U.S. patent application number 10/842547 was filed with the patent office on 2004-10-21 for methods of searching for solid forms and screening a sample according to its forms.
This patent application is currently assigned to Purdue Research Foundation. Invention is credited to Coates, David, Morris, Kenneth R., Stahly, Barbara C., Stahly, G. Patrick.
Application Number | 20040209304 10/842547 |
Document ID | / |
Family ID | 25028160 |
Filed Date | 2004-10-21 |
United States Patent
Application |
20040209304 |
Kind Code |
A1 |
Stahly, G. Patrick ; et
al. |
October 21, 2004 |
Methods of searching for solid forms and screening a sample
according to its forms
Abstract
Methods for searching for possible forms of a sample and methods
of screening a sample according to its form comprise disposing the
sample in at least one receptacle that defines a capillary space,
such as a capillary tube. The sample is solidified to generate at
least one solid form or semisolid form, and the generated form is
analyzed and classified. The analysis may determine differences in
molecular arrangement of the various forms or characteristics that
reflect the form. The methods may employ a plurality of samples,
conditions, or receptacles in an effort to generate a variety of
forms, so that all or a high percentage of possible forms are
obtained.
Inventors: |
Stahly, G. Patrick; (West
Lafayette, IN) ; Morris, Kenneth R.; (West Lafayette,
IN) ; Stahly, Barbara C.; (West Lafayette, IN)
; Coates, David; (West Lafayette, IN) |
Correspondence
Address: |
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER
LLP
1300 I STREET, NW
WASHINGTON
DC
20005
US
|
Assignee: |
Purdue Research Foundation
S.S.C.I., Inc.
|
Family ID: |
25028160 |
Appl. No.: |
10/842547 |
Filed: |
May 11, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10842547 |
May 11, 2004 |
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09752857 |
Dec 28, 2000 |
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6750064 |
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Current U.S.
Class: |
435/6.11 ;
435/6.1; 435/6.18; 436/518; 702/19 |
Current CPC
Class: |
Y10T 436/25 20150115;
Y10T 436/2575 20150115; B01J 2219/00599 20130101; B01J 2219/00702
20130101; C30B 7/00 20130101; B01J 2219/00756 20130101; C40B 40/10
20130101; B01J 2219/00585 20130101; B01J 2219/00522 20130101; B01J
2219/00725 20130101; C40B 50/08 20130101; B01L 3/06 20130101; Y10T
436/25875 20150115; G01N 25/147 20130101 |
Class at
Publication: |
435/006 ;
436/518; 702/019 |
International
Class: |
C12Q 001/68; G06F
019/00; G01N 033/48; G01N 033/50; G01N 033/543 |
Claims
1. A method of searching for possible forms of a sample, said
method comprising the steps of: disposing the sample on one or more
receptacles, where at least one of the receptacles defines a
capillary space, and the sample is disposed within the capillary
space; solidifying the sample in or on said receptacles to generate
at least one form, wherein said at least one form is a solid or
semisolid; analyzing said at least one form in a manner wherein the
analytical result is indicative of the generated form; and
classifying said at least one form.
2-56. (canceled)
Description
FIELD OF THE INVENTION
[0001] The present methods relate to searching for possible forms
of a sample and include solidifying the sample in at least one
receptacle defining a capillary space. The present methods also
relate to screening a sample according to its forms and include
solidifying the sample in a plurality of receptacles, and at least
one receptacle defines a capillary space. The form of the sample
refers to its arrangement at the molecular or atomic level in the
solid. The forms generated by solidification comprise solid forms
and semisolid forms. The generated forms are analyzed and
classified, such as by x-ray diffraction patterns. The present
methods increase the likelihood of generating all or a high
percentage of possible forms.
BACKGROUND OF THE INVENTION
[0002] In the chemical field, the unpredictability and variability
of compounds, mixtures, and processes are well established. Certain
chemical compounds or mixtures may have utility for numerous
different applications, including vital biological applications,
yet a slight change in those compounds or mixtures, even with
respect to a single atom, may reduce or eliminate their utility for
their beneficial purpose. Similarly, certain chemical processes may
have significantly better or worse performance based upon seemingly
minor differences.
[0003] In the pharmaceutical field, a great deal of time, effort
and expense is spent on the identification of particular compounds
and mixtures that will have beneficial effect. Furthermore,
exhaustive research must be done as to whether such compounds and
mixtures will have harmful effects. Once again, even slight
differences in chemical composition or structure may yield
significant differences in biological activity. Thus, researchers
frequently test many different compounds and mixtures for
biological activity and other effects as well as testing different
processes and conditions for the preparation of such chemical
compounds and mixtures.
[0004] The process of thorough analysis of different chemical
compounds, elements, mixtures, processes, or structures is commonly
referred to as screening. Screening may be a function of time and
effort, with the quality or results of screening being a function
of the number of samples prepared and/or analyzed as well as the
quality of preparation and/or analysis underlying those samples.
Screening plays a vital role in the pharmaceutical field, as the
most advantageous formulation of a biologically active compound or
mixture is frequently found through successful screening
processes.
[0005] However, screening processes can require significant amounts
of time, effort and resources. There is a continuous need for
improved screening processes having increased reliability and
efficiency.
[0006] Processes have been used for screening chemical compounds
according to their form. 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. In the past,
screening processes have not identified with sufficient consistency
and reliability a high percentage of possible solid and semisolid
forms.
[0007] The form of a compound or mixture may have an impact on
biological activity. The same chemical compound may exhibit
different properties depending upon which form (such as amorphous
or crystalline or semisolid) that compound is in. A "semisolid"
form is used herein to indicate materials like waxes, suspensions,
gels, creams, and ointments. The term "solid form" herein includes
semisolid forms. Furthermore, a chemical compound may exist in
different solid forms, and those different solid forms may also
exhibit different properties. As a result, different solid forms,
including different crystalline forms, of a chemical compound may
have greater or lesser efficacy for a particular application. The
identification of an optimal solid form is important in the
pharmaceutical field, as well as in other fields including
nutraceuticals, agricultural chemicals, dyes, explosives, polymer
additives, lubricant additives, photographic chemicals, and
structural and electronic materials. The new methods described
herein may be useful in any of these fields as well as others where
solid materials are used.
[0008] A chemical compound or mixture may be amorphous, meaning
that it is not characterized by a regular arrangement of molecules.
Alternatively (or even to a limited extent within a mostly
amorphous form), 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. The same compound or mixture may
exhibit different properties depending upon which solid form that
compound or mixture is in.
[0009] It is important in the pharmaceutical field as well as other
fields to find the form of a chemical compound that exhibits
appropriate physical and chemical properties. One form may be more
stable or have other properties that make it preferable over other
forms. One form of a chemical composition may have better
bioavailabilty, solubility, or adsorption characteristics or in
other ways be more suitable for delivery of therapeutic doses than
other forms. As part of a screening method, it may be advisable to
evaluate different salts of a chemical compound (or more precisely,
different salt compounds of a given biologically active ion). It is
frequently desirable within a screening process to generate, or at
least search for, a high percentage of the possible solid forms of
a compound or mixture. Past attempts to generate a variety of solid
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 new solid
forms.
[0010] 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.
[0011] Nucleation may be achieved by homogeneous or heterogeneous
mechanisms. In heterogeneous mechanisms, some solid particle is
present to provide a catalytic effect and reduce the energy barrier
to formation of a new phase. 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, must be
considered. Growth is the enlargement of crystals caused by
deposition of molecules on an existing surface. In homogeneous
mechanisms, it has been theorized by others that nucleation is
achieved spontaneously with the solution comprising the solute to
be crystallized in solvent typically by evaporation, temperature
reduction, or addition of antisolvent.
[0012] 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. Eventually the solution reaches a point where crystals will
grow.
[0013] A specific chemical substance may crystallize into different
forms or transition from one polymorph form, pseudopolymorph form,
or amorphous form to another form. This crystallization into a
different form or transition into a different form may be
accompanied by other physical or chemical changes. For example,
novobiocin has at least two different forms: an amorphous form and
a crystalline form. Dog plasma levels of novobiocin vary depending
on which form of novobiocin is administered. In one study, two
hours after the amorphous form of the drug was administered, the
concentration of novobiocin was 29.3 mg/mL. In contrast, when
crystalline novobiocin was administered, there was no drug
detectable in the dog plasma two hours after the drug was
administered. In another example, furosemide has two different
crystalline forms, and furosemide solubility in aqueous buffer at
pH 3.2 varied depending on which polymorph was studied. After three
hours, Form I and Form II had solubilities of approximately 0.025
mg/mL. Under the same conditions and dissolution time, the DMF and
dioxane solvates of furosemide had solubilities of approximately
0.035, and Form III had a solubility of approximately 0.045
g/mL.
[0014] 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. 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 particle
shape can be controlled using different capillary diameters, and
that it is possible to obtain individual crystals without
agglomeration.
[0015] Neither reference discloses that different forms (meaning
different arrangements on the molecular or atomic level) were
produced, nor does either reference suggest a new method for
searching for possible forms or screening a sample according to its
form. A different particle size or shape does not necessarily mean
there is 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.
[0016] It is also known to subject samples within capillary tubes
to various spectroscopic analyses, including diffraction analysis
such as x-ray diffraction analysis. However, in such instances, it
has been the common practice to prepare a solid sample outside the
capillary tube before it is placed in the capillary tube for
analysis.
[0017] 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 spaces 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 as an integral part of a screening process or to search for
and generate solid and semisolid forms.
[0018] There is a need for improved screening methods that identify
all or a high percentage of possible forms of a compound or
mixture. There is a need for improved methods of searching for the
possible forms of a sample.
SUMMARY OF THE INVENTION
[0019] As one aspect, an improved method of searching for possible
forms of a sample is provided. The method comprises the steps of
disposing the sample on one or more receptacles, where at least one
of the receptacles defines a capillary space, and the sample is
disposed within the capillary space. The method next comprises
solidifying the sample in or on the receptacles to generate at
least one form, wherein the generated form(s) is a solid or
semisolid. The form(s) is then analyzed and classified, such as by
classification according to what form it is.
[0020] As another aspect, an improved method of screening a sample
according to its form is provided. This method is especially useful
for screening a sample comprising a compound or a mixture having
biological activity in at least one form of the compound or
mixture. The screening method comprises the steps of disposing the
sample on a plurality of receptacles, where at least one of the
receptacles defines a capillary space, and the sample is disposed
within the capillary space. The method next comprises solidifying
the sample in or on the receptacles to generate at least one form,
wherein at least one form is a solid or semisolid. The method
further comprises analyzing at least one form in a manner wherein
the analytical result is indicative of the generated form(s), and
classifying the generated form(s), such as by form type or
according to analytical result.
[0021] The screening method may be particularly useful where the
compound or mixture has at least one form having biological
application and it is desirable to determine if other forms are
possible. The present methods may comprise generating at least one
other form of the compound or mixture.
[0022] The sample may comprise a known polymorphic compound or
comprise at least one material that is not recognized as a
polymorphic compound. The sample may consist essentially of a
solution of one compound, or may comprise a mixture of
compounds.
[0023] Preferably, the present methods include disposing the sample
on a plurality of receptacles, including at least two different
types of receptacles. For example, one portion of a sample may be
disposed in a capillary tube that defines a capillary space and
another portion of the sample may be disposed on a glass slide that
does not define a capillary space. The sample may be prepared in a
single batch or in multiple batches. After the portions have
solidified, the form disposed in the capillary tube and the form
disposed on the slide may be analyzed, classified and compared.
[0024] A preferred receptacle defining a capillary space is a
capillary tube, and others include a well plate, a block and a
sheet with holes or pores of appropriate size and shape.
[0025] The present methods may further comprise the step of
comparing the generated form to a known form. In many cases, the
generating step may produce at least one different form of the
sample.
[0026] At least some of the receptacles may be subjected to
substantially constant motion during the generating step. For
example, a capillary tube may be rotated along its longitudinal
axis during the generating step or subjected to centrifuging during
the generating step. Centrifuging can be sufficient to concentrate
the solid or semisolid at one end of a capillary tube and to
facilitate in-situ analysis of the generated forms. Also,
variations in centrifuging may provide environmental variation,
which is desired in a screening method. Centrifuging may move the
sample to the bottom of the receptacle when one end of the
receptacle is closed. Centrifuging may be performed at a pressure
lower than ambient pressure, or under vacuum.
[0027] In the present methods, the sample may comprise a compound
comprising a biologically active ion or one or more different salts
of the compound. A second analyzing step may be performed on
generated forms, where the second analyzing step provides data
indicative of biological activity or bioavailability.
[0028] In the present methods, the generated forms may be analyzed
by any suitable means, such as methods selected from the group
consisting of visual analysis, microscopic analysis, thermal
analysis, diffraction analysis, and spectroscopic analysis.
Preferred methods of analysis include Raman spectroscopic analysis
and x-ray diffraction analysis, more preferably using synchrotron
radiation as the radiation source for the analysis. The analysis
may determine differences in arrangement of molecules in the solid
or determine one or more other characteristics that directly or
indirectly reflect the form.
[0029] In the present methods, the step of analyzing the generated
form may comprise analyzing the form without removing it from the
receptacle in which it was generated. Thus, the present methods are
useful for in situ analysis of generated forms. The use of
capillary tubes as receptacles can facilitate such in situ
analysis.
[0030] It may be advantageous to place the sample in at least five
receptacles defining capillary spaces, alternatively at least 100
receptacles defining capillary spaces. In some embodiments, a
sample is placed in several sets of numerous capillary tubes (for
example, from 5 to 2000 capillary tubes, alternatively 5 to 100
capillary tubes), and the different sets are subjected to different
methods or conditions of solidification.
[0031] The solidifying step may comprise crystallizing the sample,
or may be selected from the group consisting of solvent
evaporation, cooling, anti-solvent addition, gel diffusion, and
thin-layer deposition.
[0032] A supersaturated solution of the sample can be formed
before, during, or after the sample is disposed on the
receptacle(s).
[0033] The generating step preferably comprises crystallizing the
sample, or alternatively is selected from the group of methods
consisting of solvent evaporation, cooling, anti-solvent addition,
gel diffusion, and thin-layer deposition (with or without
subsequent measures to quickly remove residual solvent, including
air of various temperatures forced through the capillaries).
[0034] The receptacle that defines a capillary space can be a
capillary tube or appropriately sized multi-well plate.
Alternatively, the receptacle that defines a capillary space may be
a block or a sheet made of polymer, glass, or other material, which
has holes or pores of a suitable shape and dimensions.
Alternatively, some receptacles need not define a capillary space;
indeed, it is considered preferable to employ different kinds of
receptacles for generating solid and/or semisolid forms of a given
sample. Additional receptacles may include a glass slide or a
conveyer surface in addition to the receptacle(s) defining
capillary spaces.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0035] The use of receptacles that define capillary spaces is an
improvement over more labor-intensive methods of generating solid
forms and enables one to obtain a high percentage of possible solid
and semisolid forms. Another advantage of such receptacles is that
smaller amounts of the compound or mixture are used. A compound is
a substance composed of atoms or ions in chemical combination. A
compound usually is composed of two or more elements, though as
used in accordance with the present methods, a compound may be
composed of one element.
[0036] A "polymorph" as used herein means a compound or mixture
having more than one solid or semisolid form. The "form" of a
compound or mixture refers to the arrangement of molecules in the
solid. A "semisolid" form is used herein to indicate materials like
waxes, suspensions, gels, creams, and ointments. The term "solid
form" herein includes semisolid forms.
[0037] "Capillary space" is defined herein to mean a space having
walls separated by from about 0.1 mm to about 30 mm, preferably
from about 0.5 mm to about 5 mm, more preferably from about 0.5 mm
to about 2.5 mm, in at least one dimension. A capillary tube having
an inner diameter from about 0.5 mm to about 2.5 mm , is a
preferred receptacle that defines a capillary space in the interior
of the capillary tube. It is preferred that the capillary tubes are
circular in their interior shapes.
[0038] As used herein, the generation of solid and semisolid forms
includes any suitable technique for solidification including but
not limited to crystallization. Indeed, the 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.
[0039] In certain embodiments of the present methods, solid samples
are generated in receptacles through a suitable means of
solidification. Typically, a solution containing a compound or
mixture to be solidified and a solvent is placed in a receptacle
defining a capillary space, such as 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
a capillary tube. Through evaporation, the use of an antisolvent,
temperature variation, and/or other suitable means, the system
reaches a point where solidification begins. After a suitable
amount of time, when solid or semisolid appears, the resulting
sample is ready for analysis.
[0040] 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 form. 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.
[0041] 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 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.
[0042] In other embodiments of the present methods, the form is
generated other than by crystallization. The sample may be in the
form of a melt that is then added to the capillary tube and allowed
to solidify in an amorphous form. Alternatively, the mechanism by
which solidification is accomplished may include gel diffusion
methods, thin-layer 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 cold anti-solvent is a
typical kinetic condition.
[0043] Any material capable of forming a solid or semisolid may be
used in the present methods. In particular, the present methods are
especially suited for materials characterized by molecules which
are associated by non-bonded interactions (e.g. van der Waals
forces, hydrogen bonding, and Columbic interaction).
[0044] The present methods may be advantageously used with small
organic drug molecules having solubility of at least 1 mg/mL in
ethanol at ambient conditions. The present methods are also
contemplated for use with large organic molecules and inorganic
molecules. Examples of compounds having more than one solid form
include 5-methyl-2-[(2-nitrophe- nyl)amino]-3-thiophenecarbonitrile
and 4-methyl-2-nitroacetanilide, each of which may be different
colors in connection with different forms, and novobiocin and
furosemide, which are discussed above. This list cannot be
exhaustive as the present methods may provide significant benefits
for novel compounds and mixtures whose identities, or at least
whose possible forms, are not yet identified.
[0045] The generation of a variety of forms is an important object
of screening. A sufficient number of diverse processes and
conditions should be employed to maximize the likelihood that a
high percentage of possible solid forms of a chemical compound is
generated. Samples should be generated under various thermodynamic
and kinetic conditions.
[0046] It is preferable that the generation of solid and/or
semisolid forms within the receptacles is carried out under a wide
variety of conditions. For example, solids should be generated in
the presence and absence of various solvents, as the solvent may
play a role in the formation of certain forms.
[0047] As another example it is also preferable to prepare samples
under different conditions of temperature and pressure, as
different solid forms may be favored by different conditions.
[0048] The various forms generated 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, conducting diffraction analysis
(such as x-ray diffraction analysis, electron diffraction analysis,
neutron diffraction analysis, as well as others), conducting an
infrared spectroscopic analysis, or conducting 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.
[0049] The classifying step may comprise classifying the generated
form(s) according to any of the analytical results, such as
appearance, solubility, or x-ray diffraction pattern.
[0050] In a preferred embodiment, a synchrotron may be used as the
source of radiation for conducting diffraction analyses. A
synchrotron is a type of particle accelerator, which emits high
energy, focused radiation. Synchrotron radiation is the byproduct
of circulating electrons or positrons at speeds very close to the
speed of light. Synchrotron radiation contains all the wavelengths
of the electromagnetic spectrum and comprises the most intense
source of wavelengths available in the x-ray and ultraviolet
region. Synchrotron radiation allows analysis of smaller quantities
of sample that would be difficult to analyze using other sources of
x-ray radiation.
[0051] One location for research using synchrotron radiation is the
Stanford Synchrotron Radiation Laboratory (SSRL), which is funded
by the Department of Energy as a national user facility. Another
location is Argonne National Laboratory, which is available to
outside users on a fee basis.
[0052] Synchrotron radiation may be used to study structural
details of solid samples with a resolution not practically
attainable using traditional x-ray instrumentation. This may enable
differentiation between different polymorphic forms or compounds
that is not attainable with other x-ray radiation sources.
[0053] Preferably, the present methods comprise generating more
than one form such that a distribution of forms is obtained.
[0054] However, by generating solid forms in receptacles defining
capillary spaces, one may favor the formation of a variety of solid
forms and increase the likelihood of generating all or a high
percentage of possible forms.
[0055] The present methods can significantly assist in the
identification of the form of a compound or a mixture that is most
stable or has other properties that make it preferable over other
forms. For example, the present methods can be used as part of a
screening method and can improve the likelihood of identifying a
form having biological activity such as better bioavailability,
solubility, or adsorption characteristics. In some cases, an
identified form may have better activity as an active agent.
[0056] After the sample is placed in a receptacle, the receptacle
may be centrifuged. Centrifugation may be employed for a variety of
reasons. First, centrifuging may assist evaporation or concentrate
solid or semisolid material at one end of a capillary space. This
has advantages in connection with in-situ analysis, in that the
generated form will be located at a consistent place in the
receptacle. Also or alternatively, centrifuging may be used to
provide additional environmental variation, which is desirable in a
screening method.
EXAMPLE 1
[0057] Portions of a sample of 4-(6-methoxy-2-naphthyl)-butan-2-one
(Compound A) were dissolved in various solvents (acetone,
acetonitrile, aqueous ethanol, ethanol, ethyl acetate,
tetrahydrofuran, toluene, benzene, chloroform, methyl ethyl ketone,
methanol, butyl acetate, methylene chloride, hexane, aqueous
tetrahydrofuran, aqueous methanol, aqueous acetone, and aqueous
acetonitrile) to make saturated solutions ranging in concentration
from 5-50 mg/ml depending on the solvent. The solutions were
filtered through 0.2 .mu.m nylon syringe filters into automatic
pipettes. Aliquots (ranging from 5-25 microliters) of the solutions
were introduced into 40 glass capillaries (thin-walled, both ends
open, half 0.7 mm inside diameter, half 1.0 mm inside diameter).
For some of the capillary tubes, the original saturated solution
was heated and more 4-(6-methoxy-2-naphthyl)-butan-2-one was added
until the concentration was twice that of the saturation
concentration. This supersaturated solution was then used.
[0058] The capillaries were rotated about their center point at
room temperature and solvent was allowed to evaporate until solid
or semisolid material was visible by eye.
[0059] The resulting capillaries containing solid or semisolid
material were analyzed by laboratory x-ray powder diffraction in
the capillary tubes without isolation of material using an INEL XRG
3000 diffractometer. Analysis of the x-ray diffraction data showed
four different x-ray powder patterns: the original crystalline form
reported in the literature, two new crystalline powder patterns,
and one amorphous pattern. These four different x-ray diffraction
patterns are indicative of four different solid forms. A
comparative study of 4-(6-methoxy-2-naphthyl)-butan-2-one using 80
traditional screening conditions (including crystallization in
vials, varying solvents, varying conditions including fast
evaporation, slow cooling, and crash cooling) showed only one new
diffraction pattern.
EXAMPLE 2
[0060] Portions of a sample of sulfathiazole (compound B) are
dissolved in various solvents (aqueous ethanol, acetonitrile,
ethanol, methanol, aqueous methanol, methylene chloride, acetone,
hexane, dioxane) to make saturated solutions ranging in
concentration from 5-50 mg/ml depending on the solvent. The
solutions are filtered through 0.2 .mu.m nylon syringe filters into
automatic pipettes. Aliquots (ranging from 5-25 microliters) of the
solutions are introduced into 100 glass capillaries (thin-walled,
single closed end, 0.7 mm inside diameter) and spun in a centrifuge
to move the solution to the bottom of the capillary tube. For some
of the capillary tubes, the original saturated solution is heated
and more Compound B is added until the concentration is twice that
of the saturation concentration. This supersaturated solution is
then used.
[0061] The capillaries are placed in a variety of environments and
solvent is allowed to evaporate until solid or semisolid material
is visible by eye. Environments include 60.degree. C. oven,
4.degree. C. freezer, ambient temperature, storage with closed end
up, storage with closed end down, and spinning of the
capillaries.
[0062] It is expected that the resulting capillaries containing
solid or semisolid material can be analyzed by laboratory x-ray
powder diffraction in the capillary tubes without isolation of
material using an INEL XRG 3000 diffractometer. Analysis of the
x-ray diffraction data would show whether different forms were
present, including forms in addition to the known forms. Different
x-ray diffraction patterns are indicative of different forms. A
comparative study of sulfathiazole using 60 traditional screening
conditions (crystallization in vials, varying conditions including
fast evaporation, slow cooling, and crash cooling) would be
expected to identify fewer different x-ray powder diffraction
patterns.
EXAMPLE 3
[0063] Portions of a sample of a polymorphic compound (compound C)
are dissolved in various solvents (aqueous ethanol, methylene
chloride, ethanol, toluene, dimethylformamide, acetone, water,
butanol, methanol, acetonitrile, methylethylketone, hexane,
dioxane, and ethyl acetate) to make solutions ranging in
concentration from 5-50 mg/ml depending on the solvent. The
solutions are filtered through 0.2 .mu.m nylon syringe filters into
automatic pipettes. Aliquots (ranging from 5-25 microliters) of the
solutions are introduced into 200 glass capillaries (thin-walled,
single closed end, 0.7 mm inside diameter) and spun in a centrifuge
to move the solution to the bottom of the capillary tube, which
facilitates in situ analysis.
[0064] Aliquots (ranging from 5-25 microliters) of the solutions
are also introduced into 100 double open-ended glass capillaries
(thin-walled, double open ends, 1.0 mm inside diameter).
[0065] The capillaries are placed in a variety of environments and
solvent is allowed to evaporate until solid or semisolid material
it was visible by eye. Environments include 60.degree. C. oven,
4.degree. C. freezer, ambient temperature, storage with closed end
up, and storage with closed end down. Some of the capillaries are
stored under centrifugation at 40.degree. C. and ambient pressure
while the solvent evaporation took place. The 100 open-ended
capillaries are rotated about their center point during solvent
evaporation.
[0066] The resulting capillary tubes containing solid or semisolid
material can be analyzed by synchrotron x-ray powder diffraction.
It is expected that this in situ analysis of the x-ray diffraction
data would show different patterns corresponding to different
forms, and that more forms would be observed than if the forms were
generated by a traditional screening method. Different x-ray
diffraction patterns are indicative of different forms of the
compound.
[0067] A comparative study using traditional screening techniques
to prepare different forms of the same compound would be expected
to identify fewer different x-ray diffraction patterns.
EXAMPLE 4
[0068] Solutions of an organic drug sample (compound D) are
prepared in a similar way as those in Example 2. Aliquots (15-20
microliters each) of the various solutions are placed in two glass,
thin-walled 96-well plates with well dimensions of approximately 2
mm.times.2 mm.times.8 mm. The solutions are evaporated by placing
one plate in a SpeedVac centrifugal evaporator at 30.degree. C. and
25 mm Hg vacuum and one in a SpeedVac centrifugal evaporator at
50.degree. C. and 100 mm Hg vacuum. The different evaporation
conditions provide different evaporation rates and other
environmental variations. The resulting solid and semisolid
residues are analyzed in situ by transmission x-ray powder
diffraction. Analysis of the x-ray data would be expected to show
distinct powder patterns for the different forms generated.
EXAMPLE 5
[0069] Following a procedure having the same steps as Example 1,
forms are generated. After solutions in capillary tubes evaporate
to leave solid or semisolid residue, the capillary tubes are cut to
a 2 cm length containing the bulk of the residue and then crushed
and analyzed by infrared (IR) spectroscopy. Analysis of the IR data
would be expected to indicate presence of several different forms,
that is, several distinguishable IR patterns. Different IR patterns
are indicative of different forms.
* * * * *