Article pubs.acs.org/IECR
Exploring the Potential of Electrospray Technology in Cocrystal Synthesis Sharvil Patil,* Jui Kulkarni, and Kakasaheb Mahadik Department of Pharmaceutics, Bharati Vidyapeeth Deemed University, Poona College of Pharmacy, Erandwane, Pune−411 038, Maharashtra, India ABSTRACT: The objective of the current paper was to screen potential of electrospray technique for synthesis of cocrystals from a most challenging caffeine (CA)/maleic acid (MA) pair. Additionally, the influence of solvent properties on the formation of a cocrystal form was also investigated. CA and MA were dissolved in a sufficient amount of methanol, ethyl acetate, acetone, and water separately so as to obtain 1:1 and 2:1 equimolar ratios. The prepared solutions were electrosprayed at a voltage of 20 kV. The cocrystals formed from these solvents with diverse physicochemical properties were analyzed by X-ray diffraction, differential scanning calorimetry, and Fourier transform infrared spectroscopy. Methanol, acetone, ethyl acetate, and water have H-bond acceptor/ donor (HBA/HBD) values of ≥0.5, 0, 0, and ≥0.5, respectively. CA/MA in 1:1 form I and II were formed predominantly from methanol, ethyl acetate, and acetone regardless of the starting composition. It was observed that, in spite of having zero HBA/HBD value, ethyl acetate and acetone showed formation of 1:1 form I and II CA/MA cocrystals. Surprisingly, 2:1 cocrystals of CA/MA were formed from water. Thus, in the current work the potential of an electrospray technique for continuous manufacturing of cocrystals has been reported for the first time. for cocrystal synthesis.11 However, the applicability of liquid assisted grinding is limited due to issues such as solvent dependency, stoichiometric diversity, and lack of scalability. Additionally, use of ultrasound,12 spray drying,13 microwaves,7 and twin-screw extrusion14 have been recently proposed for cocrystal synthesis. However, twin-screw extrusion, a solvent free continuous cocrystallization (SFCC) technique is unsuitable for thermolabile drugs. In the present work synthesis of caffeine (CA) and maleic acid (MA) cocrystals (model molecules) has been attempted using an electrospray technique. The challenges associated with this cocrystal pair include the significant difference in solubilities of CA and MA and their ability to form cocrystals in 1:1 and 2:1 stoichiometric ratio. Additionally, it is put on the record that the solubility of CA increases in the presence of MA owing to complexation between them.10 Spontaneous formation of 2:1 along with 1:1 (form II) CA/MA cocrystals using solution crystallization was been reported for the first time by Leyssens et al. 2012.15 Further formation of CA hydrate and degradation of CA with melting are other issues which need attention with regard to the synthesis of CA/MA cocrystals. Thus, to summarize, stoichiometric diversity, polymorphism,
1. INTRODUCTION The nature of a drug whether amorphous or crystalline governs its inherent solubility and in turn bioavailability. Though the amorphous form of a drug has higher solubility when compared to its crystalline counterpart, the crystalline form is commercially preferred for dosage form development owing to its stability, reproducibility, and easier scale up than other forms of solid. It is well reported in the literature that around 40% of pharmaceutical drugs suffer from the drawback of poor solubility.1,2 Co-crystallization is one of the approaches currently being investigated for resolving this problem of poor solubility of some drugs. Pharmaceutical cocrystals are crystalline molecular complexes consisting of an active pharmaceutical ingredient (API) and a coformer both solids at room temperature.3 Hydrogen bonds, halogen bonds, and π−π interactions are responsible for cocrystal formation.4 Cocrystals have been reported to be effective for altering physicochemical properties such as solubility, dissolution rate, and stability of API.5 Various techniques have been explored by many research groups for synthesis of pure cocrystals.6−8 In the present work, the suitability of an electrospray technique for cocrystal synthesis has been evaluated. Conventionally, solution crystallization has been used for cocrystal synthesis. However, it does not work for noncongruent cocrystal pairs.9,10 Liquid assisted grinding, an environmentally friendly approach is another technique used © XXXX American Chemical Society
Received: May 20, 2016 Revised: July 4, 2016 Accepted: July 7, 2016
A
DOI: 10.1021/acs.iecr.6b01938 Ind. Eng. Chem. Res. XXXX, XXX, XXX−XXX
Article
Industrial & Engineering Chemistry Research
with a voltage of 40 kV and a current of 40 mA. Samples were scanned from 5° to 20° at 2θ. 2.3.2. Differential scanning calorimetry (DSC). Differential scanning calorimetry (DSC) thermograms of CA, MA, MCA/ MA, ECA/MA, ACA/MA, and WCA/MA (1:1 and 1:2 ratios) were obtained using DSC 821e (Mettler-Toledo, Greifensee, Switzerland). Indium standards were used to calibrate the temperature and enthalpy scale. Samples (5−10 mg) were heated in hermetically sealed aluminum pan with a heating rate of 10 °C/min over a range of 25−270 °C under a nitrogen atmosphere (flow rate 50 mL/min).19 2.3.3. Fourier transform infrared spectroscopy (FTIR). KBR discs were prepared containing about 2−3 mg of CA, MA, MCA/MA, ECA/MA, ACA/MA, and WCA/MA (1:1 and 1:2 ratios) separately. IR spectra were recorded from 4000 to 400 cm−1 with a Fourier transform infrared spectrometer (FTIR8400; Shimadzu Corporation, Kyoto, Japan) equipped with a diffuse reflectance accessory (DRS-8000; Shimadzu Corporation, Japan).20
complexation between CA and MA, and solvent are the challenges posed by this pair. Electrospray involves dispersing a liquid into droplets or ions by overcoming surface tension forces of solvent with electrical forces. Droplets or ions are emitted from the tip of a Taylor cone, which is the equilibrium shape of a free liquid surface at the end of a capillary electrode in a sufficiently high electric field. The Taylor cone propagates into cone-jet which transforms into a mist of ultrafine charged solution droplets. Additionally, high-energy vibrations are observed in a Taylor cone.16,17 The technique has been successfully used to alter the physicochemical properties of active pharmaceutical ingredients (APIs). Submicron sized niflumic acid and carbamazepine nanocrystals with significant improvement in solubility and dissolution rate have been prepared using electrospray technique.16,18 It is believed that high-energy vibrations of Taylor cone and faster evaporation of solvent during electrospray might prove beneficial in cocrystal synthesis as the rate of crystal nucleation and growth is increased enormously. Moreover the electrospray technique can also be used in a continuous manner as a single step process.18 Thus, the objective of the current work was to screen an electrospray technique for cocrystal synthesis of the most challenging CA/MA pair. Further, to assess the effect of polarity and surface tension of methanol, acetone, ethyl acetate, and distilled water on cocrystal synthesis by the electrospray technique.
3. RESULTS In the present work, the suitability of the electrospray technique for cocrystal synthesis was evaluated. The CA and MA pair was used as a model cocrystal pair being well reported in the literature. Additionally, the pair is noncongruent, i.e., having high difference in the solubility of both the components. Surface tension reduces the surface area of a solution droplet at the end of capillary (tip of needle). This reduction in surface area of droplet is responsible for conversion of solution jet into very fine droplets leading to spraying of the solution. It is independent of solution concentration. The electrospraying occurs at reduced electric field when the surface tension is lower.21,22 Thus, surface tension of solvents plays a key role in the formation of mist and subsequent evaporation of solvent. Surface tensions of solvents alone and containing CA/MA in 1:1 and 2:1 ratios were determined (Table 1). Surface tensions of all the solvents were altered upon addition of CA/MA. The electrospray technique involves variables such as nozzle diameter, distance between nozzle tip and grounded collector,
2. MATERIALS AND METHODS 2.1. Materials. Caffeine (CA, 99% purity) and maleic acid (MA, 99% purity) were purchased from Sigma-Aldrich Corporation (St. Louis, MO, USA). Methanol, acetone, and ethyl acetate were purchased from Merck (Darmstadt, Germany). 2.2. Methods. 2.2.1. Preparation of CA/MA Solutions. CA and MA were dissolved in methanol (10 mL), acetone (12 mL), ethyl acetate (10 mL), and distilled water (10 mL) separately in equimolar ratios of 1:1 (194 mg CA and 116 mg MA) and 2:1 (388 mg CA and 116 mg MA). The solutions were heated at 50 °C in a water bath to dissolve the components and obtain a clear solution. 2.2.2. Determination of Surface Tension. Surface tension of solvents alone and the prepared solutions (5 μL each) containing CA and MA in different molar ratios was measured using electrowetting-based microliter drop tensiometer instrument (India). SCA 20 software was used for analyzing the data. 2.2.3. Electrospray Process. The prepared solutions of CA/ MA were electrosprayed using E-spin nano (PECO-Chennai, India) equipment. The conditions maintained for electrospraying are as follows: syringe type 10 mL, flow rate 2 mL/h, voltage 20 kV, collector plate and needle, tip to collector distance 25 cm. The electrospray process was carried out in the presence of IR lamp to raise temperature of cabinet when water was used as a solvent for cocrystallization of CA/MA. The cocrystals formed upon electrospraying of solutions containing CA/MA in different molar ratios in methanol, ethyl acetate, acetone, and distilled water are abbreviated as MCA/MA, ECA/MA, ACA/MA, and WCA/MA respectively. 2.3. Characterization. 2.3.1. Powder X-ray Diffraction (PXRD). Powder X-ray diffraction (PXRD) patterns for CA, MA, MCA/MA, ECA/MA, ACA/MA, and WCA/MA (1:1 and 1:2 ratio) were recorded using X-ray diffractometer (PW 1729; Philips, Almelo, Netherlands) using Cu Kα radiation (1.542 A)
Table 1. Surface Tension of Pure Solvent and CA/MA Solutionsa sr no. 1 2 3 4 5 6 7 8 9 10 11 12 a
B
solvent/solution methanol methanol (CA/MA 1:1) methanol (CA/MA 2:1) acetone acetone (CA/MA 1:1) acetone (CA/MA 2:1) ethyl acetate ethyl acetate (CA/ MA 1:1) ethyl acetate (CA/ MA 2:1) water water (CA/MA 1:1) water (CA/MA 2:1)
abbreviations
surface tension (N/m)
dielectric constant
0.023 ± 0.51 0.022 ± 0.42
32.7
MCA/MA1:1 MCA/MA2:1
0.023 ± 0.31
ACA/MA1:1
0.023 ± 0.28 0.023 ± 0.12
ACA/MA2:1
0.022 ± 0.34
ECA/MA1:1
0.033 ± 0.46 0.023 ± 0.25
ECA/MA2:1
0.023 ± 0.36
WCA/MA1:1 WCA/MA2:1
0.072 ± 0.37 0.068 ± 0.51 0.068 ± 0.61
20.7
6.02
80
Mean ± SD, n = 3. DOI: 10.1021/acs.iecr.6b01938 Ind. Eng. Chem. Res. XXXX, XXX, XXX−XXX
Article
Industrial & Engineering Chemistry Research flow rate, the potential difference, and solution properties like surface tension.23−25 In the preliminary studies, electrospraying of aqueous solutions of CA/MA (1:1 and 2:1 ratio) was attempted at different voltages. However, below 20 kV, water did not form cone-jet and in turn a mist. In the present work, water had highest surface tension which required voltage of 20 kV in order to form mist when the distance between needle tip and plate collector was 25 cm. Since, the objective of the present work was to determine the effect of solvent on cocrystal formation under the influence of electric charge, the optimized conditions for electrospraying consisted of 20 kV voltage and distance between needle tip and collector of 25 cm with a needle aperture of 23G (0.6 mm). 3.1. Powder X-ray Diffraction (PXRD). PXRD pattern of CA showed characteristic peak of 2θ at 12° whereas PXRD pattern of MA showed characteristic peaks at 16.78° and 17.6° revealing their purity and existence in crystalline form.7,10,12,15 The literature reports, three cocrystal forms of CA/MA which includes 1:1 form I, 1:1 form II and 2:1 cocrystal.7,10,12,15 CA/ MA (1:1 form I) shows characteristic PXRD peaks at 9.2°, 11.3°, 13.5°, 14.7°, 15.5° 2θ, whereas CA/MA (1:1 form II) shows PXRD peaks at 7.5°, 13.5°, 15.3° 2θ (Figure 1).
Table 2. Cocrystalline Forms of CA/MA Formed from Solvents with Different Polarity solvent methanol CA/MA (1:1, 2:1) acetone CA/MA (1:1, 2:1) ethyl acetate CA/MA (1:1, 2:1) water CA/MA (1:1) water CA/MA (2:1)
cocrystal form 1:1 1:1 1:1 2:1 1:1
form II form I and form II form I and form II form II and 2:1
respectively revealing formation of 1:1 form II of CA/MA cocrystals from both the ratios (Figure 2). The results were in accordance with the results of PXRD study.
Figure 2. DSC thermograms of electrosprayed CA/MA cocrystals in ratios of 1:1 and 2:1 formed from (a and b) methanol, (c and d) acetone, (e and f) ethyl acetate, and (g and h) water. Figure 1. PXRD pattern of (a) caffeine, (b) maleic acid along with electrosprayed CA/MA cocrystals in ratio of 1:1 and 2:1 formed from (c and d) methanol, (e and f) acetone, (g and h) ethyl acetate, (i and j) and water.
DSC thermogram of ACA/MA1:1 showed melting endotherms at 100.68 and 108.34 °C whereas that of ACA/MA2:1 showed two melting endotherms first at 96.51 °C while the second at 108.56 °C. Thus, the results of DSC analysis were in accordance with the PXRD study confirming formation of both 1:1 form I and form II CA/MA cocrystals. Similarly, DSC thermograms of ECA/MA (1:1 and 2:1 ratios) indicated formation of mixture of 1:1 form I and form II CA/MA cocrystals. Surprisingly, DSC thermograms of WCA/MA1:1 and WCA/ MA2:1 showed melting at 118.53 and 101.90 °C respectively. Electrospraying of WCA/MA1:1 resulted in formation of 2:1 cocrystal whereas mixture of 1:1 form II and 2:1 was obtained upon electrospraying of WCA/MA2:1. Additionally, CA/MA (2:1) showed very small endotherms for unreacted MA and CA for all the tested solvents indicating their presence in traces. 3.3. Fourier Transform Infrared (FTIR) Spectroscopy. The formation of neutral O−H···N hydrogen bond between an acid and a base during cocrystal formation can be detected using infrared spectroscopy. The FTIR spectra of a neutral
Additionally, PXRD peaks observed at 8.9°, 10.3°, 13.7° and 16.1°2θ indicated formation of CA/MA (2:1 form). The analysis of PXRD patterns of MCA/MA, ECA/MA, ACA/MA, and WCA/MA (1:1 and 1:2 ratios) showed formation of cocrystals in different forms which are depicted in Table 2. DSC analysis was performed to confirm the observations of PXRD. 3.2. Differential Scanning Calorimetry (DSC). DSC thermograms for CA and MA showed sharp, characteristic melting endothermic peaks at 235.98 and 141.57 °C, respectively. It has been well reported in the literature that CA/MA 1:1 form I, 1:1 form II, and 2:1 cocrystal show melting endotherm at 105, 99, and 119 °C respectively.7,10,12,15 DSC thermograms of MCA/MA1:1 and MCA/MA2:1 cocrystals showed melting endotherm at 97.65 and 97.13 °C C
DOI: 10.1021/acs.iecr.6b01938 Ind. Eng. Chem. Res. XXXX, XXX, XXX−XXX
Article
Industrial & Engineering Chemistry Research
integrates into the crystal lattice during the step of nucleation and crystal growth. On the other hand, the solvent molecules adsorbed on the growing crystal surface must be replaced by the incoming solute molecules so as to get integrated into the crystal lattice. Both aspects can be evaluated through the solvent−solute interaction, which involves van der Waals force and hydrogen bonding. However, in the present study CA/MA cocrystals (1:1 form II) were formed from all the solvents even though they had different HBA/HBD values. Additionally, it can be observed that the solvents having surface tension below 35 dyn/cm generated 1:1 form II CA/MA cocrystals; however, 2:1 CA/MA cocrystal were formed from water. It is known that generating cocrystals from solvent is governed by a complex interplay between solvent and rate of supersaturation. For CA/MA pair this process is further complicated as MA increases solubility of CA to a different extent depending on solvent. The solubility profile for both CA and MA in all the four solvents is reported by Pagire et al. (Table 3).7 Additionally, it has been reported that the solubility
carboxylic acid and a carboxylate anion show remarkable differences. A strong CO stretching band around 1700 cm−1 along with a weak band for C−O stretch around 1200 cm−1 is observed for a neutral carboxylate (−COOH) whereas a single C−O stretch band in the region of 1000−1400 cm−1 is displayed by a carboxylate anion (−COO−). Moreover, two broad bands around 2450 and 1950 cm−1 are observed upon formation of a neutral intermolecular O−H···N hydrogen bond between the components.26 CA showed characteristic peaks at 1659 (CO stretch), 1240, and 1359 cm−1 (C−N stretch), and the characteristic peaks for MA were observed at 1645 (CO stretch) and 3600−3000 cm−1 (−OH stretch) (Figure 3). The electro-
Table 3. Solubility of Caffeine and Maleic Acid in Different Solvents7 solubility (25 °c)
methanol (mol/L)
acetone (mol/L)
ethyl acetate (mol/L)
water (mol/L)
caffeine maleic acid
0.0804 6.284
0.0866 2.439
0.0541 0.315
0.101 7.431
of CA increases by 10-fold in water and methanol whereas around 3.5 fold in case of acetone and ethyl acetate in the presence of MA which is attributed to the complexation of between the two components.7,10 In the present work CA/MA were crystallized in 1:1 ratio which is challenging task. Additionally, it has been reported that unreacted CA and 1:1 cocrystal phase are the end products of liquid assisted grinding of CA/MA in the presence of methanol irrespective of starting composition resulting in impure cocrystal phase.11 Further it has been put on the record that the 2:1 cocrystal phase of CA/ MA is metastable and can be obtained only at high supersaturation and thus cannot be generated using conventional solvent crystallization.10,15 In the case of electrospraying during coulomb fission, high positive charge is induced on the droplet before it forms a mist which involves high frequency vibrations. Coulomb fission takes place only when the surface tension forces of solvent are overcome by the electrical forces. It is believed that during electrospray cocrystallization process simultaneous nucleation of CA and MA takes place in the Taylor cone owing to high frequency vibrations and rapid evaporation of solvent when it is pulled toward the negatively charged collector. Additionally, if the volatility of solvent is low further growth of crystals may take place in the droplets of solvents which evaporate before reaching the collector plate. The polarity (dielectric constant) of methanol, ethyl acetate and acetone is remarkably lower than water whereas their volatility is high as compared to water. Ethyl acetate and acetone are aprotic polar solvents lacking acidic hydrogen and thus cannot act as hydrogen bond donors. However, water and methanol are protic polar solvents having ability to act as hydrogen bond donors. Thus, ethyl acetate and acetone did not interfere with the hydrogen bonding between CA and MA leading to formation of 1:1 cocrystals. In spite of having ability to act as hydrogen bond donor, methanol yielded 1:1 cocrystals whereas water being highly polar formed 2:1
Figure 3. FTIR spectrum of (A) caffeine, (B) maleic acid, and (C) CA/MA cocrystal (representative).
sprayed samples (MCA/MA, ECA/MA, ACA/MA, and WCA/ MA) showed peaks at 1709, 1675, and 3057 cm−1 in CA/MA 1:1 molar ratio and 1711, 1677, 3055, 3141 cm−1 at 2:1 molar ratio. Additionally, FTIR spectra showed bands at 2363 and 1886 cm−1 confirming formation of intermolecular O−H···N hydrogen bond between CA and MA. The results of FTIR studies were in accordance with PXRD and DSC studies. Thus, to summarize, electrospraying of CA/MA solutions having diversity in polarity generated CA/MA cocrystals in different forms. It was observed that all the solvents irrespective of their polarity and dielectric constant showed formation of 1:1 form of cocrystals when results of DSC and PXRD were observed together (Table 2) except WCA/MA1:1.
4. DISCUSSION In the present work, an electrospray technique was screened for its suitability toward cocrystal synthesis. Cocrystals were generated from solvents with diverse physicochemical properties. It is put on the record that the hydrogen bond propensity of the solvent governs the nucleation of molecule. Methanol, acetone, ethyl acetate, and water have H-bond acceptor/donor (HBA/HBD) values of ≥0.5, 0, 0, and ≥0.5, respectively.27 It can be observed that in spite of having zero HBA/HBD value, 1:1 form I and form II of CA/MA cocrystals were formed from ethyl acetate and acetone. It is stated that crystal nucleation and growth rate can be affected by the solvent in two ways.28 On one hand, the solvated solute molecules must get desolvated when it D
DOI: 10.1021/acs.iecr.6b01938 Ind. Eng. Chem. Res. XXXX, XXX, XXX−XXX
Article
Industrial & Engineering Chemistry Research
Maleic acid Cocrystals: the role of the Dielectric and Physicochemical properties of the solvent. CrystEngComm 2013, 15, 3705. (8) Schultheiss, N.; Newman, A. Pharmaceutical Cocrystals and their Physicochemical Properties. Cryst. Growth Des. 2009, 9, 2950. (9) Frišcǐ ć, T. Supramolecular concepts and new techniques in mechanochemistry: cocrystals, cages, rotaxanes, open metal-organic frameworks. Chem. Soc. Rev. 2012, 41 (9), 3493. (10) Guo, K.; Sadiq, G.; Seaton, C.; Davey, R.; Yin, Q. CoCrystallization in the Caffeine/Maleic Acid System: Lessons from Phase Equilibria. Cryst. Growth Des. 2010, 10, 268. (11) Trask, A.; Motherwell, W.; Jones, W. Pharmaceutical Cocrystallization: Engineering a Remedy for Caffeine Hydration. Cryst. Growth Des. 2005, 5, 1013. (12) Aher, S.; Dhumal, R.; Mahadik, K.; Paradkar, A.; York, P. Ultrasound assisted cocrystallization from solution (USSC) containing a non-congruently soluble cocrystal component pair: Caffeine/Maleic acid. Eur. J. Pharm. Sci. 2010, 41, 597. (13) Patil, S.; Modi, S.; Bansal, A. Generation of 1:1 Carbamazepine:Nicotinamide cocrystals by spray drying. Eur. J. Pharm. Sci. 2014, 62, 251. (14) Kelly, A.; Gough, T.; Dhumal, R.; Halsey, S.; Paradkar, A. Monitoring ibuprofen−nicotinamide cocrystal formation during Solvent Free Continuous Cocrystallization (SFCC) using near infrared spectroscopy as a PAT tool. Int. J. Pharm. 2012, 426, 15. (15) Leyssens, T.; Springuel, G.; Montis, R.; Candoni, N.; Veesler, S. Importance of solvent selection for stoichiometrically diverse cocrystal systems: Caffeine/Maleic acid 1:1 and 2:1 cocrystals. Cryst. Growth Des. 2012, 12 (3), 1520. (16) Radacsi, N.; Ambrus, R.; Szunyogh, T.; Szabó-Révész, P.; Stankiewicz, A.; van der Heijden, A.; ter Horst, J. Electrospray crystallization for nanosized Pharmaceuticals with improved properties. Cryst. Growth Des. 2012, 12, 3514. (17) Rulison, A.; Flagan, R. Scale-up of Electrospray atomization using linear arrays of Taylor cones. Rev. Sci. Instrum. 1993, 64 (3), 683. (18) Wang, M.; Rutledge, G.; Myerson, A.; Trout, B. Production and Characterization of Carbamazepine Nanocrystals by Electrospraying for Continuous Pharmaceutical Manufacturing. J. Pharm. Sci. 2012, 101 (3), 1178. (19) Patil, S.; Mahadik, K.; Paradkar, A. Liquid Crystalline Phase as a Probe for Crystal Engineering of Lactose: Carrier for Pulmonary Drug Delivery. Eur. J. Pharm. Sci. 2015, 68, 43. (20) Patil, S.; Choudhary, B.; Rathore, A.; Roy, K.; Mahadik, K. Enhanced oral bioavailability and anticancer activity of novel curcumin loaded mixed micelles in human lung cancer cells. Phytomedicine 2015, 22 (12), 1103. (21) Haghi, A.; Akbari, M. Trends in Electrospinning of natural nanofibers. Phys. Status Solidi A 2007, 204, 1830. (22) Li, Z.; Wang, C. Effects of working parameters on Electrospinning. One-Dimensional Nanostructures, Part of the series. SpringerBriefs in Materials 2013, 15. (23) Leach, M.; Feng, Z.; Tuck, S.; Corey, J. Electrospinning fundamentals: optimizing solution and apparatus parameters. J. Visualized Exp. 2011, 21 (47), 2494. (24) Shin, Y.; Hohman, M.; Brenner, M.; Rutledge, G. Experimental characterization of Electrospinning: the electrically forced jet and instabilities. Polymer 2001, 42, 9955. (25) Yarin, A.; Koombhongse, S.; Reneker, D. Taylor cone and jetting from liquid droplets in Electrospinning of nanofibers. J. Appl. Phys. 2001, 90, 4836. (26) Aakeröy, C.; Salmon, D.; Smith, M.; Desper, J. Cyanophenyloximes: Reliable and Versatile Tools for Hydrogen-Bond Directed Supramolecular Synthesis of Cocrystals. Cryst. Growth Des. 2006, 6 (4), 1033. (27) Du, W.; Yin, Q.; Gong, J.; Bao, Y.; Zhang, X.; Sun, X.; Ding, S.; Xie, C.; Zhang, M.; Hao, H. Effects of solvent on Polymorph formation and Nucleation of prasugrel hydrochloride. Cryst. Growth Des. 2014, 14, 4519.
cocrystals predominantly. It is believed that volatility of solvent played a vital role in cocrystal formation. During the electrospray process, simultaneous nucleation of CA and MA might have taken place at a faster rate due to rapid evaporation of solvent (ethyl acetate, methanol, and acetone) leading formation of 1:1 cocrystals predominantly. Further as stated previously, 2:1 cocrystal phase is metastable and difficult to obtain from solutions of methanol, ethyl acetate, and acetone. Surprisingly, CA/MA was formed in a 2:1 cocrystal phase from water. The polarity of water being highest among all the tested solvents might have induced a charge to a greater extent disturbing its dipole. Such disruption of a dipole in water might have changed the orientation of solubilized CA and MA. The CA molecule has two CO groups whereas MA has two C O along with −OH groups. Thus, MA might have remained associated with water to a greater extent through hydrogen bonding and electrostatic interaction than CA molecules leading to formation of 2:1 cocrystals.26,29,30 Yet another reason for generation of 2:1 cocrystals from water could be water’s highly polar nature. It may have been pulled toward the collector plate to a greater extent providing time for nucleation and orientation of CA and MA molecules due to the fact that it has very low volatility.
5. CONCLUSION In the present work caffeine/maleic acid cocrystals were successfully prepared using an electrospray technique. Additionally, CA/MA was cocrystallized as 1:1 form I along with 2:1 cocrystal phase using this technique which has been reported to be the most challenging task. Besides generally using cocrystal synthesis techniques, a single step electrospray technique for continuous manufacturing of cocrystals can serve as an alternative for synthesis of challenging cocrystal pairs. However, the detailed mechanisms of cocrystal synthesis using electrospray technology need further investigation.
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
■
REFERENCES
(1) Arenas-Garcia, J.; Herrera-Ruiz, D.; Mondragon-Vasquez, K.; Morales-Rojas, H.; Hopfl, H. Co-Crystals of Active Pharmaceutical Ingredients − Acetazolamide. Cryst. Growth Des. 2010, 10, 3732. (2) Sarraguça, M.; Ribeiro, P.; Santos, A.; Silva, M.; Lopes, J. A PAT approach for the on-line monitoring of Pharmaceutical Co-Crystals formation with near infrared spectroscopy. Int. J. Pharm. 2014, 471, 478. (3) Food and Drug Administration. Guidance for Industry on Regulatory Classification of Pharmaceutical Co-Crystals Docket No. FDA-2011-D-0800. Federal Register 2013; Vol. 78 (81), p 24754. (4) Qiao, N.; Li, M.; Schlindwein, W.; Malek, N.; Davies, A.; Trappitt, G. Pharmaceutical Cocrystals: An overview. Int. J. Pharm. 2011, 419 (1−2), 1. (5) Brittain, H. Vibrational Spectroscopic Studies of Cocrystals and Salts. 4. Cocrystal Products formed by Benzylamine, α-Methylbenzylamine, and their Chloride Salts. Cryst. Growth Des. 2011, 11 (6), 2500. (6) Jones, W.; Motherwell, W.; Trask, A. Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement. MRS Bull. 2006, 31, 875. (7) Pagire, S.; Korde, S.; Ambardekar, R.; Deshmukh, S.; Dash, R.; Dhumal, R.; Paradkar, A. Microwave assisted synthesis of Caffeine/ E
DOI: 10.1021/acs.iecr.6b01938 Ind. Eng. Chem. Res. XXXX, XXX, XXX−XXX
Article
Industrial & Engineering Chemistry Research (28) Gu, C.; Young, V.; Grant, D. Polymorph screening: influence of solvents on the rate of solvent-mediated polymorphic transformation. J. Pharm. Sci. 2001, 90 (11), 1878. (29) Kelly, R.; Rodríguez-Hornedo, N. Solvent effects on the crystallization and preferential nucleation of Carbamazepine anhydrous polymorphs: a molecular recognition perspective. Org. Process Res. Dev. 2009, 13, 1291. (30) Jing, D.; Liu, A.; Wang, J.; Xia, H. Study on Crystal Morphology of Penicillin Sulfoxide in Different Solvents using Binding Energy. Org. Process Res. Dev. 2015, 19 (3), 410.
F
DOI: 10.1021/acs.iecr.6b01938 Ind. Eng. Chem. Res. XXXX, XXX, XXX−XXX
