Pharmaceutical Cocrystals

杜新莹 黄箫喃 王倩倩 2012/9/26

Contents

Pharmaceutical Cocrystals

Review

Preparation Characterization

Definition Reviews

Bonding form

Definition Reviews

Bonding form

Molecule

Definition Reviews

Supermolecular synthon

Intermolecularinteraction

Balance

Thermodynamics

Kinetics Molecular recognition

Hydrogen bondHalogen bond

π stackingVander Waals forces

Formation Mechanism Reviews

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

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

Formation Mechanism Reviews

π stacking

Parallel superposition Parallel displacement

Formation Mechanism Reviews

Vander Waals forces

WeakDirectivitysaturability No

Advantages

Melting point

Solubility

Dissolution rate

Stability Bioavailability

Pharmaceuticalcocrystals

Advantages Melting pointMelting point

51%39%6%4%

Drug processing

MP Change

Cocrystallization

thermal decompositioncrystal form transformation

thermodynamics behavior

Intermolecular forceCrystalline form

accumulation

Advantages

•hydrolysis •oxidation •chemical reaction

•decomposition in high temperature•drying•tabletting

StabilityStability

Equilibrium solubilitykinetic solubilityForm changesBasic media

StabilityStability

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

Advantages BioavailabilityBioavailability

Solubility

Disslutionrate

Bioavailability

circulatory system

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

Design Reviews

Design Reviews

Structural Analysis

molecular conformationCBD:Pharmaceutics molecular arrangement functional group

Molecular associationSupramolecular structure formationMolecular interaction strength

Design Reviews

Ligand Screening

Design Reviews

Structure Prediction

molecular interaction

Cocrystalstructure

Design Reviews

Bonding Effects

Competition sites

Molecular Conformation

Steric effects

Competitive dipole effect

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

GrindingGrinding

Preparation

wide applicationhigher yieldhigher crystallinitypolymorphismgreen process

neat grindingsolvent-drop grinding

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

Preparation

Growth from the meltGrowth from the melt

Kofler

DSCsimpleefficient

XRD

microscope SS-NMR

thermal analysis

Pharmaceutical cocrystals

characterization

Spectrum

Characterization

Characterization XRD

powder diffraction

single crystal diffraction

• Decide whether there is something New New

Characterization

Hot stage microscopy

polarization microscope

Scanning electron microscope(SEM)• Detect the crystal form of the cocrystrals

Microscope

Characterization

differential thermal analysis (DTA)

thermogravimetric analysis(TGA)

differential scanning calorimetry(DSC)

Thermal Analysis

•Determine thermodynamic parameter&kinetics parameter

Characterization Spectrum

infrared spectrum

raman spectroscopy

•Detect the Structure of cocrystals

•Functional group

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

CCF 的选取

苯甲酸 水杨酰胺 烟酰胺

nicotinamide (NCT)

Preparation and Chracterization

API 与 CCF 的配比

2

Cocrystal？

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

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

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

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。

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