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PHARMACEUTICAL PROCESSING Dr. Khairul Farihan Kasim School of Bioprocess Engineering UniMAP PHARMACEUTICAL PROCESSING • Describe, discuss and illustrate general technique used for extraction and isolation of phytopharmaceuticals • Illustrate principles and design pilot plant for isolation of active pharmaceuticals. Phytopharmaceuticals • Phyto = plant • Pharmaceuticals = compound manufactured for use as a medicinal drug • Phytopharmaceuticals is “a pharmaceutical agent of plant origin” Phytopharmaceuticals vs phytochemicals • Phytochemicals = Plant + chemicals • Any of various biologically active compounds found in plants Pharmaceuticals vs nutraceuticals • Nutraceuticals = food containing health-giving additives and having medicinal benefit. • A Nutraceutical is a pharmaceutical-grade and standardized nutrient. • Nutraceuticals are regulated by FDA under the authority of the Federal Food, Drug, and Cosmetic Act Phytopharmaceuticals • Phytopharmaceutical drug is defined as purified and standardized fraction with defined minimum four bio-active or phytochemical compounds (qualitatively and quantitatively assessed) of an extract of a medicinal plant or its part, for internal or external use of human beings or animals for diagnosis, treatment, mitigation, or prevention of any disease or disorder but does not include administration by parenteral route. • The regulatory requirements for NDA for the phytopharmaceutical drug include standard requirements for a new drug-safety and pharmacological information, human studies, and confirmatory clinical trials. • For phytopharmaceutical drug, there is a lot of stress on: – Available information on the plant, formulation and route of administration, dosages, therapeutic class for which it is indicated and the claims to be made for the phytopharmaceutical, and supportive information from published literature on safety and efficacy and human or clinical pharmacology information • Data generated on: – Identification, authentication, and source of the plant used for extraction and fractionation – Process for extraction and subsequent fractionation and purification – Formulation details of phytopharmaceutical drug – Manufacturing process of formulation – Stability data. • The new phytopharmaceuticals regulation permits the development of the drug development using advanced techniques of solvent extraction, fractionation, potentiating steps, modern formulation development, etc. • After NDA approval, the marketing status of the new phytopharmaceutical drug would be like that of a new chemical entity-based drug. • The new regulation for phytopharmaceutical is in line with regulations in USA, China, and other countries involving scientific evaluation and data generation. • This new regulation is expected to promote innovations and development of new drugs from botanicals in a scientific way and would help in the acceptance of the use of herbal products by modern medical profession. It would encourage research in phytopharmaceutical drug development for academia, researchers, and industry. Herbal medicine • Herbal medicine products include herbs, herbal materials, herbal preparations, and finished herbal products that contain parts of plants, other plant materials, or combinations thereof as active ingredients. • Herbs include crude plant material, for example, leaves, flowers, fruit, seed, and stems. Herbal materials include, in addition to herbs, fresh juices, gums, fixed oils, essential oils, resins, and dry powders of herbs. • Herbal preparations are the basis for finished herbal products and may include comminuted or powdered herbal materials, or extracts, tinctures, and fatty oils of herbal materials. Finished herbal products consist of herbal preparations made from one or more herbs • In most countries, the herbal drugs are poorly regulated and are often neither registered nor controlled by the health authorities. • The safety of herbal medicines remains a major concern. In the United States, the Food and Drug Administration (FDA) has estimated that over 50,000 adverse events are caused by botanical and other dietary supplements. • In addition, for most herbal drugs, the efficacy is not proved and the quality is not assured. • The World Health Organization's (WHO) Traditional Medicine (TM) Strategy 2014–2023 focuses on promoting the safety, efficacy, and quality of TM by expanding the knowledge base and providing guidance on regulatory and quality assurance standards. • The regulatory scenario regarding herbal preparations varies from country to country. • Globally, several diverse regulatory approaches are in vogue such as: – Same regulatory requirements for all products – Same regulatory requirements for all products, with certain types of evidence not required for herbal medicines – Exemption from all regulatory requirements for herbal medicines – Exemption from all regulatory requirements for herbal medicines concerning registration or marketing authorization – Herbal medicines subject to all regulatory requirements – Herbal medicines subject to regulatory requirements concerning registration or marketing authorization. Phytochemicals What is phytochemicals? • Secondary metabolite • Phyto = plant + chemical – Natural substance in plant – Bioactive compound – Not vitamin • Phytochemicals are classes of compounds that are only found in plants that do not also fall into the category of essential nutrients. – phytochemicals are compounds that we ingest when we eat plants, but they are the parts that aren’t absolutely needed by the body – in other words, they are not nutritionally essential. • Generally, the arils of fruit contain large amounts of organic acids, sugars, minerals, and vitamins, but the peels contain higher amount of phenolic compounds than the flesh. Phytochemicals classes Class Sub class Classification are based on • Biosynthetic origin • Solubility properties • Presence of certain key functional groups Phenolic compound •Recognized by their hydrophilic compounds •Common origin from the aromatic precursor shikimic acid Terpenoids •Share lipid properties •Biosysnthetic origin from isopentenyl phytophosphate Organic acids, lipid and other classes of compounds Sugar and their derivatives •Water-soluble carbohydrates Nitrogen compounds •Recognized by their positive responses to either ninhydrin or the Dragendorff reagent Macromolecules •Easily separated from other constituents by their high molecular weights Extraction and isolation of phytopharmaceuticals General consideration i. The plant materials ii. Methods of extraction iii. Choice of solvents iv. Methods of separation/purification v. Methods of identification i. The plant materials The plant material • Ideally – fresh plant tissue and should be plunged into boiling alcohol within a minutes of its collection • Alternatively – may be dried before extraction – Drying under controlled conditions to avoid chemical changes – Dried as quickly as possible without using high temp, in a good air draft • Take note for the nature of the compounds eg: – Essential oil – sensitive to temp change and decreased over time– avoid drying – Flavonoids and alkaloids – remarkably stable with time – Tannin – better to extract from vacuum-dried fresh leaves rather than air-dried • Free of contamination and disease – not affected by viral, bacteria or fungal infection • Botanical identity of the plant – not to be mistakes – taxonomy expect ii. Methods of extraction Methods of extraction • No precise mode of extraction – no right or wrong method of extraction • In general – ‘kill’ the plant tissue – Prevent enzymic oxidation or hydrolysis – Plunging fresh leaf or flower tissue – Suitably cut up where necessary • Boiling ethanol/ alcohol – good all-purpose solvent for preliminary extraction • Plant material can be macerated in a blender and filtered • Extraction will be assumed completed when its completely free of colour – repeat extraction • Classical chemical procedure for dried material – Soxhlet apparatus • The extract obtained is clarified by filtration and then concentrated in vacuo – rotary evaporator • For volatile compounds – needs special precaution and apparatus. General techniques of extraction Maceration Infusion Percolation Digestion Decoction Hot continuous extraction Soxhlet Reflux Aqueous-alcoholic extraction by fermentation Counter-current extraction Microwave-assisted extraction Ultrasound extraction (Sonication) Supercritical fluid extraction Phytonic extraction Extraction techniques for aromatic plnats Hydro distillation techniques (water distillation, steam distillation, water and steam distillation) Hydrolytic maceration followed by distillation, expression and enfleurage (cold fat extraction) Headspace trapping Solid phase microextraction Protoplast extraction Microdistilation Thermomicrodistillation Molecular distillation Steps involved in the extraction of plant • Size reduction • Extraction • Filtration • Concentration • Drying Maceration • Definition: – The process in which properly communicated drug is place or permitted to soak in a solvent for specific period of time until the cellular structure is softened and penetrated by the solvent and soluble constituents are dissolved and extracted out. • The whole/coarsely powdered crude drug is place in a stoppered container with the solvent • Allow to stand at room temp for a period of at least 3 days with frequent agitation until the soluble matter gets dissolved • The mixture then is strained, the marc (the damp solid material) is pressed • The combined liquids are clarified by filtration or decantation after standing • This method is best suitable for use in case of thermolabile drugs Maceration / soaking Infusion • Infusion are prepared by macerating the crude drug for a short period of time with cold or boiling water • These are dilute solutions of the readily soluble constituents of crude drugs Digestion • This is a form of maceration in which gentle heat is used during the process of extraction • It is used when moderately elevated temperature is not objectionable • The solvent efficiency of the menstruum is thereby increased Microwave digestion system Decoction • Decoction are prepared in a similar way to infusion, but the crude drug is boiled in a specified volume of water for a defined time; it is then cooled and strained or filtered • This procedure is suitable for extracting water-soluble, heat stable constituents • The starting ratio of crude drug to water s fixed, eg, 1:4, 1:16; the volume is then brought down to one-fourth its original volume by boiling during the extraction procedure • Then, the concentrated extract is filtered and used as such or processed further Percolation • It is most frequently to extract active ingredients in the preparation of fluid extracts • A percolator (a narrow, cone-shaped vessel open at both ends) is generally used. • The solid ingredients are moistened with an appropriate amount of the specified menstruum and allowed to stand for approximately 4 h in a well closed container, after which the mass is packed and the top of the percolator is closed • Additional menstruum is added to form a shallow layer above the mass, and the mixture is allowed to macerate in the closed percolator for 24 h • The outlet of the percolator then is opened & the liquid contained therein is allowed to drip slowly • Additional menstruum is added as required, until the percolate measures about three-quarters of the required volume of the finished product • The marc is then pressed and the expressed liquid is added to the percolate • Sufficient menstruum is added to produce the required volume, and the mixed liquid is clarified by filtration or by standing followed by decanting Finely divided material for extraction/ drug Hot continuous extraction - Soxhlet • The finely ground crude drug is placed ia a porous bag or thimble made of strong filer paper, which is placed in chamber of the Soxhlet apparatus • The extracting solvent in flask is heated, and its vapours condense in condenser • The condensed extractant drips into the thimble containing the crude drug and extracts it by contact • When the level of liquid in chamber rises to the top of siphon tube, the liquid contents of chamber siphon into flask • This process is continuous and is carried out until a drop o solvent from the siphon tube does not leave residue when evaporated • At small scale, it is employed as a batch process only, but it becomes much more economical and viable when converted into a continuous extraction procedure on medium or large scale Hot continuous extraction – Reflux Aqueous alcoholic extraction by fermentation • Some medicinal preparation of Ayurveda adopt the technique of fermentation for extraction the active principles • The extraction procedure involves soaking the crude drug (powder / a decoction) for a specified period of time • Undergoes fermentation & generates alcohol in situ • This facilitates the extraction of the active constituents contained in the plant material • The alcohol thus generated also serves as a preservative Counter-current extraction • In counter-current extraction (CCE), wet raw material is pulverized using toothed disc disintegrators to produce a fine slurry • The material to be extracted is oved in one direction (generally in the form of a fine slurry) within a cylindrical extractor where it comes in contact with extraction solvent • The further the starting material moves, the more concentrated the extract becomes • Complete extraction is thus possible when the quantities of solvent and material and their flow rates are optimized. • The process is highly efficient, requiring little time and posing no risk from high temperature • Finally, sufficiently concentrated extract comes out at one end of the extractor while the marc (practically free of visible solvent falls out from the other end • Advantages – A unit quantify of the plant material can be extracted with much smaller volume of solvent as compared to other methods like maceration, decoction, percolation – CCE is commonly done at room temperature, which spares the thermolabile constituents from exposure to heat which is employed in most other techniques – As the pulverization of the drug is done under wet conditions, the heat generated during comminution is neutralized by water. This again spare the thermolabile constituents from exposure to heat – The extraction procedure has been rated to be ore efficient and effective than continuous hot extraction Ultrasound extraction (Sonication) • It involves the use of ultrasound with frequencies ranging from 20 kHz to 2000 kHz; this increases the permeability of cell walls and produces cavitation • Although the process is useful its large-scale application is limited due to the higher costs • Disadvantage: deleterious effect of ultrasound energy (> 20 kHz) on the active constitients of medicinal plants through formation of free radicals and consequently undesirable changes in the drug molecules (occasionally happen) Supercritical fluid extraction (SFE) • It is an alternative sample preparation method with general goals of reduced use of organic solvents and increased sample throughput • The factors to consider include temperature, pressure, sample volume, analyte collection, modifier (co-solvent) addition, flow and pressure control, and restrictors • Generally, cylindrical extraction vessels are used for SFE and their performance is good beyond any doubt. • There are many advantages to the use of CO2 as the extracting fluid – Favorable physical properties – Inexpensive, safe and abundant • It possess several polarity limitations – Solvent polarity is important when extracting polar solutes and when strong analyte-matrix interactions are present • Organic solvents are frequently added to the CP2 extracting fluid to alleviate the polarity limitations • Of late, instead of carbon dioxide, argon is being used because it is inexpensive and more inert • The component recovery rates generally increase with increasing pressure of temperature: the highest recovery rates in case of argon are obtained at 500 atm and 150°C • Distinct advantages: – The extraction of constituents at low temperature, which strictly avoids damage from heat and some organic solvents – No solvent residues – Environmental friendly extraction procedure • The major drawback in the commercial application f the extraction process is its prohibitive capital investment Phytonics process • A new solvent based on hydrofluorocarbon-134a and a new technology to optimize its remarkable properties in the extraction of plant materials offer significant environmental advantages and health and safety benefits over traditional process for the production of high quality natural fragrant oils, flavors and biological extracts • Advanced Phytonics Limited (Manchester, UK) has developed this patented technology termed ‘phytonics process’ • The products mostly extracted by this process are fragrant components of essential oils and biological or phytopharmacological extracts which can be used directly without further physical or chemical treatment • A advantages of the process – Unlike other process that employ high temperatures, the phytonics process is cool and gentle and its products are never damaged by exposure to temperatures in excess of ambient – No vacuum stripping is needed which, in other process, leads to the loss of precious volatiles – The process is carried out entirely at neutral pH and, in the absence of oxygen, the products never suffer acid hydrolysis damage or oxidation – It is highly selective, offering a choice of operating conditions and a choice of end products – It is less threatening to the environment – It requires a minimum amount of electrical energy – It releases no harmful emissions into the atmosphere and the resultant waste products (spent biomass) are innocuous and pose no effluents disposal problems – The solvents used in the techniques are not flammable, toxic or ozone depleting – The solvents are completely recycled Aromatic plant extraction (Essential oil) • Steam distillation iii. Choice of solvents Choice of solvents • Successful determination of biologically active compounds depends on the type of solvent used in the extraction procedure • The choice of solvent is influenced by what is intended with the extract • Properties of a good solvent in plant extractions – Low toxicity – Ease of evaporation at low heat – Promotion of rapid physiological absorption of the extract – Preservative action – Inability to cause the extract to complex or dissociate Solvents used for active component extraction iv. Methods of separation/ purification Methods of separation / purification • Chromatography – Paper chromatography (PC) – Thin layer chromatography (TLC) – Gas chromatography (GC) – High performance liquid chromatography (HPLC) • The choice of technique depends on the solubility properties and volatilities of the compounds – PC – applicable to water-soluble compounds – TLC – separating lipid-soluble compounds – GC – volatile compounds – HPLC – less volatile compounds and polar compounds • Capillary electrophoresis, liquid-liquid extraction, droplet counter-current chromatograhy (DCCC), affinity chromatography, differential ultracentrifugation v. Methods of identification Methods of identification • Isolation and purification • First to determine the class of compound • Then to find out which particular substance it is within that class • Methods – – – – UV and visible spectroscopy Infrared spectroscopy (IR) Mass spectroscopy (MS) Nuclear magnetic resonance spectroscopy (NMR) Overall processing techniques Credit to CEPP, UTM Case study 1 Case study 2 Case study 2 Case study 2 Case study 3 Case study 3 Case study 4 Case study 4 Case study 5 Production of pegaga powder Case study 5 Case study 6 Industrial penicillin manufacturing • WH Q? – – – – – – What is penicillin? How to produce penicillin? Any specific conditions for production? What are the processes involve? Others consideration? What is the final doses to be produced? Case study 6: Industrial penicillin manufacturing • What is penicillin? – Group of antibiotics produced by the Penicillium fungi • Effective against actively growing Gram positive bacteria • Some penicillin like amoxicillin are also effective against Gram negative bacteria, except Pseudomonas aeruginosa. – It is a group of closely related compounds, not a single compound – Examples: Amoxicillin, ampicillin, phenooxymethlpenicillin – Around 50 drugs that are penicillins Case study 6: Industrial penicillin manufacturing • How to produce penicillin? – By fermentation • Fermenter Consideration – – – – Reactor size: optimum rates of production Reactor configuration: mechanical agitation or will a buble column Mode of operation: will it be fed or continuously fed? Conditions inside the reactor: how will conditions (pH, temperature, …) be controlled? – Economic requirements: • • • • • Easy to operate aseptically Reasonably flexible regarding process requirements Low power consumption Stable under fluctuating conditions Cheap, robust, simple and well understood for scale-up Case study 6: Industrial penicillin manufacturing • Specific conditions for production? – Most penicillin form filamentous broths. This means they can be difficult to mix due to their high viscosity. Also increasing viscosity of the broth can hinder oxygen transfer – Solution: bubble column (air lift reactors) – would distribute the oxygen equally and also to agitate the medium – Penicillin is an aerobic organism; oxygen supply is critical – Optimum pH for penicillin growth is 6.5: maintain pH efficiently – Strain stability problems (mutations): careful strain maintenance is required – Biomass doubling is about 6h: provisions must be made Case study 6: Industrial penicillin manufacturing • Media consideration – Provide all the elements required for the synthesis of cell materials and the formation of desired product – Provide favorable environment for the culture in question – Be cost effective Case study 6: Industrial penicillin manufacturing • Production method – Primary or secondary production? Case study 6: Industrial penicillin manufacturing • Production method – Upstream and downstream production? Case study 6: Industrial penicillin manufacturing • Overall process? Case study 6: Industrial penicillin manufacturing • Overall process? Seed culture Medium Heat sterilization Fermentation Biomass removal Final product (Penicillin G) Fluid bed drying Extraction Centrifugation extraction Addition of solvent Case study 6: Industrial penicillin manufacturing • Overall process? Case study 6: Industrial penicillin manufacturing • Overall process? Doses formulation and manufacturing Penicillin G Semi-synthetic: penicillin V, penicillin O, ampicillin & amoxycillin Route to commercialization DISCOVERING & DEVELOPING NEW DRUGS: OVERVIEW • Highly time and cost intensive • Three stages: – Discovery: identifying new compounds that help treat disease – Development: administering the new drug to animals and humans to make sure it is safe and effective – Manufacturing: Producing the new drug in large quantities for distribution Malaysian Regulation http://npra.moh.gov.my/index.php/announcement/1151-drugregistration-guidance-document-drgd-second-edition-september2016-revised-march-2017