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Effect of crystallization method on the formation of carbamazepine-saccharin co-crystal
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ScienceDirect Materials Today: Proceedings 5 (2018) 22074–22079
www.materialstoday.com/proceedings
The 3rd International Conference on Green Chemical Engineering Technology (3rd GCET_2017): Materials Science
Effect of crystallization method on the formation of carbamazepinesaccharin co-crystal Syarifah Abd Rahim* and Nur Amanina Mohamad Adaris Faculty of Chemical & Natural Resources Engineering, Universiti Malaysia Pahang, Lebuhraya Tun Razak, 26300 Kuantan, Pahang, Malaysia
Abstract Co-crystallization is a method in formulation of drug products which is believed to improve drugs solubility, stability and dissolution rate while maintaining the biological functions of its chemical properties. In this work, the carbamazepine-saccharin (CBZ-SAC) co-crystal formation using varies mol ratio of SAC to CBZ, ethyl acetate and formic acid as a solvent and two methods was studied. The physical characterization of the co-crystal was characterized using x-ray diffraction (XRD) powder and differential scanning calorimetry (DSC). The XRD pattern profile analysis had confirm that the CBZ-SAC co-crystal was successfully formed only in ethyl acetate solvent for both of the screening methods applied. The findings also revealed that two polymorphic forms of CBZ-SAC co-crystal was formed during the study. © 2018 Elsevier Ltd. All rights reserved. Selection and/or Peer-review under responsibility of The 3rd International Conference on Green Chemical Engineering and Technology (3rd GCET): Materials Science, 07-08 November 2017. Keywords: Co-crystal; Carbamazepine; Polymorphic; Saccharin
1. Introduction Co-crystal development has an increasing interest in the pharmaceutical field as it plays an important class of pharmaceutical material as it enhances the solubility, dissolution and consequent bioavailability of poor water-
* Corresponding author. Tel.: +609-549-2886; fax: +609-5492889. E-mail address: [email protected] 2214-7853 © 2018 Elsevier Ltd. All rights reserved. Selection and/or Peer-review under responsibility of The 3rd International Conference on Green Chemical Engineering and Technology (3rd GCET): Materials Science, 07-08 November 2017.
Rahim & Adaris / Materials Today: Proceedings 5 (2018) 22074–22079
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soluble drugs by forming a crystal and a co-former with specific stoichiometry composition [1]. CBZ is an insoluble drug that has a high dose requirement (>100mg/day) for therapeutic effect and poses multiple challenges for oral drug delivery, including a narrow therapeutic window, auto induction of metabolism and dissolution-limited bioavailability [2,3,4]. The co-crystallization technique is an approach that allows binding active pharmaceutical ingredient (API) with one or more components of co-crystal former (CCF) without breaking or making new covalent bond within one periodic crystalline lattice [5,6]. This will then preserve the biological function of the drugs while increasing its solubility performance. Co-crystal can be prepared by several methods such as solvent based method and solid based method. The solid based methods involve slurry conversion via solvent evaporation, cooling crystallization and precipitation while the solid based methods involve dry grinding and solvent-assisted grinding [7,8]. The crystal obtained can be characterized in wide variety of methods and the most common method to characterize co-crystal is X-ray powder diffraction (XRPD). Besides, fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) also can be used. Carbamazepine (CBZ) is classified as a class II compound with low aqueous solubility [9]. It is one of the water insoluble drug that face issues regarding poor solubility, bioavailability, stability and mechanical properties. Cocrystallization technique currently has been widely used in the pharmaceutical industry in order to improve the solubility of drugs since the drug often discarded during commercial production due to their low solubility [10,11]. Co-crystallization of CBZ with SAC has been successfully produces and shows a promising result as solubility of CBZ-SAC increase greatly compare to the CBZ [12,13]. It has been reported that CBZ-SAC co-crystal has two polymorphic form i.e. form I and form II where form II is believed to improve the bioavailability [14]. Due to the polymorphic properties of the CBZ-SAC co-crystal, thus it is important to study the method to produce the desired co-crystal which is CBZ-SAC Form II. Therefore, in this study the formation of carbamazepine-saccharin (CBZSAC) in solvent of ethyl acetate and formic acid using evaporation and cooling method with different ratio of SAC to CBZ was evaluated. 2. Materials and Methods 2.1. Chemicals Carbamazepine (CBZ) and saccharin (SAC) were ordered from ECA Corporation USA and Sigma Aldrich, respectively. Ethyl acetate and formic acid both with purity exceeding 99% were supplied by Fisher company and used as received. 2.2. Sample preparation The formation of the co-crystal was studied using two methods i.e. evaporation and cooling crystallization. The solvent used were ethyl acetate and formic acid. The CBZ and SAC were weighed according to the selected mol ratio of SAC/CBZ with the interval of 0.25 started from 1.0 to 3.0. The weighted CBZ and SAC were mixed with 30 ml of solvent in 50 ml conical flask and shook at room temperature (~25ºC) in the orbital shaker with a speed of 150 rpm until all the solids dissolved. The solution was later used in the evaporation and cooling study. 2.3. Evaporation Additional of 10 ml solvent was added to the prepared solution and continuously shaken for an hour at room temperature (~25ºC) in the orbital shaker with a speed of 150 rpm. After an hour, the solution was filtered using a syringe filter. The filtered solution was transferred into a new clean 50 ml conical flask and left to evaporate at room temperature. The flask was covered with parafilm and small holes was poked on it for the evaporation to occur.
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2.4. Cooling The prepared solution was shaking for 72 hours at room temperature (~25ºC) in the orbital shaker with a speed of 150 rpm. The temperature was then decreased by 5°C for every 1-hour interval. At temperature 50-40°C, crystal solid phase started to appear and the temperature was further lowered to 25°C to drive additional precipitation. 2.5. Characterization analysis The resulting solid for both methods were collected using vacuum filtration and left dried at room temperature and was characterized using x-ray powder diffraction (XRPD) and differential scanning calorimeter (DSC) The X-ray powder diffraction (XRPD) was used to identify the powder pattern of the sample. The phase composition of the powder was established by showing different peak profiles using RIGAKU (Miniflex II) diffractometer with Cu Kα radiation. The system was operated at 30 kV and 15 mA with the 2θ (angle) from 3° to 40°. The step size and step time were 0.01° and 1 second/step, respectively. Differential Scanning Calorimetry (DSC) was used to determine the melting point of the crystal. The sample initially was lightly ground using mortar and pestle and was weighed between 2 and 3 mg in standard aluminium pan. The sample was analyzed in the DSC from a temperature of 25 to 300°C with heating rate of 10°C/min. 3. Results and Discussions Table 1 shows the summary of co-crystal formation from evaporation and cooling crystallization methods in ethyl acetate (EA). The data in table shows both CBZ-SAC Form I and CBZ-SAC Form II were able to be formed in evaporation method and the formation was significantly affected by the concentration of the solutes in solution (ratio of SAC/CBZ) as the form I only formed at ratio SAC/CBZ of 1.0 and 1.25. On the other hand, in cooling method, the ratio of SAC/CBZ has no effect on the co-crystal formation as only CBZ-SAC Form I was successfully formed and no precipitation was obtained for ratio SAC/CBZ of 1.0 and 1.25. The finding also shows that the samples precipitated from evaporation in formic acid solvent did not indicate the presence of CBZ-SAC co-crystal whereas, no crystal was precipitated from cooling method. This suggested that to induce precipitation, the CBZSAC system may need to reach an optimum condition to induce the precipitation process [15]. Table 1. Summary of results for evaporation and cooling crystallization in ethyl acetate (EA). SAC/CBZ ratio Evaporation Cooling CBZ-SAC Form I
CBZ-SAC Form II
CBZ-SAC Form I
CBZ-SAC Form II
1.00
-
-
-
1.25
-
-
-
1.50
-
-
1.75
-
-
2.00
-
-
2.25
-
-
2.50
-
-
2.75
-
-
3.00
-
-
-
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3.1. Powder x-ray diffraction (PXRD) The pattern profiles from PXRD for CBZ-SAC form I and CBZ-SAC form II are shown in Fig. 1. The pattern profile is in good agreement with reported study [14,16,17]. The result pointed that CBZ-SAC has two polymorphic forms; form I and form II depending on the method used for the co-crystal formation. These finding are compatible with previous research reported that CBZ-SAC co-crystal are capable of producing two type of polymorph depending on method [16], addition of polymer additive [14] and antisolvent flowrates [17]. In addition, this study also found out that the mol ratio has a significant effect on CBZ-SAC polymorphs’ formation. Similar finding has been reported for polymorphic form of carbamazepine-fumaric (CBZ-FUM) co-crystal influenced by solvents, methods and mol ratio [15,18].
Fig. 1. PXRD pattern profile for CBZ-SAC form I and fom II obtained from ratio of SAC/CBZ 1.25 and 1.5 respectively in ethyl acetate for evaporation method.
3.2. Differential scanning calorimetry (DSC) Thermal properties of CBZ, SAC and its co-crystal were obtained from analysis of DSC shown in Table 2. It can be seen that the melting point for both of the CBZ-SAC co-crystal falls between the melting point of CBZ and SAC. The measure of melting point for CBZ, SAC, CBZ-SAC form 1 and CBZ-SAC form II obtained are in good agreement with the value reported [14,17,19,20]. From the data in the table, it shown that there is a polymorphic transformation of CBZ form III to Form I was best described by the thermal event where polymorphic transformations take place at 167°C and new phase of CBZ form I melted at 190°C. CBZ form III was reported as the stable phase at room temperature and undergo a polymorphic change under heating [21]. Table 2. Thermal data of CBZ form III, SAC, CBZ-SAC form I and CBZ-SAC form II. Melting point (°C) Melting point (°C) Melting point (°C) Sample
This study
[17]
[19]
CBZ
167,190
-
167,195
SAC
227
-
231
Onset(°C)
Onset(°C)
[14]
[20] 228
CBZ-SAC form I
176-178
177
177
172
176
CBZ-SAC form II
170-172
171
-
168
-
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The thermal properties from DSC for CBZ-SAC form I and CBZ-SAC form II are shown in Fig. 2. CBZ-SAC form I has a melting point in the range of 176-178°C while Form II at 170-172°C, varies depending on the mol ratio of SAC/CBZ. The figure also shown that the CBZ-SAC form II has a small endothermic peak following the melting peak which agreed with the previous reported literature with onset of 172°C [14]. The differences between melting point of the two forms possibly because of the packing nature of the crystal in CBZ-SAC co-crystal [22].
Fig. 2. DSC thermal profile for CBZ-SAC form I and form II obtained from ratio of SAC/CBZ 1.25 and 1.5 respectively in ethyl acetate for evaporation method.
4. Conclusion The formation of CBZ-SAC co-crystal was investigated using solvent evaporation and cooling crystallization in ethyl acetate and formic acid. The XPRD and DSC analysis had confirmed that CBZ-SAC co-crystal in ethyl acetate was successfully formed. It was found that CBZ-SAC Form I and Form II had been formed from evaporation method for CBZ/SAC ratio of 1.0-1.25 and 1.5-3.0 respectively. On the other hand, only CBZ-SAC form I formed in cooling crystallization method. The melting point of CBZ-SAC form I and form II were in the range of 176178°C and 170-172°C respectively. The finding suggested further study in screening is needed for co-crystal formation since many factors proven in affecting the polymorphic formation of the co-crystal such as method of formation, solvent and mol ratio. Acknowledgements The authors would like to thank University Malaysia Pahang (UMP) for grant support (RDU160338), equipment and facilities used. References [1] R.Thakuria, A. Delori,W. Jones, M.P. Lipert, L. Roy, N.R Hornedo, International Journal of Pharmaceutics (2012) 101-125. [2] M.B. Hickey, M.L. Peterson, L.A. Scoppettuolo, L.S. Morrisette, A. Vetter, H. Guzman, J.F. Remenar, Z. Zhang, M.D. Tawa, S. Haley, M.J. Zaworotko, O. Almarsson, European Journal of Pharmaceutics and Biopharmaceutics 67 (2007) 112–119. [3] L. Bertilson, Thomson, Pharmacokinet. 11 (1986) 177-198. [4] M.C. Meyer, A.B. Straughn, E. J. Jarvi, G.C. Wood, F.R. Pelsor, V.P. Shah, Pharm. Res. 9 (1992) 1612-1616. [5] A.Y. Sheikh, S. Abd Rahim, R.M. Hammond, K.J. Roberts, CrystEngComm. (2009) 501-509. [6] E. Gagniere, D. Mangin, F. Puel, A. Rivoire, O. Monnier, E. Garcia, J.P. Klein, Journal of Crystal Growth (2009) 2689-2695. [7] L. Padrela, M.A. Rodriques, S.P. Velaga, A.C. Fernandes, H.A. Matos, E.G. Azevedo, The Journal of Supecritical Fluids 53 (2010) 156-164. [8] S.R. Vippagunta, H.G. Britain, D.T.W Grant. Adv. Drug Deliv. Rev.(2001) 48. [9] N. Blagden, M.D. Matas,P.T.Gavan, P. York, Advance drug delivery 59 (2007) 617-630.
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[10] C. B. Aakeroy, D.J. Salmon, CrystEngComm. (2005) 439-448. [11] I.M.S. Miroshnyk, Expert Opin. Drug Deliv. 6 (2009) 333-41. [12] Y. Kobayashi, S. Ito, S. Itai, K. Yamamoto, Int. J. Pharm 193 (2000) 137–146. [13] A. Nangia, B.R. Bhogala, New J. Chem. 32 (2008) 800-807. [14] W.W. Porter III, S.C. Elie, A.J. Matzger, Crystal Growth & Design 8 (2008) 14-16. [15] F. Ab Rahman, S. Abd Rahim, C.C. Tan, S.H. Low, N.A. Ramle, International Journal of Chemical and Applications 8 (2017) 136-140. [16] S. Abd Rahim, R.B. Hammond, A.Y. Sheikh, K.J. Robert, CrystEngComm 15 (2013) 3862-3873. [17] M.J. Lee, I.C. Wang,M.J. Kim, P. Kim, K.H. Song, N.H. Chun, H.G. Park, G.J. Choi, Korean J. Chem. Eng., 32 (2015) 1910-1917. [18] S. Abd Rahim, F. Ab Rahman, E.N.E.M. Nasir, N.A. Ramle, International Journal of Environmental, Chemical, Ecological, Geological and Geophysical Engineering 9 (2015) 425-428. [19] S. Qiu, PhD thesis, Leicester, 2015. [20] A. Jayasankar, A. Somwangthanaroj, Z.J. Shao, N. Rodriguez-Hornedo, Pharmaceutical Research 23 (2006) 2381-2392. [21] A.L. Grzesiak, M. Lang, K. Kim, A.J. Matzger, Journal of Pharmaceutical Sciences 92 (2003) 2260-2271. [22] M. Sevukarajan, R. Thanuja, R. Sodanapalli, R. Nair, Journal of Pharmaceutical Science and Research 3 (2011) 1288-1293.
ScienceDirect Materials Today: Proceedings 5 (2018) 22074–22079
www.materialstoday.com/proceedings
The 3rd International Conference on Green Chemical Engineering Technology (3rd GCET_2017): Materials Science
Effect of crystallization method on the formation of carbamazepinesaccharin co-crystal Syarifah Abd Rahim* and Nur Amanina Mohamad Adaris Faculty of Chemical & Natural Resources Engineering, Universiti Malaysia Pahang, Lebuhraya Tun Razak, 26300 Kuantan, Pahang, Malaysia
Abstract Co-crystallization is a method in formulation of drug products which is believed to improve drugs solubility, stability and dissolution rate while maintaining the biological functions of its chemical properties. In this work, the carbamazepine-saccharin (CBZ-SAC) co-crystal formation using varies mol ratio of SAC to CBZ, ethyl acetate and formic acid as a solvent and two methods was studied. The physical characterization of the co-crystal was characterized using x-ray diffraction (XRD) powder and differential scanning calorimetry (DSC). The XRD pattern profile analysis had confirm that the CBZ-SAC co-crystal was successfully formed only in ethyl acetate solvent for both of the screening methods applied. The findings also revealed that two polymorphic forms of CBZ-SAC co-crystal was formed during the study. © 2018 Elsevier Ltd. All rights reserved. Selection and/or Peer-review under responsibility of The 3rd International Conference on Green Chemical Engineering and Technology (3rd GCET): Materials Science, 07-08 November 2017. Keywords: Co-crystal; Carbamazepine; Polymorphic; Saccharin
1. Introduction Co-crystal development has an increasing interest in the pharmaceutical field as it plays an important class of pharmaceutical material as it enhances the solubility, dissolution and consequent bioavailability of poor water-
* Corresponding author. Tel.: +609-549-2886; fax: +609-5492889. E-mail address: [email protected] 2214-7853 © 2018 Elsevier Ltd. All rights reserved. Selection and/or Peer-review under responsibility of The 3rd International Conference on Green Chemical Engineering and Technology (3rd GCET): Materials Science, 07-08 November 2017.
Rahim & Adaris / Materials Today: Proceedings 5 (2018) 22074–22079
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soluble drugs by forming a crystal and a co-former with specific stoichiometry composition [1]. CBZ is an insoluble drug that has a high dose requirement (>100mg/day) for therapeutic effect and poses multiple challenges for oral drug delivery, including a narrow therapeutic window, auto induction of metabolism and dissolution-limited bioavailability [2,3,4]. The co-crystallization technique is an approach that allows binding active pharmaceutical ingredient (API) with one or more components of co-crystal former (CCF) without breaking or making new covalent bond within one periodic crystalline lattice [5,6]. This will then preserve the biological function of the drugs while increasing its solubility performance. Co-crystal can be prepared by several methods such as solvent based method and solid based method. The solid based methods involve slurry conversion via solvent evaporation, cooling crystallization and precipitation while the solid based methods involve dry grinding and solvent-assisted grinding [7,8]. The crystal obtained can be characterized in wide variety of methods and the most common method to characterize co-crystal is X-ray powder diffraction (XRPD). Besides, fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) also can be used. Carbamazepine (CBZ) is classified as a class II compound with low aqueous solubility [9]. It is one of the water insoluble drug that face issues regarding poor solubility, bioavailability, stability and mechanical properties. Cocrystallization technique currently has been widely used in the pharmaceutical industry in order to improve the solubility of drugs since the drug often discarded during commercial production due to their low solubility [10,11]. Co-crystallization of CBZ with SAC has been successfully produces and shows a promising result as solubility of CBZ-SAC increase greatly compare to the CBZ [12,13]. It has been reported that CBZ-SAC co-crystal has two polymorphic form i.e. form I and form II where form II is believed to improve the bioavailability [14]. Due to the polymorphic properties of the CBZ-SAC co-crystal, thus it is important to study the method to produce the desired co-crystal which is CBZ-SAC Form II. Therefore, in this study the formation of carbamazepine-saccharin (CBZSAC) in solvent of ethyl acetate and formic acid using evaporation and cooling method with different ratio of SAC to CBZ was evaluated. 2. Materials and Methods 2.1. Chemicals Carbamazepine (CBZ) and saccharin (SAC) were ordered from ECA Corporation USA and Sigma Aldrich, respectively. Ethyl acetate and formic acid both with purity exceeding 99% were supplied by Fisher company and used as received. 2.2. Sample preparation The formation of the co-crystal was studied using two methods i.e. evaporation and cooling crystallization. The solvent used were ethyl acetate and formic acid. The CBZ and SAC were weighed according to the selected mol ratio of SAC/CBZ with the interval of 0.25 started from 1.0 to 3.0. The weighted CBZ and SAC were mixed with 30 ml of solvent in 50 ml conical flask and shook at room temperature (~25ºC) in the orbital shaker with a speed of 150 rpm until all the solids dissolved. The solution was later used in the evaporation and cooling study. 2.3. Evaporation Additional of 10 ml solvent was added to the prepared solution and continuously shaken for an hour at room temperature (~25ºC) in the orbital shaker with a speed of 150 rpm. After an hour, the solution was filtered using a syringe filter. The filtered solution was transferred into a new clean 50 ml conical flask and left to evaporate at room temperature. The flask was covered with parafilm and small holes was poked on it for the evaporation to occur.
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Rahim & Adaris / Materials Today: Proceedings 5 (2018) 22074–22079
2.4. Cooling The prepared solution was shaking for 72 hours at room temperature (~25ºC) in the orbital shaker with a speed of 150 rpm. The temperature was then decreased by 5°C for every 1-hour interval. At temperature 50-40°C, crystal solid phase started to appear and the temperature was further lowered to 25°C to drive additional precipitation. 2.5. Characterization analysis The resulting solid for both methods were collected using vacuum filtration and left dried at room temperature and was characterized using x-ray powder diffraction (XRPD) and differential scanning calorimeter (DSC) The X-ray powder diffraction (XRPD) was used to identify the powder pattern of the sample. The phase composition of the powder was established by showing different peak profiles using RIGAKU (Miniflex II) diffractometer with Cu Kα radiation. The system was operated at 30 kV and 15 mA with the 2θ (angle) from 3° to 40°. The step size and step time were 0.01° and 1 second/step, respectively. Differential Scanning Calorimetry (DSC) was used to determine the melting point of the crystal. The sample initially was lightly ground using mortar and pestle and was weighed between 2 and 3 mg in standard aluminium pan. The sample was analyzed in the DSC from a temperature of 25 to 300°C with heating rate of 10°C/min. 3. Results and Discussions Table 1 shows the summary of co-crystal formation from evaporation and cooling crystallization methods in ethyl acetate (EA). The data in table shows both CBZ-SAC Form I and CBZ-SAC Form II were able to be formed in evaporation method and the formation was significantly affected by the concentration of the solutes in solution (ratio of SAC/CBZ) as the form I only formed at ratio SAC/CBZ of 1.0 and 1.25. On the other hand, in cooling method, the ratio of SAC/CBZ has no effect on the co-crystal formation as only CBZ-SAC Form I was successfully formed and no precipitation was obtained for ratio SAC/CBZ of 1.0 and 1.25. The finding also shows that the samples precipitated from evaporation in formic acid solvent did not indicate the presence of CBZ-SAC co-crystal whereas, no crystal was precipitated from cooling method. This suggested that to induce precipitation, the CBZSAC system may need to reach an optimum condition to induce the precipitation process [15]. Table 1. Summary of results for evaporation and cooling crystallization in ethyl acetate (EA). SAC/CBZ ratio Evaporation Cooling CBZ-SAC Form I
CBZ-SAC Form II
CBZ-SAC Form I
CBZ-SAC Form II
1.00
-
-
-
1.25
-
-
-
1.50
-
-
1.75
-
-
2.00
-
-
2.25
-
-
2.50
-
-
2.75
-
-
3.00
-
-
-
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3.1. Powder x-ray diffraction (PXRD) The pattern profiles from PXRD for CBZ-SAC form I and CBZ-SAC form II are shown in Fig. 1. The pattern profile is in good agreement with reported study [14,16,17]. The result pointed that CBZ-SAC has two polymorphic forms; form I and form II depending on the method used for the co-crystal formation. These finding are compatible with previous research reported that CBZ-SAC co-crystal are capable of producing two type of polymorph depending on method [16], addition of polymer additive [14] and antisolvent flowrates [17]. In addition, this study also found out that the mol ratio has a significant effect on CBZ-SAC polymorphs’ formation. Similar finding has been reported for polymorphic form of carbamazepine-fumaric (CBZ-FUM) co-crystal influenced by solvents, methods and mol ratio [15,18].
Fig. 1. PXRD pattern profile for CBZ-SAC form I and fom II obtained from ratio of SAC/CBZ 1.25 and 1.5 respectively in ethyl acetate for evaporation method.
3.2. Differential scanning calorimetry (DSC) Thermal properties of CBZ, SAC and its co-crystal were obtained from analysis of DSC shown in Table 2. It can be seen that the melting point for both of the CBZ-SAC co-crystal falls between the melting point of CBZ and SAC. The measure of melting point for CBZ, SAC, CBZ-SAC form 1 and CBZ-SAC form II obtained are in good agreement with the value reported [14,17,19,20]. From the data in the table, it shown that there is a polymorphic transformation of CBZ form III to Form I was best described by the thermal event where polymorphic transformations take place at 167°C and new phase of CBZ form I melted at 190°C. CBZ form III was reported as the stable phase at room temperature and undergo a polymorphic change under heating [21]. Table 2. Thermal data of CBZ form III, SAC, CBZ-SAC form I and CBZ-SAC form II. Melting point (°C) Melting point (°C) Melting point (°C) Sample
This study
[17]
[19]
CBZ
167,190
-
167,195
SAC
227
-
231
Onset(°C)
Onset(°C)
[14]
[20] 228
CBZ-SAC form I
176-178
177
177
172
176
CBZ-SAC form II
170-172
171
-
168
-
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The thermal properties from DSC for CBZ-SAC form I and CBZ-SAC form II are shown in Fig. 2. CBZ-SAC form I has a melting point in the range of 176-178°C while Form II at 170-172°C, varies depending on the mol ratio of SAC/CBZ. The figure also shown that the CBZ-SAC form II has a small endothermic peak following the melting peak which agreed with the previous reported literature with onset of 172°C [14]. The differences between melting point of the two forms possibly because of the packing nature of the crystal in CBZ-SAC co-crystal [22].
Fig. 2. DSC thermal profile for CBZ-SAC form I and form II obtained from ratio of SAC/CBZ 1.25 and 1.5 respectively in ethyl acetate for evaporation method.
4. Conclusion The formation of CBZ-SAC co-crystal was investigated using solvent evaporation and cooling crystallization in ethyl acetate and formic acid. The XPRD and DSC analysis had confirmed that CBZ-SAC co-crystal in ethyl acetate was successfully formed. It was found that CBZ-SAC Form I and Form II had been formed from evaporation method for CBZ/SAC ratio of 1.0-1.25 and 1.5-3.0 respectively. On the other hand, only CBZ-SAC form I formed in cooling crystallization method. The melting point of CBZ-SAC form I and form II were in the range of 176178°C and 170-172°C respectively. The finding suggested further study in screening is needed for co-crystal formation since many factors proven in affecting the polymorphic formation of the co-crystal such as method of formation, solvent and mol ratio. Acknowledgements The authors would like to thank University Malaysia Pahang (UMP) for grant support (RDU160338), equipment and facilities used. References [1] R.Thakuria, A. Delori,W. Jones, M.P. Lipert, L. Roy, N.R Hornedo, International Journal of Pharmaceutics (2012) 101-125. [2] M.B. Hickey, M.L. Peterson, L.A. Scoppettuolo, L.S. Morrisette, A. Vetter, H. Guzman, J.F. Remenar, Z. Zhang, M.D. Tawa, S. Haley, M.J. Zaworotko, O. Almarsson, European Journal of Pharmaceutics and Biopharmaceutics 67 (2007) 112–119. [3] L. Bertilson, Thomson, Pharmacokinet. 11 (1986) 177-198. [4] M.C. Meyer, A.B. Straughn, E. J. Jarvi, G.C. Wood, F.R. Pelsor, V.P. Shah, Pharm. Res. 9 (1992) 1612-1616. [5] A.Y. Sheikh, S. Abd Rahim, R.M. Hammond, K.J. Roberts, CrystEngComm. (2009) 501-509. [6] E. Gagniere, D. Mangin, F. Puel, A. Rivoire, O. Monnier, E. Garcia, J.P. Klein, Journal of Crystal Growth (2009) 2689-2695. [7] L. Padrela, M.A. Rodriques, S.P. Velaga, A.C. Fernandes, H.A. Matos, E.G. Azevedo, The Journal of Supecritical Fluids 53 (2010) 156-164. [8] S.R. Vippagunta, H.G. Britain, D.T.W Grant. Adv. Drug Deliv. Rev.(2001) 48. [9] N. Blagden, M.D. Matas,P.T.Gavan, P. York, Advance drug delivery 59 (2007) 617-630.
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