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
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