Crystallization batch methods

Both continuous and batch methods may be used in methanolysis. The batch mediod requires an autoclave, crystallizer, and centrifuge and a system for the melting and distillation of the DMT obtained. In the two-stage Hoechst continuous process, waste PET is melted and fed to a reactor. Preheated methanol is added to the autoclave, which is equipped with a mixer. The conversion reaches 70-90% in the first reactor, after which the reaction stream is introduced into a second autoclave at a lower temperature near the bottom, where it rises slowly and die higher density impurities settle at the bottom. The reaction stream leaves the second autoclave and its pressure is reduced to 0.3 MPa. On further reduction of the pressure and cooling, DMT precipitates and is subsequently purified.12... 

In the disc method, the powder is compressed by a punch in a die to produce a compacted disc, or tablet. The disc, with one face exposed, is then rotated at a constant speed without wobble in the dissolution medium. For this purpose the disc may be placed in a holder, such as the Wood et al. [Ill] apparatus, or may be left in the die [112]. The dissolution rate, dmldt, is determined as in a batch method, while the wetted surface area is simply the area of the disc exposed to the dissolution medium. The powder x-ray diffraction patterns of the solid after compaction and of the residual solid after dissolution should be compared with that of the original powder to test for possible phase changes during compaction or dissolution. Such phase changes would include polymorphism, solvate formation, or crystallization of an amorphous solid [113],... 

Crystal structure of a protein molecule can also be determined by x-ray crystallography. Purified protein is crystallized either by batch methods or vapor diffusion. X-rays are directed at a crystal of protein. The rays are scattered depending on the electron densities in different positions of a protein. Images are translated onto electron density maps and then analyzed computationally to construct a model of the protein. It is especially important for structure-based drug designs. 

The simplest technique used to grow protein crystals is the batch method in which the protein is mixed with salts or other precipitants to achieve supersaturation (Fig. 2), and the vessel is sealed and set aside until crystals appear. Frequently, the supersaturation point required to induce nucleation is empirically determined by observing the onset of transient turbidity as powdered salt is progressively added to the solution. Crystals of hen egg white lysozyme used for most systematic studies of protein crystallization are grown by batch methods (Blundell and Johnson, 1976). Mouse pancreatic ribonuclease (Perry and Palmer, 1988) and the biotin operon repressor (Brennan et al., 1989) represent recent examples of use of the batch method. 

The permeability trends found in this study for the 1000 pm thick membranes under flowing 1000 ppm H2S/H2 were compared to transient permeability results reported previously . Nearly identical trends in permeability were found for the three Pd-Cu alloys by these two measurement methods reinforcing the suggested correlation between the alloy crystal structure and H2S tolerance. The results of these steady-state permeability experiments indicated that when the Pd-Cu alloys had an fee structure, H2S had little impact on flux but when the structure was bcc, H2S had a moderate to severe impact. However, both of these methods had limitations that probably impacted the results. The transient or batch method was limited by finite H2S availability, competition for the available H2S by other metal surfaces, relatively short test durations and a limited data set. The steady-state 1000 pm thick membrane method was potentially limited by membrane thickness which could have... 

In addition to the vapor diffusion method described previously, other techniques such as the batch and micro-batch methods, bulk and micro dialysis, free interface diffusion, liquid bridge, and concentration dialysis have also been developed to produce crystals for x-ray diffraction analysis (see McPherson, 1982 and McPherson, 1999). 

A comparison of the adsorption isotherm data measured by the batch method with those measured by the HPLC method for the five alcohols in silicalite is given in Figure 6. As shown in Figure 6, a remarkably good agreement is found between the two methods, verifying the validity of the present HPLC technique for the measurement of adsorption equilibrium as well as diffusion in molecular sieve crystals... 

Formation of a glass is a rather simple process. The appropriate batch is prepared, placed in a crucible, heated to form a crystal-free melt, and cooled to room temperature. The sample is examined to determine if it contains crystals, using methods ranging from casual visual examination, to X-ray or electron diffraction. If no crystals are detected, the sample is deemed to be a glass if crystals are detected, it is described as either partially- or fully- crystallized, depending upon the extent of crystallization. 

Crystallization. The crystallization procedure is taken from that described by Fujii et For crystallization experiments, the Sulfolobus sp. ferredoxin solution obtained from a preparative Sephadex G-50 gel filtration column (Amersham Pharmacia Biotech) is concentrated by pressure filtration through an Amicon YM3 or YMIO membrane at 4° and made to 5 mg/ml in 0.5 M Tris-maleate-NaOH buffer, pH 5.0, containing 1% 2-methyl-2,4-pentanediol. Crystals suitable for X-ray diffraction analysis are obtained by a batch method performed under aerobic conditions. Fine-powdered ammonium sulfate is slowly added to 300 p.1 of 5 mg/ml protein solution until the turbidity is observed to persist (1.9-2.1 M). The crystallization solution is stored at 37° in an incubator. Dark brown crystals with appropriate dimensions of 0.3 x 0.3 x 0.5 mm are obtained in 3-5 weeks. Fujii etaO reported that reproducibility of the crystallization is enhanced by seeding a drop of the mother liquor containing microcrystals into the crystallization solution just before the crystallization begins. 

For preparative purposes batch fractionation is often employed. Although fractional crystallization may be included in a list of batch fractionation methods, we shall consider only those methods based on the phase separation of polymer solutions fractional precipitation and coacervate extraction. The general principles for these methods were presented in the last section. In this section we shall develop these ideas more fully with the objective of obtaining a more narrow distribution of molecular weights from a polydisperse system. Note that the final product of fractionation still contains a distribution of chain lengths however, the ratio M /M is smaller than for the unfractionated sample. 

Chlorine and bromine add to benzene in the absence of oxygen and presence of light to yield hexachloro- [27154-44-5] and hexabromocyclohexane [30105-41-0] CgHgBr. Technical benzene hexachloride is produced by either batch or continuous methods at 15—25°C in glass reactors. Five stereoisomers are produced in the reaction and these are separated by fractional crystallization. The gamma isomer (BHC), which composes 12—14% of the reaction product, was formerly used as an insecticide. Benzene hexachloride [608-73-17, C HgCl, is converted into hexachlorobenzene [118-74-17, C Clg, upon reaction with ferric chloride in chlorobenzene solution. 

In addition to induction time measurements, several other methods have been proposed for determination of bulk crystallization kinetics since they are often considered appropriate for design purposes, either growth and nucleation separately or simultaneously, from both batch and continuous crystallization. Additionally, Mullin (2001) also describes methods for single crystal growth rate determination. 

Several authors have presented methods for the simultaneous estimation of crystal growth and nucleation kinetics from batch crystallizations. In an early study, Bransom and Dunning (1949) derived a crystal population balance to analyse batch CSD for growth and nucleation kinetics. Misra and White (1971), Ness and White (1976) and McNeil etal. (1978) applied the population balance to obtain both nucleation and crystal growth rates from the measurement of crystal size distributions during a batch experiment. In a refinement, Tavare and... 

Mathews and Rawlings (1998) successfully applied model-based control using solids hold-up and liquid density measurements to control the filtrability of a photochemical product. Togkalidou etal. (2001) report results of a factorial design approach to investigate relative effects of operating conditions on the filtration resistance of slurry produced in a semi-continuous batch crystallizer using various empirical chemometric methods. This method is proposed as an alternative approach to the development of first principle mathematical models of crystallization for application to non-ideal crystals shapes such as needles found in many pharmaceutical crystals. 

Chemical development Proof of structure and configuration are required as part of the information on chemical development. The methods used at batch release should be validated to guarantee the identity and purity of the substance. It should be established whether a drug produced as a racemate is a true racemate or a conglomerate by investigating physical parameters such as melting point, solubility and crystal properties. The physicochemical properties of the drug substance should be characterized, e.g. crystallinity, polymorphism and rate of dissolution. 

The fact that in HPLC only UV-active components are registered, whereas in titration all basic functional groups are detected constitutes a difference in specificity (quality) and sensitivity (quantity) of these two methods relative to a given impurity. See Fig. 4.17 (left). [Solvent A (water) behaves differently from the other four as can be seen from Fig. 4.17 (right). The material was known to exist in a crystal modification that theoretically contains 3.2% water, and moderate drying will most likely drive off only the excess Indeed, the best-dried batches are all close to the theoretical point (circle, arrow in Figs. 4.16-17), and not near zero. This is only partly reflected in Table 4.15, column A for this reason tabular and graphic information has to be combined. Solvent B, which is an alcohol, behaves more like water... 

The choice of crystallizer for a given separation will depend on the method used to bring about supersaturation. Batch and continuous crystallizers can be used. Continuous crystallizers are generally preferred, but special circumstances often dictate the use of batch operation, as will be discussed further in Chapter 14. The methods used to bring about supersaturation can be classified as ... 

Although cooling crystallization is the most common method of inducing supersaturation in batch crystallization processes, other methods can be used, as discussed in Chapter 10. For example, evaporation can be used, in which case the profile of the rate of evaporation through the batch can also be optimized7. Indeed, the profiles of both temperature and rate of evaporation can be controlled simultaneously to obtain greater control over the level of supersaturation as the batch proceeds7. However, it should be noted that there is often reluctance to use evaporation in the production of fine, specialty and pharmaceutical products, as evaporation can concentrate any impurities and increase the level of contamination of the final product. 

Purified MeHNL was crystallized by the sitting-drop vapor-diffusion method. The 10-20 mm bipyramidal crystals formed were cross-linked with glutaraldehyde and used as biocatalyst for the synthesis of optically active cyanohydrins. The cross-linked crystals were more stable than Celite-immobilized enzymes when incubated in organic solvents, especially in polar solvents. After six consecutive batch reactions in dibutyl ether, the remaining activity of the cross-linked crystals was more than 70 times higher than for the immobilized enzymes. Nevertheless, the specific activity of the cross-linked crystals per milligram protein was reduced compared with the activity of Celite-immobilized enzymes [53],... 

A batch cooling crystallization is one of the most commonly used crystallization method. In this process super saturation of a liquid is achieved by means of a cooling process. The solubility of the solute (in the solvent) decreases with a decrease in temperature this leads to precipitation of the solute. 

In simple experiments, particulate silica-supported CSPs having various cin-chonan carbamate selectors immobilized to the surface were employed in an enantioselective liquid-solid batch extraction process for the enantioselective enrichment of the weak binding enantiomer of amino acid derivatives in the liquid phase (methanol-0.1M ammonium acetate buffer pH 6) and the stronger binding enantiomer in the solid phase [64]. For example, when a CSP with the 6>-9-(tcrt-butylcarbamoyl)-6 -neopentoxy-cinchonidine selector was employed at an about 10-fold molar excess as related to the DNB-Leu selectand which was dissolved as a racemate in the liquid phase specified earlier, an enantiomeric excess of 89% could be measured in the supernatant after a single extraction step (i.e., a single equilibration step). This corresponds to an enantioselectivity factor of 17.7 (a-value in HPLC amounted to 31.7). Such a batch extraction method could serve as enrichment technique in hybrid processes such as in combination with, for example, crystallization. In the presented study, it was however used for screening of the enantiomer separation power of a series of CSPs. 

---