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Screening and characterization of cocrystal formation between betulin and terephthalic acid
Materials Today: Proceedings xxx (xxxx) xxx
Contents lists available at ScienceDirect
Materials Today: Proceedings journal homepage: www.elsevier.com/locate/matpr
Screening and characterization of cocrystal formation between betulin and terephthalic acid Anastasiya V. Mikhailovskaya a,b, Svetlana A. Myz a, Natalia V. Bulina a,b, Konstantin B. Gerasimov a, Svetlana A. Kuznetsova c,d, Tatyana P. Shakhtshneider a,b,⇑ a
Institute of Solid State Chemistry and Mechanochemistry SB RAS, Kutateladze str., 18, Novosibirsk 630128, Russia Novosibirsk State University, Pirogov str., 2, Novosibirsk 630090, Russia Institute of Chemistry and Chemical Technology, FRC KSC SB RAS, Academgorodok, 50/24, Krasnoyarsk 660036, Russia d Siberian Federal University, Svobodny pr., 79/10, Krasnoyarsk 660041, Russia b c
a r t i c l e
i n f o
Article history: Received 18 November 2019 Received in revised form 9 December 2019 Accepted 12 December 2019 Available online xxxx Keywords: Betulin Terephthalic acid Co-grinding Cocrystal Solubility
a b s t r a c t The pharmaceutical cocrystals are nowdays intensively studied due to the improvements of solubility, stability, processability, etc. of the drugs. In this work, the cocrystals of betulin with terephthalic acid as a coformer were prepared by liquid-assisted grinding method. The formation of cocrystals was confirmed by powder X-ray diffraction, IR spectroscopy and thermal analysis methods. HPLC analysis showed that in the case of betulin – terephthalic acid cocrystals, solubility of betulin was significantly improved compared to the initial betulin as well as betulin from cocrystals with aliphatic dicarboxylic acids which were earlier prepared. Ó 2019 Elsevier Ltd. All rights reserved. Selection and peer-review under responsibility of the scientific committee of the III All-Russian Conference (with International Participation) Hot Topics of Solid State Chemistry: From New Ideas to New Materials.
1. Introduction Preparation of cocrystals, i.e. multi-component materials of the active pharmaceutical ingredient (API) with non-toxic partner molecules have attracted interest in pharmaceutical industry as a strategy for altering the physical–chemical properties of the API such as enhancement of solubility, increasing stability to hydration, improving compaction behavior, etc. [1,2]. Betulin, lup-20(29)-ene-3b,28-diol, extracted from birch bark, exhibits various types of pharmacological activity, including antiviral, anti-bacterial, anti-inflammatory, anti-HIV or anti-cancer effects [3,4]. The major problem to develop the dosage forms, is the low solubility of betulin in aqueous medium that clearly reduces its bioavailability. Several strategies have been applied to improve the solubility and/or dissolution rate of betulin and its derivatives such as preparation of solid dispersions with watersoluble polymers [5], liposomes [6], cyclodextrin derivatives [7], entrapment in nanosystems [8].
⇑ Corresponding author at: Institute of Solid State Chemistry and Mechanochemistry SB RAS, Kutateladze str., 18, Novosibirsk 630128, Russia. E-mail address: [email protected] (T.P. Shakhtshneider).
In our previous work [9], the cocrystals of betulin with aliphatic dicarboxylic acids, adipic and suberic, were obtained by liquidassisted grinding (LAG) method [10]. At the same time, the grinding of betulin – succinic acid mixture did not yield a new crystalline material. The purpose of this research was to prepare cocrystals of betulin with terephthalic acid. Fig. 1 presents the structural formulas of both betulin and terephthalic acid. The aromatic terephthalic acid was selected to analyze the fundamental opportunity for betulin to generate cocrystals with various coformers. The formation of betulin cocrystals was investigated using powder X-ray diffraction, IR spectroscopy, and thermal analysis methods.
2. Experimental Betulin (BE) was isolated from birch bark according to the developed method [11]. BE was purified by recrystallization from ethanol. Terephthalic acid (TA) (Sigma-Aldrich, USA) was of analytical grade and was used as received. In order to prepare cocrystals, betulin-terephthalic acid (BE-TA) mixtures with different molar ratios (1:1, 2:1) were ground in an agate mortar or in a SPEX 8000 mixer mill (CertiPrep Inc., USA).
https://doi.org/10.1016/j.matpr.2019.12.096 2214-7853/Ó 2019 Elsevier Ltd. All rights reserved. Selection and peer-review under responsibility of the scientific committee of the III All-Russian Conference (with International Participation) Hot Topics of Solid State Chemistry: From New Ideas to New Materials.
Please cite this article as: A. V. Mikhailovskaya, S. A. Myz, N. V. Bulina et al., Screening and characterization of cocrystal formation between betulin and terephthalic acid, Materials Today: Proceedings, https://doi.org/10.1016/j.matpr.2019.12.096
2
A.V. Mikhailovskaya et al. / Materials Today: Proceedings xxx (xxxx) xxx
Fig. 1. Molecular structures of betulin (a) and terephthalic acid (b).
The physical mixtures were homogeneously mixed in the agate mortar for 5 min followed by the addition of 1 mL of a solvent and subsequent grinding. In the case of SPEX 8000 mixer mill, ball-milling was performed in a 60 mL steel jar with the balls of the same material and 6 mm in diameter. Ratio of mass of sample to mass of balls was 1:15. The mixtures had been pre-milled in dryness for 5 min; afterwards, 1 mL of a solvent was added and the paste was subsequently milled for 10 min. The solvents of different polarity, namely, isopropanol, acetone, dioxan, were used for screening of cocrystal formation. Powder X-ray diffraction (PXRD) analysis was carried out on a D8-Advance diffractometer (Bruker, Germany) with an onedimensional detector (Lynx Eye type), CuKa-radiation, 2h = 5-70°. Attenuated total reflectance (ATR) IR spectra were recorded without any special sample preparation in the 580–4000 cm 1 spectral range using a Digilab Excalibur 3100 FT-IR spectrometer (USA) and a Pike Miracle ATR attachment with ZnSe crystal. Thermogravimetry (TG) and mass spectrometry studies were performed using a STA 449 F1 Jupiter (Netzsch, Germany) simultaneous thermal analysis system in combination with a QMS 403C Aeolos quadrupole mass spectrometer. The measurements were carried out in flowing 99.990%-pure argon at a volumetric flow rate of 50 mL/min. A weighed sample (30–50 mg) was placed in a cell, which was then pumped down to 1 Pa by a roughing pump. Next, argon was passed through the cell. The heating rate was 10 °C/min. Calorimetric measurements (DSC) were performed using a DSC 200 F3 MAIA (Netzsch, Germany) heat flux calorimeter. About 5 mg of a solid sample was placed in 40 lL closed aluminum cap, scanned from 25 to 250 °C under argon atmosphere at a heating rate of 6 °C/min. The same procedure as in [9] was used to study dissolution behaviour of the obtained samples. High-performance liquid chromatography (HPLC) method was used to determine betulin concentration in the solutions.
3. Results and discussion Screening experiments, performed in the agate mortar, showed that in the case of 1:1 BE-TA mixture, some new reflections appeared in the PXRD pattern after grinding; nevertheless, those of initial acid were rather large (date not shown). Probably, the higher amount of betulin is required to obtain a neat product. Fig. 2a demonstrates PXRD patterns for 2:1 BE-TA mixtures ground in the SPEX mixer mill using different solvents. It can be seen that after grinding BE-TA mixtures, several reflections of the starting materials disappeared, as several new reflections appeared suggesting the formation of a BE-TA cocrystal. The effect was observed when we used acetone or isopropanol as a solvent. The changes in the IR spectra of the BE-TA mixtures ground with the addition of acetone or isopropanol proved cocrystal formation. As can be seen from Fig. 2b, once the cocrystal was formed, there was an apparent shift in betulin O–H stretching vibrations (3300–3600 cm 1). The same trend was observed for betulin C-O stretching vibrations near 1020 cm 1. This suggests that the hydroxyl groups of BE may be involved in intermolecular hydrogen bonding with carboxyl groups of the TA. Nevertheless, there were no changes in the IR spectra of the BE-TA mixture ground with the addition of dioxan which confirmed no cocrystal formation in this case. Thermal analysis studies showed that the DCS curves were different for 2:1 BE-TA physical and ground mixtures (Fig. 3a) that confirmed interaction of the components under grinding. For the ground mixture, there were no exothermic peaks of crystallization evidencing that the ground product did not contain an amorphous phase. As the TG and mass-spectrometry measurements showed (Fig. 3b), the endothermic DSC peaks at temperature near 100 °C were related to water molecules release suggesting cocrystal hydrate formation under liquid-assisted grinding. The loss of water is about 2%, which suggests the presence of one water molecule in the composition of BE-TA 2:1.
Fig. 2. (a) PXRD patterns of initial BE (1), 2:1 BE-TA mixtures ground with the addition of dioxan (2), acetone (3), and isopropanol (4); (b) IR spectra of initial BE (1); 2:1 BE-TA mixtures ground with the addition of dioxan (2) and isopropanol (3).
Please cite this article as: A. V. Mikhailovskaya, S. A. Myz, N. V. Bulina et al., Screening and characterization of cocrystal formation between betulin and terephthalic acid, Materials Today: Proceedings, https://doi.org/10.1016/j.matpr.2019.12.096
A.V. Mikhailovskaya et al. / Materials Today: Proceedings xxx (xxxx) xxx
3
Fig. 3. (a) DSC curves of initial BE (1), 2:1 BE-TA physical (2) and ground with the addition of isopropanol (3) mixtures; (b) TG and mass-spectrum curves for 2:1 BE-TA mixture ground with the addition of isopropanol.
The resulting cocrystals of betulin with terephthalic acid have demonstrated the enhanced dissolution rate and saturation solubility of betulin compared to the dissolution of betulin in the case of physical mixture with terephthalic acid and cocrystal of betulin with adipic acid. This fact evidenced that the properties of coformer molecules are crucial for generating the supramolecular structure of betulin cocrystals and their properties. CRediT authorship contribution statement Anastasiya V. Mikhailovskaya: Investigation, Writing - original draft, Visualization. Svetlana A. Myz: Investigation. Natalia V. Bulina: Formal analysis. Konstantin B. Gerasimov: Formal analysis. Svetlana A. Kuznetsova: Conceptualization. Tatyana P. Shakhtshneider: Conceptualization, Writing - review & editing. Declaration of Competing Interest
Fig. 4. Release of betulin from 2:1 BE-TA physical (1) and ground with the addition of isopropanol (2) mixtures; from 1:1 BE-adipic acid liquid-assisted ground mixture [9] (3).
Fig. 4 shows the dissolution profile for the LAG BE-TA mixture in comparison with those for the physical mixture of the components and 1:1 betulin-adipic acid cocrystal. The BE-TA cocrystal shows an increase in the dissolution rate of betulin in comparison with dissolution of betulin from physical mixture as well as from betulinadipic acid cocrystal giving an increased concentration of betulin in water which is preserved for at least two hours. It is assumed that hydrogen-bonded drug-coformer cocrystals dissociate for a short period of time (minutes to an hour) in an aqueous medium due to the fact that heteromolecular interactions in cocrystal could be weaker as compared to the homomolecular interactions in the phases of individual components [12]. Inhibition of precipitation of hydrophobic drug molecules followed by crystallization of the substance is ensured by the use of the coformer that has an effect on crystal nucleation and growth. 4. Conclusion It has been shown that betulin is able to cocrystalize with terephthalic acid by ball-milling using small additives of isopropanol or acetone. The addition of dioxan to the grinding mixture did not result in cocrystal formation. The role of the solvents in cocrystal formation will be elucidated in future investigations.
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgements The research was carried out within the state assignment to ISSCM SB RAS (project No. AAAA-A17-117030310274-5). References [1] W. Jones, W.D.S. Motherwell, A.V. Trask, MRS Bull. 31 (2006) 875–879. [2] A.M. Healy, Z.A. Worku, D. Kumar, A.M. Madi, Adv. Drug. Deliv. Rev. 117 (2017) 25–46. [3] S. Alakurtti, T. Mäkelä, S. Koskimies, J. Yli-Kauhaluoma, Eur J. Pharm. Sci. 29 (2006) 1–13. [4] S.K. Król, M. Kiełbus, A. Rivero-Müller, A. Stepulak, BioMed Res. Intern. 2015 (2015) 584189. [5] M.A. Mikhailenko, T.P. Shakhtshneider, V.A. Drebushchak, S.A. Kuznetsova, G.P. Skvortsova, V.V. Boldyrev, Chem. Nat. Compd. 47 (2010) 229–233. [6] V.P. Dobritsa, L.N. Karatushina, T.V. Kotova, O.G. Mikhailova, I.L. Potokin, O.V. Rybalchenko, RU Patent 2011; 02437649. May 10, 2011. [7] H.M. Wang, C. Soica, G. Wenz, Nat. Prod. Comm. 7 (2012) 283–418. [8] O.N. Pozharitskaya, M.V. Karlina, A.N. Shikov, V.M. Kosman, V.G. Makarov, E. Casals, J.M. Rosenholm, Eur J. Drug. Metab. Pharmacokinet 42 (2017) 327–332. [9] S.A. Myz, A.V. Mikhailovskaya, M.A. Mikhailenko, N.V. Bulina, S.A. Kuznetsova, T.P. Shakhtshneider, Materials Today: Proceed. 12 (2019) 82–85. [10] D. Hasa, W. Jones, Adv. Drug Deliv. Rev. 117 (2017) 147–161. [11] V.A. Levdanskii, A.V. Levdanskii, B.N. Kuznetsov, RU Patent 2012; 2458934. August 20, 2012. [12] N.A. Tumanov, S.A. Myz, T.P. Shakhtshneider, E.V. Boldyreva, CrystEngComm. 14 (2012) 305–313.
Please cite this article as: A. V. Mikhailovskaya, S. A. Myz, N. V. Bulina et al., Screening and characterization of cocrystal formation between betulin and terephthalic acid, Materials Today: Proceedings, https://doi.org/10.1016/j.matpr.2019.12.096
Contents lists available at ScienceDirect
Materials Today: Proceedings journal homepage: www.elsevier.com/locate/matpr
Screening and characterization of cocrystal formation between betulin and terephthalic acid Anastasiya V. Mikhailovskaya a,b, Svetlana A. Myz a, Natalia V. Bulina a,b, Konstantin B. Gerasimov a, Svetlana A. Kuznetsova c,d, Tatyana P. Shakhtshneider a,b,⇑ a
Institute of Solid State Chemistry and Mechanochemistry SB RAS, Kutateladze str., 18, Novosibirsk 630128, Russia Novosibirsk State University, Pirogov str., 2, Novosibirsk 630090, Russia Institute of Chemistry and Chemical Technology, FRC KSC SB RAS, Academgorodok, 50/24, Krasnoyarsk 660036, Russia d Siberian Federal University, Svobodny pr., 79/10, Krasnoyarsk 660041, Russia b c
a r t i c l e
i n f o
Article history: Received 18 November 2019 Received in revised form 9 December 2019 Accepted 12 December 2019 Available online xxxx Keywords: Betulin Terephthalic acid Co-grinding Cocrystal Solubility
a b s t r a c t The pharmaceutical cocrystals are nowdays intensively studied due to the improvements of solubility, stability, processability, etc. of the drugs. In this work, the cocrystals of betulin with terephthalic acid as a coformer were prepared by liquid-assisted grinding method. The formation of cocrystals was confirmed by powder X-ray diffraction, IR spectroscopy and thermal analysis methods. HPLC analysis showed that in the case of betulin – terephthalic acid cocrystals, solubility of betulin was significantly improved compared to the initial betulin as well as betulin from cocrystals with aliphatic dicarboxylic acids which were earlier prepared. Ó 2019 Elsevier Ltd. All rights reserved. Selection and peer-review under responsibility of the scientific committee of the III All-Russian Conference (with International Participation) Hot Topics of Solid State Chemistry: From New Ideas to New Materials.
1. Introduction Preparation of cocrystals, i.e. multi-component materials of the active pharmaceutical ingredient (API) with non-toxic partner molecules have attracted interest in pharmaceutical industry as a strategy for altering the physical–chemical properties of the API such as enhancement of solubility, increasing stability to hydration, improving compaction behavior, etc. [1,2]. Betulin, lup-20(29)-ene-3b,28-diol, extracted from birch bark, exhibits various types of pharmacological activity, including antiviral, anti-bacterial, anti-inflammatory, anti-HIV or anti-cancer effects [3,4]. The major problem to develop the dosage forms, is the low solubility of betulin in aqueous medium that clearly reduces its bioavailability. Several strategies have been applied to improve the solubility and/or dissolution rate of betulin and its derivatives such as preparation of solid dispersions with watersoluble polymers [5], liposomes [6], cyclodextrin derivatives [7], entrapment in nanosystems [8].
⇑ Corresponding author at: Institute of Solid State Chemistry and Mechanochemistry SB RAS, Kutateladze str., 18, Novosibirsk 630128, Russia. E-mail address: [email protected] (T.P. Shakhtshneider).
In our previous work [9], the cocrystals of betulin with aliphatic dicarboxylic acids, adipic and suberic, were obtained by liquidassisted grinding (LAG) method [10]. At the same time, the grinding of betulin – succinic acid mixture did not yield a new crystalline material. The purpose of this research was to prepare cocrystals of betulin with terephthalic acid. Fig. 1 presents the structural formulas of both betulin and terephthalic acid. The aromatic terephthalic acid was selected to analyze the fundamental opportunity for betulin to generate cocrystals with various coformers. The formation of betulin cocrystals was investigated using powder X-ray diffraction, IR spectroscopy, and thermal analysis methods.
2. Experimental Betulin (BE) was isolated from birch bark according to the developed method [11]. BE was purified by recrystallization from ethanol. Terephthalic acid (TA) (Sigma-Aldrich, USA) was of analytical grade and was used as received. In order to prepare cocrystals, betulin-terephthalic acid (BE-TA) mixtures with different molar ratios (1:1, 2:1) were ground in an agate mortar or in a SPEX 8000 mixer mill (CertiPrep Inc., USA).
https://doi.org/10.1016/j.matpr.2019.12.096 2214-7853/Ó 2019 Elsevier Ltd. All rights reserved. Selection and peer-review under responsibility of the scientific committee of the III All-Russian Conference (with International Participation) Hot Topics of Solid State Chemistry: From New Ideas to New Materials.
Please cite this article as: A. V. Mikhailovskaya, S. A. Myz, N. V. Bulina et al., Screening and characterization of cocrystal formation between betulin and terephthalic acid, Materials Today: Proceedings, https://doi.org/10.1016/j.matpr.2019.12.096
2
A.V. Mikhailovskaya et al. / Materials Today: Proceedings xxx (xxxx) xxx
Fig. 1. Molecular structures of betulin (a) and terephthalic acid (b).
The physical mixtures were homogeneously mixed in the agate mortar for 5 min followed by the addition of 1 mL of a solvent and subsequent grinding. In the case of SPEX 8000 mixer mill, ball-milling was performed in a 60 mL steel jar with the balls of the same material and 6 mm in diameter. Ratio of mass of sample to mass of balls was 1:15. The mixtures had been pre-milled in dryness for 5 min; afterwards, 1 mL of a solvent was added and the paste was subsequently milled for 10 min. The solvents of different polarity, namely, isopropanol, acetone, dioxan, were used for screening of cocrystal formation. Powder X-ray diffraction (PXRD) analysis was carried out on a D8-Advance diffractometer (Bruker, Germany) with an onedimensional detector (Lynx Eye type), CuKa-radiation, 2h = 5-70°. Attenuated total reflectance (ATR) IR spectra were recorded without any special sample preparation in the 580–4000 cm 1 spectral range using a Digilab Excalibur 3100 FT-IR spectrometer (USA) and a Pike Miracle ATR attachment with ZnSe crystal. Thermogravimetry (TG) and mass spectrometry studies were performed using a STA 449 F1 Jupiter (Netzsch, Germany) simultaneous thermal analysis system in combination with a QMS 403C Aeolos quadrupole mass spectrometer. The measurements were carried out in flowing 99.990%-pure argon at a volumetric flow rate of 50 mL/min. A weighed sample (30–50 mg) was placed in a cell, which was then pumped down to 1 Pa by a roughing pump. Next, argon was passed through the cell. The heating rate was 10 °C/min. Calorimetric measurements (DSC) were performed using a DSC 200 F3 MAIA (Netzsch, Germany) heat flux calorimeter. About 5 mg of a solid sample was placed in 40 lL closed aluminum cap, scanned from 25 to 250 °C under argon atmosphere at a heating rate of 6 °C/min. The same procedure as in [9] was used to study dissolution behaviour of the obtained samples. High-performance liquid chromatography (HPLC) method was used to determine betulin concentration in the solutions.
3. Results and discussion Screening experiments, performed in the agate mortar, showed that in the case of 1:1 BE-TA mixture, some new reflections appeared in the PXRD pattern after grinding; nevertheless, those of initial acid were rather large (date not shown). Probably, the higher amount of betulin is required to obtain a neat product. Fig. 2a demonstrates PXRD patterns for 2:1 BE-TA mixtures ground in the SPEX mixer mill using different solvents. It can be seen that after grinding BE-TA mixtures, several reflections of the starting materials disappeared, as several new reflections appeared suggesting the formation of a BE-TA cocrystal. The effect was observed when we used acetone or isopropanol as a solvent. The changes in the IR spectra of the BE-TA mixtures ground with the addition of acetone or isopropanol proved cocrystal formation. As can be seen from Fig. 2b, once the cocrystal was formed, there was an apparent shift in betulin O–H stretching vibrations (3300–3600 cm 1). The same trend was observed for betulin C-O stretching vibrations near 1020 cm 1. This suggests that the hydroxyl groups of BE may be involved in intermolecular hydrogen bonding with carboxyl groups of the TA. Nevertheless, there were no changes in the IR spectra of the BE-TA mixture ground with the addition of dioxan which confirmed no cocrystal formation in this case. Thermal analysis studies showed that the DCS curves were different for 2:1 BE-TA physical and ground mixtures (Fig. 3a) that confirmed interaction of the components under grinding. For the ground mixture, there were no exothermic peaks of crystallization evidencing that the ground product did not contain an amorphous phase. As the TG and mass-spectrometry measurements showed (Fig. 3b), the endothermic DSC peaks at temperature near 100 °C were related to water molecules release suggesting cocrystal hydrate formation under liquid-assisted grinding. The loss of water is about 2%, which suggests the presence of one water molecule in the composition of BE-TA 2:1.
Fig. 2. (a) PXRD patterns of initial BE (1), 2:1 BE-TA mixtures ground with the addition of dioxan (2), acetone (3), and isopropanol (4); (b) IR spectra of initial BE (1); 2:1 BE-TA mixtures ground with the addition of dioxan (2) and isopropanol (3).
Please cite this article as: A. V. Mikhailovskaya, S. A. Myz, N. V. Bulina et al., Screening and characterization of cocrystal formation between betulin and terephthalic acid, Materials Today: Proceedings, https://doi.org/10.1016/j.matpr.2019.12.096
A.V. Mikhailovskaya et al. / Materials Today: Proceedings xxx (xxxx) xxx
3
Fig. 3. (a) DSC curves of initial BE (1), 2:1 BE-TA physical (2) and ground with the addition of isopropanol (3) mixtures; (b) TG and mass-spectrum curves for 2:1 BE-TA mixture ground with the addition of isopropanol.
The resulting cocrystals of betulin with terephthalic acid have demonstrated the enhanced dissolution rate and saturation solubility of betulin compared to the dissolution of betulin in the case of physical mixture with terephthalic acid and cocrystal of betulin with adipic acid. This fact evidenced that the properties of coformer molecules are crucial for generating the supramolecular structure of betulin cocrystals and their properties. CRediT authorship contribution statement Anastasiya V. Mikhailovskaya: Investigation, Writing - original draft, Visualization. Svetlana A. Myz: Investigation. Natalia V. Bulina: Formal analysis. Konstantin B. Gerasimov: Formal analysis. Svetlana A. Kuznetsova: Conceptualization. Tatyana P. Shakhtshneider: Conceptualization, Writing - review & editing. Declaration of Competing Interest
Fig. 4. Release of betulin from 2:1 BE-TA physical (1) and ground with the addition of isopropanol (2) mixtures; from 1:1 BE-adipic acid liquid-assisted ground mixture [9] (3).
Fig. 4 shows the dissolution profile for the LAG BE-TA mixture in comparison with those for the physical mixture of the components and 1:1 betulin-adipic acid cocrystal. The BE-TA cocrystal shows an increase in the dissolution rate of betulin in comparison with dissolution of betulin from physical mixture as well as from betulinadipic acid cocrystal giving an increased concentration of betulin in water which is preserved for at least two hours. It is assumed that hydrogen-bonded drug-coformer cocrystals dissociate for a short period of time (minutes to an hour) in an aqueous medium due to the fact that heteromolecular interactions in cocrystal could be weaker as compared to the homomolecular interactions in the phases of individual components [12]. Inhibition of precipitation of hydrophobic drug molecules followed by crystallization of the substance is ensured by the use of the coformer that has an effect on crystal nucleation and growth. 4. Conclusion It has been shown that betulin is able to cocrystalize with terephthalic acid by ball-milling using small additives of isopropanol or acetone. The addition of dioxan to the grinding mixture did not result in cocrystal formation. The role of the solvents in cocrystal formation will be elucidated in future investigations.
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgements The research was carried out within the state assignment to ISSCM SB RAS (project No. AAAA-A17-117030310274-5). References [1] W. Jones, W.D.S. Motherwell, A.V. Trask, MRS Bull. 31 (2006) 875–879. [2] A.M. Healy, Z.A. Worku, D. Kumar, A.M. Madi, Adv. Drug. Deliv. Rev. 117 (2017) 25–46. [3] S. Alakurtti, T. Mäkelä, S. Koskimies, J. Yli-Kauhaluoma, Eur J. Pharm. Sci. 29 (2006) 1–13. [4] S.K. Król, M. Kiełbus, A. Rivero-Müller, A. Stepulak, BioMed Res. Intern. 2015 (2015) 584189. [5] M.A. Mikhailenko, T.P. Shakhtshneider, V.A. Drebushchak, S.A. Kuznetsova, G.P. Skvortsova, V.V. Boldyrev, Chem. Nat. Compd. 47 (2010) 229–233. [6] V.P. Dobritsa, L.N. Karatushina, T.V. Kotova, O.G. Mikhailova, I.L. Potokin, O.V. Rybalchenko, RU Patent 2011; 02437649. May 10, 2011. [7] H.M. Wang, C. Soica, G. Wenz, Nat. Prod. Comm. 7 (2012) 283–418. [8] O.N. Pozharitskaya, M.V. Karlina, A.N. Shikov, V.M. Kosman, V.G. Makarov, E. Casals, J.M. Rosenholm, Eur J. Drug. Metab. Pharmacokinet 42 (2017) 327–332. [9] S.A. Myz, A.V. Mikhailovskaya, M.A. Mikhailenko, N.V. Bulina, S.A. Kuznetsova, T.P. Shakhtshneider, Materials Today: Proceed. 12 (2019) 82–85. [10] D. Hasa, W. Jones, Adv. Drug Deliv. Rev. 117 (2017) 147–161. [11] V.A. Levdanskii, A.V. Levdanskii, B.N. Kuznetsov, RU Patent 2012; 2458934. August 20, 2012. [12] N.A. Tumanov, S.A. Myz, T.P. Shakhtshneider, E.V. Boldyreva, CrystEngComm. 14 (2012) 305–313.
Please cite this article as: A. V. Mikhailovskaya, S. A. Myz, N. V. Bulina et al., Screening and characterization of cocrystal formation between betulin and terephthalic acid, Materials Today: Proceedings, https://doi.org/10.1016/j.matpr.2019.12.096