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24 INTERNATIONAL PHARMACEUTICAL INDUSTRY Spring 2015 Volume 7 Issue 1

Drug Discovery, Development & Delivery

RDD Europe 2015 Scientific Conference

Register now to attend the RDD Europe 2015 scientific conference, to be held May 5-8, 2015, in Antibes, France.

The Respiratory Drug Delivery (RDD®) Europe 2015 scientific conference will welcome pulmonary and nasal drug delivery experts from around the world to Antibes, France, May 5-8, 2015. The joint organisers of this prestigious event, RDD Online® and Aptar Pharma, invite you to celebrate RDD Europe’s 10th

anniversary and announce the opening of registration at www.rddonline.com/rddeurope2015.

Bringing the Respiratory World TogetherRDD Europe is a major scientific event in the respiratory drug delivery field in 2015 and is widely regarded as the key conference for presentations on the latest pulmonary and nasal drug delivery advances. More than 450 delegates from 29 countries attended the last edition of RDD Europe in May 2013 in Berlin, Germany. RDD Europe 2015 will host high-level academic, industry and government experts who specialise in research, development and marketing in the field of pulmonary and nasal drug delivery.

An Outstanding Three-day Interactive Conference The conference will start with a plenary lecture presented by Dr Bruce K. Rubin, Professor and Chair, Department of Pediatrics, Virginia Commonwealth University, entitled “Delivering Drugs to Pediatric Airways: Unhelpful Myths and Future Directions”.

The symposium will then focus on:

• Aerosol delivery in paediatrics• Personalised medicine• Global patent practice• Nasal drug delivery• Stretching the OINDP boundaries:

exploring alternative technologies• Particle engineering and QbD• Alternative distribution practices

for inhalers

As part of the symposium, RDD Europe 2015 will highlight innovative research contributions in podium and scientific poster sessions, and will also host 12 interactive workshops led by device experts and service providers.

RDD Europe Celebrates its 10th Anniversary“Presentations this year will address major issues of interest to the industry, from paediatrics and personalised medicine to innovations and research in our field. We are especially excited to invite all of our attendees to help us celebrate the 10th anniversary of RDD Europe, the industry’s leading assembly of drug delivery experts,” said Dr Richard Dalby, one of the organisers from the University of Maryland.

“The 10th anniversary of RDD Europe is a perfect occasion to thank our sponsors, exhibitors, all participants and contributors for the great success of this scientific conference, which has rapidly become a major event in Europe,” said Pierre Carlotti, Vice President Marketing and Communication, Aptar Pharma Prescription Division. RDD Europe was launched in 2005 and welcomed 300 delegates. Building on the success of the first edition, RDD Europe has continually improved over the years, attracting world-class speakers and sponsors.

RDD Europe 2015 offers numerous opportunities for networking, including a cocktail reception on the evening of May 5th and a gala anniversary celebration dinner on May 7th, sponsored by Aptar Pharma.

RDD Europe 2015 also features a comprehensive high-profile exhibition showcasing the latest technologies and devices in this exciting field.

For many years, RDD Europe events have sold out, so early registration is strongly recommended.

Further information about RDD Europe 2015, including the detailed programme and registration details, is available now at www.rddonline.com/rddeurope2015.

About RDD Online RDD Online manages the organisation of Respiratory Drug Delivery meetings in the US, and partners with Aptar Pharma to run RDD meetings in Europe. Other RDD Online services available at www.rddonline.com include the provision of scientific and technical publications, aerosol testing equipment including dose collection tubes and mixing inlets, web-based training, textbook publishing, service directories and recruiting services of interest to companies active in pulmonary and nasal drug delivery. For more information, please visit www.rddonline.com.

About Aptar Pharma Aptar Pharma is part of the AptarGroup family of companies, along with Aptar Beauty + Home and Aptar Food + Beverage. We create innovative drug delivery systems that meet the evolving needs of biotechnology, healthcare and pharmaceutical companies around the world. We provide our customers with a wide range of delivery technologies and analytical services backed by decades of proven expertise. For more information, visit www.aptar.com/pharma.

AptarGroup, Inc. (NYSE: ATR) is headquartered in Crystal Lake, Illinois, United States, with manufacturing facilities in North America, Europe, Asia and South America.

For more information, visit - www.aptar.com/pharma.



Green Extraction to Development of New Therapeutics in the Pharmaceutical Industry

Abstract: Development of new bioactive drugs nowadays mainly involves extraction of new compounds from plants. For a few years, methods of extraction have tended to become “greener”, solvent-free, energy-efficient, and decreasing the amount of non-useful components produced during the extraction process, while ensuring quality, reproducibility and efficiency of finished products. The term “green-extraction” was coined to name new green methods, the use of which is more and more applied to processes aimed at preparing bioactive extracts or purified components from plants. Up until relatively recently, two techniques were used to extract bioactive molecules from vegetal resources: the traditional aqueous decoction and techniques using organic solvents, which are often toxic or expensive. However these methods were shown to be time- and energy-consuming. They have been therefore reconsidered because of their detrimental impact on health and environment. The new methods bypass these problems. They make use of ultrasound- or microwave-assisted extraction, or of alternative green solvent or supercritical dioxide.

1. The Medicinal Plant, an Ancestral History for Drug Discovery For millennia, plants have been used by man for medical purposes. Pollen was found in the grave of a Neanderthal man dating from approximately 60,000 years ago. Its analysis showed that it mainly consisted of pollen from plants endowed with medicinal properties.

The earliest medical document is 4000 years old; a Sumerian clay tablet indeed lists a number of plants used to treat various illnesses (Figure 1). The Sumerian pharmacopoeia consisted of about 250 species of plants. Development of writing allowed the scribes to describe their uses in the form of recipes.

Old Egyptian civilisation also accumulated a great deal of information on medicinal plants. Ebers Egyptian papyrus, dated 1500 BC, is one of the earliest documents specifically dedicated

to medicinal plants. It informs us on the composition of more than 700 preparations made of animal and/or v e g e t a b l e substances (Figure 2). Notable among these are the

remedies mentioning mandrake to relieve

pain, garlic for the treatment of heart and circulatory disorders, and black figs to treat infections of the bronchi and lungs.

The famous Greek physician in its corpus lists more than 250 medicinal plants (Figure 3).

Ancient China is an invaluable source of knowledge on medicinal of plants. Pun-Tsao,

a pharmacopeia dated 1600,

contained monographs of thousands of vegetal medicaments. This collection is traditionally attributed to Shen-nung, a mythic emperor of China who would have lived more than 4500 years ago. The first Roman physicians also influenced the development of Western medicine. Dioscorides (1st century AD), for instance, was a Roman military physician who accompanied the

armies during their military campaigns. His work deserves special attention. During his travels, indeed, he observed many useful plants and compiled his observations in the De Materia Medica, an encyclopedia and pharmacopoeia that listed about 600 plant species together with their medicinal properties (Figure 4). Dioscorides included in his opus descriptions and illustrations of plants, as well as instructions on their preparation, uses and side-effects. Thanks to Christopher Columbus and other explorers, the exchange of plants between different countries and regions has developed on an increasingly regular

basis. During the XVIth century, a whole medical European or Western system mixing the use of plants and astrology was developed by P a r a c e l s u s . For centuries, the western medicaments were almost exclusively

vegetal.

Until the Second World War, plants were the primary source of medicinal molecules or medicaments. Since that time, beside the discovery of numerous artificial new molecules, more in-depth and broader researches on natural substances have been successfully developed. They proved that numerous substances found in traditional vegetal medicaments are endowed with high efficiency, and gave rise to a new branch of pharmacology, so-called ethno-pharmacology.

2. Traditional Techniques Used to Extract Bioactive Substances from Plants.Techniques for treating raw vegetal material appeared a long time ago, in various civilisations. Man discovered very soon how beneficial these plants could be for his health. To extract active principles from a plant, several ancestral methods were used which progressively improved their efficiencies.

Figure 1: Sumerian clay tablet

Figure 2: Ebers papyrus

Figure 3: The Hippocratic corpus lists

Figure 4: De Materia Medica



Trad i t i o na l l y, plants were dried before the extraction step. In order to speed up the extraction process, the dry plants were often finely crushed using several types of mills or mortars (Figure 5). The

first historically identified extracts

were obtained by aqueous extraction or alcoholic fermentation. The different extraction techniques made use of distillation, expression, maceration, infusion, percolation and decoction. 2.1. Distillation Distillation is used to extract different volatile substances of plants; a special form is the steam distillation which is used for heat-labile compounds with a low boiling temperature. The dry vegetal powder or the entire plant is put in an alembic. The device consists of a recipient containing heated and vaporised water, a condenser which allows the condensation of vapour, and a receiver which recuperates the drops of liquid enriched in active compounds. Essential oils and other bioactive light components float above the condensed water. 2.2. Expression Expression is still used to extract essential oils from citrus, for example. It involves the application of pressure onto the raw material in order to extract active substances without using heat. This method has been largely used to extract juice from fruits, and essential oils or oil from plants or seeds.

2.3. MacerationMaceration is one of the oldest techniques used by apothecaries; the plant was immersed for various times (hours or days) in a carefully chosen solvent, at ambient temperature. Depending on the active principles to be extracted, the solvent could be water, alcohol, oil, etc. The conventional procedure left the plants in contact with the solvent for several days while shaking the mixture. The plant was then pressed to recover a maximal amount of liquid, which was then filtered. Maceration was used, and is always used in some instances, to extract heat-labile or water solvent-soluble active products.

However, maceration is time-consuming and its yields are often low, but it does not alter the structure and properties of the substances of interest.

2.4. InfusionInfusion is always in use today. This mere process is applied to fragile parts of plants such as flowers. Raw material is soaked in water for a given time, determined by experiments. Cold or hot water may be used; the process can also be carried out at room temperature. The temperature range makes it possible to dissolve (sometimes sequentially) different active substances. Sometimes, a solution can be concentrated by boiling water. Alcohol is then added to improve the conservation of the solution. Infusion is a simple and fast process that allows good extraction of heat-labile active principles.

2.5. PercolationPercolation in its primary form is different from the current percolation system used today to prepare a cup of coffee. In the medicinal version, the plant is reduced to powder and placed in a so-called percolator. It is then slowly added to a solvent which fluxes through the powder over a period from one to four days. The matrix is then pressed and the resulting solution is clarified. Percolation respects the integrity of the bioactive substances but requires time and needs to carefully calibrate the size of the powder, which should be neither too coarse (if the extraction time is long) nor too thin, to avoid stagnation of the solvent into the matrix. The hot percolation makes use of Soxhlet which makes it possible to reduce the duration of the process.

2.6. DecoctionDecoction is always in use in pharmaceutical researches as a conventional technique. It resembles infusion. It differs from infusion by the use of boiling water all along the process. This method is used for treating compact or hard parts of plants, for instance roots or ligneous stems. It allows a more complete extraction of bioactive principles than infusion. But maintaining raw material at elevated temperature could degrade heat-labile compounds. Improvements in physiology and pharmacology knowledge enabled understanding of the action mechanisms of numerous natural substances. In recent decades, unravelling the relationships existing between the structure of a molecule and its biological activity allowed the design

and manufacture of synthetic drugs endowed with better performance or lesser adverse effects than the natural molecule. But today, suitable materials, advances in engineering processes, phytochemistry and analytical methods or new technologies allow manufacturers to use "greener" extraction methods. Modern expertise in plant extraction relies on associated controlled parameters and traditional use.

3. What is Green Extraction?3.1. Definition Green extraction methods are based on discovery, design, conception and use of extraction processes allowing noticeable energy consumption savings, as well as making use of alternative solvents and renewable matrix while ensuring production of a safe and high-quality extract. New ways have been opened to imagine and develop green extraction processes. Initially, optimisation improved already existing processes (Soxhlet extraction by alternative solvents for example). Then, new equipment and innovative processes have completed the jump towards novel methods (extraction by microwaves, ultrasounds; use of alternative solvents, etc.).

3.2. Principles of Green Extraction To meet the expectations of professionals in a context of sustainable development, the concept of green extraction has been created; it relies on a few principles designed as a kind of guideline for scientists and industrials.

Principle 1: to promote selection of suitable varieties of plants and use of renewable resources.

Principle 2:to privilege the use of alternative solvents, especially those originating from agro-resources.

Principle 3: to reduce energy consumption with the assistance of innovative technologies and to promote energy recycling.

Principle 4: to privilege production of co-products instead of waste, in order to integrate bio-industries and agro-refining industries.

Figure 5: Example of several mills



Principle 5:to reduce unit operations thanks to innovative technologies and to favour safe, robust and controlled processes.

Principle 6: to privilege production of non-denatured, biodegradable and uncontaminated extracts and carriers of "eco-extract" values.

4. Modern Extraction Methods.Some more modern extraction methods are primarily used for the development of herbal medicines (capsules, syrup, or tablets). They are referred to as non-conventional extraction techniques. However, in the pharmaceutical industry, the most promising techniques for extracting active substances from plants are ultrasound-assisted extraction, microwave-assisted extraction, accelerated solvent extraction and supercritical fluid extraction (Figure 6). They are named as "green methods". They do not include hazardous chemical synthesis; but make use of safer chemicals and solvents auxiliaries, take into essential consideration optimisation of energy efficiency, treat renewable stocks of raw materials, and reduce useless steps, avoiding or preventing degradation of bioactive products. They also search to prevent or minimise environmental pollution, and to avoid

undesired issues.

4.1. Ultrasound-assisted Extraction (UAE) Ultrasounds are elastic and mechanical waves, non-audible to the human ear, whereas they can be perceived by some animals. The frequency is usually comprised of between 16 kHz and 10,000 kHz. When crossing liquid medium, it generates areas of compression and decompression and generates bubbles;

this phenomenon is called cavitation. Bubbles are produced in the medium where they grow to reach a critical size which is followed by their collapse. Implosion of cavitation bubbles releases very high energy. Each cavitation bubble can be considered as a microreactor in which extreme conditions are reached. The bubbles can reach a temperature of about 4727° K, and a pressure of about 1013 bars with a heating- and cooling-rate above737°C. Thanks to these properties, ultrasounds have been applied to extraction of natural products from raw vegetal materials. During the impact of cavitation bubbles onto a solid element such as plant tissues, the forces developed are considerable and cause serious damage to the impact point. The cavitation allows, therefore, disruption of the cell walls thanks to the asymmetric implosion of bubbles. Implosion causes bursting of the cells, enabling an improved extraction of bioactive compounds from plants. Ultrasounds can intensify mass transfer and accelerated access of solvent to cells. Two phenomena are here involved; diffusion of solvent across the cell wall, and rinsing of the cell content after disruption of the cell walls. Extraction by ultrasound depends on important factors, namely nature of the solvent, size of particles, moisture content of plant, temperature, pressure, frequency and time of extraction. Advantages of UAE comprise a noticeable reduction of extraction time, of energy consumption and of amount of solvent.

UAE is a very efficient technique to extract bioactive substances from plants. Numerous studies showed its effectiveness in the extraction of very different molecules of pharmaceutical interest: phenolic compounds, alkaloids, anthocyanins or flavonoids. Crocin and crocetin, natural carotenoids found in the saffron flower which can be used in the treatment of neurodegenerative diseases, have been extracted from Crocus sativus L. using UAE by Lydia Ferrara et al. (2014,1). In 2013, J. Prakash Maran et al. applied an optimised sonication condition to extract bioactive compounds, pigments and polyphenols from Nephelium lappaceum L. fruit peel2. They identified optimal conditions of extraction after a systematic study of four factors at three levels. Zu et al. in 2012 demonstrated extraction efficiency of three polyphenols, phenolcarboxylic acid, carnosic acid and rosmarinic acid from Rosmarinus officinalis, using

ionic liquid-based UAE3. UAE has been proved to be more efficient and less time-consuming than conventional methods. UAE has been also shown by Yang et al. (2011) as a very efficient technique for extraction of three important alkaloids: vindoline, vinblastine and catharanthine, from Catharanthus roseus4.

4.2. Microwave-assisted Extraction (MAE)Microwaves are electromagnetic waves with a frequency range between 300 MHz and up to 300 GHz (between radio waves and infrared). The frequency 2450 MHz is the most frequently used. Electromagnetic waves are characterised by an electric field E and a magnetic field H, perpendicular to the direction of propagation. The energy is dissipated into heat. The electric field exerts two effects depending on the presence of free charges and/or polar molecules. In the first case, the presence of ions in the medium and the electric field induces conduction current, causing the displacement of ions and production of heat due to shocks with fixed molecules; this phenomenon is named ionic conduction. In the second case, the polar nature of the molecules plays a role in the effect of the applied microwaves. Under the action of an electric field, the dipoles are oriented in the rapidly-changing direction of the field. This results in the collision between molecules and consequently generates heat; this phenomenon is called polarisation by dipole orientation. The MAE involves three effects: increased temperature and pressure into the cells, bursting of cells, and dissolution of solutes from matrix in the solvent. The advantages of MAE comprise quicker heating, reduced equipment size, thermal gradients and increased yield. It is a selective technique to extract organic and organometallic compounds. MAE is qualified as a green technology because of the reduction in the use of organic solvent it provides.

As for ultrasound techniques, MAE has been proved to be very efficient in different studies devoted to pharmaceutical applications. Echinacea purpurea, widely used for its immunostimulating properties, contains multiple bioactive substances, including phenolic substances (caffeic acid derivatives), flavonoids, anthocyanins and alkamides. Mona et al. (2014) have compared conventional extraction and MAE for their efficiency to extract the active constituents of

Figure 6: Conventional and new extraction techniques from plants for pharmaceutical industry

Figure 6: Conventional and new extraction techniques from plants for pharmaceutical

industry



Echinacea purpurea5. Alupului et al. (2012) extracted flavonoids and phenolic compounds from Cynara scolymus L.6, a plant used for its choleretic and hepatoprotective activities and ability to lower circulating cholesterol in humans. These properties are attributed to cynarin. The authors showed that MAE possessed advantages over other methods, such as higher yields, purity of the molecule, and extractive efficiency. As compared with conventional extraction, MAE has proved to be a simpler and more effective procedure. In 2009, Alipului et al. applied MAE to prepare Stevia rebaudiana extracts. Beside of their ability to reduce cravings for sweet foods, they are also used to treat diabetes, hypoglycemia, candidiasis, hypertension and skin lesions7. MAE is a secure and worthy method to shorten extraction time and can usefully replace conventional energy-consuming processes.

4.3. Accelerated Solvent Extraction (ASE)The abbreviation PLE, for pressurised liquid extraction, appeared in 1996. Today, this method is known under many names, such as ASE for accelerated solvent extraction or PFE for pressurized fluid extraction. This technique aims at heating a liquid (solvent) beyond its boiling point at atmospheric pressure, while maintaining sufficient pressure to maintain the solvent in a liquid state. The ASE technique allows reduced consumption of solvent thanks to the combination of pressure and temperature that allows a fast extraction. The solvent is introduced at high pressure and temperature in the recipient containing the plant. This accelerates the extraction by increasing solubility of active substances and rate of mass transfer. Moreover, it also reduces the viscosity and the surface tension of solvents, which improves the extraction rate. Nowadays, for extraction of polar molecules, ASE competes with supercritical fluid extraction and becomes a potential and credible alternative. Applications of ASE technique for the preparation of bioactive compounds are frequently described in literature. Phenolic compounds such as catechin, caffeic acid, chlorogenic acid, etc. were extracted from various parts of Anatolia propolis using ASE at optimal conditions (40°C, 103 bars, 15 min) by Ergogan et al. (2011;8.) Chen et al. (2007) applied ASE to the preparation of active components from plants traditionally used in Chinese medicine such as Salvia

miltiorrhiza and Aucklandia lappa Decne9. Optimal conditions, including extraction temperature, static extraction time, solid/liquid ratio and solvent of ASE for extraction of salvianolic acid B in Salvia miltiorrhiza were determined by orthogonal experiments. Different extraction methods (ASE, steam distillation, ultrasonic wave and Soxhlet extraction) were used to extract volatile oil in Aucklandia lappa Decne. The results indicate that ASE was the most effective method in the case of this plant. Taken together, these studies abundantly prove that ASE is a powerful tool for preparing plant extracts.

4.4. Supercritical Fluid Extraction (SFE)In 1879 and 1880, J.B. Hanny and J. Hogarth presented at the Royal Society results obtained using different pressurised fluids to solubilise at best different substances. They opened the way to the use of “supercritical fluids”. Under normal conditions of pressure and temperature, every earthly substance exists as solid, liquid and gas. The study of phase diagram (pressure, temperature) demonstrated the existence of a limit point defined by Gibbs (1876) as the critical point. The supercritical state is a distinctive state with characteristic parameters such as critical temperature (Tc) and pressure (Pc) and specific physico-chemical properties between liquid and gas phase. A supercritical fluid has a viscosity close to a gas but a density close to a liquid, and it has the same transport properties of a gas. These specific physico-chemical properties allow an adaptation to extraction of natural compounds from raw materials. Carbon dioxide is considered as an ideal solvent for SFE. Extraction by supercritical carbon dioxide is widespread in industry, especially for preparing natural substances. The critical temperature of CO2 (31 °C) is close to room temperature, and the low critical pressure (74 bars) offers the possibility to operate at pressures generally ranging between 100 and 450 bars. The solvation power of supercritical carbon dioxide varied between that of pentane and toluene; it is similar to n-hexane. It is used for extracting natural substances with a molecular weight inferior to 1500. The main drawback of supercritical carbon dioxide is its low polarity, making it ideal for a non-polar substance, but very often unsuitable for most molecules of pharmaceutical interest. In order to modify the polarity

of interesting compounds, it is possible to use a co-solvent to increase extraction yield by increasing solvation power and selectivity. Using SFE for the extraction of bioactive substances has different advantages: the supercritical fluid has a high diffusion coefficient and a low viscosity, which increases mass transfer, and makes use of low amounts of organic solvents; recycling of supercritical fluid, selectivity of supercritical fluid and its solvation power can be modulated by changing temperature and/or pressure; the separation of solute from solvent is realised by simple depressurisation.

Wang et al. (2011) extracted flavonoids from Ampelopsis grossedentata stems by supercritical carbon dioxide10. Flavonoids are often known for their antioxidant activity but also play a role in the control and prevention of cancer and tumerogenesis, probably because of their antioxidant activity. The optimal conditions were 250 bars, 40 °C, 50 min, and use of a modifier consisting of methanol/ethanol (1:3, v/v). Furthermore, several unreported flavonoids such as apigenin, vitexin and luteolin have been detected in the extracts from A. grossedentata stems. These results indicate that supercritical carbon dioxide could be a promising alternative for preparing extracts enriched in bioactive compounds from A. grossedentata stems. These extracts have effective antioxidant capacity and could act as agents belonging to several types of natural antioxidant. Liza et al. (2010) applied SFE to Strobilanthes crispus11. This plant is traditionally used as an antidiabetic, diuretic, and laxative, and is endowed with high antioxidant activity; it is also used to fight acquired immunodeficiency syndrome, and has anticancer properties. The bioactive flavonoid compounds of Strobilanthes crispus (Pecah Kaca) leaves were obtained by using supercritical carbon dioxide extraction; the yields of interesting substances in crude extracts were compared under different conditions, in order to select the optimal parameters. Verma et al. (2008) optimised conditions of SFE to extract indole alkaloids from Catharanthus roseus leaves; the best yields in catharanthine were obtained using SFE as compared with other extraction methods, with a pressure of 250 bars and a temperature of 80 °C, using 6.6% methanol as modifier, applied for 40 min12.

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Conclusion Facing the growing demand for bioactive extracts in the field of the pharmaceutical industry, scientific research dedicated to extraction methods is continuously developing and tries to meet the industrial needs. Today, the challenge for chemists is to define a new balance between all the known techniques, to accurately describe new eco-extraction processes and to obtain the highest quality of bioactive substances from plants. Of course, the process should be a viable business model and have a minimum environmental impact. To reach this very desirable aim, it is necessary to understand all the aspects of the extraction processes. The establishment of combined methods must also be developed together with improvement of conventional methods. In addition, the physical characteristics of the raw material have to be taken into account in optimisation of extraction. For instance, enzymatic extraction or application of pulsed electric fields may be effective on plant cells with specific walls (layer of mucilage, wall containing chitin). On

the other hand, the growing economic importance of the bioactive compounds in the pharmaceutical field can lead to more expensive extraction methods in order to meet the market demand.

References 1. Ferrara, L., Naviglio, D. and Gallo, M. 2014. Extraction of

bioactive compounds of saffron (Crocus sativus L.) by ultrasound assisted (UAE) and by rapid solid-liquid dynamic extraction (RSLDE). Eur. Sci. J. 10:3.

2. Prakash Maran J., Manikandan, S., Vigna Nivetha, C. and Dinesh, R. 2013. Ultrasound assisted extraction of bioactive compounds from Nephelium lappaceum L. fruit peel using central composite face centered response surface design. Arab. J. Chem. in press.

3. Zu, G., Zhang, R., Yang, L., Ma, C., Zu, Y., Wang, W. and Zhao, C. 2012. Ultrasound-Assisted Extraction of Carnosic Acid and Rosmarinic Acid Using Ionic Liquid Solution from Rosmarinus officinalis. Int. J. Mol. Sci. 13:11027-43.

4. Yang, L., Wang, H., Zu, Y.G., Zhao, C., Zhang, L., Chen, X. and Zhang, Z. 2011. Ultrasound-assisted extraction of the three terpenoid indole alkaloids vindoline, catharanthine and vinblastine from Catharanthus roseus using ionic liquid aqueous solutions. Chem. Eng. J. 172:705-712.

5. Mona, A.M. and Nazif, N. 2014. Microwave-assisted extraction of bio-active compounds (phenolics and alkamides) from Echinacea purpurea. Int. J. Pharm. Pharmaceut. Sci. 6: 265-268.

6. Alupului, A., Calinescu, I. and Lavric, V. 2012. Microwave extraction of active principles from medicinal plants. U.P.B. Sci. Bull. 74:129-142.

7. Alupului, A., Calinescu, I. and Lavric, V. 2009. Ultrasonic vs. microwave extraction intensification of active principles from medicinal. Chem. Eng. Trans. 17:1023-1028.

8. Erdogan, S., Ates, B., Durmaz, G., Yilmaz, I., and Seckin, T. 2011. Pressurized liquid extraction of phenolic compounds from Anatolia propolis and their radical scavenging capacities. Food Chem. Toxicol. 49:1592-1597.

9. Chen, J., Yang, B., Li, W., Wang, X., Lee, F.S. and Yang, H. 2007. Application of accelerated solvent extraction technique for analysis of active components in traditional Chinese medicinal herbs. Chin. J. Chromatogr./Zhongguo hua xue hui.

25:628-632.10. Wang, Y., Ying, L., Sun, D., Zhang, S., Zhu, Y. and Xu, P. 2011.

Supercritical carbon dioxide extraction of bioactive compounds from Ampelopsis grossedentata Stems: Process optimization and antioxidant activity. Int. J. Mol. Sci. 12:6856-6870.

11. Liza, M.S., Abdul Rahman, R., Mandana, B., Jinap, S., Rahmat, A., Zaidul, I.S.M. and Hamid, A. 2010. Supercritical carbon dioxide extraction of bioactive flavonoid from Strobilanthes crispus (Pecah Kaca). Food Bioprod. Process. 88:319-326.

12. Verma, A., Hartonen, K., and Riekkola, M.L. 2008. Optimisation of supercritical fluid extraction of indole alkaloids from Catharanthus roseus using experimental design methodology - comparison with other extraction techniques. Phytochem. Anal. 19:52-63.

Dr Celine DEJOYE TANZI, PhD – Green extraction Laboratory Manager at Neuro-Sys, France. Specialist in Chemistry, her researches are focused on the integration of innovative extraction techniques and

analysis of bioactive substances from natural products (herbal plant, microalgae etc.), notably for pharmaceutical applications.

New ambr® bioreactor systems enhanced with software for Design of Experiments (DoE)

Robust, Flexible Bioprocess Development in Single-use Bioreactors

Sartorius Stedim Biotech (SSB) has announced the 2015 version of the ambr® systems (ambr® 15 and ambr® 250) will be supplied with integrated BioPAT® MODDE Software for Design of Experiments (DoE), powered by Umetrics. This will allow bioprocess scientists to easily implement DoE into their work flow for simpler process optimisation and scale-up to larger single-use BIOSTAT® pilot and manufacturing scale bioreactors, making bioprocess

development faster and more cost-effective. The integrated DoE software will enable scientists to quickly establish a Design Space where relevant bioprocessing conditions are varied simultaneously. Users can rapidly configure DoE experiments via work packets that are exported from the software to the ambr system; configuring each micro bioreactor with its own DoE defined bioprocessing parameters. The data generated from ambr, including offline analytics, is analysed within the software to identify critical process parameters, optimise bioprocessing conditions and define a robust design space for implementation in larger single-use BIOSTAT pilot and manufacturing scale bioreactors.

This extended DoE functionality is also available to existing ambr users who can assess the utility

of the BioPAT MODDE software via a free 60 day trial, with the option of purchasing the full version if they want to continue to run DoE programmes.

Dr Barney Zoro, ambr15 Product Manager at SSB commented: "To facilitate greater implementation of DoE across the industry we have combined the power of ambr with the BioPAT MODDE

software. These synergistic technologies are ideally suited for media optimisation and process parameter screening applications. Additionally, the software can be used for Monte Carlo Simulations as part of a Quality by Design (QbD) programme to identify the desired operating region for manufacturing scale processes, to make scale-up quicker and simpler.”

Mario Becker, Director of Marketing, PAT and Automation at SSB, continued: “Our major goal is to ensure that bioprocess scientists can develop their processes as quickly as possible. Providing a consistent, scalable platform for DoE studies and data analysis which is seamlessly integrated with the full range of ambr and BIOSTAT systems, will help scientists develop robust and flexible manufacturing processes based on single-use bioreactor technology. Ultimately, implementing this approach and extending it with the BioPAT SIMCA MVDA toolkit will contribute to biotech and pharma firms reducing risk in bioprocess development and achieving more rapid, cost-effective production of their biologics and vaccines.”

Contact:Dominic GroneCorporate Communications, Sartorius Stedim Biotech [email protected]

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