Tài liệu 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. 1 INTRODUCTION II. BACKGROUND 4 1. Pharmaceutical solids 4 2. Hydrate 10 3. 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 1. Introduction 39 2. Experiment 40 3. 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 4. Conclusions 57   V. SOLVENT-MEDIATED PHASE TRANSFORMATION FROM HEMIPENTA TO MONO HYDRATE OF RS IN SUSPENSION 58 1. Introduction 58 2. Experiment 59 3. 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 4. Conclusions 77 VI. DEHYDRATION OF MONO HYDRATE FORM OF RS 78 1. Introduction 78 2. Experiment 79 3. 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 4. 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 .................................................................... 8 Table II-2. The examples of API polymorphism ......................................................... 9 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   LIST OF FIGURES Figure I-1. The molecule structure of hydrate of monosodium Risedronate............... 2 _________________________ Figure II-1. Schematic of pharmaceutical solid ........................................................... 4 Figure II-2. Effect of hydration on the physical and pharmaceutical properties of drug ......................................................................................................... 12 Figure II-3. Stability phase diagram for stoichiometric hydrates at constant temperature ............................................................................................. 17 Figure II-4. The course of crystallization, nucleation and growth mechanism .......... 18 Figure II-5. Supersaturation and methods to create supersaturation ........................ 19 Figure II-6. The solubility – supersolubility diagram ................................................ 20 Figure II-7. The desupersaturation curve .................................................................. 24 Figure II-8. The general view of controlling crystal form in crystallization .............. 30 Figure II-9. The measuring method of Liquisonic ...................................................... 35 Figure II-10. Focused Beam Reflectance and Particle Vision Measurement ................ 36 _________________________ Figure IV-1. The Schematic diagram for experimental apparatus .............................. 41 Figure IV-2. The solubility of hemi-penta and mono hydrate RS in water .................. 44 Figure IV-3. The PXRD patterns of the solid product obtained at various initial concentrations (Co) in crystallization at Tc=298K and that of hemi-penta hydrate RS referred in patent WO 03/086355 ........................................ 45 Figure IV-4. Typical plot of the total particle number and the mean length chord of particle with elapsed time at Tc=298K, Co=0.10g/g............................... 46 Figure IV-5. Variation of particle size distribution during crystallization of hemipenta hydrate RS at Co=0.10 g/g and Tc=298K ..................................... 47 Figure IV-6 The influence of initial concentration (Co) on shape of hemi-penta hydrate RS at Tc=298K ........................................................................... 49 v   Figure IV-7. Particle size distribution at initial solution concentrations (Co) of 0.08, 0.10, 0.12 and 0.13 g/g at Tc=298K........................................................ 49 Figure IV-8. Total number of particle according to elapsed time at various initial solution concentrations (Co), Tc=298K................................................... 51 Figure IV-9. The plot of induction time against with initial solution concentration (Co) in crystallization at Tc=298K .................................................................. 53 Figure IV-10. Plot of lntind versus (lnSmax)2 for hemi-penta hydrate RS in crystallization at Tc=298K ...................................................................... 54 Figure IV-11. Variation of median crystal size with elapsed time corresponding to various initial solution concentrations (Co) at Tc = 298K ...................... 56 Figure IV-12. The plot of maximum crystal growth rate (Gmax) with maximum allowable supersaturation (ΔCmax) ......................................................... 56 _________________________ Figure V-1. The experimental apparatus ................................................................... 61 Figure V-2: Characterization of mono and hemi-penta hydrates: DSC & TGA curve (a), PXRD patterns (b), SEM (left side of (c)) and microscopic (right side of (c)) image. ........................................................................................... 64 Figure V-3. The solubility curves of hydrate forms .................................................... 66 Figure V-4. The change of ultrasonic velocity against with time, PXRD patterns & microscopic images at T=346.5K, agitation rate of 300rpm .................. 67 Figure V-5. The mass fraction and ln(t-tind) & ln[-ln(1-x)]] plot at 346.5K .............. 69 Figure V-6. Effect of solution concentration and solid fraction on ultrasonic velocity (a) and calibration of ultrasonic velocity (b) .......................................... 70 Figure V-7. The change of solution concentration with elapsed time ........................ 72 Figure V-8. The effect of mono hydrate crystal seed on the phase transformation .... 73 Figure V-9. The ultrasonic velocity curves of seeded system experiment at various temperatures ........................................................................................... 74 Figure V-10. The effect of temperature on the transformation .................................... 75 Figure V-11. The lntind & lnΔCmax plot ......................................................................... 76 Figure V-12. The effect of agitation rate ...................................................................... 77 vi   Figure VI-1. Schematic diagram for experimental apparatus ..................................... 80 Figure VI-2. The DSC, TGA curves (a); PXRD patterns (b) and SEM images (c) of monohydrate and anhydrous form of RS ................................................ 82 Figure VI-3. The trend of particle number and particle size according to time in suspension at water Cw = 0.10 (wt %), T = 334.3 K and ω = 400rpm ... 83 Figure VI-4. The particle distributions (a), PXRD patterns (b) and PVM images (c) of samples during the transformation in suspension at Cw = 0.10 (wt %), T = 334.3 K and ω = 400rpm ................................................................. 85 Figure VI-5. The SEM images of sample during the phase transition in suspension at Cw = 0.10 (wt %), T = 334.3 K and ω =400rpm ..................................... 86 Figure VI-6. Peak selection and relationship between peak area fraction & weight fraction of monohydrate.......................................................................... 88 Figure VI-7. Solid composition during phase transformation ..................................... 88 Figure VI-8. Diagram of total transformation time according to water content ......... 92 Figure VI-9. Diagram of total transformation time according to temperature ........... 93 Figure VI-10. Diagram of total transformation time according to agitation rate ......... 94 _________________________ Figure VIII-1. The peak selection and PXRD calibration data ..................................... 98 vii   NOMENCLATURES Symbol name unit A a B C C* g G G H k kn kg L m, M n P r Rg S S t T v surface area of crystal activity nucleation rate concentration solubility growth order linear growth rate Gibbs free energy enthalpy compressibility rate constant of nucleation rate constant of crystal growth crystal size mass nucleation order pressure radius mass growth rate supersaturation ratio / entropy (residence) time temperature ultrasonic velocity m2 g/g g/g m s-1 kJ mol-1 kJ mol-1 Pa-1 s-1 s-1 m g Pa m kg m2 s-1 kJ mol-1 s, hr K m s-1 Greek letters α, fv β , fs γ ρ volume shape factor surface shape factor interfacial free energy density Indices * equilibrium f initial or first state N m-1 kg m-3 σ υ ω relative supersaturation mean linear growth velocity ms-1 volume fraction agitation rate rpm s second or final state n r s nucleation, nucleus relaxation saturation/surface/solution Nomenclature g ind lp growth induction latent period viii   ABBREVIATIONS API Active Pharmaceutical Ingredients  ATR-FTIR Attenuated Total Reflectance Fourier Transform Infrared CSD Cambridge Structural Database /or Crystal Size Distribution DSC Differential Scanning Calorimetry DTA Differential Thermal Analysis FBRM Focused Beam Reflectance Measurement HSM Hot State Microscopy IR Mix-Infrared MS Mass Spectroscopy NIR Near-Infrared PAT Process Analysis Technique ppm part per million PVM Particle Vision Microscope PXRD Powder X-Ray Diffraction rpm Revolution Per Minute RH Relative Humidity RS Risedronate Monosodium SEM Scanning Electron Microscopy SSNMR Solid-State Nuclear Magnetic Resonance TGA Thermo-Gravimetric Analysis TG/IR Thermogravimetry and Infrared Spectroscopy Ttr transition temperature wt weight v w volume water ix    국문요약 (Abstract in Korean) 용액결정화에서 리세드로네이트의 상변환 및 수화물 형성 특성    논문 제출자:   윙타이냑풍    지  도  교 수:    김광주  리세드로네이트  2.5 수화물의  결정화  메커니즘이  냉각결정화에  의하여  연구되었다.  물에서  리세드로네이트  2.5 수화물의  결정화에서  용해도,  유도기간,  핵생성 및 결정성장이 FBRM 에 의하여 분석되었다. 유도기간과 과포화의 관계는  핵생성의  메커니즘을  이해하기  위하여  분석되었다.  균일  및  불균일  핵생성  메커니즘이  과포화  관점에서  조사되었다.  핵생성  연구결과로부터  2.5 수화물의  계면장력이  실험적으로  결정되어졌다.  결정성장  메커니즘은  일차  및  이차원  성장의 혼합모델로 해석되었다.  리세드로네니트  2.5 수화물을  1 수화물로  변환하는  연구가  2.5 수화물  결정의  슬러리 용액하에서 결정화에 의하여 수행되었다. 초음파 속도의 측정 및 PXRD 을  동시에  사용하여  수화물의  변환이  실시간으로  결정되었다.  농도  및  고체분율의  초음파  속도에  미치는  영향을  측정하여  이들의  상관관계식을  도출하였다.  x    이로부터 수화물 조성, 용액 농도, 과포화도 및 결정화 정도가 결정되었다. 수화물  형태의 변환에 미치는 종, 교반속도 및 온도의 영향이 또한 고려되었다.  메탄올‐물 혼합물에서 리세드로네니트 1 수화물을 무수물로 변환하는 연구가  수행되었다.  침상모양의  1 수화물이  다면체의  무수물로  변화하는  과정을  실시간  측정방법인 FBRM 및 PVM 에 의하여 관측되었다. 고체의 결정형은 SEM, PXRD, DSC, TGA  등에  의하여  확인되었다.  리세드로네니트  1 수화물을  무수물로  상  변환에  대한  메커니즘이  분석되었다.  혼합용매에서  물의  함량이  무수물과  1 수화물의 안정성을 결정하는 주요 인자이었다. 상 변환에 요구되는 시간은 온도  및 교반속도에 의하여 영향을 받았다.     xi    I. INTRODUCTION As mentioned in many previous studies, the different solid states (polymorph, solvate, hydrate, salt, cocrystal) of active pharmaceutical ingredients (APIs) have various physical- physicochemical properties, which display a significant role in drug performance as well as drug manufacturing1-5. Recently, the understanding, monitoring and controlling solid-state form are necessary and challenge task. Bisphosphonates such as 3-pyridyl-1-hydro-cyethylidene-1,1-bisphosphonic acid (Risedronate) have been used for the treatment of diseases of bone and calcium metabolism. These diseases include oste-oporosis, hyperparathyroidism, hypercalcemia of malignancy, ostolytic bone metastases, myosistis ossifcans progressive, calcinoitis universalis, arthritis, neuritis, bursitis, tendonitis and other inflammatory conditions. Paget’s disease and heterotropic ossification are currently successfully treated with both EHDP (ethane-1-hydroxy-1,1-diphosphonic acid) and Risedronate. The bisphosphonates tend to inhibit the resorption of bone tissue, which is beneficial to patients suffering from excessive bone loss. However, in spite of certain analogies in biological activity, all bisphosphonates do not exhibit the same degree of biological activity. Some bisphosphonates have serious drawbacks with respect to the degree of toxicity in animals and the tolerability or negative side effects in human. The salt and hydrate forms of bisphosphates alter both their solubility and their bioavailability. Sodium and Calcium Risedronate are two kind of Risedronate salt often used6-8.The structure of monosodium Risedronate (RS) is shown in figure I.1. It is known in the literature that Risedronate mono-sodium commonly exists in anhydrous form and hydration states which have not only different morphologies but also various physical properties. In crystallization process, various hydrates containing either stoichiometric or nonstoichiometric amounts of water could be crystallized from the aqueous solution. By adjusting the degree of supersaturation, crystallization mode (cooling, drowning out, evaporations, ect.) and operating crystallization conditions, mono, hemi-penta and penta hydrates were selectively crystallized. In reported patents, various hydrate and anhydrous forms were obtained by crystallization from risedronic acid and sodium 1    hydroxide using water as solvent or mixture solvent of water and an alcohol, especially ethanol, methanol and isopropanol (IPA)6,7,9,10. Furthermore, it was also recognized that there was the transformation between hydrate forms by treating slurries in water, ethanol and IPA or mixture of water and ethanol; exposing to the high relative humidity environment or heating at fit temperature9,11.12. However, the controlling of these polymorphs is still complicated and unsolved problem in crystallization and particularly pharmaceutical crystallization research. To manage the solid form, it is necessary to completely understand the kinetic and mechanism of the crystallization of these polymorphs, which is not clear until now and need to be studied carefully in the future. It is known that the crystallization of various solid forms is composed of competitive nucleation, growth, and the transformation from a meta-stable to stable form. To select a desire form, the mechanism of each elementary step in the crystallization process need to be made clear in the relation to the operational conditions and the key controlling factor such as: solubility, supersaturation, temperature, stirring rate, mixing rate of reactant solutions, seed crystals, solvent, additives, interface tension, pH, etc.13 O P ONa N n= 0: n=0.5: n= 1: n=2: n=2.5: n=5: OH n. H2O  OH HO OH O anhydrous hemi hydrate mono hydrate dihydrate hemi-penta hydrate penta hydrate Figure I.1. The molecule structure of hydrate of monosodium Risedronate So, to understand the mechanism of habit modification, the formation of various hydrates and polymorphs as well as the transformation of them of Risedronate, it is necessary to study the kinetics of crystallization by measuring the nucleation rate and the growth rate which are the function of supersaturation. The in-situ measurements, inline techniques such as Focused Beam Reflectance Measurement (FBRM), PVM (Paticle Vision Microscope), Ultrasonic velocity measurement, Attenuated Total Reflectance-Fourier Transform Infrared (ATR-FTIR) spectroscopy, Raman and near infrared (NIR) measurement combine with the offline polymorph analysis technique 2    concluding: crystallography: X-Ray diffraction (single crystal and powder); morphology: polarizing optical microscopy, thermal microscopy, SEM; thermal method: TGA, DTA, DSC; molecular motion-vibrational spectroscopy: FTIR, Raman; NMR, etc. are very powerful techniques which can aid to identify and control the polymorphs and hydrate forms during crystallization process nowadays. In this study, the process analysis technique (PAT) including Ultrasonic velocity measurement, FBRM and PVM was used 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 well as the dehydration in suspension of hydrate in non-aqueous media. 3