Conference on Co- micronization by PH.D. Jérôme Hecq

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PrésentationGénérale-Confidentiel
1 - 26/05/2016
Co-micronization: innovative technology to enhance oral
bioavailability of poorly water soluble APIs
APGI Day – MERCK and GATTEFOSSE
CNAM – Paris
24/05/2016
Jerome HECQ, Pharm.D, Ph.D.

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OVERVIEW
Introduction
Factors influencing solubility and dissolution
Micronization / Co-micronization
Benefits and drawbacks
From preformulation to industrial manufacturing
Case studies
Conclusion

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INTRODUCTION
Formulation strategies used to enhance solubility /
dissolution rate / oral bioavailability
Formulation strategy selection: Consider multiple variables
- API
- Excipients
- Drug load (vs. dose)
- Manufacturing process
Composition Performance
- Solubility
- Dissolution
- Bioavailability
- Food effect
- Chemical stability (compatibility)
- Physical stability
- Safety

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INTRODUCTION
Factors influencing solubility
Molecular structure (molecular weight / size, polarity / functional
groups)
Temperature
pKa and GIT pH profile
Surfactants
Solid state (crystalline state: polymorphs, pseudopolymorphs,
amorphous)
Particle size (influence: size<100nm - Ostwald)
Illustration of the calculated effect of particle diameter on Cs/C∞ for a particle having a
molecular weight of 708, a density of 1g/ml and an interfacial surface tension of 50 (blue),
75 (green) and 100 (red) dyn cm-1. (Kipp, 2004. Int. J. Pharm., 284 (1-2), 109-122)

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INTRODUCTION
Factors influencing dissolution
Noyes-Whitney
Parameter Definition Physicochemical characteristic in vivo factor
D Diffusion coefficient (solute) Molecular size of solute particle GIT fluids viscosity
A Specific surface area of dispersed particles Particle size Presence of surfactants
h Thickness of diffusion layer - GIT motility
S Saturation solubility of API Solid state, polarity,… pH, surfactants
Cb
Solute concentration in the dissolution media at
time t - GIT fluids volume

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MICRONIZATION
Micronization
Most straightforward approach to enhance API dissolution rate:
increase of the surface area of the particles in contact of the
dissolution media

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MICRONIZATION
Micronization
« Universal » formulation strategy applicable to most APIs
independently of their physicochemical properties:
− Molecular weight / size / structure
− Log P
− pKa
− Solubility in organic solvents or excipients
− Chemical stability (temperature, compatibility issues)
− Melting point: Low MP APIs may have a tendency to show agglomeration
during the micronization process (ball milling > jet milling) => cryomilling
No use of excipients, solvents

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MICRONIZATION
Micronization vs. oral bioavailability
For drugs showing poor oral bioavailability due to low solubility
and not exclusively due to their poor dissolution behavior,
micronization may have a low or no impact on bioavailability
=> Nanomilling (PSD: 50-500nm)
=> Co-micronization with pharmaceutical excipients
allowing to increase solubility (i.e. surfactants, pH
modifying agents)

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MICRONIZATION
Micronization vs. oral bioavailability
A micronized powder will generally be presenting particle surfaces
that are highly cohesive (VDW interactions, electrostatic
attraction) due to the high energy brought during the size
reduction process and that will lead to particle agglomeration and
subsequent problems:
>Poor flowability
>Low bulk density
>Increased poor wettability characteristics
>Reduced effective surface area with potential negative impact on drug
dissolution rate
=> Co-micronization of the drug with selected
pharmaceutical excipients allows to reduce these
inter-particular attractions and thus agglomeration

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MICRONIZATION
Co-micronization vs. Micronization
Modification of surface properties of the drug particles
- Decrease of agglomeration phenomenon
Micronization Co-micronization
+
Han et al., 2011. Int. J. Pharm., 415 , 185-195
Ibuprofen / silica (99/1 w/w)

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MICRONIZATION
- Decrease of agglomeration phenomenon
Micronization Co-micronization
Spence et al., 2005. Pharm. Dev. Tech., 10, 451-460
Pfizer CI-1040 / MCC (90/10 w/w)Solubility < 1µg/ml
Log D: 3.55 (pH 7.4)
F(%) rats Micronized: 68.2
Co-micronized: 85.3

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MICRONIZATION
- Enhancement of hydrophilic character of micronized particle surface
(surfactant, water soluble excipients): Impact on wettability and
solubilization properties
Micronisation Co-micronisation Physical blend (µized API + exc)

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MICRONIZATION
Promote specific interactions between the API and the selected
pharmaceutical excipient
- Impact on solubility / dissolution
Povidone

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MICRONIZATION
- Amorphous form formation & stabilization
Maclean et al., 2011. J. Pharm. Sci., 100 (8), 3332-3344
Sulindac
Sulindac : Neusilin 1:1 w:w
→Stable > 4 months 40°C/75%RH
vs. immediate crystallization (24h at
25°C/60%RH) for amorphous sulindac (no
Neusilin) obtained by quench-cooling
→ Amorphous form of Sulindac stabilized through
interactions with Neusilin

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MICRONIZATION
- Amorphous form formation & stabilization
Maclean et al., 2011. J. Pharm. Sci., 100 (8), 3332-3344
Sulindac
Sulindac : Neusilin 1:1 w:w
Acidic drugs: reported interactions with Neusilin or other silicates:
Hydrogen bonding with silanol groups / rings
Ion Dipole-Dipole interactions with metal ions (Mg, Al)
⇒ Complex formation - salt formation?
www.neusilin.com

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MICRONIZATION
Gupta et al., 2003. J. Pharm. Sci., 92, 536-551
Ketoprofen : Neusilin 1:5 w:w
Decrease of the CO stretching peak at 1697cm-1 as function of
milling time
⇒ dissociation of the ketoprofen dimer
Amorphous state created during milling different than for the
melt-quenched amorphous ketoprofen
⇒ Preferred interaction (H bonding) with Neusilin
Hypothesis of salt formation (carboxylate formation)
Free acid carboxylic CO stretch
H-Bonding phenomenon with silicates reported for other acidic
drugs such as indomethacin and Naproxen but also for drugs not
having proton-donating groups (ex Progesterone)

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MICRONIZATION
- Solid dispersion preparation could also be achieved through co-
micronization using organic polymers such as Povidone (complete
amorphisation) and poloxamers (partial amorphisation)
Yang et al., 2012. Chem. Pharm. Bull., 60 (7), 837-845
Dipfluzine
Povidone
Dipfluzine
PVP
Dipfluzine:PVP 1:3 w:w physical blend
Dipfluzine:PVP 1:3 w:w co-grinding 30 min
Dipfluzine:PVP 1:3 w:w co-grinding 1 hour
Dipfluzine:PVP 1:3 w:w co-grinding 2 hours
Dipfluzine:PVP 1:3 w:w co-grinding 3 hours
⇒ Chemical shift of API CO stretch

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CO-MICRONIZATION
Selection of the pharmaceutical excipient
Physicochemical properties of the excipient
>Melting point: Low melting point excipient may be an issue (material
agglomeration → product properties / process jamming)
− Difference between ball milling and jet milling: process/product temperature
Pluronic F68 (poloxamer): MP: 52°C
Pluronic F68 (bulk product) Pluronic F68 (Jet-mill) Pluronic F68 (Cryo Ball-mill)
Saleem and Smith, 2010. AAPS PharmSciTech,
11 (4) , 1642-1649
50µm 50µm

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CO-MICRONIZATION
>Extent of particle size reduction dependent on the mechanical
properties of the material which determine the resistance to breaking
and the propagation of fracture
Mechanical properties (determined by nanoindentation):
− Hardness: determines the resistance of a material to plastic deformation
− Elasticity: determines the resistance of a material to elastic deformation.
Defined by Young’s modulus.
⇒ Hard and elastic material will require more energy for particle breakage
⇒ Process energy and time may be higher/longer during co-micronization
with soft materials in order to decrease API particle size (vs. micronization)

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CO-MICRONIZATION
>Particle size distribution vs. API PSD
− blend homogeneity before co-micronization
>Density vs. API density
− homogeneity during co-micronization (when considering jet-milling /
particle acceleration (Venturi) – classification)
− Particles with higher porosity may break easier

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CO-MICRONIZATION
Chemical compatibility with API
>Enhanced interactions between API and excipient
Toxicity (surfactants)
>Dependent of API/excipient ratio selected

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CO-MICRONIZATION
Surfactants:
>Sodium Lauryl sulfate
>Poloxamer (polyoxyde propylene/ polyoxyde ethylene copolymer)
Polymers:
>Povidone (polyvinylpyrrolidone)
>Copovidone (vinyl pyrrolidone / vinyl acetate copolymer)
>Crospovidone (cross-linked polyvinylpyrrolidone)
>Polyvinyl alcohol
>Vinyl alcohol / polyethylene glycol copolymer (Kollicoat IR)
>Sodium croscarmelose
>Starch
>Hydroxypropylmethylcellulose, hydroxyethylcellulose

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CO-MICRONIZATION
Diluents:
>Lactose
>Cellulose
>Maltodextrins
>Polyols (mannitol, sorbitol, isomalt,…)
Others:
>Buffering agents (succinic acid, fumaric acid, citric acid, phosphates,…)
–Micro-environnemental pH modification (weak acid/ weak base)
>Silicates

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CO-MICRONIZATION
Controls on produced samples
Particle size distribution analysis
>Diffraction laser, scanning electronic microscopy (+ morphology / API-excipient
association)
Specific surface area
> BET (Brunauer–Emmett–Teller)
Solid state (polymorphic/ crystalline modifications)
>X-ray diffraction, differential scanning calorimetry
API / excipient interactions
>Infra-Red (FTIR) spectroscopy, differential scanning calorimetry

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CO-MICRONIZATION
Controls on produced samples
Blend uniformity (API)
>Before and after co-micronization
In vitro dissolution (SINK conditions) and dynamic solubility test
(non SINK conditions – evaluation of supersaturation/precipitation
phenomenon)
Pharmacokinetic study - oral bioavailability study (rodent/ non
rodent species)

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CO-MICRONIZATION
Development: from preformulation to industrial
manufacturing

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CO-MICRONIZATION
Precellys®: Innovative technology and high performance
preformulation tool
High throughput ball milling technology developed and patented by
Bertin Technologies allowing to produce a specific 3D (precession)
movement of tubes and beads
Stainless steel or ceramic (stabilized zirconium oxyde) beads

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CO-MICRONIZATION
Precellys®: Innovative technology and high performance
preformulation tool
4 available tube size: 0,5ml / 2ml / 7ml / 15ml
>Allowing to work on very small sample size (20mg - 1000mg)
Small milling time: 30 to 90 seconds cycles (hold time of 20 to 120
seconds between cycles)
High milling speed: 4500rpm – 10000rpm
Milling chamber temperature monitoring and control possible
(range 10-20°C) in order to limit product temperature increase
during the milling operation – patented cooling system (Cryolis®)

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CO-MICRONIZATION
Micronization / co-micronization : available industrial
manufacturing equipment and process
Mechanical milling:
>Ball milling
− Stainless steel (316L), ceramic (ZrO2),…
− Particle size reduction by friction and attrition (bead/bead or bead/wall)
and little or no impact of particle/particle collision
− Non negligible risk of product contamination (bead/wall and abrasive API)
− Batch size (few grams – 100kg)
− Long milling process time (product temperature increase vs. API stability
and particle agglomeration for soft materials ><cryomilling)
− Process parameters influencing particle size distribution: bead type, bead
number, milling time, rotation/milling speed

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CO-MICRONIZATION
Air jet milling:
>Characteristics:
− Particle size reduction through particle/particle collisions (particle speed :
300-500m/s)
− Particle classification system as function of size
− Low risk of product contamination
− Batch size (10g – tons) – continuous manufacturing process
− Short milling process time (limited product temperature increase:
product temperature ∼ process gas temperature)
− Particle size distribution span: jet-mill < ball mill

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CO-MICRONIZATION
Air jet milling:
>Equipments:
− Spiral jet mill (fluid energy mill)
- Particle acceleration by Venturi effect
- Classification (size) par centrifugal force
- Process parameters influencing particle size distribution:
Feed size, Feeding pressure, Grinding pressure,
Feed rate (⇒ specific energy J/g)
⇒ Possibility to align the discharging point of 2 screw feeders
in the center of the Venturi feeding cone
http://www.sreenex.com/html/bulk_airjetmill.htm

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CO-MICRONIZATION
Air jet milling:
>Equipments:
− Fluidized-bed jet mill
- Particle acceleration by radial fluidized air jets
- Classification (size) par centrifugal force and dynamic rotors
- No limitations in feed size (vs spiral jet-mill: blockage of feed hopper)
www.hmicronpowder.com/products/product/alpine-
afg-fluidized-bed-jet-mill

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CASE STUDY(1)
Ketoprofen (BCS class 2)
Solubility: 0.2mg/ml (pH2.0)
LogP: 3.12
Initial particle size: d(v,0.5): 50µm
Tested pharmaceutical excipients: SLS, poloxamer (Kolliphor ®
P407), crospovidone (Kollidon® CLF), PVP co-PEG (Kollicoat ® IR)
>Ratio Ketoprofen / excipient: 7/3 w/w
Precellys® milling protocol: 3 cycles of 60 sec at 5500rpm (10 sec
pause between cycles)

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CASE STUDY(1)
Particle size / morphology
Dissolution (HCl 0.1N)
d(v,0.5): 50 µm d(v,0.5): 2-10 µm
SLS - Ketoprofen Poloxamer - Ketoprofen Crospovidone - Ketoprofen PVP co-PEG - Ketoprofen
0.00
10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00
90.00
100.00
0 20 40 60 80 100 120
0.00
10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00
90.00
100.00
0 20 40 60 80 100 120
0.00
10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00
90.00
100.00
0 20 40 60 80 100 120
0.00
10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00
90.00
100.00
0 20 40 60 80 100 120

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CASE STUDY(1)
X-ray diffraction
Poloxamer
0
10000
20000
30000
40000
50000
60000
8.02
9.34
10.7
12
13.3
14.6
15.9
17.3
18.6
19.9
21.2
22.5
23.9
25.2
26.5
27.8
29.1
30.5
31.8
33.1
34.4
35.7
2 Theta (°)
Intensity(a.u)Crospovidone
0
5000
10000
15000
20000
25000
30000
35000
40000
45000
50000
8.02
9.34
10.7
12
13.3
14.6
15.9
17.3
18.6
19.9
21.2
22.5
23.9
25.2
26.5
27.8
29.1
30.5
31.8
33.1
34.4
35.7
2 Theta (°)
Intensity(a.u)
PVP co-PEG
0
5000
10000
15000
20000
25000
30000
35000
40000
45000
8.02
9.32
10.6
11.9
13.2
14.5
15.8
17.1
18.4
19.7
21
22.3
23.6
24.9
26.2
27.5
28.8
30.1
31.4
32.7
34
35.3
36.6
2 Theta (°)
Intensity(a.u)
Sodium lauryl sulfate
0
5000
10000
15000
20000
25000
30000
35000
40000
45000
8.02
9.36
10.7
12
13.4
14.7
16.1
17.4
18.7
20.1
21.4
22.8
24.1
25.4
26.8
28.1
29.5
30.8
32.1
33.5
34.8
36.2
2 Theta (°)
Intensity(a.u)
Non micronisé
Co-micronisat
Mélange physique

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CASE STUDY(2)
BP002945 (BCS class 2)
Solubility: 0.007mg/ml (pH4.6) – 1.8mg/ml (pH2.0)
Initial particle size: d(v,0.5): 150µm
Tested pharmaceutical excipient: surfactant
>Ratio BP002945 / excipient: 5/5 w/w
Milling protocol
>Precellys® : 3 cycles of 60 sec at 6500 rpm (120 sec pause between cycles)
>Spiral jet mill: Feeding pressure: 8 bar / Grinding pressure: 8 bar / Feed rate:
1,2 kg/h (theoretical energy: 2900J/g)

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CASE STUDY(2)
Particle size / morphology
Non micronized API: d(v,0.5): 150 µm
Precellys® : d(v,0.5): 10 µm
Jet-Mill: d(v,0.5): 2 µm

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CASE STUDY(2)
Dissolution (pH 4.6, 0.1% SLS)
Oral bioavailability (rat)
>BP002945 micronized (F 43,1%) / co-micronized (F 58.6%)

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CONCLUSION
Co-micronization: Formulation strategy defining innovative
API/excipient associations in order to enhance oral bioavailability of
poorly water soluble APIs
Impact on physical properties of API (particle surface modification ⇒ flowability,
agglomeration, wettability, dissolution) + creation of specific API/excipient
interactions
Allows to work in favorable API / excipient ratio (highly dosed APIs – final dosage
form development)
Easily accessible at industrial manufacturing scale using well established
manufacturing process
Precellys®: High performance innovative preformulation tool to
evaluate the potential benefits of co-micronization
Work on very low amount of API (NCE)
High throughput screening capabilities: test of diverse range of pharmaceutical
excipients in one single run
Results predictive of prototypes obtained using conventional micronization
equipments (ball milling, jet milling)

Conference on Co- micronization by PH.D. Jérôme Hecq

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