Optimization crystallization

R. Hilfiker, J. Berghausen, F. Blatter, et at. Polymorphism - integrated approach from high-throughput screening to crystallization optimization, J. Therm. Anal. Calorim., 73, 429 440 (2003). 

Hilfiker, R. Berghausen, J. Blatter, F. etal Polymorphism - Integrated Approach from High-Throughput Screening to Crystallization Optimization /. Therm. Anal. Calorim. 2003, 73, 429-140. 

Initially, a pH range of 3.5 to 9.0 should be explored in intervals of 0.5, but the range should be extended, abridged, or modified as appropriate. Generally, it is sufficient to set up two parallel sets of trials and maintain one set at 4°C and the other at 25°C. This will provide an indication of the possible influence and value of temperature as a variable. If crystals of any sort are obtained in the first round of trials, then the coarse matrix of conditions is more finely sampled, evaluated, and in successive rounds, the growth of the crystals optimized. If no crystals are obtained, ligand complexes or alternative forms of the protein are explored. If this fails, then effectors such as metal ions and detergents are introduced, and so on. 

Solution check for impurity formation during crystallization optimize crystallization and/or washing protocol change crystallization solvent. 

Evenly distributed phases idiomorphic alite rounded belite finely differentiated matrix scarce, small, free-lime crystals Optimized manufacturing conditions correcf chemical composition of raw feed, well mixed, no particles too coarse, satisfactory maintenance of sintering and cooling temperatures (Hofmanner, 1973)... 

TABLE 3. n-Hexane crystal optimized with regard to inter- and intramolecular steric energies by the use of the KESSHOU program ... 

TABLE 6.2 Force Field and RMS Deviations between the Observed and the Crystal Optimized Conformations... 

Thermodynamic considerations offer a complementary approach for targeted co-crystal search and development. They can provide selection criteria for suitable co-crystal formers and can also help to predict the most promising preparation conditions. This includes the potential to reduce the experimental effort in co-crystal search and crystallization optimization significantly. Phase... 

The primary purpose of a crystallization optimization is to maximize the yield and purity of the crystallized compound. The yield requirements will typically refer to the drug substance (component A) only, which is in most cases significantly more valuable than the co-crystal former. The price per kilogram of the latter may often be comparable with that of a solvent. 

Phase diagrams are a powerful and intuitive tool for planning co-crystal screenings and crystallization optimizations. 

Easier V, Schweiss P, Meingast C, Obst B, Wuhl H, Rykov A I and Tajima S 1998 3D-XY critical fluctuations of the thermal expansivity in detwinned YBa2Cu30y g single crystals near optimal doping Phys. Rev. Lett. 81 1094-7... 

Parameters (ii)-(vii) depend on the dielectric, mechanical and optical properties of the mesogens. To optimize a dis compromise between different molecular characteristics is often required and mixtures of liquid crystals are usually commercial displays. 

Deep-level defects cannot be described by EMT or be viewed as simple perturbations to tlie perfect crystal. Instead, tlie full crystal-plus-defect problem must be solved and tlie geometries around tlie defect optimized to account for lattice relaxations and distortions. The study of deep levels is an area of active research. 

The program system COBRA [118, 119] can be regarded as a rule- and data-based approach, but also applies the principles of fragment-based (or template-based) methods extensively (for a detailed description sec Chapter 11, Sections 7.1 and 7.2 in the Handbook). COBRA uses a library of predefined, optimized 3D molecular fragments which have been derived from crystal structures and foi ce-field calculations. Each fi agment contains some additional information on... 

The next step is to obtain geometries for the molecules. Crystal structure geometries can be used however, it is better to use theoretically optimized geometries. By using the theoretical geometries, any systematic errors in the computation will cancel out. Furthermore, the method will predict as yet unsynthesized compounds using theoretical geometries. Some of the simpler methods require connectivity only. 

For crystalline polymers, the bulk modulus can be obtained from band-structure calculations. Molecular mechanics calculations can also be used, provided that the crystal structure was optimized with the same method. 

Crystal (we tested Crystal 98 1.0) is a program for ah initio molecular and band-structure calculations. Band-structure calculations can be done for systems that are periodic in one, two, or three dimensions. A separate script, called LoptCG, is available to perform optimizations of geometry or basis sets. 

---