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

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

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

<sup>1</sup> 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 (2011) American Chemical Society.

<sup>2</sup> 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: 10.1039/B809662G.

Novel Challenges in Crystal Engineering: Polymorphs

intramolecular hydrogen bond.

for a better visualization.

and New Crystal Forms of Active Pharmaceutical Ingredients 73

a b

c Fig. 3. Supramolecular arrangements of gabapentin forms (a) II, showing the double chains along b, with the substituent groups aligned, (b) III, showing the double chains along b, with the substituent groups rotated and (c) IV showing the double chains assisted by the

> **Form II Form III Form V**

Fig. 4. Gabapentin forms II, III and IV structures overlapped. Hydrogen atoms were omitted

(Figure 6). The formation of gabapentin-lactam is not surprising, and it is known that gabapentin is unstable in aqueous solutions and undergoes an intramolecular dehydration reaction yielding the lactam75; the formation of gabapentin-lactam has also been observed in the solid state74. Therefore the endothermic peak observed in the first heating cycle does not correspond to the melting of gabapentin, but covers several events: the cyclization, the release of water and the melting of gabapentin-lactam; these events could not be separated even with a slow scanning rate. Form III shows a similar thermal behaviour, with a broad endothermic peak at 165°C, which is again due to the cyclization process with formation of

As noted above, the thermodynamic form II undergoes the reaction at a slightly lower temperature than the metastable form III. The different behaviour might be explained by the

gabapentin-lactam, water release and melting of gabapentin-lactam68.

slightly different pattern of hydrogen bonds in their crystal structures70.

form IV. Kumar *et al*73 reported a form of gabapentin in an international patent application that is most likely a mixture of forms III and IV (Figure 2).

Fig. 2. Crystals' morphology of gabapentin polymorphs (a) II, (b) III and (c) IV.

In all characterized forms of gabapentin the molecule crystallizes in its zwitterionic form and hydrogen-bonds consist of charge-assisted N+-H•••O- interactions all the supramolecular arrangements relying on chain motifs.

Polymorph II forms double chains that can be seen along b, in which the molecules are oriented so that the substituent groups of the cyclohexane are turned to each other. This orientation of the NH3+ and COO- results in no interactions with neighboring chains along *b* and only one hydrogen bond is used to connect this chain to the parallel chain formed exactly in the same orientation (Figure 3).

In the crystal structure of polymorph III molecules form a 2D sheet along *b*, in which the gabapentin molecules are organized in chains. In the same chain, molecules orient the substituent groups of the cyclohexane ring in the same direction, although the cyclohexane ring is 70.52º alternately rotated. In consecutive chains, the substituent groups are antiparallel oriented and there are interactions between these two chains (Figure 3).

Several similarities between packing of both forms III and IV of gabapentin can be detected and, indeed, the main difference is that in the latter an intramolecular interaction is established. Form IV also forms chains of gabapentin molecules, in which the cyclohexane structures are rotated alternately rotated by 65.83º. Just as in form III, in each chain the substituent groups are oriented in the same direction and in the chain below have an antiparallel orientation. The chains are connected in pairs because of the anti-parallel orientation of the substituent groups, which leaves no opportunity to establish hydrogen-bonds with a third chain. However in this form no direct interactions between molecules in the same chain are observed: all of them connect with molecules in the chain above/below and that same molecule that interacts with "initial" molecule will also be connected to the molecule just besides the first one in the other chain. Consecutive parallel chains are formed just ones behind the others, exactly with the same orientation (Figure 3).

Overlapping the structures of the three gabapentin's forms (II, III and IV) it is possible to see that these are conformational polymorphs (Figure 4).

In the three known polymorphs of gabapentin, the carboxylate C-O bond lengths differ by 0.020 Å, 0.017 Å and 0.016 Å in forms II, III and V, respectively. For all these polymorphs, the longer bond involves the O atom that forms two NH···O contacts and the shorter bond is involved only in one NH···O interaction. In all the three structures, the cyclohexane ring adopts an almost perfect chair conformation.

Thermal characterization of the three polymorphs is also reported68. In the first DSC heating cycle form II shows an endothermic peak at 158°C (Figure 5) while in the second heating cycle the endothermic peak is at 87°C, thus representing the melting point of gabapentinlactam74, confirmed by recrystallization and second heating cycle from the melt on HSM

form IV. Kumar *et al*73 reported a form of gabapentin in an international patent application

a b c

In all characterized forms of gabapentin the molecule crystallizes in its zwitterionic form and hydrogen-bonds consist of charge-assisted N+-H•••O- interactions all the

Polymorph II forms double chains that can be seen along b, in which the molecules are oriented so that the substituent groups of the cyclohexane are turned to each other. This

and only one hydrogen bond is used to connect this chain to the parallel chain formed

In the crystal structure of polymorph III molecules form a 2D sheet along *b*, in which the gabapentin molecules are organized in chains. In the same chain, molecules orient the substituent groups of the cyclohexane ring in the same direction, although the cyclohexane ring is 70.52º alternately rotated. In consecutive chains, the substituent groups are anti-

Several similarities between packing of both forms III and IV of gabapentin can be detected and, indeed, the main difference is that in the latter an intramolecular interaction is established. Form IV also forms chains of gabapentin molecules, in which the cyclohexane structures are rotated alternately rotated by 65.83º. Just as in form III, in each chain the substituent groups are oriented in the same direction and in the chain below have an antiparallel orientation. The chains are connected in pairs because of the anti-parallel orientation of the substituent groups, which leaves no opportunity to establish hydrogen-bonds with a third chain. However in this form no direct interactions between molecules in the same chain are observed: all of them connect with molecules in the chain above/below and that same molecule that interacts with "initial" molecule will also be connected to the molecule just besides the first one in the other chain. Consecutive parallel chains are formed just ones

Overlapping the structures of the three gabapentin's forms (II, III and IV) it is possible to see

In the three known polymorphs of gabapentin, the carboxylate C-O bond lengths differ by 0.020 Å, 0.017 Å and 0.016 Å in forms II, III and V, respectively. For all these polymorphs, the longer bond involves the O atom that forms two NH···O contacts and the shorter bond is involved only in one NH···O interaction. In all the three structures, the cyclohexane ring

Thermal characterization of the three polymorphs is also reported68. In the first DSC heating cycle form II shows an endothermic peak at 158°C (Figure 5) while in the second heating cycle the endothermic peak is at 87°C, thus representing the melting point of gabapentinlactam74, confirmed by recrystallization and second heating cycle from the melt on HSM

<sup>+</sup> and COO- results in no interactions with neighboring chains along *b*

Fig. 2. Crystals' morphology of gabapentin polymorphs (a) II, (b) III and (c) IV.

parallel oriented and there are interactions between these two chains (Figure 3).

behind the others, exactly with the same orientation (Figure 3).

that these are conformational polymorphs (Figure 4).

adopts an almost perfect chair conformation.

that is most likely a mixture of forms III and IV (Figure 2).

supramolecular arrangements relying on chain motifs.

exactly in the same orientation (Figure 3).

orientation of the NH3

Fig. 3. Supramolecular arrangements of gabapentin forms (a) II, showing the double chains along b, with the substituent groups aligned, (b) III, showing the double chains along b, with the substituent groups rotated and (c) IV showing the double chains assisted by the intramolecular hydrogen bond.

Fig. 4. Gabapentin forms II, III and IV structures overlapped. Hydrogen atoms were omitted for a better visualization.

(Figure 6). The formation of gabapentin-lactam is not surprising, and it is known that gabapentin is unstable in aqueous solutions and undergoes an intramolecular dehydration reaction yielding the lactam75; the formation of gabapentin-lactam has also been observed in the solid state74. Therefore the endothermic peak observed in the first heating cycle does not correspond to the melting of gabapentin, but covers several events: the cyclization, the release of water and the melting of gabapentin-lactam; these events could not be separated even with a slow scanning rate. Form III shows a similar thermal behaviour, with a broad endothermic peak at 165°C, which is again due to the cyclization process with formation of gabapentin-lactam, water release and melting of gabapentin-lactam68.

As noted above, the thermodynamic form II undergoes the reaction at a slightly lower temperature than the metastable form III. The different behaviour might be explained by the slightly different pattern of hydrogen bonds in their crystal structures70.

Novel Challenges in Crystal Engineering: Polymorphs

derivative obtained at low pH was reported83.

carboxyl···carboxylate.

competition.

(Figure 8).

different carboxylic acids were also recently disclosed1, 32-34.

SCXRD, DSC, TGA, HSM and IR. The strong homomeric ��

were formed in the new crystallines with trimesic and terephthalic acids84.

and New Crystal Forms of Active Pharmaceutical Ingredients 75

Furthermore, a monohydrate76-78, two polymorphic chloride hemihydrates58, 63, 79, 80 an hemisulfate hemihydrate79, 80 and an heptahydrate under high pressure81 forms are also known. Coordination complexes of this API with Cu and Zn were isolated and characterized82. An extensive pH stability of gabapentin has been disclosed where an ester

Multicomponent crystal forms (co-crystals and molecular salts) involving GBP with

synthon is the most common between cationic amine and carboxylate moieties. The expected synthons to be formed between the API and the coformers should be based on carboxyl···carboxylate and amine···carboxylate interactions. Accordingly to a CSD23 survey (July 2011), the preferred interactions should be amine···carboxylate followed by the

Therefore, carboxylic acids were chosen as potential coformers of multicomponent crystal forms of gabapentin. Mono and di-carboxylic acids bearing one or more hydroxyl moieties have previously been exploited by Reddy et al33 revealing an important role of the OH group in the supramolecular arrangements of the new forms. A series of mono-, di- and tricarboxylic acids, without further hydroxyl moieties, were considered by André *et al*<sup>84</sup> to exploit the use of one or more equivalents of carboxylic moieties avoiding the hydroxyl

Five new multicomponent crystal forms of the neuroleptic drug gabapentin with isophthalic acid (pKa1=3.5; pKa2=4.585), phthalic acid (pKa1=3.0; pKa2=5.385), L-glutamine (pKa1=2.1; pKa2=4.385), terephthalic (pKa1=3.5; pKa2=4.585) and trimesic (pKa1=3.1; pKa2=3.9; pKa3=4.785) acids have been reported and are characterized by XRPD. Despite all the crystallization attempts, single crystals suitable for SCXRD were only grown for the compounds with terephthalic (**4**) and trimesic (**5**) acids, which are further characterized by

synthons observed in the carboxylic acids and gabapentin, respectively, were disrupted and competing synthons based on carboxyl···carboxylate and amine···carboxylate interactions

With L-glutamine, a new crystal form **1** characterized by XRPD is obtained by solution techniques. Both solution and LAG experiments with phthalic acid resulted in a mixture of the coformer and a new crystalline **2**. With isophthalic acid, a mixture of a new crystal form **3**, isophthalic acid and gabapentin polymorph III was identified. In this case, the yield of the supramolecular reaction is low and both reagents are also detected, though gabapentin is detected in a different polymorphic form from the starting material. The full conversion into the new form with terephthalic acid, **4**, was only attained by LAG, as terephthalic acid displays solubility problems and showing not only that the formation of this salt is independent of reactional pH but also the advantage of this method when using highly insoluble compounds. The multicomponent crystal form comprising gabapentin and trimesic acid, **5**, was obtained as a single phase both by solution and LAG techniques

The asymmetric unit of **4** consists on one gabapentin cation and half a terephthalic acid anion residing on an inversion centre. In this structure there is clear evidence of proton transfer between both compounds within the structure and thus this form a molecular salt. Gabapentin cations are connected to terephthalic anions through three different chargeassisted interactions (Scheme I.a), two of which involve the protonated amine moiety of the

�(8)

�(8)

�(8) and heteromeric ��

A search in the Cambridge Structural Database (CSD)23 (July 2011) has shown that the ��

Fig. 5. DSC traces (open pan) of gabapentin Form II (a), with onset temperature = 158.0°C and peak temperature = 161.1°C, and of gabapentin Form III (b), with onset temperature = 165.0°C and peak temperature = 166.6°C68.

Fig. 6. Hot-stage microscopy of crystalline gabapentin-lactam (a) as obtained in the first DSC heating cycle of gabapentin, showing melting at 89°C (b)68.

Several attempts to produce pure form IV in reasonable quantity to be used in DSC measurements were not successful; still a HSM experiment on single crystals of form IV isolated within an oil drop was possible. Figure 7 clearly shows the release of water as gas bubbles in the temperature range 152-155°C, immediately followed by melting of the gabapentin-lactam thus formed68.

Fig. 7. Hot-stage microscopy on gabapentin form IV crystals (preserved in Fomblin oil): (a) single crystal at 32ºC, (b) evolution of water bubbles at 153ºC and (c) complete melting of gabapentin-lactam at 157ºC (amplification 100x)68.

The unique presence in crystals of form IV of an intramolecular N-H···O hydrogen-bond, associated with a smaller number of intermolecular hydrogen bonds with respect to the other two forms, must be responsible for the lower reaction temperature observed70.

Fig. 5. DSC traces (open pan) of gabapentin Form II (a), with onset temperature = 158.0°C and peak temperature = 161.1°C, and of gabapentin Form III (b), with onset temperature =

a b Fig. 6. Hot-stage microscopy of crystalline gabapentin-lactam (a) as obtained in the first DSC

Several attempts to produce pure form IV in reasonable quantity to be used in DSC measurements were not successful; still a HSM experiment on single crystals of form IV isolated within an oil drop was possible. Figure 7 clearly shows the release of water as gas bubbles in the temperature range 152-155°C, immediately followed by melting of the

a b c Fig. 7. Hot-stage microscopy on gabapentin form IV crystals (preserved in Fomblin oil): (a) single crystal at 32ºC, (b) evolution of water bubbles at 153ºC and (c) complete melting of

The unique presence in crystals of form IV of an intramolecular N-H···O hydrogen-bond, associated with a smaller number of intermolecular hydrogen bonds with respect to the

other two forms, must be responsible for the lower reaction temperature observed70.

165.0°C and peak temperature = 166.6°C68.

gabapentin-lactam thus formed68.

heating cycle of gabapentin, showing melting at 89°C (b)68.

gabapentin-lactam at 157ºC (amplification 100x)68.

Furthermore, a monohydrate76-78, two polymorphic chloride hemihydrates58, 63, 79, 80 an hemisulfate hemihydrate79, 80 and an heptahydrate under high pressure81 forms are also known. Coordination complexes of this API with Cu and Zn were isolated and characterized82. An extensive pH stability of gabapentin has been disclosed where an ester derivative obtained at low pH was reported83.

Multicomponent crystal forms (co-crystals and molecular salts) involving GBP with different carboxylic acids were also recently disclosed1, 32-34.

A search in the Cambridge Structural Database (CSD)23 (July 2011) has shown that the �� �(8) synthon is the most common between cationic amine and carboxylate moieties. The expected synthons to be formed between the API and the coformers should be based on carboxyl···carboxylate and amine···carboxylate interactions. Accordingly to a CSD23 survey (July 2011), the preferred interactions should be amine···carboxylate followed by the carboxyl···carboxylate.

Therefore, carboxylic acids were chosen as potential coformers of multicomponent crystal forms of gabapentin. Mono and di-carboxylic acids bearing one or more hydroxyl moieties have previously been exploited by Reddy et al33 revealing an important role of the OH group in the supramolecular arrangements of the new forms. A series of mono-, di- and tricarboxylic acids, without further hydroxyl moieties, were considered by André *et al*<sup>84</sup> to exploit the use of one or more equivalents of carboxylic moieties avoiding the hydroxyl competition.

Five new multicomponent crystal forms of the neuroleptic drug gabapentin with isophthalic acid (pKa1=3.5; pKa2=4.585), phthalic acid (pKa1=3.0; pKa2=5.385), L-glutamine (pKa1=2.1; pKa2=4.385), terephthalic (pKa1=3.5; pKa2=4.585) and trimesic (pKa1=3.1; pKa2=3.9; pKa3=4.785) acids have been reported and are characterized by XRPD. Despite all the crystallization attempts, single crystals suitable for SCXRD were only grown for the compounds with terephthalic (**4**) and trimesic (**5**) acids, which are further characterized by SCXRD, DSC, TGA, HSM and IR. The strong homomeric �� �(8) and heteromeric �� �(8) synthons observed in the carboxylic acids and gabapentin, respectively, were disrupted and competing synthons based on carboxyl···carboxylate and amine···carboxylate interactions were formed in the new crystallines with trimesic and terephthalic acids84.

With L-glutamine, a new crystal form **1** characterized by XRPD is obtained by solution techniques. Both solution and LAG experiments with phthalic acid resulted in a mixture of the coformer and a new crystalline **2**. With isophthalic acid, a mixture of a new crystal form **3**, isophthalic acid and gabapentin polymorph III was identified. In this case, the yield of the supramolecular reaction is low and both reagents are also detected, though gabapentin is detected in a different polymorphic form from the starting material. The full conversion into the new form with terephthalic acid, **4**, was only attained by LAG, as terephthalic acid displays solubility problems and showing not only that the formation of this salt is independent of reactional pH but also the advantage of this method when using highly insoluble compounds. The multicomponent crystal form comprising gabapentin and trimesic acid, **5**, was obtained as a single phase both by solution and LAG techniques (Figure 8).

The asymmetric unit of **4** consists on one gabapentin cation and half a terephthalic acid anion residing on an inversion centre. In this structure there is clear evidence of proton transfer between both compounds within the structure and thus this form a molecular salt.

Gabapentin cations are connected to terephthalic anions through three different chargeassisted interactions (Scheme I.a), two of which involve the protonated amine moiety of the

Novel Challenges in Crystal Engineering: Polymorphs

with any of the three known polymorphic forms.

view showing the cationic GBP tape and depicting ��

clear. Color code: green – GBP; blue – coformer.

�(8) synthons (Scheme II.a).

molecules *via* N+HGBP ···OW and two OHW···O-

moieties, N+HGBP···O-

the previously mentioned GBP ��

gabapentin molecule [OHTA···O-

based on ��

formation of 4 disrupts the ��

seen that in the gabapentin tape cations are rotated by 39°.

and New Crystal Forms of Active Pharmaceutical Ingredients 77

the terephthalic acid row, the anionic spacers alternate with a rotation of 27°; it can also be

The formation of GBP tapes is a common pattern both in the structure of the three polymorphs of gabapentin and in 4, in the latter the coformer links consecutive tapes. The

the number of hydrogen-bond interactions in which gabapentin is involved when compared

Fig. 9. Packing diagrams obtained from **4**; (a) detailed hydrogen-bonding system in **4**, (b)

view along *b* of the supramolecular packing where the spacer function of the coformer is

involved in this structure are globally neutral and thus we have a hydrated co-crystal.

Two of the carboxylic acid groups of trimesic acid are used to form the usual ��

Asymmetric unit of crystalline **5** consists of one gabapentin zwitterion, one trimesic acid molecule and one water molecule. In this structure there is clear evidence that the proton transfer occurs within gabapentin, resulting in its zwitterionic form; therefore all the molecules

An intramolecular hydrogen bond is established in each gabapentin molecule [N+HGBP···O-GBP] and gabapentin zwitterions interact among them using the amine and the carboxylate

through OHTA···OTA. The third COOH no longer maintains this typical pattern but interacts with three independent gabapentin zwitterions (Scheme II.b), two of which are involved in

acceptor for one NH of gabapentin [N+HGBP···OTA]; OH works both as acceptor, from another gabapentin's amine moiety [N+HGBP···OTA], and as donor to a CO of a third

assisted by trimesic acid moieties is formed (Figure 10.b). Actually these tapes are further reinforced by water molecules as each gabapentin zwitterion interacts with three water

GBP. Both interactions are responsible for the formation of dimers

GBP (Scheme II.a).

�(8) dimer. In these GBP···TA interactions, C=O acts as an

GBP] (Figure 10.a). A tape of GBP zwitterionic dimers

�(8) synthons typical of the terephthalic acid while increasing

�(12) synthons represented in blue, (c)

�(8) synthon

Fig. 8. (a) Experimental XRPD patterns obtained from mechanochemistry (blue); a mixture of gabapentin polymorph III and **4** obtained by solution techniques (black); and gabapentin polymorph III (green); theoretical XRPD patterns obtained from SCXRD data of **4**, at 150K (pink); (b) Experimental XRPD pattern obtained from **5** obtained by LAG (blue) and solution (black) techniques; theoretical powder diffraction pattern obtained from single-crystal data, at 150K (pink).

Scheme I. Main hydrogen bond interactions present in molecular salt **4**

API and the carboxylate of the anion, N+HGBP···O-TA, and a third one concerning the carboxylic group of GBP and again the carboxylate of terephthalic acid, OHGBP···O-TA (Figure 9.a). The donor group – either the amine and/or the carboxylic moiety – belong to GBP, while the carboxylate groups of terephthalic acid always act as acceptors, with O3 behaving as a bifurcated acceptor.

Gabapentin cations interact among them by the N+HGBP···OGBP interactions (Scheme I.b), one of them being slightly longer. It is possible to see that these interactions among four gabapentin cations form a tape supported by �� �(12) synthons growing along *c* (Figure 9.b).

The interplay of these hydrogen bonds gives rise to terephthalic acid anions acting as spacers between GBP cationic tapes, very clear in a view along the *b* axis (Figure 9.c). Within

a b Fig. 8. (a) Experimental XRPD patterns obtained from mechanochemistry (blue); a mixture of gabapentin polymorph III and **4** obtained by solution techniques (black); and gabapentin polymorph III (green); theoretical XRPD patterns obtained from SCXRD data of **4**, at 150K (pink); (b) Experimental XRPD pattern obtained from **5** obtained by LAG (blue) and solution (black) techniques; theoretical powder diffraction pattern obtained from single-crystal data,

Scheme I. Main hydrogen bond interactions present in molecular salt **4**

carboxylic group of GBP and again the carboxylate of terephthalic acid, OHGBP···O-

(Figure 9.a). The donor group – either the amine and/or the carboxylic moiety – belong to GBP, while the carboxylate groups of terephthalic acid always act as acceptors, with O3

Gabapentin cations interact among them by the N+HGBP···OGBP interactions (Scheme I.b), one of them being slightly longer. It is possible to see that these interactions among four

The interplay of these hydrogen bonds gives rise to terephthalic acid anions acting as spacers between GBP cationic tapes, very clear in a view along the *b* axis (Figure 9.c). Within

TA, and a third one concerning the

�(12) synthons growing along *c* (Figure 9.b).

TA

API and the carboxylate of the anion, N+HGBP···O-

gabapentin cations form a tape supported by ��

behaving as a bifurcated acceptor.

at 150K (pink).

the terephthalic acid row, the anionic spacers alternate with a rotation of 27°; it can also be seen that in the gabapentin tape cations are rotated by 39°.

The formation of GBP tapes is a common pattern both in the structure of the three polymorphs of gabapentin and in 4, in the latter the coformer links consecutive tapes. The formation of 4 disrupts the �� �(8) synthons typical of the terephthalic acid while increasing the number of hydrogen-bond interactions in which gabapentin is involved when compared with any of the three known polymorphic forms.

Fig. 9. Packing diagrams obtained from **4**; (a) detailed hydrogen-bonding system in **4**, (b) view showing the cationic GBP tape and depicting �� �(12) synthons represented in blue, (c) view along *b* of the supramolecular packing where the spacer function of the coformer is clear. Color code: green – GBP; blue – coformer.

Asymmetric unit of crystalline **5** consists of one gabapentin zwitterion, one trimesic acid molecule and one water molecule. In this structure there is clear evidence that the proton transfer occurs within gabapentin, resulting in its zwitterionic form; therefore all the molecules involved in this structure are globally neutral and thus we have a hydrated co-crystal.

An intramolecular hydrogen bond is established in each gabapentin molecule [N+HGBP···O-GBP] and gabapentin zwitterions interact among them using the amine and the carboxylate moieties, N+HGBP···O-GBP. Both interactions are responsible for the formation of dimers based on �� �(8) synthons (Scheme II.a).

Two of the carboxylic acid groups of trimesic acid are used to form the usual �� �(8) synthon through OHTA···OTA. The third COOH no longer maintains this typical pattern but interacts with three independent gabapentin zwitterions (Scheme II.b), two of which are involved in the previously mentioned GBP �� �(8) dimer. In these GBP···TA interactions, C=O acts as an acceptor for one NH of gabapentin [N+HGBP···OTA]; OH works both as acceptor, from another gabapentin's amine moiety [N+HGBP···OTA], and as donor to a CO of a third gabapentin molecule [OHTA···O-GBP] (Figure 10.a). A tape of GBP zwitterionic dimers assisted by trimesic acid moieties is formed (Figure 10.b). Actually these tapes are further reinforced by water molecules as each gabapentin zwitterion interacts with three water molecules *via* N+HGBP ···OW and two OHW···O-GBP (Scheme II.a).

Novel Challenges in Crystal Engineering: Polymorphs

the inverted positions (Figure 11).

black84.

supramolecular interactions.

**O**

**O H**

and Kavuru et al86.

and New Crystal Forms of Active Pharmaceutical Ingredients 79

In both gabapentin multicomponent crystals' structures **4** and **5**, gabapentin's cyclohexane ring adopts a chair conformation in which the aminomethyl group is in an equatorial position, with the carboxymethyl group in the axial position. The relative positioning of the substituent groups is similar to the one observed in gabapentin polymorph IV; in the other two polymorphic forms of gabapentin the aminomethyl and carboxymethyl groups occupy

Fig. 11. A comparison of the GBP conformation in: (a) GBP:terephthalic acid molecular salt; (b) GBP:trimesic acid co-crystal; (c) GBP polymorph II; (d) GBP polymorph III; (e) GBP polymorph IV. C-C-N bond angles are given in blue and both C-C-C-O dihedral angles in

Analyzing all the unveiled multicomponent forms of gabapentin32-34, 58, 63, 76, 79, there was no systematic behavior concerning the relative positioning of the aminomethyl and carboxymethyl substituent groups, what can lead us to conclude that this is governed by the

acids are partially disrupted and new hydrogen-bonding patterns were induced by the introduction of the coformer. Although there is proton transfer in **4** and not in **5**, in both forms GBP interacts with the acid coformer through carboxyl···carboxylate and amine···carboxyl/carboxylate synthons represented in Scheme III. The interactions *via* synthons I and II are in agreement with the results previously presented by Reddy et al33

**N H**

**+**

**H**

**H**

**O**

**I II III**

**O \_**

�(8) in the carboxylic

**O**

**H O**

**N H H**

**+**

**H**

As expected the carboxylate···amine interactions in GBP and the R�

Scheme III. Main hydrogen bonded synthons observed in **4** and **5**.

**O**

**O \_**

The supramolecular arrangement of **5** can be described as alternated gabapentin zwitterionic ondulated chains and trimesic acid zigzag chains, with water molecules lying in the space between them (Figure 10.c). Trimesic acid besides supporting the gabapentin tapes also acts as spacer between them, similarly to compound **4**.

Comparing this structure with the three known GBP polymorphs, the intramolecular bond is similar to the one formed in polymorph IV and the R� �(8) synthons are observed also in polymorph III. The typical R� �(8) synthon between trimesic acid molecules is maintained in 2/3 of its interactions and it is only disrupted to establish connections with GBP zwitterions, increasing the number of hydrogen-bonds in which they both are involved.

The presence of the intramolecular bond in gabapentin zwitterions could suggest an analogue conformation of GBP molecules in this co-crystal and in polymorph IV, but this is not observed and, in fact GBP adopts different conformations.

Scheme II. Main hydrogen bond interactions present in **5**.

Fig. 10. Packing diagrams for co-crystal **5** (a) detailed hydrogen-bonding system in GBP:trimesic acid hydrate; (b) view along b showing both the tape made of GBP dimers assisted by water and trimesic acid spacers; (c) space filling diagram viewed along the *c*axis. Color code: green – GBP; blue – coformer; red- water.

The supramolecular arrangement of **5** can be described as alternated gabapentin zwitterionic ondulated chains and trimesic acid zigzag chains, with water molecules lying in the space between them (Figure 10.c). Trimesic acid besides supporting the gabapentin tapes

Comparing this structure with the three known GBP polymorphs, the intramolecular bond

2/3 of its interactions and it is only disrupted to establish connections with GBP zwitterions,

The presence of the intramolecular bond in gabapentin zwitterions could suggest an analogue conformation of GBP molecules in this co-crystal and in polymorph IV, but this is

increasing the number of hydrogen-bonds in which they both are involved.

�(8) synthons are observed also in

**\_**

**\_**

�(8) synthon between trimesic acid molecules is maintained in

also acts as spacer between them, similarly to compound **4**.

is similar to the one formed in polymorph IV and the R�

not observed and, in fact GBP adopts different conformations.

Scheme II. Main hydrogen bond interactions present in **5**.

*a b*

axis. Color code: green – GBP; blue – coformer; red- water.

Fig. 10. Packing diagrams for co-crystal **5** (a) detailed hydrogen-bonding system in GBP:trimesic acid hydrate; (b) view along b showing both the tape made of GBP dimers assisted by water and trimesic acid spacers; (c) space filling diagram viewed along the *c*-

polymorph III. The typical R�

In both gabapentin multicomponent crystals' structures **4** and **5**, gabapentin's cyclohexane ring adopts a chair conformation in which the aminomethyl group is in an equatorial position, with the carboxymethyl group in the axial position. The relative positioning of the substituent groups is similar to the one observed in gabapentin polymorph IV; in the other two polymorphic forms of gabapentin the aminomethyl and carboxymethyl groups occupy the inverted positions (Figure 11).

Fig. 11. A comparison of the GBP conformation in: (a) GBP:terephthalic acid molecular salt; (b) GBP:trimesic acid co-crystal; (c) GBP polymorph II; (d) GBP polymorph III; (e) GBP polymorph IV. C-C-N bond angles are given in blue and both C-C-C-O dihedral angles in black84.

Analyzing all the unveiled multicomponent forms of gabapentin32-34, 58, 63, 76, 79, there was no systematic behavior concerning the relative positioning of the aminomethyl and carboxymethyl substituent groups, what can lead us to conclude that this is governed by the supramolecular interactions.

As expected the carboxylate···amine interactions in GBP and the R� �(8) in the carboxylic acids are partially disrupted and new hydrogen-bonding patterns were induced by the introduction of the coformer. Although there is proton transfer in **4** and not in **5**, in both forms GBP interacts with the acid coformer through carboxyl···carboxylate and amine···carboxyl/carboxylate synthons represented in Scheme III. The interactions *via* synthons I and II are in agreement with the results previously presented by Reddy et al33 and Kavuru et al86.

Scheme III. Main hydrogen bonded synthons observed in **4** and **5**.

Novel Challenges in Crystal Engineering: Polymorphs

and New Crystal Forms of Active Pharmaceutical Ingredients 81

IR spectroscopy (Figure 15) complemented the characterization of the new crystal forms **4**  and **5**. In both spectra, the presence of the NH3+ group is evidenced by the peaks corresponding to the symmetric and antisymmetric bending frequencies (1500 and 1610 cm-1) and by the peak corresponding to the stretching frequency (2650 cm-1). In **4**, the carboxylate group of the acid and the carboxylic group of the API are also well distinguished: the carbonyl band is exhibited at frequency > 1700 cm-1 typical of a aliphatic carboxylic group; proton transfer between the coformer and the API is confirmed by the presence of coformer carboxylate bands together with the absence of the carbonyl band typical (1680 cm-1) of the terephthalic group. In **5**, although a clear identification of the carboxylate of the API and the carboxylic group of the acid is not so ascertained, it is possible to note the absence of the carboxylic moiety of gabapentin and identify, by comparison with the spectra of the pure coformer, the peak of the carboxylic moieties of

trimesic acid; therefore the existence of the carboxylate in gabapentin is inferred.

a b

Transmittance (%)

500 1000 1500 2000 2500 3000 3500 4000

Wavenumber (cm-1)

The solubility of the new multicomponent forms is lower than that for gabapentin, as desired. As previous studies on gabapentin indicate that this API is especially dependent on the pH of the environment31, pH dependent stability of these two new forms was also studied and significant differences were found for **4** and **5**, the first being stable in quite a

Fig. 15. IR spectra for **4** (a) and **5** (b) obtained by liquid-assisted grinding84.

narrower pH range (Figures 16 and 17).

Transmittance (%)

500 1000 1500 2000 2500 3000 3500 4000

Wavenumber (cm-1)

Fig. 16. pH dependent stability of **4** 

Thermal studies were performed on the new crystal forms **4** and **5** and a combination of DSC, TGA and HSM data allowed some conclusions on the thermal stability of these compounds. The thermogram of **4** (Figure 12.a) is characterized by an endothermic peak at 150ºC, corresponding to the melting of the compound. The melting peak is found at a lower temperature than any of the reported polymorphic forms of gabapentin32 and within the range obtained for other multicomponent forms33, 34. This peak encloses the cyclisation/ lactamization of gabapentin32 implying water release that is observed on HSM experiments (Figure 13) and detected in TGA.

The thermogram obtained from **5** (Figure 12.b) is characterized by a wide bump between 70 and 120°C and one broad endothermic peak at 159ºC. The first peak is due to the slow release of crystallization water and the second peak encloses lactamization of gabapentin and melting as seen in **4**. Both these phenomena are supported by TGA and HSM (Figures 12 and 14).

Fig. 12. DSC and TGA obtained for (a) molecular salt **4**, and (b) co-crystal **5**.

As previously mentioned, HSM experiments with compounds **4** and **5** were also performed and are in agreement with what was observed in the DSC and TGA experiments and were used in the interpretation of these results.

Fig. 13. HSM images for **4** at a) 25 ºC; b) 140ºC – water being released in the lactamization process; c) 144.5ºC – crystal appearance just before melting84.

Fig. 14. HSM images for **5** at a) 25 ºC; b) 90ºC – slow release of crystallization water; c) 160ºC – lactamization and melting84.

Thermal studies were performed on the new crystal forms **4** and **5** and a combination of DSC, TGA and HSM data allowed some conclusions on the thermal stability of these compounds. The thermogram of **4** (Figure 12.a) is characterized by an endothermic peak at 150ºC, corresponding to the melting of the compound. The melting peak is found at a lower temperature than any of the reported polymorphic forms of gabapentin32 and within the range obtained for other multicomponent forms33, 34. This peak encloses the cyclisation/ lactamization of gabapentin32 implying water release that is observed on HSM experiments

The thermogram obtained from **5** (Figure 12.b) is characterized by a wide bump between 70 and 120°C and one broad endothermic peak at 159ºC. The first peak is due to the slow release of crystallization water and the second peak encloses lactamization of gabapentin and melting as seen in **4**. Both these phenomena are supported by TGA and HSM (Figures 12 and 14).

a b


60 70 80 90 100 110 120 130 140 150 160 170 180

3

4

5

Heat Flow (mW)

6

7

Temperature (؛C)

 Mass Heat Flow

As previously mentioned, HSM experiments with compounds **4** and **5** were also performed and are in agreement with what was observed in the DSC and TGA experiments and were

Fig. 13. HSM images for **4** at a) 25 ºC; b) 140ºC – water being released in the lactamization

Fig. 14. HSM images for **5** at a) 25 ºC; b) 90ºC – slow release of crystallization water; c) 160ºC

Fig. 12. DSC and TGA obtained for (a) molecular salt **4**, and (b) co-crystal **5**.

0 -2 -4 -6 -8 -10 -12 -14 -16

Heat Flow (mW)

Mass loss (%)

process; c) 144.5ºC – crystal appearance just before melting84.

(Figure 13) and detected in TGA.

used in the interpretation of these results.

40 60 80 100 120 140 160 180

Temperature (؛C)

 Mass Heat

50

40

30

20

Mass loss (%)

10

0

– lactamization and melting84.

IR spectroscopy (Figure 15) complemented the characterization of the new crystal forms **4**  and **5**. In both spectra, the presence of the NH3+ group is evidenced by the peaks corresponding to the symmetric and antisymmetric bending frequencies (1500 and 1610 cm-1) and by the peak corresponding to the stretching frequency (2650 cm-1). In **4**, the carboxylate group of the acid and the carboxylic group of the API are also well distinguished: the carbonyl band is exhibited at frequency > 1700 cm-1 typical of a aliphatic carboxylic group; proton transfer between the coformer and the API is confirmed by the presence of coformer carboxylate bands together with the absence of the carbonyl band typical (1680 cm-1) of the terephthalic group. In **5**, although a clear identification of the carboxylate of the API and the carboxylic group of the acid is not so ascertained, it is possible to note the absence of the carboxylic moiety of gabapentin and identify, by comparison with the spectra of the pure coformer, the peak of the carboxylic moieties of trimesic acid; therefore the existence of the carboxylate in gabapentin is inferred.

Fig. 15. IR spectra for **4** (a) and **5** (b) obtained by liquid-assisted grinding84.

The solubility of the new multicomponent forms is lower than that for gabapentin, as desired. As previous studies on gabapentin indicate that this API is especially dependent on the pH of the environment31, pH dependent stability of these two new forms was also studied and significant differences were found for **4** and **5**, the first being stable in quite a narrower pH range (Figures 16 and 17).

Fig. 16. pH dependent stability of **4** 

Novel Challenges in Crystal Engineering: Polymorphs

Fig. 18. Chemical diagram of perindopril erbumine salt.

dissolution profile studies were performed.

anions in the adjacent chain. Consequently two related types of ��

both chains that are connected among them by ��

hydrogen bonds among them neither in α nor β forms.

dehydrate.

and New Crystal Forms of Active Pharmaceutical Ingredients 83

Careful searches in the literature and in the Cambridge Structural Database112 revealed that, although this API is known since 1981, until very recently only the crystal structure of perindoprilat, the pharmacologically active compound, had been determined in 199193. In 2011, Remko and co-workers41 unveiled the crystal structure of perindopril erbumine

Also in 2011, during a polymorphic screening of perindopril erbumine, the molecular structures of its α and β polymorphs45, 113 have been determined by SCXRD as well as an unprecedented hydrated form of formula (C4H12N)(C19H31N2O5)1.25H2O40, 114. Elemental and Karl-Fischer analyses confirmed the water contents of the three forms, that were were fully characterized by XRPD, vibrational spectroscopy (ATR-FT-IR and FT-Raman) and thermal analysis methods (TGA, DSC and HSM)40. Furthermore, stability, solubility and

The crystal packing of polymorphic forms α and β show similar hydrogen bonding interactions involving the perindopril and the erbumine ions. Perindopril anions interact with erbumine cations in an extended NH···O hydrogen bonding network leading to a supramolecular structure with the moieties organized in a double-chain arrangement. Each erbumine cation connects with three perindopril anions *via* the amine moiety: two of them are in the same chain whereas the other perindopril belongs to the opposite chain where the positioning of the anions in their respective chains, it is possible to notice that they assume antiparallel orientations i.e., perindopril anions of one chain are rotated of 180º relatively to the

The NH···O hydrogen bond distances are within the ranges of 2.707 - 2.803 Å and 2.738 - 2.788 Å in α and β forms, respectively. These double-chains do not establish classical

The new 1:1:1.25 hydrated form crystallizes with a triclinic symmetry, in the P1 chiral space group. This hydrated form was obtained both by solution and by LAG, which, as previously said, has several advantages not only in the preparation process, where equally yield and

�(2) motifs.

�(6) synthons are formed in

Fig. 17. pH dependent stability of **5**. [Ester derivative reported in83]
