U.S. patent application number 11/363530 was filed with the patent office on 2007-03-08 for method of searching for and generating high free energy forms.
Invention is credited to Kenneth R. Morris, G. Patrick Stahly.
Application Number | 20070051298 11/363530 |
Document ID | / |
Family ID | 25027842 |
Filed Date | 2007-03-08 |
United States Patent
Application |
20070051298 |
Kind Code |
A1 |
Morris; Kenneth R. ; et
al. |
March 8, 2007 |
Method of searching for and generating high free energy forms
Abstract
A method for generating and isolating a high free energy form of
a compound or a mixture of compounds comprises the steps of placing
a sample in a capillary tube, solidifying the sample in the
capillary tube, and isolating a high free energy form of the
sample. A method for searching for a high free energy form of a
sample comprises the steps of placing the compound or mixture in a
capillary tube, generating a solid in the capillary tube, and
determining whether a high free energy form of the sample was
generated. The sample may be a compound or mixture.
Inventors: |
Morris; Kenneth R.; (West
Lafayette, IN) ; Stahly; G. Patrick; (West Lafayette,
IN) |
Correspondence
Address: |
MCANDREWS HELD & MALLOY, LTD
500 WEST MADISON STREET
SUITE 3400
CHICAGO
IL
60661
US
|
Family ID: |
25027842 |
Appl. No.: |
11/363530 |
Filed: |
February 27, 2006 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10688123 |
Oct 17, 2003 |
7041169 |
|
|
11363530 |
Feb 27, 2006 |
|
|
|
09752788 |
Dec 28, 2000 |
6642060 |
|
|
10688123 |
Oct 17, 2003 |
|
|
|
Current U.S.
Class: |
117/23 |
Current CPC
Class: |
Y10T 436/25375 20150115;
Y10T 436/25 20150115; G01N 1/44 20130101; C30B 29/54 20130101; G01N
2001/4027 20130101; G01N 1/40 20130101; C30B 7/00 20130101; Y10T
436/25875 20150115 |
Class at
Publication: |
117/023 |
International
Class: |
C30B 15/00 20060101
C30B015/00; C30B 21/06 20060101 C30B021/06; C30B 27/02 20060101
C30B027/02; C30B 28/10 20060101 C30B028/10; C30B 30/04 20060101
C30B030/04 |
Claims
1. A method of generating a high free energy form of a sample, said
method comprising the steps of: disposing a sample in at least one
capillary tube; solidifying the sample in said at least one
capillary tube; and isolating at least one high free energy form of
the sample.
2. The method of claim 1 wherein the solidifying step comprises
crystallizing the sample.
3. The method of claim 1 wherein the solidifying step comprises the
use of an antisolvent.
4. The method of claim 1 wherein the solidifying step is selected
from the group consisting of solvent evaporation, antisolvent
addition, gel diffusion, and thin-layer deposition.
5. The method of claim 1, further comprising the step of preparing
the sample from a supersaturated solution of at least one
compound.
6. The method of claim 1, wherein said isolated high free energy
form is stabilized within the capillary tube.
7. The method of claim 6, wherein said isolated high free energy
form is stable within the capillary tube for at least 24 hours.
8. The method of claim 1, further comprising the step of
stabilizing the high free energy form.
9. The method of claim 8, wherein said stabilizing step consists
essentially of maintaining the high free energy form of the sample
in the capillary tube.
10. The method of claim 1, further comprising the step of
identifying the high free energy form by a method selected from the
group consisting of visual analysis, microscopic analysis, thermal
analysis, diffraction analysis, and spectroscopic analysis.
11. A method of searching for a high free energy form of a sample
comprising the steps of: disposing a sample in a capillary tube;
solidifying the sample in the capillary tube; and determining
whether a high free energy form of the sample is in the capillary
tube.
12. The method of claim 11, wherein the sample is placed in at
least five capillary tubes.
13. The method of claim 11, wherein the sample is placed in at
least 10 capillary tubes.
14. The method of claim 11, wherein the sample is placed in at
least two sets of capillary tubes, and at least one set differs
from at least one other set.
15. The method of claim 14, wherein the capillary tubes of said at
least one set have a different inner diameter than the capillary
tubes of said at least one other set.
16. The method of claim 14, wherein the sample is placed in at
least four sets of capillary tubes, and each set differs from the
other set with respect to the size or surface of the capillary
tubes within said sets.
17. The method of claim 11, wherein said at least one capillary
tube is coated with a substance on the interior of said tube.
18. The method of claim 11, wherein the step of determining whether
the high free energy form was generated comprises an analytical
method selected from the group consisting of visual analysis,
microscopic analysis, thermal analysis, diffraction analysis, and
spectroscopic analysis.
19. The method of claim 18, wherein the step of determining whether
the high free energy form was generated consists essentially of
visual analysis of said form.
20. The method of claim 18, wherein the step of determining whether
the high free energy form was generated comprises generating data
indicative of the relative free energy of the generated form and
comparing said data to data relating to a known form.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 10/688,123, filed Oct. 17, 2003, which is a continuation of
U.S. application Ser. No. 09/752,788, filed Dec. 28, 2000, now U.S.
Pat. No. 6,642,060. Each of the foregoing applications is
incorporated by reference herein.
FIELD OF THE INVENTION
[0002] The present methods relate to searching for and generating
high free energy forms of a sample comprising a compound, an
element, or a mixture. More particularly, samples are solidified in
capillary tubes, and a distribution of solid forms is generated,
including high free energy forms. The generated forms may be more
stable within the capillary tubes and may be isolated and analyzed
within the capillary tubes.
BACKGROUND OF THE INVENTION
[0003] A chemical compound, or a mixture of compounds, may exist in
different solid forms, each of which has a characteristic free
energy at a given temperature. A compound is a substance composed
of atoms or ions in chemical combination. A compound will usually
include atoms or ions of two or more elements, but as used herein,
may include substances composed of one element. The "form" of a
compound or mixture refers to its arrangement of molecules or atoms
in the solid or semi-solid state. Different forms of a compound or
mixture may be distinguished by their x-ray diffraction patterns as
well as other suitable means. A compound or mixture may be arranged
in a crystalline state, where the molecules exist in fixed
conformations and are arranged in a regular way. A compound or
mixture may exist in different possible crystalline forms. Further,
a compound or mixture may have different crystalline forms that
correspond to different free energy levels. A chemical compound or
mixture may be amorphous, meaning that it is not characterized by a
regular arrangement of molecules, which tends to indicate a
relatively high free energy state. The same compound or mixture may
exhibit different properties depending upon which form it is in
(such as amorphous or crystalline, or such as one of several
different crystalline forms).
[0004] A compound or mixture will have a most stable solid form at
a given temperature (that is, its lowest free energy form at that
temperature), and may have less stable forms, which are referred to
herein as high free energy forms, or as metastable forms in some
contexts. For example, if a compound crystallizes in a stable
crystal form that is the most stable form that can be found, then
any other form that is found may be considered a high free energy
form, in that it has higher free energy than the most stable form.
Such forms are metastable thermodynamically in that they are stable
enough to be found in solid form, at least for some period of
time.
[0005] Past attempts to generate high free energy forms involved
flash evaporations, cooling under different conditions, and/or the
addition of seeds of solid material. However, some materials
strongly resist the generation of high free energy forms, and
previous attempts to generate high free energy forms of such
materials have not been satisfactory. For example, some systems,
such as glycogen, do not form high free energy forms unless there
is a change in pH or temperature. However, for a variety of
reasons, it may not be desirable to alter pH, temperature or other
conditions when attempting to generate high free energy forms.
[0006] When a compound has different solid or crystalline forms,
the different forms are frequently referred to as polymorphs of the
compound. A "polymorphic" compound as used herein means a compound
having more than one solid form. For example, a polymorphic
compound may have different forms of its crystalline structure, or
different forms based upon hydration, or it may have a crystalline
form and an amorphous form.
[0007] There are several reasons why it may be desirable to search
for different polymorph forms, including different free energy
forms, of a compound or mixture. Different free energy forms of the
same compound or mixture may exhibit different properties. As a
result, different free energy forms, including different
crystalline forms, of a compound or mixture may have greater or
lesser efficacy for a particular application.
[0008] One or more solid forms may be generated by crystallization
of the sample. Among the phenomena in crystallization are
nucleation and growth. Crystal nucleation is the formation of an
ordered solid phase from liquids, supersaturated solutions,
saturated vapors, or amorphous phases. Crystals may originate on a
minute trace of a foreign substance (either impurities or container
walls) acting as a nucleation site. Since nucleation may set the
character of the crystallization process, the identity of the
foreign substance is an important parameter. The presence of
"seeds" of other crystalline compounds in a crystallization
environment can be beneficial, detrimental, or both, but in any
event, usually has an influence. Growth is the enlargement of
crystals caused by deposition of molecules on an existing
surface.
[0009] Typically, a solid to be crystallized is present in a
solution at, above, or below its saturation point at a given
temperature. Crystallization is initiated or facilitated by
removing solvent, changing temperature, and/or adding an
antisolvent. The solvent may be removed by evaporation or other
means. Alternatively, the temperature of the solution is changed,
resulting in crystallization. Eventually the solution reaches a
point where crystals will grow.
[0010] During a crystallization process, a specific chemical
substance may crystallize into different forms. For example,
ammonium nitrate exhibits different crystal forms depending on the
temperature. Below -18.degree. C., ammonium nitrate exhibits a
tetragonal crystal form, and above that temperature, it exhibits an
orthorhombic form. Above 32.3.degree. C., ammonium nitrate exhibits
a different type of orthorhombic form, and above 84.2.degree. C. it
exhibits a trigonal form. Above 125.2.degree. C., ammonium nitrate
exhibits a cubic crystal form, and at 169.6.degree. C. ammonium
nitrate will liquefy at atmospheric pressure. At a given
temperature the lowest free energy form frequently is
preferentially formed and the others have relatively higher free
energy. Transitions from one polymorph form, pseudopolymorph form,
or amorphous form to another form may be accompanied by other
physical or chemical changes. The different forms of ammonium
nitrate arise from the different packing arrangements into which
the molecules crystallize at different temperatures. Some compounds
may have different colors that indicate different free energy
forms. For example, the compound
5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile exhibits
different colors depending on which solid form it is in.
[0011] A specific solid form may be more preferable than another
solid form. For example, one polymorph may have a more desirable
color or greater hardness or disperse in water more easily than
another polymorph. Often one polymorph form is more stable than
another form. For example, at 80.degree. C., one orthorhombic form
of ammonium nitrate is more stable than the trigonal form. One
approach to keeping a less stable polymorph from transforming to a
more stable but less desirable polymorph form requires the use of
an additive to block rearrangement of the crystal structure leading
to the undesired form.
[0012] It is known to generate crystalline samples in capillary
tubes. For example, U.S. Pat. No. 5,997,636 discusses a method for
growing crystals within a capillary tube. The patent primarily
discloses crystallizing proteins, and the patent does not disclose
the relative free energy of the proteins formed or that different
forms of proteins were formed.
[0013] As another example, D. Amaro-Gonzalez et al., "Gas
Antisolvent Crystallization Of Organic Salts From Aqueous
Solution", Journal Of Supercritical Fluids, 17 (2000) 249-258,
discloses results of crystallization of lobenzarit, including
crystallizations in capillaries. Lobenzarit is an anti-arthritic
agent. Amaro-Gonzalez et al. state that particle size and
agglomeration varied depending on the size of the capillary, that
it is shown that the size distribution and morphology can be
controlled using different capillary diameters, and that it is
possible to obtain individual crystals without agglomeration.
[0014] The reference does not disclose that different crystal forms
(arrangements at the molecular or atomic level in the solid) were
produced. A different particle size or shape does not imply a
different crystal form since a solid form can crystallize into many
different shapes. For example, snowflakes may comprise a single
crystal form having many different crystal shapes. The reference
also does not disclose that a plurality of different forms may be
generated in a plurality of capillary tubes having the same size
and shape.
[0015] As another example, U.S. Pat. No. 4,290,835 discloses that
various processes are known for growing crystalline bodies and that
one such process, referred to as the "capillary die process,"
generally uses a capillary die or forming member from which the
crystalline body can be grown.
[0016] As yet another example, U.S. Pat. No. 4,295,857 discusses a
process of the crystalline precipitation of a chromogen within a
capillary. A chromogen is an aromatic compound having a chemical
grouping, the chromophore, which gives color to the compound. The
patent discloses that it is desirable to prepare a reagent
component or mixture in a capillary because it allows for handling
of very small amounts of substance and it excludes or at least
reduces the danger of errors in dosing of the substance, such as in
clinical chemical applications. The examples disclosed the
crystallization of 4-aminophenazone in numerous capillary tubes,
such as in wheels of five to ten capillary tubes.
[0017] As a final example, U.S. Pat. No. 5,363,797 discloses a
method for producing a single organic crystal in a capillary
tube.
[0018] None of the foregoing references disclose that a high free
energy form of a compound or mixture may be obtained by
solidification or crystallization within a capillary tube. Indeed,
none of those references are directed to generating or searching
for different free energy forms of a compound or mixture, and none
disclose that a high free energy form may be isolated, analyzed
and/or stabilized within a capillary tube.
[0019] There are several factors that discourage the use of
capillary tubes for solidifying compounds or mixtures. One factor
is that capillary tubes are more difficult to work with than other
containers. Another factor is that there has been no general
recognition that the use of capillary tubes may affect reactions or
lead to compositional or chemical differences. Thus, since it was
believed that the same forms and reactions could be done in other
containers, it is believed that capillary tubes have not been used
to search for and generate high free energy forms.
SUMMARY OF THE INVENTION
[0020] As one aspect, a method of generating a high free energy
form of a sample is provided. The method comprises the steps of
disposing a sample in at least one capillary tube, solidifying the
sample in the capillary tube(s), and isolating at least one high
free energy form of the sample.
[0021] The solidifying step can comprise crystallizing the sample,
using solvent evaporation or antisolvent addition, gel diffusion,
and thin-layer deposition. Alternatively, change in temperature can
be used to crystallize the sample.
[0022] The method may further comprise the step of preparing the
sample from a supersaturated solution of at least one compound.
[0023] It has been discovered that an isolated high free energy
form is readily stabilized within the capillary tube and further
efforts at stabilization may not be necessary. Indeed, in many
cases, the high energy form is sufficiently stable within the
capillary tube for at least 24 hours. The method may further
comprise the step of stabilizing the high free energy form, such as
by adding a stabilizing agent or subjecting the form to stabilizing
conditions. More preferably, the stabilizing step consists
essentially of maintaining the high free energy form of the sample
in the capillary tube, without adding a stabilizing agent or
subjecting the form to stabilizing conditions.
[0024] The method may further comprise the step of identifying the
high free energy form by a method selected from the group
consisting of visual analysis, microscopic analysis, thermal
analysis, diffraction analysis, and spectroscopic analysis.
[0025] As another aspect, a method of searching for a high free
energy form of a sample is provided. The method comprises the steps
of disposing a sample in a capillary tube, solidifying the sample
in the capillary tube, and determining whether a high free energy
form of the sample is in the capillary tube.
[0026] In the present methods, the sample may be placed in at least
five capillary tubes, alternatively at least 10 capillary tubes.
The sample may be placed in at least two sets of capillary tubes,
and at least one set differs from at least one other set. For
example, the capillary tubes of at least one set may have a
different inner diameter than the capillary tubes of at least one
other set. The sample may be placed in at least four sets of
capillary tubes, and each set may differ from the other sets with
respect to the size or surface of the capillary tubes within the
sets. In some cases, it is advantageous to use at least one
capillary tube coated with heparin on the interior of the tube.
[0027] The step of determining whether a high free energy form was
generated can comprise an analytical method selected from the group
consisting of visual analysis, microscopic analysis, thermal
analysis, diffraction analysis, and spectroscopic analysis.
[0028] Depending on the sample, visual analysis of said form may be
sufficient and is relatively quick and easy. In some cases, the
determination of whether a high free energy form was generated will
comprise generating data indicative of the form or the relative
free energy of the generated form and comparing that data to
similar data relating to a known form.
BRIEF DESCRIPTION OF THE DRAWINGS
[0029] FIG. 1 is an energy-temperature diagram showing the relative
thermodynamic stabilities of the various forms of
5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile.
[0030] FIG. 2 is an energy-temperature diagram showing the relative
thermodynamic stabilities of the various forms of
4-methyl-2-nitro-acetanilide.
DETAILED DESCRIPTION OF DRAWINGS AND PREFERRED EMBODIMENTS
[0031] The present methods relate to searching for and generating
high free energy forms of a compound or mixture of compounds by
generating solid forms or semisolid forms in one or more capillary
tubes. The sample may comprise one compound, an element, a mixture
of compound(s), a solution, a suspension, or a dispersion of
compound(s) or other material.
[0032] A "semisolid" form is used herein to indicate materials like
waxes, suspensions, gels, creams, and ointments. The term "solid
form" is used herein to also indicate semisolid forms as well. As
used herein, the term "compound" may include elemental compounds,
the term "molecule" includes collections of atoms, and the term
"polymorph" includes allotropes, which are forms based on
arrangements of atoms. As used herein, solidifying and
solidification include but are not limited to crystallizing and
crystallization. As used herein, isolating a high free energy form
simply means obtaining it for a sufficient time so that it could be
identified, analyzed, or otherwise utilized. The high free energy
form need not be isolated in totally pure form; it can be mixed
with one or more other forms, so long as it is distinguishable
physically, chemical or analytically.
[0033] As mentioned above, the step of solidifying the sample may
include but is not limited to crystallizing the sample. Indeed, the
high free energy forms which may be sought or generated may include
amorphous forms, mixtures of amorphous forms, eutectic mixtures,
mixed crystal forms, solid solutions, co-crystals and other
forms.
[0034] Nonetheless, in preferred embodiments of the present
methods, solid samples are generated in capillary tubes through a
suitable means of crystallization. Typically, a solution containing
a compound or mixture to be crystallized and a solvent is placed in
a capillary tube. The compound or mixture can be present in a
solution below, at, or above its saturation point at a given
temperature at the time it is placed in the capillary tube. The
concentration of the compound or mixture is increased, through
evaporation of the solvent, the use of an antisolvent, or other
suitable means, eventually to a concentration where crystallization
begins. After a suitable amount of time, when solid or semisolid
appears, the resulting sample is ready for analysis, such as
diffraction analysis. Alternatively, the solution is cooled or
heated so that crystallization occurs.
[0035] Suitable capillary tubes tend to include an enclosed space
measuring 0.1 mm to about 20 mm, preferably from about 0.5 mm to
about 5 mm, most preferably from about 0.5 mm to about 2.5 mm, in
at least one dimension. It is preferred that the capillary tubes
are circular in their interior shapes and have an inner diameter
from about 0.1 mm to about 5 mm, more preferably from about 0.5 mm
to about 2.5 mm. The inner diameters of commercially available
capillary tubes are sometimes stated as ranges, such as 1.5-1.8 mm,
and it is preferred that the stated range fall partially or wholly
within one of the preferred ranges described above. Presently
preferred capillary tubes are exemplified in the examples
below.
[0036] Any suitable crystallization technique may be employed for
obtaining crystals. For example, crystals may be obtained through
cooling, heating, evaporation, addition of an antisolvent, reactive
crystallization, and using supercritical fluids as solvents.
Additionally, melt crystallization techniques may be used to
generate a solid or semisolid. Through such techniques, the use of
a solvent can be avoided. In such techniques, formation of
crystalline material is from a melt of the crystallizing species
rather than a solution. Additionally, the crystallization process
may be done through sublimation techniques.
[0037] Nucleation and growth of a crystal normally occur after the
concentration of the material to be crystallized in solution has
reached supersaturation. The concentration may increase as a result
of evaporation of the solvent, addition of antisolvent, or
absorption of the solvent by another material.
[0038] In the present methods, crystallization may be performed as
a seeded operation or an unseeded operation. In a seeded operation,
a selected quantity of seed crystals is included in the system. The
seed crystals may be a high free energy form, which will further
encourage the generation of high free energy forms. The
characteristics of the seed crystals typically influence the
characteristics of the crystals generated from the system.
Crystallization may be performed by heterogeneous or homogeneous
mechanisms.
[0039] In other embodiments of the present methods, the sample is
solidified other than by crystallization. The sample may be in the
form of a melt which is then added to the capillary tube and
allowed to solidify in an amorphous form.
[0040] Alternatively, the mechanism by which solidification is
accomplished may include gel diffusion methods, thin-layer (with or
without subsequent measures to quickly remove residual solvent,
including air of various temperatures forced through the
capillaries) deposition methods, or other suitable methods. Other
thermodynamic and kinetic conditions may be employed to solidify
the compound or mixture. Cooling of a saturated solution is a
typical thermodynamic condition. An addition of a solution of the
compound or mixture to an excess of antisolvent is a typical
kinetic condition.
[0041] As a further aspect, it has been found that if the capillary
tube is held motionless and the material therein is at a suitably
high level of supersaturation, there is an advantage for finding
high free energy forms.
[0042] It may be desirable to determine which solid form is the
most stable. Furthermore, relative stability among the various
forms can be placed in order either qualitatively or
quantitatively. However, these stability orders may differ under
different conditions, as the thermodynamic relationship of forms is
dependent upon the temperature and pressure conditions under which
the sample generations were carried out.
[0043] The high free energy forms may be identified by any suitable
method, including but not limited to visual analysis (such as when
different forms exhibit different colors), microscopic analysis
including electron microscopy, thermal analysis such as determining
the melting points, x-ray diffraction analysis, infrared
spectroscopic analysis, or other spectroscopic analysis. Any
appropriate analytical technique that is used to differentiate
structural, energetic, or performance characteristics may be used
in connection with the present methods. From the analyses, data
indicative of the relative free energy of the forms may be obtained
and used to identify whether a high free energy form was generated.
This data may be compared to other data generated or to
pre-existing data for a known form.
[0044] Preferably, the method comprises generating more than one
solid form such that a distribution of solid forms is created. From
such a distribution, one may determine the frequency of higher
versus lower energy forms, and the number of occurrences of them.
It is expected that a distribution will typically be heavily skewed
towards low free energy forms unless one alters conditions to skew
the distribution toward high free energy forms. For example, one
may undertake a number of crystallizations of a given compound or
mixture and can obtain both low and high free energy forms. In
order to obtain a suitable distribution, one should put the sample
into a suitable number of individual capillary tubes, for example,
five or more capillary tubes, alternatively 50 or more capillary
tubes.
[0045] However, by generating solid forms in capillary tubes, one
may favor the formation of high free energy forms. While the
inventors do not wish to be bound by theory, it is believed that
capillary tubes may not offer the opportunity for early nucleation,
thereby favoring the formation of high free energy forms, and once
a high free energy form is crystallized, its transformation into a
low energy form will be inhibited by the low perturbation
conditions within the capillary tube. Thus, the use of capillary
tubes skews the distribution towards less probable high free energy
forms without eliminating the formation of low free energy forms.
In fact, it is likely that one may still get a majority of low free
energy forms.
[0046] Again, while the inventors do not wish to be bound by
theory, it is presently hypothesized that the use of a capillary
tube is advantageous in generating high free energy forms because
one can maintain a higher level of supersaturation within the
capillary tube, thereby reducing the tendency for premature
solidification as a low free energy form. Also, it is presently
believed that the dimensions and possibly curved shape of the
capillary tubes promote generation of unusually high free energy
forms. Furthermore, the capillary tube may provide a way of
matching dimensions between the crystal structures and the medium.
Regardless of the correctness of any theory, the use of capillary
tubes has been empirically demonstrated to be a successful method
of generating high free energy forms of certain compounds, as shown
in the following examples.
EXAMPLE 1
[0047] For this example, the compound
5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile was used.
This compound has conformational forms having three different
colors: Red, Orange and Yellow. In view of this variety of colors,
the compound has been referred to as "ROY". There are six known
conformational polymorph forms in which ROY may exist. FIG. 1 is an
energy-temperature diagram showing the relative thermodynamic
stabilities of the various forms of the ROY compound. As indicated
in FIG. 1, the form indicated by yellow needles is the least stable
(that is, it is the highest free energy form shown) at room
temperature. In FIG. 1, "YN" indicates yellow needles, "R"
indicates the red form, "ON" indicates orange needles, "OP"
indicates orange plates, and "Y" indicates yellow. "L" demarcates
the conditions beyond which the compound will be in liquid
form.
[0048] For this example, a solution of ROY in ethanol was prepared.
A supersaturated solution of 160.3 mg of ROY in 2 mL of ethanol was
prepared, having a supersaturation ratio of 6.7. The ROY compound
has solubility in ethanol of approximately 12 mg/mL at 25 degrees
C.
[0049] Two sets of capillary tubes were used in this example, and
each set included five capillary tubes. The first set were
open-ended Kimox-51 capillary tubes having a stated inner diameter
of 1.5-1.8 mm. The second set were open-ended capillary tubes
having a stated inner diameter of 0.5-0.6 mm. When the smaller
capillary tubes were initially received from the supplier, they
were coated with heparin. In this example, the smaller tubes were
"washed" by soaking them in distilled water for about 10 minutes,
rinsing with ethanol, and drying in an oven at 65 degrees C. for at
least one hour.
[0050] The ROY/ethanol solution was introduced to each capillary
tube by capillary action, and then the solution was poured out the
opposite end. This was to remove all but a thin layer of solution
clinging to the walls of the capillary. Both ends of the capillary
tubes were open and free of plugs.
[0051] In some instances with larger capillary tubes, one end
became plugged with ROY crystals, and the plugged end was broken
off so that the end was open. In the smaller capillary tubes, the
residual remaining in the tubes was found mostly as small droplets
on the interior surface of the tubes, although some residual was
found as plugs in the capillary. The capillary tubes were allowed
to sit for several hours at room temperature.
[0052] After solidification, the following results were seen. In
the larger capillary tubes, high free energy yellow needles formed,
with red plates forming later among the yellow needles. However, a
majority of the high free energy yellow needles remained. In the
smaller capillary tubes, approximately one-half of the small
droplets crystallized, initially displaying high free energy yellow
needles, which eventually converted to orange needles. The small
droplets were red in color, and the residual plugs were yellow.
[0053] This example indicates that high free energy forms may be
obtained by solidification in capillary tubes. The highest free
energy form known for the ROY compound was preferentially obtained
in capillary tubes of two different sizes by crystallization from a
supersaturated solution. Furthermore, the high free energy form
yellow needles were sufficiently stabilized in the capillary tubes
without other stabilizing efforts, particularly in the larger
capillary tubes.
EXAMPLE 2
[0054] In this example, the ROY compound was solidified in
capillary tubes by a process including the use of water as an
anti-solvent. The ROY compound is generally insoluble in water.
[0055] Two sets of five capillary tubes were used in this example,
the first having a stated inner diameter of 1.5-1.8 mm and the
second having a stated inner diameter of 0.5-0.6 mm. The capillary
tubes all contained water toward one end of the tubes.
[0056] Attempts were made to introduce a solution containing 16.5
mg/mL of ROY in ethanol to each of the capillary tubes. The ROY
solution was not pulled into the smaller capillary tubes containing
water. In the larger capillary tubes, the ROY solution was
successfully introduced by capillary action, and an open gap
(containing air) was maintained between the ROY solution and the
water in the capillary tubes.
[0057] The ethanol of the ROY solution evaporated from the open end
with the water acting as an anti-solvent to increase the
supersaturation. The ROY compound solidified by crystallization in
the places from which the ethanol evaporated. In most of the larger
capillary tubes, the solids comprised approximately 75% to 90%
yellow needles, which are a high free energy form, with the
remainder comprising red plates and orange needles. By breaking the
capillary tube, it is possible to separate the various forms for
separate analyses. This would be useful for single crystal
structure determination studies. The capillary tubes were allowed
to sit at room temperature, with the effect that more red plates
began to appear, at the expense of yellow needles. However, the red
plates also constitute a high free energy form, and a significant
amount of yellow needles remained.
[0058] This example shows that it may be easier to introduce
solutions to capillary of certain sizes when relying on capillary
action alone. This example also shows that a wide variety of forms
may be obtained in a single solidification, as a mixture of forms
corresponding to each of the three colors of the ROY compound were
obtained.
EXAMPLE 3
[0059] This example was performed in a fashion similar to Example
2, except that the ends of the capillary tubes were plugged to
prevent evaporation to the atmosphere.
[0060] Three larger capillary tubes (having a stated inner diameter
of 1.5-1.8 mm) with water as an antisolvent contained therein had
the ROY solution of Example 2 introduced by capillary action. An
air gap remained between the ROY solution and the water within each
capillary tube. Both ends of each tube were plugged with clay.
[0061] After approximately one hour, a faint dark red band of
solids appeared near the front of the water layer in two of the
three capillary tubes. After three days, the red band in the two
capillary tubes was slightly fainter but still present, but no band
or other solids had formed in the third capillary tube. After six
days the faint red band was still present in two tubes and small
spots of red appeared near the front of the ROY solution.
Microscopic analysis showed no obvious crystalline phase. The
significance is that the amorphous form is the highest energy solid
form, demonstrating that a high free energy form was generated and
stabilized by the method.
EXAMPLE 4
[0062] In this example, a supersaturated solution of ROY in ethanol
was solidified by evaporation in capillary tubes of different
sizes. A large number of solidifications were performed in order to
generate a distribution of solid forms, some being high free energy
forms.
[0063] A supersaturated solution of ROY in ethanol was prepared by
mixing approximately 250 mg of the ROY compound in 20 mL of
ethanol. The ROY solution was introduced into about 150 capillary
tubes having different inner diameters or preparation procedures.
More specifically, four sets of capillary tubes were used (with
about 10 tubes in each set), the first set being capillary tubes
having a stated inner diameter of 1.5-1.8 mm, the second set being
capillary tubes having a stated inner diameter of 1.1-1.2 mm, the
third set being capillary tubes having a stated inner diameter of
0.5-0.6 mm and used as received from the supplier (that is, coated
with heparin), and the fourth set being capillary tubes having a
stated inner diameter of 0.5-0.6 mm and which were "washed" by
soaking for 10 minutes in distilled water, rinsing with ethanol,
and drying for at least an hour at 65 degrees C.
[0064] After approximately 20 minutes, the capillary tubes were
checked for solid forms and re-checked at intervals. In the first
set, the ROY compound crystallized primarily as yellow needles,
with a small percentage of capillary tubes containing some orange
needles instead of yellow needles. In the second set, a few
capillary tubes contained yellow needles exclusively, but most
tubes contained a mixture of about 75-90% yellow needles with the
remainder of solids comprising red plates. In the third set, all
the capillary tubes contained yellow needles. In the fourth set,
most of the capillary tubes contained yellow needles with a small
amount of red plates mixed in, though a few capillary tubes
contained yellow needles exclusively or orange needles
exclusively.
[0065] In this example, the high free energy form yellow needles
were preferentially formed in all four sets of capillary tubes. The
0.5-0.6 mm capillary tubes coated with heparin exclusively produced
yellow needles. The washed 0.5-0.6 mm capillary tubes and the
1.1-1.2 mm capillary tubes contained a mixture that included forms
corresponding to the color red, while the 1.5-1.8 mm capillary
tubes contained a mixture that included forms corresponding to the
color orange. This indicates that the use of capillary tubes of
different sizes may be desirable in order to obtain a greater
variety of high free energy forms.
EXAMPLE 5
[0066] For this example, the compound 4-methyl-2-nitro-acetanilide
was used. This compound has conformational forms having three
different colors: White, Amber and Yellow. In view of this variety
of colors, the compound has been referred to as "WAY". FIG. 2 is an
energy-temperature diagram showing the relative thermodynamic
stabilities of the various forms of the WAY compound. "H.sub.L"
indicates the enthalpy of the liquid. "H.sub.A" indicates the
enthalpy of the amber form. "H.sub.Y" indicates the enthalpy of the
yellow form. "H.sub.W" indicates the enthalpy of the white form.
"G.sub.L" indicates the free energy of the liquid. "G.sub.A"
indicates the free energy of the amber form. "G.sub.Y" indicates
the free energy of the yellow form. "G.sub.W" indicates the free
energy of the white form. The white forms are the most stable, the
yellow forms are less stable than the white, and the amber forms
are the least stable (that is, they have the highest free
energy).
[0067] A supersaturated solution of WAY in ethanol was prepared,
having a supersaturation ratio of 2. The WAY solution was
introduced into 95 capillary tubes. The tubes were left open at
both ends and allowed to evaporate to the atmosphere. After about
25 minutes, sixty-two capillary tubes contained crystals. Of these,
forty contained white crystals and twenty-two contained yellow
crystals. After about one hour, four additional capillary tubes
contained white crystals, nine additional capillary tubes contained
yellow crystals, and one additional capillary tube contained a
mixture of white and yellow crystals. After about 95 minutes, two
additional capillary tubes contained white crystals, and seventeen
capillary tubes did not yet contain solids.
[0068] After waiting overnight (for a total of about thirteen hours
and forty minutes after introducing the WAY solution to the
capillary tubes), of the remaining seventeen capillary tubes, six
contained yellow crystals, three contained a mixture of yellow and
white crystals, five contained white crystals, and three did not
contain solids. Of the twenty-two capillary tubes that showed
yellow crystals after 25 minutes, the crystals in nineteen of those
tubes had transformed to white crystals, which reflects the fact
that the yellow crystals were less stable and had a higher free
energy than the white crystals. However, of the nine capillary
tubes that contained yellow crystals after one hour, six still
contained yellow crystals after waiting overnight, and one
contained a mixture of yellow and white crystals.
[0069] These results are significant and unexpected because yellow
crystals are relatively less stable at room temperature and readily
transform to white crystals. The persistence of yellow crystals
overnight while in the solid state is unexpected, and it will
facilitate the study of the higher free energy yellow crystals.
Furthermore, in this case, slower generation of higher free energy
yellow crystals tended to improve the likelihood that those high
free energy crystals would last a longer period of time.
[0070] Although the example did not generate amber crystals, it is
expected that the use of different procedures employing capillary
tubes may lead to the generation of amber crystals.
EXAMPLE 6
[0071] For this example, solutions of the WAY compound were
prepared at a supersaturation ratio of 2 in ethanol and in 10%
aqueous ethanol. Each of these WAY solutions was introduced into
twenty capillary tubes having a stated inner diameter of 0.5-0.6 mm
and which had been washed by soaking in distilled water for about
10 minutes, rinsing with ethanol, and drying for at least an hour
at 65 degrees C. The capillary tubes were maintained at room
temperature and pressure (about 23 degrees C. and at about 45%
relative humidity) and were observed periodically.
[0072] Of the capillary tubes containing the WAY/ethanol solution,
after about 40 minutes, the solution had evaporated from fourteen
of these capillary tubes, and they contained either white crystals
or a mixture of white and yellow crystals; after about 20.5 hours,
only one tube still did not show any crystallization, and all the
other capillary tubes contained yellow crystals or white crystals,
with a couple of exceptions.
[0073] Of the capillary tubes containing the WAY/aqueous ethanol
solution, after one hour, there was no crystallization in any of
the capillary tubes; after 21 hours, nine of the twenty capillary
tubes did not show any crystallization, but the other eleven
contained either yellow crystals or white crystals, with a couple
of exceptions.
[0074] Solidification of the WAY compound from ethanol and aqueous
ethanol solutions was also done at different temperatures (reported
below in degrees Celsius). Table 1 summarizes the results of seven
sets of twenty capillary tubes under set different sets of
conditions. TABLE-US-00001 TABLE 1 Solvent Temp Time Result Ethanol
-2 4 10/20: white crystals 2/20: white and yellow crystals Aqueous
ethanol -2 4:35 19/20: yellow crystals 1/20: white crystals Ethanol
38 0:50 16/20: mixture of white and yellow crystals, with more
white than yellow and with white crystals grown out of end of the
capillary tube; 4/20: no solids formed Ethanol 38 1:43 17/20:
mixture of yellow and white crystals; 3/20: no solids formed
Aqueous ethanol 38 0:50 2/20: mixture of yellow and white crystals;
18/20: no solids formed Aqueous ethanol 38 1:13 5/20: mixture of
yellow and white crystals; 15/20: no solids formed Aqueous ethanol
38 1:42 19/20: mixture of yellow and while crystals; 1/20: no
solids formed
[0075] As shown above, all the conditions were at least partly
successful in generating high free energy forms, in that all
produced at least a mixture of yellow and white crystals. The use
of an aqueous ethanol solution at low temperature was particularly
successful in generating high free energy forms.
[0076] In general, when crystals are generated under similar
conditions in a similar timeframe using traditional containers,
only white crystals are found.
* * * * *