U.S. patent application number 11/730639 was filed with the patent office on 2007-08-23 for novel forms of pravastatin sodium.
This patent application is currently assigned to TEVA Gyogyszergyar Zartkoruen Mukodo Reszvenytarsasag. Invention is credited to Judith Aronhime, Edit Nagyne Arvai, Vilmos Keri, Csaba Szabo.
Application Number | 20070197633 11/730639 |
Document ID | / |
Family ID | 26866349 |
Filed Date | 2007-08-23 |
United States Patent
Application |
20070197633 |
Kind Code |
A1 |
Keri; Vilmos ; et
al. |
August 23, 2007 |
Novel forms of pravastatin sodium
Abstract
New polymorphic forms of pravastatin sodium are provided. Each
of the new forms is selectively obtained by crystallization from
different solvent systems, each solvent system having a protic
component, and by controlling the rate of crystallization through
temperature. The new polymorphic forms are suitable for use as
active substances of pharmaceutical dosage forms for reduction of
serum cholesterol levels in the bloodstream.
Inventors: |
Keri; Vilmos; (Debrecen,
HU) ; Szabo; Csaba; (Debrecen, HU) ; Arvai;
Edit Nagyne; (Debrecen, HU) ; Aronhime; Judith;
(Rechovot, IL) |
Correspondence
Address: |
KENYON & KENYON LLP
ONE BROADWAY
NEW YORK
NY
10004
US
|
Assignee: |
TEVA Gyogyszergyar Zartkoruen
Mukodo Reszvenytarsasag
Debrecen
HU
|
Family ID: |
26866349 |
Appl. No.: |
11/730639 |
Filed: |
April 3, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11200794 |
Aug 9, 2005 |
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11730639 |
Apr 3, 2007 |
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09736796 |
Dec 14, 2000 |
7001919 |
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11200794 |
Aug 9, 2005 |
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60170685 |
Dec 14, 1999 |
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60190649 |
Mar 20, 2000 |
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Current U.S.
Class: |
514/449 |
Current CPC
Class: |
A61K 31/335 20130101;
A61P 3/06 20180101; C07C 67/52 20130101; C07C 2602/28 20170501;
C07C 69/33 20130101; C07C 67/52 20130101; C07C 69/33 20130101; A61P
9/10 20180101 |
Class at
Publication: |
514/449 |
International
Class: |
A61K 31/335 20060101
A61K031/335 |
Claims
1-203. (canceled)
204. A pharmaceutical composition comprising a crystalline
pravastatin sodium or hydrate thereof comprising an X-ray powder
diffraction pattern comprising characteristic peaks at 4.8, 7.6,
8.6, 10.0, 11.8, 12.4, 13.0, 15.5, 16.0, 17.4, 17.9, 18.4, 19.7,
21.0, 21.8 and 22.8.+-.0.2 degrees measured at reflection angle
2.theta. and a pharmaceutically acceptable carrier, wherein the
pharmaceutical composition has a coating.
205. A pharmaceutical composition of claim 204, wherein the coating
comprises at least one material selected from the group consisting
of phthalic acid cellulose acetate, hydroxypropylmethyl cellulose
phthalate, polyvinyl alcohol phthalate,
carboxymethylethyl-cellulose, a copolymer of styrene and maleic
acid, a copolymer of methacrylic acid, methyl methacrylate and
mixtures thereof.
206. A pharmaceutical composition of claim 204, wherein the coating
is an enteric coating.
207. A pharmaceutical composition of claim 204, wherein the
pharmaceutical composition is selected from a dosage form selected
from the group consisting of granules, aggregates, a tablet, a
capsule, powder, and combinations thereof.
208. A pharmaceutical composition of claim 207, wherein the
pharmaceutical composition is an oral dosage form and contains from
about 10 mg to about 40 mg of pravastatin sodium.
Description
RELATED APPLICATION
[0001] This application claims the benefit under 35 U.S.C.
.sctn.119(e) of U.S. Provisional Patent Application No. 60/170,685,
filed Dec. 14, 1999 and U.S. Provisional Patent Application No.
60/190,649, filed Mar. 20, 2000.
FIELD OF THE INVENTION
[0002] The present invention relates to statins, and more
particularly to novel polymorphic forms of pravastatin sodium.
BACKGROUND OF THE INVENTION
[0003] Pravastatin is a member of the class of pharmaceutical
compounds called statins. Statins currently are the most effective
treatment for lowering serum cholesterol levels in patients with
atherosclerosis and hypercholesteremia. Pravastatin is the common
medicinal name of the chemical compound
[1S-[1.alpha.(.beta.*,.delta.*)2.alpha.,6.alpha.,8.beta.(R*),8a.alpha.]]--
1,2,6,7,8,8a-hexahydro-.beta.,.delta.,6-trihydroxy-2-methyl-8-(2-methyl-1--
oxobutoxy)-1-naphthalene-heptanoic acid. (CAS Registry No.
81093-37-0) The molecular structure of pravastatin is represented
by Formula (I). "Pravastatin sodium" is defined as the monosodium
salt of pravastatin, whether hydrated or anhydrous, solvated or
unsolvated. ##STR1##
[0004] According to U.S. Pat. No. 4,346,227, incorporated herein by
reference, pravastatin is reported as having been first isolated as
a metabolite of compactin by M. Tanaka et al. during a study of
compactin metabolism. The '227 patent discloses the isolation of
pravastatin in its lactone form, as the methyl ester of the free
carboxylic acid and as the monosodium salt of the free carboxylic
acid ("pravastatin sodium"). Pravastatin sodium was analyzed by
nuclear magnetic resonance spectroscopy, infrared ("IR")
spectroscopy, ultraviolet spectroscopy and thin layer
chromatography. Pravastatin sodium was analyzed in solid form by IR
spectroscopy using the conventional technique of co-mixing with
potassium bromide ("KBr") and then compressing to form a KBr window
or pellet. The IR spectrum of the pravastatin sodium obtained by
absorption bands at 3400, 2900, 1725, 1580 cm.sup.-1. All other
spectral measurements are repeated on pravastatin sodium in
solution.
[0005] The present invention relates to new crystal forms of
pravastatin sodium and compositions containing them. Polymorphism
is the property of some molecules and molecular complexes to assume
more than one crystalline form in the solid state. A single
molecule may give rise to a variety of crystal forms (also called
"polymorphs") having distinct physical properties. The existence of
more than one crystal form can be determined in a laboratory by
comparison of the angles at which X-ray radiation reflected from
the forms undergoes constructive interference and by comparing the
absorptions of incident infrared radiation at different
wavelengths. The former technique is known as X-ray diffraction
spectroscopy and the angles at which constructive interference
occurs are known as reflections.
[0006] The differences in the physical properties of polymorphs
result from the orientation and intermolecular interactions of
adjacent molecules (complexes) in the bulk solid. Accordingly,
polymorphs are distinct solids sharing the same molecular formula
yet having distinct advantageous and/or disadvantageous physical
properties compared to other forms in the polymorph family.
[0007] One of the most important physical properties of a
polymorphic pharmaceutical compound is the solubility of each of
its forms in aqueous solution, particularly the solubility in
gastric juices of a patient. Other important properties relate to
the ease of processing the form into pharmaceutical dosages, such
as the tendency of a powdered or granulated form to flow and the
surface properties that determine whether crystals of the form will
adhere to each other when compacted into a tablet.
SUMMARY OF THE INVENTION
[0008] The present invention is directed to new polymorphic forms
of pravastatin sodium. These forms are designated Form A, Form B,
Form C, Form D, Form E, Form F, Form G, Form H, Form H1, Form I,
Form J, Form K and Form L. The invention is also directed to
methods of making each of the pravastatin sodium polymorphs.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 is a characteristic powder X-ray diffraction pattern
of pravastatin sodium Form A.
[0010] FIG. 2 is a characteristic infrared absorption spectrum of
pravastatin sodium Form A.
[0011] FIG. 3 is a characteristic powder X-ray diffraction pattern
of pravastatin sodium Form B.
[0012] FIG. 4 is a characteristic infrared absorption spectrum of
pravastatin sodium Form B.
[0013] FIG. 5 is a characteristic powder X-ray diffraction pattern
of pravastatin sodium Form C.
[0014] FIG. 6 is a characteristic infrared absorption spectrum of
pravastatin sodium Form C.
[0015] FIG. 7 is a characteristic powder X-ray diffraction pattern
of pravastatin sodium Form D.
[0016] FIG. 8 is a characteristic infrared absorption spectrum of
pravastatin sodium Form D.
[0017] FIG. 9 is a characteristic powder X-ray diffraction pattern
of pravastatin sodium Form E.
[0018] FIG. 10 is a characteristic infrared absorption spectrum of
pravastatin sodium Form E.
[0019] FIG. 11 is a characteristic powder X-ray diffraction pattern
of pravastatin sodium Form F.
[0020] FIG. 12 is a characteristic infrared absorption spectrum of
pravastatin sodium Form F.
[0021] FIG. 13 is a characteristic powder X-ray diffraction pattern
of pravastatin sodium Form G.
[0022] FIG. 14 is a characteristic powder X-ray diffraction pattern
of pravastatin sodium Form H.
[0023] FIG. 15 is a characteristic powder X-ray diffraction pattern
of pravastatin sodium Form H1.
[0024] FIG. 16 is a characteristic powder X-ray diffraction pattern
of pravastatin sodium Form I.
[0025] FIG. 17 is a characteristic powder X-ray diffraction pattern
of pravastatin sodium Form J.
[0026] FIG. 18 is a characteristic powder X-ray diffraction pattern
of pravastatin sodium Form K.
[0027] FIG. 19 is a characteristic powder X-ray diffraction pattern
of pravastatin sodium Form L.
DETAILED DESCRIPTION OF THE INVENTION
[0028] We have discovered new polymorphic forms of pravastatin
sodium that can be distinguished from the known amorphous
pravastatin sodium and from each other by their powder X-ray
reflections and their infrared absorption spectra.
[0029] All powder X-ray diffraction patterns were obtained by
methods known in the art using a Philips X-ray powder
diffractometer, with goniometer model 1050/70, at scanning speed of
2.degree. min..sup.-1. Copper radiation of .pi.=1.5418 .ANG. was
used.
[0030] The infrared spectrum was obtained in a Nujol mull using a
Perkin Elmer Paragon 1000 FT-IR spectrometer at 4 cm.sup.-1
resolution with 16 scans. The characteristic infrared absorption
bands of the novel forms of pravastatin sodium will not necessarily
be observed in the IR spectrum of a sample that has been dissolved,
as for example in chloroform or carbon tetrachloride, for IR
analysis. That is: some IR bands may be characteristic of
pravastatin in the solid state; others are characteristic of
pravastatin sodium whether in the solid or solution phase.
[0031] Pravastatin crystal forms show DSC curves with multiple
endothermic and exothermic events due to water desorption and phase
transitions. The melting peak observed in all forms except form B
is in the range of about 174-176.degree. C. Form B has a melting
point at about 187.degree. C.
[0032] Pravastatin crystal forms exhibit hygroscopic behavior. The
water uptake at 80% relative humidity after 1 week was up to about
15%. After exposure at 100% relative humidity, all the forms of
pravastatin sodium transform to Form C with about 30% relative
humidity. It was also found that all the crystal forms, except Form
B, were transformed to Form D by heating at 120.degree. C. for 2
hours.
Characteristics of Pravastatin Sodium Polymorphs
[0033] Pravastatin sodium Form A is characterized by reflections in
the powder X-ray diffraction pattern at 3.9, 4.5, 6.2, 7.2, 8.6,
9.2, 10.0, 11.6, 12.0, 17.0 and 20.0.+-.0.2 degrees, detected at
reflection angle 2.theta.. The diffraction pattern is reproduced in
FIG. 1. Of these, the reflections at 3,9, 4.5, 6.2, and 7.2.+-.0.2
degrees are especially characteristic. Form A may also be
distinguished by its infrared absorption spectrum which is shown in
FIG. 2 obtained in a Nujol mull. Form A has characteristic;
absorption bands at 686, 826, 842, 864, 917, 939, 965, 1013, 1040,
1092, 1111, 1156, 1184, 1265, 1310, 1330, 1576 and 1726,.+-.2
cm.sup.-1.
[0034] Pravastatin sodium Form B is distinguished by reflections in
the powder X-ray diffraction pattern that are observed at 3.6, 6.1,
6.6, 9.0, 9.6, 10.1, 1.6.4, 16.8 and 18.6.+-.0.2 degrees detected
at the reflection angle 2.theta.. The diffraction pattern is
reproduced in FIG. 3. The reflections at 3.6, 6.1, 6.6, 9.0, 9.6,
10.1 and 18.6.+-.0.2 degrees are the most intense and in that sense
the most characteristic, the reflections at 3.6, 6.1 and 6.6.+-.0.2
degrees being the most intense of all. Form B may further be
distinguished by its IR spectrum, provided as FIG. 4, obtained from
a Nujol mull. Absorption bands are observed at 614, 692, 739, 824,
842, 854, 868, 901, 914, 936, 965, 1011, 1028, 1039, 1072, 1091,
1111, 1129, 1149, 1161, 1185, 1232, 1245, 1318, 1563, 1606, 1711
and 1730.+-.2 cm.sup.-1.
[0035] Pravastatin sodium Form C may be distinguished by
reflections in the powder X-ray diffraction pattern that are
observed at about 4.8, 7.6, 8.6, 10.0, 11.8, 12.4, 13.0, 15.5,
16.0, 17.4, 17.9, 18.4, 19.7, 21.0, 21.8 and 22.8.+-.0.2 degrees,
detected at reflection angle 2.theta.. The reflections observed at
4.8, 7.6, 8.7, 10.0, 13.0, 16.0, 17.4 and 19.7.+-.0.2 degrees are
characteristic and, of these, the reflections at 4.8, 10.0, 13.0,
16.0 and 17.4.+-.0.2 degrees are especially characteristic. The
diffraction pattern is reproduced in FIG. 5. Form C may further be
distinguished by its IR spectrum, provided as FIG. 6, obtained from
a Nujol mull. Absorption bands of pravastatin sodium Form C are
observed at 742, 829, 851, 870, 926, 940, 964, 1013, 1038, 1078,
1090, 1146, 1166, 1174, 1194, 1257, 1268, 1313, 1328, 1567 and
1728.+-.2 cm.sup.-1.
[0036] Pravastatin sodium Form D may be distinguished from the
other forms of crystalline and amorphous pravastatin sodium by
reflections in the powder X-ray diffraction pattern that are
observed at 3.6, 6.3, 9.8 and 17.1.+-.0.2 degrees, detected at
reflection angle 2.theta.. The diffraction pattern is reproduced in
FIG. 7. Form D may further be distinguished by its IR spectrum,
provided as FIG. 8, obtained from a KBr window using the same
equipment and methodology as was used to obtain the IR spectrum of
Form A. Characteristic absorption bands of pravastatin sodium Form
D are observed at 824, 843, 854, 914, 939, 965, 1013, 1041, 1079,
1091, 1157, 1186, 1266, 1566, 1606 and 1728.+-.2 cm.sup.-1.
[0037] Pravastatin sodium Form E exhibits reflections in the powder
X-ray diffraction pattern at about 4.6, 9.2, 10.3, 11.2, 12.1,
16.6, 18.3 and 20.6.+-.0.2 degrees, detected at a reflection angle
of 2.theta.. Form E is readily distinguished from the other forms
of crystalline and amorphous pravastatin sodium by the reflections
at 4.6, 9.2, 10.3, 12.1, 16.6, 18.3 and 20.6.+-.0.2 degrees, the
reflections at 10.3, 12.1 and 16.6 degrees being especially
characteristic of Form E. The diffraction pattern is reproduced in
FIG. 9. Form E may further be distinguished by its IR spectrum,
provided as FIG. 10, obtained from a Nujol mull. Characteristic
absorption bands of pravastatin sodium Form E are observed at 781,
829, 853, 939, 964, 1016, 1043, 1078, 1158, 1179, 1266, 1300, 1329,
1401, 1573 and 1727.+-.2 cm.sup.-1.
[0038] Pravastatin sodium Form F may be distinguished from the
other forms of pravastatin sodium by the reflection in the powder
X-ray diffraction pattern that occurs at about 4.6.+-.0.2 degrees,
detected at reflection angle 2.theta.. The absence of other
diffraction peaks points to the amorphous nature of this form. The
diffraction pattern is reproduced in FIG. 11. Form F may be
distinguished by its IR spectrum, provided as FIG. 12, obtained
from a KBr window. Absorption bands are observed at 781, 829, 853,
939, 964, 1016, 1043, 1079, 1157, 1181, 1265, 1300, 1330, 1400,
1576 and 1727.+-.2cm.sup.-1.
[0039] Pravastatin sodium Form G may be distinguished by
reflections in the powder X-ray diffraction pattern that are
observed at about 4.5, 9.2, 10.0, 12.2, 16.0, 16.5, 17.6, 18.6,
19.5, 20.5, and 22.8.+-.0.2 degrees, detected at reflection angle
2.theta.. The diffraction pattern is reproduced in FIG. 13.
Pravastatin sodium Form G has a DSC scan characterized by two
endotherms at about 165.degree. and 173.degree. C. followed by
decomposition.
[0040] Pravastatin sodium Form H may be distinguished by
reflections in the powder X-ray diffraction pattern that are
observed at about 3.5, 5.9, 9.0, 10.1, 11.7, 12.1, 14.7, 17.0 19.0,
19.9, 20.6, 21.8 and 22.9.+-.0.2 degrees, detected at reflection
angle 2.theta.. Of these, the peaks at 3.5, 5.9, 9.0, 10.1 and
17.0.+-.0.2 degrees are particularly diagnostic. The diffraction
pattern is reproduced in FIG. 14.
[0041] Pravastatin sodium Form H1 may be distinguished from the
other forms of crystalline and amorphous pravastatin sodium by
reflections in the powder X-ray diffraction pattern that are
observed at about 3.5, 5.9, 6.8, 8.9, 10.1, 11.7, 12.3, 13.3, 14.8,
17.6, 18.8, 20.0, 20.8, and 22.9.+-.0.2 degrees, detected at
reflection angle 2.theta.. Of these, the peaks at 3.5, 5.9, 8.9,
10.1, 17.6, 18.8 and 20.8.+-.0.2 degrees are particularly
diagnostic. The diffraction pattern is reproduced in FIG. 15.
[0042] Pravastatin sodium Form I may be distinguished from the
other forms of crystalline and amorphous pravastatin sodium by
reflections in the powder X-ray diffraction pattern that are
observed at about 4.4, 5.2, 5.8, 6.5, 7.5, 8.3, 9.0, 9.8, 10.2,
11.2, 13.2, 14.0, 16.5, 17.5, 18.3, 18.7, 19.5, 20.5, 21.5 and
23.0.+-.0.2 degrees, detected at reflection angle 20. Of these, the
peaks at 4.4, 5.2, 5.8, 6.5, 9.0, 13.2, and 14.0.+-.0.2 degrees are
particularly diagnostic. The diffraction pattern is reproduced in
FIG. 16.
[0043] Pravastatin sodium Form J may be distinguished from the
other forms of crystalline and amorphous pravastatin sodium by
reflections in the powder X-ray diffraction pattern that are
observed at about 3.3, 3.8, 6.0, 6.8, 7.5, 8.8, 9.3, 10.2, 11.2,
11.7, 13.5, 13.9, 14.5, 15.6, 16.3, 17.7, 18.1, 18.7, 19.5, 20.0,
20.4, 21.7, 22.3, 24.2, and 26.1.+-.0.2 degrees, detected at
reflection angle 2.theta.. Of these, the peaks at 3.8, 6.0, and
16.3.+-.0.2 degrees are particularly diagnostic. The diffraction
pattern is reproduced in FIG. 17.
[0044] Pravastatin sodium Form K may be distinguished by
reflections in the powder X-ray diffraction pattern that are
observed as a broad peak between 15 and 25 as well as peaks at 4.1,
6.8 and 10.2 degrees measured at reflection angle 2.theta.. The
diffraction pattern is reproduced in FIG. 18.
[0045] Pravastatin sodium Form L may be distinguished from the
other forms of crystalline and amorphous pravastatin sodium by
reflections in the powder X-ray diffraction pattern that are
observed at about 4.5, 5.0, 9.0, 10.1, 12.3, 13.4, 15.0, 16.6,
17.6, 18.5 19.5, 20.2, 21.2 and 22.7.+-.0.2 degrees, detected at
reflection angle 2.theta.. Of these, the peaks at 16.6, 17.6, and
18.5.+-.0.2 degrees are particularly diagnostic. The diffraction
pattern is reproduced in FIG. 19.
Procedures for Crystallizing Polymorphs of Pravastatin Sodium
[0046] It will be appreciated by those skilled in the art of
crystallization that attainment of a particular crystalline form of
a compound is highly dependent upon exacting control of conditions.
These conditions include, among other parameters, the composition
of the solvent system employed, the pH of the solvent system, the
temperature profile and the form of any crystals that are added to
induce crystallization from a supersaturated solution.
[0047] Pravastatin sodium Forms A though F may each be obtained by
recrystallization from two-component solvent systems having a
protic component and an aprotic component. The term "protic" refers
to the presence of a labile proton like a hydroxyl proton or
carboxylic acid proton. Water is a protic solvent. "Aprotic" means
the absence of labile protons. The term "solvents" is used
conventionally to mean chemical compounds into which a solute, such
as pravastatin sodium, is dissolved or dispersed.
[0048] The pravastatin sodium polymorphs A-F, obtained by
recrystallization, are highly dependent upon the solvent system
from which the form is crystallized. Pravastatin sodium tends to
crystallize as Forms A, B and E from solvent systems having a
protic component that is either ethanol or an ethanol:water
mixture. In contrast, pravastatin sodium tends to crystallize as
forms C, D and F from solvent systems that have a protic component
that is water alone. We have been able to obtain each of the
different forms described above by crystallizing pravastatin sodium
from a solvent mixture consisting of a protic solvent and an
aprotic solvent. The aprotic solvent is selected from ethyl
acetate, acetonitrile, acetone and acetonitrile:acetone
mixtures.
[0049] Temperature is another important parameter for, among other
reasons, its effect on the economics of producing a particular
form. It is highly desirable to be able to conduct a
crystallization of pravastatin sodium at temperatures of
-10.degree. C. or above. -10.degree. C. is approximately the lower
limit of temperatures that are obtainable by cooling with cold
brine. To obtain lower temperatures, a specialized cooling
apparatus, or equivalently, a cooled material like dry ice or
liquid nitrogen that has been made cold with a special cooling
apparatus must be used. Consequently, the attainment of lower
temperatures increases the cost of production. The increased cost
may, in fact, be enough to discourage the use of pharmaceuticals in
certain crystalline forms with an attendant sacrifice in solubility
properties and other desirable properties of the crystalline forms.
Accordingly, we have developed procedures for crystallizing
pravastatin sodium in each of the forms of the present invention
that may be conducted at a crystallization temperature of about
-10.degree. C. or above. The choice to use a lower temperature is
within the province of one skilled in the art informed by this
disclosure.
[0050] In order to obtain each of the pravastatin sodium Forms A
through F in high yield with only moderate cooling, solvent systems
that are moderately to highly concentrated (i.e. typically greater
than 0.05 M) in pravastatin sodium have been developed. According
to these preferred solvent systems, the pravastatin sodium is
preferably first dissolved in the protic component of the solvent
system. Then, the protic component is preferably diluted with the
aprotic component in order to decrease the solubility of the
pravastatin sodium. The concentration of the pravastatin sodium in
the protic component before dilution is not critical. However,
after dilution, the concentration of pravastatin sodium is
preferably in the range of 0.05 to 0.5 M. Dilution may be conducted
either before, during or after cooling the solution to the
crystallization temperature.
[0051] The aprotic solvent may be a nonpolar solvent, such as
hexane, petroleum ether, carbon tetrachloride and the like. The
aprotic solvent may also be a polar aprotic solvent. In particular,
acetonitrile, acetone, ethyl acetate and acetonitrile:acetone
mixtures comprise a spectrum of aprotic components from which each
of the novel pravastatin sodium forms may be obtained. Aprotic
solvents are preferably used from 4 to 20 fold excess on a
volume-to-volume basis over the protic component.
[0052] The use of ethanol alone as the protic component of the
solvent system favors the crystallization of pravastatin sodium
Form B, provided the solvent system has been adjusted to a pH of
about 8.2 to about 8.7, preferably about 8.5. Equal-volume mixtures
of ethanol and water, on the other hand, tend to favor
crystallization of Form A. Comparison of Examples 1 and 2 with
Example 3 demonstrates this solvent effect with specific
illustrative embodiments.
[0053] While, generally speaking, the form of pravastatin sodium
obtained by recrystallization is not especially sensitive to the
choice of aprotic solvent among these exemplary aprotic solvents,
it will be noted that the use of ethyl acetate in a 20:1 excess
over a 1:4 H.sub.2O:ethanol protic component promotes
crystallization of pravastatin sodium in Form E (See Example 8).
This result is to be compared to crystallization from ethanol and
ethanol:water mixtures in Forms A and B which is promoted by an
acetonitrile aprotic component (See Examples 1-3). In addition,
when the acetonitrile is used in an amount that is around the lower
range of the proportion of aprotic component in the solvent system,
i.e. about 4 to about 7 fold excess over the protic component,
pravastatin sodium Form B is favored. On the other hand, when
acetonitrile is used in an intermediate amount, i.e. about 13 to
about 17 fold excess, Form A is favored.
[0054] As noted above, a solvent system having a protic component
of water alone favors the section crystallization of pravastatin
sodium as Forms C, D or amorphous Form F. Formation of amorphous
Form F is promoted by adjustment of the pH of the solvent system
from about pH 8.7 to about pH 10.3, preferably about pH 9 to about
pH 10. The pH may be adjusted by contacting with a weak cationic
exchange resin such as Amberlite.RTM. IRC-50 (See Examples 9 and
10). If the pH is not adjusted, Form F typically is not obtained in
pure form. Forms C and D may be obtained from a solvent system
wherein water is the only protic component and wherein the pH of
the solution is not adjusted for the purpose of obtaining Form
F.
[0055] None of the aforementioned parameters operates
independently. So, in the examples concluding this description and
preceding the claims, which disclose the best mode for obtaining
each of the forms, it will be seen that variations in several
parameters at once combine to produce an optimal yield and purity
of the desired form. In particular, the choice of solvent system,
concentration and temperature profile are not independent. The use
of acetonitrile, acetone and acetonitrile:acetone mixtures as the
aprotic component, rather than ethyl acetate, allows for a greater
concentration of pravastatin sodium in solution at ambient
temperature without premature crystallization. Thus, without
heating of the solution of pravastatin sodium in the protic
component prior to dilution, the solution may be diluted with
acetone and/or acetonitrile to a range of 0.1 to 0.2 M without
premature crystallization (See, e.g. Examples 7, 9-11). When ethyl
acetate is used as the aprotic component, the solution of
pravastatin sodium in the protic component is preferably heated to
about 40.degree. C. or above, more preferably about 60.degree. C.
before addition of the ethyl acetate. Preferably, with heating,
ethyl acetate is added to dilute the solution to less than 0.1
M.
[0056] The rate of cooling from ambient or elevated temperature,
whichever the case may be, should not be excessively rapid in order
to realize maximum selectivity of the other conditions that have
been chosen in order to obtain the desired form. Rapid cooling,
typically, will tend to reduce selectivity and result in mixtures
of two or more forms rather than an individual pure form.
Accordingly, manipulation of the recrystallization parameters to
obtain mixtures of the novel forms of pravastatin having desirable
characteristics is considered to be within the scope of the
invention. Typically, in order to obtain any one of the forms in
high purity the rate of cooling may be about from 2.degree. C.
h.sup.-1 to 35.degree. C. h.sup.-1, but the rate of cooling is
preferably between about 2.degree. C. h.sup.-1 to 5.8.degree. C.
h.sup.-1.
[0057] Once crystallization is complete, the crystals are then
isolated by filtration, decantation of the solvent, removal of the
solvent or other such method, preferably filtration. The crystals
optionally may then be washed and dried according to methods known
to the art.
[0058] Pravastatin sodium Form G may be prepared by storing
pravastatin sodium Form F for 2 weeks at a relative humidity of
about 40 to about 80%.
[0059] Pravastatin sodium Forms A, H, H1, I, J, K may each be
obtained by conversion from Form D or F. The conversion process
consists of treating pravastatin sodium Form D or F with an
alcohol. In one embodiment the alcohol treatment consists of
exposing the first polymorph to the vapors of a solvent for a time
period. The period of time may be overnight or may last for three
weeks. In an alternative embodiment the solvent treatment comprises
suspended Form D or F in a solvent for a period of time.
[0060] The treatment is performed at room temperature. The
temperature may be between about 15.degree. C. and 35.degree. C.
Optimally, the temperature is about 25.degree. C.
[0061] The polymorphic form of pravastatin sodium obtained is
dependent on the treatment solvent. For example, treating Form D or
F with ethanol vapors produces Form A. Treating form D or F with
methanol vapors produces Form H. The relationship between the
treatment solvent and the polymorphic form of pravastatin sodium
produced is summarized in Table I, and illustrated in Example 15,
16, 17, 18, 19, and 20. TABLE-US-00001 TABLE I Starting Resulting
Incubation Polymorph Polymorph Solvent Time Exposure D or F A
Ethanol 3 weeks Vapors D or F H Methanol 3 weeks Vapors D or F H1
Methanol Overnight Suspension D or F I Isopropyl 3 weeks Vapors
Alcohol D or F J Butanol 3 weeks Vapors D or F K Ethanol, Overnight
Suspension Isopropyl Alcohol and Butanol
[0062] Most of these forms have a jelly appearance. By drying these
samples at 60.degree. C., vacuum overnight, the powdered Form D is
obtained.
Treatment of Hypercholesteremia with Pravastatin Sodium
Polymorphs
[0063] More pravastatin sodium Forms A, B, C, D, E, F, G, H, H1, I,
J, K and L are useful for hypercholesteremia therapy and for this
purpose they are administered to a mammalian patient in a dosage
form. Dosage forms may be adapted for administration to the patient
by oral, buccal, parenteral, ophthalmic, rectal and transdermal
routes. Oral dosage forms include tablets, pills, capsules,
troches, sachets, suspensions, powders, lozenges, elixirs and the
like. The pravastatin sodium forms also may be administered as
suppositories, ophthalmic ointments and suspensions, and parenteral
suspensions, which are administered by other routes. The most
preferred route of administration of the pravastatin sodium forms
of the present invention is oral.
[0064] While the description is not intended to be limiting, the
invention does not pertain to true solutions of any of the novel
pravastatin sodium forms in which the properties of the solid forms
of pravastatin sodium are lost. However, the use of the novel forms
to prepare such solutions (e.g. so as to deliver, in addition to
pravastatin sodium, a solvate to said solution in a certain ratio
with a solvate) is considered to be within the contemplated
invention.
[0065] The dosage forms may contain one or more of the novel forms
of pravastatin sodium or, alternatively, may contain one or more of
the novel forms of pravastatin sodium in a composition. Whether
administered in pure form or in a composition, the pravastatin
sodium form(s) may be in the form of a powder, granules, aggregates
or any other solid form. The compositions of the present invention
include compositions for tableting. Tableting compositions may have
few or many components depending upon the tableting method used,
the release rate desired and other factors. For example,
compositions of the present invention may contain diluents such as
cellulose-derived materials like powdered cellulose,
microcrystalline cellulose, microfine cellulose, methyl cellulose,
ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and
other substituted and unsubstituted celluloses; starch;
pregelatinized starch; inorganic diluents like calcium carbonate
and calcium diphosphate and other diluents known to the
pharmaceutical industry. Yet other suitable diluents include waxes,
sugars and sugar alcohols like mannitol and sorbitol, acrylate
polymers and copolymers, as well as pectin, dextrin and
gelatin.
[0066] Further excipients that are within the contemplation of the
present invention include binders, such as acacia gum,
pregelatinized starch, sodium alginate, glucose and other binders
used in wet and dry granulation and direct compression tableting
processes. Excipients that may also be present in a solid
composition of the novel forms of pravastatin sodium further
include disintegrants like sodium starch glycolate, crospovidone,
low-substituted hydroxypropyl cellulose and others. Additional
excipients include tableting lubricants like magnesium and calcium
stearate and sodium stearyl fumarate; flavorings; sweeteners;
preservatives; pharmaceutically acceptable dyes and glidants such
as silicon dioxide.
[0067] Capsule dosages, of course, will contain the solid
composition within a capsule which may be made of gelatin or other
encapsulating material. Tablets and powders may be coated. Tablets
and powders may be coated with an enteric coating. The
enteric-coated powder forms may have coatings comprising phthalic
acid cellulose acetate, hydroxypropylmethyl cellulose phthalate,
polyvinyl alcohol phthalate, carboxymethylethylcellulose, a
copolymer of styrene and maleic acid, a copolymer of methacrylic
acid and methyl methacrylate, and like materials, and if desired,
they may be employed with suitable plasticizers and/or extending
agents. A coated tablet may have a coating on the surface of the
tablet or may be a tablet comprising a powder or granules with an
enteric-coating.
[0068] In human subjects with normal hepatic function and moderate
body weight, a reduction in serum cholesterol levels is typically
observed with daily dosages of 10 mg or more of pravastatin sodium.
A daily oral regimen is the most commonly prescribed method of
administration. Preferred oral dosages of the present invention
contain from about 10 mg to about 40 mg of pravastatin sodium Forms
A, B, C, D, E, F, G, H, H1, I, J, K, and L or their mixtures.
[0069] Having thus described the present invention with reference
to certain preferred embodiments, the following examples are
provided to further illustrate methods by which novel Forms A, B,
C, D, E, F, G, H, H1, I, J, K, and L of pravastatin sodium may be
obtained. One skilled in the art will recognize variations and
substitutions in the methods as described and exemplified which do
not depart from the spirit and scope of the invention.
EXAMPLES
[0070] "Ethanol" refers to absolute ethanol. Acetonitrile, acetone
and ethyl acetate were regular grade.
Example 1
Preparation of Pravastatin Sodium Form A
[0071] Pravastatin sodium (5 g) was dissolved in a 1:1 mixture of
ethanol:water (5 ml). The pH was raised to 8.5 by addition of 2M
sodium hydroxide in water (1.2 ml) and the solution was heated to
50.degree. C. Acetonitrile (90 ml) was added to the mixture and
then the mixture was stirred at elevated temperature for one hour.
The mixture was allowed to cool to 20-25.degree. C. ("ambient
temperature"), was held at ambient temperature for two hours and
then cooled to 5.degree. C. and maintained at 5.degree. C. for 12
hours, whereupon pravastatin sodium crystallized. The crystals were
then isolated by filtration and washed with acetonitrile
(2.times.10 ml) and dried under vacuum at 50.degree. C. X-ray
diffraction analysis revealed the presence of Form A. Pravastatin
Form A was obtained in 92% yield.
Example 2
Preparation of Pravastatin Statin Form A
[0072] Pravastatin sodium (5 g.) was dissolved in a 2.85:1 mixture
of ethanol:water (10.8 ml). The pH was raised to 8.5 by addition of
2M sodium hydroxide in water (1.2 ml). Acetonitrile (200 ml) was
then slowly added to the mixture at ambient temperature over a two
hour period. The mixture was stirred at ambient temperature for
another two hours and then cooled to 5.degree. C. and maintained at
5.degree. C. for 12 hours, whereupon pravastatin sodium
crystallized. The crystals were then isolated by filtration and
washed with acetonitrile (2.times.10 ml) and dried under vacuum at
50.degree. C. X-ray diffraction analysis revealed the presence of
Form A. Pravastatin sodium Form A was obtained in 96% yield.
Example 3
Preparation of Pravastatin Sodium Form B
[0073] Pravastatin sodium (5 g) was dissolved in ethanol (35.5 ml).
The pH was raised to 8.5 by addition of 2M sodium hydroxide in
water (1.5 ml). The basic solution was heated to 60.degree. C. and
then diluted with acetonitrile (213 ml). The solution was
maintained at elevated temperature for one hour and then was
allowed to cool to ambient temperature and was maintained at
ambient temperature for two hours. The solution was then cooled to
5.degree. C. and maintained at that temperature for 12 hours,
whereupon pravastatin sodium crystallized. The crystals were
isolated by filtration and rinsed, first with ethyl acetate
(2.times.45 ml) and second with n-hexane (2.times.45 ml). The rinse
solvents had been precooled to 5.degree. C. After rinsing, the
crystals were dried under vacuum at 50.degree. C. X-ray diffraction
analysis revealed the presence of Form B. Pravastatin sodium Form B
was obtained in 87% yield.
Example 4
Preparation of Pravastatin Sodium Form C
[0074] Pravastatin sodium (10 g) was dissolved in deionized water
(26 ml) and diluted with a 2:3 mixture of acetonitrile:acetone (130
ml). The resulting solution was then warmed to 40.degree. C. and
maintained at that temperature for one half hour while acetonitrile
(160 ml) was slowly added. The solution was then cooled to
5.degree. C. While cooling, pravastatin sodium began to crystallize
at 19.5.degree. C. The mixture was maintained at 5.degree. C. for
five hours, after which time the crystals were isolated by
filtration, washed with acetone that had been pre-cooled to
5.degree. C., and dried under vacuum at 50.degree. C. X-ray
diffraction analysis revealed the presence of Form C. Pravastatin
sodium Form C was obtained in 76% yield.
Example 5
Preparation of Pravatatin Sodium Form D
[0075] Pravastatin sodium (600 g) was dissolved in 0.73 M sodium
hydroxide in water (600 ml). The resulting solution was diluted
with acetonitrile (1.2 L) and then decolorized by stirring over
charcoal (30 g) for 30 min. The charcoal was removed by filtration
and rinsed with 2:1 acetone:water (1.8 L). The pravastatin sodium
solution and rinsate were combined and diluted with acetonitrile
(17 L). The dilute solution was maintained at ambient temperature
(20-25.degree. C.) for one hour and then cooled to 5.degree. C. and
stirred at that temperature for 4 hours, whereupon pravastatin
sodium crystallized. The crystals were filtered and slurried with
ethyl acetate (6 L) at 5.degree. C. to remove residual
acetonitrile. The crystals were then washed with ethyl acetate that
had been pre-cooled to -5.degree. C. and dried under vacuum at
50.degree. C. X-ray diffraction analysis revealed the presence of
Form D. Pravastatin sodium Form D was obtained in 97% yield.
Example 6
Preparation of Pravastatin Sodium Form D
[0076] Pravastatin sodium (7 g) was dissolved in deionized water
(13 ml) and diluted with acetone (14.3 ml). The resulting solution
was stirred over charcoal (0.07 g.) to decolorize. The charcoal was
removed by filtration and rinsed with a 10:1 mixture of
acetone:water (15.7 ml). The combined pravastatin sodium solution
and rinsate was then diluted with acetone (42.8 ml) and cooled to
-10.degree. C. At the reduced temperature, more acetone (143 ml)
was slowly added over one half hour. The solution was then
maintained at -10.degree. C. for three hours during which time
pravastatin sodium crystallized. The crystals were then isolated by
filtration, washed with 1% water in acetone that had been
pre-cooled to -10.degree. C. (28 ml) and then again with anhydrous
acetone (28 ml). The crystals were then dried under vacuum at
50.degree. C. X-ray diffraction analysis revealed the presence of
Form D. The conversion of amorphous pravastatin sodium to
pravastatin sodium Form D occurred in 85% yield. Before drying the
crystals were Form L, after drying the crystals were Form D.
Example 7
Preparation of Pravastatin Sodium Form D
[0077] Pravastatin sodium (25 g) was dissolved in deionized water
(65 ml) and diluted with 1:1.44 acetonitrile:acetone (330 ml). The
resulting solution was cooled to 5.degree. C. While cooling,
pravastatin sodium started to crystallize at 9.degree. C. After
crystallization appeared to cease, acetone that had been precooled
to 5.degree. C. (650 ml) was added to the mixture and the mixture
was maintained at 5.degree. C. for another three hours. The
crystals were isolated by filtration and washed with 1:3:22
water:acetone:acetonitrile that had been pre-cooled to 5.degree. C.
(25 ml). The crystals were then slurried with ethyl acetate that
had been pre-cooled to 5.degree. C. (50 ml) and dried under vacuum
at 50.degree. C. X-ray diffraction analysis revealed the presence
of Form D. Pravastatin sodium Form D was obtained in 70% yield.
Example 8
Preparation of Pravastatin Sodium Form E
[0078] Pravastatin sodium (5 g) was dissolved in 4:1 ethanol:water
(12.5 ml) and warmed to 60.degree. C. The solution was then diluted
with ethyl acetate (250 ml) and the dilute solution was maintained
at elevated temperature for one hour. The solution was then allowed
to cool to ambient temperature and was maintained at that
temperature for two hours. The solution was then cooled to
5.degree. C. and maintained at reduced temperature for three hours,
whereupon pravastatin sodium crystallized. The crystals were
isolated by filtration, rinsed with ethyl acetate (2.times.30 ml)
and dried under vacuum at 50.degree. C. X-ray diffraction analysis
showed the presence of Form E. Pravastatin sodium Form E was
obtained 87% yield.
Example 9
Preparation of Pravastatin Sodium Form F
[0079] Pravastatin sodium (10 g) was dissolved in water (24.5 ml)
and diluted with acetonitrile (26 ml). The resulting solution was
stirred over charcoal (0.1 g.) to decolorize. Amberlite.RTM. IRC-50
cationic ion exchange resin (H.sup.+ form) was added to the stirred
mixture to raise the pH to 9.09. The charcoal and ion exchange
resin were removed by filtration and rinsed with a 10:1 mixture of
acetonitrile:water (16.5 ml). The combined pravastatin sodium
solution and rinsate was diluted with 2.1:1 acetone:acetonitrile
(115 ml), cooled to 5.degree. C. and maintained at reduced
temperature for two hours, pravastatin sodium crystallized. After
crystallization appeared to cease, acetonitrile (260 ml) that had
been pre-cooled to 5.degree. C. was added and the mixture was
maintained at reduced temperature for another three hours. The
crystals were isolated by filtration and washed With 1:3:22
water:acetone:acetonitrile (40 ml) that had been pre-cooled to
5.degree. C. The crystals were then slurried with precooled ethyl
acetate (100 ml) and dried under vacuum at 50.degree. C. X-ray
diffraction analysis showed the presence of Form F. Pravastatin
sodium Form F was obtained in 74% yield.
Example 10
Preparation of Pravastatin Sodium Form F
[0080] Pravastatin sodium (10 g) was dissolved in deionized water
(24.5 ml) and diluted with acetonitrile (26 ml). The resulting
solution was stirred over charcoal (0.1 g.) to decolorize. Then,
the pH was raised to 9.01 by addition of Amberlite.RTM. IRC-50
cationic exchange resin (H.sup.+ form). The charcoal was removed by
filtration and rinsed with a 10:1 mixture of acetonitrile:water
(16.5 ml). The combined pravastatin sodium solution and rinsate was
then diluted with 2.1:1 acetone:acetonitrile (115 ml) and cooled to
5.degree. C. The solution was maintained at reduced temperature for
three hours, during which time pravastatin sodium crystallized. The
crystals were isolated by filtration and washed with 1:3:22
water:acetone:acetonitrile that had been pre-cooled to 5.degree. C.
(40 ml). The crystals were slurried with ethyl acetate that had
been pre-cooled to 5.degree. C. and then dried under vacuum at
50.degree. C. X-ray diffraction analysis showed the presence of
Form F. Pravastatin sodium Form F was obtained in 90% yield.
Example 11
Preparation of Pravastatin Sodium Form F
[0081] Pravastatin sodium (5 g) was dissolved in deionized water
(13 ml) and diluted with acetone (65 ml). The resulting solution
was cooled to 5.degree. C. While cooling, pravastatin sodium Form F
began to crystallize at 9.degree. C. The mixture was maintained at
5.degree. C. for five hours. Then, acetone that had been pre-cooled
to 5.degree. C. was added to the mixture and the mixture was kept
at 5.degree. C. for another three hours, after which time
crystallization was judged to be complete. The crystals were then
isolated by filtration, washed with acetone that had been
pre-cooled to 5.degree. C. (10 ml) and dried under vacuum at
50.degree. C. Pravastatin sodium Form F was obtained in 87%
yield.
Example 12
Preparation of Mixture of Pravastatin Sodium Forms D and F
[0082] Pravastatin sodium (10 g.) was dissolved in deionized water
(24.5 ml) and diluted with acetonitrile (26 ml). The resulting
solution was stirred over charcoal (0.1 g.) to decolorize. The
charcoal was removed by filtration and rinsed with a 10:1 mixture
of acetonitrile:water (16.5 ml). The combined pravastatin sodium
solution and rinsate was diluted with acetonitrile (11 ml) and
warmed to 40.degree. C. At the elevated temperature, acetone (60
ml) was slowly added over one half hour. The solution was then
cooled to a temperature of 10.degree. C. over three hours. After
the solution had attained a temperature of 12.degree. C., the
mixture was seeded with a crystal of pravastatin sodium Form D. At
11.3.degree. C., the solution was diluted with acetone (200 ml).
After the three hours had passed, the mixture of solution and
crystals was cooled to 5.degree. C. and maintained at that
temperature for three hours. The crystals were then removed by
filtration, washed with acetone that had been pre-cooled to
5.degree. C. (40 ml) and dried under vacuum at 50.degree. C. The
crystals were found by X-ray diffraction to be a mixture of
pravastatin sodium Form D and Form F. The mixture of pravastatin
sodium Forms D and F was obtained in 77% yield.
Example 13
Preparation of Mixture of Pravastatin Sodium Forms C and D
[0083] Pravastatin sodium (10 g) was dissolved in deionized water
(18 ml) and diluted with acetone (20 ml). The resulting solution
was stirred over charcoal (0.1 g) to decolorize. The charcoal was
removed by filtration and rinsed with a 10:1 mixture of
acetonitrile:water (20 ml). The combined pravastatin sodium
solution and rinsate was then diluted with acetone (60 ml) and
warmed to 40.degree. C. The solution was maintained at elevated
temperature for half an hour while acetone (190 ml) was slowly
added. The solution was cooled to 10.degree. C. While being cooled,
the solution was seeded with a crystal of pravastatin sodium Form D
at 13.degree. C. The solution was then maintained at 10.degree. C.
for three hours. Then acetone (190 ml) was added and the solution
was cooled to 5.degree. C. Another 190 ml of acetone was added and
the mixture was stirred at 5.degree. C. for three hours, during
which time crystallization was complete. The crystals were isolated
by filtration, washed with acetone that had been pre-cooled to
5.degree. C., and dried under vacuum at 50.degree. C. The crystals
were identified by X-ray diffraction as a mixture of pravastatin
sodium Forms C and D. The mixture of pravastatin sodium Forms C and
D was obtained in 89% yield.
Example 14
Preparation of Pravastatin Sodium Form F
[0084] Pravastatin sodium (10 g) was dissolved in deionized water
(20 ml). The pH of the aqueous solution was adjusted to 7.1 by
addition of Amberlite.RTM. IRC-50 cationic ion exchange resin
(H.sup.+ form). The solution was then diluted with acetone (120 ml)
and then heated to 40.degree. C. Another 130 ml of acetone was
slowly added to the mixture over a period of 30 min. The solution
was then cooled to 5.degree. C. over 3 hours. When the mixture
reached a temperature of 25.degree. C., it was seeded with crystals
of Form F. The mixture was maintained at 5.degree. C. for 20 h,
over which time pravastatin sodium crystallized from the mixture.
The crystals were isolated by filtration and washed with acetone
(40 ml). The crystals were then dried under vacuum at 60.degree. C.
X-ray diffraction analysis showed the presence of Form F.
Pravastatin sodium Form F was obtained in 84% yield.
Example 15
Preparation of Pravastatin Sodium Form G
[0085] Pravastatin Form G is obtained when pravastatin Form F is
stored for two weeks at relative humidity of between 40-80%. The
resulting solid was analyzed by X-ray diffraction without further
treatment.
Example 16
Preparation of Pravastatin Sodium Form H
[0086] Pravastatin sodium Form H was prepared by treating Form D or
F with ethanol vapors for three weeks at room temperature. The
procedure was as follows. A 100-200 g sample of pravastatin sodium
Form D or F was kept in a 10 ml open glass bottle. The open bottle
was introduced into a larger bottle containing ethanol. The larger
bottle was sealed in order to create a saturated atmosphere. The
resulting solid was analyzed by X-Ray diffraction without further
treatment. Form H could also be converted to Form D by drying under
vacuum overnight.
Example 17
Preparation of Pravastatin Sodium Form H1
[0087] Pravastatin sodium Form H1 was prepared by suspending about
0.5 to 1.4 g of Form D in about 0.6 ml methanol overnight at room
temperature, in a sealed 1.10 ml bottle with a sealed cap and a
magnetic stirrer The resulting solid was analyzed by X-ray
diffraction analysis without further treatment.
Example 18
Preparation of Pravastatin Sodium Form I
[0088] Pravastatin sodium Form I was prepared by treating Form D or
F with isopropyl vapors for three weeks at room temperature. The
procedure was as follows. A 100-200 g sample of pravastatin sodium
Form D or F was kept in a 10 ml open glass bottle. The open bottle
was introduced into a larger bottle containing few ml of isopropyl
alcohol. The larger bottle was sealed in order to create a
saturated atmosphere. The resulting solid was analyzed by X-Ray
diffraction analysis without further treatment. Form I could also
be transformed to Form D by drying under vacuum overnight.
Example 19
Preparation of Pravastatin Sodium Form J
[0089] Pravastatin sodium Form J was prepared by treating Form D or
F with butanol vapors for three weeks at room temperature. The
procedure was as follows. A 1 00-200 g sample of pravastatin sodium
Form D or F was kept in a 10 ml open glass bottle. The open bottle
was introduced into a larger bottle containing few ml of butanol.
The larger bottle was sealed in order to create a saturated
atmosphere. The resulting solid was analyzed by X-Ray diffraction
analysis without further treatment. Form J could also be
transformed to Form D by drying under vacuum overnight.
Example 20
Preparation of Pravastatin Sodium Form K
[0090] Pravastatin sodium Form K was obtained by suspending 0.8 g
pravastatin in about 2 ml ethanol and stirring overnight at RT. The
resulting solid was analyzed by X-Ray diffraction analysis without
further treatment.
Example 21
Preparation of Pravastatin Sodium Form D
[0091] Pravastatin sodium(about 100 mg) of any polymorph beside
Forms B or D was kept in an oven at 120.degree. C. for 2 hours. The
powder was then analyzed by X-ray diffraction and found to be Form
D.
Example 22
Preparation of Pravastatin Sodium Form C
[0092] Pravastatin sodium was exposed at 100% relative humidity for
one week. The power was then analyzed by X-ray diffraction without
further treatment and was found to be Form C.
Example 23
Preparation of Pravastatin Sodium Form L and Form D
[0093] A solution was prepared, containing 80 kg pravastatin sodium
and 144 kg water. The pH of the solution was set to 7.2, by IRC-50
weakly acidic cation exchange resin. Acetone (320 L) was added to
the solution and it was treated with 0.8 kg charcol to decolorize.
The charcoal was filtered with a solution of acetone:water, 10:1
(176 L). The solution was warmed to 40.degree. C. Acetone (176 L)
was added to the solution. The mixture is cooled at a rate of
2.degree. C./h.sup.-1 rate. The solution is seeded at 32.degree. C.
by 0.1% (0.08 kg) pravastatin sodium (Form D). The mixture was
cooled to 2.degree. C. and stirred for 2-4 hour.
[0094] Pravastatin crystals were filtered and washed with 160 L
acetone containing 2% water and cooled to between 2-5.degree. C.
Then the wet cake was washed once more with 160 L of pure acetone.
The product was dried under vacuum by gradual heating to 60.degree.
C. The crystals were identified by X-ray diffraction as Form L. The
water content was 16.8% and the acetone content was 0%. After
prolonged drying the water content was reduced to 10.7%. A mixture
of Form L and D was identified. Further drying reduced the water
content to 2.5% water content and the pravastatin sodium was
transformed to pure Form D.
* * * * *