Amorphous Ipatasertib Granulation for High-Speed Tableting
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Solution Overview
Problem
Conventional pharmaceutical compositions of ipatasertib monohydrochloride face challenges due to its high brittleness, solubility, and hygroscopicity, leading to processing difficulties, lamination issues, and instability, making high-speed tableting and uniform granulation processes difficult to achieve.
Innovation Solution
The use of intragranular materials with plastic deformation characteristics, such as microcrystalline cellulose, and moisture adsorbents, combined with fluid bed granulation and a rotary wheel type spray-drying process, produces amorphous ipatasertib with improved flowability and particle size distribution, overcoming brittleness and solubility issues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If conventional mechanical compression is used for tableting, then manufacturing process is simple, but tablet lamination and crack formation occur due to high brittleness
Solution Approach 1:
The patent introduces granulation as an intermediary process between powder preparation and tableting. The granulation process creates granules with improved mechanical properties that serve as a mediator, preventing direct compression of brittle ipatasertib powder and eliminating lamination issues while maintaining manufacturing simplicity
Solution Approach 2:
The patent changes the physical state and mechanical properties of the material through granulation, transforming brittle powder into granules with enhanced compressibility and reduced elasticity. This parameter change enables successful tableting without lamination while keeping the process simple
2Ease of operation
If high solubility and hygroscopicity are present, then dissolution and absorption may be improved, but processing difficulty and stability decrease
Solution Approach 1:
The patent converts the harmful high hygroscopicity and solubility properties into benefits by using them to create a highly soluble amorphous granulated product. The high solubility ensures rapid dissolution and absorption, while the granulation process controls the hygroscopicity to prevent processing issues, turning potential drawbacks into therapeutic advantages
Solution Approach 2:
The patent creates a composite granulated material combining ipatasertib with excipients that modulate the solubility and hygroscopicity characteristics. This composite structure maintains the beneficial high solubility for drug release while the excipients help control moisture uptake during processing
3Ease of operation
If amorphous form is used, then solubility and dissolution are improved, but manufacturing stability and uniformity become difficult to achieve
Solution Approach 1:
The patent performs preliminary granulation action before tableting to create uniform granules with consistent amorphous characteristics. This preliminary processing ensures that the amorphous material is uniformly distributed and stabilized in the granule structure, enabling subsequent high-speed tableting to produce uniform tablets with improved dissolution
4Productivity
If high-speed tableting is implemented, then productivity increases, but lamination problems become more severe
Solution Approach 1:
The granulation process serves as a mediator that transforms the brittle powder into granules suitable for high-speed compression. These granules act as an intermediary material that can withstand the high compression speeds without lamination, enabling increased productivity while maintaining tablet integrity
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The process results in chemically stable, uniform amorphous ipatasertib with enhanced flowability and bulk density, enabling efficient high-speed tableting and improved tablet disintegration, while meeting ICH Q3C(R5) limits without additional drying steps.
Implementation Method 1
a rotary wheel type spray-drying process, produces amorphous ipatasertib with improved flowability and particle size distribution
Implementation Method 2
combined with fluid bed granulation and a rotary wheel type spray-drying process
Implementation Method 3
The use of intragranular materials with plastic deformation characteristics, such as microcrystalline cellulose, and moisture adsorbents
Implementation Method 4
ipatasertib exhibits a very high solubility (>1 g/g water; >2 g/g water/ethanol 1:1) and a very high hygroscopicity (∼6% at 50% RH, >35% at 95% RH)
Data Source
AI summary
The present invention relates to pharmaceutical compositions comprising Akt protein kinase inhibitors with therapeutic activity against diseases such as cancer as well as processes for their preparation and their use as medicament.