Download pharmaceutical processing

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