CRS Young Scientist 2010 Final 2

Solubility Improvement by Solid State
Properties Modification
2002-2010 Eurand. All rights reserved.
Young Scientist Workshop Development of Poorly Soluble Drugs
Portland (OR)
July, 10, 2010
Paolo Gatti, PhD
Senior Scientist,
Formulation Team Leader
1. Influence of drug solid state properties
on solubility
Increases by:
Increasing surface area (A)
Increasing equilibrium solubility (Cs)
Increases by:
Reducing melting enthalpy
Reducing melting tempertature (T
m
)
Solubility and Solid State Properties
Cs: Equilibrium solubility of the drug R: gases constant
D: Diffusion coefficient of the drug in solution V: Volume of the solution
h: stagnant layer thickness A: Surface area of the solid drug (bulk property)
S
: Activity coefficient of the drug in solution : Melting molar enthalpy of the drug
T: Solution temperature T
m
: Melting temperature of the drug
AH
m
Solubilization rate Equilibrium solubility
(AH
m
)
( ) C C
hV
DA
dT
dC
S =
)] ( [
1 1
1
m
m
s
S
T T R
H
e C
Micronized crystalline solid

Dissolution rate increase (Kinetic effect)
Crystalline structure
Long range order H
m
>0
Micrometric size range
(Indicative: 1-100 micron)
Higher surface area
than original solid
Nanocrystalline solid
than original
solid
Solubility increase (Thermodynamic effect)
Nanometric size range
<1000 nm
Higher surface area
Possibly lower melting enthalpy
and melting temperature
Crystallite size below 50 nm
Crystalline structure
Long range order H
m
>0
Crystals and crystallites
Most solid crystalline materials are polycrystalline, that is they are made of
a large number of crystallites possibly randomly oriented.
Crystallites can have contact interfaces (boundaries), can be separated by
distortions or strains in the solid structure and/or can be embedded in
region of amorphous material.
Crystallite is a domain of solid having the same properties of a single
crystal
Structure stress
Amorphous solid
No long range order
(Less than 2 nm extension)
+
Negligible melting enthalpy compared to original solid
+
Solubility increase (Thermodynamic effect)
Griseofulvin case study
Griseofulvin
solid state
Crystalline domains
average diameter
Equilibriumsolubility
(g/ml)
Amorphous -- 235.0 2.0
Nanocrystals 89.8 nm 60.2 4.3
Micronized crystals 6 m 11.9 0.5
Grassi, Grassi, Lapasin, Colombo, Understanding Drug
Release and Absorption Mechanisms, Chap. VI, CRC
Press,2007
From IDR data
DSC and XRPD traces color code
Blue line: native drug nanocrystals Red line: recrystallized drug microcrystals
DSC Pattern
Temperature (C)
200 205 210 215 220 225 230
H
e
a
t

F
l
o
w

(
m
W

g
-
1
)
2
4
6
8
10
12
14
16
18
20
native drug
re-crystallized drug
XRD Pattern
2u (deg)
10 15 20 25 30
I
n
t
e
n
s
i
t
y

(
a
.
u
.
)
0
2000
4000
6000
8000
10000
re-crystallized drug
native drug
Grassi, Grassi, Lapasin, Colombo, Understanding Drug
Release and Absorption Mechanisms, Chap. VI, CRC
Press,2007
Griseofulvine solid state analysis
DSC trace XRPD trace
2.Solid state properties modifications:
applications to pharmaceutical product
development
Solid state properties modifications
Property change Final drug status Bulk product type
Crystal size
reduction
Microcrystals
Micronized API powder
Solid dispersion (micro)
Nanocrystals
Nanosuspension
Solid nanocrystals
Solid dispersion (nano)
Nanocomposite
Solid phase
transition
Amorphous
Solid dispersion (Solid solution)
Amorphous powder
Metastable
(pseudo)Polymorph
API Powder
Solid (nano)dispersion
Molecular dispersion Solid solution (true)
Modified solid
Bottom-Up
technologies
Top-Down
technologies
Demolition
Original solid phase is disintegrated
Solid state properties modifications
Build-up
From free molecules
to the new solid phase
Two possible strategies
2.1 Size reduction
Size reduction - Nanocrystals
Top-Down
Dry Milling
Wet Milling
High Pressure Homogenization
Bottom-Up
Precipitation
Process type
Applicable technologies
BioriseHEMA (Eurand)
Dissocubesand IDD-P (Skyepharma)
Nanocrystals(Elan-Nanosystems)
BioriseSIA (Eurand)
NanoEdge(Baxter)
Elan-Nanosystems nanocrystal formulations
Wet process conducted in bead or pearl mill loaded with:
Crystalline drug suspended in aqueous or organic vehicle
Suspension stabilizers and wetting agents
Size reduction Top-Down
Marketed technologies examples
Milling media (up to 75% of the mill volume)
Low energy process
Minor risk of degradation / phase transition
than in dry or high pressure homogenization
processes
Suspension of nanocrystals into the
process vehicle
Application for parenteral administration
(nanocrystals smaller than 200 nm)
Schematic representation of media milling process
(From E.Merisko- Liversidge et al., Eur.J.Ph.Sci ,18(2003), 113)
Pros
Low energy milling
Suitable for drugs insoluble both in water and organic solvents
Wide suspension concentration range 1-400 mg/ml
Cons
Possible milling material erosion
Nanosuspension stabilization against aggregation is needed
Time consuming (from hours up to days)
Solvent removal step in downstreamprocess to solid dosage forms
Spray-drying, freeze drying, wet granulation,
Possible nanocrystals aggregation
Four products on the market (oral administration)
Rapamune (2000, Wyeth) Syrolimus Immunosuppressant
Emend (2001, Merck) Aprepitant Antiemetic
TriCor (2004, Abbott) Fenofibrate treatment of hypercholesterolemia
MegAce ES (2005, Par Pharmaceuticals) Megestrol acetate Anticachetic
Dissocube e IDD-P by Skyepharma
Working pressure up to 4000 bar
Cavitation shockwaves energy breaks solid particles
in the region across the gap
Gap diameter between 5 and 30 microns
Drug suspension pass through the homogenizer one
or more times depending on the desired final size and
drug milling behaviour
Wet process in high pressure or jet stream homogenizers
Crystalline drug suspended in aqueous or hydrophilic organic solvent
Stabilizer / wetting agent might be added
High pressur piston-gap homogenizer (Dissocube)
Jet stream homogenizer (IDD-P)
Particle collisions, shear
force, cavitation
Microfluidizer
processor (Microfluidics)
Z or Y shaped fluidizer
Working pressure up to 2000 bar
Particles collision and shear force at the flows conjunction
results in size reduction
Drug suspension pass through the homogenizer usaully 10-30 time.
Up to 50-100 cycles could be required depending on drug properties
One product on the market (oral administration)
Triglide (Sciele Pharma Inc, 2005) Fenofibrate treatment of hypercholesterolemia
Pros
No milling media contamination
Suitable for drugs insoluble both in water and organic solvents
Cons
Drug has to be micronized before processing
Equipment high cost
Time consuming (IDD-P)
Several cycles into homogenizers (10-15 to 50-100)
Nanosuspension stabilization against aggregation is needed
Solvent removal step in downstream process to solid dosage forms
Spray-drying, freeze drying, wet granulation,
Possible nanocrystals aggregation
Dry milling into vibrating or oscillating mill
Crystalline active ingredient and carrier are coprocessed
Composite product is obtained
Nanocrystals dispersed into the carrier
Possible formation of amorphous phase
Biorise HEMA by Eurand
Milling energy, drug/carrier interactions and
drug/carrier ratio mainly influence finished
product characteristics
Nanocrystalline domains average size
Amorphous content
Pros
Carrier stabilized nanocrystals
Possibility to obtain stabilized amorphous phase triggering process
conditions
Suitable for drugs insoluble both in aqueous and organic vehicles
Cons
High energy process product heating
Mill cooling during process
Low melting point or thermally unstable drugs: case by case verification
Possible milling media contamination
Product adhesion to mill wall and milling media
One product on the market (oral administration)
Nimedex (Italfarmaco, ) Nimesulide Antiinflammatory
FAST ONSET
Size reduction Bottom-Up
Biorise SIA by Eurand
Precipitation on solid
Drug dissolved in suitable organic solvent
Organic solution mixed with insoluble crosslinked carrier swelling
Solvent removed
Solid drug entrapment into/onto crosslinked carrier
Nanocrystalline and/or amorphous phases solid dispersions
Drug solubility into carrier solid solutions
Crosslinked carrier network is a constrain to crystals growth
Average size below 100 nm
Stabilizing effect
Maximum polymer network opening
i.e. 40-50 nm for crospovidone
Size reduction Bottom-Up
NanoEdge by Baxter
Precipitation in liquid + homogenization
Drug and surfactant dissolved in suitable water miscible solvent
Aqueous buffer containing surfactant added into drug solution
Drug precipitation
Homogenization of the suspension contributes to reduce drug
crystal size
Solid powder can be obtained
Spray drying, freeze drying, etc.
2.2 Amorphous phase
Amorphous Phase
Bulk Drug
Solid dispersion
Homogeneous mixture of solid drug into solid carrier(s)
Amorphous
Crystalline (micro-, nano-)
Solid Solution
Molecular dispersion of drug into solid carrier(s)
Some authors consider in this category also amorphous
drug dispersions
Amorphous Phase
Solid Dispersions (Solid Solutions)
Top-Down
Dry Co-Milling
Bottom-Up
Solvent evaporation
Hot melt processing
Process type
Applicable technologies
BioriseHEMA (Eurand)
BioriseSIA (Eurand)
Meltrex(Soliqs)
Nanomorph(Soliqs)
Thermal
Solvent
Mechanical
Co-milling Biorise HEMA
Solvent evaporation
Precipitation
Hot Melt Extrusion Meltrex
Hot Melt Granulation
Spray congealing
Ultra-raffreddamento
Top-Down
Bottom-Up
Amorphous Phase
Solid Dispersions
Biorise SIA
Nanomorph
Solid API
Solid
Excipient
Mixing
Liquid mixture Hard capsules filling
Melting
Molten
Excipient
Cooling
Spray
congealing
Multiparticolate
(mcrospheres, pellets)
Cool down to
solid
Milling, sizing
Multiparticolate
(granules, powder)
Solid dosage form
downstream
Melting
Molten API
Amorphous Phase
Solid Dispersions
Drug
Solid
excipient(s)
Mixing
Physical blend
Hot melt extrusion
Monolithic
matrix
Hot melt granulation
Multiparticulate
(granules, pellets)
Solid forms
downstream
High
shear
Low
shear
Fluid
bed
Pelletization
Multiparticulate
(granules, pellets)
Amorphous Phase
Solid Dispersions
Amorphous Phase
Solid Dispersions
From http://www.soliqs.com/Technology.17.0.html
Melt Extrusion line for production of tablet shaped dosage form by
Meltrex Technology
Drug
Solid
excipient(s)
Mixing
Solvent evaporation
Filtration / solvent
removal
Solid
(micro/nanoparticles)
Solvent
Superctitical fluid Spray drying Vacuum drying Freeze drying
Solid product Solid forms downstream
Solid
(powder)
Amorphous Phase
Solid Dispersions
Antisolvent
precipitation
Liquid
Suspension
Solution
Promising approach with several applications and advantages
Solubility enhancement, controlled release, stability enhancement, etc.
Much research work both in academia and industry but.
.limited practical application..
Few marketed products based on solid dispersion/solution technologies
Gris-PEG
(Pedinol Pharm.) Griseofulvine dispersed in Poliethylene glycol

Cesamet (Valeant Pharm.) Nabilone dispersed in Polyvinylpyrrolidone
Prograf (Fujisawa) Tacrolimus dispersed in HPMC
Certicabe (Novartis) Everolimus dispersed in HPMC
Kaletra (Abbott) Lopinavir and Ritonavir in solid matrix by Meltrex technology
.because of some formulation and development issues
Amorphous Phase
Solid Dispersions
Example of success: Kaletra
Meltrextablets
Lopinavir+Ritonavir Anti-HIV product (Abbott)
FDAApproved in 2005
Designed as an improvement of origina Kaletra Soft-gel capsules
Amorphous Phase
Solid Dispersions
Meltrex technology
PK profile comparable to that of capsules, but no food effect
Dosing regimen and patient compliance improvement
From three-six capsules/day to two-four tablets/day of comparable size
Solid formulation more stable than liquid
Room temperature instead refrigerated storage
Major issues
Chemical and/or physical stability
Crystallization of amorphous phases impacts product performance, i.e.
drug solubility / solubility rate
Carrier and/or drug
Molecular mobility - Promoted by
Exceeding glass transition temperature of the system
Plasticizing effect of water (or other solvents)
Limited drug load for molecular and amorphous dispersions
Drug solubility / miscibility in the carrier at solid state
oversaturation drug crystallization
Product characterization
Special technique required for solid phases characterization
Validation for submission purposes could be complex
Amorphous Phase
Solid Dispersions
2.3 Physical-chemical characterization of composite
systems containing nanocrystalline and
amorphous domains
Bulk analysis
Particle Size
Laser light diffraction (LLD)
Mercury porosimetry (MP)
Solid Phases (Qualitative and Quantitative)
X-Ray powder diffraction analysis (XRPD)
Differential scanning calorimetry (DSC)
Solubilization Kinetic
Surface analysis
Specific Surface Area
Mercury Porosimetry
Gas Adsorption
Surface Mapping
Liquid-Solid contact angle
Atomic force microscopy + micro thermal analysis (AFM-TA)
Scanning electron microscopy + energy dispersive spectroscopy (SEM-EDS)
X-Ray Photo-electron spectroscopy (XPS)
Micro Raman Spectroscopy
Techniques useful for Solid Phases Characterization
Solid state characterization
Qualitative evaluation of solid phases
Crystalline vs amorphous
Quantitative evaluation of solid phases
Calibration curve : i.e. crystalline drug and carrier at different ratios
Crystallite size estimation
Scherrer equation relates increase of full-width of the peak at half of its maximal intensity
(FWHM, ) with size of crystallites (), through a costant (K), x-Ray wavelength () and the
Bragg angle ()
Other microstructures features could affect FWHM enlargement beside crystallite size,
therefore peaks fitting refinement (i.e. Rietveld method) and deconvolution analysis (i.e.
Warren-Averbach) have to be applied
X Ray Powder Diffraction
u t

|
cos
K
=
2u (deg)
8 12 16 20 24 28 32 36 40
I
n
t
e
n
s
i
t
y

(
a
.
u
.
)
composite system
raw material
DSC Qualitative evaluation
Temperature (C)
60 80 100 120 140 160 180 200 220
H
e
a
t

F
l
o
w

(
W
/
g
)

(
c
o
m
p
o
s
i
t
e
)
0.76
0.80
0.84
0.88
H
e
a
t

F
l
o
w

(
W
/
g
)

(
r
a
w

m
a
t
e
r
i
a
l
)
5
10
15
20
W
e
i
g
h
t

(
%
)

(
c
o
m
p
o
s
i
t
e
)
99.3
99.4
99.5
99.6
99.7
99.8
99.9
100.0
DSC signal of composite system
DSC signal of raw material
TGA signal of composite system
Raw griseofulvin (red trace): Solid-Liquid Phase transition happens at about 220C Heat flow
scale 5-20 W/g
Composite system (blue trace): Endotherm at about 180C corresponds to Solid-Liquid phase
Transition of nanocrystalline griseofulvin (nanocomposite griseofulvin/crospovidone) Heat flow
scale 0.76-0.88 W/g
For a composite sample containing drug in crystalline and amorphous phases the enthalpy of
fusion is the sum of enthalpy of fusion of each of the j solid phases:
Specific enthalpy of fusion usually is estimated using DSC data from pure crystalline drug / matrix
physical mixtures of known drug content.
Nanocrystalline phase specific melting enthalpy, being temperature dependant, can be calculated
applying Kirchoff law starting from parameters experimentally measured for standard drug
DSC Quantitative evaluation
=
j
j
m
j
s
m
h m H
m : mass of the j
th
phase
h
m
: specific enthalpy of fusion of the j
th
phase
Drug X/Crospovidone 1:2 w/w
Biorise HEMA composites
Drug X melting points
About 148C: nanocrystals
About 160C: standard product
Surface Mapping Techniques Phases
Liquid Solid Contact Angle Measurement
Solid phase type impact on contact angle value
Technique useful only for non swellable carriers
Atomic Force Microscopy+micro Thermal Analysis
Images obtained based on both
Topography
Thermal conductivity/diffusivity
40-50 nm resolution
Micro-Raman
Raman Microscope is a conventional Raman spectrometer confocally coupled
with an optical microscope
Laser beam can be focused at the sample surface with resolution down to 1 m
Scanning Electron Microscopy+Energy Dispersive X-Ray Spectroscopy (SEM-EDS)
Scanning electron microscope is coupled with a probe detecting X-Ray produced
by the interaction of electrons with the sample
X-Ray emission is different for each atom chemical mapping
Composite microstructure and
morphology investigation
Nimesulide-Crospovidone Case Study
Nimesulide-Crospovidone composite case study
2u (deg)
5 10 15 20 25 30
I
n
t
e
n
s
i
t
y

(
a
.
u
.
)
NN
PN
NC
NN : native (raw) nimesulide - PN : polymorphic nimesulide: mixture of forms I and II
NC : nimesulide/crospovidone nanocomposite
Coherent domain (crystallite) size by XRPD
profile analysis using double-Voight and FPA#
<DV> = 17 3 nm
Strain: 3%-17%
# D. Balzar in R.L. Snyder, H.J. Bunge, J. Fiala (Eds),
Defect and Microstructure analysis by diffraction;;
International Union of Crystallography, Oxford
University Press, New York, 1999
Nimesulide/Crospovidone nanocomposites (1/2.5 w/w ) prepared by solvent
induced activation (F. Carli et al. Int. J. Pharm. 33, 115 (1986))
Nimesulide exists in two polymorphic modifications (P. Bergese et al. Comp. Sci. Technol.,
63, 1197 (2003))
Form I (Native material)
Form II that is metastable
Solid state characterization - microstructure
Morphology Scanning electron microscopy
Epossidic
resin
NC particles
Ultramicrotome
Molecular Dispersion Scanning electron microscopy + energy dispersive X-ray
spectroscopy (SEM-EDS)
Nimesulide: nonsteroidal antiinflammatory,
C
13
H
12
N
2
O
5
S
Crospovidone:
cross-linked polyvinylpirrolidone, [C
6
H
9
NO]
n
Sulphur main X-ray emission(Ka, 2.307 keV) overlaps with principal gold X-ray emissions:
the sample was sputtered with titanium
Sulphur can be used to track nimesulide molecules eventually dispersed into the
crospovidone network
Molecular Dispersion Scanning electron microscopy + energy dispersive X-ray
spectroscopy (SEM-EDS)
1.174
0.542
0.304
Energy (KeV)
1 2 3 4
c
p
s
0
5
10
15 peak area=0.542
peak area=0.304
peak area=1.174
S
C
J. Phys. Chem. B, 2004, 108, 15488-15493
Composites Part. A, 2005, 36, 443-448
Raman shift (cm
-1
)
300 400 500 600 700 800 900
I
n
t
e
n
s
i
t
y

(
a
.
u
.
)
4000
6000
8000
10000
12000
14000
I
n
t
e
n
s
i
t
y

(
a
.
u
.
)
4000
4400
4800
5200 2
1
402
20
25
30
35
40
L
e
n
g
t
h

Y

(
m
)
25 30 35 40
Length X (m)
200
150
100
50
Phases distributionRaman microscopy (Raman)
Amorphous
Crystalline
Surface scanning by collecting a Raman
spectrum with steps of 1 m
2
Intensity projection of the crystalline
nimesulide peak at 402 cm
-1
MAP
Conclusions
XRD: crystalline nimesulide is packed in 17 nm crystallites
SEM: nimesulide micro- and nanoparticles segregated onto the
crospovidone surface as well as wrapped up by the crospovidone matrix
EDS: there is a presence of nimesulide also in zones where the polymer
surface is free from nimesulide particles
Raman: domains of crystalline nimesulide surrounded by amorphous
nimesulide
Conclusions
Nimesulide is constrained by the crospovidone into three main
arrangements:
an amorphous phase dispersed into the molecular crosslinked
network of the polymer
nanocrystals wrapped up by the polymer
drug layers, made of micro- and nanocrystals, segregated onto the
popcorn-like surface of the polymer
According to XRD data, the micro- and nanocrystals are highly
disordered and made of crystallites with an average diameter of 17 nm
Caratterizzazione
chimico-fisica
Paolo Gatti, PhD
Eurand RD Senior Scientist
paolo.gatti@eurand.com
Or come at
Both 722
Technical questions
Thanks for Your Attention !!!
SOLVATION AND DIFFUSION DEPEND ON
SOLUTE AND SOLVENT CHEMICAL
NATURE AND ON SYSTEM CONDITIONS
WETTINGAND FUSION DEPEND ALSO
ON MICROSTRUCTURE OF THE SOLUTE
IN THE SOLID STATE
Time (s)
0 100 200 300 400
C
o
n
c
e
n
t
r
a
t
i
o
n

(
m
g
/
m
l
)
0
200
400
600
0 20 40 60
0
1
2
3
4
experimental data for 100% amorphous TEM
simulations
experimental data for 100% nanocrystalline MPA
Solubilization Kinetic
Amorphous and Nanocrystalline Composite Materials
Comparison of solubilization kinetics in non-sink conditions
(Dispersed Amount Method)
M. Grassi, I. Colombo, R. Lapasin,
J. Controlled Release 68 (2000), 97-113

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Solubility Improvement by Solid State

Micronized crystalline solid

(Pedinol Pharm.) Griseofulvine dispersed in Poliethylene glycol

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