Hydrate formation and phase transformation of risedronate monosodium in solution crystallization

INTRODUCTION As mentioned in many previous studies, the different solid states polymorph, solvate, hydrate, salt, cocrystal of active pharmaceutical ingredients APIs have various physica

HYDRAT E FORMATIO N 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

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

HYDRATE FORMATION AND PHASE TRANSFORMATION

OF RISEDRONATE MONOSODIUM IN SOLUTION

by Nguyen, Thi Nhat Phuong

Title: Hydrate Formation and Phase Transformation of Risedronate Monosodium in Solution Crystallization

December, 2008

Hanbat National University

Hanbat National University

LG Life Sciences Co., Ltd

Graduate School Hanbat National University

i

CONTENTS

CONTENTS I LIST OF TABLES IV LIST OF FIGURES V NOMENCLATURES VIII

IV KINETIC STUDY ON THE HEMI-PENTA HYDRATE RS IN BATCH

3.1 Solubility and the crystallization of hemi-penta hydrate Risedronate

monosodium 42 3.2 In-situ monitoring the crystallization by FBRM 46

3.3 Effect of initial solution concentration 48

V SOLVENT-MEDIATED PHASE TRANSFORMATION FROM

3.1 Characterization of solid forms and solid composition 62 3.2 In-situ monitoring the phase transformation 65

3.1 Characterization of monohydrate and anhydrous of Risedronate monosodium 81 3.2 In-situ measurement in the phase transformation 82

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

v

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 (C o ) in crystallization at T c =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 T c =298K, C o =0.10g/g 46

Figure IV-5 Variation of particle size distribution during crystallization of hemi-penta hydrate RS at C o =0.10 g/g and T c =298K 47

Figure IV-6 The influence of initial concentration (C o ) on shape of hemi-penta hydrate RS at T c =298K 49

Figure IV-7 Particle size distribution at initial solution concentrations (C o ) of 0.08,

0.10, 0.12 and 0.13 g/g at T c =298K 49

Figure IV-8 Total number of particle according to elapsed time at various initial solution concentrations (C o ), T c =298K 51

Figure IV-9 The plot of induction time against with initial solution concentration (C o ) in crystallization at T c =298K 53

Figure IV-10 Plot of lnt ind versus (lnS max ) 2 for hemi-penta hydrate RS in crystallization at T c =298K 54

Figure IV-11 Variation of median crystal size with elapsed time corresponding to various initial solution concentrations (C o ) at T c = 298K 56

Figure IV-12 The plot of maximum crystal growth rate (G max ) with maximum allowable supersaturation (ΔC max ) 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-t ind ) & 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 lnt ind & lnΔC max plot 76

Figure V-12 The effect of agitation rate 77

vii

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 C w = 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 C w = 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 C w = 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

NOMENCLATURES

kn rate constant of nucleation s-1

kg rate constant of crystal growth s-1

α, fv volume shape factor -

β , fs surface shape factor -

γ interfacial free energy N m-1

σ relative supersaturation - mean linear growth velocity ms-1

Indices

* equilibrium

f initial or first state

s second or final state

ABBREVIATIONS

ATR-FTIR Attenuated Total Reflectance Fourier Transform Infrared CSD Cambridge Structural Database /or Crystal Size Distribution DSC Differential Scanning Calorimetry

DTA Differential Thermal Analysis

PVM Particle Vision Microscope

PXRD Powder X-Ray Diffraction

rpm Revolution Per Minute

SEM Scanning Electron Microscopy

SSNMR Solid-State Nuclear Magnetic Resonance

TGA Thermo-Gravimetric Analysis

Ttr transition temperature

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. 

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.    

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

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

OH OH

P ONa

O OH

N

O H

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

n. H 2 O 

n= 0: anhydrous n=0.5: hemi hydrate n= 1: mono hydrate n=2: dihydrate n=2.5: hemi-penta hydrate n=5: penta hydrate

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

Figure II.1 Schematic of pharmaceutical solid 3,14

The common crystalline forms found for a given drug substance are polymorph and solvates4 A substance capable of crystallizing into different, but chemically identical, crystalline forms, is said to exhibit polymorphism15 On other hand, polymorphism is

Nonstoichiometric adducts

Stoichiometric adducts

Layer Cage (Clathrate)

Polymorph I Polymorph II

Solvate (water)

Counter ion Excipient

the ability of a substance to exist in two or more crystalline phases that have different arrangement or conformation of molecules in crystal lattice However, they share a common form in solution phase1 In pharmaceuticals, polymorphic forms may refer to crystalline and amorphous forms Crystalline forms have different arrangements and/or conformations of the molecules in the crystal lattice Amorphous forms consist of disordered arrangements of molecules that do not possess a distinguishable crystal lattice The occurrence of polymorphism is quite common among organic molecules and a large number of polymorphic drug compounds have been noted and catalogued4 Solvates are crystalline solid adducts containing solvent molecules within the crystal structure, in either stoichiometric or nonstoichiometric amounts of a solvent If the incorporated solvent is water, the solvate is commonly known as a hydrate4,16 Adducts frequently crystallize more easily because two molecules often can pack together with less difficulty than single molecules While no definite explanations can

be given, possible reasons include adduct symmetry, adduct-induced conformation changes, and the ability to form hydrogen bonds through the solvent molecules4 In this

report, the term “polymorphism” is used to refer to both polymorphs and solvates

Co-crystals consist of a single crystalline phase of multiple components in a given stoichiometric ratio, where the different molecular species interact by hydrogen bonding or by other non-covalent bonds These components are solids in their pure states at room temperature Because of its strength and directionality, the hydrogen bond has been the most important interaction in cocrystal formation17

As different crystalline polymorphs and solvates differ in crystal packing, and /or molecular conformation as well as in lattice energy and entropy, there are usually significant differences in their physical properties which are classified as packing, thermodynamic, spectroscopic, kinetic, surface, mechanical ones and showed in detail

in following table II.1.4,18 Differences in physical properties of various solid forms have

an important effect on the processing of drug substance into drug product19, while difference in solubility may have implications on the absorption of the active drug form

it dosage form13, by affecting the dissolution rate and possibly the mass transport of the

molecule These concerns have led to an increased regulatory interest in understanding the solid-state properties and behavior of drug substances4

1.2 Role of polymorphism in pharmaceuticals

Such as mentioned, polymorphism has contributed significant variability in product performance in many industrial fields, especially in pharmaceuticals It is recognized that a very large number of pharmaceuticals exhibit the phenomenon of polymorphism For example, 70% of barbiturates, 60% of sulfonamides and 23% of steroids exist in different polymorphic forms Table II.1 shows the list of examples of API polymorphisms These forms with different physical properties can significantly affect the physicochemical, formulation and processing parameters as well as the shelf-life (stability) of drug substance and excipients.18

Firstly, the solid-state properties of drug substance or API can have an important influence of solubility, dissolution, bioavailability, and bioequivalence of the final product As solid forms differ in their internal structure in solid state, the drug product including in various polymorphic forms can have different aqueous solubility and dissolution rates The change of 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 factor of the drug absorption, and large differences in solubility of the various polymorphic forms are likely to affect bioavailability and bioequivalence On the other hand, if solubility of polymorphs is high enough to obtain a rapid drug dissolving, variety of them is unlikely to perform the influence on drug effect The high energy amorphous form and meta-stable polymorphs and solvate expose a high solubility which aid to improve the disadvantage of poorly soluble forms So, drug product dissolution testing frequently provides a suitable means to identify and control the quality of the product from both the bioavailability and stability perspectives In particular, inadvertent changes to the polymorphic form which may affect drug product

bioavailability and bioequivalence can often be detected by drug product dissolution testing

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 Although the habit of a macroscopic crystal is not necessarily indicative of its polymorphic form, it can influence on the filtration or other processes

Furthermore, polymorphic forms can undergo phase conversion during manufacturing processes, such as drying, milling, grinding, wet granulation, spray-drying and compaction Besides, environment conditions including humidity, temperature, light, mechanic press can also reduce the phase transition in pharmaceutical solid, particularly solvate forms The extent of the polymorphic conversion will depend on the relative stability of polymorphs, kinetic barriers for phase conversion, type and degree of mechanical processing applied All of mentioned influences of polymorphs can affect the stability and effect of final product.16

Chloramphenicol palmitea (CAP) and Ritonnavir are good instances of polymorphism influence on the drug properties.18,20

In addition to its impact on chemical and physical properties, polymorphism is also relevant for intellectual considerations because polymorphs and solvates with superior properties can be protected, which is known in term intellectual property The alternate polymorphs give opportunities to obtain novel inventions and significant industrial applicability Inventing new polymorphs or solid forms effectively means synthesis of new material, which can be patented and increase the revenue potential of a company Many patents of new polymorph substance such as rantidine, ritonavir, ampicillin, fluroquinolone, chloramphenicol palmitate, celecoxib novobiocin, griseofulvin, indomethacin, mefenamic acid, etc are issued

− Free energy and chemical potential

− Internal energy and entropy

− Surface free energy

− Habit (ie shape)

− Interfacial tensions

Mechanical properties:

− Hardness, compactness and tablet property

− Tensile strength, flow, blending and handling

2.1 The importance of hydrate in pharmaceutical

Such as mentioned above, with various crystal lattices, hydrate (or solvate and polymorph) can be existed in different physical properties, which have significant effect

on the pharmaceutical performance of drug product The general role of polymorph and solvate (including hydrate) is made clear in section 1.2 In this section, the importance

of hydrate is mentioned in detail Hydrate is the most popular type of solvate occurring

in the pharmaceutical solid The potential pharmaceutical impact of changes in hydration state of crystalline drug substances and excipients exists throughout the development process The behavior of pharmaceutical hydrates has become the object

of increasing attention over last decade, primarily due (direct or indirectly) to the potential impact on the development process and dosage form performance Substances may hydrate or dehydrate in response to changes in environmental conditions, processing, or over time if in a metastabe thermodynamic state.1

Table II-3 CSD statistics of crystal solids 27

Organic crystal structures

Hydrates

Single component molecular organic structures

Single component polymorphic structures

The other consideration is the frequency with which hydrates are encountered in real life A search of Cambridge Structural Database (CSD) of crystal solid shows that approximately 7.3% of all the studied organic structures contain molecular water (see

table II.3) It is about seven-time of polymorph and cocrystal occurring ability Focusing on active drug substances, it is estimated that approximately one-third of the pharmaceutical actives are capable of forming crystalline hydrates

High potential occurrence in pharmaceutical solid phase and the difference in physical properties of drug substance, hydrate is very importance object on the first consideration of pharmaceutical compound as well as drug development to achieve the desire efficacy

2.2 Why do hydrates perform different physical properties? 28

Incorporation of the water molecule(s) in the crystal lattice of the anhydrate or a lower hydrate changes the dimensions, shape, symmetry and capacity (number of molecules, Z) of the unit cell As a result, the anhydrate and each hydrate of a given chemical compound exhibit different physical properties as described.29

A change in the volume of the unit cell upon hydration corresponds to a change in the molar volume and hence to a change in the density of the substance 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 the electrical conductivity

Formation of additional bonds between the host molecules and the water molecules and changes in the bonding between the host molecules themselves alter the cooperatively of the molecules in the crystal lattice and hence alter the melting point Fig II.2 summarizes the effect of hydration of a drug on its physical properties30 Incorporation of the water molecule(s) into the crystal lattice of the 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, the modification of the

2.3.1 Classical Higuchi/Grant Treatment

The equilibrium thermodynamics of stoichiometric hydrates has been described by several authors The overview presented here is intended both to review the basic thermodynamics of crystalline hydrate formation/stability and to highlight the intrinsic

Water molecule(s) in the crystal structure

Interactions between the molecules within the solid

Free energy (G) = Enthalpy (H) –T Entropy (S)

Partial molar free energy = Chemical potential

Stability = 1/Rate of decomposition

Bioavailability and product performance

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

O mH solid

A( )+ 2 ⇌A.mH2O(solid ) II.1

Where

m h

O H a solid A a

solid O mH A a K

] [

* )]

( [

)]

( [

2 2

solid O mH A

*)]

([

)]

(.[

activity), then K h = a[H 2 O] -m (and m = 1 for a monohydrate)

So, clearly, the stability of a hydrate relative to the anhydrate (or lower hydrate) depends upon the activity of water in the vapor phase, or the partial vapor pressure or relative humidity (the ratio of the vapor pressure of water to the saturation vapor pressure at that temperature P/P0) This straightforward thermodynamic 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 hydrates be addressed in the same general area of the pharmaceutical development process (for both technical and regulatory concerns) However, the differences between polymorphs and hydrates are significant The basic for all these

differences is that polymorphs are different crystal structure of the same molecules while hydrates are crystals of drug molecule with different numbers of water molecules31 With special hydrate state, it may be also existed the polymorphism

phenomena related to the different arrangement of molecules in crystal structure Therefore, the hydration state of crystalline hydrate is a function of water activity

Table II-4 The similarities and differences between polymorphs and hydrates

Polymorphs and hydrates

− Both polymorphs and hydrates

exist in different physical properties of

solid-state form

− Members of both polymorphic and

hydrates systems have different crystal

structures and exhibit different x-ray

powder diffraction patterns (PXRD),

thermograms (DSC or TGA), infrared

spectra, dissolution rates,

hygroscopicity, etc

− Interconversion between

polymorphs or hydrates may occur as

a function of temperature and/or

pressure or be solution mediated

− The potential for interconversion

during processing, stability testing,

and storage is present for both

polymorphs and hydrates

substance (including API and water molecule)

of hydrate may be different

crystalline hydrate is a function

of the water vapor pressure (water activity) above the solid

change is larger than polymorphs

physical properties is larger than polymorphs

substance (only API)

properties of polymorphs are same

typically only affected by changes in water vapor pressure if water sorption allows molecular motion causing a solution mediated transformation

change is smaller than hydrates

of physical properties is smaller than hydrates

In while, the stability of polymorphs is not depend on the solvent as well as water Polymorphs are typically only affected by the change in water vapor pressure or solvent

if water (solvent) sorption allows molecular motion, which in turn allows reorganization into a different polymorph (i.e., solution mediated transformation) This

distinction is particularly important in defining the relative free energy of hydrates31

A simple (only one molecule) anhydrous crystalline form is a one component system, and the free energy is, practically, specified by temperature and pressure A crystalline hydrate is a two-component system and is specified by temperature, pressure, and water activity

There are many implications of the relatively more complex structure of hydrates

As water is included or lost from the crystal structure, there must be a change in the volume of the unit cell (corrected for Z, the number of molecules per unit cell) at least

as large as the volume of the water molecule (15–40 Å3) Although there is no study known to the author comparing the relative volume change between polymorphic pairs

vs hydrate pairs, it must be assumed that the trend would be that the volume change is larger for hydrates, which have to accommodate the additional volume occupied by the water molecules

The obvious problem for pharmaceutical development is that the water activity can vary throughout the lifetime of the compound, and it is for this reason that knowledge

of the water sorption behavior of active substances and excipients is so critical31

2.3.3 The classify of hydrate

The water molecule, because of its small size, can easily fill structure voids and because of its multidirectional hydrogen bonding capability, is also ideal for linking a majority of drug molecules into stable crystal structures4,34 The crystalline hydrates, based on their structure may be classified into three categories (see table II.5) The first

category (class 1) are the isolated site hydrates, where the water molecules are isolated

from direct contact with other water molecules by intervening drug molecules, e.g., cephradine dihydrate

The second category (class 2) are channel hydrates where the water molecules

included in the lattice lie next to other water molecules of adjoining unit cells along an axis of the lattice, forming channels through the crystal, e.g., ampicillin trihydrate The channel hydrates can be subclassified into three subcategories One category comprises

the expanded-channel or nonstoichiometric hydrates, which may take up additional

moisture in the channels when exposed to high humidity and for which the crystal lattice may expand or contract as the hydration or dehydration proceeds effecting changes in the dimensions of unit cells, e.g cromolyn sodium The second subcategory

comprises the planar hydrates, which are channel hydrates in which water is localized

in a two-dimensional order, or plane, e.g., sodium ibuprofen And the other is

dehydrated hydrate, which may in principle belong to any of classes just discussed, but

the cases with which the author is familiar (finding not yet published) have all been either channel hydrates or “clathrate” type structures where water is the guest instead of the host in a cavity and in a non-stoichometric amount This subclass deals with crystals that dehydrate even at relatively high partial pressures of water Therefore, the hydrate that forms in solution dehydrates almost immediately on removal from the mother liquor When dehydration leaves an intact anhydrous structure that is very similar to the hydrate structure but lower density, it is classified as a dehydrated hydrate

If there have already existed an anhydrous crystalline form of the molecule, the dehydrated hydrate is classified as a polymorph The third category (class 3) of

crystalline hydrates are the ion-associated hydrates, in which the metal ions are

coordinated with water, e.g., calteridol calcium.4,31,35

Table II-5 Classification of crystalline hydrates 31

1

2

2a 2b 2c

3

Isolated lattice sites Lattice channel Expanded channels (non-stoichiometric) Lattice planes

Dehydrated hydrates Metal-ion coordinated water

2.3.4 Hydration and dehydration 2

Hydration and dehydration refers to the conversion between crystalline anhydrates and hydrates, and between lower hydrates and higher hydrates The stability of

stoichiometric hydrates usually is represented by a constant-temperature phase diagram

of the type shown in Fig II.3

Figure II.3 Stability phase diagram for stoichiometric hydrates at constant

temperature

At constant temperature, one crystal form is stable over a range of water activities (or relative humidity, RH) At the critical water activities, the anhydrate/hydrate or lower hydrate/higher hydrate pairs can coexist However, kinetic considerations often lead to transient meta-stable regions, especially for hydration With increasing temperature, the critical water activity usually shifts to a lower value because of the endothermic nature of dehydration Hydration typically proceeds via solution or solution- mediated mechanisms The solution-mediated mechanism is more likely for a high load formulation Occasionally, for channel-type hydrates, hydration may proceed via the solid-state mechanism Dehydration can proceed via solid-state, solution, and occasionally via the melt mechanism If a non-aqueous solvent is used, the solution-mediated mechanism can operate as well It is important to recognize the variation of phases in the product resulting from dehydration of different hydrates36, and from dehydration of the same hydrate under different conditions37,38 Mechanical treatments, such as milling, tend to accelerate the kinetics of dehydration by generating

surface/defects and by local heating

Identify of crystal form

Hydrate 2 Hydrate 1

Anhydrate

1(100%) 0(0%)

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 associated with crystallization39 The general course of solute form the solution to crystal in crystallization is shown in Fig II.4

Surface-integration controlled

Surface-integration controlled

Surface-integration controlled

Figure II.4 The course of crystallization, nucleation and growth mechanism 1,39,

3.1 Nucleation

3.1.1 Supersaturation

Supersaturation is the basic driving force for kinetic of crystallization (nucleation and crystal growth) (see table II.6 and Fig II-5) and may be expressed in a number of different ways such as:

Concentration driving force: ΔC = C – C*

Supersaturation ratio:

*

C C

Absolute or relative supersaturation: 1

For melts, the driving force is usually expressed in terms of the supercooling;

ΔT = T*- T Which represents the difference between the melting temperature T* and the actual temperature T

Solubility’

1

2 3

4 5

6

4 Drowning out 5 Chemical reaction 6 Salting out

Figure II.5 Supersaturation and methods to create supersaturation

Table II-6 Driving force for nucleation and growth 41

A saturated solution is in thermodynamic equilibrium with the solid phase at specified temperature40 The nucleation rate, i.e the number of nuclei formed per unit time and unit volume, is neglectable for small supersaturations Only when a critical supersaturation is reached, it increases distinctly This may be taken as an explanation for the so-called metastable zone, which constitutes the allowable supersaturation level for all crystallization operations42 Ostwald (1897) first introduce the terms ‘labile’ and

‘metastable’ superasturation to classify supersaturated solutions in which spontaneous (primary) nucleation would or would not occur, respectively40 The diagrammatic representation of the metastable zone on a solubility-supersolubility diagram is display

in figure II.6

Figure II.6 The solubility – supersolubility diagram 40,41,43

From this figure, it can be seen that various stages of stability exist in solution

crystallization for primary nucleation Below the solubility curve all solutions are unsaturated Since no crystallization is possible in unsaturated solutions, this region is said to be stable The solubility curve represents an equilibrium state where growth and dissolution processes take place at the same magnitude, thus the induction time for nucleation is infinite Assuming a cooling crystallization, solutions will be

supersaturated when reaching a temperature below the saturation temperature However, supersaturated solutions do not necessarily crystallize, but the tendency to crystallize increases with increasing supersaturation At a certain temperature a point is reached, where the induction time equals zero, meaning that when a solution is cooled to that temperature, instantaneous crystallization starts This point, defined by temperature and concentration, is called the metastable limit The zone between the saturation curve and this supersaturation limit is called metastable zone The metastability describes a state

in which instantaneous nucleation does not take place, however, after a certain induction period nucleation cannot be excluded Furthermore, crystals present in the solution or added to it, will grow and therewith deplete supersaturation In laboratory experiments it has been shown that this meta-stable limit can be exceeded and a transitional state will be obtained In this case, a level of supersaturation is reached at which the liquid becomes to viscous to nucleate At even higher supersaturations a system is said to be unstable In practice, this region can hardly be reached in solution crystallization, because of the presence of dust and dirt, the employed cooling rate, use

of agitation etc., as described later in this section However, e.g for some systems in melt crystallization, the unstable region has been proven to exist The meta-stable limit

is, in contrast to the solubility curve, thermodynamically not founded and kinetically not well defined The width of the meta-stable zone depends on a number of parameters such as temperature level, rate of generating the supersaturation, solution history, impurities, fluid dynamics, viscosity, mechanical forces, friction, extreme pressures etc

crystals In general, the width of the meta-stable zone for seeded solutions is smaller in comparison to solutions without crystals being present.42

3.1.3 Fundamentals of nucleation

Also shown in figure II.4 a diagrammatic representation of the meta-stable zone for

different nucleation mechanisms is shown Besides the lower continuous solubility curve, three broken supersolubility curves indicate different mechanisms for nucleation

Common is a differentiation between primary and secondary nucleation Primary

nucleation is the formation of nuclei that are able to grow without presence of any

crystalline matter, whereas secondary nucleation requires the presence of crystals

Primary nucleation can be subdivided into homogeneous nucleation – spontaneous in the solution bulk - and heterogeneous nucleation - induced e.g by surface roughness,

and especially by foreign micro and nano particles that cannot be excluded from being present in the solution Homogeneous nucleation is not very common, in most cases dissolved impurities and physical features such as crystallizer walls, stirrers, and baffles function as heteronuclei to induce crystal formation The reason for this is the energetic barrier to build a species with a large surface area to volume ratio where the full stabilization of the bulk is not given for many of the molecules A heteronucleus reduces the energetic barrier by providing stabilization of a growing face of the crystal Therefore, nucleation in a heterogeneous system generally occurs at a lower supersaturation than in a homogeneous system

Secondary nuclei can originate from attrition fragments, i.e from seed crystals

interacting with the above-mentioned physical features Furthermore, secondary nuclei are formed either as preordered species, as clusters in the boundary layer of the crystal surface, or on the crystal surface by dendritic growth and dendrite coarsening These parent crystals have a catalyzing effect on the nucleation phenomena, and thus, nucleation occurs at a lower supersaturation than needed for primary nucleation Mechanisms of secondary nucleation are e.g initial breeding, polycrystalline breeding, macroabrasion, dendritic, fluid shear, and contact nucleation Secondary nucleation is the most relevant mechanism for industrial crystallization operations. 40,44, 46-48

A control of the actual supersaturation in the crystallizer is mandatory to be able to exert a targeted influence on nucleation and growth processes and therewith on the product quality Very high supersaturations usually cause primary nucleation, and thus

a large number of nuclei For this reason many fine crystals are obtained, and a product with a specified mean crystal size distribution is not recoverable anymore Furthermore,

at very high supersaturations crystal growth is well enhanced, and often the outcome is

dendritic growth and a diminished purity due to liquid inclusions On the other hand, operating a crystallizer closed to the saturation curve results in slow growth rates and high purities However, this is not desirable for economic reasons, because slow growth rates require too long retention times of the product in the solution On this account, in industrial crystallization a compromise has to be made between product quality and process safety or economical efficiency According to a rule of thumb the crystallizer should be operated approximately in the middle of the metastable zone 42

3.1.4 Induction time 40,42

The period of time, which usually elapses between the achievement of supersaturation and the point at which crystals are first detected, is generally referred to

as the induction period The induction period can be divided into several parts: at the

beginning, a certain relaxation time tr is required for this system to achieve a steady-state distribution of molecular clusters Further time is required for the formation

quasi-of a stable nucleus, tn, and then for the nucleus to grow to a detectable size, tg However,

in practice it is difficult to isolate these separate quantities The relaxation time depends

to a great extent on the viscosity of the solution and, hence, on the diffusivity The nucleation time depends on the supersaturation which affects the size of the critical nucleus, and the growth time depends on the size at which nuclei can be detected, thus

on the measuring technique In some systems, particularly at low supersaturation,

another time lag may be observed, which is referred to as the latent period To

distinguish it from the induction period, the latent period is defined as the period of time between the achievement of supersaturation and the onset of a significant change

in the system, e.g the occurrence of massive nucleation or some clear evidence of

substantial solution desupersaturation (see FigII.7)

This further distinction is helpful, because at the end of the induction period and often for a considerable time afterwards, no significant changes in the solution may be detected until, at the end of the latent period, rapid desupersaturation occurs At very high supersaturations, the induction and latent periods can be extremely short and virtually indistinguishable Factors that can influence the induction and latent periods