crystals Article A Combined Crystallographic and Computational Study on Dexketoprofen Trometamol Dihydrate Salt Patrizia Rossi 1 , Paola Paoli 1,* , Stella Milazzo 1, Laura Chelazzi 2 , Maria Paola Giovannoni 3, Gabriella Guerrini 3 , Andrea Ienco 4,* , Maurizio Valleri 5 and Luca Conti 6 1 Department of Industrial Engineering, University of Florence, via Santa Marta 3, 50139 Florence, Italy; p.rossi@unifi.it (P.R.); stella.milazzo@unifi.it (S.M.) 2 Centro di Cristallografia Strutturale, University of Florence, via della Lastruccia 3, Sesto F.no, 50019 Florence, Italy; laura.chelazzi@unifi.it 3 NEUROFARBA, Sezione Farmaceutica e Nutraceutica, University of Florence, Via Ugo Schiff 6, Sesto F.no, 50019 Florence, Italy; mariapaola.giovannoni@unifi.it (M.P.G.); gabriella.guerrini@unifi.it (G.G.) 4 CNR-ICCOM, via Madonna del Piano 10, Sesto F.no, 50019 Florence, Italy 5 A. Menarini Manufacturing Logistics and Services s.r.l., via R. Pilo 4, 50131 Florence, Italy; [email protected] 6 Department of Chemistry “U. Schiff”, University of Florence, via della Lastruccia 3, Sesto F.no, 50019 Florence, Italy; luca.conti@unifi.it * Correspondence: paola.paoli@unifi.it (P.P.); [email protected] (A.I.) Received: 29 June 2020; Accepted: 30 July 2020; Published: 31 July 2020 Abstract: Dexketoprofen trometamol is the tromethamine salt of dexketoprofen [(2S)-2-(3-benzoylphenyl) propanoic acid-2-amino-2-(hydroxymethyl)propane-1,3-diol], a nonsteroidal anti-inflammatory drug (NSAID) used for the treatment of moderate- to strong-intensity acute pain. The crystal structure of the hitherto sole known hydrate phase of dexketoprofen trometamol (DK-T_2H2O), as determined by single-crystal X-ray diffraction, is presented. The water molecules are arranged in dimers included in isolated sites and sandwiched between piles of trometamol cations. The molecular and crystal structures of DK-T_2H2O are analyzed and compared to those of the parent anhydrous crystal form DK-T_A. In both the crystal structures, all the potential H-bond donors and acceptor of the dexketoprofen and trometamol ions are engaged, and both the species crystallize in the P21 space group. However, during the DK-T_A:DK-T_2H2O hydration process, the unique symmetry axis is not conserved, i.e., the ions are arranged in a different way with respect to the screw axis, even if the two crystal structures maintain structural blocks of DK anions and T cations. Quantum mechanical solid-state calculations provide some hints for the possible intermediate structure during the crystalline–crystalline hydration/dehydration process. Keywords: dexketoprofen trometamol; hydrates; crystal structure; NSAIDs 1. Introduction Upon crystallization, a large number of active pharmaceutical ingredients (APIs) incorporate solvent molecules into their crystal lattice [1]. The inclusion of solvent molecules in the crystal lattice leads to changes in the unit cell dimensions, content and intermolecular interactions with respect to the pristine compound. As a consequence, the solvate of a drug molecule usually presents different physical, chemical and mechanical properties with respect to its unsolvated species, which obviously has a significant impact on the stability, solubility and performance of the API, as well as on the related regulatory issues. For this phenomenon, i.e., the possibility for a given substance to exist in different crystal forms, with each one having a different elemental composition as a result of the inclusion of Crystals 2020, 10, 659; doi:10.3390/cryst10080659 www.mdpi.com/journal/crystals Crystals 2020, 10, 659 2 of 14 Crystals 2020, 10, 659 2 of 14 inclusion of one or more solvent molecules, several authors have used the terms “pseudopolymorphism” [2] or “solvatomorphism” [3]. one orThe more most solvent common molecules, type of severalsolvate, authors where the have trap usedped the solvent terms is “pseudopolymorphism” water, is called a hydrate [2] [4] or “solvatomorphism”which, according to [Morris3]. and Rodriguez-Hornedo, can be classified in three categories, depending on howThe the most water common molecules type are of organized solvate, where into the the crystal trapped lattice solvent [5]: (i) is channel water, is hydrates; called a hydrate(ii) isolated [4] which,site hydrates; according (iii) tometal Morris ion andassociated Rodriguez-Hornedo, hydrates. can be classified in three categories, depending on howMany the APIs water are molecules able to form are organized hydrates intodue theto the crystal capability lattice [of5]: the (i) water channel molecule hydrates; to (ii)act isolatedboth as siteH-bond hydrates; donor (iii) and metal acceptor ion associated and also hydrates. because water is often present in the manufacturing environmentMany APIs of pharmaceuticals are able to form hydratessolids. In duefact, to APIs the capabilitycan be in ofcontact the water with moleculewater during to act different both as H-bondprocessing donor steps and (crystal acceptorlization, and also lyophilization, because water wet is often granulation, present in aqueous the manufacturing film coating environment or spray ofdrying) pharmaceuticals and are exposed solids. to In water fact, APIsduring can storage be in contactin an atmosphere with water containing during different water processing vapor. In some steps (crystallization,cases, water molecules lyophilization, can improve wet granulation, the stability aqueous of metastable film coating solid or sprayforms. drying) The formation and are exposed of strong to waterintermolecular during storage hydrogen in anatmosphere bonding may containing improve water the vapor.stability In of some the cases,hydrated water crystal molecules form can compared improve theto the stability corresponding of metastable anhydrate, solid forms. providing The formation stability of strong to the intermolecular crystal lattice hydrogen [6]. The bondingcardiovascular may improve drug thecreatine stability phosphate of the hydrated sodium crystal tetrahydrate, form compared the beta-l to theactam corresponding antibiotic anhydrate, ampicillin providing trihydrate stability and to the crystalsynthetic lattice broad-spectrum [6]. The cardiovascular cephalosporin drug creatine antibiotic phosphate, cephalexin sodium monohydrate tetrahydrate, the are beta-lactam some examples antibiotic of ampicillinmarketed trihydratestable hydrated and the forms synthetic of APIs broad-spectrum [7–9]. Finally, cephalosporin various hydrates antibiotic, of the cephalexin same compound monohydrate can areexhibit some different examples properties. of marketed For example, stable hydrated olanzapin formse has of three APIs hydrated [7–9]. Finally, polymorphs: various hydratesdihydrate of D, the B sameand E. compound Dihydrate can D exhibitis the differentmost thermodynamically properties. For example, stable olanzapine form and hashas three the most hydrated efficient polymorphs: crystal dihydratepacking and D, Bhence and E.the Dihydrate highest density D is the [6]. most thermodynamically stable form and has the most efficient crystalX-ray packing crystallography and hence the is highest the key density to studying [6]. structure–property relationships and single crystal X-rayX-ray diffraction crystallography (SCXRD) is is the the key method to studying of choice structure–property for molecular and relationships crystal structure and single determination crystal X-ray diffractionwhen crystals (SCXRD) are isavailable, the method as of well choice as for X-ray molecular powder and crystaldiffraction structure (XRPD), determination which whenprovides crystals an arealternative available, valuable as well astool X-ray for powderthe characterization diffraction (XRPD), of crystalline which provides powder an materials alternative [10]. valuable Both of tool these for thetechniques characterization [11–15], ofcomplemented crystalline powder by differential materials [scanning10]. Both calorime of these techniquestry [16–18], [11 solid–15], state complemented NMR [19], byIR-UV differential and Raman scanning spectroscopy calorimetry [ 16[20–22]–18], solid and state mode NMRlling [19 ],[23–29], IR-UV andcan Raman be successfully spectroscopy used [20– 22to] andcharacterize modelling the [23 solid–29], canstate be features successfully and usedbehavior to characterize (e.g., phase the solidstability, state polymorphism, features and behavior phase (e.g.,transformation) phase stability, of polymorphism,a large variety phaseof compounds transformation) including of a largeAPIs’ variety key precursors, of compounds well-known including APIs APIs’ keyas well precursors, as new promising well-known active APIs aspharmaceutical well as new promising compounds. active pharmaceutical compounds. Non-steroidal anti-inflammatoryanti-inflammatory drugs (NSAIDs) represent a widespread class of analgesicanalgesic medications which are usedused toto reducereduce painpain andand inflammation.inflammation. Dexketoprofen (Scheme 11 top),top), i.e., the S-enantiom S-enantiomerer of of ketoprofen; ketoprofen; is is usually usually formulated formulated as as 2- 2-amino-2-(hydroxymethyl)-1,3-propanediolamino-2-(hydroxymethyl)-1,3-propanediol (TRIS (TRIS or or trometamol, trometamol, Scheme Scheme 11 bottom) saltsalt whichwhich isis absorbed rapidly [[30].30]. Scheme 1. Schematic drawing of dexketoprofen (top) and trometamol (bottom). Crystals 2020, 10, 659 3 of 14 The anhydrate salt dexketoprofen trometamol, DK-T hereafter, is known to exhibit different crystal forms [31,32]: polymorph A (DK-T_A) and polymorph