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制剂中的晶型控制和评估

主讲人：李盈博士，亚太区商务发展副总裁Crystal Pharmatech

苏州晶云药物科技有限公司Email：sales@crystalpharmatech.com

电话：0512-69561921

晶云药物第二届晶型专题技术培训

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提纲

• 晶型研究在制剂开发中的重要性

• 制剂中晶型的定性和定量分析

• 制剂工艺中原料药的晶型转变

• 原料药在制剂中的歧化反应

• 制剂中的成像

• 总结

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药物剂型

Tablets

Capsules

Solutions

Suspensions

Intravenous (IV)

Soft gel

Capsules

Inhalers

Implants/stent

Suppositories

Patches

Emulsions

Depot

Other

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常见辅料及功能

Component Functions Common Examples

Diluent/Filler •Bulk up the formulation

•Compensate API properties

•inert

Lactose

Dicalcium phosphate

Microcrystalline cellulose

Binder •Adhesive •Usually water soluble•Wet or dry

Hydroxypropyl cellulosePolyvinyl pyrolidonePregel starch

Disintegrant •Hydrophilic •water swellable polymer

Sodium starch glycolate

Croscarmellose sodium

Lubricant •Hydrocarbon tail with polar head group

Magnesium stearateSodium stearyl fumarate

Others •Antioxidant•Solubilizer, surfactant•Flow aid•Film former•Waxing agent•Colorants, sweeteners

•BHT, BHA, propyl gallate•Poloxamer, polyoxy 40 hyrdro-genated castor oil, sodium lauryl sulfate•Colloidal silicon dioxide•HPC, HPMC, PVA•Carnauba wax

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API+

Excipients+

MixingGranulation

MillingCompaction

Coating

Dosage Form

Formulation Process 1. Stability2. Mechanical Strength3. Content Uniformity4. Dissolution rate5. Scalability

制剂大致生产流程

晶型研究在制剂开发中的重要性

• 制剂中原料药晶型的变化会引起

–性能的变化(生物利用度、稳定性、可生产性等)

–药品的质量问题，比如批次的不合格

• 对制剂工艺中晶型的深入理解有助于

–预测工艺中可能发生的原料药晶型转变

–增强制剂工艺的可重复性,提高产品质量

–药物申报和专利保护

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制剂开发中的晶型问题– 如何监控制剂中晶型的相互转变？

– 如何对制剂中药物晶型进行定性和定量分析？

– 晶型的粒径分布对溶出率，生物利用度，及制剂工艺的影响？

– 如何判定晶型对药物溶出度，生物利用度的影响？

– 如何预测和评估晶型在制剂中的化学和物理稳定性？

– 晶型在湿法制粒过程是否稳定？

– 如何预测和评估无定形药物在制剂中的重结晶风险？

– 如何确定盐类晶型在制剂中是否发生歧化反应？

制剂中固态分析手段

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制剂中晶型的定性定量分析

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定性和定量分析• When multiple forms are known:

– need test/assay to show control of process

– assay can be qualitative or quantitative

– can be an issue in API and drug product

• Different levels of use and validation throughout development– Early development: qualitative/visual

– Late development: increase level of validation

• Univariate vs. multivariate approaches

Newman and Byrn, Drug Discovery Today, 2003, 8, 898-905

用固态核磁共振定量

• Highest strength tablet 8.1% w/w drug

• IR and Raman did not have needed sensitivity

• XRPD had significant overlap with Form 1 and excipients; Form 2 did not show drug significant overlap

• 13C SSNMR had sufficient sensitivity and resolution– Limit test method developed

– 4000 scans; 20 hr data acquisition; 10 % w/w LOD; 0.8 % drug

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Katrincicet al. IntJ Pharm. 2009, 366, 1-13

• Improved method developed with 19F NMR– 19F NMR is more sensitive than 13C– Reduces long analysis times– Transfer to other sites may be

limited

• Limit of detection of 19F method 1.5% w/w Form 1– Absolute detection limit 0.12%

w/w Form 1– 4.2 hr acquisition time

• Can be used for lower dose tablets– 0.3% w/w drug in tablets (1 mg

drug in 300 mg tablets)

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Katrincicet al. IntJ Pharm. 2009, 366, 1-13

用固态核磁共振定量

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制剂及制剂工艺中原料药的晶型转变

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制剂工艺中原料药晶型的转变 Form changes can occur

– Mixed/dissolved/ suspended in solvent

– Drying

– Milling

– Compaction

– RH exposure

• Interactions between drug substance and excipients can cause form changes

Zhang et al. Adv Drug Delivery Rev. 2004, 56, 371-390

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制剂工艺中原料药晶型的转变• Can involve one component or more

• Can be solid-solid or solid-liquid-solid

Basic Process State of Aggregation Specific Process

Transformations(One component)

Solid-solid Polymorphic transformationsCrystallization of the amorphous form and vice versaIncongruent melting (melting followed by crystallization of a more stable form)Solution mediated polymorphic transformation

Solid-liquid -solid

Physical interactions(multicomponent)

Solid-solid Eutectic reaction

Solid-liquid -solid Formation of a molecular compound or a solid solution (including solvate formation) cocrystals, salts

Solid-solid or Solid-liquid -solid

Hydrate formation in humid air

Physical decompositions(multicomponent)

Solid-solid or Solid-liquid -solid

Desolvation dissociation

Types of the most important phase transitions during processing of pharmaceuticalsa

a Does not consider a chemical change Morris et al. Adv Drug Delivery Rev. 2001, 48, 91-114

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如何通过工艺改进避免晶型转变• Transformations can be controlled and circumvented

by selecting the appropriate process

Zhang et al. Adv Drug Delivery Rev. 2004, 56, 371-390

Multi-step dry blending

• Mill drug with lactose monohydrate to reduce particle size and improve flow properties

• Form 1 converts to Form 2 during milling

17Katrincicet al. Int. J. Pharm. 2009, 366, 1-13

案例一：亚稳态晶型的制剂开发

Form 2 was chosen for development even though it wasn’t the stable form at RT

•Milling and hygroscopicity were important

•Showed that Form 2 was stable for 1 year under stability conditions

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案例二：原料药和辅料在制剂中形成共晶

AMG517

• A number of crystalline forms found for free base

• Numerous solvates also isolated

• Salt formation not feasible– Disproportionated in aqueous solution

– Resulting pH was low and acid mediated cleavage occurred at ether bond

• Form A selected for early development

– Insoluble in water

• A suspension in 10% (w/v) PluronicF108(R) in OraPlus(R) was selected for pre-clinical formulation

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Bak et al. J PharmSci. 2008, 97, 3942-3956

• At high doses, found absorption limited by solubility– Due to new solid form in suspension

• OraPlus(R) contains 0.1% sorbic acid as a preservative

• New form was 1:1 AMG517:sorbic acid cocrystal

• Found 12 additional cocrystals in subsequent studies

• Know what is in your solutions– can also happen with buffers

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Baket al. J PharmSci. 2008, 97, 3942-3956

案例三：选择适当的制剂方法以避免晶型转变

• Capsules and tablets prepared by wet granulation or dry blending

– Clinical formulations: 1:10 and 1:15 drug:excipient

– Prototype formulation: 1:2.8 drug: excipient

• Dry blend showed no change in crystallinity

• Wet granulation resulted in mostly amorphous drug

• Dry blend was adopted for clinical supplies

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• Siramesine HCl

– Anhydrous

– Hydrate

• Simulated wet granulation used to investigate conversion of anhydrate to hydrate

– Water

– 60% ethanol

• Analyzed by offline Raman spectroscopy

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案例四： 湿法制粒中溶剂的选择

Zimmerman et al. Pharm.Res. 2009, 26, 846-854

• No conversion over time observed with water as the granulating liquid– Due to poor wetting and poor solubility

(150 μg/mL) of the anhydrate in water

• Conversion was observed with 60% v/v ethanol– Started at 45 min; mostly complete at 180

min

– Solubility in ethanol 24 mg/ml

• Solubility can play a key role in conversion

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Zimmerman et al. Pharm.Res. 2009, 26, 846-854

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原料药在制剂中的歧化反应

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案例五：原料药在制剂中的歧化反应

• Compound A is a bis-HCl salt• Risk of disproportionation with basic excipients

(e.g., MgSt, SSF, CCNa)

• Binary compact studies were performed to evaluate the disproportion risk

Magnesium Stearate Sodium stearyl fumarate

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歧化反应的检测手段

XRPD, Raman or solid state NMR can be used.

Raman was chosen since

The compound is amorphous and XRPD is

not sufficient to monitor the physical

changes associated with possible

disproportionation

less API and less resources are required

E:\MK-8325\MK-8325 75% HCl Salt 25% FB std 19Apr2011 502 mW 5 minute scan.0 MK-8325 75% HCl Salt 25% FB std 19Apr2011 502 mW 5 minute scan powder E:\MK-8325\MK-8325 80% HCl Salt 20% FB std 19Apr2011 502 mW 5 minute scan.0 MK-8325 80% HCl Salt 20% FB std 19Apr2011 502 mW 5 minute scan powder E:\MK-8325\MK-8325 85% HCl Salt 15% FB std 19Apr2011 502 mW 5 minute scan.0 MK-8325 85% HCl Salt 15% FB std 19Apr2011 502 mW 5 minute scan powder E:\MK-8325\MK-8325 90% HCl Salt 10% FB std 19Apr2011 502 mW 5 minute scan.0 MK-8325 90% HCl Salt 10% FB std 19Apr2011 502 mW 5 minute scan powder E:\MK-8325\MK-8325 amor Bis HCl standard 5 minute 502 mW 13Apr11.0 MK-8325 amor Bis HCl standard 5 minute 502 mW 13Apr11 powder E:\MK-8325\MK-8325 amor FB standard 5 minute 502 mW 13Apr11.0 MK-8325 amor FB standard 5 minute 502 mW 13Apr11 powder

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歧化反应的检测-拉曼光谱应用

100% bis HCl

90% bis HCl

85% bis HCl

80% bis HCl

75% bis HCl

100% free base

Sensitive regions

1. 选取原料药的特征峰

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辅料干扰是制剂中晶型检测最主要的问题

E:\MK-8325\MK-8325 75% HCl Salt 25% FB std 19Apr2011 502 mW 5 minute scan.0 MK-8325 75% HCl Salt 25% FB std 19Apr2011 502 mW 5 minute scan powder E:\MK-8325\MK-8325 80% HCl Salt 20% FB std 19Apr2011 502 mW 5 minute scan.0 MK-8325 80% HCl Salt 20% FB std 19Apr2011 502 mW 5 minute scan powder E:\MK-8325\MK-8325 85% HCl Salt 15% FB std 19Apr2011 502 mW 5 minute scan.0 MK-8325 85% HCl Salt 15% FB std 19Apr2011 502 mW 5 minute scan powder E:\MK-8325\MK-8325 90% HCl Salt 10% FB std 19Apr2011 502 mW 5 minute scan.0 MK-8325 90% HCl Salt 10% FB std 19Apr2011 502 mW 5 minute scan powder E:\MK-8325\MK-8325 amor Bis HCl standard 5 minute 502 mW 13Apr11.0 MK-8325 amor Bis HCl standard 5 minute 502 mW 13Apr11 powder E:\MK-8325\MK-8325 amor FB standard 5 minute 502 mW 13Apr11.0 MK-8325 amor FB standard 5 minute 502 mW 13Apr11 powder E:\MK-8325\26Apr2011 40C-35RH Mgst spin only 502 mW 5 min scan.0 26Apr2011 40C-35RH Mgst spin only 502 mW 5 min scan powder E:\MK-8325\26Apr2011 40C-75RH MgSt spin only 502 mW 5 min scan.0 26Apr2011 40C-75RH MgSt spin only 502 mW 5 min scan powder E:\MK-8325\26Apr2011 5C Mgst spin only 502 mW 5 min scan.0 26Apr2011 5C Mgst spin only 502 mW 5 min scan powder E:\MK-8325\MgSt MID10000598 10min scan 500mW 23March2011.0 MgSt MID10000598 10min scan 500mW 23March2011

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100% bis HCl

90% bis HCl

85% bis HCl

80% bis HCl

75% bis HCl

100% free base

MgSt Blank

• Regions of interest without significant interference from MgSt include: 1640,

1555, 1505, and 1355 cm-1

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Binary with MgSt – 1555 wave number

E:\MK-8325\initials\MK-8325 amor Bis HCl 90 10 MgSt spin and up down 5C 5 minute 502 mW 13Apr11.0 MK-8325 amor Bis HCl 90 10 MgSt spin and up down 5C 5 minute 502 mW 13Apr11 powder E:\MK-8325\2 wk\26Apr2011 40C-35RH Mgst spin only 502 mW 5 min scan.0 26Apr2011 40C-35RH Mgst spin only 502 mW 5 min scan powder E:\MK-8325\2 wk\26Apr2011 40C-75RH MgSt spin only 502 mW 5 min scan.0 26Apr2011 40C-75RH MgSt spin only 502 mW 5 min scan powder E:\MK-8325\2 wk\26Apr2011 5C Mgst spin only 502 mW 5 min scan.0 26Apr2011 5C Mgst spin only 502 mW 5 min scan powder E:\MK-8325\4 week samples\11May2011 4 wk 502 mW 5 minutes MgSt 5C.0 11May2011 4 wk 502 mW 5 minutes MgSt 5C powder E:\MK-8325\4 week samples\11May2011 4 wk 502 mW 5 minutes MgSt 40C 35% RH.0 11May2011 4 wk 502 mW 5 minutes MgSt 40C 35% RH powder E:\MK-8325\4 week samples\11May2011 502 mW 5 minutes MgSt 40C 75% RH.0 11May2011 502 mW 5 minutes MgSt 40C 75% RH powder E:\MK-8325\calibration samples\MK-8325 amor Bis HCl standard 5 minute 502 mW 13Apr11.0 MK-8325 amor Bis HCl standard 5 minute 502 mW 13Apr11 powder E:\MK-8325\calibration samples\MK-8325 amor FB standard 5 minute 502 mW 13Apr11.0 MK-8325 amor FB standard 5 minute 502 mW 13Apr11 powder E:\MK-8325\calibration samples\MK-8325 75% HCl Salt 25% FB std 19Apr2011 502 mW 5 minute scan.0 MK-8325 75% HCl Salt 25% FB std 19Apr2011 502 mW 5 minute scan powder E:\MK-8325\calibration samples\MK-8325 90% HCl Salt 10% FB std 19Apr2011 502 mW 5 minute scan.0 MK-8325 90% HCl Salt 10% FB std 19Apr2011 502 mW 5 minute scan powder

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• All peaks normalized to the peak at 1610 cm-1

• Significant decrease in signal with the 40C/75% RH sample

100% bis HCl

90% bis HCl

75% bis HCl

100% free base

Initial

5°C 2 weeks

5°C 4 weeks

40°C/35%RH 2 weeks

40°C/35%RH 4 weeks

40°C/75%RH 2 weeks

40°C/75%RH 4 weeks

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Sucrose Stearate

E:\MK-8325\MK-8325 75% HCl Salt 25% FB std 19Apr2011 502 mW 5 minute scan.0 MK-8325 75% HCl Salt 25% FB std 19Apr2011 502 mW 5 minute scan powder E:\MK-8325\MK-8325 80% HCl Salt 20% FB std 19Apr2011 502 mW 5 minute scan.0 MK-8325 80% HCl Salt 20% FB std 19Apr2011 502 mW 5 minute scan powder E:\MK-8325\MK-8325 85% HCl Salt 15% FB std 19Apr2011 502 mW 5 minute scan.0 MK-8325 85% HCl Salt 15% FB std 19Apr2011 502 mW 5 minute scan powder E:\MK-8325\MK-8325 90% HCl Salt 10% FB std 19Apr2011 502 mW 5 minute scan.0 MK-8325 90% HCl Salt 10% FB std 19Apr2011 502 mW 5 minute scan powder E:\MK-8325\MK-8325 amor Bis HCl standard 5 minute 502 mW 13Apr11.0 MK-8325 amor Bis HCl standard 5 minute 502 mW 13Apr11 powder E:\MK-8325\sucrose stearate 5C 5 minute 502 mW 13Apr11.0 sucrose stearate 5C 5 minute 502 mW 13Apr11 powder E:\MK-8325\MK-8325 amor FB standard 5 minute 502 mW 13Apr11.0 MK-8325 amor FB standard 5 minute 502 mW 13Apr11 powder

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• Regions of interest without significant interference from Sucrose Stearate

include: 1640, 1555, 1505 cm-1

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Binary with Sucrose Stearate – 1555 wave number

• All peaks normalized to the peak at 1610 cm-1

• Slight decrease in signal with the 40C/75% RH sample and possibly with the 40C/35% RH samples

E:\MK-8325\calibration samples\MK-8325 amor Bis HCl standard 5 minute 502 mW 13Apr11.0 MK-8325 amor Bis HCl standard 5 minute 502 mW 13Apr11 powder E:\MK-8325\calibration samples\MK-8325 amor FB standard 5 minute 502 mW 13Apr11.0 MK-8325 amor FB standard 5 minute 502 mW 13Apr11 powder E:\MK-8325\calibration samples\MK-8325 75% HCl Salt 25% FB std 19Apr2011 502 mW 5 minute scan.0 MK-8325 75% HCl Salt 25% FB std 19Apr2011 502 mW 5 minute scan powder E:\MK-8325\calibration samples\MK-8325 90% HCl Salt 10% FB std 19Apr2011 502 mW 5 minute scan.0 MK-8325 90% HCl Salt 10% FB std 19Apr2011 502 mW 5 minute scan powder E:\MK-8325\initials\MK-8325 amor Bis HCl 90 10 sucrose St spin only 5C 5 minute 502 mW 13Apr11.0 MK-8325 amor Bis HCl 90 10 sucrose St spin only 5C 5 minute 502 mW 13Apr11 powder E:\MK-8325\2 wk\26Apr2011 40C-35RH SFS spin only 502 mW 5 min scan.0 26Apr2011 40C-35RH SFS spin only 502 mW 5 min scan powder E:\MK-8325\2 wk\26Apr2011 40C-75RH SFS spin only 502 mW 5 min scan.0 26Apr2011 40C-75RH SFS spin only 502 mW 5 min scan powder E:\MK-8325\2 wk\26Apr2011 5C SFS spin only 502 mW 5 min scan.0 26Apr2011 5C SFS spin only 502 mW 5 min scan powder E:\MK-8325\4 week samples\11May2011 4 wk 502 mW 5 minutes SSF 5C.0 11May2011 4 wk 502 mW 5 minutes SSF 5C powder E:\MK-8325\4 week samples\11May2011 4 wk 502 mW 5 minutes SSF 40C 35% RH.0 11May2011 4 wk 502 mW 5 minutes SSF 40C 35% RH powder E:\MK-8325\4 week samples\11May2011 4 wk 502 mW 5 minutes SSF 40C 75% RH.0 11May2011 4 wk 502 mW 5 minutes SSF 40C 75% RH powder

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案例五小结

• Disproportionation risk with MgSt is higher than with sucrose stearate.

• 5C storage with desiccant is recommended for the clinical supplies.

• Physically stability on the probes formulations will need to be monitored.

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制剂中的成像

Spectroscopic Imaging

– IR

– NIR

– Raman

– XRPD

– Thermal imaging (AFM)

– Scanning Electron Microscope (SEM) with

elemental imaging (EDX)

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制剂中的成像方法

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NIR成像

Formulation Characterization

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缓控制剂的成像

Cross-section

SEM

SEM

Raman

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总结

• 晶型研究对于成功开发制剂至关重要

– 确保选择的剂型适合所选的晶型

– 确保选择的晶型在制剂工艺和保存过程中的稳定性

• 制剂中的晶型研究需要利用多种固态表征方法，包括定性和定量分析

• 一个成功制剂的开发必须综合考虑原料药，辅料，还有制剂生产工艺

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谢谢大家！

影响制剂中晶型转变的因素

• Poor API-excipient or API-API compatibility– Changes that can be monitored using x-ray diffraction,

spectroscopy, calorimetry etc

– Quantitative capabilities – multivariate analysis

• API Phase changes upon typical pharmaceutical processing– Compaction/compression, extrusion, spray-drying

• API Phase changes upon storage (temperature/moisture)– Long-term stability study to monitor API phase change

• API Phase/Form changes in amorphous formulations– Amorphous API crushed out as crystalline phase

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药物制剂中晶型控制的有关规定

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ICH Guideline Q6A on Drug Product

FDA Guidance on Pharmaceutical Solid Polymorphism in ANDAs:

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Dissolution Mechanism based on BCS

Formulateddrug

Absorbeddrug

Solubilized drugkd kp

kd = dissolution rate (solubility, formulation)

kp = permeability rate (API structure)

kd & kp fast - Well absorbed

BCS Class I, like dosing an oral solution

kd >> kp - permeation control

BCS Class III, still like dosing an oral solution

kd << kp - dissolution controlled

BCS Class I (ER or CR), or Class II & IV (IR)

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Dissolution Mechanism based on BCS

Formulated drug

or “granule”Solubilized

drugkd

Drug Particlekid

kdd

kdd = disintegration (cohesive properties of the formulation)

kid = solubilization of the drug (API particle size or surface area)

Understand the relative importance of kdd and kid provide a mechanistic framework to assess where dissolution tests adds value