Decreasing Time-to-Market via Synchrotron Utilization to Discover Stable Formulation
- 1. Pamela A. Smith, Ph.D. pam@leadingsmartscience.com (765)412-2677 1 Decreasing Time-to-Market via Synchrotron Utilization to Discover Stable Formulation Focus on Finding a Solid Form that will Increase Exposure
- 2. Outline 2
- 3. Outline Decrease time to market ⚫ fIND ⚫ Synchrotron ⚫ Amorphous complexes Predict/anticipate stability ⚫ Synchrotron Sameness and problem solving ⚫ Synchrotron 3
- 4. DECREASE TIME TO MARKET 4
- 5. 5 Expensive, long, risky, highly regulated 8-10 years development Billion dollar development cost for a new drug Classical New Drug R&D
- 6. 6 Chorus Timeframe & Costs ⚫ Timeframe (Chorus) • Ind. Av.: 42 mo. • Chorus: 30 mo. ⚫ Costs (Chorus) • Ind. Av.: $30M • Chorus: $3M
- 7. Byrn/Chen EAS2018 7 New Business Model ➢ Accelerating Proof-of-Concept Study Phase I and Phase IIa ➢ Make amorphous complexes of most candidates for accelerated toxicology and early animal studies ➢ Faster turnaround, more opportunities
- 8. 8 fIND Strategy – Improved Pharma
- 10. The Advanced Photon Source 10
- 11. 11 Synchrotron high energy x-ray experiment
- 12. Resources Advanced Photon Source (Argonne) ⚫ Chris Benmore National Synchrotron Light Source (Brookhaven) ⚫ Simon Billinge Swiss Light Source (Paul Scherrer Institute) ⚫ Excelsus Structural Solutions 12
- 13. GO DIRECTLY TO COMPLEXES 13
- 16. Solid SEDDS-like Formulation Drug Alcohol Non-ionic surfactant Triglyceride Example - Ritonavir 16
- 17. Ritonavir + surfactants + polymers 17 I. Tho et al. / European Journal of Pharmaceutical Sciences 40 (2010) 25–32 Only the complexes give a nano- suspension
- 18. Amorphous Complexes 18 Log in Samples Make Complexes Stability 1 Week X-ray Argonne PDF Diff. PDF PDF Action Spray-dry Evaporation X-ray Argonne PDF Diff. PDF Scale up
- 19. Design Complexes Utilize structural knowledge of drug and excipients Utilize literature on solid SEDDs formulations Utilize literature on hydrogen bonding Utilize solution NMR to test association and chemical shift changes 19
- 20. SYNCHROTRON 20
- 21. PDF Structure Analysis – Domains in Drug Amorphous Preparations 21 Arrows Represent Nearest Neighbor (NN) and NNN and NNNN Contacts Benmore, Byrn, et a., Journal of Pharmaceutical Sciences (2013), 102(4), 1290-1300.
- 23. Need to Work at a Synchrotron for PDF 23
- 24. Lapatinib PDF – Left HPMC, Right HPMCP - Differential PDFs are Shown 24 Pure LP 3:1 1:1 1:3 Pure LP 3:1 1:1 1:3 This is the only dispersion lacking domains
- 25. N-15 SSNMR of Lapatinib with HPMCP 25
- 26. SYNCHROTRON “LAB ON A DROP” TO SAVE MATERIAL 26
- 28. Amorphous Screen Using Levitated Drops 28 http://www.youtube.com/watch?v=669AcEBpdsY
- 29. Levitation Equipment on Beamline 11- ID-C 29 Each drop contains about 0.1 mg of drug (assuming solubility = 10 mg/mL)
- 30. Fast Evaporation in Levitator 30 Complete evaporation takes about 16 min
- 31. X-ray Patterns from Levitation Experiments 31 -2000 0 2000 4000 6000 8000 10000 12000 14000 0 2 4 6 8 x-rayintensity(abs.counts) Q (A-1) 4-Bromoacetanilid -2000 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 0 2 4 6 8 x-rayintensity(abs.counts) Q (A-1) Itraconazole Ketoconazole Ritonavir efavirenz
- 32. Acoustic Levitation – A First Step in Finding the Right Formulation Avoids need for large quantities of API required in standard amorphous screens Avoids crystallization induced by containers Is much faster than standard screens Allows detection of domains in amorphous screens – predicts stability Simulates spray-drying Finds the best formulation 32
- 34. Lapatinib PDF – Left HPMC, Right HPMCP - Differential PDFs are Shown 34 Pure LP 3:1 1:1 1:3 Pure LP 3:1 1:1 1:3 This is the only stable dispersion – a lapatinib-HPMC salt complex
- 35. SAMENESS OF CLINICAL SUPPLIES AND PROBLEM SOLVING 35
- 37. Sameness Study - Noise 37
- 38. Conclusion 38