Salmeterol Xinafoate Polymorph I Crystallization
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Conventional methods for producing micronized salmeterol xinafoate suffer from poor powder flow properties and economic disadvantages due to the use of supercritical fluids or mixed solvents, making them unsuitable for industrial-scale production with good stability and flowability.
Innovation Solution
A novel micronizable form of salmeterol xinafoate polymorph I is developed, characterized by a mean particle size between 5 and 15 µm and a bulk density between 0.1 to 0.2 g/mL, achieved through a conventional crystallization process involving seeding a solution in an organic solvent and subjecting it to a stepwise profile cooling process, which is economical and easily industrialized.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If conventional crystallisation process is used to produce salmeterol xinafoate, then the drug substance can be obtained, but the powder flow properties are very poor making it unsuitable for micronisation
Solution Approach 1:
The patent applies parameter changes by modifying the crystallisation conditions (temperature profile, cooling rate, solvent composition) to produce salmeterol xinafoate with altered physical properties. The specific parameter changes include controlling crystallisation temperature between -10°C to 50°C and adjusting cooling rates to achieve particles with mean size 5-15 μm and bulk density 0.1-0.2 g/mL, which exhibit improved flow properties and micronisability while maintaining polymorph I structure
Solution Approach 2:
The patent employs preliminary action through a two-stage process: first producing micronisable crystals with controlled size and morphology through specific crystallisation conditions, then performing size reduction to achieve the final respirable particle size distribution. This preliminary preparation of crystals with suitable properties enables successful micronisation and improves powder flow before final processing
2Ease of manufacture
If fast cooling crystallisation process is used to produce spherical agglomerates, then good flowability is achieved, but the process complexity increases
Solution Approach 1:
The patent achieves good flowability through parameter changes in the crystallisation process, specifically controlling temperature profiles and cooling rates to produce particles with bulk density 0.1-0.2 g/mL and mean size 5-15 μm. These parameter adjustments create particles with inherent good flow properties without requiring complex processing equipment or additional formulation steps
3Productivity
If supercritical carbon dioxide crystallisation is used, then micronisation is avoided, but the equipment complexity and cost increase
Solution Approach 1:
The patent employs conventional crystallisation equipment and standard size reduction machinery instead of expensive supercritical fluid equipment. The approach uses readily available crystallisers and micronisers, making the process more economically viable and easier to implement in standard pharmaceutical manufacturing facilities
Solution Approach 2:
The patent segments the process into conventional crystallisation followed by size reduction, rather than attempting to produce final respirable particles in a single supercritical fluid step. This segmentation allows use of simpler, more economical equipment for each stage while achieving the same ultimate goal
4Reliability
If SEDS technology is used to produce high pure polymorphs, then purity is improved, but the use of supercritical fluids makes the procedure economically disadvantageous
Solution Approach 1:
The patent achieves high purity polymorph I through parameter changes in conventional crystallisation, specifically controlling temperature profiles, cooling rates, and solvent composition. These parameter adjustments ensure preferential crystallisation of the desired polymorph with purity comparable to SEDS technology, but using economical conventional equipment and solvents
Solution Approach 2:
The patent replaces expensive supercritical fluids with conventional organic solvents that are easier to handle, more economical, and compatible with standard pharmaceutical manufacturing infrastructure. The process uses readily available solvents and equipment while maintaining high product purity through controlled crystallisation parameters
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 novel form exhibits improved stability and flowability, facilitating efficient micronization and enabling effective delivery by inhalation or insufflation with reduced bulk density and cohesive forces, thus overcoming the limitations of existing methods.
Implementation Method 1
seeding a solution of salmeterol xinafoate in an organic solvent with salmeterol xinafoate polymorph I at a temperature approximately between 40 and 50°C; subjecting the seeded solution of step a) to a stepwise profile cooling process
Data Source
AI summary
The present invention relates to micronisable salmeterol xinafoate polymorph I characterized by a mean particle size between 5 and 15 μm and a bulk density between 0.1 and 0.2 g/mL, to a method for its preparation and to its use in the preparation of micronised salmeterol xinafoate.