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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

CbSolute 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 surfacesthat are highly cohesive (VDW interactions, electrostaticattraction) due to the high energy brought during the sizereduction process and that will lead to particle agglomeration andsubsequent 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

�Co-micronization vs. Micronization

�Modification of surface properties of the drug particles

- 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/mlLog D: 3.55 (pH 7.4)

F(%) rats Micronized: 68.2Co-micronized: 85.3

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MICRONIZATION

�Co-micronization vs. Micronization

�Modification of surface properties of the drug particles

- 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

�Co-micronization vs. Micronization

�Promote specific interactions between the API and the selected pharmaceutical excipient

- Impact on solubility / dissolution

Povidone

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MICRONIZATION

�Co-micronization vs. Micronization

�Promote specific interactions between the API and the selected pharmaceutical excipient

- 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

�Co-micronization vs. Micronization

�Promote specific interactions between the API and the selected pharmaceutical excipient

- 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 / ringsIon Dipole-Dipole interactions with metal ions (Mg, Al)

⇒ Complex formation - salt formation?

www.neusilin.com

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MICRONIZATION

�Co-micronization vs. Micronization

�Promote specific interactions between the API and the selected pharmaceutical excipient

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 NeusilinHypothesis 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

�Co-micronization vs. Micronization

�Promote specific interactions between the API and the selected pharmaceutical excipient

- 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

�Selection of the pharmaceutical excipient

�Physicochemical properties of the excipient

>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

�Selection of the pharmaceutical excipient

�Physicochemical properties of the excipient

>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

�Selection of the pharmaceutical excipient

�Chemical compatibility with API

>Enhanced interactions between API and excipient

�Toxicity (surfactants)

>Dependent of API/excipient ratio selected

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CO-MICRONIZATION

�Selection of the pharmaceutical excipient

�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

�Selection of the pharmaceutical excipient

�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

�Micronization / co-micronization : available industrial manufacturing equipment and process

�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

�Micronization / co-micronization : available industrial manufacturing equipment and process

�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

�Micronization / co-micronization : available industrial manufacturing equipment and process

�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)

�Ketoprofen (BCS class 2)�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 - K etoprofen PVP co-PEG - Ketoprofen

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CASE STUDY(1)

�Ketoprofen (BCS class 2)�X-ray diffraction

Poloxamer

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10000

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8.02

9.34

10.7 12

13.3

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Inte

nsity

(a.

u)Crospovidone

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Sodium lauryl sulfate

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Non microniséCo-micronisatMélange 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)

�BP002945 (BCS class 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)

�BP002945 (BCS class 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)