Experimental and Computational Techniques for Overcoming the Challenges of Quantitative Crystallinity Measurements Using Terahertz Spectroscopy

Transcription

1 Experimental and Computational Techniques for Overcoming the Challenges of Quantitative Crystallinity Measurements Using Terahertz Spectroscopy Mark Sullivan, Edward King, David Heaps, Xiao Hua Zhou, Richard McKay and Wiphusanee Dendamrongvit* Advantest America, Inc., Princeton, NJ *Oncobiologics, Inc., Cranbury, NJ IFPAC 2014, Arlington, VA

2 Outline Introduction to THz Instrumentation Challenges for Quantitative THz Measurements Quantitative Crystalline/ Amorphous Content Applications for Pharmaceuticals Taking Advantage of Physical Effects 2

3 TAS7500SP unit block diagram Time domain waveform Laser 1 emitter Synchronized Control Laser 2 detector Amplitude (a.u.) Time (ps) Frequency domain spectrum sample A/D FFT 3

4 Measurement Unit and Sample Stage 4

5 Optical Parameters Related to Transmission Scattering Absorption Transmission Reflection E(ω) ssssss E(ω) rrrrrrrrr = T η ω eee α(ω)d 2 + iη(ω)ωd c α(ω), absorption coeff η(ω), refractive index d, thickness c, speed of light 5 Wallace et al., Terahertz pulsed imaging and spectroscopy for biomedical and pharmaceutical applications. Faraday Discuss. 126, 1 9.

6 Challenges for Quantitative THz Measurements Particle Size - Scattering Sample Loading - Absorption Sample Saturation Sample Porosity - Scattering Change in refractive index Non-uniformities Moisture Content - Absorption 6

7 Particle Size Scattering Effects: smaller is better Particle Size, microns Less than Greater than μm 200μm 115μm 7

8 Particle Size Averaging Replicates with Different Orientations to Reduce Scattering Effects Particle Size, microns Less than Greater than

9 Particle Size Extended MSC modeling of scattering effects Particle Size, microns Less than Greater than

10 Porosity Powder Compacts Made With Varying Compaction Force 200 g Sample Weight 10mm Diameter Compaction Force, kn Path Length, mm

11 Sample Loading Linear Response Range vs. wt% Sample (threshold for sample saturation) Absorbance vs. Air Reference Frequency, THz

12 Sample Loading THz Transmission Spectra of Amorphous Polymers Polymer Pellets 100 mg Sample Weight 10 mm Diameter PVP Kollidon VA64 Methocel HPC HPMC Avicel PH102 PEG 12

13 Typical Quantitative Pharmaceutical Measurements Using THz Spectroscopy Polymorphism - Polymorph composition - Solid form conversion Hydration/Solvation Tablet Composition - API - Excipients Crystalline/Amorphous content - API - Amorphous Dispersions 13

14 XRPD and THz Spectroscopy Measure Crystallinity Directly Lactose H 2 O Microcrystalline cellulose XRPD THz

15 Crystallinity in an Amorphous Matrix Calibration Set 0.6 to 10% Crystalline Content Lactose Monohydrate in MCC THz Transmission Spectra SNV Normalized 15

16 Crystallinity in an Amorphous Matrix Calibration Set 0.6 to 10% Crystalline Content Lactose Monohydrate in MCC THz Transmission Spectra Savitzky-Golay 1 st derivative 16

17 Crystallinity in an Amorphous Matrix Multivariate Calibration and Validation with an Independent Test Set Calibration Validation 17

18 Amorphous in a Crystalline Matrix Calibration Set 0.6 to 8% Amorphous Content Variable Selection for PLS Modeling 18

19 Amorphous in a Crystalline Matrix Multivariate Calibration and Cross- Validation Calibration Cross-Validation 19

20 THz Scattering at Interfaces Controlled atmosphere packaging integrity Layer 1 Layer 2 Layer 3 t 0 t 1 t 2 t 3 Layer 2 Layer 1 Layer 3 250µm 60µm 310µm t 0 t 1 t 2 t 3

21 Porosity Measurement of Refractive Index in 100g tablets of MCC with Varying Compaction Force 1.9 Compaction of MCC Refractive Index 0.8 THz Compaction Force (kn) 21

22 Porosity Calibration of Refractive Index vs. Porosity Compaction of MCC % pppppppp = 1 eeeeeeee ddddddd tttt ddddddd 100 Refractive Index Fresh tablet Relaxed tablet Porosity (%) 22

23 Conclusions Optical effects must be considered in method development and robustness testing for quantitative THz spectroscopy THz spectroscopy is sensitive to physical changes that may affect product quality - e.g., particle size distribution, porosity of powder compacts THz spectroscopy is suitable for quantitative measurement of both Crystallinity in an Amorphous Matrix and Amorphous Content in a Crystalline Matrix - THz spectroscopy is dominated by long range lattice vibrations and is specific for crystallinity Physical effects in THz spectroscopy provide to means to measure material properties in solids - Layer thickness - Porosity 23

24 Thank you for your attention