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

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,

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 bond 22 .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 date 24 .Even though co-crystals are traditionally obtained by solution techniques, often limited by differences in solubility of co-crystal components and/or solvent/solute interactions 25 , 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 proven [26][27][28][29][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 reported [31][32][33][34] and a few multicomponent crystal forms with carboxylic acids have been exploited and will be deeply discussed in this chapter.orm 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).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 NH 3 + 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 reported 68 .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 gabapentinlactam 74 , confirmed by recrystallization and second heating cycle from the melt on HSM  (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 lactam 75 ; the formation of gabapentin-lactam has also been observed in the solid state 74 .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-lactam 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 formed 68 .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 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 observed 70 .
Furthermore, a monohydrate [76][77][78] , two polymorphic chloride hemihydrates 58,63,79,80 an hemisulfate hemihydrate 79,80 and an heptahydrate under high pressure 81 forms are also known.Coordination complexes of this API with Cu and Zn were isolated and characterized 82 .An extensive pH stability of gabapentin has been disclosed where an ester derivative obtained at low pH was reported 83 .
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 CSD 23 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 al 33 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 84 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=4.5 85 ), phthalic acid (pKa1=3.0;pKa2=5.3 85), L-glutamine (pKa1=2.1;pKa2=4.3 85), terephthalic (pKa1=3.5;pKa2=4.5 85 ) and trimesic (pKa1=3.1;pKa2=3.9;pKa3=4.7 85 ) 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 acids 84 .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.

c). Within
Novel Challenges in Crystal Engineering: Polymorphs 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 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.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.  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 gabapentin 32 and within the range obtained for other multicomponent forms 33,34 .This peak encloses the cyclisation/ lactamization of gabapentin 32 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    Heat Flow (mW)

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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 NH 3 + 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 Fig. 15.IR spectra for 4 (a) and 5 (b) obtained by liquid-assisted grinding 84 .
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 environment 31 , 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).
Over the last years, several forms of perindopril erbumine have been disclosed and several patents have been filed mainly based on their typical powder XRPD patterns 44,45,[102][103][104][105] .
Perindopril erbumine is known to exist in several polymorphic forms 46,48,102,103,[105][106][107] , as well as mono-, di-and sesqui-hydrated forms, characterized by XRPD, vibrational spectroscopy and thermal analysis methods 47,108 .Also amorphous compositions have been patented 42 as well as a perindopril tosylate form 109 .Some of the different pharmacological and adverse effects exerted by ACE inhibitors may depend on the different phisicochemical (solubility, lipophilicity, acidity) and pharmacokinetic (absorption, protein binding, half-life and metabolic disposition) properties but also on their ability to penetrate and bind tissue sites 110 .Theoretical studies on pKa, lipophilicity, solubility, absorption and polar surface of ACE inhibitors, including perindopril, and its active metabolite, perindoprilat, have been reported 111 .In 2009, Remko presented theoretical calculations of molecular structure and stability of the arginine and erbumine salts of perindopril 43 .Careful searches in the literature and in the Cambridge Structural Database 112 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 1991 93 .In 2011, Remko and co-workers 41 unveiled the crystal structure of perindopril erbumine dehydrate.Also in 2011, during a polymorphic screening of perindopril erbumine, the molecular structures of its and polymorphs 45,113 have been determined by SCXRD as well as an unprecedented hydrated form of formula (C 4 H 12 N)(C 19 H 31 N 2 O 5 )•1.25H 2 O 40, 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 dissolution profile studies were performed.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 anions in the adjacent chain.Consequently two related types of 6 synthons are formed in both chains that are connected among them by motifs.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 hydrogen bonds among them neither in α nor β forms.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 purity are obtained, but also in an environmental context [115][116][117][118][119] .Its asymmetric unit consists of two crystallographic independent perindopril anions, two erbumine cations and 2.5 water molecules.The CO distances in the carboxylate moiety and the location of the three hydrogen atoms in the amine moieties from the electron density map confirmed the presence of the salt.The chiral centers in both perindopril crystallographic independent anions of the hydrated form exhibit the (S) configuration, corresponding exactly to the same configuration of the starting form α as well as of form β, what is important to assure the pharmacological activity of the API (Figure 18).The main conformational differences between these crystallographic independent anions are noted in the -CH 2 CH 2 CH 3 terminal groups (torsion angles of -58.2(4)° vs 175.1(9)°).The crystal packing of this hydrated form is very similar to the one described for polymorphic forms α and β, involving similar hydrogen bonding interactions between the perindopril and the erbumine ions (Figure 19)  bands (Figure 21).In particular the strong bands in the range of 3200-2600 cm -1 of the FT-Raman spectra are attributed to the υ s (C-H) and υ s (N-H) stretching vibrational modes diagnosing the presence of NH and NH 3 + groups in the perindopril and erbumine cation, respectively.The strong bands around 1642, 1569 cm -1 and 1387 cm -1 (observed in both the FT-IR and FT-Raman spectra) are assigned to the υ s (COO -) and υ as (COO -) respectively, confirming the deprotonation of the carboxylic acid group.Contrasting with the FT-IR spectra of forms and , the spectrum of the hydrated form in the 3200-2600 cm -1 range reflects the presence of crystallization water molecules involved in well defined hydrogen bonds, by the presence of resolved peaks.
The combination of data obtained from DSC, TGA and HSM indicates that the novel hydrated form is stable until approximately 80°C, temperature at which a peak is observed in the DSC (Figure 21.a), a smooth mass loss is detected in the TGA (Figure 21.b) and bubbles start to appear in the HSM.The water loss occurs from this temperature until approximately 120°C.At 164ºC melting and decomposition take place.TGA for forms α and β reveals that there is no mass loss before 120°C, confirming the absence of water in both these forms.
The new 1:1:1.25 hydrate has shown to be as stable on shelf as form α for eighteen months and water slurry experiments revealed that it as a thermodynamically stable form.It has also shown to have a similar dissolution profile (Figure 22) as the commercially available drug and to be slightly more soluble in water than the α form 40 .A probable reason for this is the enhanced stability provided by the presence of the water molecules linking the erbumine-perindopril double chains.Analysis of crystal structure has again proven to be quite important for the establishment of the intermolecular interactions responsible for the supramolecular arrangement and thus the physicochemical properties of APIs.

Concluding remarks
Over the last two decades crystal engineering, a key tool for the design of new crystal forms, has made possible the synthesis of novel pharmaceutical materials as well as molecular level control of crystallization and phase transformations.Advances in crystal engineering and supramolecular chemistry invite us to consider new perspectives and perhaps definitions of the various solid-state forms that the same and/or different molecules may adopt in terms of molecular assemblies and architectures.Pharmaceutical co-crystals have proven to offer potential benefits of superior efficacy, solubility and stability in drug formulation.It seems reasonable to assert that co-crystal approaches should be considered routinely as part of a broader set of form and formulation explorations to achieve the best possible drug products.Although the interest in co-crystals and polymorphs and their utility is obvious, identifying and implementing an efficient discovery and control method remains a challenge.

Fig. 3 .
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 .
Fig. 4. Gabapentin forms II, III and IV structures overlapped.Hydrogen atoms were omitted for a better visualization.
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).

Fig. 9 .
Fig. 9. Packing diagrams obtained from 4; (a) detailed hydrogen-bonding system in 4, (b) view showing the cationic GBP tape and depicting 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 + H GBP •••O - GBP ] and gabapentin zwitterions interact among them using the amine and the carboxylate moieties, N + H GBP •••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 OH TA •••O TA .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 + H GBP •••O TA ]; OH works both as acceptor, from another gabapentin's amine moiety [N + H GBP •••O TA ], and as donor to a CO of a third gabapentin molecule [OH TA •••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 + H GBP •••O W and two OH W •••O -GBP (Scheme II.a).

Fig. 10 .
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 caxis.Color code: green -GBP; blue -coformer; red-water.

Fig. 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 .

Fig. 12 .
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.
. The NH•••O hydrogen bond distances are within the ranges of 2.75 -2.781 Å.The main difference between this hydrate and the polymorphs previously described is that while the double-chains do not establish classical hydrogen bonds among them neither in α nor β forms, in the hydrated form water molecules play an important role by linking adjacent chains through interactions between two crystallographically independent perindopril anions via the carbonyl group of one [O W •••O C=O distance of 2.717Å] and the amine moiety of the other [N N-H •••O W distance of 2.430Å].Water molecules lie in the free spaces arising from the supramolecular arrangement described (Figure 19) and interact through cooperative O W -H•••O W hydrogen bonds forming trimeric water clusters [O•••O distances in the cluster: 2.644, 2.687 and 2.932 Å] (Figures 19 and 20

Fig. 19 . 85 Fig. 20 . 2 2Fig. 21 .
Fig. 19.Crystal packing of the novel hydrated form of perindopril erbumine (1:1:1.25):(a) supramolecular arrangement with the perindopril anions and erbumine cations organized in double-chains; H bonds represented as blue dashed lines; water molecules were omitted for clarity; (b) detailed hydrogen bonding within the water cluster.Only hydrogen atoms involved in hydrogen bonding are shown, with exception of water molecules for which no hydrogen atoms are displayed 40 .