Solid form screening

Pseudopolymorphs are not strictly polymorphs because they differ from each other in the solid crystalline phase, such as through the incorporation of solvents (solvates) or water (hydrates). Pseudopolymorphsmay also be suitable for development and should be identified and evaluated during solid form screening activities. 

Computational Crystal Structure Prediction Towards In Silico Solid Form Screening... 

R. Storey, R. Docherty, P. Higginson, C. Dallman, C. Gilmore, G. Barr and W. Dong, Automation of solid form screening procedures in the pharmaceutical industry - How to avoid the bottlenecks, Crystallogr. Rev., 10, 45-56 (2004). 

Other reports show that SSNMR methods were explored to prove cocrystal formation of the solids produced during solid form screening activities [54]. H ICS and H correlation experiments were found to be the fastest and most definite methods to prove molecular association. The authors first recommend screening solids by C and H spectra to assess phase purity, confirm the presence of new crystalline species, and identify strong H-bonding between conformers from the downfield H ICS. H- C CP-HETCOR and H- H DQ recoupling experiments can then provide dipolar connectivity to demonstrate molecular association between components. CST calculations can further confirm molecular association. This protocol was vetted with nine cocrystal systems to prove complexation. 

This strategy involves performing a solid form screen as soon as possible after the candidate is selected. This solid form screen should include co-crystals. Once the screen is completed the most beneficial solid form is identified and a... 

Solubility is highly influenced by the solid-state form (e.g., crystalline or amorphous) of the drug. Rigorous solubility studies using the final solid form (i.e., salt form or crystal form) as a function of temperature (i.e., 25 and 37°C) and pH (range 1 to 7.5) are conducted during preformulation. Solubility in nonaqueous solvents is also screened. Solubility in simulated gastrointestinal fluids is also important. 

Automated sample preparation suitable for the assays starting with solid or oily material is rather complicated and causes problems. This highly labour intensive procedure caused problems when it was done manally due to the nature of the material to be handled. Thus, only certain percentages of the compounds delivered in solid form can be handled by robotics. For this procedure in screening companies, only a low rate of automation is observable so far. Nevertheless, first automated filling stations exist in which a defined amount of a powder can be transferred from standardized vessels to test tubes for subsequent dilution. 

Figure 17. Polymorph screen for carbamazepine using one solvent, cumene temperature-solubility curves (forms I and III) and solid forms initially crystalbzed at various temperature-concentration conditions. The blue (solid) line and the green (dotted) line represent the temperature-solubility curves of form III and form I respectively. From Getsoian et al., 2006.

A number of statistical analyses of the literature have been carried out in an attempt to estimate the extent of polymorphism. A search of the Cambridge Structural Database on the keywords polymorph , form , modification and phase indicates that about 3.5% of the -350 000 entries fall into this category. Approximately 25 % of the entries are either solvates or hydrates. At the other end of the spectrum, Byrn has reported that of the >150 compounds submitted for crystal form screening and analysis to SSCI, Inc. 85 % exhibit more than one crystal form, 37% are solvates and 31 % are hydrates [40]. Other studies based on different selection criteria reveal results falling somewhere between these two extremes [41]. For instance, Griesser and Burger have collected information on about 600 polymorphic forms and solvates (including hydrates) pharmaceutical compounds that are solid at 25 °C [41c],... 

Given all the possible structures available to an organic solid, form selection can be a daunting task. The process typically begins once the molecular structure of the active has been selected, but can also accompany salt selection (see above). The first step in solid form selection is to determine if polymorphic and/or amorphous forms of the molecule of interest (drug substance) exist. This process is called polymorph screening (46). Once forms are identified, they must be characterized and their important properties determined. Only with such data in hand can a rational selection of final solid form be made. 

The next step of the polymorph screening process is to collect additional data which will allow identification and characterization of each solid form. Additional material is usually required. Attempts to scale up the production of each type of material should first involve simply repeating the procedures, at larger scale, that provided each material in the first place. If this is unsuccessful, other methods of production may need to be developed. 

At this stage in the polymorph screen, enough data should be available to sort out the number and nature of solid forms obtained from crystallization experiments. As part of the characterization process, and to continue attempts to generate new forms, hot-stage microscopic and moisture sorption/desorption analyses should be carried out. 

Drug substance solid form selection can be approached in a rational manner. The process consists primarily of salt selection and polymorph screening, both of which involve preparation and property evaluation of many samples. It is critical that multiple analytical techniques be employed during this work. The amount of information that needs to be collected is large, and evaluation of it requires experience and flexibility. 

In the coke drum, foaming occurs. As the bulk viscosity of the resid increases and solids form, a stable foam front forms, and it rises higher in the drum as the coke level rises. If left unchecked, the foam will reach near the top of the coke drum and potentially go overhead, or foam-over . The consequences of a foam-over are immediate and disastrous. The transfer line from the coke drum to the fractionator becomes fouled with coke particles. As the solids reach the fractionation tower, the suction screens in the bottom of the tower become plugged. Finally, the finer particles of coke that pass through the suction screens will... 

---