Thermodynamics of Pharmaceutical Systems

Transcription

1 Biochemical and Chemical Engineering Thermodynamics of Pharmaceutical Systems Gabriele Sadowski TU Dortmund Dortmund March 4, 2014

2 Motivation APIs are complex molecules Most APIs are classified in class II or IV of the Biopharmaceutics Classification System (BCS) Limited bioavailability due to poor solubility and/or low dissolution rate permeability Class II Class I Class IV Class III solubility Strategies to improve solubility: Cosolvents Salt formation Amorphous solid (dispersions) Strategies to improve dissolution rate: Particle-size reduction Salt formation Amorphous solid (dispersions) Cocrystals

3 Motivation APIs are complex molecules Most APIs are classified in class II or IV of the Biopharmaceutics Classification System (BCS) Limited bioavailability due to poor solubility and/or low dissolution rate permeability Class II Class I Class IV Class III solubility Strategies to improve solubility: Cosolvents Salt formation Amorphous solid dispersions Strategies to improve dissolution rate: Particle-size reduction Salt formation Amorphous solid dispersions Cocrystals

4 Solubility calculation x L i 1 L γ h exp RT 1 SL 0i = SL i T0i T Does only depend on the API; NOT on the solvent! activity coefficient the solvent influences the activity coefficient of the API γ L i same activity coefficients (e.g. γ il =1) would lead to the same solubility in all solvents!

5 Solubility in pure solvents Determination of PC-SAFT parameters by fitting to solubility data (five data points) Example: Ibuprofen in acetone 2000 solubility [g/kg solv.] 1500 symbols: exp. data line: PC-SAFT T [ C] CH 3 H 3 C exp. data: Gracin and Rasmuson 2002 Ruether and Sadowski, J Pharma Sci 98 (2009) CH 3 OH O

6 Salt formation - ph influence S + X - Acid XH Solubility SX Solute S ph

7 Solubility of thiabendazole 0.08 Solubility [mol/kg] 0.06 HCl CH 3 3 COOH H 3 PO PO ph [-] J. Cassens, A. Prudic, F. Ruether, G. Sadowski, submitted to IEC Res Solubility strongly depends on ph Addition of acid induces formation of salt which has higher solubility Maximum in solubility depends on the acid used for the ph shift

8 Modeling results for thiabendazole ph dependent solubility of Thiabendazole in water using HCl as ph-changing agent Thiabendazole salt as solid Solubility [mol/kg] Calculation epc-saft Solubility product of the salt fitted ph [-]

9 Solubility of Amino Acids At low ph and high ph SH + S - Acid H + Base OH - Solubility Solubility Solute S ph

10 Solubility of Amino Acids m [mol/kg] K K a2 = a1 = C O OH NH 2 NH 2 O L-Alanine pH OH 15 C 59 C L-Leucine 25 C K a1 = K a2 =

11 Crystallization from homogeneous solution product liquid Temperature metastable zone solid/liquid concentration

12 Oiling out in API solutions product liquid Temperature liquid/ liquid solid/liquid concentration

13 Solubility of amorphous vs. crystalline API solubility ratio x aaaaaaaaa ccccccccccc AAA / x AAA 2x10-6 amorphous [1] x Indomethacin [mol/mol] 1x10-6 5x10-7 crystalline [1] Time [min] [1] Hancock, B. C. ; Parks, M.: What is the True Solubility Advantage for Amorphous Pharmaceuticals? Pharmaceutical Research 17 (2000), Nr. 4, S

14 State of art solubility ratio x aaaaaaaaa ccccccccccc AAA / x AAA [1;2] Calculated using the common method according to Parks et al. [3] predicted solubility ratios are typically much higher than the experimental values Solubility ratio is not considered to depend on the solvent [1] Hancock, B. C. ; Parks, M.: What is the True Solubility Advantage for Amorphous Pharmaceuticals? Pharmaceutical Research 17 (2000), Nr. 4, S [2] Babu, N. J. ; Nangia, A.: Solubility Advantage of amorphous drugs and pharmaceutical cocrystals; Crystal Growth and Design 2011, 11, [3] Parks, G. S. :Studies on Glass: XI. Some Thermodynamic relations of Glassy and Alpha-Crystalline Glucose. In: The Journal of Chemical Physics 2 (1934)

15 Phase-equilibrium approach SLE measured Glibenclamide in water Solubility I II LLE API amorphous LLE predicted with PC-SAFT aaaaaaaaa ccccccccccc x AAA / xaaa 25

16 Solubility of amorphous vs. crystalline API Prediction of the solubility ratio x i aaaaaaaaa / xi ccccccccccc by PC-SAFT [1;2] * * * * On-going work Solubility ratios from PC-SAFT are more suitable than those from literature PC-SAFT accounts for the solvent influence [1] Hancock, B. C. ; Parks, M. Pharm. Res. 17 (2000), Nr. 4, S [2] Hajime K., Tetsurou H., European J. Pharmaceutics Biopharmaceutics 70 (2008)

17 Solid dispersions Stable solid dispersion Temperature [K] glass crystals demixing polymer Weight fraction w API [-] API

18 Phase behavior as function of the polymer 440 Artemisinin / PVP K25 Temperature [K] SLE API crystalline 440 LLE API amorphous Artemisinin Artemisinin / PDLA PDLA Artemisinin / PEG 6000 SLE API crystalline LLE API amorphous 400 SLE API crystalline Weight fraction 320 w A [-] No LLE Temperature [K] Temperature [K] Weight fraction w A [-] Weight fraction w A [-]

19 Phase behavior of solid dispersions Temperature T [ C] Indomethacin in VP/VA copolymers PVA PVP 75 PVPVA 64 lit. 50 PVPVA 37 PVPVA Weight fraction w IND [-] w H2 O [-] Water sorption in 25 C PVP PVPVA :70 IND:PVPVA PVA Relative humidity [%] Lit. data: Sun et. al., J. pharm. Sci., 2010 Solubility of indomethacin depends on the (co)polymer Solid dispersions often (can) absorb remarkable amounts of water

20 Phase behavior as function of RH% Temperature [ C] Indomethacin in PVP Tg % H 2 O % H 2 O 15% H 2 O Weight fraction w IND [-] T g prediction using Gordon-Taylor equation Water absorption increases the probability of API recrystallization and therewith decreases bioavailability.

21 Summary API systems show usual thermodynamic phase behavior Using state of the art thermodyanmic models, it is possible to predict solubility in solvents and solvent mixtures predict the crystalline/amorphous API solubility in solvent (mixtures) model the phase behavior of solid dispersions predict solubility as function of ph (salt formation) describe cocrystal systems describe/predict the API dissolution/release rates