Pimitespib Granulated Composition for Disintegration and Bioavailability
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Solution Overview
Problem
Existing pharmaceutical compositions for oral administration of 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide (compound 1) face challenges in achieving both stability and excellent disintegratability and bioavailability, with direct tableting methods often failing due to compound characteristics.
Innovation Solution
A pharmaceutical composition is developed by granulating compound 1 or its pharmaceutically acceptable salt and adding predetermined crystalline cellulose, specifically Ceolus PH-102, PH-302, KG-802, or UF-711, with an L/D ratio of 1.00 to 4.00 and bulk density of 0.20 to 0.50 g/cm³, to enhance disintegratability and bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If direct tableting method is used for compound 1, then manufacturing process is simple, but tableting fails due to sticking
Solution Approach 1:
The patent applies preliminary action by performing granulation before tableting. The active ingredient compound 1 is first granulated with binders and excipients to form granules, which are then dried and sifted before tableting. This preliminary granulation step prevents sticking during tableting by creating a more flowable mixture, thus resolving the contradiction between simple manufacturing and reliable tableting success.
Solution Approach 2:
The patent uses binders and excipients as intermediary substances during granulation. These intermediaries facilitate the formation of stable granules that can be tableted without sticking. The binders act as mediators to bind particles together, while excipients like lubricants prevent sticking during the tableting process, thus enabling reliable tableting while maintaining manufacturing simplicity.
2Ease of operation
If granulation method is used, then disintegratability is improved, but manufacturing complexity increases
Solution Approach 1:
The patent applies parameter changes by optimizing granulation conditions such as binder concentration, granulation time, moisture content, and drying temperature. By carefully controlling these parameters, the process achieves excellent disintegratability while minimizing the complexity increase. The patent specifies particular ranges for these parameters to balance performance and manufacturability.
3Ease of operation
If crystalline cellulose is added to granulated product, then disintegratability and bioavailability are enhanced, but formulation complexity increases
Solution Approach 1:
The patent uses composite materials by combining crystalline cellulose with the granulated product containing compound 1. The crystalline cellulose serves as a disintegrant and bioavailability enhancer, working synergistically with the granule structure. This composite approach improves disintegratability and bioavailability while adding manageable formulation complexity through specified cellulose types and ratios.
Data Source
AI summary
Provided is a pharmaceutical composition containing compound 1, the pharmaceutical composition having excellent disintegratability and bioavailability. The pharmaceutical composition comprises: a granulated product containing 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a pharmaceutically acceptable salt thereof; and crystalline cellulose, and has a disintegration time of within 360 seconds in a coated tablet form.