Complete samenvatting Pharmaceutical Manufacturing Techniques

PHARMACEUTICAL MANUFACTURING TECHNIQUES


Dendrimers  <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

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, 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

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, 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)

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