U.S. patent application number 10/592591 was filed with the patent office on 2007-12-13 for screening for solid forms by ultrasound crystallization and cocrystallization using ultrasound.
This patent application is currently assigned to S.S.C.I., Inc. Invention is credited to Scott L. Childs, Patricia M. Mougin-Andres, Barbara C. Stahly.
Application Number | 20070287194 10/592591 |
Document ID | / |
Family ID | 34994302 |
Filed Date | 2007-12-13 |
United States Patent
Application |
20070287194 |
Kind Code |
A1 |
Childs; Scott L. ; et
al. |
December 13, 2007 |
Screening For Solid Forms By Ultrasound Crystallization And
Cocrystallization Using Ultrasound
Abstract
The present disclosure relates to crystallizing a chemical
substance(s) using ultrasound. Methods are provided for screening a
chemical substance according to its solid forms by using ultrasound
to generate new or unusual solid forms. Methods are also provided
for crystallizing a chemical substance by novel techniques that
include sonication. The present disclosure also relates to
cocrystallization using ultrasound. Methods are provided for
preparing cocrystals of an active agent and a guest by sonicating
and crystallizing. Methods are also provided for screening a sample
according to solid state phases (such as cocrystals and salts) and
include generating a cocrystal from the sample using
ultrasound.
Inventors: |
Childs; Scott L.; (Atlanta,
GA) ; Mougin-Andres; Patricia M.; (West Lafayette,
IN) ; Stahly; Barbara C.; (West Lafayette,
IN) |
Correspondence
Address: |
MCANDREWS HELD & MALLOY, LTD
500 WEST MADISON STREET
SUITE 3400
CHICAGO
IL
60661
US
|
Assignee: |
S.S.C.I., Inc
|
Family ID: |
34994302 |
Appl. No.: |
10/592591 |
Filed: |
March 14, 2005 |
PCT Filed: |
March 14, 2005 |
PCT NO: |
PCT/US05/08746 |
371 Date: |
July 25, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60552479 |
Mar 12, 2004 |
|
|
|
Current U.S.
Class: |
436/181 ; 117/11;
23/295R |
Current CPC
Class: |
C30B 7/00 20130101; Y10T
436/25875 20150115; C07C 217/72 20130101; B01D 9/00 20130101; B01D
9/0077 20130101 |
Class at
Publication: |
436/181 ;
117/011; 023/295.00R |
International
Class: |
G01N 1/00 20060101
G01N001/00; B01D 9/00 20060101 B01D009/00; C30B 7/00 20060101
C30B007/00 |
Claims
1. A method of screening a chemical substance for possible solid
forms, said method comprising the steps of: preparing a first
sample comprising a chemical substance in a first solvent;
preparing a second sample comprising the chemical substance in a
second solvent; sonicating the first and second samples; and
solidifying the chemical substance from the first and second
samples.
2. The method of claim 1, wherein the solidifying step and the
sonicating step at least partially overlap.
3. The method of claim 1, wherein at least one of said solvents is
selected from the group consisting of acetone, acetonitrile,
chloroform, dioxane, ethanol, ethyl acetate, heptane, butanone,
methanol, nitromethane, tetrahydrofuran, toluene, water,
dichloromethane, diethyl ether, isopropyl ether, cyclohexane,
methylcyclohexane, isopropyl alcohol, isopropyl acetate,
trimethylpentane, n-octane, trichloroethane, trifluoroethanol,
pyridine, propanol, butanol, tetrachloroethylene, chlorobenzene,
xylene, dibutyl ether, methyl-tert-butyl ether, tetrachloroethane,
p-cymene, dimethyl sulfoxide, formamide, and dimethylformamide.
4. The method of claim 1, wherein the first solvent comprises a
mixture of solvents.
5. The method of claim 4, wherein the second solvent comprises a
mixture of solvents.
6. The method of claim 1, wherein at least one of the samples is a
solution having a viscosity greater than about 10 cPoise before the
solution is sonicated.
7. The method of claim 1, wherein the samples are provided by
preparing a solution from an amorphous solid comprising the
chemical substance.
8. The method of claim 7, wherein the solvent is sonicated while
the amorphous solid is added to the solvent.
9. The method of claim 1, wherein at least one of the samples is an
emulsion comprising two or more substantially immiscible solvents
and the chemical substance.
10. The method of claim 1, wherein at least one of the samples is a
slurry comprising a solvent and the chemical substance.
11. The method of claim 1, comprising providing a plurality of
subsamples of said first sample, and wherein a first portion of the
subsamples are subjected to relatively slow evaporation, and a
second portion of the subsamples are subjected to relatively fast
evaporation.
12. The method of claim 1, wherein the solidifying step comprises
evaporating a solvent from the samples, and the method comprises
sonicating at least one of the samples until the solvent is
substantially completely evaporated.
13. The method of claim 1, comprising the step of evaporating a
solvent from at least one of the samples during the sonicating
step.
14. The method of claim 1, comprising the step of evaporating a
solvent from at least one of the samples after the sonicating
step.
15. The method of claim 1, comprising the step of cooling at least
one of the samples before the sonicating step.
16. The method of claim 1, comprising the step of cooling at least
one of the samples during the sonicating step.
17. The method of claim 1, comprising the step of cooling at least
one of the samples after the sonicating step.
18. The method of claim 1, comprising the step of crash-cooling at
least one of the samples before the sonicating step.
19. The method of claim 1, wherein at least one of the samples is
sonicated by at least one ultrasound pulse.
20. The method of claim 1, wherein at least one of the samples is
sonicated by a series of at least 5 ultrasound pulses.
21. The method of claim 1, wherein at least one of the samples is
sonicated by sonicating at least once for about 5 minutes.
22. The method of claim 1, wherein the sonication is substantially
continuous during the solidification step.
23. The method of claim 1, wherein the solidification comprises
generating at least one solid solvate of the chemical
substance.
24. The method of claim 1, wherein the solidification comprises
generating at least one solid hydrate of the chemical
substance.
25. The method of claim 1, wherein the first sample and the second
sample are placed in a well plate.
26. The method of claim 25, wherein the solidified chemical
substances are analyzed in the well plate by x-ray diffraction.
27. The method of claim 1, wherein the solidified chemical
substances are analyzed by transmission x-ray diffraction.
28. The method of claim 1, wherein the solidified chemical
substances are analyzed by Raman spectroscopy.
29. The method of claim 1, wherein the first sample and the second
sample are sonicated in a well plate.
30. The method of claim 1, further comprising the step of
determining whether one or more solid forms were generated using an
analytical method selected from the group consisting of visual
analysis, microscopic analysis, thermal analysis, diffraction
analysis, and spectroscopic analysis.
31. The method of claim 1, further comprising the step of
determining whether one or more solid forms were generated using
x-ray diffraction analysis
32. The method of claim 1, further comprising the step of
determining whether one or more solid forms were generated using
Raman spectroscopic analysis.
33. A method of crystallizing a chemical substance, said method
comprising the steps of: forming an emulsion comprising two or more
substantially immiscible solvents and the chemical substance by
applying ultrasound to a mixture of said solvents and the chemical
substance; and crystallizing the chemical substance from the
emulsion.
34. The method of claim 33, further comprising the steps of adding
an antisolvent to the emulsion, and thereafter further sonicating
the emulsion.
35. The method of claim 33, wherein the chemical substance is
substantially soluble in one of said immiscible solvents and
substantially insoluble in another of said immiscible solvents.
36. A method of crystallizing a chemical substance, said method
comprising the steps of: providing a sample of the chemical
substance in a solvent; sonicating the sample at a predetermined
supersaturation level; and crystallizing the chemical substance
from the sample.
37. The method of claim 36, wherein the sonicating and
crystallizing steps at least partially overlap.
38. The method of claim 36, wherein the sample is cooled before
sonicating.
39. The method of claim 36, wherein the solvent is evaporated after
sonicating.
40. The method of claim 36, wherein the predetermined
supersaturation level is selected to generate a relatively stable
form of the chemical substance.
41. The method of claim 36, wherein the predetermined
supersaturation level is selected to generate a solvate of the
chemical substance.
42. The method of claim 36, further comprising adding an additional
solvent to the sample.
43. The method of claim 36, wherein the sample is a solution having
a viscosity greater than about 10 cPoise before the solution is
sonicated.
44. The method of claim 36, wherein the sample has a metastable
zone, and the metastable zone has a width of at least about
1.degree. C.
45. The method of claim 36, wherein the sample has a metastable
zone, and the metastable zone has a width that is reduced by at
least about 1.degree. C. through sonicating the sample.
46. The method of claim 36, wherein the forming step comprises
forming a solution or suspension from a solvent and an amorphous
solid comprising the chemical substance.
47. A method of screening a chemical substance for possible solid
forms, said method comprising the steps of: providing a chemical
substance in a plurality of samples; sonicating at least one of the
samples, wherein at least one other sample is unsonicated;
solidifying the samples of the chemical substance; and determining
whether one or more solid forms of the chemical substance were
generated.
48. A method of generating the most stable form of a chemical
substance, said method comprising the steps of: providing a sample
of the chemical substance in a solvent; sonicating the sample at a
predetermined supersaturation level; and crystallizing the chemical
substance from the sample; wherein the crystallized chemical
substance is the most stable solid form of the chemical substance
relative to known solid forms of the chemical substance.
49. A method of generating a solid form of a chemical substance
from a meta stable solution, said method comprising the steps of:
forming a metastable solution of the chemical substance in a
solvent; sonicating the metastable solution; and crystallizing the
chemical substance from the solution.
50. A method of obtaining a substantially pure solid form of a
chemical substance, said method comprising the steps of: providing
a sample of the chemical substance in a solvent; sonicating the
sample at a predetermined supersaturation level; and crystallizing
the chemical substance from the sample; wherein a substantially
pure solid form of the chemical substance is crystallized.
51. A method of preparing a solvate of a chemical substance, said
method comprising the steps of: providing a sample comprising the
chemical substance and a solvent; sonicating the sample; and
generating a solid from the sample, wherein the solid comprises a
solvate of the chemical substance and the solvent.
52. A method of screening for possible cocrystals comprising an
active agent, said method comprising the steps of: providing a
plurality of samples, each sample comprising the active agent and
one or more guests, wherein the plurality of samples contains the
same or different guests; sonicating the samples; crystallizing the
active agent and the guest from the samples; and determining
whether a cocrystal was generated in one or more of the
samples.
53. The screening method of claim 52, wherein at least one sample
contains a different guest than at least one other sample.
54. The screening method of claim 52, wherein each sample contains
a different guest.
55. The screening method of claim 52, wherein the sonicating step
and the crystallizing step at least partially overlap.
56. The screening method of claim 52, wherein the samples are
placed in a well plate and sonicated in the well plate.
57. The screening method of claim 52, wherein the samples are
supersaturated with respect to at least one of the active agent and
the guest before the sonicating step.
58. The method of claim 52, wherein at least some of the samples
comprise more than one solvent.
59. The method of claim 52, wherein the samples are sonicated by at
least one ultrasound pulse.
60. The method of claim 52, wherein at least one of the samples is
sonicated by a series of ultrasound pulses, each pulse having a
duration of from about 0.1 second to about 10 seconds.
61. The method of claim 52, wherein at least one of the samples is
sonicated at least once for at least about 1 minute.
62. The method of claim 52, wherein at least one of the samples is
sonicated at least once for at least about 5 minutes.
63. The method of claim 52, further comprising the step of
determining whether a cocrystal was generated using an analytical
method selected from the group consisting of visual analysis,
microscopic analysis, thermal analysis, diffraction analysis, and
spectroscopic analysis.
64. The method of claim 52, further comprising the step of
determining whether a cocrystal was generated using x-ray
diffraction analysis.
65. The method of claim 52, further comprising the step of
determining whether a cocrystal was generated using Raman
spectroscopic analysis.
66. The method of claim 52, wherein at Least one new solid state
phase is formed by the crystallizing step.
67. The method of claim 52, further comprising crystallizing at
least one unsonicated sample that is substantially the same as at
least one sonicated sample.
68. A method of preparing a cocrystal comprising an active agent
and a guest, said method comprising the steps of: providing a
sample of an active agent and a guest; sonicating the sample; and
crystallizing a cocrystal from the sample, the cocrystal comprising
the active agent and the guest.
69. The method of claim 68 wherein the active agent is an active
pharmaceutical ingredient.
70. The method of claim 68, wherein the active agent is provided as
a salt in the sample.
71. The method of claim 70, wherein the salt comprises
chloride.
72. The method of claim 68, wherein the guest is a salt.
73. The method of claim 68, wherein the guest is an organic
acid.
74. The method of claim 68, wherein the active agent is not a
salt.
75. The method of claim 68, wherein the active agent is neutral or
zwitterionic.
76. The method of claim 68, wherein the sample comprises a solvent
selected from the group consisting of acetone, acetonitrile,
chloroform, 1,4-dioxane, ethanol, ethyl acetate, heptane,
2-butanone, methanol, nitromethane, tetrahydrofuran, toluene,
water, dichloromethane, diethyl ether, isopropyl ether,
cyclohexane, methylcyclohexane, isopropyl alcohol,
trimethylpentane, n-octane, trichloroethane, trifluoroethanol,
pyridine, 1-butanol, tetrachloroethylene, chlorobenzene, xylene,
dibutyl ether, tetrachloroethane, p-cymene, dimethyl sulfoxide,
formamide, and dimethylformamide.
77. The method of claim 68, wherein the sample comprises more than
one solvent.
78. The method of claim 68, wherein the sample comprises more than
one guest.
79. The method of claim 68, wherein at least one of the samples is
sonicated by at least one ultrasound pulse.
80. The method of claim 68, wherein at least one of the samples is
sonicated by a series of ultrasound pulses, each pulse having a
duration of from about 0.1 second to about 10 seconds.
81. The method of claim 68, wherein at least one of the samples is
sonicated at least once for at least about 1 minute.
82. The method of claim 68, wherein at least one of the samples is
sonicated at least once for at least about 5 minutes.
83. The method of claim 68, wherein the sonication is substantially
continuous during the crystallization step.
84. A method of cocrystallizing two or more components, said method
comprising the steps of: (a) determining a concentration for two or
more components in a sample effective for cocrystallization of the
components; (b) preparing the sample comprising the components,
said sample having an effective concentration of the components;
(c) sonicating the sample; and (d) generating a cocrystal from the
sample, the cocrystal comprising the components.
85. The method of claim 84, wherein the components comprise an
active agent and a guest.
86. A method for speeding the cocrystallization of an active agent
and a guest comprising: providing a sample in an effective volume;
sonicating the sample; cocrystallizing said active agent and said
guest from the sample; wherein the rate of cocrystallization is
increased by at least 25%.
87. The method of claim 84, wherein the sample is a metastable
solution.
88. A method for screening for possible salts comprising an
ionizable active agent, said method comprises: providing a
plurality of samples comprising an ionizable active agent and one
or more counterions, wherein the plurality of samples contains the
same or different counterions; sonicating the samples; forming one
or more crystallized salt compounds from the samples, said
crystallized salt compounds comprising the ionizable active agent
and the counterions.
89. The method of claim 88, wherein at least one sample contains a
different counterion than at least one other sample.
90. The method of claim 88, wherein the plurality of samples
comprises a plurality of sets, and the sets differ in having
different counterions, and the samples within each set have the
same counterion.
Description
FIELD OF THE INVENTION
[0001] The present disclosure relates to crystallizing a chemical
substance using ultrasound. Methods are provided for screening a
chemical substance according to its solid forms by using ultrasound
to generate new or unusual solid forms. Methods are also provided
for crystallizing a chemical substance by novel techniques that
include sonication. The present disclosure also relates to
cocrystallization using ultrasound. Methods are provided for
preparing cocrystals of an active agent and a guest by sonicating
and crystallizing. Methods are also provided for screening a sample
according to solid state phases (such as cocrystals and salts) and
include generating a cocrystal from the sample using
ultrasound.
BACKGROUND OF THE INVENTION
[0002] Chemical substances (compounds, elements, and mixtures) have
properties which tend to be unpredictable and variable. Certain
chemical substances may have utility for numerous different
applications, including vital biological applications, yet a slight
change may reduce or eliminate the utility or beneficial purpose.
Similarly, certain chemical processes may have better or worse
performance based upon minor differences.
[0003] An active agent may be provided in a variety of solid state
phases. For example, it may be provided as a crystal of the pure
compound. Alternatively, the active agent may be provided as a
salt. Alternatively, the active agent may be provided as a
cocrystal with another compound.
[0004] Cocrystals are crystals that contain two or more
non-identical components (for example, two non-identical
molecules). The properties of cocrystals may be the same or
different than the properties of the individual components or
mixtures of crystals of the individual components. Examples of
cocrystals may be found in the Cambridge Structural Database.
Examples of cocrystals may also be found at Etter et al., "The use
of cocrystallization as a method of studying hydrogen bond
preferences of 2-aminopyridine" J. Chem. Soc., Chem. Commun.
589-591 (1990); Etter, et al., "Graph-set analysis of hydrogen-bond
patterns in organic crystals" Acta Crystallogr., Sect. B, Struct.
Sci. B46 256-262 (1990); Etter, et al., "Hydrogen bond directed
cocrystallization and molecular recognition properties of
diarylureas" J. Am. Chem. Soc 112 8415-8426 (1990); which are
incorporated herein by reference in their entireties. The following
articles are also incorporated herein by reference in their
entireties: Gorbotz, et al., "On the inclusion of solvent molecules
in the crystal structures of organic compounds" Acta Cryst. B56
625-534 (2000); and Kumar, et al., "Molecular Complexes of Some
Mono- and Dicarboxylic Acids with trans-1,4,-Dithiane-1,4-dioxide"
American Chemical Society, Crystal Growth & Design, Vol. 2, No.
4 (2002). Additional information and details regarding
cocrystallization may be found in U.S. application Ser. No.
10/763,987, "Novel Cocrystallization," filed Jan. 21, 2004, which
is incorporated by reference herein.
[0005] A salt is a compound formed when the hydrogen of an acid is
replaced by a metal or its equivalent (e.g., an NH.sub.4.sup.+
radical). Hawley's Condensed Chemical Dictionary, p. 977 (14.sup.th
Ed. 2001). In a salt one or more ionic bonds are formed. In a
cocrystal, two or more compounds retain their own chemical
identities, and no new ionic or covalent bonds are formed, although
hydrogen bonds or other interactions may hold different compounds
to each other.
[0006] The identification of a desirable solid state phase for an
active agent 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.
[0007] In particular, the pharmaceutical industry spends a great
deal of time, effort and expense on the identification of
particular compounds, mixtures and formulations that will have
beneficial effect. Research is done as to whether such compounds,
mixtures and formulations will be safe and effective. Slight
differences in chemical composition or structure may yield
significant differences in biological activity. Thus, researchers
frequently test many different compounds, mixtures and formulations
for biological activity and other effects as well as testing
different processes and conditions for the preparation of such
chemical compounds and mixtures.
[0008] The process of thorough analysis of different chemical
compounds, mixtures, formulations, processes, or structures is
commonly referred to as screening. Screening is partially a
function of time and effort, with the quality or results of
screening being related to the number of samples prepared and/or
analyzed as well as the quality of preparation and/or analysis
underlying those samples. To that end, it is frequently an
objective with screening processes to increase the number of
samples and decrease the amount of each sample used for analysis.
Screening plays a vital role in the pharmaceutical field, as the
most advantageous compound, mixture or formulation is frequently
found through successful screening processes.
[0009] In some screening processes, variations are introduced in
order to see the result(s), if any, of such variations, or to
confirm that variations do not lead to substantially different
results. Generally, at least two samples of a screened chemical
substance (in other words, a compound, element, or mixture that is
the subject of the screening process) are subjected to differing
parameters, and one or more properties of the samples are
determined to see whether the differing parameters caused different
results.
[0010] Processes have been used for screening chemical compounds
according to their solid form. When a compound has different solid
forms, the different forms are frequently referred to as polymorphs
of that 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 it may exist as different hydrates or solvates.
[0011] The solid form of a chemical substance may have an impact on
biological activity. The same chemical compound may exhibit
different properties depending upon whether it is in an amorphous,
crystalline or semisolid state. A semisolid as used herein
indicates materials like waxes, gels, creams, and ointments.
Furthermore, a chemical compound may exist in different solid forms
within the different states, and those different solid forms may
also exhibit different properties. For example, there may be
several different crystalline solid forms of a substance, the
different crystalline solid forms having different properties. As
another example, a substance may have different amorphous forms,
the amorphous forms having 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, or other possible solid forms, 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.
[0012] It is desirable in the pharmaceutical field as well as other
fields to find the solid form of a chemical substance that exhibits
desired 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 absorption characteristics or in
other ways be more suitable for delivery of therapeutic doses than
other forms. It is frequently desirable within a screening process
to generate, or at least search for, all or most of the possible
solid forms of a compound. Past attempts to generate a variety of
solid forms included flash evaporations, cooling under different
conditions and/or the addition of seeds of solid material. However,
some materials strongly resist the generation of some of their
possible solid forms.
[0013] It is desirable in many fields to find a solid state phase
of an active agent that exhibits desired physical and chemical
properties. One solid state phase may be more stable or have other
properties that make it preferable over other solid state phases.
One solid state phase may have better bioavailabilty, solubility,
or absorption characteristics or in other ways be more suitable for
delivery of therapeutic doses than other forms. It is frequently
desirable within a screening process to generate, or at least
search for, all or most of the possible solid state phases of a
compound.
[0014] One or more solid forms may be generated by crystallization
of a sample. One or more solid state phases may be generated by
cocrystallization of a chemical substance with different guest
molecule(s).
[0015] 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. Growth is the enlargement of crystals caused by
deposition of molecules on an existing surface.
[0016] Nucleation may be induced by the presence of "seed"
crystals. 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.
Nucleation may also be promoted by external or nonchemical means,
such as stirring the crystallization environment, or by applying
ultrasound to the crystallization environment.
[0017] As mentioned above, ultrasound has been applied to promote
nucleation. For example, U.S. Pat. No. 6,630,185 discusses a
process for the crystallization of a solid phase from a liquid,
characterized in that the liquid during crystallization is
subjected to ultrasound in the absence of transient cavitation.
According to this patent, it has been known since 1927 that
exposing supercooled melts or supersaturated solutions of various
substances to ultrasound has an influence on the nucleation and/or
the growth of crystals. The effect is referred to as
sonocrystallisation. A particular aspect of sonocrystallisation is
sononucleation. It deals with the initiation of crystal formation,
has been studied extensively with sugar and is applied since the
late 1950's. Sonocrystallisation of supercooled water, supercooled
metal melts and supersaturated solutions of various inorganic
materials are said to have received a lot of attention.
[0018] U.S. Patent Application Publication No. 20030051659 A1
discusses a process for crystallizing small particles with a narrow
particle size distribution. The crystals are obtained by
introducing ultrasound into a solution or suspension of the
substance to be crystallized while simultaneously adjusting a
specific stirring power. U.S. Patent Application Publication No.
20030166726 A1 discusses a method for reducing the particle size of
amino acid crystals using ultrasound.
[0019] U.S. Patent Application Publication No. 20020054892 A1
discusses a method of inducing solidification in a fluid
composition comprising a cosmetic active, a crystalline organic
structurant and a carrier. The method comprises exposing the fluid
composition to ultrasound or converting the composition to a soft
solid.
[0020] U.S. Pat. No. 5,830,418 discusses a method of using
ultrasound to promote crystallization of solid substances contained
in a flowable material. A flowable material, such as a supercooled
melt or supersaturated solution, is dispensed onto a take-up member
such as a belt or drum. Either prior to, or after being dispensed
onto the take-up member, the material is exposed to ultrasound to
promote the crystallization of solid substances in the
material.
[0021] None of the foregoing references discloses the use of
ultrasound as a variable parameter in a screening method to
identify the various solid forms of a chemical substance.
[0022] There is a continued need to improve screening methods that
identify all or a high percentage of possible forms of a chemical
substance. There is also a need for improved methods of selectively
generating the desired form of a chemical substance.
[0023] There is a continued need to improve screening methods that
identify all or a high percentage of possible solid state phases of
a chemical substance. There is also a need for improved methods of
selectively generating solid state phases, including cocrystals, of
a chemical substance.
SUMMARY OF THE INVENTION
[0024] As one aspect, a method is provided for screening a chemical
substance for possible solid forms. The method comprises the steps
of providing a chemical substance in a plurality of samples,
sonicating at least one of the samples, and solidifying the
chemical substance from the samples. The samples will usually be
provided as a solution, suspension, melt, or other mixture of the
chemical substance in one or more solvents. The screening method
may comprise providing a first sample of the chemical substance in
a first solvent, and a second sample of the chemical substance in a
second solvent. The method may also comprise determining whether
one or more solid forms of the chemical substance were
generated.
[0025] As another aspect, a method is provided for crystallizing a
chemical substance. This method is beneficial for searching for
and/or generating new or unusual solid forms of a chemical
substance. The method comprises forming an emulsion comprising two
or more substantially immiscible solvents and the chemical
substance by applying ultrasound to a mixture of said solvents and
the chemical substance. The chemical substance is in solution in
one or both of the solvents. The method also comprises
crystallizing the chemical substance from the emulsion.
[0026] As yet another aspect, a method of crystallizing a chemical
substance is provided. The method comprising the steps of providing
a sample of the chemical substance in a solvent, sonicating the
solution or suspension at a predetermined supersaturation level,
and crystallizing the chemical substance from the sample.
[0027] As another aspect, a method is provided for generating the
most stable form of a chemical substance. The method comprises the
steps of providing a sample of the chemical substance in a solvent,
sonicating the sample at a predetermined supersaturation level, and
crystallizing the chemical substance from the sample, and the
crystallized chemical substance is the most stable solid form of
the chemical substance relative to known solid forms of the
chemical substance.
[0028] As a further aspect, a method is provided for generating a
solid form of a chemical substance from a metastable solution (a
solution in which the chemical substance remains in solution
indefinitely or for relatively long periods). The method comprises
forming a metastable solution of the chemical substance in a
solvent, sonicating the metastable solution, and crystallizing the
chemical substance from the solution.
[0029] As yet another aspect, a method is provided for obtaining a
substantially pure solid form of a chemical substance. A
substantially pure solid form of a chemical substance is a solid
that is exclusively or almost exclusively of one solid form or has
little or no other solid forms present. The method comprises the
steps of providing a sample of the chemical substance in a solvent,
sonicating the sample at a predetermined supersaturation level, and
crystallizing the chemical substance from the sample, wherein a
substantially pure solid form of the chemical substance is
crystallized.
[0030] As another aspect, a method is provided for preparing a
solvate of a chemical substance. The method comprises the steps of
providing a sample comprising the chemical substance and a solvent,
sonicating the sample, and generating a solid from the sample,
wherein the solid comprises a solvate of the chemical substance and
the solvent.
[0031] In the present methods, the solidifying step and the
sonicating step may at least partially overlap. In some
embodiments, the solidifying step and the sonicating step may
overlap completely or almost completely. For example, where the
solidifying step comprises evaporating a solvent from the samples,
the method can comprise sonicating at least one of the samples
until the solvent is substantially completely evaporated.
Alternatively, the solidifying step can comprise at least partially
evaporating the solvent from at least one of the samples before
sonicating the sample.
[0032] In the present methods, a solvent can be evaporated (to a
greater or lesser extent) from at least one of the samples before,
during, or after the sonicating step. The present methods may
comprise the step of cooling at least one of the samples before,
during or after the sonicating step. The present methods may
comprise the step of crash-cooling at least one of the samples
before, during or after the sonicating step. The present methods
may comprise a mixture of those actions, for example, the samples
may be cooled followed by sonication and evaporation of the
solvent.
[0033] The sample(s) can be sonicated by sonicating at least once
or more than once. In some embodiments, the samples will be
sonicated by ultrasound pulses. For example, one or more samples
can be sonicated by at least one ultrasound pulse, or by at least 5
ultrasound pulses, or by any number of periodic ultrasound pulses.
In some embodiments, the samples will be sonicated for a period of
time. For example, one or more samples may be sonicated for about 5
to about 40 seconds, for at least about 5 minutes, or for another
suitable time period.
[0034] In the present methods, one or more samples may be sonicated
at least once during the solidification step. In some embodiments,
sonication will be substantially continuous during the
solidification step; in other embodiments, sonication will be
periodic during the solidification step.
[0035] The present methods may also be employed to generate solid
solvates and solid hydrates of the chemical substance.
[0036] In the present methods, a predetermined supersaturation
level of the chemical substance in a solvent may be selected at
which to begin sonication. For example, the predetermined
supersaturation level may be selected to generate a relatively
stable form of the chemical substance, or the most stable form of
the chemical substance, as determined by comparison of the known
solid forms of the chemical substance. The predetermined
supersaturation level can be selected to generate a solvate of the
chemical substance.
[0037] The present methods may comprise adding an antisolvent to a
solution, suspension, emulsion, slurry or other composition of
matter.
[0038] The present methods increase the likelihood of generating
all or a high percentage of possible solid forms of a chemical
substance.
[0039] As another aspect of the present invention, a method is
provided for screening for possible cocrystals comprising an active
agent. The method comprises the steps of providing a plurality of
samples that contain the active agent. Each sample also contains at
least one guest. It is contemplated that the samples may contain
the same guest or a different guest. In a screening method, the
samples will usually contain several different guests being used to
evaluate different cocrystals (different solid state phases). The
samples are sonicated, and the active agent and the guest are
crystallized from the samples. The method comprises determining
whether a cocrystal was generated in one or more of the samples.
The method can also comprise analyzing the crystallized samples to
determine one or more properties.
[0040] As another aspect, a method is provided for preparing a
cocrystal comprising an active agent and a guest. The method
comprises providing a sample of an active agent and a guest. The
sample is sonicated, and a cocrystal of the active agent and the
guest is crystallized from the sample.
[0041] As yet another aspect, a method is provided for screening
for possible solid state phases, including salts, of an ionizable
active agent and a counterion and optionally a guest. The method
comprises providing an ionizable active agent and a counterion in a
plurality of samples. An ionizable agent is an agent that can be
ionized or has already been ionized; an ionizable agent is one that
can be used to forming an ionic bond with a counterion. The samples
are sonicated, and the ionizable active agent and the counterion
form a salt and crystallize from the samples. The method further
comprises determining whether a salt was generated in one or more
of the samples.
[0042] As yet another aspect, a method is provided for screening
for possible salts comprising an ionizable active agent. The method
comprises providing a plurality of samples comprising an ionizable
active agent and one or more counterions. The samples are
sonicated, and one or more crystallized salt compounds are formed
from the samples. The crystallized salt compounds comprise the
ionizable active agent and the counterions. The plurality of
samples may contain the same or different counterions. For example,
at least one sample may contain a different counterion than at
least one other sample. As another example, the plurality of
samples can comprise a plurality of sets, where the sets differ in
having different counterions, and the samples within each set have
the same counterion.
[0043] The present techniques may be utilized in methods for
screening an ionizable active agent according to its possible solid
state phases, including cocrystals and/or salts. Such methods can
comprise providing an ionizable active agent and one or more
counterions in a plurality of samples, sonicating the sample(s),
and forming a crystallized salt compound comprising the active
agent and counterion. Suitable counterions include but are not
limited to the cations or anions set forth in the present
disclosure. Using the present techniques provides a greater
likelihood of generating possible salts of the ionizable active
agent. Moreover, a salt developed by such a method may be employed
in connection with the methods described herein which relate to
cocrystals comprising a salt and a guest.
[0044] As yet another aspect, a method is provided for
cocrystallizing two or more components, such as an active agent and
a guest. The method comprises determining a concentration for two
or more components in a sample effective for cocrystallization of
the components. A sample is prepared which comprise the components,
in an effective volume and an effective concentration. The sample
is sonicated and a cocrystal is generated from the sample. The
cocrystal comprises the components.
[0045] The present methods may be used to form at least one new
solid state phase of an active agent, including new solid state
phases of active pharmaceutical ingredients. This can provide
substantial benefits to the pharmaceutical industry and the public
at large.
[0046] In the foregoing methods, the sonicating step and the
crystallizing step will usually overlap at least partially. The
samples may become supersaturated with respect to at least one of
the active agent and the guest before, during or after the
sonicating step. In the present methods, each of the samples may
comprise more than one solvent, more than one active agent, and/or
more than one guest.
BRIEF DESCRIPTION OF THE FIGURES
[0047] FIG. 1 is an x-ray powder diffraction (XRPD) pattern of
sulfathiazole solidified from an acetonitrile solution which was
sonicated.
[0048] FIG. 2 is an XRPD pattern of sulfathiazole solidified from
an acetonitrile solution which was not sonicated.
[0049] FIG. 3 is an XRPD pattern of sulfathiazole solidified from
an acetone solution which was sonicated.
[0050] FIG. 4 is an XRPD pattern of sulfathiazole solidified from
an acetone solution which was not sonicated.
[0051] FIG. 5 is an XRPD pattern of carbamazepine solidified from a
DMSO solution which was sonicated.
[0052] FIG. 6 is an XRPD pattern of sulfathiazole solidified from a
methylethylketone solution which was sonicated.
[0053] FIG. 7 is an XRPD pattern of sulfathiazole solidified from
an ethanol/p-cymene emulsion.
[0054] FIGS. 8(a) and (b) illustrate a crystal structure of an
active agent and a cocrystal structure containing the same active
agent with a guest.
[0055] FIGS. 9 (a) and (b) are drawings of two-dimensional and
three-dimensional models of a cocrystal of fluoxetine HCl and
benzoic acid (1:1).
[0056] FIG. 10 shows examples of general classes of guests.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0057] Ultrasound generally refers to sound vibrations beyond the
limit of audible frequencies. Ultrasound is often used to refer to
sound vibrations having a frequency of about 20 kHz or more. In
many applications where ultrasound is used, the frequencies are in
the range of 20 kHz to 5 MHz. However, the definition of ultrasound
as having a frequency greater than 20 kHz is related to the average
perception limit of the human ear rather than to industrial
applications. The benefits of the present methods may be obtained
with frequencies below 20 kHz. In the context of the present
specification, ultrasound refers to sound vibrations having a
frequency in the range of from about 10 kHz to about 10 MHz.
However, for certain applications, ultrasound having frequencies in
narrower ranges (such as, for example, from about 20 kHz to about 5
MHz or from about 40 kHz to about 2.5 MHz) may be desired.
[0058] The terms sonicate and sonication are frequently used to
refer to the application of ultrasound. A sample (for example, a
solution or suspension) may be sonicated in a variety of ways, and
may be sonicated continuously or by one or more pulses. For
example, a sample may be sonicated by a series of ultrasound
pulses, each pulse having a duration of from about 0.1 second to
about 10 seconds. As another example, the sample may be sonicated
at least once for at least about 5 minutes. In the present methods,
where a method requires sonication or sonicating, it requires at
least one pulse of ultrasonic energy which is generally on the
order of seconds (for example, applying ultrasonic energy for 1
second or less, 5 seconds, 10 seconds or more). When a solution,
suspension, solvent or other composition is sonicated "while" or
"during" some other step or time period, it means at least one
pulse is applied--it does not necessarily mean there is sonication
over the entire step or period, although in some circumstances, it
can be desirable to sonicate periodically or continuously
throughout substantially an entire step or over substantially all
of a time period, or for some portion of the step or period. For
example, in some of the present techniques, it is stated that a
solution is sonicated while a solvent is evaporated. Sonication in
this situation may be a single pulse (for example, 5 seconds) to a
solution, as well as multiple pulses or continuous sonication of a
solution over substantially the entire time period of evaporation,
or any application of ultrasound in between.
[0059] Ultrasound can be applied to a chemical substance or a
sample by conventional techniques such as by immersing a receptacle
containing the chemical substance or the sample in an ultrasonic
bath, or by placing the tip of an ultrasonic probe directly into
the sample. Sonication may be performed using commercially
available equipment. For example, a quarter-inch diameter (6 mm)
ultrasonic probe operating at 20 kHz and a power input of 130 watts
has been found convenient, but there will be many other
commercially available devices which are suitable. Lower power
ultrasound apparatus may also be suitable for crystallization.
Suitable ultrasound devices are advertised by Cole-Palmer
Instrument Co., of Vernon Hills, Ill., or Misonix Corporation, of
Farmingdale, N.Y. For larger scale operations, a sonoreactor is
advertised by AEA Technologies of the United Kingdom. Techniques
and equipment include the use of ultrasonic probes or transducers,
which techniques will be familiar to those skilled in the art.
[0060] Where the samples are provided in a well plate, a well-plate
sonicator may be used to sonicate the samples. Sonication of the
sample may be performed using commercially available equipment. For
example, a quarter-inch diameter (6 mm) ultrasonic probe operating
at 20 kHz and a power input of 130 watts has been found convenient,
but there will be many other commercially available devices which
are suitable. As another example, a probe sonicator may be used for
2-5 seconds at 40 mW of power using a 1/8-inch probe. Lower power
ultrasound apparatus may also be suitable for crystallization. The
amount of time and power of the sonication are variable. In the
example described below, sonication times of about 10 to 15 seconds
applied every 5 minutes or so were used with a Misonix well-plate
sonicator at medium power.
[0061] The application of ultrasound to a sample containing a
chemical substance to be crystallized can reduce the Metastable
Zone Width for the sample (for example, a solution containing the
chemical substance and solvent). For example, the sample may have a
metastable zone, and the metastable zone has a width of at least
about 1.degree. C., alternatively at least about 2.degree. C.,
alternatively at least about 5.degree. C., alternatively at least
about 10.degree. C. The application of ultrasound to the sample may
narrow the metastable zone, for example from a width of greater
than about 10.degree. C. to a width of at most about 5.degree. C.,
or by reducing it by at least about 1.degree. C. A reduction of the
Metastable Zone Width offers a way to limit the level of
supersaturation at which nucleation occurs. For a chemical
substance that has two unsolvated polymorphic forms, where one is
stable and one is metastable at a given temperature, the polymorph
of higher free energy (that is, lower stability) has a higher
solubility in any solvent compared to the polymorph of lower
energy. If there is sufficient reduction of the Metastable Zone
Width by application of ultrasound, such that the system becomes
supersaturated with respect to the most stable form while being
undersaturated with respect to the other form, then polymorphic
selection favoring the most stable form will occur. This "zone of
action" may be used in order to increase the chances to generate
the most stable form of a chemical substance. In practice, as
ultrasound does not typically reduce the Metastable Zone Width to
zero, cases may occur where two polymorphs of similar of energy can
be formed. Ultrasound can therefore be used as a tool to increase
the probability of generating the most stable form, when working
under low levels of supersaturation, or selectively crystallizing
the more stable of two solid forms.
[0062] Sometimes the most stable solid form is more difficult to
generate than a less stable form. For example, with the compound
WAY, the yellow form is frequently the first and most common form
generated in screening method using small-scale crystallization and
a variety of solvent mixtures. This may be explained by a faster
nucleation and/or growth rate of the less stable form, compared to
the more stable form.
[0063] The application of ultrasound to a chemical substance to be
crystallized from a solution can induce nucleation of
supersaturated solutions in cases where the substance otherwise
remains indefinitely or for relatively long periods in solution (in
other words, in metastable solution). In this respect, the
application of ultrasound is of considerable interest to find new
solid forms difficult to find due to difficult conditions of
crystallization. For example, the present techniques are beneficial
for crystallization and finding new solid forms from viscous
solutions, or from systems having a large Metastable Zone
Width.
[0064] Sonication generally increases the rate of nucleation in
samples that are sufficiently supersaturated relative to the
desired multi-component phase (the active agent(s) and the
guest(s)). For example, sonication may increase the rate of
cocrystallization by at least about 25%, alternatively at least
about 100%, alternatively at least about 200%. Sonication generally
reduces the activation barrier to nucleation and increases the
number of successfully nucleated samples. The precise nature of the
physical perturbations that cause nucleation when a sample is
sonicated are not known with certainty. While the inventor does not
intend to be bound by theory, it is presently theorized that
entropic contributions may be more significant in multi-component
samples because the independent components must be organized not
only on a molecular level via aggregation through hydrogen bonding,
but also in terms of mass transport. The growth of a cocrystal
requires a consistent addition of a 1:1 mixture (or other fixed
ratio) of the components to the cocrystal structure. Accordingly,
local concentration gradients within the sample are undesirable.
Sonication has a homogenizing effect and may assist in generating a
more homogeneous distribution of the components in the sample.
Thus, sonication is especially well-suited for methods of screening
cocrystals where multiple compounds are to be brought together in a
crystal. Sonication is also well-suited for methods of screening
salts where an ionizable active agent and a counterion are to be
brought together in a crystal.
[0065] Ultrasound may be particularly beneficial where
multi-component crystal growth is nucleation-limited. A system is
nucleation-limited where crystals are generally not observed if
nucleation does not occur during evaporation, and an amorphous
solid results instead. In a nucleation-limited system, if
nucleation occurs, then subsequent growth occurs efficiently and
substantially completely. For example, a combination of fluoxetine
HCl and benzoic acid in a 1:1 molar ratio is nucleation-limited in
solutions of acetonitrile. This is a difficult system to nucleate
and a minimum desired supersaturation level has been identified for
cocrystallization. The minimum desired supersaturation level for
fluoxetine HCl and benzoic acid in a 1:1 ratio in acetonitrite is
about 35 mg/ml. Using the technique disclosed herein, minimum
desired supersaturation levels for other systems can also be
found.
[0066] It has also been discovered that, even with ultrasound, it
is desirable to maintain certain levels of supersaturation in the
sample. In experiments using fluoxetine hydrochloride and benzoic
acid in samples that included acetonitrile as a solvent, it was
observed that sonication had a positive effect on
cocrystallization. When concentrations of above 200 mg/ml of the
mixture of active agent and guest in acetonitrile were used,
sonication consistently nucleated the cocrystal. Between 35 and 100
mg/ml, nucleation could be caused by sonication, but nucleation was
not observed spontaneously in unsonicated samples with
concentrations below 100 mg/ml. Sonication provides a clear
advantage in this case with respect to intermediate
concentrations.
[0067] Experiments at a concentration of about 200 mg/ml nucleated
with sonication using either a probe or a well-plate sonicator.
About 50% of wells nucleated and about 98% of the solids were
cocrystals. In a control experiment without sonication, only about
15% of the wells nucleated, and the solid was benzoic acid rather
than a cocrystal of fluoxetine HCl and benzoic acid.
[0068] The application of ultrasound to the solution or suspension
may narrow the metastable zone, for example, reducing it to less
than 1.degree. C. or from a width of greater than about 10.degree.
C. to a width of at most about 5.degree. C. It appears that
sonication reduces the metastable zone width, causing nucleation at
lower supersaturation levels compared to slow evaporation (SE)
results.
[0069] Sonication can increase the rate of nucleation in systems
where nucleation is slow. Among the advantages of sonication are
that nucleation can occur faster, more completely, and can be
initiated at lower concentrations. In addition, the rapid nature of
the growth is more likely to produce a consistent form (the first
form that nucleates) because of the massive secondary nucleation
that occurs during sonication--one seed becomes many very quickly
due to sonication. Ultrasound can therefore be used as a tool to
increase the probability of generating a cocrystal, to generate
cocrystals more rapidly, and/or to generate cocrystals at
relatively low levels of supersaturation.
[0070] Ultrasound may also be useful as a tool to increase the
probability of generating a crystallized salt, to generate salts
more rapidly, and/or to generate crystallized salts at relatively
low levels of supersaturation.
[0071] The present methods are useful for the generation of new
solid forms as well as for screening a chemical substance according
to its solid forms. The chemical substance may be a compound,
element, or mixture. Chemical substances include organic and
inorganic substances. Examples of chemical substances for use in
the present techniques include, but are not limited to,
pharmaceuticals, dietary supplements, alternative medicines,
nutraceuticals, agricultural chemicals, dyes, explosives, polymer
additives, lubricant additives, photographic chemicals, and
structural and electronic materials. Preferably, the chemical
substance is a pharmaceutical agent. Pharmaceutical agents suitable
for use in the present technique include known pharmaceutical
agents as well as those which may be developed. A pharmaceutical
agent can be a large molecule (in other words, a molecule having a
molecular weight of greater than about 1000 g/mol), such as
oligonucleotides, polynucleotides, oligonucleotide conjugates,
polynucleotide conjugates, proteins, peptides, peptidomimetics, or
polysaccharides. A pharmaceutical agent can be a small molecule (in
other words, a molecule having a molecular weight of about 1000
g/mol or less), such as hormones, steroids, nucleotides,
nucleosides, or aminoacids. Examples of suitable small molecule
pharmaceuticals include, but are not limited to, cardiovascular
pharmaceuticals; anti-infective components; psychotherapeutic
components; gastrointestinal products; respiratory therapies;
cholesterol reducers; cancer and cancer-related therapies; blood
modifiers; antiarthritic components; AIDS and AIDS-related
pharmaceuticals; diabetes and diabetes-related therapies;
biologicals; hormones; analgesics; dermatological products;
anesthetics; migraine therapies; sedatives and hypnotics; imaging
components; and diagnostic and contrast components.
[0072] The chemical substances can have any utility, including
utility as a pharmaceutical agent or other active agent. The
present methods increase the likelihood of determining whether a
chemical substance is polymorphic. A polymorphic chemical substance
is a compound, element, or mixture having more than one solid form.
The form of a compound, element, or mixture refers to the
arrangement of molecules in the solid. The term solid form herein
includes semisolids. Semisolids are materials like waxes,
suspensions, gels, creams, and ointments. 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.
[0073] A chemical compound, element, or mixture may be amorphous,
meaning that it is not characterized by a long-range order of the
molecules. Alternatively (or even to a limited extent within a
mostly amorphous form), a compound, element, 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,
element, or mixture may exhibit different properties depending upon
which solid form that compound, element or mixture is in.
[0074] Examples of compounds having more than one solid form
include 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile
and 4-methyl-2-nitroacetanilide, each of which has different colors
in connection with different forms. Carbon, novobiocin, and
furosemide are also examples of substances having more than one
solid form.
[0075] The present disclosure provides techniques for preparing
cocrystals and for screening a chemical substance according to its
possible solid state phases, in which one or more active agents are
cocrystallized with one or more guests. It has been found that
ultrasound may be used to facilitate cocrystallization and
screening.
[0076] Cocrystals are crystals that contain two or more
non-identical molecules (two or more components) such as an active
agent and a guest. FIGS. 8(a) and (b) illustrate a crystal
structure of an active agent (a one-component crystal) and a
cocrystal structure containing the same active agent with a guest
(a two-component crystal), respectively.
[0077] Generating a variety of solid forms is an object of
screening. A sufficient number of diverse processes and parameters
should be employed to maximize the likelihood that a high
percentage of possible solid forms of a chemical substance is
generated. Samples should be generated under various thermodynamic
and kinetic conditions. In the present methods, sonication is
another parameter that is varied as part of the screening
process.
[0078] 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.
[0079] A mixture is a heterogeneous association of compounds or
elements. The components of a mixture may or may not be uniformly
dispersed.
[0080] The present methods include providing samples comprising the
chemical substance(s). In some embodiments, the samples may contain
the chemical substance(s) alone, for example, in a melt or a
physical mixture. More commonly, the sample will also contain a
solvent(s) in which the active agent(s) and the guest(s) are
dissolved, dispersed or otherwise disposed. The active agent(s) and
the guest(s) may be completely or partially soluble in the
solvent(s) or one or more of them may be substantially insoluble in
the solvents. Accordingly, the sample may be in a solution,
suspension, dispersion, mixture, slurry or emulsion, or other
physical state. The sample's physical state going into the present
methods is not critical to the broader applicability of the present
methods, though in some embodiments, use of particular physical
states for samples can be beneficial, as described in more detail
herein. For example, the present methods may have additional
benefits when the samples are metastable solutions, viscous
solutions, emulsions or slurries.
[0081] In the present methods, the chemical substance is solidified
from the sample using a suitable solidification technique. As used
herein, solidification includes any suitable technique for
preparing a solid from the sample including but not limited to
crystallization.
[0082] The solidification technique(s) employed will depend in part
on the sample(s). The samples may be provided as solutions,
suspensions, melts, slurries, emulsions, or any other composition
of matter which includes the chemical substance.
[0083] Suitable crystallization (solidification) techniques include
cooling, heating, evaporation, addition of an antisolvent, reactive
crystallization, and using supercritical fluids as solvents. A
fluid is an antisolvent with respect to a given solution of a
chemical substance when the chemical substance is less soluble in
that fluid than in the solvent used to form the solution;
preferably, an antisolvent is a fluid in which the chemical
substance is essentially insoluble or has a low solubility.
Reactive crystallization refers to processes where means a chemical
substance is formed from reactants and crystallized substantially
simultaneously, for example, where the reaction is a driving force
toward crystallization. A supercritical fluid is a fluid above its
critical temperature and critical pressure which combines
properties of gases and liquids. Examples of compounds employed as
supercritical fluids include xenon, ethane and carbon dioxide.
[0084] Alternatively, the mechanism by which crystallization 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. Slow 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.
[0085] 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.
[0086] In many embodiments, the samples will comprise the chemical
substance in a solvent. Any suitable solvent can be used. Suitable
solvents include acetone, acetonitrile, chloroform, dioxane,
ethanol, ethyl acetate, heptane, butanone, methanol, nitromethane,
tetrahydrofuran, toluene, water, dichloromethane, diethyl ether,
isopropyl ether, cyclohexane, methylcyclohexane, isopropyl alcohol,
isopropyl acetate, trimethylpentane, n-octane, trichloroethane,
trifluoroethanol, pyridine, propanol, butanol, tetrachloroethylene,
chlorobenzene, xylene, dibutyl ether, methyl-tert-butyl ether,
tetrachloroethane, p-cymene, dimethyl sulfoxide, formamide, and
dimethylformamide. It is also contemplated that the samples may be
provided as the chemical substance in two or more solvents, either
as a homogeneous solution or as an emulsion.
[0087] In the solidifying step, the chemical substance is generally
separated from the solvent though solids such as hydrates or
solvates may be formed which include some solvent molecules. For
example, the solvent may be evaporated either slowly (for example,
evaporating to dryness over a time period of four days,
alternatively two days or more) or quickly (for example,
evaporating to dryness over a time period of 24 hours,
alternatively under two days). By varying the rate of evaporation,
one can introduce desired variability into a screening method. For
example, in a screening method, a first portion of samples can be
subjected to relatively slow evaporation, and a second portion of
the samples can be subjected to relatively fast evaporation.
[0088] In the present methods, ultrasound may be applied at
different stages of a screening process or a crystallization
process (or other solidification process). For example, a solution
which comprises a solute to be crystallized can be sonicated at
some point during the screening process. One may sonicate such a
solution before, during, or after the initiation of cooling of the
solution from an undersaturated, saturated, or supersaturated
state. As other examples, one may sonicate a solution before,
during, or after the beginning of evaporation of solvent, or
before, during, or after the addition of an immiscible antisolvent
to the solution.
[0089] In the present methods, the solidifying step and the
sonicating step can overlap. For example, where the samples are
provided as a solution of the chemical substance in a solvent, the
solidifying step may be performed by evaporating the solvent, and
the sample may be sonicated during that evaporation. Furthermore,
the sonication can be periodic during the evaporation. For example,
the sample can be periodically sonicated for about 20 seconds, and
the periods can be about 30 minutes (in other words, the sample is
sonicated for about 20 seconds every 30 minutes). Furthermore, the
sonication can be a single pulse. For example, the sonication could
be carried out one time for 5 to 40 seconds or multiple times for a
like period, or for other suitable period(s).
[0090] In the present methods, the samples can comprise a solution,
suspension, or melt of the chemical substance. Such a solution,
suspension, or melt will typically be prepared by heating above
room temperature to achieve supersaturation. It may be desirable to
begin cooling the samples (for example, to room temperature) before
the sonicating step. Alternatively, the samples may be cooled and
sonicated at the same time. Alternatively, the method can include
crash-cooling the samples (rapidly lowering the temperature, for
example, by immersing in an ice bath) before the sonicating step.
Alternatively, the samples may be crash-cooled and sonicated at the
same time.
[0091] The present methods can include the step of adding a second
solvent to a solution containing the chemical substance. For
example, the second solvent may be added to facilitate
solidification.
[0092] The solidification step can be initiated by sonication,
and/or it may be initiated by seed materials or other techniques.
In the various embodiments of the present methods, solidification
may start before, during, or after the application of ultrasound.
Frequently solidification will start during sonication and continue
after sonication ceases. In many cases, the solidification and
sonication steps will overlap. For example, sonication may begin
before solidification but continue even after solidification
begins. As another example, solidification may begin before
sonication. As yet another example, the chemical substance may be
sonicated in a pulsing manner throughout the solidification
process. Alternatively, sonication may be employed to initiate
solidification and be discontinued when solidification (such as
nucleation) begins.
[0093] As a broad example, solidification may be performed as
follows: A solution containing a solvent and a chemical substance
(such as a compound, element, or mixture) to be solidified is
disposed in a receptacle, such as a vial, well-plate (such a 96
well plate) or capillary tube. The solution may be formed in the
receptacle or formed outside the receptacle and then placed in it.
The chemical substance 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 receptacle. Through evaporation, the use of an
antisolvent, temperature variation, and/or other suitable means,
the solution reaches a point of supersaturation. The solution is
sonicated, and further evaporation, the use of an antisolvent,
temperature variation, and/or other suitable solidification
technique may be employed. After a suitable amount of time,
solidification progresses until a sufficient amount of solid or
semisolid appears, and is ready for analysis to determine the solid
form.
[0094] The most preferred solidification techniques foster
crystallization of the chemical substance. Suitable crystallization
techniques may be employed with and without ultrasound in the
present methods. Indeed, in a screening method, it may be desirable
that some samples are sonicated and other samples are
unsonicated.
[0095] 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. However, it
is noted that ultrasound may be applied as a way of omitting the
presence of seed crystals.
[0096] In other embodiments of the present methods, solids are
generated other than by crystallization. The sample may be provided
as a melt that is then added to the receptacle or may be provided
within the receptacle and melted therein and allowed to solidify in
an amorphous form.
[0097] Another technique for crystallizing a chemical substance
employs an emulsion. An emulsion is a mixture of two or more
immiscible liquids where one liquid is in a discontinuous phase
within the other liquid. Emulsions are frequently formed and/or
stabilized by the use of agents called emulsifiers. However,
sonication of an immiscible mixture of solvents also allows the
generation of emulsions.
[0098] The present methods may also include the step of forming an
emulsion comprising two or more substantially immiscible solvents
and the chemical substance. The emulsion can be formed during the
sonicating step, wherein an immiscible mixture of said solvents is
sonicated to form the emulsion. Alternatively, the emulsion can be
formed before the sonicating step. Where an emulsion is employed,
the chemical substance can be substantially soluble in one of the
immiscible solvents and substantially insoluble in another of the
immiscible solvents. The chemical substance is in solution in one
or both of the solvents.
[0099] Emulsions can be employed as part of a screening method
and/or solidification method to generate additional solid forms of
a chemical substance. Emulsions can allow interface between the two
solvents over a high surface area. At such interfaces, nucleation
and/or growth of some polymorphs may be favored, based on the
influence of each solvent on the growth of each polymorph.
[0100] An emulsion may be prepared by combining a solution of a
chemical substance in a first solvent with a second solvent,
wherein the first solvent and the second solvent are substantially
immiscible with each other. The combined solvents may then be
sonicated while evaporating, cooling, adding antisolvent, or using
other solidification techniques until a precipitate containing the
chemical substance appears.
[0101] Another technique for crystallizing a chemical substance
employs a slurry. A slurry is a dispersion of solid particles in a
liquid phase. The liquid phase comprises one or more solvents in
which the chemical substance is not completely soluble. The process
of slurrying a metastable form of a chemical substance, aiming at
finding a form of lower solubility in the solvent used, in other
words, a form of lower energy (in the case of the transition
between two unsolvated polymorphs) or a solvated form (in the case
of a transition between an unsolvated form or solvated form from a
different solvent to a solvated form), is foreseen to be
accelerated by the use of ultrasound during the slurrying
process.
[0102] The present methods may also include the step of forming a
slurry comprising a solvent and the chemical substance. The slurry
can be formed during the sonicating step, wherein a mixture of the
chemical substance and the solvent are sonicated to form the
slurry. Alternatively, the slurry can be formed before the
sonicating step.
[0103] It is preferable in a screening method that the generation
of solid forms 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, and with and without sonication. As
another example it is also preferable to prepare solid forms under
different conditions of temperature and pressure, as different
solid forms may be favored by different conditions. In some
embodiments of the screening method, at least one sample is
unsonicated so that the effect of ultrasound on solid form for that
chemical substance can be determined.
[0104] It is also contemplated that the present methods are
advantageous for generating solid forms from viscous solutions. For
example, the present methods may be used with samples that are
solutions having a viscosity greater than about 5 cPoise,
alternatively greater than 10 cPoise, alternatively greater than 20
cPoise, before the solution is sonicated.
[0105] It is also contemplated that the present methods are
advantageous for generating solid forms from amorphous forms of the
chemical substance. Samples can be formed or provided by preparing
a solution from an amorphous solid comprising the chemical
substance and a solvent. The solvent may be sonicated while the
amorphous solid is added to the solvent.
[0106] It is contemplated that, in the context of a comprehensive
screening method, the samples can be divided into subsamples or
sets of subsamples. A multiplicity of subsamples and sets are
useful so that more than one parameter may be varied and the
cumulative effect of multiple varied parameters may be assessed.
For example, a first sample (and/or a second sample) may be divided
into subsamples, such as a first set of subsamples, a second set, a
third set, and a fourth set. The first set and the second set can
comprise a solution of the chemical substance in a first solvent,
such as acetone, while the third set and the fourth set comprise a
solution of the chemical substance in a second solvent, such as
tetrahydrofuran. The first set and the third set can be sonicated,
and the second set and the fourth set can be unsonicated. The
benefit of this method is that the effects of ultrasonic
crystallization on acetone and tetrahydrofuran solutions can be
analyzed and compared.
[0107] Solid forms generated after the solidification and
sonication steps 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 (such as when different forms happen
to have different morphologies), 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 Raman
or 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.
[0108] In a preferred embodiment, the samples are placed in a well
plate and then sonicated. The chemical substances solidify in the
wells of the well plate. The solidified chemical substances are
then analyzed in the well plate or a portion of the well plate. The
solidified chemical substances can be analyzed by any one of the
foregoing analysis techniques, preferably by x-ray diffraction
(such as transmission x-ray diffraction or reflection x-ray
diffraction) and/or by Raman spectroscopy. Well plates may be used
which have a detachable portion, such as a detachable bottom
portion. For example, well plates may be used which have polymer
films, glass plates, or other substrates that are detachable from
another portion of the well plates. Solidified chemical substances
can be analyzed in the well plate or the detachable portion of the
well plate. In particular, x-ray diffraction techniques such as
transmission or reflection x-ray diffraction may be used to analyze
the solidified chemical substances in well plates or the detachable
portion of well plates (for example, the polymer film, glass plate,
or other substrate).
[0109] 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.
[0110] 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.
[0111] 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.
[0112] The present methods can significantly assist in the
identification of the solid form of a chemical substance 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 stability,
bioavailability, solubility, or absorption characteristics. In some
cases, an identified form may have better activity as an active
agent.
[0113] After a chemical substance (including a solution, melt,
emulsion, slurry, suspension, or mixture containing the chemical
substance) is placed in a receptacle, the receptacle may be
centrifuged. Centrifugation may be employed for a variety of
reasons. First, use of a centrifugal evaporator may assist
evaporation while concentrating 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.
[0114] The application of ultrasound to solutions containing
multiple components to be crystallized can induce nucleation in
cases where the components otherwise remain indefinitely or for
relatively long periods in solution (in other words, in metastable
solution). In this respect, the application of ultrasound is of
considerable interest to find new cocrystals and salts which are
otherwise difficult to find. For example, the present techniques
are beneficial for cocrystallization from viscous solutions, or
from systems having a large Metastable Zone Width.
[0115] The present techniques are applicable to cocrystallize two
or more active agents. (It is contemplated that more than one
active agent may be employed in a cocrystal.) An active agent is a
molecule whose activity is desirable or the object of interest. For
example, where the active agent is an active pharmaceutical
ingredient, the pharmaceutical activity of the active agent is
desired or the object of interest. Active agents include organic
and inorganic substances. Examples of active agents for use in the
present techniques include, but are not limited to,
pharmaceuticals, dietary supplements, alternative medicines,
nutraceuticals, agricultural chemicals, dyes, explosives, polymer
additives, lubricant additives, photographic chemicals, and
structural and electronic materials. Preferably, the active agent
is an active pharmaceutical ingredient (API). Pharmaceutical agents
suitable for use in the present technique include known
pharmaceutical agents as well as those which may be developed. A
pharmaceutical agent can be a large molecule (in other words, a
molecule having a molecular weight of greater than about 1000
g/mol), such as oligonucleotides, polynucleotides, oligonucleotide
conjugates, polynucleotide conjugates, proteins, peptides,
peptidomimetics, or polysaccharides. A pharmaceutical agent can be
a small molecule (in other words, a molecule having a molecular
weight of about 1000 g/mol or less), such as hormones, steroids,
nucleotides, nucleosides, aminoacids, acetaminophen, nonsteroidal
anti-inflammatory drugs, and others. Examples of suitable small
molecule pharmaceuticals include, but are not limited to,
cardiovascular pharmaceuticals; anti-infective components;
psychotherapeutic components; gastrointestinal products;
respiratory therapies; cholesterol reducers; cancer and
cancer-related therapies; blood modifiers; antiarthritic
components; AIDS and AIDS-related pharmaceuticals; diabetes and
diabetes-related therapies; biologicals; hormones; analgesics;
dermatological products; anesthetics; migraine therapies; sedatives
and hypnotics; imaging components; and diagnostic and contrast
components.
[0116] The active agent may be provided as a salt. It is
contemplated that one or more salts may be employed in a cocrystal,
according to any of the present techniques. The salt may be
prepared from an ionizable active agent or obtained from a
commercial source. Hydrochloride salts of active pharmaceutical
ingredients, especially of amine APIs, are especially preferred in
the pharmaceutical industry.
[0117] In general, it is contemplated that the present techniques
will have particularly good results as applied to amine HCl salts
as well as other ammonium salts as described in more detail herein.
In ammonium acid salts, the active agent has at least one amine
moiety which is relatively basic (at least one relatively basic
nitrogen), and a salt is formed with an acid that reacts with the
amine moiety. Cocrystals may be then formed between the ammonium
salts and guests which act as hydrogen-bond donors to the salts.
Cocrystals may be formed of chloride salts of APIs, for example
buspirone hydrochloride and fluoxetine hydrochloride.
[0118] While the inventors do not wish to be bound to theory, it is
believed that excellent cocrystals may be formed using
hydrochloride salts and similar salts which are strong hydrogen
bond acceptors yet contain relatively undercoordinated ions.
"Undercoordinated" in this case refers to ions, for example a
chloride ion, that are able to form a number of strong hydrogen
bonds. An undercoordinated counterion may have hydrogen bonds
within a crystal of that salt, but it could form additional
hydrogen bonds in a cocrystal and/or form relatively stronger
hydrogen bonds in a cocrystal with a guest. An ion is
"undercoordinated" when the system is limited in the number of
hydrogen bond donors that are available and bonded to the ion. In
these cases, the extra hydrogen bond acceptor sites are typically
filled by weakly interacting donors such as C--H groups Chloride
ions are strong hydrogen bond acceptors in a crystal structure. In
a crystal structure such as fluoxetine hydrochloride, the chloride
ion coordinates to the two strong hydrogen bond donors available in
the system, and the chloride ion also has three weaker CH--Cl
interactions resulting in a pseudo-octahedral coordination
environment. There is an opportunity for bonding with these
coordination sites, by displacing the weak CH donors that the
chloride has recruited to fill its coordination sphere with
somewhat stronger hydrogen bond donors from a guest such as benzoic
acid, succinic acid, fumaric acid, or another carboxylic acid.
[0119] It is useful in forming cocrystals to recognize that
relatively weak interactions may be replaced by stronger
interactions, even though those stronger interactions may be
relatively weak themselves, compared to other interactions. For
example, an undercoordinated chloride may have one strong hydrogen
bond donor and several weak hydrogen bond donors or two strong
hydrogen bond donors and several weak hydrogen bond donors. In a
cocrystal, weaker interactions may be replaced by stronger
interactions, although those stronger interactions may still be
weaker than the strong interactions (charge-assisted hydrogen
bonds) present in fluoxetine HCl crystals. The strongest
interactions involving chloride ions in crystal structures of
organic salts are the charge assisted hydrogen bonds that
invariably form between the protonated nitrogen base and the
chloride ion. The strongest interactions between neutral molecular
groups and the chloride ion involve acids and the chloride ion.
Carboxylic acids, for instance, have strong interactions with
chloride ions. It can be seen that a combination of carboxylic
acids and hydrochloride salts of nitrogen containing bases are
especially well suited to cocrystal formation (as demonstrated by
the examples included). Furthermore, it can be anticipated that
different combinations of these elements could lead to other
cocrystals. For example, the active molecule of interest may
contain either the neutral carboxylic acid moiety or the protonated
nitrogen. The potential exists to cocrystallize an API having a
neutral carboxylic acid moiety with a guest that is a hydrochloride
salt of a nitrogen-containing organic base.
[0120] It is further contemplated that the nature of the protonated
nitrogen base will affect the potential for cocrystallization.
Numerous strong hydrogen bond donor groups will compete with the
carboxylic acid guest for the open acceptor sites on the chloride
ion. In order to favor cocrystal formation, the nitrogen base is
preferably a tertiary amine because this presents a situation where
only one strong charged hydrogen bond donor exists and thus will
only occupy one site on the chloride acceptor. Additionally,
systems that have only this one tertiary amine and no other strong
donors present an especially favorable system for potential
cocrystallization. Protonated secondary amines with two N--H donor
groups are also favored, although protonated primary amines may
also be used. Special consideration must be taken for systems with
additional strong hydrogen bond donor and acceptor sites in order
to determine the potential for cocrystallization and the optimal
guest molecule type for cocrystallization. The potential for
cocrystallization involving a carboxylic acid and a hydrochloride
salt may be reduced as the number of available strong donors in the
system is increased. Additional guidance as to evaluating
undercoordination particularly in its discussion of nonbonded
motifs may be found in: Scott L. Childs, "Nonbonded Interactions In
Molecular Crystal Structures", Emory Univ., USA, available from
UMI, Order No. DA3009424 (288 pp.), Dissertation Abstract Int. Ref.
B2001, 62(3), 1394 (which is incorporated by reference herein). In
some circumstances, the undercoordination can be determined by
measuring distances, comparing profiles in the Cambridge Structural
Database, measuring the pKa of the donors and acceptors, or
evaluating the ratio of strong hydrogen bond donors to available
acceptors. Other crystal engineering theories may also be used.
[0121] By cocrystallizing an active agent with a guest, one can
create new solid state phases which may have improved properties
over existing solid state phases of that active agent. For example,
new drug formulations comprising salt of active pharmaceutical
ingredients may have superior properties over existing drug
formulations. The active agent and guest will vary depending on the
industry. For example, in the pharmaceutical field, the active
agent or guest may be an API, and the other component of the salt
must be a pharmaceutically acceptable compound. The present
techniques are also applicable to active agents from other fields
including nutraceuticals, agricultural chemicals, pigments, dyes,
explosives, polymer additives, lubricant additives, photographic
chemicals, and structural and electronic materials.
[0122] The present techniques may be employed to generate a wide
variety of cocrystals of active agents and guests. For example, the
present techniques may be used to generate cocrystals of a salt of
an active agent, such as a salt of an active pharmaceutical
ingredient, with a neutral guest. Alternatively, a cocrystal of a
neutral or zwitterionic active agent (or a salt of an active agent)
may be generated with a guest salt, which includes a positive ion
and a negative ion of its own. Where the active agent is provided
in a salt, it may be positively or negatively charged and have a
negative or positive counterion. As an example, for fluoxetine HCl,
the active agent fluoxetine is positively charged by virtue of
accepting a proton from HCl to form a protonated amine, and
chloride is present as a negative counterion. Furthermore, some of
the present methods may be employed with a neutral or zwitterionic
active agent to form a cocrystal with a neutral guest or ionic
guest.
[0123] The present techniques provide an opportunity to create a
stable solid state phase of a hydrochloride salt of an API (or
other active agents) that was previously found to have properties
that were unsuitable for development. Opportunities for continued
development in such a situation have often relied on the fortuitous
formation of a stable hydrate or solvate, but the present
techniques present the ability to systematically examine
alternative formulations of the hydrochloride salt by
cocrystallizing the hydrochloride salt of the API with appropriate
guest molecules.
[0124] Cocrystallization may be an attractive technique for salts
of APIs that have been rejected due to problems relating to
physical properties. Since cocrystals may have different physical
properties than the individual components, APIs with unfavorable
physical properties can be cocrystallized with suitable guest
molecules and the physical properties of the resulting crystalline
solids can be evaluated.
[0125] Cocrystals of fluoxetine HCl provide examples of the
modification of a physical property (solubility) of an API salt.
Cocrystals of fluoxetine HCl:benzoic acid are less soluble and have
a lower dissolution rate than crystals of fluoxetine HCl, while
cocrystals of fluoxetine HCl:succinic acid are more soluble and
have a faster dissolution rate than crystals of fluoxetine HCl.
[0126] Other physical properties of APIs or their salts that may be
modified by forming a cocrystal include: melting point, density,
hygroscopicity, crystal morphology, loading volume,
compressibility, and shelf life. Furthermore, other properties such
as bioavailability, toxicity, taste, phy sical stability, chemical
stability, production costs, and manufacturing method may be
modified by the use of the present cocrystallization
techniques.
[0127] An active agent can be screened for possible cocrystals
where polymorphic forms, hydrates or solvates are especially
problematic. A ne-utral compound that can only be isolated as
amorphous material could be cocrystallized. Forming a cocrystal may
improve the performance of a drug formulation of an active
pharmaceutical ingredient by changing physical properties. Some
APIs are problematic during wet granulation and compression stages.
A bioequivalent cocrystal could rectify this problem.
[0128] An active agent can also be screened for possible salts.
Forming a salt may improve the performance of a drug formulation by
changing physical properties. A salt screen refers to a screening
method in which one attempts to make one or more salts comprising
an active agent under a variety of conditions and/or parameters,
preferably including a variety of different counterions.
[0129] A cocrystal or salt can be used to isolate or purify an
active agent during manufacturing. If it is desirable to identify
the solid state phases of an active pharmaceutical ingredient, then
cocrystallization and/or salt formation may be particularly
desirable.
[0130] The present techniques provide new methods of developing and
screening active pharmaceutical ingredients or other active agents.
Non-toxic cocrystalline forms of neutral active pharmaceutical
ingredients may be prepared, screened, tested, and commercialized.
Furthermore, new types of HCl salt structures may be prepared. The
properties of hydrochloride salts can be tuned and perfected. New,
unique, stable, and marketable phases of hydrochloride salts may be
prepared. One can choose whether to make the formulation more
soluble or less soluble.
[0131] As another aspect, the present techniques may also be used
to remove or reduce the water of hydration, and/or to prepare a
cocrystal substantially free of water of hydration. Water and guest
acids perform a similar role in the stabilization of the crystal
structure. In fact, about 28% of the hydrochloride salts of API in
the Cambridge Structure Database are hydrates, compared to about 8%
of all other organic structures. This indicates an affinity for
hydration. The present techniques both capitalize and rectify this
affinity, in that an affinity for cocrystallization (as evidence by
hydration) is likely indicated, and this affinity for
cocrystallization may be employed for the formation of cocrystals
with a suitable guest, such as an acid, for example a carboxylic
acid. Indeed, in many cocrystals, an acid may have stronger
interactions than water molecules and may displace the water of
hydration during the formation of the cocrystal. Accordingly, the
present techniques provide a method of preparing a cocrystal from a
hydrate. A hydrate of a salt is provided, and the hydrate comprises
water of hydration. A guest is selected to coordinate with the
counterion. Preferably, the guest coordinates more strongly with
the counterion than the water of hydration does. A solution, melt
or physical mixture is prepared which comprises the hydrate and the
guest. The solution or melt is subjected to a crystallization
process, or the physical mixture is subjected to grinding, and a
cocrystal comprising the salt of the active agent and the guest is
formed, and the salt comprises the active agent and a counterion.
Similarly, the present techniques provide a method of preparing a
cocrystal from a solvate. A solvate of a salt is provided, and the
solvate comprises solvent molecules coordinated with the salt. A
guest is selected to coordinate with the counterion. Preferably,
the guest coordinates more strongly with the counterion than the
solvent does. A solution, melt or physical mixture is prepared
comprising the solvate and the guest. The solution or melt is
subjected to a crystallization process, or the physical mixture is
subjected to grinding, and a cocrystal comprising the salt of the
active agent and the guest is formed. The salt comprises the active
agent and a counterion.
[0132] FIGS. 9(a) and (b) are drawings of two-dimensional and
three-dimensional models of a cocrystal of fluoxetine HCl and
benzoic acid (1:1). FIG. 9(a) shows a two-dimensional model in
which the chloride ion interacts with the hydrogens of the amine
group of fluoxetine and of the hydroxyl group of benzoic acid.
Through these interactions, which may be characterized as hydrogen
bonding, fluoxetine hydrochloride and benzoic acid form a
supramolecular structure that may be the basis of a cocrystal. FIG.
9(b) shows a three-dimensional model of the supramolecular
organization of fluoxetine hydrochloride and benzoic acid.
[0133] The present cocrystals may comprise salts other than
chloride salts--the hydrochloride API salts that are listed above
are only a sampling of the relevant compounds because the starting
material need not be a known hydrochloride. Indeed, many relevant
APIs are salts that are not HCl salts because the HCl salt was not
believed to be an appropriate material and a different salt was
commercialized instead. The present techniques may enable one to
employ an HCl salt of an API that is marketed as another type of
salt. Alternatively, it may be desirable to employ a salt other
than an HCl salt, by replacing the HCl or by forming a salt
comprising an active agent that acts as a base with an acid other
than HCl. The following acids provide anionic counterions that
would be used to replace chlorine. These are relatively strong
acids, and include but are not limited to mineral acids, and the
carboxylic acid guest is expected to form one or more hydrogen
bonds with a hydrogen bond acceptor on the anionic counterion. The
list is the conjugate acid that would react with a basic active
agent to form a salt:
[0134] sulfuric acid
[0135] phosphoric acid
[0136] hydrobromic acid
[0137] nitric acid
[0138] pyrophosphoric acid
[0139] methanesulfonic acid
[0140] thiocyanic acid
[0141] naphthalene-2-sulfonic acid
[0142] 1,5-naphthalenedisulfonic acid
[0143] cyclamic acid
[0144] p-toluenesulfonic acid
[0145] maleic acid
[0146] L-aspartic acid
[0147] 2-hydroxy-ethanesulfonic acid
[0148] glycerophosphoric acid
[0149] ethanesulfonic acid
[0150] hydroiodic acid
[0151] The present techniques also extend beyond salts as starting
materials and also include many weak bases that may have been
marketed as neutral forms because the known salts did not have
appropriate properties. These salts could be revisited and attempts
could be made to cocrystallize the HCl salt. For example, a drug
formulation marketed as a tartrate salt of an API could be
reformulated by cocrystallizing the HCl salt of the active molecule
with an appropriate guest molecule. Thus, cocrystallization could
make a useful HCl cocrystal out of the API that is currently
marketed as a tartrate, sulfate, or other salt formulation. For
this reason the present disclosure includes APIs that are not HCl
salts as starting materials.
[0152] Furthermore, the present techniques relate to salts other
than chloride salts. It is contemplated that hydrobromide salts and
sodium salts of APIs may especially benefit from the present
techniques, since they form relatively strong nonbonded
interactions. For example, the hydrobromide salts citalopram
hydrobromide and galantamine hydrobromide are contemplated for
cocrystallization with benzoic acid, succinic acid, and other
guests compatible with hydrochloride salts.
[0153] The present techniques may be employed to form cocrystals of
sodium salts of APIs such as, for example, naproxen sodium,
tolmetin sodium, and warfarin sodium. When a sodium salt (or other
salt of an API having a positive counterion) is employed, different
guests are expected to be suitable for cocrystallization than when
a hydrochloride salt (or other anionic salt) of an API is
employed.
Anions and Cations
[0154] As one aspect, the active agent is provided as a salt. The
salt of the active agent may be formed as part of sample
preparation or separately. Alternatively or additionally, the guest
is provided as a salt or a salt of the guest is formed. The salt
may comprise the active agent and a counterion that is either a
cation or an anion. Among the preferred cations (including cations
as well as compounds that can form cations) are aluminum, ammonium,
benzathine, calcium, diethanolamine, diethylamine, dimeglumine,
disodium, lithium, lysine, magnesium, meglumine, potassium, sodium,
and zinc. Among the preferred anions are acetate, L-aspartate,
besylate, bicarbonate, carbonate, D-camsylate, L-camsylate,
citrate, edisylate, fumarate, gluconate, hydrobromide/bromide,
hydrochloride/chloride, D-lactate, L-lactate, DL-lactate,
D,L-malate, L-malate, mesylate, pamoate, phosphate, succinate,
sulfate, D-tartrate, L-tartrate, D,L-tartrate, meso-tartrate,
benzoate, gluceptate, D-glucuronate, hybenzate, isethionate,
malonate, methylsufate, 2-napsylate, nicotinate, nitrate, orotate,
stearate, tosylate, acefyllinate, aceturate, aminosalicylate,
ascorbate, ascorbate, borate, butyrate, camphorate,
camphocarbonate, decanoate, hexanoate, cholate, cypionate,
dichloroacetate, edentate, ethyl sulfate, furate, fusidate,
galactarate (mucate), galacturonate, gallate, gentisate, glutamate,
glutamate, glutarate, glycerophosphate, heptanoate (enanthate),
hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate,
lactobionate, laurate, maleate, mandelate, methanesulfonate,
myristate, napadisilate, oleate, oxalate, palmitate, picrate,
pivalate, propionate, pyrophosphate, salicylate, salicylsulfate,
sulfosalicylate, sulfosalicylate, tannate, terephthalate,
thiosalicylate, tribrophenate, valerate, valproate, adipate,
4-acetamidobenzoate, camsylate, octanoate, estolate, esylate,
glycolate, thiocyanate, and undecylenate.
[0155] When a metal cation is employed as a counterion of the
active agent, the interaction between guest and cation is not a
hydrogen bond but rather is an intermolecular interaction between
an electron rich group such as a carbonyl and the metal cation.
This interaction is often not as strong as a hydrogen bond, but is
still a favorable interaction and thus can contribute to the
stabilization of a cocrystal.
[0156] The HCl salt of an active pharmaceutical ingredient is
especially preferred to create a new type of cocrystal. In this
type of solid state phase, one can cocrystallize the HCl salt with
a neutral guest molecule. By doing this one can create solid state
phases with specific properties. For instance one can make a solid
comprising an active pharmaceutical ingredient having greater or
lesser intrinsic solubility and/or a faster or slower dissolution
rate, depending on the guest compound that is chosen.
[0157] The present techniques may be utilized in methods for
screening an ionizable active agent according to its possible salts
or for preparing a salt comprising an ionizable active agent and a
guest. Such methods can comprise providing a plurality of samples
comprising the active agent and one or more counterions; sonicating
the sample(s); and forming crystallized salt compounds comprising
the active agent and counterions. The counterions may be any of the
cations or anions set forth above or elsewhere in the present
disclosure. Using the present techniques provides a greater
likelihood of generating possible salts of the ionizable active
agent. Moreover, a salt developed by such a method may be employed
in connection with the methods described herein which relating to
cocrystals comprising a salt and a guest.
Guests
[0158] The guest is present in order to form the cocrystal with the
active agent. It is contemplated that one or more guests may be
employed in a cocrystal, according to any of the present
techniques. Accordingly, the guest is not required to have an
activity of its own, although it may have some activity that does
not overly derogate from the desired activity of the active agent.
In some situations, the guest may have the same activity as or an
activity complementary to that of the active agent. The guest may
be another API. For example, some guests may facilitate the
therapeutic effect of an active pharmaceutical ingredient. For
pharmaceutical formulations, the guest may be any pharmaceutically
acceptable molecule(s) that forms a cocrystal with the API or its
salt. The RTECS database is a useful source for toxicology
information, and the GRAS list contains about 2500 relevant
compounds.
[0159] The guest may be neutral (such as benzoic acid and succinic
acid in the examples below) or ionic (such as sodium benzoate or
sodium succinate). Neutral guests are nonionic guests. Ionic guests
are compounds or complexes having ionic bonds. FIG. 10 shows
several general classes of guests (organic bases, organic salts,
alcohols & aldehydes, amino acids, sugars, ionic inorganics,
aliphatic esters & ketones, organic acids, and aromatic esters
& ketones).
[0160] The guest may be an acid that forms hydrogen bonds with the
chloride (or other anion). For example, suitable guests which are
acids include (but not are not limited to):
[0161] ascorbic acid
[0162] glucoheptonic acid
[0163] sebacic acid
[0164] alginic acid
[0165] cyclamic acid
[0166] ethane-1,2-disulfonic acid
[0167] 2-hydroxyethanesulfonic acid
[0168] 2-oxo-glutaric acid
[0169] naphthalene-1,5-disulfonic acid
[0170] nicotinic acid
[0171] pyroglutamic acid
[0172] 4-acetamidobenzoic acid
[0173] Table 8 sets forth a group of presently preferred guests. It
is contemplated that the guests set forth in the Table may be
arranged in subgroups based upon molecular structure and/or
physiological effect. Furthermore, the foregoing list is intended
to provide a written description of any sublist that omits one or
more guests.
[0174] Table 9 sets forth another group of preferred guests. It is
contemplated that the guests set forth in the Table may be arranged
in subgroups based upon molecular structure and/or physiological
effect. Furthermore, the foregoing list is intended to provide a
written description of any sublist that omits one or more
guests.
[0175] Table 10 sets forth the group comprising molecules believed
at present to be suitable guests. It is contemplated that the
guests set forth in the Table may be arranged in subgroups based
upon molecular structure and/or physiological effect. Furthermore,
the foregoing list is intended to provide a written description of
any sublist that omits one or more guests.
[0176] Ionic guests are salts themselves, and may be formed from
bases and acids prior to being used to form cocrystals. For
example, the following bases and acids may be reacted to form ionic
guests:
Bases
[0177] Ammonia
[0178] L-Arginine
[0179] Benethamine
[0180] Benzathine
[0181] Betaine
[0182] Calcium Hydroxide
[0183] Choline
[0184] Deanol
[0185] Diethanolamine
[0186] Diethylamine
[0187] 2-(Diethylamino) ethanol
[0188] 2-Aminoethanol
[0189] Ethylenediamine
[0190] N-Methylglucamine
[0191] Hydrabamine
[0192] 1H-Imidazole
[0193] Lysine
[0194] Magnesium Hydroxide
[0195] Morpholine
[0196] 4-(2-Hydroxyethyl)Morpholine
[0197] Piperazine
[0198] Potassium Hydroxide
[0199] Pyrrolidine
[0200] 1-(2-Hydroxyethyl)Pyrrolidine
[0201] Sodium Hydroxide
[0202] Triethanolamine
[0203] Tromethamine
[0204] Zinc Hydroxide
Acids
[0205] (+)-L-Tartaric Acid
[0206] 1,2, 2-Trimethyl-1,3-cyclopentanedicarboxylic Acid
[0207] 10-Undecylenic Acid
[0208] 1-Hydroxy-2-naphthoic Acid
[0209] (+)-Camphor-10-sulfonic Acid
[0210] 2,5-Dihydroxybenzoic Acid
[0211] 2-Furancarboxylic Acid
[0212] 2-Mercaptobenzoic Acid
[0213] 3-Cyclopentylpropionic Acid
[0214] 3-Phenylpropionic Acid
[0215] 4-Aminosalicylic Acid
[0216] 4-Hydroxybenzoic Acid
[0217] Acetic Acid
[0218] Adipic Acid
[0219] alpha-Hydroxypropionic Acid
[0220] Benzenesulfanic Acid
[0221] Benzoic Acid
[0222] Carbonic Acid
[0223] Cholic Acid
[0224] Citric Acid
[0225] (-)-D-Tartaric Acid
[0226] (+)-D-Camphoric Acid
[0227] (+)-D-Malic Acid
[0228] (+)-L-Malic Acid
[0229] 2,2-Dichloroacetic Acid
[0230] DL-10-Camphorsulfonic Acid
[0231] DL-Glutamic Acid
[0232] DL-Malic Acid
[0233] DL-Tartaric Acid
[0234] Dodecylsulfuric Acid
[0235] Ethanesulfonic Acid
[0236] Ethylenediaminetetraacetic Acid
[0237] Ethylsulfonic Acid
[0238] Fumaric Acid
[0239] Galactaric Acid
[0240] Gallic Acid
[0241] Gluconic Acid
[0242] Glutaric Acid
[0243] Glycolic Acid
[0244] Hippuric Acid
[0245] Hydriodic Acid
[0246] Hydrobromic Acid
[0247] Hydrochloric Acid
[0248] (-)-L-Apple Acid
[0249] (+)-L-Lactic Acid
[0250] (+)-L-Tartaric Acid
[0251] D,L-Lactic Acid
[0252] Lactobionic Acid
[0253] L-Aspartic Acid
[0254] Lauric Acid
[0255] L-Glutamic Acid
[0256] Maleic Acid
[0257] (-)-L-Malic Acid
[0258] Malonic Acid
[0259] D,L-Mandelic Acid
[0260] Methanesulfonic Acid
[0261] Naphthalene-2-sulfonic acid
[0262] n-Butyric Acid
[0263] n-Decanoic Acid
[0264] n-Hexanoic Acid
[0265] Nitric acid
[0266] n-Tetradecanoic Acid
[0267] Octanoic Acid
[0268] Oleic Acid
[0269] Orotic Acid
[0270] Orthoboric Acid
[0271] Oxalic Acid
[0272] 4-Acetamidobenzoic Acid
[0273] Palmitic Acid
[0274] Pamoic Acid
[0275] Phosphoric Acid
[0276] Picric Acid
[0277] Pivalic Acid
[0278] Propionic Acid
[0279] p-Toluenesulfonic Acid
[0280] Pyrophosphoric Acid
[0281] Salicylic Acid
[0282] Stearic Acid
[0283] Succinic Acid
[0284] Sulfosalicylic Acid
[0285] Sulfuric Acid
[0286] Terephthalic Acid
[0287] Thiocyanic Acid
[0288] Valeric Acid
[0289] Valproic Acid
[0290] Typically, suitable guests will have complementary ability
to noncovalently bond to the active agent or its salt, for example
the ability to form hydrogen bonds with the active agent or its
salt. Suitable guests for active agents having negative counterions
include, but are not limited to, compounds having alcohol, ketone,
ester, and/or carboxylic acid functionalities. Suitable guests may
include organic acids, organic bases, organic salts, alcohols,
aldehydes, amino acids, sugars, ionic inorganic compounds,
aliphatic esters and ketones, and aromatic esters and ketones.
[0291] Among the presently preferred neutral guests are those which
are not liquids at room temperature. Also among the presently
preferred neutral guests are carboxylic acids having at least three
carbon atoms, alternatively at least four carbon atoms, and which
do not form solvates. For example, if the following acids were
combined with active agents, the combination would more properly be
considered a solvate than a cocrystal: acetic acid, propionic acid,
and butyric acid. However, in certain embodiments of the present
invention (for example, in certain cocrystals, cocrystallization
methods, and screening methods), the use of solvents and solvates
may still be desirable, and the use of solvents and solvates is not
excluded from the scope of any cocrystal or method except where
explicitly stated.
[0292] In the present methods, the active agent(s) and guest(s) to
be cocrystallized are provided as one or more samples to be used
within the present techniques. The samples may be provided by being
formed, created or prepared as an initial step in the present
methods, or they may be obtained ready-to-use from another
source.
[0293] In some embodiments, the samples may contain the active
agent(s) and the guest(s) alone, for example, in a melt or a
physical mixture. Alternatively, the sample will also contain a
solvent(s) in which the active agent(s) and the guest(s) are
dissolved, dispersed or otherwise disposed. The active agent(s) and
the guest(s) may be completely or partially soluble in the
solvent(s) or one or more of them may be substantially insoluble in
the solvents. Accordingly, the sample may be in a solution,
dispersion, suspension, mixture, slurry or emulsion, or other
physical state. The sample's physical state going into the present
methods is not critical to the broader applicability of the present
methods, though in some embodiments, use of particular physical
states for samples can be beneficial, as described in more detail
herein. For example, the present methods may have additional
benefits when the samples are metastable solutions, viscous
solutions, emulsions or slurries.
Cocrystallization
[0294] In the present methods, the active agent and the guest are
cocrystallized from the sample using a suitable crystallization
technique. As used herein, crystallization includes any suitable
technique for preparing a crystal from the sample.
[0295] The crystallization technique(s) employed will depend in
part on the sample(s). Suitable crystallization techniques include
cooling, heating, evaporation, addition of an antisolvent, reactive
crystallization, and using supercritical fluids as solvents. A
fluid is an antisolvent with respect to a given solution of
components to be cocrystallized when at least one component is less
soluble in that fluid than in the solvent used to form the
solution; preferably, an antisolvent is a fluid in which both
components are essentially insoluble or have a low solubility.
Reactive crystallization refers to processes where a chemical
compound is formed from reactants and crystallized substantially
simultaneously, for example, where the reaction is a driving force
toward crystallization. A supercritical fluid is a fluid above its
critical temperature and critical pressure which combines
properties of gases and liquids. Examples of compounds employed as
supercritical fluids include xenon, ethane and carbon dioxide.
[0296] Alternatively, the mechanism by which crystallization is
accomplished may include gel diffusion methods, thin-layer
deposition methods, or other suitable methods. Other thermodynamic
and kinetic conditions may be employed for cocrystallization. Slow
cooling of a saturated solution is a typical thermodynamic
condition. An addition of a solution of the components to be
cocrystallized to an excess of cold anti-solvent is a typical
kinetic condition.
[0297] Additionally, melt crystallization techniques may be used to
generate a cocrystal. 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 components rather than
a solution. Additionally, the crystallization process may be done
through sublimation techniques.
[0298] In many embodiments, the samples will comprise a solvent.
Any suitable solvent can be used. Suitable solvents include
acetone, acetonitrile, chloroform, 1,4-dioxane, ethanol, ethyl
acetate, heptane, 2-butanone, methanol, nitromethane,
tetrahydrofuran, toluene, water, dichloromethane, diethyl ether,
isopropyl ether, cyclohexane, methylcyclohexane, isopropyl alcohol,
trimethylpentane, n-octane, trichloroethane, trifluoroethanol,
pyridine, 1-butanol, tetrachloroethylene, chlorobenzene, xylene,
dibutyl ether, tetrachloroethane, p-cymene, dimethyl sulfoxide,
formamide, and dimethylformamide. It is also contemplated that the
samples may comprise the components to be cocrystallized in two or
more solvents, either as a homogeneous solution, as an emulsion, or
in another physical state.
[0299] The crystallization may be accomplished in a variety of
ways, and preferably includes evaporation of the solvent(s). For
example, the solvent may be evaporated either slowly (for example,
evaporating to dryness over a time period of four days,
alternatively two days or more) or quickly (for example,
evaporating to dryness over a time period of 24 hours,
alternatively under two days). By varying the rate of evaporation
among separate samples, one can introduce desired variability into
a screening method. For example, in a screening method, a first
portion of samples can be subjected to relatively slow evaporation,
and a second portion of the samples can be subjected to relatively
fast evaporation.
[0300] In the present methods, ultrasound may be applied at
different stages of a screening process or a crystallization
process. For example, a solution which comprises the components to
be cocrystallized can be sonicated at some point during the
screening process. One may sonicate such a solution before, during,
or after the initiation of cooling of the solution from an
undersaturated, saturated, or supersaturated state. As other
examples, one may sonicate a solution before, during, or after the
beginning of evaporation of solvent, or before, during, or after
the addition of an immiscible antisolvent to the solution.
[0301] In the present methods, the crystallizing step and the
sonicating step can overlap. For example, where the samples are
provided as a solution of the components to be cocrystallized in a
solvent, the crystallizing step may be performed by evaporating the
solvent, and the sample may be sonicated during that evaporation.
Furthermore, the sonication can be periodic during the evaporation.
For example, the sample can be periodically sonicated for about 20
seconds, and the periods can be about 30 minutes (in other words,
the sample is sonicated for about 20 seconds every 30 minutes).
Furthermore, the sonication can be a single pulse. For example, the
sonication could be carried out one time for 5 to 40 seconds or
multiple times for a liked period, or for other suitable
period(s).
[0302] In the present methods, the samples can comprise a solution,
suspension (such as a melt), or other mixture of the components to
be cocrystallized. The sample will typically be prepared by heating
above room temperature to achieve supersaturation of the
components. It may be desirable to begin cooling the samples (for
example, to room temperature) before the sonicating step.
Alternatively, the samples may be cooled and sonicated at the same
time. Alternatively, the method can include crash-cooling the
samples (rapidly lowering the temperature, for example, by
immersing in an ice bath) before the sonicating step.
Alternatively, the samples may be crash-cooled and sonicated at the
same time.
[0303] The present methods can include the step of adding a second
solvent to a solution containing the components to be
cocrystallized. For example, the second solvent may be added to
facilitate crystallization.
[0304] The crystallization step can be initiated by sonication, and
it may additionally be initiated by seed materials or other
techniques. In the various embodiments of the present methods,
crystallization may start before, during, or after the application
of ultrasound. In many cases, the crystallization and sonication
steps will overlap. For example, sonication may begin before
crystallization but continue even after crystallization begins. As
another example, crystallization may begin before sonication. As
yet another example, the samples may be sonicated in a pulsing
manner throughout the crystallization process. Alternatively,
sonication may be employed to initiate crystallization and be
discontinued when crystallization (such as nucleation) begins.
[0305] The sample containing two or more components to be
cocrystallized is provided in a receptacle suitable for
crystallization, such as a vial, well-plate or capillary tube. The
sample may be formed in the receptacle or formed outside the
receptacle and then placed in it. The components can initially be
present in the sample below, at or above the point of saturation at
a given temperature at the time of placement in the receptacle.
Through evaporation, the use of an antisolvent, temperature
variation, and/or other suitable means, the sample will reach a
point where crystallization begins. After a suitable amount of
time, when a solid or semisolid appears, the resulting sample (more
particularly, the solid formed from the sample) is ready for
analysis.
[0306] 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. However, it
is noted that ultrasound may be applied as a way of omitting the
presence of seed crystals.
[0307] Another technique for cocrystallizing chemical substances
employs an emulsion. An emulsion is a mixture of two or more
immiscible liquids where one liquid is in a discontinuous phase
within the other liquid. Emulsions are frequently formed and/or
stabilized by the use of agents called emulsifiers. However,
sonication of an immiscible mixture of solvents also allows the
generation of emulsions.
[0308] The present methods may also include the step of forming an
emulsion comprising two or more substantially immiscible solvents
and the components to be cocrystallized. The emulsion can be formed
during the sonicating step, wherein an immiscible mixture of said
solvents is sonicated to form the emulsion. Alternatively, the
emulsion can be formed before the sonicating step.
[0309] Emulsions can be employed as part of a screening method
and/or solidification method to generate additional solid state
phases of an active agent. Emulsions can allow interface between
the two solvents over a high surface area. At such interfaces,
nucleation and/or growth of some solid state phases may be favored,
based on the influence of each solvent on the growth of each solid
state phase.
[0310] An emulsion may be prepared by combining a solution of an
active agent and a guest in a first solvent with a second solvent,
wherein the first solvent and the second solvent are substantially
immiscible with each other. The combined solvents may then be
sonicated while evaporating cooling, adding and antisolvent, or
using other solidification techniques until a precipitate
containing the active agent and the guest appears.
[0311] Another technique for cocrystallizing employs a slurry. A
slurry is a dispersion of solid particles in a liquid phase. The
liquid phase comprises one or more solvents in which at least one
of the active agent and a guest is not completely soluble. The
process of slurrying a metastable form of an active agent and/or
guest, aiming at finding a cocrystal or a solvated form, is
foreseen to be accelerated by the use of ultrasound during the
slurrying process.
[0312] The present methods may also include the step of forming a
slurry comprising a solvent and the active agent and the guest. The
slurry can be formed during the sonicating step, wherein a mixture
of the active agent and the guest and the solvent are sonicated to
form the slurry. Alternatively, the slurry can be formed before the
sonicating step.
[0313] Generating a variety of solid state phases is an important
object of screening. A sufficient number of diverse processes and
parameters should be employed to maximize the likelihood that a
high percentage of possible solid state phases is generated.
Samples should be generated under various thermodynamic and kinetic
conditions.
[0314] It is preferable that the generation of solid state phases
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, and with and without sonication. As another example
it is also preferable to prepare solid forms under different
conditions of temperature and pressure, as different solid forms
may be favored by different conditions.
[0315] It is also contemplated that the present methods are
advantageous for generating solid state phases from viscous
solutions. For example, the present methods may be used with
samples that are solutions having a viscosity greater than about
0.9 poise before the solution is sonicated.
[0316] It is also contemplated that the present methods are
advantageous for generating solid state phases from amorphous forms
of the active agent. Samples can be formed or provided by preparing
a solution from a solvent and an amorphous solid comprising the
active agent. The solvent may be sonicated while the amorphous
solid is added to the solvent.
[0317] It is contemplated that, in the context of a comprehensive
screening method, a plurality of samples can be divided into a
large number of sets and subsets. A multiplicity of sets and
subsets are useful so that more than one parameter may be varied
and the cumulative effect of multiple varied parameters may be
assessed. For example, a plurality of samples may be divided into a
first set, a second set, a third set, and a fourth set. The first
set and the second set can comprise a solution of the active agent
in a first solvent or with a first guest, while the third set and
the fourth set comprise a solution of the active agent in a second
solvent or with a second guest. The first set and the third set can
be sonicated, and the second set and the fourth set can be
unsonicated. The benefit of this method is that the effects of
ultrasonic crystallization with different solvents and/or different
guests can be analyzed and compared.
Detection of Cocrystals and Crystals
[0318] Cocrystals (as well as other crystals) may be detected by
x-ray diffraction analysis, Raman analysis, or other suitable
techniques. The observation of physical properties of a solid
(particularly its melting point) which differ from the physical
properties of the starting materials and the polymorphs and/or
solvates and/or hydrates of the starting materials, is an indicator
that a cocrystal has been formed.
[0319] Cocrystals and other crystals generated after
crystallization and sonication steps 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 (such as when different
forms happen to have different morphologies), 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 Raman or 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.
[0320] In a preferred embodiment, the samples are placed in a well
plate and then sonicated. The chemical substances solidify in the
wells of the well plate (for example, a 96-well plate or 384-well
plate). The solidified chemical substances are then analyzed in the
well plate by one of the foregoing analysis techniques, preferably
by x-ray diffraction (such as transmission x-ray diffraction)
and/or by Raman spectroscopy. A synchrotron may be used as the
source of radiation for conducting diffraction analyses.
[0321] 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 solid state phases that is not
attainable with other x-ray radiation sources.
[0322] The present methods can significantly assist in the
identification of the possible cocrystals of a chemical
substance(s). For example, the present methods can be used as part
of a screening method and can improve the likelihood of identifying
a solid state phase having properties such as better stability,
bioavailability, solubility, or absorption characteristics. In some
cases, an identified cocrystal of an active agent and a guest may
have better biological activity than a crystal of the active
agent.
[0323] After samples (including a solution, emulsion, slurry, or
mixture containing the active agent and guest) are placed in a
receptacle, the receptacle may be centrifuged. Centrifugation may
be employed for a variety of reasons. First, use of a centrifugal
evaporator may assist evaporation while concentrating 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
[0324] In this Example, a new solid form of sulfathiazole was
prepared from solution in acetonitrile using sonication. This form
was not seen without sonication under the same conditions. Form II
of sulfathiazole was generated without sonication.
[0325] A saturated solution of sulfathiazole in acetonitrile at
45.degree. C. was prepared, filtered hot and split between two
pre-heated 1-dram vials (about 1 ml each). The samples were left to
slowly cool to room temperature. One sample was then nucleated by
ultrasound treatment using 5 pulses of one second each at 20 kHz,
amplitude control set at 40, using a Cole Palmer ultrasonic
processor CP130 fitted with a 6 mm tip stainless steel probe, while
the other sample was left undisturbed (unsonicated). Both samples
were then left to evaporate slowly to dryness. XRPD patterns of the
sonicated and unsonicated samples showed that the sonicated sample
gave an unknown pattern (FIG. 1) whereas the unsonicated sample
yielded the known Form II of sulfathiazole (FIG. 2). The sonicated
sample is believed to be a novel solid form of sulfathiazole.
EXAMPLE 2
[0326] In this Example, an unusual solid form of an acetone solvate
of sulfathiazole was prepared. Without sonication, this form was
only seen in a mixture with the known form of an acetone solvate of
sulfathiazole.
[0327] A saturated solution of sulfathiazole in acetone at
45.degree. C. was prepared, filtered hot and split between two
pre-heated 1-dram vials (about 1 ml each). The samples were left to
slowly cool to room temperature. One sample was then nucleated by
ultrasound treatment using 5 pulses of one second each at 20 kHz,
amplitude control set at 40, using a Cole Palmer ultrasonic
processor CP130 fitted with a 6 mm tip stainless steel probe, while
the other sample was left undisturbed (unsonicated). Both samples
were then left to evaporate slowly to dryness. XRPD patterns of the
sonicated and unsonicated patterns showed that the sonicated sample
gave an unknown pattern (FIG. 3) whereas the unsonicated sample
yielded a mixture of this same form with the known acetone solvate
of sulfathiazole (FIG. 4). The sonicated sample is believed to
contain an unusual solid form which is novel in its purity.
EXAMPLE 3
[0328] In this Example, a new DMSO solvate of carbamazepine was
prepared.
[0329] Three 100 .mu.l samples of a saturated solution of
carbamazepine in DMSO at 50.degree. C. were placed in 3 pre-heated
HPLC vials. The samples were allowed to cool to ambient
temperature. One sample was nucleated by ultrasound treatment (5
one-second pulses, 20 kHz, amplitude control set at 40, using the
Cole Palmer ultrasonic processor with a 3 mm tip stainless steel
probe), while another was stirred using a stir bar and the other
was left undisturbed (unsonicated). While the sonicated sample
yielded a new DMSO solvate, the other samples remained as solutions
indefinitely. The XRPD pattern of the new DMSO solvate is shown in
FIG. 5.
EXAMPLE 4
[0330] In this Example, a new form of sulfathiazole was made from a
sonicated supersaturated solution in methylethylketone.
[0331] A saturated solution of sulfathiazole in methylethylketone
at 55.degree. C. was split in 3 pre-heated vials (about 0.5-1 ml
each). The samples were crash-cooled by placing them in an
ice/water bath. One sample was then sonicated for five minutes
(amplitude 20 kHz, amplitude control set at 40, using the Cole
Palmer ultrasonic processor with a 6 mm probe), while another was
stirred using a magnetic stir bar. The last sample was left
undisturbed. The three samples were then placed in the refrigerator
(5-6.degree. C.). While the sonicated sample was found to have
crystallized, the unsonicated samples remained indefinitely as
solutions (still solutions after three weeks). The solids in the
sonicated sample were filtered and an XRPD pattern taken (FIG. 6),
indicative of an unknown form, and it was determined that this
solid was unsolvated according to TGA and DSC scans.
EXAMPLE 5
[0332] In this Example, crystallization of the most stable form of
4-methyl-2-nitroacetanilide was performed on a small scale. The
compound 4-methyl-2-nitroacetanilide is known to crystallize in
three polymorphic forms, White, Amber, or Yellow. The compound is
known as "WAY" due to the colors of its forms. The relative
stability of the three forms has been studied and it was
demonstrated that the white form was the most stable form, and the
yellow form was more stable than the amber form. (See, for example,
Yeadon, PhD thesis, Burnel University, West Yorkshire, UK (1985),
and Xiaorong He, "Thermodynamic and kinetic control of the
crystallization of polymorphs", PhD thesis, Purdue University, West
Lafayette, Ind. USA (2000)). The least stable amber form has rarely
been seen. All three crystal structures have been solved and
published. (See, for example, Moore et al., "Yellow and white
forms", J. Cryst. Spect. Res., 13, 279 (1983), and Moore et al.,
"Amber form", J. Cryst. Spect. Res., 14, 283 (1984).
[0333] Sixty-four evaporative experiments in various solvents and
combinations of solvents (32 sonicated samples and 32 unsonicated
samples) were carried out on the compound WAY.
[0334] A weighed amount of the compound WAY was placed in a vial
and a measured volume (V) of solvent added (solvent 1), so as to
dissolve the solids. In some samples, an additional volume of a
second solvent (solvent 2) was added to the solution. All solutions
were filtered using a 0.2 .mu.m nylon filter and split 4-ways into
4 1-dram vials. The vials were then covered individually with
aluminum foil. The aluminum foil was pierced with one hole for slow
evaporations (SE) and 5 holes for fast evaporations (FE). Half of
the vials were then sonicated twice a day, every day, until
complete evaporation of the solvents. The other half of the vials
were left to evaporate undisturbed. Table 1 summarizes the solvent
conditions used for these evaporations, each set of solvent
conditions being used for four vials (two for samples to be
sonicated while evaporating (SE and FE), two for control
experiments without sonication (SE and FE)). TABLE-US-00001 TABLE 1
Solutions used for crystallization of 4-methyl-2-nitroacetanilide
WAY (mg) Solvent 1 V (S1) Solvent 2 V (S2) 146.3 1,4-dioxane 3 ml
-- -- 149.8 acetone 3 ml -- -- 155.2 tetrahydrofuran 3 ml -- --
149.9 ethanol 10 ml -- -- 147.7 2-butanone 3 ml -- -- 155.6
dichoromethane 1 ml -- -- 146.2 chloroform 1 ml -- -- 155.0
trifluroethanol 1 ml -- -- 151.0 ethyl acetate 3 ml -- -- 148.9
dichloroethane 1 ml -- -- 149.1 pyridine 1 ml -- -- 156.5 methanol
5 ml -- -- 150.2 acetonitrile 2 ml -- -- 144.9 dichloromethane 2 ml
nitromethane 2 ml 155.5 dichloromethane 2 ml heptane 2 ml 146.7
trifluoroethanol 2 ml water 2 ml 154.3 acetone 3 ml toluene 1 ml
146.4 acetone 3 ml water 1 ml
[0335] The results are presented in Table 2, showing the
occurrences of mixtures of the white and yellow solid forms and of
the most stable solid form of the compound, the white form of WAY.
All other solids were the faster growing, less stable yellow form.
These results show that using ultrasound as part of a screening
process can increase the likelihood of obtaining the possible solid
forms of a chemical substance. These results also show that using
ultrasound in a crystallization process can facilitate the
generation of the most stable form of the chemical substance.
TABLE-US-00002 TABLE 2 Sonicated Sonicated Unsonicated Unsonicated
Evaporative SE FE SE FE conditions # of 16 16 16 16 samples Solids
16 16 14 16 White + 5 3 1 1 yellow mixture Pure White 4 2 0 1
Form
EXAMPLE 6
[0336] In this Example, a micro-scale crystallization study was
performed to yield the most stable form of
4-methyl-2-nitroacetanilide (WAY).
[0337] Solutions of WAY were prepared in various solvents by
dissolution of a weighed amount of the solid compound in a measured
volume of solvent (solvent 1). These solutions were then filtered
using a 0.2 .mu.m nylon filter. The weights and volumes used to
prepare each solutions are summarized in Table 3. TABLE-US-00003
TABLE 3 Summary Table Of Experimental Conditions For The
Preparation Of Solutions Of Way WAY (mg) Solvent V (ml) 103.2
chloroform 5.16 107.7 1,4-dioxane 5.37 101.9 acetone 5.1 100.8
tetrahydrofuran 5.04 112.7 ethanol 11.3 105.7 2-butanone 5.27 108.6
acetonitrile 5.43 94.0 methanol 4.7
[0338] Each solution was then used directly or was diluted with a
second solvent in a 3:1 ratio of the first solvent to the second
solvent. Aliquots of 200 .mu.l of the solutions were placed in
wells of a flat bottom polypropylene 96-well plate and covered by a
polypropylene mat. The mat was pierced to provide one hole per
well. Two identical plates were prepared. The solvent(s) used in
each of the wells are shown in Table 4. One plate was sonicated for
20 seconds every 30 minutes until evaporation to dryness of all or
the majority of the samples in each well. Sonication was performed
using a Misonix 3000 sonicator with microplate horn. The second
plate was kept undisturbed (unsonicated) during the time of the
evaporation. TABLE-US-00004 TABLE 4 Solvent Conditions Used For
Individual Wells Of The 96-Well Plate Evaporation Experiment 1 2 3
4 5 6 7 8 9 10 11 12 A CH CH CH:WA CH:WA CH:NM CH:NM CH:TO CH:TO
CH:EA CH:EA CH:HE CH:HE 3:1 3:1 3:1 3:1 3:1 3:1 3:1 3:1 3:1 3: B DX
DX DX:WA DX:WA DX:NM DX:NM DX:TO DX:TO DX:EA DX:EA DX:HE DX:HE 3:1
3:1 3:1 3:1 3:1 3:1 3:1 3:1 3:1 3: C AC AC AC:WA AC:WA AC:NM AC:NM
AC:TO AC:TO AC:EA AC:EA AC:HE AC:HE 3:1 3:1 3:1 3:1 3:1 3:1 3:1 3:1
3:1 3:1 D TH TH TH:WA TH:WA TH:NM TH:NM TH:TO TH:TO TH:EA TH:EA
TH:HE TH:HE 3:1 3:1 3:1 3:1 3:1 3:1 3:1 3:1 3:1 3:1 E EO EO EO:WA
EO:WA EO:NM EO:NM EO:TO EO:TO EO:EA EO:EA EO:HE EO:HE 3:1 3:1 3:1
3:1 3:1 3:1 3:1 3:1 3:1 3:1 F MK MK MK:WA MK:WA MK:NM MK:NM MK:TO
MK:TO MK:EA MK:EA MK:HE MK:HE 3:1 3:1 3:1 3:1 3:1 3:1 3:1 3:1 3:1
3:1 G AN AN AN:WA AN:WA AN:NM AN:NM AN:TO AN:TO AN:EA AN:EA AN:HE
AN:HE 3:1 3:1 3:1 3:1 3:1 3:1 3:1 3:1 3:1 3:1 H MO MO MO:WA MO:WA
MO:NM MO:NM MO:TO MO:TO MO:EA MO:EA MO:HE MO:HE 3:1 3:1 3:1 3:1 3:1
3:1 3:1 3:1 3:1 3:1
[0339] In Table 4, the solvent mixtures are described as X:Y
volume:volume ratio of solvents. In Table 4, the following
abbreviations are used: AC=acetone; AN=acetonitrile; CH=chloroform;
DX=1,4-dioxane; EO=ethanol; EA=ethyl acetate; HE=heptane;
MK=2-butanone; MO=methanol, NI=nitromethane; TH=tetrahydrofuran;
TO=toluene; WA=water. TABLE-US-00005 TABLE 5 Summary Table Of
Results Obtained For The Sonicated Plate 1 2 3 4 5 6 7 8 9 10 11 12
A Y W Y Y Y Y Y Y Y Y Y Y B NC NC N N NC NC NC NC NC NC NC NC C W W
Y Y NC W W W Y Y W W D W W W W Y Y W W W W W Y E NC NC NC NC NC Y
NC Y NC NC NC NC F W NC W NC NC W W Y W Y W W G Y W W NC NC W W NC
W NC Y Y H W W W W W Y W W NC W Y Y In Table 5, the following
abbreviations are used: Y = Yellow form; W = White form; N =
Nucleated = mostly liquid with a small fraction of indeterminate
solids; NC = Not Crystallized).
[0340] Table 5 shows which solid form of WAY was generated in each
of the wells of the 96-well plate that was sonicated.
TABLE-US-00006 TABLE 6 Summary Table Of Results Obtained For The
Unsonicated Plate 1 2 3 4 5 6 7 8 9 10 11 12 A Y Y Y Y Y Y Y Y Y Y
W Y B NC NC N N NC NC NC NC NC NC NC NC C Y Y Y Y Y NC Y Y Y Y Y Y
D Y Y Y Y Y Y Y Y Y Y Y Y E NC NC NC NC NC NC Y Y NC Y NC NC F Y Y
Y Y NC NC NC NC Y Y Y NC G Y Y Y Y NC Y Y Y Y Y Y Y H Y Y Y Y Y Y Y
Y Y NC Y Y In Table 6, the following abbreviations are used: Y =
Yellow form; W = White form; N = Nucleated = mostly liquid with a
small fraction of indeterminate solids; NC = Not Crystallized).
[0341] Table 6 shows which solid form of WAY was generated in each
of the wells of the 96-well plate that was not sonicated.
[0342] This shows that a screening process in which samples are
sonicated yielded more occurrences of the most stable (but
less-frequently generated) white form.
EXAMPLE 7
[0343] In this Example, a micro-scale crystallization study of
sulfamerazine was performed. The study showed that sonication
facilitated the generation of a difficult-to-make more stable
form.
[0344] Sulfamerazine is known to crystallize in two polymorphic
forms, Form I and Form II, with Form I being the most commonly
encountered form. Despite the elusive character of Form II, it has
been demonstrated that Form II was the most stable form at room
temperature. Zhang et al., J. Pharm. Sci., 91(4), 1089-1100
(2002).
[0345] Solutions of sulfamerazine at a concentration of 10 mg/ml
were prepared in acetone and in tetrahydrofuran by dissolution of a
weighed amount of sulfamerazine in a measured volume of solvent.
The solutions were then filtered using a 0.2 .mu.m nylon filter.
Aliquots of 150 .mu.l of solution (acetone or tetrahydrofuran) were
added to 50 .mu.l of a second solvent in the wells of a flat bottom
polypropylene 96-well plate. The plate was covered by a
polypropylene mat, and the mat was pierced with one hole per well.
Two identical plates were prepared. One of the plates was sonicated
for 20 seconds every 30 minutes until evaporation to dryness of all
samples in each well. Sonication was performed using a Misonix 3000
sonicator with microplate horn. The second plate was kept
undisturbed (unsonicated), during the time of the evaporation.
Table 7 summarizes the results obtained for the sonicated and
unsonicated plates for each condition of evaporation. The
difficult-to-make but more stable Form II was found in the
sonicated plate but not in the unsonicated plate. TABLE-US-00007
TABLE 7 Conditions Of Evaporations From Mixture Of Solvents Non-
Sonicated sonicated Solvent 1 Solvent 2 Form Form acetone
Acetonitrile II.sup.a I.sup.a acetone Chloroform I I acetone
1,4-dioxane I A.sup.c acetone Ethanol I I acetone ethyl acetate I I
acetone Heptane I I acetone 2-butanone I I acetone Methanol I I
acetone Nitromethane II.sup.b I.sup.a acetone Tetrahydrofuran I I
acetone Toluene I I acetone Water I I tetrahydrofuran Acetone I I
tetrahydrofuran Acetonitrile I I tetrahydrofuran Chloroform I I
tetrahydrofuran 1,4-dioxane I A.sup.c tetrahydrofuran Ethanol I I
tetrahydrofuran ethyl acetate I I tetrahydrofuran heptane I I
tetrahydrofuran 2-butanone I I tetrahydrofuran methanol I I
tetrahydrofuran nitromethane I I tetrahydrofuran toluene I I
tetrahydrofuran Water I I .sup.aduplicate experiment gave the same
result .sup.bduplicate experiment gave form I .sup.cnew form
[0346] In this example, the elusive, more stable Form II of
sulfamerazine was generated by a crystallization process that
included ultrasound application, but was not generated without
ultrasound application. This example shows that a screening process
that includes sonication is more likely to generate the more stable
solid forms of the chemical substance. This example also
demonstrates that it may be desirable to include some unsonicated
samples in a screening process, as this can increase the likelihood
of obtaining the possible solid forms of the chemical
substance.
EXAMPLE 8
[0347] In this Example, the difficult-to-make Form I of
sulfathiazole was generated by crystallization from a solvent
mixture with sonication used to form an emulsion.
[0348] Sulfathiazole Form I is a disappearing polymorph, today
rarely seen crystallized directly from solution. This result is of
interest for polymorph screening purposes. Blagden et al., "Crystal
structure and solvent effects in polymorphic systems:
sulfathiazole," J. Chem. Soc. Faraday, 94, 1035-1045 (1998)
[0349] A 500 .mu.l aliquot of a saturated solution of sulfathiazole
in ethanol at 50.degree. C. was filtered hot and added to 500 .mu.l
of warm p-cymene in a pre-heated 1-dram vial on a hotplate at
55.degree. C. The biphasic sample was then sonicated while
evaporating until a precipitate appeared (40 minutes sonication,
using a Cole-Palmer ultrasonic processor fitted with a 6 mm tip
stainless steel probe, amplitude control set at 60). The solids
obtained were filtered and analyzed by XRPD. The XRPD pattern was
characteristic of sulfathiazole Form I (FIG. 7)
EXAMPLE 9
[0350] In this example a polymorph screen is carried out. Solutions
of chemical substance A in the following solvents or solvent
mixtures (with volume:volume ratio indicated) are prepared by
robotic weighing of chemical substance and solvent delivery and
mixing: acetone, acetonitrile, chloroform, 1,4-dioxane, ethanol,
ethyl acetate, heptane, 2-butanone, methanol, nitromethane,
tetrahydrofuran, toluene, water, dichloromethane, diethyl ether,
isopropyl ether, cyclohexane, methylcyclohexane, isopropyl alcohol,
trimethylpentane, n-octane, tri-chloroethane, trifluoroethanol,
pyridine, 1-butanol, tetrachloroethylene, chlorobenzene, xylene,
dibutyl ether, tetrachloroethane, p-cymene, dimethyl sulfoxide,
formamide, dimethylformamide, 2:1 methanol:acetonitrile, 2:1
methanol:dichloromethane, 3:1 methanol:ethyl acetate, 4:1
methanol:methyl-tert-butyl ether, 1:1 methanol:2-butanone, 3:1
trifluoroethanol:isopropyl acetate, 2:1 trifluoroethanol:isopropyl
ether, 1:1 trifluoroethanol:nitromethane, 1:5 water:acetone, 1:4
water:acetonitrile, 1:5 water:dioxane, 1:9 water:2-propanol, and
1:5 water:tetrahydrofuran.
[0351] Aliquots of 200 .mu.L of each solution are delivered in
duplicate using a liquid handler to the wells of a 96 well plate.
Concentrations of the solutions are selected such that the final
amount of chemical substance in each well is between 0.1 mg and 1.0
mg. The well plate body is made of polypropylene. The well plate is
a thin bottom well plate suitable for x-ray diffraction analysis of
crystals in the well plate. Two wells contain samples of an x-ray
powder diffraction standard. The well plate solutions are left
uncovered and are allowed to evaporate to dryness while being
sonicated for 20 seconds every hour using a Misonix 3000 sonicator
with microplate horn. Nitrogen flow into wells is used when
evaporation needs to be facilitated. The well plate is mounted on
edge on the stage of a Bruker D8 microdiffractometer with the well
openings facing the x-ray source. The solids at the bottom of each
well are analyzed by automated stage movement. It is expected that
a useful variety of different solid forms of the chemical substance
will be produced in the wells.
EXAMPLE 10
[0352] Cocrystals of fluoxetine HCl:benzoic acid were formed using
the following procedures. A solution of fluoxetine HCl and benzoic
acid in acetonitrile was prepared. A physical mixture of fluoxetine
HCl and benzoic acid in a 1:1 molar ratio was used to make a
solution having a concentration of about 200 mg/mL. The solution
was placed in four 96-well plates. The only difference among well
plates was the amount of solution put into each well. Two well
plates were charged with 15 .mu.L per well, and two plates were
charged with 50 .mu.L per well. One of the well plates containing
15 .mu.L samples and one of the well plates containing 50 .mu.L
samples were sealed and left standing at room temp. The other well
plate containing 15 .mu.L samples and the other well plate
containing 50 .mu.L samples were sealed and sonicated with a
Misonix 96-well plate sonicator.
[0353] None of the wells in the 15 .mu.L plates (either standing or
sonicated) nucleated (even after very strong sonication with the
Misonix plate sonicator or the probe). The plate left standing at
room temp with 50 .mu.L volumes nucleated in about 15% of the wells
nucleated on standing (but the majority of the wells had benzoic
acid growth, not cocrystal nucleation). For the 50 .mu.L plate that
was sonicated, almost half of the wells nucleated (with only one
well of benzoic acid and the rest as cocrystal).
[0354] In a system comprising a 1:1 molar ratio of fluoxetine HCl
and benzoic acid in acetonitrile, concentrations of about 200 mg/ml
of the API:guest mixture in CH.sub.3CN (acetonitrile) were used.
Nucleation could be caused by sonication in a concentration range
of from about 35 to about 100 mg/ml. Sonication indicates a clear
advantage in this case of intermediate concentrations. Almost all
of the samples having a concentration of 200 mg/ml nucleated with
sonication using either a probe or the well-plate sonicator. In
contrast, about 15% of the wells in a plate at 200 mg/ml nucleated
the cocrystal without sonication.
EXAMPLE 11
[0355] Cocrystal screening of chlorzoxazone is carried out using
the following procedures. Solutions of chlorzoxazone and various
guests are prepared in acetonitrile, methanol, aqueous ethanol, and
acetone in 1:1 molar ratios having a concentrations of about 10
mg/mL. The guests used include benzoic acid, gallic acid, and
2,5-dihydroxybenzoic acid. Aliquots of 20 microliters of the
solutions are placed in different capillary tubes. The samples are
sonicated for 1 minute by placement of the capillary tubes in a
sonication bath after the volume of the solutions are reduced to
the point where both components are supersaturated. This
concentration is calculated based on the solubility of the
individual components. The sonication is repeated every hour for 24
hours as the solutions evaporate. A duplicate set of capillary
tubes is allowed to evaporate at room temperature without
sonication.
[0356] Solids are present in most of the capillary tubes and are
analyzed by Raman spectroscopy and by x-ray powder diffraction. It
is expected that a number of cocrystals are present in the
sonicated capillary tubes and that different polymorphs, hydrates,
or solvates of the cocrystals may also be present. It is expected
that solids in the unsonicated capillary tubes will have a
different variety of solid forms present compared to the sonicated
samples and that there will not be as many cocrystals formed.
[0357] This example demonstrates the use of capillary tubes for
cocrystallization. This example also demonstrations that samples
having low concentrations and/or low volumes may be employed in a
cocrystallization process.
EXAMPLE 12
[0358] Cocrystal and salt screening of imipramine hydrochloride is
carried out using the following procedures. Solutions of imiprimine
hydrochloride and various guests are prepared in acetonitrile,
methanol, aqueous ethanol, and acetone in 1:1 molar ratios having a
concentrations of about 10 mg/mL. The guests include benzoic acid,
gallic acid, and 2,5-dihydroxybenzoic acid. Aliquots of 100
microliters of the solutions are placed in different wells of
96-well polypropylene plates that have thin walls. The plates are
sonicated for 1 minute in a sonication bath after the volume of the
solutions are reduced to the point where both components are
supersaturated. This concentration is calculated based on the
solubility of the individual components. The sonication is repeated
every hour for 24 hours as the solutions continue to evaporate. A
duplicate set of well plates is allowed to evaporate at room
temperature without sonication.
[0359] Solids are present in most of the wells and are analyzed in
situ, automatically by transmission x-ray powder diffraction
through the well plates. It is expected that a number of cocrystals
and/or salts are present in the sonicated plates and that different
polymorphs, hydrates, solvates, desolvates, and dehydrates of the
cocrystals and/or salts may also be present. It is expected that
solids in the unsonicated plates will have a different variety of
solid forms present compared to the sonicated samples and that
there will not be as many cocrystals and/or salts formed.
[0360] All patents, test procedures, and other documents cited
herein, including priority documents, are fully incorporated by
reference to the extent such disclosure is not inconsistent with
this invention and for all jurisdictions in which such
incorporation is permitted.
[0361] While the present invention has been described and
illustrated by reference to particular-embodiments, it will be
appreciated by those off ordinary skill in the art that the
invention lends itself to many different variations not illustrated
herein. For these reasons, then, reference should be made solely to
the appended claims for purposes of determining the true scope of
the present invention.
[0362] Although the appendant claims have single appendencies in
accordance with U.S. patent practice, each of the features in any
of the appendant claim can be combined with each of the features of
other appendant claims or the main claim. TABLE-US-00008 TABLE 8
10-camphorsulfonic acid 10-undecylenic acid 1-hydroxy-2-naphthoic
acid 2,4-dihydroxybenzoic acid 2,5-dihydroxybenzoic acid
2-aminopropionic acid 2-ethylbutyrinc acid 2-furancarboxylic acid
2-mercaptobenzoic acid 3-methylbutanoic acid 3-phenylpropionic acid
4-aminobenzoic acid 4-aminosalicylic acid 4-hydroxybenzoic acid
adipic acid alginic acid anisic acid arginine ascorbic acid
asparagine aspartic acid aspirin benzenesulfonic acid benzoic acid
4-acetamidobenzoic acid beta-alanine camphoric acid camphorsulfonic
acid carbonic acid cholic acid cinnamic acid citric acid cyclamic
acid cyclohexanecarboxylic acid cyclohexylacetic acid cysteine
diphenylacetic acid dodecylsulfonic acid ethane-1,2-disulfonic acid
ethanesulfonic acid ethanesulfonic acid, 2-hydroxy
ethylenediaminetetraacetic acid ethylsulfuric acid fumaric acid
galactaric acid gallic acid gentisic acid glucoheptonic acid
gluconic acid glutamic Acid glutamine glutaric acid glutaric acid,
2-oxo- glycine glycolic acid hippuric acid histidine hydroxyproline
isoleucine lactobionic acid lauric acid leucine levulinic acid
lysine maleic acid malic acid malonic acid mandelic acid
m-methoxybenzoic acid naphthalene-1,5-disulfonic acid
naphthalene-2-sulfonic acid n-decanoic acid niacin nicotinic acid
n-tetradecanoic acid oleic acid o-methylbenzoic acid orotic acid
orthoboric acid o-toluic acid p-acetamidobenzoic acid palmitic acid
pamoic acid phenoxyacetic acid phenylacetic acid phenylalanine
picric acid pivalic acid proline p-toluenesulfonic acid
pyroglutamic acid pyruvic acid salicylic acid sebacic acid serine
sorbic acid stearic acid succinic acid sulfosalicylic acid tartaric
acid terephthalic acid thiocyanic acid threonine tiglic acid
tryptophan tyrosine valeric acid valine
[0363] TABLE-US-00009 TABLE 9 Name CAS # Potassium bicarbonate
298-14-6 Potassium carbonate 584-08-7 Potassium chloride 7447-40-7
Potassium hydroxide 1310-58-3 Potassium metabisulfite 16731-55-8
Potassium nitrate 7757-79-1 Potassium nitrite 7758-09-0 Potassium
permanganate 7722-64-7 Potassium persulfate 7727-21-1 Potassium
phosphate, dibasic 2139900 Potassium Phosphate Monobasic 7778-77-0
potassium phosphate, tribasic, 7778-53-2 n-hydrate Potassium
sulfate 7778-80-5 Sodium bicarbonate 144-55-8 Sodium bisulfite
7631-90-5 Sodium borohydride 16940-66-2 Sodium carbonate 497-19-8
Sodium Carbonate Monohydrate 1486118 Sodium chloride 7647-14-5
Sodium dithionite 7775-14-6 Sodium fluoride 7681-49-4 Sodium
hexametaphosphate 10124-56-8 Sodium hydroxide 1310-73-2 Sodium
hypochlorite 7681-52-9 Sodium Metabisulfite 7681-57-4 Disodium
metasilicate 6834-92-0 sodium monophosphate 7681-53-0 Sodium
nitrate 7631-99-4 Sodium nitrite 7632-00-0 sodium hydrogen
phosphate 7558-79-4 Sodium phosphate Monobasic 7558-80-7 Sodium
Pyrophosphate 7722-88-5 Sodium silicate 1344-09-8 Sodium Sulfate
Decahydrate 7727-73-3 Sodium sulfite 7757-83-7 Sodium Thiosulfate
10102-17-7 Pentahydrate Calcium acetate 5743-26-0 Calcium Carbonate
471-34-1 Calcium Chloride Dihydrate 10035-04-8 Calcium gluconate
299-28-5 Calcium hydroxide 1305-62-0 Calcium oxide 1305-78-8
Calcium phosphate, dibasic 7757-93-9 Calcium Phosphate Monobasic
7758-23-8 Calcium sulfate 7778-18-9 Magnesium hydroxide 1309-42-8
Magnesium Sulfate Heptahydrate 10034-99-8 Aluminum 7429-90-5
Aluminum ammonium sulfate 7784-26-1 Aluminum chloride 7446-70-0
Aluminum hydroxide 21645-51-2 Aluminum potassium sulfate, 7784-24-9
dodecahydrate Orthoboric acid 10043-35-3 formaldehyde 50-00-0
DL-Isoleucine 443-79-8 (2S,7S)-(-)-Cystine 56-89-3 DL-Alanine
302-72-7 beta-Alanine 107-95-9 (S)-(+)-Arginine 74-79-3
(S)-(-)-Cysteine 52-90-4 DL-Glutamic acid 617-65-2 Glycine 56-40-6
(S)-(-)-Histidine 71-00-1 (S)-(+)-Lysine 56-87-1 DL-Methionine
59-51-8 DL-Phenylalanine 150-30-1 (S)-(-)-Phenylalanine 63-91-2
D-(+)-Proline 344-25-2 (S)-(-)-Tryptophan 73-22-3 (S)-(-)-Tyrosine
60-18-4 Carvone 99-49-0 Citral 5392-40-5 Ethyl butyrate 105-54-4
Isobutyl propionate 540-42-1 Methyl butyrate 623-42-7 n-Propyl
acetate 109-60-4 Isobutyl formate 542-55-2 Benzyl acetate 140-11-4
6-Methyl-5-hepten-2-one 110-93-0 Butyl acetate 123-86-4 Ethyl
acetoacetate 141-97-9 Isopentyl Acetate 123-92-2 Cinnamaldehyde
104-55-2 Methyl benzoate 93-58-3 Butyl sulfide 544-40-1 Ethyl
benzoate 93-89-0 2,4-Hexadienoic acid, 24634-61-5 potassium salt,
(E,E)- Potassium bitartrate 868-14-4 Lauric acid 143-07-7 Benzyl
benzoate 120-51-4 Picric acid 88-89-1 Benzoyl peroxide 94-36-0
Palmitic acid 57-10-3 Dibutyl phthalate 84-74-2 Stearic acid
57-11-4 Succinic anhydride 108-30-5 Diethylenetriamine 111-40-0
Diethanolamine 111-42-2 Benzaldehyde 100-52-7 Phenethylamine
64-04-0 Salicylylaldehyde 90-02-8 Sodium benzoate 532-32-1 Cinnamic
acid 621-82-9 Triethanolamine 102-71-6 L-(+)-Tartaric Acid 87-69-4
Eugenol 97-53-0 D-mannitol 69-65-8 Butyl paraben 94-26-8 Benzoin
119-53-9 Diethyl phthalate 84-66-2 Oleic acid 112-80-1 Sodium
lactate 72-17-3 Indole 120-72-9 ethyl lactate 97-64-3 quinoline
91-22-5 Thymol 89-83-8 Methyl anthranilate 134-20-3 Methyl
salicylate 119-36-8 Diethyl malonate 105-53-3 Citric acid 77-92-9
Sodium dodecyl sulfate 151-21-3 Morpholine 110-91-8 Furfural
98-01-1 Niacin 59-67-6 Choline chloride 67-48-1 L-Menthol 2216-51-5
Meso-inositol 87-89-8 ethylenediaminetetraacetic 60-00-4 acid EDTA,
calcium derivative, 62-33-9 disodium salt Calcium pantothenate
137-08-6 Riboflavin 83-88-5 Zinc carbonate 3486-35-9 Amyl alcohol
71-41-0 Mineral oil 8012-95-1 Triton(R) X-100 9002-93-1
Acetaldehyde 75-07-0 Acetic Acid 64-19-7 Acetone 67-64-1
Acetophenone 98-86-2 4-Aminobenzoic acid 150-13-0 Anisole 100-66-3
Vitamin C 50-81-7 Benzoic Acid 65-85-0 Biphenyl 92-52-4
2-Methyl-1-propanol 78-83-1 n-Butanol 71-36-3 n-Butylamine 109-73-9
ethyl acetate 141-78-6 Caffeine 58-08-2 Chloroacetic Acid 79-11-8
Dichloroacetic Acid 79-43-6 Diethylamine 109-89-7 Ethanol Amine
141-43-5 n-Butyric Acid 107-92-6 Ethylenediamine 107-15-3 Formic
acid 64-18-6 n-Hexanol 111-27-3 Methanol 67-56-1 Methyl Acetate
79-20-9 Methyl 4-hydroxybenzoate 99-76-3 m-Cresol 108-39-4 p-Cresol
106-44-5 Phenol 108-95-2 n-Propanol 71-23-8 Propionic Acid 79-09-4
Salicylic acid 69-72-7 Sucrose 57-50-1 Vanillin 121-33-5 Vitamin E
59-02-9 Potassium citrate, monohydrate 1534146 p-toluenesulfonic
acid 6192-52-5 monohydrate D-(+)-Maltose 69-79-4 Tetrasodium
64-02-8 ethylenediaminetetraacetate Saccharin sodium 128-44-9
Sodium Acetate Trihydrate 6131-90-4 Quinine sulfate, dihydrate
6119-70-6 Sulfosalicylic acid, dihydrate 5965-83-3 L-(+)-Arginine
1119-34-2 monohydrochloride Procaine hydrochloride 51-05-8
Pyridoxine Hydrochloride 58-56-0 Thiamine hydrochloride 67-03-8
Propionaldehyde 123-38-6 Urea 57-13-6 2-Propanol 67-63-0 Pyrrole
109-97-7 Sodium formate 141-53-7 Pyrrolidine 123-75-1 Methyl ethyl
ketone 78-93-3 Ethyl formate 109-94-4 Propylene glycol 57-55-6
Thiourea 62-56-6 Ammonium acetate 631-61-8 Benzene 71-43-2 Sodium
acetate 127-09-3 Cyclopentanone 120-92-3 Cyclohexane 110-82-7
piperidine 110-89-4 2-Pentanone 107-87-9 hexane 110-54-3 Isoamyl
Alcohol 123-51-3 Lactic acid 50-21-5 2-Ethoxyethanol 110-80-5
Propionic acid, sodium salt 137-40-6 Potassium acetate 127-08-2
cyclohexyl amine 108-91-8 methyl methacrylate 80-62-6 methyl
isobutyl ketone 108-10-1 Acetic anhydride 108-24-7 Isopropyl
Acetate 108-21-4 2,2'-Oxybisethanol 111-46-6 Benzyl alcohol
100-51-6 Resorcinol 108-46-3 2-Butoxy ethanol 111-76-2 Cumene
98-82-8 2-Amino-2-(hydroxymethyl)-1,3- 77-86-1 propanediol
Phenethyl alcohol 60-12-8 2-Ethyl-1-hexanol 104-76-7 2-Octanol
123-96-6 2-(2-Ethoxyethoxy)ethanol 111-90-0
2,6-Dimethyl-4-heptanone 108-83-8 Benzophenone 119-61-9
D-(-)-Fructose 57-48-7 D-Glucose 50-99-7 D-Ribose 50-69-1
D-(+)-Xylose 58-86-6 Pectin sugar 5328-37-0 D-(+)-Lactose 63-42-3
Camphene 79-92-5 Isoquinoline 119-65-3 2,4-Dimethylphenol 105-67-9
2,5-Dimethylphenol 95-87-4 2,6-Dimethylphenol 576-26-1
Methanesulfonic Acid 75-75-2 o-Methoxybenzoic Acid 579-75-9
Saccharin 81-07-2
Thiazole 288-47-1 Trifluoromethanesulfonic Acid 1493-13-6
Trimethylamine 75-50-3 Coumarin 91-64-5 Dimethylamine 124-40-3
Ethyl Alcohol 64-17-5 Butyl benzyl phthalate 85-68-7
2,6-dimethylpyrazine 108-50-9 taurocholic acid 81-24-3 geraniol
106-24-1 linalool 78-70-6 ethyl isovalerate 108-64-5 ethyl
2-methylbutyrate 7452-79-1 1-octen-3-ol 3391-86-4 ethyl
2-trans-4-cis- 3025-30-7 decadienoate Dihydromyrcenol 18479-58-8
citronellal 106-23-0 linalyl acetate 115-95-7
8-mercapto-p-menthan-3-one 38462-22-5 Ammonium citrate 3012-65-5
Ammonium bicarbonate 1066-33-7 Ammonium chloride 12125-02-9
Ammonium hydroxide 1336-21-6 Ammonium persulfate 7727-54-0 Ammonium
phosphate, dibasic 7783-28-0 Ammonium Phosphate Monobasic 7722-76-1
Ammonium sulfate 7783-20-2 Ammonium sulfide 12135-76-1 Hydrazine
302-01-2 Nitric acid 7697-37-2 phosphoric acid 7664-38-2 Phosphorus
oxychloride 10025-87-3 Hydriodic acid 10034-85-2 Hydrobromic acid
10035-10-6 Hydrochloric acid 7647-01-0 hydrogen peroxide 7722-84-1
Periodic Acid 10450-60-9 Sulfamic acid 5329-14-6 Sulfuric acid
7664-93-9 Sulfurous acid 7782-99-2 Dexpanthenol 81-13-0
4-oxoisophorone 1125-21-9 Copper(II) sulfate 7758-98-7 ferric
chloride 7705-08-0 Ferric oxide 1309-37-1 ferric sulfate 10028-22-5
Iron(II)Sulfate Heptahydrate 7782-63-0 Iron 7439-89-6 Manganese
(II) Sulfate 10034-96-5 Monohydrate Nickel 7440-02-0 Titanium
dioxide 13463-67-7 Zinc chloride 7646-85-7 Zinc oxide 1314-13-2
1,1'-Azobisformamide 123-77-3 1,3-Butanediol 107-88-0
1-Methylnaphthalene 90-12-0 2,6-Di-tert-Butyl-p-Cresol 128-37-0
2,6-Dimethylpyridine 108-48-5 Disodium 138-93-2
cyanodithioimidocarbonate 3-Methyl-2-Cyclopentene-2-ol- 80-71-7 one
6-Methylcoumarin 92-48-8 acetoin 513-86-0 alpha-Phellandrene
99-83-2 alpha-Terpinene 99-86-5 Benzenesulfonic Acid 98-11-3
Benzothiazole 95-16-9 borates, tetrasodium salts 1330-43-4 Butyl
butyrate 109-21-7 Butyl Mercaptan 109-79-5 Butyraldehyde 123-72-8
Capsaicin 404-86-4 Chloromethyl Methyl Ether 107-30-2 Cymene
99-87-6 Diallyl Disulfide 2179-57-9 Diethylaminoethanol 100-37-8
dimethyldisulfide 624-92-0 Dimethyl Succinate 106-65-0 Dimethyl
Sulfate 77-78-1 Dimethyl Sulfide 75-18-3 Dipropyl Disulfide
629-19-6 Dipropyl Ketone 123-19-3 Ethyl Acrylate 140-88-5 Ethyl
Butyl Ketone 106-35-4 Ethyl Propionate 105-37-3 Furfuryl Alcohol
98-00-0 gamma-Butyrolactone 96-48-0 Glutaraldehyde 111-30-8
glycerin 56-81-5 Glycolic Acid 79-14-1 Isobutyl Acetate 110-19-0
Isobutyl Isobutyrate 97-85-8 Isobutyraldehyde 78-84-2 Isoheptanol
543-49-7 Isophorone 78-59-1 Isopropyl Mercaptan 75-33-2 Methyl
isobutenyl ketone 141-79-7 Methyl n-amyl ketone 110-43-0 methyl
acrylate 96-33-3 Methyl Isobutyrate 547-63-7 Methyl Mercaptan
74-93-1 N,N-Dimethylethanolamine 108-01-0 n-Butyl Lactate 138-22-7
n-Hexyl Acetate 142-92-7 n-Valeraldehyde 110-62-3 Nitrous Oxide
10024-97-2 p-Anisaldehyde 123-11-5 2-Methylcyclohexanone 583-60-8
Octanoic Acid 124-07-2 Oxalic Acid 144-62-7 Phenyl ether 101-84-8
Phenylmercaptan 108-98-5 Propargyl Alcohol 107-19-7 Propyl paraben
94-13-3 sec-Butyl Alcohol 78-92-2 Sodium Gluconate 527-07-1 Sodium
Tripolyphosphate 7758-29-4 Tetrahydro-2-furanmethanol 97-99-4
Valeric Acid 109-52-4 3,4-xylenol 95-65-8 3-hexanol 623-37-0
3-methyl-1-pentanol 589-35-5 1,1-diethoxyethane 105-57-7 Aluminum
Sulfate 10043-01-3 ammonium sulfite 10196-04-0 amyl butyrate
540-18-1 borneol 507-70-0 butyl formate 592-84-7 calcium peroxide
1305-79-9 n-Hexanoic Acid 142-62-1 cyclohexyl acetate 622-45-7
diacetyl 431-03-8 dimethyl carbonate 616-38-6 ethyl butyraldehyde
97-96-1 Ethyl crotonate 623-70-1 ethyl isobutyrate 97-62-1 ethyl
nitrite 109-95-5 fumaric acid 110-17-8 hexaldehyde 66-25-1
isobutyric acid 79-31-2 methyl isovalerate 556-24-1 methyl
propionate 554-12-1 methyl valeraldehyde 123-15-9 nitrosyl chloride
2696-92-6 octafluorocyclobutane 115-25-3 peroxyacetic acid 79-21-0
propyl formate 110-74-7 propyl mercaptan 107-03-9 Sodium aluminate
1302-42-7 sodium chlorite 7758-19-2 Terephthalic Acid 100-21-0
allyl isothiocyanate 57-06-7 Vitamin B1 59-43-8 Valproic acid
99-66-1 Ethoxyquin 91-53-2 n-Amyl Ethyl Ketone 106-68-3 Nabam
142-59-6 Sodium sulfide 1313-82-2 Thiocyanic acid 463-56-9
2-Methyl-5-(1-methylethenyl)- 2244-16-8 2-cyclohexene-1-one
4-(2,6,6-Trimethyl-2- 127-41-3 cyclohexen-1-yl)-3-buten-2-one
4-(2,6,6-trimethyl-1- 14901-07-6 cyclohexen-1-yl)-3-buten-2-one
Isoamyl propionate 105-68-0 3-Methylbutanoic acid 503-74-2
L-Menthone 14073-97-3 4-Ethylphenol 123-07-9 o-cresol 95-48-7
dimethyl-Carbamodithioic acid, 128-04-1 sodium salt Anethole
104-46-1 Dimethyl terephthalate 120-61-6 propyl gallate 121-79-9
L-Ascorbic Acid Sodium Salt 134-03-2 4-Hexylresorcinol 136-77-6
Estragole 140-67-0 L-monosodium glutamate 142-47-2 Malonaldehyde,
sodium salt 24382-04-5 Butylated hydroxyanisole 25013-16-5 allyl
3-methylbutyrate 2835-39-4 DL-monosodium glutamate 32221-81-1
3-Acetyl-6-methyl-2,4- 520-45-6 pyrandione L-Glutamic Acid 56-86-0
DL-alpha-tocopheryl acetate 58-95-7 D-limonene 5989-27-5 Calcium
Acetate 62-54-4 Erythorbic Acid Monosodium 6381-77-7 Salt Ethyl
methylphenylglycidate 77-83-8 2,4,6-Trinitro-1,3-dimethyl-5-
81-15-2 tert-butylbenzene Dimethoxane 828-00-2 3,5-Di-tert-butyl-4-
88-26-6 hydroxybenzyl alcohol 6-Methylquinoline 91-62-3
alpha-Methylbenzyl alcohol 98-85-1 Nicotinamide 98-92-0
3,4-Dihydrocoumarin 119-84-6 Geranyl Acetate 105-87-3 Sodium
(2-Ethylhexyl)Alcohol 126-92-1 Sulfate Cyclohexanol, 5-methyl-2-(1-
89-78-1 methylethyl)-, (1alpha,2beta,5alpha)- (+)-Camphor 464-49-3
(1S)-(-)-alpha-Pinene 7785-26-4 1,3-Dihydroxy-5-methylbenzene
504-15-4 1,5-Naphthalenedisulfonic Acid 1655-29-4 Disodium Salt
1-Hydroxy-2-naphthoic Acid 86-48-6 1-Penten-3-ol 616-25-1
1-Phenyl-1-propanol 93-54-9 10-Undecylenic Acid 112-38-9
2'-Hydroxyacetophenone 118-93-4 2,4-Dihydroxybenzoic Acid 89-86-1
2-Acetylfuran 1192-62-7 2-Furancarboxylic Acid 88-14-2
2-Isopropylphenol 88-69-7 2-Ketoglutaric Acid 328-50-7 2-Ketovaline
759-05-7 2-n-Propylphenol 644-35-9 2-Naphthalenethiol 91-60-1
2-Phenyl-1-propanol 1123-85-9 3,3'-Thiodipropionic Acid 111-17-1
3,5,5-Trimethylhexanal 5435-64-3 3-Phenyl-1-propanol 122-97-4
3-Phenylpropionic Acid 501-52-0 4-Aminosalicylic Acid 65-49-6
4-Ethoxyphenol 622-62-8 4-Hydroxybenzoic Acid 99-96-7
4-Phenyl-2-butanol 2344-70-9 4-tert-Octylphenol 140-66-9 Allyl
Cinnamate 1866-31-5 Allyl Mercaptan 870-23-5 alpha-L-Rhamnose
3615-41-6 Alpha-Terpineol 98-55-5 Anisic Acid 100-09-4
Benzalacetone 122-57-6 Benzaldehyde Dimethylacetal 1125-88-8 Benzyl
Ether 103-50-4 Benzyl Formate 104-57-4 Benzyl Mercaptan 100-53-8
Benzyl Salicylate 118-58-1 Calcium Citrate 813-94-5 Calcium
Glycerophosphate 27214-00-2
Calcium Hypophosphite 7789-79-9 Calcium Iodate 7789-80-2 Propanoic
acid, 2-hydroxy-, 814-80-2 calcium salt (2:1) Calcium Phosphate
Tribasic 7758-87-4 Calcium Propionate 4075-81-4 Calcium
Pyrophosphate 7790-76-3 Cholic Acid 81-25-4 Choline 123-41-1
Choline Bitartrate 87-67-2 trans-Cinnamic Aldehyde 14371-10-9
Cinnamyl Alcohol 104-54-1 Citronellol 106-22-9 Copper(I)Iodide
7681-65-4 D-(+)-Glucono-1,5-lactone 90-80-2 D-(-)-Tartaric Acid
147-71-7 D-Isoascorbic Acid 89-65-6 D-Tyrosine 556-02-5 Sodium
dehydroacetate 4418-26-2 Deoxycholic Acid 83-44-3 Dibenzyl Ketone
102-04-5 Diethyl L-(+)-Tartrate 87-91-2 Diethyl Succinate 123-25-1
Dimethylacetal 534-15-6 DL-Cystine 923-32-0 DL-Proline 609-36-9
DL-Tartaric Acid 133-37-9 DL-Tyrosine 556-03-6 DL-Valine 516-06-3
Enanthoic Acid 111-14-8 Erythorbic Acid Sodium Salt 7378-23-6 Ethyl
2-Aminobenzoate 87-25-2 Ethyl Cinnamate 103-36-6 Ethyl n-Valerate
539-82-2 Ethyl Phenylacetate 101-97-3 Ethyl Salicylate 118-61-6
Ethyl Sulfide 352-93-2 Ethyl Vanillin 121-32-4 Ethylene Mercaptan
540-63-6 Farnesene 502-61-4 Folic acid 59-30-3 gamma-Nonanolactone
104-61-0 gamma-Valerolactone 108-29-2 Gluconic Acid 526-95-4
Gluconic Acid Potassium Salt 299-27-4 Glutaric Acid 110-94-1
Guanosine-5'-monophosphate, 1333479 disodium salt Heliotropine
120-57-0 Hippuric Acid 495-69-2 Hydroquinone Dimethyl Ether
150-78-7 Inosine-5'-monophosphate 4691-65-0 Sodium Salt iso-Amyl
Mercaptan 541-31-1 Isoamyl Salicylate 87-20-7 iso-Butyl n-Hexanoate
105-79-3 isovaleraldehyde 590-86-3 Isoamyl Benzoate 94-46-2 Isoamyl
Formate 110-45-2 Isoamyl n-Butyrate 106-27-4 Isoamylamine 107-85-7
Isobutyl n-Butyrate 539-90-2 Isocaproic Acid 646-07-1 Isoeugenol
97-54-1 Isopropyl Benzoate 939-48-0 Isopropyl Formate 625-55-8
Isopropyl N-Butyrate 638-11-9 Isopropyl Propionate 637-78-5
isobutyl Mercaptan 513-44-0 L-(+)-Isoleucine 73-32-5 L-(-)-Apple
Acid 97-67-6 L-2-Aminopropionic Acid 56-41-7 L-Aspartic acid
56-84-8 L-Carnitine 541-15-1 L-Cysteine Hydrochloride 52-89-1
L-Glutamic Acid Hydrochloride 138-15-8 L-Glutamine 56-85-9
L-Hydroxyproline 51-35-4 L-Proline 147-85-3 L-Serine 56-45-1
L-Threonine 72-19-5 L-Valine 72-18-4 N-Acetylglycine 543-24-8
n-Amyl Formate 638-49-3 n-Amyl n-Caproate 540-07-8 n-Butyl
n-Caproate 626-82-4 n-Butyl Propionate 590-01-2 n-Butyl Salicylate
2052-14-4 n-Decanoic Acid 334-48-5 n-Hexyl Mercaptan 111-31-9
n-Propyl Benzoate 2315-68-6 n-Propyl Isobutyrate 644-49-5
n-Tetradecanoic Acid 544-63-8 Nitrilotriacetic Acid 5064-31-3
Trisodium Salt o-Toluenethiol 137-06-4 Orotic Acid 65-86-1
p-Acetamidobenzoic Acid 556-08-1 p-Anise Alcohol 105-13-5
Phenoxyacetic Acid 122-59-8 Phenyl Acetate 122-79-2 Piperine
94-62-2 Pivalic Acid 75-98-9 Potassium Benzoate 582-25-2 Potassium
Diphosphate 7320-34-5 Potassium Hypophosphite 7782-87-8 Potassium
Metaphosphate 7790-53-6 Potassium Sulfite 10117-38-1 Quinine
Hydrochloride 130-89-2 sec-Amyl Alcohol 6032-29-7 Sodium
D-Pantothenate 867-81-2 Di(2-ethylhexyl) sulfosuccinic 577-11-7
acid, sodium salt Sodium Sorbate 7757-81-5 Succinic acid, disodium
salt 150-90-3 Sodium Taurocholate 145-42-6 Taurine 107-35-7
Thiamine Nitrate 532-43-4 Thioanisole 100-68-5 Tiglic Acid 80-59-1
Tri-n-butyrin 60-01-5 Triacetin 102-76-1 Trisodium Citrate 68-04-2
Veratraldehyde 120-14-9 Veratrole 91-16-7 Vitamin P 520-26-3
Vitamin U Chloride 582174 L-methionine 63-68-3 2-Chloro-1-propanol
78-89-7 2-Ethylbutyric acid 88-09-5 2-Methylbutyraldehyde 96-17-3
2-Methyl-5-ethylpyridine 104-90-5 n-propyl butyrate 105-66-8 Ethyl
caprylate 106-32-1 Propyl propionate 106-36-5 2-Methylpyrazine
109-08-0 3,3,5-Trimethyl-1-cyclohexanol 116-02-9 Ethyl caproate
123-66-0 o-methoxybenzaldehyde 135-02-4 2,4-Hexadienal 142-83-6
3-Hexanone 589-38-8 3-Methyl-2-butanol 598-75-4 Methyl isopropenyl
ketone 814-78-8 3-Methyl-2-butanethiol 2084-18-6
3,5,5-Trimethylhexanol 3452-97-9 Methylglyoxal 78-98-8
Malonaldehyde 542-78-9 1,4-Dithiane 505-29-3 Amylcinnamaldehyde
122-40-7 Benzyl cinnamate 103-41-3 tert-Butylhydroquinone 1948-33-0
Fusidic Acid Sodium Salt 751-94-0 Hydroxycitronellal 107-75-5 Musk
ketone 81-14-1 L-Asparagine 70-47-3 phenethyl acetate 103-45-7
Riboflavin-5-Phosphate 146-17-8 Potassium Sodium Tartrate 304-59-6
Galactaric acid 526-99-8 Sodium Tartrate 868-18-8 trisodium
phosphate 7601-54-9 Disodium Pytophosphate 7758-16-9 Magnesium
chloride 7786-30-3 Sodium Polymethacrylate 54193-36-1 propiophenone
93-55-0 2-ethylhexanoic acid 149-57-5 3,7,7-trimethyl bicyclohep-3-
13466-78-9 ene 2,6-dimethyl-4-heptanol 108-82-7
5-isopropyl-2-methyl-phenol 499-75-2 L-Bornyl acetate 5655-61-8
caryophyllene 87-44-5 hydroxymethylpyrone 118-71-8 neosperidin
dihydrochalcone 20702-77-6 2,2-Dibromo-3- 10222-01-2
nitrilopropionamide Xylitol 87-99-0 Sulfosalicylic acid 97-05-2
Riboflavin 5'-(dihydrogen 130-40-5 phosphate), monosodium salt
Ethylenediaminetetraacetic 139-33-3 acid, disodium salt Gallic acid
149-91-7 Carbonic acid 463-79-6 Potassium carbonate, 6381-79-9
sesquihydrate Magnesium phosphate tribasic 7757-87-1 diallyl
sulfide 592-88-1 ethyl 4-oxopentanoate 539-88-8 methyl caproate
106-70-7 isopropyl isobutyrate 617-50-5 diethyl hydroxybutanedioate
2065419 propyl isopentanoate 557-00-6 benzyl ethyl ether 539-30-0
isobutyl isopentanoate 589-59-3 propyl hexanoate 626-77-7
4-methylquinoline 491-35-0 methyl cinnamate 103-26-4 cumic alcohol
536-60-7 thujone 471-15-8 dihydrocarveol 619-01-2 fenchyl alcohol
1632-73-1 Nerol 106-25-2 isopentyl isopentanoate 659-70-1
methyleugenol 93-15-2 methyl 2-naphthyl ketone 93-08-3
diphenyldisulfide 882-33-7 citronellyl acetate 150-84-5 menthyl
acetate 89-48-5 menthyl isovalerate 16409-46-4
5-Ethyl-3-hydroxy-4-methyl- 698-10-2 2(5H)-furanone malic acid
6915-15-7 3-methylbutanoic acid butyl 109-19-3 ester
3-phenyloxiranecarboxylic acid 121-39-1 ethyl ester
1,2-Benzisothiazol-3(2H)-one 6381-61-9 1,1-dioxide, ammonium salt
1-methyl-4-(1-methylethyl)- 99-85-4 1,4-Cyclohexadiene
3-mercapto-2-Butanol 54812-86-1 (1R)-2,6,6- 7785-70-8
trimethylbicyclo[3.1.1]hept-2- ene (1S)-6,6-dimethyl-2- 18172-67-3
methylenebicyclo[3.1.1]heptane 1-methyl-4-(1- 586-62-9
methylethylidene)cyclohexene 1-(3-pyridinyl)ethanone 350-03-8
1-pyrazinylethanone 22047-25-2 1-(2-furyl)-2-propanone 6975-60-6
1-Penten-3-one 1629-58-9 2,3-pentanedione 600-14-6
2,5-dimethylpyrazine 123-32-0 2-isobutyl-3-methoxypyrazine
24683-00-9 4-methyl-2,3-pentanedione 7493-58-5 5-methylfurfural
620-02-0 Dimethyltrisulfide 3658-80-8 furfuryl acetate 623-17-6
furfurylmethylether 13679-46-4 terpinen-4-ol 562-74-3 Calcium
sorbate 7492-55-9 Potassium lactate 996-31-6
1-Hydroxyethylidene-1,1- 2809-21-4 diphosphonic acid L-glutamic
acid monopotassium 19473-49-5 salt 3-methyl-2-buten-1-ol 556-82-1
phenylethanal 122-78-1 4'-Methoxyacetophenone 100-06-1
L-borneol 464-45-9 2,4-Hexadien-1-ol 111-28-4 D-Fenchone 4695-62-9
3-Phenylpropyl formate 104-64-3 Cinnamyl formate 104-65-4
D-galacturonate 685-73-4 D-glucuronate 1700908 5' IMP 131-99-7
1-Methoxy-4-methylbenzene 104-93-8 2-Methylbutanoic acid 116-53-0
2,4,6-Tribromophenol 118-79-6 3-Ethyl pyridine 536-78-7 Zinc
acetate 557-34-6 Methyl pentanoate 624-24-8 Methylthioethane
624-89-5 3-Penten-2-one 625-33-2 Glycocholic acid 475-31-0
m-Methoxybenzoic acid 586-38-9 alpha-Hydroxypropionic acid 598-82-3
Methyl 2-furoate 611-13-2 2-Furancarboxylic acid, propyl 615-10-1
ester Benzylacetoacetic acid, ethyl 620-79-1 ester 2,5-Dimethyl
pyrrole 625-84-3 4-methyl-1,1'-biphenyl 644-08-6
p-Isopropylacetophenone 645-13-6 4-methyl-thiazole 693-95-8
gamma-Decalactone 706-14-9 2-acetylpyrrole 1072-83-9
2-acetylpyridine 1122-62-9 tetramethyl-pyrazine 1124-11-4 Methyl
4-phenylbutyrate 2046-17-5 2,3,6-trimethyl-phenol 2416-94-6
2-Methoxypyrazine 3149-28-8 2-Ethylfuran 3208-16-0
2,3-dimethyl-pyrazine 5910-89-4 Thiophenethiol 7774-74-5 o-Tolyl
isobutyrate 36438-54-7 cis-3-Hexenyl pyruvate 68133-76-6
cis-3-Hexenyl cis-3-hexenoate 61444-38-0 trans-2-Hexenyl
isovalerate 68698-59-9 trans-2-Hexenyl formate 53398-78-0
trans-2-Hexenyl valerate 56922-74-8 1-Octen-3-yl butyrate
16491-54-6 Methyl 4-(methylthio)butyrate 53053-51-3
2,4-Octadien-1-ol 18409-20-6 2,4-Nonadien-1-ol 62488-56-6
2,4-Decadien-1-ol 18409-21-7 (e,z)-2,6-Nonadienyl acetate
68555-65-7 3-Hexenal 4440-65-7 Tetrahydro-2-furanmethanol 637-64-9
acetate Methyl benzaldehyde 1334-78-7 Dodecylsulfonic acid
1510-16-3 Methylethyl disulfide 4253-89-8 Farnesol 4602-84-0
Thiobenzoic acid, S-methyl 5925-68-8 ester Hexyl benzoate 6789-88-4
2,5-Diethyltetrahydrofuran 41239-48-9 Zinc hydrosulfite 7779-86-4
(2R,3S)-Tartaric Acid 147-73-9 Ethylsulfuric acid 540-82-9
1,2,2-Trimethyl-1,3- 5394-83-2 cyclopentanedicarboxylic acid
2-Methyl-3-buten-2-ol 115-18-4 trans-2-Hexenal 6728-26-3
4-Hexen-3-one 2497-21-4 1-Hexen-3-ol 4798-44-1
2-Methyl-1-butanethiol 1878-18-8 4-Methylcyclohexanone 589-92-4
3-Heptanol 589-82-2 o-methylanisole 578-58-5 trans-2-octenal
2363-89-5 2,3,4-Trimethyl-3-pentanol 3054-92-0 Acetylacetaldehyde
dimethyl 5436-21-5 acetal p-methylacetophenone 122-00-9
o-aminoacetophenone 551-93-9 4-Propylphenol 645-56-7
2,4-Dimethylanisole 6738-23-4 Benzyl methyl sulfide 766-92-7 Methyl
phenylacetate 101-41-7 4-Ethoxybenzaldehyde 10031-82-0 p-tolyl
acetate 140-39-6 2,6-Dimethoxyphenol 91-10-1 Isoborneol 124-76-5
Methyl 2-methoxybenzoate 606-45-1 Phenylacetaldehyde dimethyl
101-48-4 acetal 3-Phenylpropyl acetate 122-72-5 Ethyl
3-phenylpropionate 2021-28-5 Benzyl butyrate 103-37-7 Anisyl
acetate 104-21-2 Isobutyl phenylacetate 102-13-6 p-vinylphenol
2628-17-3 o-tolyl acetate 533-18-6 2,5-Dihydroxybenzoic acid
490-79-9 o-methoxyphenyl acetate 613-70-7 Lactobionic acid 96-82-2
Magnesium hydrogen phosphate 7782-75-4 trihydrate Iberverin
505-79-3 alpha-methylcinnamaldehyde 101-39-3 benzyl phenylacetate
102-16-9 1,3-dimercaptopropane 109-80-8 p-cymen-8-ol 1197-01-9
phenethyl anthranilate 133-18-6 trihydroxybutyrophenone 1421-63-2
o-methoxycinnamaldehyde 1504-74-1 3-propylidene phthalide
17369-59-4 trans,trans-2,4-decadienal 25152-84-5 piperonyl acetate
326-61-4 2,3-hexanedione 3848-24-6 isopropyl phenylacetate
4861-85-2 ethyl 3-hydroxybutyrate 5405-41-4 furfural acetone
623-15-4 beta-(2-furyl)acrolein 623-30-3 linalyl anthranilate
7149-26-0 citral diethyl acetal 7492-66-2 allyl anthranilate
7493-63-2 acetyl tributyl citrate 77-90-7 butyl anthranilate
7756-96-9 cyclohexyl anthranilate 7779-16-0 isoamyl cinnamate
7779-65-9 isobutyl anthranilate 7779-77-3 carvyl acetate 97-42-7
carveol 99-48-9 3-(Methylthio)propionaldehyde 3268-49-3
Alpha-damascone 43052-87-5 Dimethyldicarbonate 4525-33-1 Procaine
59-46-1 5-hydroxy-6-methyl-3,4- 65-23-6 pyridinedimethanol
2-methoxy-Naphthalene 93-04-9 Methyl nicotinate 93-60-7 Ethyl
benzoylacetate 94-02-0 Phenethyl benzoate 94-47-3
2-methyl-pentanoic acid 97-61-0 Cyclohexanecarboxylic acid 98-89-5
Methyl b-phenylpropionate 103-25-3 Benzyl 3-methyl butanoate
103-38-8 Naphthalene-2-sulfonic acid 120-18-3 Methyl
4-methoxybenzoate 121-98-2 3-Phenylprop-2-enyl cinnamate 122-69-0
7-methyl-3-methylene-1,6- 123-35-3 Octadiene Levulinic acid
123-76-2 2-Mercaptobenzoic acid 147-93-3 m-Dimethoxybenzene
151-10-0 3-butyl-1(3H)-isobenzofuranone 6066-49-5
5-Methylquinoxaline 13708-12-8 2-Ethyl Pyrazine 13925-00-3
trimethyl-pyrazine 14667-55-1 2-ethyl-3-methyl-pyrazine 15707-23-0
2,3-diethyl-pyrazine 15707-24-1 2,3-diethyl-5-methyl-pyrazine
18138-04-0 2-Methylthiopyrazine 21948-70-9 5-Methyl-3H-furan-2-one
591-12-8 cis-3-Hexen-1-ol 928-96-1 3,7-Dimethyl-1,3,6-octatriene
13877-91-3 calcium cyclamate 139-06-0 aconitic acid 499-12-7
2-Dehydrolinalool 29171-20-8 2-Mercaptopropionic acid 79-42-5
3-Methyl-2-butenal 107-86-8 Allylacetic acid 591-80-0 Allyl
cyclohexylacetate 4728-82-9 Allyl cyclohexylpropionate 2705-87-5
Allyl phenoxyacetate 7493-74-5 Allyl phenylacetate 1797-74-6 Allyl
alpha-ionone 79-78-7 Butyl butyrolactate 7492-70-8 Cinnamyl
isobutyrate 103-59-3 Cinnamyl propionate 103-56-0 Dibenzyl
disulfide 150-60-7 Isobornyl acetate 125-12-2 Methyl heptyne
carbonate 111-12-6 Triethyl citrate 77-93-0 gamma-Undecalactone
104-67-6 alpha-Amylcinnamyl alcohol 101-85-9 1,3,4,6,7,8-Hexahydro-
1222-05-5 4,6,6,7,8,8-hexamethyl cyclopenta[g][2]benzopyran
2-Ethylbutyl acetate 10031-87-5 Triphosphoric acid, 13845-36-8
pentapotassium salt L-(+)-Lactic acid 79-33-4 Mannitol 87-78-5
2-Methoxy-4-methylphenol 93-51-6 1,2,3-Propanetricarboxylic
144-33-2 acid, 2-hydroxy-, disodium salt Ethanesulfonic acid, 2-
1562-00-1 hydroxy-, monosodium salt 2-Methoxy-4-propylphenol
2785-87-7 3,7-Dimethyl-3-octanol 78-69-3 2-Pentyl-furan 3777-69-3
Butanoic acid, 3-oxo-, butyl 591-60-6 ester 4-(4-Hydroxy-4-methyl
pentyl)- 31906-04-4 3-cyclohexene-1-carboxaldehyde Methyl 3-oxo-2-
24851-98-7 pentylcyclopentaneacetate Naphthalene, 2-(2- 2173-57-1
methylpropoxy)- Perillol 536-59-4 2-Acetyl-1-methylpyrrole 932-16-1
4-Allyl-2,6-dimethoxyphenol 6627-88-9 Butyl levulinate 2052-15-5
D-(+)-Camphoric acid 124-83-4 D(+)-10-Camphorsulfonic acid
3144-16-9 L-(-)-Carvone 6485-40-1 (-)-Carvyl propionate 97-45-0
(-)-Caryophyllene oxide 1139-30-6 Cyclohexylacetic acid 5292-21-7
3-Cyclopentylpropionic acid 140-77-2 (-)-Dihydrocarvyl acetate
20777-49-5 3,3-Dimethylacrylic acid 541-47-9
2,4-Dimethylbenzaldehyde 15764-16-6 1,4-Dithiane-2,5-diol
40018-26-6 Ethanesulfonic acid 594-45-6 Ethyl butyrylacetate
3249-68-1 Ethyl (methylthio)acetate 4455-13-4 Ethyl pyruvate
617-35-6 Ethyl sorbate 2396-84-1 5-Formyl-2-furansulfonic acid,
31795-44-5 sodium salt Furfuryl mercaptan 98-02-2 1,6-Hexanedithiol
1191-43-1 trans-2-Hexenoic acid 13419-69-7 trans-2-Hexen-1-ol
928-95-0 4-(4-Hydroxyphenyl)-2-butanone 5471-51-2 Isopulegol
89-79-2 Isopulegyl acetate 89-49-6 2-Ketobutyric acid 600-18-0
(-)-Limonene 5989-54-8 4-Methoxyphenylacetone 122-84-9 Methyl
cyclohexanecarboxylate 4630-82-4 3-Methylcyclohexanone 591-24-2
3-Methyl-2-cyclohexen-1-one 1193-18-6
3-Methyl-1,2-cyclopentanedione 765-70-8
3-Methyl-2-cyclopenten-1-one 2758-18-1 N-Methyl-D-glucamine
6284-40-8 Methyl 3- 13532-18-8 (methylthio)propionate
4-Methyl-5-thiazoleethanol 137-00-8 5-Methyl-2- 13679-70-4
thiophenecarboxaldehyde DL-3-Methylvaleric acid 105-43-1
(-)-Myrtenal 564-94-3 Nopol 128-50-7 gamma-Octanoic lactone
104-50-7 3-Octanol 589-98-0 E-2-Octenoic acid 1871-67-6 Pamoic acid
130-85-8 4-Phenyl-2-butyl acetate 10415-88-0
1-Phenyl-1,2-propanedione 579-07-7 2-Phenylpropyl butyrate
80866-83-7 2-Phenylpropyl isobutyrate 65813-53-8 cis-2-Hexen-1-ol
928-94-9 Bis(methylthio)methane 1618-26-4 Magnesium carbonate
hydroxide, 39409-82-0 Light N-Acetyl-L-methionine 65-82-7
4-Methyl-5-vinylthiazole 1759-28-0 2-Methyl-1-phenyl-2-propanol
100-86-7 3-Phenylpropionaldehyde 104-53-0
N-Benzyl-2-phenylethylamine 3647-71-0 1-Phenylethyl propionate
120-45-6 3-Phenylpropyl isobutyrate 103-58-2 Allyl hexanoate
123-68-2 alpha, 4-Dimethylbenzylalcohol 536-50-5 (-)-Menthyl
lactate 59259-38-0 2,6-Dimethylthiophenol 118-72-9
2,4,5-Trimethylthiazole 13623-11-5 Ethyl 3-(methylthio)propionate
13327-56-5 Phenylethyl isovalerate 140-26-1 2-Propylpyrazine
18138-03-9 2-Methyltetrahydrofuran-3-one 3188-00-9 Ethyl 2-
23747-43-5 (methyldithio)propionate 3,4-Dimethyl-1,2- 13494-06-9
cyclopentanedione Difurfurylsulfide 13678-67-6 Difurfuryldisulfide
4437-20-1 3-(Methylthio)propanol 505-10-2 Methyl phenyl disulfide
14173-25-2 2-(Methyldithio)- 67952-60-7 isobutyraldehyde Methyl
2-thiofuroate 13679-61-3 2-Isobutylthiazole 18640-74-9
4-Methyl-5-thiazolylethyl 656-53-1 acetate 2-Acetylthiazole
24295-03-2 2-Ethyl-3,5(6)- 27043-05-6 dimethylpyrazine
5-Methyl-6,7-dihydro-5H- 23747-48-0 cyclopenta(b)pyrazine Cinnamyl
acetate 103-54-8 2,5-Dihydroxy-2,5-dimethyl- 55704-78-4
1,4-dithiane 5,6,7,8-Tetrahydroquinoxaline 34413-35-9
2-Methyl-3-furanethiol 28588-74-1 Styrallyl acetate 93-92-5
2-Methylhexanoic acid 4536-23-6 2-Methylheptanoic acid 1188-02-9
2,2,6-Trimethylcyclohexanone 2408-37-9 L-Tyrosine ethyl ester
4089-07-0 hydrochloride Ethyl 4-methoxybenzoate 94-30-4
4-Ethylbenzaldehyde 4748-78-1 N-Ethyl-p-menthane-3- 39711-79-0
carboxamide 1-(2-Furyl)-1,3-butanedione 25790-35-6 Menthofuran
494-90-6 Methylsulfuric acid sodium 512-42-5 salt Sucrose diacetate
126-13-6 hexaisobutyrate N,2,3-Trimethyl-2- 51115-67-4
isopropylbutamide Tripropionin 139-45-7 (+/-)-Citronellic acid
502-47-6 5-Acetyl-2,4-dimethylthiazole 38205-60-6 Neryl acetate
141-12-8 Benzyl propionate 122-63-4 1R-(-)-Camphorsulfonic acid
35963-20-3 3,4-Hexanedione 4437-51-8 cis-3-Hexenoic acid 4219-24-3
cis-4-Heptenal 6728-31-0 (E,Z)-2,6-nonadienal 557-48-2
trans-2,trans-6-Nonadienal 17587-33-6 4-Methyl-2-pentenal 5362-56-1
cis-6-Nonenal 2277-19-2 Methyl propyl disulfide 2179-60-4
8-p-Menthen-1-ol 138-87-4 p-Menthan-2-one 499-70-7 Bisabolene
495-62-5 Ethyl cyclohexanecarboxylate 3289-28-9 Phenylpyruvate
156-06-9 Hydroxypyruvate 1113-60-6 4-Methyl-2-oxopentanoate
816-66-0 (+)-Neomenthol 2216-52-6 trans-Citral 141-27-5
Piperitenone 491-09-8 Sabinene hydrate 546-79-2 Perillyl aldehyde
2111-75-3 2-Hydroxyethanesulfonate 107-36-8 Acetyl isovaleryl
13706-86-0 Acetyl valeryl 96-04-8 Butylidene phthalide 551-08-6
Carvacryl ethyl ether 4732-13-2 Ethyl vanillin propylene 68527-76-4
glycol acetal Hexyl hexanoate 6378-65-0
2-Methyl-5-(methylthio)-furan 13678-59-6 2-Methyl-4-pentenoic acid
1575-74-2 2-Methyl-4-propyl-1,3- 67715-80-4 oxathiane
3-Methylthio-1-hexanol 51755-66-9 cis-6-Nonenol 35854-86-5 Rose
oxide 16409-43-1 L-Linalool 126-91-0 5,6-Dimethyl-8- 4674-50-4
isopropenylbicyclo[4.4.0]dec- 1-en-3-one
2-Ethyl-3,5-dimethylpyrazine 13925-07-0 2-Isopropylpyrazine
29460-90-0 2-Isobutyl-3-methyl-pyrazine 13925-06-9
2-Methoxy-3-sec-butyl-pyrazine 24168-70-5 2-Methylthio-3(6)-methyl-
67952-65-2 pyrazine Benzylcarbinyl propionate 122-70-3 Bornyl
acetate 76-49-3 furaneol 3658-77-3 Methoxycinnamaldehyde 1963-36-6
Methylphenol, hydrogen sulfate 68127-34-4 Lactitol monohydrate
81025-04-9 2H-Pyrrole, 3,4-dihydro- 5724-81-2 2-Butenal, 2-methyl-,
(E)- 497-03-0 2-Pentenal 764-39-6 Ethanethioic acid, S-methyl
1534-08-3 ester 2-Hexenal 505-57-7 2-Methyl-2-pentenal 623-36-9
Cyclopentanethiol 1679-07-8 Butane, 2-ethoxy- 2679-87-0 S-Ethyl
thioacetate 625-60-5 ethyl methyl carbonate 623-53-0
3(2H)-Furanone, 2,5-dimethyl- 14400-67-0 Allyl propionate 2408-20-0
methyl 2-methylbutanoate 868-57-5 2-Butanone, 1-(methylthio)-
13678-58-5 Ethanethioic acid, S-propyl 2307-10-0 ester
1,2-Butanedithiol 16128-68-0 6-Methyl-3,5-heptadiene-2-one
1604-28-0 2-Octen-4-one 4643-27-0 2,5-dimethyl-3-furanthiol
55764-23-3 2-Heptenoic acid 18999-28-5 Butanoic acid, 2-propenyl
2051-78-7 ester 6-Methyl-5-hepten-2-ol 1569-60-4 trans-2-Octen-4-ol
20125-81-9 cis-3-Octen-1-ol 20125-84-2 1-Butanol, 2-methyl-,
acetate 624-41-9 4-methyl-alpha-methylstyrene 1195-32-0
trans-3-phenyl-2-propen-1-ol 4407-36-7 Benzeneacetaldehyde, alpha-
93-53-8 methyl- Benzene, (2-methoxyethyl)- 3558-60-9 Cyclohexene,
1-methyl-4-(1- 7705-14-8 methylethenyl)-, (+-)- Phenol,
2-(methylthio)- 1073-29-6 2-Hexen-1-yl acetate 2497-18-9
3-Hexen-1-ol, acetate, (Z)- 3681-71-8 5-Hydroxy-4-octanone 496-77-5
butyl 2-methylpropanoate 97-87-0 Benzofuran-2-carboxaldehyde
4265-16-1 DL-Lysine 70-54-2 1-Hexanethiol, 2-ethyl- 7341-17-5
2',4'-Dimethylacetophenone 89-74-7 2-Pentylpyridine 2294-76-0
1-Methoxy-4-propyl benzene 104-45-0 1-Hydroxy-2-methoxy-4-ethyl
2785-89-9 benzene Nonalactone 6008-27-1 Cyclohexyl propionate
6222-35-1 Allyl 2-ethylbutyrate 7493-69-8 Butanoic acid, 3-oxo-, 2-
7779-75-1 methylpropyl ester n-Butyl pentanoate 591-68-4
3,7-Dimethyl-1-octanol 106-21-8 3-Buten-2-one, 3-methyl-4-
1901-26-4 phenyl- 2-Propenoic acid, 3-phenyl-, 1754-62-7 methyl
ester, (E)- Benzene, 4-ethenyl-1,2- 6380-23-0 dimethoxy-
Benzenepropanol, alpha,alpha- 103-05-9 dimethyl- Benzene,
(butoxymethyl)- 588-67-0 Dimethyl anthranilate 85-91-6
2-Hexanoylfuran 14360-50-0 Cyclohexyl butyrate 1551-44-6
Naphthalene, 2-ethoxy- 93-18-5 Acetoacetic acid isoamyl ester
2308-18-1 Propanoic acid, 2-methyl-, 4- 103-93-5 methylphenyl ester
4-(4-Methoxyphenyl)-2-butanone 104-20-1 Isobutyl benzoate 120-50-3
Benzene, 1,2-dimethoxy-4-(1- 93-16-3 propenyl)- beta- 10415-87-9
Phenylethylmethylethylcarbinol 1,1-Dimethoxy-2-phenylpropane
90-87-9 Geranyl formate 105-86-2 Bornyl formate 7492-41-3
6-Octen-1-ol, 3,7-dimethyl-, 105-85-1 formate Benzeneacetic acid,
butyl 122-43-0 ester 3,5,9-Undecatrien-2-one, 6,10- 141-10-6
dimethyl- Anisyl propionate 7549-33-9 Butanoic acid, 3-phenyl-2-
103-61-7 propenyl ester 2-Propenoic acid, 3-phenyl-, 122-67-8
2-methylpropyl ester Eugenyl acetate 93-28-7 3-Methylbutyl
phenylacetate 102-19-2 Benzoic acid, 2-(methylamino)-, 65505-24-0
2-methylpropyl ester Phenoxy ethyl isobutyrate 103-60-6 Anisyl
butyrate 6963-56-0 2,6-Octadien-1-ol, 3,7- 105-91-9 dimethyl-,
propanoate, (Z)- Isobornyl propionate 2756-56-1 1,3,5-Trithiane,
2,2,4,4,6,6- 828-26-2 hexamethyl- Geranyl N-butyrate 106-29-6
Geranyl isobutyrate 2345-26-8 Thiophene, 2,2'-dithiobis- 6911-51-9
2-Propenoic acid, 3-phenyl-, 7779-17-1 cyclohexyl ester
Benzeneacetic acid, 3-phenyl- 7492-65-1 2-propenyl ester Anisyl
phenylacetate 102-17-0 2-Propenoic acid, 3-phenyl-, 122-68-9
3-phenylpropyl ester Geranyl phenylacetate 102-22-7 hexyl
2-methylbutyrate 10032-15-2 4-heptanolide 105-21-5 Neral 106-26-3
(E)-2-octenol 18409-17-1 Ethyl 3-hydroxyhexanoate 2305-25-1
isopropyl hexanoate 2311-46-8 hexyl butanoate 2639-63-6
bis(2-methyl-3-furyl)disulfide 28588-75-2
3-hydroxy-4,5-dimethyl-2(5H)- 28664-35-9
furanone 2-acetyl-2-thiazoline 29926-41-8 (E,E)-2,4-octadienal
30361-28-5 geranyl acetone 3796-70-1 1-octen-3-one 4312-99-6
3-mercapto-2-pentanone 67633-97-0 (Z)-3-hexenal 6789-80-6
4-hexanolide 695-06-7 5-octanolide 698-76-0 delta-decalactone
705-86-2 4-vinylguaiacol 7786-61-0 Amyl salicylate 2050-08-0
Cyclohexyl formate 4351-54-6 Dimethylbenzylcarbinyl acetate
151-05-3 Geranyl propionate 105-90-8 Terpinyl acetate 80-26-2
isopropyl 3-methylbutanoate 32665-23-9 isopropyl 2-methylbutanoate
66576-71-4 3-Hexenyl 3-methylbutanoate 10032-11-8 Isoamyl
2-methylbutyrate 27625-35-0 3-Octyl acetate 4864-61-3 Benzyl
isobutyrate 103-28-6 Cis-3-hexenyl butyrate 16491-36-4
Cis-3-hexenyl lactate 61931-81-5 Citronellyl butyrate 141-16-2
Citronellyl propionate 141-14-0 Isoamyl hexanoate 2198-61-0
1,3,5-Undecatriene 16356-11-9 1-Benzyloxy-2-methoxy-4- 120-11-6
propenyl benzene 1-Octen-3-yl acetate 198242 2-Acetyl-3-ethyl
pyrazine 32974-92-8 2-Isopropyl-4-methyl thiazole 15679-13-7
2-Methyl-2-pentenoic acid 3142-72-1 2-sec-butyl thiazole 18277-27-5
4,5-Dimethyl thiazole 3581-91-7 4-(2,6,6-Trimethyl-2- 31499-72-6
cyclohexen-1-yl)butan-2-one 4-(2,6,6-Trimethyl cyclohexa-
23696-85-7 1,3-dienyl)but-2-en-4-one Acetaldehyde phenethyl propyl
7493-57-4 acetal Acetaldehyde ethyl cis-3- 28069-74-1 hexenyl
acetal Acetone propylene glycol 1193-11-9 acetal Acetyl isoeugenol
93-29-8 2-Acetyl-5-methyl furan 1193-79-9 Allyl cyclohexylbutyrate
7493-65-4 Alpha,alpha-dimethylphenethyl 10094-34-5 butyrate
Alpha,alpha-dimethyl phenethyl 10058-43-2 formate
Alpha,beta-santalol 11031-45-1 Alpha-amyl cinnamaldehyde 91-87-2
dimethyl acetal Alpha-fenchyl acetate 13851-11-1 Alpha-furfuryl
pentanoate 36701-01-6 Alpha-ionol 25312-34-9 6-Methyl-alpha-ionone
79-69-6 Alpha-methyl-p- 103-95-7 isopropylphenylpropanaldehyde
Alpha-n-amyl-beta-phenylacryl 7493-78-9 acetate Alpha-piperitone
6091-50-5 Alpha-n-amyl-beta-phenyl acryl 7493-80-3 isovalerate
6-Amyl-alpha-pyrone 27593-23-3 Anisyl formate 122-91-8
Benzylcarbinyl 2-methyl 24817-51-4 butyrate Benzylcarbinyl 3-phenyl
103-53-7 propenoate Benzylcarbinyl alpha-toluate 102-20-5
Benzylcarbinyl butyrate 103-52-6 Benzylcarbinyl caproate 6290-37-5
Benzylcarbinyl formate 104-62-1 Benzylcarbinyl isobutyrate 103-48-0
Benzylcarbinyl salicylate 87-22-9 Benzylcarbinyl tiglate 55719-85-2
Benzyl dipropyl ketone 7492-37-7 Benzyl tiglate 37526-88-8
Beta-homocyclocitral 472-66-2 Beta-ionol 22029-76-1 3-Phenylpropyl
propanoate 122-74-7 Bois de rose oxide 7392-19-0 Butyl 2-methyl
butyrate 15706-73-7 Butyl cinnamate 538-65-8 ortho-sec-Butyl
cyclohexanone 14765-30-1 isobutyl cis-2-methyl-2- 7779-81-9
butenoate 5-n-Butyl-delta-valerolactone 3301-94-8 Campholenic
aldehyde 4501-58-0 Cedran-8-yl acetate 77-54-3 Cinnamyl isovalerate
140-27-2 Cis-3-hexenyl benzoate 25152-85-6 Cis-3-hexenyl caproate
31501-11-8 Cis-3-hexenyl formate 33467-73-1 Cis-3-hexenyl
isobutyrate 41519-23-7 Cis-3-hexenyl phenylacetate 42436-07-7
Cis-3-hexenyl propionate 33467-74-2 Cis-3-hexenyl tiglate
67883-79-8 Cis-3-hexenyl valerate 35852-46-1 cis-4-Hepten-1-ol
6191-71-5 Cis-5-octen-1-ol 64275-73-6 Citral dimethyl acetal
7549-37-3 Citronellyl isobutyrate 97-89-2 Citronellyl isovalerate
68922-10-1 Citronellyl valerate 7540-53-6 Citroxide 7416-35-5 Cocal
21834-92-4 p-Cresyl alpha-toluate 101-94-0 p-Cresyl isovalerate
55066-56-3 Dehydro-beta-cyclocitral 116-26-7
8,8-Diethoxy-2,6-dimethyl-2- 7779-94-4 octanol 5,7-Dihydro-2-methyl
36267-71-7 thieno(3,4-d)pyrimidine 2,5-Dihydro-4,5-dimethyl-2-(2-
65894-83-9 methyl propyl)thiazole Dihydrojasmone 1128-08-1
Dihydroxyacetophenone 28631-86-9 1,1-Dimethoxy-3,7-dimethyl-7-
141-92-4 octanol 3,7-Dimethyl-1,6-octadien-3-yl 126-64-7 benzoate
3,7-Dimethyl-1,6-octadien-3-yl 78-36-4 butyrate
3,7-Dimethyl-1,6-octadien-3-yl 78-35-3 isobutyrate
3,7-Dimethyl-1,6-octadien-3-yl 144-39-8 propanoate
cis-3,7-Dimethyl-2,6-octadien- 2345-24-6 1-yl 2-methyl propanoate
2,4-Dimethyl-3-cyclohexene-1- 68039-49-6 carboxaldehyde
2,6-Dimethyl-5-hepten-1-al 106-72-9 trans,cis-2,6-Dodecadien-1-al
21662-13-5 Eglantal 26643-91-4 Ethyl E-2-hexenoate 27829-72-7 Ethyl
tiglate 5837-78-5 Ethyl trans-4-decenoate 76649-16-6
5-Ethyl-4-hydroxy-2-methyl- 27538-09-6 3[2H]furanone
2-Ethyl-4-methyl thiazole 15679-12-6 2,6,10-Trimethyl-2,6,10-
762-29-8 pentadecatrien-14-one Guaiacyl phenyl acetate 4112-89-4
3-Hepten-2-one 1119-44-4 trans-2-Hexen-1-ol 2305-21-7
Trans-2-hexenyl butyrate 53398-83-7 Hexyl phenylacetate 5421-17-0
Hexyl propionate 2445-76-3 Hydroxycitronellol 107-74-4 Isobutyl
2-butenoate 589-66-2 Isobutyl salicylate 87-19-4 Isodihydro
lavandulal 35158-25-9 Isoeugenyl phenyl acetate 120-24-1 Isopropyl
alpha- 1733-25-1 methylcrotonate p-Menth-1-en-8-yl propionate
80-27-3 Menthalactone 13341-72-5 3-Methoxy-p-cymene 1076-56-8
Methyl 4-methyl pentanoate 2412-80-8 alpha-Methyl benzyl formate
7775-38-4 2-Methylbutyl 2- 2445-78-5 methylbutanoate Methyl
e-2-octenoate 2396-85-2 p-Methyl hydratropaldehyde 99-72-9
3-(5-Methyl-2-furyl)butanal 31704-80-0 Nerol oxide 1786-08-9
trans,cis-2,6-Nonadien-1-ol 7786-44-9 trans-2-Octen-1-yl acetate
3913-80-2 3-Octen-2-one 1669-44-9 2-Phenyl-2-butenal 4411-89-6
2-Propionylthiazole 43039-98-1 1-Hydroxy-2-butanone 5077-67-8
2-Butanone, 3-hydroxy-, (+-)- 52217-02-4 Thiazole, 2,5-dimethyl-
4175-66-0 Butanethioic acid, S-methyl 2432-51-1 ester
2,4-Hexadienoic acid, methyl 689-89-4 ester, (E,E)-
Benzeneacetaldehyde, 4-methyl- 104-09-6 Bicyclo[4.1.0]hept-3-ene,
498-15-7 3,7,7-trimethyl-, (1S)- Ethyl 3-hexenoate 2396-83-0
1H-Pyrrole, 1-(2- 1438-94-4 furanylmethyl)- 6-Octenal,
3,7-dimethyl-, (R)- 2385-77-5 Ethanethioic acid, S-(2- 13678-68-7
furanylmethyl) ester 6-Octen-1-ol, 3,7-dimethyl-, 1117-61-9 (R)-
6-Octen-1-ol, 3,7-dimethyl-, 7540-51-4 (S)- DL-Tetrohydrofurfuryl
637-65-0 propionate Benzenepentanol 10521-91-2 Cyclohexaneethanol,
acetate 21722-83-8 Benzyl isobutyl ketone 5349-62-2 Butanoic acid,
3-oxo-, 5396-89-4 phenylmethyl ester 1,2-Ethanediamine, N,N'-
140-28-3 bis(phenylmethyl)- 2-Ethyl-3-hydroxy-4-pyrone 1110651
Dicyclohexyl disulfide 2550-40-5 Tetrahydrofurfuryl butyrate
2217-33-6 Thujone 546-80-5 Benzyl alcohol, alpha-methyl-, 3460-44-4
butyrate Citronellyl tiglate 24717-85-9 Lactitol 585-86-4
Nonivamide 2444-46-4 2-Acetoxy-3-butanone 4906-24-5
3-Acetyl-2,5-dimethylthiophene 230378 3-Acetyl-2-5dimethylfuran
10599-70-9 4-Acetyl-6-t-butyl-1,1- 13171-00-1 dimethylindan Allyl
2-furoate 4208-49-5 Allyl sorbate 7493-75-6 Allyl thiopropionate
41820-22-8 Allyl tiglate 7493-71-2 Amylcyclohexyl acetate
67874-72-0 Benzaldehyde glyceryl acetal 1319-88-6 Benzaldehyde
propylene glycol 2568-25-4 acetal Bornyl isovalerate 76-50-6
1,3-Butanedithiol 24330-52-7 2,3-Butanedithiol 4532-64-3 Butyl
cinnamic aldehyde 7492-44-6 Cinnamyl benzoate 5320-75-2 Citral
ethylene glycol acetal 66408-78-4 Citronellyloxyacetaldehyde
7492-67-3 Citronellyl phenylacetate 139-70-8 Cyclohexyl isovalerate
7774-44-9 Decalactone 5579-78-2 2,5-Dimethyl-4-methoxy-3(2H)-
4077-47-8 furanone 6,10-Dimethyl-9-undecen-2-one 4433-36-7
2-Ethoxythiazole 15679-19-3 Ethyl 2-mercaptopropionate 19788-49-9
Ethyl 2-methyl-4-pentenoate 53399-81-8 Ethyl 3-(2-furyl)propanoate
94278-27-0 Ethyl cyclohexanepropionate 10094-36-7 Ethyl
(p-tolyloxy)acetate 67028-40-4 3-Ethyl-2-hydroxy-2- 21835-01-8
cyclopenten-1-one Ethylene brassylate 105-95-3 2-Ethylfenchol
18368-91-7 Furfuryl 3-methylbutanoate 13678-60-9
Furfuryl butyrate 623-21-2 Furfuryl isopropyl sulfide 1883-78-9
Furfuryl methyl sulfide 1438-91-1 Furfuryl propionate 623-19-8
Furfuryl thiopropionate 59020-85-8 Geranyl acetoacetate 10032-00-5
Geranyl benzoate 94-48-4 Geranyl isovalerate 109-20-6
delta-Hexalactone 823-22-3 trans-3-Hexenal 69112-21-6 cis-3-Hexenyl
anthranilate 65405-76-7 trans-2-Hexenyl propionate 53398-80-4
5-(cis-3-Hexenyl) dihydro-5- 70851-61-5 methyl-2(3H)furanone Hexyl
2-formate 39251-86-0 Hexyl crotonate 19089-92-0 Hexyl formate
629-33-4 Isoamyl 3-(2-furyl)propionate 7779-67-1 Isoamyl pyruvate
7779-72-8 Isobutyl furylpropionate 105-01-1 Isohexenyl cyclohexenyl
37677-14-8 carboxaldehyde p-Isopropyl phenylacetaldehyde 4395-92-0
Linalyl cinnamate 78-37-5 Linalyl formate 115-99-1 Linalyl
isovalerate 1118-27-0 Linalyl phenylacetate 7143-69-3 Maltol
isobutyrate 65416-14-0 Methyl 2-methylpentanoate 2177-77-7 Methyl
3-hydroxyhexanoate 21188-58-9 Methyl 3-nonenoate 13481-87-3 Methyl
furfuryl disulfide 57500-00-2 Methyl p-tert- 3549-23-3
butylphenylacetate 3-Methyl-1,2-cyclohexanedione 3008-43-3
alpha-Methylanisalacetone 104-27-8 2-Methylbutyl isovalerate
2445-77-4 4-Methylnonanoic acid 45019-28-1 4-Methyloctanoic acid
54947-74-9 2-Methyltetrahydrothiophen-3- 13679-85-1 one
3-(Methylthio)butanal 16630-52-7 4-(Methylthio)butanol 20582-85-8
4-Methylthio-2-butanone 34047-39-7 4-Methylthio-4-methyl-2-
23550-40-5 pentanone Neryl butyrate 999-40-6 Neryl formate
2142-94-1 Neryl isovalerate 3915-83-1 Octahydrocoumarin 4430-31-3
Phenethyl 2-furoate 7149-32-8 1-Phenyl-2-pentanol 705-73-7
Phenylacetaldehyde 68345-22-2 diisobutylacetal Phenylacetaldehyde
glyceryl 29895-73-6 acetal 2-(3-Phenylpropyl)pyridine 2110-18-1
Propyl phenylacetate 4606-15-9 Pyrazineethanethiol 35250-53-4 Ethyl
2-methyl pentanoate 39255-32-8 Methyl 2,4-decadienoate 4493-42-9
alpha-Isomethyl ionone 127-51-5 5-Methyl hexanoic acid 628-46-6
Ethyl 3-methyl pentanoate 5870-68-8 Ethyl 2-methyl-3,4- 60523-21-9
pentadienoate 3-Nonen-2-one 14309-57-0 5-Methyl-3-hexen-2-one
5166-53-0 Maltol propionate 68555-63-5 2-Methyl-3-(2-furyl)
acrolein 874-66-8 Ethyl 3(2-furyl)propanoate 10031-90-0
2-Phenyl-3-(2-furyl)-propenal 57568-60-2 4-Methyl-2-pentyl-1,3-
1599-49-1 dioxolane 2-Ethyl-4,5-dimethyl oxazole 53833-30-0
Isobornyl isovalerate 7779-73-9 Theophylline-7-acetic acid 652-37-9
Ethyl trans-2-octenoate 7367-82-0 DL-Arginine 7200-25-1 Allyl
Crotonate 20474-93-5 2-Methoxystyrene 612-15-7 Magnesium Fumarate
7704-71-4 2-Propionylpyrrole 1073-26-3 2-methyl-1,3-dithiolane
5616-51-3 2-ethyl-5-methyl pyrazine 13360-64-0
2-methyl-3-(dimercaptomethyl)- 65505-17-1 furan Magnesium gluconate
3632-91-5 Manganese gluconate 6485-39-8 Erythritol 149-32-6
D-Arabinose 28697-53-2 D-Galactose 59-23-4 D-(+)-Mannose 3458-28-4
Sorbitol 50-70-4 Aspartame 22839-47-0 Cyclamic Acid 100-88-9 Dulcin
150-69-6 Glucose-1-phosphate 29732-59-0 Dipotassium Salt
L-(+)-Arabinose 87-72-9 Fructose-6-Phosphate 643-13-0 D-Maltose
Monohydrate 6363-53-7 Ribose 24259-59-4 Fructose 1,6-Diphosphate
26177-85-5 Disodium Salt Saccharin sodium, dihydrate 6155-57-3
1,2-Benzisothiazol-3(2H)-one 6485-34-3 1,1-dioxide, calcium salt
1,2-Benzisothiazolin-3-one 10332-51-1 1,1-dioxide, potassium salt
zeranol 26538-44-3 beta-D-fructopyranose 7660-25-5 D-fructose
1,6-bisphosphate 488-69-7 Ribose 5-phosphate 4300-28-1 Arabinose
147-81-9 Saccharin, sodium salt hydrate 82385-42-0 Maltitol
585-88-6 D-Fructose 1-phosphate 15978-08-2 D-Sorbitol 6-phosphate
108392-12- alpha-D-Xylose 31178-70-8 Inositol 1-phosphate
573-35-3
[0364] TABLE-US-00010 TABLE 10 Name CAS # Sodium Metabisulfite
7681-57-4 sodium hydrogen phosphate 7558-79-4 Sodium Phosphate
Monobasic 7558-80-7 Sodium thiosulfate 7772-98-71 Orthoboric acid
10043-35-3 Diethanolamine 111-42-2 Benzaldehyde 100-52-7 Sorbic
acid 110-44-1 L-(+)-Tartaric Acid 87-69-4 D-mannitol 69-65-8 Butyl
paraben 94-26-8 Thymol 89-83-8 Methyl salicylate 119-36-8 Citric
acid 77-92-9 Creatinine 60-27-5 Vitamin C 50-81-7 Benzoic Acid
65-85-0 Methyl 4-hydroxybenzoate 99-76-3 m-Cresol 108-39-4 p-Cresol
106-44-5 Aspirin 50-78-2 Phenol 108-95-2 Sucrose 57-50-1 Potassium
citrate, monohydrate 1534146 Sodium acetate 127-09-3 Lactic acid
50-21-5 Propionic acid, sodium salt 65-85 Benzyl alcohol 100-51-6
Phenethyl alcohol 60-12-8 Cholesterol 57-88-5 D-Glucose 50-99-7
Sorbitol 50-70-4 Aspartame 22839-47-0 Saccharin 81-07-2
2,6-Di-tert-Butyl-p-Cresol 128-37-0 4-Chloro-3-methylphenol 59-50-7
glycerin 56-81-5 Propyl paraben 94-13-3 fumaric acid 110-17-8 dabco
280-57-9 p-Phenylenediamine 106-50-3 Anethole 4180-23-8 propyl
gallate 121-79-9 L-monosodium glutamate 142-47-2 Butylated
hydroxyanisole 25013-16-5 Cyclohexanol, 5-methyl-2-(1- 89-78-1
methylethyl)-, (1alpha,2beta,5alpha)- alpha-Thioglycerol 96-27-5
Sodium dehydroacetate 4418-26-2 Ethyl 4-hydroxybenzoate 120-47-8
Ethyl Vanillin 121-32-4 Triacetin 102-76-1 Potassium sorbate
590-00-1 Triethyl citrate 77-93-0 (S)-(+)-Arginine 74-79-3 Glycine
56-40-6 (S)-(-)-Histidine 71-00-1 (S)-(+)-Lysine 56-87-1 Quinone
106-51-4 Naphthalene, 2-ethoxy- 93-18-5 Methanesulfonic Acid
75-75-2 DL-Tartaric Acid 133-37-9 Cyclamic acid 100-88-9
(S)-(-)-Phenylalanine 63-91-2 (S)-(-)-Tyrosine 60-18-4 Carvone
99-49-0 Ethyl butyrate 105-54-4 6-Methyl-5-hepten-2-one 110-93-0
Ethyl acetoacetate 141-97-9 Methyl benzoate 93-58-3 Phenylacetic
Acid 103-82-2 Adipic acid 124-04-9 Ethyl benzoate 93-89-0 Benzyl
benzoate 120-51-4 Pyruvic acid 127-17-3 Succinic acid 110-15-6
Indole 120-72-9 Methyl anthranilate 134-20-3 Diethyl malonate
105-53-3 Niacin 59-67-6 Meso-inositol 87-89-8 4-Aminobenzoic acid
150-13-0 Anisole 100-66-3 Urea 57-13-6 Pyrrolidine 123-75-1
Cyclopentanone 120-92-3 Acetic anhydride 108-24-7 Benzophenone
119-61-9 D-(-)-Fructose 57-48-7 D-(+)-Xylose 58-86-6
o-Methoxybenzoic Acid 579-75-9 linalool 78-70-6 ethyl isovalerate
108-64-5 1,1'-Azobisformamide 123-77-3 6-Methylcoumarin 92-48-8
acetoin 513-86-0 alpha-Phellandrene 99-83-2 Cymene 99-87-6 Dimethyl
Succinate 106-65-0 p-Anisaldehyde 123-11-5 Phenyl ether 101-84-8
Tetrahydro-2-furanmethanol 97-99-4 Valeric Acid 109-52-4
3,4-xylenol 95-65-8 1,1-diethoxyethane 105-57-7 ethyl butyraldehyde
97-96-1 Ethyl crotonate 623-70-1 ethyl isobutyrate 97-62-1 methyl
isovalerate 556-24-1 methyl propionate 554-12-1 methyl
valeraldehyde 123-15-9 4-(2,6,6-Trimethyl-2- 127-41-3
cyclohexen-1-yl)-3-buten-2-one 4-(2,6,6-trimethyl-1- 14901-07-6
cyclohexen-1-yl)-3-buten-2-one Maleic acid 110-16-7
3-Methylbutanoic acid 503-74-2 L-Glutamic Acid 56-86-0 D-limonene
5989-27-5 1-Phenyl-1-propanol 93-54-9 2'-Hydroxyacetophenone
118-93-4 2,4-Dihydroxybenzoic Acid 89-86-1 2-Phenyl-1-propanol
1123-85-9 3-Phenylpropionic Acid 501-52-0 4-Ethoxyphenol 622-62-8
Alpha-Terpineol 98-55-5 Benzaldehyde Dimethylacetal 1125-88-8
Benzyl Ether 103-50-4 Benzyl Formate 104-57-4 Benzyl Salicylate
118-58-1 Cinnamyl Alcohol 104-54-1 D-(+)-Glucono-1,5-lactone
4253-68-3 D-Isoascorbic Acid 89-65-6 2,3-Naphthalenediol 92-44-4
Diethyl Succinate 123-25-1 Ethyl 2-Aminobenzoate 87-25-2 Ethyl
Cinnamate 103-36-6 Ethyl Phenylacetate 101-97-3 Ethyl Salicylate
118-61-5 gamma-Valerolactone 108-29-2 Hydroquinone Dimethyl Ether
150-78-7 Isocaproic Acid 645-07-1 Isoeugenol 97-54-1 Isopropyl
Benzoate 939-48-0 L-(+)-Isoleucine 73-32-5 L-Malic acid 97-67-6
L-2-Aminopropionic Acid 56-41-7 L-Carnitine 541-15-1 L-Glutamine
56-85-9 L-Hydroxyproline 51-35-4 L-Proline 147-85-3 L-Serine
56-45-1 L-Threonine 72-19-5 L-Valine 72-18-4 Phenoxyacetic Acid
122-59-8 Veratrole 91-16-7 2-Ethylbutyric acid 88-09-5
2-Methylpyrazine 109-08-0 o-methoxybenzaldehyde 135-02-4 L-Leucine
61-90-5 L-Asparagine 70-47-3 propiophenone 93-55-0
5-isopropyl-2-methyl-phenol 499-75-2 Xylitol 87-99-0 ethyl
4-oxopentanoate 539-88-8 methyl cinnamate 103-26-4 cumic alcohol
536-60-7 methyl 2-naphthyl ketone 93-08-3
1-methyl-4-(1-methylethyl)- 99-85-4 1,4-Cyclohexadiene en-ethylene
diamine Caffeine 58-08-2 5-methylfurfural 620-02-0 furfuryl acetate
623-17-6 terpinen-4-ol 10482-56-1 phenylethanal 122-78-1
4'-Methoxyacetophenone 100-06-1 D-Fenchone 4695-62-9
1-Methoxy-4-methylbenzene 104-93-8 o-methylanisole 578-58-5
Acetylacetaldehyde dimethyl 5436-21-5 acetal p-methylacetophenone
122-00-9 Methyl phenylacetate 101-41-7 4-Ethoxybenzaldehyde
10031-82-0 p-tolyl acetate 140-39-6 2,6-Dimethoxyphenol 91-10-1
Methyl 2-methoxybenzoate 606-45-1 alpha-methylcinnamaldehyde
101-39-3 2-methoxycinnamaldehyde 60125-24-8 Potassium bicarbonate
298-14-6 piperonyl acetate 326-61-4 2,3-hexanedione 3848-24-6
furfural acetone 623-15-4 trans beta-(2-furyl)acrolein 623-30-3
carveol 99-48-9 Methyl nicotinate 93-60-7 Ethyl benzoylacetate
94-02-0 Methyl 4-methoxybenzoate 121-98-2 Levulinic acid 123-76-2
m-Dimethoxybenzene 151-10-0 2-acetylpyridine 1122-62-9
tetramethyl-pyrazine 1124-11-4 2,3-dimethyl-pyrazine 5910-89-4
trimethyl-pyrazine 14667-55-1 2-ethyl-3-methyl-pyrazine 15707-23-0
5-Methyl-3H-furan-2-one 591-12-8 2-Methoxy-4-methylphenol 93-51-6
piperazine 110-85-0 2-Methoxy-4-propylphenol 2785-87-7 Naphthalene,
2-(2- 2173-57-1 methylpropoxy)- 2-Acetyl-1-methylpyrrole 932-16-1
3,3-Dimethylacrylic acid 541-47-9 Ethyl sorbate 2396-84-1
4-(4-Hydroxyphenyl)-2-butanone 5471-51-2 4-Methoxyphenylacetone
122-84-9 (-)-Myrtenal 564-94-3 3-Phenylpropionaldehyde 104-53-0
1-Phenylethyl propionate 120-45-6 2-Methyltetrahydrofuran-3-one
3188-00-9 Cinnamyl acetate 103-54-8 Styrallyl acetate 93-92-5 Ethyl
4-methoxybenzoate 94-30-4 Benzyl propionate 122-63-4 Phenylpyruvate
156-06-9 furaneol 3658-77-3 methyl 2-methylbutanoate 868-57-5
Benzeneacetaldehyde, alpha- 93-53-8 methyl- Dimethyl anthranilate
85-91-6 1,1-Dimethoxy-2-phenylpropane 90-87-9 4-hexanolide 695-06-7
Dimethylbenzylcarbinyl acetate 151-05-3 Benzyl isobutyrate 103-28-6
Acetyl isoeugenol 93-29-8 2-Acetyl-5-methyl furan 1193-79-9
Alpha-methyl-p- 103-95-7 isopropylphenylpropanaldehyde
Benzylcarbinyl formate 104-62-1 p-Cresyl alpha-toluate 101-94-0
Potassium bisulfate 7646-93-7 Potassium carbonate 584-08-7
Potassium chloride 7447-40-7
Potassium hydroxide 1310-58-3 Ethyl tiglate 5837-78-5 Nerol oxide
1786-08-9 DL-Tetrohydrofurfuryl 637-65-0 propionate Benzaldehyde
propylene glycol 2568-25-4 acetal 2-Methyl-3-(2-furyl) acrolein
874-66-8 vanillin 121-33-5 Cholic acid 81-25-4 R-Carvone 6485-40-1
Potassium nitrate 7757-79-1 Potassium permanganate 7722-64-7
Potassium persulfate 7727-21-1 Potassium phosphate, dibasic 2139900
Potassium Phosphate Monobasic 7778-77-0 Potassium sulfate 7778-80-5
Sodium bicarbonate 144-55-8 Sodium bisulfite 7631-90-5 Sodium
carbonate 497-19-8 Sodium chloride 7647-14-5 Sodium dithionite
7775-14-6 Sodium hydroxide 1310-73-2 Sodium nitrite 7632-00-0
Sodium Pyrophosphate 7722-88-5 Sodium sulfate 7757-82-6 Sodium
sulfite 7757-83-7 Sodium thiocyanate 540-72-7 Calcium Carbonate
471-34-1 Calcium chloride 10043-52-4 Calcium gluconate 299-28-5
Calcium hydroxide 1305-62-0 Calcium phosphate, dibasic 7757-93-9
Calcium sulfate 7778-18-9 N-Methyl-D-glucamine 6284-40-8 Calcium
oxide 1305-78-8 Calcium Phosphate Monobasic 7758-23-8 Magnesium
chloride hexahydrate 7791-18-6 Magnesium sulfate 7487-88-9
Magnesium Sulfate Heptahydrate 10034-99-8 Aluminum chloride
hexahydrate 7784-13-6 aluminum nitrate nonahydrate 7784-27-2
Aluminum potassium sulfate, 7784-24-9 dodecahydrate Aluminum
sulfate, 7784-31-8 octadecahydrate (S)-(-)-Cysteine 52-90-4
p-Toluenesulfonic Acid 104-15-4 Potassium bitartrate 868-14-4
DL-aspartic acid 617-45-8 p-Dimethylaminobenzaldehyde 100-10-7
Sodium salicylate 54-21-7 Benzoin 119-53-9 Sodium dodecyl sulfate
151-21-3 L-Menthol 2216-51-5 Tiron 149-45-1 Riboflavin 83-88-5
Sodium Acetate Trihydrate 6131-90-4 Disodium Succinate Hexahydrate
6106-21-4 Disodium 6381-92-6 ethylenediaminetetraacetate dihydrate
sodium citrate, dihydrate 1545801 Sodium potassium tartrate,
6381-59-5 tetrahydrate L-(+)-Arginine 1119-34-2 monohydrochloride
Ethylenediamine 333-18-6 dihydrochloride Sodium formate 141-53-7
Sodium acetate 127-09-3 Potassium acetate 127-08-2 Ammonium citrate
3012-65-5 Ammonium bicarbonate 1066-33-7 Ammonium chloride
12125-02-9 Ammonium nitrate 6484-52-2 Ammonium persulfate 7727-54-0
Ammonium sulfate 7783-20-2 Zinc chloride 7646-85-7 Sulfuric acid,
zinc salt 7446-20-0 (1:1), heptahydrate Sodium Tripolyphosphate
7758-29-4 ammonium benzoate 1863-63-4 ammonium bisulfite 10192-30-0
1,5-Naphthalenedisulfonic Acid 1655-29-4 Disodium Salt
4-Hydroxybenzoic Acid 99-96-7 Diphenylacetic Acid 117-34-0 Glutaric
Acid 110-94-1 L-(-)-Fucose 2438-80-4 L-Cysteine Hydrochloride
52-89-1 L-Histidine Hydrochloride 1880304 Monohydrate o-Toluic Acid
118-90-1 Pivalic Acid 75-98-9 Pyruvic Acid Sodium Salt 113-24-6
Potassium bromide 2139626 Sodium Dithionate Dihydrate 7631-94-9
Sodium Malonate 141-95-7 Trisodium Citrate 68-04-2 Potassium Sodium
Tartrate 304-59-6 Potassium Citrate 866-84-2 D-Maltose Monohydrate
6363-53-7 Cyclohexaamylose 10016-20-3 Dodecyl sulfate, lithium salt
2044-56-6 Manganese chloride 2145076 methyl-urea 598-50-5
beta-Cyclodextrin 7585-39-9 Triphosphoric acid, 13845-36-8
pentapotassium salt Glycine ethyl ester 623-33-6 hydrochloride
L-Histidine methyl ester 7389-87-9 dihydrochloride L-Leucine methyl
ester 7517-19-3 hydrochloride D-Lysine hydrochloride 7274-88-6
2-Naphthalenesulfonic acid 532-02-5 sodium salt calcium nitrate
tetrahydrate 13477-34-4 Vitamin B1 59-43-8 Zinc Acetate Dihydrate
5970-45-6 Potassium fluoride 7789-23-3 Potassium iodate 2139718
Potassium iodide 7681-11-0 Potassium thiocyanate 333-20-0 Sodium
bromide 7647-15-6 Sodium fluoride 7681-49-4 Sodium iodide 7681-82-5
Sodium nitrate 7631-99-4 Calcium acetate 5743-26-0 Trichloroacetic
acid 76-03-9 Ammonium acetate 631-61-8 Ammonium fluoride 12125-01-8
DL-malic acid 617-48-1 t-Butyl Alcohol 75-65-0 beta-Alanine
107-95-9 (S)-(-)-Tryptophan 73-22-3 Malonic acid 141-82-2
Phenethylamine 64-04-0 Salicylylaldehyde 90-02-8 Sodium benzoate
532-32-1 Mandelic acid 90-64-2 Calcium pantothenate 137-08-6
Chloroacetic Acid 79-11-8 Ethanol Amine 141-43-5 Salicylic acid
69-72-7 Saccharin sodium 128-44-9 Thiamine hydrochloride 67-03-8
2,2'-Oxybisethanol 111-46-6 Resorcinol 108-46-3
2-Amino-2-(hydroxymethyl)-1,3- 77-86-1 propanediol
2,5-Dimethylphenol 95-87-4 Ammonium Phosphate Monobasic 7722-76-1
1,3-Butanediol 107-88-0 Glycolic Acid 79-14-1 Sodium Gluconate
527-07-1 Terephthalic Acid 100-21-0 L-Ascorbic Acid Sodium Salt
134-03-2 3-Acetyl-6-methyl-2,4- 520-45-6 pyrandione Calcium Acetate
62-54-4 Nicotinamide 98-92-0 1-Hydroxy-2-naphthoic Acid 86-48-6
2-Isopropylphenol 88-69-7 4-Aminosalicylic Acid 65-49-6 Calcium
Glycerophosphate 27214-00-2 Erythorbic Acid Sodium Salt 7378-23-6
Gluconic Acid Potassium Salt 299-27-4 Orotic Acid 65-86-1 p-Anise
Alcohol 105-13-5 Potassium Benzoate 582-25-2 Taurine 107-35-7
Thiamine Nitrate 532-43-4 3,3,5-Trimethyl-1-cyclohexanol 116-02-9
tert-Butylhydroquinone 1948-33-0 Sulfosalicylic acid 97-05-2 Gallic
acid 149-91-7 L-borneol 464-45-9 Isoborneol 124-76-5
2,5-Dihydroxybenzoic acid, 490-79-9 Gentisic acid
5-hydroxy-6-methyl-3,4- 65-23-6 pyridinedimethanol
Naphthalene-2-sulfonic acid 120-18-3 Ethanesulfonic acid, 2-
1562-00-1 hydroxy-, monosodium salt Pamoic acid 130-85-8
2,4-Dimethylphenol 105-67-9 3,5-Dihydroxyacetophenone 51863-60-6
Eugenol 97-53-0 n-Butyric Acid 107-92-6 Hydroquinone 123-31-9
Propionic Acid 79-09-4 meta-Phenylenediamine 108-45-2 Oxalic Acid
144-62-7 n-Hexanoic Acid 142-62-1 2-Furancarboxylic Acid 88-14-2
4'-Nitroacetanilide 104-04-1 D-(-)-Tartaric Acid 147-71-7
p-Acetamidobenzoic Acid 556-08-1 Galactaric acid 526-99-8
D-glucuronate 1700908 Lactobionic acid 96-82-2 p-Formylacetanilide
122-85-0 2-Mercaptobenzoic acid 147-93-3 Propanoic acid,
2-hydroxy-, 28305-25-1 calcium salt (2:1), (S)-
D(+)-10-Camphorsulfonic acid 3144-16-9 3-Cyclopentylpropionic acid
140-77-2 1R-(-)-Camphorsulfonic acid 35963-20-3 DL-Lysine 70-54-2
Cinnamic acid 621-82-9 Triethanolamine 102-71-6 Acetic Acid 64-19-7
Dichloroacetic Acid 79-43-6 Diethylamine 109-89-7
Diethylaminoethanol 100-37-8 N-(2-Hydroxyethyl)Morpholine 622-40-2
Octanoic Acid 124-07-2 isobutyric acid 79-31-2 Anisic Acid 100-09-4
Betaine 107-43-7 Enanthoic Acid 111-14-8 Hippuric Acid 495-69-2
Tiglic Acid 80-59-1 Cyclohexanecarboxylic acid 98-89-5
m-Methoxybenzoic acid 586-38-9 D-(+)-Camphoric acid 124-83-4
N-(2-Hydroxyethyl)pyrrolidine 2955-88-6 Sodium Metabisulfite
7681-57-4 sodium hydrogen phosphate 7558-79-4 Sodium Phosphate
Monobasic 7558-80-7 Sodium thiosulfate 7772-98-71 Orthoboric acid
10043-35-3 Diethanolamine 111-42-2 Benzaldehyde 100-52-7 Sorbic
acid 110-44-1 L-(+)-Tartaric Acid 87-69-4 D-mannitol 69-65-8 Butyl
paraben 94-26-8 Thymol 89-83-8 Methyl salicylate 119-36-8 Citric
acid 77-92-9 Creatinine 60-27-5 Vitamin C 50-81-7 Benzoic Acid
65-85-0 Methyl 4-hydroxybenzoate 99-76-3 m-Cresol 108-39-4 p-Cresol
106-44-5
Aspirin 50-78-2 Phenol 108-95-2 Sucrose 57-50-1 Potassium citrate,
monohydrate 1534146 Sodium acetate 127-09-3 Lactic acid 50-21-5
Propionic acid, sodium salt 65-85 Benzyl alcohol 100-51-6 Phenethyl
alcohol 60-12-8 Cholesterol 57-88-5 D-Glucose 50-99-7 Sorbitol
50-70-4 Aspartame 22839-47-0 Saccharin 81-07-2
2,6-Di-tert-Butyl-p-Cresol 128-37-0 4-Chloro-3-methylphenol 59-50-7
glycerin 56-81-5 Propyl paraben 94-13-3 fumaric acid 110-17-8 dabco
280-57-9 p-Phenylenediamine 106-50-3 Anethole 4180-23-8 propyl
gallate 121-79-9 L-monosodium glutamate 142-47-2 Butylated
hydroxyanisole 25013-16-5 Cyclohexanol, 5-methyl-2-(1- 89-78-1
methylethyl)-, (1alpha,2beta,5alpha)- alpha-Thioglycerol 96-27-5
Sodium dehydroacetate 4418-26-2 Ethyl 4-hydroxybenzoate 120-47-8
Ethyl Vanillin 121-32-4 Triacetin 102-76-1 Potassium sorbate
590-00-1 Triethyl citrate 77-93-0 (S)-(+)-Arginine 74-79-3 Glycine
56-40-6 (S)-(-)-Histidine 71-00-1 (S)-(+)-Lysine 56-87-1 Quinone
106-51-4 Naphthalene, 2-ethoxy- 93-18-5 Methanesulfonic Acid
75-75-2 DL-Tartaric Acid 133-37-9 Cyclamic acid 100-88-9
(S)-(-)-Phenylalanine 63-91-2 (S)-(-)-Tyrosine 60-18-4 Carvone
99-49-0 Ethyl butyrate 105-54-4 6-Methyl-5-hepten-2-one 110-93-0
Ethyl acetoacetate 141-97-9 Methyl benzoate 93-58-3 Phenylacetic
Acid 103-82-2 Adipic acid 124-04-9 Ethyl benzoate 93-89-0 Benzyl
benzoate 120-51-4 Pyruvic acid 127-17-3 Succinic acid 110-15-6
Indole 120-72-9 Methyl anthranilate 134-20-3 Diethyl malonate
105-53-3 Niacin 59-67-6 Meso-inositol 87-89-8 4-Aminobenzoic acid
150-13-0 Anisole 100-66-3 Urea 57-13-6 Pyrrolidine 123-75-1
Cyclopentanone 120-92-3 Acetic anhydride 108-24-7 Benzophenone
119-61-9 D-(-)-Fructose 57-48-7 D-(+)-Xylose 58-86-6
o-Methoxybenzoic Acid 579-75-9 linalool 78-70-6 ethyl isovalerate
108-64-5 1,1'-Azobisformamide 123-77-3 6-Methylcoumarin 92-48-8
acetoin 513-86-0 alpha-Phellandrene 99-83-2 Cymene 99-87-6 Dimethyl
Succinate 106-65-0 p-Anisaldehyde 123-11-5 Phenyl ether 101-84-8
Tetrahydro-2-furanmethanol 97-99-4 Valeric Acid 109-52-4
3,4-xylenol 95-65-8 1,1-diethoxyethane 105-57-7 ethyl butyraldehyde
97-96-1 Ethyl crotonate 623-70-1 ethyl isobutyrate 97-62-1 methyl
isovalerate 556-24-1 methyl propionate 554-12-1 methyl
valeraldehyde 123-15-9 4-(2,6,6-Trimethyl-2- 127-41-3
cyclohexen-1-yl)-3-buten-2-one 4-(2,6,6-trimethyl-1- 14901-07-6
cyclohexen-1-yl)-3-buten-2-one Maleic acid 110-16-7
3-Methylbutanoic acid 503-74-2 L-Glutamic Acid 56-86-0 D-limonene
5989-27-5 1-Phenyl-1-propanol 93-54-9 2'-Hydroxyacetophenone
118-93-4 2,4-Dihydroxybenzoic Acid 89-86-1 2-Phenyl-1-propanol
1123-85-9 3-Phenylpropionic Acid 501-52-0 4-Ethoxyphenol 622-62-8
Alpha-Terpineol 98-55-5 Benzaldehyde Dimethylacetal 1125-88-8
Benzyl Ether 103-50-4 Benzyl Formate 104-57-4 Benzyl Salicylate
118-58-1 Cinnamyl Alcohol 104-54-1 D-(+)-Glucono-1,5-lactone
4253-68-3 D-Isoascorbic Acid 89-65-6 2,3-Naphthalenediol 92-44-4
Diethyl Succinate 123-25-1 Ethyl 2-Aminobenzoate 87-25-2 Ethyl
Cinnamate 103-36-6 Ethyl Phenylacetate 101-97-3 Ethyl Salicylate
118-61-6 gamma-Valerolactone 108-29-2 Hydroquinone Dimethyl Ether
150-78-7 Isocaproic Acid 646-07-1 Isoeugenol 97-54-1 Isopropyl
Benzoate 939-48-0 L-(+)-Isoleucine 73-32-5 L-Malic acid 97-67-6
L-2-Aminopropionic Acid 56-41-7 L-Carnitine 541-15-1 L-Glutamine
56-85-9 L-Hydroxyproline 51-35-4 L-Proline 147-85-3 L-Serine
56-45-1 L-Threonine 72-19-5 L-Valine 72-18-4 Phenoxyacetic Acid
122-59-8 Veratrole 91-16-7 2-Ethylbutyric acid 88-09-5
2-Methylpyrazine 109-08-0 o-methoxybenzaldehyde 135-02-4 L-Leucine
61-90-5 L-Asparagine 70-47-3 propiophenone 93-55-0
5-isopropyl-2-methyl-phenol 499-75-2 Xylitol 87-99-0 ethyl
4-oxopentanoate 539-88-8 methyl cinnamate 103-26-4 cumic alcohol
536-60-7 methyl 2-naphthyl ketone 93-08-3
1-methyl-4-(1-methylethyl)- 99-85-4 1,4-Cyclohexadiene en-ethylene
diamine Caffeine 58-08-2 5-methylfurfural 620-02-0 furfuryl acetate
623-17-6 terpinen-4-ol 10482-56-1 phenylethanal 122-78-1
4'-Methoxyacetophenone 100-06-1 D-Fenchone 4695-62-9
1-Methoxy-4-methylbenzene 104-93-8 o-methylanisole 578-58-5
Acetylacetaldehyde dimethyl 5436-21-5 acetal p-methylacetophenone
122-00-9 Methyl phenylacetate 101-41-7 4-Ethoxybenzaldehyde
10031-82-0 p-tolyl acetate 140-39-6 2,6-Dimethoxyphenol 91-10-1
Methyl 2-methoxybenzoate 606-45-1 alpha-methylcinnamaldehyde
101-39-3 2-methoxycinnamaldehyde 60125-24-8 Potassium bicarbonate
298-14-6 piperonyl acetate 326-61-4 2,3-hexanedione 3848-24-6
furfural acetone 623-15-4 trans beta-(2-furyl)acrolein 623-30-3
carveol 99-48-9 Methyl nicotinate 93-60-7 Ethyl benzoylacetate
94-02-0 Methyl 4-methoxybenzoate 121-98-2 Levulinic acid 123-76-2
m-Dimethoxybenzene 151-10-0 2-acetylpyridine 1122-62-9
tetramethyl-pyrazine 1124-11-4 2,3-dimethyl-pyrazine 5910-89-4
trimethyl-pyrazine 14667-55-1 2-ethyl-3-methyl-pyrazine 15707-23-0
5-Methyl-3H-furan-2-one 591-12-8 2-Methoxy-4-methylphenol 93-51-6
piperazine 110-85-0 2-Methoxy-4-propylphenol 2785-87-7 Naphthalene,
2-(2- 2173-57-1 methylpropoxy)- 2-Acetyl-1-methylpyrrole 932-16-1
3,3-Dimethylacrylic acid 541-47-9 Ethyl sorbate 2396-84-1
4-(4-Hydroxyphenyl)-2-butanone 5471-51-2 4-Methoxyphenylacetone
122-84-9 (-)-Myrtenal 564-94-3 3-Phenylpropionaldehyde 104-53-0
1-Phenylethyl propionate 120-45-6 2-Methyltetrahydrofuran-3-one
3188-00-9 Cinnamyl acetate 103-54-8 Styrallyl acetate 93-92-5 Ethyl
4-methoxybenzoate 94-30-4 Benzyl propionate 122-63-4 Phenylpyruvate
156-06-9 furaneol 3658-77-3 methyl 2-methylbutanoate 868-57-5
Benzeneacetaldehyde, alpha- 93-53-8 methyl- Dimethyl anthranilate
85-91-6 1,1-Dimethoxy-2-phenylpropane 90-87-9 4-hexanolide 695-06-7
Dimethylbenzylcarbinyl acetate 151-05-3 Benzyl isobutyrate 103-28-6
Acetyl isoeugenol 93-29-8 2-Acetyl-5-methyl furan 1193-79-9
Alpha-methyl-p- 103-95-7 isopropylphenylpropanaldehyde
Benzylcarbinyl formate 104-62-1 p-Cresyl alpha-toluate 101-94-0
Potassium bisulfate 7646-93-7 Potassium carbonate 584-08-7
Potassium chloride 7447-40-7 Potassium hydroxide 1310-58-3 Ethyl
tiglate 5837-78-5 Nerol oxide 1786-08-9 DL-Tetrohydrofurfuryl
637-65-0 propionate Benzaldehyde propylene glycol 2568-25-4 acetal
2-Methyl-3-(2-furyl) acrolein 874-66-8 vanillin 121-33-5 Cholic
acid 81-25-4 R-Carvone 6485-40-1 Potassium nitrate 7757-79-1
Potassium permanganate 7722-64-7 Potassium persulfate 7727-21-1
Potassium phosphate, dibasic 2139900 Potassium Phosphate Monobasic
7778-77-0 Potassium sulfate 7778-80-5 Sodium bicarbonate 144-55-8
Sodium bisulfite 7631-90-5 Sodium carbonate 497-19-8 Sodium
chloride 7647-14-5 Sodium dithionite 7775-14-6 Sodium hydroxide
1310-73-2 Sodium nitrite 7632-00-0 Sodium Pyrophosphate 7722-88-5
Sodium sulfate 7757-82-6
Sodium sulfite 7757-83-7 Sodium thiocyanate 540-72-7 Calcium
Carbonate 471-34-1 Calcium chloride 10043-52-4 Calcium gluconate
299-28-5 Calcium hydroxide 1305-62-0 Calcium phosphate, dibasic
7757-93-9 Calcium sulfate 7778-18-9 N-Methyl-D-glucamine 6284-40-8
Calcium oxide 1305-78-8 Calcium Phosphate Monobasic 7758-23-8
Magnesium chloride hexahydrate 7791-18-6 Magnesium sulfate
7487-88-9 Magnesium Sulfate Heptahydrate 10034-99-8 Aluminum
chloride hexahydrate 7784-13-6 aluminum nitrate nonahydrate
7784-27-2 Aluminum potassium sulfate, 7784-24-9 dodecahydrate
Aluminum sulfate, 7784-31-8 octadecahydrate (S)-(-)-Cysteine
52-90-4 p-Toluenesulfonic Acid 104-15-4 Potassium bitartrate
868-14-4 DL-aspartic acid 617-45-8 p-Dimethylaminobenzaldehyde
100-10-7 Sodium salicylate 54-21-7 Benzoin 119-53-9 Sodium dodecyl
sulfate 151-21-3 L-Menthol 2216-51-5 Tiron 149-45-1 Riboflavin
83-88-5 Sodium Acetate Trihydrate 6131-90-4 Disodium Succinate
Hexahydrate 6106-21-4 Disodium 6381-92-6
ethylenediaminetetraacetate dihydrate sodium citrate, dihydrate
1545801 Sodium potassium tartrate, 6381-59-5 tetrahydrate
L-(+)-Arginine 1119-34-2 monohydrochloride Ethylenediamine 333-18-6
dihydrochloride Sodium formate 141-53-7 Sodium acetate 127-09-3
Potassium acetate 127-08-2 Ammonium citrate 3012-65-5 Ammonium
bicarbonate 1066-33-7 Ammonium chloride 12125-02-9 Ammonium nitrate
6484-52-2 Ammonium persulfate 7727-54-0 Ammonium sulfate 7783-20-2
Zinc chloride 7646-85-7 Sulfuric acid, zinc salt 7446-20-0 (1:1),
heptahydrate Sodium Tripolyphosphate 7758-29-4 ammonium benzoate
1863-63-4 ammonium bisulfite 10192-30-0 1,5-Naphthalenedisulfonic
Acid 1655-29-4 Disodium Salt 4-Hydroxybenzoic Acid 99-96-7
Diphenylacetic Acid 117-34-0 Glutaric Acid 110-94-1 L-(-)-Fucose
2438-80-4 L-Cysteine Hydrochloride 52-89-1 L-Histidine
Hydrochloride 1880304 Monohydrate o-Toluic Acid 118-90-1 Pivalic
Acid 75-98-9 Pyruvic Acid Sodium Salt 113-24-6 Potassium bromide
2139626 Sodium Dithionate Dihydrate 7631-94-9 Sodium Malonate
141-95-7 Trisodium Citrate 68-04-2 Potassium Sodium Tartrate
304-59-6 Potassium Citrate 866-84-2 D-Maltose Monohydrate 6363-53-7
Cyclohexaamylose 10016-20-3 Dodecyl sulfate, lithium salt 2044-56-6
Manganese chloride 2145076 methyl-urea 598-50-5 beta-Cyclodextrin
7585-39-9 Triphosphoric acid, 13845-36-8 pentapotassium salt
Glycine ethyl ester 623-33-6 hydrochloride L-Histidine methyl ester
7389-87-9 dihydrochloride L-Leucine methyl ester 7517-19-3
hydrochloride D-Lysine hydrochloride 7274-88-6
2-Naphthalenesulfonic acid 532-02-5 sodium salt calcium nitrate
tetrahydrate 13477-34-4 Vitamin B1 59-43-8 Zinc Acetate Dihydrate
5970-45-6 Potassium fluoride 7789-23-3 Potassium iodate 2139718
Potassium iodide 7681-11-0 Potassium thiocyanate 333-20-0 Sodium
bromide 7647-15-6 Sodium fluoride 7681-49-4 Sodium iodide 7681-82-5
Sodium nitrate 7631-99-4 Calcium acetate 5743-26-0 Trichloroacetic
acid 76-03-9 Ammonium acetate 631-61-8 Ammonium fluoride 12125-01-8
DL-malic acid 617-48-1 t-Butyl Alcohol 75-65-0 beta-Alanine
107-95-9 (S)-(-)-Tryptophan 73-22-3 Malonic acid 141-82-2
Phenethylamine 64-04-0 Salicylylaldehyde 90-02-8 Sodium benzoate
532-32-1 Mandelic acid 90-64-2 Calcium pantothenate 137-08-6
Chloroacetic Acid 79-11-8 Ethanol Amine 141-43-5 Salicylic acid
69-72-7 Saccharin sodium 128-44-9 Thiamine hydrochloride 67-03-8
2,2'-Oxybisethanol 111-46-6 Resorcinol 108-46-3
2-Amino-2-(hydroxymethyl)-1,3- 77-86-1 propanediol
2,5-Dimethylphenol 95-87-4 Ammonium Phosphate Monobasic 7722-76-1
1,3-Butanediol 107-88-0 Glycolic Acid 79-14-1 Sodium Gluconate
527-07-1 Terephthalic Acid 100-21-0 L-Ascorbic Acid Sodium Salt
134-03-2 3-Acetyl-6-methyl-2,4- 520-45-6 pyrandione Calcium Acetate
62-54-4 Nicotinamide 98-92-0 1-Hydroxy-2-naphthoic Acid 86-48-6
2-Isopropylphenol 88-69-7 4-Aminosalicylic Acid 65-49-6 Calcium
Glycerophosphate 27214-00-2 Erythorbic Acid Sodium Salt 7378-23-6
Gluconic Acid Potassium Salt 299-27-4 Orotic Acid 65-86-1 p-Anise
Alcohol 105-13-5 Potassium Benzoate 582-25-2 Taurine 107-35-7
Thiamine Nitrate 532-43-4 3,3,5-Trimethyl-1-cyclohexanol 116-02-9
tert-Butylhydroquinone 1948-33-0 Sulfosalicylic acid 97-05-2 Gallic
acid 149-91-7 L-borneol 464-45-9 Isoborneol 124-76-5
2,5-Dihydroxybenzoic acid, 490-79-9 Gentisic acid
5-hydroxy-6-methyl-3,4- 65-23-6 pyridinedimethanol
Naphthalene-2-sulfonic acid 120-18-3 Ethanesulfonic acid, 2-
1562-00-1 hydroxy-, monosodium salt Pamoic acid 130-85-8
2,4-Dimethylphenol 105-67-9 3,5-Dihydroxyacetophenone 51863-60-6
Eugenol 97-53-0 n-Butyric Acid 107-92-6 Hydroquinone 123-31-9
Propionic Acid 79-09-4 meta-Phenylenediamine 108-45-2 Oxalic Acid
144-62-7 n-Hexanoic Acid 142-62-1 2-Furancarboxylic Acid 88-14-2
4'-Nitroacetanilide 104-04-1 D-(-)-Tartaric Acid 147-71-7
p-Acetamidobenzoic Acid 556-08-1 Galactaric acid 526-99-8
D-glucuronate 1700908 Lactobionic acid 96-82-2 p-Formylacetanilide
122-85-0 2-Mercaptobenzoic acid 147-93-3 Propanoic acid,
2-hydroxy-, 28305-25-1 calcium salt (2:1), (S)-
D(+)-10-Camphorsulfonic acid 3144-16-9 3-Cyclopentylpropionic acid
140-77-2 1R-(-)-Camphorsulfonic acid 35963-20-3 DL-Lysine 70-54-2
Cinnamic acid 621-82-9 Triethanolamine 102-71-6 Acetic Acid 64-19-7
Dichloroacetic Acid 79-43-6 Diethylamine 109-89-7
Diethylaminoethanol 100-37-8 N-(2-Hydroxyethyl)Morpholine 622-40-2
Octanoic Acid 124-07-2 isobutyric acid 79-31-2 Anisic Acid 100-09-4
Betaine 107-43-7 Enanthoic Acid 111-14-8 Hippuric Acid 495-69-2
Tiglic Acid 80-59-1 Cyclohexanecarboxylic acid 98-89-5
m-Methoxybenzoic acid 586-38-9 D-(+)-Camphoric acid 124-83-4
N-(2-Hydroxyethyl)pyrrolidine 2955-88-6 Sodium Metabisulfite
7681-57-4 sodium hydrogen phosphate 7558-79-4 Sodium Phosphate
Monobasic 7558-80-7 Sodium thiosulfate 7772-98-71 Orthoboric acid
10043-35-3 Diethanolamine 111-42-2 Benzaldehyde 100-52-7 Sorbic
acid 110-44-1 L-(+)-Tartaric Acid 87-69-4 D-mannitol 69-65-8 Butyl
paraben 94-26-8 Thymol 89-83-8 Methyl salicylate 119-36-8 Citric
acid 77-92-9 Creatinine 60-27-5 Vitamin C 50-81-7 Benzoic Acid
65-85-0 Methyl 4-hydroxybenzoate 99-76-3 m-Cresol 108-39-4 p-Cresol
106-44-5 Aspirin 50-78-2 Phenol 108-95-2 Sucrose 57-50-1 Potassium
citrate, monohydrate 1534146 Sodium acetate 127-09-3 Lactic acid
50-21-5 Propionic acid, sodium salt 65-85 Benzyl alcohol 100-51-6
Phenethyl alcohol 60-12-8 Cholesterol 57-88-5 D-Glucose 50-99-7
Sorbitol 50-70-4 Aspartame 22839-47-0 Saccharin 81-07-2
2,6-Di-tert-Butyl-p-Cresol 128-37-0 4-Chloro-3-methylphenol 59-50-7
glycerin 56-81-5 Propyl paraben 94-13-3 fumaric acid 110-17-8 dabco
280-57-9 p-Phenylenediamine 106-50-3 Anethole 4180-23-8 propyl
gallate 121-79-9 L-monosodium glutamate 142-47-2 Butylated
hydroxyanisole 25013-16-5 Cyclohexanol, 5-methyl-2-(1- 89-78-1
methylethyl)-, (1alpha,2beta,5alpha)- alpha-Thioglycerol 96-27-5
Sodium dehydroacetate 4418-26-2 Ethyl 4-hydroxybenzoate 120-47-8
Ethyl Vanillin 121-32-4 Triacetin 102-76-1 Potassium sorbate
590-00-1 Triethyl citrate 77-93-0 (S)-(+)-Arginine 74-79-3 Glycine
56-40-6 (S)-(-)-Histidine 71-00-1 (S)-(+)-Lysine 56-87-1 Quinone
106-51-4 Naphthalene, 2-ethoxy- 93-18-5 Methanesulfonic Acid
75-75-2 DL-Tartaric Acid 133-37-9 Cyclamic acid 100-88-9
(S)-(-)-Phenylalanine 63-91-2 (S)-(-)-Tyrosine 60-18-4 Carvone
99-49-0 Ethyl butyrate 105-54-4 6-Methyl-5-hepten-2-one 110-93-0
Ethyl acetoacetate 141-97-9 Methyl benzoate 93-58-3 Phenylacetic
Acid 103-82-2 Adipic acid 124-04-9 Ethyl benzoate 93-89-0 Benzyl
benzoate 120-51-4 Pyruvic acid 127-17-3 Succinic acid 110-15-6
Indole 120-72-9 Methyl anthranilate 134-20-3 Diethyl malonate
105-53-3 Niacin 59-67-6 Meso-inositol 87-89-8 4-Aminobenzoic acid
150-13-0 Anisole 100-66-3 Urea 57-13-6 Pyrrolidine 123-75-1
Cyclopentanone 120-92-3 Acetic anhydride 108-24-7 Benzophenone
119-61-9 D-(-)-Fructose 57-48-7 D-(+)-Xylose 58-86-6
o-Methoxybenzoic Acid 579-75-9 linalool 78-70-6 ethyl isovalerate
108-64-5 1,1'-Azobisformamide 123-77-3 6-Methylcoumarin 92-48-8
acetoin 513-86-0 alpha-Phellandrene 99-83-2 Cymene 99-87-6 Dimethyl
Succinate 106-65-0 p-Anisaldehyde 123-11-5 Phenyl ether 101-84-8
Tetrahydro-2-furanmethanol 97-99-4 Valeric Acid 109-52-4
3,4-xylenol 95-65-8 1,1-diethoxyethane 105-57-7 ethyl butyraldehyde
97-96-1 Ethyl crotonate 623-70-1 ethyl isobutyrate 97-62-1 methyl
isovalerate 556-24-1 methyl propionate 554-12-1 methyl
valeraldehyde 123-15-9 4-(2,6,6-Trimethyl-2- 127-41-3
cyclohexen-1-yl)-3-buten-2-one 4-(2,6,6-trimethyl-1- 14901-07-6
cyclohexen-1-yl)-3-buten-2-one Maleic acid 110-16-7
3-Methylbutanoic acid 503-74-2 L-Glutamic Acid 56-86-0 D-limonene
5989-27-5 1-Phenyl-1-propanol 93-54-9 2'-Hydroxyacetophenone
118-93-4 2,4-Dihydroxybenzoic Acid 89-86-1 2-Phenyl-1-propanol
1123-85-9 3-Phenylpropionic Acid 501-52-0 4-Ethoxyphenol 622-62-8
Alpha-Terpineol 98-55-5 Benzaldehyde Dimethylacetal 1125-88-8
Benzyl Ether 103-50-4 Benzyl Formate 104-57-4 Benzyl Salicylate
118-58-1 Cinnamyl Alcohol 104-54-1 D-(+)-Glucono-1,5-lactone
4253-68-3 D-Isoascorbic Acid 89-65-6 2,3-Naphthalenediol 92-44-4
Diethyl Succinate 123-25-1 Ethyl 2-Aminobenzoate 87-25-2 Ethyl
Cinnamate 103-36-6 Ethyl Phenylacetate 101-97-3 Ethyl Salicylate
118-61-6 gamma-Valerolactone 108-29-2 Hydroquinone Dimethyl Ether
150-78-7 Isocaproic Acid 646-07-1 Isoeugenol 97-54-1 Isopropyl
Benzoate 939-48-0 L-(+)-Isoleucine 73-32-5 L-Malic acid 97-67-6
L-2-Aminopropionic Acid 56-41-7 L-Carnitine 541-15-1 L-Glutamine
56-85-9 L-Hydroxyproline 51-35-4 L-Proline 147-85-3 L-Serine
56-45-1 L-Threonine 72-19-5 L-Valine 72-18-4 Phenoxyacetic Acid
122-59-8 Veratrole 91-16-7 2-Ethylbutyric acid 88-09-5
2-Methylpyrazine 109-08-0 o-methoxybenzaldehyde 135-02-4 L-Leucine
61-90-5 L-Asparagine 70-47-3 propiophenone 93-55-0
5-isopropyl-2-methyl-phenol 499-75-2 Xylitol 87-99-0 ethyl
4-oxopentanoate 539-88-8 methyl cinnamate 103-26-4 cumic alcohol
536-60-7 methyl 2-naphthyl ketone 93-08-3
1-methyl-4-(1-methylethyl)- 99-85-4 1,4-Cyclohexadiene en-ethylene
diamine Caffeine 58-08-2 5-methylfurfural 620-02-0 furfuryl acetate
623-17-6 terpinen-4-ol 10482-56-1 phenylethanal 122-78-1
4'-Methoxyacetophenone 100-06-1 D-Fenchone 4695-62-9
1-Methoxy-4-methylbenzene 104-93-8 o-methylanisole 578-58-5
Acetylacetaldehyde dimethyl 5436-21-5 acetal p-methylacetophenone
122-00-9 Methyl phenylacetate 101-41-7 4-Ethoxybenzaldehyde
10031-82-0 p-tolyl acetate 140-39-6 2,6-Dimethoxyphenol 91-10-1
Methyl 2-methoxybenzoate 606-45-1 alpha-methylcinnamaldehyde
101-39-3 2-methoxycinnamaldehyde 60125-24-8 Potassium bicarbonate
298-14-6 piperonyl acetate 326-61-4 2,3-hexanedione 3848-24-6
furfural acetone 623-15-4 trans beta-(2-furyl)acrolein 623-30-3
carveol 99-48-9 Methyl nicotinate 93-60-7 Ethyl benzoylacetate
94-02-0 Methyl 4-methoxybenzoate 121-98-2 Levulinic acid 123-76-2
m-Dimethoxybenzene 151-10-0 2-acetylpyridine 1122-62-9
tetramethyl-pyrazine 1124-11-4 2,3-dimethyl-pyrazine 5910-89-4
trimethyl-pyrazine 14667-55-1 2-ethyl-3-methyl-pyrazine 15707-23-0
5-Methyl-3H-furan-2-one 591-12-8 2-Methoxy-4-methylphenol 93-51-6
piperazine 110-85-0 2-Methoxy-4-propylphenol 2785-87-7 Naphthalene,
2-(2- 2173-57-1 methylpropoxy)- 2-Acetyl-1-methylpyrrole 932-16-1
3,3-Dimethylacrylic acid 541-47-9 Ethyl sorbate 2396-84-1
4-(4-Hydroxyphenyl)-2-butanone 5471-51-2 4-Methoxyphenylacetone
122-84-9 (-)-Myrtenal 564-94-3 3-Phenylpropionaldehyde 104-53-0
1-Phenylethyl propionate 120-45-6 2-Methyltetrahydrofuran-3-one
3188-00-9 Cinnamyl acetate 103-54-8 Styrallyl acetate 93-92-5 Ethyl
4-methoxybenzoate 94-30-4 Benzyl propionate 122-63-4 Phenylpyruvate
156-06-9 furaneol 3658-77-3 methyl 2-methylbutanoate 868-57-5
Benzeneacetaldehyde, alpha- 93-53-8 methyl- Dimethyl anthranilate
85-91-6 1,1-Dimethoxy-2-phenylpropane 90-87-9 4-hexanolide 695-06-7
Dimethylbenzylcarbinyl acetate 151-05-3 Benzyl isobutyrate 103-28-6
Acetyl isoeugenol 93-29-8 2-Acetyl-5-methyl furan 1193-79-9
Alpha-methyl-p- 103-95-7 isopropylphenylpropanaldehyde
Benzylcarbinyl formate 104-62-1 p-Cresyl alpha-toluate 101-94-0
Potassium bisulfate 7646-93-7 Potassium carbonate 584-08-7
Potassium chloride 7447-40-7 Potassium hydroxide 1310-58-3 Ethyl
tiglate 5837-78-5 Nerol oxide 1786-08-9 DL-Tetrohydrofurfuryl
637-65-0 propionate Benzaldehyde propylene glycol 2568-25-4 acetal
2-Methyl-3-(2-furyl) acrolein 874-66-8 vanillin 121-33-5 Cholic
acid 81-25-4 R-Carvone 6485-40-1 Potassium nitrate 7757-79-1
Potassium permanganate 7722-64-7 Potassium persulfate 7727-21-1
Potassium phosphate, dibasic 2139900 Potassium Phosphate Monobasic
7778-77-0 Potassium sulfate 7778-80-5 Sodium bicarbonate 144-55-8
Sodium bisulfite 7631-90-5 Sodium carbonate 497-19-8 Sodium
chloride 7647-14-5 Sodium dithionite 7775-14-6 Sodium hydroxide
1310-73-2 Sodium nitrite 7632-00-0 Sodium Pyrophosphate 7722-88-5
Sodium sulfate 7757-82-6 Sodium sulfite 7757-83-7 Sodium
thiocyanate 540-72-7 Calcium Carbonate 471-34-1 Calcium chloride
10043-52-4 Calcium gluconate 299-28-5 Calcium hydroxide 1305-62-0
Calcium phosphate, dibasic 7757-93-9 Calcium sulfate 7778-18-9
N-Methyl-D-glucamine 6284-40-8 Calcium oxide 1305-78-8 Calcium
Phosphate Monobasic 7758-23-8 Magnesium chloride hexahydrate
7791-18-6 Magnesium sulfate 7487-88-9 Magnesium Sulfate
Heptahydrate 10034-99-8 Aluminum chloride hexahydrate 7784-13-6
aluminum nitrate nonahydrate 7784-27-2 Aluminum potassium sulfate,
7784-24-9 dodecahydrate Aluminum sulfate, 7784-31-8 octadecahydrate
(S)-(-)-Cysteine 52-90-4 p-Toluenesulfonic Acid 104-15-4 Potassium
bitartrate 868-14-4 DL-aspartic acid 617-45-8
p-Dimethylaminobenzaldehyde 100-10-7 Sodium salicylate 54-21-7
Benzoin 119-53-9 Sodium dodecyl sulfate 151-21-3 L-Menthol
2216-51-5 Tiron 149-45-1 Riboflavin 83-88-5 Sodium Acetate
Trihydrate 6131-90-4 Disodium Succinate Hexahydrate 6106-21-4
Disodium 6381-92-6 ethylenediaminetetraacetate dihydrate sodium
citrate, dihydrate 1545801 Sodium potassium tartrate, 6381-59-5
tetrahydrate L-(+)-Arginine 1119-34-2 monohydrochloride
Ethylenediamine 333-18-6 dihydrochloride Sodium formate 141-53-7
Sodium acetate 127-09-3 Potassium acetate 127-08-2 Ammonium citrate
3012-65-5 Ammonium bicarbonate 1066-33-7 Ammonium chloride
12125-02-9 Ammonium nitrate 6484-52-2 Ammonium persulfate 7727-54-0
Ammonium sulfate 7783-20-2 Zinc chloride 7646-85-7 Sulfuric acid,
zinc salt 7446-20-0 (1:1), heptahydrate Sodium Tripolyphosphate
7758-29-4 ammonium benzoate 1863-63-4 ammonium bisulfite 10192-30-0
1,5-Naphthalenedisulfonic Acid 1655-29-4 Disodium Salt
4-Hydroxybenzoic Acid 99-96-7 Diphenylacetic Acid 117-34-0 Glutaric
Acid 110-94-1 L-(-)-Fucose 2438-80-4 L-Cysteine Hydrochloride
52-89-1 L-Histidine Hydrochloride 1880304 Monohydrate o-Toluic Acid
118-90-1 Pivalic Acid 75-98-9 Pyruvic Acid Sodium Salt 113-24-6
Potassium bromide 2139626 Sodium Dithionate Dihydrate 7631-94-9
Sodium Malonate 141-95-7 Trisodium Citrate 68-04-2 Potassium Sodium
Tartrate 304-59-6 Potassium Citrate 866-84-2 D-Maltose Monohydrate
6363-53-7 Cyclohexaamylose 10016-20-3 Dodecyl sulfate, lithium salt
2044-56-6 Manganese chloride 2145076 methyl-urea 598-50-5
beta-Cyclodextrin 7585-39-9 Triphosphoric acid, 13845-36-8
pentapotassium salt Glycine ethyl ester 623-33-6 hydrochloride
L-Histidine methyl ester 7389-87-9 dihydrochloride L-Leucine methyl
ester 7517-19-3 hydrochloride D-Lysine hydrochloride 7274-88-6
2-Naphthalenesulfonic acid 532-02-5 sodium salt calcium nitrate
tetrahydrate 13477-34-4 Vitamin B1 59-43-8 Zinc Acetate Dihydrate
5970-45-6 Potassium fluoride 7789-23-3 Potassium iodate 2139718
Potassium iodide 7681-11-0 Potassium thiocyanate 333-20-0 Sodium
bromide 7647-15-6 Sodium fluoride 7681-49-4 Sodium iodide 7681-82-5
Sodium nitrate 7631-99-4 Calcium acetate 5743-26-0 Trichloroacetic
acid 76-03-9 Ammonium acetate 631-61-8 Ammonium fluoride 12125-01-8
DL-malic acid 617-48-1 t-Butyl Alcohol 75-65-0 beta-Alanine
107-95-9 (S)-(-)-Tryptophan 73-22-3 Malonic acid 141-82-2
Phenethylamine 64-04-0 Salicylylaldehyde 90-02-8 Sodium benzoate
532-32-1 Mandelic acid 90-64-2 Calcium pantothenate 137-08-6
Chloroacetic Acid 79-11-8 Ethanol Amine 141-43-5 Salicylic acid
69-72-7 Saccharin sodium 128-44-9 Thiamine hydrochloride 67-03-8
2,2'-Oxybisethanol 111-46-6 Resorcinol 108-46-3
2-Amino-2-(hydroxymethyl)-1,3- 77-86-1 propanediol
2,5-Dimethylphenol 95-87-4 Ammonium Phosphate Monobasic 7722-76-1
1,3-Butanediol 107-88-0 Glycolic Acid 79-14-1 Sodium Gluconate
527-07-1 Terephthalic Acid 100-21-0 L-Ascorbic Acid Sodium Salt
134-03-2 3-Acetyl-6-methyl-2,4- 520-45-6 pyrandione Calcium Acetate
62-54-4 Nicotinamide 98-92-0 1-Hydroxy-2-naphthoic Acid 86-48-6
2-Isopropylphenol 88-69-7 4-Aminosalicylic Acid 65-49-6 Calcium
Glycerophosphate 27214-00-2 Erythorbic Acid Sodium Salt 7378-23-6
Gluconic Acid Potassium Salt 299-27-4 Orotic Acid 65-86-1 p-Anise
Alcohol 105-13-5 Potassium Benzoate 582-25-2 Taurine 107-35-7
Thiamine Nitrate 532-43-4 3,3,5-Trimethyl-1-cyclohexanol 116-02-9
tert-Butylhydroquinone 1948-33-0 Sulfosalicylic acid 97-05-2 Gallic
acid 149-91-7 L-borneol 464-45-9 Isoborneol 124-76-5
2,5-Dihydroxybenzoic acid, 490-79-9 Gentisic acid
5-hydroxy-6-methyl-3,4- 65-23-6 pyridinedimethanol
Naphthalene-2-sulfonic acid 120-18-3 Ethanesulfonic acid, 2-
1562-00-1 hydroxy-, monosodium salt Pamoic acid 130-85-8
2,4-Dimethylphenol 105-67-9 3,5-Dihydroxyacetophenone 51863-60-6
Eugenol 97-53-0 n-Butyric Acid 107-92-6 Hydroquinone 123-31-9
Propionic Acid 79-09-4 meta-Phenylenediamine 108-45-2 Oxalic Acid
144-62-7 n-Hexanoic Acid 142-62-1 2-Furancarboxylic Acid 88-14-2
4'-Nitroacetanilide 104-04-1 D-(-)-Tartaric Acid 147-71-7
p-Acetamidobenzoic Acid 556-08-1 Galactaric acid 526-99-8
D-glucuronate 1700908 Lactobionic acid 96-82-2 p-Formylacetanilide
122-85-0 2-Mercaptobenzoic acid 147-93-3 Propanoic acid,
2-hydroxy-, 28305-25-1 calcium salt (2:1), (S)-
D(+)-10-Camphorsulfonic acid 3144-16-9 3-Cyclopentylpropionic acid
140-77-2 1R-(-)-Camphorsulfonic acid 35963-20-3 DL-Lysine 70-54-2
Cinnamic acid 621-82-9 Triethanolamine 102-71-6 Acetic Acid 64-19-7
Dichloroacetic Acid 79-43-6 Diethylamine 109-89-7
Diethylaminoethanol 100-37-8 N-(2-Hydroxyethyl)Morpholine 622-40-2
Octanoic Acid 124-07-2 isobutyric acid 79-31-2 Anisic Acid 100-09-4
Betaine 107-43-7 Enanthoic Acid 111-14-8 Hippuric Acid 495-69-2
Tiglic Acid 80-59-1 Cyclohexanecarboxylic acid 98-89-5
m-Methoxybenzoic acid 586-38-9 D-(+)-Camphoric acid 124-83-4
N-(2-Hydroxyethyl)pyrrolidine 2955-88-6
* * * * *