Pharmaceutical Development and Technology
ISSN: 1083-7450 (Print) 1097-9867 (Online) Journal homepage: http://www.tandfonline.com/loi/iphd20
A new polymorphic form of metoprolol succinate Mengqing Zhou, Ju Ao, Song Liu, Chaogang Wu, Pingan Lai, Haitao Gao & Guoqing Zhang To cite this article: Mengqing Zhou, Ju Ao, Song Liu, Chaogang Wu, Pingan Lai, Haitao Gao & Guoqing Zhang (2016): A new polymorphic form of metoprolol succinate, Pharmaceutical Development and Technology, DOI: 10.3109/10837450.2016.1146295 To link to this article: http://dx.doi.org/10.3109/10837450.2016.1146295
Published online: 24 Feb 2016.
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http://informahealthcare.com/phd ISSN: 1083-7450 (print), 1097-9867 (electronic) Pharm Dev Technol, Early Online: 1–5 ! 2016 Taylor & Francis. DOI: 10.3109/10837450.2016.1146295
RESEARCH ARTICLE
A new polymorphic form of metoprolol succinate Mengqing Zhou1, Ju Ao1, Song Liu1, Chaogang Wu2, Pingan Lai2, Haitao Gao2, and Guoqing Zhang1 1
Engineering Research Center for Eco-Dyeing and Finishing of Textiles, Ministry of Education, Zhejiang Sci-Tech University, Hangzhou, China and Zhejiang Apeloa Medical Technology Co, Ltd, Jinhua, China
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2
Abstract
Keywords
Only one crystal form of metoprolol succinate (Form I) was reported during previous researches and production. In this study, a new polymorph of metoprolol succinate (here named as Form II) was discovered and investigated by X-ray diffraction, thermoanalysis and infrared spectroscopy. The results show its crystal structure and thermal properties are significantly different with Form I. Compared with Form I, Form II exhibits specific diffraction pattern, lower melting temperature and weaker hydrogen bond effect. The thermostability testing suggests Form II is a metastable crystal form and will gradually transform into Form I undergoing treatment of high temperature and humidity. Metastable crystal form generally has better dissolubility than its corresponding stable form. Subsequent measurement also verified that Form II can dissolve in the water more quickly than Form I.
Hydrogen bond, metoptolol succinate, polymorphic form, thermostability
Introduction Polymorphism is a widespread phenomenon for small molecule drugs, and increasingly draws people’s concern in the pharmaceutical research field. Polymorphism of a molecule compound is mainly from conformational flexibility, hydrogen bond and so on1. Many researches verified that different crystal forms of a drug compound may exhibit distinctive properties such as bioavailability, dissolution rate, stability, morphology and solubility2–6. In fact, deep investigation for polymorphism of drug compound not only contributes to understand molecular behavior, intermolecular interactions and the relationship between crystal structure, crystal growth and their influence on bulk properties7–9, but is an important research content in pharmaceutical development and production. Polymorphic forms of a drug compound can traditionally be obtained by changing the crystallization processes and conditions, such as the use of different solvents, temperature and pressure controlling, pseudo-seeding the supersaturated solution and polymer-induced heteronucleation (PIHn)2,10–12. For a polymorphic drug compound, each crystal form has unique physicochemical properties, for example thermostability is an important parameter to evaluate whether a crystal form can be used in pharmaceutical preparation or not. For those instable and metastable polymorphs, they easily degrade due to phase transforming upon manipulation, recrystallization or thermal treatment13, so that it is vital to investigate the stability of the crystal forms during the R&D and production of a polymorphic drug. Metoprolol succinate, chemical name 1-[4-(2-methoxyethyl)phenoxy]-3-(propan-2-ylamino)propan-2-ol butanedioate (2:1), as shown in Figure 1, is a selective ß(1)-adrenergic antagonist and has been proven its high efficacy in treating hypertension, angina Address for correspondence: Guoqing Zhang, Engineering Research Center for Eco-Dyeing and Finishing of Textiles, Ministry of Education, Zhejiang Sci-Tech University, Hangzhou 310018, China. Tel: +86 571 86843588. E-mail: [email protected]
History Received 16 November 2015 Revised 4 January 2016 Accepted 20 January 2016 Published online 23 February 2016
pectoris and chronic heart failure with abnormal left ventricle contraction function and stable symptoms in the clinic14. Previous researches reported the existence of only one form (Form I) of metoprolol succinate in the patent CN20 1110 341 837.9 (Patented 2012). In this study, a new polymorphic form (Form II) of metoprolol succinate is discovered and characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and Fourier transform infrared spectroscopy (FTIR). The new Form II, with totally different crystal structure and thermal property, has been proven to be a new polymorphic form of metoprolol succinate.
Experimental Materials The metoprolol succinate drug substance was provided by Zhejiang Apeloa Medical Technology Co., Ltd (Jinhua, China). The chemicals such as methanol and ethanol were bought from Tianjing YongDa Chemical Reagent Co., Ltd (Tianjing, China) with a purity exceeding 99.5%. Preparation and characterization of the form II The Form II powder was prepared by evaporating a methanol or aqueous solution of metoprolol succinate with a ratio of 1:25–30 or 1:10–15 in mass, respectively, at a temperature range of 70– 100 C for 2–24 h. The solubility measurements for both crystal forms were then performed by HPLC analysis. Both crystal forms were, respectively, weighted 750 mg and added into 3.0 ml water at the same time. Two solutions were stirred at room temperature with same rotating speed, and then, respectively, sampling at set intervals of 10 min, 30 min, 1, 3 and 8 h for HPLC testing. An Agilent 1100 (Agilent Co.) equipped with an Agilent G1316B UV Detector was used for the measurements. The analysis was carried out on an octadecylsilyl silica gel C18 column with a pore size of 10 nm and
M. Zhou et al.
a carbon loading of 19% with a mobile phase consisting of isocratic mixture of buffer (ammonium acetate–acetic acid; pH 3.7; 0.05 M) and acetonitrile in the ratio of 84:16 (v/v). The column temperature was maintained at 30 C. Injection volume was 50 ml and the flow rate was maintained at 1 ml/min and column eluent was monitored at 280 nm for 15 min. A powder Xray diffractometer (Thermal ARL X’TRA, Thermal Technology Co.) was used to identify the crystal form of powder products, using Cu Ka radiation at 40 kV and 40 mA. Diffraction data were collected from 2 to 50 at a scanning rate of 1.2 /min with a step size of 0.02 . Thermal behaviors of the samples were performed using a differential scanning calorimetry (PYRIS Diamond DSC, PerkinElmer Co.) and a thermogravimetric analyzer (PYRIS 1 TGA, PerkinElmer Co.). For DSC testing, samples were weighted and sealed in aluminum pans and heated from 40 C to 200 C at a rate of 10 C/min under N2 gas purge at flow rate of 20 ml/min. For TGA testing, 4 mg of samples were placed in an open platinum crucibles and raise temperature from ambient temperature to 600 at a rate of 10 C/min under nitrogen gas flow of 20 ml/min. Fourier transform infrared spectroscopy (Thermo Nicolet 370) was used to analyze the difference of the two crystal forms with scan range 675–4000 cm1, 1024 scans and a resolution of 1 cm1. In order to evaluate the thermostability of Form II product, a long-term stability testing was carried out under certain temperature and humility. During this process, Form II sample was stored under an accelerated condition of 40 C and 75% RH for 14 weeks. The crystal transformation of the sample, including crystal structure and thermal behavior, was monitored periodically by PXRD and DSC.
Results and discussion Pure crystal Form II was obtained by evaporating a methanol or aqueous solution of metoprolol succinate, and Form II show better dissolubility in the water than Form I during the subsequent dissolution measurements. Both polymorphic forms of metoprolol succinate were characterized using PXRD, DSC, TGA and FTIR. From the testing results, Form II shows significant differences in contrast with Form I, such as unique diffraction peaks and lower melting point.
Pharm Dev Technol, Early Online: 1–5
O H N
O
+
OH H O O
−
O −
O H
+
OH
N
O
H O
Figure 1. Molecular structure of metoprolol succinate.
120
115
ppm×103
110
105
100 0
100
200
300
400
t(h)
Figure 2. The solubility trends of Form I and Form II, insert is the picture of the ending solutions of the two crystal forms.
Solubility testing As well known, a solid drug compound maybe has different solubility due to its polymorphism. For the two crystal forms of metoprolol succinate, the measured concentrations by HPLC at set intervals are reported in Figure 2, both crystal forms show similar dissolving process. From the concentration curves, both solutions reached equilibrium after original fluctuation and Form II shows higher solubility with 110 g/l than 100 g/l of Form I. Inset in Figure 2 shows the picture of the solutions of two forms after 8 h stirring, it can be observed that Form II is clear but Form I is still in suspension form. Solubility of a drug substance is a very important parameter, which to some extent determines the bioavailability of the drug. Therefore, the new crystal Form II is of potential to be an active pharmaceutical ingredient (API) for drug product. X-ray diffraction As a most effective method to identify a drug polymorphic form, PXRD patterns of both Forms I and II are presented in Figure 3 and the data of main diffraction peaks are also listed in Table 1. Form II, different from Form I reported in patent CN20 1110 341 837.9, has characteristic diffraction peaks at
Intensity
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2
Form II
Form I 5
10 15 20 25 30 35 40 45
2-theta
Figure 3. PXRD diffractograms of Form I and Form II.
3.834 , 7.668 , 10.666 , 14.253 , 19.450 , 23.348 , 23.406 and so forth, which means Form II is a new polymorphic form of metoprolol succinate. Thermoanalysis Thermal behaviors of both polymorphic forms were tested using DSC and TGA, and the heating curves of the two crystal forms are shown in Figure 4(a) and (b). From the DSC curves, sharp
New polymorphic form of metoprolol succinate
DOI: 10.3109/10837450.2016.1146295
3
Table 1. Comparison of diffraction data of Form I and Form II. Form I
Form II
2-Theta
˚ dA
I%
2-Theta
˚ dA
I%
6.994 11.419 14.030 20.040 21.125 23.058 24.159 27.116
12.6284 7.7427 6.3072 4.4273 4.2022 3.8540 3.6808 3.2859
61.7 1.2 100.0 18.5 20.2 2.6 5.3 4.4
3.834 7.668 10.666 11.989 14.253 15.925 19.450 20.348
23.0279 11.5202 8.2881 7.3758 6.2090 5.5607 4.5601 4.3610
58.2 22.5 71.5 44.3 60.9 36.2 85.5 100.0
Table 2. The melting range, melting point and enthalpy calculated from DSC traces.
(a)
Endo up
80
Melting point ( C) Melting range ( C) Enthalpy (J/g)
Form II 60
40
Form I
Form II
138.00 3.24 218.81
125.99 2.85 182.19
Form I
80
100
120
In addition, it can be noticed in Figure 4(b), the two TGA curves are of similar decomposition trend. In the temperature range before decomposition, there are no any weightlessness steps caused by solvent evaporation, which illustrates that both crystal forms of metoprolol succinate are anhydrous polymorphs.
140
Temperature (°C) (b) 100
Infrared spectroscopy
80 Weight (%)
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100
60 Form I Form II
40 20 100
200
300
400
Temperature (°C)
Figure 4. (a) DSC and (b) TGA curves of Form I and Form II.
endothermic peaks can be seen and the thermal data of the two crystal forms were calculated and listed in Table 2. Form II has a melting point at 126 C, significantly lower than that of Form I at 138 C. Melting point, as an important characteristic parameter for a drug compound, is generally unique for some spatial crystal structure, which further indicates that Form II is a new polymorphic form. At the same time, only a single endothermic melting peak also means it is a pure crystalline product and no phase transformation during heating. The difference of melting point between two forms shows that their lattice energy are quite different, the intermolecular forces of Form II is weaker than that Form I. According to the heat-offusion rule of polymorphism15, the higher melting polymorph has the lower heat of fusion in an enantiotropic system, otherwise the modification is monotropic. In this study, Form I has higher melting point and enthalpy of 218.81 J/g comparing to lower melting Form II with an enthalpy of 182.19 J/g. It is clear that the thermodynamic relation between the two forms of metoprolol succinate belongs to monotropic system.
As well known, hydrogen bond forming can cause polymorphism in many organic compounds, such as sulfonamides, barbiturate derivatives and oxalic acid2. From the chemical structure of metoprolol succinate (Figure 1), there are several functional groups in the molecule, like –OH and –NH, are available for hydrogen bond forming, such as intermolecular and intramolecular hydrogen bond, which can be detected using IR spectroscopy. In general, –OH and –NH stretching vibration bands can be found within the wavenumber range of 4000–3000 cm1 in IR pattern. However, these peaks will get broadder and have a shift to low wavenumber owing to the hydrogen bond effect. Therefore, the occurrence of hydrogen bonds in the two crystal forms can be understood by comparing their IR spectra specifically. Figure 5 exhibits the IR spectra of both polymorphic forms within the wavenumber range of 4000–3000 cm1, where several broad peaks can be seen on the curves. These peaks exhibit broadder profile and a blue shift compared with free –OH or –NH groups. Above broaden and shift of IR peaks indicate hydrogen bonds occur in the two polymorphic products. However, IR pattern of Form II has only one broad peak at 3420 cm1, while Form I has a broader peaks at 3410 cm1, and another small peak at 3150 cm1. The difference between the IR patterns of the two crystal forms suggests that there are different hydrogen bonds forming in Form I and Form II, respectively. Long-term stability testing Long-term thermostability testing for the two polymorphic forms was conducted by respectively storing them at an accelerated condition of 40 C and 75% RH for 14 weeks. During the testing, a few batches of specimens were in turn taken out at intervals for PXRD and DSC measurements to monitor their structure changes.
4
M. Zhou et al.
Pharm Dev Technol, Early Online: 1–5
Reflectance%
Form II
3800
For such a big molecule with rich C–C bonds and functional groups, molecule conformation easily change to be more stable structure with torsion of carbon chain under certain driving force. In this transformation, Form II crystals with high energy state geometry configuration will spontaneously transform into low energy state crystal structure (Form I) at certain condition.
Form I
Conclusion
3600
3400
3200
3000
2800
Wavenumber(cm−1)
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Figure 5. FTIR spectra of Form I and Form II in the wavenumber range of 2500–3800 cm1.
In this study, a new polymorphic form (Form II) of metoprolol succinate, with main characteristic diffraction peaks at 3.765 , 7.599 , 10.597 , 14.184 , 19.381 , 23.337 and so forth, was discovered by slowly evaporating its methanol or aqueous solution. Its melting point was measured to be 126.0 C using DSC. Compared with Form I, Form II have sole diffraction pattern and lower meting temperature. The thermostability testing exhibits Form II is a metastable crystal form and will gradually transform into Form I after long time high temperature and humidity treatment. The discovery of the new crystal form undoubtedly increases a number for the polymorphic form family of metoprolol succinate. Although Form II is a metastable crystal form, it shows better dissolubility compared with Form I, which makes it a potential API to be used in pharmaceutical production.
Acknowledgements The authors would like to express the gratitude to Min Shao for consultation in FTIR testing and financial support from the Young Researchers Foundation of Zhejiang Provincial Top Key Academic Discipline of Chemical Engineering and Technology, Zhejiang Sci-Tech University (ZYG2015007), Zhejiang Provincial Natural Science Foundation under Grant No. LY16B010002.
Declaration of interest This work was supported by National Natural Science Foundation of the Young Researchers Foundation of Zhejiang Provincial Top Key Academic Discipline of Chemical Engineering and Technology, Zhejiang Sci-Tech University and Zhejiang Provincial Natural Science Foundation. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.
References
Figure 6. (a) The XRD patterns of metoprolol succinate Form II during the long-term thermostability testing and (b) corresponding DSC thermograms of these specimens: (A) 0 weeks, (B) 2 weeks, (C) 4 weeks, (D) 6 weeks, (E) 8 weeks, (F) 10 weeks, (G) 12 weeks and (H) 14 weeks.
From XRD patterns shown in Figure 6(a), Form II gradually changed into hybrid of Form I and II after 4 weeks, even then fully Form I after 8 weeks. Corresponding thermograms of the two samples also suggest the same trend as exhibited in Figure 6(b). Above results suggest that Form I can keep its crystal structure even under harsh environment for 14 weeks, but Form II is a metastable polymorphic form and would transform into Form I after 4 weeks treatment under present condition.
1. Yu L, Reutzel-Edens SM, Mitchell CA. Crystallization and polymorphism of conformationally flexible molecules: problems, patterns, and strategies. Org Process Res Dev 2000;4:396–402. 2. Nagai K, Ushio T, Miura H, et al. Four new polymorphic forms of suplatast tosilate. Int J Pharm 2014;460:83–91. 3. Li Y, Chow PS, Tan RBH. Quantification of polymorphic impurity in an enantiotropic polymorph system using differential scanning calorimetry, X-ray powder diffraction and Raman spectroscopy. Int J Pharm 2011;415:110–118. 4. Ashizawa K. Polymorphism and crystal structure of 2R,4S,6-fluoro2-methyl-spiro[chroman-4,40 -imidazoline]-20 ,5-dione (M79175). J Pharm Sci 1989;78:256–260. 5. Elguero J. Polymorphism and desmotropy in heterocyclic crystal structures. Cryst Growth Des 2011;11:4731–4738. 6. Vega D, Petragalli A, Ferna´ndez D, Ellena JA. Polymorphism on leflunomide: stability and crystal structures. J Pharm Sci 2006;95: 1075–1083. 7. Threlfall TL. Analysis of organic polymorphs – a review. Analyst 1995;120:2435–2460. 8. Dong Jr Z, Young V, Sheth A, et al. Crystal structure of neotame anhydrate polymorph G. Pharm Res 2002;19:1549–1553. 9. Dimitris P, PapadopoulosMD F, Vasilios Papademetriou MFF. Metoprolol succinate combination in the treatment of hypertension. Angiology 2009;60:608–613.
DOI: 10.3109/10837450.2016.1146295
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10. Price CP, Grzesiak AL, Matzger AJ. Crystalline polymorph selection and discovery with polymer heteronuclei. J Am Chem Soc 2005;127:5512–5517. 11. Lang M, Grzesiak AL, Matzger AJ. The use of polymer heteronuclei for crystalline polymorph selection. J Am Chem Soc 2002;124: 14834–14835. 12. Zhang GGZ, Gu C, Zell MT, et al. Crystallization and transitions of sulfamerazine polymorphs. J Pharm Sci 2002;91: 1089–1100.
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13. Zhang G, Gao L, Zhang Z, et al. Heating-induced phase transition of bupropion hydrobromide polymorphs. J Pharm Sci 2012;101: 3091–3095. 14. Appelgen CH, Eskilsson EC. Pharmaceutical composition comprising metroprolol succinate. US 5001161; 1988 15. Grunenberg A, Henck JO, Siesler HW. Theoretical derivation and practical application of energy/temperature diagrams as an instrument in preformulation studies of polymorphic drug substances. Int J Pharm 1996;129:147–158.
ISSN: 1083-7450 (Print) 1097-9867 (Online) Journal homepage: http://www.tandfonline.com/loi/iphd20
A new polymorphic form of metoprolol succinate Mengqing Zhou, Ju Ao, Song Liu, Chaogang Wu, Pingan Lai, Haitao Gao & Guoqing Zhang To cite this article: Mengqing Zhou, Ju Ao, Song Liu, Chaogang Wu, Pingan Lai, Haitao Gao & Guoqing Zhang (2016): A new polymorphic form of metoprolol succinate, Pharmaceutical Development and Technology, DOI: 10.3109/10837450.2016.1146295 To link to this article: http://dx.doi.org/10.3109/10837450.2016.1146295
Published online: 24 Feb 2016.
Submit your article to this journal
Article views: 5
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iphd20 Download by: [University of California, San Diego]
Date: 03 March 2016, At: 02:58
http://informahealthcare.com/phd ISSN: 1083-7450 (print), 1097-9867 (electronic) Pharm Dev Technol, Early Online: 1–5 ! 2016 Taylor & Francis. DOI: 10.3109/10837450.2016.1146295
RESEARCH ARTICLE
A new polymorphic form of metoprolol succinate Mengqing Zhou1, Ju Ao1, Song Liu1, Chaogang Wu2, Pingan Lai2, Haitao Gao2, and Guoqing Zhang1 1
Engineering Research Center for Eco-Dyeing and Finishing of Textiles, Ministry of Education, Zhejiang Sci-Tech University, Hangzhou, China and Zhejiang Apeloa Medical Technology Co, Ltd, Jinhua, China
Downloaded by [University of California, San Diego] at 02:58 03 March 2016
2
Abstract
Keywords
Only one crystal form of metoprolol succinate (Form I) was reported during previous researches and production. In this study, a new polymorph of metoprolol succinate (here named as Form II) was discovered and investigated by X-ray diffraction, thermoanalysis and infrared spectroscopy. The results show its crystal structure and thermal properties are significantly different with Form I. Compared with Form I, Form II exhibits specific diffraction pattern, lower melting temperature and weaker hydrogen bond effect. The thermostability testing suggests Form II is a metastable crystal form and will gradually transform into Form I undergoing treatment of high temperature and humidity. Metastable crystal form generally has better dissolubility than its corresponding stable form. Subsequent measurement also verified that Form II can dissolve in the water more quickly than Form I.
Hydrogen bond, metoptolol succinate, polymorphic form, thermostability
Introduction Polymorphism is a widespread phenomenon for small molecule drugs, and increasingly draws people’s concern in the pharmaceutical research field. Polymorphism of a molecule compound is mainly from conformational flexibility, hydrogen bond and so on1. Many researches verified that different crystal forms of a drug compound may exhibit distinctive properties such as bioavailability, dissolution rate, stability, morphology and solubility2–6. In fact, deep investigation for polymorphism of drug compound not only contributes to understand molecular behavior, intermolecular interactions and the relationship between crystal structure, crystal growth and their influence on bulk properties7–9, but is an important research content in pharmaceutical development and production. Polymorphic forms of a drug compound can traditionally be obtained by changing the crystallization processes and conditions, such as the use of different solvents, temperature and pressure controlling, pseudo-seeding the supersaturated solution and polymer-induced heteronucleation (PIHn)2,10–12. For a polymorphic drug compound, each crystal form has unique physicochemical properties, for example thermostability is an important parameter to evaluate whether a crystal form can be used in pharmaceutical preparation or not. For those instable and metastable polymorphs, they easily degrade due to phase transforming upon manipulation, recrystallization or thermal treatment13, so that it is vital to investigate the stability of the crystal forms during the R&D and production of a polymorphic drug. Metoprolol succinate, chemical name 1-[4-(2-methoxyethyl)phenoxy]-3-(propan-2-ylamino)propan-2-ol butanedioate (2:1), as shown in Figure 1, is a selective ß(1)-adrenergic antagonist and has been proven its high efficacy in treating hypertension, angina Address for correspondence: Guoqing Zhang, Engineering Research Center for Eco-Dyeing and Finishing of Textiles, Ministry of Education, Zhejiang Sci-Tech University, Hangzhou 310018, China. Tel: +86 571 86843588. E-mail: [email protected]
History Received 16 November 2015 Revised 4 January 2016 Accepted 20 January 2016 Published online 23 February 2016
pectoris and chronic heart failure with abnormal left ventricle contraction function and stable symptoms in the clinic14. Previous researches reported the existence of only one form (Form I) of metoprolol succinate in the patent CN20 1110 341 837.9 (Patented 2012). In this study, a new polymorphic form (Form II) of metoprolol succinate is discovered and characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and Fourier transform infrared spectroscopy (FTIR). The new Form II, with totally different crystal structure and thermal property, has been proven to be a new polymorphic form of metoprolol succinate.
Experimental Materials The metoprolol succinate drug substance was provided by Zhejiang Apeloa Medical Technology Co., Ltd (Jinhua, China). The chemicals such as methanol and ethanol were bought from Tianjing YongDa Chemical Reagent Co., Ltd (Tianjing, China) with a purity exceeding 99.5%. Preparation and characterization of the form II The Form II powder was prepared by evaporating a methanol or aqueous solution of metoprolol succinate with a ratio of 1:25–30 or 1:10–15 in mass, respectively, at a temperature range of 70– 100 C for 2–24 h. The solubility measurements for both crystal forms were then performed by HPLC analysis. Both crystal forms were, respectively, weighted 750 mg and added into 3.0 ml water at the same time. Two solutions were stirred at room temperature with same rotating speed, and then, respectively, sampling at set intervals of 10 min, 30 min, 1, 3 and 8 h for HPLC testing. An Agilent 1100 (Agilent Co.) equipped with an Agilent G1316B UV Detector was used for the measurements. The analysis was carried out on an octadecylsilyl silica gel C18 column with a pore size of 10 nm and
M. Zhou et al.
a carbon loading of 19% with a mobile phase consisting of isocratic mixture of buffer (ammonium acetate–acetic acid; pH 3.7; 0.05 M) and acetonitrile in the ratio of 84:16 (v/v). The column temperature was maintained at 30 C. Injection volume was 50 ml and the flow rate was maintained at 1 ml/min and column eluent was monitored at 280 nm for 15 min. A powder Xray diffractometer (Thermal ARL X’TRA, Thermal Technology Co.) was used to identify the crystal form of powder products, using Cu Ka radiation at 40 kV and 40 mA. Diffraction data were collected from 2 to 50 at a scanning rate of 1.2 /min with a step size of 0.02 . Thermal behaviors of the samples were performed using a differential scanning calorimetry (PYRIS Diamond DSC, PerkinElmer Co.) and a thermogravimetric analyzer (PYRIS 1 TGA, PerkinElmer Co.). For DSC testing, samples were weighted and sealed in aluminum pans and heated from 40 C to 200 C at a rate of 10 C/min under N2 gas purge at flow rate of 20 ml/min. For TGA testing, 4 mg of samples were placed in an open platinum crucibles and raise temperature from ambient temperature to 600 at a rate of 10 C/min under nitrogen gas flow of 20 ml/min. Fourier transform infrared spectroscopy (Thermo Nicolet 370) was used to analyze the difference of the two crystal forms with scan range 675–4000 cm1, 1024 scans and a resolution of 1 cm1. In order to evaluate the thermostability of Form II product, a long-term stability testing was carried out under certain temperature and humility. During this process, Form II sample was stored under an accelerated condition of 40 C and 75% RH for 14 weeks. The crystal transformation of the sample, including crystal structure and thermal behavior, was monitored periodically by PXRD and DSC.
Results and discussion Pure crystal Form II was obtained by evaporating a methanol or aqueous solution of metoprolol succinate, and Form II show better dissolubility in the water than Form I during the subsequent dissolution measurements. Both polymorphic forms of metoprolol succinate were characterized using PXRD, DSC, TGA and FTIR. From the testing results, Form II shows significant differences in contrast with Form I, such as unique diffraction peaks and lower melting point.
Pharm Dev Technol, Early Online: 1–5
O H N
O
+
OH H O O
−
O −
O H
+
OH
N
O
H O
Figure 1. Molecular structure of metoprolol succinate.
120
115
ppm×103
110
105
100 0
100
200
300
400
t(h)
Figure 2. The solubility trends of Form I and Form II, insert is the picture of the ending solutions of the two crystal forms.
Solubility testing As well known, a solid drug compound maybe has different solubility due to its polymorphism. For the two crystal forms of metoprolol succinate, the measured concentrations by HPLC at set intervals are reported in Figure 2, both crystal forms show similar dissolving process. From the concentration curves, both solutions reached equilibrium after original fluctuation and Form II shows higher solubility with 110 g/l than 100 g/l of Form I. Inset in Figure 2 shows the picture of the solutions of two forms after 8 h stirring, it can be observed that Form II is clear but Form I is still in suspension form. Solubility of a drug substance is a very important parameter, which to some extent determines the bioavailability of the drug. Therefore, the new crystal Form II is of potential to be an active pharmaceutical ingredient (API) for drug product. X-ray diffraction As a most effective method to identify a drug polymorphic form, PXRD patterns of both Forms I and II are presented in Figure 3 and the data of main diffraction peaks are also listed in Table 1. Form II, different from Form I reported in patent CN20 1110 341 837.9, has characteristic diffraction peaks at
Intensity
Downloaded by [University of California, San Diego] at 02:58 03 March 2016
2
Form II
Form I 5
10 15 20 25 30 35 40 45
2-theta
Figure 3. PXRD diffractograms of Form I and Form II.
3.834 , 7.668 , 10.666 , 14.253 , 19.450 , 23.348 , 23.406 and so forth, which means Form II is a new polymorphic form of metoprolol succinate. Thermoanalysis Thermal behaviors of both polymorphic forms were tested using DSC and TGA, and the heating curves of the two crystal forms are shown in Figure 4(a) and (b). From the DSC curves, sharp
New polymorphic form of metoprolol succinate
DOI: 10.3109/10837450.2016.1146295
3
Table 1. Comparison of diffraction data of Form I and Form II. Form I
Form II
2-Theta
˚ dA
I%
2-Theta
˚ dA
I%
6.994 11.419 14.030 20.040 21.125 23.058 24.159 27.116
12.6284 7.7427 6.3072 4.4273 4.2022 3.8540 3.6808 3.2859
61.7 1.2 100.0 18.5 20.2 2.6 5.3 4.4
3.834 7.668 10.666 11.989 14.253 15.925 19.450 20.348
23.0279 11.5202 8.2881 7.3758 6.2090 5.5607 4.5601 4.3610
58.2 22.5 71.5 44.3 60.9 36.2 85.5 100.0
Table 2. The melting range, melting point and enthalpy calculated from DSC traces.
(a)
Endo up
80
Melting point ( C) Melting range ( C) Enthalpy (J/g)
Form II 60
40
Form I
Form II
138.00 3.24 218.81
125.99 2.85 182.19
Form I
80
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In addition, it can be noticed in Figure 4(b), the two TGA curves are of similar decomposition trend. In the temperature range before decomposition, there are no any weightlessness steps caused by solvent evaporation, which illustrates that both crystal forms of metoprolol succinate are anhydrous polymorphs.
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Temperature (°C) (b) 100
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Temperature (°C)
Figure 4. (a) DSC and (b) TGA curves of Form I and Form II.
endothermic peaks can be seen and the thermal data of the two crystal forms were calculated and listed in Table 2. Form II has a melting point at 126 C, significantly lower than that of Form I at 138 C. Melting point, as an important characteristic parameter for a drug compound, is generally unique for some spatial crystal structure, which further indicates that Form II is a new polymorphic form. At the same time, only a single endothermic melting peak also means it is a pure crystalline product and no phase transformation during heating. The difference of melting point between two forms shows that their lattice energy are quite different, the intermolecular forces of Form II is weaker than that Form I. According to the heat-offusion rule of polymorphism15, the higher melting polymorph has the lower heat of fusion in an enantiotropic system, otherwise the modification is monotropic. In this study, Form I has higher melting point and enthalpy of 218.81 J/g comparing to lower melting Form II with an enthalpy of 182.19 J/g. It is clear that the thermodynamic relation between the two forms of metoprolol succinate belongs to monotropic system.
As well known, hydrogen bond forming can cause polymorphism in many organic compounds, such as sulfonamides, barbiturate derivatives and oxalic acid2. From the chemical structure of metoprolol succinate (Figure 1), there are several functional groups in the molecule, like –OH and –NH, are available for hydrogen bond forming, such as intermolecular and intramolecular hydrogen bond, which can be detected using IR spectroscopy. In general, –OH and –NH stretching vibration bands can be found within the wavenumber range of 4000–3000 cm1 in IR pattern. However, these peaks will get broadder and have a shift to low wavenumber owing to the hydrogen bond effect. Therefore, the occurrence of hydrogen bonds in the two crystal forms can be understood by comparing their IR spectra specifically. Figure 5 exhibits the IR spectra of both polymorphic forms within the wavenumber range of 4000–3000 cm1, where several broad peaks can be seen on the curves. These peaks exhibit broadder profile and a blue shift compared with free –OH or –NH groups. Above broaden and shift of IR peaks indicate hydrogen bonds occur in the two polymorphic products. However, IR pattern of Form II has only one broad peak at 3420 cm1, while Form I has a broader peaks at 3410 cm1, and another small peak at 3150 cm1. The difference between the IR patterns of the two crystal forms suggests that there are different hydrogen bonds forming in Form I and Form II, respectively. Long-term stability testing Long-term thermostability testing for the two polymorphic forms was conducted by respectively storing them at an accelerated condition of 40 C and 75% RH for 14 weeks. During the testing, a few batches of specimens were in turn taken out at intervals for PXRD and DSC measurements to monitor their structure changes.
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Reflectance%
Form II
3800
For such a big molecule with rich C–C bonds and functional groups, molecule conformation easily change to be more stable structure with torsion of carbon chain under certain driving force. In this transformation, Form II crystals with high energy state geometry configuration will spontaneously transform into low energy state crystal structure (Form I) at certain condition.
Form I
Conclusion
3600
3400
3200
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Wavenumber(cm−1)
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Figure 5. FTIR spectra of Form I and Form II in the wavenumber range of 2500–3800 cm1.
In this study, a new polymorphic form (Form II) of metoprolol succinate, with main characteristic diffraction peaks at 3.765 , 7.599 , 10.597 , 14.184 , 19.381 , 23.337 and so forth, was discovered by slowly evaporating its methanol or aqueous solution. Its melting point was measured to be 126.0 C using DSC. Compared with Form I, Form II have sole diffraction pattern and lower meting temperature. The thermostability testing exhibits Form II is a metastable crystal form and will gradually transform into Form I after long time high temperature and humidity treatment. The discovery of the new crystal form undoubtedly increases a number for the polymorphic form family of metoprolol succinate. Although Form II is a metastable crystal form, it shows better dissolubility compared with Form I, which makes it a potential API to be used in pharmaceutical production.
Acknowledgements The authors would like to express the gratitude to Min Shao for consultation in FTIR testing and financial support from the Young Researchers Foundation of Zhejiang Provincial Top Key Academic Discipline of Chemical Engineering and Technology, Zhejiang Sci-Tech University (ZYG2015007), Zhejiang Provincial Natural Science Foundation under Grant No. LY16B010002.
Declaration of interest This work was supported by National Natural Science Foundation of the Young Researchers Foundation of Zhejiang Provincial Top Key Academic Discipline of Chemical Engineering and Technology, Zhejiang Sci-Tech University and Zhejiang Provincial Natural Science Foundation. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.
References
Figure 6. (a) The XRD patterns of metoprolol succinate Form II during the long-term thermostability testing and (b) corresponding DSC thermograms of these specimens: (A) 0 weeks, (B) 2 weeks, (C) 4 weeks, (D) 6 weeks, (E) 8 weeks, (F) 10 weeks, (G) 12 weeks and (H) 14 weeks.
From XRD patterns shown in Figure 6(a), Form II gradually changed into hybrid of Form I and II after 4 weeks, even then fully Form I after 8 weeks. Corresponding thermograms of the two samples also suggest the same trend as exhibited in Figure 6(b). Above results suggest that Form I can keep its crystal structure even under harsh environment for 14 weeks, but Form II is a metastable polymorphic form and would transform into Form I after 4 weeks treatment under present condition.
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