HR-XRPD and Polymorph Stability

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1 HR-XRPD and Polymorph Stability HR-XRPD, A CRUCIAL FACTOR IN THE DETERMINATION OF THE STABILITY HIERARCHY OF POLYMORPHS BY TOPOLOGICAL AND EXPERIMENTAL PRESSURE- TEMPERATURE DIAGRAMS Ivo B. Rietveld, M. Barrio, J.-Ll. Tamarit, R. Céolin

$This document was presented at PPXRD - Pharmaceutical Powder X-ray Diffraction Symposium Sponsored by The International Centre for Diffraction Data This presentation is provided by the International$

2 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. All copyrights for the presentation are retained by the original authors. The ICDD has received permission from the authors to post this material on our website and make the material available for viewing. Usage is restricted for the purposes of education and scientific research. PPXRD Website ICDD Website -

3 Paracetamol Two known polymorphs: Form I: Monoclinic P2 1 /a fusion: K, J g -1 Form II: Orthorhombic Pbca fusion: K, J g -1 Which is the most stable?

4 Paracetamol Form II Form I 430 K 448 K T

5 Paracetamol Where is the equilibrium between form I and form II? Liquid E Form II Form I 430 K 443 K T

6 Gibbs Energy Liquid G = H -TS E Form II Form I dg = -SdT +Vdp 430 K 443 K T G is characteristic for the variables: Temperature and Pressure

7 Gibbs Energy G p p Form I T Form II T

8 Clapeyron Equation The slope of a two-phase equilibrium: dp dt = DS Dv = DH TDv Calorimetry X-ray diffraction p Form I Pressure can be incorporated by X-ray diffraction without even measuring it! Form II T

9 Paracetamol Form II Form I 430 K 443 K T

Paracetamol Volume Differences Liquid Enthalpy Differences At 442 K Form I Δv ΔH 191.

10 Paracetamol Volume Differences Liquid Enthalpy Differences At 442 K Form I Δv ΔH Jg -1 Liquid Form II 3.4 Jg -1 Form II Form I dp/dt (I L) =3.7 MPa K -1 dp/dt (II L) = 3.1 MPa K -1 dp/dt (I II) = -0.3 MPa K -1

11 Pressure, Triple Points, and Alternation Rule p Rigid DSC capsule Vapor Solid? P vap I L Vapor Melting Triple point The pressure of the system is its vapor pressure 443 K T dp/dt (I L) =3.7 MPa K -1 At Fusion: Three Phases Triple point

12 Paracetamol p I, L, V dp/dt (I L) =3.7 MPa K K T

13 Paracetamol p II, I, L II, L, V I, L, V dp/dt (I L) =3.7 MPa K K dp/dt (II L) = 3.1 MPa K -1 T dp/dt (I II) = -0.3 MPa K -1

14 Paracetamol p II, I, L II, L, V I, L, V 443 K T

15 Paracetamol p II, I, L II, L, V I, L, V 443 K T Espeau et al, J. Pharm Sci 94 (3), 2005,

16 Bakhuis-Roozeboom 4 Phases 4 Phase Diagrams

7 MPa Melting Form I II I II, I, L Melting

17 Paracetamol Experimental Verification Experimental Triple Point T = K p = MPa Melting Form I II I II, I, L Melting Form II J. Ledru et al., J Pharm Sci 96 (10), 2007,

18 Biclotymol Pulmonary antiseptic Form I Form II P2 1 /c T fus : 400 K 374 K ΔH fus : 36.6 kj mol kj mol -1

19 Biclotymol Volume of form I and liquid Melting peaks versus pressure

20 High Pressure DTA Heater block E = Sample (échantillon) T = Reference (témoin) Supply of pressure transmission liquid Piston Thermocouples Manometer

21 Biclotymol Form II - L Form I - L

22 Biclotymol Le Chatelier H phase A < H phase B Form II - L T Observation Form II into Form I transition exothermic Form I - L H form I < H form II I II T

23 Biclotymol Overall monotropy Form II - L Form I - L Céolin et al. J. Pharm Sci 97 (9), 2008,

24 Dimorphic Tyrosine Ethyl Ester Prodrug against tyrosine deficiency

25 Crystal Structure Ethyl ester, Phase II: orthorhombic P

26 P-T, Necessary Data Form I Form II DSC: temperature and enthalpy X-ray: Volume difference

27 P-T, Necessary Data DSC: temperature and enthalpy DSC: T II I and heating rate

28 Pressure Topological Pressure Temperature Diagram Clapeyron Equation: dp dt = DH TDv The slope of a phase equilibrium By DSC, high pressure DTA and X-ray: Transition temperature Enthalpy of transition Volume change at transition DSC Clapeyron Triple point I-II-liq DSC: T, DH; X-ray: Dv Temperature DSC: T, DH; X-ray + V liq : Dv

Pressure (MPa ) Construction of P-T Diagram 300 250 200 150 100 50 0 I, Liq, Vap 250 300 350 400 450 Temperature (K) Solid I Melting

29 Pressure (MPa ) Construction of P-T Diagram I, Liq, Vap Temperature (K) Solid I Melting point solid II P, T, ΔH II, I, Vap ln P = - DH RT + B II, I, Liq Liquid Boiling point T = 590 K ΔH = 65 kj/mol P = 1 bar Vapor Solid II Vapor

30 Pressure (MPa ) Dimorphism stability regions (P, T) Solid II II, I, L Liquid II, I, Vap Solid I II, L, Vap I, L, Vap Temperature (K) Vapor

31 Specific volume of liquid without measurement Estimate of steepest slope +10% Clapeyron ΔV(I-L) V liquid dp dt = DH TDv Tg Céolin, Rietveld, J Therm Anal Calorim 102, 2010, Rietveld et al. J Pharm Sci submitted (tyrosine ethyl ester, previous slides)

32 Heat Flow Endo Up (mw) Area = mj Delta H = J/g 5.5 II 6.0 Benfluorex (Mediator) anorectic and hypolipidemic agent Peak = C K I PerkinElmer Thermal Analysis L Filename: C:\Program Fil...\benfluo_5mg_1c-min_b.ds8d Operator ID: Sample ID: benfluo_ _9_1c-min Sample Weight: mg Comment: benfluorex lotto n 9 pesato il mg misurato con testa a -30 C dai 100 C Form I highest melting point Stable form? Maccaroni et al. J. Pharm. Biomed. Analysis 53, 2010, 1-6 Form I Monoclinic P2 1 /n, Z = 4 Form II Orthorhombic Pbca, Z = 8

33 Benfluorex High Pressure Data Form II - L Lines parallel - Measured Form I - L - Calculated No v spec of liquid No triple point!?

34 P V decreases From melting enthalpies: H II < H I From X-ray measurements v II < v I Le Chatelier: II Benfluorex Triple point down I-L II-L II-I I L Triple point up I-L II-L L II I T H increases II II L II-I I L Inconsistent Consistent

35 Benfluorex A transition at about 420 K! Invisible in all DSC measurements Form I!?!? Form II

36 Benfluorex 1) Heat from C to C at 1.00 C/min 7/27/2010 3:38:02 PM Temperature ( C) K/min Onset = C 4.0 Heat Flow Endo Up (mw) K/min The transition is only visible at very low heating rate 5.0 Area = mj Delta H = J/g Peak = C PerkinElmer Thermal Analysis Filename: C:\Program Fil...\benfluo_5mg_1c-min_b.ds8d Operator ID: Sample ID: benfluo_ _9_1c-min Sample Weight: mg Comment: benfluorex lotto n 9 pesato il mg misurato con testa a -30 C dai 100 C

37 T / o K C Benfluorex 0.1 K/min 0.05 K/min T I-L 420 T II-L T II-I T E II-I =395.6 K Heating Rate / K min -1 Solid-solid transition heating rate dependent and disappearing in II melt

38 II stable at RT Benfluorex

39 Pressure Temperature - Composition D-Camphor DL-Camphor

40 Experimental P-T data Solid-solid equilibria! DL-camphor D-camphor Vapor pressure 0,05 MPa

41 P-T-x Phase Diagram of the camphor melting transition

42 T / o C K Toolbox Conclusions 1/4 Pressure is the pressure of the system, not 1 atm! Vapor Solid Always check heating rate dependence of solid-solid transitions! T I-L 420 T II-L T II-I T E II-I =395.6 K Heating Rate / K min -1

43 Toolbox Conclusions 2/4 Required data: DSC X-ray High Pressure Differential Thermal Analysis Glass transition Liquid volume 10% Specific volume of liquid serves the topological approach T g

44 Toolbox Conclusions 3/4 Le Chatelier H II < H I T p v II < v I Clapeyron dp dt = DS Dv = DH TDv Vapor pressure ln P = - DH RT + B Alternation Rule Triple points Each case is a different puzzle!

45 Toolbox Conclusions 4/4 4 phases (solid 1, solid 2, liquid, vapor): 4 phase diagram options

46 Acknowledgements P. Espeau J. Ledru M.-A. Perrin J.-P. Gauchi F. Leveiller C.T. Imrie C.R. Pulham J.M. Hutchinson E. Maccaroni N. Mahé B. Nicolai J v. d. Streek L. Malpezzi W. Paneri N. Masciocchi Carnot Clapeyron Le Chatelier Clausius Helmholtz GIBBS Kirchhoff Riecke Bakhuis-Roozeboom Ostwald Tamman

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