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

2. Contents Pharmaceutical Cocrystals Review Preparation Characterization

3. Definition Reviews

4. Bonding form Definition Reviews Bonding form Molecule

5. Definition Reviews

6. Supermolecular synthon Intermolecular interaction Balance T hermodynamics Kinetics Molecular recognition Hydrogen bond Halogen bond π stacking Vander Waals forces Formation MechanismReviews

7. Formation MechanismReviews 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 Hydrogen bond

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

9. Formation MechanismReviews π stacking Parallel superposition Parallel displacement

10. Formation MechanismReviews Vander Waals forces Weak Directivity saturability No

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

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

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

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

15. Advantages Bioavailability Solubility Disslution rate Bioavailability circulatory system

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

17. DesignReviews

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

19. DesignReviews Ligand Screening

20. DesignReviews Structure Prediction molecular interaction Cocrystal structure

21. DesignReviews Bonding Effects Competition sites Molecular Conformation Steric effects Competitive dipole effect

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

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

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

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

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

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

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

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

30. Characterization Spectrum infrared spectrum raman spectroscopy 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 2 Cocrystal ？

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１２ 4 ℃）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 SLC100μL 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 、 1 HNMR