**Novel Challenges in Crystal Engineering: Polymorphs and New Crystal Forms of Active Pharmaceutical Ingredients**

Vânia André and M. Teresa Duarte

*Centro de Química Estrutural, Dept. of Chemical and Biological Engineering, Instituto Superior Técnico, Universidade Técnica de Lisboa, Lisbon Portugal* 

### **1. Introduction**

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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 assemblies that imply an energetic interplay between enthalpy and entropy.

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 and potential intellectual property.

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,

Novel Challenges in Crystal Engineering: Polymorphs

nickel were prepared and characterized49.

improving the limited bioavailability of the drug7, 33, 61, 62.

this chapter.

(2011) American Chemical Society.

10.1039/B809662G.

upmost importance.

and New Crystal Forms of Active Pharmaceutical Ingredients 71

Another example is the widely used paracetamol, which also presents multicomponent crystal forms that were identified and characterized37-39. Perindopril erbumine is an antihypertensive drug existent in quite a few polymorphic forms and several hydrates were also disclosed40-48. A detailed discussion of some of these compounds will be addressed in

But as important as the synthesis of these new compounds is the injunction of their structure-properties relationships. Solubility is a major factor that is known to strongly affect API's performance and therefore its correlation with structural and thermal data is of

API coordination complexes are another related topic that has recently been disclosed as a new pathway for the development of improved crystal forms. In this area, as example, two complexes of 4ASA with silver and one complex coordinating piracetam, a nootropic API, to

Gabapentin (1-(aminomethyl)cyclohexane acetic acid, GBP) is an analogue of gammaaminobutyric acid (GABA) and exhibits anticonvulsant properties. It is a neuroleptic drug prescribed for the prevention of seizure, for the treatment of mood disorders, anxiety and tardive diskinesia50-57, as well as for the treatment of neuropathic pain58. More recently, GBP has also been applied in the treatment of limb tremor59, 60. This API is highly soluble but has limited and variable bioavailability, probably due to its dependence on a low-capacity aminoacid transporter expressed in a limited region of the upper small intestine. Changes in solid state structure can have marked influence on the physiological absorption characteristics supporting the search for multicomponents crystal forms as means of

Gabapentin is known to exist in three anhydrous polymorphic forms32, 63, 64, which have been the object of many patent applications and issued patents. The nomenclature is not uniform and different publications refer to different forms making use of the same name. One hydrate form, labelled form I, is known65, while form II is the anhydrous commercial form66. The crystal structures of these forms are present in the Cambridge Structural Database (CSD) with the refcodes QIMKOM for form I67 at -120°C and QIMKIG and QIMKIG01 for form II at -120°C67 and at RT58, respectively. Form III as labelled by Braga and co-workers68, has been described by Pesachovich *et al* 69, and its crystal structure has been reported by Reece and Levendis as form α70. A patent by Chen et al71. describes a new form of gabapentin, dehydrated A, which is consistent with form β reported by Reece and Levendis70, labelled form IV by Braga and co-workers68. Another crystalline form of gabapentin was described by Lladò *et al*72, but its powder pattern is very similar to that of

1 Adapted with permission from On the Track of New Multicomponent Gabapentin Crystal Forms: Synthon Competition and pH Stability,Vânia André, Auguste Fernandes, Pedro Paulo Santos, and M. Teresa Duarte, *Crystal Growth & Design*, 2011, *11* (6), pp 2325–2334,DOI: 10.1021/cg200008z. Copyright

2 Adapted with permission of the Royal Society of Chemistry (RSC) from Polymorphic gabapentin: thermal behaviour, reactivity and interconversion of forms in solution and solid-state Dario Braga, Fabrizia Grepioni, Lucia Maini, Katia Rubini, Marco Polito, Roberto Brescello, Livius Cotarca, M. Teresa Duarte, Vânia André and M. Fátima M. Piedade *New J. Chem.*, 2008, 32, 1788-1795, DOI:

**2. Gabapentin: Polymorphs and multicomponent crystal forms1,2**

if the groups involved in these bonds have the tendency to transfer protons between acids and bases, then the result may be a molecular salt instead of a co-crystal. In principle, this event replaces the X-H···Y interaction by a charge assisted X-···H-Y+ hydrogen bond22.

The formation of multicomponent crystal forms relies mainly on the hydrogen-bond synthons that are possible to form and their relative robustness. Hence a thorough datamining based on the Cambridge Structural Database (CSD)23, is required for a successful design of the new crystallines. One notable obstacle in the path of rational cocrystal design is the phenomenon of polymorphism, to which organic molecules are predisposed. Polymorphic co-crystals are also not uncommon and a few systems have already been reported to date24.

Even though co-crystals are traditionally obtained by solution techniques, often limited by differences in solubility of co-crystal components and/or solvent/solute interactions25, the best strategies to attain the desired forms consist on a judicious choice of synthetic and crystallization conditions, which also contemplate the environment-friendly techniques of mechanochemistry (neat (NG), liquid-assisted (LAG) and ion- and liquid-assisted grinding (ILAG)) that have demonstrated to be an efficient method in co-crystallization screening and synthesis: solid-state grinding allows the formation of multicomponent forms even with low-solubility components that would be difficult to use with the traditional solution techniques; the addition of catalytic amounts of a liquid to the grinding mixture further improves the efficiency of grinding co-crystallization, as already proven26-30.

Novel crystallines are usually fully characterized using powder (XRPD) and single crystal (SCXRD) X-ray diffraction techniques, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot-stage microscopy (HSM) and spectroscopic methods, such as Fourier transform infrared (FTIR) and Raman.

A wide range of studies have been performed in the last few years, here we will focus on some of those we have been recently engaged. Several studies with gabapentin, a neuroleptic drug, have been reported31-34 and a few multicomponent crystal forms with carboxylic acids have been exploited and will be deeply discussed in this chapter. With the antibiotic 4-aminosalicylic acid (4ASA) some new crystal forms were disclosed, solvates, and molecular salt35, showing a clear tendency of this API to form multicomponent crystallines with lone-pair containing heterocycles, such as dioxane, morpholine and piperazine, disrupting the typical R� �(8) homosynthon in 4ASA (Figure 1).

Fig. 1. (a) R� �(8) synthon in the 4ASA crystal packing; (b) disrupted �� �(�) synthon in the 4ASA:morpholine molecular salt.36

if the groups involved in these bonds have the tendency to transfer protons between acids and bases, then the result may be a molecular salt instead of a co-crystal. In principle, this event replaces the X-H···Y interaction by a charge assisted X-···H-Y+ hydrogen bond22. The formation of multicomponent crystal forms relies mainly on the hydrogen-bond synthons that are possible to form and their relative robustness. Hence a thorough datamining based on the Cambridge Structural Database (CSD)23, is required for a successful design of the new crystallines. One notable obstacle in the path of rational cocrystal design is the phenomenon of polymorphism, to which organic molecules are predisposed. Polymorphic co-crystals are also not uncommon and a few systems have

Even though co-crystals are traditionally obtained by solution techniques, often limited by differences in solubility of co-crystal components and/or solvent/solute interactions25, the best strategies to attain the desired forms consist on a judicious choice of synthetic and crystallization conditions, which also contemplate the environment-friendly techniques of mechanochemistry (neat (NG), liquid-assisted (LAG) and ion- and liquid-assisted grinding (ILAG)) that have demonstrated to be an efficient method in co-crystallization screening and synthesis: solid-state grinding allows the formation of multicomponent forms even with low-solubility components that would be difficult to use with the traditional solution techniques; the addition of catalytic amounts of a liquid to the grinding mixture further

Novel crystallines are usually fully characterized using powder (XRPD) and single crystal (SCXRD) X-ray diffraction techniques, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot-stage microscopy (HSM) and spectroscopic methods,

A wide range of studies have been performed in the last few years, here we will focus on some of those we have been recently engaged. Several studies with gabapentin, a neuroleptic drug, have been reported31-34 and a few multicomponent crystal forms with carboxylic acids have been exploited and will be deeply discussed in this chapter. With the antibiotic 4-aminosalicylic acid (4ASA) some new crystal forms were disclosed, solvates, and molecular salt35, showing a clear tendency of this API to form multicomponent crystallines with lone-pair containing heterocycles, such as dioxane, morpholine and

a b

�(8) synthon in the 4ASA crystal packing; (b) disrupted ��

�(8) homosynthon in 4ASA (Figure 1).

�(�) synthon in the

improves the efficiency of grinding co-crystallization, as already proven26-30.

such as Fourier transform infrared (FTIR) and Raman.

piperazine, disrupting the typical R�

4ASA:morpholine molecular salt.36

Fig. 1. (a) R�

already been reported to date24.

Another example is the widely used paracetamol, which also presents multicomponent crystal forms that were identified and characterized37-39. Perindopril erbumine is an antihypertensive drug existent in quite a few polymorphic forms and several hydrates were also disclosed40-48. A detailed discussion of some of these compounds will be addressed in this chapter.

But as important as the synthesis of these new compounds is the injunction of their structure-properties relationships. Solubility is a major factor that is known to strongly affect API's performance and therefore its correlation with structural and thermal data is of upmost importance.

API coordination complexes are another related topic that has recently been disclosed as a new pathway for the development of improved crystal forms. In this area, as example, two complexes of 4ASA with silver and one complex coordinating piracetam, a nootropic API, to nickel were prepared and characterized49.
