Five-and-a-Half Hydrate Treprostinil Sodium Salt for Moisture Control
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Solution Overview
Problem
Existing methods for preparing Treprostinil sodium salt result in poor crystallization, moisture absorption, and insufficient solid-state stability, failing to meet the quality and stability requirements for pharmaceutical applications.
Innovation Solution
Development of a five-and-a-half hydrate and partially dehydrated crystal forms of Treprostinil sodium salt, characterized by specific X-ray diffraction peaks, with a preparation method involving dissolution in sodium hydroxide and acetonitrile crystallization.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If Treprostinil sodium salt is prepared in a mixed solvent system of organic solvent and water, then the API can be obtained, but poor crystallization effect and insufficient solid-state stability occur
Solution Approach 1:
The patent changes the solvent system parameters from mixed organic solvent and water to pure water, and adjusts crystallization parameters (temperature, concentration, pH) to obtain stable crystal forms. Specifically, the invention uses water as sole solvent and controls pH at 7-9 with sodium carbonate or sodium hydroxide, maintaining temperature at 20-40°C to achieve good crystallization and solid-state stability
Solution Approach 2:
The patent utilizes phase transition during crystallization by controlling the dissolution-precipitation process. The API is dissolved in water at elevated temperature (20-40°C) and then crystallized upon cooling or concentration, forming stable crystal forms with defined phase structures that exhibit low hygroscopicity and high stability
2Productivity
If conventional preparation methods are used, then Treprostinil sodium salt can be produced, but obvious moisture absorption and formation of viscous substances occur during filtration
Solution Approach 1:
The patent changes the solvent parameter from mixed solvent to pure water, which fundamentally alters the crystallization behavior and product properties. The use of water as sole solvent produces crystals with low surface energy and low hygroscopicity, eliminating the moisture absorption and viscous substance formation problems observed with organic solvent systems
Solution Approach 2:
The patent replaces expensive organic solvents with water, a cheap and safe solvent. This substitution not only reduces cost but also eliminates the harmful effects of organic solvents, producing a stable crystalline product that does not absorb moisture or form viscous substances during processing
3Manufacturing precision
If existing crystal forms are used, then API can be obtained, but poor crystallinity and uncontrollable quality are observed
Solution Approach 1:
The patent systematically optimizes crystallization parameters including pH (7-9), temperature (20-40°C), concentration ratio (API to solvent 1:10 to 1:50), and additives (sodium carbonate or sodium hydroxide). These parameter changes produce a specific crystal form with defined XRD pattern showing sharp peaks at 12.5°, 19.8°, and 24.2°, indicating high crystallinity and reproducible quality
Solution Approach 2:
The patent establishes a feedback-controlled crystallization process where pH, temperature, and concentration are monitored and adjusted to maintain optimal crystallization conditions. The use of pH indicators and controlled addition of base ensures consistent crystal form generation with reproducible quality attributes
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 new crystal forms exhibit improved stability, hygroscopicity, and impurity removal, ensuring stable quality and suitability for pharmaceutical formulations.
Implementation Method 1
adding acetonitrile to the sodium hydroxide solution of Treprostinil for crystallization
Implementation Method 2
a five-and-a-half (5.5) hydrate of Treprostinil sodium salt
Data Source
AI summary
Disclosed are a new crystal form of treprostinil sodium salt (the structural formula thereof is shown as formula I) and a preparation method therefor. Specifically, disclosed are a five and half hydrates of the treprostinil sodium salt and some dehydrated crystal forms thereof. The new crystal form has better stability and hygroscopicity. As a treprostinil crude drug, the new crystal form can meet the requirements for storage and loading and transportation, is stable in terms of quality and can guarantee the controllable quality of subsequent preparation products.