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    Home > Biochemistry News > Biotechnology News > Talk about drug cocrystalline preparation technology

    Talk about drug cocrystalline preparation technology

    • Last Update: 2021-02-23
    • Source: Internet
    • Author: User
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    The early stages of research and development of new drug projects require screening of compound molecules and a comprehensive assessment of their physical, biological and production feasibility.
    recognition of compound properties will pose significant challenges to late-stage research and development, and there is even a risk of changes to candidate compounds.
    solid forms (Solidforms) of different APIs, such as crystalline, amorphous, solvent, salt and cocrystalline, differ in physical and chemical properties, mechanical properties, chemical stability, bio-utilization and process feasibility.
    the screening of API solid-state forms and the locking of clinical drug compound molecules are important part of the development of new drugs.
    API can form two types of solid-state forms, crystalline and amorphoous.
    crystalline states include polycrystalline, solvent, salt and cocrystalline.
    only API molecules are contained in polycrystalline cells.
    molecules are introduced in solvents, salt types and cocrystalline cells in addition to API molecules.
    as shown in Figure 1 for the API solid-state classification.
    amorphoation has higher free energy and stronger molecular activity than crystalline state, and therefore has better solubility.
    high freedom can make amorphous stability poor, high temperature or long-term preservation has the tendency to turn into crystalline state.
    API molecules often choose crystalline states for development.
    form polycrystalline forms in different ways and filling forms of molecules or atoms within a compound in lattic space.
    common polycrystalline phenomenon in organic matter.
    polymorphisms differ in melting point, density, crystal form (crystal habit or crystalline habit), moisture absorption, stability, solubility, solubility, etc., and thus reflect different bio-utilization degrees.
    potential crystals for therefore efficient screening of compounds are of strategic importance for the selection of clinical supply molecules.
    solvent molecules enter the cells and bond with the compound molecules during crystallization, solvents are formed.
    molecules present in the cells affect the inter-molecular forces, thus changing the physical and chemical properties of solvents.
    solvent stability is poor, it is easy to lose solvent molecules during drying or storage into amorphomorphoies or other crystalline, thus changing the physical and chemical properties.
    ionized API molecules (cations and anions) and anti-ions combine through ion bonds to form a drug salt type.
    salt type is a common means of API correction, according to statistics, about 50% of the declared crystal types of drugs are salt type.
    non-ionized compound molecules cannot be salted and need to be cocrystalline with ligation molecules.
    EMA defines cocrystalline as an ionized crystal formed by combining two or more components in a cell with a certain chemical metering ratio of non-ion bonds.
    APIs and liants can be acids, alkalis, or neutral compounds.
    for ion compounds, API and lithosomes bind to non-ion bonds to form cocrystallines.
    fda uses the difference between the API and the dissocation constant of the lison, pKa, to distinguish between salinity and cocrystalline.
    is when the pKa-lt;1, the formation of cocrystalline.
    is more likely to form a salt type if it is 2.7 to 3.
    can be used to distinguish between salt type and cocrystalline by using effective detection methods such as single crystal diffraction, Raman spectroscopy and nuclear magnetic resonance.
    , it should be pointed out that the salt type and cocrystalline also exist polycrystalline and solvent phenomenon.
    but it is rarer than the API molecule itself.
    the general cocrystalline solubility is higher than that of API polycrystalline and has a good solubility and bio-utilization.
    cocrystalline is an effective method to improve the solubility of BSC II. and IV. compounds.
    is described in detail from the three aspects of cocrystalline preparation technology, cocrystalline screening method and cocrystalline production process.
    2 cocrystalline preparation method directly affects the physical and chemical properties of finished product content, crystalline, particle size distribution and crystalform.
    we should fully understand the solubility and thermal stability of API, ligation and cocrystalline, consider the energy consumption, unit yield, process amplification feasibility and regulation of the preparation method, and choose the optimal method for development.
    the cocrystalline preparation technology is divided into solvent-dependent and solvent-free according to whether solvents are involved in the method.
    solvent-dependent type is a traditional cocrystalline preparation method, which should be widely used for cocrystalline screening and batch production at different sizes.
    solvent-free cocrystalline preparation technology upholds the principle of green chemical industry, the preparation process does not require the participation of solvents, reducing the possibility of solvent production.
    the following cocrystalline preparation technology to introduce one by one.
    2.1 solvent-dependent cocrystalline preparation technology 2.1.1 evaporative crystallization The method is to dissolve the API and lid in a certain proportion in the solvent.
    decompression heating evaporation solvent to make cocrystalline extraction.
    simple and efficient, it is a common method of cocrystalline screening.
    the ratio of the material and the crystallization temperature to the analysis of the ingredients.
    it is necessary to construct API-lix-solvent trational system phase diagram, in the cocrystalline crystallization area and other temperature evaporation to obtain cocrystalline.
    if evaporated in the API or lithostal crystalline region, there is a risk of the development of single-parts.
    addition, evaporative crystallization may obtain cocrystalline solvents.
    2.1.2 Cooling crystallization Cooling crystallization by reducing the temperature, so that the solution obtains oversaturation, thereby the cocrystalline.
    cooling crystallization also requires a 3-way system phase diagram as a guide.
    selected system points are in an unsaturated zone at high temperatures, at which point the ratio is distributed according to each group of system points, equal temperature balance stirring, API and the ingredients can be completely dissolved.
    is then cooled, and the system point is located in the cocrystalline crystalline region in the low-temperature binary phase diagram, where the cocrystalline can be obtained by stirring at the same temperature.
    2.1.3 Dissolved crystallization Reduces the solubility of the solution in the solution by adding anti-solvents (bad solvents), and increases the oversaturation of the solution to promote the nucleation of the crystal, which is the solution crystallization.
    is essential for the selection of dissolved crystals, solvents and anti-solvents.
    the two should be mutually soluble, and cocrystalline in the mixed solvent should have a small solubility.
    , it is possible to optimize the solvent-to-anti-solvent ratio and ensure yield without solvent generation.
    when the solubility of cocrystalline in the mixed solvent is significantly lower than that of the pure solvent, priority can be given to the dissolving crystallization.
    can be carried out at ambient temperatures, reducing energy consumption compared to evaporative crystallization and cooling crystallization.
    2.1.4 balanced stirring crystal at a certain temperature, the API, lid and cocrystalline added to the solution medium temperature stirring.
    if the cocrystalline is a stable equilibrium solid phase at this temperature, the API and liants dissolve continuously during the pulping process, increasing the oversaturation of the solution and dissecting the cocrystalline.
    the nucleation and growth consumption solution persaturation of the cocrystalline, while API and liant dissolution compensate for the oversaturation of the solution.
    finally balance solid phase only cocrystalline.
    the pulping method is simple, the product is pure cocrystalline, effectively avoid the API or ligand analysis.
    usually requires a longer balancing stirring time and there is a risk of obtaining solvents.
    often use the slurry method for cocrystalline screening.
    2.1.5 ultrasound-assisted ultrasound can reduce the induction period into a nucleus, shorten the median region, so that the solution in a low oversaturation spontaneous nucleation.
    ultrasound is often used as an auxiliary means in the crystallization process of the solution to promote crystal nucleation.
    ultrasonic solution crystallization method can be used to obtain a specific ratio of cocrystalline, can also be applied to cocrystalline screening.
    2.1.6 Supercritical Fluid Technology is a supercritical fluid technology that reduces pressure to produce oversaturation in a supercritical state, allowing solids to crystallize from supercritical solutions.
    supercritical fluid has the properties of both liquid and gas, the diffusion coefficient is large, the viscosity is small, the permeability is good, the mass can be completed more quickly, the balance is achieved, and the high efficiency separation is promoted.
    is used as a supercritical fluid there are many substances, CO2 critical temperature close to room temperature, critical pressure is easy to achieve, colorless, non-toxic, tasteless, non-flammable, chemical inert, cheap, easy to make high purity gas, in the experimental use of more applications.
    has put forward a variety of supercritical techniques, among which the process of supercritical rapid expansion (RESS) and anti-solvent crystallization (SAS) is more in-depth, and has a wide range of applications in drug preparation.
    RESS method uses the characteristics of the solute solubility with the supercritical fluid density, the solute solubility decreases sharply from the supercritical fluid state to the low temperature and low pressure gas state.
    the API and the mating body dissolved in supercritical fluids and expanded rapidly through special nozzles, resulting in a large number of nucleosomes due to a sudden increase in the oversaturation of the solution in a very short period of time.
    the chemical and chemical properties of the finished product can be adjusted by temperature, pressure, nozzle caliber, fluid spewing speed, etc.
    the current RESS method is mainly laboratory-scale research, mainly focused on the exploration of test conditions, for the rational research is not perfect enough, industrial application is very lacking, process amplification equipment is not mature.
    SAS method can solve the problem of poor solubility of drugs in supercritical fluids.
    and the method can be produced continuously, increasing the yield per unit of time.
    process principle is: some compounds are soluble in organic solvents, but not in supercritical fluids.
    At high pressure, gases such as CO2 are highly soluble in most organic solvents, and when the pharmaceutical solution and supercritical fluid are sprayed into the sedimentator at the same time, the solvent volume expands rapidly after the two liquids are mixed with each other, and the solution reaches a high oversaturation state to precipitate the drug core.
    the lack of this method is that the two solutions in a very short period of time is difficult to achieve even mixing, the solution of local oversaturation is not uniform resulting in uneven product granularity, and easy to cause reunion.
    report on the SAS process is still mainly based on laboratory and pilot scale.
    because the collection of solid materials is difficult to achieve continuity, so only a small number of semi-continuous production has been reported.
    applications of RESS and SAS processes in cocrystalline preparation, for example.
    padrela and so on.
    resS method: the API and the mating body are dissolved in supercritical CO2 in a high-pressure closed container.
    solution is sprayed by nozzle decompression, and the supercritical fluid expands rapidly to obtain the finished product.
    , the supercritical CO2 is sprayed into the precipitation chamber at the same time with the pharmaceutical solution, which expands rapidly to obtain crystal particles.
    test results show that the RESS method failed to obtain cocrystalline, and the SAS method successfully prepared the cocrystalline of pyridine-saccharin.
    2.1.7 Spray drying Spray drying is the rapid injection of the drug-containing solution from the nozzle, the formation of fog droplets through high temperature drying air flow is quickly steamed dry to obtain solid powder.
    the use of spray drying technology for cooling crystallization method is difficult to prepare cocrystalline material system.
    compared with supercritical fluid technology, spray drying cost is low, in the laboratory scale to the production scale are used.
    experimenters can use small test equipment to explore parameters, and then assess the feasibility of amplification, reduce production risks.
    general spray drying solution for aqueous solution, if the use of organic solvents need to do explosion-proof treatment, increase the cost of equipment.
    also spray drying is not suitable for thermally sensitive systems.
    2.1.8 freeze-drying Freeze-drying is to reduce pressure after rapid freezing of a certain concentration of pharmaceutical-containing solution, solvent sublimation, cocrystalline.
    the solvent sublimation process produces a very high degree of oversaturation, often obtain the drug cocrystalline amorphous shape.
    amorphoation is crystallization by saving or heating recrystration.
    method is stable, easy to enlarge and has a high yield.
    not suitable for less soluble systems.
    diffusion of steam 2.1.9 is commonly used in monocrystalline culture and is a relatively rare cocrystalline preparation technique.
    the general drug in the water solubility difference, high humidity conditions, water vapor diffusion into the drug solution, so that the solubility is reduced, resulting in oversaturation to produce crystals.
    the diffusion of steam is characterized by a slow increase in local supersaturation of the surface of the solution, which promotes stable crystalline nucleation.
    the key to this method is the choice of benign solvent and bad solvent vapor, which should be soluble, and the solubility of cocrystalline in mixed solvent should be significantly lower than that of benign solvent.
    preparation of non-performing solvent vapor energy consumption is high, low yield, can hardly be applied to industrial production, suitable for laboratory-scale cocrystalline screening.
    2.1.10 High-pressure homogeneity High-pressure homogeneity is often used in food engineering, and is a relatively novel technical method in the pharmaceutical field.
    process includes the injection of mechanical energy and the crushing of particles in the suspension.
    mechanical energy accelerates the interaction between the API and the li piping to produce cocrystallines.
    the mixture is stirred at a certain temperature in the autoclave and sprayed from the high-pressure pump to the homogenizer.
    decompression and high-speed flow allow the suspension particles to be fully mixed to form a cocrystalline.
    to prevent solvent production, liquid CO2 can be used as a mixed-suspension solvent.
    non-toxic, non-flammable and affordable characteristics of liquid CO2 make it as a green solvent in the decompression process with the finished particles.
    high-pressure homogeneity will be cocrystalline preparation and granularity control into one, without the need to crush the product again, reduce energy consumption, improve yield.
    2.2 solvent-free cocrystalline preparation technology 2.2.1 grinding 2.2.1.1 dry grinding the resulting machinery enhances the interaction between the API and ligand molecules to form a cocrystalline.
    grinding methods are divided into artificial grinding and mechanical grinding.
    poor reproduction of artificial grinding and is often used in laboratory cocrystalline preparation.
    ball mill is a commonly used equipment for mechanical grinding, adding stainless steel, tungsten carbide or zirconium oxide balls to the cylinder body to mix the material evenly and increase the input of mechanical energy to promote the formation of cocrystalline.
    the mechanism of grinding legal cocrystalline is not clear, but it can be divided into three kinds: molecular diffusion, the formation of co-integration and non-stereotyped recrystration.
    three thermodysms have their own mesostatic states, namely gaseous (molecular diffusion), liquid (co-melt) and solid (non-stereotyped recrystrystation).
    (1) molecular diffusion mechanism: when the API or ligation is present at a higher vapor pressure, the reactant forms a cocrystalline by molecular diffusion, sometimes without even grinding
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