Pharmaceutical Cocrystals of Diflunisal and ... - ACS Publications

Article pubs.acs.org/molecularpharmaceutics

Pharmaceutical Cocrystals of Diflunisal and Diclofenac with Theophylline Artem O. Surov,† Alexander P. Voronin,† Alex N. Manin,† Nikolay G. Manin,† Lyudmila G. Kuzmina,‡ Andrei V. Churakov,‡ and German L. Perlovich*,† †

G.A. Krestov Institute of Solution Chemistry RAS, 153045, Ivanovo, Russia Institute of General and Inorganic Chemistry RAS, Leninskii Prospekt 31,119991 Moscow, Russia

‡

S Supporting Information *

ABSTRACT: Pharmaceutical cocrystals of nonsteroidal antiinflammatory drugs diflunisal (DIF) and diclofenac (DIC) with theophylline (THP) were obtained, and their crystal structures were determined. In both of the crystal structures, molecules form a hydrogen bonded supramolecular unit consisting of a centrosymmetric dimer of THP and two molecules of active pharmaceutical ingredient (API). Crystal lattice energy calculations showed that the packing energy gain of the [DIC + THP] cocrystal is derived mainly from the dispersion energy, which dominates the structures of the cocrystals. The enthalpies of cocrystal formation were estimated by solution calorimetry, and their thermal stability was studied by differential scanning calorimetry. The cocrystals showed an enhancement of apparent solubility compared to the corresponding pure APIs, while the intrinsic dissolution rates are comparable. Both cocrystals demonstrated physical stability upon storing at different relative humidity. KEYWORDS: pharmaceutical cocrystals, diflunisal, diclofenac, theophylline, enthalpy of formation, dissolution, intrinsic dissolution rate, crystal lattice energy

■

INTRODUCTION

In this paper, we report new cocrystals of nonsteroidal antiinflammatory drugs (NSAID) diflunisal (DIF) and diclofenac (DIC) with theophylline (THP) (Figure 1). According to the Biopharmaceutics Classification System (BCS), DIF and DIC belong to class II drugs with low solubility and high permeability as most NSAIDs.13 Only three cocrystals of DIF with structurally related compounds pyrazinamide,3a nicotinamide, and isonicotinamide14 have been reported until now. However, attempts to obtain single crystals of those cocrystals suitable for determination of crystal structure have not been successful. In turn, crystal structures for DIC cocrystals with isonicotinamide,15 pyrazoles, pyridines, and pyrimidine derivatives16 are known. In this study, theophylline was employed as a model cocrystal former with DIC and DIF. Theophylline is known to have good potential for cocrystal formation due to the presence of donor and acceptor sites of hydrogen bonding in the molecule. Being well soluble in water, THP is able to improve the aqueous solubility of DIC and DIF to obtain novel solid-state forms of the API with enhanced physicochemical properties. In addition, a set of data has been

The development of pharmaceutical cocrystals is one of the hot topics in the field of crystal engineering nowadays as cocrystals can fine-tune relevant physicochemical properties of active pharmaceutical ingredients (API).1 All pharmaceutical cocrystals can be conventionally divided into two groups: with cocrystal formers (coformers) appearing on the Generally Recognized as Safe (GRAS) list2 and the so-called “drug−drug” cocrystals which consist of different API molecules.3 Theophylline used in asthma therapy belongs to both groups. Therefore, cocrystal formation of theophylline as a model API or as a coformer has been extensively studied. For example, theophylline hygroscopicity decrease through cocrystallization with a range of dicarboxylic acids has been described by Trask et al.4 Cocrystals of theophylline with nicotinamide,5 saccharin,6 phthalic acid,7 etc. are also known in the literature. Karki et al. have reported an improvement in the compactibility of the cocrystal form of paracetamol with theophylline compared to the pure drug.8 A number of cocrystals between carboxylic acids and theophylline as a coformer have been studied by Childs et al.9 Dissolution behavior and physicochemical properties of theophylline cocrystals with p-coumaric acid,10 flufenamic acid,11 and sulfacetamide12 have also been reported. © 2014 American Chemical Society

Received: Revised: Accepted: Published: 3707

July 5, 2014 August 14, 2014 September 3, 2014 September 3, 2014 dx.doi.org/10.1021/mp5004652 | Mol. Pharmaceutics 2014, 11, 3707−3715

Molecular Pharmaceutics

Article

solution was filtered and allowed to evaporate slowly. Diffraction quality crystals were grown over a week. 2.3.2. [DIC + THP] (1:1). Diclofenac and theophylline in a 3:1 molar ratio were dissolved in hot methanol. The obtained clear solution was slowly cooled, covered by parafilm perforated with a few small holes, and allowed to evaporate slowly. Diffraction quality crystals were obtained over few days. 2.4. X-ray Diffraction Experiments. Single-crystal X-ray diffraction data were collected on a Bruker SMART APEX II diffractometer using graphite-monochromated Mo Kα radiation (λ = 0.71073 Å). Absorption corrections based on measurements of equivalent reflections were applied.19 The structures were solved by direct methods and refined by full matrix leastsquares on F2 with anisotropic thermal parameters for all nonhydrogen atoms.20 In the structure DIC-THP all carbonbonded hydrogen atoms were placed in calculated positions and refined using a riding model; amino and carboxyl atoms H1, H11, and H2 were found from difference Fourier synthesis and refined isotropically. In DIF-THP, all H atoms were found from difference Fourier map and refined with isotropic thermal parameters. X-ray powder diffraction data were recorded under ambient conditions in Bragg−Brentano geometry with Bruker D8 Advance diffractometer with Cu Kα1 radiation (λ = 1.5406 Å). Crystallographic data (excluding structure factors) for the structures DIC-THP and DIF-THP have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-1009734 and 1009735, respectively. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax, + 44-1223-336-033; e-mail, [email protected]]. 2.5. DSC Experiments. Thermal analysis was carried out employing a DSC 204 F1 Phoenix differential scanning heat flux calorimeter (NETZSCH, Germany) with a high sensitivity μ-sensor. The sample was heated at the rate of 10 K·min−1 in an argon atmosphere and cooled with gaseous nitrogen. The temperature calibration of the DSC was performed against six high-purity substances, cyclohexane (99.96%), mercury (99.99+ %), biphenyl (99.5%), indium (99.999%), tin (99.999%), and bismuth (99.9995%). The accuracy of the weighing procedure was ±0.01 mg. 2.6. Aqueous Dissolution and Intrinsic Dissolution Rate Experiments. Dissolution measurements were carried out by the shake-flask method at 25.0 ± 0.1 °C. The samples were suspended in 10 mL of pH 7.4 phosphate buffer in Pyrex glass tubes. The amount of DIC or DIF and the cocrystals dissolved was measured by taking aliquots of 1 mL of the respective media. The solid phase was removed by isothermal filtration (Rotilabo syringe filter, PTFE, 0.2 μm), and the concentration was determined by HPLC. The results are stated as the average of at least three replicated experiments. HPLC was performed on Shimadzu Prominence model LC-20AD equipped with a PDA detector and a C-18 column (150 mm × 4.6 mm i.d., 5 μm particle size and 100 Å pore size). Elution was achieved by a mobile phase made of 78:22 ratio of water:acetonitrile in an isocratic method. An injection volume of 20 μL was used with an eluant flow rate of 1 mL·min−1. Concentrations were calculated according to the established calibration curve. Intrinsic dissolution rate (IDR) measurements were carried out on a USP-certified Electrolab EDT-08LX dissolution tester by the disk intrinsic dissolution method. For IDR experiments, approximately 200 mg of pure DIC or DIF and the cocrystals

Figure 1. Molecular structures of diflunisal, diclofenac acid, and theophylline. For diclofenac acid, flexible torsion angle is indicated by τ1.

reported suggesting the anti-inflammatory, antiarthritic, and anti-hyperalgesia effects of theophylline.17 Therefore, THP cocrystals with NSAIDs are of considerable interest because of its potential application in a combination drug therapy. The cocrystals are characterized by single-crystal X-ray diffraction, differential scanning calorimetry (DSC), and solution calorimetry. In addition, analysis of crystal lattice energies of the cocrystals was done using the PIXEL approach. Pharmaceutically relevant properties such as aqueous dissolution, intrinsic dissolution rate, and relative humidity stability are also reported.

2. MATERIAL AND METHODS 2.1. Compounds and Solvents. Diflunisal (C13H8F2O3, MW 250.2), diclofenac acid (C14H11Cl2NO2, MW 296.1), and theophylline (C7H8N4O2, MW 180.2) were purchased from Sigma-Aldrich (purity >99.5%). All solvents were of analytical grade and used as received without further purification. It is known that both APIs and theophylline have different polymorphic forms. Therefore, before cocrystallization experiments all substances were characterized by X-ray powder diffraction (XRPD) and compared to the calculated XRPD patterns obtained based on their single crystal structure data (see Figures S1−S3 of the Supporting Information). Diflunisal was identified as form I (ref code FAFWIS01).18 The experimental XRPD pattern of diclofenac acid was found to be in good agreement with form II (SIKLIH07). The theophylline sample was confirmed as form II (BAPLOT06). The crystal structures of DIF (form I), DIC (form II), and THP (form II) are briefly described in the Supporting Information (see Figure S4). 2.2. Cocrystal Preparation. Solvent-drop grinding experiments were performed using a Fritsch planetary micromill, model Pulverisette 7, in 12 mL agate grinding jars with ten 5 mm agate balls at a rate of 600 rpm for 60 min. The experiments were carried out with stoichiometric amounts of diflunisal or diclofenac and theophylline and a few drops of solvent (methanol or acetonitrile) added with a micropipette. 2.3. Crystallization Procedure. 2.3.1. [DIF + THP] (1:1). Equimolar amounts of diflunisal and theophylline were dissolved in an acetonitrile−methanol−water mixture (2:1:1 v:v:v) and stirred at room temperature. The resulting clear 3708

dx.doi.org/10.1021/mp5004652 | Mol. Pharmaceutics 2014, 11, 3707−3715


Article

2.9. Computational Procedure. Intermolecular interaction energies were calculated using the PIXEL approach developed by Gavezzotti.24 This method provides quantitative determination of crystal lattice energies and pairwise intermolecular interactions, with a breakdown of these energies into Coulombic, polarization, dispersion, and repulsion terms. The molecular electron densities for the cocrystals were calculated at the MP2/6-31G** level of theory in the GAUSSIAN03 program.25

were compressed by a hydraulic press for 5 min to form a nonporous compact of 8 mm diameter. The intrinsic attachment with the sample was rotated at 120 rpm in 500 mL of pH 7.4 phosphate buffer preheated to 37.0 °C. The cumulative amount dissolved per unit surface area was determined by taking aliquots of 1 mL of the respective media every 5−6 min with the volume replacement and concentration measured by HPLC. The slope of the plot of mass dissolved per unit surface area vs time gives the intrinsic dissolution rate in appropriate units, e.g., mg min−1 cm−2. 2.7. Relative Humidity (RH) Stability Studies. In order to compare the stability of the cocrystals under different relative humidity (RH) conditions, samples (40−50 mg) were placed into sealed glass desiccator jars at 40, 75, and 100% RH at ambient temperature. Relative humidity conditions of 0, 40, and 75% RH were achieved using aqueous solutions of the sulfuric acid at the following concentrations: 91.5 (0% RH), 48.0(40% RH), and 30.2 (75% RH)%. Distilled water was used for the 100% RH condition. All the samples were dried under reduced pressure before being subjected to experiment. The stored samples were analyzed for physical stability once every 7 days for 2 months at least. Upon removal from the chamber, the samples were promptly weighed on an A&D GR-200 lab balance (Japan) and evaluated for any form change by PXRD and DSC. 2.8. Solution Calorimetry Experiments. Enthalpies of solution were measured by using an ampule-type isoperibolic calorimeter with a 50 cm3 titanium reaction vessel.21 The automated control scheme allowed the temperature to be maintained with the accuracy over 6 × 10−4 K. The temperature and thermal sensitivities of the calorimeter measuring cell were 10−4 K and 10−3 J, respectively. The instrumental errors were 0.6−1%. The accuracy of weight measurements corresponded to ±10−5 g. Due to small values of the solution heat effects, a correction (q(T)) was introduced to account for the heat of breaking of the ampule and evaporation of the solvent in the ampule free volume: q(293.15 K) = 0.034 J, q(303.15 K) = −0.018 J, q(318.15 K) = −0.059 J. Other corrections were negligibly small. The calorimeter was calibrated using KCl (Merck analysis grade >99.5%) in water over a wide concentration interval with more than 20 measurements made. The obtained standard value of solution enthalpy was 17240 ± 36 J·mol−1, which is in good agreement with the value 17241 ± 18 J·mol−1 recommended by IUPAC.22 A minimum of four measurements were made for each of the analyzed samples. The enthalpy of formation, ΔHTf (AB), of a cocrystal with 1:1 stoichiometry can be calculated as23 T T T ΔHfT(AB) = ΔHsol (A)B + ΔHsol (B)A − ΔHsol (AB)B

3. RESULTS AND DISCUSSION 3.1. Crystal Structures. There are three cocrystals of DIF with structurally related compounds reported in the literature: pyrazinamide,3a nicotinamide, and isonicotinamide.14 However, a number of attempts to obtain single crystals of those cocrystals suitable for crystal structure determination have not been successful. It is possible that the DIF cocrystal systems are very sensitive to seeding. Another explanation is a considerable difference in solubilities of cocrystal components in the chosen solvent, while the latter is the actual problem for the [DIF + THP] system as well. The solubility of DIF in methanol (0.0151 mole fraction) is higher by a factor of 10 compared to THP (0.0014 mole fraction).26 It leads to formation of a noncongruently saturating system without cocrystal nucleation and growth. This challenge can be overcome by using a multicomponent solvent which reduces the solubility differences between different compounds as compared to pure solvents.27 For the [DIF + THP] cocrystal crystallization, the solvent mixture consisted of acetonitrile−methanol−water (2:1:1 v:v:v). In the case of DIC, the solubility difference between the components is not so large as for [DIF + THP] (methanol solubility of DIC equals 0.0059 mole fraction26). The diffraction quality single crystals of the [DIC + THP] cocrystal were obtained by cooling crystallization using a 3:1 DIC:THP molar ratio. Crystallographic data of the cocrystal are summarized in Table 1. In each structure, the asymmetric unit contains API and THP molecules connected by O−H···N hydrogen bonds involving the carboxylic acid of the API and an unsaturated N atom of the imidazole ring of THP (acid−imidazole heterosynthon) (Figure 2). In addition, the API forms the C−H···O contacts with the neighboring THP molecule. The THP molecules are connected to each other by N−H···O hydrogen bonds to form centrosymmetric dimers that may be described in graph set notation as R22(10).28 In the [DIF + THP] crystal, DIF molecules also form dimer motifs through O−H···O hydrogen bonds between the hydroxyl and carboxylic groups (R22(12)) (Figure 2b). Furthermore, the hydroxyl group of DIF accepts the C−H···O contacts from the neighboring THP molecule and participates in intramolecular hydrogen bond formation. It is evident that the conformational state of API molecules alters under the influence of new supramolecular surroundings, i.e., cocrystal formation. The conformation comparison between pure DIC (forms I and II) and its cocrystal form indicates a considerable change in the carboxylic group orientation, which is described by the torsion angle τ1 as shown in Figure 1. In DIC forms I and II, the τ1 angle equals −81.9° and −68.8°, respectively, while in [DIC + THP] τ1 = 114.0°. In other words, the carboxylic group in the [DIC + THP] cocrystal is rotated by approximately 180° compared to pure DIC. A similar rotation effect of the carboxylic group in the DIC molecule is also observed in DIC cocrystals with

(1)

where ΔHTsol(A)B and ΔHTsol(B)A are the solution heat values for solid A in a solution containing B and solid B in a solution containing A, respectively. It is essential to consider that the solution enthalpy of one of the pure solid coformers may be affected by the presence of the other coformer in the solution. Thus, it is necessary to measure the solution heat in the presence of the second coformer. This ensures that the same solute A−solute B interactions that occur during cocrystal dissolution are accounted for in the calculation of the formation enthalpy. All experiments were conducted at T = 298.15 K. Methanol was chosen as the solvent as the cocrystals dissolve well with a large endothermic heat effect. 3709



Article

component supramolecular unit which consists of a THP centrosymmetric dimer and two API molecules. A search of the CSD (Version 5.35, 2013 Release with Nov 2013 update)18 and literature analysis show that analogous hydrogen bonded systems are found in cocrystals with THP for variety of APIs: 5-chlorosalicylic acid (CSATEO), 2,5-dihydroxybenzoic acid (DUCROJ), salicylic acid (KIGLES), 1-hydroxy-2-naphthoic acid (KIGLIW), paracetamol (KIGLUI), DL-tartaric acid (NEYCIE), oxalic acid (XEJWUF), malonic acid (XEJXAM), maleic acid (XEJXEQ), glutaric acid (XEJXIU), and flufenamic acid.11 If the [DIF + THP] and [DIC + THP] cocrystals are considered, the number of such systems comprises essentially half of all known THP cocrystals. It can be assumed that formation of this supramolecular unit must be energy-profitable because of efficient crystal packing. A considerable role in the supramolecular unit stabilization is obviously played by the hydrogen bonded dimers of THP molecules linked with each other via API molecules through different intermolecular interactions to form crystals. It is known that THP is tetramorphic. Crystal structures of forms I, II, and IV have been determined.30 For forms I and II, the THP molecules form hydrogen bonded chains, while form IV consists of discrete dimer pairs with a R22(10) motive similar to those in the cocrystals listed above. Moreover, Khamar et al. have shown that form IV of THP is the most thermodynamically stable polymorph under ambient conditions. Commercially available form II has been found to be less stable, and it undergoes solvent-mediated transformation to generate form IV.31 This leads to the possibility that the cocrystal formation process, for example, during solvent-drop grinding, is followed by polymorphic conversion from form II to form IV of THP. A similar phenomenon has been recently investigated for the sulfathiazole cocrystals with dicarboxylic acids obtained by mechanoactivation.32 3.2. Crystal Lattice Energy Calculations. The energies of intermolecular interactions in the cocrystals were analyzed according to the PIXEL approach developed by Gavezzotti.24 In the case of multicomponent crystals, the PIXEL model is especially useful to indicate the interaction energy between different types of molecules. The calculation results are summarized in Table 2. The strongest interactions between the closest molecules in the cocrystals are described in the Supporting Information (see Table S1). Calculations show that the lattice energy value obtained for [DIC + THP] is ca. 15 kJ·mol−1 lower than the one for [DIF + THP]. It is evident that the packing energy gain for the [DIC + THP] cocrystal is derived only from the dispersion energy

Table 1. Crystallographic Data for the Cocrystals Studied [DIC + THP] chem formula cryst syst space group a/Å b/Å c/Å α/deg β/deg γ/deg unit cell vol/Å3 temp/K no. of formula units per unit cell, Z abs coeff, μ/mm−1 no. of reflns measd no. of indep reflns Rint no. of variables final R1 values (I > 2σ(I)) final wR(F2) values (all data) goodness of fit on F2 largest diff peak and hole, e· Å−3

[DIF + THP]

C14H11Cl2NO2· C7H8N4O2 triclinic P−1̅ 7.525(3) 12.138(4) 12.231(4) 73.505(6) 80.547(6) 80.693(6) 1048.8(6) 173(2) 2

C13H8F2O3· C7H8N4O2 monoclinic P21/c 7.0731(4) 35.014(2) 7.6856(4) 90.00 100.827(1) 90.00 1869.54(18) 150(2) 4

0.350 7642 3724 0.0436 303 0.0539 0.1384 0.970 0.513/−0.339

0.125 14696 4051 0.0333 344 0.0394 0.1010 1.023 0.292/−0.258

isonicotinamide15 and 2-aminopyrimidine.16 Probably, this reflects the relatively low energy barrier for rotation of the COOH group due to the decrease in the conjugation effect and attenuation of the intramolecular hydrogen bond energy. The conformational flexibility of the COOH group promotes the most efficient hydrogen bonding between DIC and coformer molecules in a crystal. The packing arrangement of [DIC + THP] can be described as alternating layers of THP dimers and DIC molecules forming hydrogen bonds to each other (Figure 3a). In contrast to the [DIC + THP] cocrystal, the conformational state of DIF in [DIF + THP] is comparable to that in the known polymorphs and solvates of pure DIF.29 In a crystal, the DIF and THP molecules are arranged as “face-to-face” stacks of centrosymmetric dimers in the (020) planes (Figure 3b). It should be noted that such hydrogen bonded dimers are not seen in any of the DIF polymorphs, which are constructed from classical acid−acid homosynthons. As it was mentioned above, both cocrystals have a similar organization of intermolecular hydrogen bonds to form a four-

Figure 2. Hydrogen bonded supramolecular units in the crystal structures of (a) [DIC + THP] and (b) [DIF + THP]. 3710



Article

Figure 3. Molecular packing projections for (a) [DIC + THP] and (b) [DIF + THP].

Table 2. Results of PIXEL Calculations:a Lattice Energies (Elatt), Coulombic Energies (Ecoul), Polarization Energies (Epol), Dispersion Energies (Edisp), and Repulsion (Erep) Terms in kJ·mol−1 [DIC + THP] [DIF + THP]

Ecoul

Epol

Edisp

Erep

Elatt

−104.9 −108.4

−50.0 −54.1

−140.6 −120.9

156.0 159.4

−139.6 −124.1

an increase in the energy of dispersion interactions due to more effective packing of the DIC molecules in the cocrystal. In both cases, the API−THP interactions provide the largest contribution to the lattice energy (more than 40%). The THP− THP interactions comprise approximately a quarter of the total energy, while in [DIF + THP], the contributions of the THP− THP and API−API interactions are comparable. 3.3. Thermal Analysis and Solution Calorimetry. The DSC traces for the cocrystals, APIs, and THP are shown in Figure 4, and the thermal data are given in Table 4. DSC thermograms show only one major endotherm for the cocrystals which corresponds to the melting process, whereas other phase transitions are not observed. The difference in the melting temperatures between different APIs is equal to ca. 38 °C, while the difference in Tfus between APIs and THP is more than 70 °C. However, the cocrystals melting points are closely comparable. As it is seen, the melting temperature of [DIC + THP] is higher than that of pure API. In the case of [DIF + THP], the cocrystal formation decreases the melting temperature compared to the pure DIF. It seems that the intermolecular interactions (including hydrogen bonds), which are responsible for the thermal stability of the pure DIC crystal, are energetically comparable to those in the [DIC + THP] cocrystal. For DIF, however, change of the supramolecular surroundings leads to formation of intermolecular contacts, which are less thermally stable. In spite of the marginal difference in the melting temperatures (ca. 2 °C), the cocrystal fusion enthalpies are distinguishable (ca. 9 kJ mol−1), indicating a greater stability of [DIC + THP], which is qualitatively consistent with the PIXEL calculations.

a

An uncertainty in the calculated crystal lattice energy values is less than 10%.24,33

which dominates the structures of the cocrystals, while the Coulombic, the polarization, and the repulsion terms are comparable. Table 3 shows sums of the intermolecular interaction energies between the different types of molecules calculated using the PIXEL method. The main energy difference is observed in API−API interactions, but the API− THP and THP−THP interactions have closely comparable total energies. Therefore, the crystal lattice energy gain for the [DIC + THP] compared to [DIF + THP] is accompanied by Table 3. Sums of the Intermolecular Interaction Energies (kJ·mol−1) between the Different Types of Molecules Calculated Using the PIXEL Method

[DIC + THP] [DIF + THP]

API−API

API−THP

THP−THP

total

−47.6 (34.1%) −34.3 (27.7%)

−57.0 (40.8%) −56.5 (45.5%)

−34.9 (25.0%) −33.3 (26.8%)

−139.6 −124.1

3711



Article

In case of THP form II, the chain organization based on N− H···N hydrogen bonds resulted in transformation to the N− H···O hydrogen bonded dimers. Therefore, the experimental formation enthalpies suggest that energies of hydrogen bonds in the cocrystals and pure components are comparable, and the packing energy gain is obtained mainly from weak van der Waals forces. The cocrystal formation enthalpies can also be calculated based on the thermophysical data (Table 4). However, using the fusion enthalpies of [DIC + THP] and [DIF + THP] this method shows positive or close to zero values of formation enthalpies: 4.1 ± 3.0 kJ·mol−1 for [DIF + THP] and −0.1 ± 3.2 kJ·mol−1 for [DIC + THP]. This example indicates that it is necessary to take into account the heat of the mixing effect in calculating cocrystal formation enthalpies.34b 3.4. Solubility and Intrinsic Dissolution Rate (IDR). It is known that solubility and dissolution rate in aqueous media are key parameters among other physicochemical properties for pharmaceutical cocrystals. The results of intrinsic dissolution studies and dissolution profiles of the cocrystals are shown in Figures 5 and 6 and Table S4 (see Supporting Information). The stability of the cocrystals during the IDR experiment was checked by XRPD.

Figure 4. DSC curves of the cocrystals, diclofenac acid, diflunisal, and theophylline recorded at 10 °C·min−1 heating rate.

Table 4. Thermophysical Data for the Cocrystals, Compared to DIC, DIF, and THP Tfus, °C (onset) [DIC + THP] [DIF + THP] DIC DIF THP

186.9 184.8 179.8 211.8 271.3

± ± ± ± ±

0.3 0.4 0.2 0.2 0.2

ΔHfus, kJ mol−1

ΔSfus, J mol−1 K−1

± ± ± ± ±

153.4 134.2 90.2 74.3 65.2

70.6 61.5 40.9 36.0 29.6

2.0 2.0 0.7 0.5 0.5

In spite of the great interest in the structure, preparation, and properties of cocrystals, there is relatively little data about their thermodynamic properties, which are fundamental measures of their stability.14b,23,34 In order to establish the thermodynamic characteristics for the formation of the [DIC + THP] and [DIF + THP] cocrystals, we conducted solution calorimetry experiments. The results are summarized in Table 5 (see Tables S2 and S3 of the Supporting Information for the full data set). In contrast to the fusion enthalpies, the solution enthalpies of the cocrystals coincide within experimental error, which seems to be a likely influence of the solvation effects. It should be noted that the formation enthalpy is an integral parameter which incorporates the sum of energetic and structural changes of the system. Such important interactions in a crystal as hydrogen bonds make a significant contribution to the formation enthalpies. In this case, however, small values of the formation enthalpies indicate that a large portion of that contribution was used to compensate for the breaking of the lattice energy of the original components. In fact, cocrystal formation between APIs and THP leads to considerable changes in the supramolecular surroundings for both components compared to their initial state. For APIs, which consist of discrete hydrogen bonded dimers, the acid−acid homosynthons are replaced by acid−imidazole heterosynthons.

Figure 5. Intrinsic dissolution rates of the cocrystals and APIs in pH 7.4 phosphate buffer at 37.0 °C. The results are expressed as mean ± SD, n = 3.

Figure 5 shows that the intrinsic dissolution rate of [DIF + THP] is comparable to that of pure DIF. In the case of [DIC + THP], the dissolution rate of the cocrystal form is found to be ca. 1.3 times higher compared to the initial API. Therefore, in the pH 7.4 phosphate buffer under consideration, the cocrystallization of DIF and DIC with THP has almost no influence on the intrinsic dissolution rate of the pure APIs. It should be noted that similar results have been reported for various pharmaceutical cocrystals with THP. For example, the IDR for the flufenamic acid cocrystal with THP is higher by a factor of 1.97 compared to pure API.11 For the [sulfacetamide + THP] cocrystal, its IDR is found to be equal to that for the pure drug.12

Table 5. Solution Enthalpies, ΔH0sol, (in Methanol) and Calculated Enthalpies of Formation, ΔH0f , at 298 K (kJ mol−1) [DIC + THP] [DIF + THP] a

ΔH0sol(API + THP)

ΔH0sol(API)THPa

ΔH0sol(THP)APIb

ΔH0f (API + THP)

46.3 ± 0.5 47.1 ± 0.2

17.2 ± 0.2 14.5 ± 0.3

24.2 ± 0.2 21.4 ± 0.2

−4.8 ± 0.9 −11.2 ± 0.7

Heat of solution of APIs in the presence of THP. bHeat of solution of THP in the presence of APIs. 3712



Article

Figure 6. Dissolution profiles for (a) DIF and [DIF + THP] and (b) DIC and [DIC + THP] in pH 7.4 phosphate buffer at 25.0 °C. The results are expressed as mean ± SD, n = 3.

■

CONCLUSIONS Pharmaceutical cocrystals of nonsteroidal anti-inflammatory drugs diflunisal and diclofenac with theophylline were obtained, and their crystal structures were determined. Both cocrystals show a similar organization of intermolecular hydrogen bonds to form a four-component supramolecular unit, which consists of a centrosymmetric THP dimer and two API molecules. CSD survey and literature analyses show that analogous hydrogen bonded systems are quite common in THP cocrystals. PIXEL calculations reveal that the crystal lattice energy of [DIC + THP] is higher than that of [DIF + THP] on account of increased dispersion energy between the DIC molecules. The cocrystal formation enthalpies are small. It suggests that energies of hydrogen bonds in the cocrystals and pure components are comparable, and the packing energy gain is obtained mainly from weak van der Waals forces. The intrinsic dissolution studies show that [DIF + THP] IDR is comparable to that of pure DIF. In the case of [DIC + THP], the cocrystal form dissolution rate is found to be ca. 1.3 times higher compared to the initial API. The aqueous dissolution profile of [DIF + THP] demonstrates a classical “spring and parachute” shape, while for [DIC + THP] the “spring” effect cannot be easily seen. The cocrystals show the enhanced apparent solubility compared to the corresponding pure APIs. Both cocrystals demonstrate physical stability upon storing at different relative humidity.

In the case of a longer-term dissolution experiment, the cocrystals behave differently compared to a relatively short-time IDR study. Figure 6a shows that, after ca. 300 min (5 h) of [DIF + THP] dissolution, the amount of DIF reaches the maximum concentration, which is higher by a factor of 2.3 compared to the pure DIF solubility. As is seen, the dissolution profile for [DIF + THP] demonstrates a classical so-called “spring and parachute” behavior. This concept has been introduced to describe the dissolution process of cocrystals in aqueous media.1d,e,h,35 For the [DIF + THP] cocrystal, a 5 h time period corresponds to the “spring” phase. This is followed by a longer-term “parachute” phase, when slow crystallization and precipitation of the unstable DIF species occurs. The latter process lasts the following 25 h. In the case of the [DIC + THP] system (Figure 6b), the “spring” effect is not so evident. After 5−6 h of dissolution, the concentration of [DIC + THP] cocrystal is equal to ca. 1.6 times the solubility of pure DIC. It should be noted that the enhanced concentration level of DIC remains stable for quite a long time (at least 25 h), which indicates a greater stability of [DIC + THP] in aqueous media compared to [DIF + THP]. In fact, for [DIC + THP], the decrease in the API concentration with respect to the peak value is found to be only ca. 4.5%, while for [DIF + THP] this ratio is ca. 38.0%. It has been established in the literature that an increase in the cocrystal solubility of a poorly soluble API is effectively correlated with an enhancement of its oral bioavailability.36 Therefore, the results of the dissolution experiments suggest that a bioavailability of DIC and DIF can be increased by cocrystallization of the drugs with THP. It is especially important for these BCS class II compounds, where the solubility is a limiting factor of the oral bioavailability. 3.5. Relative Humidity (RH) Stability of the Cocrystals. Relative humidity experiments were conducted in order to compare the RH storage stability of the cocrystals to that of anhydrous theophylline. It was found that, at 75% RH and below, all the samples including THP were physically stable. At 100% RH, anhydrous THP converted into the monohydrate form, which was monitored by the weight gain of the sample and checked by PXRD. This fact is consistent with the literature data.37 In contrast to THP, both cocrystals were stable at 100% RH. Further observations up to 2 months at 100% RH did not show any destruction or transformations of the cocrystals.

■

ASSOCIATED CONTENT

S Supporting Information *

Experimental and calculated PXRD patterns of diclofenac acid, diflunisal, theophylline, and the [DIF + THP], [DIC + THP] cocrystal; molecular packing projections of diclofenac acid, diflunisal, and theophylline; tables of interaction energy, results of solution calorimetry experiments, and intrinsic dissolution rates; crystallographic data in CIF format. This material is available free of charge via the Internet at http://pubs.acs.org.

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel: +7 4932 533784. Fax.: +7 4932 336237. Notes

The authors declare no competing financial interest. 3713



■

Article

(12) Goud, N. R.; Khan, R. A.; Nangia, A. Modulating the solubility of Sulfacetamide by means of cocrystals. CrystEngComm 2014, 16, 5859−5869. (13) Takagi, T.; Ramachandran, C.; Bermejo, M.; Yamashita, S.; Yu, L. X.; Amidon, G. L. A Provisional Biopharmaceutical Classification of the Top 200 Oral Drug Products in the United States, Great Britain, Spain, and Japan. Mol. Pharmaceutics 2006, 3, 631−643. (14) (a) Wang, L.; Tan, B.; Zhang, H.; Deng, Z. Pharmaceutical Cocrystals of Diflunisal with Nicotinamide or Isonicotinamide. Org. Process Res. Dev. 2013, 17, 1413−1418. (b) Évora, A. O. L.; Castro, R. A. E.; Maria, T. M. R.; Silva, M. R.; ter Horst, J. H.; Canotilho, J.; Eusébio, M. E. S. A thermodynamic based approach on the investigation of a diflunisal pharmaceutical co-crystal with improved intrinsic dissolution rate. Int. J. Pharm. 2014, 466, 68−75. (15) Báthori, N. B.; Lemmerer, A.; Venter, G. A.; Bourne, S. A.; Caira, M. R. Pharmaceutical Co-crystals with Isonicotinamide Vitamin B3, Clofibric Acid, and Diclofenac - and Two Isonicotinamide Hydrates. Cryst. Growth Des. 2011, 11, 75−87. (16) Aakeröy, C. B.; Grommet, A. B.; Desper, J. Co-Crystal Screening of Diclofenac. Pharmaceutics 2011, 3, 601−614. (17) (a) Mascali, J. J.; Cvietusa, P.; Negri, J.; Borish, L. Antiinflammatory effects of theophylline: modulation of cytokine production. Ann. Allergy Asthma Immunol. 1996, 77, 34−38. (b) Banner, K. H.; Page, C. P. Anti-inflammatory effects of theophylline and selective phosphodiesterase inhibitors. Clin. Exp. Allergy 1996, 26 (Suppl. 2), 2−9. (c) Kumar, A.; Jain, N. K.; Kulkarni, S. K. Analgesic and anti-inflammatory effect of phosphodiesterase inhibitors. Indian J. Exp. Biol. 2000, 28, 26−30. (d) ChorostowskaWynimko, J.; Kus, J.; Skopinska-Rozewska, E. Theophylline inhibits free oxygen radicals production by human monocytes via phosphodiesterase inhibition. J. Physiol. Pharmacol. 2007, 95−103. (e) Kanehara, M.; Yokoyama, A.; Tomoda, Y.; Shiota, N.; Iwamoto, H.; Ishikawa, N.; Taooka, Y.; Haruta, Y.; Hattori, N.; Kohno, N. Antiinflammatory effects and clinical efficacy of theophylline and tulobuterol in mild-to-moderate chronic obstructive pulmonary disease. Pulm. Pharmacol. Ther. 2008, 21, 874−878. (f) Gomaa, A.; Elshenawy, M.; Afifi, N.; Mohammed, E.; Thabit, R. Enhancement of the anti-inflammatory and anti-arthritic effects of theophylline by a low dose of a nitric oxide donor or non-specific nitric oxide synthase inhibitor. Br. J. Pharmacol. 2009, 158, 1835−1847. (18) Allen, F. H. The Cambridge Structural Database: a quarter of a million crystal structures and risin. Acta Crystallogr., B 2002, B58, 380−388. (19) Sheldrick, G. M. SADABS, Program for scaling and correction of area detector data; University of Göttingen: Germany, 1997. (20) Sheldrick, G. M. A short history of SHELX. Acta Crystallogr., Sect. A: Found. Crystallogr. 2007, 64, 112−122. (21) Manin, N. G.; Fini, A.; Perlovich, G. L. Thermodynamics of potassium diclofenac salt aqueous solutions at various temperatures. J. Therm. Anal. Calorim. 2011, 104, 279−289. (22) Cox, J. D.; Pilcher, G. Thermochemistry of Organic and Organometallic Compounds; Academic Press: London, U.K., 1970. (23) Oliveira, M. A.; Peterson, M. L.; Davey, R. J. Relative Enthalpy of Formation for Co-Crystals of Small Organic Molecules. Cryst. Growth Des. 2011, 11, 449−457. (24) (a) Gavezzotti, A. Calculation of Intermolecular Interaction Energies by Direct Numerical Integration over Electron Densities. 2. An Improved Polarization Model and the Evaluation of Dispersion and Repulsion Energies. J. Phys. Chem. B 2003, 107, 2344−2353. (b) Gavezzotti, A. Non-conventional bonding between organic molecules. The ‘halogen bond’ in crystalline systems. Mol. Phys. 2008, 106, 1473−1485. (25) Frisch, M. J. et al. GAUSSIAN 03, Revision B. 03; Gaussian Inc.: Pittsburgh, PA, USA, 2003. (26) Jouyban, A. Handbook of Solubility Data for Pharmaceuticals; CRC Press: Boca Raton, 2010. (27) Rager, T.; Hilfiker, R. Cocrystal Formation from Solvent Mixtures. Cryst. Growth Des. 2010, 10, 3237−3241.

ACKNOWLEDGMENTS This work was supported by the Russian Scientific Foundation (No. 14-13-00640). We thank “the Upper Volga Region Centre of Physicochemical Research” for technical assistance with DSC and XRPD experiments.

■

REFERENCES

(1) (a) Almarsson, Ö .; Zaworotko, M. J. Crystal engineering of the composition of pharmaceutical phases. Do pharmaceutical co-crystals represent a new path to improved medicines? Chem. Commun. 2004, 1889−1896. (b) Vishweshwar, P.; McMahon, J. A.; Bis, J. A.; Zaworotko, M. J. Pharmaceutical Co-Crystals. J. Pharm. Sci. 2006, 95, 499−516. (c) Good, D. J.; Rodriguez-Hornedo, N. Solubility Advantage of Pharmaceutical Cocrystals. Cryst. Growth Des. 2009, 9, 2252−2264. (d) Schultheiss, N.; Newman, A. Pharmaceutical Cocrystals and Their Physicochemical Properties. Cryst. Growth Des. 2009, 9, 2950−2967. (e) Babu, N. J.; Nangia, A. Solubility Advantage of Amorphous Drugs and Pharmaceutical Cocrystals. Cryst. Growth Des. 2011, 11, 2662−2679. (f) Qiao, N.; Li, M.; Schlindwein, W.; Malek, N.; Davies, A.; Trappitt, G. Pharmaceutical cocrystals: An overview. Int. J. Pharm. 2011, 419, 1−11. (g) Schultheiss, N.; Henck, J.-O. Role of Co-crystals in the Pharmaceutical Development Continuum. In Pharmaceutical Salts and Co-crystals; Wouters, J., Quéré, L., Eds.; RSC Publishing: Cambridge, 2011. (h) Thakuria, R.; Delori, A.; Jones, W.; Lipert, M. P.; Roy, L.; Rodriguez-Hornedo, N. Pharmaceutical cocrystals and poorly soluble drugs. Int. J. Pharm. 2013, 453, 101−125. (i) Steed, J. W. The role of co-crystals in pharmaceutical design. Trends Pharmacol. Sci. 2013, 3, 185−193. (j) Brittain, H. G. Pharmaceutical Cocrystals: The Coming Wave of New Drug Substances. J. Pharm. Sci. 2013, 102, 311−317. (2) See US FDA GRAS List. http://www.fda.gov/food/ ingredientspackaginglabeling/gras/default.htm. (3) (a) Evora, A. O. L.; Castro, R. A. E.; Maria, T. M. R.; Rosado, M. T. S.; Silva, M. R.; Beja, A. M.; Canotilho, J.; Eusebio, M. E. S. Pyrazinamide-Diflunisal: A New Dual-Drug Co-Crystal. Cryst.Growth Des. 2011, 11, 4780−4788. (b) Sekhon, B. S. Drug-drug co-crystals. Daru, J. Pharm. Sci. 2012, 20, 45. (c) Grobelny, P.; Mukherjee, A.; Desiraju, G. R. Drug-drug co-crystals: Temperature-dependent proton mobility in the molecular complex of isoniazid with 4-aminosalicylic acid. CrystEngComm 2011, 13, 4358−4364. (4) Trask, A. V.; Motherwell, W. D. S.; Jones, W. Physical stability enhancement of theophylline via cocrystallization. Int. J. Pharm. 2006, 320, 114−123. (5) Lu, J.; Rohani, S. Preparation and Characterization of Theophylline-Nicotinamide Cocrystal. Org. Process Res. Dev. 2009, 13, 1269−1275. (6) Lu, E.; Rodriguez-Hornedo, N.; Suryanarayanan, R. A rapid thermal method for cocrystal screening. CrystEngComm 2008, 10, 665−668. (7) Bán, M.; Bombicz, P.; Madarász, J. Thermal stability and structure of a new co-crystal of theophylline formed with phthalic acid. J. Therm. Anal. Calorim. 2009, 95, 895−901. (8) Karki, S.; Frišcǐ ć, T.; Fábián, L.; Laity, P. R.; Day, G. M.; Jones, W. Improving Mechanical Properties of Crystalline Solids by Cocrystal Formation: New Compressible Forms of Paracetamol. Adv. Mater. 2009, 21, 3905−3909. (9) Childs, S. L.; Stahly, G. P.; Park, A. The Salt-Cocrystal Continuum: The Influence of Crystal Structure on Ionization State. Mol. Pharmaceutics 2007, 4, 323−338. (10) Schultheiss, N.; Roe, M.; Boerrigter, S. X. M. Cocrystals of nutraceutical p-coumaric acid with caffeine and theophylline: polymorphism and solid-state stability explored in detail using their crystal graphs. CrystEngComm 2011, 13, 611−619. (11) Aitipamula, S.; Wong, A. B. H.; Chow, P. S.; Tan, R. B. H. Cocrystallization with flufenamic acid: comparison of physicochemical properties of two pharmaceutical cocrystals. CrystEngComm 2014, 16, 5793−5801. 3714



Article

(28) (a) Etter, M. C. Encoding and decoding hydrogen-bond patterns of organic compounds. Acc. Chem. Res. 1990, 23, 120−126. (b) Bernstein, J.; Davis, R. E.; Shimoni, L.; Chang, N.-L. Patterns in Hydrogen Bonding: Functionality and Graph Set Analysis in Crystals. Angew. Chem., Int. Ed. Engl. 1995, 34, 1555−1573. (29) (a) Cross, W. I.; Blagden, N.; Davey, R. J.; Pritchard, R. G.; Neumann, M. A.; Roberts, R. J.; Rowe, R. C. A Whole Output Strategy for Polymorph Screening: Combining Crystal Structure Prediction, Graph Set Analysis, and Targeted Crystallization Experiments in the Case of Diflunisal. Cryst. Growth Des. 2003, 3, 151−158. (b) Hansen, L. Kr.; Perlovich, G. L.; Bauer-Brandl, A. The 1:1 hydrate of diflunisal. Acta Crystallogr., Sect. E 2001, 57, o477−o479. (c) Hansen, L. Kr.; Perlovich, G. L.; Bauer-Brandl, A. Diflunisal-hexane (4/1). Acta Crystallogr., Sect. E 2001, 57, o604−o606. (30) (a) Fucke, K.; McIntyre, G. J.; Wilkinson, C.; Henry, M.; Howard, J. A. K.; Steed, J. W. New Insights into an Old Molecule: Interaction Energies of Theophylline Crystal Forms. Cryst. Growth Des. 2012, 12, 1395−1401. (b) Khamar, D.; Pritchard, R. G.; Bradshaw, I. J.; Hutcheon, G. A.; Seton, L. Polymorphs of anhydrous theophylline: stable form IV consists of dimer pairs and metastable form I consists of hydrogen-bonded chains. Acta Crystallogr., Sect.C 2011, 67, o496− o499. (31) Khamar, D.; Bradshaw, I. J.; Hutcheon, G. A.; Seton, L. Solid State Transformations Mediated by a Kinetically Stable Form. Cryst. Growth Des. 2012, 12, 109−118. (32) Hu, Y.; Gniado, K.; Erxleben, A.; McArdle, P. Mechanochemical Reaction of Sulfathiazole with Carboxylic Acids: Formation of a Cocrystal, a Salt, and Coamorphous Solids. Cryst. Growth Des. 2014, 14, 803−813. (33) (a) Gavezzotti, A. Calculation of lattice energies of organic crystals: the PIXEL integration method in comparison with more traditional methods. Z. Kristallogr. 2005, 220, 499−510. (b) Gavezzotti, A. Efficient computer modeling of organic materials. The atom−atom, Coulomb−London−Pauli (AA-CLP) model for intermolecular electrostatic-polarization, dispersion and repulsion energies. New J. Chem. 2011, 35, 1360−1368. (c) Maschio, L.; Civalleri, B.; Ugliengo, P.; Gavezzotti, A. Intermolecular Interaction Energies in Molecular Crystals: Comparison and Agreement of Localized Møller-Plesset 2, Dispersion-Corrected Density Functional, and Classical Empirical Two-Body Calculations. J. Phys. Chem. A 2011, 115, 11179−11186. (34) (a) Chadha, R.; Saini, A.; Arora, P.; Jain, D. S.; Dasgupta, A.; Row, T. N. G. Multicomponent solids of lamotrigine with some selected coformers and their characterization by thermoanalytical, spectroscopic and X-ray diffraction methods. CrystEngComm 2011, 13, 6271−6284. (b) Zhang, S.-W.; Guzei, I. A.; de Villiers, M. M.; Yu, L.; Krzyzaniak, J. F. Formation Enthalpies and Polymorphs of Nicotinamide−R-Mandelic Acid Co-Crystals. Cryst. Growth Des. 2012, 12, 4090−4097. (c) Zhang, S.-W.; Harasimowicz, M. T.; de Villiers, M. M.; Yu, L. Cocrystals of Nicotinamide and (R)-Mandelic Acid in Many Ratios with Anomalous Formation Properties. J. Am. Chem. Soc. 2013, 135, 18981−18989. (d) Surov, A. O.; Solanko, K. A.; Bond, A. D.; Bauer-Brandl, A.; Perlovich, G. L. Polymorphism of felodipine co-crystals with 4,4′-bipyridine. CrystEngComm 2014, 16, 6603−6611. (35) (a) Guzmán, H. R.; Tawa, M.; Zhang, Z.; Ratanabanangkoon, P.; Shaw, P.; Gardner, C. R.; Chen, H.; Moreau, J.-P.; Almarsson, Ö .; Remenar, J. F. Combined use of crystalline salt forms and precipitation inhibitors to improve oral absorption of celecoxib from solid oral formulations. J. Pharm. Sci. 2007, 96, 2686−2702. (b) Chen, J.; Sarma, B.; Evans, J. M. B.; Myerson, A. S. Pharmaceutical Crystallization. Cryst. Growth Des. 2011, 11, 887−895. (36) (a) Hickey, M. B.; Peterson, M. L.; Scoppettuolo, L. A.; Morrisette, S. L.; Vetter, A.; Guzman, H.; Remenar, J. F.; Zhang, Z.; Tawa, M. D.; Haley, S.; Zaworotko, M. J.; Almarsson, O. Performance comparison of a co-crystal of carbamazepine with marketed product. Eur. J. Pharm. Biopharm. 2007, 67, 112−119. (b) Bak, A.; Gore, A.; Yanez, E.; Stanton, M.; Tufekcic, S.; Syed, R.; Akrami, A.; Rose, M.; Surapaneni, S.; Bostick, T.; King, A.; Neervannan, S.; Ostovic, D.; Koparkar, A. The co-crystal approach to improve the exposure of a

water-insoluble compound: AMG 517 sorbic acid cocrystal characterization and pharmacokinetics. J. Pharm. Sci. 2008, 97, 3942−3956. (c) Jung, M. S.; Kim, J. S.; Kim, M. S.; Alhalaweh, A.; Cho, W.; Hwang, S. J.; Velaga, S. P. Bioavailability of indomethacin-saccharin cocrystals. J. Pharm. Pharmacol. 2010, 62, 1560−1568. (d) Stanton, M. K.; Kelly, R. C.; Colletti, A.; Langley, M.; Munson, E. J.; Peterson, M. L.; Roberts, J.; Wells, M. Improved pharmacokinetics of AMG 517 through co-crystallization part 2: Analysis of 12 carboxylic acid cocrystals. J. Pharm. Sci. 2011, 100, 2734−2743. (e) Smith, A. J.; Kavuru, P.; Wojtas, L.; Zaworotko, M. J.; Shytle, R. D. Cocrystals of Quercetin with Improved Solubility and Oral Bioavailability. Mol. Pharmaceutics 2011, 8, 1867−1876. (f) Weyna, D. R.; Cheney, M. L.; Shan, N.; Hanna, M.; Zaworotko, M. J.; Sava, V.; Song, S.; Sanchez-Ramos, J. R. Improving Solubility and Pharmacokinetics of Meloxicam via MultipleComponent Crystal Formation. Mol. Pharmaceutics 2012, 9, 2094− 2102. (g) Sanphui, P.; Tothadi, S.; Ganguly, S.; Desiraju, G. R. Salt and Cocrystals of Sildenafil with Dicarboxylic Acids: Solubility and Pharmacokinetic Advantage of the Glutarate Salt. Mol. Pharmaceutics 2013, 10, 4687−4697. (37) Amado, A. M.; Nolasco, M. M.; Ribeiro-Claro, P. J. Probing pseudopolymorphic transitions in pharmaceutical solids using Raman spectroscopy: Hydration and dehydration of theophylline. J. Pharm. Sci. 2007, 96, 1366−1379.

3715


Pharmaceutical Cocrystals of Diflunisal and ... - ACS Publications

Recommend Documents