Solids solvent selection

Successful recrystallization of an impure solid is usually a function of solvent selection. The ideal solvent, of course, dissolves a large amount of the compound at the boiling point but very little at a lower temperature. Such a solvent or solvent mixture must exist (one feels) for the compound at hand, but its identification may necessitate a laborious trial and error search. Solvent polarity and boiling point are probably the most important factors in selection. Benzhydrol, for example, is only slightly soluble in 30-60 petroleum ether at the boiling point but readily dissolves in 60-90° petroleum ether at the boiling point. 

Solubilizing all or part of a sample matrix by contacting with liquids is one of the most widely used sample preparation techniques for gases, vapors, liquids or solids. Additional selectivity is possible by distributing the sample between pairs of immiscible liquids in which the analyte and its matrix have different solubilities. Equipment requirements are generally very simple for solvent extraction techniques. Table 8.2 [4,10], and solutions are easy to manipulate, convenient to inject into chromatographic instruments, and even small volumes of liquids can be measured accurately. Solids can be recovered from volatile solvents by evaporation. Since relatively large solvent volumes are used in most extraction procedures, solvent impurities, contaminants, etc., are always a common cause for concern [65,66]. 

Sample preparation for analysis by hyphenated methods requires some additional planning when compared to nonhyphenated methods. All steps, extraction, concentration, and final solvent selection must take into consideration and be compatible with all the components of the hyphenated instrumentation. For gas chromatographic methods, all the components in the mixture must be in the gaseous state. For liquid chromatography (LC) or high-performance liquid chromatography (HPLC), the samples of the analytes of interest can be solids or liquids, neutral or charged molecules, or ions, but they must be in solution. If the follow-on analysis is by MS, then each of the analytes may require a different method of introduction into the MS. Metals and metal ions may be introduced by HPLC if they are in solution but commonly are introduced via AAS or inductively coupled plasma (ICP). Other analytes may be directly introduced from HPLC to MS [2],... 

The non-random two-liquid segment activity coefficient model is a recent development of Chen and Song at Aspen Technology, Inc., [1], It is derived from the polymer NRTL model of Chen [26], which in turn is developed from the original NRTL model of Renon and Prausznitz [27]. The NRTL-SAC model is proposed in support of pharmaceutical and fine chemicals process and product design, for the qualitative tasks of solvent selection and the first approximation of phase equilibrium behavior in vapour liquid and liquid systems, where dissolved or solid phase pharmaceutical solutes are present. The application of NRTL-SAC is demonstrated here with a case study on the active pharmaceutical intermediate Cimetidine, and the design of a suitable crystallization process. 

Zeolites are aluminosilicate crystallines consisting of pores of molecular dimensions, interconnected by small windows(5-8A diameter). Strict regularity of the pore structure enables higher slectivities to be achieved in both catalysis and sorption processes. The intrazeolite circumstances alike a "solid-solvent" accomodate the selected reactant molecules and promote some inorganic and organic synthetic reactions, similarly in solution. 

Practical advantage of this resolution method is that most of the investigated racemates could be solved in hexane but DBTA and the complex was insoluble in it. Consequently, complete separation of the solid diastereoisomeric complex and the remained free enantiomeric mixture of the alcohol is simple and chemists can avoid the exhausting work of solvent selection and concentration optimization. 

Solvent selection depends largely on the nature of the analytes and the matrix. Although the discussions in Chapter 2 can be used as a guideline to account for the solvent-analyte interactions, the matrix effects are often unpredictable. There is no single solvent that works universally for all analytes and all matrices. Sometimes, a mixture of water-miscible solvents (such as acetone) with nonmiscible ones (such as hexane or methylene chloride) are used. The water-miscible solvents can penetrate the layer of moisture on the surface of the solid particles, facilitating the extraction of hydrophilic organics. The hydrophobic solvents then extract organic compounds of like polarity. For instance, hexane is efficient in the extraction of nonpolar analytes, and methylene chloride extracts the polar ones. 

Trial and error is usually required in selecting a second solvent for a mixture. There are some generally successful mixtures, such as diethyl ether/methanol (or ethanol) for highly associated solids (especially amides and alcohols) and many natural products, and diethyl ether/petroleum ether (or benzene) for dipolar compounds (especially esters and alcohols) and hydrocarbons . Cf. also J. B. Baumann Solvent Selection for Recrystallization. J. Chem. Educ. 56, 64 (1979) R. E. R. Craig Rapid, Efficient Determination of Recrystallization Solvents at the Microscale Level, J. Chem. Educ. 66, 88 (1989). 

J. J. Kirkland, J. L. Glajch, and L. R. Snyder, Practical optimization of solvent selectivity in liquid-solid chromatography using a mixture-design statistical technique,... 

These properties are listed in order of usefulness for comparative review purposes. Liquid surface tension is the most fundamental property, because it pertains only to the material in question (provided the material is adequately pure) and the technique used for measurement. All the other properties listed are dependent also on solvents, contact-angle test liquids, and liquid or solid substrates selected. For solids, approaches such as the Owens-Wendt analysis (7) have supplanted the Zisman method (18) in recent years, but data from the Zisman method for organosilicon polymers are more available compared with data from the Owens-Wendt approach. Some useful data on aqueous surface tensions and Langmuir troughs are also available. Data for other listed properties are of less fundamental use and rather scanty. 

It is important to remember that for a successful recrystalUzation, you need to use equipment of a size appropriate to the amount of solid and the volume of solvent you are likely to use. You can estimate the volume of solvent to be used by extrapolation of the data from your solvent selection tests. In general terms, conical flasks, beakers and round-bottom flasks should never be more than half-full of solution but, on the other hand, using small volumes of solutions in large flasks will result in losses of the compound on the sides of the vessels. 

---