pharmaceutical cocrystals
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
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Pharmaceutical Cocrystals
杜新莹 黄箫喃 王倩倩 2012/9/26
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Contents
Pharmaceutical Cocrystals
Review
Preparation Characterization
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Definition Reviews
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Bonding form
Definition Reviews
Bonding form
Molecule
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Definition Reviews
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Supermolecular synthon
Intermolecularinteraction
Balance
Thermodynamics
Kinetics Molecular recognition
Hydrogen bondHalogen bond
π stackingVander Waals forces
Formation Mechanism Reviews
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Formation Mechanism Reviews
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 – pyridinealcohol - amine
Hydrogen bond
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Formation Mechanism Reviews
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
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Formation Mechanism Reviews
π stacking
Parallel superposition Parallel displacement
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Formation Mechanism Reviews
Vander Waals forces
WeakDirectivitysaturability No
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Advantages
Melting point
Solubility
Dissolution rate
Stability Bioavailability
Pharmaceuticalcocrystals
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Advantages Melting pointMelting point
51%39%6%4%
Drug processing
MP Change
Cocrystallization
thermal decompositioncrystal form transformation
thermodynamics behavior
Intermolecular forceCrystalline form
accumulation
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Advantages
•hydrolysis •oxidation •chemical reaction
•decomposition in high temperature•drying•tabletting
StabilityStability
Equilibrium solubilitykinetic solubilityForm changesBasic media
StabilityStability
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Advantages SolubilityDissolution rate
SolubilityDissolution rate
Solid form
Disintegrationdissolve Solution
for low solubility
even saturation
no effect
absorption rate
dissolution rate
dissolution ratetoo low
intenseHigh dissolution velocity danger
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Advantages BioavailabilityBioavailability
Solubility
Disslutionrate
Bioavailability
circulatory system
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SolubilityAMG517 + sorbic acid
Better solubilitypharmacokineticsCmax: 30 mg/kg
500 mg/kg AUC: 1/2
Bioavailability
carbamazepine + saccharin
Good chemical stability;
Better physical stability than
solvate & anhydrous,
polymorphism
Advantages
Stability2-[4-(4-chloro-2-fluorphenoxy)-phenyl]pyrimidine-4-carboxamide
+glutaric acid
dissolution rate: 18Bioavailability: 3
ExamplesExamples
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Design Reviews
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Design Reviews
Structural Analysis
molecular conformationCBD:Pharmaceutics molecular arrangement functional group
Molecular associationSupramolecular structure formationMolecular interaction strength
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Design Reviews
Ligand Screening
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Design Reviews
Structure Prediction
molecular interaction
Cocrystalstructure
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Design Reviews
Bonding Effects
Competition sites
Molecular Conformation
Steric effects
Competitive dipole effect
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Methods
reactive crystallization
reactive crystallization
neat grinding
solvent-drop grindingcooling
crystallization cooling
crystallization
evaporative crystallizationevaporative
crystallization
slurry crystallization
slurry crystallization
spray crystallization
spray crystallization
DSC
Kofler
Preparation
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GrindingGrinding
Preparation
wide applicationhigher yieldhigher crystallinitypolymorphismgreen process
neat grindingsolvent-drop grinding
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SublimationSublimation
Preparation
Thermodynamic advantage
Similar solubility
Polymorphism
evaporative crystallizationevaporative
crystallization
cooling crystallization
cooling crystallization
slurry crystallization
slurry crystallization
Stability
Separate precipitation
Ligand screening
Simple opration
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Preparation
Growth from the meltGrowth from the melt
Kofler
DSCsimpleefficient
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XRD
microscope SS-NMR
thermal analysis
Pharmaceutical cocrystals
characterization
Spectrum
Characterization
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Characterization XRD
powder diffraction
single crystal diffraction
• Decide whether there is something New New
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Characterization
Hot stage microscopy
polarization microscope
Scanning electron microscope(SEM)• Detect the crystal form of the cocrystrals
Microscope
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Characterization
differential thermal analysis (DTA)
thermogravimetric analysis(TGA)
differential scanning calorimetry(DSC)
Thermal Analysis
•Determine thermodynamic parameter&kinetics parameter
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Characterization Spectrum
infrared spectrum
raman spectroscopy
•Detect the Structure of cocrystals
•Functional group
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ExperimentsExperimentsAPI 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
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CCF 的选取
苯甲酸 水杨酰胺 烟酰胺
nicotinamide (NCT)
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Preparation and Chracterization
API 与 CCF 的配比
2
Cocrystal?
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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
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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
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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
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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。
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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