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

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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.