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The effect of surfactant and polymer on solution stability and solubility of tadalafil-methylparaben cocrystal
Journal of Molecular Liquids 281 (2019) 86–92
Contents lists available at ScienceDirect
Journal of Molecular Liquids journal homepage: www.elsevier.com/locate/molliq
The effect of surfactant and polymer on solution stability and solubility of tadalafil-methylparaben cocrystal Amin Alvani a,b, Abolghasem Jouyban c, Ali Shayanfar d,⁎ a
Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Student Research Committee and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran Pharmaceutical Analysis Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran d Drug Applied Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran b c
a r t i c l e
i n f o
Article history: Received 20 November 2018 Received in revised form 6 February 2019 Accepted 15 February 2019 Available online 16 February 2019 Keywords: Cocrystal Polymer Solubility Solution stability Surfactant
a b s t r a c t Cocrystal formation is a novel method to enhance physicochemical properties of pharmaceuticals. However, instability in solution is one of the challenging issues of cocrystals and surfactants/polymers could have a positive effect on cocrystal solubility and stability. In this study, tadalafil cocrystal was prepared via the solvent drop grinding method with methylparaben as a cocrystal former. The thermodynamic solubility of cocrystal was determined in phosphate buffer solution (pH = 6.8) and in the presence of different concentrations of sodium lauryl sulfate (SLS) and polyvinylpyrrolidone (PVP), followed by investigating their effects on solution stability of cocrystal. The prepared cocrystal showed enhancement in solubility compared with tadalafil, but the solution stability analysis indicated it is an incongruently saturating cocrystal that could transform to a less soluble solid form during slurring and dissolution. Moreover, PVP and SLS improved the cocrystal solution stability, however, the solubility advantage for the prepared cocrystal is not obtained because of preferential solubilization for tadalafil that is less soluble than methylparaben. Overall, the results showed that cocrystal formation of tadalafil with methylparaben has the ability to change its physicochemical properties. In addition, polymer and surfactant could have a significant effect on the solubility and the stability of the cocrystal. © 2019 Elsevier B.V. All rights reserved.
1. Introduction One of the major issues about the marketed drug and drug candidates is their low solubility in aqueous media, which can affect their oral bioavailability. Using different approaches to improve water solubility has been considered in several applications such as cosolvency, salt formation, crystal engineering, preparation of cocrystals, using surfactants, complexing agents, and polymers [1]. Cocrystal formation as a novel method was applied to impact physicochemical properties of pharmaceutical components that can be used as an alternative for salt formation, especially for drugs that have a nonionizable group [2,3]. It was prepared using two or more different molecules with non-bonded interactions (usually hydrogen bonding) which finally made one crystalline lattice. Active pharmaceutical ingredient (API), inside cocrystal lattice, and coformer molecule(s) act as an extra agent to modify physicochemical and pharmacokinetic properties of the proposed drug [4,5]. Thermodynamic solubility of a cocrystal depends on its components in the solution phase. Therefore, whenever the cocrystal dissociates into ⁎ Corresponding author at: Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran. E-mail address: [email protected] (A. Shayanfar).
https://doi.org/10.1016/j.molliq.2019.02.080 0167-7322/© 2019 Elsevier B.V. All rights reserved.
its components in solution or a slight excess coformer exists as the impurity in the structure of cocrystal, the mass of excess solid phase is an important issue that should be considered. To address this issue, the solubility can be estimated using the approach proposed by RodríguezHornedo and coworkers. [6]. In this approach, transition concentration (i.e., eutectic points) of each component after equilibrium of cocrystal and drug or coformer with solution phase is quantified. The eutectic concentrations, which give information about cocrystal stability, are directly related to cocrystal solubility [7]. Surfactants and polymers can change the solubility of cocrystal components and have a significant effect on solubility and solution stability of cocrystal [8,9]. Tadalafil (TDF), Fig. 1a, is a white crystalline powder found mainly in erectile dysfunction (ED) treatment [10] and arterial hypertension [11] that has a positive effect in the patients with benign prostatic hyperplasia [12]. It has specific selectivity to type V phosphodiesterase, lower side effects, and longer half time in comparison to sildenafil [13,14]. TDF belongs to class II of the biopharmaceutical classification system (BCS), which have low solubility and high permeability. In this regard, modifying the solubility of TDF can enhance its oral bioavailability [15,16]. Various strategies such as using complexing agents [17], surfactants [18], liquisolid technique [19], solid dispersion [20–22], preparation of nanocrystals [23], and amorphization methods [23] have been applied
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hydrogen phosphate for preparation of phosphate buffer solution (PBS) were provided from Scharlau Chemie (Barcelona, Spain). Ethanol (96% w/w) was supplied from Kimia Alcohol (Zanjan, Iran) and labmade distilled water was used for the preparation of the stock and working solutions, respectively. 2.2. Preparation and characterization of cocrystal
Fig. 1. Structure of (a) TDF and (b) MPB.
to improve solubility and dissolution rate of TDF. A common method for solubilization of a compound is the salt formation and pH adjustment. However, TDF is a very weak basic drug (pKa = 0.85) and a nonionizable compound in biological pHs. Therefore, these methods have been not proposed for TDF for improving solubility. Cocrystal formation is an alternative method for salt formation for non-ionizable drugs such as carbamazepine (CBZ). Previous studies have shown cocrystal formation of CBZ with various coformer can significantly increase the solubility and dissolution rate [24,25]. In contrary to CBZ, few reports have been reported about TDF cocrystal. Zaworotko's research group in 2012 [26] described the preparation of TDF cocrystals with hydroxysubstituted benzoic acid conformers such as methylparaben (MPB). However, there is no report about their physicochemical properties in literature. Parabens are used mainly as preservative agents in pharmaceutical industries [27]. MPB (Fig. 1b), which possesses hydroxyl (OH) functional group, is selected as cocrystal former (coformer) considering accessible nitrogen of TDF. Theoretically, H-bond interaction is possible between these two materials [28]. Developing a simple, fast, and valid analysis method is essential for quantifying physicochemical properties; i.e., solubility and dissolution rate of pharmaceuticals. In these cases, UV-spectrophotometry is a common analysis method for determination of concentration. Chromatography methods are the main approach to determine two materials that have UV-spectra overlapping [29,30]. Nevertheless, these methods are time-consuming and costly. Therefore, chemometric-based methods have recently been interested in the quantification of drug concentration in aqueous solutions. Net analyte signal standard addition method (NASSAM) is a novel method with the ability to determine the analyte concentration in the multicomponent system. NASSAM can be used for measuring the analyte (drug) concentration in the presence of known interferents such as coformers [31,32]. In this study, a cocrystal of TDF and MPB was synthesized by the solvent-drop grinding method and characterized by instrumental analysis methods. Thermodynamic and solubility solution of cocrystal were evaluated in the aqueous medium and in the presence of surfactant and polymer. Moreover, the concentration of drug in the presence of coformer that overlaps UV spectra was quantified by a fast and applicable chemometrics method using UV–Vis spectrophotometer. 2. Materials and methods 2.1. Materials TDF powder and polyvinylpyrrolidone K 17 (PVP) were purchased from Osve pharmaceutical company (Tehran, Iran) and Rahavard Tamin Pharmaceutical Co. (Tehran, Iran), respectively. MPB, sodium lauryl sulfate (SLS) and acetonitrile were supplied from Merck (Darmstadt, Germany). Sodium dihydrogen phosphate and disodium
TDF-MPB cocrystal was prepared via solvent drop grinding based on the method reported by Weyna et al. [26]. TDF (400 mg) with MPB (156 mg) was placed in a mortar and pestle was ground for 1 h in the presence of 80 μL acetonitrile as solvent. Thermal behavior of the cocrystal was evaluated via differential scanning calorimetry (DSC) (Shimadzu, Kyoto, Japan). Five milligrams of samples were located into aluminum pans for analysis while a 10 °C min−1 rate was chosen for analyzing method from 40 to 340 °C. PXRD pattern was determined using an X-ray diffractometer (XRD) instrument within the range of (4°–40°) with steps of 0.026°. Mercury software (Version 3.8, Cambridge Crystallographic Data Centre) was applied to generate calculated PXRD patterns of TDF and MPB from the single crystal structure. These patterns are available online in https:// www.ccdc.cam.ac.uk/. 2.3. Thermodynamic solubility of TDF and MPB The solubility of TDF and MPB was determined by equilibrating an excess amount of solid powder to a phosphate buffer solution (pH = 6.8, 0.1 M). It was prepared using an appropriate amount of disodium hydrogen phosphate and sodium dihydrogen phosphate (0.40 g and 0.86 g in 100 mL, respectively). The pH of the solution was adjusted by sodium hydroxide (1 M). The powder was prepared in the presence of SLS (0.2% and 3%) and PVP (0.5%, 1%, and 2%) using a shakerincubator equipped with a temperature controlling system (Heidolph, Schwabach, Germany) at 37 ± 0.1 °C. After a sufficient period of time (N72 h), the saturated solutions of the drugs were filtered through a 0.45 μm filter and diluted with water. Then, the diluted samples were assayed by UV–Vis spectrophotometer (Shimadzu, Japan) in 283 and 251 nm, respectively. The concentrations were determined from the calibration curves. Each experimental data point represents the average of at least three repetitive experiments. 2.4. Thermodynamic solubility and solution stability of TDF-MPB cocrystal Thermodynamic solubility and solution stability of TDF-MPB cocrystal were determined based on the method reported by Rodriguez-Hornedo et al. [6]. An excess amount of TDF and cocrystal was suspended in an appropriate volume of the mentioned aqueous solutions in the previous section. After an appropriate equilibrium time (72 h), the remained solid samples were verified to have a mixture of two solid phases (TDF and cocrystal) by DSC. Then, the eutectic concentrations of TDF and MPB in solution were determined to calculate the thermodynamic solubility and solution stability of cocrystal in studied media. For quantification of TDF and MPB using a UV-spectrophotometry, a chemometric-based method (i.e., NASSAM) was used. This method was applied to determine TDF in the presence of MPB. It was applied in cocrystal studies for the quantification of an analyte in solution by our group [25,32]. Stock solutions of TDF and MPB were prepared via dissolving their powder in ethanol. Distilled water was used to obtain working solutions. Binary synthetic mixtures of TDF (analyte) and MPB (interferent) were prepared as standard solutions, including 15 solutions (five different concentrations of TDF versus three concentrations of MPB). In another way, TDF in different concentrations was added to the sample in the presence of a constant concentration of MPB in three levels. The mixtures of TDF and MPB spectra were divided into two parts: NAS is
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only dependent on TDF and the second part of the spectrum that was produced by the spectra of MPB that is orthogonal to its spectra. After determining their absorption spectra (range of 220–400 nm) using a UV spectrophotometer and analyzing the data by MATLAB software, NAS curves for each analyte versus standard concentrations were applied to calculate the concentration of the analytes. The accuracy of this method to recognize TDF concentration was evaluated with nine samples with a known concentration of TDF and MPB in the range of calibration. The eutectic concentrations of MPB were determined by UVspectrophotometry at 251 nm after 200-fold dilution of the solution. At this wavelength, TDF has no significant absorbance. 3. Results and discussion Fig. 3. PXRD patterns of TDF, MPB and TDF-MPB cocrystal.
3.1. Characterization of TDF-MPB cocrystal DSC thermogram of TDF-MPB and PXRD patterns of TDF, MPB, and TDF-MPB are illustrated in Figs. 2 and 3, respectively. It displays a single endothermic peak corresponding to the melting point of the studied compound at 180 °C. A distinct single endothermic peak in agreement with reported DSC thermograms of TDF-MPB cocrystal and a significant difference between the melting of TDF (301 °C) and MPB (126 °C) confirm the formation of cocrystal between drug and coformer. PXRD of cocrystal shows distinctly different patterns and the appearance of new diffraction peaks from TDF and MPB and a good agreement between PXRD patterns reported in a previous work by Weyna et al. [26]. 3.2. Developing of analysis method for quantification of TDF and MPB The solubility of TDF and MPB was determined based on the saturated concentration of TDF and MPB by a plotted calibration curve by standard solutions at 283 and 251 nm after appropriate dilution of saturated solutions. Linear ranges for TDF and MPB were 2–20 mg/L (R2 = 0.997) and 8–40 mg/L (R2 = 0.999), respectively. 3.3. The solubility of TDF and MPB in phosphate buffer solution (0.1 M, pH = 6.8) and in presence of different concentration of SLS and PVP Solubility data of TDF and MPB in PBS (0.1 M, pH = 6.8) are shown in Figs. 4 and 5, respectively. A good agreement is observed between the determined solubility of TDF (0.04 mM at 37 °C) and MPB (17 mM at 37 °C) with reported solubility data in the literature (0.047 mM for
TDF and 25 mM for MPB at 37 °C) [33,34]. It indicates the accuracy of the applied method for determination of solubility. The solubility of TDF and MPB was investigated in the presence of 0.2% of SLS (less than critical micelle concentration (CMC) of SLS which is 0.24% [35]) and 3% (NCMC). Moreover, three concentrations of PVP can be seen in Fig. 4. A considerable solubilization was observed in the presence of SLS and PVP. The effective mechanism for solubilization by surfactants is the formation of micelles [36], however, solubilization effect in the low concentration of SLS (bCMC) has been reported for some chemical compounds [37]. Moreover, PVP as hydrophilic polymer also increases the solubility of chemical compounds because of the interaction with the drug by hydrogen bonds and complex formation [38,39]. 3.4. Developing analysis method for simultaneous quantification of TDF and MPB by UV-NASSAM The norm of NASs versus added concentrations of TDF in three-level concentrations of MPB is illustrated in Fig. 5. There is a good linear correlation between concentration and norm of NAS of TDF and various concentrations of MPB. NAS of TDF is not dependent on MPB concentration and its NAS value is constant in presence of different concentrations of TDF. Validation of the developed method was checked by three known concentrations of TDF (i.e., 3.5, 5.5, and 8.5 mg/L) in binary mixture with MPB. Table 1 presents the accuracy of the proposed NASSAM
Fig. 2. DSC patterns of TDF-MPB cocrystal.
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Fig. 4. Solubility of TDF (a) and MPB (b) in PBS (pH = 6.8, 0.1 M), PBS + SLS 0.2%, PBS + SLS 3%, PBS + 0. 5% PVP, PBS + 1% PVP and PBS + 2% PVP.
method for determination of TDF in nine synthetic mixtures (in the presence of various concentrations of MPB). The overall mean of percentage deviation was 5.2 ± 3.0%.
The concentration of MPB because of higher concentration compared with TDF was determined at 251 nm by UV–Vis spectrophotometry which TDF (after at least 200 fold dilution of solutions). As can be noticed, at this wavelength, TDF has no significant absorbance.
Table 1 Synthetic mixtures of TDF and MPB to evaluate accuracy and precision of the proposed NASSAM method.
Fig. 5. Norm of NASs for TDF and MPB versus added concentration of TDF in three level concentrations (10, 20, 30 mg/L) of MPB.
Sample number
TDF concentration (mg/L)
MPB concentration (mg/L)
Obtained concentration (mg/L)
% Deviation
1 2 3 4 5 6 7 8 9
3.50 5.50 8.50 3.50 5.50 8.50 3.50 5.50 8.50
10 10 10 20 20 20 30 30 30
3.87 5.75 8.86 3.52 5.97 8.12 3.26 5.36 8.12
10.6 4.5 4.2 0.6 8.5 −4.5 −6.9 −2.5 −4.5
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Table 2 Eutectic concentrations, Keu of TDF-MPB cocrystal in phosphate buffer solution (PBS, pH = 6.8, 0.1 M) and in presence of various concentrations of SLS and PVP. Medium
Eutectic concentration of TDF (mM) (mean ± SD)
Eutectic concentration of MPB (mM) (mean ± SD)
Keu
Thermodynamic solubility (mM) (mean ± SD)
PBS PBS + SLS 0.2% PBS + SLS 3% TDF-MPB (PVP 0.5%) TDF-MPB (PVP 1%) TDF-MPB (PVP 2%)
0.20 ± 0.02 0.12 ± 0.01 1.22 ± 0.17 0.47 ± 0.04 0.95 ± 0.15 1.52 ± 0.30
11.34 ± 0.68 4.71 ± 0.90 9.80 ± 1.35 0.32 ± 0.01 0.38 ± 0.03 0.14 ± 0.03
57.0 39.7 8.0 0.7 0.4 0.1
1.50 ± 0.11 0.75 ± 0.075 3.46 ± 0.481 0.39 ± 0.022 0.60 ± 0.062 0.47 ± 0.089
3.5. Thermodynamic solubility and solution stability of TDF-MPB in phosphate buffer solution (0.1 M, pH = 6.8) and in the presence of various concentrations of SLS and PVP Thermodynamic solubility is determined by adding an excess amount of solute to the certain volume of solvent. After appropriate equilibrium time, the saturated concentration of drug is quantified. However, because of the cocrystal instability in solution, and/or a slight excess of coformer in the structure of synthesized cocrystal, it is not appropriate to determine its thermodynamic solubility using the classical shake-flask method. Thermodynamic solubility of a cocrystal (e.g., TDFMPB) is dependent on the concentration of its components (TDF and MPB) in the solution phase. The cocrystal dissociates into their components; thus, thermodynamic solubility should be described by a solubility product [6]. The equilibrium for TDF-MPB cocrystal (1:1, based on the reported work by Weyna et al. [26]) is: TDF−MPB→TDF ðaqÞ þ MPBðaqÞ Therefore, the eutectic point of drug and coformer at the three-phase equilibrium (i.e., cocrystal, drug, and solution phase) was used to calculate thermodynamic solubility as follows: STDF−MPB ¼
qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi ½TDF eu ½MPBeu
Moreover, estimation of the cocrystal eutectic constant (Keu, the eutectic concentration of coformer/eutectic concentration of drug) would be used to evaluate the solution stability of cocrystals. The thermodynamic solubility of TDF-MPB in PBS are listed in Table 2. Thermodynamic solubility of TDF-MPB (1.50 mM) in PBS is higher than TDF (0.04 mM). These results are in agreement with previous reports that coformer solubility should be 10 or more times greater than that of the drug (37.5 in this case) to observe an improvement in solubility [7]. Ksp can be calculated by multiply eutectic concentrations of drug and coformer in nonionizable form, TDF (pKa = 0.85, very weak basic compound) and MPB (pKa = 8.5, acidic compound) are non-ionizable in the studied medium (pH~6 after equilibrium). Therefore, Ksp of TDF–MPB in non-ionizable form is 2.29 × 10−6. The Keu of TDF-MPB is 57, suggesting that it is an incongruently saturating cocrystal system that could transform to a less soluble solid during slurring and dissolution advantage is not possible for the prepared cocrystal [40,41]. Similar results have been reported for cocrystal of CBZ with nicotinamide (NIC). Although the reported thermodynamic solubility of CBZ-NIC is 152-folds more than CBZ [7], it is unstable in water and converts to dihydrate form of CBZ and the apparent solubility and dissolution of CBZ-NIC is the same with CBZ [42,43]. However, a cocrystal of CBZ with cinnamic acid (CIN), which its coformer is very low soluble than NIC, shows a significant increase in solubility and dissolution rate compared with CBZ because of acceptable solution stability, especially in water and acidic media [25,32].
Fig. 6. Solubility ratio of TDF-MPB cocrystal to TDF in PBS (pH = 6.8, 0.1 M), PBS + SLS 0.2%, PBS + SLS 3%, PBS + 0. 5% PVP, PBS + 1%PVP and PBS + 2% PVP.
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Surfactants and polymers such as SLS [44] and PVP [45] have shown a significant effect on solubility and solution stability of cocrystals. Table 2 shows eutectic concentrations, Keu of TDF-MPB cocrystal in PBS (pH = 6.8, 0.1 M) and in the presence of various concentrations of SLS and PVP. Keu is a crucial factor to evaluate the solution stability of cocrystal. Keu b 1, cocrystal is stable in solution and dissolution advantage is possible while Keu N 1 indicates it is unstable in solution and in the high value of Keu, dissolution advantage is not possible [40,41]. However, SLS and PVP could have a significant effect on Keu and conversion of incongruently to the congruent system. Two concentrations of SLS (0.2% and 3%) decrease the Keu value (39.7 and 8.0, respectively). However, they still are incongruently saturating cocrystal system. In comparison, different concentrations of PVP (0.5%, 1%, and 2%) have a considerable change in Keu value to 0.7, 0.4, and 0.1, respectively, and change it to congruently saturating cocrystal system; suggesting that stable cocrystal and dissolution advantage can be reached. Although the solution stability of TDF-MPB cocrystal in the presence of SLS and PVP significantly was improved, in most of the studied cases, the thermodynamic solubility was decreased and solubility advantage of cocrystal in comparison with TDF (Fig. 6) was not attained in the presence of SLS and PVP. As illustrated in Fig. 4, MPB is much more hydrophilic than TDF and, preferential solubilization for the drug in comparison with coformer is a well-known mechanism for this behavior [46]. 4. Conclusion Thermodynamic solubility of TDF in cocrystal form with MPB significantly increased. However, solution stability analysis of studied cocrystal showed that it is an incongruently saturating cocrystal system that could transform to a less soluble solid form during slurring and dissolution. Two applied compounds (i.e., SLS and PVP) can significantly increase both drug (i.e., TDF) and coformer (i.e., MPB) solubility. However, the solubility advantage for the prepared cocrystal is not obtained because of preferential solubilization for the drug by SLS and PVP that is less soluble than coformer. However, they considerably increased the solution stability of cocrystal. The findings of this study provide useful insight for understanding the solubility and solution stability and designing a new formulation for cocrystals in future studies. Acknowledgments This article is a part of the results of A.A's Pharm.D thesis No.4035 registered in the Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran. The authors would like to thank PXRD Lab Razi Applied Science Foundation, Tehran, Iran for providing PXRD patterns and Pharmaceutical Analysis Research Center, Tabriz University of Medical Sciences, Tabriz, Iran for financial support. References [1] R.G. Strickley, Solubilizing excipients in oral and injectable formulations, Pharm. Res. 21 (2004) 201–230. [2] D.D. Gadade, S.S. Pekamwar, Pharmaceutical cocrystals: regulatory and strategic aspects, design and development, Adv. Pharm. Bull. 6 (2016) 479–494. [3] S. Aitipamula, R. Banerjee, A.K. Bansal, K. Biradha, M.L. Cheney, A.R. Choudhury, G.R. Desiraju, A.G. Dikundwar, R. Dubey, N. Duggirala, P.P. Ghogale, S. Ghosh, P.K. Goswami, N.R. Goud, R.R.K.R. Jetti, P. Karpinski, P. Kaushik, D. Kumar, V. Kumar, B. Moulton, A. Mukherjee, G. Mukherjee, A.S. Myerson, V. Puri, A. Ramanan, T. Rajamannar, C.M. Reddy, N. Rodriguez-Hornedo, R.D. Rogers, T.N.G. Row, P. Sanphui, N. Shan, G. Shete, A. Singh, C.C. Sun, J.A. Swift, R. Thaimattam, T.S. Thakur, R. Kumar Thaper, S.P. Thomas, S. Tothadi, V.R. Vangala, N. Variankaval, P. Vishweshwar, D.R. Weyna, M.J. Zaworotko, Polymorphs, salts, and cocrystals: what's in a name? Cryst. Growth Des. 12 (2012) 2147–2152. [4] N.J. Babu, A. Nangia, Solubility advantage of amorphous drugs and pharmaceutical cocrystals, Cryst. Growth Des. 11 (2011) 2662–2679. [5] S. Emami, M. Siahi-Shadbad, K. Adibkia, M. Barzegar-Jalali, Recent advances in improving oral drug bioavailability by cocrystals, BioImpacts 8 (2018) 305–320. [6] R. Thakuria, A. Delori, W. Jones, M.P. Lipert, L. Roy, N. Rodríguez-Hornedo, Pharmaceutical cocrystals and poorly soluble drugs, Int. J. Pharm. 453 (2013) 101–125.
91
[7] D.J. Good, N. Rodríguez-Hornedo, Solubility advantage of pharmaceutical cocrystals, Cryst. Growth Des. 9 (2009) 2252–2264. [8] M.P. Lipert, L. Roy, S.L. Childs, N. Rodríguez-Hornedo, Cocrystal solubilization in biorelevant media and its prediction from drug solubilization, J. Pharm. Sci. 104 (2015) 4153–4163. [9] A. Alhalaweh, H.R.H. Ali, S.P. Velaga, Effects of polymer and surfactant on the dissolution and transformation profiles of cocrystals in aqueous media, Cryst. Growth Des. 14 (2014) 643–648. [10] G.B. Brock, C.G. McMahon, K.K. Chen, T. Costigan, W. Shen, V. Watkins, G. Anglin, S. Whitaker, Efficacy and safety of tadalafil for the treatment of erectile dysfunction: results of integrated analyses, J. Urol. 168 (2002) 1332–1336. [11] N. Galiè, B.H. Brundage, H.A. Ghofrani, R.J. Oudiz, G. Simonneau, Z. Safdar, S. Shapiro, R.J. White, M. Chan, A. Beardsworth, L. Frumkin, R.J. Barst, Tadalafil therapy for pulmonary arterial hypertension, Circulation 119 (2009) 2894–2903. [12] R.B. Egerdie, S. Auerbach, C.G. Roehrborn, P. Costa, M.S. Garza, A.L. Esler, D.G. Wong, R.J. Secrest, Tadalafil 2.5 or 5mg administered once daily for 12 weeks in men with both erectile dysfunction and signs and symptoms of benign prostatic hyperplasia: results of a randomized, placebo-controlled, double-blind study, J. Sex. Med. 9 (2012) 271–281. [13] J.D. Corbin, S.H. Francis, Pharmacology of phosphodiesterase-5 inhibitors, Int. J. Clin. Pract. 56 (2002) 453–459. [14] D.T. Manallack, R.A. Hughes, P.E. Thompson, The next generation of phosphodiesterase inhibitors: structural clues to ligand and substrate selectivity of phosphodiesterases, J. Med. Chem. 48 (2005) 3449–3462. [15] K. Wlodarski, W. Sawicki, K.J. Paluch, L. Tajber, M. Grembecka, L. Hawelek, Z. Wojnarowska, K. Grzybowska, E. Talik, M. Paluch, The influence of amorphization methods on the apparent solubility and dissolution rate of tadalafil, Eur. J. Pharm. Sci. 62 (2014) 132–140. [16] A.A.M. Abdel-Aziz, Y.A. Asiri, A.S. El-Azab, M.A. Al-Omar, T. Kunieda, Tadalafil, Profiles of Drug Substances, Excipients and Related Methodology, 2011 287–329. [17] S.M. Badr-Eldin, S.A. Elkheshen, M.M. Ghorab, Inclusion complexes of tadalafil with natural and chemically modified β-cyclodextrins. I: preparation and in-vitro evaluation, Eur. J. Pharm. Biopharm. 70 (2008) 819–827. [18] S.M. Badr-Eldin, S.A. Elkheshen, M.M. Ghorab, Improving tadalafil dissolution via surfactant-enriched tablets approach: statistical optimization, characterization, and pharmacokinetic assessment, J. Drug Deliv. Sci. Technol. 41 (2017) 197–205. [19] M. Lu, H. Xing, T. Yang, J. Yu, Z. Yang, Y. Sun, P. Ding, Dissolution enhancement of tadalafil by liquisolid technique, Pharm. Dev. Technol. 22 (2017) 77–89. [20] J.S. Choi, S.E. Lee, W.S. Jang, J.C. Byeon, J.S. Park, Tadalafil solid dispersion formulations based on PVP/VA S-630: improving oral bioavailability in rats, Eur. J. Pharm. Sci. 106 (2017) 152–158. [21] J.S. Choi, S.H. Kwon, S.E. Lee, W.S. Jang, J.C. Byeon, H.M. Jeong, J.S. Park, Use of acidifier and solubilizer in tadalafil solid dispersion to enhance the in vitro dissolution and oral bioavailability in rats, Int. J. Pharm. 526 (2017) 77–87. [22] K. Wlodarski, W. Sawicki, K. Haber, J. Knapik, Z. Wojnarowska, M. Paluch, P. Lepek, L. Hawelek, L. Tajber, Physicochemical properties of tadalafil solid dispersions - impact of polymer on the apparent solubility and dissolution rate of tadalafil, Eur. J. Pharm. Biopharm. 94 (2015) 106–115. [23] P.R. Vuddanda, M. Montenegro-Nicolini, J.O. Morales, S. Velaga, Effect of surfactants and drug load on physico-mechanical and dissolution properties of nanocrystalline tadalafil-loaded oral films, Eur. J. Pharm. Sci. 109 (2017) 372–380. [24] M. Ullah, I. Hussain, C.C. Sun, The development of carbamazepine-succinic acid cocrystal tablet formulations with improved in vitro and in vivo performance, Drug Dev. Ind. Pharm. 42 (2016) 969–976. [25] A. Shayanfar, K. Asadpour-Zeynali, A. Jouyban, Solubility and dissolution rate of a carbamazepine-cinnamic acid cocrystal, J. Mol. Liq. 187 (2013) 171–176. [26] D.R. Weyna, M.L. Cheney, N. Shan, M. Hanna, L. Wojtas, M.J. Zaworotko, Crystal engineering of multiple-component organic solids: pharmaceutical cocrystals of tadalafil with persistent hydrogen bonding motifs, Crystengcomm 14 (2012) 2377–2380. [27] M.G. Soni, I.G. Carabin, G.A. Burdock, Safety assessment of esters of phydroxybenzoic acid (parabens), Food Chem. Toxicol. 43 (2005) 985–1015. [28] M. Khan, V. Enkelmann, G. Brunklaus, Crystal engineering of pharmaceutical cocrystals: application of methyl paraben as molecular hook, J. Am. Chem. Soc. 132 (2010) 5254–5263. [29] B.G. Chaudhari, N.M. Patel, P.B. Shah, Stability indicating RP-HPLC method for simultaneous determination of atorvastatin and amlodipine from their combination drug products, Chem. Pharm. Bull. 55 (2007) 241–246. [30] N. Patel, V.K. Parmar, A sensitive high-performance thin layer chromatography method for simultaneous determination of salbutamol sulphate and beclomethasone dipropionate from inhalation product, Pharm. Sci. 24 (2018) 131–140. [31] K. Asadpour-Zeynali, M. Bastami, Net analyte signal standard addition method (NASSAM) as a novel spectrofluorimetric and spectrophotometric technique for simultaneous determination, application to assay of melatonin and pyridoxine, Spectrochim. Acta A Mol. Biomol. Spectrosc. 75 (2010) 589–597. [32] F. Keramatnia, A. Shayanfar, A. Jouyban, Thermodynamic solubility profile of carbamazepine-cinnamic acid cocrystal at different pH, J. Pharm. Sci. 104 (2015) 2559–2565. [33] G.M. El Maghraby, F.K. Alanazi, I.A. Alsarra, Transdermal delivery of tadalafil. I. Effect of vehicles on skin permeation, Drug Dev. Ind. Pharm. 35 (2009) 329–336. [34] S.H. Yalkowsky, Y. He, Handbook of Aqueous Solubility Data, CRC Press, Boca Raton, Fl, 2016. [35] J.P. Marcolongo, M. Mirenda, Thermodynamics of sodium dodecyl sulfate (SDS) micellization: an undergraduate laboratory experiment, J. Chem. Educ. 88 (2011) 629–633.
92
A. Alvani et al. / Journal of Molecular Liquids 281 (2019) 86–92
[36] C.D. Rangel-Yagui, A. Pessoa Jr., L.C. Tavares, Micellar solubilization of drugs, J. Pharm. Pharm. Sci. 8 (2005) 147–163. [37] M.N. Alizadeh, A. Shayanfar, A. Jouyban, Solubilization of drugs using sodium lauryl sulfate: experimental data and modeling, J. Mol. Liq. 268 (2018) 410–414. [38] H.A. Garekani, F. Sadeghi, A. Ghazi, Increasing the aqueous solubility of acetaminophen in the presence of polyvinylpyrrolidone and investigation of the mechanisms involved, Drug Dev. Ind. Pharm. 29 (2003) 173–179. [39] T. Loftsson, Drug solubilization by complexation, Int. J. Pharm. 531 (2017) 276–280. [40] A. Alhalaweh, A. Sokolowski, N. Rodríguez-Hornedo, S.P. Velaga, Solubility behavior and solution chemistry of indomethacin cocrystals in organic solvents, Cryst. Growth Des. 11 (2011) 3923–3929. [41] A. Alhalaweh, S.P. Velaga, Formation of cocrystals from stoichiometric solutions of incongruently saturating systems by spray drying, Cryst. Growth Des. 10 (2010) 3302–3305.
[42] A. Shayanfar, S. Velaga, A. Jouyban, Solubility of carbamazepine, nicotinamide and carbamazepine-nicotinamide cocrystal in ethanol-water mixtures, Fluid Phase Equilib. 363 (2014) 97–105. [43] Z. Rahman, C. Agarabi, A.S. Zidan, S.R. Khan, M.A. Khan, Physico-mechanical and stability evaluation of carbamazepine cocrystal with nicotinamide, AAPS PharmSciTech 12 (2011) 693–704. [44] N. Huang, N. Rodríguez-Hornedo, Effect of micellar solubilization on cocrystal solubility and stability, Cryst. Growth Des. 10 (2010) 2050–2053. [45] C. Wang, Q. Tong, X. Hou, S. Hu, J. Fang, C.C. Sun, Enhancing bioavailability of dihydromyricetin through inhibiting precipitation of soluble cocrystals by a crystallization inhibitor, Cryst. Growth Des. 16 (2016) 5030–5039. [46] M.P. Lipert, N. Rodríguez-Hornedo, Cocrystal transition points: role of cocrystal solubility, drug solubility, and solubilizing agents, Mol. Pharm. 12 (2015) 3535–3546.
Contents lists available at ScienceDirect
Journal of Molecular Liquids journal homepage: www.elsevier.com/locate/molliq
The effect of surfactant and polymer on solution stability and solubility of tadalafil-methylparaben cocrystal Amin Alvani a,b, Abolghasem Jouyban c, Ali Shayanfar d,⁎ a
Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Student Research Committee and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran Pharmaceutical Analysis Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran d Drug Applied Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran b c
a r t i c l e
i n f o
Article history: Received 20 November 2018 Received in revised form 6 February 2019 Accepted 15 February 2019 Available online 16 February 2019 Keywords: Cocrystal Polymer Solubility Solution stability Surfactant
a b s t r a c t Cocrystal formation is a novel method to enhance physicochemical properties of pharmaceuticals. However, instability in solution is one of the challenging issues of cocrystals and surfactants/polymers could have a positive effect on cocrystal solubility and stability. In this study, tadalafil cocrystal was prepared via the solvent drop grinding method with methylparaben as a cocrystal former. The thermodynamic solubility of cocrystal was determined in phosphate buffer solution (pH = 6.8) and in the presence of different concentrations of sodium lauryl sulfate (SLS) and polyvinylpyrrolidone (PVP), followed by investigating their effects on solution stability of cocrystal. The prepared cocrystal showed enhancement in solubility compared with tadalafil, but the solution stability analysis indicated it is an incongruently saturating cocrystal that could transform to a less soluble solid form during slurring and dissolution. Moreover, PVP and SLS improved the cocrystal solution stability, however, the solubility advantage for the prepared cocrystal is not obtained because of preferential solubilization for tadalafil that is less soluble than methylparaben. Overall, the results showed that cocrystal formation of tadalafil with methylparaben has the ability to change its physicochemical properties. In addition, polymer and surfactant could have a significant effect on the solubility and the stability of the cocrystal. © 2019 Elsevier B.V. All rights reserved.
1. Introduction One of the major issues about the marketed drug and drug candidates is their low solubility in aqueous media, which can affect their oral bioavailability. Using different approaches to improve water solubility has been considered in several applications such as cosolvency, salt formation, crystal engineering, preparation of cocrystals, using surfactants, complexing agents, and polymers [1]. Cocrystal formation as a novel method was applied to impact physicochemical properties of pharmaceutical components that can be used as an alternative for salt formation, especially for drugs that have a nonionizable group [2,3]. It was prepared using two or more different molecules with non-bonded interactions (usually hydrogen bonding) which finally made one crystalline lattice. Active pharmaceutical ingredient (API), inside cocrystal lattice, and coformer molecule(s) act as an extra agent to modify physicochemical and pharmacokinetic properties of the proposed drug [4,5]. Thermodynamic solubility of a cocrystal depends on its components in the solution phase. Therefore, whenever the cocrystal dissociates into ⁎ Corresponding author at: Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran. E-mail address: [email protected] (A. Shayanfar).
https://doi.org/10.1016/j.molliq.2019.02.080 0167-7322/© 2019 Elsevier B.V. All rights reserved.
its components in solution or a slight excess coformer exists as the impurity in the structure of cocrystal, the mass of excess solid phase is an important issue that should be considered. To address this issue, the solubility can be estimated using the approach proposed by RodríguezHornedo and coworkers. [6]. In this approach, transition concentration (i.e., eutectic points) of each component after equilibrium of cocrystal and drug or coformer with solution phase is quantified. The eutectic concentrations, which give information about cocrystal stability, are directly related to cocrystal solubility [7]. Surfactants and polymers can change the solubility of cocrystal components and have a significant effect on solubility and solution stability of cocrystal [8,9]. Tadalafil (TDF), Fig. 1a, is a white crystalline powder found mainly in erectile dysfunction (ED) treatment [10] and arterial hypertension [11] that has a positive effect in the patients with benign prostatic hyperplasia [12]. It has specific selectivity to type V phosphodiesterase, lower side effects, and longer half time in comparison to sildenafil [13,14]. TDF belongs to class II of the biopharmaceutical classification system (BCS), which have low solubility and high permeability. In this regard, modifying the solubility of TDF can enhance its oral bioavailability [15,16]. Various strategies such as using complexing agents [17], surfactants [18], liquisolid technique [19], solid dispersion [20–22], preparation of nanocrystals [23], and amorphization methods [23] have been applied
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hydrogen phosphate for preparation of phosphate buffer solution (PBS) were provided from Scharlau Chemie (Barcelona, Spain). Ethanol (96% w/w) was supplied from Kimia Alcohol (Zanjan, Iran) and labmade distilled water was used for the preparation of the stock and working solutions, respectively. 2.2. Preparation and characterization of cocrystal
Fig. 1. Structure of (a) TDF and (b) MPB.
to improve solubility and dissolution rate of TDF. A common method for solubilization of a compound is the salt formation and pH adjustment. However, TDF is a very weak basic drug (pKa = 0.85) and a nonionizable compound in biological pHs. Therefore, these methods have been not proposed for TDF for improving solubility. Cocrystal formation is an alternative method for salt formation for non-ionizable drugs such as carbamazepine (CBZ). Previous studies have shown cocrystal formation of CBZ with various coformer can significantly increase the solubility and dissolution rate [24,25]. In contrary to CBZ, few reports have been reported about TDF cocrystal. Zaworotko's research group in 2012 [26] described the preparation of TDF cocrystals with hydroxysubstituted benzoic acid conformers such as methylparaben (MPB). However, there is no report about their physicochemical properties in literature. Parabens are used mainly as preservative agents in pharmaceutical industries [27]. MPB (Fig. 1b), which possesses hydroxyl (OH) functional group, is selected as cocrystal former (coformer) considering accessible nitrogen of TDF. Theoretically, H-bond interaction is possible between these two materials [28]. Developing a simple, fast, and valid analysis method is essential for quantifying physicochemical properties; i.e., solubility and dissolution rate of pharmaceuticals. In these cases, UV-spectrophotometry is a common analysis method for determination of concentration. Chromatography methods are the main approach to determine two materials that have UV-spectra overlapping [29,30]. Nevertheless, these methods are time-consuming and costly. Therefore, chemometric-based methods have recently been interested in the quantification of drug concentration in aqueous solutions. Net analyte signal standard addition method (NASSAM) is a novel method with the ability to determine the analyte concentration in the multicomponent system. NASSAM can be used for measuring the analyte (drug) concentration in the presence of known interferents such as coformers [31,32]. In this study, a cocrystal of TDF and MPB was synthesized by the solvent-drop grinding method and characterized by instrumental analysis methods. Thermodynamic and solubility solution of cocrystal were evaluated in the aqueous medium and in the presence of surfactant and polymer. Moreover, the concentration of drug in the presence of coformer that overlaps UV spectra was quantified by a fast and applicable chemometrics method using UV–Vis spectrophotometer. 2. Materials and methods 2.1. Materials TDF powder and polyvinylpyrrolidone K 17 (PVP) were purchased from Osve pharmaceutical company (Tehran, Iran) and Rahavard Tamin Pharmaceutical Co. (Tehran, Iran), respectively. MPB, sodium lauryl sulfate (SLS) and acetonitrile were supplied from Merck (Darmstadt, Germany). Sodium dihydrogen phosphate and disodium
TDF-MPB cocrystal was prepared via solvent drop grinding based on the method reported by Weyna et al. [26]. TDF (400 mg) with MPB (156 mg) was placed in a mortar and pestle was ground for 1 h in the presence of 80 μL acetonitrile as solvent. Thermal behavior of the cocrystal was evaluated via differential scanning calorimetry (DSC) (Shimadzu, Kyoto, Japan). Five milligrams of samples were located into aluminum pans for analysis while a 10 °C min−1 rate was chosen for analyzing method from 40 to 340 °C. PXRD pattern was determined using an X-ray diffractometer (XRD) instrument within the range of (4°–40°) with steps of 0.026°. Mercury software (Version 3.8, Cambridge Crystallographic Data Centre) was applied to generate calculated PXRD patterns of TDF and MPB from the single crystal structure. These patterns are available online in https:// www.ccdc.cam.ac.uk/. 2.3. Thermodynamic solubility of TDF and MPB The solubility of TDF and MPB was determined by equilibrating an excess amount of solid powder to a phosphate buffer solution (pH = 6.8, 0.1 M). It was prepared using an appropriate amount of disodium hydrogen phosphate and sodium dihydrogen phosphate (0.40 g and 0.86 g in 100 mL, respectively). The pH of the solution was adjusted by sodium hydroxide (1 M). The powder was prepared in the presence of SLS (0.2% and 3%) and PVP (0.5%, 1%, and 2%) using a shakerincubator equipped with a temperature controlling system (Heidolph, Schwabach, Germany) at 37 ± 0.1 °C. After a sufficient period of time (N72 h), the saturated solutions of the drugs were filtered through a 0.45 μm filter and diluted with water. Then, the diluted samples were assayed by UV–Vis spectrophotometer (Shimadzu, Japan) in 283 and 251 nm, respectively. The concentrations were determined from the calibration curves. Each experimental data point represents the average of at least three repetitive experiments. 2.4. Thermodynamic solubility and solution stability of TDF-MPB cocrystal Thermodynamic solubility and solution stability of TDF-MPB cocrystal were determined based on the method reported by Rodriguez-Hornedo et al. [6]. An excess amount of TDF and cocrystal was suspended in an appropriate volume of the mentioned aqueous solutions in the previous section. After an appropriate equilibrium time (72 h), the remained solid samples were verified to have a mixture of two solid phases (TDF and cocrystal) by DSC. Then, the eutectic concentrations of TDF and MPB in solution were determined to calculate the thermodynamic solubility and solution stability of cocrystal in studied media. For quantification of TDF and MPB using a UV-spectrophotometry, a chemometric-based method (i.e., NASSAM) was used. This method was applied to determine TDF in the presence of MPB. It was applied in cocrystal studies for the quantification of an analyte in solution by our group [25,32]. Stock solutions of TDF and MPB were prepared via dissolving their powder in ethanol. Distilled water was used to obtain working solutions. Binary synthetic mixtures of TDF (analyte) and MPB (interferent) were prepared as standard solutions, including 15 solutions (five different concentrations of TDF versus three concentrations of MPB). In another way, TDF in different concentrations was added to the sample in the presence of a constant concentration of MPB in three levels. The mixtures of TDF and MPB spectra were divided into two parts: NAS is
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only dependent on TDF and the second part of the spectrum that was produced by the spectra of MPB that is orthogonal to its spectra. After determining their absorption spectra (range of 220–400 nm) using a UV spectrophotometer and analyzing the data by MATLAB software, NAS curves for each analyte versus standard concentrations were applied to calculate the concentration of the analytes. The accuracy of this method to recognize TDF concentration was evaluated with nine samples with a known concentration of TDF and MPB in the range of calibration. The eutectic concentrations of MPB were determined by UVspectrophotometry at 251 nm after 200-fold dilution of the solution. At this wavelength, TDF has no significant absorbance. 3. Results and discussion Fig. 3. PXRD patterns of TDF, MPB and TDF-MPB cocrystal.
3.1. Characterization of TDF-MPB cocrystal DSC thermogram of TDF-MPB and PXRD patterns of TDF, MPB, and TDF-MPB are illustrated in Figs. 2 and 3, respectively. It displays a single endothermic peak corresponding to the melting point of the studied compound at 180 °C. A distinct single endothermic peak in agreement with reported DSC thermograms of TDF-MPB cocrystal and a significant difference between the melting of TDF (301 °C) and MPB (126 °C) confirm the formation of cocrystal between drug and coformer. PXRD of cocrystal shows distinctly different patterns and the appearance of new diffraction peaks from TDF and MPB and a good agreement between PXRD patterns reported in a previous work by Weyna et al. [26]. 3.2. Developing of analysis method for quantification of TDF and MPB The solubility of TDF and MPB was determined based on the saturated concentration of TDF and MPB by a plotted calibration curve by standard solutions at 283 and 251 nm after appropriate dilution of saturated solutions. Linear ranges for TDF and MPB were 2–20 mg/L (R2 = 0.997) and 8–40 mg/L (R2 = 0.999), respectively. 3.3. The solubility of TDF and MPB in phosphate buffer solution (0.1 M, pH = 6.8) and in presence of different concentration of SLS and PVP Solubility data of TDF and MPB in PBS (0.1 M, pH = 6.8) are shown in Figs. 4 and 5, respectively. A good agreement is observed between the determined solubility of TDF (0.04 mM at 37 °C) and MPB (17 mM at 37 °C) with reported solubility data in the literature (0.047 mM for
TDF and 25 mM for MPB at 37 °C) [33,34]. It indicates the accuracy of the applied method for determination of solubility. The solubility of TDF and MPB was investigated in the presence of 0.2% of SLS (less than critical micelle concentration (CMC) of SLS which is 0.24% [35]) and 3% (NCMC). Moreover, three concentrations of PVP can be seen in Fig. 4. A considerable solubilization was observed in the presence of SLS and PVP. The effective mechanism for solubilization by surfactants is the formation of micelles [36], however, solubilization effect in the low concentration of SLS (bCMC) has been reported for some chemical compounds [37]. Moreover, PVP as hydrophilic polymer also increases the solubility of chemical compounds because of the interaction with the drug by hydrogen bonds and complex formation [38,39]. 3.4. Developing analysis method for simultaneous quantification of TDF and MPB by UV-NASSAM The norm of NASs versus added concentrations of TDF in three-level concentrations of MPB is illustrated in Fig. 5. There is a good linear correlation between concentration and norm of NAS of TDF and various concentrations of MPB. NAS of TDF is not dependent on MPB concentration and its NAS value is constant in presence of different concentrations of TDF. Validation of the developed method was checked by three known concentrations of TDF (i.e., 3.5, 5.5, and 8.5 mg/L) in binary mixture with MPB. Table 1 presents the accuracy of the proposed NASSAM
Fig. 2. DSC patterns of TDF-MPB cocrystal.
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Fig. 4. Solubility of TDF (a) and MPB (b) in PBS (pH = 6.8, 0.1 M), PBS + SLS 0.2%, PBS + SLS 3%, PBS + 0. 5% PVP, PBS + 1% PVP and PBS + 2% PVP.
method for determination of TDF in nine synthetic mixtures (in the presence of various concentrations of MPB). The overall mean of percentage deviation was 5.2 ± 3.0%.
The concentration of MPB because of higher concentration compared with TDF was determined at 251 nm by UV–Vis spectrophotometry which TDF (after at least 200 fold dilution of solutions). As can be noticed, at this wavelength, TDF has no significant absorbance.
Table 1 Synthetic mixtures of TDF and MPB to evaluate accuracy and precision of the proposed NASSAM method.
Fig. 5. Norm of NASs for TDF and MPB versus added concentration of TDF in three level concentrations (10, 20, 30 mg/L) of MPB.
Sample number
TDF concentration (mg/L)
MPB concentration (mg/L)
Obtained concentration (mg/L)
% Deviation
1 2 3 4 5 6 7 8 9
3.50 5.50 8.50 3.50 5.50 8.50 3.50 5.50 8.50
10 10 10 20 20 20 30 30 30
3.87 5.75 8.86 3.52 5.97 8.12 3.26 5.36 8.12
10.6 4.5 4.2 0.6 8.5 −4.5 −6.9 −2.5 −4.5
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Table 2 Eutectic concentrations, Keu of TDF-MPB cocrystal in phosphate buffer solution (PBS, pH = 6.8, 0.1 M) and in presence of various concentrations of SLS and PVP. Medium
Eutectic concentration of TDF (mM) (mean ± SD)
Eutectic concentration of MPB (mM) (mean ± SD)
Keu
Thermodynamic solubility (mM) (mean ± SD)
PBS PBS + SLS 0.2% PBS + SLS 3% TDF-MPB (PVP 0.5%) TDF-MPB (PVP 1%) TDF-MPB (PVP 2%)
0.20 ± 0.02 0.12 ± 0.01 1.22 ± 0.17 0.47 ± 0.04 0.95 ± 0.15 1.52 ± 0.30
11.34 ± 0.68 4.71 ± 0.90 9.80 ± 1.35 0.32 ± 0.01 0.38 ± 0.03 0.14 ± 0.03
57.0 39.7 8.0 0.7 0.4 0.1
1.50 ± 0.11 0.75 ± 0.075 3.46 ± 0.481 0.39 ± 0.022 0.60 ± 0.062 0.47 ± 0.089
3.5. Thermodynamic solubility and solution stability of TDF-MPB in phosphate buffer solution (0.1 M, pH = 6.8) and in the presence of various concentrations of SLS and PVP Thermodynamic solubility is determined by adding an excess amount of solute to the certain volume of solvent. After appropriate equilibrium time, the saturated concentration of drug is quantified. However, because of the cocrystal instability in solution, and/or a slight excess of coformer in the structure of synthesized cocrystal, it is not appropriate to determine its thermodynamic solubility using the classical shake-flask method. Thermodynamic solubility of a cocrystal (e.g., TDFMPB) is dependent on the concentration of its components (TDF and MPB) in the solution phase. The cocrystal dissociates into their components; thus, thermodynamic solubility should be described by a solubility product [6]. The equilibrium for TDF-MPB cocrystal (1:1, based on the reported work by Weyna et al. [26]) is: TDF−MPB→TDF ðaqÞ þ MPBðaqÞ Therefore, the eutectic point of drug and coformer at the three-phase equilibrium (i.e., cocrystal, drug, and solution phase) was used to calculate thermodynamic solubility as follows: STDF−MPB ¼
qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi ½TDF eu ½MPBeu
Moreover, estimation of the cocrystal eutectic constant (Keu, the eutectic concentration of coformer/eutectic concentration of drug) would be used to evaluate the solution stability of cocrystals. The thermodynamic solubility of TDF-MPB in PBS are listed in Table 2. Thermodynamic solubility of TDF-MPB (1.50 mM) in PBS is higher than TDF (0.04 mM). These results are in agreement with previous reports that coformer solubility should be 10 or more times greater than that of the drug (37.5 in this case) to observe an improvement in solubility [7]. Ksp can be calculated by multiply eutectic concentrations of drug and coformer in nonionizable form, TDF (pKa = 0.85, very weak basic compound) and MPB (pKa = 8.5, acidic compound) are non-ionizable in the studied medium (pH~6 after equilibrium). Therefore, Ksp of TDF–MPB in non-ionizable form is 2.29 × 10−6. The Keu of TDF-MPB is 57, suggesting that it is an incongruently saturating cocrystal system that could transform to a less soluble solid during slurring and dissolution advantage is not possible for the prepared cocrystal [40,41]. Similar results have been reported for cocrystal of CBZ with nicotinamide (NIC). Although the reported thermodynamic solubility of CBZ-NIC is 152-folds more than CBZ [7], it is unstable in water and converts to dihydrate form of CBZ and the apparent solubility and dissolution of CBZ-NIC is the same with CBZ [42,43]. However, a cocrystal of CBZ with cinnamic acid (CIN), which its coformer is very low soluble than NIC, shows a significant increase in solubility and dissolution rate compared with CBZ because of acceptable solution stability, especially in water and acidic media [25,32].
Fig. 6. Solubility ratio of TDF-MPB cocrystal to TDF in PBS (pH = 6.8, 0.1 M), PBS + SLS 0.2%, PBS + SLS 3%, PBS + 0. 5% PVP, PBS + 1%PVP and PBS + 2% PVP.
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Surfactants and polymers such as SLS [44] and PVP [45] have shown a significant effect on solubility and solution stability of cocrystals. Table 2 shows eutectic concentrations, Keu of TDF-MPB cocrystal in PBS (pH = 6.8, 0.1 M) and in the presence of various concentrations of SLS and PVP. Keu is a crucial factor to evaluate the solution stability of cocrystal. Keu b 1, cocrystal is stable in solution and dissolution advantage is possible while Keu N 1 indicates it is unstable in solution and in the high value of Keu, dissolution advantage is not possible [40,41]. However, SLS and PVP could have a significant effect on Keu and conversion of incongruently to the congruent system. Two concentrations of SLS (0.2% and 3%) decrease the Keu value (39.7 and 8.0, respectively). However, they still are incongruently saturating cocrystal system. In comparison, different concentrations of PVP (0.5%, 1%, and 2%) have a considerable change in Keu value to 0.7, 0.4, and 0.1, respectively, and change it to congruently saturating cocrystal system; suggesting that stable cocrystal and dissolution advantage can be reached. Although the solution stability of TDF-MPB cocrystal in the presence of SLS and PVP significantly was improved, in most of the studied cases, the thermodynamic solubility was decreased and solubility advantage of cocrystal in comparison with TDF (Fig. 6) was not attained in the presence of SLS and PVP. As illustrated in Fig. 4, MPB is much more hydrophilic than TDF and, preferential solubilization for the drug in comparison with coformer is a well-known mechanism for this behavior [46]. 4. Conclusion Thermodynamic solubility of TDF in cocrystal form with MPB significantly increased. However, solution stability analysis of studied cocrystal showed that it is an incongruently saturating cocrystal system that could transform to a less soluble solid form during slurring and dissolution. Two applied compounds (i.e., SLS and PVP) can significantly increase both drug (i.e., TDF) and coformer (i.e., MPB) solubility. However, the solubility advantage for the prepared cocrystal is not obtained because of preferential solubilization for the drug by SLS and PVP that is less soluble than coformer. However, they considerably increased the solution stability of cocrystal. The findings of this study provide useful insight for understanding the solubility and solution stability and designing a new formulation for cocrystals in future studies. Acknowledgments This article is a part of the results of A.A's Pharm.D thesis No.4035 registered in the Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran. The authors would like to thank PXRD Lab Razi Applied Science Foundation, Tehran, Iran for providing PXRD patterns and Pharmaceutical Analysis Research Center, Tabriz University of Medical Sciences, Tabriz, Iran for financial support. References [1] R.G. Strickley, Solubilizing excipients in oral and injectable formulations, Pharm. Res. 21 (2004) 201–230. [2] D.D. Gadade, S.S. Pekamwar, Pharmaceutical cocrystals: regulatory and strategic aspects, design and development, Adv. Pharm. Bull. 6 (2016) 479–494. [3] S. Aitipamula, R. Banerjee, A.K. Bansal, K. Biradha, M.L. Cheney, A.R. Choudhury, G.R. Desiraju, A.G. Dikundwar, R. Dubey, N. Duggirala, P.P. Ghogale, S. Ghosh, P.K. Goswami, N.R. Goud, R.R.K.R. Jetti, P. Karpinski, P. Kaushik, D. Kumar, V. Kumar, B. Moulton, A. Mukherjee, G. Mukherjee, A.S. Myerson, V. Puri, A. Ramanan, T. Rajamannar, C.M. Reddy, N. Rodriguez-Hornedo, R.D. Rogers, T.N.G. Row, P. Sanphui, N. Shan, G. Shete, A. Singh, C.C. Sun, J.A. Swift, R. Thaimattam, T.S. Thakur, R. Kumar Thaper, S.P. Thomas, S. Tothadi, V.R. Vangala, N. Variankaval, P. Vishweshwar, D.R. Weyna, M.J. Zaworotko, Polymorphs, salts, and cocrystals: what's in a name? Cryst. Growth Des. 12 (2012) 2147–2152. [4] N.J. Babu, A. Nangia, Solubility advantage of amorphous drugs and pharmaceutical cocrystals, Cryst. Growth Des. 11 (2011) 2662–2679. [5] S. Emami, M. Siahi-Shadbad, K. Adibkia, M. Barzegar-Jalali, Recent advances in improving oral drug bioavailability by cocrystals, BioImpacts 8 (2018) 305–320. [6] R. Thakuria, A. Delori, W. Jones, M.P. Lipert, L. Roy, N. Rodríguez-Hornedo, Pharmaceutical cocrystals and poorly soluble drugs, Int. J. Pharm. 453 (2013) 101–125.
91
[7] D.J. Good, N. Rodríguez-Hornedo, Solubility advantage of pharmaceutical cocrystals, Cryst. Growth Des. 9 (2009) 2252–2264. [8] M.P. Lipert, L. Roy, S.L. Childs, N. Rodríguez-Hornedo, Cocrystal solubilization in biorelevant media and its prediction from drug solubilization, J. Pharm. Sci. 104 (2015) 4153–4163. [9] A. Alhalaweh, H.R.H. Ali, S.P. Velaga, Effects of polymer and surfactant on the dissolution and transformation profiles of cocrystals in aqueous media, Cryst. Growth Des. 14 (2014) 643–648. [10] G.B. Brock, C.G. McMahon, K.K. Chen, T. Costigan, W. Shen, V. Watkins, G. Anglin, S. Whitaker, Efficacy and safety of tadalafil for the treatment of erectile dysfunction: results of integrated analyses, J. Urol. 168 (2002) 1332–1336. [11] N. Galiè, B.H. Brundage, H.A. Ghofrani, R.J. Oudiz, G. Simonneau, Z. Safdar, S. Shapiro, R.J. White, M. Chan, A. Beardsworth, L. Frumkin, R.J. Barst, Tadalafil therapy for pulmonary arterial hypertension, Circulation 119 (2009) 2894–2903. [12] R.B. Egerdie, S. Auerbach, C.G. Roehrborn, P. Costa, M.S. Garza, A.L. Esler, D.G. Wong, R.J. Secrest, Tadalafil 2.5 or 5mg administered once daily for 12 weeks in men with both erectile dysfunction and signs and symptoms of benign prostatic hyperplasia: results of a randomized, placebo-controlled, double-blind study, J. Sex. Med. 9 (2012) 271–281. [13] J.D. Corbin, S.H. Francis, Pharmacology of phosphodiesterase-5 inhibitors, Int. J. Clin. Pract. 56 (2002) 453–459. [14] D.T. Manallack, R.A. Hughes, P.E. Thompson, The next generation of phosphodiesterase inhibitors: structural clues to ligand and substrate selectivity of phosphodiesterases, J. Med. Chem. 48 (2005) 3449–3462. [15] K. Wlodarski, W. Sawicki, K.J. Paluch, L. Tajber, M. Grembecka, L. Hawelek, Z. Wojnarowska, K. Grzybowska, E. Talik, M. Paluch, The influence of amorphization methods on the apparent solubility and dissolution rate of tadalafil, Eur. J. Pharm. Sci. 62 (2014) 132–140. [16] A.A.M. Abdel-Aziz, Y.A. Asiri, A.S. El-Azab, M.A. Al-Omar, T. Kunieda, Tadalafil, Profiles of Drug Substances, Excipients and Related Methodology, 2011 287–329. [17] S.M. Badr-Eldin, S.A. Elkheshen, M.M. Ghorab, Inclusion complexes of tadalafil with natural and chemically modified β-cyclodextrins. I: preparation and in-vitro evaluation, Eur. J. Pharm. Biopharm. 70 (2008) 819–827. [18] S.M. Badr-Eldin, S.A. Elkheshen, M.M. Ghorab, Improving tadalafil dissolution via surfactant-enriched tablets approach: statistical optimization, characterization, and pharmacokinetic assessment, J. Drug Deliv. Sci. Technol. 41 (2017) 197–205. [19] M. Lu, H. Xing, T. Yang, J. Yu, Z. Yang, Y. Sun, P. Ding, Dissolution enhancement of tadalafil by liquisolid technique, Pharm. Dev. Technol. 22 (2017) 77–89. [20] J.S. Choi, S.E. Lee, W.S. Jang, J.C. Byeon, J.S. Park, Tadalafil solid dispersion formulations based on PVP/VA S-630: improving oral bioavailability in rats, Eur. J. Pharm. Sci. 106 (2017) 152–158. [21] J.S. Choi, S.H. Kwon, S.E. Lee, W.S. Jang, J.C. Byeon, H.M. Jeong, J.S. Park, Use of acidifier and solubilizer in tadalafil solid dispersion to enhance the in vitro dissolution and oral bioavailability in rats, Int. J. Pharm. 526 (2017) 77–87. [22] K. Wlodarski, W. Sawicki, K. Haber, J. Knapik, Z. Wojnarowska, M. Paluch, P. Lepek, L. Hawelek, L. Tajber, Physicochemical properties of tadalafil solid dispersions - impact of polymer on the apparent solubility and dissolution rate of tadalafil, Eur. J. Pharm. Biopharm. 94 (2015) 106–115. [23] P.R. Vuddanda, M. Montenegro-Nicolini, J.O. Morales, S. Velaga, Effect of surfactants and drug load on physico-mechanical and dissolution properties of nanocrystalline tadalafil-loaded oral films, Eur. J. Pharm. Sci. 109 (2017) 372–380. [24] M. Ullah, I. Hussain, C.C. Sun, The development of carbamazepine-succinic acid cocrystal tablet formulations with improved in vitro and in vivo performance, Drug Dev. Ind. Pharm. 42 (2016) 969–976. [25] A. Shayanfar, K. Asadpour-Zeynali, A. Jouyban, Solubility and dissolution rate of a carbamazepine-cinnamic acid cocrystal, J. Mol. Liq. 187 (2013) 171–176. [26] D.R. Weyna, M.L. Cheney, N. Shan, M. Hanna, L. Wojtas, M.J. Zaworotko, Crystal engineering of multiple-component organic solids: pharmaceutical cocrystals of tadalafil with persistent hydrogen bonding motifs, Crystengcomm 14 (2012) 2377–2380. [27] M.G. Soni, I.G. Carabin, G.A. Burdock, Safety assessment of esters of phydroxybenzoic acid (parabens), Food Chem. Toxicol. 43 (2005) 985–1015. [28] M. Khan, V. Enkelmann, G. Brunklaus, Crystal engineering of pharmaceutical cocrystals: application of methyl paraben as molecular hook, J. Am. Chem. Soc. 132 (2010) 5254–5263. [29] B.G. Chaudhari, N.M. Patel, P.B. Shah, Stability indicating RP-HPLC method for simultaneous determination of atorvastatin and amlodipine from their combination drug products, Chem. Pharm. Bull. 55 (2007) 241–246. [30] N. Patel, V.K. Parmar, A sensitive high-performance thin layer chromatography method for simultaneous determination of salbutamol sulphate and beclomethasone dipropionate from inhalation product, Pharm. Sci. 24 (2018) 131–140. [31] K. Asadpour-Zeynali, M. Bastami, Net analyte signal standard addition method (NASSAM) as a novel spectrofluorimetric and spectrophotometric technique for simultaneous determination, application to assay of melatonin and pyridoxine, Spectrochim. Acta A Mol. Biomol. Spectrosc. 75 (2010) 589–597. [32] F. Keramatnia, A. Shayanfar, A. Jouyban, Thermodynamic solubility profile of carbamazepine-cinnamic acid cocrystal at different pH, J. Pharm. Sci. 104 (2015) 2559–2565. [33] G.M. El Maghraby, F.K. Alanazi, I.A. Alsarra, Transdermal delivery of tadalafil. I. Effect of vehicles on skin permeation, Drug Dev. Ind. Pharm. 35 (2009) 329–336. [34] S.H. Yalkowsky, Y. He, Handbook of Aqueous Solubility Data, CRC Press, Boca Raton, Fl, 2016. [35] J.P. Marcolongo, M. Mirenda, Thermodynamics of sodium dodecyl sulfate (SDS) micellization: an undergraduate laboratory experiment, J. Chem. Educ. 88 (2011) 629–633.
92
A. Alvani et al. / Journal of Molecular Liquids 281 (2019) 86–92
[36] C.D. Rangel-Yagui, A. Pessoa Jr., L.C. Tavares, Micellar solubilization of drugs, J. Pharm. Pharm. Sci. 8 (2005) 147–163. [37] M.N. Alizadeh, A. Shayanfar, A. Jouyban, Solubilization of drugs using sodium lauryl sulfate: experimental data and modeling, J. Mol. Liq. 268 (2018) 410–414. [38] H.A. Garekani, F. Sadeghi, A. Ghazi, Increasing the aqueous solubility of acetaminophen in the presence of polyvinylpyrrolidone and investigation of the mechanisms involved, Drug Dev. Ind. Pharm. 29 (2003) 173–179. [39] T. Loftsson, Drug solubilization by complexation, Int. J. Pharm. 531 (2017) 276–280. [40] A. Alhalaweh, A. Sokolowski, N. Rodríguez-Hornedo, S.P. Velaga, Solubility behavior and solution chemistry of indomethacin cocrystals in organic solvents, Cryst. Growth Des. 11 (2011) 3923–3929. [41] A. Alhalaweh, S.P. Velaga, Formation of cocrystals from stoichiometric solutions of incongruently saturating systems by spray drying, Cryst. Growth Des. 10 (2010) 3302–3305.
[42] A. Shayanfar, S. Velaga, A. Jouyban, Solubility of carbamazepine, nicotinamide and carbamazepine-nicotinamide cocrystal in ethanol-water mixtures, Fluid Phase Equilib. 363 (2014) 97–105. [43] Z. Rahman, C. Agarabi, A.S. Zidan, S.R. Khan, M.A. Khan, Physico-mechanical and stability evaluation of carbamazepine cocrystal with nicotinamide, AAPS PharmSciTech 12 (2011) 693–704. [44] N. Huang, N. Rodríguez-Hornedo, Effect of micellar solubilization on cocrystal solubility and stability, Cryst. Growth Des. 10 (2010) 2050–2053. [45] C. Wang, Q. Tong, X. Hou, S. Hu, J. Fang, C.C. Sun, Enhancing bioavailability of dihydromyricetin through inhibiting precipitation of soluble cocrystals by a crystallization inhibitor, Cryst. Growth Des. 16 (2016) 5030–5039. [46] M.P. Lipert, N. Rodríguez-Hornedo, Cocrystal transition points: role of cocrystal solubility, drug solubility, and solubilizing agents, Mol. Pharm. 12 (2015) 3535–3546.