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When the stability of the drug molecule is poor and solubility is not good, we recommend screening for salt form or eutectic to obtain the desired solid form of the drug. Salt form is where the drug is ionized and bound to a counter ion to form a crystal, while eutectic is where the API molecule is bound to a CCF molecule in the same lattice. Developing salt/eutectic form of a drug is a common method of improving the physicochemical properties of drug molecules, enhancing drug stability, improving solubility and dissolution rate.
The salt/eutectic is prepared by screening the counter ion/eutectic formers (CCF) according to the pKa value of Free Base. Salt formation is generally recommended for ΔpKa ≥ 2 and eutectic formation for ΔpKa < 2.
Both salt and eutectic can significantly improve the physicochemical properties of drug molecules, such as melting point, solubility, dissolution rate, permeability, stability, bioavailability and mechanical properties, without breaking the covalent bonds of drug molecules, thereby improving their drug properties and reducing adverse effects. In drug development, salt/eutectic can be used to extend the patent protection period of a drug or to circumvent the patent protection of an originator drug. In industrial manufacturing, suitable salt/eutectics can also be used to improve drug compression performance and scale up.
The methods of crystallization for salt types include solution reaction crystallization, mixed suspension reaction crystallization and volatile crystallization.
The methods of crystallization for eutectics include solution crystallization and solid phase grinding crystallization.
2. Characterization and preparation
After obtaining salt/eutectics sample of the drug molecule, a variety of solid state analytical techniques are used to characterize the physicochemical properties of the individual salt/eutectics. Commonly used techniques include PXRD, TGA, DSC, GC, K-F etc.
• Powder X-Ray Diffraction (PXRD)
PXRD allows rapid and non-destructive analysis of multi-component mixtures without the need for extensive sample preparation. PXRD provides information on the microstructure in terms of diffraction peak shape, diffraction position and diffraction intensity. The diffraction position provides information on the shape and size of the crystal monoliths and the diffraction intensity gives an indication of the position of the atoms in the crystal structure.
• Thermal Gravimetric Analyzer (TGA)
TGA is an instrument that uses thermogravimetry to determine the “temperature-mass” relationship of a substance. It is highly quantitative and can accurately measure the change in mass of a substance and the rate of change to obtain information on the thermal stability of crystals, thermal decomposition and the composition of impurities.
• Differential Scanning Calorimetry (DSC)
DSC is a thermal analysis method that measures the power difference versus temperature between the input to the specimen and the reference material at a specific program-controlled temperature. With a wide temperature range (-175-725°C), high resolution and low specimen usage, this technique is widely used for the analysis of organic compounds, pharmaceuticals etc. It can quickly and accurately measure a wide range of thermodynamic and kinetic parameters such as reaction rate, crystallization rate, crystallinity and sample purity etc.
• Gas Chromatography (GC)
GC is a chromatographic method using gas as the mobile phase, which can be further divided into gas-liquid chromatography and gas-solid chromatography according to the different stationary phases. Gas chromatography has the advantages of high separation efficiency, low sample usage, high detection sensitivity and a wide range of applications. Depending on the type of resins used, gas chromatography can perform qualitative and quantitative analysis of drugs, determination of impurities, residual solvents, monitoring of drug intermediates, etc.
3. Dominant Salt/Eutectic evaluation
Once different salt/eutectics of the drug molecule have been prepared and characterized by a variety of techniques, the dominant salt/eutectic is evaluated. Our scientific team will adapt the salt/eutectics according to the intended use of the drug and will also measure parameters such as solubility, hygroscopicity, crystallinity, physical stability and processability. The aim of this phase if to achieve better dosage forms in terms of stability, solubility, efficacy and processability, which will have a significant impact on the development, manufacture, transport and clinical performance of the drug. Screening for superior salt/eutectics in early drug development can help pharmaceutical companies save significant time and money costs and reduce risk during the drug is developed and brought to market.
Subject: Eutectic screening of a drug
Background: API for eutectic screening (fewer drugs are currently marketed in eutectic form)
Difficulty: The stability of each crystalline form of API's Free Base and its acid salts is problematic.
Breakthrough: API and maleic acid were prepared by miscible suspension reaction crystallization to obtain eutectic crystals with good crystalline stability. Maleic acid eutectic crystals were used as the declared crystalline form, while a solution crystallization process for this eutectic was developed.