Correlation of human and biorelevant media solubility for poorly soluble compounds. Patrick Augustijns
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1 Correlation of human and biorelevant media solubility for poorly soluble compounds Patrick Augustijns Nottingham, September
2 Low solubility: a growing problem -HTS - Combinatorial chemistry - More lipophilic targets More lipophilic More solubility issues - Higher risk of failing during early or late development. - Appropriate solubility measurements necessary
3 Pharmaceutical profiling - Solubility Disintegration Absorption Dissolution Solubility Permeation Van Herwaarden et al., Trends Pharmacol. Sci /06/2012 3
4 Overview Intestinal drug behavior Solubility Supersaturation
5 Definition Solubility: The maximum quantity of a substance that can be completely dissolved in a given amount of solvent. Solvent used and its composition Temperature ph Degradation Solid state (polymorph type) Aggregation Counter ions (salts) Ionic strength
6 Determination of thermodynamic solubility Thermodynamic solubility (equilibrium solubility): starting with crystalline material equilibrium with solid compounds (time consuming) 24-48h timescale C Disruption of crystal lattice Dissolution t
7 Determination of kinetic solubility Kinetic Solubility: precipitation from organic solvent C Supersaturation Precipitation - DMSO - Ethanol - Dimethoxyethane t - Appropriate up to lead optimization - Solubility data are time-dependent - Likely to overpredict thermodynamic solubility
8 Pharmaceutical profiling - Solubility Thermodynamic solubility Crystalline material Equilibrium with solid form Shake flask method C t Put excess of compound in Eppendorf tube Add solvent Shake for 24h at 37 C Centrifuge for 15min at 14000rpm Analyse supernatans with HPLC 06/06/2012 8
9 Key questions Which solvent systems?
10 Solubility of Itraconazole in different solvent systems µm 5 4 SGF ph = 1 Phosphate Buffer ph = 6 FaSSIF FeSSIF Fasted HIF
11 Biorelevance of solubility assays in vivo in vitro BS PL + LP D D
12 Introduction Intraluminal conditions fasted fed state: 1)pH ( ) 2)Bile salts ( ) 3)Biliary Phospholipids ( ) 4)Dietary digestion products Lipolytic digestion products => Mixed micelles
13 Collection of HIF Administration of liquid meal Aspiration state (duodenum) Fasted Fed Fat-enriched fed 250 ml water 400 ml Ensure Plus ml water 300 ml Scandishake Mix ml water Fat content 30% 46% Energy content 600 kcal 600 kcal Collection period 2h 5h 5h Used for: characterization in vitro solubility
14 ph 10 fasted 10 fed 8 8 ph 6 ph collection time (min) collection time (min) S1 S2 S3 S4 S5 ph fat-enriched fed collection time (min)
15 Bile salts total bile salt conc (mm) fasted collection time (min) total bile salt conc (mm) fed collection time (min) S1 S2 S3 S4 S5 total bile salt conc (mm) 35 fat-enriched fed collection time (min)
16 Phospholipids total phospholipid conc (mm) fasted collection time (min) S1 S2 S3 S4 S5 total phospholipid conc (mm) total phospholipid conc (mm) collection time (min) 10 fed fat-enriched fed collection time (min)
17 Solubility indomethacin Indomethacin: acid, pka = 4.6, logp = fed fasted solubility (µm) solubility (µm) time (min) fat-enriched fed time (min) S1 S2 S3 S4 S5 solubility (µm) time (min)
18 Correlations - ph Indomethacin (acid, pka = 4.6, logp = 3.4) 5 log (solubility) (µm) R² = 0.86 fasted fed enriched pk a 6 8 ph
19 Correlations BS, PL Danazol (neutral, logp = 4.2) solubility (µm) solubility (µm) bile salts (mm) fasted fed enriched phospholipids (mm)
20 Correlations LP Diazepam (basic, pka = 3.3, logp = 2.9) 8000 solubility (µm) fasted fed enriched lipolytic products (mg/ml)
21 Biorelevant Conditions in-vitro surrogate medium Composition Fassif Updated Fassif Fessif Na Taurocholate (mm) Lecithine (mm) ph Maleic Acid (mm) / / Sodium Hydroxide (mm) Sodium Chloride (mm) Osmolality (mosmol/kg) ±
22 Intestinal drug solubility solubility of 17 model drugs with different physicochemical characteristics were investigated: danazol hydrochlorothiazide prednisolone glipizide quinidine indomethacin carbamazepine nifedipine glibenclamide furosemide diazepam sulfasalazine ritonavir loviride ketoconazole cinnarizine fenofibrate logp in: - HIF -SIF -d-α-tocopheryl polyethyleneglycol 1000 succinate (TPGS) in phosphate buffer
23 Mean solubility in fasted HIF versus FaSSIF solubilty in fasted HIF (µm) y = 5,4x 0,79 R 2 = 0, solubility in FaSSIF c (µm)
24 Fold error between solubility in FaSSIF, corrected solubility in FaSSIF and solubility in fed HIF.
25 Mean solubility in fed HIF versus FeSSIF solubility in fed HIF (µm) y = 4,3x 0,86 R 2 = 0, solubility in FeSSIF c (µm)
26 Fold error between solubility in FeSSIF, corrected solubility in FeSSIF c and solubility in fed HIF.
27 solubility in fasted HIF (µm) y = 5,2x 0,79 R 2 = 0,84 solubility in fed HIF (µm) y = 0,098x 1,20 R 2 = 0, solubility in 0,1% TPGS (µm) solubility in 2% TPGS (µm)
28 Overview Intestinal drug behavior Solubility Supersaturation
29 Beyond solubility: supersaturation Supersaturation refers to a solution that contains more of the dissolved material than could be dissolved by the solvent under normal circumstances.
30 Concept of supersaturation Concentration Supersaturation zone Equilibrium solubility Time
31 PH-Shift method Only useful for basic compounds (80%) Stomach Low ph Good Solubility through ionization + H 3 N GI Tract Poor solubility due to neutralization NH 2 Similar results compared to solvent shift method for itraconazole
32 Supersaturation Assay 37 C Supersaturated Test Medium Concentrated drug solution Degree of supersaturation (DS) Time (min) 5 Poorly soluble model drugs Initial DS of 20 DS = t Ct solubility in testmedium
33 Itraconazole Supersaturation in FaSSIF Degree of supersaturation 20,0 18,0 16,0 14,0 12,0 10,0 8,0 6,0 4,0 2,0 0,0 Supersaturation profile of Itraconazole Fassif Time (min)
34 Itraconazole Supersaturation in FeSSIF Degree of supersaturation 25,0 20,0 15,0 10,0 5,0 0,0 Supersaturation profile of Itraconazole Fessif Fassif Time (min)
35 Human intestinal Fluids? What about supersaturation in human intestinal fluids?
36 Itraconazole supersaturation in Fasted State Human Intestinal Fluids Fasted HIF V1 14,0 12,0 Degree of Supersaturation 10,0 8,0 6,0 4,0 2,0 0, Time (min)
37 Itraconazole supersaturation in Fed State Human Intestinal Fluids Fed HIF V3 10,0 9,0 Degree of supersaturation 8,0 7,0 6,0 5,0 4,0 3,0 2,0 1,0 0, time (min)
38 Impact of medium on precipitation Degree of supersaturation Supersaturation factor A B Time (min) C 0-2h = A + B A DS 1 (solubility)
39 Impact of medium on precipitation 12 FaHIF Supersaturation Factor 0-2h Etravirine Ritonavir Loviride Danazol Fenofibrate Bevernage et al, 2010, J Pha Sci 99:4525 Increasing solubility
40 Impact of medium on precipitation FaHIF FeHIF Supersaturation Factor 0-2h Etravirine Ritonavir Loviride Danazol Fenofibrate Bevernage et al, 2010, J Pha Sci 99:4525
41 Impact of medium on precipitation FaHIF FaSSIF FeHIF FeSSIF Supersaturation Factor 0-2h Etravirine Ritonavir Loviride Danazol Fenofibrate Bevernage et al, 2010, J Pha Sci 99:4525
42 Impact of medium on precipitation FaHIF FaSSIF FeHIF FeSSIF Buffer 10 Supersaturation Factor 0-2h Etravirine Ritonavir Loviride Danazol Fenofibrate Bevernage et al, 2010, J Pha Sci 99:4525
43 Influence solubility on supersaturation 10,00 f 9,00 8,00 Itraconazole Etravirine Loviride 25 7,00 6,00 5,00 Degree of supersaturation Itraconazole Etravirine Loviride 4,00 3,00 2,00 1,00 0, Time (min)
44 Absorption assessment: Caco-2 OMS formulation (1) crystalline itraconazole (2) (1) (2)
45 In vivo exposure (rats) Itraconazole OH-itraconazole Plasma concentration (nm) 400 Plasma concentration (nm) Crystalline ITZ ITZ:SBA-15 1:4 Sporanox Time (hrs) Time (hrs)
46 Precipitation inhibition in human gastric fluid: excipient effects Concentration + excipient HPMC E5 solubility Time Eudragit E-PO PVP K25
47 Effect of HPMC on ITZ precipitation in FaSSIF (ph 6.5) Conc (µg/ml) µg/ml 3 FaSSIF FaSSIF % HPMC Time (min)
48 In vivo exposure Effect of HPMC Itraconazole OH-itraconazole Plasma concentration (nm) Plasma concentration (nm) Crystalline ITZ:SBA-15 1:4 Sporanox ITZ:SBA-15:HPMC 1:4:1.5 ITZ:SBA-15:HPMC 1:4: Time (hrs) Time (hrs)
49 Solubility-limited absorption J = P C Concentration Intestine solubility Time Concentration Plasma Time
50 Supersaturation J = P C Concentration Intestine solubility Time Concentration Plasma Time
51 Supersaturation + precipitation J = P C Concentration Intestine solubility Time Concentration Plasma Time
52 Supersaturation + precipitation: low permeability J = P C Concentration Intestine solubility Time Concentration Plasma Time
53 Supersaturation + precipitation: high permeability J = P C Concentration Intestine solubility Time Concentration Plasma Time
54 Solubility profiling of HIV-PI Solubility (µm) 06/06/
55 Solubility profiling of HIV-PI 55
56 Solubility profiling of HIV-PI 56
57 Solubility profiling of HIV-PI Prediction of food-effects 57
58 Conclusions High intra/inter subject variability FaSSIF & FeSSIF: adequate solvent systems for: Solubility estimation Supersaturation evaluation Prediction of food effects
59 Acknowledgements Laboratory for Pharmacotechnology & Biopharmacy, KU Leuven Jan Bevernage Michiel Van Speybroeck Nico Holmstock Randy Mellaerts Joachim Brouwers Center for Gastroenterology, University Hospitals Leuven Rita Vos, Jan Tack Funding Research Foundation Flanders ( FWO ); Agency for Innovation by Science and Technology ( IWT ); KU Leuven
60 Overview Intestinal drug behavior Solubility Supersaturation Gastric drug behavior: Case study posaconazole
61 Posaconazole in the lab XLogP = 4.6 aqueous solubilty < 1 µg/ml high permeability BCS II weak base (pka 3.6 and 4.6)
62 Posaconazole: influence of gastric conditions Posaconazole pharmacokinetics and gastrointestinal behavior crossover study (5 healthy volunteers) oral administration of a single dose (400 mg) of Noxafil posaconazole concentration-time assessment plasma gastric fluid intestinal fluid 4 different conditions water PPI / water PPI / cola cola
63 Posaconazole & PPI Stomach Water PPI - Water ph Posaconazole (µm) Time (min) Time (min)
64 Posaconazole & PPI Plasma Posaconazole (µm) 0.20 Water PPI - Water Time (h)
65 Posaconazole & PPI & Cola Stomach Water PPI - Water PPI - Cola ph Posaconazole (µm) Time (min) Time (min)
66 Posaconazole & PPI & Cola Plasma Posaconazole (µm) 0.20 Water PPI - Water PPI - Cola Time (h)
67 Posaconazole & Cola Plasma Posaconazole (µm) 0.4 Water Cola Time (h)
68 Posaconazole & Cola Stomach Water Cola ph Posaconazole (µm) Time (min) Time (min)
69 Posaconazole & Cola: effects of cola Solubilization Increased gastric dissolution time Posaconazole solubility (µm) ph 1.2 ph 2.5 ph 6.5 Cola SGF FaSSIF Posaconazole (µm) Water Cola Time (min) normal gastric ph: dissolution-limited absorption
70 Summary: gastric conditions & fasted state posaconazole absorption Gastric dissolution affects posaconazole absorption Clinically: coadminister posaconazole with cola with PPI: partially restored fasted state absorption without PPI: improved fasted state absorption Posaconazole formulation improvements are desirable dissolution rate / solubility Mechanistically: effect of cola ph-dependent increase in solubility (in case of abnormal gastric ph levels) ph-independent increase in solubility increased gastric dissolution time
71 10000 solubility in fasted HIF (µm) y = 34,3x 0,56 R 2 = 0,81 solubility in fed HIF (µm) y = 64,4x 0,55 R 2 = 0,75 1 0, solubility in blank FaSSIF (µm) 1 0, solubility in blank FeSSIF (µm)
72 Conclusions High intra/inter subject variability FaSSIF & FeSSIF: adequate solvent systems for: Solubility estimation Supersaturation evaluation Conditioning environment of the stomach Preparation room Waiting room
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