U.S. patent application number 13/262652 was filed with the patent office on 2012-04-12 for crystal forms of saxagliptin.
This patent application is currently assigned to SANDOZ AG. Invention is credited to Christoph Langes, Arthur Pichler, Milica Vukicevic, Josef Wieser.
Application Number | 20120088808 13/262652 |
Document ID | / |
Family ID | 42935672 |
Filed Date | 2012-04-12 |
United States Patent
Application |
20120088808 |
Kind Code |
A1 |
Pichler; Arthur ; et
al. |
April 12, 2012 |
CRYSTAL FORMS OF SAXAGLIPTIN
Abstract
The present invention relates to novel polymorphic forms of
Saxagliptin Hydrochloride. The present invention also relates to
methods of making polymorphic forms of Saxagliptin
Hydrochloride.
Inventors: |
Pichler; Arthur; (Kundl,
AT) ; Wieser; Josef; (Kundl, AT) ; Langes;
Christoph; (Kundl, AT) ; Vukicevic; Milica;
(Kundl, AT) |
Assignee: |
SANDOZ AG
Basel
CH
|
Family ID: |
42935672 |
Appl. No.: |
13/262652 |
Filed: |
April 9, 2010 |
PCT Filed: |
April 9, 2010 |
PCT NO: |
PCT/EP10/54692 |
371 Date: |
November 28, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61167918 |
Apr 9, 2009 |
|
|
|
Current U.S.
Class: |
514/412 ;
548/452 |
Current CPC
Class: |
A61K 31/403 20130101;
A61P 3/00 20180101; A61K 45/06 20130101; A61P 3/10 20180101; A61P
3/04 20180101; C07D 209/52 20130101 |
Class at
Publication: |
514/412 ;
548/452 |
International
Class: |
C07D 209/52 20060101
C07D209/52; A61P 3/10 20060101 A61P003/10; A61K 31/403 20060101
A61K031/403 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 9, 2009 |
EP |
09157723.9 |
Nov 6, 2009 |
EP |
09175259.2 |
Claims
1. Anhydrous crystalline forms of Saxagliptin hydrochloride having
a water content of not more than 1.5% w/w.
2. Saxagliptin hydrochloride according to claim 1 of the formula
##STR00002##
3. Crystalline Form I-S of Saxagliptin hydrochloride according to
claim 1 having a x-ray powder diffraction pattern comprising peaks
at 6.7.+-.0.2, 14.6.+-.0.2, 15.2.+-.0.2, 16.6.+-.0.2 and
17.9.+-.0.2 degrees two-theta and/or having an infrared spectrum
comprising peaks at wavenumbers of 2907, 2853, 1637, 1589, 1462,
1391, 1318, 1045, 1014 and 775+/-2 cm.sup.-1.
4. Crystalline Form HT-S of Saxagliptin hydrochloride according to
claim 1 having a x-ray powder diffraction pattern comprising peaks
at 6.6.+-.0.2, 13.3.+-.0.2 and 17.6.+-.0.2 degrees two-theta and/or
having an infrared spectrum comprising peaks at wavenumbers of
2906, 2854, 1649, 1574, 1513, 1459, 1338, 1124, 1032 and 851+/-2
cm.sup.-1.
5. Crystalline Form HT-IV-S of Saxagliptin hydrochloride according
to claim 1 having a x-ray powder diffraction pattern comprising
peaks at 2.6, 4.5, 6.8, 14.6 and 18.1.+-.0.2 degrees two-theta
and/or having an infrared spectrum comprising peaks at wavenumbers
of 3495, 2921, 1637, 1616, 1464, 1242, 1103, 1013, 940 and 774+/-2
cm.sup.-1.
6. Crystalline Form IV-S of Saxagliptin hydrochloride according to
claim 1 having an x-ray powder diffraction pattern comprising peaks
at 2.4, 4.1, 4.7, 6.3 and 15.6.+-.0.2 degrees two-theta.
7. Pharmaceutical composition comprising an crystalline form of
Saxagliptin according to claim 1 in an effective amount.
8. A process for the preparation of crystalline Saxagliptin
hydrochloride Form I-S according to claim 3 comprising the step of
allowing Saxagliptin hydrochloride to crystallize from an alcohol
in the presence of seed crystals of Saxagliptin hydrochloride Form
I-S.
9. A process for the preparation of crystalline Saxagliptin
hydrochloride Form HT-S according to claim 4 comprising the step of
heating the known crystalline forms of Saxagliptin hydrochloride
form H2-1, H1.25-2 or H.75-3 to about 160.degree. C. to 180.degree.
C., and isolating Form HT-S.
10. A method of using crystalline Saxagliptin hydrochloride
according to claim 1 alone or in combination with one or more types
of antidiabetic agents and/or one or more other types of
therapeutic agents which may be administered orally in the same
dosage form for the preparation of a medicament in a separate
dosage form or by injection.
11. A pharmaceutical composition comprising crystalline Saxagliptin
hydrochloride according to claim 1, wherein the equilibrium
relative humidity of the composition is below 50%.
12. The pharmaceutical composition of claim 11, wherein the
equilibrium relative humidity of the composition is from 10% to
40%.
13. A method of using Saxagliptin hydrochloride form IV-S according
to claim 6 for the preparation of Saxagliptin hydrochloride form
HT-IV-S according to claim 5.
14. The crystalline Form I-S of Saxagliptin hydrochloride according
to claim 3 having a x-ray powder diffraction pattern comprising
peaks at 24.5.+-.0.2 and 28.2.+-.0.2 degrees two-theta.
15. The crystalline Form HT-S of Saxagliptin hydrochloride
according to claim 4 having a x-ray powder diffraction pattern
comprising peaks at 11.5.+-.0.2 and 16.7.+-.0.2 degrees
two-theta.
16. The crystalline Form HT-IV-S of Saxagliptin hydrochloride
according to claim 5 having a x-ray powder diffraction pattern
comprising peaks at 2.6.+-.0.2 and 6.8.+-.0.2 two theta.
17. The pharmaceutical composition according to claim 7, formulated
for use in treating diabetes and/or related diseases.
Description
[0001] The present invention relates to novel polymorphic forms of
Saxagliptin Hydrochloride, their preparation and compositions
containing them.
[0002]
Saxagliptin(1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1-adamantyl)acet-
yl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile or its hydrochloride
salt is an orally active reversible dipeptidyl peptidase-4 (DD4)
inhibitor, which is a therapeutic agent for treatment of type-2
diabetes mellitus, obesity or related diseases, and is disclosed
for example in U.S. Pat. No. 6,395,767 B2, example 60.
[0003] Certain crystal forms of Saxagliptin and certain acid
addition salts including Saxagliptin Hydrochloride are disclosed in
WO 2008131149 A2. The occurrence of different crystalline forms of
a single compound is known as polymorphism and is a property of
some compounds and complexes and pseudopolymorphs. Polymorphic
forms each have distinct physical properties, such as a distinct
solubility profile, different melting point and/or different x-ray
diffraction peaks.
[0004] Since the solubility of each polymorph may vary, identifying
the existence of pharmaceutical polymorphs is important for
providing pharmaceutical compositions with predictable solubility
profiles. It is desirable to investigate all solid state forms of a
drug, including all polymorphic forms, pseudopolymorphs and
hydrates, and to determine the stability, dissolution and flow
properties of each polymorphic form. For a general review of
polymorphs and the relevance of solid state properties for
pharmaceutical products see e.g. Rolf Hilfiker, Polymorphism in the
Pharmaceutical industry, Wiley-VCH 2006.
[0005] The discovery of new polymorphic forms of a pharmaceutically
useful compound provides a new opportunity to improve the
performance characteristics of a pharmaceutical product. It
enlarges the repertoire of materials that a formulation scientist
has available for designing, for example, a pharmaceutical dosage
form of a drug with a targeted release profile or other desired
characteristic.
[0006] The known polymorphic forms of Saxagliptin hydrochloride are
all hydrated forms having a relatively high water content.
High-water content forms have certain drawbacks, as a compound
prone to hydrolysis like Saxagliptin can show decreased chemical
stability when present in such forms. Moreover, from a galenical
perspective, bulk quantities of active pharmaceutical ingredients
having a high water content tend to clog or stick together, thus
sometimes having poor processing behavior in the formulation
processes for the production of pharmaceutical compositions.
[0007] There is thus a need for solid forms of Saxagliptin
hydrochloride which avoid one or more problems of the known crystal
forms.
[0008] In accordance with the present invention new anhydrous forms
of Saxagliptin Hydrochloride preferably of the formula
##STR00001##
are provided having a water content of not more than 1.5% w/w
preferably in substantially pure form as a) an anhydrous form
designated as Form I-S b) an anhydrous form designated as form HT-S
c) an anhydrous form designated as form HT-IV-S d) an anhydrous
form designated as form IV-S.
[0009] The water content is determined according to the Karl
Fischer method.
[0010] An anhydrous form of Saxagliptin hydrochloride in the
context of the present invention is defined as a form of
Saxagliptin hydrochloride which, after storage at 30% relative
humidity at 25.degree. C. for 24 hours shows a water content of not
more than 1.5% w/w according to the Karl Fischer method.
DETAILED DESCRIPTION
[0011] The Saxagliptin hydrochloride used as educt is one of the
known forms containing water, e.g. forms H2-1, H1.25-2 or H.75-3 as
identified in WO 2008/131149 A2 on page 2.
[0012] Form I-S
[0013] In a first aspect the present invention provides a
crystalline form of Saxagliptin hydrochloride, designated as form
I-S, which can be characterized by x-ray powder diffraction
reflections at about 6.7, 14.6, 15.2, 16.6 and 17, 9.+-.0.2 degrees
two-theta, in particular comprising further peaks at about 13.5,
24.5 and 28.1. Form I S of Saxagliptin can be further characterized
by a PXRD pattern substantially in accordance with FIG. 1.
[0014] Alternatively crystalline form I-S of Saxagliptin
hydrochloride can be described by an infrared spectrum comprising
peaks at wavenumbers of 2907, 2853, 1637, 1589, 1462, 1391, 1318,
1045, 1014 and 775+/-2 cm-1. Form I S of Saxagliptin hydrochloride
can be further characterized by an FTIR spectrum substantially in
accordance with FIG. 2.
[0015] Anhydrous crystalline Saxagliptin hydrochloride in the form
of form I-S can be prepared by crystallization of Saxagliptin
hydrochloride from an alcohol, preferably ethanol in the presence
of seeds of from I-S, for example as described in example 2. Seeds
of from I-S were surprisingly obtained by dissolving Saxagliptin
free base hemihydrate in an organic solvent, precipitation with an
alkyl halide dihydrate, removing precipitated Saxagliptin
monohydrochloride dehydrate and crystallizing from the mother
liquor after cooling, see example 1. Crystalline Saxagliptin
hydrochloride form I-S is a particularly preferred crystal form due
to its high chemical stability combined with its high dissolution
rate.
Form HT-S
[0016] In a second aspect the present invention provides a
crystalline form of Saxagliptin hydrochloride, designated as form
HT-S, which can be characterized by x-ray powder diffraction
reflections at about 6.6, 11.5, 13.3, 16.7 and 17.6.+-.0.2 degrees
two-theta, in particular comprising further peaks at about 11.5 and
15.3. Form HT-S of Saxagliptin can be further characterized by a
PXRD pattern substantially in accordance with FIG. 4.
[0017] Alternatively crystalline form HT-S of Saxagliptin
hydrochloride can be described by an infrared spectrum comprising
peaks at wavenumbers of 2906, 2854, 1649, 1574, 1513, 1459, 1338,
1124, 1032 and 851+/-2 cm-1. Form HT-S of Saxagliptin hydrochloride
can be further characterized by an FTIR spectrum substantially in
accordance with FIG. 5.
[0018] The crystalline Saxagliptin hydrochloride in the form of
HT-S can be prepared by heating known forms Saxagliptin
hydrochloride to about 160.degree. C. to 180.degree. C. and
isolating form HT-S. In particular, form HT-S may be prepared as
described in example 3.
Form HT-IV-S
[0019] In a third aspect the present invention provides a
crystalline form of Saxagliptin hydrochloride, designated as form
HT-IV-S, which can be characterized by x-ray powder diffraction
reflections at about 2.6, 4.5, 6.8, 14.6 and 18.1.+-.0.2 degrees
two-theta. Form HT-IV-S of Saxagliptin can be further characterized
by a PXRD pattern substantially in accordance with FIG. 7.
[0020] Alternatively crystalline form HT-IV-S of Saxagliptin
hydrochloride can be described by an infrared spectrum comprising
peaks at wavenumbers of 3495, 2921, 1637, 1616, 1464, 1242, 1103,
1013, 940 and 774+/-2 cm-1. Form HT-IV-S of Saxagliptin
hydrochloride can be further characterized by an FTIR spectrum
substantially in accordance with FIG. 8.
[0021] The crystalline Saxagliptin hydrochloride in the form
HT-IV-S can be prepared by removing bound solvent from
Saxagliptin-IV-S. In particular the form HT-IV-S can be obtained by
drying the form IV-S described below in vacuo, e.g. at ambient
temperature to about 100.degree. C., e.g. at about 80.degree.
C..+-.10.degree. C. for several hours, e.g. for 3 to 24 hours. In
particular form HT-IV-S may be prepared as described in example 4.
In one preferred embodiment Saxagliptin hydrochloride form HT-IV-S
is prepared in a process comprising the steps of [0022] a)
dissolving Saxagliptin monohydrochloride in n-butanole, [0023] b)
removing n-butanole under reduced pressure to obtain a residue,
[0024] c) adding 2-methyl-2-butanol to obtain a slurry, [0025] d)
allowing a solvated crystalline form of Saxagliptin hydrochloride
to form in the slurry, [0026] e) removing the solvated crystalline
form from the slurry, and [0027] f) drying the solvated crystalline
form obtained from step e) to obtain the anhydrous crystalline
Saxagliptin hydrochloride form HT-IVs. Drying in step f) is
preferably carried out at 80.degree. C.+/-10.degree. C. for 3-24
hours.
Form IV-S
[0028] Saxagliptin form IV-S can be characterized by x-ray powder
diffraction reflections at about 2.4, 4.1, 4.7, 6.3 and 15,
6.+-.0.2 degrees two-theta. Form IV-S of Saxagliptin can be further
characterized by a PXRD pattern substantially in accordance with
FIG. 1.
[0029] The crystalline Saxagliptin hydrochloride in the form of
form IV-S can be, and preferably is prepared by crystallisation of
Saxagliptin hydrochloride from tert. Amylalkohol
(2-methyl-2-butanol) as described in example 5. A solution of
Saxagliptin Hydrochloride in n-butanole is evaporated to dryness to
produce an amorphous or weakly crystalline residue. Upon suspending
the residue in tert.amylalkohol the novel crystalline form IV-S of
Saxaglipin Hydrochloride is formed, which is a tert.amylcohol
solvate of Saxagliptin hydrochloride.
[0030] Saxagliptin hydrochloride form IV-S is a valuable
intermediate in the preparation of Saxagliptin hydrochloride form
HT-IV-S.
[0031] Most preferably the solution of Saxagliptin hydrochloride is
prepared using known form Dihydrate H2.1. The crystals are then
isolated and kept at a relative humidity of less than to about
40%.
Pharmaceutical Formulations and Compositions
[0032] Any one of the crystal forms of Saxagliptin Hydrochloride of
the invention as described above may be employed in various
pharmaceutical formulations for use in treating diabetes and
related diseases in accordance with the present invention. The
present invention therefore also relates to a pharmaceutical
composition which includes any one of the crystalline forms of
saxagliptin hydrochloride as described above and a pharmaceutically
acceptable carrier.
[0033] The novel crystal forms of Saxagliptin Hydrochloride may be
used alone or in combination with one or more types of antidiabetic
agents (employed to treat diabetes and related diseases) and/or one
or more other types of therapeutic agents which may be administered
orally in the same dosage form, in a separate dosage form or by
injection.
[0034] The other types of antidiabetic agent which may optionally
be employed in combination with the novel crystal forms of the
compound of formula I are further antidiabetic agents or
antihyperglycemic, hypolipidemic or lipid-modulating agents
including insulin secretagogues or other antidiabetic agents
preferably having a mechanism different from DP4 inhibition and may
include biguanidines, sulfonyl ureas, glucosidase inhibitors, PPAR
.gamma. agonists, such as thiazolidinediones, SGLT2 inhibitors, PAR
.alpha./.gamma. dual antagonists, aP'' inhibitors, glycogen
phosphorylase inhibitors, and/or meglitinides, as well as insulin
and/or glucagons-like peptide-1 (GLP-1) or mimetics thereof.
[0035] The present invention also relates to a pharmaceutical
composition containing the novel crystalline forms form I-S, form
HT-S, form HT-IV or form IV-S of the compound of formula I, with or
without another antidiabetic agent and/or other therapeutic agent,
in association with a pharmaceutical vehicle or diluent. The
pharmaceutical composition can be formulated employing conventional
solid or liquid vehicles or diluents and pharmaceutical additives
of a type appropriate to the mode of desired administration. For
example, for the administration by an oral route the pharmaceutical
composition of the invention may be in the form of tablets,
capsules, granules or powders. The dose for adults is preferably
between 5 mg to 1000 mg per day, preferably between 5 and 100 mg
per day, which can be administered in a single dose or in the
individual doses from 1-4 times a day.
[0036] The pharmaceutical compositions of the invention comprising
the crystalline form of Saxagliptin hydrochloride according to the
present invention may further comprise one or more pharmaceutically
acceptable excipients which are preferably selected from the group
consisting of fillers, sweeteners, buffering agents, glidants,
flowing agents, flavoring agents, lubricants, preservatives,
surfactants, wetting agents, binders, disintegrants and thickeners.
Other excipients known in the field of pharmaceutical compositions
may also be used. Furthermore, the pharmaceutical compositions may
comprise a combination of 2 or more excipients also within one of
the members of the above mentioned group. Preferably, the fillers
are also sweeteners.
[0037] A typical tablet contains a one or more excipients such as
bulking agents, optionally a binder and optionally a disintegrant.
Examples of bulking agents include cellulose derivatives, such as
microcrystalline cellulose, lactose, sucrose, starch,
pregelatinized starch, dextrose, mannitol, fructose, xylitol,
sorbitol, corn starch, inorganic salts such as calcium salts, e.g.
calcium carbonate, calcium phosphate, dicalcium phosphate, dextrin
or dextrates, maltodextrin compressable sugars and/or other known
bulking agents or fillers.
[0038] Examples of binders suitable for use include
hydroxypropylcellulose, PVP, starch, hydroxypropylcellulose,
cellulose acetate as well as a wax binder such as carnauba wax,
polyethylenes or other conventional binding agents or mixtures
thereof.
[0039] Examples of disintegrants include croscarmellose sodium,
crospovidone, starch, low substituted hydroxypropyl cellulose as
well as other conventional desintegrants.
[0040] The lubricant optionally present include for example
magnesium stearate, zinc stearate, calcium stearate, talc, carnauba
wax, stearic acid, palmitinic acid, sodium laurylsulfate or
hydrogenated vegetable oils and fats or other known lubricats or
mixtures thereof.
[0041] Tablets may be coated including a tablet core and a inner
seal coating layer coated on the tablet core, a second coating
layer containing the crystals of the present invention coated on
the inner seal coating on the tablet core and optionally an outer
protective coating layer coated on the second coating layer of the
tablet as e.g. disclosed in US 2005/0266080.
[0042] The present invention therefore also provides such coated
tablets as described in sections [0014] to section [0073] of US
2005/0266080 A1, where it is to be understood that whenever US
2005/0266080 A1 is using the term "medicament", the crystalline
saxagliptin hydrochloride of the present invention is to be used
instead of the "medicament" of US 2005/0266080 A1. It goes without
saying that especially when form I-S, form IV-S or form HT-IV-s is
used, all steps are typically carried out under such conditions
which avoid polymorphic transformation, such as conditions of
relatively low relative humidity.
[0043] Typical capsules for oral administration containing the
novel crystalline forms of the invention contain e.g, lactose,
crosscarmelose, magnesium stearate or e.g. sodium stearyl
fumararte.
Purity
[0044] The present inventors have found ways to stabilize
especially form I-S, form HT-IV-S and form IV-S during the
formulation and storage process.
[0045] The present invention therefore also relates to a
pharmaceutical composition comprising the crystalline form of
Saxagliptin hydrochloride designated as form I-S, wherein more than
95% of the crystalline form of Saxagliptin hydrochloride,
designated as form I-S, present in said composition is stably
present as form I-S, in particular, the present invention relates
to such pharmaceutical compositions wherein form I-S is the only
detectable crystalline from of Saxagliptin hydrochloride.
[0046] The present invention therefore also relates to a
pharmaceutical composition comprising the crystalline form of
Saxagliptin hydrochloride designated as form HT-IV-S, wherein more
than 95% of the crystalline form of Saxagliptin hydrochloride,
designated as form HT-IV-S, present in said composition is stably
present as form HT-IV-S, in particular, the present invention
relates to such pharmaceutical compositions wherein form HT-IV-S is
the only detectable crystalline from of Saxagliptin
hydrochloride.
[0047] The present invention therefore also relates to a
pharmaceutical composition comprising the crystalline form of
Saxagliptin hydrochloride designated as form IV-S, wherein more
than 95% of the crystalline form of Saxagliptin hydrochloride,
designated as form IV-S present in said composition is stably
present as form IV-S, in particular, the present invention relates
to such pharmaceutical compositions wherein form IV-S is the only
detectable crystalline from of Saxagliptin hydrochloride.
[0048] "Stably present" as defined herein means that even after
storage of the pharmaceutical composition for 180 days, and
preferably even after storage for two years, the crystalline form
of Saxagliptin hydrochloride initially comprised in the
pharmaceutical composition is still present as crystalline form of
Saxagliptin hydrochloride after storage for the indicated period.
Such compositions can be produced by avoiding humid conditions,
such as high relative humidity of the air, during the formulation
steps. Furthermore, the above-identified humid conditions are to be
avoided during storage in order to preserve the pharmaceutical
composition of the invention.
[0049] In a preferred embodiment the pharmaceutical composition of
the invention comprises the crystalline form of Saxagliptin
hydrochloride designated as form I-S as the only detectable form of
Saxagliptin hydrochloride. Analysis of the polymorphic state of
Saxagliptin hydrochloride in a pharmaceutical composition can be
performed by any suitable method known in the art, for example by
XRPD.
Equilibrium Humidity
[0050] It is preferred that the pharmaceutical composition of the
invention comprising the crystalline form of Saxagliptin
hydrochloride designated as form I-S or form HT-IV-S exhibits an
equilibrium relative humidity of below 50%, preferably of from 3%
to 50%, more preferably of from 10% to 45%, preferably from 15% to
45%, in particular more preferably of from 15% to 40% or from 25%
to 35%, for at least 180 days, preferably for at least two
years.
[0051] It is preferred that the pharmaceutical composition of the
invention comprising the crystalline form of Saxagliptin
hydrochloride designated as form IV-S exhibits an equilibrium
relative humidity of below 40%, preferably of from 3% to 40%, more
preferably of from 10% to 40%, preferably from 15% to 40%, in
particular more preferably of from 15% to 40% or from 25% to 35%,
for at least 180 days, preferably for at least two years.
[0052] The equilibrium relative humidity of the pharmaceutical
compositions comprising the crystalline form of Saxagliptin
hydrochloride is measured by determining the relative humidity in %
in the air above a test sample, e.g. a pharmaceutical composition
of the invention comprising the crystalline form of Saxagliptin
hydrochloride designated as form I-S or form HT-IV-S, after
establishment of a humidity equilibrium in a closed system at a
constant temperature according to the following method: the
equipment used is the commercially available measuring chamber
Rotronic AW-VC comprising a hygrometer of the type BT-RS1. The test
sample, e.g. a pharmaceutical composition of the invention is
filled into a sampling dish which is placed into the measuring
chamber which has been thermostated to a temperature of
25+/-1.degree. C., said chamber is subsequently closed and sealed.
After establishment of an equilibrium of the relative humidity
which state is typically shown by the disappearance of a trend
indication, the value of the relative humidity in % is read from
the hygrometer. Relative humidity is defined as the equilibrium
relative humidity of the pharmaceutical compositions as measured as
herein described. Filling of the chamber is to be performed in such
a way as to provide complete filling of said chamber according to
the instructions of the manufacturers. In case the test sample is a
powder or granules for oral suspension, or a liquid suspension,
said sample is directly placed into the above mentioned sampling
dish. In case the test sample is a capsule, the appropriate number
of capsules is opened and their contents is filled into the
sampling dish. In case the test sample is a tablet, the appropriate
number of tablets is crushed by using a mortar, and filled into the
sampling dish. In cases where the equilibrium humidity is expected
to be below 20%, the above described preparation of the test
samples before measurement and the measurement itself as herein
described is to be performed in a glove box being equipped with a
hygrometer wherein a relative humidity of about 5% is to be
established by e.g. flushing with dried air or nitrogen. The above
described method for measurement of the equilibrium relative
humidity of the pharmaceutical compositions of the invention is
herein also called ERH method.
Storage Conditions
[0053] The pharmaceutical composition of the present invention
comprising the crystalline form of Saxagliptin hydrochloride
designated as form I-S, IV-S or form HT-IV-S is preferably stored
in a relatively dry environment, and preferably it is to be assured
that the storage environment remains relatively dry during the
lifetime of the pharmaceutical composition.
[0054] In one preferred embodiment the compounds and compositions
especially form I-S and HT-IV-S according to the present invention
are stored in a container capable to keep the equilibrium relative
humidity of the composition at below 50%, preferably at from 10% to
45%, more preferably at from 15% to 40%, for at least 180 days,
more preferably for at least two years. This can be achieved, for
example, by use of a tightly sealed container, or by equipping the
container with a means to keep the composition relatively dry.
[0055] In another preferred embodiment, the invention therefore
also relates to a container comprising a pharmaceutical composition
of the invention comprising the crystalline form of Saxagliptin
hydrochloride designated as form IV-S, which container is capable
to keep the equilibrium relative humidity of the composition at
below 40%, preferably at from 10% to 40%, more preferably at from
15% to 40%, for at least 180 days, more preferably for at least two
years. This can be achieved, for example, by use of a tightly
sealed container, or by equipping the container with a means to
keep the composition relatively dry.
[0056] Such a drying means may be, for example, desiccant bags,
e.g. as commercially available under the trade name MINIPAX and
containing 2 g of molecular sieve 4 Angstrom; or desiccant
canisters, e.g. as available under the trade name SORBIT and
containing 1 g Silicagel; desiccant capsules, e.g. as available
under the trade name DRICAP, and containing 0.9 g Silicagel, or
desiccant stoppers containing 2 g Silicagel.
Storage Container
[0057] The products or intermediate products obtained in the
various steps of herein described processes are preferably stored
at an environmental relative humidity of below 50%, preferably
below 40%. Said products may thus be stored in aluminium barrels or
drums, in so-called Nirosta.RTM. drums, such as commercially
available as Muller.RTM. drums. Said drums may be made gas-tight,
e.g. air-tight by applying a sealing means, such as sealing rings
to the lid thereof. Said products may also be stored in containers
made of aluminium or Nirosta.RTM.-material as mentioned above
whereof the closures or lids are provided with a sealing means,
such as a sealing ring.
[0058] The pharmaceutical compositions of the invention comprising
the crystalline form of Saxagliptin hydrochloride especially
designated as form I-S or form HT-IV-S are preferably packaged or
filled into containers as herein described at an environmental
relative humidity of below 50%, preferably at from 10% to 45%.
Subsequently, said containers are tightly closed as herein
described. Preferably, said containers are used for stable storage
of the pharmaceutical compositions of the invention, for example at
room temperature, such as at a temperature of about 20.degree. C.
to 30.degree. C., e.g. at about 25.degree. C., for a prolonged
period, e.g. for at least 6 months, preferably at least about 24
months, e.g. for up to at least 24 months, e.g. for up to at least
about 30 months, such as for up to about 60 months.
[0059] The pharmaceutical compositions of the invention comprising
the crystalline form of Saxagliptin hydrochloride designated as
form IV-S are preferably packaged or filled into containers as
herein described at an environmental relative humidity of below
40%, preferably at from 10% to 40%. Subsequently, said containers
are tightly closed as herein described. Preferably, said containers
are used for stable storage of the pharmaceutical compositions of
the invention, for example at room temperature, such as at a
temperature of about 20.degree. C. to 30.degree. C., e.g. at about
25.degree. C., for a prolonged period, e.g. for at least 6 months,
preferably at least about 24 months, e.g. for up to at least 24
months, e.g. for up to at least about 30 months, such as for up to
about 60 months.
[0060] A preferred container is a bottle, e.g. a glass or plastic
bottle, e.g. a polyethylene bottles, such as known as securitainer,
having e.g. a screw closure, or is a blister, e.g. an aluminium
blister or strip, e.g. a blister consisting of 2 aluminum foils or
strips, or a blister comprising an Aclar.RTM. foil and an aluminum
cover foil, or may be any other suitable container. More preferably
said container is a gas-tight container, such as an air-tight
container.
[0061] Preferred containers are glass or plastic bottles sealed
with an aluminum membrane, alu-alu-blisters or strips, or blisters
comprising an Aclar.RTM. foil and an aluminum cover foil. The
container according to the invention is obtained by filling the
pharmaceutical compositions of the invention into said container
under the conditions as herein described.
[0062] Preferably, the container in combination with the drying
means is capable of maintaining the equilibrium relative humidity
of the pharmaceutical composition of the invention comprising the
crystalline form of Saxagliptin hydrochloride designated as form
I-S or form HT-IV-S therein at below 50%, preferably at from 10% to
45%, for at least 6 months, preferably for at least two years. In a
preferred embodiment the container further encloses a gaseous
atmosphere with a relative humidity of below 50%, preferably of
from 10% to 45%. Equipping the container with a dry gaseous
atmosphere, for example dry air or dry nitrogen gas, can be
performed as known in the art. With regard to form IV-S the
container in combination with the drying means is capable of
maintaining the equilibrium relative humidity of the pharmaceutical
composition at below 40%, preferably at from 10% to 40%, for at
least 6 months, preferably for at least two years. In a preferred
embodiment the container further encloses a gaseous atmosphere with
a relative humidity of below 40%, preferably of from 10% to
40%.
[0063] Preferred combinations of container and drying means are
aluminum-foil-sealed polyethylene-bottles (PE-bottles) containing
desiccant capsules and/or canisters or glass bottles with desiccant
stoppers.
Preparation of Compositions
[0064] Special care as to the relative environmental humidity and
as to the equilibrium relative humidity of the composition has to
be taken during the production of pharmaceutical compositions of
the invention comprising form I-S, IV-S or form HT-IV-S. Therefore,
the present invention also relates to a process for preparing a
pharmaceutical composition of the invention comprising the
crystalline form of Saxagliptin hydrochloride designated as form
I-S, IV-S or form HT-IV-S comprising the steps of [0065] a) mixing
the crystalline form of Saxagliptin hydrochloride designated as
form I-S or form HT-IV-S with one or more pharmaceutically
acceptable excipients at a relative humidity of below 50%,
preferably at from 10% to 45% and as regards form IV-S at a
relative humidity of below 40%, preferably at from 10 to 40%;
[0066] b) optionally granulating the mixture obtained in step a) at
a relative humidity of below 50%, preferably at from 10% to 45% as
regards form I-S and HT-IV-S and at a relative humidity of below
50%, preferably at from 10% to 40% as regards form IV-S; and [0067]
c) further processing the mixture obtained in step a) or the
granulate obtained in step b) at a relative humidity of below 50%,
preferably at from 10% to 45% as regards form I-S and HT-IV-S and
at a relative humidity of below 40%, preferably at from 10% to 40%
as regards form IV-S, to obtain a pharmaceutical composition of the
invention comprising the crystalline form of Saxagliptin
hydrochloride designated as form I-S or as form HT-IV-S or as form
IV-S. It is preferred that the obtained pharmaceutical composition
of the invention exhibits an equilibrium relative humidity of below
50%, preferably of from 10% to 45%, more preferably of from 15% to
30% or of from 20% to 45% as regards form I-S and HT-IV-S and an
equilibrium relative humidity of below 40%, preferably of from 10
to 40%, more preferably of from 15 to 30% as regards form IV-S.
[0068] The mixture obtained from step a) or the granulate obtained
from step b) as described above is preferably processed into an
oral dosage form, like a capsule or a tablet, or granules for oral
suspension, or a powder for oral suspension.
[0069] In a preferred embodiment, the obtained pharmaceutical
composition comprising the crystalline form of Saxagliptin
hydrochloride designated as form I-S or form HT-IV-S having an
equilibrium relative humidity of below about 50%, preferably of
from 10% to 45%, is filled into a container capable of maintaining
the equilibrium relative humidity of the pharmaceutical composition
at below 50%, preferably at from 10% to 45%, for at least 6 months,
for examples the containers mentioned above, which may optionally
further comprise a drying means sufficient to maintain the
equilibrium relative humidity of the pharmaceutical composition at
below 50%, preferably at from 10% to 45%.
[0070] The proper storage conditions for the pharmaceutical
compositions of the invention comprising the crystalline form of
Saxagliptin hydrochloride designated as form I-S or form HT-IV-S
are important for maintaining the compositions in the desired form.
Thus, preferably a container is used capable of maintaining a
gaseous atmosphere at a relative humidity of below 50%, preferably
at from 10% to 45%, for at least 6 months for storage of a
pharmaceutical composition of the invention. Preferably, a gaseous
atmosphere having a relative humidity of below 50%, preferably at
from 10% to 45%, is used to stabilize the crystalline form of
Saxagliptin hydrochloride designated as form I-S or form HT-IV-S
and a relative humidity of below 40%, preferably at from 10% to 40%
as regards form IV-S.
[0071] After the pharmaceutical compositions of the invention have
been filled into the herein mentioned containers, said containers
are preferably tightly closed, e.g. tightly or hermetically sealed,
e.g. in a way to prevent any gaseous atmosphere from diffusing
through the walls and/or closure of said containers. Methods of
tightly sealing and/or closing said containers are known, such as
sealing of glass or plastic bottles by applying an aluminium
membrane to the bottle opening of said bottle by induction sealing
and by applying a closure, e.g. a screw closure, or such as sealing
of alu-alu blisters or strips, of blisters comprising an Aclar.RTM.
foil and an aluminium cover foil by heat sealing according, e.g.
analogously to known methods.
[0072] The temperature applied during the herein described
processes is preferably room temperature, e.g. is a temperature of
about 20.degree. C. to about 30.degree. C., such as about
25.degree. C.
BRIEF DESCRIPTION OF THE DRAWINGS
[0073] FIG. 1: PXRD pattern of Saxagliptin Hydrochloride form
I-S
[0074] FIG. 2: FTIR spectrum of Saxagliptin Hydrochloride form
I-S
[0075] FIG. 3: DSC of Saxagliptin Hydrochloride form I-S
[0076] FIG. 4: PXRD pattern of Saxagliptin Hydrochloride form
HT-S
[0077] FIG. 5: FTIR spectrum of Saxagliptin Hydrochloride form
HT-S
[0078] FIG. 6: DSC of Saxagliptin Hydrochloride form HT-S
[0079] FIG. 7: PXRD pattern of Saxagliptin Hydrochloride form
HT-IV-S
[0080] FIG. 8: FTIR spectrum of Saxagliptin Hydrochloride form
HT-IV-S
[0081] FIG. 9: DSC of Saxagliptin Hydrochloride form HT-IV-S
[0082] FIG. 10: PXRD pattern of Saxagliptin Hydrochloride form
IV-S
[0083] FIG. 11: TGA of Saxagliptin Hydrochloride form IV-S
EXAMPLES
[0084] X-ray powder diffraction patterns (XRPD) were obtained with
a PANalytical X'Pert PRO diffractometer equipped with a theta/theta
coupled goniometer in transmission geometry, Cu-K.alpha..sub.1,2
radiation (wavelength 0.15419 nm) with a focusing mirror and a
solid state PIXcel detector. The patterns were recorded at a tube
voltage of 40 kV, tube current of 40 mA, applying a stepsize of
0.006.degree. 2.theta. with 80 s per step in the angular range of
2.degree. to 40.degree. 2.theta. at ambient conditions. A typical
precision of the 2-theta values is in the range of about
.+-.0.2.degree. 2-theta. Thus a diffraction peak that appears at
5.0.degree. 2-theta can appear between 4.8 and 5.2.degree. 2-theta
on most X-ray diffractometers under standard conditions.
[0085] Infrared spectra (IR) were collected on a MKII Golden
Gate.TM. Single Reflection Diamond ATR (attenuated total
reflection) cell with a Bruker Tensor 27 FTIR spectrometer with 4
cm.sup.-1 resolution. To collect a spectrum a spatula tip of a
sample was applied to the surface of the diamond in powder form.
Then the sample was pressed onto the diamond with a sapphire anvil
and the spectrum was recorded. A spectrum of the clean diamond was
used as background spectrum. A typical precision of the wavenumber
values is in the range of about .+-.2 cm.sup.-1. Thus, an infrared
peak that appears at 1716 cm.sup.-1 can appear between 1714 and
1718 cm.sup.-1 on most infrared spectrometers under standard
conditions.
[0086] Differential scanning calorimetry (DSC) was performed with a
DSC 7 (Perkin-Elmer, Norwalk, Conn., USA) using the Pyris software.
A sample of about 4 mg was weighed into a 25 .mu.l Al-pan. Dry
nitrogen was used as the purge gas (purge: 20 ml min.sup.-1). When
used herein, the term "T.sub.onset" determined by Differential
Scanning calorimetry means the temperature corresponding to the
intersection of the pretransition baseline with the extrapolated
leading edge of the transition.
[0087] Thermogravimetric analysis was performed with the
thermogravimetric system TGA-7 using the Pyris Software for Windows
NT (Perkin-Elmer, Norwalk, Conn., USA), 50 .mu.l platinum pans,
nitrogen purge gas (sample purge: 20 ml min.sup.-1, balance purge:
40 ml min.sup.-1).
[0088] The moisture sorption isotherm was recorded with a SPS-11
moisture sorption analyzer (MD Mess-technik, Ulm, D). The
measurement cycle was started at 0% relative humidity (RH),
increased in 10% steps up to 90% RH and in a 5% step up to 95% RH.
The equilibrium condition for each step was set to a constant mass
.+-.0.003% over 49 min. The temperature was 25.+-.0.1.degree.
C.
[0089] HPLC assay was performed by applying the following
conditions:
Column: YMC-Ultra HT Pro C 18 3.0.times.50.0 mm, 2 .mu.m
[0090] Eluent: A 10 mM Sulfamic acid Eluent: B 250 ml 10 mM SAS+750
ml acetonitril Flow rate: 0.64 ml/min
Temperature: 15.degree. C.
Detection: UV at 210 nm
Gradient:
TABLE-US-00001 [0091] t [min] 0 10 12 12.1 15 % B 0 70 70 0 0
Stop time: 15 min Sample concentration: about 0.5 mg/ml
Solvent: Eluent A
Injection Vol: 5 .mu.l
Example 1
Preparation of Anhydrous Form I-S of Saxagliptin
Monohydrochloride
[0092] 4.58 g Saxagliptin free base hemihydrate were dissolved in
230 ml acetone. To this solution 2.2 ml Trimethylchlorosilane were
added under stirring. After one hour the mixture containing a
gelatinous precipitate was evaporated. To the solid residue 80 ml
ethanol was added and the slurry was stirred in an open flask for
about one hour. The product was filtered off, washed with
tert.-Butyl methyl ether and then dried in a vacuum oven to give
1.65 g Saxagliptin Monohydrochloride Dihydrate. Polymorphism of
Saxagliptin Monohydrochloride Dihydrate was determined by X-ray
diffraction, FT-IR and DSC.
[0093] The mother liquor was put into a refrigerator at -5.degree.
C. for 48 hours. Surprisingly, additional crystals had formed from
the mother liquor. The so obtained crystalline precipitate was
filtered off, washed with tert.-Butyl methyl ether and then dried
in a vacuum oven. The crystals were analyzed and found to be 1.22 g
Saxagliptin Monohydrochloride. The obtained product from the mother
liquor was found to be a new anhydrous polymorphic form of
Saxagliptin Monohydrochloride, denominated as form I-S.
purity by HPLC: 99.7 area % (max individual impurity 0.09%, total
impurities 0.33%)
[0094] The powder X-ray diffraction pattern of Saxagliptin
Monohydrochloride form I-S is shown in FIG. 1. Characteristic XRPD
angles, d-spacings and relative intensities are shown in Table
1.
TABLE-US-00002 TABLE 1 Angles 2-theta, d-values and relative
intensities of form I-S Angle d value rel. Int. [2-Theta .degree.]
[Angstrom] [%] 6.72 13.145 100 10.30 8.591 4 11.68 7.577 3 13.52
6.548 12 14.63 6.054 46 15.15 5.846 36 16.60 5.340 32 17.91 4.952
53 18.80 4.721 7 19.19 4.624 7 20.33 4.368 4 21.46 4.141 4 22.17
4.010 5 24.50 3.634 17 27.01 3.301 6 28.16 3.169 12 29.78 3.001 9
30.59 2.922 9 31.33 2.855 9 31.87 2.808 3 34.27 2.616 4 36.25 2.478
5
[0095] Crystalline form I-S of Saxagliptin Monohydrochloride
obtained above has an attenuated total reflectance IR spectrum with
absorption bands at 2907, 2853, 1637, 1589, 1462, 1391, 1318, 1045,
1014 and 775 cm.sup.-1 (.+-.2 cm.sup.-1; FIG. 2)
[0096] The obtained crystalline form I-S was subjected to
differential thermal analysis. As can be seen in FIG. 3 (lower
curve), crystalline form I-S shows no significant dehydration
endotherm but only a peak at 241.degree. C. (T.sub.onset
230.degree. C.; heating rate 10.degree. C./minute, pinholed
capsule).
Ionic chlorine was determined as 10.7% (theory 10.08%)
[0097] The water content of the obtained crystalline form I-S was
determined as 1.2% w/w using a Karl Fischer apparatus. At about 50%
relative humidity at 25.degree. C. form 1 S of Saxagliptin
Hydrochloride shows a water content of about 1.5%. This water is
lost completely when lowering the relative humidity at 25.degree.
C. to about 0.5%. The process is reversible when exposing
Saxagliptin hydrochloride to a humidity of about 50%.
[0098] Form I-S is stable below 50% relative humidity. Above about
50% relative humidity Form I-S transforms to the known Dihydrate
H2-1. This transformation is not reversible.
Example 2
Preparation of Anhydrous Form I-S of Saxagliptin Monohydrochloride
from Ethanol by Seeding
[0099] 2.31 g Saxagliptin Monohydrochloride was suspended in 62 ml
ethanol and the resultant mixture was heated at reflux. The hot
solution was filtered, then seeded with the product of example 1.
The mixture was cooled to 25.degree. C. and then put into a
refrigerator over night. The white solid was collected by
filtration and dried in a vacuum oven to give 0.78 g of Saxagliptin
Monohydrochloride form I-S.
Example 3
Preparation of Form HT-S of Saxagliptin Monohydrochloride
[0100] 10 mg Saxagliptin Monohydrochloride Dihydrate was heated up
to 180.degree. C. with 10.degree. K/min under Nitrogen. Form HT-S
was obtained.
[0101] The powder X-ray diffraction pattern of Saxagliptin
Monohydrochloride form HT-S is shown in FIG. 4. Characteristic XRPD
angles, d-spacings and relative intensities are shown in Table
2.
TABLE-US-00003 TABLE 2 Angles 2-theta, d-values and relative
intensities of form HT-S Angle d value rel. Int. [2-Theta .degree.]
[Angstrom] [%] 6.62 13.357 100 7.63 11.591 3 10.11 8.749 7 11.48
7.707 7 12.08 7.326 3 13.27 6.673 14 15.28 5.799 40 16.69 5.313 18
17.60 5.039 35 19.15 4.635 8 19.97 4.446 14 21.32 4.168 9 24.11
3.691 9
[0102] Crystalline form HT-S of Saxagliptin Monohydrochloride
obtained above has an attenuated total reflectance IR spectrum with
absorption bands at 2906, 2854, 1649, 1574, 1513, 1459, 1338, 1124,
1032 and 851 cm.sup.-1 (.+-.2 cm.sup.-1; FIG. 5)
[0103] The obtained crystalline form HT-S was subjected to
differential thermal analysis. As can be seen in FIG. 3 (lower
curve), crystalline form HT-S shows no significant dehydration
endotherm but only a peak at 230.degree. C. (heating rate
10.degree. C./minute, pinholed capsule).
[0104] The obtained crystalline form HT-S showed a water loss of
not more than 0.5% w/w based on thermogravimetric analysis (FIG. 6,
upper line).
Example 4
Preparation of Form HT-IV-S
Step 1, Preparation of Form IV-S
[0105] 105 mg of Saxagliptin Monohydrochloride dihydrate form H2-1
were dissolved in 11 ml of n butanole. The solution obtained was
filtered and the solvent was removed by vacuo at approximately 20
mbar using a rotavap. To the residue 4 ml of tert. amylalkohol were
added and a suspension was obtained. The suspension was stirred for
3 days and the crystals were than isolated by suction and kept in a
dessicator at about 30% relative humidity overnight.
Yield: 97 mg Saxagliptin Hydrochloride form IV-S
Step 2, Preparation of Form HT-IV-S
[0106] The crystalline product Saxagliptin Hydrochloride IV-S was
dried in a vacuum oven at 50.degree. C. for approximately 10 hours
at a vacuum of about 40.degree. C. followed by drying at about
80.degree. C. for 5 hours to yield crystalline form HT-IV S
Water (KF): 0.7%
[0107] A sample was stored at 45-49% relative humidity for 12
hours.
Water (KF): 1.2%
[0108] No change in the crystal form was observed (FTIR).
[0109] The powder X-ray diffraction pattern of Saxagliptin
Monohydrochloride form HT-IV S is shown in FIG. 7. Characteristic
XRPD angles, d-spacings and relative intensities are shown in Table
3.
TABLE-US-00004 TABLE 3 angles 2-theta, d-values and relative
intensities of form HT-IV-S Angle d value rel. Int. [2-Theta
.degree.] [Angstrom] [%] 2.56 34.561 100 4.46 19.832 69 5.14 17.191
6 6.82 12.965 74 7.73 11.433 7 8.94 9.889 6 13.69 6.47 15 13.93
6.357 6 14.64 6.05 70 15.1 5.866 23 15.77 5.618 20 15.97 5.551 35
16.6 5.342 6 17.19 5.158 23 18.14 4.89 54 18.88 4.7 17 20.27 4.381
9 26.99 3.304 6 27.67 3.223 5 28.11 3.175 7 28.47 3.135 7 29.53
3.026 13 31.92 2.804 7
[0110] Crystalline form HT-IV-S of Saxagliptin hydrochloride
obtained above has an attenuated total reflectance IR spectrum with
absorption bands at wavenumbers of 3495, 2921, 1637, 1616, 1464,
1242, 1103, 1013, 940 and 774 (.+-.2 cm.sup.-1; FIG. 8).
[0111] The obtained crystalline form HT-IV-S was subjected to
differential thermal analysis. As can be seen in FIG. 9,
crystalline form HT-IV-s shows no significant dehydration endotherm
but only a peak at 240.degree. C. (T.sub.onset 232.degree. C.
(heating rate 10.degree. C./minuter, pinholed capsule).
Example 5
Preparation of Form IV-S of Saxagliptin Monohydrochloride
[0112] 105 mg of Saxagliptin Monohydrochloride dihydrate form H2-1
were dissolved in 11 ml of n butanole. The solution obtained was
filtered and the solvent was removed by vacuo at approximately 20
mbar using a rotavap. To the residue 4 ml of tert. amylalkohol were
added and a suspension was obtained. The suspension was stirred for
3 days and the crystals were than isolated by suction and kept in a
dessicator at about 30% relative humidity overnight.
Yield: 97 mg
[0113] The powder X-ray diffraction pattern of Saxagliptin
Monohydrochloride form IV-S is shown in FIG. 10. Characteristic
XRPD angles, d-spacings and relative intensities are shown in Table
4.
TABLE-US-00005 TABLE 4 Angles 2-theta, d-values and relative
intensities of form IV-S Angle d value rel. Int. [2-Theta .degree.]
[Angstrom] [%] 2.35 37.566 14 4.08 21.652 100 4.72 18.738 15 6.25
14.143 29 13.91 6.368 6 14.51 6.104 23 14.89 5.948 5 15.64 5.667 39
16.69 5.312 22 18.55 4.784 29 19.37 4.582 10 19.8 4.484 6
[0114] The obtained crystalline form IV-S was subjected to
thermogravimetric analysis. As can be seen in FIG. 11 crystalline
form IV-S shows a mass loss of about 12.8% starting up to
100.degree. C. This mass loss corresponds to 2.86 mol of water.
[0115] Moisture sorption analysis shows a water content of 13.1% at
40% relative humidity at 25.degree. C. corresponding to 2.94 mol of
water. Moisture sorption analysis shows a water content of 12.8%
corresponding to 2.86% relative humidity at 0% relative humidity.
The process is reversible.
[0116] At above 40% relative humidity form IV-S irreversible
transforms to known form Dihydrate H2-1.
* * * * *