U.S. patent application number 14/822872 was filed with the patent office on 2016-04-07 for methods of making cocrystals.
This patent application is currently assigned to AMRI SSCI, LLC. The applicant listed for this patent is AMRI SSCI, LLC. Invention is credited to Ekaterina V. Albert, Patricia Andres, Melanie Janelle Bevill, Richard James Ely, Christopher Scott Seadeek, Petinka I. Vlahova.
Application Number | 20160097142 14/822872 |
Document ID | / |
Family ID | 48136497 |
Filed Date | 2016-04-07 |
United States Patent
Application |
20160097142 |
Kind Code |
A1 |
Bevill; Melanie Janelle ; et
al. |
April 7, 2016 |
METHODS OF MAKING COCRYSTALS
Abstract
Disclosed are processes for preparing cocrystals, including
processes for scaling up of cocrystal formation, as well as
scalable processes for preparing cocrystals. Also disclosed are
processes for scaled-op preparation of pterostilbene, progesterone,
p-coumaric, and minoxidil cocrystals. Minoxidil cocrystals, such as
minoxidil:benzoic acid 1:1 monohydrate cocrystals are also
disclosed herein.
Inventors: |
Bevill; Melanie Janelle;
(West Lafayette, IN) ; Seadeek; Christopher Scott;
(West Lafayette, IN) ; Albert; Ekaterina V.; (West
Lafayette, IN) ; Vlahova; Petinka I.; (West
Lafayette, IN) ; Ely; Richard James; (Williamsport,
IN) ; Andres; Patricia; (West Lafayette, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AMRI SSCI, LLC |
West Lafayette |
IN |
US |
|
|
Assignee: |
AMRI SSCI, LLC
West Lafayette
IN
|
Family ID: |
48136497 |
Appl. No.: |
14/822872 |
Filed: |
August 10, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13657259 |
Oct 22, 2012 |
9120766 |
|
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14822872 |
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61550341 |
Oct 21, 2011 |
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Current U.S.
Class: |
117/68 |
Current CPC
Class: |
C07D 473/12 20130101;
C07C 51/43 20130101; C30B 29/54 20130101; C07C 51/43 20130101; C07D
213/82 20130101; C07C 51/43 20130101; C07D 401/04 20130101; C07C
63/06 20130101; C07C 59/52 20130101; C07C 65/21 20130101; C07C
57/44 20130101; C30B 7/08 20130101; C07C 51/43 20130101; C07C 51/43
20130101; C07D 239/50 20130101; C07J 7/002 20130101; C30B 29/68
20130101 |
International
Class: |
C30B 7/08 20060101
C30B007/08; C30B 29/68 20060101 C30B029/68; C30B 29/54 20060101
C30B029/54 |
Claims
1.-79. (canceled)
80. A process for making a cocrystal of a compound and a coformer
comprising combining the compound dissolved in a solvent solution
with the coformer dissolved in the solvent solution wherein the
solubilities of the compound and the coformer in the solvent
solution are each of a value sufficiently similar to form a
cocrystal of the compound and the coformer as a single crystal
phase, and precipitating a cocrystal of the compound and the
coformer from the solvent solution.
81. The process of claim 80 wherein the solubilities of the
compound and the coformer in the solvent solution are within a
factor of ten.
82. The process of claim 80, wherein the compound is a salt.
83. The process of claim 81, wherein the compound is a salt.
84. The process of claim 80, wherein the solvent solution comprises
two or more solvents.
85. The process of claim 81, wherein the solvent solution comprises
two or more solvents.
86. The process of claim 80, wherein the compound is a
pharmaceutical compound.
87. The process of claim 81, wherein the compound is a
pharmaceutical compound.
88. The process of claim 80, wherein the coformer is a
pharmaceutical compound.
89. The process of claim 81, wherein the coformer is a
pharmaceutical compound.
90. The process of claim 80, wherein the coformer is a carboxylic
acid, an amino acid, a sugar, a flavoring agent, or a
nutraceutical.
91. The process of claim 81, wherein the coformer is a carboxylic
acid, an amino acid, a sugar, a flavoring agent, or a
nutraceutical.
92. The process of claim 80, wherein the solubility of the compound
in the solvent solution is equal to the solubility of the coformer
in the solvent solution.
93. The process of claim 80, wherein the solubility of the compound
in the solvent solution is within a factor of 2 of the solubility
of the coformer in the solvent solution.
94. The process of claim 80, wherein the cocrystal yield is greater
than 70%.
95. The process of claim 81, wherein the cocrystal yield is greater
than 70%.
96. The process of claim 80, further comprising the step of seeding
the solvent solution.
97. The process of claim 81, further comprising the step of seeding
the solvent solution.
98. The process of claim 97 wherein the seeding comprises adding
one or more seed crystals of the cocrystal to the solvent
solution.
99. The process of claim 80 wherein the cocrystal of the compound
and the coformer from the solvent solution are in the single
crystal phase.
Description
TECHNICAL FIELD
[0001] The disclosure relates to processes for making cocrystals,
including processes for scaling up of cocrystal formation, as well
as to scalable processes for preparing cocrystals. In at least one
embodiment, the disclosure relates to scaling up processes for
preparing pterostilbene, p-coumaric, minoxidil, and progesterone
cocrystals. Also disclosed herein are minoxidil cocrystals, such as
minoxidil:benzoic acid cocrystals.
BACKGROUND
[0002] Cocrystals are crystals that contain two or more
non-identical molecules. Examples of cocrystals may be found in the
Cambridge Structural Database. Examples of cocrystals may also be
found at Etter, Margaret C., and Daniel A. Adsmond (1990) "The use
of cocrystallization as a method of studying hydrogen bond
preferences of 2-aminopyridine" J. Chem. Soc., Chem. Commun. 1990
589-591, Etter, Margaret C., John C. MacDonald, and Joel Bernstein
(1990) "Graph-set analysis of hydrogen-bond patterns in organic
crystals" Acta Crystallogr., Sect. B, Struct. Sci. B46 256-262,
Etter, Margaret C., Zofia Urba czyk-Lipkowska, Mohammad
Zia-Ebrahimi, and Thomas W. Panunto (1990b) "Hydrogen bond directed
cocrystallization and molecular recognition properties of
diarylureas" J. Am. Chem. Soc. 112 8415-8426, which are
incorporated herein by reference in their entireties.
[0003] The following articles are also incorporated herein by
reference in their entireties: Carl Henrik Gorbotz and Hans-Petter
Hersleth, 2000, "On the inclusion of solvent molecules in the
crystal structures of organic compounds"; Acta Cryst. (2000), B56,
625-534; and V. S. Senthil Kumar, Ashwini Nangia, Amy K. Katz and
H. L. Carrell, 2002, "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.
[0004] By cocrystallizing a compound with another compound,
referred to as a "coformer", one creates a new solid form which has
unique properties compared with existing solid forms of that
compound. For example, a cocrystal may have different dissolution
and solubility properties than the compound itself or as a salt. In
the pharmaceutical field, the compound is often known as an active
pharmaceutical ingredient ("API"), and the other component of the
cocrystal (the coformer) is often a pharmaceutically acceptable
compound (which could also be an API). Cocrystals containing APIs
can be used to deliver APIs therapeutically. New drug formulations
comprising cocrystals of APIs with pharmaceutically acceptable
coformers may have superior properties over existing drug
formulations. Compounds and coformers may also include, by way of
example only, nutraceuticals, agricultural chemicals, pigments,
dyes, explosives, polymer additives, lubricant additives,
photographic chemicals, and structural and electronic
materials.
[0005] When the compound, such as an API, is a hydrochloride (HCl)
salt, for example, one can cocrystallize the HCl salt with a
neutral coformer molecule. By doing this, one can create a
cocrystal with specific properties. For instance one can make a
cocrystal comprising an active pharmaceutical ingredient having
greater or lesser intrinsic solubility and/or a faster or slower
dissolution rate, depending on the coformer compound that is
chosen.
[0006] By "coformer" what is meant is the component of the
cocrystal that is not the compound of the cocrystal. The coformer
is present in order to form the cocrystal with the compound. Thus,
the coformer is part of the crystal lattice. It is contemplated
that one or more coformers may be employed in a cocrystal,
according to any of the techniques of the disclosure. Accordingly,
the coformer is not required to have an activity of its own,
although it may have some activity. In some situations, the
coformer may have the same activity as or an activity complementary
to that of the compound.
[0007] For example, some coformers may facilitate the therapeutic
effect of an active pharmaceutical ingredient. For pharmaceutical
formulations, the coformer may be any pharmaceutically acceptable
molecule that forms a cocrystal with the API or its salt. The
Registry of Toxic Effects of Chemical Substances (RTECS) database
is a useful source for toxicology information, and the GRAS list
contains about 2500 relevant compounds. Both sources may be used to
help identify suitable coformers.
[0008] The coformer may be non-ionized, such as, for example,
benzoic acid, succinic acid, and caffeine, or zwitterionic, such
as, for example, L-lysine, L-arginine, or L-proline, or may be a
salt, such as, for example, sodium benzoate or sodium succinate.
Coformers may include, but are not limited to, organic bases,
organic salts, alcohols, aldehydes, amino acids, sugars, ionic
inorganics, carboxylic acids, amines, flavoring agents, sweeteners,
neutraceuticals, aliphatic esters, aliphatic ketones, organic
acids, aromatic esters, alkaloids, and aromatic ketones. In at
least certain embodiments, the coformer may be a carboxylic acid or
an alkaloid. Typically, coformers will have the ability to form
complementary non-covalent interactions with the compound or its
salt, including APIs and salts thereof, for example the ability to
form hydrogen bonds with the compound or its salt.
[0009] Properties of compounds or their salts, such as APIs or
salts thereof, may be modified by forming a cocrystal. Such
properties include, for example, melting point, density,
hygroscopicity, crystal morphology, loading volume,
compressibility, and shelf life. Furthermore, other properties such
as bioavailability, dissolution, solubility, toxicity, taste,
physical stability, chemical stability, production costs, and
manufacturing method may be modified by using a cocrystal, rather
than the API alone or as a salt.
[0010] A compound, such as an API, can be screened for possible
cocrystals, for example where polymorphic forms, hydrates, or
solvates do not readily form from the compound. For example, a
neutral 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 API, for example by
changing one or more properties identified earlier. A cocrystal may
also optionally be used to isolate or purify a compound during
manufacturing. If it is desirable to identify all of the solid
state phases of an active pharmaceutical ingredient, then
cocrystallization may be particularly desirable.
[0011] While much interest has been paid to preparing cocrystals of
APIs and other compounds such as nutraceuticals, a recurring
challenge has been the ability to prepare cocrystals in sufficient
quantity or scale for commercialization. When cocrystals are
prepared in a laboratory, techniques, such as with seeds or
non-solvent approaches used to screen for the cocrystals, are
typically not scalable and yields are in the milligram scale.
Further, reports by others have shown thermodynamic and kinetic
limitations for using solvent-based approaches. In particular, the
inability to obtain congruent dissolution with compounds and
coformers in a solvent has been a barrier to successful and
reproducible sealed-up manufacture of cocrystals (Chiarella). Such
dissolution problems are especially acute when the solubilities of
the compound and the coformer differ substantially in the solvent
selected. Thus, there is a need to develop a process whereby
cocrystals can be sealed-up to at least gram-scale quantities.
[0012] By way of example only, both resveratrol and pterostilbene
have been reported to exhibit a range of biological activities
including anti-cancer, antioxidant, anti-inflammatory and other
potential health benefits. Pterostilbene is found in nature in a
variety of grapes and berries as well as plants commonly used in
traditional folk medicine. Significant interest in pterostilbene
has been generated in recent years due to its perceived health
benefits, leading to increased consumption of foods that contain
the compound such as grapes and berries.
[0013] Pterostilbene has, however, been noted to have poor
solubility in water, making it difficult to incorporate in food
extracts or supplements ("nutraceuticals") (Lopez-Nicolas, J. M.;
Rodriguez-Bonilla, P.; Mendez-Cazorla, L.; Garcia-Carmona, F.,
Physicochemical Study of the Complexation of Pterostilbene by
Natural and Modified Cyclodextrins. Journal of Agricultural and
Food Chemistry 2009, 57, (12), 5294-5300.). In addition,
pterostilbene exhibits poor bioavailability and is easily oxidized
by various enzymes (Pezet, R., Purification and characterization of
a 32-kDa laccase-like stilbene oxidase produced by Botrytis
cinerea. FEMS Microbiol. Lett. 1998, 167, 203-208 and Breuil, A.
C.; Jeandet, P.; Adrian, M.; Chopin, F.; Pirio, N.; Meunier, P.;
Bessis, R., Characterization of a pterostilbene dehydrodimer
produced by laccase of Botrytis cinerea. Phytopathology 1999, 89,
(298-302).). The melting point has been reported as 82.degree. C.
(Mallavadhani, U. V.; Sahu, G., Pterostilbene: A Highly Reliable
Quality-Control Marker for the Ayurvedic Antidiabetic Plant
`Bijasar`. Chromatographia 2003, 58, 307-312.). Efforts to improve
the solubility of pterostilbene have focused on formulation
approaches, such as by using cyclodextrins (LoI 2009).
[0014] Recently, cocrystals and polymorphs of pterostilbene have
been reported in WO/2011/09372, which is herein incorporated by
reference.
SUMMARY
[0015] The disclosure relates, in various embodiments, to processes
for preparing cocrystals, including scalable processes and
processes for preparing scaled-up cocrystals. Exemplary processes
may maintain congruent dissolution during the crystallization
process. In further embodiments, the disclosure relates to the
scaling up of pterostilbene cocrystals, such as, tor example,
pterostilbene:caffeine cocrystals and pterostilbene:piperazine
cocrystals; progesterone cocrystals, such as progesterone:vanillic
acid and progesterone cinnamic acid cocrystals; p-coumaric acid
crystals, such as p-coumaric:nicotinamide cocrystals; and minoxidil
cocrystals, such as minoxidil:benzoic acid cocrystals.
[0016] According to one aspect of the disclosure, processes for
making a cocrystal of a compound and a coformer are described,
comprising combining the compound dissolved in a solvent solution
with the coformer dissolved in the solvent solution, wherein the
solubilities of the compound and the coformer in the solvent
solution are approximately equal and wherein the resulting
cocrystal is crystallized from the solution.
[0017] According to another aspect of the disclosure, processes for
making a cocrystal of a compound, and a coformer are described,
comprising combining the compound dissolved in a solvent solution
with the coformer dissolved in the solvent solution, wherein the
resulting cocrystal is crystallized from the solvent solution
wherein the solubilities of the compound and the coformer in the
solvent solution are each of a value sufficiently similar to form a
cocrystal of the compound and the coformer as a single crystal
phase.
[0018] According to yet another aspect of the disclosure, processes
for sealed-up preparation of a cocrystal of a compound and a
coformer are described, comprising combining the compound dissolved
in a solvent solution with the coformer dissolved in the solvent
solution, wherein the resulting cocrystal is crystallized from the
solvent solution wherein the solubilities of the compound and the
coformer in the solvent solution are each of a value sufficiently
similar to form a cocrystal of the compound and the coformer as a
single crystal phase.
[0019] According to a further aspect of the disclosure, processes
for scaled-up preparation of a cocrystal of a compound and a
coformer are described, comprising combining the compound dissolved
in a solvent solution with the coformer added to form a slurry,
wherein the resulting cocrystal is crystallized from the
slurry.
[0020] In a still further aspect of the disclosure, a
mimoxidil:benzoic acid cocrystal is disclosed. The cocrystal may,
in various embodiments, have, in its XRPD pattern, a peak at about
7.3.degree.2.THETA.; at least two peaks at about
7.3.degree.2.THETA. and 11.4.degree.2.THETA.; or at least three
peaks at about 7.3.degree.2.THETA., 11.4.degree.2.THETA., and
14.7.degree.2.THETA.. In various embodiments, the cocrystal may
have at least one peak chosen from 7.3.degree.2.THETA.,
11.4.degree.2.THETA., 14.7.degree.2.THETA., 16.4.degree.2.THETA.,
19.2.degree.2.THETA., 20.0.degree.2.THETA., 20.6.degree.2.THETA.,
21.3.degree.2.THETA., 23.1.degree.2.THETA., or
26.5.degree.2.THETA.. The cocrystal is believed to be a
monohydrate.
BRIEF DESCRIPTION OF FIGURES
[0021] FIG. 1 is a phase diagram illustrating congruent
dissolution.
[0022] FIG. 2 is a phase diagram illustrating incongruent
dissolution.
[0023] FIG. 3 is pterostilbene:caffeine cocrystal
solubility/temperature graph under varying water:IPA solvent
ratios.
[0024] FIG. 4 is a solubility and metastable zone width graph at
varying temperatures at a 60:40 water to IPA solvent ratio.
[0025] FIG. 5 is an overlay of Raman spectra of
pterostilbene:caffeine cocrystal (red), pterostilbene and caffeine
in the 565-540 cm.sup.-1 region.
[0026] FIG. 6 is an overlay of Raman spectra of
pterostilbene:caffeine cocrystal (red), pterostilbene, and caffeine
in the 1185-1165 cm.sup.-1 region.
[0027] FIG. 7 is a time-resolved graph for the formation of a
pterostilbene:caffeine cocrystal based on peak center in the
565-540 cm.sup.-1 region and based on peak center in the 1185-1165
cm.sup.-1 region.
[0028] FIG. 8 is an overlay of the x-ray powder diffraction (XRPD)
pattern of pterostilbene:caffeine cocrystal obtained upon scale up
as described in Example 4, a calculated pattern based on single
crystal data for pterostilbene:caffeine cocrystal Form I reported
previously (N. Schultheiss, S. Bethune, and J.-O. Henck,
Nutraceutical cocrystals: utilizing pterostilbene as a cocrystal
former, Crystal Engineering Communications, 2010, 12, 2436-2442),
and XRPD patterns of pterostilbene and caffeine forms used for the
cocrystallization experiments.
[0029] FIG. 9 is a microscopy image of an unseeded cooling
experiment of the scale-up of pterostilbene:caffeine.
[0030] FIG. 10 is a microscopy image of a seeded cooling experiment
of the scale-up of pterostilbene:caffeine.
[0031] FIG. 11 is the XRPD pattern of scaled up
pterostilbine:piperazine 2:1 cocrystal obtained in Example 8.
[0032] FIG. 12 is the XRPD pattern of scaled up
progesterone:vanillic acid 1:1 cocrystal obtained in Example 9.
[0033] FIG. 13 is the XRPD pattern of scaled up
progesterone:cinnamic acid .about.1:1 cocrystal obtained in Example
10.
[0034] FIG. 14 is the XRPD pattern of scaled up p-coumaric
acid:nicotinamide 1:1 cocrystal obtained in Example 11.
[0035] FIG. 15 is the XRPD pattern of scaled up
p-coumaric:nicotinamide 2:1 cocrystal obtained in Example 12.
[0036] FIG. 16 is the XRPD pattern of scaled up minoxidil:benzoic
acid 1:1 monohydrate cocrystal obtained in Example 13.
[0037] FIG. 17 illustrates the solution proton NMR (.sup.1H NMR)
analysis of scaled up minoxidil:benzoic acid 1:1 monohydrate
cocrystal obtained in Example 13.
[0038] FIG. 18 illustrates the differential scanning calorimetry
(DSC) and thermogravimetric (TG) analyses of scaled up
minoxidil:benzoic acid 1:1 monohydrate cocrystal obtained in
Example 13.
[0039] FIG. 19 is an ORTEP drawing of minoxidil:benzoic acid
monohydrate.
[0040] FIG. 20 is a packing diagram of minoxidil:benzoic acid
monohydrate, viewed down the crystallographic a axis.
[0041] FIG. 21 is a packing diagram of minoxidil:benzoic acid
monohydrate, viewed down the crystallographic b axis.
[0042] FIG. 22 is a packing diagram of minoxidil:benzoic acid
monohydrate, viewed down the crystallographic c axis.
[0043] FIG. 23 is a graphical representation of potential hydrogen
bonding points of contact around the water molecules in
minoxidil:benzoic acid monohydrate.
[0044] FIG. 24 is a graphical representation of hydrogen bonding in
the bc plane of minoxidil:benzoic acid monohydrate.
[0045] FIG. 25A is a graphical representation of hydrogen bonding
along the b axis of minoxidil:benzoic acid monohydrate.
[0046] FIG. 25B is a graphical representation of hydrogen bonding
along the c axis of minoxidil:benzoic acid monohydrate.
[0047] FIG. 26 is the calculated XRPD of minoxidil:benzoic acid
monohydrate (single crystal analysis).
DETAILED DESCRIPTION
[0048] The term "solvent solution" as used herein describes two or
more solvents which are miscible with one another. Examples of
miscible solvent solutions include, but are not limited to,
isopropanol/water, acetone/water, acetonitrile/water,
ethanol/water, methanol/water, butanol/water,
tetrahydrofuran/heptane, isopropanol/heptane, acetone/heptane,
ethyl acetate/heptane, methanol/tert-butyl methyl ether, or
acetone/tert-butyl methyl ether.
[0049] The solvent solution may be composed of two or more solvents
in different ratios. In one embodiment, the solvent solution is
isopropanol/water and the ratio of isopropanol to water is 40:60 or
45:55, including between about 40% to about 50% isopropanol to
water. In another embodiment, the solvent solution may be
water/ethanol in a ratio of about 50:50, isopropanol/heptane in a
ratio of about 50:50, ethyl acetate/heptane in a ratio of about
25:75, acetonitrile:water in a ratio of about 97:3, or
isopropanol/water in a ratio of about 50:50.
[0050] In at least one further embodiment, a single solvent, in
which the compound and conformer exhibit sufficiently similar
solubilities, such as methylethylketone (MEK), may be used in place
of a solvent system. In such embodiments, the use of the terms
"solvent" and "solvent system" may be used interchangeably, without
intending to alter the scope of the disclosure.
[0051] Once dissolved, the cocrystal may be prepared by
precipitating the cocrystal from the solvent solution. Such
precipitation may, for example, be a crystallization, and may occur
by, for example, lowering the temperature of the solvent solution
which contains the compound and coformer or removing the solvent
solution via evaporation.
[0052] The term "approximately" as used herein in the context of
the solubility of the compound in the solvent solution and the
solubility of the coformer in the solvent solution means that the
respective solubilities are sufficiently close so that congruent
dissolution and congruent precipitation of the resulting cocrystal
occurs.
[0053] FIG. 1 and FIG. 2 provide illustrations of congruent
dissolution and incongruent dissolution, respectively. In these
figures, A and B refer to two components (compound and coformer), L
refers to a liquid phase containing solvent and two components
(compound and coformer), A.sub.s and B.sub.s refer to single phase
solids containing one component (compound or coformer), while
AB.sub.s refers to a two-component 1:1 cocrystal.
[0054] FIG. 1 illustrates congruent dissolution where the
solubility of the two components is similar, resulting in an
approximately symmetric phase diagram where the dashed line
corresponding to a system containing a 1:1 ratio of each component
crosses the region of the diagram where the cocrystal AB.sub.s can
exist as a single solid phase. FIG. 1 demonstrates that for a
solution of components A and B with a 1:1 ratio, the equilibrium
solid phase is the single phase of the cocrystal AB.sub.s when the
solubility of the two components is similar.
[0055] FIG. 2 illustrates incongruent dissolution, where the
solubility of the two components is dissimilar, resulting in an
asymmetric phase diagram where the dashed line corresponding to a
system containing a 1:1 ratio of each component does not cross the
region of the diagram where the cocrystal AB.sub.s can exist as a
single solid phase. FIG. 2 demonstrates that for a solution of
components A and B with a 1:1 ratio, the equilibrium solid phase is
a mixture of one of the solid components (A.sub.s in the figure)
and the cocrystal AB.sub.s when the solubility of the two
components is dissimilar.
[0056] Overall, FIG. 1, and FIG. 2 together illustrate the fact
that when preparing a 1:1 cocrystal using a 1:1 ratio of the two
components, approximate matching of solubilities is essential to
obtain the cocrystal as single phase solids upon filtration.
Similar considerations exist when attempting cocrystals of other
ratios of compound to coformer.
[0057] In at least one embodiment of the disclosure, the cocrystal
is composed of a compound and a coformer wherein the cocrystal is a
compound which is an active pharmaceutical ingredient or a
nutraceutical and wherein the coformer is any acceptable coformer
for use in humans. Examples of such acceptable coformers include
compounds which appear on the GRAS (Generally Recognized as Safe)
or EAFUS (Everything Added to Food in the United States) lists.
Coformers may also include active pharmaceutical ingredients or
nutraceuticals. One class of coformers useful according to various
embodiments of the disclosure is carboxylic acid and salts thereof.
Other examples of coformers according to the processes of the
disclosure include, but are not limited to, sugars, amino-acids and
salts thereof, alkaloid and salts thereof, amines, sweeteners, and
flavor agents.
[0058] The compound may be an acid or a base or neither. It may
also be in the form of a salt. In one exemplary embodiment, the
salt is a hydrochloride salt. Examples of compounds can be found,
for example, in WO/2004/064762, which is herein incorporated by
reference.
[0059] Crystallization of the cocrystals according to various
embodiments of the disclosure may optionally be assisted by adding
seeds to the crystallization vessel.
[0060] In one exemplary and non-limiting embodiment, caffeine is a
coformer and pterostilbene is a compound. As shown in Table 1,
pterostilbene was measured to have a solubility of 0.02 mg/mL in
water whereas caffeine has a solubility of 18 mg/mL, nearly one
thousand times higher. By comparison, pterostilbene's solubility
was found to be 399 mg/ml in isopropyl alcohol, whereas the
solubility of caffeine in isopropyl alcohol was found to be only 3
mg/mL. This large difference in solubility makes the scale-up of
pterostilbene:caffeine challenging due to incongruent
crystallization. Attempts to scale-up this cocrystal using a
methyl-tert-butyl ether/heptane mixture, for example, have led to a
physical mixture of cocrystal and caffeine.
TABLE-US-00001 TABLE 1 Solubility Estimates at Ambient Temperature
Pterostilbene Caffeine Cocrystal Solvent (mg/mL) (mg/mL) (mg/mL)
ACN >203 21 34 EtOAc >201 7 17 EtOH 410 6 12 Heptane <2
<1 <1 IPA 399 3 9 MEK >200 8 18 MTBE >200 <1 2 Water
0.02 18 0.5 Water:IPA 22 38 28 55:45 Water:IPA 22 37 20 60:40
Water:IPA 2 39 4 70:30
[0061] As can be seen from Table 1, there is a general disparity
between the solubility of pterostilbene and caffeine in a range of
solvents. Pterostilbene tends to be more soluble in organic
solvents than in water, whereas caffeine has a reverse
tendency.
[0062] FIG. 3 illustrates the solubility of a cocrystal of
pterostilbene:caffeine measured under different water:IPA
conditions. Under such solvent conditions, sufficient dissolution
from both components reduced the disparity between the solubility
of each component, as for example, the 60:40 IPA:water mixture as
seen in FIG. 4. In FIG. 4, the metastable zone width represented by
the region between the solid and dashed lines was determined based
on unseeded cooling at 0.2.degree. C./min. Adequate seeding within
this region using the desired form of a cocrystal allows control of
solid form and particle size by avoiding spontaneous nucleation.
FIG. 9 shows an image of a pterostilbene:caffeine cocrystals made
without using seeds whereas in FIG. 10 seeds were used. The larger
particles generated with seeds are advantageous for filtration and
flow properties.
[0063] A 40:60 isopropanol to water mixture was used as a solvent
solution and found to have comparable solubilities for both
pterostilbene and caffeine at approximately 22 mg/L and 37 mg/mL,
respectively. Increasing the water content to 70% and higher
dropped the solubility of pterostilbene to approximately 2 mg/mL or
less. In this solvent solution, the pterostilbene:caffeine 1:1
cocrystal had a solubility of approximately 18 mg/mL at room
temperature.
[0064] In a further exemplary embodiment, the compound has a
greater solubility in organic solvents than the coformer and the
coformer has greater solubility in water than the compound. The
solubility of the compound may be two times or more, three times or
more, four times or more, five times or more, six times or more,
seven times or more, eight times or more, nine times or more, ten
times or greater, a hundred times or greater, or a thousand times
or more greater than the solubility of the coformer in an organic
solvent. The solubility of the coformer may be two times or more,
three times or more, four times or more, five times or more, six
times or more, seven times or more, eight times or more, nine times
or more, ten times or greater, a hundred times or greater, or a
thousand times or more greater than the solubility of the compound
in water.
[0065] Table 2 illustrates the estimated solubilities of various
compounds and coformers useful according to various embodiments of
the disclosure, as well as their cocrystals, in various solvents
and solvent solutions.
TABLE-US-00002 TABLE 2 Solubility Estimates at Ambient Temperature
Cocrystal Compound 1: Solubility Solubility Solubility Coformer 2
Compound 1 Coformer 2 Cocrystal (molar ratio) Solvent system
(mg/mL) (mg/mL) (mg/mL) p-Coumaric acid: Methylethyl- 70 22 10
nicotinamide ketone (1:1) p-Coumaric acid: Acetonitrile: 28 42 22
nicotinamide water (2:1) 97:3 v/v Pterostilbene: Water:ethanol 54
>324 10 piperazine 50:50 v/v (1:1) Minoxidil: Isopropanol: 27 26
14 benzoic acid water (1:1) 50:50 v/v Progesterone: Isopropanol: 30
15 23 vanillic acid heptane (1:1) 50:50 v/v Progesterone: Ethyl 16
13 24 cinnamic acid acetate:heptane (1:1) 25:75 v/v
[0066] As illustrated in Table 2 above, and according to various
non-limiting embodiments of the disclosure, the solubility of the
compound in the solvent or solvent solution, may be approximately
equal to the solubility of the coformer in the solvent or solvent
solution. In other exemplary and non-limiting embodiments, the
solubility of the compound in the solvent or solvent solution is
within a factor of 2 of the solubility of the coformer in the
solvent or solvent solution. According to further non-limiting
embodiments, the solubility of the compound in the solvent or
solvent solution is within a factor of 10 of the solubility of the
coformer in the solvent or solvent solution.
[0067] In Table 3, pterostilbene:caffeine cocrystals were prepared
using the solvents indicated with the initial concentration of
pterostilbene in the appropriate solvent provided. Upon addition of
caffeine and a suitable anti-solvent, the resulting cocrystal is
prepared, with a yield as provided in Table 3.
TABLE-US-00003 TABLE 3 Experimental Slurry Conditions Initial
Pterostilbene Solvent Concentration (mg/mL) Yield EtOH 80 65%.sup.
100 71%.sup. 120 74%.sup. 150 79%.sup. MTBE 100 81%.sup. MTBE 100
91% .sup.a addition of heptane MTBE:heptane 1:1 MTBE addition of
100 86%.sup. heptane MTBE:heptane 1:1 wash with water .sup.a
Residual caffeine detected
[0068] Table 4 illustrates varying water:IPA ratios, seeding
conditions, starting concentrations, and yields for the scale-up of
pterostilbene:caffeine cocrystals. FIG. 8 shows an overlay of the
x-ray powder diffraction pattern of a material obtained at large
scale by a cooling, seeded method, compared to the calculated x-ray
powder pattern from single crystal data published for
pterostilbene:cocrystal Form I (N. Schultheiss, S. Bethune, and
J.-O. Henck, Nutraceutical cocrystals: utilizing pterostilbene as a
cocrystal former, Crystal Engineering Communications, 2010, 12,
2436-2442), and XRPD patterns of pterostilbene and caffeine forms
used for the cocrystallization experiments.
TABLE-US-00004 TABLE 4 Cooling process experimental conditions
Water:IPA Starting Ratio (v/v) Scale .sup.a Conditions .sup.b
concentration Yield 55:45 7.2 g unseeded 90 mg/mL 81% (11 vol)
60:40 7.2 g unseeded 90 mg/mL 73% (11 vol) 60:40 7.2 g seeded 90
mg/mL 81% (11 vol) 60:40 5.6 g unseeded 70 mg/mL 77% (14 vol) 60:40
5.6 g seeded 70 mg/mL 83% (14 vol) 60:40 56 g seeded 70 mg/mL 90%
(14 vol) .sup.a Mass refers to pterostilbene .sup.b Cooling
crystallizations with a cooling rate of 0.2.degree. C./min
[0069] In a further embodiment of the disclosure, processes for the
scaled-up preparation of a cocrystal of a compound and a coformer
are described comprising combining the compound dissolved in a
solvent solution with the coformer added to form a slurry and
wherein the resulting cocrystal is crystallized from the slurry.
Such crystallization may also be done in the presence of an
anti-solvent such as a hydrocarbon.
[0070] In one embodiment, a slurry for the preparation of a
pterostilbene:caffeine cocrystal is described. An exemplary
preparation is described in Example 8. In this and other
embodiments, Raman spectroscopy, including Raman microscopy, may be
used to monitor the formation of the cocrystal from the compound
and the coformer. FIG. 5, for example, shows specificity between
pterostilbene, caffeine, and the pterostilbene:caffeine cocrystal
in one region of the Raman spectrum. FIG. 6 shows specificity in
another region. By monitoring a slurry process with Raman
microscopy in situ, one is, therefore, able to monitor the
formation of a cocrystal and differentiate it from the
corresponding compound and coformer. FIG. 7 shows such real-time
monitoring of the formation of the pterostilbene:caffeine cocrystal
using Raman spectroscopy.
[0071] By "specificity" what is meant is sufficient separation
between selected Raman peaks in Raman spectra collected on the
compound, the coformer and the cocrystal of interest so that one of
ordinary skill in the art can readily determine which signal
corresponds to which of the three of compound, coformer, or
cocrystal. In the case of pterostilbene:caffeine cocrystal, this
separation is visually apparent since the corresponding peak maxima
do not overlap.
[0072] Many different analytical techniques are available to detect
and analyze the cocrystals made according to the processes
disclosed herein. A number of solid-state analytical techniques
that can be used to provide information about solid-state structure
and may be used to analyze cocrystals made according to the
disclosure, including, by way of example only, single crystal x-ray
diffraction, x-ray powder diffraction (XRPD), solid-state .sup.13C
NMR, Raman spectroscopy, and thermal techniques such as
Differential Scanning Calorimetry (DSC), melting point, and hot
stage microscopy.
EXAMPLES
Prophetic Example 1
No Seeding
[0073] A reactor vessel is charged with a solid compound and a
solid coformer and a solvent system comprising of a miscible
water-solvent solution. The solubility of each of the component is
within a factor of ten in the solution. The system is heated until
dissolution and then is cooled to form a suspension. The suspension
is filtered and vacuum dried, yielding a cocrystal of the compound
and the coformer at gram scale quantities.
Prophetic Example 2
With Seeding
[0074] The procedures of Example 1 are carried out with the
addition of seed crystals of the cocrystal of the compound to the
reactor vessel containing a solution of the compound and coformer
prior to spontaneous nucleation.
Methods
[0075] Solubility estimations were performed gravimetrically or via
slow incremental addition of solvent to weighted amounts of solids.
Slurry experiments and small scale cooling experiments were
performed in vials or small round bottom flasks which were
magnetically stirred. Multi-gram cooling experiments were performed
using a 100 mL or 1 L round bottom controlled laboratory reactor
(Radleys Lara CLR) equipped with a Mettler Toledo turbidity probe,
a Teflon anchor impeller, Julabo temperature control unit, and a
temperature probe for monitoring the reactor temperature throughout
the experiments. The Lara Technologies software (v. 2.0.0.49)
tracked circulator temperature, vessel temperature, stir rate, and
turbidity. Slurry experiments were typically conducted by preparing
a solution of pterostilbene in solvent and subsequent addition of
coformer solids. Cooling experiments were conducted by mixing
pterostilbene and caffeine and then adding the aqueous isopropanol
mixture. The system was heated at a rate of 2 degrees per minute to
60 or 70 degrees followed by cooling to 5 degrees with a cooling
rate of 0.2 degrees per minute (all Celsius).
[0076] Raman measurements of the slurry experiments were performed
using a Kaiser dispersive Raman RXN3 with 785 nm excitation.
[0077] X-ray powder diffraction (XRPD) data were taken either on a
PANalytical X'Pert Pro or a INEL XRG-3000 diffractometer using Cu
K.alpha. radiation (.lamda.=1.54059 .ANG.).
[0078] Polarized light microscopy was collected using a Leica DMLP
microscope equipped with a Spot Insight Color Camera. Crossed
polarizers with first order red compensators and Kohler
illumination were used.
[0079] Differential scanning calorimetry (DSC) analyses were
performed using a TA Instruments 2920 differential scanning
calorimeter. The samples were heated from 25.degree. C. to
300.degree. C. at a rate of 10.degree. C./min.
[0080] Thermogravimetric (TG) analyses were performed using a TA
Instruments 2950 thermogravimetric analyzer. The sample was heated
from room temperature to 350.degree. C. at a rate of 10.degree.
C./min.
[0081] Solution proton NMR (.sup.1H NMR) spectra were acquired at
ambient temperature with a Varian.sup.UNITY INOVA-400 spectrometer
at a .sup.1H Larmor frequency of 399.796 MHz. The spectrum was
acquired with a .sup.1H pulse width of 9.0 .mu.s, a 5.00 second
acquisition time, a 2.50 second delay between scans, a spectral
width of 6400 Hz with 64000 data points.
[0082] Coulometric Karl Fischer (KF) analysis for water
determination was performed using a Mettler Toledo DL39 KF
titrator.
Example 3
100 mL Reactor Pterostilbene:Caffeine Scale-Up Cocrystals
Process--With Seeding
[0083] A 100 mL reactor vessel was charged with solid pterostilbene
(7.20 g; 28.1 mmol) and caffeine (5.46 g, 28.1 mmol), and 80 ml of
water:isopropanol 60:40 solvent mixture. The pterostilbene
concentration was 90 mg/mL. The system was heated from 40 to
70.degree. C. for 15 minutes or with heating rate 2.degree. C./min,
hold at 70.degree. C. for 10 minutes, and then cooled from
70.degree. C. to 60.degree. C. with cooling rate 0.2.degree.
C./min. The system was seeded with 145 mg (.about.2 wt %) of
pterostilbene:caffeine 1:1 cocrystal, Form I as a slurry with
concentration of 90 mg/mL in water:isopropanol 60:40 while holding
the temperature for 30 minutes at 60.degree. C. The system was
cooled from 60 to 5.degree. C. with cooling rate of 0.2.degree.
C./min. The solution became cloudy at 57.degree. C. The system was
allowed to cool to 5.degree. C. with cooling rate of 0.2.degree.
C./min. The resulting suspension was stirred at 5.degree. C. for
17.5 hours. One volume wet cake of water:isopropanol 60:40 was
added into the reactor. The system was slurried at 5.degree. for 40
minutes. After the discharge of the suspension, the reactor was
washed with one volume wet cake (19 mL) of chilled
water:isopropanol 60:40 solvent mixture. The suspension was
filtered to dry land using a Buchner funnel and a filter paper and
washed with the washing from the reactor filtered to completion.
The solid was vacuum dried at approximately 40.degree. C. for 25.5
hours yielding 12.66 g of pterostilbene:caffeine 1:1 cocrystal,
Form I (81% yield).
[0084] Structure was confirmed by comparison of XRPD data with
calculated XRPD data from single crystal x-ray data available for
the cocrystal.
Example 4
1 L Reactor Pterostilbene:Caffeine Scale-Up Cocrystal Process--With
Seeding
[0085] A 1 L reactor vessel was charged with solid pterostilbene
(56.0 g; 0.2185 mol) and caffeine (42.43 g, 0.2185 mol), and 800 ml
of water:isopropanol 60:40 solvent mixture. The pterostilbene
concentration was 70 mg/mL. The system was heated from 30 to
60.degree. C. for 15 minutes or with 2.degree. C./min heating rate,
hold at 60.degree. C. for 30 minutes, and then cooled from
60.degree. C. to 42 with cooling rate of 0.2.degree. C./min. The
system was seeded with 1.12 g (.about.2 wt %) of
pterostilbene:caffeine 1:1 cocrystal. Form I as a slurry with
concentration of 110 mg/mL in water:isopropanol 60:40 while holding
the temperature for 1 hour at 42.degree. C. The system was cooled
from 42 to 5.degree. C. with cooling rate of 0.2.degree. C./min.
The resulting suspension was stirred at 5.degree. C. for 13.5
hours. After the discharge of the suspension, the reactor was
washed with one volume wet cake (250 mL) of chilled
water:isopropanol 80:20 solvent mixture. The suspension was
filtered to dry land using a Buchner funnel and a filter paper and
washed with the washing from the reactor and filtered to
completion. The solid was vacuum dried at approximately 40.degree.
C. for 20 hours yielding 89.13 g of pterostilbene:caffeine 1:1
cocrystal, Form I (90% yield). A microcraph of the
pterostilbene:caffeine cocrystal thus formed is illustrated in FIG.
10.
Example 5
Pterostilbene:Caffeine Scale-Up Cocrystal Process--Without
Seeding
[0086] A 100 mL reactor vessel was charged with solid pterostilbene
(7.2 g; 28.1 mmol) and caffeine (5.457 g, 28.1 mmol), and 80 ml of
water:isopropanol 60:40 solvent mixture. The pterostilbene
concentration was 90 mg/mL. The system was heated from 30 to
70.degree. C. for 20 minutes or with heating rate 2.degree. C./min,
held at 70.degree. C. for 10 minutes, and then cooled from
70.degree. C. to 5.degree. C. with cooling rate 0.2.degree. C./min.
The resulting suspension was stirred at 5.degree. C. for 18 hours.
After the discharge of the suspension, the reactor was washed twice
with one volume wet cake (2.times.19 mL) of chilled
water:isopropanol 60:40 solvent mixture. The suspension was
filtered to dry land using a Buchner funnel and a filter paper and
washed with the washings from the reactor also to dry land. The
final wash of the filter cake was performed using one cake of wash
solvent system (chilled water:isopropanol 60:40) and filtered to
completion. The solid was vacuum dried at 40.degree. C. yielding
9.202 g of pterostilbene:caffeine 1:1 cocrystal, Form I (73%
yield). A micrograph of the pterostilbene:caffeine cocrystal thus
formed is illustrated in FIG. 9.
Prophetic Example 6
Slurry Process
[0087] A solid compound is dissolved in a solvent to form a
solution. A solid coformer is added to the solution. The suspension
is stirred until the formation of cocrystal is complete. In some
cases, aliquots of an anti-solvent may subsequently be added to the
solution. Solids formed in the solution are filtered and dried. The
solid is a cocrystal of the compound and the coformer.
Example 7
Preparation of Pterostilbene:Caffeine Cocrystal by a Slurry
Process
[0088] Solid pterostilbene (1.5 g, 5.86 mmol) was dissolved in 15
mL of t-butyl methyl ether (MTBE). The concentration of
pterostilbene was calculated to be 100 mg/mL. Caffeine (1.14 g,
5.86 mmol) was added to the solution and the resulting slurry was
allowed to stir at ambient temperature for 24 hours. Then aliquots
of heptane (total 15 mL) were added with stirring to reach
MTBE:heptane ratio 1:1. The system was allowed to stir at ambient
temperature for 4 hours. The solid was collected by vacuum
filtration on paper filter, washed 2.times.5 mL of heptane, and
air-dried under reduced pressure for 10 minutes. The solid was
transferred in an Erlenmeyer flask and 13 mL of water were added.
The resulting slurry was allowed to stir at ambient temperature for
0.5 hour. The solid was isolated by vacuum filtration on a paper
filter, washed 2.times.5 mL of water and then air-dried under
reduced pressure for 40 minutes. The solid was vacuum dried at
approximately 40.degree. C. for 3 days yielding 2.26 g of
pterostilbene:caffeine 1:1 cocrystal Form I (86% yield).
Example 8
Preparation of Pterostilbene:Piperazine 2:1 Cocrystal With
Seeding
[0089] An Erlenmeyer flask was charged with solid pterostilbene
(1.0038 g) and piperazine (0.1688 mg), and 12.5 mL of an
ethanol:water 50:50 solvent mixture. The system was heated to
59.degree. C. with stirring, resulting in a slightly turbid yellow
solution. The sample was then cooled at a rate of 0.2.degree.
C./min to 51.degree. C. The system was seeded with 4 wt %
pterostilbene:piperazine 2:1 cocrystals, which dissolved upon
addition. The system was further cooled at a rate of 0.2.degree.
C./min to 48.degree. C. The system was again seeded with 3 wt %
pterostilbene:piperazine 2:1 cocrystals, which did not dissolve
upon addition. The system was stirred at 48.degree. C. for 30
minutes and then cooled to 25.degree. C. at a cooling rate of
0.2.degree. C./min. Upon reaching 25.degree. C., 2 the sample was
placed in a cold room and allowed to stir at subambient temperature
for 19 hours. The solid was then collected by vacuum filtration on
a paper filter, washed three times with 3.0 mL (3.times.3.0 mL) of
chilled ethanol:water 50:50 solvent mixture. The solid was vacuum
dried at 41.degree. C. for 23 hours, yielding 0.9753 g of
pterostilbene:piperazine 2:1 cocrystal (76% yield). The structure
of the pterostilbene:piperazine 2:1 cocrystal was confirmed by
XRPD, as illustrated in FIG. 11.
Example 9
Preparation of Progesterone:Vanillic Acid 1:1 Cocrystal With
Seeding
[0090] A 100 mL reactor was charged with progesterone (8.45 g) and
vanillic acid (4.55 g), and 85 mL of an isopropanol:heptane 50:50
solvent mixture. The system was heated from room temperature to
about 75.degree. C. over a period of approximately one hour. The
resulting solution was cooled to approximately 60.degree. C. over a
period of 30 minutes. The system was seeded with 78.8 mg
progesterone:vanillic acid 1:1 cocrystals, added as a suspension in
2 mL of heptane. The system was held for one hour before cooling to
10.degree. C. over a period of five hours. The system was stirred
overnight at 10.degree. C. and the solids were subsequently
isolated by vacuum filtration on a paper filter. The solids were
dried in a vacuum oven at ambient temperature for one day, yielding
10.8 g of progesterone:vanillic acid 1:1 cocrystal (83% yield). The
structure of the progesterone:vanillic acid 1:1 cocrystal was
confirmed by XRPD, as illustrated in FIG. 12.
Example 10
Preparation of Progesterone:Cinnamic Acid .about.1:1 Cocrystal With
Seeding
[0091] A 100 mL reactor was charged with progesterone (9.338 g) and
cinnamic acid (4.416 g), and 75 mL of an ethyl acetate:heptane
25:75 solvent mixture. The system was heated from room temperature
to about 65.degree. C. and held at this temperature until a clear
solution was obtained. The resulting solution was cooled to
55.degree. C. over a period of 15 minutes. The system was seeded
with 9.7 mg progesterone:cinnamic acid .about.1:1 cocrystals, added
as a suspension in 1 mL of heptane. The system was cooled from
55.degree. C. to 50.degree. C. over a period of 75 minutes and then
cooled to 15.degree. C. over a period of 12 hours. The solids were
isolated by vacuum filtration on a paper filter and dried in a
vacuum oven at ambient temperature for approximately one day,
yielding 10.2 g of progesterone:cinnamic acid .about.1:1 cocrystal
(74% yield). The structure of the progesterone:cinnamic acid
.about.1:1 cocrystal was confirmed by XRPD, as illustrated in FIG.
13.
Example 11
Preparation of P-Coumaric Acid:Nicotinamide 1:1 Cocrystal With
Seeding
[0092] A 100 mL reactor was charged with a 1:1 molar ratio of solid
p-coumaric acid (6.5211 g) and nicotinamide (4.7544 g), and 100 mL
of methylethylketone (MEK) with overhead stirring. The system was
heated to 78.degree. C. with stirring, and an additional 10 mL of
MEK was added to the reactor, resulting in a clear solution. The
system was cooled to 69.degree. C. over a period of 50 minutes. The
system was seeded with 0.1358 g p-coumaric acid:nicotinamide 1:1
cocrystals, added as a slurry in 3 mL of MEK. The system was held
for one hour at 69.degree. C. before cooling to 10.degree. C. over
a period of 295 minutes. The system was held overnight at
10.degree. C. and the solids were subsequently isolated by vacuum
filtration on a paper filter. The solids were dried in a vacuum
oven at ambient temperature for one day, yielding a p-coumaric
acid:nicotinamide 1:1 cocrystal (81% yield). The structure of the
p-coumaric acid:nicotinamide 1:1 cocrystal was confirmed by XRPD,
as illustrated in FIG. 14.
Example 12
Preparation of P-Coumaric Acid:Nicotinamide 2:1 Cocrystal With
Seeding
[0093] A 100 mL reactor was charged with solid p-coumaric acid
(7.6892 g) and nicotinamide (2.8060 g), and 100 ml of acetonitrile
(ACN):water 97:3 solvent mixture with overhead stirring. The system
was heated to 76.degree. C. over a period of 30 minutes with
stirring, and an additional 10 mL of ACN:water 97:3 solvent mixture
was added to the reactor. The system was cooled to 70.degree. C. at
a rate of 0.2.degree. C./min. The system was seeded with 0.1544 g
p-coumaric acid:nicotinamide 2:1 cocrystals, added as a slurry in 6
mL of ACN:water 97:3 solvent mixture. The system was held for 30
minutes at 70.degree. C. before cooling to 10.degree. C. at a rate
of 0.2.degree. C./min. The system was held overnight at 10.degree.
C. and the solids were subsequently isolated by vacuum filtration
on a paper filter. The solids were dried in a vacuum oven at
ambient temperature for one day, yielding a p-coumaric
acid:nicotinamide 2:1 cocrystal (73% yield). The structure of the
p-coumaric acid:nicotinamide 2:1 cocrystal was confirmed by XRPD,
as illustrated in FIG. 15.
Example 13
Preparation of Minoxidil:Benzoic Acid 1:1 Monohydrate Cocrystal
Without Seeding
[0094] A 250 mL round bottom flask was charged with solid minoxidil
(21.209 g), 85 mL isopropanol, and 85 mL water. The system was
heated from room temperature to approximately 75.degree. C. with
stirring, until the solids dissolved. A 50 mL round bottom flask
was charged with benzoic acid (12.421 g), 21 mL of isopropanol, and
21 mL of water. The system was heated from room temperature to
approximately 75.degree. C. with stirring, until the solids
dissolved. The benzoic acid solution was added to the minoxidil
solution and the resulting system was cooled to approximately
69.degree. C. and held at this temperature for one hour.
Precipitation of white solids was observed. The system was slowly
cooled to room temperature before being placed in a refrigerator
with stirring for about one day. Solids were collected by vacuum
filtration and dried under vacuum at room temperature, yielding
31.8 g of minoxidil:benzoic acid 1:1 monohydrate cocrystal (90%
yield).
[0095] The structure of the minoxidil:benzoic acid 1:1 monohydrate
cocrystal was confirmed by XRPD, as illustrated in FIG. 16.
Solution proton NMR data confirmed the presence of minoxidil and
benzoic acid in a 1:1 ratio, as illustrated in FIG. 17.
Differential scanning calorimetry (DSC) and thermogravimetric (TG)
analyses were performed on the minoxidil:benzoic acid cocrystal,
the results of which are illustrated in FIG. 18. A Karl Fischer
analysis of the cocrystal yielded approximately 4.9 wt % water,
which is approximately consistent with the presence of 1 mole of
water per mole of cocrystal (theoretical value is approximately 5.2
wt % water).
[0096] Tables 5 and 6 below describes in more detail the peaks
observed in the XRPD pattern depleted in FIG. 16. Specifically,
Table 5 lists the observed peaks and Table 6 lists the
representative peaks.
TABLE-US-00005 TABLE 5 XRPD Observed Peaks for Minoxidil:Benzoic
Acid 1:1 Monohydrate .degree.2.theta. d space (.ANG.) Intensity (%)
7.29 .+-. 0.20 12.130 .+-. 0.342 100 11.42 .+-. 0.20 7.752 .+-.
0.138 28 12.47 .+-. 0.20 7.099 .+-. 0.115 3 14.66 .+-. 0.20 6.044
.+-. 0.083 39 15.38 .+-. 0.20 5.763 .+-. 0.075 13 16.38 .+-. 0.20
5.412 .+-. 0.066 34 17.03 .+-. 0.20 5.206 .+-. 0.061 11 19.15 .+-.
0.20 4.634 .+-. 0.048 67 20.02 .+-. 0.20 4.435 .+-. 0.044 64 20.56
.+-. 0.20 4.321 .+-. 0.042 28 20.84 .+-. 0.20 4.262 .+-. 0.041 10
21.09 .+-. 0.20 4.212 .+-. 0.040 8 21.28 .+-. 0.20 4.176 .+-. 0.039
24 21.81 .+-. 0.20 4.075 .+-. 0.037 2 22.04 .+-. 0.20 4.032 .+-.
0.036 7 22.44 .+-. 0.20 3.961 .+-. 0.035 4 22.86 .+-. 0.20 3.890
.+-. 0.034 24 23.11 .+-. 0.20 3.848 .+-. 0.033 76 24.27 .+-. 0.20
3.668 .+-. 0.030 13 24.67 .+-. 0.20 3.609 .+-. 0.029 3 25.14 .+-.
0.20 3.543 .+-. 0.028 4 25.79 .+-. 0.20 3.455 .+-. 0.027 2 26.51
.+-. 0.20 3.363 .+-. 0.025 36 27.39 .+-. 0.20 3.256 .+-. 0.023 4
27.66 .+-. 0.20 3.225 .+-. 0.023 4 27.96 .+-. 0.20 3.191 .+-. 0.023
7 28.78 .+-. 0.20 3.102 .+-. 0.021 4 28.95 .+-. 0.20 3.085 .+-.
0.021 6 29.58 .+-. 0.20 3.020 .+-. 0.020 11 29.88 .+-. 0.20 2.990
.+-. 0.020 7
TABLE-US-00006 TABLE 6 XRPD Representative Peaks for
Minoxidil:Benzoic Acid 1:1 Monohydrate .degree.2.theta. d space
(.ANG.) Intensity (%) 7.29 .+-. 0.20 12.130 .+-. 0.342 100 11.42
.+-. 0.20 7.752 .+-. 0.138 28 14.66 .+-. 0.20 6.044 .+-. 0.083 39
16.38 .+-. 0.20 5.412 .+-. 0.066 34 19.15 .+-. 0.20 4.634 .+-.
0.048 67 20.02 .+-. 0.20 4.435 .+-. 0.044 64 20.56 .+-. 0.20 4.321
.+-. 0.042 28 21.28 .+-. 0.20 4.176 .+-. 0.039 24 23.11 .+-. 0.20
3.848 .+-. 0.033 76 26.51 .+-. 0.20 3.363 .+-. 0.025 36
Example 14
Preparation of Minoxidil:Benzoic Acid 1:1 Monohydrate Cocrystal
(Single Crystal Preparation)
[0097] A vial was charged with 30 mg of minoxidil:benzoic acid 1:1
monohydrate cocrystal, 2 ml of acetonitrile, and 1 mL of water. The
sample was sonicated until a clear solution was obtained. The vial
was covered with paraffin and five holes were paced into the film
to allow for the slow evaporation of the solvent mixture. Solids
were observed in the vial after approximately 8 days. The sample
was capped and the crystals were harvested for the single crystal
analysis, described in more detail below.
Example 15
Single Crystal Structure Determination of Minoxidil:Benzoic Acid
1:1 Monohydrate Crystal
Experimental
Data Collection
[0098] A colorless chunk of C.sub.16H.sub.23N.sub.5O.sub.4 having
approximate dimensions of 0.20.times.0.18.times.0.14 mm, was
mounted on a fiber in random orientation. Preliminary examination
and data collection were performed with Cu K.sub..alpha. radiation
(.lamda.=1.54184 .ANG.) on a Rigaku Rapid II diffractometer
equipped with confocal optics. Refinements were performed using
SHELX97[i].
[0099] Cell constants and an orientation matrix for data collection
were obtained from least-squares refinement using the setting
angles of 15819 reflections in the range
3.degree.<.theta.<66.degree.. The refined mosaicity from
CrystalClear is 0.66.degree. indicating moderate crystal quality.
The space group was determined by the program XPREP. From the
systematic presence of the following conditions: hkl h+k=2n; h0l
l=2n, and from subsequent least-squares refinement, the space group
was determined to be C2/c (no. 4). The data were collected to a
maximum 2.theta. value of 133.20.degree., at a temperature of
200.+-.I K.
Data Reduction
[0100] Frames were integrated with CrystalClear. A total of 15819
reflections were collected, of which 3060 were unique. Lorentz and
polarization corrections were applied to the data. The linear
absorption coefficient is 0.810 mm.sup.-1 for Cu K.sub..alpha.
radiation. An empirical absorption correction using CrystalClear
was applied. Transmission coefficients ranged from 0.782 to 0.893.
A secondary extinction correction was applied. The final
coefficient, refined in least-squares, was 0.002450 (in absolute
units). Intensities of equivalent reflections were averaged. The
agreement factor for the averaging was 5% based on intensity.
Structure Solution and Refinement
[0101] The structure was solved by direct methods using SIR2004.
The remaining atoms were located in succeeding difference Fourier
syntheses. Some hydrogen atoms were refined independently,
including all hydrogens residing on nitrogen or oxygen atoms. Other
hydrogen atoms were included in the refinement but restrained to
ride on the atom to which they are bonded. The structure was
refined in full-matrix least-squares by minimizing the
function:
.SIGMA.w(|F.sub.o|.sup.2-|F.sub.c|.sup.2).sup.2
The weight w is defined as 1/[.sigma..sup.2(F.sub.o.sup.2)+(0.0594
P).sup.2+(1.8017 P)], where P=(F.sub.o.sup.2+2F.sub.c.sup.2)/3.
[0102] Scattering factors were taken from the "International Tables
for Crystallography". Of the 3060 reflections used in the
refinements, only the reflections with
F.sub.o.sup.2>2.sigma.(F.sub.o.sup.2) were used in calculating
the fit residual, R. A total of 2449 reflections were used in the
calculation. The final cycle of refinement included 260 variable
parameters and converged (largest parameter shift was <0.01
times its estimated standard deviation) with unweighted and
weighted agreement factors of:
R=.SIGMA.|F.sub.o-F.sub.c|.SIGMA.F.sub.o=0.043
R.sub.w= {square root over
((.SIGMA.w(F.sub.o.sup.2-F.sub.c.sup.2).sup.2/.SIGMA.w(F.sub.o.sup.2).sup-
.2))}{square root over
((.SIGMA.w(F.sub.o.sup.2-F.sub.c.sup.2).sup.2/.SIGMA.w(F.sub.o.sup.2).sup-
.2))}=0.111
[0103] The standard deviation of an observation of unit weight
(goodness of fit) was 1.045. The highest peak in the final
difference Fourier had a height of 0.29 e/.ANG..sup.3. The minimum
negative peak had a height of -0.20 e/.ANG..sup.3. Note that the
0.29 e/.ANG..sup.3 peak is in the position of a hydrogen residing
on N12. While the residual electron density is much less than a
full hydrogen atom, it likely indicates some hydrogen interaction
with N12.
Calculated X-Ray Powder Diffraction (XRPD) Pattern
[0104] A calculated XRPD pattern was generated for Cu radiation
using PowderCell 2.3 and the atomic coordinates, space group, and
unit cell parameters from the single crystal structure. Because the
single crystal data are collected at low temperatures (200 K), peak
shifts may be evident between the pattern calculated from low
temperature data and the room temperature experimental powder
diffraction pattern, particularly at high diffraction angles.
ORTEP and Packing Diagrams
[0105] The ORTEP diagram was prepared using the ORTEP III program
within the PLATON software package. Atoms are represented by 50%
probability anisotropic thermal ellipsoids. Packing diagrams were
prepared using CAMERON modeling software. Additional figures were
generated with the Mercury 3.0 visualization package. Hydrogen
bonding is represented as dashed lines.
Results
[0106] The monoclinic cell parameters and calculated volume are:
.alpha.=25.2302 (10) .ANG., b=8.9582 (3) .ANG., c=16.2196 (13)
.ANG., .alpha.=90.00.degree., .beta.=107.744 (17).degree.,
.gamma.=90.00.degree., V=3491.5 (3) .ANG..sup.3. The formula weight
of the asymmetric unit in the crystal structure of
minoxidil:benzoic acid monohydrate is 349.39 g mol.sup.-1 with Z=8,
resulting in a calculated density of 1.329 g cm.sup.-3. The space
group was determined to be C2/c. The space group and unit cell
parameters are consistent with those determined previously from
XRPD indexing. A summary of the crystal data and crystallographic
data collection parameters are provided in Table 7 below.
TABLE-US-00007 TABLE 7 Crystal Data and Data Collection Parameters
Formula C.sub.16H.sub.23N.sub.5O.sub.4 formula weight 349.39 space
group C2/c (No. 15) a, .ANG. 25.2302(10) b, .ANG. 8.9582(3) c,
.ANG. 16.2196(13) .beta., deg 107.744(17) V, .ANG..sup.3 3491.5(3)
Z 8 d.sub.cale, g cm.sup.-3 1.329 crystal dimensions, mm 0.20
.times. 0.18 .times. 0.14 temperature, K 200 radiation (wavelength,
.ANG.) Cu K.sub..alpha. (1.54184) Monochromator confocal optics
linear abs coef, mm.sup.-1 0.810 absorption correction applied
empirical.sup.a transmission factors: min, max 0.782, 0.893
Diffractometer Rigaku RAPID-II h, k, l range -29 to 30 -10 to 10
-14 to 19 2.theta. range, deg 7.36-133.20 mosaicity, deg 0.66
programs used SHELXTL F.sub.000 1488.0 weighting
1/[.sigma..sup.2(F.sub.o.sup.2) + (0.0610P).sup.2 + 1.8746P] where
P = (F.sub.o.sup.2 + 2F.sub.c.sup.2)/3 data collected 16767 unique
data 3060 R.sub.int 0.050 data used in refinement 3060 cutoff used
in R-factor calculations F.sub.o.sup.2 >
2.0.sigma.(F.sub.o.sup.2) data with I > 2.0.sigma.(I) 2449
refined extinction coef 0.0025 number of variables 260 largest
shift/esd in final cycle 0.00 R(F.sub.o) 0.042
R.sub.w(F.sub.o.sup.2) 0.107 goodness of fit 1.027
.sup.aCrystalClear: An Integrated Program for the Collection and
Processing of Area Detector Data, Rigaku Corporation, .COPYRGT.
1997-2002. bFlack, H.D. Acta Cryst., 1983 A39, 876. .sup.cHooft,
R.W.W., Straver, L.H., and Spek, A.L. J. Appl. Cryst., 2008, 41,
96-103
[0107] The quality of the structure obtained is high, as indicated
by the fit residual, R of 0.043 (4.3%). R-values in the range of
0.02 to 0.06 are quoted for the most reliably determined
structures.
[0108] An ORTEP drawing of minoxidil:benzoic acid monohydrate is
shown in FIG. 19. The molecules observed in the asymmetric unit of
the single crystal structure are consistent with the proposed
molecular structures of minoxidl and benzoic acid. The asymmetric
unit shown in FIG. 19 contains one minoxidil, one benzoic acid, and
one water. There are two sites for water molecules that both reside
on the 2-fold axis. Therefore, half of the water shown in FIG. 19
is symmetry generated, and therefore the stoichiometry is a
monohydrate.
[0109] Packing diagrams viewed along the a, b, and c
crystallographic axes are shown in FIGS. 20-22 respectively. A
strong hydrogen bond occurs between the minoxidil N-oxide and the
benzoic acid COOH group. The hydrogen was refined independently,
and positioned 1.16 .ANG. from the N-oxide and 1.28 .ANG. from the
COOH. Both of the water molecules are positioned with six potential
hydrogen bonding contacts around them in nearly octahedral
coordination, shown in FIG. 23. Assuming some interaction between
the water and each of the potential contacts, the overall hydrogen
bonding network is two-dimensional in the bc plane, depicted in
FIG. 24. No hydrogen bonding occurs along the a axis (see FIGS.
25A-B).
[0110] FIG. 9 shows a calculated XRPD pattern of minoxidil:benzoic
acid monohydrate, generated from the single crystal structure.
[0111] Tables of the positional parameters and their estimated
deviations (Table 8), anisotropic temperature factor coefficients
(Table 9), bond distances (Table 10), bond angles (Table 11), and
hydrogen bonds and angles (Table 12) and torsion angles (Table 13)
are provided below.
TABLE-US-00008 TABLE 8 Positional Parameters (.times.10.sup.4) and
Their Estimated Standard Deviations (A.sup.2 .times. 10.sup.3) x y
z U (eq) O (14) 313 (1) 1121 (1) 755 (1) 36 (1) O (1W) 0 3840 (3)
-2500 90 (1) O (21) 1191 (1) 10228 (2) 1750 (1) 48 (1) O (22) 811
(1) 8859 (2) 2566 (1) 55 (1) O (2W) 0 9060 (2) -2500 42 (1) N (1)
1078 (1) 6246 (2) -240 (1) 40 (1) N (12) 786 (1) 3790 (2) -522 (1)
36 (1) N (13) 542 (1) 1287 (2) -729 (1) 41 (1) N (14) 484 (1) 2455
(1) 498 (1) 31 (1) N (15) 328 (1) 3545 (2) 1685 (1) 45 (1) C (2)
1161 (1) 7628 (2) 268 (1) 51 (1) C (3) 1712 (1) 8333 (2) 314 (1) 54
(1) C (4) 1777 (1) 8565 (2) -572 (1) 55 (1) C (5) 1693 (1) 7104 (2)
-1063 (1) 50 (1) C (6) 1138 (1) 6412 (2) -1106 (1) 46 (1) C (11)
848 (1) 5023 (2) -4 (1) 32 (1) C (13) 604 (1) 2536 (2) -263 (1) 32
(1) C (15) 496 (1) 3702 (2) 989 (1) 33 (1) C (16) 687 (1) 5003 (2)
739 (1) 32 (1) C (21) 1793 (1) 8762 (2) 2844 (1) 39 (1) C (22) 2258
(1) 9444 (2) 2731 (1) 52 (1) C (23) 2786 (1) 8975 (3) 3207 (2) 66
(1) C (24) 2848 (1) 7820 (3) 3792 (2) 68 (1) C (25) 2389 (1) 7139
(2) 3904 (1) 62 (1) C (26) 1860 (1) 7606 (2) 3435 (1) 49 (1) C (27)
1219 (1) 9305 (2) 2359 (1) 38 (1) H (14) 716 (11) 660 (30) 1253
(17) 91 (8) H (2A) 1150 7405 860 61 H (2B) 856 8336 -2 61 H (3A)
2018 7686 659 65 H (3B) 1744 9308 613 65 H (4A) 2153 8962 -514 65 H
(4B) 1500 9305 -897 65 H (5A) 1997 6405 -773 60 H (5B) 1710 7281
-1658 60 H (6A) 834 7050 -1463 55 H (6B) 1106 5421 -1387 55 H (16)
683 (8) 5780 (20) 1029 (13) 45 (5) H (22) 2215 10235 2326 63 H (23)
3104 9449 3131 79 H (24) 3210 7496 4117 81 H (25) 2434 6343 4306 74
H (26) 1542 7134 3518 58 H (1W) 270 (20) 3390 (60) -2280 (40) 240
(30) H (2W) 276 (10) 9700 (30) -2542 (16) 84 (8) H (131) 627 (8)
1280 (20) -1206 (14) 51 (6) H (132) 338 (9) 570 (20) -616 (13) 53
(6) H (151) 211 (8) 2650 (30) 1805 (13) 55 (6) H (152) 258 (8) 4410
(30) 1952 (14) 59 (6) Starred atoms were refined isotropically
U.sub.eq =
(1/3).SIGMA..sub.i.SIGMA..sub.jU.sub.ija*.sub.ia*.sub.ja.sub.i.-
a.sub.j Hydrogen atoms are included in calculation of structure
factors but not refined
TABLE-US-00009 TABLE 9 Anisotropic Displacement Factor Coefficients
- U's U11 U22 U33 U23 U13 U12 O (14) 45 (1) 31 (1) 32 (1) 3 (1) 11
(1) -9 (1) O (1W) 116 (2) 41 (1) 108 (2) 0 24 (2) 0 O (21) 50 (1)
53 (1) 41 (1) 14 (1) 12 (1) 4 (1) O (22) 45 (1) 69 (1) 55 (1) 23
(1) 22 (1) 14 (1) O (2W) 51 (1) 37 (1) 46 (1) 0 25 (1) 0 N (1) 55
(1) 33 (1) 39 (1) 0 (1) 23 (1) -8 (1) N (12) 41 (1) 34 (1) 34 (1) 3
(1) 14 (1) -1 (1) N (13) 58 (1) 36 (1) 35 (1) -3 (1) 21 (1) -6 (1)
N (14) 37 (1) 28 (1) 28 (1) 3 (1) 10 (1) -4 (1) N (15) 69 (1) 37
(1) 33 (1) -4 (1) 23 (1) -11 (1) C (2) 68 (1) 32 (1) 64 (1) -6 (1)
38 (1) -8 (1) C (3) 63 (1) 42 (1) 62 (1) -11 (1) 26 (1) -14 (1) C
(4) 52 (1) 49 (1) 69 (1) 6 (1) 28 (1) -12 (1) C (5) 52 (1) 57 (1)
47 (1) 6 (1) 24 (1) -8 (1) C (6) 54 (1) 52 (1) 36 (1) 7 (1) 17 (1)
-9 (1) C (11) 31 (1) 31 (1) 31 (1) 4 (1) 8 (1) 0 (1) C (13) 32 (1)
34 (1) 29 (1) 4 (1) 9 (1) 2 (1) C (15) 34 (1) 35 (1) 27 (1) 0 (1) 6
(1) -3 (1) C (16) 38 (1) 28 (1) 29 (1) -3 (1) 10 (1) -4 (1) C (21)
43 (1) 44 (1) 32 (1) -3 (1) 15 (1) 7 (1) C (22) 50 (1) 65 (1) 45
(1) 2 (1) 18 (1) 2 (1) C (23) 42 (1) 88 (2) 66 (1) -8 (1) 14 (1) -1
(1) C (24) 47 (1) 79 (2) 64 (1) -10 (1) -2 (1) 17 (1) C (25) 66 (1)
55 (1) 56 (1) 6 (1) 5 (1) 21 (1) C (26) 52 (1) 46 (1) 48 (1) 3 (1)
15 (1) 11 (1) C (27) 44 (1) 41 (1) 33 (1) 1 (1) 15 (1) 5 (1) The
form of the anisotropic temperature factor is: exp[-2.pi.
h.sup.2a*.sup.2U(1,1) + k.sup.2b*.sup.2U(2,2) +
l.sup.2c*.sup.2U(3,3) + 2hka*b*U(1,2) + 2hla*c*U(1,3) +
2klb*c*U(2,3)] where a*, b*, and c* are reciprocal lattice
constants.
TABLE-US-00010 TABLE 10 Bond Distances in Angstroms Bond Distance
(.ANG.) O (14)--N (14) 1.3772 (15) O (14)--H (14) 1.16 (3) O
(1W)--N (1W) 0.77 (5) O (21)--C (27) 1.274 (2) O (22)--C (27) 1.241
(2) O (2W)--H (2W) 0.92 (2) N (1)--C (11) 1.349 (2) N (1)--C (6)
1.465 (2) N (1)--C (2) 1.466 (2) N (12)--C (13) 1.329 (2) N (12)--C
(11) 1.368 (2) N (13)--C (13) 1.333 (2) N (13)--H (131) 0.86 (2) N
(13)--H (132) 0.88 (2) N (14)--C (13) 1.3583 (19) N (14)--C (15)
1.367 (2) N (15)--C (15) 1.328 (2) N (15)--H (151) 0.89 (2) N
(15)--H (152) 0.93 (2) C (2)--C (3) 1.508 (3) C (2)--H (2A) 0.9900
C (2)--H (2B) 0.9900 C (3)--C (4) 1.509 (3) C (3)--H (3A) 0.9900 C
(3)--H (3B) 0.9900 C (4)--C (5) 1.514 (3) C (4)--H (4A) 0.9900 C
(4)--H (4B) 0.9900 C (5)--C (6) 1.515 (2) C (5)--H (5A) 0.9900 C
(5)--H (5B) 0.9900 C (6)--H (6A) 0.9900 C (6)--H (6B) 0.9900 C
(11)--C (16) 1.385 (2) C (15)--C (16) 1.369 (2) C (16)--H (16) 0.84
(2) C (21)--C (22) 1.384 (3) C (21)--C (26) 1.386 (2) C (21)--C
(27) 1.503 (2) C (22)--C (23) 1.384 (3) C (22)--H (22) 0.9500 C
(23)--C (24) 1.380 (3) C (23)--H (23) 0.9500 C (24)--C (25) 1.369
(3) C (24)--H (24) 0.9500 C (25)--C (26) 1.385 (3) C (25)--H (25)
0.9500 C (26)--H (26) 0.9500 Numbers in parentheses are estimated
standard deviations in the least significant digits.
TABLE-US-00011 TABLE 11 Bond Angles in Degrees Angle Degree
(.degree.) N (14)--O (14)--H (14) 103.1 (13) C (11)--N (1)--C (6)
122.26 (14) C (11)--N (1)--C (2) 121.75 (14) C (6)--N (1)--C (2)
114.47 (14) C (13)--N (12)--C (11) 118.29 (13) C (13)--N (13)--H
(131) 119.9 (13) C (13)--N (13)--H (132) 118.1 (14) H (131)--N
(13)--H (132) 120.2 (19) C (13)--N (14)--C (15) 120.91 (13) C
(13)--N (14)--O (14) 119.89 (12) C (15)--N (14)--O (14) 119.06 (12)
C (15)--N (15)--H (151) 119.5 (13) C (15)--N (15)--H (152) 117.4
(13) H (151)--N (15)--H (152) 121.5 (19) N (1)--C (2)--C (3) 110.72
(15) N (1)--C (2)--H (2A) 109.5 C (3)--C (2)--H (2A) 109.5 N (1)--C
(2)--H (2B) 109.5 C (3)--C (2)--H (2B) 109.5 H (2A)--C (2)--H (2B)
108.1 C (2)--C (3)--C (4) 112.05 (17) C (2)--C (3)--H (3A) 109.2 C
(4)--C (3)--H (3A) 109.2 C (2)--C (3)--H (3B) 109.2 C (4)--C (3)--H
(3B) 109.2 H (3A)--C (3)--H (3B) 107.9 C (3)--C (4)--C (5) 110.12
(15) C (3)--C (4)--H (4A) 109.6 C (5)--C (4)--H (4A) 109.6 C (3)--C
(4)--H (4B) 109.6 C (5)--C (4)--H (4B) 109.6 H (4A)--C (4)--H (4B)
108.2 C (4)--C (5)--C (6) 110.84 (16) C (4)--C (5)--H (5A) 109.5 C
(6)--C (5)--H (5A) 109.5 C (4)--C (5)--H (5B) 109.5 C (6)--C (5)--H
(5B) 109.5 H (5A)--C (5)--H (5B) 108.1 N (1)--C (6)--C (5) 111.23
(14) N (1)--C (6)--H (6A) 109.4 C (5)--C (6)--H (6A) 109.4 N (1)--C
(6)--H (6B) 109.4 C (5)--C (6)--H (6B) 109.4 H (6A)--C (6)--H (6B)
108.0 N (1)--C (11)--N (12) 117.40 (14) N (1)--C (11)--C (16)
121.59 (14) N (12)--C (11)--C (16) 121.00 (14) N (12)--C (13)--N
(13) 121.42 (15) N (12)--C (13)--N (14) 121.80 (14) N (13)--C
(13)--N (14) 116.76 (14) N (15)--C (15)--N (14) 116.94 (14) N
(15)--C (15)--C (16) 125.00 (15) N (14)--C (15)--C (16) 118.06 (14)
C (15)--C (16)--C (11) 119.47 (15) C (15)--C (16)--H (16) 118.2
(13) C (11)--C (16)--H (16) 122.2 (13) C (22)--C (21)--C (26)
119.43 (17) C (22)--C (21)--C (27) 120.65 (16) C (26)--C (21)--C
(27) 119.87 (16) C (21)--C (22)--C (23) 120.2 (2) C (21)--C (22)--H
(22) 119.9 C (23)--C (22)--H (22) 119.9 C (24)--C (23)--C (22)
119.9 (2) C (24)--C (23)--H (23) 120.0 C (22)--C (23)--H (23) 120.0
C (25)--C (24)--C (23) 120.12 (19) C (25)--C (24)--H (24) 119.9 C
(23)--C (24)--H (24) 119.9 C (24)--C (25)--C (26) 120.4 (2) C
(24)--C (25)--H (25) 119.8 C (26)--C (25)--H (25) 119.8 C (25)--C
(26)--C (21) 120.0 (2) C (25)--C (26)--H (26) 120.0 C (21)--C
(26)--H (26) 120.0 O (22)--C (27)--O (21) 124.36 (15) O (22)--C
(27)--C (21) 120.04 (15) O (22)--C (27)--C (21) 115.60 (15) Numbers
in parentheses are estimated standard deviations in the least
significant digits.
TABLE-US-00012 TABLE 12 Hydrogen Bond Distances in Angstroms and
Angles in Degrees D H A D-H A-H D-A D-H-A O(1W) H(1W) O(22) 0.77
2.49 3.15 144 O(2W) H(2W) O(22) 0.92 1.84 2.75 169 O(14) H(14)
O(21) 1.16 1.28 2.44 174 N(13) H(131) O(22) 0.86 2.18 3.04 177
N(13) H(132) O(14) 0.88 2.30 2.65 104 N(13) H(132) O(14) 0.88 2.19
3.04 162 N(15) H(151) O(2W) 0.89 2.07 2.92 160 N(15) H(151) O(14)
0.89 2.26 2.64 105 N(15) N(152) O(1W) 0.93 2.00 2.93 172 Numbers in
parentheses are estimated standard deviations in the least
significant digits.
TABLE-US-00013 TABLE 13 Torsion Angles in Degrees Angle Degree
(.degree.) C (11)--N (1)--C (2)--C (3) 140.07 (17) C (6)--N (1)--C
(2)--C (3) -53.7 (2) N (1)--C (2)--C (3)--C (4) 53.7 (2) C (2)--C
(3)--C (4)--C (5) -55.3 (2) C (3)--C (4)--C (5)--C (6) 55.1 (2) C
(11)--N (1)--C (6)--C (5) -139.36 (17) C (2)--N (1)--C (6)--C (5)
54.5 (2) C (4)--C (5)--C (6)--N (1) -54.4 (2) C (6)--N (1)--C
(11)--N (12) 14.6 (2) C (2)--N (1)--C (11)--N (12) 179.76 (15) C
(6)--N (1)--C (11)--C (16) -166.21 (15) C (2)--N (1)--C (11)--C
(16) -1.0 (2) C (13)--N (12)--C (11)--N (1) 174.44 (14) C (13)--N
(12)--C (11)--C (16) -4.8 (2) C (11)--N (12)--C (13)--N (13)
-178.94 (14) C (11)--N (12)--C (13)--N (14) -0.5 (2) C (15)--N
(14)--C (13)--N (12) 6.4 (2) O (14)--N (14)--C (13)--N (12) -177.95
(13) C (15)--N (14)--C (13)--N (13) -175.12 (14) O (14)--N (14)--C
(13)--N (13) 0.6 (2) C (13)--N (14)--C (15)--N (15) 174.49 (14) O
(14)--N (14)--C (15)--N (15) -1.2 (2) C (13)--N (14)--C (15)--C
(16) -6.7 (2) O (14)--N (14)--C (15)--C (16) 177.56 (13) N (15)--C
(15)--C (16)--C (11) -179.79 (16) N (14)--C (15)--C (16)--C (11)
1.5 (2) N (1)--C (11)--C (16)--C (15) -174.94 (14) N (12)--C
(11)--C (16)--C (15) 4.2 (2) C (26)--C (21)--C (22)--C (23) -0.1
(3) C (27)--C (21)--C (22)--C (23) 177.32 (18) C (21)--C (22)--C
(23)--C (24) 0.4 (3) C (22)--C (23)--C (24)--C (25) -0.2 (3) C
(23)--C (24)--C (25)--C (26) -0.2 (3) C (24)--C (25)--C (26)--C
(21) 0.4 (3) C (22)--C (21)--C (26)--C (25) -0.2 (3) C (27)--C
(21)--C (26)--C (25) -177.72 (17) C (22)--C (21)--C (27)--O (22)
-168.08 (17) C (26)--C (21)--C (27)--O (22) 9.4 (2) C (22)--C
(21)--C (27)--O (21) 11.5 (2) C (26)--C (21)--C (27)--O (21)
-171.06 (16) Numbers in parentheses are estimated standard
deviations in the least significant digits.
* * * * *