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Crystal form screening & Developability Assessment
Compounds can exist in two or more crystalline states. When the same molecule is crystallized in different crystalline forms, its bioavailability, solubility, dissolution rate, physico-chemical stability, melting point and other properties may be different. Therefore, crystallization screening focuses on obtaining the various possible solid forms of a drug through high-throughput screening and screening out the superior drug crystalline forms that are easy to produce, highly bioavailable and formulation-friendly. Excellent crystallization screening is an efficient method to reduce R&D risks, reduce production costs and improve product quality.
Innovative drugs：Crystal form study is a key step in the development of innovative drugs. Screening for the right crystal form plays a crucial role in improving the pharmaceutical developability of raw materials and extending the life cycle of innovative drugs.
Generic medicines：It is difficult to screen crystal form during generic drug development. However, effective study of crystal form can help generic drugs break through the new crystallographic protection of commercialized drugs during development, thus breaking the original patent and accelerating to market.
1. Crystal form screening
One or more unknown crystal form may be present in the sample. When we design the protocol, all possible crystal forms should be screened by corresponding techniques (e.g. chemical recrystallization, rapid solvent removal, physical lattice disruption, etc.) in combination with the properties of the compound. We will also growth crystal forms as many as possible according to the crystallization and culture ways of the compounds.
2.Characterization and preparation
After obtaining polymorphic forms of a specific drug molecule, a variety of analytical techniques are used to characterize the physicochemical properties of the individual crystal forms. Commonly used techniques include PXRD, TGA, DSC, GC, K-F etc.
• Powder X Ray Diffraction (PXRD)
Powder X ray diffraction (PXRD) diffraction 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 between the input to the specimen and the reference material as a function of temperature 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, 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. Crystal form evaluation
After preparing different crystal forms of the same drug molecule and obtaining their respective characterization information through a variety of techniques, the crystallization phase of the drug will be evaluated. Our team of expert researchers will evaluate each crystal form for its physical and chemical properties, physicochemical stability, process exploitability, interconversion, powder properties, solubility, crystal habit, etc. to ensure the selection of a crystal form with good safety, stability, exploitability and drug efficacy.
Subject:Generic drug crystal form screen
Background:Structure of the API is sugar ring (hydrogen bonded), it is difficult to crystallize, and the original crystal form is a solvate.
Difficulty:None of the conventional crystal form screening methods can obtain an amorphous form (mostly declared as amorphous in China).
Breakthrough: API was frozen with solvent to obtain multiple pipeline solvates, which in turn were desolvated to obtain crystal-free forms. By comparing the physicochemical properties of each crystal form such as melting point, crystallinity and moisture attraction, the crystal form E was finally determined as the declared crystal form.