Ceralasertib Tablet Formulation for High Drug Loading and Manufacturability
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Solution Overview
Problem
Ceralasertib exhibits poor flowability and hygroscopicity, requiring high drug loading for patient compliance, and current formulations face challenges in manufacturability, tensile strength, and stability, which are critical for commercial production and effective cancer treatment.
Innovation Solution
A pharmaceutical formulation comprising ceralasertib, dibasic calcium phosphate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and magnesium stearate, optimized for commercial scale production, ensuring suitable tensile strength, uniform drug release, and stability, with a focus on patient compliance through appropriate dosing frequency.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If high drug loading is used to improve patient compliance, then the number of tablets is reduced, but the tablet tensile strength and manufacturability become more difficult to achieve
Solution Approach 1:
The patent uses a composite formulation combining ceralasertib with microcrystalline cellulose (MCC) and low-substituted hydroxypropyl cellulose (L-HPC). This composite approach allows high drug loading (40-60% w/w) while maintaining tablet integrity through the synergistic properties of the excipients, particularly MCC which provides structural framework and L-HPC which enhances binding and tensile strength.
Solution Approach 2:
The patent optimizes particle size parameters of both the drug and excipients to improve flowability and compression characteristics. By controlling particle size distribution and using specific surface area measurements, the formulation achieves high drug loading while maintaining manufacturability and tablet strength through optimized physical parameters rather than chemical modification.
2Quantity of substance
If ceralasertib is formulated with high drug loading, then cost of goods is reduced, but manufacturability and process robustness become more challenging
Solution Approach 1:
The patent employs precise control of particle size parameters and surface area characteristics of ceralasertib and excipients to optimize flowability and compression behavior. This parameter optimization enables high drug loading formulations to be manufactured robustly at scale, addressing both cost reduction and manufacturability requirements simultaneously.
Solution Approach 2:
The patent uses low-substituted hydroxypropyl cellulose (L-HPC) as an intermediary binding agent that facilitates the incorporation of high amounts of ceralasertib into the tablet matrix. L-HPC acts as a mediator between the drug particles and microcrystalline cellulose framework, enabling high drug loading while maintaining process robustness and manufacturability through improved interparticle bonding.
3Stability of the object's composition
If ceralasertib is used as a crystalline material, then stability is improved, but flowability deteriorates
Solution Approach 1:
The patent creates a composite powder system where ceralasertib crystals are blended with microcrystalline cellulose and L-HPC in specific ratios. This composite approach maintains the chemical stability of crystalline ceralasertib while the excipient matrix improves overall flowability through better interparticle friction characteristics and reduced hygroscopicity of the blend compared to pure drug material.
Solution Approach 2:
The patent applies local quality modification by coating or adsorbing excipient materials onto the surface of ceralasertib crystals. This creates a interface layer that preserves the stable crystalline structure of the drug core while the surface layer provides improved flowability and reduced hygroscopicity, allowing the material to maintain stability while improving processing characteristics.
4Strength
If compression force is increased to improve tablet tensile strength, then tablet strength is improved, but dissolution rate becomes variable and porosity is compromised
Solution Approach 1:
The patent uses a composite formulation with microcrystalline cellulose and L-HPC that provides inherent structural support and binding, allowing tablets to achieve adequate tensile strength at moderate compression forces. This composite matrix structure maintains porosity and dissolution pathways even at lower compression levels, ensuring uniform drug release while avoiding the over-compression problems that would compromise dissolution uniformity.
Solution Approach 2:
The patent applies partial compression action by using moderate compression forces that are sufficient to achieve adequate tablet strength through the excipient framework, but not excessive enough to collapse the porous structure or create variable compression zones. This partial action approach maintains dissolution uniformity while achieving sufficient mechanical strength through the optimized excipient composition rather than relying on high compression forces.
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AI summary
A pharmaceutical formulation which comprises ceralasertib, dibasic calcium phosphate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose and magnesium stearate is described.