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Pharmaceutical Cocrystals

Pharmaceutical Cocrystals. 杜新莹 黄箫喃 王倩倩 2012/9/26. Preparation. Review. Characterization. Contents. Pharmaceutical Cocrystals. Reviews. Definition. Molecule. Reviews. Definition. Bonding form. Bonding form. Reviews. Definition. Molecular recognition. T hermodynamics.

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Pharmaceutical Cocrystals

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  1. Pharmaceutical Cocrystals 杜新莹 黄箫喃 王倩倩 2012/9/26

  2. Preparation Review Characterization Contents Pharmaceutical Cocrystals

  3. Reviews Definition

  4. Molecule Reviews Definition Bonding form Bonding form

  5. Reviews Definition

  6. Molecular recognition Thermodynamics Kinetics Supermolecular synthon Intermolecular interaction Balance Formation Mechanism Reviews Hydrogen bond Halogen bond π stacking Vander Waals forces

  7. Formation Mechanism Reviews Hydrogen bond the most important O-H…X(X= O, N) C-H…X(X= O, N, π) N-H…N carboxylic acid - carboxylic acid carboxylic acid - pyridine carboxylic acid - amide alcohol – pyridine alcohol - amine

  8. Heteroatom with lone pair electron(N, O, S) non-covalent bond Formation Mechanism Reviews Halogen bond Lewis acid halogen atom（Cl,Br,I）

  9. Formation Mechanism Reviews Parallel superposition Parallel displacement π stacking

  10. Weak Directivity saturability Formation Mechanism Reviews No Vander Waals forces

  11. Advantages Pharmaceutical cocrystals Solubility Dissolution rate Melting point Stability Bioavailability

  12. Cocrystallization MP Change Drug processing Advantages Melting point 51% 39% 6% 4% • thermal decomposition • crystal form transformation • thermodynamics • behavior • Intermolecular force • Crystalline form • accumulation

  13. Equilibrium solubility kinetic solubility Form changes Basic media Advantages Stability solution Stability Chemical stability • decomposition • in high temperature • drying • tabletting • hydrolysis • oxidation • chemical reaction

  14. for low solubility even saturation no effect absorption rate dissolution rate Disintegration dissolve Solid form Solution Solubility Dissolution rate Advantages dissolution rate too low intense High dissolution velocity danger

  15. Disslution rate Bioavailability Solubility Bioavailability Advantages circulatory system

  16. Bioavailability carbamazepine ＋ saccharin Good chemical stability; Better physical stability than solvate & anhydrous, polymorphism Solubility AMG517＋sorbic acid Better solubility pharmacokinetics Cmax: 30 mg/kg 500 mg/kg AUC: 1/2 Stability 2-[4-(4-chloro-2-fluorphenoxy)-phenyl]pyrimidine-4-carboxamide ＋ glutaric acid dissolution rate: 18 Bioavailability: 3 Advantages Examples

  17. Design Reviews

  18. molecular conformation • CBD:Pharmaceutics molecular arrangement • functional group Design Reviews Structural Analysis • Molecular association • Supramolecular structure formation • Molecular interaction strength

  19. Design Reviews Ligand Screening

  20. molecular interaction Design Reviews Structure Prediction Cocrystal structure

  21. Design Reviews Bonding Effects • Competition sites • Molecular Conformation • Steric effects • Competitive dipole effect

  22. DSC Kofler solvent-drop grinding neat grinding Preparation Methods evaporative crystallization cooling crystallization reactive crystallization slurry crystallization spray crystallization

  23. neat grinding solvent-drop grinding Preparation Grinding • wide application • higher yield • higher crystallinity • polymorphism • green process

  24. Preparation Sublimation evaporative crystallization • Thermodynamic advantage • Similar solubility • Polymorphism cooling crystallization • Stability • Separate precipitation • Ligand screening • Simple opration slurry crystallization

  25. Kofler DSC Preparation Growth from the melt • simple • efficient

  26. Characterization SS-NMR microscope Pharmaceutical cocrystals characterization XRD thermal analysis Spectrum

  27. powder diffraction single crystal diffraction XRD Characterization • Decide whether there is something New

  28. Microscope Characterization Hot stage microscopy polarization microscope Scanning electron microscope(SEM) • Detect the crystal form of the cocrystrals

  29. Thermal Analysis Characterization differential thermal analysis (DTA) thermogravimetric analysis(TGA) differential scanning calorimetry(DSC) • Determine thermodynamic parameter&kinetics parameter

  30. infrared spectrum raman spectroscopy Spectrum Characterization • Detect the Structure of cocrystals • Functional group

  31. Experiments API的选取 非那雄胺（finasteride） 水中难溶，属于BCS Ⅱ类药物 （低溶解度、高渗透度） 已有方法： 包合物、固体分散体 （PEG6000、Kollidon K25与非那雄胺固体分散体和非那雄胺与β-环糊精包合物） 目标：提高该药物的溶解度，进而提高该药物的溶出速率及其生物利用度

  32. CCF的选取 苯甲酸 水杨酰胺 烟酰胺 nicotinamide (NCT)

  33. Preparation and Chracterization API与CCF的配比 ？ Cocrystal 2

  34. 干磨 1mmol API+1mmol SLC 室温下研磨30min　　 XRD 结果分析：8、23附近特征峰得到明显增强，可能有新的物质形成

  35. 溶剂挥发法 0.5mmol API + 0.5mmol SLC 2mL乙醇溶解挥发１天　 　　　XRD　　DSC　　FT-IR 0.5mmol API + 1mmol SLC 2mL乙醇溶解挥发１天　 　　　XRD　　DSC　　FT-IR 现象：溶液变粘稠 XRD图分析：两者几乎在相同位置处有新的特征峰出现，可能产生新的物质 DSC图分析：１：１时发现有API的熔点峰出现，１:２时则没有 FT-IR图谱 结果表明：API与SLC的完全反应配比应为１:２，但是１:１时也会产生新的晶体

  36. 0.5mmol API + 1mmol NCT 2mL乙醇溶解挥发２天 XRD DSC FT-IR XRD图谱分析：某些位置处的峰强度增强 DSC图谱分析：新的熔点峰（大约１２4℃）出现 FT-IR图谱 结果表明：API与NCT可以以１:２的比例形成新的物质

  37. 溶剂滴加辅助法（solvent-drop grinding） 0.5mmol API + 1mmol SLC 100μL乙醇　边滴加边研磨 XRD图　DSC图谱 现象：固体粉末黏在一起 结果分析：１:２时API 与SLC确实可以形成新的晶体，但是由于研磨时间、力度等的影响，与溶剂挥发法所制得的晶体仍有一定差距，可以改进。但是，此时API 与SLC所形成的晶体会涉及到晶型的转变。

  38. 溶析结晶法（solvent-out crystallization） 0.25mmol API+0.5mmol BEN 0.8mL乙醇 待溶解后，加入4mL水静置冷却 其余可行方法：熔融结晶法 其余表征方法：TGA、1HNMR

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