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Complete samenvatting Pharmaceutical Manufacturing Techniques
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- Universiteit Gent (UGent)
Complete samenvatting Pharmaceutical Manufacturing Techniques van vak gegeven door Prof Bruno de Geest (+ gastlessen)
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PHARMACEUTICAL MANUFACTURING TECHNIQUESDendrimers <5nm
Branched macromolecule
Small molecules: filtered through kidney
Solubilisation in core: hydrophobic core – hydrophilic
ends
Covalent conjugations of drug molecules to the end
groups
Reptitive units : generations
Polymer 10 – 20 nm
Block copolymer micelle (20-200)
PEG: hydrophilic & PLA (degradable) hydrophobic
Self-assembly in aqueous medium
Drugs in the hydrophobic core pocket
Escape the vasculature, infiltrate in tissue &
lymphatic like proteins
Liposome >150 nm
Phospholipid bilayer vesicles
Hollow inside (water) lipid nanoparticles (LNP):
massive core
Taken up by phagocytic cells
BCS Biopharmaceutical classification system
Class I: ++, eg paracetamol
Class II: increase surface area (particle size
reduction, solid solution, solid dispersion), solutions
using solvents & surfactants, eg carbamazepine
Class III: permeability enhancers (bile salts, fatty
acids), mucoadhesive formulations increase luminal
concentration, eg acyclovir
Class IV: combine II & III, eg furosemide
Class I & III: high solubility => highest dose strength
can be dissolved in 250 mL in the pH range 1-7
Nanosuspension Submicron colloidal crystalline dispersion in liquid
media
Stabilized by surfactant or polymer or both
Higher surface to volume ratio
++ Faster dissolution rate (dissolution rate limited
drugs; NOYES-WHITNEY)
higher drug levels in plasma
++ oral formulation
++ Good manufacturing technique
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, PHARMACEUTICAL MANUFACTURING TECHNIQUES
++ high drug loading
++Increased mucoadhesion: increased GI retention
=> enhanced bioavailability
-- high energy input
-- Require stabilizator
-- Not ideal for IV
Eg maxitrol: eye infection (dexamethasone)
Production: top down or bottom up (solvent)
o Top down (large crystals to small crystals,
input energy)
High pressure homogenization: drug micro
suspension through narrow gap at high pressure,
cavitation, collision & shear forces disintegrate
the drug into nanocrystals
Milling: in milling chamber grinding beads, a
liquid, stabilizing agent & drug, rotate at high
speed to generate shear forces that disintegrate
the drug into nanocrystals
Small scale (pre-clinical), in cylindrical flask with
aqueous suspension of drug microcrystals
o Bottom up (start from solution)
Solvent: miscible with water, eg ethanol, acetone,
acetonitrile, DMSO, THF
Precipitation of the drug
Good surfactant: uncontrolled aggregation
avoided
Dissolve the drug in water-miscible organic
solvent, add anti-solvent (eg water), use
stabilisers to control particle size and avoid
agglomeration
Supersaturation-nucleation-growth-coagulation
Nano emulsion Oil phase in water phase with surfactants
Non-equilibrium, heterogeneous system of 2
immiscible liquids, one liquid is dispersed in the other
Require stabilising surfactants (Tween, span)
Hydrophobic drugs are solubilised in internal oil
phase
Produced spontaneous, high pressure
homogenisation, microfluidics, ultrasonication
Droplet size: 20-200 nm
++ high drug load
++ Approved pharmaceutical ingredients
-- potential flocculation & coalescence
Polymeric Amphiphilic block co polymer
micelles Self assembly in aqueous medium
20-200 nm
Hydrophobic drug in core, hydrophilic ends
++ multifunctional design
++ suitable for IV
-- limited number of polymers for clinical use
Eg paclitaxel
To formulate paclitaxel into the Genexol-PM drug
2
, PHARMACEUTICAL MANUFACTURING TECHNIQUES
product, paclitaxel is first solubilized in an organic
solvent together with block copolymer composed
of PEG & PLA
The solvent is evaporated at 60°C under reduced
pressure to yield an amorphous film consisting of
polymer & paclitaxel
The film is rehydrated with water, also at 60°C to
increase the mobility of the polymer chains: PEG-
PLA spontaneously forming micelles, paclitaxel
encapsulated in the hydrophobic core of these
micelles
Removing larger precipitates with a 200 nm filter
Freeze drying to obtain a solid product
Noyes-Whitney Describes the relationship between the dissolution
equation rate of a drug crystal and the surface area of the
drug crystal
NANOSUSPENSION
Dissolution rate solubility
Factors solubility: temperature, pH, ionic strength
Chemical structure & external factors
Formulation Preclinical
screening Scientific literature: chemical/physical stability
nanosuspension Liquid formulations: microbial growth absence
A long shelf life (> 1 year), avoid COOL storage
Early development: low amount of API, short time
Nano suspension: water, API, stabiliser
Also containing sometimes: buffer, preservatives,
antioxidant
Phase I NS: crude, Phase II: retains stabiliser, Phase
III: ready for the market
Goals of formulation screening:
Most physically & chemically stable NS
Low amount of stabiliser (toxicity)
Most resistance to added ions or changes pH
(growth potential)
Short milling time (efficiency)
Cheap excipients
Screening steps:
Solubility: shake flask method
Stability: agglomeration avoidance by adding ionic
surfactants or polymers
Milling: small scale
3
, PHARMACEUTICAL MANUFACTURING TECHNIQUES
Compatibility: store at 60°C and assess pH and
purity over 2 week interval
Stress test: dilution in buffer, addition
preservative
Follow up: PK studies in animals, long term &
accelerated stability
Downstream Why
processing of Physical instability: aggregation, particle fusion,
nanosuspension crystal growth, sedimentation, creaming
Chemical instability
Facilitate drug administration: patient
convenience & medication compliance
Functionality: controlled release, enteric coating,
taste masking
Goal
Restore nanometre size
Index of polydispersity (distribution size)
Zeta potential
Composition of nanosuspension
API, surfactants & polymers
Quality: -entanglement of polymer chains
-Ostwald ripening
-recrystallization of the polymer
-poloxamer: non resistant to freeze-
drying
Composition:
Stability excipients:
- Cellulose derivates (HEC,
HMC): increasing viscosity
- Sugars & sugar alcohols
(lactose, sucrose): matrix
formers
- Water insoluble (MCC):
permanent barrier
Drying process
Stress : thermal, mechanical, drying
Technology : freeze drying (lyophilization), spray
drying, bead layering, fluid bed granulation
Freeze-drying = lyophilisation
Removing water from a frozen sample by sublimation
& desorption under vacuum
Adding lyoprotectant: formation of hydrogen bonds
between lyoprotectant and polar groups at surface
nanoparticle
Water replacement therapy, preserve native
structure of nanoparticles as water substitutes
Eg: trehalose, glucose, PVP
Fluffy product
Used for reconstitution (easily dissolved)
4
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