Fenofibrate Form IV Crystalline Solubility and Stability
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Solution Overview
Problem
Fenofibrate's existing crystalline forms, particularly Form I, exhibit poor solubility and stability, limiting its bioavailability and pharmaceutical value due to its insolubility in water and metastable nature.
Innovation Solution
A new crystalline form IV of fenofibrate is developed, characterized by specific X-ray diffraction and FTIR patterns, and a method involving mixing fenofibrate Form I with a polymer like polyvinylpyrrolidone or polyethylene-glycol, using a protic solvent, and controlled heating and cooling to achieve higher solubility and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If Form I of fenofibrate is used, then stability is maintained, but solubility remains poor
Solution Approach 1:
The patent applies parameter changes by transforming fenofibrate from its stable crystalline Form I to a metastable crystalline Form IV through controlled crystallization conditions. This phase transition changes the molecular packing arrangement in the crystal lattice, thereby improving solubility while maintaining acceptable stability for pharmaceutical use.
Solution Approach 2:
The patent creates a composite crystalline structure (Form IV) that combines fenofibrate molecules in a new spatial arrangement within the crystal lattice. This composite crystalline form exhibits different physical properties including enhanced solubility compared to the original Form I, while maintaining the chemical identity of fenofibrate.
2Quantity of substance
If Form II or Form III of fenofibrate is used, then solubility is improved, but stability deteriorates
Solution Approach 1:
The patent optimizes the stability parameter by developing Form IV, which maintains its crystalline structure under various storage conditions (temperature, humidity, light) without transforming to other forms. This controlled parameter change ensures that the solubility benefits of metastable forms are achieved while eliminating the instability problems of Forms II and III.
3Ease of manufacture
If conventional crystallization methods are used, then manufacturing simplicity is maintained, but product performance remains limited
Solution Approach 1:
The patent modifies the crystallization parameters including solvent selection (water or alcohol), temperature profile (heating to melt then controlled cooling), and pH control to produce Form IV. These parameter changes enable the formation of the desired crystalline form using simple conventional equipment, maintaining ease of manufacture while dramatically improving bioavailability through enhanced solubility.
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 IV demonstrates enhanced water solubility and stability, improving bioavailability and suitability for pharmaceutical production, with a simple, non-toxic, and environmentally friendly preparation method that maintains stability under various conditions.
Implementation Method 1
heating until fenofibrate melts
Implementation Method 2
cooling to crystallize
Data Source
AI summary
The present invention relates to Form IV of fenofibrate and its preparation methods thereof. Its X-ray powder diffraction pattern expressed as 2θ angle has characteristic peaks at 14.15±0.2°, 15.94±0.2°, 16.49±0.2°, 17.45±0.2°, 20.21±0.2°, and 22.87±0.2°. The present invention also provides preparation methods of Form IV. The preparation methods are simple, easy to operate, short, and have good repeatability. The methods are also non-toxic and non-polluting by using water as a medium and using a pharmaceutically accepted excipient, such as polyvinylpyrrolidone or polyvinyl alcohol as an inducer. The results of stability experiments (light exposure, high humidity and grinding) and solubility tests show that Form IV is stable and has a higher solubility than the prior art crystal form.