Valbenazine Ditosylate Form A Crystallization Yield and Solubility
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Solution Overview
Problem
Existing crystalline forms of valbenazine ditosylate, particularly Form I, suffer from low yield, poor solubility, high hygroscopicity, and adverse powder properties, which affect clinical efficacy and safety.
Innovation Solution
A new crystalline form, referred to as Form A, is developed with improved physicochemical properties, including higher yield, solubility, stability, and reduced hygroscopicity, achieved through a process involving the use of a 2-MeTHF and water co-solvate in anisole, with specific X-ray powder diffraction patterns and infrared spectrum characteristics.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If crystalline form I of valbenazine ditosylate is used, then the yield is low (69%), but the manufacturing process is well-established
Solution Approach 1:
The patent changes the crystallization parameters by using a different solvent system (2-MeTHF and water co-solvate in anisole) and temperature conditions (stirring at 4°C) to obtain crystalline form A with 84% yield, representing a 23-34% improvement over form I
Solution Approach 2:
The invention uses a composite solvent system consisting of 2-MeTHF, water, and anisole to create optimal crystallization conditions that simultaneously achieve high yield and good crystal properties, rather than using a single solvent
2Quantity of substance
If crystalline form I of valbenazine ditosylate is used, then the solubility is poor, but the formulation is simpler
Solution Approach 1:
The patent changes the physical state parameters of the drug substance by obtaining a different crystalline form (form A) with altered lattice energy and molecular packing, which directly improves solubility in aqueous media compared to form I
3Object-affected harmful factors
If crystalline form I of valbenazine ditosylate is used, then the hygroscopicity is high, but the storage conditions are simpler
Solution Approach 1:
The invention changes the crystalline structure parameters (lattice arrangement, intermolecular interactions) to produce form A which has lower hygroscopicity, thereby improving stability under ambient storage conditions without requiring special humidity control
4Ease of operation
If crystalline form I of valbenazine ditosylate is used, then the powder properties are adverse, but the handling is conventional
Solution Approach 1:
The patent changes the crystal morphology and particle size distribution by modifying the crystallization conditions (solvent system, temperature, stirring rate), resulting in form A with superior powder flowability and compressibility that enhances manufacturing efficiency
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
Form A exhibits increased yield, solubility, and stability, leading to enhanced bioavailability, reduced side effects, and improved manufacturing efficiency, while maintaining chemical and mechanical stability under various storage conditions.
Implementation Method 1
a process involving the use of a 2-MeTHF and water co-solvate in anisole
Implementation Method 2
crystalline form A of compound I ditosylate is provided
Data Source
AI summary
A crystalline form of valbenazine ditosylate, processes for preparation thereof, a pharmaceutical composition containing the crystalline form, use of the crystalline form for preparing vesicular monoamine transporter 2 inhibitor drugs, and use of the crystalline form for preparing drugs treating tardive dyskinesia.