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 i  CONTENTS CONTENTS I LIST OF TABLES IV LIST OF FIGURES V NOMENCLATURES VIII ABBREVIATIONS IX ABSTRACT (IN KOREAN) X I. INTRODUCTION 1 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 46 ii  3.3. Effect of initial solution concentration 48 3.4. Kinetic of crystallization 50 4. Conclusions 57  V. SOLVENT-MEDIATED PHASE TRANSFORMATION FROM HEMI- PENTA 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 iii  VIII.APPENDIX 98 IX. REFERENCES 100 ABSTRACT 107 ACKNOWLEDGEMENT iv  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 [...]... 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. .. anhydrate or of a lower hydrate changes the intermolecular interactions within the solid and hence modifies the internal energy and therefore the enthalpy of the solid As a result of hydration of the solid, changes in the shape and symmetry of the unit cell alter the entropy of the solid These changes in the enthalpy and entropy result in changes in the free energy and chemical potential of the solid Finally,... 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... solubility and dissolve rate can affect the ability of drug absorption that alters the bioavailability, bioequivalence and particularly efficiency of the drug product In deed, the rate and extent of drug absorption is depended on the various physiological factors including gastrointestinal motility, intestinal permeability and drug dissolution In the case, the dissolve rate of drug is low, it is determining... Incorporation of water molecules into the crystal lattice of the anhydrate or of the lower hydrate alters the following behavior of the crystals: (a) the interaction of the electron vibrations with light quanta changing the refractive index; (b) the interactions of the molecular motions with heat quanta changing the thermal conductivity; (c) the movement of the electrons in an electric field changing... 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. .. description of hydrate equilibria is the key to understanding not only the stability of hydrated forms but the inherent differences between hydrates and polymorphs 2.3.2 Similarities and differences between polymorphs and hydrates The summary of similarities and differences between polymorphs and hydrate is shown in Table II.4 Given the long list of similar behaviors, it is generally proper that polymorphs and. .. treatments, such as milling, tend to accelerate the kinetics of dehydration by generating surface/defects and by local heating 17    3 Crystallization Crystallization is a process whereby a crystalline phase is created as a consequence of molecular aggregation in a solution, leading to formation of nuclei and later, crystal growth Supersaturation, nucleation and crystal growth are the predominant physical phenomena... Secondly, in turn different physical and mechanical properties, for example, melting point, hygroscopicity, particle shape, density, flow-ability, and compactness may influence processing and/ or manufacturing of API or drug product Particularly, melting point and hygroscopicity are very important factors both for the design of an optimal formulation process and for selecting storage and packaging conditions... basic thermodynamics of crystalline hydrate formation/ stability and to highlight the intrinsic 12    differences between polymorphic systems and hydrate The following description is a hybrid based on the work of Grant and Higuchi 32 and that of Carstensen 33 The equilibrium between a hydrate and an anhydrous crystal (or between levels of hydration) may be described by the following relationship A ( . for the Degree of Master of Science HYDRATE FORMATION AND PHASE TRANSFORMATION OF RISEDRONATE MONOSODIUM IN SOLUTION CRYSTALLIZATION Department of Chemical Engineering Graduate School. 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. 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