Research Achievement Winner Lecture AAPS Annual Meeting 2010 Abu T. M. Serajuddin, Ph.D. St. John’s University, Queens, New York E-mail: serajuda@stjohns.edu; Phone: 718-990-7822 Formulation of Poorly Water-Soluble Drugs: Drug Delivery Strategies 1

Two-thirds (?): Insoluble or Practically Insoluble Recent Trends in New Molecule Solubility Two-thirds (?): Insoluble or Practically Insoluble Very slightly soluble or soluble New Generation <10µg/mL 10-100µg/mL >100µg/mL Solubility < 1 μg/mL (0.001 mg/mL) is common 2 Source: Personal experience, literature data and anecdotal information

Dosage Form Development Strategies 97MAY08 EC A few common strategies to overcome impacts of low solubility on product development: Particle size reduction Milling Nanosizing Salt formation Solubilization Solid dispersion Lipid-based drug delivery To save time and resources in product development, relatively simpler approaches should be tried first.

Salt Formation 4

How Does Salt Formation Increase Dissolution Rate? 97MAY08 EC Diffusion Layer Model DA h (Cs - C ) J = = dM dt Stagnant Diffusion Layer Bulk Liquid Phase (Dissolution Medium) Cs, h=0 >> Cs, bulk medium …. by changing microenvironmental pH and solubility Solid (salt) Saturate Supersaturate, and/or Fine precipitate C h 5 5

Effect of Salt Formation on Drug Solubility 30 mg/mL Line: fitted by equation Mesylate HCl Phosphate 2.5 µg/mL Mesylate > HCl > Phosphate Ref: S. Li, S.M. Wong, S. Sethia, H. Almoazen, Y.M. Joshi and A.T.M. Serajuddin. Investigation of Solubility and Dissolution of a Free Base and Two Different Salt Forms as a Function of pH. Pharm. Res. 22:628-635 (2005)

Dissolution Profiles of a Free Base Solubility is practically zero under intestinal pH conditions (5 and higher) Ref: S. Li, S.M. Wong, S. Sethia, H. Almoazen, Y.M. Joshi and A.T.M. Serajuddin. Investigation of Solubility and Dissolution of a Free Base and Two Different Salt Forms as a Function of pH. Pharm. Res. 22:628-635 (2005)

Dissolution Rates of Salt Forms of a Basic Compound Ref: S. Li, S.M. Wong, S. Sethia, H. Almoazen, Y.M. Joshi and A.T.M. Serajuddin. Investigation of Solubility and Dissolution of a Free Base and Two Different Salt Forms as a Function of pH. Pharm. Res. 22:628-635 (2005)

Limitation of Salt Formation 9

X X Diffusion Layer Model Limitation of Salt Formation for the New Generation of Poorly Water-soluble Drugs 97MAY08 EC Diffusion Layer Model When the intrinsic solubility is very low, the precipitated free base coats the dissolving surface, preventing further dissolution of salt. Stagnant Diffusion Layer Bulk Liquid Phase (Dissolution Medium) Cs, h=0 >> X Cs, bulk medium Solid (salt) X Please note: Precipitation at the surface, not in the bulk medium. No increase in surface area. Precipitated Free Base C h 10 10

High-energy Solid

High-energy amorphous Structure of High-energy Solids liquid High-energy amorphous solid Super-cooled liquid Glass Heat content (enthalpy, H) Crystal Low-energy crystalline solid Temperature 2

Solid Dispersion

Advantage of Solid Dispersion: Better Stability than Purely Amorphous System Storage temperature Drug only Tg (mixture) Drug - polymer miscible blend Super-cooled liquid Heat content (enthalpy, H) Elevated Tg Glassy state Tg (drug) Temperature 2

What is Solid Dispersion ? “the dispersion of one or more active ingredients in an inert carrier or matrix, where the active ingredients could exist in finely crystalline, solubilized or amorphous state” - Chiou and Riegelman, J Pharm Sci 1971, 60, 1281-1302 Drug (crystalline) Carrier (amorphous) + Partial miscibility Complete miscibility No miscibility

Advantage of Solid Dispersion: Higher Dissolution Rate 96JUN10 KF/JH Poorly Water-Soluble Drug Solid Dispersion Tablet/Capsule Dosage Form Disintegration Matrix Dissolves Large Solid Particles (Usually 5-100 microns) Drug in G.I. Tract Colloidal Drug Particles/Globules Lower Dissolution Rate Higher Dissolution Rate Absorption into Body Systems Ref: Serajuddin, J. Pharm. Sci. 1999, 88, 1058

Surfactant-based Solid Dispersions

Solid Dispersion by Melt-Filling: Advantage of Surfactant 96OCT14 KF/JAM Aqueous Dispersion of Solid Plug Solid dispersion Disintegration of capsule shell Solid Plug with Layer Solid Plug Non-Surface active vehicle Forms drug-rich surface layer Retards/prevents dissolution of drug Surface active vehicle Disperses/emulsifies drug Rapid dissolution rate

Composition of Solid Dispersion Prepared Development of Solid Dispersion: Compound A 97MAY28 VG/EC Composition of Solid Dispersion Prepared Compound A (LAB687) 20 mg Polysorbate 80 0-120 mg PEG 3350 360-0 mg Total Weight 500 mg Capsule size # 0 Ref: Dannenfelser et al., J. Pharm. Sci. 93:1165-1175 (2004) 19 19

Composition of Solid Dispersion Solid Dispersion Selected for Clinical Study: Compound A 97MAY28 VG/EC Composition of Solid Dispersion Compound A 20 mg Polysorbate 80 120 mg PEG 3350 360 mg Capsule size # 0 Ref: Dannenfelser et al., J. Pharm. Sci. 93:1165-1175 (2004)

Bioavailability in Dogs from Solid Dispersion: Compound A 97MAY28 VG/EC Formulation AUC (0-48h) Relative (ng.h/mL) Bioavailability Solid dispersion 6960 100 Solubilized system 6900 100 Capsule (mic. Powder) 681 10 Ref: Dannenfelser et al., J. Pharm. Sci. 93:1165-1175 (2004)

Solid Dispersion by Melt Extrusion

Solid Dispersion by Melt Extrusion Technology Melt extrusion is a single-step process ideally suitable to manufacture solid dispersion Homogeneous mixture of active, polymer plasticizer, surfactant Reality TV / Easier to discuss what wouldn’t work rather than what would Now one must deal with different cultures: European, South American, Chinese As well as the language of these foreign commercial launch centers. This is not unique to Foreign Based Pharma Companies but also domestic ones Global economy has changed the landscape completely. Not that long ago dev centers & manufacturing plants were across the street from each other now the global economy has changed this completely Who controls the Batch manufacture at the launch site the Dev QA group, Local QA? All hurdles for failure. But I will not focus on this rather I'd like to focus on what has worked well for Novartis. Ref: Adapted from J. Kowalski (Novartis) presentation

Lower Temperature Melt Extrusion – A Novel Strategy Crystalline drug subs. High temperature melt extrusion Drug degradation + Polymer Amorph. extrudate Amorphous drug subs. Lower temperature melt extrusion + Stable product Polymer Ref: Lakshman et al., Molecular Pharmaceutics, 5:994-1002, 2008

Microemulsion 25 25

What is Microemulsion? -‘Cyclosporine A’ Example 20 – 150 nm ( < 200 nm) Microemulsion (o/w) Without dilution Cyclosporin A Sandimmune® Neoral® Dilution with water Ref:A. Meinzer et al, BT Gattefosse 88 :21-26, 1995

Systematic Screening of Lipids for Microemulsion Formation

Structures of Lipids C8 Chain fatty acid Glyceryl Caprylate/Caprate (Capmul MCM; ABITEC Co.) Glyceryl Dicaprylate (ABITEC Co.) Glyceryl Tricaprylate (Captex 8000; ABITEC Co.)

Ternary System for Monoglyceride (Glyceryl Caprylate/Caprate), Cremophor EL and Water Oil : Surfactant 9:1 7:3 5:5 3:7 2:8 1:9 70 4815 7865 1215 2481 28 15 80 7126 3859 1532 1265 18 12 90 1609 3242 743 473 99 2978 1173 578 430 14 Particle Size, nm Gel

Ternary System for Diglyceride( Glyceryl Dicaprylate), Cremophor EL and Water Oil : Surfactant 9:1 7:3 5:5 3:7 2:8 1:9 70 2788 492 90 17 80 32 2007 286 55 20 77 14 1844 222 35 18 19 99 1903 153 16 Particle Size, nm

Ternary System for Triglyceride (Caprylate/ Caprate Triglyceride), Cremophor EL and Water Oil : Surfactant 9:1 7:3 5:5 3:7 2:8 1:9 70 1580 619 1296 533 867 116 80 1794 463 634 390 685 39 90 2136 380 383 334 402 22 99 3851 291 218 172 154 20 Particle Size, nm

Pseudo-Ternary System using 1:1-Tri- + Mono-Glycerides, Cremophor EL and Water Oil : Surfactant 9:1 7:3 6:4 5:5 4:6 3:7 2:8 1:9 70 3353 1105 115 43 22 20 18 24 80 5303 395 153 21 17 15 14 33 90 875 546 44 16 99 338 41 30 25 Particle Size, nm

Pseudo-Ternary System using 1:1-Di- + Mono-Glycerides, Cremophor EL and Water Oil : Surfactant 7:3 5:5 3:7 2:8 1:9 70 1029 1079 150 82 80 1063 442 22 18 17 90 870 252 16 99 50 78 20 Particle Size, nm

Solid Microemulsion Preconcentrate - A Novel Solid Dispersion

Solid Microemulsion Preconcentrate Solid dispersion Solid preconcenrate Liquid preconcentrate Component Solid Microemulsion Preconcentrate Compound A (%w/w) 4 8 Capmul PG8 (%w/w) 28.8 27.6 Cremophor EL (%w/w) PEG 3350 (%) 38.4 36.8 Compound A Ref: Li et al., J. Pharm. Sci., 98:1750-1763, 2009

Formulation of Poorly Water-Soluble Drugs 96JUN05 KF Concluding Remarks Almost one-third of compounds synthesized by discovery scientists is extremely water-insoluble (solubility in water: <10 µg/mL) Conventional formulation techniques may no longer be applicable to most, if not all, of them. Special formulation approaches are necessary to enable development of such compounds. Formulation strategies must be selected based on dose, solubility and other physicochemical properties of NCEs. 36 36