Crystallization, solvent

There is a very important point to stress about the above procedure. Strike listed ether, DCM and ethanol as crystallization solvents. But the one chemists should use is DCM. That s right...DCM Strike is telling all of you right now that DCM is an absolutely superior solvent for crystallization. In fact it is so good that one need not purify the freebases acquired from the ends of half of the recipes in this book. 

Most of the final product producing recipes in this book will provide for the chemist to take up the final free base product in DCM. Usually the freebase oil in the DCM is dark. Used to be that Someone-Who-ls-Not-Strike (SWINS) would have to distill the freebase to get clear yellow oil before crystallizing because when SWINS used ether or ethanol as a crystallization solvent, the colored crap would contaminate the final product. But not with DCM. Even with the grungiest (well...not too grungy) freebase, the crystals that come out are pure snow. The DCM so strongly solvates the contaminants that none remain in the mass of crystalled final product. The filter cake is sooooo clean even in the darkest solvent ... 

The combined pharmaceutical appHcations account for an estimated 25% of DMF consumption. In the pharmaceutical industry, DMF is used in many processes as a reaction and crystallizing solvent because of its remarkable solvent properties. For example, hydrocortisone acetate [50-03-3] dihydrostreptomycin sulfate [5490-27-7] and amphotericin A [1405-32-9] are pharmaceutical products whose crystallization is faciHtated by the use of DMF. Itis also a good solvent for the fungicide griseofulvin/72%(97-< 7 and is used in its production. 

The direct coupling constants (A/) of pyridine, obtained from a spectrum of the molecule in a nematic liquid crystal solvent, are listed in Batterham s monograph (B-73NMR, p. lo). These data provide information about the geometry of the molecule, as the couplings are proportional to the inverse cube of the distance (r,/) between the nuclei. 

On the other hand, in the single crystals prepared from equivalent amounts of heterochiral 1 1 complexes, a pair of two heterochiral 1 1 complexes are incorporated in a unit cell to form a layered structure with alternate layer distances of 7.33 and 7.6 A. Two perchlorate ions stay in the narrower gap, and two additional acetone molecules as crystallization solvent occupy the wider gap. The perchlorate ions interact with two axial water ligands by hydrogen bonds (3.71 and 3.77 A) to construct a layered structure. The adjacent two molecules of heterochiral 1 1 com-... 

J. W. Emsley and J. C. Lindon, NMR Spectroscopy Using Liquid Crystal Solvents, Pergamon, Oxford, 1975. 

Two solutes were used to study diffusion in liquids, methylbenzene, which is a small molecule that can be approximated as a sphere, and a liquid crystal that is long and rodlike. The two solutes were found to move and rotate in all directions to the same extent in benzene. In a liquid crystal solvent the methylbenzene again moved and rotated to the same extent in all directions, but the liquid crystal solute moved much more rapidly along the long axis of the molecule than it... 

Benzene is an isotropic solvent its viscosity is the same in every direction. However, a liquid crystal solvent is an anisotropic solvent its viscosity is smaller in the direction parallel to the long axis of the molecule than the perpendicular direction. Methylhenzene is a small, spherical molecule, so its interactions with either solvent are similar in all directions. 

The Curtius rearrangement procedure described here is a modification of one reported by Winestock. The submitters have found this procedure to be considerably more reproducible when N,N-diisopropylethylamine is substituted for triethylamine. The procedure described for the preparation of trans-2,4-pentadienoic acid is a modification of an earlier one by Doebner. The submitters have found this method to give reproducibly higher yields, and to be more convenient, than other commonly used procedures for preparing this material. The use of dichloromethane as the extracting and crystallizing solvent greatly simplifies the isolation of polymer-free samples of the crystalline acid. 

Giitlich et al. [4, 6] have studied SCO in solid [Fe(2-pic)3]Cl2-EtOH (2-pic = 2-picolylamine), particularly the influence of dilution with Zn and Co, the nature of noncoordinated anions and crystal solvent, the HID and isotope effect,... 

Our Chemical Engineering colleagues had developed an elegant impinging jet crystallization which provided excellent particle size control for the finasteride process [13]. In the final pilot plant campaign just before the factory start-up, the crystallization suddenly started producing a different particle size distribution and lower recovery. The problem was traced to a new finasteride solvate which reduced the solubility in the crystallization solvent system. Fortunately, only relatively... 

NMR using liquid crystal solvents is now a well-established tool for the investigation of molecular structure. Selenophene was studied in a liquid crystal composed of sodium sulfate, decanol, deuterium oxide, and sodium decylsulfate.12 The refined direct couplings were obtained iteratively with the help of a computer. The ratios of the interproton distances were calculated from the direct couplings and found to be in good agreement with corresponding values calculated from the microwave data. 

The habit of pharmaceutical compounds has been used for purposes of identification, although the method can only be reliably used when the crystallization solvent used to generate the test crystals is carefully controlled. Since the faces of a crystal must reflect the internal structure of the solid, the angles between any two faces of a crystal will remain the same even if the crystal growth is accelerated or retarded in one direction or another. Toxicologists have made extensive use of microscopy following multiple recrystallization, and they have developed useful methods for compound identification [5]. 

The effect of polymorphism becomes especially critical on solubility since the rate of compound dissolution must also be dictated by the balance of attractive and disruptive forces existing at the crystal-solvent interface. A solid having a higher lattice free energy (i.e., a less stable polymorph) will tend to dissolve faster, since the release of a higher amount of stored lattice free energy will... 

The more sterically demanding phosphide KPH(mes ) crystallizes solvent-free, even from solutions containing THF, as the ladder polymer [K PH(mes ) ]x (25) (72). Coordination about each K atom is completed by multihapto interactions (approximately if ) between the cation and the mesityl ring of an adjacent phosphide ligand. A... 

Separation can also be accomplished by solvent extraction, adsorption, and crystallization. Solvent extraction is accomplished by selectively dissolving certain hydrocarbon components. Adsorption is similar to solvent extraction but uses a solid to separate out various components selectively based on their tendency to adhere to the surface of the solid adsorbent. Crystallization uses the differing melting points of the components during cooling, which causes some of its compounds to solidify or crystallize, and separate out of the liquid. 

Karunanithi, A., Achenie, L. E. K. Gani, R. (2006), A computer aided molecular design framework for crystallization solvent design, Chemical Engineering Science, 61, 1243-1256. 

In electrolytic systems the crystallization solvent type will affect the degree of solute ionization. This is an important factor in the rate of nucleation and can be successfully utilized for polymorphic control [11]. 

It is important to understand this behaviour when selecting a crystallization solvent and the operating temperature range for a new process. The temperature range for the crystallization should be selected so that the desired polymorph is always the thermodynamically stable form. If this is not feasible then kinetic studies will be required to confirm that the polymorphic form that crystallizes first is subsequently converted to the desired form during processing. It is also possible that more than two polymorphic forms could be involved in this type of system, increasing its complexity. 

The selection of a potential list of crystallization solvents is made against the following criteria ... 

For the purpose of this case study we will select Isopropyl alcohol as the crystallization solvent and assume that the NRTL-SAC solubility curve for Form A has been confirmed as reasonably accurate in the laboratory. If experimental solubility data is measured in IPA then it can be fitted to a more accurate (but non predictive) thermodynamic model such as NRTL or UNIQUAC at this point, taking care with analysis of the solid phase in equilibrium. As the activity coefficient model only relates to species in the liquid phase we can use the same model with each different set of AHm and Tm data to calculate the solubility of the other polymorphs of Cimetidine, as shown in Figure 21. True polymorphs only differ from each other in the solid phase and are otherwise chemically identical. 

Karunanithi, A.T., Achenie, L.E.K., Gani, R., 2005, A Computer Aided Molecular Design Framework for Crystallization Solvent Design, Chemical Engineering Science, In Press. 

Case Study 1 Cooling Crystallization Solvent Design... 

This chapter provides a framework for the design of crystallization solvents for pharmaceutical products. The design part involves application of a... 

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