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[email protected] 2018 1
Likun Wang, Ph.D.
Kenneth C. Waterman, Ph.D.
FreeThink Technologies, Inc.
Branford, CT USA
制剂稳定性: 超越原辅料相容性的研究方案
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• 有些降解源于原料和辅料之间的化学反应
• 例子: 米拉德反应 between secondary amines (amino
acids) and reducing carbohydrates (e.g., lactose)—leads
to brown colors + multiple products
• 比较少见 (除了以上反应之外)
可以反应的辅料
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• 载药量的影响(approximation):
log 𝑘 = 𝛼𝑙𝑜𝑔100%
%𝑎𝑐𝑡𝑖𝑣𝑒+ 𝑙𝑜𝑔𝑘0
• α may be independent of temperature/RH• α may depend on T/RH (catalysis)
载药量对稳定性的影响
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G. Scrivens; 2017 Presentation from Science of Stability Conference
Mixed with MCC
案例
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Prasugrel Pediatric
案例
A. Dill; 2015 Presentation from Science of Stability Conference
1.7 2.0 2.2 2.4 2.6 2.8log(100%/%API)
25°C
30°C
40°C
-1.3
-0.9
-0.4
0
0.4
log
k
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二元混合相容性测试的问题
• 对于含量低的辅料，经常放大问题
• 经常排除使用硬脂酸镁
• 真正的速率随浓度呈现log-log 变化, 制剂稳定性并
不是1：1稳定性的加权加和
• 排序意义不大
• 可能排除掉好的处方
• 稳定性研究可能导致项目进度滞后
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11
筛选稳定性 (排序)两个处方放置了2 周加速稳定性, 70°C/75%RH
Formulation 70°C
A 0.18
B 0.90
常温存储条件下(25°C/60%RH) ，应该选哪个处方呢?
Copyright FreeThink Technologies, Inc. 2018 freethinktech.com
12
-7
-6
-5
-4
-3
-2
-1
0
0.0029 0.003 0.0031 0.0032 0.0033 0.0034
ln k
1/T
70°C
60°C
50°C
25°C
B
A
更长的货架周期
Copyright FreeThink Technologies, Inc. 2018 freethinktech.com
13
• 基于高温稳定性的排序经常与室温稳定性排序
相反
• 排序在所有处方都稳定、都不稳定时不能区分
稳定性筛选(排序)
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传统的制剂稳定性研发流程
API-excipient binary blends
Use data to design formulations
Develop final formulation
3-6 mo 3-6 mo
典型的开发周期: 6-12 mos.
需要花费大量的时间
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Rapid Formulation Development: ASAPprime® Tiered Approach
• Full formulations prepared (e.g., tablets, capsules) • 3-4 Tier 1 full formulations• Low API concentration (worst case)
• ASAP studies conducted• Tier 1 formulations work for most APIs and enable
fast development• If Tier 1 fails, Tier 2 formulations used• Rare that we need to go past this• Must justify formulation used: do not need
excipient compatibility for regulatory submissions.
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快速处方开发
2-3 1st tier formulations
Develop final formulation
2-3 2nd tier formulations
Develop final formulation
2-3 3rd tier formulations Develop final
formulation
ASAP-Based Formulation Development using Tiers: 1-4 mos.
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例子：第一梯队片剂处方
Function Ingredient Formulation 1 wt%
Formulation 2 wt%
Active API 5 5
Diluent (ductile) MCC 54 54
Diluent (brittle) Lactose 25
Diluent (brittle) Mannitol 25
Disintegrant Croscarmellose sodium 10
Disintegrant Crospovidone 10
Binder HPC 5
Binder Povidone 5
Lubricant Magnesium stearate 1
Lubricant Stearic acid 1
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使用梯队方法进行处方开发
ASAP方式的优势
• 需要更少资源、速度更快
• 大部分时候可以直接生成可生产、放大的处方
• 避免直接排除由于排序、二元法过度区分的制剂处方
