1. The Application of Scientific Principles to Pharmaceutical Formulation Design Stephen R. Wicks PhD FAPS FRPharmS University of Greenwich

2. Science and Formulation Design The Team Human Biology The Drug The Dosage Form Khartoum, November 2015 - Stephen Wicks2

3. Science and Formulation Design The Team Human Biology The Drug The Dosage Form Khartoum, November 2015 - Stephen Wicks3

4. 4 Decision-making in the Pharmaceutical Industry Manufacturing Pharmaceutical Science Process Chemistry Formulation Analytical Drug Metabolism Pharmaceutical Science Process Chemistry Formulation Analytical Drug Metabolism API Clinical Development Research Clinical Development Research Sales/ Marketing Sales/ Marketing Biology Stakeholders Patient Payer Shareholder Stakeholders Patient Payer Shareholder Drug Safety Clinical Toxicology Drug Safety Clinical Toxicology

5. Khartoum, November 2015 - Stephen Wicks5 Critical Transactions in Successful Drug Development Manufacturing Pharmaceutical Science Process Chemistry Formulation Analytical Drug Metabolism Pharmaceutical Science Process Chemistry Formulation Analytical Drug Metabolism API Clinical Development Research Clinical Development Research Sales/ Marketing Sales/ Marketing Biology Stakeholders Patient Payer Shareholder Stakeholders Patient Payer Shareholder Drug Safety Clinical Toxicology Drug Safety Clinical Toxicology General Pharmacology Drug Design ‘Preformulation’ Technology Transfer Output Market Research Label Patient Safety Clinical Pharmacology Label

6. Drug Development –Does the molecule have drug-like properties? –What is the mechanism of action in animal/in vitro models? Main effect Side effect –Can I formulate the molecule into a medicine? –Is my dosage form design relevant to clinical use? –Is the formulated molecule safe to give to humans? –Will the formulated molecule meet clinical need? Is it safe in humans? –Can I mass produce the medicine? –Can the rate of manufacture meet demand? Khartoum, November 2015 - Stephen Wicks6

7. 7 Decision Making in Dosage Form Design Manufacturing Pharmaceutical Science Process Chemistry Formulation Analytical Drug Metabolism Pharmaceutical Science Process Chemistry Formulation Analytical Drug Metabolism API design Clinical Development Research Clinical Development Research Sales/ Marketing Sales/ Marketing Biology Stakeholders Patient Payer Shareholder Stakeholders Patient Payer Shareholder Drug Safety Clinical Toxicology Drug Safety Clinical Toxicology

8. Khartoum, November 2015 - Stephen Wicks8 Critical Transactions in Dosage Form Design Manufacturing Pharmaceutical Science Process Chemistry Formulation Analytical Drug Metabolism Pharmaceutical Science Process Chemistry Formulation Analytical Drug Metabolism API Clinical Development Research Clinical Development Research Sales/ Marketing Sales/ Marketing Biology Stakeholders Patient Payer Shareholder Stakeholders Patient Payer Shareholder Drug Safety Clinical Toxicology Drug Safety Clinical Toxicology Drug Product Design Drug Delivery Drug Product Safety Mass Production

9. Dosage Form Design –Is my dosage form safe? –Does my dosage form express optimum biology? –Does my dosage form meet the needs of the market? Unmet clinical need Satisfactory dosage form –Can it be mass produced? Quality Robust, well-understood process Consistent API and excipients Acceptable cost Manufacturing capital equipment available Khartoum, November 2015 - Stephen Wicks9

10. Science and Formulation Design The Team Human Biology The Drug The Dosage Form Khartoum, November 2015 - Stephen Wicks10

11. Reliable Once Daily ACE Inhibition: Addition of 1- (methylsulphonyl)piperidine enhances angiotensin converting enzyme (ACE) inhibition Enalapril – Merck 60% oral bioavailablity UK-64,143 – Pfizer Not orally bioavailable UK-64,143 and enalapril structures from Peter Dunn and Michael Williams courtesy of Pfizer Ltd. Khartoum, November 2015 - Stephen Wicks11

12. Drug-like Properties Compounds having MWs not exceeding 450 Da, cLogP values between 4.5 and 3.5 A maximum of four rings A maximum of ten non-terminal single bonds No more than five hydrogen-bond donors, and A maximum of eight hydrogen-bond acceptors Oprea TI: Current trends in lead discovery: Are we looking for the appropriate properties? J Comput Aided Mol Des (2002) 16(5-6):325-334. Khartoum, November 2015 - Stephen Wicks12

13. Drug Absorption Gut Anatomy and Physiology Physicochemical Properties Cell Monolayer Permeability

14. Gastrointestinal Transit Gastric emptying is unpredictable –It depends on whether the subject is fed or has been fasting –Objects less than 10mm can empty from a fed stomach –Objects >20mm in size will be retained in the fed stomach In humans, transit in the small intestine is constant –Transit is 3 hours Although the colon is shorter, the transit time is much longer –Transit can be 20 hours or, in some cases, longer In the fasted state, a dosage form can reach the ileo-caecal junction in 4-5 hours

15. Biopharmaceutical Evaluation The starting point is generally a reference oral liquid formulation –Ideal for rapid, low-cost entry into Phase I studies –Based on solutions or oral suspensions, these systems avoid solid dosage form complications, e.g. disintegration and dissolution (solutions) –API may be fluid energy milled (‘micronized’) if low solubility and dissolution rate is suspected. –Caution: there are reports in the literature of oral liquid formulations being less bioavailable than tablets and capsules Late Phase I crossover studies with the oral liquid formulation and an evaluable Phase II dosage form, e.g. tablet or hard gelation capsule Absolute bioavailability –If an IV injection formulation is feasible Crossover studies if formulation changes are made Studies aimed to establish an in vivo-in vitro relationship or correlation

16. Preformulation Studies The Distribution Coefficient (Log D) and the Partition Coefficient (Log P) are important starting points: –Referenced to the octanol:water partition coefficient –Many alternative high-throughput methods now available, e.g. reverse phase HPLC –Public domain algorithms now available for reliable calculation Solubility –Particularly pH-solubility relationships Dissolution rate Permeability studies in Caco-2 or other cell monolayers –The process can now be automated Permeability and solubility estimates will allow determination of the Biopharmaceutics Classification System (BCS) profile

17. Biopharmaceutics Classification System Khartoum, November 2015 - Stephen Wicks17

18. The pH Partition Hypothesis Plasma Compartment Gut Compartment Lipid Barrier pH = 1.0 pH = 7.0 R – NH 2 R – NH + R – NH 2 R – NH + Khartoum, November 2015 - Stephen Wicks18

19. The Caco-2 Monolayer and absorption Passive Active Facilitate Passive Efflux Gut Receptor Transcellular Paracellular Mediated Khartoum, November 2015 - Stephen Wicks19

21. Physicochemical and Cell Monolayer Prediction High Molecular Weight Cohort Salicylate Cohort

23. Drug Efflux

24. Drug Transporters

25. UK-64,143: Addition of 1-(methylsulphonyl)piperidine enhances angiotensin converting enzyme (ACE) inhibition Enalapril – Merck 60% oral bioavailablity UK-64,143 – Pfizer Not orally bioavailable UK-64,143 and enalapril structures from Peter Dunn and Michael Williams courtesy of Pfizer Ltd. Khartoum, November 2015 - Stephen Wicks25

27. Differential Solubility, Stability and Absorption: The ‘Absorption Window’ ‘Absorption windows’ can arise from a number of physiological and physical reasons –Environmental changes in the gut pH, gut enzymes, bile –Active transporters –Paracellular absorption –Gut wall metabolism (Cytochrome P450 3A4) –Efflux pumps, e.g. P-glycoprotein In general –Drugs absorbed by passive diffusion can be absorbed from the small intestine and the colon –Drugs absorbed via the paracellular route or by active transporters are absorbed from the small intestine only. i.e. they appear to have an absorption window of about 4-5 hours at which point absorption rates reduce dramatically or absorption ceases

28. Absorption Windows Frustrate Controlled Release Acyclovir Bisphosphonates ACE inhibitors Frusemide Metformin Gabapentin Penicillin and Cephalosporin antibiotics Levodopa Baclofen Ciprofloxacin

30. ACE InhibitorsNameActivityHepatic Metabolism ExcretionFt 1/2 (hr) CaptoprilActiveYesRenal70-75%1.9 EnalaprilatActiveYesRenalNil11.0 EnalaprilEnalaprilat prodrug YesRenal60%n/a LisinoprilActiveNoRenal unchanged25% (6-60%) 12.0

31. Science and Formulation Design The Team Human Biology The Drug The Dosage Form Khartoum, November 2015 - Stephen Wicks31

32. Polymorphism: a philosophy of science problem Fewer, smaller API batches being manufactured due to minimalism Poor analytical characterisation –Limited to IR spectroscopy and thermal analysis Understanding of the importance of polymorphism Lack of control –Manage the problem when it happens –Damage limitation Khartoum, November 2015 - Stephen Wicks32

33. 1998 — Abbott Laboratories announced that it was experiencing manufacturing difficulties with the capsule formulation of its HIV protease inhibitor, Norvir®. "We have encountered an undesired formation of a Norvir® (Ritonavir) crystalline structure (Form II) that affects how the capsule form of Norvir® dissolves” “In Form II all of the strong hydrogen bond donors and acceptors have been satisfied and are strong….Since the strength and completeness of the hydrogen bonding has attained the maximum possible in the Form II lattice, it is not thought possible that another undiscovered polymorph of ritonavir would exist with equivalent or lower solubility than that of Form II’’ In 2003, it was reported that 2000 high throughput crystallisations had identified two new solvates plus an additional anhydrous form. Chemburkar, et al. (2000) Org. Process Res. Dev. 4(5), 413. Bauer, et al. (2001) Pharm. Res. 18(6), 859. Morissette, et al. (2003) PNAS. 100, 2180. Norvir® Khartoum, November 2015 - Stephen Wicks33

34. Conventional Solid State Unit Processing Mixing and Granulation Compression Coating Khartoum, November 2015 - Stephen Wicks34

35. 2.454 Å 2.415 Å 2.241 Å First Form Crystallised Weak H-Bonding ‘3-Centred’ Architecture 3-Centred interaction absent from the database Linear Interaction more common and shorter A more stable form predicted Second Form Crystallised Stronger, Linear H-Bonding More stable form Solid Form Data Mining Crystallisation Experiments Courtesy – R. Docherty, Pfizer Ltd Structural Frequency Analysis Khartoum, November 2015 - Stephen Wicks35

36. Sitting Drop Robot Crystallisation Robustness Robot Polymorph/Hydrate hunting- Robot Image Analysis Solids Dosing Robot From 10 to 100 to 1000 crystallisations Increase in diversity of experiments (robustness) Courtesy – R. Docherty, Pfizer Ltd Robotic Screening Khartoum, November 2015 - Stephen Wicks36

37. Solid Form Selection Lead and CAN Nomination Clinical Commercial Manufacture Tablet Dosage Form Design Solubility/Stability Solid Form ScreeningInformatics Science Of Scale Expert Systems DS Technology Met demands of dynamic fast moving program Embraced the technology opportunity Courtesy – R. Docherty, Pfizer Ltd Optimisation of Properties Khartoum, November 2015 - Stephen Wicks37

38. Pharmaceutical Materials Science QUANTUM BULK TABLET SINGLE TABLET MOLECULAR (CRYSTAL) PARTICULATE Scale-upBlending, granulation, compression Crystallization, spray drying, lyophilization Crystal structure Courtesy – R. Docherty, Pfizer Ltd Khartoum, November 2015 - Stephen Wicks38

39. 2.454 Å 2.415 Å Maraviroc: Putting it all together Maraviroc: Putting it all together Courtesy : Pfizer Ltd; Cambridge Crystallographic Database Khartoum, November 2015 - Stephen Wicks39

40. Thank You Khartoum, November 2015 - Stephen Wicks40