API Separation from Excipients via Density Gradient Centrifugation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current methods, such as HPLC, are inadequate for analyzing the crystal form of active pharmaceutical ingredients (APIs) in pharmaceutical formulations due to interference from excipients, and existing techniques like XRPD, infrared, and Raman spectroscopy are limited by the need to separate APIs from excipients without dissolving them.
Innovation Solution
A density separation method using liquid media with selected densities, where the API is insoluble, to physically separate APIs from excipients, allowing for characterization by standard techniques like XRPD, DSC, and solid-state NMR.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If HPLC is used to analyze the API, then the analysis of the compound itself is accomplished, but the crystal form of the API cannot be determined
Solution Approach 1:
The patent applies segmentation by physically separating the API from excipients using density gradient centrifugation. This divides the formulation into distinct components based on density differences, allowing the API to be isolated in a purified state for subsequent crystal form analysis by XRPD and other spectroscopic techniques.
Solution Approach 2:
The patent extracts the API from the formulation matrix by utilizing density-based separation. The API is taken out from the mixture of excipients through controlled density gradient centrifugation, enabling independent characterization of its crystal form without interference from other formulation components.
2Measurement precision
If XRPD and spectroscopy techniques are used for crystal form analysis, then crystal form characterization is achieved, but the presence of excipients interferes with the analysis
Solution Approach 1:
The patent extracts the API from the formulation matrix by utilizing density-based separation. The API is taken out from the mixture of excipients through controlled density gradient centrifugation, enabling independent characterization of its crystal form without interference from other formulation components.
Solution Approach 2:
The patent introduces a density gradient medium as an intermediary substance that facilitates separation between the API and excipients. This mediator allows differential sedimentation based on density differences, effectively isolating the API for clean spectral analysis.
3Ease of manufacture
If dissolution is used to separate API from excipients, then separation is achieved, but the crystal form is lost in solution
Solution Approach 1:
The patent replaces the chemical dissolution process with a physical separation method based on density gradient centrifugation. This mechanical/physical approach separates components based on density differences while maintaining the solid-state crystal structure of the API, avoiding the loss of crystal form information that occurs with dissolution.
Solution Approach 2:
The patent changes the separation parameter from chemical solubility (dissolution) to physical density differences. By utilizing density gradient centrifugation, the separation is achieved based on density parameters rather than solubility, thereby preserving the crystal form while still achieving effective separation from excipients.
4Measurement precision
If density separation is performed to isolate API, then excipient interference is eliminated, but multiple separation steps are required to achieve high purity
Solution Approach 1:
The patent applies dynamics by using a continuous density gradient that allows for dynamic separation. The gradient creates a range of densities that enable different components to separate at different positions, achieving high purity in a single centrifugation step rather than requiring multiple discrete separation operations.
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
Effectively separates APIs from excipients, enabling precise characterization of the API's crystal form, melting point, and state of hydration, achieving purity levels of 85% to 99% by weight and maintaining the API's solid form.
Implementation Method 1
The liquid separation media are generated by mixing two miscible liquids, one less dense and one denser, so that liquid separation media having a wide range of precisely selected densities may be produced
Implementation Method 2
The powdered form of the formulation, including API particulates and excipient particulates, may be introduced to a vessel containing the first liquid separation medium. The vessel containing the first liquid separation medium and the particulates may then be centrifuged so that the particulates having a density less than the density of the first liquid separation medium are floated to form a first floated fraction while the particulates having a density greater than the first liquid separation medium forms a first pellet fraction
Data Source
AI summary
The present invention provides a method for physically separating the active pharmaceutical ingredient (API) from the excipients in a pharmaceutical formulation before the API is fully characterized by standard techniques. The presently disclosed method is based on making use of the difference in density of the API and that of the excipients. In the method, the API is not dissolved, nor is the crystal form of the API changed.