Solid-State NMR Utility in API and Formulation Process Development

Robert WenslowVP Business DevelopmentCrystal Pharmatechwww.crystalpharmatech.com

*BiopharmaceuticsOrganic Process Granulation Bulk API CharacterizationIn Formulation Samples Tableting In vivo performance ExcipientInteractions Produce Stable,Single Phase Bulk EngineeringProcessingConditions SolventStystem MillingIssues Compaction AnalyticalPhys/ChemStability Spec.Justification Areas of Application

*Salt Disproportionation

Polymorphs

Solvates and Hydrates

Amorphous dispersions

Motivation is regulation

Challenging Pharmaceutical Issues

*Solid-State NMRhttp://www.dur.ac.uk/resources/SSNMR/Training_course_PH.pdfMolecular TumblingRigid SolidOrientation leads to CS difference

*Cross-Polarization (CP/MAS)J. Chem. Phys. 1973, 59, 5691H13CDetectDecouple(90)Contact TimeSignal IntensityContact TimeSignal Buildup through dipole coupling (D)

K-salt disproportionates in water to the free acid

19F NMR was used to determine the kinetics

Fast experiments, quantitative information

Can also probe in formulationStructure: Disproportionantion*

Chart6

16.8

18.9

19.8

45.1

47.5

52.6

88

Disprop

Time (Hrs)

% Disproportionated

Sheet1

TimeDisprop

116.8

318.9

519.8

845.1

1647.5

2452.6

4888

0.006295

25.15336

0.0062064613

1.0142655753

0.0883798612

Sheet1

Disprop

Time (Hrs)

% Disproportionated

Sheet2

Sheet3

Lower decoupling obscures Ns connected to H

Disappearance of 2 peak predicted

Salt forms at 3 Nitrogen

Contact time can also be used to discriminateUseful information but long measuring times*Structure: Salt Formation

19F NMR spectra of I and II19F relaxation curves for I and IIAt 8.5 seconds FII shows zero signal

19F relaxometry can be used*Polymorph Quantitation

Chart1

-0.5807269-0.4939289

-0.5810331-0.4942855

-0.5568303-0.4558982

-0.5507627-0.4184494

-0.4175438-0.1495996

-0.27229190.1078467

0.075989820.5871925

0.470460.8698628

0.81680510.9658363

0.9867451

11

Form I

Form II

Form I-II D1=300 Sec

Time (sec)Form IForm ITime (sec)Form IIForm II

1.00E-04-5.81E-011.58E+004.58E-011.00E-04-4.94E-014.01E-01

1.00E-03-5.81E-011.58E+004.58E-011.00E-03-4.94E-014.02E-01

5.00E-01-5.57E-011.56E+004.43E-015.00E-01-4.56E-013.76E-01

1.00E+00-5.51E-011.55E+004.39E-011.00E+00-4.18E-013.50E-01

5.00E+00-4.18E-011.42E+003.49E-015.00E+00-1.50E-011.39E-01

1.00E+01-2.72E-011.27E+002.41E-011.00E+011.08E-01-1.14E-01

2.50E+017.60E-029.24E-01-7.90E-022.50E+015.87E-01-8.85E-01

5.00E+014.70E-015.30E-01-6.36E-015.00E+018.70E-01-2.04E+00

1.00E+028.17E-011.83E-01-1.70E+001.00E+029.66E-01-3.38E+00

2.00E+029.87E-011.33E-02-4.32E+002.00E+021.00E+00

3.00E+021.00E+000.00E+003.00E+021.00E+00

42.4626647021

25.4452926209

19.4234779062

10.2151930461

Form I-II D1=300 Sec

00

00

00

00

00

00

00

00

00

0

Form I

Form II

Time (sec)

ln((Me-Mt))

FORM I-II D1=150sec

00

00

00

00

00

00

00

00

00

00

00

Form I

Form II

Time (sec)Form IForm ITime (sec)Form IIForm II10%formI

1.00E-04-5.31E-011.53E+004.26E-011.00E-04-4.96E-014.02E-01-4.99E-01

5.00E-04-5.24E-011.52E+004.21E-015.00E-04-4.98E-014.04E-01-5.01E-01

1.00E-03-5.28E-011.53E+004.24E-011.00E-03-4.99E-014.04E-01-5.02E-01

1.00E-01-5.22E-011.52E+004.20E-011.00E-01-4.93E-014.00E-01-4.96E-01

5.00E-01-5.13E-011.51E+004.14E-015.00E-01-4.58E-013.76E-01-4.63E-01

1.00E+00-4.93E-011.49E+004.01E-011.00E+00-4.21E-013.51E-01-4.29E-01

5.00E+00-3.61E-011.36E+003.08E-015.00E+00-1.47E-011.37E-01-1.69E-01

1.00E+01-2.19E-011.22E+001.98E-011.00E+011.20E-01-1.29E-018.59E-02

2.50E+011.36E-018.64E-01-1.46E-012.50E+016.03E-01-9.26E-015.56E-01

5.00E+015.17E-014.83E-01-7.27E-015.00E+018.95E-01-2.27E+008.58E-01

1.00E+028.66E-011.34E-01-2.01E+001.00E+021.00E+009.87E-01

1.50E+021.00E+000.00E+001.50E+029.99E-019.99E-01

1.5398730839

1.4981035377

18.7371182312

41.4937759336

1.28445

0.1493546512

0.26759375

d1=150 seconds

-0.5307115-0.4958495

-0.5237158-0.4981392

-0.5275536-0.4990657

-0.5223509-0.4925636

-0.5134394-0.4579279

-0.4927269-0.4213933

-0.3609177-0.1474032

-0.21891840.1198224

0.13559550.6029713

0.51675220.8954934

0.86575741

10.9991535

Form I

Form II

0.425732660.4021282135

0.42115195690.4036586107

0.42366750150.4042772028

0.42025578480.3999278725

0.4143848090.3764353939

0.40060458150.3510418679

0.30815925160.136763277

0.1979639081-0.1285937742

-0.1457144484-0.9258810725

-0.7272257134-2.2666380015

-2.0081066682

Form I

Form II

Time (sec)

ln(Me-Mt)

d1=150 seconds

CP discriminates against the more mobile regions

DP discriminates against the more rigid regions

Spectral editing combination is powerful to study solvates* Peaks from EtOHSplit CH3 indicates multiple environmentsStraight forward measurements High information contentForm II CP/MASForm II DP/MAS*Solvate Identification

19F SSNMR was used, measurements done at 5 oC

Formulation: API + PEG 600

At 40 mgs/mL API completely dissolved

At 80 and 100 mgs/mL shoulder observedL454 Freebase*API in Drug Product

Expanded spectrumShoulder at 80 and 100 mgs/mL due to crystalline freebase.Rapid measurements, quantitative estimation of solubility possible.*API in Drug Product

1H NMR was used

Rigid: Gaussian

Mobile: Lorentzian

Fitting provides quantitationAmorphous content 22.5%

Extremely rapid measurements, quantitative

No chemical shift resolution*Amorphous API

Amorphous has a very short T1 ~ 250 ms

Crystal had a very long T1 ~ 25 sec31P NMRMaterial stuck on pins ~ 12 wt% amorphous 10X compaction at 200 MPa (RT) ~ 5 wt%10X compaction at 200 MPa (85 oC) ~ 2 wt%*Amorphous API

Broadening due to defects or phase separated amorphous??*Amorphous API

M(tau)/M0= 1-2*exp(-tau/T1) Each Phase in multi-phase system will yield unique T1 value*Amorphous API

Can detect amorphous content without any apriori knowledge of system. Was also used identify presence of multiple crystalline phasesMonitoring in-process samples*Amorphous API

Intensity directly proportional to amorphous contentQualitative amorphous content readily achievedLOD exceedingly low (limited only by NMR time)Quantitation requires calibration curveMonitoring stability samples*Amorphous API

*DECRA

*19F CP/MASDECRAComponent 2200msec T1rho65% of total spectraComponent 139msec T1rho35% of total spectraStability SamplePrevious ID of multiple Phases by 1H T1rho Filter1H T1rho DECRA

*Can we quantify second phaseAPI process involves desolvation to get the anhydrous formMaterial forms amorphous on compactionA second phase observed in 19F SSNMR spectra for different batches Similar XRPD and DSC19F CP/MASXRPDDECRAPolymorph ID

*1H T1r DECRA

19F CP/MASComponent 26msec T1rho20% of total spectraComponent 120msec T1rho80% of total spectraDECRADECRA

*Wet milling in IPAc followed by Drying at 50 oC recommendedDECRADriving Process Definition

Chart2

533314

56368

75250

46540

62308

90100

75250

10000

10000

Component I

Component II

Component III

Wt% of component

Sheet1

FilenameSampleEXPNOExp

30Jan06l395bFZ0066 to 85T1rhoDECRA

30Jan06l395bFZ0061CPMAS

01Feb06l395FZ006 heated1 to 66T1rhoDecra

01Feb06l395FZ006 heated67CPMAS

SampleComponentT1rho (m)Wt%

Z00611353

Z00622233

Z0063314

Z006 Heated11156

Z006 Heated22136

Z006 Heated318

Acetone Slurry11162

Acetone Slurry22530

Acetone Slurry338

Acetonitrile Slurry11275

2625

Continued Slurry11590

2*510

*2nd component believed due to difference in 1H T1rho of fluorophenyl and CF3

Will be tested using smaller sweep width to only include CF3 Iso

224032-78-211475

2425

Z00816**46

216*54

12.6666666667

desolvate1161003.6666666667

2022.6666666667

Z008 IPAC Desolvated 80C11587

2313

acetone solvate desolvated at 80 oC11780

2520

Z008 IPAC Desolvated 80C114100

PACKED LOOOSELY

0248637-0003-1

223052-95 dried at 80 oC12082

2518

223052-95 heat cycled on NMR11690

2210

0248637-0003-111950

223052-95 ground mortar pestle2750

0248637-0003-111577

Temp Cycled 70C o/n2723

225032-99-112090

dried at 80 oC2310

225032-99-211793

dried at 50 oC247

Sheet2

SampleComponent IComponent IIComponent IIISampleComponent IComponent IIComponent III

Z006 as received533314225032-99-1 dried at 25533314

Z006 heated to 80 oC56368225032-99-1 dried at 50 oC56368

Z006 slurry in acetonitrile75250225032-99-1 dried at 80 oC75250

Z008Z00846540

Z008 slurry in acetone62308

Z008 slurry in acetone-heptane90100

224032-78-275250

Ipac desolvate at 50 oC10000

Z008 slurry in Ipac heated to 80 oC10000

11-16 ms21-25 ms1-6 ms

Sheet2

000

000

000

000

000

000

000

000

000

Component I

Component II

Component III

Wt% of component

Sheet3

MBD00E0ACA6.wmf

MBD00E0BC98.wmf

MBD00E0C556.wmf

MBD00E0B268.wmf

*1H T1r DECRA13C CP/MASComponent 291msec T1rho22% of total spectraComponent 1193msec T1rho78% of total spectraDECRAMy API doesnt have a 19F

T1rhoWt%Comp 113370Comp 25530

Heteronuclear Dipolar Correlation1H-13C, 1H-15N, and 1H-23Na HETCOR spectra for a hydrated APICryst. Growth & Des., 2006, 6, 2333-2354.Correlations indicate atoms near in space (~3 )13C15N23Na1H*

* Amorphous Dispersions

2D 1H-19F Correlation1H-19F CP-HETCOR easily proves molecular association on the < 10 scaleExperiments such as these take 1-2 hours to perform for typical drug loads (20-60% w/w)500 s2 ms (spin diffusion)Mol. Pharmaceutics, 7, 16671691 (2010).PVPSolid amorphous solutionDiflunisal

Amorphous DispersionsA dispersion that greatly improves the dissolution of tenoxicam in water (via a high degree of supersaturation)Contains four discrete componentsPolyvinylpyrrolidineSolid amorphous solution= tenoxicam (singly ionized)= L-arginine (singly ionized)= L-arginine (zwitterionized)J. Pharm. Sci. 2012, 101, 641-663.

Nanocrystallline dispersionPharm. Res. 2012, 29, 1866-1881PolymerCrystallineDomains~50 nm

*Concluding ThoughtsMultitude of options to characterize API and drug product material

Relaxation methodology very powerful

Expanding into 2D offers significant structure information