Hydrate formation and phase transformation of risedronate monosodium in solution crystallization

Dissertation for the Degree of Master of Science HYDRATE FORMATION AND PHASE TRANSFORMATION OF RISEDRONATE MONOSODIUM IN SOLUTION CRYSTALLIZATION Department of Chemical Engineering Graduate School Hanbat National University by Nguyen, Thi Nhat Phuong Advisor: Prof Kwang Joo Kim February, 2009   碩士學位論文       용액결정화에서 리세드로네이트의 상변환 및  수화물 형성 특성              HYDRATE FORMATION AND PHASE TRANSFORMATION OF RISEDRONATE MONOSODIUM IN SOLUTION CRYSTALLIZATION               한밭大學校 産業大學院   化學工學科  Nguyễn Thị Nhật Phương   2009 년 2 월      Hydrate Formation and Phase Transformation of Risedronate Monosodium in Solution Crystallization Advisor: Prof Kwang Joo Kim Thesis submitted in partial fulfillment of the requirement for the degree of Master of Science November, 2008 Department of Chemical Engineering Graduate School Hanbat National University Nguyen Thi Nhat Phuong 용액결정화에서 리세드로네이트의 상변환 및 수화물 형성 특성 HYDRATE FORMATION AND PHASE TRANSFORMATION OF RISEDRONATE MONOSODIUM IN SOLUTION CRYSTALLIZATION 指導敎授 김 광 주 이 論文을 工學碩士學位 請求論文으로 제출함 2008 년 11 월 한밭大學校 産業大學院 化學工學科 Nguyễn Thị Nhật Phương Nguyen Thi Nhat Phuong 의 碩士學位 論文을 認准함 審査委員長 (인) 審査 委 員 (인) 審査 委 員 (인) 2008 년 12 월 한밭大學校 産業大學院 To Approve the Submitted Dissertation for the Degree of Master of Science by Nguyen, Thi Nhat Phuong Title: Hydrate Formation and Phase Transformation of Risedronate Monosodium in Solution Crystallization December, 2008 Chairman of Committee Prof Dr Seong Uk Hong Hanbat National University Member of Committee Prof Dr Kwang Joo Kim Hanbat National University Member of Committee Dr Seong Hoon Jeong LG Life Sciences Co., Ltd Graduate School Hanbat National University CONTENTS CONTENTS I LIST OF TABLES IV LIST OF FIGURES V NOMENCLATURES VIII ABBREVIATIONS IX ABSTRACT (IN KOREAN) X I INTRODUCTION II BACKGROUND Pharmaceutical solids Hydrate 10 Crystallization 18 3.1 Nucleation 18 3.2 Crystal growth 24 3.3 Phase transformation 25 3.4 Process control 29 III AIM OF THE STUDY 38 IV KINETIC STUDY ON THE HEMI-PENTA HYDRATE RS IN BATCH COOLING CRYSTALLIZATION 39 Introduction 39 Experiment 40 Results and discussions 42 3.1 Solubility and the crystallization of hemi-penta hydrate Risedronate monosodium 42 3.2 In-situ monitoring the crystallization by FBRM i   46 3.3 Effect of initial solution concentration 48 3.4 Kinetic of crystallization 50 Conclusions 57   V SOLVENT-MEDIATED PHASE TRANSFORMATION FROM HEMIPENTA TO MONO HYDRATE OF RS IN SUSPENSION 58 Introduction 58 Experiment 59 Results and discussions 62 3.1 Characterization of solid forms and solid composition 62 3.2 In-situ monitoring the phase transformation 65 3.3 Phase transformation kinetic 68 3.4 Concentration of solution 70 3.5 Effect of mono hydrate seeding 72 3.6 Effect of temperature 73 3.7 Effect of agitation rate 75 Conclusions 77 VI DEHYDRATION OF MONO HYDRATE FORM OF RS 78 Introduction 78 Experiment 79 Results and discussions 81 3.1 Characterization of monohydrate and anhydrous of Risedronate monosodium 81 3.2 In-situ measurement in the phase transformation 82 3.3 Kinetic of phase transformation 87 3.4 The effect of water content 90 3.5 The effect of temperature 92 3.6 The effect of agitation rate 93 Conclusions 95 VII CONCLUSIONS 96 ii   VIII.APPENDIX 98 IX REFERENCES 100 ABSTRACT 107 ACKNOWLEDGEMENT iii   LIST OF TABLES Table II-1 Various physical properties of pharmaceutical solids and pharmaceutical performance Table II-2 The examples of API polymorphism Table II-3 CSD statistics of crystal solids 10 Table II-4 The similarities and differences between polymorphs and hydrates 14 Table II-5 Classification of crystalline hydrates 16 Table II-6 Driving force for nucleation and growth 19 Table II-7 Phase transition and their underlying mechanism 28 Table II-8 List of analytical techniques for solid-state characterization 34 _ Table IV-1 Solubility (C*) data of hemi-penta and mono hydrate RS in water 43 Table IV-2 Summarized experimental conditions 43 Table IV-3 Calculation of the shape factor, molecular volume and interfacial free energy 55 _ Table V-1 The crystal structure data of mono and hemi-penta hydrate 62 Table V-2 Summary the function of induction, phase transformation time and time for the monohydrate crystallization according to temperature 75 _ Table VI-1 Results of kinetic parameters 90 _ Table VIII-1 The relation ship of ultrasonic velocity with concentration and solid fraction 99 iv   VII CONCLUSIONS In many case, the substance can be crystallized with the incorporated solvent If the aqueous solution was applied for the crystallization, hydrates form can be obtained Because of difference in crystal structure and molecular arrangement, they perform various physical properties which directly impact on the drug performance as well as the manufacturing process In this study, the different in solubility of mono, hemi-penta hydrate and anhydrous of Risedronate monosodium was found as an example Based on the solubility curve, the crystallization process was predicted and designed to successfully collect the desired form (hemi-penta hydrate) It is no doubt that the FBRM can be used as very useful in-situ technique for kinetic study as a process analysis technique Two different nucleation mechanisms of hemi-penta hydrate crystallization by cooling mode were found with varied supersaturation ranges The kinetic of crystal growth of this hydrate was also found Furthermore, crystallization may lead to the formation of a metastable phase which will eventually transform into a more stable one The behaviors of hydrates of RS and dehydration of hydrate forms were made clear It was discovered that the transformation of one hydrate to another with lower hydrated level can be generated even suspended in aqueous solution based on the different thermodynamic properties (solubility) as well as the various stabilities And the dehydration of hydrate to anhydrate form was also taken place by settling down in suitable non-aqueous solvent (methanol) The ultrasonic velocity measuring technique, FBRM and PVM have proven to be suitable for individually monitoring the phase transformation of hydrate forms and anhydrous even though in suspension The kinetic of the phase transformations were found Moreover, the ultrasonic velocity measurement was also used to determine the solid composition of hydrate as the first time Integrated peak area of PXRD patterns was applied to quantify the solid composition as the offline and confirmation technique The transformation rate of hydrates and anhydrous was strongly dependent on kinetics 96    Temperature had the significant kinetic effects in all cases The integration rate, impingement and attrition had great effect on the dehydration of the mono hydrate in non-aqueous solvent In contrast, in case of the solvent mediated transition of hemipenta to mono hydrate, the kinetic of transition was strongly influenced by temperature and seed crystal Water activity was the major factor determining the nature of anhydrous and mono hydrate of RS Moreover, other factors also effecting on the kinetic of phase transformation such as the additive, original crystal size were not investigated in this study It should be considered in the further studies in the future In summary, this study supports the useful information of the hydrate behavior as well as the phase transformation of RS The application of PATs such as ultrasonic velocity measurement, FBRM & PVM, PXRD in monitoring and kinetic study of crystallization as well as phase transformation of hydrates and anhydrous form was introduced 97    VIII APPENDIX Determination of solid composition of mono-hemi-penta hydrate mixture The mass fraction of hydrate solids was estimated from PXRD based on the integrated peaks area ratio The elucidation of this method was clearly shown in previous reports96-97 The compacts with known composition of two hydrate forms (w/w %) were prepared The peaks at 24.7o and 30.27o 2θ were representative peaks respectively for calibration (see Fig VII.1) The integrated peak area ratio, F was determined from the equation: F = A A 24h + A 30m 27 h 24 are area of peak at position 24,7o and 30.27o 2θ PXRD pattern Where of hemi-penta and mono hydrate respectively The calibration line and function were also shown in Fig VIII.1 From that, the mass fraction of hydrates of unknown composition sample during the phase transformation can be estimated from the calibration function 600 mass fraction of hemipenta hydrate = 0.4 500 24.7 - hemipenta 30.27 - mono 400 0.6 F Intensity, [cps] y = 0.28554x2 + 0.78173x R² = 0.98610 0.8 300 0.4 200 0.2 100 0 20.0 22.5 25.0 27.5 30.0 32.5 35.0 Theta, [deg] 0.2 0.4 0.6 0.8 Mass fraction of hemipenta hydrate Figure VIII.1 The peak selection and PXRD calibration data The calibration of ultrasonic velocity The change of ultrasonic velocity was dependent on the change of the concentration and solid fraction all described as the concentration unit (g of anhydrous RS/g of 98    solvent) following the linear function The detail functions of lines shown in Fig V.6b were summarized in Table VIII.1 In this section the change was default as the difference of the first state (f) and the second state (s) With assumption that the effect of the change of solid fraction of hemi-penta hydrate is negligible due to the small solid fraction of the initial suspension and it transfers into monohydrate We assume that the system in the phase transformation was the closed system, in where, there was no the loss of substance through out the outside environment The volume of solvent was constant during the phase transformation Therefore, the decrease of concentration of solution was equal with the increase of solid fraction: x1 = -x2 = x So, the combination of ultrasonic function during the phase transformation is expressed: y = y1+y2 = 201.4x Table VIII-1 The relation ship of ultrasonic velocity with concentration and solid fraction Function R2 Unsaturated hemi-penta and mono hydrate solution y1 = 304.2x1 0.996 Solid faction of mono hydrate y2 = 102.8x2 0.995 Solid fraction of hemi-penta hydrate y3= 159.7x3 0.999 Calibration line y = 201.4x y: the change of ultrasonic velocity, Δν = νf – νs (m/s) x: the change of concentration (1): the change of unsaturated solution of hemi-penta and mono hydrate (2): the change of solid fraction of mono hydrate (3): the change of solid fraction of hemi-penta hydrate             99    IX 10 11 12 13 14 15 REFERENCES D.J.W Grant, Theory and origin of polymorphism, in : H.G Brittain (Ed.), Polymorphism in Pharmaceutical Solids, Vol.95, Marcel Dekeker, New York, pp – 33, 1999 Geoff G.Z Zhanga, Devalina Lawa, Eric A Schmittb, Yihong Qiu, Phase transformation considerations during process development and manufacture of solid oral dosage forms, Advanced Drug Delivery Reviews, Vol 56, pp 371– 390, 2004 Andre S Raw*, M Scott Furness, Devinder S Gill, Richard C Adams, Frank O Holcombe Jr., Lawrence X Yu, Regulatory considerations of pharmaceutical solid 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H Zhu, C Yuen, D.J.W Grant, Influence of water activity in organic solvent + water mixtures on the nature of the crystallizing drug phase Theophylline, Int J Pharm., Vol 135, pp 151 – 160, 1996 103 H Zhu, D.J.W Grant, Influence of water activity in organic solvent + water mixtures on the nature of the crystallizing drug phase Ampicillin, Int J Pharm., Vol 139, pp 33 – 43, 1996 104 M Sacchetti, Determining the relative physical stability of anhydrous and hydrous crystal forms of GW 2016, Int J Pharm., Vol 273, No – 2, pp 195 – 202, April 2004 106    ABSTRACT HYDRATE FORMATION AND PHASE TRANSFORMATION OF RISEDRONATE MONOSODIUM IN SOLUTION CRYSTALLIZATION Nguyen, Thi Nhat Phuong Dept of Chemical Engineering Graduation School of Industry Hanbat National University Advisor: Prof Kwang Joo Kim This study was focus on the screening and controlling of hydrate form as well as understanding the phase transformation between solid forms of Risedronate monosodium (RS) in crystallization process using the in-situ measurement technique Firstly, the crystallization kinetic of hemi-penta hydrate RS was investigated in cooling mode The solubility, induction time, nucleation rate and growth rate in the crystallization of hemi-penta hydrate RS in water as a solvent were determined by the in-situ measurement using Focused Beam Reflectance Measurement (FBRM) The relationship between the induction time and the supersaturation was obtained for understanding mechanism of nucleation The nucleation mechanism including homogeneous and heterogeneous nucleation was grasped with respect to the supersaturation From the results of nucleation experiments, the interfacial tension of hemi-penta hydrate RS was determined Furthermore, the kinetic of crystal growth was also obtained As a function of suspersaturation, the crystal growth of hemi-penta 107    hydrate RS was controlled by the combination of one and two dimension growth mechanisms Secondly, the transformation from hemi-penta to mono hydrate form of Risedronate monosodium was studied by crystallization from the suspension of hemi-penta hydrate solid in the saturated solution with unseeded and seeded monohydrate By using both in-situ measurement of ultrasonic velocity and offline analysis technique such as optical microscopic, crystallography (PXRD), hydrate forms and transformation of them were determined in real time The effect of concentration and solid fraction in suspension on the ultrasonic velocity was found From that, the hydrate composition, concentration of solution and supersaturation during the phase transformation and crystallization were estimated with elapsed time The effect of mono hydrate seed, agitation rate and temperature on the phase transformation and crystallization was also considered Finally, the transformation of monohydrate into anhydrous form of Risedronate monosodium (RS) in methanol + water mixture was investigated The morphology of crystals was also measured in real time by in-line process monitoring number of particle, particle size and shape The phase transformation was detected by monitoring the variation of number of particle and morphology At the same time, solid forms were identified by various offline techniques Kinetic of phase transformation was found to be controlled by three-dimensional nuclear growth Water content in solvent mixture was a main factor determining the stability of anhydrous and monohydrate in the methanol + water mixture The time required for phase transformation was strongly affected by temperature and especially agitation rate 108    ACKNOWLEDGEMENT This study was carried out at the Crystallization and Engineering Laboratory (CPEL), Department of Chemical Engineering, Hanbat National University (HNU), Daejeon, South Korea First of all, I would like to show my deep gratitude to my advisor, Professor Kwang Joo Kim who supported to me this scholarship and the best conditions for my researching as well as living in Korea His encouragement and inspiring guidance have definitely made my work a lot easier and also much more interesting Secondly, I would like to express my thanks to Professor Joachim Ulrich (MartinLuther University Halle-Wittenberg, Germany) who gave me very useful advices during my studying process I wish to thank Prof Seong Uk Hong (HNU) and Dr Seong Hoon Jeong (LG Life Sciences Co., Ltd.) for their comments and suggestion as committee members I am also very thankful to all professors at Department of Chemical Engineering, Hanbat National University for their support, instruction and stimulation during my study period at HNU I am sincerely grateful to Mr Hoang Minh Nam, Dr Hoang Dong Nam and Dr Pham Thanh Quan (Faculty of Chemical Engineering, Ho Chi Minh City University of Technology, Viet Nam) for creating the advantageous conditions to me for further study in Korea It is a pleasure to thank all members of CPEL group, my classmates for the scientific contributions, fruitful discussions, technical assistance, guidance and friendship throughout the course of this work I also want to tell all of you that I am happy to work and study with you here I am also thankful to all my Vietnamese friends for their help in research as well as encouraging me during my study period To some one I might have misses to acknowledgement here: I beg your pardon     Special thanks to Mr Hoang Khoa Anh Tuan for introducing me to this laboratory, Mr Ngo Thanh An, Dr Pham Anh Tuan for their sincere helps and instructions for preparation of life in the beginning days in Korea Particularly, I express my deepest gratitude to my parents, my brothers, my sisters and my family for the endless support, love as well as encouragement which are the base point for my mind in all time Finally, I am honestly grateful to all of you again Daejeon, Korea, 24th December, 2008 Nguyen, Thi Nhat Phuong     ... Characterization of monohydrate and anhydrous of Risedronate monosodium 81 3.2 In- situ measurement in the phase transformation 82 3.3 Kinetic of phase transformation 87 3.4 The effect of water content... together with offline analysis technique to find the kinetic of hydrate formation; the phase transformation between hydrate forms in suspension of solid hydrate in saturated aqueous solution as... the phase transformation of compound during the heating/cooling recycle above/under the melting point The other one – solution phase transition occur during recrystallization of solution in a