Polymorph Screening Strategies and a Concomitant Polymorph Case Study

Transcription

1 Polymorph Screening Strategies and a Concomitant Polymorph Case Study Aniruddh Andy Singh, Ph.D. Mahmoud Mirmehrabi, Ph.D., P.Eng. Johnson Matthey Pharma Services Chemical and Crystallization Research & Development Information Sharing Symposium 25-April-2013

2 Motivation for Solid Form Screening Majority of APIs (Active Pharmaceutical Ingredients) exhibit polymorphism: May have significant legal, financial and medical implications Polymorphism could have significant impact on API and drug product properties Number of incidents forced pharmaceutical companies to withdraw their drugs from market or repeat some clinical tests Ritonavir: Introduced in 1996, two years after entry into the market, several lots of capsules began failing dissolution specifications Lower energy, more stable polymorph appeared: Slowed dissolution of marketed dosage form and compromising the oral bioavailability of the drug At considerable cost new formulation was eventually developed and launched (estimated $250 million of sales for the entire year of 1998 plus R& D costs) Morissette et al. (2003), PNAS, 100 (5), pp

3 Motivation for Solid Form Screening FDA Guidance for Industry on ANDAs (Abbreviated New Drug Applications): Pharmaceutical Solid Polymorphism Contains FDA recommendations on assessing sameness when the drug substance exists in polymorphic forms Polymorphism and Sameness in ANDAs: Differences in drug substance polymorphic forms do not render drug substances different active ingredients for the purposes of ANDA approvals within the meaning of the Act and FDA regulations Important to get IP protection on all forms of an API Guidance for Industry, ANDAs: Pharmaceutical Solid Polymorphism, Chemistry, Manufacturing, and Controls Information, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), July 2007, OGD 3

4 Motivation for Solid Form Screening Examples of cases that FDA approved Generic ANDAs of a different polymorph/hydrate from the drug substance in the Reference Listed Drug (RLD) Ampicillin Cefadroxil Famotidine Ranitidine Terazosin hydrochloride Warfarin sodium Guidance for Industry, ANDAs: Pharmaceutical Solid Polymorphism, Chemistry, Manufacturing, and Controls Information, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), July 2007, OGD 4

5 Solid Forms Important Parameters Mixing Solvent Type Drying Regime Crystallization Regime Seeding Solid Forms Additives Impurities Grinding Epitaxial Growth Supersaturation 5

6 Solid Form Screening Standard Screening Slurry Ripening Evaporation Cooling Amorphous Slurrying Solvent Vapor Diffusion High/Low Humidity Anti-Solvent (Direct and Reverse) Grinding (Wet and Dry) Thermal Treatment Comprehensive Screening All Standard Techniques Anti-Solvent Diffusion Crystallization with Additives/Templates Compression Spray Drying Lyophilization Disproportionation of Weak Salts ph Change 6

7 Standard Polymorph Screening Workflow Phase I (Characterization) Starting Solid DSC, TGA XRPD Dry (same sample) Y XRPD, DSC, TGA, NMR, KF, DVS (w/post-xrpd), high humidity form stability 48 hr Slurrying, ~ 24 solvents 1, (2 Temp points) Phase II Solubility Data DSC, TGA Evap. Cryst. (Phase II) New XRPD (wet/dry) Stop N New XRPD? Wet solids Centrifugation Supernatant Evaporation 1- Mirmehrabi and Rohani, 2005, An Approach to Solvent Screening for Crystallization of Polymorphic Pharmaceuticals and Fine Chemicals, J. Pharm. Sci., vol. 94, No. 7,

8 Standard Polymorph Screening Workflow Phase II (Screening) Phase II Design of screening experiments (completed in Phase I) Cooling, anti-solvent, thermal treatment, solvent vapor diffusion, dry and wet grinding, evaporation (completed in Phase I) etc. Amorphous material generation and slurrying All new XRPD patterns analyzed wet and dry, followed by DSC and TGA Phase III 8

9 Standard Polymorph Screening Workflow Phase III (Scale up/thermodynamic Stability) Phase III Scale up of new crystal forms (~ 200 mg) XRPD, DSC, TGA, NMR, IR, KF, microscopy, DVS, solid form stability at high RH Relative thermodynamic stability of forms (Competitive slurry, thermal data, solubility etc.) Identification of most viable polymorph for development Process Development 9

10 Crystallization Process Development 10

11 Polymorph Screening Example Compound 1 Eight forms obtained (Forms A to H) including five known polymorphs (A, B, C, D, E) and three new forms (F, G and H) The five known forms of Compound 1 had been obtained in two separate studies Over 100 experiments carried out (ml scale) 6 forms obtained in Phase I including the most stable polymorph 2 additional forms obtained in Phase II Competitive slurry experiments (using Forms A to H) confirmed Form A is thermodynamically most stable at room temperature Timeline: 4 weeks 11

12 Concomitant Nucleation of ROY 12

13 Concomitant Nucleation of ROY Polymorph Screening Recrystallization from solution widely used to discover polymorphs Various crystallization factors controlled Does not guarantee the discovery of all polymorphs Concomitant Nucleation Simultaneous nucleation and growth of solid forms Different polymorphic forms created under seemingly identical conditions Competing kinetic and thermodynamic factors direct the crystallization of polymorphs * Brittain, H.G., Polymorphism in Pharmaceutical Solids, Marcel Dekker, New York,

14 Concomitant Nucleation of ROY Crystallization on bifunctional patterned gold islands Polymorph characterization by Raman Spectroscopy 725 μm Crystallization Solution 14

15 Concomitant Nucleation of ROY ROY ROY 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile ROY Red, Orange and Yellow crystals 10 polymorphs including 7 with solved structures Most polymorphic system of known structures Crystallization on bifunctional patterned gold islands Study concomitant nucleation and the stochastic nature of nucleation from solution Effect of increasing the number of crystallization trials on polymorphs crystallized 15

16 Concomitant Nucleation of ROY Polymorphs of ROY With solved structures Y Yellow Prism (most stable) OP** Orange Plate ON Orange Needle YT04* Y04 Transformed R Red Prism YN Yellow Needle ORP** Orange Red Plate Structure not yet solved Red Plate RPL Yellow (2004) Y04 Red (2005) R05 *Prepared by melt crystallization/seeding in literature **Only preparation by seeding reported in literature Chen et al. J. Am. Chem. Soc. 2005, 127,

17 Concomitant Nucleation of ROY ROY Crystallization Experiments Experiment No. Concentration (M) No. of islands Crystallization time Monolayer Forms Obtained ~ 4 days 4-MBA ON, R, Y, YN, YT ~ 1 week 3-MPA ON, R, Y, YN ~ 2 weeks 3-MPA ON, R, Y, YN ~ 3 weeks 3-MPA ON, R, Y, YN 17

18 Concomitant Nucleation of ROY Microscope Image of ROY Crystals on Gold Islands ROY crystals on 725 μm islands 18

19 Concomitant Nucleation of ROY Crystallization Trials to Study Concomitant Nucleation islands analyzed 725 μm islands used with M ROY in DMSO solution Crystallization time ~ 1 week T! P ( T, Si, k) = ( k) (1 k) ( T S )!( S )! i i S i T-S i Probability of failure to obtain particular polymorphs calculated 19

20 Concomitant Nucleation of ROY Crystallization Trials Key Result Form ORP Crystals Obtained ROY polymorphs obtained during crystallization trials Orange Red Plate crystals on a 725 μm island 20

21 Concomitant Nucleation of ROY Probability of failure to crystallize particular polymorphs for 100 trials Polymorph P i P i range (99% confidence) P (T=100, S i =0, P i =k) P range (99%) (T=100, S i =0, P i =k) Y 0.38 (0.37, 0.39) 3 x (2x10-20, 4 x ) ON 0.27 (0.26, 0.28) 4 x (2 x 10-13, 9 x ) R 0.15 (0.14, 0.16) 1 x 10-7 (3 x 10-7, 4 x 10-8 ) YT (0.0021, ) 0.70 (0.81, 0.61) YN (0.0005, ) 0.87 (0.95, 0.79) ORP (0.0002, ) 0.91 (0.98, 0.85) Estimated probabilities of yielding particular ROY polymorphs on an island (P i ) and the probability of failure to crystallize particular polymorphs for 100 trials. 21

22 Concomitant Nucleation of ROY Significant Results Forms YT04 and ORP (without seeds) obtained from solution crystallization 6 out of 7 stable polymorphs of ROY obtained under almost identical conditions 3 polymorphs obtained in very low percentages (< 1% of total trials) Form Orange Red Plate obtained only after trials were conducted ~ 200 mg ROY used for independent crystallization trials 22

23 Questions? 23

24 Solid Form Screening/Characterization Equipment Bruker D8 Advance X-ray Powder Diffractometer Differential Scanning Calorimetry (DSC) Thermal Gravimetric Analysis (TGA) Dynamic Vapor Sorption (DVS) Polarized Microscope Equipped with Hot Stage, Digital Camera and Image Analysis Software Malvern Particle Size Analyzer Attenuated Total Reflectance (ATR) FTIR Liquid Nuclear Magnetic Resonance (NMR) Karl Fischer Temperature Controlled Centrifuge Temperature Controlled 48-wells Crystallization Blocks 24

25 Polymorph Screening Work Flow Phase 1 Batch Profiling and Design of Screening Experiments Characterization of the starting solid Solubility assessment of starting solid Design of the polymorph screening experiments Phase 2 Polymorph Screening Generation of amorphous material Screening experiments Phase 3 Polymorphs Characterization Scale up of new crystal forms Establish the thermodynamic relative stability of forms using one or all of the following techniques Comparison of thermal properties of anhydrous forms, e.g. heat of fusion and melting point Solubility differences Determining whether the forms are enantiotropically or monotropically related. Slurry stability of forms at two different temperatures and 3 solvents 25