Transcript Industrial Pharmaceutical Technology / Part 1

INDUSTRIAL
PHARMACEUTICAL
TECNOLOGY
(ESSENTIALS)
Part 1
Yauheni Hryniuk,
Associate professor
History
Real birth of industrial Pharmaceutical Technology –
first half of XIX century
 Merck – established in 1668. But it was only a
drugstore, in XIX c. on the drugstore basis factory was
established. Today – huge company (~ 40 000
employees).
 Shering – drugstore – 1851, factory – 1864. In 2006 –
takeover by Bayer.
 Bayer – 1863. Today – one of the biggest company with
111500 workers among the world.
Pfizer
Johnson & Johnson
GlaxoSmithKlein
Roche Holding
Novartis
Sanofi-Aventis
Astra Zeneca
Merck
Eli Lilly & Co.
Wyeth
Source: Yahoo Finance
182.15 B
180.88 B
141.87 B
135.28 B
128.65 B
122.80 B
75.70 B
72.71 B
64.67 B
62.78 B
History
in Belarus
 JSC “Borisovsky zavod medpreparatov”
- 1962
 RUE “Belmedpreparaty” - 1929
 RUE “Minskinterkaps” - 1995
Modern-day drug discovery and
development
L eading Pharmaceutical Companies Ranked
by R&D Spending (US$ in Billions) in 2010
Advantages of the industrial production
 Low prime cost (including innovations)
 Large scale production
 Unified package (good for
transportation)
 Quality control processes (standard
technical documentation)
Standard technical documentation
Pharmacopoeia
Technology and technical
regulations
State standards
Producer Pharmacopoeia articles
SOPs
…
It is extremely needed to provide us
with safe, effective and
qualitative medicines
Basis of the most tecnological
processes – dosage form of drug
 Solid dosage forms (tablets, capsules,
powders, granules, dragee, …)
 Liquid dosage forms (solutions,
suspension, emulsion)
 Soft dosage forms (ointments,
liniments, capsules, patches, gels…)
 Gaseous dosage forms (gases, aerosols)
Some special areas of drug
production
 drugs Galenical (extraction of medicinal
plants: tinctures, extracts …)
 biotech pharmaceuticals
 children's medicines
 ophthalmic formulations
 geriatric medicines
…
Tecnology of drug production
according to the peculiarities of
production and dosage form
Drugs Galenical
The process of extraction
refers to the mass-transfer
processes and flows through
the diffusion laws
The main factors are:
1) nature and characteristics of medicinal
herbs
2) Properties of the extracting agent (water,
ethanol, ethyl ether, chloroform, acetone,
liquefied gases )
Main stages of production:
 Raw material preparation
 Extraction process
 Purification (settling, filtration,
centrifugation)
 Concentration or drying
 Filling and packing
Quality control
 Organoleptic characteristics (transparency,
chromaticity, taste, flavor)
 Ethanol content and dencity (in tinctures)
 Dry residue
 Heavy metals
Solid dosage forms
tablets
capsules
sugar-coated tablets (dragee)
powders
granules
sachets
Powders
latin - pulvis (pulv.)
Powders are drugs or drug extracts that are
dried and ground and micronized into fine
particles.
According to the division into prescribed doses
powders are pulveres indivisi (all doses are given
inseparably) and pulveres divisi (they are divides
into the prescribed number of doses).
According to the composition are simplex
powders (consist one active ingredient) and
complex powders (a mixture of more than one
active ingredient).
Solid dosage forms
Тablets
A tablet is a solid dosage form that is
prepared by compressing or molding of
the drug into various sizes and shapes.
Dissolution is the rate-limiting step in
the delivery of drug from a tablet to the
systemic circulation.
Advantages
 Production aspect
 Large scale production at
lowest cost
 Easiest and cheapest to
package and ship
 High stability
 User aspect (doctor, pharmacist,
patient)
 Easy to handling
 Lightest and most compact
 Greatest dose precision &
least content variability
Disadvantages
 Some drugs resist compression
into dense compacts
 Drugs with poor wetting, slow
dissolution, intermediate to
large dosages may be difficult or
impossible to formulate and
manufacture as a tablet that
provide adequate or full drug
bioavailability
 Bitter taste drugs, drugs with an
objectionable odor, or sensitive
to oxygen or moisture may
require encapsulation or
entrapment prior to
compression or the tablets may
require coating
Types of tablets:
Tablets for oral administration
Tablets for vaginal administration
Tablets for implantation (pellets)
Solid dosage forms
Tablets for oral administration
Film coated tablets
Enteric coated tablets
Effervescent tablets
Sublingual tablets
Buccal tablets
Troches (lozenges)
Chewable tablets
Controlled release tablets - slow release tablets
(SR) and modified release tablets (MR)
Compressed Tablets contains:
 Medicinal agent
 Diluents or filler
 Binders or adhesives
 Disintergrants
 Lubricants
 Miscellaneous adjuncts
 Colorants and flavorants
DILUENTS
Diluents increase the volume to a formulation to
prepare tablets of the desired size. Widely used
fillers are lactose, dextrin, microcrystalline cellu-
lose starch, pregelatinized starch, powdered
sucrose, and calcium phosphate.
BINDERS
 Binders promote the adhesion of particles of the
formulation. Such adhesion enables preparation of
granules and maintains the integrity of the final tablet.
Commonly used binding agents include: water, ethanol,
starch, gelatin and sugars (sucrose, glucose, dextrose, and
lactose).
DISINTEGRANTS

The breakup of the tablets to smaller particles is important for
dissolution of the drug and subsequent bioavailability. Disintegrators
promote such breakup. To rupture or breakup of tablets,
disintegrating agents must swell or expand on exposure to aqueous
solution. Thus, the most effective disintegrating agents in most tablet
systems are those with the highest water uptake property. In general,
the more hydrophilic, the better disintegrating agents are therefore
highly hydrophilic.
LUBRICANTS
 Lubricant is a substance capable of reducing or preventing
friction, heat, and wear when introduced as a film between
solid surfaces. It works by coating on the surface of
particles, and thus preventing adhesion of the tablet
material to the dies and punches.
 Lubricants play more than one role in the preparation of
tablets.
 Commonly used lubricants include: talc, magnesium
stearat, calcium stearate ,stearic acid, hydrogenated
vegetable oils and PEG.
Compressed tablet manufacturing
•The classification of manufacturing methods
granulation
wet granulation: suitable for drugs that are stable to moisture and
heat
dry granulation: suitable for drugs that are sensitive to moisture
and heat
direct
compression
powder compression : suitable for drugs that are sensitive to
moisture and heat, fill material possessing, good flowability and
compressibility
crystal compression：suitable for drugs with proper
crystal form and good flowability
The classification of tablet presses
 Tablet presses:
a. single-punch presses
b. multi-station rotary presses
The main components of single-punch
tablet presses
Core components:
die
lower punch
upper punch
Tablet coating
The reasons for tablet coating
1) to protect the medicinal agent against
destructive exposure to air and/or humidity;
2) to mask the taste of the drug;
3) to provide special characteristics of drug
release;
4) to provide aesthetics or distinction to the
product;
5) to prevent inadvertent contact by
nonpatients with the drug substance
Tablet coating
The general methods involved in coating
tablets are as follows
1) sugarcoating tablets
2) film-coating tablets
3) fluid-bed or air suspension coating
4) compression coating
Quality standards and compendial
requirements
The apparent physical features of compressed tablets:
1) shape: round, oblong, unique
2) thickness: thick or thin
3) diameter: large or small
4) flat or convex
5) unscored or scored in halves, thirds and quadrants
6) engraved or imprinted with an identifying symbol
and/or code number
7) coated or uncoated
8)colored or uncolored
9) number of layers.
Quality standards and compendial
requirements
Other physical specifications and quality
standards:
tablet weight
weight variation
content uniformity tablet thickness
tablet hardness
tablet disintegration
drug dissolution
in-process controls
verification after the production
Quality standards and compendial
requirements
Tablet hardness
1)The greater the pressure applied, the harder the
tablets.
2) The hardness required by different tablets
a) lozenges and buccal tablets: hard (dissolve
slowly)
b) the tablets for immediate drug release: soft
3) Measurement
a) special dedicated hardness testers
b) multifunctional equipment
Quality standards and compendial
requirements
Friability
1) It is used to determine a tablet’s durability
2) Method: allowing the tablets to roll and
fall within the rotating apparatus
(friabilator); determine the loss in weight;
3) requirement: weight loss ≤1%
Quality standards and compendial
requirements — tablet dissolution
1) The importance of in vitro dissolution test
a) to guide the formulation and product
development process toward product optimization
b) to monitor the performance of manufacturing
process
c) to assure bioequivalence from batch to batch
d) as a requirement for regulatory approval for
product marketing for products registered with the
FDA and regulatory agencies of other countries.
2) The goal of in vitro dissolution is to provide a
reasonable prediction of the product’s in vivo
bioavailability.
Basis: The combinations of a drug’s solubility and its
intestinal permeability are supposed as a basis for
predicting the likelihood of achieving a successful
in vivo – in vitro correlation (IVIVC).
3) The formulation and manufacturing factors
affecting the dissolution of a tablet
a) the particle size of the drug substance
b) the solubility and hygroscopicity of the
formulation
c) the type and concentration of the disintegrant,
binder, and lubricant used
d) the manufacturing method, particularly, the
compactness of the granulation and the
compression force
e) the in-process variables