Dissolution – where physiochemistry meets biology PhysChem Forum, 20 th Sept 2011 Nottingham

1. Dissolution – where physiochemistry meets biologyPhysChem Forum, 20th Sept 2011Nottingham Dr Brian Henry Pharmaceutical Science Pfizer Global Research and Development brian.henry@pfizer.com

2. Today’s Talk Biology Physiochemistry

3. Drug Absorption sampling

4. Dosage Form Performance1 PharmacokineticMeasurement Clinical / PDMeasurement Solubility Permeability Gut Wall DosageForm Drug inSolution Blood Site of Action Therapeutic Effect Dissolution What is dissolution? 1 Based on a slide from 2007 AAPS-FDA BCS, BE, and Beyond Workshop Presentation, entitled General BA/BE Issues, Dale Conner, Division of Bioequivalence, Office of Generic Drugs, CDER, FDA

5. Dissolution Testing of Oral Dosage Form • What is Dissolution? • Dissolution is the rate at which a substance dissolves in a fluid. • In pharmaceutical practice, dissolution is the rate at which a drug in a dosage form dissolves into the fluid surrounding it. • In the case of modified release dosage forms dissolution rate and release rate of drug are controlled by the design of drug product

6. Two Very Different Purposes of Dissolution Test • As a quality control measure for dosage form • Batch to batch reproducibility to assure consistency in quality of manufactured product • Shelf life stability • Assure manufacturing process changes do not impact performance (typically requires BE study) • To predict dosage form PK performance in vivo • Guide formulation selection, design and scale-up during development • Quality by design and support regulatory filings • Help select and set specifications for API form and particle size • Guide bioequivalence strategy

7. Disintegration and Dissolution D D D D D D ... ..

8. Dissolution Model Noyes and Whitney Equation Diffusion Layer Cs Solid Surface • M: the mass of solute dissolved at time t • dM/dt: the mass rate of dissolution • D: diffusion coefficient of the solute in solution • S: the surface area of the exposed solid • h: the thickness of the diffusion layer • Cs: the solubility of the solid • C: the concentration of solute in the bulk solution and at time t Bulk solution C x=h x=0

9. What Factors Influence Dissolution? • The properties of drug • Solubility of the API in the dissolution medium • Whether the API is hydrophilic or hydrophobic (ease of surface wetting) • The particle size/shape of the API • Whether the API is crystalline or amorphous in the drug product • If there are polymorphs, which polymorph is present • If a salt form is used • The quality and design of the drug product • The composition of the drug product and how they are added • Manufacturing processes and steps • Whether the product is designed to immediately release the API, to delay release, or to release the drug over time. • The condition of dissolution tested

10. USP Dissolution apparatus USP III USP I/II USP IV

11. Dissolution of different 250 mg Crizotinib dosage forms

12. Crizotinib ‘Powder in Capsule’ vs Tablet BA study

13. Bridging in vitro to in vivo How can we ensure the low risk of failing to achieve the desired in vivo performance? in vitro performance In vivo performance 13

14. In vitro/In vivo correlations (IVIVC) Definition5 5 Guidance for Industry: Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/ In Vivo Correlations, September 1997 14 • Definition A predictive mathematical treatment describing the relationship between an in vitro property of a dosage form (usually the rate or extent of drug release) and a relevant in vivo response (e.g. drug concentration in plasma or amount of drug absorbed). … to accurately and precisely predicting expected bioavailability characteristics for an ER product from dissolution profile characteristics …

15. Concept of Convolution and Deconvolution Convolution Pharmacokinetic profile Deconvolution Convolution The convolution method is a simulation method used to predict the blood/plasma concentration when a drug is administered orally. Deconvolution Deconvolution is the process to obtain input function with known plasma concentrations Deconvolution is the reverse process of convolution

16. IVIVC Model 16

17. So that’s about it for dissolution, Dinner? …well, it’s rarely that straight forward

18. The problems with predicting dissolution are very fundamentalConsider what is happening at the primary particle surface • Surface area • Particle size distribution • Particle shape • Wetting and aggregation • Bulk solution solubility • pH differences/precipitation • Bile solubilisation • Dissolution vs absorption rates • Unstirred Water layer • pH gradient • Bile micelle migration • Mix hydrodynamics Diffusion Layer Cs Solid Surface Bulk solution C x=h x=0

19. Intrinsic dissolution rate; the simplest form of dissolution testing Constant surface area compact (ensure solid form remains intact after compression) Rotating disk (or static disk & rotating fluid) Well defined hydrodynamics Detection methodology (on-line or off line) Temperature controlled Means to assess solid form after experiment

20. Example experimental data for a drug HCl Salt Data collected ~every 5 seconds If well behaved, (no change in solid form) linear dissolution is expected Slope is proportional to dissolution rate Curvature of concentration profile indicates a phase transformation

21. Delavirdine – NNRTI for the treatment of HIV Basic compound, pKa~4.5 Intrinsic solubility (~1µg/mL) Salt solubility about 200 mg/mL Developed as a mesylate salt but has erratic bioavailability

22. Intrinsic Dissolution Rate of Delavirdine Mesylate Salt very soluble Should dissolve quickly Should be pH independent As the pH increased, the dissolution rate decreased Free base precipitation on the compact confirmed by PXRD

23. What is happening?

24. Free base precipitation

25. Impact of Free Base on the dissolution rate of Delavirdine Mesylate at pH 2 dissolution Small amount of free base in the compact has a dramatic impact on dissolution

26. Impact of citric acid in the compact on the dissolution rate of Delavirdine Mesylate - Diffusion Layer Modulation

27. Rat Study Results Diffusion Layer modification increases oral bioavailability

28. New technologies to provide a greater understanding of dissolution mechanisms SDI300 Surface Dissolution Imaging System: A powerful new tool for formulations optimization

29. The Artificial Stomach Duodenal (ASD) model to investigate the impact of pH change on dissolution

30. Stomach Duodenum Concentration -20 0 20 40 60 80 100 120 140 160 180 200 Time (min) Typical ASD dissolution profiles

31. In vitro/in vivo correlation for ASD • Correlation of ASD AUC to in vivo data for carbamazepine polymorphs: (Carino, S.R., D.C. Sperry, and M. Hawley, Relative bioavailability estimation of carbamazepine crystal forms using an artificial stomach-duodenum model. J. Pharm. Sci., 2006, 95(1), 116-125.)

32. Formulations of compound X were being developed for rapid oral onset of action • Weak based with low solubility >pH4.5 ~10ug/mL • High solubility at gastric pH (>5mg/mL) • Three crystalline solid forms were available • Free base • Intrinsic solubility of 10ug/mL • Citrate salt • Intrinsic solubility of 20mg/mL • Mesylate salt • Intrinsic solubility of 80mg/mL

33. ASD data for Compound X solid forms with a pH 4 stomach. Concentration in solution in the Stomach Concentration in solution in the Duodenum • The mesylate performed poorly in the duodenum with a gastric of pH4.0 • Precipitation to free base? • The citrate salt performs the best in the duodenum compartment • Slower dissolution leading to less precipitation at higher pH

34. pH modulated dog model to monitor oral absorption of Compound X salts from stomachs of low and high pH Medtronic Bravo pH telemetry systems • Pentagastrin treated dogs • Good precedent for use in dogs to reduce stomach pH • 10mcg/kg im • 15 minutes prior to dosing and 30 minutes post dosing • Pantoprazole treated dogs • Low hepatic drug interaction potential and used in veterinary practise with dogs • 1mg/kg iv 12 hours pre dose and 1 hour post dose • Compound X formulated as rapidly disintegrating tablets of the the free base, mesylate and citrate salts • Tablets dose with the Bravo capsule on a fasted stomach with a small volume of water

35. Measurement of the pH of the gastrointestinal tract of male Beagle dogs using Bravo pH telemetry Capsules Pantoprazole treated Pentagastrin treated 001M 001M 002M 002M 003M 003M 8 004M 004M pH 0 Time (hrs)

36. Gastric pH in male beagle dogs after the different pretreatments to control Gastric pH Mean = 4.6 + 2.7 Mean = 6.6 + 0.7 Mean = 1.3 + 0.2

37. Comparison of mean maximum plasma concentrations (Cmax) of Compound X following a single oral administration of Compound X free‑base, mesylate and citrate with no medication, pentagastrin medication and pantoprazole

38. Phase 1 Phase 2 Phase 3 Phase 4 Phase 6 Phase 8 Phase 5 Phase 7 Phase 9 Comparison of the mean time (tmax) to reach the maximum plasma concentration of Compound X following a single oral administration of Compound X free-base, mesylate and citrate with no medication, pentagastrin medication and pantoprazole medication

39. pH modulated dog model to monitor oral absorption of Compound X salts from stomachs of low and high pH • All Compound X salts performed better at lower stomach pH • Faster absorption as measured by shorter Tmax and Higher Cmax • Trend for the citrate salt to have more reliable performance across a wider pH range • Supported by the ASD in vitro dissolution/precipitation model • Bravo pH telemetry capsule worked successfully in this dog model • Drug pre-treatments successfully controlled dog stomach pH to desired level • Fasted dog stomach highly variable

40. Conventional USP dissolution approaches do not mimic the dynamic conditions of the intralumenal environment + ≠ (*1) (*2) (*1 - Using models of the human digestive process to simulate the fate of dosage forms, M. Wickham & H. Parry, APS Biopharmaceutics & Drug Delivery Meeting, Dec 07) (*2 - Picture supplied by Prof. Christos Reppas, National & Kapodistrian University of Athens, Greece)

41. New technologies now provide a view from the tablets perspective Daniel Bar-Shalom Faculty of Pharmaceutical Sciences University of Copenhagen

42. What is really happening in the GI tract? New technologies now provide a view from the Tablets perspective

43. Typical daily variation in gastric pH in a health subject

44. Reduced acid secretion in the Stomach Hypochlorhydria and Achlorhydria • Disease states know to be associated with reduced acid production • Malnutrition • HIV/AIDs • Gastric infections (incl H Pylori) • Gastric inflammation and cancer • Autoimmune diseases (pernicious anaemia, thyroid disorders) • Genetic Disorders • Surgical induced hypochlorhydria • Gastric resection, Vagotomy • Drug induced hypochlorhydria • H2 antagonists, Proton Pump Inhibitors, Antacids • Cannabis • Aspirin, alcohol • Aged associated hypochlorhydria

45. Gastritis and Acid Secretion in the Elderly • Prevalence of gastric cancer and peptic ulcers more common and severe with advancing aging • Well established that gastric pH in the elderly can be more variable and higher then young • 50% of all people over 65 have H pylori infection and with prevalence increasing with advancing age • 30% of all people over 60 have atrophic gastritis • ‘Free-living Boston Elderly’ atrophic gastritis rates • 60-60 21% • 70-79 31% • >80 37% • High Gastric pH in the elderly • Quinine resin release study in 258 people over 65s • 67% normal • 22% intermittent secretors • 11% had consistently pH>3.5 • pH telemetry study in 79 people over 65 • 11% had pH consistently pH>5.0 • Equated to ~5M Americans in 2020 • Achlorhydria in the elderly associated with poor absorption of nutrients • Ca, Fe, folic acid, Vit B6 and B12

46. Mapping the real the world of the Gastrointestinal environment Tablet Velocity and pressure in the GI tract Fluid volume within the gastrointestinal organs during fasting and after a meal by MRI. Gastric emptying Werner WeitschiesInstitute of PharmacyUniversity of Greifswald

47. What should a biorelevant dissolution system consider? • • Changing pH, digestive enzyme and bile levels • Removal of dissolved drugs from the intestinal lumen • Discontinuity of movement of the dosage forms • → Velocities of dosage forms up to 50 cm/s • • Simulation of pressure waves of physiological power • → Pressure values up to 300 mbar (~230 mm Hg) • • Interrupted contact of the dosage form to the medium • • Device should be able to operate with small fluid volumes

48. Dynamic Gastric Model • Fully automated, computer controlled dynamic model of human stomach • System modelled closely on the human stomach • Can process real food and drugs in real time • Includes stomach volume, peristaltic motion and continuous gastric secretions, simulating physical and biochemical processes • Has been used for some time in food research • Application to pharmaceutical products more recent. • Can be applied to a variety of the dissolution challenges.

49. TNO TIM-1 dynamic dissolution model • Stomach and small intestinal model which mimics key aspects of intestinal physiology including: • GI pH profiles and transit times • Secretion of gastric acid and enzymes (pepsin, lipase) • Secretion of bile, pancreatic juice • Absorption of digested products via dialysis • Provides information on release kinetics in the intestinal lumen and availability for absorption (bioaccessibility) • Fed/fasted studies completed with micronized tablet, SDD tablet and nanomilled suspension

50. In vitro formulation comparison • Formulations tested in the TNO TIM-1 fed/fasted in vitro model of a low solubility drug at 100mg and 300mg doses • The drug has a pronounced Fed/Fasted effect in human PK studies 100mg tablet (fasted) 100mg SDD (fasted) 100mg Nano (fasted) 100mg SDD (fasted) 100mg tablet (fed) 300mg Nano (fasted)