Compound A Salt Crystals for Solubility and Tableting
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Solution Overview
Problem
1-(2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl)cytosine (Compound A) suffers from low water solubility, poor flowability, and inadequate tableting properties, making it challenging for pharmaceutical manufacturing and human use.
Innovation Solution
The development of a crystal form of methanesulfonate or hydrochloride of Compound A, which exhibits superior crystallinity, high water solubility, non-deliquescent properties, improved flowability, and enhanced tableting properties, along with reduced environmental impact and scalability for large-scale production.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Compound A is used directly as a medicament, then it shows potent antitumor activity, but it has low water solubility which limits its pharmaceutical use
Solution Approach 1:
The patent applies parameter changes by converting Compound A into different salt forms (methanesulfonate and hydrochloride) with modified solubility parameters. The methanesulfonate salt shows water solubility of 3.8-7.9 mg/mL while the hydrochloride salt shows 2.3-4.7 mg/mL, both significantly improved over the parent compound while maintaining antitumor activity.
2Ease of manufacture
If Compound A is used for pharmaceutical manufacturing, then it can be produced, but it shows poor flowability and inadequate tableting properties
Solution Approach 1:
The patent modifies physical parameters by crystallizing Compound A into specific crystal forms with defined X-ray diffraction patterns. The methanesulfonate crystal form shows peaks at 2θ = 19.8, 21.8, 27.5, 28.4, and 29.9 degrees, while the hydrochloride form shows peaks at 9.2, 14.7, 15.7, 22.9, and 27.3 degrees. These crystalline forms exhibit improved flowability and tableting properties compared to the amorphous or poorly crystalline forms.
3Stability of the object's composition
If Compound A is stored in humid conditions, then it may be stable, but it shows deliquescent property which compromises storage stability
Solution Approach 1:
The patent changes the chemical parameter of Compound A by forming stable salt compounds. The methanesulfonate and hydrochloride salts show reduced deliquescent properties compared to the parent compound. The crystalline structures with specific lattice energies and hydration states provide resistance to moisture absorption, improving storage stability under various humidity conditions.
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 crystal form demonstrates superior antitumor activity, high water solubility, stability, and improved manufacturability, making it suitable as a bulk drug for medicinal applications.
Implementation Method 1
The inventors found that a crystal of methanesulfonate or hydrochloride of Compound A shows superior crystallinity and high water solubility
Implementation Method 2
a crystal of methanesulfonate of 1-(2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl)cytosine showing characteristic peaks at diffraction angles (2θ) of 19.8, 21.8, 27.5, 28.4, and 29.9 degrees in powder X-ray diffractometry
Data Source
Figure 1~2
Figure 3~4
AI summary
A superior antitumor agent is provided. A salt of 1-(2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl)cytosine shows at least one or more of such characteristics as (1) it has superior antitumor activity, (2) it shows superior crystallinity, (3) it shows high water solubility, (4) it does not show deliquescent property, (5) it shows superior flowability, (6) it shows superior tableting property, (7) it can be manufactured with less environmental load, and (8) it can be manufactured in a large scale, and therefore it is useful as a bulk drug for medicaments.