amorphous form as possible
API properties different solubility in the solvent
poor solubility or good solubility
Solvent properties
Polarity-different sort of solvents (alcohols, ethers, ester etc.) Boiling point Freezing point Toxicity miscibility
recrystallization from a neat compound
(thermal heating/cooling, grinding , and high pressure )
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polymorph screening —— crystallization from solution
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Experience sharing on polymorph screening ——solvent selection
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The purpose of polymorph screening
For Innovator companies - select the optimal solid-state of API for development -study relevant polymorphs for IP protection
• degree of supersaturation and Temperature are
considered as the driving force of crystallisation
• diverse solvents result in the discovery of more
polymorphs
For CRO companies based on the customers needs
- to identify as many new polymorphs (include solvate / hydrate) and amorphous form as possible
- or to find the most stable form
药物的多晶型研究
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提纲
什么是晶体，多晶型？ 多晶型研究对药物开发的重要性 如何筛选和选择药物的新晶型 多晶型的主要分析手段 晶型筛选实验的经验分享----溶剂选择
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什么是晶体？
Crystal
A solid material whose constituent atoms,molecules, or ions are arranged in an orderly repeating pattern extending in all three spatial dimensions.
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crystallization from solution——
Solvent selection
Solvent MeOH
Visual solubility (mg/mL)
EtOH
• Slurry
IPA 1-Butanol
ACN
• Anti-solvent precipitation
1,4-Dioxane
Heptane
THF
Acetone
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Water
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crystallization from solution——
rational experimental design
• Limited resource
•
？ How to find as many new polymorphs and
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多晶型研究对药物开发的重要性
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药物多晶型研究的重要性
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如何筛选和选择药物的新晶型
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晶型的化学和物理分析手段
-132020Fra bibliotek5/4MEK
MIBK
EtOAc
• Solvent-thermal
iPrOAc
heating/cooling experiments
MTBE
2-MeTHF
• Slow/fast precipitation from
DMF
saturated solutions method
NMP
DMSO
CH2Cl2 Toluene
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The method of polymorph screening
crystallization
crystallization from solution
(slurry, anti-solvent precipitation , Solvent-thermal heating/cooling Slow/fast precipitation from saturated solutions)
• Polymorphs
▪ Sold phase ▪Same chemical composition ▪Different molecular arrangements
• In practice, we are interested in all the crystalline and amorphous phases for a chemical/pharmaceutical
Pharmaceutical crystals
Most drugs are developed as crystalline
Stability Processability IP protection
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什么是多晶型？
• Polymorphism is the ability of a solid material to exist in more than one form or crystal structure.