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© Fraunhofer
ASSESSING THE DRUG RELEASE FROM NANOFORMULATIONS – WHEN, WHY AND HOW?
Matthias G. Wacker, PhD
Pharma Test Workshop Series 2016
NANOTECHNOLOGY IN THE PHARMACEUTICAL
INDUSTRY
© Fraunhofer
DRUG RELEASE FROM NANOFORMULATIONS
• Dissolution rate increases with surface area (Noyes-Whitney)
• Rising saturation solubility for small particles occurs (Ostwald ripening)
• Nanocrystals are synthesized to achieve high dissolution pressure
• “Burst release“ is a common problem of nanocarrier technology
Surface area
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DRUG RELEASE TESTING
• Quality control
Testing dosage forms in a standardized setup
Detecting different formulation qualities from batch to batch
• Biorelevant release testing
Discriminating between different formulations
Simulating physiological environment
Predicting the in vivo performance of dosage forms (IVIVC)
• In vitro digestion testing of nanomaterials
Investigating material degradation in biorelevant medium
Simulating physiological environment
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QUALITY CONTROL
• Discriminating between batch qualities in a low-cost procedure
with simple medium composition
• Detect changes in manufacturing process, excipients or stability issues
• Short release interval and automated setup where possible
Source: Pharmatest Apparatebau GmbH
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BIORELEVANT RELEASE TESTING
• Simulate physiological environment, e.g. by using biorelevant media
containing physiological dissolution enhancers (proteins, bile salts)
• Simulate effects that were be observed in vivo (e.g. gastric emptying)
• Predict in vivo data based on in vitro experiments
Source: Pharmatest Apparatebau GmbH; AGW
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IN VITRO DIGESTION MODELS
Confirming particle size properties to characterize nanomaterials after
exposure to biorelevant media
Detect particle dissolution, aggregation or degradation in biorelevant media
Comply with EU and US guidelines
Particle size
Dynamic light scattering
Powder diffration
Electron microscopy
AFM
TEM
SEM Analytical
ultracentrifugation
Field flow fractionation
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DRUG RELEASE MEDIA
• Quality control
Aqueous buffer media
Surfactants and other excipients to support dissolution process
• Biorelevant release testing
Physiological fluids (e.g. blood, plasma, intestinal fluids)
Simulated physiological fluids
• In vitro digestion models
Physiological fluids optimized to monitor degradation
Enzymes and proteins
Optimized to allow size measurement from medium
© Fraunhofer
DRUG RELEASE MEDIA FOR NANOFORMULATIONS
Medium Setup for drug release Reference
Human plasma Non-compendial flow-through cell setup (Gido, Langguth et al. 1993;
Gido, Langguth et al. 1994)
HEPES buffer 7.4
Dialysis bag (USP2)
Reverse dialysis bag (USP2)
Flow-through cell(USP4) with A4D adapter
(Bhardwaj and Burgess 2010)
Phosphate buffer saline 7.4 Modified basket (USP1) (Abdel-Mottaleb and
Lamprecht 2011)
Phosphate buffer 7.4 supplemented
with fetal calf serum (10-90%) Dispersion releaser (USP2) (Janas, Dressman et al. 2013)
Phosphate buffer 7.4 supplemented
with fetal calf serum (50%) Dispersion releaser (USP2) (Villa Nova, Janas et al.)
FaSSGF / FaSSIF / FaSSIF V2
FeSSGF / FeSSIF / FeSSIF V2 USP apparatus 2 with syringe filters
(Juenemann, Jantratid et al.
2010)
FaSSIF V2 USP apparatus 2 with syringe filters (Beyer, Moosmann et al.
2015)
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METHODOLOGY FOR DRUG RELEASE TESTING
• Nanoformulations require optimized separation technology
• Methods must discriminate between nanoparticles and dispersed drug
molecules
• Careful sampling is required to detect drug release without disrupting
formulation structure
Methodology for drug release testing includes
Sample and separate
Dialysis
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SAMPLE AND SEPARATE
• Separation techniques such as mechanical filtration or solid phase
extraction are applied
• Both methods may affect stability of the carrier
• Accurate selection of filter pore size, SPE or filter material and medium
Disruption
Separation (Cut-off)
Adsorption
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SAMPLE AND SEPARATE
Mechanical filtration devices
• Careful selection of filter membrane
and pore size required
• Not applicable to sensitive formulations
such as micelles, liposomes, emulsions
• Relevant for solubility-driven release
• Applicable to many peroral IR
nanocrystal formulations
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SAMPLE AND SEPARATE
• Biorelevant release test of microsized fenofibrate by applying sample and
separate with syringe filters of different pore sizes
• Microparticle are well-separated by different filter pore sizes
Source: Juenemann et al. 2011, Eur. J. Pharm. Biopharm.
© Fraunhofer
SAMPLE AND SEPARATE
• Release samples collected with nanoparticles from FaSSIF
• Only one filter reflects equilibrium solubility of fenofibrate over 24 h
Source: Juenemann et al. 2011, Eur. J. Pharm. Biopharm.
Filte
r pore
siz
e
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SAMPLE AND SEPARATE
• Solid particle formulation of poorly soluble compound TMP001 (logP=10,417)
• Microparticle formulation and nanoparticle formulation
○ Free drug
■ Nanoformulation
● Microformulation
Setup USP2/syringe filter 0.1 µm
pH 6.8
Medium FaSSIF V2
Source: Beyer et al. 2015, Pharm Res
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SAMPLE AND SEPARATE
Solid phase extraction
• Affinity-based separation technique
• SPE column must have poor affinity to
formulation excipients
• Applicable to some core-loaded liposome
formulations
• Requires careful validation to separate
excipient and API by affinity
Source: Guillnot et al. 2015, Pharm Res
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DIALYSIS
• Separation by dialysis in combination with the compendial equipment
such as USP apparatus 2 (paddle) or USP apparatus 4 (flow-through cell)
• Sensitive when k1 << k2
• k2 is higher for compounds with moderate or good solubility
k1 k2
Source: Ashtikar et al. 2016, J Pharm Pharmacol (In preparation)
© Fraunhofer
DIALYSIS
• Evaluating different membranes in a continously
monitored dialysis setup (optimal data collection)
• Membrane transport for one compound
comparing CE and RC membranes
• Calculation of k2 from the release profile
Source: Xie et al. 2015; Int J Pharm
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DIALYSIS
• Same pore size but different
membrane materials
• Sensitivity of measurement with
cellulose ester (CE) is much higher
than with RC (regenerated cellulose)
• Pore size and membrane material are
essential
Source: Xie et al. 2015; Int J Pharm
© Fraunhofer
DIALYSIS
• Membrane transport k2 needs to quick when release rate is high
• Comparing dialysis techniques needs to be done with fast and slow-releasing
drug delivery systems
Source: Xie et al. 2015; Int J Pharm
© Fraunhofer
DIALYSIS
Dialysis bag
• Dialysis membrane closed by two
clamps
• Poor membrane penetration
and partitioning
• High variability at high dissolution rates
• Works well for slow-releasing dosage forms or
drugs with moderate or good solubility
Source: Ashtikar et al. 2016 (In preparation)
© Fraunhofer
DIALYSIS
Flow-through cell
• USP4 allows release testing in
open-loop and closed loop systems
• Sotax offers the A4D adapter for
nanoformulations
• High cell-to-cell variability in flow rate
when used at a pumping rates of
below 1 mL/min
• Works well for API with moderate or
good solubility and/or high flow rate (low k2)
• No evaporation in open-loop configuration
Source: Ashtikar et al. 2016 (In preparation); European Pharmacopeia; www.sotax.com
© Fraunhofer
DIALYSIS
• Investigation of Dexamethasone liposomes in different systems compared to
A4D
• Sink conditions were applied
• Reduced sensitivity especially when release rate is high
Source: Bhardwaj et al. 2010, Int J Pharm
© Fraunhofer
DIALYSIS
Dispersion releaser
• USP2 is a robust standard setup
used for quality control of IR
formulations
• Pharma Test offers the “dispersion
releaser”
• High sensitivity for fluctuations in
release rate
• Works well for compounds with poor,
moderate and good solubility (high k2)
• Evaporation occurs in long-term
experiments
Source: Ashtikar et al. 2016 (In preparation); Janas and Wacker 2013, DE102013015522.3
© Fraunhofer
DIALYSIS
• Parenteral polymeric micelle formulation of poorly soluble API (logP=9,57)
• Batch-to-batch reproducibility in quality control
• Formulation highly sensitive to shear forces
○ Batch 1
● Batch 2
Setup USP2/dispersion releaser
pH 7.4
Medium phosphate buffer saline
foetal calf serum 10%
Source: Villa Nova et al. 2015, Int J Pharm
© Fraunhofer
DIALYSIS
• Dialysis bag vs. dispersion releaser tested with free compound assuring sink
conditions
• Solid particle formulation with sustained release properties
● Free drug, dispersion releaser
● Free drug, dialysis bag
●/○ SR formulation 1 /2
Setup USP2 / dialysis bag or
dispersion releaser
pH 7.2
Medium phosphate buffer saline
10% FCS
Source: Janas et al. 2016 (In preparation)
© Fraunhofer
DIALYSIS
• Sampling from inner compartment during dialysis-based release test
• Particle aggregation and dissolution effects after administration
• Biorelevant media specifically designed to monitor degradation but to allow
size measurement
Source: Modified from Janas et al. 2013, AAPS Annual Meeting & Exposition
F1-4 0h 24 h
Water Medium 1-2 Medium 1-2
200 nm200 nm
© Fraunhofer
SUMMARY
Nanoformulations have high dissolution pressure compared to other
formulations
Release rate can be quantified by sample and separate or dialysis
Sample and separate approaches require careful sampling to avoid shear
forces and “forced extraction“
Dialysis requires additional care in membrane selection and needs to be
optimized to increase membrane transport
Biorelevant release testing can also be employed for nanomaterial testing to
comply with EU guidelines
© Fraunhofer
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NanoMetrX is a Fraunhofer IME project setting up methodology for testing
nanomaterials, e.g.
Analytical technology identifying nanomaterials
Analytical technology identifying degradation and dissolution behavior
Analytical technology identifying routes of release
Open platform is provided to all manufacturers
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