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Solid-State NMR Utility in API and Formulation Process Development Robert Wenslow VP Business Development Crystal Pharmatech www.crystalpharmatech.com Slide 2 2 Biopharmaceutics Organic Process Granulation Bulk API Characterization In Formulation Samples Tableting In vivo performance Excipient Interactions Produce Stable, Single Phase Bulk Engineering Processing Conditions Solvent Stystem Milling Issues Compaction Analytical Phys/Chem Stability Spec. Justification Areas of Application Slide 3 3 Salt Disproportionation Polymorphs Solvates and Hydrates Amorphous dispersions Motivation is regulation Challenging Pharmaceutical Issues Slide 4 4 Solid-State NMR http://www.dur.ac.uk/resources/SSNMR/Training_course_PH.pdf Molecular Tumbling Rigid Solid Orientation leads to CS difference Slide 5 5 Cross-Polarization (CP/MAS) J. Chem. Phys. 1973, 59, 569 1H1H 13 C Detect Decouple (90) Contact Time Signal Intensity Contact Time Signal Buildup through dipole coupling (D) 1H1H 13 C D 1/r 6 Slide 6 ** K-salt disproportionates in water to the free acid 19 F NMR was used to determine the kinetics Fast experiments, quantitative information Can also probe in formulation Structure: Disproportionantion 6 Slide 7 Lower decoupling obscures Ns connected to H Disappearance of 2 peak predicted Salt forms at 3 Nitrogen Contact time can also be used to discriminate 4 3 Useful information but long measuring times 7 Structure: Salt Formation Slide 8 19 F NMR spectra of I and II 19 F relaxation curves for I and II At 8.5 seconds FII shows zero signal 19 F relaxometry can be used 8 Polymorph Quantitation Slide 9 CP discriminates against the more mobile regions DP discriminates against the more rigid regions Spectral editing combination is powerful to study solvates * Peaks from EtOH Split CH 3 indicates multiple environments Straight forward measurements High information content Form II CP/MAS Form II DP/MAS 9 Solvate Identification Slide 10 19 F SSNMR was used, measurements done at 5 o C Formulation: API + PEG 600 At 40 mgs/mL API completely dissolved At 80 and 100 mgs/mL shoulder observed L454 Freebase 10 API in Drug Product Slide 11 Expanded spectrum Shoulder at 80 and 100 mgs/mL due to crystalline freebase. Rapid measurements, quantitative estimation of solubility possible. 11 API in Drug Product Slide 12 1 H NMR was used Rigid: Gaussian Mobile: Lorentzian Fitting provides quantitation Amorphous content 22.5% Extremely rapid measurements, quantitative No chemical shift resolution 12 Amorphous API Slide 13 Amorphous has a very short T 1 ~ 250 ms Crystal had a very long T 1 ~ 25 sec 31 P NMR Material stuck on pins ~ 12 wt% amorphous 10X compaction at 200 MPa (RT) ~ 5 wt% 10X compaction at 200 MPa (85 o C) ~ 2 wt% 13 Amorphous API Slide 14 Broadening due to defects or phase separated amorphous?? -130-120-110-100-90 Time = 0 2 weeks ambient 2 weeks 25C/60%RH 2 weeks 40C/75%RH 14 Amorphous API Slide 15 M(tau)/M0= 1-2*exp(-tau/T1) -130-120-110-100-90 Pure Crystalline T1 = 5 seconds Pure Amorphous T1 = 1 second Each Phase in multi-phase system will yield unique T1 value 15 Amorphous API Slide 16 -130-120-110-100-90 End of Drying Sample (MAS) T1 Filter 2.55 sec Can detect amorphous content without any apriori knowledge of system. Was also used identify presence of multiple crystalline phases Monitoring in-process samples 16 Amorphous API Slide 17 -130-120-110-100-90 Time = 0 2 weeks ambient 2 weeks 25C/60%RH 2 weeks 40C/75%RH Intensity directly proportional to amorphous content Qualitative amorphous content readily achieved LOD exceedingly low (limited only by NMR time) Quantitation requires calibration curve Monitoring stability samples 17 Amorphous API Slide 18 18 DECRA Slide 19 19 19 F CP/MAS DECRA Component 2 200msec T1rho 65% of total spectra Component 1 39msec T1rho 35% of total spectra -100-80-60-40 -20 Stability Sample Previous ID of multiple Phases by 1 H T 1rho Filter 1 H T 1rho DECRA Slide 20 20 Can we quantify second phase API process involves desolvation to get the anhydrous form Material forms amorphous on compaction A second phase observed in 19 F SSNMR spectra for different batches Similar XRPD and DSC 19 F CP/MASXRPD DECRA Polymorph ID Slide 21 21 -CF 3 F 1 H T 1 DECRA 19 F CP/MAS Component 2 6msec T1rho 20% of total spectra Component 1 20msec T1rho 80% of total spectra DECRA Slide 22 22 Wet milling in IPAc followed by Drying at 50 o C recommended DECRA Driving Process Definition Slide 23 23 1 H T 1 DECRA Through 19 F 1 H T 1 DECRA 13 C CP/MAS Component 2 91msec T1rho 22% of total spectra Component 1 193msec T1rho 78% of total spectra T 1rho Wt% Comp 113370 Comp 25530 DECRA My API doesnt have a 19 F Slide 24 Heteronuclear Dipolar Correlation 1 H- 13 C, 1 H- 15 N, and 1 H- 23 Na HETCOR spectra for a hydrated API Cryst. Growth & Des., 2006, 6, 2333-2354. Correlations indicate atoms near in space (~3 ) 13 C 15 N 23 Na 1H1H 24 Slide 25 25 Amorphous Dispersions Slide 26 2D 1 H- 19 F Correlation 1 H- 19 F CP-HETCOR easily proves molecular association on the < 10 scale Experiments such as these take 1-2 hours to perform for typical drug loads (20-60% w/w) 500 s 2 ms (spin diffusion) Mol. Pharmaceutics, 7, 16671691 (2010). n N O OH OHO FF PVP Solid amorphous solution Diflunisal Slide 27 Amorphous Dispersions A dispersion that greatly improves the dissolution of tenoxicam in water (via a high degree of supersaturation) Contains four discrete components Polyvinylpyrrolidine Solid amorphous solution = tenoxicam (singly ionized) = L-arginine (singly ionized) = L-arginine (zwitterionized) J. Pharm. Sci. 2012, 101, 641-663. Slide 28 Nanocrystallline dispersion Pharm. Res. 2012, 29, 1866-1881 Polymer Crystalline Domains ~50 nm Slide 29 29 Concluding Thoughts Multitude of options to characterize API and drug product material Relaxation methodology very powerful Expanding into 2D offers significant structure information