total equipment cost for the liposomal plant with a pro-
duction capacity of 86 400 L/year is ca. $ 134 500, and it is eas-
ily seen that more than 58 % of the equipment cost is asso-
ciated with the five stirred tanks. It is well known that the
equipment price in a chemical industrial process may be af-
fected by different factors, e.g., size, construction material, in-
strumentation, inflation, and other market conditions. In the
biochemical industry, the main equipment employed is fre-
quently constructed of stainless steel, and in this case, capacity
is the aspect that most strongly affects price [32].
The fixed investment cost was based on the total purchased
equipment cost using typical percentages [32] of fixed-capital
investment (FCI), and the results are detailed in Tab. 2. Ac-
cording to the values obtained, the direct investment cost of a
liposome plant of the proposed capacity is ca. $ 0.75 million,
and this capital investment is ca. 5.6 times the cost for equip-
ment purchase. This relation is usually a multiple of 58 times
[32]. The data in Tab. 2 clearly shows that the fixed investment
cost is considerably reduced in this design, mainly due to the
simplicity and low cost requirements of the ethanol injection
technique, and consequently, this is a quite attractive aspect of
this process.
It is known that the ratio of the cost of raw materials to total
production cost varies considerably for different types of
plants. However, the raw materials cost is usually in the range
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Table 1. Estimated costs of equipment.
Major equipment specification Working capacity Unit Cost ($) Cost ($)
Stirred tank 1 (T1) 15 L 3 000.00 3 000.00
Stirred tanks 2 to 5 (T2, T3, T4, T5) 200 L 19 000.00 76 000.00
Centrifugal pump 1 (P1) 0.5 HP 1 000.00 1 000.00
Centrifugal pumps 2 to 4 (P2, P3, P4) 1 HP 1 500.00 4 500.00
Supplementary equipment (heat exchangers,
condensers and NaOH solution storage tanks)
50 000.00
Total Equipment Cost (EC) 134 500.00
18 O. Rodriguez Justo, . M. Moraes
of 1060 % of the total production cost [34]. Thus, it was esti-
mated that the raw materials cost represented 10 % of the total
production cost in this instance. The amount of raw material
that should be supplied per batch (144 L) was determined
from the material balance in accordance with Fig. 2. The costs
of all chemicals were based on average bulk market prices, as
listed in Tab. 3. The total annual raw materials cost was simply
the sum of the costs of the individual raw materials ($ 283 670/
year). Cholesterol was the most expensive component, consti-
tuting ca. 42 % of the overall raw material cost. In this study,
the use of high-purity raw materials was considered and it is
important to note that the raw materials cost can
vary extensively depending on the required purity.
Therefore, small changes in the quality of the raw
materials can significantly increase or reduce the
total production cost of liposomes using this pro-
cess. Under the proposed conditions, the overall
production cost is ca. $ 32.83 per L of liposomal
suspension at 5 mM.
Other economical factors of importance are
listed in Tab. 4. Based on sales prices of ca. $ 50/L
for the liposomal suspension (meaning an average
increase of this amount in the aggregate value of
the bioactive compound produced at the original
plant) and considering taxes of 40 % on annual
gross profit, the estimated revenues were calculated
as $ 4 320 000/year and the net profit attained
would be $ 889 980/year.
When one possesses estimates of capital invest-
ment, operating costs, and revenues for a project,
it is possible to proceed to profitability and attrac-
tiveness evaluation. To assess the profitability of
this project, the time of return on investment (pay-
back time) was estimated at ca. 1.17 year (ca.
14 months) for an interest rate of 20 % per year.
Based on the preliminary economic evaluation
of the plant for the production of liposomes by the
ethanol injection process through the total invest-
ment cost, annual production cost, annual net
profits, and payback time, it can be considered that
the liposomal suspension plant using the ethanol
injection technique is economically attractive.
4 Conclusions
The profitability of liposome plant production by the ethanol
injection technique with an annual capacity of 86 400 L was
examined. According to the preliminary economic evaluation
analysis of this project, the results attained show that this pro-
cess has good potential for implementation on an industrial
scale with equipment costs, fixed capital investment, and total
capital investment for the project of ca. $ 0.13, $ 0.75 and $
0.86 million, respectively. The annual production cost of the li-
posome plant was ca. $ 2.84 million. The total annual raw ma-
terials cost ($ 0.28 million) was high, mainly due to the high-
purity chemicals required. The results of economic
analysis suggest the economical feasibility for
scale-up of this process with a return on invest-
ment of 1.17 year.
Acknowledgements
The authors are grateful to FAPESP (Research
Foundation of the State So Paulo, Brazil) for its
financial support. A. M. Moraes is a recipient of a
CNPQ fellowship.
The authors have declared no conflict of interest.
Chem. Eng. Technol. 2010, 33, No. 1, 1520 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.cet-journal.com
Table 2. Typical percentages of fixed-capital investment (FCI) used to estimate
the fixed investment cost based on the total cost of purchased equipment.
Cost Item Index Investment ($)
A Total Plant Direct Cost (TPDC)
1. Equipment Cost (EC) 134 500.00
2. Installation 0.50 EC 67 250.00
3. Process Piping 0.40 EC 53 800.00
4. Instrumentation 0.35 EC 47 075.00
5. Isolation 0.03 EC 4 035.00
6. Electrical 0.15 EC 20 175.00
7. Buildings 0.10 x EC 13 450.00
8. Yard Improvement 0.15 EC 20 175.00
9. Auxiliary Facilities 0.35 EC 47 075.00
TPDC 407 535.00
B Total Plant Indirect Cost (TPIC)
10. Engineering 0.25 TPDC 101 883.75
11. Construction 0.35 TPDC 142 637.25
TPIC 244 521.00
C Total Plant Cost (TPC = TPDC + TPIC) 652 056.00
Contractor Fees (CF) 0.05 TPC 32 602.80
Contingency (C) 0.10 TPC 65 205.60
D Direct Fixed Capital (DFC = TPC + CF + C) 749 864.40
Table 3. Raw materials cost summary.
Raw Material Annual Amount (kg) Unit Cost ($/kg) Cost ($/year)
Phosphatidylcholine 90.48 1 000.00 90 480.00
Cholesterol 29.52 4 000.00 118 080.00
Ethanol 1 920.00 20.00 38 400.00
Citric acid 2.30 100.00 230.00
Water 72 960.00 0.50 36 480.00
Total 283 670.00
Ethanol injection method 19
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www.cet-journal.com 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eng. Technol. 2010, 33, No. 1, 1520
Table 4. Other economical factors of importance for evaluating
the cost of the process.
Item Value
Direct Fixed Capital ($) 49 864.40
Working Capital ($) 74 986.44
Start-up Cost ($) 37 493.22
Total Investment ($) 862 344.06
Annual Raw Materials Cost ($) 283 670.00
Annual Operating Cost ($) 2 836 700.00
Annual Capacity (L) 86 400.00
Product Price ($/L) 50.00
Revenues ($/year) 4 320 000.00
Gross Profit ($/year) 1 483 300.00
Taxes ($) 593 320.00
Net Profit ($) 889 980.00
Payback Time (year) 1.17
20 O. Rodriguez Justo, . M. Moraes

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