Valnemulin Hydrochloride Hydrate Crystal Form for Stable Formulation
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Solution Overview
Problem
Existing valnemulin hydrochloride drugs are predominantly amorphous, leading to issues such as poor stability, hygroscopicity, and difficulty in formulation due to low bulk density and solubility, which affects their efficacy and bioavailability.
Innovation Solution
Development of a valnemulin hydrochloride hydrate crystal form with characteristic X-ray diffraction peaks and a preparation method involving thermal dissolution in organic solvents and purified water, followed by cooling and solvent equilibration to achieve high bulk density and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If ordinary crystallization methods are used to prepare valnemulin hydrochloride, then the production process is simple, but the product remains amorphous with poor stability and hygroscopicity
Solution Approach 1:
The patent applies parameter changes by modifying the crystallization conditions including using specific solvent systems (water-alcohol mixtures), controlling temperature ranges (cooling from room temperature to 4°C), and adjusting concentration parameters to transform the amorphous product into a stable crystal form with defined XRD patterns
Solution Approach 2:
The patent utilizes phase transitions by inducing crystallization from an amorphous state to a crystalline state through controlled cooling and solvent equilibration processes, resulting in a hydrate crystal form with specific water content (5-15%) and characteristic diffraction peaks
2Ease of manufacture
If amorphous valnemulin hydrochloride is used, then the product can be produced easily, but it exhibits poor fluidity and difficult storage
Solution Approach 1:
The patent changes the physical state parameters by forming a hydrate crystal structure with specific water content (5-15%), which fundamentally alters the material's handling properties, improving bulk density, fluidity, and storage stability compared to the amorphous form
3Reliability
If cooling-ultrasonic crystallization method is used, then the product shows improved hygroscopicity, but the crystallization process is not easy to industrialize
Solution Approach 1:
The patent extracts the ultrasonic treatment step from the process, achieving crystallization through simple cooling and solvent equilibration without ultrasonic assistance, thereby maintaining improved hygroscopicity while enabling easy industrialization through conventional equipment
Solution Approach 2:
The patent replaces expensive and complex ultrasonic crystallization equipment with simple, inexpensive conventional crystallization equipment, achieving the same crystallization effect through cost-effective means suitable for industrial production
4Object-affected harmful factors
If solvent-free compound is prepared from solvent-containing compound, then the bulk density is reduced to 0.305 g/ml, but the process eliminates solvent residues
Solution Approach 1:
The patent changes the physical form parameters by producing a hydrate crystal form with water molecules incorporated into the crystal lattice, which increases bulk density to 0.45-0.65 g/ml while maintaining solvent-free characteristics through controlled crystallization that excludes organic solvents
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 hydrate crystal form exhibits improved stability, non-hygroscopicity, and enhanced bulk density, facilitating its use in various pharmaceutical preparations like tablets, injections, and oral liquids.
Implementation Method 1
thermally-dissolving valnemulin hydrochloride in a mixture of organic solvent/purified water
Implementation Method 2
cooling at -5 °C to 15 °C to precipitate a crystal from the mixed solution
Implementation Method 3
drying the filter cake A under vacuum at 20 °C to 40 °C
Data Source
Figure 1~2
Figure 3~4
Figure 5~6
AI summary
The present application relates to a crystal form of a valnemulin hydrochloride hydrate, a preparation method therefor, and a pharmaceutical composition containing the crystal form. Specifically, the present application relates to a crystal form of a valnemulin hydrochloride hydrate, wherein the crystal form shows characteristic peaks 2θ at 9.2+/-0.2°, 9.5+/-0.2°, 10.3+/-0.2°, 11.8+/-0.2°, 12.3+/-0.2°, 12.8+/-0.2°, 15.1+/-0.2°, 17.5+/-0.2°, and 18.2+/-0.2° in an X-ray powder diffraction pattern. The crystal form of the valnemulin hydrochloride hydrate has a high bulk density, no hygroscopicity, and good stability. The present application also provides a method for preparing the above crystal form of the valnemulin hydrochloride hydrate and a pharmaceutical composition containing the crystal form, wherein the composition can be used for preparing various preparations, such as a soluble powder, an oral liquid, a sustained-release particle, an injection, and other dosage forms, and has broad clinical application prospects.