Multicomponent Crystal of Metformin and Barbital: Design, Crystal Structure Analysis and Characterization

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Article Multicomponent Crystal of Metformin and Barbital: Design, Crystal Structure Analysis and Characterization

Linhong Cai 1,†, Lan Jiang 2,†, Cong Li 1, Xiaoshu Guan 1, Li Zhang 1 and Xiangnan Hu 1,*

1 Department of Medicinal Chemistry, School of Pharmacy, Chongqing Medical University, Chongqing 400016, China; [email protected] (L.C.); [email protected] (C.L.); [email protected] (X.G.); [email protected] (L.Z.) 2 College of Environment and Resources, Chongqing Technology and Business University, Chongqing 400067, China; [email protected] * Correspondence: [email protected]; Tel.: +86-133-0836-0519 † These authors contributed equally to this work.

Abstract: The formation of most multicomponent crystals relies on the interaction of hydrogen bonds between the components, so rational crystal design based on the expected hydrogen-bonded supramolecular synthons was employed to establish supramolecular compounds with desirable properties. This theory was put into practice for metformin to participate in more therapeutic ﬁelds to search for a fast and simple approach for the screening of candidate crystal co-formers. The prediction of intermolecular synthons facilitated the successful synthesis of a new multicomponent crystal of metformin (Met) and barbital (Bar) through an anion exchange reaction and cooling crystallization method. The single crystal X-ray diffraction analysis demonstrated the hydrogen bond-based ureide/ureide and guanidine/ureide synthons were responsible for the self-assembly of

the primary structural motif and extended into infinite supramolecular heterocatemeric structures. Keywords: multicomponent crystal; crystal design; supramolecular synthon; metformin; barbital Citation: Cai, L.; Jiang, L.; Li, C.; Guan, X.; Zhang, L.; Hu, X. Multicomponent Crystal of Metformin and Barbital: Design, Crystal Structure Analysis and 1. Introduction Characterization. Molecules 2021, 26, Metformin (Met), a first-line oral hypoglycemic drug, is widely used in type 2 dia- 4377. https://doi.org/10.3390/ betes [1]; the chemical structure is shown in Figure1a. Patients with diabetes usually have a molecules26144377 high co-prevalence rate of depression and neurodegenerative diseases such as Parkinson’s Molecules 2021, 26, x 3 of 14 disease and Alzheimer’s disease [2–4]. The pharmacokinetics show that Met can rapidly Received: 19 June 2021 arrive at the peak concentration in the cerebrospinal fluid and hippocampus crossing Accepted: 16 July 2021 blood–brain barriers within 30 min; it has received a lot of attention in terms of decreasing Published: 20 July 2021 thesorption oxidative (DVS) stress was of conducted the brain and to measure neuronal the apoptosis moisture in patients sorption with behavior neurodegenerative, of multicom- affective,ponent crystals. and metabolic diseases [5,6]. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations.

Licensee MDPI, Basel, Switzerland. This article is an open access article FigureFigure 1.1.Chemical Chemical structuresstructures ofof (a(a)) metformin metformin and and ( b(b)) barbital. barbital. distributed under the terms and conditions of the Creative Commons In recent years, more and more attention has been given to the ﬁeld of multicompo- Attribution (CC BY) license (https:// nent crystals including salts or cocrystals [7,8] because they are superior to compound creativecommons.org/licenses/by/ preparations and provide an alternative for pharmaceutical combination application [9–11]. 4.0/). Through the action of ionic bonds or non-covalent bonds, active pharmaceutical ingredients

Molecules 2021, 26, 4377. https://doi.org/10.3390/molecules26144377 https://www.mdpi.com/journal/molecules

Figure 2. Several examples of multicomponent chemical structures: (a) gliclazide metformin; (b) amino-methaniminium(butylcarbamoyl)(4-methylbenzene-1-sulfonyl)azanide; (c) metformin acesulfame; (d) amino[(diaminomethylidene)amino]-N,N-dimethylmethaniminium 2-(acetyloxy)benzoate. Supramolecular homo- and/or heterosynthons A, B, and C are highlighted with red, blue, and orange boxes, respectively.

Figure 3. Several examples of multicomponent chemical structures: (a) melamine barbital; (b) bis(zidovudine) 2,4,6-triaminopyrimidine; (c) 4-amino-2-oxopyrimidine 2,4-dioxo-5-fluoropyrimidine; (d) bis(barbital)–caffeine complex; (e) bis(barbital) 1-methylimidazole; (f) 5,5-diethylpyrimidine-2,4,6(1H,3H,5H)-trione bis(5-nitropyridin-2-amine). Su- pramolecular homo-and/or heterosynthons I, II, and III are highlighted with red, blue, and orange boxes, respectively.

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(APIs) and crystal co-formers (CCFs) are combined into one unit cell without changing the covalent structure of the drug molecule, which may not only improve druggability, stability, and bioavailability by altering the solubility, moisture absorption, and other physicochemical or mechanical properties of APIs, but also interact with different drug targets, causing a synergistic effect between drugs, a new choice for solid pharmaceutical preparations [12–15]. Multicomponent crystals represent the application of supramolecular concepts in the pharmaceutical industry [16]. In supramolecular chemistry, a supramolecular compound is deﬁned as a product of intermolecular recognition and self-assembly through hydrogen bonds or van der Waals forces, π–π stacking, electrostatic attraction, and other non-covalent bonds connecting active pharmaceutical ingredients with other organic molecules [17,18]. Among these interactions, hydrogen bonds are the most important force in the formation of supramolecular compounds due to their high strength, directionality, saturation, and multiple bonding modes [19]. Accordingly, the rational design of multiple component crystals is usually based on hydrogen-bonded supramolecular synthons [20]. Based on the synthon theory, Met can introduce a CCF to be a new entry with intellec- Molecules 2021, 26, x 3 of 14 tual property rights used in the central nervous system. Therefore, a set of multicomponent crystal structures of metformin was extracted from the Cambridge Structural Database (CSD). As drawn in Figure2, two Met molecules form a centrosymmetric dimer structure throughsorption the (DVS) N–H was···N conducted hydrogen bonds to measure based onthe homosynthonmoisture sorption A [15 ].behavior The imine of multicom- groups of Metponent can crystals. also interact with sulfonyl groups of gliclazide or tolbutamide or amide groups of acesulfame via the N–H···O and N–H···N hydrogen bonds building heterosynthon B to establish intermolecular interactions [12,21]. In addition, metformin can also construct supramolecular heterodimers with deprotonated aspirin via synthon C [13]. Not only that, the introduction of CCFs has changed the way of connection and stacking between metformin molecules, showing better physicochemical and pharmaceutical properties, and signiﬁcantly improved moisture absorption and stability [12,13,15,21]. In the existing literature, metformin has been proven to be a promising co-former with multiple hydrogen bond donors and acceptors during theformation of multicomponent crystals, making it suitable as an API for this experiment. Figure 1. Chemical structures of (a) metformin and (b) barbital.

FigureFigure 2.2. SeveralSeveral examples examples of multicomponent of multicomponent chemical chemical structures: structures: (a) gliclazide (a) gliclazide metformin; met- (b) formin;amino-methaniminium(butylcarbamoyl)(4 (b) amino-methaniminium(butylcarbamoyl)(4-methylbenzene-1-sulfonyl)azanide;-methylbenzene-1-sulfonyl)azanide; (c) metformin (c) met- forminacesulfame; acesulfame; (d ()d ) amino[(diaminomethylidene)amino]-amino[(diaminomethylidene)amino]-N,N-dimethylmethaniminiumN,N-dimethylmethaniminium 2- 2-(acetyloxy)benzoate. Supramolecular homo- and/or heterosynthons A, B, and C are highlighted (acetyloxy)benzoate. Supramolecular homo- and/or heterosynthons A, B, and C are highlighted with with red, blue, and orange boxes, respectively. red, blue, and orange boxes, respectively.

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sorption (DVS) was conducted to measure the moisture sorption behavior of multicomponent crystals.

Figure 1. Chemical structures of (a) metformin and (b) barbital.

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Barbiturates, derivatives of the barbituric acid, were commonly used as sedative– hypnotics in the mid-twentieth century [22]. In 1903, diethyl barbituric acid (barbital) was created as the ﬁrst barbiturate with central nervous system inhibitory effects [23]. Barbital (Bar) is mostly infrequently used in human medical treatment today but is still listed in pharmacopeias (e.g., in the European and Japanese Pharmacopeias) [24]. Barbital is characterized by symmetry, small molecular weight, and multiple hydrogen bonding sites, which makes it easy as a model CCF to generate some supramolecular compounds, as shown in Figure1b. In Figure3, barbital and melamine, which features an equally high symmetry, form a strong hydrogen bond through the three-point synthon I [25]. The supramolecular compound formed between 2,4,6-triamino-pyrimidine and zidovudine, which also has the

groups of acylurea, further conﬁrmed the rational existence of synthon I [26]. Barbital can Figurealso form 2. Several homodimers examples like of metforminmulticomponent through chemical two-point structures: supramolecular (a) gliclazide synthon metformin; II, and (b) amino-methaniminium(butylcarbamoyl)(4then another nitrogen–hydrogen bond-methylbenzene-1-sulfonyl)azanide; interacts with another molecule containing(c) metformin an N acesulfame; (d) amino[(diaminomethylidene)amino]-N,N-dimethylmethaniminium atom to form N–H···N and/or N–H···O interactions based on synthon III, similar to the 2-(acetyloxy)benzoate. Supramolecular homo- and/or heterosynthons A, B, and C are highlighted withhydrogen red, blue, bonding and orange of 5-ﬂuorouracil boxes, respectively. [27–30 ].

Figure 3.3. SeveralSeveral examplesexamples of of multicomponent multicomponent chemical chemical structures: structures: (a) melamine(a) melamine barbital; barbital; (b) bis(zidovudine) (b) bis(zidovudine) 2,4,6- 2,4,6-triaminopyrimidine; (c) 4-amino-2-oxopyrimidine 2,4-dioxo-5-fluoropyrimidine; (d) bis(barbital)–caffeine complex; triaminopyrimidine; (c) 4-amino-2-oxopyrimidine 2,4-dioxo-5-ﬂuoropyrimidine; (d) bis(barbital)–caffeine complex; (e) (e) bis(barbital) 1-methylimidazole; (f) 5,5-diethylpyrimidine-2,4,6(1H,3H,5H)-trione bis(5-nitropyridin-2-amine). Su- bis(barbital) 1-methylimidazole; (f) 5,5-diethylpyrimidine-2,4,6(1H,3H,5H)-trione bis(5-nitropyridin-2-amine). Supramolecu- pramolecular homo-and/or heterosynthons I, II, and III are highlighted with red, blue, and orange boxes, respectively. lar homo-and/or heterosynthons I, II, and III are highlighted with red, blue, and orange boxes, respectively.

We, therefore, postulated that guanidine/ureide-based supramolecular assembly would employ supramolecular homo- or heterosynthons for constructing hydrogen bonds with other supramolecular reagents. Consequently, by allowing APIs containing guanidino groups to associate with a co-former involving the –(CONHCO)– group, we surmised that guanidino and acylurea moieties would organize supramolecular synthon assemblies formed via N–H···O and N–H···N hydrogen bonds into extended architectures. It was expected, therefore, that Met and/or Bar were able to form a homodimer through synthon A and I, respectively, and then linked with each other via synthon B or synthon III to form a 1D chain. To test our design strategy, the anion exchange reaction was employed, and the result- ing crystal was determined primarily by single crystal X-ray diffraction (SCXRD). The other characterization methods included powder X-ray diffraction (PXRD), Fourier-transform infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and 1H NMR spectroscopy analysis. Dynamic vapor sorption (DVS) was conducted to measure the moisture sorption behavior of multicomponent crystals. Molecules 2021, 26, x 4 of 14

2. Results and Discussion Molecules 2021, 26, 4377 2.1. Single Crystal X-ray Diffraction Analysis of the Crystal Structure 4 of 13 Single crystalline materials of 1:1 Met–Bar isolated by cooling crystallization of 1,1-dimethyl-biguanidhydrochloride and 5,5-diethylbarbituric acid sodium (1:1) from methanol2. Results were and Discussionsuitable for analysis by SCXRD. The corresponding crystallographic data and2.1. Singlerefinement Crystal details X-ray are Diffraction summarized Analysis in ofTable the Crystal 1. It crystallized Structure in the triclinic space group P-1: a = 7.3409(7) Å, b = 11.1698(10) Å, c = 13.0980(9) Å, α = 74.680(7)°, β = Single crystalline materials of 1:1 Met–Bar isolated by cooling crystallization of 78.624(7)°, γ = 84.157(8)°, Z = 2, and the final R1 was 0.0525 (I > 2σ(I)) and wR2 was 0.1552 1,1-dimethyl-biguanidhydrochloride and 5,5-diethylbarbituric acid sodium (1:1) from (all data). There were one molecule of Met, one molecule of Bar, and two molecules of methanol were suitable for analysis by SCXRD. The corresponding crystallographic data methanol in an asymmetric unit in Figure 4. The N–H hydrogen atom of the malonylurea and refinement details are summarized in Table1. It crystallized in the triclinic space group group of Bar transferred to the imine group of Met, which proved that this was a P-1: a = 7.3409(7) Å, b = 11.1698(10) Å, c = 13.0980(9) Å, α = 74.680(7)◦, β = 78.624(7)◦, salt-typeγ = 84.157(8) multicomponent◦, Z = 2, and thecrystal. final R1 was 0.0525 (I > 2σ(I)) and wR2 was 0.1552 (all data). There were one molecule of Met, one molecule of Bar, and two molecules of methanol Table 1. Crystal data and structure refinement for Met–Bar. in an asymmetric unit in Figure4. The N–H hydrogen atom of the malonylurea group of Bar transferredEmpirical to the Formula imine group of Met, which proved C14 thatH31N this7O5 was a salt-type multicomponentFormula crystal. weight 377.46 Temperature (K) 293(2) Table 1. Crystal dataCrystal and structuresystem refinement for Met–Bar. Triclinic

EmpiricalSpace Formulagroup C14H31P-1N7 O5 a (Å) 7.3409(7) Formula weight 377.46 Temperatureb (Å) (K)11.1698(10) 293(2) Crystalc (Å) system 13.0980(9) Triclinic Spaceα group(°) 74.680(7) P-1 aβ (Å) (°) 7.3409(7)78.624(7) b (Å) 11.1698(10) γ (°) 84.157(8) c (Å) 13.0980(9) Volumeα (◦) (Å3) 1014.08(15) 74.680(7) β (Z◦) 78.624(7)2 ◦ ρcalcgγ ( )(cm3) 84.157(8)1.236 3 1014.08(15) Volumeμ/mm (Å−1 ) 0.791 Z 2 ρcalcgF(000) (cm3 ) 1.236408 Crystalµ/mm size−1 (mm3) 0.12 0.791× 0.1 × 0.09 RadiationF(000) CuKα ( 408λ = 1.54184) 3 2Θ rangeCrystal for sizedata (mm collection) (°) 0.127.11× to0.1 134.102× 0.09 α λ IndexRadiation ranges −8 ≤ h ≤ CuK 8, −13( ≤ =k 1.54184)≤ 13, −15 ≤ l ≤ 13 2Θ range for data collection (◦) 7.11 to 134.102 ReflectionsIndex ranges collected −8 ≤ h ≤ 8, −13 ≤7079k ≤ 13, −15 ≤ l ≤ 13 IndependentReflections collected reflections 3627 (Rint = 0.0330, 7079 Rsigma = 0.0556) Data/restraints/parametersIndependent reflections 3627 (Rint = 0.0330,3627/0/278 Rsigma = 0.0556) Data/restraints/parametersGoodness-of-fit on F2 3627/0/2781.04 Goodness-of-fit on F2 1.04 Final RR indexesindexes (I (I≥ ≥2 σ2σ(I)) (I)) R1 == 0.0525, wR2 wR2 = = 0.1313 0.1313 FinalFinal R indexesindexes (all (all data) data) R1 == 0.0805, wR2 wR2 = = 0.1552 0.1552 LargestLargest diff., diff., peak/hole peak/hole (e/Å (e/Å−3–3) ) 0.25/0.25/–0.17−0.17 CCDCCCDC depositdeposit number number 20750032075003

Figure 4. Thermal ellipsoid ﬁgure drawn at the 50% probability level.

As shown in Table2 and Figure5, the crystal structure generated a centrosymmetric dimeric unit of the Bar molecule assembled by the expected amide–amide homosynthon Molecules 2021, 26, x 5 of 14

Figure 4. Thermal ellipsoid figure drawn at the 50% probability level.

Molecules 2021, 26, 4377 As shown in Table 2 and Figure 5, the crystal structure generated a centrosymmetric5 of 13 dimeric unit of the Bar molecule assembled by the expected amide–amide homosynthon II with the N6···O1 distance of 2.931 Å. The Met molecule linked two Bar molecules into IIan with infinite the N6one-dimensional···O1 distance (1D) of 2.931 chain Å. via The N(4)–H(4D)···O(3) Met molecule linked and N(1)–H(1A)···O(2) two Bar molecules hy- intodrogen an inﬁnite bonding one-dimensional interactions with (1D) the chain N4···O via3 and N(4)–H(4D) N1···O2 ···distancesO(3) and of N(1)–H(1A) 3.057 and 2.967···O(2) Å, hydrogenrespectively. bonding The interactionsN–H···O hydrogen with the bonds N4···O3 created and N1 a··· 1DO2 rod distances motifof by 3.057 the andpredicted 2.967 Å,one-point respectively. synthon The III N–H instead···O of hydrogen forming bondsa centrosymmetric created a 1D 0D rod dimer motif through by the predictedsynthon A one-pointbetween the synthon Met IIImolecules. instead ofAdjacent forming antipa a centrosymmetricrallel chains were 0D dimer arranged through into synthon ribbons Athrough between pairs the Metof molecules.symmetry Adjacentbetween antiparallelthe related chainsBar homodimeric were arranged motif into ribbonsand the throughN(1)-H(1B)···O(1) pairs of symmetry hydrogen betweenbond; r(N1···O1), the related 2.939 Bar Å; homodimeric ∠(N–H–O), 142°. motif In and addition, the N(1)- the ◦ H(1B)two eight-membered···O(1) hydrogen rings bond; formed r(N1··· throughO1), 2.939 the Å; co∠nnectivity(N–H–O), of 142 the. N(1) In addition, atom of theMet two and eight-memberedthe O(1) atom of rings Bar further formed stabilized throughthe the connectivity crystal structure of the together N(1) atom with of a Met homodimer and the O(1)ring atomof Bar. of Based Bar further on the stabilized intermolecular the crystal interactions structure described together withabove, a homodimerall donor and ring ac- ofceptor Bar. Basedmoieties on thein Bar intermolecular except for the interactions ionized N(7) described atom generated above, all hydrogen donor and bonds acceptor with moietiesMet molecules in Bar exceptor Bar for itself. the ionizedThis indicated N(7) atom that generated Bar could hydrogen be a promising bonds with crystal Met moleculesco-former orduring Bar itself. the formation This indicated of multicomponent that Bar could crystals. be a promising crystal co-former during the formation of multicomponent crystals. Table 2. Hydrogen bonds for Met–Bar. Table 2. HydrogenD–H···A bonds for Met–Bar. d(D–H) (Å) d(H–A) (Å) d(D–A) (Å) D–H–A (◦) N(1)–H(1A)···O(2)D–H···A 1 d(D–H)0.84 (Å) d(H–A)2.15 (Å) d(D–A)2.967 (Å) D–H–A163 (◦ ) N(1)–H(1B)···O(1) 0.83 2.24 2.939 142 N(1)–H(1A)···O(2) 1 0.84 2.15 2.967 163 N(1)–H(1B)N(2)–H(2A)···O(4)···O(1) 0.830.88 2.242.10 2.9392.951 142161 N(2)–H(2A)N(2)–H(2B)···O(4)···O(4)2 0.880.92 2.101.99 2.9512.908 161175 N(2)–H(2B)N(4)–H(4D)···O(3)···O(4) 2 2 0.920.89 1.992.19 2.9083.057 175166 ··· 2 N(4)–H(4D)N(4)–H(4E)···O(5)O(3) 2 0.890.89 2.192.02 3.0572.901 166171 N(4)–H(4E)···O(5) 2 0.89 2.02 2.901 171 N(6)–H(6)···O(1)1 0.80 2.13 2.931 179 N(6)–H(6)···O(1) 1 0.80 2.13 2.931 179 2 O(4)–H(4)O(4)–H(4)···N(7)···N(7) 2 0.860.86 1.881.88 2.7392.739 172172 O(5)–H(5)O(5)–H(5)···O(3)···O(3) 3 3 0.780.78 1.971.97 2.7552.755 175175 SymmetrySymmetry transformations transformations used used to generate to generate equivalent equivalent atoms: 1 atoms:1 − X, 1 1 −1 Y,− X,−Z; 1 2− −Y,X, − 1Z;− 2 Y,−X, 1 −1 −Z; Y,3 − 1X, − Z;−Y, 3 1−−X,Z. −Y, 1 − Z.

FigureFigure 5. 5.One-dimensional One-dimensional layered layered structure structure connected connected by by hydrogen hydrogen bonds bonds of of Met–Bar. Met–Bar.

ComparedCompared with with the the pure pure crystal crystal structure structure of Bar of Bar extracted extracted from from the CSD the inCSDFigure in Figure6 [31] ,6 the[31], multicomponent the multicomponent crystal crystal structure structure reassembled reassembled the packing the packing arrangements arrangements of the struc-of the turestructure at the at molecular the molecular level level in that in that the the blue blue 5,5-diethylbarbituric 5,5-diethylbarbituric acid acid molecules molecules were were substitutedsubstituted with with metformin metformin molecules molecules (Figure (Figure4). Met–Bar 4). Met–Bar was thereby was sustainedthereby throughsustained supramolecularthrough supramolecular hydrogen-bonded hydrogen-bonded homo- and homo- heterosynthons and heterosynthons (synthons II (synthons and III) in II such and aIII) manner in such that a amanner heterocatemeric that a heterocatemeric chain similar to chain the homomeric similar to catemerthe homomeric present incatemer pure 5,5-diethylbarbituricpresent in pure 5,5-diethylbarbituric acid was generated. acid Towa summarize,s generated. the To rationalsummarize, design the of rational this mul- de- ticomponentsign of this multicomponent crystal based on crystal supramolecular based on synthonsupramolecular analysis sy workednthon analysis very well, worked and the expected synthons II and III were observed in the crystal structure sustained by a supramolecular heterocatemer.

Molecules 2021, 26, x 6 of 14

very well, and the expected synthons II and III were observed in the crystal structure sustained by a supramolecular heterocatemer.

Molecules 2021, 26, x 6 of 14

Molecules 2021, 26, 4377 6 of 13 very well, and the expected synthons II and III were observed in the crystal structure sustained by a supramolecular heterocatemer.

Figure 6. Cooperative N–H···O hydrogen-bonded linear chain supramolecular homosynthons ex- hibited in the crystal structure of barbital.

2.2. Characterization of the Crystal Structure The thermal behavior was analyzed using the TGA and DSC techniques. We obtained the weight change values of the substance converted to the percentage by weight within a specific heating temperature range of 25–500 °C, as drawn in Figure 7 (represented by the red lines). In the unit cell diagram of the monocrystalline solid, as shown in Figure 4, we observed that the multicomponent crystal contained two methanol molecules, which wasFigureFigure consistent 6.6. CooperativeCooperative with the N–H···O N–HTGA··· profileO hydrogen hydrogen-bonded of the-bonded solvate linear linear with chain a chain continuous supram supramolecularolecular weight homosynthons homosynthons ex- loss of 16.62% beforeexhibitedhibited melting in in the the crystal crystal(theoretical structure structure weight of of barbital. barbital. loss, 16.7%) in Figure 7b. However, after the solvate was dried under vacuum at 55 °C, TGA demonstrated that when Met–Bar disintegrated at2.2.2.2. 216.38 Characterization Characterization °C, there was of of the the no Crystal Crystal significant Structure Structure downward tendency of weight (%) from 25 °C to 216.38TheThe °C. thermal thermal It proved behavior behavior that wasour was analyzedmulticomponent analyzed using using the crystal TGAthe TGA and had DSCand undergone techniques.DSC techniques. a We obtained We ob- crystal transformationthetained weight thephenomenon. changeweight valueschange The of valuespr theepared substance of theMet–Bar substa converted hadnce beenconverted to thetransformed percentage to the percentage from by weight by within weight ◦ a solvate to a desolvateawithin specific a andspecific heating further heating temperature identified temperature rangeby DSC of rangeand 25–500 1H of NMR 25–500C, as spectroscopy drawn°C, as drawn in Figure analy- in 7Figure (represented 7 (repre- sis. Unfortunately,bysented the thered bysingle the lines). crystalred lines). In of the the In unit thedesolvate cellunit diagramcell could diagram not of thebe of obtained.the monocrystalline monocrystalline solid, solid, as as shown shown in in As drawnFigure inFigure Figure4, 4, we 7a,we observed consistentobserved that withthat the the multicomponent TGAmulticomponent thermogram crystal crystal of contained the containeddesolvate, two methanol twothere methanol molecules, mole- was only a relativelywhichcules, waswhichprominent consistent was consistentendothermic with the with TGApeak; the profile TGAno endothermic profile of the solvateof the peak solvate with caused a with continuous by a continuousen- weight weight loss dothermic desolvationofloss 16.62% of 16.62% which before beforewas melting different melting (theoretical from (theoretical the weightendothermic weight loss, loss, 16.7%) peak 16.7%) of in the in Figure Figuresolvate7b. 7b. at However, However, after after ◦ 95.72 °C due tothe thedesolvation solvate solvate was wasin Figure dried dried 7b under under was vacuum observed.vacuum at at In 55 55 the C,°C, DSC TGA TGA curve demonstrated demonstrated of the desolvate, that that when when Met–Bar Met–Bar ◦ the intersectiondisintegrated disintegratedof the maximum atat 216.38216.38 slope of°C,C, the therethere front waswas of no theno significant peaksignificant and the downward downward baseline extensiontendency tendency of ofweight weight(%) (%) ◦ ◦ line was the meltingfromfrom 25 25point C°C to ofto 216.38 Met–Bar216.38 C.°C. (213.97 ItIt proved proved °C), that whichthat our our was multicomponent multicomponent much higher than crystal crystal that had hadof undergone undergone a a Met (112.5 °C) crystal[12,13]crystal transformation andtransformation Bar (190 °C) phenomenon. phenomenon. [32] but lower The The than prepared pr thatepared of Met–Bar Met·HCl Met–Bar had (223–226 had been been transformed °C). transformed from from a 1 Combined withsolvatea thesolvate TGA to ato desolvatethermogram, a desolvate and and it further was further proved identified identified that by the DSCby meltingDSC and andH of 1 NMR HMet–Bar NMR spectroscopy spectroscopy oc- analysis. analy- curred before decompositionUnfortunately,sis. Unfortunately, at the 216.38 single the single°C. crystal crystal of the of desolvate the desolvate could could not be not obtained. be obtained. As drawn in Figure 7a, consistent with the TGA thermogram of the desolvate, there was only a relatively prominent endothermic peak; no endothermic peak caused by endothermic desolvation which was different from the endothermic peak of the solvate at 95.72 °C due to desolvation in Figure 7b was observed. In the DSC curve of the desolvate, the intersection of the maximum slope of the front of the peak and the baseline extension line was the melting point of Met–Bar (213.97 °C), which was much higher than that of Met (112.5 °C) [12,13] and Bar (190 °C) [32] but lower than that of Met·HCl (223–226 °C). Combined with the TGA thermogram, it was proved that the melting of Met–Bar occurred before decomposition at 216.38 °C.

Figure 7. Thermal analysis of the desolvate (a) and the solvate (b) of Met–Bar. The red and black lines represent the TGA and DSC curves, respectively.

As drawn in Figure7a, consistent with the TGA thermogram of the desolvate, there was only a relatively prominent endothermic peak; no endothermic peak caused by endothermic desolvation which was different from the endothermic peak of the solvate at 95.72 ◦C due to desolvation in Figure7b was observed. In the DSC curve of the desolvate, the intersection of the maximum slope of the front of the peak and the baseline extension line was the melting point of Met–Bar (213.97 ◦C), which was much higher than that of Met (112.5 ◦C) [12,13] and Bar (190 ◦C) [32] but lower than that of Met·HCl (223–226 ◦C). Combined with the TGA thermogram, it was proved that the melting of Met–Bar occurred before decomposition at 216.38 ◦C.

Molecules 2021, 26, x 7 of 14

Figure 7. Thermal analysis of the desolvate (a) and the solvate (b) of Met–Bar. The red and black Molecules 2021, 26, 4377 7 of 13 lines represent the TGA and DSC curves, respectively.

We further conducted 1H NMR spectroscopy analysis to characterize molecular structuresWe further of Met·HCl, conducted Bar·Na,1H NMR and spectroscopy the solvate analysis and desolvate to characterize samples molecular of Met–Bar. struc- In turesFigure of Met8c, ·sinceHCl, Barthe ·twoNa, andmethyl the solvategroups andin Met desolvate and the samples two ethyl of Met–Bar. groups in In Bar Figure did8 c,not sinceparticipate the two in methyl the formation groups inof Methydrogen and the bond twos, ethyl their groups chemical in Barshifts did did not not participate change in inthe the salt-type formation crystalline of hydrogen compound, bonds, theirwhich chemical were 2.92, shifts 1.64, did and not 0.63, change respectively. in the salt-type Due to crystallinethe occurrence compound, of the whichion exchange were 2.92, reaction, 1.64, and sodium 0.63, chloride respectively. was removed Due to the to occurrence form a new ofionic theion bond, exchange and the reaction, N–H bond sodium in Met chloride participated was removed in the toformation form a new of hydrogen ionic bond, bonds, and theincreasing N–H bond chemical in Met participatedshifts in the inmulticomponent the formation of crystal, hydrogen which bonds, appeared increasing at 7.28, chemical a single shiftsabsorption in the multicomponentpeak. However, owing crystal, to whichthe influence appeared of the at 7.28,water a peak single of absorption DMSO-d6, peak.the ac- However,tive hydrogen owing atom to the with inﬂuence a chemical of the watershift of peak 9.70 of on DMSO- Bar disappeard6, the activeed. Additionally, hydrogen atom the withmethanol a chemical peaks shift were of shown 9.70 on at Bar 3.16 disappeared. in the solvate Additionally, crystal in Figure the methanol 8d but did peaks not appear were shownin the at desolvate 3.16 in the samples. solvate crystalIt was inproved Figure that8d but the did crystal not appear was a inmethanol-free the desolvate compound samples. Itwhose was proved stoichiometric that the crystalratio of was Met a and methanol-free Bar was 1:1, compound as shown in whose Figure stoichiometric 8. Compared ratio to the ofcommonly Met and Bar applied was 1:1, doses as shownof Met inand Figure Bar, this8. Compared constant ratio to the of commonly this form of applied APIs might doses be ofpossible Met and to Bar, administer this constant as a drug. ratio ofThe this genera forml oforal APIs dosage might of be Met, possible marketed to administer under the astrade a drug. name The Glucophage, general oral was dosage 0.5 g of twice Met, daily marketed or 0.85 under g once the daily trade with name meals. Glucophage, The daily wasdosage 0.5 g was twice increased daily or by 0.85 0.5 g at once weekly daily interval with meals.s or by The0.85 dailyg at biweekly dosage was(every increased 2 weeks) byintervals 0.5 g at up weekly to a intervalsmaximum or of by 2.55 0.85 gg daily at biweekly given in (every divided 2 weeks) doses intervals[33]. Barbital up to was a maximummarketed ofby 2.55Bayer g dailyas Veronal, given and in divided 3.5–4.4 dosesg was the [33]. deadly Barbital dose, was but marketed sleep had by also Bayer been asprolonged Veronal, andup to3.5–4.4 ten days g was with the recovery deadly dose,[34]. The but doses sleep used had alsorange been from prolonged 0.25 g to 3.5 up g to to tenproduce days with weak, recovery moderate, [34]. or The strong doses effects; used the range therapeutic from 0.25 dose g to frequently 3.5 g to produce was 0.6–1.0 weak, g; moderate,a dose of or0.5 strong g sufficed effects; to produce the therapeutic sleep within dose frequentlyan hour [35]. was From 0.6–1.0 this g;point a dose of view, of 0.5 the g sufﬁcedpossible to use produce of 0.5 sleepg Met–Bar within once an houror twice [35]. a Fromday could this point be administered of view, the based possible on usethis of 1:1 0.5constant g Met–Bar ratio. once or twice a day could be administered based on this 1:1 constant ratio. 1 TheThe H1H NMR NMR data data of of Met Met·HCl,·HCl, Bar Bar·Na,·Na, multicomponent multicomponent crystal crystal of of Met–Bar, Met–Bar, and and the the solvatesolvate crystal, crystal, respectively, respectively, were: were: 1 H1 NMR (600 MHz, DMSO-d ) δ 7.22 (s, 2H), 6.79 (s, 4H), 2.93 (s, 6H). H NMR (600 MHz, DMSO-6d6) δ 7.22 (s, 2H), 6.79 (s, 4H), 2.93 (s, 6H). 1H NMR (600 MHz, DMSO-d ) δ 9.70 (s, 1H), 1.64 (q, J = 7.4 Hz, 4H), 0.63 (t, 1H NMR (600 MHz, DMSO-d6)6 δ 9.70 (s, 1H), 1.64 (q, J = 7.4 Hz, 4H), 0.63 (t, J = 7.4 Hz, J =6H). 7.4 Hz, 6H). 1H NMR (600 MHz, DMSO-d ) δ 7.28 (s, 6H), 2.92 (s, 6H), 1.64 (q, J = 7.4 Hz, 4H), 0.63 1H NMR (600 MHz, DMSO-6d6) δ 7.28 (s, 6H), 2.92 (s, 6H), 1.64 (q, J = 7.4 Hz, 4H), 0.63 (t, J = 7.4 Hz, 6H). (t, J1 = 7.4 Hz, 6H). H NMR (600 MHz, DMSO-d6) δ 7.26 (s, 6H), 2.92 (s, 6H), 1.64 (q, J = 7.4 Hz, 4H), 0.63 1H NMR (600 MHz, DMSO-d6) δ 7.26 (s, 6H), 2.92 (s, 6H), 1.64 (q, J = 7.4 Hz, 4H), 0.63 (t, J = 7.4 Hz, 6H). (t, J = 7.4 Hz, 6H).

Figure 8. Cont.

Molecules 2021, 26, 4377 8 of 13 Molecules 2021, 26, x 8 of 14

1 FigureFigure 8. 81. HH NMR NMR spectra spectra of of Met Met·HCl·HCl ( a(a),), Bar Bar·Na·Na ((bb),), multicomponentmulticomponent crystalcrystal ofof Met–BarMet–Bar ((cc),), andand the solvate crystal (d). the solvate crystal (d).

PowderPowder X-ray X-ray diffraction diffraction had had much much broader broader applications applications than than single single crystal crystal X-ray X-ray diffraction,diffraction, which which could could quickly quickly identify identify the th structurale structural difference difference between between our rawour raw materi- ma- alsterials and Met–Bar,and Met–Bar, and the and results the results are shown are shown in Figure in 9Figure. The diffraction9. The diffraction peaks (14.08 peaks◦, (14.08°, 16.8◦, 23.3616.8°,◦, 24.4823.36°,◦, 28.324.48°,◦, 29.1 28.3°,◦) of the29.1°) experimental of the experimental PXRD pattern PXRD of the pattern solvate of matched the solvate the simulatedmatched PXRDthe simulated pattern PXRD based onpattern SCXRD based well, on showing SCXRD thatwell, the showing prepared that crystals the prepared were ofcrystals pure crystalline were of pure phases. crystalline Additionally, phases. theAddi characteristictionally, the diffractioncharacteristic peaks diffraction of Met· HClpeaks withof Met·HCl 2θ were atwith 12.6 2◦θ, 17.54were◦ ,at 24.42 12.6°,◦, 31.1617.54°,◦, 32.4624.42°,◦, and31.16°, Bar ·32.46°,Na was and characterized Bar·Na was with charac- 2θ atterized 10.82◦ ,with 15.08 2◦θ, 16.88 at 10.82°,◦, 21.28 15.08°,◦, 27.06 16.88°,◦, 31.9 ◦21.28°,. Obviously, 27.06°, the 31.9°. diffraction Obviously, peaks the of diffraction Met–Bar (8.04peaks◦, 10.76 of Met–Bar◦, 12.0◦, 14.6(8.04°,◦, 18.12 10.76°,◦, 21.34 12.0°,◦, 24.114.6°,◦) were18.12°, different 21.34°, from24.1°) those were of different the two rawfrom materialsthose of andthe thetwo solvate raw materials crystal because and the there solv wereate crystal completely because different there were and new completely peaks emergingdifferent atand 8.04 new◦, 14.02 peaks◦, 14.6 emerging◦, etc., indicating at 8.04°, 14.02°, that the 14.6°, PXRD etc., pattern indicating of Met–Bar that the was PXRD not

MoleculesMolecules 20212021,, 2626,, 4377x 99 of 1314

apattern simple of superposition Met–Bar was of thenot patterns a simple of Metsupe·HClrposition and Bar of· Na.the Met–Barpatterns wasof Met·HCl an absolutely and newBar·Na. compound, Met–Bar notwas a an mixture absolutely of the new two comp rawound, materials, not a which mixture was of consistent the two raw with mate- the FT-IRrials, which spectrum. was consistent with the FT-IR spectrum.

Figure 9.9. Powder X-ray diffractograms of MetMet·HCl,·HCl, BarBar·Na,·Na, and Met–Bar.

By meansmeans of of Fourier-transform Fourier-transform infrared infrared spectroscopy spectroscopy analysis, analysis, we observed we observed the shifts the inshifts the locationin the location and intensity and intensity of absorption of absorp peakstion of thepeaks characteristic of the characteristic functional functional groups in Molecules 2021, 26, x 10 of 14 thegroups molecules in the molecules of Met·HCl, of Bar Met·HCl,·Na, and Bar·Na, Met–Bar, and testifying Met–Bar, whether testifying there whether were newthere bonds were innew the bonds multicomponent in the multicomponent crystal of Met–Bar crystal based of onMet–Bar their differences, based on as their shown differences, in Figure 10as. shown in Figure 10. The C=O stretching vibration, the carbonyl group of Bar·Na, showed characteristic absorption peaks at 1697 cm−1 and 1667 cm−1, which corresponded to the absorption peaks of the multicomponent crystal of Met–Bar at 1715 cm−1 and 1668 cm−1, suggesting the formation of the hydrogen bond between N–H in Met and C=O in Bar. In the fingerprint region of the infrared absorption spectrum, 1303 cm−1 and 653 cm−1 were the absorption peaks of the C–N stretching vibration in the structure of Bar·Na, and the positions in the multicomponent crystal were 1305 cm-1 and 652 cm−1, almost unchanged (not involved in hydrogen bonding). The absorption frequencies of the N–H stretching vibration in Met·HCl were 3371 cm−1, 3294 cm−1, and 3173 cm−1, which were very similar to the vibrational frequencies of the newly formed compound at 3369 cm−1, 3299 cm−1, and 3177 cm−1, indicating that the new compound may also be a salt-type compound with proton transfer like Met·HCl. It agreed with the single crystal X-ray diffraction data. The absorption signal of the C=N stretching vibration was 1625 cm−1 in Met·HCl and 1644 cm−1 in the structure of the multicomponent crystal, which was shifted to high frequency.

FigureFigure 10.10. FT-IR spectraspectra ofof BarBar·Na,·Na, MetMet·HCl·HCl and Met–Bar.

2.3. CharacterizationThe C=O stretching of the vibration,Moisture Sorption the carbonyl Behavior group of Bar·Na, showed characteristic −1 −1 absorptionDVS was peaks used at 1697 to evaluate cm and hy 1667groscopicity cm , which of Met–Bar. corresponded Barbiturate to the absorptiondrugs with peaks low −1 −1 ofsolubility the multicomponent are mainly made crystal into of alkali Met–Bar metal at salts 1715 to cm increaseand 1668solubility, cm ,such suggesting as barbital the formationsodium, phenobarbital of the hydrogen sodium. bond betweenHowever, N–H the inaqueous Met and solution C=O in of Bar. sodium In the salts ﬁngerprint is usu- −1 −1 regionally unstable, of the infrared easy to absorptionhydrolyze spectrum,when placed 1303 at cm roomand temperature, 653 cm wereso it theis often absorption added · peaksto powder of the needles C–N stretching for injection vibration use, limiting in the structure the diversity of Bar ofNa, formulation and the positions of this class in the of multicomponent crystal were 1305 cm−1 and 652 cm−1, almost unchanged (not involved drugs [36]. Besides, it is known from the literature that Met is highly hygroscopic. It ab- in hydrogen bonding). sorbed a large amount of water after 60% RH, and the weight change was as high as 60% The absorption frequencies of the N–H stretching vibration in Met·HCl were 3371 cm−1, at 80% RH, causing the drug to deliquesce in a short period of time due to the sorption 3294 cm−1, and 3173 cm−1, which were very similar to the vibrational frequencies of the of water [12,13,15]. The structures determined the properties, whether new crystals synthesized by design were able to improve the properties of individual components. Hence, the investigation and verification of the hygroscopicity of Met–Bar was an essential part of our research. As shown in Figure 11, the weight change values of Met–Bar within a certain relative humidity range of 0–80% could be clearly observed to determine the ability of the crystal’s moisture sorption behavior in the air. However, Met and Bar were combined into a multicomponent crystal, and even when the relative humidity reached 80%, the weight change of the sample was only 0.25%, which well overcame the shortcoming of Met’s high moisture sorption behavior, suggesting that the new compound could be stored stably at ambient RH.

Molecules 2021, 26, 4377 10 of 13

newly formed compound at 3369 cm−1, 3299 cm−1, and 3177 cm−1, indicating that the new compound may also be a salt-type compound with proton transfer like Met·HCl. It agreed with the single crystal X-ray diffraction data. The absorption signal of the C=N stretching vibration was 1625 cm−1 in Met·HCl and 1644 cm−1 in the structure of the multicomponent crystal, which was shifted to high frequency.

2.3. Characterization of the Moisture Sorption Behavior DVS was used to evaluate hygroscopicity of Met–Bar. Barbiturate drugs with low solubility are mainly made into alkali metal salts to increase solubility, such as barbital sodium, phenobarbital sodium. However, the aqueous solution of sodium salts is usually unstable, easy to hydrolyze when placed at room temperature, so it is often added to powder needles for injection use, limiting the diversity of formulation of this class of drugs [36]. Besides, it is known from the literature that Met is highly hygroscopic. It absorbed a large amount of water after 60% RH, and the weight change was as high as 60% at 80% RH, causing the drug to deliquesce in a short period of time due to the sorption of water [12,13,15]. The structures determined the properties, whether new crystals synthesized by design were able to improve the properties of individual components. Hence, the investigation and veriﬁcation of the hygroscopicity of Met–Bar was an essential part of our research. As shown in Figure 11, the weight change values of Met–Bar within a Molecules 2021, 26, x 11 of 14 certain relative humidity range of 0–80% could be clearly observed to determine the ability of the crystal’s moisture sorption behavior in the air.

FigureFigure 11.11. DVS isotherm plotplot forfor thethe multicomponentmulticomponent crystalcrystal ofof Met–Bar.Met–Bar.

3. ConclusionsHowever, Met and Bar were combined into a multicomponent crystal, and even when the relativeIn this humidity experiment, reached successful 80%, the simple weight changesynthesis of theof samplea multicomponent was only 0.25%, crystal which of well overcame the shortcoming of Met’s high moisture sorption behavior, suggesting that Met-Bar demonstrated that the method of designing crystals based on supramolecular the new compound could be stored stably at ambient RH. synthons with valence bond strength is trustworthy. The crystal structure-based pre- 3.dicted Conclusions synthon II formed a homodimer and assembled into a larger architecture through the expected one-point synthon III. Additionally, the hydrogen bonds network estab- In this experiment, successful simple synthesis of a multicomponent crystal of Met-Bar lished by Met and Bar changed the molecular arrangement of individual components demonstrated that the method of designing crystals based on supramolecular synthons and generated a new unit cell packing form, which structurally affected the physico- with valence bond strength is trustworthy. The crystal structure-based predicted synthon chemical properties of the crystal, reduced the moisture sorption of Met, and increased II formed a homodimer and assembled into a larger architecture through the expected the stability of Bar. one-point synthon III. Additionally, the hydrogen bonds network established by Met and However, systemic studies of the structure–properties relationship of multicompo- Bar changed the molecular arrangement of individual components and generated a new nent crystals are only rarely conducted at present. Accordingly, the mechanism of mul- unit cell packing form, which structurally affected the physicochemical properties of the ticomponent crystals formation should be discussed in depth to improve crystal screen- crystal, reduced the moisture sorption of Met, and increased the stability of Bar. ing efficiency. In particular, the main challenge that the emerging research field of multicomponent crystals faces is that the interaction and stacking arrangement between drug molecules can be controlled through other rational and precise crystal designs to achieve targeted changes in the drug melting point, dissolution rate, solubility, bioavailability, biological activity, and other desirable properties to increase the speed of drug development.

4. Materials and Methods 4.1. Materials Barbital sodium (Chengdu Chemical Reagent Factory, Chengdu, Sichuan, China) was used as received. Metformin hydrochloride and other solvents and chemicals were purchased from Adamas Reagent Company (Shanghai, China) and used without further purification unless otherwise stated.

4.2. Methods 4.2.1. Preparation of Met–Bar Met·HCl (0.165 g) and Bar·Na (0.206 g) were dissolved in 20 mL boiling methanol and stirred for 1 h. The filtrate was transferred to a 50 mL Petri dish sealed with a parafilm perforated with a few small holes, and finally left undisturbed in a refrigerator at 4 °C to allow cooling crystallization. Crystals were obtained within a week, which were suitable for single crystal X-ray diffraction analysis. For preparing the bulk sample of

Molecules 2021, 26, 4377 11 of 13

However, systemic studies of the structure–properties relationship of multicomponent crystals are only rarely conducted at present. Accordingly, the mechanism of multicomponent crystals formation should be discussed in depth to improve crystal screening efﬁciency. In particular, the main challenge that the emerging research ﬁeld of multicomponent crystals faces is that the interaction and stacking arrangement between drug molecules can be controlled through other rational and precise crystal designs to achieve targeted changes in the drug melting point, dissolution rate, solubility, bioavailability, biological activity, and other desirable properties to increase the speed of drug development.

4.2. Methods 4.2.1. Preparation of Met–Bar Met·HCl (0.165 g) and Bar·Na (0.206 g) were dissolved in 20 mL boiling methanol and stirred for 1 h. The filtrate was transferred to a 50 mL Petri dish sealed with a parafilm perforated with a few small holes, and finally left undisturbed in a refrigerator at 4 ◦C to allow cooling crystallization. Crystals were obtained within a week, which were suitable for single crystal X-ray diffraction analysis. For preparing the bulk sample of Met–Bar, 1.650 g Met·HCl and 2.060 g Bar·Na were transferred to 100 mL boiling methanol in a beaker and heated to 90 ◦C while continuously stirring for 2 h. The filtrate was left to cool at 4 ◦C with the beaker covered by the parafilm. Large crystals of Met–Bar grew overnight. The crystals were harvested by filtration and dried at 55 ◦C in a vacuum oven overnight. The crystals were milled for further characterization and formulation.

4.2.2. Single Crystal X-ray Diffraction (SCXRD) SCXRD data were collected using a Bruker SMART CCD diffractometer (Bruker, Karlsruhe, Germany), with Cu-Kα radiation (λ = 1.54184 Å) at 293 K. Integration and scaling of the intensity data were corrected for empirical absorption effects with the spherical harmonics implemented in the SCALE3 ABSPACK scaling algorithm. The structure was solved with the SHELXS-97 program by direct methods and refined with the least squares minimization using the SHELXL-2014 refinement package. All the non-hydrogen atoms were refined with anisotropic displacement parameters, and the hydrogen atoms were located in the differential Fourier map and refined with isotropic displacement parameters.

4.2.3. Thermal Analysis (TGA and DSC) The samples (2.307 mg) were heated in a hermetically sealed aluminum pan containing a pinhole on a thermogravimetry analyzer (Q600 SDT, TA Instruments, New Castle, DE, USA) from 25 ◦C to 500 ◦C at 10 ◦C/min under 100 mL/min nitrogen gas. Differential scanning calorimetry (DSC) was performed with a TA DSC25 (TA Instru- ments, New Castle, DE, USA). Sample weights of 1.20 mg were heated in Tzero aluminum pans at the scan rate of 10 ◦C min−1 under nitrogen gas.

4.2.4. Powder X-ray Diffraction (PXRD) PXRD data were collected using a Bruker D8 Advance X-ray diffractometer (Bruker, Karlsruhe, Germany) coupled with Cu-Kα radiation (40 kV, 200 mA, λ = 1.5406 Å). The data for each sample were recorded over the 2θ range from 5◦ to 50◦ (step size, 0.02◦) at ambient temperature with a scan speed of 5◦/min. Molecules 2021, 26, 4377 12 of 13

4.2.5. Fourier-Transform Infrared Spectroscopy (FT-IR) Each sample was compressed into a tablet made using the KBr pellet technique and collected by a Nicolet Spectrum FT-IR spectrometer (Nicolet iS10, Waltham, MA, USA) in the 4000–500 cm−1 range at the resolution of 4 cm−1 with 12 accumulative scans under ambient conditions.

4.2.6. 1H NMR Spectroscopy Analysis 1H NMR data were collected on a Bruker AVANCE III NMR spectrometer operating at 600 MHz and using DMSO-d6 as the NMR solvent.

4.2.7. Dynamic Vapor Sorption (DVS) The materials’ water sorption and desorption proﬁles were measured using an au- tomated vapor sorption analyzer (Surface Measurement Systems Ltd., Wembley, UK) at 25 ◦C. The samples of Met–Bar, 26.86 of the mass at the end of the ﬁrst 0% RH stage, were studied at each step size of 5% RH, following the 0%–80%–0% sorption and desorption cycle. If the weight change within 10 min was smaller than 0.02%, relative humanity (RH) was changed to the next step, with the maximum hold time of 3 h.

Author Contributions: Data curation, L.C., C.L. and X.G.; formal analysis, L.C., C.L. and L.Z.; funding acquisition, X.H. and L.J.; investigation, L.C.; project administration, X.H. and L.J.; software, L.C.; writing—original draft preparation, L.C. All authors have read and agreed to the published version of the manuscript. Funding: The authors acknowledge the financial support received from the Chongqing Science and Technology Commission (cstc2019jscx-msxmX0096). We also appreciate that the undergrad- uate Everyone Innovation Program of the School of Pharmacy of Chongqing Medical University (DXSZCXM201905) provides partial financial aid for our work. Data Availability Statement: The data presented in this study are available on request from the corresponding author. Conflicts of Interest: The authors declare no conflict of interest. Sample Availability: Samples of the compounds are not available from the authors.

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