Plataforma de Polimorfisme i Calorimetria Crystal Engineering Strategies: Design of new Synthons and Enhancement of API s Solubility Dr. Rafel Prohens
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...
Solid State Methods For Improving Solubility And Dissolution Rates abit modification Crystal Polymorphism Solvates and hydrates Salts Cocrystals
Crystal Engineering Strategies For Improving Solubility And Dissolution Rates abit modification Crystal Polymorphism Solvates and hydrates Salts Cocrystals
VERVIEW Crystal Engineering Strategies Enhancement of solubility and other properties Salts ydrates Cocrystals Study of Supramolecular Synthons Squaramides
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
A Supramolecular Synthon is... Component A Component B Complementary Functional Groups
A Supramolecular Synthon is...
A Supramolecular Synthon is...
A Supramolecular Synthon is...
A Supramolecular Synthon is...
A Supramolecular Synthon is...
A Supramolecular Synthon is...
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, 120-126
Three case-studies Solvent API Acid/base + - + - - + - + Coformer Solvates/ydrates Salts Cocrystals
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
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
Three case-studies API Capsules API Coformer Cocrystals
Design and study of new synthons Coformer 1 Synthon 1 Coformer 2 Synthon 2
Ziprasidone Low Solubility in water ~ 0.3 µg/ml Two ionisable groups in the molecule with pk a values 8.4 and 13.3
Salt or Cocrystal? pk a = pka (base) - pka (acid) Cl Salt pka > 3 S R Cl R Cocrystal pka < 3 S
Microscale salt screening Acid pk a Salt Acid pk a Salt 3 P 4 1.96 Phosphoric Fumaric 3.03 3.13 1.27 Citric xalic Malic Lactic 3.46 3.85 X S Isethionic Glutaric 1.66 4.34 X 3.86 X 2 4.25 X Gluconic Glutamic 1.97 X S S -3.37 X Maleic Armstrong s
Aqueous solubilities of Ziprasidone salts µg/ml 1200 1000 1000 1121 800 600 475 400 236 200 0.3 80 28 30 55 0 Free base Cl Mesylate 3 P 4 Citrate Fumarate xalate Isethionate Malate
Polymorphic Salt Screening AcEt / 60ºC Malic acid Form A S Cl Ac / 60ºC Malic acid Form B Ac / r.t. Malic acid Form C
Polymorphism of Ziprasidone Malate Form C Form B Form A Form A 5 15 25 35 2 Theta ^exo Form C Form B Form B Form A 50 100 150 Temperature (ºC) 250 300 Form C
Polymorphism of Ziprasidone Malate A - B Enantiotropy B - C Monotropy Form A ^exo Form C Form B Form B Form A 50 100 150 Temperature (ºC) 250 300 Form C
Aqueous solubilities of Ziprasidone malates 1200 1000 989 1084 1000 800 600 475 400 200 0.3 80 0 Free base Cl Mesylate Malate A Malate B Malate C
Ziprasidone Malate Form C
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%
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
orfloxacin 3 polymorphic anhydrous forms Methanolate Several ydrates Salts Cocrystals
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. 2006 eutral Anhydrous forms Zwitterionic hydrates F F n 2 Lower Solubility igher Piperazinyl protonated ring in hydrates explains greater solubility
A new polymorphic sesquihydrate Cooling I II eating II I 22 ºC -69 ºC -35 ºC
A new polymorphic sesquihydrate Form I Form II
A new polymorphic sesquihydrate Form I Form II Water Channels
A new polymorphic sesquihydrate Form I Form II ne conformation Two conformations Different Ethyl Conformation
ydrates vs Anhydrous R 2 2 10 ( ) R 2 2 8 ( ) F F F 2 F 2
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
Polymorphism Screening G C and D Form A B Metastable forms Form C Form A Concomitant Polymorphs Significantly different synthons
Polymorphism Screening G C and D C D B Enantiotropy Metastable forms Form C Form A 50ºC 100ºC 120ºC 140ºC Form D
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
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
API- 3 - Cocrystal 3 R (10) 3 API- 2 -Me 2 - Cocrystal R (10) 3 3 Form C 3 R (10) 3
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)
Squaramides in Supramolecular Synthons: a case study
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
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
The anti/syn synthon is also geometrically favorable 2 + Et Very insoluble 2
Conformational Equilibrium in Solution (CDCl 3 ) c c b a a b c
2D-MR Dilution Experiment c c b a a b c 240 K 10 9 8 ppm
Thermodynamic Equilibrium in Solution Approximate Values of the Equilbrium Constants K CM K CD K Dab K Dc 790 2.5 0.56 8600
Molecular Electrostatic Potential Surface ighest β value ighest α value unter, C. A. Angew. Chem. Int. Ed. 2004, 43, 5310-5324
Solution vs Solid State β Ο 5.1 α 2.1 β 4.2 1 β 5.1 β 4.0 α 2.8
Solution vs Solid State α 2.8 β 4.0 β 5.1 α 2.1 β 4.2 β Ο 5.1 1 1a 1b 1c
Two Polymorphs ^exo Solid-solid transition
Two Polymorphs ^exo Melting and crystallization
Two Polymorphs Solid transition 120 ºC 130 ºC 150 ºC Melting Solid transition Crystallization from the melt
Two Polymorphs Form I Form II R 2 2 (10) irshfeld s Surfaces
Two Polymorphs Form I Form II R 2 2 (10) irshfeld s Surfaces
Breaking the head-to-tail motif β 4.2 α 2.9 β 4.8 2 MEP Surface β > β
α 2.9 β 4.8 β 4.2 2 β > β 2c 2a 2b or Breaking the head-to-tail motif
Breaking the head-to-tail synthon β 4.2 α 2.9 R 2 2 (12) β 4.8 2 β > β
Stronger competitors cannot inhibit the head-to-tail synthon β = 4.3 α = 3.4 β = 4.9
SQ head-to-tail as a scaffold for new cocrystal structures
SQ head-to-tail as a scaffold for new cocrystal structures
SQ head-to-tail as a scaffold for new cocrystal structures
Cocrystal Screening Fumaric acid squaramide cocrystal Synthons not found
SQ head-to-tail as a scaffold for new cocrystal structures
Cocrystal Screening Fumaric acid squaramide cocrystal
SQ head-to-tail as a scaffold for new cocrystal structures
Plataforma de Polimorfisme i Calorimetria Acknowledgements Dr. Cristina Puigjaner Rafa Barbas Anna Portell Dr. Xavier Alcobé Dr. Mercè Font-Bardia