**3. Conclusions**

Solid-state characterization of calix[8]arene derivatives involves subtle details, but general trends emerge from an analysis of the reported structures. Complete functionalization at the penolic rim with substituents capable of filling the cavity by self-inclusion may result in derivatives that can be crystallized from non-polar solvents. This method may also be applied to calix[8]arenes with light *p*-block elements. Introduction of organic bridges at the phenolic OH groups, together with complex formation of alkali, alkaline earth, and openshell (*d*- and *f*-block) metals may result in crystalline derivatives primarily from polar aprotic solvents that can H-bond to the remaining OH functional groups, and coordinate to the electron-deficient metals. The presence of solvent molecules is stabilized by collection of diffraction data at low temperature, although crystal formation appears to be facilitated by slow evaporation of solvent, rather than by cooling. These general guidelines should serve as a first approximation for crystal growth of calix[8]arene derivatives.

#### **4. Acknowledgment**

The authors thank CONACyT (Proyecto 58408, Beca 239715) for financial support.

### **5. References**


For this purpose, volatile solvents such as acetone or dichloromethane are ideal, since slow evaporation tends to result in saturated solutions of the desired compounds predominantly in the high-boiling solvent. Alternatively, heating solutions of the calix[8]arene derivatives followed by slow cooling may result in crystal formation. These guidelines apply for unsubstituted and partially substituted calix[8]arenes with phenolic OH groups, including the covalently bridged derivatives, thiacalixarenes, and complexes with electron-deficient metals. Regarding water as a solvent, most macrocycles are insoluble with the exception of *p*-sulfonatocalix[8]arene, providing the opportunity to further test the interfacial technique. Finally, a summary of the calix[8]arene conformations determined in the solid state is presented in Figs. 6 and 7, complementing those already presented in previous sections. While it is expected that the macrocycles characterized in the future will adopt one of the conformations herein included, novel structures cannot be ruled out, including variations and intermediate structures related to those already described in the current Chapter.

Solid-state characterization of calix[8]arene derivatives involves subtle details, but general trends emerge from an analysis of the reported structures. Complete functionalization at the penolic rim with substituents capable of filling the cavity by self-inclusion may result in derivatives that can be crystallized from non-polar solvents. This method may also be applied to calix[8]arenes with light *p*-block elements. Introduction of organic bridges at the phenolic OH groups, together with complex formation of alkali, alkaline earth, and openshell (*d*- and *f*-block) metals may result in crystalline derivatives primarily from polar aprotic solvents that can H-bond to the remaining OH functional groups, and coordinate to the electron-deficient metals. The presence of solvent molecules is stabilized by collection of diffraction data at low temperature, although crystal formation appears to be facilitated by slow evaporation of solvent, rather than by cooling. These general guidelines should serve

as a first approximation for crystal growth of calix[8]arene derivatives.

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**3** 

*Portugal* 

 **Novel Challenges in Crystal Engineering:** 

*Centro de Química Estrutural, Dept. of Chemical and Biological Engineering,* 

*Instituto Superior Técnico, Universidade Técnica de Lisboa, Lisbon* 

**Pharmaceutical Ingredients** 

Vânia André and M. Teresa Duarte

**Polymorphs and New Crystal Forms of Active** 

Crystal engineering and co-crystallization have evolved in recent years and gained a special interest not only in academia but also in the pharmaceutical field as it has been shown that the physical and pharmacokinetic properties of new crystal forms (solvates, salts, molecular salts, co-crystals, polymorphs) are different when compared to pure APIs1-16. Actually, producing co-crystals of pharmaceuticals has been reported to change their melting points3, solubility and dissolution rates2, 4, moisture uptake17, physical and chemical stability18 and *in vivo* exposure9, 19-21. The leading idea is that the potentiality of new different forms may open to innovation and new drug discoveries as well as to intellectual property protection via patenting of new forms of "old drugs"5, 7, 22. The diversity of forms that crystalline solids may attain is mainly due to non-covalent interactions resulting in different molecular

Although organic salts are traditionally the preferred crystal form of APIs because of their higher solubility and/or increased degree of crystallinity, the potential number of suitable organic salts is limited to the counterions specified by the Food and Drug Administration (FDA) as generally regarded as safe (GRAS). This limitation stimulates the development of other suitable forms and recently co-crystals have been gaining relevance in studies and some of them have already shown to improve therapeutic utility as well as reducing the side effects even when compared with marketed drugs. Consequently, APIs represent a particular great challenge to crystal engineers, because they are inherently predisposed for self-assembly since their utility is usually the result of the presence of one or more exofunctional supramolecular moieties. However, the crystal packing of APIs is even less predictable than that of other organics due to their multiple avenues for self-assembly. Additionally, APIs are commonly valuable chemical entities and therefore the diversity of the crystal forms of those molecules is of great importance for the variability of properties

Co-crystals are most commonly thought of as structural homogeneous crystalline materials that contain two or more neutral building blocks that are present in definite stoichiometric amounts and are obtained through the establishment of strong hydrogen bonds and other non-covalent interactions such as halogen bonds, π-π and coulombic interactions. However,

assemblies that imply an energetic interplay between enthalpy and entropy.

**1. Introduction** 

and potential intellectual property.

