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Gerhard Scriba Slides CE Enantioseparations and Application to the Determination of the Stereoisomeric Purity of Drugs Gerhard K. E. Scriba Friedrich Schiller University Jena, Pharmaceutical Chemistry Philosophenweg 14, 07743 Jena, Germany [email protected] Outline Introduction Mechanistic aspects Examples of selector combinations Determination of chiral purity Levomepromazine Dextromethorphan Conclusions 2 Why chiral analysis of drugs? Enantiomers: The same thing – only different? different pharmacological activities different toxicological profiles different pharmacokinetic properties Enantiomers should be considered different entities. Drug Activity eutomer Activity distomer Penicillamine (S): antiarthritic (R): toxic Ethambutol (S,S): tuberculostatic (R,R): causes blindness Cetirizine (R): antihistaminic (S): inactive DOPA (S): antiparkinsonian (R): agranulocytoxic Ketamine (S): anesthetic/analgesic (R): hallucinogenic 3 Top ten best selling non-peptide drugs in 2016 # Product (company) API Form US $ billions 1 Harvoni TM (Gilead Sciences) ledipasvir enantiomer 9.081 sofosbuvir enantiomer 2 Revlimid TM (Celegene) lenalidomide racemate 6.974 3 Xarelto TM (Bayer) rivaroxaban enantiomer 5.392 4 Lyrica TM (Pfizer) pregabalin enantiomer 4.966 5 Advair TM / Seretide TM fluticasone enantiomer 4.252 (GlaxoSmithKline) salmeterol racemate 6 Sovaldi TM (Gilead Sciences) sofosbuvir enantiomer 4.001 7 Tecfidera TM (Biogen) dimethyl fumarate achiral 3.968 8 Januvia TM (Merck & Co) sitagliptin enantiomer 3.908 9 Truvada TM (Gilead Sciences) emtricitabine enantiomer 3.566 tenofovir enantiomer 10 Crestor TM (AstraZeneca) rosuvastatin enantiomer 3.401 4 Enantioseparation in HPLC versus CE HPLC CE S R S R v free v free µfree µfree KS KR KS KR R µ cplx S µ cplx Enantioseparation Enantioseparation KS ≠ KR KS ≠ KR S R µcplx ≠ µcplx 5 Enantiomer separation by capillary electrophoresis S R anode detector cathode µfree µfree + + + + EOF K K + + S R + R R S µ cplx µ + µ K [C] µ + µ K [C] ∆µ = µ − µ = f cplx R − f cplx S µ S R S 1 + K [C] 1+ K [C] cplx R S Chromatographic principle: KS ≠ KR Electrokinetic principle: µ S ≠ µ R cplx cplx 6 Enantioseparation of Aly-Tyr by cyclodextrins β-CD DM-β-CD TM-β-CD pH 2.5 pH 3.5 pH 2.5 pH 3.5 pH 2.5 pH 3.5 DD DD DD DD DD DD LL LL LL LL LL LL 14 16 18 20 12 14 18 19 11 12 15 20 25 [min] 40/47 cm, 50 µm fused-silica capillary, 50 mM sodium phosphate buffer, 25 kV 7 pH-dependent enantiomer migration order pH 2.5 pH 3.5 Ala-Tyr DD DD pH 2.5 pH 3.5 LL -1 2 -1 -1 -1 2 -1 -1 LL K [M ] µc [cm V s ] K [M ] µc [cm V s ] x 105 x 105 LL 96 7.10 35 3.12 DD 114 7.32 40 3.43 12 14 [min] 18 19 Asp-PheOMe LL LL pH 2.5 pH 3.5 DD DD -1 2 -1 -1 -1 2 -1 -1 K [M ] µc [cm V s ] K [M ] µc [cm V s ] x 105 x 105 LL 73 4.50 43 0.56 DD 84 4.65 50 0.71 14 16 18 [min] 28 30 40/47 cm, 50 µm fused-silica capillary, 50 mM sodium phosphate buffer, 20 mg/mL DM-β-CD, 25 kV 8 Complexation equilibria of chargeable analytes µB = 0 µB·CD = 0 Kn Enantiomer 1 and 2 B B-CD ± µ CD S = eff1 µeff2 + + pKa ± H ± H pKa/c µHB+ ≠ µHB+⋅CD and ± CD µ + ≠ µ + HB+ HB+-CD HB ⋅CD1 HB ⋅CD2 and / or K+ K ≠ K µ µ +1 +2 HB+ HB+·CD and / or Kn1 ≠ Kn2 µ + +µ + ⋅K + ⋅[CD] 1 µ = HB HB ⋅CD ⋅ eff 1+K ⋅[CD] 1+K + ⋅[CD] pH− pK + log + a + ⋅ 1+10 1 Kn [CD] 9 Complexation-induced pKa shift µB = 0 µB·CD = 0 Kn Enantiomer 1 µf Enantiomer 2 B B-CD ± CD µc + + pKa ± H ± H pKa/c 0 ± CD pK pK + + a a/c HB HB -CD pH → K+ µ + µ + HB HB ·CD − µ + 10pKa / c pKa > HB + µHB⋅CD µ + K+ > HB K > K pH ↓ pH ↑ +1 +2 + Kn µHB⋅CD Kn1 > Kn2 µf µc µc µf 10 Enantioseparation of Ala-Tyr by DM-β-CD Parameter Ala-Tyr 9 mol/L 60 mol/L DD LL -9 2 -1 -1 µHB+ [10 m s V ] 15,88 ± 0,07 DD -9 2 -1 -1 µHB⋅CD+ [10 m s V ] 6,68 ± 0,06 6,55 ± 0,06 pH 2,2 µHB+ / µHB⋅CD+ 2,38 ± 0,02 2,42 ± 0,03 LL -1 K+ [M ] 165 ± 7 139 ± 6 -1 Kn [M ] 18,5 ± 1,5 15,0 ± 1,5 K+ / Kn 9,0 ± 0,6 9,2 ± 0,6 9.5 10.0 16 17 pK 3,12 ± 0,01 a [min] [min] pKa/c 4,07 ± 0,03 4,08 ± 0,03 9 mol/L 60 mol/L DD µf DD μ LL LL pH 3,8 µc 16 17 21 22 2.0 2.5 3.0 3.5 4.0 4.5 5.0 [min] [min] pH 11 Enantioseparation of Asp-PheOMe by DM-β-CD Parameter Asp-PheOMe DD LL 9 mol/L 60 mol/L -9 2 -1 -1 µHB+ [10 m s V ] 15,66 ± 0,08 DD DD -9 2 -1 -1 µHB⋅CD+ [10 m s V ] 5,89 ± 0,09 5,84 ± 0,10 ± ± LL µHB+ / µHB⋅CD+ 2,66 0,04 2,68 0,05 pH 2,2 LL -1 K+ [M ] 141 ± 6 116 ± 5 -1 Kn [M ] 114 ± 7 94 ± 6 K+ / Kn 1,23 ± 0,06 1,23 ± 0,06 pKa 2,99 ± 0,01 10 11 18 19 [min] [min] pKa/c 3,08 ± 0,02 3,08 ± 0,02 9 mol/L 60 mol/L µ f DD DD LL μ pH 3,0 LL µc 12 13 20 21 2.0 2.5 3.0 3.5 4.0 4.5 5.0 [min] [min] pH 12 Dexamfetamine Treatment of attention deficit hyperactivity disorders Impurities from chiral starting materials or synthetic intermediates Achiral impurities from synthesis of racemic amphetamine followed by fractional crystallization with L-(+)-tartaric acid OH OH CH3 CH3 CH3 NH2 NH2 NH2 S-amphetamine 1S,2S-(+)-norpseudoephedrine 1R,2S-(–)-norephedrine (dexamphetamine) CH3 CH3 CH3 NH2 O N OH R-amphetamine phenylacetone phenylacetone oxime 13 Dexamphetamine CE assays Single CD Dual CD MEEKC-CD 100 mM sodium phosphate pH 2.5 50 mM sodium phosphate pH 3.0 0.5% ethyl acetate, 1.5% SDS, 20 °C, 25 kV 20 °C, –10 kV 3.5% 1-butanol, 2.5% 2-propanol, 10 mg/mL HDAS-β-CD 80 mg/mL SBE-β-CD 92.0% 50 mM sodium phosphate, 25 mg/mL S-β-CD pH 3.0, 20 °C, –14 kV 5.5% S-β-CD 1 1 1 IS 2 3 4 2 3 IS 2 4 6 IS 7 3 4 7 5 6 5 5 7.5 10 12.5 15 20 25 30 10 12 14 16 18 20 22 [min] [min] [min] 1 – dexamphetamine 2 – levoamphetamine 3 – norpseudoephedrine 4 – norephedrine 5 – phenylacetone 6 – phenylacetone Z-oxime 7 – phenylacetaone E-oxime 14 Analysis of dexamfetamine sulfate sample 1 2 IS 5 7 1 6 2 IS 12 14 16 18 20 22 24 26 [min] 40.2/35 cm, 50 mm ID fused-silica capillary, 50 mM sodium phosphate, pH 3.0 80 mg/mL SBE-β-CD, 25 mg/mL S-β-CD–10 kV, 20°C, 200 nm 5 mg/mL dexamphetamine sulfate , 70 mg/mL ephedrine (IS) 1 – dexamphetamine 2 – levoamphetamine 3 – norpseudoephedrine 4 – norephedrine 5 – phenylacetone 6 – phenylacetone Z-oxime 7 – phenylacetaone E-oxime 15 Dexamfetamine sulfate assay comparison Single CD Dual CD CD-mediated MEEKC Selector HDAS-β-CD SBE-β-CD, S-β-CD S-β-CD Buffer phosphate buffer, pH 2.5 phosphate buffer, pH 3.0 microemulsion in phosphate buffer, pH 3.0 Range 0.06 – 5.0 % 0.05 – 1.0% 0.1 – 1.0% to 0.5 – 1.0% 0.05 – 5.0% (R-AM) 0.1 – 5.0% (R-AM) LOD 0.02 – 0.03% 0.01 – 0.02% 0.05 – 0.2% Precision < 6.7% < 7.5% < 8.2% Comments only charged impurities charged and uncharged charged and uncharged impurities impurities expensive CD expensive CD inexpensive CD HDAS-β-CD, heptakis-(2,3-di-O-acetyl-6-O-sulfo)-β-CD SBE-β-CD, sulfobutylether-β-CD S-β-CD, sulfated β-CD 16 Separation of Met(O) peptide diastereomers NH2 NH2 O CH3 S NO2 O O O H H H N N N H3C N N N N H H H H O O O NO2 COOH NH2 pH range: pH 2.5 – 9.5 no separation CDs: β-CD, γ-CD, CM-β-CD, (partial) separation SBE-β-CD, S-β-CD CM-β-CD, S-β-CD Crown ethers: 15-crown-5, no separation 18-crown-6, Kryptofix 21, Kryptofix 22 17 Met(O) peptide separation - crown ethers ac-KEM(O)KK-Dnp 15-crown-5 18-crown-6 Kryptofix 21 Kryptofix 22 O O O O O O NH O O O O HN O O O HN O O NH O O O 4 3 4 ] 3 3 3 2 mAU [ 2 2 2 2 1 1 Absorbance 1 1 1 0 0 0 0 0 11 12 13 11 12 13 14 12 13 14 17 18 19 20 19 20 21 Time [min] Time [min] Time [min] Time [min] Time [min] Experimental conditions: 40/50.2 cm, 50 µm ID FS capillary, 50 mM Tris-HCl, pH 8.0 20 kV, 20 °C, 214 nm, 10 mg/mL S-β-CD, 10 mM crown ether 18 Met(O) reductase assay Time course hMsrA Stereospecificity Dnp - Dnp Ala - - K - K β - - Dnp - Dnp Dnp K - S(O) - - - R(O) K Ala - - Fmoc - 8 β 6 - R(O) - KIFM S(O) KIFMK KIFM - Dnp 5 - Fmoc ] ] 6 KIFM 4 KIFM mAU mAU KIFMK 3 4 15 min 2 Absorbance [ Absorbance [ hMsrB2 1 2 10 min hMsrA 0 no enzyme 3 min blank 0 -1 6 8 10 12 6 8 10 12 Time [min] Time [min] Enzyme incubation: 50 mM Tris-HCl, pH 8.0, 20 mM DTT, 15 µg/mL Msr, 160 µM ac-KIFM(O)K-Dnp, 37 °C Separation conditions: 45/55.2 cm, 50 µm ID FS capillary, 50 mM Tris-HCl, pH 7.85, 14.3 mg/mL S-β-CD, 5 mM 15-crown-5, 25 kV, 21.5 °C, 214 nm 19 Analytical Quality by Design (AQbD) Definition of ATP Selection of technique Selection of experimental conditions Method design Continuous verification Multifactor experimental Life cycle Method design Continuous management evaluation improvement Risk assessment Knowledge management Method control Definition of Method operable method control design region strategy 20 Levomepromazine Levomepromazine is a chiral antipsychotic phenothiazine drug No test for enantiomeric purity is described in pharmacopeias CH3 CH3 CH3 CH3 Analytical target profile N N CH3 Determination of CH3 N OCH3 dextromepromazine with N OCH3 CH3 CH3 precision and accuracy of S N CH3 S ≤ 15 % at the 0.1 % level O N OCH Levomepromazine and ≤ 10 % at > 0.1 % levels Levomepromazine 3 sulfoxide The diastereomers of S levomepromazine sulfoxide Dextromepromazine should not be separated allowing the determination with precision and accuracy of ≤ 15 % at the 0.1 % level and ≤ 10 % at > 0.1 % levels 15 20 25 30 time [min] Experimental conditions: 40/50.2 cm, 50 µm ID fused-silica capillary; 20 °C; 20 kV 110 mM sodium citrate, pH 4.0; 30 mg/mL HP-γ-CD 21 Selector screening CD conc.
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