Differential Solution Behavior of the New APIâAPI Co-Crystal of

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Differential Solution Behavior of the New API-API Co-Crystal of TramadolCelecoxib (CTC) versus its constituents and their combination. Adriana Port, Carmen Almansa, Raquel Enrech, Magda Bordas, and Carlos R. Plata-Salamán Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.9b00008 • Publication Date (Web): 06 May 2019 Downloaded from http://pubs.acs.org on May 7, 2019

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Differential Solution Behavior of the New API-API Co-Crystal of Tramadol-Celecoxib (CTC) versus its constituents and their combination.

Adriana Port*, Carmen Almansa, Raquel Enrech, Magda Bordas, Carlos R. Plata-Salamán. ESTEVE Pharmaceuticals S.A., Drug Discovery and Preclinical Development, Parc Científic de Barcelona, Baldiri Reixac, 4-8, 08028 Barcelona. Co-crystal of tramadol-celecoxib (CTC) is a novel active pharmaceutical ingredient API-API co-crystal formed by an intrinsic 1:1 molecular ratio of rac-tramadol.HCl (TRM) and celecoxib (CXB) in late-stage development for the treatment of pain. In line with previous intrinsic dissolution rate (IDR) studies, we report here that the kinetic dissolution profile of CTC in hydroxypropyl methyl cellulose (HPMC) and buffered solutions led to a supersaturation state of CXB and a release significantly faster from CTC than from the free combination, which in turn was quite similar to the release from CXB alone. Inversely, TRM was released much more slowly from CTC than from the free combination and TRM alone. Experimental and predicted solubility-pH curves showed that the thermodynamic solubility of CTC lies in between those of TRM and CXB within the physiologically meaningful pH range. The lattice and solvation contributions to CTC aqueous solubility was studied, showing that the solvation factor is the most important, but it appears to be proportionally lower and more similar to the more soluble component, TRM. These results, together with those obtained in the hygroscopicity studies, show that CTC co-crystal structure provides a clear differential profile versus the free combination or the two APIs alone. Solubility-pH profile of CTC and its individual components

1.E+08

CTC

CXB

TRM

S CTC

1.E+06

1.E+04

1.E+02

logS (M)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

1.E+00

1.E-02

1.E-04

1.E-06 1

2

3

4

5

6

7

8

9

10

11

pH

*Dr Adriana Port Drug Discovery and Preclinical Development ESTEVE Pharmaceuticals S.A., Baldiri Reixac, 4-8 08028, Barcelona, Spain Tel: +34 934 46 60 67 Fax: +34 934 46 64 32 Email: [email protected] Web address: http://www.esteve.com/ Page 1 ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Differential Solution Behavior of the New APIAPI Co-Crystal of Tramadol-Celecoxib (CTC) versus its constituents and their combination. Adriana Port*, Carmen Almansa, Raquel Enrech, Magda Bordas, Carlos R. Plata-Salamán. ESTEVE Pharmaceuticals S.A., Drug Discovery and Preclinical Development, Parc Científic de Barcelona, Baldiri Reixac, 4-8, 08028 Barcelona.

ABSTRACT Co-crystal of tramadol -celecoxib (CTC) is a novel active pharmaceutical ingredient API-API co-crystal formed by an intrinsic 1:1 molecular ratio of rac-tramadol.HCl (TRM) and celecoxib (CXB) in late-stage development for the treatment of pain. In line with previous intrinsic dissolution rate (IDR) studies, we report here that the kinetic dissolution profile of CTC in hydroxypropyl methyl cellulose (HPMC) and buffered solutions led to a supersaturation state of CXB and a release significantly faster from CTC than from the free combination, which in turn was quite similar to the release from CXB alone. Inversely, TRM was released much more slowly from CTC than from the free combination and TRM alone. Experimental and predicted solubility-pH curves showed that the thermodynamic solubility of CTC lies in between those of TRM and CXB within the physiologically meaningful pH range. The lattice and solvation contributions to CTC aqueous solubility was studied, showing that the solvation factor is the most important, but it appears to be proportionally lower and more similar to the more soluble component, TRM. These results, together with

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those obtained in the hygroscopicity studies, show that CTC co-crystal structure provides a clear differential profile versus the free combination or the two APIs alone.

TEXT Introduction Co-crystals incorporating two active pharmaceutical ingredients (APIs) constitute an innovative approach to multimodal therapy1 and may help to address multifactorial/polygenic pathologies of high complexity and multiple etiology, such as pain.2,3 They present advantages over current multimodal therapy approaches, such as ad hoc polypharmacy and fixed-dose combinations (FDCs). Ad hoc polypharmacy can provide tailored therapy, but compliance is often low and maintaining optimal dosing and administration schedules is challenging. FDCs offer a more standardized approach4 and reduce pill burden, but their development can be hampered by issues relating to stability and solubility differences of the constituent APIs, as well as by chemical and pharmacokinetic interactions between the respective APIs. Contrary to FDCs, which are physical mixtures of the constituent drugs, API–API co-crystals are unique single entities with differentiated physicochemical profiles that may translate into modified biopharmaceutical properties affecting the rate and extent of absorption and ultimately clinical pharmacokinetic and pharmacodynamic parameters. Importantly, cocrystallization leads to a synchronized release of both drugs, thus potentially allowing favorable pharmacodynamic interactions in time. In addition, API–API co-crystals may also facilitate formulation by improving stability or tabletability.5,6 Co-crystal of tramadol-celecoxib (CTC) is a first-in-class API–API co-crystal of rac-tramadol.hydrochloride (TRM) and celecoxib (CXB) in 1:1 molecular ratio (1:1.27 Page 3 ACS Paragon Plus Environment


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weight ratio), currently in phase 3 clinical trials for the treatment of moderate to severe acute pain (Figure 1).7 CTC may provide a relevant addition to pain therapy, since it recruits four of the more relevant mechanisms involved in analgesia (cyclo-oxygenase-2 inhibition, opioid agonism and inhibition of serotonin and noradrenaline reuptake). From the efficacy standpoint, in preclinical studies CTC has shown synergistic antinociceptive effects with respect to individual APIs, without potentiation of adverse effects.8 In a phase 2 clinical trial of moderate to severe pain, CTC also exerted pain-relieving effects superior to TRM.9 From the structural point of view, CTC is a supramolecular 3D network in which the two active enantiomers of TRM and CXB are linked via hydrogen bonding and chloride ions, and thus it can be considered an ionic co-crystal.10 This unique structure provided differentiated intrinsic dissolution rates (IDRs) in water as compared to the constituent APIs.11 The IDR of TRM was shown to be slower from CTC than from TRM alone and, in contrast, the IDR of CXB was faster from CTC than from CXB alone. This was subsequently correlated with a positively modified clinical pharmacokinetic profile in comparison with commercially available single-entity reference products and the open combination.12 In humans, TRM was absorbed more slowly from CTC, resulting in a reduction in peak plasma concentration (Cmax), while CXB was absorbed faster from CTC.

HO

HO O

(R)

O

(R)

.HCl

N

(S)

SO2NH2

(S)

.HCl

N N

N

Tramadol Hydrochloride of the racemic mixture of the 1R,2R-(+) and 1S,2S-(-) enantiomers

F3C

Celecoxib


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Figure 1. Structures of rac-tramadol.HCl (TRM) and celecoxib (CXB) and asymmetric unit of CTC.

We report here several additional studies that were carried out in order to further profile the distinctive solution behavior of CTC suggested in IDR studies. In the first instance, the behavior of CTC in several formulation systems was studied, including an analysis of the integrity of the co-crystal structure in the formulation used for in vivo administration in pharmacological and toxicological studies (0.5% hydroxypropyl methyl cellulose, HPMC), which was essential in order to assure the physical integrity of the co-crystal at the time of administration. These studies were deemed to be interesting in view of the scarce publicly available information related to co-crystal solubility and stability in formulation vehicles.13 In addition, we investigated the impact on the behavior of CTC by the gastrointestinal tract (GIT) dissolution media FaSSIF-v2 and FeSSIF-v2, simulated fasted or fed state human intestinal fluids, respectively,14 as it is suitable to predict the effect of food on CTC absorption. In addition to the kinetic dissolution measurements, we also studied CTC from a thermodynamic solubility perspective. The methodology for measurement of equilibrium cocrystal solubility is well defined15 and involves a single measurement of solution concentration in equilibrium assuring the presence of both solid drug and co-crystal. This Page 5 ACS Paragon Plus Environment


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point is defined as the eutectic point, where the co-crystal solubility and stability domains can be readily characterized. Drug and coformer solution concentrations, at this invariable point, are referred as the transition concentrations (Ctr). A mathematical model for predicting the solubility-pH relationship of the co-crystal can be derived from the Ctr values and can be compared with experimental values.16 In addition, studies to determine which factor, strength of the crystal lattice or solvation17, are critically involved in the solubility of CTC and their components were also carried out. Finally, we determined the hygroscopicity of CTC, as an indicator of the impact of atmospheric water on the co-crystal structure stability. Adsorption/desorption profiles, aimed at measuring the tendency for a solid to take up water vapor at constant temperature with changes in relative humidity (RH), are now determined as routine pre-formulation activity intended to provide an early assessment of the potential effects of moisture on the physical and chemical properties of drug candidates. This measure is even more relevant in the case of co-crystals since their dissociation has been reported to be influenced by the product environment, i.e., storage at high RH and temperature.18 In particular, it has been shown that co-crystals have a higher tendency to dissociate when the solubility of the components is very different, as is the case in CTC.19 Overall, the results reported herein helped to establish the boundaries of the physical stability of CTC, showing that its co-crystal structure confers a substantially distinctive profile versus the free combination and constituent APIs alone. We hope that these studies will also contribute to the better understanding of the solution behavior of API-API co-crystals, which has been under reported to date.

Experimental Methods. Materials. TRM and CXB were provided by Sigma-Aldrich and Molekula Limited, respectively. The term free combination used throughout this manuscript means the physical


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mixture of CXB and TRM in a 1:1 molar proportion. CTC was obtained using the procedure previously described.11 All other agents and solvents were purchased from Sigma-Aldrich and were used without further purification. General instrumentation. High-performance liquid chromatography (HPLC) was performed with an Alliance 2695 (Waters, Milford, MA 01757, USA) equipped with a 2996 UVdetector; differential scanning calorimetry (DSC) analysis was carried out using a Mettler Toledo instrument DSC3 (Mettler-Toledo LLC, Columbus, OH 43240, USA); proton nuclear magnetic resonance (1H-NMR) was recorded in CD3OD with a Varian Mercury 400 spectrometer (Agilent, Santa Clara, CA 95051, USA), equipped with a 5 mm 1H/19F/X automated triple broadband probe; X-Ray powder diffraction (XRPD) patterns were collected in reflection θ-θ geometry in a PANalytical X'Pert PRO diffractometer (Malvern Panalytical Ltd, Malvern, WR14 1XZ, UK), equipped with Cu Kα radiation (λ = 1.5406 Å) and a PIXcel detector, operated at 45 kV and 40 mA; dynamic vapor sorption (DVS) was measured using a Q5000 SA equipment (TA instruments Inc, NewCastle, DE 19720, USA); selective dissolution profiles were obtained using a T3 instrument (Pion INC, Billerica, MA 01821, USA). DSC experiments. Crystalline samples (2-4 mg) were analyzed by heating the sample at a rate of 10 °C/min under a dry nitrogen atmosphere. Temperature and enthalpy calibration of the instrument were achieved using a high purity indium standard. HPLC analysis. HPLC was carried out using a reverse-phase column XBridge BEH C18 (50×4.6mm, 2.5μm) (Waters, Milford, MA 01757, USA). The mobile phase consisted of a gradient of acetonitrile:trifluoroacetic acid 0.5% and the UV detector was set at 254 nm for CXB and 220 nm for TRM. The flow rate was maintained at 2.0 mL/min and 5 μL of sample was injected, yielding a retention time of around 5.2 min for CXB and 3.4 min for TRM. Quantifications of CXB and TRM were performed with two calibration curves, daily



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prepared, with ranges of 9 to 140 ng for CXB and 0.1 to 1 µg for TRM. Samples were diluted conveniently to have a value in between the ranges of the calibration curves. Preparation of dissolution media. Saline (NaCl at 0.5%), HPMC solutions (0.5 and 1%) and Tween 80 (0.1%) were prepared by dissolving the corresponding solids in MilliQ water. FeSSIF-V2 and FaSSIF-V2 were prepared, degassed and used within 48 h of preparation as recommended by the supplier.20 Dissolution profile of CTC, free combination, CBX and TRM in buffer solutions. The dissolution profiles were obtained in a T3 instrument working in the GI dissolution assay module. The buffer solutions used were 25 mM phosphate-buffered saline (PBS) adjusted to pH 7 with 0.1 N HCl and 50 mM sodium formate adjusted to pH 3 with 0.1 N NaOH. To 510 mg of solid sample of CTC, free combination, CXB or TRM, 20 mL of buffer was added. The concentration of the sample in solution was monitored every 50 seconds by UVabsorption spectroscopy for a total of 15 min. Studies in HPMC. For the integrity study in the in vivo formulation, CTC in suspension (1 and 8 mg/mL) or the free combination were stirred in 0.5% HPMC aqueous solution for 10 min at 25 °C. For the solubility study, suspensions of CTC, free combination, or CXB or TRM alone (6 mg/mL) were stirred in 0.5 or 1% HPMC aqueous solution for 1 to 6 h at 25 °C. Then the samples were centrifuged at 3000 rpm for 30 min at 25 °C. The supernatants were extracted and CXB and TRM were quantified by HPLC. The remaining solids were freeze-dried overnight in a lyophilizer and analyzed by DSC, NMR and XRPD. Dissolution of CTC and free combination in several media. CTC or the free combination of CXB and TRM (16 mg/mL) were stirred at 25 °C in the corresponding dissolution media (saline, Tween 80, 0.5% HPMC, FaSSIF or FeSSIF) for variable time (from 1 to 24 h), after which they were centrifuged at 3000 rpm for 20 min. The clear solution was then diluted conveniently for quantification of CXB and TRM by HPLC, as described above.


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pKa determination of CXB and TRM. Drug pKa values were determined by potentiometric titration (TRM) or spectroscopic (UV) titration (CXB). For TRM, 1-2 mg of sample was dissolved in 1.5 mL of 0.15 M KCl, pre-acidified to pH 2.0 with 0.5 M HCl, and then titrated with 0.5 M KOH solution. pKa values were fitted from the titration curve (mL of titrant vs. pH) by applying equations based on mass and charge balances. For CXB, an acid/base titration was performed over a 10 mM DMSO solution of CXB using in-situ UV absorbance profile at each pH point during the titration. The pKa was determined by monitoring the change in UV absorbance with pH as CXB undergoes ionization. Intrinsic solubility of CXB and TRM. Intrinsic solubility values were obtained at pH values lower than pKa-2 for CXB (pKa= 9.6, 0.01 N HCl pH 2) and higher than pKa+2 for TRM (pKa=9.5, CAPS 50 mM pH 11.5) in order to assure the compounds are in their unionized state. A sample excess of TRM or CXB was stirred in the corresponding buffer solution for 24 h at 25 °C. Then the samples were centrifuged at 3000 rpm for 30 min at 25 °C. The supernatants were extracted and CXB and TRM were quantified by HPLC. Solubility profiles of CXB and TRM, obtained using equations 2 and 3, respectively, are represented in dependence on pH in Figure 7. Determination of transition concentrations (Ctr) and CTC solubility. Co-crystal Ctr values at the eutectic point were obtained following the co-crystal dissolution method described by Good et al,15 consisting on the dissolution of co-crystal in saturated solutions containing excess solid of one of the co-crystal constituents, in this case the more insoluble CXB. One proportion of CTC/CXB was used (95/5), since low amounts of CXB were sufficient to get saturated solutions. Ctr values were determined at the following initial buffer pHs: 2.0 (0.01 N HCl), 7.4 (phosphate buffer), 9.9 (CAPS 50 mM adjusted with 0.01 N HCl) and 11.5 (CAPS 50 mM). Samples were stirred for 24 h at 25 °C (equilibrium), pHs were measured and the solutions were isolated from the solids by centrifugation and quantified by HPLC for both



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components. It was confirmed that the results are the same using either 0, 6 or 12 hours of equilibration time after stirring. The solid samples were freeze-dried overnight in a lyophilizer and analyzed by XRPD but only samples at pH 7.4 and 2 confirmed the presence of two phases, CXB and CTC (Figure 3). From the Ctr values, the solubility product (Ksp) and co-crystal solubility (SCTC) mean values were determined through the use of equation 1 described by Bethune et al21 and root square of Ctr, respectively. The values are displayed in Table 1 and Figure 7. DVS measurements. Adsorption/desorption profiles were measured at 25 °C. Samples were placed in a hemispherical metallized quartz pan of 180 L and left to equilibrate at 40% RH for 1 h. RH was then increased with a pace of 10% every 3 h up to 90%, followed by a decrease to 0% using the same rate. The cycle was repeated, by increasing RH from 0 to 90% at a rate of 10% every 3 h.

Results and discussion The analysis of the dissolution behavior of CTC was challenging, since: i) there are few reports in the literature of this type of studies on co-crystals in general and API-API cocrystals in particular. In our case, some of the tests were performed by considering CXB (the more insoluble component) as the drug and TRM (the more soluble), as the conformer; ii) the same nature of the API–API co-crystal complicates the picture in relation to a standard drug, since two components must be taken into account; iii) assuring the presence of the co-crystal structure of CTC can only be done by analysis of the solids remaining at certain times using techniques such as DSC, NMR and XRPD; and iv) both components are quite different in terms of solubility: CXB is a highly insoluble molecule with no ionizable groups at physiological pH, while TRM is much more soluble and has a positive ionizable group within the physiologically meaningful pH range. In addition, it should be considered that CXB may


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exist as four different polymorphs, form III is the most stable and is commercially marketed.22 Form III also corresponds (as indicated by XRPD analysis) to the one isolated in all samples where the solid state of CXB (that was released from CTC) was analyzed (data not shown). As described previously, the IDR studies11 of CTC had shown that in water TRM dissolved more slowly (7-fold) from CTC than from TRM alone and in contrast, CXB dissolved faster (3-fold) from CTC than from CXB alone. This demonstrated the synchronized release of the constitutive products as a differential feature of CTC versus the individual compounds. We then investigated the profile of CTC, the free combination or the individual APIs in formulations used for in vivo administration in the preclinical pharmacological and toxicological studies, such as HPMC and buffered aqueous solutions at different pH values (3 and 7). The first study was aimed at establishing that CTC was the true entity administered as a suspension in vivo when prepared in 0.5% HPMC. It was determined that crystalline integrity was maintained, since in the concentration range evaluated (1 and 8 mg/mL) and after 10 min stirring, the remaining solids were shown to be CTC, which was recovered in 94-97 % weight. The free combination treated in the same conditions, provided a solid containing only CXB and a solution consisting of a 10:1 mixture of TRM and CXB, thus supporting a differential behavior of the co-crystal CTC in 0.5% HPMC. The dissolution profiles of CXB and TRM from CTC, the free combination or the individual compounds at two concentrations of HPMC (0.5 and 1%) and different times (1, 3 and 6 h), were also investigated (Figure 2). CXB release was significantly faster from CTC than from the free combination, which in turn was quite similar to the release from CXB alone. The largest differences were seen at the 3 h point and at the highest HPMC concentration (1%) wherein a supersaturation state was achieved. Inversely, when looking at TRM, dissolution was completely achieved after 1 h both from the free combination and individual TRM, but in



the case of CTC TRM dissolution was much slower and it was not completed until 6 later. On the occasions where dissolution testing was performed on CTC, analysis of solids remaining indicated that CTC was the only constituent up to 6 h, as can be concluded by the joint inspection of NMR, DSC and XRPD (Figure 3, only the 6 h results are shown).

CXB 0.900 0.800

CTC 0.5% HPMC

CTC 1% HPMC

Free comb. 1% HPMC

CXB 0,5% HPMC

Free comb. 0.5% HPMC

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CXB (mM)

0.600 0.500 0.400 0.300 0.200 0.100 0.000 0

1

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TRM 12.000

CTC 0.5% HPMC

CTC 1% HPMC

Free comb. 1% HPMC

TRM 0.5% HPMC

Free comb. 0.5% HPMC

10.000 8.000

TRM (mM)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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6.000 4.000 2.000 0.000 0

1

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3

4

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Stirring time (h)

Figure 2. Dissolution profiles of CXB and TRM coming from CTC, the free combination or the individual compounds (6 mg/mL) at different times (1, 3 and 6 h) and different concentrations of HPMC (0.5 and 1%). In the case of TRM the free combination and individual TRM show superimposing curves.


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Figure 3. Data (DSC, NMR and XRPD) of the solids isolated after treatment of CTC for 6 h in 0.5% HPMC (red) and free combination (black) in relation to CTC (dark blue), TRM (blue) and CXB (grey). The NMR signals correspond to an aromatic proton of TRM (6.83 ppm) and the pyrazole proton of CXB (6.91 ppm).

A similar study using two different buffered solutions was then carried out. These represented the pH of oral (3, simulating stomach pH) and intravenous (7, simulating blood pH) drug administrations. In both cases similar profiles were obtained, but only those of pH 3 are depicted in Figure 4. It was observed that CXB coming from CTC was released faster and presented a supersaturation state, not detectable when CXB was released from the free combination. This supersaturation is a physically unfavorable state which after ca 8 min reverted to the concentration corresponding to the thermodynamic solubility. Inversely, TRM had a slower release when comparing CTC to the free combination or TRM alone.



CXB

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Free comb.

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0.8 0.6 0.4 0.2 0

0

2

4

6

8

10

12

14

time (min)

Figure 4. Dissolution of CXB (a) and TRM (b) from CTC in buffer solution (pH 3, 25 °C) in comparison to the free combination and CXB or TRM alone.

The behavior of CTC in the GIT dissolution media FaSSIF-V2 and FeSSIF-V2, in comparison to saline, 0.5 % HPMC and Tween 80 at a concentration of 16 mg/mL was then studied (Figure 5). As stated above, this is relevant for orally administered drugs in order to predict if their absorption is likely to be affected by food. The concentration curve of CXB in FaSSIF was very similar to that observed in saline. However, CXB release was substantially increased in the presence of FeSSIF (fed state). The FeSSIF-V2 dissolution curve shows an initial supersaturation state that reverts after 2 h, but maintains a clear superior release in relation to the other formulations (about 7-fold higher versus FaSSIF-V2). This study was shown to be highly predictive of the results obtained in the food interaction clinical study,23 where increased bioavailability and delayed absorption of CXB were identified as food effects. In fact, CXB administration was already known to be affected by the presence of food both in vitro (7-fold times higher)24 and in the clinic.25 In the case of TRM, both FaSSIF


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and FeSSIF solutions showed a similar behavior, again in agreement with the results of the food interaction clinical study, where no food effect was observed for TRM. This behavior matched as well the one obtained in the case of TRM alone.26 Altogether, these results indicate that the co-crystal structure of CTC does not affect the food interaction behavior in comparison to both single components.

CXB Saline

0.6

Tween 80

HPMC 0.5%

FeSSIF

FaSSIF

0.5

CXB (mM)

0.4 0.3 0.2 0.1 0 0

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A

TRM 35

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Tween 80

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20 15 10 5 0 0

B

15

20

25

Stirring time (h)

Figure 5. Dissolution profile of CXB (A) and TRM (B) coming from CTC (16 mg/mL) in different media: saline, Tween 80, 0.5% HPMC, FeSSIF-V2 and FaSSIF-V2.

An interesting finding shown in Figure 2 and Figure 5 is that the dissolution rate of TRM coming from CTC was greatly affected by HPMC, displaying a gradual release along 24 h (the dissolution was slower at the highest concentration of 16 mg/mL). However, this effect was not observed in the case of the free combination or TRM alone. It seems that the coPage 15 ACS Paragon Plus Environment


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crystal effect is clearly discriminated from its individual component APIs in solutions containing HPMC, a known hydrophilic matrix system commonly used in solid sustained release formulations.27 The gradual release was not observed in the other systems, including Tween 80. Altogether, the previous kinetic solubility results indicate that the co-crystal CTC shows a substantially different dissolution behavior in comparison to the free combination in several vehicles, including relevant preclinical and clinical formulation systems. Largest differences are obtained during the first minutes of dissolution in buffer solutions and in HPMC. It seems clear that heteromolecular interactions (mainly hydrogen and ionic bonding) in the co-crystal structure are the determinant forces behind this differential behavior. The kinetic dissolution profiles add valuable information to in vivo studies since they influence the absorption rate. On the other hand, the solubility-pH profile is a thermodynamic measure at solid-solution equilibrium that assesses the solubility of a co-crystal with respect to their individual components. The thermodynamic analysis was thus initiated by evaluation of the intrinsic solubility of CTC (SCTC) in the whole pH range. To this aim the solubility product constant (Ksp) was determined, since both parameters are related through equation 1.

Equation 1

(

𝑆𝑐𝑜𝑐𝑟𝑦𝑠𝑡𝑎𝑙 = 𝐾𝑠𝑝 1 +

[𝐻 + ] 𝐾𝑎 𝐵𝐻

)(

1+

[𝐻 + ] 𝐾𝑎 𝐻𝐴

)

where Ksp is the solubility product of the co-crystal and Ka is the acid ionization constant for the acid (HA, CBX, pKa 9.6) and for the conjugate acid of the base (BH, TRM, pKa 9.5), respectively (pKa values were determined as described in the experimental section). Equation 1 was derived by Bethune et al21 for a 1:1 co-crystal with an acidic drug (CXB) and a monoprotic conjugate acid (protonated form of TRM) coformer under stoichiometric conditions. Page 16 ACS Paragon Plus Environment

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The Ksp of CTC, which is a binary system where both components have dependence on pH, is described by the co-crystal-solution equilibrium and the ionization reactions: HABH+Cl-solid

HA + BH+Cl-

K sp= [HA][BH+Cl-] A- + H+

HA

K a= [H+][A-]/[HA] BH+Cl-

B + HCl K a= [HCl][B]/[BH+]

The Ksp is the product of the equilibrium concentration (after 24 h) or Ctr of CXB and TRM in the eutectic point. Experimentally, these Ctr were determined at pH 7.4 and 2 at a 95/5 proportion of CTC/CXB, considering CXB as the drug, since it is the more insoluble component. To ensure eutectic point conditions, the presence of the two phases (CXB and CTC) was confirmed by XPRD analysis of the solids isolated (Figure 6, only pH 7.4 is shown). From these experiments the Ksp of CTC and the solubility of CTC, represented by the root square of the concentration product of CXB and TRM at each pH value were calculated (Table1). Ksp was calculated to be 5.93 ± 0.2 E-07 (mean of two experiments at pH 2 and 7.4) and the mean solubility of CTC (SCTC) was determined to be 7.8 ± 0. 2 E-04 M in the whole range of physiological pH (2 to 7.4). The same procedure was repeated at all additional pHs to give the experimental values represented in Figure 7.

Ksp (10-7 M2) SCTC (10-4M)

pH 2

5.83 ±0.1

7.6

7.4

6.02±0.5

8.0

Mean

5.93±0.2

7.8 ±0.2

Table 1. Ksp and solubility values of CTC obtained experimentally at two different pHs at 25 °C.



Page 18 of 32

Figure 6. Comparison of the diffractograms of the solid isolated after stirring a mixture of CTC and CXB 95/5 at pH=7.4 for 24 h (red) with CTC (dark blue), CXB (grey) and TRM (blue). Peaks correspond mainly to CXB and small signals attributable to CTC (pointed with green arrows) are observed. No clear signs of TRM are detected.

Since co-crystal solubility is related to the values of Ksp, Ka and [H+] through equation 1, the pH-solubility curve for CTC can be easily predicted from the Ksp value. As shown in Figure 7, good correlation was obtained between the experimental values and the predicted curve in the range of pH below de value of pKa-1 of both components (9.5 and 9.6). Above this pH a deviation was observed, which could probably be explained by the change in the ionization state of each component around their pKa values.


Page 19 of 32

CTC

1.E+08

CXB

TRM

S CTC

1.E+06 1.E+04 1.E+02

logS (M)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1.E+00 1.E-02 1.E-04 1.E-06 1

3

5

pH

7

9

11

Figure 7. Theoretical solubility-pH profile of CTC (dark blue curve) in comparison to its individual components, TRM (blue curve) and CXB (grey curve). Experimental solubility values of CTC (dark blue diamonds) are compared with the theoretical curve.

In Figure 7 the theoretical pH-solubility profiles of CXB and TRM are also represented. They were calculated through the use of the Henderson–Hasselbalch equations (equations 2 and 3), which relate the solubility of a monoprotic compound to its pKa and its intrinsic solubility (So), that is when the compound is in its unionizable state.28

Equation 2

𝑆 = 𝑆𝑜(1 + 10𝑝𝐻 ― 𝑝𝐾𝑎)

for a monoprotic acid

Equation 3

𝑆 = 𝑆𝑜(1 + 10𝑝𝐾𝑎 ― 𝑝𝐻)

for a monoprotic base

In this case, the So were obtained at pH values lower than pKa-2 (pH=2) for CXB and higher than pKa+2 (pH=11.5) for TRM, thus ensuring their uncharged state. The So of CXB was 4.49 E-06 M and for TRM it was 6.61 E-03 M, endorsing the large differences in solubility (more than 1000 times) between both components. The So value obtained in this study for CXB is quite similar to the reported thermodynamic solubility (2.89 E-06 M).29 No intrinsic



Page 20 of 32

solubility value was found in the literature for TRM, probably because of its high solubility in the pharmacologically meaningful pH range. Figure 7 indicates that CTC solubility lies between those of TRM and CXB, with greater differences observed at lower pH. CTC is approximately 171 times more soluble than CXB at the pH range from 1 to 8. On the contrary, CTC is 3400 times less soluble than TRM at pH=7 and these differences increase substantially at pH=2. At pH>11 all the solubilities were predicted to be in a similar range. The notable increase in solubility of CTC respect to CXB, the less soluble API, could be related to the high solubility of the second API, TRM. This fact had been already found in some studies15,30 where co-crystal solubility is directly proportional to coformer solubility. It is interesting to note that co-crystal formation is the only possibility to increase the solubility of CBX, since it is a drug unsuitable for salt formation due to its high acid pKa. On the other hand, TRM dissolving from CTC shows diminished solubility versus the API alone, but still in the acceptable range. Since solubility is inversely related to stability, these results also indicate that CTC, as the majority of co-crystals, is metastable in aqueous solutions. This means that it will revert to the individual components at a rate depending on the particular composition of the solutions, as stated above in the kinetic studies. Also interesting are the main factors affecting the solubility of CTC. The free energy of solubilization of a co-crystal is the sum of the free energy associated with the release of the solute molecules, i.e. the strength of the co-crystal lattice and the free energy of solvation of those released solute molecules.31 The lattice energy contribution (Log χideal) is calculated from the ideal solubility given by Van’t Hoff’s equation (equation 4).32

Equation 4

∆𝐻𝑓

log 𝜒𝑖𝑑𝑒𝑎𝑙 = ― 2.303𝑅

(

𝑇𝑓 ― 𝑇 𝑇𝑓𝑇

) Page 20

ACS Paragon Plus Environment

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where χideal is the ideal mole fraction solubility of a solute at a temperature (T), Tf is the fusion temperature, ΔHf is the enthalpy of fusion and R is the universal gas constant. This equation assumes that the heat capacity change upon melting is negligible. The term “ideal solubility” refers to the situation where there is no energy penalty associated with the dissolution of a solute in a perfect solvent. The solvation energy (Log ɣ) is calculated according to equation 5 from the experimental solubility and the ideal solubility, taking into account that the co-crystal components are non– electrolytes or are in their unionized form.

Equation 5

𝑙𝑜𝑔𝜒 = log 𝜒𝑖𝑑𝑒𝑎𝑙 ― log Ɣ

where χ denotes mole fraction solubility, χideal is the ideal mole fraction solubility and ɣ is the activity coefficient. The activity coefficient is a measure of the free energy required to solvate the solute. The melting data obtained from the DSC analysis as well as the ideal solubility values, calculated from equation 5, are depicted in Table 2. Also the intrinsic solubility of both components in their unionized form and the solubility of CTC in its isoelectric point (calculated from equation 1 at pI (pH=9.55), where CTC has the main fraction of unionized compound) are indicated.



Crystalline phase Tf (° C)

Page 22 of 32

TRM

181

ΔHf (KJmol-1) 41.22

Ideal solubility ( 𝜒𝑖𝑑𝑒𝑎𝑙, m)a 0.18

Experimental intrinsic solubility (m)b 6.61x 10-3

CXB

162

33.58

0.79

4.49 x 10-6

CTC

165

34.26

0.67

1.54 x 10-3

Table 2. Melt temperature and enthalpy used in the calculation of ideal solubility and experimental intrinsic solubility (at 25 °C). aIdeal solubility calculated from eq 4, where mole fractions were converted to molality units in water. bIntrinsic solubility determined with unionized form of TRM and CXB and at pH=pI for CTC.

Figure 8 shows the lattice energy (log χideal) and solvation energy (log ɣ) contributions to the experimental aqueous solubility of TRM, CXB and CTC. The ideal solubility of CTC is intermediate between those of CXB and TRM, as is the case of experimental solubility. In all cases, solvation is the dominating factor, but in CXB the contribution of solvation is 50 times that of lattice strength, while for CTC the relation is 15 fold and for TRM two fold only. The solvation factor in the co-crystal appears to be proportionally lower and more similar to the more soluble component, TRM, which can explain why CTC dissolves better in water, compared to CXB.


Page 23 of 32

log χ ideal

TRM

-log ɣ

CXB

CTC

0 log X

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


-2 -4 -6

Figure 8. Lattice energy (log χideal) and solvation energy (log ɣ) contributions to the experimental aqueous solubility of TRM, CXB and CTC at pH 9.55. The black area represents χ

ideal

calculated from equation 4 and the grey area represents the activity

coefficient, or the contribution of solute-solvent interactions, calculated from equation 5.

Finally, hygroscopicity analyses were performed with CTC, the free combination and the individual components, CXB and TRM. In the adsorption/desorption isotherms depicted in Figure 9, CXB was shown to be a very stable solid in all percentages of RH, while TRM presented a deliquescent profile, where the solid was transformed into a hydrate after 90% RH. The combination showed some hygroscopicity and a profile that reminded that of TRM, with a deliquescent profile and no transformation into a hydrate. However, CTC presented a very stable profile, with no gain of weight at any RH, reinforcing again the differential properties provided by the heteromolecular bonds in the co-crystal structure, which in this case hamper the entrance of water in relation to the free combination.



a (CXB)

b (TRM)

c (free comb)

d (CTC)

Page 24 of 32

(CTC)

Figure 9. DVS studies at room temperature and increasing relative humidity of CXB (a), TRM (b), free combination (c) and CTC (d).

Conclusions Co-Crystal of Tramadol-Celecoxib (CTC) is a first-in-class API–API co-crystal of rac-tramadol.hydrochloride (TRM) and celecoxib (CXB) in 1:1 molecular ratio (1:1.27 weight ratio), currently in phase 3 clinical trials for the treatment of moderate to severe acute pain. This work has shown that regarding kinetic dissolution profiles, often related to the rate of absorption of a drug, CTC behaves in a quite distinctive manner with respect to the free combination or the individual components CXB and TRM in all the systems studied. First, it was verified that in the conditions used for preclinical in vivo administration (0.5 % HPMC), CTC maintained its crystalline integrity in all the concentration range evaluated, the free combination remaining as discrete molecular entities. In agreement with previously reported IDR results in water, the dissolution profiles in HPMC (0.5 and 1%) showed that CXB release was significantly faster from CTC than from the free combination, which in turn was Page 24 ACS Paragon Plus Environment

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quite similar to the release from CXB alone. Conversely, TRM was released much more slowly from CTC than from the free combination and TRM alone. Similar results were obtained in buffered solutions, where a supersaturation effect was only observed for CXB coming from CTC. Interestingly, the slower release of TRM from CTC was more pronounced in the presence of HPMC, a known sustained release formulation agent. The study on the behavior of CTC in the GIT dissolution media FaSSIF-v2 and FeSSIF-v2 was highly predictive of the results shown in the food interaction clinical study, where a food effect consisting of increased bioavailability and delayed absorption was found for CXB and no food effect was observed for TRM. This was the same behavior observed for the individual components, indicating that the co-crystal structure in this case does not exert any influence. The solubility-pH curves of CTC versus the two individual components showed that the thermodynamic solubility of CTC lies in between those of TRM and CXB within the physiologically meaningful pH range, with greater differences observed at lower pH. With a solubility of 0.0008 M at pH=7.4, CTC was approximately 171 times more soluble than CXB and 3400 times less soluble than TRM. Finally, the hygroscopicity study of CTC showed that it was not hygroscopic, presenting a very stable profile, with no gain of weight at any RH. On the contrary, the free combination showed some hygroscopicity and a DVS diagram more similar to that of TRM. Overall, the results reported herein show that the co-crystal structure of CTC provides several distinctive features versus the free combination and the constituent APIs alone in relation to its dissolution profile and physical stability in aqueous solutions. The heteromolecular interactions (mainly hydrogen and ionic bonding) present in the 3D supramolecular network that conforms the co-crystal structure impart strength to the crystal lattice and are the determinant forces behind the differential behavior over the free combination. In relation to



Page 26 of 32

the individual components, one could argue that the co-crystal structure confers a resistance to the otherwise predominant dissolution of TRM, a highly soluble compound, in the presence of water. However, the solvation factor in the co-crystal appears to be lower than in the case of CXB and more similar to the more soluble component, TRM, which could also explain why CTC dissolves better in water, compared to CXB.

AUTHOR INFORMATION Corresponding Author *Dr Adriana Port. Drug Discovery and Preclinical Development ESTEVE Pharmaceuticals S.A., Baldiri Reixac, 4-8 08028, Barcelona, Spain Tel: +34 934 46 60 67;

Fax: +34 934 46 64 32; Email: [email protected]

ACKNOWLEDGEMENTS This research was funded by Esteve Pharmaceuticals, S.A. We thank Joan Farran and Nicolas Tesson (Enantia S.L., Barcelona, Spain) for generating the XRPD data. We also thank Clara Rafols (Department of Chemical Engineering and Analytical Chemistry, Universitat de Barcelona) for helpful advice and revision of the manuscript.

ABBREVIATIONS 1H-NMR, proton nuclear magnetic resonance; API, active pharmaceutical ingredient; CAPS, N-cyclohexyl-3-aminopropanesulfonic acid; COX-2, cyclo-oxygenase-2; CTC, co-crystal of tramadol hydrochloride-celecoxib; CXB, celecoxib; DSC, differential scanning calorimetry; DVS, dynamic vapor sorption; FDC, fixed-dose combination; HPMC, hydroxypropyl methyl cellulose; IDR, intrinsic dissolution rate; NSAID, non-steroidal anti-inflammatory drug; PBS,


Page 27 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


phosphate-buffered saline; RH, relative humidity; TRM, tramadol; XRPD, X-ray power diffraction.

CONFLICT OF INTEREST STATEMENT The authors are employees of Esteve Pharmaceuticals, S. A. and declare no conflict of interest.

REFERENCES 1. Thipparaboina, R.; Kumar, D.; Chavan, R. B.; Shastri, N. R. Multidrug co-crystals: towards the development of effective therapeutic hybrids. Drug Discov. Today 2016, 21, 481–490. 2. Polomano, R.C.; Fillman, M.; Giordano, N. A; Vallerand, A.; Nicely, K. L.; Jungquist, C. R. Multimodal analgesia for acute postoperative and trauma-related pain. Am. J. Nurs. 2017, 117, 12–26. 3. Elvir-Lazo, O. L.; White, P. F. The role of multimodal analgesia in pain management after ambulatory surgery. Curr. Opin. Anaesthesiol. 2010, 23, 697–703. 4. Raffa, R.B.; Pergolizzi, J. V.; Tallarida, R. J. The determination and application of fixeddose analgesic combinations for treating multimodal pain. J. Pain 2010, 11, 701–9. 5. Sherman, B. Solid substances comprising valproic acid and sodium valproate. U.S. Patent 6077542, 2000. 6. Maeno, Y.; Fukami, T.; Kawahata, M.; Yamaguchi, K.; Tagami, T.; Ozeki, T.; Suzuki, T.; Tomono, K. Novel pharmaceutical cocrystal consisting of paracetamol and trimethylglycine, a new promising cocrystal former. Int. J. Pharm. 2014, 473, 179–86.



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7. Gascón, N.; Almansa, C.; Merlos, M.; Vela, J. M.; Encina, G.; Morte, A.; Smith, K.; PlataSalamán, C. Co-Crystal of Tramadol-Celecoxib: preclinical and clinical evaluation of a novel analgesic. Expert Opin. Invest. Drugs, 2018, submitted. 8. Merlos, M.; Portillo-Salido, E.; Brenchat, A.; Aubel, B.; Buxens, J.; Fisas, A.; Codony, X.; Romero, L.; Zamanillo, D.; Vela, J. M. Administration of a co-crystal of tramadol and celecoxib in a 1:1 molecular ratio produces synergistic antinociceptive effects in a postoperative pain model in rats. Eur. J. Pharmacol. 2018, 833, 370–8. 9. López-Cedrún, J.; Videla, S.; Burgueño, M.; Juárez, I.; Aboul-Hosn, S.; Martín-Granizo, R.; Grau, J.; Puche, M.; Gil-Diez, J. L.; Hueto, J. A.; Vaqué, A.; Sust, M.; Plata-Salamán, C.; Monner, A. Co-crystal of Tramadol–Celecoxib in patients with moderate to severe acute post-surgical oral pain: a dose-finding, randomised, double-blind, placebo- and activecontrolled, multicentre, phase II trial. Drugs 2018, 18, 137–48. 10. Duggirala, N. K.; Perry, M. L.; Almarsson, Ö.; Zaworotko, M. J. Pharmaceutical cocrystals: along the path to improved medicines. Chem. Commun. 2016, 52, 640–655. 11. Almansa, C.; Merce, R.; Tesson, N.; Farran, J.; Tomas, J.; Plata-Salamán, C. R. CoCrystal of Tramadol Hydrochloride-Celecoxib (ctc): A Novel API-API Co-Crystal for the Treatment of Pain. Cryst. Growth Des. 2017, 17, 1884–1892. 12. Videla, S.; Lahjou, M.; Vaque, A.; Sust, M.; Escriche, M.; Soler L; Sans, A.; Sicard, E.; Gascón, N.; Encina, G.; Plata-Salamán, C. Single-dose pharmacokinetics of co-crystal of tramadol-celecoxib: results of a four-way randomized open-label phase I clinical trial in healthy subjects. Br. J. Clin. Pharmacol. 2017, 83, 2718–28. 13. Bhardwaj, S.; Lipert, M.; Bak, A. Mitigating cocrystal physical stability liabilities in preclinical formulations. J. Pharm. Sci. 2017, 106, 31–38.


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following oral administration of Co-Crystal of Tramadol-Celecoxib (CTC): A randomised, open-label, single dose, crossover study in healthy volunteers. Clin. Drug Investig. 2018, 38, 819–827 24. Shono, Y.; Jantratid, E.; Janssen, N.; Kesisoglou, F.; Mao, Y.; Vertzoni, M.; Reppas, C.; Dressman, J. B. Prediction of food effects on the absorption of celecoxib based on biorelevant dissolution testing coupled with physiologically based pharmacokinetic modelin. Eur. J. Pharm. Biopharm. 2009, 73, 107–114. 25. European Medicines Agency. Summary of product characteristics for Celebrex 100 mg capsule. 2018; Available at: http://www.medicines.org.uk/emc/medicine/14534. Accessed 30 April 2018. 26. European Medicines Agency. Summary of product characteristics for tramadol hydrochloride

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For Table of Contents Use Only Differential Solution Behavior of the New API-API Co-Crystal of Tramadol-Celecoxib (CTC) versus its constituents and their combination. Adriana Port*, Carmen Almansa, Raquel Enrech, Magda Bordas, Carlos R. Plata-Salamán. ESTEVE Pharmaceuticals S.A., Drug Discovery and Preclinical Development, Parc Científic de Barcelona, Baldiri Reixac, 4-8, 08028 Barcelona. Solubility-pH profile of CTC and its individual components

1.E+08

CTC

CXB

TRM

S CTC

1.E+06

1.E+04

1.E+02

logS (M)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 32 of 32

1.E+00

1.E-02

1.E-04

1.E-06 1

2

3

4

5

6

7

8

9

10

11

pH

Synopsis Co-Crystal of Tramadol Hydrochloride-Celecoxib, CTC, shows a thermodynamic solubility in between those of tramadol and celecoxib in the whole physiologically meaningful pH range. In several formulation systems CTC displays a distinctive dissolution profile, where celecoxib release is significantly faster and tramadol release much slower from CTC than from the free combination of celecoxib and tramadol or constituents alone.


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