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Article / Book Information
題目(和文)

粉末X線結晶構造解析による有機結晶溶媒和/溶媒脱離転移挙動の解明

Title(English)

Solid-state solvation & desolvation process of organic crystals
investigated by ab initio powder crystal structure analysis

著者(和文)

藤井孝太郎

Author(English)

Kotaro Fujii

出典(和文)

学位:博士(理学),学位授与機関:東京工業大学,
報告番号:甲第7500号,
授与年月日:2009年3月31日,
学位の種別:課程博士,
審査員:

Citation(English)

Degree:Doctor (Science),
Conferring organization: Tokyo Institute of Technology,
Report number:甲第7500号,
Conferred date:2009/3/31,
Degree Type:Course doctor,
Examiner:

学位種別(和文)

博士論文

Type(English)

Doctoral Thesis

Powered by T2R2 (Tokyo Institute Research Repository)

2009 Doctoral Dissertation

Solid-State Solvation & Desolvation Process ofOrganic Crystals Investigated by ab initio
Powder Crystal Structure Analysis

Kotaro Fujii
Department of Chemistry and Materials Science, Tokyo Institute of Technology

Acknowledgement
The author wishes to express his gratitude to Associate Professor Hidehiro
Uekusa for his valuable guidance, helpful suggestion and continual discussion
throughout the course of this study. The author also thanks to Emeritus Professor
Yuji Ohashi, Associate Professor Tomoji Ozeki, Dr. Akiko Sekine, and thecolleagues of research groups for their suggestions and encouragements. The
author wishes to thank Professor Kenneth D. M. Harris, Professor Katsuhide
Terada, and Associate Professor Etsuo Yonemochi for appropriate advises andsuggestive discussions.
Finally, the author wishes to give a huge thanks to his parents for theiraffectionate encouragement.
December 2008
Kotaro FUJII

2009 DOCTORAL DISSERTATIONSOLID-STATE SOLVATION & DESOLVATION PROCESS OF ORGANIC CRYSTALSINVESTIGATED BY AB INITIO POWDER CRYSTAL STRUCTURE ANALYSISCHAPTER 1

GENERAL INTRODUCTION ································································· 1

1.1.

Polymorph and Pseudopolymorph ····································································································· 1

1.2.

Crystal structure analysis from powder X-ray diffraction data ··························································· 8

1.3.

Purpose of This Dissertation ············································································································ 19

CHAPTER 2

VAPOR INDUCED CRYSTALLINE TRANSFORMATION ················· 27

2.1.

Abstract ··········································································································································· 27

2.2.

Introduction ····································································································································· 28

2.3.

Experimental···································································································································· 30

2.4.

Results and Discussion ···················································································································· 36

2.5.

Concluding Remarks························································································································ 46

CHAPTER 3

DEHYDRATION AND HYDRATION OF LISINOPRIL ······················ 51

3.1.

Abstract ··········································································································································· 51

3.2.

Introduction ····································································································································· 52

3.3.

Experiment ······································································································································ 55

3.4.

Results and Discussion ···················································································································· 57

3.5.

Concluding Remarks························································································································ 70

CHAPTER 4

DEHYDRATION AND PHASE TRANSFORMATION OF ACRINOL 74

4.1.

Abstract ··········································································································································· 74

4.2.

Introduction ····································································································································· 76

4.3.

Experiment ······································································································································ 78

4.4.

Result and discussion ······················································································································· 80

4.5.

Concluding Remarks························································································································ 92

CHAPTER 5
APPENDIX

GENERAL CONCLUSION···································································· 95

Chapter 1
General Introduction
1.1. Polymorph and Pseudopolymorph
1.1.1. Polymorphism and Properties
Many organic crystals are known to have alternative crystalline phases,
polymorph and pseudopolymorph crystal, in which same compound has
different crystal packing and molecular conformations. When the difference isonly in the crystal packing and/or molecular conformations, it is calledpolymorph(1), and if the difference is due to the existence of solvent molecule inthe crystal lattice, it is called solvates or pseudopolymorph(2). The polymorphs
and pseudopolymorphs attract a lot of interest, because they exhibit different
solid-state properties, such as electric conductivity, magnetic property,
photovoltaicity, photoconductivity, nonlinear optical activity, photochromic andthermochromic property, and photoreactivity.
For example, Moorthy and Venkatesan reported the different photoreactivity
between two polymorphs of the 4-styrylcoumarin(3). They found that thecompound crystallize into two polymorphic forms, needles and prisms, and,interestingly, while the monoclinic form (needle, P21/c) undergoes stereospecificphotodimerization producing anti-head-to-tail dimer across pyrone double bond,the triclinic form (prism, P 1 ) dimerizes to the anti-head-to-tail dimer acrossstyrenic double bond(Figure 1-1). In addition, the reaction efficiencies aredifferent between these two forms (almost 100% for needle form and 45-50%
for prism form). The different photoreactivities can be explained by the crystal
structures. In needle form crystal, as shown in Figure 1-1b, the nearest neighbormolecules are arranged in opposite direction and the pyrone double bonds are1the nearest reactive position. On the other hands, in prism form, there are two
independent molecules in the asymmetric unit. One molecule is also arranged in
opposite direction each other with the nearest double bonds of not pyrone but
styrenic double bond (Figure 1-1c). However, there is no sufficiently nearreactive double bonds for the other molecule and this can be considered as thereason of lower reaction efficiencies of prism form.

Figure 1-1 : (a) Different photoreactivities of two polymorphic forms of
4-styrylcoumarin. Nearest neighbor molecules which exist in the (b)needle form and (c) prism form. The orange dash lines show thereactive positions. (3)2Another good example can be seen in the field of pharmaceuticals. Shinzer
et al. investigated the properties for polymorph form I and form III ofpremafloxacin which is well known quinolone antibiotic(4). In this report, there
are large difference on the moisture sorption property and the solubility. As
shown in Figure 1-2, form I was found to absorb a water and transform tohydrate form at RH80%, whereas form III is stable for the moisture and it
doesn’t transform to hydrate form. In addition, the solubility of form I ismeasured as 3.23mg/ml which is about 23 times larger than that of form III(0.14 mg/ml). As can be seen in this example, polymorphs show large differencein their properties and these results show the importance of investigation of thepolymorphs.

Figure 1-2 : (a) molecular structure of premafloxacin. Dynamic moisturesorption gravimetry of premafloxacin at 25.0 °C of (b) Form I and(c) Form III.(4)3As shown in the second example, the considerable awareness ofpolymorphism and/or pseudopolymorphism (mostly about the hydrates), is seenin the field of pharmaceuticals. Further examples which focused on thepharmaceutical polymorphism and/or pseudopolymorphism and the interests are
summarized in the books and reviews(1), (5)-(7).

1.1.2. Polymorphic Transformation and Pseudopolymorphic
Transformation
Another important feature of the polymorphism and pseudopolymorphism is atransformation between them. Generally, these alternative crystalline phases(polymorphs and pseudopolymorphs) are often known to undergotransformations among these phases induced by the change of environment. For
example, thermal phase transformation(8)-(12), which usually accompanied by thechanges of the molecular conformations and/or molecular packing arrangement,
mechanically induced phase transformation(13), thermal desolvation(14)-(16),solvent (guest) exchanges or solvation induced by the change of humidity
condition(17)-(23) are known. Because the resultant crystalline phase by thetransformations usually possesses the different solid-state properties, as
described above, there are several reports which focused on the relationshipbetween the transform and the properties. For example, Bashkirava et al. foundthe color change was caused by the transformation from β form (orange) to γ
form (yellow) of N-(4’-methoxy-phenyl)-3-bromothiobenzamide polymorphs
and they concluded that the color difference was comes from the conformationalchange in the transformation(24). Yamamura showed the dielectric propertychange caused by the transformation for tetramethylammonium ando-phenylenebis organic salt(25). Interestingly, the low temperature form does notexhibit the dielectric response, the high temperature form exhibits the extensive
dielectric response.
The recent interesting example is that the racemic crystal transforms to theconglomerate crystals. The phenomena was first reported by Yoshizawa et al.(26).
They found that the racemic complex of binaphtol and tetramethylammonium
chloride undergoes the spontaneous chiral separation and gave the mixture ofchiral crystals which is so-called conglomerate by heating or by exposure to themethanol vapor(Figure 1-3a). After his repot, Van Eupen et al. reported thesimilar racemic to conglomerate transformation by heating for4

venlafaxine(27)(Figure 1-3b). As can be seen in these examples, such a racemic toconglomerate transformation is noteworthy because it has a potential for an
application to the chiral separation technique.

Figure 1-3 : The examples of the transformation from racemic crystal toconglomerate crystals. (a) The racemic inclusion crystal 4 ofbinaphtol and tetramethylammonium chloride undergoes thetransformation by heating or methanol vapor and gave theconglomerate crystal 5. (26) (b) The racemic venlafaxine form I
undergoes the racemic to conglomerate tranfromation which givechiral form III. (27)5Other examples of the polymorph transformations are well reported in thefield of pharmaceuticals, such as physical transformations of active
pharmaceutical ingredients during manufacturing processes(7), solution-mediatedpolymorphic phase transformation(28), pressure and thermal effect on thepharmaceutical hydrates(29) and dehydration process studied by IR spectra(30)(31),
X-ray powder diffraction(32)-(35) and single crystal structure analyses(36)-(40).

1.1.3. Problem in Study of Polymorphic Transformation and
Pseudopolymorphic Transformation
Many techniques were used for understanding the transformation mechanism
and/or the properties of the resultant forms. Among them, single crystal structure
analysis acted very important role in such studies. The technique to determine
the crystal structures from single crystal diffraction data provides the three
dimensional information (molecular structure and molecular arrangement), thus
the technique acted an important role in several literatures shown above.
However, unfortunately, most transformations accompanied by disintegration of
single crystal, and in such cases, the technique to solve the crystal structuresfrom single crystal diffraction cannot be applied. Especially, thepseudopolymorphic transformations (desolvation and solvation) are notsufficiently studied because it generally accompanied by large structural changes
which caused by the solvent release and/or sorption (Figure 1-4). Thus,
systematic studies of the pseudopolymorphic transformations have notsufficiently been achieved until today. In this context, the technique to determine
the crystal structures of polycrystalline forms is the key problem forunderstanding the pseudopolymorphic transformations. Recently, the technique
to determine the crystal structures from powder diffraction data has been
dramatically developed and it has a potential to solve the problem that “ thedifficulty to determine the crystal structures of transformed phases “.

6Figure 1-4 : The example of desolvation accompanied the disintegration of
single crystal. (a) shows the disintegration by desolvation induced
by temperature increasing, and (b) shows the diffraction patternchange.
7

1.2. Crystal structure analysis from powder X-ray
diffraction data
1.2.1. Powder X-ray diffraction
The powder diffraction measurements are traditionally widely used in many
fields. It can be easily measured and can use for phase characterization. For
some inorganic materials, the powder diffraction data were used to analyze thecrystal structures by using direct method and/or Rietveld structural refinement,
however, traditionally, it was not applied to the organic crystals. Because,
generally, organic crystalline materials have worse crystallinity and lower
symmetry than those of inorganic materials, the powder diffraction patterns oforganic crystalline materials have broad and extremely overlapped peaks and,thus, it is difficult to extract accurate intensity data for the crystal structure
analysis.
On the other hands, recently, several techniques to determine the organic
crystal structures from powder X-ray diffraction are developed. The key
technology which enable to solve the organic crystal structures are theimprovement of the X-ray source, the calculation ability of computers and thedevelopment of the crystal structure determination calculation methodology.
Because the powder diffraction data have only one dimensional diffraction
information which is considered as the collapse of the three dimensional
crystallographic information such as the single crystal diffraction data(seeFigure 1-5). Thus the structure determination from powder diffraction data ismuch more difficult than from single crystal data and the same techniques ofsingle crystal analysis are usually failed in the powder diffraction analysis.
Therefore, the unique techniques to analyze the powder diffraction data havelong been developed.

8Figure 1-5 : Diffraction Images from (a) Single Crystal and (b) Crystalline
Powder. (c) Powder X-ray Diffraction pattern.

91.2.2. Indexing
The most important procedure is the indexing, because the determined unit
cell parameters are most important crystallographic information and arenecessary for the subsequent structure analysis procedures. Generally, theindexing of powder diffraction data is carried out using peak positions whichwere detected from the experimental powder patterns. The following threeprograms are most famous and widely used for powder diffraction indexing; theprogram ITO(41) which is based on the zone-finding procedure(42); the program
TREOR(43)(44) which adopted the trial-and-error indexing; the program
DICVOL(45)-(49) in which the cell parameters are exhaustively explored thespecified unit cell space. The success rate of these programs to give the correct
solution is very high if the precise peak positions are inputted. However it isusually difficult to obtain the precise peak positions from powder diffraction
data, especially for the organic crystals, because of the peak overlaps, impurity
peaks, and the systematic errors such as zero position error, sample positional
error. Thus, recent indexing programs were written to improve the treatment ofsuch peak overlap effect, impurity peaks, and systematic errors. For example,
program DICVOL incorporated the technique to estimate the zero positional
error, which is called reflection-pair method(50). The recent notable programs
such as the program TOPAS(51) which is based on the trial-and-error technique,
McMaille(52) which adopted the genetic algorithm indexing, X-Cell(53) which isbased on dichotomy method as well as DICVOL, also consider the existence ofthe peak position errors and the existence of impurity peaks in order to gain the
success rate of indexing calculation.

1.2.3. Rietveld Method (Crystal Structure Refinement)
The most famous and widely used original method in the powder diffraction
analysis is Rietveld method. The crystal structure refinement is usually carriedout using integrated intensities in a single crystal diffraction analysis. However,it has problem to apply to the powder diffraction data, because of the difficulty
to estimate the precise integrated intensity from extremely overlapped powder
diffraction pattern. In this context, Rietveld proposed in 1969 the technique torefine the crystal structure using whole profile patterns (which means one profile
10

point is considered as a one data instead of integrated intensity)(55). The
advantage of this technique is that this technique does not require the extractionof the integrated intensity prior to the refinement.
The powder diffraction pattern of the structural model is calculated using thefollowing information: (1) lattice parameters (peak positions); (2) atomic
positions and atomic displacement parameters (peak intensities); (3)2θ-dependent analytical functions to describe the peak shapes and peak widths;(4) a description of the background intensity. In the least-square refinement
process, not only the crystal structure parameters such as atomic positions or
atomic displacement parameters, but also the profile shape and the backgroundparameters are refined.
Actually, the first proposal of Rietveld was applied to analyze the neutron
powder diffraction data. However, now the technique was applied to not only toneutron but also to X-ray powder diffraction data(56), and many Rietveld method
software were developed (57)-(63). Also, this technique is recently used for organic
crystal structure refinement and most of recent ab initio powder diffraction
analysis carried out the Rietveld refinement as the final procedure of powder
diffraction analysis.
Usually, the goodness of the refinement is judged by reliable factors as shownin Table 1-1. The most important R factor is Rwp because in the Rietveld
refinement the parameters are refined to reduce this value. The lowest Rwp isdifferent for the measurement conditions and/or the compounds, because the Rwp
is not determined only by the crystal structure but also it is affected by the peak
shape, backgroud level. Thus, the value of Rwp given by Rietveld refinement
should be compared with the value which is obtained by pattern decomposition,
because the Rwp given by pattern decomposition is the theoretically lowest value.
If the Rwp given by Rietveld refinement is near to the value given by patterndecomposition such as Le Bail method and Pawley method(which is describedin the next section), the crystal structure would be correctly analyzed.

11

Table 1-1 : Some often-used reliable factors. (R. A. Young, The Rietveld
Method, 1993,Oxford Univ. Press).

121.2.4. Pattern Decomposition
In the structure analysis, the powder diffraction pattern is decomposed into
the individual reflection using pattern decomposition technique, in order toestimate the integrated intensities and/or estimate the profile parameters of thepowder diffraction pattern. The obtained information, such as integrated
intensities, profile parameters and unit cell parameters, is used in the subsequent
analysis such as structure solution procedure or in the Rietveld structuralrefinement.
The most commonly used “pattern decomposition” techniques are based on
the use of Rietveld method in which the whole powder diffraction pattern isdecomposed in one step. These techniques adopt a least-squares approach to fit a
calculated profile and the experimental powder diffraction pattern by refinementof the lattice parameters, the zero-point error, the peak profile parameters, andthe background parameters. Two methodologies are proposed for handling the
integrated intensities. One is proposed by Pawley that is the integrated
intensities are also treated as refinement parameters and the integrated intensities
are determined from least-square fitting(64)(65). However, this “Pawley method” isusually unstable in the refinement procedure, because of the higher correlation
between the integrated intensities of the overlapped reflections and because therefined parameters become great number according to the number of reflections.
Thus, Le Bail proposed another method in which the integrated intensities are
not treated as parameters(66). This method called “Le Bail method” is succeeded
to stabilize the refinement and is now used in many programs. Usually, thesetechniques have similar routine with Rietveld method, thus, these techniques arealso incorporated in a Rietveld method softwares which showed in the foregoing
section(57)-(63).

1.2.5. Crystal Structure Determination
If the decomposition of powder diffraction pattern has succeeded, one canapply the Patterson method or direct method to determine the crystal structure.
In 1992, Giaccovazzo and his co-worker reported a software of direct method
which was optimized to the powder diffraction data by considering the peakover lap effect and by special treatment of weak reflection intensities(67). Further
13

investigations to determine the crystal structures from powder diffraction data
were carried out by same group(68)-(79) and this technique has incorporated into
program EXPO package which consists of indexing, intensity extraction,
structure determination by direct method and Rietveld refinement(80)-(82).
However, the technique of a direct method itself is not sufficiently effective forthe structure determination of organic crystal structure and it was failed in manycases, therefore, the group incorporates the concept of the direct space strategy
into the software and is combined with direct method (83)-(88).
The direct space strategy acted a most important role in the recent
development of organic crystal structure analysis from powder diffraction data.
In the direct-space method for solving crystal structures from powder diffraction
data, trial crystal structures are generated in direct space(also it can be called
real space). The trial structure is compared directly between the powder
diffraction pattern calculated for the trial structure and the experimental powder
diffraction pattern and the goodness of the structure is calculated using a reliablefactor such as Rwp, Rp, RI. The direct space strategy for structure solution aims tofind the trial crystal structure that has the lowest possible R factor, and theapproach is equivalent to exploring R factor hypersurface to find the global
minimum on the hypersurface (Figure 1-6a). The parameters are traditionallyconsidered as atom coordinates, however, if considering all atoms in the unit cell,the number of parameters extremely increase and it makes difficult to solve thecrystal structures. Thus, in a recent direct space strategy, only torsional freedoms
are permit to the molecules which exist in the crystal lattice and the otherparameters are constrained to the reference values (this means there is no
freedom for the bond length and angle). By using of this kind of rigid molecules
model, the crystal structure is expressed in following parameters; positionalparameters of molecule (x, y, z), orientational parameters of molecule (θ, φ, ψ)and torsional parameters of rigid molecule (τ1, τ2, τ3, …), thus, the problem todetermine the crystal structure can be converted to the problem to determine
these parameters.
The most straightforward way to determine these parameters, which can
explain the experimental powder diffraction pattern, is exhaustive search of R
factor hypersurface. The method is called grid search method(GS). In GS
technique the parameter space is split into grid and all grid points are searchedexhaustively. This technique is incorporated into program Organa(89). Because
14GS is the exhaustive search technique, it is most certain way to explore thecrystal structure. However, it requires a lot of time to calculate the whole
hypersurface, thus, it is not suitable for a crystal structures which have a large
number of parameters should be determined.
The alternative technique to determine the parameter set is the global
optimization method. In the global optimization method, the parameters which
achieve the lower R factor is considered as the more optimal parameter set andthe parameters are optimized for it. As the optimization method, three following
techniques were used in the powder diffraction analysis. Monte-Carlo
method(MC): a new trial structure is generated randomly around the present
parameter set and if the new model has lower R factor, the model is accepted andif the new model has higher R factor, parameters are accepted stochastically. The
program ESPIOR(90) is known to adopt MC strategy. Simulated Annealing
method(SA): the main strategy is the similar to that of MC but the stochastic
tolerance to accept the new trial structure is decrease in proportion to thenumber of movement. This strategy can be considered as the similar process ofannealing process of metal, thus, this method is called simulated annealing
method. The program DASH(91), TOPAS(92), FOX(93) and PSSP(94) are known to
adopt SA for solving the crystal structure. Genetic Algorithm method(GA): theparameter sets (the number of parameter sets are called population) are
optimized by mating(parameter exchange), mutation(random movement), andselection(only suitable parameter sets remains in the next generation) (Figure1-6b). The direct space GA technique is incorporated in the program
EAGER(95)-(100). These techniques (MC, SA, GA) are good match nicely with the
problem to determine the crystal structure from powder diffraction data, thus,
the programs, as shown above, gave the number of successes in determination of
the organic crystal structures.

15

Figure 1-6 (a) A two-dimensional section through the Rwp hypersurface forlithium zirconate (Li6Zr2O7). (b) Flow chart representing theevolution of the population from one generation (population Pj) tothe next generation (population Pj+1) in the genetic algorithm for
powder structure solution. K. D. M. Harris, et. al. Angew. Chem. Int.
Ed. 2001, 40, 1626- 1651.

16

1.2.6. Practical Examples of ab initio Powder Crystal Structure
Analysis
The direct space crystal structure determination successfully boosted thepossibilities to determine and analyze the unknown organic crystal structurefrom powder diffraction data, which is generally called “ab initio crystal
structure determination from powder diffraction data”. This technique has been
applied to several situations such as difficult to obtain single crystals byrecrystallization(101)-(114), the phase could obtain only by polymorphic
transformations(115)(116), and the phase obtained by solid-state grinding(117)(118).
Figure 1-7 shows some examples. From small simple molecule (such astrithiocyanuric) to complex organic salt (such as melaminium
dihydrogenpyrophosphate), the crystal structures have been successfully
determined from powder diffraction data.
Also, there are some examples that the crystal structures of the desolvatedcrystalline phases have been determined from powder diffraction data. Platteau
reported the crystal structures of hygroscopic and stable anhydrous forms of
α-lactose which were determined from powder X-ray diffraction data. They
revealed that the instability of hydroscopic anhydrous form comes from thedestruction of hydrogen bonds which exists in the hydrate form(120)(121). Other
unstable unsolvated examples were reported by Guo et al.. In their studies, thecrystal structures of unsolvated trithiocyanuric acid benzene-1,2,3-tricarboxylic
acid were determined from powder X-ray diffraction data. All these studies areimportant because such transformed phases are impossible to solve the crystal
structure by conventional single diffraction method and ab initio powder crystal
structure analysis is necessary for revealing these crystal structures. However, it
is regret that all these studies did not discuss the transformation mechanisms.

17

Figure 1-7 : Some examples of ab initio crystal structure determination frompowder diffraction data. (a) Trithiocyanuric acid unsolvatedform.(123) (b) Termisaltan form A.(102) (c) Melaminium
dihydrogenpyro- phosphate.(107)18

1.3. Purpose of This Dissertation
As described in section 1.1.2, there are lots of interests in the polymorphic
and pseudopolymorphic transformations. In order to understand thetransformation mechanisms and to reveal the properties of the transformed
phases, the crystal structures are most important information. However, in manycases, such transformation gave the polycrystalline materials, although thestarting phase can be obtained as a single crystal, so that the single crystal X-ray
diffraction analysis cannot apply to the investigation such transformations.
Therefore many interesting and/or important transformations mechanism havenot been revealed. Especially, the pseudopolymorphic transformations(desolvation and solvation) are not sufficiently studied because it generallyaccompanied large structural changes which caused by the solvent release and/or
sorption (Figure 1-4).
On the other hands the opportunities for carrying out complete structure
determination of organic molecular materials from powder X-ray diffraction
data (ab initio powder crystal structure analysis) have developed considerably inrecent years. This technique enables us to analyze the crystal structures whichcannot obtain as single crystal form as described in section 1.2 (obviously
include polycrystalline phase obtained by the transformations). Therefore, this
newly technique, ab initio powder crystal structure analysis, would be the key
technology to reveal the pseudopolymorphic transformations.
In this context, the purpose of the dissertation is the establishing thepseudopolymorphic transformation mechanisms using ab initio powder crystal
structure analysis technique. The target phenomenon are the solvent vapor
induced pseudopolymorphic transformations of co-crystal of 5-methyl-2pyridone and trimesic acid, dehydration of pharmaceutical lisinopril dihydrate,and dehydration and polymorphic transformation of pharmaceutical acrinol.
These phenomenon are very interesting and important in the scientific andindustrial points of view (the details are described in each sections), however,the detail mechanisms of the phenomenon have not been established because of
the problem discussed above.

19

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J. Bernstein, Polymorphism in Molecular Crystals, Clarendon Press, Oxford, UK,
2002.

(2)

A. Nangia, Cryst. Growth Des., 2006, 6, 2-4.

(3)

J. N. Moorthy and K. Venkatesan, Bull. Chem. Soc. Jpn., 1994, 67, 1-6.

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W. C. Schinzer, M. S. Bergren, D. S. Aldrich, R. S. Chao, M. J. Dunn, A.
Jeganathan, L. M. Madden, J. Pharm. Sci., 1997, 86, 1426-1431.

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S. R. Vippagunta, H. G. Brittain, D. J.W. Grant, Adv. Drug Del. Rev., 2001, 48,
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26

Chapter 2
Vapor Induced Crystalline Transformation
2.1. Abstract
A new co-crystal (phase H) of 5-methyl-2-pyridone (5MP) and trimesic acid
(TMA) has been prepared by grinding a methanol solvate co-crystal (phase M)
of 5MP and TMA under ambient conditions. Powder X-ray diffraction indicatesthat the new co-crystal phase H is structurally different from the methanol
solvate co-crystal (phase M) and an unsolvated co-crystal (phase U) of 5MP and
TMA reported previously. In the present work, the crystal structure of the newphase H has been determined directly from powder X-ray diffraction data,
allowing insights to be gained regarding the mechanism of the transformationfrom M to H. The structural analysis reveals that phase H is a hydrate of 5MP
and TMA, and thus the transformation from M to H is a solvent exchange
process. The rate of this process is shown to be accelerated significantly bygrinding. Further vapor induced transformations have been investigated forphases M, H and U, and insights regarding transformation mechanisms havebeen established from consideration of the crystal structures. Interestingly, while
the phase M and H are not photoreactive phase of 5MP, the unsolvated phase U
is photoreactive and it produced a pure [4+4] cis-syn dimer of 5MP. From
crystal structure comparison, it was revealed that the difference ofphotoreactivities can be clearly explained from the reaction cavities but not only
from the distance or arrangement of reaction centers.

27

2.2. Introduction
The effect of solvent vapors on the properties of solids is widely studied inmany fields. In pharmaceutical sciences, the effect of water vapor has been
investigated extensively in relation to hydration and dehydration phenomena,
because such transformations can often affect the physical properties orbioavailability of drugs(1)(2). In materials sciences, solvent adsorption andexchange phenomena are widely studied for metal-organic framework
structures(3)(6) and inclusion compounds(5)-(9), because of their potential
applications, for example in storage, separation and sensor technologies.
Furthermore, solvent vapor has also been exploited to accelerate reactions thesolid state.(10) An important aspect of exposure of a solid material to solvent
vapors is to understand whether any changes of crystal structure occur, as
structure clearly has an important bearing on the physical, chemical andbiological properties of the material. However, in many cases, single crystals of
the starting phase are found to disintegrate to produce a polycrystalline material
upon transformations induced by solvent vapor, thus limiting the opportunities
to obtain information on the structural changes associated with such processes
by single crystal X-ray diffraction analysis. In some cases, it might be possible
to obtain a single crystal of the transformed phase (as confirmed by comparisonof powder X-ray diffraction data) by another crystallization method, but in manycases, single crystals of the transformed phase cannot be obtained by any othermethod. Techniques for carrying out structure determination directly frompowder X-ray diffraction data are clearly essential for structural characterizationof the polycrystalline product materials obtained directly in suchtransformations.
The opportunities for carrying out complete structure determination of organic
molecular materials from powder X-ray diffraction data have developed
considerably in recent years(11)-(24), particularly through the development of thedirect-space strategy for structure solution(25). Because these techniques have thepotential to provide structural understanding of polycrystalline products
obtained from solid state transformations (e.g. originating from single crystal
materials of the type discussed above), these techniques have a key role to playin understanding structural properties of materials produced from solid state
grinding processes, solid state reactions, desolvation processes, and polymorphic
28

transformations(26)-(32).
Previously, the solvent-vapor induced transformation of a co-crystal of
5-methyl-2-pyridone (5MP; Figure 2-1) and trimesic acid (TMA; Figure 2-1)
was studied as part of an investigation of the photoreactivity of 2-pyridone
derivatives in co-crystals(33). Although a methanol solvate co-crystal (denoted
M; 5MP:TMA:MeOH = 1:1:1) obtained from methanol solution was notphotoreactive, this co-crystal transforms to a photoreactive co-crystal on
exposure to acetonitrile vapor, or on heating. Structure determination frompowder X-ray diffraction data revealed that the transformed material is anunsolvated co-crystal (denoted U; 5MP:TMA = 1:1). Thus, it is clear that thetransformation induced by acetonitrile vapor is a desolvation process.

Figure 2-1 : Molecular structures of 5MP and TMA.

The present paper reports experiments in which we have shown that grinding
M under ambient conditions gives rise to a transformation to produce a
polycrystalline sample of a new co-crystal, denoted H. Structural properties ofthis new phase have been established by structure determination from powder
X-ray diffraction data, and further investigations of transformations induced bysolvent vapors for phases M, H and U have been investigated, yielding further
insights regarding the transformation mechanisms. Finally, the difference of thephotoreactivities in each crystals is discussed from the analyzed crystal
structures.

29

2.3. Experimental
The new co-crystal material H was obtained by grinding a polycrystalline
sample of M for about 10 mins using a mortar and pestle under ambientconditions. As shown in Figure 2-2, the powder X-ray diffraction pattern of H isdifferent from those of M and U, and thus the crystal structure of H is different
from M and U. TGA studies suggest that H contains one water molecule foreach molecule of 5MP and TMA. The crystal structure of H has been
determined directly from powder X-ray diffraction data as discussed below.
Upon heating, we have found that H transforms to U (we recall that M alsotransforms to U upon heating(33)).

Figure 2-2. Powder X-ray diffraction patterns (CuKα, λ = 1.5418 Å) for (a)phase M, (b) phase H, and (c) phase U.

30

2.3.1. Synchrotron X-ray Powder Diffraction Measurement
Synchrotron X-ray powder diffraction data were recorded for H at 300 K on
beamline BL19B2 at SPring-8 (Debye-Scherer camera equipped with a curved
Imaging Plate detector) with wavelength 1.23689(2) Å (0.3 mm diameterborosilicate glass capillary, with sample spinning during measurement; datacollection time 15 mins).

2.3.2. Structure Determination of Phase H from Powder X-ray
Diffraction Data
The powder X-ray diffraction pattern of H was indexed using the program
ITO,(34) giving the following unit cell (M20 = 21.9(35)) with triclinic metricsymmetry: a = 10.526 Å, b = 10.973 Å, c = 7.094 Å, α = 107.939°, β = 97.628°,
γ = 88.137°, V = 772.57 Å3. Given the volume of this unit cell, and considerationof density, the number of formula units in the unit cell is assigned as Z = 2.
Structure determination focused first on space group P 1 (with the intention toconsider space group P1 if structure determination in P 1 proved unsuccessful).
Profile fitting using the Le Bail method(36) gave a good quality fit with Rwp =3.81% and Rp = 2.51%. The unit cell parameters and profile parameters obtained
from the Le Bail fitting procedure were used in the subsequent structure solution
calculation. Structure solution was carried out using the direct-space genetic
algorithm (GA) technique incorporated in the program EAGER(37)-(41). The
structural fragment comprised one 5MP molecule, one TMA molecule and one
water molecule, representing a total of 18 structural variables (three translationalvariables for each of the 5MP, TMA and water molecules, three orientationalvariables for each of the 5MP and TMA molecules, and three torsional variables
for the carboxylic acid groups of the TMA molecule). The GA calculation
involved the evolution of 20 generations for a population of 100 structures, with
50 mating operations and 25 mutation operations carried out per generation.
Following structure solution, Rietveld refinement(42) was carried out using the
GSAS program(43). Standard restraints were applied to bond lengths and bondangles, planar restraints were applied to aromatic rings, and a global isotropic
displacement parameter was used. As the 5MP molecule has pseudo-symmetry(see Figure 2-3), the orientation of the 5MP molecule in the structure was given
31

careful scrutiny. In the best structure solution obtained from the GA calculation,
5MP forms a dimer with a carboxylic acid group of TMA through the formationof N–H…O and O–H…O hydrogen bonds, and there are no unreasonable shortcontacts. On the other hand, in the structures obtained by flipping the 5MP
molecule according to the pseudo-symmetry (Figure 3), some unreasonablestructural features are observed for hydrogen bonding and intermoleculardistances, suggesting that the structure obtained from the GA calculation iscorrect. Similarly, the C–OH and C=O bonds of the carboxylic acid groups of
TMA were assigned from the formation of reasonable hydrogen bonding
interactions. The final Rietveld refinement gave following parameters: a =10.5423(2) Å, b = 10.9487(3) Å, c = 7.0994(1) Å, α = 107.910(2)°, β =97.747(1)°, γ = 88.088(1)°, V = 772.58(3) Å3, Rwp = 5.17%, Rp = 3.53%, RF2 =8.03% (2θ range, 5.0 – 69.99°; 6500 profile points; 126 refined variables). The
final Rietveld plot is shown in Figure 2-4 and crystal structures is shown in
Figure 2-5 and Figure 2-6.

Figure 2-3 : Pseudo-symmetry of 5MP.

32

Figure 2-4 : Final Rietveld refinement for phase H, showing the experimental
powder X-ray diffraction pattern (+ marks), calculated powder
X-ray diffraction pattern (solid line) and difference profile (lowerline). Tick marks indicate peak positions.

Figure 2-5 : Crystal structure of phase H, with hydrogen bonds indicated bydashed lines. The hydrogen bond donor O8–H15 interacts with O5
in the upper layer, which is labeled O5". The part of the structure
shown as a ball-and-stick model represents the "hydrogen bondingunit".
33

Figure 2-6 : Crystal structure of phase H viewed along the a-axis (parallel to theplane of the hydrogen bonding unit), showing the sheet-like natureof the structure.

2.3.3. Transformations on Exposure to Solvent Vapor
The apparatus used to expose solid materials to solvent vapor is shown in
Figure 2-7a, and comprises a closed plastic container that was half filled bysolvent. The solvent vapors considered in this work were water, methanol,
acetonitrile, ethanol, acetone, hexane and diethyl ether. A powder sample of thematerial of interest was packed into a sample holder for powder X-ray
diffraction measurements, and placed on an upturned beaker to expose thesample to the solvent vapor. All experiments were carried out at ambient
temperature, and the plastic container was not evacuated prior to the start of theexperiments. After removal of the solid material, powder X-ray diffraction data
were recorded on a Rigaku RINT-2400 powder X-ray diffractometer to monitor(ex situ) any structural changes that had occurred due to exposure to solvent
vapor (Figure 2-2). If no changes were observed in the powder X-ray diffraction
pattern after 4 days, it was concluded that no transformation occurs for the given
material on exposure to the solvent vapor. If, on the other hand, changes wereobserved in the powder X-ray diffraction pattern within 4 days, the exposure tosolvent vapor was continued for as long as necessary until the powder X-ray
diffraction pattern showed that the transformation had reached completion.
34

Figure 2-7 : Schematic illustration of the experimental set-up for exposing solidmaterials to solvent vapor under (a) static conditions and (b) flow
conditions.

In another type of experiment, phase H was exposed to acetonitrile vapor
under flow conditions at ambient temperature, using the apparatus shown in
Figure 2-7b. In this experiment, flowing air was passed initially through CaCl2(to dry the air), then bubbled through liquid acetonitrile, and finally flowed overthe polycrystalline sample of H. Changes in the solid sample were monitored (exsitu) by powder X-ray diffraction, as discussed above. Also, in order to explore
the role of acetonitrile vapor in this experiment, a control experiment was
carried out in which dry air containing no acetonitrile vapor (i.e. without
bubbling the dry air through acetonitrile) was flowed over a sample of H.
In addition, for phases M and H, further experiments were performed
involving drying the solid material and exposure of the solid material to vacuum.
Drying was carried out using a desiccator with silica gel as desiccant, andexposure to vacuum was carried out using a rotary pump (6.7 × 10–2 Pa) connect
to a desiccator.
35

2.4. Results and Discussion
2.4.1. Structural Properties of Phase H
As shown in Figure 2-5, the crystal structure of the new phase H comprises
sheets of 5MP, TMA and water molecules. The 5MP and TMA molecules forma ring with N1–H10…O5 (N…O, 2.75 Å) and O6–H5…O7 (O…O, 2.53 Å)hydrogen bonds, and TMA and water molecules form a ring (with inversion
symmetry) constructed from O2–H6…O8 (O…O, 2.67Å) and O8–H14…O3 (O…O, 2.74Å) hydrogen bonds. These hydrogen bonding motifs give rise to the"hydrogen bonding unit" defined in Figure 2-5. A similar hydrogen bonding unit
is also observed in the structure of M (Figure 2-8a, CCDC deposition number
263741), but the structures of M and H differ in the arrangement of thesehydrogen bonding units. Although a given hydrogen bonding unit is connected
to neighbouring hydrogen bonding units by O–H…O hydrogen bonds in both
structures, the structures differ in the details of how these units are connected toeach other. In M, the hydrogen bonding units are connected not only to adjacentunits in the same plane (light blue dashed lines in Figure 2-8a) but also to units
above and below (red dashed lines). In H, on the other hand, the hydrogenbonding units are connected only to adjacent units in the same plane (light bluelines in Figure 2-5). As a result, the structure of H is sheet-like (Figure 2-6),
whereas the structure of M is not sheet-like (Figure 2-8b). The difference in thearrangement of hydrogen bonding units is manifested in the difference of spacegroups for M (P21/n) and H ( P 1 ). Further comparison between these structures
is discussed later.

36

Figure 2-8 : (a) Crystal structure of phase M, with hydrogen bonds indicated bydashed lines. The part of the structure shown as the ball-and-stickmodel represents the hydrogen bonding unit. (b) Crystal structure ofphase M viewed along the c-axis (parallel to the plane of thehydrogen bonding unit), showing that the structure is not sheet-like.

2.4.2. Transformation Induced by Grinding
Clearly, the transformation induced by grinding crystals of M is a solvent
exchange process, as the methanol present in M is replaced by the water present
in H. In order to investigate whether grinding is critical for this transformation, asingle crystal of M was left under ambient conditions, without grinding. Over a
period of time, the crystal of M was observed to transform to H, with theoriginal single crystal disintegrating to form a polycrystalline material (butmaintaining the overall shape of the original crystal). The time required for thistransformation (about one month) was significantly longer than with grinding.
This observation indicates that exposing crystals of M to an ambient atmosphere(without grinding) is sufficient to bring about the transformation from M to H,
but it is clear that grinding serves to accelerate the transformation. Following
this observation, we now assess in more detail the effect of solvent vapor in
relation to transformations between phases M, H and U.
37

2.4.3. Transformations Induced by Solvent Vapor
The results from the experiments involving exposure of materials M, H and U
to a range of different solvent vapors are summarized in Scheme 2-1. As
expected, H and U are observed to transform to M on exposure to methanol
vapor, and M and U are observed to transform to H on exposure to water vapor.
Furthermore, exposure of M and H to acetonitrile, acetone or ethanol vapors
gives rise to desolvation transformations to produce U. Although thetransformation from M to U on exposure to acetonitrile vapor was alreadyreported in previous literature(33), the transformations that occur on exposure toacetone and ethanol vapors were newly discovered in the present study. It isrelevant to note that crystals of M, H and U are insoluble in acetonitrile, acetone
and ethanol, so it is unlikely that partial dissolution of these materials can
explain the results of the experiments involving exposure to the solvent vapors.

Scheme 2-1: Summary of results of experiments involving exposure ofmaterials to solvent vapor, drying, and exposure to vacuum.

In addition to the experiments to investigate exposure of phase H to solvent
vapors under "static" conditions (using the apparatus shown in Figure 2-7a), we
have also investigated the exposure of H to acetonitrile vapor in a flow
experiment, in which dry air, bubbled through liquid acetonitrile, was flowed38

over a sample of H. Under these conditions, we also observe that H undergoes adesolvation process to produce U, reaching completion within 4 days. On theother hand, no structural change was observed in a control experiment carriedout under the same conditions but with only dry air (not containing acetonitrile
vapor) flowed over the sample of H. Thus, these experiments confirm that thesolvent vapor plays a direct role in mediating the transformation from H to U
(and rules out the possibility that the transformation observed in the "static"
experiments might arise only from the role of the liquid phase present within thesealed vessel (see Figure 2-7a)).
In contrast to the desolvation processes observed on exposure of M and H toacetonitrile, acetone and ethanol vapors, these phases do not to undergo anytransformations in the experiments involving drying, exposure to vacuum,
exposure to hexane vapor, or exposure to diethyl ether vapor. These observations
suggest that, in the desolvation processes induced by solvent vapor, a specificaffinity between the solvent present in the vapor phase and the solvent present in
the crystal structure may be necessary.
An interesting aspect of these experiments is the time required for thetransformations to occur on exposure to solvent vapors. The solvent exchangetransformation from M to H is complete in a few hours. However, thetransformations of U to form the solvate structures M or H on exposure tomethanol and water vapors respectively require about two days. In order toinvestigate the transformation times in greater detail, dynamic vapor sorption(DVS) experiments were carried out for samples of M and U. Figure 2-9 shows
the mass changes observed for M and U under conditions of 97% relative
humidity and 25°C. The decrease in mass observed for M corresponds to theexchange of methanol by water, whereas the increase in mass observed for U
corresponds to hydration (theoretical mass changes for complete
transformations: –3.99% for M, 5.64% for U). The transformation from M to H
reaches completion in about 180 minutes with a mass change of –3.25% (Figure2-9a). The observed mass loss is close to the theoretical value, and thediscrepancy may be attributed to the difficulty in maintaining a pure sample of
M at the start of the DVS measurement (the DVS experiment requires time tostabilize the balance and humidity before measurement, and it is likely that someamount of H is formed before the actual start of the measurement, leading to themeasured mass loss being lower than the theoretical value). In contrast, the39

transformation from U to H does not reach completion after 10000 mins (masschange +1.85%). In this case, the increase of mass is very gradual, and themeasurement was stopped before the transformation was complete. These results
indicate that the solvent exchange transformation between M and H proceeds
readily, but that hydration of U is a much less facile process. The results of the
DVS experiments are consistent with the results of the experiments involving
exposure of the materials to solvent vapors, and confirmed by powder X-ray
diffraction analysis, although the transformation time is quite different in eachcase because of the different experimental conditions.

Figure 2-9 : DVS plots, measured at 25°C and 97% relative humidity, for (a)phase M, and (b) phase H. The transformation did not reachcompletion in the case of phase H, with the measurement stopped at
10000 mins.
40

From the experiments discussed above, it is clear that solvent exchange
between M and H proceeds readily, but the transformations from U to either M
or H proceed much more slowly. We now assess the extent to which the relative
ease of these transformations can be rationalized on the basis of the structuralproperties of M, H and U.

2.4.4. Mechanistic Aspects of Solvent Exchange Transformationsof M and H
As discussed above, the structures of M and H have similar hydrogenbonding units, and the relative arrangements of these hydrogen bonding units areshown in Figure 2-10(a) and 10(b) respectively. Although the stacking ofhydrogen bonding units is different in these structures, both structures haveclearly defined solvent channels (indicated by light blue dashed lines). In Figure2-10(c) and 10(d), the structures are viewed along the direction of the solvent
channel (b-axis for M; c-axis for H), showing a straight solvent channel in bothcases. The existence of solvent channels often affects the ease of occurrence ofsolvation or desolvation processes. However, the experiments involving drying
and exposure to vacuum of M and H did not induce desolvation and dehydration,and the stability to loss of methanol and water under these conditions may
reflect the fact that the methanol and water molecules are held in these structures
through robust hydrogen bonding. The stabilities of M and H under these
conditions, in which solvent vapor is absent, suggest that interaction between
solvent vapor and the crystalline solid plays a direct and important role inmediating the solvent exchange transformations in these materials.

41

Figure 2-10 : Stacking of hydrogen bonding units in the crystal structures of (a)phase M and (b) phase H. The orange solid line shows a hydrogenbonding unit and the light blue dashed lines show the solvent
channels. The figures on the right side show the crystal structures of(c) phase M viewed along the b-axis and (d) phase H viewed along
the c-axis. The solvent molecules are shown as a ball-and-stickmodel.

From the structural similarities between M and H and the stabilities of thesolvate structures (with respect to desolvation), it is expected that solvent
exchange might occur through the solvent channel, with preservation of thehydrogen bonding unit, thus promoting the facile occurrence of thetransformations between M and H. Furthermore, the fact that a significantly
longer time is required for U to transform to the solvate phases M and H
suggests that the solvent exchange transformations between M and H do notproceed via the unsolvated phase U.

2.4.5. Transformations from U to M or H
The structure of U (Figure 2-11, CCDC deposition number 602110) differs
significantly from the structures of M and H, and comprises layers of 5MP and
TMA molecules (Figure 2-11(a)) with a hydrogen bonding scheme (Figure2-11(b)) that is quite different from those in M and H. Given the differences in
the hydrogen bonding schemes, and the absence of solvent channels, it isanticipated that the transformation from U to either M or H would involve42

significant structural reorganization, which is reflected in the much longer
transformation times observed. Although the powder sample of U does notappear to dissolve upon exposure to solvent vapors, the possibility that thetransformations from U to M or H may proceed through the occurrence of local
recrystallization cannot be ruled out.

Figure 2-11 : Crystal structure of phase U: (a) showing the stacking of thelayered structure, and (b) viewed along the c-axis [corresponding to
the view along the arrow shown in (a)].

43

2.4.6. Photoreactivities
Finally, the difference of the photoreactivities is discussed. Although themethanol solvated M and hydrate H are not photoreactive for the 5MP
molecules by UV irradiation, the unsolvated crystal U is photoreactive andwhich produced [4+4] cis-syn dimer. In order to reveal the mechanism of suchdifferent photoreactivities, the nearest 5MP pairs, which can be considered as
the most reactable molecules in the crystal, in each crystal are investigated. As
shown in Figure 2-12, the nearest 5MP pairs have parallel olefin arrangement(the pairs are all related by symmetry operations, such as inversion center ortranslation operations) in there crystals. In such cases, it was said that the mostimportant factor is the distance between the reaction center and the π-overlap ofreacted olefin(43). Generally, the distance between the reaction centers is lessthan 4.2Å for the reactive phase, however, the distances look sufficiently satisfy
this condition in all cases (as shown in Figure 2-12 , M for 3.55Å,H for 4.08
Å,U for 3.84 Å). On the other hands, the degree of the π-overlaps, which can beevaluated by the displacement of double bonds upon projection, clearly suggestthat the crystal H does not have suitable condition for the photo-dimerization
reaction because the usual reactive double bond have less than 1.6Å(43). However,
if only the distances of reactive double bonds and the degree of the π-overlaps
are compared between crystal M and U, crystal M has better conditions thancrystal U. Thus these values cannot be considered as the sufficient criteria forunderstanding the photoreactivities of 5MP. Thus another concept which iscalled “reaction cavity” was introduced into these crystals, in order to establish
the precise criteria for understanding the photoreactivity of 5MP. The reaction
cavity defined by Y. Ohashi(45) was used here. The drawn reaction cavities ofcrystal M, H and U, and the calculated volume of the reaction cavities are also
shown in Figure 2-12. Clearly the reaction cavities are different for thesecrystals and it was revealed that the reactive crystal U has the largest volume. In
addition to the volume, the shape of reaction cavity of crystal U looks to havesuitable space for approaching the 5MP pair than those of crystal M and H.
Therefore, in the 5MP case, the precise criteria of photoreactivity might bedetermined by their reaction cavity volumes and/or the cavity shape.

44

Figure 2-12 The nearest 5MP pair in the crystal (a) M, (b) H, and (c) U. The
values show the distances of reactive double bonds, thedisplacement of double bonds upon projection, and the reaction
cavity volume.

45

2.5. Concluding Remarks
As discussed above, a new hydrate co-crystal (H) of 5MP and TMA has beenobtained on grinding the methanol solvate co-crystal (M) of 5MP and TMA
under ambient conditions, and the structure has been determined directly frompowder X-ray diffraction data. The transformation is a solvent exchange process
induced by water vapor in the ambient atmosphere, and the role of grinding is
primarily to accelerate the transformation. In order to obtain further insights
regarding solvation and desolvation processes within this series of co-crystals,
experiments involving exposure of the methanol solvate (M), hydrate (H) andunsolvated (U) co-crystals to different solvent vapors were carried out. The
various transformations induced among these co-crystals by exposure to solvent
vapors are summarized in Scheme 2-1.
For solvent exchange processes, aspects of the transformation mechanism
may be understood by considering changes in the crystal structure and the rateof the transformation. The similarity of crystal structures (in terms of hydrogenbonding units) of M and H, and the fact that the rate of transformation from M
to H is higher than the rate of transformation of U to form M or H, areconsistent with the solvent exchange process occurring through the solvent
channel, with the intermediate state preserving this channel and the basic
hydrogen bonding unit. On the other hand, transformation of U to form solvate
structures, upon exposure to solvent vapors, involves major structural changes,
and consequently may require considerably longer time to complete thestructural transformation.
In addition, we have found that desolvation processes of M and H may be
induced by exposure of these materials to different solvent vapors (acetonitrile,ethanol and acetone), but not by exposure to other vapors (hexane or diethyl
ether) or by drying or exposure to vacuum. These observations suggest that acertain degree of affinity between the solvent molecules included in the solid
solvate structure and the solvent molecules in the vapor phase is necessary to
induce such desolvation processes. One interesting point is that, in the cases
reported here, exposure to solvent vapor is able to effect desolvation, whereas
the physical forces of drying or exposure to vacuum are unable to effectdesolvation. As shown in this paper, exposure of solid materials to solvent vapor
can produce interesting and specific effects to modify solid state structures and46

properties.

47

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50

Chapter 3
Dehydration and Hydration of Lisinopril
3.1. Abstract
A widely used anti-hypertension drug, lisinopril is known to be obtained as
dihydrate form by recrystallization and the dihydrate form was known toundergo two step dehydration via monohydrate form. Such a dehydration is very
important in the pharmaceutical area because such solid state transformations
usually affect to the pharmaceutical properties such as solubility, dissolution rate,bioavailability and so on. However, although crystal structures of these hydrates
or anhydrous form are necessary for understanding the transformation
mechanisms and the properties of resulted forms, there is no report on theircrystal structures because of difficulty to obtain a single crystal for these forms.
Thus, in the present work, crystal structures of lisinopril dihydrate, monohydrate
and anhydrous forms are determined from powder X-ray diffraction data and themechanistic aspects of two step dehydration process has been established fromthe crystal structural changes. Furthermore, the hydration mechanisms ofmonohydrate and anhydrous forms were clearly understood from these crystal
structures and it was revealed that the hydration process is not a simple reverse
pathway of the dehydration process. Finally, DVS measurements were carriedout and the results clearly support these dehydration and hydration mechanisms.

51

3.2. Introduction
Many organic crystalline solids can exist as polymorphs, hydrates or solvates,or the combination of these. The existence of these alternative crystalline phasesis critical problem, especially for the pharmaceutical compounds, because thesealternative phases usually have different physical or chemical properties which
are important for the drug use, such as solubility, dissolution rate, stability andbioavailability(1)(2). Thus, well investigation about the existence of alternative
phases and well understanding about their properties are very important forpharmaceutical compounds. Also, understanding the transformation mechanism
among these alternative phases is very important, because such transformations
are frequently occurred during the drug manufacturing process or upon storageof the drug substance or dosage form(3).
Grant et. al. reported the nature of pharmaceutical hydrates and he showed
many analytical techniques for understanding the properties of pharmaceuticalhydrates and the mechanistic aspects of the hydration or dehydration processes(4).
Among these analytical techniques, crystal structure analysis is one of thepowerful techniques to understand the mechanistic aspects of the hydration or
dehydration process. According to such background, there are several literatures
which focused on the mechanistic aspects of hydration or dehydration processusing single crystal structure analysis technique(5)(6). However, in many cases,
single crystals of the starting phase are found to disintegrate to produce a
polycrystalline material upon dehydration or hydration process, thus limiting theopportunities to obtain information on the structural changes associated withsuch processes by single crystal X-ray diffraction analysis. In some cases, it
might be possible to obtain a single crystal of the transformed phase (asconfirmed by comparison of powder X-ray diffraction data) by anothercrystallization method, but in many cases, single crystals of the dehydrated or
hydrated phase cannot be obtained by any other method. Techniques for carryingout structure determination directly from powder X-ray diffraction data areclearly essential for structural characterization of the polycrystalline productmaterials obtained directly in such dehydration or hydration.
The opportunities for carrying out complete structure determination of organic
molecular materials from powder X-ray diffraction data have developed
considerably in recent years(7)-(19), particularly through the development of the52

direct-space strategy for structure solution(20). Because these techniques have thepotential to provide structural understanding of polycrystalline products
obtained from solid state transformations (e.g. originating from single crystal
materials of the type discussed above), these techniques have a key role to playin understanding structural properties of materials produced from solid state
grinding processes, solid state reactions, desolvation processes, and polymorphic
transformations(21)-(28).

Figure 3-1 : Molecular structure of Lisinopril.

In the present work, lisinopril was focused for the target compound for thesystematic understanding about the pharmaceutical dehydration or hydration
process. Lisinopril (N2-[(S)-1-carboxy-3-phenylpropil]-L-lysyl)-L-proline, ) is
widely used anti-hypertension drug, based on the ability to inhibit the activity ofangiotensin-converting enzyme (ACE)(30)-(32). The inhibiting activity of lisinopril
is considered to be related to the ability to interact with ACE, thus, there wereseveral studies to investigate the interaction between lisinopril and ACE(33)(34) ormetal ion(35)(36) (because ACE is known as zinc metalloenzyme) from crystal
structure analysis. Dihydrate form is known as the most stable crystalline form
which is used as ethical medicine and is known to dehydrate via monohydrate
form to anhydrous form by temperature elevating(37)(38). However, because ofdifficulty to obtain a single crystal which is suitable size for diffraction
measurement, there is no structural report for these lisinopril crystalline phases,
including stable dihydrate form. Thus, the structural information of hydrates and53

the mechanism of dehydration or hydration process are unknown. In the present
study, in order to reveal the structural properties and mechanistic aspects ofdehydration or hydration, crystal structures of lisinopril hydrates, including
anhydrous form, were determined from powder diffraction data.

54

3.3. Experiment3.3.1. Preparation
Lisinopril dihydrate was purchased from Wako Pure Chemical Industries, Ltd.
Recrystallization of lisinopril from water solution gave pure powdered dihydrate
form and was used for synchrotron X-ray diffraction measurement, thermal
analysis(TG/DTA, DSC, XRD-DSC) and dynamic vapor sorption experiments.
The preparation of monohydrate and anhydrous forms for synchrotron X-ray
powder measurement is described in the synchrotron measurement section.

3.3.2. Thermal analysis
TG/DTA was measured on a Rigaku Thermo Plus 2. 6.026 mg of lisinopril
dihydrate form was heated in a rate of 0.5 K/min. The TG curve was recorded
from 27°C up to 180°C under a dry nitrogen atmosphere with a flux of 100
ml/min. The simultaneous DSC and X-ray diffraction measurement (XRD-DSC)
was performed on a Rigaku D/MAX 2400 diffractometer and a Rigaku Thermo
Plus 2 differential scanning calorimeter at a heating rate of 3°C/min.

3.3.3. Dynamic Vapor Sorption
Dynamic vapor sorption was measured on Dynamic vapor sorption –advantage (SMS Ltd, UK). 3.96 mg of powdered dihydrate form was mouted ona valence and the dehydration process was monitored by mass change at 38.7°C
with relative humidity 0% condition. After complete dehydration, relative
humidity was set to 10 % and hydration process was measured for anhydrous
form. The measurement was continued until no mass change was observed.

3.3.4. Synchrotron X-ray powder diffraction measurement
Synchrotron X-ray powder diffraction data were recorded for lisinopril
dihydrate form at ambient condition on beamline 4B2 (Multiple Detector
System) at Photon Factory, Tsukuba, Japan with wavelength 1.20853 (2) Å. The
sample was mounted on flat sample holder and diffraction measurement was
performed using reflection mode with rotation of sample holder. Data collection
55

time was ca. 12 hours.
For monohydrate and anhydrous forms, synchrotron X-ray powder diffraction
data were recorded on beamline BL19B2 at SPring-8 (Debye-Scherer camera
equipped with a curved Imaging Plate detector). Because monohydrate form
easily returns to dihydrate form at ambient condition and the transformation
temperature of dihydrate to monohydrate form and monohydrate to anhydrous
form is not sufficiently separate, monohydrate form is difficult to prepare purely.
However, pure monohydrate form was successfully prepared by slow
temperature elevating of dihydrate form, which was introduced into 0.3 mm
diameter borosilicate glass capillary without sealed, on the goniometer. Thus,
synchrotron powder X-ray diffraction measurement was carried out in situ
condition at 84°C with sample spinning and wavelength 1.20033 (1) Å. The datacollection time was 20 minutes. Also, lisinopril anhydrous form easily returns todihydrate form as well as monohydrate form at ambient condition, however,
hydration of anhydrous form can be prevented in a dried condition, so that thesynchrotron measurement was performed at ambient condition using sealed 0.3
mm diameter borosilicate glass capillary. The measurement was performed withwavelength 1.19770(1) Å and the data collection time was 60 minutes.

56

3.4. Results and Discussion
3.4.1. Thermal Analysis
As already reported, two step dehydration can be seen by two DTA
endothermic peaks (Figure 3-2). The mass decrease of 4.1% for first dehydration
and 8.5% for second dehydration suggests the existence of monohydrate form.
In order to characterize these forms, XRD-DSC measurement (simultaneous
XRD and DSC measument) was carried out for dihydrate form. The XRD
pattern changes were observed by first and second dehydration process (Figure3-3). As shown in close-up XRD pattern (Figure 3-4), dihydrate form andmonohydrate form have quite similar XRD pattern, although anhydrous form
has different XRD pattern from those of dihydrate and monohydrate forms.
These results indicate that the first dehydration takes small structural change andthe second dehydration takes lager structural change than that of first
dehydration process. In order to reveal the structural changes in detail, crystal
structure analyses were carried out for dihydrate, monohydrate and anhydrous
form. Unfortunately, suitable single crystal for X-ray diffraction was not
obtained for dihydrate form by recrystallization from solution, thus, all crystal
structures were determined from powder X-ray diffraction data.

Figure 3-2 : TG/DTA plot of lisinopril dihydrate form.
57

Figure 3-3 : XRD-DSC plot of lisinopril dihydrate form

Figure 3-4 : XRD patterns of Lisinopril (a) dihydrate, (b) monohydrate and (c)anhydrous form, measured on XRD-DSC instrument.
58

3.4.2. Structure Determination from Powder X-ray Diffraction
Data
The powder X-ray diffraction pattern of dihydrate form was indexed using the
program DICVOL04(39) giving the following unit cell (M20 = 39.7(40), F20 =139.7(41)) with monoclinic metric symmetry: a = 14.6516 Å, b = 5.9015 Å, c =14.2884 Å, β = 113.162°, V = 1135.89 Å3. Given the volume of this unit cell,and consideration of density, the number of formula units in the unit cell is
assigned as Z = 2. From the estimated Z value and systematic absences, thespace group was determined as P21. Profile fitting using the Pawley method(42)gave a good quality fit with Rwp = 9.55% and χ2 = 17.240(these values were
calculated on background subtracted intensity). Structure solution was carriedout using the simulated annealing method incorporated in the program DASH(43).
The structural fragment comprised one lisinopril molecule and two waters,
representing a total of 24 structural variables. Twenty runs with 107 simulated
annealing moves per run were performed for structure solution. The bestsolution had profile χ2 73.70 and intensity χ2 66.25. Following structure solution,
Rietveld refinement(44) was carried out using the GSAS program(45). Standard
restraints were applied to bond lengths and bond angles, planar restraints wereapplied to aromatic rings, and a global isotropic displacement parameter wasused. The final Rietveld refinement gave following parameters: a = 14.6607(1)Å, b = 5.91012(6) Å, c = 14.3052(1) Å, β = 113.1447(6)°, V = 1139.73(2) Å3,
Rwp = 5.83%, Rp = 4.40%, RF2 = 6.30% (corresponding Le Bail profile fitting
gave Rwp = 4.08%, Rp = 2.95%). The final Rietveld plot is shown in Figure 3-5a.
The powder X-ray diffraction pattern of monohydrate form was analyzed withthe same manner with dihydrate form. The indexed unit cell was a = 14.6610 Å,
b = 5.9094 Å, c = 14.2186 Å, β = 112.859°, V = 1135.13 Å3 (DICVOL04, M20 =83.6, F20 = 278.1, monoclinic) and which is similar with the unit cell of
dihydrate form, thus, the space group was determined as P21 which is same withdihydrate form. Profile fitting using the Pawley method gave a good quality fit
with Rwp = 10.35% and χ2 = 3.171. The structure was determined by the
program DASH (structural fragment comprised one lisinopril molecule and one
water, representing a total of 21 structural variables) and twenty runs with 107
simulated annealing moves per run gave the best solution with profile χ2 8.33
and intensity χ2 40.24. The final Rietveld refinement (GSAS) gave following
59parameters: a = 14.6677(3) Å, b = 5.9124(1) Å, c = 14.2254(3) Å, β =112.880(1)°, V = 1136.58(5) Å3, Rwp = 4.90%, Rp = 3.44%, RF2 = 11.14%(corresponding Le Bail profile fitting gave Rwp = 3.23%, Rp = 2.41%). The final
Rietveld plot is shown in Figure 3-5b.
Also, the powder X-ray diffraction pattern of anhydrous form was analyzed
with the same manner with dihydrate form and monohydrate form. The indexed
unit cell was a = 14.6193 Å, b = 5.9409 Å, c = 14.2894 Å, β = 116.527°, V =1110.41 Å3 (DICVOL04, M20 = 57.3, F20 = 196.0, monoclinic) and which issimilar with the unit cell of dihydrate form, thus, the space group wasdetermined as P21 which is same with dihydrate form. Profile fitting using the
Pawley method gave a good quality fit with Rwp = 19.80% and χ2 = 25.574. The
structure was determined by the program DASH (structural fragment comprised
one lisinopril molecule, representing a total of 18 structural variables) andtwenty runs with 107 simulated annealing moves per run gave the best solution
with profile χ2 89.58 and intensity χ2 42.51. Because the measured sample
contained some dihydrate form, multi phase Rietveld refinement was performed
for anhydrous form with dihydrate form as Le Bail refinement mode. The final
Rietveld refinement gave following parameters: a = 15.1769 (3) Å, b =5.94511(8) Å, c = 14.2291 (3) Å, β = 120.6209(9)°, V = 1104.84 (4) Å3, Rwp =6.56%, Rp = 4.35%, RF2 = 4.69% (corresponding Le Bail profile fitting gave Rwp= 3.89%, Rp = 2.50%). The final Rietveld plot is shown in Figure 3-5c.

60Figure 3-5 : Final Rietveld refinement for Lisinopril (a) dihydrate form, (b)monohydrate form and (c) anhydrous form, showing theexperimental powder X-ray diffraction pattern (+ marks), calculated
powder X-ray diffraction pattern (solid line) and difference profile(lower line). Tick marks indicate peak positions. For anhydrous form(c), upper and lower tick mark indicate peak positions of anhydrous
form and impurity dihydrate form, respectively.

61

3.4.3. Crystal Structure of Dihydrate Form
As shown in Figure 3-6(a), lisinopril dihydrate form has a stacking oflisinopril molecule along the b axis (21 screw axis) and it makes two types ofwater channels. One channel is labeled as central channel, which exists at thecenter of unit cell, and the other channel is labeled as side channel, which exists
at the side of unit cell (Figure 3-6(a)). In these two channels each watermolecules are hydrogen bonded to adjacent water and lisinopril molecules.
Figure 3-7 shows hydrogen bonds of these two waters in dihydrate form. In theside channel water (H62-O61-H63), there are three types of hydrogen bonds for
one water molecule, O61-H62…N13’ (O…N, 2.80Å), O61-H63…O11’’ (O…O,
2.84Å), O11-H40…O61 (O…O, 2.65Å). The central channel water is, also,
connected by three hydrogen bonds, however, two of them are equivalent
O65-H65…O64 (O…O, 3.10Å) hydrogen bond and the other is O64-H66…O12(O…O, 2.86Å) hydrogen bond. Comparing these hydrogen bonds of the side
and central channel waters, it is obvious that the side channel water has shorterhydrogen bonds than those of the central channel water. The difference ofhydrogen bond distances indicates that the side channel water is the strongerhydrogen bonded than the central channel water. From these considerations, it isnatural to expect that the weaker hydrogen bonded central channel water will be
released in the first dehydration, and subsequently the side channel water will be
released in the second dehydration process.

62

Figure 3-6 : Crystal structures of Lisinopril (a) dihydrate, (b) monohydrate and(c) anhydrous form, view along the b axis.
63

Figure 3-7 : Side view of water channels in lisinopril dihydrate form. Sky blue
dash lines show the hydrogen bonds.

3.4.4. Crystal Structure of Monohydrate Form and Mechanism ofFirst Dehydration
Figure 3-6(b) shows the crystal structure of monohydrate form view along theb axis. The crystal structure of monohydrate form has similar packing that ofdihydrate structure with same space group P21 and molecular stacking exists
along the b axis according to the 21 screw axis. As expected from the structure ofdihydrate form, the central channel water was removed in this structure.
However, interestingly, after removal of central channel water, the channel was
not closed and a vacant channel remains in its structure.
Generally, such a large empty channel is considered as unstable structure and,in such dehydration processes, the conformational changes or modifications ofmolecular arrangement are required (for example see ref. (5),(6)). The vacantchannel volume is calculated to be 67.9 Å3 per unit cell(46) and the central
channel volume of dihydrate form is calculated to be 75.0 Å3 per unit cell. Even
allowing a consideration about the difference in temperature conditions for64synchrotron measurement (357K for monohydrate form and at ambient
temperature (ca. 300K) for dihydrate form.), the central channel volume issignificantly decreased after first dehydration. The reason of such volume
decrease can be explained by the force to close the vacant central channel. The
decrease of the central channel volume is considered to affect the hydrogenbonds in the side channel and the hydrogen bond lengths in the side channel aresomewhat increased averagely compare to those of dihydrate structure,
O61-H62…N13’ (O…N, 2.73Å), O61-H63…O11’’ (O…O, 2.93Å),O11-H40…O61 (O…O, 2.80Å).
Although it is difficult to establish the reason of why the vacant central
channel is not closed, one of the reasons can be considered from the structure in
the central channel. As shown in the Figure 3-7, it is obvious that the central
channel does not have well defined hydrogen bond donor or acceptor, such ascarboxylic acid or amine which can be seen in the side channel. The absence ofstrong hydrogen donor or acceptor means that the large stabilization by
conformational change in the central channel is not expected and theconformational change might not be necessary in this vacant channel.
On the other hands, there is not significant structural change in the sidechannel except the extension of hydrogen bonds as discussed above. Thus, thestructural change in first dehydration process is only loss of water of the central
channel. The small structural change is consistent with the similarity of XRD
pattern (Figure 3-4). There is no significant change for unit cell constants andmolecular packing and conformation, the diffraction positions and intensities areto be quite similar. However, the existence of the vacant central channel (67.9 Å3
per unit cell) is considered as the reason of instability for a vapor and the vacantcentral channel will take in water (volume of a water is ca. 32Å3) readily, thus
the monohydrate form easily returns to dihydrate form.

3.4.5. Crystal Structure of Anhydrous Form and Mechanism ofSecond Dehydration
Crystal structure of anhydrous form is shown in Figure 3-6(c). Anhydrous
form has also similar packing with those of dihydrate and monohydrate form.
However, the large difference can be seen in the closed side channel. In thesecond dehydration process, water of the side channel was removed and the65side channel was closed. The interesting point is a twist motion of ethylphenyl
substitute of lisinopril molecule which is accompanied of closing of the sidechannel. Because of steric repulsion, lisinopril molecules cannot approach eachother to close the side channel with retaining its conformation. Thus, the twistof ethylphenyl substitute about 160° make the suitable conformation toapproach each other and it enables to close the side channel.
The hydrogen bonds in the closed side channel are shown in Figure 3-8.
Instead of water mediated hydrogen bonds which exists in dihydrate andmonohydrate structure, there are O11-H40...N13’ (O…N, 3.05Å) andN13’’-H41’’...O12 (N...O, 3.13Å) hydrogen bonds. In addition, a weak
O11-H40…O11’ (O…O, 3.48Å) hydrogen bond is observed. These hydrogenbonds are relatively long (standard O…O is 2.8Å and O…N is 2.7Å) and arefar from ideal hydrogen bond conditions. However, under the restrictions ofmolecular shape or crystal packing effect, so that it can be considered that it isdifficult to construct ideal hydrogen bonds. The non-ideal hydrogen bonding
conditions can be considered as one of the reasons of instability of anhydrous
form and why dihydrate form usually appears by recrystallization.
The primary reason of easy hydration of anhydrous form is the existence ofthe vacant central channel which is also observed in monohydrate form. The
vacant central channel volume of anhydrous structure is 96.0Å3 per unit cell.
This volume is significantly larger than that of monohydrate central channel(67.9 Å3 per unit cell). This volume is also significant size to take in a water aswell as monohydrate structure and this can be considered as the primary reasonof easy hydration.
The reason of increasing of the vacant central channel can be explained fromthe channel closing motion of the side channel. By closing of the side channel,
lisinopril molecules translated to the opposite direction from the central
channel, in order to construct hydrogen bonds in the side channel as explained
above, thus, as a result, the volume of the vacant central channel is increased inanhydrous strcture. In another view point, the reason of why the side channel
was closed and the vacant central channel was increased can be explained by
the difference of the existence of hydrogen bond donor and acceptor in thesetwo channels. Although the central channel does not have definitive hydrogenbond donor or acceptor, the side channel has relatively strong hydrogen bonddonor and acceptor (carboxylic acid and secondary amine). The existence of66

relatively strong hydrogen bond donor and acceptor in the side channel mightcause the interaction between each other to construct the more stable conditions,thus, the closing motion of the side channel might occur. On the other hands,
large stabilization by closing of the central channel cannot be expected becauseof the nonexistence of well defined hydrogen bond donor or acceptor. From
this reason, the central channel does not close and it retains the vacant channel.
The difference of XRD pattern of anhydrous form from those of dihydrate andmonohydrate form can be explained from the change of crystal structure in thesecond dehydration process. The change of diffraction intensities comes fromclosing of the side channel and the change of diffraction peak positions comesfrom the change of unit cell parameters which is due to the closing of the sidechannel.

3.4.6. Hydration Mechanism
The dehydration mechanism is clearly revealed from the structural change in
two step dehydration process. Now, we focus on the mechanistic aspects ofhydration process. As mentioned above, the reason of why monohydrate andanhydrous forms easily return to dihydrate form can be explained from theexistence of the vacant central channel which is formed in the first dehydration
process. If this expectation is correct, it can be said that the hydration process is
not a simple reverse of dehydration process, because the dehydration of
dihydrate form was start from the central channel. In order to confirm thedifference of the dehydration and hydration process, DVS measurement werecarried out for dihydrate form and anhydrous form. The mass changes of thedehydration and hydration process were shown in Figure 3-9. The observed
mass decrease in dehydration process was 8.37% and mass increase in hydration
process was 8.22%. These mass change is corresponding to two water molecules(ideal mass % for one water is 4.08%). In the dehydration process, two step
mass changes were observed which can be seen as the rate change of masschange, however, there is no rate change in the hydration process and it
proceeded in one step. These results clearly suggest the difference of hydrationand dehydration pathway and also it can be concluded that the hydration process
is not a simple reverse process of dehydration process. Unfortunately, thehydration completed in 15 mins while only in the condition of 10% relative67

humidity, so that it is difficult to observe the XRD change in hydration process.
However, from the DVS observation, it is obvious that the hydration is not a
simple reverse of the dehydration process and anhydrous form might be directly
converted to dihydrate form. The fact of that the anhydrous form for thesynchrotron measurement contained some dihydrate form also suggests the
direct conversion from anhydrous form to dihydrate form. In the diffraction
pattern of anhydrous form, any monohydrate peaks or another unknown form
was not observed.

Figure 3-8 : Side view of closed side channel and vacant central channel inlisinopril anhydrous form. Sky blue dash lines show the hydrogenbonds. Pale orange dash lines show the weak hydrogen bonds.

68Figure 3-9 : DVS plot of (a) dehydration process of dihydrate form and (b)hydration process of anhydrous form. Solid line shows the masschanges and dash line shows the rate of mass changes.

693.5. Concluding Remarks
Crystal structures of lisinopril dihydrate, monohydrate and anhydrous forms
were successfully determined from powder X-ray diffraction data, and themechanism of two step dehydration of lisinopril dihydrate form was clearly
revealed from these structures. The order of dehydration was determined fromthe hydrogen bond conditions of water channels. In the first dehydration,
relatively weak hydrogen bonded water (the central channel) was released and,in the second dehydration, stronger hydrogen bonded water (the side channelwater) was released. Interestingly, although the side channel was closed bydehydration process, the central channel was not closed in the dehydration
process. Because the remaining vacant central channel in monohydrate andanhydrous form has significant volumes for taking in water, it can be consideredas the reason of easily hydration of these forms. From this consideration, themechanism of hydration process is expected as not a simple reverse of
dehydration process. The expectation can be confirmed from the DVS
measurement of the dehydration process and hydration process. Although two
step dehydration can be seen in the result of DVS measurement, the hydration
proceeded in one step and which clearly suggests that the hydration process is
not a simple reverse pathway of dehydration process.
As shown in this study, investigation of pharmaceutical dehydration processusing ab initio powder X-ray diffraction analysis is powerful technique tounderstand the dehydration or hydration process. Further investigations about
the pharmaceutical dehydration or hydration mechanism are expected forsystematic understand.

70

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73

Chapter 4
Dehydration and Phase Transformation of
Acrinol
4.1. Abstract
An extensive used antibacterial agent, acrinol is known to be obtained as
monohydrate form by recrystallization. From thermal and powder X-ray
diffraction experiments, the crystal to crystal dehydration and polymorphic
transformation were found for acrinol monohydrate form by heating.
Interestingly, a large difference was observed for the relative humidity on thehydration of anhydrous A (after dehydration; hydrated at RH10%) and B (after
polymorphic transformation; hydrated at RH80%). The crystal structures ofthese anhydrous forms are necessary for understanding the transformation
mechanisms and their hydration properties, however, because of a disintegrationof single crystal while transformations, it is impossible to determine thesecrystal structures by single crystal diffraction analysis. Therefore, the techniqueof crystal structure determination from powder X-ray diffraction data wereapplied to these unknown forms and successfully the crystal structures of acrinol
anhydrous A and B were determined. The mechanistic aspects of thedehydration and polymorphic transformation were established from the crystal
structural changes and the difference in the hydration humidity of anhydrous A
and B was clearly understood from the crystal structures similarity anddifference. In addition to the understanding the transformation mechanisms, alarge differences of the initial dissolution rate were found among acrinol hydrate,
anhydrous A and B. The fastest dissolution rate was achieved for anhydrous B
74

and which has five times faster than well used hydrate form. These results
clearly suggest the effectiveness of an investigation of alternative forms such as
hydrates and polymorphs.

75

4.2. Introduction
Many organic crystalline solids can exist as polymorphs, hydrates or solvates,or the combination of these. The existence of these alternative crystalline phasesis critical problem, especially for the pharmaceutical compounds, because thesealternative phases usually have different physical or chemical properties which
are important for the drug use, such as solubility, dissolution rate, stability andbioavailability(1)(2). Thus, well investigation about the existence of alternative
phases and well understanding about their properties are very important forpharmaceutical compounds. Also, understanding the transformation mechanism
among these alternative phases is very important, because such transformations
are frequently occurred during the drug manufacturing process or upon storageof the drug substance or dosage form(3).
Grant et. al. reported the nature of pharmaceutical hydrates and he showed
many analytical techniques for understanding the properties of pharmaceuticalhydrates and the mechanistic aspects of the hydration or dehydration processes(4).
Among these analytical techniques, crystal structure analysis is one of thepowerful techniques to understand the mechanistic aspects of the hydration or
dehydration process. According to such background, there are several literatures
which focused on the mechanistic aspects of hydration or dehydration processusing single crystal structure analysis technique(5)(6). However, in many cases,
single crystals of the starting phase are found to disintegrate to produce a
polycrystalline material upon dehydration or hydration process, thus limiting theopportunities to obtain information on the structural changes associated withsuch processes by single crystal X-ray diffraction analysis. In some cases, it
might be possible to obtain a single crystal of the transformed phase (asconfirmed by comparison of powder X-ray diffraction data) by anothercrystallization method, but in many cases, single crystals of the dehydrated or
hydrated phase cannot be obtained by any other method. Techniques for carryingout structure determination directly from powder X-ray diffraction data areclearly essential for structural characterization of the polycrystalline productmaterials obtained directly in such dehydration, hydration or polymorphic
transformations.
The opportunities for carrying out complete structure determination of organic
molecular materials from powder X-ray diffraction data have developed76considerably in recent years(7)-(19), particularly through the development of thedirect-space strategy for structure solution(20). Because these techniques have thepotential to provide structural understanding of polycrystalline products
obtained from solid state transformations (e.g. originating from single crystal
materials of the type discussed above), these techniques have a key role to playin understanding structural properties of materials produced from solid state
grinding processes, solid state reactions, desolvation processes, and polymorphic
transformations(21)-(28).
In the present work, acrinol (Figure 4-1) was focused for the target compound
for the systematic understanding for the pharmaceutical dehydration or
hydration process. Acrinol, which consist of ethacridine (3,9-diamino-7ethoxyacridine) and latcid acid, is extensive use as an antibacterial agent. It is
known that the monohydrate form is usually appeared by recrystallization andthe crystal structure of monohydrate form was already reported(29). However,there is no report regarding the thermal behavior or crystal structural changes inthe dehydration process of acrinol. Thus, the structural information of anhydrous
form and the mechanism of dehydration process were not revealed. In thepresent study, in order to reveal the structural properties thermal analyses werecarried for acrinol hydrate and the crystal structures of newly found two
anhydrous forms were determined from powder X-ray diffraction data.

Figure 4-1 : Molecular structure of acrinol.

77

4.3. Experiment4.3.1. Preparation
Acrinol was purchased from Tokyo Chemical Industry co., Ltd.. The sample
was confirmed as pure hydrate phase from powder X-ray pattern and the sample
was used for other experiment without further purification. Anhydrous forms (Aor B) were prepared by heating of this hydrate sample.

4.3.2. Thermal Analysis
TG/DTA was measured on a Rigaku Thermo Plus 2. 16.136 mg of acrinol
hydrate was heated in a rate of 0.5 °C/min. The TG curve was recorded from
50 °C up to 350 °C under a dry nitrogen atmosphere with a flux of 100 ml/min.
The simultaneous DSC and X-ray diffraction measurement (XRD-DSC) was
performed on a Rigaku D/MAX 2400 diffractometer and a Rigaku Thermo Plus
2 differential scanning calorimeter at a heating rate of 3 °C/min.

4.3.3. Dynamic Vapor Sorption
Dynamic vapor sorption was measured on Dynamic vapor sorption –advantage (SMS Ltd, UK) at 40°C. Anhydrous form A or B was mounted on avalance and the relative humidity was increase from 0% to 100% with
monitoring the weight by valance.

4.3.4. Synchrotron X-ray powder Diffraction Measurement
Synchrotron X-ray powder diffraction data were recorded for acrinol
anhydrous phase A on beamline BL19B2 at SPring-8 (Debye-Scherer camera
equipped with a curved Imaging Plate detector). Because anhydrous phase A
easily returns to hydrate form at ambient condition, the prepared sample, which
was obtained by heating of acrinol hydrate, was sealed into 0.3 mm diameterborosilicate glass capillary quickly in order to prevent a hydration. The
measurement was carried out with wavelength 1.197120(4) Å and the datacollection time was 30 minutes.
The powder X-ray diffraction data of acrinol anhydrous phase B was recorded78

at ambient temperature on a Bruker D8 diffractometer using CuKα1 radiation
with linear position-sensitive detector VANTEC which covering 12°in 2θ. The
measurement was carried out by transmission mode with the foiled sample
which was totated during measurement [2θ range 5°- 70°; step size 0.0167°;
data collection time 13 h].

4.3.5. Initial Dissolution Rate
The initial dissolution rates were measured using rotating disk method. The
disk was of 10 mm diameter and the each samples were compacted at the forceof 1.96x104 N/cm2. The disk was rotated at 50 rpm at 37°C. The solvent was
900 ml of distilled water. The drug release was determined
spectrophotometrically.

79

4.4. Result and discussion
4.4.1. Characterization of Acrinol Polymorphs
TG and DTA curves of acrinol hydrate were shown in Figure 4-2. On the DTA
curve, a decomposition was observed at 242°C as endothermic peak andexothermic polymorphic transformation was found at 187.7°C after dehydration
at 100.4°C, which can be confirmed from the mass degrease 5.55% (ideal one
water is 4.98%). In order to characterize these phases, simultaneous powder
X-ray diffraction and DSC measurement (XRD-DCS) was carried out for acrinol
hydrate. As shown in Figure 4-3, it was found that the crystalline acrinol hydrate
was transformed to crystalline anhydrous form and this new phase was alsotransformed to another crystalline form by polymorphic transformation. Thus, it
can be said that the dehydration and the polymorphic transformation of acrinol
are crystal to crystal transformations. The resulted newly discovered crystalline
anhydrous forms are named anhydrous A for before polymorphic transformation
and anhydrous B for after polymorphic transformation.

Figure 4-2 : TG/DTA plot of acrinol hydrate.

80

Figure 4-3 : XRD-DSC measurement of acrinol hydrate.

The hydration properties of acrinol anhydrous A and B were investigated by
DVS measurement. Figure 4-4 shows the DVS plots of anhydrous (a) A and (b)B. Although hydration of anhydrous A was occurred at RH10% condition,anhydrous B did not hydrate until RH80% condition. Interestingly, the hydration
RH conditions are quite different between anhydrous A and B, and anhydrous B
is significantly stable for the hydration compare to anhydrous A. The large
difference in the hydration humidity of anhydrous A and B is expected to relate
to their crystal structures, thus the information on their crystal structures arenecessary for understanding their properties. However, a disintegration of single
crystal was observed for acrinol hydrate in the dehydration process and ,inaddition, the attempt to obtain single crystal of anhydrous phases byrecrystallization was failed. Thus the crystal structures of acrinol anhydrous A
and B were determined powder X-ray diffraction data.

81

Figure 4-4 : DVS measurement of acrinol (a) anhydrous A and (b) anhydrous B.

4.4.2. Structure Determination from Powder X-ray Diffraction
Data
The powder X-ray diffraction pattern of anhydrous A was indexed using the
program DICVOL04(39), giving the following unit cell (M20=38.4(31),F20=95.4(41)) with triclinic metric symmetry; a = 8.051 Å, b = 9.355 Å, c =11.912 Å, α = 102.45°, β = 103.23°, γ = 98.64°, V = 834.76 Å3. The unit cellparameters are similar to those of acrinol hydrate (a = 7.719 Å, b = 10.043 Å, c
= 12.246 Å, α = 108.14°, β = 102.98°, γ = 94.67°, V = 867.3 Å3, -100°C, P 1 ),thus, the space group of anhydrous A was estimated as P 1 . Profile fitting using
the Le Bail method(36) gave a good quality fit with Rwp = 4.02% and Rp = 2.71%.
The unit cell parameters and profile parameters obtained from the Le Bail fitting
procedure were used in the subsequent structure solution calculation. Structure
solution was carried out using the direct-space genetic algorithm (GA) techniqueincorporated in the program EAGER(34)-(38). The structural fragment comprised
one ethacridine molecule and one lactic acid molecule, representing a total 14
variables (three translational variables for each of the ethacridine and lactic acidmolecules, three orientational variables for each of the ethacridine and lactic82

acid, and two torsional variables for the ethoxy group of the ethacridine
molecule). The GA calculation involved the evolution of 60 generations for a
population of 100 structures, with 50 mating operations and 25 mutation
operations carried out per generation. Following structure solution, Rietveld
refinement(44) was carried out using the GSAS program(45). Standard restraints
were applied to bond lengths and bond angles, planar restraints were applied toaromatic rings, and a global isotropic displacement parameter was used. The
final Rietveld refinement gave following parameters: a = 8.0467(2) Å, b =9.3558(2) Å, c = 11.9151(2) Å, α = 102.436(2)°, β = 103.177(3)°, γ =98.648(2)°, V =833.92(3) Å3. Rwp = 5.80%, Rp = 4.31%, RF2 = 8.42% (2θ range,
4.01 – 77.13°; 7313profile points; 85 refined variables). The final Rietveld plotis shown in Figure 4-5a.
The powder X-ray diffraction pattern of anhydrous B was indexed using the
program DICVOL04, giving the following unit cell (M20 = 16.0, F20 = 34.1)
with triclinic metric symmetry; a = 14.0307 Å, b = 11.7879 Å, c = 20.9120 Å, β= 100.937°, V = 3395.88 Å3. Given the volume of this unit cell, andconsideration of density, the number of formula units in the unit cell is assigned
as Z = 8. From the estimated Z value and systematic absences, the space group
was determined as C2/c. Profile fitting using the Le Bail method gave a goodquality fit with Rwp = 2.99% and Rp = 2.08%. The unit cell parameters andprofile parameters obtained from the Le Bail fitting procedure were used in thesubsequent structure solution calculation. Structure solution and subsequent
Rietveld refinement were carried out with the same strategy of anhydrous A,
except a treatment of one hydrogen (H46) because, considering the hydrogen
position from hydrogen bonds and the existence of inversion center at the
middle position of two O25 oxygens, H46 hydrogen looks to be disordered andit should split into H46A and H46B to avoid the unreasonable hydrogen contacts.
In this structure, one H46 hydrogen bonds to O25 and the other H46 will directs
to N19. The final Rietveld refinement gave following parameters: a =14.0496(5) Å, b = 11.8040(2) Å, c = 20.9323(8) Å, β = 100.936(3)°, V =3468.4(2) Å3. Rwp = 4.53%, Rp = 3.28%, RF2 = 8.54% (2θ range, 5.017 –69.9299°; 3888profile points; 83 refined variables). The final Rietveld plot isshown in Figure 4-5b.

83

Figure 4-5 : Final Rietveld refinement for acrinol (a) anhydrous A (b)anhydrous B, showing the experimental powder X-ray diffraction
pattern (+ marks), calculated powder X-ray diffraction pattern (solidline) and difference profile (lower line). Tick marks indicate peak
positions.

844.4.3. Crystal Structure of Anhydrous A and the Mechanistic
Aspects of Dehydration Process
The crystal structure of acrinol hydrate(36) is shown in Figure 4-6 (a) and (b),and the crystal structure of acrinol anhydrous A is shown in Figure 4-6 (c) and(d). As it can be also seen in the crystal structure of hydrate, the crystal structureof anhydrous A has similar packing arrangements of ehtacridine molecule andlactic acid molecule. The differences among crystal structures of hydrate andanhydrous A can be seen in the position of ethacridine molecule and theorientation of lactic acid molecule. In the dehydration process, a translation of
ethacridine molecule, which might be caused to close the vacant place made byloss of water, and a rotation of lactic acid, which might be occurred to makereasonable hydrogen bonds, are observed. The hydrogen bonds of hydrate andanhydrous A are shown in Figure 4-7b and the distances of donor and acceptor
are listed in Table 4-1. Although both structures have hydrogen bonding bridgeby lactic acid, they have different bridge conditions. In anhydrous A, as shownin Figure 4-7b, O15, which is hydrogen bond acceptor, and N19-H39, which isconsidered as hydrogen bond donor, do not make hydrogen bond with anyhydrogen bond donor and acceptor, while the hydrogen bond donor and acceptor
are fully hydrogen bonded in hydrate form . Thus, anhydrous A is expected lessstable than hydrate form from hydrogen bond conditions points of view, and thiscan be considered as the reason of why hydrate form is usually appeared byrecrystallization and why anhydrous A easily returns to hydrate form. Also, thedifference of the calculated density supports this assumption. Hydrate (1.35
g/cm3 at 27°C) has lower density than that of anhydrous A (1.37 g/cm3 at 27°C),
thus, hydrate is also expected stable than anyhdrous A from the density point of
view.

85

Figure 4-6 : Crystal structures of acrinol (a) hydrate view along b axis, (b)anhydrous A view along b axis, (c) hydrate view along a axis, (d)anhydrous B view along a axis.

86

Figure 4-7 : Drawing of hydrogen bonds in crystal structure of acrinol (a)hydrate, (b) anhydrous A, (c) anhydrous B.
87Hydrate

Anhydrous A

Anhydrous B

N11-H41…O21

2.80 Å

N11-H41…O21

2.65 Å

N11-H41…O21

2.56 Å

N18-H37…O47

2.91 Å

N18-H37…O20

3.02 Å

N18-H37…O20

3.10 Å

N18-H38…O25

2.98 Å

N18-H38…O25

3.30 Å

N18-H38…O25

3.05 Å

N19-H39…O20

3.05 Å

N19-H40…O20

2.82 Å

N19-H39…O20

3.36 Å

N19-H40…O20

2.92 Å

O25-H46…O21

2.78 Å

N19-H40…O21

2.97 Å

O47-H48…O15

2.99 Å

O25-H46B…O25

3.13 Å

O47-H49…O21

2.76 Å

O25-H46A…O25

3.56 Å

Table 4-1 : Hydrogen bonds list of acrinol hydrate, anhydrous A and

The dehydration mechanism can be drawn from the crystal structures ofhydrate and anhydrous A. Take it in to account the facts of similarity of crystal
structures between hydrate and anhydrous A which can be seen in the existenceof the arrangement of water molecule along a axis in hydrate form, as shown in
Figure 4-6(c), the dehydration might be undergo through the a axis. Because thewater remove can proceed through the a axis, the crystal packing can retain after
dehydration, thus, the transformation can proceed with minor structural changes,
such as the translation of ethacridine and the rotation of lactic acid in order tomake the reasonable crystal packing and hydrogen bonds. The requirement ofminor structural changes in dehydration process is very important information to
explain the easy hydration of anyhdrous A, because, in another saying, thehydration of anhydrous A will also require minor structural changes, as well as
dehydration process, and it can consider that it will occur easily.

4.4.4. Crystal Structure of Anhydrous B and the Mechanistic
Aspects of Polymorphic Transformation Process
The crystal structure of anyhdrous B is shown in Figure 4-8. The structure isquite different from those of hydrate and anhydrous B. The similarity of thecrystal structures between anhydrous B and hydrate(or anhydrous A) is thestacking of ethacridine and one dimensional arrangement of the lactic acid88

molecule and the difference is the direction of the stacking arrangement of
ethacridine molecule as can be seen from the comparison of Figure 4-6(a) (or(b)) and Figure 4-8(a). Although the directions of the stacking arrangement of
ethacridine molecule are same in hydrate and anhydrous A, the directions are
not same in anhydrous B and, finally, these differences result in the difference of
space group (hydrate and anyhdrous A is P 1 and anhydrous B is C2/c).

Figure 4-8 : Crystal structures of acrinol (a) anhydrous B view along a axis, (b)anhydrous B view along b axis.

89

The hydrogen bonds of anhydrous B are shown in Figure 4-7 c and are listed
in Table 4-1. There are also similar hydrogen bonds with those of hydrate andanhydrous A, one N-H+…O- (N…O, 2.56Å); one N-H…O- (N…O, 3.36Å),three N-H…O (N…O, 3.10Å, 3.05Å and 2.97Å) and two disordered O-H…O(O…O, 3.13Å and 3.56Å). The hydrogen bonding donors and acceptors are fullyinteracted each other, thus, it can be considered that this structure is sufficiently
stabilized compare to anhydrous A in which the hydrogen bonding donors andacceptors are not fully occupied. The expectation of that anhydrous B is morestable than anhydrous A can be confirmed from the fact of the transformation ofanhydrous A to B is exothermic transformation. Because the system lost internalenergy in the transformation process, the resulted phase (anhydrous B) is morestable than initial state (anhydrous B). Actually the term of stability should
consider the contribution of entropy, however, only the contribution of enthalpy
has been considered here.
The reason of why anhydrous B does not easily return to hydrate can be
explained from the difference of crystal structures. Because the polymorphic
transformation from anhydrous A to B accompanied large structural change as
discussed above, in turn, the hydration of anhydrous B requires large structuralchange. As a result, anhydrous B is stable for the humidity and the hydration
occurred only in high humidity condition (RH 80%). The stability for thehydration such like anhydrous B is very useful property for pharmaceutical,
because usually the hydration is one of the problems in the storage or processing.
This result and structural consideration will be useful information for drug use.

4.4.5. Initial Dissolution Rate
The initial dissolution rates are shown in Figure 4-9. By liner least square
fitting, the initial dissolution rates of hydrate, anhrdous A and B are calculated
as follows; hydrate 7.8mg/ml min, anhydrous A 19.9mg/ml min and anhydrous
B 39.8mg/ml min. Interestingly, the newly obtained anhydrous B has a highest
initial dissolution rate which is five times faster than hydrate form. Such a large
difference in the dissolution rates is very important and useful information in thepractical use and these results clearly suggest the effectiveness of aninvestigation of alternative forms such as hydrates and polymorphs. In addition,
the slowest initial dissolution rates of hydrate is consistent with the fact of that90

the monohydrate form is usually obtained by recrystallization.

Figure 4-9 : Initial dissolution rates of acrinol (a) hydrate, (b) anhydrous A, (c)anhydrous B.

91

4.5. Concluding Remarks
In present work, new two anhydrous phases were found for acrinol. One isanhydrous A which was obtained by dehydration of acrinol hydrate and anotheris anhydrous B which was obtained by polymorphic transformation ofanhydrous A. Interestingly, from DVS measurements, large difference in thehydration properties were found. Although the hydration of anhydrous A wasoccurred at low humidity condition (RH10%), the hydration of anhydrous B was
occurred at high humidity condition (RH80%). In order to reveal themechanistic aspects in the transformations and their hydration properties, crystal
structures of anhydrous A and B were analyzed from powder X-ray diffraction
data. The mechanistic aspects of the dehydration and polymorphic
transformation were clearly drawn from resulted crystal structures and thedifference in hydration properties were understood from the similarity of hydrate
and anhydrous A and the large structural difference of hydrate and anhydrous B.
As shown in this work, the technique of crystal structure determination frompowder X-ray diffraction data can act a key role for understanding crystallinetransformation such as dehydrations or polymorphic transformations. In addition
to the understanding the transformation mechanisms, a large differences of theinitial dissolution rate were found among acrinol hydrate, anhydrous A and B.
The fastest dissolution rate was achieved for anhydrous B and which has fivetimes faster than well used hydrate form. These results clearly suggest theeffectiveness of an investigation of alternative forms such as hydrates andpolymorphs.

92

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94

Chapter 5General Conclusion
In this dissertation, the crystal-to-crystal pseudopolymorphic transformations,such as desolvation, solvation and solvent exchange phenomenon, were
investigated by ab initio powder X-ray diffraction analysis technique. In all
studies, the ab initio powder X-ray diffraction analysis technique acted the very
important role, because these transformations could not reveal using traditional
single crystal diffraction analysis.
In chapter 2, the unknown crystalline phase obtained by grinding of methanol
solvate co-crystal of 5-methyl-2-pyridone and tirimesic acid was successfully
revealed as hydrate phase by ab initio powder X-ray diffraction analysis. The
result gave the idea that the transformations might be induced by solvent vapors,
then, newly vapor induced crystalline transformations between co-crystal
solvates are discovered and the mechanistic aspects are clearly revealed from thecrystal structures. Furthermore, the differences of photoreactivities are revealed
using the concept of reaction cavity.
In chapter 3, the three crystalline hydrates (dihydrate, monohydrate andanhydrous) of pharmaceutical lisinopril were determined by ab initio powder
X-ray diffraction analysis, and the mechanistic aspects of two step dehydrations
were clearly revealed. In addition to the dehydration mechanism, the expectationof the hydration mechanism was also speculated from the existence of vacantchannel which can be considered as the reason of the instability of monohydrate
and anhydrous phases for the humidity.
In chapter 4, new two anhydrous phases were found for pharmaceuticalacrinol and the crystal structures of these phases were successfully determinedby ab initio powder X-ray diffraction analysis. The mechanistic aspects of thedehydration and polymorphic transformations were clearly revealed from thestructures. From the comparison of the crystal structures, it was also revealed95that the difference of the hydration properties comes from the structuralsimilarity of anhydrous forms and hydrate form.
Clearly, the ab initio powder X-ray diffraction analysis technique is thepowerful technique to investigate such transformations, because the technique
has a potential to give the three dimensional information – “crystal structure” –from crystalline powder or polycrystalline materials which is generated bytransformations. Thus, the technique enables us to establish the detailed
structural changes and the relationship between properties and structures. The
new strategies to investigate crystalline transformations were exhibited in thepresent dissertation. The strategy is expected to be used for many scenes infuture.

96

Appendix : Crystallographic Data
APPENDIX : CRYSTALLOGRAPHIC DATA ·································································· A-1
CO-CRYSTAL HYDRATE OF 5-METHYL-2-PYRIDONE AND TRIMESIC ACID ······ A-2
LISINOPRIL DIHYDRATE ······························································································· A-6
LISINOPRIL MONOHYDRATE ····················································································· A-12
LISINOPRIL ANHYDROUS ··························································································· A-18
ACRINOL ANHYDROUS A ··························································································· A-23
ACRINOL ANHYDROUS B ··························································································· A-28

A-1

Co-crystal hydrate of 5-methyl-2-pyridone and trimesicacid
SampleCo-crystal hydrate of 5-methyl-2-pyridone and trimesic acid

Computing details
Program(s) used to refine structure: GSAS.

Crystal data
C15H15NO8
Mr = 337.28
Triclinic, P 1
a = 10.5423 (2) Å
b = 10.9487 (3) Åc = 7.09939 (11) Å

α = 107.9100 (16)ºβ = 97.7464 (16)ºγ = 88.0882 (10)º
V = 772.59 (4) Å3
Z=2
synchrotron radiation
λ = 1.2368 Å

Data collection
2θmin = 5.0, 2θmax = 70.0º

Increment in 2θ = 0.01º

Refinement
Least-squares matrix: full
Rp = 0.036
Rwp = 0.052
Rexp = 0.010
S = 5.32

163 parameters
113 restraints(∆/σ)max = 0.04

Profile function: CW Profile function number 2 with 18 terms Profile coefficients for
Simpson's rule integration of pseudovoigt function C.J. Howard (1982). J. Appl.
Cryst.,15,615-620. P. Thompson, D.E. Cox & J.B. Hastings (1987). J. Appl.
Cryst.,20,79-83. #1(GU) = 125.278 #2(GV) = -21.681 #3(GW) = 3.937 #4(LX) = 0.394#5(LY) = 18.193 #6(trns) = 0.000 #7(asym) = 0.3896 #8(shft) = -0.0699 #9(GP) = 0.000#10(stec)= 0.00 #11(ptec)= 0.00 #12(sfec)= 0.00 #13(L11) = 0.000 #14(L22) = 0.000#15(L33) = 0.031 #16(L12) = -0.001 #17(L13) = 0.004 #18(L23) = 0.013 Peak tails are
ignored where the intensity is below 0.0010 times the peak Aniso. broadening axis 0.0
0.0 1.0

A-2

Fractional atomic coordinates and isotropic or equivalentisotropic displacement parameters (Å2)
C1
C6
C5
C4
C3
C2
C7
C9
C8
O1
O2
O5
O6
O3
O4
H6
H3
H5
H2
H4
H1
C10
C11
C12
C13
C14
C15
N1
O7
H7
H8
H9
H10
H11
H12
H13

x
0.7818 (6)0.8848 (6)0.8671 (6)0.7438 (6)0.6410 (6)0.6593 (6)0.8041 (6)0.9784 (5)0.5083 (5)0.9093 (6)0.7024 (6)0.9645 (7)1.0888 (6)0.4233 (6)0.5004 (7)0.7203 (13)0.9683 (7)1.1535 (9)0.7298 (11)0.4247 (8)0.5893 (9)0.7219 (6)0.6115 (6)0.6226 (6)0.7422 (7)0.8462 (6)0.7552 (8)0.8355 (6)0.7242 (7)0.5313 (8)0.5474 (8)0.9313 (7)0.9070 (8)0.759 (8)0.833 (4)0.681 (5)y0.7031 (4)0.7886 (6)0.9165 (5)0.9568 (5)0.8712 (5)0.7434 (5)0.5706 (5)1.0063 (5)0.9129 (5)0.5375 (7)0.4957 (7)1.1109 (6)0.9579 (7)0.8398 (6)1.0380 (5)0.4156 (7)0.7596 (11)1.0131 (13)1.0440 (6)1.0605 (13)0.6846 (9)0.7704 (5)0.6913 (6)0.5650 (6)0.5100 (5)0.5886 (6)0.3699 (5)0.7155 (5)0.8898 (5)0.7289 (12)0.5130 (10)0.5623 (12)0.7676 (10)0.3189 (18)0.357 (2)0.3426 (16)z−0.0005 (5)0.0621 (5)0.1669 (5)0.2049 (5)0.1421 (5)0.0386 (5)−0.1315 (4)0.2556 (5)0.1808 (4)−0.1796 (6)−0.1775 (4)0.3739 (6)0.2030 (5)0.1772 (6)0.2538 (4)−0.2505 (6)0.0346 (8)0.2663 (8)0.2759 (7)0.2993 (6)−0.0049 (8)0.5449 (5)0.4797 (5)0.3775 (5)0.3337 (5)0.3977 (5)0.2204 (6)0.5006 (5)0.6418 (6)0.5098 (7)0.3350 (6)0.3769 (7)0.5432 (6)0.313 (3)0.156 (10)0.118 (8)A-3

Uiso*/Ueq
0.0368 (11)*0.0368 (11)*0.0368 (11)*0.0368 (11)*0.0368 (11)*0.0368 (11)*0.0368 (11)*0.0368 (11)*0.0368 (11)*0.0368 (11)*0.0368 (11)*0.0368 (11)*0.0368 (11)*0.0368 (11)*0.0368 (11)*0.0371 (13)*0.0371 (13)*0.0371 (13)*0.0371 (13)*0.0371 (13)*0.0371 (13)*0.0368 (11)*0.0368 (11)*0.0368 (11)*0.0368 (11)*0.0368 (11)*0.0368 (11)*0.0368 (11)*0.0368 (11)*0.0371 (13)*0.0371 (13)*0.0371 (13)*0.0371 (13)*0.0371 (13)*0.0371 (13)*0.0371 (13)*

O8
H14
H15

0.7439 (9)0.711 (3)0.823 (2)0.2503 (11)0.220 (9)0.215 (6)−0.3660 (15)−0.271 (7)−0.401 (3)0.0368 (11)*0.0371 (13)*0.0371 (13)*Geometric parameters (Å, °)
C1—C6
C1—C2
C1—C7
C6—H3
C5—C6
C5—C9
C4—C5
C4—H2
C3—C4
C3—C8
C2—C3
C2—H1
O1—C7
O2—C7
O2—H6
O5—C9
O6—C9
O6—H5
O3—C8

1.3903 (23)1.3871 (23)1.4937 (23)0.9500 (12)1.3890 (23)1.4955 (23)1.3922 (23)0.9500 (12)1.3900 (23)1.4920 (23)1.3866 (23)0.9499 (12)1.2150 (23)1.3150 (23)0.8999 (12)1.2119 (23)1.3152 (23)0.8999 (12)1.2135 (23)

O4—C8
O4—H4
C10—C11
C11—C12
C11—H7
C12—C13C12—H8
C13—C14
C13—C15
C14—H9C15—H11
C15—H12
C15—H13
N1—C10N1—C14
N1—H10O7—C10O8—H14
O8—H151.3112 (23)0.9000 (12)1.4131 (23)1.3589 (23)0.9500 (12)1.4107 (23)0.9501 (12)1.3551 (23)1.5094 (23)0.9499 (12)0.9804 (12)0.9801 (12)0.9801 (12)1.3529 (23)
1.3653 (23)0.9201 (12)1.2752 (23)0.9427 (12)0.9423 (12)C6—C1—C2
C6—C1—C7
C2—C1—C7
C1—C6—C5
C1—C6—H3
C5—C6—H3
C6—C5—C4
C6—C5—C9
C4—C5—C9
C5—C4—C3
C5—C4—H2
C3—C4—H2
C4—C3—C2
C4—C3—C8
C2—C3—C8

121.0 (4)117.9 (4)120.6 (4)120.5 (4)120.1 (6)119.4 (6)118.3 (4)121.2 (4)120.1 (4)121.1 (4)119.5 (5)119.4 (5)120.4 (4)121.7 (4)117.9 (4)C8—O4—H4
O6—H5—O7i
C11—C10—N1
C11—C10—O7
N1—C10—O7
C10—C11—C12
C10—C11—H7
C12—C11—H7
C11—C12—C13
C11—C12—H8
C13—C12—H8
C12—C13—C14
C12—C13—C15
C14—C13—C15
C13—C14—N1

110.7 (7)174.0 (7)117.5 (4)125.7 (5)116.8 (5)119.7 (4)118.1 (6)122.1 (6)121.6 (4)118.7 (6)119.7 (6)117.2 (4)121.9 (5)120.9 (5)121.3 (4)A-4

C1—C2—C3
C1—C2—H1
C3—C2—H1
C1—C7—O1
C1—C7—O2
O1—C7—O2
C5—C9—O5
C5—C9—O6
O5—C9—O6
C3—C8—O3
C3—C8—O4
O3—C8—O4
C7—O2—H6
C9—O6—H5

118.7 (4)120.6 (6)120.7 (6)121.2 (5)113.5 (4)125.2 (5)120.8 (4)114.1 (4)125.0 (4)123.7 (5)112.0 (4)123.3 (5)111.2 (7)111.0 (7)C13—C14—H9
N1—C14—H9
C13—C15—H11
C13—C15—H12
C13—C15—H13
H11—C15—H12
H11—C15—H13
H12—C15—H13
C10—N1—C14
C10—N1—H10
C14—N1—H10
H14—O8—H15

A-5

124.6 (6)114.1 (6)109.5 (9)109.5 (19)109.2 (19)109.8 (13)109.7 (16)109.0 (7)122.6 (4)117.1 (6)120.3 (6)114.6 (35)Lisinopril dihydrate
SampleLisinopril dihydrate

Computing details
Program(s) used to refine structure: GSAS.

Crystal data
C21H35N3O7
Mr = 441.52
Monoclinic, P21
a = 14.66066 (14) Å
b = 5.91012 (6) Åc = 14.30517 (14) Å
β = 113.1447 (6)ºV = 1139.73 (2) Å3
Z=2
synchrotron radiation
λ = 1.20854 Å

Data collection
2θmin = 4.52, 2θmax = 72.99º

Increment in 2θ = 0.01º

Refinement
Least-squares matrix: full

244 parameters

Rp = 0.044

191 restraints

Rwp = 0.058
Rexp = 0.012(∆/σ)max = 0.68

S = 5.65
Profile function: CW Profile function number 2 with 18 terms Profile coefficientsfor Simpson's rule integration of pseudovoigt function C.J. Howard (1982). J.
Appl. Cryst.,15,615-620. P. Thompson, D.E. Cox & J.B. Hastings (1987). J. Appl.
Cryst.,20,79-83. #1(GU) = 61.131 #2(GV) = -15.447 #3(GW) = 0.502 #4(LX) =3.542 #5(LY) = 3.798 #6(trns) = 0.000 #7(asym) = 0.4251 #8(shft) = -0.0005#9(GP) = 0.000 #10(stec)= 10.74 #11(ptec)= -1.64 #12(sfec)= 0.00 #13(L11) =0.000 #14(L22) = 0.004 #15(L33) = 0.000 #16(L12) = 0.000 #17(L13) = 0.000#18(L23) = 0.000 Peak tails are ignored where the intensity is below 0.0010 times
the peak Aniso. broadening axis 0.0 0.0 1.0

A-6

Fractional atomic coordinates and isotropic or equivalentisotropic displacement parameters (Å2)
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
O11
O12
N13
C14
C15
C16
C17
C18
N19
C20
O21
N22
C23
C24
C25
C26
C27
O28
O29
H30
H31
H32
H33
H34

x
0.7757 (3)0.8581 (4)0.9517 (3)0.9632 (2)0.8809 (3)0.7871 (2)0.6725 (3)0.6060 (3)0.50229 (17)0.50890 (13)0.49748 (15)0.5256 (2)0.4446 (3)0.3364 (2)0.3063 (3)0.1976 (3)0.1677 (4)0.1528 (3)0.0547 (4)0.28635 (17)0.2951 (3)0.2453 (2)0.2566 (5)0.2296 (5)0.1808 (4)0.2038 (2)0.10894 (17)0.0718 (3)0.0733 (2)0.8503 (6)1.0077 (4)1.0270 (3)0.8888 (5)0.7311 (3)y
0.0−0.1405 (6)−0.0686 (11)0.1435 (11)0.2842 (6)0.2124 (3)−0.0799 (8)−0.1141 (14)−0.2047 (11)−0.4203 (10)−0.4156 (12)−0.5905 (11)−0.0265 (11)0.0101 (11)0.0733 (15)0.0828 (14)0.1963 (12)0.4371 (11)0.4863 (10)−0.2080 (10)−0.3847 (11)−0.2203 (10)−0.0662 (10)−0.2003 (11)−0.3924 (12)−0.4455 (9)−0.5100 (8)−0.3853 (9)−0.7059 (8)−0.2847 (6)−0.1638 (14)0.1923 (14)0.4284 (6)0.3077 (6)A-7z
0.8469 (2)0.8930 (2)0.90186 (17)0.8649 (3)0.8188 (3)0.80981 (17)0.8372 (3)0.7267 (3)0.7160 (2)0.77722 (19)0.8623 (2)0.7383 (3)0.7488 (3)0.6863 (2)0.5769 (3)0.5244 (4)0.4137 (3)0.4178 (5)0.4254 (4)0.69911 (13)0.65364 (19)0.76657 (19)0.8516 (4)0.9243 (4)0.8786 (4)0.7845 (3)0.6936 (3)0.6198 (3)0.7029 (4)0.9182 (3)0.93315 (18)0.8710 (4)0.7936 (4)0.77853 (18)

Uiso*/Ueq
0.0441 (7)*0.0441 (7)*0.0441 (7)*0.0441 (7)*0.0441 (7)*0.0441 (7)*0.0441 (7)*0.0441 (7)*0.0441 (7)*0.0441 (7)*0.0441 (7)*0.0441 (7)*0.0441 (7)*0.0441 (7)*0.0441 (7)*0.0441 (7)*0.0441 (7)*0.0441 (7)*0.0441 (7)*0.0441 (7)*0.0441 (7)*0.0441 (7)*0.0441 (7)*0.0441 (7)*0.0441 (7)*0.0441 (7)*0.0441 (7)*0.0441 (7)*0.0441 (7)*0.0536 (11)*0.0536 (11)*0.0536 (11)*0.0536 (11)*0.0536 (11)*

H35
H36
H37
H38
H39
H40
H41
H42
H43
H44
H45
H46
H47
H48
H49
H50
H51
H52
H53
H54
H55
H56
H57
H58
H59
H60
O61
H62
H63
O64
H65
H66

0.6433 (3)0.6791 (5)0.6368 (3)0.5975 (5)0.4638 (3)0.5038 (2)0.4749 (3)0.3124 (3)0.3323 (7)0.3341 (7)0.1703 (6)0.1705 (7)0.1062 (6)0.2208 (6)0.1534 (7)0.2067 (4)0.0179 (6)0.0647 (10)0.2119 (11)0.3255 (7)0.1866 (11)0.2900 (9)0.2027 (10)0.1092 (4)0.2555 (3)0.0168 (2)0.5132 (8)0.542 (5)0.512 (5)0.5171 (6)0.491 (6)0.519 (4)0.0343 (16)−0.2231 (12)−0.223 (2)0.0305 (19)−0.2482 (14)−0.5596 (13)0.0994 (11)0.1377 (10)−0.039 (2)0.222 (2)0.174 (2)−0.0709 (19)0.1269 (13)0.1691 (17)0.5078 (17)0.5005 (15)0.3671 (13)0.527 (8)0.0636 (12)−0.014 (2)−0.1095 (15)−0.2412 (18)−0.5188 (11)−0.370 (3)−0.5617 (10)−0.7347 (9)−0.3194 (16)−0.435 (8)−0.366 (5)−0.6002 (17)−0.741 (9)−0.596 (10)0.8667 (6)0.8738 (4)0.6965 (5)0.6907 (5)0.6452 (3)0.8885 (3)0.7585 (6)0.7141 (3)0.5435 (5)0.5727 (5)0.5646 (6)0.5166 (6)0.3662 (4)0.3897 (6)0.3561 (9)0.4773 (10)0.409 (4)0.4868 (9)0.8271 (9)0.8841 (7)0.9475 (13)0.9828 (4)0.9267 (6)0.8576 (7)0.8019 (7)0.6462 (5)1.0624 (5)1.111 (3)0.9983 (14)0.5353 (6)0.505 (7)0.6026 (12)0.0536 (11)*0.0536 (11)*0.0536 (11)*0.0536 (11)*0.0536 (11)*0.0536 (11)*0.0536 (11)*0.0536 (11)*0.0536 (11)*0.0536 (11)*0.0536 (11)*0.0536 (11)*0.0536 (11)*0.0536 (11)*0.0536 (11)*0.0536 (11)*0.0536 (11)*0.0536 (11)*0.0536 (11)*0.0536 (11)*0.0536 (11)*0.0536 (11)*0.0536 (11)*0.0536 (11)*0.0536 (11)*0.0536 (11)*0.0441 (7)*0.0536 (11)*0.0536 (11)*0.0441 (7)*0.0536 (11)*0.0536 (11)*Geometric parameters (Å, °)
C1—C2
C1—C6
C1—C7
C2—C3

1.3992 (19)1.3983 (19)1.538 (5)1.3936 (19)C16—C17
C16—H45
C16—H46
C17—H47
A-8

1.6136 (20)0.9800 (5)0.9800 (5)0.9800 (5)C2—H30
C3—C4
C3—H31
C4—C5
C4—H32
C5—C6
C5—H33C6—H34
C7—C8
C7—H35
C7—H36
C8—C9
C8—H37
C8—H38
C9—C10C9—N13
C9—H39
C10—O11
C10—O12
O11—H40
O11—H63
N13—C14
N13—H41
C14—C15
C14—C20
C14—H42
C15—C16
C15—H43
C15—H440.9500 (5)1.3960 (19)0.9500 (5)1.3989 (19)0.9500 (5)1.3953 (19)0.9500 (5)0.9500 (5)1.5104 (20)0.9800 (5)0.9800 (5)1.5613 (19)0.9800 (5)0.9800 (5)1.5281 (20)
1.5357 (20)0.9800 (5)1.2926 (20)1.2200 (20)0.9200 (5)1.896 (7)1.4994 (19)0.8500 (5)1.4977 (20)
1.5290 (20)0.9800 (5)1.4713 (19)0.9800 (5)0.9800 (5)C17—H48
C18—N19
C18—H49
C18—H50
N19—H51
N19—H52
C20—O21
C20—N22
N22—C23
N22—C26
C23—C24
C23—H53
C23—H54
C24—C25
C24—H55
C24—H56
C25—C26
C25—H57
C25—H58
C26—N22
C26—C27
C26—H59
C27—O28
C27—O29
O29—H60
O64—H65
O64—H66

0.9800 (5)1.5125 (20)0.9800 (5)0.9800 (5)0.8616 (20)0.8664 (20)
1.2634 (20)
1.3252 (19)1.4756 (19)1.526 (5)1.4796 (20)0.9800 (5)0.9801 (5)1.3641 (20)0.9800 (5)0.9800 (5)1.5438 (19)0.9800 (5)0.9800 (5)1.526 (5)1.5323 (19)0.9799 (5)1.2257 (20)
1.2981 (20)0.9200 (5)0.9502 (11)0.9501 (11)C2—C1—C6
C2—C1—C7
C6—C1—C7
C1—C2—C3
C1—C2—H30
C3—C2—H30
C2—C3—C4
C2—C3—H31

120.09 (12)119.80 (19)120.11 (20)119.95 (11)120.04 (9)120.02 (9)120.00 (10)119.99 (9)C15—C16—H45
C15—C16—H46
C17—C16—H45
C17—C16—H46
H45—C16—H46
C16—C17—C18
C16—C17—H47
C16—C17—H48

109.42 (12)109.42 (15)109.38 (19)109.39 (22)109.41 (14)110.94 (22)109.18 (13)109.19 (15)

A-9

C4—C3—H31
C3—C4—C5
C3—C4—H32
C5—C4—H32
C4—C5—C6
C4—C5—H33
C6—C5—H33
C1—C6—C5
C1—C6—H34
C5—C6—H34
C1—C7—C8
C1—C7—H35
C1—C7—H36
C8—C7—H35
C8—C7—H36
H35—C7—H36
C7—C8—C9
C7—C8—H37
C7—C8—H38
C9—C8—H37
C9—C8—H38
H37—C8—H38
C8—C9—C10
C8—C9—N13
C8—C9—H39
C10—C9—N13
C10—C9—H39
N13—C9—H39
C9—C10—O11
C9—C10—O12
O11—C10—O12
C10—O11—H40
C9—N13—C14
C9—N13—H41
C14—N13—H41
N13—C14—C15
N13—C14—C20

120.00 (9)120.14 (10)119.92 (9)119.94 (9)119.92 (11)120.05 (9)120.03 (9)119.90 (11)120.05 (9)120.04 (9)110.08 (16)109.33 (18)109.34 (16)109.36 (11)109.35 (16)109.36 (11)110.61 (18)109.23 (13)109.23 (15)109.26 (15)109.26 (17)109.23 (11)112.95 (21)111.55 (23)109.51 (12)108.33 (25)
104.74 (32)
109.51 (11)121.29 (23)113.87 (23)124.84 (24)109.49 (11)119.83 (22)109.49 (20)109.49 (14)117.86 (22)104.57 (23)

C18—C17—H47
C18—C17—H48
H47—C17—H48
C17—C18—N19
C17—C18—H49
C17—C18—H50
N19—C18—H49
N19—C18—H50
H49—C18—H50
C18—N19—H51
C18—N19—H52
H51—N19—H52
C14—C20—O21
C14—C20—N22
O21—C20—N22
C20—N22—C23
C20—N22—C26
C23—N22—C26
N22—C23—C24
N22—C23—H53
N22—C23—H54
C24—C23—H53
C24—C23—H54
H53—C23—H54
C23—C24—C25
C23—C24—H55
C23—C24—H56
C25—C24—H55
C25—C24—H56
H55—C24—H56
C24—C25—C26
C24—C25—H57
C24—C25—H58
C26—C25—H57
C26—C25—H58
H57—C25—H58
N22—C26—C25
A-10

109.17 (12)109.18 (17)109.16 (13)110.78 (21)109.21 (13)109.21 (13)109.19 (17)109.22 (13)109.22 (12)109.7 (13)109.9 (4)109.6 (7)119.00 (22)120.67 (20)119.77 (22)129.04 (22)119.71 (22)108.85 (17)105.90 (16)110.19 (18)110.19 (13)110.15 (20)110.14 (13)110.20 (12)110.17 (33)109.32 (32)109.34 (14)109.34 (14)109.34 (15)109.32 (11)109.46 (20)109.47 (11)109.47 (14)109.47 (21)109.49 (12)109.47 (15)101.97 (25)N13—C14—H42
C15—C14—C20
C15—C14—H42
C20—C14—H42
C14—C15—C16
C14—C15—H43
C14—C15—H44
C16—C15—H43
C16—C15—H44
H43—C15—H44
C15—C16—C17

109.48 (11)112.17 (24)103.1 (4)109.53 (14)110.94 (20)109.17 (23)109.16 (21)109.18 (14)109.17 (18)109.19 (12)109.81 (19)N22—C26—C27
N22—C26—H59
C25—C26—C27
C25—C26—H59
C27—C26—H59
C26—C27—O28
C26—C27—O29
O28—C27—O29
C27—O29—H60
H62—O61—H63
H65—O64—H66

A-11

111.30 (24)109.50 (14)110.78 (20)109.47 (16)113.23 (35)121.92 (22)113.71 (22)124.37 (23)109.51 (11)109.6 (17)109.5 (26)Lisinopril monohydrate
SampleLisinopril monohydrate

Computing details
Program(s) used to refine structure: GSAS.

Crystal data
C7H11NO2
Mr = 141.17
Monoclinic, P21
a = 14.6677 (3) Å
b = 5.91243 (11) Åc = 14.2254 (3) Å
β = 112.8796 (13)º
V = 1136.58 (5) Å3
Z=2
synchrotron radiation
λ = 1.200253 Å

Data collection
2θmin = 3.0, 2θmax = 79.02º

Increment in 2θ = 0.01º

Refinement
Rp = 0.034
Rwp = 0.049
Rexp = 0.024
S = 2.36

Least-squares
matrix: full

232 parameters
185 restraints(∆/σ)max = 0.08
Profile function: CW Profile function number 2 with 18 terms
Profile coefficients for Simpson's rule integration ofpseudovoigt function C.J. Howard (1982). J. Appl.
Cryst.,15,615-620. P. Thompson, D.E. Cox & J.B. Hastings(1987). J. Appl. Cryst.,20,79-83. #1(GU) = 102.403 #2(GV) =-15.612 #3(GW) = 1.125 #4(LX) = 3.505 #5(LY) = 6.436#6(trns) = 0.000 #7(asym) = 0.3874 #8(shft) = 0.0000 #9(GP) =0.000 #10(stec)= 13.03 #11(ptec)= -1.69 #12(sfec)= 0.00
#13(L11) = 0.000 #14(L22) = 0.000 #15(L33) = 0.000#16(L12) = -0.002 #17(L13) = 0.000 #18(L23) = -0.001 Peaktails are ignored where the intensity is below 0.0010 times thepeak Aniso. broadening axis 0.0 0.0 1.0

A-12

Fractional atomic coordinates and isotropic or equivalentisotropic displacement parameters (Å2)
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
O11
O12
N13
C14
C15
C16
C17
C18
N19
C20
O21
N22
C23
C24
C25
C26
C27
O28
O29
H30
H31
H32
H33
H34

x
0.7680 (5)0.8492 (6)0.9439 (5)0.9575 (5)0.8764 (5)0.7816 (5)0.6622 (3)0.5981 (3)0.49649 (19)0.50775 (19)0.4965 (2)0.5278 (3)0.4416 (3)0.3341 (3)0.3031 (4)0.2003 (4)0.1748 (7)0.1496 (8)0.0501 (10)0.2864 (2)0.2952 (3)0.2460 (2)0.2612 (8)0.2258 (9)0.1795 (5)0.2054 (3)0.1113 (3)0.0756 (3)0.0750 (4)0.8400 (8)0.9990 (6)1.0218 (5)0.8857 (7)0.7266 (5)y0.0−0.1433 (7)−0.0738 (14)0.1390 (14)0.2822 (7)0.2127 (2)−0.0767 (10)−0.114 (2)−0.2113 (17)−0.4226 (15)−0.4152 (18)−0.5919 (17)−0.0339 (15)0.0022 (15)0.0440 (19)0.120 (3)0.216 (2)0.452 (2)0.481 (3)−0.2150 (14)−0.3952 (15)−0.2216 (12)−0.0646 (14)−0.1855 (16)−0.3805 (15)−0.4362 (12)−0.5026 (11)−0.3802 (13)−0.6966 (11)−0.2879 (7)−0.1711 (18)0.1862 (19)0.4267 (7)0.3101 (5)A-13z
0.8410 (3)0.8872 (4)0.8979 (3)0.8624 (5)0.8162 (5)0.8055 (3)0.8288 (3)0.7176 (3)0.7072 (3)0.7729 (3)0.8590 (3)0.7356 (5)0.7433 (4)0.6825 (2)0.5711 (3)0.5280 (7)0.4146 (4)0.4090 (12)0.4161 (13)0.69875 (15)0.65587 (17)0.76628 (15)0.8509 (6)0.9213 (6)0.8773 (5)0.7844 (4)0.6938 (5)0.6192 (5)0.7049 (8)0.9113 (5)0.9293 (3)0.8696 (6)0.7921 (6)0.7741 (3)Uiso*/Ueq
0.0372 (15)*0.0372 (15)*0.0372 (15)*0.0372 (15)*0.0372 (15)*0.0372 (15)*0.0372 (15)*0.0372 (15)*0.0372 (15)*0.0372 (15)*0.0372 (15)*0.0372 (15)*0.0372 (15)*0.0372 (15)*0.0372 (15)*0.0372 (15)*0.0372 (15)*0.0372 (15)*0.0372 (15)*0.0372 (15)*0.0372 (15)*0.0372 (15)*0.0372 (15)*0.0372 (15)*0.0372 (15)*0.0372 (15)*0.0372 (15)*0.0372 (15)*0.0372 (15)*0.043 (2)*0.043 (2)*0.043 (2)*0.043 (2)*0.043 (2)*

H35
H36
H37
H38
H39
H40
H41
H42
H43
H44
H45
H46
H47
H48
H49
H50
H51
H52
H53
H54
H55
H56
H57
H58
H59
H60
O61
H62
H63

0.6323 (3)0.6669 (5)0.6309 (4)0.5881 (6)0.4575 (3)0.5060 (4)0.4718 (4)0.3106 (4)0.3093 (11)0.3456 (5)0.1909 (12)0.1565 (7)0.1188 (13)0.2325 (12)0.1467 (15)0.2001 (11)0.023 (2)0.0579 (15)0.2225 (15)0.3316 (10)0.1793 (15)0.2823 (15)0.2017 (10)0.1078 (5)0.2569 (4)0.0188 (4)0.5017 (14)0.544 (6)0.503 (7)0.040 (2)−0.2181 (16)−0.220 (3)0.031 (3)−0.249 (2)−0.5573 (19)0.0918 (15)0.1302 (14)−0.096 (2)0.161 (3)0.240 (4)−0.007 (4)0.131 (3)0.196 (4)0.515 (3)0.533 (2)0.351 (4)0.55 (4)0.0736 (15)−0.028 (3)−0.089 (2)−0.221 (3)−0.5042 (16)−0.362 (3)−0.5527 (13)−0.7267 (12)−0.354 (3)−0.44 (2)−0.409 (8)0.8566 (9)0.8664 (4)0.6881 (6)0.6811 (7)0.6357 (3)0.8876 (4)0.7517 (6)0.7108 (3)0.5373 (6)0.5604 (5)0.5708 (8)0.5250 (12)0.3661 (7)0.3967 (10)0.3441 (17)0.4655 (19)0.41 (2)0.473 (9)0.8257 (13)0.8855 (10)0.937 (2)0.9845 (5)0.9269 (8)0.8547 (8)0.8034 (7)0.6481 (9)1.0654 (12)1.121 (5)1.003 (2)0.043 (2)*0.043 (2)*0.043 (2)*0.043 (2)*0.043 (2)*0.043 (2)*0.043 (2)*0.043 (2)*0.043 (2)*0.043 (2)*0.043 (2)*0.043 (2)*0.043 (2)*0.043 (2)*0.043 (2)*0.043 (2)*0.043 (2)*0.043 (2)*0.043 (2)*0.043 (2)*0.043 (2)*0.043 (2)*0.043 (2)*0.043 (2)*0.043 (2)*0.043 (2)*0.0372 (15)*0.043 (2)*0.043 (2)*Geometric parameters (Å, °)
C1—C2
C1—C6
C1—C7
C2—C3
C2—H30
C3—C4
C3—H31

1.3999 (14)1.3985 (14)1.561 (7)1.3999 (14)0.9500 (4)1.3984 (14)0.9500 (4)C15—H44
C16—C17
C16—H45
C16—H46
C17—C18
C17—H47
C17—H48
A-14

0.9800 (4)1.6105 (15)0.9800 (4)0.9800 (4)1.4403 (15)0.9800 (4)0.9800 (4)C4—C5
C4—H32
C5—C6
C5—H33C6—H34
C7—C8
C7—H35
C7—H36
C8—C9
C8—H37
C8—H38
C9—C10C9—N13
C9—H39
C10—O11
C10—O12
O11—H40
N13—C14
N13—H41
C14—C15
C14—C20
C14—H42
C15—C14
C15—C16
C15—H431.3987 (14)0.9500 (4)1.4001 (14)0.9500 (4)0.9500 (4)1.5100 (15)0.9800 (4)0.9800 (4)1.5513 (15)0.9800 (4)0.9800 (4)1.5296 (15)1.5273 (15)0.9800 (4)1.2993 (15)1.2214 (15)0.9200 (4)1.4896 (15)0.8500 (4)1.4899 (15)1.5225 (15)0.9800 (4)1.4899 (15)1.4602 (15)0.9800 (4)C18—N19
C18—H49
C18—H50
N19—H51
N19—H52
C20—O21
C20—N22
N22—C23
N22—C26
C23—C24
C23—H53
C23—H54
C24—C25
C24—H55
C24—H56
C25—C26
C25—H57
C25—H58
C26—C27
C26—H59
C27—O28
C27—O29
O29—H60
O61—H62
O61—H631.5102 (15)0.9800 (4)0.9800 (4)0.8600 (4)0.8600 (4)1.2589 (15)1.3100 (15)1.4673 (15)1.467 (6)1.4793 (15)0.9800 (4)0.9800 (4)1.3611 (15)0.9800 (4)0.9800 (4)1.5453 (14)0.9800 (4)0.9800 (4)1.5285 (15)0.9800 (4)1.2214 (15)1.2996 (15)0.9200 (4)0.9505 (15)0.9504 (15)

C2—C1—C6
C2—C1—C7
C6—C1—C7
C1—C2—C3
C1—C2—H30
C3—C2—H30
C2—C3—C4
C2—C3—H31
C4—C3—H31
C3—C4—C5
C3—C4—H32
C5—C4—H32

119.92 (9)120.25 (16)119.83 (16)120.05 (8)119.98 (7)119.97 (7)119.99 (8)120.01 (7)120.00 (6)119.98 (7)120.01 (7)120.01 (7)C17—C16—H45
C17—C16—H46
H45—C16—H46
C16—C17—C18
C16—C17—H47
C16—C17—H48
C18—C17—H47
C18—C17—H48
H47—C17—H48
C17—C18—N19
C17—C18—H49
C17—C18—H50

109.52 (30)
109.52 (20)109.52 (13)110.54 (34)109.25 (18)109.26 (20)109.25 (11)109.25 (27)109.26 (19)109.92 (30)109.38 (27)109.38 (18)

A-15

C4—C5—C6
C4—C5—H33
C6—C5—H33
C1—C6—C5
C1—C6—H34
C5—C6—H34
C1—C7—C8
C1—C7—H35
C1—C7—H36
C8—C7—H35
C8—C7—H36
H35—C7—H36
C7—C8—C9
C7—C8—H37
C7—C8—H38
C9—C8—H37
C9—C8—H38
H37—C8—H38
C8—C9—C10
C8—C9—N13
C8—C9—H39
C10—C9—N13
C10—C9—H39
N13—C9—H39
C9—C10—O11
C9—C10—O12
O11—C10—O12
C10—O11—H40
C9—N13—C14
C9—N13—H41
C14—N13—H41
N13—C14—C15
N13—C14—C20
N13—C14—H42
C15—C14—C20
C15—C14—H42
C20—C14—H42

120.04 (8)119.98 (6)119.98 (7)120.02 (8)119.99 (6)120.00 (7)110.16 (16)109.33 (20)109.33 (20)109.33 (9)109.33 (18)109.34 (9)109.67 (14)109.44 (10)109.43 (15)109.44 (16)109.43 (20)109.43 (9)111.97 (19)109.00 (20)109.49 (9)107.57 (21)109.26 (23)109.49 (8)121.68 (18)113.02 (18)125.30 (18)
109.50 (8)118.77 (20)109.48 (15)109.49 (12)117.20 (20)103.67 (21)109.47 (9)109.48 (21)107.36 (30)109.49 (11)N19—C18—H49
N19—C18—H50
H49—C18—H50
C18—N19—H51
C18—N19—H52
H51—N19—H52
C14—C20—O21
C14—C20—N22
O21—C20—N22
C20—N22—C23
C20—N22—C26
C23—N22—C26
N22—C23—C24
N22—C23—H53
N22—C23—H54
C24—C23—H53
C24—C23—H54
H53—C23—H54
C23—C24—C25
C23—C24—H55
C23—C24—H56
C25—C24—H55
C25—C24—H56
H55—C24—H56
C24—C25—C26
C24—C25—H57
C24—C25—H58
C26—C25—H57
C26—C25—H58
H57—C25—H58
N22—C26—C25
N22—C26—C27
N22—C26—H59
C25—C26—C27
C25—C26—H59
C27—C26—H59
C26—C27—O28
A-16

109.38 (24)109.38 (18)109.38 (13)109 (7)109.5 (29)109.5 (23)120.03 (18)120.11 (17)119.38 (17)127.96 (18)119.01 (20)110.22 (18)105.58 (17)110.22 (23)110.22 (12)110.22 (26)110.23 (10)110.27 (13)109.9 (4)109.4 (4)109.38 (12)109.37 (15)109.37 (17)109.37 (9)109.25 (22)109.51 (10)109.51 (14)109.52 (21)109.52 (9)109.51 (14)102.57 (24)111.67 (21)109.50 (12)109.51 (19)109.51 (13)113.51 (30)121.44 (17)

C14—C15—C16
C14—C15—H43
C14—C15—H44
C16—C15—H43
C16—C15—H44
H43—C15—H44
C15—C16—C17
C15—C16—H45
C15—C16—H46

109.64 (20)109.44 (26)109.43 (19)109.44 (10)109.44 (19)109.44 (13)109.23 (24)109.52 (16)109.52 (26)C26—C27—O29
O28—C27—O29
C27—O29—H60
H62—O61—H63

A-17

113.74 (18)124.82 (18)
109.50 (8)109.8 (21)Lisinopril anhydrous
SampleLisinopril anhydrous

Computing details
Program(s) used to refine structure: GSAS.

Crystal data
C21H31N3O5
Mr = 405.49
Monoclinic, P21
a = 15.1769 (3) Å
b = 5.94511 (8) Åc = 14.2291 (3) Å
β = 120.6209 (9)º
V = 1104.84 (4) Å3
Z=2
synchrotron radiation
λ = 1.1977 ÅData collection
2θmin = 4.01, 2θmax = 77.13º

Increment in 2θ = 0.01º

Refinement
Least-squares matrix: full
Rp = 0.044
Rwp = 0.058
Rexp = 0.012
S = 5.65

244 parameters
191 restraints(∆/σ)max = 0.68

Profile function: CW Profile function number 2 with 18 terms Profile coefficients for Simpson'srule integration of pseudovoigt function C.J. Howard (1982). J. Appl. Cryst.,15,615-620. P.
Thompson, D.E. Cox & J.B. Hastings (1987). J. Appl. Cryst.,20,79-83. #1(GU) = 61.131 #2(GV) =-15.447 #3(GW) = 0.502 #4(LX) = 3.542 #5(LY) = 3.798 #6(trns) = 0.000 #7(asym) = 0.4251#8(shft) = -0.0005 #9(GP) = 0.000 #10(stec)= 10.74 #11(ptec)= -1.64 #12(sfec)= 0.00 #13(L11) =0.000 #14(L22) = 0.004 #15(L33) = 0.000 #16(L12) = 0.000 #17(L13) = 0.000 #18(L23) = 0.000
Peak tails are ignored where the intensity is below 0.0010 times the peak Aniso. broadening axis 0.0
0.0 1.0

A-18

Fractional atomic coordinates and isotropic or equivalent isotropic
displacement parameters (Å2)
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
O12
O11
N13
C14
C15
C16
C17
C18
N19
C20
O21
N22
C23
C24
C25
C26
C27
O28
O29
H30
H31
H32
H33
H34
H35

x
−0.7325 (5)−0.7504 (5)−0.8480 (6)−0.9289 (4)−0.9116 (5)−0.8137 (7)−0.6238 (7)−0.6136 (5)−0.5079 (5)−0.5153 (4)−0.5543 (6)−0.4809 (5)−0.4563 (6)−0.3484 (5)−0.3267 (6)−0.2202 (6)−0.2101 (7)−0.1574 (9)−0.0649 (8)−0.2893 (5)−0.2966 (6)−0.2339 (5)−0.2468 (9)−0.1951 (9)−0.1423 (7)−0.1848 (4)−0.0955 (3)−0.0675 (6)−0.0543 (4)−0.6952 (6)−0.8600 (8)−0.9962 (5)−0.9670 (7)−0.8016 (9)−0.5975 (8)y0.00.2066 (8)0.2659 (11)0.1185 (17)−0.0891 (17)−0.1491 (10)−0.0516 (14)−0.1344 (19)−0.2395 (17)−0.4544 (15)−0.6165 (18)−0.4508 (19)−0.0802 (18)−0.0194 (16)0.037 (2)0.125 (2)0.223 (3)0.4398 (19)0.440 (3)−0.2263 (15)−0.4104 (17)−0.2137 (17)−0.0528 (17)−0.1518 (18)−0.337 (2)−0.4133 (16)−0.4890 (13)−0.3823 (16)−0.6742 (15)0.3077 (12)0.4083 (11)0.160 (2)−0.190 (2)−0.2922 (11)−0.167 (2)z0.2160 (5)0.2480 (5)0.2221 (7)0.1636 (6)0.1314 (5)0.1574 (6)0.2494 (6)0.1572 (6)0.2010 (5)0.1397 (3)0.1616 (6)0.0716 (4)0.1619 (6)0.2376 (5)0.3513 (7)0.4226 (9)0.5350 (8)0.5667 (12)0.5511 (9)0.2334 (3)0.2733 (5)0.1841 (6)0.0986 (10)0.0447 (10)0.1014 (9)0.1758 (6)0.2869 (5)0.3719 (7)0.2805 (7)0.2881 (6)0.2437 (10)0.1454 (9)0.0915 (6)0.1365 (9)0.3067 (9)A-19

Uiso*/Ueq
0.0108 (11)*0.0108 (11)*0.0108 (11)*0.0108 (11)*0.0108 (11)*0.0108 (11)*0.0108 (11)*0.0108 (11)*0.0108 (11)*0.0108 (11)*0.0108 (11)*0.0108 (11)*0.0108 (11)*0.0108 (11)*0.0108 (11)*0.0108 (11)*0.0108 (11)*0.0108 (11)*0.0108 (11)*0.0108 (11)*0.0108 (11)*0.0108 (11)*0.0108 (11)*0.0108 (11)*0.0108 (11)*0.0108 (11)*0.0108 (11)*0.0108 (11)*0.0108 (11)*0.0051 (13)*0.0051 (13)*0.0051 (13)*0.0051 (13)*0.0051 (13)*0.0051 (13)*

H36
H37
H38
H39
H40
H41
H42
H43
H44
H45
H46
H47
H48
H49
H50
H51
H52
H53
H54
H55
H56
H57
H58
H59
H60

−0.5828 (8)−0.6217 (8)−0.6665 (5)−0.4711 (6)−0.4898 (7)−0.4919 (8)−0.3305 (8)−0.3355 (15)−0.3757 (8)−0.2069 (15)−0.1708 (10)−0.1720 (17)−0.2789 (10)−0.1343 (15)−0.2049 (12)−0.0453 (8)−0.0825 (14)−0.2152 (18)−0.3197 (10)−0.1475 (15)−0.2461 (17)−0.1516 (16)−0.0693 (6)−0.2360 (6)−0.0014 (4)0.0854 (19)−0.008 (3)−0.247 (2)−0.240 (2)−0.590 (2)0.0388 (19)0.1123 (15)−0.098 (3)0.152 (4)0.246 (3)0.003 (4)0.115 (3)0.242 (5)0.469 (3)0.559 (3)0.285 (3)0.519 (4)0.0917 (16)−0.032 (4)−0.042 (3)−0.194 (3)−0.458 (2)−0.301 (5)−0.5317 (17)−0.7129 (16)0.2787 (10)0.1093 (9)0.1157 (10)0.2811 (5)0.0398 (5)0.1375 (10)0.2093 (7)0.3847 (13)0.3458 (9)0.3845 (16)0.4402 (13)0.5941 (12)0.5242 (18)0.6436 (15)0.522 (2)0.547 (2)0.4831 (17)0.132 (2)0.0454 (15)0.044 (3)−0.0303 (6)0.0503 (16)0.1466 (13)0.1390 (13)0.3487 (9)0.0051 (13)*0.0051 (13)*0.0051 (13)*0.0051 (13)*0.0051 (13)*0.0051 (13)*0.0051 (13)*0.0051 (13)*0.0051 (13)*0.0051 (13)*0.0051 (13)*0.0051 (13)*0.0051 (13)*0.0051 (13)*0.0051 (13)*0.0051 (13)*0.0051 (13)*0.0051 (13)*0.0051 (13)*0.0051 (13)*0.0051 (13)*0.0051 (13)*0.0051 (13)*0.0051 (13)*0.0051 (13)*Geometric parameters (Å, °)
C1—C2
C1—C6
C1—C7
C2—C3
C2—H30
C3—C4
C3—H31
C4—C5
C4—H32
C5—C6
C5—H33C6—H34

1.385 (5)1.397 (5)1.498 (10)1.377 (5)0.9499 (14)1.388 (5)0.9499 (14)1.387 (5)0.9499 (14)1.384 (5)0.9499 (14)0.9494 (14)C15—H44
C16—C17
C16—H45
C16—H46
C17—C18
C17—H47
C17—H48
C18—N19
C18—H49
C18—H50
N19—H51
N19—H52
A-20

0.9803 (14)1.635 (5)0.9801 (14)0.9801 (14)1.460 (5)0.9801 (14)0.9800 (14)1.529 (5)0.9803 (14)0.9800 (14)0.9800 (14)0.9807 (14)C7—C8
C7—H35
C7—H36
C8—C9
C8—H37
C8—H38
C9—C10C9—N13
C9—H39
C10—O12
C10—O11
O11—H40
N13—C14
N13—H41
C14—C15
C14—C20
C14—H41
C14—H42
C15—C16
C15—H431.480 (5)0.9797 (14)0.9799 (14)1.528 (5)0.9798 (14)0.9797 (14)1.518 (5)1.505 (5)0.9800 (14)1.251 (5)1.314 (5)0.9199 (14)1.475 (5)0.8499 (14)1.516 (5)1.541 (5)1.932 (6)0.9800 (14)1.498 (5)0.9801 (14)C20—O21
C20—N22
N22—C23
N22—C26
C23—C24
C23—H53
C23—H54
C24—C25
C24—H55
C24—H56
C25—C26
C25—H57
C25—H58
C26—N22
C26—C27
C26—H59
C27—O28
C27—O29
O29—H60

1.263 (5)1.344 (5)1.480 (5)1.438 (10)1.471 (5)0.9799 (14)0.9801 (14)1.361 (5)0.9801 (14)0.9802 (14)1.562 (5)0.9801 (14)0.9801 (14)1.438 (10)1.535 (5)0.9800 (14)1.233 (5)1.292 (5)0.9199 (14)C2—C1—C6
C2—C1—C7
C6—C1—C7
C1—C2—C3
C1—C2—H30
C3—C2—H30
C2—C3—C4
C2—C3—H31
C4—C3—H31
C3—C4—C5
C3—C4—H32
C5—C4—H32
C4—C5—C6
C4—C5—H33
C6—C5—H33
C1—C6—C5
C1—C6—H34
C5—C6—H34
C1—C7—C8

119.90 (26)116.5 (4)123.6 (4)120.20 (23)119.89 (23)119.91 (22)120.07 (24)119.95 (21)119.97 (24)120.13 (22)119.95 (20)119.92 (20)119.92 (22)120.04 (23)120.04 (22)119.77 (24)120.21 (23)120.01 (21)112.5 (5)

C15—C16—C17
C15—C16—H45
C15—C16—H46
C17—C16—H45
C17—C16—H46
H45—C16—H46
C16—C17—C18
C16—C17—H47
C16—C17—H48
C18—C17—H47
C18—C17—H48
H47—C17—H48
C17—C18—N19
C17—C18—H49
C17—C18—H50
N19—C18—H49
N19—C18—H50
H49—C18—H50
C18—N19—H51

108.5 (5)109.64 (29)109.7 (4)109.7 (5)109.7 (4)109.64 (29)112.3 (7)108.9 (4)108.9 (4)108.89 (22)108.9 (5)108.9 (4)110.8 (6)109.2 (4)109.21 (31)109.21 (32)109.2 (4)109.16 (32)
109.5 (9)A-21

C1—C7—H35
C1—C7—H36
C8—C7—H35
C8—C7—H36
H35—C7—H36
C7—C8—C9
C7—C8—H37
C7—C8—H38
C9—C8—H37
C9—C8—H38
H37—C8—H38
C8—C9—C10
C8—C9—N13
C8—C9—H39
C10—C9—N13
C10—C9—H39
N13—C9—H39
C9—C10—O12
C9—C10—O11
O12—C10—O11
C10—O11—H40
C9—N13—C14
C9—N13—H41
C14—N13—H41
N13—C14—C15
N13—C14—C20
N13—C14—H42
C15—C14—C20
C15—C14—H42
C20—C14—H42
C14—C15—C16
C14—C15—H43
C14—C15—H44
C16—C15—H43
C16—C15—H44
H43—C15—H44

108.90 (33)108.84 (32)108.84 (31)108.84 (35)108.91 (22)109.7 (4)109.28 (35)109.84 (35)109.28 (34)109.44 (30)109.33 (22)110.8 (4)103.2 (4)109.42 (26)102.5 (4)119.9 (5)109.53 (24)114.3 (5)118.0 (4)127.7 (5)109.52 (29)118.5 (5)109.4 (5)109.47 (30)113.0 (4)103.1 (5)109.43 (24)113.9 (5)107.8 (7)109.48 (31)111.9 (5)109.0 (6)109.0 (4)108.99 (25)109.0 (4)108.97 (29)

C18—N19—H52
H51—N19—H52
C14—C20—O21
C14—C20—N22
O21—C20—N22
C20—N22—C23
C20—N22—C26
C23—N22—C26
N22—C23—C24
N22—C23—H53
N22—C23—H54
C24—C23—H53
C24—C23—H54
H53—C23—H54
C23—C24—C25
C23—C24—H55
C23—C24—H56
C25—C24—H55
C25—C24—H56
H55—C24—H56
C24—C25—C26
C24—C25—H57
C24—C25—H58
C26—C25—H57
C26—C25—H58
H57—C25—H58
N22—C26—C25
N22—C26—C27
N22—C26—H59
C25—C26—C27
C25—C26—H59
C27—C26—H59
C26—C27—O28
C26—C27—O29
O28—C27—O29
C27—O29—H60

A-22

109.6 (5)109.5 (5)119.2 (4)120.4 (4)120.3 (4)127.5 (4)119.0 (4)108.8 (4)106.7 (4)110.1 (4)110.01 (28)110.0 (5)109.98 (25)110.05 (26)109.0 (7)109.5 (8)109.58 (25)109.55 (31)109.60 (32)
109.54 (33)108.3 (5)109.69 (24)109.70 (31)109.7 (5)109.72 (28)109.70 (31)103.2 (5)112.3 (5)109.50 (29)109.3 (4)109.5 (4)112.6 (7)122.8 (4)112.5 (5)124.7 (5)109.49 (24)Acrinol anhydrous A
SampleAcrinol anhydrous A

Computing details
Program(s) used to refine structure: GSAS.

Crystal data
C18H21N3O4
Mr = 343.38
Triclinic, P 1
a = 8.0467 (3) Å
b = 9.3558 (2) Åc = 11.9151 (2) Å

α = 102.4356 (19)ºβ = 103.177 (3)ºγ = 98.648 (3)º
V = 833.92 (3) Å3
Z=2
synchrotron radiation
λ = 1.19712 ÅData collection
2θmin = 4.01, 2θmax = 77.13º

Increment in 2θ = 0.01º

Refinement
Least-squares matrix: full
Rp = 0.043
Rwp = 0.058
Rexp = 0.018
S = 3.45

85 parameters
151 restraints(∆/σ)max = 0.05

Profile function: CW Profile function number 2 with 18 terms Profile coefficientsfor Simpson's rule integration of pseudovoigt function C.J. Howard (1982). J.
Appl. Cryst.,15,615-620. P. Thompson, D.E. Cox & J.B. Hastings (1987). J. Appl.
Cryst.,20,79-83. #1(GU) = 414.614 #2(GV) = -10.965 #3(GW) = 3.344 #4(LX) =0.837 #5(LY) = 21.327 #6(trns) = 0.000 #7(asym) = -0.2559 #8(shft) = 0.0697#9(GP) = 0.000 #10(stec)= 0.00 #11(ptec)= 0.00 #12(sfec)= 0.00 #13(L11) =0.023 #14(L22) = 0.006 #15(L33) = 0.000 #16(L12) = 0.000 #17(L13) = -0.002#18(L23) = 0.001 Peak tails are ignored where the intensity is below 0.0010 times
the peak Aniso. broadening axis 0.0 0.0 1.0

A-23

Fractional atomic coordinates and isotropic or equivalentisotropic displacement parameters (Å2)
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
N11
C12
C13
C14
O15
C16
C17
N18
N19
O20
O21
C22
C23
C24
O25
H26
H27
H28
H29
H30
H31
H32
H33
H34

x
−0.1431 (2)−0.19855 (15)−0.2299 (2)−0.2875 (2)−0.3151 (2)−0.37259 (14)−0.39936 (8)−0.37053 (18)−0.31435 (14)−0.2871 (2)−0.23264 (14)−0.2052 (2)−0.14438 (14)−0.11289 (8)−0.0992 (3)−0.09704 (10)−0.10800 (10)−0.30924 (7)−0.39892 (7)−0.4272 (7)−0.1787 (5)−0.3073 (5)−0.3257 (2)−0.44971 (13)−0.1635 (3)−0.21113−0.39179−0.43814−0.29243−0.1268−0.07337
0.01195−0.19723−0.09423

y0.6870 (3)0.8104 (2)0.9224 (3)1.0534 (3)1.1586 (3)1.29201 (18)1.39361 (9)1.3697 (3)1.23999 (19)1.1361 (3)1.01154 (19)0.9089 (3)0.78384 (18)0.67500 (10)0.5684 (4)0.56573 (16)0.40374 (13)1.07189 (8)1.47481 (8)0.7724 (5)0.9482 (7)0.8686 (4)0.88769 (16)0.76035 (12)0.9063 (4)0.82201
1.31252
1.484211.22266
0.77292
0.58870.62806
0.60091
0.39708
A-24

z
0.3921 (3)0.36116 (9)0.4506 (3)0.4257 (3)0.5211 (3)0.50322 (10)0.59462 (16)0.7124 (2)0.73230 (10)0.6382 (2)0.65976 (10)0.5693 (2)0.59785 (9)0.51204 (16)0.3209 (3)0.19914 (15)0.13712 (8)0.31582 (10)0.80147 (8)0.8042 (5)0.8695 (6)0.8829 (3)1.01031 (19)1.01984 (7)1.0947 (3)0.280020.42451
0.58061
0.812120.679470.53501
0.19849
0.15880.05665

Uiso*/Ueq
0.0631 (8)*0.0631 (8)*0.0631 (8)*0.0631 (8)*0.0631 (8)*0.0631 (8)*0.0631 (8)*0.0631 (8)*0.0631 (8)*0.0631 (8)*0.0631 (8)*0.0631 (8)*0.0631 (8)*0.0631 (8)*0.0631 (8)*0.095 (4)*0.095 (4)*0.0631 (8)*0.0631 (8)*0.0841 (15)*0.0841 (15)*0.0841 (15)*0.0841 (15)*0.0841 (15)*0.0841 (15)*0.0707 (10)*0.0707 (10)*0.0707 (10)*0.0707 (10)*0.0707 (10)*0.0707 (10)*0.109 (5)*0.109 (5)*0.109 (5)*

H35
H36
H37
H38
H39
H40
H41
H42
H43
H44
H45
H46

−0.2218−0.01512−0.39087−0.27767−0.3817−0.4349−0.22917−0.37174−0.56916−0.42554−0.43427−0.08809

0.343750.36544
1.11426
1.01166
1.46201
1.556760.99032
0.978110.768410.66649
0.76432
0.968630.13171
0.182620.287090.26305
0.87568
0.785810.73206
1.03125
0.98290.97778
1.10484
1.08194

0.109 (5)*0.109 (5)*0.0707 (10)*0.0707 (10)*0.0707 (10)*0.0707 (10)*0.0707 (10)*0.0959 (18)*0.0959 (18)*0.0959 (18)*0.0959 (18)*0.0959 (18)*

Geometric parameters (Å, °)C1—C2
C1—C14
C1—O15
C2—C3
C2—H26
C3—C4
C3—C12
C4—C5
C4—N18
C5—C6
C5—C10
C6—C7
C6—H27
C7—C8
C7—H28
C8—C9
C8—N19C9—C10C9—H29
C10—N11
N11—C12
N11—H41
C12—C13
C13—C141.3897 (28)1.4262 (30)
1.3871 (34)1.4208 (32)0.9801 (10)1.4380 (32)1.4186 (31)1.4177 (32)1.3329 (31)1.4356 (30)1.4283 (32)1.3634 (25)0.9801 (10)1.4412 (27)0.9800 (10)1.4044 (26)1.3689 (29)1.3984 (31)0.9801 (10)1.3591 (30)
1.3636 (31)0.9201 (10)1.4115 (30)
1.3761 (24)

C13—H30
C14—H31
O15—C16
C16—C17
C16—H32
C16—H33
C17—H34
C17—H35
C17—H36
N18—H37
N18—H38
N19—H39
N19—H40
O20—C22
O21—C22
C22—C23
C23—C24
C23—O25
C23—H42
C24—H43
C24—H44
C24—H45
O25—H46
A-25

0.9801 (10)0.9802 (10)1.4501 (33)
1.5161 (18)0.9800 (9)0.9800 (9)0.9799 (9)0.9801 (9)0.9799 (8)0.8603 (9)0.8606 (9)0.9000 (9)0.9001 (8)1.259 (4)1.243 (4)1.5337 (32)1.4765 (22)1.4155 (28)0.9801 (9)0.9831 (8)0.9830 (9)0.9836 (9)0.8400 (10)

C2—C1—C14
C2—C1—O15
C14—C1—O15
C1—C2—C3
C1—C2—H26
C3—C2—H26
C2—C3—C4
C2—C3—C12
C4—C3—C12
C3—C4—C5
C3—C4—N18
C5—C4—N18
C4—C5—C6
C4—C5—C10
C6—C5—C10
C5—C6—C7
C5—C6—H27
C7—C6—H27
C6—C7—C8
C6—C7—H28
C8—C7—H28
C7—C8—C9
C7—C8—N19
C9—C8—N19
C8—C9—C10
C8—C9—H29
C10—C9—H29
C5—C10—C9
C5—C10—N11
C9—C10—N11
C10—N11—C12
C10—N11—H41
C12—N11—H41
C3—C12—N11
C3—C12—C13
N11—C12—C13
C12—C13—C14

120.72 (22)128.37 (26)110.78 (23)118.77 (18)120.60 (18)120.58 (19)122.10 (24)120.76 (25)117.14 (26)117.74 (26)119.10 (25)123.15 (24)120.99 (25)
121.48 (27)117.53 (25)
121.27 (15)120.20 (18)118.52 (17)120.66 (14)119.99 (16)119.35 (16)119.20 (18)118.61 (18)122.19 (18)119.91 (17)120.28 (17)119.80 (18)121.43 (25)119.78 (23)118.79 (21)119.72 (17)119.83 (19)119.91 (19)124.14 (25)118.77 (24)117.08 (20)120.94 (14)C1—C14—C13
C1—C14—H31
C13—C14—H31
C1—O15—C16
O15—C16—C17
O15—C16—H32
O15—C16—H33
C17—C16—H32
C17—C16—H33
H32—C16—H33
C16—C17—H34
C16—C17—H35
C16—C17—H36
H34—C17—H35
H34—C17—H36
H35—C17—H36
C4—N18—H37
C4—N18—H38
H37—N18—H38
C8—N19—H39
C8—N19—H40
H39—N19—H40
O20—C22—O21
O20—C22—C23
O21—C22—C23
C22—C23—C24
C22—C23—O25
C22—C23—H42
C24—C23—O25
C24—C23—H42
O25—C23—H42
C23—C24—H43
C23—C24—H44
C23—C24—H45
H43—C24—H44
H43—C24—H45
H44—C24—H45
A-26

120.00 (15)121.49 (17)118.47 (16)121.02 (29)106.06 (15)109.99 (12)110.90 (16)110.07 (12)109.74 (12)110.00 (10)109.42 (10)109.54 (8)109.62 (9)109.41 (9)109.39 (9)109.45 (9)120.04 (16)120.08 (16)114.58 (13)120.03 (13)120.00 (12)119.97 (12)128.1 (4)114.6 (4)117.3 (4)111.84 (21)112.18 (19)107.98 (18)109.18 (14)107.70 (15)107.78 (21)108.82 (10)108.99 (9)108.49 (11)109.78 (9)110.40 (9)110.32 (9)C12—C13—H30
C14—C13—H30

119.69 (17)119.36 (17)

C23—O25—H46

A-27

109.43 (21)Acrinol anhydrous B
SampleAcrinol anhydrous B

Computing details
Program(s) used to refine structure: GSAS.

Crystal data
C18H21.00N3O4
Mr = 343.38
Monoclinic, C2/c
a = 14.0496 (5) Å
b = 11.80399 (19) Åc = 20.9323 (8) Å
β = 100.936 (3)ºV = 3408.38 (17) Å3
Z=8
CuKα1 radiation
λ = 1.5406 Å

Data collection
2θmin = 5.02, 2θmax = 69.93º

Increment in 2θ = 0.02º

Refinement
Rp = 0.033
Rwp = 0.045
Rexp = 0.013
S = 3.61

Least-squares
matrix: full

83 parameters
153 restraints(∆/σ)max = 0.07
Profile function: CW Profile function number 3 with 19 terms
Pseudovoigt profile coefficients as parameterized in P.
Thompson, D.E. Cox & J.B. Hastings (1987). J. Appl.
Cryst.,20,79-83. Asymmetry correction of L.W. Finger, D.E.
Cox & A. P. Jephcoat (1994). J. Appl. Cryst.,27,892-900.
#1(GU) = 479.806 #2(GV) = -2.528 #3(GW) = 2.949 #4(GP) =0.000 #5(LX) = 3.510 #6(LY) = 14.186 #7(S/L) = 0.0182#8(H/L) = 0.0204 #9(trns) = 0.00 #10(shft)= 0.0000 #11(stec)=
0.00 #12(ptec)= 0.00 #13(sfec)= 0.00 #14(L11) = 0.000#15(L22) = 0.000 #16(L33) = 0.000 #17(L12) = 0.000#18(L13) = 0.000 #19(L23) = 0.000 Peak tails are ignored
where the intensity is below 0.0010 times the peak Aniso.
broadening axis 0.0 0.0 1.0

A-28

Fractional atomic coordinates and isotropic or equivalentisotropic displacement parameters (Å2)
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
N11
C12
C13
C14
O15
C16
C17
N18
N19
O21
O20
C22
C23
C24
O25
H26
H27
H28
H29
H30
H31
H32
H33

x

y

z

Uiso*/Ueq

0.3231 (2)0.23238 (16)0.1659 (3)0.0698 (2)0.0081 (2)−0.08785 (14)−0.14342 (8)−0.1071 (2)−0.01442 (15)0.0427 (3)0.13387 (15)0.1943 (2)0.28160 (14)0.34451 (8)0.3878 (3)0.36862 (8)0.45252 (8)0.04322 (6)−0.16199 (7)0.1619 (3)0.16466 (12)0.16349 (10)0.16422 (7)0.14071 (6)0.10007 (9)0.21236−0.11236−0.20578
0.008560.300620.407630.36477
0.308110.42919 (14)0.38026 (6)0.38846 (15)0.33945 (14)0.35227 (15)0.30764 (5)0.32234 (8)0.38359 (11)0.42799 (5)0.41267 (13)0.45797 (6)0.44678 (14)0.51069 (6)0.50267 (8)0.44017 (18)0.36849 (9)0.38391 (7)0.28082 (6)0.39845 (5)0.5826 (5)0.7500 (6)0.6889 (4)0.74709 (19)0.86794 (11)0.68858 (10)0.34373
0.25787
0.283070.47770.55449
0.540640.289260.390640.97122 (15)0.95508 (5)0.99840 (14)0.98491 (14)1.03163 (15)1.02350 (5)1.06953 (8)1.12817 (12)1.13754 (5)1.08999 (13)1.10132 (5)1.05729 (13)1.06760 (5)1.02497 (8)0.93021 (16)0.87362 (8)0.83868 (5)0.93024 (5)1.17436 (4)0.2030 (4)0.1498 (3)0.19860 (18)0.26395 (10)0.25399 (4)0.29766 (12)0.91262
0.98656
1.065141.17477
1.10777
1.03501
0.886890.844810.0823 (11)*0.0823 (11)*0.0823 (11)*0.0823 (11)*0.0823 (11)*0.0823 (11)*0.0823 (11)*0.0823 (11)*0.0823 (11)*0.0823 (11)*0.0823 (11)*0.0823 (11)*0.0823 (11)*0.0823 (11)*0.0823 (11)*0.093 (4)*0.093 (4)*0.0823 (11)*0.1189 (11)*0.146 (2)*0.146 (2)*0.146 (2)*0.146 (2)*0.146 (2)*0.146 (2)*0.0938 (14)*0.0938 (14)*0.0938 (14)*0.0938 (14)*0.0938 (14)*0.0938 (14)*0.103 (6)*0.103 (6)*

A-29

Occ.
(<1)

H34
H35
H36
H37
H38
H39
H40
H41
H42
H43
H44
H45
H46A
H46B

0.45367
0.513450.44479−0.01506
0.07974−0.138−0.22233
0.15655
0.22989
0.11794
0.198840.08984
0.120450.043210.321
0.385280.455480.24656
0.28352
0.437140.369620.493280.74133
0.89779
0.90934
0.876930.622310.69296

0.808290.87052
0.81453
0.92186
0.899291.21092
1.16841.140430.28989
0.292110.247990.215220.306170.276250.103 (6)*0.103 (6)*0.103 (6)*0.0938 (14)*0.0938 (14)*0.0938 (14)*0.0938 (14)*0.199 (6)*0.171 (3)*0.171 (3)*0.171 (3)*0.171 (3)*0.171 (3)*0.171 (3)*

0.5
0.5

Geometric parameters (Å, °)C1—C2
C1—C14
C1—O15
C2—C3
C2—H26
C3—C4
C3—C12
C4—C5
C4—N18
C5—C6
C5—C10
C6—C7
C6—H27
C7—C8
C7—H28
C8—C9
C8—N19C9—C10C9—H29
C10—N11
N11—C12
N11—H41

1.3813 (30)
1.4074 (32)1.370 (4)1.4226 (33)0.9800 (10)1.4477 (33)
1.4022 (33)
1.4324 (34)1.3287 (32)1.4269 (32)1.4183 (33)
1.3615 (25)0.9800 (10)1.4325 (28)0.9800 (10)1.3827 (27)1.3575 (31)1.4034 (33)0.9799 (10)1.3671 (32)1.3724 (32)0.9200 (10)O15—C1
O15—C16
C16—C17
C16—H32
C16—H33
C17—H34
C17—H35
C17—H36
N18—H37
N18—H38
N19—H39
N19—H40
O21—C22
O20—C22
C22—C23
C23—C22
C23—C24
C23—O25
C23—H42
C24—H43
C24—H44
C24—H45A-30

1.370 (4)1.439 (4)1.5116 (19)0.9799 (9)0.9800 (9)0.9800 (9)0.9801 (9)0.9799 (9)0.9002 (9)0.9000 (9)0.9000 (9)0.9000 (9)1.259 (4)1.253 (4)1.5289 (34)1.5289 (34)1.4701 (23)1.4244 (23)0.9800 (8)0.9800 (9)0.9800 (9)0.9800 (9)C12—C13
C13—C14
C13—H30
C14—H31
C2—C1—C14
C2—C1—O15
C14—C1—O15
C1—C2—C3
C1—C2—H26
C3—C2—H26
C2—C3—C4
C2—C3—C12
C4—C3—C12
C3—C4—C5
C3—C4—N18
C5—C4—N18
C4—C5—C6
C4—C5—C10
C6—C5—C10
C5—C6—C7
C5—C6—H27
C7—C6—H27
C6—C7—C8
C6—C7—H28
C8—C7—H28
C7—C8—C9
C7—C8—N19
C9—C8—N19
C8—C9—C10
C8—C9—H29
C10—C9—H29
C5—C10—C9
C5—C10—N11
C9—C10—N11
C10—N11—C12
C10—N11—H41

1.4215 (32)1.3732 (25)0.9801 (10)0.9801 (10)120.05 (24)125.28 (28)112.08 (24)120.14 (19)119.90 (18)119.85 (19)123.34 (25)118.86 (26)117.80 (27)119.20 (27)118.37 (24)122.40 (24)124.03 (26)119.24 (27)116.73 (25)
121.60 (16)119.87 (18)118.16 (17)120.79 (14)119.72 (17)119.07 (17)119.05 (19)121.16 (19)119.79 (18)120.00 (17)119.94 (18)119.65 (18)121.82 (26)120.18 (24)118.00 (21)121.63 (18)119.12 (18)O25—H46A
O25—H46B

0.8404 (10)0.8402 (10)C1—C14—H31
C13—C14—H31
C1—O15—C16
O15—C16—C17
O15—C16—H32
O15—C16—H33
C17—C16—H32
C17—C16—H33
H32—C16—H33
C16—C17—H34
C16—C17—H35
C16—C17—H36
H34—C17—H35
H34—C17—H36
H35—C17—H36
C4—N18—H37
C4—N18—H38
H37—N18—H38
C8—N19—H39
C8—N19—H40
H39—N19—H40
O21—C22—O20
O21—C22—C23
O20—C22—C23
C22—C23—C24
C22—C23—O25
C22—C23—H42
C24—C23—O25
C24—C23—H42
O25—C23—H42
C23—C24—H43
C23—C24—H44
C23—C24—H45

120.06 (18)119.79 (17)114.67 (30)
106.63 (19)109.86 (12)110.78 (15)110.01 (13)109.58 (13)109.94 (11)109.47 (10)109.48 (9)109.47 (9)109.52 (9)109.40 (10)109.50 (9)119.87 (15)119.75 (14)119.83 (13)119.97 (13)119.99 (13)120.04 (12)129.5 (5)112.3 (5)118.2 (4)110.22 (23)109.15 (21)108.08 (16)113.24 (13)107.97 (16)108.04 (16)109.43 (12)109.37 (10)109.36 (10)A-31

C12—N11—H41
C3—C12—N11
C3—C12—C13
N11—C12—C13
C12—C13—C14
C12—C13—H30
C14—C13—H30
C1—C14—C13

119.15 (19)121.95 (25)119.13 (24)118.22 (21)120.55 (14)119.81 (17)119.31 (17)119.71 (16)

H43—C24—H44
H43—C24—H45
H44—C24—H45
C23—O25—H46A
C23—O25—H46B
H46A—O25—H46B

A-32

109.50 (10)109.62 (9)109.54 (9)109.51 (19)109.44 (17)114.95 (15)