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Environmental sustainability analysis of chitosan microbeads production for pharmaceutical applications via computer-aided simulation, WAR and TRACI assessments
Sustainable Chemistry and Pharmacy 15 (2020) 100212
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Environmental sustainability analysis of chitosan microbeads production for pharmaceutical applications via computer-aided simulation, WAR and TRACI assessments �lez-Delgado * K. Moreno-Sader 1, S.I. Meramo-Hurtado 1, A.D. Gonza Chemical Engineering Department, Nanomaterials and Computer Aided Process Engineering Research Group (NIPAC), University of Cartagena, Avenida del Consulado St. 30, Cartagena de Indias, 130015, Colombia
A R T I C L E I N F O
A B S T R A C T
Keywords: Chitosan Pharmaceutical Environmental assessment CAPE
In recent decades, pharmaceutical uses of chitosan microbeads have been identified owing to their low toxicity, biocompatibility and biodegradability. However, many contributions have limited such microbeads preparation to lab-scale and there are no works reported in the literature about the scaling-up of chitosan microbeads pro duction. To fill the knowledge gap, this research attempts to simulate and evaluate the environmental perfor mance of large-scale production of chitosan microbeads under sustainability concept using computer-aided process engineering (CAPE). The extended energy and mass balances were provided by process simulation using the commercial software Aspen Plus ®. The environmental assessment was performed through two computeraided tools: waste reduction (WAR) algorithm and Tool for the Reduction and Assessment of Chemical and other Environmental Impacts (TRACI). Results reported negatives values for total generation rate of Potential Environmental Impacts (PEI) ( 1.16 � 10þ2, 9.25 � 10þ1, 1.00 � 10þ2 and 7.66 � 10þ1 PEI/hr) and highest total output rate of PEI for cases 4 and 3 (considering energy flows contributions). For TRACI tool, potential environmental impacts were low, however, the freshwater ecotoxicity potential for freshwater emis sions was higher (6.03Eþ02 CTUeco/hr) than for natural soil emissions (1.55Eþ02 CTUeco/hr). These results showed good environmental performance of the process and can be used as a benchmark in the production of more environmental-friendly chitosan microbeads at large-scale.
1. Introduction Chitosan is a natural cationic polysaccharide that supports the structural components of living organism, e.g., crustacean, insect exoskeleton and the cell walls of fungi and some algae (Moeini et al., 2018). This biopolymer, as well as its derivatives, has received great attention due to its remarkable physicochemical properties derived from the large number of primary amino groups in its molecule (Kuroiwa et al., 2017). Examples of such properties are low cytotoxicity, biode gradability, biocompatibility and ability to complex nucleic acid (Yu et al., 2019). Chitosan is also known as a bioactive compound with biological properties such as antitumor, immunoenhancing, antifungal, antimicrobial, antioxidant and wound healing activities (Shariatinia, 2019). Despite all the advantages offering by chitosan, many efforts have been made to improve its properties related to specific uses in food
industry, biomedicine, agriculture and pharmaceutical industry. The literature documents a wide range of pharmaceutical applications of chitosan and its modifications, including biomedicine, clinical use, drug delivery, gene delivery and binding to protein drugs (Olinda et al., 2019; Chuan et al., 2019). Hydrogel microbeads made of chitosan have extended their appli cations to pharmaceutical field owing to their low toxicity, high binding capacity to specific chemical species, and the ability to adsorb or release molecules in response to external signals or stimuli (Mark et al., 2009). Karlovic et al. (2015) prepared chitosan-coated beads to encapsulate caffeine and reported food efficiency at retarding the release of caffeine in water and decreased the bitterness intensity of caffeine in water medium. Rivera et al. (2015) developed biodegradable nanocapsules using chitosan as carrier of bioactive compounds such as 5-aminosaly cilic acid and glycomacropeptide. Bel et al. (2011) prepared
* Corresponding author. E-mail address: [email protected] (A.D. Gonz� alez-Delgado). 1 These authors contributed equally to this work. https://doi.org/10.1016/j.scp.2020.100212 Received 9 July 2019; Received in revised form 31 December 2019; Accepted 4 January 2020 Available online 9 January 2020 2352-5541/© 2020 Elsevier B.V. All rights reserved.
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system and identify the streams that most affect the environment. 2. Methodology The methodology selected for performing this work is depicted in Fig. 1. The scaling up of chitosan microbeads production was simulated using Aspen Plus based on the information collected at lab-scale by authors. Possible pharmaceutical applications of such product were identified according to other contributions found in the literature (Yu et al., 2019; Shariatinia, 2019; Ahmed et al., 2019). The large-scale process was assessed through environmental evaluation tools such as TRACI and WAR algorithm to address sustainability aspects during chitosan microbeads preparation. The chitosan used for preparing the microbeads was obtained from shrimp shell wastes that contribute to reduce the environmental impacts by employing environmental-friendly raw materials. For first time, the scaling up of chitosan microbeads preparation was simulated and evaluated towards a more sustainable production system. 2.1. Process description The scaling up of chitosan microbeads production was based on the experimental methodology followed at lab-scale. Many methods for chitosan microbeads preparation have been published up to date (e.g. ionic gelation, emulsification, coagulation, among others); among them, coagulation with sodium hydroxide seems to be the most convenient method (Balcerzak et al., 2013). The general description of this process is shown in Fig. 2. Two separate aqueous phases were prepared before starting microbeads formation: chitosan phase and coagulant phase. The chitosan phase was prepared by dissolving 2% w/v chitosan into 4% w/v acetic acid under continuous stirring in order to form a gelling solution and remove any undissolved material (Teresa et al., 2018). The coagu lant phase is a solution of 4.7% w/w sodium hydroxide, which was mixed with the gelling solution using a stirring system with ultrasound. During this process, coagulation and precipitation of chitosan microbeads occurred; however, a secondary reaction took place between acetic acid and sodium hydroxide producing sodium acetate. The resulting chitosan microbeads were washed thoroughly with plenty of water until the complete removal of undesired byproducts. Finally, microbeads were left in an oven at 105 � C to reduce moisture content and cooled to achieve ambient temperature (25 � C).
Fig. 1. Schematic representation of the methodology.
chitosan-alginate microbeads to encapsulate the extract of leaf from rapberry and olive and found significant polyphenol content and anti oxidant activity (Bel et al., 2011). Trifkovi et al. (2014) produced chi tosan microbeads as carrier for thymepolyphenols, recognized to have antimicrobial, antifungal and antibacterial properties. The authors found that such encapsulation system can be used as a functional additive. The sustainable production of pharmaceutical products is a key aspect for the development of companies and many environmental is sues have been considered during any process operation in order to maintain the long-term well-being of all living species (Raju et al., 2016). It is well-known that environmental impacts left uncontrolled, may result in major changes to both the climate and the environmental systems (Zahiri et al., 2017). Hence, the assessment of environmental impacts is a remarkable tool to identify opportunities for improvement towards a more sustainable chemical process. In this work, an envi ronmental sustainability analysis was carried out to quantify the po tential environmental impacts of producing chitosan microbeads at large-scale. To date, there are no contributions that address the scaling-up of such microbeads preparation and many works are limited to their synthesis at lab-scale for different purposes. For first time, large-scale production of chitosan microbeads was simulated using Aspen Plus ® based on synthesis protocols previously developed by authors. In addition, two computer-aided tools (TRACI and WAR algo rithm) were used to quantify the potential environmental impacts of this
2.2. Environmental assessment The environmental assessment of chitosan microbeads production was accomplished by the waste reduction (WAR) algorithm and Tool for the Reduction and Assessment of Chemical and other Environmental Impacts (TRACI). Both computer-aided tools are widely used for eval uating potential environmental impacts of wastes from chemical pro cess. The WAR algorithm was first introduced by Hilaly and Sikdar attending to minimize the potential environmental impacts (PEI) for a
Fig. 2. Schematic representation of chitosan microbeads production. 2
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Sustainable Chemistry and Pharmacy 15 (2020) 100212
Fig. 3. Scheme of pharmaceutical applications of chitosan microbeads in various areas.
process instead of minimizing the amount of waste (pollutants) gener ated by a process (Young et al., 2000). The TRACI tool was developed by the United States Environmental Protection Agency (EPA) in order to provide environmental characterization factors for Life Cycle Impact Assessment (LCIA), industrial ecology, and sustainability metrics (Ojoawo and Gbadamosi, 2013).
open-access excel spreadsheet of TRACI 2.1 provided by EPA (Ojoawo and Gbadamosi, 2013). The impact categories considered by this methodology are: ozone depletion, climate change, acidification, eutrophication, smog formation, human health impacts and ecotoxicity (Bare et al., 2003). The potential impacts of chemical emitted to the environment are determined by Eq. (5), where Ii is the potential impact of all chemicals (x) for a specific impact category of concern (i), CFixm is the characterization factor of chemical (x) emitted to media (m) for impact category (i), Mxm is the mass of chemical (x) emitted to media (m). X Ii ¼ CF ixm *Mxm (5)
2.2.1. Waste reduction (WAR) algorithm This approach uses data from the process such as stream flow rates and mass fractions, and toxicological data in order to quantify the po tential environmental impacts. The four environmental impact in dicators used in WAR Algorithm and calculated for the cases under study
xm
are: iout - rate of PEI leaving the system due to chemical interactions, iout ðcpÞ
ðepÞ
- rate of PEI out of the system due to energy generation processes, iðcpÞ we PEI out of a system as a result of the release of waste energy due to
3. Results and discussion
energy generation and iðepÞ we - PEI out of a system as a result of the release of waste energy due to chemical processes (Okoro et al., 2018). The following mathematical expressions to calculate total output rate of PEI and total generation rate of PEI were reported by Moreno-Sader, Meramo-Hurtado & Gonzalez-Delgado (2019).
ðepÞ ðcpÞ ðepÞ iðcpÞ out þ iout þ iwe þ iwe P P P P
ðcpÞ iðtÞ gen ¼ iout
iðtÞ gen ¼
iðcpÞ out
ðcpÞ
iin þ iðepÞ out ðcpÞ
The process scale-up becomes easier for more robust small-scale work due to the availability of detailed lab data. The step by step pro tocol of chitosan microbeads preparation was employed to define the batch size and select the process ranges. However, the market growth of chitosan microbeads for pharmaceutical applications must be consid ered to identify how large of the batch size is required. To this end, it was reviewed several works about pharmaceutical uses of chitosan microbeads. After identifying such applications, an estimated produc tion capacity was set according to market demand. Shariatinia (2019). classified the most recent pharmaceutical applications of chitosan into drug delivery, gene delivery, binding to protein drugs, tissue engineer ing, preparation of implants, wound healing, bioimaging, preparation of contact lenses as well as cell/virus/bacteria encapsulation. Chitosan has reported several properties such as the ability to control release, can be combined with anionic materials, free of toxic organic reagent, available for crosslinking and biodegradability (Yu et al., 2019). The main uses of chitosan microbeads for pharmaceutical industry are shown in Fig. 3, which were reported by several works. For example, Yadaorao et al. (2019) synthesized microbeads by using chitosan and nanocomposite clays for controlled release of diclofenac sodium concluding that such microbeads enhance therapeutic efficacy of drugs. Omer et al. (2016) used a new amphoteric biopolymer carrier from chitosan and alginate for bovine serum albumin (BSA) protein delivery reporting good results for site-specific release of protein drugs. Calija et al. (2016) studied the encapsulation of α-lipoic acid (LA) onto chi tosan microbeads, which synthesized by inverse emulsion technique, demonstrating sustained release of LA. Moeini et al. (2018) prepared
(1)
ðcpÞ ðepÞ ðcpÞ ðepÞ iðtÞ out ¼ iout þ iout þ iwe þ iwe
iðtÞ out ¼
3.1. Scaling-up and pharmaceutical applications of chitosan microbeads
� (2) (3)
ðepÞ
ðepÞ iin þ iðcpÞ we þ iwe ðepÞ
ðepÞ iin þ iðepÞ i þ iðcpÞ out we þ iwe P in P P P
� (4)
Where PP represents the mass flow rate of the product p. The WAR al gorithm is focused on eight impact categories that are classified into two groups: toxicological impacts (Human Toxicity Potential by Ingestion or HTPI, Human Toxicity Potential by Exposure or HTPE, Aquatic Toxicity Potential or ATP, Terrestrial Toxicity Potential or TTP) and atmospheric impacts (Global Warming Potential or GWP, Ozone Depletion Potential or ODP, Photochemical Oxidation Potential or PCOP and Acidification Potential or AP) (Cassiani-Cassiani et al., 2018). 2.2.2. Tool for the Reduction and Assessment of Chemical and other environmental impacts (TRACI) The TRACI tool also uses process data from mass balance around the system and the characterization factors of all chemicals are found in the 3
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Fig. 4. Simulation of chitosan microbeads scaling-up.
A residual stream (R1) leaves the washing stage containing sodium hydroxide, sodium acetate and water. The cleaned microbeads (P3) are fed into a dryer to reduce moisture content (R2). Finally, the dried product (P4) is cooled until 25 � C. The operating conditions for these process streams were summarized in Appendix section (seeTable A1 and Table A2). To support the process simulation results, some chemical properties of chitosan microbeads estimated by the software were compared with the properties calculated experimentally by authors and other re searchers (Paz et al., 2013; Cho et al., 1998; Bonfante-Alvarez et al., 2018). The stream properties were simulated by the SOLID thermody namic model available in Aspen database. Detailed validation of the selected model is summarized in Table 1 for chitosan microbeads. Mo lecular weight reached high accuracy (>90%) when comparing this simulation with experimental measurement found in literature (Paz et al., 2013). The bulk density reported acceptable accuracy of 79% because of the physicochemical differences between chitosan from shrimp wastes (simulation) and the synthetic chitosan chemically pre pared (experimental data in literature). The production yield reached at lab-scale by authors was 2.02 g microbeads/2 g raw chitosan, which differs in 99% from simulation. The deacetylation degree was calculated in previous contributions (Bonfante-Alvarez et al., 2018) and reported in this work owing to its influence on other chemical properties of chitosan microbeads.
Table 1 Chemical properties of chitosan microbeads provided by Aspen Plus software. Property
Simulation
Experimental
Accuracy (%)
Molecular weight (g/mol) Bulk density (g/mL) Production yield (kg microbeads/kg chitosan) Deacetylation degree
322,315 0.46 1
310,000a 0.38b 1.01
96 79 99
–
81.81c
-
a b c
(Paz et al., 2013). (Cho et al., 1998). (Bonfante-Alvarez et al., 2018).
chitosan based microbeads with ungeremine that showed antimicrobial activity against Penicillium roqueforti. According to these recent con tributions, it was selected the drug delivery as the main pharmaceutical application of chitosan microbeads. Fig. 3 shows a schematic represen tation of reported uses of chitosan microbeads. 3.2. Process simulation The scaled-up plant was simulated through Aspen Plus ® in order to obtain extended mass and energy balances, operational conditions and estimation of thermodynamic properties for chitosan microbead pro duction. The processing capacity was selected according to the demand for drug delivery and the availability of chitosan from shrimp shell wastes. The production yield was estimated in 1 kg microbeads/kg chitosan. Fig. 4 shows the process flowsheet of chitosan microbeads production. The raw material (I1) with a flow rate of 78 kg/h of chitosan is mixed with acetic acid (I2) to form a gel (P1). Such gel is sent to a tank for microbeads formation (P2), in which contacted a NaOH solution (I3). Then, distilled water (I4) is employed to remove undesired compounds.
3.3. Environmental assessment Waste reduction (WAR) algorithm: The extended energy and mass balances from process simulation were employed to quantify the po tential environmental impacts (PEI) of producing chitosan microbeads through WAR algorithm. To this end, four cases were considered: case 1 includes neither energy nor product streams contributions, case 2 in cludes only product stream contributions, case 3 considers only energy
Fig. 5. Total environmental impacts of chitosan microbeads production. 4
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Fig. 6. Potential environmental impacts for toxicological categories.
Fig. 7. Potential environmental impacts for atmospheric categories.
contributions, case 4 includes both energy and product streams contri butions. Fig. 5 shows the total environmental impacts of such process associated with generation or output rate of PEI. The total generation rate of PEI was negative for all cases ( 1.16 � 10þ2, 9.25 � 10þ1, 1.00 � 10þ2 and 7.66 � 10þ1 PEI/hr) suggesting that chitosan microbeads production consumes environmental impacts and its per formance is environmental-friendly. This result may be explained by using raw chitosan from natural sources, i.e. shrimp shells, instead of the commercial chitosan produced synthetically, which may generate more negative impacts to the environment. It is important to highlight that the extraction of chitosan from the shrimp exoskeleton also generates its own environmental contribution; however, Meramo-Hurtado et al. (2019) have estimated environmental benefits in the step of the chitosan processing owing to the negatives rates of total PEI generation. The highest total output rate of PEI was reached by case 4 (6.26 � 10þ2), followed by case 3 (6.10 � 10þ2); both cases consider energy contri butions indicating that energy flows affect more the environment than the product streams generated over the process. Fig. 6 shows the environmental impacts of chitosan microbeads production for toxicological categories. The total output of PEI was higher for impact categories of human toxicity (HTPI & HTPE) and terrestrial toxicity (TTP) than for aquatic toxicity (ATP). The low po tential impacts of ATP category (5.04 PEI/h, 2.29 � 10þ1 PEI/h, 5.28
PEI/h and 2.31 � 10þ1) indicated that such process does not represent any danger to aquatic ecosystems. For all toxicological categories, the total generation rate of PEI was negative supporting the results shown in Fig. 5. Fig. 7 depicts potential atmospheric impacts during the produc tion of chitosan microbeads. For cases 1 and 2, the total output rate of PEI was zero for categories of global warming, ozone depletion and acidification potential. This result suggested that product streams do not contain acids, greenhouse gases or any chemical at high oxidation state persisting longer in the environment. The photochemical oxidation po tential reported negative values for generation rate of PEI in all cases, which indicated that neither product streams nor energy flows emit nitrogen oxides, sulfur oxides or VOCs into the atmosphere. Due to the use of acetic acid in the mixing stage that is considered as a volatile organic compound (Risholm-Sundman et al., 1998), it was expected positive values in PEI generation rate. The main responsible of atmo spheric impacts is the energy source as confirmed the PEI output rate in acidification potential (14.3 PEI/h) for cases 3 and 4. Tool for the Reduction and Assessment of Chemical and other Environmental Impacts (TRACI): The process streams leaving the sys tem (R1, R2 and O1) were considered to perform TRACI assessment. The stream R1 is mainly composed of water, sodium hydroxide and sodium acetate, stream R2 is just water and product stream O1 is made up of chitosan. The stream R2 was discarded from this analysis due to the 5
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Fig. 8. Inventory of waste streams during chitosan microbeads production.
Fig. 9. Environmental impacts of chitosan microbeads production using TRACI 2.1.
characterization factor for such compound is zero in all impact cate gories. As chitosan microbeads (O1) are prepared from natural sources, i.e., they are biodegradable and environmental-friendly. So, this product stream was also discarded from environmental assessment. Fig. 8 depicts an inventory of emissions to the media (air, water, soil). The selected categories of TRACI tools for emissions to water and soil media are: eutrophication potentials for water emissions (kg N eq/kg substance), freshwater ecotoxicity potentials for water and natural soil emissions (CTUeco/kg), human health cancer potentials for water and natural soil emissions (CTUcancer/kg) and human health non-cancer potentials for water and natural soil emissions (CTUnon-cancer/kg). As shown in Fig. 9, environmental performance of chitosan microbeads production at large-scale showed to be promising because of the low environmental impacts associated with freshwater and natural soil emissions. Among process streams, residual water (R1) was identi fied as the main responsible for negative contributions to the environ ment due to the presence of sodium hydroxide and sodium acetate. For such compounds, the characterization factors for human health cancer and non-cancer potentials for water and natural soil emissions have not yet been reported in TRACI 2.1 database. Hence, it is not possible to quantify the environmental impacts of stream R1 on human health. The eutrophication potential was zero indicating that these substances do not contribute to the fast-growing of algae. Similar results were reported by Thannimalay et al. (2013), who performed the life cycle assessment of sodium hydroxide and found that NaOH contributes 0% to the eutrophication potential. The freshwater ecotoxicity potential for freshwater emissions was higher (6.03Eþ02 CTUeco/hr) than for
natural soil emissions (1.55Eþ02 CTUeco/hr), which indicated that stream R1 can exert tremendous effects on the environment when is emitted to water media instead of soil media. 4. Conclusions This work attempted to scale up the production of chitosan microbeads for pharmaceutical applications and evaluate its environ mental performance using two computer-aided tools (TRACI and WAR algorithm). The selected plant processing capacity was 78 kg/h of raw chitosan due to the availability of such raw material extracted from shrimp shells wastes. It was identified the main pharmaceutical use of chitosan microbeads in drug delivery because of their ability to control release and biodegradability. The environmental assessment through WAR algorithm reported negatives values for total generation rate of PEI ( 1.16 � 10þ2, 9.25 � 10þ1, 1.00 � 10þ2 and 7.66 � 10þ1 PEI/hr) and highest total output rate of PEI for cases 4 and 3. These results indicated that: i) such process is environmental-friendly, ii) energy flows generate higher environmental impacts than product streams, iii) the scaling-up of chitosan microbeads preparation is sustainable from environmental point of view. The toxicological categories of impact reported a higher PEI output rate than atmospheric categories. The TRACI tool also showed good environmental performance of this process despite the emission of residual water (stream R1) to natural soil and freshwater. These results can be used as a benchmark in the production of more environmental-friendly chitosan microbeads at large-scale.
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K. Moreno-Sader et al.
Funding acquisition, Investigation, Methodology, Project administra tion, Resources, Supervision, Validation, Visualization, Writing - orig inal draft, Writing - review & editing.
Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgment
CRediT authorship contribution statement
Authors thank University of Cartagena and Colombian Administra tive Department of Science, Technology and Innovation COLCIENCIAS for providing financial support with the project “Removal of polycyclic aromatic hydrocarbons (PAHs), present in coastal waters Cartagena bay by using shrimp exoskeleton as a source of nanoparticle-modified bio adsorbents”, grant code 1107748593351 CT069/17.
K. Moreno-Sader: Conceptualization, Investigation, Methodology, Writing - original draft, Writing - review & editing, Validation. S.I. Meramo-Hurtado: Conceptualization, Investigation, Methodology, Writing - original draft, Writing - review & editing, Validation. A.D. �lez-Delgado: Conceptualization, Data curation, Formal analysis, Gonza
Appendix
Table A1 Mass flow rates and operational conditions of main process streams Stream name Temperature ( C) Pressure (bar) Mass flow (kg/h) �
I1
I2
I3
I4
O1
25 1.01325 77.6168
25 1.01325 3104.67
25 1.01325 36221.2
25 1.01325 69855.1
25 1.01325 77.6168
1 0 0 0 0
0 0.0796 0 0.9204 0
0 0 0.0469448 0.953055 0
0 0 0 1 0
1 0 0 0 0
Mass Fractions CHITO-01 ACETI-01 SODIU-01 WATER SODIU-02
Table A2 Mass flow rates and operational conditions of main process streams (continue) Stream name
P1
P2
P3
P4
R1
R2
Temperature (� C) Pressure (bar) Mass flow (kg/h)
25 1.01325 3182.29
25 1.01325 39403.4
25 1.01325 5442.99
105 1.01325 77.6168
25 1.01325 103816
105 1.01325 5365.38
0.0243902 0.0776585 0 0.897951 0
0.0019698 0 0.0389762 0.950486 0.00856759
0.0142599 0 0 0.98574 0
1 0 0 0 0
0 0 0.0147935 0.981955 0.00325185
0 0 0 1 0
Mass Fractions CHITO-01 ACETI-01 SODIU-01 WATER SODIU-02
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Ojoawo, S.O., Gbadamosi, A.A., 2013. Application of TRACI and CML modeling tools in life cycle impact assessment of municipal wastes. Sci. Res. 4, 602–617. Okoro, O., Sun, Z., Birch, J., 2018. Catalyst-free biodiesel production methods: a comparative technical and environmental evaluation. Sustainability 10, 127. Olinda, G., Segalla, M., Margarete, A., et al., 2019. Amphipathic chitosans improve the physicochemical properties of siRNA- chitosan nanoparticles at physiological conditions. Carbohydr. Polym. 216, 332–342. Omer, A.M., Tamer, T.M., Hassan, M.A., et al., 2016. Development of amphoteric alginate/aminated chitosan coated microbeads for oral protein delivery. Int. J. Biol. Macromol. 92, 362–370. Paz, N., P� erez, D., Fern� andez, M., et al., 2013. Evaluaci� on viscosim� etrica del quitosano derivado de la quitina de langosta. Rev Iberoam Polímeros 14, 84–91. Raju, G., Sarkar, P., Singla, E., et al., 2016. Comparison of environmental sustainability of pharmaceutical packaging. Perspect. Sci. 8, 683–685. Risholm-Sundman, M., Lundgren, M., Vestin, E., et al., 1998. Emissions of acetic acid and other volatile organic compounds from different species of solid wood. Holz als Rohund Werkstolt 56, 125–129. Rivera, M.C., Pinheiro, A.C., Bourbon, A.I., et al., 2015. Hollow chitosan / alginate nanocapsules for bioactive compound delivery. Int. J. Biol. Macromol. 79, 95–102.
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Sustainable Chemistry and Pharmacy journal homepage: http://www.elsevier.com/locate/scp
Environmental sustainability analysis of chitosan microbeads production for pharmaceutical applications via computer-aided simulation, WAR and TRACI assessments �lez-Delgado * K. Moreno-Sader 1, S.I. Meramo-Hurtado 1, A.D. Gonza Chemical Engineering Department, Nanomaterials and Computer Aided Process Engineering Research Group (NIPAC), University of Cartagena, Avenida del Consulado St. 30, Cartagena de Indias, 130015, Colombia
A R T I C L E I N F O
A B S T R A C T
Keywords: Chitosan Pharmaceutical Environmental assessment CAPE
In recent decades, pharmaceutical uses of chitosan microbeads have been identified owing to their low toxicity, biocompatibility and biodegradability. However, many contributions have limited such microbeads preparation to lab-scale and there are no works reported in the literature about the scaling-up of chitosan microbeads pro duction. To fill the knowledge gap, this research attempts to simulate and evaluate the environmental perfor mance of large-scale production of chitosan microbeads under sustainability concept using computer-aided process engineering (CAPE). The extended energy and mass balances were provided by process simulation using the commercial software Aspen Plus ®. The environmental assessment was performed through two computeraided tools: waste reduction (WAR) algorithm and Tool for the Reduction and Assessment of Chemical and other Environmental Impacts (TRACI). Results reported negatives values for total generation rate of Potential Environmental Impacts (PEI) ( 1.16 � 10þ2, 9.25 � 10þ1, 1.00 � 10þ2 and 7.66 � 10þ1 PEI/hr) and highest total output rate of PEI for cases 4 and 3 (considering energy flows contributions). For TRACI tool, potential environmental impacts were low, however, the freshwater ecotoxicity potential for freshwater emis sions was higher (6.03Eþ02 CTUeco/hr) than for natural soil emissions (1.55Eþ02 CTUeco/hr). These results showed good environmental performance of the process and can be used as a benchmark in the production of more environmental-friendly chitosan microbeads at large-scale.
1. Introduction Chitosan is a natural cationic polysaccharide that supports the structural components of living organism, e.g., crustacean, insect exoskeleton and the cell walls of fungi and some algae (Moeini et al., 2018). This biopolymer, as well as its derivatives, has received great attention due to its remarkable physicochemical properties derived from the large number of primary amino groups in its molecule (Kuroiwa et al., 2017). Examples of such properties are low cytotoxicity, biode gradability, biocompatibility and ability to complex nucleic acid (Yu et al., 2019). Chitosan is also known as a bioactive compound with biological properties such as antitumor, immunoenhancing, antifungal, antimicrobial, antioxidant and wound healing activities (Shariatinia, 2019). Despite all the advantages offering by chitosan, many efforts have been made to improve its properties related to specific uses in food
industry, biomedicine, agriculture and pharmaceutical industry. The literature documents a wide range of pharmaceutical applications of chitosan and its modifications, including biomedicine, clinical use, drug delivery, gene delivery and binding to protein drugs (Olinda et al., 2019; Chuan et al., 2019). Hydrogel microbeads made of chitosan have extended their appli cations to pharmaceutical field owing to their low toxicity, high binding capacity to specific chemical species, and the ability to adsorb or release molecules in response to external signals or stimuli (Mark et al., 2009). Karlovic et al. (2015) prepared chitosan-coated beads to encapsulate caffeine and reported food efficiency at retarding the release of caffeine in water and decreased the bitterness intensity of caffeine in water medium. Rivera et al. (2015) developed biodegradable nanocapsules using chitosan as carrier of bioactive compounds such as 5-aminosaly cilic acid and glycomacropeptide. Bel et al. (2011) prepared
* Corresponding author. E-mail address: [email protected] (A.D. Gonz� alez-Delgado). 1 These authors contributed equally to this work. https://doi.org/10.1016/j.scp.2020.100212 Received 9 July 2019; Received in revised form 31 December 2019; Accepted 4 January 2020 Available online 9 January 2020 2352-5541/© 2020 Elsevier B.V. All rights reserved.
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system and identify the streams that most affect the environment. 2. Methodology The methodology selected for performing this work is depicted in Fig. 1. The scaling up of chitosan microbeads production was simulated using Aspen Plus based on the information collected at lab-scale by authors. Possible pharmaceutical applications of such product were identified according to other contributions found in the literature (Yu et al., 2019; Shariatinia, 2019; Ahmed et al., 2019). The large-scale process was assessed through environmental evaluation tools such as TRACI and WAR algorithm to address sustainability aspects during chitosan microbeads preparation. The chitosan used for preparing the microbeads was obtained from shrimp shell wastes that contribute to reduce the environmental impacts by employing environmental-friendly raw materials. For first time, the scaling up of chitosan microbeads preparation was simulated and evaluated towards a more sustainable production system. 2.1. Process description The scaling up of chitosan microbeads production was based on the experimental methodology followed at lab-scale. Many methods for chitosan microbeads preparation have been published up to date (e.g. ionic gelation, emulsification, coagulation, among others); among them, coagulation with sodium hydroxide seems to be the most convenient method (Balcerzak et al., 2013). The general description of this process is shown in Fig. 2. Two separate aqueous phases were prepared before starting microbeads formation: chitosan phase and coagulant phase. The chitosan phase was prepared by dissolving 2% w/v chitosan into 4% w/v acetic acid under continuous stirring in order to form a gelling solution and remove any undissolved material (Teresa et al., 2018). The coagu lant phase is a solution of 4.7% w/w sodium hydroxide, which was mixed with the gelling solution using a stirring system with ultrasound. During this process, coagulation and precipitation of chitosan microbeads occurred; however, a secondary reaction took place between acetic acid and sodium hydroxide producing sodium acetate. The resulting chitosan microbeads were washed thoroughly with plenty of water until the complete removal of undesired byproducts. Finally, microbeads were left in an oven at 105 � C to reduce moisture content and cooled to achieve ambient temperature (25 � C).
Fig. 1. Schematic representation of the methodology.
chitosan-alginate microbeads to encapsulate the extract of leaf from rapberry and olive and found significant polyphenol content and anti oxidant activity (Bel et al., 2011). Trifkovi et al. (2014) produced chi tosan microbeads as carrier for thymepolyphenols, recognized to have antimicrobial, antifungal and antibacterial properties. The authors found that such encapsulation system can be used as a functional additive. The sustainable production of pharmaceutical products is a key aspect for the development of companies and many environmental is sues have been considered during any process operation in order to maintain the long-term well-being of all living species (Raju et al., 2016). It is well-known that environmental impacts left uncontrolled, may result in major changes to both the climate and the environmental systems (Zahiri et al., 2017). Hence, the assessment of environmental impacts is a remarkable tool to identify opportunities for improvement towards a more sustainable chemical process. In this work, an envi ronmental sustainability analysis was carried out to quantify the po tential environmental impacts of producing chitosan microbeads at large-scale. To date, there are no contributions that address the scaling-up of such microbeads preparation and many works are limited to their synthesis at lab-scale for different purposes. For first time, large-scale production of chitosan microbeads was simulated using Aspen Plus ® based on synthesis protocols previously developed by authors. In addition, two computer-aided tools (TRACI and WAR algo rithm) were used to quantify the potential environmental impacts of this
2.2. Environmental assessment The environmental assessment of chitosan microbeads production was accomplished by the waste reduction (WAR) algorithm and Tool for the Reduction and Assessment of Chemical and other Environmental Impacts (TRACI). Both computer-aided tools are widely used for eval uating potential environmental impacts of wastes from chemical pro cess. The WAR algorithm was first introduced by Hilaly and Sikdar attending to minimize the potential environmental impacts (PEI) for a
Fig. 2. Schematic representation of chitosan microbeads production. 2
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Fig. 3. Scheme of pharmaceutical applications of chitosan microbeads in various areas.
process instead of minimizing the amount of waste (pollutants) gener ated by a process (Young et al., 2000). The TRACI tool was developed by the United States Environmental Protection Agency (EPA) in order to provide environmental characterization factors for Life Cycle Impact Assessment (LCIA), industrial ecology, and sustainability metrics (Ojoawo and Gbadamosi, 2013).
open-access excel spreadsheet of TRACI 2.1 provided by EPA (Ojoawo and Gbadamosi, 2013). The impact categories considered by this methodology are: ozone depletion, climate change, acidification, eutrophication, smog formation, human health impacts and ecotoxicity (Bare et al., 2003). The potential impacts of chemical emitted to the environment are determined by Eq. (5), where Ii is the potential impact of all chemicals (x) for a specific impact category of concern (i), CFixm is the characterization factor of chemical (x) emitted to media (m) for impact category (i), Mxm is the mass of chemical (x) emitted to media (m). X Ii ¼ CF ixm *Mxm (5)
2.2.1. Waste reduction (WAR) algorithm This approach uses data from the process such as stream flow rates and mass fractions, and toxicological data in order to quantify the po tential environmental impacts. The four environmental impact in dicators used in WAR Algorithm and calculated for the cases under study
xm
are: iout - rate of PEI leaving the system due to chemical interactions, iout ðcpÞ
ðepÞ
- rate of PEI out of the system due to energy generation processes, iðcpÞ we PEI out of a system as a result of the release of waste energy due to
3. Results and discussion
energy generation and iðepÞ we - PEI out of a system as a result of the release of waste energy due to chemical processes (Okoro et al., 2018). The following mathematical expressions to calculate total output rate of PEI and total generation rate of PEI were reported by Moreno-Sader, Meramo-Hurtado & Gonzalez-Delgado (2019).
ðepÞ ðcpÞ ðepÞ iðcpÞ out þ iout þ iwe þ iwe P P P P
ðcpÞ iðtÞ gen ¼ iout
iðtÞ gen ¼
iðcpÞ out
ðcpÞ
iin þ iðepÞ out ðcpÞ
The process scale-up becomes easier for more robust small-scale work due to the availability of detailed lab data. The step by step pro tocol of chitosan microbeads preparation was employed to define the batch size and select the process ranges. However, the market growth of chitosan microbeads for pharmaceutical applications must be consid ered to identify how large of the batch size is required. To this end, it was reviewed several works about pharmaceutical uses of chitosan microbeads. After identifying such applications, an estimated produc tion capacity was set according to market demand. Shariatinia (2019). classified the most recent pharmaceutical applications of chitosan into drug delivery, gene delivery, binding to protein drugs, tissue engineer ing, preparation of implants, wound healing, bioimaging, preparation of contact lenses as well as cell/virus/bacteria encapsulation. Chitosan has reported several properties such as the ability to control release, can be combined with anionic materials, free of toxic organic reagent, available for crosslinking and biodegradability (Yu et al., 2019). The main uses of chitosan microbeads for pharmaceutical industry are shown in Fig. 3, which were reported by several works. For example, Yadaorao et al. (2019) synthesized microbeads by using chitosan and nanocomposite clays for controlled release of diclofenac sodium concluding that such microbeads enhance therapeutic efficacy of drugs. Omer et al. (2016) used a new amphoteric biopolymer carrier from chitosan and alginate for bovine serum albumin (BSA) protein delivery reporting good results for site-specific release of protein drugs. Calija et al. (2016) studied the encapsulation of α-lipoic acid (LA) onto chi tosan microbeads, which synthesized by inverse emulsion technique, demonstrating sustained release of LA. Moeini et al. (2018) prepared
(1)
ðcpÞ ðepÞ ðcpÞ ðepÞ iðtÞ out ¼ iout þ iout þ iwe þ iwe
iðtÞ out ¼
3.1. Scaling-up and pharmaceutical applications of chitosan microbeads
� (2) (3)
ðepÞ
ðepÞ iin þ iðcpÞ we þ iwe ðepÞ
ðepÞ iin þ iðepÞ i þ iðcpÞ out we þ iwe P in P P P
� (4)
Where PP represents the mass flow rate of the product p. The WAR al gorithm is focused on eight impact categories that are classified into two groups: toxicological impacts (Human Toxicity Potential by Ingestion or HTPI, Human Toxicity Potential by Exposure or HTPE, Aquatic Toxicity Potential or ATP, Terrestrial Toxicity Potential or TTP) and atmospheric impacts (Global Warming Potential or GWP, Ozone Depletion Potential or ODP, Photochemical Oxidation Potential or PCOP and Acidification Potential or AP) (Cassiani-Cassiani et al., 2018). 2.2.2. Tool for the Reduction and Assessment of Chemical and other environmental impacts (TRACI) The TRACI tool also uses process data from mass balance around the system and the characterization factors of all chemicals are found in the 3
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Fig. 4. Simulation of chitosan microbeads scaling-up.
A residual stream (R1) leaves the washing stage containing sodium hydroxide, sodium acetate and water. The cleaned microbeads (P3) are fed into a dryer to reduce moisture content (R2). Finally, the dried product (P4) is cooled until 25 � C. The operating conditions for these process streams were summarized in Appendix section (seeTable A1 and Table A2). To support the process simulation results, some chemical properties of chitosan microbeads estimated by the software were compared with the properties calculated experimentally by authors and other re searchers (Paz et al., 2013; Cho et al., 1998; Bonfante-Alvarez et al., 2018). The stream properties were simulated by the SOLID thermody namic model available in Aspen database. Detailed validation of the selected model is summarized in Table 1 for chitosan microbeads. Mo lecular weight reached high accuracy (>90%) when comparing this simulation with experimental measurement found in literature (Paz et al., 2013). The bulk density reported acceptable accuracy of 79% because of the physicochemical differences between chitosan from shrimp wastes (simulation) and the synthetic chitosan chemically pre pared (experimental data in literature). The production yield reached at lab-scale by authors was 2.02 g microbeads/2 g raw chitosan, which differs in 99% from simulation. The deacetylation degree was calculated in previous contributions (Bonfante-Alvarez et al., 2018) and reported in this work owing to its influence on other chemical properties of chitosan microbeads.
Table 1 Chemical properties of chitosan microbeads provided by Aspen Plus software. Property
Simulation
Experimental
Accuracy (%)
Molecular weight (g/mol) Bulk density (g/mL) Production yield (kg microbeads/kg chitosan) Deacetylation degree
322,315 0.46 1
310,000a 0.38b 1.01
96 79 99
–
81.81c
-
a b c
(Paz et al., 2013). (Cho et al., 1998). (Bonfante-Alvarez et al., 2018).
chitosan based microbeads with ungeremine that showed antimicrobial activity against Penicillium roqueforti. According to these recent con tributions, it was selected the drug delivery as the main pharmaceutical application of chitosan microbeads. Fig. 3 shows a schematic represen tation of reported uses of chitosan microbeads. 3.2. Process simulation The scaled-up plant was simulated through Aspen Plus ® in order to obtain extended mass and energy balances, operational conditions and estimation of thermodynamic properties for chitosan microbead pro duction. The processing capacity was selected according to the demand for drug delivery and the availability of chitosan from shrimp shell wastes. The production yield was estimated in 1 kg microbeads/kg chitosan. Fig. 4 shows the process flowsheet of chitosan microbeads production. The raw material (I1) with a flow rate of 78 kg/h of chitosan is mixed with acetic acid (I2) to form a gel (P1). Such gel is sent to a tank for microbeads formation (P2), in which contacted a NaOH solution (I3). Then, distilled water (I4) is employed to remove undesired compounds.
3.3. Environmental assessment Waste reduction (WAR) algorithm: The extended energy and mass balances from process simulation were employed to quantify the po tential environmental impacts (PEI) of producing chitosan microbeads through WAR algorithm. To this end, four cases were considered: case 1 includes neither energy nor product streams contributions, case 2 in cludes only product stream contributions, case 3 considers only energy
Fig. 5. Total environmental impacts of chitosan microbeads production. 4
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Fig. 6. Potential environmental impacts for toxicological categories.
Fig. 7. Potential environmental impacts for atmospheric categories.
contributions, case 4 includes both energy and product streams contri butions. Fig. 5 shows the total environmental impacts of such process associated with generation or output rate of PEI. The total generation rate of PEI was negative for all cases ( 1.16 � 10þ2, 9.25 � 10þ1, 1.00 � 10þ2 and 7.66 � 10þ1 PEI/hr) suggesting that chitosan microbeads production consumes environmental impacts and its per formance is environmental-friendly. This result may be explained by using raw chitosan from natural sources, i.e. shrimp shells, instead of the commercial chitosan produced synthetically, which may generate more negative impacts to the environment. It is important to highlight that the extraction of chitosan from the shrimp exoskeleton also generates its own environmental contribution; however, Meramo-Hurtado et al. (2019) have estimated environmental benefits in the step of the chitosan processing owing to the negatives rates of total PEI generation. The highest total output rate of PEI was reached by case 4 (6.26 � 10þ2), followed by case 3 (6.10 � 10þ2); both cases consider energy contri butions indicating that energy flows affect more the environment than the product streams generated over the process. Fig. 6 shows the environmental impacts of chitosan microbeads production for toxicological categories. The total output of PEI was higher for impact categories of human toxicity (HTPI & HTPE) and terrestrial toxicity (TTP) than for aquatic toxicity (ATP). The low po tential impacts of ATP category (5.04 PEI/h, 2.29 � 10þ1 PEI/h, 5.28
PEI/h and 2.31 � 10þ1) indicated that such process does not represent any danger to aquatic ecosystems. For all toxicological categories, the total generation rate of PEI was negative supporting the results shown in Fig. 5. Fig. 7 depicts potential atmospheric impacts during the produc tion of chitosan microbeads. For cases 1 and 2, the total output rate of PEI was zero for categories of global warming, ozone depletion and acidification potential. This result suggested that product streams do not contain acids, greenhouse gases or any chemical at high oxidation state persisting longer in the environment. The photochemical oxidation po tential reported negative values for generation rate of PEI in all cases, which indicated that neither product streams nor energy flows emit nitrogen oxides, sulfur oxides or VOCs into the atmosphere. Due to the use of acetic acid in the mixing stage that is considered as a volatile organic compound (Risholm-Sundman et al., 1998), it was expected positive values in PEI generation rate. The main responsible of atmo spheric impacts is the energy source as confirmed the PEI output rate in acidification potential (14.3 PEI/h) for cases 3 and 4. Tool for the Reduction and Assessment of Chemical and other Environmental Impacts (TRACI): The process streams leaving the sys tem (R1, R2 and O1) were considered to perform TRACI assessment. The stream R1 is mainly composed of water, sodium hydroxide and sodium acetate, stream R2 is just water and product stream O1 is made up of chitosan. The stream R2 was discarded from this analysis due to the 5
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Fig. 8. Inventory of waste streams during chitosan microbeads production.
Fig. 9. Environmental impacts of chitosan microbeads production using TRACI 2.1.
characterization factor for such compound is zero in all impact cate gories. As chitosan microbeads (O1) are prepared from natural sources, i.e., they are biodegradable and environmental-friendly. So, this product stream was also discarded from environmental assessment. Fig. 8 depicts an inventory of emissions to the media (air, water, soil). The selected categories of TRACI tools for emissions to water and soil media are: eutrophication potentials for water emissions (kg N eq/kg substance), freshwater ecotoxicity potentials for water and natural soil emissions (CTUeco/kg), human health cancer potentials for water and natural soil emissions (CTUcancer/kg) and human health non-cancer potentials for water and natural soil emissions (CTUnon-cancer/kg). As shown in Fig. 9, environmental performance of chitosan microbeads production at large-scale showed to be promising because of the low environmental impacts associated with freshwater and natural soil emissions. Among process streams, residual water (R1) was identi fied as the main responsible for negative contributions to the environ ment due to the presence of sodium hydroxide and sodium acetate. For such compounds, the characterization factors for human health cancer and non-cancer potentials for water and natural soil emissions have not yet been reported in TRACI 2.1 database. Hence, it is not possible to quantify the environmental impacts of stream R1 on human health. The eutrophication potential was zero indicating that these substances do not contribute to the fast-growing of algae. Similar results were reported by Thannimalay et al. (2013), who performed the life cycle assessment of sodium hydroxide and found that NaOH contributes 0% to the eutrophication potential. The freshwater ecotoxicity potential for freshwater emissions was higher (6.03Eþ02 CTUeco/hr) than for
natural soil emissions (1.55Eþ02 CTUeco/hr), which indicated that stream R1 can exert tremendous effects on the environment when is emitted to water media instead of soil media. 4. Conclusions This work attempted to scale up the production of chitosan microbeads for pharmaceutical applications and evaluate its environ mental performance using two computer-aided tools (TRACI and WAR algorithm). The selected plant processing capacity was 78 kg/h of raw chitosan due to the availability of such raw material extracted from shrimp shells wastes. It was identified the main pharmaceutical use of chitosan microbeads in drug delivery because of their ability to control release and biodegradability. The environmental assessment through WAR algorithm reported negatives values for total generation rate of PEI ( 1.16 � 10þ2, 9.25 � 10þ1, 1.00 � 10þ2 and 7.66 � 10þ1 PEI/hr) and highest total output rate of PEI for cases 4 and 3. These results indicated that: i) such process is environmental-friendly, ii) energy flows generate higher environmental impacts than product streams, iii) the scaling-up of chitosan microbeads preparation is sustainable from environmental point of view. The toxicological categories of impact reported a higher PEI output rate than atmospheric categories. The TRACI tool also showed good environmental performance of this process despite the emission of residual water (stream R1) to natural soil and freshwater. These results can be used as a benchmark in the production of more environmental-friendly chitosan microbeads at large-scale.
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Sustainable Chemistry and Pharmacy 15 (2020) 100212
K. Moreno-Sader et al.
Funding acquisition, Investigation, Methodology, Project administra tion, Resources, Supervision, Validation, Visualization, Writing - orig inal draft, Writing - review & editing.
Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgment
CRediT authorship contribution statement
Authors thank University of Cartagena and Colombian Administra tive Department of Science, Technology and Innovation COLCIENCIAS for providing financial support with the project “Removal of polycyclic aromatic hydrocarbons (PAHs), present in coastal waters Cartagena bay by using shrimp exoskeleton as a source of nanoparticle-modified bio adsorbents”, grant code 1107748593351 CT069/17.
K. Moreno-Sader: Conceptualization, Investigation, Methodology, Writing - original draft, Writing - review & editing, Validation. S.I. Meramo-Hurtado: Conceptualization, Investigation, Methodology, Writing - original draft, Writing - review & editing, Validation. A.D. �lez-Delgado: Conceptualization, Data curation, Formal analysis, Gonza
Appendix
Table A1 Mass flow rates and operational conditions of main process streams Stream name Temperature ( C) Pressure (bar) Mass flow (kg/h) �
I1
I2
I3
I4
O1
25 1.01325 77.6168
25 1.01325 3104.67
25 1.01325 36221.2
25 1.01325 69855.1
25 1.01325 77.6168
1 0 0 0 0
0 0.0796 0 0.9204 0
0 0 0.0469448 0.953055 0
0 0 0 1 0
1 0 0 0 0
Mass Fractions CHITO-01 ACETI-01 SODIU-01 WATER SODIU-02
Table A2 Mass flow rates and operational conditions of main process streams (continue) Stream name
P1
P2
P3
P4
R1
R2
Temperature (� C) Pressure (bar) Mass flow (kg/h)
25 1.01325 3182.29
25 1.01325 39403.4
25 1.01325 5442.99
105 1.01325 77.6168
25 1.01325 103816
105 1.01325 5365.38
0.0243902 0.0776585 0 0.897951 0
0.0019698 0 0.0389762 0.950486 0.00856759
0.0142599 0 0 0.98574 0
1 0 0 0 0
0 0 0.0147935 0.981955 0.00325185
0 0 0 1 0
Mass Fractions CHITO-01 ACETI-01 SODIU-01 WATER SODIU-02
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