Crystal Engineering Strategies: Design of new Synthons and Enhancement of API s Solubility

Transcription

1 Plataforma de Polimorfisme i Calorimetria Crystal Engineering Strategies: Design of new Synthons and Enhancement of API s Solubility Dr. Rafel Prohens

2 Solubility Enhancement of an API Physical modification: particle size reduction Drug dispersion in carriers: solid dispersions Additives/Complexation: cyclodextrins Surfactants: microemulsions Co-solvents (GRAS approved) Solid-state modification: salt formation, solidstate stabilisation of the amorphous state, etc...

3 Solid State Methods For Improving Solubility And Dissolution Rates abit modification Crystal Polymorphism Solvates and hydrates Salts Cocrystals

4 Crystal Engineering Strategies For Improving Solubility And Dissolution Rates abit modification Crystal Polymorphism Solvates and hydrates Salts Cocrystals

5 VERVIEW Crystal Engineering Strategies Enhancement of solubility and other properties Salts ydrates Cocrystals Study of Supramolecular Synthons Squaramides

6 A Supramolecular Synthon is a structural unit within supermolecules which can be formed and/or assembled by known or conceivable synthetic operations involving intermolecular interactions G. Desiraju. Angew. Chem Int. Ed 1995, 34, 2311

7 A Supramolecular Synthon is... Component A Component B Complementary Functional Groups

8 A Supramolecular Synthon is...

9 A Supramolecular Synthon is...

10 A Supramolecular Synthon is...

11 A Supramolecular Synthon is...

12 A Supramolecular Synthon is...

13 A Supramolecular Synthon is...

14 Using Graph Sets in ydrogen-bond arrays To define the morphology of hydrogen bonding patterns in crystal structures ACCEPTR D R G a d (n) n: number of atoms G -bonding motif D: Dimer or finite C: Chain S: Intramolecular R: Ring a: number of acceptors d: number of donors Etter, M. C. Acc. Chem. Res. 1990, 23,

15 Three case-studies Solvent API Acid/base Coformer Solvates/ydrates Salts Cocrystals

16 Three case-studies Ziprasidone API Cl Acid/base Salts S Portell, A; Barbas, R; Font-Bardia, M; Dalmases, P; Prohens, R; Puigjaner, C. CrystEngComm 2009, 11(5), 791

17 Three case-studies Solvent orfloxacin API Solvates/ydrates F Puigjaner, C; Barbas, R; Portell, A; Font-Bardia, M; Alcobe, X; Prohens, R. Crystal Growth & Design, 2010, 10(7), 2948

18 Three case-studies API Capsules API Coformer Cocrystals

19 Design and study of new synthons Coformer 1 Synthon 1 Coformer 2 Synthon 2

20 Ziprasidone Low Solubility in water ~ 0.3 µg/ml Two ionisable groups in the molecule with pk a values 8.4 and 13.3

21 Salt or Cocrystal? pk a = pka (base) - pka (acid) Cl Salt pka > 3 S R Cl R Cocrystal pka < 3 S

22 Microscale salt screening Acid pk a Salt Acid pk a Salt 3 P Phosphoric Fumaric Citric xalic Malic Lactic X S Isethionic Glutaric X 3.86 X X Gluconic Glutamic 1.97 X S S X Maleic Armstrong s

23 Aqueous solubilities of Ziprasidone salts µg/ml Free base Cl Mesylate 3 P 4 Citrate Fumarate xalate Isethionate Malate

24 Polymorphic Salt Screening AcEt / 60ºC Malic acid Form A S Cl Ac / 60ºC Malic acid Form B Ac / r.t. Malic acid Form C

25 Polymorphism of Ziprasidone Malate Form C Form B Form A Form A Theta ^exo Form C Form B Form B Form A Temperature (ºC) Form C

26 Polymorphism of Ziprasidone Malate A - B Enantiotropy B - C Monotropy Form A ^exo Form C Form B Form B Form A Temperature (ºC) Form C

27 Aqueous solubilities of Ziprasidone malates Free base Cl Mesylate Malate A Malate B Malate C

28 Ziprasidone Malate Form C

29 Ziprasidone Malate Form C Possible Synthons bserved Synthons Cl S 2 R (8) 2 Carboxylic homo synthon S Ionic Interaction Cl Cl S Cl 2 R (9) 2 34% S ther functional group 66%

30 ierarchy of Synthons: 32 malate structures in the CCDC 1 hit 2 hits 3 hits 17 hits 30 hits 31 hits Cl Second best donor S Best donor Third best acceptor Second best acceptor Third best donor Best acceptor

31 orfloxacin 3 polymorphic anhydrous forms Methanolate Several ydrates Salts Cocrystals

32 orfloxacin Bioavailability It is a rule that a solvate is always the most stable and therefore the least soluble form in its own solvent Rolf ilfiker. Polymorphism in the Pharmaceutical Industry eutral Anhydrous forms Zwitterionic hydrates F F n 2 Lower Solubility igher Piperazinyl protonated ring in hydrates explains greater solubility

33 A new polymorphic sesquihydrate Cooling I II eating II I 22 ºC -69 ºC -35 ºC

34 A new polymorphic sesquihydrate Form I Form II

35 A new polymorphic sesquihydrate Form I Form II Water Channels

36 A new polymorphic sesquihydrate Form I Form II ne conformation Two conformations Different Ethyl Conformation

37 ydrates vs Anhydrous R ( ) R ( ) F F F 2 F 2

38 API: non-disclosure agreement API Capsules The most stable polymorph (Form A) is protected by patent Polymorph Screening 3 new metastable polymorphs obtained always with traces of Form A

39 Polymorphism Screening G C and D Form A B Metastable forms Form C Form A Concomitant Polymorphs Significantly different synthons

40 Polymorphism Screening G C and D C D B Enantiotropy Metastable forms Form C Form A 50ºC 100ºC 120ºC 140ºC Form D

41 Polymorphism Screening G C and D C D B Enantiotropy Metastable forms Form A Form A Form A Form A Form A Form C C D Form D C D 23 ºC 113 ºC 116 ºC 119 ºC

42 Polymorphism Screening G C and D C D B Enantiotropy Metastable forms Form A C and D forms cannot be obtained totally free of the patented form A Cocrystal Screening

43 API- 3 - Cocrystal 3 R (10) 3 API- 2 -Me 2 - Cocrystal R (10) 3 3 Form C 3 R (10) 3

44 Ammonia Cocrystal API- 3 - Cocrystal 2.9 % Form D API- 3 - Cocrystal 50 ºC Intensity (a.u.) 70 ºC 90 ºC 100 ºC 110 ºC 120 ºC Form D 2Θ (º)

45 Squaramides in Supramolecular Synthons: a case study

46 Double Donor-Acceptor -bonding Supramolecular Synthons catemer R R R' R' R R' R' R dimer A A R D R D A R D R anti / anti R 2 2 (n) anti / syn

47 ead-to-tail -bonding motif Form A Form B C2/c C2 nly soluble in DMS Portell, A; Barbas, R; Braga, D; Polito, M; Puigjaner, C; Prohens, R. CrystEngComm, 2009, 11(1), 52-54

48 The anti/syn synthon is also geometrically favorable 2 + Et Very insoluble 2

49 Conformational Equilibrium in Solution (CDCl 3 ) c c b a a b c

50 2D-MR Dilution Experiment c c b a a b c 240 K ppm

51 Thermodynamic Equilibrium in Solution Approximate Values of the Equilbrium Constants K CM K CD K Dab K Dc

52 Molecular Electrostatic Potential Surface ighest β value ighest α value unter, C. A. Angew. Chem. Int. Ed. 2004, 43,

53 Solution vs Solid State β Ο 5.1 α 2.1 β β 5.1 β 4.0 α 2.8

54 Solution vs Solid State α 2.8 β 4.0 β 5.1 α 2.1 β 4.2 β Ο a 1b 1c

55 Two Polymorphs ^exo Solid-solid transition

56 Two Polymorphs ^exo Melting and crystallization

57 Two Polymorphs Solid transition 120 ºC 130 ºC 150 ºC Melting Solid transition Crystallization from the melt

58 Two Polymorphs Form I Form II R 2 2 (10) irshfeld s Surfaces

59 Two Polymorphs Form I Form II R 2 2 (10) irshfeld s Surfaces

60 Breaking the head-to-tail motif β 4.2 α 2.9 β MEP Surface β > β

61 α 2.9 β 4.8 β β > β 2c 2a 2b or Breaking the head-to-tail motif

62 Breaking the head-to-tail synthon β 4.2 α 2.9 R 2 2 (12) β β > β

63 Stronger competitors cannot inhibit the head-to-tail synthon β = 4.3 α = 3.4 β = 4.9

64 SQ head-to-tail as a scaffold for new cocrystal structures

65 SQ head-to-tail as a scaffold for new cocrystal structures

66 SQ head-to-tail as a scaffold for new cocrystal structures

67 Cocrystal Screening Fumaric acid squaramide cocrystal Synthons not found

68 SQ head-to-tail as a scaffold for new cocrystal structures

69 Cocrystal Screening Fumaric acid squaramide cocrystal

70 SQ head-to-tail as a scaffold for new cocrystal structures

71 Plataforma de Polimorfisme i Calorimetria Acknowledgements Dr. Cristina Puigjaner Rafa Barbas Anna Portell Dr. Xavier Alcobé Dr. Mercè Font-Bardia