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Laboratoire de Dynamique et Structure des Matériaux Moléculaires
SOLID STATE TRANSFORMATIONS OF
PHARMACEUTICAL COMPOUNDS UPON MILLING:
LACTOSE & MANNITOL(authorized version)
V. Caron, J-F. Willart, R. Lefort, J. Lefebvre, M. Descamps
UMR 8024 – Université de Lille 1-France
PPXRD 08, Glasgow, 04-07 May 2009
This document was presented at PPXRD -Pharmaceutical Powder X-ray Diffraction Symposium
Sponsored by The International Centre for Diffraction Data
This presentation is provided by the International Centre for Diffraction Data in cooperation with the authors and presenters of the PPXRD symposia for the express purpose of educating the scientific community.
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Phase transformations under milling
A very active field of researches in metallurgy :
• Sursaturated solid solutions
• Amorphous alloys
• Nanomaterials
Several theoretical approaches developed
but
Description of transformation mechanismsPrediction of final states
No universallyaccepted
In the field of
MOLECULAR MATERIALS(i.e. pharmaceutical compounds) :
NOSYSTEMATIC
INVESTIGATIONS(theoretical or experimental)
Milling of pharmaceutical compounds
No systematic investigations
In spite of :
• Importancy ofapplications
• Original aspects ofmolecular materials
(Fundamental studies)Tg
G
TTm
Milling : numerous
contradictoryeffects
Solubility,bioavailability
Pharma Grainsize
Millingfield
Molecular compounds specificities
a
b
Contrast between :
Weak inter-molecular interactions
Strong intra-molecular interactions
Low SymmetryImportant size
Moleculescells (often tricl., mono. or ortho.)
• Low melting temperatures
• Low kinetics of cryst
• Very sensitive to mechanical and thermal perturbations
Quench-VitrificationEasy
• Glass transition temperature close of RT ≅Tmilling
Tmilling≅ RT
MannitolTg = 13 °C < Tmi
Richpolymorphism
LactoseTg = 115°C >Tmi
Mutarotationcaramelization
Tg<Tmilling
Tg>Tmilling
Transfo. on milling of pharmaceutical compoundsMaterials selection
Plan of speech
I – MillingCharacteristics of milling experiments realized at the laboratory
II – Stable anhydrous α-lactose• Solid-state amorphization of αLS• Mutarotation (13C NMR)
III – Mannitol
Polymorphic transformationsMannitol δMannitol β
Characteristics of milling
N xpause (10min)
milling (20min)
Pulverisette 7Fritsch
400 rpm
N2 N2
Prevention of hygroscopy
ZrO2
Various solid-state forms:
• Monohydrated α lactose (Lα-H2O) (stable)
• Hygroscopic anhydrousα lactose
• Stable anhydrous α lactose (αLS)
• Anhydrous β lactose
• Molecular compounds α/β withvarious stœchiometries
Disaccharid often used in Pharmaceutical and Food industries
2 types of molecules of lactose :
α-lactose
β-lactose
Lactose – possible solid-state forms
Problems encountered for producing amorphous
α-lactose β-lactose
(in solution…)
Mutarotation
Thermal degradations and caramelization
lactose
Amorphization of αLS under milling
Crystallineα lactose
Glassy α lactose without degradations
Crystallineα/β lactose
milling recrys
2 θ (degrees)10 15 20 25 30
Before milling
β crystal
After 30h milling
After recrys
Temperature (°C)
80 120 160 200 240
DSC
Ch. Shift (ppm)6.06.57.0
PXRDNMR 1H liq
α
β∼α
∼α
α/β
Muta.5°C/min
degradationsBefore milling
After 30 h milling
Solid-state NMR 13C : characterization in situ % β
C1 gluαlactose≠
C1 gluβlactoseCrystalline or amorphous states
• Detection mutarotation
• Quantification % β in situ
• % β = f(T°C)
C1 glu
Chemical Shift (ppm)20406080100120140
C1 gal C1 glu
C4 glu
C4 gal
C1 galC1 gluC4 gal
C4glu
crys β lactose
αLS
13CSolidNMR
Inte
nsity
(a.u
.)
crys
Mutarotation during heating of amorphous αL
Chemical Shift (ppm)406080100120
Inte
nsity
(a.u
.)
21,5 °C
63 °C
85 °C
102 °C
132 °C
β αSolidNMR
13C
Milling amorphization ≠ local melting-quench
Tmil < 85°C < TmMutarotation Structural relaxation
below Tg Local melting / quench
Glassy αL Out of equilibriumTemperature (°C)
0 20 40 60 80 100 120 140 160 180
β-la
ctos
e (%
)
0
10
20
30
40
50
60
70
Tg
13C NMR
Irreversible
α/β crystal
Time (h)0 1 2 3 4
30
35
40
45
50
55
T = 85 °C
13C NMR
β-la
ctos
e (%
)
No mutarotation during heating of crystalline αLS
Chemical Shift (ppm)406080100120
Inte
nsity
(a.u
.)
18°C
71,5°C
160°C
SolidNMR
13C
Crystalline αLS
MannitolCharacteristics of Mannitol :
• Acyclic polyol present in seafood, fruits, mushrooms…
• Used as excipient, sweetener, API
G
T (°C)
Gβ
Gliq
Gα
Gδ
Tmδ TmαTmβ0°C
Tg=
13°C
Adapted from Burger et al.,
J. Pharm. Sciences,
2000, 89, 457
Polymorphic transformation under milling of Mβand Mδ
Mannitol β
Mannitol δMannitol α Mannitol βmilling
Aging
Room T°C
10 15 20 25 30 35 40
2 θ (degrees)
Mβ
Non milled
milled 10 h
milled 10 h, aging 8 days
XRDαβ
2 θ (degrees)10 15 20 25 30 35 40
Mδ
Non milled
Milled 52 h, aging 5h
Milled 52 h, aging 17h
XRD
αβ
δ
Interpretation of amorphization αLS under millingas a « Driven system* »
Teff
TTmilling
Tmelt
Teff
)1(DDTT
ch
baleff +=
Milling αLS
Dbal > Dch
Teff > Tfusion
Amorphization*Driven alloys, Martin et al, Solid State Physics, 50, p189 (1997)
G
T (°C)
Gβ
Gliq
Gα
Gδ
Tmδ TmαTmβ0°C
β α
δ αTtransition
Interpretations polymorphic transformationsmannitol under milling as a Driven system
Single Teff > Tfusion
Mβ, Mδ glass
glass Mα
milling
milling
stop
2 Teff
Mβ, Mδ glass
glass Mα
Teff >Tm
Teff < Tm
Adapted from Burger et al., J.
Pharm. Sciences, 2000, 89,457
Conclusion
Crystallineα lactose
Glassy α lactosewithout degradations
milling
Mannitol β
Mannitol δMannitol α Mannitol βMilling
Aging
Room T°C
States reached are stationary states rather than thermodynamic equilibrium states
Glassy αL Out of
equilibrium
Local quench melting
Irreversible
at T < Tg
GlassyαL
heatingMutarotation
Acknowledgements• Pr. Marc Descamps
• Dr. Jean-François Willart
• Dr. Ronan Lefort
• Pr. Jacques Lefebvre
• Dr. Patrick Derollez
• Mme. Florence Danede
• M. Dominique Prevost
Publications related to this presentation
• J.F. Willart, V. Caron, R. Lefort, F. Danède, D. Prévost and M.Descamps, "Athermal character of the solid state amorphization oflactose induced by ball milling", Solid State Communications, 2004, 132,pp. 693.
• J. Lefebvre, J.F. Willart, V. Caron, R. Lefort, F. Affouard and F.Danede, "Structure determination of the 1/1 α/β mixed lactose by X-raypowder diffraction", Acta Cryst. B, 2005, 61, pp. 455.
•R. Lefort, V. Caron, J.F. Willart and M. Descamps, "Mutarotationalkinetics and glass transition of lactose", Solid State Communications,2006, 140, pp. 329.
• P. Zhang, N. Klymachyov, S. Brown, J.C. Ellington and P.J.Grandinetti, "Solid state 13C NMR investigations of the glycosidiclinkage in a-a’ trehalose", Solid state Nuclear Magentic Resonance,1998, 12, pp 221.
Publications related to this presentation• R. Lefort, A. De Gusseme, J.F. Willart, F. Danede and M. Descamps,"Solid State NMR and DSC methods for quantifying the amorphouscontent in solid dosage forms: an application to ball-milling oftrehalose", International Journal of Pharmaceutics, 2004, 280, pp. 209.
• M. Descamps, J.F. Willart, E. Dudognon and V. Caron,“Transformation of Pharmaceutical Compounds upon milling andcomilling : The role of Tg”, Journal of Pharmaceutical Sciences, 2007,96, 00, pp. 1-10.
• J. Rodriguez-Carvajal, T. Roisnel, “Fullprof 98 and WinPLOTR: NewWindows 95/NT Application for Diffraction”, Newletter 20, 1998.
• H.M. Rietveld, "Line profiles of neutron powder diffraction peaks forstructure refinement", Acta Cryst, 1967, 22, pp 151.
• H.M. Rietveld, "A profile refinement method for nuclear and magneticstructures", J. Appl. Cryst., 1969, 2, pp 65.