Crystallizers solubility issues

In this chapter, we present results of the testing of a broad spectrum of polymers in carbon dioxide over a range of temperatures and pressures and evaluation of the effect of the high pressure carbon dioxide on the chemical/physical properties of materials tested. The testing was performed in a static manner with four controlled variables, namely temperature, pressure, treatment time and decompression time. The evaluation of the interaction of high pressure carbon dioxide with polymers included sorption and swelling behavior, solubility issue, plasticization and crystallization, and mechanical properties. The results of these evaluations are discussed in three sections Sorption, Swelling and Dissolution of Carbon Dioxide in Polymers at Elevated Pressure, Thermal Properties, and Mechanical Properties. ... 

D.W. Bolen, Effects of naturally occurring osmolytes on protein stability and solubility issues important in protein crystallization, Methods 34 (2004) 312-322. 

When improvements in the physical stability of a product are needed, choices must be based upon the nature of the problem and the desired goal. One of the first choices made is to use the most stable polymorph of the drug. This may involve an extensive polymorph screening effort to attempt to find the most stable polymorph. If the most stable polymorph is undesirable for some reason (e.g., solubility issues), then avoiding contamination of the desired polymorph with seeds of the most stable polymorph becomes very important. In a product that uses an amorphous form of a drug, it is critical to inhibit crystallization to avoid dramatic changes in stability and solubility. 

Because of the anion complexation observed in the solid state, it was proposed that cyclo[8]pyrrole could function as an anion extractant, specifically for sulfate. Sulfate receptors that can act as extractants of this ion are highly desirable because sulfate is a problematic species in the vitrification process that is proposed for the disposal of certain radioactive wastes. The original reported short-chained forms of cyclo[8]pyrrole presented solubility issues, but a newer derivative, octamethyl-octaundecylcyclo[8]pyrrole, 2b, originally developed as a precursor for liquid crystals, proved to be amenable to extraction studies. It was found that 2b was able to selectively extract sulfate in the presence of high levels of nitrate. This cyclo[8]pyrrole was thus able to overcome the so-called Hofmeister bias or the inherent propensity for nitrate to partition before sulfate. While the kinetics are slow—reducing utility in the context of near-term applications—this is the first example where this level of selectivity is seen in a sulfate versus nitrate extraction experiment. ... 

In addition to the challenges cited above, there are some special issues associated with steroid chemistry that should be noted. The steroidal impurities formed in the process are generally similar in structure to the desired product and, in some cases, co-crystallization with the product is a problem. It is, therefore, critical to limit the formation of steroidal impurities in the reactions. The structural similarity between product and impurities also creates challenges in developing assays for reaction monitoring and purity determination. Furthermore, the poor solubility of these compounds in the solvents typically used in a manufacturing process makes it very difficult to achieve practical volume productivity in process development. 

It should also be stressed here that many of these complexes are neutral and therefore relatively soluble in common organic solvents, an important issue for their purification and crystallization. Among all these paramagnetic complexes, only a fraction has been investigated for their magnetic properties in the solid state,... 

When making pharmaceuticals, one critical issue is to control and minimize metal impurities in the product, often to less than 10 ppm. Each product requires a different work-up and purification protocol, and it is difficult to describe a general solution. On some occasions washing removes the catalyst, but at other times the product is crystallized and the catalyst remains in the mother liquors occasionally, the product is volatile and can be distilled. Sometimes the catalyst is carried forward to the next stage and is removed at this point. In our experience, residual metal has not been problematic, but if it is then either immobilized or water-soluble catalysts, as described in this chapter, can be employed. 

The design of crystallization processes for the manufacture of Active Pharmaceutical Ingredients is a significant technical challenge to Process Research and Development groups throughout the Pharmaceutical and related industries. It requires an understanding of both the thermodynamic and kinetic aspects of crystallization, to ensure that the physical properties of the product will consistently meet specification. Failure to address these issues may lead to production problems associated with crystal size, shape and solubility, and to dissolution and bioavailability effects in the formulated product. 

Solubility is a complex issue, since solubihty of crystalhne sohds, for example, reflects a balance between the attractive forces in the crystal and those in the dissolved ions. 

Pentacene ethers 37-39 (Fig. 3.8) were prepared in an attempt to reduce the HOMO energy level relative to functionalized pentacene 29 [52]. These cyclic ether compounds were surprisingly stable, soluble and easily crystallized. Saturated diox-ane compound 37 has an oxidation potential of 0.580 V vs SCE (similar to that of unfunctionalized pentacene), but the axial hydrogen atoms on the dioxane ring prevent -stacking interactions in the crystal. Derivatives 38 and 39 were synthesized to overcome this structural issue. Although the change of oxidation potential... 

An issue of debate is the relative roles of internal and external sites in the catalytic process. The effects of shape selectivity, clearly present in product distribution, seem to indicate a predominance of intra-porous hydroxylation. However, the different catechol/hydroquinone ratio in methanol (0.5) and acetone (1.3), could indicate a significant contribution of sites located on the outer surface of the crystals, particularly for crystallite sizes <0.3 xm. Tuel and others, studying the time course of the reaction and the solubility of tarry deposits, went further and concluded that catechol and hydroquinone were produced on different sites, external and internal respectively [49]. The effect of acetone and methanol simply reflected their ability to maintain external sites clean from tar deposits, which are soluble in the former and insoluble in the latter. On the other hand, Wilkenhoner and others concluded, with the support of kinetic constants estimated independently for internal and external sites, that catechol was also produced in the pores over the entire reaction profile, albeit at a lower rate [47]. The contribution of the outer surface for crystal sizes close to 0.1 (xm ranged from 46% in methanol to 69% in acetone. 

The importance of identifying the mode of delivery to the lung (i.e., nebulizer, MDI, DPI) as early as possible cannot be overemphasized. A drug salt form selected assuming development of a propellant-based MDI suspension formulation may be wholly unsuited for application in an aqueous-based nebulizer suspension on the basis of solubility and crystal growth potential. Physicochemical properties and stability issues considered to be of importance in the development of inhalation formulations are discussed later, as they relate to the individual dosage forms. 

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